Nucleic acid related compounds. 93. A solution for the historic problem of regioselective sugar-base coupling to produce 9-glycosylguanines or 7-glycosylguanines

Article abstract of DOI:10.1021/jo9617023

Per(trimethylsilyl)-2-N-acylguanine derivatives and tetra-O-acylpentofuranoses were coupled [tin(IV) chloride or titanium(IV) chloride catalysis] to give predominant formation of 7-glycosylguanines. With TiCl₄, a fortuitous organic/aqueous partitioning allowed isolation of 7-glycosylguanines from the 7/9 isomer mixtures. Per(trimethylsilyl)-2-N-acyl-6-O-(diphenylcarbamoyl)guanine derivatives and tetra-O-acylpentofuranoses underwent regioselective coupling (trimethylsilyl trifluoromethanesulfonate catalysis) to give 9-glycosylguanines. The 6-O-(diphenylcarbamoyl)peracyl-9-β-D-ribofuranosyl isomer was shown to be both the xinetic and thermodynamic coupling product. Deprotection of all of the peracyl coupling products was effected under mild conditions to give good to high yields of guanine nucleoside analogues. These methodologies provide solutions for the regioselective synthesis of 7- and 9-glycosylguanine nucleosides.

Full text of DOI:10.1021/jo9617023

J . Org. Chem. 1996, 61, 9207-9212
9207
Nu cleic Acid Rela ted Com p ou n d s. 93. A Solu tion for th e Histor ic
P r oblem of Regioselective Su ga r -Ba se Cou p lin g To P r od u ce
9-Glycosylgu a n in es or 7-Glycosylgu a n in es1
Morris J . Robins,* Ruiming Zou,† Zhiqiang Guo, and Stanislaw F. Wnuk
Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602-5700, and
Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada
Received September 4, 1996X
Per(trimethylsilyl)-2-N-acylguanine derivatives and tetra-O-acylpentofuranoses were coupled [tin-
(IV) chloride or titanium(IV) chloride catalysis] to give predominant formation of 7-glycosylguanines.
With TiCl4, a fortuitous organic/aqueous partitioning allowed isolation of 7-glycosylguanines from
the 7/9 isomer mixtures. Per(trimethylsilyl)-2-N-acyl-6-O-(diphenylcarbamoyl)guanine derivatives
and tetra-O-acylpentofuranoses underwent regioselective coupling (trimethylsilyl trifluoromethane-
sulfonate catalysis) to give 9-glycosylguanines. The 6-O-(diphenylcarbamoyl)peracyl-9-â-D-ribo-
furanosyl isomer was shown to be both the kinetic and thermodynamic coupling product.
Deprotection of all of the peracyl coupling products was effected under mild conditions to give good
to high yields of guanine nucleoside analogues. These methodologies provide solutions for the
regioselective synthesis of 7- and 9-glycosylguanine nucleosides.
In tr od u ction
9-isomers predominated (7/9, ∼1:6) under thermody-
namic conditions (TMSOTf/1,2-dichloroethane (DCE)/∆).6
Similar results (with variable isomer ratios) have been
observed by others.7,8 It was recently suggested that
initial glycosylation of 2-N-acetylguanine and 2-N,9-
diacetylguanine occurs at the unsubstituted imidazole
ring nitrogen. Reversible 7/9 acetyl tautomerization and
transglycosylation occur under different reaction condi-
tions to give observed product ratios.9 It is undisputed
that Vorbru¨ggen’s procedure4 gives naturally occurring
guanosine in good yields by fortuitous crystallization of
the 9-isomer from aqueous solutions of the 7/9 mix-
tures.3,10 However, this facile fractional crystallization
has not been demonstrated with other analogues derived
from different sugars or with biologically relevant acyclic
side chains such as the (2-hydroxyethoxy)methyl moiety
of acyclovir and related antiviral agents.
The most problematic chemistry and greatest difficul-
ties with manipulation of the five common bases found
in DNA and RNA occurs with the polyfunctional guanine
(pKa1 ∼1.7, pKa2 ∼9.2) nucleosides and nucleotides.
Coupling of guanine-type bases with protected sugar
derivatives produces N7/N9 isomeric mixtures of nucleo-
sides that are frequently difficult to separate.2,3 Coupling
of “directly protected” derivatives of guanine have con-
sistently produced 7/9 isomer mixtures, whereas constric-
tion of the guanine system into “6-enolate” derivatives
can result in enhancement of 9/7 isomer ratios.3 The
Vorbru¨ggen procedures overcame many difficulties with
base-sugar couplings, and high regioselectivities were
obtained with most bases. It was reported that coupling
per(trimethylsilyl)-2-N-acetylguanine and 1-O-acetyl-
2,3,5-tri-O-benzoyl-â-D-ribofuranose [trimethylsilyl trif-
luoromethanesulfonate (TMSOTf) catalysis] at elevated
temperature, followed by deprotection and recrystalliza-
tion, afforded pure guanosine (66%).4
However, Dudycz and Wright observed that 7-isomers
were formed as kinetic products of glycosylation of per-
(trimethylsilyl)-2-N-(substituted)guanines, and mixtures
rich in the more thermodynamically stable 9-isomers
were obtained upon heating.5 Garner and Ramakanth
also found that coupling of glycosyl acetates with per-
(trimethylsilyl)-2-N-acetylguanine gave 7-glycosyl prod-
ucts (7/9, ∼95:1 with a ribose derivative) under kinetic
conditions (SnCl4/CH3CN/room temperature), whereas
We now report studies on regioselective kinetic forma-
tion of 7-(D-pentofuranosyl)guanine derivatives by ambi-
ent temperature coupling of per(trimethylsilyl)-2-N-
acetylguanine and tetra-O-acetyl-D-pentofuranoses [tin(IV)
chloride or titanium(IV) chloride catalysis]. With TiCl4,
fortuitousorganic/aqueous partitioning resulted in isola-
(6) Garner, P.; Ramakanth, S. J . Org. Chem. 1988, 53, 1294.
(7) Coupling catalyzed by TMSOTf: (a) Mikhailopulo, I. A.; Poopei-
ko, N. E.; Pricota, T. I.; Sivets, G. G.; Kvasyuk, E. I.; Balzarini, J .; De
Clercq, E. J . Med. Chem. 1991, 34, 2195. (b) Sheppard, T. L.;
Rosenblatt, A. T.; Breslow, R. J . Org. Chem. 1994, 59, 7243. (c)
Chamberlain, S. D.; Biron, K. K.; Dornsife, R. E.; Averett, D. R.;
Beauchamp, L.; Koszalka, G. W. J . Med. Chem. 1994, 37, 1371.
(8) Coupling catalyzed by SnCl4: (a) Poopeiko, N. E.; Kvasyuk, E.
I.; Mikhailopulo, I. A.; Lidkas, M. J . Synthesis 1985, 605. (b) Rao, T.
S.; Durland R. H.; Revenkar G. R. J . Heterocycl. Chem. 1994, 31, 935.
(c) Hunziker, J .; Priestley, E. S.; Brunar, H.; Dervan, P. B. J . Am.
Chem. Soc. 1995, 117, 2661. (d) Reference 7b.
(9) (a) Boryski, J .; Manikowski, A. Nucleosides Nucleotides 1995,
14, 287. (b) Boryski, J . Nucleosides Nucleotides 1996, 15, 771.
(10) (a) Zou, R.; Robins, M. J . Can. J . Chem. 1987, 65, 1436. (b)
Zou, R. Ph.D. Dissertation, University of Alberta, 1986. (c) 13C NMR
correlations for 7/9 isomer structures and examples of couplings to give
anomeric 2′-deoxyguanosines and arabino analogues are in ref 10b.
(d) Difficulties were encountered during preliminary investigations
with preparation of and/or coupling reactions with derivatives of
2-amino-6-[benzyloxy, (dimethylcarbamoyl)oxy, (2,4,6-triisopropylben-
zenesulfonyl)oxy, and 2-(4-nitrophenyl)ethoxy]purine10b and derivatives
of 2-amino-6-(alkyl and aryl)thiopurines, their sulfone oxidation
products, and 2-amino-6-[(diisopropylcarbamoyl)oxy]purine (Zou, R.;
Guo, Z. unpublished results).
* Author to whom inquiries should be addressed at Brigham Young
University.
† Present address: Gilead Sciences, Foster City, CA.
X Abstract published in Advance ACS Abstracts, December 15, 1996.
(1) Part 92: Robins, M. J .; Guo, Z.; Samano, M. C.; Wnuk, S. F. J .
Am. Chem. Soc. 1996, 118, 11317.
(2) Shabarova, Z. A.; Polyakova, Z. P.; Prokof’ev, M. A. J . Gen. Chem.
USSR 1959, 29, 218.
(3) (a) For a discussion of prior methods and limitations see: Robins,
M. J .; Zou, R.; Hansske, F.; Madej, D.; Tyrrell, D. L. J . Nucleosides
Nucleotides 1989, 8, 725 and references cited therein. (b) J enny, T. F.;
Benner, S. A. Tetrahedron Lett. 1992, 33, 6619.
(4) (a) Vorbru¨ggen, H.; Krolikiewicz, K.; Bennua, B. Chem. Ber.
1981, 114, 1234. (b) Vorbru¨ggen, H. Acta Biochim. Pol. 1996, 43, 25.
(5) (a) Dudycz, L. W.; Wright, G. E. Nucleosides Nucleotides 1984,
3, 33. (b) Wright, G. E.; Dudycz, L. W. J . Med. Chem. 1984, 27, 175.
S0022-3263(96)01702-1 CCC: $12.00 © 1996 American Chemical Society

9208 J . Org. Chem., Vol. 61, No. 26, 1996
Robins et al.
Sch em e 1a
(NH3/H2O/MeOH) and crystallization gave analytically
pure hemihydrates of the 7-(D-pentofuranosyl)guanines
5b (78%, â-ribo), 5d (86%, â-xylo), and 5f (85%, R-ara-
bino).
Analogous coupling of silylated 2-N-isobutyrylgua-
nine12 (1b) with the tetra-O-acetyl ribo- and xylofuranose
derivatives in CH3CN or DCE with TiCl4 as catalyst
resulted in isolation of the 7-isomers 7a and 7c in
moderate yields (43-67%, after workup and chromatog-
raphy) without detected contamination by the 9-isomers
6a and 6c. We were surprised to discover that only the
7-isomers were isolated after the initial reaction mixtures
were heated at 80 °C for 3 h. However, the aqueous
layers after workup contained 7/9 isomer mixtures.
Apparently, stronger complexation between the guanine
base and TiCl4 (and/or hydrolysis products) occurs with
the 9-isomers, which results in clean partitioning of the
9-regioisomers 6a and 6c into the water layer. It is
noteworthy, in harmony with prior results,6 that solvent
and reaction temperature changes failed to alter the 7/9
isomer compositions significantly. Therefore, accelera-
tion of the coupling reaction rate by reflux and fortuitous
enhanced partitioning of the 9-isomers into the aqueous
layer provides a convenient selective procedure for prepa-
ration of the 7-isomers 7a and 7c. Deprotection of 7a
and 7c and crystallization gave the hemihydrates of 5b
(78%) and 5d (76%), respectively.
a
Key: (a) BSA/DCE/∆; (b) TMSOTf or SnCl4 or TiCl4; (c) 1,2,3,5-
tetra-O-acetyl-D-pentofuranose; (d) NH3/H2O/MeOH/∆.
tion of 7-isomers. We also have developed glycosyl
couplings with per(trimethylsilyl)-2-N-acetyl-6-O-(diphe-
nylcarbamoyl)guanine (TMSOTf catalysis) to give high-
yield preparations of 9-(D-pentofuranosyl)guanines, with-
out contamination by 7-isomers,10 and a completely
regioselective synthesis of guanosine with per(trimeth-
ylsilyl)-2-N-isobutyryl-6-O-(diphenylcarbamoyl)guanine
and 1,2,3,5-tetra-O-acetyl-â-D-ribofuranose.
Literature precedents indicated that coupling of 2,6-
disubstituted purines with protected sugars generally
gave enhanced 9/7 isomer ratios, and the 9-isomer was
sometimes the only product isolated.3,13 We reasoned
that nucleoside regioisomers derived from appropriate
“lactim” structures (masked guanine precursors) might
have sufficiently different thermodynamic stabilities to
strongly favor formation of the 9-isomer. Attachment of
a bulky electron-withdrawing group at O6 of 1 (peri to
N7) might also favor kinetic coupling at N9 to directly
produce the more thermodynamically stable regioisomer.
Several 2-amino-6-(substituted)purine derivatives were
prepared and subjected to coupling with glycosyl acetate
derivatives.10d We found that 2-N-acetyl-6-O-(diphenyl-
carbamoyl)guanine (8a , Scheme 2), prepared readily from
guanine in high yield, gave excellent results in coupling
reactions under controlled conditions.10 The 6-O-(diphe-
nylcarbamoyl) (DPC) group was quite stable in aprotic
coupling media and was removed by mild deacylation
procedures. It is crucial to avoid cleavage of the (diphe-
nylcarbamoyl)oxy function during coupling reactions,
since the resulting 2-N-acetylguanine derivatives give 7/9
isomer mixtures (vide supra). Treatment of 2-N,9-
diacetylguanine10a with DPC chloride/ethyldiisopropy-
lamine/pyridine at ambient temperature14 followed by
solvolysis of the 9-acetyl group11 gave crystalline 2-N-
acetyl-6-O-(diphenylcarbamoyl)guanine (8a , 92%).
Resu lts a n d Discu ssion
Trimethylsilylation of 2-N-acetylguanine11 (1a ) [hex-
amethyldisilazane (HMDS)/(NH4)2SO4] and coupling of
the derivative [tris(trimethylsilyl)] with 1,2,3,5-tetra-O-
acetyl- (or 1-O-acetyl-2,3,5-tri-O-benzoyl)-â-D-ribofura-
nose under Vorbru¨ggen’s conditions4a [TMSOTf/DCE/80
°C overnight] gave mixtures of protected guanosine 2a
and its 7-isomer 3a (or the 2′,3′,5′-tri-O-benzoyl deriva-
tives) (2-5:1, respectively)6,10b in high yields (Scheme 1).
Analogous coupling with the 1,2,3,5-tetra-O-acetyl-D-xylo-
and -arabinofuranose derivatives gave similar mixtures
of 9/7-isomers (2c/3c and 2e/3e).10b Workup conditions
alter the relative amounts of minor isomers retained,
especially when emulsions result with SnCl4 catalysis.
Small differences in integrated intensity measurements
(1H NMR) for the minor-isomer peaks cause amplified
differences in normalized isomer ratios since the values
for the minor isomers are in the denominator. However,
the relative percentages reported for major and minor
isomers are quite similar.3a,5-8,10
Treatment of a suspension of 1a with bis(trimethylsi-
lyl)acetamide (BSA)/DCE/80 °C gave a solution that was
then cooled, and g2 equiv of SnCl4 was added to give an
active organometallic complex. A solution of the respec-
tive tetra-O-acetylpentofuranose in DCE was added to
this complex, and the mixture was stirred overnight at
ambient temperature. 1H NMR analysis of crude cou-
pling mixtures indicated maximum normalized 7/9 iso-
mer ratios of ∼13:1 (3a /2a ), ∼15:1 (3c/2c), and ∼18:1 (3e/
2e). Ratios varied somewhat, but isolated yields of the
7-isomers were quite consistent when emulsions were
allowed to separate adequately. Flash chromatography
gave purified 7-isomers 3a (70%), 3c [76%; plus the
isolated 9-isomer 2c (3%)], and 3e (72%). Deprotection
Per(trimethylsilyl)-8a (BSA/DCE) and tetra-O-acetyl-
ribofuranose (1.2 equiv) were coupled (TMSOTf/anhy-
drous toluene/80 °C/1 h) to give 9-isomer 9a (91% after
chromatography). No 7-isomer was detected (1H NMR)
in purified 9a , or in the crude coupling mixture, but a
(12) J enny, T. F.; Schneider, K. C.; Benner, S. A. Nucleosides
Nucleotides 1992, 11, 1257.
(13) Lee, W. W.; Martinez, A. P.; Goodman, L.; Henry, D. W. J . Org.
Chem. 1972, 37, 2923.
(14) Kamimura, T.; Tsuchiya, M.; Urakami, K.-I.; Koura, K.; Sekine,
M.; Shinozaki, K.; Miura, K.-I.; Hata, T. J . Am. Chem. Soc. 1984, 106,
4552.
(11) Hrebabecky, H.; Farkas, J. In Nucleic Acid Chemistry; Townsend,
L. B., Tipson, S., Eds.; Wiley: New York, 1978; Part I, pp 13-15.

Nucleic Acid Related Compounds
J . Org. Chem., Vol. 61, No. 26, 1996 9209
Sch em e 2a
rearrangement to the 9-glycosyl isomer 9a . Stirring a
solution of per(trimethylsilyl)-8a , tetra-O-acetylribofura-
nose, and TMSOTf in anhydrous toluene at ambient
temperature for 4 days resulted in progressive formation
of the 9-glycosyl isomer 9a , without observed formation
of its 7-isomer 12a . These two experiments indicate that
9-isomer 9a is both the kinetic and thermodynamic
product. Absence of detected 7-isomer 12a in the ambi-
ent temperature coupling indicates kinetic formation of
9a , and this also is supported indirectly by the longer
time (∼2 h) required for the rearrangement of 12a f 9a
at 80 °C relative to the standard N9 glycosylation (1 h).
Complete isomerization of 12a f 9a under the standard
coupling conditions, however, demonstrated the enhanced
thermodynamic stability (9a . 12a ) of the 9-isomer of
this 6-O-DPC pair relative to that of the 6-oxo pair (2a
> 3a ).
The broader generality of our methodology was dem-
onstrated by coupling per(trimethylsilyl)-8a and (2-
acetoxyethoxy)methyl bromide15a at 80 °C in anhydrous
toluene (no catalyst required). The “acyclovir”15 deriva-
tive 13 (63%) was produced plus traces of the 2-N,9-bis-
(acetoxyethoxymethyl) byproduct 14. Deprotection of 13
and crystallization gave the hemihydrate of acyclovir (15,
91%).
a
Key: (a) the structures of “Sug” are in Scheme 1; (b) BSA/
DCE/∆; (c) 1,2,3,5-tetra-O-acetyl-D-pentofuranose/TMSOTf/toluene/
∆; (d) NH3/H2O/MeOH/D; (e) AcOCH2CH2OCH2Br/toluene; (f)
Ph2NCOCl/EtN(i-Pr)2/pyridine; (g) TMSOTf/toluene/∆.
In summary, we have discovered a fortuitous organic/
aqueous partitioning that allows isolation of 7-glyco-
sylguanines from 7/9 isomer mixtures obtained by cou-
pling per(trimethylsilyl)-2-N-acylguanine derivatives and
tetra-O-acylpentofuranoses (TiCl4 catalysis). A com-
pletely regioselective synthesis of 9-glycosylguanine iso-
mers has been developed by coupling per(trimethylsilyl)-
2-N-acyl-6-O-(diphenylcarbamoyl)guanine derivatives and
tetra-O-acylpentofuranoses (TMSOTf catalysis). The
protected 9-isomer, 2-N-acetyl-2′,3′,5′-tri-O-acetyl-6-O-
(diphenylcarbamoyl)guanosine (9a ), was shown to be both
the kinetic and thermodynamic coupling product. Quan-
titative deprotection of all of the per(acyl) coupling
products occurred under mild conditions to give good to
high yields (recrystallization recovery) of guanine nucleo-
side analogues. These methodologies provide generally
applicable solutions to the prior absence2-9 of demon-
strated regioselective syntheses of 7- and 9-glycosylgua-
nine nucleosides in the cases we have investigated.
trace byproduct 10a (second sugar residue at N2) was
present. Excess (2.5 equiv) tetra-O-acetylribofuranose
gave enhanced formation of the bis(ribosyl) byproduct
10a , whose composition was analyzed by NMR and FAB
MS. Coupling of the tetra-O-acetyl derivatives of xylose
and arabinose produced 9c (86%, 9-â) and 9e (82%, 9-R),
respectively. Trace bis(glycosyl) byproducts were de-
tected, and 10c was isolated (4%) in one experiment, but
1
no 7-isomers were observed. The H-coupled 13C NMR
spectrum of the bis(xylosyl) byproduct 10c had three-
bond coupling to C2 of the guanine base in harmony with
attachment of the second sugar residue at N2. Depro-
tection (NH3/H2O/MeOH/60 °C) of 9a , 9c, and 9e and
crystallization gave analytically pure hemihydrates of
guanosine (4b, 75%), 4d (67%), and 4f (84%), respectively.
Analogous treatment of 10c gave 4d . This demonstrated
that the bis(sugar) byproduct was cleaved during depro-
tection and did not interfere with overall regioselective
production of the desired 9-isomer.
Treatment14 of 2-N-acetyl-2′,3′,5′-tri-O-acetylguanosine
(2a ) with DPC chloride gave a compound that was
identical to the coupling product 9a . This verified the
same site of attachment of the DPC group, and X-ray
crystallographic analysis of 13 proved that site to be
O6.10a,b
We considered that a more bulky acyl group on N2
might impede formation of the bis(sugar) byproduct.
Guanine was readily converted into 2-N-isobutyryl-6-O-
(diphenylcarbamoyl)guanine (8b, 87%). Coupling of per-
(trimethylsilyl)-8b and tetra-O-acetylribofuranose under
standard conditions gave the 9-isomer 11a (89%). No bis-
(sugar) byproduct, or 7-isomer, was detected in crude
coupling mixtures or in a control reaction with excess
sugar derivative. Deprotection (NH3/H2O/MeOH/60 °C)
of 11a gave 4b (80%).
We then investigated mechanistic aspects of this
synthesis. Diphenylcarbamoylation of synthetic tet-
raacetyl 7-isomer 3a occurred without difficulty to give
the corresponding 6-O-DPC derivative 12a . Treatment
of 12a by the standard coupling conditions (TMSOTf/
anhydrous toluene/80 °C) required ∼2 h for its complete
Exp er im en ta l Section
Uncorrected melting points were obtained with a hot stage
apparatus. UV spectra were determined with solutions in
MeOH unless otherwise noted. Table 1 (1H) and Table 2 (13C)
contain NMR spectral data (solutions in Me4Si/Me2SO-d6).
Mass spectra (EI MS, CI, FAB) were determined with direct
probe techniques at 20 or 70 eV. Solvents were purified, dried
(CaH2 or LiAlH4), and distilled before use. Pyridine was dried
by refluxing with and distillation from CaH2. Reagent-grade
chemicals were used without further purification. TLC was
performed with silica gel 60 F254 sheets, and silica gel (200-
425 mesh) was used for column chromatography. General
“procedures” are illustrated with specific examples and can be
applied to other compounds with minor noted modifications.
2-N-Acet yl-2′,3′,5′-t r i-O-a cet ylgu a n osin e (2a ). Gua-
nosine (4b; 283 mg, 1 mmol) was acetylated as described14
(Ac2O: 1.42 mL, 1.54 g, 15 mmol) to give a residue that was
chromatographed (CHCl3 f 3% MeOH/CHCl3) to give 2a (255
(15) (a) Robins, M. J .; Hatfield, P. W. Can. J . Chem. 1982, 60, 547.
(b) Shiragami, H.; Koguchi, Y.; Tanaka, Y.; Takamatsu, S.; Uchida,
Y.; Ineyama, T.; Izawa, K. Nucleosides Nucleotides 1995, 14, 337.

9210 J . Org. Chem., Vol. 61, No. 26, 1996
Ta ble 1. 1H NMR Sp ectr a l Da ta a ,b
Robins et al.
H1′c
(J 1′-2′
H2′d
(J 2′-3′
H3′d
(J 3′-4′
H4′e
(J 4′-5′,5′′
H5′,5′′e
(J 5′-5′′
(N1H
compd
)
)
)
)
)
H8f
or N2H)g
othersf
2c
5.97
(3.0)
6.31
(6.0)
6.36
(3.0)
6.36
(5.0)
5.98
(5.5)
6.08
(1.0)
5.91
(5.0)
6.30
(6.0)
6.37
(3.0)
6.26
(5.0)
6.18
(3.5)
6.32
(4.0)
6.29
(5.0)
6.09
(6.0)
5.58h
(2.5)
5.80h
(6.0)
5.58h
(2.5)
5.93
(5.0)
4.36e
(5.5)
4.23e
(1.5)
4.49e
(5.5)
5.80
(6.5)
5.58h
(2.5)
5.95h
(5.5)
5.81h
(2.5)
6.04h
(5.0)
5.99h
(5.5)
5.68h
(6.5)
5.52
(4.5)
5.44
(5.0)
5.48
(4.5)
5.37
(6.0)
4.56
(4.5, 7.0)
4.32
(4.0, 6.0)
4.61
(4.5, 7.0)
4.83
(3.5, 6.0)
3.89
(4.0, 4.0)
4.15
(5.0, 6.5)
4.19
(3.5, 5.5)
4.28-4.56
8.18 11.70, 12.10 2.02, 2.08, 2.10, 2.18 (Ac’s)
8.52 11.66, 12.24 2.04, 2.11, 2.17 (Ac’s)
8.40 11.63, 12.20 2.05, 2.06, 2.10 2.18 (Ac’s)
(11.5)
3a
3c
3e
5b
5d
5f
4.24d
(12.0)
4.34
(12.0)
4.18,d 4.28d 8.44 11.66, 12.23 2.03, 2.04, 2.06, 2.16 (Ac’s)
(12.0)
3.53, 3.66
(12.0)
3.67, 3.74
(12.0)
3.47, 3.58
(12.0)
4.07e
(4.0)
4.01e
(3.5)
3.93
(6.5)
5.44
(6.0)
5.49
(5.0)
5.78h
(5.5)
5.55
(4.5)
5.40
(6.5)
5.80
(6.0)
5.44h
(4.5)
8.30 10.96, 6.25
8.12 10.98, 6.25
8.16 10.92, 6.24
5.01,h 5.10,c 5.36,c (OH’s)
4.73,h 5.45,c 5.80c (OH’s)
4.84, 5.45, 5.68 (OH’s)
7a
7c
9a
9c
9e
11a
12a
4.19-4.44
4.19-4.44
8.51 11.62, 12.24 1,11,c 2.74i (i-Pr), 2.03, 2.10 (Ac’s)
8.41 11.24, 11.63 1.13,c 2.76i (i-Pr), 2.05, 2.11 (Ac’s)
(11.0)
4.62d
(5.0, 5.0)
4.38
(3.5, 6.0)
4.61
(4.0, 7.0)
5.00
(3.5, 5.5)
4.34-4.48
(4.0, 4.0)
4.47
4.34c
4.33,d 4.43d 8.61 10.77
(11.0)
4.29
1.99, 2.05, 2.12, 2.18 (Ac’s), 7.28-7.54e (Ph2)
2.01, 2.09, 2.10, 2.22 (Ac’s), 7.28-7.56e (Ph2)
2.04, 2.22 (Ac’s), 7.26-7.56e (Ph2)
8.59 10.74
(12.0)
4.20,d 4.32d 8.59 10.76
(12.0)
4.34-4.48
(12.0)
4.21,d 4.32d 8.91 10.70
(12.0)
8.66 10.78
1.11,c 2.81i (i-Pr), 2.01, 2.10, 2.25 (Ac’s),
7.36-7.61e (Ph2)
1.95, 2.00, 2.16, 2.20 (Ac’s), 7.30-7.65e (Ph2)
(3.5, 6.0)
a
b
Chemical shifts (δ; 400 or 200 MHz). “Apparent” first-order coupling constants (Hz; in parentheses). c Doublet unless otherwise
noted. Doublet of doublets unless otherwise noted. e Multiplet unless otherwise noted. f Singlet unless otherwise noted. Broad singlet.
Triplet. Septet.
d
g
h
i
Ta ble 2. 13C NMRa ,b
compd
C2
C4
C5
C6
C8
C1′
C2′
C3′
C4′
C5′
2cc
147.97
147.35
147.00
147.48
152.87
152.60
152.83
148.01
147.76
152.16
152.33
152.18
152.69
149.19
148.33
158.26
157.35
158.42
160.63
159.98
160.66
158.66
157.87
153.98
154.23
153.99
154.49
164.84
119.81
110.49
110.55
110.45
107.67
107.41
107.49
110.84
111.00
120.26
119.69
120.09
120.84
110.59
154.50
152.07
152.10
152.48
154.31
154.36
154.28
152.46
152.63
155.25
155.12
155.18
155.57
152.33
136.98
143.85
142.02
143.80
142.36
141.75
142.44
144.45
142.73
144.10
143.18
143.95
144.60
147.73
85.58
87.50
88.16
88.18
89.10
91.11
90.33
87.78
89.69
86.27
86.15
86.71
86.29
87.21
78.82
73.00
79.35
79.01
74.39
81.39
80.26
73.32
79.73
72.16
78.25
78.26
72.58
72.86
73.86
69.58
73.89
74.54
69.69
75.11
75.03
69.93
74.27
70.25
73.98
74.87
70.74
69.87
77.74
79.40
77.96
79.86
85.17
83.44
84.82
79.77
78.54
79.76
77.69
80.18
80.29
80.00
60.92
62.79
60.96
63.08
61.12
59.31
61.13
63.27
61.64
63.04
61.11
62.56
63.54
62.95
3a c
3cc
3ec
5b
5d
5f
7a c,d
7cc,d
9a c,e
9cc,e
9ec,e
11a c-e
12a c,e
a
b
d
Chemical shifts (δ; 100 or 50 MHz). Proton-decoupled singlets. c Also peaks at δ 19.80-24.40 and 168.50-173.50 (Ac’s). Also peaks
at δ 19.00-19.20, 34.90-35.10, and 175.00-180.40 (i-PrCO). e Also peaks at δ 126.60-141.80 and 149.70-150.40 (Ph2NCO).
mg, 57%; white foam): MS m/ z 451.1348 (11, M+[C18H21N5O9]
) 451.1339) with spectral data as reported.16
as reported:6 UV max 263 nm; MS m/ z 451.1331 (6, M+-
[C18H21N5O9] ) 451.1339).
7-(â-D-Ribofu r a n osyl)gu a n in e (5b). Meth od A. P r o-
ced u r e A. A suspension of 2-N-acetylguanine11 (1a ; 193 mg,
1 mmol) and BSA (0.5 mL, 407 mg, 2 mmol) in dried DCE (10
mL) was stirred in a stoppered flask at 80 °C until a clear
solution was obtained (∼2.5 h). The solution was cooled, SnCl4
(0.25 mL, 550 mg, 2.1 mmol) was added, and stirring was
continued at ambient temperature for 30 min. A solution of
tetra-O-acetyl-â-D-ribofuranose (350 mg, 1.1 mmol) in DCE (5
mL) was added, and stirring was continued for 1 day. MeOH
(5 mL) was added, the reaction mixture was diluted with
CHCl3 (50 mL), and the solution was washed [brine (50 mL),
saturated NaHCO3/H2O (50 mL × 2), brine (50 mL)]. The
organic layer was dried (Na2SO4) and filtered, and the filtrate
was evaporated. The residue was chromatographed (Et2O f
10% MeOH/Et2O) to give 2-N-acetyl-7-(2,3,5-tri-O-acetyl-â-D-
ribofuranosyl)guanine (3a ; 317 mg, 70%; white foam) with data
Meth od B. P r oced u r e B. A suspension of 2-N-isobu-
tyrylguanine12 (1b; 221 mg, 1 mmol) and BSA (0.5 mL, 407
mg, 2 mmol) in dried CH3CN (15 mL) was heated at 80 °C
under argon until a clear solution was obtained (∼1.5 h). The
solution was cooled to ambient temperature, TiCl4 (0.23 mL,
398 mg, 2.1 mmol) was added, and stirring was continued for
30 min. A solution of tetra-O-acetyl-â-D-ribofuranose (350 mg,
1.1 mmol) in dried CH3CN (8 mL) was added, the reaction
mixture was heated at 80 °C for 3 h and cooled to ambient
temperature, and MeOH (5 mL) was added. Volatiles were
evaporated, and the residue was dissolved (EtOAc, 150 mL).
The solution was washed [brine (50 mL), saturated NaHCO3/
H2O (2 × 50 mL), brine (50 mL)], dried (Na2SO4), and
chromatographed (3% MeOH/EtOAc) to give 7-(2,3,5-tri-O-
acetyl-â-D-ribofuranosyl)-2-N-isobutyrylguanine (7a ; 320 mg,
67%; white foam): UV max 264 nm (ꢀ 13 600); MS (FAB) m/ z
480.1728 (100, MH+[C20H26N5O9] ) 480.1731).
Analogous coupling with 1b (TiCl4/DCE) and workup gave
7a (43%). Combined aqueous wash layers were evaporated,
(16) Reese, C. B.; Saffhill, R. J . Chem. Soc., Perkin Trans. 1 1972,
2937.

Nucleic Acid Related Compounds
J . Org. Chem., Vol. 61, No. 26, 1996 9211
and the residue was subjected to procedure C. Volatiles were
evaporated, and the residue was extracted (MeOH). The
combined extracts were evaporated, and the residue was
crystallized (H2O) to give 4b/5b (∼1.5:1, 29%). Treatment of
1b by procedure A (with TiCl4 as catalyst instead of SnCl4)
gave 7a /6a (∼16:1, 44%).
(m, 10), 8.46 (s, 1), 10.66 (br s, 1), 13.02 (br s, 1). Anal. Calcd
for C20H16N6O3: C, 61.85; H, 4.15; N, 21.64. Found: C, 61.84;
H, 4.24; N, 21.51.
6-O-(Dip h en ylca r ba m oyl)-2-N-isobu tyr ylgu a n in e (8b).
Treatment of 9-acetyl-2-N-isobutyrylguanine12 (2.63 g, 10
mmol) by procedure E gave 8b (3.71 g, 87%; white powder):
mp ∼218-220 °C dec; UV max 278 (ꢀ 12 600); MS (FAB) m/ z
417.1693 (100, MH+[C22H21N6O3] ) 417.1675); 1H NMR δ 1.03
(d, J ) 6 Hz, 6), 2.78 (septet, 1), 7.28-7.54 (m, 10), 8.44 (s, 1),
10.59 (br s, 1), 13.58 (br s, 1); 13C NMR (10 mol % CF3CO2H/
DMSO-d6) δ 19.53, 34.75, 118.81* (C5), 127.49, 129.23, 129.65,
141.90, 144.87* (C8), 150.52 (6-COO), 152.34 (C2), 154.19*
(C4), 157.41* (C6), 174.81 (signals followed by an asterisk were
observed only after adding TFA). Anal. Calcd for C22H20N6O3‚
0.5H2O: C, 62.11; H, 4.98; N, 19.75. Found: C, 62.13; H, 4.86;
N, 19.65.
Gu a n osin e (4b). Meth od A. P r oced u r e F . BSA (0.5
mL, 407 mg, 2 mmol) was added to a suspension of 8a (388
mg, 1 mmol) in dried DCE (10 mL), and stirring was continued
in a stoppered flask at 80 °C for 15 min. The clear solution
was evaporated, the residue was dissolved in dried toluene (5
mL), and TMSOTf (0.24 mL, 289 mg, 1.3 mmol) and a solution
of tetra-O-acetyl-â-D-ribofuranose (382 mg, 1.2 mmol) in dried
toluene (5 mL) were added. The solution was stirred at 80 °C
for 1 h and cooled, and EtOAc (50 mL) was added. The organic
phase was washed [saturated NaHCO3/H2O (50 mL × 2), brine
(50 mL)], dried (Na2SO4), and evaporated. The residue was
chromatographed (Et2O f 20% Me2CO/Et2O) to give 2-N-
acetyl-9-(2,3,5-tri-O-acetyl-â-D-ribofuranosyl)-6-O-(diphenyl-
carbamoyl)guanine (9a ; 589 mg, 91%; white foam): UV max
278 nm; MS (FAB) m/ z 647 (3, MH+).
Dep r otection . P r oced u r e C. A solution of 3a (451 mg,
1 mmol) in NH3/MeOH (20 mL; saturated at -10 °C) in a
sealed flask was stirred at ambient temperature for 24 h.
Volatiles were evaporated, and the residue was washed (2 ×
CHCl3) and then crystallized (H2O) to give 5b hemihydrate
(228 mg, 78%): mp ∼275 °C dec (lit.17 mp 230-260 °C dec,
lit.6 mp 298 °C dec); UV (H2O) max 286 nm (ꢀ 6800); MS m/ z
283.0910 (1, M+[C10H13N5O5] ) 283.0917), (FAB) m/ z 284 (12,
MH+).
Analogous treatment of 7a (240 mg, 0.5 mmol) [the residue
was dissolved (H2O), the solution was washed (CHCl3), the
aqueous layer was evaporated, and the residue was crystal-
lized (H2O)] gave 5b hemihydrate (110 mg, 78%) with identical
data.
7-(â-D-Xylofu r a n osyl)gu a n in e (5d ). Meth od A. Tetra-
O-acetyl-D-xylofuranose (350 mg, 1.1 mmol) was subjected to
procedure A to give a residue that was chromatographed
(CHCl3 f 2% MeOH/CHCl3) to give 2-N-acetyl-7-(2,3,5-tri-O-
acetyl-â-D-xylofuranosyl)guanine (3c; 341 mg, 76%; white
foam): UV max 264 nm; MS m/ z 451.1338 (9, M+[C18H21N5O9]
) 451.1339). Further elution gave 2-N-acetyl-9-(2,3,5-tri-O-
acetyl-â-D-xylofuranosyl)guanine (2c; 13 mg, 3%): UV max 258
and 280 nm.
Meth od B. Treatment of 1b (1 mmol) and tetra-O-acetyl-
â-D-xylofuranose (350 mg, 1.1 mmol) by procedure B gave
7-(2,3,5-tri-O-acetyl-â-D-xylofuranosyl)-2-N-isobutyrylgua-
nine (7c; 56% with CH3CN; 59% with DCE): UV max 264 nm
(ꢀ 12 900); MS (FAB) m/ z 480.1725 (100, MH+[C20H26N5O9] )
480.1731).
Dep r otection . P r oced u r e D. NH3/H2O (28-30%; 20 mL)
was added to a stirred solution of 3c (451 mg, 1 mmol) in
MeOH (20 mL). The flask was sealed and heated at 60 °C for
1 day. Volatiles were evaporated, and the residue was washed
(2 × CHCl3) and crystallized (H2O) to give 5d hemihydrate
(251 mg, 86%; two crops): mp ∼285 °C dec (Lit.8a mp > 220
°C dec); UV (H2O) max 285 (ꢀ 7300); MS (FAB) m/ z 284 (26,
MH+). Anal. Calcd for C10H13N5O5‚0.5H2O: C, 41.10; H, 4.83;
N, 23.96. Found: C, 41.01; H, 4.58; N, 23.78.
Meth od B. Treatment of 2a (177 mg, 0.39 mmol) by
procedure E [chromatography (CHCl3 f 1% MeOH/CHCl3)]
gave 9a (194 mg, 77%) with NMR (1H and 13C) and UV spectra
identical with those of 9a from method A. The two samples
comigrated in three TLC systems.
Meth od C. Treatment of 8a (388 mg, 1 mmol) in DCE (15
mL) with BSA (0.5 mL, 407 mg, 2 mmol) followed by tetra-O-
acetyl-â-D-ribofuranose (796 mg, 2.5 mmol) and TMSOTf (0.38
mL, 467 mg, 2.1 mmol) by procedure F (80 °C, 2 h) gave a
residue that was chromatographed (3 f 10% Me2CO/CHCl3).
Early fractions contained 2-N-acetyl-2-N,9-bis(2,3,5-tri-O-
acetyl-â-D-ribofuranosyl)-6-O-(diphenylcarbamoyl)guanine (10a;
26 mg, 3%; white foam): UV max 263 (sh) nm; MS (FAB) m/ z
905 (1, MH+); 1H NMR δ 1.60, 1.95, 2.04, 2.06, 2.12, 2.14 (6 ×
s, 21), 3.83, 4.18, 4.23, 4.37 (4 × m, 6), 5.28, 5.60, 5.80, 5.97 (4
× m, 4), 6.11, 6.36 (2 × d, 2), 7.30-7.60 (m, 10), 8.55 (s, 1).
Intermediate fractions contained 9a and 10a (115 mg), and
later fractions contained 9a (160 mg, 25%).
Deprotection of 7c (479 mg, 1 mmol) by procedure C and
crystallization (H2O) gave 5d (215 mg, 76%; white powder)
with identical data.
7-(r-D-Ar a bin ofu r a n osyl)gu a n in e (5f). Tetra-O-acetyl-
D-arabinofuranose (350 mg, 1.1 mmol) was subjected to
procedure A to give a residue that was chromatographed (Et2O
f 10% MeOH/Et2O) to give 2-N-acetyl-7-(2,3,5-tri-O-acetyl-
R-D-arabinofuranosyl)guanine (3e; 326 mg, 72%; white foam):
UV max 263 nm; MS m/ z 451.1328 (4, M+[C18H21N5O9] )
451.1339). Deprotection of 3e (451 mg, 1 mmol) by procedure
C and crystallization (H2O) gave 5f hemihydrate (249 mg,
85%): mp 250 °C dec; UV (H2O) max 286 nm (ꢀ 7500); MS
(FAB) m/ z 284 (12, MH+). Anal. Calcd for C10H13N5O5‚
0.5H2O: C, 41.10; H, 4.83; N, 23.96. Found: C, 41.35; H, 4.83;
N, 24.18.
2-N-Acetyl-6-O-(diph en ylcar bam oyl)gu an in e (8a). P r o-
ced u r e E. Diphenylcarbamoyl chloride (6.37 g, 2.75 mmol)
was added portionwise to a suspension of 2-N,9-diacetyl-
guanine10a (5.88 g, 25 mmol) in EtN(i-Pr)2 (8.7 mL, 6.46 g, 50
mmol) and dried pyridine (120 mL), and stirring was continued
at ambient temperature for 1 h. H2O (10 mL) was added,
stirring was continued for 10 min, and volatiles were evapo-
rated. The residue was coevaporated (toluene, 3 × 20 mL)
and then was heated (steam bath) with EtOH/H2O (1:1, 300
mL) for 1.5 h. The cooled suspension was filtered, and the
product was washed (98% EtOH) until the washings were
colorless. 8a (8.93 g, 92%; white powder): mp ∼254-256 °C
(dec; fast heating); UV max 278 nm; MS m/ z 388.1283 (8, M+-
[C20H16N6O3] ) 388.1284); 1H NMR δ 2.18 (s, 3), 7.26-7.56
Meth od D. Treatment of 8b (416 mg, 1 mmol) by procedure
F gave 9-(2,3,5-tri-O-acetyl-â-D-ribofuranosyl)-6-O-(diphenyl-
carbamoyl)-2-N-isobutyrylguanine (11a ; 619 mg, 89%; white
foam): UV max 278 nm (ꢀ 13 400); MS (FAB) m/ z 675.2420
(100, MH+[C33H35N6O10] ) 675.2415). Anal. Calcd for C33H34
-
N6O10‚1.25H2O: C, 56.85; H, 5.28; N, 12.05. Found: C, 56.83;
H, 5.24; N, 11.79.
Dep r otection . Treatment of 9a (647 mg, 1 mmol) (or 9a
plus 10a ) by procedure C gave 4b hemihydrate (from H2O)
(220 mg, 75%): mp ∼265 °C dec (authentic sample, mp ∼250
°C dec); UV (H2O) max 252 nm (ꢀ 13 800), (0.1 M HCl) max
255 nm (ꢀ 12 300), (0.1 M KOH) max 264 nm (ꢀ 11 500); MS
(FAB) m/ z 284 (23, MH+). Anal. Calcd for C10H13N5O5‚
0.5H2O: C, 41.10; H, 4.83; N, 23.96. Found: C, 41.03; H, 4.63;
N, 23.99.
Analogous deprotection of 11a gave 4b (80%).
9-(â-D-Xylofu r a n osyl)gu a n in e (4d ). Treatment of tetra-
O-acetyl-D-xylofuranose (1.2 mmol) by procedure F [chroma-
tography (CHCl3 f 1% MeOH/CHCl3)] gave 2-N-acetyl-9-
(2,3,5-t r i-O-a cet yl-â-D-xylofu r a n osyl)-6-O-(diph en ylca r -
bamoyl)guanine (9c; 553 mg, 86%; white foam): UV max 278
nm; MS (FAB) m/ z 647 (4, MH+) plus 2-N-acetyl-2-N,9-bis-
(2,3,5-tri-O-acetyl-â-D-xylofuranosyl)-6-O-(diphenylcarbamoyl)-
guanine (10c; 40mg, 4%): UV max 263 nm (sh); MS (FAB)
m/ z 905 (6, MH+); 1H NMR δ 1.43, 1.90, 1.96, 2.02, 2.10 (5 ×
s, 21), 3.88, 4.03, 4.30, 4.62 (4 × m, 6), 5.22, 5.52, 5.75, 5.80 (4
× m, 4), 6.14, 6.29 (2 × d, 2), 7.30-7.60 (m, 10), 8.83 (s, 1);
(17) Rousseau, R. J .; Robins, R. K.; Townsend, L. B. J . Am. Chem.
Soc. 1968, 90, 2661.

9212 J . Org. Chem., Vol. 61, No. 26, 1996
Robins et al.
13C NMR δ 19.27, 20.15, 20.28, 23.28, 61.02, 61.20, 74.13,
74.79, 75.54, 76.94, 78.07, 78.40, 86.83, 87.72, 122.59, 126.72,
127.21, 129.24, 141.35, 145.73, 149.62, 151.82 (C2), 154.12,
155.17, 168.83, 169.09, 169.63, 169.75, 170.13.
Dep r otection . Treatment of 9c (647 mg, 1 mmol) (or 9c
and 10c) by procedure D gave 4d hemihydrate (from H2O) (197
mg, 67%; two crops): mp ∼250 °C dec (lit.8a mp 241-243 °C
dec); UV (H2O) max 252 nm (ꢀ 13 700); MS (FAB) m/ z 284
(14, MH+). Anal. Calcd for C10H13N5O5‚0.5H2O: C, 41.10; H,
4.83; N, 23.96. Found: C, 40.97; H, 4.52; N, 23.83.
9-(r-D-Ar a bin ofu r a n osyl)gu a n in e (4f). Treatment of
tetra-O-acetyl-D-arabinofuranose (382 mg, 1.2 mmol) by pro-
cedure F [chromatography (Me2CO/Et2O, 1:4)] gave 2-N-acetyl-
9-(2,3,5-tri-O-acetyl-R-D-arabinofuranosyl)-6-O-(diphenylcar-
bamoyl)guanine (9e; 531 mg, 82%; white foam): UV max 278
nm; MS (FAB) m/ z 647 (1, MH+). Deprotection of 9e (647 mg,
1 mmol) by procedure D gave 4f hemihydrate (from H2O) (246
mg, 84%): mp ∼290 °C dec (lit.18 mp >300 °C dec); UV (H2O)
max 252 nm (ꢀ 13 000); MS (FAB) m/ z 284 (16, MH+). Anal.
Calcd for C10H13N5O5‚0.5H2O: C, 41.10; H, 4.83; N, 23.96.
Found: C, 41.23; H, 4.57; N, 24.08.
Rea r r a n gem en t of 2-N-Acetyl-7-(2,3,5-tr i-O-a cetyl-â-D-
r ibofu r a n osyl)-6-O-(d ip h en ylca r ba m oyl)gu a n in e (12a )
To Give 9a . Treatment of 3a (226 mg, 0.5 mmol) by procedure
E (ambient temperature, 3 h) [chromatography (CHCl3 f 2%
MeOH/CHCl3)] gave 12a (264 mg, 82%): MS (FAB) m/ z 647
(25, MH+). Subjection of 12a to the conditions of procedure F
for 2 h (TMSOTf/dried toluene/80 °C/2 h) resulted in its
complete conversion to 9a .
that was chromatographed (Et2O f 30% Me2CO/Et2O). Evapo-
ration of later fractions gave a white foam that was recrystal-
lized (Et2O/CH3CN) to give 9-[(2-acetoxyethoxy)methyl]-2-N-
acetyl-6-O-(diphenylcarbamoyl)guanine (13; 319 mg, 63%): mp
136-138 °C; UV max 278 nm (ꢀ 13 600); MS m/ z 504.1770
(1, M+[C25H24N6O6] ) 504.1757), (FAB) m/ z 505 (25, MH+);
1H NMR δ 1.91 (s, 3), 2.22 (s, 3), 3.78 (m, 2), 4.08 (m, 2), 5.62
(s, 2), 7.30-7.56 (m, 10), 8.60 (s, 1), 10.76 (br s, 1); 13C NMR
δ 20.16, 24.27, 62.44, 67.20, 72.47, 119.54, 126.64, 126.97,
129.08, 141.43, 145.36, 149,81, 152.33, 154.88, 155.04, 168.62,
169.83. Evaporation of earlier fractions gave 2-N,9-bis[(2-
acetoxyethoxy)methyl]-2-N-acetyl-6-O-(diphenylcarbamoyl)-
guanine (14; 20 mg, 3%) [repurified on a silica plate (5 × 20
cm, developed twice with Me2CO/Et2O (3:7) before NMR
analysis]: 1H NMR δ 1.85, 1.86, 2.28 (3 × s, 9), 3.66, 3.74 (2
× m, 4), 4.03 (m, 4), 5.42, 5.68 (2 × s, 4), 7.30-7.60 (m, 10),
8.73 (s, 1).
Dep r otection . Treatment of crystalline 13 (504 mg, 1
mmol) by procedure D gave 15 hemihydrate (from H2O) (212
mg, 91%; two crops): mp 250-253 °C (lit.15a mp 265-266 °C,
lit.15b mp 247-248 °C); UV (H2O) max 251 nm (ꢀ 13 200); MS
m/ z 225.0865 (7, M+[C8H11N5O3] ) 225.0862), (FAB) m/ z 226
(80, MH+); 1H NMR δ 3.46 (s, 4), 4.67 (br s, 1), 5.35 (s, 2), 6.51
(br s, 2), 7.81 (s, 1), 10.64 (br s, 1); 13C NMR δ 59.88, 70.34,
72.01, 116.43 (C5), 137.71 (C8), 151.39 (C4), 153.78 (C2),
156.76 (C6).
Ack n ow led gm en t. We thank the Natural Sciences
and Engineering Research Council of Canada, the
University of Alberta, and Brigham Young University
development funds for support and Mrs. J eanny Gordon
for assistance with the manuscript.
9-[(2-Hyd r oxyeth oxy)m eth yl]gu a n in e (Acyclovir ) (15).
Treatment of 8a (388 mg, 1 mmol) and (2-acetoxyethoxy)-
methyl bromide15a (0.158 mL, 236 mg, 1.2 mmol) by procedure
F (ambient temperature, 1.5 h; no TMSOTf) gave a residue
(18) Lee, W. W.; Martinez, A. P.; Blackford, R. W.; Bartuska, V. J .;
Reist, E. J .; Goodman, L. J . Med. Chem. 1971, 14, 819.
J O9617023