Development of a concise, enantioselective synthetic route to analogs of salinosporamide A

This thesis describes an enantioselective synthesis of dihydrosalinosporamide A (23) proceeding in 12 steps and 18% yield. (S)-4-(Trimethylsilyl)-3-butyn-2-ol was used as a novel chiral controller group to control the absolute stereochemistry of the key bond-forming event: aldol addition of the pyrrole ester 96 to cyclohexanecarboxaldehyde. A second key reaction in the synthetic route is the alkylation-epoxidation sequence (112 → 77), which introduces the C2 alkyl substituent and the C3 oxygenation (salinosporamide A numbering). In addition, two radical-mediated side-reactions were discovered, both of which lead to functionalization of the cyclohexane ring of dihydrosalinosporamide A. These reactions likely arose as a consequence of the compact structure of the substrate and inspired the use of the Hofmann-Loffler-Freytag reaction as a method for introducing bromide into the cyclohexane ring of dihydrosalinosporamide A.;The route to dihydrosalinosporamide A described also enables the synthesis of analogs modified at C2 and C5, compounds that are not accessible through existing methods. Ten new analogs of salinosporamide A were synthesized and were evaluated for their ability to inhibit the proteasome. Notably, this work revealed that the chloropropyl analog 156 effectively inhibits the chymotryptic activity of the proteasome with an IC50 value of 50 nM.;Because this synthetic route is short and convergent, it should facilitate the preparation of other derivatives of salinosporamide A, and should provide access to these compounds in quantities sufficient for preclinical evaluation.*;*Please refer to dissertation for diagrams.