MiPNO, a new chiral cyclic nitrone for enantioselective amino acid synthesis: the cycloaddition approach

Abstract

The resolution of chiral nitrones via derivatization of hydroxylamines was applied to MiPNO, a new, stable, easily prepared chiral cyclic nitrone. The application of MiPNO in totally regio- and diastereo-selective 1,3-dipolar cycloaddition reactions provides an expeditious enantioselective access to unusual gamma-hydroxy alpha-amino acids.

Stereoselective Synthesis of Enantiopure Cycloalkylglycines by 1,3‐Dipolar Cycloaddition of a Chiral Nitrone to Cycloalkenes

“…The epimerization of the C-α stereogenic center occurred to a limited extent probably during the cleavage of the chiral auxiliary in 3a and 3b, as previously observed in our studies. [7] A similar transformation was reported [16] with a reducing agent (Pd/C and H 2 ), but its absence was not detrimental to the outcome of the reaction. The present reaction condi-tions triggered the unanticipated spontaneous reduction of the N-O bond with ethanol as the solvent and as the presumed reducing agent, as reported for silver nanoparticles.…”

“…The 1,3-dipolar cycloaddition of chiral nitrones to alkenes has been investigated for the preparation of tailor-made amino acids from a nitrone incorporating a chiral glycine equivalent. [4][5][6][7][8][9][10][11][12][13][14][15][16] enantiopure cycloalkylglycine derivatives in good overall yields (Ͼ40 %) in three simple synthetic steps from the menthone-based chiral nitrone. The conformational analysis of these analogues by DFT calculations highlight some interesting features of the volume occupied by the cycloalkyl residues in comparison to that occupied by the natural 4hydroxyisoleucine.…”

“…In view of optimization, we investigated a modified preparation of these cyclic amino acids through the conversion of isoxazolidines A into α-amino-γ-lactones B [15] followed by hydrolysis to the corresponding γ-hydroxy-α-amino acids C (Scheme 2) as shown in recently reported microwave-assisted procedure under acidic and hydrogenolytic conditions. [16] The last steps would then be the lactone ring opening with a base. Scheme 2.…”

“…-2Ј-Isopropyl-2,5Ј-dimethylhexahydro-2H-spiro[benzo[d]imidazo[1,5-b]isoxazole-3,1Ј-cyclohexane]-1,9dione (9): As described for 3c, prepared from cyclohexenone (2e; 1.6 g,16.8 mmol, 5 equiv.) to afford 9 (900 mg, 80 %) as a white solid after 3 d of reaction, m.p.…”

Approaches to α-amino acids via rearrangement to electron-deficient nitrogen: Beckmann and Hofmann rearrangements of appropriate carboxyl-protected substrates

“…Classical approaches continue to be investigated (most notably the Strecker reaction) [2], but recent developments focus on cycloadditions [3], rare amino acids [4], chiral catalysis [5], etc. It is noteworthy, however, that two of the most widely applied methods for the introduction of the amine group – the Beckmann [6–9] and the Hofmann [10–13] rearrangements – are not represented in these approaches.…”