Enantiodivergent synthesis of P-chirogenic phosphines

Several approaches for the enantiodivergent synthesis of P-chirogenic mono- and diphosphines are described, using ephedrine methodology and phosphine borane chemistry. Firstly, both enantiomers of a tertiary phosphine can be obtained starting from the same oxazaphospholidine borane complex, prepared from (+)-ephedrine, when changing the order of addition of the organolithium reagents during the synthetic pathway. The second approach is based on the chlorophosphine boranes, which react with an organolithium reagent, to afford the corresponding phosphines with inversion of configuration. In the case where the chlorophosphine borane reacts with the t-butyl lithium reagent, a metal-halogen exchange occurs to afford the corresponding phosphide borane with retention of the configuration. The reaction of the phosphide borane with an alkyl halide leads to the same phosphine, but with the opposite configuration. Another approach depends on the diastereoselective preparation of the starting oxazaphospholidine borane complex from (?)-ephedrine, which leads according the case, to either one or the other enantiomer of a phosphine. Finally, the synthesis of (R,R)- and (S,S)-1,2-bis(methylphenylphosphino)ethane is also demonstrated using both enantiomers of the P-chirogenic diphosphinite diborane, which simultaneously allows the introduction of alkyl- or aryl substituents on the phosphorus atoms. In summary, these approaches show the great efficiency of the “ephedrine methodology” for the enantiodivergent synthesis of P-chirogenic mono- and diphosphines, and bearing alkyl or aryl substituents.     

Highly enantiomerically enriched chlorophosphine boranes: synthesis and applications as P-chirogenic electrophilic blocks

The stereoselective synthesis of P-chirogenic chlorophosphine boranes 4 was investigated by HCl acidolysis of the corresponding aminophosphine boranes 10. The reaction afforded the P-N bond cleavage with inversion of the configuration at the phosphorus center, leading to the chlorophosphine boranes 4 with high to excellent enantiomeric purities (80-99% ee), except in the case of the chloro-1-naphthylphenylphosphine borane 4d. Reaction conditions and workup significantly influence the enantiomeric purity of the product, with the exception of the o-anisyl- and o-tolylchlorophenylphosphine boranes, 4b and 4c, which were found to be particularly stable even after purification by chromatography on silica gel. Reaction of the chlorophosphine boranes 4 with various nucleophiles, such as carbanions, phenolates, thiophenolates, or amides, afforded the corresponding organophosphorus borane complexes via P-C, P-O, P-S, and P-N bond formation, respectively, in 34-93% yield and with up to 99% ee. This work demonstrates the importance of chlorophosphine boranes 4 as new and powerful electrophilic building blocks for the highly stereoselective synthesis of P-chirogenic organophosphorus compounds.     

Synthesis of allyl phosphine oxides/boranes via Horner reaction of bis(diphenylphosphine)ethane monoxide reagent with an aldehyde

The Horner-Wittig addition-elimination reaction using bis(diphenylphosphine)ethane monoxide [DIPHOS(O)] with an aldehyde affords Z-allyl phosphine oxides/boranes. Alternatively, the stereoselective Lewis acid mediated intermolecular reduction of its γ-ketobisphosphoranes and stereoselective intramolecular reduction of γ-ketophosphine·borane derivatives followed by elimination of diphenylphosphinate affords E-allyl phosphine oxides/boranes with good to high selectivity. Allyl phosphine oxides are common intermediates in the synthesis of polyenes.     

A P-chirogenic β-aminophosphine synthesis by diastereoselective reaction of the α-metallated PAMP–borane complex with benzaldimine

The diastereoselective synthesis of a P-chirogenic β-aminophosphine ligand with carbon–carbon bond formation of the ethano bridge in a 3:1 ratio via reaction of an α-metallated P-chirogenic phosphine borane with a benzaldimine is described. The diastereoselectivity is attributed to a transition state where the lithium cation chelates the phosphine borane carbanion and the nitrogen of the imine and the attack of the CN occurs on the face opposite to the P–B bond, due to its interaction with the antibonding P–B bond. The major diastereoisomeric β-aminophosphine borane was then separated and decomplexed into the corresponding β-aminophosphine under neutral conditions and without epimerization by heating at reflux in EtOH. This synthesis offers a short hemisynthetic route to the P-chirogenic β-P,N-ligands, by bridge formation starting from methylphosphine boranes.     

Modular asymmetric synthesis of P-chirogenic beta-amino phosphine boranes

A short concise route to beta-aminophosphine boranes is presented via the desymmetrization of prochiral phosphine boranes, forming P-chirogenic aldehydes that are rapidly transformed to the target compounds employing reductive amination under microwave irradiation. This sequence provides a modular route to P-chirogenic P,N ligands, and in addition, the intermediate aldehydes are versatile P-chiral building blocks for ligand design in general. An alternative pathway via the corresponding alpha-carboxyphosphines is also described. The ligands were subsequently evalutated in the asymmetric conjugate addition of diethylzinc to trans-beta-nitrostyrene.     

Lipase-mediated stereoselective transformations of chiral organophosphorus P-boranes revisited: revision of the absolute configuration of alkoxy(hydroxymethyl)phenylphosphine P-boranes

The lipase-promoted kinetic resolution of a series of alkoxy(hydroxymethyl)phenylphosphine P-boranes proceeded with moderate stereoselectivity to give both the unreacted substrates and their O-acetyl derivatives. The absolute configurations of the products, which were earlier ascribed on the basis of the stereoselective reduction of the corresponding phosphine oxides with borane and comparison with the literature data concerning bicyclic phosphine oxides, were disputed by theoretical calculation. Some additional studies were carried out, including theoretical calculations and more accurate chemical correlation, which proved that the borane reduction of acyclic phosphine oxides proceeded with inversion of configuration at the phosphorus center and, therefore, the former assignment of the absolute configurations was incorrect. On this basis, the stereochemistry of the enzymatic reaction was ultimately determined. A mechanism of the borane reduction of acyclic phosphine oxides explaining inversion of configuration at phosphorus is proposed.     

Isolable Diaminophosphide Boranes

Metalation of secondary diaminophosphine boranes by alkali metal amides provides a robust and selective access route to a range of metal diaminophosphide boranes M[(R₂N)₂P(BH₃)] (M=Li, Na, K; R=alkyl, aryl) with acyclic or heterocyclic molecular backbones, whereas reduction of a chlorodiaminophosphine borane gave less satisfactory results. The metalated species were characterized in situ by NMR spectroscopy and in two cases isolated as crystalline solids. Single-crystal XRD studies revealed the presence of salt-like structures with strongly interacting ions. Synthetic applications of K[(R₂N)₂P(BH₃)] were studied in reactions with a 1,2-dichlorodisilane and CS₂, which afforded either mono- or difunctional phosphine boranes with a rare combination of electronegative amino and electropositive functional disilanyl groups on phosphorus, or a phosphinodithioformate. Spectroscopic studies gave a first hint that removal of the borane fragment may be feasible.     

Versatile synthesis of P-chiral (ephedrine) AMPP ligands via their borane complexes. Structural consequences in Rh-catalyzed hydrogenation of methyl α-acetamidocinnamate

An efficient and versatile synthesis of aminophosphine phosphinite (AMPP) ligands derived from ephedrine, with possible stereogenic P(III)-center(s) is described, using the borane complex methodology. The reaction of oxazaphospholidine borane with an organolithium reagent, leads to the formation of the ring-opened product, which is trapped by a chlorophosphine (borane), to afford the corresponding aminophosphine phosphinite boranes in good yields. Treatment of the borane complexes with dabco, gives the corresponding aminophosphine phosphinite ligands in 70–90% yield. These ligands are used for the preparation of Rh catalysts applied to the asymmetric hydrogenation of methyl α-acetamidocinnamate yielding the phenylalanine derivative with (R) 22% to (S) 99% e.e. These results show the importance of the structural modification at the P-stereogenic center(s), which could either amplify or cancel out the asymmetric induction resulting from the ephedrine backbone, for enantioselective catalysis.     

Configurational stability of chlorophosphines

The configurational stability of chlorophosphines is investigated. Several mechanisms involving chlorophosphine monomer, dimers, and adducts with HCl are evaluated by density functional theory calculations. The presence of HCl in the medium is found to catalyze the P-center chiral inversion at room temperature. The reaction involves a two-step mechanism with low transition states (10 kcal.mol-1) and a stabilized achiral intermediate (-2.6 kcal.mol-1). Further calculations and experiments on the halogen exchange with HBr corroborate this mechanism, with bromophosphines being formed instantaneously. Finally, to avoid the racemization, the borane is found to be a very promising protecting group for the configurational stability of the P-chirogenic chlorophosphines.     

Mechanism of Phosphine Borane Deprotection with Amines: The Effects of Phosphine,Solvent and Amine on Rate and Efficiency

The kinetics of borane transfer from simple tertiary phosphine borane adducts to a wide range of amines have been determined. All data obtained, including second‐order kinetics, lack of cross‐over, and negative entropies of activation for reaction of triphenylphosphine borane with quinuclidine and triethylamine, are consistent with a direct (S_N2‐like) transfer process, rather than a dissociative (S_N1‐like) process. The identities of the amine, phosphine, and solvent all impact substantially on the rate (k) and equilibrium (K) of the transfer, which in some cases vary by many orders of magnitude. P‐to‐N transfer is more efficient with cyclic amines in apolar solvents due to reduced entropic costs and ground‐state destabilisation. Taken as a whole, the data allow informed optimisation of the deprotection step from the stand‐point of rate, or synthetic convenience. In all cases, both reactants should be present at high initial concentration to gain kinetic benefit from the bimolecularity of the process. Ultimately, the choice of amine is dictated by the identity of the phosphine borane complex. Aryl‐rich phosphine boranes are sufficiently reactive to allow use of diethylamine or pyrrolidine as a volatile low polarity solvent and reactant, whereas more alkyl‐rich phosphines benefit from the use of more reactive amines, such as 1,4‐diaza[2.2.2]bicyclooctane (DABCO), in apolar solvents at higher temperatures.     

Asymmetric hydrogenation of unsaturated ureas with the BIPI ligands

Asymmetric hydrogenation of unsaturated urea esters with the BIPI Ligands has been examined. Optimization of the P-N ligand structure has led to the development of chiral rhodium catalysts capable of producing the targets with >99% ee. The critical phosphine borane SNAr reaction needed for ligand synthesis has been optimized to give the adducts in high yield at ambient temperature with no racemization. An extremely concise, economical, and scalable sequence to these important new ligands for catalysis of asymmetric hydrogenation has been developed.     

P-chirogenic phosphines. MOP/diPAMP hybrids, their oxide crystal structures, reduction studies and alternative syntheses

The novel P-chirogenic anisylphenylMOP derivatives (R,R) and (R,S)-2-(anisylphenylphosphino)-2′-methoxy-1,1′-binaphthyl (10a and b) have been synthesized and their corresponding oxides characterised by X-ray crystallography. The results of a parallel screening regimen with various reducing agents highlight the sensitivity of the tertiary phosphine oxides to epimerisation and, interestingly, reveal that the PO, O-CH₃ and P-C₆H₅ bonds can all be cleaved selectively depending on the reducing agents employed. An alternative synthesis was provided by direct coupling of the secondary phosphine with (R)-methoxytriflate 4, which led to the isolation of the optically pure P-chirogenic phosphines via their borane adducts. A brief study of the coordination chemistry of 10a with different rhodium precursors, relevant to the catalytic asymmetric addition of boronic acids to aldehydes is also reported.     

Stereospecific Synthesis of α‐ and β‐Hydroxyalkyl P‐Stereogenic Phosphine–Boranes and Functionalized Derivatives: Evidence of the PO Activation in the BH3‐Mediated Reduction

Access to hydroxy‐functionalized P‐chiral phosphine–boranes has become an important field in the synthesis of P‐stereogenic compounds used as ligands in asymmetric catalysis. A family of optically pure α and β‐hydroxyalkyl tertiary phosphine–boranes has been prepared by using a three‐step procedure from readily accessible enantiopure adamantylphosphinate, obtained by semi‐preparative HPLC on multigram scale. Firstly, a two‐step one‐pot transformation affords the enantiopure hydroxyalkyl tertiary phosphine oxides in good yields and enantioselectivities. The third step, BH₃‐mediated reduction, allows the formation of the desired phosphine–boranes with excellent stereospecifity. The mechanistic study of this reduction provides new evidence to elucidate the crucial role of the pendant hydroxy group and the subsequent activation of the P?O bond by the boron atom.     

1,2-Nucleophilic addition of 2-(picolyl)organoboranes to nitrile, aldehyde, ketone, and amide

A series of 2-(picolyl)borane molecules were synthesized as products of the reaction between 2-(picolyl)lithium and R(2)BOMe (R = ethyl, 9-BBN, phenyl, 9-borafluorenyl). The 2-(picolyl)boranes were dimeric; whereas, monomers coordinated to LiOMe could be isolated when the synthesis was carried out in the presence of TMEDA and THF. The 2-(picolyl)boranes undergo reaction with nitriles, ketones, aldehydes, and amides with apparent 1,2-addition of the B-C(picolyl) bond to the unsaturated bond. Theoretical models reveal the presence of a donor orbital on the 2-(picolyl)borane with significant electron density at the benzylic carbon that we conclude was involved in nucleophilic attack on the electrophilic center of unsaturated organic functional groups.     

Direct preparation and structure determination of tertiary and secondary amine boranes from primary or secondary amine boranes

New secondary and tertiary amine borane derivatives were prepared in a one-pot reaction starting from primary amine boranes. The reaction involves treatment of an amine borane with 2 equivalents of s-BuLi at −78 °C. In general, mixtures of mono and di metallated products were obtained. Alkyl iodides and benzyl chloride reacted with the lithiated amine, but aldehydes and ketones were reduced. Conversion was high as determined by NMR, but moderate to low yields were obtained after chromatography, possibly due to decomposition on silica. Crystal structures were obtained for the compounds 3a, 3b and 3c.     

Homometathesis and cross-metathesis coupling of phosphine-borane templates with electron-rich and electron-poor olefins

Ruthenium-catalysed olefin cross-metathesis can be used to synthesise structurally diverse acyclic phosphines protected as their borane complexes. Homodimerisations have been investigated and proved successful only for the allyl-substituted borane-protected phosphines. In the presence of various olefinic partners, allyl-substituted P templates reacted in cross-couplings to give predominantly the E products but traces of the Z isomers were always detected in the crude reaction mixtures. In contrast, cross-metathesis of vinyl-substituted phosphine boranes took place with exclusive E-selectivity. Although the conversions were consistently very good to excellent, the yields of purified products were often significantly lower suggesting that some of the newly formed compounds are prone to decompose upon purification.     

Photo‐promoted Skeletal Rearrangement of Phosphine–Borane Frustrated Lewis Pairs Involving Cleavage of Unstrained C−C σ‐Bonds

An unprecedented photo‐promoted skeletal rearrangement reaction of phosphine–borane frustrated Lewis pairs, o‐(borylaryl)phosphines, involving cleavage of an unstrained sp²C–sp³C σ‐bond is reported. The reaction realizes an efficient synthesis of cyclic phosphonium borate compounds. The reaction mechanism via a boranorcaradiene intermediate is proposed based on theoretical calculations. This work sheds light on the new photoreactivity of phosphine–borane FLPs.     

Photo-promoted Skeletal Rearrangement of Phosphine–Borane Frustrated Lewis Pairs Involving Cleavage of Unstrained C−C σ-Bonds

An unprecedented photo-promoted skeletal rearrangement reaction of phosphine–borane frustrated Lewis pairs, o-(borylaryl)phosphines, involving cleavage of an unstrained sp²C–sp³C σ-bond is reported. The reaction realizes an efficient synthesis of cyclic phosphonium borate compounds. The reaction mechanism via a boranorcaradiene intermediate is proposed based on theoretical calculations. This work sheds light on the new photoreactivity of phosphine–borane FLPs.     

Alkylation of phosphine boranes by phase-transfer catalysis

The alkylation of phosphine boranes with various electrophiles proceeds with good to excellent yields in a biphasic solution in the presence of tetrabutylammonium bromide as a phase-transfer catalyst. [reaction: see text]     

Stereoselective generation of (E)- and (Z)-2-fluoroalkylidene-type carbenoids from (2-fluoro-1-alkenyl)iodonium salts and their application for stereoselective synthesis of fluoroalkenes

Alkylidene-type carbenoids, generated from (Z)- or (E)-(2-fluoro-1-alkenyl)iodonium salts by treatment with LDA, reacted with trialkylboranes to give (E)- or (Z)-(fluoroalkenyl)boranes stereoselectively. The resulting (fluoroalkenyl)borane can be used for the selective synthesis of (E)- or (Z)-fluoroalkenes, (E)- or (Z)-fluoroiodoalkenes, and alpha-fluoroketones. [reaction: see text]