Total synthesis of α-elvucitabine

Article abstract of DOI:10.1080/00397911.2011.571805

(Chemical Equation Presented) Total synthesis of α-elvucitabine was achieved in 26% overall yield by a concise nine-step procedure starting from L-lyxose, with trimethylsilyl trifluoromethaneoulfonate (TMSOTf)-mediated stereocontrolled α-N-glycosidation and olefination through Barton-McCombie deoxygenation being the key steps, and the stereochemistry of the product was determined by nuclear Overhauser effect spectroscopy. Copyright Taylor & Francis Group, LLC.

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Total Synthesis of α-Elvucitabine
Guilong Zhao a , Yuanyuan Lou b , Linshan Zhang b , Hua Shao a ,
Weiren Xu a , Lida Tang a & Meixiang Zou a
a Tianjin Key Laboratory of Molecular Design and Drug Discovery,
Tianjin Institute of Pharmaceutical Research, Tianjin, China
b College of Chemistry and Molecular Engineering, Qingdao
University of Science and Technology, Qingdao, China
Accepted author version posted online: 02 Jan 2012.Version of
record first published: 29 May 2012.
To cite this article: Guilong Zhao , Yuanyuan Lou , Linshan Zhang , Hua Shao , Weiren Xu , Lida Tang
& Meixiang Zou (2012): Total Synthesis of α-Elvucitabine, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 42:19, 2885-2893
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Synthetic Communications1, 42: 2885–2893, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.571805
TOTAL SYNTHESIS OF a-ELVUCITABINE
Guilong Zhao,1 Yuanyuan Lou,2 Linshan Zhang,2 Hua Shao,1
Weiren Xu,1 Lida Tang,1 and Meixiang Zou1
1Tianjin Key Laboratory of Molecular Design and Drug Discovery,
Tianjin Institute of Pharmaceutical Research, Tianjin, China
2College of Chemistry and Molecular Engineering, Qingdao University of
Science and Technology, Qingdao, China
GRAPHICAL ABSTRACT
Abstract Total synthesis of a-elvucitabine was achieved in 26% overall yield by a concise
nine-step procedure starting from L-lyxose, with trimethylsilyl trifluoromethaneoulfonate
(TMSOTf)–mediated stereocontrolled a-N-glycosidation and olefination through
Barton–McCombie deoxygenation being the key steps, and the stereochemistry of the
product was determined by nuclear Overhauser effect spectroscopy.
Keywords Deoxygenation; a-elvucitabine; NOESY; nucleoside analoge; olefination;
total synthesis
INTRODUCTION
Nucleoside analogs represent the most important class of antiviral drugs,
which find wide application in the treatment of hepatitis B virus (HBV) and human
immunodeficiency virus (HIV). Elvucitabine,[1–3] also known as ACH123,446 or b-
L-Fd4C, is now in phase II clinical trials in development as an antiviral drug indi-
cated for the treatment of HBV and HIV (Fig. 1). Elvucitabine is a nucleoside analog
with an unnatural L-configuration designed to reduce the long-term adverse effects
observed with the commonly encountered D-nucleoside analogs that are thought to
be due to mitochondrial toxicity.
During the development of elvucitabine as an antiviral drug for the treatment
of HBV, its a-anomer, a-elvucitabine, was needed for the assignment of the
Received January 13, 2011.
Address correspondence to Guilong Zhao, Tianjin Key Laboratory of Molecular Design and Drug
Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China. E-mail: zhao_guilong@126.com
2885

2886
G. ZHAO ET AL.
Figure 1. Structures of elvucitabine and a-elvucitabine.
Scheme 1. Retrosynthetic analysis of a-elvucitabine.
impurities in the elvucitabine sample (Fig. 1). Herein we report a concise nine-step
approach to the total synthesis of a-elvucitabine from L-lyxose (Schemes 1 and 2).
RESULTS AND DISCUSSION
Almost all the nucleoside analogs now in clinical use have a b-D-configuration
(Fig. 2), and this configuration was designed to mimic that in the natural nucleosides.
In these b-D-nucleoside analogs, the two groups at 10- and 40-positions adapt a cis-
geometry with respect to the five-membered furanoside ring. Because of the prevalence
of b-D-nucleoside analogs, a variety of stereocontrolled synthetic approaches both in lab-
oratory and in industry are now available to construct the nucleoside analogs with b-
D-configuration. However, stereocontrolled methods to build a nucleoside analog with
a-L-configuration where the two groups at 10- and 40-positions adapt a trans-geometry
are rarely found,[4] and most of the nucleoside analogs with a trans-geometry[1,5] were
often isolated as by-products when a cis-geometry was intended. Consequently, total syn-
thesis of a-elvucitabine with the rarely observed a-L-configuration corresponding to a
trans-geometry by a stereocontrolled approach seems challenging.
Retrosynthetic analysis of a-elvucitabine is summarized in Scheme 1. The
olefin functionality in the sugar moiety of a-elvucitabine can be built through
Barton–McCombie bis-deoxygenation, and in view of the requirement for the a-
induction of the 5-fluorocytosine moiety to the sugar moiety, both of the two
hydroxyl groups to be removed in the sugar moiety should adapt b-configurations

TOTAL SYNTHESIS OF a-ELVUCITABINE
2887
Scheme 2. Synthetic approach to a-elvucitabine.
(see intermediate A), leading to the identification of the sugar needed as L-lyxose.
The formation of nucleoside C-N bond through the coupling of the 5-fluorocytosine
moiety and the L-lyxose moiety can be effected by the treatment of the mixture of
bis-tetramethylsilane (TMS)-5-fluorocytosine and peracetylated L-lyxofuranose with
trimethylsilyl trifluoromethane sulfonate(TMSOTf). Thus, herein we devise and
report a stereocontrolled approach for the synthesis of a-elvucitabine starting from
L-lyxose, and in L-lyxose the three substituents at 20-, 30-, and 40-positions of the
five-membered furanoside ring all adapt a b-orientation that can unambiguously
lead to the desired a-anomeric center (Scheme 2).
The synthetic route of a-elvucitabine is summarized in Scheme 2.
L-Lyxofuranose tetraacetate 3 was prepared as a mixture of anomers from L-lyxose
according to a similar procedure reported earlier.[6] TMSOTf-mediated coupling of 3
and bis(TMS)-5-fluorocytosine[1] produced a-N-glycoside 4 with the desired a-
configuration at the anomeric position. This a-configuration was determined by
nuclear Overhauser effect spectroscopy (NOESY) of the finally isolated a-elvucita-
1
bine (Fig. 3) and confirmed by comparison of the H NMR data of the finally iso-
lated a-elvucitabine with those of the authentic elvucitabine sample,[2,3] and the
stereoselectivity observed was also consistent with theoretical prediction and similar
reported results.[4] Triacetate 4 was ammonolyzed with saturated NH3=MeOH at
room temperature to give rise to triol 5, whose primary hydroxyl group was pro-
tected with a t-butyldiphenylsilyl (TBDPS) group following standard procedure to
yield the vicinal diol 6. Olefination to obtain 8 was accomplished by conversion of
vicinal diol 6 to its corresponding bisxanthate 7 followed by Barton–McCombie

2888
G. ZHAO ET AL.
Figure 2. Selected nucleoside analogues with b-D-configuration.
Figure 3. Useful NOEs observed in elvucitabine and a-elvucitabine.
deoxygenation with azobisisobutyronitrile (AIBN)-initiated n-Bu3SnH reduction at
reflux. Silyl ether 8 was treated with n-Bu4NF in tetrahydrofuran (THF) at room
temperature for the cleavage of the silyl ether functionality to smoothly furnish
the desired a-elvucitabine.
The NOESY data of both the isolated a-elvucitabine and the authentic sample
of elvucitabine were collected and examined, and as depicted in Fig. 3, some useful
correlations were observed, which unambiguously confirmed the isolated product to
be a-elvucitabine.
Figure 4. Two potential anomers of elvucitabine.

TOTAL SYNTHESIS OF a-ELVUCITABINE
2889
As depicted in Fig. 4, two stereogenic centers exist in the molecule of elvucita-
bine, and the one corresponding to the 40-position was established by the starting
L-lyxose. Therefore, variation at the other stereogenic center, the anomeric center,
would lead to two potential anomers, a-elvucitabine and elvucitabine, and because
the 1H NMR data of the finally isolated product and the authentic sample were sig-
nificantly different, the isolated product from this synthetic approach can be further
confirmed to be a-elvucitabine.
EXPERIMENTAL
Melting points were determined with an XT-4 microscopic melting-point
apparatus and are uncorrected. 1H NMR spectra were recorded on a Bruker
AV400 spectrometer, with dimethylsulfoxide (DMSO-d6) as solvent and TMS as
internal standard. The high-resolution mass spectrography (HR-MS) data were
obtained on an Agilent Q-TOF 6510 mass spectrometer using the electrospray ioni-
zation (ESI) technique. The specific rotation was measured with a Perkin-Elmer
automatic polarimeter with sodium (589 nm). The silica gel used in column
chromatography was H60 (200–300 mesh) from Haiyang Chemical Ltd.
Dried dichloromethane and dimethylformamide (DMF) were distilled from
calcium hydride at atmospheric pressure and under reduced pressure, respectively.
Dried THF and toluene were distilled from sodium=benzophenone ketyl.
Synthetic Procedure of 1,2,3,5-Tetra-O-acetyl-a/b-L-
lyxofuranoside (3)
A 250-mL, round-bottomed flask was charged with 5.00 g (33.3 mmol) of com-
mercially available L-lyxose and 100 mL of methanol, and the resulting white slurry
was stirred on an ice bath followed by dropwise addition of 1 mL of concentrated
sulfuric acid. The reaction mixture was stirred at room temperature until all the
starting L-lyxose was consumed completely as indicated by thin-layer chromato-
graphic (TLC) analysis (typicaly 5 h).
The reaction mixture was cooled with an icewater bath once again, and 5 mL of
pyridine was added dropwise. After addition, the reaction mixture was evaporated
on a rotary evaporator to afford crude product 1 as a colorless oil, which was further
chased with 30 mL ꢀ 3 of pyridine, and the residue was dissolved in 50 mL of pyri-
dine. The mixture thus obtained was cooled with an ice-water bath, and 17.00 g
(167 mmol) of acetic anhydride was added dropwise. The resulting mixture was stir-
red at room temperature overnight.
The reaction mixture was poured into 300 mL of icewater, and the mixture thus
obtained was extracted with three 50-mL portions of dichloromethane. The com-
bined extracts were washed successively with 200 mL of 2% hydrochloric acid and
saturated aqueous sodium chloride, dried over sodium sulfate, and evaporated on
a rotary evaporator to afford the crude product 2 as a pale yellow oil.
The crude 2 was dissolved in 50 mL of glacial acetic acid and 15 mL of acetic
anhydride, and the resulting mixture was stirred on an ice bath followed by addition
of 2 mL of concentrated sulfuric acid. The reaction mixture was stirred at room

2890
G. ZHAO ET AL.
temperature until all the starting 2 was consumed completely as indicated by TLC
analysis (typicaly 5 h).
The reaction mixture was poured into 300 mL of icewater, and the mixture was
stirred at room temperature for 3 h and extracted with three 50-mL portions of
dichloromethane. The combined extracts were washed sequentially with 200 mL of
saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride,
dried over sodium sulfate, and evaporated on a rotary evaporator to afford the crude
3 as a pale yellow oil, which was purified by column chromatography (EtOAc=pet-
roleum ether ¼ 1=2 by v=v) to yield pure 3 as a colorless oil, 7.63 g (overall 72% from
1
L-lyxose). The pure sample 4 was found to be an anomeric mixture by H NMR.
Synthetic Procedure of 1-(2,3,5-Tri-O-acetyl-a-L-lyxofuranosyl)-
5-fluorocytosine (4)
A dried 250-mL, round-bottomed flask was charged with 7.93 g (29 mmol) of
bis(TMS)-5-fluorocytosine prepared according to a known procedure,[1] 7.58 g
(23.8 mmol) of 3, and 150 mL of dried dichloromethane. The resulting mixture
was stirred on an ice bath, and 7.78 g (35 mmol) of TMSOTf in 20 mL of dried
dichloromethane was added dropwise through a pressure-equalizing funnel. The
mixture thus obtained was refluxed overnight under nitrogen until TLC analysis
found that almost all the starting 3 was consumed.
On cooling, the reaction mixture was diluted with 100 mL of dichloromethane
and slowly poured into 300 mL of icewater, and the resulting mixture was brought to
pH 7–8 with saturated aqueous sodium bicarbonate and stirred for 5 min before the
organic phase was separated. The aqueous phase was back-extracted with 50 mL of
dichloromethane, and the combined extracts were washed in turn with 100 mL of
saturated sodium bicarbonate and saturated aqueous sodium chloride, dried over
sodium sulfate, and evaporated on a rotary evaporator to afford the crude product
4 as a colorless oil, which was purified by column chromatography (EtOAc=MeOH=
Et3N ¼ 100=2=1 by v=v) to afford the pure product 4 as a white foam.
White foam, 8.20 g, yield 89%. 1H NMR (DMSO-d6, 400 MHz): d 8.09–8.11 (d,
1H, J ¼ 7.2 Hz), 7.92 (bs, 1H), 7.66 (bs, 1H), 5.88–5.89 (d, 1H, J ¼ 6.4 Hz), 5.79–5.82
(m, 1H), 5.54–5.56 (m, 1H), 4.88–4.91 (m, 1H), 4.15–4.16, 4.18–4.19 (dd, 1H,
J ¼ 4.2 Hz and 11.8 Hz), 4.07–4.08, 4.10–4.11 (dd, 1H, J ¼ 7.4 Hz and 11.8 Hz),
2.11 (s, 3H), 2.01 (s, 3H), 1.97 (s, 3H). HR-ESI-MS, calcd. for C15H19FN3O8
([M þ H]þ) 388.3245; found 388.3251.
Synthetic Procedure of 1-(a-L-Lyxofuranosyl)-5-fluorocytosine (5)
A dried 100-mL, round-bottomed flask was charged with 8.13 g (21 mmol) of 4
and 60 mL of saturated NH3=MeOH (ca 16% by w=w) prepared by bubbling dried
ammonia into cooled methanol, and the resulting white slurry was stirred at room
temperature to give a colorless solution. The stirring was continued until all the start-
ing 4 was consumed completely as indicated by TLC analysis (typicaly 5 h).
The reaction mixture was evaporated on a rotary evaporator to afford the
crude product 5 as a white residue, which was triturated with 10 mL of methanol

TOTAL SYNTHESIS OF a-ELVUCITABINE
2891
and 40 mL of isopropanol to yield the pure product 5 as a white solid after suction
filtration and drying in vacuo at room temperature.
White solid, mp 232–233 ꢁC, 4.99 g, yield 91%. 1H NMR (DMSO-d6,
400 MHz): d 7.95–7.97 (d, 1H, J ¼ 7.2 Hz), 7.74 (bs, 1H), 7.50 (bs, 1H), 5.75–5.76,
5.77–5.78 (dd, 1H, J ¼ 1.6 Hz and 7.2 Hz), 5.23–5.24 (d, 1H, J ¼ 6.4 Hz), 4.93–4.94
(d, 1H, J ¼ 4.0 Hz), 4.57–4.60 (t, 1H, J ¼ 5.6 Hz), 4.28–4.33 (m, 2H), 3.99–4.02 (m,
1H), 3.56–3.61 (m, 1H), 3.44–3.50 (m, 1H). HR-ESI-MS, calcd. for C9H13FN3O5
([M þ H]þ) 262.2145; found 262.2143.
Synthetic Procedure of 1-[5-O-(t-Butyldiphenylsilyl)-a-L-lyxofuranosyl]-
5-fluorocytosine (6)
A dried 100-mL, round-bottomed flask was charged with 4.70 g (18 mmol) of 5,
3.68 g (54 mmol) of imidazole, and 20 mL of dried DMF, and the resulting mixture
was stirred on an ice bath, followed by addition of 7.42 g (27 mmol) of TBDPSCl in a
dropwise manner. After addition, the reaction mixture was stirred at room tempera-
ture overnight when TLC analysis demonstrated that almost all the starting 5 was
consumed.
The reaction mixture was poured into 200 mL of saturated aqueous sodium
chloride, and the mixture thus obtained was extracted with three 50-mL of portions
of dichloromethane. The combined extracts were washed with saturated aqueous
sodium chloride, dried over sodium sulfate, and evaporated on a rotary evaporator
to afford the crude product as a colorless oil, which was purified by column chroma-
tography (EtOAc=MeOH=Et3N ¼ 100=5=1.5 by v=v) to give rise to the pure product
6 as a white foam.
White foam, 7.73 g, yield 86%. 1H NMR (DMSO-d6, 400 MHz): d 7.99–8.01 (d,
1H, J ¼ 6.8 Hz), 7.77 (bs, 1H), 7.63–7.66 (m, 4H), 7.52 (bs, 1H), 7.39–7.47 (m, 6H),
5.78–5.79, 5.80–5.81 (dd, 1H, J ¼ 1.6 Hz and 7.2 Hz), 5.25–5.27 (d, 1H, J ¼ 6.4 Hz),
4.99–5.00 (d, 1H, J ¼ 4.0 Hz), 4.52–4.56 (m, 1H), 4.31–4.35 (m, 1H), 4.03–4.06 (m,
1H), 3.86–3.90 (m, 1H), 3.69–3.73 (m, 1H), 0.98 (s, 9H). HR-ESI-MS, calcd. for
C25H30FN3NaO5Si ([M þ Na]þ), 522.5959; found 522.5960.
Synthetic Procedure of 1-f5-O-t-Butyldiphenylsilyl-2,3-di-O-
[methylthio(thiocarbonyl)]-a-L-lyxofuranosylg-5-fluorocytosine (7)
A dried 100-mL, round-bottomed flask was charged with 7.49 g (15 mmol) of 6,
3.42 g (45 mmol) of carbon disulfide, and 40 mL of DMSO, and the mixture was stir-
red on an ice bath, followed by addition of 1.52 g (38 mmol) of sodium hydroxide
dissolved in 5 mL of water. After addition, the stirring was continued for half an
hour on an ice-water bath, and 5.39 g (38 mmol) of methyl iodide was added in
one portion. The resultant mixture was stirred at room temperature for 2 h.
The reaction mixture was poured into 200 mL of saturated aqueous sodium
chloride, and the mixture thus obtained was extracted with three 50-mL portions
of dichloromethane. The combined extracts were washed with saturated aqueous
sodium chloride, dried over sodium sulfate, and evaporated on a rotary evaporator
to give rise the crude product as a yellow oil, which was purified by column

2892
G. ZHAO ET AL.
chromatography (EtOAc=petroleum ether ¼ 4=1 by v=v) to furnish the pure product
7 as a white foam.
White foam, 7.96 g, yield 78%. 1H NMR (DMSO-d6, 400 MHz): d 8.11–8.12 (d,
1H, J ¼ 6.8 Hz), 7.96 (bs, 1H), 7.69 (bs, 1H), 7.58–7.61 (m, 4H), 7.39–7.48 (m, 6H),
6.78–6.80 (t, 1H, J ¼ 5.4 Hz), 6.63–6.65 (t, 1H, J ¼ 4.6 Hz), 5.98–5.99 (d, 1H,
J ¼ 6.0 Hz), 5.08–5.09 (m, 1H), 3.78–3.80, 3.81–3.83 (dd, 1H, J ¼ 3.2 Hz and
10.4 Hz), 3.69-3.70, 3.71–3.73 (dd, 1H, J ¼ 5.8 Hz and 10.2 Hz), 2.54 (s, 3H), 2.49
(s, 3H), 0.95 (s, 9H). HR-ESI-MS, calcd. for C29H35FN3O5S4Si ([M þ H]þ)
680.9487; found 680.9490.
Synthetic Procedure of 2’,3’-Dideoxy-5-fluoro-5’-O-(t-
butyldiphenylsilyl)-a-l-cytidine (8)
A dried 100-mL, round-bottomed flask was charged with 7.48 g (11 mmol) of 7,
14.55 g (50 mmol) of n-Bu3SnH, 0.82 g (5 mmol) of AIBN, and 60 mL of dried tolu-
ene, and the resulting mixture was refluxed under nitrogen for 1 h when TLC analysis
indicated that all the starting 7 was consumed completely.
On cooling, the reaction mixture was evaporated on a rotary evaporator to
afford the crude product 8 as a yellow oil, which was purified by column chromato-
graphy (EtOAc=MeOH ¼ 20=1) to produce the pure product 8 as a white foam.
White foam, 3.89 g, yield 76%. 1H NMR (DMSO-d6, 400 MHz): d 7.80 (bs, 1H),
7.62–7.64 (m, 4H), 7.50–7.51 (bs þ d, 2H, for the doublet J ¼ 6.8 Hz), 7.40–7.48 (m,
6H), 6.92–6.93 (m, 1H), 6.37–6.39 (m, 1H), 5.96–5.98 (m, 1H), 5.22–5.24 (m, 1H),
3.74–3.75, 3.77–3.78 (dd, 1H, J ¼ 3.8 Hz and 10.6 Hz), 3.66–3.67, 3.69–3.70 (dd,
1H, J ¼ 4.0 Hz and 10.8 Hz), 0.98 (s, 9H). HR-ESI-MS, calcd. for C25H29FN3O3Si
([M þ H]þ), 466.5994; found 466.5999.
Synthetic Procedure of a-Elvucitabine
A dried 100-mL, round-bottomed flask was charged with 3.72 g (8 mmol) of 8
and 20 mL of dried THF, and the mixture thus obtained was stirred at room tem-
perature followed by addition of 9 mL (9 mmol) of 1.0 M n-Bu4NF in THF. The stir-
ring was continued for 1 h when all the starting 8 was consumed completely as shown
by TLC analysis.
The reaction mixture was evaporated on a rotary evaporator to afford the
crude product as a yellow oil, which was purified by column chromatography
(EtOAc=MeOH ¼ 5=1) to yield the pure a-elvucitabine as a white solid.
20
White solid, mp 128–130 ꢁC, 1.60 g, yield 88%. [a]D ¼ þ 262.3ꢁ (c ¼ 1,
MeOH). 1H NMR (DMSO-d6, 400 MHz): d 7.76 (bs, 1H), 7.52 (bs, 1H),
7.45–7.47 (d, 1H, J ¼ 6.8 Hz), 6.84–6.85 (m, 1H), 6.34–6.36 (m, 1H), 5.88–5.90 (m,
1H), 5.06–5.08 (m, 1H), 4.82 (s, 1H), 3.41–3.47 (m, 2H). HR-ESI-MS, calcd. for
C9H11FN3O3 ([M þ H]þ), 228.1998; found 228.2002. NOESY data were collected,
and the useful correlations are summarized in Fig. 3.
ACKNOWLEDGMENT
The authors express their sincere gratitude to Key the Project of National
Innovative Drug (2009ZX09301-008-P-05) of China for financial support.

TOTAL SYNTHESIS OF a-ELVUCITABINE
2893
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