44127-G4
Cooperative Binding of Molecular Oxygen via Mechanochemical Coupling
Martin D. Burke, University of Illinois at Urbana-Champaign
Cooperative Binding of Molecular Oxygen by a Hemoglobin Mimic aims to
combine rational design with combinatorial chemistry to d
This project aims to advance our fundamental
understanding of mechanochemical coupling,
i.e., the coupling of an
exergonic chemical reaction with endergonic changes in molecular
conformation.Albeit only
minimally studied in small molecule systems to date, this phenomenon is widely
utilized by natural macromolecules to perform a variety of important functions.
A prototypical example is the respiratory protein hemoglobin, which utilizes
mechanochemical coupling to achieve cooperative binding and release of
molecular oxygen ligands. The project combines rational design with
combinatorial chemistry to develop small molecules with the capacity to
replicate these properties.A new
graduate student joined my group this past year and began to lead this project
in November, 2007.
The mimimum structural and energetic requirements to
display cooperativity in this system are unknown. A model system was envisioned
for an initial approach, maintaining the essential rotation scaffold of this
proposed structure, but simplifying the binding domains. In this way, the
structural details of this rotation are more easily assessed, and this
information will be applied to the final design of the hemoglobin mimic. The
model system is predicted to display cooperative metal-binding – the
porphyrin sites and histidyl ligands are replaced with metal-binding domains,
rotating around the same bis-alkynylphenyl-anthryl core (see TOC graphic). The
pyridyl ligands bind two equivalents of a Zn(II) salt, with the endothermic
rotation to appoximate the pyridyls for the second binding event paid for by
the first binding event. This model system will explore the competency of this
scaffold for providing the energetic requirements that permit observation of
mechanochemical coupling. Our efforts have thus far focused around the
synthesis of this model system.
With
examples of the key upper and lower fragments in hand, the fastening of the two
coupling partners of the molecule was planned as a very demanding aryl chloride
Suzuki coupling. Multiple conditions were screened for the deprotection and
subsequent coupling of the MIDA boronate with 9-chloroanthracene as model
coupling experiments. Through variation of Pd sources, bases, and reaction
conditions, the coupling has been achieved, albeit at very low yield. The
coupling is among the most demanding seen in a literature survey, with the
added disadvantage of carrying free pyridyl units, potentially complicating the
coupling further. While attempts to optimize the coupling are in progress,
these results challenge the first generation plan, which hinges around this
late-stage aryl chloride Suzuki coupling. Other approaches will also be
explored that place the central aryl chloride Suzuki coupling earlier in the
route, followed by derivitization around the central bond, but these approaches
have not yet provided an efficient solution to the problem.
By modification of the transmetallating partner, the
documented anthracene structure can be maintained in the synthetic plan –
while departure from the proposed 2,7-dibromo-9-chloro-anthracene and
reassessment of the substitutions around this coupling partner also provides
avenues by which the target core structure can be assembled. Exploring many
synthetic possibilities focused on this core rotational structure may also
provide a collection of different compounds with distinct, unpredicted
functionality. As the basic structural requirements for displaying
mechanochemical coupling are as yet unknown, attempting to circumnavigate the
synthetic challenges of this structure may provide even more competent
scaffolds. With a structure, or a collection of structures, in hand, we will
begin to delve into the fascinating concept driving the project – a small
molecule that mimics hemoglobin in function, allowing transfer of the most
essential responsibility of human blood from a natural protein to an unnatural
synthetic compound.
The funds provided by the PRF G grant have been
instrumental in making this project possible, and enabled me to accept this new
student into my group with the confidence that partial funding of his graduate
education is secured.This
experience will provide this student with the opportunity to gain a world-class
education in the synthesis of organic molecules and the systematic testing of
their functions. If it were not for the PRF G grant being funded, this high
risk (but potentially very high reward) project may have been relegated to
later in my career, after my laboratory was more established.Thanks to this funding, we are poised
to commit serious resources and energy in this exciting direction in the coming
year.