A synthetic approach to determine the stereochemistry of diepomuricanin A

Abstract

The total synthesis of bis-epoxide acetogenin, diepomuricanin, has been investigated in order to determine the absolute stereochemistry within the bis-epoxide region. Two approaches (linear and tethered-metathesis) were attempted. In the linear approach, two routes were investigated. In the first one an intermediate aldehyde 248 was created in six steps in order to investigate the asymmetric ?-oxidation and diastereoselective additions of organometallic reagents. Model studies using octanal met with moderate success, and highlighted the sensitivity of the ?-oxidation products. The instability of the ?-oxidation products prevented a proper study of the additions of Grignard and organozinc reagents. In a second route, hydrolytic kinetic resolution of terminal epoxides was investigated in order to obtain optically enriched 1,2-diols suitable for elaboration to diepomuricanins. A revised, convergent approach to diepomuricanin A stereoisomers was developed based on a silicon-tethered metathesis of allylic alcohol fragments. Sharpless asymmetric kinetic resolution (SAKR) of allylic alcohols (±)-305 and (±)-306 was the key step towards the left hand fragments (19S,20S)-302, and (19R,20R)-302, and the right hand fragments (15S,16S)-303, and (15R,16R)-303. Combining them together via a tethered alkene metathesis, led to the key siloxytriene 308.

An investigation of the Alder-ene reactions of right hand fragment (15S,16S)-303 display the low selectivity of the less hindered and more electron-rich C27-C28 doble bond. Therefore, the route was modified to proceed by new right hand fragment epoxyalcohols (15S,16S)-354, and (15R,16R)-354, which allowed formation of butenolide 363 towards the synthesis of the diepomuricanin A stereoisomer (anti-5d).

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ORCID for Richard C.D. Brown: orcid.org/0000-0003-0156-7087

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