Highly stereoselective allylic ethylation with alkoxytitanacyclopropane reagents. Synthesis of (1R/S,7R)-1,7-dimethylnonyl propanoate, the Western corn rootworm sex attractant Vladimir E. Isakov, Oleg G. Kulinkovich * Department of Organic Chemistry, Belarusian State University, Nezavisimosti Av. 4, Minsk 220030, Belarus article info Article history: Received 9 July 2008 Revised 11 August 2008 Accepted 19 August 2008 Available online 23 August 2008 Keywords: Alkoxytitanacyclopropane reagents Allylic ethers Allylic ethylation Diastereoselectivity Pheromones abstract Allylic ethylation of 2-((E)-dodec-2-en-4-yloxy)tetrahydro-2H-pyran with ethylmagnesium bromide in the presence of titanium(IV) isopropoxide proceeds via a S N 2 0 pathway to afford (E)-3-methyltridec-4- ene with excellent syn-diastereoselecivity. This transformation is used as a key step in the synthesis of (1R/S,7R)-1,7-dimethylnonyl propanoate, the Western corn rootworm (Diabrotica virgifera virgifera) sex attractant. Ó 2008 Published by Elsevier Ltd. The development of efficient methods for the preparation of chiral allylic alcohols 1 and their derivatives 2 increases the syn- thetic importance of stereoselective carbon–carbon bond forming reactions. Highly anti-S N 2 0 stereoselective alkylations of allylic esters have been observed in copper-catalyzed 2k–o and hetero- atom-assisted noncatalyzed reactions of organomagnesium com- pounds. 3 In contrast, the use of o-diphenylphosphanylbenzoate as a reagent-directing leaving group permits reactions of the corresponding allylic esters with organomagnesium compounds in a highly syn-S N 2 0 stereoselective fashion. 2p–s Herein, we disclose the ability of a tetrahydropyranyloxy group to play the same directing role toward alkoxytitanacyclopropane reagents. As an application of this method of regio- and diastereoselective ethylation of THP-protected allylic alcohols, we have synthesized (1R/S,7R)-1,7-dimethylnonyl propanoate 3, the Western corn root- worm sex attractant. 4 Recently, we reported that interaction of racemic allylic alco- hols and their ethers with alkoxytitanacyclopropane reagents, gen- erated in situ by treatment of titanium(IV) alkoxides 5,6 with ethylmagnesium bromide, afforded the products of S N 2 0 substitu- tion of hydroxy or alkoxy groups with an ethyl group. 7 For exam- ple, allylic alcohol 1a and its derivatives 1b,c were converted under these conditions into methyl-branched alkenes 2. The suggested mechanism of the reaction includes coordination of the substrate 1 with alkoxytitanacyclopropane species A, followed by transformation of the resulting complex B to titanacyclopentane ate-complex C, intramolecular 1,2-elimination of a metal oxide fragment, and disproportionation of dialkyltitanium intermediate D (Scheme 1). 7a Among the compounds 1a–c, only tetrahydro- pyranyl derivative 1c gave alkene 2 with high trans- diastereoselectivity. Herein, we report the trans-diastereoselectivity of the allylic ethylation of tetrahydropyranyl derivative 1c combined with high 1,3-asymmetric induction during the formation of a stereogenic center in a syn-S N 2 0 stereoselective fashion. Thus, treatment of a 0.4 M solution of allylic alcohol (2E,4R)-1a (ee 88%) 8 and tita- nium(IV) isopropoxide in ether with a 1.2 M solution of ethylmag- nesium bromide gave alkene (3R,4E)-2 with a de of 15% and an ee of 14%, whereas its THP analogue (2E,4R)-1c (a mixture of diaste- reomers) afforded the same product with much better stereoselec- tivity (de 90%, ee 69%). The concentration of the reagent solutions influenced the stereoselective formation of the stereogenic center significantly. Thus, the use of fourfold diluted solutions of tetrahy- dropyranyl derivative 1c, titanium(IV) isopropoxide, and ethyl- magnesium bromide led to the formation of alkene (3R,4E)-2 with de 90% and ee 87%, 9 corresponding to 99% syn-S N 2 0 chirality transfer (Scheme 2). The enantiomeric purity and absolute config- uration of the mixture of alkenes 2 obtained were ascertained by ozonolysis, followed by reduction with sodium borohydride and analysis of the 1 H NMR spectrum of the (+)-MTPA ester of the resulting 2-methylbutanol (Scheme 2). 10,11 0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd. doi:10.1016/j.tetlet.2008.08.063 * Corresponding author. Tel.: +375 17 2095459; fax: +375 17 2265609. E-mail address: kulinkovich@bsu.by (O. G. Kulinkovich). Tetrahedron Letters 49 (2008) 6959–6961 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet