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Issue 39, 2012
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Total synthesis of epothilones using functionalised allylstannanes for remote stereocontrol

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Abstract

Two syntheses of the C(7)–C(16)-fragment 41 of epothilone D 2 were developed that were based on tin(IV) bromide mediated reactions of 5,6-difunctionalised hex-2-enylstannanes with aldehydes. In the first synthesis, (5S)-6-tert-butyldimethylsilyloxy-5-hydroxy-2-methylhex-2-enyl(tributyl)stannane 20 was reacted with (E)-but-2-enal to give (2S,7R,4Z,8E)-1-tert-butyldimethylsilyloxy-5-methyldeca-4,8-diene-2,7-diol 26 containing ca. 20% of its (7S)-epimer. Following desilylation, the crystalline (2S,7R)-triol 32 was protected as its acetonide 33 and esterified to give the (4-methoxybenzyloxy)acetate 34. An Ireland–Claisen rearrangement of this ester gave methyl (2R,3S,10S,4E,7Z)-3,7-dimethyl-10,11-(dimethylmethylene)dioxy-2-(4-methoxybenzyloxy)undeca-4,7-dienoate 35 that was converted into (2S,9S,6Z)-2,6-dimethyl-9,10-(dimethylmethylene)dioxydec-6-en-1-ol 41 by regioselective alkene manipulation, ester reduction and cleavage of the resulting terminal diol 40 with a reductive work-up. The second synthesis involved the tin(IV) bromide mediated reaction between the stannane 20 and (3S)-4-(4-methoxybenzyloxy)-3-methylbutanal 44 that gave (2S,7S,9S,4Z)-1-tert-butyldimethylsilyloxy-5,9-dimethyl-10-(4-methoxybenzyloxy)dec-4-ene-2,7-diol 45 containing ca. 20% of its (7R)-epimer. After desilylation and protection of the vicinal diol as its acetonide 46, a Barton–McCombie reductive removal of the remaining hydroxyl group gave the (2S,9S,6Z)-2,6-dimethyl-9,10-(dimethylmethylene)dioxydec-6-en-1-ol 41 after oxidative removal of the PMB-ether. The first of these syntheses uses just one chiral starting material, but the second is shorter and more convergent. It was therefore modified by the use of (5S)-6-tert-butyldimethylsilyloxy-5-(2-trimethylsilylethoxy)methoxy-2-methylhex-2-enyl(tributyl)stannane 49 that reacted with (3S)-4-(4-methoxybenzyloxy)-3-methylbutanal 44 to give a 50 : 50 mixture of the C(4)-epimers of (2S,9S,6Z)-10-tert-butyldimethylsilyloxy-1-(4-methoxybenzyloxy)-2,6-dimethyl-9-(2-trimethylsilylethoxy)methoxydec-6-en-4-ol 50 with high fidelity for formation of the (Z)-alkene. Following the Barton–McCombie deoxygenation, the product 52 was taken through to (2S,9S,6Z,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-(2-trimethylsilylethoxy)methoxyundeca-6,10-dienal 59 that corresponded to the fully functionalised C(7)–C(17) fragment of epothilone D 2. A precedented stereoselective aldol condensation followed by O-protection, selective deprotection, oxidation and macrocyclisation then gave the macrolide 71 that was deprotected to complete a synthesis of epothilone D 2. Finally regio- and stereo-selective epoxidation gave epothilone B 1.

Graphical abstract: Total synthesis of epothilones using functionalised allylstannanes for remote stereocontrol

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Publication details

The article was received on 09 Jul 2012, accepted on 22 Aug 2012 and first published on 23 Aug 2012


Article type: Paper
DOI: 10.1039/C2OB26310F
Citation: Org. Biomol. Chem., 2012,10, 7952-7964
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    Total synthesis of epothilones using functionalised allylstannanes for remote stereocontrol

    N. Martin and E. J. Thomas, Org. Biomol. Chem., 2012, 10, 7952
    DOI: 10.1039/C2OB26310F

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