<p>Chiral molecules with their defined 3-D structures are of
paramount importance for the study of chemical biology and drug discovery. Having
rich structural diversity and unique stereoisomerism, chiral molecules offer a large
chemical space that can be explored for the design of new therapeutic agents.<sup>1</sup> Practically, chiral architectures are
usually prepared from organometallic and organocatalytic processes where a transition
metal or an organocatalyst is tailor-made for desired reactions. As a result,
developing a method that enables rapid assembly of chiral complex molecules
under metal- and organocatalyst-free condition represents a daunting challenge.
Here we developed a straightforward route to create a chiral 3-D structure from
2-D structures and an amino acid without any chiral catalyst. The center of
this research is the design of a <a>special chiral
spiroimidazolidinone cyclohexadienone intermediate</a>, a merger of a chiral
reactive substrate with multiple nucleophillic/electrophillic sites and a
transient organocatalyst. <a>This unique substrate-catalyst
(“subcatalyst”) dual role of the intermediate enhances </a><a>the coordinational
proximity of the chiral substrate and catalyst</a> in the key Aza-Michael/Michael cascade
resulting in a substantial steric discrimination and an excellent overall
diastereoselectivity. Whereas the “subcatalyst” (hidden catalyst) is not
present in the reaction’s initial components, which renders a chiral
catalyst-free process, it is strategically produced to promote sequential self-catalyzed
reactions. The success of this methodology will pave the way for many efficient
preparations of chiral complex molecules and aid for the quest to create next
generation of therapeutic agents.</p>
Chemoenzymatic one-pot reaction of noncompatible catalysts: combining enzymatic ester hydrolysis with Cu(i)/bipyridine catalyzed oxidation in aqueous medium