Enantioselective Synthesis of N-Protected α-Amino Acid Hydrazides

Abstract

A new, mild, general, and efficient synthesis of N-protected α-amino acid hydrazides is described. This two-step preparation uses N-aminophthalimide as protected hydrazine to prepare N-protected α-amino acid hydrazide precursors, and subsequent de­phthaloylation with an aminomethyl polystyrene resin yields N-protected α-amino acid hydrazides. It has the advantages of avoiding the use of the toxic hydrazine reagent and being compatible with the most commonly used N-protecting groups. This strategy is particularly interesting in the case of N-(9-fluorenylmethoxycarbonyl)-protected amino acids. Within the limits of chiral HPLC detection, no epimerization is apparent.

Key words

amino acids - hydrazides - epimerization - protecting groups - aminomethyl resins

References

• 1 Yale HL. Losee K. Martins J. Holsing M. Perry FM. Bernstein J. J. Am. Chem. Soc.  1953,  75:  1933 
• 2 Schnyder J. Rottenberg M. Helv. Chim. Acta  1975,  58:  521 
• 3a Boeglin D. Cantel S. Heitz A. Martinez J. Fehrentz JA. Org. Lett.  2003,  5:  4465 
• 3b Moulin A. Demange L. Ryan J. Mousseaux D. Sanchez P. Berge G. Gagne D. Perrissoud D. Locatelli V. Torsello A. Galleyrand JC. Fehrentz JA. Martinez J. J. Med. Chem.  2008,  51:  689 
• 4 Rauf A. Sharma S. Gangal S. ARKIVOC  2007,  (xvi):  137 
• 5 Krysin EP. Karel’skii VN. Antonov AA. Rostovskaya GE. Khim. Prir. Soedin.  1979,  5:  684 
• 6 Quibell M. Turnell WG. Johnson T. J. Chem. Soc., Perkin Trans. 1  1993,  2843 
• 7 Martinez J. Tolle JC. Bodanszky M. J. Org. Chem.  1979,  44:  3596 
• 8 Stravropoulos G. Gatos D. Magafa V. Barlos K. Lett. Pept. Sci.  1996,  2:  315 
• 9 Brosse N. Pinto M.-F. Jamart-Gregoire B. J. Chem. Soc., Perkin Trans. 1  1998,  3685 
• 11 Mitchell AR. Kent SBH. Erickson BW. Merrifield RB. Tetrahedron Lett.  1976,  3795 
• 12 Adams JH. Cook RM. Hudson D. Jammalamadaka V. Lyttle MH. Songster MF. J. Org. Chem.  1998,  63:  3706 

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Chiral HPLC: Chiracel OD column, 1 mL/min, hexane- i-PrOH, 80:20 with 0.1% TFA, monitoring at λ = 280 nm.