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open flask october 2016 monday october 17 2016 araiosamines the long journey from vanuatu to la jolla today our work on the total synthesis of the araiosamines is out in jacs while the chemistry success and unexpected failures was detailed in the paper and si i would like to share some stories from the science behind the construction of these molecules on the first day i joined the lab i told phil that my motivation was to get extensive training in natural product total synthesis in a top tier synthetic chemistry lab phil immediately suggested the araiosmianes isolated from a sponge collected from vanuatu in 2011 saying if you want an education in total synthesis these molecules would be an excellent option when i had a first glance at these molecules in the isolation paper i thought they were only trimers of three bromoindoles and there were only six carbons in the skeleton no big deal at all however a very talented graduate student ming yan had been struggling with these molecules for two years when involved in the project i found these molecules are really tough to make to say the least during the first two weeks we continued to work on the strategy which employed an achmatowicz reaction however due to the failure of indole installation phil decided to abandon this route we met phil in his office early on the following morning and tried to come up with new ideas after one hour of discussion we left his office without feasible plans in mind we thought it was the time to move on maybe a guanidine related methodology project five minutes later we received an email from phil asking did we consider the sulfones we immediately went to the library to mine the literature and found that α amido sulfone is actually a stable acylimine precursor for the mannich reaction eventually the amido sulfone approach saved the project and opened the door to a completely new strategy stepwise construction of the linear carbon skeleton the first mannich reaction gave two diasteremers however favoring the undesired one when performing the dibal reduction with either one we always got the aldehyde as two inseparable diastereomers poor yields irreproducible and variable dr we thought epimerization might be an unavoidable problem of the aldehyde the next aldol reaction with the aldehyde as a mixture of diastereomers indeed gave the trimer product but again in irreproducible and variable yields during the attempts for the second mannich reaction through nitrile hydrozirconition si we found the nitrile could be reduced to the aldehyde with the schwartz reagent without epimerization this tricky reaction the concentration and stoichiometry are both critical must be quenched by loading the reaction mixture on the tlc plates fortunately 1 tlc plate could quench about one gram scale reaction trace of etoac in the starting material or quenching the reaction by silica gel powder or aqueous solution would induce epimerization with pure aldehydes prepared we observed their interesting reactivities towards the subsequent aldol reaction the desired diastereomer 4 worked well to give the trimer product whereas undesired diastereomer 3 gave a complex mixture which could not be identified fortunately what we needed to do was to epimerize the undesired nitrile to the desired 2 with t bunh2 moreover this unusual reactivity also inspired us to solve a key problem of c h gunidinylation in parallel to the skeleton construction we also attempted the key c h guanidinylation by indole oxidation of 6 prepared from the undesired mannich product as a model substrate due to the scarcity of the desired but minor mannich product after screening ca 100 conditions including ddq only mixture of diastereomers in extremely poor yields was observed when we figured out that the aldol reaction worked only with the desired diastereomer the question arose what about this c n guanidinylation with the desired diastereomer surprisingly ddq mediated c n guanidinylaiton worked very well with the desired diastereomer in quantitative yield and with complete stereoselectivity to make a long story short we combined both a linear and a cyclic strategy to finally make the mesylate 10 for the sn2 reaction the subsequent reaction sequence of substitution reduction and guanidinylation worked very well it seemed that ariaosmiane c would be conquered very soon however two months of effort did not lead to any trace of the natural product that was the most difficult time for us we were so close to the natural product the mass was always correct but the nmr spectra never matched we began to doubt the stereochemistry the only reaction that could give the wrong stereochemistry would be the sn2 reaction because all other stereogenic centers were confirmed by x ray crystallography of the precursors the 2 d nmr spectra did not help very much in this case some signals supported the right stereochemistry whereas some did not phil said we would definitely need x ray crystallography given that palau amine s structure was misassigned by noe which was not conclusive for such a complex structure we decided to determine the stereochemistry of azide 11 by x ray however to grow a crystal of such a late stage intermediate was not an easy task we spent a lot of effort on the scale up and obtained 20 mg of the azide 11 unexpectedly too many bromines hindered the crystallization process probably due to their too much lipophilicity after extensive solvent screening we eventually grew a crystal from a solvent mixture of mecn meoh and h2o after obtaining the x ray crystallography we were completely shocked the configuration was retained when the azide was introduced in the displacement step we also found that the six membered n o acetal ring has a perfect chair conformation while the unexpected axial bromoindole and azide have an antiperiplanar conformation clearly due to the neighboring group participation of the axial bromoindole a double inversion took place how could we prevent the neighboring group participation we tried many approaches including indole protection as the most straightforward but none of these worked the final idea was to employ a reductive amination albeit not anticipated to be stereospecific interestingly hydroxylamine was the only nucleophile that could condense with the ketone fortunately after extensive experimentation the stereo and chemoselective oxime reduction was achieved with smi2 in the presence water we were quite lucky because initially we used the methoxy substituted compound 14 as the substrate to investigate the reduction in a later study we found otbs substituted compound 16 completely reversed the stereoselectivity of this reduction possibly ome directed the protonation from bottom face to give the desired stereochemistry the desired product 15 showed very broad 1h nmr peaks some are missing compared with the undesired isomer probably due to various conformers our tremendous effort spent on characterization of the undesired isomer was quite helpful without the x ray of the undesired azide 11 how could we confirm the stereochemistry of desired amine 15 from its low quality nmr spectra and the amine 15 was decidedly more difficult to crystallize with the correct stereochemistry established after guanidinylation we thought the natural product araiosamine c could be obtained immediately after exposure of 18 to tfa indeed we observed a clean conversion to a product showing the mass of araiosamine c while we were planning our celebration misery beset us again but not without company the nmr spectrum did not match that of the natural product it was actually the elimination product enamine 19 hoping to cyclize the guanidine though enamine iminium equilibrium we subjected 19 to various acidic conditions however no reaction took place this intermediate s inertia was confusing we also attempted cyclization by mesylation of the anomeric alcohol of 22 in addition to the enamine product 23 we unintentionally choreographed an indole dance see 24 apparently the pesky neighboring group participation happened again but this time at another position with this result we finally came to the conclusion that cyclization via an iminium intermediate would not be possible because the guanidine could not outcompete the anchimeric indole at this time an idea of ring chain tautomerization between cyclic hemiaminal 25 and acyclic aldehyde 26 emerged we proposed that a carefully controlled boc deprotection of 22 would equilibrate to araiosamine a after a discussion on the morning of once de mayo 2016 i said to ming maybe today we could actually make the natural product but both of us weren t too optimistic because we hoped so many times and were subsequently disappointed again the result was frustrating as boc deprotection in tfa dcm induced instant dehydration to give again the enamine 19 the hemiaminal ring was not opened to allow equilibration to araiosamine a maybe boc deprotection in an aqueous acidic environment would suppress the dehydration thus in another attempt the deprotection was performed in tfa mecn h2o 1 5 4 at 90 c the lcms showed a very complex mixture nevertheless i still took the crude nmr spectrum which looked hopelessly complicated i thought it must be as usual that some isomers had the same mass as natural product but their structures could never be identified when coming back from the nmr lab and comparing the nmr spectrum with that of natural araiosamine a i was completely surprised we made the natural product later we found the crude pruduct was a mixture of three interconvertible compounds 25 araiosamine a and epi araiosamine a although it was around mid night i immediately called ming to tell him this great news he drove back to the lab and we sent phil an email together i was too excited to sleep on that night at 6 am we met phil in his office phil said in order to confirm it was the natural product we needed to scale up the reaction and get a 13c nmr spectrum during the scale up the hydrolysis product 22 was originally planned to be isolated before deprotection unfortunately the hydrolysis reaction ended up with being heated up to 90 c by accident another completely different reaction was planned to be performed at 90 c at the same time but i was too excited and heated up this hydrolysis reaction mixture by carelessness again the lcms showed a major product of dehydration we were not quite sure if it was the natural product or enamine 19 meanwhile the group had been waiting outside the nmr lab for celebrating our success much to our relief we got a clean 1h nmr spectrum of the dehydration product which completely matched that of araiosamine c the mechanism of this cascade transformation is detailed in our manuscript with some luck in the final step we made the entire family of araiosamines in one pot employing the ellman auxiliary we also achieved the asymmetric synthesis of araiosamine c to establish the absolute stereochemistry of the natural product additionally in stark contrast to the initial isolation report we have found that these molecules are actually potent broad spectrum antibacterial agents this is a rare example of a natural product synthesis enabled discovery of bioactivity after the isolation chemists explicitly stated that this class of alkaloids had no observable activity lastly i would say without the accident in the final step we would have definitely made araiosmaines c and d after isolation of araiosamine a and epi araiosamine a and subsequent subjection to dehydration however as 11 step syntheses have been trending in our lab we were happy to keep it that way maoqun tian note from ming i remembered vividly during my first day of graduate school when phil described to me the remarkable similarities between araiosamines ring chain tautomerization to that of carbohydrates these alkaloids can be viewed as having an outward experience of sea sugar though their structures are way more mystifying compared to fellow sea salt this sugar coating was rather deceiving enticing me to this sweet looking project which turned out to be a bitter pill at the outset our earliest effort in the synthesis attempts to make araiosamine through direct trimerization of indolylacetaldehyde imines enamines this aldehyde which rapidly polymerizes in its neat form was later referred to by my colleagues as the mingaldehyde it gave me an early exposure to interdisciplinary research i would be making polymeric materials together with small molecules the polymers thus produced have translational potentials from bench to the coal tar industry together with julian shaw an extremely talented visiting student we surveyed an assortment of indolylacetaldehyde surrogates discussed in the si we gained valuable insights on the reactivity and stability of various indole building blocks which would find use in our later efforts but the end result of trimerization studies may be presented in a highly similar fashion as this legendary publication https www ncbi nlm nih gov pmc articles pmc1311997 pdf jaba00061 0143a pdf thus half a year into the project we decided to target the chain topology of araiosamines embarking on what we dubbed as the cyclic logic in the paper admittedly the amount of black tar i produced every day was dramatically reduced but extraneous functional groups present a significant hurdle this was when we decided to combine lessons from all these approaches and formulate a new strategy to araiosamines having worked solo for a while after julian s departure i was fortunate to be joined by marc posted by baranlab at 9 01 am 15 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 april 1 january 1 2019 7 september 1 july 1 april 1 february 1 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