Padwa A, Beall L S, Heidelbaugh T M, Liu B, Sheehan S M
Department of Chemistry, Emory University, Atlanta, Georgia 30322, USA.
J Org Chem. 2000 May 5;65(9):2684-95. doi: 10.1021/jo991742h.
A highly effective method for the synthesis of the core indolo[2,3-alpha]quinolizidine skeleton found in yohimbine is described. The reaction of N-monosubstituted thioamides with bromoalkenoyl chlorides furnishes thioisomünchnones as transient 1,3-dipoles that undergo ready intramolecular cycloaddition across the tethered pi-bond to give thio-bicycloannulated products in a one-pot operation. The stereochemical outcome of the intramolecular reaction is the consequence of an endo cycloaddition of the neighboring pi-bond across the transient thioisomünchnone dipole. A major limitation of the method is that when a hydrogen is present in the alpha-position of the thioamide the initially formed thio-N-acyliminium ion undergoes proton loss to produce a S,N-ketene acetal at a faster rate than dipole formation. Treatment of tetrahydro-beta-carboline-1-thione with 2-bromooct-7-enoyl chloride followed by reductive removal of sulfur from the cycloadduct resulted in the formation of (+/-)-alloyohimbanone. Attempts to cycloadd the thioisomünchnone dipole across several nucleophilic pi-bonds failed, and instead, products derived from cyclization of the pi-bond onto the initially formed thio-N-acyliminium ion were formed. The resulting N,S-ketals were further converted into several tetrahydroisoquinoline alkaloids in good yield.
描述了一种用于合成育亨宾中发现的核心吲哚并[2,3-α]喹嗪骨架的高效方法。N-单取代硫代酰胺与溴代烯酰氯的反应生成硫代异慕尼黑酮，作为瞬态1,3-偶极子，其通过连接的π键进行分子内环加成，在一锅操作中得到硫代双环稠合产物。分子内反应的立体化学结果是相邻π键通过瞬态硫代异慕尼黑酮偶极子进行内型环加成的结果。该方法的一个主要限制是，当硫代酰胺的α位存在氢时，最初形成的硫代-N-酰基亚胺离子会发生质子损失，以比偶极子形成更快的速率生成S,N-乙烯酮缩醛。用2-溴辛-7-烯酰氯处理四氢-β-咔啉-1-硫酮，然后从环加成物中还原除去硫，得到(±)-别育亨宾酮。尝试使硫代异慕尼黑酮偶极子通过几个亲核π键进行环加成均失败，相反，形成了由π键环化到最初形成的硫代-N-酰基亚胺离子上得到的产物。所得的N,S-缩酮进一步以良好的产率转化为几种四氢异喹啉生物碱。
