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A Study on the Diastereoselective Synthesis of α ‐Fluorinated β 3 ‐Amino Acids by α ‐Fluorination
Author(s) -
Peddie Victoria,
Abell Andrew D.
Publication year - 2012
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.201200520
Subject(s) - chemistry , lithium diisopropylamide , amine gas treating , yield (engineering) , protecting group , electrophilic fluorination , halogenation , amino acid , fluorine , lithium (medication) , selectivity , medicinal chemistry , organic chemistry , methyl group , side chain , group (periodic table) , catalysis , ion , polymer , electrophile , biochemistry , deprotonation , metallurgy , endocrinology , medicine , materials science , alkyl
The treatment of a β 3 ‐amino acid methyl ester with 2.2 equiv. of lithium diisopropylamide (LDA), followed by reaction with 5 equiv. of N ‐fluorobenzenesulfonimide (NFSI) at −78° for 2.5 h and then 2 h at 0°, gives syn ‐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 N‐ Boc‐protected β 3 ‐homophenylalanine, β 3 ‐homoleucine, β 3 ‐homovaline, and β 3 ‐homoalanine methyl esters, 5 and 9 – 11 , respectively, all proceeded with high de (>86% of the syn ‐isomer). However, fluorination of N‐ Boc‐protected β 3 ‐homophenylglycine methyl ester ( 16 ) occurred with a significantly reduced de. The use of a Cbz or Bz amine‐protecting group (see 3 and 15 ) did not improve the de of fluorination. However, an N ‐Ac protecting group (see 17 ) gave a reduced de of 26%. Thus, a large N ‐protecting group should be employed in order to maximize selectivity for the syn ‐isomer in these fluorination reactions.