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Azabicyclic Compounds | N-Nitrosopiperidines | CHEMISTRY

JEYARAMAN

PIPERIDINE CHEMISTRY

Ramasubbu Jeyaraman (RJ)
5280, NW 126th Terrace, Portland, OR 97229
Phone: 503-465-4142; mobile: 503-332-7875

List of Publications
Ramasubbu Jeyaraman (RJ)
5280, NW 126th Terrace, Portland, OR 97229
Phone: 503-465-4142; mobile: 503-332-7875
email: chemrj@gmail.com ; rjchem@yahoo.com
Member of ACS: 01760037

===== Highlights =====
Organic Chemist (PhD in Chemistry and MS in Computers (MCA)
Over 30 years of Research experience in Organic Chemistry.
Over 20 years of experience in IT and Computer applications.
Experience in Informatics as applied to Drug discovery.
Specialized in Organic Synthesis and Drug Discovery
Areas of Research work:
Organic Synthesis, Heterocyclic compounds, Dioxiranes,
Stereochemistry, Conformational analysis, Nitrenium ions,
carcinogenesis, anticancer drugs and antihypertensive drugs,
Analytical Methods, Spectroscopy, Chromatography,
Molecular Modeling, Computational Chemistry, and Data Analysis
Software development
Worked at Clemson University and University of Missouri-St. Louis, USA (1981-86, 1988, 1989).

===== Education =====
PhD: Organic Chemistry
MS: Computer Applications (M.C.A)
MS: Organic Chemistry
BS: Chemistry (Physics, & Mathematics)

===== Recognitions =====
High citation ranking. In the top 1% of world Chemists, in terms of Publication impact and discovery: (Source: Science Citation Index compilation for 1981-97 period + ISI’s citation counts till April 2005).
Listing of the work on dimethyldioxirane in Encyclopedia Britannica year book as one of the most pioneering discoveries in 1985.
High impact papers: A paper published in 1985 continues to be one of the most referred articles in Chemistry. Listed in “100 Most-Accessed Articles from ACS Journal Archives in 2004” by ACS.



===== Achievements =====
1968-78: First synthesis of 2,4-diphenyl-3-azabicyclo[3.3.1]nonan-9-one. The synthesis of this compound has been attempted from the time of Mannich, including Professor Baliah at Stanford, several researchers at Annamalai University. Strategic manipulation of the reaction conditions yielded the compound and a number of similar structures. The reaction conditions were made very simple subsequently. Solved the structures of two other groups of compounds, which remained unsolved for decades.
1978-81: American College: Started a Research Laboratory. Established a research laboratory. First publications from the department. The first funding for a project from University Grants Commission. Publications included papers in Synthesis, two reviews in Chemical Reviews and one chapter in Synthetic Reagents, a Wiley book. The 11 publications from the department was considered a remarkable achievement.
1981-82: Clemson University: (with Prof. R.A. Abramovitch): Successful completion of intramolecular cyclizations involving nitrenium ions. A review on nitrenium ions (Academic Press) was written. First experience with PCs and PC-controlled instruments, worked with many GC, HPLC, IR, NMR instruments.
1983-86: University of Missouri - St. Louis (with R. W. Murray): Isolation of dimethyldioxirane may be considered as a discovery (Most accessed paper). Showed the relationship of dioxirane with environmental carcinogenesis.
1986-2004: Bharathidasan University: Discovered the connection between rotation barrier and anticancer activity of N-nitrosopiperidines (NCI/NIH). Found new rearrangements, new reagents and reactions. Several applications of computers and software codes were developed, postulated a new hypothesis for antihypertensive drugs and anticancer mechanism. A few leads are in hand out of the molecular modeling and drug discovery applications.

=====Expertise =====
Synthesized a variety of organic compounds, including dimethyldioxirane, azabicyclic compounds, N-nitrosopiperidines, teterahydrobenzopyrans, tetrahydrobenzodiazepines, oxygenated polycyclic aromatic hydrocarbons,
Can handle Research Management, Spectroscopic Analysis, IT aspects, Decision support systems, Informatics, Drug Discovery and Modeling, software codes for data analysis of combinatorial library screening data, and any aspect of Computer Applications to Science and Medicine.
Teaching experience: Organic reaction mechanisms, Spectroscopy, Programming languages, Computer-aided Chemistry, Synthetic Methods, Medicinal Chemistry, Computational Techniques, and Molecular Modeling. Rated as one of the best teachers in the University


===== Work Experience =====
Well versed in handling GC, HPLC, IR, and NMR instruments and Computers.
Well versed in handling computers, workstations and PC-based instruments.
Good experience in C, C++, Fortran, Oracle (one paper each in MS);
Moderate knowledge of many other languages. including SPL of Tripos..
Knowledge of various operating systems, DOS, Windows, Unix, etc.,
Good Experience in Computational Methods in MOPAC, SYBYL, Cerius2,.
Moderate experience in Informatics as applied to Drug discovery
Spectroscopic analysis, data analysis.
Strong in structure determination of organic compounds and mixtures.
Some exposure to X-ray crystal determination of single crystals.
Strong in advanced NMR techniques.
Strong in modern synthetic methods and Conformational Analysis.
Strong Experience in troubleshooting and performance improvement of PCs.
Synthesis of drug intermediates.
Head assembly replacement and data recovery from broken hard disks.
Some experience in modern business applications and forecasting.
Good in installation of operating systems, Windows, Unix, Linux, IRIX.
Good in installation and maintenance of network.
Good in comparison and purchase decisions
Maintained uptodate knowledge of computer systems and peripherals.

===== My top 10 Citations (as of April 2005) =====
Times Cited; Cited Work; Year; Volume; Page
562 J ORG CHEM 1985 50 2847
103 J AM CHEM SOC 1986 108 2470
94 CHEM REV 1981 81 149
91 J ORG CHEM 1987 52 746
77 TETRAHEDRON LETT 1986 27 2335
67 CHEM REV 1983 83 379
65 J AM CHEM SOC 1984 106 2462
44 J AM CHEM SOC 1992 114 1346
41 INDIAN J CHEM 1971 9 1020
36 J ORG CHEM 1991 56 4833




===== Citation ranking among world scientists =====
One of the top 10858 most cited Chemists (1981-1997). There were 627,871 unique author names found in a survey conducted on all scientific articles published during 1981-1997. Only 10,858 (1.7%) unique authors were cited 500 times or more. **
Rank among 10858 Chemistry authors whose citations are 500 or more : Top 2032; till 1997;
% Rank among total Chemistry authors: Top 0.85 % (as in 1997). That is within the top 1 %.
One of the most cited authors in India in scientific publications.
One of the most referred Indian authors in India in textbooks like Jerry March.

** Sources: http://sdpd.univ-lemans.fr/chimie/chimistes.html (See notes by D. Pendlebury); http://www-public.tu-bs.de:8080/~gdanitz/isi/sort.txt (sorted by author names): Title: ISI’s 10858 Most Cited Chemists, 1981-June 1997, ranked by total citations:

===== Major Discovery: =====
First isolation of Dimethyldioxirane: Major discovery is the isolation of solutions of Dimethyldioxirane, a powerful stereoselective oxygen transfer agent, which is considered the best mimic for monooxygenase enzymes. It also brings about a number of selective oxidations and oxygenations in an amazingly simple way. See item # 38 in: “100 Most-Accessed Articles from ACS Journal Archives in 2004”: ttp://pubs.acs.org/archives/articles2004.html. (38th item in the list is “Dioxiranes: synthesis and reactions of methyldioxiranes, Robert W. Murray, Ramasubbu Jeyaraman, J. Org. Chem. 1985, 50(16), pp 2847-2853.”)


===== Papers Published (list enclosed below) =====
Journal of American Chemical Society 3
Journal of Organic Chemistry 9
Tetrahedron Let 5
Chemical Review 2
Other International foreign journals 33
Indian J. Chem. 42
Other Journals 8
Total Publications 102



===== Post-Doctoral Research: =====
Research Associate: Aug’81-Dec’82: Clemson University, Clemson, SC-29631 USA: Worked with Professor R.A. Abramovitch, Professor & Chairman. (Area: Research on azides and nitrenium ion intermediates).
Research Associate: Jan’83-Jul’86: University of Missouri-St.Louis, St.Louis, MO 63121, USA: Worked with Professor R. W. Murray, Senior Professor in Chemistry. (Area: Studies on dioxirane chemistry, synthetic methods /involving dioxiranes, oxidation of amines to nitro compounds)
Visiting Professor 89 & 90 summer sessions University of Missouri-St.Louis, St.Louis, MO 63121, USA.

===== Positions Held: =====
1986 TO June 2005: Professor: Bharathidasan University; Teaching Organic Chemistry, Spectroscopy, Physical Organic Chemistry, Computational Chemistry, Synthetic Methods and Synthetic Analysis to M.Sc., M.Phil., and Ph.D. classes. (A variety of activities in research and development. University assignments).
1987 - 1996: Head-in-charge, University Computer Centre, Bharathidasan University, Additional charge as Head-in-charge (while being a Professor of Chemistry): Development of Computer Facilities, Software, Courses, Computerization and processing of the results of University Examinations.
1978 to 1986: Assistant Professor: The American College, Madurai: M.Sc.Organic Chemistry: Theory and Practicals, 50% of all Organic Chemistry and Advanced Chemistry classes and practicals. (1981-86: on study leave).
1973 to 1978: Assistant Professor: Annamalai University: Pre-University and Final year B.Sc. classes. About 5-6 hours of theory and about 12 hours of practicals.
1972 to 1973: Demonstrator: Annamalai University: 14-18 hours per week theory and practical classes: B.Sc. and P.U.C. Classes: Theory and Practicals.

===== Additional Positions by nomination by Government : =====
Member of the Syndicate, the highest administrative body of the University Member of the Quality Assurance Committee Member in various other committees of the University. (2003-2005)
Member, Management Committees for SAP-II and COSIST Bharathidasan University (1999-2001)
Member of the Finance Committee, Bharathidasan University (2003-2005)
Member, Armament Research Board (1997-2004).
Member of Text book Committees (1975-1979).


===== Other Positions held: =====
Member, Monitoring Committee, Sophisticated Instruments Facility, IISc, (91-94).
Member, Research Committee, Bharathidasan University (till 1999).
Chairman or member of several Inspection Commissions & Selection Committees (periodic assignments).
Member, Boards of Studies in Chemistry (two years)
Member, Boards of Studies in Computer Science. (two years)

===== Research Projects Completed: =====
Funding agencies: University Grants Commission: UGC; Department of Science and Technology: DST; DRDO: Defence Research & Development Organization: DRDO; Council of Scientific and Industrial Research: CSIR; Period; Title and amount in Indian Rupees (INR) are listed.
UGC: 2001-2004: Title: Stereodynamics of N-substituted Enantiomeric Piperidines and Piperazines in relation to Selectivity Mechanisms in Drug Action: INR 300,000
DST: 1999-2002: Title: Conformations and Binding Potentials of Antihypertensive Drugs: INR 1,700,000
DST: 1995-1998: Title: Diazacycles: Conformations, Stereodynamics, Reactivity, and Properties of Diazacyclic Compounds Possessing A1,3-strain. :INR 900,000
DRDO: 1992-1995: Title: High Energy Heterocycles: Calculations, Synthesis and Evaluation: INR. 668,000:
CSIR: 1992-1995: Title: Dioxiranes: Selectivity in the Reactions with Heterocycles, Aromatics, and Heteroaromatics: Stereochemistry and Mechanisms. INR 380,000.
UGC: 1989-1992: Title: Experimental and Theoretical Studies on some Oxidations involving Aromatic and Heterocyclic Compounds: INR 136,000
DST: 1988-1991: Title: Heterocycles: Synthesis, Stereochemistry and Reactivity INR 539,310
7 minor Research projects and 3 Industrial projects have been completed successfully and technology transferred.

===== Research Supervision =====
Ph.D. (completed): 10
M.Phil. (completed): 14
Ph.D. (current): 1
Research Associates: 2


===== PhD awardees under my guidance: =====
(Name of Student, Year of Award, Title of Thesis)
T. Ravindran: 1994: Synthesis, Stereodynamics and Reactivity of N-Nitrosopiperidines and N-Nitroso-3-azabicyclo[3.3.1]nonanes
U.P. Senthilkumar: 1994: Conformational Studies on Hexahydro-1,4-diazepines with N-X=Y groups
R. Vijayalakshmi: 1995: Studies on the Stereochemistry and Reactions of Piperidines having Heteroconjugate Groups
J.C. Thenmozhiyal: 1996: Synthesis and Stereodynamics of Piperidines and 3-Azabicyclo[3.3.1]nonan-9-ones containing N-X=Y Functions.
M. Sujatha: 1996: Synthesis and Stereochemistry of Certain spiroheterocycles
S. Ponnusamy: 1999: Stereochemistry of N-Substituted Cyclic Secondary Amines
R. Murugadoss: 2001: Conformational Preferences of N substituted Piperazines and Related Compounds.
B. Sivakumar: 2000: Investigations on a New Rearrangement of Azabicyclic Compounds and Stereochemistry of N-Substituted Heterocycles
M. Muthukumar: 2001: Conformational Studies on Certain Seven-membered Azacycles Containing N-X=Y Functions
M. Venkatraj: 2001: Conformational preferences of azacycles containing N-acyl functions



===== List of publications: =====

102. Crystal structures of a pair of benzothiazepines. Nallini, A.; Saraboji, K.; Ponnuswamy, M. N.; Muthukumar, M.; Jeyaraman, R Molecular Crystals and Liquid Crystals (2003), 393 83-93.
101. Crystal structure and conformation of a pair of piperidine derivatives. Nallini A.; Saraboji K.; Ponnuswamy M N.; Venkatraj M.; Jeyaraman R. Mol. Cryst. Liq. Cryst. 2003, 403, 57-65.
100. Crystal structure and conformation of two similar piperidones, Nalini, A.; Saraboji, K.; Ponnuswamy, M. N.; Venkatraj, M.; Jeyaraman, R. Molecular crystals and Liquid Crystals, 2003, 403, 49-56.
99. 4-Furoyl-2,3,4,5,6,7-hexahydro-r-2,c-7-diphenyl-1H-1,4-diazepin-5-one: Supramolecular aggregation through C-H...O interactions, S.Thamotharan, V. Parthasarathi, M. Muthukumar, K. Thanikasalam, R.Jeyaraman, Anthony Linden, Acta Cryst., 2003, E59, o1117-o1119.
98. r-2,c-6-Bis(4-chlorophenyl)-t-3,t-5-dimethyltetrahydropyran-4-one. Kavitha, S.J.; Sarangarajan, T.R.; Thanikasalam, K.; Panchanatheeswaran, K.; Jeyaraman, R. Acta Cryst, .2003, E59, o463-o465.
97. r-2,c-6-Bis(p-tolyl)-t-3,t-5-dimethyltetrahydropyran-4-one., Krishnamoorthy, B.S.; Sarangarajan, T.R.; Thanikasalam, K.; Panchanatheeswaran, K.; Jeyaraman, R Acta Cryst., 2003, E59, o461-o462.
96. 2-Nitroso-1,3-diphenyl-1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridine. Sivakumar, B.; Sethusankar, K., Senthil Kumar, U.P.; Jeyaraman, R.; Velmurugan, D. Acta Cryst., 2003, E59, o153-o155.
95. r-2,c-6-Bis(4-chlorophenyl)-3,5-dimethyltetrahydropyran-t-4-ol, B.S. Krishnamoorthy; T.R. Saranngarajan; K. Thanikasalam; K. Panchanatheswaran; R. Jeyaraman, Acta Cryst., 2003, E59, o111-o113.
94. 3,5 -Bis(2 -Chlorophenyl)-4-formyl-2,6-dimethylcyclohexan-1-one, T.R. Sarangarajan; K. Panchanatheswaran; K. Thanikachalam; R. Jeyaraman. Acta Cryst., 2002, E58, o1053-o1054.
93. 2,3,4,5-Tetrahydro-r-2,c-4-diphenyl-1,5-benzothiazepine, Laavanya, P.; Panchanatheswaran, K.; Muthukumar, M.; Jeyaraman, R.; Bauer, J.A.K., Acta Cryst., 2002, E58, o701-o702.
92. Crystal structure of N-nitroso-2,3,4,5-tetrahydro-2,2,4-trimethyl-1,5-benzothiazepine, C12H16N2OS. Laavanya, P.; Panchanatheswaran, K.; Muthukumar, M.; Jeyaraman, R.; Bauer, J. A. K. Z. Kristallogr. NCS217, 2002, 605-606.
91. Fast N-CO rotational equilibria in twist-boat conformations of N-ethoxycarbonyl-r-2,c-6-diphenylpiperidin-4-ones and N-ethoxycarbonyl-r-2,c-6-diphenylpiperidines. Ponnuswamy, S.; Venkatraj, M.; Jeyaraman, R.; Sureshkumar, M.; Kumaran, D.; Ponnuswamy, M.N., Indian J. Chem., 2002, 41B, 614-627.
90. N6-acetyl-5,7-diphenyl-5,6,7,8-tetrahydro-benzo[b]-1,6-naphthyridine P. Laavanya, K. Panchanatheswaran, B. Sivakumar, R. Jeyaraman, J. A. K. Bauer, , Acta Cryst, ., 2001, E57, o599-o601.
89. Crystal and Molecular Structure of the monothioketal of 2,4-diphenyl-3- azabicyclo[3.3.1] nonan-9-one P. Laavanya, K. Panchanatheswaran, M. Sujatha, R. Jeyaraman, N. K. Lokanath, J. Shashidhara Prasad, , Indian J. Chem., 2001, 40B, 299-302.
88. Chemical Characterization of Bovine Urine with Special Reference to Oestrus, K. Ramesh Kumar, G. Aruchunan, R. Jeyaraman and S. Narasimhan, Verterinary Research Communications, 2000, 24, 445-454.
87. 2,4-bis(o-tolyl)-3-azabicyclo[3.3.1]nonan-9-one. Vijayalakshmi, L.; Parthasarathi, V.; Venkatraj, M.; Jeyaraman, R. Acta Cryst. C 2000, C56, 1240-1241.
86. Influence of competing A1,3 strain on the conformational preferences of N1,N4-diformylpiperazines. Jeyaraman, R.; Murugadoss, R., Indian J. Chem., 2000, 39B, 826-835.
85. Stereochemistry of N-Formyl-cis-2,4-diaryl-3-azabicyclo[3.3.1]nonanes, Jeyaraman, R.; Thenmozhiyal, J. C.; Murugadoss, R.; Venkatraj, M.; Laavanya, P.; Panchanatheswaran, K.; Bhadbhade, M, Indian J. Chem., 2000, 39B, 497-503.
84. Stereodynamics of diheteroarylpiperidines and their derivatives, R,Jeyaraamn; J.C.Thenmozhiyal; R.Murugadoss and M.Muthukumar J. Indian Chem. Soc. 1999, 76, 527-536.
83. Molecular Structures and Conformations of Three 3-Azabicyclononanes. Kumaran, D.; Ponnuswamy, M.N.; Shanmugam, G.; Ponnuswamy, S.; Jeyaraman, R.; Shivakuamr, K.; Fun, H.K., Acta Cryst, allogr. B, 1999, 55, 793-798.
82. Crystal structure and conformational analysis of N-formyl and N-nitroso derivatives of piperidinone. Kumaran, D.; Ponnuswamy, M. N.; Shanmugam, G.; Thenmozhiyal, J. C.; Jeyaraman, R.; Panneerselvam, K.; Soriano-Garcia, M., J. Chem. Crystallography, 1999, 29, 769-775.
81. 1-acetyltetrahydro1,2,3,4-tetrahydro-4-methyl-2,4-diphenyl-5H-1,5-benzodiazepine, Laavanya, P.; Panchanatheswaran, K.; Venkatraj, M.; Jeyaraman, R.; Marshall, W. Acta Cryst. C, 1999, C55,1355-57.
80. 1,4-Diformyl-t-5-methyl-r-2,t-3-diphenylpiperazine-1,4-dicarbaldehyde, Laavanya, P.; Panchanatheswaran, K.; Murugadoss, R.; Jeyaraman, R. Acta Cryst. 1999, C55, 410-411.
79. Influence of A1,3-strain on the conformational preferences and stereodynamics of N-formyl-cis-2,6-diarylpiperidines, Jeyaraman, R.; Thenmozhiyal, J. C.; Murugadoss, R.; Venkatraj, M, Indian J. Chem., 1999, 38B, 325-336.
78. Lowering of Bohlmann band intensities in conformationally homogeneous 2,6-diarylpiperidines due to ring distortion, Jeyaraman, R.; Ravindran, T.; Sujatha, M.; Venkatraj, M. Indian J. Chem., 1999, 38B, 52-55.
77. Ethyl 3,5-dimethyl-4-oxo-cis-2,6-diphenylpiperidine-1-carboxylate, Kumar, M.S.; Ponnuswamy, M.N.; Ponnuswamy, S.; Jeyaraman, R.; Paneerselvam, K.; Sorianogarcia, M., Acta Cryst, allogr. C, Cryst. Str., 1998, 54, 870-872.
76. Stereochemistry of 4-cyano-4-phenylamino-2,6-diphenylpiperidines, Jeyaraman, R. Ponnusamy, S.; Indian J. Chem., 1998, 37B, 224-29.
75. Fast eqilibrium in Twist-boat Conformations of N-Ethoxycarbonyl-r-2-c-7-diphenylhexahydro-1,4-diazepin-5-ones in Flattened Boat Conformations, Jeyaraman, R. Ponnusamy, S.; Ponnusamy, M.N. J. Org. Chem. 1997, 62, 7984-7990.
74. Stereochemistry of N-acetyl-r-2,c-4-diphenyl-3-azabicyclo[3.3.1]nonanes and N-ethoxycarbonyl-r-2-c-4-diphenyl-3-azabicyclo[3.3.1]nonane, Jeyaraman, R.; Ponnusamy, S. Indian J. Chem., 1997, 36B, 730.
73. Kinetic and theoretical studies on the reaction of phenacyl bromide with 4dmap in the presence of certain phenols. Pillay, M.K.; Jeyaraman, R.; Nallu, M.; Venuvanalingam, P.; Ramalingam, M, Indian J. Chem., 1997, 36A, 414-7.
72. Structural characterization of 2,6-di(2-thienyl)-3,5-dimethyl piperidin-4-one (DTMP) in solution and solid state. Sukumar, N.; Ponnuswamy, M. N.; Thenmozhiyal, J. C.; Jeyaraman, R., J. Chem. Crystallography, (1995), 25(4), 177-9.
71. Chemistry of N-nitroso compounds. 7. Conformational preferences of hexahydro-N,N-dinitroso-2,7-diphenyl-1H-1,4-diazepines. Use of modified 1D HOHAHA and NOE Techniques. Jeyaraman, R.; Senthilkumar, U.P.; Bigler, P., J. Org. Chem., 1995, 60, 7461-70.
70. Nirdosh, I., Muthuswami, S. V., Natarajan, R. and Jeyaraman, R., Dev. Chem. Eng. Miner. Process, 1994, 4, 202-217.
69. Crystal and Molecular Structure of 3,5-dimethyl-N-Nitroso-2,6-diphenylpiperidin-4-one oxime Sukumar, N.; Ponnusamy, M. N.; Vijayalakshmi, R.; Jeyaraman, R. Z. Kristallogr. 1994, 209, 823.
68. Structural Investigation of 2,6-Di-2-furyl-3,5-dimethyl-4-piperidinone and its N-nitroso derivative in solution and in the solid state - Influence of the Nitroso moity on the conformation of the piperidine ring and orientation of its substituents. Sukumar, N.; Ponnusamy, M.N.; Thenmozhiyal, J.C.; Jeyaraman, R.; Bull. Chem. Soc. Jpn., 1994, 67, 1069-1073.
67. A new Rearrangement of 2,4-Diphenyl-3-azabicyclo[3.3.1]nonan-9-one leading to 8,10-diphenyl-1,9-diazabicyclo[5.3.0]decan-2-one, R. Jeyaraman, U. P. Senthilkumar, Tetrahedron Lett. 1994, 35, 9279-80.
66. t-3-Isopropyl-r-2,c-7-diphenylhexahydro-1,4-diazepin-5-one, C20H24N2O, Ravikumar, K.; Rajan, S.S.; Parthasarathi, V.; Thiruvalluvar, A.; Jeyaraman, R.; Senthilkumar, U. P., Acta Cryst. 1994, C50, 827-829.
65. High Energetic High Density Materials: A Basic Program (FCALC) for the Design and Selection of Efficient High Energy Materials containing Nitro and Azido Groups, Senthilkumar, U.P.; Vijayalakshmi, R.; Jeyaraman, R., Propellants, Explosives, Pyrotechnics, 1994, 19, 295-299.
64. Structure of N-nitroso-2,4-diphenyl-3-azabicyclo[3.3.1]nonane, Priya, V.; Shamala, N.; Viswamitra, M.A.; Ravindran, T.; Jeyaraman, R.; Acta Cryst. (c), 1993, C49, 1519-22.
63. Crystal and Molecular Structure of 2,6-Di(o-Chlorophenyl)-3,5-dimethyl-N-nitrosopiperidin-4-one, Sukumar, N.; Ponnusamy, M.N.; Thenmozhiyal, J.C.; Jeyaraman, R. J. Cryst. Spectros. Res., 1993, 23, 871-5.
62. Structure of 2,4-bis-(p-methoxyphenyl)-N-nitroso-3-azabicyclo[3.3.1]nonan-9-one, Priya, V.; Shamala, N.; Viswamitra, M.A.; Ravindran, T.; Jeyaraman, R.; Acta Cryst. C, 1993, C49, 983-5.
61. Electron Impact Mass Spectral Fragmentation of some Piperidine Derivatives, Ganapathy, K.; Gopalakrishnan, V.; Pandiarajan, K.; Jeyaraman, R. Indian J. Heterocycl. Chem., 1993, 2, 159-164.
60. Formation of nitrone from the reaction between alpha-nitrosostyrene and o-methylstyrene. Pillay, M. K; Jeyaraman, R.; Kumar, R. K., J. Indian Chem. Soc. (1992), 69, 24-5.
59. Structure of N-Nitroso-r-2,c-7-diphenylhexahydro-1,4-diazepin-5-one, Priya, V.; Shamala, N.; Viswamitra, M.A.; Senthilkumar, U.P.; Jeyaraman, R., Acta Cryst. 1992, C48, 1048-1051.
58. Conformational Analysis of r-2,c-6-diphenylpiperidines by NMR and molecular mechanics methods, Ravindran, T.; Jeyaraman, R. Indian J. Chem., 1992, 31B, 677-682.
57. Pi-Facial Diastereoselective additions to carbonyl group of 2,6-diphenylpiperidin-4-ones and 2,4-diphenyl-3-azabicyclo[3.3.1]nonan-9-one, Sujatha, M.; Jeyaraman, R. Indian J. Chem., 1992, 31B, 507-512.
56. A simple method for the preparation of 4,8,9,10-tetraphenyl-1,3-diazaadamantanes, Jeyaraman, R.; Ravindran, T.; Sujatha, M. Indian J. Chem., 1992, 31B, 362.
55. Dioxiranes 20. Preparation and Properties of Some New Dioxiranes, Murray, R.W.; Singh, M.; Jeyaraman, R. J. Am. Chem. Soc., 1992, 114, 1346-1351.
54. Chemistry of N-nitroso compounds 3. Synthesis and conformational analysis of N-nitrosohexahydro-1 4-diazepin-5-ones, Senthilkumar, U.P.; Jeyaraman, R.; Murray, R.W.; Singh, M. J. Org. Chem. 1992, 57, 6006-6014.
53. Effect of addition of phenols on the rate of Menschutkin reaction - Reaction between phenacyl bromide and triethylamine, Pillay, M.K.; Jeyaraman, R.; Nallu, M. Indian J. Chem., 1991, 30A, 432-436.
52. Steric enhancement of resonance. 13C NMR spectroscopic studies of certain anisoles, Baliah, V.; Mangalamudaiyar, A.; Jeyaraman, R. Indian J. Chem., 1991, 30B, 1046-1051.
51. Chemistry of N-nitroso compounds 1. Synthesis and Stereodynamics of N-nitrosopiperidin-4-ones and N-nitrosopiperidines, Ravindran, T.; Jeyaraman, R.; Murray, R.W.; Singh, M. J. Org. Chem., 1991, 56, 4833-4840.
50. Deacetylation of N-acetylpiperidin-4-ones by a novel electrochemical method, Rajanarayanan, A.; Jeyaraman, R. Tetrahedron Lett., 1991, 32, 3873-3874.
49. A BASIC Program for Computing Reactant Combinations, from approximate elemental analysis data, SenthilKumar, U.P.; Vijayalakshmi, R.; Jeyaraman, R., J. Chem. Educ. 1991, 68, 773-76.
48. Facile denitrosation of cyclic N-Nitrosamines with Boron trifluoride, Jeyaraman, R., Ravindran, T., Tetrahedron Lett., 1990, 31, 2787-88.
47. Activation of PAH by Ozone Derived Oxidants, Murray, R.W.; Rajadhayaksha, S.N.; Jeyaraman, R. in Polynuclear Aromatic Hydrocarbons; Physical and Biological Chemistry, M.Cooke and A.J. Dennis, 12th Symposium Volume, NBS, Washington, 1990, 1, 213-219.
46. Stereochemical Studies on 7-and 9-substituted 3-Azabicyclo[3.3.1]nonanes (3-ABNs), Jeyaraman, R., Manoharan, M., Heterocycles, 1989, 29, 1191-1197.
45. Unsymmetrical Distortion of Piperidine Ring: Evidence from Rates of N-Methylation of Piperidines and Piperidin-4-ones, Jeyaraman, R.; Chandrasekaran, L.; Ganapathy, K.; Gopalakrishnan, V. Indian J. Chem., 1988, 27A, 695-697.
44. Synthesis of 2-(o-Hydroxyphenyl)-5,6-benzo-1,3-oxazine, SenthilKumar, U.P., Jawaharsingh, C.B.; Jeyaraman, R., Indian J. Chem., 1988, 27B, 352.
43. Carbon-13 NMR Spectra of p-Methoxyacetophenones: Further Evidence for Steric Enhancement of Resonance, Baliah, V., Premasagar, V.; Krishnakumar, R., Jeyaraman, R., Indian J. Chem., 1988, 27B, 151.
42. Chemistry of Dioxiranes. 10. Oxidation of Quadricyclane and Norbornadiene by Dimethyldioxirane, Murray, R.W., Pillay, M.K., Jeyaraman, R., J. Org. Chem., 1988, 53, 3007-3011.
41. A Water-powered Magnetic Stirrer for Laboratory Use, Nallu, M. and Jeyaraman, R., Chemistry Education, 1987, 4, 54-55.
40. Chemistry of Dioxiranes 6. Electronic Effects in the Oxidation of Sulfides and Sulfoxides by Dimethyldioxirane. Murray, R.W.; Jeyaraman, R., Pillay, M.K. J. Org. Chem., 1987, 52, 746-748.
39. Reactions of Nitrogen Containing Organic Compounds with Dioxiranes. Jeyaraman, R.; Mohan, L.; Murray, R.W., Proceedings of the Fifth Annual Working Group Meeting on Synthesis of High Energy High Density Materials; U.S. Army Armament Research, Development and Engineering Center (ARDEC), Dover, NJ; 1986.
38. Remote Intramolecular Functionalization of Arylnitrenium Ions: Synthesis of Amino-dihydrophenanthridines and Benzo[c]chromans. Abramovitch, R.A.; Cooper, M.M.; Jeyaraman, R.; Rusek, G., Tetrahedron Lett., 1986, 27, 3705-3708.
37. A New Synthesis Nitro Compounds Using Dimethyldioxirane. Murray, R.W.; Jeyaraman, R.; Mohan, L., Tetrahedron Lett. 1986, 27, 2335-2336.
36. Dioxiranes 3. Activation of Polycyclic Aromatic Hydrocarbons by Reaction with Dimethyldioxirane. Murray, R.W.; Jeyaraman, R., Polynuclear Aromatic Hydrocarbons: Physical and Biological Chemistry, Edited by M. Cooke and A.J. Dennis, Battelle Press, Columbus, Ohio; 1985, pp 595-607.
35. Chemistry of Dioxiranes. 4. Oxygen Atom Insertion into Carbon-Hydrogen Bonds by Dimethyldioxirane. Murray, R.W.; Jeyaraman, R.; Mohan, L., J. Am. Chem. Soc., 1986, 108, 2470.
34. Dioxiranes: Synthesis and Reactions of Methyldioxiranes. Murray, R.W.; Jeyaraman, R., J. Org. Chem., 1985, 50, 2847-2853.
33. Remote Intramolecular Functionalization of Arylnitrenium Ions. Seven-membered Ring Formation. Abramovitch, R. A.; Jeyaraman, R.; Yannakopoulou, K., J. Chem. Soc., Chem. Commun., 1985, 1107-1108.
32. A One-Step Synthesis of 2-Aryl-5-arylmethyl-4,6-dimethylpyrimidines. Jeyaraman, R.; Jawaharsingh, C.B., Synthetic Commun., 1985, 15, 417.
31. The Portable STM Personal Computer. Jeyaraman, R. Byte, 1985, 10, 270.
30. Production of Arene Oxides by the Caroate-Acetone System (Dimethyldioxirane). Jeyaraman, R.; Murray, R.W., J. Am. Chem. Soc., 1984, 106, 2462-63.
29. Stereochemical Factors in Mass Spectral Fragmentation of 2,4-Diaryl-3-azabicyclo[3.3.1]nonane System. Jeyaraman, R.; Jawaharsingh, C.B.; Avila, S.,Indian J. Chem., 1984, 23B, 550.
28. Nitrenium Ions. Abramovitch, R.A.; Jeyaraman, R., in Azides and Nitrenes, Ed. Scriven, E.F.V., Academic Press, 1984, p297.
27. Effect of 2,4-Diaryl-3-azabicyclo[3.3.1]-nonan-9-ones on polarographic Maxima of Oxygen, Lead, and Nickel. Rajendran, T.; Jeyaraman, R.; Rajasekaran, B.; John, M., Indian J. Chem., 1983, 22A, 485.
26. Synthesis of 2,6-Disubstituted Piperidines, Oxanes and Thianes. Baliah, V.; Jeyaraman, R.; Chandrasekaran, L. Chem. Rev., 1983, 83, 379.
25. Ammonia. Jeyaraman, R. in "Synthetic Reagents" Vol. 5 Edited by Pizey, J.S.; Ellis Horwood: Wiley-Interscience, Chichester, England; 1983; Chapter 1.
24. Conformational and Configurational Studies on 3-Azabicyclo[3.3.1]nonane (3-ABN) Derivatives and Related Systems Employing Carbon-13 NMR Spectroscopy. Jeyaraman, R.; Jawaharsingh, C.B.; Avila, S.; Ganapathy, K.; Eliel, E.L.; Manoharan, M.; Morris- Natschke, S., J. Heterocycl. Chem. 1982, 19, 449.
23. Conformational Analysis. 43. A boat-shaped Piperidine Ring in 6,8-Diphenyl-3-thia-7-azabicyclo[3.3.1]nonan-9-ol, Eliel, E.L.; Manoharan, M.; Hodgson, D.J.; Eggleston, D.S.; Jeyaraman, R., J. Org. Chem., 1982, 47, 4353.
22. Intramolecular Cyclization of Arylnitrenium Ions. Formation of Carbon-Carbon Bonds and of Lactones. Abramovitch, R.A.; Cooper, M.; Iyer, S.; Jeyaraman, R.; Rodriguez, J.A.R., J. Org. Chem., 1982, 47, 4819.
21. Synthesis and Stereochemistry of 4-Amino-4-cyano-3-methyl-2,6-diphenylpiperidine. Jeyaraman, R.; Thanaraj, A.E.; Chockalingam, KN. Indian J. Chem., 1981, 20B, 555.
20. Synthesis of 5-Aryl-4,6-bis[alkoxycarbonyl]-1,3-dithiane 1,1,3,3-tetroxides. Baliah, V.; Prema, S.; Jawaharsingh, C.B.; Chockalingam, KN.; Jeyaraman, R., Synthesis 1981, 995.
19. Facile Formation of 3-Aryl-2-carbethoxythiomorpholine 1,1-dioxides through an Unusual Condensation-Substitution Reaction. Jeyaraman, R.; Jayaraj, C.D.; Chockalingam, KN, Indian J. Chem., 1981, 20B, 333.
18. Chemistry of 3-Azabicyclo[3.3.1]nonanes. Jeyaraman, R.; Avila, S., Chem. Rev., 1981, 81, 149.
17. Structure and Conformation of 7-Dimethylamino-1-methyl-3-methylene-2,8-diphenyl-1- azacyclooctane. Jeyaraman, R.; Thanaraj, A.E.; Chockalingam, KN. Indian J. Chem., 1980, 19B, 522.
16. Synthesis and Conformational Analysis of Ethyl 2,4-Diaryl-3-azabicyclo[3.3.1]nonan-9-hydroxy-9-acetates. Jeyaraman, R.; Thanaraj, A.E., Indian J. Chem., 1980, 19B, 521.
15. Synthesis of some 3-Azabicyclo[3.3.1]nonane Derivatives. Jeyaraman, R.; Chockalingam, KN.; Rajendran, T. Indian J. Chem., 1980, 19B, 519.
14. Reactions of Sulfonylacetic Acids: Part 1. Condensation of Aldehydes with Methylenedisulfonylacetic Acid. Jawaharsingh, C.B.; Jeyaraman, R., Indian J. Chem., 1980, 19B, 517.
13. Kinetics of Alkaline Hydrolysis of some 9-Acetoxy-3-methyl-2,4-diaryl-3-azabicyclo[3.3.1]nonanes. Ganapathy, K.; Gopalakrishnan, V.; Jeyaraman, R. Indian J. Chem., 1979, 17B, 417-412.
12. Mass Spectral Studies of 8-Aryl-3,5-diarylidene-1,2,6,7-tetrahydrodicyclopenta[b,e]pyridines. Ganapathy, K.; Jeyaraman, R., Indian J. Chem., 1979, 17B, 389.
11. Splitting of the Carbonyl Stretching Band in the IR Spectra of Certain 3-Azabicyclo[3.3.1]nonan-9-ones. Baliah, V.; Jeyaraman, R., Indian J. Chem., 1978, 16B, 1127.
10. Synthesis of 2N, 4N-Bis (o-hydroxyphenylmethylene)-2,3-dialkyl-2,3-dihydro-4H-1-benzopyran-2,4-diamines. Baliah, V.; Gopalakrishnan, V.; Jeyaraman, R. Indian J. Chem., 1978, 16B, 1065.
9. Conformations of some 2,4-Diaryl-3-azabicyclo[3.3.1]nonan-9-ols. Baliah, V.; Jeyaraman, R., Indian J. Chem., 1978, 16B, 597.
8. Infrared Spectra of 2,4-Diaryl-3-azabicyclo[3.3.1]nonan-9-ols, 7,9-Diaryl-8-azabicyclo[4.3.1]decan-10-ols and 6,8-Diaryl-7-aza-3-thiabicyclo[3.3.1]nonan-9-ols. Baliah, V.; Jeyaraman, R., Indian J. Chem., 1977, 15B, 852.
7. Rates of Esterification of some Azabicyclo[3.3.1]nonan-9-ols. Baliah, V.; Jeyaraman, R., Indian J. Chem., 1977, 15B, 832.
6. 8-Aryl-3,5-diarylidene-1,2,6,7-tetrahydrodicyclopenta[b,e]pyridines by the Condensation of Cyclopentanone with Substituted Benzaldehydes in the presence of Ammonium Acetate. Baliah, V.; Jeyaraman, R.; Indian J. Chem., 1977,15B, 798.
5. Synthesis of some Azacyclooctene Derivatives through a Selective Hofmann Degradation of 2,4-Diphenyl-3-azabicyclo[3.3.1]nonan-9-one. Baliah, V.; Jeyaraman, R., Indian J. Chem., 1977, 15B, 796.
4. Conformational Studies on the Reduction of 2,4-Diaryl-3-azabicyclo[3.3.1]nonan-9-ones, 7,9-Diaryl-8-azabicyclo[4.3.1]decan-10-ones and 6,8-Diaryl-3-thia-7-azabicyclo[3.3.1]nonan-9-ones. Baliah, V.; Jeyaraman, R., Indian J. Chem., 1977, 15B, 791.
3. 6,8-Diaryl-3-thia-7-azabicyclo[3.3.1]nonan-9-ones. Baliah, V.; Jeyaraman, R., Indian J. Chem., 1977, 15B, 91.
2. Synthesis of some Azabicyclic Ketones. Baliah, V.; Jeyaraman, R.; Usha, R., Indian J. Chem., 1977, 15B, 90.
1. Synthesis of some 3-Azabicyclo[3.3.1]nonanes. Baliah, V.; Jeyaraman, R., Indian J. Chem., 1971, 9, 1020.



====== Work done ========

Summary of some significant work done
(Seniors with whom Jeyaraman worked: V. Baliah, R. A. Abramovitch, R. W. Murray.
Principal Collaborators: E. L. Eliel, P. Bigler, M. Manoharan, M.A. Viswamitra, V. Parthasarathy, M. N. Ponnusamy, K. Panchanatheswaran.
Partial list of students: T. Ravindran, U.P. Senthilkumar, R. Vijayalakshmi, J.C. Thenmozhiyal, M. Sujatha, S. Ponnusamy, R. Murugadoss, B. Sivakumar, M. Muthukumar, M. Venkatraj.
Industries which supported some work: Torrent Pharmaceuticals, Shanth Pharmaceuticals


Synthesis and anticancer activity of N-nitrosopiperidines

Though N-nitrosopiperidines are generally considered carcinogenic (inducing cancer) the degree of carcinogenicity depends on the conformational characteristics of N-nitrosamines. It decreases with twisting of the ring and introduction of the additional substituents at the a-position to the ring nitrogen atom. Simple N-nitrosopiperidine is a potent carcinogen. When one of the two -carbons is blocked by alkyl substituents, the nitrosamine becomes a moderate carcinogen. When both -positions are blocked by at least one alkyl group at each position the nitrosamine becomes a noncarcinogen. By invoking the principles of conformational analysis of piperidines and azabicyclic compounds that we have studied during the past four decades it was thought that the N-nitrosopiperidines might be possess anticancer properties. It has been found to be so indeed.

We have prepared several N-nitroso derivatives of 5-, 6- and 7- membered heterocyclic compounds and bicyclic compounds and examined their anticancer activity with the help of National Cancer Institute, NIH, Maryland, USA. It was found that five compounds have high activity. These studies led to a postulate that when both a-carbon atoms of N-nitrosopiperidines are blocked by two aryl groups they become anticancer active.

NCI Numbers:
626734: Ar = p-Anisyl 627000 626737: Ar = p-Anisyl
626735: Ar = Phenyl 626741: Ar = Phenyl

See: Open repository and carry out “Compare” to know the relative efficiencies of these leads.
Dose Response Curve of Compound 657000
Data Search in http://www.dtp.nci.nih.gov/
Cancer Screening Data (February 2003 Release)” And COMPARE”.
QSAR Analysis on anticancer activities of N-Nitrosopiperidines

The anticancer activity of N-nitrosopiperidines correlated with their physical properties such as logP, conformational properties such as rotation barriers, NMR chemical shifts and other molecular orbital properties such as HOMO, LUMO using Cerius2 on Silicon Graphics systems at Torrent Research Center, Ahmedabad (Thanks to Torrent Pharmaceuticals Ltd., Ahmedabad). Hydrophobic property, logP of the above compounds calculated using ClogP software. HOMO and LUMO energies of them were calculated by semi-empirical method MOPAC. These HOMO and LUMO energies were required for molecular shape comparison method, which is used for the prediction of the bioactive conformation of molecules.
Some selected piperidines used for QSAR analysis in Cerius2 are shown in fig. 1. The QSAR analysis gives excellent linear correlations (r2= 0.91 to 0.99) (Eqns. 1 –5) (fig.2). It was found that N-nitroso-3,5-dimethyl-2,6-diarypiperdones and 2 N-nitroso-2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ones with flattened or twist boat conformations in which the N-N=O functionality deviates from C2NC6 plane in piperidones and C2NC4 plane in azabicyclic nonanes leading to rotation barriers for N-N rotation well below 50KJ mol-1, could evolve as potent anticancer drugs when suitable functional groups are attached at the phenyl substituents.

QSAR Equations derived using Cerius2:

Eqn. 1: PCRPA = -2.6*Rotbar + 10.5*logP + 10.3 HOMO – 16.7*LUMO
r2 = 0.901

Eqn. 2: SPA = 216.6 – 3.96*Rotbar + 30.0*logP – 72.6*LUMO
r2 = 0.904

Eqn. 3: SPA = 811.7 + 44.2*logP + 49.3*HOMO – 113.4*LUMO
r2 = 0.933

Eqn. 4: SPA = 178.7 + 30.3*logP – 19.7*CSDIFFH2–73.1*LUMO
r2 = 0.904

Where,
PCRPA is Principal Component Regression Predicted Activity
SPA is Stepwise Predicted Activity
Rotbar is Rotation Barrier
P is Partition Coefficient
CSDIFFH2 is Chemical Shift Difference of H2 proton
Hf is Heat of Formation
r is Regression Coefficient

Finding:

1. The anticancer activity is high if the rotation barrier (for N-N=O) is low.
2. The activity is related to logP.


Dimethyldioxirane:

The most exciting discovery is the isolation of dimethyldioxirane in acetone solution from a reaction mixture containing acetone and Oxone (an inorganic peroxide). Though dioxirane has been proposed as an intermediate in some reactions during the past no isolation was reported. The easy and simple methods of preparation of dimethyldioxirane has led to many interesting studies such as fast and clean oxidations of a variety of organic compounds, involvement of dioxirane intermediate in monooxygenase enzyme reactions, atmospheric pollution involving PAH, carcinogenesis mechanisms. Many research groups and industries have used Dimethyldioxirane for selectiveoxidations.


Synthesis and NMR Studies in relationship to Cancer and Hypertension:

Stereochemical studies of the dynamic equilibrium in N-substituted heterocycles have resulted in establishing the correlations between the dynamics and special arrangement needed for potential, highly active and selective anticancer and antihypertensive drugs. An entirely new hypothesis on the mechanisms of Drug-receptor interactions has been proposed. New structures for synthesis were derived as part of the Drug Discovery process.

(1) NNitroso-2,6-diarylpiperidines as Anticancer Materials: Though N-nitrosopiperidines are generally carcinogenic we have prepared new N-nitrosopiperidines that show anticancer activities. Several N-nitroso-2,6-diaryl-piperidines have been synthesized and extensive stereochemical analysis has been carried out using NMR spectral techniques such as COSY, NOESY, DNMR, etc., and Xray crystallography. Most of these Nnitrosopiperidines adopt twistboat conformations with quasiaxial or quasiequatorial aryl groups while the parent piperidines preferred chair conformations with equatorial aryl groups. In the 1H & 13C NMR spectra, two signals were appeared for each of the benzylic protons and carbons at room temperature, respectively, which indicated the coplanar orientation of the nitroso function with reference to the C2N1C6 plane of the piperidine ring with hindered rotation at NN bond. Due to hindered rotation around NN bond equilibrium exists between syn rotamer (nitroso oxygen being cis to C2) and anti rotamer (nitroso oxygen being trans to C2) of the nitroso derivatives. Dynamic 1H NMR spectral studies were used to calculate the energy barriers for the restricted NN bond rotation of the NNO group. The hybridization of ring nitrogen is sp2 with the C2N1C6 bond angle close to 120 indicated by crystal structure data. The strain due to the expansion of C2N1C6 angle can be alleviated by the contraction of C3C4C5 angle.

(2) Correlation with Anticancer Activity: A clear correlation of the rotation barrier with anticancer activity has been established by employing QSAR studies using Cerius2 and Sybyl software on Silicon Graphics work stations. Nitrosopiperidines that have high rotation barriers are carcinogenic and those with low barriers enough to show multiplicity in NMR have significant anticancer activities. If the barrier is introduced at two sites the activity is maximum. Using this principle Drug designs have been made and suitable structures for synthesis have been postulated. The synthesis of the target compounds is underway as part of the Ph.D. work of a research fellow who might complete his work in about six months.

(3) NFormyl-2,6-diarylpiperidines and other N-acyl derivatives: Most AT1 selective Antihypertensive agents are N-acyl derivatives. The conformational equilibrium in such compounds is interesting and bear a relationship with the mode of action. Hence the detailed investigations on the dynamic equilibrium between the syn and anti rotamers of N-acylpiperidines an other Heterocycles have been carried out. The restricted rotation at NC bond in several Nacyl derivatives of azacycles is known to be fast at room temperature and it was studied by various NMR spectral methods. The stereochemistry of several Nacyl derivatives of piperidines, 3-azabicyclo[3.3.1]nonanes, hexahydro-1,4-diazepines, tetrahydro-1,5-benzodiazepines and piperazines have also been examined. These compounds prefer flattened boat conformations with coplanar orientations of NC=O function resulting in the conformational equilibrium between syn and anti rotamers. N-Nitroso and N-acyl-2,6-di(heteroaryl)piperidines prefer twistboat conformations with quasiaxial or quasiequatorial aryl groups while the N-formyl derivatives prefer flattened boat conformations. The study has led to a clear mechanistic view of the mode of action of antihypertensive drugs and the need for groups that induce dynamic equilibrium at room temperature. Several new targets have also been designed. Synthesis has not been commensed.

(4) NNitroso3azabicyclo[3.3.1]nonanes: Several 2,4-diaryl-3-azabicyclo[3.3.1]nonan-ones, 3,7-diaza, 3-oxa-7-aza and 3-thia-7-azabicyclic compounds and their derivatives were synthesized. N-nitroso and N-acyl derivatives 3-aza and 3,7-diazabicyclic compounds have been studied in detail. The 3azabicyclo[3.3.1]nonanes adopt twinchair conformations with equatorial aryl groups, while the 3,7diazabicyclo[3.3.1]nonanes prefer chairboat conformations with two equatorial groups (at 2,4 positions) and two axial aryl groups (6,8 positions). The newly formed piperidine ring in the 3,7-diaza and 3-thia-7-azabicyclic compounds adopts boat conformation. The Nnitroso2,4diaryl3azabicyclo[3.3.1]nonanes prefer twinchair conformations with aryl groups at the quasiequatorial orientations while N3nitroso and N3,N7dinitroso2,4,6,8tetraphenyl3,7diazabicyclo[3.3.1]nonanes adopt twin chair conformations with two of the phenyl groups occupying axial orientations. Moreover, the delocalisation in these rigid bicyclic amines was partial resulting in a slightly nonplanar geometry around nitrogen.

(5) NAcyl3azabicyclo[3.3.1]nonanes and 3-Acyl3,7diazabicyclo-[3.3.1]nonanes : The Nacyl2,4diaryl3azabicyclo[3.3.1]nonanes prefer twinchair conformations with aryl groups at the quasiaxial orientations while N3acyl-r2,c4,t6,t8tetraphenyl3,7diazabicyclo[3.3.1]nonanes adopt twin chair conformations with two of the phenyl groups occupying axial orientations as in the case of Nnitroso analogues.

(6) N1,N4Dinitroso- and N1,N4diacylpiperazines: With a view to understanding the competition between A1,3strains at more than one site by introducing two rotationally restricted NNO groups at N1,N4 positions in piperazines, a study on the stereochemistry of N1,N4dinitrosopiperazines was undertaken. The stereochemical investigation on the dinitrosopiperazines by NMR spectral techniques showed the existence of conformational equilibria involving four rotational isomers arising from the restricted rotation around NN single bond of the NN=O groups. The N1,N4-dinitrosopiperazine exists as an equilibrium mixture of four rotamers. Two of them prefer to adopt twistboat conformations and other two prefer flipped chair conformations. The stereochemical investigations on the N1,N4-diacylpiperazines by NMR techniques and semi-empirical calculations showed the existence of a conformational equilibria involving four rotational isomers arising from the restricted rotation around the N-C single bond of the N-C=O groups. The A1,3- strain and the resonance energy were found to be the most important factors in determining the conformational preferences of all the piperazines investigated. The semi-empirical molecular orbital calculations supported the conformational preferences and and the nature of the conformational equilibria derived from the NMR results.

(7) NNitrosohexahydro1,4diazepines: With a view to understand the effect of introduction of nitroso group on the conformational preferences of azacyclic seven membered rings containing αequatorial phenyl groups, several r2,c7diphenylhexahydro1,4diazepin5ones and their N-nitroso and N-acyl derivatives have been prepared and their stereochemistry of was studied. The parent hexahydrodiazepin5ones were found to adopt chair conformations with equatorial orientations of both the phenyl and alkyl substituents in the seven membered ring on the basis of IR, 1H and 13C NMR spectra and Xray crystallography. The Nnitrosohexahydrodiazepin5ones were found to adopt flattened boat conformations. The phenyl groups at the αcarbons preferred pseudoaxial orientations while the alkyl groups at the bcarbons were shown to prefer equatorial positions. In each case two major rotamers were found to be in equilibrium at room temperature involving syn and anti orientations of the coplanar (with reference to C2N1C7 plane) nitroso group. The solid state conformations of the Nnitrosohexahydrodiazepin5ones were found to be similar to those predicted in the solution state. The influence of allylic strains at two locations of a ring was estimated in N1,N4dinitrosor2,c7diphenylhexahydro 1,4diazepines. With the help of a combination of multipulse experiments (HOHAHA, NOE, etc.,) and variable temperature 1H NMR spectra recorded from 50 to +120C, it was shown that N1,N4dinitroso-r2,c7diphenylhexahydro3isopropyl1,4diazepine exists as an equilibrium mixture of two sets of conformations, a major set consisting of four rotamers and a minor set consisting of possibly four rotamers resulting from two parallel dynamic processes viz., the restricted NN rotations at two NN(O) bonds and the pseudorotations of the seven membered ring. While the pseudorotation was found to bring about the inter conversion within a pair of twistchair conformations of the hexahydrodiazepine ring, the restricted rotation at NN bond caused each twistchair conformation to exist as an equilibrium mixture of four rotameric states containing different relative orientations of the two nitroso groups viz., synanti, synsyn, antisyn and antianti. The relative conformational dispositions of the alkyl groups and various protons in were determined from the NOE experiments. In all the three dinitroso compounds, between the two sets of twistchair conformers, the major rotamers (95%) were shown to have the alkyl group at C3 axially oriented while the minor rotamers were considered to have equatorial alkyl groups. On the other hand, the alkyl group at C6 of the 3,6dimethyl derivative was shown to be in equatorial orientation in all the conformations. In the major conformer, the phenyl groups at C2 and C7 were shown to be in pseudoaxial and equatorial positions, respectively. Xray crystallographic studies on the 3isopropyl derivative showed that the dinitroso compound adopts partially twisted chair conformation with equatorial orientation of the isopropyl as well as the phenyl substituents. This conformation was analogous to one of the conformers in the minor set (5%) indicating that it was the minor conformer that crystallized preferentially.

(8) N1,N5Dinitrosotetrahydro1,5benzodiazepines and N5-Nitrosotetrahydro- 1,5-benzodiazepin-2-one: The stereochemical influences of the two nitroso groups on the preferred conformations of N1,N5dinitrosotetrahydro1,5benzodiazepines and N5-Nitrosotetrahydro-1,5-benzodiazepin-2-one have been studied. The parent benzodiazepines are known to adopt chair conformations and the parent benzodiazepin-2-one is known to adopt a boat conformation. The dinitrosotetrahydrobenzodiazepines were found to exist as a mixture of two conformers, the major conformer adopts chair conformation while the minor adopts flexible boat form and the nitroso groups prefer endoendo orientations in both the conformers. The examination of the stereochemical consequences of introducing one or two nitroso groups at the nitrogens of seven membered ring system containing two, one and zero torsional constraints revealed that (i) the absence of torsional constraints allows the molecule to prefer twist-chair conformation, (ii) the presence of one torsional constraint such as an amide or a benzo group results in the presence of a boat or a chair conformation flattened at the nitroso end of the ring, (iii) the introduction of two torsional constraints discourages the delocalization of lone pair of electrons with the nitroso/acyl groups and results in the pyramidal geometry for the amine-nitrogen. As a result, the energy barrier to N-X rotation is relatively low in these systems.

(9) NAcyltetrahydro1,5benzodiazepines: We have studied the stereochemical influences of the acyl groups on the preferred conformations of Nacyltetrahydro1,5-benzodiazepines. N5benzoyl and N5phenylcarbamoyltetrahydro1,5benzodiazepines were found to prefer boat conformations with exo orientation of acyl groups. The N1,N5diacetyltetrahydro1,5benzodiazepine was found to adopt boat conformation with endo and exo orientations of acetyl groups at N1 and N5, respectively. The N1,N5diformyl derivative was found to exist in an equilibrium mixture of major and minor conformers and the orientations of the formyl groups at N1 and N5 positions of both the conformers were endo & exo, respectively. The major conformer prefers a boat conformation while the minor one prefers to adopt a chair conformation. The results obtained from semi-empirical calculations were in good agreement with the results obtained from solution (NMR) and solid (X-RAY) states.


(10) Strained Oximes and Semicarbazones of NNitrosopiperidin4ones: We have studied the influence of two competing A1,3-strain factors (at N1 and C4 positions) over the conformational preferences of the piperidine ring systems, such as Nnitrosor2,c6diphenylpiperidin4one oximes and semicarbazones of Nnitrosor2,c6diphenylpiperidin4ones. It was shown that these compounds prefer twistboat conformations with an equilibrium involving coplanar syn and anti orientations of the nitroso function. The preferred conformation of the 3,5dimethylNnitrosopiperidin4-one oxime determined from Xray crystallography was also found to be twistboat. Stereodynamics of these compounds have been studied using dynamic NMR and semi-empirical calculations.

(11) Dimethyldioxirane oxidation of N-nitrosoazabicyclic compounds :Several N-nitroso compounds were prepared in our laboratory and their anticancer activities were also tested. Among the several N-nitroso compounds 3,5-dimethyl-N-nitroso-2,6-diphenylpiperidin-4-one have the highest anticancer activity and selectivity. Also DMDO was proposed to mimic monooxygenase enzymes especially cytochrome P450. So, we have carried out the reaction of DMDO (in-situ) with N-nitroso-2,4-diaryl-3-azabicyclo[3.3.1]nonane to explore the anticancer activity of the same. The mechanism by which the product was formed in the reaction appeared to be the same as the metabolic pathway of N-nitrosonornicotine.
(12) New rearrangement: Reaction of 2,4-diphenyl-3-azabicyclo[3.3.1]nonan-9-one with hydrazoic acid: Since the N-nitroso azabicyclic compounds possessed high activity against certain cancer cells the lactam derivatives were required to be tested as prodrug candidates. The stereochemical influences of N-X=Y functions on the conformations of the bicyclic lactam, r-2-c-4-diphenyl-3,9-diazabicyclo[3.3.2]decan-10-one were also studied. Though the lactam, 8,10-diphenyl-1,9-diazabicyclo[5.3.0]decan-2-one, was prepared by Beckmann rearrangement route we desired to examine the Schmidt reaction route for improving the net yield of the product. We treated hydrazoic acid with r-2-c-4-diphenyl-3-azabicyclo[3.3.1]nonan-9-one and obtained a new rearrangement product, a tertiary amide, 8,10-diphenyl-1,9-diazabicyclo[5.3.0]decan-2-one (18) instead of the expected lactam.
(13) Reaction of 2,4,6,8-tetraphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one with hydrazoic acid: To study the new rearrangement in detail and to explore the mechanism of the same we examined the reaction of 2,4,6,8-tetraphenyl-3,9-diazabicyclo[3.3.1]nonan-9-one with hydrazoic acid under different reaction conditions. It was observed that the rearrangement took a different course yielding the naphthyridine derivative instead of the lactam. The diazabicylic ketone, r-2,c-4,t-6,t-8-tetraphenyl-3,7-diazabicyclo [3.3.1]nonan-9-one was dissolved in chloroform/conc. H2SO4 mixture and then treated with NaN3. Similar to the case of the hydrazoic acid reaction of r-2,c-4-diphenyl-3-azabicyclo[3.3.1]nonan-9-one, we got a new unexpected product. The compound was identified as r-5,c-7-diphenyl-5,6,7,8-tetrahydrobenzo[b]-1,6-naphthyridine on the basis of various spectral data. IR, mass, 1H and 13C NMR and elemental analysis agree with the naphthyridine compound.


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