Scope and limitation of organocuprates, and copper or nickel catalyst-modified Grignard reagents for installation of an alkyl group onto cis-4-cyclopentene-1,3-diol monoacetate

Alkylation of the title compound 1 was investigated with two types of reagents. One is a copper reagent derived from (RMgX)-Mg-T (X = Cl, Br) and CuX (X = CN, I) and the other is RTMgX in the presence of a copper or a nickel catalyst. First, butylation was studied with BuCu(CN)(MgX), Bu-2-Cu(CN)(MgX)(2), BuMgX/CuCN (10 mol %), BuCu (derived from BuMgCl and CuI), and BuMgCl/ CuI (10 mol %) in THF or Et2O. We found that trans 1,4-isomer 2a and/or trans 1,2-isomer 3a were produced exclusively with these reagents and that the stoichiometry of BuMgX/CUX and the choice of solvent were critical to attain high regioselectivity and efficient yield. Reaction with Bu-2-Cu(CN)(MgCl)(2) and BuMgCl/CuX (X = CN, 1; 10 mol %) both in THF produced 2a with 93-94% regioselectivity in 87-92% yields. On the other hand, BuCu(CN)(MgX) in THF, Bu2Cu(CN)(MgX)2 in Et2O, and BuMgX/CuCN (10 mol %) in Et2O furnished 3a in good yields with > 90% selectively, irrespective of X of BuMgX. In the nickel-catalyzed butylation of 1 with BuMgCl, NiCl2(dppp) among NiCl2(tpp)(2), NiCl2(dppf), and NiCl2(dppp) furnished the best result to produce 2a. The CuCN-based protocol was then applied to other alkyl Grignard reagents, which include Me, Et, (CH2)(3)Ph, c-C6H11, (CH2)(6)OMOM, (CH2)(9)CH=CH2, and CH2Ph as the alkyl group (R-T). In addition, the Mitsunobu inversion of 2a and 3a afforded the corresponding cis isomers stereoselectively with AcOH as an acid at -78 degreesC in toluene for 2a and with 4-(NO2)C6H4COOH in THF at r.t. for 3a. No racemization during the alkylation was confirmed by the reaction using (1R,3S)-1 (> 99% ee) to produce (1S,4S)2a and (1S,2S)-3a, respectively.