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Bioorg Med Chem Lett. 2013 Dec 15;23(24):6905-10. doi: 10.1016/j.bmcl.2013.09.066. Epub 2013 Sep 30.

(S)-4-Trimethylsilyl-3-butyn-2-ol as an auxiliary for stereocontrolled synthesis of salinosporamide analogs with modifications at positions C2 and C5.

Author information

1
The Pennsylvania State University, PA, USA.

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.

KEYWORDS:

Chiral auxiliary; Mukaiyama aldol reaction; Proteasome inhibitor; Salinosporamide A

PMID:
24269479
PMCID:
PMC3854947
DOI:
10.1016/j.bmcl.2013.09.066
[Indexed for MEDLINE]
Free PMC Article

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