Diastereoselective Synthesis of Bridged Polycyclic Alkaloids via Tandem Acylation/Intramolecular Diels–Alder Reaction

A mild
and efficient stereoselective synthesis of hexacyclic indole
alkaloids with a tetrahydro-β-carboline motif has been developed
by utilizing the Pictet–Spengler reaction and tandem N-acylation followed by intramolecular Diels–Alder
cyclization. Initially, a diene unit was installed in the tetrahedron
β-carboline skeleton through Pictet–Spengler cyclization
of the corresponding aldehyde with tryptophan ester. The dienophile
moiety was introduced by N-acylation of tetrahydro-β-carboline.
Successive, in situ, [4 + 2] intramolecular Diels–Alder cycloaddition
of the activated dienophile and conjugated diene containing intermediate
furnished bridged polycyclic heterocycles with high diastereoselectivity.
Formation of four new rings, five new covalent bonds, and five new
chiral centers with excellent stereoselectivity is the key feature
of this strategy. The diastereoselective formation of product was
attributed to intramolecular chirality transfer through a chiral amino
acid. The stereoselective outcome of this tandem reaction was confirmed
by X-ray crystallographic studies. The developed synthetic strategy
was also explored on a soluble polymer support to incorporate the
advantage of rapid synthesis and a high-throughput workup process
toward the development of a green synthetic protocol for polycyclic
alkaloids.