Phillip Gulliver Dominic Greenwood
a-Amino ketones and 1,2-amino alcohols are important structural motifs in organic chemistry, that
can be observed in natural products, pharmaceutically and bioactive compounds. For these reasons,
they constitute privileged targets for the development of new and effective synthetic methods.
The dual-functionalisation of unsaturated carbon-carbon bonds is a powerful approach to access
these crucial motifs. In this context, Pd catalysis has been comprehensively investigated and has
consistently demonstrated its capability. Methods enabling the concomitant formation of a carbonâ
heteroatom and a carbonâcarbon bond are highly valuable, but the challenges of intermolecular
reactions have led to the development of tether systems that require additional steps for their introduction
and removal. In situ tethering strategies have previously been explored within the Waser
group to circumvent these limitations. This approach relies on a one-pot, three component, Pd catalysed
carboetherification or amination reaction, leading to rapidly increase in complexity of simple
substrates. So far, the in situ methodologies developed by the Waser group have focused on the
functionalisation of alkenes from allylic amines and alcohols.
In this regard, the goal of my PhD was to expand the in situ tethering methodologies established
within the Waser group, to the synthesis of a-amino ketones and 1,2-amino alcohols. Specifically,
my focus was on the formation a trifluoromethyl hemiaminal with a propargylic amine and using
the resulting aminal to direct the oxyalkynylation and oxyarylation of the alkyne substrate via a Pd
catalysed transformation. Upon optimisation, the reaction of a protected terminal propargylamine,
trifluoroacetaldehyde ethyl hemiacetal and silylbromoacetylene using a Pd0 complex with DPEPhos
as the catalytic system and Cs2CO3 as the base gave the desired oxazolidine alkenes in high yields
and E:Z selectivity. Substrates with substitution on the terminal position and at the propargylic
required a change of ligand and base. The transformation was broadly tolerant towards substitution
on the nitrogen and the alkyne. An oxyarylative variant was also developed, using Ruphos
as ligand, and worked well with a range of iodoarene partners. The obtained oxazolidines could
be conveniently orthogonally deprotected to access the a-amino ketone and terminal alkyne; the
hydrogenation of the unsaturated oxazolidines has allowed access to 1,2-amino alcohol scaffolds
and the application of gold catalysis converted the enyne-oxazolidine system into trisubstituted silyl
furans.
The identification of a sideproduct of the oxyalkynylation process led to the development of a
carboxy-alkynylation reaction using a "CO2" unit derived from the carbonate base. Optimisation
established CsHCO3 to the best base/"CO2" source, using DPEPhos as ligand. This transformation
gave convenient access to diverse library of cyclic carbamates.
Work is ongoing to achieve an enantioselective oxyarylation using chiral phosphine ligands. The
asymmetric synthesis of oxazolidines, followed by the diastereoselective alkene hydrogenation and
subsequent tether removal would allow the stereodivergent access to interesting diarylalkyl-1,2-
amino alcohols. Most recently, the product was synthesised in 66% yield, with 66%ee using commercially
available Trost ligand.
EPFL2020
