First evident generation of purin-2-yllithium: Lithiation of an 8-silyl- protected 6-chloropurine riboside as a key step for the synthesis of 2- carbon-substituted adenosines

Article abstract of DOI:10.1021/jo9906577

Lithiation at the 2-position of purine ring has been accomplished for the first time by using 6-chloro-9-(2,3-O-isopropylidene-5-O-trityl-β-D- ribofuranosyl)-8-(triisopropylsilyl)purine (7) as a substrate and LTMP as a lithiating agent. The 8-triisopropylsilyl group in 7 did not undergo anionic migration and, thus, allowed the ready generation of the C2-lithiated species by preventing deprotonation at the 8-position. The electron-withdrawing 6- chlorine atom plays an essential role to this C2-lithiation. Reactions of the lithiated species with electrophiles gave the 2-substituted products (Me, Et, i-Pr, CH(OH)C₆H₁₁, C(OH)Me₂, CHO, CO₂Me, and I) mostly in good yields. Ammonolysis of the 6-chlorine atom of these products (heating at 110 °C in a sealed tube with NH₃/MeOH) effected simultaneous desilylation at the 8- position to give the corresponding adenosine analogues. The whole sequence provides a new and highly general method for the synthesis of 2-substituted adenosines.

Full text of DOI:10.1021/jo9906577

J . Org. Chem. 1999, 64, 7773-7780
7773
F ir st Evid en t Gen er a tion of P u r in -2-yllith iu m : Lith ia tion of a n
8-Silyl-P r otected 6-Ch lor op u r in e Ribosid e a s a Key Step for th e
Syn th esis of 2-Ca r bon -Su bstitu ted Ad en osin es†
Hiroki Kumamoto, Hiromichi Tanaka,* Ryota Tsukioka, Yumiko Ishida, Akiko Nakamura,
Satoe Kimura, Hiroyuki Hayakawa,‡ Keisuke Kato,§ and Tadashi Miyasaka
School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku,
Tokyo 142-8555, J apan
Received April 20, 1999
Lithiation at the 2-position of purine ring has been accomplished for the first time by using 6-chloro-
9-(2,3-O-isopropylidene-5-O-trityl-â-D-ribofuranosyl)-8-(triisopropylsilyl)purine (7) as a substrate
and LTMP as a lithiating agent. The 8-triisopropylsilyl group in 7 did not undergo anionic migration
and, thus, allowed the ready generation of the C2-lithiated species by preventing deprotonation at
the 8-position. The electron-withdrawing 6-chlorine atom plays an essential role to this C2-lithiation.
Reactions of the lithiated species with electrophiles gave the 2-substituted products (Me, Et, i-Pr,
CH(OH)C6H11, C(OH)Me2, CHO, CO2Me, and I) mostly in good yields. Ammonolysis of the 6-chlorine
atom of these products (heating at 110 °C in a sealed tube with NH3/MeOH) effected simultaneous
desilylation at the 8-position to give the corresponding adenosine analogues. The whole sequence
provides a new and highly general method for the synthesis of 2-substituted adenosines.
In tr od u ction
Although the lithiation of 9-[2,3,5-tris-O-(tert-butyldi-
methylsilyl)-â-D-ribofuranosyl]-6-chloropurine (1) recently
reported from this laboratory also follows the same
regioselectivity, reaction of its 8-lithiated species with
TMSCl provides the 2-silylated product 2, as a result of
intermolecular anionic migration of the initially intro-
duced 8-TMS group to the 2-position as depicted in
Scheme 1 (1fAfBfCfDf2).6
This migration also takes place by using Bu3SnCl as
an electrophile. The resulting 2-stannylated product has
been found to be useful for the synthesis of 2-substituted
purine nucleosides by manipulation of its 2-stannyl
group.6 Although this method has made the introduction
of halogen and certain types of carbon-functionalities
possible, we thought it would be beneficial to develop an
alternative method in which the 2-lithio intermediate
reacts directly with added electrophiles.
Synthetic methods for the base-modified nucleosides
can be classified into the following three categories: (1)
condensation of the modified bases with appropriately
protected sugar derivatives, (2) cyclization of ribosyl
precursors (N-substituted ribosylamines for pyrimidine
analogues and ribosylimidazoles for purine analogues),
and (3) manipulation of the base moieties of naturally
occurring nucleosides.1 In the third category, halogena-
tion and subsequent nucleophilic substitution have been
employed in many occasions. This approach is particu-
larly useful for the introduction of heteroatom-substitu-
ents, while there seems to be a considerable limitation
in introducing carbon-substituents.
Lithiation (hydrogen-lithium exchange) chemistry of
nucleosides, which also falls into the third category, has
been recognized to compensate the above-mentioned
nucleophilic approach, since the lithiated species of
nucleosides allow the reaction with a wide range of
carbon-electrophiles, as exemplified already in the syn-
thesis of 6-substituted uridines.2 Lithiation of purine
nucleosides started with the finding that N6-methylated
2′,3′-O-isopropylideneadenosine undergoes exclusive depro-
tonation at the 8-position with BuLi.3 This regiochemical
outcome has been observed for a series of lithiation
studies of adenosine, inosine, and 6-chloropurine riboside,
in which LDA (lithium diisopropylamide) was used as a
lithiating agent.4,5
This paper describes the first example of evident
lithiation at the 2-position of purine ring by the use of
an 8-silylated 6-chloropurine riboside. As a synthetic
application, various types of 2-carbon-substituted adeno-
sines were synthesized by employing the lithiation as a
key reaction step.
Resu lts a n d Discu ssion
P r ep a r a tion a n d C2-lith ia tion of 9-[2,3,5-Tr is-O-
(ter t-bu tyldim eth ylsilyl)-â-D-r ibofu r an osyl]-6-ch lor o-
8-(tr iisop r op ylsilyl)p u r in e. The reaction mechanism
given in Scheme 1 clearly indicates involvement of the
2-lithiated species (B) of a purine ring. It may also
suggest that the difficulty in lithiating the 2-position
could possibly be due to prior deprotonation at the
† This paper is dedicated to the memory of Professor Richard T.
Walker (The University of Birmingham, U.K.) who died in November
1997.
‡ Currrent address: Tsumura Central Research Laboratories, 3586
Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki 300-1155, J apan.
§ Current address: School of Pharmaceutical Sciences, Toho Uni-
versity, 2-2-1 Miyama, Funabashi, Chiba 274-8510, J apan.
(1) For a review article, see: Srivastava, P. C.; Robins, R. K.; Meyer,
R. B., J r. In Chemistry of Nucleosides and Nucleotides; Townsend, L.
B., Ed.; Plenum Press: New York, 1988; Vol. 1, pp 1-281.
(2) Tanaka, H.; Hayakawa, H.; Miyasaka, T. Tetrahedron 1982, 38,
2635-2642.
(4) Tanaka, H.; Uchida, Y.; Shinozaki, M.; Hayakawa, H.; Matsuda,
A.; Miyasaka, T. Chem. Pharm. Bull. 1983, 31, 787-790.
(5) Hayakawa, H.; Haraguchi, K.; Tanaka, H.; Miyasaka, T. Chem.
Pharm. Bull. 1987, 35, 72-79.
(6) (a) Kato, K.; Hayakawa, H.; Tanaka, H.; Kumamoto, H.; Mi-
yasaka, T. Tetrahedron Lett. 1995, 36, 6507-6510. (b) Kato, K.;
Hayakawa, H.; Tanaka, H.; Kumamoto, H.; Shindoh, S.; Shuto, S.;
Miyasaka, T. J . Org. Chem. 1997, 62, 6833-6841.
(3) Barton, D. H. R.; Hedgecock, C. J . R.; Lederer, E.; Motherwell,
W. B. Tetrahedron Lett. 1979, 279-280.
10.1021/jo9906577 CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/28/1999

7774 J . Org. Chem., Vol. 64, No. 21, 1999
Kumamoto et al.
Sch em e 1
Sch em e 2
8-position.7 We considered, therefore, that C2-lithiation
would be possible by introducing a more bulky silyl group,
such as TIPS (triisopropylsilyl) group, to the 8-position,
which is expected to prevent silaphilic attack of the
2-lithiated species.
as the compatibility of the 8-TIPS group to the reaction
conditions. As anticipated, LDA was not a suitable
reagent for the lithiation of 3, it simply gave the N,N-
diisopropyladenosine derivative 4 (88%). The use of
LTMP (4 equiv), on the other hand, did not cause such
displacement at the 6-position, but TLC analysis (hexane:
EtOAc ) 10:1) of the deuterated reaction mixture showed
that an unexpected product 5 (Rf 0.85, isolated in 11%
yield) was formed in addition to the deuterated 3 (Rf 0.65,
isolated in 67% recovery, 92% D-incorporation as calcu-
Introduction of a TIPS group into the 8-position of 1
was first carried out based on LTMP (lithium 2,2,6,6-
tetramethylpiperidide) lithiation, since the use of LDA
in combination with TMSCl resulted in the displacement
of the 6-chlorine atom with diisopropylamino group in
our previous study.6 When 1 was treated with LTMP (1.2
equiv) in THF below -70 °C and then reacted with
TIPSCl (1.2 equiv), no reaction took place, showing that
there is a significant difference in reactivity between
TMSCl and TIPSCl. However, by adding HMPA (0.5
equiv) to the above reaction mixture, the 8-TIPS deriva-
tive 3 was formed and was isolated in 88% yield after
silica gel column chromatography (Scheme 2). It should
be mentioned that the corresponding 8-TMS derivative,
prepared in our previous study,6 is highly susceptible to
protonolysis, forming 1 during silica gel column chroma-
tography. It was found later that LHMDS in the presence
of HMPA can also be employed for the preparation of 3
(99% yield).
1
lated by H NMR spectroscopy).
The 1H NMR spectrum of 5 showed no aromatic proton,
and the presence of four TBDMS groups in addition to
one TIPS group. Although unambiguous regiochemical
assignment of 5 could not be made, and thus the depicted
structure is tentative, it was confirmed that 5 was also
formed upon reacting the lithiated species of 3 with
TBDMSCl (90% yield) in the presence of HMPA. The
formation of 5 clearly indicates that the C-2 lithiation of
3 had accompanied with an intermolecular migration of
TBDMS group from the sugar to the base moiety.10
Indeed, TLC analysis of the deuterated reaction mixture
in more polar solvent system (CHCl3:MeOH ) 10:1)
showed the presence of byproducts (Rf 0.45-0.60), which
could not be isolated even by HPLC separation. This
result led us to change the sugar protecting group of the
substrate.
The depicted regiochemistry of 3 was readily assumed
1
by the H NMR observation of a significant deshielding
in H-2′ (δ 5.98 ppm) as compared with that of 2 (H-2′, δ
4.58 ppm).8 It was also confirmed by HMBC (hetero-
nuclear multiple bond connectivity) experiments: the
H-1′ (δ 6.04 ppm) showed correlations with two quater-
nary carbon atoms (C-4, δ 153.4 ppm; C-8, δ 164.2 ppm).9
Lithiation of 3 at the 2-position was next examined by
deuteration to see the efficiency of the lithiation as well
9-(2,3-O-Isop r op ylid en e-5-O-tr ityl-â-D-r ibofu r a n o-
syl)-6-ch lor o-8-(tr iisop r op ylsilyl)p u r in e As a Su it-
a ble Su bstr a te for C2-lith ia tion . As the hydroxyl-
protecting groups of the sugar portion of 6-chloropurine
(9) HMBC has been used to determine the regiochemistry of adenine
adduct formed in the reaction of aflatoxin B1 epoxide with calf thymus
DNA: Iyer, R. S.; Voehler, M. W.; Harris, T. M. J . Am. Chem. Soc.
1994, 116, 8863-8869.
(10) For reports concerning anionic migration of TBDMS and TIPS
groups from oxygen to carbon, see: (a) Bures, E. J .; Keay, B. A.
Tetrahedron Lett. 1987, 28, 5965-5968. (b) Lautens, M.; Delanghe, P.
H. M.; Goh, J . B.; Zhang, C. H. J . Org. Chem. 1992, 57, 3270-3272.
(c) He, H.-M.; Fanwick, P. E.; Wood, K.; Cushman, M. J . Org. Chem.
1995, 60, 5905-5909.
(7) The 2-lithio derivative of an 8-azapurine, 3H-1,2,3-triazolo-[4,5-
d]pyrimidine, has been generated through a halogen-lithium exchange
reaction: Tanji, K.; Kato, H.; Higashino, T. Chem. Pharm. Bull. 1991,
39, 3037-3040.
(8) This deshielding effect is ascribed to the preferred syn-glycosidic
conformation of 8-substituted purine nucleosides: Sarma, R. H.; Lee,
C.-H.; Evans, F. E.; Yathindra, N.; Sundaralingam, M. J . Am. Chem.
Soc. 1974, 96, 7337-7348.

First Evident Generation of Purin-2-yllithium
J . Org. Chem., Vol. 64, No. 21, 1999 7775
Ta ble 1. D-In cor p or a tion to th e 2-P osition u p on LTMP
Lith ia tion of 7a
Sch em e 3
entry
LTMP (equiv)
D-incorporation
recovery (%)
1
2
3
4
1.2
3.0
4.0
5.0
11
56
86
96
99
89
93
99
a
The extent of D-incorporation was calculated on the basis of
1H NMR spectroscopy by integrating H-2 versus H-1′.
The deuteration reaction of 10 was performed under
the identical conditions used for 7 in entry 3 in Table 1.
Although the recovery (56%) was rather low due to the
1
formation of several unidentified products, the H NMR
Sch em e 4
analysis of the deuterated 10 revealed a C2-lithiation
level of 91%. Therefore, it can be assumed that, once
dissociation at the 8-position is prevented, lithiation at
the 2-position of a purine ring becomes a feasible event.
An additional question would be whether the electron-
withdrawing 6-chlorine atom plays an important role in
the C2-lithiation of 7 or not. When N,N-dimethyladeno-
sine derivative 11 was lithiated with 5 equiv of LTMP
and then quenched by adding CD3OD, no appreciable
deuterium incorporation was observed in the recovered
11 (recovery 98%). Therefore, the successful C2-lithiation
of 7 is a likely consequence of the presence of an
electronegative chlorine atom at the 6-position which
renders H-2 more acidic.
Syn t h esis of 2-Ca r b on -Su b st it u t ed Ad en osin es.
Unlike the 8-substituted analogues of purine nucleosides,
the 2-substituted counterparts adopt an anti-glycosidic
conformation, which mimics naturally occurring purine
nucleosides, due to the absence of a substituent ortho to
the glycosidic bond.12 This fact when combined with well
appreciated diverse biological properties of adenosine13
provides an appeal to 2-substituted adenosines as a
biologically attractive group of nucleoside anlogues.
The precedent of the first synthesis of 2-carbon-substi-
tuted adenosines goes back to 1952, which deals with that
of 2-methyladenosine by classical condensation method.14,15
An alternative method, the cyclization of 5-amino-1-â-D-
ribofuranosylimidazole-4-carboxamide or its 4-carboni-
trile,16 has been used for the synthesis of 2-methyl,17,18
2-aryl,18 and 2-formyl19 analogues of adenosine.20
Approaches that utilize naturally occurring purine
nucleosides as starting materials involve a homolytic
methylation of adenosine,21 nucleophilic substitution of
riboside, isopropylidene, and trityl groups were selected.
Compound 6 was prepared in 95% yield by tritylation
(TrCl/Et3N/CH2Cl2, reflux for 18 h) of 6-chloro-9-(2,3-O-
isopropylidene-â-D-ribofuranosyl)purine.4 Introduction of
the 8-TIPS group to 6 was carried out by using LHMDS
and TIPSCl as mentioned in the preparation of 3, which
gave 7 in 99% yield (Scheme 3).
The extent of LTMP lithiation of 7 was analyzed again
by 1H NMR measurement of the deuterated product. The
results (entries 1-4) are given in Table 1. As can be seen
in entry 4 (Table 1), almost quantitative lithiation at the
2-position was attained by the use of 5 equiv of LTMP.
It is apparent from the observed high level of recovery
that no appreciable side reaction occurred during the
lithiation, indicating that the 8-TIPS group in 7 did not
undergo the anionic migration.
We also examined the possibility of using a less bulky
TES (triethylsilyl) group. However, LTMP lithiation and
subsequent deuteration of 8, carried out under the
conditions used in entry 3 in Table 1, resulted in the
formation of a mixture of three products: 2,8-bis-TES
derivative (11%), C2-deuterated 8 (36%, D-incorporation
76%), and the desilylated 6-chloropurine riboside (31%,
D-incorporation at the 2- and 8-positions 56% and 34%,
respectively).
(11) For a review concerning the Stille reaction, see: Mitchell, T.
N. Synthesis 1992, 803-815.
(12) Saenger, W. Principles of Nucleic Acid Structure; Springer-
Verlag: New York, 1984.
(13) Fox, I. H.; Kelley, W. N. Annu. Rev. Biochem. 1978, 47, 655-
686.
(14) Davoll, J .; Lowy, B. A. J . Am. Chem. Soc. 1952, 74, 1563-1566.
(15) This method has been applied to the synthesis of 2-(trifluoro-
methyl)adenosine: Gough, G.; Maguire, M. H. J . Med. Chem. 1965, 8,
866-867.
(16) For a review article, see: Yamazaki, A.; Okutsu, M. J . Hetero-
cycl. Chem. 1978, 15, 353-358.
(17) Yamazaki, A.; Kumasiro, I.; Takenishi, T. J . Org. Chem. 1968,
33, 2583-2586.
(18) Marumoto, R.; Yoshioka, Y.; Miyashita, O.; Shima, S.; Imai,
K.; Kawazoe, K.; Honjo, M. Chem. Pharm. Bull. 1975, 23, 759-774.
(19) Murakami, T.; Otsuka, M.; Kobayashi, S.; Ohno, M. Heterocycles
1981, 16, 1315-1319.
(20) For the synthesis of 2-carbon-substituted analogues of other
purine nucleosides by this method: (a) Yamazaki, A.; Kumashiro, I.;
Takenishi, T. J . Org. Chem. 1967, 32, 3258-3260. (b) Zhang, H.-Z.;
Fried, J . Synth. Commun. 1996, 26, 351-355. (c) Zhang, H.-Z.; Rao,
K.; Carr, S. F.; Papp, E.; Straub, K.; Wu, J . C.; Fried, J . J . Med. Chem.
1997, 40, 4-8.
To see if the 8-TIPS group has any beneficial effect on
facilitating C2-deprotonation, the 8-phenyl derivative 10
was used as a substrate for the lithiation. Compound 10
was prepared from 6 in 2 steps: LDA lithiation-based
iodination leading to 9 (90%); the Stille reaction11 be-
tween 9 and Ph4Sn (the yield of 10, 83%).

7776 J . Org. Chem., Vol. 64, No. 21, 1999
Kumamoto et al.
Ta ble 2. Rea ction s of th e C2-Lith ia ted Sp ecies of 7 w ith
Electr op h ilesa
the preparation of 19 (95%, Ph3PCHCO2Me in THF). The
use of ClCO2Me in the reaction with the lithiated species
of 7 gave a complex mixture of products, from which the
methoxycarbonyl derivative 20 was isolated only in a poor
yield (entry 6, Table 2). Entry 7 (Table 2) demonstrates,
by the preparation of the 2-iodo derivative (21), that this
reaction is also applicable to the introduction of hetero-
atom-substituents.
At this stage, by using 18, we intended to confirm the
regiochemical outcome of the present lithiation-based
electrophilic substitution. Thus, desilylation of 18 was
effected with TBAF in THF to give 22 in 99% yield.
Among the five purine-ring-carbon atoms of 22, the
C-5 resonates at the highest field of δ 131.1 ppm, be-
cause this is the sole carbon atom that is bound to only
one electronegative atom (N-7). The fact that this C-5
showed a correlation with an aromatic proton (δ 8.21
ppm) in the HMBC spectrum clearly supports the regio-
chemistry of 22. An additional support came also from
the HMBC spectrum: correlations of H-1′ (δ 6.19 ppm)
were seen with two carbon atoms, one of which was
tertiary (C-8, δ 144.1 ppm) and the other quaternary (C-
4, δ 151.1 ppm).
Finally, conversion of these 2-substituted products to
the corresponding adenosine analogues was carried out.
It appeared that the reaction conditions required for the
ammonolysis of the 6-chlorine atom, heating at 110 °C
in a sealed tube with NH3/MeOH, effect simultaneous
desilylation at the 8-position, and the 2-substituted
adenosines 23-29 were obtained uniformly in good yields
(65-99%). In the case of the 2-methoxycarbonyl deriva-
tive 20, ammonolysis of the ester also occurred to give
the 2-carbamoyladenosine 28.
entry electrophile product
E
isolated yield (%)
1
MeI
12
13
14
15b
15b
16
17
20
21
Me
Et
i-Pr
CH(OH)C6H11
CH(OH)C6H11
C(OH)Me2
CHO
28
37
15
58
97
67
98
46
78
2
C6H11CHO
C6H11CHO
Me2CO
HCO2Me
ClCO2Me
iodine
3c
4
5
6
7
CO2Me
I
a
All reactions were carried out with 5.0 equiv of LTMP. After
the respective electrophile (10 equiv) was added, the reaction
b
mixture was stirred for 5 min below -70 °C. A mixture of two
diastereomers (ca 5:3). c The reaction was carried out in the
presence of HMPA.
2-(methylsulfonyl)adenosine with cyanide,22 and more
recent cross-coupling reaction of 2-iodoadenosine.23 Va-
sodilating activity has been reported for the 2-alkynyl
derivatives of adenosine,23c 5′-N-(ethylcarboxamido)ad-
enosine,24 and 3′-deoxyadenosine.25
As an application of the present lithiation study,
reactions of the C2-lithiated species of 7 with carbon
electrophiles, as well as with iodine, were carried out.
The results are summarized in Table 2. Also investigated
here is the conversion of the resulting 2-substituted
products to adenosine analogues.
When MeI was used as an electrophile (entry 1, Table
2), the 2-methylated product 12 was accompanied by the
2-ethyl (13) and 2-isopropyl (14) derivatives, the forma-
tion of which is apparently a consequence of further
C-methylation of the intially formed 12. In the reaction
with cyclohexanecarboxaldehyde (entries 2 and 3, Table
2), the presence of HMPA as an additive appeared to be
effective to improve the yield of product (15). As shown
in entry 4 (Table 2) by the reaction with acetone, an
enolizable ketone also works satisfactorily to yield a
tertiary alcohol 16. The reaction with HCO2Me (entry 5,
Table 2) gave the 2-formyl derivative 17 in high yield.
As all of the attempts to get its correct elemental analysis
data failed, the purity of 17 was proved by its high-yield
coversion (92%) to the 2-hydroxymethyl derivative 18
with NaBH4 in MeOH. Compound 17 can also be used
Con clu sion
By protecting the 8-position of a 6-chloropurine riboside
with TIPS group,26 lithiation of purine ring at the
2-position has become possible for the first time. As
the actual substrate and lithiating agent, 6-chloro-9-(2,3-
O-isopropylidene-5-O-trityl-â-D-ribofuranosyl)-8-(triiso-
propylsilyl)purine (7) and LTMP were found to be suit-
able.
Since the lithiated species of 7 showed reactivity
toward a variety of electrophiles and since ammonolysis
of the resulting 2-substituted products afforded the cor-
responding adenosine analogues with simultaneous desi-
lylation, the present method constitutes a highly general
approach to the synthesis of 2-substituted adenosines.
The likely possibility that the synthesis of 2-substituted
analogues of inosine, 6-mercaptopurine riboside, and
nebularine can also be accomplished, by manipulation
of desilylated intermediates such as 22, makes the
present method more attractive.
(22) Matsuda, A.; Nomoto, Y.; Ueda, T. Chem. Pharm. Bull. 1979,
27, 183-192.
(23) (a) Nair, V.; Purdy, D. F.; Sells, T. B. J . Chem. Soc., Chem.
Commun. 1989, 878-879. (b) Nair, V.; Purdy, D. F. Tetrahedron 1991,
47, 365-382. (c) Matsuda, A.; Shinozaki, M.; Yamaguchi, T.; Homma,
H.; Nomoto, R.; Miyasaka, T.; Watanabe, Y.; Abiru, T. J . Med. Chem.
1992, 35, 241-252.
(24) Camaioni, E.; Di Francesco, E.; Vittori, S.; Volpini, R.; Cristalli,
G. Bioorg. Med. Chem. 1997, 5, 2267-2275.
(25) Kumamoto, H.; Hayakawa, H.; Tanaka, H.; Shindoh, S.; Kato,
K.; Miyasaka, T.; Endo, K.; Machida, H.; Matsuda, A. Nucleosides
Nucleotides 1998, 17, 15-27.
(26) In the lithiation of tert-benzamides, the TMS group has been
used to mask the more reactive site ortho to a carboxamide: Mills, R.
J .; Snieckus, V. J . Org. Chem. 1983, 48, 1565-1568.
as a substrate for the Wittig reaction, as exemplified by
(21) Maeda, M.; Nushi, K.; Kawazoe, Y. Tetrahedron 1974, 30,
2677-2682.

First Evident Generation of Purin-2-yllithium
J . Org. Chem., Vol. 64, No. 21, 1999 7777
prpylidene-â-D-ribofuranosyl)purine (500 mg, 1.53 mmol), trityl
chloride (853 mg, 3.06 mmol), and Et3N (2.13 mL, 15.3 mmol)
in CH2Cl2 (10 mL) was heated under reflux for 20 h. Evapora-
tion of the reaction mixturte followed by column chromatog-
raphy (hexane:EtOAc ) 2:1) gave 6 (830 mg, 95%) as a foam:
UV (MeOH) λmax 264 nm (ꢀ 6500), λmin 244 nm (ꢀ 4900); 1H
NMR (CDCl3) δ 1.40 (3H, s), 1.63 (3H, s), 3.27-3.29 (2H, m),
4.58-4.60 (1H, m), 4.96 (1H, dd, J ) 2.7 and 6.0 Hz), 5.47
(1H, dd, J ) 2.2 and 6.0 Hz), 6.17 (1H, d, J ) 2.2 Hz), 7.18-
Exp er im en ta l Section
Melting points are uncorrected. 1H and 13C NMR spectra
were measured at 23 °C (internal standard, Me4Si) at 500
MHz. 13C NMR chemical shifts are shown only for purine ring
carbons. Mass spectra (MS) were taken in FAB mode (m-
nitrobenzyl alcohol as a matrix). For compounds containing
Cl, ion peaks corresponding to 35Cl are shown. Column
chromatography was carried out on silica gel (Silica Gel 60,
Merck). Thin-layer chromatography (TLC) was performed on
silica gel (precoated silica gel plate F254, Merck).
7.20 (9H, m), 7.29-7.31 (6H, m), 8.21 (1H, s), 8.60 (1H, s); 13
C
NMR (CDCl3) δ 132.4, 144.3, 150.8, 151.3, 151.9; FAB-MS m/z
569 (M+ + H). Anal. Calcd for C32H29ClN4O4‚1/5H2O: C, 67.12;
H, 5.17; N, 9.78. Found: C, 67.12; H, 5.04; N, 9.71.
9-[2,3,5-Tr is-O-(ter t-b u t yld im et h ylsilyl)-â-D-r ib ofu r a -
n osyl]-6-ch lor o-8-tr iisop r op ylsilylp u r in e (3). Meth od A.
To a THF (10 mL) solution containing LTMP (2.39 mmol) and
TIPSCl (450 µL, 2.39 mmol) was added dropwise 1 (1.0 g, 1.59
mmol) dissolved in THF (5 mL) under positive pressure of dry
Ar, while the temperature was maintained below -70 °C. After
3 min of stirring, HMPA (140 µL, 0.80 mmol) was added and
the whole mixture was stirred for 5 min. The reaction was
quenched by adding saturated aqueous NH4Cl. Extraction with
EtOAc followed by column chromatography (hexane:EtOAc )
80:1) gave 3 (1.10 g, 88%) as an oil. Meth od B. To a THF (10
mL) solution containing 1 (400 mg, 0.64 mmol), TIPSCl (205
µL, 0.95 mmol), and HMPA (1.1 mL, 6.40 mmol) was added
LHMDS (1.0 M THF solution, 1.6 mL, 1.6 mmol) under positive
pressure of dry Ar, while the temperature was maintained
below -70 °C. After 5 min of stirring, the reaction mixture
was worked up as described in Method A to give 3 (496 mg,
99%): UV (MeOH) λmax 274 nm (ꢀ 13900), λmin 238 nm (ꢀ 3700);
1H NMR (CDCl3) δ -0.35, -0.91, 0.07, 0.10, 0.14, and 0.16
(18H, each as s), 0.69, 0.93, and 0.95 (27H, each as s), 1.09,
1.17, and 1.20 (18H, each as d, J ) 7.4 Hz), 1.61-1.67 (3H,
m), 3.68 (1H, dd, J ) 4.6 and 10.4 Hz), 3.95 (1H, t, J ) 10.4
Hz), 4.03 (1H, dd, J ) 4.6 and 10.4 Hz), 4.34 (1H, d, J ) 4.0
Hz), 5.98 (1H, dd, J ) 8.2 and 4.0 Hz), 6.04 (1H, d, J ) 8.2
Hz), 8.64 (1H, s); 13C NMR (CDCl3) δ 134.0, 150.6, 150.7, 153.4,
6-Ch lor o-9-(2,3-O-isop r op ylid en e-5-O-t r it yl-â-D-r ib o-
fu r a n osyl)-8-(tr iisop r op ylsilyl)p u r in e (7). This compound
was obtained from 6 by the procedure (Method B) described
for the preparation of 3. Column chromatography (hexane:
EtOAc ) 20:1) of the reaction mixture gave 7 as a foam in
99% yield: UV (MeOH) λmax 274 nm (ꢀ 8700), λmin 245 nm (ꢀ
4200); 1H NMR (CDCl3) δ 1.21-1.24 (18H, m), 1.36 (3H, s),
1.57 (3H, s), 1.60-1.67 (3H, m), 3.29 (1H, dd, J ) 4.9 and 9.9
Hz), 3.34 (1H, dd, J ) 7.7 and 9.9 Hz), 4.52-4.58 (1H, m),
5.09 (1H, dd, J ) 3.4 and 6.5 Hz), 5.53 (1H, dd, J ) 2.1 and
6.5 Hz), 6.13 (1H, d, J ) 2.1 Hz), 7.11-7.18 (9H, m), 7.31-
7.34 (6H, m), 8.30 (1H, s); 13C NMR (CDCl3) δ 133.5, 150.7,
150.7, 152.3, 162.3; FAB-MS m/z 725 (M+ + H). Anal. Calcd
for C41H49ClN4O4Si: C, 67.89; H, 6.81; N, 7.72. Found: C,
67.92; H, 6.51; N, 7.74.
LTMP Lith ia tion a n d Su bsequ en t Deu ter a tion of 7.
This reaction was carried out with the procedure described
for the LTMP lithiation of 3.
6-Ch lor o-9-(2,3-O-isop r op ylid en e-5-O-t r it yl-â-D-r ib o-
fu r a n osyl)-8-(tr ieth ylsilyl)p u r in e (8). This compound was
obtained from 6 by the procedure (Method B) described for the
preparation of 3, except that TESCl was used instead of
TIPSCl. Purification was carried out by Florisil (Merck)
column chromatography (hexane:EtOAc ) 6:1), in this par-
ticular case. Compound 8 was isolated as a foam in 97%
yield: UV (MeOH) λmax 273 nm (ꢀ 12 100), λmin 245 nm (ꢀ 5200);
1H NMR (CDCl3) δ 1.07-1.08 (15H, m), 1.37 (3H, s), 1.62 (3H,
s), 3.20-3.26 (2H, m), 4.53-4.56 (1H, m), 5.08 (1H, dd, J )
3.1 and 6.4 Hz), 5.63 (1H, dd, J ) 2.1 and 6.4 Hz), 6.14 (1H,
d, J ) 2.1 Hz), 7.12-7.18 (9H, m), 7.26-7.33 (6H, m), 8.30
164.2; FAB-MS m/z 785 (M+ + H). Anal. Calcd for C37H73
ClN4O4Si4: C, 56.55; H, 9.36; N, 7.13. Found: C, 56.60; H, 9.67;
N, 7.11.
-
2′,3′,5′-Tr is-O-(ter t-bu tyldim eth ylsilyl)-N,N-diisopr opyl-
8-(tr iisop r op ylsilyl)a d en osin e (4). Physical data of this
compound obtained as an oil are as follows: UV (MeOH) λmax
299 nm (ꢀ 12300) and 250 nm (ꢀ 11300), λmin 274 nm (ꢀ 8300)
1
(1H, s); FAB-MS m/z 683 (M+ + H). Anal. Calcd for C38H43
-
and 233 nm (ꢀ 9200); H NMR (CDCl3) δ -0.11, -0.04, 0.04,
0.11, and 0.13 (18H, each as s), 0.82, 0.89, and 0.93 (12H, each
as s), 1.11-1.18 (18H, m), 1.22, 1.23, 1.35, and 1.36 (12H, each
as d, J ) 7.0 Hz), 1.47-1.60 (3H, m), 3.51 (1H, t, J ) 10.7
Hz), 3.62 (1H, sept, J ) 6.7 Hz), 3.69 (1H, dd, J ) 4.6 and
10.7 Hz), 3.85 (1H, dd, J ) 4.6 and 10.7 Hz), 4.86 (1H, sept, J
) 7.0 Hz), 4.13 (1H, d, J ) 3.3 Hz), 5.46 (1H, dd, J ) 3.3 and
8.3 Hz), 5.73 (1H, d, J ) 8.3 Hz), 8.18 (1H, s); FAB-MS m/z
850 (M+ + H). Anal. Calcd for C43H87N5O4Si4: C, 60.72; H,
10.31; N, 8.23. Found: C, 60.93; H, 10.54; N, 8.17.
ClN4O4Si: C, 66.79; H, 6.34; N, 8.20. Found: C, 66.67; H, 6.20;
N, 8.18.
6-Ch lor o-8-iod o-9-(2,3-O-isop r op ylid en e-5-O-tr ityl-â-D-
r ibofu r a n osyl)p u r in e (9). To a THF (5 mL) solution contain-
ing LDA (5.28 mmol), 6 (1.0 g, 1.76 mmol) dissolved in THF
(5 mL) was added dropwise under positive pressure of dry Ar,
while the temperature was maintained below -70 °C. After 5
min stirring, the lithiated mixture was treated with iodine
(1.34 g, 5.28 mmol as I2) in THF (5 mL). The reaction mixture
was stirred for 5 min and then partitioned between aqueous
Na2S2O3 and CHCl3. Column chromatography (hexane:EtOAc
) 5:1) of the organic layer gave 9 (1.1 g, 90%) as a foam: UV
(MeOH) λmax 277 nm (ꢀ 14 000), λmin 245 nm (ꢀ 6300); 1H NMR
(CDCl3) δ 1.39 (3H, s), 1.65 (3H, s), 3.12-3.18 (2H, m), 4.58-
4.61 (1H, m), 5.12 (1H, dd, J ) 3.1 and 6.4 Hz), 5.69 (1H, dd,
J ) 1.8 and 6.4 Hz), 6.17 (1H, d, J ) 1.8 Hz), 7.17-7.19 (9H,
LTMP Lith ia tion a n d Su bsequ en t Deu ter a tion of 3.
F or m a tion of 5. To a THF (10 mL) solution containing LTMP
(4.53 mmol) was added dropwise 3 (712 mg, 0.91 mmol)
dissolved in THF (5 mL) under positive pressure of dry Ar,
while the temperature was maintained below -70 °C. After 5
min of stirring, the reaction mixture was treated with CD3-
OD (0.75 mL). The reaction mixture was partitioned between
saturated aqueous NH4Cl and EtOAc. Column chromatogra-
phy (hexane:EtOAc ) 100:1 to 70:1) of the organic layer gave
5 (oil, 88 mg, 11%) and the deuterated 3 (oil, 474 mg, 67%).
Physical data of 5 are as follows: UV (MeOH) λmax 279 nm (ꢀ
16 300), λmin 243 nm (ꢀ 5500); 1H NMR (CDCl3) δ -0.41, -0.16,
0.07, 0.10, 0.14, 0.18, 0.37, and 0.39 (24H, each as s), 0.68,
0.91, 0.96, and 1.01 (36H, each as s), 1.15-1.22 (18H, m), 1.57-
1.67 (3H, m), 3.71 (1H, dd, J ) 4.6 and 10.1 Hz), 3.89 (1H, t,
J ) 10.1 Hz), 4.00 (1H, dd, J ) 4.6 and 10.1 Hz), 4.29 (1H, d,
J ) 3.9 Hz), 5.89 (1H, dd, J ) 3.9 and 8.2 Hz), 6.05 (1H, d, J
m), 7.28-7.32 (6H, m), 8.31 (1H, s); FAB-MS m/z 694 (M+
+
H). Anal. Calcd for C32H28ClIN4O4: C, 55.31; H, 4.06; N, 8.06.
Found: C, 55.21; H, 3.90; N, 7.98.
6-Ch lor o-9-(2,3-O-isop r op ylid en e-5-O-t r it yl-â-D-r ib o-
fu r a n osyl)-8-p h en ylp u r in e (10). A dioxane (40 mL) solution
containing 9 (950 mg, 1.37 mmol), (Ph3P)2PdCl2 (96 mg, 0.14
mmol), CuI (52 mg, 0.27 mmol), and Ph4Sn (1.47 g, 3.43 mmol)
was heated at 110 °C for 15 h under positive pressure of dry
Ar. The reaction mixture was diluted by adding EtOH (50 mL),
and the resulting precipitate was removed by filtration.
Column chromatography (hexane:EtOAc ) 9:1) of the filtrate
gave 10 (730 mg, 83%) as a foam: UV (MeOH) λmax 283 nm (ꢀ
16 700), λmin 249 nm (ꢀ 6400); 1H NMR (CDCl3) δ 1.34 (3H, s),
1.55 (3H, s), 3.26-3.33 (2H, m), 4.62-4.65 (1H, m), 5.18 (1H,
dd, J ) 2.8 and 6.1 Hz), 5.60 (1H, dd, J ) 1.5 and 6.1 Hz),
) 8.2 Hz); FAB-MS m/z 900 (M+ + H). Anal. Calcd for C43H87
ClN4O4Si5: C, 57.38; H, 9.74; N, 6.22. Found: C, 57.51; H, 9.95;
N, 6.19.
6-Ch lor o-9-(2,3-O-isop r op ylid en e-5-O-t r it yl-â-D-r ib o-
fu r a n osyl)p u r in e (6). A mixture of 6-chloro-(2,3-O-iso-
-

7778 J . Org. Chem., Vol. 64, No. 21, 1999
Kumamoto et al.
6.10 (1H, d, J ) 1.5 Hz), 7.14-7.16 (9H, m), 7.31-7.35 (6H,
m), 7.57-7.63 (3H, m), 7.93-7.95 (2H, m), 8.39 (1H, s); FAB-
MS m/z 645 (M+ + H). Anal. Calcd for C38H33ClN4O4: C, 70.75;
H, 5.16; N, 8.68. Found: C, 70.63; H, 5.12; N, 8.73.
LTMP Lith ia tion a n d Su bsequ en t Deu ter a tion of 10.
This reaction was carried out by the procedure described for
the LTMP lithiation of 3.
amounts of reagents and 7 (600 mg, 0.83 mmol) were used:
LTMP (4.14 mmol), HMPA (1.45 mL, 8.27 mmol), cyclohex-
anecarbaldehyde (500 µL, 4.14 mmol). Column chromatogra-
phy (hexane:EtOAc ) 20:1) gave 15 (foam, 675 mg, 97%) as a
mixture of two diastereomers (ca. 5:3): UV (MeOH) λmax 278
nm (ꢀ 14 100), λmin 245 nm (ꢀ 5900); 1H NMR of the major
diastereomer (CDCl3) δ 1.20-1.25 (18H, m), 1.31 (3H, s), 1.60
(3H, s), 1.56-1.69 (11H, m), 1.65-1.68 (3H, m), 3.14 (1H, dd,
J ) 3.4 and 9.8 Hz), 3.37 (1H, dd, J ) 9.2 and 9.8 Hz), 3.44
(1H, d, J ) 6.4 Hz, D2O exchangeable), 4.19 (1H, dd, J ) 4.9
and 6.4 Hz), 4.49-4.53 (1H, m), 4.92 (1H, dd, J ) 4.0 and 6.4
Hz), 5.40 (1H, dd, J ) 1.8 and 4.0 Hz), 6.17 (1H, d, J ) 1.8
Hz), 7.06-7.14 (9H, m), 7.27-7.36 (6H, m); 1H NMR of the
minor diastereomer (CDCl3) δ 0.88-0.92 (11H, m), 1.16-1.25
(18H, m), 1.32 (3H, s), 1.59 (3H, s), 1.48-1.54 (3H, m), 2.65
(1H, d, J ) 5.8 Hz, D2O exchangeable), 3.21 (1H, dd, J ) 3.4
and 9.8 Hz), 3.35 (1H, dd, J ) 9.5 and 9.8 Hz), 4.39-4.43 (2H,
m), 4.93 (1H, dd, J ) 4.6 and 6.4 Hz), 5.49 (1H, dd, J ) 1.8
and 6.4 Hz), 6.14 (1H, d, J ) 1.8 Hz), 7.07-7.13 (9H, m), 7.28-
7.32 (6H, m); FAB-MS m/z 837 (M+ + H). Anal. Calcd for
N,N-Dim eth yl-2′,3′-O-isop r op ylid en e-5′-O-tr ityl-8-(tr i-
isop r op ylsilyl)a d en osin e (11). To a THF (5 mL) solution of
LDA (1.56 mmol) was added dropwise N,N-dimethyl-2′,3′-O-
isopropylidene-5′-O-trityladenosine (300 mg, 0.52 mmol) dis-
solved in THF (5 mL) under positive pressure of dry Ar, while
the temperature was maintained below -70 °C. To the
resulting solution was added TIPSCl (225 µL, 1.04 mmol) neat,
and the reaction mixture was stirred for 5 min. Quenching
with saturated aqueous NH4Cl was followed by extraction with
EtOAc. Column chromatography (hexane:EtOAc ) 10:1) of the
extract gave 11 (313 mg, 82%) as a foam: UV (MeOH) λmax
1
282 nm (ꢀ 17 400), λmin 245 nm (ꢀ 3700); H NMR (CDCl3) δ
1.18-1.21 (18H, m), 1.35 (3H, s), 1.52-1.58 (3H, m), 1.58 (3H,
s), 3.27 (1H, dd, J ) 5.9 and 9.8 Hz), 3.44 (1H, dd, J ) 7.8 and
9.8 Hz), 3.55 (6H, br), 4.41-4.44 (1H, m), 5.09 (1H, dd, J )
3.6 and 6.4 Hz), 5.59 (1H, dd, J ) 2.1 and 6.4 Hz), 6.03 (1H,
d, J ) 2.1 Hz), 7.10-7.16 (9H, m), 7.33-7.36 (6H, m), 7.95
(1H, s); FAB-MS m/z 734 (M+ + H). Anal. Calcd for C43H55N5O4-
Si: C, 70.36; H, 7.55; N, 9.54. Found: C, 70.64; H, 7.58; N,
9.62.
C
48H61ClN4O4Si‚H2O: C, 67.38; H, 7.42; N, 6.55. Found: C,
67.36; H, 7.36; N, 6.51.
6-Ch lor o-2-(1-h yd r oxy-1-m eth yl)eth yl-9-(2,3-O-isop r o-
p ylid en e-5-O-tr ityl-â-D-r ibofu r a n osyl)-8-(tr iisop r op ylsi-
lyl)p u r in e (16). This compound was prepared with the
procedure described for the preparation of 12-14. The follow-
ing amounts of reagents and 7 (300 mg, 0.41 mmol) were
used: LTMP (2.07 mmol), acetone (305 µL, 4.14 mmol).
Column chromatography (hexane:EtOAc ) 20:1) gave 16
(foam, 218 mg, 67%): UV (MeOH) λmax 277 nm (ꢀ 13 600), λmin
245 nm (ꢀ 5700); 1H NMR (CDCl3) δ 1.20-1.28 (18H, m), 1.25
(3H, s), 1.33 (3H, s), 1.44 (3H, s), 1.60 (3H, s), 1.66-1.71 (3H,
m), 3.12 (1H, dd, J ) 3.6 and 9.6 Hz), 3.34(1H,t, J ) 9.6 Hz),
4.08 (1H, br), 4.46-4.50 (1H, m), 4.94 (1H, dd, J ) 4.0 and
6.4 Hz), 5.52 (1H, dd, J ) 1.6 and 6.4 Hz), 6.20 (1H, d, J ) 1.6
Hz), 7.04-7.22 (9H, m), 7.27-7.30 (6H, m); FAB-MS m/z 783
(M+ + H). Anal. Calcd for C44H55ClN4O5Si: C, 67.45; H, 7.08;
N, 7.15. Found: C, 67.60; H, 7.23; N, 7.18.
6-Ch lor o-2-for m yl-9-(2,3-O-isop r op ylid en e-5-O-tr ityl-â-
D-r ibofu r an osyl)-8-(tr iisopr opylsilyl)pu r in e (17). This com-
pound was prepared with the procedure described for the
preparation of 12-14. The following amounts of reagents and
7 (327 mg, 0.45 mmol) were used: LTMP (2.25 mmol), HCO2-
Me (140 µL, 2.25 mmol). Column chromatography (hexane:
EtOAc ) 10:1) gave 17 (oil, 331 mg, 98%). Partial physical
data of 17 are as follows: 1H NMR (CDCl3) δ 0.12-0.26 (18H,
m), 1.34 (3H, s), 1.62 (3H, s), 1.65-1.89 (3H, m), 3.25 (1H, dd,
J ) 3.7 and 9.2 Hz), 3.51 (1H, t, J ) 9.2 Hz), 4.61 (1H, dt, J
) 4.0 and 9.2 Hz), 5.13 (1H, dd, J ) 4.0 and 6.5 Hz), 5.39 (1H,
dd, J ) 1.8 and 6.5 Hz), 6.23 (1H, d, J ) 1.8 Hz), 7.03-7.11
(10H, m), 7.23-7.24 (5H, m), 9.72 (1H, s); FAB-MS m/z 753
(M+ + H).
6-Ch lor o-2-(h yd r oxym eth yl)-9-(2,3-O-isop r op ylid en e-
5-O-t r it yl-â-D -r ib ofu r a n osyl)-8-(t r iisop r op ylsilyl)p u -
r in e (18). To a MeOH (10 mL) solution of 17 (217 mg, 0.29
mmol), NaBH4 (33 mg, 0.87 mmol) was added. The reaction
mixture was stirred for 20 min at room temperature and
filtrated. Column chromatography (hexane:EtOAc ) 10:1) of
the filtrate gave 18 (foam, 202 mg, 92%): UV (MeOH) λmax
278 nm (ꢀ 9000), λmin 245 nm (ꢀ 4400); 1H NMR (CDCl3) δ 1.21-
1.24 (18H, m), 1.34 (3H, s), 1.60 (3H, s), 1.61-1.69 (3H, m),
2.89 (1H, t, J ) 5.4 Hz, D2O exchangeable), 3.19 (1H, dd, J )
4.0 and 10.0 Hz), 3.41 (1H, dd, J ) 8.6 and 10.0 Hz), 4.42 (1H,
dd, J ) 5.4 and 15.8 Hz), 4.50-4.53 (1H, m), 4.55 (1H, dd, J
) 5.4 and 15.8 Hz), 4.96 (1H, dd, J ) 4.0 and 6.4 Hz), 5.43
(1H, dd, J ) 2.0 and 6.4 Hz), 6.14 (1H, d, J ) 2.0 Hz), 7.07-
7.16 (9H, m), 7.29-7.32 (6H, m); FAB-MS m/z 755 (M+ + H).
Anal. Calcd for C42H51ClN4O5Si: C, 66.78; H, 6.81; N, 7.24.
Found: C, 66.53; H, 6.80; N, 7.42.
Rea ction of th e C2-Lith ia ted Sp ecies of 7 w ith MeI.
F or m a tion of 2-Meth yl (12), 2-Eth yl (13), a n d 2-Isop r op yl
(14) Der iva tives of 6-Ch lor o-9-(2,3-O-isop r op ylid en e-5-
O-tr ityl-â-D-r ibofu r a n osyl)-8-(tr iisop r op ylsilyl)p u r in e. To
a THF (5 mL) solution of LTMP (4.0 mmol), 7 (580 mg, 0.8
mmol) dissolved in THF (5 mL) was added dropwise under
positive pressure of dry Ar, while the temperature was
maintained below -70 °C. To this was added MeI (280 µL,
4.0 mmol) neat. After 5 min of stirring, the reaction mixture
was quenched by adding saturated aqueous NH4Cl. Extraction
with EtOAc followed by column chromatography gave 14
(eluted with hexane:EtOAc ) 25:1, foam, 145 mg, 24%), 13
(eluted with hexane:EtOAc ) 20:1, foam, 320 mg, 53%), and
12 (eluted with hexane:EtOAc ) 5:1, oil, 130 mg, 22%).
Physical data of 12 are as follows: UV (MeOH) λmax 278 nm
(ꢀ 13 200), λmin 246 nm (ꢀ 5600); 1H NMR (CDCl3) δ 1.20-1.24
(18H, m), 1.34 (3H, s), 1.60 (3H, s), 1.61-1.67 (3H, m), 2.41
(3H, s), 3.20 (1H, dd, J ) 4.0 and 9.8 Hz), 3.45 (1H, t, J ) 9.8
Hz), 4.51-4.54 (1H, m), 5.02 (1H, dd, J ) 3.7 and 6.4 Hz),
5.40 (1H, dd, J ) 1.9 and 6.4 Hz), 6.14 (1H, d, J ) 1.9 Hz),
7.06-7.15 (9H, m), 7.30-7.34 (6H, m); FAB-MS m/z 739 (M+
+ H). Anal. Calcd for C42H51ClN4O4Si‚H2O: C, 66.66; H, 7.05;
N, 7.40. Found: C, 66.47; H, 6.77; N, 7.27.
Physical data of 13 are as follows: UV (MeOH) λmax 277 nm
(ꢀ 8900), λmin 246 nm (ꢀ 4600); 1H NMR (CDCl3) δ 1.11 (3H, t,
J ) 7.3 Hz), 1.21-1.25 (18H, m), 1.34 (3H, s), 1.61 (3H, s),
1.63-1.70 (3H, m), 2.60-2.80 (2H, m), 3.16 (1H, dd, J ) 3.7
and 9.8 Hz), 3.42 (1H, t, J ) 9.8 Hz), 4.49-4.54 (1H, m), 5.04
(1H, dd, J ) 4.0 and 6.3 Hz), 5.48 (1H, dd, J ) 1.5 and 6.3
Hz), 6.17 (1H, d, J ) 1.5 Hz), 7.05-7.09 (6H, m), 7.11-7.14
(3H, m), 7.26-7.29 (6H, m); FAB-MS m/z 753 (M+ + H). Anal.
Calcd for C43H53ClN4O4Si: C, 68.55; H, 7.09; N, 7.44. Found:
C, 68.73; H, 7.18; N, 7.46.
Physical data of 14 are as follows: UV (MeOH) λmax 277 nm
(ꢀ 9100), λmin 245 nm (ꢀ 4400); 1H NMR (CDCl3) δ 1.06 (3H, d,
J ) 6.7 Hz), 1.15 (3H, d, J ) 6.7 Hz), 1.22-1.25 (18H, m),
1.34 (3H, s), 1.60 (3H, s), 1.65-1.72 (3H, m), 2.97-3.07 (1H,
m), 3.12 (1H, dd, J ) 3.3 and 9.8 Hz), 3.39 (1H, t, J ) 9.8 Hz),
4.48-4.51 (1H, m), 5.06 (1H, dd, J ) 3.9 and 6.4 Hz), 5.51
(1H, dd, J ) 1.2 and 6.4 Hz), 6.19 (1H, d, J ) 1.2 Hz), 7.03-
7.09 (6H, m), 7.10-7.13 (3H, m), 7.23-7.28 (6H, m); FAB-MS
m/z 767 (M+ + H). Anal. Calcd for C44H55ClN4O4Si: C, 68.86;
H, 7.22; N, 7.30. Found: C, 68.68; H, 7.37; N, 7.23.
6-Ch lor o-2-(cycloh exyl)h ydr oxym eth yl-9-(2,3-O-isopr o-
p ylid en e-5-O-tr ityl-â-D-r ibofu r a n osyl)-8-(tr iisop r op ylsi-
lyl)p u r in e (15). This compound was prepared with the
procedure described for the preparation of 12-14, except that
HMPA was added to a THF solution of LTMP. The following
6-Ch lor o-9-(2,3-O-isop r op ylid en e-5-O-t r it yl-â-D-r ib o-
fu r a n osyl)-2-[(E)-2-(m eth oxyca r bon yl)vin yl]-8-(tr iisop r o-
p ylsilyl)p u r in e (19). A mixture of 17 (290 mg, 0.38 mmol)
and (carbomethoxymethylene)triphenylphosphorane (191 mg,
0.57 mmol) in THF (10 mL) was stirred for 4 h at room
temperature. The reaction mixture was partitioned between

First Evident Generation of Purin-2-yllithium
J . Org. Chem., Vol. 64, No. 21, 1999 7779
H2O and CHCl3. Column chromatography (hexane:EtOAc )
25:1) of the organic layer gave 19 (foam, 293 mg, 95%): UV
(MeOH) λmax 302 nm (ꢀ 22 500), λmin 264 nm (ꢀ 7200); 1H NMR
(CDCl3) δ 1.20-1.28 (18H, m), 1.35 (3H, s), 1.61 (3H, s), 1.63-
1.70 (3H, m), 3.14 (1H, dd, J ) 3.2 and 10.0 Hz), 3.47 (1H, dd,
J ) 9.6 and 10.0 Hz), 3.87 (3H, s), 4.55-4.59 (1H, m), 4.99
(1H, dd, J ) 3.6 and 6.4 Hz), 5.46 (1H, dd, J ) 1.6 and 6.4
Hz), 6.19 (1H, d, J ) 1.6 Hz), 6.94 (1H, d, J ) 16.0 Hz), 7.01-
7.15 (10H, m), 7.23-7.25 (5H, m), 7.42 (1H, d, J ) 16.0 Hz);
FAB-MS m/z 809 (M+ + H). Anal. Calcd for C45H53ClN4O6Si‚
1/2H2O: C, 66.03; H, 6.65; N, 6.85. Found: C, 65.98; H, 6.58;
N, 6.85.
MeOH in a similar manner as described in the preparation of
23. The reaction was continued for 84 h. Column chromatog-
raphy (4% MeOH in CHCl3) of the reaction mixture gave 24
(foam, 122 mg, 91%): UV (MeOH) λmax 261 nm (ꢀ 11 500), λmin
1
241 nm (ꢀ 6600); H NMR (CDCl3) δ 1.14 (3H, t, J ) 7.5 Hz),
1.37 (3H, s), 1.61 (3H, s), 2.57-2.70 (2H, m), 3.17 (1H, dd, J )
4.0 and 10.1 Hz), 3.40 (1H, dd, J ) 7.9 and 10.1 Hz), 4.49-
4.52 (1H, m), 5.01 (1H, dd, J ) 3.4 and 6.4 Hz), 5.46 (1H, dd,
J ) 1.8 and 6.4 Hz), 6.11 (1H, d, J ) 1.8 Hz), 7.13-7.16 (9H,
m), 7.29-7.32 (6H, m), 7.81 (1H, s); FAB-MS m/z 578 (M+
+
H). Anal. Calcd for C34H35N5O4‚1/2H2O: C, 69.61; H, 6.19; N,
11.94. Found: C, 69.96; H, 5.98; N, 11.71.
6-Ch lor o-9-(2,3-O-isop r op ylid en e-5-O-t r it yl-â-D-r ib o-
fu r a n osyl)-2-(m eth oxyca r bon yl)-8-(tr iisop r op ylsilyl)p u -
r in e (20). This compound was prepared with the procedure
described for the preparation of 12-14. The following amounts
of reagents and 7 (608 mg, 0.84 mmol) were used: LTMP (4.2
mmol), ClCO2Me (325 µL, 4.2 mmol). Column chromatography
(hexane:EtOAc ) 10:1) gave 20 (foam, 303 mg, 46%): UV
(MeOH) λmax 283 nm (ꢀ 14 200), λmin 250 nm (ꢀ 7100); 1H NMR
(CDCl3) δ 1.12-1.26 (18H, m), 1.33 (3H, s), 1.61 (3H, s), 1.65-
1.71 (3H, m), 3.25 (1H, dd, J ) 2.7 and 10.4 Hz), 3.54 (1H, dd,
J ) 2.7 and 10.4 Hz), 3.92 (3H, s), 4.59-4.62 (1H, m), 5.20
(1H, dd, J ) 4.0 and 6.4 Hz), 5.29 (1H, dd, J ) 1.0 and 4.0
Hz), 6.26 (1H, d, J ) 1.0 Hz), 7.00-7.03 (6H, m), 7.06-7.10
(3H, m), 7.22-7.23 (6H, m); FAB-MS m/z 783 (M+ + H). Anal.
Calcd for C43H51ClN4O6Si‚3/2H2O: C, 63.73; H, 6.71; N, 6.91.
Found: C, 63.84; H, 6.33; N, 6.89.
6-Ch lor o-2-iod o-9-(2,3-O-isop r op ylid en e-5-O-tr ityl-â-d -
r ibofu r a n osyl)-8-(tr iisop r op ylsilyl)p u r in e (21). This com-
pound was prepared with the procedure described for the
preparation of 12-14. The following amounts of reagents and
7 (500 mg, 0.69 mmol) were used: LTMP (3.44 mmol), iodine
(880 mg, 0.69 mmol as I2) in THF (5 mL). Column chroma-
tography (hexane:EtOAc ) 30:1) gave 21 (foam, 458 mg,
78%): UV (MeOH) λmax 291 nm (ꢀ 11 900), λmin 252 nm (ꢀ 5600);
1H NMR (CDCl3) δ 1.20-1.25 (18H, m), 1.34 (3H, s), 1.60 (3H,
s), 1.61-1.68 (3H, m), 3.23 (1H, dd, J ) 3.0 and 10.0 Hz), 3.44
(1H, t, J ) 10.0 Hz), 4.53-4.57 (1H, m), 4.92 (1H, dd, J ) 3.9
and 6.4 Hz), 5.26 (1H, dd, J ) 1.3 and 6.4 Hz), 6.15 (1H, d, J
) 1.3 Hz), 7.04-7.13 (9H, m), 7.32-7.36 (6H, m); FAB-MS m/z
851 (M+ + H). Anal. Calcd for C41H48ClIN4O4Si: C, 57.85; H,
5.68; N, 6.58. Found: C, 58.23; H, 5.89; N, 6.47.
6-Ch lor o-2-(h yd r oxym eth yl)-9-(2,3-O-isop r op ylid en e-
5-O-tr ityl-â-D-r ibofu r a n osyl)p u r in e (22). To a solution of
18 (315 mg, 0.42 mmol) in THF (5 mL) was added TBAF (1 M
THF solution, 500 µL, 0.50 mmol), and the reaction mixture
was stirred for 0.5 h at room temperature. Evaporation of the
solvent followed by column chromatography (CHCl3) gave 22
(foam, 250 mg, 99%): UV (MeOH) λmax 267 nm (ꢀ 8400), λmin
246 nm (ꢀ 6200); 1H NMR (CDCl3, after addition of D2O) δ 1.39
(3H, s), 1.63 (3H, s), 3.27 (1H, dd, J ) 6.4 and 10.4 Hz), 3.34
(1H, dd, J ) 6.4 and 10.4 Hz), 4.56-4.59 (1H, m), 4.71 (1H, d,
J ) 16.2 Hz), 4.77 (1H, d, J ) 16.2 Hz), 4.90 (1H, dd, J ) 2.8
and 6.3 Hz), 5.35 (1H, dd, J ) 2.5 and 6.3 Hz), 6.19 (1H, d, J
) 2.5 Hz), 7.19-7.20 (9H, m), 7.31-7.32 (6H, m), 8.21 (1H, s);
13C NMR (CDCl3) δ 131.1, 144.1, 151.1, 151.4, 162.9; FAB-MS
m/z 599 (M+ + H). Anal. Calcd for C33H31ClN4O5‚1/2H2O: C,
65.18; H, 5.30; N, 9.21. Found: C, 64.99; H, 4.92; N, 9.14.
2′,3′-O-Isop r op ylid en e-2-m et h yl-5′-O-t r it yla d en osin e
(23). A mixture of 12 (218 mg, 0.29 mmol) in THF (10 mL)
and saturated NH3/MeOH (40 mL) was placed in a sealed tube
and heated at 110 °C for 95 h. Column chromatography (5%
MeOH in CHCl3) of the reaction mixture gave 23 (oil, 165 mg,
99%): UV (MeOH) λmax 262 nm (ꢀ 9900), λmin 240 nm (ꢀ 6400);
1H NMR (CDCl3) δ 1.37 (3H, s), 1.61 (3H, s), 2.36 (3H, s), 3.21
(1H, dd, J ) 4.3 and 10.1 Hz), 3.42 (1H, dd, J ) 7.0 and 10.1
Hz), 4.50-4.52 (1H, m), 4.97 (1H, dd, J ) 3.2 and 6.1 Hz),
5.39 (1H, dd, J ) 2.1 and 6.1 Hz), 5.59 (2H, br), 6.10 (1H, d, J
) 2.1 Hz), 7.15-7.20 (9H, m), 7.31-7.34 (6H, m), 7.81 (1H, s);
FAB-MS m/z 564 (M+ + H). Anal. Calcd for C33H33N5O4‚
1/2H2O: C, 69.21; H, 5.98; N, 12.23. Found: C, 69.51; H, 5.97;
N, 12.14.
2-((Cycloh exyl)h yd r oxym eth yl)-2′,3′-O-isopr op ylid en e-
5′-O-tr ityla d en osin e (25). Compound 15 (400 mg, 0.48 mmol)
was reacted with NH3/MeOH in a similar manner as described
in the preparation of 23. The reaction was continued for 90 h.
Column chromatography (2% MeOH in CHCl3) of the reaction
mixture gave 25 (foam, 305 mg, 96%) as a mixture of two
diastereomers (ca. 5:3): UV (MeOH) λmax 261 nm (ꢀ 9200), λmin
1
241 nm (ꢀ 5400); H NMR of the major diastereomer (CDCl3,
after addition of D2O) δ 1.05-1.36 (11H, m), 1.35 (3H, s), 1.61
(3H, s), 3.21 (1H, dd, J ) 3.8 and 10.2 Hz), 3.37 (1H, dd, J )
7.0 and 10.2 Hz), 4.22 (1H, d, J ) 4.0 Hz), 4.48-4.52 (1H, m),
4.89 (1H, dd, J ) 3.6 and 6.4 Hz), 5.36 (1H, dd, J ) 2.0 and
6.4 Hz), 6.13 (1H, d, J ) 2.0 Hz), 7.15-7.23 (9H, m), 7.29-
7.37 (6H, m), 7.87 (1H, s); 1H NMR of the minor diastereomer
(CDCl3, after addition of D2O) δ 1.36 (3H, s), 1.67 (3H, s), 1.67-
1.84 (11H, m), 3.30-3.31 (2H, m), 4.41 (1H, d, J ) 4.0 Hz),
4.41-4.47 (1H, m), 4.84 (1H, dd, J ) 3.0 and 6.4 Hz), 5.32
(1H, dd, J ) 2.4 and 6.4 Hz), 6.15 (1H, d, J ) 2.4 Hz), 7.15-
7.24 (9H, m), 7.29-7.37 (6H, m), 7.88 (1H, s); FAB-MS m/z
662 (M+ + H). Anal. Calcd for C39H43N5O5: C, 70.78; H, 6.55;
N, 10.58. Found: C, 70.96; H, 6.59; N, 10.55.
2-[(1-Hyd r oxy-1-m eth yl)eth yl]-2′,3′-O-isop r op ylid en e-
5′-O-tr ityla d en osin e (26). Compound 16 (473 mg, 0.61 mmol)
was reacted with NH3/MeOH in a similar manner as described
in the preparation of 23. The reaction was continued for 69 h.
Column chromatography (2% MeOH in CHCl3) of the reaction
mixture gave 26 (foam, 317 mg, 87%): UV (MeOH) λmax 261
1
nm (ꢀ 13 300), λmin 241 nm (ꢀ 7500); H NMR (CDCl3) δ 1.34
(3H, s), 1.36 (3H, s), 1.46 (3H, s), 1.61 (3H, s), 3.21 (1H, dd, J
) 4.0 and 10.0 Hz), 3.34 (1H, dd, J ) 7.6 and 10.0 Hz), 4.47-
4.51 (1H, m), 4.73 (1H, br), 4.90 (1H, dd, J ) 3.2 and 6.2 Hz),
5.41 (1H, dd, J ) 2.0 and 6.2 Hz), 5.63 (2H, br), 6.15 (1H, d, J
) 2.0 Hz), 7.13-7.19 (9H, m), 7.27-7.35 (6H, m), 7.89 (1H, s);
FAB-MS m/z 608 (M+ + H). Anal. Calcd for C37H37N5O5‚
1/2H2O: C, 68.16; H, 6.21; N, 11.35. Found: C, 67.79; H, 5.90;
N, 11.03.
2-(Hyd r oxym et h yl)-2′,3′-O-isop r op ylid en e-5′-O-t r it yl-
a d en osin e (27). Compound 18 (432 mg, 0.57 mmol) was
reacted with NH3/MeOH in a similar manner as described in
the preparation of 23. The reaction was continued for 80 h.
Column chromatography (5% MeOH in CHCl3) of the reaction
mixture gave 27 (foam, 304 mg, 92%): UV (MeOH) λmax 261
1
nm (ꢀ 12 300), λmin 241 nm (ꢀ 6800); H NMR (CDCl3) δ 1.37
(3H, s), 1.62 (3H, s), 3.25 (1H, dd, J ) 4.0 and 10.1 Hz), 3.37
(1H, dd, J ) 6.4 and 10.1 Hz), 4.45 (1H, d, J ) 15.5 Hz), 4.53
(1H, d, J ) 15.5 Hz), 4.50-4.53 (1H, m), 4.88 (1H, dd, J ) 3.1
and 6.4 Hz), 5.35 (1H, dd, J ) 2.4 and 6.4 Hz), 6.13 (1H, d, J
) 2.4 Hz), 5.75 (2H, br), 7.17-7.21 (15H, m), 7.88 (1H, s); FAB-
MS m/z 580 (M+ + H). Anal. Calcd for C33H33N5O5‚1/2H2O:
C, 67.33; H, 5.82; N, 11.90. Found: C, 67.12; H, 6.16; N, 11.51.
2-Ca r b a m oyl-2′,3′-O-isop r op ylid en e-5′-O-t r it yla d en o-
sin e (28). Compound 20 (340 mg, 0.43 mmol) was reacted with
NH3/MeOH in a similar manner as described in the prepara-
tion of 23. The reaction was continued for 79 h. Column
chromatography (5% MeOH in CHCl3) of the reaction mixture
gave 28 (foam, 166 mg, 65%): UV (MeOH) λmax 265 nm (ꢀ
10 600) and 294 nm (ꢀ 5500), λmin 245 nm (ꢀ 6000) and 275 nm
(ꢀ 4400); 1H NMR (CDCl3) δ 1.39 (3H, s), 1.63 (3H, s), 3.31
(1H, dd, J ) 4.0 and 10.4 Hz), 3.37 (1H, dd, J ) 5.8 and 10.4
Hz), 4.51-4.54 (1H, m), 4.93 (1H, dd, J ) 3.1 and 6.1 Hz),
5.33 (1H, dd, J ) 2.7 and 6.1 Hz), 5.92 (2H, br), 6.10 (2H, br),
6.18 (1H, d, J ) 2.7 Hz), 7.17-7.22 (9H, m), 7.30-7.35 (6H,
m), 8.01 (1H, s); FAB-MS m/z 593 (M+ + H). Anal. Calcd for
2-Eth yl-2′,3′-O-isopr opyliden e-5′-O-tr ityladen osin e (24).
Compound 13 (174 mg, 0.23 mmol) was reacted with NH3/

7780 J . Org. Chem., Vol. 64, No. 21, 1999
Kumamoto et al.
C33H32N6O5‚5/4H2O: C, 64.43; H, 5.65; N, 13.66. Found: C,
64.14; H, 5.25; N, 13.60.
(1H, s); FAB-MS m/z 676 (M+ + H). Anal. Calcd for C32H30
-
IN5O4: C, 56.90; H, 4.48; N, 10.37. Found: C, 57.13; H, 4.45;
N, 10.11.
2-Iod o-2′,3′-O-isop r op ylid en e-5′-O-tr ityla d en osin e (29).
Compound 21 (300 mg, 0.35 mmol) was reacted with NH3/
MeOH in a similar manner as described in the preparation of
23. The reaction was continued for 90 h. Column chromatog-
raphy (3% MeOH in CHCl3) of the reaction mixture gave 29
(foam, 187 mg, 79%): UV (MeOH) λmax 265 nm (ꢀ 12 900), λmin
243 nm (ꢀ 7400); 1H NMR (CDCl3) δ 1.36 (3H, s), 1.62 (3H, s),
3.22 (1H, dd, J ) 3.7 and 10.4 Hz), 3.46 (1H, dd, J ) 7.7 and
10.4 Hz), 4.50-4.53 (1H, m), 4.90 (1H, dd, J ) 3.4 and 6.4
Hz), 5.27 (1H, dd, J ) 1.8 and 6.4 Hz), 5.80 (2H, br), 6.09 (1H,
d, J ) 1.8 Hz), 7.15-7.18 (9H, m), 7.33-7.37 (6H, m), 7.78
Ack n ow led gm en t. Financial support from the Min-
istry of Education, Science and Culture (Grant-in-Aid
No. 09672159 to H.T.) is gratefully acknowledged. Part
of this work has been supported by J apan Society for
the Promotion of Science (to H.T.). The authors thank
Dr. Martin J . Slater (Glaxo-Wellcome Medicine Re-
search Centre, U.K.) for proof-reading this manuscript.
J O9906577