Smith MW, Snyder SA * Columbia University, New York, USA
A Concise Total Synthesis of (+)-Scholarisine A Empowered by a Unique C–H Arylation.
J. Am. Chem. Soc. 2013;
135: 12964-12967
Key words
scholarisine A - pyrone Diels–Alder reaction - C–H arylation - Keck allylation - radical
cyclization
Significance
The structural complexity of the akuammiline alkaloid scholarisine A poses considerable
synthetic challenges. Snyder and Smith report an elegant and short route to this natural
product that relies on a Diels–Alder reaction and radical cyclization to provide rapid
access to the target’s core. The indolenine is introduced in an intriguing late-stage
C–H-arylation step. The architecturally unique alkaloid could thus be prepared in
merely 15 steps. It is noteworthy that only one other synthesis of this challenging
target has been reported so far (G. L. Adams, P. J. Carroll, A. B. Smith, III. J. Am. Chem. Soc. 2012, 134, 4037).
Comment
The lactone of the natural product was introduced early in the synthesis through the
Diels–Alder cycloaddition of dienophile A and pyrone B, which afforded C in 83% yield and 3:1 dr. Cleavage of the acetonide followed by displacement of the
resulting primary alcohol furnished bromide D. Radical cyclization and subsequent trapping gave key intermediate E in 59% yield as a single diastereomer. An epimerization–lactamization sequence afforded
F which was treated with 2-iodoaniline to give imine G. This underwent the challenging tertiary C–H arylation, affording I. A few transformations later the synthesis was completed.
