7/11/2007

You're a Good Isomerizer, Charlie Brown

I've gushed about Paul Docherty's Totally Synthetic blog before, and the gushing is well-deserved: every week or so he summarizes the latest and greatest in total synthesis so I don't have to read those papers (and so I can read the ones pertinent to my own research). After reading his synopsis on Dave Evans' latest JACS on the synthesis of Salvinorin A, I fell in love with a particular step that Paul also lauded (if I may just steal the image from his post):


They took an internal alkyne with a stereocenter and isomerized it to the terminal alkyne in one step in good yield. This reaction, called the "acetylene zipper" by its creator, Charles Brown (the son of boron guru and Nobel Laureate H.C Brown), might be the simplest method of generating terminal alkynes, as internal alkynes are, by contrast, much easier to make by cross-coupling reactions.* The acetylene zipper, which, aside from having an awesome name, is a very simple, elegant reaction and it really works! (It's not terribly functional group-tolerant, but who needs those?)

The acetylene zipper works by generating a strong base that can "walk" the alkyne to the terminal position, where it's held in place by the formation of a terminal acetylide ion. Since acetylene protons are much more acidic than propargylic protons (pKa 25 vs 40ish), there is a large energetic barrier to deprotonate the propargylic proton once the acetylene is at the terminal position. Acetylenes have been reported zipping across alkyl chains anywhere from 1 to 30 carbons long. Any secondary carbons (bearing methyl groups or what have you) stop the zipper, and the acetylene isomerizes until it hits the terminal position. The best part of the reaction? It's done in seconds. Most substrates can be worked up in no time after adding the starting material. It literally takes more time to set up the reaction than it does for the reaction to complete!

The reaction requires a special superbase, potassium 3-aminopropylamide (KAPA). No other base works with this reaction (although the sodium analogue does work but in lower yield). There is something special about the "spacing" between the amine groups in KAPA that allows this isomerization to occur, as neither ethylenediamine nor putrescine work. There are several ways to generate it, the most common being 1,3-diaminopropane and KH. KH is a pain in the ass to deal with, so an alternative prep using lithium and KOt-Bu has been done which works nicely too.

Sorry, not materials-related, but still a very cool reaction. As Paul said, it "engenders incredible synthetic utility, and seems so simple," and I would have to agree.

** In my experience, anyway. Corey-Fuchs reactions never worked for me. Sonogashiras always do.

13 comments:

Ψ*Ψ said...

Awesome! Looks like fun.
Also, I second the love for the Sonogashira coupling. It has always been kind to me as well.

Matt Jenks said...

The mechanism of the acetylene zipper reaction was one of the questions on my exit exam. In that regard, it will always have a very special place in my heart.

Kyle Finchsigmate said...

You mean propargylic position, which is the methylene unit alpha to the alkyne. (i.e. the analogous allylic position). I had to double check that too... *shrug* It's certainly not something one uses every day.

Excimer said...

propargylic. That's the word. I wrote this at 1 am last night, I can be forgiven for minor grammatical mishaps. I changed it. Thanks Kyle.

Uncle Al said...

"There shall be no terminal alkyne but that is sigma-bonded to a silicon or pi-bonded to a cobalt." What good is faith-based science unless there are stonings? Oh, wait... Salvinorin A. Never mind.

Greg the Chemist said...

This reaction is awesome. I first used it in 1989 and still suggest it to my students today. Be careful with 1,3-diaminopropane, though. As a graduate student I spilled some on my leg. It left quite a nasty burn on my skin.

taitauwai said...

I really envy you guys. Got to do "exciting" chemistry. The best fun I had so far ... TiCl4. It got smookie.

squirmy said...

i've run a few of those and they worked like a champ! very nifty reaction if you have a chance to use it and it gets my vote for the best reaction name.

Paul said...

Thanks for the link, dude; I'm glad you like this reaction too! I've finally got around to fixing the KAPA image, so you'll need to resize for 400,81px

Anonymous said...

I too fell in love with this reaction after seeing the Salviniorum A synthesis. No more expensive and volatile TMS-Acetylene, just add a propargyl via Sonogashira coupling and then zip the acetylene to the end of the chain. Two steps, wonderful!

kiwi said...

Don't forget lithium acetylide ethylenediamine complex as a substitute for TMS-acetylene. Reasonable nucleophile in DMSO, will substitute bromides at least.

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