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

本文报道了在α，β-不饱和酮与手性硫醇的迈克尔加成和Meerwein-Ponndorff-Verley(Mpv)还原反应中，三个连续的立体中心的高度立体选择性的构建。在Me_2AlCl存在下，α，β-不饱和酮与(-)-10-巯基异龙脑醇的反应包括迈克尔加成步骤中的不对称质子化和1，i-氢化物移动还原羰基。由于在串联反应过程中，巯基醇起到了手性模板的作用，Michael加合物(10元过渡态)的构象受到了相当大的限制，以控制产物的立体化学。α，β-二取代乙烯基苯基酮与(-)-10-巯基异龙脑醇的反应在没有添加剂的情况下，伴随着三个连续的手性碳的立体选择性构筑，获得了很好的结果。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。通过对多种添加剂的筛选，五氟苯甲酸(PKA 1.7)具有较高的立体选择性。此外，通过Wagner-Meerwein重排反应去除了反应中的手性助剂异龙脑部分，得到了具有三个邻接手性中心的对映体纯的1，3-巯基醇。利用上述串联反应，可以方便地制备出光学纯的威士忌内酯和白兰地内酯。此外，基于(-)-10-巯基-异龙脑气味微弱的特点，我们还成功地合成了以10个碳为烷基的无味硫醇(Dodesyl-SH)和无味硫化物(Dodesyl-S-Me)。通过使用无味试剂，可以在无味条件下实现Corey-Kim和Swern氧化、与硫醇结合的脱烷基反应和臭氧氧化还原功

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