66214 - Organic Sythesis

Course Unit Page

Academic Year 2018/2019

Learning outcomes

After completing this course, students are able to plan a few hypothese 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, Baldwin rules.

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

6. Practicing retrosynthetic analysis of complex organic molecules.

Lab contents: after a preliminary presentation of mechanistic features and experimental details of cross-coupling reactions, olefin metathesis and organocatalyzed processes, students carry out a Sonogashira cross-coupling, a ring closing metathesis reaction, the preparation of an organocatalyst followed by its application in an asymmetric reaction.

Readings/Bibliography

Slides available for download. Lesson handouts will be essential.

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 (5)", 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 three teaching units: the first two consist 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. These two units are delivered by Prof. Claudio Trombini and Prof. Marco Lombardo. The third teaching unit is a laboratory activity consisting of 6 experiments (4 hours lab each), and it is aimed at providing practical skills in a few modern synthetic methodologies, from an experimental point of view. Students will operate in groups of 2-3 people. This teaching unit is delivered by Prof. Alessandra Tolomelli.

Attendance to the lab activities is mandatory. Attendance signatures will be taken at the end of each lab session.

Assessment methods

The final exam is designed to assess student knowledge and skills in synthetic organic chemistry and consists of a written 2-hours long test (no handouts or books are allowed) followed by an oral exam. The written test consists of 10 items, 5 refer to the application of general synthetic methodologies, 5 to lab activity.

Each question has associated a maximum score of 3. Only the students who get a written test evaluation no lower than 18 can take the oral test.

The oral exam will consist of the planning of a few alternative syntheses of the target molecule assigned and in their critical assessment on the basis of economic and sustainability grounds. The oral exam lasts about 30-40 minutes. To achieve the top score, student must put in the correct context the problem assigned and be confident in devising acceptable solutions.

The student's final score is calculated as the weighted average of his/her written (40%) and oral (60%) test scores.

Teaching tools

Multimedia supported lectures.

Office hours

See the website of Claudio Trombini

See the website of Marco Lombardo

See the website of Alessandra Tolomelli