Unexpected rapid P-stereomutation of phosphine oxides catalysed by chlorophosphonium salts.

P-Stereomutation of phosphine oxides is extremely slow. We show that it is catalysed by chlorophosphonium salts (CPS) which can directly be formed in the system in situ. The racemization of phosphine oxides at ambient conditions catalysed by 1 mol% of CPS takes 1-2 hours and can be arrested by additon of a primary alcohol. The process probably proceeds via the development of oxodiphosphonium P-O-P species.

Asymmetric addition of Grignard reagents to ketones: culmination of the ligand-mediated methodology allows modular construction of chiral tertiary alcohols.

A new class of biaryl chiral ligands derived from 1,2-diaminocyclohexane (1,2-DACH) has been designed to enable the asymmetric addition of aliphatic and, for the first time, aromatic Grignard reagents to ketones for the preparation of highly enantioenriched tertiary alcohols (up to 95% ee). The newly developed ligands L12 and L12' together with the previously reported L0 and L0' define a set of complementary chiral promoters, which provides access to the modular construction of a broad range of structurally diverse non-racemic tertiary alcohols, bearing challenging quaternary stereocenters. The present advancements bring to completion our asymmetric Grignard methodology by expanding the scope to aromatic organomagnesium reagents, while facilitating its implementation in organic synthesis thanks to improved synthetic routes for the straightforward access to the chiral ligands. The synthetic utility of the method has been demonstrated by the development of a novel and highly enantioselective formal synthesis of the antihistamine API clemastine via intermediate (R)-3a. Exploiting the power of the 3-disconnection approach offered by the Grignard synthesis, (R)-3a is obtained in 94% ee with ligand (R,R)-L12. The work described herein marks the finalization of our ongoing effort towards the establishment of an effective and broadly applicable methodology for the asymmetric Grignard synthesis of chiral tertiary alcohols.

Wittig Olefination Using Phosphonium Ion-Pair Reagents Incorporating an Endogenous Base.

Despite common perception, the use of strong bases in Wittig chemistry is utterly unnecessary: we report a series of novel ion-pair phosphonium carboxylate reagents which are essentially "storable ylides". These reagents are straightforwardly prepared in excellent yields, and their fluxional nature permits clean olefination of a broad range of aldehydes and even hemiacetals.

Harnessing the Power of the Asymmetric Grignard Synthesis of Tertiary Alcohols: Ligand Development and Improved Scope Exemplified by One-Step Gossonorol Synthesis.

A series of N-substituted cyclohexyldiaminophenolic ligands for the asymmetric Grignard synthesis of tertiary alcohols is reported. The 2,5-dimethylpyrrole-decorated ligand led to improved enantioselectivities and broadened the scope of the methodology. As an exemplar, we report an unprecedented highly selective one-step synthesis of gossonorol in 93% ee, also constituting the shortest formal syntheses of natural products boivinianin B and yingzhaosu C.

Very short highly enantioselective Grignard synthesis of 2,2-disubstituted tetrahydrofurans and tetrahydropyrans.

Phenones with elongated chains are shown to be excellent substrates for ligand-promoted asymmetric Grignard synthesis of tertiary alcohols. In turn this enables the simple, short and highly enantioselective (up to 96% ee) preparation of chiral 2,2-disubstituted THFs and THPs. Thus, asymmetric addition of Grignard reagents to γ-chlorobutyrophenones and δ-chlorovalerophenones takes place in the presence of a chiral diaminocyclohexyl-derived tridentate ligand and subsequent base-promoted intramolecular cyclisation occurs with complete retention of asymmetry. As examples of the methodology, we report the shortest syntheses of gossonorol, γ-ethyl-γ-phenylbutyrolactone and δ-methyl-δ-tolylvalerolactone, the joint-shortest and flexible synthesis of boivinianin A and the shortest formal syntheses of boivinianin B and yingzhaosu C.

Long sought synthesis of quaternary phosphonium salts from phosphine oxides: inverse reactivity approach.

Quaternary phosphonium salts (QPS), a key class of organophosphorus compounds, have previously only been available by routes involving nucleophilic phosphorus. We report the realisation of the opposite approach to QPS utilising phosphine oxides as the electrophilic partner and Grignard reagents as nucleophiles. The process is enabled through the crucial intermediacy of the derived halophosphonium salts. The route does not suffer from the slow kinetics and limited availability of many parent phosphines and a broad range of QPS were prepared in excellent yields.

Dynamic Cross-Exchange in Halophosphonium Species: Direct Observation of Stereochemical Inversion in the Course of an SN 2 Process.

The complex fluxional interconversions between otherwise very similar phosphonium bromides and chlorides R3 PX+ X- (R=Alk, Ar, X=Cl or Br) were studied by NMR techniques. Their energy barriers are typically ca. 11 kcal mol-1 , but rise rapidly as bulky groups are attached to phosphorus, revealing the importance of steric factors. In contrast, electronic effects, as measured by Hammett analysis, are modest (ρ 1.46) but still clearly indicate negative charge flow towards phosphorus in the transition state. Most significantly, detailed analysis of the exchange pathways unequivocally, and for the first time in any such process, shows that nucleophilic attack of the nucleophilic anion on the tetrahedral centre results in inversion of configuration.

Highly stereoselective construction of the C2 stereocentre of α-tocopherol (vitamin E) by asymmetric addition of Grignard reagents to ketones.

Tertiary alcohol precursors of both C2 diastereoisomers of α-tocopherol were prepared in three ways by our recently reported asymmetric Grignard synthesis. The versatility of Grignard chemistry inherent in its three-way disconnection was exploited to allow the synthesis of three product grades: 77 : 23 dr (5 steps), 81 : 19 dr (5 steps) and 96 : 4 dr (7 steps, one gram scale) from readily available and abundant starting materials. The products were converted to their respective α-tocopherols in 3 steps, which allowed a definitive re-assignment of their absolute configurations.

Asymmetric Grignard Synthesis of Tertiary Alcohols through Rational Ligand Design.

A simple, general and practical method is reported for highly enantioselective construction of tertiary alcohols through the direct addition of organomagnesium reagents to ketones. Discovered by rational ligand design based on a mechanistic hypothesis, it has an unprecedented broad scope. It utilizes a new type of chiral tridentate diamine/phenol ligand that is easily removed from the reaction mixture. It is exemplified by application to a formal asymmetric synthesis (>95:5 d.r.) of vitamin E.

Mysterious Decomposition of Alkoxyphosphonium Chlorides: Postulated Involvement of the HCl2 Anion and Its Capture in the Solid State.

P-Alkoxyphosphonium (AP) chlorides were generated by reacting P-chlorophosphonium chlorides with alcohols. Their well-known spontaneous Arbuzov-type collapse leading to phosphine oxides was studied and its rate found to be dependent on a number of factors in an unexpected fashion: it is inversely proportional to the initial concentration and it shows strong dependence on the acidity of the media but is not very sensitive to the presence of base. To explain these observations, we evoke a self-inhibition model with the formation of the less nucleophilic hydrodichloride anion HCl2 in solution. Detailed analysis of the kinetic data yields the association constant (K=3×102 m-1 ) of the putative HCl2 species in chloroform. Experimental observations for the collapse of highly enriched diastereomeric alkoxyphosphonium (DAP) chlorides are fully analogous to the achiral AP also implying the involvement of HCl2 anions. Moreover, crystallisation of a highly enriched DAP salt derived from (-)-menthol furnished, for the first time, crystals of individual (RP )-DAP hydrodichloride as confirmed by X-ray diffractometry. Importantly, the P-configuration and detailed conformation of the DAP moiety is in good agreement with DFT-level computational results. The thermal collapse of (RP )-DAP⋅HCl2 proceeds with complete retention of the P-configuration furnishing the phosphine oxide of exceptional enantiomeric purity.

Two Independent Orthogonal Stereomutations at a Single Asymmetric Center: A Narcissistic Couple.

The energy barriers in our recently discovered Walden-type inversion of chlorophosphonium salts are similar to those for Cope rearrangements of caged cyclic hydrocarbons. Therefore, we have designed a molecular system that integrates the two processes, thereby producing the first embodiment of a chemical species that can undergo two entirely different and independent stereomutation mechanisms at the same nominal asymmetric center. Thus, the energy barrier to the rearrangement of 9-phenyl-9-phosphabarbaralane oxide, which is easily prepared by a new high-yielding synthesis, was found to be roughly 11 kcal mol-1 . This value is in contrast to the parent barbaralane (7.3 kcal mol-1 ) but in good agreement with our computational results for the rearrangement barriers. Crucially, in the corresponding chlorophosphonium derivative, two stereomutations occur simultaneously: a fast Cope rearrangement (barrier ≈12 kcal mol-1 ) and a slow Walden-type inversion of the phosphorus center (barrier ≈21 kcal mol-1 ). The computational model also revealed a relationship between the Cope rearrangement barrier and the bridgehead distance. The phenomenon of two independent and geometrically orthogonal stereomutations at a single asymmetric center provided important general insights into reaction pathway bifurcation, microscopic reversibility, and dynamic stereochemistry. This first example of coexisting alternative mechanisms that involve covalent bonds may encourage the design of new types of dynamic molecular structures.

The Mechanism of Phosphonium Ylide Alcoholysis and Hydrolysis: Concerted Addition of the O-H Bond Across the P=C Bond.

The previous work on the hydrolysis and alcoholysis reactions of phosphonium ylides is summarized and reviewed in the context of their currently accepted mechanisms. Several experimental facts relating to ylide hydrolysis and to salt and ylide alcoholysis are shown to conflict with those mechanisms. In particular, we demonstrate that the pKa values of water and alcohols are too high in organic media to bring about protonation of ylide. Therefore, we propose concerted addition of the water or alcohol O-H bond across the ylide P=C bond. In support of this, we provide NMR spectroscopic evidence for equilibrium between ylide and aclohol that does not require the involvement of phosphonium hydroxide. We report the first P-alkoxyphosphorane to be characterised by NMR spectroscopy that does not undergo exchange on an NMR timescale. Two-dimensional NMR spectroscopic techniques have been applied to the characterisation to P-alkoxyphosphoranes for the first time.

Chemoselective reduction of the phosphoryl bond of O-alkyl phosphinates and related compounds: an apparently impossible transformation.

A method is reported for the phosphoryl bond cleavage of O-alkyl phosphinates, phosphinothioates and certain phosphonamidates to furnish the corresponding P(III) borane adducts. The two-step procedure relies upon initial activation of the phosphoryl bond with an alkyl triflate, followed by reduction of the resulting intermediate using lithium borohydride.

Hammond Postulate Mirroring Enables Enantiomeric Enrichment of Phosphorus Compounds via Two Thermodynamically Interconnected Sequential Stereoselective Processes.

The dynamic resolution of tertiary phosphines and phosphine oxides was monitored by NMR spectroscopy. It was found that the stereoselectivity is set during the formation of the diastereomeric alkoxyphosphonium salts (DAPS), such that their initial diastereomeric excess (de) limits the final enantiomeric excess (ee) of any phosphorus products derived from them. However, (31)P NMR monitoring of the spontaneous thermal decomposition of the DAPS shows consistent diastereomeric self-enrichment, indicating a higher rate constant for decomposition of the minor diastereomer. This crucial observation was confirmed by reductive trapping of the unreacted enriched DAPS with lithium tri-sec-butylborohydride (commercially distributed as L-Selectride reagent) at different time intervals after the start of reaction, which gives progressively higher ee of the phosphine product with time. It is proposed that the Hammond postulate operates for both formation and decomposition of DAPS intermediate so that the lower rate of formation and faster subsequent collapse of the minor isomer are thermodynamically linked. This kinetic enhancement of kinetic resolution furnishes up to 97% ee product.

First ever observation of the intermediate of phosphonium salt and ylide hydrolysis: P-hydroxytetraorganophosphorane.

P-Hydroxytetraorganophosphorane, the long-postulated intermediate in phosphonium salt and ylide hydrolysis, has been observed and characterised by low temperature NMR, finally definitively establishing its involvement in these reactions. The results require modification of the previously accepted mechanism for ylide hydrolysis: P-hydroxytetraorganophosphorane is generated directly by 4-centre reaction of ylide with water.

Degenerate nucleophilic substitution in phosphonium salts.

Rates and energy barriers of degenerate halide substitution on tetracoordinate halophosphonium cations have been measured by NMR techniques (VT and EXSY) using a novel experimental design whereby a chiral substituent ((s)Bu) lifts the degeneracy of the resultant salts. Concomitantly, a viable computational approach to the system was developed to gain mechanistic insights into the structure and relative stabilities of the species involved. Both approaches strongly suggest a two-step mechanism of formation of a pentacoordinate dihalophosphorane via backside attack followed by dissociation, resulting in inversion of configuration at phosphorus. The experimentally determined barriers range from <9 kcal mol(-1) to nearly 20 kcal mol(-1), ruling out a mechansm via Berry pseudorotation involving equatorial halides. In all cases studied, epimerization of chlorophosphonium chlorides has a lower energy barrier (by 2 kcal mol(-1)) than the analogous bromo salts. Calculations determined that this was due to the easier accessibility in solution of pentacoordinate dichlorophosphoranes when compared to analogous dibromophosphoranes. In line with the proposed associative mechanism, bulky substituents slow the reaction in the order Me < Et < (i)Pr < (t)Bu. Bulky substituents affect the shape of the reaction energy profile so that the pentacoordinate intermediate is destabilized eventually becoming a transition state. The magnitude of the steric effects is comparable to that of the same substituents on substitution at primary alkyl halides, which can be rationalized by the relatively longer P-C bonds. The reaction displays first-order kinetics due to the prevalence of tight- or solvent-separated ion pairs in solution. Three-dimensional reaction potential energy profiles (More O'Ferrall-Jencks plots) indicated a relatively shallow potential well corresponding to the trigonal bipyramid intermediate flanked by two transition states.

Turning regioselectivity into stereoselectivity: efficient dual resolution of P-stereogenic phosphine oxides through bifurcation of the reaction pathway of a common intermediate.

Synthetic routes that provide facile access to either enantiomeric form of a target compound are particularly valuable. The crystallization-free dual resolution of phosphine oxides that gives highly enantioenriched materials (up to 94 % ee) in excellent yields is reported. Both enantiomeric oxides have been prepared from a single intermediate, (RP )-alkoxyphosphonium chloride, which is formed in the course of a selective dynamic kinetic resolution using a single enantiomer of menthol as the chiral auxiliary. The origin of the dual stereoselectivity lies in bifurcation of the reaction pathway of this intermediate, which works as a stereochemical railroad switch. Under controlled conditions, Arbuzov-type collapse of this intermediate proceeds through CO bond fission with retention of the configuration at the phosphorus center. Conversely, alkaline hydrolysis of the PO bond leads to the opposite SP  enantiomer.

Synthesis of 2,3-dihydro-1-phenylbenzo[b]phosphole (1-phenylphosphindane) and its use as a mechanistic test in the asymmetric Appel reaction: decisive evidence against involvement of pseudorotation in the stereoselecting step.

Racemic 2,3-dihydro-1-phenylbenzo[b]phosphole was obtained by reduction of 1-phenylbenzo[b]phosphole-1-oxide, itself derived by ring-closing metathesis of phenylstyrylvinylphosphine oxide. The title compound was then reoxidized under asymmetric Appel conditions. Comparison of the sense and degree of the stereoselectivity to those obtained with an open-chain analogue indicated that the ring system does not affect the selectivity of the process. This in turn strongly suggests that the stereoselection is not related to pseudorotamer preferences in putative phosphorane intermediates.

Cleavage of P=O in the presence of P-N: aminophosphine oxide reduction with in situ boronation of the P(III) product.

In contrast to tertiary phosphine oxides, the deoxygenation of aminophosphine oxides is effectively impossible due to the need to break the immensely strong and inert PO bond in the presence of a relatively weak and more reactive PN bond. This long-standing problem in organophosphorus synthesis is solved by use of oxalyl chloride, which chemoselectively cleaves the PO bond forming a chlorophosphonium salt, leaving the PN bond(s) intact. Subsequent reduction of the chlorophosphonium salt with sodium borohydride forms the P(III) aminophosphine borane adduct. This simple one-pot procedure was applied with good yields for a wide range of PN-containing phosphoryl compounds. The borane product can be easily deprotected to produce the free P(III) aminophosphine. Along with no observed PN bond cleavage, the use of sodium borohydride also permits the presence of ester functional groups in the substrate. The availability of this methodology opens up previously unavailable synthetic options in organophosphorus chemistry, two of which are exemplified.