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Totally Synthetic by Paul H. Docherty, 10 August 2006

Total Synthesis of Milbemycin β3


M. Li, G. A. O'Doherty, Org. Lett. 2008, 8, 3987-3990.

DOI: 10.1021/ol061439k

A very succinct paper by O’Doherty in Org. Lett. this week, showcasing his work on asymmetric hydration in a total synthesis of Milbemycin β3. This macrolide has a huge range of activity, from antibiotic to pesticidal, so is a tempting target, exemplified by the previous syntheses by Amos Smith, Tony Barrett and Phil Kocienski amongst others. The principle disconnection left them with a spiroketal unit and a remote stereodefined methyl group to consider, which they tackled with some interesting methodology.

Very early in their work, they create a diene via a ynoate isomerisation simply using triphenyl phosphine in phenol, delivering the diene in 97%. I hadn’t seen this procedure before, so was quite impressed. The cited literature for this is a Trost paper from the last decade. With this unit in hand, they were able to use their own ideas for asymmetric hydration to establish the stereochemistry in four steps, commencing with an asymmetric Sharpless dihydroxylation, followed by carbonate formation and Pd catalysed reduction, and finally diastereoselective hydration with benzaldehyde to generate the 3,5-benzylidene actetal. Good work!

Further elaboration of this fragment eventually led to the desired spiroketal, with the remaining methyl group the last stereocenter to consider. They completed this by using chemistry originally developed by Scott Nelson; an alkene isomerisation and Claisen rearrangement. This approach is very similar to the route used by Amos Smith, who used an Ireland-Claisen, but is still impressive:

Then the intermediate was ready to couple with the less complex bottom-fragment (again, previously made by Amos Smith) via a Wittig olefination, and lastly a Mitsunobu macrolactonisation previously used by Tony Barrett in his synthesis followed. This process, as the name suggests, inverts the stereochemistry of the hydroxyl partner in the macrolactonisation, potentially removing a laborious inversion protocol.

Altogether an impressive piece of work, containing a lot of interesting chemistry!

Selected Comments

10 August, 2006 at 22:44, secret milkshake says:
The PMP/benzylidene/ethyl ester intermediate obtained in four steps from the diene (which has to be made by extra 3 steps) happens to be exactly the protected Lipitor side-chain, with the right stereochemistry. Companies like Kaneka and Takasago are now manufacturing the triol-ester-acetonide in tonn amounts by enzymatic methods/fermentation for the statin market. We have a 1kg bottle of the (3R,5S)-t-Bu ester acetonide sitting on the shelf here…
10 August, 2006 at 23:59, HOMO-LUMO says:
Sorry for my ignorance, but would be possible to buy building blocks/expensive ligands to pharmaceutical companies, in particular japanese, from an university, is that a common practice?
11 August, 2006 at 00:43, secret milkshake says:
Probably not, although I am in nominaly academic institute and we used government funding to buy the stuff. Also, Kaneka was nice enough to airmail us first a 10g sample free of charge.
Any tot-synth professor worth his reputation would hate to buy and then re-protect an advanced piece (and have this in his publication). Medicinal chemistry approach is different - we were not in it for glory and we also did not have extra manpower to expend 2 man-months for scaling up the piece. We paid 10k (USD) for 1kg, (100g would be 5k). With the lab overhead and salary, it was not a such a bad deal. Also we had deadlines, there were provisional patents runing out of time.
I just wanted to point out that the problem of synthesizing this piece has been solved - that when some underpaid undelings were scaling up gram quantities of the stuff from acetylene, some other (japanese) underlings were already churning out 100kg batches of it.