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.     

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.     

Optically active P-chiral phosphinoselenoic amides: stereochemical outcome at the P-stereogenic center in the synthesis of these substances and their characterization

A variety of optically active P-chiral phosphinoselenoic amides were synthesized with high efficiency by reacting racemic P-chiral phosphinoselenoic chlorides with optically active lithium amides. Some of the diastereomers of the amides were separated by column chromatography on silica gel. The absolute configurations of the phosphinoselenoic amides were determined by X-ray molecular structure analyses. Optically active P-chiral phosphinoselenoic chlorides were also reacted with optically active lithium amide. The reaction proceeded predominantly with inversion of configuration, but also involved retention of stereochemistry at the phosphorus atom during the substitution reaction.     

Selective reductions in the sphere of organophosphorus compounds

Recent results on the selective reduction of cyclic vinylphosphine oxides and vinylphosphinates, as well as their refunctionalization by the use of borane, are summarized. The selective reduction of the phosphorus moiety of unsaturated phosphonates, phosphinates, and phosphine oxides is also discussed. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:161–167, 2001     

Regioselective functionalisation of nitrobenzene and benzonitrile derivatives via nucleophilic aromatic substitution of hydrogen by phosphorus-stabilized carbanions

The synthesis of P-benzylic products by reaction of anions stabilised by N-phosphorylphosphazenyl, N-methoxycarbonylphosphazenyl, phosphine borane complex, and phosphine oxide groups by displacement of hydrogen of a variety of electron-deficient benzene derivatives is described. Lithium phosphazenes were the most suitable nucleophiles for the substitution of hydrogen in nitrobenzene and some ortho-, meta-, and para- substituted nitrobenzenes. Lithiated phosphine borane complexes produced efficiently the substitution of the hydrogen at the para position of a cyano group in cyanobenzenes, whereas the anion of ethyldiphenylphosphine oxide lead to complex mixtures with all electrophiles assayed. The method reported here represents a convenient alternative to the vicarious nucleophilic substitution for the synthesis of benzylic phosphorus derivatives using phosphorus-stabilised anions that do not bear a leaving group at the carbanionic centre.     

Synthesis of ferrocene-based phosphine ligands via Cu-catalyzed reductive coupling of ferrocenyl ketone-derived tosylhydrazones and H-phosphorus oxides

Ferrocene-based phosphine oxides with various substituents at phosphorous atoms were synthesized by Cu-catalyzed reductive coupling of ferrocenyl ketone-derived tosylhydrazones and H-phosphorus oxides. Followed by the reduction of ferrocene-based phosphine oxides, 1-substituted ferrocene-based phosphine ligand 7 and 1,1′-disubstituted ferrocene-based phosphine ligand 9 were obtained. Josiphos type ligand 8 were produced after ortho-lithiation of 7 and trapping with chlorodiphenyl phosphine or chlorodicyclohexylphosphine.     

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.     

Cyclopentannulation on 3-phospholenes: an expedient route to the 2-phosphabicyclo[3.3.0]octene ring system

Treatment of 1-phenyl-3-phospholene derivatives with 2 equiv. of LDA followed by quenching the metallated intermediates with 1,3-dihaloalkanes affords 2-phosphabicyclo[3.3.0]oct-3-ene derivatives in good yield. The annulation reactions are highly regio- and stereoselective and lead to the formation of exo-Ph-P substituted products exclusively. Reduction of the resulting bicyclic phosphine oxides by phenylsilane gives the corresponding phosphines with complete retention of configuration at P. Application of this annulation procedure to acyclic allylic substrates leads to the corresponding monocyclic annulation products.     

Synthesis of Glycosylphosphine Oxides and Related Compounds

The benzyl-protected glycosyl acetates 1 , 6 , 11 , and 15 react with MeOPPh₂ under catalysis by TMSOTf to yield diastereoselectively the glycosylphosphine oxides 2 , 3 , 8 , 12 , 13 , and 16 , with a strong preference for the 1,2-cis-configurated anomers. Hydrogenolysis of the major products gave the crystalline, unprotected phosphine oxides 4 , 9 , 14 , and 17 , of which 4 was transformed in to the acetate 5 , and 9 into the benzoate 10 . The benzylated phosphine oxides 4 , 8 , 12 , and 16 were reduced with Cl₃SiH in the presence of a tertiary amine to form the phosphines 18 , 21 , 24 , and 26 , which were transformed into the phosphine sulfides 19 , 22 , 25 , and 27 . Moreover, 18 and 21 , were characterized as the borane adducts 20 , and 23 . The structure of the (arabinofuranosyl)phosphine oxide 12 , the corresponding sulfide 25 , and of the borane complex 20 were established by X-ray analysis. According to NMR spectroscopy, the equatorial pyranosylphosphine oxide 8 , the sulfide 22 , and the borane complex 23 adopt a ⁴C₁ conformation. The axial phosphine oxide 2 is a flattened ⁴C₁, the sulfide 19 exists as a B_2,5, and the borane complex 20 is a flattened ⁴C₁ in the solid sate and a B_2,5 in solution. Thus, the conformational behavior of these α-D -glucopyranose derivatives reflects the steric requirement of the P-substituents.     

Experimental and Theoretical Investigations of the Stereoselective Synthesis of P‐Stereogenic Phosphine Oxides

An efficient enantioselective strategy for the synthesis of variously substituted phosphine oxides has been developed, incorporating the use of (1S,2S)‐2‐aminocyclohexanol as the chiral auxiliary. The method relies on three key steps: 1) Highly diastereoselective formation of P^V oxazaphospholidine, rationalized by a theoretical study; 2) highly diastereoselective ring‐opening of the oxazaphospholidine oxide with organometallic reagents that takes place with inversion of configuration at the P atom; 3) enantioselective synthesis of phosphine oxides by cleavage of the remaining P?O bond. Interestingly, the use of a P^III phosphine precursor afforded a P‐epimer oxazaphospholidine. Hence, the two enantiomeric phosphine oxides can be synthesized starting from either a P^V or a P^III phosphine precursor, which constitutes a clear advantage for the stereoselective synthesis of sterically hindered phosphine oxides.     

Stereospecific nucleophilic substitution of optically pure H-phosphinates: a general way for the preparation of chiral P-stereogenic phosphine oxides

Contrary to the generally held view, it is found that the rapid epimerization of (-)-menthyl (RP)-phenylphosphinate under basic conditions is not due to the so far believed inherent stereolability of its corresponding anion but due to a reaction of the hydrogen phosphinate ester with a metal alkoxide. This finding successfully leads to a discovery that, by adding an H-phosphinate to organolithiums or Grignard reagents at a low temperature, the nucleophilic substitution of the alkoxy group of the H-phosphinate with organolithiums or Grignard reagents proceeds stereospecifically with inversion of configurations at phosphorus to give a wide range of P-stereogenic secondary phosphine oxides and tertiary phosphine oxides, by quenching the reaction mixture with water and alkyl halides, respectively. This finding establishes a general protocol for the preparation of optically active secondary phosphine oxides and tertiary phosphine oxides from the easily accessible optically pure H-phosphinates. Mechanistic studies show that the substitution reactions of H-phosphinates with organolithiums and Grignard reagents proceed via two competing reaction paths, that is, a two-step reaction path involving first a deprotonation of H-phosphinates followed by a substitution of the corresponding anion with inversion of configuration at phosphorus and a direct substitution of RM with H-phosphinates generating the SPO directly.     

Study of asymmetric reduction of 1-substituted fluorenone with borane in the presence of several chiral amino alcohols

The enantioselective reduction of 1-bromofluorenone by borane in the presence of different chiral amino alcohols has been studied. The alcohol obtained has the (S) or (R) configuration depending on the nature of the substitution of the amino alcohol. The experimentally determined absolute configuration can be explained when a four-center cyclic transition state consisting of the oxazaborolidine and fluorenone compound is considered.     

Theoretical investigation of the mechanisms and stereoselectivities of reductions of acyclic phosphine oxides and sulfides by chlorosilanes

Computational studies were performed to explain the highly varied stereoselectivities obtained in the reductions of acyclic phosphine oxides and sulfides by different chlorosilanes. The reductions of phosphine oxides by HSiCl(3), HSiCl(3)/Et(3)N, and Si(2)Cl(6) and the reductions of phosphine sulfides by Si(2)Cl(6) (all in benzene) were explored by means of B3LYP, B3LYP-D, and SCS-MP2 calculations. For the reductions of phosphine oxides by HSiCl(3), the calculations support the mechanism proposed by Horner in which a hydride is transferred from silicon to phosphorus through a four-centered, frontside transition state. This mechanism leads to retention of stereochemistry at phosphorus. For the other three reductions, two classes of mechanisms were explored. Phosphorane-based mechanisms that were previously proposed by Mislow and involve SiCl(3)(-) were compared with novel alternative mechanisms that involve nonionic rearrangement processes. In one of these, donor-stabilized SiCl(2) is formed as an intermediate. The calculations support a phosphorane-based mechanism for the reductions of phosphine oxides by HSiCl(3)/Et(3)N and Si(2)Cl(6) (which proceed with inversion) but favor the rearrangement pathways for the reductions of phosphine sulfides by Si(2)Cl(6) (which proceed with retention).     

Sodium in liquid ammonia—a versatile tool in modifications of arylphosphine oxides

A simple and practical method for modifications of tertiary arylphosphine oxides based on their reaction with sodium in liquid ammonia is presented. Depending on the structure of the starting compounds, either dearomatisation of the phenyl substituent or cleavage of a P-aryl bond from phosphorus atom can be selectively performed and the corresponding (1,4-cyclohexadien-3-yl)phosphine oxides or secondary phosphine oxides were obtained in good to excellent yields.     

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.     

Steric and Electronic Effects on the Configurational Stability of Residual Chiral Phosphorus‐Centered Three‐Bladed Propellers: Tris‐aryl Phosphane Oxides

A series of tris‐aryl phosphane oxides existing as residual enantiomers or diastereoisomers with substituents on the aryl rings differing in size and electronic properties were synthesized and characterized. Their electronic properties were evaluated on the basis of their electrochemical oxidation and reduction potentials together with those of the corresponding “blade bromides” (i.e., the naphthalene derivatives displaying the same substitution pattern of the tris‐naphthyl phosphane oxide blades, with a bromo substituent where the phosphorus atom is located) determined by CV. The residual stereoisomeric phosphane oxides were isolated in a stereochemically pure state and were found to be highly configurationally stable at room temperature (stereoisomerization barriers of about 27 kcal mol^?1). The chiroptical properties of the residual stereoisomers and the assignments of absolute configuration are discussed. The configurational stability of residual tris‐aryl phosphane oxides was found to be scarcely influenced by the electronic properties of the substituents present on the aromatic rings constituting the blades, while steric effects play the most relevant role. Detailed theoretical calculations are in agreement with the experimental results and also contribute to a rational interpretation of the stereodynamics of these systems.     

Rh2[(R)-(+)-MTPA]4 as an NMR auxiliary for the enantiodifferentiation of chiral secondary and tertiary phosphine–borane complexes

The direct chiral recognition of secondary and tertiary phosphine–borane complexes is made possible by applying the dirhodium method (NMR in the presence of Rh₂[(R)-(+)-MTPA]₄, Rh¹). Due to the acid lability of the phosphine–borane complexes, it is advisable to use deuterated benzene as solvent rather than deuterated chloroform. The decomposition of the phosphine–borane complexes and the resulting Rh¹–phosphine adducts are also studied.     

Generation of 1,2-azaboretidines via reduction of ADC borane adducts

Reaction of the acyclic (diamino)carbene (ADC) :C(NiPr₂)₂ (1) with different dihaloboranes of the type RBX₂ (R = Mes, Dur; X = Cl, Br) smoothly afforded a novel class of ADC-stabilized borane adducts. For MesBBr₂ however, the reaction did not stop at the adduct level, but an uncommon rearrangement process occurred, which eventually resulted in the formation of a 5-membered boracycle after elimination of mesitylene. Chemical reduction of the ADC borane adducts by KC₈ selectively yielded air stable 1,2-azaboretidines. Detailed DFT studies suggest a reduction mechanism involving a highly reactive borylene intermediate, which is converted into the boracycles via a rearrangement/C–H activation sequence.     

Heterohelicenes with Embedded P‐Chiral 1H‐Phosphindole or Dibenzophosphole Units: Diastereoselective Photochemical Synthesis and Structural Characterization

The oxidative photocyclization reactions of olefins that contain 1H‐phosphindole or dibenzophosphole substituents have been applied to the synthesis of P/N‐bi‐heterosubstituted dimeric helicenes, as well as of new [6]‐ and [8]phosphahelicenes. In these photocyclization processes, the configuration of the stereogenic phosphorus center dictates the sense of helical chirality. Thus, by starting from enantiomerically pure P‐menthylphosphole‐oxide units, this method affords enantiopure helical compounds. The helical phosphine oxides were characterized by X‐ray diffraction. After reduction of the phosphine‐oxides, the corresponding helical phosphines have been used as ligands in transition‐metal complexes. The X‐ray crystal structure of a gold chloride complex of a [6]helicene is reported.     

Development of P-stereogenic 2-phenyl-1,3,2-oxazaphosphorine ligands and their unexpected sensitivity to oxidation

P-Stereogenic oxazaphosphorine compounds of the form 4 have not previously been reported as asymmetric ligands for metal-catalyzed reactions. In an effort to explore the behavior of such oxazaphosphorine ligands, monomeric oxazaphosphorine borane 9 and dimeric oxazaphosphorine boranes 25 and 26 were synthesized as catalyst precursors. The absolute configuration of the phosphorus center contained in the oxazaphosphorines was determined by X-ray crystallography. Rhodium-catalyzed hydrogenation of methyl 2-acetamidoacrylate using a dimerized spiro oxazaphosphorine ligand was performed with up to 15% ee. The extreme sensitivity of the oxazaphosphorine ligands toward oxidation prevented further optimization of the enantioselectivity.