Synthesis of isomeric corniculatolides

Article abstract of DOI:10.1016/j.tetlet.2012.09.010

Synthesis of three natural macrolides 11-O-methylcorniculatolide A, 11-O-methylisocorniculatolide A and isocorniculatolide A is reported using a simple, straight forward and high-yielding route. The present synthesis confirms the assigned molecular struct

Full text of DOI:10.1016/j.tetlet.2012.09.010

Tetrahedron Letters 53 (2012) 6343–6346
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Tetrahedron Letters
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Synthesis of isomeric corniculatolides
Gajanan N. Raut a, Kasturi Chakraborty a, , Priyanka Verma b, Rajesh S. Gokhale b,c, D. Srinivasa Reddy a,
⇑
a CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
b National Institute of Immunology, New Delhi 110 067, India
c CSIR-Institute of Genomics and Integrative Biology, New Delhi 110 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 July 2012
Revised 3 September 2012
Accepted 5 September 2012
Available online 21 September 2012
Synthesis of three natural macrolides 11-O-methylcorniculatolide A, 11-O-methylisocorniculatolide A
and isocorniculatolide A is reported using a simple, straight forward and high-yielding route. The present
synthesis confirms the assigned molecular structures and provides an access to sufficient quantities of
the natural products for the biological evaluation. In addition, we have determined the anti-TB potential
of the three natural compounds using Alamar-Blue assay (H37Rv) and found no significant inhibitory
activity at 100
the present work.
lg/ml. Excellent yields, short sequence and useful SAR information are the highlights of
Keywords:
Total synthesis
Isocorniculatolide
Macrocyclization
Mitsunobu reaction
Diaryl ether
Ó 2012 Elsevier Ltd. All rights reserved.
Very recently, five isomeric macrolides of combretastatin D-2
congeners called 11-O-methylcorniculatolide A (1), corniculatolide
A (2), 11-O-methylisocorniculatolide A (3), isocorniculatolide A (4)
and 12-hydroxy-11-O-methylcorniculatolide A (5) were isolated
from the bark of a mangrove Aegiceras corniculatum by Gowri’s re-
search group from India.1 This particular mangrove has been used
traditionally to treat various inflammatory and metabolic disorders
and possesses a range of interesting biological properties.2 Out of
the five isolated natural products, only corniculatolide A (2) was
the previously known compound.3 The structures of these new
compounds were established using extensive NMR experiments
and X-ray crystal structure analysis of one of the natural products.
The related compounds of interesting diarylheptanoid structure
coupled with interesting biological properties4 have already been
the target of several synthetic groups.5,6 Majority of the groups fo-
cused their research using this class of compounds towards devel-
oping anti-cancer agents. Unlike many others, the novel
macrocyclic compounds 1–5 attracted our attention because of
their close structural resemblance with one of the potent antitu-
berculosis lead compound called engelhardione/pterocarine, 6.7,8
activity towards finding novel chemotypes for antituberculosis
drug discovery,9 we have initiated the proposed work. Our plan
is to synthesize the target macrolide compounds in sufficient
quantities using efficient routes for biological screening, in partic-
ular, antituberculosis assay. The present effort may provide a way
forward for a drug discovery program10 using this chemotype. In
addition, the total syntheses further confirm the assigned struc-
tures by Gowri’s group and the results are disclosed here in this
Letter.
We have planned the synthesis of the target molecules 1–5 by
relying on two key steps (i) diarylether formation11 and (ii) macrol-
actonization12 starting from readily available building blocks
(Fig. 2).
The planned synthesis began with the first key step diarylether
formation between the readily accessible partners, compound 75b
and para-fluorocinnamaldehyde 8. The reaction between 7 and 8
using Cs2CO3 in DMSO (at 120 °C for 8 h) was very clean and re-
sulted in a high yield of the desired compound 9. Next, we sub-
jected compound 9 to hydrogenation using 10% Pd/C under
hydrogen balloon pressure to remove both the unwanted double
bonds in molecule 9. We were pleased to find saturated alcohol
10 in very high yield during the hydrogenation step which is the
result of further reduction of intermediate saturated aldehyde.13
The acyclic compound 11 obtained from 10 through hydrolysis
was subjected to the second key step macrolactonization. After a
few attempts, we found that Mitsunobu12 conditions (PPh3, DIAD,
0.0025 M final concentration of solution in toluene, rt) produced
the desired macrocycle 11-O-methylcorniculatolide A (1) in 65%
isolated yield (Scheme 1). We did not isolate dimers or oligomers
The compound 6 is reported to have MIC of 0.2 lg/ml when
screened against Mycobacterium tuberculosis (H37Rv).7 Based on
the structural similarity, the title compounds 1–5 are expected to
show antitubercular activity (Fig. 1). As part of our research group
⇑
Corresponding author. Tel.: +91 20 25902445; fax: +91 20 25902629.
E-mail address: ds.reddy@ncl.res.in (D. Srinivasa Reddy).
Summer project student (as part of M. Sc. program) from Department of
Chemistry, Pune University, Pune, India.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.010

6344
G. N. Raut et al. / Tetrahedron Letters 53 (2012) 6343–6346
O
from this reaction. We believe that the addition of acyclic precur-
O
sor 11 to a solution of Ph3P and DIAD over a period of ꢀ24 h is
important.14 The spectral data (1H NMR and 13C NMR) of synthetic
compound 1 and those of natural compound 1 are identical.1,15
Having seen the success with the synthesis of 11-O-methyl-
corniculatolide A (1), we attempted the synthesis of isomeric iso-
corniculatolides 3 and 4. The compound diarylether 14 was
prepared from the alcohol 125d by reacting with para-fluorobenzal-
dehyde 13 in the presence of Cs2CO3 in DMSO. It is important to
note that phenolic OH is more reactive than aliphatic OH which
can be explained by the difference in nucleophilicity between the
O
O
O
O
R1
R2
R1
R2
R1 = OMe, R2 = H
11-O-methylcorniculatolide A (1)
R1 = OMe, R2 = H
11-O-methylisocorniculatolide A (3)
R1 = OH, R2 = H
corniculatolide A (2)
R1 = OH, R2 = H
isocorniculatolide A (4)
groups. Horner-Wittig reaction on aldehyde 14 produced the
a,b-
unsaturated ester 15 which was further transformed to saturated
ester 16 using 10% Pd/C under the hydrogen atmosphere. Horn-
er-Wittig reaction on aldehyde 14 also produced small amounts
of corresponding Z-isomer of 15. As it is not relevant for the pres-
ent purpose, we reduced the mixture to furnish 16 as a single com-
pound. Ester hydrolysis in compound 16 using aq NaOH in THF–
MeOH mixture produced the acyclic precursor 17 in 93% yield.
The macrocyclization under similar conditions of compound 1 syn-
thesis (PPh3, DIAD, 0.0025 M final concentration),14 natural prod-
uct 11-O-methylisocorniculatolide A (3) was prepared in high
yield. Finally, compound 3 was transformed to third natural prod-
uct isocorniculatolide A (4) through demethylation using AlCl3 in
DCM under reflux conditions. The spectral data of both the natural
products 3 and 4 were compared with those of reported data and
they are found to be identical.1,15 Thus, we have synthesized 11-
O-methylcorniculatolide A (1), 11-O-methylisocorniculatolide A
(3), and isocorniculatolide A (4) using a high yielding route and fur-
ther confirmed the assigned structures based on spectral data
(Scheme 2).
O
O
O
HO
O
O
OMe
OH
OH
12-hydroxy-11-O-
methylcorniculatolide A (5)
engelhardione/pterocarine (6)
potent antituberculosis agent
MIC = 0.2 g/ml (H37Rv)
µ
Figure 1. Structures of isomeric corniculatolides and engelhardione.
macrolactonization
O
O
All the three synthesized natural products 11-O-methylcornicu-
latolide A (1), 11-O-methylisocorniculatolide A (3) and isocornicu-
latolide A (4) were tested for antitubercular activity through
inhibition of growth of the virulent strain of Mycobacterium tuber-
culosis H37Rv using Alamar-Blue assay method. To our surprise, the
results show that none of the compounds are significantly active
O
O
O
O
R1
R2
R1
R2
up to 100 lg/ml. This suggests the presence of additional substitu-
diaryl ether formation
Figure 2. Key steps in planned synthesis.
ent (like OH) on the second aromatic ring and/or absence of oxygen
atom in the ring (in the form of lactone) of pterocarine chemotype
are/is important for the antitubercular activity.16 One of the
O
H
8
O
OEt
OH
F
COOEt
O
OH
COOEt
O
O
H2, 10% Pd/C,
EtOAc, RT, 4h
Cs2CO3, DMSO,
120 oC, 8h
H
95%
90%
OMe
7
OMe
OMe
9
10
O
PPh3, DIAD,
toluene (0.0025M)
slow addition
COOH
O
OH
aq. NaOH, THF-MeOH,
0 oC, 3h
O
90 %
65 %
O
OMe
OMe
11-O-methylcorniculatolide A (1)
11
Scheme 1. Synthesis of 11-O-methylcorniculatolide A.

G. N. Raut et al. / Tetrahedron Letters 53 (2012) 6343–6346
6345
CHO
F
CH2OH
OH
13
CH2OH
O
OMe
14
Ph3P
CH2OH
O
O
COOEt
Cs2CO3, DMSO,
120 oC, 2h
O
toluene, reflux, 8h
Et
CHO
98%
99%
OMe
OMe
15
12
CH2OH
O
O
CH2OH
O
aq. NaOH, THF-MeOH
0 oC, 2h
H2, 10% Pd/C,
EtOAc, RT, 4h
OEt
OH
93 %
95%
O
OMe
OMe
16
17
O
O
O
PPh3, DIAD,
toluene (0.0025M)
slow addition
O
O
AlCl3, DCM,
reflux, 5h
94 %
77 %
O
OH
isocorniculatolide A (4)
OMe
11-O-methylisocorniculatolide A (3)
Scheme 2. Synthesis of 11-O-methylisocorniculatolide A and isocorniculatolide A.
2. (a) Talat, R.; Ahsana, D.; Shamsher, A.; Sabira, N.; Muhammad, I. C. J.
Ethnopharmacol. 2008, 118, 514; (b) Talat, R.; Ahsana, D.; Shamsher, A.;
Sabira, N.; Muhammad, I. C. J. Ethnopharmacol. 2008, 118, 248; (c) Xu, V.; Deng,
Z.; Li, M.; Li, J.; Fu, H.; Proksch, P.; Lin, W. J. Nat. Prod. 2004, 67, 762; (d)
Bandaranayake, W. M. Mangroves Salt Marshes 1998, 2, 133.
reviewers pointed out that compounds of this type have the poten-
tial to exist as atropisomers.17We agree with the reviewer and it
may not be appropriate to compare the activities with natural
pterocarine as our method cannot produce the single atropisomers.
In short, we have achieved the synthesis of three out of four re-
cently isolated isomeric corniculatolide natural products using a
simple and efficient synthetic route. The present route can be used
for the synthesis of most of the related compounds of this family
and their analogues towards generating interesting chemotypes
for drug discovery programs. Also, the route is capable of produc-
ing gram-scale materials which may be useful in further biological
profiling. Although, in the present case we did not see significant
3. Vongvanich, N.; Kittakoop, P.; Charoenchai, P.; Intamas, S.; Danwisetkanjana,
K.; Thebtaranonth, Y. Planta Med. 2005, 71, 191.
4. (a) Ishida, J.; Kozuka, M.; Wang, H.-K.; Konoshima, T.; Tokuda, H.; Yang Mou, X.;
Nishino, H.; Sakurai, N.; Lee, K.-H.; Nagai, V. Cancer Lett. 2000, 159, 135; (b)
Ishida, J.; Kozuka, M.; Tokuda, H.; Nishino, H.; Nagumo, S.; Lee, K.-H.; Nagai, M.
Bioorg. Med. Chem. 2002, 10, 3361; (c) Morikawa, T.; Tao, J.; Toguchida, I.;
Matsuda, H.; Yoshikawa, M. J. Nat. Prod. 2003, 66, 86; (d) Akihisa, T.; Taguchi,
Y.; Yasukawa, K.; Tokuda, H.; Akazawa, H.; Suzuki, T.; Kimura, Y. Chem. Pharm.
Bull. 2006, 54, 735; (e) Kang, H.-M.; Kim, J. R.; Jeong, T.-S.; Choi, S.-G.; Ryu, Y.-H.
Oh, G. T.; Baek, N.-I.; Kwon, B.-M. Nat. Prod. Res. 2006, 20, 139.
5. Selected refs for the synthesis of related natural products (a) Shen, L.; Sun, D.
Tetrahedron Lett. 2011, 52, 4570; (b) Pettit, G. R.; Quistorf, P. D.; Fry, J. A.; Herald, D.
L.; Hamel, E.; Chapuis, J. C. J. Nat. Prod. 2009, 72, 876; (c) Cousin, D.; Mann, J.;
Nieuwenhuyzena, M.; van den Berg, H. Org. Biomol. Chem. 2006, 4, 54; (d)
Gonzalez, G. I.; Zhu, J. J. Org. Chem. 1997, 62, 7544; (e) Gonzalez; Zhu, J. J. Org. Chem.
1999, 64, 914; (f) Kumar, G. D. K.; Natarajan, A. Tetrahedron Lett. 2008, 49, 2103;
(g) Wang, Q.; Son, J.-K.; Jahng, Y. Synth. Commun. 2007, 37, 675; (h) Jeong, B.-C.;
Wang, Q.; Son, J.-K.; Jahng, Y. Eur. J. Org. Chem. 2007, 1338; (i) Ingerl, A.; Justus, K.;
Hellwiga, V.; Steglich, W. Tetrahedron 2007, 63, 6548; (j) Keserü, G. M.; Nogradi,
M.; Szöllösy, A. Eur. J. Org. Chem. 1998, 521; (k) Couladouros, E. A.; Soufli, I. C.;
Moutsos, V. I.; Chadha, R. K. Chem. Eur. J. 1998, 4, 33. and refs cited therein.
6. While preparing the manuscript, Google search resulted in one e-poster
claiming the first synthesis of isocorniculatolides. However, we could not find
any publication in scientific journals. V.K. Tulam, S.C. Bose, K.S. Kumar, P.S.
Mainkar, P.M. Murali, K. Mukkanti, e-Posters.net, Poster no. 41410. http://
www.eposters.net/index.aspx?ID=4140.
inhibitory activity (even at 100 lg/ml) in our antituberculosis as-
say, it provides useful SAR information on this scaffold for medic-
inal chemists. We are yet to explore other biological screenings like
anti-cancer, anti-inflammatory and other anti-bacterial assays.
Acknowledgements
Financial support from NCL, Pune (Start-up Grant, MLP022126)
and CSIR, New Delhi (NCL-IGIB joint research collaboration pro-
gram, NWP0013) is gratefully acknowledged. G.N.R. thanks CSIR,
New Delhi, for the award of junior research fellowship. We thank
the reviewer of this manuscript for useful suggestions.
7. Lin, W. Y.; Peng, C. F.; Tsai, I. L.; Chen, J. J.; Cheng, M. J.; Chen, I. S. Planta Med.
2005, 71, 171.
8. The proposed structure of engelhardione was revised as that of pterocarine
through synthesis. See Ref. 4a
Supplementary data
9. Swaroop, P. S.; Raut, G. N.; Gonnade, R. G.; Verma, P.; Gokhale, R. S.; Reddy, D. S.
Org. Biomol. Chem. 2012, 10, 5385.
Supplementary data (1H and 13C NMR data comparison tables of
the natural products with that of synthetic samples, and copies of
NMR spectra for all the new compounds)associated with this arti-
cle can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2012.09.010.
10. (a) Koul, A.; Arnoult, E.; Lounis, N.; Guillemont, J.; Andries, K. Nature 2011, 469,
483; (b) Ma, Z.; Lienhardt, C.; Mcilleron, H.; Nunn, A. J.; Wang, X. Lancet 2010,
375, 2100; (c) World Health Organization. Global tuberculosis control: a short
update to the 2009 report, Geneva, Switzerland, WHO/HTM/TB/2009, 426.; (d)
Foster, K. R.; Grundmann, H. PLoS Med. 2006, 3, 29; (e) Overbye, K. M.; Barrett, J.
F. Drug Discovery Today 2005, 10, 45.
11. Selected review on diaryl ether formation Pitsinos, E. N.; Vidali, V. P.;
Couladouros, E. A. Eur. J. Org. Chem. 2011, 1207.
References and notes
12. Selected reviews on macrolactonization (a) Parenty, A.; Moreau, X.; Campagne,
J.-M. Chem. Rev. 2006, 106, 911; (b) Swamy, K. C. K.; Kumar, N. N. B.; Balaraman,
E.; Kumar, K. V. P. P. Chem. Rev. 2009, 109, 2551.
1. Ponnapalli, M. G.; Annam, S. Ch.; Ravirala, S.; Sukki, S.; Ankireddy, M.; Tuniki, V.
R. J. Nat. Prod. 2012, 75, 275.

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G. N. Raut et al. / Tetrahedron Letters 53 (2012) 6343–6346
13. This is very interesing finding and needs further exploration. See refs for
related transformation (a) Choi, J.-G.; Park, C.-Y.; Oh, W.-C. Asian J. Chem. 2011,
23, 3476; (b) Akiharu, U.; Satoru, T.; Masunori, K.; Takashi, O.; Shigeki, S.;
Yoshimitsu, N. Heterocycles 2003, 61, 449.
14. Detailed procedure for macrolactonization is available in Supplementary data.
15. See Supplementary data for the spectra and data comparison tables.
16. We have contacted Prof. Dianqing Sun for the verififcation of pterocarine’s
anti-TB activity as they have synthesized the molecule in their lab. We were
informed that engelhardione/pterocarine showed only marginal antitubercular
activity in their assays. Sun, D. et al., Unpublished results.
17. While this manuscript was under review, in recent publication, it was shown
that compounds of pterocarine (6) and related compounds are resolvable using
chiral HPLC. This further supports reviewer’s suggestion. See, refs (a) Salih, M.
Q.; Beaudry, C. M. Org. Lett. 2012, 14, 4026; (b) Costantino, V.; Fattorusso, E.;
Mangoni, A.; Perinu, C.; Teta, R.; Panza, E.; Ianaro, A. J. Org. Chem. 2012, 77,
6377.