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• Organocatalysis
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Albrecht Berkessel, Harald Groeger, Asymmetric Organocatalysis, 2005, Wiley-VCH,
p409-435.
M.T. Reetz, B. List, S. Jaroch, H. Weinmann (Editors), Ernst Schering Foundation
Symposium Proceedings 2007-2 Organocatalysis
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http://onlinelibrary.wiley.com/book/10.1002/3527604677
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• Total Synthesis
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C. Bittner, A. S. Busemann, U. Griesbach, F. Haunert, W.-R. Krahnert, A. Modi, J.
Olschimke, P. L. Steck, Organic Synthesis Workbook II, 2001 Wiley-VCH Verlag
GmbH
http://onlinelibrary.wiley.com/book/10.1002/3527600132
1
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
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
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
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
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.
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dimeric cinchona alkaloid derivatives
1) α-Halogenation of carbonyl compounds
2) Carboethyoxycyanation of ketones
3) Desymmetrization of meso-anhydrides
4) (Dynamic) kinetic resolution of racemic Anhydrides
Commercially available
1) Kinetic resolution of racemic alcohols by acylation
2) Desymmetrization of meso-diols by acylation
Preparation starting from L-proline in multi-step
syntheses
L-proline-derived diamines
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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
8
Reference:
Albrecht
Berkessel, Harald
Groeger,
Asymmetric
Organocatalysis,
2005, Wiley-VCH,
P10-11.
9
10
11
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Pioneering work by Pracejus et al. in 1960, again using alkaloids as
catalysts, afforded quite remarkable 74% ee in the addition of methanol to
phenylmethylketene. In this particular reaction 1 mol% O-acetylquinine (10,
Scheme 1.2) served as the catalyst
13
1971 saw the discovery of the Hajos–Parrish–Eder–Sauer–Wiechert
reaction, i.e. the proline (1)-catalyzed intramolecular asymmetric aldol
cyclodehydration of the achiral trione 11 to the unsaturated Wieland–Miescher
ketone 12 (Scheme 1.3) [12, 13]. Ketone 12 is an important intermediate in
steroid synthesis.
14
Surprisingly, the catalytic potential of proline (1) in asymmetric aldol
reactions was not explored further until recently. List et al. reported
pioneering studies in 2000 on intermolecular aldol reactions. For example,
acetone can be added to a variety of aldehydes, affording the corresponding
aldols in excellent yields and enantiomeric purity.
15
In the same year, MacMillan et al. reported that the phenylalanine-derived
secondary amine 5 catalyzes the Diels–Alder reaction of a,b-unsaturated
aldehydes with enantioselectivity up to 94% (Scheme 1.4).
16
A similarly remarkable event was the discovery of the cyclic peptide 14 shown
in Scheme 1.5. In 1981 this cyclic dipeptide – readily available from l-histidine
and l-phenylalanine – was reported, by Inoue et al., to catalyze the addition of
HCN to benzaldehyde with up to 90% ee (Scheme 1.5). Again, this observation
sparked intensive research in the field of peptide-catalyzed addition of
nucleophiles to aldehydes and imines.
17
Also striking was the discovery, by Julia’, Colonna et al. in the early 1980s,
of the poly-amino acid (15)-catalyzed epoxidation of chalcones by alkaline
hydrogen peroxide. In this experimentally most convenient reaction,
enantiomeric excesses > 90% are readily achieved (Scheme 1.6).
18
An example is the finding by Rawal et al. that hetero-Diels–Alder reactions –
a classical domain of metal-based Lewis acids – can be effected with very high
enantioselectivity by hydrogen bonding to chiral diols such as TADDOL (16,
Scheme 1.7).
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Chapter 3. Nucleophilic Substitution at
Aliphatic Carbon
20
Phase-transfer catalysts are used and form a chiral ion pair of type 4 as an
key intermediate. In a first step, an anion, 2, is formed via deprotonation with an
achiral base; this is followed by extraction in the organic phase via formation of
a salt complex of type 4 with the phase-transfer organocatalyst, 3.
Subsequently, a nucleophilic substitution reaction furnishes the optically
active alkylated products of type 6, with recovery of the catalyst 3.
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3.1 α-Alkylation of Cyclic Ketones and Related Compounds
The first example of the use of an alkaloid-based chiral phase-transfer catalyst
as an efficient organocatalyst for enantioselective alkylation reactions was reported in
1984. Researchers from Merck used a cinchoninium bromide, 8, as a catalyst in the
methylation of the 2-substituted indanone 7. The desired product, 9, a key
intermediate in the synthesis of (+)-indacrinone was formed in 95% yield and with
92% ee (Scheme 3.2).
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3.2 α-Alkylation of α-Amino Acid Derivatives
Attachment of the 9-anthracenylmethyl group to a bridgehead nitrogen gave high
enantioselectivity in the biscinchona-alkaloid-catalyzed dihydroxylation of olefins by
osmium tetroxide, Corey and co-workers designed the structurally rigidified chiral
quaternary ammonium salt 25 (Scheme 3.6).
23
The development of dimeric cinchona
alkaloids as very efficient and practical catalysts
for asymmetric alkylation of the N-protected
glycine ester 18 was reported by the Park and
Jew group.
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3.2.2 Improving Enantioselectivity During Work-up
Because of the high potential of alkaloid-based alkylations for synthesis of
amino acids, several groups focused on the further enantiomeric
enrichment of the products.
In addition to product isolation issues, a specific goal of those
contributions was improvement of enantioselectivity to ee values of at least
99% ee during downstream-processing (e.g. by crystallization).
For pharmaceutical applications high enantioselectivity of >99% ee is
required for optically active α-amino acid products.
25
3.2.3 Specific Application in the Synthesis of Non-natural Amino Acids
The Maruoka group used their highly enantioselective, structurally rigid, chiral spiro
catalysts of type 29 in the synthesis of L-Dopa ester (S)-40 and an analog thereof. Initial
asymmetric alkylation in the presence of 1 mol% (R,R)-29 gave the intermediate (S)-20q
in 81% yield and 98% ee (Scheme 3.16). Subsequent debenzylation provided the desired
L-Dopa ester (S)-40 in 94% yield and 98% ee. This reaction has also already been
performed on a gram-scale.
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3.2.4 Synthesis of α,α-Dialkylated Amino Acids
27
The enantioselective PTC-alkylation starting from racemates can be also achieved
very efficiently when using the ammonium salt catalyst, 29, developed by Maruoka
and co-workers.
28
The Maruoka group recently reported an alternative concept based on a one-pot double
alkylation of the aldimine of glycine butyl ester, 44a, in the presence of the chiral
ammonium salt 29 as chiral phase-transfer catalyst
29
3.2.6 Solid-phase Syntheses
The solid-phase synthesis of α-amino acids via alkaloid-catalyzed alkylation has been
investigated by the O’Donnell group. The solid-phase based synthetic approach is particularly
useful for rapid preparation of a-amino acids for combinatorial application.
30
3.4 Fluorination, Chlorination, and Bromination Reactions
3.4.1 Fluorination Reactions
An enantioselective fluorination method with catalytic potential has not been realized
until recently, when Takeuchi and Shibata and co-workers and the Cahard group
independently demonstrated that asymmetric organocatalysis might be a suitable tool
for catalytic enantioselective construction of C-F bonds.
31
32
3.4.2 Chlorination and Bromination Reactions
A similar catalytic procedure for enantioselective formation of C-Br and C-Cl bonds
has been reported recently by the Lectka group.
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34
35
4. Nucleophilic Addition to Electron-deficient C=C Double Bonds
4.1 Intermolecular Michael Addition
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37
One of these approaches consists in activating the acceptors – mostly α,β-unsaturated aldehydes
(R4 = H) and ketones (R4 = alkyl) – by reversible conversion to a chiral iminium ion. As shown in
Scheme 4.2a, reversible condensation of an α,β-unsaturated carbonyl compound with a chiral
secondary amine provides a chiral α,β-unsaturated iminium ion. Face-selective reaction with the
nucleophile provides an enamine which can either be reacted with an electrophile then hydrolyzed
or just hydrolyzed to α,β-chiral carbonyl compound.
The second approach is the enamine pathway. If the nucleophile is an enolate anion, it can be
replaced by a chiral enamine, formed reversibly from the original carbonyl compound and a chiral
secondary amine (Scheme 4.2b).
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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%.
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40
41
42
43
44
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4.1.1.2 Activation of Michael Acceptors by Iminium Ion Formation,
Activation of Carbonyl Donors by Enamine Formation
Cheap and readily available Lproline 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%.
46