Department of Chemistry, Chemistry Research Laboratory, University of Oxford , Mansfield Road, Oxford OX1 3TA, U.K.
J Org Chem. 2016 Jun 17;81(12):4907-22. doi: 10.1021/acs.joc.6b00362. Epub 2016 May 13.
Efficient de novo asymmetric syntheses of (+)-preussin B, the C(2)-epimer of (-)-preussin B, and 3-deoxy-(+)-preussin B have been developed, using the diastereoselective conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide to tert-butyl 4-phenylbut-2-enoate and diastereoselective reductive cyclizations of γ-amino ketones as the key steps to set the stereochemistry. Conjugate addition followed by enolate protonation generated the corresponding β-amino ester. Homologation using the ester functionality as a synthetic handle gave the corresponding γ-amino ketone. Hydrogenolytic N-debenzylation was accompanied by diastereoselective reductive cyclization in situ; reductive N-methylation then gave 3-deoxy-(+)-preussin B as the major diastereoisomeric product. Meanwhile, the same conjugate addition but followed by enolate oxidation with (+)-camphorsulfonyloxaziridine gave the corresponding anti-α-hydroxy-β-amino ester. α-Epimerization by oxidation and diastereoselective reduction then gave access to the corresponding syn-α-hydroxy-β-amino ester. Homologation of both of these diastereoisomeric α-hydroxy-β-amino esters gave the corresponding β-hydroxy-γ-amino ketones. N-Debenzylation and concomitant diastereoselective reductive cyclization, followed by reductive N-methylation, provided the C(2)-epimer of (-)-preussin B and (+)-preussin B as the major diastereoisomeric products, respectively. The overall yields (from phenylacetaldehyde) were 19% for 3-deoxy-(+)-preussin B over seven steps, 8% for the C(2)-epimer of (-)-preussin B over nine steps, and 7% for (+)-preussin B over eleven steps.
已发展出高效的 (+)-普雷斯宾 B、(-)-普雷斯宾 B 的 C(2)-差向异构体和 3-脱氧-(+)-普雷斯宾 B 的不对称从头合成方法，该方法使用立体选择性的锂（S）-N-苄基-N-（α-甲基苄基）酰胺与叔丁基 4-苯基丁-2-烯酸酯的共轭加成以及γ-氨基酮的立体选择性还原环化作为关键步骤来设置立体化学。共轭加成后烯醇化物质子化生成相应的β-氨基酯。使用酯官能团作为合成手性的同系化得到相应的γ-氨基酮。氢解去苄基化伴随着立体选择性的原位还原环化；随后的还原 N-甲基化得到 3-脱氧-(+)-普雷斯宾 B 作为主要的非对映异构体产物。同时，相同的共轭加成，但随后用（+）-樟脑磺酰基恶唑啉进行烯醇化物氧化，得到相应的反-α-羟基-β-氨基酯。然后通过氧化和立体选择性还原使α-差向异构化得到相应的顺-α-羟基-β-氨基酯。这两种非对映异构体的α-羟基-β-氨基酯的同系化得到相应的β-羟基-γ-氨基酮。去苄基化和伴随的立体选择性还原环化，然后进行还原 N-甲基化，分别提供（-）-普雷斯宾 B 的 C(2)-差向异构体和（+）-普雷斯宾 B 作为主要的非对映异构体产物。从苯乙醛开始的总收率分别为 7 步合成 3-脱氧-(+)-普雷斯宾 B 的 19%、9 步合成（-）-普雷斯宾 B 的 C(2)-差向异构体的 8%和 11 步合成（+）-普雷斯宾 B 的 7%。
