ASYMMETRIC-SYNTHESIS AND CRAMS (CHELATE) RULE

The asymmetric synthesis based on a chiral 1,3-oxathiane developed some years ago (ref. 1,4) has been applied (ref. 6) to an efficient synthesis of the sex attractant pheromone of the bark beetle hyelocoetus dermestoides L., (R)-2,3-dihydro-2,5-dimethyl-2-isopropylfuran (Scheme 1). This work raised the question as to whether the intermediacy of chelates in Cram's "chelate rule" (ref. 15) is real. This question was answered (ref. 23) in the affirmative by kinetic and stereochemical studies of the reaction C2H5COCH(R)CH3 + (CH3)2Mg. The rate of this bimolecular reaction was measured by rapid injection nmr (ref. 24) and it was found for a variety of R's [OSi(iPr)3, OSi(C6H5)2t-Bu, OSiMe2t-Bu, OSiEt3, OSiMe3, OCH3] that stereoselectivity parallels rate qualitatively and quantitatively, with the non-chelating (ref. 17) OSi(iPr)3 derivative reacting slowest (and at the same rate as propiophenone, R = H) and the chelating OCH3 compound reacting ca. 2000 times faster. The results are interpreted in terms of a competition between a non-chelating and a highly organized chelating transition state, with the R = OCH3 compound - which chelates extensively - reacting fastest and with over 99% stereoselectivity giving the Cram product.