Recently, a novel chiral cubane-based Schiff base ligand was reported to yield modest enantioselectivity in the Henry reaction. To further explore the utility of this ligand in other asymmetric organic transformations, we evaluated its stereoselectivity in cyclopropanation and Michael addition reactions. Although there was no increase in stereocontrol, upon computational evaluation using both M06L and B3LYP calculations, it was revealed that a pseudo six-membered ring exists, through H-bonding of a cubyl hydrogen to the copper core. This decreases the steric bulk above the copper center and limits the asymmetric control with this ligand.The authors thank the Niagara University Academic Center for Integrated Science and the Rochester Academy of Science for their financial support. MLI would like to thank the Barbara S. Zimmer Memorial Research Award for financial aid. MLC gratefully acknowledges generous allocations of supercomputing time from the Australian National Computational Infrastructure, support from the Australian Research Council under its Centers of Excellence program, and an ARC Future Fellowship. RP would also like to thank Western New England University, College of Pharmacy for generous financial support

Biegasiewicz, Kyle F

Coote, Michelle

Gleason, James L

Ho, Junming

Ingalsbe, Michelle L

Priefer, Ronny

Savage, G Paul

St. Denis, Jeffrey D

Beilstein Journal of Organic Chemistry

The Australian National University

1814Evaluation of a chiral cubane-based Schiff baseligand in asymmetric catalysis reactionsKyle F. Biegasiewicz1, Michelle L. Ingalsbe1, Jeffrey D. St. Denis2,James L. Gleason2, Junming Ho3, Michelle L. Coote3, G. Paul Savage4and Ronny Priefer*1,5Letter Open AccessAddress:1Department of Chemistry, Biochemistry, and Physics, NiagaraUniversity, NY 14109, USA, 2Department of Chemistry, McGillUniversity, Montreal, QC, H3A 2K6, Canada, 3ARC Centre ofExcellence for Free-Radical Chemistry and Biotechnology, ResearchSchool of Chemistry, Australian National University, Canberra ACT0200, Australia, 4CSIRO Materials Science and Engineering, ClaytonSouth MDC 3169, Australia and 5College of Pharmacy, Western NewEngland University, Springfield, MA 01119, USAEmail:Ronny Priefer* - ronny.priefer@wne.edu* Corresponding authorKeywords:chiral ligand; cubane; M06L and B3LYP calculations; Michael additionBeilstein J. Org. Chem. 2012, 8, 1814–1818.doi:10.3762/bjoc.8.207Received: 09 August 2012Accepted: 19 September 2012Published: 22 October 2012Associate Editor: P. R. Schreiner© 2012 Biegasiewicz et al; licensee Beilstein-Institut.License and terms: see end of document.AbstractRecently, a novel chiral cubane-based Schiff base ligand was reported to yield modest enantioselectivity in the Henry reaction.To further explore the utility of this ligand in other asymmetric organic transformations, we evaluated its stereoselectivity incyclopropanation and Michael addition reactions. Although there was no increase in stereocontrol, upon computational evaluationusing both M06L and B3LYP calculations, it was revealed that a pseudo six-membered ring exists, through H-bonding of a cubylhydrogen to the copper core. This decreases the steric bulk above the copper center and limits the asymmetric control with thisligand.IntroductionSince the initial synthesis of cubane in 1964 by Eaton and Cole[1,2], numerous studies have been undertaken on its derivatives:Nitrated cubanes are remarkably explosive [3,4]; cubylaminespossess antiviral activity [5]; and cubylamides have been shownto be P2X7 receptor antagonists [6]; whereas other cubanederivatives were examined as narcotic antagonists against bothμ and ĸ receptors [7], as well as being monoamine oxidase(MAO) inactivators [8-10]. Cubanes have also shown a propen-sity to undergo cage opening. In particular, syn-tricyclooctadi-enes are formed when rhodium(I) salts are introduced [11],while with silver(I) or palladium(II) catalysts, cuneane isobtained [12]. Spontaneous cage opening has been observedwith cubanol yielding vinylcyclobutenylketene [13,14], whereasdicubyl disulfide is remarkably stable [15]. More recently,Beilstein J. Org. Chem. 2012, 8, 1814–1818.1815Table 1: Cyclopropanation with cubane ligand 1.Entry Catalyst precursor Conv (%)a cis/transb eebcis (%)eebtrans (%)1 Cu(OTf) toluene complex 53 45:55 9 52 Cu(OTf) tetrakisacetonitrile 13 29:71 14 93 CuCl 77 37:63 1 14 Cu(OTf)2 82 42:58 8 6aThe conversion was determined by analysis of the 1H NMR spectra. bDetermined by GC analysis using a Chirasil-Dextrin CB column.4-iodo-1-vinylcubane was shown to undergo cage opening/rearrangement to form 4-vinyl-trans-β-iodostyrene [16,17],whereas 1-iodocubane-4-carboxaldehyde undergoes cageopening/fragmentation to afford benzaldehyde, which furtherreacts to give benzyl benzoate [18].Recently, we synthesized the first cubane-based Schiff baseligand (Figure 1) and screened it in the Henry reaction in thesynthesis of β-nitroalcohols [19]. The cubyl moiety can beconsidered a cross between a tert-butyl and a phenyl group. Infact, the C–H bond of cubane has been shown to have ~31%s-character [20], compared to 25% for a simple alkane and 33%for an aromatic hydrogen. Due to the bulk of the cube it wasinitially envisioned that there would be high stereocontrol;however, the stereoselectivity was modest-at-best with only thehighest ee value of 39% being achieved when copper(I) chlo-ride was used at 65 °C. Therefore, we decided to examine thisnovel ligand further in the hope of increasing the stereoselec-tivity in other organic transformations.Figure 1: Structure of (1R,2R)-N,N’-bis[(4-iodocuban-1-yl)methylene]-trans-1,2-diamino cyclohexane (1).Results and DiscussionWe began by initially evaluating this cubane-based ligand withcyclopropanation reactions. When no chiral ligand was addedthere was a 2.6:1 ratio of trans to cis products with no eecontrol. We then introduced our cubane-based chiral ligand 1 toour cyclopropanation protocol with four different coppersources (Table 1). The highest ee value of 14% was found withthe use of Cu(I) triflate tetrakisacetonitrile as catalyst. For thereaction with Cu(I) chloride, values of only 1% ee wereobtained for both cis and trans products. In all reactions, thetrans product was favored over the cis. Overall, this reactionwas unsuccessful in obtaining high stereoselectivity, and thuswe decided to switch to Michael addition with organomagne-sium and organozinc reagents.Since the copper source that produced the highest ee value withthe cyclopropanation above was Cu(I) triflate tetrakisacetoni-trile, we decided to initially focus on this catalyst precursor. Wewere pleased to observe an ee value of 16% in the Michael ad-dition of EtMgBr to 2-cyclohexen-1-one at 0 °C in Et2O(Table 2, entry 1). We next screened a variety of solvents in thisreaction. With both CH2Cl2 and THF the ee values signifi-cantly dropped (Table 2, entry 2 and 3). As previously reported,CuCl gave the best results with the Henry reaction [19]; hence,we decided to evaluate this copper source. This, however, didnot yield any encouraging results with only a maximum eevalue of 4% when performed in Et2O (Table 2, entry 4). Wenext evaluated a Cu(OTf) toluene complex, as well asCu(OTf)2; however, we only obtained a maximum value of12% ee with Cu(OTf) 2 in Et2O (Table 2, entry 10). The use ofBeilstein J. Org. Chem. 2012, 8, 1814–1818.1816Table 2: Asymmetric ethyl addition to 2-cyclohexen-1-one under different conditions.Entry Catalyst precursor Alkylating reagent Solvent Conv (%)a ee (%)b1 Cu(OTf) tetrakisacetonitrile EtMgBr Et2O >99 16 (R)2 Cu(OTf) tetrakisacetonitrile EtMgBr CH2Cl2 89 <1 (S)3 Cu(OTf) tetrakisacetonitrile EtMgBr THF >99 3 (R)4 CuCl EtMgBr Et2O >99 4 (S)5 CuCl EtMgBr CH2Cl2 92 1 (S)6 CuCl EtMgBr THF >99 2 (R)7 Cu(OTf) toluene complex EtMgBr Et2O >99 1 (R)8 Cu(OTf) toluene complex EtMgBr CH2Cl2 >99 15 (S)9 Cu(OTf) toluene complex EtMgBr THF 94 11 (R)10 Cu(OTf)2 EtMgBr Et2O >99 12 (S)11 Cu(OTf)2 EtMgBr CH2Cl2 >99 5 (S)12 Cu(OTf)2 EtMgBr THF >99 1 (S)13 Cu(OTf) tetrakisacetonitrile Et2Zn Et2O 86 3 (S)14 Cu(OTf) tetrakisacetonitrile Et2Zn CH2Cl2 87 9 (R)15 CuCl Et2Zn Et2O >99 9 (S)16 CuCl Et2Zn CH2Cl2 >99 11 (S)17 CuCl Et2Zn THF >99 4 (S)18 Cu(OTf) toluene complex Et2Zn Et2O >99 4 (S)19 Cu(OTf) toluene complex Et2Zn CH2Cl2 >99 1 (S)20 Cu(OTf)2 Et2Zn Et2O >99 12 (S)21 Cu(OTf)2 Et2Zn CH2Cl2 97 6 (S)22 Cu(OTf)2 Et2Zn THF >99 1 (S)aThe conversion was determined by analysis of the 1H NMR spectra. bDetermined by HPLC (OD Column, 0.5 mL/min, 99.7:0.3 hexanes/iPrOH) afterderivatization with (R,R)-1,2-diphenylethane-1,2-diol.Et2Zn has also been used to provide excellent stereoselectivityin Michael addition reactions [21,22]. However, with ourcubane-based chiral ligand 1 we did not have this success. Ourbest result with this anion source was with Cu(OTf)2 in Et2Oreaching an ee value of only 12% (Table 2, entry 20).At the onset we had anticipated much stronger results as thelarge bulky nature of the cube should likely block one side ofthe copper complex, thus hopefully increasing stereoselectivity.Appropriate crystals for X-ray analysis were not obtained, thuswe decided to look into computational simulations. On the basisof earlier assessment studies [23,24], we chose the M06L [25]density functional theory method (and B3LYP [26] for compari-son) to locate the global minimum-energy structures for theligands and their Cu(I) complexes. The computations employedthe 6-31+G(d) basis set, and for iodine the LAN2DZdp basis set[27] with an effective core potential was used instead of6-31+G(d). All calculations were performed with Gaussian09[28].Using both B3LYP and M06L density functional theorymethods, we observed N–C–C–N dihedral angles of 65.0 and62.7°, respectively for the ligand 1 on its own (Figure 2a).When this was complexed with a Cu+1, however, the cyclo-hexyl moiety retained its chair conformation, but the N–C–C–Ndihedral angles dropped to 49.7° and 48.5°, in the B3LYP andM06L calculations, respectively (Figure 2b). In addition, thecopper is observed to exhibit either an agostic interaction [29]or a H-bond [30] with the “meta” cubyl hydrogens (with respectto the iodine). The H…Cu bond lengths of 2.06 Å with M06Land 2.29 Å with B3LYP calculations are well within therequired H-bonding length of <3.2 Å [31]. In addition, theC…Cu lengths of 2.85 and 3.03 Å with M06L and B3LYP, res-pectively, were well within the required 4.0 Å limit [31]. Thisproduces pseudo six-membered rings having a C–H…Cu bondangle of 125.1° or 122.9° with M06L and B3LYP calculations,respectively. As Cu(I) is a late transition metal in a low oxi-dation state [32], the H…Cu bond length is shorter than that ofC…Cu [27], and the C–H…Cu bond angle is >100° [33], it canBeilstein J. Org. Chem. 2012, 8, 1814–1818.1817Figure 2: M06L DFT global minima for (a) (1R,2R)-N,N’-bis[(4-iodocuban-1-yl)methylene]-trans-1,2-diaminocyclohexane (1) and (b) Cu+1 complexwith ligand 1.be stated that the H…Cu interaction is a true intermolecularmulticenter hetero-acceptor hydrogen bond as opposed to anintermolecular pseudo-agostic bond. Cubyl hydrogens partici-pating in H-bonding have been reported previously withnitrocubanes [34], as well as with dicubyl vic-disulfone [35].From the computational results it would appear that the cubesplay very little role in blocking either side for selective coordi-nation with the copper. In fact, it would appear that the verymodest selectivity is due to the axial hydrogens on the cyclo-hexyl moiety since the copper is best described as beingstrained square planar with a N–Cu–H bond angle of 93.7° forM06L and 91.0° for B3LYP.ConclusionWe obtained slight stereoselectivity for both cyclopropanationas well as Michael addition. A maximum ee value of 16% wasobserved when Michael addition was performed with EtMgBrat 0 °C in Et2O. The poor stereoselectivity is explained compu-tationally by the lack of steric hindrance on either face of thecopper complex. In addition, H-bonding with cubyl hydrogensand the copper core yielded a pseudo six-membered ring, whichdecreased the N–C–C–N dihedral angle.Supporting InformationSupporting Information File 1Gaussian archives of(1R,2R)-N,N’-bis[(4-iodocuban-1-yl)methylene]-trans-1,2-diaminocyclohexane (1) and Cu+1 complex with ligand 1.[http://www.beilstein-journals.org/bjoc/content/supplementary/1860-5397-8-207-S1.pdf]AcknowledgementsThe authors thank the Niagara University Academic Center forIntegrated Science and the Rochester Academy of Science fortheir financial support. MLI would like to thank the Barbara S.Zimmer Memorial Research Award for financial aid. MLCgratefully acknowledges generous allocations of supercom-puting time from the Australian National Computational Infra-structure, support from the Australian Research Council underits Centers of Excellence program, and an ARC Future Fellow-ship. RP would also like to thank Western New EnglandUniversity, College of Pharmacy for generous financial support.References1. Eaton, P. E.; Cole, T. W. J. Am. Chem. Soc. 1964, 86, 962.doi:10.1021/ja01059a0722. Eaton, P. E.; Cole, T. W. J. Am. Chem. Soc. 1964, 86, 3157.doi:10.1021/ja01069a0413. Eaton, P. E.; Zhang, M.-X.; Gilardi, R.; Gelber, N.; Iyer, S.;Surapaneni, R. Propellants, Explos., Pyrotech. 2002, 27, 1.doi:10.1002/1521-4087(200203)27:1<1::AID-PREP1>3.0.CO;2-64. Zhang, M.-X.; Eaton, P. E.; Gilardi, R. Angew. Chem., Int. Ed. 2000,39, 401.doi:10.1002/(SICI)1521-3773(20000117)39:2<401::AID-ANIE401>3.0.CO;2-P5. Camps, P.; Duque, M. D.; Vázquez, S.; Naesens, L.; De Clercq, E.;Sureda, F. X.; López-Querol, M.; Camins, A.; Pallàs, M.;Prathalingam, S. R.; Kelly, J. M.; Romero, V.; Ivorra, D.; Cortés, D.Bioorg. Med. Chem. 2008, 16, 9925. doi:10.1016/j.bmc.2008.10.0286. Gunosewoyo, H.; Guo, J. L.; Bennett, M. R.; Coster, M. J.; Kassiou, M.Bioorg. Med. Chem. Lett. 2008, 18, 3720.doi:10.1016/j.bmcl.2008.05.0627. Cheng, C.-Y.; Hsin, L.-W.; Lin, Y.-P.; Tao, P.-L.; Jong, T.-T.Bioorg. Med. Chem. 1996, 4, 73. doi:10.1016/0968-0896(95)00165-48. Zhou, J. J. P.; Li, J.; Upadhyaya, S.; Eaton, P. E.; Silverman, R. B.J. Med. Chem. 1997, 40, 1165. doi:10.1021/jm9606249Beilstein J. Org. Chem. 2012, 8, 1814–1818.18189. Silverman, R. B.; Zhou, J. J. P.; Eaton, P. E. J. Am. Chem. Soc. 1993,115, 8841. doi:10.1021/ja00072a04810. Silverman, R. B. Acc. Chem. Res. 1995, 28, 335.doi:10.1021/ar00056a00311. Cassar, L.; Eaton, P. E.; Halpern, J. J. Am. Chem. Soc. 1970, 92,3515. doi:10.1021/ja00714a07512. Eaton, P. E.; Cassar, L.; Halpern, J. J. Am. Chem. Soc. 1970, 92,6366. doi:10.1021/ja00724a06113. Cole, T. W., Jr. Ph.D. Thesis, University of Chicago, 1966.14. Hormann, R. E. Ph.D. Thesis, University of Chicago, 1987.15. Priefer, R.; Lee, Y. J.; Barrios, F.; Wosnick, J. H.; Lebuis, A.-M.;Farrell, P. G.; Harpp, D. N.; Sun, A.; Wu, S.; Snyder, J. P.J. Am. Chem. Soc. 2002, 124, 5626. doi:10.1021/ja025823y16. Carroll, V. M.; Harpp, D. N.; Priefer, R. Tetrahedron Lett. 2008, 49,2677. doi:10.1016/j.tetlet.2008.02.16117. Griffiths, J. R.; Tsanaktsidis, J.; Savage, G. P.; Priefer, R.Thermochim. Acta 2010, 499, 15. doi:10.1016/j.tca.2009.10.01518. Heaphy, P. J.; Griffiths, J. R.; Dietz, C. J.; Savage, G. P.; Priefer, R.Tetrahedron Lett. 2011, 52, 6359. doi:10.1016/j.tetlet.2011.09.03719. Ingalsbe, M. L.; St Denis, J. D.; Gleason, J. L.; Savage, G. P.;Priefer, R. Synthesis 2010, 98. doi:10.1055/s-0029-121708320. Della, E. W.; Hine, P. T.; Patney, H. K. J. Org. Chem. 1977, 42, 2940.doi:10.1021/jo00437a04021. Shibata, N.; Yoshimura, M.; Yamada, H.; Arakawa, R.; Sakaguchi, S.J. Org. Chem. 2012, 77, 4079. doi:10.1021/jo300472r22. Matsumoto, Y.; Yamada, K.-i.; Tomioka, K. J. Org. Chem. 2008, 73,4578. doi:10.1021/jo800613h23. Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215.doi:10.1007/s00214-007-0310-x24. Zhao, Y.; Truhlar, D. G. Acc. Chem. Res. 2008, 41, 157.doi:10.1021/ar700111a25. Zhao, Y.; Truhlar, D. G. J. Chem. Phys. 2006, 125, 194101.doi:10.1063/1.237099326. Becke, A. D. J. Chem. Phys. 1993, 98, 5648. doi:10.1063/1.46491327. Wadt, W. R.; Hay, P. J. J. Chem. Phys. 1985, 82, 284.doi:10.1063/1.44880028. Gaussian 09, Revision A.1; Gaussian, Inc.: Wallingford CT, 2009.29. Brookhart, M.; Green, M. L. H. J. Organomet. Chem. 1983, 250, 395.doi:10.1016/0022-328X(83)85065-730. Thakur, T. S.; Desiraju, G. R. Chem. Commun. 2006, 552.doi:10.1039/b514427b31. Jeffrey, G. A. An Introduction to Hydrogen Bonding; Oxford UniversityPress: New York, 1997.32. Braga, D.; Grepioni, F.; Desiraju, G. R. Chem. Rev. 1998, 98, 1375.doi:10.1021/cr960091b33. Braga, D.; Grepioni, F.; Tedesco, E.; Biradha, K.; Desiraju, G. R.Organometallics 1997, 16, 1846. doi:10.1021/om960836434. Zhou, G.; Zhang, J.-L.; Wong, N.-B.; Tian, A. J. Mol. Struct. 2003, 639,43. doi:10.1016/j.theochem.2003.07.00735. Priefer, R.; Martineau, E.; Harpp, D. N. J. Sulfur Chem. 2007, 28, 529.doi:10.1080/17415990701684701License and TermsThis is an Open Access article under the terms of theCreative Commons Attribution License(http://creativecommons.org/licenses/by/2.0), whichpermits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.The license is subject to the Beilstein Journal of OrganicChemistry terms and conditions:(http://www.beilstein-journals.org/bjoc)The definitive version of this article is the electronic onewhich can be found at:doi:10.3762/bjoc.8.207

English

Evaluation of a chiral cubane-based Schiff base ligand in asymmetric catalysis reactions

Evaluation of a chiral cubane-based Schiff base ligand in asymmetric catalysis reactions

Abstract

Similar works

Full text

Available Versions

The Australian National University