Post on 21-Mar-2018
Organic Synthesis:
The Science Behind the Art
Prof. Sambasivarao Kotha (FNASc, FASc, FRSC, FNA) J. C. Bose Fellow (DST )
Department of Chemistry
Indian Institute of Technology-Bombay
srk@chem.iitb.ac.in
http://www.chem.iitb.ac.in/
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T R O U B L E
S H O O T I N G
P R O D U C T
E X E C U T I O N
(T E C H N IQ U E )
S T R A T E G Y
(R E A C T I O N S )
D E S I G N
O P T IO N S
(C O N N E C T I V IT Y )
P R IO R I T I E S &
C O N S T R A IN T S
S Y N T H E S I S S T A R
ID E A L L Y .... . .
P R I O R IT IE S &
C O N S T R A IN T S
T R O U B L E -S H O O T IN G
• Readily available starating materials
• One step
• 100% yield
• Operationally simple
• Fast, Safe
• Environmentally acceptable
• Resource efficacious
Change in
• Conditions
• Mechanism
• Reactants
• Strategy
• Personnel
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1. Organic Synthesis
Solvent free
Conditions
Aqueous
Conditions Ionic Liquid
Conditions
Supercritical
Conditions
2. Synthetic Efficiency
Tandem
Process
Multicomponent
Reactions
Multidirectional
Synthesis
3. Synthetic Methodology
Generation of molecular
Diversity
Suitable for Combinatorial
Synthesis
4. Catalytic Processes
Asymmetric synthesis
Using small molecules
Environmentally Friendly
Processes
Salt Free Processes
5. Organometallics in Organic Synthesis
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ORGANIC SYNTHESIS
Target Oriented
(Total Synthesis) Methods Oriented
Natural
Products
Designed
Molecules Reagents Catalysts Synthetic
Strategies
Synthetic
Tactics
Material Science
Interesting
Molecules
Biologicall
y
Interesting
Molecules
Theoretically
Interesting
Molecules
Medically
Interesting
Molecules
Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis, VCH, Weinheim, Germany, 1996.
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Organic Reaction Vs Synthetic Method
General approach to the solution of organic synthesis problems
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Organic Synthesis: The Science Behind the Art W. A. Smit, A. F. Bochkov and R. Caple
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Our research topics
a-Amino Acids J. Indian Inst. Sci. 2001, 81, 277.
Acc. Chem. Res. 2003, 342
Synlett 2010, 337
Suzuki-Metathesis
Chem. Asian J. 2009, 354
Metathesis Indian J. Chem. 2001,763
Synlett 2007, 2767
Chem. Soc. Rev. 2009, 2065
Org. Biomol. Chem. 2011, 5597
Tetrahedron 2012, 397
Curr. Org. Chem, 2013, 17, 2774
Suzuki Coupling Tetrahedron 2002, 58, 9633
Eur. J. Org. Chem. 2007, 1221
Polycyclics Tetrahedron 2001, 57, 625
Tetrahedron 2008, 64, 10775
Synthesis 2009, 165
RSC Adv., 2013, 7642
Peptide Modifications Curr. Med. Chem. 2005, 12, 849
[2+2+2] Cycloaddition Eur. J. Org. Chem. 2005, 4741
Chem. Rev. 2012, 1650
Rongalite
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G. Poli, Org. Lett. 2008, 10, 405. S. Kotha, Synlett 1999, 1618.
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Spirocycles through Alkylation and RCM Strategies
Dialkylation and RCM Sequence
Tetra- or Hexaallylation and RCM Sequence
S. Kotha, E. Manivannan, T. Ganesh, N. Sreenivasachary, A. Deb, Synlett 1999, 1618-1620. S. Kotha, E. Manivannan, Arkivoc 2003, iii, 67-76. S. Kotha, A. C. Deb, R. V. Kumar, Bioorg. Med. Chem. Lett. 2005, 15, 1039-1043. S. Kotha, K. Mandal, A. Tiwari, S. M. Mobin, Chem. Eur. J. 2006, 12, 8024-8038. S. Kotha, A. C. Deb, Indian J. Chem. 2008, 47B, 1120-1134.
S. Kotha, R. Ali, A. K. Chinnam, Tetrahedron Lett. 2014, 55, 4492-4495. Synthesis of complex spiro-polyquinane derivatives
S. Kotha, A. K. Chinnam, R. Ali, Beilstein J. Org. Chem. 2015, 11, 1123-1128. 18
C3-Symmetric spirotruxenes using alkylation, RCM and SM cross-coupling strategy
Spirofluorenes using alkylation, RCM and SM cross-coupling strategy
R. Ali, Ph. D. Thesis, IIT-Bombay, Mumbai, India, 2015.
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Spirocycles through [2+2+2], DA Cycloaddition Strategies
Spirocycles via [2+2+2] and [4+2] sequence
S. Kotha, R. Ali, A. Tiwari, Synlett 2013, 1921-1926. S. Kotha, R. Ali, Heterocycles 2014, 88, 789-797. S. Kotha, R. Ali, Tetrahedron 2015, 71, 1597-1603.
S. Kotha, G. Sreevani, Tetrahedron Lett. 2015, 56, 5903-5908.
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Spirocycles through alkylation, RCEM and DA strategy
S. Kotha, R. Ali, A. Tiwari, Synlett 2013, 1921-1926.
T. M. Swager, Synfacts 2013, 1172.
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DA and rDA reaction of spiroheptadiene with quinones
Attempted rDA reaction of the norbornene system
Spirocycles via DA, rDA strategy
S. Kotha, S. Banerjee, M. P. Patil, R. B. Sunoj, Org. Biomol. Chem. 2006, 4, 1854-1856.
S. Kotha, S. Banerjee, M. Shaikh, J. Chem. Sci. 2014, 126, 1369-1371.
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Spirocycles via Grignard Addition and RCM-RRM or RCEM-RRM Sequence
S. Kotha, O. Ravikumar, Eur. J. Org. Chem. 2016, 3900-3906.
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Spirocycles from 1, 2, 4, 5-Tetrakis-(bromomethyl)benzene as a Useful Synthon
Reagents and conditions: (a) NBS, CH2Cl2, 500 W lamp, reflux, 20 h, 47 %; (b) NaH or K2CO3, TBAHS, MeCN or THF, r.t., 8-24 h, 8-68 %; (c) DEAM, K2CO3, TBAHS, MeCN, r.t., 15-20 h, 37-66 %; (d) (i) EICA, K2CO3, TBAHS, MeCN, r.t., 14-17 h, 45-59 %, R=H; (ii) acetic ahydride (Ac2O), MeCN, 29-30 h, 39-42 %, R=Ac; (e) rongalite, TBAB, DMF, 0 oC-r.t., 3-6 h, 64-92 %; (f) toluene, reflux, 10-15 h, 76-91 %;
Reagents and conditions: (a) K2CO3, TBAHS, MeCN, 15-24 h, not isolated; (b) rongalite, TBAB, DMF, 6 h, not isolated; (c) (i) dienophiles, toluene, reflux, 10-24 h; (ii) DDQ, toluene, reflux, 24 h, 20-33 % overall yields (three steps).
S. Kotha, R. Ali, Tetrahedron 2015, 71, 6944-6955. S. Kotha, R. Ali, Tetrahedron Lett. 2015, 56, 3992-3995. S. Kotha, R. Ali, Heterocycles 2015, 90, 645-658.
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Importance of Symmetry
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Cyclopentane annulation
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Reagents and conditions: (a) allyl bromide, Mg-ether/THF, 0 oC-r.t., 4 h, (9:1) 89 %; (b) NaBH4, BF3.OEt2, THF, Jones reagent, 0 oC-r.t., 5 h, 63 % (i) and 62 % (ii); (c) methanesulphonic acid, P2O5, 55 oC-0 oC, 6 h, (3:1) 66 %; (d) reaction with major isomer, 10 % Pd/C, EtOAc, 3 atm, r.t., 4 h, 74 %; (e) allyl bromide, Mg-ether/THF, 0 oC-r.t., 4 h, (3:1) 78 %; (f) NaBH4, BF3.OEt2, THF, Jones reagent, 0 oC-r.t., 5 h, 81 % (i) and 77 % (ii); (g) methanesulphonic acid, P2O5, 55 oC, 6 h, (1:1) 26 %; (h) 10 % Pd/C, EtOAc, 3 atm, r.t., 3 h, 70 %.
S. Kotha, E. Brahmachary, R. Sivakumar, A. Joseph, N. Sreenivasachary, Tetrahedron Lett. 1997, 38, 4497-4500; S. Kotha, R. Sivakumar, L. Damodharan, V. Pattabhi, Tetrahedron Lett. 2002, 43, 4523-4525; S. Kotha, R. Sivakumar, Arkivoc 2005, xi, 78-88;
Spirocycles reported by our group in the last two decades (1999-2017)
1. Spirocycles through Alkylation, RCM, CR, Grignard Addition, FI and SM Cross-Coupling Strategies (1-106)
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2. Spirocycles through DA, [2+2] Photocycloaddition, CR, Grignard Addition and RCM Strategies (107-143)
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3. Spirocycles through Alkylation, DA, RCM, ROCM, RCEM and RRM Strategies (144-178)
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4. Spirocycles through [2+2+2] and [4+ 2] Cycloaddition Strategies (179-234)
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5. Spirocycles from 1, 2, 4, 5-Tetrakis-(bromomethyl)benzene as a Useful Synthon (235-270)
Ph. D.
1. Dr. E. Brahmachary
2. Dr. N. S. Chary
3. Dr. R. Sivakumar
4. Dr. E. Manivannan
5. Dr. S. Halder
6. Dr. (Ms). K. Lahiri
7. Dr. K. Mohanraja
8. Dr. M. Behera
9. Dr. A. Ghosh
10. Dr. A. C. Deb
11. Dr. D. Kashinath
12. Dr. K. Mandal
13. Dr. S. Banerjee
14. Dr. K. Singh
15. Dr. V. Shah
16. Dr. (Ms). P. Khedkar
17. Dr. M. K. Dipak
18. Dr. S. Vittal
19. Dr. (Ms). S. Misra
20. Dr . (Ms). A. Tiwari
21. Dr. (Ms). N. G. Krishna
22. Dr. A. S. Chavan
23. Dr. (Ms). D. Bansal
24. Dr. M. P. Meshram
25. Dr. G. T. Waghule
26. Dr. M. E. Shirbhate
27. Dr. R. Ali
28. Dr. A. Chinnam
29. Dr. Ravi kumar Ongolu
30. Ms. Rama G.
31. Ms. Sreevani G.
32. Mr. V. Aswar
33. Mr. S. Todeti
34. Mr. C. Subba Rao
35. Ms. Asha. G
36. Mr. P. Sunil
37. Ms. Saima Ansari
38. Ms. Ambareen Fatma
39. Mr. Naveen K. Gupta
40. Mr. Ramakrishna R. K.
41. Mr. N. Sudhakar S.
42. Mr. G. Vidyasagar B.
17. Mr. U. Basu
18. Mr. K. Raju
19. Ms. G. Rama
20. Mr. P. K. Shee
21. Ms. B. Mandal
22. Mr. Rohit Lakhan
23. Mr. C. Sarkar
24. Mr. J. Rana
25. Mr. H. Bharadwaj
26. Mr. Abranil. B
27. Mr. A. Biswas
28. J. Mazi
29. Ms. Architha. D
30. Mr. Suman. D
31. Mr. Gourav
32. Mr. Tushar
33. Mr. Himandhi Setti
34. Mr. Tarun Sudan
Post-doctoral
1. Dr. T. Ganesh
2. Dr. R. Vinod Kumar
3. Dr. S. Kumar
4. Dr. (Ms). K. Lahiri
5. Dr. D. Nagaraju
6. Dr. (Ms). P. Khedkar
7. Dr. T. Niranjan
8. Dr. Venu Srinivas
9. Dr. V. B. Bangarugutta
10. Dr. A. V. Chavan
11. Dr. D. Deodhar
12. Dr. M. E. Shirbhate
13. Dr. M. Saifuddin
14. Dr. N. Nageswararao
15. Dr. M. P. Meshram
16. Dr. P. Nageswara Rao
17. Dr. D. Yuvraj
1. Mr. S. M. Husian
2. Mr. M. J. Rihan
3. Ms. M. Sridevi
4. Mr. A. Pradeesh
5. Ms. Rama G.
6. Mr. K. Raju
7. Ms. B. V. Lakshmi
8. Mr. Amrendar M.
9. Mr. Unmesh. N
10. Mr. Gopinath M.
M. Sc.
1. Mr. S. A. Jothi
2. Mr. G. Giridharan
3. Ms. R. Deshpande
4. Ms. M. S. Subhashi
5. Mr. S. R. Subbaiah
6. Mr. A. Mehta
7. Mr. C. Chatterjee
8. Mr. AP. Suresh Babu
9. Ms. S. Bhattacharjee
10. Mr. P. Charkrabarty
11. Mr. T. Kesharwani
12. Mr. A. Singh
13. Mr. V. Rane
14. Mr. A. Pal
15. Mr. T. T. Rao
16. Mr. M. Banik
17. Mr. R. K. Das
18. Mr. V. Shukla
11. Mr. M. Madasu
12. Mr. Sathyamurthy
13. Mr. Rajdeep. C
14. Mr. Amardeep. A
15. Mr. Mohitosh. B
16. Mr. Rama krishna
17. Mr. M. K. Raut
18. Ms. Tanu Jain
19. Mrs. B. Makhal
20. Karan Selarka
Project/Summer
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Acknowledgements for Providing Mass/NMR/Data/SAIF
1. Hoechst, Mumbai
2. Ciba Geigy, Mumbai, India
3. Glenmark, Pharmaceuticals, Navi Mumbai
4. NCL, Pune
5. IISC, Organic Chemistry Dept, Bangalore
6. IISC – NMR, Bangalore
7. CDRI, Lucknow
8. University of Hyderabad, Hyderabad
9. CSIR – Central Salt & Marine Chemical Research Institute, Bhavnagar
10. TIFR, Mumbai
11. RRL, Trivandrum
12. IICT, Hyderabad
13. Kent - England
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The Secret of our Progress
When we find a KEY to Success the lock is changed.
We continue to find new KEYS for the new locks and
journey continues………
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