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Hydrogen bond directed epoxidation: diastereoselective olefinic oxidation of allylic alcohols and amines† Stephen G. Davies,* Ai M. Fletcher and James E. Thomson This article compares the diastereoselective epoxidation of acyclic and cyclic allylic alcohols, with the chemo- and diastereoselective olefinic oxidation of a range of acyclic and cyclic allylic amines. The
Received 22nd March 2014, Accepted 16th May 2014
diastereoselectivity in these systems is compared and a discussion about the origin of this high diastereocontrol is also presented. The ammonium directed epoxidation methodology has been extended to more
DOI: 10.1039/c4ob00616j
complex substrates and representative applications of this protocol in natural product synthesis are also
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summarised.
Hydrogen bond directed epoxidation of allylic alcohols Peracid-mediated olefinic epoxidation1 is arguably one of the most frequently used transformations in organic synthesis. The diastereoselective epoxidations directed by a functional group within the olefinic substrate, for example a hydroxyl Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK. E-mail: [email protected]; Fax: +44 (0)1865 275633; Tel: +44 (0)1865 275695 † This article is part of the Royal Society of Chemistry web theme issue commemorating the 65th birthday of Professor Richard J. K. Taylor.
Steve Davies is the fifth Waynflete Professor of Chemistry at the University of Oxford. He has been the recipient of numerous prizes, including the following Royal Society of Chemistry awards: Hickinbottom Fellowship, Corday Morgan Medal and Prize, Award for Organometallic Chemistry, Bader Award, Tilden Lectureship, Award for Stereochemistry, Perkin Prize for Organic Chemistry and Dr Honoris Causa Steve Davies from the University of Salamanca. He has published more than 540 papers and has research interests ranging from organometallic chemistry, asymmetric synthesis and natural product chemistry to medicinal chemistry and drug discovery.
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group via H-bonding,2 has been known since Henbest’s pioneering work in 1957.3 Henbest investigated the oxidation of 2-cyclohexene-1-ol 1 and the corresponding O-acetyl protected substrate 4 with perbenzoic acid: oxidation of 1 gave synepoxide 3 in 95 : 5 dr, whereas epoxidation of 4 showed the opposite diastereofacial selectivity, resulting in anti-epoxide 5 in 90 : 10 dr (Scheme 1). The high syn-diastereofacial selectivity observed upon epoxidation of 1 can be rationalised by a transition state in which the hydroxyl group directs the incoming peracid on the syn-face of the olefin via H-bonding. A significant number of studies concerning the detailed mechanisms of the H-bond directed oxidations have been reported, and currently the “modified Henbest” transition state 2 is widely
Ai Fletcher obtained a B.En. from Keio University, Japan, and then moved to the U.K. where she pursued Ph.D. at Imperial College London under the supervision of Dr Chris Braddock. After completing her Ph.D. in 2004, she has explored a range of chemistry topics as a post-doctoral researcher at the University of Regensburg (Professor Oliver Reiser) and at the University of Bath (Professor Michael Willis). Ai M. Fletcher In 2007 she joined the group of Professor Steve Davies in Oxford, where she has been involved in the development of the asymmetric synthetic methodology and its application to the total synthesis of natural products.
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Scheme 2 Reagents and conditions: (i) m-CPBA, CH2Cl2, 0 °C. [Ar = m-ClC6H4]. Scheme 1 Reagents and conditions: (i) PhCO3H, C6H6, 0 °C, 2.5 h; (ii) PhCO3H, C6H6, 0 °C, 31 h.
accepted.4 On the other hand, oxidation on the anti-face of the olefin within 4 occurs due to steric control or minimisation of dipole–dipole interactions.5 Furthermore, from the decreased relative rates observed upon epoxidation of 1 (Krel = 11) and 4 (Krel = 1) compared with that of cyclohexene (Krel = 20), it has been postulated3,5a that a decrease in the nucleophilicity of the double bonds within 1 and 4 is due to the inductive electron withdrawing effect of the allylic substituent. H-bond directed epoxidations of acyclic allylic alcohols with peracids have also been reported.6 For example, epoxidation of 7 and 8 with m-CPBA gave epoxides 11 and 12 in 95 : 5 dr in each case, while treatment of 6 (R1 = R2 = H) with m-CPBA proceeded to give 10 with essentially no diastereoselectivity.6a,7 The stereochemical outcome of the highly diastereoselective epoxidations of 7 and 8 is consistent with H-bond directed epoxidation via a “modified Henbest” type transition state 9 in which 1,3-allylic strain is minimised (Scheme 2). The analogous oxidations with a range of substrates with different ring sizes were studied independently by Pizzo8 and Teranishi:9 epoxidation with high syn-diastereoselectivity was observed for both 13 and 1 (84 : 16 dr and >98 : 2 dr), whereas epoxidation of 15 and 16 gave anti-epoxides 17 and 18 as the major products in 61 : 39 dr and >99 : 1 dr, respectively (Scheme 3).
Jim Thomson studied chemistry at the University of Oxford where he obtained an M.Chem. (2003) and then a D.Phil. (2007), working with Professor Steve Davies in the area of β-amino acid organocatalysis. He then took up a post-doctoral position with Professor Davies, as a Junior Research Fellow, and in 2010 he was awarded a Research Fellowship in association with St. Catherine’s College, Oxford. James E. Thomson His research interests centre upon the development of novel asymmetric transformations and the total synthesis of natural products.
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Scheme 3 Reagents and conditions: (i) m-CPBA, CH2Cl2, 0 °C, 24 h; (ii) CF3CO3H, CH2Cl2, −40 °C.
Ammonium directed epoxidation of allylic amines Fewer examples of peracid-mediated epoxidations of allylic amines have been reported in the literature10 due to the competitive N-oxidation of amines upon treatment with peracids.11 However, we have utilised amine N-oxide 20, derived from the in situ N-oxidation of 19, in a diastereoselective olefinic oxidation. Chemoselective N-oxidation of 19 with m-CPBA at 0 °C for 30 min gave 20 in situ, and subsequent further oxidation with m-CPBA in the presence of Cl3CCO2H gave 21 with high diastereoselectivity (>98 : 2 dr). Regioselective ring-opening of 21 at C(1) and transesterification of 22 gave 23 in 63% yield and >99 : 1 dr. Hydrogenolysis of 23 gave 24 in quantitative yield and >99 : 1 dr. The stereochemical outcome of this oxidation reaction indicated that the protonated form of N-oxide 20 does not promote H-bond directed oxidation but is consistent with the oxidation either under steric control or through minimisation of the dipolar interactions in the transition state (Scheme 4).12 In addition, we have developed an efficient protocol for the chemo- and diastereoselective ammonium directed oxidation of allylic amines:13 when the amine moiety is converted to the corresponding ammonium species (i.e., protected from N-oxidation) chemoselective olefinic oxidation of allylic amines is achieved.14–16 For example, in situ protection of 19 with Cl3CCO2H followed by treatment with m-CPBA gave synepoxide 26 in 95 : 5 dr, via the “modified Henbest” transition state 25.17 In situ trans-diaxial ring-opening of 26 at C(1) gave the corresponding trichloroacetate 27 with complete regioselectivity, and subsequent hydrolysis of 27 gave 28 in quantitative yield and 95 : 5 dr (Scheme 5).
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Scheme 6 Reagents and conditions: (i) m-CPBA, CH2Cl2, rt, 1 h; (ii) m-CPBA, CH2Cl2, rt, 21 h. [Ar = m-ClC6H4].
Scheme 4 Reagents and conditions: (i) m-CPBA, CH2Cl2, 0 °C, 30 min; (ii) Cl3CCO2H, m-CPBA, CH2Cl2, rt, 3 days; (iii) K2CO3, MeOH, rt, 16 h; (iv) H2 (1 atm), Pd(OH)2/C, MeOH, rt, 24 h. [Ar = m-ClC6H4].
Scheme 7 rt, 3.5 h.
Scheme 5 Reagents and conditions: (i) Cl3CCO2H, m-CPBA, CH2Cl2, rt, 21 h; (ii) K2CO3, MeOH, rt, 16 h. [Ar = m-ClC6H4].
This methodology is also applicable to acyclic allylic amines:18 for example, oxidation of either 29 or 30 with m-CPBA in the presence of Cl3CCO2H gave 32 and 33 in >99 : 1 dr in both cases. The stereochemical outcomes of these oxidation reactions are also consistent with an ammonium directed process via a “modified Henbest” type transition state 31 in which 1,3-allylic strain is minimised (Scheme 6).19 The analogous oxidations of a range of cyclic allylic amines was also studied via sequential treatment of 3-(N,N-dibenzylamino) substituted cycloalkenes 34, 36 and 37 with excess Cl3CCO2H20 and m-CPBA. Epoxidation of 34 proceeded with high syn-diastereoselectivity (>99 : 1 dr) which was consistent with the syn-selectivity observed upon the H-bond directed epoxidation of the corresponding 3-hydroxy substituted cycloalkene 13. Epoxidation of 36 and 37 gave 38 and 39 in 94 : 6 dr and >99 : 1 dr, respectively (Scheme 7). The detailed mechanistic aspects of this reaction were investigated by comparing the H-bond directing ability of amino groups bearing different N-substituents (R = H, Me, i Pr and Bn).13d Based on the kinetic data obtained in this
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Reagents and conditions: (i) Cl3CCO2H, m-CPBA, CH2Cl2,
study both the ring size, and the identity and number of the substituents on nitrogen are important in determining both the overall rate and stereochemical outcome of the epoxidation reaction: secondary amines or tertiary amines with non-sterically demanding substituents (R = H and Me) on nitrogen are superior to tertiary amines with sterically demanding substituents (R = Bn and iPr) in their ability to promote the oxidation reaction. This is presumably due to the reduction of the steric bulk of the ammonium moiety which may then achieve the optimum reactive conformation more easily. Furthermore, in all cases, the ability of the (in situ formed) ammoniumsubstituent to direct the epoxidation reaction is either comparable or superior to that of the analogous hydroxyl substituent, which could also be ( partially) due to minimisation of torsional strain.21
Origin of the diastereoselectivity The stereochemical outcomes of these H-bond directed oxidations can be rationalised by considering the reactive conformations. In acyclic systems 40, the diastereoselectivity is driven by minimisation of 1,3-allylic strain, as in the large ring size substrates (≥8-membered rings) 43, which give antiepoxides 42 and 45, respectively, as the major products. However, the normal ring substrates (5 and 6-membered rings) 46 have little conformational flexibility, and H-bond directed epoxidation results in syn-epoxides 48. The superior diastereoselectivity observed in the oxidation of 7-membered ring allylic amine 36 (94 : 6 dr) over that of the corresponding allylic alcohol 17 (61 : 39 dr) is presumably due to the fact that the N,N-dibenzylammonium group allows for a more defined reactive conformation (Fig. 1). Contrary to the conventional
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Fig. 1 Stereochemical rationale for the oxidation of cyclic allylic alcohols and amines. [X = O or +NR2].
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Scheme 8 Reagents and conditions: (i) HBF4 (40% aq.), m-CPBA, CH2Cl2, rt, 48 h; (ii) H2 (5 atm), Pd(OH)2/C, Boc2O, EtOAc, rt, 48 h; (iii) DIBAL-H, CH2Cl2, −78 °C, 30 min; (iv) MeOH, HCl, rt, 48 h; (v) Ac2O, pyridine, DMAP, rt, 30 min.
dogma, the 5- and 6-membered ring substrates (such as 1 used by Henbest in his seminal work)3 are somewhat anomalous in that syn-epoxides resulted from their H-bond directed epoxidations, as opposed to the acyclic and large ring substrates in which anti-epoxides are formed.
Applications of the ammonium directed epoxidation methodology in target syntheses The chemo- and diastereoselective epoxidation of allylic amines with m-CPBA in the presence of Brønsted acids has been employed in target syntheses of various natural products of biological significance.18a,b,22,23 For example, treatment of enantiopure allylic amine 49 [which is readily derived from conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to methyl sorbate]24 with 40% aq. HBF4 followed by m-CPBA gave an ∼70 : 30 mixture of lactones 52 and 53. This is consistent with a mechanism whereby highly diastereoselective (>95 : 5 dr) ammonium directed epoxidation of 49, followed by regioselective ring-opening at the C(5) position within 50 with water to give 51. Subsequent in situ lactonisation gave a 70 : 30 mixture of 52 and 53, which was converted to 54, a protected form of L-acosamine, over a four step procedure (Scheme 8). An analogues strategy was also used in synthesis of 55, a protected form of D-3-epi-α-daunosamine.22b The transannular ammonium directed epoxidation of bishomoallylic amine was also demonstrated as the key step in a total synthesis of (−)-isoretronecanol 62: conjugate addition of lithium amide (S)-57 to 56, followed by alkylation of the
Org. Biomol. Chem.
Scheme 9 Reagents and conditions: (i) (S)-57, THF, −78 °C, 2 h then allyl bromide, −78 °C to rt, 18 h; (ii) Grubbs I, CH2Cl2, 35 °C, 18 h; (iii) KHMDS, tBuOH, THF, rt, 18 h; (iv) HBF4 (40% aq.), m-CPBA, CH2Cl2, rt, 48 h; (v) LiAlH4, THF, 0 °C, 2 h; (vi) NaIO4, MeOH, rt, 1 h; (vii) H2 (5 atm), Pd(OH)2/C, MeOH–AcOH (19 : 1), rt, 24 h.
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resultant lithium (Z)-β-amino enolate25 with allyl bromide, gave β-amino ester 58 in 60% yield and 85 : 15 dr. Treatment of 58 with Grubbs I catalyst followed by treatment with KOtBu gave 59 in 70% yield and >99 : 1 dr. Key intermediate 59 was treated under our ammonium directed oxidation conditions (HBF4 and m-CPBA) followed by in situ acid-mediated ringopening/lactonisation to give 60 with complete diastereo- and regioselectivity. Reduction of 60 with LiAlH4 gave 61 in 80% yield and >99 : 1 dr. Treatment of 61 with NaIO4 gave the corresponding dialdehyde which was followed by hydrogenolytic removal of the N-protecting groups, also facilitating in situ cyclisation/reduction of the resultant imines to give (−)-isoretronecanol 62 in 65% yield and >99 : 1 dr (Scheme 9).22c,26
Conclusions In conclusion, the origin of diastereoselectivity in the H-bond directed epoxidations of allylic alcohols and allylic amines is compared. Ammonium directed oxidation of allylic amines with peracids in the presence of a Brønsted acid, such as Cl3CCO2H, has shown both excellent diastereoselectivity and isolated yields. This robust and reliable methodology has many potential benefits for synthesis.
Notes and references 1 N. Prileschajew, Chem. Ber., 1909, 42, 4811. 2 (a) P. Chamberlain, M. L. Roberts and G. H. Whitham, J. Chem. Soc. B, 1970, 1374; (b) R. B. Dehnel and G. H. Whitham, J. Chem. Soc., Perkin Trans. 1, 1979, 954. 3 H. B. Henbest and R. A. L. Wilson, J. Chem. Soc., 1957, 1958. 4 (a) M. Freccero, R. Gandolfi, M. Sarzi-Amadè and A. Rastelli, J. Org. Chem., 2004, 69, 7479; (b) M. Freccero, R. Gandolfi, M. Sarzi-Amadè and A. Rastelli, J. Org. Chem., 2005, 70, 9573. 5 (a) H. B. Henbest, Proc. Chem. Soc., 1963, 159; (b) H. B. Henbest, B. Nicholls, W. R. Jackson, R. A. L. Wilson, N. S. Crossley, M. B. Meyers and R. S. McElhinney, Bull. Soc. Chim. Fr., 1960, 1365; (c) N. S. Crossley, A. C. Darby, H. B. Henbest, J. J. McCullough, B. Nicholls and M. F. Stewart, Tetrahedron Lett., 1961, 2, 398. 6 For example, see: (a) W. Adam and B. Nestler, Tetrahedron Lett., 1993, 34, 611; (b) M. R. Johnson and Y. Kishi, Tetrahedron Lett., 1979, 20, 4347; (c) A. K. Ghosh and Y. Wang, J. Org. Chem., 1999, 64, 2789. 7 B. E. Rossiter, T. R. Verhoeven and K. B. Sharpless, Tetrahedron Lett., 1979, 20, 4733. 8 D. Ye, F. Fringuelli, O. Piermatti and F. Pizzo, J. Org. Chem., 1997, 62, 3748. 9 T. Itoh, K. Kaneda and S. Teranishi, J. Chem. Soc., Chem. Commun., 1976, 421.
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10 (a) J. Quick, Y. Khandelwal, P. C. Meltzer and J. S. Weinberg, J. Org. Chem., 1983, 48, 5199; (b) J. Quick, C. Mondello, M. Humora and T. Brennan, J. Org. Chem., 1978, 43, 2705; (c) W. D. Emmons, A. S. Pagano and J. P. Freeman, J. Am. Chem. Soc., 1954, 76, 3472; (d) L. Gil, D. Compère, B. Guilloteau-Bertin, A. Chiaroni and C. Marazano, Synthesis, 2000, 2117; (e) G. V. Grishina, A. A. Borisenko, I. S. Veselov and A. M. Petrenko, Russ. J. Org. Chem., 2005, 41, 272. 11 S. Miyano, L. D.-L. Lu, S. M. Viti and K. B. Sharpless, J. Org. Chem., 1985, 50, 4350. 12 C. Aciro, S. G. Davies, W. Kurosawa, P. M. Roberts, A. J. Russell and J. E. Thomson, Org. Lett., 2009, 11, 1333. 13 (a) C. Aciro, T. D. W. Claridge, S. G. Davies, P. M. Roberts, A. J. Russell and J. E. Thomson, Org. Biomol. Chem., 2008, 6, 3751; (b) C. Aciro, S. G. Davies, P. M. Roberts, A. J. Russell, A. D. Smith and J. E. Thomson, Org. Biomol. Chem., 2008, 6, 3762; (c) C. W. Bond, A. J. Cresswell, S. G. Davies, A. M. Fletcher, W. Kurosawa, J. A. Lee, P. M. Roberts, A. J. Russell, A. D. Smith and J. E. Thomson, J. Org. Chem., 2009, 74, 6735; (d) M. B. Brennan, T. D. W. Claridge, R. G. Compton, S. G. Davies, A. M. Fletcher, M. C. Henstridge, D. S. Hewings, W. Kurosawa, J. A. Lee, P. M. Roberts, A. K. Schoonen and J. E. Thomson, J. Org. Chem., 2012, 77, 7241; (e) A. J. Cresswell, S. G. Davies, D. S. Hewings, W. Kurosawa, J. A. Lee, M. J. Morris, P. M. Roberts, A. L. Thompson and J. E. Thomson, J. Chem. Crystallogr., 2013, 43, 646; (f ) S. G. Davies, D. S. Hewings, W. Kurosawa, J. A. Lee, P. M. Roberts, A. L. Thompson and J. E. Thomson, J. Chem. Crystallogr., 2014, 44, 30. 14 (a) G. Asensio, R. Mello, C. Boix-Bernardini, M. E. González-Núñez and G. Castellano, J. Org. Chem., 1995, 60, 3692; (b) G. Asensio, C. Boix-Bernardini, C. Andreu, M. E. González-Núñez, R. Mello, J. O. Edwards and G. B. Carpenter, J. Org. Chem., 1999, 64, 4705; (c) G. Asensio, M. E. González-Núñez, C. B. Bernardini, R. Mello and W. Adam, J. Am. Chem. Soc., 1993, 115, 7250. 15 V. K. Aggarwal and G. Y. Fang, Chem. Commun., 2005, 3448. 16 A. S. Edwards, R. A. J. Wybrow, C. Johnstone, H. Adams and J. P. A. Harrity, Chem. Commun., 2002, 1542. 17 The diastereoselectivity upon the epoxidation was determined based on the established completely regioselective ring-opening of the corresponding epoxide 26 upon treatment with Cl3CCO2H; see: ref. 13a. 18 (a) A. J. Cresswell, S. G. Davies, J. A. Lee, M. J. Morris, P. M. Roberts and J. E. Thomson, J. Org. Chem., 2012, 77, 7262; (b) A. J. Cresswell, S. G. Davies, J. A. Lee, M. J. Morris, P. M. Roberts and J. E. Thomson, J. Org. Chem., 2011, 76, 4617; (c) S. G. Davies, A. M. Fletcher, W. Kurosawa, J. A. Lee, G. Poce, P. M. Roberts, J. E. Thomson and D. M. Williamson, J. Org. Chem., 2010, 75, 7745. 19 We have also reported highly diastereoselective substrate controlled cyclopropanation of tertiary allylic amine, see: (a) S. G. Davies, K. B. Ling, P. M. Roberts, A. J. Russell and J. E. Thomson, Chem. Commun., 2007, 4029; (b) K. Csatayová,
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S. G. Davies, J. A. Lee, K. B. Ling, P. M. Roberts, A. J. Russell and J. E. Thomson, Tetrahedron, 2010, 66, 8420. 20 It is noted that in the place of Cl3CCO2H, various other Brønsted acids such as TsOH, AcOH, CF3CO2H and H2SO4 can be employed; see: ref. 13a and b. 21 (a) G. Poli, Tetrahedron Lett., 1989, 30, 7385; (b) P. H.-Y. Cheong, H. Yun, S. J. Danishefsky and K. N. Houk, Org. Lett., 2006, 8, 1513. 22 (a) S. K. Bagal, S. G. Davies, A. M. Fletcher, J. A. Lee, P. M. Roberts, P. M. Scott and J. E. Thomson, Tetrahedron Lett., 2011, 52, 2216; (b) K. Csatayová, S. G. Davies, J. G. Ford, J. A. Lee, P. M. Roberts and J. E. Thomson, J. Org. Chem., 2013, 78, 12397; (c) M. Brambilla, S. G. Davies, A. M. Fletcher, P. M. Roberts and J. E. Thomson, Tetrahedron, 2014, 70, 204; (d) S. K. Bagal, S. G. Davies, J. A. Lee, P. M. Roberts, A. J. Russell, P. M. Scott and J. E. Thomson, Org. Lett., 2010, 12, 136; (e) S. K. Bagal, S. G. Davies,
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24
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26
J. A. Lee, P. M. Roberts, P. M. Scott and J. E. Thomson, J. Org. Chem., 2010, 75, 8133. (a) Y. Xie, M. Sun, H. Zhou, Q. Cao, K. Gao, C. Niu and H. Yang, J. Org. Chem., 2013, 78, 10251; (b) V. A. McKay, S. J. Thompson, P. M. Tran, K. J. Goodall, M. A. Brimble and D. Barker, Synlett, 2010, 2631. The diastereoselective conjugate addition of enantiopure lithium amides to α,β-unsaturated esters has been reviewed; see: (a) S. G. Davies, A. D. Smith and P. D. Price, Tetrahedron: Asymmetry, 2005, 16, 2833; (b) S. G. Davies, A. M. Fletcher, P. M. Roberts and J. E. Thomson, Tetrahedron: Asymmetry, 2012, 23, 1111. (a) S. G. Davies and I. A. S. Walters, J. Chem. Soc., Perkin Trans. 1, 1994, 1129; (b) S. G. Davies, E. M. Foster, C. R. McIntosh, P. M. Roberts, T. E. Rosser, A. D. Smith and J. E. Thomson, Tetrahedron: Asymmetry, 2011, 22, 1035. M. Brambilla, S. G. Davies, A. M. Fletcher and J. E. Thomson, Tetrahedron: Asymmetry, 2014, 25, 387.
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Hydrogen bond directed epoxidation: diastereoselective olefinic oxidation of allylic alcohols and amines† Stephen G. Davies,* Ai M. Fletcher and James E. Thomson This article compares the diastereoselective epoxidation of acyclic and cyclic allylic alcohols, with the chemo- and diastereoselective olefinic oxidation of a range of acyclic and cyclic allylic amines. The
Received 22nd March 2014, Accepted 16th May 2014
diastereoselectivity in these systems is compared and a discussion about the origin of this high diastereocontrol is also presented. The ammonium directed epoxidation methodology has been extended to more
DOI: 10.1039/c4ob00616j
complex substrates and representative applications of this protocol in natural product synthesis are also
www.rsc.org/obc
summarised.
Hydrogen bond directed epoxidation of allylic alcohols Peracid-mediated olefinic epoxidation1 is arguably one of the most frequently used transformations in organic synthesis. The diastereoselective epoxidations directed by a functional group within the olefinic substrate, for example a hydroxyl Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK. E-mail: [email protected]; Fax: +44 (0)1865 275633; Tel: +44 (0)1865 275695 † This article is part of the Royal Society of Chemistry web theme issue commemorating the 65th birthday of Professor Richard J. K. Taylor.
Steve Davies is the fifth Waynflete Professor of Chemistry at the University of Oxford. He has been the recipient of numerous prizes, including the following Royal Society of Chemistry awards: Hickinbottom Fellowship, Corday Morgan Medal and Prize, Award for Organometallic Chemistry, Bader Award, Tilden Lectureship, Award for Stereochemistry, Perkin Prize for Organic Chemistry and Dr Honoris Causa Steve Davies from the University of Salamanca. He has published more than 540 papers and has research interests ranging from organometallic chemistry, asymmetric synthesis and natural product chemistry to medicinal chemistry and drug discovery.
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group via H-bonding,2 has been known since Henbest’s pioneering work in 1957.3 Henbest investigated the oxidation of 2-cyclohexene-1-ol 1 and the corresponding O-acetyl protected substrate 4 with perbenzoic acid: oxidation of 1 gave synepoxide 3 in 95 : 5 dr, whereas epoxidation of 4 showed the opposite diastereofacial selectivity, resulting in anti-epoxide 5 in 90 : 10 dr (Scheme 1). The high syn-diastereofacial selectivity observed upon epoxidation of 1 can be rationalised by a transition state in which the hydroxyl group directs the incoming peracid on the syn-face of the olefin via H-bonding. A significant number of studies concerning the detailed mechanisms of the H-bond directed oxidations have been reported, and currently the “modified Henbest” transition state 2 is widely
Ai Fletcher obtained a B.En. from Keio University, Japan, and then moved to the U.K. where she pursued Ph.D. at Imperial College London under the supervision of Dr Chris Braddock. After completing her Ph.D. in 2004, she has explored a range of chemistry topics as a post-doctoral researcher at the University of Regensburg (Professor Oliver Reiser) and at the University of Bath (Professor Michael Willis). Ai M. Fletcher In 2007 she joined the group of Professor Steve Davies in Oxford, where she has been involved in the development of the asymmetric synthetic methodology and its application to the total synthesis of natural products.
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Scheme 2 Reagents and conditions: (i) m-CPBA, CH2Cl2, 0 °C. [Ar = m-ClC6H4]. Scheme 1 Reagents and conditions: (i) PhCO3H, C6H6, 0 °C, 2.5 h; (ii) PhCO3H, C6H6, 0 °C, 31 h.
accepted.4 On the other hand, oxidation on the anti-face of the olefin within 4 occurs due to steric control or minimisation of dipole–dipole interactions.5 Furthermore, from the decreased relative rates observed upon epoxidation of 1 (Krel = 11) and 4 (Krel = 1) compared with that of cyclohexene (Krel = 20), it has been postulated3,5a that a decrease in the nucleophilicity of the double bonds within 1 and 4 is due to the inductive electron withdrawing effect of the allylic substituent. H-bond directed epoxidations of acyclic allylic alcohols with peracids have also been reported.6 For example, epoxidation of 7 and 8 with m-CPBA gave epoxides 11 and 12 in 95 : 5 dr in each case, while treatment of 6 (R1 = R2 = H) with m-CPBA proceeded to give 10 with essentially no diastereoselectivity.6a,7 The stereochemical outcome of the highly diastereoselective epoxidations of 7 and 8 is consistent with H-bond directed epoxidation via a “modified Henbest” type transition state 9 in which 1,3-allylic strain is minimised (Scheme 2). The analogous oxidations with a range of substrates with different ring sizes were studied independently by Pizzo8 and Teranishi:9 epoxidation with high syn-diastereoselectivity was observed for both 13 and 1 (84 : 16 dr and >98 : 2 dr), whereas epoxidation of 15 and 16 gave anti-epoxides 17 and 18 as the major products in 61 : 39 dr and >99 : 1 dr, respectively (Scheme 3).
Jim Thomson studied chemistry at the University of Oxford where he obtained an M.Chem. (2003) and then a D.Phil. (2007), working with Professor Steve Davies in the area of β-amino acid organocatalysis. He then took up a post-doctoral position with Professor Davies, as a Junior Research Fellow, and in 2010 he was awarded a Research Fellowship in association with St. Catherine’s College, Oxford. James E. Thomson His research interests centre upon the development of novel asymmetric transformations and the total synthesis of natural products.
Org. Biomol. Chem.
Scheme 3 Reagents and conditions: (i) m-CPBA, CH2Cl2, 0 °C, 24 h; (ii) CF3CO3H, CH2Cl2, −40 °C.
Ammonium directed epoxidation of allylic amines Fewer examples of peracid-mediated epoxidations of allylic amines have been reported in the literature10 due to the competitive N-oxidation of amines upon treatment with peracids.11 However, we have utilised amine N-oxide 20, derived from the in situ N-oxidation of 19, in a diastereoselective olefinic oxidation. Chemoselective N-oxidation of 19 with m-CPBA at 0 °C for 30 min gave 20 in situ, and subsequent further oxidation with m-CPBA in the presence of Cl3CCO2H gave 21 with high diastereoselectivity (>98 : 2 dr). Regioselective ring-opening of 21 at C(1) and transesterification of 22 gave 23 in 63% yield and >99 : 1 dr. Hydrogenolysis of 23 gave 24 in quantitative yield and >99 : 1 dr. The stereochemical outcome of this oxidation reaction indicated that the protonated form of N-oxide 20 does not promote H-bond directed oxidation but is consistent with the oxidation either under steric control or through minimisation of the dipolar interactions in the transition state (Scheme 4).12 In addition, we have developed an efficient protocol for the chemo- and diastereoselective ammonium directed oxidation of allylic amines:13 when the amine moiety is converted to the corresponding ammonium species (i.e., protected from N-oxidation) chemoselective olefinic oxidation of allylic amines is achieved.14–16 For example, in situ protection of 19 with Cl3CCO2H followed by treatment with m-CPBA gave synepoxide 26 in 95 : 5 dr, via the “modified Henbest” transition state 25.17 In situ trans-diaxial ring-opening of 26 at C(1) gave the corresponding trichloroacetate 27 with complete regioselectivity, and subsequent hydrolysis of 27 gave 28 in quantitative yield and 95 : 5 dr (Scheme 5).
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Scheme 6 Reagents and conditions: (i) m-CPBA, CH2Cl2, rt, 1 h; (ii) m-CPBA, CH2Cl2, rt, 21 h. [Ar = m-ClC6H4].
Scheme 4 Reagents and conditions: (i) m-CPBA, CH2Cl2, 0 °C, 30 min; (ii) Cl3CCO2H, m-CPBA, CH2Cl2, rt, 3 days; (iii) K2CO3, MeOH, rt, 16 h; (iv) H2 (1 atm), Pd(OH)2/C, MeOH, rt, 24 h. [Ar = m-ClC6H4].
Scheme 7 rt, 3.5 h.
Scheme 5 Reagents and conditions: (i) Cl3CCO2H, m-CPBA, CH2Cl2, rt, 21 h; (ii) K2CO3, MeOH, rt, 16 h. [Ar = m-ClC6H4].
This methodology is also applicable to acyclic allylic amines:18 for example, oxidation of either 29 or 30 with m-CPBA in the presence of Cl3CCO2H gave 32 and 33 in >99 : 1 dr in both cases. The stereochemical outcomes of these oxidation reactions are also consistent with an ammonium directed process via a “modified Henbest” type transition state 31 in which 1,3-allylic strain is minimised (Scheme 6).19 The analogous oxidations of a range of cyclic allylic amines was also studied via sequential treatment of 3-(N,N-dibenzylamino) substituted cycloalkenes 34, 36 and 37 with excess Cl3CCO2H20 and m-CPBA. Epoxidation of 34 proceeded with high syn-diastereoselectivity (>99 : 1 dr) which was consistent with the syn-selectivity observed upon the H-bond directed epoxidation of the corresponding 3-hydroxy substituted cycloalkene 13. Epoxidation of 36 and 37 gave 38 and 39 in 94 : 6 dr and >99 : 1 dr, respectively (Scheme 7). The detailed mechanistic aspects of this reaction were investigated by comparing the H-bond directing ability of amino groups bearing different N-substituents (R = H, Me, i Pr and Bn).13d Based on the kinetic data obtained in this
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Reagents and conditions: (i) Cl3CCO2H, m-CPBA, CH2Cl2,
study both the ring size, and the identity and number of the substituents on nitrogen are important in determining both the overall rate and stereochemical outcome of the epoxidation reaction: secondary amines or tertiary amines with non-sterically demanding substituents (R = H and Me) on nitrogen are superior to tertiary amines with sterically demanding substituents (R = Bn and iPr) in their ability to promote the oxidation reaction. This is presumably due to the reduction of the steric bulk of the ammonium moiety which may then achieve the optimum reactive conformation more easily. Furthermore, in all cases, the ability of the (in situ formed) ammoniumsubstituent to direct the epoxidation reaction is either comparable or superior to that of the analogous hydroxyl substituent, which could also be ( partially) due to minimisation of torsional strain.21
Origin of the diastereoselectivity The stereochemical outcomes of these H-bond directed oxidations can be rationalised by considering the reactive conformations. In acyclic systems 40, the diastereoselectivity is driven by minimisation of 1,3-allylic strain, as in the large ring size substrates (≥8-membered rings) 43, which give antiepoxides 42 and 45, respectively, as the major products. However, the normal ring substrates (5 and 6-membered rings) 46 have little conformational flexibility, and H-bond directed epoxidation results in syn-epoxides 48. The superior diastereoselectivity observed in the oxidation of 7-membered ring allylic amine 36 (94 : 6 dr) over that of the corresponding allylic alcohol 17 (61 : 39 dr) is presumably due to the fact that the N,N-dibenzylammonium group allows for a more defined reactive conformation (Fig. 1). Contrary to the conventional
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Fig. 1 Stereochemical rationale for the oxidation of cyclic allylic alcohols and amines. [X = O or +NR2].
Organic & Biomolecular Chemistry
Scheme 8 Reagents and conditions: (i) HBF4 (40% aq.), m-CPBA, CH2Cl2, rt, 48 h; (ii) H2 (5 atm), Pd(OH)2/C, Boc2O, EtOAc, rt, 48 h; (iii) DIBAL-H, CH2Cl2, −78 °C, 30 min; (iv) MeOH, HCl, rt, 48 h; (v) Ac2O, pyridine, DMAP, rt, 30 min.
dogma, the 5- and 6-membered ring substrates (such as 1 used by Henbest in his seminal work)3 are somewhat anomalous in that syn-epoxides resulted from their H-bond directed epoxidations, as opposed to the acyclic and large ring substrates in which anti-epoxides are formed.
Applications of the ammonium directed epoxidation methodology in target syntheses The chemo- and diastereoselective epoxidation of allylic amines with m-CPBA in the presence of Brønsted acids has been employed in target syntheses of various natural products of biological significance.18a,b,22,23 For example, treatment of enantiopure allylic amine 49 [which is readily derived from conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to methyl sorbate]24 with 40% aq. HBF4 followed by m-CPBA gave an ∼70 : 30 mixture of lactones 52 and 53. This is consistent with a mechanism whereby highly diastereoselective (>95 : 5 dr) ammonium directed epoxidation of 49, followed by regioselective ring-opening at the C(5) position within 50 with water to give 51. Subsequent in situ lactonisation gave a 70 : 30 mixture of 52 and 53, which was converted to 54, a protected form of L-acosamine, over a four step procedure (Scheme 8). An analogues strategy was also used in synthesis of 55, a protected form of D-3-epi-α-daunosamine.22b The transannular ammonium directed epoxidation of bishomoallylic amine was also demonstrated as the key step in a total synthesis of (−)-isoretronecanol 62: conjugate addition of lithium amide (S)-57 to 56, followed by alkylation of the
Org. Biomol. Chem.
Scheme 9 Reagents and conditions: (i) (S)-57, THF, −78 °C, 2 h then allyl bromide, −78 °C to rt, 18 h; (ii) Grubbs I, CH2Cl2, 35 °C, 18 h; (iii) KHMDS, tBuOH, THF, rt, 18 h; (iv) HBF4 (40% aq.), m-CPBA, CH2Cl2, rt, 48 h; (v) LiAlH4, THF, 0 °C, 2 h; (vi) NaIO4, MeOH, rt, 1 h; (vii) H2 (5 atm), Pd(OH)2/C, MeOH–AcOH (19 : 1), rt, 24 h.
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resultant lithium (Z)-β-amino enolate25 with allyl bromide, gave β-amino ester 58 in 60% yield and 85 : 15 dr. Treatment of 58 with Grubbs I catalyst followed by treatment with KOtBu gave 59 in 70% yield and >99 : 1 dr. Key intermediate 59 was treated under our ammonium directed oxidation conditions (HBF4 and m-CPBA) followed by in situ acid-mediated ringopening/lactonisation to give 60 with complete diastereo- and regioselectivity. Reduction of 60 with LiAlH4 gave 61 in 80% yield and >99 : 1 dr. Treatment of 61 with NaIO4 gave the corresponding dialdehyde which was followed by hydrogenolytic removal of the N-protecting groups, also facilitating in situ cyclisation/reduction of the resultant imines to give (−)-isoretronecanol 62 in 65% yield and >99 : 1 dr (Scheme 9).22c,26
Conclusions In conclusion, the origin of diastereoselectivity in the H-bond directed epoxidations of allylic alcohols and allylic amines is compared. Ammonium directed oxidation of allylic amines with peracids in the presence of a Brønsted acid, such as Cl3CCO2H, has shown both excellent diastereoselectivity and isolated yields. This robust and reliable methodology has many potential benefits for synthesis.
Notes and references 1 N. Prileschajew, Chem. Ber., 1909, 42, 4811. 2 (a) P. Chamberlain, M. L. Roberts and G. H. Whitham, J. Chem. Soc. B, 1970, 1374; (b) R. B. Dehnel and G. H. Whitham, J. Chem. Soc., Perkin Trans. 1, 1979, 954. 3 H. B. Henbest and R. A. L. Wilson, J. Chem. Soc., 1957, 1958. 4 (a) M. Freccero, R. Gandolfi, M. Sarzi-Amadè and A. Rastelli, J. Org. Chem., 2004, 69, 7479; (b) M. Freccero, R. Gandolfi, M. Sarzi-Amadè and A. Rastelli, J. Org. Chem., 2005, 70, 9573. 5 (a) H. B. Henbest, Proc. Chem. Soc., 1963, 159; (b) H. B. Henbest, B. Nicholls, W. R. Jackson, R. A. L. Wilson, N. S. Crossley, M. B. Meyers and R. S. McElhinney, Bull. Soc. Chim. Fr., 1960, 1365; (c) N. S. Crossley, A. C. Darby, H. B. Henbest, J. J. McCullough, B. Nicholls and M. F. Stewart, Tetrahedron Lett., 1961, 2, 398. 6 For example, see: (a) W. Adam and B. Nestler, Tetrahedron Lett., 1993, 34, 611; (b) M. R. Johnson and Y. Kishi, Tetrahedron Lett., 1979, 20, 4347; (c) A. K. Ghosh and Y. Wang, J. Org. Chem., 1999, 64, 2789. 7 B. E. Rossiter, T. R. Verhoeven and K. B. Sharpless, Tetrahedron Lett., 1979, 20, 4733. 8 D. Ye, F. Fringuelli, O. Piermatti and F. Pizzo, J. Org. Chem., 1997, 62, 3748. 9 T. Itoh, K. Kaneda and S. Teranishi, J. Chem. Soc., Chem. Commun., 1976, 421.
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10 (a) J. Quick, Y. Khandelwal, P. C. Meltzer and J. S. Weinberg, J. Org. Chem., 1983, 48, 5199; (b) J. Quick, C. Mondello, M. Humora and T. Brennan, J. Org. Chem., 1978, 43, 2705; (c) W. D. Emmons, A. S. Pagano and J. P. Freeman, J. Am. Chem. Soc., 1954, 76, 3472; (d) L. Gil, D. Compère, B. Guilloteau-Bertin, A. Chiaroni and C. Marazano, Synthesis, 2000, 2117; (e) G. V. Grishina, A. A. Borisenko, I. S. Veselov and A. M. Petrenko, Russ. J. Org. Chem., 2005, 41, 272. 11 S. Miyano, L. D.-L. Lu, S. M. Viti and K. B. Sharpless, J. Org. Chem., 1985, 50, 4350. 12 C. Aciro, S. G. Davies, W. Kurosawa, P. M. Roberts, A. J. Russell and J. E. Thomson, Org. Lett., 2009, 11, 1333. 13 (a) C. Aciro, T. D. W. Claridge, S. G. Davies, P. M. Roberts, A. J. Russell and J. E. Thomson, Org. Biomol. Chem., 2008, 6, 3751; (b) C. Aciro, S. G. Davies, P. M. Roberts, A. J. Russell, A. D. Smith and J. E. Thomson, Org. Biomol. Chem., 2008, 6, 3762; (c) C. W. Bond, A. J. Cresswell, S. G. Davies, A. M. Fletcher, W. Kurosawa, J. A. Lee, P. M. Roberts, A. J. Russell, A. D. Smith and J. E. Thomson, J. Org. Chem., 2009, 74, 6735; (d) M. B. Brennan, T. D. W. Claridge, R. G. Compton, S. G. Davies, A. M. Fletcher, M. C. Henstridge, D. S. Hewings, W. Kurosawa, J. A. Lee, P. M. Roberts, A. K. Schoonen and J. E. Thomson, J. Org. Chem., 2012, 77, 7241; (e) A. J. Cresswell, S. G. Davies, D. S. Hewings, W. Kurosawa, J. A. Lee, M. J. Morris, P. M. Roberts, A. L. Thompson and J. E. Thomson, J. Chem. Crystallogr., 2013, 43, 646; (f ) S. G. Davies, D. S. Hewings, W. Kurosawa, J. A. Lee, P. M. Roberts, A. L. Thompson and J. E. Thomson, J. Chem. Crystallogr., 2014, 44, 30. 14 (a) G. Asensio, R. Mello, C. Boix-Bernardini, M. E. González-Núñez and G. Castellano, J. Org. Chem., 1995, 60, 3692; (b) G. Asensio, C. Boix-Bernardini, C. Andreu, M. E. González-Núñez, R. Mello, J. O. Edwards and G. B. Carpenter, J. Org. Chem., 1999, 64, 4705; (c) G. Asensio, M. E. González-Núñez, C. B. Bernardini, R. Mello and W. Adam, J. Am. Chem. Soc., 1993, 115, 7250. 15 V. K. Aggarwal and G. Y. Fang, Chem. Commun., 2005, 3448. 16 A. S. Edwards, R. A. J. Wybrow, C. Johnstone, H. Adams and J. P. A. Harrity, Chem. Commun., 2002, 1542. 17 The diastereoselectivity upon the epoxidation was determined based on the established completely regioselective ring-opening of the corresponding epoxide 26 upon treatment with Cl3CCO2H; see: ref. 13a. 18 (a) A. J. Cresswell, S. G. Davies, J. A. Lee, M. J. Morris, P. M. Roberts and J. E. Thomson, J. Org. Chem., 2012, 77, 7262; (b) A. J. Cresswell, S. G. Davies, J. A. Lee, M. J. Morris, P. M. Roberts and J. E. Thomson, J. Org. Chem., 2011, 76, 4617; (c) S. G. Davies, A. M. Fletcher, W. Kurosawa, J. A. Lee, G. Poce, P. M. Roberts, J. E. Thomson and D. M. Williamson, J. Org. Chem., 2010, 75, 7745. 19 We have also reported highly diastereoselective substrate controlled cyclopropanation of tertiary allylic amine, see: (a) S. G. Davies, K. B. Ling, P. M. Roberts, A. J. Russell and J. E. Thomson, Chem. Commun., 2007, 4029; (b) K. Csatayová,
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S. G. Davies, J. A. Lee, K. B. Ling, P. M. Roberts, A. J. Russell and J. E. Thomson, Tetrahedron, 2010, 66, 8420. 20 It is noted that in the place of Cl3CCO2H, various other Brønsted acids such as TsOH, AcOH, CF3CO2H and H2SO4 can be employed; see: ref. 13a and b. 21 (a) G. Poli, Tetrahedron Lett., 1989, 30, 7385; (b) P. H.-Y. Cheong, H. Yun, S. J. Danishefsky and K. N. Houk, Org. Lett., 2006, 8, 1513. 22 (a) S. K. Bagal, S. G. Davies, A. M. Fletcher, J. A. Lee, P. M. Roberts, P. M. Scott and J. E. Thomson, Tetrahedron Lett., 2011, 52, 2216; (b) K. Csatayová, S. G. Davies, J. G. Ford, J. A. Lee, P. M. Roberts and J. E. Thomson, J. Org. Chem., 2013, 78, 12397; (c) M. Brambilla, S. G. Davies, A. M. Fletcher, P. M. Roberts and J. E. Thomson, Tetrahedron, 2014, 70, 204; (d) S. K. Bagal, S. G. Davies, J. A. Lee, P. M. Roberts, A. J. Russell, P. M. Scott and J. E. Thomson, Org. Lett., 2010, 12, 136; (e) S. K. Bagal, S. G. Davies,
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Organic & Biomolecular Chemistry
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J. A. Lee, P. M. Roberts, P. M. Scott and J. E. Thomson, J. Org. Chem., 2010, 75, 8133. (a) Y. Xie, M. Sun, H. Zhou, Q. Cao, K. Gao, C. Niu and H. Yang, J. Org. Chem., 2013, 78, 10251; (b) V. A. McKay, S. J. Thompson, P. M. Tran, K. J. Goodall, M. A. Brimble and D. Barker, Synlett, 2010, 2631. The diastereoselective conjugate addition of enantiopure lithium amides to α,β-unsaturated esters has been reviewed; see: (a) S. G. Davies, A. D. Smith and P. D. Price, Tetrahedron: Asymmetry, 2005, 16, 2833; (b) S. G. Davies, A. M. Fletcher, P. M. Roberts and J. E. Thomson, Tetrahedron: Asymmetry, 2012, 23, 1111. (a) S. G. Davies and I. A. S. Walters, J. Chem. Soc., Perkin Trans. 1, 1994, 1129; (b) S. G. Davies, E. M. Foster, C. R. McIntosh, P. M. Roberts, T. E. Rosser, A. D. Smith and J. E. Thomson, Tetrahedron: Asymmetry, 2011, 22, 1035. M. Brambilla, S. G. Davies, A. M. Fletcher and J. E. Thomson, Tetrahedron: Asymmetry, 2014, 25, 387.
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