Highly Enantioselective Regiodivergent and Catalytic Parallel Kinetic Resolution

Abstract

The development of new methodologies for the preparation of chiral compounds of high optical purity by means of asymmetric catalysis is presently an area of great importance in organic chemistry. Kinetic resolution of a racemic mixture with a chiral reagent is a well-documented strategy in which a maximum of only one half of the racemic starting material is converted into non-racemic products. [1] Parallel kinetic resolution (PKR) is an interesting strategy recently introduced, in which both enantiomers of a racemate can be converted into useful products. [2] This conceptual variation often requires the use of two different stoichiometric chiral reagents in parallel. [3] Parallel reactions under non-stoichiometric conditions have previously been described in the asymmetric Bayer ± Villiger oxidation of racemic ketones, by means of enzymatic methods [4] or chiral catalysts, [5] and in the intramolecular cyclopropanation of racemic allylic diazoacetates catalyzed by chiral rhodium complexes. [6] The latter is the only example of a PKR reaction involving the formation of a CÀC bond. In this special case, there are distinct reactivities for both enantiomers: one enantiomer gave intramolecular cyclopropanation, whereas the other enantiomer was transformed by means of a hydride abstraction/elimination into achiral compounds.Herein we report the first highly stereocontrolled transformation of a racemic mixture by an organometallic reagent and a chiral catalyst to give separable regioisomeric products.Recently, we described a new catalytic kinetic resolution of racemic vinyloxiranes with dialkylzinc reagents (0.50 equiv) by using copper complexes of non-racemic phosphoramidite as chiral catalysts. [7a] When racemic vinyl epoxide 2 was treated with excess Et 2 Zn (1.5 equiv) in the presence of the catalyst prepared in situ from [Cu(OTf) 2 ] (1.5 mol %) (Tf triflate OSO 2 CF 3 ) and (R,R,R)-1 (3 mol %), complete conversion of 2 took place in 3 h to give, after usual work-up and chromatographic purification (see Experimental Section), the corresponding S N 2'-addition product (R)-3 a (46 % yield, 80 % ee; Scheme 1) together with the regioisomeric alcohol Scheme 1. Enantioselective and regiodivergent addition of R 2 Zn to racemic 2 catalyzed by [Cu(OTf) 2 ]/(R,R,R)-1.(1S,2S)-4 a (37 % yield) having a surprising 99 % ee! The progress of the reaction in terms of the the conversion and enantioselectivities (Figure 1 a and 1 b, respectively) was therefore closely monitored. [8] The peculiarity of this reaction stems from the fact that regioisomeric products were derived from opposite enantiomers of 2 in two clearly distinct phases: The first one was very fast, proceeding with S N 2'-regioselectivity to yield (R)-3 a (15 min at À 78 8C), whereas the second slower one which provided (1S,2S)-4 a (À 10 8C and 3 h to go to completion) exhibited a complementary S N 2 regioselectivity. In fact, after 15 min at À 78 8C, the remaining vinyloxirane (1S,2R)-2 (62 % conversion) was enantiomerically pure, (b 98 % ee) [9] and it reacted wi...