Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Feb 7;28(4):1584.
doi: 10.3390/molecules28041584.

Enantioseparation of P-Stereogenic 1-Adamantyl Arylthiophosphonates and Their Stereospecific Transformation to 1-Adamantyl Aryl- H-phosphinates

Bence Varga  1 , Levente Buna  1 , Daniella Vincze  1 , Tamás Holczbauer  2 , Béla Mátravölgyi  1 , Elemér Fogassy  1 , György Keglevich  1 , Péter Bagi  1
Affiliations

Enantioseparation of P-Stereogenic 1-Adamantyl Arylthiophosphonates and Their Stereospecific Transformation to 1-Adamantyl Aryl- H-phosphinates

Bence Varga et al. Molecules. .

Abstract

A focused library of 1-adamantyl arylthiophosphonates was prepared in racemic form. An enantioseparation method was developed for P-stereogenic thiophosphonates using (S)-1-phenylethylamine as the resolving agent. Under optimized conditions, three out of the five arylthiophosphonates were prepared in enantiopure form (ee > 99%). The subsequent desulfurization of optically active arylthiophosphonates gave the corresponding H-phosphinates without significant erosion of enantiomeric purity (ee = 95-98%). Hence, this reaction sequence can be considered an alternative method for the preparation of 1-adamantyl aryl-H-phopshinates. The absolute configuration of the (S)-1-adamantyl phenylphosphonothioic acid was assigned using single-crystal XRD and it allowed the confirmation that the removal of the P = S group proceeds with retention of configuration. The organocatalytic applicability of (S)-1-adamantyl phenylphosphonothioic acid was also evaluated as a P-stereogenic Brønsted acid.

Keywords: H-phosphinate; P-stereogenic; enantioseparation; organocatalysis; thiophosphonate.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Preparation of racemic 1-adamantyl arylthiophosphonic acid derivatives (2).
Scheme 2
Scheme 2
Development of an enatioseparation for 1-adamantyl arylthiophosphonates (2).
Scheme 3
Scheme 3
Summary of the enantioseparation results of racemic 1-adamantyl arylthiophosphonates (2) using (S)-1-phenylethylamine ((S)-3a) under optimized conditions.
Figure 1
Figure 1
The crystallographically independent molecules in the asymmetric unit of the crystal without the atomic labelling. Hydrogens were omitted for clarity as well. Displacement ellipsoids are drawn at the 30% probability level for clarity.
Scheme 4
Scheme 4
Preparation of optically active (R)-1-adamantyl aryl-H-phosphinates ((R)-1a–c) by desulfurization of enantiopure (S)-1-adamantyl aryphosphonothioic acids ((S)-2a–c).
Scheme 5
Scheme 5
Asymmetric transfer hydrogenation of N-(4-methoxyphenyl)-1-phenylethanimine (4) and 2-methylquinoline (6) using (S)-2a as the organocatalyst.
See this image and copyright information in PMC

References

    1. Eastman R.T., Roth J.S., Brimacombe K.R., Simeonov A., Shen M., Patnaik S., Hall M.D. Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19. ACS Cent. Sci. 2020;6:672–683. doi: 10.1021/acscentsci.0c00489. - DOI - PMC - PubMed
    1. Vargas D.F., Larghi E.L., Kaufman T.S. Evolution of the Synthesis of Remdesivir. Classical Approaches and Most Recent Advances. ACS Omega. 2021;6:19356–19363. doi: 10.1021/acsomega.1c03082. - DOI - PMC - PubMed
    1. Pradere U., Garnier-Amblard E.C., Coats S.J., Amblard F., Schinazi R.F. Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs. Chem. Rev. 2014;114:9154–9218. doi: 10.1021/cr5002035. - DOI - PMC - PubMed
    1. Rodriguez J.B., Gallo-Rodriguez C. The Role of the Phosphorus Atom in Drug Design. Chem. Med. Chem. 2019;14:190–216. doi: 10.1002/cmdc.201800693. - DOI - PubMed
    1. Kamer P.C.J., Van Leeuwen P.W.N.M., editors. Phosphorus(III)Ligands in Homogeneous Catalysis: Design and Synthesis. John Wiley & Sons; New York, NY, USA: 2012.

MeSH terms

Substances

LinkOut - more resources