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An Eight-Step Synthesis of Epicolactone Reveals its Biosynthetic Origin
P. Ellerbrock, N. Armanino, M. K. Ilg, R. Webster, and D. Trauner Ludwig Maximilians University
[1] Nat. Chem. 2015, 7, 879.
Evan Carder Wipf Group Current Literature
November 21, 2015
OHO
O
HO OH
O
O
O
H
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Epicolactone
§ Isolated from an endophytic fungi Epicoccum – a plant fungi found on sugar cane and cocoa tree.
§ Displays antimicrobial and antifungal
activity. § Features a pentacyclic framework that
contains four tetrasubstituted carbons and five contiguous stereocenters.
[1] Eur. J. Org. Chem. 2012, 5225–5230. [2] Eur. J. Org. Chem. 2013, 3174–3180.
11/21/15 Evan Carder @ Wipf Group 2
OHO
O
HO OH
O
O
O
H
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11/21/15 Evan Carder @ Wipf Group 3
OHHO CHO
HO CHO
OHHO
HOO
OHHO
HOO
O
OHHO
HOO
O
Fungal metabolites OH
HO
HO
OH
OH
OHO OH
Purpurogallin"
Pyrogallol" Flavipin" Epicoccine" Epicoccone A" Epicoccone B"
HO
HO CHO
OOO
HOOH
OH
H
H
Epicoccolide A"
O CHO
OHHO
HO
HO OH
CHO
Epicoccolide B"
HO
HO CHO
OOO
OHOH
OHH
H
Epicocconigrone A"
Epicolactone"
OHO
O
HO OH
O
O
O
H
Dibefurin"
O
O
O
OH
O
O
O
HO
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Pattern Recognition
Evan Carder @ Wipf Group 4 11/21/15
OHO
O
HO OH
O
O
O
H
OO
O
OHO
OHO
HOHO
O OH
O
OHO
O
O
Epicolactone from different perspectives:
Established purpurogallin biosynthesis:
OH
OH
OHO OH
Purpurogallin"
OHOH
OHHO2C
OHOH
OH -CO2
[Ox]
Gallic acid"
OO
HO
OO
OH
OHOH
OH
OOH
OC
OHOH
OH
HOOH
CO2H
(5+2)
Taut.
[Ox]
-CO2
+H2O
Me
O
OH
OH
HO
O OO
OH
Nat. Prod. Rep. 2008, 25, 118.
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Proposed biosynthesis of Epicolactone
Evan Carder @ Wipf Group 5 11/21/15
O
O OHOH
OH
OHOH
OHHO
+H2O
-CO2
HO OH
HO
O
[Ox] OO
OHHO
O O
HO
OEpicoccone B" Epicoccine"
Me
OO
OMe
OHH
HO
O OO
OHO
O
HO OH
O
O
O
H(5+2)
Me
OO
OMe
O
OOH
OC
OH
H
Epicolactone"
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Previous work: Synthesis of Dibefurin
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Epicoccine" Dibefurin"
OHHO
HOO
K3[Fe(CN)6], NaHCO3
MeCN, H2O, 0 oC
O
O
O
OH
O
O
O
HO
49%
Angew. Chem. Int. Ed. 2014, 53, 13414.
O
O
OH
O
O
O
HO
O
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Advanced intermediates
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OH
OMeOH Me
OH
OH
OH
OH
O
Epicoccine"
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Advanced intermediates
Evan Carder @ Wipf Group 8 11/21/15
1. n-BuLi, THF, -10 oC; MeI, -78 oC - 0 oC
2. DDQ, CH2Cl2/H2O, rt
OH
OMeOH
MeOH, p-TSA, rt
OH
OMeOMequant.
OH
OMeO Me
35%
Br2
AcOH, NaOAc, rt
OH
OMeO Me
97%
Br
OH
OMeOH Me
OH
1. 5 mol% Cu, NaOH, H2O, reflux
2. NaBH4, THF/H2O, 0 oC59%
OH
OMeOH Me
OH
OH
OH
OH
O
6 steps, 12%
Epicoccine"
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Advanced intermediates
Evan Carder @ Wipf Group 9 11/21/15
1. n-BuLi, THF, -10 oC; MeI, -78 oC - 0 oC
2. DDQ, CH2Cl2/H2O, rt
OH
OMeOH
MeOH, p-TSA, rt
OH
OMeOMequant.
OH
OMeO Me
35%
Br2
AcOH, NaOAc, rt
OH
OMeO Me
97%
Br
OH
OMeOH Me
OH
1. 5 mol% Cu, NaOH, H2O, reflux
2. NaBH4, THF/H2O, 0 oC59%
MeO OMe
MeO
HOO
formalin, conc, HCl
140 oC OMe
OMe
OMe
Cl
O
O
94%
Zn, KH2PO4
THF, H2O85%
OMe
OMe
OMe
O
O
DIBAL, CH2Cl2, -60 oC
Et3SiH, TFA, CH2Cl2 OMe
OMe
OMe
O
58%
BBr3, CH2Cl2
-78 oC - rt OH
OH
OH
O
80%
OH
OMeOH Me
OH
OH
OH
OH
O
6 steps, 12%
5 steps, 43%
Epicoccine"
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Synthesis of Epicolactone
Evan Carder @ Wipf Group 10 11/21/15
OHO
O
HO OMe
Me
O
O
O
H
HO
O
HO OMe
Me
O
O
O
H
O
OHHO
OH
O
OH
OMeOH Me
OH
+K3[Fe(CN)6], NaHCO3
MeCN, H2O, rt+
42% 16%
Epicolactone" Isoepicolactone"
OHO
O
HO OH
Me
O
O
O
H
MgI2, quinolineTHF, 60 oC
75%
HO
O
HO OH
Me
O
O
O
H
O
AlCl3, CH2Cl296%
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Evan Carder @ Wipf Group 11
(5+2) cycloaddition
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Key transformation
Me
OO
OMe
O
OOH
OC
OH
H
OO
O
OMe
Me
OH
O
H
OH
OO
HO
O
OMe
Me
O
O
O
H
OH
Me
OO
OMe
O
OOH
OC
OH
HHO OH
HO
O
OH
OMeOH Me
OH
O
OMeOH Me
O
O O
O
O
H
OHO
O
HO OMe
Me
O
O
O
H
OHO
O
OMe
Me
O
O
O
H
OH
OHO
O
OMe
Me
O
O
O
H
OH
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Evan Carder @ Wipf Group 12 11/21/15
Key transformation
retro-Claisen condensation
Me
OO
OMe
O
OOH
OC
OH
H
OO
O
OMe
Me
OH
O
H
OH
OO
HO
O
OMe
Me
O
O
O
H
OH
Me
OO
OMe
O
OOH
OC
OH
HHO OH
HO
O
OH
OMeOH Me
OH
O
OMeOH Me
O
O O
O
O
H
OHO
O
HO OMe
Me
O
O
O
H
OHO
O
OMe
Me
O
O
O
H
OH
OHO
O
OMe
Me
O
O
O
H
OH
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Evan Carder @ Wipf Group 13 11/21/15
Key transformation
vinylogous aldol reaction
Me
OO
OMe
O
OOH
OC
OH
H
OO
O
OMe
Me
OH
O
H
OH
OO
HO
O
OMe
Me
O
O
O
H
OH
Me
OO
OMe
O
OOH
OC
OH
HHO OH
HO
O
OH
OMeOH Me
OH
O
OMeOH Me
O
O O
O
O
H
OHO
O
HO OMe
Me
O
O
O
H
OHO
O
OMe
Me
O
O
O
H
OH
OHO
O
OMe
Me
O
O
O
H
OH
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Evan Carder @ Wipf Group 14
(5+2) cycloaddition
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Diastereoselectivity
Me
OO
OMe
O
OOH
OC
OH
HHO OH
HO
O
OH
OMeOH Me
OH
O
OMeOH Me
O
O O
O
O
H
Me
OO
OMe
O
OOH
OC
OAc
HHO OH
HO
O
OH
OMeOAc Me
OHAg2O
dioxane
Me
OHO
OMe
O
OOH
OC
OAc
Taut.
50%(single diastereomer)
Isolation of the carbonyl-bridged intermediate
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Regioisomers
O
OMeOH Me
O
O O
HO
OMe
OO
OMe
O
OOH
OC
OH
H
Epicolactone"
Isoepicolactone"
O
OMeOH Me
O
O
HO
O
O
Me
OO
OMe
OOH
OC
OH
H
O
O O
HO
O
O OH
O
O
Taut.
A! B!
A!
B!
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Conclusions
Major accomplishments: § Concise synthesis of Epicolactone in 8 steps, LLS. § The synthesis highlights a one-pot reaction cascade sequentially featuring
a (5+2) cycloaddition, retro-Claisen condensation, and vinylogous aldol reaction to afford the rather complex framework of Epicolactone.
§ Provided insight into the potential biosynthesis of Epicolactone
Evan Carder @ Wipf Group 16 11/21/15
OHO
O
HO OMe
Me
O
O
O
H
HO OH
HO
O
OH
OMeOH Me
OH
+K3[Fe(CN)6], NaHCO3
MeCN, H2O, rt
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