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Galbulimima Alkaloids (-)-GB 13 and (+)-GB 16   

25 July 2010 15,603 views 13 Comments

Ma, Zi, Yu. ACIEE, 2010, EarlyView. DOI: 10.1002/anie.201002299. Article PDF Supporting Information Group Website

Why make one natural product when you can make two just as easily?  Or three in this case, but the headline syntheses are the Galbulimima Alkaloids GB-13 and GB-16 – notable members of a family that is getting some serious attention in pharma – one analogue is currently in phase III trials.  With all that potential, it’s not surprising that these beasties have seen quite a bit of synthetic attention; indeed, GB-13 was one of the first syntheses I blogged about! Another popular member is himgaline, with two (1, 2) previous blogging efforts here.  Adding to the wealth of chemistry here is going to take quite a bit of talent, so it’s luck that Dawei Ma can bring the goods.

Ma’s approach was to work towards these targets from a common, late-stage precursor, and to build complexity as non-linearly as possible.  One thing I really appreciate about his work and this paper is his synthesis of the smaller fragments, as he describes the synthesis from the commercial precursors rather than literature intermediates.  Perhaps he’s done this as the routes are really quite neat.  Starting with 3-aminobutan-1-ol, a condensation with 1,3-cyclohexanedione gave the bicyclic intermediate after a displacement-cyclisation.  Reduction of the enone under fairly forcing conditions gave the cis-decalin-type structure, generating a pair of stereocenters and allowing completion of a complex, key intermediate in only five steps.

A second intermediate was called into existance using only one more step.  A literature intramolecular asymmetric conjugate addition was able to build a fairly busy cyclohexane, which, after a selective reduction, could be esterified to give the desired lactone with ease.

Unifying these two fragments wasn’t without it’s problems – stereoselectivity being the major issue, as the group could only acheive a 3.5:1 d.r.  However, this was actually irrelevant, as the two diastereomers were taken through a fairly busy elimination / epimerisation / reduction sequence to get to their final goal.

A few steps later, they were ready to make that ring-system even more complex!  Working with a ketone and an enone, treatment with samarium diiodide did a reaction I wasn’t too surprised to learn.  I’d seen the SmI2 mediate coupling of ketone before, so it’s not really much of a stretch to see this happen in a ‘conjugate’ sense when working with an enone.  The process was completed by a quick DMP oxidation to complete the majority of GB-13 (two more steps required).

Harking back to one of my earlier posts (the Evans’ synthesis of Himgaline), Ma also sees that GB-13 was isolated along with an equibrilating isomer, 16-oxo-Himgaline, in which the piperidine nitrogen adds into the enone.  The reversible process can be fixed by reducing the resulting ketone – something both the groups completed by addition of a bit of triacetoxysodium borohydride.  No yield is given by Ma, so I presume his result concorded with Evans.

Very nice stuff, and a well-written paper :)

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  • Ma's fan says:

    I love this paper. It is Ma’s total synthesis other than depsipeptides. Vey cool!

  • SBchemist says:

    this is a great synthesis, convergent and elegant

  • Alex says:

    Nice synthesis.
    I’m wondering about your choice of stereochemistry conventions – I was taught organic chemistry with the (fairly logical) convention that the dashed wedges have the thicker side ‘closer’ to the reader. Using the opposite makes things somewhat more confusing.

    • Martyn says:

      The narrow end of the bond should always be next to the stereocentre. In the unlikely event that you want to read a massive document about it, there’s one here: http://old.iupac.org/publications/pac/2006/pdf/7810×1897.pdf

      • Bifidus says:

        Thank you Martyn for the link you posted, it’s very well explained.
        People should read it before submitting papers. It would avoid drawing schemes with mistakes.

      • Tot. Syn. says:

        Thanks for posting that.

        I actually had a bit of a rant/discussion about drawing conventions a few years back:


        I’ve actually thought about this quite a bit, and also re-thought things when I was writing my thesis. I read the IUPAC Gold-Book information on stereochemistry, and I’ve tried to stick with it.

        However, I noticed Alex’s email address, and the university he’s at (a place familiar to me!!), and know that certain lecturers can be quite strongly opinioned about chemical nomenclature!

  • Ron says:

    Looking at the SI, the formation of the (R)-phenylethylamine adduct takes 4 weeks of stirring at rt!

  • gippgig says:

    The stereochemistry of himgaline appears to be wrong (the 2 positions clockwise from the N in the leftmost ring). Besides differing from the published structure (i.e., JACS 129 1048), the structure as drawn seems to be impossible (try making a model).

  • geng says:

    nice work! maybe ma should draw the strucure in three-dimenional, that more clearly!

  • SBchemist says:

    people don’t talk about chemistry, instead, they think the drawing is not right this time…

  • Fink2 says:

    I think geng was referring to people who draw this molecule to make it look much more complex than it actually is…

  • krish says:

    I like the beuty of smi2 reagent

  • dave says:

    great website mate you’re doing a really fine job. Little suggestion though, it’d be good if you numbered the structures, would be easier to read and to write!
    Ma’s work really impressive. Not sure what you mean by “quick NMP oxidation” in the SmI radical cascade?

    Keep up the good work!