Mohamed F. El-Mansy, Jun Yong Kang, Rajinikanth Lingampally and Rich G. Carter*

Department of ChemistryOregon State UniversityACS meeting, San Diego

March14th, 2016Paper number: ORGN 326

Proline sulfonamide-catalyzed, tandem process for asymmetric synthesis of amine- and alcohol-

containing bicyclo[2.2.2]octanes 

1

2

• Background on proline sullfonamide catalysis.

• Optimizing the reaction conditions & reaction scope.

• Mechanism.

• Discovery of [2.2.2] bicyclic alcohols.

• Conclusion.

Outline

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) 733016Catalog # (S) 733008

lycopodine Hua Cat

Evolution of Proline Sulfonamide Organocatalysis

Review: Yang, H.; Carter, R. G. Synlett 2010, 2827-2838 (Issue 19 Invited Account).

4

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

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

6El-Mansy, M. F.; Kang, J. Y.; Lingampally, R.; Carter, R. G. Eur. J. Org. Chem. 2016, 150-157.

Structure Assignment

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

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

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

9El-Mansy, M. F.; Kang, J. Y.; Lingampally, R.; Carter, R. G. Eur. J. Org. Chem. 2016, 150-157.

* Compound proved unstable to HPLC analysis.

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

10El-Mansy, M. F.; Kang, J. Y.; Lingampally, R.; Carter, R. G. Eur. J. Org. Chem. 2016, 150-157.

* Compound proved unstable to HPLC analysis.

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

Further Exploration of Reaction Scope

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

Plausible Catalytic Cycle

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

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

Discovery of [2.2.2] Bicyclic Alcohols

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

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.

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

• Supervisor Rich G. Carter

• Carter Research Group Members

• Department of Chemistry

• Oregon State University

• National Science Foundation (CHE-1363105)

Acknowledgments

19

Thank You

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.