Salinosporamide synthesis

Salinosporamide synthesis 196 Sharpless asymmetric dihydroxylation (see also Osmylation) 84,89, 141, 189 Sharpless asymmetric epoxidation 32,141 Silane, allylic synthesis 43 Sonogashira coupling (see Pd)... 

NHC-catalysed homoenolate generation has been applied by Bode and Struble in the formal synthesis of the natural product salinosporamide A [77], The key step in the synthesis is a late-stage NHC-catalysed intramolecular lactonisation step of intermediate 186. When this reaction was attempted with an achiral triazolium-derived NHC, a 4 1 diastereomeric ratio of products was obtained in preference for the undesired product 189. In order to circumvent this, chiral triazolium salt 187 was employed, giving an approximately 1 1 mixture of desired undesired diastereoisomers (Scheme 12.41). 

Synthesis of the Proteasome Inhibitors Salinosporamide A, Omuralide and Lactacystin... 

The structurally-related 7-lactams salinosporamide A 1, omuralide 2 and lactacystin 3, of bacterial origin, inhibit proteasome activity, and so are of interest as lead compounds for the development of anticancer agents. Barbara . M. Potts of Nereus Pharmaceuticals in San Diego has reported (J. Med. Chem. 2005,48,3684) a detailed structure-activity studies in this series, and E.J. Corey of Harvard University has prepared (J. Am. Chem. Soc. 2005,127, 8974, 15386) several interesting structural analogues. Susumi Hatakeyama of Nagasaki University, building on previous work in this area, has reported (J. Org. Chem. 2004, 69,7765) a synthesis of 2 and 3 from Tris. 

Shibasaki M, Kanai M, Fukuda N (2007) Total Synthesis of Lactacystin and Salinosporamide A. Chem Asian J 2 20... 

Mulholland NP, Pattenden G, Walters IAS (2008) A Concise and Straightforward Total Synthesis of ( )-Salinosporamide A, Based on a Biosynthesis Model. Org Biomol Chem 6 2782... 

A new stereocontrolled synthetic route to the potent proteasome inhibitor omuralide 46 has been developed from methyl pyroglutamate <07JOC10108>. The development of a new convertible isocyanide, indole-isocyanide, for ready access to pyroglutamic acids has culminated in the formal total synthesis of omuralide featuring a stereocontrolled Ugi reaction <07OL3631>. A novel enantioselective total synthesis of 20S proteasome inhibitor salinosporamide A 47 included, as a key feature, an intramolecular aldol cyclization <07OL2289>. A concise total synthesis of ( )-salinosporamide A, ( )-cinnabaramide A, and derivatives via a bis-cyclization process has been documented <07OL2143>. The... 

Reddy LR, Fournier J-F, Reddy BVS, Corey EJ. New synthetic route for the enantioselective total synthesis of salinosporamide A and biologically active analogues. Org. Lett. 2005 7 2699-2701. Mauger AM, Lackner H. The actinomycins. In Anticancer Agents from Natural Products. Cragg GM, Kingston DGI, Newman DJ, eds. 2005. Taylor and Francis, Boca Raton, FL. pp. 281-297. Kawamata J, Imanishi M. Interactions of actinomycin with deoxyribonucleic acid. Nature 1960 187 1112-1113. 

In the simple stereoselective total synthesis of salinosporamide A, E.J. Corey and co-workers applied the intramoiecuiar Bayiis-Hiiiman reaction to a ketoamide substrate." The reaction was catalyzed by quinuclidine and the y-lactam product was formed as a 9 1 mixture of diastereomers favoring the desired stereoisomer. 

Aldol reaction. Cyclization of a keto ester effected by t-BuOK in reasonably good yield and stereoselectivity constitutes a key step toward completion of a synthesis of (-)-salinosporamide-A. ... 

Total synthesis of lactacystin and salinosporamide, natural proteasome inhibitors 07CAJ20. 

Total synthesis of the potential anticancer drug salinosporamide A (56) represents an example where a proline-catalyzed aldol reaction between an achiral ketone donor and an a-chiral aldehyde was carried out with high selectivity. 

Scheme 14 Proline-catalyzed aldol reaction in the synthesis of salinosporamide A (56)...

Struble JR, Bode JW (2009) Eormal Synthesis of Salinosporamide A via NHC-Catalyzed Intramolecular Lactonization. Tetrahedron 65 4957... 

Scheme 6.2) [17]. Herein, acid 24 reacts with a novel isocyanide 26, which was introdnced by two different groups independently [18], and benzylamine 25 to stereoselectively yield only the cw-diastereoisomer 27. The anilide can be easily hydrolyzed to give a free pyroglutamic acid. This strategy can be used in the synthesis of molecnles bearing a pyroglutamic acid residue like as omuralide 28 or salinosporamide A. 

Such a synthetic approach was employed by Corey et al. [58] for the synthesis of optically active a-methylene-y-lactam 101 (Scheme 4.27). The starting acrylamide 100 was prepared in six steps from the cheap and readily available N-4-methoxybenzoyl r-threonine methyl ester. The quinuclidine-catalyzed intramolecular asymmetric Morita-Baylis-Hillman reaction of 100 was followed by the conversion of the introduced alcohol moiety into a bromomethyldimethylsilyl ether 101. The a-methylene-y-lactam 101 with two adjacent quaternary stereogenic centers was formed in high yield as a mixture of two diastereoisomers in 9 1 dr. Interestingly, it was a key intermediate in the total synthesis of natural product salinosporamide A (102) that was accomplished in eight steps. 

In another intramolecular MBH report, Corey and coworkers synthesized a key intermediate in their synthesis of salinosporamide A (117). The transformation was accomplished by treating the a,P-... 

Proteasome inhibitors receive widespread attention as promising treatment options in cancer chemotherapy. One of the most promising drug candidates of this class is saUnosporamide A (53), isolated from the marine bacterium Salinispora tropica (Fig. 15.3) [54], The densely functionalized y-lactam-p-lactone pharmacophore is responsible for its irreversible binding to the p subunit of the 20S proteasome [55]. Moore et al. reported a biosynthetic synthesis of antipro-tealide (52) and were furthermore able to generate other nonnatural salinosporamide derivatives 54 with C-5 modifications... 

Potts, B.C. and Lam, K.S. (2010) Generating a generation of proteasome inhibitors from microbial fermentation to total synthesis of salinosporamide A (Marizomib) and other salinosporamides. Mar. Drugs, 8, 835-880. 

---