A New Route to Roseophilin

In an effort to educate my readers, I’ve put together an analogy.  Admittedly, you probably won’t see this sort of problem on any SAT (maybe a MENSA-qualifying exam one day), but here it goes:

Stoltz : Wolff/Cope :: Frontier : ____________

• (a) Wynn/Trump
  
• (b) Jahn-Teller
  
• (c) Nazarov
  
• (d) Knoevenagel/Diels-Alder
  
• (e) Corey
  

I enjoy reading work from Alison Frontier’s group; they handle a good array of challenging projects that contribute to the overall (practical) growth of synthetic organic chemistry.  Admittedly, I’ve even gone so far as to ask a prof in our department to invite her for a guest seminar.  The Frontier group invests a large amount of research effort towards Nazarov chemistry—that would be answer (c)—those pesky 4-pi, conrotary, electrocyclization reactions that are often covered in physical organic chemistry to highlight the importance of orbital overlap. 

Nazarov chemistry can be used to construct cyclopentanones from divinyl or allyl-vinyl ketones.  I became interested in Nazarov chemistry when I saw Frontier’s total synthesis of merilactone A (J. Am. Chem. Soc. 2008, 130, 300-308).  Despite the modest yield, Frontier eloquently demonstrated an Ir(III)-catalyzed Nazarov cyclization (historically, Nazarov reactions require an excess of Lewis acid).  I continue to check in on her publications from time to time.

Frontier and Bitar have recently carried the Nazarov chemistry into the formal synthesis of roseophilin (Org. Lett. 2009, 11, 49-52), an antitumor antibiotic of medium-size, and fairly complex functionality.  Fuchs and co-workers are credited with the first formal synthesis of racemic roseophilin (Tetrahedron Lett. 1997, 38, 2601-2604), and over the past 10 years (or so), several other groups have thrown their respective hats into the ring (Trost, Boger, Fürstner, Dudley, etc.).  While several of these synthetic routes focus on Paal-Knor conditions, Frontier’s approach made use of Nazarov chemistry to access the [3.3.0] bicycle. 

Frontier’s Nazarov conditions required catalytic use Sc(III) salts and 1 molar equivalent of lithium perchlorate.  Presence of the LiClO₄ is believed to convert the Sc(OTf)₃ to Sc(ClO₄)₃—a highly active catalyst in Nazarov cyclizations (Tetrahedron Lett. 1994, 35, 3319).  In methodological studies prior to this synthesis, Frontier noted a similar effect (Org. Lett. 2006, 8, 5661).  While I like the method Frontier developed, I wonder if there was a way around the dichloroethane. 

Tsuji-Trost allylation of the enone gave the tricyclic roseophilin frame in 82%.  I have a few comments to make about this step.  First, the large amount of palladium(II) acetate and air-sensitive ligand makes this specific allylation chemistry slightly undesirable.  Second, the product contained ~20% of a diene side product, which taken into accound, adjusts the yield to ~66%.  Also, sodium hyride is not terribly practical given the pKa of the active methylene moiety; a better bet may have been to use K₂CO₃.

All in all, a good chapter in the roseophilin saga. 

Happy New Year from the RoOC staff—me.