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.
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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.
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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).
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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.
Con lic o In e es
The au ho s decla e no con lic o in e es .
Keywo ds: Kiyooka aldol ·polyke ides ·s uc u e elucida ion ·
edanolie C · e ia y alcohol
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Ve sion o eco d online: Ap il 9, 2021
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