B.R.S.M. To strive, to seek, to find and not to give a yield



Three Rings in One Step: A Quick Approach to IKD-8344

Zou and Wu, Angew. Chemie. Int. Ed., Early View, 2012


It's feels like ages since my last total synthesis post, but I couldn't resist writing something about this unusual looking macrodiolide with its rather unmemorable name and ridiculous number of THF rings. Aesthetic reasons aside, with subnanomolar activity against leukaemia in mice, as well as some antiparasitic effects, this Steptomyces-derived natural product appears to be a more worthy target than many. Wu and single co-author Zou reported a modern yet slightly oldschool synthesis in Angewandte a couple of weeks back and it's been high up my 'to blog' list ever since. The route used is a delightful blend of old and new marrying modern asymmetric aldol chemistry with every first year undergrad's favourite way to make ethers - the trusty SN2 Williamson ether synthesis. This disconnection, leading back to a substrate containing two β-mesyloxyketones (with α-stereogenic centres!), would definitely have worried me, but the methodology, which the group has developed over a number of years, works very well. The synthesis is simplified somewhat by the fact that the natural product is dimeric, as macrodiolides tend to be, and the group are really able to showcase their methodology here, forming all three THF rings in the monomer unit in a single step.

The route began with some Crimmins asymmetric aldol methodology, leading to isolation of the desired enantiopure allylic alcohol in 86% yield, when (-)-sparteine was used as the base. The auxilliary was then removed by reduction with DIBAL and the aldehyde and secondary alcohol were protected as the dithiane and TBS ether respectively. The dithiane was then deprotonated with t-Buli and the anion formed was used to open epoxide A, unfortunately requiring a good amount of every's least favourite co-solvent, HMPA. Benzylation of the resulting alcohol proved unexpectedly difficult; standard conditions with NaH as the base in DMSO or DMF caused unwanted by-products and poor yields. Eventually, optimised conditions with NaHMDS as the base, in a mixture of THF and DMF at -10 °C allowed the desired compound to be obtained in excellent yield. The primary TBS group was then removed selectively in the presence of the secondary, by treatment with CSA in methanol, again at -10 °C. Parikh-Doering oxidation gave an aldehyde that was then the substrate for another asymmetic aldol reaction, this one using (+)-sparteine as the base.[1] Finally, oxidative deprotection of the dithiane with PIFA (PhI(OCOCF3)2) and cleavage of the TBS ether with a little HF gave the completed fragment - one half of the monomer chain.

Preparation of the second half began with some more aldol chemistry, again using the expensive (+)-sparteine as a base, although with a yield of 99% for this step, the group certainly got their money's worth. TBS protection of the newly formed alcohol, followed by reductive cleavage of the chiral auxiliary with DIBAL, gave the group another aldehyde ready for the final - and most challenging - aldol reaction of the synthesis.[2] Surprisingly, the group obtained very satisfactory results using an oxazolidinethione auxiliary and quite ordinary conditions (TiCl4 and Hünig's base). They claim that this is the first instance of this set of conditions being used with this auxiliary, and that the corresponding oxazolidinone is less effective. The desired alcohol was isolated as a single enantiomer in an impressive 77% yield (accompanied by 15% of material epimeric at the newly formed stereogenic centre). The auxiliary was then swapped for a Weinreb amide to which vinyllithium, prepared by tin-lithium exchange, was added.[3] The enone carbonyl was then reduced to the 1,3-anti-diol using the Evans' conditions, and this was protected as the acetonide, to give the second half of the monomer chain.

The group then used an impressive cross-coupling reaction to unite the two halves. Only a very slight excess of the acetonide component was used (1.2 equivalents), and the extra material was recoverable from the reaction mixture. The reaction also occurred surprisingly rapidly at ambient temperature, giving a 44% yield after just 1 hour. Although the yield is a little modest, this disconnection allowed for convergent preparation of the monomer chain. It's difficult (for me, at least) to imagine an alternative way to join up these fragments with so much functionality around the bond being formed. The newly formed double bond was then reduced out using a hydrogenation with Adams' catalyst.[4] This reaction took a little optimising as the two benzyl ethers in the molecule had to be left untouched in order for mesylation of the correct alcohols to be possible in the next step, but an excellent yield of the desired product was eventually obtained, ready for the key step that followed. Mesylation of all three alcohols, followed by hydrogenolysis of the benzyl ethers and cleavage of the acetonide, followed by heating the crude triol in 2,6-lutidine gave the desired tris(THF) fragment in an impressive 60% over all three operations. It's great to see such an oldschool disconnection work so well, in such a complex setting. Not bad for a reaction first described in 1850.

With the key step out of the way the endgame proceeded smoothly. Some of the tris(THP) fragment was protected as the TES ether, and converted to the acid by cleavage of the auxiliary with lithium hydroxide.[5] This compound was then coupled with the unprotected, auxiliary capped version using Yamaguchi conditions to give the hexakis(THP) fragment shown. TES cleavage and hydrolysis of the auxiliary as before, followed by Yamaguchi macrolactonisation then gave the completed natural product.


Et cetera

1. That's the rare one, but with the world still reeling from by the Great Sparteine Shortage of 2010, it's the only one of the two that Aldrich still sell. And at £167 for 100 mg, I can't see they'll sell out very soon!

2. Acetate aldol reactions are widely considered a bit tricky, and generally get lower stereoselectivities than the corresponding propionate reactions. Having one fewer methyl group can make a big difference in the Zimmerman-Traxler transition state. One option is the Sammakia variant, discussed in my post on cyanolide A from last year, which is actually thought to proceed via an open transition state, and can work quite well for hindered aldehydes. I believe Crimmins and Nagao have also worked on this problem, using acetyl thiazolidinethiones, although I've never done an aldol reaction in my life. The downside tends to be that special auxiliaries with extra-bulky groups have to be synthesised (the Sammakia reaction requires a special t-butyl thiazolidinethione, for example).

3. If you've never used vinyllithium, this is the standard way of preparing it. So why use this inconvenient reagent in place of nice, non-toxic and commerically available vinyl magnesium bromide? The problem is that with the latter conjugate addition of Me(OMe)N- to the newly formed enone is often observed, presumably facilitated by the presence of Lewis acidic magnesium salts. The use of vinyllithium effectively suppresses this reaction.

4. Using Adams' catalyst (PtO2) for hydrogenation always makes me smile as it comes in a bottle carrying the 'oxidiser' warning symbol. The reason is that the active catalyst is actually the platinum nanoparticles resulting from reduction of PtO2 by hydrogen, not the oxide you put into the reaction. 'Adams' precatalyst' would be a more accurate name. Interestingly, you can use the thing for oxidations as well - it offers an expensive* but quite cool way of oxidising primary alcohols straight to carboxylic acids. The procedure feels a bit odd as you first stir the PtO2 under hydrogen (!) to form the active platinum black catalyst, then add the substrate and stir under oxygen. I tried to use this as the last step in a total synthesis I finished last year, but embarrassingly, after telling everyone how great this procedure was, Jones' reagent (tried afterwards, of course) turned out to work much, much better. Jacobsen had more luck, using it to finish off his synthesis of (+)-ambruticin, selectively oxidising a primary alcohol to an acid in the presence of two other secondary alcohols, which is kinda cool. Wouldn't have relied on that, myself. As far as I know this method was invented by Josef Fried for prostaglandin synthesis back in 1973. But we digress.

*Think about it: you make it by burning platinum!

5. I am shocked that the TES group survives this step. And they get 97% yield, no less!

Comments (6) Trackbacks (0)
  1. This mirrors my PhD work in a lot of eerie ways (except for the target)…

    I did a lot of these types of aldols in grad school. I don’t know why they bought both enantiomers of sparteine. The chiral auxiliaries start with amino acids… and the unnatural enantiomer of the amino acid has got to be cheaper than the unnatural enantiomer of sparteine… especially because the auxiliary is recoverable and reusable.

    Also, Crimmins published a nice procedure for a highly diastereoselective acetate aldol: http://dx.doi.org/10.1021/ol062688b

    And I definitely tried to add vinyl Grignard to a Weinreb amide and was stymied by the stupid conjugate addition of the free amine.

    Nice post. Keep up the good work 🙂

    • Thanks! That Crimmins paper looks quite useful; I knew he’d published some stuff on acetate aldols but didn’t have the references. I guess the main downside is that it’s five steps to make that imide starting material. The cool thing about what these guys do is that it works with off the shelf chemicals. I also observed that irritating vinyl Grignard side reaction. The conjugate addition product was all that I got and took me a little while to work out what had happened.

  2. In the penultimate structure, the TES group is missing.

  3. In the hydrolysis of the auxiliary in the final step should Li be LiOH?
    In note 4 Pt2O should presumably be PtO2.
    In response to the 1st comment, note that the chirality of both the auxiliary & sparteine were reversed to get the opposite enantiomer. Perhaps only reversing the auxiliary didn’t give good stereospecificity (can anyone clarify this?).

    • Thanks gippgig and mamid for the corrections! Regarding the sparteine – I know that the base used can be very important. I’ve seen papers comparing an enantiomer of sparteine (I forget which) with simple bases such as triethylamine or Hunig’s base, and finding it gave much better diastereoselectivity. I have never heard of someone swapping enantiomers of sparteine when swapping auxiliaries to get the opposite enantiomer of product, but I do not know this chemistry well. Anyone?

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