Scalable Synthesis of Biologically Relevant Spirocyclic Pyrrolidines

Synthetic
approaches toward multigram preparation of spirocyclic
α,α-disubstituted pyrrolidines from readily available
starting materials are discussed. It was shown that although a number
of synthetic methodologies have been known to date, many of the title
compounds remain hardly accessible. The most appropriate literature
method (which relied on reaction of imines and allyl magnesium halide,
followed by bromocyclization) was identified and optimized. It was
found that the method is most fruitful for simple non-functionalized
substrates. Two novel approaches based on the Sakurai or Petasis reactions
of cyclic ketones, followed by hydroboration–oxidation at the
allyl moiety thus introduced, were elaborated. The latter method had
the largest scope and was beneficial for the substrates containing
organosulfur or protected amino functions. For the synthesis of 4-azaspiro[2.4]­heptane,
an alternative synthetic scheme commencing from tert-butyl cyclopropanecarboxylate (instead of the corresponding ketone)
was developed. It was shown that the whole set of the methodologies
developed can be used for the synthesis of various spirocyclic α,α-disubstituted
pyrrolidinesadvanced building blocks of potential importance
to medicinal and agrochemistryat up to a 100 g scale.