Tag Archive | dipolar cycloaddition

How did this slip by the referees? Azomethine imines are not azomethine ylides

A recent paper by Xingwei Li and co-workers in Angewandte Chemie International Edition has some nice chemistry in it, but take a look at the title, “Rhodium(III)-catalyzed oxidative C-H functionalization of azomethine ylides.”  One might expect to see some azomethine ylides, right?  No, they are azomethine imines:

I suppose one could make the case that azomethine imines are a subset of azomethine ylides, but I’ve never seen it done.  What am I missing here?

[Edit:  Correspondence with Professor Li reveals his point of view:  “the structure can be called both azomethine ylides and azomethine imines,” (sic) and there “is not much difference,” (I strongly disagree on both counts) and “we simply want to emphasize the ylidic character of our substrate.”  Okay, I can understand wanting to emphasize that something is an ylide, but there’s no need to choose an incorrect name to do so.  Learning organic nomenclature is hard enough.  Enough said.  I’m now going to retire my Professor Pearson hat on this issue.]

[Edit: Here’s another paper from the same lab, still referring to azomethine imines as azomethine ylides.  Apparently the referees at Advanced Synthesis and Catalysis aren’t minding the store either.]

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.

Toward the ideal reaction – Part 1

Having worked in the oligonucleotide area where one often wants to snap on a label such as a fluorophore in a site-specific way, I came to appreciate the need for the “ideal reaction;” things are hard enough in this area without messy labeling methods.

Here’s what an ideal conjugation reaction might look like:

  • One step; no protecting group manipulations.
  • Fast at room temperature.
  • Quantitative.
  • Specific.  No cross-reactivity at other sites, double labeling, etc.
  • No catalyst, no additive, no external stimulus.
  • No by-products hanging around that have to be removed.

In the context of bigger molecules such as polymers and biopolymers, one also has to consider compatibility with their chemistry and synthesis.  Let’s stick with oligonucleotides for the moment, though this discussion applies pretty readily to peptides.

In this and the next post, we’ll consider some methods that approach this ideal.

The traditional methods for labeling and bioconjugation are no fun.

As it stands, the classic approach to oligonucleotide modification is a challenge.  First, you synthesize an oligonucleotide that has a protected amine or thiol hanging off somewhere, namely from a nucleobase, the 3’-phosphate terminus, or the 5’-alcohol terminus.  You then deprotect it and treat the resultant amine or thiol with the desired labeling agent, e.g., an NHS ester (for amine labeling) or a maleimide or iodoacetamide (for thiol labeling).  Such reactions are quite imperfect, proceeding in modest yield and selectivity.  A tedious purification is then required to remove the desired labeled material from unreacted starting material, labeling by-products, and other oligonucleotides that somehow aren’t the right ones.  What a blast!

There has to be a better way…

The ideal reaction:  What fits the bill?  

An attractive approach is a spontaneous reaction between the label and a handle that you’ve installed synthetically (and site-specifically) on the oligonucleotide.  Let’s stick with the simplicity of addition reactions, recognizing that there are some other great approaches such as Bertozzi’s Staudinger ligation.

To start with, you would synthesize an oligonucleotide with a handle on it so you have a chance to zero in on that site and that site only.  Check.

Now we need a label that bears a moiety that will recognize the handle (and only the handle) and snap onto it quickly and without any help.  The term “spring-loaded” often gets used.

Sharpless’s concept of click chemistry readily comes to mind.  The de facto standard click reaction, virtually synonymous with the term “click,” is the copper-catalyzed Huisgen 1,3-dipolar cycloaddition between azides and alkynes, an addition reaction that leaves behind a robust triazole linkage.  This reaction has enabled some wonderful things in the world of biomolecule labeling and conjugation.  But still, there’s that copper.  Not quite ideal.  We’ll hear more about this from Jack Hodges in the next post.

Okay, what about metal-free click reactions?  There are a growing number of copper-free azide-alkyne cycloadditions, e.g., with strained cycloalkynes (Bertozzi and others); a great idea.  Again, more on that in the next post.

Inverse-Demand Diels-Alder reactions of tetrazines

Here’s another addition reaction that I like, which draws on the 50+ year-old inverse-demand Diels-Alder reaction between tetrazines and strained alkenes to give dihydrodiazines.  Okay, technically, this is an addition-elimination reaction that produces dinitrogen, but I think we can live with that as a by-product.  On the oligonucleotide front, Jäschke and co-workers  showed that norbornenes could be incorporated into the nucleic acid using normal phosphoramidite chemistry.  Subsequent reaction with various 1,2,4,5-tetrazines, e.g., the dansyl-bearing compound shown, occurred simply by mixing at room temperature in neutral aqueous solution; no catalyst, no other reagents, no help required.   (See also O’Reilly’s very recent example involving polymer functionalization.)

Things are starting to look rather ideal!

For those of you that need to modify biomolecules and polymers, what’s your favorite approach to the ideal reaction?