Hirata Yuuki, Nakamura Seiichi, Watanabe Nobuhide, Kataoka Osamu, Kurosaki Takahiro, Anada Masahiro, Kitagaki Shinji, Shiro Motoo, Hashimoto Shunichi
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Chemistry. 2006 Dec 4;12(35):8898-925. doi: 10.1002/chem.200601212.
A carbonyl ylide cycloaddition approach to the squalene synthase inhibitors zaragozic acids A and C is described. The carbonyl ylide precursor 8 was synthesized starting from di-tert-butyl D-tartrate (47) via an eleven-step sequence involving the regioselective reduction of the mono-MPM (MPM=4-methoxybenzyl) ether 48 with LiBH4 and the diastereoselective addition of sodium tert-butyl diazoacetate to alpha-keto ester 10. The reaction of alpha-diazo ester 8 with 3-butyn-2-one (40) in the presence of a catalytic amount of [Rh2(OAc)4] gave the desired cycloadduct 59 as a single diastereomer. The dihydroxylation of enone 59 followed by sequential transformations permitted the construction of the fully functionalized 2,8-dioxabicyclo[3.2.1]octane core 5. Alkene 79 derived from 5 serves as a common precursor to zaragozic acids A (1) and C (2), since the elongation of the C1 alkyl side chain can be attained by olefin cross-metathesis, especially under the influence of Blechert's catalyst (85).
描述了一种用于合成角鲨烯合酶抑制剂扎拉戈昔酸A和C的羰基叶立德环加成方法。羰基叶立德前体8是从L-酒石酸二叔丁酯（47）开始，通过一个十一步的序列合成的，该序列包括用LiBH4对单-MPM（MPM = 4-甲氧基苄基）醚48进行区域选择性还原，以及叔丁基重氮乙酸酯对α-酮酯10的非对映选择性加成。α-重氮酯8与3-丁炔-2-酮（40）在催化量的[Rh2(OAc)4]存在下反应，得到所需的环加成物59，为单一非对映异构体。烯酮59的双羟基化反应，随后进行一系列转化，使得能够构建完全官能化的2,8-二氧杂双环[3.2.1]辛烷核心5。由5衍生的烯烃79作为扎拉戈昔酸A（1）和C（2）的共同前体，因为C1烷基侧链的延长可以通过烯烃交叉复分解反应实现，特别是在Blechert催化剂（85）的影响下。
