Overman Larry E, Watson Donald A
Department of Chemistry, 516 Rowland Hall, University of California, Irvine, CA 92697-2025, USA.
J Org Chem. 2006 Mar 31;71(7):2587-99. doi: 10.1021/jo052335a.
Diastereoselective double Heck cyclizations of cyclohexene diamides 1 and 3 form contiguous quaternary stereocenters, with diastereoselection being controlled by the trans-diol protecting group. In this, the first in a series of two papers, the origin of diastereoselection in the first ring-closure step of these reactions is examined. Nine simplified analogues of 1 and 3 were synthesized and cyclized to discern what structural features are required to realize high diastereoselection in the first intramolecular Heck reaction. These studies show that high stereoselection (>20:1) does not arise from a single structural feature: it is seen only in substrates that contain both a trans-acetonide and a tertiary amide substituent at C2. Two subtle factors appear to be involved: (1) Avoidance of eclipsing interactions between the forming C-C bond and the pseudoaxial hydrogen atom at C6 and between the pseudoequatorial hydrogen atom at C6 and the carbonyl carbon of the forming spirooxindole. (2) The vinylic amide substituent that is not involved in the insertion event preferentially adopts a perpendicular conformation, placing the sterically bulky NR(2) over the alkene pi bond. syn-Pentane-like interactions between this substituent and the C3 of the cyclohexene are avoided in the favored insertion topography. These two effects, when combined, produce a highly diastereoselective process.
环己烯二酰胺1和3的非对映选择性双Heck环化反应形成相邻的季碳立体中心，非对映选择性由反式二醇保护基控制。在这篇（两篇系列论文中的第一篇）论文中，研究了这些反应第一步闭环反应中非对映选择性的起源。合成并环化了1和3的九个简化类似物，以确定在第一次分子内Heck反应中实现高非对映选择性需要哪些结构特征。这些研究表明，高立体选择性（>20:1）并非源于单一结构特征：仅在C2位同时含有反式丙酮叉和叔酰胺取代基的底物中才能观察到。似乎涉及两个微妙因素：（1）避免形成的C-C键与C6位的假轴向氢原子之间以及C6位的假赤道氢原子与形成的螺环氧化吲哚的羰基碳之间的重叠相互作用。（2）未参与插入事件的乙烯基酰胺取代基优先采取垂直构象，使空间位阻较大的NR(2)位于烯烃π键上方。在有利的插入构象中，避免了该取代基与环己烯C3之间的顺式戊烷样相互作用。这两种效应结合起来，产生了一个高度非对映选择性的过程。
