ConspectusUmpolung, a term describing
the reversal of innate polarity, has
become an indispensable tool to unlock new chemical space by overcoming
the limitations of natural polarity. Introduced by Dieter Seebach
in 1979, this principle has had a tremendous impact on synthetic organic
chemistry, offering previously inaccessible retrosynthetic disconnections.
In contrast to the great progress made over the past decades for the
generation of effective acyl anion synthons, the umpolung at the α-position
of carbonyls (converting enolates into enolonium ions) has long proved
challenging and only recently regained traction. Aiming to develop
synthetic approaches to α-functionalization capable of complementing
enolate chemistry, our group initiated, nearly 6 years ago, a program
devoted to the α-umpolung of carbonyl derivatives. In this Account,
following an overview of established methods, we will summarize our
findings in this rapidly developing field. We focus on two distinct,
yet related, topics of two carbonyl classes: (1) amides, where umpolung
is enabled by electrophilic activation, and (2) ketones, where umpolung
is enabled using hypervalent iodine reagents. Our group has developed
several protocols to allow amide umpolung and subsequent α-functionalization,
relying on electrophilic activation. Over the course of our investigations,
transformations that are particularly challenging using enolate-based
approaches, such as the direct α-oxygenation, α-fluorination,
and α-amination of amides as well as the synthesis of 1,4-dicarbonyls
from amide substrates, have been unlocked. Based on some of our most
recent studies, this method has been shown to be so general that almost
any nucleophile can be added to the α-position of the amide.
In this Account, special emphasis will be placed on the discussion
of mechanistic aspects. It is important to note that recent progress
in this area has involved a shift in focus, moving even further away
from the amide carbonyl, a development that shall also be detailed
in a final subsection that highlights our latest investigations of
umpolung-based remote functionalization of the β- and γ-positions
of amides. The second section of this Account covers our more recent
work dedicated to the exploration of the enolonium chemistry of ketones,
unlocked through the use of hypervalent iodine reagents. By placing
our work in the context of previous pioneering achievements, which
mainly focused on the α-functionalization of carbonyls, we discuss
new skeletal reorganizations of enolonium ions enabled by the unique
properties of incipient positive charges α to electron-deficient
moieties. Transformations such as intramolecular cyclopropanations
and aryl migrations are covered and supplemented by detailed insight
into the unusual nature of the intermediate species, including nonclassical
carbocations.