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

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Examples of important drugs with uncommon amino acids

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CHIMICA OGGI Chemistry Today June 2003

Page 1 OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ 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 License

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 International

99.9% er SM  Dimer: 99.8% dr  Trimer 99.7% dr  Four-mer: 99.6% dr  Five-mer: 99.5% dr

4.0  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

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a) Schöllkopf’s chiral auxiliary

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Schöllkopf ACIE 1981, 20, 798 Attribution

b) Oppolzer’s sultam

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Oppolzer Tetrahedron Lett. 1989, 30, 6009 c) Seebach’s self-regeneration of

 Useful for synthesis of cyclic quaternary amino acids

This work This is licensedunder a Seebach JACS 1983, 105, 5390

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General strategy for synthesis of amino acid

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2 Enantioselective synthesis of -amino acids 2.1 Introduction of the -hydrogen (-amino acids)

2.1.1. of ,-didehydroamino acids (C=C bond reduction)

NonCommercial  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

Attribution

Commons  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

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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

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Noyori JACS 2002, 124, 6649

ShareAlike - Industrial synthesis of (L)-DOPA by catalytic asymmetric hydrogenation  Synthesized in multi-ton scale every year

 Important drug for Parkinson’s disease treatment

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

2.1.2. Reduction of C=N bonds Creative Ph P PPh O [Rh(COD)2]BF4 (1 mol%) O 2 2 NH2 Chiral Ligand (1 mol%) BnHN Ph OH OH Ph MeOH, rt, N O Ph Bn H2, (60 atm) (R,R) Deguphos 97% ee 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

This work This is licensedunder a  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

Page 4 OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ 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

H O [Rh(COD)2]PF6 (3 mol%) Ar Chiral Ligand (6 mol%) O Me N . OMe ArBF3K OMe Me N PPh O Toluene, 110 ºC, 2 H PPh guaiacol (H+ source) O 2

89% 81-90% ee

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R-BINAP P P P P Rh Rh O O Ar 1,4 - addition H OMe O N Me N OMe

H O Me

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Ar 4.0

Darses & Genet ACIE 2004, 43, 719

2.1.4. Asymmetric hydrogenation – Dynamic Kinetic Resolution

ShareAlike -  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

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

OEt OEt

NonCommercial - NH2HCl 2. (PhCO)2O, Et3N, DCM, 90% HN Ph

anti O 97% ee (2S,3S) O O 99% de HCl H2N P Attribution O Ru O PPh2 EtO P O PPh2

O S-Synphos

Commons 1. [Ru(S)Synphos-Br ]PF (2 mol%) O O 2 6 OH O H2 (130 atm), 80 ºC, 4 days OEt OEt HN Ph DCM, 94% HN Ph

Creative Ph

O syn O HN O 98% ee (2R,3S) O 99% de H O Ru P EtO 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

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

This work This is licensedunder a  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

Page 5 OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ 2.2.1 Enantioselective electrophilic amination

 Metal and organocatalytic variants have been developed

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List JACS 2002, 124, 5656 & Jørgensen ACIE 2002, 41, 1790 International

2.2.2 Biomimetic Transamination 4.0

 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 ShareAlike

- –amino acids from the corresponding -ketoacids

NonCommercial -

Attribution

Shi JACS 2011, 133, 12914

2.2.3 Enantioselective aziridination

Commons

 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 Creative synthesis of amino acids

Ph O Ph Ph 1.5-30 mol% B(OPh)3 N Ph OEt 0.5-10 mol% S-VAPOL N Ph OH Ar N2 DCM, rt, 24 h R CO Et 2 Ph OH R = Alkyl, aryl, heteroaryl > 90% ee > 40:1 dr

Cleavage conditions S-VAPOL 10% Pd(OH)2, H2 (1 atm)

MeOH, rt, 3h

This work This is licensedunder a (R = Alkyl, cyclic), 83-100% H or N

O3, DCM, -78º C R CO2Et NaBH (10 eq), MeOH Ph Ph 4 (R = Alkyl, cyclic, aryl) N 40-60%

R CO2Et

10% Pd(OH)2, H2 (1 atm) MeOH, rt, 3h CO2Et (R = Ph), 79% Ph H2N H

Page 6 OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/  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

License  Usually alkylation is performed with a chiral phase transfer catalyst

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 Simple reaction protocol, safe and inexpensive; very suitable for large scale synthesis  A variety of aryl, alkyl and heteroaryl halides are employed

Commons  Base employed: KOH, CsOH, NaOH

 Solvent: water and toluene (Biphasic) Br Ph Ph O O O F Creative O Chiral catalyst N Ph N OtBu F OtBu CsOH, toluene Ph O -40 ºC, 20 h F 81% O 98% ee

TFA, H2O N EtOH, rt, 1h Br F

Pd/C, H2 (S) F N CO tBu 2 N CO2tBu F H 40 ºC, 24 h

This work This is licensedunder a  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

Page 7 OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/

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

.

Mannich type reaction License

R R R R N 4 :X 1 Metal or organo 4 NH :X 1 catalyst, chiral ligand R O R R O 5 2 R 5 R R3 O R3 O R2

Metal catalyzed International Boc O Cu(OTf)2 (10 mol%) NH O

OSiMe3 4.0 N Chiral ligand EtO EtO Boc OMe Ph Ph DCM, -20 ºC O R R 82-97% Other protecting groups like R = H, CH3

Cbz, Troc, Teoc also work 90% ee HN Ph

ShareAlike - Boc Cbz HN Ph O Cbz Cu(OTf)2 (10 mol%) NH N NH N Chiral ligand EtO EtO Boc Ph Ph DCM, 0 ºC O OMe 78% 87% ee

NonCommercial

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

 Several proline catalysed Mannich reactions have been studied with mixed results Attribution

Organocatalytic PMP O HN OH N H L-Pro (5 mol%) H CO2Et O R L-Pro 1,4-dioxane, rt, 44-67% 93-99% ee

Commons up to > 19:1 syn:anti O PMP N H H CO Et R 2 PMP O HN SMP (20 mol%) O

Creative Me

H CO2Et N DMSO, rt, 44-67% H R SMP upto 92% ee up to > 1:19 syn:anti

Si O Re PMP N N syn O anti N O PMP N Me H H H Si Si H CO2Et H CO Et R R 2

L-Pro SMP

This work This is licensedunder a 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

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Shi Chem. Sci. 2013, 4, 3906

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2.4 Introduction of the carboxyl group (-amino acids) 4.0

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 ShareAlike -  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 NH + NH

NH3 NH HCN 2 H3O 2 NonCommercial - R R R CN R COOH

1. HCN (1.2 equiv) HN

N Chiral catalyst (2 mol%) Attribution

Toluene, -70 ºC CO Me H 2 2. MeOH/HCl Reflux, 8 h, 79%

92% ee

Commons

NH2HCl Dimethylbarbituric acid N N Pd(PPh3)4, (5 mol%)

CO2Me Al Creative

DCM, rt, 3 h, 60 % tBu O Cl O tBu

Recrystallization tBu tBu >99% ee

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

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Page 9 OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/

KCN, AcOH, H O 2 Ph 1. H SO , HCl, 44 - 68 h Catalyst (0.5 mol%) 2 4 NHBoc Ph 2. NaOH, NaHCO HN Ph 3 R N Ph toluene, 0 ºC, 4 - 8 h R CO2H 3. (Boc)2O, dioxane, 16 h R CN 4. Recrystallize 98-99% ee

CF

NHBoc NHBoc NHBoc 3

. CO H CO H tBuNH Me S CO2H 2 2 2 Ph N N N CF3 H H 62-65% 50-51% 48-51% Ph O

6 to 14 g scale 3.5 g scale 4 g scale

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CF3 S H Ph N N N CF3

International Ph O H H

4.0 N

H C Ph2HC N

H

ShareAlike - 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

NonCommercial

- 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 Attribution

enantioenriched -amino amides, which serve directly as building blocks or can be converted into -

aminoacids

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Reeves JACS 2013, 135, 5565

3 Enantioselective synthesis of aryl glycines

3.1 Introduction of the -hydrogen (-Aryl glycines)

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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

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H H EtO2C CO2Et OCH3 O O Me N Me PMPHN Ph O P N H OEt Ph O OH OEt Chiral catalyst (5 mol%) Toluene, 50 ºC, 93%

O

. 96% ee O S-VAPOL R or S phosphoric acid H2N

H5IO6 or OEt License

trichlorocyanuric acid

H2SO4, ACN/H2O

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

International

3.2 Introduction of the -amino group (-Aryl glycines) 4.0

 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 ShareAlike

-  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

Cl Cl Ph O O I NHNs O F3C N Rh2(s-TCPTTL)4 Cl OSiEt3 S OMe NonCommercial (1 mol%) - O N OMe Cl Benzene, rt, 3 h NO2 O 95% O O NsN=IPh (Z:E = >95:5) (Nitrene precursor) CF3 Rh Rh

Attribution 97% ee Only Z isomer reacts

Hashimoto Tetrahedron Lett. 2007, 48, 8799

Commons 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 Creative

O O R O H S Chiral catalyst (1 mol%) N O N S OEt toluene, -22 ºC, 74 % O OEt O O H P O NHTf O OMe OMe R R = 2,4,6(iPr) C H O 3 6 2

ClHH2N 1. AlCl3, anisole, OH DCM, rt, 90 - 95%

2. 4 M HCl, reflux

This work This is licensedunder a 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

Page 11 OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ 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

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CHPh CHPh2 N 2 HN Chiral catalyst (10 mol%) N H CN

License N N

HCN, 96% H 86% ee

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ShareAlike - 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 and to the hydroxy group of the ligand NonCommercial

-  The carbonyl group of AA2 of the chiral peptidic ligand associates with HCN to deliver the cyanide to the activated bound imine substrate H CHPh2 BocHN COOH N Ti(Oi-Pr)4, 10 mol%, N CN Ph HC TMSCN, iPrOH, 2 6 N HCl, 70 ºC Cl Cl Attribution H Toluene, 4 ºC, 85% (Boc)2O, NaOH Cl dioxane >99% ee >99% ee

Commons Me H C N H H O N tBuH OH Me O N O N Ar NH H

N N Me Creative O O H O N Ti H Me O O 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

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O Boc Boc N Chiral catalyst (15 mol%) HN NaNO2, AcOH BocHN CH3NO2 OH NO Ar H DCM, -78 ºC, 84 to 95% Ar 2 DMSO Ar (High yields)

>96% ee Ar = O

+ other examples

. F

OMe CF3 License S S

OAc N N N N NMe H H 2 H H N H H N AcO N N Me Me Me Me AcO H OAc O O O O

S N N International H H H H H H

4.0

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

4 Enantioselective synthesis of ,-disubstituted -amino acids

ShareAlike -  ,-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 NonCommercial

- 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

Attribution

Commons

Williams JACS 1991, 113, 9276

Creative 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

OAc or OAc

O

This work This is licensedunder a Bn O O O 3 [h -C3H5PdCl]2 (2.5 mol%) Bn NH HN N O L* (7.5 mol%) N O Ph Et3N, toluene, rt PPh Ph P Ph 2 2 * L L 72-78% yield Pd 98-99% ee

H Ph N Bn O O Trost JACS 1999, 121, 10727

Page 13 OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ 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

cat (10 mol%) O O License O ArCH2-Br 1N HCl Br 2-naphthyl N H2N F 2-naphthyl N OtBu OtBu N OtBu RbOH THF, rt Me CH Ar Me CH Ar Me toluene, -35 ºC 2 2 O F up to 96% ee

N F International

4.0

Park JOC 2003, 68, 4514

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

traditional cinchona alkaloids

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O F Cl O H2N 1) AllylBr, 2) BnBr citric acid (0.5 M) O Br N O CsOH·H2O/toluene THF N

L* (1 mol%)

NonCommercial -

99% ee F

F F

Attribution Maruoka JACS 2000, 122, 5228

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

Commons 4.2.1 Chiral metal complex-promoted electrophilic -amination

First general strategy towards , -disubstituted -amino acids via electrophilic -amination. Cu(II)-BOX Creative complex catalyzes the reaction of different racemic -alkyl--ketoesters with azodicarboxylates to obtain products in excellent ee.

Me Me O O CO2Bn BnO2C O HN O O N Cu(OTf)2 (10 mol%) Me OEt N N N N L* Me CO2Bn Me CO Bn 2 Me CO2Et Ph Ph (S)-Ph-Box 98% ee BnO C 2 N Me N Ph CO2Bn O O

N Me N

This work This is licensedunder a Cu O R Ph O R RO 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.

Page 14 OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/

Et O t H CO2 Bu Boc N CO tBu b-ICD (5 mol%) Ph Boc 2 N N N Ph -78 ºC NC N HN CN H Boc Boc > 98% ee OH

b-ICD

. Jørgensen JACS 2004, 126, 8120

License 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.

International

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Barbas Org. Lett. 2005, 7, 867

ShareAlike - 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.

NonCommercial - H H O N HCN, cat (2 mol%) Me N Ac2O Me N conc. HCl toluene, -75 ºC Ph CN HCO H 105 ºC

Ph Me Br Br 2 Ph CN Br Attribution

> 99.9% ee

tBu O H Ph N H N N H2, Pd/C Me NH •HCl H H

Me N 2 O N Commons

Ph CO H Ph CO H MeOH/aq. HCl 2 2 Br HO O

tBu O tBu Creative

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

2 3 2,3

This work This is licensedunder a -Amino acids are subdivided into  h-,  h- and  -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.

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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

ShareAlike - 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. NonCommercial - Seebach Helv. Chim. Acta 1996, 79, 913 Limitations:

Attribution  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.

Commons 5.3 Versatile scalable asymmetric synthesis of -amino acids with chiral auxiliary 5.3.1 Isoxazoline based synthesis

Creative 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)

This work This is licensedunder a 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

Page 16 OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/

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

.

License

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:

International

4.0

Noyori Tetrahedron: Asymmetry 1991, 2, 543

ShareAlike - Ru-bisphosphinite which can tolerate an E/Z mixture of substrates:

3,5-Me2C6H3 O O [p-CymeneRhCl2]2 (2 mol%) OPPh2 NH O Xylyl-o-BINAPO (4 mol%) NH O OPPh2 º

Ph OEt EtOH, H2, 50 C Ph OEt NonCommercial

- 3,5-Me2C6H3 98% ee Xylyl-o-BINAPO

Zhang JACS 2002, 124, 4952

Attribution Breakthrough: enantioselective reduction of unprotected enamino esters

[Rh(COD)Cl] (0.15 mol%) NH 2 NH2 t 2 L* (0.30 mol%) P Bu2 CO Me P(p-CF3Ph)2 Commons CO2Me 2 Fe Ph Ph 6.2-6.9 bar H2 MeOH, 50oC 96% ee

Malan JACS 2004, 126, 9918 Creative

5.4.2 (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.

N 1) H2, Pd/C, H H NHBoc NHBoc N N CF Boc cat (10 mol%) MeOH 3 N CO Bn CO H 2 1 2 BnO2C CO2Bn Ph R

acetone, -60 ºC 2) toluene, D MeO S

This work This is licensedunder a H Ph CO2Bn CF 96% ee 94% ee N 3

Deng JACS 2006, 128, 6048

Page 17 OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ The required N-Boc-imines are highly reactive and unstable. An elegant way is to generate them in situ from

N-Boc-amino sulfones.

.

License 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.

International

O

4.0 O

O HN 2 Cu(OTf)2 (10 mol%) OR O O O NaIO4 2 O L* (10 mol%) HO HN OR R1 N N HO H2O/MeOH HO2C R1 H N OR2 CH Cl , 20 ºC R1 2 2 2 20 ºC tBu tBu

88-99% ee

ShareAlike - Garcia JACS 2004, 126, 9188 3 The -hydroxy ketone was oxidatively cleaved using NaIO4 to yield the corresponding N-protected  -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 NonCommercial - the corresponding -amino acids, but have to be prepared by enantioselective reactions.

5.5.1 Asymmetric hydrogenation of aminoacrylic acid derivatives (2-amino acids)

Attribution A chiral BoPhoz-type ligand was employed for the Rh-catalyzed hydrogenation of alkyl-(E)--phenyl-- (phthalimidomethyl)acrylates to obtain 2h-amino acids.

F3C CF3 Commons

O 1 R1 O R1 Rh(COD)2BF4 (1.0 mol%) R aq. HCl

L* (1.1 mol%) 2 N HCl H2N N CO H CO2R D 2 PH CO2R CH2Cl2,20 ºC 10 bar H O HN PPh

Creative O 2 Fe 2

90-99% ee 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

This work This is licensedunder a Gellman JACS 2007, 129, 6050

Page 18 OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ 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

1 OR 1) RANEY-Nickel, R 2Zn (2.0 eq.) O OR 20 bar H Cu(OTf)2 (1 mol%) 2 Ph RO NO O

. 2 HO NHBoc b) Boc O, Et N, P N RO NO2 Toluene, -55 ºC R1 2 3 R1 O EtOH, rt Ph 88-96% ee c) H5IO6, H2O,

1% CrO3, MeCN, 0 ºC License

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 International

2,3

4.0 5.6 Catalytic asymmetric synthesis of  -amino acids

5.6.1 Mannich reaction (2,3-amino acids)

Chiral metal complex-promoted

ShareAlike - 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.

X X O O S cat. (2.5-10 mol%) 1) NaOMe, MeOH, Boc S O O NH O 0 °C NH NonCommercial O O

- N CCl3 N O THF/toluene 1:1 CO2Me R CCl3 R MS 4Å, -40 °C 2) Boc2O, DMAP, N N R H MeCN, rt La (OAr) X=2-thienyl syn:anti=8:1 - 30:1 3) Mg, MeOH, rt 3 X=2-pyridyl 92-99% ee

Ar=4-MeO-C6H4- Attribution

Shibasaki JACS 2007, 129, 9588

The product was transformed into the N-Boc protected 2,3-amino ester by a nucleophilic displacement of the Commons trichloromethyl anion and subsequent Boc-protection of the amino group

Organocatalyst-promoted

Creative 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

This work This is licensedunder a 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

Page 19 OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/

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.

BnNHOH

Mg(NTf2)2 (5 mol%) O NH2 . O O O O N Bn O L* (5 mol%) H2, Pd/C HO C 2 1 R1 N R N N H CH2Cl2, -40 ºC R2 R1 dioxane, 60 ºC 2 R2 R

93-95% de License

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. International

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Creative

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