The development of
new one-pot sequential
cyclizations involving a Vilsmeier–Haack reaction followed
by an organocatalyzed Mannich reaction is reported. This synthetic
strategy gives access to functionalized indolizidines and quinolizidines
in one operation from readily synthesized precursors. Yields and diastereoselectivities
are good to excellent when formamides are used to trigger the key
step, bearing either an electron-rich aryl or a pyrrole as the nucleophilic
partner in the first cyclization.
Arylidene
acetals are widely used protecting groups, because of
not only the high regioselectivity of their introduction but also
the possibility of performing further regioselective reductive opening
in the presence of a hydride donor and an acid catalyst. In this context,
the Et3SiH/PhBCl2 system presents several advantages:
silanes are efficient, environmentally benign, and user-friendly hydride
donors, while PhBCl2 opens the way to unique regioselectivity
with regard to all other Brønsted or Lewis acids used with silanes.
This system has been extensively used by several groups, and we have
demonstrated its high regioselectivity in the reductive opening of
4,6- and 2,4-O-p-methoxybenzylidene
moieties in protected disaccharides. Surprisingly, its use on 4,6-O-benzylidene-containing substrates 1 and 2 led to unreproducible yields due to the unexpected formation
of several side products. Their characterizations allowed us to identify
different pitfalls potentially affecting the outcome of reductive
opening of arylidenes with the Et3SiH/PhBCl2 reagent system: alkene hydroboration, azide reduction, and/or Lewis
acid-promoted cleavage of the arylidene. With this knowledge, we optimized
reproducible and high-yielding reaction conditions that secure and
extend the scope of the Et3SiH/PhBCl2 system
as a reagent for the regioselective opening of arylidenes in complex
and multifunctional molecules.
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