total synthesis of (+)-scholarisine a - ccc/upcmldccc.chem.pitt.edu/wipf/current...
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Filip Petronijević Current literature presentation February, 18th 2012
Total Synthesis of (+)-Scholarisine A
NN
O
O
H
Adams, G. L.; Carroll, P, J.; Smith, A. B. III
J. Am. Chem. Soc. ASAP
Filip Petronijević @ Wipf Group Page 1 of 11 2/18/2012
Akuammiline Alkaloids: Scholarisine
NN
O
O
H
Scholarisine A
NHN
R1
H3CO2C R
R = H, R1 = CHO Aspidophylline AR = CH2OAc, R1 = H Aspidodasycarpine
ON
N
H3CO2C R
R = H, StrictamineR = CH2OAc, Akuammiline
N NHH
OH O
OCH3
Geissoschizine
27
65
4
3
16
NN
H3CO2C R
R = H, PicrinineR = CH2OAc, Picraline
O H
1. Wenkert, E.; Wickberg, B. J. Am. Chem. Soc. 1965, 87, 1580-1589. 2. Ramirrez, A.; Garcia-Rubio, S. Curr. Med. Chem. 2003, 10, 1891-1915. 3. Cai, X. H.; Tan, Q. G.; Liu, Y. P.; Feng, T.; Du, Z. Z.; Li, W. Q.; Luo, X. D. Org. Lett. 2008, 10, 577-580. 4. http://en.wikipedia.org/wiki/Alstonia_scholaris
• isolated in 2008 from Alstonia scholaris • unprecedented skeleton • no information on the bioactivity (picraline is a target for type-II diabetes)
Filip Petronijević @ Wipf Group Page 2 of 11 2/18/2012
Biosynthetic Relationship in the Akuammiline Familiy
N NHH
OH O
OCH3
Geissoschizine
27
65
4
3
16
N NH
O O
OCH3
27
65
4
3
16+
-
N NH
OO
H3CO
27
65
4
316
NN
H3CO2C CHO7
23
45
16
Rhazinaline
C(4)-C(5)cleavage
C(5)-oxidation
NHN
R1
H3CO2C R723
5
16
R = H, R1 = CHO Aspidophylline AR = CH2OAc, R1 = H Aspidodasycarpine
O
C(5)-oxidationand nucleophilic
attack at C(2)
NN
H3CO2C R7
23
45
16
R = H, PicrinineR = CH2OAc, Picraline
O H
H+
NN
H3CO2C R7
23
45
16
R = H, StrictamineR = CH2OAc, Akuammiline
NNH
H3CO2C H7
23
5
16
ONNH
HOO - C(2) cleavage
N-C(4) cleavage
OOCH3
NN
O
O
H
Scholarisine A
Cai, X. H.; Tan, Q. G.; Liu, Y. P.; Feng, T.; Du, Z. Z.; Li, W. Q.; Luo, X. D. Org. Lett. 2008, 10, 577-580
Filip Petronijević @ Wipf Group Page 3 of 11 2/18/2012
Total Synthesis of Aspidophilline A: First Akuammiline Alkaloid Synthesized
HN
N
CO2CH3
O
OHC
(±)-Aspidophylline A
RN NH2 X
R1
OH
H+
X = O, NTs
RN
H2+
N H XH
R1
+RNHX
R1
RN
R1
XH
RNHX
R1
H2N
H
+
+RNHX
R1
H2N
Interrupted Fisher Indolization Cascade
Liansuo, Z.; Boal, B. W.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 8877-8879.
Filip Petronijević @ Wipf Group Page 4 of 11 2/18/2012
Garg’s Approach to Aspidophylline A
HN
N
CO2CH3
O
OHC
O
RN
CO2CH3H
HHO
H
HN NH2
+
NBn
O
BnO OO O
PhMe, reflux
BnN
OH
H
O
OBnO O H3COH3CO
NHTs
CO2CH3
BrI
CH3
Cs2CO3, CH3CN; 70%
H3COH3CO
TsNI
CH3
CO2CH3
1. Heck reaction2. deprotection3. reduction 90% (3 steps)
O
TsN
CO2CH3H
HO
TsN
CO2CH3H
HHO
HHN NH2
various acidsXHN
N
CO2CH3
O
Ts
1. LiHMDS, DMPU, allyl iodide -50 °C, THF; 75%2. NaBH4, MeOH; 98%
TsN
CO2CH3H
H
H
HO
TsN
H
H
O
O
O
4 steps
Liansuo, Z.; Boal, B. W.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 8877-8879.
Filip Petronijević @ Wipf Group Page 5 of 11 2/18/2012
Garg’s Approach to Aspidophylline A: End Game
TsN
H
H
O
O
O
HN NH2
HN
NTs
O O
H2+
N
TFA, DCE40 °C; 70%
N
NTs
OO
K2CO3, CH3OH60 °C
N
N
CO2CH3
-O
Ts
HN
N
CO2CH3
O
Ts
HN
N
CO2CH3
O
OHC
(±)-Aspidophylline A
RN NH2 X
R1
OH
H+
X = O, NTs
RN
H2+
N H XH
R1
+RNHX
R1
RN
R1
XH
Interrupted Fisher Indolization Cascade
Liansuo, Z.; Boal, B. W.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 8877-8879.
Filip Petronijević @ Wipf Group Page 6 of 11 2/18/2012
Smith’s Approach: Late-stage Retro-Biosynthetic Fragmentation
NN
O
O
H
Scholarisine A
HN
N
CO2CH3
O
OHC
(±)-Aspidophylline A
NN
O
O
H
Scholarisine A
NHN
H
O
O
OH
alkylation
NBnN
Bn
HOOH
OBn
ONBnN
Bz
O
O
NBz
O
OH
Fisher indolesynthesis
OO
H
H
Adams, G. L.; Carrol, P. J.; Smith, A. B., III; J. Am. Chem. Soc. ASAP
Filip Petronijević @ Wipf Group Page 7 of 11 2/18/2012
Smith’s Approach: Construction of the Tetracyclic Alcohol
OO
H
H LDA, BtCN
THF, 60%
OO
H
HNC
NN
N
CNBtCN
EtI, K2CO3
CH3CN; 71%
OO
H
HNC
m-CPBA
CHCl3
OO
H
HNC
O
OO
H
HNC
O
+
A, 58% B
(X-ray) (X-ray)
(X-ray) (X-ray)A:B = 3:1
OO
H
HNC
O
Rh/Al2O3H2 (120 psi)
THF, 50 °C64%
OO
H
H
ONH2
O
NH
O
OH
(X-ray)
1. BzCl DIPEA, CH2Cl2
2. DMP, CH2Cl271% (2 steps)
O
NBz
O
O
(X-ray)
LiAlH4
THF, 60 °C NBnN
Bn
HOOH
(X-ray)
TBDPSClEt3N
CH2Cl270% (3 steps)
NBnN
Bn
HOOTBDPS
Adams, G. L.; Carrol, P. J.; Smith, A. B., III; J. Am. Chem. Soc. ASAP
PhN
NH2
Bn
pyridine/HCl110 °C, 36 h
Fisher indole synthesis
ONBnN
Bz
O
NBnN
Bn
HOTBDPS
TPAP/NMO
CH3CN78%
O
Filip Petronijević @ Wipf Group Page 8 of 11 2/18/2012
Addition of the Stannane Reagent: Formation of the Lactone
NBnN
Bn
HOTBDPS
O
a. n-Bu3SnCH2OBn n-BuLi, THF, -78 °C
b. KOH, MeOH THF, 60 °C 63% (one pot)
NBnN
Bn
HOOH
OBn
HH
O
OTBDPS
H H
Nu
1. IBX, THF, DMSO
2. TPAP, NMO, CH2Cl2 57% (2 steps)
NBnN
Bn
OO
OBn
AlCl3, toluene
sonication, rt, 2 h83%
NHN
Bn
OO
OH
NN
O
O
H
Scholarisine A
Adams, G. L.; Carrol, P. J.; Smith, A. B., III; J. Am. Chem. Soc. ASAP
Filip Petronijević @ Wipf Group Page 9 of 11 2/18/2012
Scholarisine A: End Game
NHN
Bn
OO
OH
Pd(OH)2/CHCO2NH4
CH3OH, rt, 28 h NHN
H
OO
OH
(X-ray)
N
N
O
F3C
THFNHN
OO
OH
OF3C
1. MsCl, Et3N CH2Cl2
2. BTPP, CH3CN 40% (4 steps)
NN
O
O
H
OF3C
1. K2CO3 (aq) CH3OH
2. PhIO, CH2Cl2 77%(2 steps) N
N
O
O
H
Scholarisine A (X ray)
NN
O
O
H
Scholarisine A
Filip Petronijević @ Wipf Group Page 10 of 11 2/18/2012
Conclusions
• Effective total synthesis of (+)-Scholarisine A (20 setps) • Novel route: “retro-biosynthetic” fragmentation • Nitrile reduction on Rh/Al2O3 – epoxide opening cascade • Facial selectivity in the stannane reaction: model based on NMR-studies • Intramolecular cyclization leads to the indolenine ring of Scholarisine A
OO
H
HNC
O
Rh/Al2O3H2 (120 psi)
THF, 50 °C64%
OO
H
H
ONH2
O
NH
O
OH
NBnN
Bn
HOTBDPS
O
a. n-Bu3SnCH2OBn n-BuLi, THF, -78 °C
b. KOH, MeOH THF, 60 °C 63% (one pot)
NBnN
Bn
HOOH
OBn
HH
O
OTBDPS
H H
Nu
NHN
OO
OH
OF3C
1. MsCl, Et3N CH2Cl2
2. BTPP, CH3CN 40% (4 steps)
NN
O
O
H
OF3C
NN
O
O
H
Scholarisine A
Filip Petronijević @ Wipf Group Page 11 of 11 2/18/2012