The chiral base n-BuLi/(-)-sparteine or n-BuLi/(+)-sparteine surrogate promotes kinetic resolution of N-Boc-2-arylpiperidines by asymmetric deprotonation. The enantioenriched starting material was recovered with yields 39-48% and ers up to 97:3. On lithiation then electrophilic quench, 2,2-disubstituted piperidines were obtained with excellent yields and enantioselectivities. © 2014 the Partner Organisations

Bailey

Barker

Becker

Beng

Binanzer

Coldham

Daniele Leonori

Edward J. Cochrane

Faibish

Granander

Hardy

Harrison

Hesp

Horton

Hsieh

Iain Coldham

Kagan

Kessar

Krasnov

Kreituss

Lorraine A. Hassall

Millet

O'Brien

Pellissier

Penning

Rutherford

Seel

Sheikh

Stead

Strohmann

Xiao

Cochrane, E.J.

Leonori, D.

Coldham, I.

Hassall, L.A.

White Rose Research Online

promoting access to White Rose research papers    White Rose Research Online eprints@whiterose.ac.uk    Universities of Leeds, Sheffield and York http://eprints.whiterose.ac.uk/    This is a copy of the final published version of a paper published via gold open access in Chemical Communications.   This open access article is distributed under the terms of the Creative Commons Attribution Licence (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.  White Rose Research Online URL for this paper: http://eprints.whiterose.ac.uk/80519     Published paper  Cochrane, E.J., Leonori, D., Coldham, I. and Hassall, L.A. (2014) Synthesis and kinetic resolution of N-Boc-2-arylpiperidines. Chemical Communications, 50 (69). 9910 - 9913. Doi: 10.1039/c4cc04576a   9910 | Chem. Commun., 2014, 50, 9910--9913 This journal is©The Royal Society of Chemistry 2014Cite this:Chem. Commun., 2014,50, 9910Synthesis and kinetic resolution ofN-Boc-2-arylpiperidines†Edward J. Cochrane,a Daniele Leonori,a Lorraine A. Hassallb and Iain Coldham*aThe chiral base n-BuLi/()-sparteine or n-BuLi/(+)-sparteine surro-gate promotes kinetic resolution of N-Boc-2-arylpiperidines byasymmetric deprotonation. The enantioenriched starting materialwas recovered with yields 39–48% and ers up to 97 : 3. On lithiationthen electrophilic quench, 2,2-disubstituted piperidines wereobtained with excellent yields and enantioselectivities.Piperidines substituted in the 2-position with at least one aryl groupare a class of molecules often possessing high biological activitiesand are therefore of interest to synthetic organic, medicinal andprocess chemists.1 For example, piperidine 1 is a poly ADP ribosepolymerase inhibitor (Fig. 1).2 Piperidine 2 is a lead compound fororally active NK1 antagonists.3 Piperidine 2 was synthesised by Xiaoand co-workers as a mixture of diastereomers via the THF-mediatedlithiation-substitution of ()-N-Boc-2-phenylpiperidine.3a The needfor a stereoselective synthesis is exemplified by the B50-folddifference in activity between the HCl salt of the (R,R) and the(R,S) diastereomers (IC50 0.3 nM and 415 nM, respectively).4A general approach to the asymmetric synthesis of 2,2-disubstituted piperidines continues to pose a problem for syntheticchemists. Building on their expertise of lithiated nitrogen-containingheterocycles, Coldham and O’Brien and co-workers reported that theBoc group in N-Boc-2-phenylpiperidine rotates rapidly, even at78 1C, to allow high yields of lithiation at the benzylic positionand that the organolithium is configurationally stable at low tem-perature.5 This led to the synthesis of enantiomerically enriched2-alkyl-2-phenylpiperidines, such as piperidine 4a, using enantio-merically enriched N-Boc-2-phenylpiperidine 3a (Scheme 1).The enantioenriched N-Boc-2-phenylpiperidine (S)-3a wasobtained by an asymmetric reduction of the correspondingcyclic imine.5a An alternative approach is by Negishi reactionusing the chiral organozinc species formed either from the2-tributylstannane, itself formed by dynamic resolution of 2-lithiatedN-Boc-piperidine,6 or directly by ‘catalytic dynamic resolution’,7although the latter method was unsuccessful in our hands. Wetherefore sought a simpler method and wondered if racemic N-Boc-2-arylpiperidines were amenable to kinetic resolution. There isgrowing interest in the kinetic resolution of amines, mostly byN-acylation.8 In contrast, the kinetic resolution of amines by depro-tonation has received very little study.9 The closest example is thatfrom Beak and co-workers, who showed that the chiral base n-BuLi/()-sparteine can effect a kinetic resolution of an acyclic N-Boc-a-methylbenzylamine, albeit with fairly low selectivity (er up to 81 : 19for 12% yield of recovered starting material).9a In this paper, wereport that N-Boc-2-arylpiperidines are excellent substrates for highlyselective kinetic resolution by asymmetric deprotonation.Racemic N-Boc-2-phenylpiperidine and related 2-aryl or 2-hetero-aryl derivatives can be prepared by several different methods.10We selected to extend the method used for racemic 3a,5a for thepreparation of a variety of N-Boc-2-arylpiperidines (Scheme 2).Addition of the aryllithium, obtained by bromine–lithium exchange,to 5-bromovaleronitrile, followed by reduction of the intermediatecyclic imine with sodium borohydride and addition of Boc2O gaveFig. 1 Some biologically active 2-arylpiperidines.Scheme 1 Lithiation-substitution of piperidine 3a.a Department of Chemistry, University of Sheffield, Sheffield, S3 7HF, UK.E-mail: i.coldham@sheffield.ac.ukb AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK† Electronic supplementary information (ESI) available: Experimental proceduresand spectroscopic data. See DOI: 10.1039/c4cc04576aReceived 16th June 2014,Accepted 11th July 2014DOI: 10.1039/c4cc04576awww.rsc.org/chemcommChemCommCOMMUNICATIONOpen Access Article. Published on 11 July 2014. Downloaded on 11/09/2014 10:36:56.  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.View Article OnlineView Journal  | View IssueThis journal is©The Royal Society of Chemistry 2014 Chem. Commun., 2014, 50, 9910--9913 | 9911the desired racemic piperidines 3a–g. Reasonable yields for thethree-step procedure were obtained, except with p-MeOC6H4Liwhich gave significant amounts of methoxybenzene, perhaps dueto its propensity to abstract a proton alpha to the nitrile. Thecorresponding organomagnesium reagent was no more successful.For the kinetic resolution of these substrates, we initiallyfocused on developing conditions using the substrate 3a. A mixtureof 0.55 equiv. of n-BuLi and ()-sparteine (pre-mixed for 5 min) inPhMe was used for the lithiation of N-Boc-2-phenylpiperidine 3a(Scheme 3). After 5 min, addition of iodomethane gave the product4a in 30% yield with a promising er (79 : 21). With the electrophileethyl chloroformate, both the yield of the product 5a and the erwere improved. By changing the solvent to Et2O, a similar er(87 : 13) of 5a was obtained but in reduced yield (see ESI† for yieldand er of recovered 3a). The er was determined by chiral stationaryphase (CSP) HPLC and the optical rotation of 4a (see ESI†) matchedthat reported for the (S) enantiomer.5a These data predict, asexpected based on the lithiation of N-Boc-piperidine,11 that theenantiomer (S)-3a is preferentially lithiated by n-BuLi/()-sparteine.As an alternative, we investigated a different method of addi-tion, whereby n-BuLi and ()-sparteine were not premixed. n-BuLiwas added to a solution containing the piperidine 3a and ()-spar-teine in PhMe. After different time periods the electrophileEtOCOCl was added (Table 1). A marked improvement in the erof the product 5a was obtained, and this was associated with asignificant decrease in yield. By increasing the reaction time to 3 h,it was possible to obtain the product 5 with er 92 : 8 and a yield of42% (entry 5).To investigate the differences in reaction times for thesemethods, we performed in situ IR spectroscopy to monitor thestretching frequency of the carbonyl group (Fig. 2). When usingpre-mixed n-BuLi/()-sparteine (Fig. 2a), partial lithiationoccurs over about 15 min, as judged by the steady but partialloss of ncQo 1691 cm1 (CQO stretch for 3a) and formation of anew peak at 1640 cm1 (assigned to ncQo in the lithiatedintermediate). However, without pre-mixing, the lithiationrequired several hours (Fig. 2b). The method chosen clearlyimpacts on the selectivity, with the slower lithiation allowing aScheme 2 Synthesis of ()-N-Boc-2-arylpiperidines 3a–g.Scheme 3 Initial study of the kinetic resolution with pre-mixed n-BuLi/()-sparteine.Table 1 Kinetic resolution to give 5a with n-BuLi and ()-sparteineaEntry Time (min) Yieldb 5a (%) erc 5a1 10 16 95 : 52 30 27 95 : 53 60 33 93 : 74 120 36 93 : 75 180 42 92 : 8a For yield and er of recovered 3a, see ESI. b Yield of isolated product.c Determined by CSP HPLC.Fig. 2 In situ IR plots of the lithiation of 3a with n-BuLi/()-sparteine at78 1C in PhMe with time in h:min:s. (a) ncQo 3a (1691 cm1), pre-mixedn-BuLi/()-sparteine added at time 16 min, ncQo lithiated 3a (1640 cm1);(b) ncQo 3a (1691 cm1) and ()-sparteine then n-BuLi added at time16 min, ncQo lithiated 3a (1640 cm1).Communication ChemCommOpen Access Article. Published on 11 July 2014. Downloaded on 11/09/2014 10:36:56.  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.View Article Online9912 | Chem. Commun., 2014, 50, 9910--9913 This journal is©The Royal Society of Chemistry 2014more selective reaction. The faster reaction occurs with the pre-mixed n-BuLi/()-sparteine complex that will have a higherconcentration of the dimeric aggregation state.12With optimised conditions in-hand, we studied the use of otherelectrophiles but these gave lower yields and ers (37% yield, er82 : 18 using allyl bromide; 24% yield, er 74 : 26 using MeI). Thelower selectivities may be due to partial racemisation of thelithiated intermediate prior to slower electrophilic quench.Due to the variation in er dependent on the choice of electro-phile, we decided to focus on obtaining a good yield and er for therecovered starting material. This was investigated by varying thenumber of equivalents of the chiral base (Table 2). The bestconditions that we found used 0.7 equiv. of n-BuLi and ()-spar-teine and gave an excellent yield and er of recovered 3a (entry 2).A yield of 45% with er 96 : 4 (R : S) corresponds to a relative rate ofreaction for the two enantiomers krel B 22.13The kinetic resolution was then tested with the different2-arylpiperidines that were prepared as shown in Scheme 2. Wewere pleased to find that high levels of selectivity could be achievedwith many of these compounds (Scheme 4). The yields and er valuesof the recovered starting materials are given in Scheme 4 for thedifferent aromatic derivatives and it was found that both electron-poor (p-chloro 3b, p-fluoro 3c) and electron-rich (p-methoxy 3e)substituents are tolerated in the kinetic resolution. However, someloss in selectivity occurs with the 3,5-bis-trifluoromethyl 3f and2-pyridyl 3g derivatives. This may be due to a faster and thereforeless selective lithiation with these more acidic substrates.In addition, we have demonstrated that the other enantiomer ofthe 2-arylpiperidine can be formed by changing the chiral ligand toO’Brien’s (+)-sparteine surrogate.14 This resulted in the formationof (S)-3a (41% yield, er 91 : 9) and (S)-3b (42% yield, er 84 : 16).This methodology is reliant on using ethyl chloroformate as asacrificial electrophile, consuming the undesired enantiomer. Thekinetic resolution was tested with Me3SnCl as the electrophile(Scheme 5). This could enable a subsequent tin–lithium exchangeto recover the starting material after proton quench. The kineticresolution performed well using this electrophile to give the recov-ered piperidine 3a in 42% yield and er 94 : 6. The er of the stannane6a was not determined but this product was treated with n-BuLi inTHF followed by addition of acetic acid. When this reaction wasconducted at 78 1C, the piperidine (S)-3a was isolated with er82 : 18, suggesting that tin–lithium exchange and protonationoccurs with retention of configuration. However, when the exchangeand protonation was conducted at room temperature, racemic 3awas recovered in high yield. Therefore this approach allows recy-cling of the undesired product to allow a further kinetic resolution.Finally, we have performed THF-mediated lithiation then sub-stitution on the enantioenriched recovered starting materials toshow that these are amenable to the formation of 2,2-disubstitutedpiperidines without loss of enantioselectivity.5,15 Treatment of thepiperidine (R)-3b (er 96 : 4) with n-BuLi followed by MeI, EtOCOClor allyl bromide gave the products 4b, 5b, and 7b with good yieldsTable 2 Kinetic resolution of 3a with n-BuLi and ()-sparteineEntryEquiv. n-BuLiand ()-spYielda (%)and erb 3a (%)Yield (%)and erb 5a (%)1 0.55 50 (77 : 23) 42 (92 : 8)2 0.7 45 (96 : 4) 51 (86 : 14)3 0.8 31 (92 : 8) 56 (77 : 23)4 1.0 13 (98 : 2) 74 (57 : 43)a Yield of isolated starting material. b Determined by CSP HPLC.Scheme 4 Kinetic resolution of various N-Boc-2-arylpiperidines.Scheme 5 Kinetic resolution of N-Boc-2-phenylpiperidine with Me3SnClquench.ChemComm CommunicationOpen Access Article. Published on 11 July 2014. Downloaded on 11/09/2014 10:36:56.  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.View Article OnlineThis journal is©The Royal Society of Chemistry 2014 Chem. Commun., 2014, 50, 9910--9913 | 9913and with no loss of enantioselectivity (Scheme 6). Similarly, piperi-dines (R)-3c (er 94 : 6) and (R)-3d (er 97 : 3) gave the products 4c, 5c,and 4d with good yields and very little reduction in er. Based onrelated chemistry using piperidine 3a,5 we assume that the absoluteconfiguration of these products is as shown, in which lithiation andelectrophilic quench occur with retention of configuration.The chiral base n-BuLi with ()-sparteine or the (+)-sparteinesurrogate is effective for the kinetic resolution of racemic N-Boc-2-arylpiperidines in PhMe. The recovered starting material can beisolated with high enantiomer ratios, especially if n-BuLi and thechiral ligand are not pre-mixed. Use of in situ IR spectroscopyhelped to optimise the conditions for the kinetic resolution. Byusing a trialkyltin halide electrophile, the quenched product can berecycled by tin–lithium exchange and protonation. After kineticresolution, the recovered enantioenriched N-Boc-2-arylpiperidinescan be deprotonated with n-BuLi in THF at 78 1C and quenchedwith electrophiles without loss of enantiopurity to provide highlyenantioselective syntheses of 2,2-disubstituted piperidine products.We thank the EPSRC, the University of Sheffield and Astra-Zeneca for funding.Notes and references1 See, for example, (a) D. A. Horton, G. T. Bourne and M. L. Smythe,Chem. Rev., 2003, 103, 893; (b) S. Hardy and S. F. Martin, Org. Lett.,2011, 13, 3102.2 T. D. Penning, G.-D. Zhu, J. Gong, S. Thomas, V. B. Gandhi, X. Liu,Y. Shi, V. Klinghofer, E. F. Johnson, C. H. Park, E. H. Fry,C. K. Donawho, D. J. Frost, F. G. Buchanan, G. T. Bukofzer,L. E. Rodriguez, V. Bontcheva-Diaz, J. J. Bouska, D. J. Osterling,A. M. Olson, K. C. Marsh, Y. Luo and V. L. Giranda, J. Med. Chem.,2010, 53, 3142.3 (a) D. Xiao, B. J. Lavey, A. Palani, C. Wang, R. G. Aslanian,J. A. Kozlowski, N.-Y. Shih, A. T. McPhail, G. P. Randolph,J. E. Lachowicz and R. A. Duffy, Tetrahedron Lett., 2005, 46, 7653;(b) T. Harrison, B. J. Williams and C. J. Swain, Bioorg. Med. Chem.Lett., 1994, 4, 2733.4 (a) D. Xiao, C. Wang, A. Palani, H.-C. Tsui, G. Reichard, S. Paliwal,N.-Y. Shih, R. Aslanian, R. Duffy, J. Lachowicz, G. Varty, C. Morgan,F. Liu and A. Nomeir, Bioorg. Med. Chem. Lett., 2010, 20, 6313;(b) D. Xiao, C. Wang, H.-C. Tsui, A. Palani, R. Aslanian andA. V. Buevich, Tetrahedron Lett., 2013, 54, 6199.5 (a) N. S. Sheikh, D. Leonori, G. Barker, J. D. Firth, K. R. Campos,A. J. H. M. Meijer, P. O’Brien and I. Coldham, J. Am. Chem. Soc.,2012, 134, 5300; for further examples, see; (b) T. K. Beng, J. S. Wooand R. E. Gawley, J. Am. Chem. Soc., 2012, 134, 14764.6 I. Coldham, S. Raimbault, D. T. E. Whittaker, P. T. Chovatia,D. Leonori, J. J. Patel and N. S. Sheikh, Chem. – Eur. J., 2010,16, 4082.7 T. K. Beng and R. E. Gawley, Org. Lett., 2011, 13, 394.8 For some reviews, see (a) V. P. Krasnov, D. A. Gruzdev andG. L. Levit, Eur. J. Org. Chem., 2012, 1471; (b) H. Pellissier, Adv.Synth. Catal., 2011, 353, 1613. For some recent examples with 2-substituted piperidines, see; (c) M. Binanzer, S.-Y. Hsieh andJ. W. Bode, J. Am. Chem. Soc., 2011, 133, 19698; (d) S.-Y. Hsieh,M. Binanzer, I. Kreituss and J. W. Bode, Chem. Commun., 2012,48, 8892; (e) I. Kreituss, Y. Murakami, M. Binanzer and J. W. Bode,Angew. Chem., Int. Ed., 2012, 51, 10660; ( f ) S.-Y. Hsieh, B. Wanner,P. Wheeler, A. M. Beauchemin, T. Rovis and J. W. Bode, Chem. – Eur.J., 2014, 20, 7228.9 (a) N. C. Faibish, Y. S. Park, S. Lee and P. Beak, J. Am. Chem. Soc.,1997, 119, 11561; (b) S. V. Kessar, P. Singh, K. N. Singh,P. Venugopalan, A. Kaur, P. V. Bharatam and A. K. Sharma, J. Am.Chem. Soc., 2007, 129, 4506. For some other kinetic resolutions bydeprotonation, see; (c) J. Becker, R. Froehlich, K. Salorinne andD. Hoppe, Eur. J. Org. Chem., 2007, 3337; (d) J. Granander, F. Secci,P. O’Brien and B. Kelly, Tetrahedron: Asymmetry, 2009, 20, 2432.10 See, for example, (a) I. Coldham and D. Leonori, Org. Lett., 2008,10, 3923; (b) S. Seel, T. Thaler, K. Takatsu, C. Zhang, H. Zipse,B. F. Straub, P. Mayer and P. Knochel, J. Am. Chem. Soc., 2011,133, 4774; (c) K. D. Hesp, D. P. Fernando, W. Jiao andA. T. Londregan, Org. Lett., 2014, 16, 413; (d) Z. Zuo andD. W. C. MacMillan, J. Am. Chem. Soc., 2014, 136, 5257. See also;(e) D. Stead, G. Carbone, P. O’Brien, K. R. Campos, I. Coldham andA. Sanderson, J. Am. Chem. Soc., 2010, 132, 7260; ( f ) G. Barker,J. L. McGrath, A. Klapars, D. Stead, G. Zhou, K. R. Campos andP. O’Brien, J. Org. Chem., 2011, 76, 5936; (g) Z. Cui, H.-J. Yu,R.-F. Yang, W.-Y. Gao, C.-G. Feng and G.-Q. Lin, J. Am. Chem. Soc.,2011, 133, 12394; (h) A. Millet, P. Larini, E. Clot and O. Baudoin,Chem. Sci., 2013, 4, 2241; (i) C.-V. T. Vo and J. W. Bode, J. Org. Chem.,2014, 79, 2809.11 W. F. Bailey, P. Beak, S. T. Kerrick, S. Ma and K. B. Wiberg, J. Am.Chem. Soc., 2002, 124, 1889.12 (a) J. L. Rutherford, D. Hoffmann and D. B. Collum, J. Am. Chem.Soc., 2002, 124, 264; (b) C. Strohmann, K. Strohfeldt andD. Schildbach, J. Am. Chem. Soc., 2003, 125, 13672.13 Using the equation krel = ln[(1  C)(1  ee)]/ln[(1  C)(1 + ee)]according to H. B. Kagan and J. C. Fiaud, Top. Stereochem., 1988,18, 249.14 P. O’Brien, Chem. Commun., 2008, 655.15 X. Li and I. Coldham, J. Am. Chem. Soc., 2014, 136, 5551.Scheme 6 Lithiation-substitution of various N-Boc-2-arylpiperidines.Communication ChemCommOpen Access Article. Published on 11 July 2014. Downloaded on 11/09/2014 10:36:56.  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.View Article Online

Synthesis and kinetic resolution of N-Boc-2-arylpiperidines

The chiral base n-BuLi/(−)-sparteine or n-BuLi/(+)-sparteine surrogate promotes kinetic resolution of N-Boc-2-arylpiperidines by asymmetric deprotonation. The enantioenriched starting material was recovered with yields 39–48% and ers up to 97 : 3. On lithiation then electrophilic quench, 2,2-disubstituted piperidines were obtained with excellent yields and enantioselectivities

Cochrane, Edward J

Leonori, Daniele

Hassall, Lorraine A.

Coldham, Iain

The University of Manchester - Institutional Repository

An efficient kinetic resolution of 2-arylpiperidines was developed using a chiral base.</p

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Chemical Communications

Synthesis and kinetic resolution of <i>N</i>-Boc-2-arylpiperidines

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Synthesis and kinetic resolution of N-Boc-2-arylpiperidines

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