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Current topics in Org Synthesis
LSPN Group Seminar03.04.2012Nick Tappin
NH
How to make poly-substituted indoles skeletons?
NH
R4
R5
R7R6
R3
R2
and cyclopenta[g]indole skeletons?
NH
Challenge for natural product synthesis:
SynLett 2011, 1495
cyclopenta[g]indole skeletons
NH
Tet 2010, 66, 3875
trikentrins and herbindoles
How to make poly-substituted indoles skeletons?
NH
R4
R5
R7R6
R3
R2
and cyclopenta[g]indole skeletons?
NH
Challenge for natural product synthesis:
SynLett 2011, 1495
NH
cis-trikentrin A
NH
trans-trikentrin A
NH
cis-trikentrin B
NH
trans-trikentrin B
Et
Et
NH
R
R = Me; herbindole AR = Et; herbindole B
R = (E)-1-butenyl; herbindole C
NH
NH
NH
(+)-cis-Trikentrin A
asymmetric HV
99%, 96% ee
10 steps
22% yield in 11 steps
JACSAsymmetric Hydrovinylation of Vinylindoles. A Facile Route to
cyclopenta[g]indole Natural Products (+)-cis-Trikentrin A and (+)-cis-Trikentrin B.
W. Liu, H. J. Lim, T. V. RajanBabu.DOI: 10.1021/ja3004733
NH
NH
NH
(+)-cis-Trikentrin A
asymmetric HV
99%, 96% ee
10 steps
22% yield in 11 steps
JACSAsymmetric Hydrovinylation of Vinylindoles. A Facile Route to
cyclopenta[g]indole Natural Products (+)-cis-Trikentrin A and (+)-cis-Trikentrin B.
W. Liu, H. J. Lim, T. V. RajanBabu.DOI: 10.1021/ja3004733
NH
NH
ethylene (1 atm), [L]
[(allyl)Ni-Br]2, NaB(Ar)4,
DCM, -78oC
Ar= 3,5-(CF3)2-C6H3
2
345
6
7
[L] =OO
P
N PhPh
Ra
Sc Sc
or OOP
N napthPh
Ra
Sc
2- ,3- ,5- ,6- , or 7-vinyl indoles
>95%, >90% ee
NH
NH
NH
(+)-cis-Trikentrin A
asymmetric HV
99%, 96% ee
10 steps
22% yield in 11 steps
JACSAsymmetric Hydrovinylation of Vinylindoles. A Facile Route to
cyclopenta[g]indole Natural Products (+)-cis-Trikentrin A and (+)-cis-Trikentrin B.
W. Liu, H. J. Lim, T. V. RajanBabu.DOI: 10.1021/ja3004733
NH
R
R= Me, Et, Et(E)
(-)-herbindoles A-C
NTs
MOMO
[2 + 2 + 2]cyclization
MOMO
NTs
Org LettTotal Synthesis of (-)-Herbindoles A, B, and C via a Transition-Metal-
Catalyzed Intramolecular [2 + 2 + 2] Cyclization between Ynamide and Diynes.
N. Saito, T. Ichimaru, Y. Sato.DOI: 10.1021/ol300571b
NH
NH
ethylene (1 atm), [L]
[(allyl)Ni-Br]2, NaB(Ar)4,
DCM, -78oC
Ar= 3,5-(CF3)2-C6H3
2
34
5
6
7
[L] =OO
P
N PhPh
Ra
Sc Sc
or OOP
N napthPh
Ra
Sc
2- ,3- ,5- ,6- , or 7-vinyl indoles
>95%, >90% ee
NH
NH
NH
(+)-cis-Trikentrin A
asymmetric HV
99%, 96% ee
10 steps
22% yield in 11 steps
JACSAsymmetric Hydrovinylation of Vinylindoles. A Facile Route to
cyclopenta[g]indole Natural Products (+)-cis-Trikentrin A and (+)-cis-Trikentrin B.
W. Liu, H. J. Lim, T. V. RajanBabu.DOI: 10.1021/ja3004733
NH
R
R= Me, Et, Et(E)
(-)-herbindoles A-C
NTs
MOMO
[2 + 2 + 2]cyclization
MOMO
NTs
Org LettTotal Synthesis of (-)-Herbindoles A, B, and C via a Transition-Metal-
Catalyzed Intramolecular [2 + 2 + 2] Cyclization between Ynamide and Diynes.
N. Saito, T. Ichimaru, Y. Sato.DOI: 10.1021/ol300571b
R2
N
EWG
R1
R3
R4
+N
R1
R2
EWG
[2 + 2 + 2]cyclization
R4R3
B. WitulskiACIE 1999, 38, 2426
Chem Comm 2000, 1965ACIE 2002, 41, 3281
NH
NH
ethylene (1 atm), [L]
[(allyl)Ni-Br]2, NaB(Ar)4,
DCM, -78oC
Ar= 3,5-(CF3)2-C6H3
2
34
5
6
7
[L] =OO
P
N PhPh
Ra
Sc Sc
or OOP
N napthPh
Ra
Sc
2- ,3- ,5- ,6- , or 7-vinyl indoles
>95%, >90% ee
MacLeodFeatures: first entry into these alkaloids, racemic, cis/ trans selective, radical cyclization, Hemetsberger indole synthesis
NH
CO2Et
N3
)
Br
OH
OH
5-exo-tr ig
Bu3Sn
HO
H2, Pd/C9:1
trans
H+
radical cyclization
1 : 1
Friedel-Crafts acylations
Suf fers f rom: numerous erasures, poor cis-trans control, early-stage 4-functionalization; not general for analogues
-N2(g)
Raney Nicis
NCO2Et
Hemetsberger synthesisAldrich Acta 2001, 34, 51
Natsume
NSO2Ph
EtO2C
NSO2Ph
OHCEtO2C
enolate addition
+
ketone - cyclisation
NO
O
9 steps
O
Br
partial racemisation:HPLC sep. of cis & trans isomers
Natsume
NSO2Ph
EtO2C
NSO2Ph
OHCEtO2C
enolate addition
+
ketone - cyclisation
NO
O
9 steps
O
Br
partial racemisation:HPLC sep. of cis & trans isomers
Kanematsu
NH
Et
cis-trikentrin B
NPv
OTr
[O] cleavage, FGI DA
JSC Chem Comm1989, 953
OTr
NPv
name rxn?
OTr
NPv
Kanematsu
NH
Et
cis-trikentrin B
NPv
OTr
[O] cleavage, FGI DA
JSC Chem Comm1989, 953
OTr
NPv
name rxn?
OTr
NPv
Kanematsu
NH
Et
cis-trikentrin B
NPv
OTr
[O] cleavage, FGI DA
JSC Chem Comm1989, 953
OTr
NPv
name rxn?
OTr
NPv
Boger
NH
cis-trikentrin A
JOC 1988,53, 1415
NN
Et
SO2Me
HN
Et
NN
NN
SMe
MeS
NH2
Et
N+ +
Blechert
NH
cis-trikentrin A
Et
NO2
Et
NO2
Et
Bartolli rxn
hydrogenn
OSO2CF3
Et
OH
Intra HeckF-C Acyln
Nitran
Blechert
NH
cis-trikentrin A
Et
NO2
Et
NO2
Et
Bartolli rxn
hydrogenn
OSO2CF3
Et
OH
Intra HeckF-C Acyln
Nitran
NH
trans-trikentrin A
Et
NH
Et
ring contracn
TTN (TlIII)Tet 2002,
58, 9137
NPG
Et
CO2Et
NO2
Et
Br
Elaboran
F-C
HeckBartolli
CO2Et
+
and Silva
Kerr
NH
Et
cis-trikentrin B
NTs
HOStille coupling[O] cleavage
NTs
OCHO
DAiminoquinones
NH
Herbindole B
Et
NHTs
CHOOHC
NHTs
HO
NTs
O
FunkBuszek
NH
Herbindole B
Et
NH
Herbindole A
NTs
HO
I
HO
OH
NH
Et
cis-trikentrin B
Divergent strategy
key int.
NH
NH
NH
(+)-cis-Trikentrin A
asymmetric HV
99%, 96% ee
10 steps
22% yield in 11 steps
JACSAsymmetric Hydrovinylation of Vinylindoles. A Facile Route to
cyclopenta[g]indole Natural Products (+)-cis-Trikentrin A and (+)-cis-Trikentrin B.
W. Liu, H. J. Lim, T. V. RajanBabu.DOI: 10.1021/ja3004733
T. V. (Babu) RajanBabu received his undergraduate education in India (Kerala University and Indian Institute of Technology, Madras). He obtained a Ph. D. degree from The Ohio State University under the direction of Professor Harold Shechter, and was a postdoctoral fellow at Harvard University with the late Professor R. B. Woodward. He then joined the Research Staff of Dupont Central Research and Development, becoming a Research Fellow in 1993. He returned to OSU as a Professor of Chemistry in 1995.
Start of synthesis (buried in SI)
Br
Et
HNO3/ H2SO4
Br
Et
Br
Et
35% 27%
+NO2
NO2
MgBr
Bartolli rxn
THF, -50oC
47%NH
Et
Br
NH
Et
Pd(PPh3)4
SnBu3
70%
Br
NO2
NH
(+)-cis-Trikentrin A
NH
(+)-cis-Trikentrin B
Et
Targets:
NH
THF, -50oC
MgBr
1)
2) Pd(PPh3)4 SnBu3
42%
A
B
hydrovinylation
NH
NH
Et
NH
Et
ethylene (1 atm), [L3]
[(allyl)Ni-Br]2, NaB(Ar)4,
DCM, -78oC
Ar= 3,5-(CF3)2-C6H3
OOP
N PhPh
Ra
Sc Sc
OOP
N napthPh
Ra
Sc
99%, 96% ee
L3
ethylene (1 atm), [L3]
[(allyl)Ni-Br]2, NaB(Ar)4,
DCM, -78oC
Ar= 3,5-(CF3)2-C6H3
99%, 94% ee
NH
NTs
93%, 90% ee, L2
L2
NH
NH
NH
Et
96%, 92% ee, L3 99%, 94% ee, L3 96%, 92% ee, L3
Mechanism: SynLett 2009, 853
NH
Et
NTs
Et1) KH, TsCl, 18-crown-6 DME, 53%
2) 9-BBN, H2O2, 92%
HO
1) TPAP, NMO
2) NaClO2, NaH2PO4 NTs
Et
HO2C85%
1) (COCl)2, DMF
2) AlCl3, DCM NTs
Et
O
NTs
Et
tBuOK, Ph3PMeI
94% NTs
Et[(allyl)PdCl]2 cat.
otol3P/ AgOTf
ethylene 1 atmDCM, 95%
NTs
EtCrabtree HydrogenatnDifficult diastereocontrol
[(COD)Ir(PCy3)(Py)]+
PF6- cat. / H2 (554 psi)
17h, DCM, 95%
TBAF, THF, reflux16h, 84%
(+)-cis-trikentrin A
JOC 2009, 74, 4565
NTs
NH
H2 (275 psi)
Pd/ C, MeOH99%
NTs
NTs
II2, PhI(OCOCF3)2
MeCN, rt, 2h90%
Mn(OAc)3.H2O
AcOH, reflux87%
NTs
I
NTs
Et
EtSnBu3
Pd(Ph3P)2Cl2/ LiCl
BHT / 150oC, 15h
TBAF/ THF
60% NH
Et
(+)-cis-trikentrin B
NH
NH
NH
(+)-cis-Trikentrin A
asymmetric HV
99%, 96% ee
10 steps
22% yield in 11 steps
JACSAsymmetric Hydrovinylation of Vinylindoles. A Facile Route to
cyclopenta[g]indole Natural Products (+)-cis-Trikentrin A and (+)-cis-Trikentrin B.
W. Liu, H. J. Lim, T. V. RajanBabu.DOI: 10.1021/ja3004733
NH
R
R= Me, Et, Et(E)
(-)-herbindoles A-C
NTs
MOMO
[2 + 2 + 2]cyclization
MOMO
NTs
Org LettTotal Synthesis of (-)-Herbindoles A, B, and C via a Transition-Metal-
Catalyzed Intramolecular [2 + 2 + 2] Cyclization between Ynamide and Diynes.
N. Saito, T. Ichimaru, Y. Sato.DOI: 10.1021/ol300571b
NH
NH
ethylene (1 atm), [L]
[(allyl)Ni-Br]2, NaB(Ar)4,
DCM, -78oC
Ar= 3,5-(CF3)2-C6H3
2
34
5
6
7
[L] =OO
P
N PhPh
Ra
Sc Sc
or OOP
N napthPh
Ra
Sc
2- ,3- ,5- ,6- , or 7-vinyl indoles
>95%, >90% ee
NH
R
FGI
NH
OPG OPG
NTs
[2 + 2 + 2] C-N Coupling Br
O
Synthesis of SM
Corey-Fuchs
Retrosynthesis
OL 2006, 8, 1025
O O
meso/ dl
iPr2NEt, EA
rt, 12h, recrys.
80% OO O
mesoHO OH
LAH, Et2O, refl.
85%
OAcAmano AK
THF, rt, 80%
Tet 1996, 52, 5907JOC 2001, 66, 493
AcO OH HO OTBS
1) TBSCl, ImH
2) K2CO3
MeOH
OTBS
97% ee
OH
1) SO3.py, DMSO, NEt3,
DCM, 0oC, 1h30
2) CBr4, PPh3, DCM, 0oC, 2h
OTBS
BrBr
1) nBuLi, THF, -78oC, 1h;
TIPSCl, rt, 10h30
2) HCl, EtOH, rt, 17h
OH
TIPS
1) SO3.py, DMSO, NEt3,
DCM, 0oC, 1h30
2) CBr4, PPh3, DCM, 0oC, 2h
3) LiHMDS, THF, -78oC, 30';
rt, 12h
TIPS
Br
75%, 7 steps
JACS 2007, 129, 14788
HO
NBocTs
1) MOMCl, DCMrt, 48h
2) neat, 185oC,30', 87% 2 steps
MOMO
NHTs
TIPS
Br
CuSO4.5H2O, K3PO4
phen, PhMe, 60oC, 44hN
N
phen
JOC 2006, 71, 4170
MOMO
NTs
TIPS
MOMO
NTs
1) TBAF, THFrt, 1h30
2) LiHMDS, THF,-78oC, 1h; MeI, rt,
15h, 78% 3 steps
NTs
OMOM
[2 + 2 + 2] cyclization
RhCl(PPh3)3 5 mol%
PhMe, 50oC, 5h
97%
JCS Rev 2011, 40, 3430
NTs
OMOM1) BBr3, DCM,
-78oC, 2h30
2) nBu3SnH, AIBN
PhMe, 100oC, 1h
92%, 2 steps
NTs
1) Na, napth, THF
-78oC, 2h
2) CoII(calen), O2
MeOH, rt, 2h, 94%
NH
(-)-herbindole A
49% overall yield in 15 steps
HBF4, MeCN/H2O
60oC, 48h, 98%
NTs
OH 1) DMP, DCM, rt, 3h
2) Tebbe reagent
THF, 0oC, 2h
3) H2, Pd/ C, EA, rt, 2h70%
NTs
1) Na, napth, THF
-78oC, 1h
2) CoII(calen), O2
MeOH, rt, 1h30
93%
NH
(-)-herbindole B
36% overall yield in 17 steps
1) DMP, DCM, rt, 2h
2)nPrMgBr, THF, 0oC, 3h
3) p-TsOH, PhH, 50oC, 20h
91%
NTs
Et
1) Na, napth, THF-78oC, 1h
2) CoII(calen), O2
MeOH, rt, 1h30
93%
NH
Et
44% overall yield in 17 steps
Summary of important reactions:
1) Hemetsberger-Knittel indole synthesis
CO2R
N3
-N2(g)
CO2R
NNH
CO2R
1H-indole-2-carboxylic ester
ON3
CO2R
Aldrich Acta 2001, 34, 51
Monatsh Chem 1972, 103, 194Synthesis 1985, 186Perk Trans 1 2000, 1045: (Review of named indole syntheses)
base
Knoevenangel
2) Crabbé homologation of acetylenes to allenes
JSC Chem Comm 1979, 859Perk trans 1 1984, 747
R RHCHO, CuBr, DIPA
CuBr
R CuBr
N
RN
H
CuBr
RNCu
BrH
3) Boger tetrazine-diazine-benzene/indole/indoline DA strategy
N
N
JOC 1988, 53, 1415
SO2Me
AcN
N
NAcN
MeO2S
-N2
SO2Me
AcNH
H+
SO2Me
AcN
H
AcNR
R
RR
N
N N
N
SMe
SMe
X
R
H2N
R+ +
4) Bartolli reaction
NO2
X
X = halide
NOX
OMgBr
TMS
Perk Trans 1 1991, 2757
TMS
MgBr
TMS
MgBr NX
O
MgBr
TMS1,2-addn
[3,3] NX
O
MgBr
TMS
XN OMgBr
TMS
TMS
MgBr
HTMS
H
XN OMgBr
TMS
MgBr
X
HN
TMSH3O+
X
HN
orMgBr
with
5) Ring Contractions
6) Plienger's Indolization sequence
Birch reductn
of napth. der.
NHAc
O3, MeOH
CHO
CHO
NHAc
NAc
CHO
OH(CO2H)2
-H2O NAc
CHO
Chem Ber 1956, 89, 270
7) Aromatisation of indolines to indoles
NH
NH
dehydrogenation
CoII(salen), O2
Chem Lett 1980, 1287O
N N
OCo
OO
XN
MeO
Review: Tet 2002, 58, 9137For trans-trikentrin A: OL 2008, 10, 5417
TTN.3H2O, TMOF,
0oC, 1min
94%, X=ONO2
OMe
TlX3
OMe
Tl
-X
X X
MeOH OMe
Tl
OMe MeO
TlX
X
-X, -TlX
MeO
H+
H+
MeOH
MeO
MeOOMe