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Manzacidin C   

29 June 2008 9,443 views 17 Comments

Leighton, Tran and Lombardi. Org. Lett., 2008, ASAP. DOI: 10.1021/ol8011869. Article PDF Supporting Information Group Website ResearchBlogging.org

A nice little Org Lett, this; basically the story of one key transformation, but let’s look at the target first.  Manzacidin C would appear to have a fairly interesting biological profile, including α-adrenoceptor
blocking, but apparently there hasn’t been enough isolated to be able to assess this fully.  Ideal territory for a bit of total synthesis action, then – and there’s been quite a few.  There’s a good OBC paper reviewing the state of play as of the end of last year, but the most important work has been done by Ohfune and DuBois (we’ll come back to the DuBois paper).

This paper is all about the acylhydrazone-enol ether [3+2] cycloaddition developed by the group, which appears to be a cracking way to develop a 1,3-diamine with good stereochemical control.  Initial work on an asymmetric approach to the reaction was published by Jun Kobayashi back in 2002, where he used a chiral Lewis Acid to promote the reaction (BINOL + a bit of Zr alkoxide).  That paper was kinda limited in scope, as the reaction was only intramolecular, with a bit of Thorpe Ingold there to push the kinetics.   However, a few years later, he’d gone intermolecular; however, although the ee’s were impressive, the dr’s weren’t, with the majority around 60:40.

Leighton seems to have improved on that considerably.  In this case, the yield, dr and ee are all impressive, generating that pyrazolidine ring system with apparent ease.  However, it must be noted that the reaction isn’t catalytic – they need to use an excess (1.5 eq) of the chiral silane.  They don’t get to recover it either – but they do get a good return of the pseudoephedrine precursor.

With the key functionality in-place, it was time to cleave the hydrozine.  As might be expected, the weak N-N bond was ruptured (good word!) using a bit of radical chemistry – using what I’ll always think of as the French reagent. (I realise that the French may have made some other reagents too…).  The ring was then reformed as the analogous tetrahydropyrimidine, completing the core of the molecule. (No yields were given for the individual steps, but they look to be favourable.)  This cyclisation was also used in the DuBois paper.

Final functionalisation used a spot of acid of hydrolyse the ester and remove the thiophene-thing (which was required to give the [3+2] enough omph).  Couple the pyrrole-carboxylic acid – job done, nice work.

Tran, K., Lombardi, P.J., Leighton, J.L. (2008). An Efficient Asymmetric Synthesis of Manzacidin C. Organic Letters DOI: 10.1021/ol8011869

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  • Ondrugs says:

    Nice little synthesis by Leighton, just a little remark regarding “all about the acylhydrazone-enol ether [3+2] cycloaddition”, I would call it a further development of the acylhydrazone-enol ether [3+2] cycloaddition toward using allylic dipolarophiles.

  • InfMP says:

    When I think of French Chemistry, I think of the Luche reduction. Classic 1-man JACS.

  • WestCoast85 says:

    Jean Louis for ever !!!

  • vivek rauniyar says:

    Kagan is a real gentleman, and a heck of a chemist during his limelight. Go SmI2.

  • antiaromatic says:

    For a small natural product, the amount of work that probably went in to optimizing some of those final steps was probably pretty incredible. Tricky little compounds those can be.

  • ZAL says:

    Just a small point: the original [3+2] cycloaddition was published by SHU Kobayashi and co-workers (Jun must be a student, but I don’t know if they’re related :-) )

  • Madforit says:

    really nice target…reminds me some alfa 1 blockers or something similar…

  • antiaromatic says:

    In looking at a lot of these natural products with the bromopyrrole (if I’m not mistaken, the angeleferin/sceptrin family + the pal’auamines), it really begs two questions:

    1. Why bromine?
    2. Why that position?

    It just makes you wonder what little secrets may be hiding within that portion of these natural products.

  • milkshake says:

    to answer: various sponge-dwelling sumbiont microbes like to take bromine in seawater and put it on molecules. I suppose it is easier for them to produce Br(+) rather than Cl(+) because of its lower redox potential. (You can oxidize Br(-) with hydrogen peroxide, for example). The regioselectivity is not that unnatural – pyrroles normally like take electrophiles into the 2-position but the carboxylic acid can direct it into meta position, its not that weird – I have seen Friedel-Craft acylations done on pyrrole 2- carboxyesters that went meta also.

  • patrick29 says:

    Any method how to do asymmetric hydrogenation of the db in silylated enol ethers?

  • antiaromatic says:


    Thanks for the response! I guess the only thing that is still puzzling is why would nature feel the need to include such atoms into the molecular architecture. In other words, I wonder what benefit the organism derives from having that halogen in place.

  • Madforit says:

    drugs and natural products containing alogen atoms are “protected”from metabolism reaction,is a kind of protective group…and some alogen atom in drug subsances improve the interaction with the bio-phase,the receptor,enzyme….

  • ... says:

    There’s palau’amine, there’s monobromopalau’amine and there’s dibromopalau’amine. Several of the pyrrole-imidazole alkaloids have been isolated along with their poly- or non-brominated cousins. Probably only one of them does the sponge any good but it’s going to take several thousand years of evolution to filter out the useless ones. Nature invented combinatorial chemistry and she’s pretty darn good at it.

  • InfMP says:

    “microbes like to take bromine in seawater and put it on molecules”

    hahahha, that was awesome

  • ,,, says:

    Madforit, just a very good example – monofluoroacetic acid, that shuts down Krebs cycle.

  • Madforit says:

    yes,i know,it act as a inhibitor of aconitase,what i m trying to say is that the alogen atom in pharmaceutical molecules protect from the action of cytocrome P450 (oxidation).For example:clorine,bromine atom para position on a benzenic mojety ,protect the carbon atom from oxidation(phenol) and from acetilation of the newly formed OH group…

  • J says:

    the chiral silane (drawn at top) may need a methyl in place of the phenyl