Total Synthesis of (+)-Lactacystin from (R)-Glutamate

Abstract

The discovery by dmura' of (+)-lactacystin (1) in Streptomycessp. OM-65 19 and the finding that it possesses neurotrophic activity have created much excitement, since the role of neurotrophic proteins, such as nerve growth factors (NGFs), in diseases is the center of much current interest.2 This substance consists of two a-amino acids, (R)-N-acetylcysteine and a novel pyroglutamic acid derivative 2. The combination of biological activity and the unique structure of lactacystin encouraged us to develop a synthesis which could permit variations of both the substituents and their stereochemistry. During the course of our work two elegant syntheses were r e p ~ r t e d , ~ . ~ which are strategically different from our route. The key reaction in our synthesis involves the stereoselective aldol reaction of a siloxypyrrole, readily available from pyroglutamate, with an aldehyde, thereby assembling the quaternary center and secondary alcohol in the correct stereochemical form, Scheme 1. The bicyclic oxazolidine 3 was prepared from (R)-glutamic acid in three steps (57%)5 and was elaborated to the unsaturated derivative 4 by sequential methylation6 and selenenylation/ozonolysis (65%, Scheme 2). The key siloxypyrrole 5 was obtained as a crystalline solid (89%) by treatment with TBSOTf and 2,6-lutidine.' The aldol reaction of 5 with isobutyraldehyde was achieved at -78 OC in ether in the presence of 2 equiv of SnC14 to afford 68 and its secondary alcohol epimers in the ratio 9: 1. The major isomer 6 was obtained as a crystalline solid after chromatography (55% yield). The surprising *-facial selectivity observed here, i.e., addition to the same face as the phenyl substituent, was revealed by X-ray crystallography of thep-bromobenzoate derivative of er1t-6.~ Use of other Lewis acids and solvents led to the formation of other isomers at the quaternary and secondary alcohol centers,1° thereby permitting access to these substances. Following acetylation 7 was converted to the diol 8 as a single isomer (87%) by osmylation (OsO,, N-methylmorpholine N-oxide). The tertiary hydroxyl group was removed via the cyclic thiocarbonate with Bu3SnH in