Synthesis of P-Stereogenic Phosphorus Compounds. Asymmetric Oxidation of Phosphines under Appel Conditions

Abstract

Chiral nonracemic phosphorus compounds are ubiquitous in catalytic asymmetric synthesis, both as ligands in metal-based processes 1 and as organocatalysts in their own right. 2 However, although a very large number of such ligands have been tested, the great majority have their chirality located on the carbon backbone (C-stereogenic, e.g., BINAP and DuPHOS) 1a instead of on the phosphorus atom (P-stereogenic, e.g., DiPAMP). 1c This is despite the fact that better chiral induction might be expected by incorporation of chirality as close as possible to the catalytic center. 3 Although P-stereogenic ligands have proven to be effective, 4 relatively few have been studied because they are difficult to synthesize. 5 Early methods were based on resolution and the generation of unequal mixtures of diastereomers, 5a while more recent strategies include desymmetrization, enzymatic resolution, and catalytic asymmetric synthesis. 5b,6 Some of these methods can be very effective, but most are limited in scope in some way and there remains a clear need for a general solution. Herein we report on our efforts to provide such a methodology.We have been interested in this difficult problem for some time. 7 We felt that there was promise in strategies involving kinetic resolution (KR) or dynamic kinetic resolution (DKR) in P(III)/P(V) interconversions (Scheme 1). Our initial approach centered on KR in asymmetric reduction (Scheme 1a), but this gave uniformly low selectivity, 7a in line with previous reports, 8 and we turned our attention to asymmetric oxidation (Scheme 1b). There have been very few reported successes at KR/DKR in such systems, 5a,9 most notably by Perlikowska et al. 9a who reported up to 39% ee in the KR of P-stereogenic tertiary phosphines and 70% ee for a single example of the first DKR of a chlorophosphine. In our early experiments, 7b,c we reacted racemic phosphines with chiral nonracemic epoxides hoping that the high temperature of the reaction would allow DKR through racemization of the phosphine, but the selectivity was low (20% at best).A way to achieve facile interconversion of stereogenic phosphorus centers at low temperatures is via pseudorotation of pentavalent pentacoordinate phosphorus compounds (10P5). 10 We therefore explored a variety of processes that could involve 10P5, and we report now our preliminary results on an asymmetric version of the oxidation/reduction/dehydration system known as the Appel conditions. 11 Typically, these conditions involve use of PPh 3 /CCl 4 to convert an alcohol to an alkyl chloride in high yield. From our perspective, these conditions are an oxidation of a phosphine involving a potentially chiral reagent (Scheme 2). Therefore, we were encouraged when our first experiments with this system gave some selectivity. Treatment of racemic phenyl-ortho-anisylmethylphosphine (PAMP, the precursor of DiPAMP) with CCl 4 and (-)-menthol in benzene at reflux gave the phosphine oxide ((R)-PAMPO) in good yields and up to 24% ee.Subsequently, we used the more reactive hexachloroaceto...

P‐Stereogenic Phosphorus Compounds: Effect of Aryl Substituents on the Oxidation of Arylmethylphenylphosphanes under Asymmetric Appel Conditions

“…Exemplar: Methyl(phenyl)(o-tolyl)phosphane [36] (2e): A dry 100 mL two-necked round-bottomed flask fitted with reflux condenser, nitrogen inlet and outlet and septum was charged with magnesium turnings (0.5 g, 18.7 mmol, 1.1 equiv.). 2-Bromotoluene (3.0 g, 17 mmol, 1 equiv.)…”

“…[36] This is an oxidation/reduction/dehydration system [37] in which a racemic tertiary phosphane interacts with a source of positively charged chlorine, for example, hexachloroacetone (HCA), and a chiral non-racemic alcohol. The dynamic nature of the resolution allows high enantiomeric excesses to be obtained at full conversion.…”

Recentes aplicações sintéticas de compostos orgânicos tricloro(bromo)metila substituídos

“…Bergin e colaboradores publicaram a inédita oxidação de racematos de fosfinas por um sistema contendo álcool quiral (especialmente derivados terpênicos disponíveis comercialmente a preços acessíveis) e HCA, levando aos respectivos óxidos de fosfinas com rendimentos acima de 95% e, em alguns casos, excesso enantionético de até 80%. 97 Compostos fosforilados quirais possuem diferentes aplicações em catálise assimétrica, e, em geral, o centro estereogênico encontra-se em um átomo de carbono. Todavia, nesses exemplos a quiralidade está no átomo de fósforo.…”

Asymmetric Organocatalytic Electrophilic Phosphination

“…When the 31 P NMR spectrum of 2 ( Figure 1, spectrum a) is compared with those of mixtures of 2 with quinuclidine and with 5 31 P NMR investigations: a) 2, b) mixture of 2 with quinuclidine, c) mixture of 2 with 5, d) standard reaction at room temperature after 10 min, e) standard reaction at room temperature after 6 h, f) standard reaction with excess of 1 at room temperature after 10 min, g) standard reaction with excess of 1 at room temperature after 3 h. All solutions were at 1 m concentration. (Figure 1, spectrum b and c, respectively), two new signals (d = 36 and 37 ppm) are seen, indicating that a new species is formed (6). To verify that this species is also present during the reaction of 1 with 2 when it is catalyzed by 5, 31 P NMR spectra of the crude reaction mixture were measured after 10 minutes and after 6 hours ( Figure 1, spectrum d and e, respectively), by which time the full conversion of 1 was observed.…”

“…[5] Hence, the development of asymmetric organocatalytic approaches towards optically active organophosphorus molecules is highly important. [6] A synthetic limitation is that previously the asymmetric catalytic formation of stereogenic carbon centers bonded to phosphorus (C*ÀP) has only been performed using nucleophilic phosphorus compounds. [7] Herein we present the first asymmetric catalytic C*ÀP bond formation employing a phosphine electrophile.…”