ChemInform Abstract: Asymmetric Synthesis of α,α‐Disubstituted Amino Acids by Cycloaddition of (E)‐Ketonitrones with Vinyl Ethers.

Abstract

International audienc

Isoxazolidine: A Privileged Scaffold for Organic and Medicinal Chemistry

“…Dujardin and Py 93,105,106,118 have shown that in the presence of SmI 2 or Mo(CO) 6 the ring opening of 5-ethoxyisoxazolidines can afford β-amino aldehydes. However, these compounds were unstable due to the reaction between the amino group and the aldehyde function, resulting in the ring opening.…”

“…84,215 In the case of 5-alkoxy-isoxazolidines, the ring opening can also lead to Nprotected 1,3-aminoesters without prior quaternarization of the nitrogen atom but thanks to the influence of a strong electronwithdrawing N-acyl substituent, as demonstrated by the group of Dujardin. 105,106,118 Indeed, by a typical SmI 2 treatment that led to amidoaldehydes from N-acetyl isoxazolidines, the authors synthesized 1,3-aminoesters 185 (60−75% yields) from Ntrifluoroacetyl isoxazolidines 150, while use of the Mo(CO) 6 protocol was unsuccessful to open the isoxazolidine ring (Scheme 63).…”

δ-Valerolactamic Quaternary Amino Acid Derivatives: Enantiodivergent Synthesis and Evidence for Stereodifferentiated β-Turn-Inducing Properties

“…The latter revealed to be a key intermediate to access pseudodipeptides containing an acyclic α,α-disubstituted amino acid, through ester 4 (Pg = COCF 3 ). 14 During this work, we found an interesting chemodivergence of the SmI 2promoted reductive opening of N-acylated derivatives of isoxazolidine 2, yielding selectively either ester 4 or aldehyde 3 (Pg = COCH 3 ). We eventually realized that enantiopure isoxazolidine 2 could be exploited to access α,α-disubstituted amino acids of opposite absolute configuration through selective manipulation of the three different carbonyl groups in compounds 3 or 4.…”

“…In our previous work, the N-acetyl (6a) and N-trifluoroacetyl (6b) derivatives of enantiopure isoxazolidine 2 were nicely converted into aldehyde 3a and ester 4b, respectively, upon treatment with SmI 2 . 14 Considering that the acetyl N-substituent is not a convenient protecting group for peptide synthesis, we turned our attention to the N-pent-4enoyl isoxazolidine 6c as possible precursor of amino aldehyde 3c (Scheme 2). The pent-4-enoyl protecting group appeared particularly attractive as it can be orthogonally removed upon treatment with I 2 in THF/H 2 O.…”

“…From N-trifluoroacetyl isoxazolidine 6b, optimization of the previously described conditions 14 for SmI 2 -promoted reductive opening furnished N-trifluoroacetyl triester 4b in 91% yield (Scheme 2). Selective acidolysis of the less hindered tert-butyl ester function of 4b using diluted TFA in dichloromethane at 0 °C produced monoacid (diester) 7b in 51% isolated yield (corrected yield 85%), together with minor amounts (5%) of diacid ethyl monoester and 40% of starting material (4b).…”