Cluster Preface: Challenges of Proline-Based Aminocatalysis

proline - aminocatalysis - enamine catalysis - iminium ion catalysis

I vividly remember the day in 1999 when I set up an experiment that today likely bores to tears each and every chemist around the globe: the proline-catalyzed aldol ­reaction of acetone with p-nitro benzaldehyde. Not particularly much was expected from this experiment and I reasoned that somebody must have tried this before. Neither would I have predicted the highly successful outcome of this reaction, [¹] nor what would happen in subsequent years, which brought literally hundreds of papers suggesting to have taken inspiration from my initial observation. [²] Key to the phenomenal growth of our finding into an ­entire field was not so much the discovery of the proline-catalyzed intermolecular aldol reaction via an enamine intermediate or the subsequent amino acid derivative catalyzed Diels-Alder reactions via an iminium ion, [³] but rather the realization that enamine catalysis and iminium ion catalysis are truly generic carbonyl activation modes. [4] Once this had been fully appreciated, the ‘amino­catalysis explosion’ took off.

Some highlights of this development include the proline-catalyzed Mannich reaction, the aldehyde cross-aldolization, enamine catalytic α-alkylations and α-functionalizations, various Michael additions, SOMO catalysis, ACDC, and of course the many wonderful organocascade processes that make combined use of enamine and iminium ion catalysis (for a small collection of proline-based catalytic transformations, see Scheme  [¹] ). [4] In addition to the many new reactions that continue to be explored and advanced, several new proline-based catalysts have also been designed and discovered of which the prolinol silyl ethers are probably the most versatile. But other successful motifs have also been described, including highly ­active and enantioselective proline amides, some remarkable fully synthetic motifs, and cinchona-derived primary amines with complementary reactivity.

Benjamin List

Scheme 1 A small and incomplete selection of highly enantioselec­tive proline (derivative) catalyzed reactions. [²] [4] [5]

So what are the challenges of proline-based aminocatalysis? I think we now largely appreciate the scope of the ­catalysis principle, and to some extend the requirements for designing effective catalysts. I doubt though that there will be many more fundamentally new reactions discovered soon, although I still see substantial room for important research in the area. There are three main interrelated topics that will likely be addressed: (1) mechanistic understanding, (2) substrate scope enlargement of the various reactions, and (3) advanced catalysts. While proline-based enamine catalysis has delivered truly marvelous reactions, consider for example the scope and enantioselectivity of the proline-­catalyzed Mannich reaction, certain issues remain to be solved. It may not sound so important, but a general aldehyde cross-aldol reaction that furnishes syn instead of the common anti products would be considered a true breakthrough by many in the field. Similarly, direct aldehyde α-alkylations are still narrow in scope and yet could be ­extremely useful. These are just two high-profile challenges, but there are many other problems that remain to be solved. One issue concerns the development of advanced catalysts. Activity and selectivity need to be constantly refined and improved, and catalyst recyclability will become a more important issue. It is clear that such advancements are likely only to be achievable through further mechanistic understanding and it is therefore gratifying to see that mechanistic studies are currently a hot topic in organocatalysis as a whole.

This Cluster, edited by Hisashi Yamamoto and myself, presents some recent work by leading experts in the field of proline-based aminocatalysis that addresses some of the above issues. Isn’t it amazing how much high quality research this field continues to deliver? I am very grateful to all authors for their wonderful contributions and can’t wait to see the advancements of the next decade….

References and Notes

1 List B. Lerner RA. Barbas III CF. J. Am. Chem. Soc.  2000,  122:  2395 

2For a review on enamine catalysis, see:

2 Mukherjee S. Yang JW. Hoffmann S. List B. Chem. Rev.  2007,  107:  5471 

3 Ahrendt KA. Borths CJ. MacMillan DWC. J. Am. Chem. Soc.  2000,  122:  4243 

For other selected reviews covering aminocatalysis see:

4a List B. Synlett  2001,  1675 

4b List B. Acc. Chem. Res.  2004,  37:  548 

4c List B. Chem. Commun.  2006,  819 

4d Lelais G. MacMillan DWC. Aldrichimica Acta  2006,  39:  79 

4e List B. Yang JW. Science  2006,  313(5793):  1584 

4f Erkkilä A. Majander I. Pihko PM. Chem. Rev.  2007,  107:  5416 

4g Enders D. Grondal C. Huettl MRM. Angew. Chem. Int. Ed.  2007,  46:  1570 

4h MacMillan DWC. Nature  2008,  455:  304 

4i Enders D. Narine AA. J. Org. Chem.  2008,  73:  7857 

4j Kano T. Maruoka K. Chem. Commun.  2008,  43:  5465 

4k Bertelsen S. Jørgensen KA. Chem. Soc. Rev.  2009,  38:  2178 

4l Pihko PM. Majander I. Erkkilä A. Top. Curr. Chem.  2010,  291:  29 

4m Brazier JB. Tomkinson NCO. Top. Curr. Chem.  2010,  291:  281 

4n List B. Angew. Chem. Int. Ed.  2010,  49:  1730 

5a

see ref. 1

5b Northrup AB. MacMillan DWC. J. Am. Chem. Soc.  2002,  124:  6798 

5c List B. J. Am. Chem. Soc.  2000,  122:  9336 

5d Yang JW. Stadler M. List B. Angew. Chem. Int. Ed.  2007,  46:  609 

5e Yang JW. Chandler C. Stadler M. Kampen D. List B. Nature  2008,  452:  453 

5f Chi Y. Gellman SH. Org. Lett.  2005,  7:  4253 

5g List B. J. Am. Chem. Soc.  2002,  124:  5656 

5h Bøgevig A. Juhl K. Kumaragurubaran N. Zhuang W. Jørgensen KA. Angew. Chem. Int. Ed.  2002,  41:  1790 

5i Zhong G. Angew. Chem. Int. Ed.  2003,  42:  4247 

5j Brown SP. Brochu MP. Sinz CJ. MacMillan DWC. J. Am. Chem. Soc.  2003,  125:  10808 

5k Hayashi Y. Yamaguchi J. Hibino K. Shoji M. Tetrahedron Lett.  2003,  44:  8293 

5l Franzén J. Marigo M. Fielenbach D. Wabnitz TC. Kjærsgaard A. Jørgensen KA. J. Am. Chem. Soc.  2005,  127:  18296