Organocatalysis

CEW/BNN Group Meeting

27/10/2015

Grant Sherborne

Introduction • Term first used in 2000, though early work dates back to 1860’s

• Catalysis with small molecules where an inorganic element is not part of the active centre

• Four classes of organocatalysis, dominated by Lewis base catalysts such as amines and carbenes

Advantages Disadvantages

Easy preparation or availability

High catalyst loading

Easy handling; inert towards moisture and air

Relatively premature field

Ease of scale-up

No metal contamination

Large chiral pool

Mode of Activation

• Lewis Bases (B:) – Initiate the catalytic cycle by nucleophilic addition to the substrate (S) • Lewis Acids activate nucleophiles in a similar manner • Brønsted base and acid catalytical cycles are initiated via deprotonation or partial

deprotonation respectively

Lewis Base Catalysis

• Activation of the reaction based on the nucleophilic/electrophilic properties of the catalyst

Hajos-Parrish-Eder-Sauer-Wiechert

• An enantioselective aldol reaction, catalysed by L-proline • This reaction has been extended to other reactions, including α-alkylation,

Mannich Reaction, Michael Addition, and α-amination of ketones.

Hajos–Parrish–Eder–Sauer–Wiechert reaction

• Dehydration reaction to synthetically useful Wieland-Miescher ketone

Knoevenagel-Condensation

• Nucleophilic addition of an active hydrogen compound to a carbonyl group, followed by a dehydration reaction to make substituted olefins, using an amine catalyst

• Activated hydrogen component allows use of weak base where a strong base would result in self-condensation of the carbonyl species

Knoevenagel-Condensation Mechanism

• Formation of enolate followed by attack on iminium ion intermediate formed via reaction of the amine with an aldehyde or ketone

• Nitrogen is protonated followed by a rearrangement to produce final olefin product

Steglich esterification

• Conversion of sterically demanding substrates such as tert-butyl esters which are troublesome under Fischer esterification conditions

• DCC used to activate carboxylic acid and DMAP acts as an acyl transfer-reagent as it is a stronger nucleophile than alcohol

• Typically 3-10 mol% DMAP used

Steglich Esterification Mechanism

No DMAP Acyl migration side product

With 5 mol% DMAP

Brønsted Acid Catalysis

• BINOL-derived phosphoric acids have emerged as highly versatile catalysts

• Known for over 40 years but usage as catalysts only reported in early 2000’s

• Sir John Cornforth studied requirements of the ideal catalyst, resulting in work on phosphinic acids – the principles of which can be applied to modern phosphoric acids

Chem. Rev. 2014, 114, 9047−9153

Brønsted Acid Catalysis

• A large number of potential interactions between catalyst and variety of substrates

• Mode of bonding determined by R- groups on substrate

• Electron rich substrates tend to prefer ion-pairs

• Electron deficient substrates more prone to hydrogen bonding interactions

• Brønsted acididy and solvent can also play a part in determining which species are involved

• Mono- and dual-activation proposed

Dual-activation

Mono-activation

Brønsted Acid Catalysis Examples

PA 2 – R = SiPh3

PA 7 – R = 9-anthrecenyl

Alkylation of α-diazoesters

Mono- and dual-activation proposed

Friedel-Crafts

Enantioselective α-Vinylation of Aldehydes via the Synergistic Combination of Copper and Amine Catalysis

This work

Eduardas Skucas and David W. C. MacMillan

J. Am. Chem. Soc. 2012, 134, 9090−9093

Important yet complex synthetic task as product can undergo olefin-carbonyl exchange or racemisation Combines Cu(I)-Cu(III) and chiral amine-enamine catalysis

Reaction Mechanism and scope

Gaunt Enantioselective Cyclopropanation

• First asymmetric cyclopropanation catalysed by a chiral tertiary amine • Ammonium ylide involved in the reactive intermediate • Catalytic loadings of 1-20 mol% can provide good yields and high enantioselectivities • Effective for a range of enones, enals and other α,β-unsaturated compounds

Catalyst

Catalyst

3 1

2

Gaunt Enantioselective Cyclopropanation - Problem