B.R.S.M. When all you have is a hammer everything looks like a nail

20Nov/1110

Taxol Time Again: What now, Phil?

Update 20-11-2011: Reference added and a couple of mistakes removed. Why can I never see those the first time?

Scalable Enantioselective Total Synthesis of Taxanes

Baran et al., Nature Chemistry, 2011, [PDF][SI][GROUP]

 

The taxanes are a large family of 350 or so natural products, of which the best known is taxol itself, a multibillion dollar anticancer drug with a rich and storied history, whose name and distinctive tetracyclic system are instantly recognisable to most organic chemists. Taxol itself has already been the subject of 7 epic total syntheses (see BRSM Reviews: Taxol In 10 Minutes if you need a quick reminder), all using conventional functional group lead approaches to bond formation. Nature's (and Phil's) approach is a bit different, though, as we'll see.

As the first scheme shows, nature generally does terpenes using a 'two phase' approach. First, enzyme guided cyclisations, shifts and rearrangements of DMAPP and IPP (or products of their combination) give a hydrocarbon skeleton. For fairly obvious reasons, this has been termed the cyclase phase, and mimicking it has so far proved difficult as we tend to rely on functional groups containing electronegative atoms to make bond formation a bit easier. What comes next is seemingly even more magical,[1] as Nature then proceeds to introduce oxygen atoms all over the place, oxidising olefins and even unactivated sp3 C-H bonds with breathtaking selectivity in the so called oxidase phase. Some these are then further alkylated and acylated to introduce further diversity.

As a tactic, this is ideal for the preparation of huge numbers of different compounds from a single, simple precursor.[2] It also stands as a challenging biosynthetic method to mimic due to the still fairly limited C-H oxidation toolbox we have available to use in the lab. Historically, though, aiming for things beyond our current ability has always been a great way to drive the development of new (synthetic) technologies, and this field is likely to be no exception. With their newly reported synthetic route allowing access to larger amounts of taxadiene than anyone would have believed possible a few months ago, the Baran group are now in the exciting position of attempting to apply this paradigm to the taxol problem, and I for one am very excited to see how they get on.

As this is a synthetic blog, lets take a look at the route they came up with to reach this key precursor. The group started with the commercially available vinylogous ester shown below that was treated with vinylmagnesium bromide to give the dienone. This then underwent a fairly unusual 1,6-addition of the cuprate derived from the vinyl bromide shown. This step was highly optimised and could eventually be performed on batches of over 10 grams.[3] Enantioselective introduction of a methyl group using Alexakis' conjugate addition methodology, employing a catalytic amount of copper and a chiral phosphoramidite ligand, followed by trapping of the enolate with TMSCl gave the enol ether in excellent yield and ee. This set the target's challenging all carbon quaternary centre that could now be used to impart stereoselectivity to subsequent transformations via substrate control. Things started to get a little bit more difficult for the group at this point, however, as the proposed Mukaiyama-type aldol reaction with acrolein proved difficult, and extensive screening of catalysts and solvents was necessary. Eventually the rather unusual conditions shown were developed, with water surprisingly proving to be a key additive, and Jones' oxidation of the aldol product could be performed in the same pot. Next came the crucial Diels-Alder reaction that would be used to simultaneously form the A and B rings present in taxadiene.[4] This proceeded smoothly at 0 ºC, with the help of a little BF3•OEt2, to give the diketone in moderate yield (along with 29% of the undesired diastereomer). All that remained was the introduction of a methyl group to the C-ring, which was easily effected by formation of the vinyl triflate and cross coupling under Negishi conditions. Amazingly, all the steps up to this point were performed on at least gram scale, giving access to useful amounts of taxadienone for further studies. This could also be reduced in three steps to give taxadiene itself.

The amount of optimisation which has obviously gone into this route is enormous, and the paper is well worth reading for discussion of some unsuccessful approaches investigated, as well as how the final conditions were developed. For a taste of what the group are planning next, take a look at their recent review on 'two phase' taxol synthesis (Synlett, 2010, 12, 1733–1745).[5] Somehow this work has gotten me far more excited about an eighth synthesis of taxol than I would have previously thought possible!

 

1.  'Any sufficiently advanced [chemistry] is indistinguishable from magic' --Arthur C. Clarke

2. As I've mentioned before, approaches which allow access to a whole family of natural products are a particularly high form of the art of synthesis, as such 'general methods' can be a bit harder to come by.

3. This scheme only has a simplified version of the conditions used as there is far too much detail in the paper to fit all the times, temperatures etc. on - if you want to know more, go and read the paper!

4. The Diels-Alder approach, as Baran points out, isn't new to the area of taxane synthesis. In fact, the world's first (and only other) synthesis of (±)-taxadiene by Williams in 26 steps also used it as the key step.

5. If, like me, you don't know too much about the state of the art in C-H activation, and prefer to learn by example then this review and another (Baran again; Chem. Soc. Rev., 2011, 40, 1976-1991) have some pretty exciting stuff in (and are great problem session fodder). The synlett review obviously has some fairly taxol specific discussion, but there are also some more general references such as this brilliant table:

Comments (10) Trackbacks (0)
  1. You did it again. Awesome. Phil, on the other hand, didn’t take my advice.

  2. That table seems to be too fuzzy to read easily. Is a clearer version available?

    • Yes it it, cheers!

      Gippgig – I’ve uploaded a new higher resolution version of the table. Click on it for the full size image, which is, I think, now quite readable.

  3. Nice summary of Baran’s work and previous syntheses.

    There is also a very interesting account of Nicolaou’s synthesis here:

    http://onlinelibrary.wiley.com/doi/10.1002/anie.199520791/pdf

    Including details how the Shapiro reaction came to be used and the McMurray Machine Zhen Yang. Also interesting to note that funding was secured after the synthesis was completed!

    “Ironically, the announcement of the
    proposal’s acceptance and eventual funding would come after
    we had completed the total synthesis of taxol. “

  4. I was able to get Baran to agree to be our 2012 student invited speaker at Virginia Tech next fall… Pretty excited. I hear he’s a terrific speaker.

    • He is very good; I was lucky enough to see him when he spoke at the Bristol Synthesis Meeting in the UK a couple of years ago. He did refer to his syntheses as vignettes, though, which is possibly a little pretentious.

      • I do agree with BRSM, I saw him in a lecture in Cambridge (UK) and he’s a good speaker. However, what’s horrible is these black background with white molecule slides he uses…


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