ConspectusAn ortho-quinone methide (o-QM)
is a highly reactive chemical motif harnessed by nature for a variety
of purposes. Given its extraordinary reactivity and biological importance,
it is surprising how few applications within organic synthesis exist.
We speculate that their widespread use has been slowed by the complications
that surround the preparation of their precursors, the harsh generation
methods, and the omission of this stratagem from computer databases
due to its ephemeral nature.About a decade ago, we discovered
a mild anionic triggering procedure
to generate transitory o-QMs at low temperature from
readily available salicylaldehydes, particularly OBoc derivatives.
This novel reaction cascade included both the o-QM
formation and the subsequent consumption reaction. The overall transformation
was initiated by the addition of the organometallic reagent, usually
a Grignard reagent, which resulted in the formation of a benzyloxy
alkoxide. Boc migration from the neighboring phenol produced a magnesium
phenoxide that we supposed underwent β-elimination of the transferred
Boc residue to form an o-QM for immediate further
reactions. Moreover, the cascade proved controllable through careful
manipulation of metallic and temperature levers so that it could be
paused, stopped, or restarted at various intermediates and stages.
This new level of domestication enabled us to deploy o-QMs for the first time in a range of applications including diastereocontrolled
reactions.This sequence ultimately could be performed in either
multipot
or single pot processes. The subsequent reaction of the fleeting o-QM intermediates included the 1,4-conjugate additions
that led to unbranched or branched ortho-alkyl substituted
phenols and Diels–Alder reactions that provided 4-unsubstituted
or 4-substituted benzopyrans and chroman ketals. The latter cycloadducts
were obtained for the first time with outstanding diastereocontrol.
In addition, the steric effects of the newly created stereocenters
in subsequent reactions of chroman ketals and acetals were studied
and proved predictable. Through the use of a chiral auxiliary, Diels–Alder
products were deployed in numerous enantioselective reactions including
several complex natural products syntheses. In this Account, we summarize
our efforts, which we hope have contributed to the synthetic renaissance
for this venerable species.
The total syntheses of medicarpin, sophoracarpan A, and kushecarpin A from a common intermediate are achieved by using ortho- and para-quinone methide chemistry. Additionally, the relative stereochemistry of sophoracarpan A and B have been reassigned.
An eight-step asymmetric synthesis of (+)-marineosin A is described. The route proceeds by condensing fragments of reversed polarity relative to conventional prodiginine constructions. The resultant unstable chromophore is disrupted by a unique cycloisomerization promoted at a tailored manganese surface. This provides a premarineosin and subsequently marineosin A in a particularly concise manner. A pyridinophane N-oxide photorearrangement in flow and structural isomers of premarineosin are discussed, as is the reassignment of marineosin stereochemistry. The route gives access to the natural product as well as diastereomers, congeners and analogs that are currently inaccessible by other means.
The total syntheses of medicarpin, sophoracarpan A, and kushecarpin A from a common intermediate are achieved by using ortho‐ and para‐quinone methide chemistry. Additionally, the relative stereochemistry of sophoracarpan A and B have been reassigned.
Reaction
pathways operative when pyridinophane N-oxides are
photoirradiated have been studied using time course analyses
and careful isolation of photolabile intermediates with support from
DFT calculations. Based on the data and the isolation of two previously
unknown heterocyclophanes, we outline a unified mechanistic scheme
that explains competing processes under varying photochemical conditions.
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