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Title: Organocatalytic functionalisation of carboxylic acids using isothioureas
Author: Morrill, Louis Christian
ISNI:       0000 0004 5348 0589
Awarding Body: University of St Andrews
Current Institution: University of St Andrews
Date of Award: 2014
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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.
Supervisor: Smith, Andrew D. Sponsor: Carnegie Trust for the Universities of Scotland
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Organocatalysis ; Isothiourea ; Organic chemistry ; Asymmetry ; Lewis base