A novel and efficient synthesis of Entecavir

Article abstract of DOI:10.1016/j.tetlet.2012.05.058

A practical synthesis of Entecavir (1) has been accomplished in 10 steps with 21% overall yield. The key steps to construct the five-membered carbocyclic framework 2 are a ring-closing metathesis and a diethyl-aluminum 2,2,6,6-tetramethyl piperidide (DA-TMS) mediated epoxide isomerization. Furthermore, the guanine was introduced by modified Mitsunobu reaction.

Full text of DOI:10.1016/j.tetlet.2012.05.058

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Tetrahedron Letters 53 (2012) 3805–3807
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel and efficient synthesis of Entecavir
⇑
Xiaoyu Liu, Xiaozhen Jiao, Qian Wu, Chengsen Tian, Renze Li, Ping Xie
State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Beijing Key Laboratory of Active Substance Discovery and Drugability Evaluation,
Institute of Materia Medica, Chinese Academy of Medical Science & Pecking Union Medical College, No.1, Xiannongtan St., Beijing 100050, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 March 2012
Revised 4 May 2012
Accepted 11 May 2012
Available online 17 May 2012
A practical synthesis of Entecavir (1) has been accomplished in 10 steps with 21% overall yield. The key steps
to construct the five-membered carbocyclic framework 2 are a ring-closing metathesis and a diethyl-
aluminum 2,2,6,6-tetramethyl piperidide (DA-TMS) mediated epoxide isomerization. Furthermore, the
guanine was introduced by modified Mitsunobu reaction.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Entecavir
Carbacyclic framework
Epoxide isomerization
Mitsunobu reaction
Entecavir (1) is an oral carbocyclic analog of 2-deoxyguanosine
with selective activity against hepatitis B virus (HBV). It inhibits
DNA synthesis in HBV infected cells in three steps: the priming
of the polymerase, the reverse transcription of the pregenomic
messenger RNA and the synthesis of the positive strand of HBV
DNA. Entecavir is also effective against lamivudine- and adefovir-
resistant HBV strains. It is marked under the trade name
‘Baraclude’ and administered at 0.5 mg once daily for adults
infected with chronic hepatitis B.1–4
substituted purine, therefore 2 is believed to be an useful interme-
diate.5a,b,e Various methods for preparing 2 have been developed,
for example, patent discloses a method for the preparation of 2 from
expensive (+)-corey diol,5e Ziegler and Sarpong used
D-diacelone
glucose as the starting material to get the similar core (difference
in protection of hydroxyl group),5a and recently, Zhou and co-work-
ers have also developed a novel diastereoselective synthesis of 2
from 1,3-propanediol by an intramolecular nitrile oxide cycloaddi-
tion (INOC) reaction over 14 steps.5b However, all of them are either
Inspired by its biological importance, considerable efforts have
been made for its synthesis.5 Previous works indicated that Enteca-
vir could be prepared in a convergent manner via Mitsunobu
coupling between the chiral substituted cyclopentanol 2 and
O
Br
OH
a,b
e
+
OH
7
8
6
TBSO
TBSO
c
N
N
HO
TBSO
TBSO
O
O
N
OH
HO
HO
NH
RO
R=H
4
HO
9
d
TBSO
TBSO
NH2
5
R=TBS
3
1
2
5
TBSO
O
h
f
OH
HO
TBSO
TBSO
RO
TBSO
O
10 R=H
2
g
HO
HO
3
R=TBS
6
4
Scheme 2. Preparation of 2. Reagents and conditions: (a) Ref. 6; (b) Ref. 7, 60% for
two steps, ee 93.8%; (c) isopropenyl magnesium bromide, CuI, THF, ꢀ25 °C, 10 h,
and then NaIO4, THF/H2O, 70%; (d) TBDMSCl, imidazole, DMF, 0 °C–rt, 10 h, 90%; (e)
Grubbs 2nd (5 mol %), DCM, reflux, 3 h, 93%; (f) t-BuOOH, VO(acac)2, ClCH2CH2Cl,
0 °C–rt, 2 h, 94%; (g) TBDMSCl, imidazole, DMF, rt, 2 h, 82%; (h) diethyl-aluminum
2,2,6,6-tetramethyl piperidide (DA-TMS), toluene, 0 °C, 20 h, 93%.
Scheme 1. Structure of Entecavir (1) and its retrosynthetic analysis.
⇑
Corresponding author. Tel.: +86 10 63165245; fax: +86 10 63017757.
E-mail address: xp@imm.ac.cn (P. Xie).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.058

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3806
X. Liu et al. / Tetrahedron Letters 53 (2012) 3805–3807
Cl
N
N
N
H
N
NR2
N
Cl
N
N
N
TBSO
OTBS
HO
O
11
R=H
a
OH
N
N
12 R=Boc
N
NH
c
b
TBSO
TBSO
NR2
HO
13
NH2
R=H
1
2
14 R=Boc
Scheme 3. Synthesis of Entecavir (1). Reagents and conditions: (a) Ref. 19; (b) DEAD, Ph3P, THF, 0 °C, 30 min, 94%; (c) 2 N HCl, THF, reflux, 6 h, 90%.
lengthy, inefficient, or involving hazardous conditions, expensive
starting materials or reagents. Herein, we report a novel and effi-
cient approach for the synthesis of intermediate 2 which needs only
eight steps using propargyl alcohol as the starting material. In addi-
tion, we performed a modified Mitsunobu reaction to introduce the
guanine ring in high yield.
via modified Mitsunobu coupling22 in high yield are novel aspects
of this work. This proposed synthetic route is straightforward, flex-
ible, and effective.
Acknowledgment
Our synthetic approach ensues from the following analysis of 1
(Scheme 1). The guanine may be introduced via Mitsunobu cou-
pling of the key intermediate 2 and a substituted purine, while
the exomethylene in 2 may be expected to be formed through
DA-TMS mediated epoxide isomerization of the advanced interme-
diate 3 bearing appropriate groups. The densely functionalized
cyclopentane 3 could be achieved by VO(acac)2-catalyzed OH-di-
rected syn-epoxidation reaction from 4, which can be synthesized
from 5 under a ring closing metathesis (RCM) reaction. Compound
5 could be accessed from the easily prepared alcohol 6.
This work was partly supported by Beijing Union Pharmaceuti-
cal Factory and we thank Beijing Funsea Technology Co., Ltd for
chiral HPLC analysis.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.05.
058.
Based on the retrosynthetic analysis, our synthetic approach to
the key intermediate 2 began with the known epoxy alcohol 6
(Scheme 2). In the previous reports, compound 6 was readily pre-
pared from Indium-mediated regioselective allylation of propargyl
alcohol with allyl bromide,6 followed by Katsuki-Sharpless process.
Copper-catalyzed addition of epoxide 6 with Grignard reagent gave
diol 97,8 regioselectively, which was converted into corresponding
TBS protected (3R,4S)-diene 59 by selective protection of the
primary hydroxyl group, followed by RCM reaction10 to furnish
cyclopentanol 411 in 93% yield. The epoxy was introduced stereose-
lectively by taking advantage of the hydroxyl group of 4 via VO(a-
cac)2-catalyzed OH-directed syn-epoxidation reaction using t-
BuOOH as the oxidant,12 providing the desired stereoisomer 1013
in high yield. After the secondary hydroxyl group was protected
by TBS,14 the requisite substituted cyclopentenol 215 was obtained
in high yield with complete regioselectivity by treatment of TBS
ether 3 with diethyl-aluminum 2,2,6,6-tetramethyl piperidide
(DA-TMP) via epoxide isomerization.16
Although direct Mitsunobu coupling between 2 and 6-chloro-2-
aminopurine 11 (Scheme 3) proved to be feasible, the yield (55–
65%) of the coupling reaction is moderate and the reaction requires
a large excess of 11 (>2.5 equiv) due to low solubility of 11 under
typical Mitsunobu condition.17 Literature reported that N-6-ami-
no-bis-Boc-protected adenine, compared with adenine, is a supe-
rior Mitsunobu substrate in that it is completely soluble in THF,
and it could undergo efficient Mitsunobu coupling with versatility
of substituted cyclopentan(en)ols.18 Based on the similar consider-
ation, we tested compound 12.19 To our delight, when we treated 2
with 12 under mild condition (THF, PPh3, DEAD, 0 °C), the coupling
product 1420 could be formed in excellent yield (94%). Finally, both
the silyl groups and Boc groups were deprotected with 2.0 N HCl/
THF in one pot to afford the target compound 121 in good yield
(90%).
References and notes
1. Innaimo, S. F.; Sieffer, M.; Bisacchi, G. S.; Standring, N.; Zahler, R.; Colonno, R. J.
Antimicrob. Agents Chemother. 1997, 41, 1444.
2. Deman, R. A.; Wolters, L. M. M.; Neven, F.; Chua, D.; Sherman, M.; Lai, C. L.;
Gadano, A.; Lee, Y.; Mazzotta, F.; Thomas, N.; DeHertogh, D. Hepatology 2001,
34, 578.
3. Kwak, M. S.; Choi, J. W.; Lee, J. S.; Kim, K. A.; Suh, J. H.; Cho, Y. S.; Won, S. Y.;
Park, B. K.; Lee, C. K. J. Viral Hepat. 2011, 18, 432.
4. Chang, T. T.; Lai, C. L.; Yoon, S. K.; Lee, S. S.; Coelho, H. S. M.; Carrilho, F. J.;
Poordad, F.; Halota, W.; Horsmans, Y.; Tsai, N.; Zhang, H.; Tenney, D. J.; Tamez,
R.; Iloeje, U. Hepatology 2010, 51, 422.
5. (a) Ziegler, F. E.; Sarpong, M. A. Tetrahedron 2003, 59, 9013; (b) Zhou, B.; Li, Y. C.
Tetrahedron Lett. 2012, 53, 502; (c) Bisacchi, G. S.; Chao, S. T.; Bachard, C.; Daris,
J. P.; Innaimo, S.; Jacobs, G. A.; Kocy, O.; Lapointe, P.; Martel, A.; Merchant, Z.;
Slusarchyk, W. A.; Sundeen, J. E.; Young, M. G.; Colonno, R.; Zahler, R. Bioorg.
Med. Chem. Lett. 1997, 7, 127; (d) Bisacchi, G. S.; Sundeen, J. E. W.O. Patent
9809964, 1998.; (e) Pendri, Y. R.; Chen, C. P. H.; Patel, S. S. et al. U. S. Patent
0192912, 2004.; (f) Guo, L. W.; Xiao, Y. J.; Yang, L. P. Chin. Chem. Lett. 2006, 17,
907; (g) Zhou, M. X.; Reiff, E. A. et al. U. S. Patent 7786300, 2010.
6. Ranu, B. C.; Majee, A. Chem. Commun. 1997, 13, 1225.
7. (a) Ma, S. M.; Ni, B. Chem. Eur. J. 2004, 10, 3286. Compound 6: ½a D20
ꢀ32.0 (c
ꢁ
0.15, CHCl3); ee 93.8%; 1H NMR (300 MHz, CDCl3) d 5.89–5.76 (m, 1H), 5.19–
5.11 (m, 2H), 3.95–3.91 (m, 1H), 3.68–3.63 (m, 1H), 3.08–3.04 (m, 1H), 2.99–
2.96 (m, 1H), 2.37 (t, J = 6.0 Hz, 2H). 13C NMR (100 MHz, CDCl3) d 132.7, 117.7,
61.5, 57.8, 54.7, 35.6. The enantiomeric excess was assessed by chiral HPLC
analysis of the corresponding para-toluenesulfonate (chiral OD column
0.46 ꢂ 15 cm, n-hexane/i-prOH = 24:1, 1.0 mL minꢀ1, rt).; For
a review on
Katski-Sharpless epoxidation, see: (b) Katsuki, T.; Martin, V. S. Org. React. 1996,
48, 1–299; (c) The use of NaIO4 is for oxidative cleavage of minor amount of
1,2-diol byproduct, see: Ref. 7a
8. Compound 9: ½a D20
ꢁ
ꢀ4.9 (c 1.1, CHCl3); 1H NMR (400 MHz, CDCl3) d 5.88–5.77
(m, 1H), 5.18 (s, 1H), 5.14 (d, J = 10.8 Hz, 1H), 4.91 (s, 1H), 4.80 (s, 1H), 3.89–
3.80 (m, 2H), 3.70 (dd, J = 10.8, 5.2 Hz, 1H), 2.41–2.38 (m, 1H), 2.29–2.24 (m,
1H), 2.14–2.06 (m, 1H), 1.71 (s, 3H); 13C NMR (100 MHz, CDCl3) d 143.4, 134.4,
118.8, 113.7, 73.0, 65.0, 54.0, 40.2, 21.6; HR-MS (ESI) calcd for C9H17O2Na
(M+Na)+: 179.1048, found 179.1053.
9. Compound 5: ½a D20
ꢁ
ꢀ25.2 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) d 5.94–5.90
(m, 1H), 5.11 (d, J = 8.8 Hz, 1H), 5.07 (s, 1H), 4.86 (s, 1H), 4.75 (s, 1H), 3.92–3.78
(m, 3H), 2.35–2.31 (m, 1H), 2.28–2.22 (m, 1H), 2.17–2.11 (m, 1H), 1.71 (s, 3H),
0.90 (s, 9H), 0.08 (s, 6H); 13C NMR (100 MHz, CDCl3) d 143.6, 135.5, 116.9,
113.4, 74.0, 66.9, 53.3, 39.8, 25.8, 22.0, 18.1, ꢀ5.6, ꢀ5.6; HR-MS (ESI) calcd for
C
15H31O2Si (M+H)+: 271.2088, found 271.2087.
In summary, a simple, convenient, and efficient synthesis of
Entecavir has been developed. Using a RCM reaction followed by
VO(acac)2-catalyzed OH-directed syn-epoxidation reaction, the
DA-TMP mediated epoxide isomerization for constructing the chi-
ral substituted cyclopentanol 2, and finally introducing the purine
10. Grubbs, R. H.; Tumas, W. Science 1989, 243, 907.
11. Compound 4: ½a D20
ꢁ
+34.0 (c 0.25, CHCl3); 1H NMR (300 MHz, CDCl3) d 5.32 (s,
1H), 4.34–4.29 (m, 1H), 3.85 (dd, J = 9.9, 4.8 Hz, 1H), 3.46 (t, J = 8.4 Hz, 1H),
2.64–2.56 (m, 2H), 2.21–2.16 (m, 1H), 1.66 (s, 3H), 0.9 (s, 9H), 0.10 (s, 6H); 13
C
NMR (125 MHz, CDCl3) d 138.1, 123.4, 64.1, 59.2, 39.9, 25.9, 18.2, 15.3, ꢀ5.5,
ꢀ5.5; HR-MS (ESI) calcd for C13H27O2Si (M+H)+: 243.1775, found 243.1772.

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X. Liu et al. / Tetrahedron Letters 53 (2012) 3805–3807
3807
12. Biggadike, K.; Borthwick, A. D.; Evans, D.; Exall, A. M.; Kirk, B. E.; Roberts, S. M.;
Stephenson, L.; Youds, P. J. Chem. Soc., Perkin. Trans. 1 1988, 3, 549.
17. Lee, J. A.; Moon, H. R.; Kim, H. O.; Kim, K. R.; Lee, K. M.; Kim, B. T.; Hwang, K. J.;
Chun, M. W.; Jacobson, K. A.; Jeong, L. S. J. Org. Chem. 2005, 70, 5006.
13. The configuration of the stereocenters in 10 or 3 were confirmed by NOE
Compound 13: ½a 2D0 +33.1 (c 0.13, CHCl3); mp 37–39°C; 1H NMR (300 MHz,
ꢁ
experiment of compound 3 (see: our Supplementary data). Compound 10: ½a D20
ꢁ
CDCl3) d 7.83 (s, 1H), 5.55–5.50 (m, 1H), 5.19 (s, 1H), 4.83 (s, 1H), 4.35–4.42 (m,
1H), 3.84–3.74 (m, 2H), 2.67 (br s, 1H), 2.33–2.15 (m, 2H), 0.92 (s, 9H), 0.90 (s,
9H), 0.10 (s, 6H), 0.08 (s, 6H); 13C NMR (125 MHz, CDCl3) d 158.8, 153.9, 151.1,
148.9, 141.8, 125.4, 111.4, 72.4, 64.1, 56.3, 54.7, 40.4, 26.0, 25.8, 18.4, 18.0,
+25.6 (c 0.29, CHCl3); 1H NMR (300 MHz, CDCl3) d 3.92 (d, J = 6.3 Hz, 1H), 3.75–
3.63 (m, 2H), 3.43 (s, 1H), 2.19–2.09 (m, 2H), 1.99–1.94 (m, 1H), 1.48 (s, 3H),
0.87 (s, 9H), 0.04 (s, 6H); 13C NMR (125 MHz, CDCl3) d 75.1, 66.5, 64.8, 62.3,
54.7, 38.4, 25.8, 18.1, 15.5, ꢀ5.6, ꢀ5.8; HR-MS (ESI) calcd for C13H27O3Si
(M+H)+: 259.1724, found 259.1717.
ꢀ4.6, ꢀ4.7, ꢀ5.4, ꢀ5.4; HR-MS (ESI) calcd for
C
24H43ClN5O2Si2 (M+H)+:
524.2638, found 524.2635.
(1.41)
18. (a) Yin, X. Q.; Li, W. K.; Schneller, S. W. Tetrahedron Lett. 2006, 47, 9187; (b)
Michel, B. Y.; Strazewski, P. Tetrahedron 2007, 63, 9836.
19. Dey, S.; Garner, P. J. Org. Chem. 2000, 65, 7697.
noe
noe
TBSO
O
20. Compound 14: ½a D20
ꢁ
+23.6 (c 0.23, CHCl3); 1H NMR (300 MHz, CDCl3) d 8.22 (s,
(3.68)
noe
(4.27)
H
(3.26)
1H), 5.69–5.67 (m, 1H), 5.24 (s, 1H), 4.84 (s, 1H), 3.83–3.81 (m, 2H), 2.70 (s,
1H), 2.32–2.24 (m, 2H), 1.43 (s, 18H), 0.95–0.85 (m, 18H), 0.10–0.07 (m, 12H);
13C NMR (100 MHz, CDCl3)d 152.7, 151.7, 151.0, 150.5, 148.8, 145.5, 130.1,
111.9, 83.4, 72.3, 64.1, 57.0, 54.8, 40.8, 27.9, 26.0, 25.8, 18.4, 18.0, ꢀ4.6, ꢀ4.7,
ꢀ5.4, ꢀ5.5; HR-MS (ESI) calcd for C34H59ClN5O6Si2 (M+H)+: 724.3692, found
724.3713.
H
TBSO
14. Compound 3: ½a D20
ꢁ
+35.0 (c 0.15, CHCl3); 1H NMR (300 MHz, CDCl3) d 4.27 (d,
21. Compound 1: ½a D20
ꢁ
+28.0 (c 0.2, H2O); 1H NMR (300 MHz, CDCl3) d 10.54 (s, 1H),
J = 7.5 Hz, 1H), 3.68 (d, J = 3.3 Hz, 2H), 3.26 (s, 1H), 2.14–2.07 (m, 1H), 2.03 (s,
1H), 1.86–1.81 (m, 1H), 1.41 (s, 3H), 0.88 (s, 9H), 0.87 (s, 9H), 0.05 (s, 6H), 0.03
(s, 6H); 13C NMR (125 MHz, CDCl3)d 76.4, 66.1, 64.9, 62.6, 55.3, 39.0, 26.0, 25.8,
18.2, 18.1, 16.0, ꢀ4.5, ꢀ4.5, ꢀ5.7, ꢀ5.7; HR-MS (ESI) calcd for C19H41O3Si2
(M+H)+: 373.2589, found 373.2592.
7.65 (s, 1H), 6.40 (s, 2H), 5.34 (t, J = 9.3 Hz, 1H), 5.09 (s, 1H), 4.86 (d, J = 3 Hz,
1H), 4.84–4.80 (m, 1H), 4.55 (s, 1H), 4.22 (s, 1H), 3.52 (t, J = 5.7 Hz, 2H), 2.25–
2.16 (m, 1H), 2.06–1.99 (m, 1H); 13C NMR (125 MHz, CDCl3) d 156.8, 153.5,
151.4, 151.3, 135.9, 116.2, 109.2, 70.3, 63.0, 55.1, 54.1; HR-MS (ESI) calcd for
15. Compound 2: ½a D20
ꢁ
ꢀ34.0 (c 0.44, CHCl3); mp 63–65 °C; 1H NMR (300 MHz,
C
12H15N5O3Na (M+Na)+: 300.1067, found 300.1062.
CDCl3) d 5.37 (s, 1H), 5.11 (s, 1H), 4.34 (m, 2H), 3.55 (dd, J = 10.2, 5.4 Hz, 1H),
3.29 (dd, J = 10.2, 9.0 Hz, 1H), 2.85 (m, 1H), 2.74 (m, 1H), 1.95 (ddd, J = 13.2, 5.4,
4.5 Hz, 1H), 1.81 (dq, J = 13.2, 1.1 Hz, 1H), 0.87 (s, 18H), 0.08 (s, 6H), 0.03 (s,
3H), 0.01 (s, 3H); 13C NMR (75 MHz, CDCl3) d 154.2, 111.7, 75.4, 75.3, 64.6, 54.9,
42.0, 25.9, 25.8, 25.6, 18.2, 17.8, ꢀ4.8, ꢀ4.9, ꢀ5.5, ꢀ5.6; HR-MS (ESI) calcd for
22. During the preparation of this manuscript, we have found there are some
recent patents involving the use of a similar modified Mitsunobu coupling
in the synthesis of Entecavir. (a) Alberico, D.; Clayton, J.; Dlxon, C.; Gorin,
B. PCT Int. Appl. WO 2011/150512, 2009; (b) Hu, T. C.; Huang, H. T. U. S.
Patent 13 027 859, 2011; (c) Zheng, Z. G. PCT Int. Appl. WO 2012/006964,
2012.
C
19H41O3Si2 (M+H)+: 373.2589, found 373.2585.
16. DA-TMP base see: Magnus, P.; Westwood, N.; Spyvee, M.; Frost, C.; Linnane, P.;
Tavares, F.; Lynch, V. Tetrahedron. 1999, 55, 6435.