Telescoped Continuous Flow Synthesis of Optically Active γ-Nitrobutyric Acids as Key Intermediates of Baclofen, Phenibut, and Fluorophenibut.

Sándor B Ötvös,Patricia Llanes,C Oliver Kappe,Miquel A Pericàs

doi:10.1021/acs.orglett.0c03100

Sándor B Ötvös, Patricia Llanes + Show 2 more

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https://doi.org/10.1021/acs.orglett.0c03100

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Abstract

The two-step flow asymmetric synthesis of chiral γ-nitrobutyric acids as key intermediates of the GABA analogues baclofen, phenibut, and fluorophenibut is reported on a multigram scale. The telescoped process comprises an enantioselective Michael-type addition facilitated by a polystyrene-supported heterogeneous organocatalyst under neat conditions followed by in situ-generated performic acid-mediated aldehyde oxidation. Simple access to valuable optically active substances is provided with key advances in terms of productivity and sustainability compared to those of previous batch approaches.

Highlights

The two-step flow asymmetric synthesis of chiral γ-nitrobutyric acids as key intermediates of the GABA analogues baclofen, phenibut, and fluorophenibut is reported on a multigram scale
Synthetic Strategy toward GABA Derivatives asymmetric synthesis of these chiral GABA analogues has attracted a great deal of interest
For the organocatalytic asymmetric conjugate addition, a polystyrene-supported cis-4-hydroxydiphenylprolinol TBS ether (1) was selected as a catalyst (Figure 1A), which was chosen on the basis of our earlier results on a solvent-free asymmetric Michael-type addition of dimethyl malonate leading to a key chiral intermediate of a well-known antidepressant.13b Catalyst 1 was developed as an improved version of classical trans-diphenylprolinol analogues,[14] but it has not yet been exploited for conjugate additions of nitromethane to α,β-unsaturated aldehydes

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Corresponding Authors

Ö tvös − Institute of Chemistry, University of Graz, A8010 Graz, Austria; Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), A-8010 Graz, Austria; orcid.org/0000-0001-6673-1744; Email: sandor.oetvoes@ uni-graz.at. C. Oliver Kappe − Institute of Chemistry, University of Graz, A8010 Graz, Austria; Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), A-8010 Graz, Austria; orcid.org/0000-0003-2983-6007; Email: oliver.kappe@ uni-graz.at. Patricia Llanes − Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology (BIST), E-43007 Tarragona, Spain. Pericàs − Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology (BIST), E-43007 Tarragona, Spain; Departament de Quiḿ ica Inorgaǹ ica i Orgaǹ ica, Universitat de Barcelona (UB), E-08028 Barcelona, Spain; orcid.org/0000-0003-0195-8846.

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