Synthesis of Desepoxy-Tedanolide C.

Syn hesis o Desepoxy-Tedanolide C Daniel Lücke[a] and Ma kus Kalesse*[a, b, c] Dedica ed o P o . S e en V. Ley on he occasion o his 75 h bi hday Abs ac : The syn hesis o desepoxy- edanolide C was accomplished and p o ided expe imen al e idence on he con igu a ion o edanolide C. The epo ed chemical shi s and coupling cons an s poin o a con igu a ion di e en om he published s uc u e and analogous o he s uc u es o he o he membe s o his amily o na u al p oduc s. The key s ep is a Kiyooka aldol p o ocol o he s e eoselec i e syn hesis o he e ia y alcohol lanked by h ee addi ional oxygena ed ca bon a oms. Fu he mo e, wo addi ional aldol eac ions and a Julia–Kocienski ole ina- ion we e used o assemble he ca bon amewo k. The edanolides[1] a e a g oup o na u al p oduc s isola ed om ma ine sou ces which exhibi ema kable biological ac i i ies in he pM ange ( edanolide (1): ED50 a 26.2 pM in lymphocy ic leukemia cell lines; 13-deoxy edanolide (2) IC50 a 0.16 pM agains P388 mu ine leukemia cell lines). The inhibi ion o ansla ion was iden i ied as hei p ime biological a ge and has ini ia ed i al syn he ic ac i i ies owa ds he syn hesis o Tedanolide (1) i sel as well as 13-deoxy edanolide (2) and desepoxyiso edanolide (6).[2] The la es addi ions o his amily o na u al p oduc s we e he candidaspongolides (3)[3] and edanolide C[4] (Figu e 1). Tedanolide C was isola ed by he g oup o Ch is M. I eland om ma ine sponge I cinia sp. collec ed in Milne Bay, Papua New Guinea. I shows a ema kable cy o oxic p o ile agains HCT-116 cells a 95.3 nM. Like edanolide and 13-deoxy edano- lide i could se e as an inhibi o o p o ein biosyn hesis. The con igu a ion o edanolide C was de e mined based on coupling cons an s in combina ion wi h molecula modeling. This led o a pu a i e s uc u e which esembles he ela i e con igu a ion o he sou he n and eas e n pa o edanolide (C10-C23), albei as i s enan iome ic s uc u e. The no he n pa , howe e , pa allels he absolu e con igu a ion o edano- lide. The a ional o he p oposed de ia ion o edanolide C in compa ison o edanolide a gues ha a 9.2 Hz coupling cons an be ween H-9 and H-10 would suppo an eclipsed con o ma ion and ha only he p oposed s uc u e was in acco dance wi h compu a ionally gene a ed isome s. On he o he and he coupling cons an o he co esponding p o ons o edanolide we e epo ed o be in he same ange (Schmi z:[1d] 10.8 Hz, Kalesse:[2g] 8.5 Hz, Smi h:[2c] 10.1 Hz, Roush:[2i] 9.6 Hz). Due o he ac ha he con igu a ion would signi ican ly de ia e om edanolide e en hough a biosyn- he ic ela ionship is likely and he compu a ionally p oposed s uc u e in ol es an eclipsed o ien a ion o he p o ons H-9 and H-10, we used ins ead 5as ou a ge molecule o he syn hesis o edanolide C as he con igu a ions esemble hose o he o he membe s o his amily. Smi h and his g oup a ge ed he pu a i e s uc u e o edanolide C (4),[5] whe eas he g oups o Roush,[6] Romea and U pi[7] used he enan iome (en -4) as hei syn he ic a ge . [a] D. Lücke, P o . D . M. Kalesse Ins i u e o O ganic Chemis y Go ied Wilhelm Leibniz Uni e si ä Hanno e Schneide be g 1B, 30167 Hanno e (Ge many) E-mail: [email p o ec ed] [b] P o . D . M. Kalesse Cen e o Biomolecula D ug Resea ch (BMWZ) Go ied Wilhelm Leibniz Uni e si ä Hanno e Schneide be g 38, 30167 Hanno e (Ge many) [c] P o . D . M. Kalesse Helmhol z Cen e o In ec ion Resea ch (HZI) Inho ens asse 7, 38124 B aunschweig (Ge many) Suppo ing in o ma ion o his a icle is a ailable on he WWW unde h ps://doi.o g/10.1002/chem.202100553 © 2021 The Au ho s. Published by Wiley-VCH GmbH. This is an open access a icle unde he e ms o he C ea i e Commons A ibu ion Non-Com- me cial NoDe i s License, which pe mi s use and dis ibu ion in any medium, p o ided he o iginal wo k is p ope ly ci ed, he use is non-comme cial and no modi ica ions o adap a ions a e made. Figu e 1. Membe s o he edanolide amily. Chemis y—A Eu opean Jou nal Communica ion doi.o g/10.1002/chem.202100553 7085Chem. Eu . J. 2021,27, 7085 –7089 © 2021 The Au ho s. Published by Wiley-VCH GmbH Wiley VCH Diens ag, 20.04.2021 2124 / 200179 [S. 7085/7089] 1 Ou in e es in his amily o na u al p oduc s was ini ia ed by hei ex ao dina y biological ac i i y, he challenge o cons uc ing a polyke idal na u al p oduc wi h a wide a ie y o si es which could hampe i s syn hesis due o e o-aldol p ocesses and/o elimina ions and inally because his g oup o na u al p oduc s ea u es a a e mac olac one comp ising a p ima y alcohol. Ou syn hesis uses a Kiyooka aldol p o ocol as he key s ep which we delibe a ely de eloped o his syn hesis and which cons uc s he mo i con aining he e ia y alcohol and he h ee adjacen oxygena ed ca bon a oms selec i ely (Scheme 1).[8] Fo he syn hesis o edanolide C (5), we used aldehyde 8,[8a,9] which is de i ed om Roche es e and builds up a ma ched si ua ion wi h he oxazabo olidinone om N-Ts-d- Val as he employed Lewis acid. This s ep se s up he e ia y alcohol as well as he con igu a ion a C14. The seconda y alcohol a C15 will be oxidized la e o i s co esponding ke one bu is ca ied h ough he syn hesis in o de o p e en e o- aldol p ocesses and elimina ions. Wi h he s a e o knowledge o success ul edanolide syn heses and he appa en success o aldol disconnec ions in hese endea o s we also ook ad an age o wo aldol disconnec ions be ween C6-C7 and C12-13, espec i ely (Scheme 2). The aldol disconnec ion be ween C6 and C7 has he ad an age ha i would p o ide he desi ed C5 ke o ca bonyl g oup. The C12-C13 disconnec ion equi es an an i- selec i e educ ion o he hyd oxyl ke one. Finally, a mac o- clac oniza ion would deli e he desi ed amewo k. The syn hesis commenced wi h ca boxylic acid 15 which is accessible in 5 s eps om eadily a ailable s a ing ma e ials.[10] Gene a ion o allyl es e 11 could be accomplished in 78% yield (Scheme 3). Fo he syn hesis o eas e n agmen 13 (Scheme 4) a inylogous Mukaiyama aldol eac ion p o ides in e media e 18[11] which is TBS-p o ec ed, educed and ans o med o i s pi ala e 19. O e all, he syn hesis o he no he n 11 and eas e n segmen 13 can be ob ained apidly h ough 6 o 5 s eps, espec i ely. The syn hesis o he sou hwes e n pa o edanolide C howe e , was he subjec o in ensi e in es iga- ions as i no only holds he e ia y alcohol bu addi ionally equi ed ans o ma ions on he adjacen , pseudo neopen ylic posi ions (C15 and C17). We s a ed he syn hesis wi h he abo e desc ibed Kiyooka p o ocol (Scheme 1) o gene a e he e ia y alcohol. The so- ob ained p oduc was p o ec ed as i s PMP-ace al 21,[8b] which in u n was clea ed by DIBAL-H educ ion and he p ima y alcohol was Pi -p o ec ed (Scheme 5). TBAF dep o ec ion o he mixed ace al libe a ed aldehyde 22 which was used in he s e eoselec i e addi ion o inyl magnesium b omide o gen- e a e allylic alcohol 24. The con igu a ion was assigned ia i s co esponding ace onide[12] (suppo ing in o ma ion) and is consis en wi h C am chela ion con ol.[13] This se he s age o ole ina ion wi h segmen 28 which was ob ained h ough an ole ina ion o Roche es e (20) and subsequen gene a ion o he Julia-Kocienski sul one. Fo joining bo h segmen s, allylic alcohol 24 was dihyd oxyla ed and subjec ed o diol clea age wi h PIDA in ace one/wa e . The so-ob ained aldehyde 29 was subjec ed o he abo e men ioned Julia–Kocienski ole ina ion[14] o gene a e compound 30 in an E:Z a io o �95:5. The nex s eps we e commi ed o es ablish he app op ia e p o ec ing g oup assembly ha would allow o he mac ocycliza ion as well as o se ing he app op ia e oxida ion s a es in he C11 o C15 egion o he sou hwes e n hemisphe e. He e we will only co e he combina ion ha was inally success ul. The ials and e o s ha ul ima ely led o his ou e will be epo ed elsewhe e. Fi s , he ace onide imbedding he e ia y alcohol had o be clea ed as he p ima y alcohol needs o be selec i ely libe a ed o he mac olac oniza ion. This was achie ed in good Scheme 1. Pi o al Kiyooka aldol s ep in he syn hesis o edanolide C (o2s=o e 2 s eps). Scheme 2. Re osyn he ic analysis o edanolide C (5). Scheme 3. Syn hesis o no he n agmen 11. Scheme 4. Syn hesis o eas e n agmen 13. Chemis y—A Eu opean Jou nal Communica ion doi.o g/10.1002/chem.202100553 7086Chem. Eu . J. 2021,27, 7085–7089 www.chemeu j.o g © 2021 The Au ho s. Published by Wiley-VCH GmbH Wiley VCH Diens ag, 20.04.2021 2124 / 200179 [S. 7086/7089] 1 yields wi h TFA wi h he allylic TES-e he being simul aneously clea ed. The p ima y alcohol a C13 was Pi -p o ec ed in o de o libe a e bo h p ima y alcohols a he same ime. Then, he allylic alcohol a C17 and he e ia y alcohol we e bo h TES- p o ec ed, bo h Pi -g oups we e educ i ely emo ed and he alcohol a C13 was ans o med o i s PMP-ace al wi h DDQ. Finally, he only hyd oxyl g oup unp o ec ed was he one ha is equi ed o he mac olac oniza ion which hen was p o- ec ed as i s SEM-e he 33. A DIBAL-H educ ion libe a ed he p ima y alcohol a C13 and oxida ion wi h TPAP[15] p o ided he desi ed aldehyde 12 o he aldol eac ion wi h eas e n agmen 13. This aldol eac ion was achie ed wi h ei he DIPCl (40%) o LiHMDS (55%) and gene a ed a single isome 34. The subsequen an i-selec i e educ ion was accomplished wi h he E ans–Saksena p o ocol[16] in 67% yield. The newly gene a ed seconda y alcohol was TES-p o ec ed and he Pi -g oup educ- Scheme 5. Syn hesis o desepoxy- edanolide C (43) (o3 s =o e h ee s eps). Chemis y—A Eu opean Jou nal Communica ion doi.o g/10.1002/chem.202100553 7087Chem. Eu . J. 2021,27, 7085– 7089 www.chemeu j.o g © 2021 The Au ho s. Published by Wiley-VCH GmbH Wiley VCH Diens ag, 20.04.2021 2124 / 200179 [S. 7087/7089] 1 i ely emo ed. TPAP oxida ion se he s age o he second aldol eac ion. This was pu in o p ac ice wi h TiCl4in qui e goods yields (88%) bu wi h only a modes selec i i y o 1.6: 1 o he desi ed isome . Ne e heless, bo h isome s could be sepa a ed and he desi ed one was TIPS-p o ec ed (38). A his s age, all ca bons we e assembled and we decided o es ablish he ca bonyl g oup a C15 p io o ing closu e. Again, in o he p o ec ing g oup combina ions his p o ed o be a non- i ial ask and he e we only p esen he success ul ou e. DDQ and DMP p o ided he ca bonyl g oup in e y good yields (90%, 92%) and ea men wi h MgB 2in MeNO2 [17] libe a ed he p ima y alcohol. Du ing clea age o he SEM-e he , he TES g oups a C11 and C13 we e emo ed as well and he la e we e e-p o ec ed as ace onide 41. Finally, a palladium- ca alyzed clea age o he allyl es e ollowed by a Yamaguchi lac oniza ion[18] p o ided he mac olac one o edanolide C. E en ually, global dep o ec ion was achie ed in wo s eps wi h PPTS and HF·E 3N. Un o una ely, he ma e ial was no s able in MeOH and i slowly decomposed ( e o-aldol p oduc s) while 13C-NMR spec- a o deseopxy- edanolide C (43) we e aken. Howe e , he 1H- NMR and HSQC/HMBC spec a eco ded a e in good ag eemen wi h he ones epo ed om isola ed edanolide C. In pa icula he chemical shi and coupling cons an o he C9 and C10 p o ons a e indica i e as hey we e pa o he a gumen a ion o he p oposed s uc u e. The a ional o he p oposed s uc u e ook aid om compu a ional s udies which p oposed an eclipsed con o ma ion a ound his pa o he molecule and se ed in pa as a a ional o he con igu a ion o he sou he n pa opposi e as compa ed o he o he congene s o he edanolide amily. Since desepoxy- edanolide C (43) wi h he opposi e con igu a ion in he sou he n pa shows he same coupling cons an , one can sa ely a gue ha also his con ig- u a ion can p oduce he chemical shi s and coupling cons an s as obse ed o he na u al p oduc and he unusual con ig- u a ion is no necessa y o explain he NMR-spec a (Figu e 2). Whe he compound 5also displays an eclipsed con o ma ion o his coupling cons an esul s om an an i-o ien a ion canno be concluded a his momen . The good ag eemen o he NMR spec a poin s o a di e en con igu a ion as o iginally published. On he o he hand, he ac ha he syn he ic compound was sensi i e o decomposi ion sp eads some ques ions on his conclusion since we in gene al obse e ha mac olac ones o na u al p oduc s a e qui e s able and con o ma ionally es ic ed o p ohibi e o-aldol p ocesses and elimina ion. E en hough ou da a suppo he con igu a ion o edanolide C as a ge ed he ein, he syn hesis o he o iginally p oposed s uc u e and i s compa ison wi h he spec a o he au hen ic ma e ial would u he back up he s uc u e assign- men . In summa y, we ha e es ablished he i s syn he ic access o he ca bon amewo k o his complex membe o he edanolide amily and ha e shown how he syn hesis o he mo i con aining a e ia y alcohol can be success ully in o- duced. Fu he s udies on he con igu a ional assignmen o edanolide C a e in p og ess and will be epo ed in due cou se. Acknowledgemen s We hank D . J. Foh e , M. Re s ad and D. Kö je o de ailed NMR analysis and D . G. D äge , A. Schulz and R. Reichel o mass spec a. Bjö n Siekmeye is acknowledged o p elimina y s udies abou he Julia-Kocienski ole ina ion. In e ms o p oo eading[ 1] o his manusc ip , we hank Alina Egge , Ca oline Poock, Giada Tedesco and Alexand u-Ad ian Sa a. Open access unding enabled and o ganized by P ojek DEAL. 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