Dynamic Kinetic Resolution of Hetero biaryl Ketones by Zinc- Catalyzed Asymmetr ic Hydrosil ylation

Angewandte International Edition A Journal of the Gesellschaft Deutscher Chemiker www.angewandte.org Chemie Accepted Article Title: Dynamic Kinetic Resolution of Heterobiaryl Ketones via Zncatalyzed Asymmetric Hydrosilylation Authors: José M. Lassaletta, Valentín Hornillos, Jose Alberto Carmona, Abel Ros, Javier Iglesias-Sigüenza, Rosario Fernández, and Joaquín López-Serrano This manuscript has been accepted after peer review and appears as an Accepted Article online prior to editing, proofing, and formal publication of the final Version of Record (VoR). This work is currently citable by using the Digital Object Identifier (DOI) given below. The VoR will be published online in Early View as soon as possible and may be different to this Accepted Article as a result of editing. Readers should obtain the VoR from the journal website shown below when it is published to ensure accuracy of information. The authors are responsible for the content of this Accepted Article. To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201713200 Angew. Chem. 10.1002/ange.201713200 Link to VoR: http://dx.doi.org/10.1002/anie.201713200 http://dx.doi.org/10.1002/ange.201713200 COMMUNICATION Dynamic Kinetic Resolution of Heterobiaryl Ketones via Zncatalyzed Asymmetric Hydrosilylation Valentín Hornillos,*[a] José Alberto Carmona,[a] Abel Ros,[a,b] Javier Iglesias-Sigüenza,[b] Joaquín López- Serrano,[c] Rosario Fernández,*[b] and José M. Lassaletta*[a] Dedicated to Prof. A. Ulises Acuña on the occasion of his retirement Abstract: A diastereo and highly enantioselective dynamic kinetic resolution (DKR) of configurationally labile heterobiaryl ketones is described. The DKR proceeds by zinc-catalyzed hydrosilylation of the carbonyl group, leading to secondary alcohols bearing axial and central chirality. The strategy relies on the labilization of the stereogenic axis that takes place thanks to a Lewis acid-base interaction between a nitrogen atom in the heterocycle and the ketone carbonyl. The synthetic utility of the methodology is demonstrated through stereospecific transformations into N,N- ligands or appealing axially chiral, bifunctional thiourea organocatalysts. Axially chiral biaryl compounds are important molecular scaffolds present in many natural products and bioactive substances.[1] Furthermore, they are among the most important class of structures with extensive utility in asymmetric catalysis, particularly as ligands for metals but also as organocatalysts.[2] The asymmetric coupling of two arene derivatives by crosscoupling or oxidative dimerization is the most straightforward approach for their synthesis,[3] but these methods lack generality and fail in cases such as the heterobiaryl synthesis. Transition metal-catalyzed dynamic kinetic resolutions (DKR),[4] the novo construction of aromatic rings,[5] and a growing number of organocatalytic approaches[6] have also been reported for specific applications in this field. An appealing DKR strategy consists on the asymmetric ring-opening of biaryl lactones developed by Bringmann (Scheme 1A),[7] particularly in catalytic variants reported by the groups of Yamada[8] and Wang.[9] Closely related DKR strategies are based on racemization via ring-opening/ring-closing events. The Akiyama group realized that biaryl hemiaminals (Scheme 1B) are suitable intermediates for DKR, since they can be easily formed and opened in situ.[10] Scheme 1. Strategies for the labilization of stereogenic axis in biaryls The imine group in the open form can be then reduced by asymmetric transfer hydrogenation reaction. Conversely, this racemization strategy has been recently combined with borrowing hydrogen catalysis for a redox-neutral amination of biaryl compounds.[11] Clayden and Turner have also reported a biocatalytic DKR of atropoisomeric biaryl N-oxide-aldehydes triggered by a ketoreductase enzyme (Scheme 1C).[12] This is an appealing strategy to access new heterobiaryl scaffolds, but the dynamic racemization via six-membered transition states can only be performed in systems with reduced steric strain and the method is limited to N-oxides. We have also developed dynamic kinetic Pd-catalyzed C–C, C–P and C–N bond-forming reactions (dynamic kinetic asymmetric transformations, DYKAT) which rely in the labilization of the stereogenic axis as a consequence O O O OCO2R R*OH or ROH + catalyst* OH O H NAr OH N N CHO ONO O H δδ- E: Hydrosilylation of heterobiaryl ketones: this work N R O R O D: Cross-couplings from heterobiaryl electrophiles: ref. [13] Ar OH H NAr O H NAr OH NAr ATH N CHO O via NO OH 99% ee C: Biocatalytic reduction of N-oxide aldehydes: ref. [12] B: Asymmetric transfer hydrogenation of imino phenols: refs. [10],[11] A: Lactone ring-opening: refs [7]-[9] N X Pd0LL'* (cat) + N X N Pd L L' X + Configurationally labile OAI ZH or ZM N Z Z = Ar, RNH, PR2, alkynyl via via NN R OH ketoreductase ZnOAc/N,N ligand (cat) (EtO)2MeSiH via NR O +δ+ δ− or ‡ NR O III − ϕ1 ϕ2 ϕ1 ϕ2 ϕ1 ϕ2 [a] Dr. V. Hornillos, J. A. Carmona, Prof. J. M. Lassaletta 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], [email protected] [b] Dr. A. Ros, Dr. J. Iglesias-Sigüenza, Prof. R. Fernández 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] [c] Prof. Joaquín López-Serrano Departamento de Química Inorgánica and Centro de Innovación en Química Avanzada (ORFEO-CINQA). Universidad de Sevilla and Consejo Superior de Investigaciones Científicas (CSIC). Avda. Américo Vespucio 49, 41092 Sevilla (Spain) Supporting information for this article is given via a link at the end of the document. 10.1002/anie.201713200 Accepted Manuscript Angewandte Chemie International Edition This article is protected by copyright. All rights reserved. COMMUNICATION of the widening of angles ϕ1 and ϕ2 in five membered cyclic, oxidative addition intermediates (Scheme 1D).[13] This is also a versatile methodology for the synthesis of axially chiral heterobiaryls, but there is still the need of expensive and toxic Pd-based catalysts. Stimulated by this observation, though, we envisioned that related Lewis acid-base interactions in fivemembered cyclic intermediates could be exploited for the DKR of heterobiaryl derivatives. In other words, we speculated whether a Lewis acidic functional group could play the role of the metal center in the DYKAT approach. In spite of its modest Lewis acidity, acyl groups are appealing candidates considering the many possible transformations (quaternizations) that would eliminate its Lewis acid character, therefore stabilizing the stereogenic axis. On the basis of this idea, we now wish to report on the dynamic kinetic resolution of heterobiaryl ketones via Zn-catalyzed asymmetric hydrosilylation (Scheme 1E). As a working hypothesis, we anticipated that a relatively fast racemization, associated again with a widening of ϕ1 and ϕ2, could take place either via five-membered zwitterionic intermediates I or through transition states II with a partially developed N–C(carbonyl) covalent bond and an incipient pyramidalization of the carbonyl carbon. The asymmetric hydrosilylation of ketones is a well established method to obtain secondary alcohols under mild conditions.[14] Given the number of catalytic systems available, many of them based in nonprecious metals,[15] this reaction was chosen as the first option to explore our hypothesis. The model substrate 2a was easily synthesized by Pd-catalyzed Heck reaction of the known triflate rac-1a with butyl vinyl ether and subsequent hydrolysis of the resulting coupling product (Scheme 2). X-Ray diffraction analysis of 2a[16] showed the presence of both atropoisomers in the solid state, but the analysis by chiral HPLC pointed to their configurational lability in solution: a single Scheme 2. Synthesis of heterobiaryl ketone 2a, X-ray structure (one of the enantiomers shown, H atoms omitted for clarity) and a control experiment supporting its configurationally instability. Table 1. Screening of Reaction Conditions and Ligands.[a] Entry[a] L T (°C) time (h) conv. (%)[b] dr[b] ee (%)[c] major/minor 1 L1 20 24 >99 2:1 40/54 2 L1 0 24 85 2:1 59/44 3 L2 20 48 6 n.d. n.d./n.d. 4 L2 65 36 >99 5:1 83/52 5 L3 66 36 >99 4:1 72/31 6 L4 66 36 >99 5:1 85/53 7 L5 66 36 >99 4:1 91/72 8 L6 66 36 >99 5:1 98/89 9[d] L6 66 36 >99 5:1 98/90 10[e] L6 66 36 <5 n.d. n.d. 11[f] L6 66 36 <5 n.d. n.d. [a] Reactions at 0.1 mmol scale. [b] Determined by 1H NMR spectroscopy. [c] Determined by HPLC. [d] Zn(OAc)2 (5 mol%)/L6 (6 mol %). [e] PMHS was used instead of (EtO)2MeSiH. [f] PhMe2SiH was used instead of (EtO)2MeSiH narrow peak was regularly observed using a large variety of chiral stationary phases and elution conditions. Reduction of 2a with NaBH4 afforded a 1:1 mixture of diastereomeric alcohols 3a; HPLC analysis of this mixture revealed four distinct peaks corresponding to all possible stereoisomers. This behavior, in contrast to that observed for 2a, confirms the configurational stability of 3a. An additional proof for the configurational lability of 2a was obtained after hydrolysis of the enantioenriched (92% ee) vinyl ether 4.[17] Interestingly, this reaction requires a slow addition of the substrate over an excess of aq. HCl (conditions a). Otherwise (conditions b), unexpected isoquinolinium salt 5 is obtained as the major product. This product closely resembles the zwitterionic intermediate I that, likewise, has lost the chiral information of the stereogenic axis. Additionally, reduction of the ketone 2a obtained from 4 afforded again the mixture of racemic diastereomers 3a. Control experiments showed that alcohols 3 do not epimerize/racemize under these reductive conditions. Consequently, it can be deduced that ketone 2a quickly racemizes after hydrolysis of the parent vinyl ether 4. Further experiments and a DFT analysis for the atropoisomerization of 2c were also conducted, and the results (see the supporting information for details) are fully consistent with the starting hypothesis: according to this study, the racemization takes place via a ‘quasi zwitterionic’ transition state (type II) with a relatively low barrier of 22.1 kcal mol–1.[18] 1) Pd(OAc)2 / dppp (cat), Et3N, DMF, 80 °C N OTf N OnBu O CH3 2a ref. [17] N OnBu 4, 92% ee HCl, THF rac-1a N Me OH N Me OH N Me OH N Me OH + ++ + 2a 3a: mixture of racemic diastereomers NO 2) HCl (2M), 1h NaBH4 NaBH4 NMe OnBu + 5 (racemic) Cl − conditions a: excess HCl conditions b: slow addition of aq. HCl (EtO)2MeSiH (2 eq) Zn(OAc)2 (10 mol%) ligand L (20 mol%) THF, T °C Then HCl (1M) NH HN R R L1: R = CH3 L2: R = Bn L6: R = tBu tBu NO CH3 NO CH3 NOH CH3 (Ra,R)-3a 2a: racemic, configurationally labile L3: R = tBu L4: R = OMe MeO L5: R = Me 10.1002/anie.201713200 Accepted Manuscript Angewandte Chemie International Edition This article is protected by copyright. All rights reserved. COMMUNICATION With this key information in hand we started the screening of conditions for the asymmetric hydrosilylation of the model substrate 2a (Table 1). A first interesting result was observed by using inexpensive and environmentally benign Zn(OAc)2 [19] in combination with (S,S)-N,N´-dimethyl 1,2-diphenylethylene- diamine ligand L1: a 2:1 diastereomeric mixture of products 3a with a 40% ee for the major isomer was observed using 2 equivalents of (EtO)2MeSiH in THF at 20 °C (entry 1). At lower temperature (0 °C, entry 2) the conversion dropped and no significant improvement was observed (entry 2). The easy synthesis and structural modularity of this type of N,N ligands, however, facilitated further optimization.[20] A surprising lack of reactivity at rt was observed by introducing benzyl groups in the chiral scaffold (L2, entry 3). Nevertheless, full conversion with 5:1 diastereoselectivity and a promising 83% ee for the major isomer were achieved by simply heating the reaction to reflux (entry 4). Ligand L3 with additional tert-butyl groups at the para positions of the benzyl units afforded a slightly lower selectivity (entry 5) while ligand L4 bearing four meta methoxy groups afforded a similar result (entry 6). A significant improvement was observed for ligands L5 with ortho methyl groups (91% ee, entry 7). Finally, use of ligand L6, bearing four bulky tert-butyl groups in the meta positions, yielded 3a with excellent conversion and high diastereo- and enantioselectivity (entry 8). Moreover, the catalyst loading could be reduced to 5 mol% to obtain a similar result (Entry 9). Noteworthy, alternative silanes such as polymethylhydrosiloxane (PMHS) and PhMe2SiH were unreactive in this transformation (entries 10,11). Under optimized conditions, the scope of the process was explored for different heterobiaryl scaffolds and acyl groups (Table 2). Ketone 2b bearing a methyl group at position 4 of the naphthalene ring performed very similar to the model ketone 2a, affording alcohol 3b in 80% yield, 4.5:1 dr, and a 97% ee for the major diastereomer (entries 1 and 2). Alcohols 3c and 3d, derived from 1-(1-naphthyl)picoline and 1-(o-tolyl)isoquinoline derivatives, respectively, could also be obtained in high yields and enantioselectivities (entries 3 and 4). Remarkably, 1-(1- naphthyl)quinazoline derivative 2e afforded the corresponding alcohol with a higher 8.5:1 diastereoselectivity. Due to its high polarity, the crude alcohol 3e was acetylated (Ac2O/DMAP) before purification, yielding a mixture of the expected O-acetyl derivative 3'e and product 3''e, formally resulting from N- acylation and intramolecular 1,2 addition of the hydroxyl group. Heterobiaryl methyl ketone 2f bearing a phenyl group in position 3 was also well tolerated, although a slightly lower diastereoselectivity was observed (entry 6). More sterically demanding methyl 1-(1-pyrenyl)-isoquinoline ketone 2g also underwent hydrosilylation of the carbonyl affording 3g in high yield and enantioselectivity, (entry 7). Moreover, ketones 2h-j bearing different aliphatic substituents also provided the desired products in high yields and enantiomeric ratios (entries 8-10). Interestingly, a 20:1 dr was observed for the more sterically demanding neopentyl ketone 2i although with decreased enantioselectivity (80% ee). It is worth to stress that in all cases, without exception, the two diastereomers were readily isolated in pure form after a simple column chromatography. Importantly, the hydrosilylation of 2a was also performed on a bigger scale (1 mmol) affording 3a in better yield (95%, 77% of isolated major isomer), and diastereoselectivity (5.3:1) without compromising Table 2. Substrate scope.[a] entry[a] SM dr[b] yield[c] prod eemajor (%)[d] eeminor (%)[d] 1 2a 5:1 77(67) 3a 97 90 2 2b 4.5:1 80(64) 3b 97 89 3 2c 4:1 93(78) 3c 96 82 4 2d 3.2:1 80(61) 3d 90 88 5 2e 8.5:1 66 3’e/3’’e[e] 98/97 - 6 2f 2:1 91(59) 3f 95 95 7 2g 3.2:1 88(70) 3g 97 86 8 2h 4:1 86(70) 3h 94 94 9 2i >20:1 52 3i 80 - 10 2j 2.5:1 86(63) 3j 91 88 11 2a 5.3:1 95(77) 3a 97 90 [a] All reactions reached full conversion as determined by TLC and 1H NMR spectroscopy. [b] Determined by 1H NMR in the crude reaction mixtures. [c] Isolated overall yields after chromatography. In parenthesis, yield of pure major isomer [d] Determined by HPLC. [e] 3'e and 3''e were isolated in 41% and 25% yield, respectively. the excellent enantioselectivities (entry 11). The absolute configuration of (Ra,R)-3a and (R,R)-3’’e were determined by X- ray diffraction analysis,[16] while that of the minor isomer (Sa,R)- 3a was assigned by chemical correlation.[21] The absolute configurations of other products 3 were assigned by analogy. The newly synthesized heterobiaryl alcohols with both central and axial chirality offer many possibilities for further functionalization and are highly useful synthons for the synthesis of various chiral heterobiaryls that are otherwise difficult to access. Representative transformations from (Ra,R)-3a are (EtO)2MeSiH (2 eq.) Zn(OAc)2 (5 mol%) L6 (6 mol%) THF, reflux, 36 h Then HCl (1M) N Y R4 R5 R6 N Y R3 R4 R6 R3 R7R7 R5 R1 O (Ra,R)-3a (Ra,R)-3b (Ra,R)-3c (Ra,R)-3’e N H3C (Ra,R)-3d N (Ra,R)-3f Ph N (Ra,R)-3i N Y R4 R5 R6 R3 R7 R1 O R2 R2 2a-j: racemic, configurationally labile. Y = N, CH (Ra,R)-3a-j (major) OH R1 NOH CH3 Me N H3COH CH3CH3 OH N N OAc CH3 NOH CH3 (Ra,R)-3g OH OH CH3 tBu N (Ra,R)-3h OH CH3 N (Ra,R)-3j OH NOH CH3 (Ra,R)-3’’e N N O CH3 O Me N Y R3 R4 R6 R7 R5 OH R1 (Sa,R)-3a-j (minor) + Major products: N N O O R R 10.1002/anie.201713200 Accepted Manuscript Angewandte Chemie International Edition This article is protected by copyright. All rights reserved. COMMUNICATION shown in Scheme 3. Displacement of the secondary alcohol using diphenylphosphoryl azide (DPPA) and DBU was carried out to obtain azide (Ra,S)-7[16] with inversion of the configuration at the stereocenter. A unique class of chiral N,N-ligand (Ra,S)-8 was prepared via Cu(I)-catalyzed cycloaddition reaction of (Ra,S)-7 with phenylacetylene in good yield under mild conditions. Moreover, Staudinger reduction of (Ra,S)-7 furnished amine (Ra,S)-9, an appealing homologue of the ligand IAN,[13d,22] but incorporating an additional stereocenter. Finally, a novel class of bifunctional thiourea catalysts (Ra,S)-10 was easily Scheme 3. Representative transformations from (Ra,R)-3a. obtained by condensation of (Ra,S)-9 and 1-isothiocyanato-3,5- bis(trifluoromethyl)benzene. Importantly, the enantiomeric purity in these products was completely preserved during these reaction sequences. In conclusion, a weak Lewis acid-base interaction is the key for the atroposelective Zn-catalyzed hydrosilylation of heterobiaryl ketones via dynamic kinetic resolution. The resulting heterobiaryl carbinols containing both central and axial stereogenic elements are also direct precursors for the synthesis of chiral bidentate ligands and bifunctional thiourea-based organocatalysts. The development of related catalytic reactions based on this racemization strategy is currently under investigation in our laboratories. Acknowledgements We thank the Spanish Ministerio de Ciencia e Innovación (Grants CTQ2016-76908-C2-1-P and CTQ2016-76908-C2-2-P, contract RYC-2013-12585 for A.R.), European FEDER Funds, and Junta de Andalucía (Grant 2012/FQM 10787 and fellowship for J.A.C.) for financial support. VH thanks the Ministry of Economy, Innovation, Science and Employment of the Junta de Andalucía and the European Union’s Seventh Framework Program, Marie Skłodowska-Curie actions for a Talent Hub fellowship (COFUND - Grant Agreement nº 291780). J.L.-S. acknowledges the use of computational facilities of the Centro de Servicios de Informática y Redes de Comunicaciones (CSIRC), Universidad de Granada. Keywords: asymmetric catalysis • dynamic kinetic resolution • axial chirality • hydrosilylation • ligand design [1] a) G. Bringmann, T. Gulder, T. A. M. Gulder, M. Breuning, Chem. Rev. 2011, 111, 563; b) M. C. Kozlowski, B. J. Morgan, E. C. Linton, Chem. Soc. Rev. 2009, 38, 3193; c) J. E. Smyth, N. M. Butler, P. A. 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Bringmann, T. Hartung, Angew. Chem. Int. Ed. 1992, 31, 761; Angew. Chem. 1992, 104, 782; b) G. Bringmann, J. Kraus, M. Breuning, S. Tasler, Synthesis 1999, 525; c) G. Bringmann, S. Tasler, R.-M. Pfeifer, M. Breuning, J. Organomet. Chem. 2002, 661, 49; d) G. Bringmann, M. Breuning, P. Henschel, J. Hinrichs, Org. Synth. 2002, 79, 72. [8] a) T. Ashizawa, S. Tanaka, T. Yamada, Org. Lett. 2008, 10, 2521. [9] C. Yu, H. Huang, Y. Zhang, W. Wang, J. Am. Chem. Soc. 2016, 138, 6956. NOH CH3 (Ra,R)-3a (Major), ee 97% N O DPPA/DBU Toluene 81% NN3 CH3 (Ra,S)-7 , ee 97% N1 N2 N3 N4 RaS N CH3 N N N Ph N CH3 NH2 N CH3 HN S HN CF3 CF3 Phenylacetylene CuSO4 / Sodium ascorbate (cat) tBuOH/H2O PPh3 THF/H2O CF3 CF3 N C S CH2Cl2 56% (Ra,S)-8 (Ra,S)-9 (Ra,S)-10 N OH CH3 (Ra,R)-6 (Major), ee 97% O +− 99% RaR m-CPBA 99% quant. 10.1002/anie.201713200 Accepted Manuscript Angewandte Chemie International Edition This article is protected by copyright. All rights reserved. COMMUNICATION [10] K. Mori, T. Itakura, T. Akiyama, Angew. Chem. Int. Ed. 2016, 55, 11642; Angew. Chem. 2016, 128, 11814. [11] J. Zhang, J. Wang, Angew. Chem. Int. Ed. 2017, 57,465; Angew. Chem. 2017, 130,474. [12] S. Staniland, R. W. Adams, J. J. W. McDouall, I. Maffucci, A. Contini, D. M. Grainger, N. J. Turner, J. Clayden, Angew. Chem. Int. Ed. 2016, 55, 10755; Angew. Chem. 2016, 128, 10913. [13] a) A. Ros, B. Estepa, P. Ramírez-López, E. Álvarez, R. Fernández, J. M. Lassaletta, J. Am. Chem. Soc. 2013, 135, 15730; b) P. Ramírez- López, A. Ros, B. Estepa, R. Fernández, B. Fiser, E. Gómez-Bengoa, J. M. Lassaletta, ACS Catal. 2016, 6, 3955; c) See also: V. Bhat, S. Wang, B. M. Stoltz, S. C. Virgil, J. Am. Chem. Soc., 2013, 135, 16829; d) P. Ramírez-López, A. Ros, A. Romero-Arenas, J. Iglesias-Sigüenza, R. Fernández, J. M. Lassaletta, J. Am. Chem. Soc. 2016, 138, 12053; e) V. Hornillos, A. Ros, P. Ramirez-López, J. Iglesias-Sigüenza, R. Fernández, J. M. Lassaletta, Chem. Commun. 2016, 52, 14121. [14] a) B. Marciniec, (Ed.), in: Hydrosilylation: A Comprehensive Review on Recent Advances, Springer, Netherlands, 2009; b) S. Díez-González, P. S. Nolan, Org. Prep. Proced. Int. 2007, 39, 523. [15] Seminal work: a) H. Mimoun, J. Y. De Saint Laumer, L. Giannini, R. Scopelliti, C. Floriani, J. Am. Chem. Soc. 1999, 121, 6158; b) N. Shaikh, K. Junge, S. Enthaler, M. Beller, Angew. Chem. Int. Ed. 2008, 47, 2497; Angew. Chem. 2008, 120, 2531. Reviews: c) Y. Li, K. Junge, M. Beller, in Zinc Catalysis: Applications in Organic Synthesis, (Eds.: S. Enthaler, X.-F. Wu), Wiley-VCH, Weinheim, 2015, pp 14-19. d) 15 [16] CCDC 1589898 (2a), 1589899 [(Ra,R)-3a], 1589900 [(Ra,S)-7] and 1813056 [(R,R)-3’’e] contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_ request/cif [17] Compound 4 was synthesized by a dynamic kinetic Heck reaction between rac-1a and butyl vinyl ether: J. A. Carmona, V. Hornillos, P Ramírez-López, A. Ros, J. Iglesias-Sigüenza, R. Fernández, J. M. Lassaletta, unpublished results. [18] For the sake of comparison, Relaxed Potential Energy Scan (PES) suggest a barrier of more than 35 kcal·mol-1 for the rotation of the 3- methyl-pyridyl and naphthyl moieties of the corresponding alcohol 3c aruond the C-C axis (see supporting information). [19] For selected examples using Zn(OAc)2 and chiral diamine ligands see: b) T. Inagaki, Y. Yamada, L. T. Phong, A. Furuta, J.-I. Ito, H. Nishiyama, Synlett 2009, 253; c) S. Pang, J. Peng, J. Li, Y. Bai, W. Xiao, G. Lai, Chirality 2013, 25, 275; d) M. Szewczyk, F. Stanek, A. Bezłada, J. Mlynarskia, Adv. Synth. Catal. 2015, 357, 3727. e) K. Junge, K. Möller, B. Wendt, S. Das, D. Gördes, K. Thurow, M. Beller, Chem. Asian J. 2012, 7, 314. For a recent review see: a) D. Łowicki, S. Baś, J. Mlynarski, Tetrahedron 2015, 71, 1339. [20] Diphenylethylenediamine ligands were obtained in one-step by reaction of commercially available 1,2-diphenylethylenediamine with benzyl halides in a presence of potassium carbonate. S. Kobayashi, R. Matsubara, Y. Nakamura, H. Kitagawa, M. Sugiura, J. Am. Chem. Soc., 2003, 125, 2507. [21] Treatment of (Sa,R)-3a with mesyl chloride and Et3N in CH2Cl2 at 40 °C afforded (Sa)1-(2-vinylnaphthalen-1-yl)isoquinoline, whose configuration was assigned by comparison with literature data (See ref. 13e). [22] (3) a) S. B. Cortright, J. N. Johnston, Angew. Chem., Int. Ed. 2002, 41, 345; Angew. Chem. 2002, 114, 355; b) S. B. Cortright, J. C. Huffman, R. A. Yoder, J. N. Coalter, J. N. Johnston, Organometallics 2004, 23, 2238; c) S. B. Luesse, C. M. Counceller, J. C. Wilt, B. R. Perkins, J. N. Johnston, Org. Lett. 2008, 10, 2445. 10.1002/anie.201713200 Accepted Manuscript Angewandte Chemie International Edition This article is protected by copyright. All rights reserved. COMMUNICATION Entry for the Table of Contents COMMUNICATION The dynamic duo: A nitrogen atom and the carbonyl group in heterobiaryl ketones form a Lewis pair responsible for the labilization of the stereogenic axis, which constitutes the key strategy to develop a Zn-catalyzed asymmetric hydrosilylation via dynamic kinetic resolution. This process simultaneously installs a stereogenic axis and a stereocenter for the highly enantioselective synthesis of heterobiaryl carbinols. Valentín Hornillos,* José Alberto Carmona, Abel Ros, Javier Iglesias- Sigüenza, Rosario Fernández,* and José M. Lassaletta* Page No. – Page No. Dynamic Kinetic Resolution of Heterobiaryl Ketones via Zn-catalyzed Asymmetric Hydrosilylation N X O R N X O R Silane [Zn] (5 mol %) Then HCl N X R OH up to 98% ee via = ZZ δ+ δ− N X R O Z Z 10.1002/anie.201713200 Accepted Manuscript Angewandte Chemie International Edition This article is protected by copyright. All rights reserved.