BACKGROUND OF THE INVENTION We and others have extensively employed dithiane couplings12 with epoxides, a-alkoxy iodides and tosylates, and aldehydes for the stereocontrolled generation of protected aldol linkages and the union of advanced fragments in complex molecule synthesis. 3'4 Recent studies have also established the tactical advantages of tandem reactions'and two-direction chain extension. 6 In 1994 Tietze and co-workers described8 the symmetrical bisalkylation of trimethylsilyldithiane (1) with two equivalents of a scalemic epoxide (e. g., (+)-2, Figure 1). Following initial reaction of the lithio derivative of 1 with the epoxide, the resultant alkoxide undergoes 1,4-Brook rearrangement, transferring the silyl group to oxygen and generating the 2-alkyl lithiated dithiane; coupling with a second molecule of the epoxide then yields

(-)-3. This process requires a reaction time of two days and is inapplicable to unsymmetrical couplings.

The present invention is directed, in part, to the synthesis of intermediates using linchpin coupling of 2-trialkylsilyl-1, 3-dithiane with two different electrophiles via solvent-controlled Brook rearrangement SUMMARY OF THE INVENTION According to one aspect of the present invention, there is provided a process for producing a compound having the formula: comprising reacting a compound having the formula

with (i) a compound having the formula and with (ii) a compound having the formula

wherein R1 and R2 are independently selected from the group consisting of H, optionally substituted Cl-calo alkyl, and optionally substituted C6-C14 aryl, and R3 is a silyl protecting group. Reaction steps (i) and (ii) are preferably carried out sequentially as shown.

A second aspect of the present invention provides a process for producing a compound having the formula comprising reacting a compound having the formula with a compound having the formula

wherein R3 is a silyl protecting group, and R, is selected from the group consisting of Cl-calo alkyl and C6-C14 aryl.

Another aspect of the present invention is a process for producing a compound having the formula:

comprising reacting a compound having the formula with (i) a compound having the formula

and with (ii) a compound having the formula wherein R1 and R2 are independently selected from the group consisting of H, optionally substituted Cl-calo alkyl, and

optionally substituted C6-C14 aryl, and R3 is a silyl protecting group. Reaction steps (i) and (ii) are preferably carried out sequentially as shown.

Still another aspect of the present invention provides a process for producing a compound having the formula: comprising reacting a compound having the formula

with (i) a compound having the formula and with (ii) a compound having the formula

wherein X is a halogen, R1 and R2 are independently selected from the group consisting of H, optionally substituted C,-C1o alkyl, and optionally substituted C6-C14 aryl, and R3 is a silyl protecting group. Reaction steps (i) and (ii) are preferably carried out sequentially as shown.

Another aspect of the present invention is a process for producing a compound having the formula: comprising reacting a compound having the formula with (i) a compound having the formula and with (ii) a compound having the formula

wherein X is a halogen, R1 and R2 are independently selected from the group consisting of H, optionally substituted Cl-calo alkyl, and optionally substituted C6-C14 aryl, and R3 is a silyl protecting group. Reaction steps (i) and (ii) are preferably carried out sequentially as shown.

A further aspect of the present invention is a process for producing a compound having the formula: comprising reacting a compound having the formula

with (i) a compound having the formula and with (ii) a compound having the formula

wherein Ri and R2 are independently selected from the group consisting of H, optionally substituted C1-Clo alkyl, and optionally substituted C6-C14 aryl, R3 is a silyl protecting group, and R4 and R. are independently selected from H,

optionally substituted Cl-calo alkyl and optionally substituted C6-C14 aryl. Reaction steps (i) and (ii) are preferably carried out sequentially as shown.

Yet a further aspect of the present invention is a process for producing a compound having the formula: comprising reacting a compound having the formula

with (i) a compound having the formula and with (ii) a compound having the formula

wherein X is a halogen, R1 is selected from the group consisting of H, optionally substituted Cl-calo alkyl, and optionally substituted C6-C14 aryl, and R3 is a silyl protecting group. Reaction steps (i) and (ii) are preferably carried out sequentially as shown.

DETAILED DESCRIPTION OF THE INVENTION In our syntheses of FK506, 3a rapamycin and demethoxyrapamycin, and discodermolide, treatment with t-BuLi in 10% HMPA/THF at-78°C proved to be the optimum protocol9 for rapid generation of 2-substituted dithiane anions. 1O We began the present study by using these conditions for bisalkylation of 2-t-butyldimethylsilyl-1, 3-dithiane (4), 11 a substrate also successfully employed by Tietze which leads to installation

of the more robust TBS hydroxyl protecting group.

Metalation of 4 in 10% HMPA/THF and immediate addition of epoxide (-)-5 readily afforded (+)-6 in good yield (Figure In the presence of HMPA, both the initial alkylation of 4 and the subsequent Brook rearrangement occur within minutes at-78 °C. Accordingly, the attempted sequential reaction of 4 with epoxides (-)-5 and (-)-7 led to a mixture of symmetrical and unsymmetrical products [ (+)-6, (+)-8a and (+)-8b, Figure 3]. This result suggested that linchpin coupling of different electrophiles would be feasible only if the Brook rearrangement could be suppressed until the first alkylation was complete.

Fortuitously, an elegant recent study by Oshima, Utimoto and co-workers revealed dramatic solvent effects on similar Brook rearrangements in the adducts of lithio dihalo (trialkylsilyl) methanes with epoxides (Figure 4). 13 Rearrangement did not occur following metalation and initial alkylation in THF, but proceeded readily upon addition of HMPA; the resultant 0-silyl organolithium could then react with a second electrophile. The analogous unsymmetrical bisalkylation of TMSCHLiCN with two epoxides in DME has also been reported, l9 although in this case it is unclear how the timing of the Brook rearrangement was controlled.

Metalation of 4 and alkylation with epoxide (-)-5 in Et2O or THF likewise furnished the unrearranged carbinol (+)-13 exclusively (Figure 5, entries 1 and 2). In contrast, addition of HMPA or DMPU15tl6 (entries 3 and 4) induced 1,4-Brook rearrangement, affording predominantly silyl ether (+)-14. Following step b in Figure 5, the reaction mixture was cooled to-78 °C, treated with 0.3-0.4 equiv of additive in Et2O, and warmed to-45 °C for 1 hour.

One aspect of the present invention is synthesis, using one-pot linchpin coupling, of dithiane 4 with two different electrophiles. Following deprotonation and

addition of epoxide (-)-5 in Et2O, introduction of HMPA plus a second epoxide or benzyl bromide afforded the unsymmetrical bisalkylated products in 56-74% yields (Figure 6). Scalemic epoxides are particularly well suited to this process because the configurations of the resulting carbinol stereocenters are predetermined, circumventing the formation and separation of unwanted diastereomers. Previous studies of 2-lithio-2-alkyldithianes suggest that a variety of other electrophiles should also be accommodated in the second step. 2 Importantly, the substituents in several adducts (e. g., epoxides 22 and 24) are poised for further elaboration.

We have utilized the one-step coupling protocol to link scalemic advanced intermediates in several of our ongoing synthetic programs. For example, sequential alkylations of dithiane 4 with epoxides (+)-25 and (+)-26 gave exclusively the spongistatin13 fragment (+)-27 in 59% yield (Figure 6, entry 6). 19 A survey of the literature suggests that the new protocol should prove applicable to nearly all total syntheses utilizing dithiane coupling strategies. In runs 4 and 5 of Figure 6, only one equivalent of E2 was used. Yields were determined after chromatography.

We have further extended this methodology by assembling a five-component coupling product in a single operation. An example is shown in Figure 7. Following alkylation of dithiane 4 with epoxide (-)-5 (2.6 equiv each) to generate the unrearranged alkoxy dithiane 28, sequential addition of HMPA and (-)-epichlorohydrin (21,1 equiv) furnished the bis (silyloxy dithiane) carbinol (+)-29 in 66% yield, accompanied by a minor amount (ca. 2%) of epoxide (+)-22 (Figure 7). This new method, if general, should result in exceptionally concise routes to complex 1,3-polyol natural products, including polyene macrocycles and macrolides such as roflamycoin (30).

Example 1 2-tert-Butyldimethylsilyl-1, 3-dithiane (4).

A solution containing 1,-3-dithiane (2.432 g, 20.226 mmol) in anhydrous THF (70 mL) was cooled to-78 °C. t-BuLi (1.3 M in pentane, 16.5 mL, 21.45 mmol) was added dropwise from a syringe. After stirring at-45 °C for 15 min after t-BuLi addition, a solution of tert-butyldimethylchlorosilane (3.5423 g, 22.80 mmol) in anhydrous THF (20 mL) cooled to-45 °C was added dropwise via a cannula at-78 °C. The reaction was warmed up to 0 °C for 1 h then warmed to ambient temperature for an additional 1 h, quenched with saturated aqueous NH4Cl (10 mL), and diluted with Et2O (10 mL). The layers were separated and the aqueous phase was extracted with CH2Cl2 (3x 30 mL), dried over MgSO4, filtered and concentrated. Distillation (90-95 °C, 1 mmHg) provided 4 (4.2747 g, 90% yield) as a colorless oil: IR (film) 2951 (s), 2928 (s), 2896 (s), 2856 (s), 1470 (w), 1421 (w), 1362 (w), 1272 (w), 1257 (m), 1248 (m), 1161 (w), 1086 (w), 909 (w), 879 (w), 836 (s), 826 (s), 810 (s), 775 (s) cm-1 ; 1H NMR (500 MHZ, CDC13) d 3.80 (s, 1 H), 2.88 (ddd, J = 14.5,12.5,2.7 Hz, 2 H), 2.69 (ddd, J = 14.1, 4.2,3.1 Hz, 2 H), 0.96 (s, 9 H), 0.11 (s, 6 H); 13C NMR (125 MHZ, CDCl3) d 32.6,31.5,27.0,17.7,-7.2; high resolution mass spectrum (CI, CH4) m/z 235.1013 [ (M+H) +; calcd for CioH23S2Si : 235.1010].

Example 2 Dithiane (+)-6.

A solution containing dithiane 4, (45.3 mg, 0.193 mmol) in 10% HMPA/THF (1 mL) was cooled to-78 °C. t-BuLi (1.5 M in pentane, 130 mL, 0.195 mmol) was added dropwise from a syringe. Five min after t-BuLi addition, a solution containing benzyl (R)- (-)-glycidyl ether (5,74 mL, 0.485 mmol) in 10% HMPA/THF was added dropwise via a cannula. The reaction was warmed to-45 °C for 30 min, cooled to-78 °C,

quenched with saturated aqueous NH4Cl (0.5 mL), and warmed to ambient temperature. The layers were separated and the aqueous phase was extracted with CH2Cl2 (3x 5 mL), dried over MgSO4, filtered and concentrated. Flash chromatography (hexanes/ethyl acetate, 85: 15 « 50 : 50) provided (+)-6 (93.6 mg, 86% yield) as a pale yellow oil: [a] 23D +21.5° (c 1.1, CHC13) ; IR (film) 3600-3300 (br), 3029 (w), 2928 (s), 2855 (s), 1495 (w), 1453 (m), 1416 (m), 1362 (m), 1252 (m), 1208 (w), 1103 (s), 908 (w), 834 (m), 778 (m), 736 (m), 697 (s) cm~1 ; 1H NMR (500 MHZ, CDCl3) d 7.34-7.29 (m, 8 H), 7.28-7.25 (m, 2 H), 4.55 (s, 2 H), 4.51 (s, 2 H), 4.28-4.25 (m, 1 H), 4.24-4.20 (m, 1 H), 3.53 (d, J = 3.2 Hz, 1 H), 3.46-3.42 (m, 2 H), 3.38 (ddd, J = 9.5,5.5 Hz, 1 H), 3.34 (ddd, J = 9.5, 6.7 Hz, 1 H), 2.84-2.75 (m, 4 H), 2.49 (dd, J = 15.3,2.9 Hz, 1 H), 2.27-2.20 (m, 2 H), 2.19 (dd, J = 15.4,8.3 Hz, 1 H), 1.94-1.90 (m, 2 H), 0.85 (s, 9 H), 0.11 (s, 3 H), 0.06 (s, 3 H); 13C NMR (125 MHZ, CDC13) d 138.3,138.2,128.30, 128.28,127.7,127.59,127.56,127.5,74.6,74.5,73.2, 69.6,67.1,51.5,43.14,43.08,26.3,26.0,25.0,18.0, -3.7,-4.2; high resolution mass spectrum (CI, CH4) m/z 563.2694 [ (M+H) +; calcd for CHOSi : 563.2685].

Example 3 Dithiane (+)-6, (+)-8a, (+)-8b.

A solution containing dithiane 4, (125.6 mg, 0.5356 mmol) in 10% HMPA/THF (2 mL) was cooled to-78 °C. t-BuLi (1.7 M in pentane, 300 mL, 0.510 mmol) was added dropwise from a syringe. Five min after t-BuLi addition, a solution containing benzyl (R)- (-)-glycidyl ether (5,100mL, 0.6559 mmol) in 10% HMPA/THF (0.5 mL) was added dropwise via a cannula. After 1 h, a solution containing epoxide (7, 118.1 mg, 0.5671 mmol) in 10% HMPA/THF (0.5 mL) was added dropwise via a cannula. The reaction was warmed to ambient temperature over 1 h, and quenched with saturated aqueous NH4Cl (0.5 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3x 5 mL), dried over MgSO4,

filtered and concentrated. Flash chromatography (hexanes/ethyl acetate, 85: 15 « 50 : 50) provided (+)-6 (78.8 mg, 26% yield) as a pale yellow oil, (+)-8a (16.1 mg, 5% yield) as a pale yellow oil, and (+)-8b (100.3 mg, 29% yield) as a pale yellow oil.

(+)-8a: [a] 23D+17. 1° (c 1.94, CHCl3) ; IR (film) 3600-3300 (br), 3065 (w), 3035 (w), 2955 (s), 2935 (s), 2905 (s), 2855 (s), 1610 (m), 1585 (w), 1510 (s), 1460 (m), 1435 (m), 1415 (w), 1385 (m), 1355 (m), 1295 (m), 1245 (s), 1205 (w), 1165 (m), 1095 (s), 1025 (m), 995 (m), 935 (w), 895 (w), 825 (s), 805 (s), 765 (s), 725 (m), 685 (m) cm~l ; 1H NMR (500 MHZ, CDC13) d 7.34-7.29 (m, 4 H), 7.28-7.24 (m, 1 H), 7.24 (d, J = 8.6 Hz, 2 H), 6.84 (d, J = 8.7 Hz, 2 H), 4.51 (s, 2 H), 4.42 (s, 2 H), 4.25-4.20 (m, 1 H), 4.19-4.15 (m, 1 H), 3.77 (s, 3 H), 3.65 (d, J = 2.9 Hz, 1 H), 3.58 (t, J = 6.5 Hz, 2 H), 3.44 (dd, J = 9.4,4.7 Hz, 1 H), 3.33 (dd, J = 9.4,6.7 Hz, 1 H), 2.87-2.70 (m, 4 H), 2.48 (dd, J = 15.3, 3.0 Hz, 1 H), 2.22-2.17 (m, 2 H), 2.07 (dd, J = 15.3,1.5 Hz, 1 H), 1.95-1.85 (m, 2 H), 0.86 (s, 9 H), 0.11 (s, 3 H), 0.06 (s, 3 H); 13C NMR (125 MHZ, CDCl3) d 159.2,138.2, 130.7,129.3,128.3,127.62,127.59,113.76,74.6,73.2, 72.7,69.7,67.4,66.2,55.3,51.7,46.9,43.2,38.3,26.4, 26.05,26.03,25.0,18.1,-3.6,-4.1; high resolution mass spectrum (FAB) [M+; calcd for C32HsoOsS2Si : 606.2869].

(+)-8b: [a] 23D+15. 7° (c 0.75, CHCl3) ; IR (film) 3600-3300 (br), 2995 (w), 2945 (s), 2915 (s), 2895 (s), 2845 (s), 1605 (s), 1585 (m), 1505 (s), 1455 (m), 1435 (m), 1415 (m), 1385 (m), 1355 (m), 1295 (m), 1245 (s), 1205 (w), 1195 (s), 1165 (s), 1095 (s), 1035 (s), 900 (m), 825 (s), 765 (s) cm~l ; 1H NMR (500 MHZ, CDCl3) d 7.24-7.22 (m, 4 H), 6.84 (d, J = 8.4 Hz, 4 H), 4.42 (s, 2 H), 4.40 (s, 2 H), 4.29-4.27 (m, 1 H), 4.22-4.20 (m, 1 H), 4.14-4.11 (m, 1 H), 3.77 (s, 6 H), 3.60-3.56 (m, 2 H), 3.55-3.46 (m, 2 H), 2.76-2.69 (m, 4 H), 2.36-2.19 (m, 2 H), 2.10 (dd, J = 15.2,1.3 Hz, 1 H), 2.04-1.67 (m, 7 H), 0.87 (s, 9 H), 0.13 (s, 3 H), 0.10 (s,

3 H) ; 13C NMR (125 MHZ, CDCl3) d 159.09,159.05,130.6, 130.5,129.19,129.18,113.7,72.67,72.65,68.8,67.3, 66.5,66.0,55.2,51.7,46.4,44.7,38.7,38.4,26.2,26.04, 26.0,25.97,25.0,18.0,-3.4,-4.3; high resolution mass spectrum (FAB) [M+; calcd for C34Hs406S2Si : 650.3131].

Example 4 Dithiane (+)-13.

A solution containing dithiane 4, (69.1 mg, 0.2947 mmol) in anhydrous Et20 (1.0 mL) was cooled to-78 °C. t- BuLi (1.7 M in pentane, 170 mL, 0.2890 mmol) was added dropwise from a syringe. After stirring at-45 °C for 1 h after t-BuLi addition, a solution of epoxide (5,45 mL, 0.2952 mmol) in anhydrous Et2O (0.25 mL) was added dropwise via a cannula at-78 °C. Additional anhydrous Et2O (0.25 mL) was used to rinse residual epoxide 5 into reaction mixture via a cannula. The reaction was warmed up to-45 °C over 1 h, quenched with saturated aqueous NH4Cl (0.5 mL), and diluted with Et2O (1 mL). The layers were separated and the aqueous phase was extracted with CH2Cl2 (3x 5 mL), dried over MgSO4, filtered and concentrated. Flash chromatography (hexanes/ethyl acetate, 85: 15) provided (+)-13 (86.6 mg, 75% yield) as a colorless oil: [a] 23D+18. 67° (c 0.98, CHCl3) ; IR (film) 3600-3300 (br), 2920 (s), 2890 (s), 2840 (s), 1440 (m), 1415 (m), 1355 (w), 1240 (m), 1080 (m), 805 (m), 725 (w), 680 (w) cm-1 ; 1H NMR (500 MHZ, CDCl3) d 7.32 (d, J = 4.4 Hz, 4 H), 7.31-7.24 (m, 1 H), 4.57 (s, 2 H), 4.23 (dddd, J = 9.3,3.4,1.7 Hz, 1 H), 4.01 (d, J = 1. 6 Hz, 1 H), 3.46 (dd, J = 22.1,9.6 Hz, 1 H), 3.45 (dd, J = 21.1,9.6 Hz, 1 H), 3.19 (ddd, J = 14.0,12.6,2.8 Hz, 1 H), 3.10 (ddd, J = 14.3,12.4,2.7 Hz, 1 H), 2.68 (dd, J = 15.4,9.3 Hz, 1 H), 2.47-2.43 (m, 1 H), 2.45 (ddd, J = 30.1,3.3 Hz, 1 H), 2.41 (ddd, J = 15. 3,1.7 Hz, 1 H), 2.06-2.01 (m, 1 H), 1.93-1.84 (m, 1 H), 1. 03 (s, 9 H), 0.29 (s, 3 H), 0.22 (s, 3 H) ; 13C NMR (125 MHZ, CDC13) d 138.3,128.3,127.61,127.57,74.5, 73.4,69.7,40.9,39.3,28.5,24.4,24.1,23.6,19.9,-5.1,

-5.7; high resolution mass spectrum (CI, CH4) m/z 399.1847 [ (M+H) +; calcd for C2oH3402S2Si : 399.1841].

Example 5 Dithiane (+)-14.

A solution containing dithiane 4, (92.8 mg, 0.3957 mmol) in anhydrous Et2O (1.0 mL) was cooled to-78 °C. t- BuLi (1.45 M in pentane, 280 mL, 0.4060 mmol) was added dropwise from a syringe. After stirring at-45 °C for 1 h after t-BuLi addition, a solution of epoxide (5,72 mL, 0.4723 mmol) in anhydrous Et2O (0.25 mL) was added dropwise via a cannula at-78 °C. Additional anhydrous Et2O (0.25 mL) was used to rinse residual epoxide 5 into reaction mixture via a cannula. The reaction was warmed up to-45 °C over 1 h, cooled to-78 °C, and a solution of HMPA (90.9 qL, 0.5225 mmol) in anhydrous Et2O (0.5 mL) was added dropwise via syringe. The reaction was warmed up to 0 °C for 1 h, quenched with saturated aqueous NH4Cl (1 mL), and diluted with Et2O (1 mL). The layers were separated and the aqueous phase was extracted with CH2Cl2 (3x 5 mL), dried over MgSO4, filtered and concentrated. Flash chromatography (hexanes/ethyl acetate, 85: 15) provided (+)-14 (95.7 mg, 58% yield) as a pale yellow oil: [a] 23D +31.5° (c 1.10, CHCl3) ; IR (film) 3061 (w), 3028 (w), 2951 (s), 2927 (s), 2896 (s), 2854 (s), 2359 (m), 2340 (m), 1496 (w), 1471 (m) 1461 (m), 1453 (m), 1422 (m), 1361 (m), 1275 (m), 1250 (s), 1126 (s), 1109 (s), 1093 (s), 967 (m), 836 (s), 810 (m), 776 (s), 734 (m), 697 (s), 668 (s) cm~1 ; 1H NMR (500 MHZ, CDCl3) d 7.34-7.30 (m, 4 H), 7.27-7.25 (m, 1 H), 4.50 (s, 1 H), 4.15-4.10 (m, 1 H), 3.42 (dd, J = 9.7,5.3 Hz, 1 H), 3.36 (dd, J = 9.7,5.3 Hz, 1 H), 2.88-2.73 (m, 4 H), 2.10-2.05 (m, 1 H), 1.98 (dddd, J = 9.7,4.0 Hz, 1 H), 1.91-1.83 (m, 2 H), 0.88 (s, 9 H), 0.10 (s, 3 H), 0.06 (s, 3 H); 13C NMR (125 MHZ, CDCl3) d 138.3,128.3,127.6,127.5,74.6,73.3, 68.0,43.6,40.4,30.4,29.8,26.0,25.9,18.1,-4.4,-4.8; high resolution mass spectrum (CI, CH4) m/z 399.1849 [ (M+H) +;

calcd for C20H3402S2Si : 399.1847].

Example 6 Dithiane (+)-16.

A solution containing dithiane 4, (228 mg, 0.9714 mmol) in anhydrous Et2O (2.0 mL) was cooled to-78 °C. t- BuLi (1.7 M in pentane, 570 mL, 0.969 mmol) was added dropwise from a syringe. After stirring at-45 °C for 1 h after t-BuLi addition, a solution of benzyl (R)- (-)-glycidyl ether (5,149 mL, 0.9773 mmol) in anhydrous Et2O (0.5 mL) was added dropwise via a cannula at-78 °C. Additional anhydrous Et2O (0.5 mL) was used to rinse residual epoxide 5 into reaction mixture via a cannula. The reaction was warmed up to-45 °C over 1 h, cooled to-78 °C, and a solution of epoxide (15,385 mg, 2.042 mmol) and HMPA (45.5 dL, 0.2613 mmol) in anhydrous Et2O (0.5 mL) was added dropwise via syringe. The reaction was warmed up to 0 °C for 1 h then warmed to ambient temperature for an additional 1 h, quenched with saturated aqueous NH4Cl (1 mL), and diluted with Et2O (1 mL). The layers were separated and the aqueous phase was extracted with CH2C12 (3x 5 mL), dried over MgSO4, filtered and concentrated. Flash chromatography (hexanes/ethyl acetate 95: 5, then 85: 15) provided (+)-16 (316.4 mg, 56% yield) as a pale yellow oil: [a] 23D+30. 2° (c 1.20, CHC13) ; IR (film) 3500-3300 (br), 2910 (m), 2880 (m), 2840 (m), 1450 (w), 1430 (w), 1400 (w), 1355 (w), 1240 (m), 1085 (s), 1000 (m), 820 (s), 834 (s), 765 (m) cm-' ; 1H NMR (500 MHZ, CDCl3) d 7.32-7.26 (m, 4 H), 7.25-7.24 (m, 1 H), 4.51 (s, 2 H), 4.29-4.24 (m, 1 H), 4.00 (dddd, J = 5.1,2.2 Hz, 1 H), 3.54 (dd, J = 9.9,5.9 Hz, 1 H), 3.47-3.43 (m, 3 H), 3.35 (dd, J = 9.4,6.5 Hz, 1 H), 2.81-2.77 (m, 4 H), 2.47 (dd, J = 15.3,3.1 Hz, 1 H), 2.27 (dd, J = 15.3,1.7 Hz, 1 H), 2.22 (dd, J = 15.3,7.7 Hz, 1 H), 2.08 (dd, J = 15.4,8.4 Hz, 1 H), 1.94-1.90 (m, 2 H), 0.89 (s, 9 H), 0.86 (s, 9 H), 0. 13 (s, 3 H), 0.07 (s, 3 H), 0.05 (s, 6 H); 13C NMR (125 MHZ, CDCl3) d 138.2,128.3,127.6,127.5,74.6,

73.2,69.6,68.8,67.5,51.5,43.2,42.8,26.2,26.1,26.05, 25.99,25.96,25.90,25.87,25.03,18.3,18.1,-3.6,-4.2, -5.31,-5.32; high resolution mass spectrum (CI, CH4) m/z 587.3092 [ (M+H) +; calcd for C29H5504S2S'2 : 587.3080].

Example 7 Dithiane (+)-18.

A solution containing dithiane 4, (195 mg, 0.8307 mmol) in anhydrous Et2O (2.0 mL) was cooled to-78 °C. t- BuLi (1.38 M in pentane, 600 mL, 0.828 mmol) was added dropwise from a syringe. After stirring at-45 °C for 1 h after t-BuLi addition, a solution of benzyl (R)- (-)-glycidyl ether (5,127 mL, 0.8330 mmol) in anhydrous Et2O (0.5 mL) was added dropwise via a cannula at-78 °C. Additional anhydrous Et2O (0.5 mL) was used to rinse residual epoxide 5 into reaction mixture via a cannula. The reaction was warmed up to-25 °C over 1 h, cooled to-78 °C, and a solution of epoxide (17,197 mg, 1.345 mmol) and HMPA (45.5 qL, 0.2613 mmol) in anhydrous Et2O (0.5 mL) was added dropwise via syringe. The reaction was warmed up to 0 °C for 1 h then warmed to ambient temperature for an additional 1 h, quenched with saturated aqueous NH4Cl (1 mL), and diluted with Et2O (1 mL). The layers were separated and the aqueous phase was extracted with CH2Cl2 (3x 5 mL), dried over MgSO4, filtered and concentrated. Flash chromatography (hexanes/ethyl acetate 95: 5, then 50: 50) provided (+)-18 (332.7 mg, 74% yield) as a colorless oil: [a] 23D+26. 9° (c 1.5, CHCl3) ; IR (film) 3500-3300 (br), 2915 (m), 2895 (m), 2845 (m), 1440 (w), 1410 (w), 1395 (w), 1360 (m), 1240 (m), 1200 (m), 1170 (m), 1070 (s), 1035 (s), 820 (m), 760 (w) cm~1 ; 1H NMR (500 MHZ, CDCl3) d 7.35-7.30 (m, 4 H), 7.28-7.25 (m, 1 H), 4.51 (s, 2 H), 4.28-4.24 (m, 1 H), 4.15-4.11 (m, 1 H), 3.53 (d, J = 3.2 Hz, 1 H), 3.45 (dd, J = 9.4,4.6 Hz, 1 H), 3.40-3. 32 (m, 2 H), 3.28 (dd, J = 9.5,5.2 Hz, 1 H), 3.11 (s, 3 H), 2.86-2.75 (m, 4 H), 2.50 (dd, J = 15.3,2.9 Hz, 1 H), 2.24 (dd, J = 15.4,7.9 Hz, 1 H), 2.19 (d, J =

2 Hz, 1 H), 2.18 (s, 1 H), 1.96-1.90 (m, 2 H), 1.32 (s, 6 H), 0.86 (s, 9 H), 0.13 (s, 3 H), 0.07 (s, 3 H); 13C NMR (125 MHZ, CDCl3) d 138.2,128.3,127.6,100.0,74.6,73.2, 69.7,67.4,65.4,51.5,48.5,43.4,42.8,26.3,26.1,25.1, 24.4,18.1,-3.6,-4.3; high resolution mass spectrum (CI, CH4) m/z 562. 3049 [(M+NH4) +; calcd for C27Hs2NO5S2Si : 562.3056].

Example 8 Dithiane (+)-20.

A solution containing dithiane 4, (166 mg, 0.7079 mmol) in anhydrous Et2O (2.0 mL) was cooled to-78 °C. t- BuLi (1.5 M in pentane, 480 mL, 0.720 mmol) was added dropwise from a syringe. After stirring at-45 °C for 1 h after t-BuLi addition, a solution of benzyl (R)- (-)-glycidyl ether (5,108 mL, 0.7084 mmol) in anhydrous Et2O (0.5 mL) was added dropwise via a cannula at-78 °C. Additional anhydrous Et2O (0.5 mL) was used to rinse residual epoxide 2 into reaction mixture via a cannula. The reaction was warmed up to-25 °C over 1 h, cooled to-78 °C, and a solution of benzyl bromide (19,100 mL, 0.8407 mmol) and HMPA (45.5 qL, 0.2613 mmol) in anhydrous Et2O (0.5 mL) was added dropwise via syringe. The reaction was warmed up to 0 °C for 1 h then warmed to ambient temperature for an additional 1 h, quenched with saturated aqueous NH4Cl (1 mL), and diluted with Et2O (1 mL). The layers were separated and the aqueous phase was extracted with CH2Cl2 (3x 5 mL), dried over MgSO4, filtered and concentrated. Flash chromatography (hexanes/ethyl acetate 95: 5, then 85: 15, then 70: 30) provided (+)-20 (221.3 mg, 62% yield) as a pale yellow oil: [a] 23D +22.5° (c 0.89, CHCl3) ; IR (film) 3061 (w), 3027 (w), 2927 (s), 2854 (s), 1602 (w), 1494 (w), 1453 (w), 1362 (w), 1251 (m), 1100 (s), 1004 (m), 909 (w), 834 (s), 776 (s), 735 (s), 698 (s) cm~1 ; 1H NMR (500 MHZ, CDCl3) d 7.41 (dd, J = 7.9,1.7 Hz, 1 H), 7.40-7.32 (m, 4 H), 7.30-7.25 (m, 4 H), 4.55 (d, J = 0.9 Hz, 2 H), 4.38-4.34 (m, 1 H), 3.51 (dd, J =

9.4,4.7 Hz, 1 H), 3.43 (dd, J = 9.5,6.4 Hz, 1 H), 3.39 (d, J = 13. 8 Hz, 1 H), 3.21 (d, J = 13.8 Hz, 1 H), 2.89-2.83 (m, 2 H), 2.744 (ddd, J = 14. 4,6.7 Hz, 1 H), 2.738 (ddd, J = 14.4,3.3 Hz, 1 H), 2.43 (dd, J = 15.3,3.2 Hz, 1 H), 2.07 (dd, J = 15.3,7.2 Hz, 1 H), 1.96-1.91 (m, 1 H), 1.90-1.85 (m, 1 H), 0.91 (s, 9 H), 0.17 (s, 3 H), 0.12 (s, 3 H); 13C NMR (125 MHZ, CDC13) d 138.3,135.9,131.5,128.3,127.53, 127.47,126.8,75.0,73.2,70.0,52.9,45.8,41.8,26.5, 26.2,26.1,26.0,25.9,24.8,18.1,-3.8,-4.1; high resolution mass spectrum (CI, CH4) m/z 506.2577 [ (M+NH4) +; calcd for C27H44NO2S2Si : 506.2583].

Example 9 Dithiane (+)-22.

A solution containing dithiane 4, (175.7 mg, 0.7492 mmol) in anhydrous Et2O (2.0 mL) was cooled to-78 °C. t-BuLi (1.45 M in pentane, 520 mL, 0.754 mmol) was added dropwise from a syringe. After stirring at-45 °C for 1 h after t-BuLi addition, a solution of benzyl (R)- (-)-glycidyl ether (5,115 mL, 0.7543 mmol) in anhydrous Et2O (0.5 mL) was added dropwise via a cannula at-78 °C. Additional anhydrous Et2O (0.5 mL) was used to rinse residual epoxide 5 into reaction mixture via a cannula. The reaction was warmed up to-25 °C over 1 h, cooled to-78 °C, and a solution of (+)-epichlorohydrin (21,70 mL, 0.895 mmol) and HMPA (54.5 dL, 0.3135 mmol) in anhydrous Et2O (0.6 mL) was added dropwise via syringe. The reaction was warmed up to 0 °C for 1 h then warmed to ambient temperature for an additional 1 h, quenched with saturated aqueous NH4Cl (1 mL), and diluted with Et2O (1 mL). The layers were separated and the aqueous phase was extracted with CH2C12 (3x 5 mL), dried over MgSO4, filtered and concentrated. Flash chromatography (hexanes/ethyl acetate 85: 15) provided (+)-22 (248.8 mg, 71% yield) as a pale yellow oil: [a] 23D +12. 3° (c 1.25, CHCl3); IR (film) 3032 (w), 2950 (s), 2928 (s), 2855 (s), 1410 (w), 1416 (w), 1361 (w), 1276 (w), 1254 (m), 1103 (s), 1005 (m),

939 (w), 909 (w), 835 (s), 810 (s), 777 (s), 735 (m), 698 (m) cm~1 ; 1H NMR (500 MHZ, CDCl3) d 7.32 (s, 2 H), 7.31 (s, 2 H), 7.30-7.24 (m, 1 H), 4.52 (d, J = 2.6 Hz, 2 H), 4.22 (dddd, J = 7.8,4.8,3.2 Hz, 1 H), 3.46 (dd, J = 9.5,4.8 Hz, 1 H), 3.38 (dd, J = 9.5,6.3 Hz, 1 H), 3.24 (dddd, J = 6.2,2.8 Hz, 1 H), 2.91-2.76 (m, 3 H), 2.74 (dd, J = 4.9, 4.3 Hz, 1 H), 2.72-2.67 (m, 1 H), 2.54 (dd, J = 15.2,3.2 Hz, 1 H), 2.49 (dd, J = 5. 1,2.7 Hz, 1 H), 2.164 (dd, J = 19.9,15.0 Hz, 1 H), 2.156 (dd, J = 19.3,13.4 Hz, 1 H), 2.09 (dd, J = 15.3,6.8 Hz, 1 H), 1.94-1.87 (m, 2 H), 0.85 (s, 9 H), 0.09 (s, 3 H), 0.05 (s, 3 H) ; 13C NMR (125 MHZ, CDC13) d 138.2,128.2,127.53,127.46,74.7,73.1,69.2, 51.5,48.9,46.7,43.7,42.7,29.9,26.3,25.9,24.8,17.9, -4.0,-4.1; high resolution mass spectrum (CI, CH4) m/z 472.2368 [ (M+NH4) +; calcd for C23H42NO3S2Si : 472.2375].

Example 10 Dithiane (+)-24.

A solution containing dithiane 4, (240.3 mg, 1.0247 mmol) in anhydrous Et20 (2.5 mL) was cooled to-78 °C. t-BuLi (1.58 M in pentane, 650 mL, 1.027 mmol) was added dropwise from a syringe. After stirring at-45 °C for 1 h after t-BuLi addition, a solution of benzyl (R)- (-)-glycidyl ether (5,157 mL, 1.0298 mmol) in anhydrous Et2O (0.5 mL) was added dropwise via a cannula at-78 °C. Additional anhydrous Et2O (0.5 mL) was used to rinse residual epoxide 5 into reaction mixture via a cannula. The reaction was warmed up to-25 °C over 1 h, cooled to-78 °C, and a solution of (-)-epichlorohydrin (23,81 mL, 1.0356 mmol) and HMPA (54.5 dL, 0.3135 mmol) in anhydrous Et2O (0.5 mL) was added dropwise via syringe. The reaction was warmed up to 0 °C for 1 h then warmed to ambient temperature for an additional 1 h, quenched with saturated aqueous NH4Cl (1 mL), and diluted with Et2O (1 mL). The layers were separated and the aqueous phase was extracted with CH2Cl2 (3x 5 mL), dried over MgSO4, filtered and concentrated. Flash chromatography

(hexanes/ethyl acetate 95: 5, then 85: 15) provided (+)-24 (279.3 mg, 71% yield) as a pale yellow oil: [a] 23D +15.9° (c 1.1, CHCl3) ; IR (film) 2960 (s), 2930 (s), 2900 (s), 2890 (s), 2860 (s), 1460 (w), 1360 (w), 1250 (m), 1110 (s), 1100 (s), 1080 (s), 1000 (m), 830 (s), 800 (m), 770 (s), 730 (w), 690 (w) cm~1 ; 1H NMR (500 MHZ, CDC13) d 7.32 (s, 2 H), 7.31 (s, 2 H), 7.30-7.25 (m, 1 H), 4.52 (dd, J = 13.9,12.0 Hz, 2 H), 4.21 (dddd, J = 9.4,4.8,3.4 Hz, 1 H), 3.47 (dd, J = 9.5,4.8 Hz, 1 H), 3.37 (dd, J = 9.4,6.6 Hz, 1 H), 3.24 (dddd, J = 6.4,5.1,4.0,2.8 Hz, 1 H), 2.92-2.80 (m, 2 H), 2.77-2.67 (m, 3 H), 2.58 (dd, J = 15.2,3.3 Hz, 1 H), 2.50 (dd, J = 5.0,2.7 Hz, 1 H), 2.29 (dd, J = 14.8,5.0 Hz, 1 H), 2.05 (dd, J = 15.3,6.5 Hz, 1 H), 1.99 (dd, J = 14.8, 6.3 Hz, 1 H), 1.99-1.85 (m, 2 H), 0.86 (s, 9 H), 0.10 (s, 3 H), 0.05 (s, 3 H); 13C NMR (125 MHZ, CDCl3) d 138.2,128.3, 127.6,127.5,74.7,73.2,69.3,51.4,48.9,47.5,44.0, 43.0,26.3,25.9,25.8,24.8,18.0,-3.9,-4.1; high resolution mass spectrum (CI, CH4) m/z 472.2384 [ (M+NH4) +; calcd for C23H42NO3S2Si : 472.2375].

Example 11 Dithiane (+)-27.

A solution containing dithiane 4, (318.4 mg, 1.3577 mmol) in anhydrous Et2O (3.5 mL) was cooled to-78 °C. t-BuLi (1.48 M in pentane, 910 mL, 1.3468 mmol) was added dropwise from a syringe. After stirring at-45 °C for 1 h after t-BuLi addition, a solution of epoxide (25,227.9 mg, 1.3233 mmol) in anhydrous Et2O (0.5 mL) was added dropwise via a cannula at-78 °C. Additional anhydrous Et2O (0.5 mL) was used to rinse residual epoxide 25 into reaction mixture via a cannula. The reaction was warmed up to-25 °C over 1 h, cooled to-78 °C, and a solution of epoxide (26, 595 mg, 2.5183 mmol) and HMPA (90.9 qL, 0.5225 mmol) in anhydrous Et2O (0.5 mL) was added dropwise via syringe. The reaction was warmed up to 0 °C for 1 h then warmed to ambient temperature for an additional 1 h, quenched with

saturated aqueous NH4Cl (1 mL), and diluted with Et2O (5 mL).

The layers were separated and the aqueous phase was extracted with CH2Cl2 (3x 5 mL), dried over MgSO4, filtered and concentrated. Flash chromatography (hexanes/ethyl acetate/acetonitrile, 10: 3: 2) provided (+)-27 (502.0 mg, 59% yield) as a pale yellow oil: [a] 23p +18. 2° (c 1.02, CHC13) ; IR (film) 3600-3300 (br), 2930 (s), 2855 (m), 1592.8 (w), 1516 (s), 1463 (m), 1419 (m), 1378 (m), 1368 (m), 1257 (s), 1158 (s), 1137 (m), 1099 (m), 1055 (m), 1031 (s), 938 (w), 909 (w), 835 (m), 811 (m), 772 (m), 676 (w) cm~1 ; 1H NMR (500 MHZ, CDCl3) d 6.88 (d, J = 1. 8 Hz, 1 H), 6.85 (dd, J = 8.1, 1.8 Hz, 1 H), 6.80 (d, J = 8. 1 Hz, 1 H), 4.44 (s, 2 H), 4.29 (dddd, J = 8.3,3.7 Hz, 1 H), 4.22 (dddd, J = 8.8,4.0,2.0 Hz, 1 H), 4.03 (dd, J = 7.9,5.9 Hz, 1 H), 3.87 (s, 3 H), 3.85 (s, 3 H), 3.70 (d, J = 2.3 Hz, 1 H), 3.65-3.59 (m, 2 H), 3.43 (dd, J = 8.1 Hz, 1 H), 2.97 (ddd, J = 14.1,10.1, 3.0 Hz, 1 H), 2.89 (ddd, J = 14.3,10.1,2.9 Hz, 1 H), 2.72 (ddd, J = 13.6,3.2 Hz, 1 H), 2.69 (ddd, J = 13.5,3.2 Hz, 1 H), 2.37 (dd, J = 15.3,8.8 Hz, 1 H), 2.28 (d, J = 1. 4 Hz, 2 H), 2.18 (dd, J = 15.3,1.6 Hz, 1 H), 2.00 (dd, J = 14. 4, 7.1 Hz, 1 H), 1.97-1.93 (m, 1-H), 1.90 (dd, J = 14.5, 3.7 Hz, 1 H), 1.87-1.78 (m, 2 H), 1.76-1.71 (m, 1 H), 1.54 (s, 3 H), 1.36 (s, 3 H), 1.32 (s, 3 H), 0.86 (s, 9 H), 0.13 (s, 3 H), 0.08 (s, 3 H) ; 13C NMR (125 MHZ, CDCl3) d 149.1, 148.6,147.1,131.1,120.2,111.2,111.0,108.7,76.6,73.0, 72.9,70.3,67.6,67.1,56.0,55.9,51.5,51.0,47.9,47.4, 37.9,29.9,27.0,26.9,26.6,26.2,26.0,24.8,18.3,-1.4, -1.5; high resolution mass spectrum (FAB) m/z 667.3158 [ (M+Na) +; calcd for C32Hs6NaO7S2Si : 667.3135].

Example 12 Dithiane (+)-29.

A solution containing dithiane 4, (229.4 mg, 0.9782 mmol) in anhydrous Et2O (2.5 mL) was cooled to-78 °C. t-BuLi (1.5 M in pentane, 660 mL, 0.990 mmol) was added dropwise from a syringe. After stirring at-45 °C for 1 h

after t-BuLi addition, a solution of benzyl (R)- (-)-glycidyl ether (5,150 mL, 0.9839 mmol) in anhydrous Et2O (0.5 mL) was added dropwise via a cannula at-78 °C. Additional anhydrous Et2O (0.5 mL) was used to rinse residual epoxide 5 into reaction mixture via a cannula. The reaction was warmed up to-45 °C over 1 h, cooled to-78 °C, and a solution of HMPA (54.5 qL, 0.3133 mmol) in anhydrous Et2O (0.5 mL) was added dropwise via syringe. After 5 min, (-)-epichlorohydrin (21,32 mL, 0.4091 mmol) was added dropwise via syringe. The reaction was warmed up to 0 °C for 1 h then warmed to ambient temperature for an additional 1 h, quenched with saturated aqueous NH4Cl (1 mL), and diluted with Et2O (1 mL). The layers were separated and the aqueous phase was extracted with CH2Cl2 (3x 5 mL), dried over MgSO4, filtered and concentrated. Flash chromatography (hexanes/ethyl acetate 90: 10) provided (+)-22 (2.8 mg, 2% yield) as a clear, colorless oil, and (+)-29 (215.1 mg, 66% yield) as a colorless oil: [a] 23D +17.8° (c 1.2, CHCl3) ; IR (film) 3600-3300 (br), 3010 (w), 2925 (s), 2895 (s), 2850 (s), 1490 (w), 1460 (m), 1415 (m), 1360 (m), 1250 (s), 1100 (s), 1020 (m), 1000 (m), 930 Am), 900 (w), 830 (s), 805 (m), 770 (s), 730 (m), 690 (m) cm~1 ; 1H NMR (500 MHZ, CDC13) d 7.34-7.29 (m, 8 H), 7.27-7.22 (m, 2 H), 4.522 (s, 2 H), 4.519 (s, 2 H), 4.51-4.46 (m, 1 H), 4.28-4.10 (m, 2 H), 3.59 (d, J = 3.0 Hz, 1 H), 3.49-3.42 (m, 3 H), 3.39 (dd, J = 9.6, 6.1,1 H), 2.87-2.69 (m, 8 H), 2.49 (t, J = 15.1 Hz, 1 H), 2.48 (t, J = 15.1 Hz, 1 H), 2.27-2.18 (m, 3 H), 2.11-2.06 (m, 2 H), 1.97 (dd, J = 15.1,2.5 Hz, 1 H), 1.94-1.87 (m, 4 H), 0.87 (s, 18 H), 0.13 (s, 3 H), 0.12 (s, 3 H), 0.07 (s, 3 H), 0.06 (s, 3 H) ; 13C NMR (125 MHZ, CDC13) d 138.4,138.3, 128.26,128.22,127.63,127.59,127.47,127.40,77.2,75.1, 74.9,73.1,69.6,69.3,65.9,52.0,51.9,48.4,47.8,44.8, 43.7,26.6,26.4,26.19,26.15,26.08,25.95,24.9,24.8, 18.1,-3.7,-3.9,-4.02,-4.06; high resolution mass spectrum (FAB) m/z 875.3688 [ (M+Na) +; calcd for

C43H72Nao5S4S'2 : 875.3700].

References and Notes (1) Corey, E. J.; Seebach, D. Angew. Chem., Int.

Ed. Engl. 1965,4,1075.

(2) Reviews: (a) Seebach, D. Synthesis 1969,17.

(b) Seebach, D. Angew. Chem., Int. Ed. Engl. 1969,8,639.

(c) Gruel, B.-T.; Seebach, D. Synthesis 1977,357. (d) Seebach, D. Angew. Chem., Int. Ed. Engl. 1979,18,239. (e) Bulman Page, P. C.; van Niel, M. B.; Prodger, J. C.

Tetrahedron 1989,45,7643.

(3) (a) Smith, A. B., III ; Chen, K. ; Robinson, D.

J.; Laakso, L. M.; Hale, K. J. Tetrahedron Lett. 1994,35, 4271. (b) Smith, A. B., III ; Condon, S. M.; McCauley, J.

A.; Leazer, J. L., Jr.; Leahy, J. W.; Maleczka, R. E., Jr.

J. Am. Chem. Soc. 1995,117,5407. (c) Smith, A. B., III ; Qiu, Y.; Jones, D. R.; Kobayashi, K. Ibid. 1995,117,12011.

(4) (a) Corey, E. J.; Weigel, L. 0. ; Chamberlin, A. R.; Cho, H.; Hua, D. H. J. Am. Chem. Soc. 1980,102, 6613. (b) Corey, E. J.; Pan, B.-C.; Hua, D. H.; Deardorff, D. R. Ibid. 1982,104,6816.- (c) Redlich, H. ; Francke, W.

Angew. Chem., Int. Ed. Engl. 1980,19,630. (d) Barrett, A.

G. M.; Capps, N. K. Tetrahedron Lett. 1986,27,5571. (e) Park, P.; Broka, C. A.; Johnson, B. F.; Kishi, Y. J. Am.

Chem. Soc. 1987,109,6205. (f) Egbertson, M.; Danishefsky, S. J. J. Org. Chem. 1989,54,11. (g) Mori, Y.; Asai, M.; Furukawa, H. Heterocycles 1992,34,1281. (h) Nicolaou, K.

C.; Nadin, A.; Leresche, J. E.; Yue, E. W. ; La Greca, S.

Angew. Chem., Int. Ed. Engl. 1994,33,2190.

(5) (a) Tietze, L. F. Chem. Rev. 1996,96,115.

(b) Parsons, P. J. ; Penkett, C. S.; Shell, A. J. Chem. Rev.

1996,96,195. (c) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993,32,131. (d) Posner, G. H. Chem. Rev.

1986,86,831.

(6) (a) Schreiber, S. L. Chem. Scr. 1987,27,

563. (b) Poss, C. S.; Schreiber, S. L. Acc. Chem. Res.

1994,27,9. (c) Magnuson, S. R. Tetrahedron 1995,51, 2167.

(7) (a) Brook, A. G. Acc. Chem. Res. 1974,7,77.

(b) Brook, A. G.; Bassindale, A. R. In Rearrangements in Ground and Excited States; de Mayo, P., Ed.; Academic Press: New York, 1980 ; Vol. 2, pp 149. (c) Brook, A. G. ; Chrusciel, J. J. Organometallics 1984,3,1317. (d) Jankowski, P.; Raubo, P.; Wicha, J. Synlett 1994,985. (e) Lautens, M.; Delanghe, P. H. M.; Goh, J. B.; Zhang, C. H. J.

Org. Chem. 1995,60,4213.

(8) Tietze, L. F.; Geissler, H.; Gewert, J. A.; Jakobi, U. Synlett 1994,511.

(9) These conditions were first employed by Williams: Williams, D. R.; Sit, S.-Y. J. Am. Chem. Soc.

1984, 106, 2949.

(10) For an insightful discussion of the ion-pair solution structures of 2-lithio-1, 3-dithianes in THF and HMPA/THF,'see : Reich, H. J.; Borst, J. P.; Dykstra, R. R.

Tetrahedron 1994,50,5869.

(11) We prepared 4 in multigram quantities by addition of t-butyl-dimethylchlorosilane to the lithio derivative of 1,3-dithiane in THF at-78 °C « rt over 2 h.

(12) All synthetic compounds were purified by flash chromatography on silica gel. The structure assigned to each new compound is in accord with its infrared, 500-MHZ 1H NMR, and 125-MHZ 13C NMR spectra, as well as appropriate parent ion identification by high resolution mass spectrometry.

(13) (a) Shinokubo, H.; Miura, K.; Oshima, K.; Utimoto, K. Tetrahedron 1996,52,503. (b) Shinokubo, H.; Miura, K.; Oshima, K.; Utimoto, K. Tetrahedron Lett. 1993, 34,1951.

(14) Matsuda, I. ; Murata, S.; Ishii, Y. J. Chem.

Soc., Perkin Trans. 1 1979,26.

(15) Mukhopadhyay, T.; Seebach, D. Helv. Chim.

Acta 1982,65,385.

(16) HMPA appears to be more effective than DMPU.

(17) In preliminary studies, 2-trimethylsilyl-and 2-triethylsilyl-1, 3-dithiane afforded lower yields of coupling products.

2. Reviews: (a) Seebach, D. Synthesis 1969,17. (b) Seebach, D. Angew. Chem., Int. Ed. Engl. 1969,8,639. (c) GrUbel, B.-T.; Seebach, D. Synthesis 1977,357. (d) Seebach, D. Angew. Chem., Int. Ed. Engl. 1979,18,239. (e) Bulman Page, P. C.; van Niel, M. B.; Prodger, J. C.

Tetrahedron 1989,45,7643-7767. (f) Smith, A. B., III ; Condon, S. M.; McCauley, J. A. Acc. Chem. Res. (submitted).

(18) Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Herald, C. L.; Boyd, M. R.; Schmidt, J. M.; Hooper, J. N. A.

J. Org. Chem. 1993,58,1302.

(19) The following procedure for the preparation of (+)-27 illustrates the new coupling protocol. A solution of dithiane 4 (318.4 mg, 1.36 mmol) in anhydrous Et2O (3.5 mL) was cooled to-78 °C. t-BuLi (1.48 M in pentane, 0.910 mL, 1.35 mmol) was added dropwise via syringe, and the reaction mixture was allowed to warm to-45 °C while stirring for 1 h. The mixture was recooled to-78 °C and a solution of epoxide (+)-25 (227.9 mg, 1.32 mmol) in anhydrous Et2O (0.5 mL plus 0.5 mL rinse) was added dropwise via a cannula. The mixture was warmed to-25 °C over 1 h, recooled to-78 °C, and treated dropwise with a solution of epoxide (+)-26 (595 mg, 2.52 mmol) and HMPA (0.52 M in Et2O, 1.0 mL, 0.52 mmol) via syringe. The reaction was warmed to 0 °C for 1 h and then to ambient temperature for an additional 1 h, quenched with saturated aqueous NH4Cl (1 mL), and diluted with Et2O (5 mL). The layers were separated, the aqueous phase was extracted with CH2C12 (3 x 5 mL), and the combined organic solutions were dried over MgSO4, filtered and concentrated. Flash chromatography (hexanes/ethyl

acetate/acetonitrile, 10: 3: 2) provided (+)-27 (502.0 mg, 59% yield) as a pale yellow oil: [a] 23D +18-2° (c 1.02, CHCl3) ; IR (film) 3600-3300 (br), 2930 (s), 2855 (m), 1593 (w), 1516 (s), 1463 (m), 1419 (m), 1378 (m), 1368 (m), 1257 (s), 1158 (s), 1137 (m), 1099 (m), 1055 (m), 1031 (s), 938 (w), 909 (w), 835 (m), 811 (m), 772 (m), 676 (w) cm-1 ; 1H NMR (500 MHZ, CDCl3) d 6.88 (d, J = 1. 8 Hz, 1 H), 6.85 (dd, J = 8.1, 1.8 Hz, 1 H), 6.80 (d, J = 8. 1 Hz, 1 H), 4.44 (s, 2 H), 4.31-4.26 (m, 1 H), 4.22 (dddd, J = 12.6,4.0,4.0,2.0 Hz, 1 H), 4.03 (dd, J = 7.9,5.9 Hz, 1 H), 3.87 (s, 3 H), 3.85 (s, 3 H), 3.70 (d, J = 2.3 Hz, 1 H), 3.65-3. 59 (m, 2 H), 3.43 (t, J = 8.1 Hz, 1 H), 2.97 (ddd, J = 14.1,10.1,3.0 Hz, 1 H), 2.89 (ddd, J = 14.3,10.1,2.9 Hz, 1 H), 2.71 (tq, J = 13.6,6.5,3.2 Hz, 2 H), 2.37 (dd, J = 15.3,8.8 Hz, 1 H), 2.28 (d, J = 1. 4 Hz, 2 H), 2.18 (dd, J = 15.3,1.6 Hz, 1 H), 2.00 (dd, J = 14. 4,7.1 Hz, 1 H), 1.97-1.93 (m, 1 H), 1.90 (dd, J = 14.5,3.7 Hz, 1 H), 1.87-1.78 (m, 2 H), 1.76-1.71 (m, 1 H), 1.54 (s, 3 H), 1.36 (s, 3 H), 1.32 (s, 3 H), 0.86 (s, 9 H), 0.13 (s, 3 H), 0.08 (s, 3 H); 13C NMR (125 MHZ, CDCl3) d 149.1,148.6,147.1,131.1,120.2,111.2, 111.0,108.7,76.6,73.0,72.9,70.3,67.6,67.1,56.0, 55.9,51.5,51.0,47.9,47.4,37.9,29.9,27.0,26.9,26.6, 26.2,26.0,24.8,18.3,-1.4,-1.5; high resolution mass spectrum (FAB, NBA) m/z 667.3158 [ (M+Na) +; calcd for C32H56Nao7S2S' : 667.3135].

(20) (a) Rychnovsky, S. D. Chem. Rev. 1995,95, 2021. (b) Oishi, T.; Nakata, T. Synthesis 1990,635.