Synthesis of Methyl N-Boc-(2S,4R)-4-methylpipecolate

Abstract

An efficient stereoselective synthesis of fully protected (2S,4R)-4-methylpipecolic acid has been developed. The synthesis was achieved by initial asymmetric α-alkylation of glycine with a chiral iodide, affording the linear precursor as a single stereoisomer. Subsequent aldehyde formation using OsO(4)/NaIO(4) followed by immediate intramolecular cyclization afforded an enamine that was then subjected to hydrogenation to give the final compound in 23% yield over 10 steps.

Axially chiral Ni(II) complexes of α‐amino acids: Separation of enantiomers and kinetics of racemization

“…[7][8][9][10][11][12][13][14][15][16][17][18] For quite some time, our groups were interested in pursuing new synthetic approaches for preparation of sterically constrained, 19,20 phosphorus, 21,22 and fluorine-containing [23][24][25] AAs. 28,29 Along with other research groups, [30][31][32][33][34][35][36][37][38][39] we showed that chiral nucleophilic glycine equivalents 1 can be transformed to various AAs 2 via general reactions types, such as alkyl halide alkylations, 40,41 Michael, 42,43 aldol, 44,45 and Mannich 46,47 addition reactions. 28,29 Along with other research groups, [30][31][32][33][34][35][36][37][38][39] we showed that chiral nucleophilic glycine equivalents 1 can be transformed to various AAs 2 via general reactions types, such as alkyl halide alkylations, 40,<...>…”

“…One of the most methodologically prolific directions, inspired by the seminal work by Belokon, 26,27 has been the chemistry of Ni(II) complexes of AAs derived Schiff bases (Scheme 1). 28,29 Along with other research groups, [30][31][32][33][34][35][36][37][38][39] we showed that chiral nucleophilic glycine equivalents 1 can be transformed to various AAs 2 via general reactions types, such as alkyl halide alkylations, 40,41 Michael, 42,43 aldol, 44,45 and Mannich 46,47 addition reactions. Complexes 2 can be easily disassembled under acidic conditions to afford the target-free AAs along with recovery and recycling of the corresponding chiral ligands.…”

“…This methodology was also shown to work very well for preparation of bis-AAs, 48,49 using α,ω-di-halo-alkylating reagents, highly sterically constrained (1R,2S)-1-amino-2vinylcyclopropanecarboxylic acid derivatives, 50,51 by S N 2-S N 2′ dialkylation, and kinetic resolution of unprotected α- 52,53 and β-AAs. It was shown [30][31][32][33][34][35][36][37][38][39]61 that the benzophenone phenyl group is absolutely essential to achieve high stereocontrol of the glycine methylene homologation. 59,60 However, all these different types of complexes 1 share one key structural feature, the o-amino-benzophenone moiety.…”

“…59,60 However, all these different types of complexes 1 share one key structural feature, the o-amino-benzophenone moiety. It was shown [30][31][32][33][34][35][36][37][38][39]61 that the benzophenone phenyl group is absolutely essential to achieve high stereocontrol of the glycine methylene homologation. It is generally assumed, as shown in Figure 1, that the phenyl group cannot freely rotate due to the steric interaction with either or both the o-amino phenyl and/or glycine moieties.…”

Improved Synthesis of the Unnatural Amino Acids AHMOD and AMD, Components of the Anticancer Peptaibol Culicinin D

“…In this study we established that installation of the sidechain methyl group could be achieved by stereoselective Myers alkylation of propionate 4, 4 followed by reductive removal of the auxiliary and conversion to the iodide (5). 5 Alkylation of the Belokon nickel glycinate complex (6, inset) 6 with 5 using sodium hydroxide in acetonitrile, followed by acidic cleavage of the proline-based template, stereoselectively delivered the required α-amino acid nucleus 7. N-Boc protection, esterification and oxidative cleavage of the olefin then afforded aldehyde 8, that served as the common precursor for both unnatural amino acids.…”