One-Pot Multicomponent Coupling Methods for the Synthesis of Diastereo- and Enantioenriched (Z)-Trisubstituted Allylic Alcohols
One-Pot Multicomponent Coupling Methods for the Synthesis of Diastereo- and Enantioenriched (Z)-Trisubstituted Allylic Alcohols
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DOI：
10.1021/ja809821x
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发表时间：
2009-06-24
影响因子：
15
通讯作者：
Walsh, Patrick J.
中科院分区：
文献类型：
--
作者：
Kerrigan, Michael H.;Jeon, Sang-Jin;Walsh, Patrick J.
(Z)-三取代烯丙醇是天然产物和生物活性化合物中广泛存在的结构基元，但难以直接制备。本文介绍了合成(Z)-α，α，β-三取代烯丙醇的通用一锅多组分偶联方法。(Z)-三取代乙烯基锌试剂是通过1-溴-1-炔烃的初始氢硼化反应原位生成的。二烷基锌试剂的加入会导致1，2-金属酸重排，然后是硼到锌的转金属反应。得到的乙烯基锌试剂与各种前手性醛加成外消旋(Z)-三取代烯丙醇。当使用对映体浓缩醛底物时，(Z)-三取代烯丙醇以高DR(许多情况下为20：1)分离出来。例如，富含对映体的苄基保护的α-和β-羟基丙醛衍生物的乙烯基化通过络合控制提供了预期的反Felkin加成产物。令人惊讶的是，硅基保护的α-羟基醛也能买到反费尔金加成产品。还建立了一种以(-)-MIB为催化剂的(Z)-三取代乙烯基锌试剂与前手性醛的不对称加成反应。研究了几种添加剂作为Lewis酸性烷基卤化锌副产物的抑制剂，它们促进了背景反应形成外消旋。在二胺抑制剂存在下，α-乙基和α-环己基(Z)-三取代烯丙醇现在可以合成具有良好的对映选择性。
(Z)-Trisubstituted allylic alcohols are widespread structural motifs in natural products and biologically active compounds but are difficult to directly prepare. Introduced herein is a general one-pot multicomponent coupling method for the synthesis of (Z)-alpha,alpha,beta-trisubstituted allylic alcohols. (Z)-Trisubstituted vinylzinc reagents are formed in situ by initial hydroboration of 1-bromo-1-alkynes. Addition of dialkylzinc reagents induces a 1,2-metalate rearrangement that is followed by a boron-to-zinc transmetalation. The resulting vinylzinc reagents add to a variety of prochiral aldehydes to produce racemic (Z)-trisubstituted allylic alcohols. When enantioenriched aldehyde substrates are employed, (Z)-trisubstituted allylic alcohols are isolated with high dr (>20:1 in many cases). For example, vinylation of enantioenriched benzyl-protected alpha- and beta-hydroxy propanal derivatives furnished the expected anti-Felkin addition products via chelation control. Surprisingly, silyl-protected a-hydroxy aldehydes also afford anti-Felkin addition products. A protocol for the catalytic asymmetric addition of (Z)-trisubstituted vinylzinc reagents to prochiral aldehydes with a (-)-MIB-based catalyst has also been developed. Several additives were investigated as inhibitors of the Lewis acidic alkylzinc halide byproducts, which promote the background reaction to form the racemate. alpha-Ethyl and alpha-cyclohexyl (Z)-trisubstituted allylic alcohols can now be synthesized with excellent levels of enantioselectivity in the presence of diamine inhibitors.