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Application of 9-phenyl-fluoren-9-yl Protected Amino Acids in the Synthesis of Tetrahydro-ß-Carbolines

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dc.contributor Aalto-yliopisto fi
dc.contributor Aalto University en
dc.contributor.author Lood, Christopher
dc.date.accessioned 2015-06-05T09:01:14Z
dc.date.available 2015-06-05T09:01:14Z
dc.date.issued 2015
dc.identifier.isbn 978-952-60-6247-1 (electronic)
dc.identifier.isbn 978-952-60-6246-4 (printed)
dc.identifier.issn 1799-4942 (electronic)
dc.identifier.issn 1799-4934 (printed)
dc.identifier.issn 1799-4934 (ISSN-L)
dc.identifier.uri https://aaltodoc.aalto.fi/handle/123456789/16532
dc.description.abstract Tetrahydro-ß-carbolines are a prominent group of tricyclic natural products belonging to the indole alkaloids. The large diversity of complex polycyclic compounds in the family coupled with their medicinal properties has made them an extensively studied and extremely attractive target for synthetic organic chemists during the last decades. Reserpine, previously proscribed against hypertension, and tadalafil, a potent PDE5 inhibitor and currently one of the top grossing small molecule pharmaceuticals illustrates the importance of the compound class. The asymmetric synthesis of tetrahydro-ß-carbolines traditionally relies on a few proven methodologies. The chirality has either been introduced diastereoselectively by substrate controlled reactions, using e.g. chiral auxiliaries, or by external asymmetric induction utilizing e.g. chiral catalysts. Our knowledge and experience on the use of amino acids as starting material in natural product synthesis prompted us to investigate the possibility of transferring the inherent chirality of amino acids to the tetrahydro-ß-carboline scaffold via a chiral pool approach. The use of amino acids as chiral starting material is however hampered by their propensity to undergo racemization/epimerization under certain reaction conditions. To this effect, the 9-phenyl-fluoren-9-yl protecting group was introduced as a means to both protect the amine functionality and at the same time also to protect the vulnerable stereocenter at the alpha-position on the amino acid derivatives. This thesis aims to provide the reader with a short literature background on the chemistry of tetrahydro-ß-carbolines as well as an overview of different methods available to suppress racemization/epimerization of amino acid derived carbonyl compounds. The thesis will then culminate in the author's own work regarding the synthesis of the tetrahydro-ß-carboline natural products harmicine and eleagnine, by use of a chiral pool approach coupled with a 9-phenyl-fluoren-9-yl protecting group strategy. Herein is furthermore described the synthesis of chiral 2-indolyl methanamines, a structurally closely related group of compounds to the tetrahydro-ß-carbolines largely overlooked in the chemical literature. The thesis will finally end on a discussion regarding the mechanism behind the ability of the 9-phenyl-fluoren-9-yl amine protecting group to retain the stereochemical integrity of amino acid derived carbonyl compounds. en
dc.format.extent 64 + app. 81
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher Aalto University en
dc.publisher Aalto-yliopisto fi
dc.relation.ispartofseries Aalto University publication series DOCTORAL DISSERTATIONS en
dc.relation.ispartofseries 82/2015
dc.relation.haspart [Publication 1]: Lood, C. S.; Koskinen, A. M. P. Harmicine, a Tetracyclic Tetrahydro-beta-Carboline: From the First Synthetic Precedent to Isolation from Natural Sources to Target-Oriented Synthesis (Review). Chemistry of Heterocyclic Compounds. 2015, 50, 1367 – 1387; DOI: 10.1007/s10593-014-1602-4
dc.relation.haspart [Publication 2]: Lood, C. S.; Koskinen, A. M. P. Synthesis of (S)- and (R)-Harmicine from Proline: An Approach Toward Tetrahydro-β-carbolines. European Journal of Organic Chemistry. 2014, 2357 – 2364; DOI: 10.1002/ejoc.201301903
dc.relation.haspart [Publication 3]: Lood, C. S.; Nieger, M.; Koskinen, A. M. P. Enantiospecific Gram Scale Synthesis of (S)-Eleagnine. Tetrahedron 2015, Published Online (28 May 2015); DOI: 10.1016/j.tet.2015.05.063
dc.relation.haspart [Publication 4]: Lood, C. S.; Laine, A. E.; Högnäsbacka, A.; Nieger, M.; Koskinen, A. M. P. Synthesis of Chiral (Indol-2-yl)methanamines and Insight into the Stereochemistry Protecting Effects of the 9-Phenyl-9-fluorenyl Protecting Group. European Journal of Organic Chemistry. 2015, 17, 3793-3805; DOI: 10.1002/ejoc.201500391
dc.subject.other Chemistry en
dc.title Application of 9-phenyl-fluoren-9-yl Protected Amino Acids in the Synthesis of Tetrahydro-ß-Carbolines en
dc.type G5 Artikkeliväitöskirja fi
dc.contributor.school Kemian tekniikan korkeakoulu fi
dc.contributor.school School of Chemical Technology en
dc.contributor.department Kemian laitos fi
dc.contributor.department Department of Chemistry en
dc.subject.keyword amino acid en
dc.subject.keyword protecting group en
dc.subject.keyword natural product en
dc.subject.keyword alkaloid en
dc.subject.keyword total synthesis en
dc.identifier.urn URN:ISBN:978-952-60-6247-1
dc.type.dcmitype text en
dc.type.ontasot Doctoral dissertation (article-based) en
dc.type.ontasot Väitöskirja (artikkeli) fi
dc.contributor.supervisor Koskinen, Ari, Prof., Aalto University, Department of Chemistry, Finland
dc.opn Somfai, Peter, Prof., Lund University, Sweden
dc.contributor.lab Koskinen Research Group en
dc.rev Haug, Bengt Erik, Associate Prof., University of Bergen, Norway
dc.rev Wallén, Erik, Docent, University of Helsinki, Finland
dc.date.defence 2015-07-03
local.aalto.digifolder Aalto_64880
local.aalto.formfolder 2015_06_05_klo_10_57
local.aalto.archive yes
local.aalto.digiauth ask

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