Synthesis of a Spirocyclic Seco Structure of the Principal Vetiver Odorant Khusimone

Abstract

Abstract The three‐dimensional structure of tricyclic compounds with a zero‐bridge to one bridgehead atom is determined by the underlying spirocyclic framework. (–)‐Khusimone ( 1 ), the principal odorant of vetiver oil (content up to 2 %), is such a tricyclic norsesquiterpene, and dissection of the 7,8‐bond between the methylene and the gem ‐dimethyl unit of 1 results in a spirocycle extending over an almost identical molecular volume and shape. Given that the “vetiver rule” postulates that one α‐branched carbonyl osmophore in a certain spatial distance to a bulky moiety is responsible for the odor of vetiver, a 7,8‐seco structure of 1 could prove or disprove these structural requirements. Therefore, (4 R *,5 R *)‐7‐isopropyl‐4‐vinylspiro[4.4]nonan‐1‐one [(4 R *,5 R *)‐ 2 ] was synthesized in a 10‐step synthetic sequence commencing with Steglich esterification of allyl alcohol ( 15 ) and isovaleric acid ( 14 ). Ireland–Claisen rearrangement of the formed allyl isovalerate ( 16 ) with subsequent lithium aluminum hydride reduction of resulting γ,δ‐unsaturated acid 18 , Appel bromination of corresponding alcohol 19 , and ozonolysis provided 4‐bromo‐3‐isopropylbutanal ( 23 ) in 19 % overall yield as a building block for the projected spiroannulation reactions. Although attempts on cyclopentanone ( 7 ) failed, cyclopent‐2‐en‐1‐one, via its TMS‐trapped lithium 3‐vinylcyclopent‐1‐enolate 12 , turned out to be a successful starting material. Evans' variant of the Mukaiyama aldol reaction with 1‐trimethylsiloxy‐3‐vinylcyclopent‐1‐ene ( 12 ) in the presence of BF 3 · OEt 2 , followed by palladium‐catalyzed conjugate tin hydride reduction of resulting enone 28 provided 2‐(4′‐bromo‐3′‐isopropylbutyl)‐3‐vinylcyclopentanone ( 29 ) in 50 % overall yield as the anlation precursor. LDA‐mediated 5‐ exo ‐ tet cyclization of 29 concluded the synthesis of the racemic 7,8‐seco‐/6‐epi‐7,8‐secokhusimone mixture (4 R *,5 R *)‐ 2 , which possessed a floral, rosy, green, geranium‐like odor with a threshold of 42.0 ng L –1 air, which is 10 times less intense than that of (–)‐khusimone ( 1 ). Most importantly, seco structure (4 R *,5 R *)‐ 2 did not display any woody nor any vetiver character, which proves the postulated vetiver rule wrong.