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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