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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Org Chem. Author manuscript; available in PMC 2013 September 7.
Published in final edited form as:
PMCID: PMC3454511
NIHMSID: NIHMS400180

Synthesis and Profiling of a Diverse Collection of Azetidine-Based Scaffolds for the Development of CNS-Focused Lead-Like Libraries

Abstract

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The synthesis and diversification of a densely functionalized azetidine ring system to gain access to a wide variety of fused, bridged and spirocyclic ring systems is described. The in vitro physicochemical and pharmacokinetic properties of representative library members are measured in order to evaluate the use of these scaffolds for the generation of lead-like molecules to be used in targeting the central nervous system. The solid-phase synthesis of 1976-membered library of a spirocyclic azetidines is also described.

INTRODUCTION

Diversity-oriented synthesis (DOS) has received considerable attention from both academic and industrial sectors over the past decade as a means to access new chemical space for probe and drug discovery.1,2,3 Numerous DOS pathways have been reported which gain access to unique molecular frameworks,4 however a common perception associated with these compounds has been that they possess poor physicochemical properties.5 While some DOS pathways have yielded compounds of high molecular weight and lipophilicity, the properties of DOS molecules are not inherently unfavorable to a drug discovery program. Simple descriptors such as MW, topological polar surface area (TPSA), LogP, LogD, rotatable bonds and hydrogen bond donors/acceptors (HBD/HBA) can be readily calculated at the design stage and filters may be applied to tailor the properties of prospective library members.6 These parameters are especially important in the context of designing DOS libraries for CNS-applications where the properties that facilitate blood-brain barrier (BBB) penetration are particularly stringent.7 In this case, the collection and analysis of in vitro data such as solubility, protein binding and permeability would be especially valuable in prioritizing synthetic pathways for full library production. Herein we describe the synthesis, physicochemical and pharmacokinetic (ADME) characterization and profiling of several DOS scaffolds that have been optimized with these key CNS “drug-like” parameters in mind.8

Azetidine-based ring systems have had enormous application in medicinal chemistry in the form of β-lactams.9 The use of the fully reduced form of this four-membered heterocycle in the context of drug discovery has been less common however. This can be attributed in part to the apparent difficulty in accessing azetidines in their enantioenriched form.10 Recently, Couty and coworkers demonstrated the convenient preparation of 2-cyano azetidines from β-amino alcohols (Figure 1A).11 We envisioned that expansion of this methodology would permit access to a number of highly functionalized azetidine-based scaffolds through the manipulation of the parent core system. In addition, having the ability to access all stereochemical permutations of each scaffold would provide the ability to study stereo/structure-activity relationships (SSAR)12 in biological contexts.

Figure 1
(A) Synthesis of 2-cyano azetidines from β-amino alcohols and (B) representative CNS-active agents containing phenylethylamine motif.

In designing a template for library development, we chose to expand upon the previously described ephedrine-based scaffold.11 This scaffold was especially compelling based on the observation that embedded within the backbone resides the phenethylamine structural motif. (Figure 1B). This pharmacophoric element is common to a number of hormones, neurotransmitters, natural products and drugs known to affect the central nervous system (CNS) and provides an excellent core scaffold which can be further derivatized. The incorporation of an aryl bromide and a pendant hydroxyl group will allow for downstream functional group pairing,13 diversification and immobilization onto solid support.14

RESULTS AND DISCUSSION

Synthesis of Azetidine-based Scaffolds

The azetidine core systems required in the formation of the various library scaffolds were accessed from N-allyl amino diols 1a15 and 1b16 on multi-gram scale (20 g of 5ad) over 4 steps through adaptation of previously described conditions (Scheme 1).11 The sequence included N-alkylation of a secondary amine with bromoacetonitrile (92–95%), protection of the primary alcohol as its trityl ether (95–99%) and formation of the benzylic chloride to arrive at compounds 4a and 4b (65–71%).17 Treatment of chloride 4a with lithium hexamethyldisilylazide (LiHMDS) at −50 °C provided a ca. 1.2:1 epimeric mixture of 2-cyano azetidines 5a and 5b. The resulting products could be easily separated via flash chromatography on multi-gram scale to give 53% for 5a and 40% for 5b. The anti-configured linear template 4b could selectively provide either 5c or 5d depending on the conditions employed. Treatment of 4b with LiHMDS at −50 °C provided ca. 15:1 (5c:5d) ratio of product as a separable mixture. Alternatively, exposure of 4b to KHMDS at −78 °C gave nearly exclusively 5d in ca. 1:20 (5c:5d). This approach gave rise to multi-gram quantities of all 8 stereoisomers of 5.

Scheme 1
Synthesis of azetidine-based templates 5ad

Having developed a robust process for the synthesis of trisubstituted azetidines 5ad we turned our attention to investigating key functional group pairing reactions for generating skeletal diversity. The sequence began with DIBAL reduction of the nitrile to the primary amine, which was immediately treated with o-nitrobenzenesulfonyl chloride to obtain 6ad in 71–91% yield over 2 steps (Scheme 2). This material could then be utilized to access three structurally unique molecular scaffolds. The first of these scaffolds (8a and 8d) were inspired by recent work of Pinna and co-workers describing the synthesis and biological activity of several diazabicyclo [3.1.1] heptane ligands.18 TFA-mediated trityl deprotection and subsequent mesylation of the pendant alcohol gave an intermediate compound 7, which was heated in the presence of potassium carbonate to afford the meso-[3.1.1] bridged bicyclic system in 91% yield for 8a (from 7a) and 86% yield for 8d (from 7d) over 3 steps.19 Monoketopiperazine 10 could be readily accessed by removal of the allyl protecting group of 6ad followed by reaction of the resulting secondary amine functionalities with bromoacetyl chloride to afford 9ad. Removal of the trityl group provided 10ad in excellent yields.

Scheme 2
Synthesis of Azetidine Scaffolds 8, 10 and 12

A third scaffold containing an azetidine-fused 8-membered ring could be readily derived from azetidine 6 through the use of ring-closing metathesis. The requisite material for this approach was obtained through the N-alkylation of 6ad with allyl bromide. This material was then treated with Grubbs 1st generation catalyst to effect the formation of the eight membered ring system 11ad in 65 to 76% yield. Removal of the trityl protecting group and selective reduction of the olefin with o-nitrobenzenesulfonylhydrazide (NBSH)20 yielded the final cores 12ad in 65–72% over 2 steps.21

Several papers highlighting the synthesis and physicochemical property analysis of spirocyclic oxetanes and spirocyclic azetidines for their potential use in drug discovery have recently been published by Carreira22 and others.23 In an attempt to access compounds with similar property profiles, we turned our attention towards the formation of a novel spirocyclic azetidine scaffold derived from azetidine 5 (Scheme 3). The synthesis began with the metalation of aminonitrile 5a (or 5b) with lithium tetramethylpiperidide (LiTMP) at −78 °C in THF. The resulting anion could then be trapped with formaldehyde source benzotriazolylmethanol24 to form a single compound. Treatment of this intermediate with tosyl chloride provided 13a, which was then was reacted with a solution of DIBAL and immediately capped with o-nitrobenzenesulfonyl chloride. This material was treated with potassium carbonate to provide the spirocyclic intermediate 14 in 67% yield.25 Removal of the trityl group with trifluoroacetic acid completed the synthesis of 15a. 26

Scheme 3
Synthesis of Spirocyclic Azetidine Scaffold 15

Access to the trans-configured spirocyclic system (15c) was envisioned to be obtained through the same sequence of reactions that were used in the synthesis of 15a (Scheme 3). Thus, alkylation of 5c (or 5d) furnished approximately a 1:1 mixture of α- and β-alcohols. Tosylation of the mixture provided 13c in reasonable isolated yield. Treatment of 13c with DIBAL appeared to immediately provide a cyclized product based on the observed loss of the pendant tosylate. Capping the resulting amine with o-nitrobenzenesulfonyl chloride and unmasking the primary alcohol with trifluoroacetic acid afforded a white solid, which upon recrystallization yielded X-ray quality crystals. Surprisingly, upon examination of the structural data a [3.3.0]-spirocycle was not observed but rather a [4.2.0]-system (16).25 Ring expansions of azetidine systems have been previously described to give substituted pyrroles through an intermediate 1-azoniabicyclo [2.1.0] pentane system27 however, to the best of our knowledge this is the first example of a ring expansion followed by a spirocyclization to form a [4.2.0]-ring system.

In an attempt to circumvent this rearrangement and provide the complimentary trans-spirocyclic system 15c, the nucleophilicity of the azetidine nitrogen was attenuated with a Boc protecting group. Access to this compound was achieved through the deprotection of the allyl group followed by treatment with Boc2O. Further manipulation included alkylation and tosylation of 17 to provide compound 18, which then underwent nitrile reduction with DIBAL and nosylation to form the precyclized product. Treatment of this substrate with potassium carbonate in acetonitrile afforded the trans-azetidine ring system 19 in 51% yield over 3 steps. Subsequent removal of the Boc and trityl groups followed by N-alkylation with allyl bromide provided 15c in 45% yield.

Conversion of o-bromo amino diols 20ab to the corresponding o-bromo nitrile azetidines 21ad allowed for facile access to a number of fused ring scaffolds (Scheme 4). The first compound in this series takes advantage of an intramolecular Buchwald/Hartwig cross coupling reaction to access a tetrahydroquinoline core system.28 DIBAL reduction of the nitrile group followed by nosylation of the resulting amine yielded 22a and 22c in 68 and 79% yield over 2 steps. Treatment of each of these intermediates with copper (I) iodide, cesium carbonate and dimethylethane 1,2-diamine in toluene gave rise to the tricyclic system 23 in quantitative yield. Removal of the trityl protecting group provided the desired scaffolds 24a and 24c. Alternatively, removal of the trityl group in compounds 21ab allows for the pairing of the hydroxyl functionality through an O-arylation on the opposite side of the azetidine ring system.29 Treating the resulting deprotected product with palladium acetate and cesium carbonate in the presence of a phosphine ligand gave the desired dihydrobenzopyran in 66% and 74% yield. Finally, reduction of the nitrile using DIBAL and nosyl protection afforded scaffolds 25a and 25b.

Scheme 4
Synthesis of Scaffolds 24 and 25

In silico analysis and in vitro compound profiling

As our overall goal was to use the azetidine-based scaffolds to produce a diverse collection of compounds “pre-optimized” for CNS physicochemical and ADME requirements, we set out to validate our computational approach by collecting in vitro data on a representative set of library compounds. Early estimates of ADME properties can be useful to help guide the decision making process in how to populate a library collection with compounds having the highest likelihood of success in drug development. This property evaluation is critical when targeting the CNS due to penetration of the BBB (blood brain barrier) which has been noted to have a narrow window of physicochemical boundaries for CNS-accessible chemical space.30 A set of analogs representing various chemotypes (e.g., sulfonamide, amide, amine) were prepared to represent potential library members obtained from a full production (2632, Figure 2). Full library production would focus only on those scaffolds which satisfied our CNS “lead”-like criteria and possessed no obvious metabolic or chemical instability.

Figure 2
Representative library members synthesized for in vitro analysis.

In silico analysis of compounds 2632 for MW, TPSA, HBD, cLogP, cLogD and pka confirms that most compounds are well within the range of preferred properties for CNS compounds (Table 1) and compare well to marketed CNS drugs.31 In addition, computed models of brain partitioning (log brain/blood, BBB category) and potential P-glycoprotein (P-gp) substrate status were utilized to assess the probability of reasonable brain exposures. The CNS multiparameter optimization (MPO) algorithm developed by Pfizer was also applied and all but one compound (21d) displayed a high desirability score (≥4, using a scale of 0–6).32 Of note, while maintaining properties in the desired CNS range and containing a common core structural motif, the azetidine-based compounds exhibit a high degree of structural diversity compared to existing CNS-drugs as measured by Tanimoto co-efficient (Tc) with a mean similarity less than 0.15 and a maximum similarity less than 0.26 (Figure 3.) 33

Figure 3
Multi-fusion similarity (MFS) map, ECFP_4 fingerprints (Test set = azetidine scaffolds and derivatives (n = 64), Reference set = CNS drugs (n = 70).
Table 1
Calculated physicochemical propertiesa

As shown in Table 2, several properties were measured in vitro for compounds 2632, including solubility, protein binding, stability and permeability. Most compounds tested were found to be highly soluble (>400 µM) in water and phosphate buffered saline and displayed low to moderate protein binding in both mouse and human sera. This high proportion of free or unbound fraction of compound is an important attribute when considering diffusion into the CNS compartment.34 Notably, almost all molecules exhibited excellent stability toward human and mouse plasma, liver microsomes and hepatocytes, indicative of good pharmacokinetic properties (e.g. T1/2).

Table 2
In vitro compound profiling dataa

The permeability of compounds 2632 was evaluated using two distinct model systems: the BBB parallel artificial membrane permeability assay (BBB-PAMPA) 35 and Caco-2 cell lines. The BBB-PAMPA assay is used as a high-throughput method to predict passive BBB penetration of potential CNS drugs. Using this assay most compounds displayed high permeability values (Pe ≥ 10.0 × 10−6 cm s−1) suggestive of effective diffusion across the endothelial cells in CNS blood vessels. Next, the permeability of each compound was evaluated using the cell based Caco-2 system as a surrogate for permeability across the gut endothelial. Bidirectional analysis was conducted to evaluate the propensity of these compounds to act as substrates for efflux mechanisms expressed in Caco-2 (e.g. P-gp efflux transporter) as well as a measure of passive diffusion. Consistent with our results in the BBB PAMPA assay, all compounds displayed high rates of permeation across the Caco-2 monolayer and displayed no directional bias indicative of active efflux.36, 37 The data suggests that most of these compounds should be highly permeable at the endothelial systems present in the gut (oral absorption) and at the blood brain barrier.

Representative solid-phase library synthesis

The azetidine-based scaffolds described above have served as starting points for the production of over 30,000 CNS-focused compounds to date in our lab. Much like compounds 2632 the resulting library members retain the desired physicochemical properties for CNS-focused compounds (vide infra). As an example, we highlight below the synthesis of a 1976-membered library of spirocyclic azetidine compounds.

Starting from spirocyclic scaffold des Br-15 (Scheme 3) a virtual library was constructed using a master list of reagents, which included sulfonyl chlorides, isocyanates, acids, and aldehydes.38 All possible building block combinations at R1 (nosyl amine) and R2 (allyl amine) were employed to yield a total of 9152 compounds per scaffold. The following CNS-focused property filters were then applied to yield a total of 3089 compounds: MW ≤450, ALogP −1 to 5, H-bond acceptors <7, H-bond donors ≤3, rotatable bonds ≤8 and TPSA ≤90. Using chemical similarity principles, maximizing diversity but retaining near neighbors for built-in SAR,6 this set was further narrowed down to 494 compounds per stereoisomer (or 1976 compounds total). The same set of reagents was used for all 4 stereoisomers, thereby maintaining the ability to generate SSAR for each building block combination.

As shown in Scheme 5, all 4 stereoisomers of the spirocyclic sscaffold were loaded onto SynPhase L-series Lanterns via activation of the silicon-fuctionalized Lanterns14 with TfOH. Lanterns were equipped with radio frequency transponders to enable tracking and sorting of library members. Following removal of the nosyl group, the first diversity site (R1), an amine, was reacted with a total of 55 building blocks including isocyanates, sulfonyl chlorides, acids and aldehydes.39 The second diversity site (R2) was then revealed via removal of the allyl group upon treatment with Pd(PPh3)4 in the presence of excess 1,3–dimethyl barbituric acid. The second azetidine nitrogren was capped with 41 building blocks including isocyanates, sulfonyl chlorides, acids and aldehydes. This was followed by cleavage from the Lantern with HF/pyridine in THF, to afford a total of 1976 products (33) with an average yield of 16 µmol (~8 mg).

Scheme 5
Solid-phase library synthesis on SynPhase Lanterns

All library products were analyzed by ultra-performance liquid chromatography, and compound purity was assessed by UV detection at 210 nm. The average purity of the library was 70%.40 In general, most of the building block classes performed well with the exception of aldehydes in the first capping (R1). Interestingly, the compounds were of high purity after the initial reductive alkylation, however, after carrying the tertiary amines through allyl deprotection and subsequent capping low purities were observed.

In silico analysis of the spirocyclic azetidine library confirms that the physicochemical properties of the library members fall within the preferred range for CNS compounds (Table 3).31 Moreover, application of the CNS MPO algorithm34 showed that the majority of compounds displayed a desirability score ≥4 (Figure 4). In addition, much like other DOS compounds,41 the structural complexity of the spirocyclic azetidine library is closer to that of natural products than typical commercial compounds as measured by the fraction of sp3 centers (Fsp3).42,4c

Figure 4
CNS MPO score for the Spirocyclic Azetidine library members (n = 1976). were plotted from low to high CNS MPO score along the x-axis.
Table 3
Calculated physicochemical properties

CONCLUSIONS

In summary, we have reported the synthesis of a collection of skeletally and stereochemically diverse azetidine-based scaffolds, including a focused set of 20 representative compounds and a 1976-membered library of spirocyclic azetidines. Analysis of the library members in silico indicated the compounds demonstrate ideal physicochemical properties for CNS application and further analysis of a subset of compounds in vitro showed a very good ADME profile.

The importance of populating chemical libraries with pre-optimized structures cannot be overstated in the successful and efficient growth of new chemical entities in drug and probe development.43 By utilizing a data driven approach for scaffold selection and focusing library production into this optimized chemical space we hope to increase efficiency in downstream multi-parametric optimization activities. These considerations are particularly acute when targeting the CNS due to the stringent physicochemical requirements for successful blood-brain barrier (BBB) penetration of small molecules. These results highlight the fact that through diligent examination of the scaffold properties one can apply a DOS approach to create a collection of structurally diverse compounds with good physicochemical properties for use in screening and follow up biological evaluation.

EXPERIMENTAL SECTION

General methods

All oxygen and/or moisture sensitive reactions were carried out under N2 atmosphere in glassware that had been flame-dried under vacuum (~0.5 mmHg) and purged with N2 prior to use. All reagents and solvents were purchased from commercial vendors and used as received, or synthesized according to the footnoted references. 1H and 13C NMR spectra were recorded on 300 MHz and/or 500 MHz spectrometers. All chemical shifts are reported in ppm (δ) referenced to residual non-deuterated solvent.44 Data are reported as follows: chemical shifts, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet; coupling constant(s) in Hz; integration). Unless otherwise indicated NMR data were collected at 25 °C. IR spectra were obtained with an FTIR spectrometer and are reported in cm−1. Melting point experiments were performed on a Büchi M-560 melting point apparatus. Flash chromatography was performed using 40–60 µm silica gel (60 Å mesh) with the indicated solvent.

2-(Allyl((1R,2R)-1-(4-bromophenyl)-1,3-dihydroxypropan-2-yl)amino)acetonitrile 2a

To a solution of amino diol 1a15 (52.9 g, 185 mmol) in acetonitrile (1849 mL) was added potassium carbonate (38.3 g, 277 mmol) and 2-bromoacetonitrile (38.7 ml, 555 mmol). The resulting heterogeneous solution was heated to 85 °C and stirred for 3 h. Once the reaction was complete the mixture was concentrated under reduced pressure and the residue was taken up in water and diethyl ether. The aqueous layer was extracted two additional times with diethyl ether. The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to provide the crude product, which was purified by chromatography over silica gel to provide pure product 2a (59.5 g, 99% ) as an oil. equation M1 (c 1.45, CHCl3); IR νmax (film): 3419, 3080, 2912, 1642, 1592, 1486, 1419, 1070, 1010; 1H NMR (500 MHz, CDCl3) δ 7.48 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 5.80 (tt, J = 10.4, 6.7 Hz, 1H), 5.36 (d, J = 17.1 Hz, 1H), 5.30 (d, J = 10.1 Hz, 1H), 4.66 (d, J = 9.2 Hz, 1H), 3.91 (d, J = 17.3 Hz, 1H), 3.74 (d, J = 17.4 Hz, 1H), 3.72–3.66 (m, 1H), 3.61 (dd, J = 13.7, 5.8 Hz, 1H), 3.52 (dd, J = 11.6, 6.5 Hz, 1H), 3.44 (dd, J = 13.6, 6.9 Hz, 1H), 2.91–2.83 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 139.9, 133.8, 131.6, 128.6, 122.0, 120.1, 116.9, 70.5, 69.0, 58.2, 54.7, 39.1; HRMS (ESI) calcd for C14H18BrN2O2 [M + H]+: 325.0552, found: 325.0551.

2-(Allyl((1S,2S)-1-(4-bromophenyl)-1,3-dihydroxypropan-2-yl) amino) acetonitrile ent-2a

Following the protocol above, 62 g of amino diol ent-1a16 afforded 67 g (95%) of tertiary amine ent-2a. equation M2 (c 0.99, CHCl3).

2-(Allyl((1R,2R)-1-(4-bromophenyl)-1-hydroxy-3-(trityloxy) propan-2-yl) amino) acetonitrile 3a

To a solution of tertiary amine 2a (59.5 g, 183 mmol) in CH2Cl2 (1830 mL) was added triethylamine (77 mL, 549 mmol) and the entire solution was cooled to 0 °C. Trityl chloride (77 g, 274 mmol) was then added and the solution was allowed to slowly warm to room temperature and stirred overnight. The reaction mixture was quenched with aqueous saturated NH4Cl solution and the aqueous layer was extracted two times with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to provide the crude product, which was purified by chromatography over silica gel to provide pure product 3a (103 g, 99%) as a pale yellow oil. equation M3 (c 1.94, CHCl3); IR νmax (film): 3060, 3022, 2878, 1594, 1489, 1448, 1071, 1033; 1H NMR (500 MHz, CDCl3) δ 7.38 (d, J = 8.3 Hz, 2H), 7.22 (s, 15H), 7.08 (d, J = 8.4 Hz, 2H), 5.80–5.61 (m, 1H), 5.22 (d, J = 7.6 Hz, 1H), 5.20 (d, J = 14.2 Hz, 1H), 4.35 (d, J = 9.3 Hz, 1H), 3.85 (s, 1H), 3.65 (q, J = 17.0 Hz, 2H), 3.43 (dd, J = 13.9, 5.4 Hz 1H), 3.24 (dd, J = 10.9, 7.2 Hz, 1H), 3.16 (dd, J = 10.9, 3.5 Hz, 1H), 3.09–2.96 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 143.1, 139.9, 134.0, 131.5, 128.9, 128.4, 127.9, 127.2, 121.9, 119.8, 116.9, 87.8, 70.7, 67.8, 59.6, 54.0, 39.7; HRMS (ESI) calcd for C33H32BrN2O2 [M + H]+: 567.1647, found: 567.1646.

2-(Allyl((1S,2S)-1-(4-bromophenyl)-1-hydroxy-3-(trityloxy)propan-2-yl)amino) acetonitrile ent-3a

Following the protocol above, 67 g of ent-2a afforded 116 g (99%) of trityl protected product ent-3a. equation M4 (c 1.62, CHCl3).

2-(Allyl((1R,2R)-1-(4-bromophenyl)-1-chloro-3-(trityloxy)propan-2-yl)amino) acetonitrile 4a

To a solution of pyridine (43.2 ml, 536 mmol) in CH2Cl2 (950 mL) was added thionyl chloride (15.64 ml, 214 mmol) at room temperature. The above solution was then cooled to 0 °C and a solution of benzyl alcohol 3a (60.8 g, 107 mmol) in CH2Cl2 (100 mL) was added dropwise over 10 min and stirred for an additional 15 min at 0 °C (Note: If the solution is warmed or stirred for longer than 15 min the product decomposes). The mixture was neutralized by the addition of a saturated aqueous solution of sodium bicarbonate and the aqueous layer extracted two additional times with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to provide the crude product, which was purified by chromatography over silica gel to provide pure product 4a (44.6 g, 71%) as a white foam. equation M5 (c 1.22, CHCl3); IR νmax (film): 3057, 3022, 2933, 2885, 1593, 1489, 1448, 1072; 1H NMR (500 MHz, CDCl3) δ 7.44 (d, J = 10.2 Hz, 2H), 7.39–7.23 (m, 15H), 7.19 (d, J = 8.4 Hz, 2H), 5.72–5.56 (m, 1H), 5.26–5.10 (m, 3H), 3.68 (d, J = 17.4 Hz, 1H), 3.59 (d, J = 17.4 Hz, 1H), 3.50–3.35 (m, 2H), 3.32–3.13 (m, 3H). 13C NMR (125 MHz, CDCl3) δ 143.2, 138.2, 134.6, 131.6, 129.3, 128.5, 127.9, 127.2, 122.3, 118.9, 117.2, 87.5, 66.6, 62.8, 61.5, 55.1, 40.1; HRMS (ESI) calcd for C33H31BrClN2O [M + H]+: 585.1308, found: 585.1342. Elemental analysis (C33H30BrClN2O): calcd/found %C: 67.64%/67.76%, %H: 5.16%/5.44%, %N 4.78%/4.53%, %Cl 6.05%/6.43%, %Br 13.64%/12.13%.

2-(Allyl((1S,2S)-1-(4-bromophenyl)-1-chloro-3-(trityloxy)propan-2-yl)amino) acetonitrile ent-4

Following the protocol above, 116 g of benzyl alcohol ent-3a afforded 69 g (58%) of chloride ent-4a. equation M6 (c 0.96, CHCl3).

2-(Allyl((1S,2R)-1-(4-bromophenyl)-1,3-dihydroxypropan-2-yl)amino) acetonitrile 2b

Following the protocol above, 50 g of amino diol 1b16 afforded 54.7 g (96%) of tertiary amine 2b. equation M7 (c 1.72, CHCl3); IR νmax (film): 3393, 2889, 1485, 1419, 1068, 1023, 1008; 1H NMR (500 MHz, CDCl3) δ 7.47 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.3 Hz, 2H), 5.70 (ddt, J = 16.7, 10.0, 6.5 Hz, 1H), 5.33 (dd, J = 17.1, 1.4 Hz, 1H), 5.24 (d, J = 10.1 Hz, 1H), 5.11 (s, 1H), 3.86 – 3.72 (m, 3H), 3.68 (d, J = 11.2 Hz, 1H), 3.49 (dd, J = 13.9, 6.4 Hz, 1H), 3.40 (dd, J = 13.9, 6.6 Hz, 1H), 3.01 (br. s, 1H), 2.84 (dt, J = 5.8, 3.9 Hz, 1H), 2.38 (br. s, 1H); 13C NMR (125 MHz, CDCl3) δ 141.1, 133.8, 131.4, 127.3, 121.3, 119.5, 116.8, 71.9, 67.0, 57.9, 54.7, 38.8; HRMS (ESI) calcd for C14H18BrN2O2 [M + H]+: 325.0552, found: 325.0551.

2-(Allyl((1R,2S)-1-(4-bromophenyl)-1,3-dihydroxypropan-2-yl)amino)acetonitrile ent 2b

Following the protocol above, 50 g of amino diol ent-1b16 afforded 55.7 g (98%) of tertiary amine ent-2b. equation M8 (c 1.81, CHCl3).

2-(Allyl((1S,2R)-1-(4-bromophenyl)-1-hydroxy-3-(trityloxy)propan-2-yl)amino) acetonitrile 3b

Following the protocol above, 54 g of diol 2b afforded 91 g (97%) of trityl protected product 3b. equation M9 (c 1.9, CHCl3); IR νmax (film): 3471, 3057, 1733, 1487, 1447, 1264; 1H NMR (500 MHz, CDCl3) δ 7.40–7.31 (m, 7H), 7.30–7.23 (m, 11H), 7.07 (d, J = 8.3 Hz, 2H), 5.71–5.54 (m, 1H), 5.23 (d, J = 17.6 Hz, 1H), 5.19 (d, J = 10.2 Hz, 1H), 4.96 (d, J = 4.0 Hz, 1H), 3.49 (q, J = 17.5 Hz, 2H), 3.36 (dd, J = 10.5, 4.8 Hz, 1H), 3.30 (dd, J = 10.5, 5.4 Hz, 1H), 3.25–3.17 (m, 2H), 3.10 (q, J = 4.8 Hz, 1H), 3.03 (br. s, 1H); 13C NMR (125 MHz, CDCl3) δ 148.4, 143.1, 140.7, 134.2, 131.2, 128.5, 128.1, 127.9, 127.9, 127.6, 127.2, 126.6, 121.2, 119.3, 116.7, 87.6, 72.3, 65.9, 60.2, 54.8, 39.6; HRMS (ESI) calcd for C33H31BrN2NaO2 [M + Na]+: 589.1467, found: 589.1453.

2-(Allyl((1R,2S)-1-(4-bromophenyl)-1-hydroxy-3-(trityloxy)propan-2-yl)amino) acetonitrile ent-3b

Following the protocol above, 55.7 g of diol ent-2b afforded 95 g (98%) of trityl protected product ent-3b. equation M10 (c 1.5, CHCl3).

2-(Allyl((1S,2R)-1-(4-bromophenyl)-1-chloro-3-(trityloxy)propan-2-yl)amino) acetonitrile 4b

Following the protocol above, 91 g of benzyl alcohol 3b afforded 62 g (66%) of chloride 4b. equation M11 (c 3.06, CHCl3); IR νmax (film): 3057, 2936, 2885, 1592, 1488, 1448, 1447; 1H NMR (500 MHz, CDCl3) δ 7.42 (d, J = 7.3 Hz, 5H), 7.39 (d, J = 8.4 Hz, 2H), 7.31 (t, J = 7.5 Hz, 5H), 7.26 (d, J = 7.2 Hz, 3H), 7.12 (d, J = 8.4 Hz, 2H), 5.52 – 5.21 (m, 1H), 5.09–4.92 (m, 3H), 3.59–3.49 (m, 2H), 3.49–3.42 (m, 1H), 3.40 (s, 1H), 3.02 (dd, J = 14.1, 5.2 Hz, 1H), 2.89 (dd, J = 14.1, 7.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 143.3, 137.9, 134.2, 131.4, 129.4, 128.6, 127.9, 127.9, 127.3, 122.2, 118.9, 116.9, 87.6, 66.9, 60.9, 60.4, 54.0, 39.9. Elemental analysis (C33H30BrClN2O): calcd/found %C: 67.64%/67.57%, %H: 5.16%/5.30%, %N 4.78%/4.70%, %Cl 6.05%/6.30%, %Br 13.64%/12.63%.

2-(Allyl((1R,2S)-1-(4-bromophenyl)-1-chloro-3-(trityloxy)propan-2-yl)amino) acetonitrile ent-3b

Following the protocol above, 95 g of benzyl alcohol ent-3b afforded 60.5 g (62%) of chloride ent-4b. equation M12 (c 2.43, CHCl3).

(2S,3R,4R)-1-Allyl-3-(4-bromophenyl)-4-carbonitrile-2-((trityloxy)methyl) azetidine 5a and (2S,3R,4S)-1-Allyl-3-(4-bromophenyl)-4-carbonitrile-2-((trityloxy)methyl) azetidine 5b

A solution of benzyl chloride 4a (44.5 g, 76 mmol) in THF (1.1 L) was cooled to −50 °C. Lithium bis(trimethylsilyl)amide (1M solution in THF, 114 mL, 114 mmol) was added dropwise over 15 min and the mixture was stirred for an additional hour at −50 °C. The reaction mixture was quenched with aqueous saturated NH4Cl solution and the aqueous layer was extracted two times with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to provide the crude product, which was purified by chromatography over silica gel to provide pure products 5a (16.8 g, 40.3%) and 5b (21.9 g, 53%) as a white solid and a white foam (93% combined yield).

(2S,3R,4R)-1-Allyl-3-(4-bromophenyl)-4-carbonitrile-2-((trityloxy)methyl) azetidine 5a

equation M13 (c 1.92, CHCl3); IR νmax (film): 3057, 2866, 1488, 1448, 1264; 1H NMR (500 MHz, CDCl3) δ 7.36 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 7.23–7.14 (m, 9H), 7.14–7.11 (m, 6H), 5.74 (ddt, J = 17.0, 10.1, 6.7 Hz, 1H), 5.22 (dd, J = 17.1, 1.3 Hz, 1H), 5.11 (d, J = 10.2 Hz, 1H), 4.08 (d, J = 7.9 Hz, 1H), 3.80 (t, J = 7.8 Hz, 1H), 3.67 (td, J = 7.9, 5.3 Hz, 1H), 3.31 (dd, J = 12.9, 6.2 Hz, 1H), 3.12 (dd, J = 12.9, 7.1 Hz, 1H), 3.04 (dd, J = 9.5, 5.3 Hz, 1H), 2.80 (dd, J = 9.4, 8.2 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 143.4, 133.3, 132.8, 131.4, 131.3, 128.3, 127.7, 126.9, 121.9, 119.6, 117.3, 86.4, 66.2, 61.2, 60.7, 54.4, 42.4; HRMS (ESI) calcd for C33H30BrN2O [M + H]+: 549.1542, Found: 549.1545.

(2R,3S,4S)-1-Allyl-3-(4-bromophenyl)-4-carbonitrile-2-((trityloxy)methyl) azetidine ent-5a

Following the protocol above, 47 g of chloride ent-4a afforded 17.6 g (40%) of ent-5a. equation M14 (c 2.02, CHCl3).

(2S,3R,4S)-1-Allyl-3-(4-bromophenyl)-4-carbonitrile-2-((trityloxy)methyl) azetidine 5b

equation M15 (c 1.37, CHCl3); mp 129.5–133.5 °C IR νmax (film): 3057, 2862, 1488, 1448, 1264; 1H NMR (500 MHz, CDCl3) δ 7.32 (d, J = 8.4 Hz, 2H), 7.22–7.09 (m, 17H), 5.71–5.53 (m, 1H), 5.24 (dd, J = 17.2, 1.3 Hz, 1H), 5.09 (d, J = 10.2 Hz, 1H), 4.18 (d, J = 2.2 Hz, 1H), 4.03 (dd, J = 13.0, 7.9 Hz, 1H), 3.79 (dd, J = 7.8, 2.3 Hz, 1H), 3.31 (qd, J = 13.7, 6.2 Hz, 2H), 2.99 (dd, J = 9.5, 5.1 Hz, 1H), 2.64 (t, J = 9.15 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 143.4, 135.1, 132.9, 131.5, 130.1, 128.3, 127.7, 126.9, 121.6, 118.9, 116.9, 86.5, 66.5, 61.5, 55.8, 55.6, 43.6; HRMS (ESI) calcd for C33H30BrN2O [M + H]+: 549.1542, found: 549.1542.

(2R,3S,4R)-1-Allyl-3-(4-bromophenyl)-4-carbonitrile-2-((trityloxy)methyl) azetidine ent-5b

Following the protocol above, 47 g of chloride ent-4b afforded 20.3 g (46%) of ent-5b. equation M16 (c 2.48, CHCl3).

(2S,3S,4S)-1-Allyl-3-(4-bromophenyl)-4-carbonitrile-2-((trityloxy)methyl) azetidine 5c

A solution of benzyl chloride 4b (62 g, 106 mmol) in THF (1058 mL) was cooled to −78 °C. Lithium bis(trimethylsilyl)amide (1M solution in THF, 127 mL, 127 mmol) was added dropwise over 15 min and the mixture was stirred for an additional hour at −50 °C. The reaction mixture was quenched with aqueous saturated NH4Cl solution and the aqueous layer was extracted three times with EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to provide the crude product, which was purified by chromatography over silica gel to provide 5c (21.9 g, 53%) as a light orange foam. equation M17 (c 1.62, CHCl3); IR νmax (film): 3056, 3031, 2913, 2862, 2819, 1734, 1643, 1595, 1489, 1447; 1H NMR (500 MHz, CDCl3) δ 7.49 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 7.3 Hz, 6H), 7.33–7.24 (m, 9H), 7.16 (d, J = 8.4 Hz, 2H), 5.81–5.69 (m, 1H), 5.33 (d, J = 16.4 Hz, 1H), 5.17 (d, J = 10.2 Hz, 1H), 4.62 (d, J = 6.8 Hz, 1H), 3.85–3.75 (m, 2H), 3.52 (dd, J = 13.8, 5.0 Hz, 1H), 3.37–3.29 (m, 2H), 3.25 (dd, J = 10.2, 4.1 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 143.6, 134.5, 133.0, 131.7, 129.7, 128.5, 127.8, 127.1, 121.8, 118.9, 115.6, 86.9, 68.2, 65.7, 57.1, 55.4, 41.9. HRMS (ESI) calcd for C33H30BrN2O [M + H]+: 549.1541, found: 549.1553.

(2R,3R,4R)-1-Allyl-3-(4-bromophenyl)-4-carbonitrile-2-((trityloxy)methyl) azetidine ent-5c

Following the protocol above, 108.6 g of chloride ent-4c afforded 87.6 g (81%) of ent-5c. equation M18 (c 1.42, CHCl3).

(2S,3S,4R)-1-Allyl-3-(4-bromophenyl)-4-carbonitrile-2-((trityloxy)methyl) azetidine 5d

A solution of benzyl chloride 4b (45 g, 77 mmol) in THF (770 mL) was cooled to −78 °C. Potassium bis(trimethylsilyl)amide (1M solution in THF, 115 mL, 115 mmol) was added dropwise over 15 min and the mixture was stirred for an additional hour at −78 °C. The reaction mixture was quenched with aqueous saturated NH4Cl solution and the aqueous layer was extracted three times with EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to provide the crude product, which was purified by chromatography over silica gel to provide 5d (35 g, 83%) as a light orange foam. equation M19 (c 2.21, CHCl3); IR νmax (film): 3057, 3031, 2913, 2864, 2810, 1643, 1595, 1489, 1447; 1H NMR (500 MHz, CDCl3) δ 7.48 (d, J = 8.4, 2H), 7.42 (m, 5H), 7.36–7.25 (m, 11H), 7.10 (d, J = 8.3, 2H), 5.95–5.78 (m, 1H), 5.33 (d, J = 17.0, 1H), 5.24 (d, J = 10.2, 1H), 3.70 (t, J = 7.9, 1H), 3.61 (d, J = 8.2, 1H), 3.51 (dd, J = 5.7, 13.0, 1H), 3.44–3.33 (m, 2H), 3.32–3.22 (m, 1H), 3.16 (dd, J = 7.4, 13.1, 1H); 13C NMR (126 MHz, CDCl3) δ 143.6, 136.5, 132.6, 131.8, 128.7, 128.5, 127.8, 127.1, 121.5, 119.7, 119.1, 86.8, 69.0, 66.2, 60.4, 55.1, 44.4; HRMS (ESI) calcd for C33H30BrN2O [M + H]+: 549.1541, found: 549.1544.

(2R,3R,4S)-1-Allyl-3-(4-bromophenyl)-4-carbonitrile-2-((trityloxy)methyl) azetidine ent-5d

Following the protocol above, 30 g of chloride ent-4d afforded 23.7 g (84%) of ent-5d. equation M20 (c 1.78, CHCl3) mp 110.9–111.6 °C.

N-(((2S,3R,4R)-1-Allyl-3-(4-bromophenyl)-4-((trityloxy)methyl) azetidin-2-yl)methyl) - 2-nitrobenzene sulfonamide 6a

Nitrile azetidine 5a (12.45 g, 22.66 mmol, 1.0 equiv) was dissolved in CH2Cl2 (227 mL) and subsequently cooled to 0 °C. DIBAL (24.2 ml, 136 mmol, 6.0 equiv) was added over 15 min and the reaction mixture was allowed to warm to room temperature and stirred for approximately 2 h. The mixture was quenched by the slow addition of MeOH (5.50 mL, 136 mmol, 6.0 equiv) until gas evolution ceased. Then a saturated solution of sodium potassium tartrate (Rochelle's salt) was added and the gel like solution was allowed to stir until two separate layers could be seen. The aqueous layer was then extracted two additional times with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to provide the crude product, which was deemed pure enough for the next reaction.

A portion of the resulting amine (11.35 g, 20.50 mmol, 1.0 equiv) was dissolved in CH2Cl2 (205 mL) and cooled to 0 °C. 2,6-Lutidine (7.14 ml, 61.5 mmol, 3.0 equiv) was introduced followed by 2-nitrobenzene-1-sulfonyl chloride (5.15 g, 22.56 mmol, 1.1 equiv) in one portion. The solution was then allowed to warm to room temperature and stir for an additional 3 h. The reaction mixture was quenched with water and the aqueous layer was extracted two times with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to provide the crude product, which was purified by chromatography over silica gel using hexanes/EtOAc to provide pure product 6a (13.16 g, 87% 2-steps) as a pale yellow foam. equation M21 (c 0.50, CHCl3); IR νmax (film): 3332, 3056, 2872, 1537, 1348, 1167, 1070; 1H NMR (500 MHz, CDCl3) δ 7.88–7.79 (m, 1H), 7.75 (t, J = 7.7 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.22 – 7.16 (m, 6H), 7.16–7.11 (m, 4H), 7.09 (d, J = 2.0 Hz, 2H), 5.70 (dq, J = 6.6, 10.0 Hz, 1H), 5.20 (d, J = 17.1 Hz, 1H), 5.06 (d, J = 10.1 Hz, 1H), 4.91 (d, J = 4.2 Hz, 1H), 3.70–3.64 (m, 1H), 3.62 (dt, J = 6.4, 12.9 Hz, 1H), 3.57–3.42 (m, 1H), 3.28–3.15 (m, 2H), 3.15–2.98 (m, 2H), 2.88 (ddd, J = 6.4, 13.1 Hz, 20.4, 2H); 13C NMR (75 MHz, CDCl3) δ 147.5, 143.6, 135.2, 134.3, 133.4, 132.7, 132.6, 132.1, 130.8, 130.8, 128.3, 127.6, 126.8, 125.6, 120.9, 118.2, 86.2, 65.6, 65.4, 61.2, 60.9, 42.7, 42.2; HRMS (ESI) calcd for C39H37BrN3O5S [M + H]+: 738.1637, found: 738.1633.

N-(((2R,3S,4S)-1-Allyl-3-(4-bromophenyl)-4-((trityloxy)methyl)azetidin-2-yl)methyl)-2-nitrobenzenesulfonamide ent-6a

Following the protocol above, 19.8 g of nitrile azetidine ent-5a afforded 23 g (87%) of ent-6a. equation M22 (c 0.41, CHCl3).

N-(((2S,3R,4S)-1-Allyl-3-(4-bromophenyl)-4-((trityloxy)methyl)azetidin-2-yl)methyl)-2-nitrobenzenesulfonamide 6b

Following the protocol above, 11.4 g of nitrile azetidine 5b afforded 13.2 g (87%) of 6b. equation M23 (c 0.33, CHCl3); IR νmax (film): 3340, 3057, 2873, 1525, 1489, 1390, 1358, 1264; 1H NMR (500 MHz, CDCl3) δ 8.07 (dd, J = 1.7, 7.5 Hz, 1H), 7.86 (dd, J = 1.5, 7.7 Hz, 1H), 7.75–7.61 (m, 2H), 7.31 (d, J = 8.4 Hz, 1H), 7.27–7.17 (m, 8H), 7.17 (s, 5H), 6.89 (d, J = 8.3 Hz, 2H), 5.62–5.45 (m, 1H), 4.91 (d, J = 15.5 Hz, 1H), 4.75 (d, J = 9.0 Hz, 1H), 4.07 (dt, J = 4.6, 11.2 Hz, 1H), 3.89 (d, J = 4.4 Hz, 1H), 3.73 (t, J = 8.1, 1H), 3.29 (d, J = 11.0 Hz, 1H), 3.20 (dtd, J = 5.0, 12.5, 17.3 Hz, 3H), 2.90 (ddd, J = 6.5, 12.4, 21.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 147.9, 143.4, 135.9, 135.5, 133.4, 133.2, 132.5, 131.3, 130.9, 129.7, 128.5, 127.6, 126.9, 125.1, 120.4, 116.7, 87.1, 64.9, 64.1, 60.3, 52.8, 44.4, 40.1; HRMS (ESI) calcd for C39H37BrN3O5S [M + H]+: 738.1637, found: 738.1626.

N-(((2R,3S,4R)-1-Allyl-3-(4-bromophenyl)-4-((trityloxy)methyl)azetidin-2-yl)methyl)-2-nitrobenzene sulfonamide ent-6b

Following the protocol above, 20 g of nitrile azetidine ent-5b gave 25 g (93%) of ent-6b. equation M24 (c 0.73, CHCl3).

N-(((2S,3S,4S)-1-Allyl-3-(4-bromophenyl)-4-((trityloxy)methyl)azetidin-2-yl)methyl)-2-nitrobenzenesulfonamide 6c

Following the protocol above, 20 g of nitrile azetidine 5c afforded 18 g (67%) of 6c. equation M25 (c 0.21, CHCl3); IR νmax (film): 3332, 3056, 2871, 1539, 1346, 1264, 1168; 1H NMR (500 MHz, CDCl3) δ 7.89 (dd, J = 1.3, 7.8 Hz, 1H), 7.83 (t, J = 6.1 Hz, 1H), 7.74 (td, J = 1.2, 7.7 Hz, 1H), 7.69–7.60 (m, 1H), 7.44 (t, J = 8.9 Hz, 6H), 7.36–7.30 (m, 7H), 7.27 (dd, J = 2.9, 5.2 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 5.71 (ddd, J = 5.9, 10.9, 16.2 Hz, 1H), 5.10–4.97 (m, 2H), 4.94 (s, 1H), 3.97 (td, J = 4.7, 8.3 Hz, 1H), 3.85–3.73 (m, 1H), 3.52 – 3.45 (m, 1H), 3.45–3.32 (m, 3H), 3.19–3.02 (m, 2H), 2.75 (dt, J = 21.2, 47.3 Hz, 1H), 0.98 (dd, J = 7.5, 14.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 147.6, 143.6, 137.0, 136.0, 133.4, 133.0, 132.6, 131.4, 130.7, 130.4, 128.7, 127.8, 127.1, 125.4, 120.9, 116.6, 87.2, 65.9, 64.2, 62.8, 52.8, 43.3, 41.4; HRMS (ESI) calcd for C39H37BrN3O5S [M + H]+: 738.1637, found: 738.1642.

N-(((2R,3R,4R)-1-Allyl-3-(4-bromophenyl)-4-((trityloxy)methyl)azetidin-2-yl)methyl)-2-nitrobenzene sulfonamide ent-6c

Following the protocol above, 20 g of nitrile azetidine ent-5c afforded 24 g (90%) of ent-6c. equation M26 (c 0.45, CHCl3).

N-(((2S,3S,4R)-1-Allyl-3-(4-bromophenyl)-4-((trityloxy)methyl)azetidin-2-yl)methyl)-2-nitrobenzenesulfonamide 6d

Following the protocol above, 20 g of nitrile azetidine 5d afforded 23.5 g (88%) of 6d. equation M27 (c 0.81, CHCl3); IR νmax (film): 3332, 3056, 2869, 1533, 1489, 1447, 1394, 1357, 1264, 1166; 1H NMR (500 MHz, CDCl3) δ 8.09 (dd, J = 1.9, 7.2 Hz, 1H), 7.85 (dd, J = 1.6, 7.5 Hz, 1H), 7.74 (tt, J = 6.7, 13.1 Hz, 1H), 7.41 (t, J = 6.3 Hz, 5H), 7.31 (t, J = 7.5 Hz, 4H), 7.28–7.22 (m, 2H), 7.01 (d, J = 8.3 Hz, 1H), 6.14 (s, 1H), 5.66 (td, J = 8.9, 17.5 Hz, 1H), 5.11 (d, J = 16.8 Hz, 1H), 4.83 (d, J = 9.6 Hz, 1H), 3.43 (dd, J = 5.5, 13.0 Hz, 1H), 3.34 (dd, J = 4.9, 9.7 Hz, 1H), 3.24 (t, J = 5.8 Hz, 3H), 3.18 (dd, J = 4.0, 9.7 Hz, 1H), 3.11 – 2.99 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 148.1, 143.9, 138.7, 134.8, 133.4, 133.2, 132.4, 131.5, 131.1, 129.2, 128.6, 127.8, 126.9, 125.1, 120.6, 118.1, 86.8, 68.4, 68.0, 66.4, 60.4, 45.1, 41.2; HRMS (ESI) calcd for C39H37BrN3O5S [M + H]+: 738.1637, found: 738.1635.

N-(((2R,3R,4S)-1-Allyl-3-(4-bromophenyl)-4-((trityloxy)methyl)azetidin-2-yl)methyl)-2-nitrobenzene sulfonamide ent-6d

Following the protocol above, 25 g of nitrile azetidine ent-5d afforded 31 g (93%) of ent-6d. equation M28 (c 0.71, CHCl3).

N-(((2S,3R,4R)-1-Allyl-3-(4-bromophenyl)-4-(hydroxymethyl)azetidin-2-yl)methyl)-2-nitrobenzenesulfonamide 7a

Azetidine 6a (14.1 g, 19.09 mmol, 1.0 equiv) was dissolved in CH2Cl2 (191 mL) and cooled to 0 °C. Trifluoroacetic acid (14.9 ml, 191 mmol, 10 equiv) was then added over approximately 10 min until the yellow color persisted. The mixture was neutralized by the addition of a saturated aqueous solution of sodium bicarbonate and the aqueous layer extracted 2 additional times with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to provide the crude product, which was purified by chromatography over silica gel using hexanes/EtOAc to provide the primary alcohol 7a (8.74 g, 92%) as a foam. equation M29 (c 0.59, CHCl3); IR νmax (film): 3335, 2873, 1538, 1346, 1166, 905; 1H NMR (500 MHz, CDCl3) δ 7.83 (dd, J = 7.8, 1.4 Hz, 1H), 7.79 (dd, J = 7.9, 1.3 Hz, 1H), 7.72 (td, J = 7.7, 1.5 Hz, 1H), 7.66 (td, J = 7.6, 1.3 Hz, 1H), 7.22 (m, 4H), 5.83 (m, 1H), 5.28 (d, J = 17.1 Hz, 1H), 5.17 (d, J = 10.1 Hz, 1H), 4.92 (s, 1H), 3.64 (s, 1H), 3.54 (s, 2H), 3.49–3.42 (m, 1H), 3.37 (m, 1H), 3.21 (s, 3H), 2.92 (t, J = 10.3 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 147.6, 135.5, 133.8, 133.5, 132.7, 132.6, 132.2, 131.2, 130.9, 125.7, 121.4, 118.6, 67.3, 64.8, 61.4, 61.1, 42.8, 41.8; HRMS (ESI) calcd for C20H23BrN3O5S [M + H]+: 496.0542, found: 496.0545.

N-(((2R,3S,4S)-1-Allyl-3-(4-bromophenyl)-4-(hydroxymethyl)azetidin-2-yl)methyl)-2-nitrobenzenesulfonamide ent-7a

Following the protocol above, 23 g of ent-6a azetidine afforded 14.6 g (94%) of azetidine ent-7a. equation M30 (c 1.44, CHCl3).

N-(((2S,3S,4R)-1-Allyl-3-(4-bromophenyl)-4-(hydroxymethyl)azetidin-2-yl)methyl)-2-nitrobenzenesulfonamide 7d

Following the protocol above, 23.5 g of azetidine 6d afforded 14.6 g (92%) of azetidine 7d. equation M31 (c 0.49, CHCl3); IR νmax (film): 3320, 2872, 1537, 1342, 1162; 1H NMR (500 MHz, CDCl3) δ 8.07 (dd, J = 1.6, 6.8 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.79–7.62 (m, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 8.2 Hz, 2H), 5.97 (s, 1H), 5.69 (ddt, J = 6.7, 9.9, 16.8 Hz, 1H), 5.18 (d, J = 17.1 Hz, 1H), 5.02 (d, J = 10.1 Hz, 1H), 3.64 (dd, J = 3.1, 12.0 Hz, 1H), 3.48 (d, J = 10.1 Hz, 1H), 3.34 (t, J = 7.7 Hz, 1H), 3.30–3.18 (m, 4H), 3.18–3.05 (m, 2H), 2.27 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 147.5, 138.5, 134.1, 133.4, 132.9, 132.5, 131.2, 130.5, 129.0, 124.9, 120.2, 118.5, 70.0, 67.4, 62.1, 59.6, 45.5, 38.8; HRMS (ESI) calcd for C20H22BrN3O5S [M + H]+: 496.0542, found: 496.0541.

N-(((2R,3R,4S)-1-Allyl-3-(4-bromophenyl)-4-(hydroxymethyl)azetidin-2-yl)methyl)-2-nitrobenzenesulfonamide ent-7d

Following the protocol above, 24 g of ent-6d azetidine gave 14 g (88%) of azetidine ent-7d. equation M32 (c 0.28, CHCl3).

6-Allyl-7-(4-bromophenyl)-3-(2-nitrophenylsulfonyl)-3,6-diazabicyclo[3.1.1] heptanes 8a

Nosyl amine 7a (8.0 g, 16.1 mmol) was dissolved in CH2Cl2 (170 mL) and the reaction was subsequently cooled to 0 °C. Triethylamine (6.7 mL, 48.4 mmol) was added followed by the drop-wise addition methanesulfonyl chloride (1.37 mL, 17.7 mmol). The solution was stirred for 30 min at 0 °C. The reaction mixture was quenched with water and the aqueous layer was extracted three times with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to provide the crude product, which was deemed pure enough to continue without further purification.

The resulting sulfonate was dissolved in DMF (161 mL) and potassium carbonate (4.46 g, 32.2 mmol) was added in one portion. The reaction was heated to 65 °C for 3 h at which point the solvent was removed and the resulting residue was purified by chromatography over silica gel to provide 8.2g of pure product 8a (99%). IR νmax (film): 2934, 1542, 1372, 1169, 578, 535; 1H NMR (500 MHz, CDCl3) δ 7.66 (t, J = 7.7 Hz, 1H), 7.40 (dt, J = 17.0, 7.9 Hz, 3H), 7.07 (d, J = 8.3 Hz, 2H), 6.74 (d, J = 8.1 Hz, 2H), 5.88–5.73 (m, 1H), 5.26 (dd, J = 17.2, 1.4 Hz, 1H), 5.16 (d, J = 10.2 Hz, 1H), 4.01 (d, J = 5.7 Hz, 2H), 3.90 (t, J = 5.9 Hz, 1H), 3.84 (d, J = 11.7 Hz, 2H), 3.48 (d, J = 11.7 Hz, 2H), 3.28 (d, J = 5.9 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 147.4, 134.5, 133.8, 133.2, 131.1, 131.1, 130.4, 129.5, 127.5, 123.4, 120.0, 117.4, 59.6, 47.5, 40.2, 39.4; HRMS (ESI) calcd for C20H20BrN3O4S [M + H]+: 478.0436, found: 478.0438.

6-Allyl-7-(4-bromophenyl)-3-(2-nitrophenylsulfonyl)-3,6-diazabicyclo[3.1.1] heptanes 8d

Nosyl amine 7d (1.00 g, 2.02 mmol) was dissolved in CH2Cl2 (20 mL) and the reaction was subsequently cooled to 0 °C. Triethylamine (0.842 mL, 6.04 mmol) was added followed by the dropwise addition methanesulfonyl chloride (0.172 mL, 2.22 mmol). The solution was stirred for 30 min at 0 °C. The reaction mixture was quenched with water and the aqueous layer was extracted three times with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to provide the crude product, which was deemed pure enough to continue without further purification.

The resulting sulfonate was dissolved in DMF (20 mL) and potassium carbonate (0.557 g, 4.03 mmol) was added in one portion. The reaction was heated to 65 °C for 1 h at which point the solvent was removed and the resulting residue was purified by chromatography over silica gel to provide pure product 8d (0.902 g, 94%). IR νmax (film): 2934, 1542, 1372, 1169, 578, 535; 1H NMR (500 MHz, CDCl3) δ 8.14 (dd, J = 1.6, 7.5 Hz, 1H), 7.82–7.73 (m, 2H), 7.70 (dd, J = 1.6, 7.5 Hz, 1H), 7.47 (s, 4H), 5.75 (ddd, J = 5.8, 10.9, 16.1 Hz, 1H), 5.14–5.06 (m, 2H), 3.88 (d, J = 11.0 Hz, 2H), 3.71 (s, 2H), 3.57 (d, J = 11.0 Hz, 2H), 3.06 (d, J = 5.8 Hz, 2H), 3.00 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 148.0, 139.3, 133.9, 133.8, 131.5, 131.4, 131.2, 131.1, 129.4, 124.1, 120.5, 117.0, 62.1, 47.5, 45.6, 43.3; HRMS (ESI) calcd for C20H20BrN3O4S [M + H]+: 478.0436, found: 478.0438.

6R,7R,8S)-7-(4-Bromophenyl)-4-((2-nitrophenyl)sulfonyl)-8-((trityloxy)methyl)-1,4-diazabicyclo[4.2.0]octan-2-one 9a

To a solution of the nosylated amine 6a (13.2 g, 17.9 mmol, 1.0 equiv) in EtOH (179 mL) at room temperature was added 1,3-dimethylbarbituric acid (3.92 g, 25.1 mmol, 1.4 equiv) followed by Pd(PPh3)4 (1.66 g, 1.43 mmol, 0.08 equiv). Upon completion of the reaction the mixture was filtered through a silica gel plug, eluting with CH2Cl2/MeOH, and the filtrate was concentrated to provide the crude amine as a bright red, foamy solid.

The crude allyl deprotected product was dissolved in acetonitrile (153 mL) and Cs2CO3 (74.0 g, 227 mmol, 10.0 equiv) was added and allowed to stir at room temperature for 30 min. Bromoacetyl chloride (1.89 mL, 22.7 mmol, 1.0 equiv) was then added and stirred until deemed complete via LCMS analysis. The reaction was filtered through Celite, and the filtrate was concentrated under reduced pressure. The crude residue was partitioned in CH2Cl2 and water/brine. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel using hexanes/EtOAc, and again using CH2Cl2/EtOAc, which provided the pure product 9a (6.96 g, 59% over two steps) as a white, foamy solid. equation M33 (c 0.29, CHCl3); IR νmax (film): 3057, 1667, 1543, 1489, 1448, 1423, 1369, 1169; 1H NMR (300 MHz, CDCl3) δ 7.96 (dd, J = 7.7, 1.5 Hz, 1H), 7.77–7.58 (m, 9H), 7.30 (d, J = 8.4 Hz, 2H), 7.23–7.12 (m, 9H), 7.06 (dd, J = 6.7, 3.0 Hz, 6H), 6.99 (d, J = 8.4 Hz, 2H), 5.13 – 5.01 (m, 1H), 5.00–4.88 (m, 1H), 4.18–3.98 (m, 3H), 3.73 (dd, J = 13.1, 4.8 Hz, 1H), 3.64 (d, J = 17.1 Hz, 1H), 3.40 (t, J = 10.0 Hz, 1H), 3.23 (dd, J = 12.9, 8.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 160.6, 148.1, 143.3, 134.3, 132.9, 132.2, 131.8, 131.4, 131.0, 128.6, 127.9, 127.2, 124.7, 121.9, 86.9, 66.1, 61.4, 57.4, 48.0, 45.4, 42.8; HRMS (ESI) calcd for C38H32BrN3NaO6S [M + Na]+: 760.1093, found: 760.1097.

(6S,7R,8S)-7-(4-Bromophenyl)-4-((2-nitrophenyl)sulfonyl)-8-((trityloxy)methyl)-1,4-diazabicyclo[4.2.0]octan-2-one 9b

Following the protocol above, 7.3 g of 6b afforded 5.02 g of 9b (69% over two steps) as a white, foamy solid. equation M34 (c 0.25, CHCl3); IR νmax (film): 3057, 1668, 1543, 1490, 1448, 1415, 1370, 1170; 1H NMR (300 MHz, CDCl3) δ 8.04 (dd, J = 7.5, 2.1 Hz, 1H), 7.72–7.54 (m, 3H), 7.31 (d, J = 8.4 Hz, 2H), 7.25–7.16 (m, 9H), 7.16–7.04 (m, 6H), 6.96 (d, J = 8.3 Hz, 2H), 5.33–5.21 (m, 1H), 4.90–4.78 (m, 1H), 4.37 (dd, J = 12.6, 4.8 Hz, 1H), 4.33 (d, J = 17.1 Hz, 1H), 3.98 (t, J = 8.6 Hz, 1H), 3.76 (d, J = 17.0 Hz, 1H), 3.38 (dd, J = 10.7, 5.1 Hz, 1H), 3.20–3.03 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 165.3, 148.1, 143.4, 134.4, 134.2, 132.1, 131.6, 131.4, 131.3, 129.2, 128.6, 127.8, 127.1, 124.6, 121.2, 87.2, 66.4, 64.1, 61.7, 48.6, 48.4, 44.9; HRMS (ESI) calcd for C38H32BrN3NaO6S [M + Na]+: 760.1093, found: 760.1095.

(6S,7S,8S)-7-(4-Bromophenyl)-4-((2-nitrophenyl)sulfonyl)-8-((trityloxy)methyl)-1,4-diazabicyclo[4.2.0]octan-2-one 9c

Following the protocol above, 7.35 g of 6c afforded 4.51 g of 9c (61% over 2 steps) as a white, foamy solid. equation M35 (c 1.29, CHCl3); IR νmax (film): 3058, 1671, 1543, 1490, 1448, 1415, 1370, 1169; 1H NMR (300 MHz, CDCl3) δ 8.02 – 7.91 (m, 1H), 7.70–7.52 (m, 3H), 7.52–7.36 (m, 8H), 7.36–7.18 (m, 9H), 7.03 (d, J = 8.4 Hz, 2H), 5.09 (ddd, J = 11.4, 8.2, 4.9 Hz, 1H), 4.75 (dd, J = 7.5, 3.6 Hz, 1H), 4.32 (d, J = 17.1 Hz, 1H), 3.98 (dd, J = 8.0, 4.6 Hz, 1H), 3.80–3.62 (m, 3H), 3.40 (dd, J = 10.6, 3.5 Hz, 1H), 2.61 (dd, J = 13.1, 11.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 166.2, 148.0, 143.7, 134.39, 134.36, 132.3, 132.1, 131.7, 131.1, 129.4, 128.8, 128.1, 127.4, 124.7, 121.9, 87.2, 66.9, 64.3, 62.5, 48.7, 44.5, 42.9; HRMS (ESI) calcd for C38H32BrN3NaO6S [M + Na]+: 760.1093, found: 760.1097.

(6R,7S,8S)-7-(4-Bromophenyl)-4-((2-nitrophenyl)sulfonyl)-8-((trityloxy)methyl)-1,4-diazabicyclo[4.2.0]octan-2-one 9d

Following the protocol above, 10.0 g of 6d afforded 6.07 g of 9d (61% over 2 steps) as a white, foamy solid. equation M36 (c 0.38, CHCl3); IR νmax (film): 3058, 1673, 1544, 1490, 1448, 1419, 1370, 1170; 1H NMR (300 MHz, CDCl3) δ 8.06 (dd, J = 7.4, 1.6 Hz, 1H), 7.84–7.68 (m, 3H), 7.45 (dd, J = 8.1, 1.8 Hz, 6H), 7.32 (d, J = 8.4 Hz, 2H), 7.30–7.14 (m, 9H), 6.83 (d, J = 8.4 Hz, 2H), 4.63 (ddd, J = 10.6, 6.6, 4.2 Hz, 1H), 4.49–4.39 (m, 1H), 4.35–4.23 (m, 2H), 4.18 (dd, J = 12.4, 4.1 Hz, 1H), 3.87 (d, J = 16.9 Hz, 1H), 3.52 (t, J = 6.8 Hz, 1H), 3.31 (ddd, J = 13.0, 11.6, 6.2 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 163.3, 143.7, 137.3, 134.4, 132.1, 132.1, 131.7, 131.5, 128.8, 128.1, 127.4, 124.7, 121.7, 88.0, 72.2, 64.8, 59.4, 48.1, 47.2, 43.2; HRMS (ESI) calcd for C38H32BrN3NaO6S [M + Na]+: 760.1093, found: 760.1085.

6R,7R,8S)-7-(4-Bromophenyl)-8-(hydroxymethyl)-4-((2-nitrophenyl)sulfonyl)-1,4-diazabicyclo[4.2.0]octan-2-one 10a

To a solution of ketopiperazine 9a in CH2Cl2 (92 mL) at room temperature was added trifluoroacetic acid (7.23 mL, 94 mmol, 10 equiv), followed by triethylsilane (1.5 mL, 9.4 mmol, 1.0 equiv). The reaction was stirred for 15 min, after which analysis of the reaction by LC/MS showed complete conversion of the starting material to the product. The reaction was quenched with MeOH, and then saturated aqueous NaHCO3 solution until bubbling completely stopped. The layers were then separated, and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel using CH2Cl2/MeOH as eluent, which provided the pure product 10a (3.4 g, 73%) as a white, foamy solid. equation M37 (c 0.30, CHCl3). IR νmax (film): 3361, 2936, 1644, 1541, 1358, 1166, 1034; 1H NMR (300 MHz, CDCl3) δ 7.99 (dd, J = 7.4, 1.7 Hz, 1H), 7.80–7.63 (m, 3H), 7.44 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 5.13–4.94 (m, 2H), 4.27 (d, J = 17.3 Hz, 1H), 4.07 (dd, J = 12.9, 9.7 Hz, 1H), 4.00 (t, J = 8.2 Hz, 1H), 3.84 (d, J = 17.3 Hz, 1H), 3.74 (dd, J = 13.1, 4.8 Hz, 1H), 3.42–3.23 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.6, 148.0, 134.5, 132.3, 132.0, 131.8, 131.7, 131.4, 131.3, 124.8, 122.5, 70.5, 61.8, 60.7, 47.9, 44.8, 42.9; HRMS (ESI) calcd for C19H19BrN3O6S [M + H]+: 496.0178, found: 496.0179.

(6S,7R,8S)-7-(4-Bromophenyl)-8-(hydroxymethyl)-4-((2-nitrophenyl)sulfonyl)-1,4-diazabicyclo[4.2.0]octan-2-one 10b

Following the protocol above, product 9b (2.71 g, 81%) was obtained as a white powder. equation M38 (c 0.26, DMSO); IR νmax (film): 3419, 1667, 1548, 1362, 1171; 1H NMR (300 MHz, DMSO-d6) δ 8.14 (dd, J = 7.7, 1.4 Hz, 1H), 8.05 (dd, J = 7.8, 1.4 Hz, 1H), 7.95 (dt, J = 7.5, 1.5 Hz, 1H), 7.88 (dt, J = 7.5, 1.5 Hz, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 5.04–4.92 (m, 1H), 4.69 – 4.55 (m, 1H), 4.17–4.05 (m, 3H), 3.68 (d, J = 16.9 Hz, 1H), 3.43 (d, J = 4.6 Hz, 2H), 3.38–3.25 (obscured, 1H); 13C NMR (75 MHz, DMSO-d6) δ 165.0, 147.6, 135.4, 135.1, 132.6, 130.9, 130.5, 130.1, 129.5, 124.3, 119.8, 67.4, 63.3, 59.5, 48.2, 46.9, 43.6; HRMS (ESI) calcd for C19H19BrN3O6S [M + H]+: 496.0178, found: 496.0170.

(6S,7S,8S)-7-(4-Bromophenyl)-8-(hydroxymethyl)-4-((2-nitrophenyl)sulfonyl)-1,4-diazabicyclo[4.2.0]octan-2-one 10c

Following the protocol above, product 10c (4.18 g, 72%) was obtained as a white, foamy solid. equation M39 (c 0.92, CHCl3); IR νmax (film): 3422, 2930, 1658, 1541, 1370, 1166; 1H NMR (300 MHz, CDCl3) δ 7.95 (dd, J = 6.9, 1.5 Hz, 1H), 7.80–7.59 (m, 3H), 7.48 (d, J = 8.3 Hz, 2H), 7.06 (d, J = 8.3 Hz, 2H), 4.97 (ddd, J = 11.2, 8.7, 4.7 Hz, 1H), 4.78 (dd, J = 8.2, 4.5 Hz, 1H), 4.27 (d, J = 17.2 Hz, 1H), 4.08–3.92 (m, 2H), 3.85 (dd, J = 11.9, 5.0 Hz, 1H), 3.78–3.60 (m, 2H), 2.79 (br s, 1H), 2.64 (dd, J = 12.9, 11.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 167.6, 148.0, 134.4, 134.0, 132.4, 132.3, 131.7, 131.3, 129.4, 124.7, 122.0, 69.0, 63.7, 62.6, 48.4, 44.6, 41.8; HRMS (ESI) calcd for C19H19BrN3O6S [M + H]+: 496.0178, found: 496.0182.

(6R,7S,8S)-7-(4-Bromophenyl)-8-(hydroxymethyl)-4-((2-nitrophenyl)sulfonyl)-1,4-diazabicyclo[4.2.0]octan-2-one 10d

Following the protocol above, product 10d (4.0 g, 73%) was obtained as a white, foamy solid. equation M40 (c 0.35, CHCl3); IR νmax (film): 3389, 2923, 1645, 1541, 1360, 1169; 1H NMR (300 MHz, CDCl3) δ 8.01 (dd, J = 6.9, 1.5 Hz, 1H), 7.86–7.62 (m, 3H), 7.49 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 4.80–4.62 (m, 2H), 4.34–4.17 (m, 2H), 4.07 (dd, J = 12.8, 2.2 Hz, 1H), 3.85–3.67 (m, 2H), 3.56 (t, J = 7.5 Hz, 1H), 3.17 (dd, J = 12.7, 10.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 164.5, 148.1, 136.1, 134.5, 132.4, 132.3, 131.5, 131.5, 128.8, 124.7, 122.1, 74.6, 65.5, 62.8, 48.1, 47.6, 44.1; HRMS (ESI) calcd for C19H19BrN3O6S [M + H]+: 496.0178. Found: 496.0183.

(8R,9R,10S,Z)-9-(4-Bromophenyl)-6-((2-nitrophenyl)sulfonyl)-10-((trityloxy)methyl)-1,6-diazabicyclo[6.2.0]dec-3-ene 11a

To a solution of the nosylated amine 6a (16.5 g, 22.34 mmol, 1.0 equiv) in DMF (45 mL) at 0 °C was added potassium carbonate (4.63 g, 33.50 mmol, 1.5 equiv), and allyl bromide (2.08 mL, 24.57 mmol, 1.1 equiv). The reaction was stirred for 2 h, slowly warming to room temperature. Analysis of the reaction by LCMS indicated complete disappearance of the starting material, and the formation of a new product. The reaction mixture was quenched with water and extracted three times with EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to provide the crude product, which was purified by chromatography on silica gel using hexanes/EtOAc to obtain allylated compound (14.72 g, 85%). equation M41 (c 0.66, CHCl3). IR νmax (film): 3057, 2855, 1542, 1486, 1448, 1353, 1160, 1072; 1H NMR (300 MHz, CDCl3) δ 7.68–7.49 (m, 5H), 7.33 (d, J = 8.3 Hz, 2H), 7.28–7.12 (m, 16H), 5.72–5.59 (m, 1H), 5.52–5.39 (m, 1H), 5.10 (d, J = 17.0 Hz, 1H), 5.02 (d, J = 10.2 Hz, 1H), 4.95 (d, J = 10.2 Hz, 1H), 4.82 (d, J = 17.1 Hz, 1H), 3.84 (dd, J = 16.1, 5.7 Hz, 1H), 3.76 (dd, J = 7.4, 7.4 Hz, 1H), 3.60–3.53 (m, 2H), 3.48 (dd, J = 16.2, 6.6 Hz, 1H), 3.28–3.14 (m, 3H), 3.05 (dd, J = 9.2, 4.7 Hz, 1H), 2.96 (dd, J = 13.3, 7.2 Hz, 1H), 2.86 (dd, J = 9.0, 9.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 147.9, 143.8, 135.1, 133.4, 132.7, 132.6, 131.1, 128.4, 127.6, 126.7, 124.1, 120.7, 119.0, 117.8, 86.1, 66.6, 66.2, 60.8, 60.6, 51.6, 45.3, 44.2; HRMS (ESI) calcd for C42H41BrN3O5S [M + H]+: 778.1950, found: 778.1948.

This material (16.06 g, 20.62 mmol, 1.0 equiv) was dissolved in benzene and degassed for 30 min. Grubbs Catalyst I (4.24 g, 5.16 mmol, 0.25 equiv) was then added and the reaction was stirred for 24 h at 50 °C, after which, analysis of the reaction by LC-MS indicated complete disappearance of the starting material. The solvent was evaporated under reduced pressure, and purified by flash chromatography on silica gel using hexanes/EtOAc, which provided 11a (11.77 g, 76%) as a light brown foamy solid. equation M42 (c 1.0, CHCl3); IR νmax (film): 3057, 3030, 2927, 2865, 1543, 1488, 1448, 1352, 1162, 1073; 1H NMR (300 MHz, CDCl3) δ 7.89 (dd, J = 6.9, 2.1 Hz, 1H), 7.76–7.50 (m, 3H), 7.39–7.06 (m, 19H), 5.89–5.82 (m, 1H), 5.75–5.66 (m, 1H), 4.10 (dd, J = 15.2, 6.9 Hz, 1H), 3.98 (dd, J = 14.6, 9.2 Hz, 1H), 3.64–3.58 (m, 3H), 3.48 (dd, J = 15.3, 6.3 Hz, 1H), 3.26 (d, J = 13.8 Hz, 1H), 3.21–3.01 (m, 3H), 2.92 (dd, J = 9.2, 5.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 148.0, 143.7, 134.8, 133.4, 133.0, 132.9, 132.1, 131.6, 131.1, 130.8, 128.5, 127.7, 126.9, 124.8, 124.1, 120.9, 86.5, 77.5, 77.0, 76.6, 67.0, 66.0, 61.9, 54.9, 49.5, 43.5, 43.2; HRMS (ESI) calcd for C40H37BrN3O5S [M + H]+: 750.1637, found: 750.1639.

(8S,9R,10S,Z)-9-(4-Bromophenyl)-6-((2-nitrophenyl)sulfonyl)-10-((trityloxy)methyl)-1,6-diazabicyclo[6.2.0]dec-3-ene 11b

Following the protocol above 22.0 g of nosyl amine 6b afforded 20.99 g (91%) of the allylated product. equation M43 (c 0.26, CHCl3); IR νmax (film): 3058, 2916, 1542, 1489, 1448, 1353, 1162, 1071; 1H NMR (300 MHz, CDCl3) δ 7.94 (d, J = 7.8 Hz, 1H), 7.58 (td, J = 7.1, 3.5 Hz, 3H), 7.30 (d, J = 8.3 Hz, 2H), 7.26–7.17 (m, 9H), 7.14 (dd, J = 8.2, 5.4 Hz, 6H), 7.01 (d, J = 8.3 Hz, 2H), 5.72–5.43 (m, 2H), 5.17–5.05 (m, 2H), 4.99 (d, J = 18.1 Hz, 1H), 4.94 (d, J = 11.1 Hz, 1H), 4.05 (dd, J = 13.2, 6.0 Hz, 1H), 3.97–3.84 (m, 3H), 3.69–3.50 (m, 3H), 3.24 (dd, J = 14.6, 5.6 Hz, 1H), 3.16 (dd, J = 9.9, 5.0 Hz, 1H), 3.06 (dd, J = 14.5, 5.9 Hz, 1H), 2.86 (dd, J = 9.9, 6.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 148.0, 143.7, 137.0, 135.8, 133.6, 132.4, 131.7, 131.4, 131.1, 130.3, 128.7, 127.7, 127.0, 124.3, 120.5, 119.7, 116.5, 87.1, 64.8, 64.4, 60.8, 52.7, 51.1, 48.7, 43.3; HRMS (ESI) calcd for C42H41BrN3O5S [M + H]+: 778.1950, found: 778.1936.

A portion of alllyl intermediate (5.0 g, 6.42 mmol, 1.0 equiv) was then reacted with Grubbs Catalyst I (1.06 g, 1.28 mmol, 0.20 equiv) in the presence of styrene (2.94 mL, 25.7 mmol, 4.0 equiv) in DCE (321 mL) to provide 11b (2.46 g, 51%) as a light brown foamy solid. equation M44 (c 0.26, CHCl3); IR νmax (film): 3031, 2920, 1541, 1488, 1448, 1345, 1161, 1071. 1H NMR (300 MHz, CDCl3) δ 8.09–7.95 (m, 1H), 7.73–7.53 (m, 3H), 7.32 (d, J = 8.3 Hz, 2H), 7.25 (s, 15H), 7.12 (d, J = 8.4 Hz, 2H), 6.12–5.84 (m, 2H), 4.11–3.85 (m, 4H), 3.84–3.63 (m, 2H), 3.51 (dd, J = 12.3, 8.5 Hz, 1H), 3.27 (dd, J = 8.1, 3.7 Hz, 1H), 3.14 (dd, J = 12.5, 6.4 Hz, 1H), 3.05 (dd, J = 9.6, 5.6 Hz, 1H), 2.72 (dd, J = 9.4, 7.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 147.9, 143.8, 137.0, 133.7, 133.2, 131.8, 131.6, 131.3, 131.0, 130.5, 129.0, 128.6, 127.8, 127.0, 124.2, 120.7, 86.8, 68.2, 64.2, 62.1, 50.3, 46.1, 44.4, 42.7; HRMS (ESI) calcd for C40H37BrN3O5S [M + H]+: 750.1637, found: 750.1627.

(8S,9S,10S,Z)-9-(4-Bromophenyl)-6-((2-nitrophenyl)sulfonyl)-10-((trityloxy)methyl)-1,6-diazabicyclo[6.2.0]dec-3-ene 11c

Following the protocol above, 22.0 g of nosyl amine 6b afforded 20.99 g (91%) of the allylated product. equation M45 (c 0.11, CHCl3); IR νmax (film): 3060, 2890, 1541, 1488, 1447, 1352, 1160, 1070; 1H NMR (300 MHz, CDCl3) δ 7.61 (td, J = 7.3, 1.4 Hz, 2H), 7.53 (d, J = 7.5 Hz, 2H), 7.46 (d, J = 8.1 Hz, 8H), 7.38–7.18 (m, 11H), 5.72 – 5.54 (m, 1H), 5.54–5.38 (m, 1H), 5.04 (d, J = 10.2 Hz, 1H), 4.99–4.79 (m, 3H), 4.20 (dd, J = 9.8, 5.1 Hz, 1H), 3.84 (dd, J = 16.1, 5.8 Hz, 1H), 3.63 (d, J = 3.1 Hz, 1H), 3.59 – 3.47 (m, 2H), 3.47–3.35 (m, 2H), 3.28 (dd, J = 15.1, 6.0 Hz, 1H), 3.20-3.04 (m, 2H), 2.96 (dd, J = 15.3, 7.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 148.1, 143.9, 139.3, 136.3, 133.4, 133.4, 132.9, 131.7, 131.6, 131.3, 131.1, 129.0, 128.0, 127.3, 124.2, 120.8, 119.1, 115.7, 87.4, 67.0, 65.5, 61.9, 52.1, 51.6, 47.3, 43.0; HRMS (ESI) calcd for C42H41BrN3O5S [M + H]+: 778.1950, found: 778.1962.

This product (22.48 g, 28.90 mmol, 1.0 equiv) was then reacted with Grubbs Catalyst I (5.94 g, 7.22 mmol, 0.25 equiv) in benzene (577 mL) to provide 11c (13.10 g, 60.5%) as a light brown foamy solid. equation M46 (c 0.15, CHCl3); IR νmax (film): 3027, 2917, 1542, 1489, 1448, 1346, 1161, 1061; 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J = 7.7 Hz, 1H), 7.68–7.49 (m, 3H), 7.50–7.35 (m, 8H), 7.35–7.21 (m, 9H), 7.07 (d, J = 8.3 Hz, 2H), 6.07–5.87 (m, 2H), 4.20–3.98 (m, 2H), 3.87 (dd, J = 13.1, 5.5 Hz, 1H), 3.73 (dd, J = 15.3, 6.2 Hz, 1H), 3.61 (t, J = 8.2 Hz, 1H), 3.52–3.38 (m, 2H), 3.38–3.26 (m, 2H), 3.09 (dt, J = 21.4, 11.8 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 147.9, 144.0, 136.5, 133.5, 133.0, 131.7, 131.6, 131.4, 130.9, 130.0, 129.4, 128.8, 128.0, 127.2, 124.2, 120.7, 87.2, 66.6, 66.0, 65.3, 47.6, 46.3, 44.7, 41.8; HRMS (ESI) calcd for C40H37BrN3O5S [M + H]+: 750.1637, found: 750.1641.

(8R,9S,10S,Z)-9-(4-Bromophenyl)-6-((2-nitrophenyl)sulfonyl)-10-((trityloxy)methyl)-1,6-diazabicyclo[6.2.0]dec-3-ene 11d

Following the protocol above, 23.4 g of nosyl amine 6d afforded 22.42 g (91%) of the allylated product. equation M47 (c 1.0, CHCl3); IR νmax (film): 3058, 2911, 2863, 1542, 1490, 1448, 1353, 1161, 1072; 1H NMR (300 MHz, CDCl3) δ 7.97 (d, J = 7.5 Hz, 1H), 7.68 – 7.56 (m, 3H), 7.45–7.40 (m, 8H), 7.32–7.25 (m, 9H), 7.12 (d, J = 8.3 Hz, 2H), 5.87–5.73 (m, 1H), 5.57–5.44 (m, 1H), 5.20 (d, J = 17.1 Hz, 1H), 5.14–5.05 (m, 3H), 4.12 (dd, J = 16.4, 6.6 Hz, 1H), 3.97 (dd, J = 16.1, 6.0 Hz, 1H), 3.54 (d, J = 4.4, 2H), 3.42 – 3.08 (m, 7H); 13C NMR (75 MHz, CDCl3) δ 148.3, 144.4, 139.7, 135.3, 134.2, 133.7, 132.6, 131.9, 131.7, 131.4, 129.9, 129.1, 128.1, 127.3, 124.4, 120.7, 119.7, 118.4, 87.0, 69.7, 68.4, 67.0, 61.2, 51.5, 50.7, 44.0; HRMS (ESI) calcd for C42H41BrN3O5S [M + H]+: 778.1950, found: 778.1960.

This product (22.3 g, 28.60 mmol, 1.0 equiv) was then reacted with Grubbs Catalyst I (5.89 g, 7.16 mmol, 0.25 equiv) in benzene (573 mL) to provide product 11d (16.43 g, 76%) as a light brown foamy solid. equation M48 (c 1.11, CHCl3); IR νmax (film): 3055, 3030, 2908, 2859, 1543, 1489, 1448, 1348, 1161, 1071; 1H NMR (300 MHz, CDCl3) δ 8.02 (dd, J = 7.1, 1.8 Hz, 1H), 7.73–7.62 (m, 3H), 7.49–7.39 (m, 9H), 7.32–7.19 (m, 8H), 7.07 (d, J = 8.3 Hz, 2H), 5.90–5.81 (m, 1H), 5.69–5.54 (m, 1H), 4.44 (dd, J = 14.6, 7.9 Hz, 1H), 3.96 (dd, J = 14.6, 8.0 Hz, 1H), 3.86 (d, J = 13.9 Hz, 2H), 3.49–3.36 (m, 2H), 3.29–3.18 (m, 3H), 3.11 (dd, J = 13.5, 10.3 Hz, 1H), 2.97 (dd, J = 6.9, 6.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 148.5, 144.3, 139.4, 133.7, 133.6, 132.0, 131.9, 131.2, 129.4, 129.0, 128.1, 127.4, 125.3, 124.5, 121.0, 87.0, 71.5, 70.6, 67.2, 59.4, 54.7, 44.8, 42.5; HRMS (ESI) calcd for C40H37BrN3O5S [M + H]+: 750.1637, found: 750.1635.

((8R,9R,10S)-9-(4-Bromophenyl)-6-((2-nitrophenyl)sulfonyl)-1,6-diazabicyclo[6.2.0] decan-10-yl) methanol 12a

Compound 11a (10.0 g, 13.3 mmol, 1.0 equiv) was dissolved in CH2Cl2 (133 mL) and cooled to 0 °C. Trifluoroacetic acid (10.3 mL, 133 mmol, 10.0 equiv) was added dropwise, and the reaction was stirred for 1–2 h. Analysis of the reaction by LCMS indicated complete disappearance of the starting material, and the formation of a new product. The reaction mixture was quenched with a saturated solution of NaHCO3 and extracted three times with EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The resulting material was purified by chromatography on silica gel using hexanes/EtOAc to provide the primary alcohol (5.8 g, 86%).

To a solution of the alcohol described above (5 g, 9.84 mmol, 1.0 equiv) and triethylamine (5.5 mL, 39.3 mmol, 4.0 equiv) in dry THF (98 mL) was added 2-nitrobenzenesulfonylhydrazide (NBSH) (6.4 g, 29.5 mmol, 3.0 equiv) was added, and the reaction was heated at 40 °C for 6 h. The reaction mixture was quenched with a saturated solution of NaHCO3 and extracted three times with diethyl ether. The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to provide the crude product, which was purified by chromatography on silica gel using hexanes/EtOAc to provide pure 12a (4.0 g, 80%). equation M49 (c 0.255, CHCl3); IR νmax (film): 3380, 2937, 1541, 1372, 1340, 1160; 1H NMR (300 MHz, CDCl3) δ 7.77 (dd, J = 7.0, 2.0 Hz, 1H), 7.68–7.51 (m, 3H), 7.42 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 3.83 (ddd, J = 14.5, 10.5, 4.7 Hz, 1H), 3.72–3.64 (m, 2H), 3.58–3.48 (m, 3H), 3.24 (d, J = 13.8 Hz, 1H), 3.12–2.99 (m, 2H), 2.91 (dd, J = 14.5, 9.7 Hz, 1H), 2.60–2.39 (br m, 1H), 1.97–1.75 (m, 3H), 1.63 (br m, 2H); 13C NMR (75 MHz, CDCl3) δ 148.2, 133.3, 132.3, 131.6, 131.3, 130.2, 128.3, 124.1, 121.1, 68.2, 65.9, 60.9, 58.0, 55.1, 50.7, 42.1, 28.1, 25.4; HRMS (ESI) calcd for C21H25BrN3O5S [M + H]+: 510.0698, found: 510.0705.

((8S,9R,10S)-9-(4-Bromophenyl)-6-((2-nitrophenyl)sulfonyl)-1,6-diazabicyclo[6.2.0] decan-10-yl)methanol 12b

Following the protocol above, compound 11b afforded 3.17 g of 7b (73% over 2 steps) as a light yellow foamy solid. equation M50 (c 0.26, CHCl3); IR νmax (film): 3388, 2927, 1541, 1372, 1340, 1160; 1H NMR (300 MHz, CDCl3) δ 7.90 (dd, J = 6.9, 2.4 Hz, 1H), 7.71–7.56 (m, 3H), 7.47 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.3 Hz, 2H), 4.23 (t, J = 8.4 Hz, 1H), 3.98–3.89 (m, 1H), 3.88–3.80 (m, 2H), 3.75 (dd, J = 12.3, 4.4 Hz, 1H), 3.62 (dd, J = 12.3, 4.4 Hz, 1H), 3.51 (t, J = 8.5 Hz, 1H), 3.25–3.10 (m, 1H), 3.03 (dd, J = 14.3, 9.9 Hz, 1H), 2.96–2.84 (m, 2H), 1.87 (br s, 3H), 1.62 (br s, 2H); 13C NMR (75 MHz, CDCl3) δ 148.3, 135.9, 133.5, 133.2, 132.0, 131.8, 130.7, 129.6, 124.4, 121.0, 67.3, 65.8, 60.4, 55.6, 50.4, 49.4, 41.2, 28.1, 25.6; HRMS (ESI) calcd for C21H25BrN3O5S [M + H]+: 510.0698, found: 510.0691.

((8S,9S,10S)-9-(4-Bromophenyl)-6-((2-nitrophenyl)sulfonyl)-1,6-diazabicyclo[6.2.0] decan-10-yl)methanol 12c

Following the protocol above, 11c afforded 7.60 g of 12c (7.60 g, 76% over 2 steps) as a light yellow foamy solid. equation M51 (c 0.205, CHCl3); IR νmax (film): 3387, 2931, 1541, 1371, 1342, 1160; 1H NMR (300 MHz, CDCl3) δ 7.70 (dd, J = 7.5, 1.5 Hz, 1H), 7.67–7.49 (m, 3H), 7.44 (d, J = 8.3 Hz, 2H), 7.19 (d, J = 8.3 Hz, 2H), 4.11 (dt, J = 10.5, 1.2 Hz, 1H), 3.93–3.61 (m, 5H), 3.15 (d, J = 14.0 Hz, 1H), 3.04 (ddd, J = 14.8, 7.5, 3.8 Hz, 1H), 2.97–2.80 (m, 2H), 2.74 (dd, J = 14.8, 10.4 Hz, 1H), 2.27 (br s, 1H), 1.95–1.69 (m, 3H), 1.69–1.49 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 148.2, 137.1, 133.4, 133.0, 131.8, 131.6, 130.4, 124.3, 120.8, 67.3, 65.2, 61.5, 50.8, 49.1, 47.8, 40.0, 27.5, 25.6; HRMS (ESI) calcd for C21H25BrN3O5S [M + H]+: 510.0698, found: 510.0694.

((8R,9S,10S)-9-(4-Bromophenyl)-6-((2-nitrophenyl)sulfonyl)-1,6-diazabicyclo[6.2.0] decan-10-yl)methanol 12d

Following the protocol above, 11d afforded 7.43 g of 12d (7.43 g, 65% over 2 steps) as a light yellow foamy solid. equation M52 (c 0.185, CHCl3); IR νmax (film): 3426, 2931, 1542, 1373, 1340, 1160; 1H NMR (300 MHz, CDCl3) δ 7.92 (dd, 6.6, J = 2.5 Hz, 1H), 7.76–7.56 (m, 3H), 7.45 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 3.87–3.76 (m, 2H), 3.67–3.58 (m, 2H), 3.44 (d, J = 12.0 Hz, 1H), 3.36–3.26 (m, 1H), 3.18–3.16 (m, 2H), 2.97–2.89 (m, 2H), 2.64–2.60 (m, 2H), 2.05–1.92 (m, 2H), 1.74–1.59 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 148.6, 139.0, 133.8, 133.2, 132.1, 131.9, 131.0, 129.4, 128.7, 124.6, 121.2, 73.3, 67.5, 60.8, 56.3, 55.9, 50.6, 40.2, 28.4, 24.1; HRMS (ESI) calcd for C21H25BrN3O5S [M + H]+: 510.0698, found: 510.0681.

(2S,3S,4R)-1-Allyl-2-(trityloxymethyl)-3-para-bromophenyl-4-cyano-4-(tosyloxymethyl) azetidine 13a

To a freshly prepared solution of LiTMP (0.4 M in THF, 270.0 mL, 109.0 mmol, 3.0 eq) was added dropwise at −78 °C via addition funnel and over 30 to 40 min, a solution of azetidine 5a (20.0 g, 36.4 mmol, 1.0 equiv) in dry THF (100 mL). The mixture was stirred for 2 h at −78 °C then solid benzotriazomethanol (BTM) (10.9 g, 72.8 mmol, 2.0 equiv) was added in small portions every 15–20 min, over 1.5 h. The reaction mixture was allowed to warm to room temperature overnight and was quenched with a saturated solution of NH4Cl. The aqueous layer was separated and extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated to afford a crude material that was quickly purified on silica gel using hexanes/EtOAc to afford the desired alcohol (15.7 g, 27.1 mmol, 74.4 % yield) as a colorless foam. Only a single stereoisomer was obtained. equation M53 (c 1.5, CHCl3); mp 74.8–77.56 °C; IR νmax (film): 3483, 2996, 2958, 1412, 1139, 1073, 944; 1H NMR (300 MHz, CDCl3) δ 7.38 (d, J = 8.5 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H), 7.24–7.18 (m, 9H), 7.18–7.12 (m, 6H), 5.74 (ddt, J = 16.7, 10.1, 6.4 Hz, 1H), 5.20 (dd, J = 17.2, 1.3 Hz, 1H), 5.05 (d, J = 10.1 Hz, 1H), 4.15–3.93 (m, 3H), 3.83 (d, J = 8.0 Hz, 1H), 3.52 (dd, J = 13.8, 6.0 Hz, 1H), 3.31–3.14 (m, 2H), 2.98 (dd, J = 9.5, 7.7 Hz, 1H), 2.20 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 143.5, 134.3, 133.4, 131.3, 128.4, 127.9, 127.7, 126.9, 121.9, 118.4, 118.2, 86.6, 66.9, 64.6, 62.8, 61.1, 52.5, 45.0; HRMS (ESI+) calcd for C34H32BrN2O2 [M + H]+: 579.1647, found: 579.1643.

A portion of the primary alcohol described above (3.5 g, 6.0 mmol, 1.0 equiv) was taken up in dry THF (60 mL) and cooled to −78 °C. LiHMDS (1.0 M in THF, 6.6 mL, 6.6 mmol, 1.1 equiv) was added dropwise via an addition funnel. After 40 min, a solution of p-toluenesulfonyl chloride 1.3 g, 6.6 mmol, 1.1 equiv) in dry THF (10 mL) was quickly syringed into the mixture and the temperature was slowly raised to room temperature, allowing for complete conversion of the starting material. The reaction was quenched with sat. NH4Cl solution and the layers were separated. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. Purification on silica gel using hexanes/EtOAc afforded the sulfonate ester 13a (3.8 g, 5.2 mmol, 85.0 % yield). equation M54 (c 1.7, CHCl3); IR νmax (film): 3056, 2930, 2870, 1489, 1369, 1177, 1074, 993; 1H NMR (300 MHz, CDCl3) δ 7.86 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 7.24–7.17 (m, 11H), 7.15–7.09 (m, 6H), 5.66 (ddt, J = 16.7, 10.0, 6.4 Hz, 1H), 5.06 (dd, J = 17.2, 1.3 Hz, 1H), 4.99 (d, J = 11.2 Hz, 1H), 4.42 (s, 2H), 4.01 (app td, J = 7.8, 5.5 Hz, 1H), 3.70 (d, J = 8.0 Hz, 1H), 3.39 (dd, J = 13.7, 6.8 Hz, 1H), 3.21 (dd, J = 13.7, 6.1 Hz, 1H), 3.12 (dd, J = 9.6, 5.4 Hz, 1H), 2.87 (dd, J = 9.5, 7.9 Hz, 1H), 2.47 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 145.8, 143.4, 133.7, 132.4, 131.8, 131.4, 131.3, 130.1, 128.3, 128.1, 127.7, 126.9, 122.3, 118.8, 116.5, 86.6, 67.7, 64.4, 63.8, 61.2, 52.8, 46.0, 21.7; HRMS (ESI+) calcd for C41H38BrN2O4S [M + H]+: 733.1736, found: 733.1730.

(2R,3R,4S)-1-Allyl-2-(trityloxymethyl)-3-para-bromophenyl-4-cyano-4-(tosyloxymethyl) azetidine ent-13a

Following the above protocol, 8.3 g of ent-5a afforded 8.8 g of ent-13a (84%). equation M55 (c 1.3, CHCl3).

((2S,3S)-1-Allyl-3-(4-bromophenyl)-6-((2-nitrophenyl)sulfonyl)-1,6-diazaspiro[3.3]heptan-2-yl)methanol 14a

A 250 mL round bottom flask was charged with a solution of nitrile 13a (3.0 g, 4.1 mmol, 1.0 equiv) in dry CH2Cl2 (41 mL). At −78 °C, neat DIBAL (3.7 mL, 20.5 mmol, 5.0 equiv) was added dropwise to the mixture via syringe. The reaction was kept at this temperature until complete conversion of the starting material (30 to 45 min, LCMS analysis). A careful addition of dry MeOH (5 mL) was done in order to quench the reaction mixture, followed by Rochelle’s salts solution (50 mL). The mixture was stirred at room temperature overnight. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to dryness and taken crude to the next step.

The primary amine was then dissolved in dry CH2Cl2 (41 mL) and triethylamine (1.1 mL, 8.2 mmol, 2.0 equiv) was quickly added to the mixture. At 0 °C, nosyl chloride (1.0 g, 4.5 mmol, 1.1 equiv) was added in one portion and the reaction was stirred for three hours at room temperature resulting in partial cyclization of the nosylated amine. The mixture was washed with sat. NaHCO3 solution and the phases were separated. After extraction of the aqueous phase with CH2Cl2, the combined organic layers were dried over MgSO4, filtered and concentrated.

The nosylated material dissolved in acetonitrile (36 mL) and K2CO3 (1.5 g, 10.8 mmol, 3.0 equiv) was added and the mixture was stirred at 50 °C until complete cyclization of the intermediate as judge by LCMS analysis (8 h). Water was then added and the mixture was extracted twice with EtOAc. The combined organic fractions were washed with brine and dried over MgSO4. After filtration and removal of the solvents in vacuo, the crude was purified by chromatography on silica gel using hexanes/EtOAc to afford the spiroazetidine 14a (2.1 g, 2.8 mmol, 68 % yield over three steps) as a slightly yellow foam. equation M56 (c 1.0, CHCl3); IR νmax (film): 3026, 2870, 1544, 1488, 1368, 1169, 1073, 748; 1H NMR (300 MHz, CDCl3) δ 7.97–7.88 (m, 1H), 7.69–7.59 (m, 3H), 7.32 (d, J = 8.4 Hz, 2H), 7.20–7.14 (m, 9H), 7.13–7.08 (m, 6H), 7.06 (d, J = 8.4 Hz, 2H), 5.61 (ddt, J = 16.8, 10.2, 6.5 Hz, 1H), 5.01 (d, J = 17.1 Hz, 1H), 4.80 (d, J = 8.6 Hz, 2H), 4.12 (d, J = 8.9 Hz, 1H), 3.92 (d, J = 9.3 Hz, 1H), 3.75 (d, J = 9.3 Hz, 1H), 3.70 (dd, J = 8.1, 4.7 Hz, 1H), 3.61 (d, J = 7.6 Hz, 1H), 3.27 (dd, J = 13.3, 6.7 Hz, 1H), 3.12 (dd, J = 13.3, 6.3 Hz, 1H), 2.99 (dd, J = 9.3, 4.8 Hz, 1H), 2.71 (app t, J = 8.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 148.3, 143.6, 134.9, 133.6, 131.7, 131.3, 131.2, 130.7, 129.6, 128.3, 127.6, 126.8, 124.1, 121.1, 117.9, 86.2, 64.7, 64.3, 61.1, 60.7, 57.8, 54.2, 49.9; HRMS (ESI+) calcd for C40H37BrN3O5S [M + H]+: 750.1637, found: 750.1654.

(2R,3R)-1-Allyl-2-(trityloxymethyl)-3-para-bromophenyl-6-ortho-nosyl-1,6-diazaspiro[3.3]heptane ent-14a

Following the above protocol, 8.8 g of ent-13a afforded 6.5g of ent-14a (72%). equation M57 (c 1.8, CHCl3).

(2S,3S)-1-Allyl-2-(hydroxymethyl)-3-para-bromophenyl-6-ortho-nosyl-1,6-diazaspiro [3.3]heptane 15a

A solution of spirocycle 14a (4.3 g, 5.7 mmol, 1.0 equiv) in CH2Cl2 (55 mL) was added to a 250 mL round bottom flask. At 0 °C, neat trifluoroacetic acid (6.3 mL, 86.0 mmol, 15.0 equiv) was slowly added via syringe and the mixture was stirred at this temperature for 1 h. MeOH (25 mL) was quickly added followed by a careful addition of K2CO3 (12.0 g, 86.0 mmol, 15.0 equiv). The cold bath was removed and the reaction was left at room temperature for 1 h. The mixture was partitioned between water and CH2Cl2. The organic layer was washed one more time with water, dried over MgSO4, filtered and concentrated and purified by chromatography on silica gel using hexanes/EtOAc to afford 15a (2.0 g, 3.9 mmol) with 69 % yield. equation M58 (c 1.2, CHCl3); IR νmax (film): 3383, 2948, 2870, 1544, 1488, 1369, 1169, 1128, 1011; 1H NMR (300 MHz, CDCl3) δ 7.98–7.90 (m, 1H), 7.72–7.60 (m, 3H), 7.46 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 5.83 (ddt, J = 16.5, 10.0, 6.4 Hz, 1H), 5.21 (dd, J = 17.2, 1.5 Hz, 1H), 5.02 (dd, J = 10.1, 1.4 Hz, 1H), 4.79 (d, J = 8.9 Hz, 1H), 4.12 (d, J = 9.0 Hz, 1H), 3.99 (d, J = 9.4 Hz, 1H), 3.84 (d, J = 9.5 Hz, 1H), 3.61–3.51 (m, 2H), 3.45 (dd, J = 11.7, 4.8 Hz, 1H), 3.41 (dd, J = 14.5, 5.5 Hz, 2H), 3.25 (dd, J = 10.9, 5.1 Hz, 1H), 3.19 (dd, J = 13.7, 6.6 Hz, 1H), 1.16 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 148.3, 135.5, 134.5, 133.7, 131.8, 131.5, 131.4, 131.1, 130.7, 124.1, 121.4, 118.0, 66.4, 64.0, 61.9, 60.5, 57.8, 54.2, 49.5; HRMS (ESI+) calcd for C21H23BrN3O5S [M + H]+: 508.0542, found: 508.0542.

(2R,3R)-1-Allyl-2-(hydroxymethyl)-3-para-bromophenyl-6-ortho-nosyl-1,6-diazaspiro [3.3]heptane ent-15a

Following the protocol above, 3.3 g of ent-15a was obtained from 6.5 g of ent-14a (75% over 2 steps). equation M59 (c 1.1, CHCl3).

((3R,6S,7R)-5-Allyl-7-(4-bromophenyl)-1-((2-nitrophenyl)sulfonyl)-1,5-diazaspiro [2.4]heptan-6-yl) methanol 16

Application of the cyclization sequence described above to 13c as starting material (4.7 g, 8.6 mmol) led to the formation of spiropyrrolidino aziridine 16 (358 mg, 0.7 mmol) with 8.2% yield over five steps. [α]D21 +50.5 (c 1.1, CHCl3); mp 82.1–87.0 °C IR νmax (film): 3343, 2921, 2865, 1542, 1367, 1333, 1164; 1H NMR (300 MHz, CDCl3) δ 7.96 – 7.89 (m, 1H), 7.70–7.62 (m, 2H), 7.62–7.56 (m, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 5.90 (dddd, J = 15.3, 10.1, 7.7, 5.2 Hz, 1H), 5.29 (d, J = 16.2 Hz, 1H), 5.19 (d, J = 10.2 Hz, 1H), 3.78 (dd, J = 11.8, 2.6 Hz, 1H), 3.66 – 3.50 (m, 2H), 3.59 (d, J = 7.3 Hz, 1H), 3.36 (m, 2H), 3.10 (s, 1H), 3.03 (dd, J = 13.6, 7.8 Hz, 1H), 2.87 (d, J = 9.0 Hz, 1H), 2.54 (d, J = 9.6 Hz, 1H), 2.43 (s, 1H);13C NMR (75 MHz, CDCl3) δ 148.2, 136.7, 134.2, 134.1, 132.7, 132.0, 131.5, 131.2, 130.8, 124.0, 121.2, 118.4, 72.5, 57.8, 56.6, 56.0, 55.7, 50.7, 42.6; HRMS (ESI+) calcd for C21H23BrN3O5S [M + H]+: 508.0542, found: 508.0551.

(2S,3S,4R)-1-tert-Butyloxycarbonyl-2-(trityloxymethyl)-3-para-bromo-phenyl-4-cyano azetidine 17

A 250 mL round bottom flask was charged with a solution of N-allyl azetidine 5d (4.7 g, 8.9 mmol) in 85 mL of CH2Cl2:EtOH=1:2. N-Methyl barbituric acid (2.0 g, 12.8 mmol, 1.5 equiv) was added in one portion at room temperature, followed by Pd(PPh3)4 (0.5 g, 0.4 mmol, 0.05 equiv). The mixture was stirred at 40 °C for 72 h. The reaction was monitored by LCMS and after completion, the solvents were removed in vacuo and the crude residue was taken in CH2Cl2 (100 mL). The temperature was set to 0 °C and Boc2O (2.8 g, 12.8 mmol, 1.5 equiv) was added. The reaction was stirred at room temperature overnight and was monitored by LCMS. After evaporation of the solvent, the crude was purified on silica gel (hexanes:EtOAc = 85:15) to afford N-Boc azetidine 17 (4.7 g, 7.7 mmol, 90% yield over two steps) as a colorless foam. equation M60 (c 1.0, CHCl3); IR νmax (film): 3056, 2926, 1710, 1367, 1149, 1074, 1010. 1H NMR (300 MHz, CDCl3) δ 7.45–7.34 (m, 8H), 7.28–7.12 (m, 9H), 7.00 (d, J = 8.4 Hz, 2H), 4.57 (d, J = 6.6 Hz, 1H), 4.15 (s, 1H), 3.95 (app t, J = 6.5 Hz, 1H), 3.56 (dd, J = 4.9, 10.4 Hz, 1H), 3.21 (dd, J = 2.8, 10.4 Hz, 1H), 1.40 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 155.3, 143.6, 136.3, 132.2, 128.6, 128.5, 127.9, 127.2, 122.1, 117.4, 86.9, 82.0, 67.3, 63.1, 51.8, 42.3, 28.2; HRMS (ESI+) calcd for C35H33BrN2NaO3 [M + Na]+: 631.1572, found: 631.1574.

(2R,3R,4S)-1-tert-Butyloxycarbonyl-2-(trityloxymethyl)-3-para-bromo-phenyl-4-cyano azetidine ent-17

Following the general protocol described above, 40.0g of N-allyl azetidine ent-5d afforded 42.5 g (96%) of azetidine ent-17. equation M61 (c 1.2, CHCl3).

(2S,3R)-1-tert-Butyloxycarbonyl-2-(trityloxymethyl)-3-para-bromophenyl)-4-cyano-4-(tosyloxymethyl) azetidine 18

To a freshly prepared solution of LDA in anhydrous THF (made at 0 °C using 10.0 mL, 70.2 mmol, 3.0 equiv of DIPA in 50 mL THF and 43.0 mL, 69.9 mmol, 3.0 equiv of n- BuLi 1.6 M in hexanes) was added dropwise at −78 °C via addition funnel and over 30 to 40 minutes, a solution of N-Boc azetidine (14.1 g, 23.1 mmol, 1.0 equiv) in 150 mL dry THF. The mixture was stirred for 2 hours at −78 °C then solid benzotriazomethanol (BTM) was added in small portions every 15–20 min, over 1.5 h. The reaction mixture was stirred overnight and allowed to reach room temperature. The reaction mixture was quenched with a saturated solution of NH4Cl (100 mL) and the aqueous layer was separated and extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated to afford a crude material that was purified on silica gel (hexanes:EtOAc=75:25) to afford alcohol as a mixture of two inseparable diastereomers (10.5 g, 16.4 mmol, 71% yield, colorless foam).

A 500 mL round bottom flask was charged with a solution of alcohol intermediate (10.5 g, 16.4 mmol, 1.0 equiv) in 135 mL dry THF. At −78 °C, LiHMDS (1.0 M in THF, 19.0 mL, 19.0 mmol, 1.2 equiv) was added dropwise via an addition funnel. After 40 min, a solution of p-toluenesulfonyl chloride (TsCl, 3.9 g, 20.5 mmol, 1.3 equiv) in 15 mL dry THF was quickly syringed into the mixture and the temperature was slowly raised to room temperature, allowing for complete conversion of the starting material. The reaction was quenched with sat. NH4Cl solution and the layers were separated. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. Purification on silica gel (hexanes:EtOAc = 75:25) afforded the sulfonate ester 18 (11.4 g, 14.4 mmol, 88% yield). Due to its complexity, no NMR listing is provided for this compound. A copy of the 1H NMR spectrum is provided in the Supporting Information. HRMS (ESI+) calcd for C43H41BrN2NaO6S [M + Na]+: 815.1766, found: 815.1767.

(2R,3S)-1-tert-Butyloxycarbonyl-2-(trityloxymethyl)-3-para-bromophenyl)-4-cyano-4-(tosyloxymethyl) azetidine ent-18

Following the protocol above, 12.6 g (92% yield) of ent-18 was obtained from 11.1 g of ent-17.

(2S,3R)-1-tert-Butyloxycarbonyl-2-(trityloxymethyl)-3-para-bromophenyl-6-ortho-nosyl-1,6-diazaspiro[3.3]heptane 19

A 500 mL round bottom flask was charged with a solution of nitrile 18 (11.3 g, 14.3 mmol, 1.0 equiv) in 140 mL dry CH2Cl2. At −78 °C, neat DIBAL (12.7 mL, 71.5 mmol, 5.0 equiv) was added dropwise to the mixture via syringe. The reaction was kept at this temperature until complete conversion of the starting material (30 to 45 minutes, LCMS analysis). A careful addition of 100 mL dry MeOH was done in order to quench the reaction, followed by 100 mL Rochelle’s salts solution. The mixture was progressively brought to 50 °C and was stirred at this temperature overnight. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to dryness. The crude material was then dissolved in 140 mL dry CH2Cl2 and triethylamine (4.0 mL, 28.5 mmol, 2.0 equiv) was quickly added to the mixture. At 0 °C, nosyl chloride (3.47 g, 15.7 mmol, 1.1 equiv) was added in one portion and the reaction was stirred overnight at room temperature resulting in partial cyclization of the nosylated amine. The mixture was washed with sat. NaHCO3 solution and the phases were separated. After extraction of the aqueous phase with CH2Cl2, the combined organic layers were dried over MgSO4, filtered and concentrated. K2CO3 (4.0 g, 28.6 mmol, 2.0 equiv) was added to the crude material dissolved in acetonitrile (140 mL) and the mixture was stirred at 60 °C until complete cyclization of the intermediate (LCMS, 3 hours). Water was then added and the mixture was extracted twice with EtOAc. The combined organic fractions were washed with brine and dried over MgSO4. After filtration and removal of the solvents in vacuo, the crude was purified on silica gel (hexanes:EtOAc = 70:30) to afford the spiroazetidine 19 (5.9 g, 7.3 mmol, 51% yield over three steps) as a slightly yellow foam. equation M62 (c 1.2, CHCl3); IR νmax (film): 3056, 3021, 2974, 2930, 2870, 1698, 1544, 1367, 1164, 1074; 1H NMR (300 MHz, CDCl3) δ 7.95 (br s, 1H), 7.66 (s, 3H), 7.49–7.35 (m, 7H), 7.35–7.19 (m, 10H), 6.97 (d, J = 8.3 Hz, 2H), 4.92 (d, J = 8.8 Hz, 1H), 4.48 (br s, 1H), 4.18 (d, J = 8.9 Hz, 1H), 4.17 (br s, 1H), 3.81 (br s, 1H), 3.57 (br s, 1H), 3.49 (br d, J = 4.3 Hz, 2H), 3.15 (br d, J = 8.2 Hz, 1H), 1.57 – 1.21 (m, 9H); 13C NMR (75 MHz, CDCl3) δ 153.6, 148.2, 143.6, 135.7, 133.5, 132.1, 131.8, 129.7, 128.6, 127.9, 127.2, 124.2, 121.7, 86.9, 81.3, 64.0, 63.1, 61.5, 57.2, 47.1, 28.4; HRMS (ESI+) calcd for C42H40BrN3NaO7S [M + Na]+: 832.1668, found: 832.1669.

(2R,3S)-1-tert-Butyloxycarbonyl-2-(trityloxymethyl)-3-para-bromophenyl-6-ortho-nosyl-1,6-diazaspiro[3.3]heptane ent-19

Following the above protocol, 2.1 g of ent-19 was obtained from 3.3 g of ent-18 (61% yield). equation M63 (c 1.2, CHCl3).

(2S,3R)-1-Allyl-2-(hydroxymethyl)-3-para-bromophenyl-6-ortho-nosyl-1,6-diazaspiro [3.3]heptane 15c

A solution of trityl ether 19 (5.9 g, 7.3 mmol, 1.0 equiv) in 73 mL of CH2Cl2 was added to a 250 mL round bottom flask. At 0 °C, trifluoroacetic acid was slowly added via syringe and the mixture was stirred at this temperature for 1 h. The cold bath was then removed and the reaction was left overnight at room temperature. 36 mL of MeOH was quickly added followed by a careful addition of K2CO3 (30.2 g, 219.0 mmol, 30.0 equiv). After 1 h, the mixture was partitioned between water and CH2Cl2. The organic layer was washed one more time with water, dried over MgSO4, filtered and concentrated. The crude material was dissolved in acetonitrile (60 mL) and K2CO3 (1.5 g, 10.9 mmol, 1.5 equiv) was added, followed by allyl bromide (0.8 mL, 8.7 mmol, 1.2 equiv). The mixture was stirred at 80 °C using sealed tube conditions until complete disappearance of the starting material (3 h, monitored by LCMS). The mixture was partitioned between water and EtOAc and the organic layer was dried over MgSO4, filtered, concentrated and purified on silica gel (hexanes:EtOAc = 20:80) to afford N-allylated spiroazetidine 15c as a colorless foam (1.9 g, 3.6 mmol, 50% yield over two steps). equation M64 (c 1.3, CHCl3); IR νmax (film): 3396, 2922, 2848, 1543, 1370, 1171, 1010; 1H NMR (300 MHz, CDCl3) δ 7.87 (d, J = 7.5 Hz, 1H), 7.76–7.58 (m, 3H), 7.40 (d, J = 8.3 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 5.80 (ddt, J = 16.8, 10.0, 6.6 Hz, 1H), 5.22 (d, J = 17.1 Hz, 1H), 5.06 (d, J = 10.0 Hz, 1H), 4.34 (d, J = 9.3 Hz, 1H), 4.22 (d, J = 9.4 Hz, 1H), 4.12 (d, J = 9.4 Hz, 1H), 3.71–3.59 (m, 2H), 3.54 (d, J = 9.3 Hz, 1H), 3.51 – 3.42 (m, 2H), 3.39 (dd, J = 13.6, 6.6 Hz, 1H), 3.18 (dd, J = 13.4, 6.8 Hz 1H), 2.39 (br d, J = 7.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 148.4, 134.9, 134.5, 133.8, 132.0, 131.7, 131.0, 130.8, 129.6, 124.2, 121.4, 118.7, 66.1, 64.8, 63.6, 61.2, 53.0, 52.9, 45.1; HRMS (ESI+) calcd for C21H23BrN3O5S [M + H]+: 508.0542, found: 508.0542.

(2R,3S)-1-Allyl-2-(hydroxymethyl)-3-para-bromophenyl-6-ortho-nosyl-1,6-diazaspiro [3.3]heptane ent-15c

Following the above protocol, 2.4 g of ent-15c was obtained starting from 7.4 g of ent-19 (52% over 2 steps). equation M65 (c 1.0, CHCl3).

(2S,3R,4R)-1-Allyl-3-(2-bromophenyl)-4-carbonitrile-2-((trityloxy)methyl) azetidine 21a and (2S,3R,4S)-1-allyl-3-(2-bromophenyl)-4-carbonitrile-2-((trityloxy)methyl) azetidine 21b

Compound 20a (41.6 g, 146 mmol, 1 equiv) was treated with trityl chloride (60.9 g, 218 mmol, 1.5 equiv), triethylamine (60.9 mL, 437 mmol, 3.0 equiv) in CH2Cl2 (1450 mL). The reaction mixture was quenched with water extracts were dried over MgSO4, filtered and concentrated under reduced pressure to provide the crude product. The reaction provided, after purification, 70 g (91%) of trityl-20a. equation M66 (c 1.9, CHCl3); IR νmax (film): 3060, 3021, 1489, 1460, 1448, 1281, 1071, 1031, 753; 1H NMR (300 MHz, CDCl3) δ 7.67–7.43 (m, 8H), 7.31 (dq, J = 6.8, 14.0 Hz, 10H), 7.15 (dd, J = 4.5, 10.7 Hz, 1H), 5.82 (ddt, J = 6.0, 10.5, 16.6 Hz, 1H), 5.12–4.98 (m, 2H), 4.89 (d, J = 3.3 Hz, 1H), 3.62–3.44 (m, 1H), 3.24 (m, 2H), 3.11–2.89 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 148.6, 147.1, 143.9, 142.3, 136.6, 132.8, 128.8, 128.8, 128.3, 128.2, 128.0, 127.9, 127.4, 127.2, 126.7, 122.5, 116.2, 87.1, 70.9, 63.6, 61.5, 51.2; HRMS (ESI+) calcd for C31H30BrNO2 [M + H]+: 528.1538, found: 528.1543.

Nitrile-20a

The secondary amine (70 g, 132 mmol, 1 equiv) obtained above was treated with 2-bromoacetonitrile (27.7 g, 397 mmol, 3 equiv), potassium carbonate (27.5 g, 199 mmol, 1.5 equiv) in acetonitrile (1325 mL). Solvent was removed in vacuo and the resulting material was purified directly over silica gel to afford 67 g (89%) of pure product. equation M67 (c 0.9, CHCl3); IR νmax (film): 3472, 3059, 2359, 2342, 1490, 1448, 1219, 1073, 1032, 772; 1H NMR (300 MHz, CDCl3) δ 7.58 (d, J = 7.8 Hz, 1H), 7.50–7.05 (m, 18H), 5.83–5.55 (m, 1H), 5.32–5.12 (m, 2H), 4.92 (d, J = 7.2 Hz, 1H), 3.86–3.69 (m, 2H), 3.68 (m, 1H), 3.44 (m, 2H), 3.30 (m, 2H), 3.14 (dd, J = 7.6, 13.8 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 143.6, 140.5, 134.5, 132.6, 129.3, 129.1, 128.6, 128.0, 127.9, 127.3, 123.2, 119.6, 87.9, 70.4, 67.6, 60.6, 54.5, 40.3 ppm; HRMS (ESI+) calcd for C33H31BrN2O2 [M +Na]+: 589.1467, found: 589.1467

Chloride-20a

The resulting benzyl alcohol (nitrile-20a) (20 g, 35.2 mmol, 1 equiv) was treated with thionyl chloride (5.13 g, 70 mmol, 2 equiv), pyridine (14.25 mL, 176 mmol, 5 equiv) in CH2Cl2 (352 mL). The reaction mixture was carefully quenched with aqueous sodium bicarbonate solution and the extracts were dried over MgSO4, filtered and concentrated under reduced pressure to provide the crude product. The reaction provided, after purification, 15 g (73%) of Chloride-20a. equation M68 (c 1.8, CHCl3); IR νmax (film): 3060, 3022, 2882, 2359, 2342, 1490, 1468, 1448, 1219, 1154, 1072, 763, 747; 1H NMR (300 MHz, CDCl3) δ 7.67 (dd, J = 1.4, 7.9 Hz, 1H), 7.56 (dd, J = 0.9, 8.0 Hz, 1H), 7.51 – 7.42 (m, 6H), 7.40 – 7.09 (m, 11H), 5.76 (d, J = 4.9 Hz, 1H), 5.44 (dddd, J = 5.5, 7.5, 9.7, 15.2 Hz, 1H), 5.25 – 5.02 (m, 2H), 3.80 – 3.57 (m, 2H), 3.57 – 3.31 (m, 4H), 3.14 (dd, J = 7.5, 13.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 143.6, 138.1, 134.6, 132.7, 131.1, 129.8, 128.8, 128.1, 127.6, 127.3, 122.7, 119.0, 117.4, 87.7, 64.5, 62.6, 61.5, 55.8, 40.4; HRMS (ESI+) calcd for C33H30BrClN2O [M + Na]+: 607.1122, found: 607.1122.

Chloride-20a

(25 g, 43 mmol, 1 equiv) was treated with LiHMDS (55.5 mL, 55 mmol, 1.3 equiv) in THF (427 mL). The reaction mixture was quenched with aqueous saturated NH4Cl solution and the aqueous layer was extracted three times with EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to provide the crude product. The reaction provided, after purification, 11.5 g (49%) of 21a and 11.5g (49%) of 21b.

21a

equation M69 (c 1.5, CHCl3); IR νmax (film): 3057, 3021, 2866, 2359, 2342, 1489, 1472, 1448, 1220, 1073, 1024, 772, 749; 1H NMR (300 MHz, CDCl3) δ 7.96 (dd, J = 1.3, 7.8 Hz, 1H), 7.61 (d, J = 8.0, 1H), 7.26 (m, 17H), 5.80 (ddt, J = 6.6, 10.0, 16.6 Hz, 1H), 5.28 (d, J = 16.6 Hz, 1H), 5.17 (d, J = 10.4 Hz, 1H), 4.65 (t, J = 8.1 Hz, 1H), 4.22 (d, J = 8.2 Hz, 1H), 3.77 (td, J = 5.5, 7.9 Hz, 1H), 3.36 (dd, J = 6.2, 13.0 Hz, 1H), 3.19 (dd, J = 7.1, 12.9 Hz, 1H), 3.06 (dd, J = 5.4, 9.7 Hz, 1H), 3.01–2.86 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 143.8, 133.8, 133.1, 133.0, 131.0, 129.4, 128.7, 128.7, 127.9, 127.4 127.0, 126.0, 119.9, 117.5, 86.7, 77.6, 77.2, 76.8, 66.3, 61.7, 60.8, 54.5, 41.1; HRMS (ESI+) calcd for C33H30BrN2O [M + H]+: 549.1542, found: 549.1548.

21b

[α]D20 + 7.9 (c 0.50, CHCl3); IR νmax (film): 3057, 2864, 1489, 1474, 1448, 1069, 1028; 1H NMR (300 MHz, CDCl3) δ 7.52 (ddd, J = 10.9, 7.9, 1.4 Hz, 2H), 7.25–7.17 (m, 15H), 7.17–7.09 (m, 2H), 5.70 (ddt, J = 10.2, 6.5, 6.1 Hz, 1H), 5.27 (dd, J = 17.2, 1.5 Hz, 1H), 5.13 (dd, J = 10.2, 1.3 Hz, 1H), 4.44 (dd, J = 8.1, 3.5 Hz, 1H), 4.34 (d, J = 3.5 Hz, 1H), 4.13 (dd, J = 13.9, 5.9 Hz, 1H), 3.48–3.27 (m, 2H), 2.97 (dd, J = 10.0, 5.4 Hz, 1H), 2.85 (dd, J = 10.0, 6.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 143.7, 135.7, 133.3, 133.0, 129.2, 128.7, 128.6, 127.8, 127.7, 127.0, 125.4, 118.9, 117.4, 87.0, 66.4, 62.2, 55.6, 55.0, 43.1; HRMS (ESI) calcd for C33H30BrN2O [M + H]+: 549.1542, found: 549.1537.

(2S,3R,4R)-1-Allyl-3-(2-bromophenyl)-4-carbonitrile-2-((trityloxy)methyl) azetidine 21c

Following the protocols described above for the formation of 21a and 21b: 25 g of trityl-20b gave 40.5 g (88%) of trityl protected product. equation M70 (c 0.1, CHCl3); IR νmax (film): 3465, 3065, 2882, 1496, 1443, 904; 1H NMR (300 MHz, CDCl3) δ 7.34 (d, J = 7.8 Hz, 1H), 7.31–7.24 (m, 4H), 7.24–7.09 (m, 12H), 7.04 (t, J = 7.5 Hz, 1H), 6.99–6.89 (m, 1H), 5.91 (ddd, J = 16.1, 10.9, 5.8 Hz, 1H), 5.23 (d, J = 17.2 Hz, 1H), 5.14–5.02 (m, 2H), 4.13 (br s, 1H), 3.41 (dd, J = 14.4, 5.5 Hz, 1H), 3.30 (dd, J = 14.4, 6.1 Hz, 1H), 3.12 (dt, J = 7.0, 3.6 Hz, 1H), 2.99 (qd, J = 9.9, 5.3 Hz, 2H), 2.06 (br s, 1H). 13C NMR (75 MHz, CDCl3) δ 148.8, 143.8, 139.9, 137.1, 132.6, 128.7, 128.6, 128.3, 128.2, 128.08, 128.00, 127.3, 127.2, 126.7, 121.7, 116.2, 87.4, 71.6, 62.6, 59.0, 49.8; HRMS (ESI+) calcd for C31H30BrNO2 [M +H]+: 528.1558, found: 528.1560.

The secondary amine (40 g) described above afforded 37 g (86%) of nitrile-20b. equation M71 (c 0.1, CHCl3); IR νmax (film): 3465, 3065, 2883, 1496, 1443, 904; 1H NMR (300 MHz, CDCl3) δ 7.49 (d, J = 7.7 Hz, 1H), 7.36 (d, J = 7.1 Hz, 6H), 7.32 - 7.20 (m, 9H), 7.21–7.03 (m, 2H), 5.70 (dt, J = 17.0, 8.4 Hz, 1H), 5.30 (d, J = 17.2 Hz, 2H), 5.20 (d, J = 10.5 Hz, 1H), 3.76 (d, J = 17.2 Hz, 1H), 3.63 (d, J = 17.5 Hz, 1H), 3.54–3.40 (m, 3H), 3.30–3.17 (m, 2H), 2.91 (d, J = 4.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 143.6, 140.7, 135.0, 132.9, 129.2, 128.8, 128.5, 128.1, 127.6, 127.3, 122.2, 119.1, 117.4, 87.9, 73.3, 64.5, 60.8, 55.3, 39.6; HRMS (ESI+) calcd for C33H31BrN2O2 [M +Na]+: 589.1467, found: 589.1471.

The tertiary amine (18.5 g) described above afforded 12.5 g (65%) of chloride-20b. IR νmax (film): 3065, 2913, 1491, 1443, 1065; 1H NMR (300 MHz, CDCl3) δ 7.42 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 7.7 Hz, 6H), 7.26–7.10 (m, 9H), 7.04 (t, J = 7.3 Hz, 1H), 5.46 (d, J = 8.8 Hz, 1H), 5.28–5.09 (m, 1H), 4.94–4.77 (m, 2H), 3.69 (dd, J = 10.7, 2.0 Hz, 1H), 3.53 (dd, J = 10.6, 6.8 Hz, 1H), 3.44–3.36 (m, 1H), 3.34 (s, 2H), 3.18 (dd, J = 14.2, 5.0 Hz, 1H), 2.73 (dd, J = 14.2, 7.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 143.6, 139.0, 134.7, 132.8, 130.0, 129.8, 128.9, 128.1, 128.0, 127.4, 123.8, 118.7, 117.1, 87.9, 66.3, 60.4, 59.5, 54.1, 40.0; HRMS (ESI+) calcd for C33H30BrClN2O [M + Na]+: 607.1122, found: 607.1108.

A solution of the above chloride-20b (17 g, 29.00 mmol, 1 equiv) in THF (290 mL) was cooled to −78°C. To this mixture was addeda cooled solution of LiHMDS (1M in THF 43.5 mL, 43.5 mmol, 1.5 equiv) via cannula. The reaction mixture was stirred for 1 h and quenched with aqueous saturated NH4Cl solution and the aqueous layer was extracted three times with EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to provide the crude product. The reaction provided, after purification, 13 g (82%) of 21c and 0.110 g (~1%) of 21d.

21c

equation M72 (c 0.1, CHCl3); IR νmax (film): 3035, 2861, 1487, 1452, 1217; 1H NMR (300 MHz, CDCl3) δ 7.55 (d, J = 7.7 Hz, 1H), 7.39 (d, J = 7.8 Hz, 5H), 7.21 (m, 12H), 5.74 (m, 1H), 5.32 (d, J = 17.1 Hz, 1H), 5.15 (d, J = 10.1 Hz, 1H), 4.84 (d, J = 6.3 Hz, 1H), 3.95 (m, 2H), 3.54 (m, 1H), 3.32 (ddd, J = 6.2, 12.2, 18.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 143.9, 135.7, 133.3, 133.1, 129.6, 129.5, 128.9, 128.2, 128.1, 127.8, 127.4, 119.2, 115.5, 87.3, 66.8, 66.4, 57.2, 56.0, 43.5; HRMS (ESI+) calcd for C33H29BrN2NaO [M +Na]+: 571.1361, found: 571.1369.

21d

[α]D20 + 1.6 (c 0.63, CHCl3). IR (cm−1) 3057, 2866, 1489, 1473, 1447, 1072, 1025; 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J = 7.8 Hz, 1H), 7.45 (dd, J = 8.2, 1.4 Hz, 6H), 7.38 – 7.21 (m, 11H), 7.21–7.11 (m, 1H), 5.92 (dddd, J = 15.8, 10.1, 7.4, 5.7 Hz, 1H), 5.35 (dd, J = 17.1, 1.2 Hz, 1H), 5.25 (d, J = 10.1 Hz, 1H), 4.21 (t, J = 8.1 Hz, 1H), 3.66–3.52 (m, 3H), 3.41 (dd, J = 10.0, 5.4 Hz, 1H), 3.33 (dd, J = 10.0, 5.0 Hz, 1H), 3.21 (dd, J = 13.1, 7.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 143.9, 136.9, 133.5, 133.0, 129.3, 128.8, 128.7, 128.0, 127.7, 127.2, 124.8, 119.8, 119.5, 87.0, 68.2, 66.6, 60.6, 55.4, 44.2; HRMS (ESI) calcd for C33H29BrN2NaO [M + Na]+: 571.1361, found: 571.1350.

N-(((2S,3R,4R)-1-Allyl-3-(2-bromophenyl)-4-((trityloxy)methyl)azetidin-2-yl)methyl)-2-nitrobenzenesulfonamide 22a

Nitrile azetidine 21a (13 g, 24 mmol, 1 equiv) was treated with diisobutylaluminium hydride (25 mL, 142 mmol, 6 equiv) in CH2Cl2 (240 mL). The reaction was quenched with MeOH (5.74 mL, 6 equiv). After aqueous extraction, the crude amine (13 g, 23.5 mmol) was treated with 2-nitrobenzene-1-sulfonyl chloride (5.4g, 23.5 mmol, 1 equiv) and triethylamine (3.9 mL, 30.5 mmol, 1.3 equiv). The reaction mixture was quenched with aqueous saturated NH4Cl solution and the aqueous layer was extracted three times with EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to provide the crude product. The reaction, after purification, provided 11.7 g (68%) of pure product 22a. equation M73 (c 1.0, CHCl3); IR νmax (film): 3058, 3021, 2930, 2860, 1540, 1448, 1348, 1169, 1072, 1023, 759; 1H NMR (500 MHz, CDCl3) δ 7.90 (dd, J = 1.7, 7.4 Hz, 1H), 7.80 (dd, J = 1.7, 7.4 Hz, 1H), 7.70–7.60 (m, 2H), 7.58 (dd, J = 1.6, 7.6 Hz, 1H), 7.54 (dd, J = 1.3, 7.8 Hz, 1H), 7.21 (m, 15H), 7.00 (tdd, J = 4.5, 10.5, 14.9 Hz, 2H), 5.82–5.64 (m, 1H), 5.22 (d, J = 17.1 Hz, 1H), 5.06 (d, J = 9.5 Hz, 2H), 4.45 (t, J = 7.9 Hz, 1H), 3.70 (td, J = 5.4, 8.0 Hz, 1H), 3.60 (td, J = 5.6, 7.9 Hz, 1H), 3.35–3.19 (m, 2H), 3.18–3.05 (m, 2H), 3.00 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 147.7, 143.9, 135.4, 134.8, 133.6, 133.4, 133.4, 132.9, 131.4, 130.9, 128.6, 128.4, 127.7, 126.9, 126.7, 126.3, 125.6, 118.4, 86.3, 65.8, 65.7, 61.5, 61.2, 43.3, 40.8; HRMS (ESI+) calcd for C39H36BrN3O5S [M + H]+: 738.1637, found: 738.1635.

N-(((2R,3R,4R)-1-Allyl-3-(2-bromophenyl)-4-((trityloxy)methyl)azetidin-2-yl)methyl)-2-nitrobenzenesulfonamide 22c

Following the above protocol, 5.2 g of nitrile azetidine 21c afforded 5.5 g (79%) of nosyl amine 22c. equation M74 (c 0.1, CHCl3); IR νmax (film): 3334, 3038, 2887, 1534, 1336, 1169; 13C NMR (126 MHz, CDCl3) δ 148.1, 143.9, 137.1, 136.1, 133.8, 133.4, 133.0, 132.7, 131.1, 129.5, 128.9, 128.8, 128.0, 127.8, 127.2, 126.6, 125.4, 116.9, 87.2, 64.7, 64.6, 63.6, 52.9, 42.7, 42.4; HRMS (ESI+) calcd for C39H36BrN3O5S [M + H]+ 738.1637, found: 738.1614.

(1S,2aR,8bR)-2-Allyl-4-((2-nitrophenyl)sulfonyl)-1-((trityloxy)methyl)-1,2,2a,3,4,8b-hexahydroazeto[2,3-c]quinolone 23a

To a solution of nosyl amine 22a (11.7 g, 15.9 mmol, 1 equiv) in degassed toluene (160 mL) was added N,N dimethylethane-1,2-diamine (0.34 mL, 3.2 mmol, 0.2 equiv), cesium carbonate (7.7 g, 23.9 mmol, 1.5 equiv) and copper (I) iodide (0.3 g, 1.6 mmol, 0.1 equiv). The reaction was heated at 100 °C for 2h. The reaction was then cooled down and the solution was then filtered through a pad of silica gel. The solvent was removed under vacuum to afford 10.4 g (99%) of the desired product 23a: equation M75, (c 1.46, CHCl3); mp 96.1–100.7 °C; IR νmax (film): 3060, 3022, 2871, 1542, 1489, 1448, 1369, 1219, 1165, 1068, 761; 1H NMR (500 MHz, CDCl3, 60 °C) δ 8.02 (d, J = 8.0 Hz, 1H), 7.62–7.51 (m, 2H), 7.39–7.15 (m, 17H), 7.16–7.05 (m, 2H), 6.99 (t, J = 7.4 Hz, 1H), 5.60 (ddt, J = 6.8, 9.8, 16.8 Hz, 1H), 5.13 (d, J = 17.0 Hz, 1H), 4.99 (d, J = 10.1 Hz, 1H), 4.31 (dd, J = 2.1, 14.4 Hz, 1H), 3.77–3.58 (m, 3H), 3.17 (m, 2H), 3.08 (dd, J = 1.2, 14.4 Hz, 1H), 2.83 (dd, J = 4.2, 9.9 Hz, 1H), 2.64 (t, J = 9.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 144.5, 138.2, 136.0, 135.1, 133.1, 132.2, 131.6, 131.0, 129.3, 128.9, 128.8, 128.5, 127.8, 127.1, 127.0, 125.5, 125.5, 124.1, 123.1, 117.9, 95.2, 87.1, 66.1, 64.1, 61.8, 59.6, 48.6, 34.4; HRMS (ESI+) calcd for C39H35N3O5S [M + H]+: 658.2376, found: 658.2371.

(1R,2aR,8bR)-2-Allyl-4-((2-nitrophenyl)sulfonyl)-1-((trityloxy)methyl)-1,2,2a,3,4,8b-hexahydroazeto[2,3-c]quinolone 23c

Following the above protocol, 7.0 g of nosyl amine 22c afforded 6.2g g (99%) of 23c. equation M76 (c 1.0, CHCl3), IR νmax (film): 3010, 2891, 1539, 1365, 1209, 1156, 904; 1H NMR (300 MHz, CDCl3) δ 7.92 (d, J = 7.4 Hz, 1H), 7.69–7.54 (m, 3H), 7.43 (d, J = 7.4 Hz, 4H), 7.34–7.19 (m, 12H), 7.19–6.97 (m, 3H), 5.67 (dq, J = 11.3, 6.1 Hz, 1H), 5.04 (d, J = 17.2 Hz, 1H), 4.95 (d, J = 9.3 Hz, 1H), 4.13 (dd, J = 13.8, 5.5 Hz, 1H), 4.08 – 3.97 (m, 1H), 3.57 (ddd, J = 15.0, 11.9, 4.3 Hz, 2H), 3.41–3.12 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 148.0, 144.1, 137.3, 135.7, 135.4, 133.7, 131.9, 130.6, 129.5, 128.9, 128.0, 127.3, 126.4, 124.6, 123.9, 117.0, 87.2, 69.3, 65.1, 60.1, 52.6, 48.3, 35.5; HRMS (ESI+) calcd for C39H35N3O5S [M + H]+: 658.2376, found: 658.2368.

((1S,2aR,8bR)-2-Allyl-4-((2-nitrophenyl)sulfonyl)-1,2,2a,3,4,8b-hexahydroazeto[2,3-c]quinolin-1-yl)methanol 24a

Trityl alcohol 23a (0.120g, 0.162 mmol, 1 equiv) was treated with trifluoroacetic acid (0.10 mL, 1.30 mmol, 8 equiv) in CH2Cl2 (2 mL) at 0 °C and allowed to warm to room temperature and stir for 1 h. The reaction mixture was quenched with a saturated sodium bicarbonate solution and the aqueous layer was extracted three times with EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to provide the crude product. The reaction provided, after purification, 0.405 g (50%) of pure product 24a. equation M77 (c 1.7, CHCl3); IR νmax (film): 3417, 2922, 2857, 1541, 1498, 1350, 1161, 1130, 1027, 770; 1H NMR (300 MHz, CDCl3) δ 8.28–8.15 (m, 1H), 7.73 (m, 3H), 7.14–6.96 (m, 3H), 6.79 (d, J = 7.9 Hz, 1H), 5.95 (ddt, J = 6.8, 10.1, 16.8 Hz, 1H), 5.21 (d, J = 17.1 Hz, 1H), 5.09 (d, J = 10.1 Hz, 1H), 4.33 (dd, J = 1.9, 14.5 Hz, 1H), 3.72 (d, J = 7.2 Hz, 1H), 3.66–3.51 (m, 2H), 3.45–3.18 (m, 4H), 3.01 (d, J = 14.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 148.0, 137.9, 137.1, 135.7, 133.8, 132.5, 131.1, 131.0, 130.1, 127.2, 126.2, 124.8, 122.9, 118.0, 67.8, 62.2, 61.3, 59.3, 48.6, 34.2; HRMS (ESI+) calcd C20H21N3O5S [M + H]+: 416.1280, found: 416.1281.

((1R,2aR,8bR)-2-Allyl-4-((2-nitrophenyl)sulfonyl)-1,2,2a,3,4,8b-hexahydroazeto[2,3-c]quinolin-1-yl)methanol 24c

Following the protocol above, 0.500 g of 23c afforded 0.160 g (50%) of 24c. equation M78 (c 1.7, CHCl3); IR νmax (film): 3417, 2922, 2857, 1541, 1498, 1350, 1161, 1130, 1027, 770; 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 3.9 Hz, 2H), 7.74–7.63 (m, 1H), 7.45 (d, J = 7.2 Hz, 1H), 7.35–7.21 (m, 1H), 7.15 (s, 2H), 5.84 (qd, J = 11.6, 6.0 Hz, 1H), 5.31 (d, J = 16.7 Hz, 1H), 5.16 (d, J = 10.2 Hz, 1H), 4.39 (dd, J = 14.4, 5.0 Hz, 1H), 4.14 (s, 1H), 3.82–3.45 (m, 6H), 3.42–3.22 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 148.1, 144.1, 137.6, 135.2, 134.1, 132.4, 130.2, 128.9, 128.0, 127.6, 126.6, 125.0, 123.1, 118.3, 72.5, 61.1, 60.4, 51.5, 47.1, 33.3. HRMS (ESI+) calcd for C20H21N3O5S [M + H]+: 416.1280, found: 416.1281.

(1S,2aR,8bR)-2-Allyl-2,2a,3,8b-tetrahydro-1H-chromeno[3,4-b]azete-1-carbonitrile 25a

To a solution of o-bromonitrile azetidine 21a (500 mg, 0.91 mmol, 1.0 equiv) in CH2Cl2 (9.1 mL) at room temperature was added trifluoroacetic acid (0.5 mL, 6.5 mmol, 7.0 equiv) followed by triethylsilane (150 mL, 0.96 mmol, 1.05 equiv). The reaction was stirred for 15 min, after which analysis of the reaction by TLC and LC/MS showed that complete consumption of starting material had occurred. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by chromatography on silica gel using hexanes/EtOAc, which provided 204 mg (73%) of pure product that was used in the next reaction without further characterization.

To a flask containing palladium acetate (4.5 mg, 0.020 mmol, 0.03 equiv), 1,1’-binaphthyl-2-yldi-tert-butylphosphine (12 mg, 0.030 mmol, 0.045 equiv), and cesium carbonate (325 mg, 0.995 mmol, 1.5 equiv) was added a solution of the pure alcohol from the previous step (204 mg, 0.684 mmol, 1.0 equiv) in toluene (2.2 mL) at room temperature. The reaction was heated to 55 °C, and stirred for 16 h. Analysis of the reaction showed complete consumption of starting material, and conversion to the desired product. The reaction was diluted with CH2Cl2 and filtered through Celite. The filtrate was concentrated, and the resulting yellow residue was purified by chromatography on silica gel using hexanes/EtOAc, which provided the pure aryl ether. Enantiomer rotation [α]D20 +130.0 (c 0.24, CHCl3); IR νmax (film): 2975, 2894, 1491, 1463, 1333, 1259, 1225, 1201, 1093; 1H NMR (300 MHz, CDCl3) δ 7.29–7.20 (m, 1H), 7.09 (d, J = 8.1, 2.1 Hz, 1H), 7.03 (ddd, J = 7.4, 5.6, 1.2 Hz, 2H), 5.89 (ddt, J = 16.8, 10.1, 6.6 Hz, 1H), 5.32 (dd, J = 17.1, 1.4 Hz, 1H), 5.24 (d, J = 10.1 Hz, 1H), 4.22–4.10 (m, 2H), 3.83–3.67 (m, 2H), 3.62 (dd, J = 12.6, 1.3 Hz, 1H), 3.43–3.24 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 155.1, 133.0, 130.7, 129.1, 122.2, 120.0, 119.7, 118.3, 117.0, 65.4, 62.2, 59.5, 55.8, 31.8; HRMS (ESI) calcd for C14H15N2O [M + H]+: 227.1184. Found: 227.1178.

To a solution of the aryl ether (42 mg, 0.186 mmol, 1.0 equiv) in CH2Cl2 (1.9 mL) at 0 °C was added diisobutylaluminum hydride (0.198 mL, 1.11 mmol, 6.0 equiv). The reaction was stirred for 1 h, after which TLC showed complete consumption of starting material. The reaction was quenched with MeOH and stirred until bubbling stopped. Then a saturated solution of Rochelle’s Salt was added (25 mL), and the mixture was vigorously stirred for about 90 min until the aqueous and organic layers had clearly separated. The layers were then separated, and the aqueous layer was extracted once with CH2Cl2 (15 mL). The combined organic layers were dried, filtered, and concentrated in vacuo, and the crude material (32 mg, 75%) was used in the next step without further purification.

The crude residue was then redissolved in CH2Cl2 (1.4 mL) at 0 °C, and then triethylamine (39 mL, 0.28 mmol, 2.0 equiv), and 2-nitrobenzenesulfonyl chloride (32 mg, 0.15 mmol, 1.05 equiv) were added. The reaction was stirred until all starting material had been consumed (~60 min) as determined by LC/MS. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by chromatography on silica gel using hexanes/EtOAc, which provided 25a as a clear oil. Enantiomer rotation equation M79 (c 0.195, CHCl3). IR νmax (film): 3319, 2869, 1539, 1488, 1348, 1167; 1H NMR (300 MHz, CDCl3) δ 7.92 (dd, J = 6.9, 1.8 Hz, 1H), 7.81 (dd, J = 7.8, 2.4, 1H), 7.75–7.57 (m, 2H), 7.15–6.94 (m, 2H), 6.94–6.78 (m, 2H), 5.86 (ddt, J = 17.0, 10.9, 6.8 Hz, 1H), 5.36 (br s, 1H), 5.27 (dd, J = 17.1, 1.4 Hz, 1H), 5.16 (d, J = 10.0 Hz, 1H), 4.06 (d, J = 12.2 Hz, 1H), 3.78–3.59 (m, 3H), 3.53 (dd, J = 12.2, 1.3 Hz, 1H), 3.37 (dd, J = 12.7, 6.3 Hz, 1H), 3.24 (d, J = 12.7, 7.2 Hz, 1H), 2.87–2.70 (m, 1H), 2.70–2.53 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 155.9, 148.1, 134.7, 133.7, 133.5, 132.8, 130.9, 130.1, 128.2, 125.4, 122.0, 121.2, 119.1, 118.4, 66.7, 65.2, 61.9, 60.3, 44.9, 31.0; HRMS (ESI) calcd for C20H22N3O5S [M + H]+: 416.1280, found: 416.1278.

(1S,2aR,8bR)-2-Allyl-2,2a,3,8b-tetrahydro-1H-chromeno[3,4-b]azete-1-carbonitrile 25b

o-Bromonitrile azetidine 21b (1.89 g, 3.44 mmol, 1.0 equiv) in CH2Cl2 (69 mL) was reacted with trifluoroacetic acid (2.65 mL, 34.4 mmol, 10 equiv). The reaction was stirred for 15 min, after which analysis of the reaction by TLC and LC/MS showed that complete consumption of starting material had occurred. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by chromatography on silica gel using hexanes/EtOAc, which provided 646 mg (61% yield) of pure product was obtained, and used in the next step without further characterization.

The intermediate alcohol (124 mg, 0.404 mmol, 1.0 equiv) was reacted with palladium acetate (3.90 mg, 0.017 mmol, 4.5 mol%), 1,1’-binaphthyl-2-yldi-tert-butylphosphine (10.5 mg, 0.026 mmol, 6.5 mol%), and cesium carbonate (197 mg, 0.605 mmol, 1.5 equiv) in toluene (3.0 mL) at 55 °C for 16 hours, and then at 70 °C for 3 hours. The filtrate was concentrated, and the resulting yellow residue was purified by chromatography on silica gel using hexanes/EtOAc, which provided the pure aryl ether (62 mg, 68% yield). [α]D20 −125.9 (c 0.28, CHCl3). IR νmax (film): 2861, 2818, 1582, 1489, 1460, 1258, 1229, 1117. 1H NMR (300 MHz, CDCl3) δ 7.30 (dd, J = 14.8, 7.5 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.05 (dd, J = 7.3, 6.0 Hz, 2H), 5.89 (ddt, J = 16.5, 10.3, 6.3 Hz, 1H), 5.42 (d, J = 17.1 Hz, 1H), 5.26 (d, J = 10.1 Hz, 1H), 4.33 (d, J = 12.8 Hz, 1H), 4.10 (d, J = 7.8 Hz, 1H), 3.98 (s,1H), 3.85 (d, J = 7.7 Hz, 1H), 3.70 (d, J = 12.8 Hz, 1H), 3.49 (d, J = 6.2 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 155.0, 133.2, 129.8, 129.0, 122.4, 122.0, 119.4, 118.4, 117.6, 65.6, 63.1, 57.6, 55.4, 34.3. HRMS (ESI) calcd for C14H15N2O [M + H]+: 227.1184. Found: 227.1185.

The cyclized product (50 mg, 0.221 mmol, 1.0 equiv) was reacted with diisobutylaluminum hydride (0.28 mL, 1.571 mmol, 7.0 equiv) in CH2Cl2 (2.2 mL) at 0 °C. The reaction was stirred for 1 h, after which TLC showed complete consumption of starting material. The reaction was quenched with MeOH and stirred until bubbling stopped. Then a saturated solution of Rochelle’s Salt was added (25 mL), and the mixture was vigorously stirred for about 90 min until the aqueous and organic layers had clearly separated. The layers were then separated, and the aqueous layer was extracted once with CH2Cl2 (15 mL). The combined organic layers were dried, filtered, and concentrated in vacuo, and the crude material 51 mg (99% yield) was used in the next step without further purification.

The crude residue was reacted with triethylamine, (62 mL, 0.443 mmol, 2.0 equiv) and 2-nitrobenzenesulfonyl chloride (52 mg, 0.233 mmol, 1.05 equiv) in CH2Cl2 (4.4 mL) at 0 °C for ~60 minutes. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by chromatography on silica gel using hexanes/EtOAc, which provided after purification 23 mg (25% yield) of pure product 25b. equation M80 (c 0.51, CHCl3). IR νmax (film): 3077, 2914, 1536, 1487, 1346, 1163, 1114. 1H NMR (300 MHz, CDCl3) δ 8.12 (dd, J = 5.6, 3.6 Hz, 1H), 7.86 (dd, J = 5.8, 3.4 Hz, 1H), 7.75 (dd, J = 5.8, 3.5 Hz, 2H), 7.23–7.13 (m, 1H), 6.95 (dd, J = 6.8, 1.7 Hz, 3H), 6.46 (s, 1H), 5.66 (ddd, J = 16.6, 11.1, 6.2 Hz, 1H), 5.17 (d, J = 17.2 Hz, 1H), 4.91 (d, J = 10.2 Hz, 1H), 4.58 (d, J = 13.0 Hz, 1H), 4.18 (d, J = 8.2 Hz, 1H), 3.66 - 3.53 (m, 2H), 3.53–3.38 (m, 2H), 3.32–3.09 (m, 3H), 3.00 (dd, J = 12.7, 3.9 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 156.4, 148.3, 134.8, 133.7, 133.5, 132.7, 131.3, 128.3, 127.2, 125.4, 122.7, 118.0, 117.8, 70.9, 66.2, 61.7, 52.5, 45.2, 33.2. HRMS (ESI) calcd for C20H22N3O5S [M + H]+: 416.1280. Found: 416.1266.

(2R,3R,4S)-4-(Carbonitrile)-3-phenyl-1-propylazetidine-2-hydroxymethyl 26a

To the solution of 5a (5.00 g, 9.10 mmol) in isopropyl alcohol (91 mL) was added AIBN (0.299 g, 1.82 mmol) and tributylchlorostannane (0.368 ml, 1.37 mmol). The reaction mixture was heated to reflux (~100 °C) and was allowed to stir of 5 min. After 5 min at reflux a solution of sodium cyanotrihydroborate (0.86 g, 13.7 mmol) in isopropyl alcohol (20 mL) was added simultaneously with a solution of AIBN (0.600 g, 3.64 mmol) in 20 mL of isopropyl alcohol via two separate syringes over a 10 min period. The reaction was stirred for approximately 1 h. The reaction was cooled down to room temperature and the solvent was removed under reduced pressure. The residue was residue was purified over silica gel to obtain 3.50 g (82%) of the dehalogenated material. equation M81 (c 0.17, CHCl3); IR νmax (film): 3056, 2866, 1490, 1448, 1264, 1063; 1H NMR (500 MHz, CDCl3) δ 7.48–7.41 (m, 2H), 7.31–7.25 (m, J = 6.3, 9.6 Hz, 3H), 7.22–7.06 (m, J = 6.0, 7.9, 14H), 5.76 (ddt, J = 6.7, 10.1, 13.3 Hz, 1H), 5.21 (d, J = 17.1 Hz, 1H), 5.10 (d, J = 10.1 Hz, 1H), 4.11–4.03 (m, 1H), 3.81 (t, J = 7.9 Hz, 1H), 3.63 (dd, J = 7.4, 13.5 Hz, 1H), 3.37 (dd, J = 5.9, 12.9 Hz, 1H), 3.11 (dd, J = 7.2, 12.9 Hz, 1H), 3.03 (dd, J = 5.9, 9.6 Hz, 1H), 2.89 (dd, J = 7.3, 9.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 143.7, 134.3, 132.9, 129.8, 128.4, 128.2, 127.8, 127.6, 126.8, 119.4, 117.6, 86.5, 66.5, 62.1, 60.8, 54.7, 42.9; HRMS (ESI) calcd for C33H30N2O [M + H]+: 471.2436, found: 471.2448.

The dehalogenated intermediate (4.85 g, 10.31 mmol) was treated with trifluoroacetic acid (6.35 mL, 82.0 mmol, 8 equiv) in CH2Cl2 (103 mL) at 0 °C and allowed to warm to room temperature and stir for 1 h. The reaction mixture was quenched with a saturated sodium bicarbonate solution and the aqueous layer was extracted three times with EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to provide the crude product. The reaction provided, after purification, 1.90 g (81%) of pure product. equation M82 (c 1.21, CHCl3), IR νmax (film): 3419, 2867, 1643, 1490, 1414, 1071, 1009; 1H NMR (300 MHz, CDCl3) δ 7.55 (dd, J = 6.9, 1.5 Hz, 2H), 7.46–7.28 (m, 3H), 5.91 (dt, J = 17.0, 10.1, 6.6 Hz, 1H), 5.34 (dd, J = 17.1, 1.4 Hz, 1H), 5.25 (d, J = 10.1 Hz, 1H), 4.14 (d, J = 8.1 Hz, 1H), 3.81 (t, J = 7.9 Hz, 1H), 3.62–3.44 (m, 2H), 3.45–3.28 (m, 2H), 3.21 (dd, J = 13.1, 6.9 Hz, 1H), 1.42 (br s, 1H); 13C NMR (75 MHz, CDCl3) δ 134.1, 133.4, 129.8, 128.6, 128.3, 119.7, 117.6, 68.0, 62.0, 60.9, 54.3, 42.6; HRMS (ESI) calcd for C14H17N2O [M+H]+: 229.1341, found: 229.1333.

The primary alcohol described above (0.200 g, 0.876 mmol) was dissolved in methanol (9 mL). 10% Palladium on carbon (20 mg) was added and hydrogen gas was bubbled into the solution for 5 min. The reaction was then allowed to stir under an atmosphere of hydrogen (via balloon) for approximately 2 h. Once the reaction was complete the mixture was filtered through Celite and then a short plug of silica gel. The solvent was removed under reduced pressure to provide 190 mg (94%) of 26a. equation M83 (c 1.07, CHCl3); IR νmax (film): 3190, 2958, 2918, 2873, 1455, 1249, 1049; 1H NMR (300 MHz, CDCl3) δ 7.55 (d, J = 7.1 Hz, 2H), 7.45–7.20 (m, 3H), 4.08 (d, J = 8.0 Hz, 1H), 3.82 (t, J = 7.7 Hz, 1H), 3.65–3.28 (m, 3H), 2.80–2.61 (m, 1H), 2.61–2.40 (m, 1H), 1.69–1.49 (m, 2H), 1.42 (br s, 1H), 0.98 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 134.3, 129.9, 128.6, 128.3, 117.9, 68.2, 62.0, 60.7, 55.0, 42.4, 21.1, 11.9; HRMS (ESI) calcd for C14H19N2O [M+H]+: 231.1497, found: 231.1487.

((2S,3R,4R)-4-(Aminomethyl)-3-phenyl-1-propylazetidin-2-yl)methanol 26b

Nitrile azetidine 26a (0.200 g, 0.868 mmol) was dissolved in CH2Cl2 (10 mL) and subsequently cooled to 0 °C. DIBAL (0.929 mL, 5.21 mmol) was added over 15 min and the reaction mixture was allowed to warm to room temperature and stirred for approximately 2 h. The mixture was quenched by the slow addition of methanol (0.211 mL, 5.21 mmol) until gas evolution ceased. Then a saturated solution of sodium potassium tartrate (Rochelle's salt) was added and the gel like solution was allowed to stir until 2 separate layers could be seen. The aqueous layer was then extracted 2 additional times with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to provide the crude product which was purified over silica gel (CH2Cl2:MeOH) to obtain 58 mg (67%) of 26a. [α]D20 +13.3 (c 0.63, CHCl3); IR νmax (film): 3363, 3030, 2958, 2931, 2872, 1541, 1493, 1455, 1033; 1H NMR (300 MHz, CDCl3) δ 7.40 (t, J = 9.7 Hz, 2H), 7.35–7.03 (m, 4H), 3.64 (t, J = 8.0 Hz, 1H), 3.49 (d, J = 6.2, 2H), 3.35 (dd, J = 7.2, 13.3, 1H), 3.31–3.09 (m, 1H), 2.71 (dd, J = 9.3, 12.9 Hz, 1H), 2.65 – 2.53 (m, 1H), 2.59–2.35 (m, 2H), 1.52 (d, J = 8.4 Hz, 2H), 1.47 (s, 3H), 1.05–0.70 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 136.1, 130.8, 128.4, 127.2, 76.5, 69.4, 67.5, 61.3, 42.1, 41.9, 22.3, 12.1; HRMS (ESI) calcd for C14H23N2O [M+H]+: 235.1810, found: 235.1808.

7-Phenyl-6-propyl-3,6-diazabicyclo[3.1.1]heptane 27a

Compound 8a (0.416 g, 0.870 mmol) was dissolved in DMF (11 mL) followed by the addition of thiophenol (0.357 mL, 3.38 mmol) and potassium carbonate (0.721 g, 5.22 mmol) at room temperature and stirred overnight (Note in some cases the solution needed to be heated to 50 °C to drive the reaction to completion). The solvent was removed and the resulting residue slurried in EtOAc. The solution was acidified with 1M HCl, and the aqueous layer extracted with additional EtOAc. The resulting aqueous layer was basified with a 40% KOH solution until a pH > 10 was achieved. The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to provide the crude product, which was purified by silica gel chromatography to provide pure product (0.250 g, 98%) as an oil. mp 162.2–164.7 °C (decomp); IR νmax (film): 2917, 2857, 1487, 1398, 1176, 1008, 916, 810; 1H NMR (500 MHz, CDCl3) δ 7.44 (d, J = 8.3 Hz, 2H), 7.00 (dd, J = 8.4, 1.1 Hz, 2H), 5.86 (ddd, J = 16.2, 11.1, 6.0 Hz, 1H), 5.27 (dd, J = 17.2, 1.7 Hz, 1H), 5.14 (dd, J = 10.3, 1.6 Hz, 1H), 4.01 (t, J = 5.6 Hz, 1H), 3.87 (d, J = 5.6 Hz, 2H), 3.40 (d, J = 6.0 Hz, 2H), 3.35 (d, J = 13.5 Hz, 2H), 2.79 (d, J = 13.6 Hz, 2H), 1.67 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 138.3, 134.4, 131.6, 126.9, 119.9, 116.9, 63.2, 48.3, 41.1, 38.8; HRMS (ESI) calcd for C14H18BrN2 [M+ H]+: 293.0653, found: 293.0655.

A solution of the above amine (0.150 g, 0.512 mmol) was dissolved in methanol (5 mL) at room temperature. Platinum oxide (12 mg, 0.48 mmol) was added and hydrogen gas was bubbled into the solution for 5 min. The reaction was then allowed to stir under an atmosphere of hydrogen (via balloon) overnight (Note: The starting material must be free of sulfur impurities for reaction to proceed). Once the reaction was complete the mixture was filtered through a plug of Celite and then silica gel. The solvent was removed under reduced pressure to provide in sufficient purity for the next step.

To a solution of the above product (0.151 g, 0.511 mmol) in isopropyl alcohol (5 mL) was added AIBN (0.021 g, 0.128 mmol) and tributylchlorostannane (0.28 mL, 0.102 mmol). The reaction mixture was heated to reflux (~100 °C) and was allowed to stir for 5 min. A solution of sodium cyanotrihydroborate (0.048 g, 0.767 mmol) in isopropyl alcohol (1 mL) was the added simultaneously with a solution of AIBN (0.042 g, 0.256 mmol) in isopropyl alcohol (1 mL) via two separate syringes over a 10 min period. The reaction was stirred for approximately 1 h. The reaction was cooled down to room temperature and the solvent was removed under reduced pressure. The residue was residue was purified over silica gel using CH2Cl2/MeOH to obtain 52 mg (47% over 2 steps) of 27a. 1H NMR (500 MHz, CDCl3) δ 7.36 (t, J = 7.6, 2H), 7.26 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 7.7 Hz, 2H), 5.93 (ddd, J = 5.9, 11.1, 16.4 Hz, 1H), 5.33 (d, J = 17.2 Hz, 1H), 5.19 (d, J = 10.3 Hz, 1H), 4.16 (t, J = 5.6 Hz, 1H), 3.96 (d, J = 5.7 Hz, 2H), 3.48 (d, J = 5.9 Hz, 2H), 3.40 (d, J = 13.7 Hz, 2H), 2.88 (d, J = 13.7 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 139.0, 128.8, 126.4, 125.4, 64.2, 47.0, 41.6, 38.9, 20.6, 12.1. HRMS (ESI) calcd for C14H21N2 [M+H]+: 217.1705. Found: 217.1698.

7-Phenyl-6-propyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)ethanone 27b

A solution of amine 27a (0.90 mg, 416 mmol), triethylamine (0.218 mL, 1.25 mmol), and PyBOP (0.238 mg, 0.458 mmol) in CH2Cl2 (3mL) at 0 °C was added acetic acid (0.026 mL, 0.458 mmol). The solution was warmed to room temperature and stirred for 5 h and the solvent was removed. The residue was purified by silica gel chromatography to afford 0.025 g (24%) of 27b. 1H NMR (500 MHz, CDCl3) δ 7.30 (t, J = 7.7 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H), 7.03 (d, J = 7.4 Hz, 1H), 4.05 (d, J = 4.6 Hz, 2H), 4.02 (d, J = 2.1 Hz, 1H), 3.70 (dd, J = 8.1, 18.1 Hz, 2H), 3.58 (d, J = 14.2 Hz, 1H), 3.49 (d, J = 12.1 Hz, 1H), 2.65–2.38 (m, 2H), 1.77 (s, 3H), 1.59–1.40 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 170.6, 136.4, 128.4, 126.3, 125.8, 60.2, 59.7, 46.5, 41.1, 38.3, 21.2, 20.9, 12.0. HRMS (ESI) calcd for C16H23N2O [M + H]+: 259.1810, found: 259.1812.

3-(Methylsulfonyl)-7-phenyl-6-propyl-3,6-diazabicyclo[3.1.1]heptane 27c

To a solution of amine 27a (52 mg, 0.240 mmol), and triethylamine (0.101 mL, 0.720 mmol) in CH2Cl2 (2.5 mL) was added methanesulfonyl chloride (0.028 mL, 0.361mmol) at 0 °C. The reaction was allowed to stir for 1 h at 0 °C. Water was then added and the resulting aqueous solution was extracted (3×) with CH2Cl2. The combined extracts were dried over MgSO4, filtered and rotoevaporated to dryness. The resulting oil was chromatographed over silica gel to obtain 50.3 mg (71%) of 27c. 1H NMR (500 MHz, CDCl3) δ 7.36 (t, J = 7.6, 2H), 7.25 (dd, J = 5.1, 12.7, 1H), 7.06 (d, J = 7.7, 2H), 4.05 (s, 3H), 3.74 (d, J = 11.7, 2H), 3.26 (d, J = 11.7, 2H), 2.77–2.47 (m, 2H), 1.71 (s, 3H), 1.61–1.40 (m, 2H), 0.98 (t, J = 7.4, 3H); 13C NMR (126 MHz, CDCl3) δ 136.65, 128.84, 126.68, 126.16, 59.89, 46.34, 40.73, 39.16, 34.02, 21.21, 12.02. HRMS (ESI) calcd for C15H23N2O2S [M + H]+: 295.1480, found: 295.1477.

3-(4-Fluorobenzyl)-7-phenyl-6-propyl-3,6-diazabicyclo[3.1.1]heptane 27d

To a solution of amine 27a (0.125 g, 0.462 mmol) in ethanol (2 mL) was added 4-bromobenzaldehyde (0.049 mL, 0.462 mmol) and the reaction mixture was stirred for 1 h. An additional 1.0 mL of ethanol was added followed by 1.4 mL of THF and sodium borohydride (0.035 g, 0.925 mmol). The reaction mixture was stirred at room temperature overnight and then quenched with water (5 drops), diluted with CH2Cl2 (25 mL), and filtered. The filtrate was concentrated in vacuo and the residue was extracted with diethyl ether. The combined organics were dried over MgSO4, filtered and rotoevaporated to get an oil. The compound was purified over silica gel to afford 0.060 mg (40%) of 27d. 1H NMR (500 MHz, CDCl3) δ 7.32 (d, J = 6.9, 1H), 7.26 (d, J = 7.1, 0H), 7.05 (d, J = 7.5, 1H), 6.70 (t, J = 8.7, 1H), 6.36 (dd, J = 5.7, 8.3, 1H), 3.97 (s, 0H), 3.93 (s, 1H), 3.43 (s, 1H), 2.94 (d, J = 11.3, 1H), 2.78 (d, J = 11.2, 1H), 2.47 (s, 1H), 1.58–1.36 (m, 1H), 0.96 (t, J = 7.4, 1H); 13C NMR (126 MHz, CDCl3) δ 162.4, 160.5, 139.8, 134.7, 129.0, 129.0, 128.0, 125.1, 124.6, 114.5, 114.4, 61.8, 58.2, 46.0, 44.6, 42.3, 20.4, 12.1; HRMS (ESI) calcd for C21H26FN2 [M + H]+: 325.2080, found: 325.2091.

(6R,7R,8S)-8-(Hydroxymethyl)-4-methyl-7-phenyl-1,4-diazabicyclo[4.2.0]octan-2-one 28a

To the solution of 5a (5.00 g, 9.10 mmol) in isopropyl alcohol (91 mL) was added AIBN (0.299 g, 1.82 mmol) and tributylchlorostannane (0.368 ml, 1.37 mmol). The reaction mixture was heated to reflux (~100 °C) and was allowed to stir of 5 min. After 5 min at reflux a solution of sodium cyanotrihydroborate (0.86 g, 13.7 mmol) in isopropyl alcohol (20 mL) was added simultaneously with a solution of AIBN (0.600 g, 3.64 mmol) in 20 mL of isopropyl alcohol via two separate syringes over a 10 min period. The reaction was stirred for approximately 1 h. The reaction was cooled down to room temperature and the solvent was removed under reduced pressure. The residue was residue was purified over silica gel to afford 3.50 g (82%) of product. equation M84 (c 0.17, CHCl3); IR νmax (film): 3056, 2866, 1490, 1448, 1264, 1063. 1H NMR (500 MHz, CDCl3) δ 7.48–7.41 (m, 2H), 7.31–7.25 (m, J = 6.3, 9.6 Hz, 3H), 7.22–7.06 (m, J = 6.0, 7.9, 14H), 5.76 (ddt, J = 6.7, 10.1, 13.3 Hz, 1H), 5.21 (d, J = 17.1 Hz, 1H), 5.10 (d, J = 10.1 Hz, 1H), 4.11–4.03 (m, 1H), 3.81 (t, J = 7.9 Hz, 1H), 3.63 (dd, J = 7.4, 13.5 Hz, 1H), 3.37 (dd, J = 5.9, 12.9 Hz, 1H), 3.11 (dd, J = 7.2, 12.9 Hz, 1H), 3.03 (dd, J = 5.9, 9.6 Hz, 1H), 2.89 (dd, J = 7.3, 9.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 143.7, 134.3, 132.9, 129.8, 128.4, 128.2, 127.8, 127.6, 126.8, 119.4, 117.6, 86.5, 66.5, 62.1, 60.8, 54.7, 42.9. HRMS (ESI) calcd for C33H30N2O [M + H]+: 471.2436, found: 471.2448.

The nitrile azetidine described above (3.5 g, 7.44 mmol, 1.0 equiv) was dissolved in CH2Cl2 (75 mL) and subsequently cooled to 0 °C. DIBAL (7.95ml, 44.6 mmol, 6.0 equiv) was added over 15 minutes and the reaction mixture was allowed to warm to room temperature and stirred for approximately 2 h. The mixture was quenched by the slow addition of MeOH (5.50 mL, 136 mmol, 6.0 equiv) until gas evolution ceased. Then a saturated solution of sodium potassium tartrate (Rochelle's salt) was added and the gel like solution was allowed to stir until two separate layers could be seen. The aqueous layer was then extracted two additional times with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to provide the crude product (~3.53 g), which was deemed pure enough for the next reaction.

The resulting amine (3.5 g, 7.37 mmol, 1.0 equiv) was dissolved in CH2Cl2 (74 mL) and cooled down to 0 °C. 2,6-lutidine (2.59 ml, 22.1 mmol, 3.0 equiv) was introduced followed by 2-nitrobenzene-1-sulfonyl chloride (1.85 g, 8.11 mmol, 1.1 equiv) in one portion. The solution was then allowed to warm to room temperature and stir for an additional 3 h. The reaction mixture was quenched with water and the aqueous layer was extracted two times with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to provide the crude product, which was purified by chromatography over silica gel using hexanes/EtOAc to provide the nosylated amine (2.91 g, 60% over 2 steps) as a pale yellow foam.

To a solution of the nosylated amine (1.00 g, 1.516 mmol) and 1,3-dimethyl barbaturic acid (0.355 g, 2.273 mmol) in EtOH (30mL) was added palladium tetrakis (0.350 g, 0.303 mmol). The resulting orange solution was stirred for approximately 1 hour at room temperature. The solution was then evaporated and taken up in acetonitrile. The resulting solid was filtered through Celite and taken on imediately as a crude solution.

Potassium carbonate (210 g, 15.2 mmol) was added to the orange solution obtained above and the mixture cooled to 0 °C. 2-Bromoacetyl chloride (0.380 ml, 4.55 mmol) was then added dropwise and the resulting mixture warmed to room temperature and the solution was stirred for several hours. After the reaction was deemed complete (LCMS analysis) the mixture was concentrated in vacuo. The residue was dissolved in CH2Cl2 and water after which the aqueous layer was extracted (3×) with CH2Cl2. The combined organic layers were dried (MgSO4) and concentrated in vacuo to give an oily residue. The residue was purified by chromatography to obtain 88% of the fully protected monoketopiperazine des Br-9a. equation M85 (c 0.55; CHCl3); IR νmax (film): 3059, 3031, 2942, 1665, 1543, 1453, 1370. 1H NMR (500 MHz, CDCl3) δ 7.94 (d, J = 7.5, 1H), 7.72–7.66 (m, 1H), 7.63 (t, J = 7.0 Hz, 2H), 7.30–7.20 (m, 9H), 7.18–7.10 (m, 8H), 7.06–6.97 (m, 5H), 5.03–4.87 (m, 2H), 4.13–4.04 (m, 2H), 4.00 (dd, J = 4.7, 10.0 Hz, 1H), 3.72 (dd, J = 4.8, 13.0 Hz, 1H), 3.63 (d, J = 17.1 Hz, 1H), 3.50 (t, J = 9.9 Hz, 1H), 3.36–3.23 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 160.4, 147.8, 143.2, 134.0, 133.8, 131.9, 131.7, 131.1, 129.3, 128.5, 128.4, 127.6, 127.6, 126.8, 124.4, 86.6, 77.2, 77.0, 76.7, 66.2, 61.4, 57.5, 47.7, 45.5, 42.8. HRMS (ESI) calcd C38H33N3O6S [M + Na]+: 682.1988, found: 682.1982.

To a solution of the fully protected monoketopiperazine described above des Br-9a (0.615 g, 0.932 mmol) in CH2Cl2 (5 mL) at 0 °C was added trifluoroacetic acid (0.718 ml, 9.32 mmol). The resulting solution was then warmed to room temperature and stirred for approximately 1 h. A saturated sodium bicarbonate solution was added and stirred till bubbling ceased. The aqueous layer was extract with CH2Cl2 and the combined organics were dried over MgSO4, filtered and concentrated under reduced pressure to obtain an oil. After filtering over a plug of silica gel the detritylated product was taken forward to the next step.

The above product was dissolved in DMF (9 mL) and potassium carbonate (0.510 g, 3.69 mmol) was added and the mixture cooled to 0 °C. Thiophenol (0.303 ml, 2.95 mmol) was then added and the reaction was heated to 50 °C and stirred for 2 h. After starting material was consumed the DMF was rotoevaporated down and taken up in EtOAc. 2M HCl was then added until pH was approximately 1. The aqueous was washed with EtOAc and the organics discarded. The aqueous solution was basified with 40% KOH solution until pH >10. The solution was then extracted with CH2Cl2 (3×) and the combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure to obtain a yellowish oil which, was imediately taken on crude to the next step.

To a solution of the free amino alcohol 35 mg (0.151 mmol), acetic acid (0.086 ml, 1.507 mmol) and formaldehyde (0.021 ml, 0.753 mmol) in MeOH (5 mL) was added sodium cyanoborohydride (0.047 g, 0.753 mmol) in portions at room temperature. The mixture was then heated to 60 °C and stirred for approximately 30 min. The solvent was evaporated and to the resulting white solid was added sat. NaHCO3 was introduced until gas evolution ceased. At this point a 1 M NaOH solution was added till pH > 11 then the solution was extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), and evaporated to dryness to give a cloudy oil. Purification over silica gel afforded 15mg (42%) of 28a. equation M86 (c 1.71; CHCl3); IR νmax (film): 3057, 2944, 1641, 1489, 1447, 1409, 1216, 1071. 1H NMR (500 MHz, CDCl3) δ 7.43–7.33 (m, 3H), 7.23 (d, J = 6.1 Hz, 2H), 5.40–5.29 (m, 1H), 5.20 (t, J = 7.4 Hz, 1H), 4.23 (dd, J = 9.9, 13.0 Hz, 1H), 4.11 (t, J = 7.9 Hz, 1H), 3.75 (d, J = 16.4 Hz, 1H), 3.44 (dd, J = 2.6, 13.0 Hz, 1H), 3.35 (d, J = 16.5 Hz, 1H), 3.16 (dd, J = 4.8, 12.0 Hz, 1H), 2.93 (t, J = 11.8 Hz, 1H), 2.86 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 160.5, 132.0, 129.4, 128.9, 128.6, 71.0, 61.1, 60.0, 57.2, 54.6, 54.4, 45.4. HRMS (ESI) calcd C14H19N2O2 [M + H]+: 247.1440, found: 247.1443.

(6R,7R,8S)-7-Phenyl-8-((trityloxy)methyl)-1,4-diazabicyclo[4.2.0]octan-2-one 28b

To a solution of the fully protected monoketopiperazine des Br-9a described in the synthesis of 28a (0.580 g, 0.879 mmol) and potassium carbonate (0.607 g, 4.40 mmol) in DMF (10 mL) was added thiophenol (0.361 ml, 3.52 mmol) at 0 °C. The reaction was allowed to come to room temperature and stir for 2 h. Water was added and the solution extracted with diethyl ether (3×). The organics were combined and dried over MgSO4, filtered and concentrated under reduced pressure to obtain an oil. This material was then purified over silica gel to yield 75% of trityl protected free amine of des-Br 9a scaffold. equation M87 (c 0.42; CHCl3); IR νmax (film): 3306, 3057, 2944, 1641, 1489, 1447, 1409, 1216, 1071; 1H NMR (500 MHz, CDCl3) δ 7.33–7.22 (m, 7H), 7.23–7.14 (m, 8H), 7.09 (dd, J = 2.9, 6.6 Hz, 6H), 5.11–4.97 (m, 1H), 4.94 – 4.84 (m, 1H), 4.08 (dd, J = 4.7, 9.9 Hz, 1H), 4.02 (t, J = 7.4 Hz, 1H), 3.53 (t, J = 10.1 Hz, 1H), 3.43 (d, J = 9.3 Hz, 1H), 2.97 (dd, J = 10.7, 13.0 Hz, 1H), 2.74 (dd, J = 5.2, 13.1 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 164.2, 143.5, 134.6, 129.6, 128.4, 128.2, 127.5, 127.3, 126.7, 86.3, 77.2, 77.0, 76.7, 66.2, 63.6, 57.5, 49.2, 47.2, 41.4; HRMS (ESI) calcd C32H30N2O2 [M + Na]+: 497.2205, found: 497.2201.

To a solution of the trityl protected free amine scaffold obtained above (0.22 g, 0.46 mmol) in CH2Cl2 (9 mL) at 0 °C was added triethylamine (0.19 mL, 1.37 mmol) followed by acetyl chloride (0.051 mL, 0.683 mmol). The reaction was stirred for 30 min at which time water was added. The aqueous layer was and extracted with CH2Cl2 and dried over MgSO4, filtered and evaporated to obtain an oil. This material was used directly in the next step without purification.

The resulting oil was dissolved in CH2Cl2 (3 mL) and cooled to 0 °C. Trifluoroacetic acid (0.139 ml, 1.802 mmol) was then added and the reaction was warmed to room temperature and stirred for 1 h. A saturated sodium bicarbonate solution was added and stirred until gas evolution ceased. The aqueous layer was then extract with CH2Cl2 (3×) and the combined organics were dried over MgSO4, filtered and evaporated to obtain and oil. Purification by silica gel chromatography afforded 0.069g (74%) of 28b. equation M88 (c 0.31; CHCl3); IR νmax (film): 3401, 2930, 1636, 1417; 1H NMR (500 MHz, CDCl3) δ 7.49–7.31 (m, 3H), 7.31–7.21 (m, 2H), 5.18–5.04 (m, 1H), 4.94–4.77 (m, 1H), 4.46 (dd, J = 4.8, 13.1 Hz, 1H), 4.30–4.20 (m, J = 8.0, 20.3 Hz, 2H), 4.14–4.00 (m, 2H), 3.78 (d, J = 18.7 Hz, 1H), 3.64–3.50 (m, 1H), 3.41 (td, J = 2.7, 12.7 Hz, 1H), 3.08–2.96 (t, J = 12.7 Hz, 1H), 2.12 (s, 2H), 2.06 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 169.3, 169.0, 164.7, 163.3, 132.7, 132.6, 129.5, 129.4, 128.6, 128.5, 128.2, 128.0, 70.6, 70.3, 61.3, 61.0, 60.8, 49.4, 45.9, 44.9, 43.3, 38.6, 21.5, 21.5; HRMS (ESI) calcd C15H18N2O3 [M+ Na]+: 297.1215, found: 297.1217.

(6R,7R,8S)-8-(Hydroxymethyl)-4-(methylsulfonyl)-7-phenyl-1,4-diazabicyclo [4.2.0] octan-2-one 28c

To a solution of the trityl protected free amine scaffold described above (0.170 g, 0.358 mmol) and triethylamine (0.150 ml, 1.075 mmol) in CH2Cl2 (3 mL) was added methanesulfonyl chloride (0.042 ml, 0.537 mmol) at 0°C. The solution was allowed to warm to room temperature and stir for approximately 1 h. Water was then added and the resulting aqueous layer was extracted with CH2Cl2 (3×). The combined organics were dried over MgSO4, filter and evaporated down. This material was run through a short plug of silica gel, concentrated and taken directly to the next step in the sequence.

The resulting oil was then dissolved in CH2Cl2 (3 mL) and cooled to 0 °C. Trifluoroacetic acid (0.139 ml, 1.80 mmol) was added and the reaction was warmed to room temperature and stirred for 1 h. A saturated sodium bicarbonate solution was added and stirred till bubbles ceased. The aqueous layer was then extract with CH2Cl2 (3×) and the combined organics were dried over MgSO4, filtered and evaporated to obtain and oil. Purification by silica gel chromatography afforded 0.069g (74%) of 28c. equation M89 (c 0.40; CHCl3); IR νmax (film): 3365, 3011, 2928, 1638, 1456, 1426, 1336, 1150; 1H NMR (500 MHz, CDCl3) δ 7.36 (q, J = 6.5, 3H), 7.24 (m, 2H), 5.14 (t, J = 7.8 Hz, 1H), 5.12–4.98 (m, 1H), 4.54 (s, 1H), 4.30 (d, J = 14.6 Hz, 1H), 4.24 (dd, J = 12.6, 25.1 Hz, 2H), 4.04 (t, J = 8.1 Hz, 1H), 3.79 (d, J = 17.2 Hz, 1H), 3.64 (dd, J = 4.9, 12.5 Hz, 1H), 3.40 (t, J = 12.2 Hz, 1H), 3.27–3.13 (m, 1H), 2.87 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 162.7, 132.6, 129.5, 128.7, 128.3, 70.7, 61.8, 60.75, 47.9, 45.3, 42.2, 37.2; HRMS (ESI) calcd C14H18N2O4S [M + H]+: 311.1066, found: 311.1057.

((8R,9R,10S)-9-(4-Bromophenyl)-1,6-diazabicyclo[6.2.0]decan-10-yl) methanol 29a

Nosyl amine 12a (0.700 g, 1.37 mmol) was dissolved in DMF (20 mL) and potassium carbonate (0.948 g, 6.86 mmol) was added followed by thiophenol (0.563 mL, 5.49 mmol). The reaction mixture was heated to 50 °C and stirred for 2 h. Once the reaction was complete the solvent was removed in vacuo at which time water and EtOAc was added to the remaining residue. 2M HCl was added to the biphasic mixture until the water layer maintained a pH of approximately 1. The organics were removed and the remaining aqueous layer extracted with EtOAc. The aqueous layer was then basified to pH >10 using a 40% KOH solution. The water was then extracted with EtOAc three times and the combined organics were dried over MgSO4, filtered and rotoevaporated to dryness to afford 29a. (0.395 g, 89%). equation M90 (c 0.59, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.43 (d, J = 7.6 Hz, 2H), 7.31–7.19 (m, 2H), 3.61 (t, J = 7.9 Hz, 1H), 3.58–3.48 (m, 2H), 3.47–3.38 (m, 2H), 3.07 (dd, J = 5.0, 12.1 Hz, 1H), 2.89 (d, J = 9.1 Hz, 1H), 2.75–2.57 (m, 2H), 2.30 (d, J = 14.3 Hz, 1H), 2.23 (t, J = 11.4 Hz, 1H), 1.82 (s, 4H), 1.56–1.43 (m, 1H), 1.41–1.30 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 135.5, 132.3, 131.0, 120.7, 68.0, 67.1, 60.7, 60.0, 50.4, 48.6, 43.7, 29.2, 27.1; HRMS (ESI) calcd for C15H22BrN2O [M+H]+: 325.0916, found: 325.0902.

((8R,9R,10S)-9-Phenyl-1,6-diazabicyclo[6.2.0]decan-10-yl)methanol 29b

To the solution of aryl bromide 29a (0.395 g, 1.21 mmol) in isopropyl alcohol (12.1 mL) was added AIBN (0.050 g, 0.304 mmol) and tributylchlorostannane (0.066 ml, 0.243 mmol). The reaction mixture was then heated to reflux (~110 °C) and was allowed to stir for 10 min. A solution of sodium cyanotrihydroborate (0.114 g, 1.822 mmol) in isopropyl alcohol (5 mL) was added contemporaneously with a solution of AIBN (0.100 mg) in isopropyl alcohol (5 mL) over a 15 min period. Upon completion of the reaction the solvent was removed in vacuo and the remaining sludge taken up in EtOAc and water. 2M HCl was added to the biphasic mixture until the water layer maintained a pH of approximately 1. The organic layer was removed and the remaining aqueous layer extracted with EtOAc. The aqueous layer was then basified to pH >10 using a 40% KOH solution. The water layer was extracted with CH2Cl2 (3×) and the combined organics were dried over MgSO4, filtered and concentrated to dryness to afford 29b. equation M91 (c 0.34, CHCl3); mp 100.9–105.2 °C; IR νmax (film): 3306, 2921, 2845, 1454, 1034; 1H NMR (500 MHz, CDCl3) δ 7.34 (d, J = 6.1 Hz, 2H), 7.28 (t, J = 7.0 Hz, 2H), 7.24–7.18 (m, 1H), 3.62 (t, J = 7.9 Hz, 1H), 3.60 – 3.55 (m, 1H), 3.55–3.48 (m, 1H), 3.49–3.34 (m, 4H), 3.11–3.00 (m, 1H), 2.85 (d, J = 9.8 Hz, 1H), 2.74 (dd, J = 8.1, 14.1 Hz, 1H), 2.64 (t, J = 11.7 Hz, 1H), 2.40–2.14 (m, 2H), 1.93–1.55 (m, 6H), 1.55–1.40 (m, 2H), 1.40–1.23 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 136.7, 130.8, 128.0, 126.7, 77.4, 68.1, 67.8, 60.9, 60.3, 50.4, 44.4, 29.1, 27.3; HRMS (ESI) calcd for C15H23N2O [M+H]+: 247.1810, found: 247.1814.

((8R,9R,10S)-6-Methyl-9-phenyl-1,6-diazabicyclo[6.2.0]decan-10-yl) methanol 29c

To a solution of 29b (0.070 g, 0.284 mmol), acetic acid (0.163 ml, 2.84 mmol) and formaldehyde (0.039 ml, 1.421 mmol) in MeOH (5 ml) was added NaCNBH3 (0.089 g, 1.421 mmol) portion-wise at room temperature. The mixture was then heated to 60 °C and stirred for 30 min. The solvent was then evaporated and to the resulting white solid was added a saturated solution of NaHCO3 until gas evolution ceased. At this point a 1M NaOH solution was added till pH>11 then the solution was extracted with EtOAc (3 ×). The combined organic layers were dried over MgSO4 and evaporated to dryness to give a cloudy oil. The oil was taken up in chloroform and filtered though Celite and dried to obtain 29c as a clear oil. equation M92 (c 0.93, CHCl3); IR νmax (film): 3250, 2928, 2851, 1455, 1214, 750; 1H NMR (500 MHz, CDCl3) δ 7.43 (d, J = 7.2 Hz, 2H), 7.29 (t, J = 7.5 Hz, 2H), 7.26–7.16 (m, 1H), 3.64 (t, J = 8.2 Hz, 1H), 3.60 – 3.48 (m, 3H), 3.39 (dd, J = 7.2, 13.4 Hz, 1H), 3.04 (ddd, J = 2.9, 5.7, 12.0 Hz, 1H), 2.73–2.63 (m, 1H), 2.55 (dd, J = 8.7, 13.8 Hz, 1H), 2.43–2.35 (m, 1H), 2.33–2.26 (m, 1H), 2.21 (s, 3H), 2.10 (dd, J = 2.1, 13.8 Hz, 1H), 1.94–1.84 (m, 1H), 1.84–1.74 (m, 1H), 1.68 (s, 1H), 1.62–1.43 (m, 2H).; 13C NMR (75 MHz, CDCl3) δ 135.4, 130.8, 128.7, 127.6, 67.8, 64.9, 61.3, 59.9, 59.1, 57.1, 47.1, 44.4, 26.6, 25.0; HRMS (ESI) calcd for C16H25N2O [M+H]+: 261.1967, found: 261.1969.

Procedure for the synthesis of spiroazetidine derivatives 30a–c

To a 50 mL round bottom flask was added a solution of des-Br 14a (b or c) (1.02 g, 1.52 mmol, 1 equiv) in dry DMF (15 mL). At 0 °C, K2CO3 (0.84 g, 6.07 mmol, 4 equiv) was added, followed by thiophenol (0.31 mL, 3.04 mmol, 2 equiv). After 1 hour at 0 °C, water (15 mL) was added to the mixture and the crude was extracted with Et2O. The organic phase was dried over MgSO4, filtered and concentrated. The material was then dissolved in MeOH (9 mL) and purged with Argon for 10 min. Pd (10% on carbon, 32 mg, 0.20 equiv) was quickly added and hydrogen gas was sparged for 1 h. The mixture was stirred overnight at room temperature under an atmosphere of hydrogen, carefully filtered through a pad of Celite and concentrated. Purification over silica-supported p-TsOH using ammonia (2.0M in MeOH) as the mobile phase, afforded the desired secondary amine (439 mg, 0.90 mmol, 59.1% yield over two steps).

(2S,3S)-1-Propyl-2-hydroxymethyl-3-phenyl-1,6-diazaspiro[3.3]heptane 30a

To a solution of the amine described above (138 mg, 0.28 mmol) in CH2Cl2 (5.5 mL), was added trifluoroacetic acid (0.32 mL, 4.24 mmol, 15 equiv) dropwise at 0 °C. Upon completion of the reaction, MeOH (3 mL) was added via syringe followed by addition of K2CO3 (0.59 g, 4.24 mmol, 15 equiv) and the mixture was stirred 30 min at room temperature. The crude reaction mixture was filtered through a pad of Celite and evaporated. Purification on silica gel (CH2Cl2:MeOH:2.0M NH3 in MeOH=95:4.95:0.05) afforded amino alcohol 30a (69 mg, 0.28 mmol, 99% yield) as a pale yellow foam. [α]D21= +46.2 (c 0.9, MeOH); IR (film) ν 3382, 3204, 2965, 2874, 1668, 1182, 1132; 1H NMR (300 MHz, CD3OD) δ 7.33–7.24 (m, 6H), 4.74 (d, J = 11.8 Hz, 1H), 4.16 (d, J = 11.7 Hz, 1H), 3.98 (d, J = 12.1 Hz, 1H), 3.73 (d, J = 7.9 Hz, 2H), 3.56 (dd, J = 13.5, 6.0 Hz, 1H), 3.37 (dd, J = 11.3, 5.7 Hz, 1H), 3.25 (s, 1H), 3.20 (dd, J = 11.3, 6.2 Hz, 1H), 2.83 (app dt, J = 12.3, 7.7 Hz, 1H), 2.62 (app dt, J = 12.3, 7.0 Hz, 1H), 1.64–1.49 (m, 2H), 0.97 (app t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, MeOD) δ 136.8, 131.1, 129.7, 128.7, 68.4, 68.2, 63.0, 56.7, 54.3, 54.2, 51.2, 23.3, 12.3; HRMS (ESI+) calcd for C15H23N2O [M + H]+: 247.1810, found: 247.1813.

(2S,3S)-1-Propyl-2-hydroxymethyl-3-phenyl-6-methyl-1,6-diazaspiro[3.3]heptane 30b

To a solution of amine described above (145 mg, 0.30 mmol) in CH2Cl2 (5.5 mL) was added at rt MgSO4 (357 mg, 2.97 mmol, 10 equiv) followed by formaldehyde (37% in H2O, 0.13 mL, 1.78 mmol, 6 equiv). After 15 min at room temperature, NaBH(OAc)3 (755 mg, 3.56 mmol, 12 equiv) was added as a solid in one portion and the mixture was stirred overnight at rt. Water (10 mL) was then added and the layers separated. The organic phase was dried over MgSO4, filtered, concentrated and the crude was submitted to TFA-mediated trityl removal as described for the preparation of 30a. Compound 24b was isolated after purification on silica gel (CH2Cl2:MeOH:2.0M NH3 in MeOH=95:4.95:0.05) as a thick colorless oil (65 mg, 0.25 mmol, 84% yield over two steps). [α]D21 = +109.1 (c 0.8, CHCl3); IR (film) ν 3367, 2960, 2873, 1673, 1199, 1132; 1H NMR (300 MHz, CDCl3) δ 7.39–7.27 (m, 5H), 4.35 (br d, J = 10.0 Hz, 1H), 3.81 (d, J = 9.6 Hz, 1H), 3.65 (d, J = 7.8 Hz, 2H), 3.60–3.54 (m, 1H), 3.51 (dd, J = 11.5, 4.3 Hz, 1H), 3.45 (d, J = 4.8 Hz, 1H), 3.38 (dd, J = 11.2, 7.2 Hz, 1H), 2.79 (app dt, J = 12.0, 7.8 Hz, 1H), 2.60–2.52 (m, 1H), 2.51 (s, 3H), 1.63 – 1.41 (m, 2H), 0.97 (app t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 135.3, 129.6, 128.6, 127.5, 66.6, 64.5, 64.4, 62.3, 61.9, 53.3, 49.8, 43.6, 22.3, 11.8; HRMS (ESI+) calcd for C16H25N2O [M + H]+: 261.1967, found: 261.1964.

(2S,3S)-1-Propyl-2-hydroxymethyl-3-phenyl-6-acetyl-1,6-diazaspiro[3.3]heptane 30c

To a solution of amine described above (155 mg, 0.32 mmol) in CH2Cl2 (4 mL) at 0 °C was added NEt3 (88 µL, 0.63 mmol, 2 equiv) followed by Ac2O (36 µL, 0.38 mmol, 1.2 equiv). The mixture was stirred for 1 h at 0 °C and was then quenched with a saturated solution of aqueous NH4Cl (5 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated to afford a crude product that was submitted to the TFA-mediated trityl removal step without any further purification (see preparation of 30a). Purification by silica gel chromatography (CH2Cl2:MeOH:2.0M NH3 in MeOH=95:4.95:0.05) afforded compound 30c as a colorless foam (73 mg, 0.25 mmol, 78% yield over two steps). [α]D21 +126.2 (c 1.1, CHCl3); IR (film) ν 3376, 2959, 2873, 1622, 1455, 1033, 906; 1H NMR (300 MHz, CDCl3, two rotamers) δ 7.33–7.16 (m, 5H), 4.75 (A)/4.68 (B) (d, J = 9.4 (A)/11.1 (B) Hz, 1H), 4.05 (A)/3.92 (B) (d, J = 9.4 (A)/10.3 (B) Hz, 1H), 3.90 (s, 1H), 3.82 (app q, J = 11.9 Hz, 1H), 3.52 (br s, 2H), 3.43 (br d, J = 9.5 Hz, 1H), 3.37–3.24 (m, 1H), 2.76–2.45 (m, 2H), 2.21 (A)/1.99 (B) (br s, 1H), 1.84 (A)/1.71 (B) (s, 3H), 1.59–1.37 (m, 2H), 0.95 (app t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3, two rotamers) δ 170.5/170.2, 136.1/135.7, 129.4, 128.2, 127.2, 66.3/66.2, 64.3/64.1, 61.9, 60.5, 57.9/55.9, 53.6/53.3, 49.7, 21.9, 18.9/18.8, 11.9. HRMS (ESI+) calcd for C17H25N2O2 [M + H]+: 289.1916, found: 289.1917.

((±)-2-Propyl-1,2,2a,3,4,8b-hexahydroazeto[2,3-c]quinolin-1-yl) methanol 31a

A solution of des-Ns 24c (0.110 g, 0.478 mmol) was dissolved in methanol (5 mL) at room temperature. Platinum oxide (11 mg, 0.48 mmol) was added and hydrogen gas was bubbled into the solution for 5 min. The reaction was then allowed to stir under an atmosphere of hydrogen (via balloon) overnight. Once the reaction was complete the mixture was filtered through Celite and then a plug of silica gel. The solvent was removed under reduced pressure to provide 24 mg (22%) of 31a. 1H NMR (500 MHz, CDCl3) δ 7.16 (td, J = 1.5, 7.7 Hz, 1H), 7.04 (dd, J = 1.3, 7.5 Hz, 1H), 6.85 (td, J = 1.0, 7.5 Hz, 1H), 6.78 (d, J = 7.7 Hz, 1H), 4.87 (d, J = 6.9 Hz, 1H), 4.18 – 4.11 (m, 1H), 4.09 (s, 1H), 3.97 (dd, J = 2.0, 14.0 Hz, 1H), 3.82 (dd, J = 4.4, 14.0 Hz, 1H), 3.75 (s, 1H), 3.66 (d, J = 14.2 Hz, 1H), 3.39 (td, J = 5.4, 11.7 Hz, 1H), 3.20 (td, J = 5.2, 11.7 Hz, 1H), 3.07 (dd, J = 3.5, 14.3 Hz, 1H), 1.83–1.59 (m, 3H), 0.96 (t, J = 7.4 Hz, 4H); 13C NMR (126 MHz, CDCl3) δ 145.1, 128.6, 128.6, 122.4, 121.0, 116.2, 75.3, 63.5, 59.7, 50.3, 40.5, 31.2, 18.3, 11.2; HRMS (ESI) calcd for C14H20N2O [M+]+: 232.1654, found: 232.1656.

1-((±)-1-(Hydroxymethyl)-2-propyl-1,2a,3,8b-tetrahydroazeto[2,3-c]quinolin-4 (2H)-yl) ethanone 31b

A solution of acyl 24c (0.094 g, 0.345 mmol) was dissolved in methanol (4 mL) at room temperature. 10% Palladium on carbon (37 mg) was added and hydrogen gas was bubbled into the solution for 5 min. The reaction was then allowed to stir under an atmosphere of hydrogen (via balloon) overnight. Once the reaction was complete the mixture was filtered through a pad of Celite and then silica gel. The solvent was removed under reduced pressure to provide 91 mg (96%) of 31b. 1H NMR (500 MHz, CDCl3) δ 7.35–7.26 (m, 1H), 7.23–7.12 (m, 3H), 5.19 (s, 1H), 4.38 (s, 1H), 3.96 (s, 1H), 3.66 (d, J = 12.0 Hz, 1H), 3.55 (d, J = 11.7 Hz, 1H), 3.35 (s, 1H), 2.78 (s, 2H), 2.51 (s, 1H), 2.27 (s, 3H), 1.63 – 1.41 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 168.8, 139.9, 131.5, 128.9, 127.6, 126.2, 124.4, 72.9, 63.3, 60.5, 50.8, 40.3, 34.3, 23.2, 21.2, 11.6; HRMS (ESI) calcd for C16H23N2O2 [M+]+: 275.1760, found: 275.1749.

((±)-4-(Methylsulfonyl)-2-propyl-1,2,2a,3,4,8b-hexahydroazeto[2,3-c]quinolin-1-yl) methanol 31c

A solution of mesyl 24c (0.115 g, 0.373 mmol) was dissolved in methanol (4 mL) at room temperature. 10% Palladium on carbon (40 mg) was added and hydrogen gas was bubbled into the solution for 5 min. The reaction was then allowed to stir under an atmosphere of hydrogen (via balloon) overnight. Once the reaction was complete the mixture was filtered through Celite® and then a plug of silica gel. The solvent was removed under reduced pressure to provide 44 mg (38%) of 31c. 1H NMR (500 MHz, CDCl3) δ 7.69 (d, J = 8.2, 1H), 7.32–7.24 (m, 1H), 7.18–7.12 (m, 2H), 4.41 (dd, J = 3.7, 13.8 Hz, 1H), 4.15 (dt, J = 3.6, 7.6 Hz, 1H), 3.79–3.73 (t, 1H), 3.71 (dd, J = 3.3, 11.7, 1H), 3.61 (dd, J = 1.6, 11.7, 1H), 3.54–3.48 (m, 1H), 3.30 (dd, J = 3.7, 13.8 Hz, 1H), 3.12 (s, 3H), 2.94–2.82 (m, 2H), 2.68–2.56 (m, 1H), 1.55–1.38 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 137.9, 131.1, 128.9, 127.4, 125.2, 121.6, 71.2, 61.2, 60.9, 50.3, 46.2, 38.9, 33.6, 22.0, 11.9; HRMS (ESI) calcd for C15H22N2O3S [M+]+: 310.1429, found: 310.1433.

Procedure for the synthesis of benzopyran derivatives 32a and 32b

To a degassed solution of tetrahydrochrome derivative (see synthesis of 25a) (285 mg, 1.26 mmol, 1.0 equiv) dissolved in MeOH (12.6 mL) was added palladium hydroxide (20 wt% on activated carbon, 18 mg, 0.126 mmol, 0.1 equiv). Hydrogen gas was bubbled through the reaction mixture for 5 min, and then placed under a static H2 atmosphere (balloon pressure), and stirred for 15 h, after which analysis of the reaction mixture by LC/MS showed that the reaction was complete. The mixture was diluted with CH2Cl2, and filtered through Celite. The filtrate was concentrated under reduced pressure and the crude product (197 mg, 69% yield), was used in the next step without further purification. equation M93 (c 0.10, CHCl3); IR νmax (film): 2971, 2953, 2930, 2900, 1582, 1489, 1460, 1259, 1225, 1202, 1116, 1004; 1H NMR (500 MHz, CDCl3) δ 7.28–7.22 (m, 1H), 7.09 (d, J = 6.8 Hz, 1H), 7.03 (t, J = 7.4 Hz, 2H), 4.15 (dd, J = 12.7, 1.5 Hz, 1H), 4.11 (d, J = 7.8 Hz, 1H), 3.77 (t, J = 7.8 Hz, 1H), 3.70–3.59 (m, 2H), 2.70 dt, J = 11.3, 7.7 Hz, 1H), 2.62 dt, J = 11.4, 7.6 Hz, 1H), 1.54 (q, J = 7.5 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 155.1, 130.7, 129.1, 122.2, 119.8, 118.4, 117.3, 65.6, 62.8, 59.3, 56.6, 31.7, 20.9, 11.8; HRMS (ESI) calcd for C14H17N2O [M + H]+: 229.1341, found: 229.1344.

The resulting N-propyl nitrile azetidine (197 mg, 0.863 mmol, 1.0 equiv) was dissolved in CH2Cl2 (8.6 mL) at 0 °C, and then diisobutylaluminum hydride (0.923 mL, 5.18 mmol, 6.0 equiv) was added, and the reaction was stirred for 2 h, after which analysis of the reaction by TLC showed that all starting material had been consumed. The reaction was quenched with MeOH (10 mL) until bubbling stopped, diluted with CH2Cl2 and then quenched further with a saturated solution of potassium sodium tartrate (~100 mL). The mixture was stirred vigorously for about 1.5 h until bubbling stopped, and the two layers had clearly formed. The layers were separated, and the aqueous layer was extracted further with CH2Cl2 (2 × 15 mL). The combined organic layers were dried, filtered, and concentrated under reduced pressure to provide the crude primary amine as a clear oil, which was used without further purification.

N-(((1R,2aS,8bR)-2-Propyl-2,2a,3,8b-tetrahydro-1H-chromeno[3,4-b]azet-1-yl) methyl) benzamide 32a

To solution of the crude amine described above (50 mg, 0.215 mmol, 1.0 equiv) in CH2Cl2 (2.2 mL) at 0 °C was added diisopropylethylamine (111 mL, 0.646 mmol, 3.0 equiv), benzoic acid (39 mg, 0.323 mmol, 1.5 equiv), and PyBOP (146 mg, 0.280 mmol, 1.3 equiv). The solution was stirred for 15 h, after which LC/MS of the reaction showed that all starting material had been consumed. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by chromatography on silica gel using hexanes/EtOAc to provide 42 mg of 32a (58% yield) as a clear oil. equation M94 (c 0.14, CHCl3); IR νmax (film): 3307, 2957, 2924, 2873, 1629, 1578, 1533, 1489, 1459, 1229; 1H NMR (300 MHz, CDCl3) δ 7.61 (d, J = 6.9 Hz, 2H), 7.50–7.31 (m, 3H), 7.05–6.94 (m, 2H), 6.94–6.85 (m, 1H), 6.79 (br s, 1H), 6.75 (d, J = 8.1 Hz, 1H), 4.18 (d, J = 12.0 Hz, 1H), 3.77 (br s, 1H), 3.63 (t, J = 5.4 Hz, 3H), 3.32–3.10 (m, 2H), 2.64 (t, J = 7.6 Hz, 2H), 1.61 – 1.32 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 166.4, 155.3, 134.3, 131.2, 130.2, 128.3, 128.0, 127.0, 122.3, 122.2, 118.0, 67.4, 64.2, 62.5, 59.5, 40.5, 31.1, 21.8, 12.0; HRMS (ESI) calcd for C21H25N2O2 [M + H]+: 337.1916, found: 337.1917.

N-(((1R,2aS,8bR)-2-Propyl-2,2a,3,8b-tetrahydro-1H-chromeno[3,4-b]azet-1-yl) methyl) methanesulfonamide 26b

To solution of the crude amine described above (57 mg, 0.245 mmol, 1.0 equiv) in CH2Cl2 (2.5 mL) at 0 °C was added 2,6-lutidine (85 mL, 0.936 mmol, 3.0 equiv), and methanesulfonyl chloride (29 mL, 0.368 mmol, 1.5 equiv). The solution was stirred for 3 h, after which TLC of the reaction showed that all starting material had been consumed. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by chromatography on silica gel using hexanes/EtOAc to provide 27 mg of 26b (36% yield) as a colorless oil. equation M95 (c 0.29, CHCl3); IR νmax (film): 3283, 2959, 2930, 2872, 1581, 1489, 1459, 1317, 1228, 1147; 1H NMR (500 MHz, CDCl3) δ 7.17 (t, J = 8.0 Hz, 1H), 7.08–6.90 (m, 3H), 4.51 (br s, 1H), 4.10 (d, J = 11.3 Hz, 1H), 3.77–3.54 (m, 4H), 2.98 – 2.85 (m, 1H), 2.74 (ddd, J = 12.9, 6.1, 3.9 Hz, 1H), 2.71–2.59 (m, 2H), 2.55 (s, 3H), 1.55–1.41 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 156.1, 130.1, 128.3, 122.1, 122.0, 118.4, 67.5, 64.6, 62.4, 59.9, 43.8, 39.7, 30.7, 21.7, 12.0; HRMS (ESI) calcd for C15H23N2O3S [M + H]+: 311.1429, found: 311.1434.

(2S,3S)-1-Allyl-2-(hydroxymethyl)-3-phenyl-6-ortho-nosyl-1,6-diazaspiro[3.3]heptane des Br-15a

Scaffold des Br-15a was prepared identical to 15a. [α]D21 = +61.1 (c 0.96, CHCl3); IR νmax (film): 3387, 2952, 2874, 1544, 1370, 1356, 1169, 1031; 1H NMR (300 MHz, CDCl3) δ 7.95 (m, 1H), 7.66 (m, 3H), 7.31 (m, 5H), 5.84 (ddt, J = 6.3, 10.0, 16.4, 1H), 5.22 (d, J = 17.2, 1H), 5.02 (d, J = 10.1, 1H), 4.80 (d, J = 9.0, 1H), 4.14 (d, J = 8.9, 1H), 4.01 (d, J = 9.5, 1H), 3.92 (d, J = 9.4, 1H), 3.43 (m, 2H), 3.23 (m, 2H), 1.12 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 148.67, 136.11, 135.68, 134.01, 132.11, 131.94, 131.04, 129.73, 128.85, 127.80, 124.50, 118.24, 66.98, 64.40, 62.61, 61.21, 58.35, 54.67, 50.30; HRMS (ESI+) calcd for C21H24N3O5S [M + H]+: 430.1437, found 430.1425.

(2R,3R)-1-Allyl-2-(hydroxymethyl)-3-phenyl-6-ortho-nosyl-1,6-diazaspiro[3.3]heptane ent des Br-15a

[α]D21 = −69.3 (c 0.3, CHCl3); HRMS (ESI+) calcd for C21H24N3O5S [M + H]+: 430.1437, found 430.1428. Spectral data were identical to those provided for enantiomer des Br-15a.

(2S,3R)-1-Allyl-2-(hydroxymethyl)-3-phenyl-6-ortho-nosyl-1,6-diazaspiro[3.3]heptane des Br-15c

Scaffold des Br-15c was prepared identical to 15c. [α]D21 = +75.1 (c 1.0, CHCl3); IR νmax (film): 3399, 2922, 2873, 1542, 1354, 1169, 1126, 1030; 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J = 7.8, 1H), 7.73–7.59 (m, 3H), 7.31–7.21 (m, 3H), 7.11 (d, J = 7.7, 2H), 5.79 (ddt, J = 6.5, 10.1, 16.6, 1H), 5.18 (d, J = 17.1, 1H), 4.98 (d, J = 10.1, 1H), 4.33 (d, J = 9.3, 1H), 4.18 (dd, J = 9.4, 20.5, 2H), 3.70–3.63 (m, 2H), 3.60–3.52 (m, 2H), 3.45 (brd, J = 11.4, 1H), 3.34 (dd, J = 6.4, 13.5, 1H), 3.21 (dd, J = 6.6, 13.5, 1H), 2.83 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 148.60, 136.10, 134.83, 134.09, 131.91, 130.87, 130.24, 128.95, 128.01, 127.44, 124.29, 118.44, 66.15, 65.14, 63.86, 61.53, 53.38, 53.01, 45.79; HRMS (ESI+) calcd for C21H24N3O5S [M + H]+: 430.1437, found 430.1428.

(2R,3S)-1-Allyl-2-(hydroxymethyl)-3-phenyl-6-ortho-nosyl-1,6-diazaspiro[3.3]heptane ent des Br-15c

[α]D21 = −79.0 (c 0.38, CHCl3); HRMS (ESI+) calcd for C21H24N3O5S [M + H]+: 430.1437, found 430.1431. Spectral data were identical to those provided for enantiomer des Br-15c.

Solid-phase library synthesis

Solid-phase library synthesis was conducted on silicon-functionalized polystyrene Lanterns (L-series)14 equipped with radio frequency transponders for directed sorting and compound tracking. All reactions were conducted in heavy wall pressure vessels with agitation in an incubator shaker.

Scaffold loading

To a flame-dried flask containing silicon-functionalized Lanterns14 was added a freshly prepared solution of TfOH in anhydrous CH2Cl2 (9.0 equiv, 5 g of TfOH/100 mL of CH2Cl2) was added. Each flask was shaken at rt for 10 min at which time the Lanterns had turned bright orange. The deep red TfOH solution was removed via cannula and anhydrous 2,6-lutidine (12.0 equiv relative to Si) was added. Once the Lantern color had changed from orange to white, the appropriate stereoisomer of des-Br 15 (1.2 equiv. relative to Si) was added as a solution in anhydrous CH2Cl2 (0.4 mL/Lantern) and the reaction mixture was shaken at rt overnight. The loading mixture was removed and set aside (to recover any unreacted alcohol) and the Lanterns were washed with the following solvents for 30 min intervals: CH2Cl2, THF, 3:1 THF/IPA, 3:1 THF/H2O, DMF, 3:1 THF/H2O, 3:1 THF/IPA, THF, CH2Cl2. The Lanterns were then dried on a lyophilizer overnight prior to sorting. All 4 stereoisomers of des-Br 15 were loaded via the same protocol.

Nosyl removal

To a flask containing Lanterns was added THF (0.8 ml/Lantern) followed by thiophenol (20 eq) and potassium carbonate (30 eq). The Lanterns were shaken at rt overnight and then washed with the following solvents for 30 min intervals: DMF (two washes), THF/H2O (3:1), THF/isopropanol (3:1), THF, and CH2Cl2. The Lanterns were then dried on a lyophilizer overnight prior to sorting.

N-Capping/Sulfonyl Chlorides

To each flask containing Lanterns was added CH2Cl2 (0.8 mL/Lantern) followed by 2,6-lutidine (30 equiv) and the desired sulfonyl chloride (15 equiv). The Lanterns were shaken at rt overnight and then washed with following solvents for 30 min intervals: CH2Cl2, DMF, 3:1 THF/H2O, 3:1 THF/IPA, THF, CH2Cl2. The Lanterns were then dried on a lyophilizer overnight prior to sorting.

N-Capping/Isocyanates

To each flask containing Lanterns was added CH2Cl2 (0.8 mL/Lantern) followed the desired isocyanate (15 equiv). The Lanterns were shaken at rt overnight and then washed with following solvents for 30 min intervals: CH2Cl2, DMF, 3:1 THF/ H2O, 3:1 THF/IPA, THF, CH2Cl2. The Lanterns were then dried on a lyophilizer overnight prior to sorting.

N-Capping/Acids

To each flask containing lanterns was added CH2Cl2 (0.8mL/Lantern) followed by triethylamine (30 equiv) and the desired acid (20 equiv). PyBOP (20 equiv) was added and the Lanterns were shaken at rt overnight and then washed with following solvents for 30 min intervals: CH2Cl2, DMF, 3:1 THF/H2O, 3:1 THF/IPA, THF, CH2Cl2. The Lanterns were then dried on a lyophilizer overnight prior to sorting

N-Capping/Aromatic Aldehydes

To each flask containing Lanterns was added DMF with 2% AcOH (0.800 mL/Lantern) followed by the desired aldehyde (20 equiv). The reaction mixture was shaken at rt for 1 hr then sodium triacetoxyborohydride (25 equiv) was added and shaking was continued. After 3 days the reaction mixture was removed and the Lanterns were washed with the following solvents for 30 min intervals: DMF, 3:1 THF/H2O, 3:1 THF/IPA, THF, CH2Cl2. The Lanterns were then dried on a lyophilizer overnight prior to sorting.

N-Capping/Aliphatic Aldehydes

To each flask containing lanterns was added THF/MeOH 4:1 with 2% AcOH (0.800 mL/Lantern) followed by the desired aldehyde (20 equiv). The reaction mixture was shaken at rt for 1 hr then sodium cyanoborohydride (25 equiv) was added and shaking was continued. After 3 days the reaction mixture was removed and the Lanterns were washed with the following solvents for 30 min intervals: DMF, 3:1 THF/H2O, 3:1 THF/IPA, THF, CH2Cl2. The Lanterns were then dried on a lyophilizer overnight prior to sorting.

Allyl Removal

To a flask containing Lanterns was added EtOH (0.8 ml/Lantern) followed by Pd(PPh3)4 (2 eq) and 1,3-dimethylbarbituric acid (15 eq). The Lanterns were shaken at 40°C for 4 days and then washed with the following solvents for 30 min intervals: DMF (two washes), THF/H2O (3:1), THF/IPA (3:1), THF, and CH2Cl2. The Lanterns were then dried on a lyophilizer overnight prior to sorting.

Cleavage Protocol

To a 96-well plate containing Lanterns was added a 15% solution of HF/pyridine in stabilized THF (350 µL/Lantern). After 2 h the cleavage solution was quenched with TMSOMe (700 µL/Lantern) and the contents of each well were transferred to a pre-weighed 1-mL tube. The Lanterns were washed with an additional 200 µL of stabilized THF (or THF/MeOH) and the solution was transferred to the same 1-mL tube. The samples were concentrated on a multi-sample solvent evaporation system overnight without heating. The recovered mass for each library member was determined on an automated weighing system.

Supplementary Material

10_si_010

11_si_011

12_si_012

13_si_013

1_si_001

2_si_002

3_si_003

4_si_004

5_si_005

6_si_006

7_si_007

8_si_008

9_si_009

ACKNOWLEDGMENT

This work was funded in part by the NIGMS-sponsored Center of Excellence in Chemical Methodology and Library Development (Broad Institute CMLD; P50 GM069721), as well as the NIH Genomics Based Drug Discovery U54 grants Discovery Pipeline RL1CA133834 (administratively linked to NIH grants RL1HG004671, RL1GM084437, and UL1DE019585) and the Stanley Medical Research Institute.

Footnotes

SUPPORTING INFORMATION

1H and 13C NMR spectra for all new compounds, LCMS data for representative library members, Charts SI-1 and SI-2 which were cited in reference 41, Figure SI-1 which was cited in reference 41 and X-ray crystallographic information for select compounds.

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