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

Abstract

Bicyclic isoxazolidines displaying one or two quaternary stereocenter(s) were formed starting from functional cyclic ketonitrones equipped with a phenyl glycinol chiral auxiliary. The products were engaged in stereocontrolled 1,3‐dipolar cycloaddition reactions with a range of electron‐rich and electron‐poor dipolarophiles. A new reductive removal of the phenyl glycinol chiral auxiliary was introduced and was shown to afford chemoselectively a quaternary isoxazolidine derivative (of oxaprolinol‐type) without cleaving the N–O isoxazolidine bond. Keeping the aldehyde function masked as a cyclic pseudo‐acetal, the liberated oxy‐amine function was shown to be available for a pseudo‐peptide coupling with various N‐protected amino acids. The isoxazolidine ring was opened by a reductive N–O bond cleavage, giving a pseudo‐dipeptide that was C‐terminated with an aldehyde function.

Isoxazolidine: A Privileged Scaffold for Organic and Medicinal Chemistry

“…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.…”

“…This fruitful approach, leading to bicyclic adducts with high exo/endo and facial controls, has been essentially developed using chiral lactone and lactam nitrones under thermal conditions (Figure ). − Enantioselective access to such kind of adducts from achiral cyclic nitrones by catalytic asymmetric pathways has not yet been reported.…”

“…1,3-DC is a powerful reaction to prepare N -benzyl or N -aryl isoxazolidines, but these nitrogen-protecting groups are difficult to remove without a concomitant ring opening. 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. ,, 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. ,− N -Benzhydryl nitrones were also reported to yield cycloadducts, which could be removed by NBS oxidation, either in acidic conditions (HCl in MeOH) or via a reductive cleavage with Et 3 SiH . However, the synthesis of isoxazolidines bearing an easily removable electron-withdrawing group at nitrogen (crucial for performing further synthesis) was poorly exploited.…”

“…As previously discussed, the synthesis of isoxazolidine bearing a removable N -protecting group is highly desirable but difficult to obtain from 1,3-DC since the corresponding nitrone exhibits low stability. Access to N -acyl-protected isoxazolidines can proceed efficiently after selective N -deprotection, but this 2-step method has been only described from C -carboxyketonitrone-derived adducts. ,,, Consequently, several groups developed new strategies to obtain this interesting intermediate for further synthetic applications. Among them is the cyclization of unsaturated hydroxylamines.…”