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Valerenic Acid   

2 February 2009 16,835 views 29 Comments

valerenic_acid

Mulzer and Ramharter.  Org. Lett.2009, ASAP. DOI: 10.1021/ol9000137Article PDF Supporting Information Group Website

Mulzer’s1 work is starting to form a theme, at least in my mind, of small, complex and (mostly) highly oxidised natural products, made with whatever tools are most appropriate, rather than shoe-horning in methodology.  He also seems to work his students individually, or in small teams – not unlike my schooling, and one that I certainly appreciated.  Today’s synthesis is that of a GABA receptor modulator, valerenic acid.  For the uninitiated, the GABA receptor (?-aminobutyric acid) is a key component in neurotransmittion, but has a variety of types and subtypes, each responsible for different physical manifestations.  I’m no CNS med-chemist, so I’ll quote Mulzer’s suggestion that it could have a role in ‘panic disorders, hyperactivity, poor motor coordination, learning deficits, spontaneous epileptic seizures…’.  Importantly, it’s also a pretty small molecule – 234 gmol-1 – so there’s plenty of room for med-chemists to bolt a few morpholine groups on…

valerenic_acid_1

Mulzer first completes the synthesis in a racemic manner, and then repeats using enantiomerically pure starting materials.  Of course, the knack is getting those starting materials, and it’s in the SI we find that the synthesis is five steps from (r)-glycidol, but in a reasonable yield (32%).  The enyene was then isomerised using a bit of Grubbs I, which completed the cyclopentene with a propenyl sidechain.  This diene is perfectly set for a bit of Diels-Alder action, but there is the ever-present stereoselectivity issue.  Initially, they’d planned to do this reaction in an intramolecular fashion, but this approach ultimately failed; they then turned to metal coordination, which following Mulzer’s transitions state (shown below) gave them the product as a single diasteromer.

valerenic_acid_2

This pretty-much completed the core of the target, with only a further seven steps required to complete.  Most of this is straight forward, but I did like the control of stereochemistry.  Reduction of the lactone, and in-situ addition of the stabilised Wittig reagent allowed appendage of the sidechain, preserving the allylic stereocenter.  Then, a bit of the Crabtree catalyst in a hydrogen atmosphere delivered the reduction from the desired face.  Ultimately, two of these five stereocenters were extraneous, and were removed by oxidation of the alcohol and formation of the more-substituted enol-triflate.  The methyl group was then delivered using a Negishi coupling, rather than the Suzuki using trimethoxy trioxatriborinane; that’s not odd, but I think the boron reagent is damned funky.2

valerenic_acid_3

Nice work, as ever…

1. My next article might not be a Mulzer synthesis.

2. This gives you a little insight into what guides my retrosyntheses.  You don’t want to know the rest…

1 Star2 Stars3 Stars4 Stars5 Stars (7 votes, average: 3.86 out of 5)
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29 Comments

  • Liquidcarbon says:

    That’s a cute little molecule.

    That would be trimethylTOTB… how does it influence your retro though?

    • Liquidcarbon says:

      Comment threads! w00t!

      You should point people’s attention to this new feature, or they will still be replying in a usual fashion (like I did a few minutes ago) :)

      • Tot. Syn. says:

        I’m still tinkering with things… I’ll do a post later this week to highlight things like the comment threading, post-tagging, and article ratings.

        BTW, for those that are reading this, I’d prefer it if the ratings were used to rate the synthesis, not my wild stabs at coherent sentences.

    • Tot. Syn. says:

      Oh, not really – I’d just use it over dimethyl zinc, just ’cause I think it’s cool. Quite a few of the routes I used in my DPhil were designed with ‘reactions I thought were cool’ in them. As long as it doesn’t effect the overall efficiency of the route, it’s not a problem!

  • milkshake says:

    Mulzer is very good at finding nice thesis-sized molecules. Otherwise he is a rather distant boss (so I heard) and that means his students have to find their way through on their own – an experience that builds the character.

    Also, please give me back the old-times Tot Syn look. (Within an isolated system, all changes can make the problem only worse – its the law).

  • optional says:

    Nice work by Mulzer.

    But even a nicer Superbowl. Kudos to those Cardinals who put up such a valiant effort against the best Defense of the NFL. Warner really picked apart the secondary of the steelers.
    Oh my gosh, and Larry Fitzerald, wow, what a player he is. Amazaing.
    And what about Phelps smoking pipe????

  • Liquidcarbon says:

    Paul, sersly, stop this blasphemy. :)

  • SB says:

    Hey TS,

    This new website is sexy as hell. Nice job.

  • gyg3s says:

    Has anyone got any suggestions as to other synthetic routes?

  • pi* says:

    Mulzer’s real knack seems to be finding published methods in the literature, taking a more or less known product of the reaction, and doing a step or two to make a natural product.
    usually gives quite a nice route, but there’s something i find a bit icky about that i can’t quite put my finger on….kind of like he’s going through peoples methodology papers and beilstein-ing frameworks for natural products or vice versa.

  • Liquidcarbon says:

    Start with (R)-pulegone (~$1/g). Alkylate with crotyl halide alpha to the carbonyl group, Prins cyclization will give a [5,6] fused system with handles fix the functional groups if the cyclization is not “biomimetic enough”. :) at one point or another burn off isopropylidene to append the side chain.

  • gyg3s says:

    Hi LiquidC – I had similar thoughts when I saw the molecule: that is, I saw the terpene. However, I take on board Mulzer’s critique that the initial alkylation sets up the wrong stereochem with respect to the methyl group. Currently thinking about ring contraction reactions. But the more scribbling that I do, the more I appreciate how impressive the chemistry.

  • Tom says:

    thread highjack.. How do you guys perceive the organic chem dept at princeton? Functional?

  • Joe says:

    does anyone here attend berkeley (organic chem.)?

  • INADEQUATE Chemist says:

    ah, yes, it’s getting to be that time of year again.

  • John Wood says:

    And UC Irvine??

  • John Wood says:

    Are the Grad students happy at UC Irivine, and if so , which lab?

    • lovermanfan says:

      Overall, the students here seem pretty happy. People who are forced to TA all the time because of funding issues complain, but I assume there are good groups that are underfunded at most universities these days. We’ve got a top 10 program in organic chem and good weather almost all the time. Irvine is a pleasant city, although it is quite bland. I can speak for myself and say that I am happy. You can guess which group I’m in from my name.

      • John Wood says:

        Great! maybe I’ll see you down there on my visit, I am interested in the Vanderwal group, any insight?

        • lovermanfan says:

          Vanderwal’s got a very talented, cohesive group (at least they appear to be pretty close-knit to me). Chris seems like a good mentor and good all-around guy, and his group is going to have some nice results to publish this year from what I’ve heard.

  • TH says:

    Under scheme 1 in his paper he writes : “enolate additions to 2 are known to favor the trans-diastreomer, which would generate 4 with the wrong configuration at the ring juncture” . Shouldn’t the product of the enolate addition give a different diastereomer than the one on the scheme 1 ? So shouldn’t this also lead to the right configuration at the ring juncture ? Or am I wrong :/

    • Atticus says:

      If the two groups on the cyclohexanone are equatorial, then yes, the MVK would approach from the bottom face and give the right diastereomer. When the alpha carbon has a methyl on it, the other groups will be axial (avoiding A-1,3 strain), which would cause MVK to approach from the top face. I forget if this is true for a hydrogen…I’m also too lazy to look up the paper Mulzer references.

      • TH says:

        So how would You judge the diastereomer on the scheme in the paper ? Did Mulzer propose the correct one ?

  • GYA says:

    is it just me or has the quality of total syntheses fallen considerably since a few years ago?

  • Pete says:

    I wouldn’t say the quality of total syntheses has gone down…Rather that there are fewer syntheses. I used to think ever week there was some synthesis out there to read…Now you might go three weeks without seeing something.

    I do like Mulzer’s work…Very classical approach to these congested molecules.