Enantioseparation of P-Stereogenic Secondary Phosphine Oxides and Their Stereospecific Transformation to Various Tertiary Phosphine Oxides and a Thiophosphinate.

Bence Varga,Péter Bagi,Elemér Fogassy,Réka Herbay,Petra Nagy,Tamás Holczbauer,Péter Szemesi,György Keglevich

doi:10.1021/acs.joc.1c01364

Abstract

Secondary phosphine oxides incorporating various aryl and alkyl groups were synthesized in racemic form, and these products formed the library reported in this study. TADDOL derivatives were used to obtain the optical resolution of these P-stereogenic secondary phosphine oxides. The developed resolution method showed a good scope under the optimized reaction conditions, as 9 out of 14 derivatives could be prepared with an enantiomeric excess (ee) ≥ 79% and 5 of these derivatives were practically enantiopure >P(O)H compounds (ee ≥ 98%). The scalability of this resolution method was also demonstrated. Noncovalent interactions responsible for the formation of diasteromeric complexes were elucidated by single-crystal XRD measurements. (S)-(2-Methylphenyl)phenylphosphine oxide was transformed to a variety of P-stereogenic tertiary phosphine oxides and a thiophosphinate in stereospecific Michaelis–Becker, Hirao, or Pudovik reactions.

Highlights

P-Stereogenic phosphines, phosphine oxides, or phosphonium salts represent an important class among organophophorus compounds, as these chiral derivatives have found widespread application as ligands,[1] organocatalysts,[2] or even biologically active compounds.[3]
A synthetic strategy employing the diethylamino protecting group was selected for the synthesis of the racemic diaryl phosphine oxides (1a−i) (Scheme 1)
N,N-Diethylamino-chloro-phenylphosphine (6) was the key intermediate in our divergent synthetic strategy, and it was reacted with aryllithiums to give the corresponding aminophosphines (7)

Summary

Introduction

P-Stereogenic phosphines, phosphine oxides, or phosphonium salts represent an important class among organophophorus compounds, as these chiral derivatives have found widespread application as ligands,[1] organocatalysts,[2] or even biologically active compounds.[3] The preparation of enantiopure Pcompounds still represents a challenge, which inhibits their more diverse use. Most of the synthetic methods give the organophosphorus compound of interest in optically active form.[4] Syntheses involving the preparation of P-chiral precursors followed by their incorporation in the desired scaffold represent a modular strategy carrying high synthetic potential. Low toxicity, odorless property, and the stereospecific functionalization of their P−H bond make secondary phosphine oxides (SPOs) desired P-stereogenic precursors.[5] when the >P(O)H−>P(OH) tautomerization is utilized,[6] secondary phosphine oxides can be regarded as (pre)ligands, which can be used in transition metal catalyzed asymmetric transformations.[7]

Objectives

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Results

Conclusion