Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1998-03-03
1999-10-05
Burn, Brian M.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
560 22, 562439, 562430, 564148, 548495, 548496, 5483391, C07C20506, C07C24314, C07D20918
Patent
active
059627220
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The invention relates, by way of new industrial products, to protected .alpha.-hydrazino acid derivatives; it also relates to a method for preparing such compounds.
PRIOR ART
.alpha.-Hydrazino acids are analogs of .alpha.-amino acids in which the amine functional group has been replaced with a hydrazine functional group.
When it is desired to use these .alpha.-hydrazino acids in synthesis, and in particular to incorporate them, in place of an amino acid, into the chain of a peptide in order to form either a hydrazino peptide --CO--NHNH--C-- or an amino peptide --CO--N(NH.sub.2)--C--, the presence of the two nitrogenous functional groups in them causes, during peptide coupling reactions, problems of regioselectivity as well as parasitic reactions and undesirable molecular rearrangements.
To eliminate these disadvantages, it is necessary that at least one of the two nitrogen atoms of the hydrazino acid is temporarily neutralized with a protecting group PG. 735 (1972); J. Prakt. Chem. 316, 729 (1974); J. Prakt. Chem. 314, 751 (1972)!, a PG group was directly introduced into an .alpha.-hydrazino acid, and a mixture of N.alpha.- and N.beta.-protected products is most often obtained which should then be separated and purified. ##STR1## Commun. 435 (1991); J. Org. Chem. 58, 4791 (1993)! how the N.beta.-protected compounds can be exclusively prepared using electrophilic amination of an amino acid with an oxaziridine. In the case where PG is Boc (tert-butoxycarbonyl), this method gives poor yields because of the formation of oxazolidinone which is produced at the expense of the desired product during the isolation. The yields are better if PG is Moc (methoxycarbonyl) but this group is cleaved under excessively harsh conditions which are incompatible with peptide synthesis. carrying two identical protecting groups (Boc) on the N.alpha. and N.beta. one of the co-inventors uses the acetyl (Ac) radical to protect the two nitrogens.
The compounds of general formula ##STR2## in which the two protecting groups PG are identical are not easy to use in peptide synthesis, on the one hand because these groups cannot be selectively cleaved in relation to one another (thus liberating the two nitrogenous groups) and, on the other hand, as regards the Ac group, because its cleavage requires drastic conditions which are incompatible with peptide synthesis. (1966); Tetrahedron Lett. 31, 2701 (1975); Japanese Patent 76138602-761130 (1976); Tetrahedron Lett. 34, 6859 (1993)!, there are described compounds of general formula ##STR3## carrying two different protecting groups PG.sub.1 and PG.sub.2. However, while one of the groups proposed is standard (Boc, Z (benzyloxycarbonyl), or benzyl) the other (Ac or Tos) is unsuitable for peptide synthesis because of the drastic conditions necessary for its cleavage.
The invention overcomes these disadvantages. It relates, by way of new industrial products, to hydrazino acid derivatives in which the two amine functional groups carry orthogonal protecting groups, that is to say which can be manipulated independently of one another, for example during a peptide synthesis.
BRIEF DESCRIPTION OF THE INVENTION
The invention relates, by way of new industrial products, to hydrazino acid derivatives of general formula: ##STR4## in which: R.sub.1, R.sub.2 and R.sub.3 denote hydrogen or a carbonaceous radical, L, D or DL configuration, ##STR5## where Ar denotes a phenyl radical or a phenyl radical substituted with one or more groups X; radical different from R.sub.4.
In other words, the invention relates to .alpha.-hydrazino acids in which the two nitrogenous groups N.alpha. and N.beta. carry protecting groups which are different in nature, in particular benzyl (PhCH.sub.2) on the N.alpha., and tert-butoxycarbonyl (Boc) or fluorenylmethoxycarbonyl (Fmoc) on the N.beta., groups whose orthogonal character makes it possible to manipulate them independently of one another.
These compounds can be directly used in the syntheses of pseudopeptides by conventional solid phase or liquid phase m
REFERENCES:
Database Caplus on STN, Acc. No. 1994:218456, Niederer et al., `Amination with N-benzyloxycarbonyl-3-phenyloxaziridine as a route to sensitive chiral alpha-hydrazino acids: synthesis of L-hydrazino serine,` Tetrahedron Lett. 34(43), pp. 6859-6862, abstract 1993.
Vidal et al., `Electrophilic amination: preparation and use of N-Boc-3-(4-cyanophenyl)oxaziridine, a new reagent that transfers a N-boc group to N- and C- nucleophiles,` J. Org. Chem. 58, pp. 4791-4793 1993.
Protective Groups in Organic Synthesis 2nd ed., Theodora Green and Peter Wuts, John Wiley & Sons, Inc, NY 1991.
Tetrahedron Letters, vol. 34, No. 43, pp. 6859-6862 (1993).
Tetrahedron Letters, vol. 31, pp. 2701-2704 (1975).
Chemical Abstracts, vol. 87, No. 1, (Jul. 4, 19977) Yamada, Shunichi et al.
J. Chemical Soc. Perkin Trans. 1 (1987), Lawton, Geoffrey et al.
Collet Andre
Guy Laure
Hannachi Jean-Christophe
Vidal Joelle
Burn Brian M.
Centre National de la Recherche Scientifique
Davis Brian J.
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