Selective Synthesis of sp2 and sp3 Rich Structures via π Activation

The development of concise and selective synthetic methods is a key enabling science for areas of significant importance, such as drug discovery and materials science. This thesis describes the development of synthetic methods, dependent on the activation of π systems, which allow stereo-, regio- and chemoselective access to sp2- and sp3-rich ring structures.

Methods previously developed within our group for the asymmetric Nazarov reaction are expanded to include a general strategy to access cyclopentanoids containing multiple 4° stereocentres (Chapter 2). This relies upon carbometalation of oxazolidinyl ynamides to stereoselectively provide highly substituted divinyl and aryl vinyl ketones, which undergo Nazarov reaction to provide up to three contiguous 4° centres and two bond forming events in a single step (Scheme 1).

The oxazolidinone directed asymmetric Nazarov reaction was applied towards the asymmetric synthesis of the cyclopentabenzo[b]furan scaffold of the rocaglates, a class of natural products with potent anticancer activity. As an initial approach to the dearomatising asymmetric Nazarov reaction required for this synthesis was unsuccessful, alternative approaches were investigated and are described in Chapter 4.

To further the development of the asymmetric Nazarov reaction, novel sources of chiral anions were applied to the enantioselective Nazarov reaction as chiral catalysts (Chapter 3). This led to the development of methods for the synthesis of unsymmetrically substituted BINOL derived chiral anions through directed ortho metalation (DoM), to introduce metal coordinating groups and steric blocking groups. The resulting chiral anions are able to coordinate a Lewis acid and may be of use as ligands for chiral catalysis in the Nazarov reaction and other metal catalysed reactions which proceed through cationic intermediates. A notable development of this chemistry is the diastereoselective lithiation and unsymmetrical substitution of the BINOL scaffold directed by the prochiral N-triflyl phosphoramide (X=NTf) (Scheme 2).

The activation of the π system of alkynes for the synthesis of sp2 rich structures has been essential to access precursors of the Nazarov reaction for the synthesis of sp3 rich structures. To further develop the selective synthesis of sp2 rich structures, this thesis investigated the π activation of alkynes with iodine to intramolecular nucleophilic attack (iodocyclisation) in both mechanistic and synthetic studies (Chapter 5). These studies elucidated the unique ability of iodine to overcome the electronic balance of an alkyne to promote iodocyclisation as compared to other electrophilic iodine sources (Scheme 3). The insights gained from these studies were applied to the synthesis of poly-[2,3-b]-fused benzothiophenes through a reiterative alkyne assembly-iodocyclisation sequence (Scheme 4).

As a whole, this thesis presents a number of complementary methods for the selective synthesis of both sp2- and sp3-rich structures through the activation of alkyne π systems. A number of publications have resulted from the work in this thesis and are presented as their published versions (Chapter 5) or as a manuscript for submission (Chapter 2). As a result, each chapter has its own compound numbering scheme, references and experimental section. Digital copies of the spectra for each chapter can be found as an appendix at the end of the digital version of this thesis or on CD attached inside the back cover of the hard copy of this thesis.