Highly Enantioselective Mukaiyama Aldol Reactions Catalyzed by a Chiral Oxazaborolidinium Ion: Total Synthesis of (-)-Inthomycin C
ABSTRACT 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.
Article: Total Synthesis of Oxazolomycins[Show abstract] [Hide abstract]
ABSTRACT: The oxazolomycin family of antibiotics, isolated from several Streptomyces strains, are intriguing molecules for synthesis due to their characteristic oxazole polyene lactam–lactone structures and significant antiviral, antibacterial, and antitumor biological activities. In the last ten years, we have been addressing synthetic problems to accomplish the total syntheses of neooxazolomycin and oxazolomycin A as well as the related antibiotics, inthomycins A, B, and C, which have truncated structures corresponding to the left-hand fragments. This account describes an overview of our synthetic efforts toward these natural products focusing on the strategies and methodologies we devised.The Chemical Record 08/2014; 14(4). DOI:10.1002/tcr.201402009 · 5.58 Impact Factor
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ABSTRACT: Stereochemical evidence is presented to demonstrate that (-)-inthomycin C has (3R)- and not (3S)-stereochemistry. Careful reappraisal of the previously published work2-5 now indicates that the Hatakeyama, Hale, Ryu, and Taylor teams all have synthesized (-)-(3R)-inthomycin C. The newly measured [α]D of pure (-)-(3R)-inthomycin C (98% ee) is -7.9 (c 0.33, CHCl3) and not -41.5 (c 0.1, CHCl3) as was previously reported in 2012.ChemInform 06/2014; 16(13). DOI:10.1021/ol501484t
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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.Bulletin- Korean Chemical Society 08/2011; 32(spc8). DOI:10.5012/bkcs.2011.32.8.2885 · 0.84 Impact Factor