Reactivity series for s-BuLi/diamine-mediated lithiation of N-Boc pyrrolidine: applications in catalysis and lithiation of N-Boc piperidine

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 synthesis of ferrocenes and P-stereogenic bisphosphines

The catalytic asymmetric synthesis of planar chiral ferrocenes and P-stereogenic phosphines and bisphosphines (important classes of chiral ligands for metal-catalyzed asymmetric processes) is successfully demonstrated using n-BuLi or s-BuLi in combination with substoichiometric quantities (0.1-0.5 equiv) of (-)-sparteine or the (+)-sparteine surrogate.     

Catalytic asymmetric deprotonation using a ligand exchange approach

A novel ligand exchange approach to catalytic asymmetric deprotonation-electrophilic trapping has been developed that uses 1.3 equiv of s-BuLi, 0.06-0.2 equiv of chiral diamine ((-)-sparteine or a (+)-sparteine surrogate), and 1.2 equiv of achiral bispidine. The methodology is illustrated with a range of examples and gives access to either enantiomer of useful chiral products in good yields using substoichiometric amounts of chiral diamines.     

A new sparteine surrogate for asymmetric deprotonation of N-Boc pyrrolidine

The s-BuLi complex of a cyclohexane-derived diamine is as efficient as s-BuLi/(-)-sparteine for the asymmetric deprotonation of N-Boc pyrrolidine. This is the first example of high enantioselectivity using a non-sparteine-like diamine in such reactions. The (S,S)-diamine is a useful (+)-sparteine surrogate and was utilized in short syntheses of (-)-indolizidine 167B and an intermediate for the synthesis of the CCK antagonist (+)-RP 66803.     

On the two-ligand catalytic asymmetric deprotonation of N-boc pyrrolidine: probing the effect of the stoichiometric ligand

To map out the stoichiometric ligand requirements in the two-ligand catalytic asymmetric deprotonation of N-Boc pyrrolidine, 24 different ligands have been evaluated; the highest enantioselectivity (90:10 er) was obtained by using s-BuLi in the presence of 0.3 equiv of (-)-sparteine and 1.3 equiv of a cyclohexanediamine-derived ligand.     

Asymmetric deprotonation using s-BuLi or i-PrLi and chiral diamines in THF: the diamine matters

The solution structures of [(6)Li]-i-PrLi complexed to (-)-sparteine and the (+)-sparteine surrogate in Et(2)O-d(10) and THF-d(8) at -80 °C have been determined using (6)Li and (13)C NMR spectroscopy. In Et(2)O, i-PrLi/(-)-sparteine is a solvent-complexed heterodimer, whereas i-PrLi/(+)-sparteine surrogate is a head-to-tail homodimer. In THF, there was no complexation of (-)-sparteine to i-PrLi until ≥3.0 equiv (-)-sparteine and with 6.0 equiv (-)-sparteine, a monomer was characterized. In contrast, the (+)-sparteine surrogate readily complexed to i-PrLi in THF, and with 1.0 equiv (+)-sparteine surrogate, complete formation of a monomer was observed. The NMR spectroscopic study suggested that it should be possible to carry out highly enantioselective asymmetric deprotonation reactions using i-PrLi or s-BuLi/(+)-sparteine surrogate in THF. Hence, three different asymmetric deprotonation reactions (lithiation-trapping of N-Boc pyrrolidine, an O-alkyl carbamate, and a phosphine borane) were investigated; it was shown that reactions with (-)-sparteine in THF proceeded with low enantioselectivity, whereas the corresponding reactions with the (+)-sparteine surrogate occurred with high enantioselectivity. These are the first examples of highly enantioselective asymmetric deprotonation reactions using organolithium/diamine complexes in THF.     

Enantioselective, palladium-catalyzed α-arylation of N-Boc pyrrolidine: in situ react IR spectroscopic monitoring, scope, and synthetic applications

A comprehensive study of the enantioselective Pd-catalyzed α-arylation of N-Boc pyrrolidine has been carried out. The protocol involves deprotonation of N-Boc pyrrolidine using s-BuLi/(-)-sparteine in TBME or Et(2)O at -78 °C, transmetalation with ZnCl(2) and Negishi coupling using Pd(OAc)(2), t-Bu(3)P-HBF(4) and the aryl bromide. This paper reports several new features including in situ React IR spectroscopic monitoring of the process; use of (-)-sparteine and the (+)-sparteine surrogate to access products with opposite configuration; development of a catalytic asymmetric lithiation-Negishi coupling reaction; extension to a wide range of heteroaromatic bromides; total synthesis of (R)-crispine A, (S)-nicotine and (S)-SIB-1508Y via short synthetic routes; and examples of α-vinylation of N-Boc pyrrolidine using vinyl bromides exemplified by the total synthesis of naturally occurring (+)-maackiamine (thus establishing its configuration as (R)). In this way, the full scope and limitations of the methodology are delineated.     

(-)-Sparteine-mediated metalation of ferrocenesulfonates. The first case of double asymmetric induction of ferrocene planar chirality

[reaction: see text] A new process for induction of planar chirality via a matched chiral-directed metalation group (DMG)/(-)-sparteine interaction is demonstrated. Thus, s-BuLi metalation of (-)-menthylferrocenesulfonate (8b) with (-)-sparteine constitutes a matched pair resulting in amplification of the dr in the 2-formyl product 10a.     

Catalytic asymmetric deprotonation of phosphine boranes and sulfides as a route to P-stereogenic compounds

A comparison between phosphine boranes and sulfides in their catalytic asymmetric deprotonation using organolithiums and sub-stoichiometric amounts of (-)-sparteine has revealed superior catalytic efficiency in the phosphine sulfide deprotonation.     

Catalytic asymmetric deprotonation of a phosphine borane: comparison of two-ligand and one-ligand catalysis

The catalytic asymmetric deprotonation of tert-butyldimethylphosphine borane using s-BuLi or n-BuLi and sub-stoichiometric amounts of (?)-sparteine under one-ligand and two-ligand manifolds has been investigated. Using s-BuLi, slightly higher enantioselectivity was obtained using two-ligand catalysis (use of sub-stoichiometric (?)-sparteine in the presence of a stoichiometric amount of a second achiral ligand) compared to one-ligand catalysis (use of sub-stoichiometric (?)-sparteine only). With n-BuLi, two-ligand catalysis using LiDMAE (DMAE = dimethylaminoethanol) as the stoichiometric ligand was the only method for obtaining good yield and enantioselectivity. In this case, one-ligand catalysis failed as the (?)-sparteine was not turned over.     

Basic instinct: design, synthesis and evaluation of (+)-sparteine surrogates for asymmetric synthesis

(-)-Sparteine, a naturally occurring lupin alkaloid, is widely used as a chiral ligand for asymmetric synthesis. To address the limitation that sparteine is only available as its (-)-antipode, our group introduced a family of (+)-sparteine surrogates that are structurally similar to (+)-sparteine but lack the D-ring. After briefly summarising the design aspect, this feature article provides an overview of synthetic routes to the sparteine surrogates and a detailed comparison with (-)-sparteine in a range of asymmetric reactions. The main conclusions are: (i) the (+)-sparteine surrogates are most easily prepared starting from (-)-cytisine extracted from Laburnum anagyroides seeds; (ii) in nearly all examples, use of the (+)-sparteine surrogates produced essentially equal but opposite enantioselectivity compared to (-)-sparteine and (iii) the N-Me-substituted (+)-sparteine surrogate is the most useful and versatile of those investigated.     

Mechanistic investigations of the palladium-catalyzed aerobic oxidative kinetic resolution of secondary alcohols using (-)-sparteine

The mechanistic details of the Pd(II)/(-)-sparteine-catalyzed aerobic oxidative kinetic resolution of secondary alcohols were elucidated, and the origin of asymmetric induction was determined. Saturation kinetics were observed for rate dependence on [(-)-sparteine]. First-order rate dependencies were observed for both the Pd((-)-sparteine)Cl(2) concentration and the alcohol concentration at high and low [(-)-sparteine]. The oxidation rate was inhibited by addition of (-)-sparteine HCl. At low [(-)-sparteine], Pd-alkoxide formation is proposed to be rate limiting, while at high [(-)-sparteine], beta-hydride elimination is proposed to be rate determining. These conclusions are consistent with the measured kinetic isotope effect of k(H)/k(D) = 1.31 +/- 0.04 and a Hammett rho value of -1.41 +/- 0.15 at high [(-)-sparteine]. Calculated activation parameters agree with the change in the rate-limiting step by increasing [(-)-sparteine] with DeltaH(++) = 11.55 +/- 0.65 kcal/mol, DeltaS(++) = -24.5 +/- 2.0 eu at low [(-)-sparteine], and DeltaH(++) = 20.25 +/- 0.89 kcal/mol, DeltaS() = -5.4 +/- 2.7 eu at high [(-)-sparteine]. At high [(-)-sparteine], the selectivity is influenced by both a thermodynamic difference in the stability of the diastereomeric Pd-alkoxides formed and a kinetic beta-hydride elimination to maximize asymmetric induction. At low [(-)-sparteine], the selectivity is influenced by kinetic deprotonation, resulting in lower k(rel) values. A key, nonintuitive discovery is that (-)-sparteine plays a dual role in this oxidative kinetic resolution of secondary alcohols as a chiral ligand on palladium and as an exogenous chiral base.     

An experimental and computational investigation of the enantioselective deprotonation of Boc-piperidine

The asymmetric deprotonation of N-Boc-piperidine (3) by the 1:1 complex of a sec-alkyllithium and (-)-sparteine has been investigated both experimentally and computationally. The lithiation of 3 with sec-BuL-(-)-sparteine at -78 degrees C, which is a much slower process than is the analogous deprotonation of N-Boc-pyrrolidine (1) and a minor reaction relative to the competing addition of sec-BuLi to the carbamate, proceeds with a moderate degree of selectivity (er = 87:13) for removal of the pro-S hydrogen of 3. The related deprotonation of N-Boc-4-tosyloxypiperidine (6) with two molar equiv of sec-BuL-(-)-sparteine also involves preferential transfer of the pro-S hydrogen. The computational study of the deprotonation of (3) by i-PrL-(-)-sparteine found that the proton that is preferentially transferred within three-component intermediate complex is the thermodynamically least acidic alpha-hydrogen of 3. The asymmetric deprotonation of 3 is calculated to proceed with poor enantioselectivity and to have an activation energy considerably higher than that calculated for deprotonation of N-Boc-pyrrolidine (1). The experimental and computational results are in good agreement.     

Asymmetric deprotonation-substitution of N-Pop-benzylamines using [RLi/(-)-sparteine]. Enantioselective sequential reactions and synthesis of N-heterocycles

Pop-directed asymmetric deprotonation of benzylic amines using [n-BuLi/(-)-sparteine] provides an efficient method for the synthesis of chiral NC alpha and NC alpha,alpha' derivatives with total selectivity with respect to competing allylic and ortho lithiation. The method described herein offers a straightforward route of accessing chiral N-Pop-protected nitrogen heterocycles.     

Synthesis of both enantiomers of a P-chirogenic 1,2-bisphospholanoethane ligand via convergent routes and application to rhodium-catalyzed asymmetric hydrogenation of CI-1008 (pregabalin)

Both enantiomers of a P-chirogenic 1,2-bisphospholanoethane ligand are synthesized via two convergent methods. The first method relies on the chiral alkylation of 1-((-)-menthoxy)phospholaneborane using a s-BuLi/(-)-sparteine derived chiral base. Only one enantiomer of the catalyst could be synthesized via this method because only one antipode of sparteine is available in nature. The second route relies on the combination of methylphosphine borane and a chiral 1,4-diol. Either enantiomer of the ligand can be synthesized via the second route from the appropriate enantiomer of the 1,4-diol. Asymmetric hydrogenation using catalyst precursor 36 on acetamidoacrylic acid derivatives provided modest to good enantioselectivity (77-95% ee) under low H(2) pressure (30 psi). Asymmetric hydrogenation of CI-1008 (pregabalin) precursors, 39 and 40, provided good enantioselectivities (92%) at high catalyst loading (1 mol %) and low pressure (30 psi). Enantiomeric excesses dropped sharply with catalyst loading at this pressure. Increasing the pressure of H(2) caused a significant increase in enantiomeric excess for low catalyst loading reactions. Several studies were undertaken to further investigate the enantioselectivity dependence on both pressure and catalyst loading.     

Asymmetric alkylation of N-pivaloyl-o-benzylaniline

Alkylation of 2-methoxyethoxyphenyl phenylmethane using sec-BuLi and (−)-sparteine has been carried out in excellent yields and up to 76% ee. The use of O’Brien’s (+)-sparteine surrogate gave the opposite sense of asymmetric induction at 80% ee while the use of chiral lithium amide bases gave modest yields and ees.     

Concise asymmetric synthesis of (-)-sparteine

A six-step asymmetric synthesis of natural (-)-sparteine from ethyl 7-iodohept-2-enoate is reported, involving a connective Michael addition of an amino ester-derived enolate to an alpha,beta-unsaturated amino ester.     

Use of copper(II)/diamine catalysts in the desymmetrisation of meso-diols and asymmetric Henry reactions: comparison of (−)-sparteine and (+)-sparteine surrogates

Four new copper(II)/diamine complexes comprising some (+)-sparteine surrogates and a cyclohexane-derived diamine were prepared and evaluated as chiral catalysts in desymmetrisation of meso-diols and asymmetric Henry reactions. Mono-benzoylation reactions generated two products with high enantioselectivity (90:10 to 97:3 er). Asymmetric Henry reactions gave nitro alcohols in 90:10 to 98:2 er. Notably, the sense of induction with the (+)-sparteine surrogates was opposite to that obtained using the copper(II)/(−)-sparteine complex. One of the nitro alcohol products was utilised in a concise synthesis of a chiral morpholine.     

Absolute configuration of 2-(tributylstannyl)pyrrolidine by anomalous dispersion X-ray analysis

Enantiopure 2-(tributylstannyl)pyrrolidine hydroiodide may be prepared in excellent yield by TMSI treatment of the corresponding N-Boc compound, which is in turn prepared by asymmetric deprotonation (s-BuLi.sparteine) and stannylation, as described in the literature. Crystals of the hydroiodide salt suitable for X-ray analysis were obtained, and although there is some disorder about the butyl groups, analysis using anomalous dispersion establishes the absolute configuration as S.     

Dynamic resolution of N-alkyl-2-lithiopyrrolidines with the chiral ligand (−)-sparteine

A selection of 2-lithiopyrrolidines with different N-alkyl-substituents were prepared and tested for their dynamic resolution in the presence of the chiral ligand (−)-sparteine. Good yields of the electrophile-quenched products were obtained with enantiomer ratios up to 85:15 using branched N-alkyl derivatives. The major product was shown to have the opposite absolute configuration compared with that obtained in the asymmetric deprotonation of N-Boc-pyrrolidine with (−)-sparteine. The enantioselectivity arises from a dynamic thermodynamic resolution in which the minor diastereomeric complex reacts faster with the electrophile.