3 r formation of 3-substituted indoline scaffolds using...

Formation of 3-Substituted Indoline ScaffoldsUsing Friedel-Crafts and Radical Mediated

Processes

John Maciejewski

Research Topic SeminarJanuary 20th, 2007

NNH2

R4

R3

R2

R1R1

3

John Maciejewski @ Wipf Group 1 1/22/2007

Presentation Outline- Recent approaches toward the indoline scaffold

- Important indoline natural products

- Synthesis of 3-substituted indolines

- Friedel-Crafts approach towards indoline synthesis

- Radical cyclization approach towards indoline synthesis


Approaches Toward the Indoline Scaffold

Padwa, A. et al. J. Org. Chem. 2001, 66, 3119

Overman, L. E.; Wild, H. Tet. Lett.1989, 30, 647

Aza-Cope/Mannichrearrangement

Bailey, W. F.; Mealy, M. J. J. Am.Chem. Soc. 2000, 122, 6787

EnantioselectiveCarbolithiation

Boger, D. L.; Coleman, R. S. J. Org.Chem. 1984, 49, 2240

Intramolecular Diels-Aldercyclization

Danheiser, R. L.; Dunetz, J. R. J. Am. Chem. Soc.2005, 127, 5776

[4+2] Cycloaddition

N

R4R3

R2

R1 N

Br

Bn

tBuLi

(-)-sparteine

H

HO

N

CH3

Ar

CN

Cu(OTf)2

Br

NHBnBnO Br

CuI (10%), CsOAc (1.4 equiv)

OH

I

N

Ts

O

Me3Zn(SCN)Li2

Br

OMe

H2N

1) Ph2C=NH

2) nBu3SnH, AIBN

Johnston, J. N. et al. Org. Lett. 2001, 3, 1009

Aryl radical addition

Sakamoto, T. et al. J. Am.Chem. Soc. 1998, 120, 4934

Organozincate addition

Fukuyama, T. et al. J. Am. Chem. Soc. 2003, 125, 6630

Copper-mediated aryl amination

Intramolecular Diels-Alder reaction

O N

CO2Et

Ar

Δ

N

MeO2C

SiMe3

BHT

ΔN

N

N

MeO2C

R1

Δ

Intramolecular Diels-Alder reaction[4+2] Cycloaddition

Intramolecular Diels-Aldercyclization

EnantioselectiveCarbolithiation

Aza-Cope/Mannichrearrangement

Copper-mediated aryl amination

Organozincate addition

Aryl radical addition


Wipf Group InterestsStemona alkaloid core prepared by oxidative cyclization of L-tyrosine

Wipf, P.; Kim, Y. Tet. Lett. 1992, 33, 5477

(-)-TuberostemonineOxotuberostemonine

Wipf, P.; Rector, S. R.; Takahashi, H. J. Am.Chem. Soc. 2002, 124, 14848

No total synthesis to date

NOH

OH

CO2Me

H

NH

OH

H

O

O

O O

H

N

O

H

HO

O

OO

HH

HO

NHPG

CO2H

PhI(OAc)2, MeOHNaHCO3

PG

NOH

OH

CO2Me

H

PG


3-Substituted Indoline Natural Products

- Few examples of enantioselective preparation in literature

- Many biologically active indoline natural products are substituted at 3-position

- Demand for mild, enantioselective method of construction

N

R4

R3

R2

R1

3

Difficult to enantioselectively form quaternary centers at 3-position


Examples of 3-Substituted Indoline Natural Products

NO

O

N

H

HH

H

Strychnine

N

N

H

MeO

H3COH

OAc

CO2Me

Vindoline

HN N

MeO OHO

HNN

MeO OHO

NH2

OHN

N

O (+)-CC-1065

Fukuyama, T. et al. Synlett 2000, 6, 883

- Alkaloid of genus Catharanthus

- Highly functionalized pentacyclic core

- Synthon for natural product Vinblastine

Padwa, A. et al. Org. Lett. 2007, 9, 279

- Alkaloid of genus Strychnos

- Actively binds to glycine receptor site

- Disrupts nerve-cell signaling

Boger, D. L. et al. Chem. Rev. 1997, 97, 787

- Alkaloid of genus Streptomyces

- Structure discovered in 1980

- Potent cytotoxin


Examples of 3-Substituted Indoline Natural Products

NHO

OMe

OMe

OMe

N

O

O

HN

MeO2C

(+)-Duocarmycin A

N

NMeO

HNN

OH

MeO2C

H3C HO

OAc

CO2MeH

(+)-Vinblastine


- Alkaloid of genus Catharanthus

- Binds to tubulin, inhibits cell division

- Potent chemotherapy agent


- Alkaloid of genus Streptomyces

- More potent subunit of CC-1065

- Functions as DNA alkylating agent

Van Vranken, D. L. et al Org. Lett. 2004, 6, 1713

- Alkaloid of genus Phakellia

- Indoline moiety derived from photooxidation of Trp

- Activity against leukemia cell lines under investigation

NH

N O

NH

OHN

O

N

ONH

O

HN

O

N

O

HO

Ph

OH

H

Phakellistatin 3


Indoline Scaffolds Through Diels-Alder Chemistry

Boger, D. L.; Coleman, R. S. J. Org. Chem. 1984, 49, 2240

NNCl

Cl

NNCl

NH

O

ON N

N

O

O

OTHP

NH4OH (conc.) then

ClCO2Me, THF, K2CO3

1) H2, Pd/C, EtOH, 93%

51%

2) PPh3, DEAD, THF, 1

OTHP

HO 113%

1) PPTS, EtOH, 81%

2) TBS-Cl, imid, 96%

TIPB

230oC, 18 h N

TBSO

CO2Me N

O

CO2Me

H

N CO2MeH

MeO2C

NH

N N

N

O

O

OTBS

TBAF, THF then MnO2, DCM

92%91%

1) N3CH2CO2Me, NaOMe2) Xylene, reflux

52% (2 steps)

HN N

MeO OHO

HNN

MeO OHO

NH2

OHN

N

O (+)-CC-1065

towards


Synthesis of (±)-Mesembrane

Padwa, A. et al. J. Org. Chem. 2001, 66, 3119

Diels-Alder

(±)-crinane(±)-dendrobine

Methodology used to synthesize natural products (±)-dendrobine and (±)-crinane

O N

CO2Et

!

N

CO2Et

O

N

CO2Et

O

N

CO2Et

O

78%

1) LAH/H+

2) NaBH3CN/H+

N

CH3

HO

H

49% (2 steps)

N

CH3H

1) PCC

2) HSCH2CH2SH

3) Raney-Ni

85% (3 steps)

OMe

MeO

MeO

OMe

OMe

MeOOMe

MeO

MeOOMe

MeOOMe

3 steps

N

CH3

HH

H

H3C

H3C

CH3

O

O

O

O

N

H

(±)-mesembrane


Synthesis of 3-Substituted Indolines

Sakamoto, T. et al. J. Am. Chem. Soc. 1998, 120, 4934

I

N

SO2PhN

OH

SO2Ph

O Me3Zn(SCN)Li2

THF

92%

97 (5-exo) : 3 (6-endo)

I

N

SO2Ph

CO2Me

Me4ZnLi2

THF N

CO2Me

SO2Ph

66%

Intramolecular Michael addition

Intramolecular substitution


Synthesis of 3-Substituted Indolines

Hibbs, D. et al. J. Org. Chem. 1999, 64, 7856

Tandem Radical Cyclization Reactions

I

NHSO2Me

OH

I

N

SO O

CH3

OH

OH

I

N

SO O

CH3

OMs

1) DEAD, PPh3, 67%

2) OsO4, NMO, 86%

1) NaIO4, Et2O, 96%2) NaBH4, MeOH, 86%

3) MeSO2Cl, NEt3, DCM, 93%

I

N

SO O

CH3

N3

NaN3, DMF, 96%

1) TTMSS, AIBN2) H2O, 83% (2 steps)

3) p-TsCl, py, DMAP, 75%NH H

NTs

Mechanism for radical cyclization

Synthesis of core for Aspidosperma alkaloids

NH

NTTMS

N

N N N

N

N N N

H H

-N2

I

N

SO O

CH3

N3

TTMSS, AIBN

S S S

CH3CH3 CH3

O O O O OO


Enantioselective Synthesis of 3-Substituted IndolinesCarbolithiation in the presence of (-)-sparteine

Bailey, W. F.; Mealy, M. J. J. Am. Chem. Soc. 2000, 122, 6787Gil, G. S.; Groth, U. M. J. Am. Chem. Soc. 2000, 122, 6789

N

Br

Bn

tBuLi

(-)-sparteine N

Bn

Li

H3O+

N

Bn

Entry Solvent Temp. oC Yield, % ee, %

1

2

3

4

5

Et2O -78 60 65

THF -78 80 0

Toluene -78 90 80

Toluene -90 85 87

Cumene -90 84 75

NN

(-)-sparteine


Enantioselective Synthesis of 3-Substituted Indolines

Macchia, F. et al. Org. Lett. 2006, 8, 2627

TFAA, pyTfO

PhNHTs

94%

CuI (2 equiv)CsOAc (5 equiv)

DMSO NTs

Ph

72%

- Stereochemistry is relayed from enantioenriched starting material

- Friedel-Crafts alkylation preserves enantioenrichment moderately

O

Ph

1) NH4Cl, NaN3, MeOH, 90%

2) PPh3, ACN3) TsCl, NEt3, Et2O, 45% (2 steps)

NPh

98% ee

Ts -78oC, DCM

60% C-alkylationHO

PhNHTs

81:19 er

O B

3


Enantioselective Synthesis of Indolines

Yang, D. et al. J. Am. Chem. Soc. 2006, 128, 3130

Demonstrates tandem C-N and C-C bond formation

Ligand yield (%) ee (%)

1) (DHQ)2PHAL 89 122) (DHQ)2AQN 94 123) (DHQD)2PYR 98 84) (-)-cinchonidine 40 75) Hydroxyquinine 47 116) (S,S)-Ph-box 55 97) (-)-sparteine 75 86

Pd(TFA)2 (10 mol%), Ligand (40 mol%)

DIPEA (2 equiv) 3 AMS, O2 (1 atm), tolueneNH

ON

O

75%

(+), 86% ee

H

NN

(-)-sparteine


Enantioselective Synthesis of (+)-Duocarmycin ABr

I

BrBnO

n-BuLi, -78oC then 1Ph

NO2

O

OBr

BrBnO

58%

1) AcOH/H2O reflux, quant.

2) H5IO6 0oC then

NaBH4/MeOH, -78oC, 90%

(>98% ee)

3) (i) Fe/FeCl2, 1 N HCl, EtOH, reflux (ii) o-NsCl, NaHCO3, DCM/H2O (iii) BnBr, K2CO3, DMF then PhSH 74% (3 steps)

NHBn

OHBr

BrBnO

Ph

NO2

O

O1

1) CuI (10%), CsOAc (1.4 equiv) DMSO, 67%

2) TBSCl, imid, DMF, quant. NBn

OTBSBr

BnO

N

OOBn

O

MeO2C

n-BuLi, -78oC then 2

2

NBn

OTBS

BnO

O

CbzHN

CO2Me

75%

1) NBS, DMF, 82%

2) CuI (2 equiv), CsOAc (5 equiv), DMSO, quant.

NBn

OTBS

BnO

O

CbzN

MeO2C

1) TrocCl, NaHCO3, 70%

2) Zn, KH2PO4, THF/H2O, 69%

NH

OTBS

BnO

O

CbzN

MeO2C

1) 3, pyr, DCM, 90%

2) TBAF, THF, 76%

3) MsCl, pyr, 88%

4) H2/Pd/C. 87% NHO

OMe

OMe

OMe

N

OMs

HO

O

CbzN

MeO2C

NH

O

OMe

OMe

OMeCl

3


Cs2CO3, ACN, 77%

NHO

OMe

OMe

OMe

N

O

O

HN

MeO2C

(+)-Duocarmycin A


Part 1:

Using Intramolecular Friedel-CraftsReactions to Form Indoline Scaffolds

NNH2

R4

R3

R2

R1R1

3


Aromatic Friedel-Crafts (FC) Reactions

Intramolecular Friedel-Crafts cyclizations

H2C R2

CR3

O

R1

R1

R1

R2

R3

O

alkylation

acylation

Intermolecular Friedel-Crafts reaction

Use BrØnsted or Lewis acids to generate electrophilic species

OF3C

AlCl3

DCM

F3C

Jacquot, R. et al. J. Org. Chem. 1988, 53, 759

Gore. P. H. Chem. Rev. 1955, 55, 229-281.


Examples of Intramolecular FC Reactions

(-)-lintetralin

OO

NH3C H

1) Piperonal, NaCN, HCl

O

O

H

CNN

OO

H3C

1) Et2O, LDA -90oC

then 1, 79%

O

O

1

O

O

CNN

OO

H3C

O

O

70%

1) tBuLi, -78oC

then 2

O

O

O

O

OMe

MeO

2) AgNO3, H2O, 70% (2 steps

O

O

O

OH

OH

OMe

MeO

OH

1) LAH (4 equiv), rt 95%

OMe

OMe

OO

MeO

MeO

1) BF3.OEt2, DCM, 87%

2) NaH (2.2 equiv, MeI (8 equiv), 92%

MeO

OMe

Br

2

de, ee >98%

29% over seven steps

BF3 promoted cyclization


Examples of Intramolecular FC Reactions

Elango, S.; Yan, T-H. Tetrahedron. 2002, 58, 7335

O

ONH

OTBS

OO

O

O

ONH

OTBS

AcO

O

O

1) SnCl4 (20%)

2) Ac2O, K2CO3

O

ONH

OH

OH

OH

O

(+)-Lycoricidine93% (2 steps)

OMeO OMe

OH

BF3.Et2O

85%Nagumo, S. et al. Tet. Lett. 2002, 43, 2223

Few examples of 2,2-disubstituted epoxides used in Friedel-Crafts type alkylations

OR1Lewis acid

?

R1 = -H/

Using epoxides as electrophiles


Part 2:

Using Radical Mediated Processes toForm Indoline Scaffolds

NNH2

R4

R3

R2

R1R1

3


Radical Processes to Form Indolines

Johnston, J. N. et al. Org. Lett. 2001, 3, 1009

Review of radical additions to imines: Friestad, G. K. Tetrahedron 2001, 57, 5461

- Observed 5-exo cyclization onto nitrogen with ketimines

- Observed 6-endo cyclization onto carbon with aldimines

BrNH2

Ph

O

RN

PhR

1)

2) nBu3SnH, AIBNNH

Ph R

87% (10:1)

R = H 72% (20:1)

R = -CH3

yield, (cyclized:ArH) <1%

<1%


Radical Cyclization onto Olefins

Recall synthesis of Aspidosperma alkaloid core

I

N

SO O

CH3

N3

1) TTMSS, AIBN2) H2O, 83% (2 steps)

3) p-TsCl, py, DMAP, 75%NH H

NTs

Elegant method to form complex heterocycles

Hibbs, D. et al. J. Org. Chem. 1999, 64, 7856

Tandem C-C and C-N bond formation via radical intermediate


Literature Precedence for Titanocene Systems

OCp2TiCl2 / Zn0

OH

94%

RajanBabu, T. V.; Nugent, W. A. J. Am. Chem. Soc. 1994, 116, 986

Examples of substrates tolerated

For recent review see: Arteaga, J. F. et al. Eur. J. Org. Chem. 2006, 1627 Gansauer, A.; Pierobon, M.; Bluhm, H. Synthesis, 2001, 16, 2500

O

Cp2TiCl2 / Zn0

H

HO

88%

endo : exo 90:10

O

N

Ts

N

TsH

HO CH3

Cp2TiCl2 / Zn0

64%

78:22 dr


Acknowledgements

Prof. Peter Wipf

NIH

Wipf group members


3 r formation of 3-substituted indoline scaffolds using...

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