Total synthesis of Carpatamides A–D

Article abstract of DOI:10.1016/j.tetlet.2018.05.090

A synthetic strategy was developed for the synthesis of the common core structure of Carpatamides A–D. The total synthesis of Carpatamides A and C was completed in 6 steps and of Carpatamides B and D in 7 steps, by employing the Wittig olefination, olefin

Full text of DOI:10.1016/j.tetlet.2018.05.090

Accepted Manuscript
Total Synthesis of Carpatamides A–D
Nagaraju Madala, Venkata Rao Ghanta, Srilalitha Vinnakota, Narender Mendu,
Arun B. Ingle, Krishna Ethiraj, Vishal Sharma
PII:
S0040-4039(18)30728-7
https://doi.org/10.1016/j.tetlet.2018.05.090
TETL 50037
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
29 March 2018
24 May 2018
30 May 2018
Please cite this article as: Madala, N., Rao Ghanta, V., Vinnakota, S., Mendu, N., Ingle, A.B., Ethiraj, K., Sharma,
V., Total Synthesis of Carpatamides A–D, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.
2018.05.090
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Tetrahedron Letters
Total Synthesis of Carpatamides A–D
Nagaraju Madalaa,b, Venkata Rao Ghantaa,b, Srilalitha Vinnakotac, Narender Mendua, Arun B. Inglea,
Krishna Ethiraja, Vishal Sharmaa 
a GVK Biosciences Private Limited, Medicinal Chemistry Division, 28A, IDA Nacharam, Hyderabad - 500076, India
b Department of Chemistry, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad - 500085, India
c Department of Chemistry, Faculty of Science and Technology, ICFAI Foundation for Higher Education, Dontanpally, Hyderabad - 501203, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A synthetic strategy was developed for the synthesis of the common core structure of
Carpatamides A–D. The total synthesis of Carpatamides A and C was completed in 6 steps and
of Carpatamides B and D in 7 steps, by employing the Wittig olefination, olefin cross metathesis
and acid amine coupling reactions as key steps.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Wittig olefination
Cross metathesis
Carpatamides
NSCLC
Cytotoxicity
Corresponding author. Tel.: +91-04066281623; e-mail: vishal.sharma@gvkbio.com

1. Introduction
Non-small-cell lung cancer (NSCLC) is the most prevalent form
of lung cancer.1 It is also relatively insensitive to chemotherapy,
compared to small cell lung cancer.2 In order to identify
compounds with selective activity against NSCLC, MacMillan
and co-workers screened several natural product fractions against
a panel of comprehensively annotated NSCLC cell lines. As a
part of these studies, they isolated Carpatamides A–C (1–3, Fig.
1) from marine derived Streptomyces sp. (strain SNE-011).3
Carpatamide A and C showed cytotoxicity against the NSCLC
cell lines HCC366, A549, and HCC44 with IC50 values ranging
from 2.2 to 8.4 μM. Another compound of same family
Carpatamide D (4) was isolated from the marine derived
Streptomyces strain SNE-011.4
Scheme 2. Synthesis of acid 6
The synthesis of amine 5, started from commercially available
aldehyde 8. The regioselective nitration of 8 followed by Wittig
olefination with ylide 15 produced α,β-unsaturated ester 7. The
reduction of 7 to 5 using different reaction conditions resulted
complex reaction mixtures.9 Crude LCMS indicated in-situ
isomerization of the double bond and cyclisation with the
adjacent hydroxyl to give coumarin derivatives with different
oxidation states. The phenolic hydroxyl group was therefore
protected as a MOM ether to give compound 16, which upon
hydrogenation gave amine 17 in good yield. Amine 17 was
coupled with acid 6 to give the key intermediate 18. MOM
deprotection of compound 18 resulted in the formation of
Carpatamide
A (1), and subsequent hydrolysis afforded
Carpatamide B (2). The alkylation of compound 18 with 2-
bromoethyl acetate and aqueous work-up produced acid 19,
which was subjected to MOM deprotection by treatment with 4M
HCl in 1,4-dioxane to give Carpatamide D (4, Scheme 3).
Figure 1. Carpatamides A–D
These compounds possess a novel amide structure consisting
of an amino-phenyl propionic acid core and an unsaturated fatty
acid side-chain, which was previously observed only in
manumycin derivatives from Streptomyces parvulus.5,6
Herein, we report the first total synthesis of Carpatamides A–
D (1-4). We envisioned their synthesis from amine 5 and acid 6
by amide coupling and further functional group manipulation.
Amine 5 can be obtained from aldehyde 8 by nitration and Wittig
olefination to give compound 7 followed by reduction. Acid 6
could be synthesized in 3 steps by the cross metathesis of olefins
12 and 13 to give compound 11 followed by Horner-Wadsworth-
Emmons olefination and hydrolysis (Scheme 1).
Scheme 3. Synthesis of Carpatamides A, B and D
The synthesis of Carpatamide C (3) started with 4-hydroxy-3-
nitrobenzaldehyde (20) as shown in Scheme 4. The Wittig
olefination of aldehyde 20 with ylide 15 gave unsaturated ester
21, which was protected as the MOM ether and nitro reduction
gave the desired amine 23. The coupling amine 23 with acid 6
produced amide 24, which upon MOM deprotection and ester
1
hydrolysis gave Carpatamide C (3). The H and 13C NMR of all
synthesized Carpatamides A–D (1-4) were in agreement with the
isolated compounds by MacMillan and co-workers.1,2
Scheme 1. Synthetic strategy and retrosynthesis
2. Results and Discussion
The synthesis commenced with the preparation of acid 6. The
cross metathesis of allyl phosphonate 12 with ethyl acrylate 13
gave olefin 117 in good yield. Subsequent Horner-Wadsworth-
Emmons olefination with 3-methylbutanal (10) gave diene ester
9.8 The hydrolysis of ester 9 then gave the required acid 6 in 63%
overall yield from compound 13 (Scheme 2).

2. Alberg, A. J.; Brock, M. V.; Stuart, J. M. J. Clin. Oncol. 2005, 23, 3175–
3185.
3. Fu, P.; Johnson, M.; Chen, H.; Posner, B. A.; MacMillan, J. B. J.
Nat. Prod. 2014, 77, 1245−1248.
Scheme 4. Synthesis of Carpatamide C
4. Fu, P.; La, S.; MacMillan, J. B. J. Nat. Prod. 2017, 80, 1096−1101.
5. Zeeck, A.; Frobel, K.; Heusel, C.; Schroder, K.; Thiericke, R. J. Antibiot.
1987, 40, 1541−1548.
6. Uosaki, Y.; Agatsuma, T.; Tanaka, T.; Saitoh, Y. J. Antibiot. 1996, 49,
1079−1084.
3. Conclusion
In conclusion, we have developed a synthetic strategy for
Carpatamides A–D employing Wittig olefination, olefin cross
metathesis and acid amine coupling reactions as the key steps.
7. Toste, F. D.; Chatterjee, A. K.; Grubbs, R. H. Pure Appl. Chem. 2002,
74, 7-10.
8. Huang, Y.; Fañanás-Mastral, M.; Minnaarda A. J.; Feringa, B. L. Chem.
Commun. 2013, 49, 3309-3311.
Acknowledgments
9. The reduction was attempted with i) H2, Pd/C (10 mol%), EtOH ii) H2,
Pd(OH)2 (10 mol%), EtOH, iii) Fe/NH4Cl, EtOH then H2, Pd/C (10
mol%), EtOH.
The authors are thankful to GVK Biosciences Private Limited for
financial support and facilities for accomplishing this research.
Help from the analytical department for all spectroscopic analysis
is highly appreciated. We are thankful to Dr. Sudhir Kumar
Singh (President, Discovery and Development Services, GVK
Bioscinces) for his immense support and motivation. We are also
thankful to JNTU, Hyderabad.
References and notes
1. Molina, J. R.; Yang, P.; Cassivi, S. D.; Schild, S. E.; Adjei, A. A. Mayo
Clin. Proc. 2008, 83, 584-594.

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Total Synthesis of Carpatamides A–D
Nagaraju Madalaa,b, Venkata Rao Ghantaa,b, Srilalitha Vinnakotac, Narender Mendua, Arun B. Inglea
Krishna Ethiraja, Vishal Sharmaa
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Synthetic strategy developed for common core
structure of Carpatamides A–D
Total synthesis of Carpatamides A-D is reported
Spectroscopic data of synthesized compounds is in
agreement with reported compounds