Synthesis of 2'-O,3'-O bicyclic adenosine analogues using ring closing metathesis

Article abstract of DOI:10.1016/j.tetlet.2003.10.059

The synthesis of 2'-O,3'-O bicyclic adenosine derivatives is presented as the first examples of a new family of 13-membered ring bicyclic nucleoside analogues. Cyclisation was achieved through ring closing metathesis (RCM) on a diene intermediate using Grubbs' catalyst. The Z and E isomers were purified and characterised.

Full text of DOI:10.1016/j.tetlet.2003.10.059

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 9131–9134
Synthesis of 2%-O,3%-O bicyclic adenosine analogues using ring
closing metathesis
Patricia Busca, Me´lanie Etheve-Quelquejeu* and Jean-Marc Vale´ry
Structure et Fonction de Mole´cules Bioactives-UMR CNRS 7613-Equipe ꢀChimie des Glucidesꢁ,
Universite´ Pierre et Marie Curie, 4 place Jussieu, case 179, 75252 Paris Cedex 05, France
Received 10 September 2003; revised 1 October 2003; accepted 8 October 2003
Abstract—The synthesis of 2%-O,3%-O bicyclic adenosine derivatives is presented as the first examples of a new family of
13-membered ring bicyclic nucleoside analogues. Cyclisation was achieved through ring closing metathesis (RCM) on a diene
intermediate using Grubbs’ catalyst. The Z and E isomers were purified and characterised.
© 2003 Elsevier Ltd. All rights reserved.
Overuse and misuse of antibiotics has led to the emer-
gence of bacterial resistance to classical antibiotics,
which is a serious threat to the health care system. This
observation has generated an urgent need for discovery
of novel antibacterial agents, preferably with new
modes of action. Recently, two ligases purified from
enterococcus faecalis, namely BppA1 and BppA2, were
shown to play a crucial role in the biosynthesis of
bacterial cell-walls.1 Indeed, these enzymes specifically
a mimic of the terminal part of alanyl-tRNA but also
to act as a chain terminator.
To the best of our knowledge the 2%-O,3%-O bicyclic
adenosine derivatives reported herein are the first exam-
ples of 13-membered ring bicyclic nucleoside analogues.
The use of catalytic olefin metathesis as a car-
bonꢀcarbon bond construction method has exhibited
considerable growth in recent years.3 In particular, the
ring closing metathesis (RCM) has become an efficient
tool for the synthesis of a great variety of macrocyclic
systems.4 However, in the field of nucleoside chemistry,
very few examples of RCM have been published,5 and
none of them have dealt with the construction of a
13-membered ring in a nucleoside derivative.
and successively transfer L-alanine residues from alanyl-
tRNA to a UDP-MurNAc pentapeptide, a key precur-
sor of the bacterial peptidoglycan structure. Owing to
their unusual tRNA dependent mode of action which
has no equivalent in the other steps of cell-wall synthe-
sis, these enzymes can be considered as promising unex-
ploited targets for the development of new antibiotics,
actually, inhibition of the ligation reactions will result
in the synthesis of incomplete peptidoglycan precursors
lacking the N-terminal amino acid required for
transpeptidation.
Synthesis of the diene intermediates 6 and 7 started
with the introduction of an allyl group to position 2%
(Scheme 1). Starting from adenosine, protection of the
6-amino group with benzoyl chloride was performed
using a known procedure.6 The 3%- and 5%-hydroxyl
groups were protected under standard conditions with
1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (TIPSCl2),
affording compound 1 in 66% overall yield. The subse-
quent allylation step proceeded through palladium-cat-
alyzed chemistry.7 Allyl ethyl carbonate, the allyl
donor, was prepared from ethanol and allyl chlorofor-
mate, as described in the literature.8b A coupling reac-
tion between the latter and adenosine derivative 1, in
the presence of catalytic amounts of tris(dibenzylidene-
acetone)dipalladium(0) (Pd2(dba)3) and 1,4-bis(-
diphenylphosphino)butane8 (dppb) yielded the allyl
derivative 2 (90%). Attempts to carry out this reaction
from the N-monobenzoyl derivative (instead of N,N-
Recently, macrocycles containing an
were designed and evaluated as inhibitors of the
tamate ligase2 which catalyses the addition of
L
-alanyl group
-glu-
-gluta-
D
D
mate to UDP-MurNAc-LAla. By analogy, and in an
effort to search for potential inhibitors of the BppA1
and BppA2 enzymes, we decided to synthesise a
modified 3%-L-alanyl-adenosine with a cyclised peptidic
framework. This derivative was designed to be not only
Keywords: ligases; nucleosides; ring closure metathesis.
* Corresponding author. Tel.: +33 1 44 27 55 50; fax: +33 1 44 27 55
13; e-mail: quelque@ccr.jussieu.fr
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.059

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P. Busca et al. / Tetrahedron Letters 44 (2003) 9131–9134
and the first attempt with compound 3 resulted in
partial debenzoylation, thus lowering the yields. The
best result was obtained from compound 4 using EDCI
in presence of DMAP within 2 h giving the desired
product in 48% yield. Since the unreacted starting
material was easily recovered after chromatography,
the corrected yield is satisfactory.
The key diene 711 was subjected to an RCM reaction
with Grubbs’ second generation catalyst 812 (Scheme 3).
Under standard conditions (CH2Cl2, at 40°C, during 24
h) 9 was obtained in 25% yield. Based on previous
reported studies on large ring synthesis,13 the yield was
improved by conducting the metathesis reaction at a
higher temperature and dilution. Indeed, at 110°C in
toluene over 15 min at a concentration of 0.5 mM, we
obtained the cyclised intermediate 9 in 62% yield.
Compound 914 was obtained as a mixture of Z and E
stereoisomers in the ratio 49/51, which were separated
by chromatography. For derivative 9b, assignment by
1H NMR spectroscopy showed a coupling constant
between the two olefinic protons of 15 Hz, which is
characteristic of trans coupling (Fig. 1).
Scheme 1. Reagents and conditions: (a) (i) TMSCl, Pyr. (ii)
BzCl, Pyr. (iii) H2O, 80% overall; (b) TIPSCl2, Pyr., 82%; (c)
AllOCO2Et, Pd2(dba)3, dppb, 90%;8 (d) TBAF, AcOH, THF,
63%; (e) TBDMSCl, Pyr., 99%; (f) NH4OH, Pyr., 88%.
Table 1. Optimization of the acylation
Reagent
From 3
% 7
From 4
% 6
16
% 7
% 4
BOPa
23
11
43
38
48
17
55
dibenzoyl compound 1) afforded a complex mixture
among which simultaneous N- and O-allylation prod-
ucts were observed.
ClCO2iBub
EDCIc
22
45
57
DEPCd
The TIPDS protecting group was removed using tetra-
butyl ammonium fluoride in the presence of acetic acid
to avoid any base-mediated side-reactions.9 Position 5%
was silylated with tert-butyldimethylsilyl chloride
(TBDMSCl) under standard conditions, providing
adenosine derivative 3. Monodeprotection of the 6-
amino group with ammonium hydroxide afforded com-
pound 4 in good yield (88%).
a 5, Bop reagent, 4-pyrrolidine, Hu¨nig’s base, Pyr., rt.
b 5, ClCO2iBu, NEt3, CH2Cl2, DMAP, −10°C to rt.
c 5, EDCI, CH2Cl2, DMAP, 0°C to rt.
d 5, DEPC, DMF, NEt3, 0°C to rt.
The diene intermediates 6 and 7 (Scheme 2) were pre-
pared from the alcohol derivatives 3 and 4 by reaction
with N-pentenoyl-
-alanine 5.10 The coupling step was
L
optimised using different activating agents (Table 1)
Scheme 3. Reagents and conditions: (a) Toluene, 110°C, 8 20
mol%, 15 min, 62% (b) phenol, DCE, 76% (c) TBAF, AcOH,
85%.
Scheme 2. Reagents and conditions: (a) EDCI, DMAP,
CH2Cl2, 0°C to rt, 48%.

P. Busca et al. / Tetrahedron Letters 44 (2003) 9131–9134
9133
3. For reviews related to RCM reactions, see: (a) Grubbs,
R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28,
446; (b) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed.
Engl. 1997, 36, 2036; (c) Armstrong, S. K. J. Chem. Soc.,
Perkin Trans. 1 1997, 371; (d) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413; (e) Fu¨rstner, A. Angew.
Chem., Int. Ed. 2000, 39, 3013; (f) Trnka, T. M.; Grubbs,
R. H. Acc. Chem. Res. 2001, 34, 18.
4. (a) Biswas, K.; Lin, H.; Njardarson, J. T.; Chappell, M.
D.; Chou, T.-C.; Guan, Y.; Tong, W. P.; He, L.; Hor-
witz, S. B.; Danishefsky, J. J. Am. Chem. Soc. 2002, 124,
9825; (b) Rivkin, A.; Biswas, K.; Chou, T.-C.; Danishef-
sky, J. Org. Lett. 2002, 4, 1633; (c) Content, S.; Dutton,
C.; Roberts, L. Bioorg. Med. Chem. Lett. 2003, 13, 321;
(d) Stymiest, J. L.; Mitchell, B. F.; Wong, S.; Vederas, J.
C. Org. Lett. 2003, 5, 47; (e) Clark, J. C.; Marlin, F.;
Nay, B.; Wilson, C. Org. Lett. 2003, 5, 89.
5. (a) Montembault, M.; Bourgougnon, N.; Lebreton, J.
Tetrahedron Lett. 2002, 43, 8091; (b) Ewing, D.; Glac¸on,
V.; Mackenzie, G.; Postel, D.; Len, C. Tetrahedron Lett.
2002, 43, 3503; (c) Lee, C.; Cass, C.; Jacobson, A. Org.
Lett. 2001, 3, 597; (d) Ravn, J.; Nielsen, P. J. Chem. Soc.,
Perkin Trans. 1 2001, 985.
6. McLaughlin, L. W.; Hellman, N. P. T. Synthesis 1985,
322.
7. The use of allyl bromide and sodium hydroxide were
revealed to be less effective (30% yield).
8. (a) Lakhmiri, R.; Lhoste, P.; Sinou, D. Tetrahedron Lett.
1989, 30, 4669; (b) Sproat, B. S.; Iribarren, A. M.;
Garcia, R. G.; Beijer, B. Nucleic Acids Research 1991, 19,
733.
9. Smith, A. B.; Ott, G. R. J. Am. Chem. Soc. 1996, 118,
13095.
Figure 1. 1H NMR zoom of the 6.1–5.2 ppm region for 9a
and 9b (400 MHz, CDCl3).
Each stereoisomer was fully deprotected. Despite the
presence of an ester moiety in the macrocyclic ring,
selective N-debenzoylation was achieved in 76% yield
using phenol in refluxing dichloroethane.15 Removal of
the TBDMS group using tetrabutylammonium fluoride
in the presence of acetic acid9 afforded nucleoside ana-
logues 1016 in 85% yield.
In conclusion, we have shown that ring closing
metathesis can be used to access adenosine analogues
10. This is a new family of bicyclic nucleosides contain-
ing an olefinic moiety with a high potential for further
functionalisation. Moreover, our synthetic pathway
allows for a wide range of amino acid residues to be
introduced as well as a large variety of ring size. Efforts
to develop this family of compounds are in progress
and biological experiments on their inhibitory activity
towards tRNA dependent ligases are currently
underway.
10. Lodder, M.; Golovine, S.; Laikhter, A. L.; Karginov, V.
A.; Hecht, S. M. J. Org. Chem. 1998, 63, 794.
11. Selected spectral data for compound 7: 1H NMR (250
MHz, CDCl3) l: 0.15 (s, 6H, 2×CH3-Si), 0.90 (s, 9H,
tBu), 1.45 and 1.42 (2d, 3H, CH3, J 4.8), 2.34 (m, 4H,
2×CH2), 3.92 (m, 4H, 2H-5%, CH2), l 4.31 (dd, 1H, H-4%,
J 14), 4.62 (m, 2H, H-2%, CH), 5.05 (m, 4H, Hg, ꢁCH2),
5.44 (m, 1H, H-3%), 5.5–5.9 (2×m, 2H, Hb, CHꢁ), 6.23 (m,
2H, H-1%, NH), 7.4–7.5 (m, 3H, HBz), l 8.01 (d, 2H,
HBz, J 7), 8.32 (s, 1H, H-2 or H-8), 8.79 (s, 1H, H-2 or
H-8), 9.12 (s, 1H, NH); 13C NMR (63 MHz, CDCl3) l:
−4.5 (SiCH3), 17.15 (Cq/tBu, CH3), 24.97 (CH3/tBu),
28.37 (CH2), 34.40 (CH2), 47.17 (CH), 61.86 (C-5%), 70.95
(Ca, C-3%), 78.71 (C-2%), 82.60 (C-4%), 85.10 (C-1%), 114.65
(CH2ꢁ), 117.65 (Cg), 122 (Cq), 126.85, 127.85, 132.23,
132.34 (CBz, C-2 or C-8), 135.84, 140.40 (Cb, CHꢁ),
148.38, 150.90 (Cq), 140.25, 151.84 (C-2 or C-8), 148.51,
150.35 (Cq), 164.20, 171.11 (CO); optical rotation: [h]2D0=
−42 (c 1, DCM); MS (IC NH3+): 679 [M+H]+.
Acknowledgements
We thank the Ministe`re de la Recherche et des Nouv-
elles Technologies (MRNT) for financial support and a
Postdoctoral fellowship to P.B.
References
12. (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R.
H. Angew. Chem., Int. Ed. Engl. 1995, 34, 2039; (b)
Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org.
Lett. 1999, 1, 953.
1. (a) Bouhss, A.; Josseaume, N.; Severin, A.; Tabei, K.;
Jean-Emmanuel, H.; Schlaes, D.; Mengin-Lecreux, D.;
Van Heijenoort, J.; Arthur, M. J. Biol. Chem. 2002, 277;
(b) Bouhss, A.; Josseaume, N.; Allanic, D.; Crouvoisier,
M.; Gutmann, L.; Mainardi, J. L.; Mengi-Lecreux, D.;
Van Heijenoort, J.; Arthur, M. J. Bacteriol. 2001, 183,
5122.
2. Horton, J. R.; Bostock, J. M.; Chopra, I.; Hesse, S. E. V.;
Adams, D. J.; Johnson, A. P.; Fishwick, C. W. G. Biorg.
Med. Chem. Lett. 2003, 13, 1557.
13. Yamamoto, K.; Biswas, K.; Gaul, C.; Danishefsky, S. J.
Tetrahedron Lett. 2003, 44, 3297.
14. Selected spectral data for compound 9. 9a (Z): H NMR
1
(400 MHz, CDCl3) l: 0.10 (s, 6H, 2×CH3-Si), 0.85 (s, 9H,
tBu), 1.36 (d, 3H, CH3, J 7.0), 2.14–2.41 (m, 4H, 2×CH2),
3.67 (dd, 1H, OCH, J 8, J 10.3), 3.9 (dd, 2H, H-5%, J 3.3,
J 11.6), 4.20 (dd, 1H, CHO, J 4.0, J 10.3), 4.36 (dt, 1H,

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P. Busca et al. / Tetrahedron Letters 44 (2003) 9131–9134
H-4%, J 3, J 5.4), 4.65 (t, 1H, H-2%, J 5), 4.69 (m, 1H, CH),
(C-1%), 127.42, 127.91, 128.87, (CBz), 132.81 (CHꢁ),
133.64 (CHꢁ), 140.81 (C-2 or C-8), 149.50, 151.71 (Cq),
152.73 (C-2 or C-8), 170.96 (CO), 172.16 (CO); optical
rotation: [h]2D0=−8 (c 1.0, DCM); MS (FAB+): 651.3.
15. Ishido, Y.; Nakazaki, N.; Sakairi, N. J. Chem. Soc.,
Perkin Trans. 1 1977, 657.
5.33 (t, 1H, H-3%, J 5.3), 5.51 (m, 2H, CHꢁ), 5.98 (d, 1H,
NH, J 9), 6.10 (d, 1H, H-1%, J 4.6), 7.53 (m, 3H, HBz), l
8.01 (d, 2H, HBz, J 7.5), 8.31 (s, 1H, H-2 or H-8), 8.79 (s,
1H, H-2 or H-8), 9.1 (br s, 1H, NH); 13C NMR (100
MHz, CDCl3) l: −5.66 (SiCH3), 0.84 (Cq), 18.26 (Cq/
tBu), 18.43 (CH3), 25.77 (CH3/tBu), 29.52 (CH2), 36.44
(CH2), 47.04 (CH), 61.95 (C-5%), 71.78 (C-3%), 72.60
(CH2O), 80.67 (C-2%), 82.19 (C-4%), 87.79 (C-1%), 127.71,
127.85, 128.70 (CBz), 132.30 (CHꢁ), 132.63 (CHꢁ),
141.31 (C-2 or C-8), 149.32, 151.35 (Cq), 152.61 (C-2 or
C-8), 172.00 (CO), 173.63 (CO); optical rotation: [h]2D0=
16. Selected spectral data for compound 10. 10a (Z): 1H
NMR (500 MHz CD3OD) l: 1.39 (d, 3H, CH3, J 7.2),
2.26–2.42 (m, 4H, 2×CH2), 3.71 (m, 3H, 2H-5%, OCH),
4.7 (m, 1H, H-2%), 4.10 (m, 2H, H-4%, OCH), 4.37 (q, 1H,
CH), 5.42 (m, 3H, H-3%, 2×CHꢁ), 6.02 (d, 1H, H-1%, J 6),
8.21 (s, 1H, H-2 or H-8), 8.35 (s, 1H, H-2 or H-8). 10b
1
−31 (c 1, DCM); MS (FAB+): 651.3 [M+H]+. 9b (E): H
1
(E): H NMR (500 MHz CD3OD) l: 1.46 (d, 3H, CH3, J
NMR (400 MHz, CDCl3) l: 0.10 (s, 6H, 2×CH3-Si), 0.90
(s, 9H, tBu), 1.42 (d, 3H, CH3, J 7.3), 2.14–2.47 (m, 4H,
2×CH2), 3.88 (m, 3H, 2H-5%, OCH), 4.27 (m, 2H, H-4%,
OCH), 4.49 (t, 1H, H-2%, J 5.0), 4.62 (q, 1H, CH, J 7.5),
5.29 (m, 1H, H-3%), 5.61 (dt, 1H, CHꢁ, J 15, J 6), 5.81 (m,
1H, CHꢁ), 5.97 (d, 1H, NH, J 7.5), 6.27 (d, 1H, H-1%, J
4.8), 7.53 (m, 3H, HBz), l 8.03 (d, 2H, HBz, J 7.6), 8.45
(s, 1H, H-2 or H-8), 8.82 (s, 1H, H-2 or H-8), 9.2 (br s,
1H, NH); 13C NMR (100 MHz, CDCl3) l: −5.44
(SiCH3), 17.50 (Cq/tBu), 18.48 (CH3), 26.02 (CH3/tBu),
27.78 (CH2), 35.90 (CH2), 49.09 (CH), 62.43 (C-5%), 70.99
(C-3%), 71.42 (CH2O), 82.16 (C-2%), 83.73 (C-4%), 86.96
7.5), 2.27–2.41 (m, 4H, 2×CH2), 3.85 (m, 3H, 2H-5%,
OCH), 4.22 (m, 2H, H-4%, OCH), 4.41 (q, 1H, CH, J 7.2),
4.67 (t, 1H, H-2%, J 5.4), 5.32 (dd, 1H, H-3%, J 3.9, J 5.4),
5.61 (dt, 1H, CHꢁ, J 15.3, J 5.4), 5.79 (m, 1H, CHꢁ), 6.10
(d, 1H, H-1%, J 5.7), 8.20 (s, 1H, H-2 or H-8), 8.39 (s, 1H,
H-2 or H-8); 13C NMR (125 MHz, CD3OD) l: 15.94
(CH3), 27.82 (CH2), 34.50 (CH2), 49.74 (CH), 61.22 (C-
5%), 71.07 (CH2O), 72.48 (C-3%), 82.16 (C-2%), 85.05 (C-4%),
88.50 (C-1%), 127.54 (CHꢁ), 132.15 (CHꢁ), 149.18, 156.55
(Cq), 152.81 (C-2 or C-8), 172.39 (CO), 174.53 (CO); MS
(DCI+): 433 [M+H]+.