View Item 

Show simple item record

From Heteroaromatic Acids and Imines to Azaspirocycles: Stereoselective Synthesis and 3D Shape Analysis
dc.contributor.authorChambers, Sarah J.
dc.contributor.authorCoulthard, Graeme
dc.contributor.authorUnsworth, William P.
dc.contributor.authorO’Brien, Peter
dc.contributor.authorTaylor, Richard J. K.
dc.date.accessioned2017-06-16T20:14:18Z
dc.date.available2017-06-16T20:14:18Z
dc.date.issued2016-05-04
dc.identifier.citationChambers, Sarah J.; Coulthard, Graeme; Unsworth, William P.; O’Brien, Peter; Taylor, Richard J. K. (2016). "From Heteroaromatic Acids and Imines to Azaspirocycles: Stereoselective Synthesis and 3D Shape Analysis." Chemistry – A European Journal 22(19): 6496-6500.
dc.identifier.issn0947-6539
dc.identifier.issn1521-3765
dc.identifier.urihttps://hdl.handle.net/2027.42/137491
dc.description.abstractHeteroaromatic carboxylic acids have been directly coupled with imines using propylphosphonic anhydride (T3P) and NEt(iPr)2 to form azaspirocycles via intermediate N‐acyliminium ions. Spirocyclic indolenines (3H‐indoles), azaindolenines, 2H‐pyrroles and 3H‐pyrroles were all accessed using this metal‐free approach. The reactions typically proceed with high diastereoselectivity and 3D shape analysis confirms that the products formed occupy areas of chemical space that are under‐represented in existing drugs and high throughput screening libraries.Heteroaromatic carboxylic acids have been directly coupled with imines using T3P and NEt(iPr)2 to form azaspirocycles via intermediate N‐acyliminium ions. Spirocyclic indolenines (3H‐indoles), azaindolenines, 2H‐pyrroles and 3H‐pyrroles were all accessed using this metal‐free approach. The reactions typically proceed with high diastereoselectivity and 3D shape analysis confirms that the products formed occupy areas of chemical space that are under‐represented in existing drugs and high throughput screening libraries.
dc.publisherWiley Periodicals, Inc.
dc.subject.otherdearomatisation
dc.subject.other3D space
dc.subject.otherlead identification
dc.subject.otherN-acyliminium ions
dc.subject.otherspirocycles
dc.titleFrom Heteroaromatic Acids and Imines to Azaspirocycles: Stereoselective Synthesis and 3D Shape Analysis
dc.typeArticleen_US
dc.rights.robotsIndexNoFollow
dc.subject.hlbsecondlevelChemistry
dc.subject.hlbtoplevelScience
dc.description.peerreviewedPeer Reviewed
dc.description.bitstreamurlhttps://deepblue.lib.umich.edu/bitstream/2027.42/137491/1/chem201600823-sup-0001-misc_information.pdf
dc.description.bitstreamurlhttps://deepblue.lib.umich.edu/bitstream/2027.42/137491/2/chem201600823.pdf
dc.identifier.doi10.1002/chem.201600823
dc.identifier.sourceChemistry – A European Journal
dc.identifier.citedreferenceS. J. Heffernan, J. P. Tellam, M. E. Queru, A. C. Silvanus, D. Benito, M. F. Mahon, A. J. Hennessy, B. I. Andrews, D. R. Carbery, Adv. Synth. Catal. 2013, 355, 1149;
dc.identifier.citedreferenceK. Okano, H. Tokuyama, T. Fukuyama, J. Am. Chem. Soc. 2006, 128, 7136;
dc.identifier.citedreferenceL. Piazzi, F. Belluti, A. Bisi, S. Gobbi, S. Rizzo, M. Bartolini, V. Andrisano, M. Recanatini, A. Rampa, Bioorg. Med. Chem. 2007, 15, 575;
dc.identifier.citedreferenceN. Khorana, C. Smith, K. Herrick-Davis, A. Purohit, M. Teitler, B. Grella, M. Dukat, R. A. Glennon, J. Med. Chem. 2003, 46, 3930.
dc.identifier.citedreferenceH. Böhme, K. Hartke, Chem. Ber. 1963, 96, 600.
dc.identifier.citedreferenceJ.-Y. Mérour, F. Buron, K. Plé, P. Bonnet, S. Routier, Molecules 2014, 19, 19935.
dc.identifier.citedreference 
dc.identifier.citedreferenceF. F. Blicke, R. J. Warzynski, J. A. Faust, J. E. Gearien, J. Am. Chem. Soc. 1944, 66, 1675;
dc.identifier.citedreferenceZ. Chen, B. Lu, Z. Ding, K. Gao, N. Yoshikai, Org. Lett. 2013, 15, 1966.
dc.identifier.citedreferenceFor the dearomatisation of pyrroles, see:
dc.identifier.citedreferenceK.-J. Wu, L.-X. Dai, S.-L. You, Chem. Commun. 2013, 49, 8620;
dc.identifier.citedreferenceC.-X. Zhuo, Y. Zhou, S.-L. You, J. Am. Chem. Soc. 2014, 136, 6590;
dc.identifier.citedreferenceC. Zheng, C.-X. Zhuo, S.-L. You, J. Am. Chem. Soc. 2014, 136, 16251;
dc.identifier.citedreferenceY. Zhou, C.-X. Zhuo, Q. Gu, S.-L. You, Adv. Synth. Catal. 2015, 357, 912;
dc.identifier.citedreferenceC.-X. Zhuo, Q. Cheng, W.-B. Liu, S.-L. Zhao, Q. You, Angew. Chem. Int. Ed. 2015, 54, 8475; Angew. Chem. 2015, 127, 8595.
dc.identifier.citedreferenceThe relative stereochemistry in products 14 and 15 is the same as that in the previous indole products 8, although presumably there is an alternative explanation for the stereoselectivity.
dc.identifier.citedreferenceFor a recent report highlighting the challenges of 3 H -pyrrole synthesis see: D. A. Shabalina, M. Y. Dvorkoa, E. Y. Schmidt, I. A. Ushakov, N. I. Protsuk, V. B. Kobychev, D. Y. Soshnikov, A. B. Trofimov, N. M. Vitkovskaya, A. I. Mikhaleva, B. A. Trofimov, Tetrahedron 2015, 71, 3273.
dc.identifier.citedreferenceM. Li, P. A. Woods, M. D. Smith, Chem. Sci. 2013, 4, 2907.
dc.identifier.citedreferenceN. C. Firth, N. Brown, J. Blagg, J. Chem. Inf. Model. 2012, 52, 2516.
dc.identifier.citedreferenceFor the DrugBank bioinformatics and cheminformatics database used to acquire these data, see: http://www.drugbank.ca.
dc.identifier.citedreferenceD. G. Brown, J. Boström, J. Med. Chem. 2015, DOI 10.1021/acs.jmedchem.5b01409.
dc.identifier.citedreferenceM. S. Taylor and E. N. Jacobsen have previously reported a related asymmetric acyl Pictet–Spengler protocol for the synthesis of tetrahydrocarbolines using a range of thiourea organocatalysts. Preliminary efforts to employ such catalysts in cyclisation reactions using our in situ T3P activation conditions were unsuccessful, resulting in no enantiomeric enrichment of the product. M. S. Taylor, E. N. Jacobsen, J. Am. Chem. Soc. 2004, 126, 10558.
dc.identifier.citedreference 
dc.identifier.citedreferenceE. M. Carreira, T. C. Fessard, Chem. Rev. 2014, 114, 8257;
dc.identifier.citedreferenceA. W. Hung, A. Ramek, Y. Wang, T. Kaya, J. A. Wilson, P. A. Clemons, D. W. Young, Proc. Natl. Acad. Sci. USA 2011, 108, 6799;
dc.identifier.citedreferenceE. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem. 2014, 57, 10257.
dc.identifier.citedreference 
dc.identifier.citedreferenceW.-Y. Siau, J. W. Bode, J. Am. Chem. Soc. 2014, 136, 17726;
dc.identifier.citedreferenceK. B. Sippy, D. J. Anderson, W. H. Bunnelle, C. W. Hutchins, M. R. Schrimpf, Bioorg. Med. Chem. Lett. 2009, 19, 1682.
dc.identifier.citedreferenceM. J. James, P. O′Brien, R. J. K. Taylor, W. P. Unsworth, Chem. Eur. J. 2016, 22, 2856.
dc.identifier.citedreference 
dc.identifier.citedreferenceA. H. Jackson, A. E. Smith, Tetrahedron 1968, 24, 403;
dc.identifier.citedreferenceA. H. Jackson, P. V. R. Shannon, D. J. Wilkins, Tetrahedron Lett. 1987, 28, 4901.
dc.identifier.citedreferenceFor examples of the synthesis of spirocyclic oxindoles, see:
dc.identifier.citedreferenceC. Marti, E. M. Carreira, Eur. J. Org. Chem. 2003, 2209;
dc.identifier.citedreferenceJ. E. M. N. Klein, R. J. K. Taylor, Eur. J. Org. Chem. 2011, 6821 and references therein.
dc.identifier.citedreferenceP. Dhankher, L. Benhamou, T. D. Sheppard, Chem. Eur. J. 2014, 20, 13375.
dc.identifier.citedreferenceY.-D. Shao, S.-K. Tian, Chem. Commun. 2012, 48, 4899.
dc.identifier.citedreferenceFor representative examples, see:
dc.identifier.citedreferenceL. E. Overman, G. M. Robertson, A. J. Robichaud, J. Am. Chem. Soc. 1991, 113, 2598;
dc.identifier.citedreferenceJ. Bonjoch, D. Sole, J. Bosch, J. Am. Chem. Soc. 1995, 117, 11017;
dc.identifier.citedreferenceO. Wagnières, Z. Xu, Q. Wang, J. Zhu, J. Am. Chem. Soc. 2014, 136, 15102.
dc.identifier.citedreference 
dc.identifier.citedreferenceC.-X. Zhuo, W. Zhang, S.-L. You, Angew. Chem. Int. Ed. 2012, 51, 12662; Angew. Chem. 2012, 124, 12834;
dc.identifier.citedreferenceS. P. Roche, J.-J. Y. Tendoung, T. Tréguier, Tetrahedron 2015, 71, 3549;
dc.identifier.citedreferenceC.-X. Zhuo, C. Zheng, S.-L. You, Acc. Chem. Res. 2014, 47, 2558.
dc.identifier.citedreference 
dc.identifier.citedreferenceQ.-F. Wu, C. Zheng, S.-L. You, Angew. Chem. Int. Ed. 2012, 51, 1680; Angew. Chem. 2012, 124, 1712;
dc.identifier.citedreferenceR. D. Gao, C. Liu, L.-X. Dai, W. Zhang, S.-L. You, Org. Lett. 2014, 16, 3919;
dc.identifier.citedreferenceY. Zhu, V. H. Rawal, J. Am. Chem. Soc. 2012, 134, 111;
dc.identifier.citedreferenceK.-J. Wu, L.-X. Dai, S.-L. You, Org. Lett. 2012, 14, 3772;
dc.identifier.citedreferenceM. J. James, J. D. Cuthbertson, P. O′Brien, R. J. K. Taylor, W. P. Unsworth, Angew. Chem. Int. Ed. 2015, 54, 7640; Angew. Chem. 2015, 127, 7750;
dc.identifier.citedreferenceM. J. James, R. E. Clubley, K. Y. Palate, T. J. Procter, A. C. Wyton, P. O′Brien, R. J. K. Taylor, W. P. Unsworth, Org. Lett. 2015, 17, 4372.
dc.identifier.citedreferenceFor rare examples of dearomatising spirocyclisation involving either iminium ions or N -acyliminium ions, see:
dc.identifier.citedreferenceR. B. Woodward, M. P. Cava, W. D. Ollis, A. Hunger, H. U. Daeniker, K. Schenker, Tetrahedron 1963, 19, 247;
dc.identifier.citedreferenceK. L. Jensen, G. Dickmeiss, H. Jiang, L. Albrecht, K. A. Jørgensen, Acc. Chem. Res. 2012, 45, 248;
dc.identifier.citedreferenceP.-F. Wang, C.-H. Jiang, X. Wen, Q.-L. Xu, H. Sun, J. Org. Chem. 2015, 80, 1155.
dc.identifier.citedreferenceFor a review of N -acyliminium ion chemistry, see: B. E. Maryanoff, H-C. Zhang, J. H. Cohen, I. J. Turchi, C. A. Maryanoff, Chem. Rev. 2004, 104, 1431.
dc.identifier.citedreferencePrevious work has demonstrated that N -acyliminium ions produced in this way can be trapped by nucleophiles but, prior to this report, this method had never been used to generate a spirocyclic product, or in a dearomatisation process:
dc.identifier.citedreferenceW. P. Unsworth, C. Kitsiou, R. J. K. Taylor, Org. Lett. 2013, 15, 258;
dc.identifier.citedreferenceW. P. Unsworth, K. A. Gallagher, M. Jean, J. P. Schmidt, L. J. Diorazio, R. J. K. Taylor, Org. Lett. 2013, 15, 262;
dc.identifier.citedreferenceW. P. Unsworth, R. J. K. Taylor, Org. Biomol. Chem. 2013, 11, 7250;
dc.identifier.citedreferenceW. P. Unsworth, G. Coulthard, C. Kitsiou, R. J. K. Taylor, J. Org. Chem. 2014, 79, 1368;
dc.identifier.citedreferenceC. Kitsiou, W. P. Unsworth, G. Coulthard, C. Kitsiou, R. J. K. Taylor, Tetrahedron 2014, 70, 7172;
dc.identifier.citedreferenceG. Coulthard, W. P. Unsworth, R. J. K. Taylor, Tetrahedron Lett. 2015, 56, 3113.
dc.identifier.citedreference 
dc.identifier.citedreferenceF. Lovering, J. Bikker, C. Humblet, J. Med. Chem. 2009, 52, 6752;
dc.identifier.citedreferenceA. Y. Meyer, J. Comput. Chem. 1986, 7, 144;
dc.identifier.citedreferenceA. D. Morley, A. Pugliese, K. Birchall, J. Bower, P. Brennan, N. Brown, T. Chapman, M. Drysdale, I. H. Gilbert, S. Hoelder, A. Jordan, S. V. Ley, A. Merritt, M. E. Swarbrick, P. G. Wyatt, Drug Discovery Today 2013, 18, 1221;
dc.identifier.citedreferenceM. Lüthy, P. O′Brien, M. C. Wheldon, R. E. Hubbard, C. Haji-Cheteh, I. J. S. Fairlamb, Bioorg. Med. Chem. 2015, 23, 2680.
dc.identifier.citedreferenceW. H. B. Sauer, M. K. Schwarz, J. Chem. Inf. Comput. Sci. 2003, 43, 987.
dc.identifier.citedreference 
dc.identifier.citedreferenceJ. D. Trzupek, C. Li, C. Chan, B. M. Crowley, A. C. Heimann, S. J. Danishefsky, Pure. Appl. Chem. 2010, 82, 1735;
dc.identifier.citedreferenceJ. Stöckigt, A. P. Antonchick, F. Wu, H. Waldmann, Angew. Chem. Int. Ed. 2011, 50, 8538 – 8564;
dc.identifier.citedreferenceP. D. Bailey, M. A. Beard, M. Cresswell, H. P. T. Dang, R. B. Pathak, T. R. Phillips, R. A. Price, Tetrahedron Lett. 2013, 54, 1726 and references therein.
dc.identifier.citedreferenceCCDC  1436464 ( 8 a ), 1436396 ( 8 n ), 1436400 ( 8 o ), 1436405 ( 9 h ), 1436465 ( 15 ) and 1436401 ( 18 ) contain the supplementary crystallographic data for this paper. These data are provided free of charge by The Cambridge Crystallographic Data Centre.
dc.identifier.citedreferenceFor indole acids preparations, see:
dc.identifier.citedreferenceK. Shanker, V. K. Agarwal, R. J. Selveraj, S. S. Parmar, J. Med. Chem. 1969, 12, 324;
dc.identifier.citedreferenceA. J. Liedtke, K. Kim, D. F. Stec, G. A. Sulikowski, L. J. Marnett, Tetrahedron 2012, 68, 10049;
dc.identifier.citedreferenceC. Menciu, M. Duflos, F. Fouchard, G. Le Baut, P. Emig, U. Achterrath, I. Szelenyi, B. Nickel, J. Schmidt, B. Kutscher, E. Günther, J. Med. Chem. 1999, 42, 638;
dc.identifier.citedreferenceE. Walton, C. H. Stammer, R. F. Nutt, S. R. Jenkins, F. W. Holly, J. Med. Chem. 1965, 8, 204.
dc.identifier.citedreferenceThe stereochemistry was assigned based on diagnostic signals in their 1 H NMR spectra; the 1 H NMR spectra of the major diastereoisomers ( 8 ) contain an aromatic proton signal between 6.54–6.32 ppm and/or a methyl signal between 2.65–2.54 ppm. The corresponding signals in the minor diastereoisomers ( 9 ) appear in different ppm ranges: 5.99–5.81 ppm for the aromatic signal and 1.97–1.66 ppm for the methyl.
dc.identifier.citedreferenceFor related 1,2-migration reactions, see:
dc.identifier.citedreferenceC. Zheng, Q.-F. Wu, S.-L. You, J. Org. Chem. 2013, 78, 4357;
dc.identifier.citedreferenceFor alternative methods to characterise 3D shape, see:
dc.identifier.citedreferenceV. A. Peshkov, O. P. Pereshivko, E. V. Van der Eycken, Adv. Synth. Catal. 2012, 354, 2841.
dc.identifier.citedreferenceFor imine preparations, see ref. [13a] and:
dc.identifier.citedreferenceJ. Shi, G. Manolikakes, C.-H. Yeh, C. A. Guerrero, R. A. Shenvi, H. Shigehisa, P. S. Baran, J. Am. Chem. Soc. 2011, 133, 8014;
dc.owningcollnameInterdisciplinary and Peer-Reviewed


Files in this item

Name:
chem201600823-sup-0001-misc_in ...
Size:
6.103MB
Format:
PDF
View/Open
Name:
chem201600823.pdf
Size:
1.622MB
Format:
PDF
View/Open

Show simple item record

Remediation of Harmful Language

The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.

Accessibility

If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.