Applications of NHCs and isothioureas as Lewis base organocatalysts
Abstract
This thesis details investigations into two modes of organocatalytic enolate generation
and reactivity. The first is the addition of chiral NHCs to a ketene to form an azolium
enolate. Investigations into three different electrophiles within this system will be
discussed. The second catalytic system investigated is the formation of a
C1-ammonium enolate through the addition of chiral isothioureas to activated carboxylic acids. Studies on one electrophile within this system will be discussed.
Chapter 2 investigates the use of bespoke C₂-symmetric NHCs in the asymmetric
Staudinger reaction: the formal [2+2] cycloaddition between ketenes and imines. A
chiral relay mechanism was proposed and experimentally validated with β-lactams
prepared in good yields (up to 85%) and moderate enantioselectivity (up to 61% ee).
Chapter 3 describes the asymmetric formal [4+2] cycloaddition between
alkylarylketenes and γ-substituted-β,γ-unsaturated α-ketocarboxylates. A substrate dependant switch in diastereoselectivity was observed with γ-aryl α-ketocarboxylates giving preferentially the syn-dihydropyranones (up to 70:30 dr syn:anti, up to 98% ee
syn) and γ-alkyl α-ketocarboxylates giving preferentially the anti-dihydropyranones
(up to 18:82 dr syn:anti, up to 75% ee anti, 97% ee syn).
Chapter 4 illustrates the extension of the methodology described in Chapter 3 to
include γ-substituted-β,γ-unsaturated α-ketophosphonates. Once more, a substrate
dependant switch in diastereoselectivity was observed with γ-aryl α-ketophosphonates giving preferentially the syn-dihydropyranone-phosphonates (up to
72:28 dr syn:anti, up to 98% ee syn) and γ-methyl α-ketophosphonate giving
preferentially the anti-dihydropyranone-phosphonates (20:80 dr syn:anti, 71% ee anti,
90% ee syn). Within this system it is also possible to generate the alkylarylketenes in
situ with no loss in stereoselectivity but with typically improved yield when compared
with the corresponding two-step procedure.
Chapter 5 describes the activation of arylacetic acids via the formation of a mixed
anhydride followed by C1-ammonium enolate generation with a chiral isothiourea.
Asymmetric Michael addition and lactonisation with γ-substituted-β,γ-unsaturated α-ketophosphonates gave the corresponding anti-dihydropyranone-phosphonates (up to 89:11 dr anti:syn, up to 97% ee anti). More conveniently however, in situ ring opening with MeOH gave di-esters with excellent stereocontrol (up to >98:<2 dr
anti:syn, up to 99% ee anti) and which can be readily derivatised.
Type
Thesis, PhD Doctor of Philosophy
Rights
Embargo Date: Print and electronic copy restricted until 26th May 2016
Embargo Reason: Thesis restricted in accordance with University regulations
Collections
Items in the St Andrews Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.