Studies on the construction of multi-contiguous asymmetric synthesis using mercapto alcohol as a chiral template

本文报道了手性巯基醇对α，β-不饱和酮的Michael加成和Meerwein-Ponndorff-Verley （MPV）还原反应中三个连续立体中心的高度立体选择性构建。在Me_2AlCl存在下，α，β-不饱和酮与(-)-10-巯基异龙脑醇的反应涉及Michael加成步骤的不对称质子化和1，i-氢化物移位以还原羰基。由于巯基醇在串联反应过程中充当手性模板，因此Michael加合物（10元过渡态）的构象受到限制，从而控制了产物的立体化学性质。α，β-二取代乙烯基苯基酮与(-)-10-巯基异鸟烯醇的反应在无添加剂的情况下获得了良好的效果，并伴有三个连续手性碳的立体选择性结构。另一方面，以α，β-二取代乙烯基烷基酮为底物的反应的立体选择性范围受添加剂pH值的影响较大。经过对多种添加剂的考察，五氟苯甲酸（pKa 1.7）具有较高的立体选择性，效果最好。此外，利用Wagner-Meerwein重排法去除了手性助剂异龙脑部分，得到具有三个连续手性中心的纯1,3-巯基醇。采用上述串联反应制备了威士忌内酯和干邑内酯的光纯形式。此外，我们还根据(-)-10-巯基异鸟烯醇气味微弱的特点，成功制备了烷基链为10个碳的无味硫醇（Dodesyl-SH）和无味硫化物（Dodesyl-S-Me）。通过使用无臭试剂，可以在无臭条件下实现Corey-Kim和Swern氧化，与alcl -硫醇组合脱烷基以及臭氧分解的还原反应

We report herein the highly stereoselective construction of three contiguous stereogenic centers in tandem Michael addition and Meerwein-Ponndorff-Verley (MPV) reduction of the α,β-unsaturated ketones with chiral mercapto alcohol. The reaction of α,β-unsaturated ketones with (-)-10-mercaptoisobornenol in the presence of Me_2AlCl involved asymmetric protonation at ctposition in the Michael addition step and 1,i-hydride shift to reduce carbonyl group. Since the mercapto alcohol behaves as a chiral template during the tandem reaction proceeds, the conformation of the Michael adducts (10-membered transition-state) was rather restricted to control the stereochemistry of the products. The reaction of, α,β-disubstituted vinyl phenyl ketone with (-)-10-mercaptoisobornenol afforded excellent results accompanying the stereoselective construction of three contiguous chiral carbons in the absence ofadditives. On the other hand, the range of the stereoselectivities of the reaction choosing α,β-disubstituted vinyl alkyl ketone as a substrate was potently affected by the pH values of additives. After being scrutinized many additives, pentafluorobenzoic acid (pKa 1.7) provided the best result to afford the high stereoselectivity. Furthermore, isoborneol moiety that is the chiral auxiliary in the reaction was removed by taking advantage of Wagner-Meerwein rearrangement to afford enatiomerically pure 1,3-mercapto alcohols with three contiguous chiral centers. Whisky lactones and cognac lactones were facilely prepared in optically pure form by using the tandem reaction mentioned above. In addition, we succeeded in preparing odorless thiols (Dodesyl-SH) and odorless sulfides (Dodesyl-S-Me), which carry 10 carbons as the alkyl chain, on the basis of the fact (-)-10-mercapto-isobornenol smells faint. Corey-Kim and Swern oxidations, dealkylation with AlCls-thiols combination, and reductive work up of ozonolysis became,attainable under odorless conditions by using the odorless reagents