PRABAGARAN (PRABA) NARAYANASAMY

Department of Microbiology, Immuno. & patho. Cell : 617-230-2411 Colorado State University email: [email protected] 1682 Campus Delivery office: 970-491-6789 Fort Collins, CO 80523-1682

RESEARCH INTERESTS

- Discovery of innovative chemical reactions, mechanisms, and molecules to address unsolved challenges in organic synthesis, drug design, and development. - Utilization of organic and asymmetric synthetic technique for drug development.

Experience Research Colorado State University 2006 - present Scientist Medicinal chemist - Drug design and discovery Advisor: D.C. Crick

 Design and discovery of new enzyme inhibitors for infectious diseases like TB (e.g., IspD, IspE, MraY, MenA inhibitors).  Development of total synthesis and chemoenzymatic synthesis of MEP pathway intermediates (MEP, CDPME, MECPP) and Park’s Nucleotide (carbohydrate and peptide chemistry).

Post-Doctoral Harvard University & 2004-2006 Fellow University of Illinois, Urbana-Champaign Advisor: M. C. White

 Synthesized macromolecules by allylic oxidative cyclizations (peptides - hepatitis-C inhibitor; bisindoles - protein kinase inhibitor).  Developed a new asymmetric C-H oxidation method and a new concept of regioselective internal allylic C-H oxidation

Post-Doctoral North Dakota State University 2002-2004 Fellow Advisor: Mukund P. Sibi

 Created novel strategies for Enantioselective synthesis of all - Amino acids (mono, di, and tri-substituted amino acids).  Established chiral relay technique in radical reactions and catalyst metal geometry.

1 EDUCATION Ph.D. Indian Institute of Technology, Madras, India 2002 Organic chemistry, Advisor: G. Sundararajan

Thesis: Asymmetric induction using chiral catalyst bearing C2 symmetric amino diol.  Developed first enantioselective synthesis of quinoline derivatives by Asymmetric Diels-Alder reactions using chiral titanium monomer catalyst.  Accomplished asymmetric Michael addition reaction with new polymer anchored chiral catalyst.  Synthesized a new glucose sensor via molecular imprinting technique.

M.Sc. Pondicherry University, Pondicherry, India 1996 Chemistry (with Distinction)

P.G.D.S.D. Brilliant Computer Center, Pondicherry, India 1994 Computer Science & Applications (with Distinction)

B.Sc. Pondicherry University, Pondicherry, India 1994 Chemistry

REFEREED JOURNAL PUBLICATIONS

1. H. Eoh, P. Narayanasamy, P. J. Brennan, and D. C. Crick*. IspE – Substrate synthesis, characterization and development of a high through-put screen (submitted).

2. H. Eoh, P. Narayanasamy, P. J. Brennan and D. C. Crick*. (2008). 4- Diphosphocytidyl-2-C-Methyl-D-Erythritol Synthase from Burkholderia, Salmonella, and Vibrio Species (submitted).

3. P. Narayanasamy * and D. C. Crick*. (2008). Enantiomeric Synthesis of 4- Diphosphocytidyl-2-C-methyl-D-erythritol. (submitted).

4. P. Narayanasamy,* H. Eoh, and D. C. Crick*. (2008). Chemoenzymatic synthesis of 4-Diphosphocytidyl-2-C-methyl-D-erythritol: A substrate for IspE. Tetrahedron Letters, 4461-4463.

5. P. Narayanasamy * and D. C. Crick*. (2008). Enantiomeric Synthesis of 2-C- Methyl-D-erythritol 2, 4- cyclodiphosphate. Heterocycles, 76, 243.

6. D. C. Crick, P. Narayanasamy, and M. Kurosu. (2008). High throughput synthesis of substituted hydrazine derivatives. Heterocycles, 169-176.

2 7. D. C. Crick, P. Narayanasamy, K. Biswas, and M. Kurosu. (2007). Acid and base stable esters: A new protecting group for carboxylic acids. Synthesis, 2513-2516.

8. D. C. Crick, P. Narayanasamy, K. Biswas, R. Dhiman, and M. Kurosu. (2007). Discovery of 1, 4-dihydroxy-2-naphthoate prenyl transferase inhibitors: New drug leads for Multidrug-Resistant gram-positive pathogens. Journal of Medicinal Chemistry, 3973-3975.

9. D. C. Crick, P. Narayanasamy, and M. Kurosu (2007). Synthetic studies toward the generation of uridine-amino alcohol based small optimized libraries. Heterocycles, 72, 339-352.

10. D. C. Crick, S. Mahapatra, P. Narayanasamy, and M. Kurosu. (2007). Chemoenzymatic synthesis of Park’s nucleotide: toward the development of high- throughput screening for MraY inhibitors. Tetrahedron Letters, 48, 799-803.

11. K. Fraunhoffer, P. Narayanasamy, L. Sirois, and M. C. White. (2006). Macrolactonization via hydrocarbon oxidation. Journal of American Chemical Society, 128, 9032-9033.

12. M. S. Chen, P. Narayanasamy, N. Labenz, and M. C. White. (2005). Serial ligand catalysis: A highly selective allylic C-H oxidation. Journal of American Chemical Society, 127, 6970-6971.

13. M. P. Sibi, Z. Ma, K. Itoh, P. Narayanasamy, and C. Jasperse. (2005). Enantioselective cycloadditions with ,-disubstituted acrylimides. Organic Letters, 7, 2349-2352.

14. M. P. Sibi and P. Narayanasamy. (2004). Chiral relay in enantioselective conjugate radical additions using pyrazolidine templates. How does metal geometry impact selectivity? Synthetic Letters, 13, 2421-2424.

15. M. P. Sibi, P. Narayanasamy, S. Ghorpade, and C. Jasperse. (2003). Enantioselective synthesis of ,-disubstituted -Amino acids. Journal of American Chemical Society, 125, 11796-11797.

16. P. Narayanasamy and G. Sundararajan. (2002). Asymmetric Michael addition reactions using La-Na heterobimetallic chiral catalyst. Tetrahedron: Asymmetry, 13, 1053-1058.

17. G. Sundararajan and P. Narayanasamy. (2001). A new polymer-anchored chiral catalyst for asymmetric Michael addition reactions. Organic Letters, 3, 389-392.

18. G. Sundararajan, P. Narayanasamy, and B. Varghese. (2001). First asymmetric synthesis of quinoline derivatives by Inverse Electron Demand (IED) Diels-Alder reaction using chiral Ti(IV) complex. Organic Letters, 3, 1973-1976.

3 ABSTRACTS

1. H. Eoh, P. Narayanasamy, P. J. Brennan and D. C. Crick*. Characterization Of Mycobacterium tuberculosis 4-diphosphocytidyl-2C-methyl-D-erythritol Kinase As A New Drug Target. ICAAC/IDSA 46th Annual Meeting. Washington D.C.

2. P. Narayanasamy, H. Eoh, P.J. Brennan, and D. C. Crick. (2008). 2-C-Methyl-D- Erythritol 2,4-Cyclodiphosphate Synthase: Synthesis of Substrate, Assay Development, and Partial Characterization. Rocky Mountains Regional Centers of Excellence for Biodefense and Emerging Diseases Research, Bozeman, Montana.

3. D. C. Crick, H. Eoh, and P. Narayanasamy. (2008). IspE – Substrate synthesis, characterization and development of a high through-put screen. Fifth National Meeting of the Regional Centers of Excellence for Biodefense and Emerging Diseases, Chicago.

4. K. Fraunhoffer, P. Narayanasamy, L. Sirois, & M. C. White. (2007). Hydrocarbons to macrolactones. American Chemical Society 233rd National meeting, Chicago, Book of Abstract, orgn. 26.

5. P. Narayanasamy & G. Sundararajan. (2000). Polymer chiral catalyst for asymmetric Michael addition reactions. National Conference in Polymers & Composites: ‘Macro 2000’, Defense Materials, Stores R&D Establishment, Kanpur. Proceedings of Recent Advances in Polymers & Composites, 229-232.

6. P. Narayanasamy & G. Sundararajan (2000). Asymmetric Michael addition using a new heterobimetallic chiral catalyst, 2nd National Symposium in Chemistry, IICT, Hyderabad, Book of Abstract, p-127.

7. P. Narayanasamy & G. Sundararajan. (1998). Inverse Electron Demand Diels- Alder reactions using C2 symmetry ligated titanium (IV) derivative. International Symposium on Metallo-organic Chemistry at the Dawn of the 21st Century, University of Rajasthan, Jaipur. Book of abstract, p-35.

MINI REVIEW

P. Narayanasamy and G. Sundararajan (2002). Asymmetric Michael addition reactions using heterobimetallic chiral catalyst bearing amino diolate. Arkivoc, (VII), 212-226.

ACKNOWLEDGEMENTS OF MY EXPERIMENTAL CONTRIBUTIONS

1. M. P. Sibi (2004). Enantioselective total synthesis of (-) Stemomide. Synthetic Letters, 1211-1214.

4 2. D. C. Crick and M. Kurosu (2007). Polymer supported (2,6-dichloro-4- alkkoxyphenyl) (2,4-dichlorophenyl) methanol: A new linker for solid-phase organic synthesis. Organic Letters, 9, 1141-1144.

PATENT

1. P. Narayanasamy and D.C. Crick (2008) Sulfonamide derivatives as IspD inhibitors and IspE inhibitors (submitted to disclosure).

2. M. P. Sibi, P. Narayanasamy, C. Jasperse, and S. Ghorpade. (2004). -Amino acids synthesis and methods and intermediates for making same. U S Patent 10/895647, Provisional Patent Docket no. 047.00040 (RFT-112).

AWARDS AND HONORS

Invited Paper Heterocycles, 2008

Invited Judge Annual Colorado Science and Engineering fair, Colorado State University, 2007 & 2008; Celebrate Undergraduate Research and Creativity Symposium, Colorado State University, 2007 & 2008

Nominated MIT’s Global Indus Technovator Award, 2006

Senior Research Fellowship Council of Scientific and Industrial Research (CSIR), 1999-2001

Invited Speaker Madras Science Association, Chennai, 2001

Invited Speaker Don Bosco Higher Secondary School, Chennai, 2000, 2001

Junior Research Fellowship Council of Scientific and Industrial Research (CSIR), 1997-1998

Lectureship University Grand Commission (UGC) & Council of Scientific and Industrial Research (CSIR), 1996

Graduate Aptitude Test All India level distinction, 1996 for Engineers

Kothari Award for First Rank, Pondicherry University, 1994 Undergraduates

5 TEACHING EXPERIENCE

Colorado State University, Fort Collins, 2007 Trained Postdoc in research techniques and development Enrolled - The Certificate for College Teaching

Harvard University, 2004-2005 Trained undergraduate and graduate students in chiral techniques Presented seminars on all literature meetings in the department

Indian Institute of Technology, Madras, India, 1997-2002 Teaching Assistant Organic Structure and Synthesis (chemistry major laboratory course) Organic Chemistry (chemistry non-major laboratory course) Organic Chemistry (chemistry non-major course)

Project Supervisor Trained undergraduates in asymmetric synthesis & & Trainer supervised research projects

Shanmugam Tutorial Center, Pondicherry, India, 1995-1996 Part time Teacher Physical, analytical, inorganic, & organic chemistry for high school and undergraduate, and organic chemistry for graduate students

PROFESSIONAL EXPERIENCE

Project Officer Reliance Industries Ltd. (overseen by Indian Institute of Technology, Madras, India), 2002

Chemist Trainee Madras Rubber Factory (MRF) Tires, 1996 (production of tires, quality assurance, research and development).

CONSULTING – TECHNICAL REPORTS

Infrared (IR) Spectroscopy Analysis for Porur Polymer Company, Chennai, 2000- 2001

Quality Assurance Plan for Sugar and By-products for Pondicherry Cooperative Sugar Mill, Pondicherry, 1996

6 SERVICE

Reviewer Journal of Organic chemistry, 2008 Royal Society of Chemistry, 2008 Tetrahedron Letters, 2002, 2008 Arkivoc, 2002 Indian National Science Academy on Asymmetric Catalysis, 2002 Tetrahedron Asymmetry, 2001, 2008 Indian Journal of Chemistry, 2001 Molecules, 2001

Symposium Macromolecules, Chennai, 2001 Organizer Indian National Science Academy, Chennai, 2000 Macromolecules, Chennai, 1998

Production Agent The special issue of the Proceedings of Indian National Science Academy on Asymmetric Catalysis (PINSA-A), 2002

Resident Secretary Indian Institute of Technology, Madras, 2000-2001

Community Service, National Service Scheme (NSS), 1993-1994; 1998-1999 Volunteer Teacher

INSTRUMENTAL AND TECHNICAL SKILLS

High Performance Liquid Chromatography (Waters and Agilent) Gas Chromatography (Agilent) Nuclear Magnetic Resonance spectroscopy (Varian) IR, UV spectroscopy and Mass Spectrometry IR reactor and Gas reactor Glove box and Fraction collector Polarimeter and Chiral resolving technique Solid phase & library molecule synthesis Total synthesis of natural products including Free radical reactions Hazardous waste management

SCIENTIFIC AFFILIATION

American Chemical Society

7 Research summary

Part A: 1. Synthesis of MEP pathway intermediates. Since the MEP pathway is not found in human cells it is considered as a good target for the development of antimicrobials, antimalarial and herbicidal agents, a hypothesis being explored by many researchers. However, a major impediment in this area is the lack of availability of pure substrates. Access to MEP pathway intermediates and their analogues are essential to ongoing biochemical investigations and development of new antibiotics targeting the respective enzymes. Recently we reported kinetic studies of mycobacterial DXS, IspC, and IspD. To study the IspE, we are in need of CDPME So, I synthesized enantiomerically pure CDPME. MEP is synthesized from commercially available isopropylidene xylofuranose and coupled with cytidine monophosphate. The coupling is also done with IspD enzyme with moderate yield Tetrahedron Letters, 2008, 4461-4463. In order to extend our research to include IspG, we were in need of compound MECPP. I synthesized MECPP from commercially available isopropylidene xylofuranose involving diphosphorylation, Heterocycles, 2008.

N H 2

N - O P O H O O N O O O P P O O O - O - O - O P O O O O O H O H H O O H O H O H

2. Discovery of prenyl transferase inhibitors- new drug lead

Since utilization of menaquinone in the electron transport system is a characteristic of Gram-positive organisms, the MenA inhibitors, act as selective antibacterial agents. Growth of drug resistant Gram-positive organisms was sensitive to the MenA inhibitors, indicating that menaquinone synthesis is a valid new drug target in Gram-positive organisms. we have shown, for the first time, that MenA inhibitors, exhibited growth of drug resistant Mycobacterium spp. and other Gram-positive bacteria at low concentrations. The MenA inhibitors described here can be synthesized cost-effectively and structural modifications to improve the inhibitory activity in vitro can be achieved in a time efficient manner. The results are expected to be of significance in terms of discovering new lead molecules that can be developed into new drugs to combat Gram-positive pathogens. J. Med. Chem. 2007, 3973-3975

H 2 N

F O O H D M F , N a H C O 3 O O H

H O B r O N C l O C l O F

8 3. Solid phase synthesis of hydrazine derivatives

We recently validated that MenA (1,4-dihydroxy-2-naphthoate prenyltransferase)1, the sixth enzyme in menaquinone biosynthesis, is a novel target for the development of new drug leads for MDR Gram-positive pathogens.2 In the discovery of MenA inhibitors, we have generated a library of molecules based on the 4-alkoxydiphenylmethanones which contain tertiary, secondary amines and hydrazines. Regioselective alkylations of the hydrazine derivatives are achieved by using the (2,6-dichloro-4-methoxyphenyl)(2,4- dichlorophenyl)methoxycarboxyl resin. Heterocycles 2008, 169.

O N H R 1 B r N R 2 C l O C l C l 2 0 % T F A N H N H R 2 P o l y m e r C l C l C l O 7 C O N H p o l y R 2 = H , M e , P h R 1 = B o c R 2 = H , M e , P h

Part B:

1. Synthesis of Macromolecules by allylic oxidative cyclization

Macromolecules are very important in common because it has significant characteristics of chemical nature. These Macromolecules can be synthesized by different methods of cyclization. Our group was successful in doing cyclization by allylic oxidation method. The Same Allylic C-H oxidation method is used for cyclization in compounds containing chiral backbone, leading to synthesize macromolecules of peptides and bisindoles J. Am. Chem. Soc., 2006, 128, 9032-9033.

O N O O N O N H H N H O N N O O H 3 C O O O O O O 5 H 3 C O H O O O

2. Highly regioselective internal C-H oxidation using new sulfoxide ligand and Benzoquinone –by serial ligand catalysis

C-H oxidation at the internal position of terminal olefins was carried out with new category of sulfoxide ligand leading to high selectivity over wacker product or linear product. Varies substrates and carboxylic acids were successfully used leading to 60-85 % yield (of biologically important compounds), and more than 95:5 selectivity and studied part of the mechanism leading to serial ligand catalysis concept. J. Am. Chem. Soc., 2005, 127, 6970- 6971.

9 O S

O O C R ' 1 0 m o l % P d ( O A c ) 2 R R d i o x a n e , B Q , 4 0 oC R ' C O O H

3. A new asymmetric C-H oxidation method using chiral Chromium(III) complex. Asymmetric C-H oxidation is an important method to make biologically active small molecules and complex molecules. In this regard now we are able to make asymmetric C-H oxidation with high yield (95%) and moderate enantioselectivity using chiral chromium(III) salen catalyst as a chiral Lewis acid. O S O 1 0 m o l % P d ( O A c ) 2 O R T B M E , C H 3 C O O H 4 3 o C , B Q

H H N N C r O O C l

Part C:

1. Enantioselective synthesis of -amino acids (biologically active compounds)

Development of new and novel methodologies for the synthesis of ,-disubstituted - amino acids has received considerable attention in recent years. A novel catalytic method for the preparation of  ,  -disubstituted  -amino acids has been developed in our laboratory (Mukund P. Sibi, Narayanasamy Prabagaran, Sandeep Ghorpade and Craig Jasperse, J. Am. Chem. Soc., 2003, 125, 11796-11797). We surmised that rotomer control for the substrate combined with concerted addition of N-benzylhydroxylamine to ,-disubstituted and unsaturated imides in the presence of a chiral Lewis acids (prepared from Mg(NTf2)2 and bisoxazoline) provided 70-95 % yield, 90-95 % de and 80-95 % ee.

O O M g ( N T f 2 ) 2 O O H 2 N R ( S , R ) c y c l o p r o p y l i n d e n e b o x N P d / C , d i o x a n e , H 2 N R H N - b e n z y l h y d r o x y l a m i n e R ' 6 0 C , 1 6 h H O O C R ' C H 2 C l 2 . - 4 0 ÞC R ' R

O O R = a l k y l , p h e n y l N N R ' = a l k y l , p h e n y l , B r , F , a l k o x y

Using this method we are able to synthesize,  -fluoro (halo) substituted  -amino acids and

10  -alkoxy substituted  -amino acids in good yield. We are also able to alkylate the - position to obtain -quaternary centered -amino acids. Other diastereomer of the isoxazolidinone can be synthesized by isomerisation of the obtained isoxazolidinone by forming enolate ion with lithium base and quenching the enolate ion with aceitic acid at lower temperature (58 % yield).  ,  ’,  -trisubstituted  - amino acids also can be synthesized by addition of electrophile to the lithium enolate ion.

O N - 7 8 ÞC , L i H M D S , 1 h O N H O - 9 8 ÞC , a c i d , 5 m i n O H R ' R ' H R H R We extended our methodologies for the synthesis of  -substituted  -amino acids and  - substituted  -amino acids which is being given more importance in recent years. This process also involves the conjugate addition of N-benzylhydroxylamine to the respective substituted and unsaturated imides using catalytic amounts of a chiral Lewis acids prepared from Mg(NTf2)2 and bisoxazoline leading to 75-85 % yield and 70-95 % ee.

2. Asymmetric Diels-Alder reaction-disubstituted dienophile-MMP inhibitor As an extension of the above synthesised ,-disubstituted unsaturated imides, they were used as dienophiles in Diels-Alder reaction. The highly functionalized Diels-Alder adducts were obtained in good yield(75% ) and enantioselectivity(80 % ee). (For MMP inhibitor sudy) Org. Lett. 2005, 7, 2349-2352.

O O S c ( O T f ) 3, C H 2C l 2 O O R N + N H - 4 0 C , 2 4 h N N O N H l i g a n d O R

3. Enantioselective conjugate radical addition –using chiral relay (for mechanistic study). conjugate radical addition reaction was successfully carried out using Cu(II) Lewis acids leading to 99 % enantioselectivity and chiral relay technique is used to study the effect of metal geometry in the impact of enantioselectivity. Syn. Letters, 2004, 13, 2421-2424. (compounds also can be used for MMP Inhibitor)

O O O O R R I , B u 3S n H , E t 3B , O 2 N P h N P h o N C u ( O T f ) 2, C H 2C l 2, - 7 8 C N P h P h O O N N

11 Part D:

1. First asymmetric synthesis of quinoline derivatives

Amino diol, I was synthesized and single crystal XRD of this ligand was taken. Amino diol, I was complexed with titanium alkoxide to prepare a chiral titanium complex. This complex was used for promoting asymmetric inverse electron demand Diels-Alder reaction. This favours the reaction for synthesis of chiral quinoline derivatives (Org. Lett. 2001, 3, 1973-1976). The reactions were carried out in different solvent medium, temperature, wt % of molecular sieves and other supporting catalyst. The reaction conditions were optimized, which led to optimum yield and high enantioselectivity (65 % yield and 92 % ee). 1 R R1 2 2 R1 o R R 1-TiCl2 , 4A MS + + N toluene:dcm R2 N Ph N Ph H H P h P h P h N 1 2 O O R , R = (-OCH2CH2-), (-OCH2CH2CH2-), (-CH=CH-CH2-), (-OCH2CH3, H) T i C l C l 1 - T i C l 2 2. New polymer anchored chiral catalyst for asymmetric Michael addition of amines and nitro alkanes for amino acid

To use the ligand more economically and stereoselectively we synthesised polymer anchored chiral catalyst which was designed by vinylating the present amino diol. This vinylated amino diol was synthesized by different methods and different chiral polymeric ligand was synthesised by varying the ratio of comonomer and its activity towards the asymmetric Michael addition reactions were also studied. Michael addition reactions of nitromethane to chalcone led to high yield and enantiomeric excess at less time. Michael addition reactions of thiols to cycloalkenones were carried out resulting in high enantiomeric excess (Org. Lett. 2001, 3, 389-392). Michael addition reactions of amines were also carried out and led to good yield and enantioselectivity (for beta –amino acids). These polymeric chiral ligands are reusable and this method also provides very easy way of purification of products. 75 % yield and 82 % ee. Y O O Ph R Ph R HY LiAl-poly2a Y : -CH2NO2, -NHCH2Ph O THF HX Ph R' O

n n X Ph R'

12 3. Glucose sensor- molecular imprinting technique.

As an extension of our asymmetric synthesis, we attempted the design of a glucose sensor by applying molecular imprinting technique. Here methyl-D-glucopyranoside was used as a template for imprinting. After the organometallic monomer (vinyl amino diol-Cu- glucopyranoside) was synthesized it was polymerized with N,N’-methylene bisacrylamide, a crosslinking reagent using an initiator. The template was leached out of the polymer matrix to obtain a glucose molecule imprinted polymer. The imprinted polymer was capable of sensing glucose. However it also sensed other carbohydrates. So, to increase the selectivity, an enzyme was added before polymerization and was used for sensing purposes.

* p

q * p O

q P h P h H N O N O O H N O P h P h H N C u N O O H O H H N O O H C u S O 4 H 2 O O H r D - G l u c o s e H H r H H O O H n O H

n

13