Current topics in Org Synthesis

LSPN Group Seminar03.04.2012Nick Tappin

NH

How to make poly-substituted indoles skeletons?

NH

R4

R5

R7R6

R3

R2

and cyclopenta[g]indole skeletons?

NH

Challenge for natural product synthesis:

SynLett 2011, 1495

cyclopenta[g]indole skeletons

NH

Tet 2010, 66, 3875

trikentrins and herbindoles

How to make poly-substituted indoles skeletons?

NH

R4

R5

R7R6

R3

R2

and cyclopenta[g]indole skeletons?

NH

Challenge for natural product synthesis:

SynLett 2011, 1495

NH

cis-trikentrin A

NH

trans-trikentrin A

NH

cis-trikentrin B

NH

trans-trikentrin B

Et

Et

NH

R

R = Me; herbindole AR = Et; herbindole B

R = (E)-1-butenyl; herbindole C

NH

NH

NH

(+)-cis-Trikentrin A

asymmetric HV

99%, 96% ee

10 steps

22% yield in 11 steps

JACSAsymmetric Hydrovinylation of Vinylindoles. A Facile Route to

cyclopenta[g]indole Natural Products (+)-cis-Trikentrin A and (+)-cis-Trikentrin B.

W. Liu, H. J. Lim, T. V. RajanBabu.DOI: 10.1021/ja3004733

NH

NH

NH

(+)-cis-Trikentrin A

asymmetric HV

99%, 96% ee

10 steps

22% yield in 11 steps

JACSAsymmetric Hydrovinylation of Vinylindoles. A Facile Route to

cyclopenta[g]indole Natural Products (+)-cis-Trikentrin A and (+)-cis-Trikentrin B.

W. Liu, H. J. Lim, T. V. RajanBabu.DOI: 10.1021/ja3004733

NH

NH

ethylene (1 atm), [L]

[(allyl)Ni-Br]2, NaB(Ar)4,

DCM, -78oC

Ar= 3,5-(CF3)2-C6H3

2

345

6

7

[L] =OO

P

N PhPh

Ra

Sc Sc

or OOP

N napthPh

Ra

Sc

2- ,3- ,5- ,6- , or 7-vinyl indoles

>95%, >90% ee

NH

NH

NH

(+)-cis-Trikentrin A

asymmetric HV

99%, 96% ee

10 steps

22% yield in 11 steps

JACSAsymmetric Hydrovinylation of Vinylindoles. A Facile Route to

cyclopenta[g]indole Natural Products (+)-cis-Trikentrin A and (+)-cis-Trikentrin B.

W. Liu, H. J. Lim, T. V. RajanBabu.DOI: 10.1021/ja3004733

NH

R

R= Me, Et, Et(E)

(-)-herbindoles A-C

NTs

MOMO

[2 + 2 + 2]cyclization

MOMO

NTs

Org LettTotal Synthesis of (-)-Herbindoles A, B, and C via a Transition-Metal-

Catalyzed Intramolecular [2 + 2 + 2] Cyclization between Ynamide and Diynes.

N. Saito, T. Ichimaru, Y. Sato.DOI: 10.1021/ol300571b

NH

NH

ethylene (1 atm), [L]

[(allyl)Ni-Br]2, NaB(Ar)4,

DCM, -78oC

Ar= 3,5-(CF3)2-C6H3

2

34

5

6

7

[L] =OO

P

N PhPh

Ra

Sc Sc

or OOP

N napthPh

Ra

Sc

2- ,3- ,5- ,6- , or 7-vinyl indoles

>95%, >90% ee

NH

NH

NH

(+)-cis-Trikentrin A

asymmetric HV

99%, 96% ee

10 steps

22% yield in 11 steps

JACSAsymmetric Hydrovinylation of Vinylindoles. A Facile Route to

cyclopenta[g]indole Natural Products (+)-cis-Trikentrin A and (+)-cis-Trikentrin B.

W. Liu, H. J. Lim, T. V. RajanBabu.DOI: 10.1021/ja3004733

NH

R

R= Me, Et, Et(E)

(-)-herbindoles A-C

NTs

MOMO

[2 + 2 + 2]cyclization

MOMO

NTs

Org LettTotal Synthesis of (-)-Herbindoles A, B, and C via a Transition-Metal-

Catalyzed Intramolecular [2 + 2 + 2] Cyclization between Ynamide and Diynes.

N. Saito, T. Ichimaru, Y. Sato.DOI: 10.1021/ol300571b

R2

N

EWG

R1

R3

R4

+N

R1

R2

EWG

[2 + 2 + 2]cyclization

R4R3

B. WitulskiACIE 1999, 38, 2426

Chem Comm 2000, 1965ACIE 2002, 41, 3281

NH

NH

ethylene (1 atm), [L]

[(allyl)Ni-Br]2, NaB(Ar)4,

DCM, -78oC

Ar= 3,5-(CF3)2-C6H3

2

34

5

6

7

[L] =OO

P

N PhPh

Ra

Sc Sc

or OOP

N napthPh

Ra

Sc

2- ,3- ,5- ,6- , or 7-vinyl indoles

>95%, >90% ee

MacLeodFeatures: first entry into these alkaloids, racemic, cis/ trans selective, radical cyclization, Hemetsberger indole synthesis

NH

CO2Et

N3

)

Br

OH

OH

5-exo-tr ig

Bu3Sn

HO

H2, Pd/C9:1

trans

H+

radical cyclization

1 : 1

Friedel-Crafts acylations

Suf fers f rom: numerous erasures, poor cis-trans control, early-stage 4-functionalization; not general for analogues

-N2(g)

Raney Nicis

NCO2Et

Hemetsberger synthesisAldrich Acta 2001, 34, 51

Natsume

NSO2Ph

EtO2C

NSO2Ph

OHCEtO2C

enolate addition

+

ketone - cyclisation

NO

O

9 steps

O

Br

partial racemisation:HPLC sep. of cis & trans isomers

Natsume

NSO2Ph

EtO2C

NSO2Ph

OHCEtO2C

enolate addition

+

ketone - cyclisation

NO

O

9 steps

O

Br

partial racemisation:HPLC sep. of cis & trans isomers

Kanematsu

NH

Et

cis-trikentrin B

NPv

OTr

[O] cleavage, FGI DA

JSC Chem Comm1989, 953

OTr

NPv

name rxn?

OTr

NPv

Kanematsu

NH

Et

cis-trikentrin B

NPv

OTr

[O] cleavage, FGI DA

JSC Chem Comm1989, 953

OTr

NPv

name rxn?

OTr

NPv

Kanematsu

NH

Et

cis-trikentrin B

NPv

OTr

[O] cleavage, FGI DA

JSC Chem Comm1989, 953

OTr

NPv

name rxn?

OTr

NPv

Boger

NH

cis-trikentrin A

JOC 1988,53, 1415

NN

Et

SO2Me

HN

Et

NN

NN

SMe

MeS

NH2

Et

N+ +

Blechert

NH

cis-trikentrin A

Et

NO2

Et

NO2

Et

Bartolli rxn

hydrogenn

OSO2CF3

Et

OH

Intra HeckF-C Acyln

Nitran

Blechert

NH

cis-trikentrin A

Et

NO2

Et

NO2

Et

Bartolli rxn

hydrogenn

OSO2CF3

Et

OH

Intra HeckF-C Acyln

Nitran

NH

trans-trikentrin A

Et

NH

Et

ring contracn

TTN (TlIII)Tet 2002,

58, 9137

NPG

Et

CO2Et

NO2

Et

Br

Elaboran

F-C

HeckBartolli

CO2Et

+

and Silva

Kerr

NH

Et

cis-trikentrin B

NTs

HOStille coupling[O] cleavage

NTs

OCHO

DAiminoquinones

NH

Herbindole B

Et

NHTs

CHOOHC

NHTs

HO

NTs

O

FunkBuszek

NH

Herbindole B

Et

NH

Herbindole A

NTs

HO

I

HO

OH

NH

Et

cis-trikentrin B

Divergent strategy

key int.

NH

NH

NH

(+)-cis-Trikentrin A

asymmetric HV

99%, 96% ee

10 steps

22% yield in 11 steps

JACSAsymmetric Hydrovinylation of Vinylindoles. A Facile Route to

cyclopenta[g]indole Natural Products (+)-cis-Trikentrin A and (+)-cis-Trikentrin B.

W. Liu, H. J. Lim, T. V. RajanBabu.DOI: 10.1021/ja3004733

T. V. (Babu) RajanBabu received his undergraduate education in India (Kerala University and Indian Institute of Technology, Madras). He obtained a Ph. D. degree from The Ohio State University under the direction of Professor Harold Shechter, and was a postdoctoral fellow at Harvard University with the late Professor R. B. Woodward. He then joined the Research Staff of Dupont Central Research and Development, becoming a Research Fellow in 1993. He returned to OSU as a Professor of Chemistry in 1995.

Start of synthesis (buried in SI)

Br

Et

HNO3/ H2SO4

Br

Et

Br

Et

35% 27%

+NO2

NO2

MgBr

Bartolli rxn

THF, -50oC

47%NH

Et

Br

NH

Et

Pd(PPh3)4

SnBu3

70%

Br

NO2

NH

(+)-cis-Trikentrin A

NH

(+)-cis-Trikentrin B

Et

Targets:

NH

THF, -50oC

MgBr

1)

2) Pd(PPh3)4 SnBu3

42%

A

B

hydrovinylation

NH

NH

Et

NH

Et

ethylene (1 atm), [L3]

[(allyl)Ni-Br]2, NaB(Ar)4,

DCM, -78oC

Ar= 3,5-(CF3)2-C6H3

OOP

N PhPh

Ra

Sc Sc

OOP

N napthPh

Ra

Sc

99%, 96% ee

L3

ethylene (1 atm), [L3]

[(allyl)Ni-Br]2, NaB(Ar)4,

DCM, -78oC

Ar= 3,5-(CF3)2-C6H3

99%, 94% ee

NH

NTs

93%, 90% ee, L2

L2

NH

NH

NH

Et

96%, 92% ee, L3 99%, 94% ee, L3 96%, 92% ee, L3

Mechanism: SynLett 2009, 853

NH

Et

NTs

Et1) KH, TsCl, 18-crown-6 DME, 53%

2) 9-BBN, H2O2, 92%

HO

1) TPAP, NMO

2) NaClO2, NaH2PO4 NTs

Et

HO2C85%

1) (COCl)2, DMF

2) AlCl3, DCM NTs

Et

O

NTs

Et

tBuOK, Ph3PMeI

94% NTs

Et[(allyl)PdCl]2 cat.

otol3P/ AgOTf

ethylene 1 atmDCM, 95%

NTs

EtCrabtree HydrogenatnDifficult diastereocontrol

[(COD)Ir(PCy3)(Py)]+

PF6- cat. / H2 (554 psi)

17h, DCM, 95%

TBAF, THF, reflux16h, 84%

(+)-cis-trikentrin A

JOC 2009, 74, 4565

NTs

NH

H2 (275 psi)

Pd/ C, MeOH99%

NTs

NTs

II2, PhI(OCOCF3)2

MeCN, rt, 2h90%

Mn(OAc)3.H2O

AcOH, reflux87%

NTs

I

NTs

Et

EtSnBu3

Pd(Ph3P)2Cl2/ LiCl

BHT / 150oC, 15h

TBAF/ THF

60% NH

Et

(+)-cis-trikentrin B

NH

NH

NH

(+)-cis-Trikentrin A

asymmetric HV

99%, 96% ee

10 steps

22% yield in 11 steps

JACSAsymmetric Hydrovinylation of Vinylindoles. A Facile Route to

cyclopenta[g]indole Natural Products (+)-cis-Trikentrin A and (+)-cis-Trikentrin B.

W. Liu, H. J. Lim, T. V. RajanBabu.DOI: 10.1021/ja3004733

NH

R

R= Me, Et, Et(E)

(-)-herbindoles A-C

NTs

MOMO

[2 + 2 + 2]cyclization

MOMO

NTs

Org LettTotal Synthesis of (-)-Herbindoles A, B, and C via a Transition-Metal-

Catalyzed Intramolecular [2 + 2 + 2] Cyclization between Ynamide and Diynes.

N. Saito, T. Ichimaru, Y. Sato.DOI: 10.1021/ol300571b

NH

NH

ethylene (1 atm), [L]

[(allyl)Ni-Br]2, NaB(Ar)4,

DCM, -78oC

Ar= 3,5-(CF3)2-C6H3

2

34

5

6

7

[L] =OO

P

N PhPh

Ra

Sc Sc

or OOP

N napthPh

Ra

Sc

2- ,3- ,5- ,6- , or 7-vinyl indoles

>95%, >90% ee

NH

R

FGI

NH

OPG OPG

NTs

[2 + 2 + 2] C-N Coupling Br

O

Synthesis of SM

Corey-Fuchs

Retrosynthesis

OL 2006, 8, 1025

O O

meso/ dl

iPr2NEt, EA

rt, 12h, recrys.

80% OO O

mesoHO OH

LAH, Et2O, refl.

85%

OAcAmano AK

THF, rt, 80%

Tet 1996, 52, 5907JOC 2001, 66, 493

AcO OH HO OTBS

1) TBSCl, ImH

2) K2CO3

MeOH

OTBS

97% ee

OH

1) SO3.py, DMSO, NEt3,

DCM, 0oC, 1h30

2) CBr4, PPh3, DCM, 0oC, 2h

OTBS

BrBr

1) nBuLi, THF, -78oC, 1h;

TIPSCl, rt, 10h30

2) HCl, EtOH, rt, 17h

OH

TIPS

1) SO3.py, DMSO, NEt3,

DCM, 0oC, 1h30

2) CBr4, PPh3, DCM, 0oC, 2h

3) LiHMDS, THF, -78oC, 30';

rt, 12h

TIPS

Br

75%, 7 steps

JACS 2007, 129, 14788

HO

NBocTs

1) MOMCl, DCMrt, 48h

2) neat, 185oC,30', 87% 2 steps

MOMO

NHTs

TIPS

Br

CuSO4.5H2O, K3PO4

phen, PhMe, 60oC, 44hN

N

phen

JOC 2006, 71, 4170

MOMO

NTs

TIPS

MOMO

NTs

1) TBAF, THFrt, 1h30

2) LiHMDS, THF,-78oC, 1h; MeI, rt,

15h, 78% 3 steps

NTs

OMOM

[2 + 2 + 2] cyclization

RhCl(PPh3)3 5 mol%

PhMe, 50oC, 5h

97%

JCS Rev 2011, 40, 3430

NTs

OMOM1) BBr3, DCM,

-78oC, 2h30

2) nBu3SnH, AIBN

PhMe, 100oC, 1h

92%, 2 steps

NTs

1) Na, napth, THF

-78oC, 2h

2) CoII(calen), O2

MeOH, rt, 2h, 94%

NH

(-)-herbindole A

49% overall yield in 15 steps

HBF4, MeCN/H2O

60oC, 48h, 98%

NTs

OH 1) DMP, DCM, rt, 3h

2) Tebbe reagent

THF, 0oC, 2h

3) H2, Pd/ C, EA, rt, 2h70%

NTs

1) Na, napth, THF

-78oC, 1h

2) CoII(calen), O2

MeOH, rt, 1h30

93%

NH

(-)-herbindole B

36% overall yield in 17 steps

1) DMP, DCM, rt, 2h

2)nPrMgBr, THF, 0oC, 3h

3) p-TsOH, PhH, 50oC, 20h

91%

NTs

Et

1) Na, napth, THF-78oC, 1h

2) CoII(calen), O2

MeOH, rt, 1h30

93%

NH

Et

44% overall yield in 17 steps

Summary of important reactions:

1) Hemetsberger-Knittel indole synthesis

CO2R

N3

-N2(g)

CO2R

NNH

CO2R

1H-indole-2-carboxylic ester

ON3

CO2R

Aldrich Acta 2001, 34, 51

Monatsh Chem 1972, 103, 194Synthesis 1985, 186Perk Trans 1 2000, 1045: (Review of named indole syntheses)

base

Knoevenangel

2) Crabbé homologation of acetylenes to allenes

JSC Chem Comm 1979, 859Perk trans 1 1984, 747

R RHCHO, CuBr, DIPA

CuBr

R CuBr

N

RN

H

CuBr

RNCu

BrH

3) Boger tetrazine-diazine-benzene/indole/indoline DA strategy

N

N

JOC 1988, 53, 1415

SO2Me

AcN

N

NAcN

MeO2S

-N2

SO2Me

AcNH

H+

SO2Me

AcN

H

AcNR

R

RR

N

N N

N

SMe

SMe

X

R

H2N

R+ +

4) Bartolli reaction

NO2

X

X = halide

NOX

OMgBr

TMS

Perk Trans 1 1991, 2757

TMS

MgBr

TMS

MgBr NX

O

MgBr

TMS1,2-addn

[3,3] NX

O

MgBr

TMS

XN OMgBr

TMS

TMS

MgBr

HTMS

H

XN OMgBr

TMS

MgBr

X

HN

TMSH3O+

X

HN

orMgBr

with

5) Ring Contractions

6) Plienger's Indolization sequence

Birch reductn

of napth. der.

NHAc

O3, MeOH

CHO

CHO

NHAc

NAc

CHO

OH(CO2H)2

-H2O NAc

CHO

Chem Ber 1956, 89, 270

7) Aromatisation of indolines to indoles

NH

NH

dehydrogenation

CoII(salen), O2

Chem Lett 1980, 1287O

N N

OCo

OO

XN

MeO

Review: Tet 2002, 58, 9137For trans-trikentrin A: OL 2008, 10, 5417

TTN.3H2O, TMOF,

0oC, 1min

94%, X=ONO2

OMe

TlX3

OMe

Tl

-X

X X

MeOH OMe

Tl

OMe MeO

TlX

X

-X, -TlX

MeO

H+

H+

MeOH

MeO

MeOOMe