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Just look at the structure of this alkaloid!

Sometimes you just have to step back and marvel at the structures that are found in nature.  Check out zamamiphidin A, a new manzamine alkaloid isolated from an Okinawan sponge by J. Kobayashi and co-workers (Organic Letters).  Heptacyclic.  Quaternary ammonium.  Massively bridged.  Well done, sponges!

Zamamiphidin A

Saturated nitrogen heterocycles by intramolecular CH amination reactions

Here’s a process that I think needs continued attention from the synthetic community:  Making saturated nitrogen heterocycles from simple N-alkylamines by intramolecular CH amination reactions.  There’s a lot of great chemistry out there for related process where there is an electron-withdrawing group attached to the nitrogen within the tether (vide infra), but let’s focus on N-alkyl groups.  With all the activity on CH functionalization chemistry in general, I hope this reaction will become routine at some point.  Let’s take a look at some recent work in this area.

The basic CH amination reaction

The Hoffmann-Löffler-Freytag reaction – An medicinal chemistry application

To exemplify the need for such a reaction, consider the compounds shown below, appearing in a recent J. Med. Chem. paper by McClure and coworkers at Pfizer.  The diazatricyclodecane (or diazaadamantane) heterocycles in the dotted boxes were proposed as conformationally restricted piperidines that might make good agonists of G-protein-coupled receptor 119.

Pfizer diazatricyclodecanes

The Pfizer group settled on a Hoffmann-Löffler-Freytag (HLF) reaction to form the heterocycle.  In their initial work, they were unable to reproduce Rassat’s route to such diazatricyclodecanes (JACS 1974), which involved heating the N-bromoamine in acid.  Switching to the N-chloroamine led to only 14% of the desired compound accompanied by 40% of an elimination product involving the N-benzyl group.

Initial HLF route

Ultimately, forgoing the protecting group was fruitful.  N-Chlorination of the primary amine shown below was followed by photolysis with a 450 W mercury lamp to provide multigram quantities of the crude cyclization product.  Acylation followed by demethylation of the other amino group provided the key diazatricyclodecane for their studies.

Final HLF route

One curious bit is the chlorination reaction:  The authors do not state how many equivalents of t-butylhypochlorite are used.  This seems rather important, since primary amines are well-known to form dichloroamines.  I’ve contacted to authors, so hopefully we’ll know soon whether they were dealing with the monochloroamine or the dichloroamine. [Update: Dr. McClure responded that 1.2 equivalents of t-BuOCl were used.]

The Pfizer compounds did not pan out, so we’ll never know if their process research wizards would be able to employ the HLF route in a scaleup setting, but I imagine it would be an uphill battle.  If photochemistry is ruled out, I imagine the “acid and heat” HLF would have to be sorted out somehow.

Now it’s easy to see why a more modern CH functionalization reaction with a catalytic transition metal would be useful, right?

Toward a practical intramolecular CH functionalization reaction

In recent work, Chen (Penn State) and Daugulis (U. Houston) and their coworkers have independently described palladium-catalyzed picolinamide-directed intramolecular CH amination reactions:

Chen + Daugulis insertions

This seems like an excellent strategy, and I look forward to seeing where this research will go.  How about metal-free, light-free, halogen-free versions?  There’s a worthy goal!

[Edit: More Chen goodness covered by See Arr Oh at Just Like Cooking: Remote alkylation directed by PA groups.]

Finally, I’d be remiss if I didn’t mention the extensive work in the literature on intramolecular aminations using nitrenoids that are substituted by strong electron-withdrawing groups (DuBois, Sanford, Davies, White, Lebel, Panek, and others, leading reference here).  It’s a bit different from what we’re talking about here, since the electron-withdrawing group ends up in the tether, making cyclic sulfamates, carbamates, and the like.

By the way, if you’re interested in this topic, you might also look at some nice recent work by Tom Driver at UIC, who is using aryl azides as the nitrogen source for metal-catalyzed intramolecular CH aminations.  His paper is also a good entry to the literature of CH aminations in general.

Fun new alkaloids: Let the synthesizing begin!

For the alkaloid lovers out there, here are a couple of new structures that made me say aloud, “Cool!”

Shi-Shan Yi and co-workers at the Chinese Academy of Medical Sciences and Peking Union Medical College (Beijing) just reported (Organic Letters) the isolation and structure determination of several new alkaloids from Lycopodium japonicum including the two compounds lycojaponicumin B and C shown above.  (I’ve drawn them a bit differently; I can’t resist tinkering.)

Natural products that feature an isoxazolidine ring?  Nice.  There may be others… I haven’t checked.  Anyone?

How long will it take for someone to fire up the total synthesis machinery to make these?  And how long will it take for someone to say, “Hey, let’s employ an intramolecular 1,3-dipolar cycloaddition of a nitrone!” I’ll save everyone the trouble of disconnecting these alkaloids into the two obvious nitrone precursors by showing them here:

It’s possible that nature has already accomplished the first route.  The authors propose that lycojaponicumins B and C are produced biosynthetically from fawcettimine as shown below.

Let the synthesizing begin!

By the way… The Heterocyclist is relocating from Chicago to Raleigh this month, so things might be a bit quiet around here.