Diastereoselective synthesis of highly functionalized cis-1-oxadecalines via 6-endo-tet-cyclizations of 2-C-branched sugars

Abstract

Zinc mediated Barbier reaction of 4-chloro-2-eno-C-allyl pyranoside with aryl aldehydes provided benzylic alcoholic products which underwent FeCl₃ catalyzed highly stereoselective 6-endo-tet cyclization giving access to functionalized cis-1-oxadecalins at room temperature.

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Introduction

Optimal drug-like parameters and characteristics are a prerequisite for medicinal chemistry and the understanding of a successful drug profile is vital in the development of future small molecule New Chemical Entities (NCEs).¹ One of the key components in medicinal chemistry is the ring system, the fundamental building block of most drugs in the market today. The importance of rings is not difficult to realize because they play a significant role in molecular properties such as the electronic distribution, three dimensionality, lipophilicity or polarity, metabolic stability, toxicity and scaffold rigidity.²

1-Oxadecalins are ubiquitous in several bioactive natural products which contain cis/trans fused 6,6 bicyclic framework.³ These structurally intriguing compounds are selective antagonists of platelet activating factor⁴ and show antifungal,^5a antitumor,^5b adenylyl cyclase inhibitory,⁶ and glycosidase inhibitory activities.⁷ There are methods⁸ available in the literature which describe the construction of 1-oxadecalin ring system as depicted in Fig. 1 Most of the methods^9–11 deal with the construction of cyclohexane ring on the pyran backbone through intermolecular Diels–Alder reaction of pyran based dienes or dienophiles except one which starts from anisole.⁹ While the synthesis using pyranyl dienophiles suffer from lack of stereoselectivity,¹⁰ synthesis from pyranyl dienes with electron deficient alkenes have issues such as poor reactivity or the requirement of drastic reaction conditions.¹¹ The use of Lewis acid promoters to enhance the reactivity of dienophiles with these pyranyl dienes remains largely unexplored, most likely due to the low reactivity of the dienes and their high propensity to decompose in the presence of Lewis acids.

Fig. 1 Prior art to the synthesis of 1-oxadecalin scaffolds.

Rich in functionality and stereochemistry, carbohydrates are excellent “chiral pool” constituents for the enantioselective synthesis of biologically active natural and non-natural products.¹² Advantages of using carbohydrates as starting materials include their known absolute stereochemistry, low cost in many cases, and multifarious synthetic utility. Even so, the synthesis of key intermediates by incorporation of suitable functional groups onto carbohydrates, which can then be further exploited, has always been a challenging task. Out of all the methods, there is only one report. where enantiomerically pure carbohydrate dienes have been utilized for the synthesis of 1-oxadecalin scaffolds.^11c With our continuing interest in the synthesis of useful derivatives from carbohydrates,¹³ we planned the use of 2-C branched sugar derivatives derived from D-glucal as starting material for the synthesis of cis fused highly functionalized enantiopure oxadecalin core.

There are several notable contributions to the area of carbohydrate annulations involving ring-closing metathesis,¹⁴ Robinson annulation,¹⁵ intramolecular aldol condensation,¹⁶ radical cyclization,¹⁷ and Diels–Alder cycloaddition¹⁸ for the construction 6,6 bicyclic rings. In order to assemble 1-oxadecalin framework in stereoselective fashion, we thought of a new cyclization method as depicted in Fig. 2. The idea was to generate a benzylic carbocation (stabilized by aromatic ring) at C2-position of a suitably substituted pyranose sugar carrying a C-allyl moiety at C1 position. Subsequent electrophilic attack of benzylic carbocation¹⁹ by the terminal alkene at C-1 of the pyranose in 6-endo-trig fashion followed by capture of a nucleophile would constitute an efficient synthesis of highly functionalized 1-oxadecalins (Fig. 2). This may be considered as Prins type cyclization without aldehyde component.

Fig. 2 Schematic route to 1-oxadecalin scaffolds.

In this communication we would like to report the successful use of suitably protected D-glucal as chiral pool for the synthesis of cis fused highly functionalized diastereopure oxadecalin core from iron catalysed ring annulation of 2-C-branched sugar derivatives.

In order to construct the building block for cyclization we selected 4-chloro-2-eno-C-allyl pyranoside (4), a side product we earlier encountered while working with the synthesis of pyran embedded macrolides.²⁰ To obtain the desired derivative 4 as the sole product, the tosyl hydroxy derivative (3) was chlorinated in satisfactory yield under Appel reaction condition.²¹ Our next aim was to covert this chloro derivative 4 into a 2-C-branched sugar carrying a phenyl hydroxymethyl side chain. For this purpose we replaced the earlier reported indium²² with cheaper Zn powder for the synthesis of the C-branched sugar derivatives under Barbier condition (Scheme 1).

Scheme 1 Synthesis of various 2-C branched sugars under zinc mediated Barbier conditions.

The structure of the product was confirmed by spectroscopic analysis. The appearance of new peaks at δ 7.46–7.44 (m, 2H) and 7.20–7.16 (m, 2H) for aromatic protons, and at δ 4.62 (d, J = 3.2 Hz) for the benzylic proton is in agreement with the proposed structure. Further, the migration of double bond from 2,3 to 3,4 position was confirmed from the observed coupling constant of H-5 (J_3,5 = 2.8 Hz) indicative of SN₂′ type substitution. The reaction proceeds smoothly with other electron donating group and halogen substituted aromatic aldehydes as listed in Table 1.

Table 1 Synthesis of various C-branched sugar derivatives

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In this particular Barbier type allylation we obtained a mixture of two diastereomeric products only. This may be due to the fact that the electrophile prefers to approach from the side opposite to the departing group (Fig. 3). However, we failed to control the enantioselectivity at the benzylic position and in most of the cases almost equal amounts of diastereomers were obtained except in cases of halogen substituted compounds (Table 1) where the S isomer was the major product. Nonetheless, this was not a hindrance as the subsequent cyclization step (possibly passing through the carbocation derived by elimination of hydroxy group) provided a single stereoisomer at benzylic position in all the cases as detailed below.

Fig. 3 Conformation of 2,3-D-glycals for the formation Barbier product.

After achieving the synthesis of 2-C branched sugar derivatives (5a–5h), we turned our attention to the synthesis of the 1-oxadecalin framework. In order to prove our hypothesis put forward in Fig. 2, compound 5g was chosen as the model substrate for annulations under Prins reaction conditions without aldehyde component. The optimization studies under different acid catalysts similar to Prins reaction revealed FeCl₃ as the most suitable catalyst for the 6-endo-tet cyclization reaction (see optimization Table in ESI†). When compound 5g was treated with 1.0 mmol of FeCl₃ in DCM, the desired oxadecalin derivative 6 was obtained modest yield (30%, entry 1, Table S1, ESI†).²³ Gratifyingly, lowering the molar proportion of FeCl₃ increased the yield of cyclization product and 0.5 mol FeCl₃ was found to be the best (68%, entry 3, Table S1, ESI†). The structure of 6 was confirmed by detailed spectroscopic analysis. Disappearance of peaks characteristic of allyl group such as peaks at δ = 4.98–5.09 (=CH₂, 2H), 5.73–5.65 (=CH, 1H) in ¹H NMR, and of δ = 117 (=CH₂) in ¹³C NMR, combined with appearance of new peaks at δ = 4.65–4.57 (m, 1H, H-7) and 2.74 (td, J = 12.1, 3.1 Hz, 1H, H-5) in 1H NMR, and at δ = 57.6 (C-Cl, C-7), 44.7 (C-Ph, troscopic analysis (Fig. 4). The cross peaks between H-9, H-5 and H-10 indicated all these protons as cis related (all βH), and no cross peaks between H-5, H-7 suggested them to be trans related (i.e. αH-7). This confirms S configurations at C-5 and C-7 of the products.

Fig. 4 NOSEY correlations of compound 6.

Annulation reactions of the all the synthesized 2-C-branched sugars proceeded smoothly to form the corresponding 1-oxadecalins (6–13, Scheme 2) with moderate yields. Reactions proceeded faster and the yields were also better when substrates carrying electron donating groups on the aromatic rings were employed (Scheme 2).

Scheme 2 Synthesis of various highly functionalized 1-Oxadecalins under FeCl₃ mediated Prins cyclizations.

Conclusion

In conclusion we have developed the iron catalyzed room temperature ring annulation reactions of C-branched sugars, themselves synthesized from Barbier reaction of 4-chloro-2-eno-allyl-pyranoside, leading to the formation of the biologically significant functionalized 1-oxadecalin products diastereoselectively and in moderate yields. This is the first example of halo-Prins type annulation where carbocation instead of oxocarbenium ion involved in cyclization step preclude carbonyl component such as aldehyde or ketone.

Experimental section

All the reagents used were purchased from sigma Aldrich and Alfa Aesar. Solvents were distilled before use. ¹H and ¹³C NMR spectra were recorded on 400 and 500 MHz spectrometers (Model no. D 205/52-2382, Avance 500) with TMS as the internal standard. Chemical shifts are expressed in parts per million (δ ppm). Silica gel coated aluminium plates were used for TLC. The products were purified by column chromatography on silica gel (60–120/100–200 mesh) using petroleum ether–ethyl acetate as the eluent to obtain the pure products. Elemental analyses were performed on Elementar. LCMS was recorded on waters (Model no. Symapt MS) and optical rotation was measured with Perkin Elmer (Model no. 241). The molecular formula some of compounds were determined by HRMS (Agilent, Model no. 6540).

General procedure for the synthesis of C-branched sugar derivatives (I)

To a solution of 4-chloro-2-eno-C-allyl pyranoside (4) in THF were added zinc powder (4.0 equiv.) and aromatic aldehyde (1.5 equiv.). The resulting reaction mixture was refluxed at 60 °C until the reaction was complete as monitored by TLC. Saturated NH₄Cl solution was poured on to reaction mixture which was extracted with ethyl acetate (thrice). The combined organic layers were dried with anhydrous Na₂SO₄ and concentrated under vacuum. The resulting crude mixture was subjected to column chromatography using petroleum ether/ethyl acetate as eluent to give the corresponding 2-C-branched sugars.

Spectral analysis of the compound 5a

It was prepared by the general procedure I using 0.73 mmol (250 mg) of 4, 4-chloro benzaldehyde (102 mg) to yield the desired product 5a (72%, 235 mg) as oily liquid. ¹H NMR (400 MHz, CDCl₃) δ 7.84–7.71 (m, 2H), 7.38–7.20 (m, 6H), 5.80–5.69 (m, 2H), 5.44 (d, J = 10.3 Hz, 1H), 5.13–4.98 (m, 2H), 4.65 (dd, J = 16.7, 7.3 Hz, 1H), 4.41–4.26 (m, 1H), 4.26–4.18 (m, 1H), 4.12–3.96 (m, 2H), 2.45 (s, 3H), 2.25 (dd, J = 17.1, 11.0 Hz, 1H), 2.21–2.07 (m, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 144.9, 141.3, 140.8, 134.5, 133.6, 133.5, 133.2, 132.8, 132.7, 130.9, 129.9 (2C), 128.6, 128.5 (2C), 128.02, 127.9, 127.0, 126.3, 123.47, 117.9, 71.3, 69.3, 66.8, 44.3, 36.1, 21.7. ESI-MS; 461 (M + Na)⁺; Anal. calc. For C₂₃H₂₅ClO₅S; C, 61.53; H, 5.61; Cl, 7.90; S, 7.14; Found C, 61.58; H, 5.57; Cl, 7.95; S, 7.18.

Spectral analysis of compound 5b

It was prepared by the general procedure I using 0.73 mmol (250 mg) of 4, 4-bromo benzaldehyde (133 mg) to yield the desired product 5b (68%, 244 mg) as oily liquid. ¹H NMR (400 MHz, CDCl₃) δ 7.86–7.82 (m, 2H), 7.46–744 (m, 2H), 7.38–7.34 (m, 2H), 7.20–7.16 (m, 2H), 5.85–5.60 (m, 2H), 5.43 (dd, J = 10.0, 5.3 Hz, 1H), 5.11–4.98 (m, 2H), 4.62 (dd, J = 18.7, 7.5 Hz, 1H), 4.32–4.25 (m, 1H), 4.25–4.19 (m, 1H), 4.11–3.99 (m, 2H), 2.45 (s, 4H), 2.29–2.22 (m, 1H), 2.22–2.13 (m, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 145.2, 141.8, 134.5, 133.6, 132.2, 130.6, 129.9, 129.7, 128.3, 128.1, 127.9, 127.7, 127.0, 126.4, 121.5, 117.3, 74.7, 71.3, 71.0, 66.8, 44.3, 36.1, 21.7. ESI-MS; 515 (M + Na)⁺; Anal. calc. For C₂₃H₂₅BrO₅S; C, 55.99; H, 5.11; Br, 16.19; S, 6.50; Found. C, 55.93; H, 5.16; Br, 16.23; S, 6.53.

Spectral analysis of compound 5d

It was prepared by the general procedure I using 0.87 mmol (300 mg) of 4, 4-methoxy benzaldehyde (119 mg), to yield the desired product 5d (78%, 313 mg) as oily liquid. ¹H NMR (400 MHz, CDCl₃) δ 7.82–7.78 (m, 2H), 7.38–7.31 (m, 2H), 7.23–7.19 (m, 2H), 6.91–6.86 (m, 2H), 5.90–5.71 (m, 2H), 5.65 (dd, J = 20.0, 10.4 Hz, 1H), 5.15–5.03 (m, 2H), 4.59 (dd, J = 14.6, 7.9 Hz, 1H), 4.33–4.20 (m, 2H), 4.11–3.98 (m, 2H), 3.81 (s, 3H), 2.45 (s, 3H), 2.32–2.10 (m, 3H). ¹³C NMR (101 MHz, CDCl₃) δ (S-isomer) 159.2, 144.8, 134.7, 133.8, 130.5, 130.0, 129.0, 128.0, 127.9, 127.7, 123.9, 117.6, 113.8, 74.9, 71.1, 69.5, 68.6, 55.2, 44.6, 39.2, 21.6. (R-isomer) 159.1, 144.8, 134.9, 134.5, 133.0, 129.0, 127.9, 127.4, 125.8, 117.0, 113.7, 71.5, 69.3, 66.9, 55.2, 42.0, 36.24, 21.6. ESI-MS; 445 (M + H)⁺; Anal. calc. For C₂₄H₂₈O₆S; C, 64.84; H, 6.35; S, 7.21; Found. C, 64.87; H, 6.41; S, 7.25.

Spectral analysis of the compound 5e

It was prepared by the general procedure I using 1.0 mmol (250 mg) of 4, 2,3-dimethoxy benzaldehyde (121 mg) to yield the desired product 5e (70%, 242 mg) as oily liquid. ¹H NMR (400 MHz, CDCl₃) δ 7.81–7.77 (m, 2H), 7.35–7.31 (m, 2H), 7.09–6.99 (m, 1H), 6.94–6.80 (m, 2H), 5.89–5.57 (m, 3H), 5.16–4.97 (m, 2H), 4.83 (dd, J = 16.4, 7.6 Hz, 1H), 4.37–4.20 (m, 2H), 4.08–3.95 (m, 2H), 3.85 (s, 3H), 3.82 (d, J = 8.1 Hz, 3H), 2.74 (s, 1H), 2.51 (s, 3H), 2.37–2.08 (m, 3H). ¹³C NMR (126 MHz, CDCl₃) 152.5, 146.2, 135.7, 134.7, 132.9, 129.8 (2C), 128.1, 127.4 (2C), 124.1, 119.9, 117.6, 111.7, 71.6, 69.4, 68.5, 60.8, 55.7 (2C), 43.5, 39.2, 21.6. ESI-MS; 497 (M + Na)⁺; Anal. calc. For C₂₅H₃₀O₇S; C, 63.27; H, 6.37; S, 6.76; Found. C, 63.31; H, 6.40; S, 6.72.

Spectral analysis of compound 5g

It was prepared by the general procedure I using 0.73 mmol (250 mg) of 4, and 109 mg of 3,4-methylene dioxy benzaldehyde to yield the desired product 5g (dr = 1;1, 73%, 244 mg) as oily liquid. ¹H NMR (400 MHz, CDCl₃) δ 7.81–7.77 (m, 2H), 7.35–7.32 (m, 2H), 6.84–6.69 (m, 3H), 5.86–5.71 (m, 2H), 5.64 (m, 1H), 5.14–5.00 (m, 2H), 4.53 (dd, J = 17.1, 8.0 Hz, 1H), 4.29–4.24 (m, 2H), 4.09–3.97 (m, 2H), 2.51 (m, 3H), 2.35–2.05 (m, 3H). ESI-MS; 481 (M + Na)⁺; ¹³C NMR (126 MHz, CDCl₃) δ 147.8, 147.2, 144.9, 136.8, 134.7, 132.9, 129.8, 128.6, 128.0, 127.9, 127.3, 125.9, 120.0, 117.7, 108.0, 106.8, 101.0, 75.15, 71.07, 69.4, 66.8, 44.5, 39.17, 21.6. Anal. calc. For C₂₄H₂₆O₇S; C, 62.87; H, 5.72; S, 6.99; Found. C, 62.91; H, 5.67; S, 6.95.

General procedure for the synthesis of highly functionalized 1-oxadecalines using FeCl₃ (II)

To a solution of C-branched sugar compound (5a–5h,1 mmol) in dry DCM, add the FeCl₃ (0.5 equiv.) was added and stirred at rt for 12–15 h, after completion of reaction as monitored by TLC, the reaction mixture was diluted with water and extracted with DCM (3 × 15 mL). The combined organic layers were dried with anhydrous Na₂SO₄ and concentrated under vacuum. The crude reaction mixture was subjected to silica gel chromatography using petroleum ether/ethyl acetate as elute to yield the desired products 6–13.

Synthesis of ((2S,4aS,5S,7S,8aR)-5-(benzo[d][1,3]dioxol-5-yl)-7-chloro-4a,5,6,7,8,8a-hexahydro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate (6)

It was prepared by the general procedure II using 0.43 mmol (200 mg) of 5g to yield the desired product 6 (68%, 141 mg) as a white powder. [α]²⁰_D = +4.2 (c, 1.0, CHCl₃), ¹H NMR (400 MHz, CDCl₃) δ 7.84–7.82 (m, 2H), 7.37–7.35 (m, 2H), 6.76 (d, J = 7.9 Hz, 1H), 6.65 (d, J = 1.4 Hz, 1H), 6.62 (dd, J = 7.9, 1.6 Hz, 1H), 5.94 (s, 2H), 5.60 (d, J = 10.3 Hz, 1H), 5.52 (dt, J = 10.3, 2.5 Hz, 1H), 4.65–4.57 (m, 1H), 4.47–4.37 (m, 1H), 4.11 (dd, J = 10.6, 7.4 Hz, 1H), 4.00 (dd, J = 10.5, 3.9 Hz, 1H), 3.73–3.64 (m, 1H), 2.74 (td, J = 12.1, 3.1 Hz, 1H), 2.19–2.05 (m, 3H), 1.97–1.79 (m, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 147.8, 146.4, 144.8, 135.2, 132.6, 130.3, 130.2, 129.9, 128.0, 127.9, 124.2, 121.1, 108.4, 100.8, 71.1, 69.8, 68.3, 57.6, 44.7, 42.5, 40.4, 38.7, 21.5. ESI-MS; 477 (M + H)⁺; Anal. calc. For C, C₂₄H₂₅ClO₆S; C, 60.44; H, 5.28; Cl, 7.43; S, 6.72; Found; C, 60.48; H, 5.25; Cl, 7.46; S, 6.76.

Synthesis of ((2S,4aS,5S,7S,8aR)-5-(4-bromophenyl)-7-chloro-4a,5,6,7,8,8a-hexahydro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate (7)

It was prepared by the general procedure II using 0.38 mmol (190 mg) of 5b to yield the desired product 7 (55%, 108 mg) as oily liquid. [α]²⁰_D = +7.6 (c, 1.0, CHCl₃), ¹H NMR (400 MHz, CDCl₃) δ 7.84–7.82 (m, 2H), 7.45–7.43 (m, 2H), 7.37–7.35 (m, 2H), 7.06–7.03 (m, 2H), 5.56–5.50 (m, 2H), 4.70–4.57 (m, 1H), 4.44–4.35 (m, 1H), 4.15–4.08 (m, 1H), 4.00 (dd, J = 10.6, 3.8 Hz, 1H), 3.76–3.68 (m, 1H), 2.80 (td, J = 12.1, 3.3 Hz, 1H), 2.47 (s, 3H), 2.20–2.08 (m, 3H), 1.97–1.80 (m, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 144.9, 140.6, 132.7, 131.9, 131.8, 131.6, 130.5, 129.9, 129.7, 129.4, 128.2, 128.0, 124.6, 120.7, 71.5, 69.8, 68.3, 57.8, 44.5, 42.4, 40.4, 38.7, 21.7. ESI-MS; 511 (M + H)⁺; Anal. calc. For C, C₂₃H₂₄BrClO₄S; C, 53.97; H, 4.73; Br, 15.61; Cl, 6.93; S, 6.26. Found; C, 53.93; H, 4.76; Br, 15.58; Cl, 6.95; S, 6.22.

Synthesis of ((2S,4aS,5S,7S,8aR)-7-chloro-5-(4-fluorophenyl)-4a,5,6,7,8,8a-hexahydro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate (8)

It was prepared by the general procedure II using 0.32 mmol (140 mg) of 5c to yield the desired product 8 (60%, 87.5 mg) as oily liquid. [α]²⁰_D = +2.3 (c, 1.0, CHCl₃), ¹H NMR (400 MHz, CDCl₃) δ 7.84–7.82 (m, 2H), 7.37–7.35 (m, 2H), 7.14–7.11 (m, 2H), 7.03–6.99 (m, 2H), 5.58–5.48 (m, 2H), 4.62 (s, 1H), 4.40 (dd, J = 10.8, 7.3 Hz, 1H), 4.11 (dd, J = 10.1, 7.6 Hz, 1H), 4.01 (dd, J = 10.6, 3.7 Hz, 1H), 3.75–3.68 (m, 1H), 2.81 (td, J = 12.1, 3.0 Hz, 1H), 2.46 (s, 3H), 2.20–2.08 (m, 3H), 1.98–1.81 (m, 2H).¹³C NMR (101 MHz, CDCl₃) δ 160.5, 144.9, 137.1, 132.8, 132.2, 130.0, 129.9, 129.8, 129.4, 129.3, 128.0, 124.5, 115.7, 115.5, 71.2, 69.8, 68.4, 57.8, 44.6, 42.5, 40.2, 38.8, 21.6. ESI-MS; 473 (M + Na)⁺; Anal. calc. For C, C₂₃H₂₄ClFO₄S; C, 61.26; H, 5.36; Cl, 7.86; F, 4.21; S, 7.11; Found. C, 61.23; H, 5.39; Cl, 7.82; F, 4.25; S, 7.14.

Synthesis of ((2S,4aS,5S,7S,8aR)-7-chloro-5-(4-chlorophenyl)-4a,5,6,7,8,8a-hexahydro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate (9)

It was prepared by the general procedure II using 0.34 mmol (170 mg) of 5a to yield the desired product 9 (58%, 94 mg) as oily liquid. [α]²⁰_D = +3.8 (c, 1.0, CHCl₃), ¹H NMR (400 MHz, CDCl₃) δ 7.85–7.83 (m, 2H), 7.39–7.34 (m, 2H), 7.33–7.27 (m, 2H), 7.13–7.08 (m, 2H), 5.59–5.48 (m, 2H), 4.69–4.56 (m, 1H), 4.48–4.37 (m, 1H), 4.14–4.08 (m, 1H), 4.00 (dd, J = 10.6, 3.9 Hz, 1H), 3.75–3.68 (m, 1H), 2.81 (td, J = 12.1, 3.3 Hz, 1H), 2.46 (s, 3H), 2.19–2.08 (m 3H), 1.98–1.81 (m, 2H).¹³C NMR (126 MHz, CDCl₃) δ 144.9, 139.9, 132.7, 132.6, 130.1, 130.0, 129.9, 129.8, 129.3, 128.9, 128.5, 128.0, 124.6, 71.1, 69.8, 68.3, 57.8, 44.5, 42.3, 40.3, 38.7, 21.7. ESI-MS; 489 (M + Na)⁺; Anal. calc. For C₂₃H₂₄Cl₂O₄S; C, 59.10; H, 5.18; Cl, 15.17; S, 6.86; Found. C, 59.14; H, 5.13; Cl, 15.19; S, 6.82.

Synthesis of ((2S,4aS,5S,7S,8aR)-7-chloro-4a,5,6,7,8,8a-hexahydro-5-(4-methoxyphenyl)-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate (10)

It was prepared by the general procedure II using 0.42 mmol (200 mg) of 5d to yield the desired product 9 (66%, 137 mg) as white powder. [α]²⁰_D = +4.2 (c, 1.0, CHCl₃), ¹H NMR (400 MHz, CDCl₃) δ 7.84–7.82 (m, 2H), 7.37–7.35 (m, 2H), 7.08–7.06 (m, 2H), 6.86–6.84 (m, 2H), 5.57 (d, J = 10.3 Hz, 1H), 5.50 (dt, J = 10.3, 2.5 Hz, 1H), 4.70–4.55 (m, 1H), 4.46–4.37 (m, 1H), 4.11 (dd, J = 10.5, 7.4 Hz, 1H), 4.06–3.96 (m, 1H),3.79 (s, 3H), 3.74–3.66 (m, 1H), 2.76 (td, J = 12.1, 3.2 Hz, 1H), 2.13–2.09 (m, 3H), 1.98–1.89 (m, 1H), 1.89–1.80 (m, 1H).¹³C NMR (126 MHz, CDCl₃) δ 158.2, 144.9, 133.3, 132.7, 130.4, 130.2,129.97, 127.95, 128.9, 128.00, 127.9, 124.1, 114.1, 114.0, 71.2, 69.8, 68.4, 58.0, 55.2, 44.7, 42.6, 39.9, 38.7, 21.4. ESI-MS; 485 (M + Na)⁺; Anal. calc. For C, C₂₄H₂₇ClO₅S; C, 62.26; H, 5.88; Cl, 7.66; S, 6.93; Found. C, 62.30; H, 5.85; Cl, 7.69; S, 6.96.

Synthesis of ((2S,4aS,5S,7S,8aR)-7-chloro-5-(2,3-dimethoxyphenyl)-4a,5,6,7,8,8a-hexahydro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate (11)

It was prepared by the general procedure II using 0.37 mmol (180 mg) of 5e to yield the desired product 10 (60%, 122 mg) as oily liquid. [α]²⁰_D = + 5.6 (c, 1.0, CHCl₃), ¹H NMR (400 MHz, CDCl₃) δ 7.84–7.82 (m, 2H), 7.38–7.36 (m, 2H), 7.05 (dd, J = 16.5, 8.2 Hz, 1H), 6.82 (t, J = 9.8 Hz, 1H), 6.74 (d, J = 7.8 Hz, 1H), 5.59–5.44 (m, 2H), 4.62 (s, 1H), 4.42 (s, 1H), 4.19–4.08 (m, 1H), 3.99 (dd, J = 10.6, 3.5 Hz, 1H), 3.87 (s, 3H), 3.78 (s, 3H), 3.74–3.72 (m, 1H), 3.45 (t, J = 12.8 Hz, 1H), 2.46 (s, 3H), 2.13–2.06 (m, 3H), 1.89–1.83 (m, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 152.9, 148.3, 144.9, 135.4, 132.8, 130.6, 129.99, 129.94, 129.88, 128.02, 128.00, 124.4, 118.7, 110.4, 71.4, 69.7, 68.4, 61.0, 58.1, 55.7, 44.4, 42.0, 38.8, 32.0, 21.7. ESI-MS; 493 (M + H)⁺; Anal. calc. For C, C₂₅H₂₉ClO₆S; C, 60.90; H, 5.93; Cl, 7.19; S, 6.50. Found. C, 60.93; H, 5.97; Cl, 7.15; S, 6.47.

Synthesis of ((2S,4aS,5S,7S,8aR)-7-chloro-4a,5,6,7,8,8a-hexahydro-5-(2,4,5-trimethoxyphenyl)-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate (12)

It was prepared by the general procedure II using 0.33 mmol (150 mg) of 5f to yield the desired product 11 (65%, 113 mg) as white powder. [α]²⁰_D = + 2.9 (c, 1.0, CHCl₃), ¹H NMR (400 MHz, CDCl₃) δ 7.85–7.81 (m, 2H), 7.40–7.36 (m, 2H), 6.64 (s, 1H), 6.54–6.50 (m, 1H), 5.57–5.45 (m, 2H), 4.39 (s, 1H), 4.13 (dd, J = 10.6, 7.3 Hz, 1H), 4.08–3.96 (m, 1H), 3.93–3.89 (m, 1H) 3.88 (s, 3H), 3.82 (s, 3H), 3.78 (s, 3H), 3.24–3.11 (m, 1H), 2.85 (td, J = 12.2, 3.1 Hz, 1H), 2.47 (s, 3H), 2.28–2.16 (m, 2H), 2.13–2.02 (m, 1H), 1.80–1.64 (m, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 151.5, 148.3, 145.0, 143.6, 133.1, 130.5, 129.9, 129.7, 128.0, 124.0, 120.5, 110.8, 97.8, 71.6, 71.3, 69.9, 56.8, 56.5, 56.2, 55.1, 44.3, 43.2, 41.9, 34.9, 21.6. HRMS calc. 523.1557 (M + H)⁺; HRMS found 523.1556 (M + H)⁺.

Synthesis of ((2S,4aS,5S,7S,8aR)-7-chloro-5-(naphthalen-2-yl)-4a,5,6,7,8,8a-hexahydro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate (13)

It was prepared by the general procedure II using 0.21 mmol (100 mg) of 5h to yield the desired product 12 (54%, 56 mg) as oily liquid. [α]²⁰_D = +3.0 (c, 1.0, CHCl₃), ¹H NMR (400 MHz, CDCl₃) δ 7.85–7.77 (m, J = 20.7, 10.2 Hz, 5H), 7.63 (s, 1H), 7.47–7.43 (m, 1H), 7.41–7.27 (m, 4H), 5.63–5.41 (m, 2H), 4.66 (s, 1H), 4.53–4.38 (m, 1H), 4.22–4.11 (m, 2H), 4.02 (dd, J = 10.6, 3.5 Hz, 2H), 3.87–3.71 (m, 1H), 3.07–2.97 (m, 1H), 2.49 (s, 3H), 2.35 (dd, J = 25.6, 14.5 Hz, 1H), 2.25–2.05 (m, 3H), 1.97–1.88 (m, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 145.6, 139.6, 133.4, 130.2, 130.1, 130.01, 129.7, 129.4, 128.7, 128.5, 128.0, 127.7, 127.0, 126.9, 126.4, 126.2, 126.01, 125.7, 124.4, 124.2, 71.3, 69.8, 68.5, 58.0, 44.5, 42.4, 41.2, 38.8, 21.7. ESI-MS; 483 (M + H)⁺; Anal. calc. For C, C₂₇H₂₇ClO₄S; C, 67.14; H, 5.63; Cl, 7.34; S, 6.64. Found; C, 67.17; H, 5.60; Cl, 7.30; S, 6.67.

Acknowledgements

Authors are thankful to Dr Ram A Vishwakarma, Director IIIM Jammu, DST (GAP 1145) for generous funding, MRL thankful to CSIR-UGC New Delhi for senior research fellowship.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra06554a

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