Premium
Utility of the Ammonia‐Free Birch Reduction of Electron‐Deficient Pyrroles: Total Synthesis of the 20S Proteasome Inhibitor, clasto ‐Lactacystin β‐Lactone
Author(s) -
Donohoe Timothy J.,
Sintim Herman O.,
Sisangia Leena,
Ace Karl W.,
Guyo Paul M.,
Cowley Andrew,
Harling John D.
Publication year - 2005
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200401119
Subject(s) - lactacystin , stereoselectivity , chemistry , pyrrole , total synthesis , aldol reaction , dihydroxylation , regioselectivity , lactone , natural product , stereochemistry , sharpless asymmetric dihydroxylation , birch reduction , proteasome inhibitor , combinatorial chemistry , organic chemistry , proteasome , enantioselective synthesis , catalysis , biochemistry
A new synthesis of the 20S proteasome inhibitor clasto ‐lactacystin β‐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.