Synthesis of Robalzotan, Ebalzotan, and Rotigotine Precursors via the Stereoselective Multienzymatic Cascade Reduction of α,β-Unsaturated Aldehydes
Synthesis of Robalzotan, Ebalzotan, and Rotigotine Precursors via the Stereoselective Multienzymatic Cascade Reduction of α,β-Unsaturated Aldehydes
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DOI：
10.1021/jo4003097
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发表时间：
2013-05-17
影响因子：
3.6
通讯作者：
Sacchetti, Alessandro
中科院分区：
文献类型：
--
作者：
Brenna, Elisabetta;Gatti, Francesco G.;Sacchetti, Alessandro
报道了一种基于四氢萘或苯并二氢吡喃结构部分的双环伯胺或双环仲胺的立体选择性合成方法。这些胺是重要活性药物成分如罗替戈汀（Neupro）、robalzotan和ebalzotan的前体。关键步骤是基于α，β-不饱和醛或酮的多酶还原，以高产率和高ee得到饱和伯醇或仲醇。催化体系由烯还原酶（ER;即，属于老黄酶家族的OYE 2或OYE 3）与醇脱氢酶（ADH）反应，应用原位底物进料产物去除技术。通过该系统，烯丙醇副产物的形成和手性不稳定的α-取代的醛中间体的外消旋化被最小化。伯醇通过Curtius重排来制备。OYE 2与Prelog或anti-Prelog ADH的组合允许制备ee > 99%和de > 87%的仲醇。伯胺的绝对构型通过与真实样品的比较明确地分配。通过Mosher酯的X-射线晶体结构和NMR分析，确定了仲醇的立体化学结构。
A stereoselective synthesis of bicyclic primary or secondary amines, based on tetralin or chroman structural moieties, is reported. These amines are precursors of important active pharmaceutical ingredients such as rotigotine (Neupro), robalzotan, and ebalzotan. The key step is based on a multienzymatic reduction of an alpha,beta-unsaturated aldehyde or ketone to give the saturated primary or secondary alcohol, in a high yield and with a high ee. The catalytic system consists of the combination of an ene-reductase (ER; i.e., OYE2 or OYE3 belonging to the Old Yellow Enzyme family) with an alcohol dehydrogenase (ADH), applying the in situ substrate feeding product removal technology. By this system the formation of the allylic alcohol side product and the racemization of the chirally unstable alpha-substituted aldehyde intermediate are minimized. The primary alcohols were elaborated via a Curtius rearrangement. The combination of OYE2 with a Prelog or an anti-Prelog ADH allowed the preparation of the secondary alcohols with ee > 99% and de > 87%. The absolute configuration of the primary amines was unambiguously assigned by comparison with authentic samples. The stereochemistry of secondary alcohols was assigned by X-ray crystal structure and NMR analysis of Mosher esters.