A Methodological Improvement?

Once in a while I'll catch an interesting methodology that’s an improvement on what’s currently available.  In my mind, nine times out of ten, I often regard “new methods” for what they’re worth (sometimes garbage) and go about my day.  Not trying to copy Excimer’s recent post on CBC, I’ll propose a different analogy for synthetic methodology.  Do you remember when the Coca-Cola Company came out with New Coke (c. 1985)?  Coca-Cola pumped millions of dollars into formulation research and marketing analysis to come up with a new recipe for Coke Classic, which they dubbed as New Coke—the new, next best thing.  However, when the new formulation came to market, it tanked (evidenced by dormant sales) eventually causing Coca-Cola to switch back to their original formulation.  Sometimes synthetic methodology is (or has the makings to be) a diamond in the rough (i.e. Diet Coke); most often it’s largely unimportant (i.e. New Coke).  This notion is especially true when the chemistry hits close to home. 

Have you ever done a Wittig reaction?  I do them quite often and they have the propensity to be disastrous: lots of phosphine oxide byproducts (often requiring several purifications to remove); the reagents can be somewhat expensive; the chemistry often requires the use of benzene/toluene as a solvent (many see this as a health hazard) and some of the reagents are air sensitive (at least, according to my PI).  That said, the “homologative” properties of Wittig-type reactions are unparalleled.  Several methods and or total syntheses require installation of an a,b-unsaturated carbonyl (or nitro, nitrile, imine, etc.) at some step. 

Enter Greg Dudley—an alkyne Jedi—and his tweeked Meyer-Schuster methodology, a viable alternative to Wittig reactions (or keeping with the Coca-Cola analogy, it would be the Coke Zero of the Wittig world).  Dudley and Engel first reported their chemistry a couple years ago (Org. Lett. 2006, 8, 4027-4029) and recently put out a follow up paper earlier this year (Tetrahedron 2008, 64, 6988-6996).  Dudley’s methodology originally involved nucleophilic addition of an alkyne followed by rearrangement to the desired ethyl enoate using gold(III) chloride.  The beauty of this chemistry, according to Dudley, was that the reactions (both steps) could be done in air without external heating.  The team demonstrated the proof of concept in the conversion of adamanilone to the corresponding ester enoate. 

The caveat to this methodology was two-fold.  First, the early methodology offered essentially no stereocontrol about the olefin geometry.  Second, rearrangement involved 5 mol % of the gold catalyst.  Of course, this reagent is remarkably expensive.  For what it’s worth, in a follow up to the 2006 paper, Dudley and co-workers reported on the wonders of the mixed catalyst gold(I) chloride and silver(I) hexafluoroantimonate where inclusion of CSA resulted in marked selectivity improvements (Synlett 2007, 949-953).

I came across Dudley’s recent paper a couple days ago, which is worth taking a look at if you’re a synthetic nerd like me.  Essentially, Dudley and co-workers demonstrated methodology similar to his previous papers only now he made use of cheaper catalysts.  Starting from benzaldehyde, for example, he’s able to install the ethoxyalkynyl moiety in excellent yields (already been demonstrated).  By treating the corresponding carbinol with catalytic quantities of copper(II)- or scandium(III) triflate, he’s able to isolate the desired ester enoate in high yields with reasonably good stereocontrol (~3:1 mix of E/Z).  The mechanism proceeds through the allene intermediate, which is hydrolyzed to the hemi-estertal (I think I just invented a term) finally giving the enoate upon elimination of the alcohol. 

Impressive chemistry, though I’d like to see preparation of a nucleophilic alkynyl reagent where this chemistry can occur in one pot.  That’d rock for 2 reasons.  First, it would rival Wittig reagents as we know them.  There’s nothing more convenient then measuring out your reagent and dumping it into your reaction mixture.  Second, there would be very little waste generated in these reactions.  Can you imagine doing Wittig-type transformations without generating triphenylphosphine oxide (for example)?  Purification may not be necessary in these cases!  (This is sounding more and more like an ORP idea.)

P.S. My eye’s doing much better, though I’ve learned that grad school has essentially murdered my long distance vision.

P.P.S. In the spirit of olefination chemistry I’ll leave you with a homework assignment.  Recall that “normal” Wittig reagents predominantly give Z-olefins whereas Horner-Wadsworth-Emmons and “stabilized”-type reagents tend to give E-olefins.  In the example below, the acetonide aldehyde is treated with a “stabilized” ylide to predominantly give the unexpected Z-olefin (Org. Synth., Coll. 2004, 10, 152).  How do you account for this phenomenon?