Stereo- and Regiocontrolled Syntheses of Exomethylenic Cyclohexane β-Amino Acid Derivatives.

Loránd Kiss,Enikő Forró,Ferenc Fülöp,Renáta Ábrahámi,György Orsy

doi:10.3390/molecules201219749

Loránd Kiss, Enikő Forró + Show 3 more

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https://doi.org/10.3390/molecules201219749

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Abstract

Cyclohexane analogues of the antifungal icofungipen [(1R,2S)-2-amino-4-methylenecyclopentanecarboxylic acid] were selectively synthesized from unsaturated bicyclic β-lactams by transformation of the ring olefinic bond through three different regio- and stereocontrolled hydroxylation techniques, followed by hydroxy group oxidation and oxo-methylene interconversion with a phosphorane. Starting from an enantiomerically pure bicyclic β-lactam obtained by enzymatic resolution of the racemic compound, an enantiodivergent procedure led to the preparation of both dextro- and levorotatory cyclohexane analogues of icofungipen.

Highlights

As a consequence of their high biological potential, cyclic β-amino acids are of importance in medicinal chemistry
An exomethylene function plays an essential role in the structures of some cyclic β-amino acids
Icofungipen is a cyclic β-amino acid, which differs in chemistry, biology, and mechanism of action from other antifungal compound classes

Summary

Introduction

As a consequence of their high biological potential, cyclic β-amino acids are of importance in medicinal chemistry. Icofungipen is a cyclic β-amino acid, which differs in chemistry, biology, and mechanism of action from other antifungal compound classes. Enantiomers of 29 could be obtained by starting from an enantiomerically pure bicyclic lactam For this purpose, enantiomerically pure β-lactam (+)-30 (ee = 99%) was prepared by CAL-B-catalyzed ring-opening of racemic lactam (±)-30 (Scheme 9) [24]. Rf = 0.65 (n-hexane/EtOAc 4:1); 1H-NMR (CDCl3, 400 MHz): δ = 1.22 (t, 3H, CH3, J = 7.10 Hz), 1.22–1.30 (m, 1H, CH2) 1.40 (s, 9H, t-Bu), 1.75–1.84 (m, 2H, CH2), 1.95–2.02 (m, 1H, CH2), 2.07–2.19 (m, 1H, CH2), 2.21–2.28 (m, 1H, CH2), 2.39–2.43 (m, 1H, H-1), 4.11–4.20 (m, 2H, OCH2), 4.24–4.35 (m, 1H, H-2), 4.39 (brs, 1H, N-H), 4.79–4.83 (m, 2H, CH2). Calcd for C15H25NO4: C 63.58, H 8.89, N 4.94; found: C 63.80, H 8.60, N 5.22

Characterization of the Enantiomerically Pure Substances

Conclusions