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European Journal of Organic Chemistry
 
European J Org Chem. 2017 March 3; 2017(9): 1262–1271.
Published online 2017 March 8. doi:  10.1002/ejoc.201601432
PMCID: PMC5347843

Stereoselective Synthesis of Functionalized Bicyclic Scaffolds by Passerini 3‐Center‐2‐Component Reactions of Cyclic Ketoacids

Abstract

We report the use of bifunctional starting materials (ketoacids) in a diastereoselective Passerini three‐center‐two‐component reaction. Study of the reaction scope revealed the required structural features for stereoselectivity in the isocyanide addition. In this system, an interesting isomerization of the primary Passerini product – the α‐carboxamido lactone – into an atypical product, an α‐hydroxy imide, was found to occur under acidic conditions. Furthermore, enantioenriched Passerini products can be generated from an enantioenriched ketoacid obtained by chemoenzymatic synthesis.

Keywords: Multicomponent reactions, Cyclization, Ketoacids, Diastereoselectivity, Lactones, Rearrangement

Introduction

Isocyanide‐based multicomponent reactions (IMCRs) are essential tools in combinatorial and diversity‐oriented synthesis. Based on the unique reactivity of the formally divalent isocyanide carbon atom, this chemistry facilitates the efficient exploration of chemical space, rapidly generating complexity from simple starting materials. Importantly, the primary MCR (multicomponent reaction) products provide numerous opportunities for further synthetic elaboration, for instance into planar heterocycles as well as sp3‐rich structures1 The first discovered IMCR, the Passerini reaction, in which an aldehyde (or ketone), a carboxylic acid, and an isocyanide are combined,2 still represents one of the most widely used IMCRs in various applications3 owing to its many advantages (convergence, atom economy, simple operation, broad scope).4 However, its most important limitation, the poor control over the stereochemistry of the newly formed stereocenter, is also well recognized in the multicomponent reaction community.5 Despite the great efforts that have been made to address this issue, successful asymmetric Passerini reactions are still limited to just a few examples of catalytic enantioselective variants6 and diastereoselective reactions (with chiral isocyanides,7 chiral carboxylic acids,8 or chiral aldehydes/ketones,9 respectively). Some representative examples of diastereoselective Passerini reactions are shown in Scheme Scheme1.1. A relatively simple strategy to improve the modest stereocontrol involves the use of bifunctional starting materials (oxoacids), as the (partially) intramolecular reaction benefits from a more sterically constrained transition state for the isocyanide addition. The bifunctional nature of oxoacid components has been strategically exploited in isocyanide chemistry to create a broad spectrum of heterocycles through the Ugi reaction (Scheme (Scheme22).10 However, similar examples of the Passerini reaction are scarce (Scheme (Scheme1D1D and E).11

Scheme 1
Diastereoselective Passerini reactions. PMP = p‐methoxyphenyl; Boc = tert‐butoxycarbonyl.
Scheme 2
Use of oxoacids in Ugi reactions.

In this paper, we report a new diastereoselective Passerini reaction using simple cyclic oxoacids as starting materials. The reaction proceeds through a fused bicyclic transition state with additional steric constraints, thus leading to improved stereoselectivity. Furthermore, we report the unusual rearrangement of these Passerini products to give unprecedented α‐hydroxy bicyclic imides.

Results and Discussion

We began our investigation with the reaction between 2‐(2‐oxocyclohexyl)acetic acid (1a) and tert‐butyl isocyanide (2a; 1.5 equiv.). Under standard Passerini conditions (CH2Cl2, room temp.), the reaction proceeded smoothly to give the desired product with already good diastereoselectivity (85:15) in favor of the trans‐fused isomer (Table 1, entry 1). The stereochemistry corresponds to an axial attack of the isocyanide (expected for a non‐sterically‐demanding nucleophile12) to yield a cis‐fused O‐acyl imidate α‐adduct, which, upon Mumm rearrangement, gives trans‐fused bicyclic lactone 3a (see also Scheme Scheme3).3). This structure was unambiguously confirmed by X‐ray diffraction analysis, as shown in Figure Figure11.

Figure 1
X‐ray structure of major trans diastereoisomer 3a (some H atoms omitted for clarity).
Scheme 3
Negative control experiments in the formal 1,3(O–N) Mumm rearrangement of scaffold 3.
Table 1
Optimization of the intramolecular Passerini reaction with 1a a

Encouraged by this initial result, we attempted to improve the diastereomeric ratio of the isocyanide addition by varying the solvent. The reaction was found to proceed in most of the solvents investigated (toluene, dimethyl carbonate, tert‐butanol, methanol, and even water) but with lower stereoselectivity. We then resorted to Lewis acid catalysis with the hypothesis that coordination of both carbonyl groups (and possibly the isocyanide as well) to a metal center would lead to a more rigid transition state.[9c] A small screening13 identified Zn(OTf)2 as a promising candidate for improved diastereoselectivity (Table 1, entry 3). Since the Lewis acid also led to an increase in the reaction rate, we repeated the solvent screening and focused on the solvent with the slowest background (uncatalyzed) reaction. Thus, the reaction with Zn(OTf)2 (20 mol‐%) in dimethylcarbonate (DMC)14 gave complete conversion and a 9:1 diastereomeric ratio (Table 1, entry 9). Carrying out the reaction at 0 °C was detrimental to both the yield and the selectivity (possibly due to the insolubility of the catalyst), but we observed that we could significantly decrease both the catalyst loading (to 10 mol‐%) and the reaction time (to 2 h) without adverse effects. These conditions turned out to be optimal, as any further decrease in the amount of isocyanide (Table 1, entry 14) or in the catalyst loading (entry 15) did not lead to improved results.

Having established this optimal protocol, we went on to investigate the scope of the reaction in terms of the isocyanide component. Gratifyingly, all classes of isocyanides are accepted in this reaction (Table 2): aliphatic (tertiary [products 3a, 3b], secondary [products 3c, 3d], primary [products 3e, 3f]), aromatic (including the bulky 2,6‐dimethylphenyl derivative [product 3h]), and α‐acidic (products 3i, 3j). In general, the diastereoisomers of the products were readily separated by flash chromatography, and the isolated yields of the pure trans‐fused Passerini products 3a3j were moderate to high. As expected for relatively small linear nucleophiles like isocyanides, the diastereoselectivity was well conserved across the series (ca. 9:1, as in the parent example 3a).

Table 2
Scope of the reaction in terms of isocyanidesa

Next, we sought to extend this intramolecular Passerini reaction to other oxoacids in order to rationalize the structural features required for high diastereoselectivity. In this context, we focused on the ring size, the distance between the ketone and carboxylic acid, and the conformational flexibility of the oxoacid 1.

First, the introduction of a carbamate group into the cyclohexanone ring (starting material 1b) led to a drastic decrease in the reaction rate (Table 3, entry 1), possibly due to a preferential binding of the Zn ions to this additional coordinating group. A starting material with the keto and carboxylic groups in a 1,5‐relationship reacted somewhat more slowly (the imidate α‐adduct is a seven‐membered ring in this case) but still gave the products 3l and 3m in reasonable yield under the standard conditions (with tBuNC and TsCH2NC, Table 3, entries 2 and 3). The diastereoselectivity was found to be lower (3:1), but the direction of isocyanide attack was preserved (trans‐fused products predominated). Unfortunately, we found that the reaction is not tolerant of variation in the nature of the cyclic ketone; starting materials based on a cyclopentanone (1d), cycloheptanone (1e), or tetralone (1f) motif gave slow conversions and side reactions (Table 3, entries 4–7). Due to ring strain, the carbonyl group is particularly reactive in the cyclohexanone system compared to the C5 and C7 homologs; conjugation with the aromatic ring drastically decreases the reactivity of 1f. Furthermore, side reactions (e.g., multiple isocyanide addition) may take place as a result of conformational/strain effects disfavoring the formation of the usual reaction intermediates. Indeed, for starting material 1d, a more ionic mechanism (i.e., isocyanide addition to generate a nitrilium ion followed by addition of the carboxylate15) can be expected, since the nucleophilic attack would presumably take place from the least hindered diastereotopic face of the carbonyl group leading to a strained trans‐fused α‐adduct16 This adduct may be difficult to form, and may not evolve cleanly into a single product. Additionally, intermolecular reactions can take place if the transition state for the intramolecular condensation is not favorable. Evidence for these side reactions was obtained in the reaction of 1d with tBuNC under the standard conditions: a complex mixture of products was observed (Table 3, entry 4). Moreover, in the case of the less reactive isocyanide TsCH2NC, the conversion was low, and product formation could not be confirmed. In the case of the seven‐membered homolog 1e, HRMS analysis indicated the formation of the desired product 3p, but we were unable to isolate it from the complex product mixture. A similar outcome was observed for tetralone‐based acid 1f. On the other hand, the simple acyclic derivative 1g reacted cleanly, albeit slowly and with no stereoselectivity (Table 3, entry 8). Extending the reaction time to 24 h allowed the isolation of the expected Passerini product of 1g and TsCH2NC in 82 % yield (Table 3, entry 9), but for this scaffold the diastereoisomers could not be separated. As a control experiment, the Passerini reaction of tBuNC, AcOH, and cyclohexanone proceeded to completion within 24 h, even in the absence of a Lewis acid catalyst (Table 3, entry 10). This result confirms the particularly high electrophilicity of cyclohexanone. Remarkably, the addition of catalytic Zn(OTf)2 gave a much lower yield (ca. 50 %; Table 3, entry 11) due to side reactions. Thus, the Lewis acid not only enhances the rate of the desired pathway but also that of alternative pathways, possibly by a switch in the reaction mechanism. Clearly, the success of the reaction depends on a fine balance between the rigidity of the transition state required for good diastereoselectivity (1a vs. 1g, 1c vs. 1g) and some degree of conformational flexibility to prevent side reactions (1g vs. 1d).

Table 3
Scope of the reaction in terms of ketoacidsa

Upon crystallization of Passerini product 3j from ethanol, we were intrigued to find that the structure revealed by X‐ray diffraction analysis corresponded to a rearrangement of the scaffold to α‐hydroxy imide 4j (Figure (Figure2).2). We then investigated this unusual transformation further, and found that it is amenable to Brønsted acid catalysis. Surprisingly, the conditions required to drive this rearrangement [MeSO3H (1 equiv.), CHCl3, 80 °C] are not as mild as might be expected from the crystallization experiment,17 and the rate varies significantly and relatively inconsistently with the type of secondary amide substituent.

Figure 2
X‐ray structure of 4j (some H atoms omitted for clarity).

Nevertheless, this transformation is general in the series of Passerini products 3a3j and can be pushed to near completion over 24 h (Table 4). The tertiary derivatives 3a and 3b represent a special case as they undergo dealkylation under these conditions: for 3a, the conversion was slow, and led to a mixture of products, whereas for the tert‐octyl derivative 3b the corresponding free α‐hydroxy imide (4b, R = H) could be isolated in reasonable yield (Table 4, entry 2). We hypothesize that ring strain plays an important role in this rearrangement, which corresponds to a formal 1,3(O–N) acyl transfer in the Passerini α‐adduct instead of acyl migration to the OH group. The thermodynamic driving force for this isomerization is most probably the release of strain in moving from the trans‐fused [4.3.0] bicyclic system to the more relaxed cis‐hexahydroisoquinolinedione scaffold. This premise is supported by negative control experiments: the minor diastereoisomer 3h′ was stable under the rearrangement conditions, whereas homolog 3m and monocyclic lactone 3r gave at best low conversions over 24 h (Scheme (Scheme33).

Table 4
Rearrangement of Passerini products to α‐hydroxyimidesa

Finally, we attempted to control not only the diastereoselectivity, but also the absolute stereochemistry during our intramolecular Passerini reaction.18 Thus, asymmetric bioreduction of unsaturated keto ester 5 with the nicotinamide‐dependent ene‐reductase NCR from Zymomonas mobilis 19 and subsequent hydrogenolysis delivered (R)‐1a.20 This can then react with isocyanides to give enantioenriched Passerini products,21 as exemplified for 3a (Scheme (Scheme4).4). This result underlines the fruitful complementarity of biocatalysis and multicomponent reactions in the asymmetric synthesis of valuable small molecules.22

Scheme 4
Chemoenzymatic preparation of enantioenriched 3a. NADH = nicotinamide adenine dinucleotide.

Conclusions

In conclusion, we report a new diastereoselective intramolecular Passerini reaction with cyclic ketoacids leading to interesting sp3‐rich bicyclic lactones. The structural features required for high stereoselectivity in the isocyanide addition were identified and discussed. Interestingly, these Passerini products can isomerize to α‐hydroxy imide derivatives as formal 1,3(O–N) Mumm rearrangement products of the α‐adducts. Furthermore, complete stereocontrol can be achieved by combining this diastereoselective isocyanide addition with a chemoenzymatic preparation of the nonracemic ketoacid building block.

Experimental Section

General Information: Unless stated otherwise, all solvents and commercially available reagents were used as purchased. Melting points were recorded with a Büchi M‐565 melting‐point apparatus. Nuclear magnetic resonance (NMR) spectra were recorded with a Bruker Avance 500 (125.78 MHz for 13C) or Bruker Avance 400 (100.62 MHz for 13C) instrument with the residual solvent as an internal standard (1H: δ = 7.26 ppm, 13C{1H}: δ = 77.16 ppm for CDCl3; 1H: δ = 2.50 ppm, 13C{1H}: δ = 39.52 ppm for [D6]DMSO). Chemical shifts (δ) are given in ppm, and coupling constants (J) are quoted in Hertz (Hz). Resonances are described as s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), sex (sextet), sep (septet), br. (broad singlet), and m (multiplet) or combinations thereof. Infrared (IR) spectra were recorded neat by using a Shimadzu FTIR‐8400s spectrophotometer, and data are reported in wavenumbers (cm–1). Electrospray ionization (ESI) high‐resolution mass spectrometry (HRMS) was carried out by using a Bruker microTOF‐Q instrument in positive‐ion mode (capillary potential of 4500 V). Chiral GC analysis was carried out with a Shimadzu GC‐2010 Plus chromatograph. Flash chromatography was carried out on Silicycle Silia‐P flash silica gel (particle size 40–63 µm, pore diameter 60 Å) by using the indicated eluent. Thin‐layer chromatography (TLC) was carried out with TLC plates from Merck (SiO2, Kieselgel 60 F254 neutral, on aluminium with fluorescence indicator). X‐ray structures were determined with an Agilent Supernova diffractometer equipped with a Cu microsource, mirror monochromator, and Atlas CCD detector. Omega scans were used at liquid‐nitrogen temperatures. Additional experimental details can be found in the CIFs in the Supporting Information. The ketoacids 1a and 1c1f are known compounds, and were prepared according to literature procedures: 1a,23 1c,24 1d,25 1e,25 1f.26 Compound 1g is commercially available.

General Optimization Procedure: Zn(OTf)2 (0.05 mmol, 0.1 equiv.) and isocyanide 2a (0.75 mmol, 1.5 equiv.) were added to a solution of ketoacid 1a (0.5 mmol, 1 equiv.) in solvent (1 mL). The solution was stirred at room temperature for 2–20 h. Then the mixture was diluted with CH2Cl2, and quenched with a saturated NaHCO3 solution. The organic layer was separated, and the aqueous layer was extracted again with CH2Cl2. The combined organic layers were dried with Na2SO4, and concentrated in vacuo. The crude yield of 3a and the ratio 3a/3a′ were determined by NMR spectroscopic analysis with mesitylene as an internal standard.

Procedure A – Intramolecular Passerini Reaction: Zn(OTf)2 (0.1 mmol, 0.1 equiv.) and isocyanide 2 (1.5 mmol, 1.5 equiv.) were added to a solution of ketoacid 1 (1 mmol, 1 equiv.) in dimethyl carbonate (2 mL). The solution was stirred at room temperature for 2 h. Then the mixture was diluted with CH2Cl2, and quenched with a saturated NaHCO3 solution. The organic layer was separated, and the aqueous layer was extracted again with CH2Cl2. The combined organic layers were dried with Na2SO4, and concentrated in vacuo. The crude product 3 was purified by column chromatography on silica gel.

Procedure B – Rearrangement of Passerini Products: Passerini product 3 (0.1 mmol) was dissolved in CHCl3, and CH3SO3H (0.1 mmol, 1 equiv.) was added. The solution was heated at 80 °C in a sealed vial for 1–24 h (conversion monitored by TLC). The solution was then diluted with CH2Cl2, and quenched with a saturated NaHCO3 solution. The organic layer was separated, and the aqueous layer was extracted again with CH2Cl2. The combined organic layers were dried with Na2SO4, and concentrated in vacuo. The yield and the ratio 4/3 were determined by NMR spectroscopic analysis.

N‐(tert‐Butyl)‐2‐oxohexahydrobenzofuran‐7a(2H)‐carboxamide (3a/3a′): Prepared from 2‐(2‐oxocyclohexyl)acetic acid (1a; 156 mg, 1 mmol, 1 equiv.) and tert‐butyl isocyanide (170 µL, 1.5 mmol, 1.5 equiv.) according to Procedure A. Purification: column chromatography on silica (cyclohexane/ethyl acetate, 4:1); the diastereoisomers could be separated [R f = 0.50 (major) and R f = 0.34 (minor)].

Data for major diastereoisomer 3a (trans): Isolated as a slowly crystallizing solid (182 mg, 0.76 mmol, 76 %). M.p. 50–54 °C. 1H NMR (500 MHz, CDCl3): δ = 6.08 (br., 1 H), 2.52 (qd, J = 12.5, J = 3.5 Hz, 1 H), 2.46–2.34 (m, 2 H), 2.18–2.06 (m, 2 H), 2.01–1.87 (m, 2 H), 1.78 (d, J = 13.0 Hz, 1 H), 1.76–1.66 (m, 2 H), 1.47–1.37 (m, 1 H), 1.35 (s, 9 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 175.9 (C), 170.2 (C), 86.5 (C), 51.6 (C), 48.5 (CH), 34.6 (CH2), 33.8 (CH2), 28.7 (CH3), 25.3 (CH2), 24.0 (CH2), 22.1 (CH2) ppm. IR (neat): [nu with tilde] = 3396 (m), 2924 (w), 2868 (w), 1790 (s), 1665 (s), 1522 (s), 1452 (m), 1180 (s), 1024 (s), 901 (m), 881 (m), 552 (m) cm–1. HRMS (ESI): calcd. for C13H22NO3 [M + H]+ 240.1595; found 240.1594. Crystals for single‐crystal X‐ray diffraction were grown from dichloromethane.

Data for minor diastereoisomer 3a′ (cis): Isolated as a white solid (14 mg, 0.06 mmol, 6 %). M.p. 93–105 °C. 1H NMR (500 MHz, CDCl3): δ = 6.15 (br., 1 H), 2.88–2.77 (m, 1 H), 2.51 (dd, J = 17.0, J = 7.0 Hz, 1 H), 2.19 (dd, J = 17.0, J = 2.0 Hz, 1 H), 1.97–1.87 (m, 3 H), 1.73–1.57 (m, 2 H), 1.47–1.34 (m, 2 H), 1.32 (s, 9 H), 1.21–1.10 (m, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 176.2 (C), 171.8 (C), 87.2 (C), 51.6 (C), 36.4 (CH), 36.3 (CH2), 31.3 (CH2), 28.7 (CH3), 28.0 (CH2), 22.3 (CH2), 20.4 (CH2) ppm. IR (neat): [nu with tilde] = 3354 (m), 2951 (w), 1780 (s), 1736 (s), 1670 (s), 1533 (m), 1414 (m), 1188 (s), 1011 (s), 935 (s), 885 (s), 710 (m), 548 (m) cm–1.

N‐(2,4,4‐Trimethylpentan‐2‐yl)‐2‐oxohexahydrobenzofuran‐7a(2H)‐carboxamide (3b): Prepared from 2‐(2‐oxocyclohexyl)acetic acid (1a; 156 mg, 1 mmol, 1 equiv.) and 1,1,3,3‐tetramethylbutyl isocyanide (263 µL, 1.5 mmol 1.5 equiv.) according to Procedure A. Purification: column chromatography on silica (cyclohexane/ethyl acetate, 4:1); the diastereoisomers could be separated [R f = 0.50 (major) and R f = 0.37 (minor)]. The major diastereoisomer 3b (trans) was isolated as a white solid (200 mg, 0.68 mmol, 68 %). M.p. 59–67 °C. 1H NMR (500 MHz, CDCl3): δ = 6.11 (br., 1 H), 2.52 (qd, J = 12.7, J = 4.0 Hz, 1 H), 2.42–2.32 (m, 2 H), 2.13–2.04 (m, 2 H), 1.94–1.82 (m, 2 H), 1.79–1.61 (m, 5 H), 1.39–1.31 (m, 1 H), 1.35 (s, 6 H), 0.96 (s, 9 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 175.7 (C), 169.6 (C), 86.3 (C), 55.4 (C), 55.8 (CH2), 48.3 (CH), 34.2 (CH2), 33.6 (CH2), 31.6 (C), 31.4 (CH3), 28.8 (CH3), 25.0 (CH2), 23.7 (CH2), 21.8 (CH2) ppm. IR (neat): [nu with tilde] = 3394 (m), 2948 (w), 2868 (w), 1788 (s), 1675 (s), 1522 (s), 1454 (m), 1177 (s), 1018 (s), 878 (m), 718 (m) cm–1. HRMS (ESI): calcd. for C17H30NO3 [M + H]+ 296.2220; found 296.2215.

N‐Cyclohexyl‐2‐oxohexahydrobenzofuran‐7a(2H)‐carboxamide (3c): Prepared from 2‐(2‐oxocyclohexyl)acetic acid (1a; 156 mg, 1 mmol, 1 equiv.) and cyclohexyl isocyanide (187 µL, 1.5 mmol, 1.5 equiv.) according to Procedure A. Purification: column chromatography on silica (cyclohexane/ethyl acetate, 4:1); the diastereoisomers could be separated [R f = 0.46 (major) and R f = 0.23 (minor)]. The major diastereoisomer 3c (trans) was isolated as a white solid (180 mg, 0.68 mmol, 68 %). M.p. 111–114 °C. 1H NMR (500 MHz, CDCl3): δ = 6.19 (br., 1 H), 3.75–3.64 (m, 1 H), 2.49 (qd, J = 12.0, J = 4.0 Hz, 1 H), 2.42–2.28 (m, 2 H), 2.17–2.06 (m, 2 H), 1.90–1.62 (m, 9 H), 1.62–1.53 (m, 1 H), 1.44–1.27 (m, 3 H), 1.20–1.06 (m, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 175.9 (C), 169.8 (C), 86.5 (C), 48.5 (CH), 34.5 (CH2), 33.7 (CH2), 33.1 (CH2), 32.8 (CH2), 31.1 (CH), 25.5 (CH2), 25.3 (CH2), 24.9 (CH2), 24.9 (CH2), 23.9 (CH2), 22.1 (CH2) ppm. IR (neat): [nu with tilde] = 3323 (w), 2930 (m), 2851 (m), 1784 (s), 1643 (s), 1518 (s), 1445 (m), 1194 (m), 1180 (m), 1024 (s), 918 (m), 883 (m), 725 (w), 694 (s), 538 (m) cm–1. HRMS (ESI): calcd. for C15H24NO3 [M + H]+ 266.1751; found 266.1751.

N‐Isopropyl‐2‐oxohexahydrobenzofuran‐7a(2H)‐carboxamide (3d): Prepared from 2‐(2‐oxocyclohexyl)acetic acid (1a; 156 mg, 1 mmol, 1 equiv.) and isopropyl isocyanide (141 µL, 1.5 mmol 1.5 equiv.) according to Procedure A. Purification: column chromatography on silica (cyclohexane/ethyl acetate, 3:1); the diastereoisomers could be separated [R f = 0.5 (major) and R f = 0.25 (minor)]. The major diastereoisomer 3d (trans) was isolated as a white solid (124 mg, 0.55 mmol, 55 %). M.p. 84–86 °C. 1H NMR (500 MHz, CDCl3): δ = 6.19 (d, J = 12.0 Hz, 1 H), 4.04–3.96 (m, 1 H), 2.49 (qd, J = 12.6, J = 3.8 Hz, 1 H), 2.44–2.30 (m, 2 H), 2.16–2.07 (m, 2 H), 1.98–1.84 (m, 2 H), 1.80–1.65 (m, 3 H), 1.43–1.31 (m, 1 H), 1.11 (d, J = 6.5 Hz, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 175.6 (C), 169.5 (C), 86.1 (C), 48.1 (CH), 41.1 (CH), 34.1 (CH2), 33.4 (CH2), 24.9 (CH2), 23.6 (CH2), 22.4 (CH3), 22.2 (CH3), 21.7 (CH2) ppm. IR (neat): [nu with tilde] = 3310 (w), 2927 (m), 1784 (s), 1645 (s), 1521 (s), 1450 (m), 1196 (m), 1026 (s), 906 (m), 883 (m), 696 (s) cm–1. HRMS (ESI): calcd. for C12H20NO3 [M + H]+ 226.1438; found 226.1437.

N‐Pentyl‐2‐oxohexahydrobenzofuran‐7a(2H)‐carboxamide (3e): Prepared from 2‐(2‐oxocyclohexyl)acetic acid (1a; 156 mg, 1 mmol, 1 equiv.) and n‐pentyl isocyanide (188 µL, 1.5 mmol, 1.5 equiv.) according to Procedure A. Purification: column chromatography on silica (cyclohexane/ethyl acetate, 5:1); the diastereoisomers could be separated [R f = 0.30 (major)]. The major diastereoisomer 3e (trans) was isolated as a white solid (177 mg, 0.70 mmol, 70 %). M.p. 55–57 °C. 1H NMR (500 MHz, CDCl3): δ = 6.33 (br., 1 H), 3.25–3.14 (m, 2 H), 2.50 (dq, J = 12.6, J = 3.9 Hz, 1 H), 2.44–2.29 (m, 2 H), 2.18–2.09 (m, 2 H), 1.99–1.83 (m, 2 H), 1.81–1.64 (m, 3 H), 1.50–1.33 (m, 3 H), 1.32–1.19 (m, 4 H), 0.87 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 175.7 (C), 170.5 (C), 86.5 (C), 48.4 (CH), 39.1 (CH2), 34.3 (CH2), 33.5 (CH2), 29.0 (CH2), 28.9 (CH2), 25.1 (CH2), 23.7 (CH2), 22.2 (CH2), 21.8 (CH2), 13.9 (CH3) ppm. IR (neat): [nu with tilde] = 3312 (w), 2928 (m), 2866 (w), 1788 (s), 1651 (s), 1533 (s), 1439 (m), 1194 (m), 1184 (m), 1026 (s), 943 (m), 881 (m), 704 (m), 561 (w) cm–1. HRMS (ESI): calcd. for C14H24NO3 [M + H]+ 254.1751.1751; found 254.1745.

N‐Benzyl‐2‐oxohexahydrobenzofuran‐7a(2H)‐carboxamide (3f): Prepared from 2‐(2‐oxocyclohexyl)acetic acid (1a; 156 mg, 1 mmol, 1 equiv.) and benzyl isocyanide (183 µL, 1.5 mmol 1.5 equiv.) according to Procedure A. Purification: column chromatography on silica (cyclohexane/ethyl acetate, 4:1); the diastereoisomers could be separated [R f = 0.5 (major) and R f = 0.3 (minor)]. The major diastereoisomer 3f (trans) was isolated as a yellowish solid (200 mg, 0.73 mmol, 73 %). M.p. 56–66 °C. 1H NMR (500 MHz, CDCl3): δ = 7.32–7.29 (m, 2 H), 7.27–7.25 (m, 1 H), 7.20 (d, J = 7.3 Hz, 2 H), 6.78 (br., 1 H), 4.33 (dd, J = 14.8, J = 5.5 Hz, 1 H), 4.45 (dd, J = 14.8, J = 6.1 Hz, 1 H), 2.51 (dq, J = 12.7, J = 4.0 Hz, 1 H), 2.44–2.34 (m, 2 H), 2.17–2.10 (m, 2 H), 1.98–1.88 (m, 2 H), 1.80–1.78 (m, 1 H), 1.74–1.69 (m, 2 H), 1.42–1.35 (m, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 175.6 (C), 170.5 (C), 137.7 (C), 128.7 (CH), 127.5 (CH), 127.3 (CH), 86.5 (C), 48.3 (CH), 34.2 (CH2), 33.5 (CH2), 29.6 (CH2), 25.0 (CH2), 23.7 (CH2), 21.8 (CH2) ppm. IR (neat): [nu with tilde] = 3315 (w), 2930 (m), 1782 (s), 1653 (s), 1522 (s), 1427 (m), 1194 (m), 1183 (m), 1021 (s), 938 (m), 885 (m), 733 (s), 693 (s), 557 (s) cm–1. HRMS (ESI): calcd. for C16H20NO3 [M + H] + 274.1438; found 274.1435.

N‐(2‐Naphthyl)‐2‐oxohexahydrobenzofuran‐7a(2H)‐carboxamide (3g): Prepared from 2‐(2‐oxocyclohexyl)acetic acid (1a; 78 mg, 0.5 mmol, 1 equiv.) and 2‐naphthyl isocyanide (115 mg, 0.75 mmol, 1.5 equiv.) according to Procedure A. Purification: column chromatography on silica (cyclohexane/ethyl acetate, 7:1); the diastereoisomers could be partially separated [R f = 0.20 (major) and R f = 0.18 (minor)]. The major diastereoisomer 3g (trans) was isolated as a white solid (77 mg, 0.25 mmol, 50 %). M.p. 115–129 °C (dec.). 1H NMR (500 MHz, CDCl3): δ = 8.23 (br., 1 H), 8.22 (d, J = 13.5 Hz, 1 H), 7.78 (t, J = 8.0 Hz, 3 H), 7.46 (t, J = 8.0 Hz, 1 H), 7.42 (t, J = 7.0 Hz, 2 H), 2.65 (qd, J = 13.0, J = 4.2 Hz, 1 H), 2.54–2.46 (m, 2 H), 2.37–2.29 (m, 1 H), 2.28–2.17 (m, 1 H), 2.07–1.92 (m, 2 H), 1.91–1.75 (m, 3 H), 1.52–1.40 (m, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 175.5 (C), 169.2 (C), 134.5 (C), 133.8 (C), 131.0 (C), 129.0 (CH), 127.8 (CH), 127.6 (CH), 126.7 (CH), 125.4 (CH), 120.2 (CH), 117.2 (CH), 86.7 (C), 48.5 (CH), 34.4 (CH2), 33.7 (CH2), 25.2 (CH2), 23.9 (CH2), 22.0 (CH2) ppm. IR (neat): [nu with tilde] = 3332 (w), 2937 (w), 1772 (s), 1684 (s), 1540 (m), 1223 (m), 1021 (s), 810 (m) cm–1. HRMS (ESI): calcd. for C20H23NNaO4 [M + MeOH + Na]+ 364.1519; found 364.1564.

N‐(2,6‐Dimethylphenyl)‐2‐oxohexahydrobenzofuran‐7a(2H)‐carboxamide (3h/3h′): Prepared from 2‐(2‐oxocyclohexyl)acetic acid (1a; 156 mg, 1 mmol, 1 equiv.) and 2,6‐dimethylphenyl isocyanide (196 mg, 1.5 mmol, 1.5 equiv.) according to Procedure A. Purification: column chromatography on silica (cyclohexane/ethyl acetate, 4:1); the diastereoisomers could be separated [R f = 0.21 (major) and R f = 0.10 (minor)].

Data for major diastereoisomer 3h (trans): Isolated as a white solid (194 mg, 0.68 mmol, 68 %). M.p. 157–159 °C. 1H NMR (500 MHz, CDCl3): δ = 7.61 (br., 1 H), 7.14–7.04 (m, 3 H), 2.58 (qd, J = 13.0, J = 3.5 Hz, 1 H), 2.51 (d, J = 10.5 Hz, 2 H), 2.36 (d, J = 12.5 Hz, 1 H), 2.28–2.18 (m, 1 H), 2.18 (s, 6 H), 2.01–1.83 (m, 4 H), 1.74 (d, J = 12.5 Hz, 1 H), 1.50–1.38 (m, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 175.7 (C), 169.3 (C), 135.3 (C), 132.9 (C), 128.4 (CH), 127.7 (CH), 87.1 (C), 48.5 (CH), 34.7 (CH2), 33.8 (CH2), 25.3 (CH2), 23.9 (CH2), 22.1 (CH2), 18.5 (CH3) ppm. IR (neat): [nu with tilde] = 3294 (w), 2922 (w), 1782 (s), 1655 (m), 1499 (m), 1190 (m), 1020 (s), 912 (m), 883 (m), 770 (m), 706 (m), 519 (m) cm–1. HRMS (ESI): calcd. for C17H22NO3 [M + H]+ 288.1595; found 288.1594.

Data for minor diastereoisomer 3h′ (cis): Isolated as a white solid (23 mg, 0.08 mmol, 8 % (contains 10 % of the trans diastereoisomer). 1H NMR (500 MHz, CDCl3): δ = 7.71 (br., 1 H), 7.15–7.03 (m, 3 H), 3.02–2.92 (m, 1 H), 2.68 (dd, J = 17.0, J = 7.0 Hz, 1 H), 2.29 (d, J = 17.0 Hz, 1 H), 2.21–2.14 (m, 1 H), 2.16 (s, 6 H), 2.09–1.93 (m, 2 H), 1.80–1.65 (m, 2 H), 1.56–1.35 (m, 2 H), 1.28–1.17 (m, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 176.0 (C), 171.0 (C), 135.3 (C), 132.7 (C), 128.4 (CH), 127.8 (CH), 87.7 (C), 36.6 (CH2), 36.3 (CH), 31.5 (CH2), 28.1 (CH2), 22.3 (CH2), 20.3 (CH2), 18.4 (CH3), ppm. IR (neat): [nu with tilde] = 3288 (w), 2924 (w), 1782 (s), 1655 (m), 1499 (m), 1190 (m), 1113 (s), 912 (m), 883 (m), 770 (m), 706 (m), 519 (m) cm–1.

N‐(Tosylmethyl)‐2‐oxohexahydrobenzofuran‐7a(2H)‐carboxamide (3i): Prepared from 2‐(2‐oxocyclohexyl)acetic acid (1a; 156 mg, 1 mmol, 1 equiv.) and tosylmethyl isocyanide (196 mg, 1 mmol, 1 equiv.) according to Procedure A. Purification: column chromatography on silica (cyclohexane/ethyl acetate, 3:1 to cyclohexane/ethyl acetate, 1:1); the diastereoisomers could be separated [R f = 0.15 (major) in cyclohexane/ethyl acetate, 3:1]. The major diastereoisomer 3i (trans) was isolated as a gummy white solid (280 mg, 0.80 mmol, 80 %). 1H NMR (500 MHz, CDCl3): δ = 7.71 (d, J = 7.5 Hz, 2 H), 7.53 (t, J = 6.3 Hz, 1 H), 7.28 (d, J = 7.5 Hz, 2 H), 4.66 (d, J = 6.5 Hz, 2 H), 2.36 (s, 3 H), 2.33–2.11 (m, 2 H), 2.11–2.93 (m, 3 H), 1.76–1.50 (m, 4 H), 1.40–1.17 (m, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 175.4 (C), 170.1 (C), 145.3 (C), 133.8 (C), 129.9 (CH), 128.9 (CH), 86.4 (C), 59.6 (CH2), 47.9 (CH), 33.8 (CH2), 33.3 (CH2), 24.7 (CH2), 23.4 (CH2), 22.6 (CH3), 22.5 (CH2) ppm. IR (neat): [nu with tilde] = 3377 (w), 2935 (w), 1786 (s), 1686 (s), 1597 (w), 1499 (m), 1321 (m), 1286 (m), 1140 (s), 1018 (s), 925 (m), 727 (s) cm–1. HRMS (ESI): calcd. for C18H25NNaO6S [M + MeOH + Na]+ 406.1295; found 406.1341.

Methyl (2‐Oxooctahydrobenzofuran‐7a‐carbonyl)glycinate (3j): Prepared from 2‐(2‐oxocyclohexyl)acetic acid (1a; 156 mg, 1 mmol, 1 equiv.) and methyl isocyanoacetate (136 µL, 1.5 mmol, 1.5 equiv.) according to Procedure A. Purification: column chromatography on silica (cyclohexane/ethyl acetate, 4:1); the diastereoisomers could be separated [R f = 0.07 (major)]. The major diastereoisomer (trans) was isolated as a colorless oil (217 mg, 0.85 mmol, 85 %). 1H NMR (500 MHz, CDCl3): δ = 6.79 (s, 1 H), 3.99 (d, J = 5.5 Hz, 2 H), 3.74 (s, 3 H), 2.52–2.38 (m, 3 H), 2.27–2.12 (m, 2 H), 1.96–1.85 (m, 2 H), 1.84–1.67 (m, 3 H), 1.50–1.35 (m, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 175.7 (C), 171.5 (C), 169.8 (C), 86.6 (C), 52.6 (CH), 48.5 (CH3), 41.0 (CH2), 34.2 (CH2), 33.6 (CH2), 25.2 (CH2), 23.9 (CH2), 21.9 (CH2) ppm. IR (neat): [nu with tilde] = 3356 (m), 2951 (w), 1780 (m), 1736 (s), 1672 (s), 1531 (m), 1414 (s), 1188 (s), 1011 (s), 935 (s), 885 (s) cm–1. HRMS (ESI): calcd. for C12H18NO5 [M + H]+ 256.1180; found 256.1179.

tert‐Butyl 7a‐(tert‐Butylcarbamoyl)‐2‐oxohexahydrofuro[3,2‐c]‐pyridine‐5(4H)‐carbamate (3k): Prepared from 2‐[1‐(tert‐butoxycarbonyl)‐4‐oxopiperidin‐3‐yl]acetic acid (1b; 132 mg, 0.51 mmol, 1 equiv.) and tert‐butyl isocyanide (87 µL, 0.77 mmol 1.5 equiv.) according to Procedure A (reaction time 6 h). Purification: column chromatography on silica (cyclohexane/ethyl acetate, 3:1); the diastereoisomers could be separated [R f = 0.40 (major) and R f = 0.23 (minor)]. The major diastereoisomer 3k (trans) was isolated as a white solid (40 mg, 0.12 mmol, 23 %). M.p. 132–144 °C. 1H NMR (500 MHz, CDCl3): δ = 6.15 (s, 1 H), 4.42–37.74 (m, 3 H), 3.55–3.25 (m, 1 H), 2.49 (dd, J = 16.2, J = 6.4 Hz, 1 H), 2.43–2.33 (m, 1 H), 2.31–2.21 (m, 1 H), 2.14–2.00 (m, 1 H), 1.96–1.84 (m, 1 H), 1.45 (s, 9 H), 1.33 (s, 9 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 174.5 (C), 169.3 (C), 155.0 (C), 84.1 (C), 80.1 (C), 51.8 (C), 46.7 (CH), 41.8 (CH2), 39.6 (CH2), 33.8 (CH2), 31.3 (CH2), 28.5 (CH3), 28.3 (CH3) ppm. IR (neat): [nu with tilde] = 3342 (w), 2972 (w), 1793 (s), 1664 (s), 1526 (m), 1418 (s), 1163 (s), 1015 (s), 974 (w), 849 (m) cm–1. HRMS (ESI): calcd. for C18H33N2O6 [M + H]+ 373.2333; found 373.2330.

N‐(tert‐Butyl)‐2‐oxooctahydro‐8aH‐chromene‐8a‐carboxamide (3l): Prepared from 3‐(2‐oxocyclohexyl)propanoic acid (1c; 170 mg, 1 mmol, 1 equiv.) and tert‐butyl isocyanide (124 µL, 1.1 mmol, 1.1 equiv.) according to Procedure A (reaction time 2 h). Purification: column chromatography on silica (cyclohexane/ethyl acetate, 6:1); the diastereoisomers could be separated [R f = 0.22 (major) and R f = 0.13 (minor)]. The major diastereoisomer 3l (trans) was isolated as a white solid (148 mg, 0.58 mmol, 58 %). M.p. 101–104 °C. 1H NMR (500 MHz, CDCl3): δ = 6.00 (br., 1 H), 2.69–2.65 (m, 2 H), 2.23 (qd, J = 13.5, J = 3.5 Hz, 1 H), 2.01 (d, J = 9.0 Hz, 1 H), 1.93–1.58 (m, 9 H), 1.33 (s, 9 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 171.6 (C), 171.1 (C), 85.0 (C), 51.4 (C), 42.2 (CH), 37.4 (CH2), 29.8 (CH2), 29.0 (CH2), 28.9 (CH3), 25.3 (CH2), 23.0 (CH2), 21.8 (CH2) ppm. IR (neat): [nu with tilde] = 3327 (w), 2932 (m), 2868 (w), 1744 (s), 1666 (s), 1537 (m), 1450 (m), 1354 (m), 1244 (m), 1157 (m), 1059 (m), 1032 (s), 989 (m), 631 (w), 542 (m), 488 (m) cm–1. HRMS (ESI): calcd. for C14H24NO3 [M + H]+ 254.1751; found 254.1751.

N‐(Tosylmethyl)‐2‐oxooctahydro‐8aH‐chromene‐8a‐carboxamide (3m): Prepared from 3‐(2‐oxocyclohexyl)propanoic acid (1c; 85 mg, 0.5 mmol) and tosylmethyl isocyanide (148 mg, 0.75 mmol, 1.5 equiv.) according to Procedure A (reaction time 2 h). Purification: column chromatography on silica (cyclohexane/ethyl acetate, 1:1); the diastereoisomers could be partially separated. The major diastereoisomer contained a small amount of the minor diastereoisomer. The major diastereoisomer (trans) was isolated as a gummy white solid (91 mg, 0.50 mmol, 50 %). 1H NMR (500 MHz, CDCl3): δ = 7.75 (d, J = 7.6 Hz, 2 H), 7.46 (t, J = 7.0 Hz, 1 H), 7.32 (d, J = 7.6 Hz, 2 H), 4.80–4.70 (m, 1 H), 4.68–4.58 (m, 1 H), 2.57 (t, J = 6.2 Hz, 2 H), 2.40 (s, 3 H), 2.05–1.93 (m, 1 H), 1.88 (d, J = 12.5 Hz, 1 H), 1.80–1.47 (m, 7 H), 1.30–1.05 (m, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 171.0 (C), 171.0 (C), 145.4 (C), 134.1 (C), 130.0 (CH), 128.9 (CH), 85.0 (C), 59.7 (CH2), 42.0 (CH), 37.8 (CH2), 29.7 (CH2), 28.4 (CH2), 25.0 (CH2), 22.6 (CH2), 21.7 (CH3), 21.3 (CH2) ppm. IR (neat): [nu with tilde] = 3315 (w), 2938 (w), 1742 (s), 1686 (s), 1501 (m), 1448 (m), 1321 (s), 1286 (m), 1229 (m), 1140 (s), 1084 (s), 1030 (s), 914 (w), 727 (s) cm–1. HRMS (ESI): calcd. for C18H23NNaO5S [M + Na]+ 388.1189; found 388.1181.

N‐(tert‐Butyl)‐2,3‐dimethyl‐5‐oxotetrahydrofuran‐2‐carboxamide (3r): Prepared from 3‐methyl‐4‐oxopentanoic acid (1g; 130 mg, 1 mmol, 1 equiv.) and tert‐butyl isocyanide (170 µL, 1.5 mmol, 1.5 equiv.) according to Procedure A (reaction time 2 h). The diastereoisomers were not separated by chromatographic purification. Isolated as a colorless oil (24 mg, 0.11 mmol, 11 %). In the NMR spectroscopic data, D1 and D2 denote the two diastereomers. 1H NMR (500 MHz, CDCl3): δ = 6.26 (br., 1 H, D1), 6.19 (br., 1 H, D2), 2.88 (dd, J = 10.0, J = 8.0 Hz, 1 H, D1), 2.75–2.57 (m, 1 H, D1/D2, 1 H, D2), 2.57–2.49 (m, 1 H, D2/D1), 2.28–2.15 (m, 1 H, D1, 1 H, D2), 1.53 (s, 3 H, D2), 1.42 (s, 3 H, D1), 1.33 (s, 9 H, D1), 1.32 (s, 9 H, D2), 1.20 (d, J = 7.0 Hz, 3 H, D2), 1.04 (d, J = 7.0 Hz, 3 H, D1) ppm. 13C NMR (125 MHz, CDCl3): δ = 175.2 (C, D1/D2), 174.8 (C, D2/D1), 171.6 (C, D1/D2), 169.2 (C, D2/D1), 88.5 (C, D2), 87.6 (C, D1), 51.7 (C, D1), 51.3 (C, D2), 38.2 (CH, D1), 37.1 (CH, D2), 36.7 (CH2, D2), 36.3 (CH2, D1), 28.7 (CH3, D1), 28.7 (CH3, D2), 24.0 (CH3, D1), 18.9 (CH3, D2), 16.4 (CH3, D1/D2), 15.2 (CH3, D2/D1) ppm. IR (neat): [nu with tilde] = 2972 (w), 1784 (s), 1670 (s), 1521 (m), 1456 (m), 1365 (m), 1223 (s), 1194 (m), 1123 (s), 1059 (m), 1010 (w), 926 (m), 768 (w) cm–1. HRMS (ESI): calcd. for C12H23NNaO4 [M + MeOH + Na]+ 268.1519; found 268.1513.

N‐(Tosylmethyl)‐2,3‐dimethyl‐5‐oxotetrahydrofuran‐2‐carboxamide (3s): Prepared from 3‐methyl‐4‐oxopentanoic acid (1g; 130 mg, 1 mmol, 1 equiv.) and tosylmethyl isocyanide (294 mg, 1.5 mmol, 1.5 equiv.) according to Procedure A (reaction time 2 h). Purification: column chromatography on silica (cyclohexane/ethyl acetate, 2:1 to cyclohexane/ethyl acetate, 1:1); the diastereoisomers could not be separated (R f = 0.32 and R f = 0.27). Isolated as a gummy white solid containing 2 wt.‐% EtOAc. Yield (corrected): 266 mg, 0.82 mmol, 82 %. In the NMR spectrascopic data, D1 and D2 denote the two diastereomers. 1H NMR (500 MHz, CDCl3): δ = 7.76 (d, J = 8.0 Hz, 2 H, D1, 2 H, D2), 7.70 (t, J = 6.6 Hz, 1 H, D1/D2), 7.69 (t, J = 7.0 Hz, 1 H, D2/D1), 7.30 (d, J = 8.0 Hz, 2 H, D1, 2 H, D2), 4.73–4.53 (m, 2 H, D1, 2 H, D2), 2.80 (dd, J = 17.0, J = 9.0 Hz, 1 H, D2), 2.57 (dd, J = 17.0, J = 9.0 Hz, 1 H, D1), 2.50–2.38 (m, 1 H, D1, 1 H, D2), 2.37 (s, 3 H, D1), 2.37 (s, 3 H, D2), 2.23–2.14 (m, 1 H, D1, 1 H, D2), 1.40 (s, 3 H, D2), 1.26 (s, 3 H, D1), 1.00 (d, J = 7.5 Hz, 3 H, D1), 0.81 (d, J = 7.5 Hz, 3 H, D2) ppm. 13C NMR (125 MHz, CDCl3): δ = 174.9 (C, D2), 174.6 (C, D1), 171.9 (C, D1), 170.1 (C, D2), 145.4 (C, D1, D2), 133.9 (C, D2), 133.8 (C, D1), 129.9 (CH, D1), 129.8 (CH, D2), 129.0 (CH, D2), 129.0 (CH, D1), 88.4 (C, D2), 87.3 (C, D1), 59.9 (CH2, D1), 59.8 (CH2, D2), 38.5 (CH, D2), 37.1 (CH, D1), 36.2 (CH2, D2), 35.6 (CH2, D1), 23.9 (CH3, D1/D2), 21.7 (CH3, D1, D2), 18.2 (CH3, D2/D1), 15.9 (CH3, D2), 14.3 (CH3, D1) ppm. IR (neat): [nu with tilde] = 3354 (w), 1784 (s), 1676 (s), 1518 (s), 1294 (s), 1220 (m), 1148 (s), 1088 (s), 1053 (m), 926 (m), 750 (m) cm–1. HRMS (ESI): calcd. for C16H23NNaO6S [M + MeOH + Na]+ 380.1138; found 380.1178.

8a‐Hydroxyhexahydroisoquinoline‐1,3‐(2H,4H)‐dione (4b): Prepared from 3b (6 mg, 0.2 mmol) according to Procedure B (reaction time 7 h). Purification: column chromatography on silica (cyclohexane/ethyl acetate, 4:1, to cyclohexane/ethyl acetate, 2:1, R f = 0.13). Isolated as a white solid (22 mg, 0.12 mmol, 60 %). M.p. 150–158 °C. 1H NMR (500 MHz, CDCl3/[D6]DMSO): δ = 9.32 (br., 1 H), 4.73 (br., 1 H), 2.76 (d, J = 16.6 Hz, 1 H), 2.20 (d, J = 16.6 Hz, 1 H), 2.11–1.97 (m, 1 H), 1.95–1.84 (m, 1 H), 1.67–1.45 (m, 2 H), 1.43–1.31 (m, 1 H), 1.28–0.95 (m, 4 H) ppm. 13C NMR (125 MHz, CDCl3/[D6]DMSO):27 δ = 172.5 (C), 71.4 (C), 37.5 (CH), 34.4 (CH2), 32.8 (CH2), 29.5 (CH2), 22.6 (CH2), 22.2 (CH2) ppm. IR (neat): [nu with tilde] = 3166 (m), 2923 (m), 1722 (s), 1668 (s), 1358 (s), 1209 (s), 1068 (s), 1041 (m), 840 (m), 732 (m) cm–1. HRMS (ESI): calcd. for C9H13NNaO3 [M + Na]+ 206.0788; found 206.0786.

2‐Cyclohexyl‐8a‐hydroxyhexahydroisoquinoline‐1,3‐(2H,4H)‐dione (4c): Prepared from 3c (27 mg, 0.1 mmol) according to Procedure B (reaction time 24 h). Isolated as a white solid (24 mg, 0.089 mmol, 89 %). M.p. 110–117 °C. 1H NMR (500 MHz, CDCl3): δ = 4.48 (tt, J = 12.5, J = 4.0 Hz, 1 H), 3.25 (br., 1 H), 2.82–2.64 (m, 2 H), 2.28–2.08 (m, 3 H), 1.97–1.40 (m, 12 H), 1.37–1.06 (m, 4 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 171.9 (C), 72.4 (C), 53.9 (CH), 35.2 (CH2), 34.5 (CH), 32.6 (CH2), 29.3 (CH2), 28.7 (CH2), 26.4 (CH2), 26.4 (CH2), 25.6 (CH2), 25.3 (CH2), 21.0 (CH2), 20.4 (CH2) ppm. IR (neat): [nu with tilde] = 3377 (w), 2927 (m), 1719 (m), 1654 (m), 1358 (s), 1225 (s), 1136 (m), 1043 (m), 729 (m) cm–1. HRMS (ESI): calcd. for C15H23NNaO3 [M + Na]+ 288.1570; found 288.1572.

2‐Isopropyl‐8a‐hydroxyhexahydroisoquinoline‐1,3‐(2H,4H)‐dione (4d): Prepared from 3d (23 mg, 0.1 mmol) according to Procedure B (reaction time 24 h). Isolated as a white solid (22 mg, 0.096 mmol, 96 %). M.p. 81–89 °C. 1H NMR (500 MHz, CDCl3): δ = 4.90 (sep, J = 7.9 Hz, 1 H), 2.82–2.64 (m, 2 H), 2.22–2.12 (m, 1 H), 1.97–1.70 (m, 3 H), 1.55–1.42 (m, 4 H), 1.41–1.28 (m, 1 H), 1.36 (d, J = 7.0 Hz, 3 H), 1.34 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 177.5 (C), 171.9 (C), 72.4 (C), 45.4 (CH), 35.2 (CH2), 34.4 (CH), 32.6 (CH2), 25.6 (CH2), 21.0 (CH2), 20.4 (CH2), 19.8 (CH3), 19.4 (CH3) ppm. IR (neat): [nu with tilde] = 3400 (w), 2935 (m), 1719 (m), 1668 (s), 1346 (m), 1244 (m), 1221 (m), 1116 (w), 1045 (w) cm–1. HRMS (ESI): calcd. for C12H19NNaO3 [M + Na]+ 248.1257; found 248.1249.

2‐Pentyl‐8a‐hydroxyhexahydroisoquinoline‐1,3‐(2H,4H)‐dione (4e): Prepared from 3e (25 mg, 0.1 mmol) according to Procedure B (reaction time 2 h). Isolated as a colorless oil (19 mg, 0.075 mmol, 75 %). 1H NMR (500 MHz, CDCl3): δ = 4.83–3.63 (m, 2 H), 2.90–2.70 (m, 3 H), 2.24–2.12 (m, 1 H), 1.99–1.65 (m, 3 H), 1.57–1.40 (m, 6 H), 1.38–1.15 (m, 5 H), 0.87 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 171.9 (C), 72.2 (C), 40.4 (CH2), 34.8 (CH), 34.7 (CH2), 32.7 (CH2), 29.1 (CH2), 27.7 (CH2), 25.9 (CH2), 22.4 (CH2), 21.6 (CH2), 20.7 (CH2), 14.1 (CH3) ppm. IR (neat): [nu with tilde] = 3411 (w), 2932 (m), 1724 (m), 1653 (s), 1346 (s), 1254 (m), 1176 (s), 1118 (s), 1047 (m), 734 (w) cm–1. HRMS (ESI): calcd. for C14H23NNaO3 [M + Na]+ 276.1570; found 276.1558.

2‐Benzyl‐8a‐hydroxyhexahydroisoquinoline‐1,3‐(2H,4H)‐dione (4f): Prepared from 3f (28 mg, 0.1 mmol) according to Procedure B (reaction time 4 h). Isolated as a pale yellow oil (26 mg, 0.093 mmol, 93 %). 1H NMR (500 MHz, CDCl3): δ = 7.34–7.19 (m, 5 H), 4.95 (d, J = 13.5 Hz, 1 H), 4.93 (d, J = 13.5 Hz, 1 H), 3.01 (br., 1 H), 2.86 (dd, J = 19.0, J = 4.5 Hz, 1 H), 2.74 (dd, J = 19.0, J = 9.0 Hz, 1 H), 2.21 (sex, J = 5.0 Hz, 1 H), 1.98–1.85 (m, 2 H), 1.85–1.73 (m, 1 H), 1.55–1.37 (m, 4 H), 1.33–1.25 (m, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 171.5 (C), 136.9 (C), 128.6 (CH), 128.5 (CH), 127.6 (CH), 72.3 (C), 43.5 (CH2), 34.8 (CH), 34.7 (CH2), 32.7 (CH2), 26.0 (CH2), 21.2 (CH2), 20.7 (CH2) ppm. IR (neat): [nu with tilde] = 3445 (w), 2929 (m), 1726 (m), 1670 (s), 1346 (s), 1173 (m), 1076 (w), 733 (w) cm–1. HRMS (ESI): calcd. for C16H19NNaO3 [M + Na]+ 296.1257; found 296.1249.

2‐(Naphthalen‐2‐yl)‐8a‐hydroxyhexahydroisoquinoline‐1,3‐(2H,4H)‐dione (4g): Prepared from 3g (31 mg, 0.1 mmol) according to Procedure B (reaction time 24 h). Isolated as a brown solid containing 15 % 2‐naphthylamine. Yield (corrected): 20 mg, 0.064 mmol, 64 %. M.p. 141–147 °C. 1H NMR (500 MHz, CDCl3): δ = 7.93 (d, J = 8.5 Hz, 1 H), 7.88 (d, J = 8.0 Hz, 1 H), 7.83 (d, J = 8.5 Hz, 1 H), 7.60 (s, 1 H), 7.56–7.46 (m, 2 H), 7.16 (dd, J = 8.5, J = 2.0 Hz, 1 H), 3.06 (dd, J = 18.5, J = 5.0 Hz, 1 H), 2.93 (dd, J = 18.5, J = 10.0 Hz, 1 H), 2.41 (sex, J = 4.0 Hz, 1 H), 2.16 (t, J = 11.0 Hz, 1 H), 2.10–2.01 (m, 1 H), 1.92–1.80 (m, 1 H), 1.71–1.44 (m, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 171.9 (C), 133.5 (C), 133.2 (C), 132.3 (C), 129.4 (CH), 128.2 (CH), 128.0 (CH), 127.4 (CH), 127.0 (CH), 126.7 (CH), 125.8 (CH), 72.8 (C), 34.8 (CH), 34.7 (CH2), 32.7 (CH2), 26.0 (CH2), 21.2 (CH2), 20.7 (CH2) ppm. IR (neat): [nu with tilde] = 3446 (w), 2936 (w), 1734 (m), 1680 (s), 1370 (m), 1202 (m), 1073 (w), 746 (w) cm–1. HRMS (ESI): calcd. for C20H23NNaO4 [M + MeOH + Na]+ 364.1519; found 364.1564.

2‐(2,6‐Dimethylphenyl)‐8a‐hydroxyhexahydroisoquinoline‐1,3‐(2H,4H)‐dione (4h): Prepared from 3h (29 mg, 0.1 mmol) according to Procedure B (reaction time 3 h). Isolated as a colorless oil (29 mg, 0.01 mmol, 99 %). 1H NMR (500 MHz, CDCl3): δ = 7.21 (t, J = 7.5 Hz, 1 H), 7.16–7.10 (m, 2 H), 3.08 (dd, J = 18.5, J = 5.0 Hz, 1 H), 2.89 (dd, J = 18.5, J = 10.0 Hz, 1 H), 2.77 (br., 1 H), 2.36 (sex, J = 4.5 Hz, 1 H), 2.20–2.11 (m, 1 H), 2.08–1.98 (m, 1 H), 2.06 (s, 3 H), 2.04 (s, 3 H), 1.92–1.80 (m, 1 H), 1.68–1.44 (m, 5 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 175.8 (C), 171.0 (C), 135.4 (C), 135.1 (C), 133.3 (C), 129.0 (CH), 128.7 (CH), 128.6 (CH), 72.8 (C), 35.5 (CH), 35.1 (CH2), 33.1 (CH2), 26.6 (CH2), 21.6 (CH2), 21.3 (CH2), 18.2 (CH3), 17.6 (CH3) ppm. IR (neat): [nu with tilde] = 3390 (w), 2927 (m), 1734 (m), 1670 (s), 1364 (s), 1238 (s), 1207 (s), 1186 (s), 1132 (m), 1003 (m), 768 (m), 725 (m) cm–1. HRMS (ESI): calcd. for C17H22NO3 [M + H]+ 288.1594; found 288.1597.

2‐Tosylmethyl‐8a‐hydroxyhexahydroisoquinoline‐1,3‐(2H,4H)‐dione (4i): Prepared from 3i (29 mg, 0.1 mmol) according to Procedure B (reaction time 1 h). Isolated as a white solid (24 mg, 0.083 mmol, 83 %). M.p. 149–163 °C. 1H NMR (500 MHz, CDCl3): δ = 7.76 (d, J = 7.5 Hz, 2 H), 7.34 (d, J = 7.5 Hz, 2 H), 5.26 (s, 2 H), 3.08 (br., 1 H), 2.99 (dd, J = 18.5, J = 5.0 Hz, 1 H), 2.65 (dd, J = 18.5, J = 7.0 Hz, 1 H), 2.44 (s, 3 H), 2.21–2.12 (m, 2 H), 1.94–1.64 (m, 2 H), 1.65–1.27 (m, 5 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 170.3 (C), 145.4 (C), 136.0 (C), 130.0 (CH), 128.6 (CH), 72.7 (C), 59.4 (CH2), 35.7 (CH), 34.5 (CH2), 33.5 (CH2), 27.1 (CH2), 21.9 (CH2), 21.8 (CH2), 21.8 (CH3) ppm. IR (neat): [nu with tilde] = 3420 (w), 2939 (m), 1734 (m), 1686 (s), 1304 (s), 1288 (s), 1138 (s), 1043 (m), 927 (m), 820 (m), 735 (m) cm–1. HRMS (ESI): calcd. for C17H21NNaO5S [M + Na]+ 374.1033; found 374.1025.

Methyl 2‐[8a‐Hydroxy‐1,3‐dioxooctahydroisoquinolin‐2(1H)‐yl]acetate (4j): Prepared from 3j (26 mg, 0.1 mmol) according to Procedure B (reaction time 3 h). Isolated as a white solid (20 mg, 0.076 mmol, 76 %). M.p. 122–126 °C. 1H NMR (500 MHz, CDCl3): δ = 4.57 (d, J = 16.5 Hz, 1 H), 4.52 (d, J = 16.5 Hz, 1 H), 3.73 (s, 3 H), 2.96 (dd, J = 19.0, J = 5.5 Hz, 1 H), 2.80 (br., 1 H), 2.75 (dd, J = 19.0, J = 8.0 Hz, 1 H), 2.28–2.19 (m, 1 H), 2.16–2.05 (m, 1 H), 1.98–1.88 (m, 1 H), 1.86–1.75 (m, 1 H), 1.64–1.40 (m, 5 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 171.3 (C), 168.5 (C), 72.4 (C), 52.5 (CH3), 40.8 (CH2), 35.6 (CH), 34.5 (CH2), 33.3 (CH2), 26.7 (CH2), 21.7 (CH2), 21.7 (CH2) ppm. IR (neat): [nu with tilde] = 3404 (w), 2948 (w), 1753 (s), 1720 (m), 1664 (s), 1380 (s), 1329 (s), 1218 (s), 1173 (s), 1130 (s), 1070 (s), 1022 (s), 940 (m), 744 (m) cm–1. HRMS (ESI): calcd. for C12H17NNaO5 [M + Na]+ 278.0999; found 278.0989. Crystals for single‐crystal X‐ray diffraction were grown by slow evaporation of an ethanolic solution.

(3aR,7aS)‐N‐(tert‐butyl)‐2‐oxohexahydrobenzofuran‐7a(2H)‐carboxamide [(3aR,7aS)‐3a]: Zn(OTf)2 (4 mg, 0.011 mmol, 0.1 equiv.) and tert‐butyl isocyanide (18.5 µL, 0.165 mmol 1.5 equiv.) were added to a solution of (R)‐1a (17 mg, 0.11 mmol, 1 equiv.) in dimethyl carbonate (0.45 mL). The solution was stirred at room temperature for 6 h. Then the mixture was diluted with CH2Cl2, and quenched with saturated NaHCO3 solution. The organic layer was separated, and the aqueous layer was extracted again with CH2Cl2. The combined organic layers were dried with Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (cyclohexane/ethyl acetate, 6:1) to give (3aR,7aS)‐3a (18 mg, 0.075 mmol, 68 %). The spectroscopic data are in accordance with racemic 3a. The enantiomeric ratio was determined by chiral GC on the chiral phase ChiraSil Dex CB (25 m × 0.25 µm); temperature program 130 °C, hold for 60 min. Retention times: t R(major) = 23.5 min, t R(minor) = 25.6 min; er = 92:8. [α]D 20 = –54 (c = 0.67, CHCl3).

CCDC 1511110 [for 3a (trans)] and 1511111 (for 4j) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre.

Supporting Information (see footnote on the first page of this article): Copies of the 1H and 13C NMR spectra for all new compounds, and CIF files for 3a and 4j.

Supporting information

Supporting Information

Acknowledgements

The authors thank Prof. Dr. Kristof Van Hecke (University of Ghent, Belgium) for kindly providing diffractometer time, and the Hercules Foundation (project AUGE/11/029 “3D‐SPACE: 3D Structural Platform Aiming for Chemical Excellence”) for funding the diffractometer. We also acknowledge John Braun for HRMS measurements, Elwin Janssen for technical assistance, and Dr. Andreas W. Ehlers for NMR maintenance (all Vrije Universiteit Amsterdam). The research leading to these results received funding from the Innovative Medicines Initiative Joint Undertaking project CHEM21 (http://www.chem21.eu) under grant agreement No. 115360, resources of which come from financial contributions from the European Union's Seventh Framework Programme (FP7/2007–2013) and from companies belonging to the European Federation of Pharmaceutical Industries and Associations (EFPIA).

Contributor Information

Eelco Ruijter, ln.uv@retjiur.e, http://syborch.com/

Romano V. A. Orru, ln.uv@urro.a.v.r, http://syborch.com/

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