A straightforward stereoselective synthesis of D- and L-5-hydroxy-4-hydroxymethyl-2-cyclohexenylguanine

Article abstract of DOI:10.1021/jo015924z

A novel and facile synthesis of 5-hydroxy-4-hydroxymethyl-2-cyclohexenylguanine 1 is described. The key steps involve a Diels-Alder reaction of ethyl (2E)-3-acetyloxy-2-propenoate 2 as dienophile with Danishefsky's diene 3 to build up the six-membered ring skeleton, a Fraser-Reid reductive rearrangement of the adduct using LiAlH₄, and base-moiety introduction using a Mitsunobu reaction. Optically pure D- and L-1 were obtained via resolution of intermediate 7 with (R)-(-)-methylmandelic acid. The synthetic procedure toward racemic 1 consists of only five steps and has proven to be highly efficient toward the synthesis of cyclohexenyl nucleosides.

Full text of DOI:10.1021/jo015924z

8478
J . Org. Chem. 2001, 66, 8478-8482
A Str a igh tfor w a r d Ster eoselective Syn th esis of D- a n d
L-5-Hyd r oxy-4-h yd r oxym eth yl-2-cycloh exen ylgu a n in e
J ing Wang, J ordi Morral, Chris Hendrix, and Piet Herdewijn*
Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, Katholieke Universiteit Leuven,
Minderbroedersstraat 10, B-3000 Leuven, Belgium
Piet.Herdewijn@rega.kuleuven.ac.be
Received J uly 13, 2001
A novel and facile synthesis of 5-hydroxy-4-hydroxymethyl-2-cyclohexenylguanine 1 is described.
The key steps involve a Diels-Alder reaction of ethyl (2E)-3-acetyloxy-2-propenoate 2 as dienophile
with Danishefsky’s diene 3 to build up the six-membered ring skeleton, a Fraser-Reid reductive
rearrangement of the adduct using LiAlH4, and base-moiety introduction using a Mitsunobu
reaction. Optically pure D- and L-1 were obtained via resolution of intermediate 7 with (R)-(-)-
methylmandelic acid. The synthetic procedure toward racemic 1 consists of only five steps and has
proven to be highly efficient toward the synthesis of cyclohexenyl nucleosides.
In tr od u ction
Recently, we have demonstrated1 that both D- and
L-cyclohexenylguanine (1) (Figure 1) are highly potent
and selective anti-herpes virus (HSV-1, HSV-2, VZV,
CMV) agents. Their activity profile is similar to that of
the known antiviral drugs acyclovir and ganciclovir, and
they represent the most potent antiviral nucleosides
containing a six-membered carbohydrate mimic that have
ever been reported. Remarkably, the antiviral activity
profiles of both enantiomers are very similar.
We have described an enantioselective synthesis of the
D- and L-enantiomers of 1 starting from (R)-carvone.1,2
However, the synthesis is long and time-consuming, and
it is not suited for the preparation of large amounts of
the final products that are needed for full biological
evaluation.
We hereby report a short and facile synthesis of 1 and
its two enantiomers (Schemes 1-3). The key step is a
Diels-Alder reaction3 of ethyl (2E)-3-acetyloxy-2-prope-
noate 2 with Danishefsky’s diene 3 to construct the six-
membered ring skeleton (4) with the desired trans
orientation of the substituents in positions 4 and 5.
Simultaneous reduction and rearrangement using lithium
aluminum hydride (LAH) leads to triol 6. After protection
as benzylidene acetal 7, the base moiety is introduced
using a Mitsunobu reaction.
F igu r e 1. Structure of (()-cyclohexenyl G and assignment
of D- and L-nomenclature.
(2E)-3-acetyloxy-2-propenoate 24 can easily be obtained
on a multigram scale by formylation of ethyl acetate and
acetylation of the sodium salt of the R-formyl ester using
acetyl chloride. A mixture of (E)-2 and (Z)-2 was obtained
when the temperature during reaction and distillation
was not well controlled. However, the (Z)-2 isomer can
easily be converted quantitatively into (E)-2 via treat-
ment of the mixture of (Z)-2 and (E)-2 with thiophenol
in the presence of 2,2′-azobis(2-methylpropionitrile)
(AIBN). Danishefsky’s diene 35 was readily obtained (50
g scale) by silylation of (E)-4-methoxy-3-buten-2-one
(TMSCl, ZnCl2, Et3N) followed by distillation.
The Diels-Alder reaction was carried out by heating
a mixture of neat 2 and 3 in the presence of hydroquinone
at 180 °C for 1.5 h (Scheme 1). After removal of the
volatiles, the residue was distilled under high vacuum
and the adduct was obtained in 71% yield as a 4:1
Resu lts a n d Discu ssion
The preparation of dienophile (E)-2 and diene 3 for the
Diels-Alder reaction is presented in Scheme 4. Ethyl
* To whom correspondence should be addressed. Phone: +32-16-
337387. Fax: +32-16-337340.
(1) Wang, J .; Froeyen, M.; Hendrix, C.; Andrei, G.; Snoeck, R.; De
Clercq, E.; Herdewijn, P. J . Med. Chem. 2000, 43(4), 736-745.
References of related six-membered carbocyclic nucleosides are cited
therein.
(2) (a) Wang, J .; Herdewijn, P. J . Org. Chem. 1999, 64, 7820-7827.
(b) Wang, J .; Busson, R.; Blaton, N.; Rozenski, J .; Herdewijn, P. J .
Org. Chem. 1998, 63, 3051-3058.
(3) Reviews: (a) Danishefsky, S. Acc. Chem. Res. 1981, 14, 400. (b)
Danishefsky, S.; DeNinno, M. P. Angew. Chem., Int. Ed. Engl. 1987,
15. (c) Danishefsky, S. Chemtracts: Org. Chem. 1989, 2, 273.
(4) (a) Wislicenus, W. Chem. Ber. 1887, 20, 2930-2934. (b) Von-
Pechman, H. Chem. Ber. 1892, 25, 1040-1045. For the use of ethyl
(2E)-3-acetyloxy-2-propenoate as a dienophile, see: Ranganathan, S.;
Ranganathan, D.; Mehrota, A. K. Synthesis 1976, 620-621. (c) Blancou,
H.; Casadevall, E. Tetrahedron 1976, 32, 2907-2913.
(5) Danishefsky, S.; Kitahara, T. J . Am. Chem. Soc. 1974, 96, 7807-
7808.
10.1021/jo015924z CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/13/2001

Synthesis of Cyclohexenyl G
J . Org. Chem., Vol. 66, No. 25, 2001 8479
Sch em e 1. Syn th esis of th e Cycloh exen yl
P r ecu r sor a
yield over the two steps. The R-configuration of the 1-OH
substituent of 7 was established by an NOE experiment
(Figure 2): irradiation of the proton at C1 gave enhanced
signals of H2â, H3, and H6.
Introduction of the purine base moiety was performed
according to our previously reported procedure;2 i.e., 7
was reacted with 2-amino-6-chloropurine under Mit-
sunobu reaction conditions to generate the chloropurine
10a with inversion of the configuration at C1 (Scheme
2). The N7-isomer (14%) 10b was also isolated. Finally,
acidic hydrolysis of 10a gave the racemic (()-1 in 27%
overall yield starting from 7. The spectral data of (()-1
are identical to those of the previously reported enanti-
omer(s).1,2
The synthesis of optically pure D-1 and L-1 was
achieved via resolution of intermediate 7 followed by
introduction of the base moiety on the enantiopure
cyclohexene precursor using a Mitsunobu reaction (Scheme
3). Several methods for resolving 7 could be envisaged,
i.e., kinetic resolution using Sharpless epoxidation,9
enzymatic methods such as enantioselective esterification
using a lipase,10 or formation of diastereomeric esters.11
Sharpless epoxidation has the disadvantage that half of
the material will be lost because conversion of the
resulting epoxide back to the double bond is rather
tedious. In a first experiment, esterification of 7 using
vinyl acetate and Lipase PS (Amano) gave only 33% of
enantiomeric excess. As both enantiomers of 7 were
needed, we preferred to synthesize the diastereomeric
esters of 7 using a chiral acid. The use of the cheap and
commercially available pyroglutamic acid 11 for this
purpose was not satisfactory due to the difficult separa-
tion of the resulting diastereomeric esters. The use of (+)-
naproxene 12 was also attempted. However, the best
result with this chiral acid was 38% of diastereomeric
excess because only partial separation of its esters on
silica gel could be obtained. Finally, we retained (R)-
(-)-O-methylmandelic acid, which has been applied
earlier to resolve the diastereomeric esters of cyclohexa-
nyl nucleosides.11
a
Key: (a) 180 °C, hydroquinone, 1.5 h, 62%; (b) LiAlH4, THF,
0 °C, 66%; (c) PhCH(OMe)2, PTSA, 1,4-dioxane, rt, 24 h, 70%; (d)
MnO2, CH2Cl2, rt, 21 h, 83%; (e) NaBH4, CeCl3‚7H2O, MeOH, rt,
2 h, 90%.
F igu r e 2. Assignment of the R-configuration of 1-OH using
NOE experiments.
mixture of the endo and exo adducts 4a and 4b, respec-
tively (as determined by H NMR analysis). During the
1
distillation, the temperature should be carefully con-
trolled to avoid the formation of phenol derivative 5 as
the major product. The highly functionalized adduct 4 is
sensitive to acid and moisture and is best reduced
immediately. The stereochemical ambiguity in the adduct
is removed during the next reaction. Reduction of the
mixture 4a /4b with excess LiAlH4, according to the
procedure of Fraser-Reid,6 gave triol 6 in 64% yield. This
reaction involves the reduction of two ester groups and
concomitant rearrangement of the silyloxyenol ether to
the enone intermediate, which is then further reduced
to 6.
Acylation of 7 was carried out with (R)-(-)-methyl-
mandelic acid in the presence of DCC and DMAP in 79%
yield. Careful separation of the two diastereoisomers 13a
and 13b by chromatography with a gradient of hexane
and EtOAc gave pure 13a (eluting first) and 13b,
respectively. The diastereomeric purity of 13a and 13b
was checked by HPLC and found to be 97% for 13a and
98% for 13b. Hydrolysis of the ester group of 13a or 13b
with KOH/MeOH provided D-7a and L-7b in good yields.
The enantiomeric purity D-7a and L-7b was examined
by chiral chromatography, and was 97% and 98%,
respectively.
Reaction of triol 6 with benzaldehyde dimethyl acetal7
in the presence of PTSA at room temperature for 1 day
gave rise to benzylidene acetal 7 (70% yield). Prolongation
of the reaction time (2 days) gave rise to a mixture of 7
and 8 (ranging from 6:1 to 3:1). As separation of 7 and 8
proved difficult, the mixture was oxidized to enone 9,
which was then reduced using NaBH4 in the presence of
CeCl3‚7H2O.8 In this way, only 7 was obtained in 74%
Conversion of D-7a into D-1 and of L-7b into L-1 was
accomplished according to the same procedure as for (()-
1. The enatiomeric purity of D-1 and L-1 was 99% and
(9) (a) Trost, B. M.; Fleming, I. Comprehensive Organic Synthesis,
1991, Vol. 7, 389-436. (b) Martin, V. S.; Woodard, S. S.; Katsuki, T.;
Yamada, Y.; Ikeda, M.; Sharpless, B. J . Am. Chem. Soc., 1981, 103,
6237-6240.
(10) (a) J ohnson, C. R.; Golebiowski, A.; Steensma, D. H. J . Am.
Chem. Soc. 1992, 114, 9414-9418. (b) Pearson, A. J .; Lai, Y. S.; Lu,
W.; Pinkerton, A. J . Org. Chem. 1989, 54, 3882-3893. (c) Tsuji, T.;
Onishi, T.; Sakata, K. Tetrahedron: Asymmetry 1999, 10, 3819-3825.
(11) Maurish, Y.; Rosemeyer, H.; Esnouf, R.; Medvedovici, 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.
(6) Fraser-Reid, B.; Rahman, M.-D. A.; Kelly, D. R.; Srivastava, R.
M. J . Org. Chem. 1984, 49, 1835-1837.
(7) Crimmins, M. T.; Hollis, W. G., J r.; Lever, G. J . Tetrahedron Lett.
1987, 28, 3647-3650.
(8) Gemal, A. L.; Luche, J . L. J . Am. Chem. Soc. 1981, 103, 5454-
5459.

8480 J . Org. Chem., Vol. 66, No. 25, 2001
Sch em e 2. Syn th esis of (()-Cycloh exen yl G
Wang et al.
Sch em e 3. Sep a r a tion of En a n tiom er s of (()-Cycloh exen yl G
97%, respectively, according to chiral chromatographical
analysis (Figure 3). The absolute configuration of D-1 and
L-1 was established via comparison with an authentic
sample of D-1 that was obtained via the enantioselective
synthesis starting from (R)-carvone.1 By analogy, the
absolute configuration of the intermediates 13a /13b and
7a /7b were also established.
Sch em e 4. Syn th esis of Diels-Ald er P r ecu r sor s
In summary, we have developed a short and facile
synthesis for the preparation of racemic 1 and its two
enantiomers. The key steps involve a Diels-Alder reac-
tion of enone 2 with Danishefsky diene 3 and the
reductive rearrangement of the adduct 4. The synthesis
consists of only 5 steps (for (()-1) and it represents a
highly efficient approach toward the preparation of
cyclohexenyl nucleosides.
Exp er im en ta l Section
Gen er a l Meth od s. All air-sensitive reactions were carried
out under nitrogen. THF and Et2O were distilled from sodium/
benzophenone, 1,4-dioxane from CaH2, and CH2Cl2 from P2O5.

Synthesis of Cyclohexenyl G
J . Org. Chem., Vol. 66, No. 25, 2001 8481
with dry THF (110 mL). The mixture was cooled in an ice bath
and carefully treated with water (25 mL) for 15 min, a 15%
aqueous NaOH solution (25 mL) for 15 min, and finally water
(75 mL). After being stirred at room temperature for 0.5 h,
the resulting mixture was filtered and the slurry was washed
with water (5 × 100 mL) and EtOAc (3 × 100 mL). The layers
were separated, and the aqueous layer was washed with ethyl
acetate (3 × 100 mL). The aqueous layer was evaporated to
dryness to give a brown gummy residue, which was chromato-
graphed on silica gel (EtOAc/MeOH 91:9) to give 6 (6.74 g,
66%) as a light yellow syrup: 1H NMR (DMSO-d6) δ 1.37 (td,
1H, J ) 11.7, 9.9 Hz), 1.92-2.10 (m, 2H), 3.24-3.45 (m, 2H),
3.63 (dt, 1H, J ) 10.2, 4.4 Hz), 4.07 (m, 1H), 4.49 (t, 1H, J )
5.3 Hz, OH), 4.63 (d, 1H, J ) 5.1 Hz, OH), 4.70 (d, 1H, J ) 5.9
Hz, OH), 5.52 (d, 1H, J ) 11.0 Hz), 5.57 (d, 1H, J ) 11.0 Hz);
13C NMR (DMSO-d6) δ 42.0 (t), 47.2 (d), 62.2 (t), 65.9 (d), 66.3
(d), 127.7 (d), 132.8 (d); HRMS m/z calcd for C7H12O3Na (M +
Na+) 167.0684, found 167.0675.
(()-(4a R*,7S*,8a R*)-2-P h en yl-4a ,7,8,8a -tetr a h yd r o-4H-
1,3-ben zod ioxin -7-ol (7). Compound 6 (4.49 g, 31.1 mmol)
was treated with benzaldehyde dimethyl acetal (6.2 mL, 41.2
mmol) in the presence of p-toluenesulfonic acid monohydrate
(PTSA, 300 mg, 1.58 mmol) in dry 1,4-dioxane (140 mL) at
r.t. for 24h. Ice was added, the mixture was stirred at r.t. for
0.5 h and extracted with EtOAc (3x). The combined organic
layers were washed with water and brine, dried over sodium
sulfate and concentrated. The residue was purified on silica
gel (hexanes-EtOAc 1:1) to afford 7 (5.06 g, 70% yield) as a
white crystalline solid. A total of 600 mg (13%) of 6 was
F igu r e 3. Chiral HPLC analysis of the racemate 1 (A) and
its enantiomers D-1 (B) and L-1 (C) (see the Experimental
Section for HPLC conditions).
1
Ethyl (2E)-3-acetyloxy-2-propenoate 24 and Danishefsky’s di-
ene 35 were prepared according to the literature procedures.
HPLC analysis was performed on a Merck-Hitachi L-6200 A
liquid chromatograph equipped with a Merck-Hitachi L-4000
UV detector, using a Bio-Sil D90-10 column (250 × 10 mm).
Eluent: hexane-diisopropyl ether 65:35, flow: 3.5 mL/min,
detection: 225 nm. Chiral HPLC analysis was performed on
a Waters 6000 controller liquid chromatograph equipped with
a Waters 2487 UV detector, using a Chiralpak AD column (250
× 4.6 mm). Eluent A: hexanes-EtOH 95:5, flow: 1.0 mL/min,
detection: 200 nm; Eluent B: hexanes-EtOH 70:30 containing
0.2% TFA, flow: 1.0 mL/min, detection: 260 nm.
Isom er iza tion of th e Z/E Mixtu r e 2 to Eth yl (2E)-3-
Acetyloxy-2-p r op en oa te (2). A mixture of (Z)-2 and (E)-2
(39:100, 52.5 g, 332 mmol) was treated with thiophenol (16.3
mL, 17.5 g, 159 mmol) and 2,2′-azobis(2-methylpropionitrile)
(AIBN, 8.31 g, 50.6 mmol) at 80 °C for 2.5 h. The reaction
mixture was cooled to rt and taken up in ethyl acetate (400
mL) that was washed with an 0.01 N NaOH aqueous solution
(400 mL). The organic layer was dried over Na2SO4 and
concentrated to leave a pale yellow oil. Distillation under
vacuum (53 °C, 0.5-1.0 mmHg) afforded pure (E)-2 (55.8 g,
quantitative yield), slightly contaminated with aromatic thiol
product: 1H NMR (CDCl3) δ 1.30 (t, 3H, J ) 7.2 Hz), 2.22 (s,
3H), 4.21 (q, 2H, J ) 7.2 Hz), 5.72 (d, 1H, J ) 12.6 Hz), 8.30
(d, 1H, J ) 12.6 Hz).
recovered: mp 105-106 °C; H NMR (CDCl3) δ 1.78 (td, 1H,
J ) 12.1, 9.9 Hz), 2.17 (br-s, 1H, OH), 2.44-2.66 (m, 2H), 3.61
(t, 1H, J ) 10.8 Hz), 3.67 (ddd, 1H, J ) 11.1, 9.2, 2.9 Hz), 4.26
(dd, 1H, J ) 10.8, 4.6 Hz), 4.49 (m, 1H), 5.41 (dt, 1H, J ) 9.9,
1.6 Hz), 5.60 (s, 1H), 5.72 (dm, 1H, J ) 9.9 Hz), 7.36-7.55 (m,
5H); 13C NMR (CDCl3) δ 38.4 (t), 39.9 (d), 67.7 (d), 70.6 (t),
77.7 (d), 102.1 (d), 124.9 (d); HRMS m/z calcd for C14H16O3Na
(M
+
Na+) 255.0997, found 255.0995. Anal. Calcd for
C
14H16O3: C, 72.39; H, 6.94. Found: C, 72.07; H, 6.82.
When the reaction time was prolonged for 2 days, a mixture
of 7 and 8 (ratio ranging from 3:1 to 6:1) was obtained.
(()-(4a R*,8a R*)-2-p h en yl-4,4a ,8,8a -t et r a h yd r o-4H -1,3-
ben zod ioxin -7-on e (9). A mixture of 7/8 (3:1, 415 mg, 1.79
mmol) and activated manganese dioxide (MnO2, 1.56 g, 17.9
mmol, 10 equiv) in dry CH2Cl2 (15 mL) was stirred at rt for
21 h. The black reaction mixture was diluted with CH2Cl2 and
filtered through Celite. The filtrate was concentrated, and the
residue was chromatographed on silica gel (hexanes-EtOAc
2:1) to afford 9 (340 mg, 83%) as a white solid: mp 92-93 °C;
1H NMR (CDCl3) δ 2.65 (dd, 1H, J ) 16.4, 13.1 Hz), 2.83 (m,
1H), 2.95 (dd, 1H, J ) 16.4, 4.8 Hz), 3.79 (t, 1H, J ) 11.1 Hz),
4.04 (ddd, 1H, J ) 13.1, 9.2, 4.8 Hz), 4.45 (dd, 1H, J ) 11.1,
4.8 Hz), 5.63 (s, 1H), 6.13 (dd, 1H, J ) 9.9, 2.9 Hz), 6.58 (dd,
1H, J ) 9.9, 1.8 Hz), 7.39 (m, 3H), 7.51 (m, 2H); 13C NMR
(CDCl3) δ 39.9 (d), 44.3 (t), 69.2 (t), 77.4 (d), 101.7 (d), 126.1
(d), 128.4 (d), 129.2 (d), 132.1 (d), 137.5 (s), 144.9 (d), 196.8
(s); HRMS m/z calcd for C14H14O3Na (M + Na+) 253.0841.
found 253.0855. Anal. Calcd for C14H14O3: C, 73.03; H, 6.13.
Found: C, 72.75; H, 5.98.
Con ver sion of 9 to 7. To a solution of 9 (340 mg, 1.5 mmol)
in MeOH (15 mL) at rt was addded CeCl3‚7H2O (838 mg, 2.25
mmol, 1.5 equiv). After the mixture was stirred at rt for 1 h,
NaBH4 (68 mg, 1.8 mmol, 1.2 equiv) was added in portions.
The reaction was stirred at rt for 2 h and quenched with
crushed ice. The resulting mixture was stirred at rt for 0.5 h
and concentrated. The residue was diluted with EtOAc,
washed with water and brine, dried over sodium sulfate, and
concentrated. The residue was chromatographed on silica gel
(hexanes-EtOAc 5:1 and 1:1) to give 7 (307 mg, 90%) as a
white solid.
(()-Eth yl (1R*,6R*)-6-Acetoxy-2-m eth oxy-4-(tr im eth yl-
silyl)oxy-3-cycloh exen e-1-ca r boxyla te (4). A mixture of 2
(55.8 g, 353 mmol) and 3 (72.9 g, 423 mmol) in the presence of
a small amount of hydroquinone (372 mg) was heated at 180
°C for 1.5 h. The reaction mixture was distilled under vacuum
(130 °C/0.18 mmHg) to afford 4 as a light-yellow oil (72 g, 62%)
and as a 4:1 mixture of 4a and 4b (according to 1H NMR).
Data for major compound 4a : 1H NMR (CDCl3) δ 0.21 (s, 9H),
1.27 (t, 3H, J ) 7.3 Hz), 2.01 (s, 3H), 2.19 (m, 1H), 2.55 (dd,
1H, J ) 16.7, 5.5 Hz), 2.77 (dd, 1H, J ) 11.4, 8.4 Hz), 3.31 (s,
3H), 4.20 (m, 2H), 4.35 (dm, 1H, J ) 8.4 Hz), 4.94 (t, 1H, J )
2.2 Hz), 5.13 (ddd, 1H, J ) 11.0, 9.2, 5.9 Hz); 13C NMR (CDCl3)
δ 0.06 (q), 14.2 (q), 20.8 (q), 35.4 (t), 51.1 (t), 55.4 (q), 60.9 (t),
68.8 (d), 76.5 (d), 103.3 (d), 149.3 (s), 170.0 (s), 172.2 (s).
(()-(1R*,3S*,6R*)-6-Hyd r oxym eth yl-4-cycloh exen e-1,3-
d iol (6). To a mixture of LiAlH4 (25 g, 658 mmol) in dry THF
(220 mL) at 0 °C under nitrogen was added dropwise a solution
of 4 (21.49 g, 70.6 mmol) in dry THF (85 mL). After the mixture
was stirred at 0 °C for 2 h, the reaction was continued at room
temperature for 19 h. The viscous reaction mixture was diluted
(4a R,7R,8a R)-7-[(R)-(O-Meth ylm a n d elyl)oxy]-2-p h en yl-
4a,7,8,8a-tetr ah ydr o-4H-1,3-ben zodioxin e (13a)an d (4aS,7S,
8a S)-7-[(R)-(O-m eth ylm a n d elyl)oxy]-2-p h en yl-4a ,7,8,8a -
tetr a h yd r o-4H-1,3-ben zod ioxin e (13b). To a mixture of 7
(3.48 g, 15 mmol), (R)-(-)-methylmandelic acid (2.73 g, 16.5
mmol) and DMAP (202 mg, 1.65 mmol) in dry CH2Cl2 (48 mL)

8482 J . Org. Chem., Vol. 66, No. 25, 2001
Wang et al.
at 0 °C was added DCC (3.42 g, 16.5 mmol) in portions. The
reaction mixture was allowed to warm to rt over 1.5 h and
was stirred for an additional 1.5 h at rt. CH2Cl2 (500 mL) was
added, and the mixture was filtered. The filtrate was washed
with an aqueous 1 M H3PO4 solution (90 mL), water (90 mL),
and a saturated aqueous NaHCO3 solution (45 mL), dried over
Na2SO4, and concentrated. The crude product as white crystals
(7.11 g) was subjected to chromatography on silica gel (35-70
nm) packed with hexane and eluting with a mixture of
hexanes-EtOAc, slowly increasing the polarity. On elution
with hexanes-EtOAc 71:29, 1.34 g of 13a (93% de), a mixture
of 13a and 13b (1.96 g), and 1.22 g of 13b (79% de) were
obtained (4.52 g, 79% yield). The diastereomeric excess was
determined by HPLC.
silica gel (hexanes-EtOAc 2:1) to give D-7a (291 mg, 95% yield,
97% ee according to chiral HPLC analysis using eluent A) as
a white solid: mp 95 °C. Anal. Calcd for C14H16O3: C, 72.39;
H, 6.94. Found: C, 72.33; H, 6.70.
The same procedure was followed for conversion of 13b to
L-7b (91% yield, 99% ee):mp 94-95 °C. Anal. Calcd for
C14H16O3‚0.5H2O: C, 69.69; H, 7.10. Found: C, 69.57; H, 6.94.
(()-(1S*,4R*,5S*)-9-(5-Hyd r oxy-4-h yd r oxym et h yl-2-cy-
cloh exen -1-yl)gu a n in e (1). To a mixture of 7 (696 mg, 3
mmol), 2-amino-6-chloropurine (1.02 g, 6 mmol), and triph-
enylphosphine (PPh3, 1.57 g, 6 mmol) in dry 1,4-dioxane (30
mL) was added slowly a solution of DEAD (945 mL, 6 mmol)
in dry 1,4-dioxane (10 mL). The reaction was stirred at rt
overnight and concentrated. The residue was absorbed on silica
gel and chromatographed (CH2Cl2-MeOH 100:1 and 50:1) to
afford crude 10a (2 g) and the N7-epimer 10b (140 mg) as a
white solid.
Crude 10a (2 g) was treated with TFA-H2O (3:1, 20 mL) at
rt for 2 days. The reaction mixture was concentrated and
coevaporated with toluene. The residue was chromatographed
on silica gel (CH2Cl2-MeOH 50:1 and 10:1) to give (()-1 (220
mg, 27% overall yield starting from 7). The physicochemical
properties (1H NMR, 13C NMR, MS, UV) of 1 are identical to
those previously reported.1
(1S,4R,5S)-9-(5-Hydr oxy-4-h ydr oxym eth yl-2-cycloh exen -
1-yl)gu a n in e (D-1). The same procedure as described for the
preparation of (()-1 was used. The analytical sample was
obtained by crystallization with a mixture of diisopropyl
ether-MeOH (8:2). The enantiomeric excess (99% ee) was
determined by Chiral HPLC analysis using eluent B): mp
275-280 °C dec. Anal. Calcd for C12H19N5O3.2(H2O): C, 46.00;
H, 6.11; N, 22.35. Found: C, 46.30; H, 5.81; N, 22.18.
(1R,4S,5R)-9-(5-Hyd r oxy-4-h yd r oxym eth yl-2-cycloh ex-
en -1-yl)gu a n in e (L-1). The same procedure as described for
the preparation of (()-1 was used. The analytical sample (97%
ee) was obtained by crystallization from a mixture of EtOAc-
MeOH (4:3): mp 273-277 °C dec. Anal. Calcd for C12H19N5O3.2-
(H2O): C, 46.00; H, 6.11; N, 22.35. Found: C, 46.21; H, 5.86;
N, 21.73.
The fractions containing 13a and 13b were again submitted
to chromatographic purification yielding 589 mg (97% of
diastereomeric purity) of 13a and 426 mg (99% of diastereo-
meric purity) of 13b.
Compound 13a : mp 67-68 °C; 1H NMR (CDCl3) δ 1.91 (dt,
1H, J ) 12.0, 10.2 Hz), 2.55 (ddd, 1H, J ) 11.1, 7.5, 3.5 Hz),
2.60 (ddd, 1H, J ) 10.9, 7.0, 3.9 Hz), 3.41 (s, 3H), 3.61 (t, 1H,
J ) 11.4 Hz), 3.71 (ddd, 1H, J ) 11.4, 9.1, 3.1 Hz), 4.24 (dd,
1H, J ) 11.0, 4.4 Hz), 4.78 (s, 1H,), 5.47 (s, 1H), 5.59 (s, 1H),
5.59-5.68 (m, 1H), 7.32-7.54 (m, 10H, aromatic protons); 13
C
NMR (CDCl3) δ 34.1 (t), 39.7 (d), 57.3 (q), 70.3 (t), 70.6 (d),
77.1 (d), 82.6 (d), 102.1 (d), 126.1 (d), 127.2 (d), 127.4 (d), 128.0
(d), 128.4 (d), 128.7 (d) 128.8 (d), 129.0 (d), 136.1 (s), 138.0 (s),
170.4 (s, CO). Anal. Calcd for C23H24O5: C, 72.61; H, 6.36.
Found: C, 72.64; H, 6.40.
Compound 13b: 1H NMR (CDCl3) δ 1.91 (dt, 1H, J ) 12.0,
9.9 Hz), 2.37 (ddd, 1H, J ) 10.8, 7.3, 2.9 Hz), 2.56 (m, 1 H),
3.39 (s, 3H), 3.57 (t, 1H, J ) 11.4 Hz), 3.64 (ddd, 1H, J ) 12.4,
9.2, 3.2 Hz), 4.24 (dd, 1H, J ) 11.0, 4.6 Hz), 4.76 (s, 1H), 5.47
(s, 1H), 5.43-5.57 (m, 1H), 5.54-5.70 (m, 1H), 7.30-7.48 (m
10 H, aromatic protons); 13C NMR (CDCl3) δ 33.6 (t), 39.5 (d),
57.1 (q), 70.1 (t), 70.4 (d), 76.8 (d), 82.3 (d), 101.8 (d), 126.0
(d), 127.0 (d), 127.4 (d), 128.0 (d), 128.1 (d), 128.7 (d), 128.5
(d), 128.8 (d), 129.3 (s), 135.9 (s), 137.9 (s), 170.2 (s, CO); HRMS
m/z calcd for C23H24O5Na (M + Na+) 403, found 403. Anal.
Calcd for C23H24O5: C, 72.61; H, 6.36. Found: C, 72.44; H,
6.42.
Ack n ow led gm en t. The authors cordially thank
Prof. P. Sandra (Ghent University, Belgium) for help
with chiral HPLC analysis and Prof. J . Van der Eycken
(Ghent University, Belgium) for enzymatic experiments.
We are indebted to Prof. W. Pfleiderer for elemental
analysis. Financial support from the Katholieke Uni-
versiteit Leuven (GOA 97/11) is gratefully acknowledged.
Hyd r olysis of 13a to D-7a a n d 13b to L-7b. A solution of
13a (500 mg, 1.31 mmol, 97% de) in 20% aqueous NaOH (27
mL, 133 mmol), THF (27 mL), and MeOH (27 mL) was heated
under reflux for 2 h. The organic solvent was evaporated under
vacuum, and the remaining aqueous phase was diluted with
water (30 mL) and extracted with CH2Cl2 (4 × 60 mL). The
combined organic layers were washed with
a saturated
NaHCO3 solution (60 mL) and brine (60 mL), dried over Na2-
SO4, and evaporated. The residue was chromatographed on
J O015924Z