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Tetrahydrofuran synthesis using 5-endo-trig cyclisation reactions. Studies towards the synthesis of the C19-C26 fragment of tetronasin

Donald Craig,*a Neil J. Ikina and Neil Mathewsb

aDepartment of Chemistry, Imperial College of Science, Technology and Medicine, London, UK SW7 2AY
bGlaxo Wellcome Research and Development Limited, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, UK SG1 2NY

Introduction

For a number of years we have been looking at the utility of 5-endo-trig cyclisation reactions for the stereoselective synthesis of polysubstituted tetrahydrofurans. We have found that on treatment with base, sulfonyl-substituted homoallylic alcohols 1 and 2 undergo cyclisation to give 2,5-disubstituted tetrahydrofurans 3 bearing a phenylsulfonyl substituent at the 3-position. The selectivity of these processes may be changed simply by changing the geometry of the vinylic sulfone double bond. Thus, whereas the cyclisation reactions of the E-isomers 1 proceeded with modest selectivity for the 2,5-syn-isomers 3s,1 those of the isomeric substrates 2 exhibited good anti-selectivity to give 3a;2 a model has been proposed to explain these results. Vinylic sulfones 1 and 2 bearing a range of R1 and R2 substituents may readily be made using established sulfone chemistry3 via common late-stage intermediates. The routes used in pursuit of the chosen synthetic strategy start from (phenylsulfonyl)methane, an epoxide and an aldehyde, and the three-component nature of this approach allows the incorporation of a wide variety of R1 and R2 (Scheme 1). This paper presents the application of this chemistry to the enantiospecific preparation of a late-stage intermediate in the synthesis of the C19-C26 fragment of the acyltetronic acid ionophore tetronasin 4.4

Results and discussion

Inspection of the C19-C26 portion of tetronasin reveals the anti-disposition of the groups attached to the tetrahydrofuran at C21 and C24, and the presence at C22 of a methyl moiety positioned syn with respect to the vicinal substituent. This appeared to be an ideal target on which to assess the effectiveness of the anti-selective cyclisation reactions of 2 in a stereochemically complex environment. Thus, disconnection of the C18-C19 bond in 4 led back to a simpler fragment 5, which in turn would be accessible by functional group transformations of the (phenylsulfonyl)-substituted 5-endo-trig cyclisation product 6 (Scheme 2). Tetrahydrofuran 6 would be the expected product of 5-endo-trig cyclisation of vinylic sulfone 11, which would be assembled according to the methods described in our earlier work2 from (phenylsulfonyl)methane, aldehyde 9 and epoxide 10 (Scheme 2). The proposed conversion of 11 to 6 using our method raised a crucial issue: would the stereocentre at C20 in 9 serve to enhance or reduce the inherent directing effect of that at C24? To address this question the model compound 7 was synthesised2 and subjected to the standard cyclisation conditions (Scheme 2). The formation of a 1:1 mixture of tetrahydrofurans 8 indicated the absence of a directing effect due to the ultimately exocyclic stereocentre, and it was considered therefore that cyclisation of 11 should be a viable way of preparing 6 with high levels of 21,24-anti-selectivity.

The synthesis of aldehyde 9 proceeded uneventfully, starting from commercially available5 methyl (S)-3-hydroxy-2-methylpropionate. Protection of the primary hydroxy group using benzyl trichloroacetimidate-TfOH6 followed by reduction to the alcohol and oxidation gave the desired aldehyde in acceptable overall yield. Synthesis of the epoxide 10 was less straightforward. Initial attempts centred on enantioselective epoxidation via kinetic resolution7 with in situ silyl protection8 of commercially available9 but-3-en-2-ol. However, consisently low yields were obtained despite numerous attempts, and we turned our attention to a less direct, but ultimately more effective strategy. In this alternative approach, TBDPS-protected methyl (S)-lactate was reduced to the corresponding aldehyde and then methylenated via a Wittig reaction. Crucial to the success of the latter transformation was the use of toluene as solvent. Reaction of the alkene 12 with m-CPBA in dichloromethane gave a 2:1 mixture of the undesired and required epoxides 13 and 10; the latter could be isolated diastereomerically pure by simple flash chromatography on silica gel (Scheme 3).

With the components required for the synthesis of cyclisation substrate 11 in hand, we were in a position to look at the carbon-carbon bond-forming reactions required for the assembly of the sigma-framework. Reaction of lithiated (phenylsulfonyl)methane with 10 in THF-DMPU in the usual way gave ring-opened product 15, together with a small amount of the isomer 14 arising from silyl migration. Protection of the newly formed secondary alcohol group in 15 and reaction of the lithio-anion of the resulting bis-silyl ether with 9 gave 16 as a mixture of all four possible diastereomers. Oxidation using PDC and re-reduction with NaBH4-CeCl3 gave the two threo-isomers 17 and 18. Tosylation as described previously,2 elimination with EtONa-EtOH3 and finally selective mono-deprotection using HF-MeCN gave 11. Cyclisation occurred smoothly on exposure to ButOK-ButOH-THF to give almost exclusively (10:1 C21-C24 anti:syn) the desired tetrahydrofuran 6 in high yield (Scheme 4).

The remaining challenge in the synthesis of the C19-C26 tetronasin fragment 5 lies in the conversion of the C22 phenylsulfonyl function to the b-configured methyl group present in the natural product. Studies to date2 have shown that analogues of 6 may be lithiated a to the sulfonyl group, and that these reactive intermediates are sufficiently stable to undergo efficient reactions with diphenyldisulfide and, more importantly for the present target, aldehydes. Methods currently being investigated for methylation at C22 include hydroxymethylation a to the sulfonyl group followed by functionalisation of the resulting hydroxy group in such a way that reductive elimination may be effected to give a C22 methylene-containing internmediate 19. Desilylation, methylation, and finally hydrogenation with in situ cleavage of the benzylic ether should give the target molecule 5 (Scheme 5).

Conclusions

The foregoing results demonstrate that sulfonyl-substituted homoallylic alcohols are viable substrates for 5-endo-trig cyclisation reactions, and that these transformations may be applied in the context of target-orientated synthesis. In addition to the completion of the synthesis of 5, the work is being extended currently to the preparation of pyrrolidines and pyrrolidine-containing natural products such as pyrrolizidines and indolizidines.

Acknowledgements

We thank the EPSRC and GlaxoWellcome Research and Development Limited (Earmarked/CASE Studentship to N.J.I.) for financial support of this research.

Experimental

Preparation of (S)-2-(tert-butyldiphenylsilyloxy)propanal

To a stirred solution of methyl (S)-2-(tert-butyldiphenylsilyloxy)propanoate (6.6 g, 19.44 mmol, 1.0 equiv.) in hexane (25 ml) at -78 oC was added slowly over 15 min DIBAL-H (16.2 ml of a 1.5 M solution in hexanes, 24.31 mmol, 1.25 equiv.). The mixture was stirred for 2 h after which time water was added cautiously as a quench. The mixture was allowed to reach room temp. and solid NaHCO3 was added to bind the precipitate and absorb water. The solids were removed by filtration and the residues washed with diethyl ether. The organics were dried (MgSO4) and concentrated in vacuo to yield a colourless oil which was purified by chromatography (50% CH2Cl2-light petroleum) to give (S)-(tert-butyldiphenylsilyloxy)propanal (2.7 g, 44%) as a colourless oil; Rf 0.43, 50% CH2Cl2-light petroleum; [a]D25 -14.2 (c 0.550, CHCl3); vmax (film) 3072, 3050, 3014, 2959, 2933, 2893, 2859, 2804, 1739, 1590, 1472, 1427, 1390, 1375, 1363, 1112 cm-1; dH (270 MHz) 9.80 (1H, d, J 1.0, H-3), 7.62 (4H, m, ortho protons on Ph), 7.40 (6H, m, meta and para protons on Ph), 4.10 (1H, q, J 6.5, H-2), 1.23 (3H, d, J 6.5, H-1), 1.10 (9H, s, ButSi); m/z (CI) 330 [M+NH4]+, 313 [M+H]+, 283, 274, 255, 239, 235, 216, 199, 194, 181, 177, 156, 139, 135, 122, 117, 105, 94, 78 (Found: [M+NH4]+, 330.1899. C19H24O2Si requires [M+NH4]+, 330.1889).

Preparation of (S)-3-(tert-butyldiphenylsilyloxy)propene (12)

To a stirred suspension of Ph3CH3PBr (37.7 g, 105.6 mmol, 2.2 equiv.) in toluene (200 ml) at 5 oC was added KHMDS (211 ml of a 0.5 M solution in toluene, 105.6 mmol, 2.2 equiv.). The mixture was stirred for 1 h after which time it was transferred via cannula into a solution of (S)-(tert-butyldiphenylsilyloxy)propanal (15 g, 48.0 mmol, 1.0 equiv.) in toluene (82 ml) also at 5 oC. TLC after 15 min revealed complete reaction and and water was added. The organic phase was separated and the aqueous phase extracted with diethyl ether (4 x 100 ml). The combined organic layers were washed with water (100 ml) and brine (100 ml), dried (MgSO4) and concentrated in vacuo to yield a colourless oil which was purified by chromatography (0.5% diethyl ether-light petroleum) to give the olefin (10.9 g, 73%) as a colourless oil; Rf 0.71, 20% diethyl ether-light petroleum; [a]D25 -0.5 (c 0.100, CHCl3); vmax (film) 3071, 3051, 3028, 3013, 2958, 2960, 2930, 2891, 2857, 1472, 1367, 1361, 1150, 1111, 1082, 1033, 1027, 1006, 998, 989, 960, 921, 822, 740, 701, 615, 506, 488 cm-1; dH (270 MHz) 7.82-7.78 (4H, m, ortho protons on Ph), 7.46-7.36 (6H, m, meta and para protons on Ph), 5.83 (1H, ddd, J 17.5, 9.0, 6.5, H-3), 5.14 (1H, dd, J 17.0, 1.5, H-4), 4.95 (1H, dd, J 8.5, 1.5, H-4), 4.25 (1H, q, J 7.5, H-2), 1.22 (3H, d, J 7.5, H-1), 1.20 (9H, s, ButSi); m/z (CI) 328 [M+NH4]+, 316, 295, 270, 253, 233, 216, 196, 183, 175, 155, 138, 92, 78, 57 (Found: C, 77.09; H, 8.36. C20H26OSi requires C, 77.35 ; H, 8.46%).

Preparation of [2R,1'S]-2-[1-(tert-butyldiphenylsilyloxy)ethyl]oxirane (10) and [2S,1'S]-2-[1-(tert-butyldiphenylsilyloxy)ethyl]oxirane (13)

To a stirred mixture of m-CPBA (30.3 g, 175.5 mmol, 5.0 equiv.) in CH2Cl2 (35 ml) at 0 oC was added olefin 12 (10.9 g, 25.1 mmol, 1.0 equiv.) in CH2Cl2 (10 ml). The mixture was stirred for 12 h after which time tlc showed no starting material and so an aqueous saturated solution of NaHCO3 (100 ml) was added as a quench. The organic phase was separated and the aqueous layer extracted with CH2Cl2 (4 x 75 ml). The combined organic layers were washed with water (75 ml), an aqueous solution of NaOH (2 M, 75 ml), water (75 ml), brine (75 ml), dried (MgSO4) and concentrated in vacuo to yield a colourless oil which was purified by chromatography (5% diethyl ether-light petroleum) to give a 2:1 mix of epoxides 13 and 10 (7.5 g, 74%) as a colourless oil; Rf 13 0.53, 20% diethyl ether-light petroleum ; [a]D28+10.67 (c 0.003, CHCl3) vmax (film) 3071, 3052, 2961, 2932, 2894, 2858, 1428, 1111, 1071, 996, 822 cm-1; dH (270 MHz) 7.78-7.61 (4H, m, ortho protons on Ph), 7.42-7.28 (6H, m, meta and para protons on Ph), 3.62 (1H, m, H-2), 2.98 (1H, m, H-1'), 2.60 (1H, t, J 4.0, H-3), 2.33 (1H, dd, J 5.0, 2.5 Hz, H-3), 1.22 (3H, d, J 6.0, H-2'), 1.13 (9H, s, ButSi); m/z (CI) 344 [M+NH4]+, 269, 249, 238, 221, 210, 198, 188, 183, 155, 131, 94, 78; (Found: [M+NH4]+, 344.2046. C20H26O2Si requires [M+NH4]+, 344.2054). NMR data inter alia Rf 10 0.46, 20% diethyl ether-light petroleum; dH (270 MHz) 7.78-7.61 (4H, m, ortho protons on Ph), 7.42-7.28 (6H, m, meta and para protons on Ph), 3.62 (1H, m, H-2), 3.02 (1H, m, H-1'), 2.83 (1H, t, J 4.0 Hz, H-3), 2.50 (1H, dd, J 5.0, 2.5, H-3, 1.10 (3H, d, J 6.0, H-2'), 1.05 (9H, s, ButSi).

Preparation of [2S,3R]-2-(tert-butyldiphenylsilyloxy)-5-(phenylsulfonyl)pentan-3-ol (15) and [2S,3R]-3-(tert-butyldiphenylsilyloxy)-5-(phenylsulfonyl)pentan-2-ol (14)

To a stirred solution of (phenylsulfonyl)methane (1.25 g, 8 mmol, 1.0 eq) in THF (30 ml) under argon at -78 oC was added, dropwise via syringe BuLi (3.7 ml of a 2.5 M solution in hexanes, 8.1 mmol, 1.1 equiv.) causing a bright yellow coloration. After stirring for 2 min the mixture was warmed to room temperature during which time a precipitate appeared. DMPU (30% v/v) was added causing the precipitate to disappear and the solution to turn deep orange.The epoxide 10 (2.1 g, 6.43 mmol, 0.8 equiv.) was added and the mixture allowed to warm to room temp. Simple extractive work-up gave after chromatography ( 60% diethyl ether-light petroleum) a 9:1 mixture of hydroxysulfones 15 (2.2 g, 71%) and 14 as a colourless oil; Rf 0.41, 20% diethyl ether-light petroleum; vmax (film) 3517, 3530, 3519, 3512, 3506, 3497, 3451, 3444, 3437, 3419, 3413, 3400, 3070, 3052, 2996, 2959, 2931, 2892, 2857, 1472, 1446, 1427, 1305, 1148, 1111, 1086, 922, 822, 739, 703, 688, 533, 508, 489 cm-1; dH (500 MHz) 7.80-7.75 and 7.70-7.30 (15H, m, Ph and PhSO2), 3.80 (1H, m, H-2), 3.52 (1H, m, H-3), 3.35 (1H, ddd, J 15.5, 10.5, 5.0 Hz, H-5), 3.05 (1H, ddd, J 16.0, 10.5, 5.5, H-5), 2.15 (1H, d, J 4.5, OH), 1.85-1.68 (2H, m, H-4), 1.05 (9H, s, ButSi), 1.00 (3H, d, J 6.5 Hz, H-1); m/z (CI) 500 [M+NH4]+, 422, 405, 347, 327, 263, 246, 229, 216, 196, 183, 174, 160, 150, 98, 85, 78, 58, 47 (Found: [M+NH4]+, 500.2242. C27H34O4SSi requires [M+NH4]+, 500.2291).

Preparation of [2S,3R]-3-(tert-butyldimethylsilyloxy)-2-(tert-butyliphenylsilyloxy)-5-(phenylsulfonyl)pentane

To a stirred solution of hydroxysulfone 15 (1.5 g, 3.1 mmol, 1.0 eq; contaminated with ca. 10 mol% 14) in CH2Cl2 (6 ml) under argon at 0 oC was added pyridine (0.5 ml, 1.5 equiv.). After stirring for 2 min TBSOTf (1 ml, 1.5 equiv.) was added dropwise and TLC after 30 min revealed full reaction. CuSO4 (aq) was added as a quench, and the organic phase separated. Simple exractive work-up (CH2Cl2) followed by chromatography (50% diethyl ether-light petroleum) gave the silyl ether (1.7 g, 92%) as a colourless oil; Rf 0.46, 40% diethyl ether-light petroleum; vmax (film) 3906, 3856, 3071, 3054, 2955, 2932, 2891, 2858, 2360, 2342, 1472, 1447, 1428, 1318, 1257, 1150, 1110, 1088, 941, 836, 777, 741, 703, 689, 509 cm-1; dH (270 MHz) 7.88 (2H, d, J 9.0, ortho protons on PhSO2), 7.55-7.30 (13H, m, meta and para protons on PhSO2 and Ph), 3.55 (2H, m, H-2 and H-3), 3.08 (2H, m, H-5), 2.15-2.05 (1H, m, H-4), 1.90-1.73 (1H, m, H-4), 0.96 (9H, s, ButSi on TBDPS), 0.85 (3H, d, J 7.0, H-1), 0.77 (9H, s, ButSi on TBDMS), -0.05 (3H, s, MeSi), -0.08 (3H, s, MeSi); m/z (CI) 614 [M+NH4]+, 597 [M+H]+, 539, 519, 465, 455, 441, 397, 377, 341, 330, 283, 244, 210, 152, 132, 85 (Found: [M+H]+, 597.2899. C33H48O4SSi2 requires [M+H]+, 597.2890).

Preparation of [2S,3R,5R,6R,7R]-8-benzyloxy-3-(tert-butyldimethylsilyloxy)-2-(tert-butyldiphenylsilyloxy)-7-methyl-5-(phenylsulfonyl)octan-6-ol (17) and [2S,3R,5S,6S,7R]-8-benzyloxy-3-(tert-butyldimethylsilyloxy)-2-(tert-butyldiphenyl-silyloxy)-7-methyl-5-(phenylsulfonyl)octan-6-ol (18)

To a stirred solution of [2S,3R]-3-(tert-butyldimethylsilyloxy)-2-(tert-butyliphenylsilyloxy)-5-(phenylsulfonyl)pentane (1.4 g, 2.35 mmol, 1.0 equiv.) under nitrogen at -78 oC in THF (15 ml) was added BuLi (1 ml of a 2.5 M solution in hexanes, 2.5 mmol, 1.06 eq), causing the appearance of a bright yellow colour. After 5 min aldehyde 9 (418 mg, 2.35 mmol, 1 equiv.) was added resulting in the discharge of most of the yellow colour. TLC indicated almost complete consumption of starting material so the reaction was quenched by the addition of AcOH (2.5 ml of a 1 M solution in THF, 2.5 mmol, 1.0 equiv.) and allowed to warm to room temp. Simple extractive work-up and chromatography (20% diethyl ether-light petroleum) gave a 1:1:1:1 mixture of diastereomeric hydroxysulfones 16 (1.6 g, 88%) as a colourless oil; Rf 0.15, 20% diethyl ether-light petroleum; vmax (film) 3501, 3493, 3088, 3070, 3032, 2957, 2931, 2888, 2857, 2802, 1603, 1589, 1497, 1473, 1462, 1447, 1427, 1389, 1044, 1361, 1304, 1255, 1145, 1112, 1084, 1044, 1029, 1006, 837, 824 cm-1. The mixture of alcohols 16 was dissolved in CH2Cl2 (20 ml), and the solution added to a mixture of PDC (1.1 g, 1.5 equiv.) and powdered 4Å molecular sieves (2 g). The resulting mixture turned brown within 5 min and TLC after 3 h revealed complete reaction. The mixture was diluted with diethyl ether and filtered through silica. The filtrate was concentrated in vacuo to yield a yellow oil which was purified by chromatography (20% diethyl ether-light petroleum), a 1:1 mixture of diastereomeric ketones (1.12 g, 70%) as a colourless oil; Rf 0.34, 20% diethyl ether-light petroleum; vmax (film) 3070, 2954, 2932, 2893, 2858, 1717, 1472, 1462, 1448, 1428, 1321, 1254, 1150, 1111, 1086, 1029, 999, 837, 824, 777, 740, 702, 689 cm-1. To a mixture of CeCl3.7H2O (0.51 g, 1.0 equiv.) and the ketones (1.1 g, 1.42 mmol, 1.0 equiv.) in MeOH (4 ml) at room temp. was added NaBH4 (107 mg, 2.0 equiv.) in one portion. Gas was evolved and an exothermic reaction was observed. After 5 min the exotherm subsided, and TLC 25 min later revealed no further reaction. The mixture was poured into diethyl ether (15 ml) and washed with aqueous HCl (0.1 M, 15 ml). Simple extractive work-up followed by chromatography (20% diethyl ether-light petroleum) gave a 7:8 mixture of diastereomeric threo-hydroxysulfones 17 and 18 (1.0 g, 93%) (contaminated with ca. 10% of the erythro-isomers) as a colourless oil; Rf 0.15, 20% diethyl ether-light petroleum; vmax (film) 3645, 3639, 3586, 3571, 3562, 3551, 3526, 3466, 2939, 2890, 2860, 1300, 1141, 1103, 1039, 834, 739 cm-1; dH (500 MHz) 7.90-7.90 (2H, d, J 8.0, ortho protons on PhSO2), 7.83 (2H, d, J 8.0, ortho protons on PhSO2), 7.70-7.50 and 7.48-7.22 (36H, m, meta and para protons on PhSO2 and Ph), 4.56 (1H, d, J 12.0, PhCH2), 4.53 (1H, d, J 12.0, PhCH2), 4.46 (2H, s, PhCH2), 4.14 (1H, br d, J 10.0, H-5), 4.04 (1H, dt, J 11.5, 2.5, H-5), 3.83 (1H, d, J 5.5, H-8), 3.75-3.65 (3H, m, H-8), 3.59-3.36 (6H, m, H-3, H-2 and H-6), 2.12 (2H, m, H-7), 2.02 (1H, m, H-4), 1.92-1.82 (2H, m, H-4), 1.65 (1H, ddd, J 15.5, 9.5, 3.0, H-4), 1.04 (9H, s, ButSi on TBDPS), 1.00 (9H, s, ButSi on TBDPS), 0.98-0.87 (12H, m, H-7 Me and H-1), 0.85 (9H, s, ButSi on TBDMS) 0.74 (9H, s, ButSi on TBDMS), 0.12 (3H, s, MeSi), 0.03 (3H, s, MeSi), -0.10 (3H, s, MeSi), -1.26 (3H, s, MeSi); m/z [FAB] 775 [M+H]+, 759, 717, 519, 485, 387, 323, 271, 259, 245, 227, 209, 197, 181, 165, 147, 135, 105, 91, 73, 59 (Found: [M+H]+, 775.3841. C44H62O6SSi2 requires [M+H]+, 775.3884).

Preparation of [2S,3R,7R]-(Z)-8-benzyloxy-2-(tert-butyldipheylsilyloxy)-7-methyl-5-(phenylsulfonyl)oct-5-en-3-ol (11)

To a stirred solution of threo-enriched hydroxy sulfones 17/18 (1.02 g, 1.32 mmol, 1.0 equiv.) in THF (6 ml) under nitrogen at 0 oC was added BuLi (0.58 ml of a 2.30 M solution in hexanes, 1.32 mmol, 1.0 equiv.) causing the mixture to become yellow. After stirring for 2 min, TsCl (0.7 g, 3.45 mmol, 1.5 equiv.) in THF was added via cannula resulting in the disappearance of the yellow colour. TLC revealed full reaction and so saturated aqueous NH4Cl was added as a quench. Extractive work-up gave a 1:1 mixture of diastereomeric threo tosylates as a colourless oil; Rf 0.97, 5% diethyl ether-CH2Cl2; vmax (film) 3070, 3059, 3036, 3027, 2954, 2932, 2889, 2857, 1472, 1462, 1448, 1428, 1375, 1308, 1189, 1176, 1148, 1110, 1086, 919, 837, 814, 777, 739, 703, 689 cm-1. Without further purification these were dissolved in EtOH (13 ml) and treated with NaOEt (2.64 ml of a 1 M solution in EtOH, 2.64 mmol, 2.0 equiv.), causing the mixture to become yellow. TLC after 30 min revealed full reaction and so saturated aqueous NH4Cl (5 ml) was added as a quench. Simple extractive work-up followed by chromatography (20% diethyl ether-light petroleum) gave [2S,3R,7R]-(Z)-8-benzyloxy-3-(tert-butyldimetylsilyloxy)-2-(tert-butyldiphenylsilyloxy)-7-methyl-5-(phenylsulfonyl)oct-5-ene (900 mg, 90%, two-step yield from threo alcohol; contaminated with ca. 9% of the E-isomer) as a colourless oil; Rf 0.32, 20% diethyl ether-light petroleum; vmax (film) 3398, 2953, 2931, 2896, 2888, 2856, 1472, 1461, 1447, 1427, 1305, 1146, 1109, 1058, 1029, 1005, 837, 777, 732, 702, 508 cm-1; dH (500 MHz) 7.87 (2H, dd, J 8.0, 1.0, ortho protons on PhSO2), 7.69-7.66 (18H, m, meta and para protons on PhSO2 and Ph), 5.87 (1H, d, J 11.0, H-6 vinylic proton on Z isomer), 4.46 (1H, d, J 12.0, PhCH2), 4.43 (1H, d, J 12.0, PhCH2), 4.19 (1H, dt, J 6.5, 1.5, H-3), 3.92-3.81 (2H, m, H-2 and H-7), 3.31 (1H, dd, J 9.0, 6.0, H-8), 2.29 (1H, dd, J 9.0, 6.5, H-8), 2.39 (1H, dd, J 15.0, 7.0, H-4), 2.32 (1H, dd, J 15.0, 6.5, H-4), 1.05 (9H, s, ButSi on TBDPS), 0.90 (3H, d, J 6.5, H-7 Me), 0.84 (3H, d, J 6.5 Hz, H-1), 0.83 (9H, s, ButSi on TBDMS), 0.03 (3H, s, MeSi), 0.01 (3H, s, MeSi); m/z [FAB] 757 [M+H]+, 699, 679, 625, 501, 377, 271, 259, 227, 209, 197, 181, 147, 135, 125, 115, 105, 91, 73, 59 (Found: [M+H]+, 757.3771. C44H60O5SSi2 requires [M+H]+, 757.3778). The vinylic sulfone so formed (582 mg, 0.77 mmol) was dissolved in CH3CN (8 ml) and treated with HF (48% w/v solution in H2O) dropwise until TLC revealed full reaction. Solid NaHCO3 was added carefully as a quench and the organic phase separated. Simple extractive work-up gave after chromatography (50% diethyl ether-light petroleum) a 10:1 (Z:E) mixture of geometric isomers 11 (329 mg, 67%; contaminated with ca. 10% of the E-isomer) as a colourless oil; Rf 0.50, 50% diethyl ether-light petroleum; vmax (film) 3551, 3533, 3504, 3489, 3478, 3460, 3449, 3439, 3416, 3398, 3069, 2858, 1473, 1447, 1373, 1361, 1303, 1143, 1110, 1088, 999, 736, 703, 611, 508, 489 cm-1; major isomer: dH (270 MHz) 7.98 (2H, d, J 7.0, ortho protons on PhSO2), 7.77-7.27 (18H, m, meta and para protons on PhSO2 and Ph), 6.05 (1H, d, J 10.0, H-6 vinylic proton on Z isomer), 4.58 (1H, d, J 9.0, PhCH2), 4.51 (1H, d, J 9.0, PhCH2), 4.06 (1H, m, H-3), 3.87 (1H, m, H-2), 3.59 (1H, m, H-7), 3.51 (1H, dd, J 9.0, 6.5 Hz, H-8), 3.39 (1H, dd, J 9.0, 7.5, H-8), 2.63-2.59 (2H, m, H-4), 2.57 (1H, dd, J 10.0, 3.0, H-4), 2.30 (1H, dd, J 9.0, 6.5, H-4), 1.10 (9H, s, ButSi ), 1.02 (3H, d, J 7.0, H-7 Me), 0.91 (3H, d, J 8.0, H-1), 0.88 (3H, d, J 7.0, OH); m/z (CI) 660 [M+NH4]+, 582, 565, 501, 487, 425, 397, 374, 347, 326, 274, 255, 235, 216, 196, 172, 160, 139, 106, 91, 78 (Found: [M+NH4]+, 660.3142. C38H46O5SSi requires [M+NH4]+, 660.3179).

Preparation of [2S,3R,5R,2'S,5''S]-2-[(2-benzyloxy-1-methyl)thyl]-5-[1-(tert-butyldiphenylsilyloxy)ethyl]-3-(phenylsulfonyl)tetrahydrofuran (6)

To a stirred solution of cyclisation precursor 11 (278 mg, 0.43 mmol, 1.0 equiv.; contaminated with ca. 10% of the E-isomer) in THF (1.5 ml) and ButOH (40 ml, 0.44 mmol, 10.0 equiv.) under nitrogen at 25 oC was added ButOK (44 ul of a 1 M solution in THF, 0.044 mmol, 1.0 equiv.) causing the mixture to turn yellow. After 30 min the reaction was quenched with AcOH (44 ml of a 1 M solution in THF, 0.044 mmol, 1.0 equiv.). Simple extractive work-up gave, after chromatography (50% diethyl ether-light petroleum), a 10:1 (anti:syn) mixture of tetrahydrofurans 6 and the corresponding syn-isomer (247 mg, 89%) as a colourless oil; Rf 0.46, 50% diethyl ether-light petroleum; vmax (film) 3087, 3069, 3049, 3029, 3011, 2966, 2931, 2856, 2808, 1588, 1473, 1447, 1427, 1390, 1374, 1362, 1316, 1307, 1150, 1112, 1086, 1028, 1007, 999, 955 cm-1; 6 dH (500 MHz) (tetronasin numbering) 7.80 (2H, dd, J 8.0, 1.0, ortho protons on PhSO2), 7.70-7.55 and 7.49-7.25 (18H, m, meta and para protons on PhSO2 and Ph), 4.50 (1H, d, J 12.0, PhCH2), 4.40 (1H, d, J 12.0, PhCH2), 4.32 (1H, dd, J 7.0, 4.5, H-21), 4.20 (1H, m, H-22), 3.85 (1H, m, H-25), 3.67 (1H, m, H-24), 3.60 (1H, dd, J 9.5, 7.5, H-19), 3.28 (1H, dd, J 9.5, 5.0, H-19), 2.32 (1H, m, H-23), 2.05 (2H, m, H-20 and H-23), 1.02 (9H, s, ButSi ), 0.91 (6H, d, J 6.0, H-26 and C20 Me); m/z (CI) 660 [M+NH4]+, 565, 552, 520, 503, 425, 413, 393, 335, 319, 279, 175, 126, 106, 94 (Found: [M+NH4]+, 660.3172. C38H46O5SSi requires [M+NH4]+, 660.3179).

References

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