Concepts and methods in organic synthesis

The course illustrates the retrosynthetic approach to the elaboration of strategies for preparing organic compounds, considering regio- and stereoselectivity aspects. Following the thread of the different types of disconnection, a number of synthetic methodologies are discussed, most of which are not included in the topics studied in the basic organic chemistry courses. Synthetic methods are discussed in terms of applicability, simplicity and selectivity.
The main topics are the following:
1) The retrosynthesis approach and the concept of synthon
2) Donor synthons: i) Metal-halogen exchange; ii) alkylating and d1 synthons; iii) d1 synthons stabilized by heteroatoms; iv) d2 synthons: enolates and enolate equivalents; dn synthons (n > 3)
3) Umpolung: reversal of polarity
4) Acceptor synthons
5) One-group C-C disconnections: i) alkylation (use of organocuprates; use of boranes; use of 1,3-dithianes; alkylation of anions in α to COOR and derivatives; alkylation of anions in α to COR; alkylation of enamines; alkylation of hydrazones; alkylation of aldols; alkylation of terminal alkynes); ii) olefination (Wittig reaction; Horner-Wadsworth-Emmons reaction; Horner-Wittig reaction; Peterson reaction; Julia olefination; McMurry reaction; Barton-Kellogg reaction); iii) alkynylation (Corey-Fuchs reaction; Seyferth-Gilbert reaction; Bestmann-Ohira reaction); iv) coupling reactions (free radical coupling; coupling involving boranes; Heck reaction; Suzuki-Miyaura reaction; Stille reaction; Negishi reaction; Sonogashira reaction); v) synthesis of alcohols by addition of organometal reagents to C=O bonds (diastereoselective additions; Cram and Cram-Felkin-Anh stereoselection model); vi) synthesis of carbonyl compounds (by addition of organometal reagents to carboxylic acid derivatives; from borane-CO complexes; with the Collman reagent).
6) Two-group C-C disconnections: i) synthesis 1,2-difunctional compounds (oxidation of carbon-carbon multiple bonds; α-functionalization of carbonyl compounds; opening of epoxides with d0 synthons; use of acyl anion equivalents; use of α-methylsulfinyl ketones; reductive coupling); ii) synthesis 1,3-difunctional compounds (aldol reaction under thermodynamic control; aldol reaction under kinetic control with lithium and boron enolates; Mukaiyama aldol reaction; control of facial relative and absolute stereochemistry in aldol reactions; Claisen condensation; Dieckman condensation; Stobbe reaction; Knoevenagel reaction; Reformatsky reaction; Mannich reaction); iii) synthesis of 1,4-difunctional compounds (from enolate-type compounds and α-bromo carbonyl compounds; from enolate-type compounds and epoxides; from alkynes and epoxides; from nitroalkanes and α,β-unsaturated compounds; from cyanides and α,β-unsaturated compounds; allylation of carbonyl compounds; from allylboron compounds; from allylsilanes; from allyl trialkylstannanes; opening of carbonyl or 1-hydroxyalkyl substituted cyclopropanes; reductive coupling; oxidative coupling); synthesis of 1,5-difunctional compounds (Michael addition under thermodynamic control; Michael addition under kinetic control; Mukaiyama-Michael addition; Robinson annulation); synthesis of 1,6-difunctional compounds (the reconnection approach: ozonolysis of cyclohexenes; epoxidation followed by periodate cleavage).
7) Oxidation/reduction: oxidation of alcohols to aldehydes, ketones and carboxylic acids; addition of oxygen at carbon-carbon double bond; oxidative cleavage of carbon-carbon double bond; oxidation of ketones and aldehydes. Emphasis on methods that could be applied on large-scale. Critical analysis of synthetic procedure, with particular attention to large-scale preparation, reported in the literature.
8) Protection/deprotection (OH, NH2, CO, COOH): principal protective groups, revision of the mechanisms involved in the principal reactions for the introduction and removal of protective groups.
9) Exercises at the blackboard.