Dr. Peter Wipf Chemistry 0320 - Organic Chemistry 2 Ester Enolates and Acyl Anion Equivalents

The Claisen condensation is the ester analog of the aldol reaction. Under standard conditions (sodium alkoxide, alkohol), the equilibrium is shifted to the β-dicarbonyl compound as a consequence of the irreversible enolization to the highly resonance-stabilized dicarbonyl enolate.

O O NaOR, HOR O O O O + OR R' R' R' R'=OR, C

The intramolecular Claisen reaction is generally called the Dieckmann condensation. Another modification of the Claisen condensation is the use of strong base which leads to irreversible enolization of the carbonyl compounds.

O OLi LDA, -78 °C PhCOCl O O

OEt OEt THF Ph OEt

β-Dicarbonyl, and, generally, active methylene compounds provide a rich source of chemistry in alkylation reactions, due to their relative ease of enolization and the possibility for removal of one of the activating groups.

Z1 Z2 , Z = ester, ketone, amide, nitrile, aldehyde, nitro, sulfoxide, sulfone, sulfonate, sulfonamide H H

Especially important are acetoacetate and malonate building blocks (acetoacetic and malonic ester syntheses):

O O O O O O

OEt OEt OEt

XCH2CO2R R-X R-X (1 equiv) RCOX O O O O OH O O R R OEt O R

Dithioketals can be used in Umpolung reactions as latent carbonyl groups. Nature’s Umpolung reagent is thiamine pyrophosphate (TPP). In the pentose phosphate pathway, TPP catalyzes the conversion of erythrose into fructose. First, the carbanion of TPP attacks the carbonyl carbon of xylulose 5-phosphate, forming a proton from the TPP adduct, and subsequent electron rearrangement leads to fragmentation, releasing the first product, glyceraldehyde 3-phosphate. The remaining intermediate, a two-carbon fragment bound to TPP, is a resonance-stabilized carbanion. This fragment attacks the carbonyl carbon of ribose 5-phosphate, forming another TPP adduct. A second fragmentation yields the original TPP carbanion and the second product, sedoheptulose 7-phosphate. TPP carbanion O H C R1 R2 R1 R2 H C OH 2- CH2OPO3 R N S R N S Glyceraldehyde Enz B HO C CH2OH 3-phosphate CH2OH H O C H Fragmention Enz B H O C OH H C 2- HO C H CH2OPO3 H C OH 2- CH2OPO3 R1 R2 Xylulose TPP adduct 5-phosphate R N S C HO CH2OH

R1 R2

R N S R1 R2 C H CH2OH R1 R2 Enz B R N S N S R H O C CH2OH O H Enz B H C HO C H H C OH H C OH H C OH Enz B H H C OH H C OH Fragmention H C OH 2- 2- CH2OPO3 CH2OPO3 CH2OH C O Ribose TPP adduct 5-phosphate HO C H H C OH H C OH H C OH 2- CH2OPO3 Sedoheptulose 7-phosphate