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Totally Synthetic by Paul H. Docherty, 8 November 2008

Total Synthesis of Nakiterpiosin


S. Gao, Q. Wang, C. Chen, J. Am. Chem. Soc. 2009, 131, 1410-1412.

DOI: 10.1021/ja808110d

Now that’s an interesting architecture! The construction of homosteroids like this (and cortistatin) can often include 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 broad range of impressive reactions.

Nakiterpiosin, a C-nor-D-homosteroid to be precise, is actually isolated from the marine sponge Terpios hoshinota. Nakiterpiosin offers an interesting biological activity: an IC50 against murine P388 leukemia cells of 10 ng/mL.

The total synthesis was also accompanied by stereochemical refinement at the positions numbered in red.

The key to the construction was of course finding suitable bisection points. They are mainly located around the cyclopentanone.

First up is the left fragment with its neat bicyclic ether feature. A furanyl Diels-Alder is quite an obvious idea. Attack of the Weinreb amide with isoprenyl grignard gave them the precursor for an intramolecular Diels-Alder reaction (IMDA), generating the required stereochemistry about the cyclohexene rather neatly. This was controlled, of course, by the free hydroxyl, installed earlier using a Noyori reduction.

However, that hydroxyl is actually not in the natural product, and needs to be displaced by bromide to give the required functionality. This was done by forming a sulfonate and using lithium bromide. The sulfonate used was actually methyl 2-(chlorosulfonate)benzoate, a particularly electron withdrawing group. This may have been required to ensure inversion.

Turning focus to the right fragment, I was impressed at how early Chen installs the sensitive gem-dichloride. This was done by simply treating an aldehyde with chlorine gas, base and phosphite.

Exchange of the aryl bromide for the correspoding stannane gave a coupling partner for a Pd catalysed reaction. No screening data is given, but the conditions are fairly standard, resulting in incorporation of carbon monoxide.

Nice reaction, but there’s still quite a lot to be done - and several sensitive groups present, which always makes the chemistry tricky. A photo-Nazarov reaction completed the cyclopentane. The regioselectivity of the reaction is controlled by the cation stabilisation ability of each side - and the phenyl ring is better and also wants to remain aromatic, so the reaction results in a beautiful rearrangement and generation of a pair of stereocenters. The base was required to improve the stereoselectivity of the reaction. Deprotonation of the ‘α-position’ allowed the natural stereochemical bias to be revealed in the desired manner. A very smart method.

The last reaction featured 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). The diol was protected as an acetonide, that was inert for most of the synthesis. Removal of this protecting group, followed by oxidation with a hypervalent iodide resulted in an insertion of oxygen 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 a brilliant total synthesis! I loved reading this paper!