Stereoselective synthesis of ophiocerin B

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.


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. 2,3phiocerins A-D (1-4) are a class of natural products isolated from freshwater aquatic fungi by Reategui et al. 4 from Ophioceras venezuelense 5 (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. 6hese new tetrahydropyran derivatives appear to be the first isolated natural products from the above genus. 4Consequently, compounds 1-4 have attracted considerable synthetic attention from various laboratories, [7][8][9][10][11] including our own. 10So 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.

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 6 12 in two steps.Selective tosylation of 6 and subsequent reduction of the resulting tosylate with LiAlH4 afforded 1,3-diol 7 13,14 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 10 15,16 on oxidation under Swern conditions 17 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 dihydroxylation 18 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.

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 cyclization 15 in one step to give the cyclized product 16 in 65% yield []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, []D = -32.3(c 0.25, CHCl3), matching that of the natural product 4 []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.

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. 1 H NMR and 13 C NMR spectra were recorded on Gemini-200 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 0 C.