Target cum flexibility: Synthesis of C(3′)-spiroannulated nucleosides

Article abstract of DOI:10.1016/j.tetlet.2011.06.100

We report a simple strategy for the synthesis of a collection of C(3′)-spirodihydroisobenzo-furannulated nucleosides featuring a [2+2+2]-cyclotrimerization as the key reaction. The cyclotrimerization reactions are facile with the unprotected nucleosides having a diyne unit. When both alkynes of the diyne are terminal, the regioselectivity is poor. However, when one of the terminal alkynes is additionally substituted, the cyclotrimerizations are highly diastereoselective. Since the key bicycloannulation is the final step, this strategy provides flexibility in terms of the alkynes and is thus amenable for the synthesis of a focussed small molecule library.

Full text of DOI:10.1016/j.tetlet.2011.06.100

Tetrahedron Letters 52 (2011) 4627–4630
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Target cum flexibility: synthesis of C(30)-spiroannulated nucleosides
⇑
Mangesh P. Dushing, C. V. Ramana
National Chemical Laboratory (CSIR, India), Dr. Homi Bhabha Road, Pune 11008, India
a r t i c l e i n f o
a b s t r a c t
We report a simple strategy for the synthesis of a collection of C(30)-spirodihydroisobenzo-furannulated
nucleosides featuring a [2+2+2]-cyclotrimerization as the key reaction. The cyclotrimerization reactions
are facile with the unprotected nucleosides having a diyne unit. When both alkynes of the diyne are ter-
minal, the regioselectivity is poor. However, when one of the terminal alkynes is additionally substituted,
the cyclotrimerizations are highly diastereoselective. Since the key bicycloannulation is the final step,
this strategy provides flexibility in terms of the alkynes and is thus amenable for the synthesis of a
focussed small molecule library.
Article history:
Received 22 April 2011
Revised 22 June 2011
Accepted 26 June 2011
Available online 2 July 2011
Keywords:
Modified nucleosides
[2+2+2]-Cyclotrimerization
Dihydroisobenzofuran
Tanaka catalyst
Ó 2011 Published by Elsevier Ltd.
Willkinson catalyst
Modification of the sugar backbone in nucleosides is an impor-
tant therapeutic approach for developing small molecules that
control genetic disorders or infections.1 There are several ap-
proaches for the modification of nucleosides.2–4 The spiroannula-
tion on the sugar backbone is one of the recent approaches for
the modified nucleosides.3,4 Considering the prevalence of the
dihydroisobenzofuran structural unit in many of the naturally
occurring substances, and drug candidates, our intention has been
to spiro-annulate a dihydroisobenzofuran unit on the nucleoside
templates.5 We have recently documented the feasibility of cyclo-
trimerization of sugar derived diynes and shown that the resultant
products can be transformed to the tricyclic and C(30)-spirobenzoi-
sofuran-annulated nucleosides following a sequence of simple
chemical transformations. However, in the latter case, the sugar
ring was a pentopyranose unit. Also, this strategy is not sufficiently
effective as the number of compounds to be accessed is restricted
by the limited number of nucleobases available which are intro-
duced at the penultimate step of the synthesis. In addition, it
may require additional steps if one intends to place sensitive func-
tional groups on the isobenzofuran ring. This has prompted us to
look for an alternative approach which can effectively address
the library size and the ease of alteration of the functional groups
on the isobenzofuran ring. This has led us into the exploration of
the key C(30)-spiroannulation as the final step by means of
[2+2+2]-cyclotrimerization of completely free nucleoside-diynes
with alkynes.6–8 Figure 1 provides the salient features of this
approach.
The diynes 1–3 have been selected as suitable precursors for the
final tricyclic nucleosides. In our earlier investigations, we realized
that the peracetylation of C(30)-modified ribo-pentose derivatives
provide exclusively the corresponding pyranose derivatives.9 This
warrants a suitable protecting group at the C(5)–OH which should
be stable during the 1,2-O-acetonide hydrolysis and at the same
O
O
NH
NH
R'
N
O
R'
N
O
O
R'''
+
O
R''
R''
Final step
O
O
Focussed small
molecule library
simple
substrate
O
PivO
NH
O
O
R
HO
N
O
O
D-Xylose
O
R
O
OH
O
1 (R = H)
2 (R = Ph)
3
(R = C6H13
)
Figure 1. A flexible approach for C(30)-[2+2+2] approach for spiroannulated
nucleosides.
⇑
Corresponding author. Tel.: +91 20 25902577; fax: +91 20 25902629.
E-mail address: vr.chepuri@ncl.res.in (C.V. Ramana).
0040-4039/$ - see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2011.06.100

4628
M. P. Dushing, C. V. Ramana / Tetrahedron Letters 52 (2011) 4627–4630
TBSO
R
HO
TBSO
R
O
O
O
a)
b)
ref. 10
O
O
R
O
D-Xylose
5 steps
O
O
O
O
O
HO
4 (R = H)
7 (R = H, 83%)
8 (R = Ph, 94%)
9 (R = C6H13, 90%)
10 (R = H, 98%)
11 (R = Ph, 89%)
12 (R = C6H13, 92%)
5 (R = Ph)
6 (R = C6H13
)
c)
O
O
N
NH
NH
PivO
O
PivO
O
N
O
O
HO
f)
PivO
R
e)
d)
O
O
OAc
OAc
O
R
R
R
O
O
O
OAc
OH
O
O
1 (R = H, 78%)
2 (R = Ph, 92%)
3 (R = C6H13, 89%)
19 (R = H, 75%)
20 (R = Ph, 81%)
21 (R = C6H13, 78%)
16 (R = H, 87%)
17 (R = Ph, 78%)
18 (R = C6H13, 79%)
13
14
15
(R = H, 81%)
(R = Ph, 93%)
(R = C6H13,91%)
Scheme 1. Reagents and conditions: (a) NaH, Propargyl bromide, THF, 0 °Cꢀrt, 3 h; (b) TBAF, THF, rt, 8 h; (c) PivCl, Et3N, DMAP, CH2Cl2, 0 °C–rt, 6 h; (d) i. 60% AcOH, reflux,
2 h; ii. Ac2O, Et3N, DMAP, CH2Cl2, rt, 1 h; (e) uracil, N,O-bis(trimethylsilyl)-acetamide (BSA), TMSOTf, CH3CN, 50 °C, 2 h; (f) NaOMe, MeOH, rt, 20 min.
O
O
H
OH
H
NH
NH
OH
N
O
Cp*RuCl(cod) (5mol%)
R'
R
N
O
O
O
R1
R1
DCE-ethanol (5 :1)
rt, 3-5 h
+
OH
O
OH
O
R
R' = H / Ph / nC6H13
O
N
O
N
O
O
N
NH
NH
NH
NH
HO
Ph
HO
HO
HO
O
O
N
O
O
O
O
O
O
O
O
O
AcOH2C
R''
R
OH
OH
OH
OH
O
AcOH2C
25 [77%]
24 (R or R'' = C5H11) [80%]
22 [79%]
23 [83%]*
O
O
N
O
O
N
NH
HO
NH
NH
NH
N
O
HO
HO
Ph
HO
Ph
O
Ph
O
N
O
O
O
Ph
O
O
Cl
H2N
OH
O
OH
OH
OH
O
O
O
C6H13
Ph
26 [78%]
27 [85%]
28 [85%]
29 [83%]
O
O
N
O
O
N
NH
NH
NH
NH
HO
C6H13
HO
C6H13
HO
C6H13
HO
C6H13
N
O
O
N
O
O
O
O
O
O
Cl
OH
OH
OH
O
OH
O
O
O
C6H13
Ph
30 [75%]
31 [74%]
32 [78%]
33 [78%]
* Wilkinson catalyst, toluene/ethanol (4:1), 80 °C, 8 h.
Scheme 2. Scope of cyclotrimerization reactions of the diynes 1–3.
time, should be removed during the saponification. A pivaloyl pro-
tection at C(5)-OH has been opted for in this regard.
compounds 7–9 were subjected to the deprotection of the TBS
ether using TBAF in THF to afford the alkynols 10–12 respectively.
The free hydroxyl group in alkynols 10–12 was protected as
pivolate by treatment with pivaloyl chloride and Et3N. Selective
Synthesis of the key diynes 1–3 started with the propargylation
of the known intermediates 4–6 (Scheme 1).10 The resulting

M. P. Dushing, C. V. Ramana / Tetrahedron Letters 52 (2011) 4627–4630
4629
acetonide hydrolysis of the resulting pivaloates 13–15 followed by
References and notes
peracetylation (Ac2O/Et3N) gave a 1:1 anomeric mixture of diace-
tates 16ꢀ18, respectively. The glycosidation of the anomeric mix-
tures of 16–18 was carried out under modified Vorbrüggen11
conditions employing uracil as the glycosyl acceptor to afford the
protected nucleosides 19–21, respectively. Subjecting 19–21 to
Zemplen’s deacetylation afforded the uridines 1–3 having the key
diyne unit for the cycloisomerization reactions.
With the fully elaborated diyne frameworks in place, we at-
tempted the cyclotrimerization of diynes 1–3 with symmetric and
unsymmetric alkynes (Scheme 2). The trimerization reactions with
acetylene proceeded effectively with 5 mol % of Cp⁄RuCl(cod)12 (in
dichloroethane–ethanol mixture) at rt in a sealed tube to afford the
products 22,14 25 and 30, respectively from the diynes 1–3 (75–79%
yield). The diacetate of 2-butyne-1,4-diol, bis-(trimethylsilyl)-acety-
lene and dimethylacetylene dicarboxylate were explored as the rep-
resentative symmetric disubstituted alkynes for the trimerization
reactions. Amongst the three alkynes, the cyclotrimerization of diyne
1 with the diacetate of 2-butyne-1,4-diol was facile with the Wilkin-
son’s catalyst13 (4:1 toluene-ethanol, 80 °C, 8 h) and yielded 23.
With the other two alkynes, the formation of a complex mixture
was observed. The attempted cyclotrimerization of diynes 2 and 3
with any of the above alkynes was found to be unsuccesful at differ-
ent temperatures and intact diynes 2 or 3 were isolated.
Coming to the terminal alkynes, the cyclotrimerization reaction
of diyne 1 with 1-heptyne [using 5 mol % of Cp⁄RuCl(cod) in dichlo-
roethane, rt] is clean and gave a 1:1 regiomeric mixture 24 in 80%
yield. Under similar conditions, the cyclotrimerization of diynes 2
and 3 with 1-octyne as a substrate proceeded smoothly and gave
the corresponding nucleosides 26 and 31 in good yields (78% and
74%) and with complete regioselectivity. For example in the 1H
NMR spectrum of 31, the two aromatic protons appeared as singlets
at d 6.85 and 6.95 ppm. The regioselectivity noticed with the trimer-
ization of diynes 2 and 3 endorses them for further exploration in
constructing the spiro-nucleosides library. Next the cyclotrimeriza-
tion reactions with the diynes 2 and 3 were explored employing di-
verse terminal alkynes such as phenyl acetylene15 and 1-chloro-4-
pentyne and 3-aminophenylacetylene to understand the tolerance
for the functional groups such as the alkyl chloride and the amino
group. The reactions in general are clean, the regioselectivity was
excellent, and products are obtained in good yields (78–83%). The
chloro functional group present in the products 29 and 33, amino
group in 28 provide a suitable handle for further diversification.
In conclusion, a simple protocol comprising the [2+2+2]-cyclotri-
merisation of the fully deprotected nucleoside diynes as the last step
of the process has been developed for a rapid access to C(30)-
dihydroisobenzofuran spiroannulated nucleosides. During the syn-
thesisofthe penultimate furanose-nucleoside diynes, wehave shown
that proceeding with ribofuranose intermediates having a pivaloyl
protection at C(5)-OH is a reliable approach to avoiding unwanted
pyranose formation during the hydrolysis and peracetylation.
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Acknowledgments
We thank the Ministry of Science and Technology for funding
through the Department of Science and Technology under the
Green Chemistry Program (NO. SR/S5/GC-20/2007). Financial sup-
port from the CSIR (New Delhi) in the form of research fellowships
to MPD is gratefully acknowledged.
Supplementary data
9. Suryawanshi, S. B.; Dushing, M. P.; Gonnade, R. G.; Ramana, C. V. Tetrahedron
2010, 66, 6085–6096.
Supplementary data (1H-, 13C- DEPT and MS of selected com-
pounds) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2011.06.100.
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4630
M. P. Dushing, C. V. Ramana / Tetrahedron Letters 52 (2011) 4627–4630
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Chem. Soc. 2004, 126, 3712–3713.
(s, 1H), 7.45 (d, J = 8.2 Hz, 1H), 9.40 (br s, 1H) ppm; 13C NMR (CDCl3, 100 MHz):
d 14.1 (q), 22.6 (t), 29.7 (t), 31.7 (t), 31.9 (t), 32.3 (t), 33.4 (t), 33.8 (t), 44.1 (t),
61.7 (t), 71.9 (t), 76.3 (d), 86.5 (d), 89.0 (d), 92.1 (s), 103.2 (d), 118.9 (d), 129.8
(d), 131.1 (s), 137.7 (s), 140.4 (d), 141.2 (s), 142.1 (s), 150.7 (s), 163.0 (s) ppm;
MALDI-TOF: 515.03 (82%, [M+Na]+), 531.00 (100%, [M+K]+).
15. General Procedure for [2+2+2]-cyclotrimerization: A solution of diyne (0.6 mmol)
with terminal alkyne (0.6 mmol) in dry 1,2-dichloroethane was degassed with
dry argon for 20 min. To this, Cp⁄RuCl(cod) catalyst (0.03 mmol) was added,
and the mixture was stirred for 4–6 h at room temperature. The solvent
evaporated under reduced pressure. The residue was purified by silica gel
chromatography to procure the cyclotrimerization product. Spectral data of
13. (a) Grigg, R.; Scott, R.; Stevenson, P. Tetrahedron Lett. 1982, 23, 2691–2692; (b)
Sridharan, V.; Grigg, R.; Wang, J.; Xu, J. Tetrahedron 2000, 56, 8967–8976.
14. General Procedure for compounds 22, 25, and 30: A solution of diyne 1–3
(0.6 mmol) in 1,2-dichloroethane (10 mL) was degassed with dry acetylene for
20 min; then, Cp⁄RuCl(cod) catalyst (0.03 mmol) was introduced into the
mixture. The reaction mixture was sealed with septum and a copper wire and
cooled to ꢀ78 °C, and acetylene gas was condensed by continuous bubbling for
25 min. and the mixture was stired for 4–6 h at room temperature. The solvent
was evaporated under reduced pressure. The residue was purified by silica gel
chromatography to afford the cyclotrimerized product. Spectral data of
compound 27: White solid, yield: 85%, mp: 270ꢀ272 °C; ½a D25
ꢁ
+35.0 (c 0.3,
CHCl3); IR (CHCl3) m ;
: 3020, 2925, 1694, 1526, 1046, 929, 669 cmꢀ1 1H NMR
(CDCl3+CD3OD, 400 MHz): d 3.29 (dd, J = 6.6, 12.1 Hz, 1H), 3.35 (dd, J = 4.0,
12.1 Hz, 1H), 4.20 (dd, J = 4.2, 6.4 Hz, 1H), 4.47 (d, J = 8.2 Hz, 1H), 5.25 (s, 2H),
5.58 (d, J = 8.2 Hz, 1H), 6.07 (d, J = 8.1 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H),
7.36ꢀ7.51 (m, 10H), 7.60 (dd, J = 1.2, 7.3 Hz, 2H); 13C NMR (CDCl3+CD3OD,
100 MHz): d 61.8 (t), 70.4 (t), 76.4 (d), 85.4 (d), 86.6 (d), 93.1 (s), 102.7 (d),
118.8 (d), 127.0 (3C, d), 127.8 (d), 128.0 (d), 128.3 (d), 128.7 (2C, d), 129.4 (2C,
d), 130.0 (s), 130.8 (d), 138.5 (s), 139.5 (s), 139.8 (s), 139.9 (d), 142.0 (s), 142.9
(s), 151.0 (s), 163.7 (s) ppm; MALDI-TOF: 507.02 (70%, [M+Na]+), 522.97 (100%,
[M+K]+).
compound 22: Colorless liquid, yield: 78%, ½a D25
ꢁ
+5.7 (c 0.3, CHCl3); IR (CHCl3)
m: ;
3020, 2929, 1698, 1385, 1216, 1046, 929, 669 cmꢀ1 1H NMR (CDCl3,
400 MHz): d 0.87 (t, J = 6.8 Hz, 3H), 1.24ꢀ1.37 (m, 6H), 1.53ꢀ1.66 (m, 2H), 2.05
(quint, J = 7.3 Hz, 2H), 2.59ꢀ2.66 (m, 1H), 2.75 (t, J = 7.3 Hz, 3H), 3.43 (dd,
J = 3.3, 12.1 Hz, 1H), 3.51 (t, J = 6.3 Hz, 3H), 3.75 (dd, J = 7.5, 12.1 Hz, 1H), 4.33
(dd, J = 3.3, 7.3 Hz, 1H), 4.56 (t, J = 8.2 Hz, 1H), 5.06 (d, J = 12.3 Hz, 1H), 5.13 (d,
J = 12.3 Hz, 1H), 5.78 (d, J = 8.1 Hz, 1H), 5.87 (d, J = 8.1 Hz, 1H), 6.88 (s, 1H), 6.98