Expanding the Synthetic Potential of Asymmetric Deprotonation: Arylation of Carbanions

Abstract

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...

Homologation and alkylation of boronic esters and boranes by 1,2‐metallate rearrangement of boron ate complexes

“…Aggarwal et al have shown that the direct reaction of lithiated carbamates with boranes and boronic esters shows considerable scope and therefore potential for synthesis (Table 4). In all cases high enantioselectivities were observed (er 95 : 5–98 : 2) 30,31…”

Stereocontrolled Synthesis of β‐Amino Alcohols from Lithiated Aziridines and Boronic Esters

“…[1] The importance of this motif to such a broad spectrum of chemistry has prompted the development of a range of methodologies for its synthesis which include Sharpless aminohydroxylation [2] as well as the addition of nucleophiles to aminocarbonyls, [3] imines, [4] epoxides, and aziridines. [5] We considered a conceptually different route to prepare this class of compound: namely, the lithiation/borylation [6] of aziridines [7] (Scheme 1, pathway a).This route was attractive because: 1) it combines readily available aziridines 1 and boronic esters 2, and creates a C À C bond, 2) high stereoselectivity for the overall process could be expected since lithiation of N-Boc [8] (tert-butoxycarbonyl) and N-Bus [9] (tert-butylsulfonyl) aziridines [10] had been shown to occur trans to the aziridine substituent, and the subsequent steps (3 ! 4 !…”

“…[1] The importance of this motif to such a broad spectrum of chemistry has prompted the development of a range of methodologies for its synthesis which include Sharpless aminohydroxylation [2] as well as the addition of nucleophiles to aminocarbonyls, [3] imines, [4] epoxides, and aziridines. [5] We considered a conceptually different route to prepare this class of compound: namely, the lithiation/borylation [6] of aziridines [7] (Scheme 1, pathway a).…”

Stereocontrolled Synthesis of β‐Amino Alcohols from Lithiated Aziridines and Boronic Esters

“…[1] The importance of this motif to such a broad spectrum of chemistry has prompted the development of a range of methodologies for its synthesis which include Sharpless aminohydroxylation [2] as well as the addition of nucleophiles to aminocarbonyls, [3] imines, [4] epoxides, and aziridines. [5] We considered a conceptually different route to prepare this class of compound: namely, the lithiation/borylation [6] of aziridines [7] (Scheme 1, pathway a).This route was attractive because: 1) it combines readily available aziridines 1 and boronic esters 2, and creates a C À C bond, 2) high stereoselectivity for the overall process could be expected since lithiation of N-Boc [8] (tert-butoxycarbonyl) and N-Bus [9] (tert-butylsulfonyl) aziridines [10] had been shown to occur trans to the aziridine substituent, and the subsequent steps (3 ! 4 !…”

“…[1] The importance of this motif to such a broad spectrum of chemistry has prompted the development of a range of methodologies for its synthesis which include Sharpless aminohydroxylation [2] as well as the addition of nucleophiles to aminocarbonyls, [3] imines, [4] epoxides, and aziridines. [5] We considered a conceptually different route to prepare this class of compound: namely, the lithiation/borylation [6] of aziridines [7] (Scheme 1, pathway a).…”