Synthesis of 2-Amino-apopinan-3-ol and Applications of Its Derivatives in Asymmetric Reduction of Ketones

Anna Kmieciak,Marek P Krzemiński

doi:10.3390/ecsoc-23-06509

Abstract

Monoterpenes are optically active compounds which occur in nature. This fact makes them interesting precursors for the synthesis of optically active ligands, which can be applied in various asymmetric reactions. In this work, we present the synthesis of optically pure 2-amino-apopinan-3-ol from (−)-α-pinene. The obtained amino alcohol was used as a precursor of oxazaborolidine, which was used as catalyst in the asymmetric reduction of aryl-alkyl ketones with borane. In the second part, we transformed 2-amino-apopinan-3-ol into PHOX ligand in a three-step reaction. The complex of ruthenium precursor with PHOX ligand was used as a catalyst in the asymmetric transfer hydrogenation of aryl-alkyl ketones. Alcohols with enantiomeric excesses of up to 97% were isolated using both reduction methods.

Highlights

Active monoterpenes widely occur in nature, they are readily used in organic synthesis as a valuable chiral platform. β-Pinene, α-pinene, 2-carene, and 3-carene are chiral bicyclic compounds that can be modified by generating new stereogenic centers
The bicyclic framework of these compounds makes them rigid structures with well defined steric hindrance. These properties induce applications of monoterpene derivatives as chiral ligands in catalytic asymmetric synthesis, which is an important part of organic synthesis
The nitrogen atom with sp3 hybridization occurs both in the form of NH2, N-alkyl or aryl substituted and cyclic structures (Figure 1A). These ligands were used in iridium-catalyzed asymmetric reduction of α,βunsaturated ketones [5] and α-substituted derivatives of acrylic acid [6,7], copper-catalyzed addition of diethylzinc to imines [8,9], and palladium-catalyzed asymmetric allylic substitution reactions [10,11,12]

Summary

Introduction

Active monoterpenes widely occur in nature, they are readily used in organic synthesis as a valuable chiral platform. β-Pinene, α-pinene, 2-carene, and 3-carene are chiral bicyclic compounds that can be modified by generating new stereogenic centers. The nitrogen atom with sp hybridization occurs both in the form of NH2, N-alkyl or aryl substituted and cyclic structures (Figure 1A) These ligands were used in iridium-catalyzed asymmetric reduction of α,βunsaturated ketones [5] and α-substituted derivatives of acrylic acid [6,7], copper-catalyzed addition of diethylzinc to imines [8,9], and palladium-catalyzed asymmetric allylic substitution reactions [10,11,12]. Most likely this is due to the trans position of the oxazoline ring in ligand 9 relative to the gem-dimethyl bridge in the pinane system [36] Another way to reduce prochiral ketones to chiral secondary alcohols is enantioselective reduction with borane catalyzed by chiral oxazaborolidines. We present our work on application of β-amino alcohols synthesized from the (−)α-pinene in enantioselective reduction of ketones by ATH method and using oxazaborolidine

Synthesis of β-Amino Alcohols

Findings

Asymmetric Reduction of Aryl-Alkyl Ketones with Borane