oc vi (hs 2015) bode research group ......2.2.3 enantioselective aziridination 4 few methods known...

OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/

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Catalytic Enantioselective Synthesis of Amino Acids

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


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1.2 Why are we interested in the synthesis of amino acids 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

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

Relevant protecting group for further modifications (Boc, Fmoc, Cbz)

Generality – methodology should be widely applicable for a large range of substrates

1.4 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

http://dx.doi.org/10.1002/anie.198107981

http://dx.doi.org/10.1016/S0040-4039(01)93840-7

http://dx.doi.org/10.1021/ja00354a034


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General strategy for synthesis of amino acid

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 difference in reactivity and the substrate scope between Rh and Ru-complexes arise because of the differences in the basic mechanism

http://dx.doi.org/10.1021/cr050580o


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Noyori JACS 2002, 124, 6649

Industrial synthesis of (L)-DOPA by catalytic asymmetric hydrogenation

Synthesized in multi-ton scale every year

Important drug for Parkinson’s disease treatment

Federsel Nat. Rev. Drug Discovery 2005, 4, 685

2.1.2. Reduction of C=N bonds

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, 4067

Indirect method – Reduction of -imino esters

Again only very few examples known

Preparation and isolation of -imino esters can be challenging

Uneyama Org. Lett. 2001, 3, 313

O

O

OHPh

Ph

NH2

[Rh(COD)2]BF4 (1 mol%)

Chiral Ligand (1 mol%)

MeOH, rt,

H2, (60 atm)

BnHN

O

OH

Ph

97% ee

NBn

Ph2P PPh2

(R,R) Deguphos

PPh2

PPh2

R-BINAP

http://dx.doi.org/10.1021/ja010982n

http://dx.doi.org/10.1038/nrd1798

http://dx.doi.org/10.1021/jo020690k

http://dx.doi.org/10.1021/ol0002471


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2.1.3. Protonation of enolates

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

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

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

2.2 Introduction of the -amino group (-amino acids)

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

HN

O

Me

O

OMe

[Rh(COD)2]PF6 (3 mol%)

Chiral Ligand (6 mol%)

Toluene, 110 ºC,

guaiacol (H+ source)

89%

NH

O

Me

O

OMe

Ar

PPh2

PPh2

R-BINAP

ArBF3K

NH

O

Me

O

OMe

Rh

Ar

PP

1,4 - addition HNO

Me

O

OMe

Rh

P P

Ar

81-90% ee

O

OEt

O

NH2HCl

1. [Ru(S)SynphosBr2]PF6 (2 mol%)H2 (12 atm), 50 ºC, 24 hDCM + EtOH, 89%

2. (PhCO)2O, Et3N, DCM, 90%

O

O

O

O PPh2

PPh2

S-Synphos

OH

OEt

O

HN

O

Ph

97% ee (2S,3S)99% de

anti

O

OEt

O

HN

1. [Ru(S)Synphos-Br2]PF6 (2 mol%)H2 (130 atm), 80 ºC, 4 days

DCM, 94%

OH

OEt

O

HN

O

Ph

98% ee (2R,3S)99% de

synO

Ph

OO

EtO

H2NHClRu

P

P

OO

EtORu

P

P

HN O

Ph

H


http://dx.doi.org/10.1002/ejoc.200400078


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2.2.1 Enantioselective electrophilic amination

Metal and organocatalytic variants have been developed

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

N

Ar

Ph

Ph

N2

O

OEt

1.5-30 mol% B(OPh)30.5-10 mol% S-VAPOL

DCM, rt, 24 h

R = Alkyl, aryl, heteroaryl

N

R

Ph Ph

CO2Et

> 90% ee> 40:1 dr

OH

OHPh

Ph

S-VAPOL

N

R

Ph Ph

CO2Et

10% Pd(OH)2, H2 (1 atm)MeOH, rt, 3h(R = Alkyl, cyclic), 83-100%or

O3, DCM, -78º CNaBH4 (10 eq), MeOH(R = Alkyl, cyclic, aryl)40-60%

10% Pd(OH)2, H2 (1 atm)MeOH, rt, 3h(R = Ph), 79%

HN

R CO2Et

PhCO2Et

H2N H

Cleavage conditions

http://dx.doi.org/10.1021/ja0261325

http://dx.doi.org/10.1002/1521-3773(20020517)41:10%3C1790::AID-ANIE1790%3E3.0.CO;2-Y

http://dx.doi.org/10.1021/ja203138q


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Ring opening of aziridine under reductive conditions to give the amino acid worked only with Ph group

Wulff Org. Lett. 2005, 7, 2201

2.3 Introduction of the -side chain (-amino acids)

One of the most reliable method for the synthesis of amino acids 2.3.1 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)

The enantioselectivity arises from interactions of the enolate generated under phase transfer conditions with the chiral ligand

Maruoka Chem. Sci. 2010, 1, 499

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

N

Ph

Ph

O

OtBu

Br

Chiral catalyst

CsOH, toluene-40 ºC, 20 h81%

N

PhPhO

OtBu

O O

OO 98% ee

TFA, H2OEtOH, rt, 1h

NH

CO2tBu N CO2tBu

Pd/C, H2

40 ºC, 24 h

N

Br

F

F

F

F

F

F(S)

http://dx.doi.org/10.1021/ol050597t

http://dx.doi.org/10.1039/C0SC00250J


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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 metal and organocatalysts. Silyl enol ethers and enamides have been used as the nucleophiles

Kobayashi Org. Lett. 2003, 5, 2481 & Kobayashi ACIE 2004, 43, 1679

Several proline catalysed Mannich reactions have been studied with mixed results

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

Mannich type reaction

N

O

R5O

R4 :X

R3

R2

R1

N

O

EtO Boc

OSiMe3

Other protecting groups like Cbz, Troc, Teoc also work

Ph

Cu(OTf)2 (10 mol%)Chiral ligand

DCM, -20 ºC82-97%

NH

O

EtO

O

Ph

R

R = H, CH390% ee

R

Boc

N

O

EtO Boc

HN

OMe

HN

Ph

Ph

OMe

NH

Ph

Cbz Cu(OTf)2 (10 mol%)Chiral ligand

DCM, 0 ºC78%

NH

O

EtO

N

Ph

87% ee

Boc Cbz

NH

O

R5O

:X

R

R2

R4Metal or organocatalyst, chiral ligand

R3

R

R1

Metal catalyzed

H

O

R

NPMP

CO2EtH

NH

OMe

SMP

SMP (20 mol%)

DMSO, rt, 44-67% H

O

R

HN

CO2Et

PMP

L-Pro (5 mol%)

1,4-dioxane, rt, 44-67%

H

O

R

HN

CO2Et

PMP

NH

OH

L-Pro

O

93-99% eeup to > 19:1 syn:anti

upto 92% eeup to > 1:19 syn:anti

NO

O

H

R

HN

PMP

CO2EtH

NPMP

CO2EtH

NO

Me

R

HSi

Si Re

Si

syn anti

L-Pro SMP

Organocatalytic

http://dx.doi.org/10.1021/ol034717d


http://dx.doi.org/10.1021/ja017833p

http://dx.doi.org/10.1016/S0040-4039(02)01772-0


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Shi Chem. Sci. 2013, 4, 3906

2.4 Introduction of the carboxyl group (-amino acids) 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

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

H

N1. HCN (1.2 equiv)Chiral catalyst (2 mol%)Toluene, -70 ºC

2. MeOH/HClReflux, 8 h, 79%

CO2Me

HN

92% ee

Dimethylbarbituric acidPd(PPh3)4, (5 mol%)

DCM, rt, 3 h, 60 %

CO2Me

NH2HCl

Recrystallization>99% ee

N N

O O

tBu

tBu

tBu

tBu

Al

Cl

Al-Salen

O

R

NH3 HCN NH2

R CN

H3O+ NH2

R COOH

Strecker Synthesis of a-amino acids (Year 1850)Oldest known amino acid synthesis

NH

R

http://dx.doi.org/10.1039/C3SC51747K

http://dx.doi.org/10.1021/ja980299+


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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 Carbamoyl anion addition to N-sulfinyl imines

Carbamoyl 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 Enantioselective synthesis of aryl glycines

3.1 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

NR

Ph

Ph

KCN, AcOH, H2OCatalyst (0.5 mol%)

toluene, 0 ºC, 4 - 8 hHN

R CN

Ph

Ph

1. H2SO4, HCl, 44 - 68 h2. NaOH, NaHCO3

3. (Boc)2O, dioxane, 16 h4. Recrystallize

NHBoc

R CO2H

NHBoc

CO2H

NHBoc

CO2H

NHBoc

CO2H tBuNH2

98-99% ee

62-65%6 to 14 g scale

50-51%3.5 g scale

48-51%4 g scale

Ph

Ph

N

O

NH

S

NH

CF3

CF3

N

H

H

Ph

Ph

HN

O

N

S

N

CF3

CF3

Me

Ph2HC

H H

N

C

http://dx.doi.org/10.1038/nature08484


http://dx.doi.org/10.1021/ja402647m


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Antilla JACS 2007, 129, 5830 Rutjes Tetrahedron Lett. 2006, 47, 8109

3.2 Introduction of the -amino group (-Aryl glycines)

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

Hashimoto Tetrahedron Lett. 2007, 48, 8799

3.3 Introduction of the aryl side chain (-Aryl glycines)

Enders reported an organocatalytic Friedel-Crafts type reaction with N-sulfonyl--imino esters

Importantly the protecting group could be removed under relatively mild conditions

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

N

O

OEt

OCH3

NH

H HCO2EtEtO2C

Me Me

Chiral catalyst (5 mol%)Toluene, 50 ºC, 93%

O

OPh

Ph

S-VAPOLphosphoric acid

P

O

OH

96% ee

H5IO6 ortrichlorocyanuric acid

H2SO4, ACN/H2O

H2N

O

OEt

O

OEtPMPHN

R or S

OSiEt3

OMe

(Z:E = >95:5)

NO2

SN

O

O

I

NsN=IPh(Nitrene precursor)

Ph

Rh2(s-TCPTTL)4 (1 mol%)

Benzene, rt, 3 h95%

O

OMeNHNsF3C

CF3

97% ee

N

O

OO O

Rh Rh

Cl Cl

Cl

Cl

Only Z isomer reacts

N

H

SO

O

O

OEt

OMe

O

OP

O

NHTf

R

R

R = 2,4,6(iPr)3C6H2

Chiral catalyst (1 mol%)toluene, -22 ºC, 74 %

HN

S

O

O

O

OEt

OMe

1. AlCl3, anisole,DCM, rt, 90 - 95%

2. 4 M HCl, reflux

OMe

ClHH2N

O

OH

http://dx.doi.org/10.1021/ja070519w

http://dx.doi.org/10.1016/j.tetlet.2006.09.044

http://dx.doi.org/10.1016/j.tetlet.2007.10.087

http://dx.doi.org/10.1002/adsc.201000143

http://dx.doi.org/10.1002/1521-3773(20001117)39:22%3C4114::AID-ANIE4114%3E3.0.CO;2-V


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3.4 Introduction of the carboxyl group (-Aryl glycines) 3.4.1 Strecker reaction

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

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

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

H

NCHPh2

N

NH

N

Chiral catalyst (10 mol%)

HCN, 96%CN

HNCHPh2

86% ee

H

NCHPh2

Cl

Ti(Oi-Pr)4, 10 mol%, TMSCN, iPrOH,

Toluene, 4 ºC, 85%

CNHN

Ph2HC

Cl

>99% ee

6 N HCl, 70 ºC

(Boc)2O, NaOHdioxane

COOHBocHN

Cl

>99% ee

O

N

Ti

OO

O

HN

H

MeO

O

NH

MeH

N

Ar

HC N H

tBu OH

N

O

NH

Me O

O

HN Me

http://dx.doi.org/10.1021/ja952686e

http://dx.doi.org/10.1021/ol990623l

http://dx.doi.org/10.1021/ja011875w


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Review: Herrera Eur. J. Org. Chem. 2009, 2401 & Zhou Org. Lett. 2008, 10, 1707

4 Enantioselective synthesis of ,-disubstituted -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 -disubstituted -amino acids is the electrophilic -alkylation of amino acid enolate equivalents

Williams JACS 1991, 113, 9276

Catalytic asymmetric synthesis of -disubstituted -amino acids

4.1 Enantioselective introduction of the -side chain (,-disubstituted -amino acids) 4.1.1 Chiral metal complex-promoted electrophilic addition

Azalactones 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

Trost JACS 1999, 121, 10727

Ar

NBoc

H

CH3NO2

Chiral catalyst (15 mol%)

DCM, -78 ºC, 84 to 95% Ar

HNBoc

NO2

Ar =

+ other examples

OMe

O

CF3

F

HN

S

HN

NMe2

OAc

AcOOAc

AcO

N

S

N

NMe Me

H H

NO O

HH

H

N

S

N

NMe Me

H H

NO O

HH

H

H

NaNO2, AcOH

DMSO

BocHN

O

OH

Ar(High yields)

>96% ee

N O

O

Ph

Bn

OAc

OAcor

[h3-C3H5PdCl]2 (2.5 mol%)

L* (7.5 mol%)Et3N, toluene, rt

N O

O

Ph

Bn NH HN

OO

PPh2 Ph2P

O

HN

O

BnPh

PdL L

*72-78% yield98-99% ee

http://dx.doi.org/10.1002/ejoc.200801097

http://dx.doi.org/10.1021/ol8003035

http://dx.doi.org/10.1021/ja00024a038

http://dx.doi.org/10.1021/ja992754n


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Facial discrimination in the coordination of the allylic species to the metal center, in combination with the minimalization of charge separation in the transition state, is thought to be responsible for the selectivity 4.1.2 Organocatalyst-promoted electrophilic addition 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

Park JOC 2003, 68, 4514

The C2-symmetric chiral quaternary ammonium bromides provide greater stability and higher ees than the traditional cinchona alkaloids

Maruoka JACS 2000, 122, 5228

4.2 Enantioselective introduction of the -amino group (,-disubstituted -amino acids)

4.2.1 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.

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.

N2-naphthylOtBu

Me

OArCH2-Br

RbOH

toluene, -35 ºC

cat (10 mol%)

N2-naphthylOtBu

O

Me CH2Ar

up to 96% ee

N

N

O

F

F

F

BrH2NOtBu

O

Me CH2Ar

1N HCl

THF, rt

Cl

N

O

O

1) AllylBr, 2) BnBr

CsOH·H2O/toluene

L* (1 mol%)

citric acid (0.5 M)

THF

H2N

O

O

N

Br

F

F

FF

99% ee

N

N

BnO2C

CO2Bn

O

Me

O

OEt

Me

O

N N

O

MeMe

N

O

Me CO2Bn

HNCO2Bn

CO2EtMe Ph Ph

Cu(OTf)2 (10 mol%)

(S)-Ph-Box

98% ee

N

O

N

O

Ph

PhMe

Me

Cu

N

N CO2Bn

BnO2C

O

O

ROR

R

L*

http://dx.doi.org/10.1021/jo034006t




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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.

Jacobsen Org. Lett. 2000, 2, 867

Hydrolysis succeeded only after formylation of the amine, as the unformylated species underwent a retro-Strecker reaction under the required reaction conditions. The free amino acid was subsequently obtained by hydrogenation.

5 Enantioselective synthesis of -amino acids

5.1 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.

N

N

Boc

Boc

Ph

CO2tBu

CN

b-ICD (5 mol%)

-78 ºCN

OEt

N

OH

H

H

b-ICD

> 98% ee

Ph

NCN

CO2tBu

HN

Boc

Boc

Ph Me

N

Br

N

NH

NH

HNPh

OtBu

O

HO

tBu O tBu

O

HCN, cat (2 mol%)

toluene, -75 ºC Ph CN

NMe

H

Br

> 99.9% ee

Ph CN

NMe

Br

HO

Ac2O

HCO2H

Ph CO2H

NMe

Br

H

Ph CO2H

NH2•HClMeH2, Pd/C

MeOH/aq. HCl

conc. HCl

105 ºC

http://dx.doi.org/10.1021/ja047704j

http://dx.doi.org/10.1021/ol047368b

http://dx.doi.org/10.1021/ol005636+


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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 Versatile scalable asymmetric synthesis of -amino acids with chiral auxiliary 5.3.1 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.

Bode Chem. Sci. 2010, 1, 637 and Bode OPRD 2012, 16, 687

http://dx.doi.org/10.1002/hlca.19960790402


http://dx.doi.org/10.1039/C0SC00317D

http://dx.doi.org/10.1021/op300069n


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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:

Zhang JACS 2002, 124, 4952

Breakthrough: enantioselective reduction of unprotected enamino esters

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.

Deng JACS 2006, 128, 6048

Ph

NH

[p-CymeneRhCl2]2 (2 mol%)

O

OEt Ph

NH O

OEt

O O

Xylyl-o-BINAPO (4 mol%)

98% ee

OPPh2

OPPh2

3,5-Me2C6H3

3,5-Me2C6H3

EtOH, H2, 50 ºC

Xylyl-o-BINAPO

Ph

NH2

CO2Me

[Rh(COD)Cl]2 (0.15 mol%)

L* (0.30 mol%)

MeOH, 50oC

6.2-6.9 bar H2Ph

NH2

CO2Me

96% ee

P(p-CF3Ph)2

PtBu2

Fe

CO2BnBnO2C

H Ph

NBoc

cat (10 mol%)

acetone, -60 ºCPh

CO2Bn

CO2Bn

NHBoc 1) H2, Pd/C,

MeOH

2) toluene, DR1

CO2H

NHBoc

N

MeO

NHN

S

HN CF3

CF396% ee 94% ee

http://dx.doi.org/10.1016/S0957-4166(00)86107-8

http://dx.doi.org/10.1021/ja020121u

http://dx.doi.org/10.1021/ja047901i

http://dx.doi.org/10.1021/ja060716f


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The required N-Boc-imines are highly reactive and unstable. An elegant way is to generate them in situ from N-Boc-amino sulfones.

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.

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.

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

R1

Cu(OTf)2 (10 mol%)

CH2Cl2, 20 ºC

88-99% ee

O

HOH2N OR2

O L* (10 mol%)R1

O

HO

HN OR2

O

HO2CR1

HN OR2

O

NaIO4

H2O/MeOH

20 ºC

O

N N

O

tBu tBu

N

O

O

CO2R

R1 Rh(COD)2BF4 (1.0 mol%)

L* (1.1 mol%)

CH2Cl2,20 ºC

10 bar H2

N

O

O

CO2R

R1

90-99% ee

aq. HCl

DH2N

CO2H

R1

HCl

92% ee

PPh2FeHN

PH

F3C CF3

2

http://dx.doi.org/10.1021/ja408747m


http://dx.doi.org/10.1021/ja047004e

http://dx.doi.org/10.1021/jo702510m

http://dx.doi.org/10.1021/ja070063i


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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 chemo- and regio-selectivity

Feringa JACS 2003, 125, 3700

The corresponding N-Boc protected 2-amino acids were formed via RANEY

®-Nickel 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 pyridyl- or thienylsulfonyl- protected imines. The syn isomers were preferentially formed with high ee (up to >99%) using the thienylsulfonyl protecting group.

Shibasaki JACS 2007, 129, 9588

The product was transformed into the N-Boc protected 2,3

-amino 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

NO2

R12Zn (2.0 eq.)

Cu(OTf)2 (1 mol%)

Toluene, -55 ºCNO2

R1

OR

RO

OR

RO

1) RANEY-Nickel,

20 bar H2

b) Boc2O, Et3N,

EtOH, rt

c) H5IO6, H2O,

1% CrO3, MeCN, 0 ºC

88-96% ee

O

OP N

Ph

Ph

NHBoc

R1

O

HO

R H

NS O

O

X

CCl3

O

THF/toluene 1:1MS 4Å, -40 °C

cat. (2.5-10 mol%)

R

NHSO

O

X

O

CCl3

syn:anti=8:1 - 30:192-99% ee

R

NH

CO2Me

Boc1) NaOMe, MeOH,0 °C

2) Boc2O, DMAP,

MeCN, rt

3) Mg, MeOH, rt

NO

N N

O

La

(OAr)3

Ar=4-MeO-C6H4-

X=2-thienylX=2-pyridyl

http://dx.doi.org/10.1021/ja029817d

http://dx.doi.org/10.1021/ja073285p


http://dx.doi.org/10.1039/B602221A


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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.

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.

NH

R1

R2

O ON

OO Bn

R2 R1

BnNHOH

Mg(NTf2)2 (5 mol%)

L* (5 mol%)

CH2Cl2, -40 ºC

93-95% de60-96% ee

H2, Pd/C

dioxane, 60 ºC

HO2CR1

R2

NH2 O

N N

O


oc vi (hs 2015) bode research group ......2.2.3 enantioselective aziridination 4 few methods known...

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