Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1988-09-14
1997-04-29
Kunz, Gary L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 268, 536 276, 536 2781, 536 285, 536 2853, 546192, 546194, 546242, C07H 19067, C07H 19167, C07H 2102, C07D21144
Patent
active
056250460
DESCRIPTION:
BRIEF SUMMARY
This invention relates to protecting groups for organic synthesis; more particularly it relates to acetal groups suitable for the protection of 2'-hydroxy functions in rapid oligoribonucleotide synthesis.
A 4-methoxytetrahydropyran-4-yl group has proved to be particularly suitable for the protection of 2'-hydroxy functions in oligoribonucleotide synthesis in solution. In the development of methods for the rapid synthesis of oligo- and poly-ribonucleotides both on solid supports and in solution, for reasons of practical convenience, it is advisable to use a modified trityl group, such as 4,4'-dimethoxytrityl or 9-phenylxanthen-9-yl, to protect terminal 5'-hydroxy functions. It has recently been shown that the relatively drastic protic acid conditions required for the removal of a 5'-O-(9-phenylxanthen-9-yl) group from a fully-protected dinucleoside phosphate lead to appreciable concomitant removal of the 2'-O-(4-methoxytetrahydropyran-4-yl) group. In order to overcome such problems, there is a need for a better protecting group, more particularly for an alternative to 4-methoxytetrahydropyran-4-yl.
A 1-methoxycyclohex-1-yl group has been found to be much too acid-labile to be of use in oligoribonucleotide synthesis. However, acetals may be stabilized to acidic hydrolysis by the introduction of electron-withdrawing groups. For example, 2'-O-(4-methoxytetrahydropyran-4-yl)-uridine undergoes acid-catalyzed hydrolysis at a rate that is more than two orders of magnitude slower than that of the corresponding 1-methoxycyclohex-1-yl-protected compound. Later studies on the hydrolysis of 5'-protected thymidine derivatives suggested that the replacement of O by S in the six-membered ring of 2'-O-(4-methoxytetrahydropyran-4-yl)-uridine would increase the rate of acetal hydrolysis by a factor of ca 5, whereas the replacement of the same oxygen atom by a sulphone group would decrease the rate of hydrolysis by a factor of more than 400.
Given that it is desirable to retain an acid-labile group for the protection of 2'-hydroxy functions, an object of the present invention was to design weakly basic 1-N-substituted-, preferably 1-N-aryl-, 4-alkoxy-, preferably 4-methoxy-, piperidin-4-yl groups, which, for example, at pH 2-2.5, would be unprotonated to a significant extent on N-1 and thus as labils as, say, the 4-methoxytetrahydropyran-4-yl group, but which, under the more strongly acidic conditions required for the removal of, say, the 9-phenylxanthen-9-yl protecting group, would be largely protonated and perhaps therefore have a similar stability to acidic hydrolysis as the sulphone system referred to above. Certain groups have now surprisingly been found which exhibit essentially the desired advantageous properties.
The present invention provides a method of organic synthesis comprising the protection of a hydroxy function characterised in that a 1-N-substituted-4-alkoxy-piperidin-4-yl group is used as the protecting group.
More particularly the present invention relates to such a method wherein a 1-N-aryl-4-alkoxy-piperidin-4-yl group is used to protect a 2'-hydroxy function in an oligo- or poly- ribonucleotide synthesis.
In a preferred embodiment, the present invention relates to the use as a protecting group for organic synthesis, in particular for 2'-hydroxy functions in oligo-ribonucleotide synthesis, of groups corresponding to the following general formula: ##STR1## wherein R' independently represents alkyl, preferably C.sub.1 -C.sub.4 alkyl, typically methyl; preferably one, electron-withdrawing substituent, for example, halogeno, typically fluoro or chloro, and optionally one or more further substituents, for example C.sub.1 -C.sub.4 alkyl, typically methyl.
As preferred examples of such groups, there may be mentioned the 1-[(2-chloro-4-methyl)phenyl]-4-methoxy-piperidin-4-yl and 1-(2-fluorophenyl)-4-methoxy-piperidin-4-yl groups: ##STR2## As will be appreciated by those skilled in the art, other effective, possibly more effective, groups may result, for example, by exchanging C1 for F or Br, and/or CH.sub.3 for
REFERENCES:
patent: 4167573 (1979-09-01), Himmete et al.
White et al. Principles of Biochemistry. Fifth Edition (McGraw-Hill Book Co.: New York, 1973), pp. 250-251.
Taylor et al. (1981) Synthesis pp. 606-608.
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Chemical Abstract--CA 61: 8267c Sep., 1964.
Chemical Abstract--CA 58: 3456g Feb., 1963.
Chemical Abstract--CA 51: 17909a Nov., 1957.
King's College London
Kunz Gary L.
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