Download Presented by Arianne Hunter

Site–Selective and Stereoselective
Functionalization of Unactivated
C–H Bonds
Presented by Arianne Hunter
Sharma Lab Literature Meetings
August 27th 2016
Mechanism of the Week
Reference: J. Org. Chem., 44(25), 1979, (4742–4744)
C–H Activation
 The
synthesis
organic
of
complex
molecules
requires
introduction and manipulation
of various functional groups
 By
providing
functionalize
the
tools
C–H
to
bonds
selectively in the midst of a
complex
molecule,
the
synthetic chemists tool kit will
become far more valuable
Chem. Soc. Rev., 2011, 40, 1857–1869
What is Metal Carbene C–H
Activation
•
•
Catalytically generated metal carbenes are highly versatile for insertion into carbon–
hydrogen and heteroatom–hydrogen bonds
C–H bond insertions are mechanistically different from X–H bond insertions due to their
low bond polarity
Mechanistic Insight
MECHANISM:
• Metal carbene’s p orbital overlaps with the σ orbital of the
reacting C–H bond.
• The character of the metal center greatly effects selectivity
Effects of Metal on Selectivity
Increased electron withdrawal by the ligand from the metal increases
the electrophilicity of the carbene and causes bond formation to take
place at a greater distance from the reacting C–H bond resulting in lower
selectivity.
Problems with C–H Activation

A
key
challenge
in
functionalization is achieving
selectivity

Selectivity in intermolecular reactions is
highly difficult unless donor/acceptor
carbenes are used


C–H
high
Donor group stabilizes electron deficient
carbene and stabilizes its reactivity
Also, control of C–H functionalization is
challenging due to an organic
substrate having many different C–H
bonds
Chem. Soc. Rev., 2011, 40, 1857–1869
Increasing Selectivity in C–H Activation
 Donor/acceptor
rhodium
carbenes are sensitive to both
steric and electronic factors
 From the reacting substrate and
the employed catalyst
 Sites that stabilize positive
charge are very susceptible to
C–H activation
 But due to the typical bulkiness
of dirhodium catalysts sterics
also play a hand in reactivity
Chem. Soc. Rev., 2011, 40, 1857–1869
Chem. Soc. Rev., 2011, 40, 1857–1869
Recent Advances
 Recently
Davies
has
pioneered
advancements
toward high selectivity in C–H
activation through catalyst
control
 Rh2(S-DOSP)4
prefers
functionalization
at
secondary and tertiary C–H
bonds
 Rh2(R-p-PhTPCP)2
functionalization at
C–H bonds
Nature, 2016, 533, 230–234
prefers
primary
TPCP Ligands and Selectivity

Electronic and steric biases in the
reacting substrate can be
overcome through use of the
sterically
demanding
triphenylcyclopropane
carboxylate (TPCP) ligand.

These
bulky
ligands
favor
functionalization at less crowded
C–H bonds

(Trichloroethyl [TCE] esters were
used to limit intramolecular C-H
activation of ester to form betalactone)
J. Am. Chem. Soc. 2016, 138, 5761−5764
The Optimal TPCP Ligand for 2º
Unactivated C–H Bond Functionalization
 The Davies Group synthesized a
variety of TPCP ligands and
found the optimal catalyst was
Rh2[R-3,5-di(p-tBuC6H4)TPCP]4
 Provided the highest selectivity
for
secondary
C–H
functionalization and gave the
best d.r. and e.e.
 Gave prime selectivity in
reactions with modifications at
diazo ester, diazo aromatic,
and alkyl group of the reacting
substrate
Nature, 2016, 533, 230–234
Application of Methodology

The biggest complaint received when
developing methodology, especially in the
field of C–H activation, is the lack of
applicability.

Davies has shattered this perception by
applying his methods in key steps toward the
total synthesis of natural products

In an unprecedented (in synthetic organic
chemistry) multi-lab collaboration, Sorensen
(Princeton), Davies (Emory), and Yu (Scripps)
rapidly assembled the tricyclic core of
indoxamycins
using
their
respective
specialties
Angew. Chem. Int. Ed. 2016, 55, 8270 –8274
Angew. Chem. Int. Ed. 2016, 55, 8270 –8274
Angew. Chem. Int. Ed. 2016, 55, 8270 –8274
Thank You For Listening
Any Questions?