Stereochemistry and

stereocontrolled synthesis (OC 8)

A lecture from Prof. Paul Knochel,

Ludwig-Maximilians-Universität München
WS 2015-16

1
 Wichtig!
• Prüfung Stereochemistry
02. Februar 2016
8:00 – 10:00
Willstätter-HS

• Nachholklausur Stereochemistry
5. April 2016
9:00 – 11:00
Willstätter-HS
2
Problem set part I

3
Problem set part II

4
Problem set part III

5
 Recommended Literature

• E. Juaristi, Stereochemistry and Conformational Analysis, Wiley, 1991.

• E. Eliel, Stereochemistry of Organic Compounds, Wiley, 1994.
• A. Koskinen, Asymmetric Synthesis of Natural Products, Wiley, 1993.
• R. Noyori, Asymmetric Catalysis, Wiley, 1994.
• F. A. Carey, R. J. Sundberg, Advanced Organic Chemistry, 5th Edition, Springer,
2007.
• A. N. Collins, G. N. Sheldrake, J. Crosby, Chirality in Industrie, Vol. I and II, Wiley,
1995 and 1997.
• G.Q. Lin, Y.-M. Li, A.S.C. Chan, Asymmetric Synthesis, 2001, ISBN 0-471-40027-0.
• P. Deslongchamps, Stereoelectronic Effects in Organic Chemistry, Pergamon, 1983.
• M. Nogradi, Stereoselective Synthesis, VCH, 1995.
• E. Winterfeldt, Stereoselective Synthese, Vieweg, 1988.
• R. Mahrwald (Ed.), Modern Aldol Reactions, Vol. I and II, Wiley, 2004.
• C. Wolf, Dynamic Stereochemistry of Chiral Compounds, RSC Publishing, 2008.
• A. Berkessel, H. Gröger, Asymmetric Organocatalysis, Wiley-VCH, 2005.
• J. Christoffers, A. Baro (Eds.), Quaternary Stereocenters, Wiley-VCH, 2005.
• Catalytic Asymmetric Synthesis, I. Oshima (Ed.), Wiley, 2010.

6
Recent advances of asymmetric catalysis

7
 Asymmetric Hydrogenation of Heterocyclic Compounds

8
R. Kuwano, N. Kameyama, R. Ikeda, J. Am. Chem. Soc. 2011, 133, 7312-7315.
 Camphor-Derived Organocatalytic Synthesis of Chromanones

9
Z.-Q. Rong, Y. Li, G.-Q. Yang, S.-L. You, Synlett 2011, 1033-1037.
 Stereochemical principles - introduction and definitions

- Isomers are molecules having the same composition

- Structural isomers have different connectivities:

10
 Classification of stereoisomers

Enantiomers are two stereoisomers which are mirror images

Diastereomers are stereoisomers which are not enantiomers

Configuration isomers:

Conformation isomers:

The energy barrier has to be over 25 kcal/mol in order to speak of configurational isomers.

11
 Introduction: classification of stereoisomers

- Conformation isomers:

12
 Introduction: classification of stereoisomers

Lactic acid as example

1874 suggestion by Van’t Hoff; LeBel

The tetrahedral arrangement of substituents at Csp3 carbon centers.
13
 Definitions
Chirality: A molecule is chiral if it is not identical with its mirror image.

A chiral carbon-center bears 4 different substituents.

An organic molecule with n chiral centers has 2n stereoisomers,
if no additional symmetry element is present in this molecule.

A molecule is achiral if it contains a plane of symmetry or a center of inversion

or a Sn symmetry element.
A chiral molecule may contain only Cn symmetry element and identity (E)

Tartaric acid exists only as 3 different stereoisomers:

14
 Properties of enantiomers

Two enantiomers have identical physical properties but show the opposite rotation
of polarized light in a polarimeter.

Importantly, the biological properties of enantiomers are different!

95% of all drugs are chiral, therefore the enantioselective synthesis of organic molecules is of key importance.

15
Chiral molecules not centered at carbon

16
 Nomenclature of stereoisomers

The Cahn-Ingold-Prelog rules (CIP rules)

17
 Nomenclature of stereoisomers

1. Highest atomic number: I > Br > Cl; D > H

2. CH2Br > CH2Cl > CH2OH > CH2CH3 > CH3 CH2Br > CCl3 !

3. The case of multiple bonds

18
 Nomenclature of stereoisomers

Ascending Order of Priority of Some Common Groups, According to the Sequency Rules

19
 Nomenclature of stereoisomers

4. R,S-nomenclature for compounds with an axial chirality

20
 Prochirality: homotopicity, enantiotopicity, diastereotopicity

Relevance of symmetry:

21
Pseudo-asymmetric and chirotopic centers

22
Molecules with a chirotopic center or a chirotopic center

23
 Symmetry and stereochemistry

Symmetric operations:

1. Cn: n-fold rotation axes: rotation by an angle 360°/n

24
 Symmetry and stereochemistry

2. σh: mirror plane

25
 Symmetry and stereochemistry

3. Rotating mirror axis

26
 Symmetry and stereochemistry

Rotating mirror axis

27
Symmetry and stereochemistry

28
 Heterotopic groups and faces
(Prochirality)

Two identical groups in one molecule can be either

homotopic, enantiotopic or diastereotopic and show the corresponding properties.
Definition: The groups are homotopic if there can be transformed into each other by a symmetry operation Cn

The reactivity of homotopic groups is the same towards all reagents. It is not possible to make a chemical
distinction between homotopic groups.

29
 Homotopic groups and faces

Substitution test: The susbtitution of an homotopic group by another group leads

to the same molecule

Feature: Homotopic groups and faces cannot be distinguished by any reagent.

The same chemical behaviour towards all reagents is observed.

30
 Homotopic faces of a molecule

Homotopic faces: two faces are homotopic, if the plane defined by the two faces contains a
C2 axis.

31
 Enantiotopic groups and faces

Definition: The two groups in a molecule are enantiotopic, if they can be converted into one another by a
Sn-or σh-operation.

Enantiotopic groups are always found in achiral molecules.

Substitution test: The substitution of one group of two enantiotopic groups gives two
enantiomeric compounds.

32
 Enantiotopic groups and faces

Enantiotopic faces are 2 faces that are defined by a plane of symmetry.

Features: Only chiral reagents can distinguish between enantiotopic groups.

Achiral reagents can not differentiate between enantiotopic groups and faces.

33
 Diastereotopic groups and faces

Diastereomeric groups can be transformed into one another only by the identity symmetry operation.

Substitution test:
provides two diastereoisomers.

Features: 2 diastereotopic groups and faces are distinguished by any reagent.

Diastereotopic faces are defined by a plane which is not a symmetry plane. 34

 Additions to homotopic and enantiotopic faces

Topicity Groups Faces Reactivity

Homotopic no differenciation
Cn C2
groups and faces possible

differenciation by chiral
Enantiotopic
groups and faces σh or Sn σh reagents (or
catalysts)

Diastereotopic differenciation by any

groups and faces
none ≠ σh reagent
35
 Enantiomers and racemates

Racemization: Processes which convert a pure enantiomer into a 1:1 mixture of enantiomers

36
 Racemization

Process which convert a pure enantiomer into the racemate

A racemization – process implies an achiral intermediate

37
Racemization

38
 Epimerization of diastereoisomers

Epimerization: racemization of only one from several chiral centers.

39
Selective inversion of the configuration at Csp3-centers

40
 Inversion of alcohols: Mitsunobu reaction

Mitsunobu reaction: D. L. Hughes, Org. React. 1992, 42, 335-656.

41
SNi-reaction

42
 Substitution with retention of configuration

J. J. Almena Perea, T. Ireland, P. Knochel, Tetrahedron Lett. 1997, 38, 5961-5964.

43
 Methods for Racemate Resolution
Separation of enantiomers

1) Separation based on the crystal shape. Pasteur (1845): crystal picking. Triage

2) Selective crystallization using a seed crystal

Example: (+)-tartaric acid is easily crystallized by the addition of (-)-asparagine

44
 Resolution via separation of diastereomers

(±)-acids can be separated using chiral bases such as alkaloids: quinine, brucine, morphine.

J. F. Larrow, E. N. Jacobsen, Y. Gao, Y. Hong, X. Nie, C. M. Zepp, J. Org. Chem. 1994, 59, 1939. 45
 Resolution of 3-methyl-2-phenylbutanoic acid

C. Aaron, D. Dull, J. L. Schmiegel, D. Jaeger, Y. Ohahi,

46
H. S. Mosher, J. Org. Chem. 1967, 32, 2797.
 Resolution via separation of diastereomers

Commonly used resolving agents

For acids For bases

α-Methylbenzylamine 1-Camphor-10-sulphonic acid

α-Methyl-p-nitrobenzylamine Malic acid
α-Methyl-p-bromobenzylamine Mandelic acid
2-Aminobutane α-Methoxyphenylacetic acid
N-Methylglucamine α-Methoxy-α-trifluoromethylphenylacetic acid
Dehydroabietylamine 2-Pyrrolidone-5-carboxylic acid
α-(1-Naphthyl)ethylamine Tartaric acid
threo-2-amino-1-(p-nitrophenyl)-propane-1,3-diol
Cinchonine
Cinchonidine
Quinine
Ephedrine

47
 Separation of enantiomers

The resolution of enantiomers by preferential crystallization

is the most common method used in industry:

Resolution of Naproxen using Quinidine

C. G. M. Villa and S. Panossian, Chirality in industry, 1992, Vol. 1, 303.

48
Preparation of acidic resolution agents

49
Extension to the resolution of alcohols

50
Resolution of ketones by the formation of diastereoisomers

51
 Improved resolution procedure: the method of Wynberg

Racemate resolution through the formation of two diastereoisomers (salts).

T. Vries, H. Wynberg, E. van Echten, J. Koek, W. ten Hoeve, R. M. Kellogg, Q. B. Broxterman, A. Minnaard,
B. Kaptein, S. van der Sluis, L. Hulshof, J. Kooistra Angew. Chem. 1998, 110, 2491; Angew. Chem. Int. Ed.
1998, 37, 2349.

52
Resolution with in situ racemization

53
Separation using a chiral chromatographic columns

• Gas chromatography: the solvent is a gas

• HPLC (High Presssure Liquid Chromatography): the solvent is a

mixture of liquids

polysaccharides (α-Cyclodextrin)

54
Enzymatic resolution: an example of kinetic resolution

55
Kinetic resolution

56
 Dependence of enantiomeric excess on relative rate of reaction

57
V. S. Martin, S. S. Woodard, T. Katsuki, Y. Yamada, M. Ikeda, K. B. Sharpless, J. Am. Chem. Soc. 1981, 103, 6237.
 Kinetic resolution

M. Tokunaga, J. F. Larrow, F. Kakiuchi, E. N. Jacobsen, Science 1997, 277, 936.

B. E. Rossiter, T. Katsuki, K. B. Sharpless, J. Am. Chem. Soc. 1981, 103, 464.

P. R. Carlier, W. S. Mungall, G. Schroder, K. B. Sharpless, J. Am. Chem. Soc. 1988, 110, 2978.

58
 Examples of kinetic resolution

M. Kimura, I. Kasahara, K. Manabe, R. Noyori, H. Takaya, J. Org. Chem. 1988, 53, 708.

U. Salz, C. Rüchardt, Chem. Ber. 1984, 117, 3457.

P. Stead, H. Marley, M. Mahmoudoan, G. Webb, D. Noble, Y. T. Ip, E. Piga, S. Roberts,

M. J. Dawson, Tetrahedron: Asymmetry 1996, 7, 2247. 59
 Determination of the enantiomeric purity by NMR methods

Use of chiral shifts reagents:

C. C. Hinckley, J. Am. Chem. Soc. 1969, 91, 5160.

A. Alexakis, J. C. Frutos, S. Mutti, P. Mangeney, J. Org. Chem. 1994, 59, 3326.

Determination of ee% by NMR Methods: review article D. Parker Chem. Rev. 1991, 91, 1441

60
 Determination of the absolute configuration

Classical X-ray analysis does not allow to distinguish between two enantiomeric structures.

The method of Bijvoet (1951) uses heavy metal salts and allows the determination
of the absolute configuration of molecules.

J. M. Bijvoet, A. F. Peerdeman, A. J. van Bommel, Nature, 1951, 168, 271.

61
Chemical correlation (1)

62
Chemical correlation (2)

63
 Determination of the relative stereochemistry by NMR methods

Diastereisomers have different properties: compare with

In general - 1H and 13C NMR analysis allows to differenciate diastereoisomers

Karplus Rules

64
Determination of the relative stereochemistry by NMR methods

65
Determination of the configuration of the anomeric center of sugar

66
 Conformational analysis

1943: X-Ray analysis shows a chair conformation for cyclohexane derivatives

1950: Barton shows the difference between axial and equatorial positions in cyclohexane derivatives

67
 Conformational analysis

Isomeric ratios at equilibrium (T = 25 °C)

percent of more stable isomer K DG°25°C (Kcal/mol)

50 1.0 0.0
55 1.22 0.12
60 1.50 0.24
70 2.33 0.50
75 3.0 0.65
85 5.67 1.03
90 9.0 1.30
95 19.0 1.75
99 99.0 2.72
99.9 999.0 4.09

68
Conformational analysis

69
Conformational analysis of butane

70
 Conformational analysis

Rotational barriers of compounds of type CH3-X

Heteroatom
Alkanes Barrier (kcal/mol) Barrier (kcal/mol)
compounds

CH3-CH3 2.9 CH3-NH2 2.0

CH3-CH2CH3 3.4 CH3-NHCH3 3.0

CH3-CH(CH3)2 3.9 CH3-N(CH3)2 4.4

CH3-C(CH3)3 4.7 CH3-OH 1.1

(CH3)3C-C(CH3)3 8.4 CH3-OCH3 4.6

J. P. Lowe, Prog. Phys. Org. Chem. 1968, 6, 1.

71
Conformational analysis of bonding between Csp2 and Csp3

72
 1,3-Diaxial strain

R. W. Hoffmann, Chem. Rev. 1989, 89, 1841

73
A. Bienvenue, J. Am. Chem. Soc. 1973, 95, 7345
1,3-Diaxial strain

74
Conformational analysis of cyclic systems: Bayer strain

75
 Classification of cyclic organic molecules

Cyclic molecules can be classified in 4 categories: small rings: 3-4;

normal rings: 5-7;
medium-sized rings: 8 -12;
large rings: 13-membered rings and larger

ring size strain energy

per methylene group

small rings 3 9
4 6.8

5 1.4
normal rings 6 0.2
7 1.1

8 1.4
9 1.6
medium-sized rings 10 1. transannular interaction
11 1.3
12 0.5

76
large rings behave like a per-chain systems
 The cyclopropane ring

planar ring system: Pitzer strain 6 Kcal/mol

J. Wemple, Tetrahedron Lett., 1975, 38, 3255.

77
Conformation of the cyclopropylmethyl cation

78
 Synthesis of cyclopropanes

H.-D. Beckhaus, C. Rüchardt, S. I. Kozhushkov, V. N. Belov, S. P. Verevkin, A. de Meijere,

J. Am. Chem. Soc. 1995, 117, 11854.

C. Mazal, O. Skarka, J. Kaleta, J. Michl, Org. Lett. 2006, 8, 749.

79
 Synthesis of cyclopropanes

J. E. Argüello, A. B. Peñéñory, R. A. Rossi, J. Org. Chem. 1999, 64, 6115.

H.-C. Militzer, S. Schömenauer, C. Otte, C. Puls, J. Hain, S. Bräse, A. de Meijere, Synthesis 1993, 998.

80
The cyclobutane and cyclopentane systems

81
The conformations of cyclohexane

82
 Energy diagram for ring inversion of cyclohexane

N. Leventis, S. B. Hanna, C. Sotiriou-Leventis, J. Chem. Educ. 1997, 74, 813.

83
The conformation of substituted cyclohexane

84
 Inversion of cyclohexane

Half-life for conformation inversion of cyclohexane at various temperatures

T (°C) Half-life
25 1.3 x 10-5 s

-60 0.03 s

-120 23 min

-160 22 years !
A crystallization of the equatorial isomer at -150 °C is possible
F. R. Jensen, J. Am. Chem. Soc. 1969, 91, 3223.

60-MHz 1H-NMR spectrum for the C(1)H in chlorocyclohexane. a) axial-equatorial equilibrium at -115 °C,
b) axial enriched mixture at -150 °C, c) pure equatorial conformer at -150 °C
85
 Cyclohexyl iodide

100 MHz 1H-NMR spectrum of iodocyclohexane at -80 °C. Only the low field C(1)H signal is shown.

F. R. Jensen, J. Am. Chem. Soc. 1969, 91, 344.

86
Temperature depending NMR-spectra / exchange rate of protons

87
 Conformational free energies (-DG) for some substituents

Substituent -DGc Substituent -DGc

F 0.26 C6H5 2.9
Cl 0.53 CN 0.2
I 0.47 CH3CO2 0.71
CH3 1.8 HO2C 1.35
CH3CH2 1.8 C2H5O2C 1.1-1.2
(CH3)2CH 2.1 HO (aprotic solvent) 0.52
(CH3)3C >4.7 HO (protic solvent) 0.87
CH2=CH 1.7 CH3O 0.60
HC≡C 0.5 O2N 1.16

88
 F. Johnson, Chem. Rev. 1968, 68, 375

S. Seel, T. Thaler, K. Takatsu, C. Zhang, H. Zipse, B. F. Straub, P. Mayer, P. Knochel, J. Am. Chem. Soc., 2011, 133, 4774.

89
 Stereoselective effects: Curtin-Hammett principle

According to the Curtin-Hammett principle, the position of the equilibrium between two molecules
A and B cannot be used to predict the ratio between the products PA and PB, only the difference
between the activation energies DGB* - DGA* is relevant 90
 The Curtin-Hammett principle

Stereoselective E2-elimination

91
Example of the Curtin-Hammett principle

92
 The Curtin-Hammett principle

According to the Curtin-Hammett principle, the position of the equilibrium between two molecules A and B
cannot be used to predict the ratio between the products.

Exception: when the activation energy are very similar

W. C. Still, Tetrahedron 1981, 23, 3981 93

 The anomeric effect

Anomeric effect: 0.9 kcal/mol

The tendency to prefer a substituent in an axial position increases with the

electronegativity of the substituents. X = OAc, Cl, F,…

E. Juaristi, Tetrahedron, 1992, 48, 5019

94
 Origin of the anomeric effect

Most probable origin: hyperconjugation effect between electron lone pair of oxygen and the s* (C-X) bond

95
 The anomeric effect

H. Paulsen, P. Luger, F. P. Heiker, Anomeric Effect: Origin and Consequences, ACS Symposium
Series No. 87, ACS, 1975, Chap. 5 96
 The anomeric effect

Application: Determination of the conformation of a ketal

97
 The anomeric effect

The anomeric effect allows to predict the preferred conformation of organic molecules:

Preferred conformation for

Preferred conformation of esters :

98
 The kinetic anomeric effect

Kinetic effects:

99
 Effects on spectra and structure

Antiperiplanar lone pairs weaken C-H bonds and reduce their IR wavenumber

100
 Stereoelectronic effects and the Baldwin rules

Stereochemical requirements for the SN2-substitution: linear arrangement between the leading group
and the entering nucleophile

J. E. Baldwin, J. Chem. Soc., Chem. Commun., 1976, 734-736.

101
 Epoxide-opening

G. Stork, L. D. Cama, D. R. Coulson, J. Am. Chem. Soc. 1974, 96, 5268.

102
Epoxide-opening

103
Baldwin rules

104
Stereoselective reactions

105
SN2‘-substitutions

106
 SN2‘-substitutions with organocopper

D. Soorukram, P. Knochel Org. Lett. 2004, 6 , 2409

107
Anti-SN2‘-substitutions with organocopper

108
Anti-substitutions at propargylic systems

109
 Stereoselective palladium-catalyzed allylic substitutions

B. M. Trost, Acc. Chem. Res. 1980, 13, 385.

110
 Electrophilic substitutions

SE2

111
First synthesis of an optically active zinc reagent

112
Preparation of chiral zinc reagents

113
 Stereoselective rearrangements

Only the bond in anti-arrangement to the leading group undregoes the migration

M. Chérest, H. Felkin, J. Chem. Soc. 1965, 2513. 114

Nucleophilic addition to ketones and aldehydes

115
Diastereoselective reactions

116
The aldol reaction: the acidity of various C-H bonds

pKDMSO

MeCH2-NO2 16.7
PhCOCH3 24.7
EtCOCH2Me 27.1
PhSO2CH3 29.0
(Me3Si)2NH 30.0
CH3CN 31.0
i-Pr2NH 35.0
PhCH3 43.0
CH4 56.0

Bordwell acidity scala in DMSO: Acc. Chem. Res. 1988, 21, 456.

117
The aldol reaction

118
The aldol reaction

119
Stereoselectivity in the aldol reaction

120
 Enantioselective aldol synthesis

C. Heathcock, J. Am. Chem. Soc. 1977, 99, 2337;

J. Org. Chem. 1981, 46, 191;
J. Org. Chem. 1985, 50, 2095.

121
The aldol reaction

122
The aldol reaction

123
 The aldol reaction

General synthesis of Z-enolates

Boron enolates are usually more selective than Li-enolates

124
Enantioselective aldol reaction

125
Enantioselective aldol reaction via Ti-enolates

126
Enantioselective enolate synthesis

127
 Enantioselective enolate synthesis

Organocatalysis

128
The aldol reaction via ester enolates – the Ireland-Claisen reaction

129
The aldol reaction via ester enolates – the Ireland-Claisen reaction

130
The aldol reaction via ester enolates – the Ireland-Claisen reaction

131
Alternative synthesis of aldol products

132
 Asymmetric catalysis – Asymmetric oxidations

The Sharpless oxidation

133
Kinetic resolution of secondary alcohols

134
Matched and mismatched cases

135
 Mechanism of Ti-catalyzed Sharpless epoxidation

M. G. Finn, K. B. Sharpless, J. Am. Chem. Soc. 1991, 113, 113.

136
Synthetic applications of the Sharpless epoxidation

137
Ring opening with cuprates

138
Desymmetrization of meso-epoxides

139
Desymmetrization of meso-epoxides

140
Asymmetric dihydroxylation

141
Asymmetric dihydroxylation leading to (2S)-propanolol

142
Asymmetric aminohydroxylation

143
Epoxidation of non-functionalized epoxides

Substrate Yield (%) ee(%) config.

73 >95 R, R

81 88 R, R

61 93 2S, 3R

73 92 R, R

69 91 R, R 144
Epoxidation of non-functionalized epoxides

145
Ligands for asymmetric hydrogenation

146
Catalytic hydrogenation of enamides

147
Ru-catalyzed hydrogenations

148
Rh-catalyzed hydrogenations

149
Asymmetric hydrogenation of carbonyl compounds

150
The oxazaborolidine catalyst system

151
The oxazaborolidine catalyst system

152
CBS-Reduction

153
CBS-Reduction

154
 Asymmetric transfer hydrogenation

Meerwein-Ponndorf-Verley reaction

155
Enantioselective imine hydrogenation

156
Asymmetric Diels-Alder reaction

157
Asymmetric Diels-Alder reaction

158
Hetero Diels-Alder reaction

159
Hetero Diels-Alder reaction

160
Asymmetric synthesis in Natural Product Chemistry

Prof. E. J. Corey

161
Corey‘s rethrosynthetic analysis of aspidophytine

162
Corey‘s rethrosynthetic analysis of aspidophytine

163
Corey‘s total synthesis of aspidophytine

164
Corey‘s total synthesis of aspidophytine

165
Corey‘s total synthesis of aspidophytine

166
Corey‘s total synthesis of aspidophytine
The final cascade sequence

167
Corey‘s total synthesis of aspidophytine
Final stages and completion

168
A domino olefin metathesis strategy for the synthesis of (-)halosalin

169
Conjugated addition-alkylation route to prostaglandins

170
Conjugated addition-alkylation route to prostaglandins
Synthesis of fragment A

171
 Conjugated addition-alkylation route to prostaglandins
Alternative synthesis of fragment A starting from diethyl (S,S)-tartrate

172
Conjugated addition-alkylation route to prostaglandins
Synthesis of fragment B

173
Conjugated addition-alkylation route to prostaglandins
Synthesis of fragment C

174
Conjugated addition-alkylation route to prostaglandins
Final assembly of the PGE1

175
Additional asymmetric syntheses

176
Enantioselective alkylation by chiral phase-transfer catalysis

177
 Enantioselective fluorination reactions

H
N R R
CHCl O AcO O Cl
N N O
H H TiL 2
N Cl O
2 BHF 4 O OMe O Cl
F H H R R
OMe
1: Selectfluor N
4: R = 1-Naph
N 3 L2 = (CH3CN)2
2 O
OTMS
1/2 F
Bn Bn
CH3CN
99 %; 89 % ee
-20 °C

CN F CN
1/3
p-Tol CO2Me p-Tol CO2Me
CH2Cl2, -60 °C 80 %; 87 % ee

O O 1 (116 mol%) O O

Et OChPh2 Et OCHPh2
4 (5 mol%) Me F
Me CH3CN, rt 81 % ee
20 min

Munoz, K. Angew. Chem. Int. Ed. 2001, 40, 1653

178
 Asymmetric reduction of C=C-bonds

Synthesis of amino-alcohol derivatives

Rh(COD)2OTf (1 mol%) OMOM

H OMOM 1 (1 mol%)
P P
H2 (10 atm) Ph NHAc
Ph NHAc
PhCH3, rt, 12 h

95 %, 98 %ee 1: R,R-Me-DuPhos

Zhang, X. J. Org. Chem. 1998, 63, 8100.

179
Chiral monophosphines for the enantioselective hydrogenation of functionalized
olefins

O
P R R = t-Bu, Et, NMe2, (R)-O-CH(Me)Ph
O

High enantioselectivities are reached with BINAP-derived phosphines and

phosphoramidates for asymmetric hydrogenations.

Review: Börner, A. Angew. Chem. Int. Ed. 2001, 40, 1197

180
 Asymmetric reduction of C=O bonds

Rapid, catalytic and stereoselective hydrogenation of ketones

Noyori, R. Pure Appl. Chem. 1999, 71, 1493.

H O Cl
O
R N P* N*
Ru
Ru H Ru H P* N*
*L
*L Cl
difficult easy
chiral Ru-complex

181
 Noyori-catalyst system

RuCl2 + P2 + N2
ligand ligand

P2
ligand

PAr2 Ar = C6H5: (R)-BINAP

PAr2 Ar = 4-Me-C6H4: (R)-TolBINAP
Ar = 3,5-Me2C6H3: (R)-XylBINAP

OMe
N2
ligand

Ph NH2
MeO
NH2 (R)-DAIPEN (R,R)-DPEN
Ph NH2
NH2

NH2
(R,R)-cyclohexanediamine
NH2

182
 Asymmetric reduction of ketones

O OH

R Ru-complex R
+ H2
KOtBu, iPrOH
(1 - 10 atm) 26 - 30 °C
> 97 %, 99 %ee

R = Me, Et, iPr

Ru : ketone = 1 : 500 to 1 : 5000 R = cyclopropyl: 96 %ee

O Ru-complex OH
+ H2
Ph K2CO3, iPrOH Ph
(80 atm) 30 °C
100 %, 97 %ee
ketone : Ru : K2CO3 = 100 000 : 1 : 10 000
Ru-complex: RuCl2-(S)-XylBINAP-(S)-DAIPEN

OH OH
OH OH OH

Pent Ph iPr iPr

97 %ee 86 %ee 90 %ee 100 %ee 99 %ee

183
 Asymmetric transfer hydrogenation

Tos OH
N O 1 (0.5 mol%)
RuCp*(Cl) Ph
Ph KOtBu (0.6 mol%)
N iPrOH, rt, 12 h 85 %, 96 %ee
H2
1

Noyori, R. J. Org. Chem. 1999, 64, 2186.

184
 Asymmetric reduction of C=N-bonds

1. NH2OH, NaOAc Ac
O MeOH, rt, 8h NH

P P tBu Me 2. Ac2O, AcOH, Fe tBu Me

70 °C, 4 h
3. 1·Ru(COD)BF4 (0.2 mol%)
H2 (200 psi), MeOH), rt, 20 h
1: R,R-Me-DuPhos

Burk, M.J. J. Org. Chem. 1998, 63, 6084.

185
Catalytic asymmetric reductive amination

186
 Asymmetric C-C-bond formation

1,4-Addition using Zn-reagents

O O
Et2Zn

-20 °C, Cu(OTf)2

up to 98 % ee

O
SO2
N O Ph
N HN c-Hex
H N N PPh2 P N
PPh2 O Ph
Cl OH Me
Me t-Bu O

Cl

Zhang (3 mol %) Tomioka (4.5 equiv.) Gennari (3 mol %) Feringa

Zhang, X. Angew. Chem. 1999, 111, 3720.

Tomioka, K. Tetrahedron 1999, 55, 3831.
Gennari, C. Angew. Chem. Int. Ed. Engl. 2000, 39, 916.
Feringa, B.L. Angew. Chem. Int. Ed. Engl. 1997, 36, 916.
Review: Feringa, B. L. Acc. Chem. Res. 2000, 33, 346 and Krause, N. Synthesis, 2001, 171

187
 Catalytic enantioselective synthesis of prostaglandin E1 methyl ester

O O SiMe2Ph PhMe2Si
1) Cu(OTf)2 (3 mol%) HO Pent
H
HO H
O O +
Zn CO2Me
CO2Me
Ph H
Ph Ph 2 O O
O
P N : Cat*1 ca. 40 %; 94 % ee
O Ph
(6 mol%) Ph
Ph

toluene, -40 °C, 18 h

HO
2) Zn(BH4)2, ether, -30 °C
HO H Pent

Feringa, B. L. J. Am. Chem. Soc. 2001, 123, 5841

H CO2Me
O

Et2Zn
Et
Ph Br
CuBr.Me2S (1 mol%) Ph
diglyme
54 %; 77 % ee
-40 °C, 18 h
Cat*1: 2 mol%

Feringa, B. L. Org. Lett. 2001, 3, 1169 188

Asymmetric conjugated additions

189
Hayashi-Michael-addition

190
Rh-catalyzed asymmetric conjugate addition of organoboronic acids to
nitroalkenes

Ph Ph
NO2 NO2 1) NaOMe, MeOH O
PhB(OH)2

Rh(acac)(C2H4)2 (3 mol %) 2) H2SO4 conc.

dioxane / H2O (10 : 1) -40 °C 76 %; 90 %ee
100 °C, 3 h
79 %, 98 % ee

Ph
1) O
CO2Me
N
H
PhCH2NMe3+ OH-
dioxane / H2O
98 %ee
2) H2; Ni/Ra

Hayashi, T. J. Am. Chem. Soc., 2000, 122, 10716

191
Zinc(II) mediated enantioselective synthesis of propargylic alcohols

192
Lanthanide trifluoromethanesulfonate - catalyzed asymmetric aldol
reaction
in water

Ce(OTf)3 cat. OH O
O OSiMe3
Ph Ph
Ph H Ph
N
H
O O
86 %de; 82 %ee
O O
N
cat.

H2O - EtOH (1 : 9)

Kobayashi, S. Org. Lett. 2001, 3, 165

193
Asymmetric aldol reaction via a dinuclear zinc catalyst

194
Catalytic synthesis of 1,2-diols mediated by (L)–proline

195
Enantioselective cross-aldol reaction of aldehydes

196
Catalytic asymmetric Mannich reaction mediated by (L)-proline

197
Organocatalytic Diels - Alder reaction

198
Organocatalytic alkylation of methyl 4-oxobutenoate

199