Total synthesis of (-)-hennoxazole A.
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.
Department of Chemistry, Williams College, Williamstown, Massachusetts 01267, USA. tsmith@williams.edu
Thomas E
TE
Smith
Wen-Hsin
WH
Kuo
Emily P
EP
Balskus
Victoria D
VD
Bock
Jennifer L
JL
Roizen
Ashleigh B
AB
Theberge
Kathleen A
KA
Carroll
Tomoki
T
Kurihara
Jeffrey D
JD
Wessler
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry; D008968:Molecular Conformation; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
D000998:Antiviral Agents; D010080:Oxazoles; C108742:hennoxazole A