Total synthesis of (+)-ambruticin S

被引:47
作者
Berberich, SM [1 ]
Cherney, RJ [1 ]
Colucci, J [1 ]
Courillon, C [1 ]
Geraci, LS [1 ]
Kirkland, TA [1 ]
Marx, MA [1 ]
Schneider, MF [1 ]
Martin, SF [1 ]
机构
[1] Univ Texas, Dept Chem & Biochem, Austin, TX 78712 USA
基金
美国国家卫生研究院;
关键词
oxygen heterocycles; furan; carbohydrates; enantioselective; rearrangement; ring closing metathesis; Julia coupling;
D O I
10.1016/S0040-4020(03)00370-3
中图分类号
O62 [有机化学];
学科分类号
070303 ; 081704 ;
摘要
A convergent total synthesis of the novel antifungal agent ambruticin S (1) has been completed from the assembly of intermediates 18, 33 and 52 that served as the respective A-, B-, and C-ring precursors. The first generation approach to a potential A-ring intermediate eventuated in the synthesis of 9a via a route that featured oxidation of the dihydroxy furan 2 and elaboration of the dihydropyranone 3 derived therefrom. Although 9a served as a precursor of 31E to complete a formal synthesis of 1, there were several inefficiencies associated with the preparation of 9a. A more expedient and efficient route to an A-ring subunit was devised that commenced with the carbohydrate-derived bisacetonide aldehyde 10 and produced 18 in five steps and 46% overall yield. The synthesis of the cyclopropyl sulfone 33 was initiated with the enantioselective cyclopropanation of 19 catalyzed by Rh-2[5(S)-MEPY](4). Ring opening of the resultant lactone 20 followed by a series of refunctionalizations gave 33 in a total of seven steps and 46% yield from 19. Coupling of the A- and B-ring precursors 18 and 33 was then achieved via a modified Julia coupling followed by deprotection and oxidation to furnish the key intermediate 35. The dihydropyran core of the C-ring subunit precursor 49 was formed from the ring closing metathesis of the diene 48, which was prepared in three steps from the known epoxide 45, followed by oxidation. A chelation-controlled addition to the methyl ketone 49 set the stage for a stereoselective [2,3]-Wittig rearrangement that delivered the alcohol 51 that was then transformed in two steps to the sulfone 52. A traditional Julia coupling of 52 and 35 proceeded with excellent stereoselectivity, and subsequent removal of the various protecting groups gave ambruticin S (1). The longest linear sequence was 13 steps and proceeded in 4.3% overall yield. (C) 2003 Elsevier Ltd. All rights reserved.
引用
收藏
页码:6819 / 6832
页数:14
相关论文
共 99 条