Tag Archive | nitrones

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.

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Toward the ideal reaction – Part 2

Toward the Ideal Reaction – Part 2

In Part 1, the concept of an ideal reaction for biomolecule labeling was outlined:  One step, no protecting groups, fast, efficient, specific, no catalyst or reagents, no external stimulus, and easy cleanup.  Jäschke’s work on oligonucleotide labeling via the inverse-demand Diels-Alder cycloaddition of tetrazines with norbornenes was featured.

Let’s look at some other chemistry and invite an expert guest, Jack Hodges, to chime in.  He also has a few things to say about big pharma versus small companies.

What about click chemistry?  Well, about that copper…

When one thinks of simple addition reactions for biomolecule labeling, click chemistry comes to mind.  Sharpless’s copper-catalyzed dipolar cycloaddition of azides with alkynes to produce triazoles is the de facto standard click reaction, but, well, it uses copper.  Not ideal.  Plus, the copper may cause problems in the applications we’re focusing on.

Naturally, ingenious chemists have jumped on that problem.

Copper-free click reactions – dial in some strain, maybe change the dipole

How do you speed up dipolar cycloadditions to alkynes without using copper?

You can fool around with the electronics of the alkyne, but then you run the risk of making it susceptible to unwanted reactions.

Alternatively, it’s well-known that dipolar cycloadditions are faster with strained dipolarophiles.  Bertozzi harnessed this effect for click chemistry via cyclooctynes (so-called SPAAC reactions, for strain-promoted alkyne-azide cycloadditions).  Others have joined the fray.

Another approach is to swap out the azide for a speedier nitrone dipole (SPANC reactions), as reported by the groups of van Delft and McKay.

Here’s an example of what we’re talking about, using van Delft’s bicyclononynes (BCNs):

Insights from a guest expert:  Dr. Jack Hodges

To give us an inside look at the state of the art in this area, we have with us my colleague Jack Hodges, ex-WLPD/Pfizer, who now leads the chemistry effort at Berry & Associates, Inc. (B&A), a firm that specializes in nucleic acids chemistry.  Some of you may recall Jack’s prominence in the early days of combinatorial chemistry, where he published seminal articles on the use of polymer-supported scavengers.  He has recently negotiated a scientific and business relationship between B&A and SynAffix, B.V. to provide a line of SPAAC reagents for the oligonucleotide field that are derived from van Delft’s BCN.

Will Pearson:  Jack, what are some of the challenges of using click chemistry in the oligonucleotide field?  

Jack Hodges:  There are plenty of examples of people who have used Cu-catalyzed Click reactions on oligonucleotides but there are also other examples where the Cu(I) catalyst has been reported to cause partial degradation of the oligo.  The partial degradation paper we always note in our product literature is Kanan, M.W., et al., Nature, 2004, 431, 545-9.  There are probably other similar reports.  This problem doesn’t seem too surprising to me since both Cu(I) and Cu(II) can coordinate to heteroatoms, and nucleic acids are full of heteroatoms.  Whether or not you believe Cu(I) is a serious problem around oligos, my feeling is that if you don’t need it, why bother?  There are numerous recipes for making Cu(I) in-situ for traditional Click reactions and often it takes a fair amount of investigation to find the one that will work for your application.  The Cu-free approach does away with all that.  Just put the strained alkyne and the azide together and the triazole forms.  The old fashioned expression is “dump and stir”.  Somehow “dump and stir” doesn’t have as nice a connotation as “Cu-free Click” or the sound of the quirky acronym “SPAAC” (short for strain-promoted azide/alkyne cycloaddition), but in practice it is just that simple.

WP:  For copper-free click reactions of azides with alkynes, there are quite a few competing techniques.  Would you please tell us about your path to selecting van Delft’s BCNs, giving us a little perspective on the various technologies that are available?  What made BCNs your top choice for commercialization?  (B&A also sells compounds based on Schultz & Pigge’s MFCOs.)

JH:  There are two things that attracted us to BCN.  First the BCN synthesis looks attractive from a commercial standpoint.  It starts with 1,5-cyclooctadiene (which is about as cheap an 8-membered ring compound as one can buy) and requires relatively few synthetic steps, each of which look to be scalable.  Second, BCN has the lowest calculated LogP value among the other popular cyclooctynes in the literature.  This makes BCN desirable in terms of maintaining the viable biological properties for oligos and other biological macromolecules to which it is attached.  DIFO is pretty close to BCN in terms of LogP but it is much harder to synthesize.  To be fair, BCN-OH is still hugely more lipophilic than propargyl alcohol.  So if you absolutely need to avoid lipophilicity, maybe the traditional Cu-catalyzed Click is your best bet.

WP:  What should we know about IP and licensing in this field?

JH:  So far as I am aware, the only issued US Patent for Cu-free Click reagents and methods belongs to UC Berkeley (US 7,807,619).  There are other published patent applications that may well lead to additional patent coverage in this field.  It seems pretty clear that SPAAC reagents and methods fall outside the broad coverage of the Scripps patents that cover Sharpless’s Cu-Catalyzed Click methodology.

WP:  The classic ways to attach things to oligonucleotides involve amine acylation or thiol alkylation.  Besides click chemistry, what other bioorthogonal conjugation methods do you believe are useful for the modification of oligonucleotides?

JH:  Another Click reaction, oxime formation, is gaining steam with oligos.  B&A now sells some oxyamine and aldehyde reagents that can be incorporated during oligo synthesis or via post-synthetic modification.  Based upon their current popularity, we will be expanding our oxyamine product offerings.

WP:  While I’ve got you here, is there anything you’d like to say about your experience of working in a small chemistry company versus your time in big pharma?

JH:  On the whole both experiences have been very positive.  I had a great run in the pharma industry when it was still a vibrant place for doing top notch research.  For most of my 22-year career in pharma, drug companies embraced the financial risk of drug discovery.  That made it fun to be a chemist working in big pharma.  I don’t think the same fun is there today because drug companies got too big via mergers.  As they grew, the lower productivity of research staff that occurred while they were distracted immediately following a merger (when there is an inevitable re-evaluation, repositioning, and reorganization of research endeavors) somehow became part of the justification for the industry to reduce the overall amount of research investment.  To me, pharma companies today have all caught the same disease.  They all seem downright fearful of research investment.  To the scientists in the trenches, it can appear as if their management puts as high a priority on trying to minimize risk as it does trying to discover drugs.  Perhaps Bruce Roth’s recent article in C&E News says it better than I do here. (WP:  Links here and at Chemjobber here; see also Firestone’s perspective here and at In the Pipeline here.)

Today, I am very happy working in a privately-held specialty chemical company.  The ‘you eat if you can sell it’ attitude of small company life certainly keeps a scientist’s daily activities interesting, especially in a world where foreign competitors seem to always have a lower labor cost.  This environment drives Berry & Associates to work on the most difficult problems of our customers.  There we can provide products of tremendous value to cutting edge biological technologies.  To highly educated and experienced chemists, such work is as fun as it is profitable.

WP:  You’ve been working with heterocycles for most of your career.  Looking back so far, what accomplishment in that field do you feel is most significant?

JH:  Ten years later, I still get inquiries about my lithiooxazole paper that was published in JOC in 1991.  It didn’t feel like super-remarkable chemistry at the time but people still read that paper.  Editorially speaking, I guess that is a darn good reason to publish results that initially surprise you.  You can save others from the same surprises!