Selected organic reactions for stereoselective and asymmetric synthesis. Polar organometallic derivatives. Covalent organometallic derivatives. Nucleophilic addition to carbonyl compounds. Allyl metal additions to aldehydes. Enols and enolates. Alkylation of enolates. Direct aldol reaction of carbonyl and carboxyl derivatives.
R. E. Gawley, J. Aubé, Principles of Asymmetric Synthesis, Chp. 1-5, Pergamon
E. L. Eliel, S. H. Wilen, L. N. Mander, Stereochemistry of Organic Compounds, Chp. 12, Wiley-Interscience
J. Clayden, N. Greeves, S. Warren, P. Wothers, Organic Chemistry, Chp. 8, 21, 26, 27
F. A. Carey, R. J. Sundberg, Advanced Organic Chemistry, Part B, Chp. 7 e 9, Kluwer Academic/Plenum Publishers
Ch. Elschenbroich, A. Salzer, Organometallics, Chp. 1-8, VCH Publishers
Learning Objectives
Knowledge of the basic concepts of the reaction mechanism and stereoselectivity of key reactions for organic synthesis. Experimental data interpretation concerning the stereoselectivity of organic reactions. Knowledge of the basic concepts of the chemistry of polar and covalent organometallic derivatives.
Methods and procedures in the use of polar and covalent organometallic derivatives.
Organic synthesis planning with stereoselectivity prediction and control of the reactions. Understanding and foreseeing opportunities and problems of utilizing polar and covalent organometallic derivatives in organic synthesis planning.
Prerequisites
Courses to be used as requirements (required and/or recommended)
Courses required: none
Courses recommended: none
Teaching Methods
Lectures (hours): 48.
Subjects are explained with the aid of blackboard; a guide is given by projection of transparents which are available via Moodle.
Type of Assessment
Oral final examination.
There are at least 8 examination sessions, especially in February, June, July, and September.
Course program
C-C bond formation: organometallic derivatives. Classes of organometallics. Properties of M-C bond. Polarity and reactivity. Methods for the preparation of polar organometallic derivatives: direct synthesis, reductive insertion, metal-halogen exchange, metal-metal exchange, metallation. Structure, Schlenk equilibrium, coordination, aggregation, compatibility with functional groups. Superbases. Allyl and benzyl potassium derivatives: regio and stereoselectivity in reactions with electrophiles. Reactivity of polar organometallics with electrophiles. Alkyl lithium as bases for the preparation of lithio amides. CIPE (complex induced proximity effect), directed ortho metalation (DoM), directing metalation groups (DMG). Configurational stability of carbanions. Enantioselective syntheses with organolithium derivatives. Use of chiral auxiliaries. Asymmetric deprotonations with organolithiums and chiral ligands (sparteine). Use of chiral lithio amides. Covalent organometallic derivatives. Organoboranes. Hydroboration: regio, stereo, chemoselectivity. Mechanism of hydroboration, hydroboration reagents and their selectivity. Preparation of organoboranes via metathesis. Reactivity of organoboranes. FGI via organoboranes. Oxidation, hydroamination, hydrohalogenation. Enantioselective hydroborations with Ipc2BH, IpcBH2 and DMB. Transformations of alkenylboranes: protonolysis, oxidation, halogenations to E and Z alkenes. Formation of C-C bonds: carbonylation of organoboranes, reactions with α–halogen and α–diazo esters and ketones, conjugate addition to α,β-unsaturated C=O. Stereocontrolled syntheses of alkenes and alkynes. Suzuki-Miyaura reaction. Organosilanes and organostannanes. Preparation by metathesis and hydrosylation or hydrostannation. Reactivity: stabilization of anions and radicals, expansion of coordination, β effect. Reactivity and selectivity of reactions of alkenyl, epoxy, allyl silanes and stannanes with electrophiles. Peterson olefination and elimination. Stille reaction: cross-coupling and carbonylative coupling. Reactions of organometal derivatives with carbonyl compounds. Stereoselectivity of the addition to diastereotopic aldehydes and ketones. Stereoselectivity of the addition to C=O in acyclic compounds: Cram rule. TS models: Cram, Cornforth, Karabatsos, Felkin. Bürgi-Dunitz trajectory and Felkin-Anh TS model. Heathcock model. Flippin-Lodge angle. Effects of Lewis acids. Chelate TS. Rigid and non rigid cyclic ketones. Stereoselectivity of the addition to cyclohexanones. Addition of allyl metals to aldehydes: stereoselectivity. Type 1, 2 and 3 allyl metals. Zimmerman-Traxler like and acyclic TS. Enantioselectivity of the addition of crotyl metals to aldehydes: Brown and Keck methods. Simple diastereoselectivity of the addition of crotyl metals to aldehydes. Single absolute diastereoselectivity with chiral aldehydes or allyl metals. Absolute diastereoselectivity with double asymmetric induction. Reactivity of carbonyl and carboxylic derivatives. Enols and enolates: alkylation, direct aldol addition. Metal enolates: generation, regio and stereoselectivity. Equivalents of enols and enolates. Li, Na, K enolates, silyl enolethers. Use of enones for the specific generation of enolates. Alkylation of enolates: regio and stereoselectivity. Enantioselectivity of the alkylation of enolates: chiral auxiliaries. Simple diastereoselectivity in the direct aldol addition. Zimmerman-Traxler and open TS. Absolute stereoselectivity. Single asymmetric induction. Chiral aldehydes: combination of Felkin-Anh and Zimmerman-Traxler or open TS. Chelation and dipolar effects. Double asymmetric induction.