Enantioselective Synthesis and Conformational Study of Cyclohexene Carbocyclic Nucleosides

Article abstract of DOI:10.1021/jo9908288

Enantioselective synthesis of a new family of unsaturated six-membered carbocyclic nucleosides using (R)-(-)-carvone as starting material is described. Introduction of the base moiety via Mitsunobu reaction proceeded regio- and stereoselectively and with good chemical yield, while the Pd-coupling approach failed. ¹H NMR study and molecular modeling show the adenine compound exists in an equilibrium of ³H₂ and ²H₃ conformers (ratio 7:3) in favor of the 3′-endo half-chair conformation, with the base oriented in a pseudoaxial position. This conformational preference can be explained by the π→σ*_C1′-N1 interaction involving the antibonding orbital of the C1′-N bond.

Full text of DOI:10.1021/jo9908288

7820
J . Org. Chem. 1999, 64, 7820-7827
En a n tioselective Syn th esis a n d Con for m a tion a l Stu d y of
Cycloh exen e Ca r bocyclic Nu cleosid es
J ing Wang and Piet Herdewijn*
Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, Katholieke Universiteit Leuven,
Minderbroedersstraat 10, B-3000 Leuven, Belgium
Received May 19, 1999
Enantioselective synthesis of a new family of unsaturated six-membered carbocyclic nucleosides
using (R)-(-)-carvone as starting material is described. Introduction of the base moiety via
Mitsunobu reaction proceeded regio- and stereoselectively and with good chemical yield, while the
1
Pd-coupling approach failed. H NMR study and molecular modeling show the adenine compound
3
exists in an equilibrium of H2 and 2H3 conformers (ratio 7:3) in favor of the 3′-endo half-chair
conformation, with the base oriented in a pseudoaxial position. This conformational preference
can be explained by the π f σ*C1′-N1 interaction involving the antibonding orbital of the C1′-N
bond.
In tr od u ction
Most antiviral compounds belong to the nucleoside
field, and the development of new modified nucleosides
as antiviral agents has remained a very active field of
research. One particularly interesting domain of antiviral
nucleoside research is that of carbocyclic nucleosides. In
these nucleoside analogues the ring oxygen atom is
replaced by a methylene group. Due to the absence of
the ring oxygen atom, the anomeric effect as well as the
gauche effects of O-4′ with 3′-OH and/or 2′-OH are
removed. This research has led to the discovery of potent
and selective antiviral agents.1 Our current work has
been focusing on six-membered carbocyclic nucleosides
and is based on the discovery that the hexitol nucleosides
1 (Figure 1) were found to exhibit antiviral activity.2 We
synthesized their carbocyclic congeners 2, but these
compounds did not demonstrate antiviral activity.3 From
a conformational point of view, this different biological
behavior was initially explained by the fact that these
(1) (a) Herdewijn, P.; De Clercq, E.; Balzarini, J .; Vanderhaeghe,
H. J . Med. Chem. 1985, 28, 550-555. (b) Agrofoglio, L.; Suhas, E.;
Farese, A.; Condom, R.; Challend, S. R.; Earl, R. A.; Guedj, R.
Tetrahedron 1994, 50, 10611-10670. (c) Marquez, V. E.; Lim, M.-U.
Med. Res. Rev. 1986, 6, 1-40. (d) Yaginuma, S.; Muto, N.; Tsujino,
M.; Sudate, Y.; Hayashi, M.; Ohani, M. J . Antibiot. 1981, 34, 359-
366. (e) Somekawa, K.; Hara, R.; Kinnami, K.; Muraoka, F.; Suishu,
T.; Shimo, T. Chem. Lett. 1995, 407. (f) Slusarchyk, W.; Bisacchi, G.
S.; Field, A. K.; Hockstein, D. R.; J acobs, G. A.; McGeever-Rubin, B.;
Tino, J . A.; Tuomari, A. V.; Yamanaka, G. A.; Young, M. G.; Zahler,
R. J . Med. Chem. 1992, 35, 1799. (g) Norbeck, D. W.; Kern, E.; Hayashi,
S.; Rosenbrook, W.; Sham, H.; Herrin, T.; Plattner, J . J .; Erickson, C.;
Clement, J .; Swanson, R.; Shipkowitz, N.; Hardy, D.; Marsh, K.; Arnett,
G.; Shannon, W.; Broder, S.; Mitsuya, H. J . Med. Chem. 1990, 33,
1281-1285. (h) Vince, R.; Hua, M. J . Med. Chem. 1990, 33, 17-21. (i)
Tsai, C.-C., Follis, K. E.; Sabo, A.; Beck, T. W.; Grant, R. F.;
Bischofberger, N.; Benveniste, R. E.; Black, R. Science 1995, 270,
1197-1199. (j) Cheng, C.-M.; Shimo, T.; Somekawa, K.; Baba, M.
Tetrahedron 1998, 54, 2031-2040. (k) Csuk, R.; Von Scholz, Y.
Teterahedron, 1995, 51, 7139-7206.
(2) (a) Verheggen, I.; Van Aerschot, A.; Toppet, S.; Snoeck, R.;
J annsen, G.; Balzarini, J .; De Clercq, E.; Herdewijn, P. J . Med. Chem.
1993, 36, 2033-2040. (b) Verheggen, I.; Van Aerschot, A.; Van
Meervelt, L.; Rozenski, J .; Wiebe, L.; Snoeck, R.; Andrei, G.; Balzarini,
J .; Claes, P.; De Clercq, E.; Herdewijn, P. J . Med. Chem. 1995, 38,
826-835. (c) Ostrowski, T.; Wroblowski, B.; Busson, R.; Rozenski, J .;
De Clercq, E.; Bennett, M. S.; Champness, J . N.; Summers, W. C.;
Sanderson, M. R.; Herdewijn, P. J . Med. Chem. 1998, 4343-4353. (d)
De Winter, H.; Lescrinier, E.; Van Aerschot, A.; Herdewijn, P. J . Am.
Chem. Soc. 1998, 120, 5381-5394.
F igu r e 1. Conformational equilibrium of anhydrohexitol,
cyclohexane, and cyclohexene nucleoside analogues.
two families exist in opposite chair conformations. In
addition to anomeric effects and gauche effects, steric
effects play an important role in the conformational
preference of these nucleoside analogues. Indeed, the
hexitol nucleosides 1 exist predominantly in the 1C4
conformation, with the base occupying an axial position,
while their carbocyclic congeners 2a adopt the opposite
4C1 conformation having the base in an equatorial posi-
tion. The hexitol nucleoside can be considered as a mimic
of a furanose nucleoside frozen in the 3′-endo conforma-
tion. In an attempt to force the carbocyclic congeners of
10.1021/jo9908288 CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/21/1999

Synthesis of Cyclohexene Carbocyclic Nucleosides
J . Org. Chem., Vol. 64, No. 21, 1999 7821
1
hexitol nucleosides into the C4 conformation, we intro-
duced an additional R-oriented hydroxyl group at C5′
1
4
(2b), but according to H NMR analysis, the C1 confor-
mation with equatorial base is still preferred, despite the
presence of three axial substituents. Likewise, com-
pounds 2b did not show antiviral activity.3b
The antiviral activity of a nucleoside analogue is the
result of a complex interaction with several metabolic
viral/human enzymes. It is generally accepted that the
structural and conformational requirements of nucleo-
sides to function as substrates or inhibitors for the
different metabolic enzymes may be different. We, re-
cently cocrystallized the antiviral hexitol nucleoside 1 in
the active site of herpes virus type 1 thymidine kinase
and observed a chair inversion2c when the nucleoside
analogue is bound in the active site of the enzyme (1C4 is
the energetically most stable conformation in solution,
while in the crystal form of the enzyme the compound is
bound in the 4C1 conformation). Moreover, as oligonucleo-
tides composed of 1 hybridize with RNA and DNA only
1
when the monomeric nucleotides adopt the C4 confor-
mation,2d we expect that this conformation might be
important for the hexitol nucleotides to be recognized by
viral DNA polymerases. It can therefore be advantageous
for antiviral activity if a nucleoside can adopt several
conformations that are interconvertable. In this way, the
conformation can adapt to different enzymatic require-
ments. To reduce the energy difference between different
conformers of carbocyclic six-membered nucleosides, so
that interconversion is facilitated, we introduced a double
bond in the six-membered ring and obtained a carbocyclic
cyclohexene nucleoside 3.3d Not only are cyclohexene
derivatives such as 3 more flexible than cyclohexanes 2,
molecular mechanics calculations show that the energy
F igu r e 2. Comparison between the two lowest energy half-
2
chair conformations (3H2 and H3) of a cyclohexene nucleoside
with a normal nucleoside with its sugar moiety modeled in
the two most common puckering conformations (C3′-endo and
2
C2′-endo). 3H2 versus 3′-endo and H3 versus 2′-endo. The base
is adenine. Figure produced with a locally modified version of
Molscript.24
3
2
difference between the H2 and H3 conformations of the
cyclohexene nucleoside 3 is low (1.6 kJ /mol) and that the
half-chair conformation with the base in a pseudoaxial
position (3H2) is preferred. This conformation is a good
mimic of the geometry of the active hexitol nucleoside 1
exo double bond of cyclohexene 6b to afford hydroxy-
methyl-substituted 7b with the correct stereochemistry
at C4. Precursor 6a provided us with an ideal starting
material for the synthesis of 3 as it has (1) a protected
hydroxyl group at C3, (2) a protected hydroxyl substitu-
ent at C1, which at a final stage can be used to introduce
a base moiety with retention of the configuration using
Pd-chemistry, and (3) a free hydroxyl group at C5, which
could be used to introduce the double bond.
The most straightforward approach seemed to intro-
duce the C5-C6 double bond via conversion of the OH
at C5 into a suitable leaving group, followed by a
regioselective elimination. The latter might be achieved
via a E2-type elimination reaction by treatment with
base, which requires a neighboring hydrogen trans to the
leaving group, only available on C6. To explore this
strategy, alcohol 6a was converted into diol 7a via
hydroboration using 9-BBN in THF as described for 7b.3b
The reaction gave 7a as the major isomer, together with
a small amount of epimer 8a . The â-stereochemistry at
C4 was easily established by NMR spectrometry. Selec-
tive protection of the primary hydroxyl group of 7a
(TBDMSCl, imidazole, DMF) gave 9 (Scheme 2), and the
leaving group was introduced (MsCl, Et3N, dichlo-
romethane) to give 10. However, upon treatment of
mesylate 10 with DBU4 in toluene, cyclohexene 11 was
not formed. More vigorous reaction conditions (KOH,
H2O-THF),5 likewise, failed to yield the unsaturated
compound 11. Direct elimination of the 5-OH of 9 under
1
in its C4 form. Moreover, the electron-rich double bond
may function as a mimic of the furanose oxygen atom.
3
2
As shown in Figure 2, the H2 and H3 conformations of
3 might mimic the C3′-endo and C2′-endo conformations
of a furanose nucleoside, respectively. In summary, such
cyclohexene nucleoside may be considered as the best six-
membered-ring mimic of a natural furanose nucleoside.
We hereby report the enantioselective synthesis and
the conformational analysis of this new series of six-
membered cyclohexene nucleosides 3.
Resu lts a n d Discu ssion
Recently, we developed an enantioselective approach
to the synthesis of six-membered carbocyclic nucleosides
of type 2b (R ) OH) starting from (R)-(-)-carvone3b (4,
Scheme 1). The key step involved hydroboration of the
(3) (a) Maurinsh, Y.; Schraml, J .; De Winter, H.; Blaton, N.; Peeters,
O.; Lescrinier, E.; Rozenski, J .; Van Aerschot, A.; De Clercq, E.; Busson,
R.; Herdewijn, P. J . Org. Chem. 1997, 62, 2861-2871. (b) Wang, J .;
Busson, R.; Blaton, N.; Rozenski, J .; Herdewijn, P. J . Org. Chem. 1998,
63, 3051-3058. (c) Maurinsh, Y.; Rosemeyer, H.; Esnoef, R.; Medve-
dovici, A.; Wang, J .; Ceulemans, G.; Lescrinier, E.; Hendrix, C.; Busson,
R.; Sandra, P.; Seela, F.; Van Aerschot, A.; Herdewijn, P. Chem. Eur.
J . 1999, 5, 2139-2150. (d) For related carbocylic cyclohexene nucleo-
sides, see: Katagiri, N.; Ito, Y.; Shiraishi, T.; Maruyama, T.; Sato, Y.;
Kaneko, C. Nucleosides Nucleotides 1996, 15, 631-647. Konkel, M.
J .; Vince, R. Tetrahedron 1996, 52, 799-808. Konkel, M. J .; Vince, R.
Nucleosides Nucleotides 1995, 14, 2061-2077.
(4) Williams, R. M.; Maruyama, L. K. J . Org. Chem. 1987, 52, 4044-
4047.

7822 J . Org. Chem., Vol. 64, No. 21, 1999
Wang and Herdewijn
Sch em e 1
b
Sch em e 2a
F igu r e 4. Mechanism of Pd(0) coupling reaction that may
yield the desired compound C.
predominate over product D due to the presence of the
â-oriented substituent at C4. This effect is well-known
in five-membered ring systems,9 but has not yet been well
studied in six-membered rings. We tried this approach
via intermediate B.
a
Key: (a) TBDMSCl (1.2 equiv), imidazole (2 equiv), DMF, rt,
48% starting from 6a ; (b) MsCl, Et3N, CH2Cl2, 0 °C, 93%; (c) DBU,
toluene, or KOH, H2O/THF; (d) DEAD, PPh3, THF; (e) I2, PPh3,
imidazole, toluene, reflux, 34%; (f) DBU, toluene, reflux, 68%.
Diol 143b (Scheme 3) was protected as cyclic acetal 15
(2,2-dimethoxypropane, PPTS, acetone-THF),10 the Bn
group was removed (10% Pd on carbon, HCOONH4,
MeOH, reflux)11 to give alcohol 16, and oxidation of the
C5-OH (PDC, dichloromethane)12 provided ketone 17.
Cleavage of the TBDMS ether using tetrabutylammo-
nium fluoride (TBAF)13 in THF led mainly to diol 18.
However, under neutral reaction conditions (KF, 18-
crown-6, THF)14 the desired enone 19 was isolated in 62%
yield; the â-hydroxy ketone intermediate 20 could not be
detected. The critical reduction of enone 19 to the
corresponding allylic alcohol 22 with â-oriented OH at
C5 proved to be problematic, leading almost exclusively
to the R-isomer 21 under the applied reaction conditions
F igu r e 3. Conformational equilibrium disfavors elimination
reaction.
Mitsunobu conditions (DEAD, PPh3, THF)6 was also
unsuccessful. These failures might be explained by the
too high activation energy to interconvert the preferred
chair conformation A of 10 (Figure 3) into B, required
for an anti E2 elimination reaction. Therefore, 9 was
converted into the â-iodide 12 (I2, PPh3, imidazole,
toluene),7 with inversion of the stereochemistry at C5,
followed by treatment with DBU in refluxing toluene.
This reaction resulted in an inseparable mixture (yield
68%) of cyclohexenes 11 and 13 in a 1:2.3 ratio, respec-
tively, in favor of the undesired regioisomer.
As the previous approach failed, we turned to a new
synthetic strategy, i.e., the construction of an allylic
acetate of type A or B (Figure 4) as intermediate for the
Pd coupling reaction to introduce the base moiety.8 It can
be expected that the C1-substituted product C would
(8) For reviews, see: (a) Trost, B. M.; Verhoeven, T. R. Organopal-
ladium Compounds in Organic Synthesis and in Catalysis. In Com-
prehensive Organometallic Chemistry; Wilkinson, G., Stone, F. G. A.,
Abel, E. W., Eds.; Pergamon Press: New York, 1982; Vol. 8, Chapter
57.(b) Trost, B. M. Angew. Chem. 1989, 101, 1199-1219. (c) Godleski,
S. A. Nucleophiles with Allyl-metal Complexes. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press:
New York, 1991; Vol. 4, Chapter 3.3. (d) Trost, B. M.; Verhoeven, T.
R. J . Am. Chem. Soc. 1980, 102, 4730-4743. (e) Hayashi, T.; Hagihara,
T.; Konishi, M.; Kumada, M. J . Am. Chem. Soc. 1983, 105, 7767-7768.
(9) (a) Trost, B. M.; Li, L. P.; Guile, S. D. J . Am. Chem. Soc. 1992,
114, 8745-8747. (b) Hodgson, D. M.; Witherington, J .; Moloney, B. A.
J . Chem. Soc., Perkin Trans. 1 1994, 3373-3378. (c) Akella, L. B.;
Vince, R. Tetrahedron 1996, 52(8), 2789-279. (d) Consiglio, G.;
Waymouth, R. M. Chem. Rev. 1999, 99, 257-276. (e) Granberg, K. L.;
Backvall, J .-E. J . Am. Chem. Soc. 1992, 114, 6858-6863.
(10) Kitamura, K.; Isobe, M.; Ichikawa, Y.; Goto, T. J . Am. Chem.
Soc. 1984, 106, 3252-3257.
(11) Bieg, T.; Szeja, W. Synthesis 1985, 76-77.
(5) (a) Sasaki, T.; Eguchi, S.; Toru, T. J . Am. Chem. Soc. 1969, 91,
3390-3391. (b) Kiss, J .; Burkhardt, F. Helv. Chim. Acta 1970, 53,
1000-1011.
(12) Corey, E. J .; Ensley, H. E.; Suggs, J . W. J . Org. Chem. 1976,
41, 380-381.
(13) Corey, E. J .; Venkateswarlu, A. J . Am. Chem. Soc. 1972, 94,
6190-6191.
(6) Mitsunobu, O. Synthesis 1981, 1-28.
(7) Garegg, P. J .; Samuelsson, B. J . Chem. Soc., Chem. Commun.
1979, 978-980.
(14) Liotta, C. L.; Harris, H. P. J . Am. Chem. Soc. 1974, 96, 2250-
2252.

Synthesis of Cyclohexene Carbocyclic Nucleosides
J . Org. Chem., Vol. 64, No. 21, 1999 7823
Sch em e 3a
a
Key: (a) (CH3)2C(OCH3)2, PPTS, acetone/THF (1:2), rt, 94%; (b) Pd-C (10%), HCOONH4, MeOH, reflux, 100%; (c) PDC, CH2Cl2, rt,
94%; (d) TBAF, THF, rt; (e) KF, 18-Crown-6, THF, rt, 62% 19; (f) CeCl3‚7H2O, NaBH4, MeOH, 90%; (g) PPh3, DEAD, AcOH, THF; (h)
Ac2O, DMAP, CH2Cl2, 0 °C, 95%; (i) adenine, NaH, Pd(PPh3)4, DMF/THF; (j) PPTS, MeOH, rt, 59%; (k) Bz2O, DMAP, CH2Cl2, 0 °C, 95%.
(NaBH4, CeCl3‚7H2O, MeOH15 and 9-BBN, THF16). In an
attempt to invert the stereochemistry at C5 of R-alcohol
21, the latter was subjected to a Mitsunobu-type reaction
(DEAD, PPh3, AcOH), but the desired â-acetate 23 was
not formed. However, compound 21 might be used to
synthesize the R-analogue of the aforementioned cyclo-
hexene nucleoside, interesting for conformational analy-
sis as well as for determination of antiviral activity.
The intended Pd coupling reaction was investigated on
the R-acetate 24, easily prepared from 21 (Ac2O, DMAP,
dichloromethane). When 24 was treated with the anion
(NaH) of adenine in the presence of tetrakis(triph-
enylphosphine)palladium(0)9 in DMF-THF, only 24 was
recovered and no trace of the 1R-adenine 25 could be
detected. Reasoning that this failure might be due to the
rigidity of the cyclic acetal present, 24 was treated with
PPTS17 in MeOH to give diol 26, which was then
converted into the corresponding dibenzoate 27 (Bz2O,
DMAP, dichloromethane). However, upon subjection of
27 to the same reaction conditions for coupling as applied
above to 24, the expected 1R-adenine product 28 could
not be isolated.
The above failure having exhausted the possibilities
of the Pd coupling strategy, the most reliable alternative
for the introduction of the base moiety seemed via a
Mitsunobu reaction, i.e., by substitution with inversion
of the configuration of an R-oriented hydroxyl group at
C1. Therefore, we had to synthesize an appropriately
protected precursor 7c. Epoxide 5b (Scheme 1, R1 ) Bn)
was converted into 6c under the reported conditions3b
(LiTMP and Et2AlCl in benzene-toluene 1:1) in 79%
yield. Hydroboration of 6c with 9-BBN in THF afforded
7c as the major isomer (74%), together with its epimer
8c (20%). Similar to the configurational assignment of
7a and 7b, the â-stereochemistry at C4 of 7c was
1
established by H NMR. The primary hydroxyl group of
7c was selectively protected using 1.2 equiv of TBDMSCl
and imidazole in DMF to give 29 (70%, Scheme 4),
followed by conversion of the free alcohol at C5 into the
corresponding mesylate 30 by treatment with MsCl and
Et3N in dichloromethane. Hydrogenolytic cleavage of the
benzyl ether at C1 using 20% Pd(OH)2 on carbon in the
presence of cyclohexene18 in MeOH gave 31 in low yield
(21%), which could be improved to 76% by the use of 10%
11
Pd on carbon and HCOONH4 in refluxing MeOH.
Oxidation of alcohol 31 using PDC in dichloromethane
gave a mixture of ketone 32 and enone 33 in a combined
yield of 39%. However, using MnO219 in dichloromethane,
an incomplete but clean reaction took place. The ketone
32 was not isolated, enone 33 was obtained in 48% yield,
and recovered 31 (47%) could be recycled. Finally, enone
33 was reduced using NaBH4 in the presence of CeCl3‚
7H2O in MeOH and gave the desired R-alcohol 34 as a
single isomer in almost quantitative yield. The stereo-
chemistry of 34 was confirmed by 1H NMR spectral data.
In CDCl3, conformation A (Figure 5), with the three
substituents in a pseudoaxial position, predominates due
to intramolecular hydrogen bonding between the C1-
OH and C3-OTBDMS groups, while in DMSO-d6 it
adopts conformation B. This reflects the much lower
axial-equatorial energy differences in cyclohexenes as
compared to the corresponding cyclohexanes.
With key intermediate 34 in hand, the base moiety
(adenine) was introduced under Mitsunobu reaction
(15) Gemal, A. L.; Luche, J . L. J . Am. Chem. Soc. 1981, 103, 5454-
5459.
(16) Krishnamurthy, S.; Brown, C. H. J . Org. Chem. 1975, 40, 1864-
(18) Kitamura, K.; Isobe, M.; Ichikawa, Y.; Goto, T. J . Am. Chem.
Soc. 1984, 106, 3252-3257.
(19) Rao, A. V. R.; Reddy, S. P.; Reddy, E. R. J . Org. Chem. 1986,
51, 4158-4159.
1965.
(17) Van Rijsbergen, R.; Anteunis, M. J . O.; De Bruyn, A. Carbohydr.
Chem. 1983, 2, 395.

7824 J . Org. Chem., Vol. 64, No. 21, 1999
Wang and Herdewijn
Sch em e 4a
a
Key: (a) TBDMSCl (1.2 equiv), imidazole (1.5 equiv), DMF, rt, 70%; (b) MsCl, Et3N, CH2Cl2, 0 °C, 92%; (c) Pd-C (10%), HCOONH4,
MeOH, reflux, 76%; (d) MnO2, CH2Cl2, rt, 48% and 47% recovery of 31; (e) NaBH4, CeCl3‚7H2O, MeOH, 0 °C f rt, 91%.
Recently, we reported3a a synthesis of cyclohexane
carbocyclic nucleosides 2a . However, the synthetic ap-
proach was not enantioselective and 2a was obtained as
a racemic mixture of its D- and L-form. The separation of
both isomers proved to be not easy.3c The above inter-
mediate 36 (Scheme 5) gave us the opportunity to obtain
as yet 2a (B ) adenine) in enantiopure form via reduction
of the double bond. Thus, 36 was hydrogenated using H2
under atmospheric pressure in the presence 10% pal-
ladium on carbon in MeOH at room temperature to afford
D-2a in 75% yield. The spectral data of D-2a were
superimposable with those of a DL mixture of 2a . The
enantiomeric purity of D-2a was examined by HPLC on
a chiral column. The separation of a DL mixture of 2a
together with the HPLC profile of D-2a synthesized by
F igu r e 5. 1H NMR experiment demonstrates the solvent-
dependent conformational equilibrium of compound 34.
the above approach is depicted in ref 3c. Its enantiomeric
purity proved to be 99%, at the same time establishing
the high enantiomeric purity of 36.
conditions. Upon treatment of 34 with adenine in the
presence of DEAD and PPh3 in dioxane at room temper-
ature for 1 day, 35a was isolated in 66% yield, together
with 17% of its N7-isomer 35b (Scheme 5). Complete
deprotection of 35a using TBAF in THF at room tem-
perature afforded the desired cyclohexene carbocyclic
nucleoside 36 in almost quantitative yield. However, the
compound was contaminated with tetrabutylammonium
salts that could not be removed by standard chromato-
graphic techniques. Recently, Parlow et al.20 described a
workup procedure to remove tetrabutylammonium salts
by the direct addition to the reaction mixture of mixed
ion-exchange resins Amberlite 15 and Amberlite 15 in
the Ca2+ form. Applied to the above TBAF reaction, a
complex mixture was obtained, giving 36 in low yield.
To avoid the use of TBAF, we turned to Megron’s method:
Con for m a tion a l Stu d y
Conformational analysis of 36 was carried out using
computational methods and 1H NMR study. Molecular
mechanics calculations were performed using Macro-
Model22 with AMBER* as force field and H2O as solvent.
The global energy minimum was found to be the H2 half-
chair conformation with the adenine base moiety orient-
ing in a pseudoaxial position (Figure 1). The energy
difference between the most stable H2 and H3 confor-
mations is 1.6 kJ /mol, corresponding to a ratio of about
7:3, respectively, of these two conformers. The calculated
coupling constants (Boltzmann averaged over all 84
conformations within 50 kJ /mol of the global minimum)
are in good agreement with the experimental values
(solvent DMSO). (calcd: J 1′,2′eq ) 4.9 Hz, J 1′,2′ax ) 4.9 Hz,
J 2′eq,3′ ) 3.0 Hz, J 2′ax,3′ ) 9.2 Hz; exptl: J 1′,2′eq ) 4.9 Hz,
J 1′,2′ax ) 5.3 Hz, J 2′eq,3′ ) 2.9 Hz, J 2′ax,3′ ) 9.3 Hz). This
result confirms the expected easy interconversion among
the different conformers in a six-membered carbocyclic
nucleoside by the introduction of a double bond in the
ring.
3
3
2
21
compound 35a was treated with potassium tert-
butoxide in DMF at room temperature. However, only a
complex reaction mixture was obtained, due to the strong
basic character of the reaction conditions. Finally, 35a
was treated with a 3:1 mixture of TFA and H2O at room
temperature, which smoothly gave 36 in 54% overall yield
starting from 34. According to our experience, this is the
best procedure to cleave TBDMS ethers of this type
of compound. Finally, 36 was purified by reversed-
phase HPLC for analysis and determination of biological
activity.
The conformation of a nucleoside is determined by
competing steric and stereoelectronic effects. In the case
of hexitol nucleosides 1 and their saturated carbocyclic
congeners 2, the conformations are mainly controlled by
steric effects such as 1,3-diaxial repulsions. Because the
(20) Parlow, J . J .; Vazquez, M. L.; Flynn, D. L. Bioorg. Med. Chem.
Lett. 1998, 8, 2391-2394.
(21) Megron, G.; Vasquezy, F.; Galderon, G.; Cruz, R.; Gavino, R.;
Islas, G. Synth. Commun. 1998, 26(16), 3021-3027.
(22) Mohamadi, F.; Richards, N. G. J .; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J .
Comput. Chem. 1990, 11, 440-467.

Synthesis of Cyclohexene Carbocyclic Nucleosides
J . Org. Chem., Vol. 64, No. 21, 1999 7825
Sch em e 5
conformations with equatorially and axially oriented base
in the carbocyclic six-membered ring is therefore signifi-
cantly reduced and the interconversion among them in
a biological system might be easily possible.
The determination of the antiviral activity of 36 is in
progress and will be published separately.
Con clu sion
We have developed an enantioselective approach to-
ward the synthesis of cyclohexene carbocyclic nucleosides
starting from (R)-carvone 4. The synthetic methodology
makes use of a Mitsunobu reaction as the key step to
introduce the heterocyclic base moiety. The reaction
proved to be efficient as well as regio- and stereoselec-
tive, while the commonly applied palladium-mediated
F igu r e 6. Comparison of anomeric effect in furanose nucleo-
sides with π f σ*C1′-N effect in cyclohexene nucleosides.
axial free electron pair of the ring oxygen atom in 1 is
smaller than the axial hydrogen in the corresponding
position in 2, compound 1 favors the 1C4 conformation
and compound 2 the 4C1 conformation. As a consequence,
the axial position of the base predominates in 1, while
their carbocyclic congeners 2 have an equatorially posi-
tioned base moiety. The conformation of the cyclohexene
nucleosides 3, which can be considered as a mimic of
furanose nucleosides in which the ring oxygen atom is
replaced by a double bond, is controlled by steric effects
and by the π f σ*C1′-N interaction between the C5′-C6′
double bond and the heterocyclic aglycon (Figure 6). The
π f σ*C1′-N effect is based on a similar principle as the
anomeric effect and can be explained as an overlap
between the antibonding of C1′-N and the orbitals of the
π bond. In a 2′-deoxyfuranose nucleoside, the anomeric
effect favors the N-conformation while the gauche effect
(O4′-C4′-C3′-O) favors the S conformation. In the
cyclohexene nucleosides, the anomeric effect is taken over
by the π f σ*C1′-N interaction. This interaction drives
1
coupling strategy was unsuccessful. H NMR and com-
putation results show that in solution the synthesized
3
adenine derivative 36 exists predominantly in a H2 half-
chair conformation with the adenine base orienting in a
3
pseudoaxial position. The energy difference between H2
2
and H3 is, however, low. This compound may therefore
be considered as an ideal mimic of a furanose nucleoside,
showing two low energy conformations with a preference
for the “3′-endo conformation”. This is also the preferred
1
conformation of a hexitol nucleoside, in the C4 conforma-
tion. Moreover, the easy interconversion among both
conformers might be an essential factor for antiviral
activity.
Exp er im en ta l Section
All analytical methods are previously described.3b
(1R,3S,5R)-5-Ben zyloxy-3-(ter t-bu tyld im eth ylsilyloxy)-
2-m eth ylen ecycloh exa n ol (6c). A solution of 2,2,6,6-tetra-
methylpiperidine (TMP, 27.3 mL, 162 mmol) in dry benzene
(80 mL) and dry toluene (80 mL) was cooled to 0 °C under N2,
and a solution of n-BuLi in hexane (1.6 M, 64.8 mL, 162 mmol)
was added dropwise. The resulting mixture was stirred at 0
°C for 10 min, and a solution of Et2AlCl (1.8 M, 90 mL, 162
mmol) in toluene was slowly added over a period of 1 h. The
reaction was stirred for an additional 30 min. A solution of
5b (14.1 g, 40.5 mmol) in benzene (30 mL) was added slowly.
The reaction mixture was stirred at 0 °C for 3 h and then
poured into an ice-cold NH4Cl solution (300 mL). A 3 N HCl
solution was added until a clear emulsion was obtained. The
layers were separated, and the aqueous layer was extracted
with EtOAc (3×). The combined organic layers were washed
3
3
the H2 a 2H3 equilibrium toward the H2 conformation,
in which the base moiety is pseudoaxially oriented. Such
an effect has been well studied in a 2′,3′-unsaturated
pentopyranosyl nucleoside system.23 The absence of a ring
oxygen atom in 3 facilitates conformational studies due
to the loss of the gauche effect. The pseudo-half-chair
conformation of 3, due to the presence of the double bond,
also diminishes 1,3-diaxial repulsion as found with
hexitol nucleosides. The energy difference between the
(23) Polak, M.; Doboszewski, B.; Herdewijn, P.; Plavec, J . J . Am.
Chem. Soc. 1997, 119, 9782-9792.
(24) Kraulis, P. J . J . Appl. Crystallogr. 1991, 24, 946-950.

7826 J . Org. Chem., Vol. 64, No. 21, 1999
Wang and Herdewijn
with H2O and brine, dried over Na2SO4, and concentrated. The
residue was chromatographed on silica gel (n-hexanes-EtOAc
10:1) to give 6c (10.2 g, 71%) as a light-yellow oil: 1H NMR
(CDCl3) δ 0.09 (s, 6H), 0.92 (s, 9H), 1.90 (m, 4H), 2.69 (d, 1H,
J ) 7.3 Hz, OH), 4.05 (m, 1H), 4.45 (m, 2H), 4.58 (s, 2H), 5.05
(s, 1H), 5.07 (s, 1H), 7.33 (m, 5H); 13C NMR (CDCl3) δ -5.1
(q), 18.0 (s), 25.7 (q), 40.7 (t), 40.9 (t), 70.4 (d and t, overlapped),
70.8 (d), 71.3 (d), 107.1 (t), 127.5 (d), 128.4 (d), 138.7 (s), 150.7
(s).
(1R,2S,3S,5R)-5-Ben zyloxy-3-(ter t-bu tyld im eth ylsilyl-
oxy)-2-h yd r oxym eth yl-cycloh exa n ol (7c) a n d Its Ep im er
8c. To a solution of 6c (10.8 g, 31.03 mmol) in dry THF (80
mL) at 0 °C under N2 was added slowly a solution of 9-BBN
in THF (0.5 M, 155 mL, 77.58 mmol). The reaction mixture
was slowly warmed to room temperature overnight. The
reaction was cooled to 0 °C and treated sequentially with EtOH
(30 mL), a 2 N NaOH solution (60 mL), and a 35% H2O2
solution (60 mL) under stirring. The resulting mixture was
stirred at room temperature for 24 h and then poured into a
mixture of EtOAc (300 mL) and H2O (300 mL). The layers were
separated, and the aqueous layer was extracted with EtOAc
(3×). The combined organic layers were washed with H2O and
brine, dried over Na2SO4, and concentrated. The crude product
was separated on silica gel (n-hexanes-EtOAc 5:1, then 1:1)
to yield 7c (8.4 g, 74%) and epimer 8c (2.28 g, 20%) as a light-
yellow oils.
of MsCl (1.3 mL, 16.87 mmol). The reaction was stirred at 0
°C for 1 h and treated with ice. The resulting mixture was
separated, and the aqueous layer was extracted with CH2Cl2
(2×). The combined organic layers were washed with a diluted
HCl solution, H2O, and brine, dried over Na2SO4, and concen-
trated. The residue was chromatographed on silica gel (n-
hexanes-EtOAc 5:1) to afford 30 (5.81 g, 92%) as a white
solid: mp 100-101 °C; 1H NMR (CDCl3) δ 0.08 (2s, 12H), 0.89
(s, 9H), 0.90 (s, 9H), 1.43 (ddd, 1H, J ) 13.9, 10.0, 2.8 Hz),
1.62 (tt, 1H, J ) 10.2, 2.0 Hz), 1.71 (ddd, 1H, J ) 12.8, 10.6,
2.2 Hz), 2.24 (br-d, 1H, J ) 13.9 Hz), 2.69 (br-d, 1H, J ) 12.8
Hz), 3.01 (s, 3H), 3.74 (dd, 1H, J ) 9.9, 2.2 Hz), 3.89 (m, 1H),
3.91 (dd, 1H, J ) 9.9, 1.8 Hz), 4.19 (td, 1H, J ) 10.0, 4.7 Hz),
4.45 (d, 1H, J ) 12.0 Hz), 4.57 (d, 1H, J ) 12.0 Hz), 5.13 (td,
1H, J ) 10.6, 4.8 Hz), 7.33 (m, 5H); 13C NMR (CDCl3) δ -5.6
(q), -5.3 (q), -4.6 (q), -3.7 (q), 17.9 (s), 25.8 (q), 35.5 (t), 38.5
(t), 38.8 (q), 51.8 (d), 56.9 (t), 65.1 (d), 70.1 (t), 72.0 (d), 77.5
(d), 127.4 (d), 128.4 (d), 138.5 (s); LISMS(GLY/NBA) 559 (M
+ H)+; HRMS calcd for C27H51O6SSi2 (M + H)+ 559.2945, found
559.2979. Anal. Calcd for C27H50O6SSi2: C, 58.02; H, 9.02.
Found: C, 57.96; H, 8.82.
(1S,3R,4R,5S)-4-ter t-Bu t yld im et h ylsilyloxym et h yl-5-
ter t-bu tyld im eth ylsilyloxy-3-m eth a n esu lfon yloxycyclo-
h exa n ol (31). A mixture of 30 (3.5 g, 6.27 mmol), Pd/C (10%,
4.4 g), and HCOONH4 (2.2 g) in MeOH (100 mL) was refluxed,
and 2 × 1.1 g of HCOONH4 was added every 3 h. The reaction
was refluxed until all the starting material was consumed
(total 14 h). After being cooled to room temperature, the
reaction mixture was filtered through Celite and the residue
was washed with CH2Cl2 (3×). The filtrate was concentrated
to afford crude 31 (2,83 g, 97%) as a white solid, which was
used as such for the next step: mp 135-137 °C; 1H NMR
(CDCl3) δ 0.08, 0.09 (2s, 12H), 0.89 (s, 9H), 0.92 (s, 9H), 1.43-
1.68 (m, 3H), 1.83 (ddd, 1H, J ) 13.2, 10.6, 2.8 Hz), 2.07 (br-
d, 1H, J ) 13.2 Hz), 2.44 (br-d, 1H, J ) 13.2 Hz), 3.02 (s, 3H),
3.72 (dd, 1H, J ) 10.0, 2.4 Hz), 3.90 (dd, 1H, J ) 10.0, 2.4
Hz), 4.19 (td, 1H, J ) 10.6, 4.1 Hz), 4.26 (m, 1H), 5.14 (td, 1H,
J ) 10.6, 4.7 Hz); 13C NMR (CDCl3) δ -5.6 (q), -5.3 (q), -4.7
(q), -3.8 (q), 17.9 (s), 25.8 (q), 38.8 (q), 38.9 (t), 40.8 (t), 51.7
(d), 57.1 (t), 64.9 (d), 65.5 (d), 77.3 (d); LISMS (GLY/NBA) 469
(M + H)+; HRMS calcd for C20H45O6SSi2 (M + H)+ 469.2475,
found 469.2453. Anal. Calcd for C20H44O6SSi2: C, 51.24; H,
9.46. Found: C, 51.24; H, 9.36.
(4R,5S)-4-ter t-Bu tyld im eth ylsilyloxym eth yl-5-ter t-bu -
tyld im eth ylsilyloxycycloh ex-2-en -1-on e (33). A mixture of
crude 31 (2.83 g, 6.27 mmol) and MnO2 (13.6 g, 156.8 mmol)
in dry CH2Cl2 (100 mL) was stirred vigorously at room
temperature for 21 h. The reaction mixture was filtered
through Celite and washed with CH2Cl2. The filtrate was
concentrated, and the residue was chromatographed on silica
gel (n-hexanes-EtOAc 5:1, then 1:2) to yield starting material
31 (1.56 g, 53%) and enone 33 (920 mg, 40% over two steps)
as a light-yellow oil (solid upon storing in the refrigerator):
1H NMR (CDCl3) δ 0.07 (s, 12H), 0.89 (s, 18H), 2.50 (m, 1H),
2.46 (dd, 1H, J ) 16.1, 10.6 Hz), 2.72 (dd, 1H, J ) 16.1, 4.8
Hz), 3.73 (dd, 1H, J ) 9.9, 5.6 Hz), 3.85 (dd, 1H, J ) 9.9, 4.4
Hz), 4.09 (ddd, 1H, J ) 10.6, 8.1, 4.8 Hz), 6.06 (dd, 1H, J )
10.2, 2.6 Hz), 6.88 (dd, 1H, J ) 10.2, 2.6 Hz); 13C NMR (CDCl3)
δ -5.6 (q), -5.5 (q), -5.1 (q), -4.4 (q), 17.8 (s), 18.2 (s), 25.6
(q), 25.8 (q), 47.1 (t), 48.0 (d), 61.8 (t), 68.0 (d), 130.2 (d), 150.6
(d), 199.0 (s); LISMS (THGLY/NBA) 371 (M + H)+; HRMS
calcd for C19H39O3Si2 (M + H)+ 371.2438, found 371.2432.
(1R ,4R,5S)-5-(ter t-Bu t yld im et h ylsilyloxy)-4-(ter t-b u -
tyld im eth ylsilyloxym eth yl)cycloh ex-2-en -1-ol (34). To a
solution of 33 (920 mg, 2.49 mmol) in MeOH (35 mL) at room
temperature under N2 was added CeCl3‚7H2O (1.39 g, 3.73
mmol). The mixture was stirred for 0.5 h, and a clear solution
was obtained. NaBH4 (113 mg, 2.99 mmol) was added in
portions and H2 evolved. The reaction mixture was stirred for
1 h and quenched with H2O. The mixture was stirred for 15
min and concentrated. The residue was diluted with EtOAc,
washed with H2O and brine, dried over Na2SO4, and concen-
trated. The residue was chromatographed on silica gel (n-
hexanes-EtOAc 10:1) to give 34 (844 mg, 91%) as a colorless
oil: 1H NMR (500 MHz, CDCl3) δ 0.04 (s, 3H), 0.05 (s, 3H),
7c: 1H NMR (500 MHz, CDCl3) δ 0.09 (2s, 6H), 0.91 (s, 9H),
1.52 (ddd, 1H, J ) 13.1, 10.1, 2.8 Hz), 1.54 (ddd, 1H, J ) 13.1,
10.1, 3.1 Hz), 1.69 (tdd, 1H, J ) 10.0, 7.5, 4.1 Hz), 2.10 (dt,
1H, J ) 13.1, 4.1 Hz), 2.16 (dt, 1H, J ) 13.1, 4.1 Hz), 2.71 (s,
1H), 3.11 (s, 1H), 3.78 (dd, 1H, J ) 10.1, 7.5 Hz), 3.85 (td, 1H,
J ) 10.0, 4.2 Hz), 3.86 (m, 1H), 3.97 (br-td, 1H, J ) 10.1, 4.1
Hz), 4.04 (br-dd, 1H, J ) 10.1, 4.1 Hz), 4.51 (s, 2H), 7.26-
7.37 (m, 5H); 13C NMR (CDCl3) δ -5.0 (q), -4.3 (q), 17.8 (s),
25.7 (q), 38.1 (t), 38.4 (t), 53.2 (d), 63.4 (t), 68.0 (d), 69.4 (d),
70.3 (t), 72.4 (d), 127.4 (d), 127.6 (d), 128.4 (d), 138.7 (s); LISMS
(THGLY) 367 (M+H)+; HRMS calcd for C20H35O4Si (M + H)+
367.2305, found 367.2341.
8c: 1H NMR (CDCl3) δ 0.07 (s, 3H), 0.08 (s, 3H), 0.85 (s,
9H), 1.40-1.87 (m, 3H), 2.25 (dm, 1H, J ) 13.2 Hz), 2.48 (dm,
1H, J ) 13.2 Hz), 3.69-4.20 (m, 6H), 4.33 (m, 1H), 4.53 (d,
1H, J ) 11.7 Hz), 4.62 (d, 1H, J ) 11.7 Hz), 7.33 (m, 5H), 8.79
(s, 1H); 13C NMR (CDCl3) δ -5.6 (q), -5.0 (q), 21.9 (s), 25.5
(q), 39.2 (2t, overlapped), 45.9 (d), 61.3 (t), 69.0 (d), 69.4 (d),
70.4 (t), 70.8 (d), 127.6 (d), 127.7 (d), 128.4 (d), 138.6 (s); LISMS
(THYLY) 367 (M + H)+; HRMS calcd for C20H35O4Si (M + H)+
367.2305, found 367.2335.
(1R,2R,3S,5S)-5-Ben zyloxy-3-(ter t-bu tyld im eth ylsilyl-
oxy)-2-(ter t-bu tyld im eth ylsilyloxym eth yl)cycloh exa n ol
(29). To a solution of 7c (2.5 g, 6.83 mmol) in DMF (50 mL) at
room temperature were added imidazole (930 mg, 13.66 mmol)
and TBDMSCl (1.23 g, 8.2 mmol) in portions. The reaction was
stirred at room temperature overnight and quenched with ice.
The resulting mixture was evaporated to remove DMF, and
the residue was partitioned between EtOAc and H2O. The
layers were separated, and the aqueous layer was extracted
with EtOAc (2×). The combined organic layers were washed
with H2O and brine, dried over Na2SO4, and concentrated. The
residue was chromatographed on silica gel (n-hexanes-EtOAc
5:1) to yield 29 (2.28 g, 70%) as a light-yellow oil: 1H NMR
(CDCl3) δ 0.05, 0.06, 0.09 (3s, 12H), 0.89, 0.91 (2s, 18H), 1.53
(m, 2H), 1.72 (qd, 1H, J ) 9.5, 4.4 Hz), 2.11 (m, 2H), 3.67 (t,
1H, J ) 9.5 Hz), 3.78 (td, 1H, J ) 9.5, 4.4 Hz), 3.87 (m, 1H),
4.01 (m, 1H), 4.16 (dd, 1H, J ) 9.5, 4.4 Hz), 4.46 (d, 1H, J )
15.2 Hz), 4.48 (d, 1H, J ) 15.2 Hz), 7.33 (m, 5H); 13C NMR
(CDCl3) δ -5.7 (q), -5.1 (q), -4.3 (q), 17.8, 18.0 (2s), 25.7 (2q),
37.0 (t), 38.4 (t), 52.2 (d), 66.2 (t), 67.2 (d), 70.1 (t and d
overlapped), 72.4 (d), 127.3 (d), 127.4 (d), 128.4 (d), 138.9 (s);
LISMS (GLY): 481 (M+H)+; HRMS cald for C26H49O4Si2 (M
+ H)+ 481.3169, found 481.3199.
(1R,2R,3S,5S)-5-Ben zyloxy-2-(ter t-bu tyld im eth ylsilyl-
oxym et h yl)-3-(ter t-b u t yld im et h ylsilyloxy)-1-m et h a n e-
su lfon yloxycycloh exa n e (30). To a solution of 29 (5.4 g,
11.25 mmol) in CH2Cl2 (120 mL) at 0 °C was added triethyl-
amine (7.8 mL, 56.25 mmol), followed by dropwise addition

Synthesis of Cyclohexene Carbocyclic Nucleosides
J . Org. Chem., Vol. 64, No. 21, 1999 7827
0.10 (s, 3H), 0.11 (s, 3H), 0.89 (s, 9H), 0.90 (s, 9H), 1.94 (ddd,
1H, J ) 13.7, 5.3, 3.9 Hz), 1.99 (ddd, 1H, J ) 13.7, 4.5, 2.6
Hz), 2.36 (m, 1H), 2.94 (d, 1H, J ) 9.8 Hz), 3.38 (dd, 1H, J )
10.1, 7.8 Hz), 3.56 (dd, 1H, J ) 10.1, 5.0 Hz), 4.09 (pseudo
sext, 1H, J ) 9.8, 4.5, 4.0, 3.9 Hz), 4.20 (pseudo pent, 1H, J )
5.3, 3.4, 2.6 Hz), 5.61 (dd, 1H, J ) 10.0, 3.9 Hz), 5.95 (ddd,
1H, J ) 10.0, 4.0, 1.8 Hz); 13C NMR (CDCl3) δ -5.5 (q), -5.4
(q), -4.9 (q), -4.8 (q), 18.0 (s), 18.3 (s), 25.8 (q), 25.9 (q), 35.6
(t), 46.5 (d), 63.5 (t), 64.8 (d), 67.7 (d), 127.0 (d), 131.1 (d);
LISMS (THGLY/NBA) 373 (M + H)+; HRMS calcd for C19H40O3-
Si2 (M + H)+ 373.2594, found 373.2626. Anal. Calcd for
C19H39O3Si2: C, 61.23; H, 10.82. Found: C, 61.34; H, 10.83.
9-[(1S,4R,5S)-5-(ter t-Bu tyld im eth ylsilyloxy)-4-(ter t-bu -
tyldim eth ylsilyloxym eth yl)-2-cycloh exen yl]aden in e (35a).
To a mixture of 34 (660 mg, 1.774 mmol), adenine (480 mg,
3.55 mmol), and PPh3 (931 mg, 3.55 mmol) in dry dioxane (20
mL) under N2 at room temperature was added a solution of
DEAD (565 µL, 3.55 mmol) in dry dioxane (10 mL) over a
period of 45 min. The reaction mixture was stirred at room
temperature overnight and concentrated, and the residue was
chromatographed on silica gel (CH2Cl2-MeOH 50:1, then 20:
1) to yield crude 35a (960 mg) as a yellow foam: 1H NMR
(CDCl3) δ -0.12 (s, 3H), -0.06 (s, 3H), 0.10 (s, 3H), 0.11 (s,
3H), 0.83 (s, 9H), 0.94 (s, 9H), 2.01-2.25 (m, 2H), 2.32 (m, 1H),
3.73 (dd, 1H, J ) 9.9, 4.8 Hz), 3.82 (dd, 1H, J ) 9.9, 4.4 Hz),
3.97 (ddd, 1H, J ) 10.2, 7.0, 4.0 Hz), 5.37 (m, 1H), 5.73 (s,
2H), 5.88 (ddd, 1H, J ) 9.9, 3.7, 2.5 Hz), 6.06 (ddd, 1H, J )
9.9, 2.2, 1.1 Hz), 7.86 (s, 1H), 8.39 (s, 1H); 13C NMR (CDCl3) δ
-5.5 (q), -5.4 (q), -5.0 (q), -4.6 (q), 17.8 (s), 18.3 (s), 25.6 (q),
25.9 (q), 36.5 (t), 47.2 (d), 49.6 (d), 62.9 (t), 64.5 (d), 120.2 (s),
124.4 (d), 134.9 (d), 139.9 (d), 149.8 (s), 153.0 (d), 155.5 (s);
LISMS (THGLY/NBA) 490 (M + H)+; HRMS calcd for
MeOH 20:1, then 5:1) to afford 36 (149 mg, 54% over two
steps): mp 90-92 °C; 1H NMR (CD3OD) δ 2.01-2.33 (m, 3H),
3.80 (d, 2H, J ) 4.8 Hz), 3.84 (m, 1H), 5.33 (m, 1H), 5.94 (ddd,
1H, J ) 9.9, 3.7, 2.6 Hz), 6.13 (ddd, 1H, J ) 9.9, 2.5, 1.4 Hz),
8.09 (s, 1H), 8.21 (s, 1H); 13C NMR (CD3OD) δ 37.3 (t), 47.9
(d), 51.1 (d), 63.1 (t), 64.7 (d), 120.6 (s), 125.3 (d), 136.1 (d),
141.6 (d), 150.4 (s), 153.7 (d), 157.5 (s); UV λmax (MeOH) )
260 nm; LISMS (THGLY/NBA) 262 (M + H)+; HRMS calcd
for C12H16N5O2 (M + H)+ 262.1304, found 262.1359. Anal.
Calcd for C12H15N5O2‚0.7H2O: C, 52.62; H, 6.04; N, 25.57.
Found: C, 52.62; H, 5.95; N, 25.77.
9-[(1R,3S,4R)-3-Hyd r oxy-4-h yd r oxym et h ylcycloh exa -
n yl]a d en in e (2a ). A mixture of 36 (45 mg, 0.17 mmol) and
Pd/C (10%, 40 mg) in MeOH (5 mL) was stirred under H2 at
room temperature for 24 h. The reaction mixture was cooled
to room temperature, filtered through Celite, and washed with
MeOH. The filtrate was concentrated, and the residue was
purified by reversed-phase HPLC (5% CH3CN in H2O) to yield
2a (35 mg, 78%) as a white foam: 1H NMR (CD3OD) δ 1.71
(m, 1H), 1.87-2.18 (m, 5H), 2.39 (m, 1H), 3.69 (dd, 1H, J )
14.0, 7.3 Hz), 3.74 (dd, 1H, J ) 14.0, 6.9 Hz), 4.12 (m, 1H),
4.87 (m, 1H, overlapped with HOD), 8.18 (s, 1H), 8.21 (s, 1H);
13C NMR (CD3OD) δ 22.6 (t), 28.7 (t), 36.1 (t), 53.6 (d), 51.9
(d), 63.3 (t), 68.4 (d), 120.4 (s), 141.1 (d), 150.6 (s), 153.5 (d),
157.4 (s); LISMS (THGLY/NBA) 264 (M + H)+; HRMS calcd
for C12H18N5O2 (M + H)+ 264.1460, found 264.1449.
Ack n ow led gm en t. This research was financially
supported by a grant of the Katholieke Universiteit
Leuven (GOA 97/11) and from the Flemish National
Fund of Scientific Research. We thank Dr. Klaus Roth-
enbacher for mass spectrometric analysis and Roger
Busson for NMR analysis. We are grateful to Prof. W.
Pfleiderer for elemental analysis and Dr. R. Esnouf for
computational help.
C
24H44N5O2Si2 (M + H)+ 490.3034, found 490.3058.
9-[(1S,4R,5S)-5-Hyd r oxy-4-h yd r oxym eth yl-2-cycloh ex-
en yl]a d en in e (36). Crude 35a was treated with TFA-H2O
(3:1, 40 mL) at room temperature overnight. The reaction
mixture was concentrated and coevaporated with toluene (2×).
The residue was chromatographed on silica gel (CH2Cl2-
J O9908288