<p></p><p> Development of a rapid synthesis of complex
molecules from simple building blocks under a metal-and organocatalyst-free
condition is both conceptually and chemically challenging. Here, we developed a
hidden catalysis that allow the straightforward assembly of enantiopure
aza-tricyclic molecules containing six contiguous stereocenters from <a>aminophenols, α,β-unsaturated aldehydes </a>and α-amino
acids. <a>Without using a metal or an organocatalyst, our
approach relies on a temporary formation of a spiroimidazolidinone intermediate
and its participation in a sequential aza-Michael/Michael reaction as both a
substrate and a catalyst</a> under an iminium/enamine catalysis. The formation
of the putative iminium intermediate was supported by spectroscopic data and its
interruptive reduction derivative was isolated and fully characterized. Whereas
a conventional catalyst is always present and does not undergo a permanent
chemical change in a classic catalysis, the spiroimidazolidinone intermediate is
conceptualized as a sub-catalyst as it is only temporary produced from
precursors and catalyzes its own consumption. This unique substrate-catalyst
(sub-catalyst) dual role of the spiroimidazolidinone induces a substantial steric
discrimination in the transition state and an excellent overall
diastereoselectivity (>20:1 dr). It allows the use of an amino acid
precursor as the sole chirality genesis and avoids the use of transition metals
or organocatalysts. An enantiomer of an aza-tricyclic
imidazolidinone can be prepared from a commercially available amino acid
precursor. The aqueous-based reaction is practical and scalable for multi-gram
synthesis. The success of implementing this sub-catalysis concept in the
synthesis will pave the way for many efficient chiral catalyst-free
preparations of chiral complex molecules.<br></p><br><p></p>
A hidden catalysis: metal-, and organocatalyst-free one-pot assembly of chiral aza-tricyclic molecules