C–H FUNCTIONALIZATION: A NEW STRATEGY FOR THE SYNTHESIS OF BIOLOGICALLY ACTIVE NATURAL PRODUCTS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 1

1
C-H FUNCTIONALIZATION:
A NEW STRATEGY FOR THE
SYNTHESIS OF BIOLOGICALLY
ACTIVE NATURAL PRODUCTS

CHAPTER

SOPHIE ROUSSEAUX, BENO ˆ T LI ´ GAULT, and
KEITH FAGNOU
Department of Chemistry, University of Ottawa, Ottawa, Ontario, Canada

1.1. INTRODUCTION

The advent of transition metal-catalyzed transformations at C-H bonds has enabled
the efficient formation of a wide range of carbon-carbon and carbon-heteroatom
bonds from simple C-H bonds [1]. As a strategy, these transformations use unac-
tivated C-H bonds as functional groups to generate molecular complexity. While
these processes represent a chemical ideal from the standpoint of atom economy and
synthetic efficiency, the ubiquitous nature of C-H bonds and their relative strength [2]
pose a significant challenge for selectivity and reactivity, which has been the focus of
research efforts over the past decade. The current knowledge in the field has enabled
the use of C-H functionalization as a reliable tool for natural product synthesis, even
as a late-stage manipulation in complex targets [3].
Synthetic approaches toward transition metal-catalyzed transformations at
C-H bonds are divided between two distinct mechanisms [4]. Outer sphere mechan-
isms ( coordination chemistry ) proceed via the direct interaction of the C-H bond
being functionalized with a ligand coordinated to the transition metal. This mech-
anismhas been exploited both inmetal-catalyzed carbene/nitrene insertions into C-H
bonds and in metal-oxo-catalyzed C-H oxidations [5,6]. On the other hand, inner
sphere mechanisms ( organometallic chemistry ) involve the formation of a carbon-
metal bond as a result of C-H bond cleavage [7]. This chapter will discuss the
application of the latter form of reactivity, also known as C-H activation or C-H
functionalization, to the synthesis of biologically activemolecules. Whilemany of the