Synthesis of benzotriazole analogues of the helicobactericidal agents CJ-13,015, CJ-13,102, CJ-13,108, and CJ-13,104 using a regioselective 1,3-dipolar cycloaddition

Article abstract of DOI:10.1055/s-0030-1259081

A regioselective 1,3-dipolar cycloaddition of a disubstituted aryne and various alkyl azides facilitates access to benzotri-azole analogues of several anti-Helicobacter pylori antibiotics. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1259081

LETTER
99
Synthesis of Benzotriazole Analogues of the Helicobactericidal Agents
CJ-13,015, CJ-13,102, CJ-13,108, and CJ-13,104 Using a Regioselective
1,3-Dipolar Cycloaddition
S
ynthesis of Benzo
a
triazole
A
n
r
a
logues
c
of
H
elicob
y
actericidal
A
gents J. Atkinson,a,b Jonathan Sperry,a,b Margaret A. Brimble*a,b
a
Department of Chemistry, University of Auckland, 23 Symonds Street, Auckland, New Zealand
Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
Fax +64(9)3737422; E-mail: m.brimble@auckland.ac.nz
b
Received 19 October 2010
nessed the racemic syntheses of CJ-13,015, CJ-13,102,
CJ-13,108, CJ-13,104 (1–4)9 together with the total syn-
thesis and stereochemical assignment of the complex
spiroacetal-containing phthalides CJ-12,954 (5), CJ-
13,014 (6)10 and spirolaxine methyl ether (8).11 We have
also synthesized several indole analogues of the CJ antibi-
otics (1–4)12 that subsequently displayed inhibitory activ-
ity against H. pylori.13
Abstract: A regioselective 1,3-dipolar cycloaddition of a disubsti-
tuted aryne and various alkyl azides facilitates access to benzotri-
azole analogues of several anti-Helicobacter pylori antibiotics.
Key words: benzotriazole, helicobacter pylori, benzyne, dipolar
cycloaddition
Helicobacter pylori has been shown by epidemiological
studies to have an etiological role in several diseases, in-
cluding gastric and duodenal ulcers, distal gastric cancer,
mucosal-associated lymphoid tissue (MALT) lymphoma
(cancer of the B cell lymphocytes), and was implicated in
the cause of 5.6% of all cancers worldwide in 2002.1 This
microaerophilic, Gram-negative bacterium2 has been esti-
mated to infect the stomach of over half of the world’s
population making it the planet’s most widespread infec-
tion.3 In the majority of cases, infection will persist for the
lifetime of an individual in the absence of medical inter-
vention.4
OMe
O
O
O
MeO
7
O
CJ-13,015 (1)
OMe
O
R
O
MeO
7
O
Current treatments for H. pyroli infections are complex
and rely on broad range antibiotics in combination with
proton-pump inhibitors and bismuth salts.5 The first line
of treatment cures less than 20% of patients due to un-
pleasant side effects which often leads to noncompliance.5
H. pyroli also quickly develops resistance to the currently
used antibiotics clarithromycin and metronidazole.5 The
complex nature of current treatments combined with their
often poor success rates and side effects dictates an obvi-
ous need for new helicobactericidal treatments.5,6
R = OAc; CJ-13,102 (2)
R = H; CJ-13,108 (3)
OMe
O
O
MeO
7
OH
CJ-13,104 (4)
OMe
OMe
O
R
O
O
R
O
O
In a screening program to isolate such compounds,
Dekker and co-workers isolated several new phthalide an-
tibiotics 1–6 (Figure 1) with specific anti-H. pylori activ-
ity from the basidiomycete Phanerochaete velutina
CL6387.7 Two structurally related compounds, spirolax-
ine 78a and its methyl ether 88b have been isolated from the
cultures of Phanerochaete chrysosporium and they have
also been shown to be good inhibitors of the H. pylori bac-
terium.7,12
MeO
R
R
4
CJ-12,954 (5)
O
R
S
O
O
MeO
RO
R
R
4
CJ-13,014 (6)
OMe
O
R
O
The ongoing studies in our laboratory regarding the syn-
thesis of potential anti-H. pylori compounds has wit-
R
O
O
R
R
3
R = H; spirolaxine (7)
R = Me; spirolaxine
methyl ether (8)
SYNLETT 2011, No. 1, pp 0099–0103
Advanced online publication: 07.12.2010
x
x.
x
x.
2
0
1
1
DOI: 10.1055/s-0030-1259081; Art ID: D27810ST
© Georg Thieme Verlag Stuttgart · New York
Figure 1 Phthalide containing antibiotics with anti-H. pylori activity

100
D. J. Atkinson et al.
LETTER
OMe
OMe
OMe
N
N
N
N
N
N
N
OAc
O
N
N
MeO
MeO
MeO
7
7
7
O
O
O
11 (ketone)
12 (alcohol)
10
9
OMe
regioselective
1,3-dipolar
cycloaddition
13
13
MeO
13
OAc
O
N3
N3
N3
7
7
7
O
O
O
14
15
16
OH
common
intermediate
TBDMSO
7
17
Scheme 1 Proposed synthesis of benzotriazole analogues of selected helicobactericidal compounds
Prompted by our recent observation that indole analogues the first azide coupling partner 14. The alcohol intermedi-
of 1–4 exhibit activity against H. pylori,13 combined with ate 17 was oxidized with IBX and the resulting ketone 26
our ongoing interest in the synthesis of triazole analogues subjected to Wacker oxidation delivering 1,4-diketone 27
of biologically active natural products14 and natural prod- that underwent concomitant desilylation. Facile tosylation
uct-like scaffolds,15 we decided to undertake the synthesis to 28 and subsequent azide displacement delivered the
of benzotriazole analogues of the aforementioned CJ anti- second azide coupling partner 15. Finally, the third azide
biotics 1–4 with the idea of improving their bioactivity. coupling partner 16 was constructed.
We herein describe the convergent synthesis of several
benzotriazole analogues of the CJ antibiotics 1–4 using a
highly regioselective 1,3-dipolar cycloaddition of a dioxy-
genated benzyne and a range of alkyl azides.
Alcohol intermediate 17 was converted into xanthate 29
which underwent Barton–McCombie deoxygenation de-
livering 30. Wacker oxidation gave ketone 31 which un-
derwent smooth desilylation to alcohol 32 and azide
The planned retrosynthesis of the benzotriazole analogues displacement of the tosylate 33 delivering the final cou-
9–12 of the CJ antibiotics 1–4 is shown in Scheme 1. It pling partner 16 (Scheme 3).
was envisaged that disubstituted benzyne 13 would under-
Next, attention turned to the key benzyne–azide cycload-
go a regioselective 1,3-dipolar cycloaddition with a series
dition step. Initial attention focused on the synthesis of
of azides 14–16 which in turn would all be available from
model deoxy analogues of the CJ antibiotics 1–4 in order
to first assess the viability of the proposed cycloaddition
the same common intermediate 17. The convergent nature
of this proposed route makes it well suited for analogue
design (Scheme 1).
TBDMS-Cl
DMAP
The synthesis of the common intermediate 17 is outlined
imidazole
TBDMSO
HO
in Scheme 2. Dec-9-en-1-ol (18) underwent smooth sily-
lation affording silyl ether 19 which was subjected to stan-
dard hydroboration conditions giving alcohol 20. IBX-
mediated oxidation followed by Grignard extension of the
resulting aldehyde 21 completed a multigram synthesis of
the key intermediate 17 in excellent overall yield
(Scheme 2).
7
98%
7
BH3•DMS
NaOH
H2O2
18
19
86%
THF
IBX
O
DMSO
TBDMSO
TBDMSO
H
89%
OH
7
7
21
20
Next, the synthesis of the azides 14–16 necessary to com-
plete the synthesis of the CJ antibiotic analogues was un-
dertaken (Scheme 3). Common intermediate 17 was first
acetylated to give 22 then subjected to Wacker oxidation
conditions affording 23. Desilylation gave alcohol 24
which was converted into tosylate 25 and subsequently
BrMg
OH
Et2O
78%
TBDMSO
7
17
Scheme 2 Synthesis of common intermediate 17
Synlett 2011, No. 1, 99–103 © Thieme Stuttgart · New York

LETTER
Synthesis of Benzotriazole Analogues of Helicobactericidal Agents
101
Ac2O
Py
NaH, CS2
OH
MeI, THF
TBDMSO
95%
98%
7
17
IBX
DMSO
S
95%
OAc
O
SMe
TBDMSO
7
TBDMSO
TBDMSO
O
22
7
TBDMSO
29
PdCl2•(MeCN)2
CuCl, O2
7
Bu3SnH
AIBN
toluene
60%
26
99%
DMF–H2O
PdCl2•(MeCN)2
CuCl, O2
DMF–H2O
OAc
76%
7 30
TBDMSO
7
PdCl2•(MeCN)2
CuCl, O2
O
O
23
70%
DMF–H2O
HO
TBAF
THF
7
82%
TBDMSO
O
O
O
27
7
31
O
OAc
p-TsCl
Et3N
CH2Cl2
TBAF
THF
HO
60%
67%
7
O
24
HO
7
p-TsCl
Et3N
CH2Cl2
32
O
O
O
82%
p-TsCl
Et3N
CH2Cl2
TsO
92%
7
OAc
28
TsO
TsO
7
7
25
NaN3
DMF
33
O
O
90%
NaN3
DMF
NaN3
DMF
95%
90%
O
OAc
N3
N3
N3
7
7
7
O
14
15
16
Scheme 3 Synthesis of azide coupling partners 14, 15, and 16
approach. Accordingly, benzyne precursor 34 Treatment of the benzyne precursor 3918c with azide 14
(R1 = R2 = H) was accessed in multigram quantities using under the standard conditions described previously led to
a recent literature procedure.16 Gratifyingly, upon subject- a single product in excellent yield. 1H NMR and 13C NMR
ing azide 14 and benzyne precursor 34 to the previously analysis indicated that only one regioisomer was present
reported ‘click’ cycloaddition conditions17 the benzotriaz- in the reaction mixture and a strong NOE correlation be-
ole analogue 35 of CJ-13,102 was obtained in moderate tween 7-H and 14-CH2 gratifyingly confirmed the product
yield (Table 1, entry 1). Azide 15 was also a willing par- was the desired regioisomer 9 (Table 1, entry 5, Figure 2).
ticipant in the cycloaddition, delivering benzotriazole an- Azide 15 also participated in the benzyne cycloaddition
alogue 36 of CJ-13,015 in good yield (entry 2). Likewise, with 39 producing a single regiosiomer, confirmed as 10
azide 16 underwent cycloaddition with benzyne precursor by NOE studies (entry 6). Likewise, azide 16 underwent
34 delivering 37 (entry 3), which could be converted into regioselective cycloaddition with benzyne precursor 39
a further analogue 38 (entry 4) by straightforward reduc- delivering 11 (entry 7), which could be readily converted
tion of 37 with sodium borohydride.
OMe
Thus, with the foundations of the cycloaddition concept
N
clearly established by the successful synthesis of four
N
deoxy analogues of the CJ compounds (entries 1–4) our
N
H
14
MeO
7
7
attention turned to the use of a benzyne precursor 39 pos-
sessing the requisite 4,6-dimethoxy substitution pattern
necessary for the synthesis of the fully substituted ana-
logues 9–12. This would of course investigate the obvious
regioselectivity issues arising from the use of unsymmet-
rical arynes in the key cycloaddition step.18
H
H
NOE
benzotriazoles 9–12
Figure 2 Observed NOE correlation in benzotriazoles 9, 10, 11, and 12
Synlett 2011, No. 1, 99–103 © Thieme Stuttgart · New York

102
D. J. Atkinson et al.
LETTER
Table 1 Synthesis of Benzotriazole Analogues of the CJ Antibiotics19
CsF
18-crown-6
MeCN
r.t.
R1
4
R1
4
N3
TMS
OTf
N
N
7
N
R2
6
R2
6
7
34 R1 = R2 = H
39 R1 = R2 = OMe
Entry
1
Benzyne precursor (equiv) Azide
Time (h) Product
Yield (%)
54
N
N
OAc
OAc
N
N
N
N
N3
34 (3)
3
7
7
O
O
14
35
N
N
O
O
N3
2
3
4
34 (3)
2.5
64
26
7
7
O
O
O
O
15
36
N
N
N3
7
34 (3)
5
7
O
16
37
N
N
N3
7
18 (2 steps
26 + 68)
34 (3)
5
7
16
OH
then NaBH4, MeOH
38
OMe
OMe
OMe
OMe
OAc
N
OAc
N3
N
N
N
N
5
6
7
39 (2)
39 (2)
39 (2)
2
85
77
72
7
N
MeO
O
7
7
7
7
O
14
9
O
N
N
O
N3
1.5
7
MeO
O
O
O
O
15
10
N
N
N3
7
4.5
MeO
16
O
11
N3
N
N
7
67 (2 steps
72 + 93)
8
39 (2)
4.5
MeO
16
OH
then NaBH4, MeOH-THF
12
Synlett 2011, No. 1, 99–103 © Thieme Stuttgart · New York

LETTER
Synthesis of Benzotriazole Analogues of Helicobactericidal Agents
103
4506. (b) Brimble, M. A.; Bryant, C. J. Org. Biomol. Chem.
2007, 5, 2858.
(11) (a) Robinson, J. E.; Brimble, M. A. Chem. Commun. 2005,
1560. (b) Robinson, J. E.; Brimble, M. A. Org. Biomol.
Chem. 2007, 5, 2572.
into a further analogue 12 (entry 8) by treatment of 11
with sodium borohydride.
In conclusion, we have prepared eight benzotriazole ana-
logues of several CJ antibiotics, four of which were ob-
tained using an entirely regioselective 1,3-dipolar
cycloaddition between a disubstituted aryne and the ap-
propriate azide.19 Biological evaluation of these com-
pounds is in progress and will be reported in due course.
(12) Wilson, Z. E.; Heapy, A. M.; Brimble, M. A. Tetrahedron
2007, 63, 5379.
(13) Radcliff, F. J.; Fraser, J. D.; Wilson, Z. E.; Heapy, A. M.;
Robinson, J. E.; Bryant, C. J.; Flowers, C. L.; Brimble,
M. A. Bioorg. Med. Chem. 2008, 16, 6179.
(14) Rathwell, K.; Sperry, J.; Brimble, M. A. Tetrahedron 2010,
66, 4002.
Acknowledgment
(15) Choi, K. W.; Brimble, M. A. Org. Biomol. Chem. 2008, 6,
3518.
(16) Atkinson, D. J.; Sperry, J.; Brimble, M. A. Synthesis 2010,
911.
We thank the University of Auckland and the Maurice Wilkins Cen-
tre for Molecular Biodiscovery for financial support of this work.
(17) Campbell-Verduyn, L.; Elsinga, P. H.; Mirfeizi, L.; Dierckx,
R. A.; Feringa, B. L. Org. Biomol. Chem. 2008, 6, 3461.
(18) (a) Wenk, H. H.; Winkler, M.; Sander, W. Angew. Chem. Int.
Ed. 2003, 42, 502. (b) Cheong, P. H.-Y.; Paton, R. S.;
Bronner, S. M.; Im, G.-Y. J.; Garg, N. K.; Houk, K. N. J. Am.
Chem. Soc. 2010, 132, 1267. (c) Tadross, P. M.; Gilmore, C.
D.; Bugga, P.; Virgil, S. C.; Stoltz, B. M. Org. Lett. 2010, 12,
1224; and references therein.
References and Notes
(1) Mackay, J.; Jemal, A.; Lee, N. C.; Parkin, D. M. The Cancer
Atlas, 2nd ed.; American Cancer Society: New York, 2006.
(2) Marshall, B. J.; Warren, J. R. Lancet 1984, 323, 1311.
(3) Montecucco, C.; de Bernard, M. Microbes Infect. 2003, 5,
715.
(4) Stoicov, C.; Saffari, R.; Cai, X.; Hasyagar, C.; Houghton, J.
Gene 2004, 341, 1.
(19) General Procedure for the Synthesis of Benzotriazole
Analogues of the CJ Compounds
(5) Calvet, X. Digestion 2006, 73, 119.
To a stirred solution of azide (0.3 mmol) in MeCN (6 mL)
was added CsF (0.6 mmol, 2 equiv) and 18-crown-6 (0.6
mmol, 2 equiv), and the reaction mixture was stirred at r.t.
for 15 min. A solution of benzyne precursor 39 (0.6 mmol,
2 equiv) in MeCN (2 mL) was added dropwise, and the
reaction mixture was stirred until completion (1.5–5 h).
Aqueous NaHCO3 (10 mL) was added, and the reaction
mixture was extracted with CH2Cl2 (5 × 5 mL). The
combined organic extracts were dried over MgSO4, filtered,
and the solvent removed under reduced pressure. The
resulting residue was purified by flash chromatography
using hexanes–EtOAc as eluent to afford the desired
benzotriazole (Table 1).
(6) Muri, E. M. F.; Williamson, J. S. Mini-Rev. Med. Chem.
2004, 4, 201.
(7) Dekker, K. A.; Inagaki, T.; Gootz, T. D.; Kaneda, K.;
Nomura, E.; Sakakibara, T.; Sakemi, S.; Sugie, Y.;
Yamauchi, Y.; Yoshikawa, N.; Kojima, N. J. Antibiot. 1997,
50, 833.
(8) (a) Arnone, A.; Assante, G.; Nasini, G.; Vajna de Pava, O.
Phytochemistry 1990, 29, 613. (b) Guadliana, M. A.;
Huang, L. H.; Kaneko, T. WO 9630538, 1996.
(9) Brimble, M. A.; Flowers, C. L.; Hutchinson, J. K.; Robinson,
J. E.; Sidford, M. Tetrahedron 2005, 61, 10036.
(10) (a) Brimble, M. A.; Bryant, C. J. Chem. Commun. 2006,
Synlett 2011, No. 1, 99–103 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.