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Scalable Total Synthesis of (
-‐)-‐Berkelic Acid by Using a
Protec
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Berkeley Pit Lake • BuWe, Montana
• Formed by flooded copper mine
• pH = 2.5 (lemon juice)
• Contains high levels of arsenic,
cadmium, zinc, sulfuric acid,
and copper • Home to extremophiles
• GI50 = 91 nM (ovarian cancer)
• Contradictory bioac
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Snider’s synthesis
Wu, X.; Zhou, J.; Snider, B. Angew. Chem. 2009, 121,
1309-1312
• Key Oxa-Pictet-Spangler reaction • 13 steps (longest linear)
and 1.7% overall yield
MeO OMe
Br
HO OH
C5H11
HO
CO2H
N
NPO
OO
OTBSO OMe
CHO
O
O
H C5H11
AllylO2COAllyl
OTBSO
1. Dowex, MeOH2. Allyl Bromide
O
HO
H C5H11
HO2COH
O
TBSO
OMe
O
O
HC5H11
HO2C OH
OO
MeO2C
Berkelic acid
Jared Hammill @ Wipf Group Page 3 of 15 11/15/2012
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Furstner’s Synthesis
Snaddon, T. N.; Buchgraber, P; Schulthoff, S.; Wirtz, C.;
Mynott, R.; Furstner, A. Chem Eur. J. 2010, 16, 12133
• Key triple-deprotection,1,4-addition/spiroketalization cascade
• 19 steps (longest linear) 5% overall yield
MeO OMe
Br
AcO OTBS
O OBn
O
C5H11
TBSO
OH
O
OEt
OTBDPSO
LDA
AcO OTBS
O OBn
C5H11
OTBS
O
-O
TBDPSO
-O OTBS
O OBn
C5H11
OTBS
O
OAcTBDPSO
H H
HO OTBS
O OBn
C5H11
TBSOOTBDPSO O
O
HC5H11
BnO2C OHO
Berkelic acidO
HO
HC5H11
AllylO2C OAllylOHHCl
MeOHO
Jared Hammill @ Wipf Group Page 4 of 15 11/15/2012
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De Brabander Synthesis
MeO2C OMeO2C O
Me OH
Me
CO2MeHO OH
OHO
C5H11
EtO
HO OHCO2Me
MeO2CMe
Me
O
O
O
C5H11
O OHCO2Me
O
O
HC5H11
HO2C OH
OO
MeO2C
AgSbF6
Berkelic Acid
Bender, C. F.; Yoshimoto, F. K.; Paradise, C. L.; De Brabander,
J. K. J. Amer. Chem. Soc. 2009, 131, 11350
• Ag catalyzed dearomatization-cycloisomerization-cycloaddition
cascade • 10 steps (longest linear) 11-27% yield
Jared Hammill @ Wipf Group Page 5 of 15 11/15/2012
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Title Paper OHHO2C
O
OO
MeC5H11OMeO2C
Me Et
(-)-Berkelic Acid
Me
OH
HO
OHMeO2C
O
OO
MeOH C5H11
HO OHCO2Me
C5H11
O
H+Metal catalyzed
cascadeMeO2C
O
Me Et
Me
OH
HO
HO OHCO2Me
C5H11
O
H
Me
OMs
HO OHCO2Me
OTf
FGI
FGI
Jared Hammill @ Wipf Group Page 6 of 15 11/15/2012
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Methodology
OH
R1R3NH2
OH O
H
R2
+ OO
NHR3R1
R2
[Pd(MeCN)4](BF4)2(5 mol%)
MeCN, RT
18 examples, 70-06% yield
Barluenga, J.; Mendoza, A.; Rodriguez, F.; Fananas, F. J. Angew.
Chem. Int. Ed. 2009, 48, 1644
OO
NH
RR = OMe, F, Br, Cl, TBu
71%-90%
OO
OMe90%
OO
OMe
PhPh
96%
OO
OMe70%
OO
OMePh
72%
OO
OMe
74%
Jared Hammill @ Wipf Group Page 7 of 15 11/15/2012
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Methodology
[Pd]2+
O
NR3[Pd]+
HO+
O O
NR3[Pd]+
OH
[Pd]2+
OH
OH
[Pd]+ O
R3NH2
OHO
H+
OHN
H
R3
+
+
O O
NHR3R1
R2
Jared Hammill @ Wipf Group Page 8 of 15 11/15/2012
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Star
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Key Transforma
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Key Transforma
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Key Transforma
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Final Star
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End Game
OHMeO2C
O
OO
MeOH C5H11
I2, PPh3, imid.Et2O/CH3CN
(3:1), rt
OHMeO2C
O
OO
MeI C5H111.6 g: 52% yield
recrystallizedas a single diastereomer
LDA, DMPU, THFthen TBAF•3H2O, MeOH, rt
MeO2C CN
OTes
EtMeOHMeO2C
O
OO
MeC5H11OMeO2C
Me Et1.2 g: 88% yield
X-ray
OHMeO2C
O
OO
MeC5H11OMeO2C
Me Et
(Bu3Sn)2OTol, 115 ºC
OHHO2C
O
OO
MeC5H11OMeO2C
Me Et
(-)-Berkelic Acid25 mg: 55% yield
Stable >1 yearNot stable
Jared Hammill @ Wipf Group Page 14 of 15 11/15/2012
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Conclusions
• 14 steps (longest linear) and 12.5 % overall yield • Key
cascade sets 5 stereocenters in 83% yield (2:1 dr) • Selective
crystalization removes need for chiral chromatography • “Protecting
group free” strategy with minimal oxidation/reduction steps • All
but last step done on gram scale • Convergent, modular synthesis
allows for SAR
Jared Hammill @ Wipf Group Page 15 of 15 11/15/2012
