Methods for the Asymmetric Synthesis of α-Fluoro and α,α-Difluoro-β³-Amino Acids

Author: Taryn March

March, Taryn, 2011 Methods for the Asymmetric Synthesis of α-Fluoro and α,α-Difluoro-β³-Amino Acids, Flinders University, School of Chemical and Physical Sciences

This electronic version is made publicly available by Flinders University in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material and/or you believe that any material has been made available without permission of the copyright owner please contact copyright@flinders.edu.au with the details.

Abstract

Fluorinated β³-amino acids are becoming increasingly important due to their potential therapeutic applications, particularly with regard to enzyme inhibition, however research in this area is somewhat limited by a lack of adequate methods for their preparation. Strategies to prepare β-amino acids that feature complex side chains e.g., lysine and arginine, receive even less attention, and are thus the focus of this work, which details the development of two complementary methodologies for the asymmetric synthesis of α-fluoro- and α,α-difluoro-β³-amino acids. Chapter 1 discusses the tandem conjugate addition of a chiral lithium amide to an α,β-unsaturated ester, whereby the intermediate enolate is quenched with an electrophilic source of fluorine. A series of α-fluoro-β³-amino esters were subsequently prepared using this method, with silyl-protected substrates proving the most suitable. A stepwise method involving separate deprotonation and fluorination reactions was also investigated, however this failed to match the diastereoselectivity of the tandem reaction. Demonstrating the applicability of this tandem conjugate addition-fluorination reaction to the preparation of α-fluoro-β³-amino acids, two silyl-protected conjugate adducts were then transformed into orthogonally protected α-fluoro-β³-lysine and α-fluoro-β³-arginine derivatives, as described in Chapter 2. Access to the corresponding α,α-difluoro-β³-amino esters was achieved via the development of a Reformatsky reaction employing chiral aliphatic imines derived from phenylglycine, which is discussed in Chapter 3. This method improves upon the Reformatsky methodologies currently available for the preparation of α,α-difluoro-β³-amino esters bearing aliphatic β-substituents, which have historically given unsatisfactory yields and diastereoselectivities. The versatility of these conjugate addition and Reformatsky methodologies was further demonstrated in Chapter 4, in which the preparation of three β³-arginine analogues is detailed. An unfluorinated and α-fluoro analogue were both prepared from substrates synthesised via the conjugate addition methodology, while the corresponding α,α-difluoro analogue was prepared using the Reformatsky reaction. The complementarity of the two techniques is demonstrated by the fact that each of the analogues was derived from the same achiral aldehyde. Given the successful synthesis of these compounds, each of the two methodologies discussed in this thesis should find greater use amongst the synthetic community for the preparation of α-fluoro and α,α-difluoro-β³-amino acids.

Keywords: fluorinated,β-amino acid,lysine,arginine,Reformatsky,conjugate addition
Subject: Chemistry thesis

Thesis type: Doctor of Philosophy
Completed: 2011
School: School of Chemical and Physical Sciences
Supervisor: Martin Johnston