Uncompromising musings on total synthesis (by my former PhD student)

I was reading a maoecrystal V total synthesis paper by Regan J. Thomson and colleagues and kept telling myself: “Who would be crazy enough to do this sort of thing these days?”. And then cold sweat started pouring off my forehead… One of the co-authors on the paper was my former PhD student, Igor Dubovyk, who has been working in Regan’s lab over the last couple of years… Prior to going to Chicago, Igor was involved in some really neat palladium chemistry in my lab such that we still fondly remember his important contributions to our program. I reached over to Igor and asked him if he would be interested to sum up some elements of his approach to maoecrystal V. Here is what Igor had to say:

Ever since I purchased the 1st volume of the “Classics in Total Synthesis” by K. C. Nicolaou from the U of T used bookstore for Andrei’s graduate class, I have developed an obsessive fascination with natural products. The idea of building something so complex from simple materials available from Aldrich was so mind-boggling; it was almost too good to be true. Of course, being a young rebellious mind that I was at the time, I had no appreciation for such important factors as funding or the tremendous risks involved in pursuing such long-term highly ambitious projects. These are very important factors in research, as any professor would tell you, which is why being a grad student or a postdoc is the carefree period of our careers. It is during these very periods when we find ourselves “vulnerable” to the “unfundable” ideas incepted in us by the top researches in the field, and therefore, are less likely to resist dreaming about bringing them to life. After defending my dissertation in the area of palladium-catalyzed allylic amination I had an opportunity to work in industry, which gave me more time to read books on strategies used to devise efficient routes for the syntheses of natural products. Reading this sort of literature had not satisfied my curiosity but, on the contrary, has left me with even more unanswered questions. It has become clear to me that I would never find piece unless I get directly involved in a total synthesis project. The opportunity has presented itself when professor Regan J. Thomson from the Northwestern University has agreed to offer me a postdoctoral position in the field of total synthesis of caged terpenes. 111 I was put on the Maoecrystal V, an ongoing project in the group for several years. As I have learned, the molecule was subject of active pursuit not only due to its complex architecture, but also for its high toxicity towards human ovarian tumour HeLa cell line (IC50 = 20 nM). By the time I joined, 3 groups have already accomplished a total synthesis of the racemate and numerous others have reported their ongoing efforts. My colleague Dr. Changwu Zheng has completed about 70% of the new synthetic route towards the racemate, which I was supposed to render enantioselective before helping him finish the synthesis. The route relied on several key steps, one of which was a highly diastereoselective Heck cyclization that furnished one of the quaternary centers and a new ring, while placing the alkene in the desired position (see the Scheme shown below). The precursor to the Heck reaction was allylic alcohol 1, which, in the synthesis of the racemate came from the corresponding enone 2. Switching LAH for the CBS reagent seemed like a no-brainer until the chiral HPLC confirmed the reproducible enantioselectivity of 30%. The result was not any better for the Midland reduction. We have reasoned that the chiral catalyst could not differentiate between the two bulky substituents on either side of the ketone. 222 It became clear that at this point we had a choice to either spend another who-knows-how-long trying to optimize the system by screening solvents, additives etc. to improve the ee slightly or to take a more indirect approach by making something simple with high enantioselectivity and then find a way to convert that product to the compound of interest. In the course of our investigations we discovered that the required stereocenter could be correctly installed through the highly enantioselective Sharpless epoxidation of the starting allylic alcohol (see the Scheme shown below). 333 After several months of experimentation, a scalable route to the desired Heck precursor was finally found. Coupling the Sharpless product 3 with trichloroacetimidate 4, followed by the reduction of the ketone with sodium borohydride gave a mixture of diastereomeric epoxy alcohols (Scheme 3). Transforming the alcohols into the corresponding iodides, and subjecting them to reductive conditions using zinc led to a stereoconvergent epoxide ring opening to give 25 g of alcohol 1 in 94% ee. The rest of the core of (–)-Maoecrystal V was assembled through an oxidative dearomatization made possible due to the proximity of the secondary alcohol to the phenol moiety, as well as an intermolecular Diels-Alder cycloaddition. The end game of the synthesis consisted of selective C–H oxidation reactions:


This aggressive approach not only resulted in the synthesis of (–)-Maoecrystal V, but also allowed us to gain access to the unnatural enantiomer of the molecule. Both enantiomers as well as the advanced synthetic intermediates leading to their formation were sent for biological studies against different tumour cell lines. Although the details of the complete synthetic study of (–)-Maoecrystal V will be released sometime in the future, I would like to admit that this project was an emotional rollercoaster, especially for my colleagues Changwu and Kiel. We owe a debt of gratitude to Kiel for his PhD-long synthetic investigations that have ultimately resulted in the undertaking of this particular route. In our group pressures to develop short practical total syntheses continue to uncover new reactivity and serve as an inspiration for the development of new methodologies.

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