Donohoe Timothy J, Sintim Herman O, Sisangia Leena, Ace Karl W, Guyo Paul M, Cowley Andrew, Harling John D
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, UK.
Chemistry. 2005 Jul 4;11(14):4227-38. doi: 10.1002/chem.200401119.
A new synthesis of the 20S proteasome inhibitor clasto-lactacystin beta-lactone is described. Our route to this important natural product involves the partial reduction of an electron deficient pyrrole as a key step. By judicious choice of enolate counterion, we were able to exert complete control over the stereoselectivity of the reduction/aldol reaction. Early attempts to complete the synthesis by using a C-4 methyl substituted pyrrole are described in full, together with our attempts to promote regioselective elimination of a tertiary alcohol. The lessons learnt from this first approach led us to develop another, and ultimately successful, route that introduced the C-4 methyl group at a late stage in the synthesis. Our successful route is then described and this contains several highly stereoselective steps including a cis-dihydroxylation and an enolate methylation. The final synthesis proceeds in just 13 steps and in 15 % overall yield making it an extremely efficient route to this valuable compound.
描述了20S蛋白酶体抑制剂clasto-乳胞素β-内酯的一种新合成方法。我们合成这种重要天然产物的路线涉及将缺电子吡咯进行部分还原作为关键步骤。通过明智地选择烯醇负离子抗衡离子，我们能够完全控制还原/羟醛反应的立体选择性。详细描述了早期使用C-4甲基取代吡咯完成合成的尝试，以及我们促进叔醇区域选择性消除的尝试。从第一种方法中学到的经验教训促使我们开发了另一种最终成功的路线，即在合成后期引入C-4甲基基团。然后描述了我们成功的路线，其中包含几个高度立体选择性的步骤，包括顺式二羟基化和烯醇负离子甲基化。最终的合成仅需13步，总收率为15%，使其成为合成这种有价值化合物的极其有效的路线。
