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open flask july 2016 tuesday july 26 2016 maoecrystal v or i how i learned to cope with my mediocrity greetings and salutations ladies and gentlemen our total synthesis of maoecrystal v has been published in jacs recently it is a fascinating molecule in my opinion with a beautiful array of densely interlocked rings myriad of quaternary carbons and an intriguing bioactivity profile to back it up or not it is no wonder that it received so much attention from synthetic community especially in the first five years after its publication in org lett but don t be fooled by that pretty face this molecule is a demon in disguise making it in the lab is like having a crush on that popular girl in high school no matter what you do or how much you try the only thing you are going to get is a beat down by her much more handsome and stronger boyfriend this pretty much sums up my experience working with this molecule on the very first day in the baran lab i decided to go for the baddest molecule in town perhaps out of shear arrogance or maybe stupidity but most likely a combination of both at that time at least in my eyes such molecule was maoecrystal v this decision took me on a hell of journey a roller coaster ride if you will full of adventure and unexpected outcomes that changed me as person and a semi scientist but that is the beauty of total synthesis in my opinion it pushes you to your very limits and that is when you truly realize what you can and can t do the journey began with making the bicyclic ketone 5a or 5b which turned out to be far from a trivial task i am embarrassed to admit that it took me six months to actually make it i have no excuse for that the figure below summarizes some of the early failed approaches the journey begins when the route to 5a had finally been developed described in the paper the stage was set to explore the key addition pinacol rearrangement sequence at this point phil probably thought yea this cernijenko guy needs all the help in the world and then some so i was joined by an awesome post doc rune risgaard we actually made a really good and productive team because we were quite different and complemented each other really well united by misery and failure fueled by unhealthy obsession both of us really really wanted to make this damn molecule we became good friends and marched on to the battlefield we had absolutely no clue what was awaiting us the pinacol rearrangement and hydroxymethylation is pretty well covered in the paper and there is additional information regarding these steps in the supporting information unfortunately my therapist has forbidden me to discuss these steps to prevent further damage consequently i will skip straight to the installation of the last carbon of the molecule the cyanide was perfect for our purposes since it was a nucleophilic source of carbon that had the same oxidation sate as the ester and seemed small enough to react with a hindered c 8 ketone the figure below summarizes our attempts to accomplish this task a small glimpse of the challenge to sum up the reactivity was not the problem most of time time the yields were very good stereocontrol on the other hand was an issue the cyanide was always coming from the undesired face giving us exclusively undesired diastereoisomer we tried different cn sources lewis and bronsted acids solvents and additives the outcome was the same in almost every case interesting example is the reaction mediated by i 2 where cn approached from the desired face but attacked the more hindered bis neopentyl ketone to give 28 i was very surprised to see the x ray crystal structure and to this date i still have no clue how i 2 completely switched the chemoselectivity of this reaction other nucleophiles such as vinyl lithium furanyl lithium lithium 1 3 dithianes corresponding grignard and organocerium reagents did not solve this problem we also tried blocking the undesired face by epoxidizing the c 15 16 alkene but cn still approached from the undesired face however a very important result for us was the formation of 29 mediated by zn otf 2 because it is the only example where we achieved the desired stereo and chemoselectivity the compound itself was synthetically useless but it made us realize that if we form the thf ring first cn might approach from desired face interestingly that hypothesis lead to the synthesis that was published today in total synthesis things can go from terrible to great in just one reaction lastly i would like to discuss the very last reaction in synthesis it is quite strange to eliminate iodide with oxone initially we tried to engage iodo ketone 18 formed as 15 1 mixture of iodo epimers 18a major and 18b minor in classic base promoted e2 type elimination but not even a trace of maoecrystal v was formed despite myriad of conditions examined we believe that there was simply no antiperiplanar hydrogen available for the desired elimination to take place while the minor 18b iodo ketone in principle should have underwent e2 elimination we think that the chair conformation with axial iodide is highly disfavored due 1 3 diaxial strain as a result 18b is probably more accurate representation of its conformation where iodide is pseudoequatorial on a boat the iodide elimination this is where we got quite lucky after oxidation of the iodohydrin with one of the commercial bottles of dmp iodoketone was formed in excellent yield along with 2 4 of maoecrystal v as a by product the relevant portion of crude nmr is attached below mcv hiding in the weed s how did it form freshly made dmp or other bottles of commercial dmp did not give any traces of maoecrystal v it was just that one bottle that consistently yielded small amounts of maoecrystal v what was in it long story short we suspected that maybe it was contaminated with oxone which is used to make dmp since oxidative elimination of iodide with m cpba was known in the literature this reaction was very messy and low yielding in my crooked hands indeed simply adding buffered aq solution of oxone to the reaction mixture resulted in very clean elimination of iodide to finally give maoecrystal v that was a very good day in the lab we were able to make decent amount of this natural product using this route as a result we had the chance to explore its bioactivity profile with different collaborators unexpectedly it turned out that synthetic maoecrystal v was not active in any of the cancer cell lines even hela tested our dreams of curing cervical cancer were shattered but we received a lot of valuable lessons from this synthetic campaign that was a hell of a ride r i p mcv i hope we will never meet again art posted by baranlab at 3 38 am 10 comments email this blogthis share to x share to facebook share to pinterest newer posts older posts home subscribe to posts atom search baran lab blog recent comments recent comments widget archive 2022 1 february 1 2021 2 september 1 april 1 2020 8 october 1 july 1 june 2 may 2 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