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Stereoselective synthesis of ophiocerin B Bhasker Akkala and Krishna Damera* Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad 500 007, India E-mail: [email protected]

Abstract A stereoselective total synthesis of ophiocerin B is reported by asymmetric synthesis, starting from L-malic acid. Of the three stereogenic centers, the vic-diols C-3, C-4 were obtained by Sharpless asymmetric dihydroxylation. Keywords: Stereoselective, asymmetric synthesis, Sharpless asymmetric dihydroxylation

Introduction The tetrahydropyran skeleton features in a variety of biologically active natural products such as polyether antibiotics, marine toxins and pheromones.1 The substituted tetrahydropyran moiety is a part structure of a wide variety of natural products with diversified biological functions.2,3 Ophiocerins A-D (1-4) are a class of natural products isolated from freshwater aquatic fungi by Reategui et al.4 from Ophioceras venezuelense5 (Magnaporthaceae). The structural analysis of ophiocerins A–D was arrived at by Gloer et a1. from spectroscopic studies, while the absolute stereochemistry was assigned by CD spectrometry by the use of the excitation chirality method.6 These new tetrahydropyran derivatives appear to be the first isolated natural products from the above genus.4 Consequently, compounds 1–4 have attracted considerable synthetic attention from various laboratories,7-11 including our own.10 So far, two research groups have been reported the total synthesis of Ophiocerin B, the first total synthesis was published by Yadav group,9 using chiral epoxide as a starting material, in 2008 Lee and Kang reported total synthesis of Ophiocerin B by using α-D-glucopyranoside.7 Herein, we report the total synthesis of 2 from L-malic acid.

Figure 1. Structures of Ophiocerin A-D 1-4.

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Results and Discussion The retrosynthetic analysis is outlined in Scheme 1. Ester 5 was prepared from commercially available L-malic acid, and the target compound 2 was synthesized from ester 5.

Scheme1. Retrosynthetic route to the target molecule 2. As illustrated in Scheme 2, the synthesis of ophiocerin B 2 started from the commercially available L-malic acid. Accordingly, the known compound 10 (Scheme 2) was initiated from commercially available diol 7, which was prepared from known ester 612 in two steps. Selective tosylation of 6 and subsequent reduction of the resulting tosylate with LiAlH4 afforded 1,3- diol 713,14 in 82% yield. Reaction of 7 with benzoyl chloride and Et3N gave benzoate 8 (81%), which upon silylation with TBSCl and imidazole furnished 9 in 92% yield. Base hydrolysis of ester 9 with K2CO3 and MeOH gave 10 (87%)

Scheme 2. Synthesis of compound 10. Alcohol 1015,16 on oxidation under Swern conditions17 furnished aldehyde 11 in 84% yield, which was without further purification used for the next step. Wittig olefination of aldehyde 11 furnished the ester 12 in 75% yield. Compound 12 was subjected to Sharpless asymmetric dihydroxylation18 with ADmix-β to afford the compound 13 as pale yellow syrup in 65% yield. The acetonide was prepared under standard conditions using 2,2-dimethoxypropane (2,2-DMP) and catalytic p-toluenesulfonic acid (PTSA) in dichloromethane for 30 min at 0 ºC to provide 5 in 85% yield.

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OTBS 10

ARKIVOC 2013 (iv) 164-170

OTBS Ph3P=CHCO2Et CHO Benzene, reflux, 4 h, 75% 11

(COCl)2, DMSO, Et3N OH

CH2Cl2, -78 oC, 3 h, 84%

TBSO

AD-mix- , methanesulfonamide

TBSO

DIBAL-H CH2Cl2, 0 oC, 2 h, 86%

14

O OEt

5

TBSO

O

15

O

TBAF OTs

0 oC-r.t., 4 h, 78%

O

O

p-toluenesulfonic acid, CH2Cl2, 85%

p-TsCl, Et3N OH

OEt 12

(CH3)2C(OMe)2

13 OH

O

O

TBSO

OH O OEt

t-BuOH/H2O (1:1), 0 oC-r.t., 65%

OTBS

O

THF, r.t., 10 h, 65%

OH

O O O 16

OH

p-toluenesulfonic acid MeOH, 0 oC, 4 h, 85%

O 2

Scheme 3. Synthesis of target compound 2. The ester 5 was then treated with DIBAL-H at 0 ºC to yield alcohol 14 in 86%. Further, tosylation of the resulting alcohol 14 to afford compound 15. Treatment of compound 15 with tetra-n-butylammonium fluoride in THF at room temperature resulted in desilylation and concomitant cyclization15 in one step to give the cyclized product 16 in 65% yield [α]D = -11.8 (c 0.4, CHCl3). Tetra-n-butylammonium fluoride (TBAF) in the present study acted as a desilylating agent, as well as a base to promote a facile cyclization reaction (Scheme 3). Finally, compound 12 on treatment with p-toluenesulfonic acid in MeOH gave ophiocerin B 2 in 85% yield, [α]D = -32.3 (c 0.25, CHCl3), matching that of the natural product4 [α]D = -34.0 (c 0.25, CHCl3).

Conclusion In conclusion, we have accomplished total synthesis of ophiocerin B via Sharpless asymmetric dihydroxylation and Tetra-n-butylammonium fluoride (TBAF) mediated one-pot desilylation/cyclization. Thus, this strategy is adaptable for the generation of a library of stereoisomers. The generality of the method shown has significant potential for further extension to other isomers and related compounds.

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Experimental Section General. All reactions were carried out under argon or nitrogen in oven dried glassware using standard gas-light syringes, cannulas, and septa. Solvents and reagents were purified and dried by standard methods prior to use. IR spectra were recorded on Perkin-Elmer FT-IR 240-c spectrophotometer using KBr optics. 1H NMR and 13C NMR spectra were recorded on Gemini200 spectrometer (200 MHz) and Bruker-300 spectrometer (300 MHz) in CDCl3 using TMS as internal standard. Mass spectra were recorded on Finnigan MAT 1020 mass spectrometer operating at 70 eV. Column chromatography was performed using E. Merck 60-120, mesh silica gel. Optical rotations were measured with JASCO DIP-370 Polarimeter at 25 0C. (5R,E)-Ethyl 5-(t-butyldimethylsilyloxy)2-hexenoate (12). To a solution of oxalyl chloride (3.1 mL, 26.47 mmol) in dry CH2Cl2 (10 mL) at -78 oC, dry DMSO (3.7 g, 53.92 mmol) was added drop wise and stirred for 10 min. A solution of 10 (4.5 g, 22.05 mmol) in dry CH2Cl2 (10 mL) was added and stirred for 3 h at -78 oC. Et3N (6.0 mL, 43.6 mmol) added and diluted with CH2Cl2 (20 mL). The reaction mixture was washed with water (20 mL), brine (20mL), dried (Na2SO4) and evaporated to furnish the corresponding aldehyde 11 (3.7 g, 84%). The aldehyde 11 (3.7 g, 18.31 mmol) was dissolved in benzene and added to a refluxing solution of (ethoxycarbonylmethylene)triphenylphosphorane (9.5 g, 27.4 mmol) in benzene. After 4 h, solvent was evaporated and residue purified by column chromatography (EtOAc:hexane, 1:4) to afford 12 (3.7 g, 75%) as a pale yellow syrup. [α]D -16.2 (c 0.6, CHCl3); IR: 2924, 2854, 1745, 1460, 1376, 1105 cm-1; 1H NMR (300 MHz, CDCl3): δ 0.04 (s, 6H, 2 × CH3), 0.88 (s, 9H, 3 × CH3), 1.16 (d, 3H, J 6.0 Hz, CH3), 1.29 (t, 3H, J 7.5 Hz, CH3), 2.34-2.46 (m, 2H, CH2), 3.973.85 (m, 1H, CH), 4.21 (q, 2H, J 7.5 Hz, CH2), 5.78 (d, 1H, J 15.8 Hz, -CH), 6.89 (dt,1H, J 7.5, 15.8, Hz, -CH), 13C NMR (75 MHz, CDCl3): δ -4.62, 14.1, 17.9, 23.7, 25.7, 42.3, 59.9, 67.5, 145.8, 123.1, 166.2; HRMS: m/z [M+Na]+ calcd 295.1806 found 295.2913 for C14H28O3SiNa. (2R,3R,5R)-Ethyl 5-(t-butyldimethylsilyloxy)-2,3-dihydroxyhexanoate (13). A well stirred solution of AD-mix-β (5.7 g, 7.35 mmol) in t-BuOH/H2O (1:1, 30 mL) was treated with methanesulfonamide (0.69 g, 735 mmol) at room temperature. After 30 min, the clear yellow solution was cooled to 0 °C and a solution of ester 12 (2.0 g, 7.35 mmol) in t-BuOH (5 mL) was added. The reaction mixture was stirred vigorously at 0 °C for 12 h and then quenched with solid Na2SO4 (5 g). It was warmed to room temperature and stirred for an additional 1 h. The resultant reaction mixture was extracted with CH2Cl2 (3 × 100 mL) and the combined extracts were dried (Na2SO4), filtered and evaporated to give crude residue, which was purified by column chromatography (30:70% EtOAc:hexane) to afford 13 (1.4 g, 65%) as pale yellow syrup. [α]D 11.1 (c = 0.25, CHCl3); IR: 3426, 3019, 2916, 2859, 1760, 1216, 1017 cm-1; 1H NMR (200 MHz, CDCl3): δ 0.09 (s, 6H, 2 × CH3) 0.90 (s, 9H, 3 × CH3), 1.21 (d, 3H, J 5.9 Hz, CH3), 1.33 (t, 3H, J 7.4 Hz, CH3), 1.56-1.63 (m, 2H, CH2), 2.80-3.10 (m, 1H, CH), 4.12-3.92 (m, 2H, 2 × CH), 4.36 (q, 2H, J 7.4 Hz, CH2); 13C NMR (75 MHz, CDCl3): δ -4.12, 14.34, 23.21, 25.81, 30.71, 39.14,

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60.56, 64.72, 66.85, 79.51, 169.31; HRMS: m/z [M+Na]+ calcd 329.1863 found 329.1842 for C14H30O5SiNa. (4S,5R)-Ethyl 5-[(R)-2-(t-butyldimethylsilyloxy)propyl]-2,2-dimethyl-1,3-dioxolane-4-carboxylate (5). To a stirred solution of diol 13 (1.2 g, 3.92 mmol) in CH2Cl2 (5 mL), 2,2-dimethoxy propane (0.8 mL, 7.84 mmol), cat. p-toluenesulfonic acid (PTSA) (67 mg, 0.39) were added and stirred at room temperature for 2 h. Reaction mixture was quenched with Et3N (0.7 mL) and extracted with CH2Cl2 (10 mL). Organic layers were washed with water (10 mL), brine (10 mL), dried (Na2SO4), evaporated under reduced pressure and residue purified the by column chromatography (EtOAc:hexane, 1:10) to afford 5 (1.1 g, 85%) as a colorless oil. [α]D: -3.7 (c = 0.4, CHCl3). IR: 2960, 2858, 1741, 1243, 1128 cm-1; 1H NMR (300 MHz, CDCl3): δ 0.05 (s, 6H, 2 × CH3), 0.88 (s, 9H, 3 × CH3), 1.18 (d, 3H, J 6.2 Hz, -CH3), 1.20 (s, 6H, 2 × CH3), 1.65-1.74 (m, 2H, -CH2) 1.83 (t, 2H, J 6.0 Hz, -CH3), 3.94-4.29 (m, 5H), 13C NMR (75 MHz, CDCl3): δ 4.0, -4.9, 13.9, 24.1, 25.6, 42.2, 61.5, 68.0, 71.2, 73.2, 173.1; ESIMS: m/z 347 [M+H]+, 369 [M+Na]+ . HRMS: m/z [M+Na]+ calcd 369.2176 found 369.3142 for C17H34O5SiNa [(4R,5R)-5-[(R)-2-(t-Butyldimethylsilyloxy)propyl]-2,2-dimethyl-1,3-dioxolan-4-yl]methanol (14). To a stirred solution of 5 (1.1 g, 3.17 mmol) in dry CH2Cl2 (10 mL), DIBAL-H (5.4 mL, 3.81 mmol, 10% solution in hexane) was added at 0 ºC and stirred at the same temperature for 2 h. Methanol (0.5 mL) was added to the reaction mixture at 0 oC and stirred for 10 min. Saturated aq. solution of sodium potassium tartarate (0.5 mL) was added and after 10 min methanol was evaporated. It was diluted with water (10 mL) and extracted with dichloromethane (2 x 10 mL). The combined organic layers were washed with brine (5 mL), dried (Na2SO4), concentrated and the residue purified by column chromatography (EtOAc: hexane, 1:3) to afford 14 (0.86 g, 86%) as a colorless syrup. [α]D: -12.6 (c = 0.4, CHCl3); IR: 3473, 2930, 1112, 1058, 1013 cm-1; 1H NMR (300 MHz, CDCl3): δ δ 0.06 (s, 6H, 2 × CH3), 0.91 (s, 9H, 3 × CH3), 1.20 (d, 3H, J 6.2 Hz, -CH3), 1.41 (s, 6H, 2 × CH3), 1.57-1.74 (m, 2H, CH2), 3.59 (dd, 1H, J 3.3, 11.7 Hz, CH) 3.81-3.68 (m, 2H, 2 × CH), 4.13-3.85 (m, 2H, CH2); ESIMS: m/z 327 [M+Na]+. HRMS: m/z [M+Na]+ calcd 327.2073 found 327.3152 for C15H32O4SiNa [(4R,5R)-5-[(R)-2-(t-Butyldimethylsilyloxy)propyl]-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 4methylbenzenesulfonate (15). To a solution of 14 (1.0 g, 3.08 mmol) in CH2Cl2 (10 mL) at 0 o C, Et3N (0.64 mL, 4.62 mmol) and tosyl chloride (0.73 g, 3.70 mmol) were added sequentially and stirred at room temperature for 4 h. The reaction mixture was washed with water (10 mL), brine (10 mL), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography (EtOAc:hexane, 1:9) to furnish 15 (1.1 g, 78%) as a pale yellow oil. [α]D: -7.5 (c = 0.25, CHCl3); IR: 3473, 2984, 2930, 1345, 1112, 1058, 1013 cm-1; 1H NMR (300 MHz, CDCl3): δ 0.05 (s, 6H, 2 × CH3), 0.90 (s, 9H, 3 × CH3), 1.31 (d, 3H, J 5.1 Hz, -CH3), 1.39 (s, 3H, CH3), 1.37 (s, 3H, CH3), 1.71-1.64 (m, 2H, CH2), 2.51 (s, 3H, CH3), 4.23-3.41 (m, 5H, CH), 7.1 (d, 2H, J 7.9 Hz, Ar-H), 7.72 (d, 2H, J 7.9 Hz, Ar-H); 13C NMR (75 MHz, CDCl3): δ 4.01, 22.81, 25.51, 30.81, 38.62, 62.21, 67.31, 74.52, 82.63, 117.89; ESIMS: m/z 459 [M+H]+. (3aR,6R,7aR)-2,2,6-Trimethyltetrahydro-3H-[1,3]dioxolo[4,5-c]pyran (16). To a stirred solution of 15 (0.9 g, 1.96 mmol) in dry THF (5 mL) at 0 oC, n-Bu4N+F- in THF (4.3 mL, 4.32

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mmol) was added and stirred at room temperature for 10 h. The reaction mixture was evaporated and the residue purified by column chromatography (EtOAc: hexane, 6:4) to afford 16 (0.21 g, 65%) as a pale yellow syrup. [α]D -11.8 (c = 0.4, CHCl3); 1H NMR (200 MHz, CDCl3): δ 1.311.20 (m, 9H, 3 × CH3), 2.01-1.95 (m, 2H, CH2), 3.38-3.25 (m, 1H, CH), 3.70-3.56 (m, 2H, CH2), 4.02-3.93 (dd, 1H, J 4.4, 10.33 Hz, CH), 4.37-4.20 (m, 1H, CH); 13C NMR (75 MHz, CDCl3): δ 20.98, 24.41, 32.65, 66.68, 73.68, 76.45, 76.98, 117.28; ESIMS: m/z 172 [M+H]+, 195 [M + Na]+ ; HRMS: m/z [M+Na]+ calcd 195.1099; found 195.2234 for C9H16O3Na. (3R,4R,6R)-6-Methyltetrahydro-2H-pyran-3,4-diol (2). A solution of 16 (0.015g, 0.087 mmol) in MeOH (2 mL) was treated with catalytic p-toluenesulfonic acid (1.5 mg, 0.0087) and stirred at room temperature for 4 h. The reaction mixture was quenched with solid NaHCO3 filtered and MeOH was evaporated diluted with EtOAc (10 mL) washed with water (10 mL), brine (10 mL), dried (Na2SO4), evaporated under reduced pressure and the residue purified by column chromatography (EtOAc:hexane, 3:7) to afford ophiocerin B 2 (94 mg, 85%) as a yellow oil. [α]D -32.3 (c 0.25,CH2Cl2) [lit.9 [α]D -34.0 (c 0.25, CHCl3)]; IR: 3388, 1452,1380,1266,1079,1004 cm-1; 1H NMR (500 MHz, CDCl3): δ 1.18 (d, 3H, J 6.1 Hz, CH3), 1.64–1.59 (m, 2 H, -CH2), 1.81 (bs, 1H, -OH), 3.45 (s, 1 H, -OH), 3.67 (dd, 1H, J 2.1, 12.2 Hz, CH,), 3.73 (dd, 1H, J 2.3, 12.2 Hz, CH), 3.85 (ddq, 1H, J 2.6, 6.3,12.0 Hz, CH), 3.97 (dd, 1H, J 1.6, 12.4 Hz, CH), 3.91-3.99 (m, 1H, CH); 13C NMR (75 MHz, CDCl3): δ 21.1, 36.0, 67.2, 67.4, 68.2, 68.4; HRMS: m/z [M+Na]+ calcd 155.0684; found 155.0691 for C6H12O3Na.

Acknowledgements The authors (D.K and A.B) thankful to CSIR, New Delhi, India, for the research fellowship.

References 1. Boivin,T. L. B. Tetrahedron 1987, 43, 3309. http://dx.doi.org/10.1016/S0040- 4020(01)81626-4 2. Bode, H. B.; Zeeck, A. Journal of the Chemical Society, Perkin Transactions 1 2000, 0, 323. http://dx.doi.org/10.1039/a908387a 3. Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995, 117, 8126. http://dx.doi.org/10.1021/ja00136a009 4. Reátegui, R. F.; Gloer, J. B.; Campbell, J.; Shearer, C. A. J. Nat. Prod. 2005, 68, 701. http://dx.doi.org/10.1021/np050035i PMid:15921413 5. Pinruan, U.; Sakayaroj, J.; Jones, E. B. G.; Hyde, K. D. Mycologia 2004, 96, 1163. http://dx.doi.org/10.2307/3762100

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6. Harada, N.; Nakanishi, K. J. Am. Chem. Soc. 1969, 91, 3989. http://dx.doi.org/10.1021/ja01042a073 7. Lee, D.-M.; Kang, H.-Y. Bull. Kor. Chem.l Soc. 2008, 29, 1671. http://dx.doi.org/10.5012/bkcs.2008.29.9.1671 8. Lee, D.-M.; Lee, H.; Kang, H.-Y. Bull. Kor. Chem. Soc. 2008, 29, 535. http://dx.doi.org/10.5012/bkcs.2008.29.3.535 9. Yadav, J. S.; Lakshmi, P. N.; Harshavardhan, S. J.; Reddy, B. V. S. Synlett 2007, 1945. http://dx.doi.org/10.1055/s-2007-982579 10. Sharma, G. V. M.; Damera, K. Tetrahedron: Asymmetry 2008, 19, 2092. http://dx.doi.org/10.1016/j.tetasy.2008.08.016 11. Yadav, J. S.; Reddy, N. R.; Krishna, B. B. M.; Vardhan, C. V.; Reddy, B. V. S. Synthesis2010, 1621. 12. Saito, S.; Ishikawa, T.; Kuroda, A.; Koga, K.; Moriwake, T. Tetrahedron 1992, 48, 4067. http://dx.doi.org/10.1016/S0040-4020(01)92187-8 13. Hungerbühler, E.; Seebach, D.; Wasmuth, D. Helv. Chim. Acta 1981, 64, 1467. http://dx.doi.org/10.1002/hlca.19810640523 14. Lu, J.; Ma, J.; Xie, X.; Chen, B.; She, X.; Pan, X. Tetrahedron: Asymmetry 2006, 17, 1066. http://dx.doi.org/10.1016/j.tetasy.2006.03.027 15. Sharma, G. V. M.; Reddy, P. S. European J. Org. Chem. 2012, 2414. http://dx.doi.org/10.1002/ejoc.201101603 16. Zheng, G. R.; Lu, W.; Cai, J. C. Chin. Chem. Lett. 2001, 12, 961. 17. Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651. http://dx.doi.org/10.1016/0040-4020(78)80197-5 18. Jacobsen, E. N.; Marko, I.; Mungall, W. S.; Schroeder, G.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 1968. http://dx.doi.org/10.1021/ja00214a053

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Stereoselective synthesis of ophiocerin B - Arkivoc

Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical .... H NMR (300 MHz, CDCl3): δ 0.04 (s, 6H, 2 × CH3), 0.88 (s, 9H, 3 ×. CH3) ...

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Mar 30, 2017 - fragment is the three-component reaction of salts 3, СН-acids 8, and ..... (s, 2Н, (3`)СН2), 1.69 (s, 2Н, (2`)СН2), 4.12 (s, 2Н, (1`)СН2), 5.57 (d, ...

Synthesis and antimitotic properties of orthosubstituted ... - Arkivoc
Jun 20, 2017 - Abstract. Ortho-substituted polymethoxydiarylazolopyrimidines were synthesized using polymethoxysubstituted benzaldehydes and acetophenones as starting material. X-ray crystallography data clearly confirmed that the subsequent cyclizat