Total Synthesis of (+)-Chamuvarinin

An ASAP paper in Organic Letters from the University of St. Andrews describing the synthesis and stereochemical assignment of (+)-chamuvarinin is now accessible online.  Chamuvarinin was isolated in 2004 from extracts of a West African plant, Uvaria chamae, which is used in traditional medicine within that region.  A Google search revealed that a good number of compounds exhibiting various biological activities have been isolated from extracts of this plant which is commonly called finger root or bush banana.  The compound of interest within this paper, (+)-chamuvarinin, has shown cytotoxic behavior toward cervical cancer cell lines with IC50 = 0.8 nM.  

The structure of (+)-chamuvarinin was proposed as shown in 2004 although some ambiguity about the relative stereochemistry in the C15-C28 fragment remained.  This report’s total synthesis largely answers that question and confirmed the assignment.  The authors worked on the assumption that the C15 carbinol was the R configuration based on other related compounds.  I won’t describe the synthesis in detail here, but the C15 center was established starting from (S)-TBS glycidyl ether to eventually provide intermediate 3 with defined relative sterochemistry.  It was then coupled with intermediate 2 which led to chamuvarinin.  All spectroscopic data, as well the optical rotation, was consistent with that reported for the natural product.  The synthetic material was also observed to have similar biological activity to that reported for the isolated natural product.  So even without co-elution by HPLC or other comparison due to the absence of authentic sample, the stereochemical assignment of the C15-C28 fragment is fairly solid.

That’s fortunate, because if the data would not have been consistent they would not have known if it’s because they have the wrong diastereomer or the wrong enantiomer.  They would have been left little choice but to go back to the beginning to resynthesize the starting from R-glycidyl.  In addition there is the remote stereocenters on C15 and C36.  It is often very difficult to establish the relative stereochemistry of remote stereocenters.  So if C15 is R, how do you know that C36 is R or S?  One way of course would be prepare all possible stereoisomers.  That’s a lot of reactions and a lot of time.  (Note:  In the original paper isolating chamuvarinin, the C36 stereochemistry was assigned based on NMR experiments using Pirkle reagent, a chiral shift reagent.)

Prof. Dennis Curran has used quasiracemic fluorous mixture synthesis as a strategy to prepare all possible stereoisomers of natural products in a minimal number of steps.  Enantiomerically pure starting materials are tagged with distinct length fluorous tags.  For example the R enantiomer is tagged with a C8F17 tag while the S is C6F13 tagged.  The two compounds are combined and subjected to the same reactions which might include other uniquely tagged enantiomers.  Upon completion of the synthesis, all the steroisomers can then be separated based on their unique fluorine content by fluorous HPLC and the individual stereoisomers characterized and compared to authentic samples.

Prof. Curran’s group has synthesized a number of natural products using this approach resulting in either umabiguous or revised structural assignments.  One of the more interesting findings from his group is that diastereomeric compounds with remote stereocenters can often have indistinguishable 1H NMR.  So only by preparing all stereoisomers and ruling all but one out based on the totality of the data can the stereochemistry of some of these compounds be firmly established.  That’s probably not the case with chamuvarinin, but had the researchers used a FMS approach they could have prepared a number of different stereoisomers in only a few more steps.  This would have not only provided additional data to support the stereochemical assignment, but also added some SAR data to determine which configurations are most important to retain activity.  And that’s what research efficiency is about, isn’t it? Getting the most you can in the least amount of time.

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