1. Mohamed F. El-Mansy, Jun Yong Kang,
Rajinikanth Lingampally and Rich G. Carter*
Department of Chemistry
Oregon State University
ACS meeting, San Diego
March14th, 2016
Paper number: ORGN 326
Proline sulfonamide-catalyzed, tandem process
for asymmetric synthesis of amine- and alcohol-
containing bicyclo[2.2.2]octanes
1

2. 2
• Background on proline sullfonamide catalysis.
• Optimizing the reaction conditions & reaction scope.
• Mechanism.
• Discovery of [2.2.2] bicyclic alcohols.
• Conclusion.
Outline

3. 3
Proline Sulfonamide Organocatalysis
Publications toward Proline Sulfonamides: (a) Yang, H.; Carter, R. G. Org. Lett. 2008, 10, 4649-4652. (b) Yang, H.; Carter, R. G.
J. Org. Chem. 2009, 74, 2246-2249. (c) Yang, H.; Carter, R. G. J. Org. Chem. 2009, 74, 5151-5156. (d) Yang, H.; Carter, R. G.
Tetrahedron 2010, 66, 4854-4859. (e) Yang, H.; Carter, R. G. Org. Lett. 2010, 12, 3108-3111. (f) Yang, H.; Carter, R. G. J. Org.
Chem. 2010, 76, 4929-4938. (g) Yang, H.; Mahapatra, S.; Cheong, P. H.-Y.; Carter, R. G. J. Org. Chem. 2010, 75, 7279-7290. (h)
Yang, H.; Carter, R. G. Synlett 2010, 2827-2838 (Review). (i) Pierce, M.; Johnston, R. C.; Mahapatra, S.; Yang, H.; Carter, R. G.;
Cheong, P. H.-Y. J. Am. Chem. Soc. 2012, 134, 13624–13631. (j) Yang, H., Banerjee, S.; Carter, R. G. Org. Biomol.
Chem. 2012, 10, 4851-4863. (k) Xiao, J.-A.; Liu, Q.; Ren, J.-W.; Liu, J.; Carter, R. G.; Chen, X.-Q.; Yang, H. Eur. J. Org. Chem. 2014,
2014, 5700-5704. (l) El Mansy, M. F.; Kang, J. Y.; Lingampally, R. Eur. J. Org. Chem. 2016, 150-157.
• Novel organocatalyst for facilitating asymmetric catalysis.
• Able to catalyze a range of reactions (e.g. aldol, Mannich, aza-Diels-Alder, Michael
addition, Yamada-Otani reaction).
• Nickname “Hua Cat” comes from postdoc Hua Yang who first prepared it.
• (R)- and (S)-Hua Cat have been commercialized with Sigma-Aldrich.
Cover Article -
Issue 25 (2012)
Catalog # (R) 733016
Catalog # (S) 733008

4. lycopodine Hua Cat
Evolution of Proline Sulfonamide Organocatalysis
Review: Yang, H.; Carter, R. G. Synlett 2010, 2827-2838
(Issue 19 Invited Account).
4

5. Yang, H.; Carter, R. G. Tetrahedron 2010, 66,4854-4859.
Yang, H., Banerjee, S.; Carter, R. G. Org. Biomol. Chem. 2012, 10, 4851-4863.5
Michael / Mannich Reaction Background

6. Optimization conditions
Entry Solvent dr er Yield %
a Neat 11:1 75.5:24.5 71
b Dioxane 8:1 81.0:19.0 53
c DCE 6:1 71.0:29.0 82
d Toluene 10:1 86.5:13.5 72
e PhCF3 9:1 86.7:13.3 80
f PhCF3(4 Å MS) 6:1 82.8:17.2 67
6
El-Mansy, M. F.; Kang, J. Y.; Lingampally, R.; Carter, R. G. Eur. J. Org. Chem. 2016, 150-157.

7. Structure Assignment
7
El-Mansy, M. F.; Kang, J. Y.; Lingampally, R.; Carter, R. G. Eur. J. Org. Chem. 2016, 150-157.

8. Systematic Approach for Synthesis of Aldehydes
El-Mansy, M. F.; Kang, J. Y.; Lingampally, R.; Carter, R. G. Eur. J. Org. Chem. 2016, 150-157.
8

9. Impact of Varying Electron Withdrawing Group
Entry EWG dr er Yield %
a CO2t-Bu 9:1 86.7:13.3 80
b CO2Et 9:1 nd* 79
c CO2Bn 6:1 83.1:16.9 53
d COSEt 20:1 71.6:28.4 64
e CN 3:1 88.9:11.1 87
9
El-Mansy, M. F.; Kang, J. Y.; Lingampally, R.; Carter, R. G. Eur. J. Org. Chem. 2016, 150-157.
* Compound proved unstable to HPLC analysis.

10. Role of Primary Amine on the [2.2.2] Bicycle Formation
Entry R dr er Yield %
a Bn- 9:1 nd* 79
b Ph- 20:1 73.9:26.1 32
c p-MeOC6H4- 20:1 94.3:5.7 50
d (3,5-CF3)C6H3CH2- 11:1 88.2:12.8 53
e CH2=CHCH2- 6:1 nd* 81
10
El-Mansy, M. F.; Kang, J. Y.; Lingampally, R.; Carter, R. G. Eur. J. Org. Chem. 2016, 150-157.
* Compound proved unstable to HPLC analysis.

11. 11
El-Mansy, M. F.; Kang, J. Y.; Lingampally, R.; Carter, R. G. Eur. J. Org. Chem. 2016, 150-157.
Further Exploration of Reaction Scope

12. 12
Mechanism of The Reaction
El-Mansy, M. F.; Kang, J. Y.; Lingampally, R.; Carter, R. G. Eur. J. Org. Chem. 2016, 150-157.

13. 13
Plausible
Catalytic Cycle
El-Mansy, M. F.; Kang, J. Y.; Lingampally, R.; Carter, R. G. Eur. J. Org. Chem. 2016, 150-157.

14. 14 El-Mansy, M. F.; Kang, J. Y.; Lingampally, R.; Carter, R. G. Eur. J. Org. Chem. 2016, 150-157.

15. Discovery of [2.2.2] Bicyclic Alcohols
14
El-Mansy, M. F.; Kang, J. Y.; Lingampally, R.; Carter, R. G. Eur. J. Org. Chem. 2016, 150-157.

16. 16
Entry EWG dr er Yield %
a CO2Et 12:1 60.3:39.7 84
b CO2t-Bu - - 0
c CO2Bn 3:1 65.8:34.2 88
d C(O)SEt 3:1 nd 79
e CN >20:1 78.1:21.9 62
Effect of Electron Withdrawing Group
El-Mansy, M. F.; Kang, J. Y.; Lingampally, R.; Carter, R. G. Eur. J. Org. Chem. 2016, 150-157.

17. Conclusions
• A novel series bicyclo[2.2.2]octanols was discovered with good
yield and moderate stereoselctivity.
• A systematic way of making the aldehydes was developed.
• Generation of bicyclo[2.2.2]octanes containing amine derivatives in
good yield and excellent stereoselectivity.
17

18. 18
• Supervisor Rich G. Carter
• Carter Research Group Members
• Department of Chemistry
• Oregon State University
• National Science Foundation (CHE-1363105)
Acknowledgments

19. 19

20. Poor selectivity in the cyano series
• Lack of interamolecular hydrogen bonding with enamine N-H
bond due to sp-hybridized nature of the nitrile.
El-Mansy, M. F.; Kang, J. Y.; Lingampally, R.; Carter, R. G. Eur. J. Org. Chem. 2016, 150-157.