Total Synthesis of (+)-Isatisine A: Application of a Silicon-Directed Mukaiyama-Type [3 + 2]-Annulation

Complete details of an asymmetric
synthesis of (+)-isatisine A
(1) are described. The synthesis highlights the use of
a highly diastereoselective Mukaiyama-type [3 + 2]-annulation of allylsilane 5 with the unsaturated aldehyde 9a to assemble
the functionalized tetrahydrofuran core of isatisine A. A convergent
route to the framework of the natural product was established that
employed a substrate-controlled indole coupling that was followed
by a late-stage intramolecular copper­(I)-mediated amidation to complete
the assembly of the tetracyclic framework of (+)-isatisine A. In addition,
the scope of the [3 + 2]-annulation was evaluated and enhanced utilizing
diastereomeric allylsilanes anti-5 and syn-5 to establish an efficient route to stereochemically
well-defined tetrahydrofurans.