special Publication No. 4
Nucleic Acids Research
Course and scope of the sugar exchangereactionin purine nucleosides
W.Riess and F.W.Iichtenthaler
Institut fiir Organische Chemie und Biochemie, Technische Hochschule Darmstadt, D-6100 Darmstadt,
GFR
Abstract: The transfer of the purine moiety in
2',3'-0-isopropylidene
nucleosides from their sugar t o another, inducible by a halogenose and
mercuric cyanide, i s evaluated with respect to scope and limitations.
Mechanistically relevant data are presented that strongly indicate the
reaction to proceed via N7,N9-bis-glycosylated intermediates | , from which
the ribose i s subsequently expelled as the 1,5-anhydrosugar.
The usual N->N-transglycosylation in nucleosides, comprising the transfer
of the sugar moiety from one position of the heterocycle t o another, or
to another nucleobase a l l together , i s complemented by the counterpart of
this reaction, i . e . the transfer of the heterocyclic base of a nucleoside
from i t s sugar to another 2 ' 3 . This sugar exchange reaction, which may also
be designated as a "transpurinylation" due to i t s limitation t o purine
nucleosides, has now been studied in more detail, allowing t o specify
scope and limitations as well as i t s mechanistic course.
In the case of 2',3'-0-isopropylidene-inosine (2g), mercuric cyanide
promoted reaction with aoetobromoglucose (1) in nitromethane at 40° (5 days)
and at 70° (1-5 h) yields aside the anhydroribose 5. a mixture of N7- (3_a.)
and N9-tetraacetylglucosyl-hypoxanthine (4_a.), in which the former (3a)
strongly preponderates . The definite absence of N1-tetraacetylgluoosylhypoxanthine was proved by t.l.c. comparison with authentic material, the
presence of the N3-glucosylated isomer, as yet unknown, was not detectable
in the reaction mixture .
The 21,3'-(3-isopropylidene-1-benzylinosine (gb.), when exposed to these
conditions (20 h at 70°) similarly afforded a mixture of the N7-glucoslde
3^ [m.p. 187-188°, [ a ] 2 2 - 16.0° (c 1, CHCLj); yield after separation on
silica gel: 52 %] and its N9-iscrter 4£ [m.p. 210-211°, [a] 2 3 - 29.1° (c 1,
CHC1 3 ); 24 %] aside J (85 % ) . On following the course of the reaction on
t.l.c. it became evident that the N7-nucleoside 3J? (Rp 0.18 on silica gel
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with ethyl acetate) is the primary product, whilst the N9-iscmer 4b. (Rp =
0.27) is only formed gradually, ocnprising about 1/3 of the mixture after
20 h, i.e. after disappearance of educt 2b_. That the N9-nucleoside can
indeed originate from the N7-isaner and vice versa, was established by
individual exposure of the two nucleosides to these conditions (Hg(OJ)2/
nitromethane at 7O° in the presence of 1) whereby each afforded a N7/N9
isaneric mixture. Hence, this process is proved to be reversible, i.e. a
N7 «fe N9-transglycosylation.
Fk,
a
b
c
d
e
AcO
R
H
R1
H
H
OH
NH2
H
H
NHAc
OAc
The variability of the ribo-nucleoside component is illustrated by the
feasibility of the sugar exchange reaction with the isopropylidene
derivatives of xanthosine 2£, requiring 5 h at 70° for the disappearance
of educt, of guanosine (gd.) and tr-acetylguanosine (2c.) (6 days, 70°),
and of adenosine and its N -benzoyl derivative (6 days, 70°). The reaction
fails with the S'-O-nitro- or 5'-0-acetyl derivatives of 2§, clearly
indicating that the stabilization of the ribose portion in the form of
1,5-anhydro derivative § is one of the essential elements of the sugar
exchange reaction.
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In 21,3'-0-isopropylidene derivatives of pyrimidine nucleosides, the
N-glycosidic bond is stable towards Hg (CN) 2/nitrorcethane in the presence
of 1, 5'-0-glucosylation occuring instead, as illustrated by the ready
conversion of 2' ^'-O-isopropylidene-uridine into its 0 -tetra-0-acetylg-D-glucopyranoside, isolable after 3 h at 55° in 73 % yield; longer
5> 3
7
reaction tines led to 0 ,N -bis-glucosylated products . These results
together with the necessary presence of a sugar halide for inducing the
reaction, supports the previously advanced view that the sugar acyloxonium
ion generated from the halogenose with (Hg (CN), is attacked by N7 of the
purine nucleoside with the formation of N7 ,N9-di-glycosyl intermediates of
type £, followed by Hg(CN), promoted release of the ribose portion as the
anhydrosugar jj- The N7-nucleoside formed in this way is then subject to
N7-»N9-transglycosylation the composition of the N7,N9 isomeric mixture
being dependent on the thermodynamic stabilities of the products and on
reaction time. This interpretation of the mechanistic course is further
sustained by compounds of analogous structure, such as N7-alkyl-inosines
Q
and guanosines, isolable as halide salts of type 2 and § or as intra9
1O
molecularly neutralized species ?_ or jg , and, most decisively, by the
finding, that JO, on exposure to Hg (CN) ,/nitromethane at 70° gave 5 and
the known11 7-benzylinosine is formed.
8 R=CH3, R=NH2
References and Notes
1. Goodman, L. (1974), in Basic Principles of Nucleic Acid Chem. (Tso,
P.O.P., Editor), VoL I, 190 ff.—Watanabe, K.A., Hollenberg, D.H., and
Fox, J.J. (1974), J. Carbohydr., t/ueleosides, Nucleotides 2_, 1-37.
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2. Lichtenthaler, F.W., and Kitahara, K. (1975), Angew. Chem. 87, 83984O; Angew. Chem. Int. Ed. Engl. V4, 815-816.
3. Kitahara, K., Kraska, B., Sanemitsu, Y., and Lichtenthaler, F.W. (1975),
Nucleic Acids Res., Spec. Publ. j_, s21-s24.
4. RieS, W. (1978), Doctoral Dissertation, Technische Hochschule
Darmstadt, to be submitted.
5. Yamasaki, H., and Hashizume, T. (1968), Agria. Biol. Chem. Jap. 32,
1362-1370.
6. The previous obtention, aside from 3a and 4a, of a crystalline product
wi£h two nelting points (143-144 and" 224-226°) in 7 % yield in the
4O reaction (Ref.2) was rarely reproducible. It appears likely that
this product is conposed of dimorphic forms of 3a and/or 4a, rather
than of the N1- and N3-isomers as has prematurely (Pef. 273) been
assumed.
7.
8.
9.
10.
Nohara, T., and Lichtenthaler, F.W. (1978), unpublished experiments.
Jones, J.W., and Robins, R.K. (1963), J. Amer. Chem. Soc. J35, 193-201.
Scheit, K.H., and Holy, A. (1967), Bioohim. Biophys. Ada VQ, 344-354.
Lichtenthaler, F.W., Kitahara, K., and RieB, W. (1978), Nucleic Acids
Res., this issue.
11. Montgomery, J., and Temple, C., Jr. (1961), J. Amer. Chem. Soc. 83,
630-635.
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