Pergamon Tetrahedron Letters 40 (1999) 2917-2918 TETRAHEDRON LETTERS Effect of the Leaving Group on the Alkylation Diastereoselectivity of the Sch611kopf Chiral Auxiliary Chunrong Ma, Xiaohui He, Xiaoxiang Liu, Shu Yu, Shuo Zhao, and James M. Cook* Department of Chemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53201 Received 26 January 1999; accepted 11 February 1999 OEt 1 Summary: Tosylates, diphenylphosphates and bromides were employed to study the effect of the leaving group on the alkylation diastereoselectivity of the SchOllkopf chiral auxiliary I at aliphatic, benzylic, propargylic and allylic electrophilic centers. The diastereoselectivity generally follows the pattern: diphenylphosphate > tosylate > bromide. In terms of both diastereoselectivity and yield, each leaving group possesses a different advantage. © 1999 Elsevier Science Ltd. All rights reserved. In the early 1980s Sch611kopf developed an excellent chiral auxiliary 1 to prepare a large variety of amino acids. 1 As shown in equation 1, the metalation and subsequent diastereoselective alkylation of the bis- lactim ether 1 provided dominant trans selectivity (see 3), the products of which were hydrolyzed to furnish amino acid esters 5. Bis-lactim ether 1 can be readily prepared from L-valine and glycine on large scale 2 and is now commercially available in both enantiomeric forms. Numerous applications of this Sch611kopf chiral auxiliary in the synthesis of optically active unnatural amino acids have been reported, including the synthesis of the antitumor agents OF 4949-III/IV, 3a ~-deuteriated ct-amino acids 3b and tryptophan analogues. 2 In a few cases, however, alkylation of the Sch611kopf chiral auxiliary suffered from poor diastereoselectivity. Attempts to overcome this drawback have been carried out by modification of the chiral auxiliary through replacement of the isopropyl group in the bis-lactim ether 1 with bulkier groups such as t-butyl to increase the diastereoselectivity. 4 Although the alkylation selectivity was increased, the relative cost and availability of those modified bis-lactim ethers 4 have limited their utilization. Because of the popularity of the bis-lactim ether 1, in this letter the focus has been shifted from the Sch611kopf chiral auxiliary itself to the electrophiles (see 2). More specifically, a variety of leaving groups have been employed to provide a simple and practical solution to the problem mentioned above. Studies of the effect of the leaving group on alkylation diastereoselectivity were carried out by employing the bromide, tosylate and diphenylphosphate (see 2) to effect alkylations of the bis-lactim ether 1 at aliphatic, benzylic, propargylic and allylic electrophilic centers. (1) 1) n-BuLi, THF -78 °C ~ RH20 . + RH 2 2) RCH2X OEt OEI 2 3(trans) 4(cis) 0.25 N HC1 H21'~/CO2Et 5 0040-4039/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved. Plh S0040-4039(99)00394-9