Diastereoselectivity in the Cyclization of Alkene Radical Cations Generated under Non-Oxidizing Conditions: Contact Ion Pairs and Memory Effects David Crich* and Krishnakumar Ranganathan Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061 Received July 28, 2002 Appropriately substituted -(phosphatoxy)alkyl radicals suffer radical ionic fragmentation to highly organized contact ion pairs comprised of alkene radical cations and phosphate anions. 1-3 In the absence of nucleophiles, in nonpolar solvents, recombination occurs on a time scale competitive with reorganization within the contact ion pair, as repeatedly demonstrated by stereochemical and isotopic labeling studies, to give either the initial 4 or the rearranged radical. 5,6 When a suitable nucleophile is included, the ion pair may be trapped, leading to the formation of heterocycles 7,8 and, through radical/polar crossover processes, to alkaloid-like skeleta. 9,10 Al- though the alkene radical cations undergoing nucleophilic attack in these processes are formally planar and achiral, their association with the anion in a contact ion pair raises the possibility of enantio- and diastereoselective reactions that exhibit memory 11 of the stereogenicity of the precursor radical provided that trapping takes place before equilibration of the various possible ion pairs. The potential for such stereoselective reactions marks a significant difference between the present fragmentation approach to alkene radical cations, aside from the non-oxidizing conditions, and the more classical entries 12,13 involving one-electron oxidation of alkenes. Here, we reduce the concept to practice and illustrate the dependence of the diastereoselectivity on substitution. We first investigated the effect of a stereogenic center adjacent to the alkene radical cation. A suitable substrate was assembled from the known alcohol 1 as set out in Scheme 1. In this sequence, reduction of the ketone 5 produced a 1/1 anti/syn mixture of the nitro-aldol 6 which was conveniently separated at the level of the phosphates 7, whose stereochemistry was assigned on the basis of coupling constant and NOE data. The individual isomers were then deprotected by exposure to TMSOTf and lutidine to give the amines 8. These were then cyclized individually with tributyltin hydride and AIBN in benzene at reflux, giving in both cases a predominance of trans-N-benzyl-3-methyl-2-isopropylpyrrolidine 9 over the cis- isomer 10 (Scheme 2). 14 Two further pairs of diastereomeric substrates, with backbone substituents - and γ- to the site of reaction, were prepared by unambiguous, stereocontrolled routes 15 and subjected to the cy- clization conditions. The tin hydride-mediated cyclizations of both anti- and syn-11 were highly diastereoselective and gave the pyrrolidines 12 and 13, respectively, that is, both with effective inversion of configuration at carbon (Scheme 3). The cyclizations of anti- and syn-14, conducted in the standard manner with tributyltin hydride and AIBN in benzene at reflux, were both diastereoselective for the product arising from apparent backside attack on the parent phosphates (Scheme 4). Additionally, in this series, significant amounts of the tricyclic product 17, whose stereochemistry was unambiguously assigned by NOE measure- ments, were isolated. The formation of considerable amounts of 17 in these latter cyclizations presumably arises from the high degree of steric compression following nucleophilic ring closure according to the transition state for the formation of 15, which results in a further oxidative radical cyclization onto the benzyl group. Product 17 is therefore a derivative of the cis-pyrrolidine 15 and has been incorporated as such in the de for the overall cyclization. Of the six cyclizations presented, all but one conform to a simple model for formation of the major diastereomer. Thus, the initial radical, generated on reaction with tin hydride, undergoes frag- mentation to a contact alkene radical cation/phosphate anion pair, wherein the anion shields the face of the radical cation from which it has just departed. Nucleophilic attack then takes place on the * To whom correspondence should be addressed. E-mail: dcrich@uic.edu. Scheme 1. Preparation of anti- and syn-8 Scheme 2. Cyclization of anti- and syn-8 Published on Web 09/26/2002 12422 9 J. AM. CHEM. SOC. 2002, 124, 12422-12423 10.1021/ja027893a CCC: $22.00 © 2002 American Chemical Society