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Proline Analogs

Aldrich ChemFiles 2007, 7.9, 3.

Aldrich ChemFiles 2007, 7.9, 3.

The first examples were reported in the mid-70s, when L-proline was applied to Robinson annulation reactions. However, the big potential of proline as an organocatalyst was discovered at the beginning of the 21st century.

The bifunctional structure of the sole cyclic proteinogenic amino acid is a crucial factor. L-proline contains both a nucleophilic secondary amino group and a carboxylic acid moiety functioning as a Brønsted acid. This facilitates a highly pre-organized transition state during the reaction pathway, which results in exceptionally high enantioselectivities.

As a small organic molecule, proline is available in both enantiomeric forms, which is a definite advantage over enzymatic methods. Numerous proline-catalyzed reactions have been developed (Scheme 1).1


Scheme 1

Stimulated by such a vast number of successful examples, many research groups have developed synthetic proline analogs with optimized properties. Some examples are presented here in more detail.

The catalytic asymmetric α-alkylation of aldehydes was described by List.1 This transformation had been accomplished with the help of covalently attached auxiliaries. In comparison to L-proline, α-methyl-L-proline (17249) gives higher enantioselectivities and improved reaction rates (Scheme 2).


Scheme 2

Organocatalytic cyclopropanation reactions were typically performed using catalyst-bound ylides. However, MacMillan demonstrated that activation of olefin substrates using catalytic (S)-(–)-indoline-2-carboxylic acid (346802) is a viable route for the formation of highly enantioenriched cyclopropanes (Scheme 3).3


Scheme 3

Prof. Karl Anker Jørgensen and his group have developed (R)- and (S)-α,α-bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol trimethylsilyl ether (677019) and (677213) resp., which serve as excellent chiral organocatalysts in the direct organocatalytic α-functionalization of aldehydes. In the field of asymmetric synthesis this stereoselective functionalization certainly represents an important breakthrough. Jørgensen’s diarylprolinol silylether reagents were shown to catalyze a variety of bond-forming reactions such as C–C, C–N, C–O, C–S, and C–Hal in high yields and excellent levels of enantiocontrol (Scheme 4).4


Scheme 4

Enders and co-workers have developed a chemo-, diastereo-, and enantioselective three-component domino reaction, accomplished with proline-derived organocatalyst (677183) and low cost, simple starting materials, leading to tetra-substituted cyclohexene carbaldehydes (Scheme 5).5 The four stereogenic centers are generated in three consecutive carbon–carbon bond formations, i.e., Michael/Michael/aldol condensation with high diastereo- and complete enantiocontrol. Thus, this domino reaction opens up a simple and flexible entry to polyfunctional cyclohexene building blocks.


Scheme 5

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Materials

     

References

  1. (a) Mannich reaction: List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827. (b) α-Amination: List, B. J. Am. Chem. Soc. 2002, 124, 5656. (c) α-Aminoxylation: Zhong, G. Angew. Chem. Int. Ed. 2003, 42, 4247. Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 10808; Bøgevig, A.; Sunden, H.; Córdova. A. Angew. Chem. Int. Ed. 2004, 43, 1109. (d) Michael addition: List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3, 2423. (e) α-Oxyaldehyde dimerization: Northrup, A. B.; Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2004, 43, 2152. (f) Cross-aldol reaction: Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798.
  2. Vignola, N.; List, B. J. Am. Chem. Soc. 2003, 125, 450.
  3. Kunz, R. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3240.
  4. (a) Franzén, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.; Kjærsgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296. (b) Bøgevig, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2002, 41, 1790. (c) Marigo, M.; Jørgensen, K. A. α-Heteroatom Functionalization. In Enantioselective Organocatalysis; Dalko, P. I., Ed.; Wiley-VCH: Weinheim, 2007; Chapter 2.2. (d) Marigo, M.; Schulte, T.; Franzén, J.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 15710. (e) Marigo, M.; Franzén, J.; Poulsen, T. B.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 6964. (f) Carlone, A.; Bartoli, G.; Bosco, M.; Sambri, L.; Melchiorre, P. Angew. Chem. Int. Ed. 2007, 46, 4504. (g) Ibrahem, I.; Rios, R.; Vesely, J.; Hammar, P.; Eriksson, L.; Himo, F.; Córdova, A. Angew. Chem. Int. Ed. 2007, 46, 4507.
  5. Enders, D.; Hüttl, M. R. M.; Grondal, C.; Raabe, G. Science 2006, 441, 861.

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