Johnson, Campbell, Qi. JACS, 2009, ASAP. DOI: 10.1021/ja904136q.
Sorry for the lack of blogging, folks – I’ve been feeling a bit under the weather, but I assure you, it’s not H1N1… However, it seems like the res of the world is getting on with it, with several nice syntheses in JACS just now. Lyconadin A is headed for Chemistry World, later this month, whilst plicatic acid is line behind polyanthellin A. Hopefully, sticking the latter into the Tot. Syn. search box (operated by trained hamsters) will return this post on ‘(6Z)- and (6E)-Cladiellin Diterpenes‘ by Deukjoon Kim, an acknowledged master of this family of natural products. This sets the bar rather high – so lets look at how this fresh challenger Jeffrey Johnson deals with the target.
The target is split into two components, ready for a rather tasty unification, but first they gotta make them. The more complex cyclopropane-containing fragment was built using some really interesting chemistry. First up was an organocatalytic Michael addition of isovaleraldehyde into methyl vinyl ketone using a fairly standard proline-based catalyst, aided with a bit of a catechol to boost reaction rate and yield (another example is in this Baran paper). The remaining aldehyde was then Wittig’d to bolt-on a diene, and set them up for a bit of cyclopropanation. Initial attempts to do a direct cyclopropanation were unsuccessful, so they used an interesting Corey(and Myers)-abetted protocol, which initially diazotises the 1,3-dicarbonyl, and then using a copper(II) salen complex, does an insertion into the proximal alkene.
The other fragment, an aldehyde, was built easily; asymmetry was introduced via an SAE, and the resulting epoxide opened using in-situ-developed allyl cuperate. A few more steps including a 1-c homologation returned the desired aldehyde, ready for coupling. This Lewis-acid mediated process is a formal [3+2] cycloaddition required a pretty exotic reagent, as more commonly used LAs resulted in aldol couplings of the aldehyde. For success they used an aluminium based catalyst, based on some work by Yamamoto; it did the job nicely, but we’ll need to wait for the promised full-paper to the goods on it’s virtues.
As any reader will see, we’re now perfectly set for a bit of RCM to close the medium ring. This was done in high yield by using dilute conditions, and chlorinated solvents (70%), but not without the group enduring a fairly frequent problem. Y’see, those metathesis catalysts (be they Ru or Mo based) often take a liking for other chemistry when attached to your lovely terminal alkene. A common problem is de-methylenation – loss of methylene units – from the SM, generating a new, similar compound which can they react further. In Johnson’s case, this lead to eight-membered product, but in other systems can result in a damn mess. It’s be great to hear your experience of this thorny problem – including the additives to prevent this problem, such as acetic acid and titanium isopropoxide. In Johnson’s case, simply using DCM (presumably thoroughly de-methanol’d) did the job… others are less lucky.
The final intermediates are starting to look fairly similar to those encountered by Kim; looking back at that paper, Kim was able to do a rather tasty oxo-mercuration to form both the ethereal bridge and the tertiary alcohol. Johnson hope to do a similar reaction, forming the ether from ‘the-other-side’ (if you get me), but encountered only a 10% yield. He rescued the situation via a slightly more labourious route; iodolactonisation, followed by oxo-mercuration delivered the desired oxygenation, whilst a spot of radical tin reduction removed both the extraneous heavy atoms. Only acetylation was required to finish the target, in a synthesis that stands up well against Kims. Good job, sir.