Total Synthesis of (−)-Hennoxazole A

Abstract

An enantioselective, convergent total synthesis of the antiviral marine natural product (-)-hennoxazole A is completed in 14 steps (longest linear sequence) from commercially available 4-methyloxazole-2-carboxylic acid. Synthesis of the C(1)-C(15) pyran/bisoxazole fragment takes advantage of an aldol-like coupling between a dimethyl acetal and an N-acetylthiazolidinethione for the direct, stereoselective installation of the C(8)-methoxy-bearing stereocenter. A one-pot acetoacetate acylation/decarboxylation/cyclodehydration of another elaborate thiazolidinethione allows for rapid assembly of the pyran-based ring system. Synthesis of the C(15)-C(25) skipped triene side chain fragment makes use of a [2,3]-Wittig-Still rearrangement for efficient installation of the trisubstituted Z-double bond. Key late-stage coupling of the two fragments is effected by deprotonation of the methyl group on the bisoxazole system using lithium diethylamide, followed by alkylation with an allylic bromide side chain segment to form the C(15)-C(16) bond.

Chromatography with silver nitrate: part 2

“…Critical to the successful synthetic approach put forward by the group led by Thomas Smith 75 was the eventual side chain diastereomeric and enantiomeric purity. To initiate the sequence Smith converted the acetylenic alcohol 136 into precursor 137.…”

Thiazole and Oxazole Alkaloids: Isolation and Synthesis

“…Elaboration of a thiazolidinethione allowed for rapid assembly of the pyran-based ring system. Key late-stage coupling was effected by deprotonation of the bisoxazole methyl group, followed by alkylation with an allylic bromide side chain segment [68,69]. …”

Applications of Aza‐ and Phosphaferrocenes and Related Compounds in Asymmetric Catalysis

“…(9)) [27]. Similarly, Smith obtained a selectivity factor of 10 in a resolution of an allylic alcohol intermediate in his synthesis of (À)-hennoxazole A, although the reaction was too slow to be practical [28,29]. A second O-acylation process to which azaferrocenes and related compounds have been applied is the addition of alcohols to ketenes.…”

“…Enantiopure oxygen nucleophiles had been reported to catalyze the desymmetrization of meso epoxides through ring opening with SiCl 4 (up to 87% ee) [42], so a series of planar-chiral pyridine N-oxides (e.g., [27][28][29] were examined as potential catalysts for this transformation (Eq. (19)) [43].…”