Annulation reactions of allenyl esters: an approach to bicyclic diones and medium-sized rings.

A flexible approach to construct sterically congested bicyclo-alkenedione frameworks is reported. Under the action of potassium carbonate, α-sulphonyl cycloalkanones are added to functionalized allenyl esters, leading to a lactone intermediate that is subsequently reduced to initiate an intramolecular aldol cyclization to [3.2.1], [3.3.1], and [4.3.1] bicycles. Oxidation then affords bicyclic diones in good three-step yields. Under exceptionally mild conditions, these bicycles are converted to highly functionalized medium-sized rings through a Grob-type fragmentation.

Bridged bicyclic natural products have received considerable attention in recent years owing to their architectural complexity and biological activity. Among this class, vitisinol D containing the bicyclo[3.2.1]octane system has attracted our interest due to its unusual blood clot inhibitory activity (Figure 1).[1] This [3.2.1] skeleton is also present in a variety of other pharmacologically important natural products such as enaimeone A and cinerin C.[2] Far more numerous are bicyclo[3.3.1]nonane diketones such as garsubellin A,[3] the target of numerous successful synthesis programs.[4] Though more rare, the [4.3.1] diketone natural product family system includes N-methyl-welwitindolinone D isonitrile, the goal of many total synthesis programs for the past two decades.[5]

Figure 1

Representative bridged bicyclic natural products.

Many [3.3.1] bicyclic phloroglucinol natural products have succumbed to total synthesis,[4] most recently by Mehta and Bera[6] and Plietker et al.[7] General strategies to these various bicyclic systems are also beginning to emerge,[8] including an elegant approach by Barriault and co-workers involving a gold-catalyzed intramolecular cyclization to afford a variety of bicyclic products.[9] Because of our continuing interest in the synthesis and reactivity of allenyl esters and ketones,[10] we sought to utilize these unique axially chiral compounds[11] in the construction of vitisinol D.

Our earliest efforts to create [3.2.1] bicycles involved a double enamine addition to an allenyl ketone.[12] However, we turned to allenyl esters for the synthesis of the dione system of vitisinol D anticipating that this approach would allow us to access bicyclic diketone core A directly from cyclic ketones and allenyl esters in one step (Scheme 1). We quickly realized that the preferred double addition product was enol-lactone B (EWG = CO2Et and n = 0).[13] However, this unsaturated intermediate B was successfully transformed to the corresponding [3.2.1] bicyclic structure C via a two-step reductive aldol[14] using 2 equiv of reducing agent. A subsequent oxidation step afforded desired bicyclic diketone A in good two-step yields. We next sought to determine the generality of the annulation strategy using allenes, which is the topic of the present paper.

Scheme 1

Allene Annulation Strategy to Bridged Bicycles

Our initial studies began with the readily accessible 2-(phenylsulphonyl)-cyclohexanone (2a).[15] In the presence of K2CO3, 2a reacted with phenyl allenyl ester 4a in acetone to afford enol lactone 6a. This transformation likely proceeds via Michael addition to the reactive sp-hybridized allene-carbon, followed by ester-enolate cyclization and double bond isomerization (Scheme 2). We have previously observed similar lactone formation with 2-(ethoxycarbonyl)-cyclopentanone.[13] However, in this cyclohexanone system, the ester (as well as a ketone) electron-withdrawing group at the α-position failed to give the expected lactone. Lactone 6a was further treated with LiAlH4 (LAH) at −50 °C to afford a diol intermediate as a mixture of diastereomers. Subsequent oxidation with Dess–Martin periodinane (DMP) resulted in bicyclic diketone 9a as the exclusive product in a 60% two-step yield.[16]

Scheme 2

Initial Studies

With an optimized route to bridged bicycle 9a established, we next sought to convert it into a medium-sized ring structure. As part of this effort, we uncovered an interesting Grob-type fragmentation to convert 9a into functionalized monocyclic rings under mild conditions. We initially treated 9a with TBAF·3H2O in THF at room temperature, expecting to obtain an α-carboxylic acid ring-opened product. However, this reaction led to a rapid decarboxylation and double bond migration to afford compound 12a in quantitative yield. After examining a variety of conditions, we discovered that Et3N in MeOH led to highly conjugated medium-sized ring 15a, which retains the carbonyl from the original carbon framework of 9a.

We further evaluated the scope of this annulation strategy using 2-(phenylsulphonyl)-cycloalkanones 1–3 and variously substituted phenyl allenyl esters 4 (Table 1). These reactions delivered lactones 5–7 in good yields except with an α-substituted allenyl ester 4c (R2 = CH3; R3 = H). Specifically, the formation of lactone 6c with an α-substituted allene gave only a modest yield (48%) even after an extended reaction time (24 h). Lactones 6d and 6e, though obtained in good yields, are unstable and represent a mixture of inseparable diastereomers (approximately 5:3 and 3:1 ratios, respectively). The reactions of allenyl esters with cycloheptanone substrates to produce lactones 7a and 7b were also slow and of modest yield (entries 9 and 10). Nevertheless, with the exception of 5b, 5c, and 7b, the reduction of all lactones (5–7) using LAH and their subsequent DMP oxidation led to the formation of bridged bicyclic diones 8–10 in reasonable two-step yields. In the case of compound 9d, the two diastereomers (5:3 ratios) were inseparable. On the other hand, the reductive aldol/oxidation sequence starting from 6e afforded a product with an isolable major diastereomer 9e. An NMR analysis of this major isomer reveals that the hydrogen connected to the carbon bearing the phenyl substituent on the bicycle is strongly correlated to the adjacent C–H bond. The magnitude of the coupling constant (13.3 Hz) is only consistent with a structure in which both protons are in the axial position, which argues in favor of the exo-diastereomer (Table 1, entry 8).

Table 1

Generality Studies of Annulation Reactiona,b

Yield after column chromatography.

Oxidation of the one-carbon bridged carbinol was problematic. Unoptimized two-step yields leading to the bicyclic dione (8b) was 27%.

Bridged bicyclic ring-opening reactions are precedented and often an excellent entry into functionalized medium-sized ring systems.[17] Thus, we sought to access carbocyclic 7-, 8-, and 9-membered rings starting from the bicyclic products described in the present note. We were initially surprised by the mild conditions that were sufficient to rapidly achieve the various monocycles (Table 2). The use of TBAF·3H2O converted bicycles 9 and 10 into monocycles 12 and 13 with concomitant decarboxylation in excellent yields. Using MeOH/Et3N, a rapid ring-opening reaction led to esters 14–16 in good yields. This ring-opening reaction likely occurs via an attack of hydroxide or methanol on the carbonyl bridge, resulting in intermediate D. Subsequent collapse of this tetrahedral intermediate leads to a sulphonyl-stabilized carbanion that is rapidly protonated to give monocyclic products. In the case of TBAF·3H2O-mediated fragmentation, decarboxylation is followed by a simple double bond migration to afford more substituted double bond products 12a, 12b, 12d, and 13a. For reactions in methanol, the carbanion is immediately quenched by a proton to result in the formation of resonance stabilized dienol-containing rings 14–15 exclusively. However, in the case of dione 10b, methanol addition led to the formation of cyclononanone 16b as a single diastereomer. Other ring expansion reactions also exhibited stereoselectivity. Specifically, bicyclic diones 9d and 9e under the action of methanol/Et3N were converted to monocycles 15d and 15e, respectively, as single diastereomers (Table 2). A NOESY experiment was performed on 15d and revealed a missing correlation between the protons on the phenyl- and sulphonyl-substituted carbons. Molecular modeling reveals that these two hydrogens in the cis diastereomer should be fairly close to each other (<3 Å) and thus should exhibit a strong NOE. The absence of this NOE strongly suggests the trans isomer (which is also thermodynamically favored). We assume that 15e is also a trans isomer given its similarity to 15d.

Table 2

Medium Ring Formation

In conclusion, we have developed an efficient annulation strategy to generate [3.2.1], [3.3.1], and [4.3.1] bicycles using allenyl esters as coupling partners. The attractive feature of this method lies in its flexibility to construct an array of substituted bridged bicycles. Using these bicycles, medium-sized ring products can also be produced under mild conditions in good yields.

Experimental Section

General Information

Reactions were carried out under an argon atmosphere (unless otherwise stated) in oven-dried glassware with magnetic stirring. Purification of reaction products was carried out using flash silica gel 40–63 μ. Analytical thin-layer chromatography was performed on 200 μm silica gel 60 F-254 plates. Visualization of TLC plates was accomplished with UV light, followed by staining with vanillin or potassium permanganate and drying with a heat gun. 1H NMR were recorded on a 400 MHz spectrometer and are reported in ppm (parts per million) using solvent as an internal standard (CDCl3 at 7.26 ppm). Data are reported as b = broad, s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet; coupling constants in hertz (Hz). 13C{1H} NMR were recorded on a 100 MHz spectrometer. Chemical shifts are reported in ppm, with solvent resonance employed as the internal standard (CDCl3 at 77.0 ppm). High-resolution mass spectra were recorded by an ESI-TOF MS spectrometer (DART ion source). All reagents were purchased from commercially available sources and were used without further purification. All solvents were dried over activated 3 Å molecular sieves.

Compounds 1–3[18,19] and 4a(20) were prepared following previously reported procedures.

Phenyl 5-Phenylpenta-2,3-dienoate (4b)

A solution of phenyl(triphenylphosphoranylidene)acetate (5.9 g, 15 mmol) and triethylamine (2.2 mL, 15.6 mmol) in dichloromethane (40 mL) was charged to a round-bottom flask. To it was added hydrocinnamoyl chloride (2.4 mL, 16.2 mmol) in dichloromethane (15 mL) using an addition funnel over a period of 5–10 min. The reaction was stirred at room temperature until it turned into a dark orange color solution. This solution was concentrated under reduced pressure to about a quarter of its volume, and then diethyl ether was added to precipitate the triphenylphosphine oxide formed during the reaction. Triphenylphosphine oxide was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude residue was purified using silica gel chromatography to give phenyl 5-phenylpenta-2,3-dienoate (4b) (the minor product, an alkyne isomer, was also formed as an inseparable impurity) using ethyl acetate/hexanes (1:20). The product was obtained as a clear oil in 88% yield (3.278 g): 1H NMR (400 MHz, CDCl3) δ 3.54 (ddd, 2H, J = 7.4, 4.7, 2.7 Hz), 5.78–5.81 (m, 1H), 5.90 (td, 1H, J = 7.4, 6.3 Hz), 7.11–7.16 (m, 2H), 7.24–7.27 (m, 2H), 7.30–7.33 (m, 3H), 7.37–7.43 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 34.0, 88.3, 95.4, 121.5, 125.8, 126.7, 128.5, 128.5, 129.4, 138.3, 150.8, 164.4, 213.8; HRMS calc. for C17H14O2 [M + NH4]+: 268.1332. Found 268.1334.

Phenyl 2-Methylbuta-2,3-dienoate (4c)

A solution of phenyl 2-(triphenylphosphanylidene)propanoate (6.16 g, 15 mmol) and triethylamine (2.2 mL, 15.6 mmol) in dichloromethane (40 mL) was charged to a round-bottom flask. To it was added acetyl chloride (1.15 mL, 16.2 mmol) in dichloromethane (15 mL) through an addition funnel over a period of 5–10 min. The reaction was stirred at room temperature until it turned into a dark orange color solution. The solution was concentrated under reduced pressure to about a quarter of its volume, and diethyl ether was added to precipitate the triphenylphosphine oxide. Triphenylphosphine oxide was then removed through filtration, and the filtrate was concentrated under reduced pressure. The crude residue was purified using silica gel chromatography to give phenyl 2-methylbuta-2,3-dienoate (4c) (the minor alkyne isomer was also formed as an inseparable impurity) using ethyl acetate/hexanes (1:20). The product was obtained as a clear oil in 45% yield (0.901g): 1H NMR (400 MHz, CDCl3) δ 1.98 (t, 3H, J = 3.1 Hz), 5.20 (q, 2H, J = 3.1 Hz), 7.12 (d, 2H, J = 7.4 Hz), 7.22 (t, 1H, J = 7.4 Hz), 7.38 (t, 2H, J = 7.4 Hz; 13C NMR (100 MHz, CDCl3) δ 14.7, 78.4, 95.0, 121.5, 125.7, 129.3, 151.0, 166.2, 214.7; HRMS calc. for C11H10O2 [M + NH4]+: 192.1019. Found 192.1023.

General Procedure for the Preparation of Compounds 5a–5c

To a solution of 1 (0.37–2.0 mmol, 1 equiv) in acetone (5 mL mmol–1) was added K2CO3 (0.37–2.0 mmol, 1 equiv) and 4 (0.44–2.4 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 0.25–2 h. Upon reaction completion (as monitored by TLC), the crude reaction mixture was filtered and the filtrate was evaporated and purified using silica gel column chromatography with ethyl acetate/hexanes (3:7) to give pure 5a–5c in 56–80% yields.

4-Methyl-4a-(phenylsulfonyl)-5,6-dihydrocyclopenta[b]pyran-2(4aH)-one (5a)

Obtained in 69% yield (402 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ 2.08–2.34 (m, 3H), 2.23 (d, 3H, J = 1.2 Hz), 2.99 (dd, 1H, J = 14.1, 7.0 Hz), 5.50 (dd, 1H, J = 3.5, 2.3 Hz), 5.96 (q, 1H, J = 1.2 Hz), 7.54 (t, 2H, J = 7.8 Hz), 7.69 (t, 1H, J = 7.8 Hz), 7.86 (d, 2H, J = 7.8 Hz); 13C NMR (100 MHz, CDCl3) δ 19.3, 25.9, 29.6, 75.4, 114.9, 121.2, 128.9, 130.3, 133.9, 134.8, 146.0, 153.0, 159.0; HRMS calc. for C15H14O4S [M + NH4]+: 308.0951. Found 308.0959.

4-Phenethyl-4a-(phenylsulfonyl)-5,6-dihydrocyclopenta[b]pyran-2(4aH)-one (5b)

Obtained in 80% yield (112 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.99–2.09 (m, 1H), 2.13–2.26 (m, 2H), 2.62–2.70 (m, 1H), 2.84–2.99 (m, 3H), 3.07–3.16 (m, 1H), 5.47 (s, 1H), 6.07 (t, 1H, J = 1.6 Hz), 7.21–7.28 (m, 3H), 7.34 (t, 2H, J = 7.4 Hz), 7.50 (t, 2H, J = 7.8 Hz), 7.67 (t, 1H, J = 7.4 Hz), 7.78 (d, 2H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 25.8, 29.4, 32.4, 33.0, 75.5, 114.8, 119.8, 126.5, 128.4, 128.6, 128.9, 130.3, 133.7, 134.7, 139.7, 145.8, 155.6, 159.2; HRMS calc. for C22H20O4S [M + H]+: 381.1155. Found 381.1158.

3,4-Dimethyl-4a-(phenylsulfonyl)-5,6-dihydrocyclopenta[b]pyran-2(4aH)-one (5c)

Obtained in 56% yield (99 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.86 (d, 3H, J = 1.2 Hz), 1.99–2.07 (m, 1H), 2.09–2.21 (m, 1H), 2.12 (d, 3H, J = 1.2 Hz), 2.25–2.33 (m, 1H), 2.95 (dd, 1H, J = 14.5, 7.0 Hz), 5.42 (dd, 1H, J = 2.7, 2 Hz), 7.51 (t, 2H, J = 7.4 Hz), 7.66 (t, 1H, J = 7.4 Hz), 7.80 (d, 2H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 13.9, 16.6, 25.6, 30.1, 75.7, 113.8, 128.2, 128.8, 130.0, 134.2, 134.6, 144.7, 145.3, 160.4; HRMS calc. for C16H16O4S [M + H]+: 305.0842. Found 305.0835.

General Procedure for the Preparation of Compounds 6a–6e

To a solution of 2 (0.42–0.63 mmol, 1 equiv) in acetone (5 mL mmol–1) was added K2CO3 (0.42–0.63 mmol, 1 equiv) and 4 (0.50–0.76 mmol, 1.2 equiv). The reaction mixture was refluxed for 6–24 h. Upon reaction completion (as monitored by TLC), the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The crude product formed was purified using silica gel column chromatography with ethyl acetate/hexanes (3:7) to give pure 6a–6e.

4-Methyl-4a-(phenylsulfonyl)-4a,5,6,7-tetrahydro-2H-chromen-2-one (6a)

Obtained in 82% yield (158 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.72–1.79 (m, 1H), 1.88 (td, 1H, 13.7, 3.9 Hz), 2.17 (s, 3H), 2.19–2.30 (m, 3H), 3.01 (dt, 1H, J = 14.5, 3.5 Hz), 5.76 (d, 1H, J = 1.2 Hz), 5.80 (t, 1H, J = 3.9 Hz), 7.51 (t, 2H, J = 7.8 Hz), 7.66 (t, 1H, J = 7.8 Hz), 7.83 (d, 2H, J = 7.8 Hz); 13C NMR (100 MHz, CDCl3) δ 18.0, 19.2, 22.6, 27.4, 67.9, 117.1, 121.8, 128.8, 130.2, 134.6, 135.5, 142.6, 153.1, 159.1; HRMS calc. for C16H16O4S [M + NH4]+: 322.1108. Found 322.1108.

4-Phenethyl-4a-(phenylsulfonyl)-4a,5,6,7-tetrahydro-2H-chromen-2-one (6b)

Obtained in 82% yield (137 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.66–1.75 (m, 1H), 1.86 (td, 1H, 12.5, 3.5 Hz), 2.09–2.31 (m, 3H), 2.62–2.71 (m, 1H), 2.75–2.88 (m, 2H), 2.93–3.05 (m, 2H), 5.80 (dd, 1H, J = 4.5, 3.3 Hz), 5.87 (t, 1H, J = 1.6 Hz), 7.23–7.36 (m, 5H), 7.48 (t, 2H, J = 7.4 Hz), 7.64 (t, 1H, J = 7.4 Hz), 7.74 (d, 2H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 18.0, 22.5, 27.2, 32.4, 32.5, 68.1, 117.2, 120.2, 126.6, 128.4, 128.7, 128.8, 130.2, 134.5, 135.3, 139.6, 142.5, 155.7, 159.3; HRMS calc. for C23H22O4S [M + NH4]+: 412.1577. Found 412.1584.

3,4-Dimethyl-4a-(phenylsulfonyl)-4a,5,6,7-tetrahydro-2H-chromen-2-one (6c)

Obtained in 48% yield (78 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.69 (s, 3H), 1.72–1.79, (m, 1H), 1.85 (t, 1H, 13.7 Hz), 2.07 (s, 3H), 2.11–2.36 (m, 3H), 3.03 (d, 1H, 14.5 Hz), 5.74 (s, 1H), 7.49 (t, 2H, J = 7.4 Hz), 7.63 (t, 1H, J = 7.4 Hz), 7.76 (d, 2H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 13.5, 15.6, 18.2, 22.6, 27.8, 68.4, 116.1, 128.5, 128.8, 129.8, 134.4, 135.9, 142.2, 145.2, 160.5; HRMS calc. for C17H18O4S [M + NH4]+: 336.1264. Found 336.1259.

4-Methyl-6-phenyl-4a-(phenylsulfonyl)-4a,5,6,7-tetrahydro-2H-chromen-2-one (6d)

Obtained in 72% yield (140 mg) as a gummy compound. Compound 6d represents a mixture of diastereomers that were not stable enough to be fully characterized by NMR. A crude product 1H NMR spectrum is provided in the Supporting Information. HRMS calc. for C22H20O4S [M + NH4]+: 398.1421. Found 398.1446.

4-Phenethyl-6-phenyl-4a-(phenylsulfonyl)-4a,5,6,7-tetrahydro-2H-chromen-2-one (6e)

Obtained in 70% yield (190 mg) as a gummy compound. Compound 6e represents a mixture of diastereomers that were not stable enough to be fully be characterized by NMR. A crude product 1H NMR spectrum is provided in the Supporting Information. HRMS calc. for C29H26O4S [M – SO2Ph]+: 329.1542. Found 329.1574.

General Procedure for the Preparation of Compounds 7a–7b

To a solution of 3 (0.39–2.12 mmol, 1 equiv) in acetone (5 mL mmol–1) was added K2CO3 (0.39–2.12 mmol, 1 equiv) and 4 (0.47–2.54 mmol, 1 equiv). The reaction mixture was refluxed for 24–48 h. Upon reaction completion (as monitored by TLC), the crude reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified through silica gel column chromatography with ethyl acetate/hexanes (3:7) to give pure 7a–7b.

4-Methyl-4a-(phenylsulfonyl)-5,6,7,8-tetrahydrocyclohepta[b]pyran-2(4aH)-one (7a)

Obtained in 34% yield (228 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.35–1.46 (m, 1H), 1.51–1.68 (m, 2H), 1.73–1.88 (m, 2H), 1.88–1.98 (m, 1H), 2.17 (d, 3H, J = 1.6 Hz), 2.44 (dt, 2H, J = 5.8, 2.6), 5.70 (dd, 1H, J = 9.8, 5.8), 6.10 (s, 1H), 7.51 (t, 2H, J = 7.4 Hz), 7.65 (t, 1H, J = 7.4 Hz), 7.85 (d, 2H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 19.2, 19.5, 20.7, 23.5, 24.0, 74.6, 118.8, 123.9, 128.7, 130.5, 134.0, 134.5, 143.7, 151.4, 159.5; HRMS calc. for C17H18O4S [M + NH4]+: 336.1264. Found 336.1274.

4-Phenethyl-4a-(phenylsulfonyl)-5,6,7,8-tetrahydrocyclohepta[b]pyran-2(4aH)-one (7b)

Obtained in 44% yield (71 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.37–1.57 (m, 1H), 1.55–1.74, (m, 2H), 1.77–2.02 (m, 3H), 2.42 (m, 3H), 2.90 (t, 2H, 7.6 Hz), 3.00–3.09 (m, 1H), 5.76 (dd, 1H, J = 9.8, 5.5 Hz), 6.18 (s, 1H), 7.23–7.29 (m, 3H), 7.35 (t, 2H, J = 7.8 Hz), 7.51 (t, 2H, J = 7.4 Hz), 7.67 (t, 1H, J = 7.4 Hz), 7.81 (d, 2H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 19.46, 19.48, 23.2, 23.6, 32.7, 33.7, 75.0, 118.8, 112.4, 126.6, 128.4, 128.7, 128.8, 130.6, 134.0, 134.6, 139.7, 143.8, 153.7, 159.6; HRMS calc. for C24H24O4S [M + NH4]+: 426.1734. Found: 426.1722.

General Procedure for the Preparation of Compounds 8a–10b

To a solution of lactone (5–7) (0.041–1.1 mmol, 1 equiv) in anhydrous THF (5 mL mmol–1) at −78 °C was added 2.4 M LiAlH4 solution (0.041–1.1 mmol, 1 equiv), and the reaction mixture was stirred at −50 °C for 1–2 h. The reaction was quenched by adding acetone (2 mL) and stirred for an additional 1 h. The reaction mixture was then passed through a Celite pad and washed with CH2Cl2 (50 mL). The combined solvent was evaporated to dryness, and the crude product was subjected to oxidation without further purification. The crude product thus obtained was dissolved in CH2Cl2 (5 mL mmol–1), and to it was added DMP (2.0 equiv, 0.3 M solution in CH2Cl2). The mixture was stirred overnight at room temperature. Upon reaction completion (as monitored by TLC), the reaction mixture was filtered through Celite. The filtrate was evaporated under reduced pressure, and the residue was purified using silica gel column chromatography with ethyl acetate/hexane (3:7) to give pure 8a–10b.

(1R*,5S*)-4-Methyl-5-(phenylsulfonyl)bicyclo[3.2.1]oct-3-ene-2,8-dione (8a)

Obtained in 57% yield (17 mg) over two steps as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.73 (ddd, 1H, J = 13.7, 10.6, 5.1 Hz), 2.20–2.38 (m, 2H), 2.62 (s, 3H), 2.76 (ddd, 1H, J = 13.4, 10.7, 5.7 Hz), 3.39 (d, 1H, J = 7.4 Hz), 6.18 (s, 1H), 7.59 (t, 2H, J = 7.4 Hz), 7.70 (t, 1H, J = 7.8 Hz), 8.16 (d, 2H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 20.6, 21.4, 29.7, 62.6, 78.2, 128.9, 130.0, 131.4, 134.8, 136.4, 160.2, 194.2, 195.2; HRMS calc. for C15H14O4S [M + NH4]+: 308.0951. Found: 308.0949.

(1S*,5S*)-8-Hydroxy-4-phenethyl-5-(phenylsulfonyl)bicyclo[3.2.1]oct-3-en-2-one (8b′)

This partial oxidation product was obtained in 78% yield (60 mg) over two steps as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.44 (ddd, 1H, J = 14.7, 9.6, 5.9 Hz), 1.93 (dddd, 1H, J = 14.2, 10.7, 7.5, 3.5 Hz), 2.04–2.12 (m, 1H), 2.17–2.25 (m, 1H), 2.90–3.06 (m, 2H), 3.13–3.30 (m, 2H), 4.02 (d, 1H, J = 5.5 Hz), 6.21 (s, 1H), 7.19–7.32 (m, 5H), 7.62 (t, 2H, J = 7.4 Hz), 7.75 (t, 1H, J = 7.4 Hz), 8.01 (d, 2H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 20.5, 30.4, 34.0, 35.3, 52.4, 74.2, 78.6, 126.3, 128.0, 128.4, 128.5, 129.3, 130.3, 134.8, 134.9, 140.3, 156.8, 198.9; HRMS calc. for C22H22O4S [M + NH4]+: 400.1577. Found: 400.1527.

(1R*,5S*)-4-Phenethyl-5-(phenylsulfonyl)bicyclo[3.2.1]oct-3-ene-2,8-dione (8b)

Obtained in 27% yield (11 mg) over two steps as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.63–1.70 (m, 1H), 2.17–2.32 (m, 2H), 2.78 (ddd, 1H, J = 13.5, 10.4, 5.5 Hz), 2.91–2.98 (m, 1H), 3.02–3.09 (m, 1H), 3.23–3.31 (m, 1H), 3.39 (d, 1H, J = 7.4 Hz), 3.47–3.55 (m, 1H), 6.26 (s, 1H), 7.24 (d, 3H, J = 7.4 Hz), 7.32 (t, 2H, J = 7.4 Hz), 7.58 (t, 2H, J = 7.4 Hz), 7.70 (t, 1H, J = 7.8 Hz), 8.16 (d, 2H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 20.6, 30.1, 34.3, 34.8, 62.8, 78.5, 126.5, 128.4, 128.6, 128.7, 128.9, 131.5, 134.8, 136.5, 139.7, 163.0, 194.3, 195.3; HRMS calc. for C22H20O4S [(M – CO + H2) + NH4]+: 372.1628. Found: 372.1628.

(1R*,5S*)-3,4-Dimethyl-5-(phenylsulfonyl)bicyclo[3.2.1]oct-3-ene-2,8-dione (8c)

Obtained in 20% yield (19 mg) over two steps as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.57–1.71 (m, 1H)), 1.89 (s, 3H), 2.17–2.35 (m, 2H), 2.59 (s, 3H), 2.80 (ddd, 1H, J = 13.2, 10.7, 5.5 Hz), 3.46 (d, 1H, J = 7.4 Hz), 7.58 (t, 2H, J = 7.4 Hz), 7.69 (t, 1H, J = 7.8 Hz), 8.17 (d, 2H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 12.2, 17.2, 20.6, 29.4, 62.8, 79.4, 128.8, 131.4, 134.6, 135.3, 136.8, 153.5, 194.9, 195.5; HRMS calc. for C16H16O4S [M + NH4]+: 322.1108. Found 322.1112.

(1R*,5S*)-4-Methyl-5-(phenylsulfonyl)bicyclo[3.3.1]non-3-ene-2,9-dione (9a)

Obtained in 60% yield (182 mg) over two steps as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.59–1.87 (m, 3H), 1.99–2.09 (m, 1H), 2.24 (td, 1H, J = 12.9, 4.3 Hz), 2.55 (s, 3H), 2.57–2.68 (m, 1H), 3.26 (t, 1H, J = 3.5 Hz), 6.50 (s, 1H), 7.56 (t, 2H, J = 7.4 Hz), 7.67 (t, 1H, J = 7.4 Hz), 8.15 (d, 2H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 18.2, 22.3, 30.8, 31.2, 62.6, 79.2, 128.5, 131.7, 134.3, 135.1, 138.2, 154.5, 194.6, 199.1; HRMS calc. for C16H16O4S [M + NH4]+: 322.1108. Found 322.1110.

(1R*,5S*)-4-Phenethyl-5-(phenylsulfonyl)bicyclo[3.3.1]non-3-ene-2,9-dione (9b)

Obtained in 58% yield (87 mg) over two steps as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.39–1.50 (m, 1H), 1.69–1.78 (m, 2H), 1.99–2.09 (m, 1H), 2.24 (td, 1H, J = 12.5, 4.3 Hz), 2.60–2.66 (m, 1H), 3.05 (t, 2H, J = 7.4 Hz), 3.20–3.31 (m, 2H), 3.42–3.50 (m, 1H), 6.60 (s, 1H), 7.19–7.35 (m, 5H), 7.57 (t, 2H, J = 7.4 Hz), 7.68 (t, 1H, J = 7.4 Hz), 8.16 (d, 2H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 18.0, 30.6, 31.8, 34.2, 35.0, 62.6, 79.6, 126.5, 128.38, 128.44, 128.6, 131.8, 134.0, 134.3, 138.4, 139.8, 157.2, 194.8, 199.0; HRMS calc. for C23H22O4S [M + NH4]+: 412.1577. Found 412.1584.

(1R*,5S*)-3,4-Dimethyl-5-(phenylsulfonyl)bicyclo[3.3.1]non-3-ene-2,9-dione (9c)

Obtained in 54% yield (26 mg) over two steps as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.44–1.53 (m, 1H), 1.70–1.84 (m, 2H), 1.95–2.07 (m, 1H), 1.99 (s, 3H), 2.27 (td, 1H, J = 13.3, 3.9 Hz), 2.54 (s, 3H), 2.61–2.71 (m, 1H), 3.32 (t, 1H, J = 3.9 Hz), 7.55 (t, 2H, J = 7.4 Hz), 7.65 (t, 1H, J = 7.4 Hz), 8.14 (d, 2H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 12.5, 17.4, 18.4, 30.6, 30.9, 62.6, 80.4, 128.4, 131.6, 134.1, 138.9, 140.6, 148.3, 194.7, 199.2; HRMS calc. for C17H18O4S [M + NH4]+: 336.1264. Found 336.1277.

(1R*,5S*)-4-Methyl-7-phenyl-5-(phenylsulfonyl)bicyclo[3.3.1]non-3-ene-2,9-dione (9d)

Obtained in 52% yield (76 mg) over two steps as a white solid. The compound was isolated as an inseparable mixture of diastereomers in a 5:3 ratio. Copies of 1H NMR and 13C NMR spectra of this inseparable diastereomeric mixture are included in the Supporting Information. HRMS calc. for C22H20O4S [M + NH4]+: 398.1421. Found 398.1449.

(1S*,5S*,7S*)-4-Phenethyl-7-phenyl-5-(phenylsulfonyl)bicyclo[3.3.1]non-3-ene-2,9-dione (9e)

Obtained in 45% yield (58 mg) over two steps as an oily liquid. 1H NMR (400 MHz, CDCl3) δ 1.97 (td, 1H, J = 13.3, 4.3 Hz), 2.13–2.22 (m, 1H), 2.42–2.49 (m, 1H), 2.77–2.86 (m, 2H), 3.05–3.18 (m, 2H), 3.25–3.33 (m, 1H), 3.38 (t, 1H, J = 3.3 Hz), 3.57 (dt, 1H, J = 16.9, 8.2 Hz), 6.69 (s, 1H), 7.01 (d, 2H, J = 6.6 Hz), 7.20–7.37 (m, 8H), 7.60 (t, 2H, J = 7.4 Hz), 7.71 (t, 1H, J = 7.4 Hz), 8.18 (d, 2H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 34.1, 35.1, 36.2, 37.2, 38.2, 62.5, 79.2, 126.6, 127.0, 127.7, 128.4, 128.6, 128.8, 129.0, 131.8, 134.2, 134.4, 138.3, 139.7, 140.1, 157.6, 194.4, 198.6; HRMS calc. for C29H26O4S [M + NH4]+: 488.1890. Found 488.1878.

(1S*,6R*)-9-Methyl-1-(phenylsulfonyl)bicyclo[4.3.1]dec-8-ene-7,10-dione (10a)

Obtained in 43% yield (17 mg) over two steps as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.15–1.29 (m, 1H), 1.33–1.48 (m, 1H), 1.67 (s, 1H), 1.78–1.89 (m, 1H), 1.90–2.01 (m, 1H), 2.21 (t, 2H, J = 13.3 Hz), 2.49 (s, 3H), 2.68 (td, 1H, J = 13.7, 3.1 Hz), 3.36 (dd, 1H, J = 11.3, 3.9 Hz), 6.38 (s, 1H), 7.52 (t, 2H, J = 7.4 Hz), 7.64 (t, 1H, J = 7.4 Hz), 7.84 (d, 2H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 21.4, 25.3, 25.6, 29.5, 32.0, 62.1, 81.2, 128.6, 130.5, 133.3, 134.2, 138.2, 153.6, 195.3, 199.8; HRMS calc. for C17H18O4S [M + NH4]+: 336.1264. Found 336.1269.

(1S*,6R*)-9-Phenethyl-1-(phenylsulfonyl)bicyclo[4.3.1]dec-8-ene-7,10-dione (10b)

Obtained in 36% yield (6.0 mg) over two steps as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.14–1.19 (m, 2H), 1.30–1.40 (m, 1H), 1.67–1.85 (m, 2H), 2.11–2.22 (m, 2H), 2.63 (td, 1H, J = 13.7, 3.7 Hz), 2.85–3.00 (m, 2H), 3.12–3.15 (m, 1H), 3.34–3.46 (m, 2H), 6.58 (s, 1H), 7.22–7.36 (m, 5H), 7.50 (t, 2H, J = 7.4 Hz), 7.63 (t, 1H, J = 7.4 Hz), 7.80 (d, 2H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 25.42, 25.46, 29.4, 32.3, 33.9, 34.6, 62.0, 81.6, 126.5, 128.6, 128.62, 128.67, 130.6, 131.8, 124.1, 128.4, 140.2, 156.6, 195.4, 199.9; HRMS calc. for C24H24O4S [M + NH4]+: 426.1734. Found 426.1715.

General Procedure for the Preparation of Medium Rings 12–13

To a stirred solution of compound 9 or 10 (0.047–0.065 mmol, 1 equiv) dissolved in THF (2 mL mmol–1) was added TBAF·3H20 (10 mol %), and the reaction was stirred at room temperature for 1 h. Upon reaction completion (as monitored by TLC), solvent was evaporated and the residue was purified using silica gel column chromatography with ethyl acetate/hexanes (3:7) to afford pure 12–13.

(E)-3-Methyl-4-(phenylsulfonyl)cyclooct-3-en-1-one (12a)

Obtained in 95% yield (17 mg) as a gummy compound. 1H NMR (400 MHz, CDCl3) δ 1.73–1.86 (m, 4H), 2.23 (s, 3H), 2.42–2.48 (m, 2H), 2.66–2.73 (m, 2H), 3.32 (s, 2H), 7.54 (t, 2H, J = 7.4 Hz), 7.60 (t, 1H, J = 7.4 Hz), 7.87 (d, 2H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 21.7, 23.4, 28.5, 29.1, 42.6, 52.9, 127.2, 129.2, 133.2, 137.6, 141.7, 144.8, 208.1; HRMS calc. for C15H18O3S [M + NH4]+: 296.1315. Found 396.1327.

(E)-3-Phenethyl-4-(phenylsulfonyl)cyclooct-3-en-1-one (12b)

Obtained in 96% yield (18 mg) as a gummy compound. 1H NMR (400 MHz, CDCl3) δ 1.71–1.85 (m, 4H), 2.44–2.50 (m, 2H), 2.63–2.69 (m, 2H), 2.71–2.79 (m, 2H), 2.90–2.98 (m, 2H), 3.39 (s, 2H), 7.18–7.33 (m, 5H), 7.53 (t, 2H, J = 7.4 Hz), 7.61 (t, 1H, J = 7.4 Hz), 7.86 (d, 2H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 23.6, 28.2, 29.4, 34.4, 37.5, 42.6, 51.2, 126.3, 127.2, 128.4, 128.5, 129.3, 133.3, 138.0, 140.7, 141.6, 148.1, 208.6; HRMS calc. for C22H24O3S [M + NH4]+: 386.1784. Found 386.1794.

(E)-3-Methyl-6-phenyl-4-(phenylsulfonyl)cyclooct-3-en-1-one (12d)

Obtained in 92% yield (17 mg) as a gummy compound. 1H NMR (400 MHz, CDCl3) δ 1.90–2.01 (m, 1H), 2.09–2.17 (m, 1H), 2.30 (s, 3H), 2.46–2.53 (m, 1H), 2.62–2.76 (m, 2H), 2.98 (d, 1H, J = 14.9 Hz), 3.04 (d, 1H, J = 14.9 Hz), 3.08–3.17 (m, 1H), 3.80 (d, 1H, J = 14.9 Hz), 7.18–7.24 (m, 2H), 7.32 (t, 3H, J = 7.4 Hz), 7.52 (t, 2H, J = 7.4 Hz), 7.61 (t, 1H, J = 7.4 Hz), 7.85 (d, 2H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 21.9, 31.6, 36.6, 40.1, 45.3, 52.8, 126.6, 126.7, 127.2, 128.7, 129.2, 133.3, 137.6, 141.4, 145.6 (2C), 208.4; HRMS calc. for C21H22O3S [M + NH4]+: 372.1628. Found 372.1645.

(E)-3-Methyl-4-(phenylsulfonyl)cyclonon-3-en-1-one (13a)

Obtained in 95% yield (14 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.67–1.81 (m, 6H), 2.27 (s, 3H), 2.49 (dd, 2H, J = 7.4, 5.8 Hz), 2.78 (t, 2H, J = 6.6 Hz), 3.26 (s, 2H), 7.52 (t, 2H, J = 7.4 Hz), 7.59 (t, 1H, J = 7.4 Hz), 7.84 (d, 2H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 22.8, 23.0, 23.7, 26.2, 28.0, 44.4, 49.4, 127.0, 128.3, 129.0, 133.0, 142.0, 145.0, 208.7; HRMS calc. for C16H20O3S [M + NH4]+: 310.1471. Found 310.1480.

General Procedure for the Preparation of Compounds 14a–16b

Compounds 8–10 (0.040–0.060 mmol, 1 equiv) were dissolved in an anhydrous methanol:triethylamine solution (5:1 ratio, 2 mL mmol–1), and the reactions were allowed to stir at room temperature for 1 h. Upon reaction completion (as monitored by TLC), the solvent was evaporated and the crude residue was purified using silica gel column chromatography with ethyl acetate/hexanes (3:7) to afford pure 14a–16b.

Methyl 2-Hydroxy-4-methyl-5-(phenylsulfonyl)cyclohepta-1,3-diene-1-carboxylate (14a)

Obtained in 55% yield (8.0 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ 2.01 (d, 3H, J = 1.6 Hz), 2.21–2.31 (m, 2H), 2.51–2.65 (m, 2H), 3.74 (s, 3H), 3.98 (dd, 1H, J = 8.2, 5.5 Hz), 6.03 (d, 1H, J = 1.6 Hz), 7.53 (t, 2H, J = 7.4 Hz), 7.64 (t, 1H, J = 7.4 Hz), 7.85 (d, 2H, J = 7.4 Hz), 12.07 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 21.5, 27.4, 32.3, 51.8, 69.9, 101.9, 128.8, 129.0, 129.4, 133.9, 137.6, 141.4, 166.5, 172.4; HRMS calc. for C16H18O5S [M + NH4]+: 340.1213. Found 340.1220.

Methyl (1Z,3Z)-2-Hydroxy-4-methyl-5-(phenylsulfonyl)cycloocta-1,3-diene-1-carboxylate (15a)

Obtained in 98% yield (22 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.10–1.27 (m, 1H), 1.43–1.56 (m, 1H), 1.70 (dd, 1H, J = 14.5, 12.1 Hz), 1.84–1.95 (m, 1H), 2.07 (s, 3H), 2.30 (d, 1H, J = 12.9 Hz), 2.66 (dd, 1H, J = 14.7, 8.0 Hz), 3.78, (s, 3H), 4.12 (d, 1H, J = 9.4 Hz), 5.91 (s, 1H), 7.54 (t, 2H, J = 7.4 Hz), 7.64 (t, 1H, J = 7.4 Hz), 7.84 (d, 2H, J = 7.4 Hz), 12.16 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 19.3, 22.2, 24.5, 24.9, 52.0, 66.5, 102.7, 124.7, 128.2, 129.2, 133.7, 138.4, 139.5, 167.5, 173.0; HRMS calc. for C17H20O5S [M + NH4]+: 354.1370. Found 354.1383.

Methyl (1Z,3Z)-2-Hydroxy-4-phenethyl-5-(phenylsulfonyl)cycloocta-1,3-diene-1-carboxylate (15b)

Obtained in 90% yield (19 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.04–1.18 (m, 1H), 1.38–1.51 (m, 2H), 1.76–1.91 (m, 1H), 2.29 (d, 1H, J = 12.1 Hz), 2.57 (dd, 1H, J = 14.7, 7.6 Hz), 2.69–2.85 (m, 4H), 3.78 (s, 3H), 4.16 (d, 1H, J = 9.4 Hz), 6.01 (s, 1H), 7.14–7.24 (m, 3H), 7.26–7.35 (m, 2H), 7.55 (t, 2H, J = 7.4 Hz), 7.64 (t, 1H, J = 7.4 Hz), 7.83 (d, 2H, J = 7.4 Hz), 12.21 (s, 1H); 13C NMR (100 MHz,CDCl3) δ 22.3, 24.2, 24.8, 32.4, 33.9, 52.0, 66.9, 102.8, 123.7, 126.2, 128.2, 128.40, 128.44, 129.2, 133.7, 138.4, 140.6, 142.5, 167.8, 173.0; HRMS calc. for C24H26O5S [M + NH4]+: 444.1839. Found 444.1860.

Methyl (1Z,3Z,5R,7S)-2-Hydroxy-4-methyl-7-phenyl-5-(phenylsulfonyl)cycloocta-1,3-diene-1-carboxylate (15d)

Obtained in 98% yield (21 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.63–1.75 (m, 1H), 2.03–2.11 (m, 1H), 2.13 (d, 3H, J = 1.6 Hz), 2.43–2.53 (m, 2H), 2.75 (d, 1H, J = 14.5 Hz), 3.79 (s, 3H), 4.31 (d, 1H, J = 9.4 Hz), 5.98 (d, 1H, J = 1.6 Hz), 7.12 (d, 2H, J = 7.4 Hz), 7.23 (t, 1H, J = 7.4 Hz), 7.31 (t, 2H, J = 7.4 Hz), 7.56 (t, 2H, J = 7.4 Hz), 7.66 (t, 1H, J = 7.4 Hz), 7.85 (d, 2H, J = 7.4 Hz), 12.20 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 19.3, 29.8, 32.7, 42.8, 52.1, 66.0, 102.7, 124.8, 126.6, 128.2, 128.6, 129.2, 133.8, 138.2, 140.0, 146.2, 168.1, 173.0; HRMS calc. for C23H24O5S [M + NH4]+: 430.1683. Found 430.1666.

Methyl (1Z,3Z,5R,7S)-2-Hydroxy-4-phenethyl-7-phenyl-5-(phenylsulfonyl)cycloocta-1,3-diene-1-carboxylate (15e)

Obtained in 97% yield (21 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.53 (td, 1H, J = 14.5, 9.4 Hz), 1.70 (dd, 1H, J = 14.5, 10.6 Hz), 2.36 (td, 1H, J = 11.2, 4.7 Hz), 2.46 (dd, 1H, J = 14.1, 4.7 Hz), 2.57 (d, 1H, J = 14.5 Hz), 2.72–3.06 (m, 4H), 3.76 (s, 3H), 4.32 (d, 1H, J = 9.4 Hz), 6.09 (s, 1H), 6.92 (d, 2H, J = 7.4 Hz), 7.14–7.38 (m, 8H), 7.56 (t, 2H, J = 7.4 Hz), 7.66 (t, 1H, J = 7.4 Hz), 7.84 (d, 2H, J = 7.4 Hz), 12.24 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 29.8, 32.0, 32.2, 33.6, 42.8, 52.0, 66.4, 102.8, 123.9, 126.2, 126.5, 126.6, 128.2, 128.5, 128.6, 128.6, 129.3, 133.8, 138.3, 140.5, 142.4, 146.2, 168.4, 172.9; HRMS calc. for C30H30O5S [M + NH4]+: 520.2137. Found 520.2137.

Methyl (1R,5R,Z)-2-Oxo-4-phenethyl-5-(phenylsulfonyl)cyclonon-3-ene-1-carboxylate (16b)

Obtained in 90% yield (19 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.29–1.41 (m, 1H), 1.47–1.66 (m, 2H), 1.78–1.90 (m, 2H), 1.91–2.02 (m, 1H), 2.17 (dd, 1H, J = 15.7, 10.6 Hz), 2.26–2.34 (m, 1H), 2.80 (t, 1H, J = 13.3 Hz), 3.06 (dd, 1H, J = 16.0, 8.6 Hz), 3.21 (dd, 1H, J = 16.4, 7.0 Hz), 3.34 (dd, 1H, J = 16.0, 7.4 Hz), 3.47 (d, 2H, J = 3.9 Hz), 3.72 (s, 3H), 5.27 (t, 1H, J = 6.5 Hz), 6.94 (d, 2H, J = 7.4 Hz), 7.16–7.25 (m, 3H), 7.36 (t, 2H, J = 7.4 Hz), 7.52 (t, 1H, J = 7.4 Hz), 7.92 (d, 2H, J = 7.4 Hz), 13C NMR (100 MHz, CDCl3) δ 25.0, 27.1, 28.3, 30.6, 33.2, 35.2, 42.0, 52.3, 84.7, 126.3, 126.4, 127.8, 128.3, 128.6, 131.7, 133.4, 136.5, 138.2, 140.0, 172.0, 205.7; HRMS calc. for C25H28O5S [M + NH4]+: 458.1996. Found 458.2001.