66214 - Organic Sythesis

Learning outcomes

After completing this course, students are able to plan a few hypotheses of total synthesis of an organic molecule by mainly adopting the retrosynthetic logic, and are able to compare them on the basis of a feasibility, economy and sustainability assessment. Students also aquire practice on a few modern experimental procedures in the field of multistep organic synthesis

Course contents

Prerequisites: to attend this course, student needs a good background in fundamental organic chemistry, including structural and mechanistic features, and structure-reactivity correlations. Moreover student must known the basics of natural organic compounds and master fundamental organic chemistry laboratory techniques such as to perform simple reactions, work-ups, and purifications

Program: within the crucial topic of process innovation in applied organic chemistry, aquiring an expertise in planning new more efficient and sustainable synthetic approaches of products of different industrial sectors, is a top priority in chemical education.

Contents, concepts and theory.

1. Introduction. Nobel Recipients and Masters in synthetic organic chemistry.

a) Synthetic glossary: linear vs convergent syntheses, total yield, economic, safety and environmental factors in the assessment of a chemical process.

b) Carbon-cabon bond forming reactions, intermolecular reactions, cyclization and annulation reactions, and rearrangements.

c) Functionl group interconversions: functionality level, review of the most common refunctionalization techniques.

d) Extrasteps: separations and purifications, introduction of temporary control elements, protective groups, mobile activating groups, chiral auxiliaries.

2. Retrosynthetic analysis: glossary, three levels of retrosynthetic analysis, strategic bonds disconnection, synthons.

a) Symmetry elements as a guideline to the identification of strategic disconnections.

b) Repeated structural units as a guideline to the identification of strategic disconnections.

c) Substructure search of possible available starting materials as a guideline to the identification of strategic disconnections.

d) Strategic bond analysis in alkanes and monofunctional target molecules: functional group (FG)-strategic bond correlation tables for alkanes, alkenes, alkynes, alcohols and their derivatives, carbonyl compounds and their derivatives, carboxylic acids and their derivatives.

3. Retrosynthetic analysis of polyfunctional molecules. Span between functional groups (functionality span, FS), and FS-strategic bond disconnection correlation tables.

a) Oxygen or nitrogen containing FGs. Two functional groups with FS = 2, 3, 4 or 5.

b) Dienes, diynes and enynes. Two functional groups with FS = 2, 3, 4 or 5.

c) Compounds with an oxygen-containing group and a C=C multiple bond with FS = 2, 3, 4 or 5.

d) How to use two groups FS-strategic bond correlation tables in the case of a polyfunctional target.

4. Retrosynthetic analysis of a chiral target molecule.

a) In-depth survey of stereochemical features of complex chiral molecules.

b) Resolution techniques of enantiomers, kinetic and dynamic kinetic resolution.

c) How to exploit the "wrong" enantiomer.

d) Defensive strategies in the synthesis design of chiral target molecules by using starting materials deriving from the chiral pool of natural products.

e) Chiral auxiliary strategy.

f) Offensive strategies in the synthesis design of chiral target molecules: asymmetric induction, chiral reagents, asymmetric catalysis.

5. Retrosynthetic analysis of a cyclic target molecule.

a) Cyclization reactions leading to homo- and heterocyclic molecules.

b) Main annulation classes [1+2], [2+2], [3+2] and [4+2].

6. Practicing retrosynthetic analysis of complex organic molecules

Lab contents: after presenting and discussing the mechanisms of the reaction classes that will be carried out in the laboratory (cross-coupling reactions, organocatalyzed reactions, olefin metathesis), the student will perform in the laboratory a Sonogashira reaction (cross-coupling), a stereoselective Michael reaction (organocatalysis), and the total synthesis of a drug (a multi-step process including an olefin ring-closing metathesis). Within these experiences, the student (working individually) will apply organic synthesis techniques under inert atmosphere, enzymatic synthesis, and various chromatographic and spectroscopic methodologies.

Readings/Bibliography

Slides will be available for download.

Further readings:

• K. C. Nicolaou, E. J. Jorgensen, "Classics in Total Synthesis", VCH
• K. C. Nicolaou, S. A. Snyder, "Classics in Total Synthesis II", Wiley-VCH
• M. B. Smith, "Organic Synthesis", McGraw Hills-Chemistry Book
• S. Warren, "Organic Synthesis: The Disconnection Approach", Wiley
• P. Wyatt, S. Warren, "Organic Synthesis: Strategy and Control", Wiley
• C. Willis, M. Wills, "Organic Synthesis", Oxford Chemistry Primers N. 31
• G.D. Meakins, "Functional Groups: Characteristics and Interconversions", Oxford Chemistry Primers N. 35

Teaching methods

This course is divided in two teaching units: the first one, delivered by Prof. Marco Lombardo, consists of lectures followed by in-class practices in the applications of the main topics and retrosynthetic analysis, with the aim to train students in planning multistep syntheses. The second teaching unit, delivered by Prof. Alessandra Tolomelli and Prof. Arianna Quintavalla, is a laboratory activity consisting of 2 lab sessions (4 hours each) plus 16 hours online and lectures, aimed at providing practical skills in a few modern synthetic methodologies, from an experimental point of view.

Assessment methods

The final exam is designed to assess student knowledge and skills in synthetic organic chemistry and consists of a written 1.5-hours long test (no handouts or books are allowed) followed by an oral exam. The final grade will be calculated as the mean of the written test result and the oral examination result.

Teaching tools

Multimedia supported lectures

Office hours:

See the website of Marco Lombardo
See the website of Alessandra Tolomelli
See the website of Arianna Quintavalla

Office hours

See the website of Marco Lombardo

See the website of Claudio Trombini

See the website of Alessandra Tolomelli

See the website of Arianna Quintavalla