Enantiodivergent synthesis of cyclohexenyl nucleosides

Article abstract of DOI:10.1021/jo802492g

An enantiodivergent synthesis of several cyclohexenyl nucleosides has been efficiently completed starting from the enantiopure hydrobenzoin-derived monoketal of cyclohex-2-en-1,4-dione, (+)-5. Stereodiversity was accomplished on the base coupling step. Th

Full text of DOI:10.1021/jo802492g

Enantiodivergent Synthesis of Cyclohexenyl Nucleosides
`
Eric Ferrer, Ramon Alibe´s,* Fe´lix Busque´,* Marta Figueredo, Josep Font, and
Pedro de March
Departament de Qu´ımica, UniVersitat Auto`noma de Barcelona, 08193 Bellaterra, Spain
ramon.alibes@uab.cat
ReceiVed NoVember 7, 2008
An enantiodivergent synthesis of several cyclohexenyl nucleosides has been efficiently completed starting
from the enantiopure hydrobenzoin-derived monoketal of cyclohex-2-en-1,4-dione, (+)-5. Stereodiversity
was accomplished on the base coupling step. This methodology has proved to be useful for the synthesis
of enantiopure pyrimidine and purine nucleoside analogues, which anti-HIV activity has been evaluated.
Introduction
The considerable attention focused on finding new antiviral
and antitumor therapeutic agents has been rewarded with the
discovery of a variety of carbanucleosides exhibiting potent and
selective biological activity.1 The cyclopentenyl nucleosides (-)-
carbovir, 1,2 and abacavir, 2,3 are among the earlier examples
(Figure 1). These analogues are more resistant to hydrolytic
processes and have enhanced lipophilicity compare to regular
nucleosides, favoring absorption and penetration through the
cell membrane. Fewer efforts have been directed toward the
synthesis of six-membered carbocyclic analogues.4 However,
cyclohexenyl nucleosides are a promising class of antiviral
compounds, wherein replacement of the oxygen atom of the
furanose ring by a double bond induces annular flexibility,
FIGURE 1. Several biological active carbocyclic nucleosides 1-3 and
chiral p-benzoquinone monoketal 4.
similar to that of a natural furanose nucleoside.5 Recently, it
has been described that both enantiomers of cyclohexenylgua-
nine 3 display potent and selective anti-herpesvirus activity
(HSV-1, HSV-2, VZV, CMV).6
(1) (a) Wang, J.; Jin, Y.; Rapp, K. L.; Schinazi, R. F.; Chu, C. K. J. Med.
Chem. 2007, 50, 1828–1839. (b) Jeong, L. S.; Lee, J. A. AntiViral Chem.
Chemother. 2004, 15, 235–250. (c) Agrofoglio, L. A.; Challand, S. R. Acyclic,
Carbocyclic and L-Nucleosides; Kluwer Academic Publishers: Dordrecht, 1998.
(d) Crimmins, M. T. Tetrahedron 1998, 54, 9229–9272.
It is well-known that opposite enantiomers can display
different pharmacological and toxicological properties.7 Hence,
(2) Coates, J. A. V.; Inggall, H. J.; Pearson, B. A.; Penn, C. R.; Storer, R.;
Williamson, C.; Cameron, J. M. AntiViral Res. 1991, 15, 161–168.
(3) Daluge, S. M.; Good, S. S.; Faletto, M. B.; Miller, W. H.; St. Clair, M. H.;
Boone, L. R.; Tisdale, M.; Parry, N. R.; Reardon, J. E.; Dornsife, R. E.; Averett,
D. R.; Krenitsky, T. A. Antimicrob. Agents Chemother. 1997, 41, 1082–1093.
(4) (a) Wang, J.; Froeyen, M.; Herdewijn, P. AdV. AntiVir. Drug Des. 2004,
4, 119–145, and references cited therein.8. (b) Vijgen, S.; Nauwelaerts, K.; Wang,
J.; Van Aerschot, A.; Lagoja, I.; Herdewijn, P. J. Org. Chem. 2005, 70, 4591–
4597. (c) Horva´th, A.; Ruttens, B.; Herdewijn, P. Tetrahedron Lett. 2007, 48,
3621–3623.
(5) Herdewijn, P.; De Clercq, E. Bioorg. Med. Chem. Lett. 2001, 11, 1591–
1597.
(6) Wang, J.; Froeyen, M.; Hendrix, C.; Andrei, G.; Snoeck, R.; De Clercq,
E.; Herdewijn, P. J. Med. Chem. 2000, 43, 736–745.
(7) (a) Terry, B. J.; Cianci, C. W.; Hagen, M. E. Mol. Pharm. 1991, 40,
591–596. (b) Schinazi, R. F.; Chu, C. K.; Peck, A.; McMillan, A.; Mathis, R.;
Cannon, D.; Jeong, L.- S.; Beach, J. W.; Choi, W.-B.; Yeola, S.; Liotta, D. C.
Antimicrob. Agents Chemother. 1992, 36, 672–676. (c) Wang, P.; Gullen, B.;
Newton, M. G.; Cheng, Y. C.; Schinazi, R. F.; Chu, C. K. J. Med. Chem. 1999,
42, 3390–3399.
10.1021/jo802492g CCC: $40.75
Published on Web 02/17/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 2425–2432 2425

Ferrer et al.
SCHEME 1. Synthetic Strategy
SCHEME 2. Synthesis of Key Intermediate
(+)-(2R,3R,8R)-5
the synthesis of enantiomerically pure nucleoside analogues is
required. During the past years our research group has developed
efficient methodologies for the preparation of enantiomerically
pure cyclohexane compounds. As part of this research, we have
prepared a series of p-benzoquinone monoketals derived from
chiral C2-symmetric diols (e.g., 4),8 which have been success-
fully used as building blocks in the synthesis of several bioactive
products containing a cyclohexane unit in their structure.9
This former experience, along with the reported activity of
the six-membered carbocyclic nucleosides such as 3, prompted
us to plan the synthesis of enantiopure cyclohexenyl nucleoside
analogues designed as potential antiviral agents. Herein we
report an enantiodivergent approach to D- and L-4-hydroxycy-
clohexenyl nucleosides, starting from the common intermediate
5, which bears a hydrobenzoin moiety as the chiral auxiliary
(Scheme 1). We have designed a divergent synthesis that
involves two main transformations: (i) introduction of the
nucleobase with either inversion (Mitsunobu methodology) or
retention (Pd-catalyzed coupling reaction) of configuration,
followed by removal of the chiral auxiliary and (ii) stereose-
lective reduction of the carbonyl group to deliver the target
cyclohexene nucleosides with the cis relative configuration.
TABLE 1. Reduction of Ketone 9
entry
reducing agent
conditions
yield (%) 5:10
1
2
3
4
5
6
NaBH4, CeCl3 ·7H2O
DIBAL-H
L-Selectride
catecholborane
catecholborane, (S)-2-Me-CBS CH2Cl2, -78 °C
catecholborane, (R)-2-Me-CBS CH2Cl2, -78 °C
MeOH, -78 °C
THF, -78 °C
THF, -78 °C
CH2Cl2, -78 °C
93
71
63
33
90
95
4:1
4:1
4:1
3:1
8:1
1:1
Thus, treatment of 6 with (R,R)-hydrobenzoin in benzene at
reflux temperature afforded the monoketal (2R,3R)-7 along with
the corresponding bisketal 8 in 54% and 46% yield, respectively.
Monohydrolysis of 8 furnished an additional amount of (2R,3R)-
7, the overall yield for the conversion of 6 into 7 then being
82%. Sequential bromination of the ketone 7 with Br2 at -5
°C and dehydrobromination, using DBU in dioxane at reflux,
afforded the enone (2R,3R)-9 in 78% overall yield. Other oxidant
methodologies, using IBX11 or Mukaiyama protocol,12 proved
to be less efficient for this transformation.
The efficiency of the synthesis of the key allylic alcohol
(2R,3R,8R)-5 depends on the diastereoselectivity of the reduction
of the carbonyl group of (2R,3R)-9. Hence, we proceeded to
study this reaction using different reducing agents (Table 1).
Initially, reduction of ketone 9 was performed using NaBH4
in MeOH in the presence of CeCl3 at -78 °C, affording a ca.
4:1 mixture of (2R,3R,8R)-5 and (2R,3R,8S)-10 in 93% yield
(entry 1). Similarly, when other reducing agents based on
aluminum (entry 2) or boron (entry 3) were employed, values
of diastereoselectivity around 4:1 were achieved. When cat-
echolborane (CB) was used in the reaction, a ca. 3:1 mixture
of isomers was again obtained albeit in low yield (entry 4).
Better selectivity was achieved by using catecholborane paired
with (S)-2-Me-CBS (entry 5).13 In this case a ca. 8:1 mixture
of 5 and 10 was obtained in 90% yield, from which the major
Results and Discussion
The enantiopure allylic alcohol (2R,3R,8R)-5 was previously
synthesized in our laboratory from p-benzoquinone in three steps
involving selective ketalization with (R,R)-hydrobenzoin (81%
yield), partial hydrogenation using Wilkinson’s catalyst (41%
yield), and reduction with NaBH4 (67% yield).10 With the aim
of skipping the low-yielding hydrogenation step, we have now
set up a more practical and multigram preparation of 5 starting
from 1,4-cyclohexandione, 6 (Scheme 2).
(8) (a) de March, P.; Escoda, M.; Figueredo, M.; Font, J.; Alvarez-Larena,
A.; Piniella, J. F. J. Org. Chem. 1997, 62, 7781–7787. (b) de March, P.; Escoda,
M.; Figueredo, M.; Font, J.; Medrano, J. An. Quim., Int. Ed. 1997, 93, 81–87.
(c) de March, P.; Figueredo, M.; Font, J.; Rodr´ıguez, S. Tetrahedron 2000, 56,
3603–3609. (d) Busque´, F.; de March, P.; Figueredo, M.; Font, J.; Rodr´ıguez,
S. Tetrahedron: Asymmetry 2001, 12, 3077–3080.
(9) (a) Busque´, F.; Canto´, M.; de March, P.; Figueredo, M.; Font, J.;
Rodr´ıguez, S. Tetrahedron: Asymmetry 2003, 14, 2021–2032. (b) Alibe´s, R.;
Bayo´n, P.; de March, P.; Figueredo, M.; Font, J.; Marjanet, G. Org. Lett. 2006,
8, 1617–1620. (c) Alibe´s, R.; Busque´, F.; Bardaji, G.-G.; de March, P.; Figueredo,
M.; Font, J. Tetrahedron: Asymmetry 2006, 17, 2632–2636.
(10) de March, P.; Escoda, M.; Figueredo, M.; Font, J.; Garc´ıa-Garc´ıa, E.;
Rodr´ıguez, S. Tetrahedron: Asymmetry 2000, 11, 4473–4483.
(11) Nicolaou, K. C.; Montagnon, T.; Baran, P. S. Angew. Chem., Int. Ed.
2002, 41, 993–996.
(12) (a) Mukaiyama, T.; Matsuo, J.-I.; Kitagawa, H. Chem. Lett. 2000, 1250–
1251. (b) Matsuo, J.; Iida, D.; Tatani, K.; Mukaiyama, T. Bull. Chem. Soc. Jpn.
2002, 75, 223–234.
(13) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986–2012,
and references cited therein. .
2426 J. Org. Chem. Vol. 74, No. 6, 2009

Synthesis of Cyclohexenyl Nucleosides
SCHEME 3. Synthesis of (1′S)- and (1′R)-13
SCHEME 4. Synthesis of D-Cyclohexenyl Adenine
Nucleoside
mate, pyridine, and DMAP in CH2Cl2 and was coupled with
6-chloropurine in the presence of [η3-C3H5PdCl]2, 1,2-bis(diphe-
nylphosphino)ethane (dppe) and 1,2,2,6,6-pentamethylpiperidine
(pempidine) in DMF to afford exclusively the N9-isomer
(2′R,3′R,8′R)-15 in 68% yield. In this case, the N7 coupling
product regioisomer was not detected. The subsequent hydrolysis
of the ketal delivered (1′R)-13 in 90% yield, [R]D ) +70.6 (c
1.35, CHCl3).
Having a convenient methodology for the supply of both
enantiomers of 13, the synthesis of D-cis-1-(4-hydroxy-2-
cyclohexenyl) adenine was undertaken (Scheme 4). The first
step is the reduction of the carbonyl group of the enone (1′S)-
13, wherein ꢀ-oriented OH at C-4′ is required. Assayed
reductions with available achiral reagents (NaBH4-CeCl3 ·
7H2O, LiBH4-ZnCl2) produced chromatographically inseparable
mixtures of both isomers (1′S,4′S)-16 and (1′S,4′R)-17 in good
yields, with the trans-isomer 16 being predominant in all cases
(ca. 3:1). A reagent-controlled stereoselective reduction with
catecholborane in the presence of (R)-2-Me-CBS increased
notably the proportion of the trans alcohol, delivering a 7:1
mixture of 16 and 17 in 77% global yield. Interestingly, when
the reaction was performed with the opposite enantiomer of the
catalyst, (S)-2-Me-CBS, the trans:cis ratio dropped to 2:1. Its
relative configuration was established by detailed 1D and 2D
NMR experiments. The 1,4-trans relationship of the major
isomer 16 was assigned from the coupling constants observed
diastereoisomer 5 was isolated by crystallization in 70% yield.
Remarkably, reduction with catecholborane paired with the (R)-
enantiomer of 2-Me-CBS (entry 6) yielded a 1:1 mixture of
both diastereoisomers in 95% yield, showing a clear example
of mismatching between the sense of chirality of the reducing
agent and that of the substrate.
With (2R,3R,8R)-5 in hand, we assayed the introduction of a
purine base by a Mitsunobu type reaction, which has been shown
to give carbocyclic nucleosides with inversion of configuration.14
Thus, the allylic alcohol 5 was reacted with 6-chloropurine in
the presence of di-tert-butyl azodicarboxylate (DBAD) and
triphenylphosphine to provide the desired N9-regioisomer
(2′R,3′R,8′S)-12 in 70% yield, along with the N7-coupled
product (2′R,3′R,8′S)-11 in10% yield (Scheme 3). The attach-
1
ment site of the purine base was deduced from the H and 13C
NMR spectra wherein the H-8 proton signal and the C-4, C-8,
and C-8′ signals of the N9-isomer 12 (δ 8.21, 151.4, 153.7,
and 49.8) are shifted highfield compared to that of the N7-isomer
11 (δ 8.37, 162.4, 147.5, and 51.9). These data agree with those
reported in the literature.15 Removal of the chiral auxiliary from
12 was readily achieved by treatment with a mixture of
trifluoroacetic acid-H2O (14:1), furnishing the cyclohexenone
(1′S)-13 in 92% yield, [R]D ) - 73.3 (c 1.35, CHCl3).
Next, the synthesis of the antipode (1′R)-13 was targeted for
attention. Trost palladium-catalyzed coupling of allylic carbon-
ates with heterocyclic bases, which proceeds with retention of
configuration, has proven to be efficient for the synthesis of
carbanucleosides.16,17 The allylic carbonate (2R,3R,8R)-14 was
prepared quantitatively by reaction of 5 with ethyl chlorofor-
1
in the H NMR spectrum. For H-1′ a large coupling constant
(10.6 Hz) with H-6ax and a smaller coupling constant (5.2 Hz)
with H-6eq were detected. Similarly, H-4′ showed coupling
constants of 9.7 and 4.7 Hz with H-5ax and H-5eq, respectively.
Altogether these coupling constants indicate that both the
nucleobase on C-1 and the hydroxyl group on C-4′ occupy
pseudoequatorial positions and are arranged in a 1,4-trans
relationship.
According to these results, we decided to assay the inversion
of the hydroxyl group in 16 through a Mitsunobu reaction, using
p-nitrobenzoic acid as the nucleophile. In the event, a 7:1
mixture of alcohols (1′S,4′S)-16 and (1′S,4′R)-17 delivered a
7:1 mixture of the inverted nitrobenzoates (1′S,4′R)-18 and
(1′S,4′S)-19 in 86% yield. A final ammonolysis removed the
nitrobenzoates and converted the chloropurine derivatives to a
7:1 mixture of the adenine analogues (1′S,4′R)-20 and (1′S,4′S)-
21 in 98% yield, with the total yield from 5 being 42%.
Unfortunately, we were unable to separate these isomers, and
all attempts to obtain a pure sample of the targeted D-
(14) Pe´rez-Pe´rez, M.-J.; Rozenski, J.; Bussom, R.; Herdewijn, P. J. Org.
Chem. 1995, 60, 1531–1537.
(15) (a) Garner, P.; Ramakanth, S. J. Org. Chem. 1982, 53, 1294–1298. (b)
Rustullet, A.; Alibe´s, R.; de March, P.; Figueredo, M.; Font, J. Org. Lett. 2007,
9, 2827–2830.
(16) Trost, B. M.; Madsen, R.; Guile, S. D.; Brown, B. J. Am. Chem. Soc.
2000, 122, 5947–5956.
J. Org. Chem. Vol. 74, No. 6, 2009 2427

Ferrer et al.
(2′R,3′R,8′S)-22 in good yield.20 The O-alkyl compound, a
common byproduct of this reaction, was not detected in the
NMR spectra of the reaction crude. The attachment site of the
pyrimidine base was established by an HMBC experiment that
showed correlation between H-8′ and C-6.
SCHEME 5. Synthesis of D- and L-Cyclohexenyl Uracil
Nucleosides
Acidic hydrolysis followed by stereoselective CBS-catalyzed
reduction of (1′S)-23 generated exclusively the trans alcohol
(1′S,4′S)-24 in 88% yield for the two steps, [R]D ) +13.2 (c
0.8, CHCl3). The trans-1,4-substitution pattern of 24 was
established in a similar way as for the purine derivative by
detailed 1D and 2D NMR analyses and was further confirmed
1
from the value of the coupling constants observed in the H
NMR spectrum of its cyclohexanyl derivative 28, easily obtained
1
by an hydrogenation reaction. Thus, in the H NMR spectrum
of 28 H-1′ resonates at δ 4.44 and appears as a triplet of triplets
with coupling constants J1′,2′ax ≈ J1′,6′ax ) 11.9 Hz and J1′,2′eq
≈
J1′,6′eq ) 3.6 Hz. A similar pattern is observed for H-4′, appearing
as a triplet of triplets at δ 3.66 with large diaxial coupling
constants (J4′,5′ax ≈ J4′,3′ax ) 11.1 Hz) and small coupling
constants (J4′,5′eq ≈ J4′,3′eq ) 4.3 Hz). These data suggest a chair
conformation with both the heterocyclic base moiety and the
hydroxyl group in equatorial orientations, which is possible only
in a 1,4-trans relationship. As above, the corresponding cis-1,4
compound was obtained by using a second Mitsunobu-type
reaction between the allylic alcohol (1′S,4′S)-24 and p-nitroben-
zoic acid, furnishing the nitrobenzoate (1′S,4′R)-25, which was
treated with methylamine in ethanol solution21 to provide the
target cis-1,4-hydroxy-2-cyclohexenyl uracil, (1′S,4′R)-26, in
90% yield for the two steps, [R]D ) +73.0 (c 1.0, MeOH).
The synthesis of its enantiomer (1′R,4′S)-26 was carried out
via the palladium-catalyzed coupling reaction of the previously
described allylic carbonate (2R,3R,8R)-14 with N3-benzoylu-
racil, which afforded the uracil derivative (2′R,3′R,8′R)-27 in
72% yield.22 Acid treatment and subsequent diastereoselective
reduction furnished (1′R,4′R)-24 in 82% yield, [R]D ) +12.4
(c 1.0, CHCl3). Finally, Mitsunobu-type reaction and simulta-
neous removal of the ester protecting groups gave access to
the cyclohexenyl uracil analogue (1′R,4′S)-26 in 82% yield for
the two steps, [R]D ) -72.2 (c 1.1, MeOH). Thus, the synthesis
of both enantiomers (1′R,4′S)- and (1′S,4′R)-26 has been
successfully accomplished from the common intermediate
(2R,3R,8R)-5 in 68% and 47% yield, respectively.
As a preliminary test, the new synthesized nucleoside
analogues were evaluated on MT4 cells for anti-HIV-1 activity
against wild-type NL4-3 strain as well as cytotoxicity using AZT
and AMD3100 as the positive control. The results are sum-
marized in Table 2. Unfortunately, although a weak anti-HIV
activity was found for 11, 12, (1′S)-13, (1′R)-13, 15, (1′R)-23,
and (1′S)-23, it was not separate from cytotoxicity.
cyclohexenyl adenine 20 met with failure. The cis-1,4-substitu-
tion of the major isomer 20 was confirmed by comparing its
NMR spectra with those previously reported in the literature
for racemic 20.18
Conclusions
We then turned our attention to the synthesis of uracil
cyclohexenyl nucleoside analogues, following the same strategy
as above (Scheme 5). First, a Mitsunobu reaction was applied
for introducing the base moiety. Thus, coupling of (2R,3R,8R)-5
with N3-benzoyluracil19 gave only the N1-alkylated derivative
In summary, an enantiodivergent synthesis of adenine and
uracil cyclohexenyl nucleosides has been developed from the
unique chiral precursor (2R,3R)-9, bearing a dihydrobenzoin
(20) (a) Yamada, K.; Sakata, S.; Yoshimura, Y. J. Org. Chem. 1998, 63,
6891–6899. (b) Wang, J.; Vin˜a, D.; Busson, R.; Herdewijn, P. J. Org. Chem.
2003, 68, 4499–4505. (c) Wang, J.; Jin, Y.; Rapp, K. L.; Bennett, M.; Schinazi,
R. F.; Chu, C. K. J. Med. Chem. 2005, 48, 3736–3748.
(21) Frieden, M.; Giraud, M.; Reese, C. B.; Song, Q. J. Chem. Soc., Perkin
Trans. 1 1998, 2827–2832.
(22) Ahn, H.; Choi, T. H.; de Castro, K.; Lee, K. C.; Kim, B.; Moon, B. S.;
Hong, S. H.; Lee, J. C.; Chun, K. S.; Cheon, G. J.; Lim, S. M.; An, G. I.; Rhee,
H. J. Med. Chem. 2007, 50, 6032–6038.
(17) (a) Rosenquist, Å.; Kvarnstro¨m, I.; Classon, B.; Samuelsson, B. J. Org.
Chem. 1996, 61, 6282-6288. (b) Konkel, M. J.; Vince, R. Tetrahedron 1996,
52, 799–808.
(18) Ramesh, K.; Wolfe, M. S.; Lee, Y.; Velde, D. V.; Borchardt, R. T. J.
Org. Chem. 1992, 57, 5861–5868.
(19) Cruickshank, K. A.; Jiricny, J.; Reese, C. Tetrahedron Lett. 1984, 25,
681–684.
2428 J. Org. Chem. Vol. 74, No. 6, 2009

Synthesis of Cyclohexenyl Nucleosides
TABLE 2. Anti-HIV-1 Activity against Wild-Type NL4-3 Strain
and Cytotoxicity of the Synthesized Cyclohexenyl Nucleosides in
Comparison with AZT and AMD3100, used as Reference Drugsa
mg, 1.62 mmol), 6-chloropurine (505 mg, 3.24 mmol) and
triphenylphosphine (858 mg, 3.24 mmol) in anhydrous THF (10
mL) under argon atmosphere. The reaction mixture was allowed
to warm to room temperature and stirred overnight. The organic
solvent was removed under vacuum, and the resulting oil was
purified by flash chromatography (hexanes-EtOAc, 4:1) to afford
the N9-isomer 12 (505 mg, 1.13 mmol, 70% yield) and the
corresponding N7-isomer 11 (75 mg, 0.16 mmol, 10% yield) both
as white solids. 11 (N7-isomer): mp 196-198 °C (ethyl ether);
b
c
compd
EC50
CC50
11
12
(1′S)-13
(1′R)-13
15
20, 21
22
>2.4
>6.8
>0.5
>13.5
>6.4
>25
2.4
6.8
0.5
13.5
6.4
>25
>25
>25
4.3
10.1
>25
>25
>25
>25
[R]20 ) +44.0 (c 0.25, CHCl3); IR (ATR) υ 3027, 2880, 1597,
D
1380, 1210, 1051, 1018, 971, 694, 621 cm-1; 1H NMR (250 MHz,
CDCl3) δ 8.91 (s, 1H, H-2), 8.37 (s, 1H, H-8), 7.38-7.28 (m, 6H,
H-Ar), 7.28-7.18 (m, 4H, H-Ar), 6.49 (dd, J6′,7′ ) 10.0 Hz, J6′,8′
) 1.8 Hz, 1H, H-6′), 6.19 (dd, J7′,6′ ) 10.0 Hz, J7′,8′ ) 3.9 Hz, 1H,
H-7′), 5.73 (m, 1H, H-8′), 4.89 (d, J3′,2′ ) 8.6 Hz, 1H, H-3′), 4.79
(d, J2′,3′ ) 8.6 Hz, 1H, H-2′), 2.71-2.55 (m, 1H, H-9′), 2.35-2.15
(m, 3H, H-9′,2H-10′); 13C NMR (62.5 MHz, CDCl3) δ 162.4, 152.6,
147.5, 142.9, 136.1, 135.7, 135.5, 128.7, 128.6, 128.3, 126.7, 126.6,
126.5, 122.1, 104.3, 85.8, 85.2, 51.9, 30.7, 29.0; HRMS (ESI+)
calcd for C25H21ClN4O2Na 467.1245 [M + Na]+, found 467.1243.
12 (N9-isomer): mp 197-199 °C (ethyl ether); [R]20D ) -20.0 (c
0.25, CHCl3); IR (ATR) υ 3064, 3027, 1597, 1566, 1446, 1396,
1089, 933, 768, 695 cm-1; 1H NMR (250 MHz, CDCl3) δ 8.78 (s,
1H, H-2), 8.21 (s, 1H, H-8), 7.38-7.29 (m, 6H, H-Ar), 7.29-7.20
(m, 4H, H-Ar), 6.44 (dd, J6′,7′ ) 10.0 Hz, J6′,8′ ) 1.9 Hz, 1H, H-6′),
6.14 (dd, J7′,6′ ) 10.0 Hz, J7′,8′ ) 3.6 Hz, 1H, H-7′), 5.45 (m, 1H,
H-8′), 4.90 (d, J3′,2′ ) 8.5 Hz, 1H, H-3′), 4.82 (d, J2′,3′ ) 8.5 Hz,
1H, H-2′), 2.63-2.48 (m, 1H, H-9′), 2.35-2.22 (m, 3H, H-9′, 2H-
10′); 13C NMR (62.5 MHz, CDCl3) δ 151.9, 151.4, 151.2, 143.7,
135.8, 135.7, 135.3, 132.0, 128.7, 128.6, 127.7, 126.7, 126.6, 104.4,
85.8, 85.2, 49.8 31.8, 27.8; HRMS (ESI+) calcd for
C25H21ClN4O2Na 467.1245 [M + Na]+, found 467.1233.
>25
>25
27
(1′S)-23
(1′R)-23
(1′S,4′S)-24
(1′R,4′R)-24
(1′S,4′R)-26
(1′R,4′S)-26
AZT
>4.3
>10.1
>25
>25
>25
>25
0.0010
0.0015
>0.1
>0.1
AMD3100
a All values are in µg/mL. Data represent mean values of at least two
experiments. b EC50: effective concentration 50 or needed concentration
to inhibit 50% HIV-induced cell death, evaluated with the MTT method
in MT-4 cells. c CC50: cytotoxic concentration 50 or needed
concentration to induce 50% death of noninfected cells, evaluated with
the MTT method in MT-4 cells.
moiety as the chiral auxiliary. Alternative introduction of the
base via a Mitsunobu reaction or a Pd(0)-promoted coupling
provided the means for enantiodivergency. The synthetic
sequences are short and well yielding, and the methodology has
proved to be useful for the preparation of pyrimidine as well as
purine nucleosides.
6-Chloro-9-[(1′S)-4′-oxo-cyclohex-2′-ene-1′-yl]purine [(1′S)-
13]. To a 14:1 mixture of trifluoroacetic acid (10 mL) and water
(0.7 mL) at 0 °C was added the 6-chloropurine derivate 12 (450
mg, 1.01 mmol) in one portion. After 40 min of stirring at 0 °C,
CH2Cl2 (10 mL) and water (10 mL) were added, and the aqueous
layer was extracted with additional CH2Cl2 (2 × 10 mL). The
combined organic extracts were washed with saturated aqueous
sodium bicarbonate solution (30 mL), dried (Na2SO4), and con-
centrated under reduced pressure. Purification of the crude material
by flash chromatography (EtOAc) yielded cyclohexenone (1′S)-13
(231 mg, 0.93 mmol, 92% yield) as a white solid: mp 124-126
°C (ethyl ether); [R]20D ) -73.3 (c 1.35, CHCl3); IR (ATR) υ 3061,
2957, 1682, 1589, 1401, 1332, 1145, 937, 826, 635 cm-1; 1H NMR
(400 MHz, CDCl3) δ 8.79 (s, 1H, H-2), 8.17 (s, 1H, H-8), 6.95
(ddd, J2′,3′ ) 10.2 Hz, J2′,1′ ) 2.5 Hz, J2′,6′ ) 1.4 Hz, 1H, H-2′),
6.34 (ddd, J3′,2′ ) 10.2 Hz, J3′,1′ ) 2.6 Hz, J3′,5′ ) 0.6 Hz, 1H,
H-3′), 5.68 (m, 1H, H-1′), 2.74-2.63 (m, 2H, H-5′), 2.63-2.48
(m, 2H, H-6′); 13C NMR (62.5 MHz, CDCl3) δ 196.0, 152.2, 151.7,
151.3, 145.0, 142.9, 132.8, 131.8, 51.3, 35.8, 30.4; HRMS (ESI+)
calcd for C11H9ClN4ONa 271.0357 [M + Na]+, found 271.0351.
(2R,3R,8R)-2,3-Diphenyl-8-ethoxycarbonate-1,4-dioxaspiro[4.5]-
decan-6-ene (14). To a mixture of alcohol 5 (300 mg, 0.97 mmol)
and DMAP (24 mg, 0.19 mmol) in dry CH2Cl2 (9 mL) were added,
under argon atmosphere, pyridine (235 µL, 2.92 mmol) and,
dropwise, ethyl chloroformate (288 µL, 2.92 mmol). The reaction
mixture was stirred at room temperature for 4 h, quenched with 1
M aqueous hydrochloric acid (10 mL), and extracted with CH2Cl2
(3 × 10 mL). The organic fractions were combined, dried (Na2SO4),
and concentrated under reduced pressure. The resulting residue was
purified by flash chromatography (hexanes-EtOAc, 4:1) to furnish
carbonate 14 (366 mg, 0.96 mmol, 99% yield) as a colorless syrup:
Experimental Section
General experimental details are provided in Supporting Informa-
tion.
(2R,3R,8R)-2,3-Diphenyl-1,4-dioxaspiro[4.5]decan-6-ene-8-
ol (5). To a stirred solution of cyclohexenone 9 (5.80 g, 18.93 mmol)
in dry CH2Cl2 (130 mL) at -78 °C was added (S)-Me-CBS 1.0 M
in toluene (3.8 mL, 3.79 mmol) under argon atmosphere. Then,
catecholborane 1.0 M in THF (42 mL, 41.65 mmol) was slowly
added over 2 h, by means of a syringe pump, and the mixture was
allowed to warm to room temperature and stirred for 16 h. The
reaction was quenched by adding saturated aqueous NH4Cl (150
mL). Phases were separated and the aqueous was then extracted
with CH2Cl2 (2 × 100 mL). The combined organic extracts were
dried (Na2SO4), concentrated under reduced pressure and purified
by flash chromatography (hexanes-EtOAc, 4:1) to provide a 8:1
diastereomeric mixture of cyclohexenols 5 and 10 (5.25 g, 17.04
mmol, 90% yield) as a white solid. Recrystallization in diethyl ether-
pentane furnished pure cyclohexenol 5 (4.09 g, 13.25 mmol, 70%
overall yield). 5: mp 116-117 °C (n-pentane-ethyl ether) {lit.10
117-119 °C (n-pentane-ethyl ether)}; [R]20 ) +55.0 (c 0.6,
D
CH2Cl2), {lit.10 [R]20 ) +49.2 (c 0.6, CH2Cl2)}; H NMR (400
1
D
MHz, CDCl3) δ 7.36-7.26 (m, 6H, H-Ar), 7.26.-7.17 (m, 4H,
H-Ar), 6.05 (ddd, J6,7 ) 10.1 Hz, J6,8 ) 2.3 Hz, J6,10 ) 1.2 Hz, 1H,
H-6), 5.92 (dt, J7,6 ) 10.1 Hz, J7,8 ) J7,9 ) 1.5 Hz, 1H, H-7), 4.79
(d, J3,2 ) 8.5 Hz, 1H, H-3), 4.69 (d, J2,3 ) 8.5 Hz, 1H, H-2), 4.29
(ddt, J8,9ax ) 9.0 Hz, J8,9eq ) 4.3 Hz, J8,7 ) J8,6 ) 2.0 Hz, 1H,
H-8), 2.29-2.18 (m, 2H, H-9, H-10), 2.11-2.01 (m, 1H, H-9/H-
10), 1.93-1.80 (m, 1H, H-9/H-10); 13C NMR (62.5 MHz, CDCl3)
δ 136.3, 136.2, 135.7, 129.5, 128.5, 128.4, 128.3, 126.8, 126.6,
105.7, 85.5, 85.1, 66.6, 32.8, 31.0.
[R]20 ) +69.2 (c 2.5, CHCl3); IR (ATR) υ 1729, 1495, 1372,
D
1
1262, 1116, 952, 793, 698 cm-1; H NMR (250 MHz, CDCl3) δ
6-Chloro-9-[(2′R,3′R,8′S)-2′,3′-diphenyl-1′,4′-dioxaspiro[4.5]decan-
6′-ene-8′-yl]purine (12) and its N7-Isomer (11). A solution of DBAD
(761 mg, 3.24 mmol) in anhydrous THF (6 mL) was added
dropwise over 10 min to a -10 °C stirred suspension of 5 (500
7.36-7.27 (m, 6H, H-Ar), 7.27-7.16 (m, 4H, H-Ar), 6.05 (s, 2H,
H-7, H-6), 5.23 (br t, J ) 5.4 Hz, 1H, H-8), 4.79 (d, J3,2 ) 8.7 Hz,
1H, H-3), 4.72 (d, J2,3 ) 8.7 Hz, 1H, H-2), 4.22 (q, J ) 7.4 Hz,
2H, -CH2-), 2.37-2.45 (br dd, J ) 11.1 Hz, J ) 2.5 Hz, 2H, H-10,
J. Org. Chem. Vol. 74, No. 6, 2009 2429

Ferrer et al.
H-9), 2.18-2.01 (m, 2H, H-10, H-9), 1.32 (t, J ) 7.4 Hz, 3H,
-CH3); 13C NMR (62.5 MHz, CDCl3) δ 154.9, 136.3, 136.2, 131.9,
130.6, 128.5, 128.4, 126.7, 126.7, 126.6, 105.3, 85.7, 85.2, 72.1,
64.1, 32.4, 27.1, 14.3; HRMS (ESI+) calcd for C23H24O5Na
403.1516 [M + Na]+, found 403.1520.
cis-isomer 17) δ 151.9, 151.7, 151.3, 144.1, 136.8, 131.8, 125.7,
63.9, 50.2, 28.0, 25.7; HRMS (ESI+) calcd for C11H11ClN4ONa
273.0514 [M + Na]+, found 273.0512.
cis-6-Chloro-9-[(1′S,4′R)-4′-(p-nitrobenzoyloxy)-cyclohex-2′-
ene-1′-yl]purine (18) and its trans-Isomer (19). A solution of
DBAD (155 mg, 0.66 mmol) in dry THF (1.5 mL) was added
dropwise over 10 min to a -10 °C stirred suspension of a 7:1
mixture of trans- and cis-cyclohexenols 16 and 17 (83 mg, 0.33
mmol), p-nitrobenzoic acid (111 mg, 0.66 mmol) and triph-
enylphosphine (175 mg, 0.66 mmol) in anhydrous THF (2 mL)
under argon atmosphere. The reaction mixture was allowed to warm
to room temperature and stirred for 4 h. The organic solvent was
removed under vacuum and the resulting oil was purified by flash
chromatography (hexanes-EtOAc, 2:1) furnishing an unseparable
ca. 7:1 mixture of cis- and trans-p-nitrobenzoates 18 and 19 (114
mg, 0.26 mmol, 86% yield). IR (ATR) υ 1722, 1588, 1522, 1436,
6-Chloro-9-[(2′R,3′R,8′R)-2′,3′-diphenyl-1′,4′-dioxaspiro[4.5]decan-
6′-ene-8′-yl]purine (15). To a mixture of carbonate 14 (105 mg,
0.28 mmol), 6-chloropurine (65 mg, 0.41 mmol), allylpalladium
chloride dimer (3 mg, 0.01 mmol), and 1,4-bis(diphenylphosphi-
no)ethane (10 mg, 0.03 mmol) in anhydrous DMF (2.5 mL) was
added dropwise 1,2,2,6,6-pentamethylpiperidine (150 µL, 0.83
mmol) under argon atmosphere. The solution was stirred at 80 °C
overnight. Then, the reaction mixture was passed through a Celite
pad, and the organic layer was concentrated under reduced pressure.
The resulting oil was purified by flash column chromatography
(hexanes-EtOAc, from 4:1 to 2:1) to provide 15 (84 mg, 0.19
mmol, 68% yield) as a white solid: mp 96-98 °C (ethyl ether);
1
1332, 1270, 1117, 998, 753 cm-1; H NMR (400 MHz, CDCl3)
[R]20 ) +16.0 (c 0.25, CHCl3); IR (ATR) υ 3061, 2924, 2876,
(ca. 87% cis-isomer 18) δ 8.78 (s, 1H, H-2), 8.31 (d, J ) 8.7 Hz,
2H, Ph-NO2), 8.25 (s, 1H, H-8), 8.24 (d, J ) 8.7 Hz, 2H, Ph-
NO2), 6.40 (ddd, J3′,2′ ) 10.0 Hz, J3′,4′ ) 3.4 Hz, J ) 2.0 Hz, 1H,
H-3′), 6.16 (br dd, J2′,3′ ) 10.0 Hz, J2′,1′ ) 2.6 Hz, 1H, H-2′), 5.65
(br, 1H, H-4′), 5.40 (br, 1H, H-1′), 2.33 (m, 1H, H-6′), 2.22 (m,
2H, H-5′), 2.07 (m, 1H, H-6′); (ca. 13% trans-isomer 19, observable
signals) δ 8.78 (s, 1H, H-2), 8.17 (s, 1H, H-8), 6.35 (m, 1H, H-3′),
6.11 (br d, 1H, H-2′), 5.79 (br, 1H, H-4′), 5.49 (br, 1H, H-1′).
cis-9-[(1′S,4′R)-4′-Hydroxy-cyclohex-2′-ene-1′-yl]adenine (20)
and its trans-Isomer (21). A pressure flask was charged with a
7:1 mixture of p-nitrobenzoates 18 and 19 (25 mg, 0.06 mmol) in
MeOH (3 mL) and the solution was saturated with ammonia. Then,
the pressure flask was closed, heated up to 90 °C and stirred at this
temperature for 48 h. Once the excess of ammonia was eliminated
(by passing through a stream of nitrogen), the volatiles were
removed under reduced pressure and the remaining colorless oil
was purified by flash chromatography (CH2Cl2-MeOH, from 20:1
to 9:1) to provide an inseparable mixture of adenine derivates 20
and 21 (14 mg, 0.06 mmol, 98% yield) in a 7:1 diastereomeric
D
1
1588, 1399, 1195, 961, 793, 697, 635 cm-1; H NMR (400 MHz,
CDCl3) δ 8.76 (s, 1H, H-2), 8.23 (s, 1H, H-8), 7.37-7.28 (m, 6H,
H-Ar), 7.28-7.18 (m, 4H, H-Ar), 6.32 (dd, J6′,7′ ) 10.1 Hz, J6′,8′
) 2.2 Hz, 1H, H-6′), 6.07 (d, J7′,6′ ) 10.1 Hz 1H, H-7′), 5.46 (br
m, 1H, H-8′), 4.88 (d, J3′,2′ ) 8.5 Hz, 1H, H-3′), 4.74 (d, J2′,3′
)
8.5 Hz, 1H, H-2′), 2.55-2.43 (m, 1H, H-9′), 2.37-2.22 (m, 3H,
H-9′, H-10′); 13C NMR (62.5 MHz, CDCl3) δ 152.0, 151.4, 151.2,
143.4, 135.7, 135.6, 134.2, 131.8, 129.0, 128.7, 128.5, 126.9, 126.7,
126.5, 104.5, 85.7, 85.3, 50.8, 33.0, 29.1; HRMS (ESI+) calcd for
C25H21ClN4O2Na 467.1245 (M + Na)+, found 467.1247.
6-Chloro-9-[(1′R)-4′-oxo-cyclohex-2′-ene-1′-yl]purine [(1′R)-
13]. To a 14:1 solution of trifluoroacetic acid (2.7 mL) and water
(0.2 mL) at 0 °C was added the 6-chloropurine derivate 15 (120
mg, 0.27 mmol) in one portion. After 40 min of stirring at 0 °C,
CH2Cl2 (3 mL) and water (3 mL) were added, and the aqueous
layer was extracted with additional CH2Cl2 (2 × 3 mL). The
combined organic extracts were washed with saturated aqueous
sodium bicarbonate solution (10 mL), dried (Na2SO4), and con-
centrated under reduced pressure. Purification of the crude material
by flash chromatography (EtOAc) yielded cyclohexenone (1′R)-
13 (60 mg, 0.24 mmol, 90% yield) as a white solid: [R]20D ) +70.6
(c 1.35, CHCl3). The other physical and spectral data are identical
of those reported for its enantiomer (1′S)-13.
1
ratio. H NMR (400 MHz, d6-DMSO) (ca. 87% cis-isomer 20) δ
8.14 (s, 1H, H-2), 8.04 (s, 1H, H-8), 7.24 (br, 2H, -NH2), 6.08
(ddd, J3′,2′ ) 10.1 Hz, J3′,4′ ) 3.2 Hz, J3′,1′ ) 2.0 Hz, 1H, H-3′),
5.82 (ddd, J2′,3′ ) 10.1 Hz, J2′,1′ ) 3.5 Hz, J2′,4′ ) 1.5 Hz, 1H,
H-2′), 5.04 (dddd, J1′,6′ax ) 7.5 Hz, J1′,6′eq ) 5.5 Hz, J1′,2′ ) 3.6 Hz,
J1′,3′ ) 1.9 Hz, 1H, H-1′), 4.95 (d, JOH,1′ ) 6.6 Hz, 1H, -OH), 4.08
(qdd, J4′,5′ax ) J4′,5′eq ) J4′,0H ) 6.6 Hz, J4′,3′ ) 3.2 Hz, J4′,2′ ) 1.8
Hz, 1H, H-4′), 1.97 (m, 2H, H-5′), 1.82 (m, 1H, H-6′), 1.55 (m,
1H, H-6′); (ca. 13% trans-isomer 21, observable signals) δ 8.13
(s, 1H, H-2), 5.97 (br d, 1H, H-3′), 5.72 (br d, 1H, H-2′), 5.13
(ddt, 1H, H-1′), 4.23 (ddq, 1H, H-4′), 2.16 (m, 1H, H-5′); 13C NMR
(90 MHz, d6-DMSO) (cis-isomer 20) δ 156.1, 152.4, 149.1, 139.1,
136.7, 125.7, 119.0, 63.3, 48.6, 28.1, 25.8; (trans-isomer 21,
observable signals) δ 126.4, 64.2, 50.2, 30.7; HRMS (ESI+) calcd
for C11H13N5ONa 254.1012 [M + Na]+, found 254.1011.
trans-6-Chloro-9-[(1′S,4′S)-4′-hydroxy-cyclohex-2′-ene-1′-yl]pu-
rine (16) and its cis-Isomer (17). To a stirred solution of
cyclohexenone (1′S)-13 (120 mg, 0.48 mmol) in dry CH2Cl2 (5
mL) at -78 °C was added (R)-Me-CBS 1.0 M in toluene (97 µL,
0.097 mmol) under argon atmosphere. Then, catecholborane 1.0
M in THF (1.1 mL, 1.11 mmol) was slowly added by means of a
syringe pump (addition time 2 h), and the mixture was stirred during
16 h, allowing it to warm to room temperature. Then, the reaction
was quenched by adding of saturated aqueous NH4Cl (6 mL). The
aqueous phase was extracted with CH2Cl2 (2 × 8 mL), and the
combined organic extracts were dried (Na2SO4), concentrated under
reduced pressure, and purified by flash chromatography
(CH2Cl2-MeOH, from 50:1 to 25:1) to afford an unseparable 7:1
mixture of the trans- and cis-cyclohexenols 16 and 17 (93 mg, 0.37
N3-Benzoyl-1-[(2′R,3′R,8′S)-2′,3′-diphenyl-1′,4′-
dioxaspiro[4.5]decan-6′-ene-8′-yl]uracil (22). A solution of DBAD
(457 mg, 1.94 mmol) in dry THF (2.5 mL) was added dropwise
over 10 min to a -10 °C stirred suspension of 5 (300 mg, 0.97
mmol), N3-benzoyluracil (420 mg, 1.94 mmol), and triphenylphos-
phine (515 mg, 1.944 mmol) in anhydrous THF (4 mL) under argon
atmosphere. The reaction mixture was allowed to warm to room
temperature and stirred overnight. The organic solvent was removed
under vacuum, and the resulting oil was purified by flash chroma-
tography (hexanes-EtOAc, 4:1) to furnish 22 (428 mg, 0.85 mmol,
1
mmol, 77% yield). H NMR (400 MHz, CDCl3) (ca. 87% trans-
isomer 16) δ 8.73 (d, J ) 0.7 Hz, 1H, H-2), 8.11 (s, 1H, H-8),
6.24 (dtt, J3′,2′ ) 10.1 Hz, J3′,4′ ) J3′,1′ ) 2.9 Hz, J3′,5′ ) J3′,5′ ) 0.9
Hz, 1H, H-3′), 5.86 (dqt, J2′,3′ ) 10.0 Hz, J2′,1′ ) J2′,4′ ) J ) 1.9
Hz, J2′,6′ ) J ) 1.0 Hz, 1H, H-2′), 5.37 (ddt, J1′,6′ax ) 10.6 Hz,
J1′,6′eq ) 5.2 Hz, J1′,3′ ) J1′,2′ ) 2.6 Hz, 1H, H-1′), 4.47 (ddt, J4′,5′ax
) 9.7 Hz, J4′,5′eq ) 4.7 Hz, J4′,3′ ) J4′,2′ ) 2.2 Hz, 1H, H-4′),
2.47-2.38 (br dd, J ) 8.4 Hz, J6′,5′ ) 5.8 Hz, 1H, H-6′), 2.19-2.10
(br dd, J ) 11.7 Hz, J5′,6′ ) 5.8 Hz, 1H, H-5′), 1.96-1.86 (m, 1H,
H-6′), 1.82-1.71 (m, 1H, H-5′); (ca. 13% cis-isomer 17, observable
signals) δ 8.74 (s, 1H, H-2), 8.24 (s, 1H, H-8), 6.30 (m, 1H, H-3′),
87% yield) as a white solid: mp 110-112 °C (ethyl ether); [R]20
D
) +50.0 (c 0.5, CHCl3); IR(ATR) υ 2923, 1744, 1702, 1660, 1437,
1
1360, 1247, 1120, 788, 696 cm-1; H NMR (400 MHz, CDCl3) δ
7.95 (dd, J ) 6.4 Hz, J ) 1.3 Hz, 2H:H-Bz), 7.66 (tt, J ) 6.9 Hz,
J ) 1.1 Hz, 1H, H-Bz), 7.51 (tt, J ) 8.2 Hz, J ) 1.6 Hz, 2H,
H-Bz), 7.40 (d, J6,5 ) 8.2 Hz, 1H, H-6), 7.34 (m, 6H, H-Ar), 7.23
5.88 (br d, 1H, H-2′), 5.27 (m, 1H, H-1′), 4.37 (m, 1H, H-4′); 13
C
NMR (62.5 MHz, CDCl3) (major trans-isomer 16) δ 152.0, 151.6,
151.2, 143.4, 137.2, 131.7, 125.9, 64.9, 50.9, 30.1, 28.0; (minor
(m, 4H, H-Ar), 6.40 (ddd, J7′,6′ ) 11.8 Hz, J7′,8′ ) 2.3 Hz, J7′,9′
)
1.6 Hz, 1H, H-7′), 5.90 (dd, J6′,7′ ) 9.9 Hz, J6′,8′ ) 3.1 Hz, 1H,
2430 J. Org. Chem. Vol. 74, No. 6, 2009

Synthesis of Cyclohexenyl Nucleosides
1
H-6′), 5.82 (d, J5,6 ) 7.9 Hz, 1H, H-5), 5.30 (m, 1H, H-8′), 4.85
(d, J3′,2′ ) 8.7 Hz, 1H, H-2′/H-3′), 4.83 (d, J2′,3′ ) 8.7 Hz, 1H,
H-2′/3′), 2.43-2.35 (m, 1H, H-10′), 2.33-2.25 (td, J ) 13.8 Hz,
J ) 3.7 Hz, 1H, H-9′), 2.16 (td, J ) 10.2 Hz, J ) 2.9 Hz, 1H,
H-9′), 2.11-2.01 (m, 1H, H-10′); 13C NMR (100 MHz, CDCl3) δ
169.0, 162.2, 150.0, 141.2, 136.2, 136.0, 136.0, 135.2, 131.6, 130.6,
129.3, 129.1, 128.8, 128.7, 128.7, 126.8, 126.7, 104.5, 102.6, 86.0,
85.5, 51.6, 32.6, 27.3; HRMS (ESI+) calcd for C31H26N2O5Na
529.1734 [M + Na]+, found 529.1726.
100% yield) as a colorless syrup: H NMR (400 MHz, CDCl3) δ
7.92 (dd, J ) 8.2 Hz, J ) 1.4 Hz, 2H, H-Bz), 7.65 (tt, J ) 7.4 Hz,
J ) 1.2 Hz, 1H, H-Bz), 7.50 (tt, J ) 9.1 Hz, J ) 1.5 Hz, 2H,
H-Bz), 7.29 (d, J6,5 ) 8.0 Hz, 1H, H-6), 5.83 (d, J5,6 ) 8.0 Hz, 1H,
H-5), 4.44 (tt, J1′,2′ax ≈ J1′,6′ax ) 11.9 Hz, J1′,2′eq ≈ J1′,6′eq )3.6 Hz,
1H, H-1′), 3.66 (tt, J4′,3′ax ≈ J4′,5′ax ) 11.1 Hz, J4′,3′eq ≈ J4′,5′eq ) 4.3
Hz, 1H, H-4′), 2.13 (m, 2H, H-5′eq, H-3′eq), 2.00 (m, 2H, H-6′eq,
H-2′eq), 1.63 (m, 2H, H-6′ax, H-2′ax), 1.48 (m, 2H, H-5′ax,
H-3′ax); 13C NMR (100 MHz, CDCl3) δ 168.9, 162.0, 150.0, 140.2,
135.2, 131.6, 130.5, 129.3, 102.5, 69.4, 54.7, 34.3 (2 × C), 29.6
(2 × C); HRMS (ESI+) calcd for C17H19N2O4 315.1339 [M + H]+,
found 315.1332.
N3-Benzoyl-1-[(1′S)-4′-oxo-cyclohex-2′-ene-1′-yl]uracil [(1′S)-
23]. To a 14:1 solution of trifluoroacetic acid (8 mL) and water
(0.6 mL) at 0 °C was added the N3-benzoyluracil derivate 22 (330
mg, 0.65 mmol) in one portion. After 40 min of stirring at 0 °C,
CH2Cl2 (8 mL) and water (8 mL) were added, phases were
separated, and the aqueous layer was extracted with additional
CH2Cl2 (2 × 8 mL). The combined organic extracts were washed
with saturated aqueous sodium bicarbonate (20 mL), dried
(Na2SO4), and concentrated under reduced pressure. Purification
of the crude material by flash chromatography (EtOAc) provided
ketone (1′S)-23 (179 mg, 0.58 mmol, 89% yield) as a white solid:
N3-Benzoyl-1-[(1′S,4′R)-4′-(p-nitrobenzoyloxy)-cyclohex-2′-
ene-1′-yl]uracil (25). A solution of DBAD (165 mg, 0.70 mmol)
in dry THF (1.5 mL) was added dropwise over 10 min to a -10
°C stirred suspension of cyclohexenol (1′S,4′S)-24 (110 mg, 0.35
mmol), p-nitrobenzoic acid (118 mg, 0.704 mmol), and triph-
enylphosphine (186 mg, 0.704 mmol) in anhydrous THF (2 mL)
under argon atmosphere. The reaction mixture was allowed to warm
to room temperature and stirred for 4 h. The organic solvent was
removed under vacuum, and the resulting oil was purified by flash
chromatography (hexanes-EtOAc, 2:1) furnishing the p-nitroben-
zoate derivative25 (148 mg, 0.32 mmol, 91% yield) as a pale yellow
oil: IR (ATR) υ 2939, 1738, 1699, 1660, 1523, 1439, 1101, 722,
mp 86-88 °C (CH2Cl2-ethyl ether); [R]20 ) +12.9 (c 2.0,
D
CHCl3); IR (ATR) υ 3088, 2933, 1742, 1701, 1655, 1439, 1376,
851, 791, 683, cm-1; 1H NMR (400 MHz, CDCl3) δ 7.95 (dd, J )
8.2 Hz, J ) 1.2 Hz, 2H, H-Bz), 7.68 (tt, J ) 7.4 Hz, J ) 1.3 Hz,
1H, H-Bz), 7.52 (tt, J ) 7.4 Hz, 2H, H-Bz), 7.26 (d, J6,5 ) 8.1 Hz,
1H, H-6), 6.80 (dt, J2′,3′ ) 10.3 Hz, J2′,1′ ) 2.1 Hz, J2′,6′ ) 2.1 Hz,
1H, H-2′), 6.27 (ddd, J3′,2′ ) 10.3 Hz, J3′,1′ ) 2.8 Hz, J3′,5′ ) 0.5
651 cm-1; H NMR (400 MHz, CDCl3) δ 8.29 (dt, J ) 9.1 Hz, J
1
) 2.4 Hz, 2H, H-Ph-NO2), 8.20 (dt, J ) 8.9 Hz, J ) 2.0 Hz, 2H,
H-PhNO2), 7.93 (dd, J ) 8.3 Hz, J ) 1.0 Hz, 2H, H-Bz), 7.65 (tt,
J ) 6.9 Hz, J ) 1.4 Hz, 1H, H-Bz), 7.49 (tt, J ) 9.3 Hz, J ) 1.6
Hz, 1H, H-3′), 5.90 (d, J5,6 ) 8.1 Hz, 1H, H-5), 5.56 (ddt, J1′,6′ax
)
10.2 Hz, J1′,6′eq ) 4.9 Hz, J1′,2′ ) J1′,3′ ) 2.5 Hz, 1H, H-1′),
2.66-2.42 (m, 3H, H-6′, 2H-5′), 2.24-2.10 (m, 1H, H-6′); 13C
NMR (90 Hz, CDCl3) δ 196.1, 168.4, 161.7, 149.6, 146.2, 140.1,
135.3, 133.5, 131.3, 130.5, 129.3, 103.6, 52.7, 36.0, 30.0; HRMS
(ESI+) calcd for C17H14N2O4Na 333.0846 [M + Na]+, found
333.0838.
Hz, 2H, H-Bz), 7.39 (d, J6,5 ) 8.1 Hz, 1H, H-6), 6.36 (ddd, J3′,2′ )
10.1 Hz, J3′,4′ ) 4.2 Hz, J3′,1′ ) 2.4 Hz, 1H, H-3′), 5.95 (ddt, J2′,3′
) 10.1 Hz, J2′,1′ ) 2.8 Hz, J2′,4′ ) J2′,6′ ) 0.9 Hz, 1H, H-2′), 5.86
(d, J5,6 ) 8.1 Hz, 1H, H-5), 5.53 (qt, J4′,3′ ) J4′,5′ ) J4′,5′ ) 4.3 Hz,
J4′,2′ ) J ) 1.2 Hz, 1H, H-4′), 5.22 (br, 1H, H-1′), 2.21-2.13 (m,
1H, H-6′), 2.13-2.03 (br t, J ) 4.5 Hz, 2H, H-5′), 1.97-1.81 (m,
1H, H-6′); 13C NMR (100 MHz, CDCl3) δ 168.8, 164.1, 162.2,
150.8, 149.9, 141.0, 135.5, 135.3, 131.8, 131.5, 131.2, 130.9, 130.5,
129.3, 123.7, 102.7, 67.2, 52.0, 25.8, 25.1; HRMS (ESI+) calcd
for C24H19N3O7Na 484.1115 [M + Na]+, found 484.1105.
N3-Benzoyl-1-[(1′S,4′S)-4′-hydroxy-cyclohex-2′-ene-1′-yl]-
uracil [(1′S,4′S)-24]. To a stirred solution of cyclohexenone (1′S)-
23 (179 mg, 0.58 mmol) in dry CH2Cl2 (6 mL) at -78 °C was
added (S)-Me-CBS 1 M in toluene (115 µL, 0.115 mmol) under
argon atmosphere. Then, catecholborane 1.0 M in THF (1.15 mL,
1.15 mmol) was slowly added over 2 h, by means of a syringe
pump, and the mixture was allowed to warm to room temperature
and stirred for 16 h. At this time, saturated aqueous NH4Cl (6 mL)
was added, and the aqueous phase was extracted with CH2Cl2 (2
× 6 mL). The combined organic extracts were dried (Na2SO4),
concentrated under reduced pressure, and purified by flash chro-
matography (CH2Cl2-MeOH, from 50:1 to 25:1) to provide the
cyclohexenol (1′S,4′S)-24 (178 mg, 0.57 mmol, 99% yield) as a
white solid: mp 64-66 °C (CH2Cl2-ethyl ether); [R]20D ) -13.2
(c 0.8, CHCl3); IR (ATR) υ 3386, 2930, 1741, 1698, 1646, 1440,
1364, 953, 646 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.94 (dd, J )
8.0 Hz, J ) 1.3 Hz, 2H, H-Bz), 7.66 (tt, J ) 6.9 Hz, J ) 1.4 Hz,
1H, H-Bz), 7.50 (tt, J ) 9.2 Hz, J ) 1.6 Hz, 2H, H-Bz), 7.26 (d,
1-[(1′S,4′R)-4′-Hydroxy-cyclohex-2′-ene-1′-yl]uracil [(1′S,4′R)-
26]. A solution of p-nitrobenzoate 25 (112 mg, 0.24 mmol) in a
33% solution of MeNH2 in EtOH (3 mL) was stirred at room
temperature for 1 h. The volatiles were removed under vacuum,
and the remaining oil was purified by flash chromatography
(CH2Cl2-MeOH, from 40:1 to 20:1) provide the uracil nucleoside
derivative (1′S,4′R)-26 (50 mg, 0.24 mmol, 99% yield) as a white
solid: mp 55-57 °C (MeOH); [R]20D ) +73.0 (c 1.0, MeOH); IR
(ATR) υ 3349, 3178, 2927, 2858, 1662, 1459, 1041, 806, 644 cm-1
;
1H NMR (360 MHz, d6-DMSO) δ 11.26 (br s, 1H, -NH), 7.48 (d,
J6,5 ) 7.9 Hz, 1H, H-6), 6.08 (ddd, J3′,2′ ) 10.4 Hz, J3′,4′ ) 3.7 Hz,
J3′,1′ ) 2.4 Hz, 1H, H-3′), 5.62 (d, J5,6 ) 7.9 Hz, 1H, H-5), 5.60
(dd, J2′,3′ ) 10.4 Hz, J2′,1′ ) 2.4 Hz, 1H, H-2′), 4.91 (br d, JOH,4′
)
6.4 Hz, 2H, H-1′, -OH), 3.99 (br, 1H, H-4′), 1.74 (m, 3H, 2H-6′,
H-5′), 1.55 (m, 1H, H-5′); 13C NMR (90 MHz, d6-DMSO) δ 163.4,
150.8, 142.1, 136.8, 126.7, 101.1, 62.1, 50.4, 28.3, 24.3; HRMS
(ESI+) calcd for C10H12N2O3Na 231.0740 [M + Na]+, found
231.0738.
J6,5 ) 8.1 Hz, 1H, H-6), 6.18 (dtd, J3′,2′ ) 10.2 Hz, J3′,4′ ) J3′,1′
)
2.4 Hz, J3′,5′ ) 1.3 Hz, 1H, H-3′), 5.83 (d, J5,6 ) 8.1 Hz, 1H, H-5),
5.64 (dtd, J2′,3′ ) 10.3 Hz, J2′,1′ ) J2′,4′ ) 2.4 Hz, J2′,5′ ) 1.8 Hz,
1H, H-2′), 5.24 (ddt, J1′,6′ax ) 11.4 Hz, J1′,6′eq ) 5.3 Hz, J1′,3′ ) J1′,2′
) 2.6 Hz, 1H, H-1′), 4.37 (ddt, J4′,5′ax ) 10.4 Hz, J4′,5′eq ) 4.4 Hz,
J4′,3′ ) J4′,2′ ) 2.6 Hz, 1H, H-4′), 2.31 (m, 1H, H-6′), 2.17 (m, 1H,
H-5′); 1.72-1.54 (m, 2H, H-6′, H-5′); 13C NMR (100 MHz, CDCl3)
δ 168.7, 162.2, 149.9, 140.6, 138.4, 135.2, 131.6, 130.8, 129.1,
126.7, 102.7, 65.8, 52.4, 31.1, 27.8; HRMS (ESI+) calcd for
C17H16N2O4Na 335.1002 [M + Na]+, found 335.1010.
N3-Benzoyl-1-[(2′R,3′R,8′R)-2′,3′-diphenyl-1′,4′-dioxaspiro[4.5]-
decan-6′-ene-8′-yl]uracil (27). A mixture of carbonate 14 (154 mg,
0.41 mmol), N3-benzoyluracil (131 mg, 0.61 mmol), allylpalladium
chloride dimer (4.4 mg, 0.01 mmol), and 1,4-bis(diphenylphosphi-
no)ethane (14.5 mg, 0.04 mmol) in anhydrous DMF (4 mL) was
and stirred overnight at 80 °C. The reaction mixture was passed
through a Celite pad, and the organic layer was concentrated under
vacuum. The resulting oil was purified by flash chromatography
(hexanes-EtOAc, 4:1) to afford 27 (147 mg, 0.29 mmol, 72% yield)
trans-N3-Benzoyl-1-[4′-hydroxy-cyclohexan-1′-yl]uracil (28).
A stirred solution of cyclohexenol (1′S,4′S)-24 (10 mg, 0.03 mmol)
in absolute EtOH (1 mL) at room temperature was hydrogenated
in the presence of 10% Pd/C (3 mg) at 15 psi for 16 h. Then, the
solvent was evaporated under reduced pressure, and the resulting
oil was purified by flash column chromatography (CH2Cl2-MeOH,
100:1) affording the cyclohexane derivate 28 (10 mg, 0,03 mmol,
as a white solid: mp 99-101 °C (CH2Cl2-ethyl ether); [R]20
)
D
-38.3 (c 1.2, CHCl3); IR (ATR) υ 2873, 1744, 1702, 1660, 1439,
1
1360, 1248, 1122, 761, 696 cm-1; H NMR (400 MHz, CDCl3) δ
7.96 (dd, J ) 8.3 Hz, J ) 1.3 Hz, 2H, 2H-Bz), 7.66 (tt, J ) 7.0
J. Org. Chem. Vol. 74, No. 6, 2009 2431

Ferrer et al.
Hz, J ) 1.1 Hz, 1H, H-Bz), 7.51 (tt, J ) 9.2 Hz, J ) 1.6 Hz, 2H,
2H-Bz), 7.38-7.34 (m, 4H, H-6, 3H-Ar), 7.34-7.29 (m, 3H, H-Ar),
7.29-7.23 (m, 2H, H-Ar), 7.23-7.17 (m, 2H, H-Ar), 6.29 (ddd,
J7′,6′ ) 10.1 Hz, J7′,8′ ) 2.4 Hz, J7′,9′ ) 1.5 Hz, 1H, H-7′), 5.87 (dd,
J6′,7′ ) 10.1 Hz, J6′,8′ ) 1.5 Hz, 1H, H-6′), 5.85 (d, J5,6 ) 7.9 Hz,
1H, H-5), 5.35 (m, 1H, H-8′), 4.86 (d, J3′,2′ ) 8.5 Hz, 1H, H-3′),
4.71 (d, J2′,3′ ) 8.5 Hz, 1H, H-2′), 2.39-2.25 (m, 2H, H-9′, H-10′),
2.21 (td, J ) 13.0 Hz, J ) 3.9 Hz, 1H, H-9′), 1.98 (m, 1H, H-10′);
13C NMR (100 MHz, CDCl3) δ 169.0, 162.2, 150.0, 141.1, 135.8,
135.3, 135.2, 131.6, 130.6, 129.8, 129.3, 128.9, 128.8, 128.7, 128.6,
127.1, 126.6, 104.6, 102.9, 85.8, 85.3, 52.2, 33.3, 28.3; HRMS
(ESI+) calcd for C31H26N2O5Na 529.1734 [M + Na]+, found
529.1721.
white solid: [R]20 ) +12.4 (c 1.0, CHCl3). The other physical
D
and spectral data are identical of those reported for its enantiomer
(1′S,4′S)-24.
1-[(1′R,4′S)-4′-Hydroxy-cyclohex-2′-ene-1′-yl]uracil [(1′R,4′S)-
26). A solution of DBAD (148 mg, 0.63 mmol) in dry THF (1.5
mL) was added dropwise over 10 min to a -10 °C stirred
suspension of cyclohexenol (1′R,4′R)-24 (99 mg, 0.32 mmol),
p-nitrobenzoic acid (106 mg, 0.63 mmol), and triphenylphosphine
(167 mg, 0.63 mmol) in anhydrous THF (2 mL) under argon
atmosphere. The reaction mixture was allowed to warm to room
temperature and stirred for 4 h. The organic solvent was removed
under vacuum, and the resulting oil was purified by flash chroma-
tography (hexanes-EtOAc, 2:1) furnishing the corresponding
p-nitrobenzoate derivate (129 mg, 0.279 mmol, 88% yield) as a
pale yellow solid. A solution of the previously synthesized
p-nitrobenzoate (90 mg, 0.19 mmol) in a 33% solution of MeNH2
in EtOH (2 mL) was stirred at room temperature for 2 h. The
volatiles were removed under vacuum, and the remaining oil was
purified by flash chromatography (CH2Cl2-MeOH, 40:1 to 20:1)
to furnish the uracil nucleoside derivate (1′R,4′S)-26 (38 mg, 0.182
mmol, 94% yield) as a white solid: [R]20D ) -72.2 (c 1.1, MeOH).
The other physical and spectral data are identical of those reported
for its enantiomer (1′S,4′R)-26.
N3-Benzoyl-1-[(1′R)-4′-oxo-cyclohex-2′-ene-1′-yl]uracil [(1′R)-
23]. To a 14:1 solution of trifluoroacetic acid (3 mL) and water
(0.2 mL) at 0 °C was added the N3-benzoyluracil derivate 27 (150
mg, 0.29 mmol) in one portion. After 40 min of stirring at 0 °C,
CH2Cl2 (5 mL) and water (5 mL) were added, the phases were
separated, and the aqueous layer was extracted with additional
CH2Cl2 (2 × 5 mL). The combined organic extracts were washed
with saturated aqueous sodium bicarbonate (15 mL), dried
(Na2SO4), and concentrated under reduced pressure. Purification
of the crude material by flash chromatography (EtOAc) yielded
ketone (1′R)-23 (80 mg, 0.257 mmol, 87% yield) as a white solid:
Acknowledgment. We acknowledge financial support from
DGES (projects CTQ2004-02539 and CTQ2007-60613/BQU)
and CIRIT (2001SGR00178) and a grant of Generalitat de
Catalunya (E.F.). We also acknowledge MCYT-ERDF for a
Ramo´n y Cajal contract (F.B.) and Dr. Jose´ A. Este´ of the
Irsicaixa Foundation, Hospital Universitari Germans Trias i
Pujol, for the biological results.
[R]20 ) -11.7 (c 1.0, CHCl3). The other physical and spectral
D
data are identical of those reported for its enantiomer (1′S)-23.
N3-Benzoyl-1-[(1′R,4′R)-4′-hydroxy-cyclohex-2′-ene-1′-yl]-
uracil [(1′R,4′R)-24]. To a stirred solution of cyclohexenone (1R)-
23 (40 mg, 0.129 mmol) in dry CH2Cl2 (1.3 mL) at -78 °C was
added (R)-Me-CBS 1 M in toluene (26 µL, 0.026 mmol) under
argon atmosphere. Then, catecholborane 1.0 M in THF (258 µL,
0.258 mmol) was slowly added by means of a syringe pump over
2 h, and the mixture was stirred during 16 h, allowing it to warm
to room temperature. At this time, saturated aqueous NH4Cl (6 mL)
was added, and the aqueous phase was extracted with CH2Cl2 (2
× 3 mL). The combined organic extracts were dried (Na2SO4),
concentrated under reduced pressure, and purified by flash chro-
matography (CH2Cl2-MeOH, from 50:1 to 25:1) to provide the
cyclohexenol (1′R,4′R)-24 (38 mg, 0.122 mmol, 94% yield) as a
Supporting Information Available: General experimental
procedures, experimental details and characterization data for
1
compounds 7 and 9, and H and 13C NMR spectra of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO802492G
2432 J. Org. Chem. Vol. 74, No. 6, 2009