Organic
Letters, 2012, 14, 2078
J. P. Lajiness, W. Jiang, D. L. Boger
This paper describes the synthesis of (+)-spegazzinine,
isolated from Aspidosperma chakensis
in 1956. From a synthetic point of view,
there are 4 attached rings – two of which are spiro bound, 5 contiguous chiral
centers – 3 of which are quaternary. Boger’s
group had developed a powerful methodology to construct the core of this
molecule back in 2002, where 1,3,4-oxadiazoles undergo a intramolecular
Diels-Alder reaction with a dienophile.
The resulting adduct loses nitrogen and undergoes a 1,3-dipolar
cycloaddition reaction with an indole ring to furnish 3 atteched rings with
upto 6 chiral centers formed stereoselectively around the central ring in a
single step. (See: JACS, 2002, 124, 11292). The synthesis of (+)-spegazzinine is thus an
extension of that methodology.
In the case of (+)-spegazzinine, the vinyl ether in not
present, instead of the ester – there is an alcohol group, the aryl ring in indole
is substituted with a hydroxyl group, and lastly, instead of the amide – there
is an amine.
Retrosynthetically, (+)-spegazzinine is prepared by the
reduction of the corresponding amide 9,
since the amide is essential for the [4+2]/[3+2] cascade. The hydroxyl group in 9 comes from a cyano hydrin in 8,
which is produced by ring-opening (“reduction”) of 7. Compound 7 is derived from the ester 6 – which is the key intermediate
produced by the [4+2]/[3+2] cascade. Its
precursor, 5 has the 1,3,4-oxadiazole
ring and the alkene group, which is in turn made by coupling the appropriate
acid chloride with amine 4. The oxadiazole ring is made by the hydrazide 3, which comes from activated amine 1.
-Spegazzinine.gif)
-Okilactomycin+D.bmp)
