Nice to see Prof. Nicolaou back in the publishing game after his recent move to Texas. I read his recent comments on the state of the Pharma discovery process with interest, not much to add there, except he is quite correct. However, this week’s ASAP is his recent report of the total synthesis of a newly discovered prostaglandin; Δ12-Prostaglandin J3 :
This compound turns out to be a potent and selective antileukemic agent and as usual with such compounds they do not exist in vast amounts therefore total synthesis offers a way to obtain larger quantities and produce simpler analogues via a med. chem. program.
Nicolaou decided to go with a total synthesis employing asymmetric catalysis and dissected the molecule into 4 fragments:
So I think one can see where these fragments are going. The main difficulties here are a C-H activation/functionalisation of fragment 1 to introduce the carbonyl giving the desired enone. Also the creation of the chiral cyclopentene ester. A combination of fragments 3 & 4 lead to the chiral secondary alcohol by a asymmetric Mukaiyama aldol, catalytic, of course.
Fragment 1 was prepared from the available 2-cyclopentenonein 4 steps with an overall yield of 39%. The key step here is the use of a catalytic Tsuji-Trost coupling reaction:
The conditions are: dimethyl malonate (3.0 equiv), [η3-C3H5PdCl]2 (0.005 equiv), (S,S)-DACH-phenyl Trost ligand (0.015 equiv), Cs2CO3 (3.0 equiv), CH2Cl2, 25 8C, 3 h. The structure os the Trost ligand is:-
The thorny problem now is the C-H activation which “required considerable experimentation and was finally accomplished by a rhodium catalysed procedure that required [Rh2(cap)4] and tBuOOH as an oxidant …” The structure of the rhodium catalyst :-
The oxidation proceeds via the generation of an allylic radical and is nicely explained by the authors. The yield of this step in the prostaglandin synthesis is 48%, but that is better than nothing. I don’t think there is much room for improvement here although one never knows. It’s certainly a step requiring thorough examination in any scale up.
Yet another catalyst was employed to join fragments 3 & 4. The (R)-NOBIN Mukaiyama titanium based catalyst:
This gave the aldol product in 72% yield and 95% ee. The construction of the final molecule proceeded smoothly, as expected to produce the new prostaglandin in reasonable yield.
So lots of interesting catalysts here together with their application in a relatively complicated synthesis. Nice chemistry and a lot to learn, congratulations.
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