A Concise Synthesis ofrac‐Ambrox®viathe Palladium(0)‐Catalyzed Carboalkoxylation of an Allylic Ammonium Salt, as Compared to a Formaldehyde HeteroDiels–AlderApproach

Abstract

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.

Scalable Birch reduction with lithium and ethylenediamine in tetrahydrofuran

“…The Birch reduction dearomatizes arenes into 1,4-cyclohexadienes with lithium, sodium, or potassium in liquid ammonia at ≤−33°C (Fig. 1A) ( 2 , 3 ) and has been employed throughout the pharmaceutical industry ( 4 , 5 ), perfumery industry ( 6 , 7 ), and academia ( 8 – 11 ).…”

“…Previously, reductive ring openings of cyclic allylic ethers were performed at −78°C ( 6 ) or at ambient temperature for 48 hours ( 7 ). Here, our method reductively opened 2,5-dihydrofuran ( 39 ; Fig.…”

A Stoichiometric Haloform Coupling for Ester Synthesis with Secondary Alcohols

“…First reported in 1822 by G.-S. Serullas, the haloform reaction is one of the oldest known synthetic organic reactions. [1,2] The transformation of a methyl ketone to a carboxylic acid is conducted under such mild conditions that it has become routinely employed as a reliable method for preparing carboxylic acids in the synthesis of pharmaceutical agents, [3][4][5][6] natural products, [7][8][9][10][11][12][13][14][15][16] fragrances, [17,18] and, more recently, for biomass valorisation. [19] Exhaustive halogenation of the methyl ketone provides a sufficiently good leaving group that CÀ C bond cleavage is induced by subsequent attack from a hydroxide ion, Figure 1A.…”