Organocatalysis

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enzymes.[1][2]

In organic chemistry, organocatalysis is a form of catalysis in which the rate of a chemical reaction is increased by an organic catalyst. This "organocatalyst" consists of carbon, hydrogen, sulfur and other nonmetal elements found in organic compounds.[3][4][5][6][7][8] Because of their similarity in composition and description, they are often mistaken as a misnomer for enzymes due to their comparable effects on reaction rates and forms of catalysis involved.

Organocatalysts which display secondary amine functionality can be described as performing either enamine catalysis (by forming catalytic quantities of an active enamine nucleophile) or iminium catalysis (by forming catalytic quantities of an activated iminium electrophile). This mechanism is typical for covalent organocatalysis. Covalent binding of substrate normally requires high catalyst loading (for proline-catalysis typically 20–30 mol%). Noncovalent interactions such as hydrogen-bonding facilitates low catalyst loadings (down to 0.001 mol%).

Organocatalysis offers several advantages. There is no need for metal-based catalysis thus making a contribution to

asymmetric catalysis; for example, the use of proline in aldol reactions is an example of chirality and green chemistry.[10] Organic chemists David MacMillan and Benjamin List were both awarded the 2021 Nobel Prize in chemistry for their work on asymmetric organocatalysis.[11]

Introduction

Regular achiral organocatalysts are based on nitrogen such as

Hajos–Parrish–Eder–Sauer–Wiechert reaction. Between 1968 and 1997, there were only a few reports of the use of small organic molecules as catalysts for asymmetric reactions (the Hajos–Parrish reaction probably being the most famous), but these chemical studies were viewed more as unique chemical reactions than as integral parts of a larger, interconnected field.[15]

The original reaction

In this reaction, naturally occurring chiral proline is the chiral catalyst in an Aldol reaction. The starting material is an achiral triketone and it requires just 3% of proline to obtain the reaction product, a ketol in 93% enantiomeric excess. This is the first example of an amino acid-catalyzed asymmetric aldol reaction.[16][17]

The asymmetric synthesis of the

Robert B. Woodward (1981).[18] A mini-review digest article focuses on selected recent examples of total synthesis of natural and pharmaceutical products using organocatalytic reactions.[19]

Many chiral organocatalysts are an adaptation of

chiral ligands
(which together with a metal center also catalyze asymmetric reactions) and both concepts overlap to some degree.

A breakthrough in the field of organocatalysis came in 1997 when Yian Shi reported the first general, highly enantioselective organocatalytic reaction with the catalytic asymmetric epoxidation of trans- and trisubstituted olefins with chiral dioxiranes.[20] Since that time, several different types of reactions have been developed.

Organocatalyst classes

Organocatalysts for asymmetric synthesis can be grouped in several classes:

Examples of asymmetric reactions involving organocatalysts are:

  • Asymmetric Diels-Alder reactions
  • Asymmetric Michael reactions
  • Asymmetric Mannich reactions
  • Shi epoxidation
  • Organocatalytic transfer hydrogenation

Proline

Main article: Proline organocatalysis

Proline catalysis has been reviewed.[22][23]

Imidazolidinone organocatalysis

Imidazolidinone Catalysts
Imidazolidinone Catalysts

LUMO:[24][25]

Iminium ion activation

The transient iminium intermediate is chiral which is transferred to the reaction product via

epoxidations
.

One example is the asymmetric synthesis of the drug

4-hydroxycoumarin and benzylideneacetone:[26]

Asymmetric warfarin synthesis Jørgensen 2003

A recent exploit is the vinyl alkylation of crotonaldehyde with an organotrifluoroborate salt:[27]

Asymmetric Vinyl Alkylation Lee 2007

For other examples of its use: see

asymmetric Diels-Alder reactions
.

Thiourea organocatalysis

Main article: Thiourea organocatalysis

A large group of organocatalysts incorporate the

hydrogen-bonding interactions to coordinate and activate H-bond accepting substrates.[28]

Their current uses are restricted to asymmetric multicomponent reactions, including those involving Michael addition, asymmetric multicomponent reactions for the synthesis of spirocycles, asymmetric multicomponent reactions involving acyl Strecker reactions, asymmetric Petasis reactions, asymmetric Biginelli reactions, asymmetric Mannich reactions, asymmetric aza-Henry reactions, and asymmetric reductive coupling reactions.[29]

References

  1. doi:10.1002/jlac.18601130213
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  2. doi:10.1002/jlac.19294690103
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  3. ISBN 978-3-527-30517-9
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  4. doi:10.1021/cr078412e
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  5. PMID 15455437
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  6. PMID 17198969
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  7. PMID 17225236
    .
  8. PMID 11668532
    .
  9. ^ International Patent WO 2006068611 A1 20060629 " Direct Homogeneous and Heterogeneous Organic Acid and Amino Acid-Catalyzed Modification of Amines and Alcohols" Inventors: Armando Córdova, Stockholm, Sweden; Jonas Hafrén, Stockholm, Sweden.
  10. ^ Example 4 in U.S. Patent 3,975,440 August 17, 1976, Filed Dec. 9, 1970 Zoltan G. Hajos and David R. Parrish.
  11. ^ "2021 Nobel Prize in chemistry". Nobel Prize. Nobel Prize. Retrieved 6 October 2021.
  12. PMID 20175175
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  13. doi:10.1002/anie.197805221
    .
  14. PMID 12630854
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  15. S2CID 205215034
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  16. ^ Z. G. Hajos, D. R. Parrish, German Patent DE 2102623 1971
  17. doi:10.1021/jo00925a003
    .
  18. doi:10.1021/ja00401a049
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  19. doi:10.1016/j.tetlet.2015.03.046
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  20. ISSN 0002-7863
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  21. PMID 19623342
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  22. PMID 17198969
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  23. S2CID 93168492
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  24. ^ Gérald Lelais; David W. C. MacMillan (2006). "Modern Strategies in Organic Catalysis: The Advent and Development of Iminium Activation" (PDF). Aldrichimica Acta. 39 (3): 79.
  25. PMID 18072802
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  26. PMID 14579449
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  27. S2CID 34848947
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  28. doi:10.1021/acscatal.6b00618
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  29. doi:10.1039/D0OB00595A
    .

External links

Scholia has a profile for Organocatalysis (Q898995).
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