Stereoselective synthesis of carane-based chiral β- and γ-amino acid derivatives via conjugate addition

doi:10.1016/j.tet.2015.05.019

Tetrahedron

Volume 71, Issue 29, 22 July 2015, Pages 4846-4852

https://doi.org/10.1016/j.tet.2015.05.019 Get rights and content

Abstract

Michael addition of dibenzylamine to (−)-tert-butyl isochaminate, prepared in three steps from (−)-perillaldehyde, furnished a carane-based β-amino acid derivative in a highly stereospecific reaction. The resulting amino ester was transformed to the bicyclic amino acid, a promising building block for the synthesis of 1,3-heterocycles and peptidomimetics. The conjugate addition of nitromethane to α,β-unsaturated methyl ester likewise resulted in nitro esters in stereospecific reactions. Catalytic reduction of the nitro group yielded a γ-amino ester. Under acidic conditions, the hydrolysis of the methyl ester resulted in an unexpected aminolactone-type product through rearrangement of the bicyclic carane system, whereas an alternative synthetic pathway through α,β-unsaturated benzyl ester furnished the desired γ-amino acid.

Graphical abstract

Introduction

In view of the importance of alicyclic and bicyclic chiral β-amino acids in the synthesis of 1,3-amino alcohol, 1,3-diamine or β-amino carboxamide chiral catalysts and building blocks of β-peptidic foldamers and saturated or partially saturated 1,3-heterocycles with promising pharmacological activities, increased attention is currently turning to the stereoselective synthesis of these chiral building blocks.1, 2, 3, 4, 5, 6, 7, 8, 9

Several powerful synthetic methodologies are available via which alicyclic or bicyclic β-amino acid enantiomers can be obtained, including enzyme-catalysed kinetic resolution,10, 11 and a variety of asymmetric syntheses, e.g. the enantioselective syntheses of β-lactams followed by ring opening,12, 13 or the enantioselective desymmetrization of achiral anhydrides followed by Curtius degradation.14, 15, 16

Besides the above methods, the conjugate addition of amine nucleophiles to α,β-unsaturated carbonyl compounds has recently become a powerful procedure to obtain alicyclic β-amino acids in enantiomerically pure form on a gram scale.17, 18 The principal strategy of these methods is the use of chiral lithium amides, and only a few examples are to be found where chiral α,β-unsaturated esters are applied as the source of chirality in the conjugate addition.19, 20, 21, 22, 23

Besides the synthesis of β-amino esters, α,β-unsaturated esters are excellent starting materials to obtain γ-amino acid derivatives via the conjugate addition of nitroalkanes, followed by catalytic reduction of the nitro group and hydrolysis of the ester function.19, 24, 25, 26 Because of their promising biological and therapeutic applications, the search for efficient and versatile synthetic strategies to gain access to a variety of γ-amino acids is a very active research field.24, 27

Readily available optically active monoterpene derivatives, such as (+)- and (−)-pulegone, (+)- and (−)-verbenone, (+)-3-carene or (+)- and (−)-α-pinene, have often been considered as substrates for the synthesis of chiral reagents and as unique synthons in asymmetric syntheses of β-amino acids, 1,3-amino alcohols applied as chiral additives, catalysts or building blocks.13, 28, 29, 30, 31, 32, 33, 34 From this respect, the chiral, monoterpene-based α,β-unsaturated esters might be excellent starting materials, where the natural monoterpene skeleton may serve as the origin of the chirality for the stereoselective construction of the β- and γ-amino acid moiety.¹⁹

Our present aim was the preparation and some transformations of a new family of conformationally constrained carane-based chiral β- and γ-amino acid derivatives derived from commercially available (−)-perillaldehyde 1. Our earlier results on pinane-based β-amino acid derivatives revealed that these bicyclic building blocks with β- and γ-amino acid functions might serve as promising chiral substrates for the synthesis of chiral catalysts and foldamers.4, 7, 19, 35

Section snippets

Results

For the synthesis of β-amino acid 9, tert-butyl isochaminate 4 served as the key intermediate Michael acceptor, which was prepared from commercially available (−)-(4S)-perillaldehyde 1 by a combination of literature protocols in a three-step reaction: addition of HBr to 1, followed by treatment with KOtBu, yielded the bicyclic aldehyde 2, which was then oxidized to (+)-isochaminic acid 3 by literature method,36, 37, 38, 39 which in turn was converted to the tert-butyl ester 4 (Scheme 1).⁴⁰

Conclusions and outlook

The highly stereoselective addition of lithium amides to tert-butyl isochaminate 3 proved to be an efficient method for the synthesis of a new carane-based β-amino acid via three-step transformation of the resulting N,N-dibenzyl β-amino ester 7 on a gram scale. Conjugate addition of MeNO₂ to unsaturated esters 5 and 6 resulted in γ-nitro esters in stereoselective reactions. Acid-catalysed ring rearrangement of carane-based γ-amino ester 11 resulted in the unique bicyclic aminolactone 13, while

General

¹H NMR spectra were recorded on a Bruker Avance DRX 400 spectrometer at 400.1 MHz (¹H) and 100.6 MHz (¹³C) [δ=0 (TMS)] in CDCl₃, DMSO-d₆ or D₂O in a 5-mm tube. Chemical shifts are expressed in ppm (δ) relative to TMS as internal reference. J values are given in Hz. Microanalyses were performed on a Perkin–Elmer 2400 elemental analyser. Optical rotations were obtained with a Perkin–Elmer 341 polarimeter. Melting points were determined on a Kofler apparatus and are uncorrected. FTIR spectra were

Acknowledgements

We are grateful to the Hungarian Research Foundation (OTKA NK81371 and K112442) for financial support.

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Stereoselective synthesis of carane-based chiral β- and γ-amino acid derivatives via conjugate addition

Abstract

Graphical abstract

Introduction

Section snippets

Results

Conclusions and outlook

General

Acknowledgements

Tetrahedron

Tetrahedron: Asymmetry

Tetrahedron: Asymmetry

Tetrahedron: Asymmetry

Tetrahedron: Asymmetry

Tetrahedron: Asymmetry

Tetrahedron Lett.

Tetrahedron

Tetrahedron: Asymmetry

Tetrahedron: Asymmetry

Tetrahedron: Asymmetry

Tetrahedron: Asymmetry

Tetrahedron

Phytochemistry

Mendeleev Commun.

Chem. Rev.

Chem. Soc. Rev.

Amino Acids

Chem. Rev.

Chem. Commun.

Org. Lett.

Chem. Soc. Rev.

Mini Rev. Org. Chem.