Total Syntheses of Multiple Cladiellin Natural Products by Use of a Completely General Strategy

The enantioselective total syntheses of 10 cladiellin natural products
have been completed, starting from the known allylic alcohol (+)-14, which can be prepared in large quantities. The bridged
tricyclic core of the cladiellins has been constructed via three ring-forming
reactions: (i) an intramolecular reductive cyclization between an
aldehyde and an unsaturated ester, mediated by samarium­(II) iodide,
to form a tetrahydropyranol; (ii) reaction of a metal carbenoid, generated
from a diazo ketone, with an ether to produce an ylide-like intermediate
that rearranges to produce E- or Z-oxabicyclo­[6.2.1]-5-undecen-9-one; and (iii) a Diels–Alder
cycloaddition reaction to construct the third ring found in the core
structure of the cladiellins. The key ring-forming reaction, in which
a diazo ketone is converted into a bridged bicyclic ether, can be
tuned to give either of the isomeric oxabicyclo[6.2.1]-5-undecen-9-ones
as the major product by switching from a copper to a rhodium catalyst
and selecting the appropriate reaction conditions. The tricyclic products
obtained from the three-step sequence involving the Diels–Alder
cycloaddition reaction can be employed as advanced intermediates to
prepare a wide range of cladiellin natural products.