3 r formation of 3-substituted indoline scaffolds using...
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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
John Maciejewski @ Wipf Group 2 1/22/2007
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
John Maciejewski @ Wipf Group 3 1/22/2007
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
John Maciejewski @ Wipf Group 4 1/22/2007
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
John Maciejewski @ Wipf Group 5 1/22/2007
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
John Maciejewski @ Wipf Group 6 1/22/2007
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
Fukuyama, T. et al. J. Am. Chem. Soc. 2002, 124, 2137
- Alkaloid of genus Catharanthus
- Binds to tubulin, inhibits cell division
- Potent chemotherapy agent
Fukuyama, T. et al. J. Am. Chem. Soc. 2003, 125, 6630
- 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
John Maciejewski @ Wipf Group 7 1/22/2007
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
John Maciejewski @ Wipf Group 8 1/22/2007
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
John Maciejewski @ Wipf Group 9 1/22/2007
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
John Maciejewski @ Wipf Group 10 1/22/2007
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
John Maciejewski @ Wipf Group 11 1/22/2007
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
John Maciejewski @ Wipf Group 12 1/22/2007
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
John Maciejewski @ Wipf Group 13 1/22/2007
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
John Maciejewski @ Wipf Group 14 1/22/2007
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
Fukuyama, T. et al. J. Am. Chem. Soc. 2003, 125, 6630
Cs2CO3, ACN, 77%
NHO
OMe
OMe
OMe
N
O
O
HN
MeO2C
(+)-Duocarmycin A
John Maciejewski @ Wipf Group 15 1/22/2007
Part 1:
Using Intramolecular Friedel-CraftsReactions to Form Indoline Scaffolds
NNH2
R4
R3
R2
R1R1
3
John Maciejewski @ Wipf Group 16 1/22/2007
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.
John Maciejewski @ Wipf Group 17 1/22/2007
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
John Maciejewski @ Wipf Group 18 1/22/2007
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
John Maciejewski @ Wipf Group 19 1/22/2007
Part 2:
Using Radical Mediated Processes toForm Indoline Scaffolds
NNH2
R4
R3
R2
R1R1
3
John Maciejewski @ Wipf Group 20 1/22/2007
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%
John Maciejewski @ Wipf Group 21 1/22/2007
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
John Maciejewski @ Wipf Group 22 1/22/2007
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
John Maciejewski @ Wipf Group 23 1/22/2007
Acknowledgements
Prof. Peter Wipf
NIH
Wipf group members
John Maciejewski @ Wipf Group 24 1/22/2007