Synthetic Methods DOI: 10.1002/anie.200700681 Stereoselective Simmons–Smith Cyclopropanation of Chiral Enamides** Zhenlei Song, Ting Lu, Richard P. Hsung,* Ziyad F. Al-Rashid, Changhong Ko, and Yu Tang Enamides, unlike enamines, have remained relatively obscure in synthesis. [1,2] The limited use of enamides could be due in part to synthetic inaccessibility; however, recent develop- ments in copper- and palladium-catalyzed N alkenylation [3,4] should provoke a strong interest in the development of synthetic methods based on the use of enamides as versatile building blocks. Among notable studies, [5] there have been reports of both normal-electron-demand Diels–Alder cyclo- additions [6] and inverse-electron-demand hetero-Diels–Alder cycloadditions [7] of enamides. We reported the epoxidation of chiral enamides in the synthesis of chiral a-hydroxyhemiami- nals (1!2 in Scheme 1). [8,9] The high level of diastereoselec- tivity in this epoxidation was surprising and led us to speculate that enamides 1 could favor the conformation shown in A, [8,9] which provides an excellent p-facial bias for the observed stereochemical outcome. This conformation analysis prompted us to examine the possibility of using chiral enamides 1 as unique templates for the development of stereoselective methods. Specifically, given the significance of cyclopropanation reactions [10] and the lack of systematic studies undertaken in this area with chiral enamides, [1,11] we explored a possible stereoselective Simmons–Smith cyclopropanation [12] of chiral enamides on the basis of a related conformation analysis (see B, Scheme 1). We report herein a highly stereoselective Simmons–Smith cyclopropanation of chiral enamides for the synthesis of chiral aminocyclopropanes. The feasibility of this approach was quickly established (Table1). The use of the chiral enamide 5 led to the amidocyclopropane 7 [13] in excellent yield (80%) with a diastereomeric ratio of 95:5 (see later discussion on the assignment of configuration) after optimization of the reac- tion conditions. Key features of the reaction are the use of the more reactive dihaloalkane ICH 2 Cl (Table 1, entry 5) as the methylidene source (although ICH 2 I, which is cheaper, can also be used; Table 1, entry 1) and the presence of molecular sieves. The scope of this cycloaddition is summarized in Table 2. In general, the nature of the chiral amide, which serves as an auxiliary, does not appear to be critical for high stereose- lectivity (Table 2, entries 1–3). However, the Close auxili- ary [14] is less effective in terms of selectivity (Table 2, entries 4 and 5), although reactions with this chiral amide were faster. This result is in accord with the electrophilic nature of Simmons–Smith cyclopropanation and the fact that enamides substituted with the Close auxiliary are more electron rich [15] than those substituted with Evans-type auxiliaries. [16] Fur- thermore, chiral enamides with 1,1-disubstituted (Table2, Scheme 1. A p-facially differentiated chiral enamide template. Bz = ben- zoyl. Table 1: Feasibility and optimization of the Simmons–Smith cyclopropa- nation. Entry 6 Solvent Additive [d] Yield [%] [a,c] d.r. [b,c] 1 6a : ICH 2 I CH 2 Cl 2 none 40 95:5 2 6a CH 2 Cl 2 DME 10 95:5 3 6a CH 2 Cl 2 ZnCl 2 n.d. n.d. 4 6a CH 2 Cl 2 SnBr 4 n.d. n.d. 5 6b : ICH 2 Cl (CH 2 Cl) 2 none 80 95:5 [a] Yield of the isolated product. [b] The diastereomeric ratio was determined by 1 H NMR spectroscopy. [c] n.d.: not determined. [d] DME = 1,2-dimethoxyethane. [e] MS = molecular sieves. [*] Dr. Z. Song, T. Lu, Prof. Dr. R. P. Hsung, Dr. Z. F. Al-Rashid, C. Ko, Dr. Y. Tang Division of Pharmaceutical Sciences and Department of Chemistry University of Wisconsin at Madison 7111 Rennebohm Hall, 777 Highland Avenue Madison, WI 53705 (USA) Fax: (+ 1)680-262-5345 E-mail: rhsung@wisc.edu Homepage: http://www.pharmacy.wisc.edu/facstaff/sciences/ hsungGroup/ [**] We thank NIH-NIGMS (GM066055) and UW-Madison for financial support. We also thank Ben Kucera and Vic Young for solving the X-ray crystal structures. Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author. Angewandte Chemie 4069 Angew. Chem. Int. Ed. 2007, 46, 4069 –4072 # 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim