A study on the diastereoselective synthesis of α-fluorinated β³-amino acids by α-fluorination

Abstract

<jats:title>Abstract</jats:title><jats:p>The treatment of a <jats:italic>β</jats:italic><jats:sup>3</jats:sup>‐amino acid methyl ester with 2.2 equiv. of lithium diisopropylamide (LDA), followed by reaction with 5 equiv. of <jats:italic>N</jats:italic>‐fluorobenzenesulfonimide (NFSI) at −78° for 2.5 h and then 2 h at 0°, gives <jats:italic>syn</jats:italic>‐fluorination with high diastereoisomeric excess (de). The de and yield in these reactions are somewhat influenced by both the size of the amino acid side chain and the nature of the amine protecting group. In particular, fluorination of <jats:italic>N‐</jats:italic>Boc‐protected <jats:italic>β</jats:italic><jats:sup>3</jats:sup>‐homophenylalanine, <jats:italic>β</jats:italic><jats:sup>3</jats:sup>‐homoleucine, <jats:italic>β</jats:italic><jats:sup>3</jats:sup>‐homovaline, and <jats:italic>β</jats:italic><jats:sup>3</jats:sup>‐homoalanine methyl esters, <jats:bold>5</jats:bold> and <jats:bold>9</jats:bold>–<jats:bold>11</jats:bold>, respectively, all proceeded with high de (&gt;86% of the <jats:italic>syn</jats:italic>‐isomer). However, fluorination of <jats:italic>N‐</jats:italic>Boc‐protected <jats:italic>β</jats:italic><jats:sup>3</jats:sup>‐homophenylglycine methyl ester (<jats:bold>16</jats:bold>) occurred with a significantly reduced de. The use of a Cbz or Bz amine‐protecting group (see <jats:bold>3</jats:bold> and <jats:bold>15</jats:bold>) did not improve the de of fluorination. However, an <jats:italic>N</jats:italic>‐Ac protecting group (see <jats:bold>17</jats:bold>) gave a reduced de of 26%. Thus, a large <jats:italic>N</jats:italic>‐protecting group should be employed in order to maximize selectivity for the <jats:italic>syn</jats:italic>‐isomer in these fluorination reactions.</jats:p>