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

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School of Chemical Technology | Doctoral thesis (article-based) | Defence date: 2015-07-03
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64 + app. 81
Aalto University publication series DOCTORAL DISSERTATIONS, 82/2015
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.
Supervising professor
Koskinen, Ari, Prof., Aalto University, Department of Chemistry, Finland
amino acid, protecting group, natural product, alkaloid, total synthesis
Other note
  • [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 View at publisher
  • [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 View at publisher
  • [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 View at publisher
  • [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 View at publisher