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Germanicol   

18 June 2008 6,758 views 14 Comments

Corey and Surendra. JACS, 2008, ASAP. DOI: 10.1021/ja802730a. Article PDF Supporting Information Group Website ResearchBlogging.org

Steroids!  Or at least something close to that structure.  This little beastie is actually classed as a ‘pentacyclic triterpenoid’ according to Corey, but it’s still a resolutely old-school target.  The synthesis is formal – what we’re targeting here is an intermediate in Johnson and Irelands synthesis way back in ’70.  That synthesis is definitely a tour de force, but somewhat lacking in efficiency with 32 steps.  Corey reckons that a biomimetic approach, stitching the ring systems together like a zip, might be a bit quicker.

Bam! Straight in with the good stuff.  The diene starting material can be made easily from farnesyl acetate, using a Corey-Zhang oxidation (that’s another Corey reaction for the Named Reactions book…), though you’ll to read the SI to see this.  A spot of 2-propenyllithium did the expected carbonyl addition, which was followed by a Brook rearrangement to give the corresponding allylic anion which trapped the aryl bromide to give the product.  Sweet chain of reactions.

Next up was the key biomimetic cationic cyclisation, using a bit of Lewis acid to promote it.  This lead to formation of the psuedo A, B and C rings (were it actually a steroid), but they needed two more steps to complete the manueouver – protection of the free hydroxyl and a bit of acid to complete the final ring.  This apparently chews-off the freshly installed TBS group again too…

I’d like to think that the group went down to the pub at this point and had a good few pints before deciding ‘Nah… I’m sure we could make that even faster’, but who knows how things work in the Corey group.  Anyway, another approach was apparently brewing, using a similar substrate and key step.  However, the order in which the rings are formed has been turned over, with the ‘D-ring’ going in first.

This time, though, the LA didn’t work quite as selectively, and they got two products out of the reaction.  However, more LA didn’t convert between these species, meaning that their origins must be divergent.  Corey ascertained that the common parent to both structures is the cation shown below.  In the expected pathway, we get addition of the proximal double bond to the cation, forming a new ring and a resulting benzylic cation (nice and stable).  However, a different pathway can result in benzylic stabilisation – a [1,5] proton shift.  The group proved this by making the deuterated substrate shown and followed the deuterium on it’s way.  If you’re surprised to see this, you’re not the only one; Corey guardedly states that this might be the first example of this rearrangement.  Also interesting was the fact that there is no control over the formation of that stereocentre – so the mechanism proceeds on either face of the dihydronaphthalene.

Very interesting work.  The synthesis is efficient (relying on recursive use of similar reactions to build the substrates) and impressive – as is their dissection of the mechanistic quandry.  But not my favourite Corey synthesis – that honour goes to his work on the prostaglandins, to which I (for obvious reasons) have a strong affinity.  I’m also amazed by his Ecteinascidin 743 and Ginkgolide B syntheses.  What about you folks?


Surendra, K., Corey, E.J. (2008). Rapid and Enantioselective Synthetic Approaches to Germanicol and Other Pentacyclic Triterpenes. Journal of the American Chemical Society DOI: 10.1021/ja802730a

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14 Comments

  • Jose says:

    I feel like I just cracked open a JACS from 1958, instead of today….old skool for sure. Ect 743 is nothing short of stunning- not to mention how tightly packed that little paper is; rather a shame there wasn’t ever a full 20 pg Tet paper on it. (although, the same can be said of many targets, palytoxin for example).

  • ZZZZZ says:

    zzzzz

    …JACS? Really? That’s twice this year for Corey and this stuff in JACS. No offense to anyone, but Bill Johnson / E. E. van Tamelen, and then many others (including Corey), did all of this many, many years ago. Do cationic cascades for steroid syntheses still excite folks? OK, I digress, back to sleep for me…

    zzzzz

  • TWYI says:

    There is another Corey JACS out today on triterpenoid biosynthesis too

  • agro says:

    the rearrangement is interesting

  • milkshake says:

    1. You are missing a double bond in the first scheme, the PPA cyclization product

    2. The scheme is nice but some steps must be quite tricky, to perform right on the first trial. Also the dihydroxylation catalyst used on the farnesyl piece is very elaborate and hard to make (please note in the supplementary that the author took care to recover it on column). And the BaI2 preparation is a bit of chore (you start with Ba metal and Li-biphenilyde). Working at -94C with frozen hexane slush bath and adding -94C precooled solution via insulated canula also gets time to get used to.

    The enol-ether as a carbocation accepting terminator group is indeed very nice but depending on the Z/E ratio of the intermediate enol ether it tends to yield a mix of stereoisomers alpha to the newly formed keto group in the product. When one has a proton alpha to keto one can separate the stereoisomers (with luck) and re-equilibrate the unwanted one with a base – but in this case however you get quat carbon so no re-equilibration is possible.

    This does not detract from the elegancy – its just that the practical aspects of the methodology are quite involved when you get to the details.

  • milkshake says:

    sorry I made error and have to take it back: It was actually Riecke Ba for allyl baryums from allyl bromide that was made from BaI2 and Li-biphenylide. BaI2 is rather easy to make (from elements), you may need a hammer and anvil though because Ba metal is quite hard to cut into slices

  • Madforit says:

    Corey ‘s best syntheses…:prostaglandins,aspidophytine definitely

  • Jose says:

    Koan for the lazy chemist: Is a catalyst still a catalyst if you have to recover it?

  • Diyne says:

    Jose,

    Yes, and perhaps the ability to recover it unchanged highlights its catalystness

  • InfMP says:

    yeah I totally agree, i never recover my catalysts, but in theory i should be able to (if half didn’t turn to Pd black)

  • SiO2lungs says:

    What’s the purpose of using BaI2 after Brook rearragement? is it to get the allyl barium from the allyl lithium?

  • antiaromatic says:

    Though I agree with the ecteinstadin and aspidophytine syntheses, I wonder why no one mentioned Okaramine N. That was one beast of a target that he and Baran put down in pretty short order.

  • milkshake says:

    Yeas, its that – Wurtz-like alkylation of allyl-Ba with allyl, benzyl halides has a nearly exquisite selectivity for the least hindered carbon

  • ZZZZZ says:

    zzzzz

    …I vote for the caryophyllene synthesis – either the one from the ’60s, or the one from this year. Oh wait, same thing…

    zzzzz