Nonenzymatic, Enantioconvergent Dynamic Kinetic Resolution (DKR) of Racemic 2-(1H-Pyrrol-1-yl)alkanoic Acids as α-Amino Acid Equivalents

Abstract

We report an effective dynamic kinetic resolution (DKR) system of racemic 2-(1H-pyrrol-1-yl)alkanoic acids, which consists of a rapid racemization step via an activating substrate and an enantio-discriminating step via catalytic esterification. The combination of pivalic anhydride as an activating agent, bis(α-naphthyl)methanol as an achiral alcohol, (R)-BTM as a chiral acyl-transfer catalyst, and Hünig's base converted racemic 2-(1H-pyrrol-1-yl)alkanoic acids to the corresponding chiral carboxylates, which can be transformed into chiral α-amino acid derivatives with maintained high enantiopurity.α-Amino acids have long been considered fundamental moieties in organic chemistry, and the enantio-controlled and catalytic construction of the chiral α-position of α-amino acids has been targeted as an attractive synthetic goal. 16In order to provide large amounts of chiral α-amino acids from racemic α-amino acids, dynamic kinetic resolution (DKR) 7,8 has been anticipated to be an ideal method. While a wide range of enzymatic DKRs 911 for α-amino acid derivatives has been disclosed as reliable methodologies, non-enzymatic DKRs have also emerged as promising approaches during the last decade. However, major examples of the successful nonenzymatic DKR of chiral α-amino acids have involved the catalytic ring-opening alcoholysis of cyclic precursors, such as racemic urethane-protected α-amino acid N-carboxyanhydrides (Deng 12 ) and racemic 2-phenylazlactones (Seebach, 13 Fu,14 Berkessel, 1517 Connon,18,19 Birman,20,21 etc.). Note that the DKR systems for racemic 2-phenylazlactones principally allowed production of N-benzoyl amino acids with high enantiopurities.As illustrated in Figure 1, we have reported the effective kinetic resolution (KR) of racemic α-arylpropanoic acids 22 using carboxylic anhydride as the coupling agent, bis(α-naphthyl)-methanol as the achiral alcohol, and benzotetramisole (BTM) 23 as the chiral acyl-transfer catalyst. In this procedure, a racemic mixture of α-arylpropanoic acids was separated into the corresponding chiral carboxylates and the recovered chiral carboxylic acids with high selectivity. A mechanistic study 24 revealed that this enantioselective esterification proceeds through a mixed anhydride (MA), a reactive intermediate formed from the substrate and the coupling reagent, followed by formation of a transition state (TS) with the achiral alcohol and chiral BTM. Furthermore, acceleration of the racemization process in a polar reaction media such as DMF led to the development of the corresponding DKR system for α-arylpropanoic acids. 25Despite the growing number of DKR systems reported to date, there has yet been no example of a catalytic DKR system for protected α-amino acids via direct esterification using acyclic precursors. Moreover, to the best of our knowledge, there are no examples of catalytic DKR systems for any racemic α-nitrogencontaining carboxylic acids. In the present study, we report the first DKR of racemic 2-(1H-pyrrol-1-yl)alkanoic acids, which can then be converted to α...

Cu(OAc)2/TEMPO Cooperative Promoted Hydroamination Cyclization and Oxidative Dehydrogenation Cascade Reaction of Homopropargylic Amines

“…With TEMPO only,n or eaction was occurred. These two results demonstrated that the Cu(OAc) 2 and TEMPO are cooperative and neither can perform effectively without the other.A dditionally,i tw as observed that all reactions were ineffective when the TEMPO oxidant was replaced by another N-oxide (Table 1, entries 10-12);o r2 ,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), 1-hydroxy-1,2-benziodoxol-3(1H)-one-1-oxide (IBX), PhI(OAc) 2 ,o rK 2 S 2 O 8 (Table 1, entries [13][14][15][16]; or peroxide m-chloroperoxybenzoic acid (mCPBA) or tert-butyl hydroperoxide (TBHP) ( Table 1, entries 17-18). It was concluded that only the combinationo fC u(OAc) 2 with TEMPO was specific for the homopropargylic amine.…”

“…Unfortunately,o nly at race amount of pyrrole was generated by using the chiral Ntert-butylsulfonyl homopropargylic amine (Table 3, entry 12). By employing two different substituted aryl or alkyl (R 1 and R 2 ) substrates, all cases gave the desired products in good yields (Table 3, entries [13][14][15][16][17][18][19]. Particularlyf or the cyclohexyl-substituted homopropargylic amine, the yield of pyrrole was high at up to 82 %( Ta ble 3, entry 19).…”

Optimization of pharmacokinetic properties by modification of a carbazole-based cannabinoid receptor subtype 2 (CB2) ligand

“…Oxygen Preparation of this compound is described in the literature [25] following a different synthesis route.…”

“…HPLC method for the determination of the purity Equipment 1: Pump: L-7100, degasser: L-7614, autosampler: L-7200, UV detector: L-7400, interface: D-7000, data transfer: D-line, data acquisition: HSM-Software (all from LaChrom, Merck Hitachi); Equipment 2: Pump: LPG-3400SD, degasser: DG-1210, autosampler: ACC-3000T, UV-detector: VWD-3400RS, interface: DIONEX UltiMate 3000, data acquisition: Chromeleon 7 (Thermo Fisher Scientific); column: LiChropher ® 60 RP-select B (5 µm), LiChroCART ® 250-4 mm cartridge; flow rate: 1.0 mL/min; injection volume: 5.0 µL; detection at λ = 210 nm; solvents: A: demineralized water with 0.05 % (V/V) trifluoroacetic acid, B: acetonitrile with 0.05 % (V/V) trifluoroacetic acid; gradient elution (% A): 0 -4 min: 90 %; 4 -29 min: gradient from 90 % to 0 %; 29 -31 min: 0 %; 31 -31.5min: gradient from 0 % to 90 %; 31.5 -40 min: 90 %. Carbazol-9-yl)propan-1-ol(7) [25] …”

Catalytic Hydrogenation of N‐protected α‐Amino Acids Using Ruthenium Complexes with Monodentate Phosphine Ligands

“…The use of NH 2 OH in refluxing EtOH/H 2 O (3/1, v/v) [22] and the ozonolysis in MeOH at À 78°C [23] were both effective, affording 2amino-3-phenylpropan-1-ol (4 a) in isolated yields of 53% and 60%, respectively. The use of NH 2 OH in refluxing EtOH/H 2 O (3/1, v/v) [22] and the ozonolysis in MeOH at À 78°C [23] were both effective, affording 2amino-3-phenylpropan-1-ol (4 a) in isolated yields of 53% and 60%, respectively.…”