A Concise Synthesis of rac‐Ambrox® via the Palladium(0)‐Catalyzed Carboalkoxylation of an Allylic Ammonium Salt, as Compared to a Formaldehyde Hetero Diels–Alder Approach

• Published in: Helvetica chimica acta Vol. 102; no. 7
• Main Authors: Chapuis, Christian, Skuy, David, Richard, Claude‐Alain
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 01.07.2019; Wiley Subscription Services, Inc
• Subjects: Acetic acid; allylic compounds; Ambrox; Ammonium; Ammonium salts; carbomethoxylation; Chemistry; Chemistry, Multidisciplinary; Enantiomers; Farnesene; Organic chemistry; Palladium; Physical Sciences; Science & Technology; PALLADIUM-CATALYZED ALKOXYCARBONYLATION; ammonium; Palladium; DELTA-PYRONENE; carbomethoxylation; MEDIATED POLYENE CYCLIZATIONS; BETA-IONONE; Ambrox (R); C AROMATIC DITERPENE; ABSOLUTE-CONFIGURATION; allylic compounds; 1ST TOTAL-SYNTHESIS; (+)-13-METHYL-7-OXOPODOCARPA-8,11,13-TRIENE-12-CARBOXYLIC ACID; HIGHLY EFFICIENT SYNTHESIS; INTERNAL NUCLEOPHILIC TERMINATION
• ISSN: 0018-019X; 1522-2675
• DOI: 10.1002/hlca.201900097

Acidic cyclization of either the diethylallylamines 29b or 30, followed by a 1.5 mol‐% Pd‐catalyzed carbomethoxylation of quaternized 31b, leads to the methyl ester 36a. This latter could also be obtained in optically pure form by carbomethoxylation of the corresponding (+)‐acetate. Final reduction‐cyclization may be conducted as earlier described, towards the desired odoriferous rac‐Ambrox® 38a, or its pure (−)‐enantiomer. Generation of a π‐allyl Pd complex from an allylic ammonium salt, followed by carboalkoxylation is novel. In only five chemical steps starting from farnesene 2, the present work constitutes the most concise total synthesis of rac‐Ambrox® 38a to date.