Hydrazones, enantioselective radical additions

Enantioselective radical addition to AT-acyl hydrazone using triethylborane as chain transfer reagent has been reported by Friestad. Enantiomeric excesses up to 95% were obtained in the presence of copper(II)-bisoxazolines Lewis acid (Scheme 51) [115]. 

Scheme 31 Enantioselective radical additions onto hydrazones...

Friestad and co-workers recently demonstrated that N-acyl hydrazones were excellent radical acceptors in the presence of a chiral Lewis acid [84], Valerolactam-derived hydrazone 117 proved to be the optimal substrate for enantioselective radical additions. Upon further optimization it was found that Cu(OTf )i and f-bulyl bisoxazoline ligand 96 gave the best yields and ee s (Scheme 31). Interestingly, a mixed solvent system (benzene dichloromethane in a 2 1 ratio, respectively) in the presence of molecular sieves (4 A) were necessary to achieve high yields and selectivities. 

The assumption of an early transition state for radical addition enables the ground state structure to serve as a reasonable approximation of the transition state geom etry. With this in mind, we hypothesized that steric blocking of one of the enantio topic approach trajectories by a substituent above or below the plane of hydrazone C=N bond should lead to an enantioselective process. 

Enantioselective free-radical additions to N-acyl hydrazones mediated by chiral Cu(II) Lewis acids have been demonstrated by Friestad and coworkers [16]. Addition of a variety of alkyl radicals to valerolactam-derived N-acyl hydrazone (54) catalyzed by one equivalent of dehydrated [Cu((S,S)-tBu-box)(H20)2(OTf)](OTf) (55) proceeds with moderate to good yield and high enantioselectivity (Scheme 17.11). Catalytic loadings could be decreased without loss of reactivity, but significant erosion of enantioselectivity was observed. Nevertheless, this methodology represents a viable alternative to classical Strecker and Mannich reactions for asymmetric amine synthesis. 

---