The Total Synthesis of Inostamycin A

Abstract

The first total synthesis of inostamycin Ai s described. With efficient and stereoselective synthetic routes to aldehyde 3 and ketone 4 developed through asymmetric aldol reactions,a ddition reactions and reduction, and with chiral building blocks,t he two large fragments were coupled with remarkable anti stereoselectivity and efficiency by aldol condensation. The coupling reaction provided the complete carbon skeleton with all the requisite functional groups and stereogenic centers for inostamycin A. The two quaternary carbons at C20 and C16 of ketone 4 were elaborated in ahighly stereocontrolled manner by addition reactions of the transmetallated 5 to ethyl ketone 6 and the transmetallated 7 to methyl ketone 8,r espectively,i nw hicht he use of LaCl 3 for transmetallation was critical for high coupling efficiency.Inostamycin Awas isolated from the fermentation broth of Streptomyces sp.M H816-AF15 in 1990.[1] Its structure was first assigned by NMR spectroscopy and later confirmed by X-ray analysis of its sodium salt to manifest the relative stereochemistry.T he crystal structure of the sodium salt showed an ionophoric pseudo cyclic molecular shape,i n which the sodium cation coordinates to the two carboxylate oxygens,t he two hydroxyl oxygens at C9 and C17, the carbonyl oxygen, and the inner tetrahydrofuranyl oxygen.[1]Scrutiny of the reported crystal structure allowed us to identify am istakenly translated stereochemistry of the ethyl group at the C2 position. Accordingly,t he relative stereochemistry of inostamycin As hould be revised from 1 to 2 (Figure 1). Ther elated compounds,i nostamycins Ba nd C, were separated from the same microorganism af ew years later, and the structures were differentiated by aC 2m ethyl substituent and am issing carboxylic acid group,r espectively.[2] It is likely that the C2 stereochemistry of inostamycin Bs hould also be corrected. Inostamycins are known to display antimicrobial and cytocidal activities,w ith inostamycin As howing the highest potency.[2] Only inostamycin A exhibits inhibitory activity against cytidine-5'-d iphosphate 1,2-diacyl-sn-glycerol (CDP-DG):inositol transferase to reduce phosphatidylinositol turnover, and restrain cell proliferation and transformation.[3a] Other prospective physiological properties of inostamycin Ai nclude restoration of paclitaxel cytotoxicity to augment apoptosis, [5] and cytostatic suppression of tumor recurrence.[3b] Thes tructural complexity,anticancer agents from multidrug resistance, [4] and potentiation of and pharmacological potential of inostamycin A attracted us to attempt its synthesis.H erein, we describe the first total synthesis of inostamycin A 2.[6]Our retrosynthetic blueprint was framed by severing the C9 À C10 bond of 2 to engender the aldehyde part 3 and the ethyl ketone part 4 (Scheme 1). Forsynthesis of 3,weplanned to cleave the C2 À C3 and C5 À C6 bonds,w hich would be restored with the four stereogenic centers by aldol condensations.T he remaining asymmetric centers were to be supplied by two enantiome...