O’ Doherty and Li. Org. Lett., 2006, ASAP. DOI:10.1021/ol061439k.
A very succinct paper by O’Doherty (no relation…) in Org. Lett. this week, showcasing his work on asymmetric hydration in a total synthesis of Milbemycin ÃŸ3. 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 SAD, 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 stereocentre to consider. They completed this by using chemistry originally developed by Scott Nelson; a 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 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. 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 cool chemistry!