Enantioselectivity a-chlorination

In Communications submitted two weeks apart, David W.C. MacMillan of Caltech (7. Am. Chem. Soc. 2004,126,4108) and Karl Anker Jorgensen of Aarhus University, Denmark (7. Am. Chem. Soc. 2004, /26,4790) reported the enantioselective a-chlorination of aldehydes, using organocatalysts 14 and 15 respectively. The chloro aldehydes are promising precursors to, inter aliay enantiomerically-pure epoxides. 

The direct enantioselective a-chlorination of aldehydes leads to important intermediates 27 in organic synthesis (Scheme 2.34). This reaction was developed independently by two groups MacMillan et al. applied the salt of the imidazolidinone 3g as the catalyst, as i-proline was found to be a poor catalyst for this reaction (Scheme 2.34) [26a]. Various chlorinating reagents were tested, and the per-chlorinated quinone 28 was found to provide the best enantioselectivity. It was... 

Scheme 2.34 Organocatalytic enantioselective a-chlorination of aldehydes. (For experimental details see Chapter 14.8.2).

The other development for the direct enantioselective a-chlorination of aldehydes was reported by the present authors, and was seen to differ from the first approach in several ways. For example, the catalysts used for the a-chlorination reaction were the C2-symmetric (2R,5R)-diphenylpyrrolidine 3h and i-proline amide 3i, while the electrophilic chlorinating reagent was N-chlorosuccinimide (NCS) 29 (Scheme 2.34) [26b]. Both chiral amines were effective catalysts for the a-chlorination reaction, and the optically active products 27 were obtained in high yields the use of catalyst 3h provided generally higher enantiomeric excess (81-97% ee) than 3i (70-95% ee). 

Ketones have also been enantioselectively a-chlorinated, although the catalysts used for the a-chlorination of aldehydes were found not to be optimal for the functionalization of these substrates. Poor yields and moderate enantiomeric excess were observed with, for example, (2P,5P)-diphenylpyrrolidine 3h and i-proline amide 3i due also to poly-chlorination of the starting material [28]. A catalyst screening revealed that the C2-symmetric 4,5-diphenylimidazoline 3j constitutes, in combination with 2-nitrobenzoic acid as a rate-accelerating additive, an efficient catalytic system for the a-chlorination of both cyclic and acyclic ketones... 

The enantioselective a-chlorination of -keto esters was achieved with up to 88% ee using NCS with a commercially available TADDOL ligand. The chiral bisoxazoline copper(II) complexes have also been reported to induce the asymmetric a-chlorination of -keto esters when reacted with NCS. The asymmetric a-chlorination of aldehydes has been achieved using NCS and (2/ ,5/ )-diphenylpyrrolidine as a chiral catalyst. For example, the enantioselective chlorination of 3-methylbutanal with NCS proceeds in 95% yield and 94% ee (eq 17). ... 

The enantioselective a-chlorination reaction was also reported to proceed for keto phosphonates using NCS and bisoxazoline zinc(II) complexes in 70-91% ee. Phenylselenyl chloride has been shown to enhance the electrophilicity of NCS in chlorination reactions. Allylic chlorination of olefins with NCS catalyzed by PhSeCl was reported to occur with ene regiochemistry in high yields at room temperature. For example, methyl oct-3-enoate was... 

Enantioselective a-chlorination of cyclic 8-oxoesters was promoted by chiral amino diol derivatives. Optimization of the catalyst structure and the reaction conditions has allowed the s3mthesis of optically active products with high enantioselectivities (up to 96% ee) using inexpensive NCS as the chlorine source under mild conditions (eq 35). ... 

Catalytic enantioselective a-chlorination of carbonyl compounds, particularly, in organocatalytic synthesis of azacycHc compounds 13AJ0812. 

SCHEME 13.20. Enantioselective a-chlorination of aldehydes via enamine catalysis. 

Jprgensen et al. and Macmillan et al. independently reported on the successful enantioselective a-chlorination and a-bromination of carbonyl groups using amino catalysts. a-lodination remained unsolved until the recent discovery of the binol-derived catalysts by Maruoka et A general catalytic cycle, involving an enamine... 

Cai Y, Wang W, Shen K, Wang J, Hu X, Lin L, Liu X, Feng X. Highly enantioselective a-chlorination of cyclic P-ketoesters catalyzed by iV,iV -Dioxide using NCS as the chlorine source. Chem. Common. 2010 46 1250 1252. 

Wang L, Cai C, Curran DP, Zhang W. Enantioselective a-chlorination of aldehydes with recyclable fluorous (S)-pyr-rolidine-thiourea bifunctional organocatalyst. Synlett 2010 3 433 36. 

Etayo P, Badorrey R, Di az-de-Villegas, Galvez JA. Chiral amino diol derivatives as new modular organocatalysts for the enantioselective a-chlorination of cyclic P-keto esters. Adv. Synth. Catal. 2010 352(18) 3329-3338. 

---