Stereoselective generation of E- and Z-disubstituted amide enolates. Reductive enolate formation from bicylic thioglycolate lactams
Stereoselective generation of E- and Z-disubstituted amide enolates. Reductive enolate formation from bicylic thioglycolate lactams
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DOI：
10.1021/ja0058280
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发表时间：
2001-03-07
影响因子：
15
通讯作者：
Gleason, JL
中科院分区：
文献类型：
--
作者：
Manthorpe, JM;Gleason, JL
烯醇酸盐的形成是一系列化学转化的基础过程。在许多情况下，烯酸酯(E或Z)的立体化学是立体选择性反应的组成部分(例如，Aldol反应中的syn/anti控制)。对于单取代酯和酮烯醇酸盐，立体化学通常会受到溶剂、碱和温度的合理选择的影响。1对于单取代叔胺烯醇酸酯，A-1，3相互作用的最小化通常有利于Z-烯醇的形成。2双取代烯醇酸盐的立体控制是一项更困难的任务，必须经常在个案基础上进行评估。最高水平的立体控制通常与环状骨架有关，3包括金属络合物，4而基于不同立体环境的控制不太可靠。5，6我们已经启动了一个项目，开发基于烯醇转化的立体选择性季碳生成反应。我们的目标是开发一种通用的方法，它不依赖于特定的烯醇基特征，如螯合官能度或烯醇取代基之间的大空间差异。在这篇通讯中，我们报道了一种控制二取代胺烯醇酸盐中烯醇构型的方法，其中E/Z选择性仅取决于烯醇前体的几何结构和立体化学。我们的设计利用R，R-二烷基双环硫代乙酸内酰胺的两电子还原来提供双取代的酰胺烯醇酸酯(图1)。7假设(A)两个烷基(R1和R2)立体选择性地安装在R-位，(B)双环体系使OCCS二面角尽可能接近90，以及(C)在两电子还原过程中没有发生显著的键旋转，则烯醇的E/Z立体化学应由R1和R2在起始内酰胺中的相对位置控制。重要的是，这应该提供动力学E/Z立体控制，它与两个烯醇酸酯的相对稳定性无关，也不依赖于两个烷基的大小差异。值得注意的是，通过颠倒安装顺序来交换R1和R2的位置应该会导致烯状几何结构的反转。在许多方面，我们的模型类似于去质子化的首选过渡态，在靠近羰基的地方，硫被置换为氢。显着的区别在于，去质子化是一个协调的(两电子)过程，而还原过程无疑涉及两个单独的单电子转移步骤，因此键转动是CS键断裂导致的中间自由基阴离子中潜在的竞争过程。分子模拟计算(MM2)使用蒙特卡罗构象搜索(宏模型)来确定这种立体选择性还原过程的合适候选者。分析了几类双环硫代乙酸酯内酰胺在基态和基态2千卡/摩尔范围内所有稳定构象的加权平均值的理想OCCS二面角。根据这些计算，5，6-，5，7-和6，7-双环内酰胺1-3被确定为研究的候选化合物(见表1)。其中，5，7-和6，7-双环内酰胺2和3似乎是合理的候选者(OCCS二面角120-150)，而5，6-双环内酰胺1具有(1)(A)爱尔兰，RE；Mueller，RH；Willard，AK J.Am化学。SoC。1976年，98,2868.(B)Za的Fataftah；IE的Kopka；MW J.Am的Rathke化学。SoC。(C)Corey，EJ；Gross，AW四面体Lett。(D)爱尔兰，RE；Wipf，P.；阿姆斯特朗，JD J.Org.化学。1991年，
The formation of enolates is a process that is fundamental to a multitude of chemical transformations. In many cases, the stereochemistry of an enolate (E or Z) is an integral part of stereoselective reactions (eg, syn/anti control in aldol reactions). For monosubstituted ester and ketone enolates, stereochemistry can often be influenced by judicious choice of solvent, base, and temperature. 1 For monosubstituted tertiary amide enolates, minimization of A-1, 3 interactions usually favors Z-enolate formation. 2 Stereocontrol in disubstituted enolates is a more difficult task and must often be evaluated on a case-by-case basis. Highest levels of stereocontrol are usually associated with cyclic frameworks, 3 including metal chelates, 4 while control based on differential steric environments is less reliable. 5, 6 We have initiated a project to develop stereoselective quaternary carbon forming reactions based on enolate transformations. The goal is to develop a general method that does not rely on specific enolate features such as chelating functionality or a large steric difference between enolate substituents. In this communication, we report a method for controlling enolate geometry in disubstituted amide enolates where the E/Z selectivity is dependent only on the geometry and stereochemistry of the enolate precursor. Our design utilizes a two-electron reduction of R, R-dialkylated bicyclic thioglycolate lactams to provide disubstituted amide enolates (Figure 1). 7 Assuming that (a) two alkyl groups (R1 and R2) are installed stereoselectively at the R-position,(b) the OCCS dihedral angle is held as close to 90 as possible by the bicyclic system, and (c) significant bond rotation does not occur about the carbonyl-carbon/R-carbon bond during the two-electron reduction process, the E/Z stereochemistry of the enolate should be controlled by the relative positions of R1 and R2 in the starting lactam. Importantly, this should afford kinetic E/Z stereocontrol that is independent of the relative stabilities of the two enolates and does not depend on a large difference in size of the two alkyl groups. Significantly, switching the position of R1 and R2 by inverting the order of their installation should lead to a reversal of enolate geometry. In many regards, our model resembles the preferred transition state for deprotonation adjacent to a carbonyl group, with sulfur transposed for hydrogen. The significant difference is that deprotonation is a concerted (two-electron) process whereas the reductive process undoubtedly involves two separate one-electron-transfer steps and thus bond rotation is a potential competing process in the intermediate radical anion resulting from CS bond scission. Molecular modeling calculations (MM2) using a Monte Carlo conformational search (Macromodel) were used to identify suitable candidates for this stereoselective reduction process. Several classes of bicyclic thioglycolate lactams were analyzed for desirable OCCS dihedral angles both at the ground state and as a weighed average of all stable conformations within 2 kcal/mol of the ground state. From these calculations, the 5, 6-, 5, 7-and 6, 7-bicyclic lactams 1-3 were identified as candidates for study (see Table 1). Of these, the 5, 7-and 6, 7-bicyclic lactams 2 and 3 appear to be reasonable candidates (OCCS dihedral angles of 120-150), while the 5, 6-bicyclic lactam 1 has an (1)(a) Ireland, RE; Mueller, RH; Willard, AK J. Am. Chem. Soc. 1976, 98, 2868.(b) Fataftah, ZA; Kopka, IE; Rathke, MW J. Am. Chem. Soc. 1980, 102, 3959.(c) Corey, EJ; Gross, AW Tetrahedron Lett. 1984, 24, 495.(d) Ireland, RE; Wipf, P.; Armstrong, JD J. Org. Chem. 1991,