Catalytic Asymmetric Total Syntheses of (-)-Galanthamine and (-) …ccc.chem.pitt.edu/wipf/Current...
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6/20/15 1 Lalith P. Samankumara Wipf Group Current Literature: 05/30/2015 Catalytic Asymmetric Total Syntheses of (-)-Galanthamine and (-)-Lycoramine Li, L.; Yang, Q.; Wang, Y.; Jia, Y. Angew. Chem. Int. Ed., 2015, 54, 6255-6259.
Transcript of Catalytic Asymmetric Total Syntheses of (-)-Galanthamine and (-) …ccc.chem.pitt.edu/wipf/Current...
6/20/15 1
Lalith P. Samankumara Wipf Group Current Literature: 05/30/2015
Catalytic Asymmetric Total Syntheses of (-)-Galanthamine and (-)-Lycoramine
Li, L.; Yang, Q.; Wang, Y.; Jia, Y. Angew. Chem. Int. Ed., 2015, 54, 6255-6259.
6/20/15 2
O
N
H OH
H
O
(-)-Galanthamine
§ An alkaloid isolated form: -‐ Caucasian Snow Drop (Glanathus woronowii) -‐ Bulbs of different species of family Amaryllidaceae
§ An acetylcholinesterase inhibitor, treatment for Alzheimer’s disease and other memory impairments
§ Available as Nivalin, Razadyne, Razadyne ER, Reminyl, Lycoremine
§ Isolated form daffodils: 0.1-‐0.2% dry weight cost: $ 50 000.00/1Kg
Marco-Contelles et. al. Chem. Rev. 2006, 106, 116−133.
Lalith P. Samankumara Wipf Group Current Literature: 05/30/2015
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Lalith P. Samankumara Wipf Group Current Literature: 05/30/2015
O
N
H OH
H
O(-)-lycoramine
O
N
H
OHRO
(-)-morphine: R = H(-)-codeine: R = Me
O
HN
NH
O OR2
OR1H
H
decursivine: R1 = R2 = CH2-
serotobenine: R1 = H: R2 = Me
OOH
O
HO OH
HOdiptoindonesin G
O
OHOH
OOH
HO
HO
HO
HHO
OH
malibatol Apopulene A: !-OHpopulene B: "-OH
Representative Natural Products with a Fused Benzofuran Core Structure
Li, L.; Yang, Q.; Wang, Y.; Jia, Y. Angew. Chem. Int. Ed., 2015, 54, 6255-6259.
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Lalith P. Samankumara Wipf Group Current Literature: 05/30/2015
Different Strategies
OHOH
OOH OA B C
D
HOO O
OO
R
A
H
path a path c
path a path b path cnew strategy
A C
A C
D
B C A B
D
Trost, B. M.; Toste, D. F. J. Am. Chem. Soc. 2000, 122, 11262-11263.
Previous Syntheses: by Trost group (key steps)
OHO Br
CHO
TrocOCO2Me
+O
O Br
CHO
CO2Me OO Br OTBDMS
OTBDMS
OO
OR
OTBDMS
HPh
NH HN
PhO O
PPh3 Ph3P
L1
Pd cat., TEA, CH2Cl2
72%, 88% ee
i) DIBAL-H
ii) TBDMSOTf 2,6-Lutidine
Pd(OAc)2
Intramolecular Heck
Asymmetric Allylic Alkylation(AAA)
L1
A
BC
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Lalith P. Samankumara Wipf Group Current Literature: 05/30/2015
Previous work
Current work
YX
NH2
R
NH
R
Y
X = I, Br
4 3Pd(OAc)2, LigandK2CO3, LiClDMF, 100 ºC N
H
NO
Fargesine
HO
YX
OH
R
OR
Y4 3Pd Cat., Ligand
base, solvent
Shan, D.; Gao, Y.; Jia, Y. Angew. Chem. Int. Ed., 2013, 52, 4902-4905.
Li, L.; Yang, Q.; Wang, Y.; Jia, Y. Angew. Chem. Int. Ed., 2015, 54, 6255-6259.
6/20/15 6
O
N
H OH
H
O
O
NBoc
OH
O
O
NBoc
O
OOO
O
NBoc
O
OO
NBoc
O
OH
O
NBoc
I TES
ketone-lactonecondensation
asymmetricMichael addition oxidation
Pd catalyzedannulation
key step key step
Lalith P. Samankumara Wipf Group Current Literature: 05/30/2015
Retrosynthetic Analysis
Li, L.; Yang, Q.; Wang, Y.; Jia, Y. Angew. Chem. Int. Ed., 2015, 54, 6255-6259.
6/20/15 7
OO
OO
OO
OO
TsN TsN
NBoc CO2Me
MeO2C
OO
O
OO
NBoc
OO
NBoc
OO
NR
O
OTES
TsN
OTMS
CO2MeMeO2C
N
O
Boc
O
O
OO
TsN
OO
NBoc
O
OO
TsN
O
OTES
O
O
R = Boc, 89%R = CO2Me, 92%
95% 88% 82% 95% 44%
95%95% 67% 48% 41%
68% 50%
88% 27%
Lalith P. Samankumara Wipf Group Current Literature: 05/30/2015
YI
OH
R
OR
Y4 3
[Pd2(dba)3]CHCl3 (5mol%)Pd(tBu)3.HBF4 (20 mol%)K2CO3 (5 equiv)DMF, 100 ºC hc = 0.01 M
Development of the Proposed Strategy
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O
CHOI
OHTES
NH2 i) NaBH4, MeOH -10 ºC, 2 hii) Boc2O, Et3N MeOH 82% (2 steps)
OH
O
NBoc
I TES[Pd2(dba)3]CHCl3 (5mol%)Pd(tBu)3.HBF4 (20 mol%)K2CO3 (5 equiv)DMF, 100 ºC h 89%
OTES
NBoc
O
D
B
TBAF.H2O, THFrt, 30 min 95%
O
NBoc
O
MCPBA, CH2Cl2rt, 6 h 56%
O
NBoc
O
O
Lalith P. Samankumara Wipf Group Current Literature: 05/30/2015
O+
O
NBoc
O
O O
Synthesis of (-)-Galanthamine
Li, L.; Yang, Q.; Wang, Y.; Jia, Y. Angew. Chem. Int. Ed., 2015, 54, 6255-6259.
6/20/15 9
Chiral N,N’-oxide ligands for asymmetric catalysis
Lalith P. Samankumara Wipf Group Current Literature: 05/30/2015
O
NBoc
O
OO Catalyst, Ligand
Lewis acid (5 mol%)solvent, rt, 3 days
+O
NBoc
O
O O
NO
NO
H HN NO O
a
NO
NO
H HN NO O
b
NO
NO
H HN NO O
iPriPr iPr
iPr
c
Li, L.; Yang, Q.; Wang, Y.; Jia, Y. Angew. Chem. Int. Ed., 2015, 54, 6255-6259.
6/20/15 10
Lalith P. Samankumara Wipf Group Current Literature: 05/30/2015
O
R
O +
O
EtOH, rt, t OO
RO
OO
O
OO
O
OO
O
OO
OPh
t = 10 h84%, 90% ee
t = 5 h92%, 90% ee
t = 24 h86%, 91% ee
t = 24 h83%, 91% ee
Sc(OTf)3
NO
NO
H HN NO O
iPriPr iPr
iPr
Studying the substrate scope
Li, L.; Yang, Q.; Wang, Y.; Jia, Y. Angew. Chem. Int. Ed., 2015, 54, 6255-6259.
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Lalith P. Samankumara Wipf Group Current Literature: 05/30/2015
O
NBoc
O
O OLDA, THF, -100 ºC
95% O
NBoc
OH
O
O
O
HN
H H
OH
O
O
HN
H OH
H
O
+
73% 12%
ii) DMP, CH2Cl2 0 ºC 75% (3 steps)
i) ClCO2Me, THF aq. Na2CO3, rt
O
NCO2Me
H
O
O
O
NCO2Me
H
O
O
i) TMSOTf, Et3N CH2Cl2, 0 ºCii) Pd(OAc)2, CH3CN rt, o/n 67% (2 steps)
i) L-selectride THF, -78 ºCii) LiAlH4, THF 0 ºC to 45 ºC 60% (2 steps)
O
N
H OH
H
O
(-)-Galanthamine
BF3.Et2O, Et3SiHCH3CN, rt, 3 h
Synthesis of (-)-Galanthamine contd.
Li, L.; Yang, Q.; Wang, Y.; Jia, Y. Angew. Chem. Int. Ed., 2015, 54, 6255-6259.
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Lalith P. Samankumara Wipf Group Current Literature: 05/30/2015
O
NBoc
OH
O
O
L-selectride THF, -78 ºC
91% O
N
OH OH
H
O
Boc
BF3.Et2O, Et3SiHCH3CN 88% O
HN
H OH
H
O
CH2O/H2OHCO2HCHCl3, 60 ºC
O
N
H O
H
OO
H
K2CO3MeOH/H2O84% (2 steps) O
N
H OH
H
O(-)-lycoramine
Synthesis of (-)-Lycoramine
Li, L.; Yang, Q.; Wang, Y.; Jia, Y. Angew. Chem. Int. Ed., 2015, 54, 6255-6259.
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Lalith P. Samankumara Wipf Group Current Literature: 05/30/2015
Conclusions: § Asymmetric Total syntheses of (-)-Galanthamine and (-)-Lycoramine based on
two metal catalyzed reactions
a. Pd-catalyzed intramolecular Larock annulation to construct 3,4-fused tricyclic benzofurans
b. Enantioselective conjugate addition of 3-alkyl substituted benzofuranone to MVK; catalyzed by ScIII/N,N’-dioxide complex
Thank you!
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Lalith P. Samankumara Wipf Group Current Literature: 05/30/2015
