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

-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 . 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.

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.

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 -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% , 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% ) 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.

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.

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

The complex fluxional interconversions between otherwise very similar phosphonium bromides and chlorides R PX X (R=Alk, Ar, X=Cl or Br) were studied by NMR techniques. Their energy barriers are typically ca. 11 kcal mol , but rise rapidly as bulky groups are attached to phosphorus, revealing the importance of steric factors.

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.

Mysterious Decomposition of Alkoxyphosphonium Chlorides: Postulated Involvement of the HCl 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 HCl in solution.

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 .

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.

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.

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.

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.

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.

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.

The modern interpretation of the Wittig reaction mechanism.

The mechanism of the Wittig reaction has long been a contentious issue in organic chemistry. Even now, more than 50 years after its announcement, its presentation in many modern undergraduate textbooks is either overly simplified or entirely inaccurate. In this review, we gather together the huge body of evidence that has been amassed to show that the Li salt-free Wittig reactions of non-stabilised, semi-stabilised and stabilised ylides all occur under kinetic control by a common mechanism in which oxaphosphetane (OPA) is the first-formed and only intermediate.

Identification of a key intermediate in the asymmetric Appel process: one pot stereoselective synthesis of P-stereogenic phosphines and phosphine boranes from racemic phosphine oxides.

Sequential treatment of racemic phosphine oxides with oxalyl chloride and chiral non-racemic alcohol generates the same ratios of diastereomeric alkoxyphosphonium salts obtained in the corresponding asymmetric Appel process, strongly implicating the intermediate chlorophosphonium salt in the stereoselecting step. Subsequent reduction allows a novel synthesis of enantioenriched P-stereogenic phosphines-phosphine boranes.

Unequivocal experimental evidence for a unified lithium salt-free Wittig reaction mechanism for all phosphonium Ylide types: reactions with β-heteroatom-substituted aldehydes are consistently selective for cis-oxaphosphetane-derived products.

The true course of the lithium salt-free Wittig reaction has long been a contentious issue in organic chemistry. Herein we report an experimental effect that is common to the Wittig reactions of all of the three major phosphonium ylide classes (non-stabilized, semi-stabilized, and stabilized): there is consistently increased selectivity for cis-oxaphosphetane and its derived products (Z-alkene and erythro-β-hydroxyphosphonium salt) in reactions involving aldehydes bearing heteroatom substituents in the β-position. The effect operates with both benzaldehydes and aliphatic aldehydes and is shown not to operate in the absence of the heteroatom substituent on the aldehyde.

A convenient and mild chromatography-free method for the purification of the products of Wittig and Appel reactions.

A mild method for the facile removal of phosphine oxide from the crude products of Wittig and Appel reactions is described. Work-up with oxalyl chloride to generate insoluble chlorophosphonium salt (CPS) yields phosphorus-free products for a wide variety of these reactions. The CPS product can be further converted into phosphine.

MOP-phosphonites: a novel ligand class for asymmetric catalysis.

Chiral phosphonite ligands (S,R(b))-5a, (S,S(b))-5b, (R,R(b))-6a and (R,S(b))-6b are introduced, comprising a MOP-type backbone with a binol-based binaphthyl group bound to the phosphorus. Their reaction with [Pd(η(3)-C(4)H(7))Cl](2) affords η(3)-methallylpalladium chloride complexes 7a/b and 8a/b which have been isolated and structurally characterised. Solid-state and solution studies indicate subtle differences in their coordination behaviour, which ultimately affects their efficacy in the asymmetric hydrosilylation of styrene.