The Discorhabdin Alkaloids - Scripps Research...O3S SO3Na Fremy's Salt Review: Chem. Rev. 1971, 71, 229-246. NHR Baran Group Meeting The Discorhabdin Alkaloids Paul Krawczuk [The First]

Paul KrawczukBaran Group MeetingThe Discorhabdin Alkaloids

NH

NH

O

HN

O

BrBr

Discorhabdin C

NH

NH

O

HN

O

Br

Discorhabdin A

S

H NH

NH

O

HN

O

Br

S

H

Discorhabdin B

NH

NH

O

HN

O

Br

Discorhabdin E

NH

NH

O

N

O

Discorhabdin D

H

NH

NH

O

HN

O

Br

Discorhabdin G

NH

N

O

HN

O

Br

Discorhabdin P

Br

NH

NH

O

HN

O

Br

S

H

Discorhabdin Q

Me

NH

NH

O

HN

O

S

H

Discorhabdin R

O

NH

NH

O

HN

O

Br

S

NH

NH

O

NH

O

Br

S

Discorhabdin W

NH

NH

O

HN

O

BrBr

14-bromo-Discorhabdin C

Br

NH

NH

O

HN

OH

BrBr

Br

14-bromo-3-dihydro-7,8-dehydro-Discorhabdin C

NH

NH

O

N

O

Br

1-amino-Discorhabdin D

H

H2N

NH

NH

O

N

O

Br

1-methoxy-Discorhabdin D

H

MeO

NH

NH

O

HN

O

Discorhabdin I

S

H NH

NH

O

N

O

Discorhabdin L

S

H

HO

NH

N

O

HN

O

Br

MeS

Discorhabdin S

NH

N

O

HN

O

Br

MeS

Discorhabdin T

Representative Structures of the Discorhabdin Alkaloid Family:

S

H

For a comprehensive review see: Y. Harayama, Y. Kita. Curr. Org. Chem. 2005, 9, 1567-1588.

Paul KrawczukBaran Group Meeting The Discorhabdin Alkaloids

NH

NH

O

HN

O

BrBr

Discorhabdin C

NH

NH

O

HN

O

Br

S

H

Discorhabdin B

NH

NH

O

HN

O

Br

S

NH

NH

O

NH

O

Br

S

Discorhabdin W

Proposed Biosynthesis of the Discorhabdin core:M. Munro, J. Nat. Prod. 1995, 58, 306-311.

NH

COOH

NH

NH2

NH2

[O]NH

NH2OH

NH

NH2O

[O]

OOH

NH

HN

O [O]

OHH3N

NH

HN

O

ONH

HN

O

HO

NH

Makaluvamine D

Sulfur Insertion

NH

HN

O

HO

NH

S

Makaluvamine F

cyclization

cyclization

light

tyramine

tryptamine

OCOCF3

Ph


First Sythetic Approach to the Discorhabdin Alkaloids: Y. Kita et al Tet. Lett. 1989, 30, 1119-1120.

OH

NH2

O

O

MeO

EtOH

O

O

OH

HN

MeO

TMSO

O

O

OTMS

HN

DCM

PhI(OCOCF3)2O

O

O

NH

O

O

OMe

HN

PhI(OCOCF3)2O

O

OMe

NH

CF3CH2OH

CF3CH2OH

100%

PhI(OCOCF3)2 (PIFA)

CF3CH2OH

O

O

O

NH

32%

86%

O

O

OR

NH

R=H

R=TMS

O

O

O

NH

O

O

OTMS

NH

PIFA

PIFA

I

IPh

OCOCF3

O

O PhI(OCOCF3)2O

O

O

NH

CF3CH2OH

86%NEt

NEt

AcO AcO

O

O

OTMS

HN

PhI(OCOCF3)2O

O

O

NH

CF3CH2OH

42%

Br Br Br Br

53%

O

O

OTMS

HN

NEt

AcO

OTMS

NH

PhI(OCOCF3)2O

O

O

NH

CF3CH2OH

71%

EtN

AcO


First Total Synthesis of Discorhabdin C: Y. Kita et al J. Am. Chem. Soc. 1992, 114, 2175-2180.

NH

NH

O

HN

O

BrBr

Discorhabdin C

Route A

Route B

NH

NH

O

O

O

BrBr

NH

NH

O

HN

OH

BrBr

NH

NH

O

O

OH

BrBr

NH

NH

O

O

OH

BrBr

NH2

NH

O

OOH

BrBr

MeO

OH

CHO

MeO

OBn

MeO NH

CO2H

1) BnBr, K2CO3, EtOH, Reflux

2) N3CH2CO2Et, NaOEt, EtOH

1) Xylene Reflux

2) KOH, EtOH, Reflux

OBn

MeO

CO2Et

N3

Copper Chromite, quinoline, 215°C

OBn

MeO NH

N I-1)

2) MeI, 0°C

3) NaCN, H2O, 80°C

OBn

MeO NH

CN

OBn

MeO NH

1) H2, Raney Ni/NH3/EtOH

2) CF3COSEt,NaOMe

NHCOCF3 1) H2, Pd/C, EtOH

2) Fremy's Salt

O

MeO NH

NHCOCF3

O

OH

BrBr

NH2•HBr

TEA, Reflux

O

NH

NH

NHCOCF3

O

O

BrBr

NHR

NHR

NHR

O

NH

NH

NHCOCF3

O

OH

BrBr

OMe

OTMS

DCM

O

NH

NH

NHCOCF3

O

OTMS

BrBr PIFA,CF3CH2OH, R.T.

XNH

NH

O

HN

O

BrBr

Discorhabdin C

Intermediate A

73%68%

36%

78%

59%

58%

58%

N

O

SO3NaNaO3S

Fremy's Salt Review: Chem. Rev. 1971, 71, 229-246.

NHR


[The First] Total Synthesis of Discorhabdin C: Y. Kita et al J. Am. Chem. Soc. 1992, 114, 2175-2180.

NH

NH

O

HN

O

BrBr

Discorhabdin C

Route A

Route B

NH

NH

O

O

O

BrBr

NH

NH

O

HN

OH

BrBr

NH

NH

O

O

OH

BrBr

NH

NH

O

O

OH

BrBr

NH2

NH

O

OOH

BrBr

MeO

NHR

NHR

NHR

O

MeO NH

NHTEOC

O

X

TEOC=CO2(CH2)2TMS

Intermediate A

TsCl, t-BuOK, THF

O

MeO NTs

NHTEOC

O

N

MeO NTs

O

92%

Anhydrous TsOHMeCN

OH

BrBr

NH2•HBr

NaHCO3, EtOH, RefluxN

NH

NTs

O

OH

BrBr

51%

N

NH

NTs

O

OH

BrBr

OMe

OTMS

DCM

N

NH

NTs

O

OTMS

BrBr

NH

NH

O

HN

O

BrBr

Discorhabdin C

PIFA,CF3CH2OH, R.T.

42%

NHR


The Preparation of the Aza-Spirobicyclic System of Discorhabdin C via an Intramolecular Phenolate Alyklation: G. Kubiak, P. Confalone, Tet. Lett. 1990, 31, 3845-3848.

Ba(OH)2, Me2SO4

OH

OH

Pd/C, H2, DMF

OMe

OMe

Br2, HOAc, Fe

OMe

OMe

BrMOMO B(OH)2

Pd(Ph3P)4, Na2CO3, PhMe

92%85%

83%

OMe

OMe

MOMO

CAN

MeCN

O

O

MOMO

94%

1) HCl, 92%

2) Py•Br2•HBr, 87%

3) MOMCl, Base, 67%

O

O

MOMO

Br

Br

Br

OHH2N

2) MsCl, Py, DCM

67%

1)O

O

MOMO

Br

Br

NH

MsO

6N HCl

90%

O

O

HO

Br

Br

NH

MsO

t-BuOK

DMF, 80°C

O

O

O

BrBr

NH

33%

The Use of Hetrocyclic Chemistry in the Synthesis of Natural and Unnatural Products: Discorhabdin C P. Confalone, J. Het. Chem. 1990, 27, 31-46.

OH

CHO

OMe

1) Br2, HOAc2) Me2SO4

OMe

CHO

OMe

Br

80%

1) N3CH2CO2Me, NaOMe, 75%

OMe

OMe

Br

NH

CO2Me

MOMO B(OH)2

Pd(Ph3P)4, Na2CO3, PhMe

78%

OMe

OMe

NH

CO2Me

MOMO1) NaOH2) Cu, Quinoline3) POCl3, DMF

70%

5) HCl

6) Py•Br2•HBr

4) CAN, MeCN

O

O

NH

HO

Br

Br

CHO

71%2) Xylene, 140°C

O

O

NH

HO

Br

Br

CHO 1) MOMCl, DCM2) HO(CH2)2NH2, DMF

3) MsCl, Py, DCM

O

O

N

MOMO

Br

Br

CHO

MOM

1) 6N HCl, THF, 96%

2) tBuOK, DMF, 34%

MsOHN

O

O

N

O

BrBr

CHO

MOM

NH

1) CH3NO2, NH4OAc

2) NaBH4

O

O

N

O

BrBr

MOM

NH85%

NO2

Discorhabdin CX

O

O

i-PrO

i-PrO

Li OBn OH

O

i-PrO

i-PrO

OBn TFAA

Oi-PrO

BnO

O

79%

NTs

Li

OHi-PrO

BnO

O

TsN

50%

heat

i-PrO

BnO

NTs

OH

OH

FeCl3

i-PrO

BnO

NTs

O

O

76%

48%

An alternative squaric acid approach:

100%91%

Br

Br


Transition Metal-Diene Complexes in Organic Sythesis: Iron Mediated Approach to the Discorhabdin and Prianosin Alkaloids: H. Knölker, K. Hartmann, Synlett 1991, 428-430.

OMe

Fe(CO)3

O

NO2NAc

OMe

H2N

OMe

BF4

NAc

OMe

OMe

NH

OMe

(CO)3Fe

MeCN-20°C

O

NAc

OMe

OMe

NH

MeO

(CO)3Fe

52%

34%

Synthetic Studies on Tetrahydropyrroloquinoine-containing Natural Products: Synthesis of Discorhabdin C, Batzelline C and Isobatzelline C: S. Yamamura et al. Tetrahedron 1994, 2017-2028.

CHO

OMe

MeO NO2

1) Fe, HCl

2) CbzCl, Na2CO3

CHO

OMe

MeO NHCbz67%

1) Jones [O]2) CDI

3) NaN3, then !4) TMS(CH2)2OH

81%

NHTeoc

OMe

MeO NHCbz

1) H2, Pd/C

2) PhCHO, NaBH3CN

NHTeoc

OMe

MeO NHBn81%

O O

OEtNHTeoc

OMe

MeO

Cl

NBn

O

OEt

85%

1) H2, Pd-Black, HClO4

2) KOH, then DCC

OMe

MeO NH

O

HN

22%

1) BH3•SMe2

2) CAN51%

O

MeO NH

N3,5-dibromotyramine

74%

O

NH

NH

N

OH

BrBr

LiClO4

constantcurrentelectrolysisat 3 mA

O

NH

NH

N

O

BrBr

O

NH

NH

N

OH

Br

Br

24% 6%Discorhabdin C

Synthetic of 7,8-Dimethoxy-2-oxo-1,3,4,5-tetrahydropyrrolo[4,3,2-de]quinoline: A key Intermediate en Route to Discorhabdin C: M. Makosza et al. Synthesis 1997, 1131-1133.

OH

NO2

NO2

MeO 1) PhOCH2CN, t-BuOK, DMF

2) Me2SO4, NaHCO3, acetone

66%

OMe

NO2

NO2

MeO

CN

O

OEtBr

K2CO3MeCN

69%

OMe

NO2

NO2

MeO

CN

OEt

O

H2/PdCl2/Fe, EtOH, AcOH

4 days, 48%HN

NH

OMe

MeO

O

HN

NH

OMe

MeO

O

Discorhabdin C


A Biomimetic Approach to the Discorhabdin Alkaloids: Total syntheses of Discorhabdins C and E and Dethiadiscorhabdin D: K. Aubart, C. Heathcock, J. Org. Chem. 1999, 64, 16-22.

NTs

O

O

tyramine, MeCNNTs

O

O

NH

HO

TsN

O

O

NH

HO2:1

91%

CuCl2•2H2O, TEA, O2, MeCN

93%

NTs

O

O

NH

O

KOH, MeOH

NaOMe, MeOH

NH

O

O

NH

O

NH

O

O

NH

HO83%X

NH

OMe

OMe

1) (COCl)2, HNBn2, Et2O

2) LiAlH4, Et2O3) NaH, TsCl, THF

53%NTs

OMe

OMe

NBn2

2) Boc2O, DCM3) CAN, MeCN, H2O

1) H2, Pd(OH)2, EtOH

NTs

O

O

NHBoc

1) tyramine, O2, MeCN

49%NTs

O

O

NH

HONHBoc

+ other regioisomer

(3:2)

95%

NTs

O

N

X

TFA

NTs

O

O

NH

HONH3

X

NTs

O

NH

HON

OH

MeO NO2

1) BnBr, K2CO3, DMF2) Fe, HCl, H2O3) ICl, Et2O, Na2CO3

4) BrCHCH=CHCN5) 5% Pd(OAc)2, P(Ar)3, TEA, DCM

OBn

MeO NH

CN

53%

1) LiAlH4, Et2O2) Boc2O, DCM3) Ts2O, NaH, DMF

4) H2, Pd/C, MeOH5) Fremy's Salt, Acetone/H2O

50% O

MeO NTs

NHBoc

O

1) TFA, DCM

O

MeO NTs

N

NH2

HOR1

R2

O

NTs

N

NH

HO

R1

R2NaHCO3, EtOH

46-62%

O

NTs

N

NH

HO

R1

R2

3 equiv CuCl2, TEA, O2, MeCN

O

NTs

N

NH

O

R1R2

81-90%

R1=R2=HR1=R2=BrR1=H; R2=Br

NaOMe, MeOH

67-80%

O

NH

N

NH

O

R1R2

Discorhabdin EDiscorhabdin C

Paul KrawczukBaran Group Meeting The Discorhabdin Alkaloids

A Biomimetic Approach to the Discorhabdin Alkaloids: Total syntheses of Discorhabdins C and E and Dethiadiscorhabdin D: K. Aubart, C. Heathcock, J. Org. Chem. 1999, 64, 16-22.

O

NH

N

NH

O

H2, Pd/C, MeOH5 Min

O

NH

N

NH

O

PhNMe3Br369% CHCl3/TFA

O

NH

N

NH

OBr

Basic Alumina

O

NH

N

NH

O

Formal Total Synthesis of Damirones A and B, Batzelline C, Isobatzelline C, Discorhabdin C, and Makaluvamines A-D: J. Joule et al. J. Org. Chem. 1997, 62, 568-577.

N

MeMeO

MeO

fuming HNO3

N

MeMeO

MeO

NO2

N

CHOMeO

MeO

NO2I2, t-BuI, FeCl2 80°C

DMSO, TFAN

CH(OMe)2MeO

MeO

NO2MeOH, HCl, reflux

BH3•THF, then REDALClCO2Me N

CH(OMe)2MeO

MeO

NO2

CO2Me

H2, Pd/C, EtOH

N

CH(OMe)2MeO

MeO

NH2

CO2Me

1) 1 N HCl, THF, 55°C

N

MeO

MeO

TsN

CO2Me

2) Bu4NHSO4, NaOH, TsCl

N

OMeMeO NTs

MeO2C

7% overall

NH

CH(OMe)2MeO

MeO

NH2

Cl

1N HCl, THF, 40°C

N

O

MeO

HN

64%

Direct Synthesis of N,O-Acetal Compounds as Key Intermediates of Discorhabdin A: Y. Kita et al. Chem. Eur. J. 2006, 12, 4893-4899.

R3 R2

HO HNR1

C6F5I(OCOCF3)2 (2 equiv)MS 3Å

MeCN/MeOH10:1

R2

HNR1MeO

O R2

HO HNR1 MeCN/MeOH10:1

R2

HNR1MeO

reflux refluxO

NH

N

NH

O

OH

Br

MeCN/MeOH10:1

NaHCO3, RTO

NH

N

NH

O

MeO

Br

Discorhabdin A



79%


The First Total Synthesis of Discorhabdin A: Y. Kita et al. Angew. Chem. Int. Ed. 2002, 41, 348-350. and Y. Kita et al. J. Am. Chem. Soc. 2003, 125, 11235-11240.

NH

NH

O

HN

O

Br

Discorhabdin A

S

H

NH

NH

O

HNHO

Br S

NH

NH

O

HN

O

Br

RS NH

NH

O

HN

OH

Br

RS

NH

O

HN

MeO

OH

NH3

CO2Me

TrCl, TEA, DMF

100%

OH

NHTr

CO2Me

NBS, DMF

65%

OH

NHTr

CO2Me

Br

NTs

O

N

MeO

1) 0.1N HCl, MeOH

2)

OH

NH

Br

NTs

O

HN1) DIBAH, DCM, -78°C

2) TBSCl, DBU, DCM

OTBS

NHTr

Br

OTBS OTBS

TBAF, THF

100%

OH

NHTr

Br

OTBS

84%

54%

PIFA, MK10

CF3CH2OH, 30min45%

O

NH

Br

NTs

O

HN

OTBS

O

NH

NTs

O

HN

OTBS

Br

(3:2)desired

1) BF3•OEt22) HBr/AcOH

-78-4°C

O

NH

NTs

O

HN

O

~80%

exclusively

1) BF3•OEt22) HBr/AcOH

-78-4°C~80%

O

NH

NTs

O

HN

O

exclusively

Br Br

easily separable

1) BF3•OEt2

O

NH

MeO

Br

NTs

O

N2) Pb(OAc)4 DCM/MeOH

p-MeOBnSHBF3•OEt2

thenHBr/AcOH

O

NH

PMBS

Br

NTs

O

N

NH

NTs

O

HN

O

Br

S

H NH

NTs

O

HN

O

S

H

X

X=Br (trace)X=H (32%)

22%

NaOMe, MeOH 61%

NH

NH

O

HN

O

Br

(+) Discorhabdin A

S

H

Documents

The Discorhabdin Alkaloids - Scripps Research...O3S SO3Na Fremy's Salt Review: Chem. Rev. 1971, 71, 229-246. NHR Baran Group Meeting The Discorhabdin Alkaloids Paul Krawczuk [The First]