The enantioselective synthesis of (R)-(+)-6-isopropenyl-3-methyl-2-cycloheptenone

Abstract

final, um quiron para a síntese de produtos naturais sesquiterpênicos do tipo guaiano, foi obtido em cinco etapas com 38% de rendimento global. (R)-(+)-6-isopropenyl-3-methyl-2-cycloheptenone is synthesized from (R)-(-)-carvone byreduction and trialkylsilyl-enolether formation, cyclopropanation with methylene iodide and diethylzinc, followed by a Saegusa type oxidation with ferric chloride and finally dehydrochlorination with base. The title compound is obtained in five steps and 38% overall yield, being a useful chiron for guaiane sesquiterpene natural products.Keywords: cycloheptenone, carvone, ring expansion, perhydroazulene, enantioselectivity IntroductionThe total synthesis of guaiane sesquiterpenes 1 is of current interest due to innumerous examples of these natural products with relevant biological activities, and the challenge of the perhydroazulene carbon skeleton containing two methyl and an isopropyl groups. Our interest in their synthesis has led us to develop methods for the transformation of para-menthane monoterpenes into single isomer cycloheptenones, 2-4 and then by pent-annelation 5,6 into the required complete carbon skeleton. Scheme 1 outlines our synthetic strategy which involves two quite different routes for the ring expansion, by cyclopropanation and central sigma bond cleavage 2,3 or nucleophilic addition and rearrangement. 4 The intermediate cycloheptenone can then by pent-annelated by more classical ionic reactions (allylation, Wacker oxidation and intramolecular aldol reaction) 5 or by the ring closing metathesis 6 of a suitable neighboring allyl-vinyl derivative.Thus far we have developed several distinct methodologies for the ring expansion of different para-menthane monoterpenes, and in this paper we would like to describe a new route which transforms readily available (R)-(-)-carvone (1) into the desired (R)-(+)-6-isopropenyl-3-methyl-2-cycloheptenone (2) in five steps and 38% overall yield (Scheme 2), with complete regioselectivity and retention of stereochemical integrity. Results and DiscussionThe enantiodivergent strategy we have developed 3 requires a double bond in the para-menthane structure at the C-1 to C-2 centers for the (R)-cycloheptenone enantiomer or the C-1 to C-6 centers for the (S)-enantiomer (Scheme 3). 793The Enantioselective Synthesis of (R)-(+)-6-Isopropenyl-3-Methyl-2-Cycloheptenone Vol. 17, No. 4, 2006 Herein we describe an enantio-and regioselective route to the (R)-enantiomer of 2 by regioselective formation of the trialkylsilyl-enolether 4 of dihydrocarvone (3) followed by chemoselective cyclopropanation and oxidative cleavage of the common sigma bond. Elimination of HCl with base completes the synthesis of 2 (Scheme 4).A similar strategy was used by Marques et al. 7 in the synthesis of the sesquiterpene africanol, for the ring expansion of 2,5,5-trimethyl-cyclohexanone.The reduction of the conjugated double bond of (R)-(-)-carvone (1) can be readily effected with zinc dust in alkaline methanol/water as we have developed 3 in our laboratory, as a sim...

A Review on the Chemistry of Eremanthine: A Sesquiterpene Lactone with Relevant Biological Activity

“…Finally in strategy D, used to the synthesis of dehydrocostus lactone (10) [136], the construction of the hydroazulene skeleton was planned starting from a cycloheptane derivative (59) on which the cyclopentane ring was inserted. The most recent literature on the synthesis of sesquiterpenoids reports the preparation of a chiron derived from cycloheptenone as a building block to the synthesis of guaiane sesquiterpene natural products [137] as well as the synthetic approaches to bicyclo[5.3.0]decane sesquiterpenes [138].…”

Unequivocal structural assignments of three cycloheptenoid intermediates for guaiane sesquiterpenes: an experimental and theoretical approach

“…This has provoked studies on the synthesis of suitable seven‐membered ring intermediates, frequently by expansion of readily available cyclohexane starting materials . Our approach is to utilise para ‐menthane monoterpenes, because of their availability, price, enantiomeric purity and occurrence in both series, and diverse functionality …”