Asymmetric Access to α‐Substituted Functional Aspartic Acid Derivatives by a [3+2] Strategy Employing a Chiral Dienophile

Abstract

International audienc

Isoxazolidine: A Privileged Scaffold for Organic and Medicinal Chemistry

“…Interestingly, acyclic carboxy ketonitrones are found to display a pure and stable E geometry. Accordingly, high levels of stereocontrol were reported by our group in chiral auxiliarycontrolled thermal 1,3-DC reactions involving aspartic nitrones and vinyl ethers, 105,106 as well as in enantioselective cycloadditions involving alanine-containing nitrones and enals (Figure 10). 103,104 Recently, original studies about 1,3-DC performed through a "green protocol" have been reported such as the efficient synthesis of N-benzyl-fluoro-isoxazolidines 38 in ionic liquids described by Chakraborty et al 107 (Scheme 8).…”

“…As a valuable exception, the use of appropriate hydrogen transfer conditions proved its efficiency to achieve N-debenzylation with respect to the isoxazolidine ring of adducts produced from N-benzyl carboxy ketonitrones. 93,106,118 Glycosylnitrones and tetrahydropyranosyl-substituted nitrones lead to N-protected isoxazolidines, which may be deprotected by acidic hydrolysis, and hydroxyaminolysis while leaving the N−O bond intact. 105,119−122 N-Benzhydryl nitrones were also reported to yield cycloadducts, which could be removed by NBS oxidation, 58 either in acidic conditions (HCl in MeOH) 62 or via a reductive cleavage with Et 3 SiH.…”

“…Access to N-acyl-protected isoxazolidines can proceed efficiently after selective N-deprotection, but this 2step method has been only described from C-carboxyketonitrone-derived adducts. 83,93,106,118 Consequently, several groups developed new strategies to obtain this interesting intermediate for further synthetic applications. Among them is the cyclization of unsaturated hydroxylamines.…”

[3+2] Route to Quaternary Oxaprolinol Derivatives as Masked Precursors of Disubstituted β3,β3‐Amino Aldehyde

“…We showed previously that cleavage of the N–O bond could be achieved with reducing agents such as Mo(CO) 6 or SmI 2 when the nitrogen is equipped with an electron‐withdrawing group such as acetyl or trifluoroacetyl, giving access to the aldehyde or the ester 5. This reaction, which has been shown to be sensitive to steric hindrance,5c has never been done previously on isoxazolidines with an aminoacyl group on the nitrogen. When 8a was treated with SmI 2 , no reaction occurred.…”

“…It was underlined that the isoxazolidine ring remained intact during the N‐deprotection step with the aldehyde function still masked under a cyclic pseudo‐acetal form. For instance, aspartic aldehyde derivatives (R = CH 2 CO 2 Alk, Figure 1) were obtained by using either chiral aspartic nitrones5b or chiral vinyl ethers5c in efficient exo and asymmetrically controlled 1,3‐DC reactions 7…”