Proline Analogs

Aldrich ChemFiles 2006, 6.4, 3.

Coined by Jacobsen1 as the “simplest enzyme,” L-proline is capable of effecting a variety of catalytic asymmetric transformations. The first examples were reported in the mid-70s, when L-proline was applied to Robinson annulation reactions.2 However, the big potential of proline as an organocatalyst was discovered in the beginning of the 21st century. One explanation for such a delay might be that the scope of highly selective transformations was considered to be rather narrow, and the development of metal catalysts seemed more promising.

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 (Scheme 1).3


Scheme 1.

Moreover, 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 2).4

Stimulated by such a vast number of successful examples, many research groups have developed synthetic proline analogs with optimized properties (see: ChemFiles Vol. 5 No. 12, Tools for Drug Discovery). Some examples will be presented here in more detail.


Scheme 2.

The catalytic asymmetric α-alkylation of aldehydes was recently described by List.5 To date, this transformation was usually 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 3).


Scheme 3.

Organocatalytic cyclopropanation reactions were typically performed using catalyst-bound ylides.6 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 4).7


Scheme 4.

Aggarwal utilized protonated (S)-(–)-2-(diphenylmethyl)pyrrolidine (552534) as an organocatalyst in a novel process for the enantioselective epoxidation of alkenes.8 Although the reaction proceeds under phase-transfer conditions (PTC), it was found that secondary amines catalyzed the reaction at remarkably higher rates, implying that (552534) does not act only as a PTC. However, best results were obtained with the chiral pyrrolidine bearing 1-naphthyl substituents (Scheme 5).


Scheme 5.

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Materials

     

References

  1. Movassaghi, M.; Jacobsen, E. N. Science 2002, 298, 1904.
  2. For early examples of organocatalyzed reactions, see: (a) Pracejus, H. Justus Liebigs Ann. Chem. 1960, 634, 9. (b) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615. (c) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem. Int. Ed. Engl. 1971, 10, 496.
  3. Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J. Am. Chem. Soc. 2003, 125, 2475. .
  4. (a) Mannich reaction: List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827. (b) a-Amination: List, B. J. Am. Chem. Soc. 2002, 124, 5656. (c) a-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) a-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.
  5. Vignola, N.; List, B. J. Am. Chem. Soc. 2003, 125, 450.
  6. (a) Aggarwal, V. K.; Alonso, E.; Fang, G.; Ferrara, M.; Hynd, G.; Porcelloni, M. Angew. Chem. Int. Ed. 2001, 40, 1433. (b) Aggarwal, V. K.; Winn, C. L. Acc. Chem. Res. 2004, 37, 611.
  7. Kunz, R. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3240.
  8. Aggarwal, V. K.; Lopin, C.; Sandrinelli, F. J. Am. Chem. Soc. 2003, 125, 7596.

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