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.     

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.     

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.     

Asymmetric aldol additions: use of titanium tetrachloride and (-)-sparteine for the soft enolization of N-acyl oxazolidinones, oxazolidinethiones, and thiazolidinethiones.

Asymmetric aldol additions using chlorotitanium enolates of N-acyloxazolidinone, oxazolidinethione, and thiazolidinethione propionates proceed with high diastereoselectivity for the Evans or non-Evans syn product depending on the nature and amount of the base used. With 1 equiv of titanium tetrachloride and 2 equiv of (-)-sparteine as the base or 1 equiv of (-)-sparteine and 1 equiv of N-methyl-2-pyrrolidinone, selectivities of 97:3 to > 99:1 were obtained for the Evans syn aldol products using N-propionyl oxazolidinones, oxazolidinethiones, and thiazolidinethiones. The non-Evans syn aldol adducts are available with the oxazolidinethione and thiazolidinethiones by altering the Lewis acid/amine base ratios. The change in facial selectivity in the aldol additions is proposed to be a result of switching of mechanistic pathways between chelated and nonchelated transition states. The auxiliaries can be reductively removed or cleaved by nucleophilic acyl substitution. Iterative aldol sequences with high diastereoselectivity can also be accomplished.     

Synthesis and structural chemistry of alkali metal tris(HMDS) magnesiates containing chiral diamine donor ligands

Six alkali metal tris(HMDS) magnesiate complexes (HMDS, 1,1,1,3,3,3,-hexamethyldisilazide) containing chiral diamine ligands have been prepared and characterised in both the solid- and solution-state. Four of the complexes have a solvent-separated ion pair composition of the form [{M·(chiral diamine)(2)}(+){Mg(HMDS)(3)}(-)] [M = Li for 1 and 3, Na for 2 and 4; chiral diamine = (-)-sparteine for 1 and 2, (R,R)-TMCDA for 3 and 4, (where (R,R)-TMCDA is N,N,N',N'-(1R,2R)-tetramethylcyclohexane-1,2-diamine)] and two have a contacted ion pair composition of the form [{K·chiral diamine}(+){Mg(HMDS)(3)}(-)](n) [chiral diamine = (-)-sparteine for 5 and (R,R)-TMCDA for 6]. In the solid-state, complexes 1-4 are essentially isostructural, with the lithium or sodium cation sequestered by the respective chiral diamine and the previously reported anion consisting of three HMDS ligands coordinated to a magnesium centre. As such, complexes 1-4 are the first structurally characterised complexes in which the alkali metal is sequestered by two molecules of either of the chiral diamines (-)-sparteine (1 and 2) or (R,R)-TMCDA (3 and 4). In addition, complex 4 is a rare (R,R)-TMCDA adduct of sodium. In the solid state, complexes 5 and 6 exist as polymeric arrays of dimeric [{K·chiral diamine}(+){Mg(HMDS)(3)}(-)](2) subunits, with 5 adopting a two-dimensional net arrangement and 6 a linear arrangement. As such, complexes 5 and 6 appear to be the only structurally characterised complexes in which the chiral diamines (-)-sparteine (5) or (R,R)-TMCDA (6) have been incorporated within a polymeric framework. In addition, prior to this work, no (-)-sparteine or (R,R)-TMCDA adducts of potassium had been reported.     

Palladium catalysts for aerobic oxidative kinetic resolution of secondary alcohols based on mechanistic insight

The oxidative kinetic resolution of secondary alcohols has been accomplished using 1:1 complexes of PdCl(2) and N-heterocyclic carbenes. In these reactions, both achiral and chiral carbene ligands are used in conjunction with the chiral base (-)-sparteine. A general synthesis of 1:1 PdCl(2)-carbene complexes has been developed and is amenable to a wide range of carbene ligands. The potential of these complexes in aerobic oxidations is highlighted by the use of a chiral Pd(II) complex and the chiral base (-)-sparteine to enhance the kinetic resolution of a racemic alcohol. [reaction--see text]     

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.     

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.     

Dual role of (-)-sparteine in the palladium-catalyzed aerobic oxidative kinetic resolution of secondary alcohols

The mechanistic details of the palladium-catalyzed aerobic oxidative kinetic resolution of secondary alcohols have been elucidated. (-)-Sparteine was found to have a dual role as a chiral ligand and an exogenous base. Saturation kinetics were observed for the dependence on (-)-sparteine concentration. A first-order dependence on [alcohol] and [catalyst] as well as inhibition by addition of (-)-sparteine HCl were observed. These results are consistent with rate-limiting deprotonation under low (-)-sparteine concentrations and rate-limiting beta-hydride elimination using saturating (-)-sparteine concentrations. This conclusion is further supported by a kinetic isotope effect of 1.31 +/- 0.04 under saturation. The enantioselectivity events are also controlled by addition of (-)-sparteine in which high concentrations afford a more selective kinetic resolution.     

The crystal structures of the chiral alkyllithium bases [n-BuLi.(-)-sparteine]2 and [Et2O.(i-PrLi)2.(-)-sparteine

The crystal structures of the two chiral alkyllithium bases [n-BuLi.(-)-sparteine]2 (1) and [Et2O.(i-PrLi)2.(-)-sparteine] (2) have been determined. For compound 1, a symmetric dimer is observed in the solid state, with two (-)-sparteine ligands coordinating to the lithium centers. Because of steric reasons, compound 2 crystallizes as an unsymmetric dimer with the four methyl groups pointing away from the sterically demanding (-)-sparteine ligand. Compound 2 contains one four-coordinate lithium center [coordinated to (-)-sparteine] and one three-coordinate lithium center (coordinated to Et2O). As a result of this arrangement, significantly different Li-C distances are found in the central four-membered ring of compound 2.     

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.     

Isolation and characterisation of a (-)-sparteine coordinated mixed alkyl/amido sodium magnesiate, a chiral variant of an important utility ate base

When a 1 : 1 (n)BuNa-(n,s)Bu(2)Mg mixture is treated with two molar equivalents of TMP(H) (TMP = 2,2,6,6-tetramethylpiperidide) and one molar equivalent of (-)-sparteine in hydrocarbon medium, a new chiral mixed-metal, mixed alkyl-amide [{(-)-sparteine}.Na(mu-Bu)(mu-TMP)Mg(TMP)] can be isolated.     

Synthesis of enantiomerically enriched allenes by (-)-sparteine-mediated lithiation of alkynyl carbamates

[reaction: see text]. The alpha-deprotonation of alkynyl carbamates 3 with the chiral base (-)-sparteine (4)/n-butyllithium, transmetalation with ClTi(O(i)()Pr)3, and subsequent substitution with an aldehyde results in the formation of enantioenriched 4-hydroxyallenyl carbamates 11. Stereoselection is determined by dynamic resolution of the lithium/(-)-sparteine complexes by selective crystallization.     

One-ligand catalytic asymmetric deprotonation of a phosphine borane: synthesis of P-stereogenic bisphosphine ligands

A new protocol for the catalytic asymmetric deprotonation of a phosphine borane using s-BuLi and substoichiometric quantities of chiral diamines is reported. The method involves three sequential additions of s-BuLi, and use of (-)-sparteine or the (+)-sparteine surrogate facilitates access to P-stereogenic phosphines with opposite configuration. The method is exemplified by the catalytic asymmetric synthesis of each enantiomer of precursors to QuinoxP*, trichickenfootphos, and Mini-PHOS.     

Organolithium-mediated conversion of beta-functionalised aziridines into alkynyl amino alcohols and diamines

The direct conversion of dihydrofuran and dihydropyrrole N-triisopropylbenzenesulfonyl aziridines into alkynyl amino alcohols and diamines respectively can be achieved using 3 equiv. sec-butyllithium-PMDETA in THF; use of n-butyllithium and (-)-sparteine in Et2O gave an alkynyl amino alcohol in 60% ee.     

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.     

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.     

A readily-accessible (+)-sparteine surrogate

A "(+)-sparteine-like" chiral diamine, readily synthesized in three steps from (-)-cytisine, has been evaluated in four different asymmetric transformations; in each case, selectivity in an enantiocomplementary fashion to (-)-sparteine was observed.     

Enantioselective alkylative double ring-opening of epoxides derived from cyclic allylic ethers: synthesis of enantioenriched unsaturated diols

A screen of external chiral ligands has led to enantioselective organolithium-induced alkylative double ring-opening of 3,4-epoxytetrahydrofuran 1 with n-BuLi to give 3-methyleneheptane-1,2-diol 3 in 75% yield and 55% ee in the presence of bisoxazoline 10, and in up to 60% ee in the presence of (-)-sparteine 2. Extending the alkylative double ring-opening reaction to epoxides derived from oxabicyclo[n.2.1]alkenes (n = 2.3) results in the formation of cycloalkenediols, which, when carried out in the presence of (-)-sparteine 2 affords products in up to 85% ee.     

Effect of ligand structure on the asymmetric cyclization of achiral olefinic organolithiums

The ability of a large and chemically diverse set of 30 chiral ligands to effect asymmetric cyclization of 2-(N,N-diallylamino)phenyllithium (1), derived from N,N-diallyl-2-bromoaniline (2) by low-temperature lithium-bromine exchange, has been investigated in an attempt to elucidate the structural motifs required to provide high enantiofacial selectivity in the ring closure. Although none of the ligands examined in this study afforded 1-allyl-3-methylindoline in significantly higher ee than previously observed for the cyclization of 1 in the presence of the benchmark ligand (-)-sparteine, several ligands, structurally unrelated to sparteine and available in either enantiomeric form, were found to match the utility of (-)-sparteine in this chemistry.