Enantioselective approach to the synthesis of cyclohexane carbocyclic nucleosides

Article abstract of DOI:10.1021/jo972285c

(R)-(-)-Carvone was used as starting material for the synthesis of a new series of 2-(hydroxymethyl)-cyclohexane-1,3-diol nucleosides. The enantioselective precursors of the nucleoside analogues were obtained via a stereo- and regioselective hydroboration reaction. The compounds have equatorial oriented base moieties despite the presence of three other axial substituents.

Full text of DOI:10.1021/jo972285c

J . Org. Chem. 1998, 63, 3051-3058
3051
En a n tioselective Ap p r oa ch to th e Syn th esis of Cycloh exa n e
Ca r bocyclic Nu cleosid es
J ing Wang, Roger Busson, Norbert Blaton,† J ef Rozenski, and Piet Herdewijn*
Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, Katholieke Universiteit Leuven,
Minderbroedersstraat 10, B-3000 Leuven, Belgium, and Faculty of Pharmaceutical Sciences,
Van Evenstraat 4, B-3000 Leuven, Belgium
Received December 17, 1997
(R)-(-)-Carvone was used as starting material for the synthesis of a new series of 2-(hydroxymethyl)-
cyclohexane-1,3-diol nucleosides. The enantioselective precursors of the nucleoside analogues were
obtained via a stereo- and regioselective hydroboration reaction. The compounds have equatorial
oriented base moieties despite the presence of three other axial substituents.
In tr od u ction
Naturally occurring and synthetic carbocyclic nucleo-
sides are of broad interest as antiviral agents and as
building blocks for oligonucleotides.1,2 Their therapeutic
advantages may be attributed to their better chemical
and enzymatic stability as well as to their different
stereoelectronic properties. The difference is due to the
replacement of the ring-oxygen atom by a methylene
group and, hence, to the loss of the anomeric center.
Compared with the knowledge on five-membered ring
carbocyclic nucleosides, little is known about the confor-
F igu r e 1.
mational preference and biological activity of six-mem-
involves a stereoselective hydroboration of a 2-methyl-
enecyclohexane-1,3-diol with anti-selectivity, a regiose-
lective desilylation reaction, and a Mitsunobu type
introduction of heterocyclic rings.
(R)-(-)-carvone (4, Scheme 1) is an inexpensive and
useful chiral starting material, as illustrated by the
bered ring analogues. Recently we synthesized a series
of modified nucleosides with general formula 1 (Figure
1).3 These nucleosides can be considered as carbocyclic
congeners of the anhydrohexitol nucleosides 2.4 While
the latter show potent antiviral activity,4 the carbocyclic
analogues 1 were devoid of this activity.3 A striking
difference between both series is that the base moieties
of the anhydrohexitol nucleosides are axially oriented,
while the same bases are equatorially oriented in the case
of the carbocyclic analogues. To further study this
structure-activity relationship, we decided to synthesize
cyclohexane nucleosides of type 3. The additional hy-
droxyl group may induce an inversion of conformation
when compared with compounds of structure 1. The
synthetic strategy should take into account that we
should be able to further modify compound 3 in a
stereospecific manner. Indeed, compound 3 (where R )
H) is achiral but becomes chiral when one of the second-
ary hydroxyl groups becomes substituted or replaced by,
for example, a halogen. The enantioselective approach
presented in this work starts from (R)-(-)-carvone and
Sch em e 1
† Faculty of Pharmaceutical Sciences.
(1) (a) Marquez, V. E.; Liu, M. I. Med. Res. Rev. 1986, 6, 1-40. (b)
Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571-623. (c)
Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand, S. R.; Earl,
R. A.; Guedy, R. Tetrahedron Lett. 1994, 50, 10611-10670.
(2) Altmann, K.-H.; Imwinkelried, R.; Kesselring, R.; Rihs, G.
Tetrahedron Lett. 1994, 35, 7625-7628 and references therein.
(3) 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.
(4) (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.
asymmetric synthesis of (-)-hirsutene and its deriva-
tives.5 Its structural features make it ideally suited for
the stereocontrolled synthesis of 3; i.e., (1) a cyclohexane
ring is already present, (2) a chiral center at C1 allows
stereospecific introduction of the base moiety via trans-
formation of the isopropenyl substituent into a hydroxyl
(5) Weinge, K.; Reichert, H.; Huber-Patz, U.; Irngartinger, H. Liebigs
Ann. Chem. 1993, 4, 403-411.
S0022-3263(97)02285-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/15/1998

3052 J . Org. Chem., Vol. 63, No. 9, 1998
Wang et al.
Sch em e 2a
Sch em e 3
of larger amounts of 10. We therefore decided to first
convert the isopropenyl double bond to give the corre-
sponding ketone 8 by oxidative CdC bond cleavage using
OsO4 and NaIO4.10 This reaction could easily be per-
formed on large scale and proceeded in 83% yield. Upon
applying Baeyer-Villiger reaction conditions (CF3CO3H
in the presence of NaH2PO4)11 to 8, diol 9 was obtained
in 78% yield instead of the desired 10. To avoid epoxide
opening, the reaction was repeated under neutral condi-
tions. The oxidation was performed using m-CPBA in
the presence of a phosphate buffer pH ) 8,12 giving
acetate 10 in 73% yield. Hydrolysis of the acetate under
basic conditions (Na2CO3 in MeOH) gave 11. The hy-
droxyl group was protected as TBDMS ether using
TBDMSCl and imidazole in DMF to afford 12 in 58%
combined yield over two steps. Finally, the desired allylic
alcohol intermediate 13 with an exo double bond was
obtained in virtually quantitative yield via regioselective
opening of epoxide 12 by treatment with LiTMP/Et2AlCl13
at -65 °C for 3 h, and the alcohol function was protected
as the benzyl ether using BnBr, NaH, and tetrabutylam-
monium iodide (TBAI)14 in THF to give 14. 1H NMR
analysis showed the latter to exist in a chair conformation
with the C3-OTBDMS and C1-OBn substituents in an
equatorial position and the C5-OTBDMS group occupy-
ing an axial position.
a
(a) H2O2/NaOH, MeOH, 83%; (b) L-Selectride, THF, -65 °C;
(c) TBDMSCl, imidazole, DMF, 93% from 5; (d) 1% OsO4/KIO4,
THF, H2O, rt, 83%; (e) CF3CO3H, NaH2PO4, CH2Cl2, 0 °C, 78%;
(f) m-CPBA, CHCl3, pH ) 8 buffer solution, rt, 73%; (g) K2CO3,
MeOH, 73%; (h) TBDMSCl, imidazole, DMF, 80%; (i) LiTMP/
Et2AlCl, benzene, 0 °C, 100%; (j) NaH, BnBr, TBAI, THF, rt.
group, subsequent inversion of the configuration, and
Mitsunobu reaction, (3) an enone group allows the
introduction of a 1,3-diol function with the correct cis
stereochemistry via stereoselective epoxidation of the
double bond and reduction of the carbonyl group, and (4)
a methyl group is present at C4 that can be hydroxylated
via regioselective opening of the epoxide to give an
exocyclic double bond, followed by hydroboration. How-
ever, the success of this approach is crucially dependent
on the stereochemical outcome of the latter reaction.
Resu lts a n d Discu ssion
Epoxide 5 (Scheme 2) was obtained by a known regio-
and stereospecific epoxidation of (R)-(-)-carvone (4) in
83% yield after distillation.6 Stereoselective reduction
of the carbonyl group to obtain 6 was achieved using
L-Selectride in THF at -65 °C.7 The enantiomeric excess
The utility of the present reaction scheme is largely
dependent on the success of the regio- and stereoselective
transformation of the exo double bond at C2 of 14 into a
â-hydroxymethyl group (Scheme 3). Hydroboration of
2-methylenecyclohexanol derivatives is known to proceed
with good regioselectivity (with the borane attacking the
double bond from the least hindered site), but with poor
stereoselectivity.15 The stereoselectivity for the syn
isomer can be increased by the use of catalysts such as
Rh(PPh3)3Cl.15 However, enhancement of the selectivity
for the desired anti isomer has so far not been successful.
Hydroboration of 2-methylenecyclohexane-1,3-diol de-
rivatives as 14 has not been studied yet. One would
expect that introduction of an additional neighboring
1
at C2 was more than 90%, as established by H NMR
analysis, and the minor isomer was easily removed by
chromatography. Protection of the hydroxyl group as
TBDMS ether under standard conditions8 gave 7 in 93%
combined yield over two steps.
Oxidative degradation of the isopropenyl side chain at
C4 with retention of configuration to the corresponding
acetate 10 can be carried out by an established proce-
dure9 involving sequential ozonolysis of the double bond,
followed by Criegee rearrangement of the so-obtained
methoxy hydroperoxide intermediate. However, the
reactivity of the present epoxide moiety and scale limita-
tions of the ozonolysis reaction hampered the preparation
(10) Baggiolini, E. G.; Iacobelli, J . A.; Hennessy, B. M.; Uskokovic,
M. R. J . Am. Chem. Soc. 1982, 104, 2945-2948.
(11) J effs, P. W.; Molina, G.; Cass, M. W.; Cortese, N. A. J . Org.
Chem. 1982, 47, 3871-3875.
(6) (a) Rupe, H.; Refardt, M. Helv. Chim. Acta 1942, 25, 836-859.
(b) Klein, E.; Ohloff, G. Tetrahedron, 1963, 19, 1091-1099.
(7) (a) Brown, H. C.; Krishnamurthy, S. J . Am. Chem. Soc. 1972,
94, 7159-7161. (b) Nishiyama, S.; Ikeda, Y.; Yoshida, S.; Yamamura,
S. Tetrahedron Lett. 1989, 30, 105-108.
(8) Corey, E. J .; Venkateswarlu, A. J . Am. Chem. Soc. 1972, 94,
6190-6191.
(9) (a) Baggiolini, E. G.; Hennessy, B. M.; Iacobelli, J . A.; Uskokovic,
M. R. Tetrahedron Lett. 1987, 28, 2095-2098. (b) Aurrecoellea, J . M.;
Okamura, W. H. Tetrahedron Lett. 1987, 28, 4947-4950. (c) Schreiber,
S. L.; Liew, W.-F. Tetrahedron Lett. 1983, 24, 2363-2366. (d) Criegee,
R.; Kasper, R. J ustus Liebigs Ann. Chem. 1948, 77, 127.
(12) (a) Delay, F.; Ohloff, G. Helv. Chim. Acta 1979, 62, 2168-2173.
(b) Modern Synthetic Reactions; House, H. O., Ed.; Benjamin, Inc.,
1972; p 324.
(13) (a) Czernecki, S.; Georgoulis, C.; Provelenghiou, C. Tetrahedron
Lett. 1976, 3535-3536. (b) Kanai, K.; Sakamoto, I.; Ogawa, S.; Suami,
T. Bull. Chem. Soc. J pn. 1987, 60, 1529-1531.
(14) (a) Olofson, R. A.; Dougherty, C. M. J . Am. Chem. Soc. 1973,
95, 582-584. (b) Yasuda, A.; Tanaka, S.; Oshima, K.; Yamamoto, H.;
Nozaki, H. ibid. 1974, 96, 6513-6514.
(15) (a) Evans, D. A.; Fu, G. C.; Hoveyda, A. H. J . Am. Chem. Soc.
1988, 110, 6917-6918. (b) Evans, D. A.; Fu, G. C.; Hoveyda, A. H. J .
Am. Chem. Soc. 1992, 114, 6671-6679.

Cyclohexane Carbocyclic Nucleosides
J . Org. Chem., Vol. 63, No. 9, 1998 3053
Sch em e 4a
F igu r e 2.
R-substituent would lead to preferential attack of the
borane from the â-side and hence to an increase in syn
selectivity. Contrary to this expectation, upon treatment
of 14 with 9-BBN in THF at room temperature followed
by oxidation with hydrogen peroxide, the desired anti
isomer 15 was obtained as major product (63% starting
from 13) and the syn isomer 16 as minor compound
(16%). To the best of our knowledge, this is the first
example of the hydroboration of a 2-methylenecyclohex-
anediol derivative proceeding with good anti selectivity.
Whether the observed preferential attack of the borane
on the double bond from the R-side is due either to
complexation of the reagent involving the oxygen atoms
of the two neighboring groups or to steric hindrance of
the bulky OTBDMS group in axial position at C5 is not
clear and deserves further investigation. The two dia-
stereomers could easily be separated by chromatography.
Assignment of the relative configuration at C2 of 15
and 16 was accomplished by 1H NMR analysis. The
spectrum of 15 showed hydrogen H5 at δ ) 4.19 ppm as
a pentaplet resulting from four approximately equal
a
(a) TBAF (excess), THF, rt, 32%; (b) TBAF (1 equiv), THF, rt,
93%; (c) PhCH(OMe)2, PTSA, dioxane, 90%; (d) TBAF, THF, 93%;
(e) benzoic acid, DEAD, PPh3, dioxane; (f) K2CO3, MeOH, 72% from
20.
equatorial position. However, when 15 was treated with
1 equiv of TBAF in THF at room temperature for 3 h,
diol 18 was isolated in 93% yield as the sole product, the
equatorial TBDMS group thus having been removed
much faster. This is probably due to neighboring group
participation of the C2-CH2OH group through intramo-
lecular hydrogen bond formation which accelerates the
cleavage of the Si-O bond upon attack by fluoride anion
(Figure 3).
3
3
coupling constants J 4,5 ) J 5,6 = 2.4 Hz and H2 at δ )
1.68 ppm as a triplet of triplets including two large
3
diaxial coupling constants J 1,2 ) 3J 2,3 = 11.0 Hz. These
data are predictive for a chair conformation B (Figure 2)
with the C2-CH2OH group in an equatorial position and
anti to the substituents at C1 and C3. On the other
hand, the spectrum of 16 showed H5 at δ ) 4.14 ppm as
F igu r e 3.
3
3
a pentaplet with J 4,5 ) J 5,6 = 3.2 Hz and H2 at δ )
2.61 ppm as a pentaplet resulting from four medium
The structure of 18 was confirmed by 1H NMR in
DMSO-d6. The signal at δ ) 4.52 ppm appears as a
doublet with J ) 5.1 Hz (attributed to the C1-OH
substituent). Upon irradiation of H5 the signal remained
unchanged, while irradiation of H1 resulted in the
collapse of the signal to a singlet.
Diol 18 was then protected as cyclic benzylidene acetal
by treatment with benzaldehyde dimethyl acetal16 in 1,4-
dioxane in the presence of PTSA as a catalyst to give 19
as a single isomer in 90% yield. The formation of 19
delivers additional proof for the structure of the starting
diol 18. Cleavage of the C7-OTBDMS group using TBAF
in THF now proceeded smoothly and afforded alcohol 20
(93%). The configuration of 20 was additionally verified
by X-ray analysis (Figure 4). It showed the trans-fused
cyclohexane and 1,3-dioxane rings both to exist in a chair
conformation, with the C7-OH in an axial position and
the C5-OBn substituent in an equatorial position. These
results confirmed the configuration as established above
3
3
coupling constants J 1,2 ) J 2,3 = 5.5 Hz. These data
equally suggest a chair conformation B, but with the C2-
CH2OH group axial and syn to the substituents at C1
and C3. This conformation avoids steric clashs between
the C1-OTBDMS and the C3-OBn groups. Thus, both
isomers seem to exist in solution predominantly in a chair
conformation with the C5-OTBDMS in an axial position.
After having obtained the key intermediate 15, the
further synthetic strategy leading to the target com-
pounds is the formation of a cyclic acetal, inversion of
the configuration at C7, and introduction of the base
moieties via Mitsunobu type reaction (Scheme 4). When
15 was treated with excess TBAF8 in THF, to simulta-
neously deprotect the hydroxyl groups at C1 and C5, the
reaction proved quite sluggish and triol 17 was isolated
in low yield. Increasing the amount of TBAF and
prolonging the reaction time did not improve the yield.
We, therefore, decided to deprotect the C1 and C5
hydroxyl group in a stepwise manner and we expected
the axially oriented C5-OTBDMS group to be more
reactive than the C1-OTBDMS group occupying an
(16) Crimmins, M. T.; Hollis, W. G., J r.; Lever, G. J . Tetrahedron
Lett. 1987, 28, 3647-3650.

3054 J . Org. Chem., Vol. 63, No. 9, 1998
Wang et al.
Sch em e 5a
a
(a) adenine, DEAD/PPh3, dioxane, rt; (b) 80% HOAc, 60 °C; (c) Pd(OH)2/C, cyclohexene, MeOH, reflux; (d) chloro-2-aminopurine,
DEAD/PPh3, dioxane, rt; (e) CF3COOH/H2O (3:1), rt.
followed by careful chromatographic purification, gave
pure adenine derivative 24 in 70% combined yield over
the two steps. The guanine derivative 27 was obtained
in a similar way, i.e., reaction of 22 with 2-amino-6-
chloropurine under Mitsunobu type conditions, followed
by treatment with CF3COOH-H2O 3:118 at room tem-
perature for 4 days. These acidic conditions converted
the 2-amino-6-chloropurine base into a guanine and
simultaneously hydrolyzed the benzylidene acetal. Pure
27 was isolated in a moderate yield (27% starting from
22). The chiral nucleoside derivatives 24 and 27, with a
free C1-OH and a protected C3-OH, are valuable precur-
sors for the synthesis of a variety of chiral six-membered
carbocyclic nucleosides containing, for example, a double
F igu r e 4. Molecular structure with atom labeling scheme.
Displacement ellipsoids are plotted at the 40% probability
level. H atoms are drawn as small circles of arbitrary radius.
bond, an epoxide ring, a fluorine substituent, or with
altered stereochemistry.
To be able to evaluate the above adenine and guanine
derivatives for their antiviral activity and to study their
conformation in solution, the benzyl group of 24 and 27
for 15. It further showed the single isolated isomer of
the benzylidene acetal 20, with the phenyl group in an
was removed by hydrogenolysis using Pd(OH)2 on carbon
equatorial position, to be the thermodynamically more
and cyclohexene19 in MeOH to give the free triol 25 and
stable compound.
The inversion of the configuration at C7 was ac-
28, respectively. Applying the same reaction conditions
directly to 23 resulted in the simultaneous removal of
complished by treatment of 20 with DEAD and PPh3 in
the acetal and benzyl functions and equally resulted in
1,4-dioxane in the presence of PhCOOH,17 followed by
the formation of 25. Upon removal of the benzyl group
base-catalyzed hydrolysis. This afforded the R-alcohol 22
the chirality is lost and 25 and 28 are achiral, possessing
in 78% combined yield. The R-configuration at C7 was
a plane of symmetry. This facilitated their conforma-
1
confirmed by comparison of the H NMR spectra of 20
1
tional analysis by H NMR, which led to a remarkable
and the benzoate intermediate 21. The equatorial hy-
result. Indeed, in the spectrum recorded in DMSO-d6 as
drogen H7 in 20 appeared at δ ) 4.34 ppm as a poorly
solvent, H5 of 25 appeared at δ ) 4.98 ppm as a triplet
resolved multiplet with ∑3J ) 18 Hz as a result of four
3
of triplets with two large diaxial coupling constants J 4a,5
equatorial-equatorial and equatorial-axial coupling
= 3J 5,6a ) 9.3 Hz and two small axial equatorial coupling
constants of (4.5 Hz with the hydrogens on C6 and C8.
3
3
constants J 4e,5 = J 5,6e ) 4.5 Hz. The protons H1 ≡ H3
appeared at δ ) 3.92 ppm as a triplet of doublets with
However, in 21 the signal for H7 appeared at δ ) 5.06
ppm as a triplet of triplets including two large diaxial
coupling constants of 11.7 Hz, indicating the axial
position of H7 and thus the R-configuration at C7.
Finally, introduction of the adenine and guanine bases
in the â-position at C7 was accomplished using a second
Mitsunobu type reaction (Scheme 5). Upon treatment
of alcohol 22 with adenine base in the presence of DEAD
and PPh3, 23 could be isolated. Subsequent acid hy-
drolysis of the benzylidene acetal using 80% HOAc,
3
3
coupling constants J 1,6e = 3J 1,6a ) 3.7 Hz and J 1,2 ) 5.2
Hz. From this it can be concluded that 25 exists
predominantly in a chair conformation with the adenine
base at C5 in an equatorial position, at the expense of
three axial substituents at C1, C2, and C3. A similar
observation was made for the guanine derivative 28.
(18) J indrich, J .; Holy, A.; Dvorakova, H. Collect. Czech. Chem.
Commun. 1993, 58, 1645-1667.
(19) Tippie, M. A.; Martin, J . C.; Smee, D. F.; Matthews, T. R.;
Verheyden, J . P. H. Nucleosides Nucleotides 1984, 3, 525-535.
(17) Mitsunobu, O. Synthesis 1981, 1-28.

Cyclohexane Carbocyclic Nucleosides
J . Org. Chem., Vol. 63, No. 9, 1998 3055
1.43 (s, 3H), 1.69 (m, 1H), 1.70 (s, 3H), 2.19 (m, 2H), 2.30 (d,
1H, J ) 10.4 Hz, OH), 3.30 (m, 1H), 3.92 (ddd, 1H, J ) 10.4,
3.7, 2.2 Hz), 4.68 (s, 1H), 4.75 (s, 1H); 13C NMR (CDCl3) δ 23.0
(q), 23.6 (q), 32.1 (t), 33.6 (d), 37.8 (t), 61.9 (s), 65.2 (d), 70.0
(d), 111.5 (t), 150.0 (s); LISMS (THGLY + NaOAc) 171 (M +
Na)+; HRMS calcd for C10H16O2Na (M + Na)+ 191.1048, found
191.1017.
Con clu sion
We have successfully developed an enantioselective
approach to the synthesis of six-membered carbocyclic
nucleosides starting from (R)-(-)-carvone. The key steps
involve the regio- and stereoselective hydroboration of
the double bond of a 2-methylenecyclohexane-1,3-diol
derivative and the introduction of the base, illustrated
using adenine and guanine, via Mitsunobu reaction. The
so-obtained achiral nucleosides 25 and 28 (Scheme 5)
showed no antiviral activity,20 which confirms the previ-
ously reported observation that an axially oriented base
moiety is a prerequisite for this activity.4 The chiral
precursors 24 and 27, with differently substituted hy-
droxyl groups at C1 and C3, are versatile intermediates
for the synthesis of other six-membered carbocyclic
nucleosides with potential antiviral activity.
(1S,2S,4R,6R)-2-(ter t-Bu tyld im eth ylsilyloxy)-4-isop r o-
p en yl-1-m eth yl-7-oxa bicyclo[4.1.0.]h ep ta n e (7). To a solu-
tion of the crude 6 (30 g, 0.15 mol) in dry DMF (200 mL) at
room temperature were added imidazole (20.4 g, 0.3 mol) and
TBDMSCl (27.1 g, 0.18 mol) in portions. The reaction was
stirred at room temperature overnight and quenched with
crushed ice. The resulting mixture was concentrated under
reduced pressure and the residue was dissolved in EtOAc,
washed with water and brine, dried over Na2SO4, and con-
centrated. The residue was chromatographed on silica gel
(hexanes-EtOAc 10:1) to afford 7 (39.52 g, 93%) as a colorless
oil: 1H NMR (CDCl3) δ 0.08 (s, 3H), 0.10 (s, 3H), 0.92 (s, 9H),
1.32 (s, 3H), 1.46-1.73 (m, 2H), 1.73 (s, 3H), 1.84 (ddd, 1H, J
) 14.0, 6.5, 3.5 Hz), 2.05 (dd, 1H, J ) 14.0, 5.5 Hz), 2.33 (m,
1H), 3.10 (dd, 1H, J ) 3.5, 1.2 Hz), 3.93 (dd, 1H, J ) 6.5, 5.5
Hz), 4.63 (s, 1H), 4.80 (s, 1H); 13C NMR (CDCl3) δ -4.7 (q),
-4.4 (q), 17.9 (s), 20.9 (q), 21.5 (q), 25.7 (q), 29.0 (d), 33.6 (t),
35.1 (t), 59.1 (s), 60.6 (d), 69.1 (d), 109.4 (t), 148.0 (s); LISMS
(THYLY + NaOAc) 305 (M + Na)+; HRMS calcd for C16H30O2-
Na (M + Na)+ 305.1913, found 305.1887.
(1S,2S,4R,6R)-2-(ter t-Bu tyld im eth ylsilyloxy)-4-a cetyl-
1-m eth yl-7-oxa bicyclo[4.1.0.]h ep ta n e (8). To a mixture of
7 (23.5 g, 0.083 mol) in THF (200 mL) and water (200 mL) at
room temperature was added a 1% OsO4 aqueous solution (24
mL). After stirring for 30 min, KIO4 (48 g, 0.20 mol) was added
in portions. The resulting mixture was stirred vigorously at
room temperature for 2 days. The mixture was filtered and
the separated aqueous phase was extracted with ethyl acetate
(3×). The combined organic layers were washed with NaHSO3
(1 N), water, and brine, dried over Na2SO4, and concentrated.
The residue was chromatographed on silica gel (hexanes-
EtOAc 5:1) to provide 8 (19.5 g, 83%) as a dark oil: 1H NMR
(CDCl3) δ 0.07 (s, 3H), 0.08 (s, 3H), 0.89 (s, 9H), 1.29 (s, 3H),
1.60-2.10 (m, 4H), 2.13 (s, 3H), 2.74 (m, 1H), 3.08 (dd, 1H, J
) 3.3, 1.4 Hz), 3.82 (dd, 1H, J ) 7.6, 4.3 Hz); 13C NMR (CDCl3)
δ -4.7 (q), -4.5 (q), 17.9 (s), 20.5 (q), 24.8 (t), 25.7 (q), 27.8
(q), 31.4 (t), 43.0 (d), 59.4 (s), 60.3 (d), 68.9 (d), 210.8 (s); LISMS
(THGLY) 285 (M + H)+; HRMS calcd for C15H29O3Si (M + H)+
285.1886, found 285.1848.
(1S,2S,4R,6R)-2-(ter t-Bu tyld im eth ylsilyloxy)-4-a cetyl-
oxy-1-m eth yl-7-oxa bicyclo[4.1.0.]h ep ta n e (10). To a vigor-
ously stirring mixture of 8 (19.5 g, 0.068 mol) in CHCl3 (200
mL) and a pH ) 8 sodium phosphate buffer solution (0.1 M,
200 mL) at 0 °C was added m-CPBA (70% purity, 33.8 g, 0.136
mol) protionwise. The resulting mixture was stirred from 0
°C to room temperature overnight. The layers were separated
and the aqueous layer was extracted with CH2Cl2 (3×). The
combined organic layers were washed with NaHSO3 (1 N),
NaHCO3 (2 N), water, and brine, dried over Na2SO4, and
concentrated. The residue was chromatographed on silica gel
(hexanes-EtOAc 5:1) to afford 10 (14.85 g, 73%) as a light-
yellow oil: 1H NMR (CDCl3) δ 0.07 (s, 3H), 0.10 (s, 3H), 0.90
(s, 9H), 1.39 (s, 3H), 1.58-2.04 (m, 3H), 2.03 (s, 3H), 2.10 (dd,
1H, J ) 10.3, 5.1 Hz), 3.01 (d, 1H, J ) 4.4 Hz), 4.15 (dd, 1H,
J ) 10.3, 5.1 Hz), 4.96 (m, 1H); 13C NMR (CDCl3) δ -4.7 (q),
-4.3 (q), 18.1 (s), 19.7 (q), 21.2 (q), 25.8 (q), 29.4 (t), 32.6 (t),
58.9 (d), 60.0 (s), 68.2 (d), 69.0 (d), 170.1 (s); LISMS (NBA)
301 (M + H)+; HRMS calcd for C15H29O4Si (M + H)+ 301.1835,
found 301.1828.
(1R,3R,5S,6S)-5-(ter t-Bu tyld im eth ylsilyloxy)-6-m eth yl-
7-oxa bicyclo[4.1.0.]h ep ta n -3-ol (11). A mixture of 10 (11.5
g, 0.038 mol) and K2CO3 (26.5 g, 0.19 mol) in MeOH (200 mL)
was stirred at room temperature for 12 h. The mixture was
filtered and the filtrate was concentrated. The residue was
dissolved into EtOAc (300 mL), washed with saturated NH4-
Cl, water, and brine, dried over Na2SO4, and concentrated. The
residue was chromatographed on silica gel (hexanes-EtOAc
5:1, then 1:1) to give 11 (7.15 g, 73%) as a light-yellow oil: 1H
Exp er im en ta l Section
Liquid secondary ion mass spectra (LSIMS) were obtained
using glycerol (GLY) or thioglycerol (THGLY) or 3-nitrobenzyl
alcohol (NBA) as matrix. High performance liquid chroma-
tography (HPLC) was performed with a Gilson model 303
pump and model 802c manometric module and a Pharmacia
LKB-Uvicord SII UV detector with a fixed wavelength (254
nm) or a Waters R400 differential refractometer. Separations
were carried out on a Rogel RP column (24 × 2.5 cm) or a Bio-
Sil D 90-10 silica column (25 × 1.0 cm). All other analytical
methodes were described previously.
(1R,4R,6R)-4-Isop r op en yl-1-m eth yl-7-oxa bicyclo[4.1.0]-
h ep ta n -2-on e (5). To a solution of (R)-(-)-carvone (4, 50 g,
0.33 mol) in MeOH (300 mL) at -15 °C was added dropwise a
35% H2O2 aqueous solution (200 mL), followed by addition of
a NaOH aqueous solution (6 M, 28 mL) over a period of 1 h.
The reaction was stirred at 0 °C for 3 h and poured into ice-
water. The mixture was extracted with Et2O (3×). The
combined extracts (600 mL) were washed with brine, dried
over Na2SO4, and concentrated. The resulting colorless oil was
distilled under vacuum (82 °C/0.24 mmHg) to yield 5 (45.28
g, 83%) as a colorless oil: 1H NMR (CDCl3) δ 1.40 (s, 3H),
1.70 (s, 3H), 1.89 (ddd, 1H, J ) 14.7, 11.0, 1.2 Hz), 2.05 (dd,
1H, J ) 17.4, 11.4 Hz), 2.36 (br d, 1H, J ) 14.7 Hz), 2.57 (ddd,
1H, J ) 17.5, 4.6, 1.3 Hz), 2.71 (m, 1H), 3.42 (dd, 1H, J ) 2.0,
1.1 Hz), 4.71 (br s, 1H), 4.78 (br s, 1H); 13C NMR (CDCl3) δ
17.2 (q), 22.6 (q), 30.7 (t), 37.0 (d), 43.8 (t), 60.7 (s), 63.3 (d),
112.4 (t), 148.3 (s), 207.4 (s); LISMS (THGLY + Girard’s
reagent P) 300 (M + 134)+.
(1S,2S,4S,6R)-4-Isopropenyl-1-methyl-7-oxabicyclo[4.1.0]-
h ep ta n -2-ol (6). To a solution of 5 (25 g, 0.15 mol) in dry
THF (200 mL) under N2 at -70 °C was added a solution of
L-Selectride in THF (1 M, 180 mL, 0.18 mol). During the
addition, the reaction temperature should not exceed -65 °C.
The reaction was stirred at -70 °C for an additional 1.5 h and
treated carefully with NH4Cl solution. The resulting mixture
was warmed to room temperature and stirred overnight. The
layers were separated, and the aqueous layer was extracted
with ethyl acetate (3×). The combined organic layers were
washed with water and brine, dried over Na2SO4, and con-
centrated. The residue was purified by chromatography on
silica gel (hexanes-EtOAc 5:1, then 1:1) to give crude 6 (30 g)
as a light yellow oil which was still contaminated with borane
side products. The crude 6 was used directly in the next step
without further purification. An analytical sample was ob-
tained by HPLC purification on silica gel column (hexanes-
EtOAc 1:1): 1H NMR (CDCl3) δ 0.91 (m, 1H), 1.32 (m, 1H),
(20) Compounds 25 and 28 were tested for their antiviral activity
against herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-
2), vaccinia virus, vesicular stomatitis virus, Coxsackie virus B4,
respiratory syncytial virus (RSV), parainfluenza-3 virus, reovirus-1,
Sindbis virus, and Punta Toro virus; for their cytoxicity in E6SM cell
cultures, Hela cell cultures, and Vero cell cultures; and for inhibitory
activity against replication of HIV-1 (IIIB) and HIV-2 (ROD) in MT-4
cells.

3056 J . Org. Chem., Vol. 63, No. 9, 1998
Wang et al.
NMR (CDCl3) δ 0.09 (s, 3H), 0.11 (s, 3H), 0.91 (s, 9H), 1.38 (s,
3H), 1.52-2.13 (m, 4H), 3.03 (d, 1H, J ) 4.0 Hz), 4.04 (br s,
1H), 4.30 (dd, 1H, J ) 9.9, 5.5 Hz); 13C NMR (CDCl3) δ -4.7
(q), -4.2 (q), 18.1 (s), 19.9 (q), 25.8 (q), 32.6 (t), 35.8 (t), 59.3
(d), 60.1 (s), 65.6 (d), 68.0 (d); LISMS (THGLY) 259 (M + H)+;
HRMS calcd for C13H26O3Si (M + H)+ 259.1729, found 257.1730.
(1S,2S,4R,6R)-2,4-Bis(ter t-b u t yld im et h ylsilyloxy)-1-
m eth yl-7-oxa bicyclo[4.1.0.]h ep ta n e (12). To a solution of
11 (7.0 g, 0.027 mol) in dry DMF (100 mL) at room tempera-
ture under nitrogen were added imidazole (3.67 g, 0.054 mol)
and TBDMSCl (4.90 g, 0.032 mol) sequentially. The resulting
solution was stirred at room temperature overnight. After
addition of water, the resulting mixture was concentrated. The
residue was taken up into EtOAc (300 mL), washed with water
and brine, dried over Na2SO4, and concentrated. The residue
was purified on silica gel (hexanes-EtOAc 10:1) to afford 12
(8.0 g, 80%) as a light-yellow oil: 1H NMR (CDCl3) δ 0.03 (s,
3H), 0.04 (s, 3H), 0.08 (s, 3H), 0.11 (s, 3H), 0.88 (s, 9H), 0.92
(s, 9H), 1.38 (s, 3H), 1.41-1.88 (m, 3H), 1.98 (dd, 1H, J ) 15.7,
4.4 Hz), 3.02 (d, 1H, J ) 4.3 Hz), 3.96 (m, 1H), 4.30 (dd, 1H,
J ) 9.8, 5.1 Hz); 13C NMR (CDCl3) δ -4.9 (q), -4.7 (q), -4.2
(q), 18.0 (s), 18.1 (s), 20.0 (q), 25.7 (q), 25.9 (q), 33.3 (t), 36.3
(t), 59.4 (d), 60.0 (s), 66.2 (d), 68.6 (d); LISMS (THGLY) 373
(M + H)+; HRMS calcd for C19H41O3Si2 (M + H)+ 373.2594,
found 373.2591.
(1R,3S,5R)-3,5-Bis(ter t-bu tyld im eth ylsilyloxy)-2-m eth -
ylen ecycloh exa n ol (13). A solution of 2,2,6,6-tetramethylpi-
peridine (TMP, 9.05 mL, 53.76 mmol) in dry benzene (60 mL)
was cooled to 0 °C under N2 and a solution of n-BuLi in hexane
(2.5 M, 21.5 mL, 53.76 mmol) was added dropwise. The
resulting mixture was stirred at 0 °C for 10 min, a solution of
Et2AlCl (1.8 M, 30 mL, 54 mmol) in toluene was slowly added,
and the reaction was stirred for 30 min. A solution of 12 (5 g,
13.44 mmol) in benzene (20 mL) was added dropwise. 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 with
water and brine, dried over Na2SO4, and concentrated. The
residue was chromatographed on silica gel (hexanes-EtOAc
10:1) to give 13 (5 g, 100%) as a light-yellow oil: 1H NMR
(CDCl3) δ 0.07 (s, 6H), 0.08 (s, 6H), 0.90 (s, 9H), 0.91 (s, 9H),
1.66 (m, 2H), 1.90 (m, 2H), 2.42 (d, 1H, J ) 7.2 Hz, OH), 4.28
(m, 1H), 4.43 (m, 2H), 5.01 (br s, 1H), 5.07 (br s, 1H); 13C NMR
(CDCl3) δ -5.1 (q), -5.0 (q), 18.0 (s), 18.2 (s), 25.8 (q), 44.1 (t),
44.5 (t), 65.0 (d), 69.6 (d), 70.4 (d), 105.0 (t), 152.2 (s); LISMS
(NBA) 373 (M + H)+; HRMS calcd for C19H41O3Si2 (M + H)+
373.2594, found 373.2576.
(1S,3R,5R)-3-Ben zyloxy-1,5-bis(ter t-bu tyld im eth ylsil-
yloxy)-2-m eth ylen ecycloh exa n e (14). NaH (80% suspen-
sion, 835 mg, 27.82 mmol) was added to a solution of 13 (6.9
g, 18.55 mmol) in dry THF (60 mL) at room temperature under
nitrogen. The mixture was stirred for 0.5 h, followed by
addition of BnBr (2.65 mL, 22.25 mmol) and tetrabutylam-
monium iodide (TBAI, 103 mg). The reaction was stirred at
room temperature overnight. Crushed ice was added and the
mixture was stirred at room temperature for 0.5 h and then
poured into EtOAc (400 mL), washed with water and brine,
dried over Na2SO4, and concentrated. The residue was chro-
matographed on silica gel (hexanes-EtOAc 20:1) to give 14
(8.7 g) as a light-yellow oil which was not pure and was used
as such in the next reaction: 1H NMR (CDCl3) δ -0.08 (s, 3H),
-0.05 (s, 3H), -0.02 (s, 3H), 0.00 (s, 3H), 0.76 (s, 9H), 0.84 (s,
9H), 1.30-1.45 (m, 2H), 1.83-2.06 (m, 2H), 4.04 (br dd, 1H, J
) 11.0, 4.7 Hz), 4.09 (m, 1H), 4.32 (br dd, 1H, J ) 11.0, 4.7
Hz), 4.43 (d, 1H, J ) 12.0 Hz), 4.62 (d, 1H, J ) 12.0 Hz), 5.06
(br s, 2H), 7.12-7.40 (m, 5H); 13C NMR (CDCl3) δ -5.0 (q),
-4.9 (q), 17.9 (s), 18.4 (s), 25.7 (q), 25.9 (q), 42.0 (t), 45.1 (t),
66.2 (d), 68.5 (d), 71.4 (d), 74.7 (t), 102.4 (t), 127.5 (d), 128.3
(d), 138.8 (s), 152.6 (s); LISMS (THGLY + NaOAc) 485 (M +
H)+; HRMS calcd for C26H46O3Si2Na (M + Na)+ 485.2883,
found 485.2892.
tion of crude 14 (8.7 g, 18.55 mmol) in dry THF (60 mL) at 0
°C under nitrogen was added dropwise a solution of 9-BBN in
THF (0.5 M, 74.2 mL, 37.1 mmol). The reaction was slowly
warmed to room temperature overnight. The reaction was
cooled to 0 °C and treated sequentially with EtOH (7 mL), a
2 N NaOH solution (14 mL), and a 35% H2O2 solution while
stirring. The resulting mixture was stirred at room temper-
ature for 23 h and then poured into a mixture of EtOAc (150
mL) and water (150 mL). The layers were separated, and the
aqueous layer was extracted with EtOAc (3×). The combined
organic layers were washed with water and brine, dried over
Na2SO4, and concentrated. The crude product was separated
on silica gel (hexanes-EtOAc 20:1, then 1:1) to yield 15 (5.5
g, 62% starting from 13) as a colorless oil and the epimer 16
(1.4 g, 16%) as a light-yellow oil.
15: 1H NMR (CDCl3) δ 0.06 (2s, 9H), 0.08 (s, 3H), 0.89 (s,
9H), 0.90 (s, 9H), 1.40 (td, 1H, J ) 11.0, 2.4 Hz), 1.46 (td, 1H,
J ) 11.0, 2.4 Hz), 1.68 (tt, 1H, J ) 11.0, 4.0 Hz), 1.93 (br d,
1H, J ) 11.0 Hz), 2.17 (br d, 1H, J ) 11.0 Hz), 2.82 (dd, 1H,
J ) 7.0, 4.0 Hz, OH), 3.71 (td, 1H, J ) 11.0, 4.1 Hz), 3.78 (dt,
1H, J ) 10.6, 4.0 Hz), 3.84 (td, 1H, J ) 11.0, 4.0 Hz), 3.92
(ddd, 1H, J ) 10.6, 7.0, 4.0 Hz), 4.19 (m, 1H), 4.44 (d, 1H, J )
11.6 Hz), 4.64 (d, 1H, J ) 11.6 Hz), 7.28-7.37 (m, 5H); 13C
NMR (CDCl3) δ -5.1 (q), -5.0 (q), -4.3 (q), 17.8 (s), 25.6 (q),
25.7 (q), 37.7 (t), 42.6 (t), 53.2 (d), 63.3 (d), 66.5 (d), 67.8 (d),
70.7 (t), 75.6 (t), 127.9 (d), 128.1 (d), 128.6 (d), 138.1 (s); LISMS
(THGLY) 481 (M + H)+; HRMS calcd for C26H49O4Si2 (M +
H)+ 481.3169, found 481.3167.
16: 1H NMR (CDCl3) δ 0.02 (s, 3H), 0.03 (s, 3H), 0.07 (s,
3H), 0.10 (s, 3H), 0.85 (s, 9H), 0.90 (s, 9H), 1.53 (ddd, 1H, J )
13.0, 11.5, 2.9 Hz), 1.68 (m, 2H), 1.80 (dt, 1H, J ) 13.0, 4.2
Hz), 2.61 (app pent, 1H, J ) 5.9 Hz), 3.41 (dd, 1H, J ) 7.3, 4.9
Hz, OH), 3.91 (ddd, 1H, J ) 11.5, 4.4, 3.2 Hz), 3.92 (ddd, 1H,
J ) 11.2, 7.3, 4.9 Hz), 4.14 (app pent, 1H, J ) 3.2 Hz), 4.24
(ddd, 1H, J ) 10.2, 5.9, 5.4 Hz), 4.52 (d, 1H, J ) 11.7 Hz),
4.60 (d, 1H, J ) 11.7 Hz), 7.25-7.34 (m, 5H); 13C NMR (CDCl3)
δ -4.8 (q), -4.6 (q), 18.1 (s), 18.2 (s), 25.9 (q), 26.0 (q), 34.7
(t), 38.0 (t), 45.7 (d), 58.7 (d), 66.4 (d), 69.1 (d), 70.9 (t), 74.5
(d), 127.8 (d), 128.6 (d), 138.5 (s); LISMS (THYLY) 481 (M +
H)+; HRMS calcd for C26H49O4Si2 (M + H)+ 481.3169, found
481.3120.
(1S,2R,3R,5S)-3-Ben zyloxy-5-(ter t-bu tyld im eth ylsilyl-
oxy)-2-h yd r oxym eth yl-cycloh exa n ol (18). A solution of
TBAF in THF (1.0 M, 8.23 mL, 8.23 mmol) was added dropwise
to a solution of 15 (4.0 g, 8.23 mmol) in THF (30 mL) and the
reaction was stirred at room temperature for 3 h. TLC showed
the completion of the reaction. Ice was added and the mixture
was poured into ethyl acetate (200 mL), washed with water
and brine, dried over Na2SO4, and concentrated. The residue
was chromatographed on silica gel (hexanes-EtOAc 5:1, then
1:1) to yield 18 (2.84 g, 93%) as a light-yellow oil: 1H NMR
(CDCl3) δ -0.01 (s, 6H), 0.82 (s, 9H), 1.29-1.46 (m, 2H), 1.63
(m, 1H), 1.92 (m, 1H), 2.08 (m, 1H), 2.95 (br s, 2H, 2OH), 3.54
(td, 1H, J ) 10.4, 4.0 Hz), 3.76 (dd, 1H, J ) 10.7, 4.7 Hz), 3.85
(td, 1H, J ) 10.5, 4.2 Hz), 4.00 (dd, 1H, J ) 10.7, 4.7 Hz), 4.15
(m, 1H), 4.33 (d, 1H, J ) 11.4 Hz), 4.55 (d, 1H, J ) 11.4 Hz),
7.22-7.32 (m, 5H); 13C NMR (CDCl3) δ -5.0 (q), -4.9 (q), 17.9
(s), 25.8 (q), 37.6 (t), 41.7 (t), 52.2 (d), 64.3 (t), 66,3 (d), 68.8
(d), 70.9 (t), 74.5 (d), 127.9 (d), 128.0 (d), 128.5 (d), 138.1 (s);
LISMS (GLY) 367 (M + H)+; HRMS cald for C20H35O4Si (M +
H)+ 367.2304, found 367.2346.
(2R,5R,7R,9S,10S)-5-Ben zyloxy-7-(ter t-bu tyld im eth yl-
silyloxy)-2-p h en ylh exa h yd r oben zo[1.3]d ioxin e (19).
A
solution of 18 (2.93 g, 8.0 mmol), PhCH(OMe)2 (1.44 mL, 9.6
mmol), and p-toluenesulfonic acid monohydrate (PTSA, 76 mg,
0.4 mmol) in dry dioxane (35 mL) was stirred at room
temperature for 24 h and then poured into EtOAc (300 mL),
washed with water and brine, dried over Na2SO4, and con-
centrated. The residue was chromatographed on silica gel
(hexanes-EtOAc 20:1) to afford 19 (9.2 g, 90%) as a light-
yellow oil: 1H NMR (CDCl3) δ 0.01 (s, 6H), 0.84 (s, 9H), 1.34-
1.64 (m, 2H), 1.80-2.03 (m, 2H), 2.14 (m, 1H), 3.46 (td, 1H, J
) 10.7, 4.0 Hz), 3.53 (t, 1H, J ) 11.0 Hz), 3.87 (td, 1H, J )
10.5, 4.3 Hz), 4.23 (m, 1H), 4.32 (d, 1H, J ) 11.8 Hz), 4.49
(dd, 1H, J ) 11.0, 4.3 Hz), 4.54 (d, 1H, J ) 11.8 Hz), 5.47 (s,
(1S,2S,3R,5R)-3-Ben zyloxy-1,5-bis(ter t-bu tyld im eth yl-
silyloxy)-2-(h yd r oxym eth yl)cycloh exa n e (15). To a solu-

Cyclohexane Carbocyclic Nucleosides
J . Org. Chem., Vol. 63, No. 9, 1998 3057
1H), 7.20-7.48 (m, 10H); 13C NMR (CDCl3) δ -4.5 (q), 18.5
(s), 26.3 (q), 38.9 (t), 39.0 (t), 47.0 (d), 67.0 (d), 70,4 (t), 71.2
(t), 73.1 (d), 76.2 (d), 102.2 (d), 126.7 (d), 128.2 (d), 128.3 (d),
128.8 (d), 128.9 (d), 129.3 (d), 138.9 (s), 139.0 (s); LISMS (GLY)
455 (M + H)+; HRMS calcd for C27H39O4Si (M + H)+ 455.2618,
found 455.2610.
(d), 128.4 (d), 128.6 (d), 128.9 (d), 129.3 (d), 137.8 (s), 138.1
(s), 138.9 (d), 150.5 (s), 153.2 (d), 155.8 (s); UV λmax(MeOH) )
262 nm; LISMS (THGLY) 458 (M + H)+; HRMS calcd for
C
26H28N5O3 (M + H)+ 458.2192, found 458.2191.
(1S,2R,3R,5S)-5-Ad en in -9-yl-3-b en zyloxy-2-(h yd r oxy-
m eth yl)cycloh exa n ol (24). A mixture of 23 (214 mg, 0.47
mol) in 80% HOAc aqueous solution was heated at 60 °C for 8
h and concentrated. The residue was coevaporated with
toluene and purified by chromatography eluting with CH2Cl2-
MeOH (50:1 and 10:1) to afford 24 (150 mg, 86%) as a white
solid: 1H NMR (DMSO-d6, exchanged with D2O) δ 1.96 (m,
3H), 2.37 (m, 2H), 3.57 (d, 2H, J ) 5.5 Hz), 3.90 (m, 2H,
overlapped with DOH peak), 4.53 (s, 2H), 4.98 (m, 1H), 7.20-
7.40 (m, 5H), 8.15 (s, 2H); 13C NMR (DMSO-d6, exchanged with
D2O) δ 32.4 (t), 36.1 (t), 46.7 (d), 47.9 (d), 59.3 (t), 66.0 (d),
70.1 (t), 74.5 (d), 119.2 (s), 127.4 (d), 127.7 (d), 128.3 (d), 138.9
(s), 139.5 (d), 149.5 (s), 152.3 (d), 156.1 (s); UV λmax(MeOH) )
262 nm; LISMS (THGLY) 370 (M + H)+; HRMS calcd for
C19H24N5O3 (M + H)+ 370.1879, found 370.1848.
5-(6-Am in op u r in -9-yl)-2-(h yd r oxym eth yl)cycloh exa n e-
1,3-d iol (25). A mixture of 24 (110 mg, 0.3 mmol) and 20%
Pd(OH)2 on carbon (220 mg) in cyclohexene (6 mL) and MeOH
(12 mL) was refluxed for 2 days and then cooled to room
temperature, diluted with MeOH, and filtered through Celite.
The filtrate was concentrated to yield 25 (77 mg, 92%) as a
white solid. Compound 25 can also be prepared directly from
23 using the same procedure in 73% yield. An analytical
sample was obtained by RP HPLC purification on Rogel
column eluting with H2O-CH3CN (96:4): mp 224-226 °C; 1H
NMR (DMSO-d6, exchanged with D2O) δ 1.78 (m, 1H), 1.87
(ddd, 2H, J ) 13.6, 5.9, 4.4 Hz), 2.30 (ddd, 2H, J ) 13.6, 9.4,
2.9 Hz), 3.55 (m, 2H, overlapped with DOH peak), 3.92 (dt,
2H, J ) 5.2, 3.7 Hz), 4.98 (tt, 1H, J ) 9.3, 4.5 Hz), 8.11 (s,
1H), 8.19 (s, 1H); 13C NMR (DMSO-d6) δ 35.8 (t), 46.5 (d), 49.1
(d), 59.6 (t), 66.8 (d), 119.1 (s), 139.6 (d), 149.4 (s), 152.2 (d),
156.1 (s); UV λmax(MeOH) ) 262 nm; LISMS (THGLY) 280 (M
+ H)+; HRMS calcd for C12H18N5O3 (M + H)+ 280.1410, found
280.1401. Anal. Calcd for C12H17N5O3‚1.5 H2O: C 47.05, H
6.58, N 22.86; Found: C 47.40, H 6.44, N 22.96.
(2R,5R,7R,9S,10S)-7-Gu a n in -9-yl-5-ben zyloxy-2-p h en yl-
h exa h yd r oben zo[1.3]d ioxin e (26). Compound 26 was pre-
pared from 2-amino-6-chloropurine and 22 as described for the
synthesis of 23 in 37% yield: 1H NMR (CDCl3) δ 1.89-2.20
(m, 3H), 2.75 (m, 1H), 2.87 (m, 1H), 3.45 (td, 1H, J ) 10.6, 4.0
Hz), 3.58 (t, 1H, J ) 11.0 Hz), 3.67 (m, 1H), 4.46 (d, 1H, J )
11.9 Hz), 4.58 (dd, 1H, J ) 11.0, 4.4 Hz), 4.59 (d, 1H, J ) 11.9
Hz), 4.91 (m, 1H), 5.20 (s, 2H, NH2), 5.44 (s, 1H), 7.26-7.48
(m, 10H), 7.66 (s, 1H); 13C NMR (CDCl3) δ 34.0 (t), 34.6 (t),
46.4 (d), 50.6 (d), 69.9 (t), 71.6 (t), 72.3 (d), 75.0 (d), 102.1 (d),
126.0 (s), 126.5 (d), 128.4 (d), 128.7 (d), 129.1 (d), 129.5 (d),
137.9 (s), 138.2 (s), 140.7 (d), 152.1 (s), 154.2 (s), 159.3 (s);
LISMS (THGLY) 492 (M + H)+; HRMS calcd for C26H27N5O3-
Cl (M + H)+ 492.1802, found 492.1810.
(2R,5R,7R,9S,10S)-5-Ben zyloxy-2-p h en ylh exa h yd r o-
ben zo[1.3]d ioxin -7-ol (20). A solution of TBAF in THF (1.0
M, 13.92 mL, 13.92 mmol) and 19 (2.10 g, 4.64 mmol) in THF
(50 mL) was stirred at room temperature overnight. After
standard workup, 20 (1.47 g, 93%) was obtained as a white
solid after purification on silica gel (hexanes-EtOAc 1:1): mp
1
158-159 °C; H NMR (CDCl3) δ 1.44-1.78 (m, 3H), 1.95 (qd,
1H, J ) 10.4, 4.4 Hz), 2.08 (m, 1H), 2.31 (m, 1H), 3.56 (td, 1H,
J ) 10.4, 4.3 Hz), 3.66 (t, 1H, J ) 10.4 Hz), 3.98 (td, 1H, J )
10.4, 4.3 Hz), 4.34 (m, 1H), 4.39 (d, 1H, J ) 11.7 Hz), 4.56
(dd, 1H, J ) 10.4, 4.4 Hz), 4.62 (d, 1H, J ) 11.7 Hz), 5.52 (s,
1H), 7.24-7.51 (m, 10H); 13C NMR (CDCl3) δ 37.6 (t), 37.9 (t),
46.4 (d), 66.1 (d), 69,8 (t), 70.9 (t), 72.8 (d), 75.1 (d), 101.7 (d),
126.2 (d), 127.6 (d), 127.7 (d), 128.3 (d), 128.4 (d), 128.9 (d),
138.4 (s); LISMS (GLY) 341 (M + H)+; HRMS calcd for
C
C
21H25O4 (M + H)+ 341.1753, found 341.1745. Anal. Calcd for
21H24O4: C 74.09, H 7.11; Found: C 73.97, H 7.40.
(2R,5R,7S,9S,10S)-5-Ben zyloxy-2-p h en ylh exa h yd r o-
ben zo[1.3]d ioxin -7-ol (22). A solution of benzoic acid (939
mg, 7.69 mmol) and DEAD (1.21 mL, 7.69 mmol) in dry
dioxane (20 mL) was added dropwise to a solution of 20 (1.72
g, 5.06 mmol) and PPh3 (1.99 g, 7.69 mmol) in dioxane (40 mL)
at room temperature under N2. The reaction mixture was
stirred overnight and concentrated under reduced pressure.
The residue was chromatographed on silica gel (hexanes-
EtOAc 5:1) to yield the crude 21 (2.3 g) as a white solid which
was used directly in the next step: 1H NMR (CDCl3) δ 1.54-
2.11 (m, 3H), 2.45 (m, 1H), 2.71 (m, 1H), 3.25 (td, 1H, J )
10.9, 4.1 Hz), 3.58 (td, 1H, J ) 10.9, 4.0 Hz), 3.59(t, 1H, J )
10.3 Hz), 4.39 (d, 1H, J ) 11.7 Hz), 4.59 (dd, 1H, J ) 10.3, 4.3
Hz), 4.68 (d, 1H, J ) 11.7 Hz), 5.06 (tt, 1H, J ) 11.7, 4.7 Hz),
5.52 (s, 1H), 7.24-7.62 (m, 13H), 8.05 (m, 2H); 13C NMR
(CDCl3) δ 36.5 (t), 36.8 (t), 45.4 (d), 67.9 (d), 69,9 (t), 70.7 (t),
73.1 (d), 75.6 (d), 101.7 (d), 126.1 (d), 127.7 (d), 127.9 (d), 128.3
(d), 128.4 (d), 128.5 (d), 128.9 (d), 129.6 (d), 130.1 (s), 133.2
(d), 137.9 (s), 138.1 (s), 165.8 (s).
The crude 21 (2.3 g) was treated with K2CO3 (4 g) in MeOH
(40 mL) and THF (40 mL) at room temperature overnight.
After workup and chromatography on silica gel (hexanes-
EtOAc 5:1, then 1:2), 22 (1.24 g, 72% over two steps) was
obtained as a white solid; mp 130-132 °C; 1H NMR (CDCl3) δ
1.26-1.70 (m, 3H), 1.93 (qd, 1H, J ) 10.6, 4.4 Hz), 2.31 (m,
1H), 2.52 (m, 1H), 3.12 (td, 1H, J ) 10.6, 4.1 Hz), 3.44 (td,
1H, J ) 10.6, 4.0 Hz), 3.55 (t, 1H, J ) 10.6 Hz), 3.69 (m, 1H),
4.38 (d, 1H, J ) 12.0 Hz), 4.56 (dd, 1H, J ) 10.6, 4.4 Hz), 4.64
(d, 1H, J ) 12.0 Hz), 5.46 (s, 1H), 7.25-7.51 (m, 10H); 13C
NMR (CDCl3) δ 40.1 (t), 40.5 (t), 45.2 (d), 65.6 (d), 70.0 (t),
70.5 (t), 73.3 (d), 75.8 (d), 101.7 (d), 126.2 (d), 127.6 (d), 127.8
(d), 128.3 (d), 128.5 (d), 129.0 (d), 138.1 (s); LISMS (THGLY)
341 (M + H)+; HRMS calcd for C21H25O4 (M + H)+ 341.1753,
found 341.1758.
(1S,3R,4R,5S)-5-Gu a n in -9-yl-3-b en zyloxy-2-(h yd r oxy-
m eth yl)cycloh exa n ol (27). A solution of 26 (54 mg, 0.11
mol) in CF3COOH-H2O (3:1, 4 mL) was stirred at room
temperature for 4 days. The solution was concentrated and
the residue was coevaporated with toluene and then treated
with ammonium methanol and concentrated to yield 27 (45
mg), which was used as such in the next reaction: 1H NMR
(DMSO-d6) δ 1.86 (m, 1H), 1.96 (m, 2H), 2.85 (m, 2H), 3.56
(br t, 2H), 4.46 (d, 1H, J ) 5.1 Hz, exchangeable with D2O),
4.53 (s, 2H), 4.67 (br t, 1H, OH, exchangeable with D2O), 4.80
(m, 1H), 6.59 (s, 2H, NH2, exchangeable with D2O), 7.34 (m,
5H), 7.78 (s, 1H), 10.73 (s, 1H, NH, exchangeable with D2O);
13C NMR (DMSO-d6) δ 32.3 (t), 36.1 (t), 45.3 (d), 47.0 (d), 58.8
(t), 65.5 (d), 69.8 (t), 74.1 (d), 116.4 (s), 127.1 (d), 127.4 (d),
128.0 (d), 135.5 (d), 138.6 (s), 150.6 (s), 153.2 (s), 156.7 (s); UV
(2R,5R,7R,9S,10S)-7-Ad en in -9-yl-5-ben zyloxy-2-p h en yl-
h exa h yd r oben zo[1.3]d ioxin e (23). To a suspension of 22
(160 mg, 0.47 mmol), adenine (127 mg, 0.94 mmol), and PPh3
(246 mg, 0.94 mmol) in dry dioxane (13 mL) at room temper-
ature under nitrogen was added a solution of DEAD (154 µL,
0.94 mmol) in dry dioxane (7 mL) over a period of 1 h. The
resulting mixture was stirred at room temperature overnight.
The reaction mixture was concentrated under reduced pres-
sure and the residue was directly chromatographed on silica
gel (CH2Cl2-MeOH 50:1 to 20:1) to afford 23 (200 mg, 93%)
1
as a white solid: mp 186-188 °C; H NMR (CDCl3) δ 1.93-
2.24 (m, 3H), 2.77 (m, 1H), 3.06 (m, 1H), 3.51 (td, 1H, J )
11.0, 4.0 Hz), 3.61 (t, 1H, J ) 11.0 Hz), 3.78 (td, 1H, J ) 11.0,
4.0 Hz), 4.45 (d, 1H, J ) 12.0 Hz), 4.60 (dd, 1H, J ) 11.0, 4.4
Hz), 4.64 (d, 1H, J ) 12.0 Hz), 5.09 (m, 1H), 5.47 (s, 1H), 5.83
(br s, 2H), 7.24-7.50 (m, 10H), 7.74 (s, 1H), 8.38 (s, 1H); 13C
NMR (CDCl3) δ 34.0 (t), 34.8 (t), 46.2 (d), 50.4 (d), 69.8 (t),
71.3 (t), 72.2 (d), 75.0 (d), 101.9 (d), 120.3 (s), 126.3 (d), 128.1
λ
max(MeOH) ) 256 nm; LISMS (THGLY) 386 (M + H)+; HRMS
calcd for C19H24N5O4 (M + H)+ 386.1828, found 386.1812.
5-Gu a n in -9-yl-2-(h yd r oxym e t h yl)cycloh e xa n e -1,3-
d iol (28). The crude 27 (45 mg) was refluxed with 20% Pd-
(OH)2 on carbon (100 mg) in cyclohexene (2.5 mL) and MeOH
(5 mL) overnight. The reaction mixture was cooled to room
temperature and filtered through Celite. The filtrate was

3058 J . Org. Chem., Vol. 63, No. 9, 1998
Wang et al.
concentrated and the residue was chromatographed on a short
pad of silica gel (CH2Cl2-MeOH 2:1) to afford 28 (33 mg, 63%
over two steps) as a white solid.
Str u ctu r e Refin em en t. The structure was solved by
direct methods using SIR92.23 Full-matrix least-squares
anisotropic refinement on F2 for all non-hydrogen atoms
yielded R[I > 2σ(I)] ) 0.032 at convergence with GOF on F2 )
1.049; extinction coefficient, 0.060(2); largest peak and hole,
0.133 and -0.105 e Å3. Hydrogen atoms were placed in
idealized positions with isotropic displacement parameters
fixed at 1.3 times the value of the attached atom and were
constrained to ride on their parent atoms. PARST (Nardelli)24
and PLATON (Spek25) were used for geometry calculations.
Both the dioxane and the cyclohexane ring have a chair
conformation with puckering parameters according to Cremer
and Pople:26 Qt ) 0.579(1) Å, θ ) 177.7(1)° and Qt ) 0.560 Å,
θ ) 178.3(2). The intermolecular hydrogen bond network
consists of O2′-H21′‚‚‚O2 (-1 + x, y, z) interactions.
An analytic sample was prepared by RP HPLC purification
on Rogel column eluenting with H2O-CH3CN (96:4): mp >270
1
°C; H NMR (DMSO-d6) δ 1.73-1.92 (m, 3H), 2.16 (m. 2H),
3.56 (t, 2H, J ) 4.4 Hz), 3.96 (m, 2H), 4.59 (t, 1H, J ) 4.4 Hz,
exchangeable with D2O), 4.84 (m, 1H), 4.95 (d, 1H, J ) 5.9
Hz, OH, exchangeable with D2O), 6.37 (s, 2H, NH2, exchange-
able with D2O), 7.83 (s, 1H), 10.50 (s, 1H, NH, exchangeable
with D2O); 13C NMR (DMSO-d6) δ 36.2 (t), 45.5 (d), 49.2 (d),
59.6 (t), 66.8 (d), 116.7 (s), 135.9 (d), 150.9 (s), 153.4 (s), 157.1
(s); UV λmax(MeOH) ) 256 nm; LISMS (THGLY) 296 (M + H)+;
HRMS calcd for
296.1349. Anal. Calcd for C12H17N5O4‚2 H2O: C 43.50, H 6.39,
N 21.14; Found: C 44.04, H 6.33, N 20.95.
C
12H18N5O4 (M + H)+ 296.1359, found
X-r a y Diffr a ction Stu d ies.21 Colorless single crystals
were grown by slow evaporation from a hexanes-EtOAc
solution at room temperature. Crystal data: C21H24O4, MW
) 340.4, monoclinic, P21, a ) 8.372(5) Å, b ) 5.475(5) Å, c )
19.470(5) Å, â ) 91.970(5), V ) 892(1) Å3, Z ) 2, Dc ) 1.268
Mg/m3, F(000) ) 364, µ ) 0.700 mm-1, λ ) 1.54178 Å, T )
293(2) K, crystal size 0.40 × 0.35 × 0.20 mm.
Ack n ow led gm en t. This research was financially
supported by a grant of the Katholieke Universiteit
Leuven (GOA 97/11). We thank M. Anderson for helpful
discussions. We thank O. Peeters for assistance in X-ray
analysis and E. De Clercq for antiviral testing.
Da ta Collection . A crystal was mounted on a Siemens P4
four-circle diffractometer with graphite monochromator and
Cu KR radiation. Cell parameters were calculated from the
least-squares fitting for 35 high-angle reflections (2θ > 30°).
Omega scans for several intense reflections indicated accept-
able crystal quality. Data were collected from 4.54 to 134.10°
2θ at 293(2) K. The index range was, -10 < h < 10, -5 < k
< 6, -23 < l < 23. Scan width for data collection was 0.94°
in ω (plus R1 - R2 dispersion) with a variable scan rate
between 1 and 60°/min. The three standards, collected every
100 reflections, showed no significant trends. Lorentz and
polarization corrections were applied to 2881 reflections.
Su p p or tin g In for m a tion Ava ila ble: 13C NMR for com-
pounds 5, 7, 8, 10-16, 18-25, and 28 (20 pages). This material
is contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O972285C
(22) North A. C.; Philips, D. C.; Mathews, F. S. Acta Crystallogr.
1968, A24, 350-359.
(23) Sheldrick, G., SHELXL-97. Program for Crystal Structure
Refinement, Institut fu¨r Anorganische Chemie der Universita¨t, Tam-
manstrasse 4, D-3400 Go¨ttingen, Germany, 1997.
(24) Nardelli, M. Comput Chem. 1983, 7, 95-98.
(25) Spek, A. L. PLATON. An integrated tool for the analysis of the
results of a single-crystal structure determination. Acta Crystallogr.
1990, A46, C-34.
An empirical absorption correction (the method of North22
)
was applied. A total of 3423 unique reflections (Rint ) 0.0190)
were used in further calculations.
(21) The authors have deposited atomic coordinates for these
structures with the Cambridge Crystallographic Data Centre. The
coordinates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2, 1EZ,
UK.
(26) Cremer, D.; Pople, J . A. J . Am. Chem. Soc. 1975, 97, 1354-
1361.
(27) Bergerhoff, G. DIAMOND. Visual Structure Information Sys-
tem, Gerhard-Domagsk-Str., 53121, Bonn, Germany, 1996.