Synthetic Approaches to Pyrroloindoline Containing Natural ......Synthetic Approaches to...
Transcript of Synthetic Approaches to Pyrroloindoline Containing Natural ......Synthetic Approaches to...
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