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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Tetrahedron. Author manuscript; available in PMC 2010 June 27.
Published in final edited form as:
Tetrahedron. 2009 June 27; 65(26): 4992–5000.
doi:  10.1016/j.tet.2009.03.080
PMCID: PMC2702866
NIHMSID: NIHMS106968

Metathesis Cascade Strategies (ROM-RCM-CM): A DOS approach to Skeletally Diverse Sultams

Abstract

The development of a ring-opening metathesis/ring-closing metathesis/cross metathesis (ROM-RCM-CM) cascade strategy to the synthesis of a diverse collection of bi- and tricyclic sultams is reported. In this study, functionalized sultam scaffolds derived from intramolecular Diels-Alder (IMDA) reactions undergo metathesis cascades to yield a collection tricyclic sultams. Additional appendage based diversity was achieved by utilizing a variety of CM partners.

Keywords: cascade, sultam, RCM, DOS

1. Introduction

Diversity-oriented-synthesis (DOS) has emerged as a powerful strategy in the generation of structurally complex and skeletally diverse small molecules.i Collections of such small molecules can possess a wide range of physical and biological properties and as such are ideal for probing chemical space to identify novel lead compounds.ii The development of simple methodology, which allows for the generation of skeletal diversity is one of the most challenging facets of DOS. A number of efficient strategies have emerged employing skeletal rearrangement utilizing both functional-group-pairing (FGP)iii strategies and tandem metathesis (TM) strategies.iv In this regard, we envisioned an approach whereby skeletally diverse sultam scaffolds could be generated using a domino ring-opening metathesis (ROM)/ring-closing metathesis (RCM)/cross metathesis (CM) cascade sequence on a readily derived oxa-norbornenyl sultam. Recently a number of strategies employing ROM-CM strategies of norbornenes, oxa-norbornenes and aza-norbornenes derivatives have appeared.v In particular, a number of key metathesis cascades and strategies have emerged, some in the context of DOS.vi Herein is reported the application of a ROM-RCM-CM strategy for the generation of a collection of skeletally diverse sultams starting from a central norbornenyl sultam core derived from a diastereoselective intramolecular Diels-Alder (IMDA) reaction (Scheme 1).

Sultams (cyclic sulfonamide analogs) have emerged as important targets in drug discovery due to their potent biological activities. A number of reports have highlighted an assortment of sultams that display potent activity including inhibition of COX-2 (Ampiroxicam),vii,viii HIV integrase,ix and cysteine protease involved in the progression of maleria.x Recently, a number of transition metal-catalyzed approaches to sultams have come to light, including ring-closing metathesis (RCM).xi Our continued interest in the development of new synthetic routes towards structurally diverse sulfur-containing small moleculesxii for library production has prompted the following investigation on the application of metathesis cascade processes for their construction.

2. Results and discussion

The intramolecular Diels-Alder (IMDA) reaction of both vinyl sulfonatesxiii and vinyl sulfonamidesxiv with substituted furans, pioneered by Metz and coworkers, have provided an efficient route to highly versatile intermediates rich in stereochemistry and functionality. Norbornene systems of this type, possess a strained internal double bond, and thus are attractive scaffolds for application of the aforementioned metathesis cascades. To this effect, we set about the synthesis of IMDA derived sultams 1 and 2 from commercially available starting materials.xiv c 2-Chloroethanesulfonyl chloride was coupled with furfuryl amine to afford the corresponding sulfonamide in 86 % yield. Alkylation of the resulting sulfonamide followed by in-situ IMDA afforded the corresponding tricyclic sultams 1 and 2 in 55% and 58% yield, respectively (Scheme 2), as single diastereomers.

With scaffold 1 in hand, the application of the proposed ROM-RCM-CM cascade protocol was explored. Thus, sultam 1 was subjected to 5 mol% of (IMesH2)(PCy3)(Cl)2Ru=CHPh [cat-B],xv at 0.005 M in CH2Cl2 at 45 °C under argon for 3 hours, to afford homodimer 3 in 84% yield. In order to circumvent this homodimerization pathway, a cross metathesis partner was used to yield the desired product. Utilization of ethylene has been well reported in the application of ROM-RCM-CM, whereby a terminal olefin is ultimately produced.vi With this in mind, sultam 1 was submitted to standard cascade conditions under an atmosphere of ethylene, in ethylene degassed solvent. As anticipated, the corresponding sultam 4 bearing a terminal olefin was afforded in 74% yield with ethylene acting as the final cross-metathesis partner. Building on this result, studies were directed toward the addition of a cross-metathesis partner to prevent dimerization and incorporate an additional point of diversity.v When 1 was resubjected in the presence of 10 equivalents of ethyl acrylate, 10 mol% of cat-B in 0.005 M CH2Cl2 at 50 °C, the desired bridged tricyclic sultam 5 derived from ROM-RCM-CM was isolated in 65% yield (Scheme 3).

With the successful application of a ROM-RCM-CM protocol, the scope of possible cross metathesis partners was investigated. These included a variety of acrylates such as methyl acrylate and t-butyl acrylate affording the desired products in good yield (Table 1, entrys 1–3). Surprisingly, the application of methyl vinyl ketone (MVK) did not afford the desired product. In addition to acrylates, styrene and acrylonitrile were utilized as the cross-metathesis partner. It was found that under standard reaction conditions the desired products were isolated as the sole product in good yields (Table 1, entrys 4–6).

With this result in hand, application of the metathesis cascade was applied to the propargyl-substituted sultam 2. In this case, a ring-opening metathesis/ring-closing enyne metathesis/cross-metathesis (ROM-RCEM-CM) sequence was envisioned as a means of generating skeletal diversity. Moreover, reaction of sultam 2 in the presence of ethylene would afford the desired product 11 bearing a diene motif, allowing for additional incorporation of diversity via a [4+2] cycloaddition with activated dienophiles. However, when sultam 2 was submitted to the ROM-RCEM-CM conditions none of the desired product was obtained, instead the corresponding bicyclic tetraene 12 was isolated in good yield (75%). This result indicates that sultam 2 undergoes an intermolecular enyne metathesis with ethylene instead of the corresponding intramolecular process. Subsequent heating of 12 with maleimide afforded the corresponding [4+2] cis-cycloadduct 13 in 83% yield as an inseparable, 1:1 mixture of diastereomers (Scheme 5).xvi

Building on these results, we investigated the synthesis of a modified sultam scaffold whereby the simple relocation of the allyl group in 1 by one carbon would allow for the generation of new tricyclic sultams 1517 (Scheme 6). Relocation of the tethered allyl group also enhances structural diversity by yielding a new fused ring system. Thus, 2-furaldehyde was condensed with p-methoxy benzyl amine generating the corresponding imine, which was subsequently converted to the requisite furfuryl-substituted allyl amine by the addition of allyl magnesium bromide. Sulfonylation with 2-chloroethane sulfonyl chloride produced the corresponding vinyl sulfonamide 14, which when heated at 100 °C for 12 h afforded the desired IMDA derived scaffold 15 in 95% as a mixture of diastereomers (~1:1).xvii Addition of cat-B to sultam 15 in the presence of ethylene afforded the desired tricyclic sultam 16 as a single diastereoisomer via a ROM-RCM-CM cascade. Spectroscopic analysis including key 1H NMR nOe studies determined that diastereomer 15a selectively underwent cyclization to give the cis-fused tricyclic sultam 16.

In addition to the formation of 16, a small amount of sultam 17 resulting from ROM-CM of diastereomer 15b with ethylene was isolated. It is proposed that in the case of diastereomer 15b, an unfavourable steric interaction between the homoallyl substituent and the oxo-bridge, prevents proper alignment between the ruthenium alkylidene and the norbornenyl olefin, thus hindering metathesis. However, this interaction is alleviated in the case of the diastereomer 15a, where the allyl group is oriented away from the oxygen bridge under the bicyclic ring in direct proximity of the strained norbornenyl olefin (Scheme 7). In addition to steric effects, the corresponding cyclized RCM product of 17 would have a trans ring junction in a bicyclo[3.3.0] ring system which under the reversible conditions of the reaction would most likely be disfavored.

During this investigation we were concurrently developing the synthesis of an IMDA-derived sultam 21 bearing additional handles and therefore probed its utility in the metathesis cascade protocol. In this regard, N-Boc phenylalanine was converted to the corresponding Weinreb amide and treated with lithiated furan. Subsequent reduction of the furyl ketone yielded the corresponding N-Boc amino alcohol 20 as a mixture of diastereoisomers (~2:1) in 64% yield over 3 steps.xviii Removal of the Boc-group furnished the corresponding amino alcohol, which was taken on crude to a one-pot, sulfonylation/diastereoselective IMDA sequence to afford the desired tricyclic sultam 21, as a single diastereoisomer in 52% yield over three steps (Scheme 8).xiv

From a DOS perspective, sultam 21 represents an attractive scaffold due to a number of features, including (i) the presence of both free hydroxy (OH) and free sulfonamide (NH) groups, (ii) structural rigidity, (iii) stereochemistry and (iv) peripheral functionality. These features allow for the generation of focused libraries to probe chemical space via two approaches. One is via simple peripheral diversification and the second is via skeletal diversity utilizing the aforementioned ROM-RCM-CM cascade protocol. To this effect, chemoselective O-allylation of 21 yielded the desired intermediate 22,xix which when submitted to the standard ROM-RCM-CM sequence yielded the desired tricyclic sultam 23 in 90% yield (Scheme 9).

Building on this result, selective acylation of 21 yielded the corresponding sultam intermediate 24 in 92% yield. Submission to the standard metathesis cascade conditions in the presence of ethylene yielded the triene sultam 25 as the sole product via a ROM-CM process. Taken collectively, sultams 1, 15 and 21 are tricyclic, IMDA-derived scaffolds that upon submission to the metathesis cascade protocol generate skeletally diverse [6.6.5] or [6.5.5] fused-ring sultam systems. In addition, both pathways retain a functional handle (SO2NH) for late stage peripheral diversification. Ultimately, selective choice of the olefin appendage in 21 allows additional skeletal diversity in the formation of either tricyclic sultam 23 or bicyclic sultam 25, presumably due to variable olefin reactivity Types (I, II, II or IV) as defined by Grubbs affecting the site of the initial metathesis event.xx

The synthesis of a sultam scaffold bearing an ester functional handle was envisioned as an alternative strategy towards the synthesis of functionalized derivatives of 1. This goal could be achieved via incorporation of the ester moiety in the dienophile component of the IMDA protocol, as reported by Overman and coworkers.xxi To this effect, furfurylamine was mesylated then subsequently allylated to yield sulfonamide 26 in 82% over 2 steps. Generation of the phosphonate, followed by Horner-Wadsworth-Emmons reaction, yielded a mixture of uncyclized sulfonamide 27 and IMDA-derived sultam 28 after purification to remove any remaining starting material. Addition of hexane to the crude mixture resulted in the sole precipitation of 28, yielding X-ray quality crystals (Scheme 10).

It is noteworthy to mention that it was observed that in both CDCl3 and d4-MeOD, sultam 28 undergoes retro-IMDA to the corresponding sultam 27 over time.xxii It is believed that the nature of the solvent catalyzes the retro IMDA reaction indicating the increased reactivity of the bridged tricyclic system in comparison to sultams 1 and 15. Despite this observation, the corresponding sultam 28 underwent the metathesis cascade transformation in the presence of ethylene in CH2Cl2 to yield the desired tricyclic sultam 29 (Scheme 11). Formation of an additional lactone ring was achieved using iodolactonization between the ethyl ester and the terminal olefin in the presence of I2 to afford polycyclic product 30 as a single isomer, albeit in low yield.

Conclusion

In conclusion, the synthesis of a collection of diverse bi- and tricyclic sultams has been achieved in an overall DOS approach utilizing a ROM-RCM-CM cascade strategy. A variety of functionalized, tricyclic sultams were generated as precursors for the metathesis cascade strategy. These precursors were derived from a diastereoselective IMDA reaction in good yields and selectivity. The ROM-RCM-CM proceeded in good to excellent yields generating sultams possessing both skeletal and appendage-based diversity that was controlled by elements incorporated into the sultam precursors or via the cross metathesis partner selected.

3. Experimental Section

All air and moisture sensitive reactions were carried out in flame- or oven-dried glassware under argon atmosphere using standard gas tight syringes, cannulas and septa. Stirring was achieved with oven-dried, magnetic stir bars. CH3CN was purified by passage through the Solv-Tek purification system employing activated Al2O3 (Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics 1996, 15, 1518–1520). Et3N was purified by passage over basic alumina and stored over KOH. Flash column chromatography was performed with SiO2 obtained from Sorbent Technologies (30930M-25, Silica Gel 60A, 40–63 um). Metathesis catalysts were provided by Materia, Inc. and used without further purification. Thin layer chromatography was performed on silica gel 60F254 plates (EM-5717, Merck). Deuterated solvents were purchased from Cambridge Isotope laboratories. 1H and 13C NMR spectra were recorded on a Bruker DRX-400 spectrometer operating at 400 MHz and 100 MHz respectively; or a Bruker Avance operating at 500 MHz and 125 MHz respectively. High-resolution mass spectrometry (HRMS) and FAB spectra were obtained on a VG Instrument ZAB double-focusing mass spectrometer. Melting points were obtained on a Thomas Hoover capillary melting point apparatus. Optical rotations were carried out on a Rudolph Automatic Polarimeter (AUTOPOL IV).

6H-3a,6-Epoxy-1,2-benzisothiazole, 2,3,7,7a-tetrahydro-2-allyl, 1,1-dioxide [(±) 1]

Into a flame dried flask under argon was added furfurylamine (1.05 mL, 11.9 mmol), Et3N (1.66 mL, 11.9 mmol), and dry CH2Cl2 (20 mL). After stirring at 0 °C for 10 min, 2-chloroethanesulfonyl chloride (0.96 mL, 9.2 mmol) was added and the reaction flask stirred at rt for 2 h. The crude reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude material was dissolved in dry CH3CN (50 mL, 0.2 M) to which K2CO3 (3.9 g, 32.0 mmol) was added. After stirring for 5 mins, allyl bromide (2.8 mL, 32.0 mmol) was added and the reaction mixture was stirred at 60 °C, until SM disappeared as monitored by TLC analysis. After such time, the crude reaction mixture was filtered through a pad of celite, concentrated under reduced pressure and purified by flash chromatography (1:1 hexane:EtOAc) to yield 1 (1.15 g, 5.0 mmol, 55%) as a white solid. Mp 98 °C; FTIR (neat): 1442, 1301, 1068, 1137 cm−1; 1H NMR (500 MHz, CDCl3) δ ppm 6.53 (dd, J = 5.7, 1.7 Hz, 1H), 6.37 (d, J = 5.7 Hz, 1H), 5.88 (ddt, J = 16.6, 10.1, 6.4 Hz, 1H), 5.30 (ddq, J = 24.7, 10.1, 1.3 Hz, 2H), 5.23 (dd, J = 4.5, 1.7 Hz, 1H), 3.84 (d, J = 11.3 Hz, 1H), 3.80 – 3.75 (m, 2H), 3.62 (d, J = 11.3 Hz, 1H), 3.18 (dd, J = 7.9, 3.6 Hz, 1H), 2.61 – 2.55 (m, 1H), 1.81 (dd, J = 12.3, 7.9 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ ppm 139.5, 134.1, 132.4, 119.7, 90.5, 79.7, 60.5, 48.9, 47.6, 29.2; HRMS calculated for C10H13NNaO3S (M+Na)+ 250.0514; found 250.0518.

6H-3a,6-Epoxy-1,2-benzisothiazole, 2,3,7,7a-tetrahydro-2-propargyl, 1,1-dioxide [(±) 2]

Using a similar procedure as that used to produce sultam 1, N-(2-furanylmethyl)ethanesulfonamide (1.0 g, 5.28 mmol), propargyl bromide (2.8 ml, 32.0 mmol) yielded 2 (68.9 mg, 3.0 mmol, 58%) as a white solid. Mp 150 °C; FTIR (neat): 3226, 1304, 1282, 1140 cm−1; 1H NMR (500 MHz, CDCl3) δ ppm 6.55 (dd, J = 1.7, 5.7 Hz, 1H), 6.42 (d, J = 5.7 Hz, 1H), 5.26 (dd, J = 4.5, 1.6 Hz, 1H), 4.10 – 4.02 (m, 2H), 3.93 (dd, J = 17.7, 2.5 Hz, 1H), 3.81 (d, J = 11.4 Hz, 1H), 3.18 (dd, J = 7.9, 3.6 Hz, 1H), 2.61 – 2.55 (m, 1H), 2.37 (t, J = 2.5 Hz, 1H), 1.81 (dd, J = 12.4, 7.9 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ ppm 139.5, 134.1, 90.7, 79.8, 76.8, 74.1, 60.5, 48.8, 34.7, 29.1; HRMS calculated for C10H11NNaO3S (M+Na)+ 248.0357; found 248.0347.

Sultam (3)

To a flame dried flask was added dry CH2Cl2 (95 mL, 0.005 M), which was degassed for 30 min with argon. After such time, sultam 1 (0.1 g, 0.44 mmol) and cat-B (0.04 g, 0.044 mmol) were added and the reaction mixture was refluxed at 45 °C for 3 h. The crude reaction mixture concentrated under reduced pressure and purified by flash chromatography (1:1 hexane:EtOAc) to provide 3 (15.7 mg, 0.36 mmol, 84% yield) as a white solid. Mp 227 °C; FTIR (neat): 1336, 1164, 1112 cm−1; 1H NMR (500 MHz, CDCl3) δ ppm 6.28 (ddd, J = 10.1, 5.1, 2.1 Hz, 1H), 5.76 (ddd, J = 6.7, 3.4, 1.7 Hz, 1H), 5.55 (dt, J = 10.1, 2.5 Hz, 1H), 4.84 (d, J = 6.0 Hz, 1H), 4.19 (dt, J = 19.5, 2.5 Hz, 1H), 3.79 (dt, J = 19.6, 2.2 Hz, 1H), 3.71 (dd, J = 11.0, 5.7 Hz, 1H), 3.59 (dd, J = 12.2, 1.9 Hz, 1H), 3.24 (dd, J = 12.2, 1.8 Hz, 1H), 2.71 (dddd, J = 14.0, 8.1, 5.8, 2.1 Hz, 1H), 2.14 – 2.06 (m, 1H); 13C NMR (125 MHz, CDCl3) δ ppm 134.2, 134.2, 131.2, 130.9, 124.1, 124.1, 87.6, 80.9, 80.7, 71.0, 71.0, 51.9, 50.9, 34.1, 34.1; HRMS calculated for C18H22N2NaO6S2 (M+Na)+ 449.0817; found 449.0816.

General Procedure A for ROM-RCM-CM metathesis cascade

To a flame dried flask was added dry CH2Cl2 (0.005 M), which was degassed for 30 min with argon. To this was added, sultam (1 eq.), cat-B (10 mol%) and CM partner (10 eq.). The reaction mixture was refluxed at 45 °C for 3 h. The crude reaction mixture was concentrated under reduced pressure and purified by flash chromatography (1:1 hexane: EtOAc) to afford the desired compound.

Sultam [(±) 4]

According to general procedure A, 1 (80 mg, 0.3 mmol, cat-B (30 mg, 0.03 mmol) was added to ethylene degassed, dry CH2Cl2 (85 mL, 0.005 M) to yield (±) 4 [50 mg, 0.22 mmol, 74%] as a yellow solid. Mp 91 °C; FTIR (neat): 2925, 1350, 1338, 1166 cm−1; 1H NMR (500 MHz, CDCl3) δ ppm 6.28 (dq, J = 10.1, 2.1 Hz, 1H), 5.80 (ddd, J = 17.0, 10.4, 6.4 Hz, 1H), 5.57 – 5.48 (m, 1H), 5.33 – 5.25 (m, 1H), 5.19 (dt, J = 10.4, 1.1 Hz, 1H), 4.82 (dd, J = 14.6, 6.9 Hz, 1H), 4.18 (dt, J = 19.5, 2.4 Hz, 1H), 3.76 (dt, J = 19.5, 2.2 Hz, 1H), 3.70 (ddd, J = 10.9, 6.0, 1.9 Hz, 1H), 3.59 (dd, J = 12.2, 2.0 Hz, 1H), 3.23 (dd, J = 12.2, 2.0 Hz, 1H), 2.68 (ddd, J = 14.0, 8.0, 6.0 Hz, 1H), 2.09 (ddd, J = 14.1, 10.9, 7.1 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ ppm 135.6, 133.5, 123.0, 116.4, 86.6, 81.4, 70.2, 51.1, 50.0, 33.0; HRMS calculated for C10H13NNaO3S (M+Na)+ 250.0514; found 250.0507.

Sultam [(±) 5]

According to general procedure A, 1 (80 mg, 0.3 mmol, cat-B (30 mg, 0.03 mmol) and ethyl acrylate (3.2 mL, 30 mmol) was added to argon degassed, dry CH2Cl2 (85 mL, 0.005 M) to yield (±) 5 [58 mg, 0.19 mmol, 65%] as a pale yellow solid. Mp 232 °C; FTIR (neat): 1716, 1350, 1269, 1167 cm−1; 1H NMR (500 MHz, CDCl3) δ ppm 6.85 (dd, J = 15.6, 5.0 Hz, 1H), 6.30 (d, J = 10.1 Hz, 1H), 6.04 (d, J = 15.6 Hz, 1H), 5.57 (d, J = 10.1 Hz, 1H), 5.02 (dd, J = 6.7, 13.4 Hz, 1H), 4.24 – 4.16 (m, 3H), 3.82 – 3.75 (m, 1H), 3.75 – 3.69 (m, 1H), 3.62 – 3.56 (m, 1H), 3.30 – 3.25 (m, 1H), 2.83 – 2.74 (m, 1H), 2.21 – 2.12 (m, 1H), 1.32 – 1.27 (m, 3H); 13C NMR (125 MHz, CDCl3) δ ppm 165.9, 144.7, 134.0, 124.2, 121.7, 88.0, 80.0, 70.5, 60.8, 52.1, 51.0, 33.5, 14.2; HRMS calculated for C13H17NNaO5S (M+Na)+ 322.0725; found 322.0698.

Sultam [(±) 6]

According to general procedure A, 1 (80 mg, 0.3 mmol, cat-B (30 mg, 0.03 mmol) and methyl acrylate (2.7 mL, 30 mmol) was added to argon degassed, dry CH2Cl2 (85 mL, 0.005 M) to yield (±) 6 [48 mg, 0.16 mmol, 56%] as a pale yellow solid. Mp 144 °C; FTIR (neat): 1722, 1350, 1340, 1167 cm−1; 1H NMR (500 MHz, CDCl3) δ ppm 6.86 (d, J = 13.8 Hz, 1H), 6.30 (d, J = 8.0 Hz, 1H), 6.05 (d, J = 15.3 Hz, 1H), 5.56 (d, J = 7.9 Hz, 1H), 5.02 (s, 1H), 4.19 (d, J = 19.2 Hz, 1H), 3.85 – 3.53 (m, 6H), 3.28 (d, J = 11.6 Hz, 1H), 2.78 (s, 1H), 2.16 (s, 1H); 13C NMR (125 MHz, CDCl3) δ ppm 166.3, 145.0, 133.9, 124.2, 121.2, 88.0, 80.0, 70.5, 52.1, 51.9, 50.9, 33.5; HRMS calculated for C12H15NNaO5S (M+Na)+ 308.0569; found 308.0562.

Sultam [(±) 7]

According to general procedure A, 1 (80 mg, 0.3 mmol, cat-B (30 mg, 0.03 mmol) and t-butyl acrylate (4.3 mL, 30 mmol) was added to argon degassed, dry CH2Cl2 (85 mL, 0.005 M) to yield (±) 7 [76 mg, 0.23 mmol, 78%] as a yellow oil. FTIR (neat): 2978, 1711, 1352, 1314, 1165 cm−1; 1H NMR (400 MHz, CDCl3) δ ppm 6.77 (dd, J = 15.6, 5.0 Hz, 1H), 6.34 (d, J = 10.2 Hz, 1H), 5.99 (d, J = 15.6 Hz, 1H), 5.59 (d, J = 10.3 Hz, 1H), 5.03 (s, 1H), 4.23 (d, J = 19.6 Hz, 1H), 3.87 – 3.71 (m, 2H), 3.62 (d, J = 12.5 Hz, 1H), 3.30 (d, J = 12.2 Hz, 1H), 2.80 (s, 1H), 2.19 (ddd, J = 14.0, 10.8, 6.6 Hz, 1H), 1.51 (s, 9H); 13C NMR (125 MHz, CDCl3) δ ppm 165.1, 143.4, 134.1, 124.2, 123.6, 88.0, 81.0, 80.1, 76.8, 70.6, 52.1, 50.9, 33.5, 31.0, 28.1; HRMS calculated for C15H21NNaO5S (M+Na)+ 350.1038; found 350.1030.

Sultam [(±) 8]

According to general procedure A, 1 (80 mg, 0.3 mmol, cat-B (30 mg, 0.03 mmol) and styrene (3.4 mL, 30 mmol) was added to argon degassed, dry CH2Cl2 (85 mL, 0.005 M) to yield (±) 8 [73 mg, 0.24 mmol, 81%] as a brown liquid. FTIR (neat): 1348, 1338, 1164, 1132, 968, 750 cm−1; 1H NMR (500 MHz, CDCl3) δ ppm 7.39 (dd, J = 5.0, 3.4 Hz, 2H), 7.35 – 7.31 (m, 2H), 7.28 (dt, J = 4.7, 1.9 Hz, 1H), 6.64 (d, J = 15.8 Hz, 1H), 6.34 (dq, J = 10.1, 2.1 Hz, 1H), 6.15 (dd, J = 15.8, 7.0 Hz, 1H), 5.56 (dt, J = 10.1, 2.5 Hz, 1H), 5.01 (q, J = 7.2 Hz, 1H), 4.22 (dt, J = 19.5, 2.5 Hz, 1H), 3.84 – 3.74 (m, 2H), 3.66 (dd, J = 12.2, 2.0 Hz, 1H), 3.28 (dd, J = 12.2, 2.0 Hz, 1H), 2.78 (ddd, J = 13.9, 8.0, 5.7 Hz, 1H), 2.21 (ddd, J = 14.2, 11.1, 7.3 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ ppm 135.9, 134.4, 132.8, 128.9, 128.3, 127.3, 126.7, 124.0, 87.5, 82.2, 71.3, 51.9, 51.0, 34.4; HRMS calculated for C16H17NNaO3S (M+Na)+ 326.0827; found 326.0795.

Sultam [(±) 9]

According to general procedure, 1 (80 mg, 0.3 mmol, cat-B (30 mg, 0.03 mmol) and 4-bromostyrene (3.9 mL, 30 mmol) was added to argon degassed, dry CH2Cl2 (85 mL, 0.005 M) to yield (±) 9 [87 mg, 0.23 mmol, 80%] as a white solid. Mp 140 °C; FTIR (neat): 1487, 1350, 1338, 1164, 744 cm−1; 1H NMR (500 MHz, CDCl3) δ ppm 7.48 – 7.43 (m, 2H), 7.25 (dt, J = 9.0, 2.2 Hz, 2H), 6.58 (d, J = 15.8 Hz, 1H), 6.33 (dq, J = 10.1, 2.1 Hz, 1H), 6.14 (dd, J = 15.8, 6.9 Hz, 1H), 5.57 (dt, J = 10.1, 2.5 Hz, 1H), 4.99 (q, J = 7.1 Hz, 1H), 4.22 (dt, J = 19.5, 2.5 Hz, 1H), 3.84 – 3.73 (m, 2H), 3.65 (dd, J =12.2, 2.0 Hz, 1H), 3.28 (dd, J = 12.2, 2.0 Hz, 1H), 2.77 (ddd, J = 13.9, 8.0, 5.7 Hz, 1H), 2.19 (ddd, J = 114.2, 11.1, 7.4 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ ppm 134.8, 134.3, 131.8, 131.5, 128.2, 128.1, 124.1, 122.1, 87.6, 81.9, 71.2, 51.9, 51.0, 34.3; HRMS calculated for C16H16BrNNaO3S (M+Na)+ 403.9932; found 403.9619.

Sultam [(±) 10]

According to general procedure A, 1 (80 mg, 0.3 mmol, cat-B (30 mg, 0.03 mmol) and acrylonitrile (1.9 mL, 30 mmol) was added to argon degassed, dry CH2Cl2 (85 mL, 0.005 M) to yield (±) 10 [50 mg, 0.20 mmol, 67%] as a white solid. Mp 170 °C; FTIR (neat): 1338, 1164, 1114 cm−1; 1H NMR (500 MHz, CDCl3) δ ppm 6.67 (dd, J = 16.2, 4.3 Hz, 1H), 6.28 (dq, J = 10.1, 2.1 Hz, 1H), 5.67 (dd, J = 1.9, 16.2 Hz, 1H), 5.60 (dt, J = 10.1, 2.5 Hz, 1H), 5.03 – 4.96 (m, 1H), 4.21 (dt, J = 19.6, 2.5 Hz, 1H), 3.80 (dt, J = 19.6, 2.2 Hz, 1H), 3.72 (ddd, J = 10.8, 6.4, 1.9 Hz, 1H), 3.58 (dd, J = 2.0, 12.3 Hz, 1H), 3.29 (dd, J = 2.0, 12.3 Hz, 1H), 2.86 – 2.79 (m, 1H), 2.16 (ddd, J = 14.1, 10.9, 6.9 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ ppm 149.9, 132.3, 123.5, 115.4, 99.4, 87.1, 78.4, 69.1, 50.9, 49.9, 32.2; HRMS calculated for C11H12N2NaO3S (M+Na)+ 275.0466; found 275.0468.

Sultam [(±) 12]

According to general procedure A, 2 (80 mg, 0.3 mmol, cat-B (30 mg, 0.03 mmol) was added to argon degassed, dry CH2Cl2 (85 mL, 0.005 M) to yield (±) 12 [63 mg, 0.23 mmol, 75%] as a brown liquid. FTIR (neat): 2927, 1597, 1311, 1150, 931 cm−1; 1H NMR (500 MHz, CDCl3) δ ppm 6.36 (dd, J = 17.7, 11.1 Hz, 1H), 5.99 (dd, J = 17.0, 10.6 Hz, 1H), 5.81 (ddd, J = 17.2, 10.3, 6.9 Hz, 1H), 5.57 – 5.44 (m, 2H), 5.33 (dd, J = 17.2, 1.1 Hz, 1H), 5.28 – 5.16 (m, 5H), 4.71 – 4.65 (m, 1H), 4.15 (d, J = 13.8 Hz, 1H), 3.53 (d, J = 8.6 Hz, 1H), 3.47 (d, J = 13.8 Hz, 1H), 3.28 (d, J = 10.9 Hz, 1H), 3.10 (d, J = 10.9 Hz, 1H), 2.70 (dd, J = 5.0, 13.7 Hz, 1H), 2.00 (ddd, J = 8.7, 10.8, 13.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ ppm 139.4, 137.3, 136.2, 136.0, 119.9, 118.1, 116.4, 115.7, 85.7, 81.8, 66.6, 56.7, 44.7, 35.1; HRMS calculated for C14H19NNaO3S(M+Na)+ 304.0983; found 304.0947.

Sultam [(±) 13]

To a flame dried flask containing dry toluene (0.5 mL) was added diene 12 (30 mg, 0.1 mmol) and N-phenylmaleimide (0.23 g, 0.13 mmol). The reaction was heated at 85 °C for 24 h. The crude reaction mixture was concentrated under reduced pressure and purified by flash chromatography (3:2 hexane:EtOAc) to yield 13 (38 mg, 8.3 × 10−5 mol, 83% yield) as a yellow oil. FTIR (neat): 1709, 1498, 1383, 1309, 1147 cm−1; 1H NMR (500 MHz, CDCl3) δ ppm 7.43 (dd, J = 8.0, 16.5 Hz, 2H), 7.36 (dd, J = 7.5, 15.2 Hz, 1H), 7.32 – 7.27 (m, 1H), 7.22 (d, J = 7.3 Hz, 1H), 5.94 (td, J = 10.8, 16.7 Hz, 2H), 5.80 (dddd, J = 6.8, 10.4, 13.4, 17.0 Hz, 1H), 5.56 – 5.47 (m, 1H), 5.37 (dd, J = 17.2, 22.0 Hz, 1H), 5.28 – 5.13 (m, 2H), 4.79 – 4.71 (m, 1H), 3.81 (d, J = 14.1 Hz, 1H), 3.52 (d, J = 8. Hz, 1H), 3.42 – 3.22 (m, 3H), 3.16 (dd, J = 5.5, 10.8 Hz, 1H), 3.06 (dd, J = 3.0, 10.8 Hz, 1H), 2.76 – 2.64 (m, 3H), 2.47 – 2.32 (m, 2H), 2.00 (ddd, J = 7.7, 14.1, 17.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ ppm 178.8, 178.7, 178.4 (2), 137.3, 137.2, 136.3, 136.2, 134.4, 134.0, 131.9 (2), 129.1, 129.0, 128.6, 128.5, 126.4 (2), 125.7, 125.6, 118.2, 117.8, 116.6, 116.5, 86.0, 85.7, 82.2, 81.7, 66.7 (2), 57.9, 57.0, 49.5, 49.2, 39.4, 39.0, 38.9 (2), 34.9, 34.8, 25.6 (2), 24.3, 24.1; HRMS calculated for C24H26N2NaO5S (M+Na)+ 477.1460; found 477.1436.

Sultam [(±) 15]

To a flame dried flask under argon was added furfural (1.72 mL, 20.8 mmol), 4-methoxybenzylamine (2.7 mL, 20.8 mmol), MgSO4 (3.0 g) and dry CH2Cl2 (20 mL). After stirring at RT for 6 h, the crude reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude was dissolved in THF (20 mL) to which was added allyl magnesium bromide (5.57 mL, 11.15 mmol). The reaction mixture was stirred for 5 h. after which time NH4Cl (sat. aq., 10 mL) was added. The aqueous layer was extracted with CH2Cl2 (4 × 20 mL) and the combined organic layer was dried (MgSO4). The crude reaction mixture 14 (1.2 g) was solvated in dry toluene (5 mL) and heated at reflux for 12 h. After such time the crude reaction mixture concentrated under reduced pressure and purified by flash chromatography (1:1 hexane:EtOAc) to provide the desired compound (95% yield) as a yellow liquid. FTIR (neat): 1612, 1514, 1301, 1247, 1137 cm−1; [Mixture of Diastereoisomers (1:1)] 1H NMR (500 MHz, CDCl3) δ ppm 7.37 (d, J = 8.6 Hz, 1H), 7.32 (d, J = 8.6 Hz, 1H), 6.95 – 6.81 (m, 4H), 6.52 (dd, J = 5.8, 1.7 Hz 1H), 6.47 – 6.38 (m, 3H), 6.18 (d, J = 5.7 Hz, 1H), 5.93 – 5.78 (m, 1H), 5.74 – 5.58 (m, 1H), 5.28 (dd, J = 4.5, 1.5 Hz 1H), 5.22 – 5.14 (m, 2H), 5.09 – 4.97 (m, 2H), 4.51 (d, J = 15.7 Hz, 1H), 4.41 (d, J = 15.3 Hz, 1H), 4.28 (dd, J = 15.5, 8.7 Hz 2H), 3.81 (dd, J = 8.9, 5.6 Hz, 6H), 3.72 (t, J = 5.3 Hz, 1H), 3.24 (dd, J = 7.9, 3.2 Hz, 1H), 3.13 (dd, J = 7.8, 3.3 Hz, 1H), 2.74 – 2.59 (m, 1H), 2.56 – 2.48 (m, 1H), 2.45 (t, J = 7.2 Hz, 1H), 1.80 (td, J = 12.4, 7.9 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ ppm 159.3, 159.2, 139.7, 137.9, 135.3, 132.9, 132.6, 132.1, 130.0, 129.9, 127.6, 127.3, 119.4, 118.9, 114.1, 114.1, 94.5, 92.2, 79.4, 78.8, 60.4, 59.7, 58.6, 58.4, 55.3, 55.3, 46.6, 46.0, 34.6, 33.8, 30.1, 29.5; HRMS calculated for C18H21NNaO4S (M+Na)+ 370.1089; found 370.1075.

Sultam [(±) 16]

According to general procedure A, 15 (0.06 g, 0.17 mmol), cat-B (0.015 g, 0.017 mmol) in ethylene degassed CH2Cl2 (35 mL). The crude reaction was purified by flash chromatography (2:1 hexane:EtOAc) to provide 16 (32 mg, 54%) and 17 (10 mg, 16%). FTIR (neat): 1612, 1514, 1305, 1249, 1149 cm−1; 1H NMR (500 MHz, CDCl3) δ ppm 7.42 – 7.22 (m, 2H), 7.11 – 6.74 (m, 2H), 6.10 – 5.87 (m, 1H), 5.80 (ddd, J = 17.1, 10.4, 6.6 Hz, 1H), 5.72 (dt, J = 5.7, 2.2 Hz, 1H), 5.30 (dt, J = 17.2, 1.2 Hz, 1H), 5.23 – 5.15 (m, 1H), 4.52 – 4.38 (m, 2H), 4.05 (d, J = 14.4 Hz, 1H), 3.82 (d, J = 5.2 Hz, 3H), 3.64 – 3.54 (m, 2H), 2.75 (ddd, J = 13.8, 5.5, 2.0 Hz, 1H), 2.64 – 2.43 (m, 2H), 2.12 (dt, J = 13.8, 9.9 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ ppm 159.5, 135.9, 135.1, 130.4, 130.2, 126.8, 118.0, 114.1, 97.3, 80.1, 64.6, 63.8, 55.3, 45.4, 35.5, 35.2; HRMS calculated for C18H21NNaO4S (M+Na)+ 370.1089; found 370.1087.

Sultam [(±) 17]

FTIR (neat): 1514, 1303, 1247, 1145 cm−1; 1H NMR (500 MHz, CDCl3) δ ppm 7.31 (d, J = 8.7 Hz, 2H), 6.90 – 6.85 (m, 2H), 5.97 – 5.81 (m, 2H), 5.72 (dddd, J = 11.7, 9.5, 7.5, 6.4 Hz, 1H), 5.56 – 5.48 (m, 1H), 5.39 (ddd, J = 12.5, 4.3, 3.1 Hz, 2H), 5.27 – 5.20 (m, 1H), 5.00 – 4.92 (m, 2H), 4.76 (dd, J = 11.0, 5.9 Hz, 1H), 4.42 (d, J = 15.8 Hz, 1H), 4.10 (d, J = 15.8, 1H), 3.84 – 3.78 (s, 3H), 3.55 (d, J = 8.4 Hz, 1H), 3.38 (dd, J = 7.4, 5.2 Hz 1H), 2.75 (ddd, J = 13.6, 5.1, 0.9 Hz, 1H), 2.47 – 2.38 (m, 1H), 2.34 – 2.26 (m, 1H), 2.02 (ddd, J = 13.6, 10.8, 8.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ ppm 159.5, 139.1, 136.8, 129.8, 118.1, 118.1, 117.1, 114.3, 88.5, 82.4, 66.9, 66.1, 55.7, 46.0, 35.1, 32.5; HRMS calculated for C20H25NNaO4S (M+Na)+ 398.1402; found 398.1401.

Sultam [(±) 18]

According to general procedure A, 15 (80 mg, 0.3 mmol), cat-B (30 mg, 0.03 mmol), ethyl acrylate (3.0 mL, 30 mmol) was added to argon degassed, dry CH2Cl2 (85 mL, 0.005 M) to yield (±) 18 [61 mg, 0.147 mmol, 49%] as a yellow oil. FTIR (neat): 1718, 1514, 1303, 1149 cm−1; 1H NMR (500 MHz, CDCl3) δ ppm 7.28 – 7.24 (m, 2H), 6.90 – 6.82 (m, 3H), 6.01 (ddd, J = 9.7, 7.9, 1.9 Hz, 2H), 5.71 (dt, J = 2.2, 5.7 Hz, 1H), 4.65 – 4.60 (m, 1H), 4.46 (d, J = 14.4 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 4.04 (d, J = 14.4 Hz, 1H), 3.81 (s, 3H), 3.63 (dd, J = 9.7, 1.9 Hz, 1H), 3.59 (dd, J = 7.2, 3.7 Hz, 1H), 2.63 – 2.44 (m, 3H), 2.14 (dt, J = 13.8, 9.9 Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ ppm 165.9, 159.5, 144.1, 135.4, 130.2 130.1, 126.7, 122.2, 114.2, 97.8, 76.8, 64.6, 63.6, 60.7, 55.3, 45.5, 35.3, 35.2, 14.2; HRMS calculated for C21H25NNaO6S (M+Na)+ 442.1300; found 442.1283.

Sultam [(±) 19]

According to general procedure A, 15 (80 mg, 0.3 mmol), cat-B (30 mg, 0.03 mmol), t-butyl acrylate (4.3 mL, 30 mmol) was added to argon degassed, dry CH2Cl2 (85 mL, 0.005 M) to yield (±) 19 [69 mg, 0.156 mmol, 52%] as a yellow oil. FTIR (neat): 2978, 1710, 1514, 1308, 1151 cm−1. 1H NMR (500 MHz, CDCl3) δ ppm 7.27 – 7.23 (m, 2H), 6.90 – 6.85 (m, 2H), 6.74 (dd, J = 15.7, 5.3 Hz, 1H), 6.01 – 5.98 (m, 1H), 5.94 (dd, J = 15.7, 1.4 Hz, 1H), 5.71 (dt, J = 5.7, 2.2 Hz, 1H), 4.59 (dd, J = 7.3, 2.7 Hz, 1H), 4.46 (d, J = 14.4 Hz, 1H), 4.03 (d, J = 14.4 Hz, 1H), 3.81 (s, 3H), 3.62 (dd, J = 19.7, 1.9 Hz, 1H), 3.57 (dd, J = 7.2, 3.8 Hz, 1H), 2.80 (ddd, J = 13.8, 5.8, 2.0 Hz, 1H), 2.60 – 2.46 (m, 1H), 2.13 (dt, J = ,13.8, 9.9 Hz, 1H), 1.87 – 1.82 (m, 1H), 1.46 (s, 9H); 13C NMR (125 MHz, CDCl3) δ ppm 165.2, 159.5, 142.9, 135.4, 130.2, 130.1, 126.7, 124.1, 114.2, 97.7, 80.8, 76.8, 64.6, 63.6, 55.3, 45.4, 35.2, 35.2, 28.1; HRMS calculated for C23H29NNaO6S (M+Na)+ 470.1613; found 470.1601.

tert-Butyl (2S)-1-(furan-2-yl)-1-hydroxy-3-phenylpropan-2-ylcarbamate (20)

To a stirring suspension of imidazole (12.8 g, 188 mmol) in CH2Cl2 (40 mL) was added a solution of PhOP(O)Cl2 (5.61 mL, 37.7 mmol) in CH2Cl2 (40 mL). After stirring for 1 h, the reaction was cooled to 0 °C and a solution of Boc-phenylalanine (10.0 g, 37.7 mmol) in CH2Cl2 (28 mL) was added and the reaction mixture stirred for 1 h. After such time, Weinreb amine (3.68 g, 37.7 mmol) was added and the reaction stirred at rt for 14 h. The reaction was quenched with citric acid (2M aq., 80 mL), the organic layer washed with NaHCO3 (1M aq., 80 mL) and brine (80 mL). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to generate the desired intermediate as a clear oil (crude NMR analysis).

A portion of the crude (6.59 g, 25.3 mmol) in THF (84.5 mL) was cooled to −40 °C was stirred for 30 min. In a separate round bottom flask, a solution of furan (4.6 mL, 63.3 mmol) in THF (110 mL) was cooled to −78 °C to which nBuLi (26.3 mL) was added slowly and upon completion, was stirred for 30 min. After such time, this solution was added slowly to the crude mixture at −40 °C and the reaction mixture was subsequently stirred for an additional 6 h. After such time the reaction was quenched with NH4Cl (sat. aq., 80 mL) and the reaction mixture warmed to RT. The aqueous layer was extracted with EtOAc (3 × 120 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure to give the desired intermediate as a clear oil (crude NMR analysis). A portion of the crude (1.0 g) in THF (12 mL)/MeOH (1.5 mL) was cooled to 0 °C and after stirring for 15 min, NaBH4 (0.14 g, 3.8 mmol) was added and reaction stirred for 2 h at 0 °C. After such time the reaction was warmed to RT, diluted with EtOAc (10 mL) followed by HCl (10% aq., 10 mL). After stirring for 15 min, the organic layer was washed with HCl (10% aq., 10 mL), H2O (10 mL), NaHCO3 (sat. aq., 10 mL) and brine (10 mL). The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure to yield the desired intermediate as a white solid. Mp 144–146 °C; FTIR (neat) 1716, 1454, 1292, 1172, 1132 cm−1; [Major Isomer] 1H NMR (500 MHz, CDCl3) δ 7.48 – 7.43 (m, 1H), 7.34 – 7.17 (m, 5H), 6.38 – 6.29 (m, 2H), 4.80 (d, J = 19.2 Hz, 1H), 4.70 – 4.78 (m, 1H), 4.27 (br s, 1H), 3.55 (br s, 1H), 2.80 (d, J = 6.3 Hz, 2H), 1.35 (s, 9H). [Minor Isomer] 1H NMR (500 MHz, CDCl3) δ 7.39 (s, 1H), 7.16 – 7.35 (m, 5H), 6.43 – 6.38 (m, 2H), 4.89 (s, 1H), 4.75 (s, 1H), 4.14 (s, 1H), 3.08 (s, 1H), 2.88 – 2.99 (m, 2H), 1.41 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 156.6, 154.6, 154.0, 142.3, 142.0, 137.9, 137.6, 129.3, 129.3, 128.5, 128.5, 126.5, 126.5, 110.3, 107.8, 106.8, 80.0, 79.7, 77.3, 77.0, 76.7, 70.1, 68.7, 56.5, 55.4, 37.6, 36.6, 28.3; HRMS calculated for C18H23NO4Na (M + Na) + 340.1525; found 340.1520 (TOF MS ES+).

7H-4a,7-Epoxy-2H-1,2-benzothiazin-4-ol, 3,4,8,8a-tetrahydro-3-(phenylmethyl)-, 1,1-dioxide, (3S,4R) (21)

Carbamate 20 (2.0 g, 6.3 mmol) was dissolved in CH2Cl2 (32 mL), cooled to 0 °C and after stirring for 15 min TFA (1.95 mL, 25.2 mmol) was added cautiously. After stirring at RT for 3 h, the reaction was cooled to 0 °C and NaOH (10% aq., 35 mL) was added. The reaction was diluted with CH2Cl2 (32 mL), the aqueous layer extracted with CH2Cl2 (2 × 30 mL) and the combined organic dried (MgSO4), filtered and concentrated under reduced pressure to afford the desired carbamate intermediate as a white solid. The crude product (1.78 g) was dissolved in EtOH (40 mL) and NaOH (1M aq., 40 mL) was added. After stirring at reflux for 14 h, the organic solvent was removed under reduced pressure. The resulting aqueous layer was extracted with CH2Cl2 (3 × 30 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure to produce the desired amino alcohol intermediate as a yellow oil. The crude material was dissolved in CH2Cl2 (11.7 mL), to which was added Et3N (1.58 mL, 91 mmol) and the reaction was cooled to 0 °C. After stirring for 10 mins, 2-chloroethanesulfonyl chloride (0.52 mL, 4.89 mmol) was added drop wise over 5 min. The reaction mixture was warmed to RT and stirred for 12 hours. After which time the crude mixture was concentrated and purified by flash chromatography (1:2 hexane:EtOAc) to yield (1.0 g, 3.2 mmol, 52%) of 21 as a white solid. FTIR (neat) 3480, 3350, 2358, 1448, 1305, 1139 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.35 – 7.28 (m, 2H), 7.28 – 7.19 (m, 3H), 6.55 (dd, J = 5.7, 1.5 Hz, 1H), 6.34 (d, J = 5.7 Hz, 1H), 5.19 (dd, J = 4.7, 1.5 Hz, 1H), 4.64 (d, J = 10.6 Hz, 1H), 4.07 (dd, J = 16.4, 9.7 Hz 1H), 3.90 (s, 1H), 3.21 (dd, J = 7.9, 3.2 Hz 1H), 3.10 (dd, J = 13.9, 6.6 Hz, 1H), 2.92 (dd, J = 13.8, 8.9 Hz, 1H), 2.61 – 2.52 (m, 1H), 2.35 (s, 1H), 1.77 (dd, J = 12.2, 7.9 Hz 1H); 13C NMR (125 MHz, CDCl3) δ 140.1, 136.1, 133.4, 129.1, 129.0, 127.2, 91.2, 79.5, 64.2, 56.2, 55.6, 37.0, 28.8.; HRMS calculated for C15H17NO4SNa (M + Na)+ 330.0776; found 330.2017 (TOF MS ES+).

Sultam [22]

Into a 1 dram vial was added 21 (85 mg, 0.27 mmol), DMF (0.6 mL, 0.46 M), Cs2CO3 (0.18 g, 0.55 mmol) and allyl bromide (25 μL, 0.30 mmol). The reaction was heated at 50 °C and stirred for 4 h after which time the crude mixture was filtered and concentrated under reduced pressure. The resulting crude oil was purified by flash chromatography (1:2 hexane:EtOAc) to yield (86 mg, 2.48 mmol, 92%) of 22 as a yellow oil. FTIR (neat) 3386, 3249, 2358, 1336, 1315, 1152 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.36 – 7.30 (m, 2H), 7.25 (dd, J = 7.2, 5.2 Hz 3H), 6.57 (dt, J = 5.6, 2.8 Hz 1H), 6.27 (d, J = 5.7, 1H), 6.04 – 5.94 (m, 1H), 5.33 (ddq, J = 20.2, 10.4, 1.4 Hz 2H), 5.21 (dd, J = 4.7, 1.6 Hz 1H), 4.71 (d, J = 12.1 Hz, 1H), 4.31 (dt, J = 5.5, 1.4 Hz, 2H), 4.14 (dddd, J = 12.1, 8.3, 7.1, 1.0 Hz, 1H), 3.64 (s, 1H), 3.20 (dd, J = 7.9, 3.3 Hz, 1H), 3.11 (dd, J = 14.3, 7.1 Hz, 1H), 2.90 (dd, J = 14.3, 8.5 Hz, 1H), 2.60 (ddd, J = 12.2, 4.6, 3.4 Hz, 1H), 1.78 (dd, J = 12.1, 7.9 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 140.3, 136.5, 133.6, 133.4, 129.1, 129.0, 127.1, 118.2, 91.0, 79.5, 74.9, 72.5, 56.7, 56.1, 37.4, 29.0; HRMS calculated for C18H21NO5SNa (M + Na)+ 370.1089; found 370.1087 (TOF MS ES+).

Sultam [23]

According to general procedure A, sultam 22 (20 mg) underwent ROM-RCM-CM with ethylene to yield 23 (18 mg, 90%) as a clear oil. FTIR (neat): 3481, 2975, 1724 1445, 1308, 1139 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.25 – 7.17 (m, 3H), 7.14 (ddd, J = 9.5, 6.6, 3.4 Hz, 2H), 6.46 (d, J = 5.7 Hz, 1H), 6.37 (dd, J = 5.7, 1.6 Hz, 1H), 5.75 (dddd, J = 17.2, 10.0, 7.6, 5.7 Hz, 1H), 5.16 (ddd, J = 13.6, 11.0, 1.1 Hz, 2H), 5.02 (dd, J = 4.6, 1.6 Hz, 1H), 4.03 – 3.90 (m, 3H), 3.80 – 3.70 (m, 2H), 3.25 – 3.16 (m, 2H), 3.01 (dd, J = 13.4, 5.1 Hz 1H), 2.18 (dt, J = 12.7, 4.4 Hz, 1H), 1.87 (dd, J = 12.7, 8.5 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 137.9, 137.3, 135.3, 134.9, 129.4, 128.6, 126.7, 118.6, 91.6, 78.4, 64.2, 62.9, 57.3, 53.6, 37.1, 30.8; HRMS calculated for C18H21NO4SNa (M + Na)+ 370.1089; found 370.1087 (TOF MS ES+).

Sultam [24]

To a stirring solution of sultam 21 (50 mg, 0.16 mmol), Et3N (45 μL, 0.32 mmol), and CH2Cl2 (0.35 mL) in a 1 dram vial was added was added acryloyl chloride (17 μL, 0.21 mmol). After stirring for 4 h at RT, the reaction mixture was concentrated under reduced pressure and purified by flash chromatography (1:1 hexane:EtOAc) to yield (53 mg, 0.14 mmol, 92%) of 24 as a yellow oil. FTIR (neat): 3470, 2980, 1726 1452, 1300, 1140 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.32 – 7.22 (m, 3H), 7.17 (dd, J = 6.6, 5.0 Hz, 2H), 6.62 (dd, J = 17.3, 1.0 Hz 1H), 6.54 (dd, J = 5.8, 1.6 Hz, 1H), 6.27 (dd, J = 17.3, 10.4 Hz, 1H), 6.06 (dd, J = 10.4, 1.0 Hz, 1H), 5.95 (d, J = 5.8 Hz, 1H), 5.48 (d, J = 19.2 Hz, 1H), 5.22 (dd, J = 4.7, 1.6 Hz 1H), 4.64 (d, J = 11.6 Hz, 1H), 4.21 (dtd, J = 11.6, 7.3, 1.0 Hz, 1H), 3.19 (dd, J = 7.9, 3.2 Hz, 1H), 2.84 (qd, J = 14.3, 7.3 Hz, 2H), 2.67 – 2.57 (m, 1H), 1.79 (dd, J = 12.2, 7.9 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 137.9, 137.2, 135.3, 134.9, 129.4, 128.6, 126.7, 118.6, 91.6, 78.4, 64.2, 62.9, 57.3, 53.6, 37.1, 30.8; HRMS calculated for C18H19NO5SNa (M + Na)+ 384.0882; found 384.0886 (TOF MS ES+).

Sultam [25]

According to general procedure A, sultam 24 (18 mg) underwent ROM-RCM-CM with ethylene to yield 25 (16 mg, 85%) as a clear oil. FTIR (neat): 3480, 2982, 1726 1448, 1305, 1139 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.23 (t, J = 7.3 Hz, 2H), 7.16 (dd, J = 15.3, 7.9 Hz, 1H), 7.11 (d, J = 7.1 Hz, 2H), 6.43 (dd, J = 17.2, 0.9 Hz, 1H), 6.08 (dd, J = 17.2, 10.4 Hz 1H), 5.91 (dd, J = 10.4, 0.9 Hz, 1H), 5.77 – 5.69 (m, 1H), 5.66 (dd, J = 17.4, 10.8 Hz, 1H), 5.26 (d, J = 17.4 Hz, 1H), 5.19 (dd, J = 13.9, 7.4 Hz, 2H), 5.09 (d, J = 10.2 Hz, 1H), 5.07 (s, 1H), 4.93 (dd, J = 16.2, 7.8 Hz, 1H), 4.36 (d, J = 12.1 Hz, 1H), 4.27 – 4.19 (m, 1H), 3.63 (d, J = 6.6 Hz, 1H), 2.73 – 2.60 (m, 3H), 2.03 (ddd, J = 14.0, 9.5, 6.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 164.2, 138.9, 138.3, 135.6, 133.2, 129.1, 128.7, 127.0, 127.0, 118.2, 118.1, 87.1, 81.4, 77.3, 61.8, 54.7, 37.5, 32.8; HRMS calculated for C20H23NO5SNa (M + Na)+ 412.1195; found 412.1190 (TOF MS ES+).

N-Allyl-N-(furan-2-ylmethyl)methanesulfonamide (26)

xxiii Into a flame dried flask under argon was added methanesulfonyl chloride (2.03 mL, 26.2 mmol), Et3N (4.4 mL, 31.6 mmol) and dry CH2Cl2 (70 mL). After cooling down to 0 °C, furfurylamine (2.32 mL, 26.1 mmol) was added and the reaction flask stirred at room temperature for 5 h. After such time, the crude reaction mixture was washed with water and the organic layer dried (MgSO4), filtered and concentrated under reduced pressure to yield a yellow oil. The crude material was subsequently dissolved in CH3CN (100 mL), to which K2CO3 (7.27 g, 52.6 mmol) and allyl bromide (3.0 mL, 34.6 mmol) was added. After stirring at 60 °C for 12 h, the crude reaction mixture was filtered through a pad of celite and washed with CH2Cl2. The crude mixture was concentrated under reduced pressure and purified by flash chromatography (4:1 hexane:EtOAc) to provide (5.35 g, 24.8 mmol, 95 % yield) as a yellow oil. 1H NMR (500 MHz, CDCl3) δ ppm 7.43 – 7.40 (m, 1H), 6.36 (dd, J = 3.1, 1.9 Hz, 1H), 6.31 (d, J = 3.2 Hz, 1H), 5.78 (ddt, J = 16.4, 10.1, 6.3 Hz, 1H), 5.30 (ddd, J = 10.9, 8.7, 1.3 Hz 2H), 4.42 (s, 2H), 3.82 (d, J = 6.2 Hz, 2H), 2.79 (s, 3H); 13C NMR (125 MHz, CDCl3) δ ppm 149.7, 142.9, 132.6, 119.4, 110.5, 110.0, 49.3, 42.5, 39.4; HRMS calculated for C9H13NNaO3S (M+Na)+ 238.0514; found 238.0510.

Sultam [(±) 28]

To a flame dried flask was added, 26 (2 g, 9.29 mmol), diethyl chlorophosphate (1.6 mL, 11.1 mmol) and THF (40 mL). The reaction mixture was cooled to −78 °C and after stirring for 15 mins, LHMDS (1.0 M solution in THF) was added. The resulting solution was warmed to 0 °C and maintained for 2 h. To another flame dried flask, ethyl glyoxalate (3.7 mL, 18.7 mmol) and THF (40 mL) were added at −78 °C. After stirring for 15 min, this solution was added to the anionic solution containing 26 via cannula. The resulting solution was stirred at −78 °C for 7 h and then warmed to rt and stirred for an additional for 18 h. After such time, NH4Cl (sat. aq., 25 mL) was added and the mixture was extracted with CH2Cl2 (4 × 25 mL). The organic layer was dried (MgSO4), filtrated, concentrated under reduced pressure and purified by flash chromatography (7:1 hexane:EtOAc) to provide the mixture of Diels-Alder product 28 and precursor 27 product. Addition of hexane and Et2O followed by cooling at 0 °C, resulted in crystallization of the desired product 28 as a white solid (1.55g, 5.2 mmol, 56%). FTIR (neat): 2983, 1736, 1301, 1141, 1020 cm−1; 1H NMR (500 MHz, CDCl3) δ ppm 6.51 (d, J = 5.7 Hz, 1H), 6.48 (dd, J = 5.7, 1.5 Hz, 1H), 5.88 (ddt, J = 16.6, 10.1, 6.4 Hz, 1H), 5.40 (dd, J = 4.7, 1.4 Hz 1H), 5.34 (dd, J = 17.1, 1.3 Hz, 1H), 5.29 (dd, J = 10.1, 1.0 Hz, 1H), 4.20 – 4.12 (m, 2H), 3.84 (dd, J = 9.9, 5.9 Hz, 2H), 3.81 – 3.77 (m, 2H), 3.62 (d, J = 11.5 Hz, 1H), 3.55 (d, J = 3.7 Hz, 1H), 1.27 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ ppm 168.8, 137.4, 135.6, 132.2, 119.9, 91.8, 81.0, 63.4, 61.8, 48.8, 48.3, 47.7, 14.2; HRMS calculated for C13H17NNaO5S (M+Na)+ 322.0725; found 322.0721.

Sultam [(±) 29]

To a flame dried flask was added dry CH2Cl2 (50 mL, 0.005 M), which was degassed with ethylene 30 min. After such time, sultam 28 (0.1 g, 0.33 mmol) and cat-B (0.03 g, 0.033 mmol) were added and the reaction was refluxed at 40 °C for 1 h under ethylene (1 atm). After cooling to rt, the crude reaction mixture concentrated under reduced pressure and purified flash chromatography (6:1 hexane:EtOAc) to yield 29 (58 mg, 1.94 mmol, 59% yield) as a grey solid. Mp 155 °C; FTIR (neat): 2978, 1732, 1340, 1194, 999 cm−1; 1H NMR (500 MHz, CDCl3) δ ppm 6.34 (dq, J = 10.1, 2.1 Hz, 1H), 5.73 (ddd, J = 17.2, 10.4, 6.8 Hz, 1H), 5.58 (dt, J = 2.5, 10.1, 1H), 5.39 (dt, J = 17.1, 1.2 Hz, 1H), 5.27 (dt, J = 10.4, 1.1 Hz 1H), 5.08 (dd, J = 8.2, 7.4 Hz, 1H), 4.21 (ddd, J = 6.7, 5.7, 1.9 Hz 1H), 4.18 – 4.12 (m, 3H), 3.82 – 3.75 (m, 2H), 3.57 (dd, J = 12.3, 2.0 Hz 1H), 3.31 (dd, J = 12.3, 2.0 Hz, 1H), 1.25 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ ppm 168.9, 134.3, 132.7, 124.1, 119.3, 87.2, 84.2, 72.2, 61.8, 52.7, 51.0, 50.9, 14.1; HRMS calculated for C13H17NNaO5S (M+Na)+ 322.0725; found 322.0716.

Sultam [(±) 30]

Into a flame dried flask under argon sultam 29(862 mg, 2.88 mmol), CH3CN (11.5 mL, 0.25 M), and I2 (730 mg, 2.88 mmol) were added. The resulting solution was stirred at RT for 24 h. The reaction was quenched with aqueous NaHCO3 and the aqueous layer was extracted with EtOAc (3 × 10 mL). The organic layer was dried (MgSO4) and was filtered. The filtrate was concentrated under reduced pressure and purified by flash chromatography (6:1 hexane:EtOAc) to provide 78 mg (25% yield) of the desired compound. FTIR (neat): 2961, 1778, 1354, 1159, 1111 cm−1. 1H NMR (500 MHz, CDCl3) δ ppm 6.26 (dq, J = 10.1, 2.1 Hz, 1H), 5.61 (dt, J = 10.1, 2.5 Hz, 1H), 4.85 (d, J = 6.6 Hz, 1H), 4.66 (dd, J = 6.9, 3.4 Hz, 1H), 4.24 (dt, J = 19.7, 2.5 Hz, 1H), 3.99 (dd, J = 6.6, 3.5 Hz, 1H), 3.87 – 3.82 (m, 2H), 3.59 (dd, J = 12.4, 2.1 Hz, 1H), 3.43(dd, J = 11.1, 3.5 Hz, 1H), 3.30 (dd, J = 11.1, 6.9 Hz, 1H), 3.29 (dd, J = 12.5, 1.9 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ ppm 173.5, 132.0, 125.0, 89.4, 85.0, 81.2, 73.1, 50.9, 50.9, 49.0, 3.6. HRMS calculated for C11H12INNaO5S (M+Na)+ 419.9379; found 419.9344.

figure nihms106968f4

Acknowledgments

This work was generously supported by funds provided by the Center for Chemical Methodologies and Library Development at the University of Kansas (KU-CMLD) [P50 GM069663], Pilot Scale Libraries Program (P41 GM076302) and NIH COBRE award P20 RR015563 with additional funds from the State of Kansas. The authors thank the Umaer Basha Research fellowship for student support (I.O.) and Materia, Inc. for supplying catalyst and helpful discussion. The authors also thank Sarah Neuenswander for assistance with NMR measurements, and Dr. Victor Day for crystal structure data.

Footnotes

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