Using competition experiments between a range of ligands and (-)-sparteine, a reactivity series for N-Boc pyrrolidine lithiation using s-BuLi/diamines has been constructed; the results indicate that the s-BuLi/(+)-sparteine surrogate complex is more reactive than s-BuLi/(-)-sparteine and this has been exploited in the selection of ligand pairs for ligand exchange catalytic asymmetric lithiation of N-Boc pyrrolidine and lithiation of N-Boc piperidine.

Catalytic asymmetric deprotonation-aldehyde trapping-ring expansion from a 5- to a 6-ring delivers a concise route to each stereoisomer of beta-hydroxy piperidines starting from N-Boc pyrrolidine. The methodology is utilized in a 5-step catalytic asymmetric synthesis of the neorokinin-1 receptor antagonist, (+)-L-733,060.

[reaction: see text]. Upon treatment with lithiumorganic nucleophiles, trans-configured oxiranyl carbaldimines are transformed into anti-configured cis-aziridinyl alcohols with excellent diastereoselectivity. This conversion may be explained by a new type of the aza-Payne rearrangement, including first a nucleophilic attack on the imine carbon atom with diastereofacial differentiation followed by an intramolecular nucleophilic opening of the oxiranyl ring with simultaneous formation of the aziridine ring.

arylations · asymmetric synthesis · carbanions · Negishi coupling · transmetalation Forover15 years, synthetic organic chemists have had access to enantioenriched carbanions derived from N-Boc pyrrolidine 1 (Boc = tert-butoxycarbonyl) and O-alkyl carbamates 2 upon treatment with a chiral base comprising sBuLi and (À)-sparteine (Scheme 1). [1,2] This asymmetric deprotonation methodology was pioneered by the groups of Hoppe and Beak, [1][2][3] and has been supplemented by work in which a readily accessible (+)-sparteine surrogate (Scheme 1) was developed.[4] As a result, deprotonation and electrophilic trapping of carbamates 1 and 2 using sBuLi/(À)-sparteine or the (+)-sparteine surrogate can produce either enantiomer of the substituted pyrrolidines or protected secondary alcohols. However, the use of these types of reactions in synthesis has been hampered to some extent by the limited range of compatible electrophiles. A number of these limitations have been addressed by the groups of Dieter [5] and Taylor; [6] transmetalation of the organolithium compound to an organocopper reagent (RCu(CN)Li or R 2 CuLi·LiCl) significantly widens the range of electrophilic partners. However, there can be a loss of some enantioselectivity through these transmetalation processes, [5,7] and until recently it was not possible to arylate enantioenriched carbanions. This Highlight summarizes two rather different ways of directly arylating enantioenriched carbanions generated from N-Boc pyrrolidine 1 and O-alkyl carbamates 2. The methodology facilitates conceptually new disconnections for preparing chiral benzylic amines and alcohols (Scheme 2). Thus, aryl-substituted pyrrolidines 3 and benzylic alcohols 4 are derived from 1 and 2, respectively. These seemingly counterintuitive disconnections are made possible by either transmetalation to an organozinc reagent (for 3) or the use of organoboron intermediates (for 4), and the absolute stereochemistry is controlled by the sBuLi/(À)-sparteine or (+)-sparteine-surrogate chiral base.The direct asymmetric arylation of N-Boc pyrrolidine 1 was developed by Campos and co-workers from the Merck Process Group.[8] Their approach uses Beaks asymmetric deprotonation methodology to give an enantioenriched organolithium which is transmetalated to an organozinc species (either RZnCl, R 2 Zn, or R 3 ZnLi) before entering into a palladium-mediated Negishi coupling with an aryl bromide. The optimized reaction conditions are summarized in the example shown in Scheme 3. Thus, N-Boc pyrrolidine 1 was lithiated using sBuLi/(À)-sparteine in TBME at À70 8C, then 0.6 equivalents of ZnCl 2 were added, and the reaction was warmed to room temperature. Based on the stoichiometry, it is likely that a dialkylzinc reagent was formed, which then reacted with bromobenzene in the presence of 4 mol % of Pd(OAc) 2 and 5 mol % of [tBu 3 PH]BF 4 to give the arylated pyrrolidine (R)-5 in 82 % yield and 96:4 e.r.This enantioselective Negishi reaction is notable for several reasons. Although based to some extent on Dieter Scheme...