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Total Synthesis of Englerin AWillot, M.; Radtke, L.; Konning, D.; Frohlich, R.; Gessner, V.; Strohmann, C.; Christmann, M.
Angew, Chem, Int. Ed. 2009, 48, 9105-9108
Zhou, Q.; Chen, X.; Ma, D. Angew, Chem, Int. Ed. 2010, early view
Molawi, K.; Delpont, N.; Echavarren, A. M. Angew, Chem, Int. Ed. 2010, early view
Antoinette NibbsShort Literature Presentation
18 May 2010
O
H
HMe
H
H
OO
Ph
Me Me
MeO
O
OH
O
H
HMe
H
H
OO
Ph
MeMe
Me O
O
HO
(+)-englerin A (-)-englerin A
Renal Cell Carcinoma
•east African plant Phyllanthus engleri
•high selectivity and activity against renal cancer cellsGI50 values from 1-87nM
•when tested against other cancer cell lines, only moderate inhibition activity GI50 10-20 μM
Willot, M.; Radtke, L.; Konning, D.; Frohlich, R.; Gessner, V.; Strohmann, C.; Christmann, M. Angew, Chem, Int. Ed. 2009, 48, 9105-9108
kidney cancer is a major cause of morbidity and mortality in adults
O
H
HMe
H
H
OO
Ph
Me Me
MeO
O
OH
(+)-englerin A
•active component isolated and structure elucidated except for absolute configuration (Beutler and coworkers, 2009)
Retrosynthesis
O
H
HMe
H
H
OO
Ph
Me Me
MeO
O
OHMe H
H
HO
O
MeO
O
TBSO
Me
Me
Me H
H
O
OH
MeO
O
TBSO
Me
Me
Me
Me[M]
O
Me H
H
O
MeCHO
Me H
H
O
Me
O
trans,cis-nepetalactone
Me H
H OH
Me
Me
Me OH
Willot, M.; Radtke, L.; Konning, D.; Frohlich, R.; Gessner, V.; Strohmann, C.; Christmann, M. Angew, Chem, Int. Ed. 2009, 48, 9105-9108
O
H
HMe
H
H
OO
Ph
Me Me
MeO
O
OH
(+)-englerin A
Nepetalactones
Liblikas, I.; Santangelo E. M.; Sandell, J.; Baeckstrom, P.; Svensson, M.; Jacobsson, U.; Unelius, C. R. J. Nat. Prod. 2005, 68, 886-890
•can be obtained by distillation of commercially available catnip oil ($ 0.45 / g)•insect repellent
cis-trans
cis-cis
trans-trans
trans-cis
Me H
H
O
Me
O
Me H
H
O
Me
O Me H
H
O
Me
O
Me H
H
O
Me
O
O
H
HMe
H
H
OO
Ph
Me Me
MeO
O
OH
(+)-englerin A
=Nepeta cataria
Oxidation of Nepetalactones
Me H
H
O
Me
OmCPBA
CH2Cl2, 0 → 25 °C
Me H
H
O
Me
O
O
Me H
H
O
Me
O
O
10% 71%
10
Me H
H
O
Me
O
mCPBA
CH2Cl2, 0 → 25 °C
Me H
H
O
Me
O
O
Me H
H
O
Me
O
O
55% 36%
5
necessitated late-stage epimerization
Willot, M.; Radtke, L.; Konning, D.; Frohlich, R.; Gessner, V.; Strohmann, C.; Christmann, M. Angew, Chem, Int. Ed. 2009, 48, 9105-9108
O
H
HMe
H
H
OO
Ph
Me Me
MeO
O
OH
(+)-englerin A
Oxidative Rearrangement
O
Me H
H
O
MeCHO
Me H
H
O
Me
O
O
NaOMe
MeOH 93%
Me H
H
O
Me
O
O
Me H
HCHO
Me
O
OMe
O
MeOMe H
H
O
Me
OOMe
O
O
Me H
H MeCHO
OMeO
pdt
Willot, M.; Radtke, L.; Konning, D.; Frohlich, R.; Gessner, V.; Strohmann, C.; Christmann, M. Angew, Chem, Int. Ed. 2009, 48, 9105-9108
O
H
HMe
H
H
OO
Ph
Me Me
MeO
O
OH
(+)-englerin A
Oxidative Rearrangement
O
Me H
H
O
MeCHO
Me H
H
O
Me
O
O
NaOMe
MeOH 93%
O
Me H
H
O
MeCHO
Me H
H
O
Me
O
O
NaOMe
MeOHX
strain from trans-bicyclo-[3.3.0]octane scaffold
Gordon, H. L.; Freeman, S.; Hudlicky, T. Synlett 2005, 2911-2914
O
H
HMe
H
H
OO
Ph
Me Me
MeO
O
OH
(+)-englerin A
Installation of the Remaining Carbon Framework
O
Me H
H
O
MeCHO
Me
MeBr
Zn, sonication
aq. NH4Cl, THF, 0 → 25 °C
O
Me H
H
O
MeOH
Me
Me
93%dr 5:1
LiAlH4, THF
0 → 25 °C, 98%
MeOH
Me OH Me
Me OHH
H
confirmation of the absolute configuration of SM lactone
Willot, M.; Radtke, L.; Konning, D.; Frohlich, R.; Gessner, V.; Strohmann, C.; Christmann, M. Angew, Chem, Int. Ed. 2009, 48, 9105-9108
O
H
HMe
H
H
OO
Ph
Me Me
MeO
O
OH
(+)-englerin A
O ZnBr Me
MeH
R
H
Functional Group Manipulations
MeOH
Me OH Me
Me OHH
H
Me Me
OMeMeO
cat. pTsOH·H2O
CH2Cl2, 25 °C95%
Me OHH
H
Me
OO
Me Me
Me
MeIBX, DMSO
96%
Me OH
H
Me
OO
Me Me
Me
MeH
Me H
H
Me
OO
Me Me
Me
MeH
MePPh3Br, nBuLi
THF, 0 °C95%
Willot, M.; Radtke, L.; Konning, D.; Frohlich, R.; Gessner, V.; Strohmann, C.; Christmann, M. Angew, Chem, Int. Ed. 2009, 48, 9105-9108
C5 epimer now accessible
DBU
PhMe, 25 °C70%, 3:1
Me OH
H
Me
OO
Me Me
Me
MeH
O
H
HMe
H
H
OO
Ph
Me Me
MeO
O
OH
(+)-englerin A
RCM RCM RCM
Me H
H
Me
OO
Me Me
Me
MeH
aq. HCl
MeOH, 25 °C88%
Me H
HOH OHMe
Me
Me
Me H
HOH OMe
Me
Me
O
TBSO
Gradillas, A.; Perez-Castells, J.; Angew. Chem. Int. Ed. 2006, 45, 6086-6101; Hamel, C.; Prusov, E. V.; Gertsch, J.ʼ Schweizer, W. B.; Altmann, K. H. Angew. Chem. Int. Ed. 2008, 120, 10081-10085
Me H
H
MesN NMes
RuPCy3
ClCl Ph
CH2Cl2, Δ, 99%
O O
Me
Me Me
Me
Me
20 mol %
O
H
HMe
H
H
OO
Ph
Me Me
MeO
O
OH
(+)-englerin A
Cl
OOTBS
pyridine, CH2Cl2, 25 °C91%
Home Stretch
Me H
HOH OMe
Me
Me
O
TBSO
Me H
H OMe
Me
Me
O
TBSO
CHCl3, ΔHO
O99%
PhCO2H
Et3N, 4-DMAP, PhMe, 80 °C
60%
O
H
HMe
H
H
OO
Ph
Me Me
MeO
O
OTBSCl
Cl Cl
Cl
O
O
H
HMe
H
H
OO
Ph
Me Me
MeO
O
OH
TBAF, THF
0 → 25 °C91%
1H NMR, 13C NMR, UV matchednatural (–)-englerin A: optical rotation [a]D = –63 (c= 0.13, MeOH)synthethic: optical rotation [a]D = +51 (c= 0.58, MeOH)
Willot, M.; Radtke, L.; Konning, D.; Frohlich, R.; Gessner, V.; Strohmann, C.; Christmann, M. Angew, Chem, Int. Ed. 2009, 48, 9105-9108
mCPBA
CH2Cl2, 0 °C90%, 2.3:1
Me H
HOH OMe
Me
Me
O
TBSO
O
O
H
HMe
H
H
OO
Ph
Me Me
MeO
O
OH
(+)-englerin A
O
H
HMe
H
H
O
Me Me
MeO
O
OTBS
H
First Total Synthesis of (+)-Englerin A
epoxylactone rearrangementO
Me H
H
O
MeCHO
Me H
H
O
Me
O
O
NaOMe
MeOH 93%
diastereoselective Barbier reaction
O
Me H
H
O
MeCHO
Me
MeBr
Zn, sonication
aq. NH4Cl, THF, 0 → 25 °C
O
Me H
H
O
MeOH
Me
Me 93%dr 5:1
transannular epoxide openingMe H
HOH OMe
Me
Me
O
OTBS
O Me H
H OMe
Me
Me
O
OTBS
CHCl3, ΔHO
O99%
ring-closing metathesisMe H
H
Me
OO
Me Me
Me
MeH
NMes
MesN
Ru PCy3Cl Cl
Ph
CH2Cl2, Δ, 99%
Me H
HO O
Me
Me Me
Me
Me
20 mol %
O
H
HMe
H
H
OO
Ph
Me Me
MeO
O
OH
(+)-englerin A
First Total Synthesis of (–)-Englerin A
O
H
HMe
H
H
OO
Ph
MeMe
Me O
O
HO
(-)-englerin A
OOO
Ph
Me MeMe
O
O
OH
MeMe
H
H
OO
Me
O
O
OTBS
MeMeO
Ph
MeH
H
OO
Me
O
O OTBSMe
MeO
Ph
MeH
H
HOO
Me
O
MeMe
MeH
O
Me
OR
MeMe
Me
MeOOH
Me
Me
Zhou, Q.; Chen, X.; Ma, D. Angew, Chem, Int. Ed. 2010, early view
OHCMe
MeMe
(R)-citronellal
Generation of Cyclization Precursor
OHCMe
MeMe
Me
MeMeBr
Br
P(OPh)3, Br2, Et3N —78 °C → 23 ° C
quantitative
1. t-BuOK, 18-cr-6, pet. ether, Δ, 12 h, 41 %
2. SeO2, TBHP, salicylic acid, CH2Cl2, 23 °C, 32%
Me
MeOOR
Me
Me
R = TBS, TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 90%R = TES, TESOTf, 2,6-lutidine, CH2Cl2, 0 °C, 63% R = Me, TMSCHN2, HBF4, CH2Cl2, 0 °C, 50%
Zhou, Q.; Chen, X.; Ma, D. Angew, Chem, Int. Ed. 2010, early view
MeOH
Me 41%
CHO
Me
Me 32%
Me
MeOOH
Me
Me1. IBX, EtOAc, Δ, 95%
2a.
Me
O
Me
Me, (—)-Ipc2BCl, Et3N, 0 °C
b. CHO, —78 °Cc. MeOH, pH 7 buffer, H2O2 95%, 4:1 dr
OOO
Ph
Me MeMe
O
O
OH
Me
(-)-englerin A
Gold-Catalyzed Cyclization
Jimenez-Nunez, E.; Claverie, C. K.; Nieto-Oberhuber, C.; Echavarren, A. M. Angew. Chem. Int. Ed. 2006, 45, 5452
Jimenez-Nunez, E.; Echavarren, A. M. Chem. Commun. 2009, 45, 7327
R
O
Me
Z[Au]
CH2Cl2, 23 °C5-30 min Z
H
R
O
MeZ
H
R
O
Me
RO
Me
up to 84% yieldZ = C(CO2Me)2, NTsR = H, Me, i-Pr
Pt-But-Bu
Au-NCMe
SbF6
AuCl
Au(PPh3)Cl/AgSbF6
catalysts
OOO
Ph
Me MeMe
O
O
OH
Me
(-)-englerin A
Me
MeOOR
Me
Me
R = H, TBS, TES, Me
[Au]
MeH
O
Me
OR
MeMe
Gold-Catalyzed Cyclization
Me
MeOOR
Me
Me
R = H, TBS, TES, Me
AuCl or
Au(PPh3)Cl/AgSbF6 MeH
O
Me
OR
MeMe
A
Me
Me
OOR
Me
Me
B
Me
H
Me[AuL]+
OR
O Me
Me
Me
H
Me[AuL]+
OR
O Me
MeMe
H
Me[AuL]+
OR
O Me
Me B
Me
H
Me[AuL]+
OH
O Me
Me MeH
O
Me
OH
MeMe
[LAu]A
MeMe
O
ORMe
Me
[AuL]+ Me
H
Me[AuL]+
OR
O Me
Me
5-exo-dig
Gold-Catalyzed Cyclization
Me
MeOOR
Me
Me
R = H, TBS, TES, Me
AuCl or
Au(PPh3)Cl/AgSbF6 MeH
O
Me
OR
MeMe
A
Me
Me
OOR
Me
Me
B
Me
MeOOH
Me
Me AuCl (10 mol %)
MeH
O
Me
OH
MeMe
"some unidentified side products"CH2Cl2, 23 °C,
20 min, 48%
Gold-Catalyzed Cyclization
MeH
O
Me
OH
MeMe
mCPBA
CH2Cl2, 0 °C93% Me
H
O
Me
OH
MeMe
O
Zhou, Q.; Chen, X.; Ma, D. Angew, Chem, Int. Ed. 2010, early view
[Cp2TiCl2], Zn, 1,4-cyclohexadiene
THF, 23 °CMe
H
O
Me
OH
MeMe
HOH
MeH
O
Me
OH
MeMe
HO
OOO
Ph
Me MeMe
O
O
OH
Me
(-)-englerin A
MeH
O
Me
OH
MeMe
HO
CSA, CHCl3, 0 °C
MeH
O
Me
OH
MeMe
HO
1. TPAP, NMO, 10:1 CH2Cl2/MeCN, 23 °C2. NaBH4, MeOH,0 °C (76% over two steps)
MeH
O
Me
OH
MeMe
HOH
Raney Ni, H2, 90 atm
EtOH, 75 °C86%
94%
Home Stretch
MeH
O
Me
OH
MeMe
HOH
1. DMP, NaHCO3, CH2Cl2, 0 °C → 23 °C
2. cinnamic acid, 2,4,6-TCBC, 4-DMAP, Et3N, 78% over two steps
MeH
H
OO
Me
O
MeMeO
Ph OOO
Ph
Me MeMe
O
Me
NaBH4, MeOH, 0 °C, 95%
OOO
Ph
Me MeMe
HO
MeLiHMDS, (imid)2SO2,
THF, 0 °C → 23 °C, 99%
OOO
Ph
Me MeMe
imidO2SO
Me
HOCH2CO2Cs, 18-cr-6
PhMe, Δ, 48 h, 67%
OOO
Ph
Me MeMe
O
O
OH
Me
Zhou, Q.; Chen, X.; Ma, D. Angew, Chem, Int. Ed. 2010, early view
OOO
Ph
Me MeMe
O
O
OH
Me
(-)-englerin A
synthetic np: [a]D = –47 (c=0.55, MeOH)reported: [a]d = –63 (c=0.13, MeOH)(R)-citronellal from TCI: 77% ee
Total Synthesis of (–)-Englerin A
gold-catalyzed enyne cyclization
15 steps, 8.1% overall yield starting from (R)-citronellal
in the final route, no protecting groups need
Zhou, Q.; Chen, X.; Ma, D. Angew, Chem, Int. Ed. 2010, early view
hydroxy-directed hydrogenation of an olefin
MeH
O
Me
OH
MeMe
HO
MeH
O
Me
OH
MeMe
HOH
Raney Ni, H2, 90 atm
EtOH, 75 °C86%
OOO
Ph
Me MeMe
O
O
OH
Me
(-)-englerin A
Me
MeOOH
Me
MeAuCl (10 mol %)
MeH
O
Me
OH
MeMe
CH2Cl2, 23 °C, 20 min, 48%
hydroxy-directed hydrogenation of an olefin
Molawi, K.; Delpont, N.; Echawarren, A. M. Angew, Chem, Int. Ed. 2010, early view
OOO
Ph
Me MeMe
O
O
OH
Me
(-)-englerin A
18 steps, 7% overall yield starting from geraniol
15 steps, 8.1% overall yield starting from (R)-citronellal
gold-catalyzed enyne cyclization
Me
MeOOH
Me
Me [IPrAuNCPh]SbF6
CH2Cl2, 23 °C, 5h58% Me H
O
Me
OH
MeMeTESO
TESO
Total Synthesis of (–)-Englerin A
Me
MeOOH
Me
MeAuCl (10 mol %)
MeH
O
Me
OH
MeMe
CH2Cl2, 23 °C, 20 min, 48%
