Synthetic studies on sphingofungin E, (-)-Dysiherbaine and manzacidin C

Abstract

Synthesis of lipid tail part of sphingofungin E 1 was readily synthesized from commercially available starting materials, 1-heptanoyl chloride and 8-bromo-1-octene, which provided the intermediate for the ensuing coupling reaction. Synthesis of polar head was started protection reaction with commercially available starting material, TRIZMA-hydrochloride. tert-Alkylamine stereocenter at C2 was achieved by enantioselective deymmetrization. The requisite C3 and C4 stereocenters, Evans aldol reaction, intramolecular aldol reaction and ring-closing metathesis were attempted unsuccessfully. Dihydroxylation of conjugated ester 107 furnished diol with 6.2 to 1 diastereomeric ratio. For the coupling reaction of polar head and lipid tail, HWE olefination and vinylation was tried unsuccessfully. Lithiated acetylene was reacted with conjugated aldehyde 143 to render allylic alcohol 145. The key intermediate 145 was successfully synthesized with high yield in all key steps.Synthesis of dysiherbaine 2 was tried through several pathways. In the beginning, electrophile-promoted cyclization of 214 was intended. All trials were unsuccessful. In the second approach. We introduced the amino group by Mitsunobu reaction. Subsequently, N-Boc-protected aziridine was formed. Various metal halides were used to open the aziridine 220. The aziridine opening lacked regioselectivity. Also, epoxide opening reaction was tried to form oxazetidine 227, and iodocyclizaiton was attempted to introduce oxazolidinone to no avail. The key intermediate oxazolidinone 244 was synthesized from diol 230 in 7 steps smoothly. The following acidic hydrolysis, enantioselective desymmetrization, oxidation and cyclization afforded oxazolidione 237. A formal total synthesis of (-)-dysihebaine was completed. Synthesis of manzacidin C was tried through two pathways. Its tert-Alkylamine stereocenter at C9 was achieved by enantioselective deymmetrization. In the beginning, Strecker reaction of 290 was intended to r...