Synthesis of Enantiomerically Pure β- and γ-Amino Acid Derivatives Using Functionalized Organozinc Reagents

Abstract

β-Amido zinc reagents 4 and 5 readily undergo β-elimination when prepared in THF, but when a polar aprotic solvent such as DMF is employed, β-elimination is suppressed. Using DMF, reaction of 4 with aryl iodides provides β-homophenylalanine derivatives (12 examples, 20-89% yield), and analogous reactions of 5 give γ-bishomophenylalanine derivatives (7 examples, 34-80% yield). The related zinc/copper reagents 17 and 18 are also useful intermediates that undergo subsequent crosscoupling reactions with a wide range of electrophiles (9 examples, 28-87% yield).

LAT-1 activity of meta-substituted phenylalanine and tyrosine analogs

“…conversion of 8 to 10 ), we explored the convergent approach depicted in Scheme 3 as an alternative. Conversion of commercially available alkyl iodide 14 to Jackson's organozinc 15 39, 40 followed by an in situ Negishi coupling 41 to give 17a-f was successfully performed. Though this route added additional synthetic steps to obtain noncommercial meta substituted aryl iodides 42 16c-f , we found Scheme 3 to be a robust approach for preparing several of the desired amino acid analogs of Figure 1 (i.e.…”

Asymmetric syntheses of radioactive and stable isotope‐labeled β‐amino acids

“…Available methodology for asymmetric synthesis of β ‐amino acids with one chiral center is shown in Figure . Method I starts with unsaturated acid 6 .…”

Synthesis of γ‐Aminobutyric Acid Analogs

“…The traditional method being a double Arndt-Eistert homologation in which the multistep sequence can result in low yields [103]. Alternatively, a Wittig reaction with an alkyl (triphenylphosphoranylidene)acetate on a-amino aldehydes such as phenylalaninal (115) and subsequent reduction of the resulting alkene (116) has been employed (Scheme 14.33). Hydrolysis of the protecting group affords the g-substituted g-amino acid (117) [112].…”

“…The iodozinc derivative of (126) prepared in three steps from the protected L-glutamic acid (125) has been reported to undergo coupling with a range of substituted aryl iodides to afford enantiopure g-aryl substituted GABA (127) derivatives in moderate to good yields (Scheme 14.36) [115,116].…”