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.  

Just Being a Wise-@ss

I’m glad to see companies are selling “organic” products for your health and beauty.  Why?  Because washing your hair with chromium was so passé.  

Wagering on Chemistry

As I write this, I’m sitting at McCarran Airport in Las Vegas.  The city was crippled yesterday (Wednesday) with the first snowfall since 1979 (so much for global warming), which consequently caused the airport to close at 3 pm.  In turn, there are people everywhere, waiting to get out of this vacuum of trust funds and mortgage payments.  That sounded bitter, and I’m way off topic.

In the spirit of Vegas, I started thinking about the similarities between chemistry and gambling, more specifically blackjack.  Gambling has played a pivotal role in many discoveries.  The classic example, though controversial, is Columbus’ “discovery of America.”  Love him or hate him, he placed a heavy wager on finding a new way to India.  Jonas Salk rolled the proverbial dice when he tested his polio vaccine on himself.  I’m suddenly recalling that George and Ira Gershwin song “They all Laughed” (best performed by Ella Fitzgerald and Louis Armstrong).

Think about the traits of a good blackjack player for a moment.  You have to be well educated in the game (i.e. know your odds of success, know basic strategy, etc.).  All good blackjack players will manage their playing money well; why risk more than you can afford?  And, most critically, professionals usually don’t go on hunches.  They have a plan and stick to it.  If they keep getting bad cards they either switch tables or call it a night.

How is this any different than chemistry?  A good chemist will know the chances of a success for a given reaction in the general sense.  In my mind, a good chemist will manage money well (it’s more prudent to spend $50 here and there for chemicals you know you’ll use versus dropping $200 on long shot chemistry).  And, all good chemists know when to throw in the towel and call it a night.

Nothing groundbreaking; just a though.

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.