Department of Organic Chemistry » Solid-phase synthesis and combinatorial chemistry (OCH/PGSP)

Solid-phase synthesis and combinatorial chemistry (OCH/PGSP)

Course Guarantor

Viktor Krchňák

Form of course completion:

Exam

Annotation:

The course of (C)SPOS is designed particularly for bioorganic chemists focused on organic synthesis of pharmacologically relevant substances. The basic principles of organic synthesis on solid supports will be introduced and compared to “traditional” organic synthesis in solution. Methods of SPOS performance for the preparation of chemical libraries in a combinatorial fashion will be described as well. The course will give both theoretical and practical background for synthesis of various organic molecules on solid supports.

Content:

  • Introduction: history and basic principles of solid-phase organic synthesis, its comparison to synthesis in solution. Analytical methods for support-bound and cleaved intermediates: combustion analysis, colorimetric assays, IR spectroscopy, mass spectrometry and NMR spectroscopy.
  • Supports for SPOS: parameters and properties (including advantages and drawbacks) of currently available polymer supports (polystyrene, grafted polystyrene and macroporous polystyrene resins, polyacrylamides, polysaccharides, polyethyleneglycols and miscellaneous supports).
  • Linkers for SPOS: linker types and functions, selection of suitable linker, examples and applicability of the most common linkers (electrophilical and nucleophilical cleavage, photocleavage, reductive and oxidative cleavage, enzymatic cleavage).
  • SPOS of peptides (SPPS): historical overview, linker strategy for the first amino acid immobilization (immobilization via N, C – terminus, side chain, backbone immobilization), coupling methods, preparation of cyclic peptides, protective groups for SPPS.
  • SPOS of oligonucleotides: historical overview, the phosphotriester method, the phosphoramidite and H-phosphonate methods.
  • SPOS of heterocycles: strategy selection for the preparation of representative heterocyclic compounds.
  • Strategies for CSPOS: definition of combinatorial chemistry, definition of diversity, chemical libraries, diversity orientated synthesis, target orientated synthesis; parallel synthesis, split-split method, split-mix method (random and directed)
  • One bead-one one compound (OBOC) method: principle, historical overview, OBOC encoding methods, OBOC screening methods.
  • Resin formulation for directed split-mix method: T-bags, paper discs, resin capsules, wafers, lanterns, Kans. Chemical history of resin formulations: labeling, Rf tags, necklace, spindles and cogs.
  • Equipment and instrumentation for SPOS and CSPOS: manual solid-phase synthesis, integrated semi-automated synthesis, fully automated synthesizers, instruments for sorting and for purification of chemical libraries.

Literature:

  • Bannwarth, W.; Felder, E. Combinatorial Chemistry. Weinheim, 2000.
  • Zaragoza, F. Organic Synthesis on Solid Phase. Weinheim, 2000.
  • Kates, S. A.; Albericio, F. Solid-Phase Synthesis. A Practical Guide. New York, 2000.
  • Seneci, P. Solid-Phase Synthesis and Combinatorial Technologies. Wiley, 2000.
  • Bunin, B. A. The Combinatorial Index. San Diego, 1998.