Organocatalysis

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• Organocatalysis
•  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
• http//onlinelibrary.wiley.com/book/10.1002/352760
  4677
• http//www.springerlink.com/content/x7344h/sectio
  n210299page1
• http//www.lib.ntnu.edu.tw/eresource/wiley_ebook.h
  tm
• Total Synthesis
• 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/10.1002/352760
  0132

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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
NN double bonds (a-amination of carbonyl
compounds) 7) Addition to NO 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 a-alkylation of aldehydes
L-Enantiomer commercially available
3
1) Intermolecular Michael addition 2)
Intermolecular aldol reaction 3)
32-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
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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) 42-Cycloadditions Diels-Alder
reactions 3) 32-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
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
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1) a-Halogenation of carbonyl compounds 2)
Intermolecular Michael addition (including
cyclopropanation of enones, enoates etc.) 3)
Intramolecular Michael addition 4) ß-Lactam
synthesis from imines and ketenes 5) ß-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 (RH) are commercially
available in large quantities.
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dimeric cinchona alkaloid derivatives
1) a-Halogenation of carbonyl compounds 2)
Carboethyoxycyanation of ketones 3)
Desymmetrization of meso-anhydrides 4) (Dynamic)
kinetic resolution of racemic Anhydrides Commerci
ally 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
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Reference Albrecht Berkessel, Harald Groeger,
Asymmetric Organocatalysis, 2005,
Wiley-VCH, P10-11.
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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

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• 1971 saw the discovery of the HajosParrishEderS
  auerWiechert reaction, i.e. the proline
  (1)-catalyzed intramolecular asymmetric aldol
• cyclodehydration of the achiral trione 11 to the
  unsaturated WielandMiescher ketone 12 (Scheme
  1.3) 12, 13. Ketone 12 is an important
  intermediate in steroid synthesis.

15

• 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.

16

• In the same year, MacMillan et al. reported that
  the phenylalanine-derived secondary amine 5
  catalyzes the DielsAlder reaction of
  a,b-unsaturated aldehydes with enantioselectivity
  up to 94 (Scheme 1.4).

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• 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.

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• 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 gt 90 are readily achieved
  (Scheme 1.6).

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• An example is the finding by Rawal et al. that
  hetero-DielsAlder 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
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• 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 a-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 a-Alkylation of a-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).

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• 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 gt99 ee is required for
  optically active a-amino acid products.

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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 a,a-Dialkylated Amino Acids
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• 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.

29

• 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

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3.2.6 Solid-phase Syntheses

• The solid-phase synthesis of a-amino acids via
  alkaloid-catalyzed alkylation has been
  investigated by the ODonnell group. The
  solid-phase based synthetic approach is
  particularly useful for rapid preparation of
  a-amino acids for combinatorial application.

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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.

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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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4. Nucleophilic Addition to Electron-deficient
CC Double Bonds
4.1 Intermolecular Michael Addition
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• One of these approaches consists in activating
  the acceptors mostly a,ß-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
  a,ß-unsaturated carbonyl compound with a chiral
  secondary amine provides a chiral a,ß-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 a,ß-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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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 40ac (Scheme 4.13), with
  enantiomeric excesses as high as 77.