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. 2021 Nov 5;86(21):14493-14507.
doi: 10.1021/acs.joc.1c01364. Epub 2021 Oct 11.

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

Bence Varga  1 , Péter Szemesi  1   2 , Petra Nagy  1 , Réka Herbay  1 , Tamás Holczbauer  3 , Elemér Fogassy  1 , György Keglevich  1 , Péter Bagi  1
Affiliations

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

Bence Varga et al. J Org Chem. .

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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Selected examples showing the main methods for the preparation of P-stereogenic secondary phosphine oxides in optically active form (yields were calculated on the basis of the full amount of the racemate).
Figure 2
Figure 2
Outline of this research project.
Scheme 1
Scheme 1. Preparation of Racemic Diaryl Secondary Phosphine Oxides (1a–i)
Scheme 2
Scheme 2. Summary of the Best Results for the Resolution of P-Stereogenic Secondary Phosphine Oxides (1) with (R,R)-spiro-TADDOL [(R,R)-2]
Scheme 3
Scheme 3. Gram-Scale Resolution of (2-Methylphenyl)-phenylphosphine Oxide (1a) and (t-Butyl)-phenylphosphine Oxide (1m) with (R,R)-spiro-TADDOL [(R,R)-2]
Figure 3
Figure 3
(a) Hydrogen bonds formed in the diastereomeric complex (S)-1a·(spiro-TADDOL). Nonhydrogen atom ellipsoids are drawn on a 30% probability level. (b) The neighboring molecules with the strongest interactions of (S)-1a for the calculation of interaction energies (DFT calculation details can be found in Table 1).
Scheme 4
Scheme 4. Stereoselective Synthesis of Various P-Stereogenic Tertiary Phosphine Oxides and a Thiophosphinate (3) from (S)-(2-Methylphenyl)phenylphosphine Oxide [(S)-1a]
See this image and copyright information in PMC

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