Organocatalytic functionalisation of carboxylic acids using isothioureas
Abstract
This thesis describes investigations into the ability of isothioureas to act as organocatalysts in formal [4+2] cycloadditions between carboxylic acids and various Michael acceptors via C1-ammonium enolate intermediates.
Initial research focused upon establishing optimal reaction conditions to affect the asymmetric intermolecular formal [4+2] cycloaddition between a range of arylacetic acids and α-keto-β,γ-unsaturated esters, giving anti-dihydropyranones in high yield (49-87%) and with excellent diastereo- and enantioselectivity (up to 98:2 dr, up to 99% ee). This represented the first time that carboxylic acid derived ammonium enolates have been successfully applied towards an intermolecular reaction process.
Subsequent studies utilised trifluoromethyl enones as Michael acceptors, forming a range of C(6)-trifluoromethyl anti-dihydropyranones with good diastereoselectivity (up to 95:5 dr) and enantioselectivity (up to >99% ee). Detailed mechanistic studies were carried out, revealing that the process was stereospecific, with the diastereoisomer of product formed dependent upon the configuration of trifluoromethyl enone used. A variety of product derivatisations were demonstrated including those which introduce additional trifluoromethyl-bearing stereogenic centres with high diastereoselectivity. Kinetic studies indicated that this Michael addition-lactonisation process is first order with respect to both in situ formed anhydride and catalyst concentration, with a primary kinetic isotope effect observed using α,α-di-deuterio 4-fluorophenylacetic acid. DFT computational studies support a rate-determining formation of a reactive ammonium enolate prior to a stereochemistry-determining enone conjugate-addition step.
The isothiourea-catalysed α-amination of carboxylic acids with low catalyst loadings (as low as 0.25 mol%) using N-aryl-N-aroyl Michael acceptors was demonstrated, forming a range of 1,3,4-oxadiazin-6(5H)-ones or hydrazide products with excellent enantiocontrol (typically >99% ee). Notably, the scope of this methodology was expanded to allow the direct functionalisation of carboxylic acids bearing α-heteroatom and alkyl substitution for the first time. The synthetic utility of the hydrazide products was demonstrated through their derivatisation into a range of bespoke functionalised N-aryl-α-arylglycine derivatives in high enantiopurity (up to 99% ee).
Isothiourea-mediated functionalisation of 3-alkenoic acids was shown to occur regioselectively, giving products derived from α-functionalisation of an intermediate C1-ammonium dienolate in a range of formal [2+2] and [4+2] cycloadditions. Formal [4+2] cycloadditions with either trifluoromethyl enones of N-aryl-N-aroyl diazenes allow access to products in high diastereo- and enantiocontrol (up to 95:5 dr, up to 99% ee). The simple, two-step elaboration of stereodefined hydrazides into aza-sugar analogues without erosion of enantiopurity has also been demonstrated.
2-Arylacetic anhydrides were also demonstrated as useful precursors for the formation of C1-ammonium enolates in isothiourea-mediated Michael addition-lactonisation processes. Trifluoromethylenones,α-keto-β,γ-unsaturated esters and N-aryl-N-aroyldiazenes are reactive Michael accceptors in this process, with HBTM-2.1 (5 mol%) readily promoting heterocycle formation with high diastereo- and enantiocontrol (up to 95:5 dr, up to >99% ee). This protocol offered a useful and practical alternative to the in situ carboxylic acid activation method, in which by-product formation and the amount of sacrificial base used is minimised.
DHPB was shown to promote the one-pot synthesis of 2,4,6-subsituted pyridines bearing a readily derivatised 2-sulfonate functionality from (phenylthio)acetic acid and a range of α,β-unsaturated ketimines in moderate yields (40-66%). Functionalisation of the 2-sulfonate group via various methodologies allowed the rapid assembly of both novel and biologically relevant pyridines.
Type
Thesis, PhD Doctor of Philosophy
Collections
Items in the St Andrews Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.