PRABAGARAN (PRABA) NARAYANASAMY
Department of Microbiology, Immuno. & patho.
Colorado State University
1682 Campus Delivery
Fort Collins, CO 80523-1682
Cell : 617-230-2411
email: Praba@colostate.edu
office: 970-491-6789
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
Scientist
Colorado State University
Medicinal chemist - Drug design and discovery
Advisor: D.C. Crick


Post-Doctoral
Fellow

Post-Doctoral
Fellow
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).
Harvard University &
University of Illinois, Urbana-Champaign
Advisor: M. C. White


2004-2006
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
North Dakota State University
Advisor: Mukund P. Sibi

2006 - present
2002-2004
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
Organic chemistry, Advisor: G. Sundararajan
2002
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
Chemistry (with Distinction)
1996
P.G.D.S.D.
Brilliant Computer Center, Pondicherry, India
Computer Science & Applications (with Distinction)
1994
B.Sc.
Pondicherry University, Pondicherry, India
Chemistry
1994
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). 4Diphosphocytidyl-2-C-Methyl-D-Erythritol Synthase from Burkholderia,
Salmonella, and Vibrio Species (submitted).
3. P. Narayanasamy* and D. C. Crick*. (2008). Enantiomeric Synthesis of 4Diphosphocytidyl-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-CMethyl-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 highthroughput 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-DErythritol 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 DielsAlder 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-4alkkoxyphenyl) (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
for Engineers
All India level distinction, 1996
Kothari Award for
Undergraduates
First Rank, Pondicherry University, 1994
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
& Trainer
Trained undergraduates in asymmetric synthesis &
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, 20002001
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
Organizer
Macromolecules, Chennai, 2001
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.
NH2
N
OH
OH
OH
O
O
P
P
O -O -O
O
O
N
-O
O P
O
O
O
O
O
HO
OH
OP
O
OH OH
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
H2N
O
Cl
DMF, NaHCO3
OH
O
O
F
Br Cl
O
OH
O
O
H
N
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)(2,4dichlorophenyl)methoxycarboxyl resin. Heterocycles 2008, 169.
NHR1
NR2
Cl
O
Cl
O
Br
Cl
20% TFA
NHNHR2
Polymer
Cl
Cl
Cl
O
7CONHpoly
R2 = H, Me, Ph
R1 = Boc
R2 = H, Me, Ph
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.
N
O
N
O
O
HN
N
N
H
N
O
O
H3CO
O
H
O
O
O
O
O
O
H3CO
O
H
5
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, 69706971.
9
O
S
OOCR'
10 mol%Pd(OAc)2
R
R
dioxane, BQ,40oC
R'COOH
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
10 mol%Pd(OAc)2
TBME, CH3COOH
43oC, BQ
H
O
R
H
N
N
Cr
O
Cl
O
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
N
H
Mg(NTf2)2
(S,R )cyclopropylindenebox
O
O
N
Pd/C, dioxane, H2
H2N
R
HOOC
R'
R
R'
N-benzylhydroxylamine
CH2Cl2. -40 ÞC
O
O
N N
R'
R
60 C, 16 h
R = alkyl, phenyl
R' = alkyl, phenyl, Br, F, alkoxy
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
-78 ÞC, LiHMDS,1h
H
R'
O
HR
-98 ÞC, acid, 5 min
O N
H
R'
O
HR
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
R
O
Sc(OTf)3, CH2Cl2
+
N
H
O
-40 C, 24h
N
O
O
N
N
NH
O
R
ligand
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, 24212424.(compounds also can be used for MMP Inhibitor)
O
N
N
O
O
RI, Bu3SnH, Et3B, O2
Ph
Cu(OTf)2, CH2Cl2, -78oC
Ph
N
N
O
R
Ph
Ph
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).
R1
1
1-TiCl2 , 4A MS
toluene:dcm
+
2
R
R2
R
o
R
N
R1
2
+
N
H
Ph
N
H
Ph
Ph
Ph
R1, R2 = (-OCH2CH2-), (-OCH2CH2CH2-), (-CH=CH-CH2-), (-OCH2CH3, H)
Ph
N
O
Ti
Cl Cl
1-TiCl2
O
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
Ph
R
Ph
HY
O
X
H
n
Ph R
'
LiAl-poly2a
THF
O
R
Y : -CH2NO2, -NHCH2Ph
O
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-Cuglucopyranoside) 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.
*
*
q
p
Ph
q O
Ph
N
OH
p
Ph
OH
O
HN
HN
O
CuSO4H2O
D-Glucose
O
Cu
O
O
H
H
r
HO
H
n
Ph
N
H
OH
O
HN
HN
O
r
H
O
OH
n
13