ChemInform Abstract: Highly Enantioselective Mukaiyama Aldol Reactions Catalyzed by a Chiral Oxazaborolidinium Ion: Total Synthesis of (-)-Inthomycin C.

Department of Chemistry, Sungkyunkwan University, Suwon, 440-746, Korea.
Organic Letters (Impact Factor: 6.36). 10/2010; 12(22):5088-91. DOI: 10.1021/ol102234k
Source: PubMed


A cationic oxazaborolidinium-catalyzed asymmetric Mukaiyama aldol reaction of (1-methoxy-2-methyl-propenyloxy)-trimethylsilane with various aldehydes including α,β-disubstituted acroleins has been developed in high yields and enantioselectivities. The synthetic utility of this methodology was demonstrated in the first short synthesis of naturally occurring inthomycin C in high enantiopurity.

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    ABSTRACT: Tamiflu, a neuraminidase inhibitor, is an antiviral medica-tion used to treat influenza virus in patients who have had symptoms for less than 2 days. The current key starting material for the production of Tamiflu is (-)-shikimic acid (1). 1 However, limited availability of 1 from natural Chinese star anise has led to the development of synthetic pathways to increase the supply of shikimic acid. 2 Besides its indus-trial uses, (-)-shikimic acid is a pivotal intermediate in the biogenetic synthesis pathway of a variety of aromatic natural products in microorganisms and plants known as the shikimate pathway. 3 In 1983, Masamune and co-workers achieved the first enantiospecific synthesis of (-)-shikimic acid 4 based on the asymmetric Diels-Alder reaction. Since then, substantial syn-thetic activity has been directed toward (-)-shikimic acid. 5 In 2000, Ogasawara and co-workers reported the synthesis of (-)-shikimic acid from lipase-resolved tricyclic alcohols employing a palladium mediated elimination reaction as the key step. 6 Furthermore, an efficient synthesis of (-)-shikimic acid from D-ribose was accomplished by Vankar et al. in 2009. 7 In conjunction with our interest in enantioselective Diels-Alder reactions with furans, we have found that the Diels-Alder reaction of furans with cationic chiral oxazaborolidinium catalyst 2 provides 7-oxabicyclo[2.2.1]hept-5-enes with high endo-selectivity and excellent enantioselectivity (Scheme 1). 8 In this paper, we report a method of efficient asymmetric synthesis of (-)-shikimic acid (1) from a chiral Diels-Alder adduct 3 between furan and acrylate. Chiral oxazaborolidinium salts (2; Scheme 1) work as powerful Lewis acids and have proven to be effective catalysts for various enantioselective Diels-Alder, 9 cyanosilylation 10a,b , Michael addition 10c , 1,3-dipolar cycloaddition, 11a three com-ponent coupling 11b and Mukayama aldol 11c reactions. With the readily available catalyst 2, the Diels-Alder reaction of furan and 2,2,2-trifluoroethyl acrylate at −78 o C provided chiral adduct 3 in 95% yield with a high endo/exo ratio (91/9) and in more than 99% ee 12 (endo). After chromatographic separation of the exo isomer, enantiomerically pure endo 3 was subjected to furan ring-opening with various bases. However, ring opened alcohol 5a was obtained in very low yield (Scheme 2). Conversion of the 2,2,2-trifluoroethyl ester to an ethyl ester with weakly basic ethanolic solvent followed by ring-opening with LiHMDS gave enantiomerically enriched diene 5b in 75% overall yield from 3. To introduce the diol with the correct stereochemistry, the free hydroxyl group in 5b was protected with a bulky TBDPS group to afford 6 in 88% yield. Catalytic dihydroxy-lation of 6 provided the desired diol 7 in 80% yield with complete stereoselectivity. 13 Desilylation of 7 afforded ethyl shikimate (8a) in 90% yield. Additionally, treatment of allylic alcohol 5b with osmium tetroxide afforded triol 8 in 70% yield with good stereoselectivity (8a/8b=7/1). Finally, saponification of 8a following a reported pro-cedure furnished (-)-shikimic acid (1) in 97% yield. Identity This paper is dedicated to Professor Eun Lee on the occasion of his ho-nourable retirement. Figure 1. Structure of (-)-Shikimic acid (1) and Tamiflu. Scheme 1. Highly enantioselective Diels-Alder reaction catalyzed by oxazaborolidinium salt 2. Communications to the Editor of the synthetic material was fully established through com-parisons of the 1 H-and 13 C-NMR spectra and specific rota-tions with literature data, = 180.0 (c 1.3, H 2 O), (> 99% ee). [lit. 14 = 179.7 (c 4, H 2 O)]. In summary, the total synthesis of (-)-shikimic acid was accomplished in 43.9% overall yield (via the TBDPS ether) or 42.5% overall yield (via the allylic alcohol) from com-mercially available furan and 2,2,2-trifluoroethyl acrylate. Acknowledgments.
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