Assymetric organocatalysis of a direct aldol reaction

Synthesis of L-prolinamide for catalysis in enantioselective aldol reaction between 4-nitrobenzaldehyde and acetone

Transcript

1. Synthesis of L-prolinamide for catalysis in enantioselective aldol reaction between 4- nitrobenzaldehyde and acetone Joseph Szymborski 24/02/14 Department of Chemistry
2. Overview 1 Introduction 1.1 Motivations 1.2 Previous Work 1.3 Broader Implications 2 Results 2.1 Synthesis of L-prolinamide 2.2 Synthesis of 4-hydroxy-4(4-nitrophenyl)-2-butanone 3 Discussion 4 Conclusion 5 References
3. 1 Introduction 1.1 Motivation • Aldol reaction is very powerful/common • As a result, enantioselective aldol is important. • Enantiomers have very different properties • Two types: • Indirect – requires preconversion • Direct – atomically efficient Source: (1)
4. 1 Introduction 1.1 Motivation • Aldol reaction is very powerful/common • As a result, enantioselective aldol is important. • Two types: • Indirect – requires preconversion • Direct – atomically efficient • Very advantageous • Worth finding a catalyst Source: (1)
5. 1 Introduction 1.1 Motivation • Asymmetrical synthesis is commonly achieved by metal-based or bioorganic catalysts • Organocatalyst v. Metal-based or bioorganic catalysts • Bench top stable • Aerobic atmosphere • Compatible with wet solvent • Environmentally friendly • Low Cost • Often more efficient (“one-pot”) Source: (2,3)
6. 1 Introduction 1.2 Previous Work • Organocatalysts have a rich history • Known about for a long time, but thought impractical/too specific • Recent discoveries, new interests Source: (2,4,5)
7. 1 Introduction 1.2 Previous Work • 1970s saw discovery of (S)-proline as catalyst for aldol cyclation • Hajor & Parrish (1974, isolates 2) and Wiechart et al. (1971, report direct conversion to 3) • 2000s saw discovery of (S)-proline as catalyst for aldol intermolecular • B List, R.A Lerner, C.F Barbas III (2000) Source: (2,5) Source: (5)
8. 1 Introduction 1.3 Broader Implications • Drug and natural product synthesis • Used in the “one-pot” synthesis of Anti-H5N1 influenza neuramidase inhibitor • Antimalarial and other antiparastics • Synthesis of tetrahydropyridines Source: (4,6) Source: (3)
9. Summary of Introduction 1 Introduction 1.1 Motivations • Diels-Alder reaction is fundamental and important rx • Organocatalysts for assym. Diels-Alder are more advantageous than alternatives 1.2 Previous Work • Rich history, new interest 1.3 Broader Implications • Synthesis of stereospecific drugs (anti-influenza, anti-parasitic, etc…)
10. 2 Results 2.1 Synthesis of L-prolinamide Scheme 1 – Synthesis of L-prolinamide from L-proline and thionyl chloride
11. 2 Results 2.1 Synthesis of L-prolinamide
12. 2 Results 2.1 Synthesis of L-prolinamide A B C D E Peak Label Chemical Shift (ppm) Integration A 2.12 3.00 B 2.42 1.00 C 3.57 2.55 D 3.84 2.33 E 4.49 0.94
13. 2 Results 2.1 Synthesis of L-prolinamide
14. 2 Results 2.1 Synthesis of L-prolinamide A B C D E Peak Label Chemical Shift (ppm) Integration A 1.28 8.13 B 2.93 3.05 C 3.10 2.92 D 3.55 1.35 E 3.77 3.70 F 4.19 5.73
15. 2 Results 2.2 Synthesis of 4-hydroxy-4(4-nitrophenyl)-2-butanone Scheme 2 – Synthesis of 4-hydroxy-4(4-nitrophenyl)-2-butanone from acetone and 4-nitrobenzaldehyde
16. 2 Results 2.2 Synthesis of 4-hydroxy-4(4-nitrophenyl)-2-butanone
17. 2 Results 2.2 Synthesis of 4-hydroxy-4(4-nitrophenyl)-2-butanone • % yield of product • 4-nitrobenzaldehyde was limiting reagent • 300.0 × 1 1000 × 1 151.12 = 1.985 < 1 × 0.791 1 × 1 58.07 = 13.62 () • 0.4749g are expected • 1.985 × 1 () 1000 × 1 () 1 () × 239.22 1 () = 0.4749 • 67.11% yield (0.3187g) • % = ℎ = 0.3187 0.4749 = 67.11%
18. 2 Results 2.2 Synthesis of 4-hydroxy-4(4-nitrophenyl)-2-butanone A B C D E Peak Label Chemical Shift (ppm) Integration A 2.23 0.86 B 2.86 1.15 C 5.28 0.74 D 7.55 0.98 E 8.24 1.00
19. 2 Results 2.2 Synthesis of 4-hydroxy-4(4-nitrophenyl)-2-butanone • Determining Polarity Average: 0.342 + 0.327 + 0.415 + 0.352 + 0.401 + 0.324 + 0.416 + 0.363 + 0.371 + 0.354 10 = . We can find the angle of specific rotation as follows: = × = 0.367 × 5.00 0.3187 × 1 = +5.76 Measurement Number Optical Rotation 1 0.342 2 0.327 3 0.415 4 0.352 5 0.401 6 0.324 7 0.416 8 0.363 9 0.371 10 0.354
20. 2 Results 2.2 Synthesis of 4-hydroxy-4(4-nitrophenyl)-2-butanone • Determining Polarity Since literature values indicate a specific rotation of +58.8o, the % enantiomeric excess is equal to: % = +5.76 +58.8 = 9.80% = + 2 + 50% = 54.9% = 1 − 0.549 = 45.1%
21. 3 Discussion • L-prolinamide was successfully used to catalyse the reaction between 4- nitrobenzaldehyde and acetone to make 4-hydroxy-4(4-nitrophenyl)-2- butanone • %ee (9.8%) tells us that 54.9% of the product is (R)-4-hydroxyl-4-(4- nitrophenyl)-2-butanone • List group used 0.3 eq of proline w/ DMSO/acetone to catalyse a similar rx (shown earlier) • They obtained 76% ee • Differences include: Pro purity and amount
22. 3 Discussion • Enantiomer selectivity is especially important when dealing with pharmaceuticals •  50% marketed drugs are chiral •  50% of those are single enantiomer • Thalidomide racemate was used as a sleeping drug • One enantiomer caused sever fetal malformations • Racemate is currently used as leprosy drug S-thalidomide R-thalidomide Source: (7,8) Source: (9)
23. 4 Conclusion • Assymetric organocatalysis of direct aldol reactions are: • Very efficient • Have many applications • Have many advantages over alternatives Thank you for your Attention
24. 5 References (1) Tang, Z.; Jiang, F.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. Enantioselective direct aldol reactions catalyzed by L-prolinamide derivatives.Proceedings of the National Academy of Sciences of the United States of America 2004, 101, 5755–60 (2) Dalko, P. I. Enantioselective organocatalysis 2007. (3) Dondoni, A.; Massi, A. Asymmetric organocatalysis: from infancy to adolescence. Angewandte Chemie (International ed. in English) 2007, 47, 4638–60. (4) Alemán, J.; Cabrera, S. Applications of asymmetric organocatalysis in medicinal chemistry.Chemical Society reviews 2013, 42, 774–93. (5) Jarvo, E. R.; Miller, S. J. Amino acids and peptides as asymmetric organocatalysts. Tetrahedron 2002, 58 (6) Ishikawa, H.; Suzuki, T.; Hayashi, Y. High-yielding synthesis of the anti-influenza neuramidase inhibitor (-)- oseltamivir by three “one-pot” operations. Angewandte Chemie (International ed. in English) 2008, 48, 1304–7. (7) McConathy, J.; Owens, M. Stereochemistry in drug action 2003. (8) Eriksson, T.; Björkman, S.; Roth, B.; Fyge, A.; Höglund, P. Stereospecific determination, chiral inversion in vitro and pharmacokinetics in humans of the enantiomers of thalidomide.Chirality 1994, 7, 44–52. (9) Mills, B. Wikipedia, The Free Encyclopedia. https://en.wikipedia.org/wiki/File:Thalidomide-structures.png