ADVANCED SYNTHESIS IN ORGANIC CHEMISTRY PART. B
- Overview
- Assessment methods
- Learning objectives
- Contents
- Full programme
- Bibliography
- Teaching methods
- Contacts/Info
Deep knowledge of basic organic chemistry, with particular regard to aliphatic and aromatic reactivity. Extensive knowledge concerning the methods of transformation of the different functional groups. Fair knowledge of the concepts of retrosynthesis, protection and deprotection of functional groups, asymmetric synthesis, catalytic methods for the generation of new carbon-carbon and carbon-heteroatom bonds.
The final exam is based on a written test on the course contents (both part A e part B), through open questions and specific questions on some chemical transformations. In addition, each student will present their own literature search preparing and illustrating an oral presentation, related to a total synthesis published in a scientific journal. The written test generally lasts 2.5-3 hours, while the presentation is briefly limited to 15-20 minutes of illustration and discussion. The evaluation of the written test is approximately 80% of the final grade. The presentation, together with the possible oral exam, consists of the remaining 20%.
The course aims to provide students with advanced knowledge of organic synthesis including the most innovative methodologies for the formation of new carbon-carbon and new carbon-heteroatom bonds. The illustration of new syntheses and methodologies for the preparation of molecules with greater molecular complexity will be the subject of study of the entire course. The syntheses used to produce high added value compounds that play a fundamental role in the field of biologically and pharmacologically active derivatives will be particularly investigated. Particular attention will be devoted to the total synthesis of natural products containing a different number of stereocenters, thus investigating asymmetric preparation techniques.
Examples of total synthesis of a molecule with different methods (Total Synthesis of Lysergic Acid) (4h). Smart drugs: synthesis and properties (8h). Diastereoselection (Felkin-Ahn model) (6h). Carbocation chemistry (4h). Cyclization rules (Baldwin's Rules) (4h). Radical chemistry and Carbene and carbenoid chemistry (6h).
Diastereoselectivity. Diastereoisomers from stereospecific reactions of alkenes. Stereoselective reactions. Prochirality. Diastereoselective additions to carbonyl compounds. Felkin-Anh model. Curtin-Hammett principle. Rule of Cram. Burgi-Dunitz angle. The effect of chelation reverses stereoselectivity. Stereoselective reactions of acyclic alkenes. Stereoselective aldol reactions. Zimmermann-Traxler transition state.
Radical reactions and unpaired electrons. Radical initiators. Stable radicals. Reactivity of radical species. ESR or EPR spectroscopy. Stability of radical species. McMurry reaction. Aciloinic reaction. Chain reactions. Selectivity in chain reactions. Allyl bromination. Radical substitution of Br with H. Reactions with Bu3SnH and AIBN. Carbon-carbon bond formation. Effects of concentration. Effects of frontier orbitals. Electrophilic radicals. Copolymerization. Radical processes and polar reactions. Polarization inversion. Hg-based radicals. Alkyl radicals from boranes and oxygen. Intramolecular radical reactions.
Synthesis and reactions of carbenes and carbenoids. Use of diazomethane in the synthesis of methyl esters. Photolysis of diazomethane and carbenes. Carbene formation. Types of carbenes: triplet carbenes and singlet carbenes. Carbene structure and their reactivity. Cyclopropanation reactions. Simmons-Smith reaction. Reimer-Tiemann reaction. Insertion in C-H bonds. Rearrangement reactions. Nitrenes as analogous nitrogen carbene compounds. Carbene attack on electronic pairs. Metathesis of alkenes. Cross metathesis and enyne metathesis.
The organic chemistry of carbocations. Introduction, nomenclature, structure and stability. Hyper-conjugative effect. Carbocation generation. Classical carbocations and non-classical carbocations. Electrophilic addition to alkenes. Addition of acids. Hydration. Halogen addition. Hydroboration of olefins. Oxygen binding of olefins. Electrophilic aromatic and intermediates by Wheland. Mechanism and orientation. Nitration. Halogenation. Friedel-Crafts reactions (alkylation and acylation). Betha-elimination reactions. Rearrangement reactions (pinacol, Beckmann, Demjanov and Tiffeneau-Demjanov, Meyer-Schuster, Schmidt and Wagner-Meerwin).
Saturated heterocycles and stereoelectronic effecys. Reactions of heterocycles. Baylis-Hillman reaction. Conformational studies and anomeric effect. Heterocyclic synthesis: ring-closure reactions. Thermodynamic control. Thorpe-Ingold effect. Baldwin's Rules. Principle of microscopic reversibility and opening of the cycles.
The problem of smart drugs and their synthesis in clandestine laboratories. Categories of products that can be defined as smart drugs: ephedrines, cathinones, mescaline, tryptamines, cannabinoids and naphthoylindole derivatives. Preparation of amphetamine derivatives. Synthesis generally contaminated by the impossibility of purifying the products. Structural modifications of natural molecules having biological activity. Different categories of synthetic cannabinoids. Legislation and difficulties in defining analysis protocols.
Different examples of total syntheses of the same molecule: lysergic acid.
The reference material used during the course will be provided. Literature articles in organic synthesis will also constitute study material and analysis in the classroom. Each individual topic may also have a different reference text. A basic text of certain interest for the development of some topics is:
Clayden, Warren, Wothers, Greeves
Organic Chemistry
1st Edition - Oxford University Press
Clayden, Warren, Greeves
Organic Chemistry
2nd Edition - Oxford University Press
Some of the titles indicated below are examples of possible reference texts that can be used for some topics:
F.A.Carey, R.J.Sundberg Advanced Organic Chemistry Part B (Reactions and Synthesis) Springer Science 2007, 5th Edition
S. Warren, P. Wyatt - Organic Synthesis: the Disconnection Approach
S. Warren, P. Wyatt - Organic Synthesis: Strategy and Control
E. J. Corey, Xue-Min Cheng - The Logic of Chemical Synthesis
K. C. Nicolaou, E.J. Sorensen - Classics in Total Synthesis
K. C. Nicolaou, S.A. Snyder - Classics in Total Synthesis II
K. C. Nicolaou, J.S. Chen - Classics in Total Synthesis III
T. Hudlicky, J.W. Reed - The Way of Synthesis
K. C. Nicolaou, T. Montagnon - Molecules that changed the world
E.J. Corey, L. Kurti, B. Czako - Molecules and Medicine
M.B. Smith - Organic Synthesis
L. Kurti, B. Czako - Strategic Applications of Named Reactions in Organic Synthesis
The course will be articulated through a series of lectures on the different topics covered in the program for a duration of approximately 32 hours. During the course there will be often the possibility to refer to the current scientific literature in order to frequently correlate the arguments developed with the most recent developments in the field of organic synthesis. A critical comparison of the various publications will therefore be able to illustrate with greater detail the program carried out with the contemporaneity and actuality of the organic synthesis.
The lecturer is available to more details and clarifications on any requests made by the students receiving at his office by previous contact via email: andrea.penoni@uninsubria.it or by phone (031-2386440).