Update to 2013
Bode Research Group
http://www.bode.ethz.ch/
Topic: Catalytic Enantioselective Synthesis of Amino Acids
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
1
Brief Overview
Amino acids are one of the most important biological building blocks. Proteins in all living organism are made
up of 20 proteinogenic amino acids. A large number of amino acids (both natural and unnatural) are used in
the pharmaceutical industry, in fragrances or flavors and in material science. In this chapter, the chemical
synthesis of various classes of amino acids will be discussed.
1.1
Proteinogenic amino acids
The proteinogenic amino acids are produced on industrial scale by biochemical methods (e.g. fermentation
in genetically modified bacteria). It is a multibillion-dollar industry.
Examples of important drugs with uncommon amino acids
CHIMICA OGGI Chemistry Today June 2003
1
Update to 2013
Bode Research Group
1.2
Why are we interested in the synthesis of amino acids
http://www.bode.ethz.ch/
There are not many commercially viable biochemical methods for the synthesis of uncommon amino acids.
Many important uncommon amino acids are produced synthetically.
e.g. Unnatural -amino acids, ,-disubstituted amino acids, -arylglycine derivatives, -amino acids
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
1.3
Challenges for catalytic asymmetric synthesis of amino acids

One of the most important criteria for amino acid synthesis is obtaining very high optical purity
Most of the amino acids are used in the synthesis of polypeptides, which contain multiple
stereocenters. If the enantiopurity of the starting materials is not high enough, the ratio of the desired
stereoisomer of the product will dramatically decrease with growing chain length as illustrated here
for a five-mer.
98% er SM  Dimer: 96% dr  Trimer: 94% dr  Four-mer: 92% dr  Five-mer: 90% dr
99.9% er SM  Dimer: 99.8% dr  Trimer 99.7% dr  Four-mer: 99.6% dr  Five-mer: 99.5% dr


1.4
Relevant protecting group for further modifications (Boc, Fmoc, Cbz)
Generality – methodology should be widely applicable for a large range of substrates
Important auxiliary based approach for the synthesis of -amino acids
a) Schöllkopf’s chiral auxiliary
Schöllkopf ACIE 1981, 20, 798
b) Oppolzer’s sultam
Oppolzer Tetrahedron Lett. 1989, 30, 6009
c) Seebach’s self-regeneration of chirality
 Useful for synthesis of cyclic quaternary amino acids
Seebach, JACS, 1983, 105, 5390
General strategy for synthesis of amino acid
2
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Update to 2013
Bode Research Group
http://www.bode.ethz.ch/
2
Enantioselective synthesis of -amino acids
2.1
Introduction of the -hydrogen (-amino acids)
2.1.1.





Asymmetric hydrogenation of ,-didehydroamino acids (C=C bond reduction)
One of the most useful and well-studied method for the synthesis of amino acids
R. Noyori and W. S. Knowles were awarded Nobel prize in 2001 for developing asymmetric
hydrogenation reaction
1000’s of mono and bidentate phosphine ligands have been studied
Some of the good phosphine ligands are shown
Many of the ligands shown work at 1 atm of H2
Najera Chem. Rev. 2007, 107, 4584



Several metals-complexes have been studied for asymmetric hydrogenation with Rh and Ru being
the most versatile of them all
In general, Rh-complexes have a more narrow substrate scope than the corresponding Ru
complexes
The differene in reactivity and the substrate scope between Rh and Ru-complexes arise because of
the differences in the basic mechanism
3
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Update to 2013
Bode Research Group
http://www.bode.ethz.ch/
Noyori JACS 2002, 124, 6649
Industrial synthesis of (L)-DOPA by catalytic asymmetric hydrogenation
 Synthesized in multi-ton scale every year
 Important drug for Parkison’s disease treatment
Federsel Nat. Rev. Drug Discovery 2005, 4, 685
2.1.2.
Reduction of C=N bonds
O
NH2
OH
Ph
O
Ph
[Rh(COD)2]BF4 (1 mol%)
Chiral Ligand (1 mol%)
MeOH, rt,
H2, (60 atm)
PPh2
Ph2P
O
BnHN
OH
N
Bn
Ph
97% ee
(R,R) Deguphos
Direct method – Reductive amination
 Only very few examples for enantioselective reductive aminations are known
 Not easy to obtain high ee’s; Not often used in synthesis of amino acids
Börner JOC, 2003, 68, 4607
Indirect method – Reduction of -imino esters
 Again only very few examples known
 Preparation and isolation of -imino esters can be challenging
PPh2
PPh2
R-BINAP
Uneyama Org. Lett. 2001, 3, 313
2.1.3.
Protonation of enolates
4
Update to 2013
Bode Research Group
http://www.bode.ethz.ch/
 Interesting but understudied strategy
 Key step is the generation of chiral [Rh]-enolate with is protonated with achiral proton source
 Rh, Ni catalyst have been used albeit with very moderate ee
H
N
Me
O
[Rh(COD)2]PF6 (3 mol%)
Chiral Ligand (6 mol%)
OMe
ArBF3K
Toluene, 110 ºC,
guaiacol (H+ source)
89%
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
O
O
Me
N
H
P
P
Rh
Ar
OMe
1,4 - addition
P P
Rh
H
N
O
Ar
O
Me
OMe
N
H
PPh2
PPh2
O
81-90% ee
R-BINAP
O
OMe
Me
Ar
O
Darses & Genet ACIE, 2004, 43, 719
2.1.4.



Asymmetric hydrogenation – Dynamic Kinetic Resolution
A very elegant method for generating two adjacent asymmetric centers
Pioneered by Noyori and co-workers and improved by many others
Usual starting material is -amino -keto esters giving -hydroxy amino acid as the product
O
O
OEt
NH2HCl
1. [Ru(S)SynphosBr2]PF6 (2 mol%)
H2 (12 atm), 50 ºC, 24 h
DCM + EtOH, 89%
OH O
2. (PhCO)2O, Et3N, DCM, 90%
anti
EtO
O
97% ee (2S,3S)
99% de
O
O Ru P
HCl H2N
OEt
Ph
HN
O
PPh2
PPh2
O
O
P
O
S-Synphos
O
1. [Ru(S)Synphos-Br2]PF6 (2 mol%)
H2 (130 atm), 80 ºC, 4 days
O
OEt
Ph
HN
DCM, 94%
HN
H
O
OEt
Ph
HN
Ph
O
syn
O
O
98% ee (2R,3S)
99% de
O
O Ru P
EtO


OH
P
Usually high H2 pressure and temperatures are required for hydrogenative-DKR
Many bidendate ligands with Ru, Rh and Ir have been studied
Genet Eur. J. Org. Chem. 2004, 3017
Introduction of the -amino group (-amino acids)
2.2



2.2.1

A sophisticated strategy for synthesis of amino acids
Often requires multiple steps after amination reaction to obtain the amino acid
One major limitation is the relatively small number of electrophilic aminating reagents
Enantioselective electrophilic amination
Metal and organocatalytic variants have been developed
5
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Update to 2013
Bode Research Group
http://www.bode.ethz.ch/
List JACS 2002, 124, 5656 & Jørgensen ACIE 2002, 41, 1790
2.2.2


Biomimetic Transamination
In biological systems -amino acids are synthesized by transamination of -ketoacids with
pyridoxamine
A biomimetic approach utilizing quinine-derived catalysts allows the synthesis of various unnatural
–amino acids from the corresponding -ketoacids
Shi JACS 2011, 133, 12914
2.2.3



Enantioselective aziridination
Few methods known for enantioselective aziridination
Access to aziridines in high ee’s is challenging compared to epoxides
Another challenge is to convert the aziridines to the amino acid. The protecting groups used are very
often not relevant for further elaboration. These factors makes it an unattractive strategy for general
synthesis of amino acids
Ph
N
Ph
O
Ph
OEt
N2
Ar
R = Alkyl, aryl, heteroaryl
1.5-30 mol% B(OPh)3
0.5-10 mol% S-VAPOL
Ph
N
DCM, rt, 24 h
R
CO2Et
> 90% ee
> 40:1 dr
Ph
Ph
OH
OH
Cleavage conditions
S-VAPOL
10% Pd(OH)2, H2 (1 atm)
MeOH, rt, 3h
(R = Alkyl, cyclic), 83-100%
or
Ph
Ph
N
R
O3, DCM, -78º C
NaBH4 (10 eq), MeOH
(R = Alkyl, cyclic, aryl)
40-60%
H
N
R
CO2Et
CO2Et
10% Pd(OH)2, H2 (1 atm)
MeOH, rt, 3h
(R = Ph), 79%
Ph
CO2Et
H 2N H

Ring opening of azirdine under reductive conditions to give the amino acid worked only with Ph
group
Wulff, Org. Lett. 2005, 7, 2201
6
Update to 2013
Bode Research Group
2.3
Introduction of the -side chain (-amino acids)
 One of the most reliable method for the synthesis of amino acids
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
2.3.1


http://www.bode.ethz.ch/
Electrophilic alkylation
Organocatalytic approach is the most widely used for introduction of the -side chain
Usually alkylation is performed with a chiral phase transfer catalyst




Simple reaction protocol, safe and inexpensive; very suitable for large scale synthesis
A variety of aryl, alkyl and heteroaryl halides are employed
Base employed: KOH, CsOH, NaOH
Solvent: water and toluene (Biphasic)
O
O
Ph
N
O
Br
Ph
Ph
O
N
Chiral catalyst
OtBu
Ph
CsOH, toluene
-40 ºC, 20 h
81%
F
OtBu
F
O
O
F
98% ee
N
TFA, H2O
EtOH, rt, 1h
Br
F
Pd/C, H2
N
H

CO2tBu
40 ºC, 24 h
F
(S)
N
CO2tBu
F
The enantioselectivity arises from interactions of the enolate generated under phase transfer
conditions with the chiral ligand
Maruoka, Chem. Sci., 2010, 1, 499-501

Reaction can be performed with -imino glycine esters, amide and even with peptides
Metal catalyzed electrophilic alkylation is also known e.g. Cu, Co-Salen complexes. However the ee’s
obtained are lower and these methods hardly competes with the organocatalytic approach
2.3.2


Nucleophilic alkylation
A powerful reaction for the synthesis of a variety of -substituted -amino acids
Enantioselective Mannich type reaction with a nucleophile and -imino ester is well documented with
7
Update to 2013
Bode Research Group
http://www.bode.ethz.ch/
metal and organocatalysts. Silyl enol ethers and enamides have been used as the nucleophiles
Mannich type reaction
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
N
R4
:X
R2
R 5O
R1
R4
Metal or organo
catalyst, chiral ligand
R 5O
R
R3
O
R1
NH :X
R2
O
R3
R
Metal catalyzed
O
N
EtO
Boc
Ph
R
Cbz
N
EtO
NH O
EtO
DCM, -20 ºC
82-97%
Other protecting groups like
Cbz, Troc, Teoc also work
O
Boc
Cu(OTf)2 (10 mol%)
Chiral ligand
OSiMe3
OMe
Ph
R
O
R = H, CH3
90% ee
NH
Boc
Boc
Cu(OTf)2 (10 mol%)
Chiral ligand
Ph
NH
N
EtO
DCM, 0 ºC
78%
Cbz
HN
Ph
HN
Ph
Ph
OMe
O
87% ee
Kobayashi, Org. Lett. 2003, 5, 2481 & Kobayashi, ACIE 2004, 43, 1679

Several proline catalysed Mannich reactions have been studied with mixed results
Organocatalytic
O
H
L-Pro (5 mol%)
PMP
PMP
OH
N
H
CO2Et
O
L-Pro
R
1,4-dioxane, rt,
44-67%
O
HN
93-99% ee
up to > 19:1 syn:anti
N
H
H
R
CO2Et
O
SMP (20 mol%)
HN
H
DMSO, rt, 44-67%
PMP
O Me
CO2Et
N
H
R
SMP
upto 92% ee
up to > 1:19 syn:anti
Si
N
PMP
N
O
H
H
Si
H
CO2Et
R
Re
O
N
PMP N
syn
Si
L-Pro
H
O Me
H
R
anti
CO2Et
SMP
With L-Pro the syn isomer is believed to arise from the Si face on the imine attacked by the Si face of the
enamine assisted by the carboxyl group. In the case of SMP, the Si face of the imine is attacked by the Re
face of the enamine giving the the anti product
Barbas JACS 2002, 124, 1866 & Barbas Tetrahedron Lett. 2002, 43, 7749
2.3.3


C-H activation of side chain residues
This methodology differs from previous examples, as it uses substrates with already installed chiral
centers, for example alanine, and modifies the side chain by C-H activation
Many functional groups are tolerated, resulting in a relatively broad substrate scope of the reaction
8
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Update to 2013
Bode Research Group
http://www.bode.ethz.ch/
Shi, Chem. Sci. 2013, 4, 3906
Introduction of the carboxyl group (-amino acids)
2.4
2.4.1



Metal catalyzed asymmertric Strecker reaction
Remarkably simple reaction for synthesis of amino acids; asymmetric variant was first introduced by
Jacobsen and co-workers
Since 2005, organocatalytic Strecker reaction has been intensely investigated
Usually employs a cyanide source which serves as the carboxy group synthon
Strecker Synthesis of a-amino acids (Year 1850)
Oldest known amino acid synthesis
O
R
NH
NH3
NH2
HCN
R
R
R
1. HCN (1.2 equiv)
Chiral catalyst (2 mol%)
Toluene, -70 ºC
N
NH2
H3 O+
CN
COOH
HN
CO2Me
H
2. MeOH/HCl
Reflux, 8 h, 79%
92% ee
Dimethylbarbituric acid
Pd(PPh3)4, (5 mol%)
NH2HCl
N
CO2Me
tBu
DCM, rt, 3 h, 60 %
Recrystallization
>99% ee
N
Al
O Cl O
tBu
tBu
tBu
Al-Salen
Jacobsen, JACS, 1998, 120, 5315
2.4.2
Organocatalytic asymmetric Strecker-type reaction


Jacobsen and co-workers have developed a simple chiral amido-thiourea based organocatalysts
Inorganic cyanide source (KCN, NaCN) was employed successfully avoiding the dangerous HCN
9
Update to 2013
Bode Research Group
KCN, AcOH, H2O
Catalyst (0.5 mol%)
Ph
R
N
Ph
Ph
toluene, 0 ºC, 4 - 8 h
1. H2SO4, HCl, 44 - 68 h
2. NaOH, NaHCO 3
Ph
HN
R
http://www.bode.ethz.ch/
NHBoc
R
3. (Boc)2O, dioxane, 16 h
4. Recrystallize
CN
CO2H
98-99% ee
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
NHBoc
CO2H
62-65%
6 to 14 g scale
NHBoc
CF3
NHBoc
CO2H
CO2H tBuNH2
Ph
50-51%
3.5 g scale
48-51%
4 g scale
Me
N
Ph
O
S
N
H
N
H
CF3
CF3
S
H
N
Ph
Ph
O
H
Ph2HC N
N
H
N
H
CF3
N
C
H
The mechanism involves an initial amido-thiourea induced imine protonation by HCN to generate a
diastereomeric transition state with imine/cyanide ion pair. The ion-pair then collapses in a post rate
determining step to form the new C-CN bond
Original paper: Jacobsen, Nature 2009, 461, 968
Detailed mechanistic studies: Jacobsen, JACS, 2009, 131, 15358
2.4.3


Carbamyl anion addition to N-sulfinyl imines
Carbamyl anions are amongst the most stable carbonyl anions
They can be added in a highly diastereoselective fashion to N-sulfinyl imines yielding
enantioenriched -amino amides, which serve directly as building blocks or can be converted into aminoacids
Reeves, JACS 2013, 135, 5565
3
3.1
Enantioselective synthesis of aryl glycines
Introduction of the -hydrogen (-Aryl glycines)
Reduction of -imino esters
 Very few examples known
 Preparation and isolation of -imino esters can be tricky. In many cases it is generated in situ
 Hantzsch ester was used as the hydrogen source
10
Update to 2013
Bode Research Group
H
H
EtO2C
OMe
http://www.bode.ethz.ch/
CO2Et
O
Me
N
Me
N
H
PMPHN
OEt
OEt
Chiral catalyst (5 mol%)
Toluene, 50 oC, 93%
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
O
O
O P
OH
O
Ph
Ph
96% ee
R or S
O
H5IO6 or
trichlorocyanuric acid
H2N
OEt
S-VAPOL
phosphoric acid
H2SO4, ACN/H2O
Antilla JACS 2007, 129, 5830
Rutjes Tetrahedron Lett. 2006, 47, 8109
Introduction of the -amino group (-Aryl glycines)
3.2




A very powerful method for the introduction of -amino group
Hashimoto showed that silylketene acetals in the presence of a nitrene precursor and di-Rh catalyst
undergo a smooth highly enantioselective amination
High ee’s and yields were obtained with a variety of substrates
More interestingly only the Z isomer reacted to give the desired aryl glycine. The E isomer did not
react under these conditions which allowed the use of a mixture of E/Z isomers
O
F3C
OSiEt3
OMe
N
S
O
I
Rh2(s-TCPTTL)4
(1 mol%)
NsN=IPh
(Nitrene precursor)
Cl
O
NHNs
Cl
OMe
N
Benzene, rt, 3 h
95%
NO2
(Z:E = >95:5)
Cl
O
Ph
Cl
O
CF3
O
O
Rh
Rh
97% ee
Only Z isomer reacts
Hashimoto, Tetrahedron Lett. 2007, 48, 8799
Introduction of the aryl side chain (-Aryl glycines)
3.3


Enders reported an organocatalytic Friedel-Crafts type reaction with N-sulfonyl--imino esters
Importantly the protecting group could be removed under relatively mild conditions
O
O
S
Chiral catalyst (1 mol%)
toluene, -22 ºC, 74 %
N
OEt
H
O
O
H
N
O
S
O
OEt
O O
P
O
NHTf
OMe
OMe
ClHH2N
R
R = 2,4,6(iPr)3C6H2
O
1. AlCl3, anisole,
DCM, rt, 90 - 95%
R
OH
2. 4 M HCl, reflux
OMe

Jørgensen documented a similar reaction with R-Tol-BINAP/CuPF6 catalytic system. Importantly,
carbamate protected imines were used, facilitating further elaboration
Enders Adv. Synth. Catal. 2010, 352, 1413
Jørgensen ACIE 2000, 39, 4114
3.4
3.4.1
Introduction of the carboxyl group (-Aryl glycines)
Strecker reaction
11
Update to 2013


Bode Research Group
http://www.bode.ethz.ch/
Asymmetric Strecker reaction is also useful for the synthesis of aryl glycines
In 1996 Lipton introduced guanidine analogs for asymmetric Strecker reaction based on its similarity
to an imidazole
N
CHPh2
HN
CHPh2
N
Chiral catalyst (10 mol%)
CN
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
H
N
HCN, 96%
N
H
86% ee
Lipton JACS 1996, 118, 4910 & Corey Org. Lett. 1999, 1, 157
Ti-catalyzed Strecker reaction with peptide-based ligand reported by Hoveyda and Snapper


The Ti center coordinates to the Schiff base and to the hydroxy group of the ligand
The carbonyl group of AA2 of the chiral peptidic ligand associates with HCN to deliver the cyanide to
the activated bound imine substrate
N
CHPh2
Ti(Oi-Pr)4, 10 mol%,
TMSCN, iPrOH,
H
Toluene, 4 ºC, 85%
Ph2HC
Cl
H
N
BocHN
CN
6 N HCl, 70 ºC
Cl
(Boc)2O, NaOH
dioxane
Cl
>99% ee
>99% ee
H
COOH
Me
C N H
H
O
H
tBu
N
N
NH
N
Ar
O
O
H
O
Ti
Me
O O
OH
N
Me
O
N
H
O
H
N
Me
O
Snapper & Hoveyda JACS, 2001, 123, 11594
3.4.2





Aza-Henry reaction
Efficient organocatalytic methods have been successfully used for aza-Henry reactions
Metal catalyzed versions are known, however they require high loading of the metal in many cases
‘CH2NO2’ can be readily converted to ‘COOH’
Zhou reported an excellent thiourea based catalyst for aza-Henry reactions
Very useful method as the protecting group is relevant for further elaboration
12
Update to 2013
Bode Research Group
N
Ar
Boc
Chiral catalyst (15 mol%)
CH3NO2
O
Boc
HN
DCM, -78 ºC, 84 to 95%
H
http://www.bode.ethz.ch/
NaNO2, AcOH
NO2
Ar
BocHN
DMSO
(High yields)
OH
Ar
>96% ee
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Ar =
O
+ other examples
F
OMe
CF3
S
OAc
H
N
OAc
AcO
AcO
H
N
N
H
NMe2
S
N
H
O
N
S
H
H
Me
N
N
H
Me
O
O
H
H
N
H
N
H
Me
N
Me
H
O
H
Review: Herrera Eur. J. Org. Chem. 2009, 2401 & Zhou Org. Lett. 2008, 10, 1707
4
Enantioselective synthesis of 



tuted -amino acids
,-disubstituted -amino acid residues in peptides have been found to exhibit a
pronounced helix-inducing potential
Peptides containing ,-disubstituted -amino acids were found to display
resistance against degradation by chemicals and enzymes
They can serve as enzyme inhibitors, by mimicking the ligand properties of their
natural analogues, but preventing subsequent enzymatic reaction
Chiral auxiliary assisted synthesis of ,-disubstituted -amino acid
The most studied strategy for asymmetric synthesis of 
tuted -amino acids is the
electrophilic -alkylation of amino acid enolate equivalents
Williams JACS 1991, 113, 9276
Catalytic asymmetric synthesis of 
tuted -amino acids
4.1
Enantioselective introduction of the -side chain (,-disubstituted -amino acids)
4.1.1
Chiral metal complex-promoted electrophilic addition
Azlactones are recognized as suitable substrates for asymmetric amino acid synthesis since asymmetric
catalysis allowed for the introduction of the stereo information into the target compound by means of a chiral
catalyst
OAc
or
OAc
O
Bn
N
O
Ph
[h3-C
O
3H 5PdCl] 2 (2.5
mol%)
Bn
N
L* (7.5 mol%)
Et 3N, toluene, rt
O
O
NH HN
O
Ph
PPh 2 Ph 2P
*
L
L
Pd
H
N
Ph
72-78% yield
98-99% ee
Bn
O
O
Trost JACS 1999, 121, 10727
Facial discrimination in the coordination of the allylic species to the metal center, in combination with the
13
Update to 2013
Bode Research Group
http://www.bode.ethz.ch/
minimalization of charge separation in the transition state, is thought to be responsible for the selectivity
4.1.2
Organocatalyst-promoted electrophilic addition
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Chiral phase-transfer catalysts (PTC) can form an ion-pair with the imino ester enolate, facilitating the
transfer of a molecule or ion from one reaction phase to another. The most commonly used PTC agents are
enantiomerically enriched cinchona alkaloids
cat (10 mol%)
ArCH2-Br
O
2-naphthyl
N
OtBu
O
RbOH
toluene, -35 ºC
Me
O
1N HCl
N
2-naphthyl
OtBu
Me CH2Ar
Br
H2N
OtBu
Me CH2Ar
THF, rt
F
N
O
up to 96% ee
N
F
F
Park JOC 2003, 68, 4514
The C2-symmetric chiral quaternary ammonium bromides provide greater stability and higher ees than the
traditional cinchona alkaloids
F
O
Cl
O
N
O
1) AllylBr, 2) BnBr
citric acid (0.5 M)
CsOH·H2O/toluene
THF
H2N
Br
O
N
L* (1 mol%)
99% ee
F
F
F
Maruoka JACS 2000, 122, 5228
4.2
4.2.1
Enantioselective introduction of the -amino group (,-disubstituted -amino acids)
Chiral metal complex-promoted electrophilic -amination
First general strategy towards , -disubstituted -amino acids via electrophilic -amination. Cu(II)-BOX
complex catalyzes the reaction of different racemic -alkyl--ketoesters with azodicarboxylates to obtain
products in excellent ee.
O
O
BnO2C
N
Me
OEt
Me
O
Cu(OTf)2 (10 mol%)
N
Me
L*
CO2Bn
HN
CO2Bn
Me
N
CO2Bn
Me CO2Et
Me
O
O
N
N
Ph
Ph
(S)-Ph-Box
98% ee
BnO2C
N
Me N
Ph
O
N
CO2Bn
O
Me N
Cu
R
O
O
RO
Ph
R
Jørgensen ACIE 2003, 42, 1367
4.2.2
Organocatalyst-promoted electrophilic -amination
Cinchona alkaloid derivatives are highly efficient organocatalysts for the -amination of -substituted cyanoacetates with azodicarboxylates.
14
Update to 2013
Bode Research Group
http://www.bode.ethz.ch/
CO2tBu
Ph
b-ICD (5 mol%)
Boc
N
NC
-78 ºC
N
CN
Ph
N
N
Boc
N
HN
H
Boc
Boc
Et
H O
CO2tBu
OH
> 98% ee
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
b-ICD
Jørgensen JACS 2004, 126, 8120
The functionalized indanecarboxaldehyde was allowed to react with azodicarboxylate in the presence of (R)proline in an efficient enantioselective synthesis of the metabotropic glutamate receptor ligands (S)-AIDA.
Barbas Org. Lett. 2005, 7, 867
4.3
Enantioselective introduction of the carboxyl group (,-disubstituted -amino acids)
Strecker-type reactions
By reaction of N-protected ketimines with hydrocyanic acid under the influence of a resin-bound or soluble
Schiff base catalyst, various -methyl--arylglycine-derivatives are produced in high ee.
HCN, cat (2 mol%)
N
Ph
Br toluene, -75 ºC
Me
Me
H
N
Ph
CN
H
Br
Ac2O
O
Me
N
HCO2H
Ph
CN
conc. HCl
105 oC
Br
> 99.9% ee
Me
H
N
Ph
CO2H
Ph
H2, Pd/C
Br
Me
MeOH/aq. HCl Ph
NH2•HCl
CO2H
tBu O
H
N
O
N
H
N
H
N
HO
tBu
O
O
tBu
Jacobsen Org. Lett. 2000, 2, 867
Hydrolysis succeeded only after formylation of the amine, as the unformylated species underwent a retroStrecker reaction under the required reaction conditions. The free amino acid was subsequently obtained by
hydrogenation.
5
5.1
Enantioselective synthesis of -amino acids
General Structure of -amino acids
-Amino acids are subdivided into 2h-, 3h- and 2,3-amino acids depending on the position of the side chain
at the 3-aminopropionic acid core.
-Amino acids are key structural elements of peptidomimetics, natural products, and physiologically active
compounds.
15
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Update to 2013
Bode Research Group
http://www.bode.ethz.ch/
Peptides based on -amino acids have secondary structures comparable to their -amino acid analogues,
and display resistance against enzymatic degradation.
5.2
Classical method for -amino acid synthesis: Arndt-Eistert homologation
Prof. Seebach and co-workers have refined the Arndt–Eistert homologation of -amino acids with
diazomethane. This method is widely employed and is the basis for the commercially available 3h-amino
acids.
Seebach Helv. Chim. Acta 1996, 79, 913
Limitations:
 It is not suitable for large scale synthesis because of the explosive nature of diazomethane and the
high cost of the silver catalyst
 Inability to access  2-amino acids.
5.3
5.3.1
Versatile scalable asymmetric synthesis of -amino acids with chiral auxiliary
Isoxazoline based synthesis
Chiral isoxazolines are key intermediates for the preparation of a diverse array of -amino acids, including
the particularly challenging cyclic and highly substituted variants. Isoxazolines are readily accessible as
single stereoisomers via a 1,3-cycloaddition reaction.
Mapp JACS 2005, 127, 5376
5.3.2
Isoxazolidine fragmentation
An isoxazolidine auxiliary can be used for a three-step (cycloaddition, auxiliary removal and fragmentation)
preparation of enantiopure 3h, 2h and 2,3- amino acids. This approach works for a wide variety of “natural”
and “unnatural” side chains from the corresponding aldehydes.
16
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Update to 2013
Bode Research Group
http://www.bode.ethz.ch/
Bode Chem. Sci. 2010, 1, 637 and Bode OPRD 2012, 16, 687
5.4
Catalytic asymmetric synthesis of 3h-amino acids
5.4.1 Enantioselective hydrogenations of -substituted -(amino)acrylates
The isomers of the -(amino)acrylates show different reactivity and selectivity in metal-catalyzed
hydrogenations: reactions of E-isomers generally lead to higher enantioselectivities, and Z-isomers
frequently react faster, although the enantioselectivity is sometimes lower
The advances in Ru- and Rh-catalyzed homogeneous hydrogenations have provided standard procedure for
the synthesis of -amino acids, using a variety of chiral bidentate and monodentate phosphorous ligands.
First example:
Noyori Tetrahedron: Asymmetry 1991, 2, 543
Ru-bisphosphinite which can tolerate an E/Z mixture of substrates:
3,5-Me2C6H3
O
NH
O
[p-CymeneRhCl2]2 (2 mol%)
Xylyl-o-BINAPO (4 mol%)
O
Ph
OEt
NH
EtOH, H2, 50 ºC
OPPh2
O
OPPh2
OEt
Ph
3,5-Me2C6H3
98% ee
Xylyl-o-BINAPO
Zhang JACS 2002, 124, 4952
Breakthrough: enantioselective reduction of unprotected enamino esters
NH2
CO2Me
Ph
[Rh(COD)Cl]2 (0.15 mol%)
L* (0.30 mol%)
NH2
CO2Me
Ph
6.2-6.9 bar H2
MeOH, 50oC
Fe
PtBu2
P(p-CF3Ph)2
96% ee
Malan JACS 2004, 126, 9918
5.4.2
Mannich reaction ( 3-amino acids)
The Mannich reaction of malonates with imines was catalyzed by bifunctional cinchona alkaloids. The
thiourea group is proposed to activate and direct the electrophilic imine, the tertiary nitrogen of the quinine
moiety activates the nucleophile.
Boc
BnO2C
NHBoc
cat (10 mol%)
N
CO2Bn
H
Ph
acetone, -60 ºC
Ph
CO2Bn
CO2Bn
N
1) H2, Pd/C,
MeOH
2) toluene, D
R1
H
N
CF3
CO2H
MeO
94% ee
96% ee
H
N
NHBoc
S
N
CF3
Deng JACS 2006, 128, 6048
17
Update to 2013
Bode Research Group
http://www.bode.ethz.ch/
List JACS 2013, 135, 15334 and Maruoka ACIE 2013, 52, 5532
5.4.3
Conjugate addition (3-amino acids)
The addition of carbamates to -hydroxyenones was catalyzed by Cu(II)-bisoxazoline complex.
O
O
O
HO
Cu(OTf)2 (10 mol%)
L* (10 mol%)
O
R1
H2N
OR2
O
OR2
HN
HO
R1
CH2Cl2, 20 ºC
NaIO4
H2O/MeOH
20 ºC
O
O
OR2
HN
N
HO2C
R1
N
tBu
tBu
88-99% ee
Garcia JACS 2004, 126, 9188
The -hydroxy ketone was oxidatively cleaved using NaIO4 to yield the corresponding N-protected 3-amino
acid
5.5
Catalytic asymmetric synthesis of 2h-amino acids
In contrast to 3h-amino acids, 2h-isomers cannot be obtained simply by enantiospecific homologation of
the corresponding -amino acids, but have to be prepared by enantioselective reactions.
5.5.1
Asymmetric hydrogenation of aminoacrylic acid derivatives (2-amino acids)
A chiral BoPhoz-type ligand was employed for the Rh-catalyzed hydrogenation of alkyl-(E)--phenyl-(phthalimidomethyl)acrylates to obtain 2h-amino acids.
F3C
Rh(COD)2BF4 (1.0 mol%)
O R1
L* (1.1 mol%)
N
O
CO2R
CH2Cl2,20 ºC
10 bar H2
O
CF3
R1
R1
aq. HCl
N
CO2R
D
HCl H2N
O
90-99% ee
CO2H
2
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
The required N-Boc-imines are highly reactive and unstable. A elegant way is to generate them in situ from
N-Boc-amino sulfones.
PH
HN
Fe
PPh2
92% ee
Zheng JOC 2008, 73, 2015
5.5.2 Mannich reaction ( 2-amino acids)
An iminium species was in situ-generated by elimination of MeOH from aminal. L-Proline catalyzed the
addition of aliphatic aldehydes to give the adducts in good yield with high ee
Gellman JACS 2007, 129, 6050
5.5.3 Conjugated addition (2-amino acids)
Organozinc species have been successfully applied in copper-catalyzed conjugated additions to form chiral
-substituted nitro alkane. Catalysts with phosphoramidite ligands show high activity and excellent chemoand regio-selectivity
18
Update to 2013
OR
R1 2Zn (2.0 eq.)
OR
RO
Bode Research Group
Cu(OTf)2 (1 mol%)
RO
Toluene, -55 ºC
NO 2
NO 2
R1
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
88-96% ee
http://www.bode.ethz.ch/
1) RANEY-Nickel,
20 bar H 2
b) Boc 2O, Et 3N,
EtOH, rt
c) H 5IO 6, H 2O,
1% CrO3, MeCN, 0 ºC
O
HO
Ph
O
P N
O
NHBoc
R1
Ph
Feringa JACS 2003, 125, 3700
2-amino
RANEY®-Nickel
The corresponding N-Boc protected
acids were formed via
reduction of the
nitroalkane, followed by Boc-protection of the amine group and oxidation of the acetal under acidic
conditions to the corresponding carboxylic acid
5.6
Catalytic asymmetric synthesis of 2,3-amino acids
5.6.1 Mannich reaction ( 2,3-amino acids)
Chiral metal complex-promoted
La(III)–iPr-pybox was used in the direct asymmetric Mannich reaction of trichloromethyl ketones and pyridylor thienylsulfonyl- protected imines. The syn isomers were preferentially formed with high ee (up to >99%)
using the thienylsulfonyl protecting group.
X
X
O S
O
cat. (2.5-10 mol%)
S O
N O
R
H
CCl3
THF/toluene 1:1
MS 4Å, -40 °C
X=2-thienyl
X=2-pyridyl
O NH
R
1) NaOMe, MeOH,
0 °C
O
CCl3
2) Boc2O, DMAP,
MeCN, rt
3) Mg, MeOH, rt
syn:anti=8:1 - 30:1
92-99% ee
Boc
R
NH
O
CO2Me
O
N
N
N
La
(OAr)3
Ar=4-MeO-C6H4-
Shibasaki JACS 2007, 129, 9588
2,3-amino
The product was transformed into the N-Boc protected
ester by a nucleophilic displacement of the
trichloromethyl anion and subsequent Boc-protection of the amino group
Organocatalyst-promoted
List and co-workers reported excellent diastereoselectivities (dr up to 99:1) and enantioselectivities (ee >
98%) towards the syn-adduct for the proline catalyzed addition of aldehydes to aromatic N-Boc-protected
imines
List ACIE 2007, 46, 609
Direct asymmetric Mannich reactions of aliphatic aldehydes with -imino ethylglyoxylate were catalyzed by
alternative organocatalysts based on proline giving the anti adducts with good selectivity
Cordova Chem. Commun. 2006, 1760
5.6.2
Conjugated addition (2,3-amino acids)
The addition of N-benzyloxy amines to -disubstituted imide catalyzed by bisoxazoline ligand and
Mg(NTf2)2 leads to the formation of isoxazolidinones.
19
Update to 2013
Bode Research Group
O
R1
R2
O
N
H
BnNHOH
Mg(NTf2)2 (5 mol%)
L* (5 mol%)
CH2Cl2, -40 ºC
O
O
R2
NH2
N Bn
R1
http://www.bode.ethz.ch/
H2, Pd/C
dioxane, 60 ºC
HO2C
R1
O
O
N
N
R2
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
93-95% de
60-96% ee
Jasperse JACS, 2003, 125, 11796
The anti adducts were obtained in high yields and excellent diastereo- and enantioselectivities. Upon
hydrogenolysis, the 2,3-amino acids were obtained in high yield.
20