Bioinspired Total Synthesis and Human Proteasome Inhibitory Activity of (−)-Salinosporamide A, (−)-Homosalinosporamide A, and Derivatives Obtained via Organonucleophile Promoted Bis-cyclizations

• Published in: Journal of organic chemistry 2011-01, Vol.76 (1), p.2-12
• Main Authors: Nguyen, Henry, Ma, Gil, Gladysheva, Tatiana, Fremgen, Trisha, Romo, Daniel
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Bioconversions. Hemisynthesis; Biological and medical sciences; Biotechnology; Catalysis; Chemistry; Crystallography, X-Ray; Cyclization; Exact sciences and technology; Fundamental and applied biological sciences. Psychology; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Humans; Lactones - chemical synthesis; Lactones - chemistry; Lactones - pharmacology; Magnetic Resonance Spectroscopy; Methods. Procedures. Technologies; Molecular Conformation; Molecular Structure; Organic chemistry; Preparations and properties; Proteasome Endopeptidase Complex - chemistry; Proteasome Endopeptidase Complex - metabolism; Proteasome Inhibitors; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Stereoisomerism
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo101638r

A full account of concise, enantioselective syntheses of the anticancer agent (−)-salinosporamide A and derivatives, including (−)-homosalinosporamide, that was inspired by biosynthetic considerations is described. The brevity of the synthetic strategy stems from a key bis-cyclization of a β-keto tertiary amide, which retains optical purity enabled by A1,3-strain rendering slow epimerization relative to the rate of bis-cyclization. Optimization studies of the key bis-cyclization, enabled through byproduct isolation and characterization, are described that ultimately allowed for a gram scale synthesis of a versatile bicyclic core structure with a high degree of stereoretention. An optimized procedure for zincate generation by the method of Knochel, generally useful for the synthesis of salino A derivatives, led to dramatic improvements in side-chain attachment and a novel diastereomer of salino A. The versatility of the described strategy is demonstrated by the synthesis of designed derivatives including (−)-homosalinosporamide A. Inhibition of the human 20S and 26S proteasome by these derivatives using an enzymatic assay are also reported. The described total synthesis of salino A raises interesting questions regarding how biosynthetic enzymes leading to the salinosporamides proceeding via optically active β-keto secondary amides, are able to maintain the stereochemical integrity at the labile C2 stereocenter or if a dynamic kinetic resolution is operative.