title: (S)-4-Trimethylsilyl-3-butyn-2-ol as an auxiliary for stereocontrolled synthesis of salinosporamide analogs with modifications at positions C2 and C5.
abstract: Analogs of salinosporamide A with variations of the C2 and C5 substituents are prepared in 8-10 steps using as the first and key transformation a diastereoselective Mukaiyama aldol reaction between the chiral 5-tert-butyldimethylsiloxy-3-methyl-1H-pyrrole-2-carboxylic ester depicted and various aldehyde substrates, promoted by tert-butyldimethylsilyl triflate. In this transformation, the 4-trimethylsilyl-3-butyn-2-ol ester functions to direct the formation of predominantly one of four possible diastereomeric aldol products. Introduction of the C2 appendage by a later-stage, stereocontrolled alkylation reaction permits the construction of analogs variant at this position. Results from in vitro and cell-based assays of proteasomal inhibition are reported. Mass spectrometric studies provide mechanistic details of proteasomal modification by salinosporamide A and analogs.
authors.affiliation: The Pennsylvania State University, PA, USA.
authors.forename: Landy K
authors.initials: LK
authors.lastname: Blasdel
authors.forename: DongEun
authors.initials: D
authors.lastname: Lee
authors.forename: Binyuan
authors.initials: B
authors.lastname: Sun
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Myers
mesh_terms: D000447:Aldehydes / Q000737:chemistry; D000478:Alkylation; D000440:Butanols / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004952:Esters; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry*; D008968:Molecular Conformation; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000138:chemical synthesis / Q000737:chemistry; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry*; D013237:Stereoisomerism; D014297:Trimethylsilyl Compounds / Q000737:chemistry*
chemical_list: C448622:4-trimethylsilyl-3-butyn-2-ol; D000447:Aldehydes; D000440:Butanols; D004952:Esters; D007783:Lactones; D061988:Proteasome Inhibitors; D011758:Pyrroles; D014297:Trimethylsilyl Compounds; C475865:marizomib; C116609:3-hydroxybutanal; D046988:Proteasome Endopeptidase Complex
keywords: Chiral auxiliary; Mukaiyama aldol reaction; Proteasome inhibitor; Salinosporamide A