Rhodium catalyzed stereospecific reductive carbocyclization of 1,6-enynes and synthesis of 4′-methyl-6′-substituted aristeromycins

Article abstract of DOI:10.1080/15257770.2018.1554221

The need of long-term treatment for chronic HBV, emergence of drug-resistant viruses and inefficiency of currently approved therapies to eliminate covalently closed circular DNA (cccDNA), mandates identification of potent and selective inhibitors of HBV replication with novel mechanisms of action. Entecavir, a carbocyclic guanosine nucleoside analog, is the most potent inhibitor of HBV replication on the market. Moreover, the naturally occurring carbocyclic nucleosides aristeromycin are known for their wide range of antiviral activities. In this research, we have utilized BINAP directed rhodium catalyzed reductive carbocyclization of 1,6-enynes (8a–b) through asymmetric hydrogenation which is an approach, not yet explored in carbocyclic sugar synthesis. Interestingly, we obtained exclusive anti-(9a) and Z-anti(9b) carbocyclic sugars. The new aristeromycin analogs (10a–b) with scaffold combination of entecavir and aristeromycin were then synthesized using the Mitsunobu reaction followed by deprotection.

Full text of DOI:10.1080/15257770.2018.1554221

Nucleosides, Nucleotides and Nucleic Acids
ISSN: 1525-7770 (Print) 1532-2335 (Online) Journal homepage: https://www.tandfonline.com/loi/lncn20
Rhodium catalyzed stereospecific reductive
carbocyclization of 1,6-enynes and synthesis of 4′-
methyl-6′-substituted aristeromycins
Ramakrishnamraju Samunuri, Ashok Kumar Jha & Chandralata Bal
To cite this article: Ramakrishnamraju Samunuri, Ashok Kumar Jha & Chandralata Bal (2019):
Rhodium catalyzed stereospecific reductive carbocyclization of 1,6-enynes and synthesis of
4′-methyl-6′-substituted aristeromycins, Nucleosides, Nucleotides and Nucleic Acids, DOI:
10.1080/15257770.2018.1554221
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NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
https://doi.org/10.1080/15257770.2018.1554221
Rhodium catalyzed stereospecific reductive
carbocyclization of 1,6-enynes and synthesis of 40-
methyl-60-substituted aristeromycins
Ramakrishnamraju Samunuria,b, Ashok Kumar Jhaa, and Chandralata Balb
b
aChemistry Services, GVK Biosciences Pvt.Ltd, Hyderabad, Telangana, India; Department of
Chemistry, Birla Institute of Technology, Ranchi, Jharkhand, India
ABSTRACT
ARTICLE HISTORY
Received 11 February 2018
Accepted 20 November 2018
The need of long-term treatment for chronic HBV, emergence
of drug-resistant viruses and inefficiency of currently approved
therapies to eliminate covalently closed circular DNA (cccDNA),
mandates identification of potent and selective inhibitors of
HBV replication with novel mechanisms of action. Entecavir, a
carbocyclic guanosine nucleoside analog, is the most potent
inhibitor of HBV replication on the market. Moreover, the natur-
ally occurring carbocyclic nucleosides aristeromycin are known
for their wide range of antiviral activities.
KEYWORDS
Stereospecific reductive
carbocyclization; BINAP;
rhodium; aristeromy-
cins; entecavir
In this research, we have utilized BINAP directed rhodium cat-
alyzed reductive carbocyclization of 1,6-enynes (8a–b) through
asymmetric hydrogenation which is an approach, not yet
explored in carbocyclic sugar synthesis. Interestingly, we
obtained exclusive anti-(9a) and Z-anti (9b) carbocyclic sugars.
The new aristeromycin analogs (10a–b) with scaffold combin-
ation of entecavir and aristeromycin were then synthesized
using the Mitsunobu reaction followed by deprotection.
1. Introduction
Chronic HBV and related death due to complications remains a major
challenge for global health management. In addition, need for long-term
treatment, emergence of drug-resistant viruses and inefficiency of currently
approved therapies to eliminate covalently closed circular DNA (cccDNA)
still mandates identification of potent and selective inhibitors of HBV repli-
cation with novel mechanism(s) of action.[1,2] Chronic patients are gener-
ally treated with entecavir, which is one of the successful anti-HBV drugs.
The 60-exo double bond seems to be an essential pharmacophore, which
fits into the hydrophobic pocket at the binding site. Moreover, the anti-
HBV activity of dG2 (Figure 1) is much less than entecavir.[3] However,
when the 60-exo double bond is functionalized with a fluoro group, both E/
CONTACT Ashok Kumar Jha
Hyderabad, Telangana, India; Chandralata Bal
ashok.jha@gvkbio.com
Chemistry Services, GVK Biosciences Pvt.Ltd,
cbal@bitmesra.ac.in Department of Chemistry, Birla
Institute of Technology, Ranchi, Jharkhand, India.
ß 2019 Taylor & Francis Group, LLC

2
R. SAMUNURI ET AL.
Figure 1. Chemical structures of potential carbocyclic nucleosides and target molecules.
Z isomers (1, Figure 1) exhibited anti-HBV activity similar to entecavir.
Interestingly, the Z isomer was less cytotoxic compared to Entecavir.[4] The
cyclopropyl-spirocarbocyclic derivative of entecavir (2, Figure 1) was a hun-
dred times less potent than the parent drug,[5] which further supports the
importance of the 60-exo double bond. Naturally occurring carbocyclic
nucleoside aristeromycin and its derivatives are reported to exhibit a wide
range of antiviral activities.[6]
Nucleosides substituted at 40- have attracted attention as festinavir (anti-
HIV) and balapiravir (anti-HCV) reached a later phase of development.[7]
However, due to limited synthetic methodologies, 40-substituted carbocyclic
nucleosides have very little representation in the literature.[8,9] Owing to
the importance of aristeromycins and entecavir as antivirals, we aim to
combine their features including 40 substitution to generate new aristero-
mycin analogs (3, Figure 1)
2. Results and discussion
Kumamoto and coworkers had reported 5-exo-dig mode cyclization of a 5-
hexynyl carbon-radical to synthesize an 50-exomethylene carbocyclic sugar.
However, this methodology yielded a mixture of four [Z-syn, E-syn, Z-anti
and E-anti] isomers.[4] Herein, we report a previously unexplored key step
in carbocyclic sugar synthesis involving reductive cyclization of 1,6-enynes
via rhodium-catalyzed asymmetric hydrogenation[10] to exclusively generate
the anti-(9a) and Z-anti isomer (9b, Scheme 1). The protected sugar inter-
mediate (3) was synthesized from D-ribose in two steps.[11] Ring opening
of 3 by reaction with a Grignard reagent produced 4a–b with high stereo-
selectivity (diasteromeric ratio ꢀ 95:5). The compound 4a was reported by
Buchanan et al. in two previous reports[12,13] with different specific rota-
tions and the temperature was not mentioned. However, the major dia-
stereoisomer (4a) synthesized and purified, which gave specific rotation

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
3
Scheme 1. Reagents and conditions: (i) Conc.H2SO4, acetone, 0 ꢁC - rt 3 hours (ii) TrCl, Et3N,
DMAP, DMF: CH2Cl2 (1:4 v/v), rt, 12h (iii) ethynyl/prop-1-yne magnesium bromide (0.5 M in
THF), THF, ꢂ78 ꢁC -rt, 16 hours (iv) TBDMSCl, imidazole, DMAP, DMF, 0 ꢁC - rt, 6 hours (v)
(COCl)2, DMSO, DCM, Et3N, ꢂ60 ꢁC, 4 hour (vi) Ph3PCH3Br, n-BuLi (2.5 M in hexane), THF, 0 ꢁC -
rt, 2 hours (vii) TBAF (1.0 M in THF), THF, rt, 2 hours (viii) Rh(COD)2BF4, rac- BINAP, 1,2-dichloro-
ethane, H2 balloon, rt, 2 hours, (ix) N6,N6-Bis(tert-butoxycarbonyl)adenine, PPh3, DIAD, THF, 10 ꢁC
- rt, 1 hour (x) TFA:H2O (8:2 ratio), rt, 30 minutes.
þ1.27 at 25 ꢁC (c ¼ 1.1, CHCl3). The diastereomeric purity and the tem-
perature of measurement of specific rotation may be the reason for getting
different specific rotations for the same compound in the previous reports.
In addition, we have confirmed the D-allo configuration with a-stereo-
chemistry for the 10-anomeric hydroxy through NOE analysis (refer SI).
The 1,6-enyne intermediates (8a–b) were synthesized from 4a–b in four
consecutive reaction steps; protection of 10-OH with TBDMS, Swern oxida-
tion, Wittig reaction followed by deprotection of TBDMS by TBAF.[11] The
1,6-enynes (8a–b) were subjected to BINAP directed rhodium catalyzed
reductive cyclization through asymmetric hydrogenation.[10] This chemistry
has significant advantage for building a substituted exocyclic double bond,
which is as yet unexplored for the synthesis of carbocyclic sugars. Exposure
of 8a–b with Rh(COD)2BF4-BINAP catalyst system, H2 at ambient tem-
perature and pressure resulted in anti-(9a) and Z-anti (9b)
carbocyclic sugars exclusively. Notably, (R)-BINAP, (S)-BINAP as well as
rac-BINAP didnot affect the stereospecificity of the reaction. This result
indicates that stereospecific product formation may be controlled by the
substrate. Therefore, the role of BINAP for reaction transformation needs
to be addressed. To draw any rational conclusion, reactions were conducted
using Rh(COD)2BF4 only (without chiral ligand BINAP) and in another
reaction Rh(COD)2BF4 with non-chiral ligand PPh3. However, in both
reactions more than 80% starting material was recovered which indicates
that BINAP is necessary for the activation of the Rh-catalyst. To further
understand the stereospecific control by substrate, the 3D structure of cyc-
lization precursor 8b (Figure 2) was generated and optimized using

4
R. SAMUNURI ET AL.
Figure 2. 3D structural pre-organization of 8b before cyclization to show substrate controlled
stereoselectivity. The Rh-catalyst system has approach only through prochiral face 1 using liga-
tion with the acetonide followed by ligand exchange with the 1,6-enyne system. Prochiral face
2 is sterically crowded due to presence of trityl group.
Gaussian. It can be seen in the 3 D structural diagram that the reacting
functional groups, ene (40-methylene, blue) and yne (60-alkynyl, yellow) lie
in a plane (marked with green line) that creates two prochiral faces.
Further, the computational modeling studies indicate that the 10-OH is
involved in intramolecular O-H … p interaction [calculated H … p (cen-
troid) distance = 2.05Å] with the phenyl ring of the trityl group in prochi-
ral face-2 and in stabilizing the geometry. By that way this face will be
sterically hindered for catalyst to approach the reaction precursors (alkene
and alkyne groups) to initiate cyclization.
Therefore, catalyst may only approach from prochiral face-1 consisting
of the 20, 30-acetonide. The heterolytic activation of elemental hydrogen by
the Rh(COD)2BF4-BINAP [LnRhI] catalyst system forms the monohydride
catalyst LnRhIH. Here, we propose that the acetonide chelates with LnRhIH
(I, Figure 3) and facilitates [2 þ 2 þ 1] oxidative cyclization of the1,6-enyne
leading to C40-C6’ bond formation through II to generate a fused cyclopen-
tane metallocyclic intermediate (III). During this process, most probably,
C-C bond formation precedes C-H formation and determines the 70-Z con-
figuration in the product. Intramolecular hydrogen transfer from RhIIILnH
orients the 40-CH3 down with opening of the 5-membered metal-centered
ring (IV). The RhILn takes up H2 to form RhIII(H)2Ln (V) which transfers
hydrogen to the double bond to form 9b.
The stereochemistry of 9a and 9b were confirmed through NOE studies
separately. 50-H of 9a showed 1 D NOE correlation with 30-H and 10-H.
Further, 30-H of 9a showed 1 D NOE correlation with 50-H and 20-H, how-
ever 40-methyl didn’t show any correlation with 20-H. It confirms the

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
5
Figure 3. Proposed mechanism for stereospecific reductive cyclization of 1,6-enyne (8b).
Transition state I & II show the Rh-ligation through the acetonide face followed by ligand
exchange with the 1,6-enyne system to form Rh-complex III.
a-configuration of the methyl at 40, which confirms the anti-configuration
of 40-CH2OTr with respect to 10-OH. Similarly, 50-H of 9 b showed NOE
correlation with 30-H and 10-H. 70-CH3 of 9b showed 1 D NOE with 10-H,
10-OH and 70-H showed correlation with 40-CH3. These results confirm
that the anti-9b exists in the Z-configuration. Reaction of 9a–b with Boc-
protected adenine followed by deprotection with TFA:H2O yielded target
nucleosides (10a–b) as single stereoisomers.
The anti-HBV assays of 10a–b were carried out in HepG2.2.15.7 cells,
however, none showed significant inhibitory activity.
3. Conclusion
In conclusion, a novel BINAP directed rhodium catalyzed stereospecific
reductive carbocyclization of 1,6-enynes was established for the synthesis of
40,60-disubstitued carbocyclic sugars and utilized for generating aristereomy-
cin analogs. We found that enantioselectivity of this C-C bond formation is
independent of the chirality of ligand and controlled by substrate.
4. Experimental section
General procedure for alkynylation of D-ribose derivative (3): To a solu-
tion of 3 (11.56 mmol) in 50 mL anhydrous THF, ethynyl/prop-1-yne mag-
nesium bromide (46.24 mmol, 0.5 M in THF) was added dropwise with
stirring at ꢂ78 ꢁC under argon atmosphere. After 1 hour, the temperature

6
R. SAMUNURI ET AL.
was raised to rt and the reaction mixture was stirred for an additional
16 hours. The reaction mixture was cooled to 0 ꢁC and 40 mL saturated
NH4Cl solution was added dropwise with stirring. The organic layer was
separated and the aqueous layer was washed with EtOAc. The combined
organic layer was dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure to yield crude 4a/4b in ꢀ 95:5 diasteromeric ratio.
The crude was purified on a silica gel (100–200 mesh) column chromatog-
raphy, elution gradient 0–20% EtOAc in hexane and the major diastereo-
isomer was collected.
(1S)-1-((4S,5R)-5-(1-hydroxy-2-(trityloxy)ethyl)-2,2-dimethyl-1,3-dioxo-
lan-4-yl)prop-2-yn-1-ol (4a): purified yield: 71.2%, white solid, (TLC: Rf
25:
0.2, 20% EtOAc in hexane). [a]D þ1.2 (c ¼ 1.1, CHCl3); UV(MeOH)
1
kmax: 200.25 nm; mp: 127–129 ꢁC; H NMR (300 MHz, CDCl3) d: 1.32 (s,
3H), 1.33 (s, 3H), 2.51 (d, J ¼ 1.8 Hz, 1H), 3.09 (d, J ¼ 3.3 Hz, D2O
exchangeable, 1H), 3.34 (dd, J ¼ 7.2 and 9.9 Hz, 1H), 3.52 (dd, J ¼ 3.0 and
9.9 Hz, 1H), 3.86–3.91 (m, 1H), 4.03 (d, J ¼ 4.8 Hz, D2O exchangeable, 1H),
4.16 (dd, J ¼ 5.1 and 9.6 Hz, 1H), 4.29 (dd, J ¼ 5.4 and 8.4 Hz, 1H),
4.58–4.63 (m, 1H), 7.22–7.44 (m, 15H); 13C NMR (75 MHz, CDCl3) d:
25.4, 27.7, 61.1, 64.8, 68.6, 73.6, 76.5, 79.9, 82.3, 87.1, 109.3, 127.2, 127.9,
128.5, 143.5; HRMS (ESI-Orbitrap) m/z: Exact mass calculated for
C29H30O5Na [M þ Na]þ: 481.1991, found: 481.1993.
(1S)-1-((4S,5R)-5-(1-hydroxy-2-(trityloxy)ethyl)-2,2-dimethyl-1,3-dioxo-
lan-4-yl)but-2-yn-1-ol (4b): purified yield: 75.1%, white solid. (TLC: Rf 0.2,
20% EtOAc in hexane). [a]D25: þ 4.90 (c ¼ 0.1, CHCl3); UV(MeOH) kmax:
1
193.00 nm; mp: 96–98 ꢁC; H NMR (400 MHz, CDCl3) d: 1.31 (s, 3H), 1.33
(s, 3H), 1.88 (d, J ¼ 1.6 Hz, 3H), 3.11 (d, J ¼ 3.6 Hz, D2O exchangeable,
1H), 3.32 (dd, J ¼ 6.8 and 9.6 Hz, 1H), 3.50 (dd, J ¼ 2.8 and 9.6 Hz, 1H),
3.89 (dd, J ¼ 3.9 and 7.2 Hz, 1H), 3.91 (d, J ¼ 4.4 Hz, D2O
exchangeable, 1H), 4.13 (dd, J ¼ 5.2 and 9.6 Hz, 1H), 4.23 (dd, J ¼ 5.2 and
8.4 Hz, 1H), 4.54–4.58 (m, 1H), 7.22–7.44 (m, 15H); 13C NMR (75 MHz,
CDCl3) d: 3.9, 25.5, 27.8, 61.3, 64.8, 68.6, 77.2, 77.7, 80.3, 81.9, 87.1, 109.1,
127.2, 127.9, 128.5, 143.6; HRMS (ESI-Orbitrap) m/z: Exact mass calculated
for C30H32O5Na [M þ Na]þ: 495.2148, found: 495.2143.
General procedure for Rh-catalyzed stereospecific reductive carbocycli-
zation of 1,6-enynes (8a-b): To a stirred solution of 8a/8b (1.7 mmol) in
96 mL of 1,2-dichloroethane was degassed with argon gas for 30 minutes.
rac-BINAP (0.15 mmol) and [Rh(COD)2]BF4 (0.1 mmol) were added to the
above reaction mixture and stirred at rt for 2 hours under hydrogen atmos-
phere (1 atm). The volatiles were removed under reduced pressure and
crude 9a/9b was purified on a silica gel (100–200 mesh) column chroma-
tography, elution gradient 0–8% EtOAc in hexane.

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
7
(3aS,4S,6R,6aR)-2,2,6-trimethyl-5-methylene-6-(trityloxymethyl)tetra-
hydro-3aH-cyclo penta[d][1,3]dioxol-4-ol (9a): purified yield: 70%, white
solid. (TLC: Rf 0.3, 10% EtOAc in hexane). [a]D20: ꢂ61.7 (c ¼ 0.5, CHCl3);
UV (MeOH) kmax: 212.25 nm; mp: 144–146 ꢁC; 1H NMR (300 MHz,
CDCl3) d: 1.10 (s, 3H), 1.30 (s, 3H), 1.36 (s, 3H), 2.34 (d, J ¼ 10.8 Hz, D2O
exchangeable, 1H), 2.90 (s, 2H), 4.27 (d, J ¼ 5.7 Hz, 1H), 4.49 (t, J ¼ 6.0 Hz,
1H), 4.56–4.62 (m, 1H), 5.04 (d, J ¼ 2.4 Hz, 1H), 5.35 (d, J ¼ 1.8 Hz, 1H),
7.20–7.39 (m, 15 H); 13C NMR (75 MHz, CDCl3) d: 16.8, 24.5, 26.1, 47.1,
70.6, 73.1, 77.7, 83.7, 87.0, 108.6, 110.1, 127.0, 127.8, 128.6, 143.6, 156.9;
HRMS (ESI-Orbitrap) m/z: Exact mass calculated for C30H32O4Na
[M þ Na]þ: 479.2198, found: 479.2197.
(3aS,4S,6R,6aR,Z)-5-ethylidene-2,2,6-trimethyl-6-(trityloxymethyl)tetra-
hydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (9b): purified yield: 65%, color
25
less thick liquid. [a]D : ꢂ28.8 (c ¼ 0.45, CHCl3); mp =95–98 ꢁC; UV
1
(MeOH) kmax: 200.28 nm; H NMR (400 MHz, DMSO-d6) d: 0.94 (s, 3H),
1.24 (s, 3H), 1.35 (s, 3H), 1.83 (dd, J ¼ 1.6 and 7.2 Hz, 1H), 2.75 (s, 2H),
4.04 (d, J ¼ 6.4 Hz, D2O exchangeable, 1H), 4.13 (d, J ¼ 5.2 Hz, 1H), 4.39
(t, J ¼ 6.4 Hz, 1H), 4.57–4.60 (m, 1H), 5.33–5.36 (m. 1H), 7.21–7.36 (m,
15H); 13C NMR (75 MHz, DMSO-d6) d: 13.7, 18.0, 25.0, 26.0, 46.7, 71.2,
71.8, 78.6, 84.3, 86.3, 109.6, 121.0, 126.5, 127.0, 128.2, 143.5, 147.7; HRMS
(ESI-Orbitrap) m/z: Exact mass calculated for C31H34O4Na [M þ Na]þ:
493.2355, found: 493.2353.
General procedure for synthesis of target aristeromycin analogs (10a-
b):To a mixture of N6,N6-Bis(tert-butoxycarbonyl)adenine (0.82 mmol), 9a/
9b (0.63 mmol) and Ph3P (1.59 mmol) in 6 mL dry THF was added DIAD
(1.75 mmol) drop wise at 5–10 ꢁC under argon atmosphere and stirring was
continued at rt for 1 hour. Completion of reaction was monitored by TLC,
solvent evaporated under reduced pressure and the crude was carried for-
ward to the next step without purification. The deprotection of acetonide,
Boc and trityl protecting groups was carried out by stirring in 2 ml
TFA:water (8:2) for 0.5 hour at rt. After completion (monitored by TLC),
the reaction mixture was neutralized by sat. NaHCO3 solution and purified
on a silica gel (100–200 mesh) column chromatography, elution gradient:
0–9% MeOH in CH2Cl2.
(1S,2R,3R,5R)-5-(6-amino-9H-purin-9-yl)-3-(hydroxymethyl)-3-methyl-
4-methylene cyclopentane-1,2-diol (10a): purified yield: 60%, off white
solid (TLC: Rf 0.1, 10% MeOH in CH2Cl2). [a]D25: -10.4 (c ¼ 0.25, DMSO);
mp: 63–67 ꢁC; UV (MeOH) kmax: 204.25, 216.25 and 259.25 nm; 1H NMR
(400 MHz, CD3OD) d: 1.2 (s, 3H), 3.54 (d, J ¼ 11.2 Hz, 1H), 3.74 (d,
J ¼ 11.2 Hz, 1H), 4.03 (d, J ¼ 4.4 Hz, 1H), 4.67 (d, J ¼ 2.4 Hz, 1H), 4.87 (dd,
J ¼ 4.8 and 7.2 Hz, 1H), 5.14 (d, J ¼ 3.2 Hz, 1H), 5.40–5.44 (m, 1H), 8.20
(s, 1H), 8.25 (s, 1H); 13C NMR (75 MHz, DMSO-d6) d: 18.8, 49.6, 62.9,

8
R. SAMUNURI ET AL.
69.1, 73.3, 73.7, 108.5, 118.9, 141.4, 149.4, 150.3, 154.1, 154.6; HRMS (ESI-
Orbitrap) m/z: Exact mass calculated for C13H17N5O3 [M þ H]þ: 292.1401,
found: 292.1394
(1S,2R,3R,5R,Z)-5-(6-amino-9H-purin-9-yl)-4-ethylidene-3-(hydroxy-
methyl)-3-methyl cyclopentane-1,2-diol (10b): purified yield: 55%, off
white solid. (TLC: Rf 0.1, 10% MeOH in CH2Cl2). [a]D20: -17.7 (c ¼ 0.1,
MeOH); mp: 138–140 ꢁC; UV (MeOH) kmax: 204.25, 220.25 and
1
260.25 nm H NMR (400 MHz, CD3OD) d: 1.08 (dd, J ¼ 1.2 and 6.8 Hz,
3H), 1.14 (s, 3H), 3.58 (d, J ¼ 11.2 Hz, 1H), 3.71 (d, J ¼ 10.8 Hz, 1H), 4.00
(d, J ¼ 4.0 Hz, 1H), 4.63 (dd, J ¼ 4.8 and 7.2 Hz, 1H), 5.43 (dd, J ¼ 2.0 and
5.2 Hz, 1H), 5.64–5.66 (m, 1H), 8.16 (s, 1H), 8.26 (s, 1H); 13C NMR
(100 MHz, CD3OD) d: 13.1, 20.1, 52.0, 63.9, 71.5, 76.7, 78.2, 120.3, 125.1,
142.8, 143.1, 150.1, 153.1, 157.5; HRMS (ESI-Orbitrap) m/z: Exact mass cal-
culated for C14H20N5O3 [M þ H]þ: 306.1566, found:306.1535.
Acknowledgements
Authors acknowledge GVK Biosciences Pvt. Ltd, Hyderabad for facilitating academic
research activity. We are grateful to the Central Instruments Facility (CIF), BIT, Mesra for
analytical support. We acknowledge DST FIST at Department of Chemistry, BIT, Mesra
(SR/FST/CSI-242/2012) for NMR and computational chemistry facility.
References
[1] Yuen, M.-F.; Ahn, S. H.; Chen, D.-S.; Chen, P.-J.; Dusheiko, G. M.; Hou, J.-L.;
Maddrey, W. C.; Mizokami, M.; Seto, W.-K.; Zoulim, F.; Lai, C.-L. Chronic
Hepatitis B Virus Infection: Disease Revisit and Management Recommendations. J.
Clin. Gastroenterol. 2016, 50, 286–294. DOI: 10.1097/MCG.0000000000000478.
[2] Liu, J.; Goicochea, P.; Block, T.; Brosgart, C. L.; Donaldson, E. F.; Lenz, O.; Gee
Lim, S.; Marins, E. G.; Mishra, P.; Peters, M. G.; Miller, V. Advancing the
Regulatory Path on Hepatitis B Virus Treatment and Curative Research: a
Stakeholders Consultation. J. Virus Eradic. 2017, 3, 1–6.
[3] Innaimo, S. F.; Seifer, M.; Bisacchi, G. S.; Standring, D. N.; Zahler, R.; Colonno, R. J.
Identification of BMS-200475 as a Potent and Selective Inhibitor of Hepatitis B Virus.
Antimicrob. agents Chemother. 1997, 41, 1444–1448. DOI: 10.1128/AAC.41.7.1444.
[4] Kumamoto, H.; Fukano, M.; Nakano, T.; Iwagami, K.; Takeyama, C.; Kohgo, S.;
Imoto, S.; Amano, M.; Kuwata-Higashi, N.; Aoki, M.; et al. Diastereoselective
00
Synthesis of 6 00-(Z)-and 6 -(E)- Fluoro Analogues of anti-hepatitis B Virus Agent
Entecavir and Its Evaluation of the Activity and Toxicity Profile of the
Diastereomers. J. Org. Chem. 2016, 81, 2827–2836. DOI: 10.1021/acs.joc.6b00105.
[5] Kumamoto, H.; Fukano, M.; Imoto, S.; Kohgo, S.; Odanaka, Y.; Amano, M.;
Kuwata-Higashi, N.; Mitsuya, H.; Haraguchi, K.; Fukuhara, K. A Novel Entecavir
Analogue Constructing with a Spiro [2.4] heptane Core Structure in the Aglycon
Moiety: Its Synthesis and Evaluation for anti- hepatitis B Virus Activity. Nucleos.
Nucl. Nucleic Acids. 2017, 30, 1–11.

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
9
[6] Rawal, R. K.; Bariwal, J.; Singh, V. Chemistry and Bioactivities of Aristeromycins:
An Overview. Curr. top. med. Chem. 2016, 16, 3258–3273.
[7] Betson, M.; Allanson, N.; Wainwright, P. A Review of Methods to Synthesise 4’-sub-
stituted nucleosides. Org. Biomol. Chem. 2014, 12, 9291–9306.
[8] Kato, K.; Suzuki, H.; Tanaka, H.; Miyasaka, T. Enantio- and Diastereoselective
Synthesis of 40-a-Substituted Carbocyclic Nucleosides. Tetrahedron: Asymmetr. 1998,
9,911–914. DOI: 10.1016/S0957-4166(98)00065-2.
[9] Gumina, G.; Chong, Y.; Choi, Y.; Chu, C. K. Stereoselective Synthesis of Carbocyclic
L-4’-fluoro-2’,3’-dideoxyadenosine. Org. Lett. 2000, 2, 1229–1231.
[10] Jang, H.-Y.; Krische, M. J. Rhodium-Catalyzed Reductive Cyclization of 1, 6-Diynes
and 1, 6- Enynes Mediated by Hydrogen: Catalytic C ꢂ C Bond Formation via
Capture of Hydrogenation Intermediates. J. Am. Chem. Soc. 2004, 126, 7875–7880.
DOI: 10.1021/ja048498i.
[11] Thiyagarajan, A.; Salim, M. T.; Balaraju, T.; Bal, C.; Baba, M.; Sharon, A. Structure
Based Medicinal Chemistry Approach to Develop 4-methyl-7-deazaadenine
Carbocyclic Nucleosides as anti-HCV Agent. Bioorg. Med. Chem. Lett. 2012, 22,
7742–7747. DOI: 10.1016/j.bmcl.2012.09.072.
[12] Buchanan, J. G.; Dunn, A. D.; Edgar, A. R. Reaction of Ethynylmagnesium Bromide
with 2, 3-O-Isopropylidene-D-ribose and 2, 3: 5, 6-di-O-isopropylidene-D-manno-
furanose: Syntheses of Glycofuranosylethynes. Carbohydr. Res. 1974, 36, C5–C7.
DOI: 10.1016/S0008-6215(00)82020-0.
[13] Buchanan, J. G.; Dunn, A. D.; Edgar, A. R. C-nucleoside Studies. Part II.
Pentofuranosylethynes From 2, 3-O-isopropylidene-D-Ribose. J. Chem. Soc, Perkin
Trans. 1975, 1,1191–1200. DOI: 10.1039/p19750001191.