spiroketals - Diels-Alder reaction - hydroxybenzyl-acetates - quinone methide
Significance
Reported is the synthesis of arylsubstituted benzannulated [5,6]-spiroketals
from the thermal reaction of 2-hydroxybenzylacetates with γ-methylene-γ-butyrolactone.
The reaction proceeds via an ortho-quinone
methide which then undergoes Diels-Alder cycloaddition
to give the spiroketal products. The starting acetates were synthesized
in high yield through selective acetylation of the requisite 2-hydroxybenzyl
alcohols.
Comment
Due to their range of biological activity, spiroketals have come
to be considered privileged pharmacophores. However, methods for
their formation are few and usually require a starting material
synthesized using a difficult and protracted process, such as a
keto-diol (see Book below). In contrast, the current method uses
Diels-Alder chemistry to form the spiroketal unit in one
step. This should prove extremely useful due to the ease of the
reaction, high yields, and the ready availability and relative inexpense
of the starting materials. The scope of the reaction was explored based
only on 4- and 5-substituted benzylacetates. Nevertheless, these
were intelligently chosen examples that demonstrate a tolerance
to both electron-withdrawing and -donating groups at the 4- and
5-position of the aromatic ring.
Book: S. V. Ley, L.-G. Milroy, R. M.
Myers, In Science of Synthesis,
Vol. 29; S. Warriner, Ed.; Georg Thieme Verlag: Stuttgart, New York, 2007, 613-690.
