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


● Other methods


■ 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


■ 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


■ 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

--


■ 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


■ 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.


■ 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


■ 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



■ 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


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


Austin, J. F.; Kim, S-G.; Sinz, C. J.; Xiao, W-J.; MacMillan, D. W. C. Proc. Natl. Acad. Sci. 2004, 101, 5482.


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


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.


■ 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%


■ 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%


■ 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


■ 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


■ 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


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.


■ 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.


■ 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%


■ 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.


■ 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




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

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.


■ 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


■ 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


■ [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


■ 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


■ 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


■ 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

synthetic approaches to pyrroloindoline containing natural ......synthetic approaches to...

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