Approaches to unsaturated analogues of nucleosides comprising four- and six-membered rings

Article abstract of DOI:10.1021/jo000276p

Unsaturated nucleoside analogues 21, 22, 46, and 54, comprising four- and six-membered rings, were synthesized using two different approaches. The 2-benzyloxycycloalkanones 23a and 23b served as starting materials for both methods. Conversion to methylenecyclobutanes 29a and 29b was followed by addition of bromine via pyridinium perbromide to give vicinal dibromides 30a and 30b. Reaction of 29a with Br₂ gave a ring-contracted cyclopropane derivative 31. Alkylation - elimination of adenine with 30a gave bromoalkene 32 as the major product and adenine-containing unsaturated derivatives 33, 34, and 35 as minor components. Vicinal dibromide 30b gave the Zaitsev cyclohexene 45 as the only product. Epoxidation of 29a and 29b afforded oxiranes 36a and 36b which were used in alkylation of adenine to furnish hydroxy derivatives 37a, 37b, 38a, and 38b. β-Elimination via mesylates 39a and 40a using tBuOK/DMF gave Z- and E-methylenecyclobutanes 34 and 35. With an excess of base the E-bis-methylenecyclobutane 41 was obtained. Mesylation of cyclohexane derivatives 37b and 38b gave the Z- and E-N⁶-mesylated product 48. By contrast, the N⁶-benzoyl derivatives 49 and 50 afforded O-mesyl intermediates 51 and 52. β-Elimination gave both Hofmann and Zaitsev products 53 and 45. O-Debenzylation of 34 and 35, 45, and 53 afforded analogues 21, 22, 46, and 54. The E-isomer 22 was also obtained by hydroboration procedure from E-bis-methylenecyclobutane 41.

Full text of DOI:10.1021/jo000276p

J . Org. Chem. 2000, 65, 5177-5184
5177
Ap p r oa ch es to Un sa tu r a ted An a logu es of Nu cleosid es Com p r isin g
F ou r - a n d Six-Mem ber ed Rin gs
Hui-Ping Guan,† Mohamad B. Ksebati,‡ Earl R. Kern,§ and J iri Zemlicka*,†
Department of Chemistry, Experimental and Clinical Chemotherapy Program, Barbara Ann Karmanos
Cancer Institute, Wayne State University School of Medicine, 110 East Warren Avenue,
Detroit, Michigan 48201-1379, Central Instrumentation Facility, Department of Chemistry,
Wayne State University, Detroit, Michigan 48202, and Department of Pediatrics, The University of
Alabama at Birmingham, Birmingham, Alabama 35294
E-mail: zemlicka@kci.wayne.edu
Received February 29, 2000
Unsaturated nucleoside analogues 21, 22, 46, and 54, comprising four- and six-membered rings,
were synthesized using two different approaches. The 2-benzyloxycycloalkanones 23a and 23b
served as starting materials for both methods. Conversion to methylenecyclobutanes 29a and 29b
was followed by addition of bromine via pyridinium perbromide to give vicinal dibromides 30a and
30b. Reaction of 29a with Br2 gave a ring-contracted cyclopropane derivative 31. Alkylation-
elimination of adenine with 30a gave bromoalkene 32 as the major product and adenine-containing
unsaturated derivatives 33, 34, and 35 as minor components. Vicinal dibromide 30b gave the Zaitsev
cyclohexene 45 as the only product. Epoxidation of 29a and 29b afforded oxiranes 36a and 36b
which were used in alkylation of adenine to furnish hydroxy derivatives 37a , 37b, 38a , and 38b.
â-Elimination via mesylates 39a and 40a using tBuOK/DMF gave Z- and E-methylenecyclobutanes
34 and 35. With an excess of base the E-bis-methylenecyclobutane 41 was obtained. Mesylation of
cyclohexane derivatives 37b and 38b gave the Z- and E-N6-mesylated product 48. By contrast, the
N6-benzoyl derivatives 49 and 50 afforded O-mesyl intermediates 51 and 52. â-Elimination gave
both Hofmann and Zaitsev products 53 and 45. O-Debenzylation of 34 and 35, 45, and 53 afforded
analogues 21, 22, 46, and 54. The E-isomer 22 was also obtained by hydroboration procedure from
E-bis-methylenecyclobutane 41.
In tr od u ction
compounds9-11 8-11. This effort was undoubtedly moti-
vated by the antiviral activity of antibiotic oxetanocin A
(12a ) and the carbocyclic guanine analogue12 12b. Syn-
theses of cyclohexene analogues 13-15 related to carbo-
vir4 (3b) were also subjects of several investigations.13-15
Structures of 1-22 are shown in Chart 1.
It is noteworthy that most of the unsaturated nucleo-
side analogues studied thus far are substituted at an
allylic position of the unsaturated carbohydrate (carbocy-
clic) moiety by a nucleic acid base (compounds 2-6, 8,
10, 11, and 13-15). Nevertheless, analogues of an
enamine type, with a double bond attached to a hetero-
cyclic base, such as 1′,2′-unsaturated nucleosides16 16,
N-vinyl nucleic acid bases17a 17, and derivatives thereof17b,c
18 are known. In this group of analogues, methyl-
Unsaturated analogues of nucleosides are in the center
of current interest as potential antiviral and antitumor
agents. This diverse class of compounds includes antibi-
otics decoyinine (angustmycin A)1 (1) and neplanocin2 A
(2), AIDS drug stavudine3 (3a ), anti-HIV agents carbovir4
(3b) and (-)-BCA5 4, antitumor agent 2′-deoxy-2′-meth-
ylenecytidine6 (DMDC, 5), and carbocyclic analogue BMS
200475 (6)7 effective against hepatitis B virus (HBV). The
3′,4′-unsaturated nucleosides 7 are also known.8 Like-
wise, significant attention has been paid to the develop-
ment of synthetic methods for four-membered ring struc-
tures with exocyclic or endocyclic double bonds such as
† Wayne State University School of Medicine.
‡ Wayne State University.
§ The University of Alabama at Birmingham.
(9) Maruyama, T.; Hanai, Y.; Sato, Y. Nucleosides Nucleotides 1992,
11, 855-864.
(1) Suhadolnik, R. J . Nucleosides as Biological Probes; Wiley: New
York, 1979; pp 279-281.
(2) Marquez, V. E.; Lim, M.-I. Med. Res. Rev. 1986, 6, 1-40.
(3) Martin, J . C.; Hitchcock, M. J . M.; Fridland, A.; Ghazzouli, I.;
Kaul, S.; Dunkle, L. M.; Sterzycki, R. Z.; Mansuri, M. M. Ann. N. Y.
Acad. Sci. 1990, 616, 22-28.
(10) Gharbaoui, T.; Legraverend, M.; Bisagni, E. Tetrahedron Lett.
1992, 33, 7141-7144.
(11) Gourdel-Martin, M.-E.; Huet, F. J . Org. Chem. 1997, 62, 2166-
2172.
(12) Agrofoglio, L.; Challand, S. R. Acyclic, Carbocyclic and L-
Nucleosides; Kluwer Academic Publishers: Dordrecht, The Nether-
lands, 1998; pp 268-273.
(13) Konkel, M. J .; Vince, R. Tetrahedron 1996, 52, 799-808.
(14) Rosenquist, A° .; Kvarnstrom, I.; Classon, B.; Samuelsson, B. J .
Org. Chem. 1996, 61, 6282-6288.
(15) Wang, J .; Herdewijn, P. J . Org. Chem. 1999, 64, 7820-7827.
(16) Robins, M. J .; Trip, E. M. Tetrahedron Lett. 1974, 3369-3372.
(17) (a) Ciapetti, P.; Taddei, M. Tetrahedron 1998, 54, 11305-11310.
(b) J ohnson, F.; Pillai, K. M. R.; Grollman, A. P.; Tseng, L.; Takeshita,
M. J . Med. Chem. 1984, 27, 954-958. (c) Phadtare, S.; Zemlicka, J .
Tetrahedron Lett. 1990, 31, 43-46.
(4) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand, R.
S.; Earl, R. E.; Guedj, R. Tetrahedron 1994, 50, 10611-10670.
(5) Katagiri, N.; Nomura, M.; Sato, H.; Kaneko, C.; Yusa, K.; Tsuruo,
T. J . Med. Chem. 1992, 35, 1882-1886.
(6) Matsuda, A.; Takenuki, K.; Tanaka, M.; Sasaki, T.; Ueda, T. J .
Med. Chem. 1991, 34, 812-819.
(7) Innaimo, S. F.; Seifer, M.; Bisacchi, G. S.; Standring, D. N.;
Zahler, R.; Colonno, R. J . Antimicrob. Agents Chemother. 1997, 41,
1444-1447.
(8) Zemlicka, J .; Freisler, J . V.; Gasser, R.; Horwitz, J . P. J . Org.
Chem. 1973, 38, 990-999.
10.1021/jo000276p CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/27/2000

5178 J . Org. Chem., Vol. 65, No. 17, 2000
Ch a r t 1. Str u ctu r es 1-22
Guan et al.
Sch em e 1
enecyclopropanes18 19 and allenes19 20 exhibited potent
antiviral activity. Previously, the alkylation-elimination
procedure proved advantageous18b,20 for synthesis of
methylenecyclopropanes 19. It was therefore of interest
to investigate the scope and limitations of this procedure
for synthesis of unsaturated analogues comprising larger
than three-membered rings. Alternate approaches for
synthesis of such compounds were also in the focus of
our attention. The results obtained with four- and six-
membered ring systems are the subject of this com-
munication.
ethyl 2,2-(bismethylthio)-1-cyclobutanecarboxylate (26) in
82% yield (Scheme 1). Reduction23 with LiAlH4 in THF
gave hydroxymethyl derivative 27 (93%). Benzylation
afforded the O-benzyl thioacetal 28 which, in turn, was
hydrolyzed using N-chlorosuccinimide and AgNO3 in
aqueous MeCN20 to give the key intermediate 23a in a
total yield of 70%. The Wittig methylenation led then to
methylenecyclobutane 29a (73%). Surprisingly, addition
of bromine in CH2Cl2 at low temperature (-78 °C) did
not give any expected vicinal dibromocyclobutane 30a but
a ring-contracted derivative 31 in 70% yield. Formation
of cyclopropylmethyl, cyclobutyl, and open-chain com-
pounds was previously observed in solvolysis of cyclobutyl
derivatives.24 In our case, the reaction which proceeds
most likely via the respective bromonium cation gives 31
as a major product. By using a less reactive agent,
pyridinium hydrobromide perbromide at 0 °C, a ring
Resu lts a n d Discu ssion
Two approaches for synthesis of the Z- and E-methyl-
enecyclobutane analogues 21 and 22 were investigated.
Both approaches made use of 2-(benzyloxymethyl)cy-
clobutanone (23a ) as a key intermediate. The latter was
obtained by a modification of the procedure described for
the corresponding O-benzoate.21 Reaction of ethyl acry-
late (24) and ketene dimethyl thioacetal22 (25) furnished
(18) (a) Qiu, Y.-L.; Hempel, A.; Camerman, N.; Camerman, A.;
Geiser, F.; Ptak, R. G.; Breitenbach, J . M.; Kira, T.; Li, L.; Gullen, E.;
Cheng, Y.-C.; Kern, E. R.; Drach, J . C.; Zemlicka, J . J . Med. Chem.
1998, 41, 5257-5264. (b) Qiu, Y.-L.; Ksebati, M. B.; Ptak, R. G.; Fan,
B. Y.; Breitenbach, J . M.; Lin, J .-S.; Cheng, Y.-C.; Kern, E. R.; Drach,
J . C.; Zemlicka, J . J . Med. Chem. 1998, 41, 10-23. (c) Qiu, Y.-L.; Ptak,
R. G.; Breitenbach, J . M.; Lin, J .-S.; Cheng, Y.-C.; Kern, E. R.; Drach,
J . C.; Zemlicka, J . Antiviral Chem. Chemother. 1998, 9, 341-352.
(19) Zemlicka, J . Nucleosides Nucleotides 1997, 16, 1003-1012.
(20) Qiu, Y.-L.; Zemlicka, J . Synthesis 1998, 1447-1452.
(21) Lee-Ruff, E.; Xi, F.; Qie, J . H. J . Org. Chem. 1996, 61, 1547-
1550.
(23) Narasaka, K.; Kusama, H.; Hayashi, Y. Bull. Chem. Soc. J pn.
1991, 64, 1471-1478.
(24) March, J . Advanced Organic Chemistry; Wiley: New York,
1992; p 323.
(22) Kaya, R.; Beller, N. R. J . Org. Chem. 1981, 46, 197-201.

Synthesis of Unsaturated Analogues of Nucleosides
J . Org. Chem., Vol. 65, No. 17, 2000 5179
Sch em e 2
Sch em e 3
Sch em e 4
11% yield, respectively. It is interesting to note that the
ratio of isomers differs significantly from that obtained
by the alkylation-elimination procedure (Scheme 1, ratio
34/35 ) 2:1). Selective hydroboration of diene 41 with
9-BBN in THF and alkaline H2O2 gave the E-isomer 22
in 62% yield (Scheme 3). This result contrasts with a
previously reported26 lack of success with selective hy-
droboration of conjugated dienes. An absence of enamine
reduction27 (loss of heterocyclic base) is also noteworthy.
Deprotection of intermediates 37a and 38a afforded
diols 42 and 43 in 78 and 75% yield, respectively (Scheme
4). Although neither 42 nor 43 formed borate complexes
as indicated by paper electrophoresis in 0.1 M Na2B4O7
(pH 9), compound 42 was smoothly transformed (77%
yield) to a 1,3-dioxane derivative 44 using acetone
dimethyl ketal and TsOH in DMF. This established the
Z-isomeric structure of 42.
As expected, the UV spectra of compounds 21 and 22
were very similar to those of the corresponding Z-
methylenecyclopropane analogue 19 (B ) Ade) and its
E-isomer.18b The assignment of the Z- and E-isomers 21
and 22 and structure of diene 41 followed from the NMR
spectra and, particularly, from the NOE data (Chart 2).
A significant difference between the H8 chemical shifts
of 21 and 22 (∆δ 0.24 vs 0.26 found for the Z- and
E-isomers of synadenol18b) suggested the Z-isomeric
structure of 21. This was corroborated by NOE enhance-
ment (6.4%) between the H8 and H5′(6′) absent in the
E-isomer 22. By contrast, the E-isomer 22 exhibited NOE
enhancements of 1.3 and 3.1% of the H1′ and H5′ as well
as 1.0 and 2.4% of H1′ and H6′ that were not found in the
Z-isomer 21. Interestingly, the NOE was observed be-
tween the H1′ and both H8 and H2 (2.0-2.3 and 0.6%,
respectively) in the Z-isomer 21 indicating, on an NMR
time-scale, some freedom of rotation of the heterocyclic
base. No such interactions were observed in the E-isomer
22 where such a rotation is much less hindered. The
structure of diene 41 was confirmed by the UV spectrum
(ꢀmax 23 500 vs 13 600 for the E-isomer 22) which is
compatible with the presence of a conjugated system of
double bonds attached to a heterocyclic base. The 1H
contraction was not observed and dibromocyclobutane
30a was obtained in 95% yield. Alkylation of adenine
with 30a , using K2CO3 in DMF at 110 °C (18 h), led
predominantly to an elimination of elements of HBr to
give the E/ Z-bromomethylenecyclobutanes 32 (70%).
Products of alkylation-elimination 33 (3.5%), and 34 and
35 (4.6%, ratio 2:1) were obtained as minor components.
Interestingly, this ratio corresponded to the values
observed in the methylenecyclopropane series18b,20 (Z/ E
) 2:1 or 1:1). Reaction of 30a using sodium salt of
adenine in DMF at 100 °C for 10 h afforded a similar
distribution of the reaction products.
Because of low yields of intermediates 34 and 35 we
sought an alternate approach (Scheme 2). Protected
methylenecyclobutane 29a was converted to oxirane 36a
in quantitative yield. Opening of the epoxide ring with
adenine afforded readily separable Z- and E-hydroxy
derivatives 37a and 38a in 34 and 32% yield, respec-
tively. Mesylation of the tertiary hydroxy groups of 37a
and 38a by a routine mesyl chloride-pyridine procedure
proved difficult but catalysis with DMAP gave the Z- and
E-mesylates 39 and 40 in 50 and 69% yield. The Sc(OTf)3/
DMAP method25 recommended for acylation of tertiary
hydroxy groups was not applicable for mesylation of 37a
and 38a . It should be noted that separated isomers of
39 and 40 are not necessary for the next step. Thus, an
elimination of mesyloxy function was performed with a
mixture of mesylates 39 and 40 using a 50% excess of
tBuOK in THF to give the mixture of Z- and E-isomers
34 and 35 in 87% yield. Surprisingly, with a 2 M excess
of tBuOK, the benzyloxy group was also eliminated to
give diene 41 (Scheme 3) as an E-isomer in 78% yield.
O-Debenzylation of isomeric mixture 34 and 35 was
performed with BCl3 in CH2Cl2 at -78 °C to give target
compounds 21 and 22. The separation of both isomers
could not be accomplished on silica gel, but chromatog-
raphy on alumina led to a smooth resolution of the E-
and Z-isomers 22 and 21 which were obtained in 68 and
(26) Brown, H. C.; Bhat, K. S. J . Org. Chem. 1986, 51, 445-449.
(27) Singaram, B.; Rangaishenvi, M. V.; Brown, H. C.; Goralski, C.
T.; Hasha, D. L. J . Org. Chem. 1991, 56, 1543-1549.
(25) Zhao, H.; Pendri, A.; Greenwald, R. B. J . Org. Chem. 1998, 63,
7559-7562.

5180 J . Org. Chem., Vol. 65, No. 17, 2000
Guan et al.
Ch a r t 2. NOE Da ta of 21, 22, a n d 41
Sch em e 6
Sch em e 7
Sch em e 5
exocyclic alkenes 47a and 47b failed. Similar isomeriza-
tion was effected without difficulty in the acyclic series.17c
It is clear, then, that the stability of the endocyclic double
bond in a six-membered ring prevails over any possible
energy gain from conjugation with a heteroaromatic
system.
An alternate approach also followed the methods
described for methylenecyclobutane analogues (Scheme
2, n ) 2). Methylenecyclohexane 29b was converted to
oxiranes 36b, by reaction with m-CPBA in NaHCO3 in
CH2Cl2, in 84% yield. Alkylation of adenine with 36b
using NaH in DMF at 110 °C afforded a 1:1 mixture of
the Z- and E-isomers 37b and 38b in 45% yield. At-
tempted O-mesylation of this product with MsCl and
DMAP in pyridine gave only the N-mesylated product
48. The latter was obtained as an inseparable mixture
of Z- and E-isomers in 46% yield (Scheme 6). No O-
mesylated products were detected even if the reaction
was performed with 6 equiv of MsCl. The structure of
48 followed from the UV, NMR, and mass spectra. The
UV maximum (273 nm) is indicative of N-substitution
of the adenine moiety. As expected, the CH3 signal of the
NMR spectrum showed the presence of exomethylene
protons H6′ and H6′′ (δ 5.40 and 4.86, respectively). The
NOE data confirmed the E-isomeric structure of 41 as
based on enhancements between the H1′ and H6′ of 1.6
and 10%, respectively.
It was then of interest to investigate the applicability
of both approaches for synthesis of unsaturated nucleo-
side analogues comprising a six-membered ring. The
known28 2-(benzyloxymethyl)cyclohexanone (23b) was
converted by a Wittig methylenation to compound 29b
(88%, Scheme 1). Addition of bromine, effected by pyri-
dinium hydrobromide perbromide in CH2Cl2 at 0 °C, gave
the corresponding vicinal dibromide 30b in 98% yield.
Alkylation-elimination of adenine with 30b using K2-
CO3 or NaH in DMF gave the cyclohexene derivative 45
in 60 and 41% yield, respectively (Scheme 5). Attempted
deprotection of 45 with BCl3 in CH2Cl2 at -78 °C was
not successful, possibly, because the cleavage can occur
at benzylic and allylic sites of the molecule. However,
debenzylation with Na in liquid NH3 was uneventful in
giving the target analogue 46 in 53% yield. Attempted
isomerization of 45 and 46 with tBuOK in DMF to give
1
mesyl group in the H NMR spectrum of 48 (δ 3.28) is
shifted downfield from that of the O-mesylates 39 and
40 (δ 3.08 and 3.14, respectively). Surprisingly, no N6-
mesylation was observed in the cyclobutane series (Scheme
2). Apparently, the tertiary hydroxy groups of cyclobu-
tanes 38a and 38b are less sterically hindered than in
cyclohexanes 37b and 38b.
Therefore, compounds 37b and 38b were selectively
benzoylated using Bz2O in pyridine to give the N6-benzoyl
derivatives 49 and 50 (69%, Scheme 7). Mesylation gave
O-mesylates 51 and 52 in 50% yield. Interestingly, it
(28) Murata, S.; Suzuki, M.; Noyori, R. Tetrahedron 1988, 44, 4259-
4275.

Synthesis of Unsaturated Analogues of Nucleosides
J . Org. Chem., Vol. 65, No. 17, 2000 5181
over Na2SO4. Evaporation of solvents gave the crude 2-(ben-
zyloxymethyl)cyclobutanone bis(methylthio)ketal 28 which
was added dropwise into a stirred solution of N-chlorosuccin-
imide (NCS, 11.2 g, 84 mmol) and AgNO3 (16.1 g, 95 mmol) in
90% acetonitrile at 0 °C. After the mixture was stirred for 10
min at room temperature, saturated aqueous Na2SO3, NaH-
CO3, and brine were added successively. The solids were
removed by filtration. The filtrate was extracted with ethyl
acetate; the organic phase was washed with brine and it was
dried over Na2SO4. The solvent was evaporated and the crude
product was chromatographed on a silica gel column using
hexanes/ethyl acetate (10:1) to give 23a as a colorless oil 3.74
seems that introduction of the benzoyl group at a distant
N6 position led to a relief of steric hindrance at the
tertiary hydroxy groups. â-Elimination effected with
tBuOK in THF and debenzoylation with NH3/MeOH were
perfomed in one pot. The products were separated by
silica gel chromatography to give isomeric cyclohexenes
53 (46%) and 45 (22%). The latter was identical to the
product obtained from an alkylation-elimination proce-
dure with dibromides 30b. Both products are clearly
1
differentiated by the H NMR spectra (lack or presence
of an olefinic proton). Apparently, Hofmann-type orienta-
tion of the double bond predominates with mesylates 51
and 52, whereas dibromides 30b afforded exclusively
Zaitsev product 45. O-Debenzylation of cyclohexene 53
smoothly afforded compound 54 in 70% yield.
Compounds 21, 22, 42, 43, and 46 were tested against
HCMV, HSV-1, HSV-2, EBV, HBV, VZV, and HIV-1
using the assays described previously.18b None of them
had a significant antiviral activity. A moderate effect of
21 against EBV in Daudi cells (IC50 39 µM) was not
separated from cytotoxicity (CC50 40 µM). These ana-
logues were also ineffective as substrates for adenosine
deaminase.
1
g (70%). H NMR (CDCl3): δ 7.35 (5H, m), 4.54 (2H, s,), 3.74
(1H, dd, J ) 5.4 and 9.9 Hz) and 3.60 (1H, dd, J ) 4.5 and 9.6
Hz), 3.55 (1H, m), 3.04 (2H, m), 2.18 and 2.06 (2H, m). 13C
NMR: 210.5, 138.10, 128.34, 127.64, 127.57, 73.16, 67.56,
60.63, 45.71, 14.29. EI-MS: 190 (M, 2.0), 91 (100.0). HRMS:
calcd for C12H14O2, 190.0994; found, 190.0992.
1-(Ben zyloxym eth yl)-2-m eth ylen ecyclobu ta n e (29a ).
Butyllithium (1.6 M in hexane, 13.82 mL, 22 mmol) was added
to a suspension of methyltriphenylphosphonium bromide (7.89
g, 22 mmol) in THF (100 mL) at room temperature with
stirring under N2. After 2 h, ketone 23a (3.0 g, 16 mmol) in
THF (50 mL) was added dropwise and the resulting mixture
was stirred another 14 h. The reaction was quenched with
saturated aqueous NH4Cl (150 mL) and it was extracted with
ether. The organic phase was washed with aqueous NaHCO3
and brine, and it was dried over Na2SO4. The crude product
obtained after evaporation was chromatographed on a silica
gel column (hexanes/ethyl acetate, 100:0.5 f 100:1.5) to give
compound 29a as a colorless oil (2.20 g, 73%). 1H NMR
(CDCl3): δ 7.37 (5H, m), 4.90 (1H, m) and 4.82 (1H, m, CH2d),
4.60 (2H, s), 3.60 (2H, m), 3.32 (1H, m), 2.70 (2H, m), 2.17
(1H, m), and 1.80 (1H, m). 13C NMR: 151.36, 138.62, 128.38,
127.65, 127.55, 105.33, 73.11, 73.06, 44.05, 29.30, 21.26. EI-
MS: 188 (M, 0.3), 91 (100.0). HRMS: calcd for C13H16O,
188.1201; found, 188.1198.
1-(Ben zyloxym eth yl)-2-m eth ylen ecycloh exa n e (29b).
The procedure described above for compound 29a was followed
starting from ketone 23b (3.8 g, 17.4 mmol), methyltri-
phenylphosphonium bromide (9.35 g, 26.2 mmol), and BuLi
(1.6 M in hexane, 16.4 mL, 26.2 mmol) to give product 29b as
an oil (3.3 g, 88%). 1H NMR (CDCl3): δ 7.38 and 7.32 (5H, m),
4.74 (1H, s) and 4.61 (1H, s, CH2d), 4.56 (2H, s), 3.67 (1H, dd,
J ) 6.3 and 9.0 Hz) and 3.49 (1H, dd, J ) 7.5 and 9.0 Hz),
2.42 (1H, m), 2.28 and 2.25 (1H, m), 2.27 (1H, m), 1.90 (1H,
s), 1.70 (2H, m), 1.47 (2H, m), 1.32 (1H, s). 13C NMR: 150.30,
138.66, 128.34, 127.66, 127.49, 106.02, 73.09, 72.23, 43.00,
35.62, 31.17, 28.57, 24.72. EI-MS: 216 (M, 2.1), 91 (100.0).
HRMS: calcd for C15H20O, 216.1514; found, 216.1514.
(Z)- a n d (E)-(2-Ben zyloxym eth yl)-1-br om o-1-br om o-
m eth ylcyclobu ta n e (30a ). Pyridinium hydrobromide per-
bromide (3.4 g, 10.6 mmol) was added in portions to a solution
of methylenecyclobutane 29a (2.0 g, 10.6 mmol) in CH2Cl2 (80
mL) at 0 °C with stirring. The stirring was continued at 0 °C
for 3 h whereupon the reaction was quenched with saturated
aqueous NaHSO3 (50 mL). The product was extracted with
ether; the combined organic phase was washed with brine and
it was dried over Na2SO4. Evaporation afforded the crude
product which was chromatographed on a silica gel column
(hexanes/ethyl acetate, 100:1 f 50:1) to give compound 30a
as an oil (3.50 g, 95%). 1H NMR (CDCl3): δ 7.40 (5H, m), 4.55
(2H, m), 4.08 and 3.74 (1H, J AB ) 11.4 Hz) and 3.90 (1H, s,
1:1), 3.62 (2H, m), 3.44 (m) and 2.82 (1H, m, 1:1), 2.61 (m)
and 2.46 (2H, m, 3:1), 2.20 (m), 1.98 (m) and 1.88 (2H, m, 1:2:
1). EI-MS: 350 (M, 0.1), 348 (M, 0.2), 346 (M, 0.1), 91 (100.0).
HRMS: calcd for C13H16O79Br2, 345.9568; found 345.9564.
Anal. Calcd for C13H16OBr2: C, 44.86; H, 4.63. Found: C, 44.67;
H, 4.57.
Exp er im en ta l Section
Gen er a l Meth od s. See reference 18b. The 1H and 13C NMR
spectra were recorded with the 300 and 400 MHz instruments.
For the FAB-MS thioglycerol matrix was used, and 2-meth-
ylpropane was employed as an ionization gas in CI-MS.
(Benzyloxymethyl)cyclohexanone (23b) was prepared from
cyclohexanone and dibenzyloxymethane29 as described.28
Eth yl 2,2-Bis(m eth ylth io)-1-cyclobu ta n eca r boxyla te
(26). Diethylaluminum chloride (1.0 M in hexane, 125 mL) was
added dropwise with stirring at 0 °C to a solution of 1,1-bis-
(methylthio)ethylene22 (25, 10 g, 84 mmol) and ethyl acrylate
(24, 13.5 mL, 186 mmol) in CH2Cl2 (150 mL). The mixture was
stirred under N2 for 1 h and then at room temperature for
another 1 h. The reaction was quenched by the careful addition
of Et3N (9 mL) and 10% aqueous sodium bicarbonate (50 mL)
at 0 °C. The inorganic salt was removed by filtration and it
was washed with CH2Cl2. The combined organic phase was
washed with H2O and dried over Na2SO4. After evaporation
of solvents, the crude product was purified on a silica gel
column (hexanes/ethyl acetate, 20:1) to give the pure product
26 as an oil (16.0 g, 82%).
2,2-Bis(m eth ylth io)-1-cyclobu tylm eth a n ol (27). A solu-
tion of compound 26 (14.0 g, 6.46 mmol) in THF (80 mL) was
added to a suspension of LiAlH4 (3.55 g, 9.54 mmol) in THF
(100 mL) at 0 °C with stirring. The mixture was stirred at 0
°C for 1 h and the reaction was quenched carefully by
saturated aqueous Na2SO4. The precipitate was filtered off and
it was washed with ether. The filtrate was concentrated in
vacuo and the residue was purified by column chromatography
on silica gel (hexanes/ethyl acetate, 9:1) to give product 27 as
a colorless oil (12.0 g, 93%). The 1H NMR spectrum cor-
responded to that described for the S-enantiomer.23
2-(Ben zyloxym eth yl)cyclobu ta n on e (23a ). To a solution
of [2,2-bis(methylthio)-1-cyclobutyl]methanol (27, 5.0 g, 28
mmol) in THF (160 mL) cooled to 0 °C, NaH (50% in mineral
oil, 2.69 g, 56 mmol) was added in portions with stirring under
N2. The mixture was stirred for 30 min at room temperature,
and benzyl bromide (33.6 mmol, 4.0 mL) was added dropwise
followed by tetrabutylammonium iodide (0.1 g, 0.27 mmol). The
stirring was continued for 16 h. The reaction was quenched
with saturated aqueous NH4Cl (150 mL) and the mixture was
extracted with ethyl acetate/hexanes (1:1). The organic phase
was washed with aqueous NaHCO3 and brine and it was dried
(E)-2-(Ben zyloxym et h yl)-1-b r om o-1-b r om om et h ylcy-
cloh exa n e (30b). The procedure described for compound 30a
was followed using methylenecyclohexane 29b (1.6 g, 7.4
mmol) and pyridinium hydrobromide perbromide (2.4 g, 7.5
mmol) in CH2Cl2 (50 mL) to give product 30b as an oil (2.70
(29) Laskina, E. D. Zh. Prikl. Khim. 1959, 32, 878-882; Chem.
Abstr. 1959, 53, 17039b.
1
g, 98%). H NMR (CDCl3): δ 7.40 (5H, m), 4.56 (2H, s), 4.32

5182 J . Org. Chem., Vol. 65, No. 17, 2000
Guan et al.
and 3.86 (2H, J AB ) 10.2 Hz), 3.71 (1H, dd, J ) 5.8 and 9.7
Hz) and 3.30 (1H, dd, J ) 6.4 and 9.7 Hz), 2.17 (1H, m), 2.05
(1H, m), 1.74 (5H, m), 1.35 (2H, m). 13C NMR: 138.34, 128.39,
127.54, 127.42, 73.45, 73.21, 42.37, 42.59, 39.44, 26.59, 24.83,
22.77. EI-MS: 297 (0.2) and 295 (0.3, M - Br), 91 (100.0).
HRMS: calcd for C15H20O79Br (M - Br), 295.0692; found,
295.0697. Anal. Calcd for C15H20Br2O: C, 47.90; H, 5.36; Br,
42.49. Found: C, 48.07; H, 5.46; Br, 42.61.
1-(2-Ben zyloxy-1-b r om o)et h yl)-1-b r om om et h ylcyclo-
p r op a n e (31). Bromine was added dropwise with stirring to
a solution of compound 29a (200 mg, 1.06 mmol) in CH2Cl2
(20 mL) at -78 °C till the color did not fade. The reaction was
quenched with saturated aqueous NaHSO3 (10 mL) and the
product was extracted with ether. The combined organic phase
was washed with brine and dried over Na2SO4. Evaporation
gave the crude product, which was chromatographed on a silica
gel column (hexanes/ethyl acetate, 100:1 f 50:1) to give
compound 31 as an oil (260 mg, 70%). 1H NMR (CDCl3): δ
7.40 (5H, m), 4.60 (2H, s), 4.20 (1H, t, J ) 6.4 Hz), 3.92 (2H,
d, J ) 6.5 Hz), 3.70 and 3.54 (2H, J AB ) 11.1 Hz), 1.15-0.95
(4H, m). 13C NMR: 137.77, 128.53, 127.80, 127.76, 73.19, 72.59,
68.48, 59.73, 40.75, 19.28, 17.44. EI-MS: 350 (M, 0.1), 348 (M,
0.2), 346 (M, 0.1), 91 (100.0). HRMS: calcd for C13H16Br2O,
345.9568; found, 345.9568.
NaHCO3 and brine and then dried over Na2SO4. Evaporation
of the solvent gave the crude product which was chromato-
graphed on a silica gel column (hexanes/ethyl acetate, 20:1 f
15:1 f 10:1) to give compound 36a (1.50 g, 100%) as an oil.
1H NMR (CDCl3): δ 7.37 (5H, m), 4.58 and 4.50 (2H, 2s, 1.2:
1), 3.63 (d, J ) 5.1 Hz) and 3.42 (2H, d, J ) 4.8 Hz, 1.2:1),
3.06 and 2.95 (1H, m, 1.2:1), 2.90 and 2.65 (J AB ) 4.5 Hz), 2.75
and 2.73 (2H, J AB ) 4.5 Hz, 1:1.2,), 2.42 (m) and 2.22 (m, 2H),
2.03 (m), 1.84 (m) and 1.70 (m, 2H). EI-MS: 204 (M, 0.8), 91
(100.0). HRMS: calcd for C13H16O2, 204.1150; found, 204.1151.
(E)- an d (Z)-4-(Ben zyloxym eth yl)-1-oxaspir o[2,5]octan es
(36b). The procedure for compound 36a was followed using
methylenecyclohexane 29b (3.0 g, 13.9 mmol), NaHCO3 (1.75
g, 20.8 mmol), and m-CPBA (3.34 g, 19.43 mmol) to give 36b
1
(2.7 g, 84%) as an oil. H NMR (CDCl3): δ 7.38 (5H, m), 4.43
(2H, m), 2.00 (1H, m), 1.85-1.44 (8H, m). Resolved signals of
isomers: isomer A, 3.50 (dd, J ) 5.4 and 8.9 Hz) and 3.25 (2H,
dd, J ) 5.4 and 9.1 Hz), 2.94 (1H, d, J ) 4.5 Hz) and 2.76 (1H,
d, J ) 4.5 Hz); isomer B, 3.40 and 3.34 (2H, J AB ) 8.4 Hz),
2.54 (2H, d, J ) 4.2 Hz). The isomeric ratio was 1:1. EI-MS:
232 (M, 0.5), 91 (100.0). HRMS: calcd for C15H20O2, 232.1463;
found, 232.1464.
(Z)-9-{[2-(Be n zyloxym e t h yl)-1-h yd r oxycyclob u t yl]-
m eth yl}a d en in e (37a ) a n d (E)-9-{[2-(Ben zyloxym eth yl)-
1-h yd r oxycyclobu tyl]m eth yl}a d en in e (38a ). A mixture of
adenine (1.5 g, 11.1 mmol) and NaH (50% in mineral oil, 0.45
g, 9.3 mmol) in dry DMF (50 mL) was stirred at room
temperature for 4 h under N2. Compound 36a (1.6 g, 7.8 mmol)
in DMF (5 mL) was then added and the stirring was continued
at 110 °C for 10 h. After cooling, the solvent was evaporated
and the crude product was chromatographed on silica gel (CH2-
Cl2/MeOH, 30:1 f 20:1 f 10:1) to give the Z-isomer (0.9 g,
34%) and E-isomer (0.85 g, 32%) as foams.
(Z)- a n d (E)-1-(Ben zyloxym et h yl)-2-b r om om et h yle-
n ecyclobu ta n e (32), 9-{[2-(Ben zyloxym eth yl)cyclobu t-1-
en -1-yl]m eth yl}a d en in e (33), a n d Com p ou n d s 34 a n d 35.
Meth od A. A mixture of compound 30a (180 mg, 0.52 mmol),
adenine (180 mg, 0.73 mmol), and flame-dried K2CO3 (800 mg,
5.8 mmol) in DMF (8 mL) was stirred at 110 °C for 18 h. The
solids were filtered off and washed with DMF. The solvent was
evaporated and the crude product was chromatographed on a
silica gel column (CH2Cl2/MeOH, 30:1 f 20:1) to give first
compound 32 (97 mg, 70%) as an oil, followed by a mixture of
isomers 34 + 35 (39 mg, 4.6%) as a gum, and cyclobutene 33
(30 mg, 3.5%) as a solid.
Z-Isom er 37a . UV max (EtOH): 261 nm (ꢀ 13 900), 209 (ꢀ
1
25 000). H NMR (CDCl3): δ 8.40 (1H, s) and 8.08 (1H, s, H8
and H2), 7.37 (5H, m), 6.00 (2H, s, NH2), 4.50 (1H, brs, OH),
4.43 (2H, s), 4.37 and 4.28 (2H, J AB ) 14 Hz), 3.63 (m) and
3.52 (2H, m), 2.50 (1H, m), 2.10 (2H, m), 1.95 (1H, m), 1.77
(1H, m). 13C NMR: 155.97, 152.74, 150.34, 141.76, 137.72,
128.39, 127.70, 127.50, 118.74, 75.13, 73.13, 69.97, 51.66,
41.25, 32.40, 16.01. FAB-MS: 340 (M, 100.0).
1
The H NMR spectrum of 34 and 35 indicated a Z/ E ratio
of 2:1.
1
Com p ou n d 32. H NMR (CDCl3): δ 7.30 (5H, m), 6.10 (s)
and 5.95 (s, 2:1, 1H), 4.56 (2H, s), 4.60 (dd, J ) 6.3 and 4.0
Hz) and 4.40 (2H, m, 1:2), 3.23 (m, 1H), 2.75 (m) and 2.62 (2H,
m, 1:2), 2.23 (1H, m), 1.92 (1H, m). CI-MS: 269 (M + H, 3.4),
267 (M + H, 3.8), 91 (100.0). HRMS: calcd for C13H15O (M -
Br), 187.1123; found, 187.1121.
E-Isom er 38a . UV max (EtOH): 261 nm (ꢀ 14 200), 210 (ꢀ
1
23 900). H NMR (CDCl3): δ 8.40 (1H, s) and 8.00 (1H, s, H8
and H2), 7.37 (5H, m), 6.00 (2H, s, NH2), 4.50 (1H, brs, OH),
4.37 (2H, s), 4.52 and 4.25 (2H, J AB ) 14 Hz), 3.60 (2H, m),
2.75 (1H, m), 1.94 (1H, m), 1.80 (2H, m), 1.55 (1H, s). 13C
NMR: 155.88, 152.58, 150.32, 142.14, 137.93, 128.41, 127.75,
118.72, 75.46, 73.13, 69.03, 47.87, 41.75, 31.57, 15.40. FAB-
MS: 340 (M, 100.0).
Z- a n d E-Isom er s 34 and 35. UV max (EtOH): 261 nm (ꢀ
1
13 700), 209 (ꢀ 23 900). H NMR (CDCl3): δ 8.39 (1H, s), 8.22
(s) and 7.90 (1H, s, 1:2), 7.38, 7.27 and 7.20 (5H, m), 6.98 (s)
and 6.77 (1H, s, 2:1), 5.89 (2H, s), 4.59 (s) and 4.40 (2H, s,
2:1), 3.66 (m) and 3.50 (3H, m), 2.94 (2H, m), 2.31 (1H, m),
1.99 (m) and 1.85 (1H, m, 2:1). The Z/ E ratio (2:1) was
determined from integration of the appropriate 1H NMR
signals.
(Z)- a n d (E)-9-{[2-(Ben zyloxym et h yl)-1-h yd r oxycy-
cloh exyl]m eth yl}a d en in e (37b a n d 38b). The procedure for
compounds 37a and 38a was followed using compound 36b
(2.7 g, 11.6 mmol), adenine (2.35 g, 17 mmol), and NaH (50%
in mineral oil, 0.72 g, 15 mmol) to give Z- and E-isomers 37b
and 38b as a gum (1.9 g, 45%). The E/Z ratio was 1:1. UV
max (EtOH): 261 nm (ꢀ 14 700), 209 (ꢀ 20 600). 1H NMR
(DMSO-d6): δ 8.20 (1H, s), 8.08 and 8.06 (2s, 1H, 1:1, H8 and
H2), 7.40 (2H, NH2), 7.37 and 7.20 (5H, m), 5.05 and 4.80 (1H,
s, 1:1, OH), 4.45 (3H, m), 4.29 and 4.24 (1H, J AB ) 14.4 Hz),
3.97 (d, J ) 14.4 Hz), 3.81 (m) and 3.74 (m, 2H), 3.60 (1H, m),
1.1-1.8 (8H, m). FAB-MS: 369 (M, 100.0).
Com p ou n d 33. Mp 187-190 °C. UV max (EtOH): 261 nm
(ꢀ 13 500), 207 (ꢀ 23 800). 1H NMR (CDCl3): δ 8.37 (1H, s) and
7.81 (1H, s, H8 and H2), 7.34 (5H, m), 5.81 (2H, s, NH2), 4.87
(2H, s), 4.51 (2H, s), 3.99 (2H, s), 2.39 (2H, s), 2.34 (2H, s). 13
C
NMR: 155.68, 153.41, 153.04, 142.76, 140.81, 138.47, 136.25,
128.72, 128.05, 127.93, 112.68, 73.21, 41.47, 27.90, 27.57. FAB-
MS: 322 (M + H, 100.0).
Meth od B. A mixture of adenine (180 mg, 0.73 mmol) and
NaH (50% in mineral oil, 35 mg, 0.73 mmol) in DMF (6 mL)
was stirred at room temperature under N2 for 4 h. A solution
of compound 30a (180 mg, 0.52 mmol) in DMF (10 mL) was
added. The resulting mixture was then stirred at 100 °C for
10 h. Evaporation of all solvents and workup as described
above gave compound 32 (100 mg, 72%), isomers 34 and 35
(35 mg, 4%), and cyclobutene 33 (30 mg, 3.5%).
(E)- a n d (Z)-4-(Ben zyloxym eth yl)-1-oxa sp ir o[2,3]h ex-
a n es (36a ). m-Chloroperoxybenzoic acid (m-CPBA, 85%, 1.96
g, 9.7 mmol) was added in portions to a stirred mixture of
compound 29a (1.4 g, 7.4 mmol) and NaHCO3 (0.87 g, 10.36
mmol) in CH2Cl2 (80 mL) at 0 °C. The mixture was stirred at
0 °C for 4 h whereupon saturated aqueous Na2SO3 was added
to quench the reaction. The product was extracted with ether
(3 × 50 mL). The organic phase was washed with aqueous
(Z )-9 -{[2 -(B e n z y l o x y m e t h y l )-1 -m e t h y l s u l fo n y l -
cyclobu tyl]m eth yl}a d en in e (39). Methylsulfonyl chloride
(MsCl, 0.43 mL, 5.4 mmol) was added dropwise to a stirred
mixture of compound 37a (0.61 g, 1.8 mmol) and 4-(N,N-
dimethylamino)pyridine (DMAP, 0.26 g, 2.15 mmol) in CH2-
Cl2 (25 mL) and pyridine (5 mL) at 0 °C. The stirring was
continued at room temperature for 24 h whereupon MeOH/
H2O (2:1, 1 mL) was added. After 1 h, the solvents were
evaporated and the crude product was chromatographed on a
silica gel column (CH2Cl2/MeOH, 40:1 f 30:1 f 20:1) to give
compound 39 as a gum (256 mg, 50%) and recovered starting
1
material 37a (180 mg, 30%). H NMR (CDCl3): δ 8.36 (1H, s)
and 8.18 (1H, s, H8 and H2, adenine), 7.37 (5H, m), 6.60 (2H,
s, NH2), 4.65 (2H, d, J ) 2.4 Hz), 4.46 (2H, s), 3.50 (2H, s),

Synthesis of Unsaturated Analogues of Nucleosides
J . Org. Chem., Vol. 65, No. 17, 2000 5183
3.08 (3H, s, CH3), 2.75 (1H, m), 2.46 (1H, m), 2.0 (3H, m). 13C
NMR: 155.84, 153.03, 150.69, 141.62, 141.71, 137.95, 128.41,
127.75, 118.85, 89.55, 73.09, 69.44, 49.59, 42.31, 30.10, 17.54.
FAB-MS: 418 (M, 62.0), 136 (100.0).
(1H, t, J ) 3.0 Hz, OH), 3.42 (3H, m, H5′ + H6′, overlapped
with H2O), 2.81 (1H, m, H3′), 2.71 (1H, m, H3′′), 2.14 (1H, m,
H4′′), 1.77 (1H, m, H4′). 13C NMR: 157.10, 153.88, 149.77,
140.10, 137.84, 119.18, 113.92, 63.36, 46.04, 28.05, 21.78. EI-
MS: 231 (M, 100.0). HRMS: calcd for C11H13N5O, 231.1120;
found, 231.1120. Anal. Calcd for C11H13N5O: C, 57.13; H, 5.67;
N, 30.28. Found: C, 57.00; H, 5.73; N, 30.30.
(E )-9 -{[2 -(B e n z y l o x y m e t h y l )-1 -m e t h y l s u l fo n y l -
cyclobu tyl]m eth yl}a d en in e (40). The procedure described
above was used with compound 38a (0.80 g, 2.36 mmol), DMAP
(0.346 g, 2.83 mmol), MsCl (0.553 mL, 7.1 mmol), CH2Cl2 (30
mL), and pyridine (5 mL) to give gummy product 40 (678 mg,
69%). 1H NMR (CDCl3): δ 8.36 (1H, s) and 8.12 (1H, s, H2
and H8), 7.37 (5H, m), 6.50 (2H, s, NH2), 4.94 and 4.63 (2H,
J AB ) 15.3 Hz), 4.50 and 4.47 (2H, J AB ) 12 Hz), 3.75 (1H, dd,
J ) 10.4 and 4.7 Hz) and 3.66 (1H, dd, J ) 6.0 and 10.5 Hz),
Meth od B. (E)-9-{[2-(Hyd r oxym eth yl)cyclobu tylid en e]-
m eth yl}a d en in e (22) fr om Dim eth ylen ecyclobu ta n e 41.
9-Borabicyclo[3.3.1]nonane (9-BBN, 0.5 M in THF, 7.5 mL) was
slowly added to a solution of compound 41 (400 mg, 4.7 mmol)
in THF (5 mL) at 0 °C under N2. The mixture was stirred for
30 min and then for 8 h at room temperature. A solution of
5% NaOH in 50% H2O2 (10 mL) was added, and the resulting
mixture was stirred for 16 h and lyophilized. The residue was
washed with CH2Cl2/MeOH (10:1) with the aid of a sonicator.
The combined organic portions were evaporated and the
residue was chromatographed on a silica gel column (CH2Cl2/
MeOH, 15:1 f 12:1) to give compound 22 (269 mg, 62%)
3.50 (1H, m), 3.14 (3H, s, CH3), 2.35 (2H, m), 2.00 (2H, m). 13
C
NMR: 155.85, 152.79, 150.71, 141.68, 141.70, 137.81, 127.78,
127.68, 118.80, 89.58, 73.27, 67.64, 45.54, 44.61, 40.45, 30.15,
16.04. FAB-MS: 418 (M, 58.7), 136 (100.0).
(Z)- a n d (E)-9-{[2-(Ben zyloxym eth yl)cyclobu tylid en e]-
m eth yl}a d en in e (34 a n d 35). Freshly sublimed tBuOK (842
mg, 7.5 mmol) was added to a mixture of compounds 39 and
40 (2.08 g, 5 mmol) in THF (50 mL) with stirring at 0 °C. The
stirring was continued at room temperature for 6 h, the
reaction mixture was cooled to 0 °C, and 1 M HCl (1.0 mL)
was added dropwise. The volatile components were evaporated
and the crude product was chromatographed on a silica gel
column (CH2Cl2/MeOH, 30:1 f 20:1) to give products 34 and
1
identical (TLC, H, and 13C NMR) to the product obtained by
method A.
(Z)-9-{[1-H y d r o x y -2-(h y d r o x y m e t h y l)c y c lo b u t y l]-
m eth yl}a d en in e (42). The deprotection was performed as
described for compounds 21 and 22 (method A), using the
Z-isomer 37a (226 mg, 0.67 mmol) and BCl3 (1.0 M in CH2Cl2,
3.35 mmol, 3.35 mL) at -78 °C for 4 h. Chromatography (CH2-
Cl2/MeOH, 15:1 f 10:1) afforded product 42 (117 mg, 78%).
Mp 208-211 °C. UV max (EtOH): 260 nm (ꢀ 14 300), 209 (ꢀ
1
35 as a solid (1.40 g, 87%). H NMR spectrum was identical,
except the isomeric ratio, with that of the product obtained
from dibromo derivatives 30a . EI-MS: 321 (M, 21.0), 91
(100.0). HRMS: calcd for C18H19N5O, 321.1590; found, 321.1587.
(E)-9-[(2-Met h ylen ecyclob u t ylid en e)m et h yl]a d en in e
(41). The procedure described above was employed using a two
molar excess of tBuOK (840 mg, 7.5 mmol) and mesylates 39
and 40 (1.04 g, 2.5 mmol) in THF (30 mL) to give product 41
(414 mg, 78%). Mp 229-230 °C. UV max (EtOH): 260 nm (ꢀ
23 500), 205 (ꢀ 17 500). 1H NMR (DMSO-d6): δ 8.27 (1H, s)
and 8.17 (1H, s, H8 and H2), 7.39 (2H, s, NH2), 7.34 (1H, m,
H1′), 5.40 (1H, m, H6′), 4.86 (1H, m, H6′′), 2.99 (2H, m, H3′),
2.71 (2H, m, H4′). 13C NMR: 157.23, 154.20, 149.59, 147.20,
138.99, 133.45, 119.09, 111.43, 106.09, 29.55, 27.55. EI-MS:
213 (M, 100.0). HRMS: calcd for C11H11N5, 213.1014; found,
213.1020. Anal. Calcd for C11H11N5: C, 61.96; H, 5.20; N, 32.84.
Found: C, 61.79; H, 5.25; N, 33.01.
(Z)-9-{[2-(H yd r oxym et h yl)cyclob u t ylid en e]m et h yl}-
adenine (21)and (E)-9-{[2-(Hydroxymethyl)cyclobutylidene]-
m eth yl}a d en in e (22). Meth od A. Dep r otection of O-Ben -
zyl Der iva tives 34 a n d 35. Boron trichloride (1 M in CH2Cl2,
25.8 mL, 25.8 mmol) was added dropwise with stirring to a
solution of isomeric mixture 34 and 35 (1.38 g, 4.3 mmol)
obtained from mesylates 39 and 40 in CH2Cl2 (100 mL) at -78
°C under N2. The stirring was continued for 4 h. A 1:1 mixture
of MeOH/CH2Cl2 (10 mL) was then added. The solvents were
evaporated and the syrupy product was stirred with MeOH
(30 mL) and NaHCO3 (2.2 g, 25.8 mmol) for 2 h. The solids
were filtered off and washed with MeOH/CH2Cl2 (1:1, 2 × 10
mL). The combined filtrates were evaporated and the crude
product was chromatographed on a silica gel column using
CH2Cl2/MeOH (30:1 f 20:1 f 15:1) to give a mixture of 21
and 22 (824 mg, 83%) as a solid. Chromatography on a column
of neutral alumina (CH2Cl2/MeOH, 40:1 f 30:1 f 20:1) gave
the E-isomer 22 (676 mg, 68%) followed by Z-isomer 21 (109
mg, 11%).
1
18 600). H NMR (CDCl3): δ 8.09 (1H, s) and 8.02 (1H, s, H8
and H2), 7.39 (2H, s, NH2), 5.30 (1H, brs, OH), 4.25 and 4.17
(2H, J AB ) 14 Hz), 3.70 (1H, brs, OH), 3.53 (1H, dd, J ) 6.8
and 10.7 Hz) and 3.41 (1H, m), 2.27 (1H, m), 1.98 (1H, m),
1.82 (1H, m), 1.67 (1H, m), 1.50 (1H, m). 13C NMR: 156.22,
152.74, 150.46, 142.21, 118.48, 74.35, 61.16, 51.27, 44.46,
31.27, 16.58. EI-MS: 249 (M, 6.9), 148 (100.0). HRMS: calcd
for C11H15N5O2, 249.1226; found, 249.1224. Anal. Calcd for
C
11H15N5O2 x 0.6 H2O: C, 50.80; H, 6.28; N, 26.93. Found: C,
50.84; H, 6.15; N, 27.39. 32.84.
(E )-9-{[1-H y d r o x y -2-(h y d r o x y m e t h y l)c y c lo b u t y l]-
m eth yl}a d en in e (43). The reaction was carried out as
described above for the Z-isomer 42, starting from the E-isomer
38a (204 mg, 0.6 mmol) and BCl3 (1.0 M in CH2Cl2, 3.0 mmol,
3.0 mL) to give compound 43 (112 mg, 75%). Mp 207-209 °C.
1
UV max (EtOH): 260 nm (ꢀ 14 600), 210 (ꢀ 18 900). H NMR
(CDCl3): δ 8.14 (1H, s) and 8.05 (1H, s, H8 and H2), 7.25 (2H,
s, NH2), 5.58 (1H, s, OH), 4.56 (1H, s, OH), 4.53 and 4.06 (2H,
J AB ) 14 Hz), 3.50 (2H, m), 2.43 (1H, m), 1.82 (1H, m), 1.70
(1H, m), 1.56 (1H, m), 1.43 (1H, m). 13C NMR: 156.31, 152.86,
150.56, 142.56, 118.41, 75.04, 60.27, 49.97, 46.64, 31.27, 15.69.
FAB-MS: 249 (M, 4.9), 148 (100.0). EI-HRMS: calcd for
C
C
11H15N5O2, 249.1226; found, 249.1224. Anal. Calcd for
11H15N5O2: C, 52.99; H, 6.07; N, 28.10. Found: C, 52.89; H,
6.09; N, 28.33.
Cyclic Keta l 44. A mixture of compound 42 (26 mg, 0.064
mmol), 2,2-dimethoxypropane (5 mL), and TsOH × H2O (50
mg, 0.26 mmol) in DMF (1 mL) was stirred for 8 h at room
temperature, and then it was cooled to 0 °C. Triethylamine (1
mL) was added and the mixture was evaporated. Chromatog-
raphy on a column of silica gel (CH2Cl2/MeOH/NH4OH, 100:
2:0.1 f 90:2:0.1) gave product 44 (23 mg, 77%). Mp 244-247
1
°C. H NMR (CDCl3): δ 8.14 (1H, s) and 8.00 (1H, s, H8 and
H2, adenine), 7.20 (2H, s, NH2), 4.28 and 4.19 (2H, J AB ) 14
Hz), 3.83 (1H, dd, J ) 5.1 and 12.3 Hz) and 3.53 (1H, dd, J )
3.0 and 12.1 Hz), 2.32 (1H, m), 1.98 (2H, m), 1.75 (2H, m),
1.34 (3H, s) and 1.30 (3H, s, Me2C). 13C NMR: 156.38, 152.91,
150.52, 142.0, 118.55, 97.97, 74.56, 60.94, 50.28, 33.90, 31.34,
29.52, 25.33, 17.94. EI-MS: 289 (M, 16.5), 55 (100.0). HRMS:
calcd for C14H19N5O2, 289.1539; found, 289.1540. Anal. Calcd
for C14H19N5O2: C, 58.12; H, 6.62; N, 24.20. Found: C, 57.89;
H, 6.82; N, 24.62.
E-Isom er 22. Mp 231-233 °C. UV max (EtOH): 261 nm (ꢀ
13 600), 227 (ꢀ 24 400). 1H NMR (DMSO-d6): δ 8.14 (2H, s,
H8 and H2), 7.33 (2H, s, NH2), 6.90 (1H, m, H1′), 4.77 (1H, t, J
) 3.6 Hz, OH), 3.54 (2H, t, J ) 5.4 Hz, H6′), 3.20 (1H, m, H5′),
2.87 (2H, m, H3′), 2.10 (1H, m, H4′′), 1.79 (1H, m, H4′). 13C
NMR: 156.46, 153.25, 148.69, 138.48, 136.15, 118.36, 112.31,
64.06, 44.25, 27.69, 21.14. EI-MS: 231 (M, 100.0). HRMS:
calcd for C11H13N5O, 231.1120; found, 231.1121. Anal.Calcd for
C
11H13N5O: C, 57.13; H, 5.67; N, 30.28. Found: C, 57.29; H,
5.79; N, 30.40.
9-{2-[(Ben zyloxym et h yl)cycloh ex-1-en -1-yl]m et h yl}-
a d en in e (45). Meth od A. A mixture of adenine (468 mg, 3.47
mmol) and NaH (50% in mineral oil, 166 mg, 3.47 mmol) in
DMF (30 mL)
Z-Isom er 21. Mp 229-231 °C. UV max (EtOH): 261 nm (ꢀ
15 200), 227 (ꢀ 24 000). 1H NMR (DMSO-d6): δ 8.38 (1H, s,
H8), 8.14 (1H, s, H2), 7.29 (2H, s, NH2), 6.72 (1H, m, H1′), 4.83

5184 J . Org. Chem., Vol. 65, No. 17, 2000
Guan et al.
was stirred at room temperature for 4 h. A solution of
dibromide 30b (1.30 g, 3.47 mmol) in DMF (10 mL) was then
added. The resulting mixture was stirred at 100 °C for 10 h
under N2. Evaporation of all solvents and workup as described
above gave product 45 (0.5 g, 41%). Mp 165-167 °C. UV max
18 300), 235 (ꢀ 13 900), 206 (ꢀ 25 900). 1H NMR (DMSO-d6):
δ 11.13 (1H, s, NHCO), 8.71 (1H, s), 8.32 and 8.31 (1H, 2s, H8
and H2), 8.04 and 8.02 (2H, 2s), 7.62 (1H, m), 7.53 (2H, m),
7.33 (4H, m) and 7.26 (1H, m, aromatic H’s), 4.95 and 4.75
(1H, 2s, ratio 1:1, OH), 4.55 and 4.50 (1H, J AB ) 10.8 Hz), 4.48
(1H, s), 4.42 and 4.32 (1H, J AB ) 10.6 Hz), 4.04, 3.87, 3.77
and 3.58 (2H, m), 3.58 and 3.34 (1H, m), 1.60-1.90 (9H, m).
EI-MS: 471 (M, 1.7), 91 (100.0). HRMS: calcd for C27H29N5O3,
471.2270; found, 471.2272.
1
(EtOH): 260 nm (ꢀ 14 700), 209 (ꢀ 29 700). H NMR (DMSO-
d6): δ 8.18 (1H, s) and 8.00 (1H, s, H2 and H8), 7.29 (7H, m,
Ph and NH2), 4.80 (2H, s), 4.45 (2H, s) 4.20 (2H, s), 2.07 (2H,
m), 1.80 (2H, m) 1.40 (4H, m). 13C NMR: 156.41, 152.98,
150.19, 141.05, 138.94, 133.43, 130.45, 128.64, 127.99, 127.82,
118.94, 71.68, 69.80, 44.28, 28.37, 27.44, 22.36, 22.31. EI-MS:
350 (M + H, 1.3), 91 (100.0). CI-MS: 351 (M + 2H, 22.1), 350
(M + H, 100.0). HRMS: calcd for C20H23N5O, 349.1903; found,
349.1900. Anal. Calcd for C20H23N5O: C, 68.75; H, 6.63; N,
20.04. Found: C, 68.65; H, 6.75; N, 20.18.
Meth od B. The mixture of dibromide 30b (1.30 g, 3.47
mmol), adenine (0.61 g, 4.5 mmol), and flame-dried K2CO3 (2.8
g, 21 mmol) in DMF (30 mL) was stirred at 110 °C for 18 h.
The solid was filtered off and washed with DMF. The filtrate
was evaporated and the crude product was chromatographed
on a silica gel column (CH2Cl2/MeOH, 30:1 f 20:1) to give
product 45 (0.72 g, 60%) as a solid identical to compound
prepared by method A.
(E)- a n d (Z)-9-{[2-(Ben zyloxym eth yl)-1-m eth ylsu lfo-
n ylcycloh exyl]m eth yl}-N6-ben zoyla d en in e (51 a n d 52).
The method described for mesylates 39 and 40 was followed.
A mixture of isomers 49 and 50 (1.60 g, 3.4 mmol), DMAP (0.5
g, 4.1 mmol), MsCl (0.79 mL, 10.2 mmol), CH2Cl2 (60 mL) and
pyridine (10 mL) were used. Chromatography (CH2Cl2/MeOH,
60:1 f 50:1) afforded product 51 and 52 as a solid (0.93 g,
1
50%). H NMR (DMSO-d6): δ 9.42 (1H, s, NHCO), 8.71 (1H,
s), 8.32 and 8.31 (1H, 2s, H8 and H2), 8.03 (2H, 2s), 7.60 (1H,
m), 7.51 (2H, m), 7.32 (4H, m) and 7.26 (1H, m, aromatic H’s),
4.95 and 4.55 (1H, J AB ) 10.8 Hz) and 4.75 (1H, m), 4.30 (2H,
2s), 3.80 and 3.48 (2H, m), 3.40 and 3.24 (1H, m), 3.15 and
3.10 (3H, 2s), 1.66-2.0 (9H, m). FAB-MS: 549 (M, 100.0).
9-{[3-(Ben zyloxym et h yl)cycloh ex-1-en -2-yl]m et h yl}-
a d en in e (53) a n d 9-{[2-(Ben zyloxym eth yl)cycloh ex-1-en -
1-yl]m eth yl}a d en in e (45). The procedure described for the
E- and Z-isomers 34 and 35 was followed, using mesylates 51
and 52 (450 mg, 0.82 mmol) and tBuOK (184 mg, 1.65 mmol)
in THF (5 mL) at 0 °C. A solution of the crude product in 20%
NH3 in methanol was then allowed to stand at room temper-
ature for 4 h. Evaporation of volatile components and chro-
matography (CH2Cl2/MeOH, 30:1 f 20:1) gave compounds 53
(130 mg, 46%) and 45 (60 mg, 22%) as solids. Compound 45
was identical (TLC, 1H, and 13C NMR) to the product obtained
from dibromo derivative 30b.
9-{[2-(H yd r oxym e t h yl)cycloh e x-1-e n -1-yl]m e t h yl}-
a d en in e (46). Sodium (92 mg, 4 mmol) was added to liquid
NH3 (20 mL) under N2 with stirring at -78 °C. A solution of
compound 45 (700 mg, 2 mmol) in THF (10 mL) was added
dropwise over a period of 3 min. After an additional 15 min,
the reaction was quenched with NH4Cl (300 mg, 5.6 mmol).
Ammonia was evaporated, and the solids were filtered off and
washed with CH2Cl2/MeOH (10:1) with the aid of a sonicator.
The combined filtrates were evaporated and the crude product
was chromatographed on a silica gel column (CH2Cl2/MeOH,
20:1 f 15:1) to give compound 46 (274 mg, 53%) as a solid.
Mp 216-218 °C. UV max (EtOH): 260 (ꢀ 14 300), 208 (ꢀ
1
1
Com p ou n d 53. H NMR (CDCl3): δ 8.35 (1H, s) and 7.74
24 400). H NMR (CDCl3): δ 8.10 (1H, s) and 8.05 (1H, s, H2
(1H, s, H2 and H8, adenine), 7.28 (5H, m), 6.60 (2H, s, NH2),
5.60 (1H, m, CHd), 4.88 and 4.64 (2H, J AB ) 15.1 Hz), 4.46
(2H, s), 3.50 (2H, m), 2.27 and 2.17 (1H, m), 1.99 (2H, m), 1.85
and 1.72 (1H, m) 1.56 (3H, m). 13C NMR: 156.04, 153.19,
150.33, 140.96, 138.42, 133.75, 128.64, 127.99, 127.81, 119.57,
73.37, 72.83, 48.17, 35.92, 25.93, 25.37, 19.31.
and H8), 7.23 (2H, s, NH2), 5.01 (1H, t, J ) 4.2 Hz, OH), 4.79
(2H, s), 4.12 (2H, d, J ) 3.9 Hz), 2.08 (2H, m), 1.75 (2H, m),
1.45 (4H, m). 13C NMR: 156.44, 152.74, 150.50, 142.35, 136.97,
127.70, 127.67, 61.12, 44.36, 28.05, 27.27, 22.55, 22.42. EI-
MS: 259 (M, 2.7), 136 (100.0). HRMS: calcd for C13H17N5O,
259.1433; found, 259.1432. Anal. Calcd for C13H17N5O: C,
60.21; H, 6.61; N, 27.01. Found: C, 60.32; H, 6.49; N, 27.26.
(E)- a n d (Z)-9-{[2-(Ben zyloxym eth yl)-1-h yd r oxycyclo-
h exyl]m et h yl}-N6-m esyla d en in e (48). The method de-
scribed for mesylates 39 and 40 was followed, using a mixture
of isomers 37b and 38b (780 mg, 2.12 mmol), DMAP (337 mg,
2.76 mmol), MsCl (0.984 mL, 12.72 mmol, added in two
equimolar portions), CH2Cl2 (30 mL), and pyridine (4 mL).
Chromatography (CH2Cl2/MeOH, 100:1 f 60:1) afforded the
N6-mesyl derivatives 48 (440 mg, 46%). Mp 180-183 °C. UV
max (EtOH): 273 nm (ꢀ 14 300), 216 (ꢀ 23 600). 1H NMR
(DMSO-d6): δ 8.37 (1H, s) and 8.20 (1H, s, H8 and H2), 7.32
(4H, m) and 7.26 (1H, m, Ph), 4.92 and 4.70 (1H, 2s, ratio 1:1,
OH), 4.47 (2.5 H, m), 4.37 and 4.23 (0.5H, J AB ) 13.8 Hz), 3.98
(0.5H, 1/2 of AB, J AB ) 13.0 Hz), 3.82 (0.5H, m), 3.73 (0.5H,
m), 3.49 (0.5H, m), 3.28 (4H, CH3 and CH2), 1.86-1.08 (9H,
m). EI-MS: 445 (M, 2.3), 91 (100.0). HRMS: calcd for
9-{[3-(H yd r oxym e t h yl)cycloh e x-1-e n -2-yl]m e t h yl}-
a d en in e (54). The deprotection was carried out as described
for methylenecyclobutanes 21 and 22, with compound 53 (100
mg, 0.22 mmol) and BCl3 (1 M in CH2Cl2, 1.37 mL, 1.37 mmol)
in CH2Cl2 (3 mL). The crude product was chromatographed
on a silica gel column (CH2Cl2/MeOH, 20:1 f 15:1) to give 40
mg (70%) of 54. Mp 184-187 °C after crystallization from CH2-
Cl2/MeOH (10:1). UV max (EtOH): 261 nm (ꢀ 14 100), 209 (ꢀ
1
25 700). H NMR (DMSO-d6): δ 8.14 and 8.05 (2H, s, H8 and
H2), 7.22 (2H, s, NH2), 5.40 (1H, s, CHd), 4.76 and 4.66 (2H,
J AB ) 11.7 Hz), 4.64 (1H, brs, OH), 3.52 and 3.38 (2H, m), 2.01
(1H, m), 1.89 (2H, m), 1.70 (1H, m), 1.51 (1H, m), 1.42 (2H,
m). 13C NMR 156.44, 152.98, 150.10, 141.45, 134.98, 126.58,
119.04, 62.95, 47.30, 38.38, 25.15, 24.95, 18.87. EI-MS 259:
(M, 5.4), 228 (100.0). HRMS: calcd for C13H17N5O, 259.1433;
found, 259.1433. Anal. Calcd for C13H17N5O: C, 60.21; H, 6.61;
N, 27.01. Found: C, 60.12; H, 6.49; N, 27.18.
C
11H27N5O4S, 445.1784; found, 445.1782.
(E)- a n d (Z)-9-{[2-(Ben zyloxym eth yl)-1-h yd r oxycyclo-
h exyl]m eth yl}-N6-ben zoyla d en in e (49 a n d 50). A mixture
of isomers 37b and 38b (1.84 g, 5 mmol) and benzoic anhydride
(Bz2O, 9.0 g, 40 mmol) in pyridine (10 mL) was stirred at room
temperature for 12 h and then at 40 °C for 24 h. The resultant
solution was poured on ice (100 g) and NaHCO3 (20 g) with
stirring, whereupon it was extracted with CHCl3. The organic
phase was washed successively with saturated aqueous NaH-
CO3, H2O, 5% aqueous HCl, NaHCO3, and brine, and then it
was dried over Na2SO4. Solvents were evaporated and the
residue was chromatographed on a silica gel column (CH2Cl2/
MeOH, 90:1 f 80:1) to give product 49 and 50 (1.63 g, 69%)
as a solid. The E/Z ratio was 1:1. UV max (EtOH): 287 nm (ꢀ
Ack n ow led gm en t. Our thanks are due to L. M.
Hryhorczuk from the Central Instrumentation Facility,
Department of Chemistry, Wayne State University (R.
J . Hood, Director) for mass spectra. The work described
herein was supported by U.S. Public Health Service
Research Grant RO1-CA32779 (J .Z.) from the National
Cancer Institute and Contract NO1-AI35177 (E.R.K.)
from the National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Bethesda, MD.
J O000276P