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OC VI (HS 2015) Bode Research Group the Required N-Boc-Imines Are Highly Reactive and Unstable

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OC VI (HS 2015) Bode Research Group the Required N-Boc-Imines Are Highly Reactive and Unstable 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. International 4.0 ShareAlike - NonCommercial - Attribution Commons Creative Examples of important drugs with uncommon amino acids This work is licensed under a 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 ShareAlike - a) Schöllkopf’s chiral auxiliary NonCommercial - Schöllkopf ACIE 1981, 20, 798 Attribution b) Oppolzer’s sultam Commons Creative Oppolzer Tetrahedron Lett. 1989, 30, 6009 c) Seebach’s self-regeneration of chirality Useful for synthesis of cyclic quaternary amino acids This work is licensed under a Seebach JACS 1983, 105, 5390 Page 2 OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ General strategy for synthesis of amino acid . License International 4.0 ShareAlike - 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) 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 Creative This work is licensed under a 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 Page 3 OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ . License International 4.0 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 NonCommercial - Attribution Commons 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 is licensed under 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 License R-BINAP P P P P Rh Rh O O Ar 1,4 - addition H OMe O N Me N OMe H O Me International 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 is licensed under 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 . License 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 is licensed under 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 International 4.0 ShareAlike - NonCommercial - Attribution 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 CO2tBu N CO tBu F H 40 ºC, 24 h 2 This work is licensed under 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.
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