Bode and He have shown that chalcone-derived (acyclic) α,β-unsaturated sulfonylketimines 209
can act as competent electrophiles with enals 16, giving highly enantioenriched β-lactam
products 210.100 The scope and generality of the reaction has been widely examined and a range
of enals 16 and sulfonylketimines 209 are tolerated. Notably, alkyl-substituted enals, acrolein
and 3,3-dimethylacrolein are all suitable substrates, all giving excellent levels of enantio- and diastereoselectivity, although the acroleins give only moderate yields (45–50%) (Figure 46). Notably, this reaction follows a different pathway to the related work by the same authors using sulfonylaldimines 172, which give rise to dihydropyridone products 173.
Figure 46: Enantioselective γ-lactamisation
Related work by Nair and co-workers (using enones in place of α,β-unsaturated sulfonylimines
(see page 14), generates β-lactones with trans-ring substituents, while the β-lactam products 210
possess a cis-stereochemical relationship. A mechanistic rationale for the observed cis-selectivity has been proposed based on preorganisation of the Breslow-type intermediate and imine through hydrogen bonding 211, with an aza-benzoin oxy-Cope process proposed. Reaction via a boat
Figure 47: Rationale for enantio- and diastereoselective β-lactam formation
Bode and Kaeobamrunghave demonstrated an analogous reaction using α-hydroxyenone 217 as
the electrophile.101 Interestingly, triazolium-derived NHCs give β-lactones 219 and
imidazolium-derived NHCs give γ-lactones 218, both with excellent levels of enantioselectivity.
The authors postulate a similar benzoin oxy-Cope mechanism to account for the high level of stereoselectivity in the process. This divergence in behaviour has been attributed to the leaving group ability of the NHC: the triazolinylidene has a significantly lower pKa than the respective
imidazolinylidene, so in the case of the triazolium catalyst, the NHC is a sufficiently good leaving group to afford β-lactones as the major product. In contrast, the intermediate derived
from the imidazolium catalyst undergoes preferential alkoxide elimination to afford an acylimidazolium intermediate, which undergoes a retro-aldol–aldol sequence (Figure 48).
Figure 48: Divergence between triazolium- and imidazolium-derived NHCs in lactone formation with
hydroxyenones
Recent developments by Lupton and co-workers have shown alternative uses for NHCs in organocatalysis through trapping of α,β-unsaturated azolium intermediates.102 Treatment of enol
Mechanistically, it is proposed that nucleophilic addition of the NHC to the enol ester generates an α,β-unsaturated azolium intermediate and enolate, which recombine in a conjugate manner to
afford pyranones 221. An enantioselective variant of this reaction has been demonstrated using
chiral triazolium salt 55 as the NHC precatalyst, obtaining the product in good yield and 50% ee (Figure 49). The intermolecular version of this reaction has also been achieved with TMS enol ethers and α,β-unsaturated acyl fluorides, but not yet in an enantioselective fashion.
Figure 49: Pyranone formation
Section 1.7: Steglich rearrangement
While many developments have been made in NHC-mediated organocatalysis, their ability to mimic classical Lewis bases, such as the aminopyridine DMAP (4-dimethylaminopyridine), have been relatively less investigated. This thesis sets out to exploit this reactivity, with the goal of extending the substrate scope due to their increased reactivity in comparison with the traditional aminopyridines.
This thesis focuses on the transformation first described by Steglich and Höfle, the rearrangement of oxazolyl esters and carbonates 223 to their C-acylazlactone isomers 226 and 227. This reaction, known as the Steglich rearrangement, was shown to be catalysed by the
aminopyridines DMAP 224 and PPY (4-pyrrolidinopyridine) 225.103 Variation of the steric and
electronic properties of the substrates was investigated, whereby generally the
α-carboxyazlactone product 227 is obtained in preference over the γ-carboxyazlactone product
226. Regioselectivity in this process can be altered by choice of the R1 and R2 substituents: if R1
is highly electron-withdrawing (i.e. CF3 or 4-O2NC6H4), this overrides the general preference
for α-carboxylation, thereby giving the γ-carboxyazlactone 226; furthermore, attempts to
perform the rearrangement of the highly sterically encumbered substrate 223 with R2 = t-Bu give rise to the γ-carboxyazlactone 226, possibly due to the reduced steric interactions in this product
Figure 50: Dearomatisation of oxazolyl esters/carbonates – the Steglich rearrangement
This transformation allows for the catalytic formation of a new quaternary centre, a particular challenge in organic synthesis.104 The products of the reaction, in particular the
C-carboxyazlactones, are masked forms of quaternary amino acids, biologically important products.105 Quaternary amino acids are generally unnatural amino acids, playing a key role in higher order protein structure by giving unique folding to polypeptide structures (such as the Aib-Pro β-turn), and the amino acids have increased chemical and metabolic stability compared
to natural amino acids. The azlactone products can be treated with a range of nucleophiles106,107,108 to give access to highly functionalised products (Figure 51) which can be further elaborated as required.
Figure 51: Illustration of product derivatisation
Whilst this transformation has proven highly valuable, there are several drawbacks to the reaction. Reaction times often extend from several hours to days, and the regioselectivity of the reaction is dependent upon both the steric and electronic properties of the 2- and 4- substituents of the oxazolyl framework 223.
Mechanistically, it has been proposed that both DMAP 224 and PPY 225 act as nucleophilic
(Lewis basic) catalysts by attack at the carbonyl of 223, generating an acyl transfer agent 233
acyl transfer reagent 233 to yield the rearranged isomer 227 (or 226) with regeneration of the
DMAP catalyst 224.
Figure 52: Catalytic cycle of the Steglich rearrangement
As this rearrangement gives rise to the formation of a new stereocentre, there has been significant interest in effecting this transformation asymmetrically, with several publications detailing such efforts.109 Fu and co-workers published the first enantioselective Steglich rearrangement using a planar-chiral catalyst PPY* 235, a ferrocene-fused PPY analogue
(Figure 53).106 This catalyst promoted the enantioselective rearrangement of a number of oxazolyl carbonates 234 at low catalyst loadings (typically >2 mol%), but the reaction requires
the use of a polar solvent (tert-amyl alcohol) and a relatively long reaction time of >6 h. The synthesis of the catalyst 235 also requires numerous steps, including a late-stage resolution to
facilitate its preparation in enantiomerically pure form. Importantly, α-branched substitution at
C(4) is also not tolerated.
Figure 53: Enantioselective Steglich rearrangement using PPY* (Fu)
Subsequently, Vedejs and co-workers have introduced two new chiral Lewis basic catalysts to perform the Steglich rearrangement enantioselectively. The first is a related aminopyridine TADMAP 238, based upon the structural core of DMAP but with a proximal stereocentre.107 The
catalytic activity and level of asymmetric induction of 238 is comparable to that published by Fu
successful rearrangement substrates described by Fu and co-workers, although reaction times remain long, a polar solvent is still required, and α-branched alkyl carbonates are not tolerated.
Figure 54: Enantioselective Steglich rearrangement using aminopyridineTADMAP(Vedejs)
The second was the chiral phosphine-based catalyst 240. Similarly to the results of Fu, the
phosphine promoted rearrangement of C(4)-alkyl substituted oxazolyl carbonate substrates 234
in good yield and up to excellent levels of asymmetry, but again, α-branched substituents are not
tolerated.
Figure 55: Chiral phosphine-promoted asymmetric Steglich rearrangement
A recent publication by Richards and co-workers utilised chiral relay technology to induce enantioselectivity (Figure 56), with low catalyst loadings of cobaltocene 242 and the use of the
non-polar solvent toluene.108 Extensive reaction times were still necessary and cryogenic incubation at -20 ºC was required to induce higher enantioselectivity, at the expense of decreased product conversion.
* Determined by methanolysis of the product and analysis by chiral HPLC. Assumed retention of configuration.
Figure 56: Chiral relay effect to effect enantioselective Steglich rearrangement (Richards)
Section 1.8: Previous work in the Smith group
Preliminary work within the Smith group has utilised achiral NHCs as efficient catalysts to effect the Steglich rearrangement of oxazolyl carbonates.110 Initial investigation of model substrate 224
using the NHCs derived from imidazolium salts 79 and 245 showed limited success at effecting
the Steglich rearrangement (Figure 57). A vast improvement in the protocol was made by using triazolium salt precatalyst 128 and KHMDS as the base to generate the active NHC; using Et3N
as the base, no product conversion was observed.
Figure 57: Initial previous studies of the Steglich rearrangement using NHCs
The generality of this rearrangement protocol was demonstrated by variation of the carbonate functionality with a number of unbranched oxazolyl carbonate substrates, giving the products in generally very good isolated yield (Figure 58).
Figure 58: Demonstration of the effectiveness of the NHC in catalysis of the Steglich rearrangement
Mechanistically, a similar catalytic cycle to that for DMAP 224 is proposed, supported by
studies using crossover experiments. These studies have also shown that the C-C bond formation is irreversible with the rearrangement of oxazolyl carbonates, but full determination of the catalytic cycle was still required.
Section 1.9: Aims and objectives
This work set out to further investigate the use of NHCs as Lewis basic catalysts and efficient carboxyl transfer reagents to effect the Steglich rearrangement.
The first aim of the research was to probe the reactivity of both catalyst and substrate in order to afford an extension to the substrate scope of the rearrangement, with the potential to promote the rearrangement of α-branched substrates. Further to this, a fuller investigation of the mechanism
of the rearrangement was sought.
With an understanding of the rearrangement, the enantioselective variant of the Steglich rearrangement was to be investigated, through the design, synthesis and investigation of chiral NHCs, whilst also exploring the potential of the development of new Lewis bases capable of promoting these reactions.
The final aim of this research was to extend the synthetic utility of the Lewis base-promoted rearrangement to other heterocyclic carbonate frameworks.