Carbonyl Chemistry IV: Enolate Alkylations and Aldols. Aldol Madness O O O N M + substrate. aldehyde. (Z)-enolate H

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1 Carbonyl Chemistry IV: nolate Alkylations and Aldols Paul Bracher Chem 30 Section 9 Section Agenda 1) o office hours Thursday 2) The Great Joe Young is covering section next onday 3) andout: Carbonyl Chemistry IV Aldol adness dipoles oppose (minimize net moment) asplode! (S) chiral auxiliary 3 base 2 Your head S 1

2 odel for Asymmetric Alkylation This is relatively easy. Simply draw a 3D structure of the enolate and add the to the least hindered face of the double bond. the one carbon bridge is smaller and allows the easier access to top face of the enolate DA Use of oxazolidinone chiral auxiliaries: top bottom major minor oxazolidinone chiral auxiliary let's analyze this intermediate DA i e preferred bottom top e e major minor i These atoms are roughly in the same plane, held fixed by the chelated. ven a is chelated in these systems. C 3 The group is "up/out", so the has easier access to the bottom face of the enolate plane Addition occurs to the enolate carbon To reverse the product ratios, use the chiral auxiliary with the opposite stereochemistry 2

3 Asymmetric Aldol eactions (S) chiral auxiliary () chiral auxiliary base base Bulky substituent points AWAY from ring Bulky substituent points AWAY from ring S dipoles oppose (minimize net moment) dipoles oppose (minimize net moment) To draw the correct final product, assign and S designations to the two stereocenters that are generated in the transition state, then add solid or dashed wedges to your ewis structure to match these designations 3

4 Conjugate Additions 1,2 addition uc 1,4 addition uc uc via uc a nucleophilic intermediate! ther s add here C add here add here etc. These two additions pathways compete when a nucleophile reacts with an α,β-unsaturated. As a general rule, most 1,2 additions are faster, but they are usually more reversible. ichael reactions are those in which an enolate adds in 1,4 fashion Beware of tandem reactions in which the enolate intermediate acts as a nucleophile 1,2 Additions 1,4 Additions ard nucleophiles not polarizable/high charge density ithium Aluminum ydride (A) Alkyllithium reagents (i) ote that these are the nucleophiles we normally classify as irreversible Soft ucleophiles polarizable/low charge density S, C, enolates rganocuprates ( Cui) (via an organolic mechanism) 4

5 Synthetic Transformations lectrophiles s Synthetic Preparations Swern oxidation of alcohols; DIBA- reduction of nitriles ketones xidation of alcohols; Friedel-Crafts reaction; xidation of Grignard products esters ' Fischer esterification of acids and alcohols; acid chlorides and anhydrides with alcohols; Bayear-Villeger oxidation alkyl halides From alcohols with S 2 or PBr 3 ; alkenes with Br (with or w/o peroxides); alkanes by photohalogenation α,β-unsaturated carbonyls Aldol reactions; α-keto halogenation (ell-volhard-zelinsky) then elimination of Br nitriles C Cyanide substitution of alkyl halides; dehydration of amides by P 2 5 ; ucleophiles kinetic enolates Irreversible bases (DA), bulky bases thermodynamic enolates eversible bases (alkoxides, hydroxides) malonic ester enolates ' ' Bases with pk a >> 8 (a, - ) silyl enol ethers TBS TBS and an amine base in anhydrous solvent enamines ' ' p = 5 catalyzed condensation 5

6 Aldol Additions reversible acid or base irreversible base (e.g. DA) ' ' ' Does not work well with ketone s annich '' ' ' 2 '' Syn Aldol Products ' ' s ' Anti Aldol Products ' ' ()-enolates ' vans' Aldol eaction ' ' ' ' Use A to get terminal alcohols via alonic ster Alkylation hydrolysis and decarboxylation ' '' ' '' ' '' '' '' '' Conjugate Addition ichael eaction rganocuprate Addtion X eview which nucleophiles add 1,4 vs. 1,2 6