Asymmetric C atalysis Hot Paper Dynamic Kinetic Resolution of Alcohols by Enantioselectiv e Silylation Enabled by T w o Orthogonal T ransition-Metal Catalysts J an Seliger and Martin Oestreic h* Abstract : A nonenzymatic dynamic kinetic resolution of acyclic and cyclic benzylic alcohols is reported. The approach merges rapid transition-metal-catalyzed alcohol racemization and enantioselective Cu-H-catalyzed dehydrogenative Si-O coupling of alcohols and hydrosilanes . The catalytic processes are orthogonal, and the racemization catalyst does not promote any background reactions such as the racemization of the silyl ether and its unselective formation. Often-used ruthenium half- sandwich complexes are not suitable but a bifunctional ruthe- nium pincer complex perfectly fulfills this purpose. By this , enantioselective silylation of racemic alcohol mixtures is achieved in high yields and with good levels of enantioselec- tion. D ynamic kinetic resolution (DKR) is a powerful tool for the preparation of enantiomerically enriched chiral alcohols . [1] As an advantage over conventional kinetic resolution (KR) processes , the theoretical limit of 50 % yield for each enantiomer is overcome by rapid in situ racemization of the starting material. T racing back to an early example by W illiams and co-workers , [2] this is typically achieved by catalytic transfer hydrogenation with only a few excep- tions . [1a, 3, 4] A particularly versatile racemization catalyst is ruthenium complex 1 developed by Bckvall and co-work- ers . [3a] In combination with Candida antarctica lipase B and isopropenyl acetate as the acyl source , efficient chemoenzy- matic DKR of a number of structurally unbiased secondary alcohols was achieved (Scheme 1, top). Later, Fu and co- workers succeeded in developing a DKR of secondary alcohols using Bckvalls complex 1 and a ferrocene-based, planar chiral DMAP derivative as a nucleophilic activator towards an acyl source (Scheme 1, middle). [5] T his is the only nonenzymatic approach to date . T he acyl group introduced by these DKRs is usually cleaved to liberate the free alcohol or occasionally used further as a protecting group . Silyl ethers excel at the protection of hydroxy groups owing to the ease of their installation and removal as well as their tuneable stability and orthogonality . [6] Unlike the numerous (D)KR processes by enzymatic and nonenzymatic enantioselective acylation, [1, 5] corresponding silylation-based methods had been unknown until approximately twenty years ago. [7] Starting from an initial report by Ishikawa, [8] asymmetric alcohol silylation has undergone tremendous advances . [7] T oday , both organocata- lytic [9] and transition-metal-catalyzed [10] approaches for the KR of alcohols are available . Conversely , suitable conditions for a related DKR have remained elusive (Scheme 1, bottom). F or this , the resolving system and the racemization catalyst must be compatible , and racemization must occur significantly faster than the conversion of the slow-reacting enantiomer to the product silyl ether . Additionally , the racemization catalyst must not promote any racemic back- ground reactions , that is the racemization of the silyl ether and the coupling of the alcohol and the silylation reagent. Our study commenced with an investigation of several ruthenium and osmium complexes as potential racemization catalysts with ( S )-1-phenylethanol [( S )- 2a ] as the model substrate and benzene- d 6 as the solvent (F igure 1 and T able 1). As expected, fast racemization of ( S )- 2a was seen Scheme 1. Representative DKRs of alcohols by acylation (top) and planned silylation approach (bottom). DMAP = 4-dimethylaminopyri - dine, ( R , R )-Ph-BPE = 1,2-bis[( 2R ,5 R )-2,5-dip henylphospholan-1- yl]ethane. [*] J. Seliger , Prof. Dr . M. Oestreich Institut fr Chemie, T echnische Universitt Berlin Strasse des 17. Juni 115, 10623 Berlin (Germany) E-mail : martin.oest [email protected] Homepage : http ://www .organometallics.tu-berlin.de Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under : https ://doi.org/10.1002/anie.2020104 84. 2020 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH. This is an open access article under the terms of the C reative C ommons Attribution Non-C ommercial License, which permits use, distribution and reproducti on in any medium, provided the original work is properly cited and is not used for commercial purposes. A ngewandte Chemi e C ommunications How to cite: Angew . Chem. Int. Ed. 2021 , 60 , 247 – 251 International Edition: doi.org/10.1002/anie.202010484 German Edition: doi.org/10.1002/ange.202010484 247 Angew . Chem. Int. Ed. 2021 , 60 , 247 –251 2020 The Aut ho rs. A nge wa nd te Che mie In te rnat io nal Edit io n publ is he d by W iley -VC H Gmb H using ruthenium complex 1 as the precatalyst and NaO t Bu as the base (entry 1). T he situation changed dramatically under our established KR conditions . T he racemization was sub- stantially slowed down in the presence of 6.0 mol % of ( R , R )- Ph-BPE and stopped almost entirely when 1.3 equiv of n Bu 3 SiH were added (entries 2–4). [12] A similar result was obtained with the structurally related, more robust ruthenium complex 3a where one carbonyl ligand is replaced by triphenylphosphine (entry 5). [3b] T he electronic modification of this complex using electron-poorer and -richer phosphines as in 3b and 3c had no effect (entries 6 and 7). W e then turned our attention towards bifunctional catalysts bearing a metal- bound amino group that have been employed in transfer hydrogenation with great success . [13] In contrast to the half- sandwich complexes 1 and 3a – c operating through inner - sphere mechanisms , [14] these catalysts likely operate through outer -sphere mechanisms involving hydrogen-bonding net- works between the substrate and the NH 2 functionality as a crucial feature . [15] In recent years , transition-metal pincer complexes have emerged as highly active and robust catalysts , with [M(CNN)(dppb)Cl] 4a (M = Ru)and 4b (M = Os) as well as [Ru(PNP)(CO)HCl] 5 achieving particularly high turnover frequencies . [16] Also , ruthenium complex 5 was reported to facilitate the catalytic hydrogenolysis of chlor - osilanes to produce hydrosilanes , [17] thereby making catalyst poisoning under our setup unlikely . Indeed, fast racemization of ( S )-1-phenylethanol [( S )- 2a ] in the presence of both ( R , R )- Ph-BPE and n Bu 3 SiH was accomplished with all of the bifunctional catalysts 4a , 4b , and 5 (entries 8–10) and merely trace amounts of acetophenone were observed. W ith three promising candidates as racemization catalysts in hand, we next investigated their activity in the aforemen- tioned racemic background reactions (Scheme 2). Impor - tantly , none of the pincer complexes catalyzed the racemiza- tion of the silyl ether ( S )- 6a in basic medium (Scheme 2, top). Additionally , both the Ru- and the Os-CNN complexes 4a and 4b did not promote the dehydrogenative coupling of 1- phenylethanol ( 2a ) and n Bu 3 SiH (Scheme 2, bottom). Con- versely , when Ru-PNP complex 5 was employed as the precatalyst, substantial amounts of silyl ether 6a were formed within 14 h, therefore thwarting its suitability for our endeavor. W ithout any obvious differences in catalytic activity between 4a and 4b , we continued with Ru-CNN complex 4a as the designated racemization precatalyst. W e then tried the DKR of racemic 1-phenylethanol ( 2a ) in the presence of a copper catalyst, employing ruthenium complex 4a and our established resolving system consisting of CuCl, NaO t Bu, ( R , R )-Ph-BPE, and n Bu 3 SiH in toluene . W ith 1.1 equiv of the hydrosilane , quantitative conversion of the alcohol was achieved after stirring for 14 h at room temper - ature , and the corresponding silyl ether ( S )- 6a was isolated with 86 % ee. It is worth noting that the reaction also proceeded smoothly in polar protic solvents such as tert -amyl alcohol with unchanged reactivity and enantioselectivity (see the Supporting Information for details). However, reducing the reaction temperature to 0 8 C did not improve the enantiomeric excess although good reactivity was maintained. W ith suitable conditions established, we explored the scope of this DKR (Scheme 3). V arious sterically and electronically modified benzylic alcohols 2a – z were tested, and the corresponding silyl ethers ( S )- 6a – y were generally obtained in almost quantitative yields with good to high levels of enantioselection. Both electron-donating (Me and OMe) Figure 1. Candidates for catalytic alcohol racemization. T able 1: Identification of a suitable racemization catalyst. [a] Entry C atalyst V ariation ee [%] [c] 1 1 w/o ( R , R )-Ph-BPE, n Bu 3 SiH 0 2 1 w/o n Bu 3 SiH 32 3 1 w/o ( R , R )-Ph-BPE 93 4 1 none 95 5 3a none 93 6 3b none 94 7 3c none 90 8 4a none 0 9 4b none 0 10 5 none 0 [a] All reactions were performed on a 0.1 mmol scale. [b] Estimated by in situ 1 H NMR analysis ; ratio based on the integration of baseline- separated resonance signals. [c] Determined by HPLC analysis on a chiral stationary phase. Scheme 2. Interrogation of potential background reactions. All reac- tions were performed on a 0.2 mmol scale. Enantiomeric excesses were determined by HPLC analysis on a chiral stationary phase after cleavage of the silyl ether . Conversions were determined by GLC analysis using tetracosane as an internal standard. A ngewandte Chemi e C ommunications 248 www .angewandte.org 2020 The Au thor s. An gewa n dte C hemi e Inte rn atio nal Ed it ion pu bl is he d by Wil ey -VC H G mbH Angew . Chem. Int. Ed. 2021 , 60 , 247 –251 and electron-withdrawing substituents (aryl, heteroaryl, hal- ogens , CF 3 , and CO 2 t Bu) were well tolerated but a trend regarding the reactivity or selectivity was not apparent. A detailed survey of the aryl groups steric effects revealed that monosubstitution of the parent 1-phenylethanol ( 2a ) with methyl groups in the ortho -, meta - and para -positions as in 2b , 2d , and 2f was compatible with only little influence on the enantiomeric excess . However, when a bulkier bromine atom was installed in either of these positions a more pronounced effect was observed. Here , ortho -substituted ( S )- 6c was obtained with considerably lower ee , pointing towards a possible limitation of the racemization catalyst 4a . Con- versely , the enantioselectivities observed for meta - and para - substituted derivatives ( S )- 6e and ( S )- 6j were in the expected range , yet noticeably higher in the former case. Accordingly , disubstitution in the meta -positions led to the silyl ethers ( S )- 6n – p with improved enantioselectivities while ortho , ortho - dimethylated ( S )- 6q was isolated with drastically reduced enantiomeric excess and after prolonged reaction time . T he latter result stands in stark contrast to the outstanding selectivity factor of 170 observed in the KR of 2q with the same copper catalyst. [10e] Consequently , steric bulk in the ortho -position exerts a strong effect on the racemization ability of catalyst 4a . In line with these findings , both a - and b - naphthyl-substituted derivatives 2r and 2s as well as alcohols bearing heterocyclic furan-2-yl and thien-2-yl units as in 2t and 2u exhibited high reactivity and good enantioselectivity . Although 1-(pyridin-4-yl)ethanol ( 2v ) proved substantially less reactive , the enantiodifferentiation stayed in the same range . As expected from our previous work, [10e] both the enantiomeric excess and the reactivity dwindled with increas- ing size of the alkyl group Me < Et < Bn ! i Pr [ 2a and 2w – y ! ( S )- 6a and ( S )- 6w – y ] , and synthetically useful 2-chloro- 1-phenylethanol ( 2z ) was entirely unreactive . T his trend was further corroborated in an application to 7 , a precursor of duloxetine (gray box, left). T he thien-2-yl unit had been shown to be compatible before [cf . 2u ! ( S )- 6u ] but the ethylene-tethered, Boc-protected amino group was detrimen- tal, affording ( S )- 9 with moderate 62 % ee ; the coordination ability of the Boc group could however contribute to this outcome . In another application, carbamate-containing 8 participated in the DKR with good efficiency to yield the rivastigmine precursor ( S )- 10 in 93 % ee (gray box, right). Selected aliphatic alcohols were also included into this study (F igure 2), especially to compare 1-phenylethanol ( 2a ) with fully saturated 1-cyclohexylethanol. T he corresponding silyl ether ( S )- 11 a (79 % ee ) did form with slightly diminished ee compared to ( S )- 6a (86 % ee ), and the reaction had a significantly smaller rate (days versus hours). Both sub- stitution of the cyclohexyl moiety with a cyclopentyl group (as in ( S )- 11 b ) and slight chain elongation (i.e. Me ! Et as in ( S )- 11 c ) paired low reactivity with further deteriorated enantio- selectivity , and full conversion was not even reached in the latter case . F inally , we investigated cyclic benzylic alcohols 12 a – h with different ring sizes as substrates for our reaction (Scheme 4). Again, yields were nearly quantitative and Scheme 3. DKR of acyclic benzylic alcohols. All reactions were per- formed on a 0.2 mmol scale. Yields are isolated yields after flash chromatography on silica gel. Enantiomeric excesses were determi ned by HPLC analysis on chiral stationary phases after cleavage of the silyl ether . [a] The reaction time was 48 h. [b] Estimated enantiomeric excess since no baseline separation was achieved. [c] The reaction time was 36 h. [d] The reaction time was 84 h. [e] The reaction time was 60 h. Boc = tert -butoxycarbonyl. Figure 2. DKR of aliphatic alcohols. All reactions were performed on a 0.2 mmol scale. Yields are isolated yields after flash chromatography on silica gel. Enantiomeric excesses were determined by HPLC analysis on a chiral stationary phase after cleavage of the silyl ether and derivatization as the p -nitrobenzoate. [a] The reaction time was 84 h. [b] The reaction time was 120 h after which 65 % conversion of 1- cyclohexylpropanol was detected by GLC analysis using tetracosane as an internal standard. [c] Estimated enantiomeric excess since no baseline separation was achieved. A ngewandte Chemi e C ommunications 249 Angew . Chem. Int. Ed. 2021 , 60 , 247 –251 2020 The Au thor s. Ange wa nd te Chem ie In te rna ti on al Edit io n publ is he d by Wiley -VC H GmbH www .angewandte.org enantioselectivities were usually slightly better than for their acyclic counterparts . Hence , five- to seven-membered carbo- cyclic alcohols 12 a – c smoothly underwent the reaction, although the benzosuberol-derived silyl ether ( S )- 13 c was obtained with notably lower ee. Substitution with a heteroa- tom in the saturated ring was also tolerated, and the highly functionalized (thio)chromanol-derived silyl ethers ( S )- 13 d – f and ( S )- 13 g were amenable with high ee. Furthermore , the position of the heteroatom had no significant effect on the selectivity of our reaction as evident from the tetrahydro- (iso)quinolinol-derived silyl ethers ( S )- 13 h and ( R )- 14 (gray box). DKR of secondary alcohols is typically achieved by enantioselective acylation techniques for which several che- moenzymatic protocols are available . [1a] Fus nonenzymatic process had remained an isolated example [5] and is also a beautiful example of orthogonal tandem catalysis . [18] A cognate tool relying on the stereoselective silylation of alcohols has been unprecedented so far. W e reported here a DKR of secondary alcohols by means of a Cu-H-catalyzed dehydrogenative coupling with the simple hydrosilane n Bu 3 SiH. T he choice of the racemization catalyst is crucial as commonly used ruthenium half-sandwich complexes fail under our previously established, commercially available resolving system. [10e] In turn, bifunctional ruthenium and osmium pincer complexes were identified as suitable alter - natives and were successfully combined with our KR proce- dure . [10e] Our method is applicable to a broad range of acyclic and cyclic benzylic alcohols and exhibits good functional- group tolerance . An extension of this approach to allylic [10e, 19] and propargylic [10 f] alcohols will require further catalyst design and is currently under investigation in our laboratory . Acknowledgements T his research was supported by the Deutsche F orschungsge- meinschaft (Oe 249/14-1) and the F onds der Chemischen Industrie (predoctoral fellowship to J .S . , 2018–2020). M.O . is indebted to the Einstein F oundation Berlin for an endowed professorship . W e thank T akuya Kinoshita of Osaka Univer - sity for his experimental contributions . Open access funding enabled and organized by Projekt DEAL. C onflict of interest J .S . and M.O . filed a patent application of the reported method. Keywords : asymmetric catalysis · copper · dehydrogenative coupling · dynamic kinetic resolution · silicon [1] F or reviews of the (D)KR of alcohols by enzymatic and nonenzymatic acy lation, see : a) O . V erho , J .-E. Bckvall, J. Am. Chem. Soc. 2015 , 137 , 3996 – 4009 ; b) E. V edejs , M. J ure, Angew . Chem. Int. Ed. 2005 , 44 , 3974 – 4001 ; Angew . Chem. 2005 , 117 , 4040 – 4069 ; c) J . M. Keith, J . F . Larrow , E. N . J acobsen, Adv . Synth. Catal. 2001 , 343 , 5 – 26. [2] P . M. Dinh, J . A. Howarth, A. R. Hudnott, J . M. J . W illiams , W . Harris , T etrahedron Lett. 1996 , 37 , 7623 – 7626. [3] Selected examples of alcohol racemization catalysts operating by transfer hydrogenation mechani sms . Ruthenium(II)-based : a) B . Martn-Matute , M. Edin, K. Bogr, F . B . Kaynak, J .-E. Bckvall, J . Am. Chem. Soc. 2005 , 127 , 8817 – 8825 ; b) S .-B . K o , B . Baburaj, M.-J . Kim, J . Park, J . Org. Chem. 2007 , 72 , 6860 – 6864 ; c) G . Bossi, E. Putignano , P . Rigo , W . Baratta, Dalton T rans . 2011 , 40 , 8986 – 8995 ; d) J . A. Fernndez- Salas , S . Manzini, S . P . Nolan, Chem. Eur . J . 2014 , 20 , 13132 – 13135 ; aluminum(III)-based : e) A. Berkessel, M. L. Sebasti an-Ibarz, T . N . Mller , Angew . Chem. Int. Ed. 2006 , 45 , 6567 – 6570 ; Angew . Chem. 2006 , 118 , 6717 – 6720 ; iridium(III)-based : f) R. M. Haak, F . Berthiol, T . J erphagnon, A. J . A. Gayet, C . T arabiono , C . P . P ostema, V . Ritleng, M. Pfeffer , D . B . J anssen, A. J . Minnaard, B . L. F eringa, J . G . de Vries , J . Am. Chem. Soc . 2008 , 130 , 13508 – 13509 ; iron(II)-based : g) O . El-Sepelgy , N . Alandini, M. Rueping , Angew . Chem. Int. Ed. 2016 , 55 , 13602 – 13605 ; Angew . Chem. 2016 , 128 , 13800 – 13803. [4] Examples of alcohol racemization through dehydration-hydra- tion mechanism s . Under zeolite catalysis : a) S . W uyts , K. De T emmerm an, D . De V os , P . J acobs , Chem. Commun. 2003 , 1928 – 1929 ; b) Y . Zhu, K.-L. F ow , G .-K. Chuah, S . J aenicke , Chem. Eur . J . 2007 , 13 , 541 – 547; under vanadium(V) catalysis : c) M. Egi, K. Sugiyama, M. Saneto , R. Hanada , K. Kato, S . Akai, Angew . Chem. Int. Ed. 2013 , 52 , 3654 – 3658 ; Angew . Chem. 2013 , 125 , 3742 – 3746. [5] S . Y . Lee , J . M. Murphy , A. Ukai, G . C. Fu, J . Am. Chem. Soc. 2012 , 134 , 15149 – 15153. [6] a) P . G . M. W uts , Greenes Protective Groups in Organic Syn- thesis , 5th ed. , Wiley , Hoboken, 2014 , pp . 201 – 270 ; b) P . J . K ocien ´ sky , Protecting Groups , 3rd ed. , Thieme , Stuttgart, 2005 , pp . 188 – 230. [7] a) A. H. Hoveyda, M. L. Snapper in Organos ilicon Chemistry— Novel Approac hes and Reactions (Eds . : T . Hiyama, M. Oes- treich), W iley-VCH, W einheim, 2019 , pp . 459 – 493 ; b) J . Seliger, M. Oestreich, Chem. Eur . J . 2019 , 25 , 9358 – 9365 ; c) L.-W . Xu, Y . Chen, Y . Lu, Angew . Chem. Int. Ed. 2015 , 54 , 9456 – 9466 ; Angew . Chem. 2015 , 127 , 9590 – 9601. Scheme 4. DKR of cyclic benzylic alcohols. All reactions were per- formed on a 0.2 mmol scale. Yields are isolated yields after flash chromatography on silica gel. Enantiomeric excesses were determi ned by HPLC analysis on chiral stationary phases after cleavage of the silyl ether . A ngewandte Chemi e C ommunications 250 www .angewandte.org 2020 The Au thor s. An gewa n dte C hemi e Inte rn atio nal Ed it ion pu bl is he d by Wil ey -VC H G mbH Angew . Chem. Int. Ed. 2021 , 60 , 247 –251 [8] T . Isobe , K. Fukuda, Y . Araki, T . Ishikawa, Chem. Commun. 2001 , 243 – 244. 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T hese authors found that C 5 Ph 5 (CO) 2 RuH was completely inactive in the racemiz ation of ( S )- 2a and therefore exclude d this species as a relevant inter - mediate . See Ref . [3a] for details . [13] D . W ang, D . Astruc, Chem. Rev . 2015 , 115 , 6621 – 6686. [14] M. C. W arner, J .-E. Bckvall, Acc . Chem. Res . 2013 , 46 , 2545 – 2555. [15] P . A. Dub , J . C . Gordon, Nat. Rev . Chem. 2018 , 2 , 396 – 408. [16] a) W . Baratta, G . Chelucci, S . Gladiali, K. Siega, M. T oniutti, M. Zanette , E. Zangrando , P . Rigo , Angew . Chem. Int. Ed. 2005 , 44 , 6214 – 6219 ; Angew . Chem. 2005 , 117 , 6370 – 6375 ; b) W . Baratta, M. Ballico , G . Chelucci, K. Siega, P . Rigo , Angew . Chem. Int. Ed. 2008 , 47 , 4362 – 4365 ; Angew . Chem. 2008 , 120 , 4434 – 4437 ; c) M. Bertoli, A. Choualeb , A. J . Lough, B . Moore , D . Spasyuk, D . G . Gusev , Organometallics 2011 , 30 , 3479 – 3482. [17] A. Gler , J . I. Schweizer, U . S . Karaca, C . Wrtele , M. Die- fenbach, M. C . Holthausen , S . Schneider, Inorg . Chem. 2018 , 57 , 13822 – 13828. [18] F or reviews on tandem catalysis , see : a) T . L. Lohr, T . J . Marks , Nat. Chem. 2015 , 7 , 477 – 482 ; b) J .-C. W asilke , S . J . Obrey , R. T . Baker, G . C . Bazan, Chem. Rev . 2005 , 105 , 1001 – 1020. [19] A complex mixture was obtained when ( E )-4-phenylbut-3-en-2- ol was subjected to the reaction conditions . Another experiment revealed that the allylic alcohol was isomerized to the corre- sponding ketone , 4-phenylbutan-2-one , within seconds in the presence of ruthenium complex 4a . Manuscript received: J uly 31, 2020 Revised manuscript received: September 28, 2020 V ersion of record online: October 27, 2020 A ngewandte Chemi e C ommunications 251 Angew . Chem. Int. Ed. 2021 , 60 , 247 –251 2020 The Auth or s. 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