Total Synthesis of (+)-Corymine
Transcript of Total Synthesis of (+)-Corymine
Total Synthesis of(+)-Corymine
2020.9.12. Literature SeminarB4 Hibiki Asai
1. Introduction
2. Total synthesis of (-)-Vincorine(by MacMillan Group)
3. Total synthesis of (+)-Corymine(by Li Group)
Contents
2
Akuammiline Alkaloids
1) Zi, W.; Xie, W.; Ma, D. J. Am. Chem. Soc. 2012, 134, 4037. 2) Eckermann, R.; Gaich, T. Synthesis 2013, 45, 2813.
3
32N
N21
16
OMe
CO2MeHH
• migration of C3-N bond to C2-N• strained 7-membered azepanyl ring
A
B
D
E
C
32
16N
CO2Me
NC D
EB
A
akuammilinealkaloids
HN
N
OMe
CO2MeHH
Boc Cl(1) TMSOTf, 2,6-lutidine CH2Cl2(2) K2CO3, KI MeCN, 60 °Cconstruction of D-ring
(3) HCHO, NaBH3CN MeCN, AcOH
(-)-vincorine
by Ma Group
Vincorine and Corymine
1) Mokry,J.;Dubravkova,L.;Šefcǒvic,P.Experientia1962,18, 564. 2) Kiang, A. K.; Smith, G. F. Proc. Chem. Soc. 1962, 298.3) Zhang, M.; Huang, X.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2009, 131, 6013.4) Zi, W.; Xie, W.; Ma, D. J. Am. Chem. Soc. 2012, 134, 4037.5) Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442.6) Zhang, B.; Wang, X.; Cheng, C.; Sun, D.; Li, C. Angew. Chem., Int. Ed. 2017, 56, 74847) Zhang, B.; Wang, X.; Li, C. J. Am. Chem. Soc. 2020, 142, 3269.8) Eckermann, R.; Gaich, T. Synthesis 2013, 45, 2813.
4
32N
N
O CO2Me
OH
16
H
32N
N
16
OMe
CO2MeHH
(-)-vincorine (+)-corymineVinca minor (1962) 1) Hunteria corymbosa (1962) 2)Isolation:
Structual features: pentacyclic caged structurestrained 7-membered azepanyl ring
hexacyclic caged structurestrained 7-membeed azepanyl ringC16 extra carbon
Total synthesis: Qin (2009 (35 steps, racemic)) 3)
Ma (2012 (18 steps, enantioselective)) 4)
MacMillan (2013 (9 steps, enantioselective)) 5)
Li (2017 (21 steps, racemic), 2020 (11 steps, 99% ee)) 6) 7)
A A
B B
D DE E
C C
Introduction of Prof. MacMillan and Li
1) https://macmillan.princeton.edu2) http://www.fluorinelab.ac.cn/ketizu.jsp?name=李超忠 5
Prof. David W. C. MacMillan
1991 B.S. @ University of Glasgow1996 Ph.D @ the University of California, Irvine (Prof. Larry E. Overman)1996- Postdoctral fellow
@ Harvard University (Prof.David A. Evans) 1998- @ the University of California, Berkeley2000- @ the California Institute of Technology2004- Professor @ the California Institute of Technology2006- Professor @ Princeton University2011- Distinguished professor @ Princeton University
Research topic: photoredox, organocatalysis, total synthesis
Prof. Chaozhong Li
1988 B.S @ University of Science and Technology of China1993 Ph.D @ Shanghai Institute of Organic Chemistry1993- Assistant Researcher @ Shanghai Institute of Organic Chemistry1994- Postdoctral fellow @ Iowa State University1999- Associate professor @ Shanghai Institute of Organic Chemistry2000- Professor @ Shanghai Institute of Organic Chemistry
Research topic: free radical chemistry, organofluorine chemistry,organometallic chemistry, natural product synthesis
Retrosynthetic Analysis
1) Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442.2) Zhang, B.; Wang, X.; Li, C. J. Am. Chem. Soc. 2020, 142, 3269. 6
3N15
N 20
O CO2MeOH
16
H
N15
N 20
OMe
CO2MeH
N
OMe
NH
BocN
N
OMe
CO2MeHX
H
3N
NO
CO2Me16
CO2Me
Br
HN NBr
CO2MeCO2Me
O R
HNN
R
Br
7-memberedcyclization
; Hemiacetalization7-memberedcyclization
asymmetricalkylation
asymmetricDiels-Aider reaction
(-)-vincorine
(+)-corymine
MeO2C Oby MacMillan
by Li
D
E
D
E
CC
C
C
E
E
Y
1. Introduction
2. Total synthesis of (-)-Vincorine(by MacMillan Group)
3. Total synthesis of (+)-Corymine(by Li Group)
Contents
7
Synthesis of Diene
1) Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442.2) Biscoe, M. R.; Fros, B. P.; Buchwald, S. L. J. Am. Chem. Soc. 2008, 130, 6686. 8
HN
OMe
NH
Boc
commercially available
NaH, DMF, 0 °C; MeI
N
OMe
NH
Boc
n-BuLi1,2-dimethoxyethane, -40°C
; ZnCl2, -78 °C to rt I
N
OMe
NH
Boc
PdII
NH2
Cl
XPhos precatalyst
Negishi coupling
; XPhos precatalyst,N
OMe
NH
BocZnCl
ortho metalation
96%
PCy
CyAr
Ar =
i-Pr
i-Pr
i-Pr
71%
Diels-Alder/Cyclization Cascade (I)
1) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 2458.2) Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442. 9
N
OMe
NH
BocMeO2C O
catalyst (20 mol%)MeCN, -20 °C
N
OMeHN
CO2Me
CHO
Boc
N
HN
OMe
CO2MeHCHO
H
Boc
N
N
OMe
CO2MeHCHO
H
Boc
N
NHPh
Me
Me
MeO
catalyst
Diels-Alderreaction
+H+
-H+MeO2C O
70% yieled, 95% ee
E
E
E
C
catalyst HBF4
Diels-Alder/Cyclization Cascade (II)
1) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 2458.2) Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442.
10
N
NH Me
MeO
MeO2C
N
N Me
MeO
CO2Me
N
NH
H Me
MeO
MeO2C OH H
Diels-Alder
N
OMeHN
CO2Me
Boc
NNMe
O
Me
N
HNBoc
OMe
N
OMeHN
CO2Me
CHO
Boc
N
N
OMe
CO2MeHCHO
H
Boc
+H2O-H+
Me Me Me
Me
Ph
EZ
largeallylic strain
smallallylic strain
electrophilic
nucleophilic
H
Ph Ph Ph
Enantioselectivity of Diels-Alder
1) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 2458.2) Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442.
11
N
HN BocOMe
CO2Me
N
OMe
HNBoc
N
CO2Me
NMe
OMeMe
PhN
OMe
HNBoc
N
CO2Me
NMe
OMeMe
Ph
N
NMe O
Me
Ph
Me
N
OMeHN
CO2Me
CHO
Boc
‡ ‡
hydrolysis
Synthesis of Radical Cyclization Precursor
1) Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442.12
N
N
OMe
CO2MeHCHO
H
Boc
N
N
OMe
CO2MeHCO2H
H
Boc
N
N
OMe
CO2MeHCOTePh
H
Boc
N
N
OMe
CO2MeHCOTePh
H
NaClO2,THF/t-BuOH/H2O, 0 °C
Cl O
O
N-methylmorpholineTHF, -10 °C;
(PhTe)2, NaBH4THF/MeOH, -10 °C
(1) CF3CO2H
(2)O
St-Bu
NaBH(OAc)3CH2Cl2
acyl telluridation
N
N
OMe
CO2MeH
H
Boc
O
O
O
O
96%
87%
65% (2 steps)
St-Bu
Radical Cyclization (I)
1) Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442. 2) Chen, C.; Crich, D.; Papadatos, A. J. Am. Chem. Soc. 1992, 114, 8313. 13
N
N
OMe
CO2MeH
H N
N C
OMe
CO2MeHH
X
O radical cyclization
X condition solvent yield[%]
SePh
TePh
120 °C, 5 hBu6Sn2, hν (Hg lamp)
200 °C, 10 h
St-Bu
chlorobenzene(5 mM)
1,2-dichlorobenzene(0.5 mM)
conversion[%]
85
100
17a
51b
a Yield based on 1H NMR analysis. b Isolated yield.
D
Radical Cyclization (II)
1) Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442.2) Chen, C.; Crich, D.; Papadatos, A. J. Am. Chem. Soc. 1992, 114, 8313. 14
N
N
OMe
CO2MeH
H
N
N C
OMe
CO2MeHH
TePh
O
St-Bu
N
N
OMe
CO2MeH
H
O
St-Bu
N
N
OMe
CO2MeH
St-Bu
-t-BuS
-CO
H
-PhTe
Δ
7-exo
Total Synthesis of (-)-Vincorine
1) Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442. 15
N
N
N C
OMe
CO2MeHH
Pd/C, H2THF, -15 °C
N
N
OMe
CO2MeHH
hydrgenetion fromless hindered face
80% (-)-vincorine
H H
H H
H H
H H
MeO2C
H
CN C
MeO2C
boat skewed-boat
Short Summary
1) Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442.16
N
N
OMe
CO2MeHH
(-)-vincorine
N
OMe
NH
Boc N
N
OMe
CO2MeHCHO
H
Boc
N
N
OMe
CO2MeHCOTePh
H
2 steps fromcommercially available
compound
asymmetricDiels-Alder reaction
MeO2C O
radical cyclization
St-Bu
• 9 steps syntesis• asymmetric Diels-Alder reaction• radical cyclization using acyl telluride
C
D
E
1. Introduction
2. Total synthesis of (-)-Vincorine(by MacMillan Group)
3. Total synthesis of (+)-Corymine(by Li Group)
Contents
17
Retrosynthesis
1) Zhang, B.; Wang, X.; Li, C. J. Am. Chem. Soc. 2020, 142, 3269. 18
N
N
O CO2Me
OHH
N
NO
CO2MeCO2Me
N
NO
CO2MeCO2Me
Br
N NBr
CO2MeCO2Me
RHN N
BrO
Br
R
hemiacetalization 7-menberedcyclization
constructionof C, E-rings
chain extension;asymmetric addition
C
E
(+)-corymine
D
O OEtEtO
Synthesis of 3-bromooxindole
1) Zhang, B.; Wang, X.; Li, C. J. Am. Chem. Soc. 2020, 142, 3269. 19
HNNH
Ns HNN
Ns
Br
BrBr
NBS, H2Ot-BuOH/THF
commercially available
K2CO3DMF
HN N
O
Br
Ns
Br95%
(2 steps)
HNN
Ns
Br
OH
Br
Cu-Catalyzed Enantioselective Alkylation
1) Zhang, B.; Wang, X.; Li, C. J. Am. Chem. Soc. 2020, 142, 3269.2) Ma, S.; Han, X.; Krishnan, S.; Virgil, S. C.; Stolz, B. M. Angew. Chem. , Int. Ed. 2009. 48, 8037. 20
HN NBr
CO2MeCO2Me
O NsMeO2C CO2Me
[Cu], i-Pr2NEt, MS3ACH2Cl2, -20 °C
CuIIN
N
O
O
Ph
Ph
[Cu]
asymmetric alkylation
HN NBrO
Br
Ns
> 99% eerecrystallization, 90%
2 SbF6
65% yield, 91% ee
2
Proposed Mechanism ofCu-Catalyzed Alkylation (I)
1) Zhang, B.; Wang, X.; Li, C. J. Am. Chem. Soc. 2020, 142, 3269.2) Ma, S.; Han, X.; Krishnan, S.; Virgil, S. C.; Stolz, B. M. Angew. Chem. , Int. Ed. 2009. 48, 8037.3) D. M. Barnes, J. Ji, M. G. Fickes, M. A. Fitzgerald, S. A. King, H. E. Morton, F. A. Plagge, M. Preskill, S. H. Wagaw, S. J. Wittenberger, J. Zhang, J.
Am. Chem. Soc. 2002, 124, 13097 21
N
CuII
N
OO
Ph Ph
N
CuIIN
OO
Ph PhO O
MeO OMe
N
CuIIN
OO
Ph PhO O
MeO OMe
+H+
-H+
N NBrO
Br
Ns
H
NEt(i-Pr)2
H
i-Pr2EtNN R
O
Br=R
NO
R+H+
-H+ -Br-
22
Proposed Mechanism ofCu-Catalyzed Alkylation (II)
1) Zhang, B.; Wang, X.; Li, C. J. Am. Chem. Soc. 2020, 142, 3269.2) Ma, S.; Han, X.; Krishnan, S.; Virgil, S. C.; Stolz, B. M. Angew. Chem. , Int. Ed. 2009. 48, 8037.3) D. M. Barnes, J. Ji, M. G. Fickes, M. A. Fitzgerald, S. A. King, H. E. Morton, F. A. Plagge, M. Preskill, S. H. Wagaw, S. J. Wittenberger, J. Zhang, J.
Am. Chem. Soc. 2002, 124, 13097 22
CuII
O O
NR OMe
CO2Me
NCuIIN
OO
Ph Ph
CuII
O O
MeO OMeH
CuII
O O
MeO OMe
MeO2C CO2Me
NO
R
HNO
RBr
-HBr
-H+
iPr2EtN H
HNO
R
CO2MeCO2Me
CuII
O O
MeO OMe
N
O
R
N N N N
NNNN
2
2
Proposed Mechanism ofCu-Catalyzed Alkylation (III)
1) Zhang, B.; Wang, X.; Li, C. J. Am. Chem. Soc. 2020, 142, 3269.2) Ma, S.; Han, X.; Krishnan, S.; Virgil, S. C.; Stolz, B. M. Angew. Chem. , Int. Ed. 2009. 48, 8037.3) D. M. Barnes, J. Ji, M. G. Fickes, M. A. Fitzgerald, S. A. King, H. E. Morton, F. A. Plagge, M. Preskill, S. H. Wagaw, S. J. Wittenberger, J. Zhang, J.
Am. Chem. Soc. 2002, 124, 13097 23
HN
R
O
N
CuIIN
OO
Ph PhO O
MeO OMe
N
CuIIN
OO
Ph PhO O
MeO OMe
stericrepulsion
HN
R
O
CuII
O O
MeO OMe
N
O
R
CuII
O O
NR OMe
CO2Me
‡ ‡
N N N N
Installation of Alkyl Chain
1) Zhang, B.; Wang, X.; Li, C. J. Am. Chem. Soc. 2020, 142, 3269. 24
HN NBr
CO2MeCO2Me
O Ns alkyllithiumGrignard reagent
N
3
NBr
OEtEtO
CO2MeCO2Me
Ns
N NBr
CO2MeCO2Me
OTf Ns
Tf2O2,6-lutidine
CH2Cl2, -78 °C
EtO
OEt
B
Pd(PPh3)4, (o-tolyl)3Pborane A, K2CO3
THF, 75 °C
borane A
Suzuki coupling
N3
NBr
O OEtEtO
CO2MeCO2Me
Ns
MnO2CH2Cl2
oxidation of C3
54%, 2 steps(73% brsm, 2 steps)
65%
Attempted Construction of C,E-Rings
1) Zhang, B.; Wang, X.; Li, C. J. Am. Chem. Soc. 2020, 142, 3269. 25
N N
O OEtEtO
CO2Me
CO2Me
Ns p-thiocresolK2CO3, MeCN
N
CO2MeCO2Me
NBr
O
undesired
N N
O OEtEtO
CO2Me
CO2Me
N-deprotection
BrBr
N N
OEtO
CO2Me
CO2MeBr
E1cBeliminiation
8-endo
-EtOHHN
NO
CO2MeCO2Me
Br
desired
C
OEtOEt
5-exo
H
82%
Construction of C,E-Rings (II)
1) Zhang, B.; Wang, X.; Li, C. J. Am. Chem. Soc. 2020, 142, 3269. 26
N N
O OEtEtO
CO2Me
CO2Me
NsN
O
CO2MeCO2Me
OEt
N
Br
Ns
HN
NO
CO2MeCO2Me
Br
OEt
desired
; p-thiocresol
5-exo
Br
EtONaTHF N N
OEtO
CO2Me
CO2Me
Ns
Br
E
NO
CO2MeCO2Me
OEt
N
Br
E
C
E1cB 6-endo
66%
Formation of 7-membered Ring (I)
1) Zhang, B.; Wang, X.; Li, C. J. Am. Chem. Soc. 2020, 142, 3269.27
HN
NO
CO2MeCO2Me
Br
OEt N
NO
CO2MeCO2Me
Br
OEt
N
NO
CO2MeCO2Me
Br
N
N
OCO2Me
CO2Me
; TMSOTf
Bu3SnH or (TMS)3SiH-mediated,photoredox-catalyzed,
or cobalt-catalyzedradical cyclization
Me3O•BF4 CH2Cl2
D
72%
Formation of 7-membered Ring (II)
1) Zhang, B.; Wang, X.; Li, C. J. Am. Chem. Soc. 2020, 142, 3269.2) Sole, D.; Cancho, Y.; Llebaria, A.; Moreto, J. M.; Delgado, A. J. Am. Chem. Soc. 1994. 116, 12133.3) Nicolaou, K. C.; Roecker, A. J.; Follmann, M.; Baati, R. Angew. Chem., Int. Ed. 2002, 41, 2107.4) Okamura, H.; Mori, N.; Watanabe, H; Takikawa, H. Tetraherdon Lett. 2018, 59, 4397.
28
N
NO
CO2MeCO2Me
Br
N
N
OCO2Me
CO2Me
N
N
OCO2Me
CO2Mereductive Heck coupling
undesired
desired
Pd(OAc)2 (20 mol%)K2CO3, Bu4NCl, HCO2Na
DMF, 80 °C
Ni(cod)2 (6 eq.)NaI (10 eq.), Mg(OTf)2 (2 eq.)
DMF, 80 °C
Ni-mediated cyclyzation
Ni0
Ni0(cod)2
D
50%
46%
Ni(cod)2-Mediated Cyclization
1) Zhang, B.; Wang, X.; Li, C. J. Am. Chem. Soc. 2020, 142, 3269.2) Sole, D.; Cancho, Y.; Llebaria, A.; Moreto, J. M.; Delgado, A. J. Am. Chem. Soc. 1994. 116, 12133.3) Nicolaou, K. C.; Roecker, A. J.; Follmann, M.; Baati, R. Angew. Chem., Int. Ed. 2002, 41, 2107.4) Okamura, H.; Mori, N.; Watanabe, H; Takikawa, H. Tetraherdon Lett. 2018, 59, 4397.
29
N
NO
CO2MeCO2Me
Br
N
N
OCO2Me
CO2Me
N
NO
CO2MeCO2Me
NiIILnX
oxidativeaddition
activationof enone
N
NO
CO2MeCO2Me
NiIILnX
transferinsertion
work up
X = Br or I or OTfNi0Ln MgII
X
X
N
NO
CO2MeCO2Me
NiIILnXMgIIX
MgIIX
eliminationof NiII
N
NO
CO2MeCO2Me
MgIIX
-NiIILnX2
X
X
Total Synthesis of (+)-Corimine
1) Zhang, B.; Wang, X.; Li, C. J. Am. Chem. Soc. 2020, 142, 3269. 30
N
N
OCO2Me
CO2Me
N
N
HO CO2MeCO2Me
from less hindered face
lactonization
; i-Bu2AlH-78 °C
from lesshindered face
(+)-coryimne
KBH4MeOH
Cs2CO3toluene, 100 °C
KBH495%
82%
N
N
O CO2Me
O
N
N
O CO2Me
OH2
H BH3
N
N
O CO2Me
OHH
Extension to Other Family
1) Zhang, B.; Wang, X.; Li, C. J. Am. Chem. Soc. 2020, 142, 3269.31
OHN
NO
CO2MeCO2Me
N
N
HO CO2MeCO2Me
N
N
HO CO2MeH
(-)-deformylcorymine
(1) CS2, NaH, MeI THF, 0 °C to rt(2) (TMS)3SiH, AIBN benzene, 80 °C
N
N
CO2MeH
(-)-10-demethoxyvincorine
i-Bu2AlHtoluene, -78 °C
N
N
CO2Me
OH
HO
N
N
CO2Me
OAc
H
Ac2O/Py; CF3CO2H
(-)-3-epi-dihydrocormine-17-acetate
N
N
OCO2Me
H
N
N
CO2MeH
(1) SmI2 THF/MeOH(2) BF3•OEt2, Et3SiH CH2Cl2
(-)-2(S)-cathafoline
LiCl, DMF, 120 °C
KBH4MeOH
LiClDMF, 120 °C
95%
71%
82%70%
80%
77%
62%
Short Summary
1) Zhang, B.; Wang, X.; Li, C. J. Am. Chem. Soc. 2020, 142, 3269. 32
N
N
O CO2Me
OHH
N
NO
CO2MeCO2Me
N
NO
CO2MeCO2Me
Br
N N
O OEtEtO
CO2Me
CO2Me
NsHN N
CO2Me
CO2Me
O NsHN N
O
Br
Ns
hemiacetalization Ni-mediatedcyclization
nucleophiliccyclizatoin
Suzukicouplingasymmetric
addition
• 11 steps synthesis• Cu-catalyzed asymmetric addition• construction of C, E-rings on one step• Ni-mediated 7-endo cyclization
Br Br Br
2 steps fromcommercially available
compound
(+)-corymine
CD
E
N
N
O CO2Me
OHH
N
N
OMe
CO2MeHH
N
OMe
NH
Boc
N
N
OMe
CO2MeHCOTePh
H
StBu
N
NO
CO2MeCO2Me
Br
HN N
CO2Me
CO2Me
O Ns
HNN
Ns
Br
radicalcyclization
Ni-mediatedcyclization
; Hemiacetalization
asymmetricalkylationasymmetric
Diels-Aider reaction
(-)-vincorine (+)-corymine
achiral indol derivative
N
N
OMe
CO2MeHCHO
H
Boc
Br
by MacMillan by Li
CDE
CD
E
Summary
1) Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442.2) Zhang, B.; Wang, X.; Li, C. J. Am. Chem. Soc. 2020, 142, 3269.
33