Chen, Gao and Wang. JACS, 2008, ASAP. DOI: 10.1021/ja808110d.
Now that’s an interesting architecture! I’ve always had a soft-spot for homosteroids like this (and cortistatin), as their construction can often include that brilliant mid-20th century chemistry that folks like Corey and Woodward made their names with. However, for this particular natural product, Chuo Chen of the UT Southwestern Medical Center has used a real mixed bag of impressive reactions.
The target, a C-nor-D-homosteroid to be precise, is actually isolated from that marine goo that seems so prolific. And like a few of its neighbours in the goo, it’s pretty poky, with some mighty-fine P388 murine leukemia cell line busting moves. However, synthesis, in this case, was not enough, and and a bit of a stereochemical refinement was also required as the positions numbered in red.
The key to the construction was of course finding a suitable bisection point (of course it’s not a point, it’s a ‘line’, but I can’t think of the correct word…), and in this case, it’s about the cyclopenatone. That gives us a pair of chunks to get cracking with.
First up is the LHS, with its neat bicyclic ether feature. How to do that? A furanyl Diels-Alder is quite an obvious idea, but for some reason I didn’t expect it to work as well as it did. So attack of the Weinreb amide with isoprenyl grignard gave them the precursor for an intramolecular Diels-Alder (IMDA), generating the required stereochemistry about the cyclohexene rather neatly. This was controlled, of course, by the free hydroxyl, installed earlier by doing a Noyori reduction.
However, that hydroxyl is actually not in the natural product, and needs to be ess-en-two’d by bromide to give the required functionality. This was done by forming a sulfonate and displacing with lithium bromide, but isn’t as simple as this may sound. The sulfonate used was actually methyl 2-(chlorosulfonate)benzoate, a particularly electron withdrawing beasty. This may have been required to ensure inversion, as these aren’t as straight-forward as one might imagine.
Turning focus to the RHS, I was impressed at how early Chen installs the (what I would presumed to be sensitive) gem-dichloride. This was done by simply treating an aldehyde with chlorine gas (urgh…), base and phosphite (to capture that chlorate?). I’ve done the reverse reaction – aldehydes from gem-dibromides using silver nitrate – but never this, and I’m quite impressed with the result.
Exchange of the aryl bromide for the correspoding stannane gave them RHS partner, so it was time to crack out the palladium. No screening data is given, but the conditions are fairly standard, resulting in the ever impressive incorporation of carbon-monoxide, unifying the fragments.
Nice reaction, but there’s still quite a lot to be done – and several somewhat sensitive groups present, which always makes the chemistry tricky. First-up was to complete the cyclopentane, using a photo-Nazarov reaction – a classical method of forming cyclopentenones from dienones. The regioselectivity of the reaction (in terms of which side of the five-member ring has the unsaturation) is controlled by the ‘cation’-stabilisation ability of each side – and the phenyl ring is better (and also wants to remain aromatic), so results in a beautiful rearrangent and generation of a pair of stereocenters. The base was required to improve the stereoselectivity of the reaction, as the ‘Î± position’ was ill-defined (1:1). A bit of deprotonation allowed the natural stereochemical bias to be revealed in the desired manner. Super-smart stuff.
The last reaction I’m going to mention is the ring-expansion of the bridged cyclohexane into a caprolactol. Going back to the cyclohexane formed in the IMDA, the diol was formed by dihydroxylation (which also prevented reverse DA chemistry). This was protected-up as an acetonide, and sat inert for most of the synthesis. Freeing it up, and oxidising with a bit of hypervalent iodide resulted in an insertion of oxygen between the diol, and ring-expansion to generate a bis-hemiacetal. Selective reduction of the less-hindered bis-hemiacetal with lewis-acid mediate silane then gave the required functionality present in the natural product.
Just brilliant stuff. I loved reading this paper, and hope to read a full-paper on it in the near future.