Chemoselective coupling reactions of 5,7-dimethoxyphthalide with the remotely functionalized alkyl iodides: Facile racemic synthesis of helicobacter pylori antibiotics

Article abstract of DOI:10.1021/jo100168f

Highly chemoselective coupling reactions of 5,7-dimethoxyphthalide carbanion with the remotely functionalized long chain alkyl iodides have been demonstrated to accomplish the concise and efficient synthesis of Helicobacter pylori antibiotics, the CJ-mole

Full text of DOI:10.1021/jo100168f

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TABLE 1. New Microbial Secondary Metabolites and Their
Helicobactericidal Activities
Chemoselective Coupling Reactions of
5,7-Dimethoxyphthalide with the Remotely
Functionalized Alkyl Iodides: Facile Racemic
Synthesis of Helicobacter pylori Antibiotics
Mandeep Singh and Narshinha P. Argade*
Division of Organic Chemistry, National Chemical
Laboratory (CSIR), Pune 411 008, India
np.argade@ncl.res.in
Received February 1, 2010
1,4-dicarbonyl system.5 Recently, Brimble et al. have re-
ported the synthesis of five CJ-compounds 1a-e using an
intrinsic flexible approach.6 Soon after, Dallavalle et al.
reported the synthesis of analogues natural product sporo-
tricale methyl ether (25).7 Several elegant syntheses of
more challenging target molecules 1f-h with the spiro units
have been reported recently.8 A careful scrutiny of struc-
tures of all the CJ-molecules revealed that they are the
remotely monofunctionalized, bifunctionalized, and latent
trifunctionalized 3-alkyl-substituted 5,7-dimethoxyphtha-
lides. The phthalides substituted at the C-3 position are
found in various naturally occurring compounds and they
possess interesting biological activities.9 Synthesis of
3-substiuted phthalides is a challenging task of current
interest.10 Atom economy and the reaction selectivity are the
real keys for the synthetic efficiencies.11 Now, herein we
report a concise and efficient approach to the target com-
pounds by taking advantage of highly chemoselective cou-
pling reactions of 5,7-dimethoxyphthalide carbanion with
the remotely functionalized tailored long chain alkyl iodides
(Schemes 1 and 2).
Highly chemoselective coupling reactions of 5,7-dimeth-
oxyphthalide carbanion with the remotely functionalized
long chain alkyl iodides have been demonstrated to
accomplish the concise and efficient synthesis of Helico-
bacter pylori antibiotics, the CJ-molecules, and sporotri-
cale methyl ether.
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 There is a
need for a safe and effective treatment with a compound
having an excellent anti-H. pylori activity. In a screening pro-
gram designed to discover such compounds, Dekker et al.3
isolated the new phthalides 1a-g from the basidiomycete
Phanerochaerte velutina with promising anti-H. pylori acti-
vity (Table 1). In continuation of our ongoing studies4 on
the synthesis of recently isolated bioactive natural products,
we have reported the first total synthesis of CJ-13,015
(1a) using furan as the protected source of remotely placed
(5) Mondal, M.; Argade, N. P. Tetrahedron Lett. 2004, 45, 5693.
(6) Brimble, M. A.; Flowers, C. L.; Hutchinson, J. K.; Robinson, J. E.;
Sidford, M. Tetrahedron 2005, 61, 10036.
(7) (a) Dallavalle, S.; Nannei, R.; Merlini, L.; Nasini, G.; Bava, A.;
Nasini, G. Synlett 2005, 2676. (b) Arnone, A.; Assante, G.; Nasini, G.;
Vajna de Pava, O. Phytochemistry 1990, 29, 613.
(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.
(4) (a) Patel, R. M.; Argade, N. P. Synthesis 2009, 372 and references cited
therein. (b) Haval, K. P.; Argade, N. P. J. Org. Chem. 2008, 73, 6936 and
references cited therein. (c) Wakchaure, P. B.; Easwar, S.; Puranik, V. G.;
Argade, N. P. Tetrahedron 2008, 64, 1786 and references cited therein.
(8) (a) Trost, B. M.; Weiss, A. H. Angew. Chem., Int. Ed. 2007, 46, 7664.
(b) Keaton, K. A.; Phillips, A. J. Org. Lett. 2007, 9, 2717. (c) Nannei, R.;
Dallavalle, S.; Merlini, L.; Bava, A.; Nasini, G. J. Org. Chem. 2006, 71, 6277.
(d) Brimble, M. A.; Bryant., C. J. Chem. Commun. 2006, 4506. (e) Robinson,
J. E.; Brimble, M. A. Chem. Commun. 2005, 1560. (f) Bava, A.; Clericuzio,
M.; Giannini, G.; Malpezzi, L.; Meille, S. V.; Nasini, G. Eur. J. Org. Chem.
2005, 2292.
DOI: 10.1021/jo100168f
r
Published on Web 04/08/2010
J. Org. Chem. 2010, 75, 3121–3124 3121
2010 American Chemical Society

Singh and Argade
JOCNote
SCHEME 1. Synthesis of Remotely Functionalized Long Chain Alkyl Iodides A-D
We envisaged the stepwise preparation of the desired long
chain alkyl iodides (A-D) starting from ethyl acetoacetate
(2) and two different suitably substituted acetylene deriva-
tives 4/16 via the alkylation/condensation with aliphatic
aldehydes, followed by the systematic functional group
interconversions (Scheme 1). The base-catalyzed selective
monocoupling of ethyl acetoacetate with 1,11-diiodounde-
cane in refluxing acetone furnished the desired chain A
in 90% yield. The base-catalyzed coupling of OTBDPS-
protected acetylene derivative 4 with the ω-O-benzyl-
protected aliphatic aldehyde followed by the PCC-oxidation
of thus formed secondary alcohol furnished the ketone 6.
(9) (a) Lin, G.;Chan, S. S.-K.; Chung, H.-S.; Li, S.-L. Chemistry and Biological
ActionofNatural Occurring Phthalides. InStudies inNaturalProducts Chemistry;
Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, The Netherlands, 2005; Vol. 32, p 611
and references cited therein . (b) Palermo, J. A.; Brasco, M. V. R.; Spagnuolo, C.;
Seldes, A. M. J. Org. Chem. 2000, 65, 4482 and references cited therein. (c) Brady,
S. F.; Wagenaar, M. M.; Singh, M. P.; Janso, J. E.; Clardy, J. Org. Lett. 2000, 2,
4043 and references cited therein. (d) Yoganathan, K.; Rossant, C.; Ng, S.; Huang,
Y.; Butler, M. S.; Buss, A. D. J. Nat. Prod. 2003, 66, 1116 and references cited
therein.
(10) (a) Kuriyama, M.; Ishiyama, N.; Shimazawa, R.; Shirai, R.;
Onomura, O. J. Org. Chem. 2009, 74, 9210. (b) Mal, D.; Pahari, P.; De,
S. R. Tetrahedron 2007, 63, 11781and references cited therein 10a,b.
(11) (a) Shenvi, R. A.; O’Malley, D. P.; Baran, P. S. Acc. Chem. Res. 2009,
42, 530. (b) Trost, B. M. Science 1983, 219, 245. (c) Trost, B. M. Science 1991,
254, 1471.
3122 J. Org. Chem. Vol. 75, No. 9, 2010

Singh and Argade
JOCNote
SCHEME 2. Chemoselective Alkylation of 5,7-Dimethoxyphthalide: Synthesis of CJ-Compounds
The ketone 6 on catalytic hydrogenation underwent both the
debenzylation and reduction of carbon-carbon triple
bond in one pot to provide the reduced desired product 7.
The silyl-protected keto-alcohol 7 on tosylation followed by
treatment with sodium iodide gave the desired chain B with
69% overall yield in five steps. The common intermediate 5
on acylation followed by desilylation gave the secondary
alcohol 11, which on PCC-oxidation gave the ketone 12. The
ketone 12 on catalytic hydrogenation gave the expected
debenzylated reduced product 13, which on tosylation fol-
lowed by treatment with sodium iodide gave the desired
chain C with 51% overall yield in seven steps. Trimethyl-
silylacetylene (16) on reaction with the O-benzyl-protected
requisite aliphatic aldehyde followed by benzyl protection of
the formed secondary alcohol directly furnished an in situ
desilylated acetylene derivative 18. Compound 18 on base-
catalyzed condensation with the γ-valerolactone provided
the keto-alcohol 19. The product 19 on catalytic hydrogena-
tion formed the double debenzylated saturated ketone as an
unstable intermediate, which on rapid intramolecular dehy-
drative double cyclization provided the spiro-alcohol 20. The
alcohol 20 on treatment with iodine and triphenylphosphine
gave the desired chain D with 54% overall yield in five steps.
Thus we accomplished the smooth preparation of the desired
remotely functionalized alkyl iodide long chains A-D in a
concise and efficient fashion via the appropriate functional
group interconversion pathways.
The phthalides are widely used building blocks in organic
synthesis and the generated benzylic carbanions on them are
known to react with acid chlorides, imines, alkyl halides,
aldehydes, and esters.5,12 The preferred reactivity of phtha-
lide carbanions toward SN2-displacements of halides versus
addition to the carbonyl groups has not been studied pre-
viously. The alkyl iodide chains A-D contain remotely
placed ketone/ester, silyloxyketone, acetoxyketone, and
spiroketal units, respectively. We developed a systematic
plan to generate a 5,7-dimethoxyphthalide carbanion and
study its chemoselective coupling reactions with the primary
alkyl iodide chains A-D, with the expectation that the
stabilized benzylic carbanion will be competing for an
SN2 substitution reaction over the 1,2-addition reactions
(Scheme 2). We screened bases such as triethylamine,
DBU, NaH, n-BuLi, s-BuLi, LDA, and NaHMDS for the
generation of the necessary benzylic carbanion on phthalide
22 and studied the chemoselective coupling reactions with
the primary alkyl iodide chain A under a similar set of
reaction conditions. In our hands, the bases triethylamine,
DBU, NaH, and n-BuLi were ineffective in inducing the
coupling of phthalide 22 with the alkyl iodide chain A (3).
The use of s-BuLi as the base for the coupling of 22 with
iodide 3 formed the desired product 23, but only in 5% to 6%
yield. The use of LDA also gave the desired product with
41% yield along with the formation of some side products.
The best results were obtained with the bulky NaHMDS as
the base. The chemoselective reaction of benzylic carbanion
from 5,7-dimethoxyphthalide (1.00 equiv), generated by
using NaHMDS (1.10 equiv) as the base, with alkyl iodide
chain A (1.00 equiv) exclusively furnished the expected
(12) (a) Mali, R. S.; Babu, K. N.; Jagtap, P. G. J. Chem. Soc., Perkin
Trans. 1 2001, 3017. (b) Mali, R. S.; Babu, K. N. J. Org. Chem. 1998, 63, 2488.
(c) Mali, R. S.; Massey, A. P.; Talele, M. I. J. Chem. Res. (S) 1998, 68.
(d) Harris, T. M.; Harris, C. M.; Kuzma, P. C.; Lee, J. Y. C.; Mahalingam, S.;
Gilbreath, S. G. J. Am. Chem. Soc. 1988, 110, 6186. (e) Marsden, R.;
Maclean, D. B. Can. J. Chem. 1984, 62, 306. (f) Becker, H.-D. J. Org. Chem.
1964, 29, 3070. (g) Horton, R. L.; Murdock, K. C. J. Org. Chem. 1960, 95,
938. (h) Hauser, C. R.; Tetenbaum, M. T.; Hoffenberg, D. S. J. Org. Chem.
1958, 23, 861 and references cited therein..
J. Org. Chem. Vol. 75, No. 9, 2010 3123

Singh and Argade
JOCNote
coupled product 23 in 76% yield via the SN2-displacement
pathway. On the basis of formation of product 23, we feel
that the SN2-displacement of primary alkyl iodide in chain A
with the benzylic carbanion of phthalide 22 is faster than the
deprotonation of the acidic methine proton in chain A by the
phthalide carbanion. The base-catalyzed hydrolysis of ester
moiety in compound 23 followed an in situ decarboxylation
of the intermediate β-keto acid furnished the desired bio-
active natural product CJ-13,108 (1e) in 68% yield. Chemo-
selective NaBH4-reduction of the ketone moiety in 1e furni-
shed the desired bioactive natural product in the series, the
CJ-13,104 (1d), in 95% yield. Similarly, the chemoselective
reaction of benzylic carbanion from 5,7-dimethoxyphthalide
with chain B furnished the product 24, which on desilylation
gave the natural product sporotricale methyl ether (25). In
solution the compound 25 displays a ring-chain tauto-
merism, chloroform (hemiketal)/acetone (hydroxyketone).7
Compound 25 on PCC-oxidation provided the CJ-13,015
(1a) in very good yield. Finally, the chemoselective coup-
lings of the phthalide carbanion with chain C and chain
D respectively furnished the desired products CJ-13,102
(1b) and a diastereomeric mixture of CJ-12,954/CJ-13,014
(1f)/(1g). The analytical and spectral data obtained for CJ-
13,015 (1a), CJ-13,102 (1b), CJ-13,104 (1d), CJ-13,108 (1e),
CJ-12,954/CJ-13,014 (1f)/(1g), and sporotricle methyl ether
(25) were in complete agreement with the reported data3,6 and
were obtained in one to three steps with very good overall
yields. These results clearly demonstrate the preferential SN2
displacement ability of the NaHMDS-generated phthalide
carbanion over the 1,2-addition to carbonyl groups.
Experimental Section
Ethyl 2-Acetyl-13-(4,6-dimethoxy-3-oxo-1,3-dihydroisoben-
zofuran-1-yl)tridecanoate (23). To a stirred solution of 5,7-
dimethoxyphthalide (22, 500 mg, 2.57 mmol) in THF (25 mL)
at -20 °C was added NaHMDS (1 M in THF, 2.83 mL, 2.83
mmol) and the reaction mixture was stirred at -20 °C for
45 min, which was followed by the dropwise addition of alkyl
iodide 3 (chain A, 1.05 g, 2.57 mmol) in THF (8 mL) at -20 °C.
The reaction mixture was allowed to attain room temperature.
Saturated NH4Cl solution (5 mL) was added to the reaction
mixture and THF was removed in vacuo. To the reaction
mixture was added ethyl acetate (20 mL) and the separated
organic layer was washed with water and brine and dried over
Na2SO4. The concentration of organic layer in vacuo followed
by silica gel column chromatographic purification of the result-
ing residue with 35% ethyl acetate/petroleum ether as an eluent
1
afforded pure product 23 (932 mg, 76%) as a colorless oil. H
NMR (CDCl3, 400 MHz) δ 1.24 (br s, 14H), 1.28 (t, J = 8 Hz,
3H), 1.26-1.38 (m, 2H), 1.38-1.52 (m, 2H), 1.62-1.74 (m, 1H),
1.77-1.91 (m, 2H), 1.93-2.05 (m, 1H), 2.23 (s, 3H), 3.40
(t, J = 8 Hz, 1H), 3.90 (s, 3H), 3.95 (s, 3H), 4.20 (q, J = 8 Hz,
2H), 5.30 (dd, J = 8 and 2 Hz, 1H), 6.42 (s, 2H); 13C NMR
(CDCl3, 100 MHz) δ 14.0, 24.5, 27.3, 28.1, 28.7, 29.2, 29.3,
29.36, 29.42, 34.7, 55.8, 55.9, 59.8, 61.1, 79.9, 97.3, 98.5, 106.7,
155.1, 159.4, 166.6, 168.5, 169.8, 203.4; IR (CHCl3) vmax 1746,
1721, 1712, 1605 cm-1. Anal. Calcd for C27H40O7: C, 68.04; H,
8.46. Found: C, 67.71; H, 8.60.
Similarly, the reactions of phthalide 22 with alkyl halide
chains B-D respectively furnished the corresponding products
24, 1b, and 1f/g (see the Supporting Information).
In summary, we have reported a practical synthesis of
remotely functionalized important natural products, the
CJ-molecules, by taking advantage of highly chemoselective
carbon-carbon bond forming reactions of phthalide with
the functionalized alkyl iodides. We feel that in the present
approach, the remarkably chemoselective displacements of
primary iodides by the 5,7-dimethoxyphthalide carbanion,
specifically in the presence of a free ketone, and ester moieties
are noteworthy. Our approach is general in nature and will
be useful in designing a focused minilibrary of analogous and
congeners of CJ-molecules for SAR studies.
Acknowledgment. M.S. thanks CSIR, New Delhi for the
award of a research fellowship. N.P.A. thanks the Department
of Science and Technology, New Delhi, for financial support.
Supporting Information Available: Experimental proce-
dures and the tabulated analytical and spectral data for the
compounds 1a, 1b, 1d, 1e, 1f/g, 3, 5-15, 17-21, and 23-25
and 1H NMR, 13C NMR, and DEPT spectra of com-
pounds 1a, 1b, 1d, 1e, 1f/g, 3, 5-15, 17-21, and 23-25. This
material is available free of charge via the Internet at http://
pubs.acs.org.
3124 J. Org. Chem. Vol. 75, No. 9, 2010