Asymmetric synthesis of dibenzo[b,d]azepines by Cu-catalyzed reductive or borylative cyclization

Asymmetric synthesis of dibenzo[b,d]azepines by Cu-catalyzed reductive or borylative cyclization† Patricia Rodr´ ıguez-Salamanca, a Roc´ ıo Mart´ ın-de la Calle, a Ver´ onica Rodr´ ıguez, b Pedro Merino, c Rosario Fern´ andez, * b Jos´ e M. Lassaletta * a and Valent´ ın Hornillos * ab A copper-catalyzed asymmetric intramolecular reductive cyclization for the synthesis of dibenzo[b,d] azepines is described. Use of 20-vinyl-biaryl-2-imines as substrates and in situ formed [Cu I /(Ph-BPE)] as the catalyst enables the synthesis of 7-membered bridged biarylamines containing both central and axial stereogenic elements in high yields (up to 98%) and with excellent diastereoand enantioselectivities (>20 : 1 d.r., up to 99% ee). Moreover, the same catalyst was found to facilitate a related borylative cyclization to afford versatile boronic ester derivatives. Both reactions proceed under mild conditions (rt) and are applicable to a variety of substituted aromatic and heterocyclic derivatives. Introduction The asymmetric synthesis of biaryl atropisomers has evolved into a stimulating research eld in organic synthesis owing to the ubiquitous occurrence of this structural motif in a variety of natural products and bioactive substances, and for their wideranging utilities in catalyst design and material science. 1 Most of these compounds comprise conformers with restricted rotation around a single bond whose congurational stability is generally determined by the number and size of the substituents at the ortho positions relative to the stereogenic axis. A less common class of biaryl atropisomers consist of those where the biaryl unit is incorporated into a cyclic system, with the typical ortho,ortho0substituents being replaced by a bridge (Fig. 1). 2 In these systems, the congurational stability directly correlates with the ring size: in 5and 6-membered rings the rotation around the stereogenic axis is usually not hindered, but 7-membered bridged biaryls exhibit a higher congurational stability owing to conformational reasons and can be oen resolved as atropisomers. Additionally, the introduction of sp 2 hybridized atoms increases the rigidity in the bridging cycle, and therefore the congurational stability, 3 while the presence of stereogenic centers in the bridge is known to impose a specic conguration on the biaryl axis by a central to axial chirality relay event. 4 Notably, these properties have been recently exploited for the construction of a unidirectional rotary molecular motor based on the formation of biaryl structures featuring a seven-membered lactone bridge. 5 The most distinctive class of bridged biaryls presenting this relay phenomenon comprises chiral dibenzoazepines. These 7membered cyclic bridged biaryl amines and related analogues have received considerable attention due to their presence in several natural substances and drugs. Selected examples shown in Fig. 2 include erythrivaeine B (A), a dimeric Erythrina alkaloid isolated from E. variegate, 6 dipeptide LY-411575 (B) which has demonstrated effectivity as g-secretase inhibitor for the treatment of melanoma and Alzheimer's disease, 7 RO4929097 (C), another potent and selective g-secretase which targets Notch signaling in tumor cells, 8 indolobenzoazepinone D, a tubulin polymerization inhibitor exhibiting antiproliferative activities in a variety of cancer cell lines, 9 and paullones E, a family of cytotoxic compounds which efficiently inhibit cyclin-dependent kinases (CDKs). 10 The asymmetric synthesis of axially chiral 7-membered bridged biaryl amines has traditionally relied on chiral Fig. 1 Configurational stability of acyclic and bridged biaryls. a Instituto Investigaciones Qu´ ımicas (CSIC-US), C/Am´ erico Vespucio, 49, 41092 Sevilla, Spain. E-mail: [email protected] b Departamento de Qu´ ımica Org´ anica, Universidad de Sevilla, C/Prof. Garc´ ıa Gonz´ alez, 1, 41012 Sevilla, Spain c Instituto de Biocomputaci´ on y F´ ısica de Sistemas Complejos (BIFI), Universidad de Zaragoza, 50009 Zaragoza, Spain †Electronic supplementary information (ESI) available: Experimental protocols, characterization data. CCDC 2095490–2095492. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d1sc04980a Cite this: Chem. Sci.,2021,12,15291 All publication charges for this article have been paid for by the Royal Society of Chemistry Received 8th September 2021 Accepted 8th November 2021 DOI: 10.1039/d1sc04980a rsc.li/chemical-science © 2021 The Author(s). Published by the Royal Society of Chemistry Chem. Sci.,2021,12,15291–15297 | 15291 Chemical Science EDGE ARTICLE Open Access Article. Published on 10 November 2021. Downloaded on 3/22/2022 1:30:42 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online View Journal | View Issue auxiliaries or starting materials from the chiral pool, generally requiring multistep procedures. 3,11 The control of both central and axial chirality elements in the most interesting dibenzo[b,d] azepine derivatives constitutes a challenge: to date, only a handful of methods have been described for their catalytic asymmetric synthesis (Scheme 1). Axially chiral dibenzoazepinones with amide bridges have been prepared by desymmetrization via Pd-catalyzed C–H arylation 12 (Scheme 1A) and, very recently, by a cyclocarbopalladation-carbonylation cascade reaction using alcohols or anilines as nucleophiles 13 (Scheme 1B). To our knowledge, the tautomerization of metastable enamines promoted by a chiral phosphoric acid catalyst appears as the only catalytic method reported to obtain axially chiral dibenzo [b,d]azepines (Scheme 1C). 14,15 Hence, the development of a modular and straightforward catalytic enantioselective method, providing access to these structural motifs remains as a desirable goal. Results and discussion Inspired by the work of Buchwald 16 and Yun 17 on Cu-catalyzed cyclizations using aldimines as electrophiles, we envisioned that Schiffbases from ortho-vinyl, ortho0-amino biaryls could also be suitable substrates to perform reductive or borylative cyclizations for the construction of axially chiral dibenzo[b,d] azepine derivatives featuring a stereogenic axis and two contiguous stereogenic centers (Scheme 1D). Preliminary studies were performed with compound 1Aa, readily obtained by condensation of 20-vinyl-biphenyl-2-amine with benzaldehyde, as a model substrate (Table 1). Using Cu(OAc) 2 as the precatalyst, methyldiethoxysilane (DEMS) as the hydride source and anhydrous TBME : THF (95 : 5) mixture as the solvent at room temperature, representatives of commercially available chiral biphosphine ligands L1–L6 were tested for the synthesis of the desired azepine 2Aa. Poor reactivities were observed with BINAP L1, SEGPHOS L2, DUPHOS L3 or the JOSIPHOS representative L4 (entries 1–4), while moderate catalytic activity and enantioselectivity were observed with MeOFig. 2 Selected bioactive dibenzoazepines and related analogues. Scheme 1 Catalytic asymmetric synthesis of axially chiral 7membered cyclic bridged biaryl amines. 15292 |Chem. Sci.,2021,12,15291–15297 © 2021 The Author(s). Published by the Royal Society of Chemistry Chemical Science Edge Article Open Access Article. Published on 10 November 2021. Downloaded on 3/22/2022 1:30:42 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online SEGPHOS L5 (entry 5).Finally, (R,R)-Ph-BPE L6 proved to be the ligand of choice, affording optimal results in terms of reactivity, diastereoand enantioselectivity (99% yield, >20 : 1 d.r., 99% ee, entry 6). With the optimized conditions established, we examined the substrate scope of the 20-vinyl-biphenyl-2-imine precursors to explore the generality of this asymmetric reductive cyclization. Substrates with electron-rich methyl and methoxy substituents on the aldimine aryl ring were transformed into the corresponding dibenzoazepines 2Ab–ein high yields and excellent enantioselectivities. The steric effect of placing substituents on the ortho position of the ring has a negligible effect on reactivity and enantioselectivity as demonstrated for the synthesis of 2Ab, 2Af and 2Ai. Electron-decient substituents on the phenyl ring of the aldimine were also tolerated. Thus, uorinated substrates furnished the corresponding dibenzoazepines 2Ah and 2Ai with excellent selectivities. However, the enantioselectivity drops when a CF 3 group is located at the para position of the phenyl ring (2Am). Importantly, products bearing halide (2Af,2Ag,2Aj and 2Ak), ester (2Al) and nitrile (2An) functionalities were also Scheme 2 Substrate scope. Reactions performed on 0.2 mmol scale for a 36 h period at rt. Yields of isolated product after chromatography. A single diastereomer was observed by 1 H NMR in the crude reaction mixtures. Ee's were determined by HPLC on chiral stationary phases. a Reaction performed on 2 mmol (566 mg) scale. © 2021 The Author(s). Published by the Royal Society of Chemistry Chem. Sci.,2021,12,15291–15297 | 15293 Edge Article Chemical Science Open Access Article. Published on 10 November 2021. Downloaded on 3/22/2022 1:30:42 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online obtained in good to high yields (66–99%) and moderate to high enantioselectivities (up to 92%), providing synthetically useful functionalities for further transformations. Moreover, the method also tolerates a variety of heterocyclic substrates, leading to furan (2Ap), N-methyl pyrrole (2Aq), thiophene (2Ar), pyridine (2Av) and fused heterocyclic derivatives (benzofuran 2As,N-methylindole 2At and thianaphthene 2Au) in good yields and excellent enantioselectivities. The S a ,6S,7Rabsolute conguration of products 2Ag, and 2Aj was determined by X-ray diffraction analysis, 18 while that of other products 2was assigned by analogy. Moreover, the central to axial chirality relay phenomenon was conrmed by a dihedral angle of 39 between the two aryl groups in both compounds. It should be noted that the cis-diastereomers were exclusively formed in all cases. Biaryls decorated with several electron-donating or withdrawing groups (e.g. Me, OMe, or F) were also suitable substrates for this transformation, affording the desired products in moderate to good yields with high enantioselectivities (2Ba–2Ea,94–99% ee). We next explored the kinetic resolution (KR) of a trisubstituted, hence congurationally stable, biarylimine 1Fa via Cucatalyzed hydrocupration/cyclization followed by reduction of the unreacted, enantioenriched imine (Scheme 3). The reaction stopped at 50% conversion, despite the presence of a large excess (2 equiv.) of silane. In this way, dibenzoazepine 2Fa could be obtained in high enantioselectivity under the previously optimized conditions, while the enantioenriched starting material was transformed into amine (S)-3Fa, obtained in nearly enantiopure form (>99% ee) aer LiAlH 4 reduction (s¼98). The biaryl-2-amine 3Fa, featuring only axial chirality, shows an appealing structure with potential applications in asymmetric catalysis. Reasoning that substrates 1should form very similar organocopper intermediates aer insertion of the vinyl group into L*Cu–Bpin catalysts, we decided to explore also the Cucatalyzed enantioselective borylative cyclization of the same substrates 1as an alternative approach to axially chiral dibenzo [b,d]azepines, in this case decorated with a boryl group that should be useful for further derivatization or bioconjugation (Scheme 4). Using again 1A as a model substrate in the reaction with bis(pinacolato)diboron [B 2 (pin) 2 ], the catalyst formed by combination of [Cu(MeCN) 4 ]PF 6 with biphosphine L2,KOtBu as the base, iPrOH as the proton source and anhydrous THF as the solvent were identied as the best conditions, leading to the borylated axially chiral dibenzoazepine (S a ,6S,7R)-4Aa in 85% yield with excellent regio-, diastereoand enantioselectivity (>20 : 1 d.r. 98% ee). Single crystal X-ray analysis of this compound 18 conrmed the assigned absolute conguration. Borylative cyclization of other 20-vinyl-biphenyl-2-imines proceeded efficiently under the same conditions to afford products 4with excellent enantiocontrol (>20 : 1 d.r., 92–98% ee). Again, electron-rich and -decient substituents as well as orthosubstitution in the phenyl ring were tolerated. The reaction also accepts heteroarenes as illustrated for compound 4At. To explore the synthetic potential of the methodology, gramscale synthesis and derivatizations were performed. Asymmetric intramolecular reductive cyclization of 1Aa on a 2 mmol scale afforded the desired product 2Aa in 93% yield and 98% ee (Scheme 2). As shown in Scheme 5, demethylation of 2Ae Scheme 3 Kinetic resolution of rac-1Fa. Reaction performed on 0.2 mmol scale for a 36 h period at rt. Yields of isolated product after chromatography. Ee's were determined by HPLC on chiral stationary phases. Table 1 Screening of ligands and optimization of the reaction Entry a Ligand Conv. b (%) ee c (%) 1L1,(S)-BINAP <5 nd 2L2,(R)-DTBM-SEGPHOS <10 nd 3L3,(S,S)-Me-DUPHOS <20 nd 4L4,(R)-(S)-JOSIPHOS <20 nd 5L5,(R)-MeO-BIPHEP 42 77 6 d L6,(R,R)-Ph-BPE 99 (99 yield) 99 a Reactions performed on 0.2 mmol scale. b Estimated by 1 H-NMR spectroscopy. c Determined by HPLC on chiral stationary phases. d A single diastereomer was observed by 1 H NMR in the crude reaction mixture. 15294 |Chem. Sci.,2021,12,15291–15297 © 2021 The Author(s). Published by the Royal Society of Chemistry Chemical Science Edge Article Open Access Article. Published on 10 November 2021. Downloaded on 3/22/2022 1:30:42 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online offered the corresponding phenol product 5which can be used as synthetic handle for further transformations. Moreover, uorescent labelling of 2Ag was accomplished via SuzukiMiyaura coupling providing pyrene substituted compound 6 with emitting properties for their potential use in biological studies. 19 On the other hand, oxidation of 4Ah with sodium perborate led to chiral primary alcohol 7in high yield while intramolecular Suzuki coupling of 4Af affords cis-tetrahydrodibenzoindenoazepine 8in 56% yield. To assess the congurational stability of the biaryl axis of products 2, we calculated the rotation about the axis of the biphenyl moiety for compound 2Aa. The dibenzoazepine ring can adopt boat aand half-chair bconformations (Scheme 6). 20 A third conformation can be located but at a considerable higher energy. 21 The most stable conformation for 2Aa was found to be C1a, matching the X-ray structures of analogs 2ag,2Aj and 4Aa. Remarkably, no interconversion between C1a and C2a conformations is possible due to steric reasons. Thus, axial epimerization by biphenyl bond rotation requires a previous change from ato bconformations. The interconversion of the S a -C1a/ S a -C1b and R a -C2a/R a -C2b conformers have free energy barriers of 15.6 and 14.0 kcal mol 1 , respectively and the difference between free energy of conformers accounts for the preferred C1a and C2b conformations in each case. The interconversion between S a -C1b/R a -C2b conformations involving epimerization has free energy barriers of only 2, 6 and 8.1 kcal mol 1 . Those values clearly show that a fast equilibrium is established at 25 C (a barrier of 15.6 kcal mol 1 corresponds, approximately, to a kinetic constant of 22.4 s 1 with t 1/2 of 0.031) and, consequently, the observed population of conformers depends on their relative stability. The calculated relative energies for the most stable S a -C1a/R a -C2b conformers correspond to a 2.4 kcal difference, corresponding to a 98 : 2 ratio. Considering these values and the assumed DFT experimental error it is possible to conclude that, essentially, only S a -C1a will be observed. Low temperature 1 H-NMR experiments provided further support to this conclusion: a single set of peaks is observed at temperatures as low as 60 C. On the light of these calculations, we speculated on the possibility of freezing or shiing the conformational equilibrium by introducing a bulkier t Bu group instead of the Ph group. Interestingly, the calculation predicts that R a -C2b is the lowest energy conformation in this case (1.7 lower than S a -C1a). This result can be rationalized by the lower impact of the steric effects in the S a -C1a conformer as a result of the two gauche interactions of the R group, while there is only one in R a -C2b.In order to check whether a shiof the axial chirality could be indeed experimentally achieved, pivalaldehyde derivative 1Aw was prepared and subjected to the reductive cyclization protocol to achieve product 2Aw in 85% yield and 97% ee (Scheme 7). The R a ,6S,7Rconguration is in this case tentatively assigned on the basis of the above calculations and the absence of a NOE observed between H-7 and the Me group, clearly observed for 2Aa (R ¼Ph) due to their relative gauche disposition (supported Scheme 4 Copper-catalyzed borylative cyclization. Reactions performed on 0.2 mmol scale. Yields of isolated product after chromatography. A single diastereomer (>20 : 1 d.r.) was observed as determined by 1 H NMR in the crude reaction mixtures. Ee's were determined by HPLC analysis. Scheme 5 Derivatization reactions. © 2021 The Author(s). Published by the Royal Society of Chemistry Chem. Sci.,2021,12,15291–15297 | 15295 Edge Article Chemical Science Open Access Article. Published on 10 November 2021. Downloaded on 3/22/2022 1:30:42 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online by the computational analysis of non-covalent interactions, NCI; see ESI†). As in the precedent case, a single set of signals is visible in the 1 H-NMR spectrum upon cooling to 60 C, indicating the absence of any signicant amounts of minor conformers. Based on previous mechanistic studies by Buchwald 22 and Hartwig 23 laboratories, we assume that the hydrocupration of substrates 1, generating intermediate Ia (Scheme 8) is the stereodetermining step. Ensuing cis-selective cyclization to afford complex IIa should then proceed via a well-organized transition state TS with the assistance provided by coordination of the imine nitrogen. Then, the resulting intermediate IIa reacts with the silane reagent to regenerate the CuH catalyst. A similar model and catalytic cycle can be also proposed for the borylative cyclization (X ¼Bpin). Conclusions We have successfully developed a straightforward approach for the enantioselective synthesis of dibenzo[b,d]azepines featuring central and axial chirality elements by means of Cu-catalyzed asymmetric intramolecular reductive or borylative cyclizations. Both reactions proceed with good yields and excellent diastereoand enantioselectivities under mild conditions. Axially chiral biaryl-2-amines could also be obtained in nearly perfect enantioselectivity through a kinetic resolution process. Computational work indicates that the axial chirality is thermodynamically controlled, and that the sense of the axial chirality depends on the nature of the imine R group. Data availability All experimental and computational data associated with this study can be found in the article or in the ESI.† Author contributions R. F., J. M. L. and V. H. conceived and supervised the study. P. R.-S., R. M. C. and V. R. performed the experiments and analyzed the data. V. H. and J. M. L. wrote the manuscript. P. M. performed the computational studies. Scheme 6 Computational analysis for the axial epimerization for dibenzoazepines 2A (wb97xd/def2tzvp//wb97xd/def2svp/cpcm ¼ diisopropylether). Relative free energies are given in brackets in kcal mol 1 . Data for R ¼Ph in plain text, data for R ¼ t Bu in italics. For details see the ESI.† Scheme 7 Synthesis of tert-butyl-substituted dibenzoazepine 2Aw. Scheme 8 Catalytic cycle and stereochemical model. 15296 |Chem. Sci.,2021,12,15291–15297 © 2021 The Author(s). Published by the Royal Society of Chemistry Chemical Science Edge Article Open Access Article. Published on 10 November 2021. Downloaded on 3/22/2022 1:30:42 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online Conflicts of interest There are no conicts to declare. Acknowledgements We thank the Spanish Ministerio de Ciencia e Innovaci´ on (Grants PID2019-106358GB-C21, PID2019-106358GB-C22, PID2019-104090RB-100, contracts RYC-2017-22294 for V.H. and BES-2017-081561 for P. R-S), European funding (ERDF), Junta de Andaluc´ ıa (Grants P18-FR-3531, P18-FR-644, US1262867, and US-1260906), and Aragon Government (Grupos E34_20R). Computational resources from the super-computers “Memento”and “Cierzo”provided by BIFI-ZCAM (University of Zaragoza, Spain) are also acknowledged. 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Buchwald, Science, 2015, 349,62–66. 23 Y. Xi and J. F. Hartwig, J. Am. Chem. Soc., 2017, 139, 12758– 12772. © 2021 The Author(s). Published by the Royal Society of Chemistry Chem. Sci.,2021,12,15291–15297 | 15297 Edge Article Chemical Science Open Access Article. Published on 10 November 2021. Downloaded on 3/22/2022 1:30:42 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online