Taking a Peak at Basiliolide B

Chi-Sing Lee and co-workers recently published a route to basiliolide B that features a pretty cool transformation (Org. Lett. ASAP; doi: 10.1021/ol8022787).  This target has been the focus of research efforts of the Stoltz (Org. Lett. 2008, 10, 25–28) and Dudley (Tetrahedron Lett. 2008, 49, 2899–2901) not only because of its biological activity—an irreversible SERCA (Ca²⁺) pump inhibitor—but also due to its stereochemical complexity (I count six stereogenic centers, three of which are quaternary). 

Lee’s retrosynthesis featured the (seemingly) obvious disconnect of the 7-membered lactone in the target and deconstruction of the hexene ring via base-catalyzed Diels-Alder (essentially the primary focus of the paper).  They then hypothesized that the methyl enoate could derive from the alpha-hydroxy furan system (a transformation that was essentially claimed in one step).  It was this later step that really caught my attention. 

In the manuscript, Lee and credits the transformation of the alpha-hydroxy furan to the corresponding lactone to Achmatowiz (Tetrahedron 1971, 27, 1973–1996).  Using a model system, the team from China demonstrated the transformation using a bromonium source (i.e. NBS) and sodium acetate in THF and water.  Subsequent Jones oxidation gave the quinone-type (??) compound.  Given the excellent yield, the optimized Achmatowiz reaction conditions were applied en route to basiliolide B. 

The mechanism of the Achmatowiz reaction, sadly, won’t be found in Kürti and Czakó’s bible.  In fact, it appears a bit amorphous.  One could rely on a bit of chemical intuition to get a ballpark guestimate of how the mechanism proceeds.  Admittedly, I was stumped, however.  So, I opted to take the scholarly way out and I chase down a few references. 

Achmatowiz and co-workers originally ran their reactions with elemental bromine in methanol and suggested the formation of an isolatable 2,5-dimethoxyfuran intermediate, a transformation covered by Elming years earlier (see: Advances in Organic Chemistry, 1960, 2, 67).  Tee and Swedlund appear to have proposed a reasonable mechanism (Can. J. Chem. 1983, 61, 2171-2176) where the bromonium provides the driving force for the oxygen addition to make a new C-O bond.  Their method was demonstrated on a furan (minus the alpha,hydroxy substituent) and seemed pretty reasonable.  In any case there was no mention of regioselectivity. 

Here’s what I’ve been able to piece together: bromine addition creates an oxo-carbenium-type intermediate where the acetate can add to the 5-membered ring in the 5-position.  It’s not clear if the reaction then proceeds through the ring opening or undergoes SN2 thus displacing the bromide. 

If we assume, then, that the diacetate is formed, the rest of the mechanism appears quite easy.  Mild acid helps hydrolize the secondary acetate while opening the ring giving the intermediate hemiketal.  Collapse of the hemiketal into the dicarbonyl intermediate followed by 6-exo-trig cyclization gives the lactone.  The enol is explained by tautomerization.

It’d be nice to see a more indepth study of this mechanism to gain more information (RDS, intermediate trapping/isolation, etc.).  All in all, it seems like a pretty interesting transformation.

P.S. The primary article for this post was found courtesy of ChemFeeds (which is becoming my new favorite website).  If you haven’t yet checked out Mitch’s baby, please do so.  It’s a really useful tool in reviewing literally hundreds of articles in ~ 1 h.