‘Organic Synthesis’ Course Syllabus
Course Code: 09042002
Course Category: Major Core
Majors: Intensive Training Class
Total Hours: 36 Hours Credit: 2
Lecture Hours: 26 Hours Lab Hours: 0 Practice Hours: 10
Instructor: Vsevolod Peshkov
Textbooks: Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, Part B: Reactions and Synthesis (5th Edition), Science press, 2009
1. Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, Part A: Structure and Mechanisms (5th Edition), Science press, 2009
2. Clayden, J.; Greeves, N.; Warren, S.; Wothers, P. Organic Chemistry (2nd Edition), Oxford University Press, 2012
3. Organic Chemistry Portal (http://www.organic-chemistry.org/)
Organic synthesis is a direct extension of the basic organic chemistry course. Thus, the major goal of the organic synthesis course is to explore the organic chemistry in a greater depth particularly in terms of mechanistic details, stereoselectivity and most importantly in terms of synthetic applications. The current course will help students to become proficient in understanding major types of reactivities exhibited by the organic compounds. Upon successful completion of this course, an average student will be able to provide a detailed explanation for the outcome of the specific transformation as well as to design the optimal strategy for the target-oriented multistep synthesis of the complex organic molecules.
Chapter 1 - Introduction into organic synthesis
1. Introduction into organic synthesis
1.1 Historical prospective
Common attributes of organic substances; synthesis of urea by Friedrich Wöhler; synthesis of acetic acid by Hermann Kolbe; the importance of organic synthesis; target-oriented total synthesis of natural products and pharmaceutical drugs.
1.2 Reactivity of organic compounds
Types of reactive intermediates; Lewis acid-base theory; nucleophiles and electrophiles; electronegativity concept.
1.3 Introduction into enantioselective synthesis
Chirality; optical activity; first example of enantioselective synthesis; 2001 Nobel Prize in chemistry for enantioselective hydrogenantion and epoxidation.
1.4 Introduction into retrosynthetic analysis
Elias James Corey; terms of the retrosynthetic analysis (target molecule, disconnection, retron, transform, synthon).
1. Why we need to synthesize organic compounds?
2. What is organic synthesis?
3. What is responsible for the reactivity of organic comounds?
4. What is enantioselective synthesis?
5. How the retrosynthetic analysis helps to perform the organic synthesis?
Chapter 2 – The use of carbonyl group in organic synthesis
2. The use of carbonyl group in organic synthesis
2.1 Alkylation of Enolates
Generation of enolates (regio- and stereoselectivity aspects); stabilization by resonance; alkylation of enolates (regio-, chemo- and stereoselectivity aspects); Evans oxazalidinones; alkylation of stabilized enolates; generation and alkylation of silyl enol ethers; enamine as an N-analogue of enol; Hagemann's ester.
2.2 Nucleophilic additions to the carbonyl group and aldol reaction
Imine and enamine formation; Grignard reaction and reduction of carbonyl group; prochirality concept; Felkin-Ahn model for nucleophilic additions to the carbonyl group; extended Felkin-Ahn and chelation models; aldol reaction; Claisen-Schmidt reaction; Mukaiyama aldol reaction; diastereoselectivity of aldol reaction (enolate control versus carbonyl control); Zimmerman–Traxler and ‘open’ transition state models for aldol reaction.
2.3 Aldol-type reactions, Mannich reaction and Michael addition
Claisen and Dieckmann condensations; Knoevenagel condensation; Reformatsky reaction; Darzens reaction; Mannich reaction; Tropinone synthesis; Michael addition and Robinson annulation; conjugate addition of organometallic reagents; Morita–Baylis–Hillman reaction; retro-aldol reaction; umpolung concept; Corey-Seebach reaction; benzoin condensation.
1. How to generate the enolate in regio- / stereoselective manner?
2. How to perform the alkylation of the enolate in regio- / chemo- / stereoselective manner?
3. How to employ tertiary alkyl halides for alkylation of carbonyls?
4. How to determine the relative configuration of the stereocenters in the product of nucleophilic addition to the carbonyl group?
5. How to determine the relative configuration of the stereocenters in the aldol?
6. What is the difference between the enolate control and the carbonyl control in the diastereoselective aldol reaction?
7. How to control the addition of organometallic reagents to the α,β-unsaturated carbonyl compounds?
8. What is umpolung concept?
Chapter 3 - Palladium-catalyzed cross-couplings and organometallic chemistry
3. Palladium-catalyzed cross-couplings and organometallic chemistry
3.1 Palladium-catalyzed cross-couplings
Palladium complexes; oxidative insertion; Mizoroki-Heck reaction; Pd-catalyzed carbonylation; Pd-catalyzed reductions of aryl halides; Pd-catalyzed cross-coupling reactions; Suzuki coupling; Sonogashira coupling; Buchwald-Hartwig coupling.
3.2 Application of organometallic reagents in organic synthesis
Wacker process; Tsuji-Trost reaction; organolithium compounds (preparation and reactivity); directed ortho-metalation; organozinc compounds; Barbier reaction; organoboron compounds.
1. What are the crucial steps in the Pd-catalyzed cross-couplings?
2. What kind of organometallic compounds can be used in Pd-catalyzed cross-couplings?
3. When the organometallic compounds can be directly used in the cross-coupling and when the Pd catalysis is needed?
Chapter 4 - Pericyclic Reactions
4. Pericyclic Reactions
4.1 Diels-Alder reaction
Definition of pericyclic processes; regio- and stereoselectivity aspects of Diels–Alder reaction; the frontier orbitals symmetry in the Diels–Alder reaction; normal and inversed demand in the Diels-Alder reaction; secondary orbital effects; Danishefsky's diene and its application in organic synthesis; hetero-Diels–Alder reactions; retro Diels-Alder reaction; intramolecular Diels–Alder reaction.
4.2 1,3-Dipolar cycloadditions, sigmatropic rearrangements and electrocyclic reactions
Regio- and stereoselectivity aspects of 1,3-dipolar cycloadditions; common 1,3-dipoles; ozonolysis; azide-alkyne cycloaddition; click chemistry; sigmatropic rearrangements; Cope rearrangement; Claisen rearrangement; sigmatropic shifts; electrocyclic reactions.
1. How to determine the relative configuration of the stereocenters in the product of the Diels–Alder reaction?
2. What is the difference between normal and inversed demand in the Diels-Alder reaction?
3. What factors influence the regioselectivity of the 1,3-dipolar cycloaddition?
4. How to determine the stereoselective outcome of electrocyclic processes?
Chapter 5 - Carbon-carbon double bond
5. Carbon-carbon double bond
5.1 Wittig reaction
Wittig reaction; triphenyl phosphonium ylide; stereoselectivity of Wittig reaction; synthetic applications of Wittig reaction; Schlosser modification of Wittig reaction; Horner–Wadsworth–Emmons reaction; Johnson–Corey–Chaykovsky reaction.
5.2 Alkene metathesis
Alkene metathesis; metal carbene complexes; mechanism of alkene metathesis; ring closing metathesis (RCM); enyne metathesis.
1. What is the difference berween stabilized and unstabilized ylide?
2. What factors influence the stereoselectivity of Wittig reaction?
3. How to explain the stereoselective outcome of Wittig reaction?
4. What is the difference between the pre-catalyst and the catalyst in the alkene metathesis?
Chapter 6 - Redox reactions
6. Redox reactions
6.1 Oxidations in organic synthesis
Basics of redox organic transformations; oxidations with potassium permanganate and manganese dioxide; oxidations with with chromium(VI)-compounds; Swern oxidation; Moffat oxidation. Kornblum and Corey-Kim oxidations; hypervalent iodine(V)-based oxidizing agents; epoxidation and transformations of epoxides; Sharpless epoxidation; Baeyer-Villiger oxidation.
6.2 Reductions in organic synthesis
Heterogeneous catalytic hydrogenations; homogeneous catalytic hydrogenations; Noyori asymmetric hydrogenation; boron-based reducing agents; reductive amination; aluminium-based reducing agents; free radical reactions.
1. How to oxidize the alcohol to the aldehyde in a selective way?
2. How to control the regioselectivity of the epoxide ring-opening?
3. What are the advantages and the disadvantages of the heterogeneous catalytic hydrogenations compared to homogeneous?
4. How to reduce the ester to the aldehyde in a selective way?
5. How to perform the reductive amination?
Chapter 7 - Protecting groups chemistry, functional group interconversions and rearrengements
7. Protecting groups chemistry, functional group interconversions and rearrengements
7.1 Functional group interconversions and protecting groups chemistry
Preparation of azides; Mitsunobu reaction; Appel reaction; Corey–Fuchs reaction; synthesis of amines and amides; amide coupling; protecting groups for ethers; protecting groups for carbonyl group; protecting groups for amines; peptide synthesis.
Beckmann rearrangement; Wolff rearrangement and Arndt-Eistert synthesis; Schmidt reaction and Curtius rearrangement; Hofmann rearrangement, Ugi reaction and Mumm rearrangement.
1. How to choose the optimal strategy for the synthesis that require multiple protection-deprotection operations?
2. Explain the difference and similarity between Wolff and Curtius rearrangements.
1. Performance in the class
3. Mid-term exam
4. Final exam
Made by Vsevolod Peshkov
Date: October 16, 2016