This document provides a tabular survey and overview of various organocatalysts used in asymmetric organocatalysis reactions, including their reaction scopes and commercial availabilities. It discusses how L-proline and other amino acids like L-phenylalanine are commonly used economical organocatalysts that are readily available. It also outlines how cinchona alkaloids are widely used organocatalysts that are commercially available. In general, the document surveys different organocatalysts and their applications in asymmetric reactions.

1. Organocatalysis
1
M.Sc.(Chemistry) Ist Year

2. Asymmetric Organocatalysis
Reference: Albrecht Berkessel, Harald Groeger, Asymmetric Organocatalysis, 2005, Wiley-VCH,
p409-435.
Tabular Survey of Selected Organocatalysts: Reaction Scope and Availability:
1) Intermolecular Michael addition
2) Mannich reaction
3) Intermolecular aldol reaction
4) Intramolecular aldol reaction
5) Aldol-related reactions (addition of nitrones)
6) Addition to N=N double bonds (a-amination of carbonyl compounds)
7) Addition to N=O double bonds (a-aminoxylation/ hydroxylation of
carbonyl compounds
L-Proline is commercially available in bulk quantities and represents an
economically attractive amino acid organocatalyst.
(D-Proline is commercially available, too.)
Intramolecular α-alkylation of aldehydes
L-Enantiomer commercially available
2

3. 1) Intermolecular Michael addition
2) Intermolecular aldol reaction
3) [3+2]-Cycloadditions
4) Desymmetrization of meso-diols
5) Desymmetrization of meso-epoxides
Preparation starting from L-proline in
multi-step syntheses
Mannich reaction
Preparation starting from l-proline in
multi-step syntheses
1) Mannich reaction
2) Intermolecular aldol reaction [6.2.1]
Readily accessible, using L-penicillamine
as starting material
3

4. Intramolecular aldol reaction
Just as L-proline, L-phenylalanine is an
economically attractive amino acid organocatalyst,
readily available in bulk quantities.
1) Intermolecular Michael addition, including alkylation
of heterocyclic aromatics and aniline derivatives
2) [4+2]-Cycloadditions: Diels-Alder reactions
3) [3+2]-Cycloadditions: Nitrone-based reactions
Organocatalysts readily prepared from L-phenylalanine,
methylamine and acetone or piraldehyde
Intermolecular Michael addition
Prepared from L-phenylalanine, methylamine
and glyoxylic acid in a few steps
4

5. Tautomerization of enols
Prepared from (+)-camphor in a multi-step syntheses
Intramolecular Michael addition
Commercially available in both enantiomeric forms in
bulk quantities; economically attractive organocatalyst
5

6. 1) α-Halogenation of carbonyl compounds
2) Intermolecular Michael addition (including
cyclopropanation of enones, enoates etc.)
3) Intramolecular Michael addition
4) β-Lactam synthesis from imines and ketenes
5) β-Lactone synthesis from aldehydes and ketenes
6) Morita-Baylis-Hillman reaction
7) Hydrophosphonylation of aldehydes
8) Diels-Alder reaction
9) Desymmetrization of meso-anhydrides
10) Additions to prochiral ketenes
11) Desymmetrization of meso-diols
12) Desymmetrization of meso-epoxides
All four natural cinchona alkaloids (R=H) are
commercially available in large quantities.
6

7. 1) α-Halogenation of carbonyl compounds
2) Carboethyoxycyanation of ketones
3) Desymmetrization of meso-anhydrides
4) (Dynamic) kinetic resolution of racemic Anhydrides
Commercially available
dimeric cinchona alkaloid derivatives
L-proline-derived diamines
1) Kinetic resolution of racemic alcohols by acylation
2) Desymmetrization of meso-diols by acylation
Preparation starting from L-proline in multi-step
syntheses
7

8. 8
Chapter 1. Introduction: Organocatalysis –
From Biomimetic Concepts to Powerful
Methods for Asymmetric Synthesis
Chapter 2. On the Structure of the Book,
and a Few General Mechanistic
Considerations

9. 9
4.1.1. Intermolecular Michael Addition of C-nucleophiles
4.1.1.1 Chiral Bases and Phase-transfer Catalysis
The first examples of asymmetric Michael additions of C-nucleophiles to enones
appeared in the middle to late 1970s. In 1975 Wynberg and Helder demonstrated in a
preliminary publication that the quinine-catalyzed addition of several acidic, doubly
activated Michael donors to methyl vinyl ketone (MVK) proceeds asymmetrically.
Enantiomeric excesses were determined for addition of a-tosylnitroethane to MVK (56%)
and for 2-carbomethoxyindanone as the pre-nucleophile (68%).
Later Hermann and Wynberg reported in more detail that 2-carbomethoxyindanone
(1, Scheme 4.3) can be added to methyl vinyl ketone with ca 1 mol% quinine (3a) or
quinidine (3b) as catalyst to afford the Michael-adduct 2 in excellent yields and with up to
76% ee. Because of their relatively low basicity, the amine bases 3a,b do not effect the
Michael addition of less acidic pre-nucleophiles such as 4 (Scheme 4.3). However, the
corresponding ammonium hydroxides 6a,b do promote the addition of the substrates 4 to
methyl vinyl ketone under the same mild conditions, albeit with enantioselectivity not
exceeding ca 20%.

10. 10

11. 11

12. 12

13. 13

14. 14

15. 15

16. 16
4.1.1.2 Activation of Michael Acceptors by Iminium Ion Formation,
Activation of Carbonyl Donors by Enamine Formation
Cheap and readily available L-
proline has been used numerous
times for the intermediate and
reversible generation of chiral
iminium ions from a,b-unsaturated
carbonyl compounds.
For example, Yamaguchi et al.
reported in 1993 that the rubidium
salt of L-proline catalyzes the
addition of di-iso-propyl malonate to
the acyclic Michael acceptors 40a–c
(Scheme 4.13), with enantiomeric
excesses as high as 77%.