{"paper_id":"2ab42fe1-172a-4bc5-ad33-4ed1390bc3cb","body_text":"License and Terms: This document is copyright 2023 the Author(s); licensee Beilstein-Institut.\nThis is an open access work under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0). Please note that the reuse,\nredistribution and reproduction in particular requires that the author(s) and source are credited and that individual graphics may be subject to special legal provisions.\nThe license is subject to the Beilstein Archives terms and conditions: https://www.beilstein-archives.org/xiv/terms.\nThe definitive version of this work can be found at https://doi.org/10.3762/bxiv.2023.66.v1\nThis open access document is posted as a preprint in the Beilstein Archives at https://doi.org/10.3762/bxiv.2023.66.v1 and is\nconsidered to be an early communication for feedback before peer review. Before citing this document, please check if a final,\npeer-reviewed version has been published.\nThis document is not formatted, has not undergone copyediting or typesetting, and may contain errors, unsubstantiated scientific\nclaims or preliminary data.\nPreprint Title Enantioselective synthesis of β-aryl-γ-lactam derivatives via Heck-\nMatsuda desymmetrization of N-protected 2,5-dihydro-1-H-pyrroles\nAuthors Arnaldo G. de Oliveira Junior, Marti F. Wang, Rafaela C. Carmona,\nDanilo M. Lustosa, Sergei A. Gorbatov and Carlos Roque D. Correia\nPublication Date 28 Dez. 2023\nArticle Type Full Research Paper\nSupporting Information File 1 Supporting Information – Desymmetrization Dihydropyrroles.pdf;  9.6\nMB\nORCID® iDs Arnaldo G. de Oliveira Junior -\nhttps://orcid.org/0000-0002-2158-1110; Sergei A. Gorbatov -\nhttps://orcid.org/0000-0002-8077-3913; Carlos Roque D. Correia -\nhttps://orcid.org/0000-0001-5564-6675\n\n1 \nEnantioselective s ynthesis of β-aryl-γ-lactam \nderivatives via Heck-Matsuda desymmetrization of N-\nprotected 2,5-dihydro-1-H-pyrroles  \nArnaldo G. de Oliveira Jr.  ‡1, Martí F. Wang ‡1, Rafaela C. Carmona 1, Danilo M. \nLustosa1, Sergei A. Gorbatov1, Carlos R. D. Correia1 \n \nAddress: 1Department of Organic Chemistry , Chemistry Institute, University of \nCampinas, Rua Josué de Castro, 13083-970 Campinas, São Paulo, Brazil. \n \nEmail: Professor Carlos Roque Duarte Correia* - croque@unicamp.br \n* Corresponding author \n‡ Equal contributors \nAbstract \nWe report herein an enantioselective palladium-catalyzed Heck-Matsuda reaction for \nthe desymmetrization of N-protected 2 ,5-dihydro-1-H-pyrroles with aryldiazonium \nsalts, using the chiral N-N-ligand ( S)-PyraBOx. This strategy ha s allowed \nstraightforward access to a diversity of 4-aryl-γ-lactams via Heck arylation followed by \na sequential Jones’ oxidation. The overall method displays  broad scope and good \nenantioselectivity, favoring the ( R) enantiomer . The applicability of the protocol is \nhighlighted by the efficient enantioselective syntheses of the selective \nphosphodiesterase-4-inhibitor rolipram, and the commercial drug baclofen. \n\n2 \nKeywords \nDesymmetrization; e nantioselective Heck -Matsuda reaction ; lactam synthesis ; N,N-\nligands; palladium. \nIntroduction \nDesymmetrization reactions consist in the modification of a molecule  with the \nloss of one or more symmetry elements, such as those which preclude chirality as in \nthe transformation of a prochiral molecular entity into a chiral one. [1] It is a powerful \nand elegant strategy in asymmetric synthesis,[2] which combined with the use of chiral \nligands and transition -metal catalysts enable d many valuable  transformations to \nincrease molecular complexity in a synthetic route. The palladium-catalyzed coupling \nof arenediazonium salts with olefins, the Heck -Matsuda reaction, has been \ninstrumental in this strategy  involving the desymmetrization of cyclic systems,[3] \nespecially five-membered substrates[4–7] .  As we have demonstrated previously, key \nfive-membered olefins bearing heteroatoms can provide direct access to chiral \nsulphones, sulphoxides, phosphine oxides, [8] phtalides, isochromanones , and \nlactones[9] in a very efficient and convenient manner. Despite our previous results in \nthis area, the desymmetrization of 2,5-dihydro-1H-pyrroles posed some challenges \ndue to substrate  instability and undesirable side reactions. In 200 3, we reported the \nHeck-Matsuda arylation of N-protected 2,5-dihydro-1H-pyrroles [10] to obtain 4-aryl-γ-\nlactams in a racemic manner, [11] thus demonstrating the feasibility of this \ntransformation. The γ-lactam ring is a privileged scaffold widely present in drugs and \nnatural products [12–14], as shown in Scheme 1. \nHerein, we report the effective desymmetrization strategy of N-protected 2,5-\ndihydro-1H-pyrroles using aryldiazonium salts and the chiral N,N-ligand (S)-PyraBOx. \n\n3 \nThe obtained Heck adducts (methyl N,O acetals) were efficiently converted into several \narylated γ-lactams by a simple oxidation procedure (Jones’ oxidation). To demonstrate \nthe applicability of the strategy, two of the chiral aryl-lactams were further derivatized \nto provide the selective phosphodiesterase -4-inhibitor (R)-rolipram, [15] and the \ncommercial drug (R)-baclofen, used to treat muscle spasticity from spinal cord injury \nand multiple sclerosis [16]. \n\n4 \n \nScheme 1:  Examples of drugs containing  a γ-lactam ring by a Heck -Matsuda \ndesymmetrization strategy. \n\n5 \nResults and Discussion \nDesymmetrization of N-protected 2,5-dihydro-1-H-pyrroles \nSome initial results and reaction optimization \nBased on our previous results regarding the desymmetrization of hidantoins[17], \nwe started this study with the N-Boc-protected dihydropyrrole  1a using different \nelectronic-demanding aryldiazonium salts and the standard reaction conditions for \nsimilar Heck-Matsuda reactions (Scheme 2), i.e., Pd(TFA)2 as the palladium source in \ncombination with the pyrazinebisoxazoline ligand, (S)-PyraBOx L1, zinc carbonate as \nbase, and methanol as solvent at 40°C. \nThese initial conditions  furnished 2-methoxypyrrolidines arylated at the 4 -\nposition, compound 3, as Heck products as illustrated in Scheme 2. The addition of a \nmethoxy group after the Heck-Matsuda indicates methanolysis after arylation  (see \nScheme 6 for a mechanistic proposal) . Given the importance of the lactam rings, we \nenvisioned a sequential Jones oxidation protocol without isolation of the methyl N,O \nacetal products to obtain the correspond ing lactams. As observed in previous \nworks[18], the oxidation step is practical and high-yielding, and the overall yield can be \nreported based on the isolated lactams. \nBy evaluating the electronics of the diazonium salt , we observed that the \nelectron-donating p-OMe substituent performed better ( 4aa, 68% yield) when \ncompared to neutral (4ab, 34% yield) and electron-withdrawing (4ac, 27% yield) ones, \nbut no significant changes in the enantiomeric ratio were observed (Scheme 2). \n \n\n6 \n \nScheme 2: Heck-Matsuda reactiona and Jones oxidationb of the N-Boc protected 2,5-\ndihydro-1H-pyrrole 1a. a) Reaction conditions: pyrroline 1a (0.30 mmol, 1.0 equiv ), \naryldiazonium salt 2 (0.60 mmol, 2.0 equiv ), Pd(TFA)2 (5 mol%), L1  (S)-Pyrabox (6 \nmol%), ZnCO3 (0.15 mmol, 0.5 equiv), and MeOH (1.5 mL, 0.2 M) at 40°C. b) Reaction \nconditions: 1,0 mL of the Jones solution 2.5 M, 6 mL of acetone:water 3:1 (v/v). Isolated \nyields were calculated from an average of two runs. Enantiomeric ratio s (e.r.) were \ndetermined by high-performance liquid chromatography (HPLC) analysis of the purified \ncompounds. \nDespite the formation of the hemiaminal ether as  the major product, the \nformation of a minor N-Boc pyrrole was also observed as a side product. To circumvent \nthis side reaction, we envisioned that a more electron -withdrawing protecting group \ncould reduce the tendency of the starting olefin to oxidation. Therefore, the N-tosylated \n2,5-dihydro-1H-pyrrole was evaluated under the same reaction conditions  with the \nsame three aryldiazonium salts used before. Before exploring the reactivity of the olefin \ntowards other aryldiazonium salts, we performed a brief optimization of the process by \ntesting several other N,N-ligands. Therefore, five other N,N-ligands were evaluated as \nfollows: PyraBOx 2, QuinOx L3, PyOx L4 and L5, and PyriBOx L6 (Figure 1).  \n\n7 \n \nFigure 1. N,N-ligands evaluated in this work. \n \nHowever, neither one of these new ligands performed better than L1 (see Table \n1 below). In an attempt to enhance the protocol performance, we also evaluated the \npalladium source as indicated in Table 1. Switching Pd(TFA) 2 by Pd(OAc) 2 led to a \nminor increase in the yield, but without any changes in the er. Pd(acac)2 and \nPd(MeCN)2(OTs)2 were also tested without significant improvements.  \n  \n\n8 \nTable 1: Optimization of the reaction conditions with tosyl pyrroline 1b.a \n \nEntry Ligand [Pd] source 2a%[e] e.r.[f] \n1 L1c Pd(TFA)2 62 85:15 \n2 L2c Pd(TFA)2 56 57:43 \n3 L3d Pd(TFA)2 49 56:44 \n4 L4d Pd(TFA)2 57 77:23 \n5 L5d Pd(TFA)2 54 72:28 \n6 L6c Pd(TFA)2 51 69:31 \n7 L1c Pd(OAc)2 65 85:15 \n8 L1c Pd2dba3 64 84:16 \n9 L1c Pd(acac)2 68 84:16 \n10 L1c Pd(MeCN)2(OTs)2 62 83:17 \n \na Reaction conditions: pyrroline 1b (0.30 mmol, 1.0 equiv), 4-trifluoromethyl \nbenzenediazonium tetrafluoroborate 2c (0.60 mmol, 2.0 equiv), Pd(TFA) 2 (5 mol%), \nLigand, ZnCO3 (0.15 mmol, 0.5 equiv), MeOH (1.5 mL, 0.2 M), 40°C. Jones conditions: \n1.0 mL Jones solution 2.5 M, 6 mL of acetone:water 3:1 (v/v). c Ligand: 6 mol%. d \nLigand: 11 mol%.; eNMR yields; f Determined by HPLC analysis. \n \nDespite the fact that palladium acetate had slightly better performance as shown \nin Table 1, we decided to continue with palladium trifluoroacetate due to its higher \n\n9 \nreactivity in forming palladium complexes with N,N-ligands. Therefore, we decided to \nmaintain our initial conditions using Pd(TFA) 2 and proceeded to the evaluation of the \nscope of the Heck-Matsuda arylation  as shown in Scheme 3. Gratifyingly, the new \nreaction conditions with the tosyl pyrroline 1b showed significant improvements in yield \nand enantioselectiv ities (4ba and 4bc in Scheme 3). S omewhat s urprisingly, no \nenhancement in the enantiomeric ratio was observed for the lactam 4bb. \n\n10 \n \nScheme 3: Heck-Matsuda reaction of the N-tosyl-2,5-dihydro-1H-pyrrole 1b. a) \nReaction conditions: pyrroline 1b (0.30 mmol, 1.0 equiv), aryldiazonium salts 2 (0.60 \nmmol, 2.0 equiv), Pd(TFA) 2 (5 mol%), L1 (6 mol%), ZnCO 3 (0.15 mmol, 0.5 equiv), \n\n11 \nMeOH (1.5 mL, 0.2 M), 40°C. b) Reaction conditions: 1,0 mL Jones solution 2,5 M, 6 \nmL of acetone:water 3:1 (v/v). Isolated yields were calculated from an average of two \nruns. Enantiomeric ratio (e.r.) determined by high-performance liquid chromatography \n(HPLC) analysis of the purified compounds. \n \nWith the optimized conditions in hand, we evaluated the scope of the method \nby varying the aryldiazonium s alts. For aryldiazonium salts bearing  p-substituted \ngroups, there is  very little influence in the enantiomeric ratio s, although electron -\ndonating groups performed slightly better in terms of yield, as observed before for the \nN-Boc-protected pyrrolines. Weak electron-donating groups such as the methyl group \nfurnished compound 4bj in a higher yield and good er. Carbonyl-containing electron-\nwithdrawing groups such as methyl ester and ketone did  not show much of an effect \nin the outcome of the reaction, providing compounds 4bd and 4be in high yields and \ngood er. Disubstituted aryldiazonium salts were also evaluated , providing compound \n4bq in a lower yield (48%) when compared to other examples, but with a higher er. On \nthe other hand, 4br was obtained in a higher yield but with a lower er. The halogen-\ncontaining derivatives in the para position 4bf, 4bg, 4bh, and 4bi were all obtained in \nhigh yields and good er. We also evaluated the change of some substituents to the \northo position. This change furnished compound 4bm in higher yield and excellent er. \nHowever, when the bulkiness of the substituent was increased, as in compounds 4bl \nand 4bo (o-phenoxy and o-bromo group respectively ), the er dropped considerably. \nFinally, a strong electron -withdrawing group in the ortho position such as nitro ( 4bn) \nwas met with a decrease in yield (66%), but with a higher er.  \nDuring the development of the scope, the hemiaminal ether s (Heck-Matsuda \nproducts) were found to be somehow unsta ble when concentrated to dryness  during \nworkup. We hypothesize that a possible cause of such instability m ight consist in the \n\n12 \nformation of a highly electrophilic iminium ion upon protonation of the hemiaminal ether \nby silica or glassware acidity and furthe r elimination of methanol favored by the \nevaporation process. The instability of hemiaminal ethers was previously described in \nliterature[19] during workup. We then found that careful control of the drying conditions, \nthus avoiding complete drying of the crude mixture prevents degradation of the Heck \nproducts. We then established a robust protocol consisting of successive additions of \nacetone to the crude mixture, followed by careful rotaevaporation. Th is procedure  \ngradually removes most of the methanol, allowing the sequential Jones oxidation step \nto take place without any significant losses (see Supporting Information for details). \nGiven the presence of the 4-aryl-γ-lactam motif in the  phosphodiesterase-4-\ninhibitor rolipram, and in the baclofen drug, the Heck products 4bg and 4br were used \nas starting material for their syntheses. N-tosylated lactams 4bg and 4br were then \nsubmitted to deprotection protocols as described in the literature.[20,21]. However, the \nremoval of the tosyl group of pyrroline 1b proved to be a challenging task.  After several \nunsuccessful attempts to remove the tosyl group, we decided to evaluate the (p-\nnitrophenyl)sulfonyl (Ns) and ( o-nitrophenyl)sulfonyl (2 -Ns) as alternative protecting \ngroups of the 2,5-dihydro-1H-pyrrole (Scheme 4). Although the results with the 2-Ns \nprotecting group were somewhat disappointing, the results with 4-Ns group were more \npromising, even with a welcome increase in the enantiomeric ratio in some cases (4dd \nand 4de). \n \n\n13 \n \nScheme 4: Heck-Matsuda reaction of the protected 2,5 -dihydro-1H-pyrrole with Ns \nand 2-Ns groups (pyrrolines 1c, 1d). a) Reaction conditions: pyrroline 1c or 1d (0.30 \nmmol, 1.0 equiv), aryldiazonium salts 2 (0.60 mmol, 2.0 equiv), Pd(TFA)2 (5 mol%), L1 \n(6 mol%), ZnCO 3 (0.15 mmol, 0.5 equiv), MeOH (1.5 mL, 0.2 M). b) Reaction \nconditions: 1,0 mL Jones solution 2 .5 M, 6 mL of acetone:water 3:1 (v/v). Isolated \nyields were calculated from an average of two runs. Enantiomeric ratio (er) determined \nby high -performance liquid chromatography (HPLC) analysis of the purified \ncompounds. \n \n\n14 \nSynthesis of (R)-baclofen from 4dd and (R)-rolipram from 4de \n \nTo further demonstrate the applicability of this method, the aryl-lactams 4dd and \n4de were successfully converted into the selective phosphodiesterase-4-inhibitor (R)-\nrolipram [15] and the commercial drug (R)-baclofen for the treatment of muscle \nspasticity from spinal cord injury and multiple sclerosis [16]. Among all the sulfonyl-\nprotecting groups  used in this work , the removal of the N-nosyl requir ed milder \nconditions [22].  Deprotection of N-nosylated 4dd and 4de with thiophenol and K2CO3 \nat room temperature gave the NH-free γ-lactam 5a and the drug (R)-rolipram (5b) in \n79% and 97% yields respectively with excellent enantioselectivity. Hydrolysis of γ -\nlactam 5a in 6 N HCl aqueous solution at 100°C for 10 hours then led to the formation \nof ( R)-baclofen hydrochloride ( 6) in 76% yield ( Scheme 5). The total yield s were \ndetermined to be 49% for (R)-baclofen hydrochloride (6) and 61% (R)-rolipram (5b) \nfrom starting pyrrolidine 1d. \n \nScheme 5: Synthesis of (R)-baclofen from 4dd and (R)-rolipram from 4de. \n\n15 \na) Reaction conditions: 4dd (0.20 mmol, 1.0 equiv), PhSH (0.30 mmol, 1.5 equiv), \nK2CO3 (0.40 mmol, 2 equiv), MeCN (2 mL), DMSO (0.75 mL), 25°C, then 6 N HCl (0.5 \nmL), 100°C.  b) Reaction conditions: 4de (0.105 mmol, 1.0 equiv), PhSH (0.16 mmol, \n1.5 equiv), K 2CO3 (0.21 mmol, 2 equiv), MeCN (1 mL), DMSO (0.4 mL), 25°C. \nEnantiomeric ratio (e.r.) determined by high-performance liquid chromatography \n(HPLC) analysis of the purified compounds. \n \nDetermination of the absolute stereochemistry of the Heck adducts/lactams and \nrationalization of the enantioselectivity \n \nThe absolute stereochemistry of the products was determined by the correlation \nof their optical rotations with that of the previously reported aryl-lactam 4bb,[23] and \nits deprotected analogue ,[24] as well as with the intermediates 5b, 5a, and 6 in the \nrolipram and baclofen[25] syntheses. Assignment of the stereochemistry of all other \nlactams as R was done by analogy. The assignment of the absolute stereochemistry \nallowed us to propose a rationale for the Heck -Matsuda reaction (Scheme 6). Upon \nactivation of the catalyst  (I), oxidative addition of aryl diazonium salt  and subsequent \nnitrogen release generates the cationic palladium(II)-N,N-ligand complex (II), to which \nthe pyrrolidine substrate coordinates (III) . Next, migratory insertion takes place  \ngenerating the alkyl-palladium specie (IV), which upon a sequence of elimination (V) \nand hydride insertion leads to alkyl -palladium intermediate (IV). Finally, upon \nmethanolysis, the hemiaminal ether product 2 is formed. We hypothesize that the \nenantioselective-determining step consists in the migratory insertion of the aryl group \nbonded to palladium to the pyrroline. The steric effect of the t-Bu group favor s the \ncoordination of the pyrroline with the protecting group upward, therefore creating an \n\n16 \nasymmetric center with absolute configuration (R), in accordance with experimental \nresults. A rationalization for the transition state that would lead to the observed \noutcome is depicted in Figure 2. \n \nScheme 6: A rationale for the catalytic cycle for Heck-Matsuda reaction of the \nprotected 2,5 -dihydro-1H-pyrrole with aryl diazonium salts catalyzed by a ( S)-\nPyraBOx-palladium complex. \n \n \n\n17 \nFigure 2 : Rationalization of the enantioselectivity obtained in the Heck -Matsuda \nreaction of protected 2,5 -dihydro-1H-pyrrole with aryldiazonium salts  catalyzed by a \n(S)-PyraBOx-palladium complex. \nConclusion \nThe palladium-catalyzed Heck-Matsuda desymmetrization of N-protected 2,5-dihydro-\n1H-pyrroles with aryldiazonium salts  was successfully accomplished.  The synthetic \nprotocol employed the N,N-ligand ( S)-PyraBOx to provide several 4-substituted γ -\nlactams in an enantioselective fashion, with broad scope and good enantioselectivities, \nwith yields up to 85% and er up to 93:7. The methodology was shown to be  robust, \nallowing the use of different protecting groups in the nitrogen of the  4-pyrroline \nsubstrate. We also report straightforward synthetic routes to obtain (R)-rolipram (61% \noverall yield, 3 steps, 82:18 er) and (R)-baclofen (49% overall yield, 4 steps, 90:10 er) \nusing the Heck-Matsuda reaction as a key step for constructing the stereogenic center. \nSupporting Information \nExperimental procedures and characterization data for the new compounds. \nSupporting Information File 1: Experimental procedures for all new compounds \nFile Name: Supporting Information – Desymmetrization Dihydropyrroles \nFile Format: PDF \nTitle: Supporting information  for Synthesis of β -aryl γ -lactam derivatives by \nenantioselective Heck -Matsuda desymmetrizat ion of N -protected 2,5 -dihydro-1-H-\npyrroles \n\n18 \nAcknowledgments \nWe acknowledge the PhD student Otto Daolio Köster for the fruitful discussions and \nassistance with the experimental work, and Mr. Anderson S. Pedrosa for technical \nassistance with NMR analysis. \nFunding \nWe thank the financial support of the São Paulo Research Foundation (FAPESP, \ngrants: 2017/21494 -2 [MFW]; 2023/00025-5 [SAG]; 2014/25770-6, 2013/07600-3, \n2014/25770-6 [CRDC], and 2018/00271-8 [RCC]) and the Brazilian National Research \nCouncil (CNPq, grants 406643/2018-0, 306773/2018-0 [CRDC]). \nReferences \n(1)  Kotani, S.; Nakajima, M. 6.21 C -X Bond Formation: Organocatalytic \nEnantioselective Halogenation of Meso Epoxides. In Comprehensive Chirality; Elsevier \nLtd, 2012; Vol. 6, pp 506–517. doi:10.1016/B978-0-08-095167-6.00624-8. \n(2)  Nájera, C.; Foubelo, F.; Sansano, J. M.; Yus, M. Tetrahedron. 2022, 106–107. \ndoi:10.1016/j.tet.2022.132629. \n(3)  Angnes, R. A.; Thompson, L. M.; Mashuta, M. S.; Correia, C. R. D.; Hammond, \nG. B. Adv. Synth. Catal. 2018, 360, 3760–3767. doi:10.1002/adsc.201800785. \n(4)  de Oliveira, V. C.; Angnes, R. A.; Batista, J. M.; Correia, C. R. D . Eur. J. 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