Synthesis of (+)-disparlure from diethyl (−)-malate via opening and fragmentation of the three-membered ring in tertiary cyclopropanols

Abstract

+)-Disparlure [(7R,8S)-7,8-epoxy-2-methyloctadecane, pheromone of the gypsy moth Lymantria dispar L.] was synthesized starting from diethyl (-)-malate via cyclopropanation of the ester groups, selective protection of the 1,3-diol functionality, and successive opening and fragmentation of the three-membered rings in the corresponding tertiary cyclopropanols as key stages.THP is tetrahydropyran-2-yl. Cyclopropanols and their derivatives undergo opening of the three-membered ring with formation of aldehydes, ketones, carboxylic acids, allyl halides, and some other compounds [1]. These transformations often occur under mild conditions and with high selectivity, so that substituted cyclopropanols attract considerable interest as intermediate products in organic synthesis. A convenient synthetic approach to cyclopropanols having chiral substituents is based on titanium(IV) alkoxide-catalyzed reactions of natural hydroxy-and aminocarboxylic acid esters with alkylmagnesium halides [2,3]. The key step in the stereoselective syntheses of branched carbon skeletons of pheromones of the pine sawfly (Diprion pini L.) [4], alkaloid Heliotridane [5], and C 13 -C 21 fragments of Epothilones [6] was cleavage of the three-membered carbon ring in chiral cyclopropanols.In the present work we used the cyclopropanol strategy to synthesize (+)-disparlure [I, (7R,8S)-7,8-epoxy-2-methyloctadecane] which is sex attractant of the gypsy moth Lymantria dispar L., The stereogenic structural fragment in molecule I is oxirane ring [7,8].The key intermediate was THP-protected bis-cyclopropanol II; it was synthesized by titanium(IV) isopropoxide-catalyzed reaction of ethylmagnesium bromide with O-tetrahydropyranyl derivative of diethyl (S)-malate (III) [6], and the necessary carbon chain was built up via alkylation of products of successive oxidative cleavage and fragmentation of the threemembered rings (Scheme 1; for other synthetic approaches to (+)-disparlure (I) based on natural hydroxy carboxylic acids, see [9]).Differentiation of the cyclopropanol fragments in molecule II is readily attained via its selective transformation into 1,3-dioxane derivative IV [6] as shown in Scheme 2. Treatment of acetonide IV with sodium hypobromite in water-diethyl ether gave vinyl ketone V whose concentration in the products was more than 90% (according to the 1 H NMR data). The use of other brominating agents, such as Br 2 -MeOH, N-bromosuc-

Selective Carbon–Carbon Bond Cleavage of Cyclopropanols

“…Zhao and Loh found success in generating unsymmetrical 1,6-dicarbonyl compounds using catalytic amounts of Mn-(acac) 2 (Scheme 88). 202 This reaction is broad in scope with respect to both the cyclopropyl alcohol (385) as well as the enone (384), allowing for the synthesis of a diverse range of 1,6-dicarbonyl-containing compounds (388). Notably, no external hydrogen atom donor is required, as the initial oxidation of the cyclopropyl alcohol is proposed to go through proton-coupled electron transfer (PCET), upon which the proton from the alcohol transfers onto the acetylacetonate.…”

“…In this general strategy, treatment of a cyclopropyl alcohol ( 892 ) with PhI­(OAc) 2 in the presence of either an alcoholic solvent or water will generate the relevant carboxylic acid derivative ( 893 ) (Scheme a), with ethylene lost as the side product. Some select examples of this strategy (Scheme b) include the synthesis of the following esters: 894 , an intermediate for the synthesis of (+)-disparlure reported by Kulinkovich and co-workers; 895 , an intermediate for the synthesis of insect pheromones reported by Kananovich and co-workers; and 896 , an intermediate in the formal synthesis of arenamides A and C reported by Shklyaruck . The formations of carboxylic acid 897 , an intermediate for the synthesis of epothilone D, , and carboxylic acid 898 , an intermediate for the synthesis of capsaicin, have been reported by Kulinkovich and co-workers .…”

The Kulinkovich hydroxycyclopropanation reaction in natural product synthesis

“…In 2009, Kulinkovich et al 60 also used the previously developed bis-cyclopropanol strategy in the synthesis of (+)-disparlure 107, a sex attractant of the gypsy moth Lymantria dispar L. (Scheme 25). The synthesis also started from THP-protected (S)-diethyl malate 99 which was transformed into isopropylidene acetal 101.…”

Generation of Mixed Anhydrides via Oxidative Fragmentation of Tertiary Cyclopropanols with Phenyliodine(III) Dicarboxylates

“…For example, Kirihara and co-workers utilized oxidative fragmentation as the key step in the short synthesis of an alkaloid (−)-pinidine [ 28 , 29 ], while our group reported synthesis of natural macrolactone (+)-recifeiolide via the ring opening-macrolactonization cascade in an aprotic solvent [ 30 ]. On the other hand, cyclopropanol moiety can be considered as a convenient “protecting group” for carboxylate functionality, readily installed by Kulinkovich reaction with ethylmagnesium bromide [ 31 , 32 , 33 , 34 , 35 , 36 ]. The “deprotection” is performed by oxidative cleavage with PIDA and produces ethylene gas as the side product.…”