1,5-Asymmetric Induction in Methyl Ketone Aldol Addition Reactions

Abstract

In the addition of enol derivatives to â-alkoxy aldehydes, the influence of the â-heteroatom substituent may be regulated by the nature of the aldol process selected (eq 1). For example, good levels of 1,3-anti induction may be realized in the Lewis acid-promoted addition with enol silanes. In contrast, this same substituent possesses no control over the analogous enol borinate nucleophilic additions.2 We have speculated that the principal bias exerted by the â-alkoxy substituent is electrostatic in nature. Given the importance of these remote effects on the π-facial selectivity of aldehyde electrophiles, we have now probed the analogous polar effect of a â-heteroatom substituent on the enolate facial bias in these acetate aldol processes (eq 2).3,4 In this paper, methyl ketone enolates that undergo highly 1,5-diastereoselective aldol addition are identified, and the integration of this control element into double-stereodifferentiating aldol reactions is presented. This study was initiated with an examination of the aldol reactions of unsubstituted ketone enolates 1 (M ) TMS, Li, BR2) that contain a â-alkoxy substituent (Table 1). To isolate the contribution of electrostatic effects to the diastereoselectivity of these addition processes, enolates 1 were selected bearing â-substituents of similar steric size (-OCH2Ar vs -CH2CH2Ar) but different electronic properties. Unlike our previous study on 1,3induction (eq 1),2 the dialkylboron enolates5 displayed good levels of asymmetric induction with dihydrocinnamaldehyde, consistently favoring the 1,5-anti diol product 2 (Table 1, entries 1-5). Due to the similar steric requirements of the â-substituents, electrostatic effects might be at least partially responsible for enolate face selectivity. The enolate facial bias may be further enhanced by a decrease in reaction temperatures (Table 1, entry 5). In contrast to our previous study on 1,3induction (eq 1),2 the Lewis acid-mediated aldol reaction in this system demonstrated no asymmetric induction (Table 1, entry 6).6 Similarly, the aldol reactions of metal enolates capable of internal chelation with the â-heteroatom were also nonselective (Table 1, entry 7).7 (1) For general approaches to the synthesis of 1,3-diol relationships in conjunction with C-C bond formation see: (a) Rychnovsky, S. D.; Hoye, R. C. J. Am. Chem. Soc. 1994, 116, 1753-1765. (b) Mora, Y.; Asai, M.; Okumura, A.; Furukawa, H. Tetrahedron 1995, 51, 52995314. (c) Knochel, P.; Brieden, W.; Rozema, M. J.; Eisenberg, C. Tetrahedron Lett. 1993, 34, 5881-5884. (2) (a) Evans, D. A.; Duffy, J. L.; Dart, M. J. Tetrahedron Lett. 1994, 35, 8537-8540. (b) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem. Soc., 1996, 118, 4322-4343. (3) (a) Blanchette, M. A.; Malamas, M. S.; Nantz, M. H.; Roberts, J. C.; Somfai, P.; Whritenour, D. C.; Masamune, S. J. Org. Chem. 1989, 54, 2817-2825. (b) Seebach, D.; Misslitz, U.; Uhlmann, P. Angew. Chem., Int. Ed. Engl. 1989, 28, 472-473. (4) For 1,4-induction in acetate aldol reactions see: (a) Zibuck, R.; Liverton, N. J.; Smith, A. B. J. Am. Chem. Soc. 1986, 108, 2451-2453. (b) Braun, M. Angew. Chem., Int. Ed. Engl. 1987, 26, 24-37. (c) Paterson, I.; Goodman, J. M.; Isaka, M. Tetrahedreon Lett. 1989, 30, 7121-7124. (d) Trost, B. M.; Urabe, H. J. Org. Chem. 1990, 55, 39823983. (e) Roush, W. R.; Bannister, T. D. Tetrahedron Lett. 1992, 33, 3587-3590. (f) Lagu, B. R.; Liotta, D. C. Tetrahedron Lett. 1994, 35, 4485-4488. (5) Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am. Chem. Soc. 1981, 103, 3099-3111. The regiochemistry (CH3 vs CH2) of the enolization process with Bu2BOTf and Chx2BCl with these methyl ketone substrates is high (>95:5). In certain cases, 9-BBNOTf is nonselective in this enolization process. Table 1. 1,5-Induction with Various Metal Enolates