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Synthesis 2011(19): 3045-3079  
DOI: 10.1055/s-0030-1260173
REVIEW
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Fluorinated β-Amino Acids

Koichi Mikamia, Santos Fusterob,c, Maria Sánchez-Rosellóc, José Luis Aceñac, Vadim Soloshonokd,e, Alexander Sorochinsky*f
a Department of Applied Chemistry, Tokyo Institute of Technology, 2-12-1 Ookayama, Tokyo 152-8552, Japan
b Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Valencia, 46100 Burjassot, Valencia, Spain
c Laboratorio de Moléculas Orgánicas, Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain
d Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, 20018 San Sebastian, Spain
e IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain
f Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Murmanska Street 1, 02660 Kyiv-94, Ukraine
Fax: +380(44)5732552; e-Mail: sorochinsky@bpci.kiev.ua;
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Publikationsverlauf

Received 13 June 2011
Publikationsdatum:
16. August 2011 (online)

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Abstract

The major goal of this review is to provide an overview of the general synthetic methods available in the literature for preparing fluorinated β-amino acids and their derivatives. These compounds have been employed in combination with non-fluorinated amino acids in the design of peptides and peptidomimetics for investigation of their proteolytic stability and influence of molecular composition on the folding properties and biological activity. Fluorinated­ β-amino acids serve as precursors for the β-lactam antibiotics­ and fluoroalkene dipeptide isosteres or as structural components of analogues of natural products. There are several general methods available for introducing into β-amino acids either one or two fluorine atoms at the α-position, as well as α- or β-fluoroalkyl substituents; these methods include reduction of fluorinated β-imino esters, biomimetic transamination of fluorinated carbonyl compounds, Michael-type addition to trifluorocrotonate and α-tri­fluoromethacrylate derivatives, and Reformatsky and Mannich-type reactions of fluorinated substrates. Fluorinated aziridines and β-lactams have been employed as synthetic intermediates for the preparation of the corresponding β-amino acids by facile ring-opening reactions. Other methods discussed in review are fluorination and trifluoromethylation of β-amino acid derivatives, reactions of organometallic reagents with fluorinated imines and related compounds, and metathesis reactions of fluorinated imino esters and imidoyl halides for the synthesis of cyclic derivatives.

1 Introduction

2 Fluorination and Trifluoromethylation of β-Amino Acid Derivatives

3 Reduction of Fluorinated β-Imino Esters

4 Biomimetic Transamination of Fluorinated Carbonyl Compounds

5 Michael-Type Additions to β-Trifluorocrotonate and α-Trifluoromethacrylate Derivatives

6 Reformatsky-Type Reaction of Fluorinated Substrates

7 Mannich-Type Reactions of Fluorinated Substrates

8 Cycloaddition Reactions of Fluoroalkyl Imines

9 Reactions of Organometallic Reagents with Fluorinated Imines and Related Compounds

10 Metathesis Reactions

11 Miscellaneous Reactions

12 Conclusions

Key words

fluorine - β-amino acids - asymmetric synthesis - biomimetic synthesis - biologically active compounds - synthetic methodology