Miyamoto H, Hirano T, Okawa Y, Nakazaki A, * Kobayashi S. * Tokyo University of Science,
Chiba, Japan
Stereoselective Synthesis of Spirocyclic Oxindoles Based on a One-Pot Ullmann Coupling/Claisen
Rearrangement and its Application to the Synthesis of a Hexahydropyrrolo[2,3-
b]indole Alkaloid.
Tetrahedron 2013;
69: 9481-9493
Key words
spirocycles - oxindoles - Ullmann coupling - Claisen rearrangement
Significance
Oxindoles bearing a quaternary stereogenic center at C3 represent attractive synthetic
targets due to both their biological activity and their utility as synthetic intermediates.
Kobayashi and co-workers have previously reported a stereoselective Claisen rearrangement
of bicyclic dihydropyrans to provide multifunctionalized spiro[4.5]decanes (see Review
below). The current study extends this methodology to the rearrangement of pyranoindoles,
which are accessed from readily synthesized 2-haloindoles through an intramolecular
Ullmann condensation (IUC), to yield spirocyclic oxindoles in a stereoselective manner.
Oxidative cleavage of the olefin moiety of the products leads to stereochemically
defined oxindoles, which can be readily elaborated into members of the hexahydropyrrolo[2,3-b]indole family of alkaloids, as demonstrated by the synthesis of (–)-debromoflustramine
B.
Review
A. Nakazakia, S. Kobayashi Synlett 2012, 23, 1427–1445.
Comment
Optimization studies demonstrated that the IUC proceeded best under modified Hauptman
coupling conditions (CuCl, 2-aminopyridine, NaOMe). The Claisen rearrangement occurred
simply by heating the intermediate pyranoindoles. Due to issues with the stability
of the intermediates, a one-pot sequence was developed in which, on completion of
the IUC, the temperature was raised to effect the rearrangement. Indoles incorporating
trans substituents on the allylic alcohol afforded the oxindole as single diastereomers
(NOE, X-ray analyses), the stereochemistry of which indicated that the rearrangement
proceeds through a boat-like transition state. The cis isomers did not give the desired products, and attempts to form furanoindoles also
failed. A range of N-indole protecting groups were tolerated. A remarkable rate enhancement was observed
running the reaction in glyme solvents, which avoided the use of a sealed tube. Subjecting
enantiopure secondary alcohols to the reaction led to a slight erosion in enantiomeric
excess (10–15% ee), whereas the ee of chiral tertiary alcohols was maintained.
