Total Synthesis of Aculenes B and D

• Published in: European journal of organic chemistry Vol. 26; no. 6
• Main Authors: Yokokawa, Hinata, Ishizawa, Seiya, Saito, Katsuya, Meguro, Yasuhiro, Kuwahara, Shigefumi, Enomoto, Masaru
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 06.02.2023; Wiley Subscription Services, Inc
• Subjects: aculene; Aldehydes; Barbier reaction; Carboxylic acids; Chemistry; Chemistry, Organic; Esterification; Metathesis; Natural products; nordaucane; Physical Sciences; ring-closing metathesis; Science & Technology; Stereoselectivity; Synthesis; synthetic methods; CONCISE; METABOLITES; ACID; ENANTIOSPECIFIC SYNTHESIS; CAMPHOR; EFFICIENT SYNTHESIS; nordaucane; aculene; Barbier reaction; ring-closing metathesis; KETONES; DEHYDROGENATION; synthetic methods; CONJUGATE ADDITION
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.202201482

The first total synthesis of aculene D, a structurally rare nordaucane‐type natural product exhibiting quorum sensing inhibitory activity, has been accomplished from a known five‐membered hydroxy carboxylic acid. Nucleophilic addition of methallylzinc bromide to a β‐keto aldehyde intermediate under Barbier conditions to install the secondary hydroxy group on the seven‐membered ring of aculene D gave the corresponding alcohol with an undesired configuration predominantly. On the other hand, the protection of its keto group as the ethylene acetal induced a reversal of diastereoselectivity, affording a desired diastereomer in a selective manner. The construction of the seven‐membered ring was realized by ring‐closing metathesis using a triethylsilyl‐protected monocyclic diene ester precursor. An additional five‐step manipulation on the cyclization product including the installation of an ethyl group on the five‐membered ring completed the synthesis of aculene D, whose esterification with an N‐protected l‐proline followed by deprotection also achieved the first total synthesis of aculene B. The first synthesis of aculenes B and D was accomplished in 14 and 16 steps, respectively, from a known hydroxy carboxylic acid by employing a diastereoselective Barbier reaction as the key step. Reversal of the stereoselectivity was observed between the Barbier reaction of a β‐keto‐aldehyde intermediate and that of its acetal‐protected congener.