Enabling the Buchner ring expansion as a practical synthetic tool
Embargo Date
2021-02-10
OA Version
Citation
Abstract
Seven-membered rings are a key structural motif in many bioactive natural product
families but compared to five- and six-membered rings, there are substantially fewer
methods for their synthesis. The Buchner ring expansion provides expedient access to
seven-membered carbocycles in a single step from simple starting materials. Moreover, the
products are highly oxidized, which is ideal for downstream functionalization and
utilization in complex molecule synthesis and medicinal chemistry. Herein, we disclose
our efforts and progress towards enabling the Buchner ring expansion as a safe and
practical synthetic tool.
The intermolecular Buchner ring expansion remains largely unused as a general
method to access seven-membered rings due to poor selectivity and limited substrate scope
that arise from the exothermic nature of the reaction. We have demonstrated that the
regioselectivity of the intermolecular Buchner reaction is greatly improved under
continuous flow conditions due to improved heat transfer and mixing. We disclose the first
example of an asymmetric intermolecular Buchner reaction using disubstituted diazo esters
in good to excellent enantioselectivity (up to 98% ee).
The intramolecular Buchner reaction has been used in many total syntheses to
access 5,7- and 6,7-bicyclic carbocyclic cores. However, toxic and explosive diazomethane
has traditionally been used to synthesize the requisite a-diazocarbonyl precursors. To
enable a safer synthesis, we have developed a method to synthesize a-diazocarbonyls from
carboxylic acids via reaction of acid fluorides with trimethylsilyl diazomethane, which is
known to be less hazardous than diazomethane.
To fully leverage the potential of the novel highly oxidized seven membered rings
obtained in the Buchner reaction we embarked on a search for selective reactions of the
underexplored cycloheptatrienes. We performed reaction screens to provide a knowledge
base and toolbox of reactions for manipulating the reactivity the cycloheptatrienes through
oxidations, reductions, and cycloadditions.
Finally, we disclose our efforts towards the development of a novel method for the
synthesis of azepines from aryl diazoacetates and pyridine. Upon irradiation with blue
light, aryl diazoacetates are photolyzed and undergo Buchner-type reactivity to afford
azapines in moderate yields. Preliminary mechanistic studies and an investigation of the
scope of the reaction are discussed.