Pd(II)-Catalyzed Asymmetric Addition of Arylboronic Acids to Aliphatic N-Carbamoyl Hydrazones

Pd(II)-Catalyzed Asymmetric Addition of Arylboronic Acids to Aliphatic N-Carbamoyl Hydrazones Saúl Alberca,aMarta Velázquez,aJosé Trujillo-Sierra,aJavier Iglesias-Sigüenza,a Rosario Fernández,a,* José M. Lassaletta,b,* and David Mongea,* a Departamento de Química Orgánica, Universidad de Sevilla and Centro de Innovación en Química Avanzada (ORFEO-CINQA), C/Prof. García González, 1, 41012 Sevilla, Spain E-mail: [email protected]; [email protected] b Instituto Investigaciones Químicas (CSIC-US) and Centro de Innovación en Química Avanzada (ORFEO-CINQA), C/Américo Vespucio 49, 41092 Sevilla, Spain E-mail: [email protected] Manuscript received: April 21, 2022; Revised manuscript received: June 11, 2022; Version of record online: June 30, 2022 Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202200430 © 2022 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Abstract: Catalysts generated by combinations of Pd(TFA)2and pyridine-hydrazone ligands have been applied to 1,2 addition of arylboronic acids to aliphatic N-carbamoyl (Cbz) hydrazones, affording protected αaryl monoalkylhydrazines with high enantioselectivities (37-99% ee). Subsequent removal of the benzyloxy carbonyl protecting group provides a direct entry to free monosubstituted hydrazines, key building blocks for the synthesis of appealing 1,2-diaza-heterocycles, aminoacid derived hydrazides and other pharmacophores thereof. Keywords: Asymmetric Catalysis; Nitrogen Ligands; Arylboronic Acids; Hydrazones; α-Aryl Monoalkylhydrazines Introduction Chiral non-racemic hydrazine and hydrazide derivatives are key building-blocks for the synthesis of many biologically active molecules (see selected examples in Figure 1). The growing interest in marketed drugs such as L-Carbidopa (treatment of Parkinson’s disease)[1] and Cilazapril (hypertension)[2] has accelerated the development of strategies for accessing α-hydrazino acids.[3] However, catalytic enantioselective methods for accesing α-aryl monoalkylhydrazines, direct precursors of 1,2-diaza heterocycles such as hrFAAH (I)[4] and PDE2 (II)[5] inhibitors, remain limited. One straightforward approach relies on the transition metal-catalyzed asymmetric hydrogenation of prochiral ketone-derived hydrazones (Scheme 1A). Burk’s group reported, in 1992, the first enantioselective reduction of N-benzoyl- hydrazones, employing a Rh/Duphos catalyst.[6] Since Figure 1. Biologically active chiral hydrazinoacids and 1,2- diaza-heterocycles. RESEARCH ARTICLE doi.org/10.1002/adsc.202200430 Adv. Synth. Catal. 2022,364, 2373–2379 © 2022 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH 2373 Wiley VCH Mittwoch, 13.07.2022 2214 / 255578 [S. 2373/2379] 1 this seminal work, many catalytic systems based on rhodium in combination with phosphorous ligands have been disclosed for the hydrogenation of hydrazones with diverse substitution patterns (R=alkyl,[7] alkenyl[8] and alkynyl[9]) and fewer examples of other metals are also known: Ir/(S,S)-f-Binaphane (R=methyl),[10] Pd/(S)-SegPhos (R=CF3),[11] Co/(S,S)-Ph-BPE (R=alkyl),[12] Ru/W022-2 (R=alkyl),[13] and Ni/(R,R)- QuinoxP* (R=alkyl).[14] Although valuable progress has been made in this area, achieving stereocontrol with some alkyl-chains larger than methyl (linear or branched) still represents a challenging task, due to the E/Z isomerism inherent to the synthesis of the hydrazone precusors. Concerning the structure of the aryl groups, ortho substitution often provide the lowest enantioselectivities.[15] It’s worth to highlight that removal of acyl protecting groups from hydrazides to hydrazines has often been found to be problematic due to racemization or side-reactions involving NN bond cleavage. α-Aryl monoalkylhydrazine building blocks might be also synthesized by direct arylation of aliphatic aldehyde-derived hydrazones. However, to the best of our knowledge, catalytic enantioselective versions of this method has not been described to date.[16] Over the years, we have explored the catalytic performance of hydrazone derivatives as N,Nligands for Pd-catalyzed asymmetric reactions involving aryl boronic acids as aryl transfer reagents. Pioneered by a glyoxal-bis- hydrazone which afforded excellent results in Pd(0) catalyzed Suzuki-Miyaura cross-couplings,[17] Pd- (TFA)2complexes of pyridine-hydrazone ligand L1 allowed to expand the repertoire of the asymmetric addition of arylboronic acids to different electrophiles, such as ß-substituted cyclic enones, dienones,[18] and saccharin-derived cyclic ketimines and diketimines[19] with high yields and great stereocontrol, often outperforming other well-established pyridyl mono-oxa- zolines (pymox) ligands.[20] In the original design, a C2-symmetric 2,5-diphenylpyrrolidine scaffold was introduced to prevent the loss of optimal chiral environments around the metal by NN bond rotations, thereby facilitating the enantioinduction event. Inspired by the efficiency of [Pd(TFA)2/L1] catalyst in related contexts, we have recently developed the 1,2-addition of aryl boronic acids to N-carbamoyl protected glyoxylate-derived hydrazones, yielding α-aryl α-hydrazino esters/amides in high enantioselectivities (Scheme 1B).[21] In this work, we disclose next generation ligands bearing optimal distinctive C2-symmet- ric 2,5-diarylpyrrolidine scaffolds which have allowed expanding the scope of the previous methodology to less reactive N-protected aliphatic hydrazones (Scheme 1C). Results and Discussion Preliminary experiments were performed with N- phthaloyl hydrazone 1A and phenylboronic acid (2a) as model reactants. Complexes prepared in situ from bipyridine (bipy, 11 mol%) and different Pd(II) sources [PdCl2, Pd(OAc)2and Pd(TFA)2, 10 mol%] were initially evaluated in reactions performed in trifluoroethanol (TFE) at 60°C. From this screening, Pd- (TFA)2was identified as the best precatalyst, affording 3aA in full conversion (>95%) after 24 h. After evaluation of diverse chiral ligands, such as N,N bisoxazolines, C2-symmetric glyoxal bis-hydrazones, P,N phosphino-hydrazones, N,N' pyridine-oxazolines and pyridine-hydrazones, the latest were identified as the best option (See ESI for details). As a first promising result, the use of L1 enabled the obtention of 3aA with full conversion and 74% ee (entry 1, Table 1). Next, benzyloxycarbonyl (Cbz)-protected hydrazone 1B was selected as a less reactive mono-carbamoyl substrate. Lower conversions were observed (entries 9 and 10), reaching up to 73% ee in dichloroethane (DCE) as the Scheme 1. Catalytic asymmetric approaches towards α-aryl hydrazine blocks. RESEARCH ARTICLE asc.wiley-vch.de Adv. Synth. Catal. 2022,364, 2373–2379 © 2022 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH 2374 Wiley VCH Mittwoch, 13.07.2022 2214 / 255578 [S. 2374/2379] 1 16154169, 2022, 14, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/adsc.202200430 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License best solvent. Structural variations of pyridine-hydra- zone L1 were systematically investigated in reactions performed in TFE (for 1A) and DCE (for 1B). (2S,6S)- 2,6-Diphenyl piperidine derivative L2 provided lower conversions and enantioselectivities (3aA: 49%, 57% ee, entry 3; 3aB: 62%, 20% ee, entry 11), a fact that has been repeatedly observed in related catalysts,[17–19,21] and that could be explained by the higher pyramidalization of the piperidine N atom and hence the weaker n!π conjugation. It has been reported that in related Pd(II)/pymox systems,[20d,e] electron-deficient ligands may improve catalytic activities. Therefore, the modulation of the donor ability of the ligand by introduction of electron-withdrawing groups at C5 of the pyridine ring was also investigated. The presence of a bromide in L3 led to similar or better enantioselectivities (up to 83% ee for 3aB), albeit in lower conversions (entries 4 and 12). On the contrary, ligands L4 (R=CO2Me) and L5 (R=ArF= 3,5-bis-trifluoromethylphenyl) showed a better catalytic performance, affording 3aA with similar results than those provided by L1 (entries 5 and 6) and 3aB in higher conversions and slightly better enantioselectivities (76% ee, entries 13 and 14). Finally, the presence of (2S,5S)-2,5-di-(3,5-bis-trifluoromethylphenyl) pyrrolidine group in ligands L6 and L7 had a remarkable Table 1. Optimization of reaction conditions.[a] Entry 1Solvent L* Conv. [%][b] 3ee [%][c] 11A TFE L1 >95 3aA 74 21A DCE L1 37 3aA 66 31A TFE L2 49 3aA 57 41A TFE L3 76 3aA 72 51A TFE L4 >95 3aA 75 61A TFE L5 >95 3aA 74 71A TFE L6 >95 3aA 46 81A TFE L7 >95 3aA 46 91B TFE L1 69 3aB 59 10 1B DCE L1 70 3aB 73 11 1B DCE L2 62 3aB 20 12 1B DCE L3 45 3aB 83 13 1B DCE L4 90 3aB 76 14 1B DCE L5 82 3aB 76 15 1B DCE L6 80 3aB 86 16 1B DCE L7 91 3aB 86 17[d] 1B DCE L7 70 3aB 86 18[e] 1B DCE L7 >95 3aB 88 [a] Reaction conditions: 1(0.2 mmol), 2a (0.3mmol), L(11 mol%), Pd(TFA)2(10 mol%), solvent (0.5 mL), 60°C, 24 h. [b] Estimated by 1H-NMR. [c] Determined by HPLC on chiral stationary phases. [d] Pd(TFA)2(7.5 mol%), L7 (8.5 mol%). [e] Pd(TFA)2(12 mol%), L7 (13mol%). TFE=Trifluoroethanol. DCE=1,2-Dichloroethane. RESEARCH ARTICLE asc.wiley-vch.de Adv. Synth. Catal. 2022,364, 2373–2379 © 2022 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH 2375 Wiley VCH Mittwoch, 13.07.2022 2214 / 255578 [S. 2375/2379] 1 16154169, 2022, 14, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/adsc.202200430 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License impact in the stereochemical outcome of this process depending on the substrate. Enantioselectivity recorded for 3aA was low down to 46% ee, with both ligands (entries 7 and 8), while for 3aB was improved up to 86% ee (entries 15 and 16) with a 91% conversion employing L7. The catalyst loading could not be reduced to 7.5 mol% without compromising conversion (entry 17). Moreover, it was not possible to get higher conversions at 80°C or over prolonged times. Under these conditions boronic acid homo-coupling, among other processes led to deactivation of the Pd(II) catalyst. Conversely, a higher catalyst loading of Pd(TFA)2(12 mol%) led to full conversion after 24 hours (entry 18). Under these conditions, the reaction was performed on a 0.4 mmol scale, affording 3aB in 83% isolated yield and 88% ee (Scheme 2). The following studies were aimed at analyzing the scope and limitations of the reaction. First, the influence of the alkyl chain at the hydrazone was investigated with a representative set of aliphatic hydrazones 1C–1L (Scheme 2). α-Methyl substitution (1D) and other substitution patterns such as linear nbutyl (1E) and β-branched neopentyl (1F) were tolerated, affording hydrazines 3aD–3aF in variable yields (53-78%) and lower enantioselectivities (37– 83% ee) than that reached by model substrate 1B, while an isopropyl substituent afforded 3aG in 83% yield and an improved 96% ee. Remarkably, other α,αdialkyl cyclic substitution patterns, like cyclohexyl (1I) and cyclopentyl (1J) yielded hydrazines 3aI–3aJ in excellent enantioselectivities (96-97% ee). As an exception of this series, cyclopropyl-substituted hydrazone 1K afforded 3aK in a lower enantioselectivity (38% ee), similar to that recorded for a methyl substituent. Interestingly, hydrazone 1L, bearing a coordinating benzyloxymethyl chain, afforded 3aL in 68% yield and 87% ee. Incorporation of other removable N-protecting groups is also possible, as exemplified for Fmoc-derived hydrazones 1C and 1H. However, Fmoc-protected hydrazines 3aC and 3aH were synthesized in lower yields and variable enantioselectivities (83–96% ee). Finally, an aromatic hydrazone (R=Ph, PG=Cbz, See ESI), was unreactive under present catalytic conditions, while some substrates containing keto, amines or thiol groups remain challenging due to side reactions (addition to carbonyl) or catalyst deactivation. Next, Cbz-protected hydrazones 1B,1D,1E,1G and 1I reacted, under optimized conditions, with a variety of arylboronic acids 2, affording α-aryl alkylhydrazines 3bG–3jI in moderate-to-good yields (53–99%) and good-to-excellent enantioselectivities (89–99% ee) (Scheme 3). Mono-substituted electronrich aryl boronic acids (2b:p-Me-C6H4,2c:p-MeO- C6H4,2e:o-Me-C6H4and 2f:o-MeO-C6H4) were suitable reagents, while electron-poor p-chlorophenyl- boronic acid (2d) and o-fluorophenyl boronic acid (2g) reacted slower, and prolonged reaction times (36 and 48 h., respectively) were required for the synthesis of 3dI and 3gI in moderate yield (55–60%) and high enantioselectivities (96% ee). It is noteworthy that, independently of the type of alkyl chain, good reactivity and nearly perfect enantioselectivities were observed for ortho-methyl/methoxy boronic acids (2 e and 2f), giving practically enantiopure hydrazines 3eB, 3eD,3eE,3eG,3eI and 3fI (99% ee). The higher enantioinduction observed in this series of examples contrasts with results reported employing asymmetric catalytic hydrogenation reactions of acetophenone derived hydrazones with ortho-substitution patterns, exemplified for the synthesis of 3eD in a much lower 55% ee.[13] Disubstituted (meta/meta and meta/para) electronrich boronic acids (2h and 2i) provided also good reactivities and high enantioselectivities (94–97% ee). A challenging 1-naphtylboronic acid derivative 2 j was also well tolerated, leading to 3jI in 70% yield and 89% ee. Unfortunately, p-dimethyl amino phenyl (2k) and heteroaryl (2-furanyl and 2-thienyl) boronic acids 2l and 2m were unproductive reagents for this transformation. In order to demonstrate the applicability of the developed methodology, the synthesis of 3bG (86%, 96% ee), 3bI (97%, 96% ee) and 3eI (75%, 99% ee) were consistently performed on a 1 mmol scale. N- Carboxybenzyl hydrazines 3are precursors of appealing compounds with high molecular complexity (Scheme 4). Applying standard hydrogenolysis [Pd(C)/ Scheme 2. Scope and limitations of alkyl-substituted hydrazones. Reaction conditions: 1(0.4 mmol), 2 a (0.6 mmol), L7 (13mol%), Pd(TFA)2(12 mol%), DCE (1 mL), 60°C, 24 h. Isolated yields after column chromatography. Enantiomeric excesses (ee’s) were determined by HPLC on chiral stationary phases. RESEARCH ARTICLE asc.wiley-vch.de Adv. Synth. Catal. 2022,364, 2373–2379 © 2022 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH 2376 Wiley VCH Mittwoch, 13.07.2022 2214 / 255578 [S. 2376/2379] 1 16154169, 2022, 14, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/adsc.202200430 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License H2(1 atm), rt] for removal of the Cbz group led to partial decomposition of free hydrazines.[21] Alternatively, hydrogenolysis in presence of (Boc)2O followed by treatment with hydrogen chloride allowed isolation of the corresponding hydrazines as its hydrochloride salts. Considering the growing interest in 1,2-diaza- heterocycles as therapeutic agents,[23] the above deprotection protocol was applied to adducts 3bI and 3eI followed by in situ reaction with maleic anhydride, affording 1,2-dihydropyridazine-3,6-diones 4a and 4b in good overall yields (80–84%, 3steps) without any observable racemization. Additionally, the introduction of amino acids by CN couplings employing 3bG and different reagents was investigated. N-Boc-L-phenyl- alanine as free carboxylic acid in combination with HBTU or its acyl chloride were inefficiently coupled (<10% yield), while the corresponding symmetric aminoacid anhydride[24] afforded hydrazide 5in moderate yield. This type of hydrazide containing aminoacid, bearing two complementary protecting groups (Boc in the aminoacid and Cbz in the hydrazine building block) might be versatile intermediates for the synthesis of artificial peptides. Next, a one-pot hydrogenolysiscoupling protocol in the presence of N-Boc-aminoacid anhydrides (Aa)2O (Aa: Phe-Ala and Ala) allowed to get (N2)-hydrazides 6a–cin moderate to good yields (51-65%, two steps, only one chromatographic purification),[25] without erosion of the stereochemical integrity during the process (d.r.=98:2–>99:1). Importantly, the excess of anhydride used and the aminoacid generated in the nucleophilic acyl substitution could be recovered (85–90%) after chromatographic purification and reused. The absolute configuration of 4a was unequivocally determined to be (R) by X-ray diffraction analysis.[26] The absolute Rconfiguration of product 3aD was assigned by chemical correlation.[14c] Assuming a uniform reaction pathway, the absolute configurations of all other Cbz-protected hydrazines 3 were assigned by analogy. Scheme 3. Scope and limitations of aryl boronic acids. Reaction conditions: 1(0.4 mmol), 2(0.6 mmol), L7 (13mol%), Pd- (TFA)2(12 mol%), DCE (1 mL), 60°C, 24 h. Isolated yields after column chromatography. Enantiomeric excesses (ee’s) were determined by HPLC on chiral stationary phases. Synthesis of 3dI,3fI and 3gI required longer reaction times: 36 h., 42 h. and 48 h., respectively. Scheme 4. Representative deprotections, transformations and ORTEP drawing of (R)-4a. RESEARCH ARTICLE asc.wiley-vch.de Adv. Synth. Catal. 2022,364, 2373–2379 © 2022 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH 2377 Wiley VCH Mittwoch, 13.07.2022 2214 / 255578 [S. 2377/2379] 1 16154169, 2022, 14, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/adsc.202200430 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Conclusion In summary, a catalyst generated by combination of Pd(TFA)2and pyridine-hydrazone ligand L7, featured by a distinctive (2S,5S)-2,5-di(3,5-bis-trifluoromethyl- phenyl)pyrrolidine scaffold, has shown good to excellent activities and enantioselectivities in the 1,2- addition of arylboronic acids to N-Cbz protected aliphatic hydrazones, yielding α-aryl monoalkylhydrazines, key hydrazino blocks. Moreover, the possibilities of a readily removable protecting group such as Cbz in adducts 3have been demonstrated for targeting 1,2-dihydropyridazine-3,6-diones and aminoacid derived hydrazides en route to artificial peptides. Experimental Section General Information 1H-NMR spectra were recorded at 300 MHz or 500 MHz; 13C- NMR spectra were recorded at 75.5 MHz or 126 MHz with the solvent peak used as the internal reference (7.26 and 77.0 ppm for 1H and 13C respectively); 19F-NMR spectra were recorded at 471, 282 or 76 MHz. Column chromatography was performed on silica gel (Merck Kieselgel 60). Analytical TLC was performed on aluminum backed plates (1.5×5 cm) pre-coated (0.25 mm) with silica gel (Merck, Silica Gel 60 F254). Compounds were visualized by exposure to UV light or by dipping the plates in solutions of (ninhydrine, vainilline or phosphomolibdic acid) stains followed by heating. Melting points were recorded in a metal block and are uncorrected. Optical rotations were measured on a Perkin-Elmer 341 MC polarimeter. The enantiomeric excess (ee) of the products was determined by chiral stationary phase HPLC. Solvents were purified and dried by standard procedures. Dichloroethane was purchased from Across (99.5% Extra Dry, Over Molecular Sieves, <0.005% H2O). Unless otherwise noted, commercially available reagents were used without further purification. General Procedure for Pd(II)-Catalyzed Asymmetric 1,2-Addition of Arylboronic Acids 2 to Aliphatic Hydrazones 1 A sealed tube was charged with Pd(TFA)2(16 mg, 0.05 mmol), L7 (34 mg, 0.052 mmol), N-monoacylhydrazone 1(0.4 mmol), arylboronic acid 2(0.6 mmol), and DCE (1 mL). The mixture was stirred at 60°C for 24 h (unless otherwise stated). The solvent was removed under reduced pressure and the residue was purified by flash chromatography. Enantiomeric excess (ee) was determined by HPLC analysis. General Procedure for the Synthesis of 1,2-Dihydropyridazine-3,6-Diones 4 A 10-mL round bottom flask was charged with a solution of adduct 3(0.4 mmol) in EtOAc (4 mL), Pd/C (10% w/w) (15 mg, 0.013mmol) and di-tert-butyl dicarbonate (130 mg, 0.6 mmol). The head-space was evacuated and back-filled with hydrogen three times and then stirred under a balloon of hydrogen at room temperature for 1 h. After this time, the mixture was filtered through a celite pad and the solvent was removed under reduced pressure. The crude was dissolved in CH2Cl2(1 mL) and cooled at 0°C. Then 1.0 M HCl in Et2O (1 mL, 1 mmol) was added dropwise. The resulting mixture was stirred to warm to room temperature (1 h.) and the solvent was removed under reduced pressure. The crude was dissolved in acetic acid (4 mL) and maleic anhydride (44 mg, 0.44 mmol) was added. The mixture was heated under reflux for 2 h (monitored by TLC). The reaction was then cooled down, carefully quenched with saturated NaHCO3(aq., 20 mL) and extracted with EtOAc (15 mL ×3). The organic layers were combined, washed with brine (15 mL ×3) and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography. General Procedure for the Synthesis of Hydrazides 6 A solution of symmetric anhydride of N-protected amino acid [(Aa)2O, 1.8 equiv.] in EtOAc (0.2 M) was added dropwise to a solution of hydrazine adduct 3(1 equiv.) in EtOAc (0.2 M) at 0°C. Pd/C (10% w/w) (0.03equiv.) was subsequently added at room temperature, the headspace purged with hydrogen and the reaction mixture was stirred under hydrogen (balloon) for 3h. Additional Pd/C (0.03equiv.) was added, refilled with hydrogen and the reaction mixture was stirred for 12 h. Then, the mixture was filtered through a celite pad, the solvent was removed under reduced pressure and the residue was purified by flash chromatography. Acknowledgements This work was supported by the Spanish MINECO (CTQ2016- 76908-C2-1-PCTQ2016-76908-C2-2-P and predoctoral fellowship to S. A.), European FEDER funds and the Junta de Andalucía (Grants P18-FR-3531 and P18-FR-644). We also thank general NMR/MS services of the University of Sevilla. References [1] a) P. Burkhard, P. Dominici, C. Borri-Voltattorni, J. N. Jansonius, V. N. Malashkevich, Nat. Struct. Biol. 2001, 8, 963–967; b) T. E. Delea, S. K. Thomas, M. Hagiwara, CNS Drugs 2011,25, 53–66. [2] M. R. Attwood, C. H. Hassall, A. Kröhn, G. Lawton, S. Redshaw, J. Chem. Soc.-Perkin Trans. 1986,1, 1011– 1019. [3] J. Vidal, Synthesis and chemistry of α-hydrazino acids, in Amino Acids, Peptides and Proteins in Organic Chemistry: Modified Amino Acids, Organocatalysis and Enzyme, ed. A. B. Hughes, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2009, vol. 2. [4] J. Z. Patel, T. Parkkari, T. Laitinen, A. A. Kaczor, S. M. Saario, J. R. Savinainen, D. Navia-Paldanius, M. Cipriano, J. Leppanen, I. O. Koshevoy, A. Poso, C. J. Fowler, J. T. Laitinen, T. Nevalainen, J. Med. Chem. 2013,56, 8484–8496. RESEARCH ARTICLE asc.wiley-vch.de Adv. Synth. Catal. 2022,364, 2373–2379 © 2022 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH 2378 Wiley VCH Mittwoch, 13.07.2022 2214 / 255578 [S. 2378/2379] 1 16154169, 2022, 14, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/adsc.202200430 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License [5] S. J. Stachel, R. Berger, A. B. Nomland, A. T. Ginnetti, D. V. Paone, D. Wang, V. Puri, H. Lange, J. Drott, J. Lu, J. Marcus, M. P. Dwyer, S. 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[26] CCDC 2164728 contains the supplementary crystallographic data for (R)-4a. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. RESEARCH ARTICLE asc.wiley-vch.de Adv. Synth. Catal. 2022,364, 2373–2379 © 2022 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH 2379 Wiley VCH Mittwoch, 13.07.2022 2214 / 255578 [S. 2379/2379] 1 16154169, 2022, 14, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/adsc.202200430 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License