A new synthetic approach to (+)-lactacystin based on radical cyclisation of enantiopure alpha-ethynyl substituted serine derivatives to 4-methylenepyrrolidinones.
Treatment of the acetylenic bromoamide 42c, derived from the enantiopure alpha-amino alcohol 40, with Bu(3)SnH-AlBN results in an efficient 5-exo dig radical cyclisation to the 4-methylenepyrrolidinone 43/44 (2:1). Cleavage of the alkene bond in 43/44, using O(3)-Me(2)S, next gave the corresponding 4-ketopyrrolidinone 45/46. Alpha-phenylsulfanylation of 45/46, using S-methyl-p-toluenethiosulfonate-Et(3)N, proceeded in a stereoselective manner and led to the methylsulfanyl derivative 48 (ca. 9:1 selectivity). Manipulation of the functionality in 48, using two separate sequences, then led to the substituted pyrrolidinones 49b, 50 and 53 which are advanced intermediates in a previous synthesis of (+)-lactacystin 1. In related studies, the acetylenic bromoamide 28a containing all the carbon atoms in lactacystin was synthesised, but this substrate failed to undergo an anticipated radical cyclisation to the 4-methylenepyrrolidinone 30, analogous to 43/44. Instead, only the product of reduction of 28a, i.e. 28b, was produced, possibly resulting from adventitious intramolecular hydrogen-abstraction processes from the carbon centred radical intermediate 29, i.e. 32 to 33 and/or 31 to 34.
Pattenden
Gerald
G
School of Chemistry, The University of Nottingham, University Park, Nottingham, England NG7 2RD.
Rescourio
Gwenaëlla
G
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D003500:Cyclization; D005609:Free Radicals / Q000737:chemistry; D008745:Methylation; D015394:Molecular Structure; D011760:Pyrrolidinones / Q000737:chemistry*; D012694:Serine / Q000737:chemistry; D013237:Stereoisomerism
D005609:Free Radicals; D011760:Pyrrolidinones; C067713:lactacystin; D012694:Serine; D000111:Acetylcysteine