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TRANSCRIPT
Synthetic Approaches to Pyrroloindoline Containing Natural Products
MacMillan Group MeetingJoe Carpenter
February 18, 2009
Synthetic Approaches to Pyrroloindoline Natural ProductsPresentation outline
■ Introduction to pyrroloindolines
■ Methods to construct the pyrroloindoline core
● Biomimetic approach
i. Raceimc methods ii. Synthesis from chiral pool iii. Enantioselective synthesis
● "Oxoindole" approach
i. Raceimc methods ii. Synthesis from chiral pool iii. Enantioselective synthesis
● Other methods
i. Raceimc methods ii. Synthesis from chiral pool iii. Enantioselective synthesis
■ Conclusions
Synthetic Approaches to Pyrroloindoline Natural ProductsIntroduction
■ Diverse biological activity of pyrroloindolines
calabar alkaloidsAlzheimer's
anticholinergicorganophosphate poisoning
flustramines and pseudophyrnaminesanticancer activitymuscle relaxant
cholecystokinin antagonist
calycanthaceous alkaloidsanalgesic
antibacterialsomatostatin agoinst
echitamine alkaloidsanticancer
■ Pyrroloindolines are isolated from amphibians, marine organisms and plant sources
ardeemins and amaurominereverse multi-drug resistance in cancer cells
vasodilator
NMe
NMe
MeRO
NR
NMe
R
R
NH
NMeR
HNMeN R
NH
N
H
HN
N
HO
O
H
HNR
N
H
N
N
OMe
OH
NR
N
RCO2MeR
R
R
Synthetic Approaches to Pyrroloindoline Natural ProductsIntroduction
■ Substitution pattern around central pyrroloindoline varies greatly
calabar alkaloidsesermethole R = Me
physostigmine R = CONMephenserine R = CONPh
flustramines and pseudophyrnamines calycanthaceous alkaloidschimonanthine R = H
echitamine alkaloidsechitaminevincorine
ardeemins and amauromine
NMe
NMe
MeRO
NR
NMe
R
R
NH
NMeR
HNMeN R
NH
N
H
HN
N
HO
O
H
HNR
N
H
N
N
OMe
OH
NR
N
RCO2MeR
R
R
Synthetic Approaches to Pyrroloindoline Natural ProductsBiomimetic Approach
■ Perceived to arise via electrophilic attack at indole C-3 position of tryptophan or tryptamine
E
■ Alkylative cyclization allows rapid access to racemic flustramines
Tan, G. H.; Zhu, X.; Ganesan, A. Org. Lett. 2003, 5, 1801.
tryptamine
Zn(OTf)2, i-Pr2NEt
Br
N
N
NH
NH
Bu4NIToluene, r.t.
70 %
CO2Et
CO2Et
NH
NH2
NH
NH2
E
NH
NH
E
Red-Al
Toluene96 %
N
NMe
(±) debromoflustramine B
H
Synthetic Approaches to Pyrroloindoline Natural ProductsBiomimetic Approach
■ Perceived to arise via electrophilic attack at indole C-3 position of tryptophan or tryptamine
E
■ Alkylative cyclization allows rapid access to racemic flustramines
Tan, G. H.; Zhu, X.; Ganesan, A. Org. Lett. 2003, 5, 1801.
tryptamine
Zn(OTf)2, i-Pr2NEt
Br
N
N
NH
NH
Bu4NIToluene, r.t.
70 %
CO2Et
CO2Et
NH
NH2
NH
NH2
E
NH
NH
E
Red-Al
Toluene96 %
N
NMe
(±) debromoflustramine B
H
Synthetic Approaches to Pyrroloindoline Natural ProductsBiomimetic Approach
■ Menéndez used a similar strategy to access the flustramine core
López-Alvarado, P.; Caballero, E.; Avendaño, C.; Menéndez, C. J. Org. Lett. 2006, 8, 4303.
i. ICH2TMS, Et3Nii. LiHMDSiii. prenyl bromide
N
N
NH
NH
CO2Et
CO2Et
one-pot 86%
N N
LiOTMS
OEt
N N
OLi
OEtN N
OLi
OEt
Synthetic Approaches to Pyrroloindoline Natural ProductsBiomimetic Approach
■ Tryptophan derivitaves give rise to possible diastereomers
Crich, D.; Huang, X. J. Org. Chem. 1999, 64, 7218.
E
N
NH
N
HN
E
N
N
ECO2Me
R2
R1
CO2Me CO2Me
R2 R2
R1 R1
H N
N
E CO2Me
R2
R1
H
exo(kinetic)
endo(thermodynamic)
Combined Yield (%)
8565768340310
electrophile
HPhthSePhPhthSePhPhthSePhPhthSePhPhthSePhPhthSePh
R1
HBoc
CO2BnCO2MeSO2Ph
SO2PMPH
R2
CO2MeBoc
CO2MeCO2MeCO2MeCO2MeCO2Me
endo:exo
9:11:91:121:11
<2:98<2:98
--
Synthetic Approaches to Pyrroloindoline Natural ProductsBiomimetic Approach
■ Application in Danishefsky's synthesis of amauromine and acetylardeemin
NBoc
NHBoc
CO2MePhth SePh
pTSA, Na2SO4
CH2Cl278 %
NBoc
NBoc
PhSe CO2Me
H
9:1 d.r.
1. MeOTf, prenyl Bu3Sn
2. NaOH3. TMSI N
H
NH
CO2H
H
NBoc
NBoc
CO2H
H
BOP-Cl NBoc
NBoc
H
HN
N
CO2H
HO
TMSINH
N
H
HN
N
HO
O
amauromine
NBoc
NBoc
CO2H
H
1. D-Ala-OMe•HCl
2. TMSI NH
N
H
NH
O
OMe
N3
ClOC
1. KHMDS
2. PBu33. LDA, AcCl
N
N
HAc
N
N
OMe
O
5-N-acetylardeemin
Marsden, S. P.; Depew, K. M.; Danishefsky, S. J. J. Am. Chem. Soc. 1994, 116, 11143.
H H
H
H
Synthetic Approaches to Pyrroloindoline Natural ProductsBiomimetic Approach
■ Application in Danishefsky's synthesis of amauromine and acetylardeemin
NBoc
NHBoc
CO2MePhth SePh
pTSA, Na2SO4
CH2Cl278 %
NBoc
NBoc
PhSe CO2Me
H
9:1 d.r.
1. MeOTf, prenyl Bu3Sn
2. NaOH3. TMSI N
H
NH
CO2H
H
NBoc
NBoc
CO2H
H
BOP-Cl NBoc
NBoc
H
HN
N
CO2H
HO
TMSINH
N
H
HN
N
HO
O
amauromine
NBoc
NBoc
CO2H
H
1. D-Ala-OMe•HCl
2. TMSI NH
N
H
NH
O
OMe
N3
ClOC
1. KHMDS
2. PBu33. LDA, AcCl
N
N
HAc
N
N
OMe
O
5-N-acetylardeemin
Marsden, S. P.; Depew, K. M.; Danishefsky, S. J. J. Am. Chem. Soc. 1994, 116, 11143.
H H
H
H
Synthetic Approaches to Pyrroloindoline Natural ProductsBiomimetic Approach
■ Application in Danishefsky's synthesis of amauromine and acetylardeemin
NBoc
NHBoc
CO2MePhth SePh
pTSA, Na2SO4
CH2Cl278 %
NBoc
NBoc
PhSe CO2Me
H
9:1 d.r.
1. MeOTf, prenyl Bu3Sn
2. NaOH3. TMSI N
H
NH
CO2H
H
NBoc
NBoc
CO2H
H
BOP-Cl NBoc
NBoc
H
HN
N
CO2H
HO
TMSINH
N
H
HN
N
HO
O
amauromine
NBoc
NBoc
CO2H
H
1. D-Ala-OMe•HCl
2. TMSI NH
N
H
NH
O
OMe
N3
ClOC
1. KHMDS
2. PBu33. LDA, AcCl
N
N
HAc
N
N
OMe
O
5-N-acetylardeemin
Marsden, S. P.; Depew, K. M.; Danishefsky, S. J. J. Am. Chem. Soc. 1994, 116, 11143.
H H
H
H
Synthetic Approaches to Pyrroloindoline Natural ProductsBiomimetic Approach
■ The Joullié group synthesis of roquefortine C uses the same strategy as Danishefsky
NBoc
NBoc
CO2H
H
N
NBoc
MeO2C
NH2
HO
1. HATU, i-Pr2NEt
2. EDC CuCl2 (syn elim)3. TMSI, MeCN4. NH3•H2O
NH
N
H
NH
ON
NH
O
roquefortine C
NH
N
H
NH
O
O
isoroquefortine C
N
NH
more stable by 14kJ/molnot found in nature
H H
■ Other electrophiles are also competent for pyrroloindoline formation
Shangguan, N.; Hehre, W. J.; Ohlinger, W. S.; Beavers, M. P. Joullié, M. M. J. Am. Chem. Soc. 2008, 130, 6281.
NH
NHCO2Me
CO2Me
MeO
N SMe
MeO
O
Cl–
i-Pr2NEt, CH2Cl292 %
NH
NCO2Me
CO2MeMeO
SMe1. Raney Ni, HCHOaq2. Red-Al
3. i. Swern ii. NH2SO3H iii. NaBH4
NMe
NMe
MeMeO
(–)-esermethole
Kawahara, M.; Nishida, A.; Nakagawa, M. Org. Lett. 2000, 2, 675.
1:1 d.r.
Synthetic Approaches to Pyrroloindoline Natural ProductsBiomimetic Approach
■ The Joullié group synthesis of roquefortine C uses the same strategy as Danishefsky
NBoc
NBoc
CO2H
H
N
NBoc
MeO2C
NH2
HO
1. HATU, i-Pr2NEt
2. EDC CuCl2 (syn elim)3. TMSI, MeCN4. NH3•H2O
NH
N
H
NH
ON
NH
O
roquefortine C
NH
N
H
NH
O
O
isoroquefortine C
N
NH
more stable by 14kJ/molnot found in nature
H H
■ Other electrophiles are also competent for pyrroloindoline formation
Shangguan, N.; Hehre, W. J.; Ohlinger, W. S.; Beavers, M. P. Joullié, M. M. J. Am. Chem. Soc. 2008, 130, 6281.
NH
NHCO2Me
CO2Me
MeO
N SMe
MeO
O
Cl–
i-Pr2NEt, CH2Cl292 %
NH
NCO2Me
CO2MeMeO
SMe1. Raney Ni, HCHOaq2. Red-Al
3. i. Swern ii. NH2SO3H iii. NaBH4
NMe
NMe
MeMeO
(–)-esermethole
Kawahara, M.; Nishida, A.; Nakagawa, M. Org. Lett. 2000, 2, 675.
1:1 d.r.
Synthetic Approaches to Pyrroloindoline Natural ProductsBiomimetic Approach
■ Danishefsky used a slight variation to construct the Himastatin core
Kamanecka, T. M.; Danishefsky, S. J. Angew. Chem. Int. Ed. 1998, 37, 2993 and 2995.
NH
NHSO2anth
CO2tBu
NBS, Et3N DMDO
NH
NHSO2anth
CO2tBu
NaBH4 75 % N
H
NHSO2anth
CO2tBuHO
H80 %
NCbz
NCbz
CO2tBuTBSO
H
Me3Sn1. i. Al(Hg) ii. CbzCl iii. TBSCl
2. ICl3. Sn2Me6 Pd(PPh3)4
Pd2dba3AsPh3
NCbz
NCbz
CO2tBuTBSO
H
CbzN
CbzN
ButO2C OTBS
H
NH
N
HO
HN
O O
O
O
NH
ONH
O
OH
HN
NO
OH
HN
N
OH
NH
OO
O
O
HN
OHN
O
OH
NH
N O
HO
himastatin
Synthetic Approaches to Pyrroloindoline Natural ProductsBiomimetic Approach
■ Danishefsky used a slight variation to construct the Himastatin core
Kamanecka, T. M.; Danishefsky, S. J. Angew. Chem. Int. Ed. 1998, 37, 2993 and 2995.
NH
NHSO2anth
CO2tBu
NBS, Et3N DMDO
NH
NHSO2anth
CO2tBu
NaBH4 75 % N
H
NHSO2anth
CO2tBuHO
H80 %
NCbz
NCbz
CO2tBuTBSO
H
Me3Sn1. i. Al(Hg) ii. CbzCl iii. TBSCl
2. ICl3. Sn2Me6 Pd(PPh3)4
Pd2dba3AsPh3
NCbz
NCbz
CO2tBuTBSO
H
CbzN
CbzN
ButO2C OTBS
H
NH
N
HO
HN
O O
O
O
NH
ONH
O
OH
HN
NO
OH
HN
N
OH
NH
OO
O
O
HN
OHN
O
OH
NH
N O
HO
himastatin
Synthetic Approaches to Pyrroloindoline Natural ProductsBiomimetic Approach
■ Electophilic sources of nitrogen have also been shown to work efficiently
Newhouse, T.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 10886.
NH
NHCO2Me
Br
NIS, Et3N
I
NH267% N
H
NCO2Me
HN
Br
I
NH
NMe
N
N
NHMe
MeHN
(±)-psychotrimine
Also works with tryptophan derivatives (45%)
TMS
NHCO2Me
Pd(OAc)2
NH
NCO2Me
N
NHCO2Me
Br
NHMe
NHMe
CuI, K2CO3
85%
89%
NH
NHCO2Me
NH
NCO2Me
N
N
NHCO2Me
MeO2CHN
Red-Al
89%
Synthetic Approaches to Pyrroloindoline Natural ProductsBiomimetic Approach
■ Electophilic sources of nitrogen have also been shown to work efficiently
Newhouse, T.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 10886.
NH
NHCO2Me
Br
NIS, Et3N
I
NH267% N
H
NCO2Me
HN
Br
I
NH
NMe
N
N
NHMe
MeHN
(±)-psychotrimine
Also works with tryptophan derivatives (45%)
TMS
NHCO2Me
Pd(OAc)2
NH
NCO2Me
N
NHCO2Me
Br
NHMe
NHMe
CuI, K2CO3
85%
89%
NH
NHCO2Me
NH
NCO2Me
N
N
NHCO2Me
MeO2CHN
Red-Al
89%
■ Dimerization of benzylic radicals allows access to dimeric structures
Movassaghi, M.; Schmidt, M. A. Angew. Chem. Int. Ed. 2007, 46, 3725.
NSO2Ph
NCO2Me
CO2MeH
cyclized with H3PO4
N
NO
O
Br
Br
NSO2Ph
NCO2Me
CO2MeBr[CoCl(PPh3)3]
NSO2Ph
NCO2Me
CO2Me
SO2PhN
MeO2CN
MeO2C
4 steps to (+)-chimonanthine
NH
NMe
HN
MeN
H
H
H
H
(+)-chimonanthine
NMe
NMe
MeN
MeN
H
H
(+)-folicanthine(–)-calycanthine
HCOHaqNaBH(OAc)3
100%
N
NMeHN
Me
HN
AcOH
85:15
Synthetic Approaches to Pyrroloindoline Natural ProductsBiomimetic Approach
■ Dimerization of benzylic radicals allows access to dimeric structures
Movassaghi, M.; Schmidt, M. A. Angew. Chem. Int. Ed. 2007, 46, 3725.
NSO2Ph
NCO2Me
CO2MeH
cyclized with H3PO4
N
NO
O
Br
Br
NSO2Ph
NCO2Me
CO2MeBr[CoCl(PPh3)3]
NSO2Ph
NCO2Me
CO2Me
SO2PhN
MeO2CN
MeO2C
4 steps to (+)-chimonanthine
NH
NMe
HN
MeN
H
H
H
H
(+)-chimonanthine
NMe
NMe
MeN
MeN
H
H
(+)-folicanthine(–)-calycanthine
HCOHaqNaBH(OAc)3
100%
N
NMeHN
Me
HN
AcOH
85:15
Synthetic Approaches to Pyrroloindoline Natural ProductsBiomimetic Approach
Synthetic Approaches to Pyrroloindoline Natural ProductsBiomimetic Approach
■ Tryptophan derivatives will react with carbenes to give the pyrroloindoline core upon cyclization
He, B.; Song, H.; Du, Y.; Qin, Y. J. Org. Chem. 2009, 74, 298.Shen, L.; Zhang, M.; Wu, Y.; Qin, Y. Angew. Chem. Int. Ed. 2008, 47, 3618.
NMe
HNO
O
N2
O
OEt
Cu(OTf) NMe
HNO
O
EtO2C
NMe
HNO
O
EtO2C
NMe
NO
O
CO2Et
87%, 16:1 dr (–30 °C) 73%, 1.6:1 dr (r.t.)
15 steps
N
N
H
N
N
OMe
O (–)-ardeemin, R = H
(–)-acetylardeemin R = AcH
R
■ Qin uses a tethered carbene to access the fully substituted C-3 of Minfiensine
NMe
NHTs
O
N2
CO2Me
(10 steps)
CuOTf
81%
9 steps
(±)-minfiensine
N N
OH
CO2Me
NH
N
TsMe
OH
Synthetic Approaches to Pyrroloindoline Natural ProductsBiomimetic Approach
■ Tryptophan derivatives will react with carbenes to give the pyrroloindoline core upon cyclization
He, B.; Song, H.; Du, Y.; Qin, Y. J. Org. Chem. 2009, 74, 298.Shen, L.; Zhang, M.; Wu, Y.; Qin, Y. Angew. Chem. Int. Ed. 2008, 47, 3618.
NMe
HNO
O
N2
O
OEt
Cu(OTf) NMe
HNO
O
EtO2C
NMe
HNO
O
EtO2C
NMe
NO
O
CO2Et
87%, 16:1 dr (–30 °C) 73%, 1.6:1 dr (r.t.)
15 steps
N
N
H
N
N
OMe
O (–)-ardeemin, R = H
(–)-acetylardeemin R = AcH
R
■ Qin uses a tethered carbene to access the fully substituted C-3 of Minfiensine
NMe
NHTs
O
N2
CO2Me
(10 steps)
CuOTf
81%
9 steps
(±)-minfiensine
N N
OH
CO2Me
NH
N
TsMe
OH
Synthetic Approaches to Pyrroloindoline Natural ProductsBiomimetic Approach
Austin, J. F.; Kim, S-G.; Sinz, C. J.; Xiao, W-J.; MacMillan, D. W. C. Proc. Natl. Acad. Sci. 2004, 101, 5482.
■ Catalytic asymmetric approach to the flustramines by the MacMillan group
NR
NHR
N
NH
O
tBuBn
Me
N
N
O
tBuBn
Me
N
N
O
tBuBn
Me R
R
RN
RHN
N
N
O
tBuBn
Me
R
RN
RN
R O
NR
NR
O
R
HX
X–
X–
HX
enantioinrichedpyrroloindoline
Synthetic Approaches to Pyrroloindoline Natural ProductsBiomimetic Approach
Austin, J. F.; Kim, S-G.; Sinz, C. J.; Xiao, W-J.; MacMillan, D. W. C. Proc. Natl. Acad. Sci. 2004, 101, 5482.
■ Catalytic asymmetric approach to the flustramines by the MacMillan group
NR
NHR
N
NH
O
tBuBn
Me
N
N
O
tBuBn
Me
N
N
O
tBuBn
Me R
R
RN
RHN
N
N
O
tBuBn
Me
R
RN
RN
R O
NR
NR
O
R
HX
X–
X–
HX
enantioinrichedpyrroloindoline N
NHBoc
Br
■ Catalytic asymmetric approach to the flustramines by the MacMillan group
N
NH
O
tBuBn
Me
20 mol %
2. NaBH4
1.
• p-TSA
NBr
NBoc
OH
78% yield 90% ee
1. MsCl
2. NO2PhSeCN H2O2 89%
NBr
NBocGrubbs
metathesis94%
NBr
NBoc 1. TMSI
2. (CHO)n NaBH4 89%
NBr
NMe
(–)-flustramine B
O
Synthetic Approaches to Pyrroloindoline Natural ProductsThe 2-Oxoindole Approach
■ The pyrroloindoline core can also readily be attained through a suitable 2-oxoindole
NH
O
generic 2-oxoindole
R
alkylation
NH
O
RR
amination
reduction NH
NR
R
■ Similarities to biomimetic approach but different oxidation state utilized
NHBr
NMe
NsNBS, tBuOH
THF, H2O83%
NHBr
NMe
NsBr
O
NBr
NMe
Ns
O
Cs2CO3
SnBu3
NHBr
NMe
Ns
O
Br
NaH1.
2. Cs2CO3, PhSH NBr
NHMe
Oalane
62%
73%
N
NMe
Br
Fuchs, J. R.; Funk, R. L. Org. Lett. 2005, 7, 677.
(±)-flustramine A
Julian, P. L.; Pikl. J.; Boggess. D. J. Am. Chem. Soc. 1934, 56, 1797.
Synthetic Approaches to Pyrroloindoline Natural ProductsThe 2-Oxoindole Approach
■ The pyrroloindoline core can also readily be attained through a suitable 2-oxoindole
NH
O
generic 2-oxoindole
R
alkylation
NH
O
RR
amination
reduction NH
NR
R
■ Similarities to biomimetic approach but different oxidation state utilized
NHBr
NMe
NsNBS, tBuOH
THF, H2O83%
NHBr
NMe
NsBr
O
NBr
NMe
Ns
O
Cs2CO3
SnBu3
NHBr
NMe
Ns
O
Br
NaH1.
2. Cs2CO3, PhSH NBr
NHMe
Oalane
62%
73%
N
NMe
Br
Fuchs, J. R.; Funk, R. L. Org. Lett. 2005, 7, 677.
(±)-flustramine A
Julian, P. L.; Pikl. J.; Boggess. D. J. Am. Chem. Soc. 1934, 56, 1797.
Synthetic Approaches to Pyrroloindoline Natural ProductsThe 2-Oxoindole Approach
■ Evidence for the indole-2-one intermediate
NH
O
Fuchs, J. R.; Funk, R. L. Org. Lett. 2005, 7, 677.
Br
Cs2CO3
NO
N
O
N
–CO
■ Dalko invokes the same intermediate in the synthesis of meso-chimonanthine
NH
O
BrN3
Cs2CO3
NH
NHCO2Me
NH
O
HN
N3
NCO2Me
Red-Al
HN
NMe
NH
NH
N O
RNH
R
N
O
RNH
R
NH
O
N
N3
NCHO2Me
Menozzi, C.; Dalko, P. I.; Cossy, J. Chem. Commun. 2006, 4638.
desmethyl-meso-chemonanthine
75% 95:5 d.r. 57%
Synthetic Approaches to Pyrroloindoline Natural ProductsThe 2-Oxoindole Approach
■ Evidence for the indole-2-one intermediate
NH
O
Fuchs, J. R.; Funk, R. L. Org. Lett. 2005, 7, 677.
Br
Cs2CO3
NO
N
O
N
–CO
■ Dalko invokes the same intermediate in the synthesis of meso-chimonanthine
NH
O
BrN3
Cs2CO3
NH
NHCO2Me
NH
O
HN
N3
NCO2Me
Red-Al
HN
NMe
NH
NH
N O
RNH
R
N
O
RNH
R
NH
O
N
N3
NCHO2Me
Menozzi, C.; Dalko, P. I.; Cossy, J. Chem. Commun. 2006, 4638.
desmethyl-meso-chemonanthine
75% 95:5 d.r. 57%
Synthetic Approaches to Pyrroloindoline Natural ProductsThe 2-Oxoindole Approach
■ Radical cyclization to provide the oxoindole by Ishibashi
Ishibashi, H.; Kobayashi, T.; Machida, N.; Tamura, O. Tetrahedron 2000, 56, 1469.
NMe
MeO BrO
O
MeHWE
NMe
MeO BrO
Me
CNmix E/Z3 steps
BuSn3HAIBN
NMe
OMeO
MeCN
NMe
OMeO
MeCN LAH
HCOH NaBH4
NMe
MeOMe
NMe (±)-esermethole(formal synthesis)
72% 98%
Synthetic Approaches to Pyrroloindoline Natural ProductsThe 2-Oxoindole Approach
■ Fujisawa pharmaceuticals thio-Claisen route to flustramine C core
Takase, S.; Uchida, I.; Tanaka, H.; Aoki, H. Tetrahedron 1986, 42, 5879.
(±)-debromo-8,8a-dihydroflustramine C
NH
O
CO2Me
PS5, pyr
NH
S
CO2Me
K2CO3, MeI
Br
30%Me
not isolatedNH
SMe
NS
Me
CO2Me
R
4 steps
NH
NMe
2 steps
Synthetic Approaches to Pyrroloindoline Natural ProductsThe 2-Oxoindole Approach
■ Domino olefination/isomerization/Claisen rearrangement sequence to flustramines A and B
Kawasaki, T.; Shinada, M.; Kamimura, D.; Ohzono, M.; Ogawa, A. Chem. Commun. 2006, 420.
NBrO
O
Ac
HHex CNP
O
EtOEtO
NBrO
Ac
HHex
NC
NBrO
Ac
HHex
NC
NHBr
O
CN
Hex
70% yield98% ee
O3, PPh3then Ph3PCMe2
54%NHBr
O
CN
N
NMe
Br
(–)-flustramine B
NBrO
O
Ac
HHex
CNPO
EtOEtO
70% yield98% ee N
HBrO
CN
Hex
7 stepsN
NMe
Br
(–)-flustramine A
5 steps
Synthetic Approaches to Pyrroloindoline Natural ProductsThe 2-Oxoindole Approach
■ Domino olefination/isomerization/Claisen rearrangement sequence to flustramines A and B
Kawasaki, T.; Shinada, M.; Kamimura, D.; Ohzono, M.; Ogawa, A. Chem. Commun. 2006, 420.
NBrO
O
Ac
HHex CNP
O
EtOEtO
NBrO
Ac
HHex
NC
NBrO
Ac
HHex
NC
NHBr
O
CN
Hex
70% yield98% ee
O3, PPh3then Ph3PCMe2
54%NHBr
O
CN
N
NMe
Br
(–)-flustramine B
NBrO
O
Ac
HHex
CNPO
EtOEtO
70% yield98% ee N
HBrO
CN
Hex
7 stepsN
NMe
Br
(–)-flustramine A
5 steps
Synthetic Approaches to Pyrroloindoline Natural ProductsThe 2-Oxoindole Approach
■ Overman uses two basic strategies to access the pyrroloindoline core
Strategy 1:Intramolecular Heck reaction
OTfN
O
R
NR2
R
Pd(II) Ligand
NR
O
R NR2
reduction
NR
NR
R
Strategy 2:oxoindole alkylation
NR
OTfO
OO
OTfRN NR
OO OO
R R
R 1. H+
2. NaIO4
3. NH2R LAH N
R
NR
R
d.r. depends on R groups, base, additives
solvent and temp
Synthetic Approaches to Pyrroloindoline Natural ProductsThe 2-Oxoindole Approach
■ Overman uses two basic strategies to access the pyrroloindoline core
Strategy 1:Intramolecular Heck reaction
OTfN
O
R
NR2
R
Pd(II) Ligand
NR
O
R NR2
reduction
NR
NR
R
Strategy 2:oxoindole alkylation
NR
OTfO
OO
OTfRN NR
OO OO
R R
R 1. H+
2. NaIO4
3. NH2R LAH N
R
NR
R
d.r. depends on R groups, base, additives
solvent and temp
Synthetic Approaches to Pyrroloindoline Natural ProductsThe 2-Oxoindole Approach
H
HOO
TfOH
HOO
TfO
NR
RO M
NR
R
O
M
H
HOO
TfO RN
R
OM
H
HOO
TfO
NR
R
O
M
H
HOO
TfO NR
R
OM
Si face alkylationfavored
Re facealkylation
■ Possible alkylation transition states proposed by Overman
H
HOO
TfO
RN
ROM
Open transition states using Li or K enolates with THF/DMPU
RN NROO OO
R R
RN NROO OO
R R
RN NROO OO
R R
major C2 C1 minor C2
Huang, A.; Kodanko, J. J.; Overman, L. E.J. Am. Chem. Soc. 2004, 126, 14043.
Synthetic Approaches to Pyrroloindoline Natural ProductsThe 2-Oxoindole Approach
■ Bisalkylation strategy in the synthesis of (–)-phenserine
NMe
Me
OMeO
TfO
OO
OTfMeN NMe
OO OO
Me Me
1. p-TSA
2. NaIO4 92%
NMe
OMeO CHOMe
72%89:11:<1
major C2
NMe
OMeO CHOMe
NMe
MeOMe
NMe
NMe
PhNHCO2
Me
NMe
MeNH2•HClLiAlH4
MgSO490%
1. BBr3
2. PHNCO75%
(–)-phenserine
Huang, A.; Kodanko, J. J.; Overman, L. E.J. Am. Chem. Soc. 2004, 126, 14043.
Synthetic Approaches to Pyrroloindoline Natural ProductsThe 2-Oxoindole Approach
■ Heck cascade to chimonanthine
Overman, L. E.; Paone, D. V.; Stearns, B. A. J. Am. Chem. Soc. 1999, 121, 7702.
OBnBnO
MeO2C CO2Me
OBnBnO
I I
MeO2CCO2Me
LDA
LDA, I233%
OBnBnO
OHN
ONHI I
AlMe3
iodoanaline92%
1. NaH, BnBr2. BCl3
3. 2,2-DMP, CSA49%
OBnN
ONBnI I
OO(PH3P)2PdCl2
90% BnN
NBnO
O
OOCSA, NaBH4
Pb(OAc)4NaBH488%
BnN
NBnO
O
OHHO
6 steps
NH
NMe
HN
MeN
H
H
N
MeN
NH
N
Me
H
(–)-chimonanthine (+)-calycanthine
AcOH
68%
Synthetic Approaches to Pyrroloindoline Natural ProductsThe 2-Oxoindole Approach
■ Combination of alkylation and Heck reaction in Overman synthesis of idiospermuline
MeN NBn
OO
MeN
NBnO
O
OO
TfO
OO
OTf
LHMDS75%
10 steps
NBn
NMe
MeN
MeN
H
H
NH
NMe
MeN
MeN
H
H
NMeTs
MeN
O
OTf
4 steps
5 steps Pd(OAc)2
NH
NMe
MeN
MeN
H
H
(S)-Tol-BINAP97%, 6:1 d.r.
1. H2, Pd(OH)2
2. Red-Al then NaNH3
NMe
ONMeTs
NH
NMe
MeN
MeN
H
H
NMe
NMe
idiospermuline
Overman, L. E.; Peterson, E. A. Angew. Chem. Int. Ed. 2003, 42, 2525.
Synthetic Approaches to Pyrroloindoline Natural ProductsThe 2-Oxoindole Approach
■ Zhu uses a domino Heck-cyanation sequence to obtain the oxoindole
Pinto, A.; Jia, Y.; Neuville, L.; Zhu, J. Chem. Eur. J. 2007, 13, 961.
Pd(OAc)2
Pd0LnNMe
I
O
NMe
O
MeCN
NMe
O
MePdLnCN
NMe
O
Me
NMe
PdILn
O
base L
PdLnI
Synthetic Approaches to Pyrroloindoline Natural ProductsThe 2-Oxoindole Approach
■ Zhu uses a domino Heck-cyanation sequence to obtain the oxoindole
Pinto, A.; Jia, Y.; Neuville, L.; Zhu, J. Chem. Eur. J. 2007, 13, 961.
NMe
O
MeCN
2 steps
I
NMe
MeOO [Pd(dba)2]
(S)-DIFLUORPHOS78% yield, 72%ee
MeO
NMe
NMeMeO1. LAH
2. HCHO, NaBH460%
Me
esermethole
O
O
O
OF
FF
F
PPh2
PPh2
(S)-DIFLUORPHOS
Synthetic Approaches to Pyrroloindoline Natural ProductsThe 2-Oxoindole Approach
■ Zhu uses a domino Heck-cyanation sequence to obtain the oxoindole
Pinto, A.; Jia, Y.; Neuville, L.; Zhu, J. Chem. Eur. J. 2007, 13, 961.
NMe
O
MeCN
2 steps
I
NMe
MeOO [Pd(dba)2]
(S)-DIFLUORPHOS78% yield, 72%ee
MeO
NMe
NMeMeO1. LAH
2. HCHO, NaBH460%
Me
esermethole
O
O
O
OF
FF
F
PPh2
PPh2
(S)-DIFLUORPHOS
NMe
NMeMeO
Me
esermethole
1. HBr
NMe
NMeMeNCO2
Me
physostigmineN
O
O
ONMe
O2.
Synthetic Approaches to Pyrroloindoline Natural ProductsThe 2-Oxoindole Approach
■ Trost asymmetric allylation in the synthesis of (–)-physostigmine
Trost. B. M. Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590.
NO
R1
NH HNOO
N N
Mo(0), Base
allyl carbonate NO
R1
92-99% yield74-95% ee
R2 R2
■ Proposed model for enantiodescrimination
MoON CO
N
CO
O
NHO
Ar
N R2R1
MoON CO
N
CO
O
NHO
Ar
N R1R2
NO
R1
R2
NO
R1
R2
favored disfavored
Synthetic Approaches to Pyrroloindoline Natural ProductsThe 2-Oxoindole Approach
■ Trost asymmetric allylation in the synthesis of (–)-esermethole and (–)-physostigmine
Trost. B. M. Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590.
NMe
O
Me
NMe
O
MeMeO MeOMo(C7H8)(CO)3, L*
LiOtBu
O O
OtBu
THF98% yield82% ee
OsO4, NMO
NMe
O
Me OMeO
NaIO492%
recrystallize to 99% ee
NMe
O
Me OMeO MeNH2, Et3NLiAlH4
NMe
MeMeO
NMe
(–)-esermethole
NMe
MePhHNCO2
NMe
(–)-physostigmine
2 steps
2 steps
Synthetic Approaches to Pyrroloindoline Natural ProductsOther Methods
■ Bis-enamine rearrangement to pyrroloindoline core of calabar alkaloids
N
Me
MeN CO2Me N
MeHO2C
NMeNH
Me
NMe
HO2C
H
H200 °C
91%
Santos. P. F.; Srinivasan, N.; Almeida, P. S.; Lobo, A. M.; Prabhakar, S. Tetrahedron 2005, 61, 9147.
■ Dimethallyl rearrangement to flustramine C
Lindel, T.; Bräuchle, L.; Golz, G.; Böhrer, P. Org. Lett. 2007, 9, 283.
NH
NHMe
NBS, r.t.
90%N
NMe
Br
(±)-flustramine C
N
NHMe
Br
N
N [1,5]MeH
Synthetic Approaches to Pyrroloindoline Natural ProductsOther Methods
■ Bis-enamine rearrangement to pyrroloindoline core of calabar alkaloids
N
Me
MeN CO2Me N
MeHO2C
NMeNH
Me
NMe
HO2C
H
H200 °C
91%
Santos. P. F.; Srinivasan, N.; Almeida, P. S.; Lobo, A. M.; Prabhakar, S. Tetrahedron 2005, 61, 9147.
■ Dimethallyl rearrangement to flustramine C
Lindel, T.; Bräuchle, L.; Golz, G.; Böhrer, P. Org. Lett. 2007, 9, 283.
NH
NHMe
NBS, r.t.
90%N
NMe
Br
(±)-flustramine C
N
NHMe
Br
N
N [1,5]MeH
Synthetic Approaches to Pyrroloindoline Natural ProductsOther Methods
■ [4+1] cyclization of a bis(alkylthio)carbene and indole isocyanate
Rigby, J. H.; Sidique, S. Org. Lett. 2007, 9, 1219.
■ Aza-Pauson-Khand-type reaction of alkynecarbodiimides
Aburano, D.; Yoshida, T.; Miyakoshi, N.; Mukai, C. J. Org. Chem. 2007, 72, 6878.
NMe
MeOMe
CON3
N N
OMe
Me
PrS
PrS
PhCl, reflux
then LAH72%
NMe
MeOMe
N C O
SPrPrS
NMe
NH
MePrS SPr
O
TMS
N•
NMe
N
NMe
TMSO NaCNBH3
HCOH
79%
Co2(CO)8TMTU
74%
MeO MeO
3 steps
NMe
NMe
TMSO
MeOHO
H
3 steps to esermethole
Synthetic Approaches to Pyrroloindoline Natural ProductsOther Methods
■ [4+1] cyclization of a bis(alkylthio)carbene and indole isocyanate
Rigby, J. H.; Sidique, S. Org. Lett. 2007, 9, 1219.
■ Aza-Pauson-Khand-type reaction of alkynecarbodiimides
Aburano, D.; Yoshida, T.; Miyakoshi, N.; Mukai, C. J. Org. Chem. 2007, 72, 6878.
NMe
MeOMe
CON3
N N
OMe
Me
PrS
PrS
PhCl, reflux
then LAH72%
NMe
MeOMe
N C O
SPrPrS
NMe
NH
MePrS SPr
O
TMS
N•
NMe
N
NMe
TMSO NaCNBH3
HCOH
79%
Co2(CO)8TMTU
74%
MeO MeO
3 steps
NMe
NMe
TMSO
MeOHO
H
3 steps to esermethole
Synthetic Approaches to Pyrroloindoline Natural ProductsOther Methods
■ Asymmetric synthesis of calabar alkaloids by Ogasawara
Tanaka, K.; Taniguchi, T.; Ogasawara, K. Tetrahedron Letters 2001, 42, 1049.
O
HN
NH
MeOMe
MeO
NHNH2 O
Me
Me
O
O
Me
Me
HNMe
H2N
OMe
O
O
Me
Me
MeHN
OMe
HOO
O
O
Me
NH
O
OMeMeO
OH
71%
HCl, HCOHaqNaBH(OAc)3
NaIO452% (one pot) N
Me
MeMeO
O
CHO
NMe
NMe
MeMeOMeNH2•HCl
LiAlH454%
(–)-esermethole
3 steps
Synthetic Approaches to Pyrroloindoline Natural ProductsOther Methods
■ Overman synthesis of (+)-minfiensine
Dounay, A. B.; Humphreys, P. G.; Overman. L. E.; Wrobleski, A. D. J. Am. Chem. Soc. 2008, 130, 5368.
OTfNCO2Me
BocHN
Pd(OAc)2, L*
85% yield99% ee
NCO2Me
NHBocTFA
PPh2 N
O
t-Bu
N NBoc
MeO2C
Synthetic Approaches to Pyrroloindoline Natural ProductsOther Methods
■ Overman synthesis of (+)-minfiensine
Dounay, A. B.; Humphreys, P. G.; Overman. L. E.; Wrobleski, A. D. J. Am. Chem. Soc. 2008, 130, 5368.
OTfNCO2Me
BocHN
Pd(OAc)2, L*
85% yield99% ee
NCO2Me
NHBocTFA
PPh2 N
O
t-Bu
N NBoc
MeO2C
N NBoc
MeO2C
1. 9-BBN H2O2, NaOH
2. TPAP, NMO63%
25% isomer
O1. TFA
I
Br65%
2. N N
MeO2C
O
I
PdCl2(dppf)
MeOH74%
N N
MeO2C
O
N N
MeO2CNH
N
(+)-minfiensine
1. NaHMDS Comins' reagent
2. Pd(OAc)2, PPh3 CO, MeOH
77%
CO2Me1. LiAlH4
2. NaOH
OH
Conclusions
■ Each method has its strengths and weaknesses
■ Biomimetic approach is rapid and tryptophan is an abundant source of chiral material
■ Few enantioselective methods for pyrroloindoline construction have been developed
■ Efficiently obtaining fully-substituted vicinal stereocenters of the pyrroloindoline core remains a challenge