Synthesis of a new microbial secondary metabolite: Anti-Helicobacter pylori CJ-13,015

Article abstract of DOI:10.1016/j.tetlet.2004.05.086

A six-step, first synthesis of an anti-Helicobacter pylori secondary metabolite, CJ-13,015 (1a), in 65% overall yield, is described, starting from 5-methylfurfural (2), via a Wittig reaction of the ylide generated in situ from (8-hydroxyoctyl)triphenylpho

Full text of DOI:10.1016/j.tetlet.2004.05.086

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5693–5695
Synthesis of a new microbial secondary metabolite:
anti-Helicobacter pylori CJ-13,015q,qq
Mukulesh Mondal and Narshinha P. Argade*
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
Received 25 March 2004; revised 13 May 2004; accepted 18 May 2004
Available online 15 June 2004
Abstract—A six-step, first synthesis of an anti-Helicobacter pylori secondary metabolite, CJ-13,015 (1a), in 65% overall yield, is
described, starting from 5-methylfurfural (2), via a Wittig reaction of the ylide generated in situ from (8-hydroxyoctyl)triphenyl-
phosphonium bromide, selective reduction of the newly formed carbon–carbon double bond, conversion of the alcohol to a halide,
coupling with the anion of 3,5-dimethoxyphthalide and a chemoselective conversion of the protective furan group to a 1,4-dicar-
bonyl system as a key reaction.
Ó 2004 Elsevier Ltd. All rights reserved.
Gastric and duodenal ulcers affect a significant portion
of the human population worldwide. The root cause of
gastric and duodenal ulcers is the presence of the
microaerophilic Gram-negative bacterium Helicobacter
pylori, which appear to live beneath the mucus layer of
the stomach.1;2 Current therapy is not entirely successful
in achieving long-term eradication of H. pylori and re-
lapse is a problem.1;2 However, long-term treatment
with current therapies is not recommended and,
accordingly, there is a need for a safe and effective
treatment with a compound having an excellent anti-H.
pylori activity. Recently, in a screening programme de-
signed to discover such compounds, Dekker et al.3 iso-
lated the new phthalides 1a–g from the basidiomycete
Phanerochaerte velutina with promising anti-H. pylori
activity (Table 1). These secondary metabolites 1a–g
were isolated in very small amounts and a realistic
supply of these natural products for further biological
evaluation was required. In continuation of our on-
going studies4 on the synthesis of recently isolated bio-
active natural products, we report herein the first total
synthesis of CJ-13,015 (1a) (Scheme 1).
The retrosynthetic analysis of the microbial secondary
metabolite CJ-13,015 revealed that 5-methylfurfural,5 8-
bromo-1-octanol6 and 3,5-dimethoxyphthalide7 would
be suitable building blocks to access 1a. The Wittig
reaction of 5-methylfurfural (2) with the ylide generated
in situ from the reaction of (8-hydroxyoctyl)triphenyl-
phosphonium bromide and sodium methylsulfinyl-
methanide in a mixture of DMSO–THF (1:1) furnished
the Z- and E-isomers 3 in an 82% yield. Palladium on
charcoal induced selective catalytic hydrogenation of the
newly generated carbon–carbon double bond in 3 gave
the furan derivative 4 in quantitative yield. The primary
alcohol 4 was treated with p-toluenesulfonyl chloride to
form the corresponding tosylate 5 (96% yield), which, on
reaction with lithium bromide, yielded the desired furan-
containing alkyl halide 6 in 95% yield. The halide 6
underwent a smooth SN2 substitution reaction with the
anion of 3,5-dimethoxyphthalide in THF at 50 °C to
yield the desired coupled product 7 in 90% yield. The
furan moiety in compound 7 underwent a clean
chemoselective hydrolysis in a refluxing acetic acid–
water mixture (1:1) in the presence of a catalytic amount
of dilute sulfuric acid to furnish, exclusively, the desired
bioactive natural product CJ-13,015 (1a), in quantitative
yield. Starting from 5-methylfurfural (2), 14-(1,3-dihy-
dro-4,6-dimethoxy-3-oxo-1-isobenzofuranyl)-2,5-tetra-
decanedione (1a) was obtained in six steps and in 65%
overall yield. The analytical and spectral data obtained
Keywords: Microbial secondary metabolite CJ-13,015; anti-Helicobac-
ter pylori; 5-Methylfurfural; Coupling reactions; Furan to 1,4-dicar-
bonyl system; Total synthesis.
q NCL Communication No. 6663.
qq
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2004.05.086
* Corresponding author. Tel./fax: +91-20-25893153; e-mail: argade@
dalton.ncl.res.in
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.086

5694
M. Mondal, N. P. Argade / Tetrahedron Letters 45 (2004) 5693–5695
Table 1. New microbial secondary metabolities and their helicobactericidal activities
OMe
O
O
MeO
CH2CH2CH2CH2CH2R
1a-g
Compound
R
Activity (lg/disk that gives a 15 mm zone)
CJ-13,015 (1a)
CJ-13,102 (1b)
CJ-13,103 (1c)
CJ-13,104 (1d)
CJ-13,108 (1e)
–CH2CH2CH2CH2COCH2CH2COCH3
–CH2CH2CH2CH2CH(OAc)CH2CH2COCH3
–CH2CH2CH2CH2CH2CH2COCH2COCH3
–CH2CH2CH2CH2CH2CH2CH2CH(OH)CH3
–CH2CH2CH2CH2CH2CH2CH2COCH3
H
2
0.5
50
500
10
CJ-12,954 (1f)
CJ-13,104 (1g)
0.02
0.02
O
O
Me
Me
H
O
O
i
ii
CHO
CH2(CH2)7CH2OH
H3C
CH=CH-CH2(CH2)5CH2OH
3 (E:Z = 19:81)
H3C
H3C
O
O
O
4
2
iv
iii
v
CH2(CH2)7CH2OTs
CH2(CH2)7CH2Br
H3C
H3C
O
O
5
6
OMe
OMe
O
O
O
vi
O
MeO
MeO
CH2(CH2)7CH2COCH2CH2COCH3
CH2(CH2)
7 CH2
Me
O
7
CJ-13,015 (1a)
Scheme 1. Reagents, conditions and yields: (i) HOCH2(CH2)6CH2þPPh3BrÀ (1.1 equiv), NaþCH2ÀSOCH3 (2.2 equiv), DMSO–THF (1:1), 0 °C, 1 h
(82%); (ii) H2, Pd–C, methanol, rt, 4 h (98%); (iii) p-TsCl (1.1 equiv), TEA (2.2 equiv), DMAP, DCM, rt, 6 h (96%); (iv) LiBr (8 equiv), NaHCO3
(10 equiv), acetone, rt, 15 h (95%); (v) (a) 3,5-dimethoxyphthalide (1.5 equiv), LDA (1.5 equiv), THF, 0 °C to rt, 30 min, (b) 6 (1 equiv), 50 °C, 1 h, aq
workup, (90%); (vi) H2O–AcOH (1:1), cat. Hþ/H2SO4 (dil), reflux, 2 h, (98%).
for CJ-13,015 (1a)8 were in complete agreement with the
reported data.3
Acknowledgements
M.M. thanks UGC New Delhi, for the award of a re-
search fellowshipand N.P.A. thanks the Department of
Science and Technology, New Delhi, for financial sup-
port.
In summary, we have demonstrated a simple and effi-
cient total synthesis of the anti-H. pylori microbial sec-
ondary metabolite, CJ-13,015 in six steps and in 65%
overall yield. In the present synthesis, the use of furan to
introduce the 1,4-dicarbonyl system is noteworthy. We
feel that the present approach is general and may be
employed to design several natural and unnatural ana-
logues of this secondary metabolite. Starting from 3, our
work on the total synthesis of the more active secondary
metabolites CJ-12,954 (1f) and CJ-13,014 (1g) is in
progress.
References and notes
1. Blaser, M. J. Clin. Infect. Dis. 1992, 15, 386.
2. Rathbone, B. Scrip Magazine 1993, 25.
3. 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.
Supplementary material
4. (a) Mhaske, S. B.; Argade, N. P. Tetrahedron 2004, 60,
3417; (b) Kar, A.; Argade, N. P. Tetrahedron 2003, 59,
2991; (c) Kar, A.; Argade, N. P. Tetrahedron Lett. 2002, 43,
Analytical and spectral data for compounds 3–7 are
included.

M. Mondal, N. P. Argade / Tetrahedron Letters 45 (2004) 5693–5695
5695
6563; (d) Kar, A.; Argade, N. P. J. Org. Chem. 2002, 67,
7131; (e) Mhaske, S. B.; Argade, N. P. J. Org. Chem. 2001,
66, 9038, and references cited therein.
8. 14-(1,3-Dihydro-4,6-dimethoxy-3-oxo-1-isobenzofuranyl)-
2,5-tetradecanedione (CJ-13,015, 1a). Mp104–106 °C
(white crystalline solid); 1H NMR (CDCl3, 500 MHz): d
1.25 (b s, 8H), 1.25–1.37 (m, 2H), 1.37–1.50 (m, 2H), 1.55
(quintet, J ¼ 10 Hz, 2H), 1.63–1.73 (m, 1H), 1.92–2.01 (m,
1H), 2.17 (s, 3H), 2.43 (t, J ¼ 10 Hz, 2H), 2.63–2.72 (m,
4H), 3.89 (s, 3H), 3.94 (s, 3H), 5.28 (m, 1H), 6.40 (s, 1H),
6.41 (s, 1H); 13C NMR (CDCl3, 125 MHz): d 23.79, 24.59,
29.09, 29.24 (four carbons), 29.82, 34.81, 36.03, 36.89,
42.76, 55.86, 55.95, 79.84, 97.53, 98.67, 107.07, 155.19,
159.68, 166.69, 168.30, 207.04, 209.45; IR (Nujol) mmax 1759,
5. For the synthesis of 1,4-dicarbonyl systems, see: (a)
Piancatelli, G.; D’Auria, M.; D’Onofrio, F. Synthesis
1994, 867; For the synthesis of 1,4-dicarbonyl systems,
see: (b) Yuguchi, M.; Tokuda, M.; Orito, K. J. Org. Chem.
2004, 69, 908, and references cited therein.
6. Horiike, M.; Hirano, C. Agric. Biol. Chem. 1980, 44,
2229.
7. (a) Mali, R. S.; Babu, K. N. J. Org. Chem. 1998, 63, 2488;
(b) Mali, R. S.; Jagtap, P. G.; Patil, S. R.; Pawar, P. N. J.
Chem. Soc., Chem. Commun. 1992, 883.
1697, 1614, 1601, 1468, 837 cmÀ1
C24H34O6: C, 68.87; H, 8.19. Found: C, 68.92; H, 8.07.
; Anal. Calcd for