Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2000-03-20
2004-07-20
Wilson, James O. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S018700, C536S124000, C536S001110, C544S299000, C568S327000
Reexamination Certificate
active
06765089
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to methods for synthesis of organic compounds, and in particular to compounds useful as protecting and linking groups for use in the synthesis of peptides, oligosaccharides, glycopeptides and glycolipids. The invention provides protecting and linking groups which are useful in both solid phase and solution synthesis, and are particularly applicable to combinatorial synthesis.
BACKGROUND OF THE INVENTION
The problem of functional group incompatibility in the synthesis or complex organic structures demands the use of a functional group protection strategy. Complex synthetic intermediates and products usually contain a multiplicity of reactive groups, most of which must first be blocked, and subsequently liberated at an appropriate point in the synthesis . The problem is especially acute in the design and construction of polyfunctional molecules such as oligosaccharides, peptides, glycopeptides and glycolipids.
In oligosaccharide synthesis, a variety of protective groups are required. It is necessary to place groups regioselectively at specific locations; on primary alcohols, on cis-diols, on trans-diols, on 1,2-diols, on 1,3-diols, or on particular secondary alcohols. In addition, aminosugars are important constituents of oligosaccharides, and their amino-protection should be compatible with the hydroxy group protection strategy. The properties of the protective group adjacent to the anomeric centre are also important. Whether this group is participating or non-participating plays a significant role in control of glycoside stereochemistry. Because most reactions at the glycosidic centre proceed via electron deficient intermediates, electron-releasing substituents on the C-2 substituent accelerate the reaction at the glycosidic centre. Electron-withdrawing substituents, normally esters or amides, slow the reaction. In solid phase oligosaccharide synthesis, the stability and sensitivity of the linker between the first sugar unit and the resin becomes a crucial part of the protection plan. The presence of other functional groups, such as alkenes or esters, or features such as a furanose ring in the target oligosaccharide, may dictate that the protecting groups used for the synthesis are not sensitive to acid, base, reductive, or other commonly used cleavage techniques. The choice of protecting groups is therefore one of the decisive factors in the successful realization of solid phase oligosaccharide synthesis.
In solid phase peptide and glycopeptide synthesis the demand of a new orthogonal protective set is significant. The established orthogonal deprotection sets are based upon the well-known Fmoc and Boc protection of amino acids. The construction of complex peptides or glycopeptides often requires a third orthogonal protecting group for side-chain amino functionalities, whose removal will not affect the protecting groups in the other orthogonal sets, or vice versa.
Many protecting groups have been developed for amino group protection, and fall into seven broad classes.
1. N-Acyl Derivatives
a) Phthalimides are especially useful in the protection of amino functions in aminoglycoside synthesis (Nicolaou et al, 1992), because they are stable during the glycosylation, and because they help to control the stereochemistry by neighbouring group participation. Unfortunately, the deprotection needs vigorous conditions, which often results in partial product decomposition.
b) Trifluoroacetamides (Weygand and Czendes, 1952) Simple amide derivatives are usually worthless as protecting groups because the conditions required to remove them are too harsh. However, the trifluoroacetamide group is exceptionally labile to base hydrolysis, and is therefore useful in the protection of amines.
c) Carbamates are used as protective groups for amino acids to minimize racemization in peptide synthesis. Racemization occurs during the base-catalysed coupling reaction of an N-protected, carboxyl-activated amino acid, and takes place via the intermediate oxazolone that forms readily from an N-acyl protected amino acid. Many carbamates, for example Boc (McKay and Albertson, 1957), Cbz (Bergman and Zervas, 1932), Alloc (Kunz and Unverzagt, 1984), Teoc (Carpino et al, 1978), and Troc (Windholz and Johnston, 1967), have been used as protective groups for amino protection.
2. N-Sulfonyl Derivatives
Sulfonamide derivatives are frequently used in nitrogen heterocycles (Gribble et al, 1992), and arylsulfonyl (Fischer and Livschitz, 1915) groups are effective protective groups for a wide range of primary and secondary amines, but their deprotection requires drastic conditions. &bgr;-(Trimethylsilyl)ethanesulfonyl (Weinreb et al, 1986) derivatives are as stable as arylsulfonyl groups, but the cleavage step requires only gentle warming with TBAF or CsF.
3. N-Sulfenyl Derivatives
Sulfenamides are much more labile than sulfonamides, being sensitive to acids as well as to attack by nucleophiles. Their deprotection requires exceptionally mild conditions. Several sulfenyl groups are used for the protection of the amino function including tritylsulfenyl (Brandchaud, 1983), o-nitrophenylsulfenyl (Goerdeler and Holst, 1959), and pentachlorphenylsulfenyl (Kessler and Iselin, 1966).
4. N-Alkyl Derivatives
Benzylamines give useful protection in reactions in which metal hydrides are used and the carbamates are not stable. Benzylamines are less susceptible to catalytic hydrogenolysis than benzyl ethers or benzyl esters, and thus selective deprotection can often be achieved (Goldstein et al, 1992). The trityl group (Sieber and Riniker, 1991) is used to protect amino acids, although its steric bulk and high acid lability is detrimental to peptide coupling. The 9-phenylfluorenyl (PhFl; Koskinen and Rapoport, 1989) group is used for the protection of primary and secondary amines. Its hydrophobicity, steric bulk and ease of introduction are similar to the trityl group, but the PhFl group is about 6000 times more stable to acid than the trityl group.
5. N-Silyl Derivatives
The high acid and moisture sensitivity of silylamines has been a major obstacle to their use in amino group protection. Butyldiphenylsilylamines (Overman and Okazaki, 1986) have remarkable stability towards strong basic conditions, but they are still very acid labile.
6. Imine Derivatives
The double bond of the imine function allows for the simultaneous protection of both N—H bonds of a primary amine. Imines are generally stable towards strongly basic conditions, but they are labile to aqueous acid. N-Silyl imines (Colvin et al, 1988), N-bis(methylthio)methyleneamines (Hoppe and Beckmann, 1979) and N-diphenylmethyleneamines (Polt et al, 1979) are valuable for the protection of amino groups in the synthesis of &agr;-amino acids.
7. Enamine Derivatives
N-(5,5-Dimethyl-3-oxo-1-cyclohexenyl)amine (Halpern and James, 1964) is used to protect amino acids, giving vinylogous amide derivatives. These compounds can be cleaved by treatment with either aqueous bromine or nitrous acid. The stability of the vinylogous amide-protected primary amines mainly depends on the structure of 1,3-dione and the functional group attached to the enamine double bond. The open chain N-(4-oxopent-2-enyl)-protected amines are labile towards aqueous and mildly acidic conditions. This acid sensitivity limits their use as synthetic reagents (Kellam, 1996). The cyclic 1,3-diketone, 5,5-dimethylcyclohexane-1,3-dione (dimedone) reacts with dimethylformamide dimethylacetal affording 5,5-dimethyl-2-(dimethylaminomethylene)cyclohexane-1,3-dione. Bycroft et al (1993) used this reagent to synthesise Dmc-protected &agr;-amino acids, and found remarkable stability towards acidic conditions. The deprotection of these compounds could be rapidly achieved by a dilute hydrazine solution at room temperature. The introduction of a methyl group to the enamine double bond provided the N-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl Dde-protective group, improving the stability towards secondary amines (Bycroft et al, 1993). The N-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-
Dekany Gyula
Kellam Barry
Toth Istvan
Alchemia Pty Ltd
Crane Lawrence
Williams, Morgan and Amerson
Wilson James O.
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