Departamento de Química Orgánica I, Universidad del País Vasco, Apdo. 1072, 20080, San Sebastián, Spain.
Chemistry. 2009 Nov 9;15(44):11954-62. doi: 10.1002/chem.200902094.
The value of cyclic gem-bis(sulfone) 4 as a simple alkyl nucleophile equivalent in catalytic C-C bond-forming reactions is demonstrated. The 1,4-type nucleophilic additions of bis(sulfone) 4 to alpha,beta-unsaturated ketones take place by assistance of catalytic guanidine base. On the other hand, pyrrolidines are able to catalyze the conjugate addition of 4 to both enones and enals, likely by means of iminium ion activation. Upon exploration of the best chiral pyrrolidine catalyst, it has been found that the addition of 4 to enals catalyzed by diphenylprolinol silyl ether 10 proceeds with very high enantioselectivity (beta-aryl-substituted enals >95% ee; beta-alkyl substituted enals up to 94% ee; ee = enantiomeric excess). Further reductive desulfonation of adducts gives rise to the corresponding beta-methyl aldehydes, as well as the derived alcohols, acetals, and methyl esters after simple (Mg, MeOH) well-established protocols. Application of the procedure to the synthesis of biologically relevant phenethyl building blocks is shown. Most interestingly, alpha-alkylation of initially obtained bis(sulfone) adducts can be done even with less reactive alkylating reagents, such as long linear-chain or branched-chain alkyl halides. Accordingly, upon the desulfonation process, a general, experimentally simple and highly enantioselective access to beta-branched aldehydes, alcohols, or esters is possible. Further exploration of the method includes the use of chiral alpha,beta-unsaturated aldehydes derived from citronellal as the Michael acceptor partners. In these instances, the sense of the conjugate addition of 4 is controlled by the chirality of the pyrrolidine catalyst, thus allowing for a stereochemically predictable access to 1,3-dimethyl arrays, such as those present in deoxygenated polyketide-type natural products. The intramolecular variation of this technology by using doubly unsaturated aldehyde-ester 22 illustrated the site selectivity of the procedure and its potential for tandem processes leading to highly substituted polycyclic systems, such as 24.
展示了环状双（亚砜）4 作为一种简单的烷基亲核试剂等价物在催化 C-C 键形成反应中的价值。双（亚砜）4 对α,β-不饱和酮的 1,4-型亲核加成是通过催化胍碱的协助进行的。另一方面，吡咯烷能够通过亚胺离子活化来催化 4 与烯酮和烯醛的共轭加成。在探索最佳手性吡咯烷催化剂时，发现二苯脯氨醇硅醚 10 催化的 4 与烯醛的加成具有非常高的对映选择性（β-芳基取代的烯醛>95%ee；β-烷基取代的烯醛最高可达 94%ee；ee=对映体过量）。加合物的进一步还原脱硫会导致相应的β-甲基醛以及简单（Mg，MeOH）既定方案后衍生的醇、缩醛和甲酯。该程序在生物相关的苯乙基构建块合成中的应用得到了展示。最有趣的是，即使使用反应性较低的烷基化试剂，如长直链或支链烷基卤化物，也可以对最初获得的双（亚砜）加合物进行α-烷基化。因此，在脱硫过程中，可以通过一种通用的、实验上简单的和高度对映选择性的方法来获得β-支链醛、醇或酯。该方法的进一步探索包括使用来源于橙花醛的手性α,β-不饱和醛作为迈克尔受体。在这些情况下，4 的共轭加成的立体构型受吡咯烷催化剂的手性控制，从而允许对 1,3-二甲基结构进行立体化学可预测的访问，例如那些存在于去氧聚酮型天然产物中的结构。通过使用双不饱和醛-酯 22 对该技术的分子内变化说明了该方法的位点选择性及其在手性串联反应中的潜力，从而导致高度取代的多环体系，如 24 的形成。
