An Efficient Enantioselective Synthesis of (+)‐(R,Z)‐5‐Muscenone and (−)‐(R)‐Muscone − An Example of a Kinetic Resolution and Enantioconvergent Transformation

Abstract

An efficient catalytic kinetic resolution by CBS reduction and an original enantioconvergent transformation involving a PdII‐catalyzed position‐selective cyclization are the key steps for the synthesis of the exceptional musk odorant (R,Z)‐5muscenone [(R)‐1] and (R)‐muscone [(R)‐3]. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

On the Unpredictability of Odor

“…[49] The odors of the musks (À)-1 and (+)-1 have the same character, but the threshold of (À)-1 is 0.43 ng L À1 whereas that of its enantiomer (+)-1 is over twenty times higher at 9.5 ng L À1 . [50] The odors of the enantiomers of dihydro-a-ionone, 64 and 65, differ in both character and threshold. [51] …”

Enantioselective Intramolecular Aldol Addition/Dehydration Reaction of a Macrocyclic Diketone: Synthesis of the Musk Odorants (R)‐Muscone and (R,Z)‐5‐Muscenone

“…Subsequently, (S)-4 was transformed into the musk odorants (R)-muscone (1) and (R,Z)-5-muscenone (2) in high yield (two steps, 70 %) [2] without any loss of enantiomeric excess.…”

“…The ee value was determined by reduction of (S)-4 to the corresponding alcohol (LiAlH 4 in dry THF) and injection onto a chiral GC column (CHIRASIL DEX CB). [2] Received: November 3, 2006 Published online: January 9,2007 . Keywords: aldol reaction · amino alcohols · asymmetric synthesis · dynamic kinetic resolution · elimination…”

“…[2] Musk (R)-2 has an extremely low threshold (0.027 ng L À1 ) and possesses a highly desired nitromusk character [(S)-2: 3 ngL À1 ]. Compound (R)-1 is appreciated for its strong animal musk character [(S)-1: weakly musky].…”

Efficient Synthesis of (−)‐(R)‐Muscone by Enantioselective Protonation

“…± In recent years, macrocyclic musks [1] [2] have gained renewed interest for their excellent odor qualities (warm, sensual, animal, natural), and for their better biodegradability as compared to benzenoid musks [2] [3]. It is well-known that (À)-(R)-muscone ((R)-1), the principal odorous constituent of the male musk deer, exhibits a much more pronounced musk character than the unnatural ()-(S)-muscone [4], and, similarly, we recently established that ( )-(R,Z)-5-muscenone ((R)-2) is an outstanding musk odorant, whereas its enantiomer is only weakly musky [4]. Recently measured threshold values (in the vapor phase; 35 panelists) [4] are: (R)-1 (98% ee), 4.3 ¥ 10 À4 mg/l air; (S)-1 (98% ee), 9.5 ¥ 10 À3 mg/l air; (R)-2 (98% ee), 2.7 ¥ 10 À5 mg/l air; (S)-2 (98% ee), 3.0 ¥ 10 À3 mg/l air.…”