Novel 3′-deoxy analogs of the anti-HBV agent entecavir: Synthesis of enantiomers from a single chiral epoxide

Article abstract of DOI:10.1016/j.tetlet.2003.11.052

A synthesis of novel 3′-deoxy analogs of the anti-HBV agent entecavir (BMS-200475) was devised using regioselective ring opening of suitable cyclopentene epoxides as the key step. This versatile approach afforded access to an enantiomeric pair of carbocyclic nucleosides from a single chiral intermediate.

Full text of DOI:10.1016/j.tetlet.2003.11.052

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 739–742
Novel 30-deoxy analogs of the anti-HBV agent entecavir: synthesis
of enantiomers from a single chiral epoxide
Edward Ruediger,a,* Alain Martel,a Nicholas Meanwell,b Carola Solomona
and Brigitte Turmela
aBristol-Myers Squibb Pharmaceutical Research Institute, 100 boul. de l’Industrie, Candiac, QC, Canada J5R 1J1
bBristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA
Received 26 September 2003; revised 11 November 2003; accepted 12 November 2003
Dedicated to Professor Edward Piers, a respected mentor and friend, on the occasion of his retirement
Abstract—A synthesis of novel 30-deoxy analogs of the anti-HBV agent entecavir (BMS-200475) was devised using regioselective
ring opening of suitable cyclopentene epoxides as the key step. This versatile approach afforded access to an enantiomeric pair of
carbocyclic nucleosides from a single chiral intermediate.
Ó 2003 Elsevier Ltd. All rights reserved.
NH2
R2
N
With an estimated 400 million people being chronically
infected, Hepatitis B virus (HBV) represents one of the
most pervasive viral diseases in the world.1 Chronic
infection with HBV is a major cause of chronic liver
disease and is associated with the development of
hepatocellular carcinoma.2 Current therapy for carriers
chronically infected with HBV has focused on inter-
feron, although results have been mixed and significant
side effects have been observed.3;4 Lamivudine (3TC, 4)
(Fig. 1) has been approved for the treatment of HBV
infection, however the emergence of drug resistance has
been noted.5 More recently, the bis(pivaloyloxymethyl)
ester of adefovir6a (5) (adefovir dipivoxil) was approved
for the treatment of lamivudine-resistant HBV.6b Fam-
ciclovir (6), a pro-drug of penciclovir (7), showed good
oral bioavailability, but was dropped from Phase III
clinical trials due to a lack of efficacy.7 There remains
considerable ongoing effort to synthesize novel nucleo-
side analogs with antiviral activity and several examples
of these have been reported to exhibit potent inhibition
of HBV.8
O
HO
H2N
N
N
N
N
P
R1O
N
N
O
N
HO
R1O
N
OH
N
NH2
O
S
O
6, R1= Ac, R2= H
7, R1= H, R2= OH
4, (lamivudine, 3TC)
5, (adefovir)
Figure 1.
Entecavir (BMS-200475, 8) is a novel carbocyclic
20-deoxyguanosine analog, which has shown potent and
selective activity against HBV.9;10 During the course of
synthetic efforts to prepare novel analogs related to
BMS-200475, we were particularly interested in devising
methodology for the synthesis of 30-deoxy analogs. In
addition, we were interested in the possibility of
exploiting the known chiral epoxide 1,11 that had been
previously used to good advantage for the synthesis of
BMS-200475 itself (Fig. 2).10
N
OBn
O
O
N
HO
NH
NH2
8, (Entecavir, BMS-200475)
HO
N
HO
Keywords: HBV; Entecavir; Carbacyclic nucleosides; Epoxide rear-
rangement.
1
* Corresponding author. Tel.: +1-450-444-4127; fax: +1-450-444-4166;
e-mail: edward.ruediger@bms.com
Figure 2.
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.052

740
E. Ruediger et al. / Tetrahedron Letters 45 (2004) 739–742
Since both nucleosides with the unnatural b-
L
-configu-
the enone gave predominantly the cis-diol 14. The latter
was conveniently protected as its TBS-ether to afford the
fully protected triol 15. The 1H NMR of 1517 was found
to be identical with that of the TBDPS-ether of 10.
ration, as well as the natural b- -configuration have
D
been shown to display potent antiviral activity,8a we felt
that it was equally important to be able to access both
enantiomers in a given series from a common interme-
diate. It seemed to us that generation and desymmetri-
zation of a latent meso-diol was an overall strategy that
would allow us to do just that.
With the selectivity of the epoxide/allylic alcohol rear-
rangement established, it was felt that 1 could serve to
generate both L- and the D-enantiomeric intermediates
by using a radical deoxygenation sequence either after
or before epoxide opening, respectively. As an approach
To that end, the key step in our approach to the
synthesis of 30-deoxycarbacyclic nucleoside analogs
involved the regioselective ring opening of the
cyclopentene epoxide 1.12 Literature precedent suggested
that treatment with lithium dialkylamides (especially
lithium diethylamide or lithium di-n-propylamide)
would favor the epoxide/allylic alcohol rearrangement13a
and that deprotonation should occur at the least hin-
dered carbon.13b We were surprised to find that treat-
ment of the suitably protected epoxide 9a (R ¼ TBS)
with lithium di-n-propylamide in ether at 0 °C cleanly
afforded the unexpected allylic alcohol 1014 (Scheme 1).
Interestingly, when 9a was treated with lithium bis-
trimethylsilylamide in THF at reflux temperature for
several hours, the desired allylic alcohol 1115 was formed
exclusively. The reason for this reversal in regioselec-
tivity remains unclear.
to the
L
-series, epoxide 9b (R ¼ PMB) was rearranged at
room temperature to give the allylic alcohol 16, which
was then submitted to radical deoxygenation condi-
tions18 to give, after cleavage of the PMB-ether, a mix-
ture of the allylic and homoallylic alcohols 18 (Scheme
3). This mixture of olefins was then stereoselectively
epoxidized19 to give a separable mixture of epoxides 19
and 20, with the latter predominating. Dess–Martin
oxidation20 of 20, followed by a Wittig-type methyl-
enation,21 gave the key intermediate 21. The latter was
then coupled with O-benzylguanine and debenzylated to
give carbocyclic nucleoside 3.
In order to synthesize the enantiomeric
D-series, com-
pound 1 itself was deoxygenated to cleanly give epoxide
22 (Scheme 4). Unfortunately, efforts to convert 22 to
the allylic alcohol 23, as done previously with epoxides
9, were unsuccessful. However, 22 could be readily
opened with phenylselenide anion22 and subsequent
oxidation and warming to room temperature did in fact
afford 23. The latter was then converted to the key
epoxide intermediate 25 as done in the L-series, which
ultimately afforded the enantiomeric carbocyclic nucleo-
side 2.
Corroboration of the structure of 10 was accomplished
using the regioselective ring opening of the epoxy-
cyclopentanone 1216a (Scheme 2). Treatment of 12 with
basic alumina (Brockmann Activity I) in ether16b led to
ring opening of the epoxide, followed by based-induced
equilibration to give cyclopentenone 13 almost exclu-
1
sively (>92:<8 mixture of regioisomers by H NMR).
Subsequent protection and stereoselective reduction of
Contrary to the potent anti-HBV activity shown by
BMS-200475 (8) and similar to ent-8, both of the
OBn
OH
OBn
O
OBn
OH
b
c
TBSO
RO
TBSO
OBn
OBn
OH
OBn
O
10
1, R= H
9a,R= TBS
11
a
N
b
c
RO
PMBO
PMBO
N
O
O
1, R= H
16
17
Scheme 1. Reagents and conditions: (a) t-BuMe2SiCl, imidazole,
DMF, 90%; (b) LiN(n-Pr)2, Et2O, 0 °C, 80%; (c) LiN(SiMe3)2, THF,
reflux, 60%.
a
9b, R= PMB
d, e
OBn
+
OBn
OBn
f
HO
HO
HO
O
OBn
O
OBn
O
OBn
OH
O
62 : 38
20
19
18
a
e
b
(identical with 1)
BnO
HO
O
O
O
g, h
O
N
OBn
N
1
12
14
i, j
NH
HO
b
N
NH2
O
OH
OBn
OBn
OBn
O
21
3
c, d
TBSO
HO
Scheme 3. Reagents and conditions: (a) p-MeOPhCH2Cl, NaH, DMF,
85%; (b) LiN(SiMe3)2, THF, rt, 80%; (c) 1,10-thiocarbonyldiimidazole,
THF, 72%; (d) n-Bu3SnH, AIBN (cat), toluene, reflux, 83%; (e) DDQ,
CH2Cl2–H2O, 84%; (f) t-BuOOH, VO(acac)2, CH2Cl2, 68%; (g) Dess–
Martin periodinane, t-BuOH, CH2Cl2, 61%; (h) Ph3PCHþ3 Brꢀ, MeLi,
THF, 53%; (i) O-Benzylguanine, LiH, DMF, 120 °C, 55%; (j) BCl3,
CH2Cl2, )78 °C, 72%.
OTBDPS
OTBDPS
OH
15
13
Scheme 2. Reagents and conditions: (a) JonesÕ reagent, acetone, 95%;
(b) Al2O3 (basic), Et2O, 92%; (c) t-BuPh2SiCl, imidazole, DMF, 90%;
(d) NaBH4–CeCl3, EtOH, )50 °C, 70%; (e) t-BuMe2SiCl, imidazole,
DMF, 98%.

E. Ruediger et al. / Tetrahedron Letters 45 (2004) 739–742
741
8. (a) Lin, T. S.; Luo, M. X.; Liu, M. C.; Zhu, Y. L.; Gullen,
E.; Dutschman, G. E.; Cheng, Y. C. J. Med. Chem. 1996,
39, 1757; (b) Ma, T.; Pai, S. B.; Zhu, Y. L.; Lin, J. S.;
Shanmuganathan, K.; Du, J.; Wang, C.; Kim, H.;
Newton, M. G.; Cheng, Y. C.; Chu, C. K. J. Med. Chem.
1996, 39, 2835; (c) Kumar, R.; Nath, M.; Tyrrell, D. L. J.
J. Med. Chem. 2002, 45, 2032.
9. (a) Innaimo, S. F.; Seifer, M.; Bisacchi, G. S.; Standring,
D. N.; Zahler, R.; Colonno, R. J. Antimicrob. Agents
Chemother. 1997, 41, 1444; (b) Genovesi, E. V.; Lamb, L.;
Medina, I.; Tayler, D.; Seifer, M.; Innaimo, S.; Colonno,
R. J.; Standring, D. N.; Clark, J. M. Antimicrob. Agents
Chemother. 1998, 42, 3209.
10. Bisacchi, G. S.; Chao, S. T.; Bachand, C.; Daris, J.-P.;
Innaimo, S. F.; Jacobs, G. A.; Kocy, O.; Lapointe, P.;
Martel, A.; Merchant, Z.; Slusarchyk, W. A.; Sundeen, J.
E.; Young, M. G.; Colonno, R. J.; Zahler, R. Bioorg. Med.
Chem. Lett. 1997, 7, 127.
11. Borthwick, A. D.; Kirk, B. E.; Biggadike, K.; Exall, A.
M.; Roberts, S. M.; Knight, D. J.; Coates, J. A. V.; Ryan,
D. M. J. Med. Chem. 1991, 34, 907.
OBn
O
OBn
O
OBn
OH
a, b
c-e
HO
HO
23
1
22
f
OBn
O
OBn
N
N
i, j
g, h
NH
NH2
OH
N
OH
2
O
O
25
24
Scheme 4. Reagents and conditions: (a) 1,10-thiocarbonyldiimidazole,
THF, 96%; (b) n-Bu3SnH, AIBN (cat), toluene, reflux, 83%; (c)
(PhSe)2, NaBH4, EtOH; (d) 35% H2O2, THF; (e) rt, 49% for steps c–e;
(f) t-BuOOH, VO(acac)2, CH2Cl2, 93%; (g) Dess–Martin periodinane,
t-BuOH, CH2Cl2, 89%; (h) Ph3PCHþ3 Brꢀ, MeLi, THF, 71%; (i)
O-Benzylguanine, LiH, DMF, 120 °C, 41%; (j) BCl3, CH2Cl2, )78 °C,
88%.
12. Various examples of base-catalyzed rearrangements of
functionalized cyclopentene epoxides have recently been
reported; (a) Camps, P.; Colet, G.; Font-Bardia, M.;
Table 1. Anti-HBV activity of nucleoside analogs in HepG2.215 cells23
Compound
EC50 (lM)
ꢀ
Munoz-Torrero, V.; Solans, X.; Vasquez, S. Tetrahedron
2002, 58, 3473; (b) Hodgson, D. M.; Witherington, J.;
Moloney, B. A. Tetrahedron: Asymmetry 1994, 5, 337; (c)
Milne, D.; Murphy, P. J. J. Chem. Soc., Chem. Commun.
1993, 884; (d) Asami, M. Bull. Chem. Soc. Jpn. 1990, 63,
1402.
8, BMS-200475
ent-8
0.003
100
2
>100
>100
0.2
3
4, 3TC
13. (a) Kissel, C. L.; Rickborn, B. J. Org. Chem. 1972, 37,
2060; (b) Rickborn, B.; Thummel, R. P. J. Org. Chem.
1969, 34, 3583.
30-deoxy analogs 2 and 3 proved to be inactive against
HBV (Table 1).
1
14. Compound 10: H NMR (400 MHz, CDCl3) d 7.37–7.28
(m, 5H), 5.92 (s, 1H), 4.64 (m, 1H), 4.61 (m, 1H), 4.55 (s,
2H), 4.15 (s, 2H), 2.74 (dt, J ¼ 7:1, 13.6 Hz, 1H), 2.09 (br
s, 1H), 1.61 (dt, J ¼ 4:7, 13.6 Hz, 1H), 0.92 (s, 9H), 0.11 (s,
3H), 0.10 (s, 3H).
1
Acknowledgements
15. Compound 11: H NMR (400 MHz, CDCl3) d 7.40–7.29
(m, 5H), 5.90 (d, J ¼ 5:5 Hz, 1H), 5.83 (d, J ¼ 5:5 Hz, 1H),
4.62 (ab d, J ¼ 12:2 Hz, 1H), 4.56 (ab d, J ¼ 12:2 Hz, 1H),
4.56–4.51 (m, 2H), 3.79 (dd, J ¼ 4:7, 9.0 Hz, 1H), 3.63 (dd,
J ¼ 7:1, 9.0 Hz, 1H), 2.13 (quintet, J ¼ 5:5 Hz, 1H), 1.99
(br s, 1H), 0.90 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H).
16. (a) Stork, G.; Kowalski, C.; Garcia, G. J. Am. Chem. Soc.
1975, 97, 3258; (b) Piancatelli, G.; Scettri, A. Synthesis
1977, 116.
We thank Mr. Steven Innaimo (BMS-Virology, Wal-
lingford, CT, USA) for providing the in vitro data and
Mr. Philippe Lapointe (BMS-Discovery Chemistry,
Candiac, QC, Canada) for a generous supply of epox-
ide 1.
1
17. Compound 15: H NMR (400 MHz, CDCl3) d 7.74–7.70
(m, 5H), 7.48–7.30 (m, 10H), 5.76 (s, 1H), 4.63 (t,
J ¼ 7:1 Hz, 1H), 4.54 (t, J ¼ 4:5 Hz, 1H), 4.51 (s, 2H),
4.12 (s, 2H), 2.56 (dt, J ¼ 7:1, 13.3 Hz, 1H), 1.76 (dt,
J ¼ 5:9, 12.9 Hz, 1H), 1.10 (s, 9H), 0.93 (s, 9H), 0.08 (s,
6H).
References and notes
1. Regev, A.; Schiff, E. R. Adv. Int. Med. 2001, 46, 107.
2. Maddrey, W. C. Clin. Lab. 2001, 47, 51.
3. Perillo, R. P.; Schiff, E. R.; Davis, G. L.; Bodenheimer,
H. C., Jr.; Lindsay, K.; Payne, J.; Dienstag, J. L.; OÕBrien,
C.; Tamburro, C.; Jacobson, I. M. N. Engl. J. Med. 1990,
323, 295.
18. Rasmussen, J. R.; Slinger, C. R.; Kordish, R. J.;
Newmann-Evans, D. D. J. Org. Chem. 1981, 46, 4843.
19. Stork, G.; Paterson, I.; Lee, F. K. C. J. Am. Chem. Soc.
1982, 104, 4686.
4. Wong, D. K.; Cheung, A. M.; OÕRourke, K.; Naylor, C.
D.; Detsky, A. S.; Heathcote, J. Ann. Int. Med. 1993, 119,
312.
20. (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277; (b) Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58,
2899.
5. Tipples, G. A.; Ma, M. M.; Fischer, K. P.; Bain, V. G.;
Kneteman, N. M.; Tyrrell, D. L. J. Hepatology 1996, 24,
714.
21. Madhaven, G. V.; McGee, D. P. C.; Rydzewski, R. M.;
Boehme, R.; Martin, J. C.; Prisbe, E. J. J. Med. Chem.
1988, 31, 1798.
6. (a) Starrett, J. E., Jr.; Tortolani, D. R.; Hitchcock, M. J.;
Martin, J. C.; Mansuri, M. M. Antiviral Res. 1992, 19, 267;
(b) Perrillo, R.; Schiff, E.; Yoshida, E.; Statler, A.; Hirsch,
K.; Wright, T.; Gutfreund, K.; Lamy, P.; Murray, A.
Hepatology 2000, 32, 129.
22. Sharpless, K. B.; Lauer, R. F. J. Am. Chem. Soc. 1973, 95,
2697.
23. HepG2.2.15 human liver cells, which harbor integrated
HBV genomes, secrete substantial amounts of infectious
HBV particles bearing viral DNA genomes into the
medium. Antiviral effects were scored as reductions in
7. Zoulim, F. J. Clin. Virol. 2001, 21, 243.

742
E. Ruediger et al. / Tetrahedron Letters 45 (2004) 739–742
the amount of HBV DNA present in the media after
treatment of the cells with drug for 9 days. HBV DNA was
released from secreted virus particles by alkali treatment,
after which it was immobilized onto membranes and
quantified by hybridization with a radiolabelled HBV
DNA probe.