Research proposals for R&D

by Abhishek Dwivedi, Alumnus, University of Leeds, England.

Synthetic Organic Chemist with hand-on experience of using IR, UV, NMR, MASS, HPLC, GC, Computer-Aided Drug designing softwares [training on Q-FIT software by Dr. Richard Jakson & Sprout by Dr. Collin Fishwick] & familiar with SOP, STP, GLP & GMP.

Trained by

Prof. Adam Nelson, Director - Astbury Centre, University of Leeds, Dr. Alan Berry, School of Biological Sciences, University of Leeds, Dr. Richard Jakson, School of Bio-informatics, University of Leeds, Dr. Collin Fishwick, School of Chemistry, University of Leeds Dr. Ieuan G. Davies, Alumnus: University of Oxford, Experts of Glaxo Smith Cline & Astrazeneca - England

PROJECT 1

PREPARATION OF ACETAMPRID ANALOGUES

Acetamiprid is an organic compound with the chemical formula C10H11ClN4. It is an odorless neonicotinoid insecticide produced under the trade names Assail, Pristine, and Chipco by Aventis Crop Sciences. It is systemic and intended to control sucking insects on crops such as leafy vegetables, citrus fruits, pome fruits, grapes, cotton, cole and ornamental plants. It is also a key pesticide in commercial cherry-farming due to its effectiveness against the larvae of the cherry fruit fly. A novel synthetic method to synthesize Acetamiprid & its potential analogues
NHR Cl N
1

R (MeS)2C=NCN Cl N R H
2

N CN S Me

R Cl N
1 2

N N N

R = Me, R = Me; Acetamiprid

With the help of Computer Aided Drug Designing & docking we can check the efficiency of different analogues of acetamprid and can prepare a large library using the same novel synthetic method. Below are the world-fame products that can be prepared using the same synthetic approach.
R Cl N X N Z Cl N
1

R X

1. Imidacloprid; X = NNO2 Z = NH 2. Thiacloprid; X = NCN, Z = S 3. Nitenpyram; R1 = Et, R2 = NHMe

PROJECT 2

A NOVEL SYNTHETIC ROUTE FOR THE PREPARATION OF PLATENSIMYCIN AND ITS ANALOGUES.

Fig.1. Structure of Platensimycin made by Abhishek Dwivedi using ACD-3D Chemsketch software.

Introduction Platensimycin is a novel antibiotic lead compound recently discovered by Merck scientists from a strain of Streptomyces platensis1, 2. This compound is a member of a class of antibiotics which act by blocking enzymes involved in the condensation steps in fatty acid biosynthesis,3 which Gram-positive bacteria need to biosynthesize cell membranes (-ketoacyl-(acyl-carrier-protein (ACP)) synthase I/II (FabF/B)). Other enzymes in this pathway have similarly been proven antibiotic targets for example FabI, the enoyl-ACP (acyl carrier protein) reductase that is inhibited by isoniazid and related compounds and the antiseptic agent triclosan.4The potential medicinal applications5, 6 and challenging structure motif, especially the cage-like tetracyclic core with several stereogenic centers, made this compound very attractive as a target for chemical synthesis.

Syntheses of Platensimycin and its analogues The two successful attempts to synthesize Platensimycin and its analogues are as follows:

Fig.2. Similar steps in synthesis of ()-Reiswigin A by Nicolaou and Snider respectively

Whereas these reported routes utilized intramolecular etherification reactions between the alcohol motifs and the alkene parts as key steps, I would like to suggest an alternative intramolecular annulation approach that I feel to be more straightforward. Herein, I propose a new expected enantioselective synthesis of the key cage-like tetracyclic core structure of Platensimycin.

A NOVEL SYNTHETIC ROUTE FOR THE SYNTHESIS OF THE KEY CAGE-LIKE TETRACYCLIC CORE STRUCTURE OF PLATENSIMYCIN By ABHISHEK DWIVEDI, ALUMNUS UNIVERSITY OF LEEDS

The retrosynthetic analysis presented in Fig.2. envisions a Robinson annulation event7 of bicyclic compound 10 to give the tetracyclic core structure 116. Specifically, I expect that by using proline-type catalysts, high diastereoselectivity will be obtained7-10. Compound 10 could be constructed from bicyclic lactone 5 by adding two appendages in an appropriate manner. Lactone 5 is a known compound, which was encountered in the total synthesis of a series of natural products in the hirsutene family.11-17 In contrast to the methods in the literature, I believe the potential precursor of lactone 5 could be ketone 4, through a Baeyer-Villiger oxidation / rearrangement sequence.18-22 Utilizing recently developed Brnsted acid-assisted chiral Lewis acid (BLA)7 catalyzed highly enantio- and regioselective Diels-Alder reaction,23 and subsequent N-nitroso aldol addition / decarboxylation sequence,24 enantiomerically pure ketone 4 can be easily prepared from inexpensive, commercially available starting materials 1 & 2.

COOMe CH3 1

+
&

H3C

H3C

CH2 2 3 MeOOC 4 O

Starting material

CH3 O O H2C 6

CH3 O O 5

CH3 O CN H2C 7

CH3 O

CN H2C 8

CH3 O H2C 9

O CH3

O CH3 O OHC O CH3 O 10 H3C CH3 CHO

O OH O O H3C O H3C O OH OH O 12 H3C O CH3 NH O

11

&

11'

Platensimycin
Fig.3. Possible steps in proposed synthesis of ()-Reiswigin A by Abhishek Dwivedi Alumnus; University Of Leeds

Possible Library of Platensimycin Analogues

OH OH O OH OH O 13 H3C 18 O O O CH3 NH O O OH OH

O N

NH

O O OH OH O 14 H3C CH3 NH

OH O O OH OH 19 NH

CH3 O N

CH3 NH

O O

H3C

O CH3

O O

OH

O CH3 H3C

NH OH OH O 20

OH O 15 H3C

CH3

CH3

OH O OH OH

OH O CH3 O O OH OH NH

O CH3 H3C

NH

16

21

O CH3 NH

O O OH OH

OH

O CH3 H3C

NH

O 17 H3C 22

In conclusion, an enantioselective route to the tetracyclic core structure of platensimycin can be possible in ten steps from simple commercially available starting materials. A number of the steps in this synthesis are noteworthy or novel: (1) the regio- and enantioselective Diels-Alder reaction between methyl acrylate and methyl cyclopentadiene (2) the one-pot conversion from ester 2 to ketone 3 using nitrosobenzene under mild conditions; (3) the one-pot reductive cyanation of lactone 5; (4) the stereoselective intramolecular Michael addition25 between the -branched aldehyde moiety and the -substituted enone part of bicyclic compound 10.

References: 1. 2. 3. 4. 5. 6.

J. Wang, S.M. Soisson, K .Young, S. B. Singh etc, Nature 2006, 441, 358-61. D. T. Manallack and B. Capuano, Current Medicinal Chemistry 2008, 15, 705-710. D. Hbich, F. Von Nussbaum, Chem. Med. Chem. 2006, 1, 951-954. H. T. Wright, and K.A Reynolds, Curr. Opin. Microbiol. 2007, 10, 447-53. Zou Y, Chen C. H., Taylor C. D., Foxman B. M., Snider B. B., Org. Lett. 2007; 9:18251828. Nicolaou K. C. et al. Page 2 J. Am. Chem. Soc. Author manuscript; PMC 2008 September 24. 7. Stork G, Shiner C. S., Winkler J. D., J. Am. Chem. Soc. 1982,104, 310312. 8. Fonseca M. T. H., List B. Angew Chem, Int. Ed 2004; 43, 39583960. 9. Hayashi Y., Gotoh H., Tamura T., Shoji M., J. Am. Chem. Soc. 2005, 127, 1602816029. 10. List B. Chem. Commun. 2006, 819824. 11. Curran D. P., Rakiewicz D. M., J. Am. Chem. Soc. 1985, 107:14481449. 12. Curran D. P., Rakiewicz D. M., Tetrahedron 1985, 41, 38433958. 13. Fevig T. L., Elliott RL, Curran D. P., J. Am. Chem. Soc. 1988, 110, 50645067. 14. Weinges K., Reichert H. Syn. Let. 1991, 785786. 15. Weinges K., Reichert H, Huber-Patz U., Irngartinger H. Liebigs, Ann. Chem. 1993, 403411. 16. Weinges K., Braun R, Huber-Patz U., Irngartinger H. Liebigs, Ann. Chem. 1993, 11331140. 17. Weinges K., Braun R. Liebigs, Ann. Chem. 1994, 99101. 18. Meinwald J., Seidel M. C., Cadoff B. C., J. Am. Chem. Soc. 1958, 80, 63036305. 19. Curran D. P., Chen M., Tetrahedron Lett. 1985, 26, 49914994. 20. Corey EJ, Weinshenker NM, Schaaf T. M., J. Am. Chem. Soc. 1969, 91, 56755677. 21. Corey EJ, Schaff TK, Huber W, Koelliker V., J. Am. Chem. Soc. 1970, 92, 397398. 22. Corey, E. J., Cheng, X, John Wiley & Sons, New York: 1989. Chapter 11, Prostanoids. 23. Payette J. N., Yamamoto H., J. Am. Chem. Soc. 2007. 24. Yamamoto H., Momiyama N., Chem. Commun. 2005, 35143525. 25. Intermolecular reaction between such counterparts is still a remaining challenge in the area of organocatalysis, see: (a) Melchiorre P, Jorgensen K. A., J. Org. Chem. 2003, 68, 41514157. [PubMed: 12762713] (b) Peelen T. J., Chi Y., Gellman S. H., J. Am. Chem. Soc. 2005, 127, 1159811599. [PubMed: 16104725] (c) Chi Y., Gellman S. H., Org. Lett. 2005, 7, 42534256.

PROJECT 4
TOTAL SYNTHESIS OF ()-REISWIGIN-A (AN ANTIVIRAL DRUG) VIA A NOVEL SYNTHETIC ROUTE.

Fig.4. ()-Reiswigin A an anti-viral molecule: Structure made by Abhishek Dwivedi using ACD-3D chemsketch software.

()-Reiswigin A shows a promising antiviral activity against herpes simplex type I virus and murine A59 hepatitis virus. It has been synthesized previously in a highly stereoselective manner utilizing a sequential Claisen rearrangement intramolecular ester enolate alkylation strategy by Deukjoon Kim et al., Tetrahedron Letters Volume 35, Issue 43, 24 October 1994, Pages 7957 7960 using sequential Claisen rearrangement intramolecular ester enolate alkylation.
BnO H3C OMOM OBz O CH3 O CH3 CH3 H3C H OMOM H3C EtOOC CH3 OTs

H R

IEEA O H3C CH3 O H3C CH3

(-)-Reiswigin A

H H3C

Fig.5. Steps in synthesis of ()-Reiswigin A by Deukjoon Kim et.al. Tetrahedron Letters Volume 35, Issue 43, 24 October 1994, Pages 7957 7960

David I. MaGee and Dean E. Shannon also tried to synthesize ()-Reiswigin A with a different strategy but their strategy failed due to unknown reasons & the compound formed was ()-epi-reiswigin A.
[David I. MaGee and Dean E. Shannon, Can. J. Chem. 82(2): 333343 (2004)].

In a previous successful attempt ()-Reiswigin A was synthesized in 11 steps by Jones, D. N. et al. [Jones, D. N., Maybury, M. W. J., Swallow, S., Tomkinson, N. C.O., Tetrahedron Lett. 1993, 34, 8553].

CH3 O

H2C Li

SO2Ph CH3 OM

SO2Ph

SO 2Ph COOEt

CH3

Starting Materials

SO2Ph CH3

H SO 2Ph O

SO 2Ph COOEt

CH3 CH3

CH3 CH3

CH3 CH3

H SO 2Ph CH3 CH3 OMOM

H CH3

H CH3

CH3 OMOM

MOMO

CH3 OH

H CH3

H CH3

MOMO

CH3 O

MOMO

CH3 O

CH3 H H CH3

H3C CH3

O CH3 O

(-)-Reiswigin A

Fig.6. Steps in synthesis of ()-Reiswigin A by Jones, D. N.; Maybury, M. W. J.; Swallow, S.; Tomkinson, N. C.O.Tetrahedron Lett. 1993, 34, 8553.

PROPOSED NOVEL SYNTHETIC ROUTE THAT INVOLVES 7 STEPS FOR PREPARATION OF ()-REISWIGIN A & ITS ANALOGUES: BY ABHISHEK DWIVEDI, ALUMNUS - UNIVERSITY OF LEEDS, ENGLAND.

Retero synthesis of the above mentioned antiviral compound allows me apply a different strategy that is more efficient in terms of stereoselectivity and involves 7 steps for preparation of ()-Reiswigin A & its analogues for the synthesis of ()-Reiswigin A. ()-Reiswigin A and its analogues can also be prepared via novel synthetic route

O TMS

CH3 O CH3 CH3 CH3 H3C

H3C

Starting materials

O HO H H H3C CH3 H3C O O O CH3 HO O CH3 CH3

CH2 CH3 H3C CH3 H

t

O MgBr H H3C R

H3C

BuO O

R H2C CH3

CH3 O

H3C CH3 H2C

OH

CH3

H3C H H3C (-) - Reiswigin A, (an anti-viral medicine)

Fig.7. Proposed steps in synthesis of ()-Reiswigin A by Abhishek Dwivedi.

Some other proposals for R&D activities

10

With the help of Comparative modeling & Computer aided drug designing we can make some effective modifications in the structure of compounds mentioned below. Structural modifications will improve the activity and the site selection of the drug molecules. 1. LAMOTRIGINE Lamotrigine is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorders.
NH2 N H2N N N Cl

Cl 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine

2. MIDAZOLAM Midazolam is a short-acting drug in the benzodiazepine class that is used for treatment of acute seizures, moderate to severe insomnia, and for inducing sedation and amnesia before medical procedures.
H3C N Cl N H F 8-chloro-6-(2-fluorophenyl)-1-methyl-5,6-dihydro-4 H-imidazo[1,5- a][1,4]benzodiazepine N

3. TAMSULOSIN Tamsulosin is a selective 1 receptor antagonist that has preferential selectivity for the 1A receptor in the prostate versus the 1B receptor in the blood vessels.
O H2N H3C O S O NH CH3 O H3C O

11