The doctoral dissertations of the former Helsinki University of Technology (TKK) and Aalto University Schools of Technology (CHEM, ELEC, ENG, SCI) published in electronic format are available in the electronic publications archive of Aalto University - Aaltodoc.

Preparation of Indole Alkaloids via 1,4-Dihydropyridine Stage or Cyano-Masked Iminium Intermediates

Tiina Putkonen

Dissertation for the degree of Doctor of Science in Technology to be presented with due permission of the Department of Chemical Technology for public examination and debate in Auditorium KE 2 at Helsinki University of Technology (Espoo, Finland) on the 23rd of January, 2004, at 12 o'clock noon.

Overview in PDF format (ISBN 951-22-6861-2)   [690 KB]
Dissertation is also available in print (ISBN 951-22-6860-4)


Methods to synthesise substituted pyridine derivatives utilising 1,4-dihydropyridines were studied. Addition of nucleophiles to N-alkyl pyridinium salts and application of the products to alkaloid synthesis were investigated.

Application of the Kröhnke procedure to the synthesis of indole alkaloids is described. The feasibility of applying the Kröhnke procedure to pyridine derivatives without an electron withdrawing β-substituent at the pyridinium ring was demonstrated by adding dimethyl malonate to the γ-position of Boc protected 1-[2-(3-indolyl)ethyl]pyridinium salts. The method permits access to the indoloquinolizidine skeleton present in several indole alkaloids.

The total synthesis of (±)-tangutorine, a novel indole alkaloid, was achieved. The dithionite reduction leading to a 1,4-dihydropyridine derivative provided easy access to the tangutorine skeleton with good yields.

In a second part of the work, dihydropyridines were stabilised through the introduction of cyanide ion to iminium intermediates. The Polonovski–Potier reaction and the cyano-trapping method were used in the preparation of dimethyl malonyl substituted indolo[2,3-α]quinolizidine derivative, a potential synthon of antirhine.

A novel synthetic approach to the preparation of 2,6-dicyanopiperidine derivatives via 1,4-dihydropyridine intermediates was examined. The formation of 2,6-dicyanopiperidines in the Fry reaction was verified. The stereochemistry of 2,6-dicyanopiperidine derivatives is discussed.

This thesis consists of an overview and of the following 5 publications:

  1. Hanhinen P., Putkonen T. and Lounasmaa M., 1999. Direct introduction of nucleophilic carbanions to the γ-position of Na-Boc-protected Nb-tryptophylpyridinium salts without electron withdrawing substituents at the β-position. Heterocycles 51, number 4, pages 785-794.
  2. Hanhinen P., Putkonen T. and Lounasmaa M., 1999. General strategies in the preparation of antirhine-type indole alkaloids. Heterocycles 51, number 8, pages 1827-1842.
  3. Putkonen T., Valkonen E., Tolvanen A. and Jokela R., 2002. 1,4-Dihydropyridine equivalents: a novel approach to 2,6-dicyanopiperidine derivatives. Tetrahedron 58, number 39, pages 7869-7873.
  4. Putkonen T., Tolvanen A. and Jokela R., 2001. First total synthesis of (±)-tangutorine. Tetrahedron Letters 42, number 37, pages 6593-6594.
  5. Putkonen T., Tolvanen A., Jokela R., Caccamese S. and Parrinello N., 2003. Total synthesis of (±)-tangutorine and chiral HPLC separation of enantiomers. Tetrahedron 59, number 43, pages 8589-8595.

Keywords: indole alkaloids, 1,4-dihydropyridines, cyano-trapping

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© 2004 Helsinki University of Technology

Last update 2011-05-26