enantioselective total synthesis of ecteinascidin 743 nan li

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Enantioselective Total Synthesis of Ecteinascidin 743 Nan Li

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Page 1: Enantioselective Total Synthesis of Ecteinascidin 743 Nan Li

Enantioselective Total Synthesis of Ecteinascidin 743

Nan Li

Page 2: Enantioselective Total Synthesis of Ecteinascidin 743 Nan Li

2

OMe

MeHO

N

N

OAc

Me

OO

S

OO

NHMeO

HO

OHH

HH

H

H

Me Ecteinascidin 743, a tetrahydroisoquinoline alkaloid, was isolated from the Caribbean tunicate Ecteinascidia turbinata by Rinehart and co-workers. This alkaloid attracted strong interest as a potential anticancer agent because of its combination of strong cytostatic properties and antitumor activity, and it has recently been approved for the treatment of soft tissue sarcoma and ovarian cancer.

(a) Corey, E. J. J. Am. Chem. Soc. 1996, 118, 9202. (b) Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 6552. (c) Zhu, J. P. J. Am. Chem. Soc. 2006, 128, 87. (d) Danishefsky, S. J. Angew. Chem., Int. Ed. 2006, 45, 1754.(e) Williams, R. M. J. Org. Chem. 2008, 73, 9594.(f) Fukuyama, T. Synthesis 2012, 44, 2743.(g) Fukuyama, T. J. Am. Chem. Soc. 2013, 135, 13684.

Page 3: Enantioselective Total Synthesis of Ecteinascidin 743 Nan Li

3

Corey, E. J. Total Synthesis of Ecteinascidin 743OMe

MeHO

N

N

OAc

Me

OO

S

OO

NHMeO

HO

OHH

HH

H

H

Me

OMe

MeMOMO

N

H

H

Me

CN

N

Me

OH

OO O

O

Me

O

N

O

CN

HN CO2Allyl

HO

OMe

OH

CH2

OHOH

OMe

OTBSTBSO

HN

CHO

AllylO

O

OO

Me

OH

NH

OO

+

OBn

O

O

MeCHO

OBnO

O

Me

O

OOMe

OMe

HN

OBnO

H

+ O

O

O

O

OMe

OMeOMe

OHHO

OMeO

Page 4: Enantioselective Total Synthesis of Ecteinascidin 743 Nan Li

4

HO O

On-BuLi, TEMED, 0 oC

then MeI, - 78 oC - rt

87%

NaH, DMF,

Et2O, 0 oC,

then MOMBr

90% MOMO O

O

MOMO O

O

Me

n-BuLi,THF, -30 oC

then DMF, 0 oC

64% MOMO O

O

Me

OHC

1. CH3SO3H,

DCM, 0 oC

2. NaH, DMF,

0 oC, then BnBr

86%

BnO O

O

Me

OHC

O

O

LDA, Et2O, CO2

- 40 oC - rt

76%

O

O

OH

O+ HO

OMe

OMeBOPCl, Et3N,

DCM, rt

73%

O

O

O

O

OMe

OMe

BnO O

O

Me

OHC

+

Piperidine, AcOH,PhH, rt

99%

OBnO

O

Me

O O

OOMe

OMe

O

Et3N HCOOH, Pd(PPh3)4,

THF, rt

94%

OBnO

O

Me

O O

OOMe

OMe

HO

P

O

Cl

NNO O

OO

Page 5: Enantioselective Total Synthesis of Ecteinascidin 743 Nan Li

5

(PhO)2P(O)N3, Et3N, 4 Å ms; 70 °C, BnOH

93%

OBnO

O

Me

O

OOMe

OMe

HN

OBnO

Rh[(COD))-(R,R)-DiPAMP]+BF4-

3 atm of H2

97%, 96% ee

OBnO

O

Me

O

OOMe

OMe

HN

OBnO

H

1. BF3 OEt2, H2O;

2. BF3 OEt2, 4 Å ms.73% O

O

Me

OBn

NCO2Bn

OO

OO

Me

OBn

N

O

BnO2C

O

10% Pd/C, H2

quantO

O

Me

OH

NH

OO

P

O

P

O

OMe

OHHO

OMeO

TBSCl, Et3N,DMAP, DCM

98%

OMe

OTBSTBSO

OMeO

DIBAL, DCM

- 78 oC

quant

OMe

OTBSTBSO

OH

PDC, 4 Å ms,DCM

99%

OMe

OTBSTBSO

O

+HO O

O O

Page 6: Enantioselective Total Synthesis of Ecteinascidin 743 Nan Li

6

piperidine, AcOH,tol, 3 Å ms.

92%

OMe

OTBSTBSO

CO2H

MeO2C

(PhO)2P(O)N3, Et3N, 4 Å ms; 70 °C, BnOH

89%

OMe

OTBSTBSO

HN

MeO2C

OBn

O

Rh[(COD))-(R,R)-DiPAMP]+BF4-

3 atm of H2

quant, 96%ee

OMe

OTBSTBSO

HN

MeO2C

OBn

O

10% Pd/C, H2

quant

OMe

OTBSTBSO

H2N

CO2Me

AllylOCOCl, pyr

93%

OMe

OTBSTBSO

HN

CO2Me

AllylO

O

DIBAL, DCM

- 78 oC

without furtherpurification

OMe

OTBSTBSO

HN

CHO

AllylO

O

OO

Me

OH

NH

OO

+

1. HOAc, KCN

OO

Me

OH

N

OO

CN

HN CO2Allyl

TBSO

OMe

OTBS

61%

allyl bromide,Cs2CO3

87%

OO

Me

O

N

OO

CN

HN CO2Allyl

TBSO

OMe

OTBS

CH2

1. DIBAL, Tol

- 78 oC

2. KF, MeOH.

OO

Me

O

N

O

CN

HN CO2Allyl

HO

OMe

OH

CH2

OH

Page 7: Enantioselective Total Synthesis of Ecteinascidin 743 Nan Li

7

CH3SO3H,3 Å ms, DCM

55%

OMe

OHHO

N

H

H

CO2Allyl

CN

N

OMe

OH

OO

1. Tf2NPh, Et3N, DMAP

2. TBDPSCl, DMAP.64%

OMe

OTfHO

N

H

H

CO2Allyl

CN

N

OMe

OTBDPS

OO

MOMBr, i-Pr2NEt

92%

OMe

OTfMOMO

N

H

H

CO2Allyl

CN

N

OMe

OTBDPS

OO

1. n-Bu3SnH, PdCl2(PPh3)2, AcOH, CH2Cl2, rt,

2. CH2O, NaBH3CN, HOAc.95%

OMe

OTfMOMO

N

H

H

Me

CN

N

Me

OTBDPS

OO

PdCl2(PPh3)2, SnMe4,

LiCl, 80 oC;

83%

OMe

MeMOMO

N

H

H

Me

CN

N

Me

OTBDPS

OO

(PhSeO)2O

82%

OMe

MeMOMO

N

H

H

Me

CN

N

Me

OTBDPS

OO

OH

OH

OOH

TBAF

91%

OMe

MeMOMO

N

H

H

Me

CN

N

Me

OH

OO

OOH

Page 8: Enantioselective Total Synthesis of Ecteinascidin 743 Nan Li

SCO2H

HNCO2Allyl

EDC HCl,DMAP

91%

DMSO, Tf2O, -40 oC;

i-Pr2NEt, 0 oC;

t-BuOH, 0 oC;

(Me2N)2CN-t-Bu;

Ac2O, ;

79%

OMe

MeMOMO

N

N

OAc

Me

OO

S

OO

CNH

HH

H

H

Me

NHAllylO

O

n-Bu3SnH, PdCl2(PPh3)2, AcOH, CH2Cl2, rt,

84%

OMe

MeMOMO

N

N

OAc

Me

OO

S

OO

CNH

HH

H

H

Me

H2N

DMF-CH2Cl2, rt;DBU; oxalic acid

70%N

OMe

PhSO3

+

OMe

MeMOMO

N

H

H

Me

CN

N

Me

OH

OO

OOH

+

OMe

MeMOMO

N

H

H

Me

CN

N

Me

O

OO

OOH

O

SNH

AllylO

O

8

Page 9: Enantioselective Total Synthesis of Ecteinascidin 743 Nan Li

9

OMe

MeMOMO

N

N

OAc

Me

OO

S

OO

CNH

HH

H

H

Me

O

+HO

MeONH2

Sillca gel, EtOH

82%

OMe

MeMOMO

N

N

OAc

Me

OO

S

OO

NHMeO

HO

CNH

HH

H

H

Me

1, CF3CO2H, H2O

2. AgNO3, H2O.77%

OMe

MeHO

N

N

OAc

Me

OO

S

OO

NHMeO

HO

OHH

HH

H

H

Me

Page 10: Enantioselective Total Synthesis of Ecteinascidin 743 Nan Li

10

Zhu, J. P. Total Synthesis of Ecteinascidin 743

OMe

MeHO

N

N

OAc

Me

OO

S

OO

NHMeO

HO

OHH

HH

H

H

Me

OMe

MeHO

N

N

OAc

Me

OO

S

OO

CNH

HH

H

H

Me

O

MeO

HO

NH2

OMe

MeAllylO

N

H

H

Alloc

CN

OH

N

HOMe

OH

OO

OMe

MeAllylO

N

H

H

Alloc

OH

OTBS

NH

MOMOMe

O OEt

OO

Me

OO

OMOM

Br

CO2Et

+

OMe

MeAllylO

AllocN

AcO

HO

H2N

OMe

MeHO

H2N

+

ONBoc

CHO OH

OHMe

HO

Page 11: Enantioselective Total Synthesis of Ecteinascidin 743 Nan Li

11

OH

OO

1. MOMCl, NaH,

Et2O/DMF, 0 oC to rt,

2. n-BuLi, B(OMe)3, THF

then AcOH, H2O2,0 oC to rt,

91.2%

OMOM

OO

HO LiCl, 3 Å MS, HFIP/tol, ethyl glyoxalate, rt,

97%

OMOM

OO

HO

OH

CO2Et

O2N

OS

O

O CF3

K2CO3, DMF, rt,

94%

OMOM

OO

TfO

OH

CO2Et

trimethyl boroxine, K3PO4,Pd(PPh3)4, dioxane, reflux

93%

OMOM

OO

Me

OH

CO2Et

SOBr2, benzotriazole, CH2Cl2, rt,

91%

Me

OO

OMOM

Br

CO2Et

OH

OHMe

1. TsCl, Et3N,

CH2Cl2, -70 oC

2. MeI, K2CO3,

acetone, 55 oC

84%

OMe

OTsMeTiCl4 in CH2Cl2,

Cl2CHOCH3,

0 oC - rt

85%

OMe

OTsMe

CHOquant

NaBH4, MeOH

THF H2O

0 oC

OMe

OTsMe

OH

Page 12: Enantioselective Total Synthesis of Ecteinascidin 743 Nan Li

12

PBr3, tol CH2Cl2,

0 oC - rt

96%

OMe

OTsMe

Br

Cat (10%), CsOH H2O,

CH2Cl2, -78 oC

85%, > 90 ee

N

H

O

N

Br

+ NPh

Ph CO2tBu

OMe

OTsMe

NH2

CO2tBu

1. LiBH4, MeOH, Et2O, rt2. aq 2 N NaOH, EtOH, reflux

90%

OMe

MeHO

H2N

HO

+O

NBoc

CHO AcOH, 3 Å MS, rtCH2Cl2/CF3CH2OH

84%

OMe

MeHO

HN

HO

O

NBoc

1. AllocCl,NaHCO3, CH2Cl2, rt.

2. AllylBr, Cs2CO3, DMF, rt,

3. Ac2O, pyridine, DMAP, CH2Cl2, rt.

70%

OMe

MeAllylO

AllocN

AcO

O

N

Boc

TFA in CH2Cl2, rt,

72%

OMe

MeAllylO

AllocN

AcO

HO

H2N

Page 13: Enantioselective Total Synthesis of Ecteinascidin 743 Nan Li

13

Me

OO

OMOM

Br

CO2Et

+

OMe

MeAllylO

AllocN

AcO

HO

H2N

TEA, MeCN, 0 oC

OMe

MeAllylO

N

H

H

Alloc

OAc

OH

NH

MOMOMe

O OEt

OO

91%, 3:1 dr

1. TBSCl, imidazole, DMF, rt,

2. K2CO3, MeOH, rt,91%

OMe

MeAllylO

N

H

H

Alloc

OH

OTBS

NH

MOMOMe

O OEt

OO

Dess-Martin , rt,then TMSCN, ZnCl2, rt,

78%

OMe

MeAllylO

N

H

H

Alloc

CN

OTBS

N

MOMOMe

O OEt

OO

1. LiBH4, MeOH,

THF, 0 oC

2. Ac2O, pyridine, DMAP, CH2Cl2.

64%

OMe

MeAllylO

N

H

H

Alloc

CN

OTBS

N

MOMOMe

OAc

OO

1. HF H2O, MeCN, rt.

2. Dess-Martin , rt, 93%

OMe

MeAllylO

N

H

H

Alloc

CN

O

N

MOMOMe

OAc

OO

1. TFA, CH2Cl2, rt.

2. K2CO3, MeOH, rt, 91%;

OMe

MeAllylO

N

H

H

Alloc

CN

OH

N

HOMe

OH

OO

SCAr3

COOH

NHTroc

+ EDCI, DMAP, CH2Cl2, rt.

95%

Ar = 4-OMe C6H4

Page 14: Enantioselective Total Synthesis of Ecteinascidin 743 Nan Li

14

OMe

MeAllylO

N

H

H

Alloc

CN

OH

N

HOMe

O

OO

O

NHTroc

Ar3CS

TFA, TFE, rt, then Ac2O, pyridine,DMAP, CH2Cl2.

77%

OMe

MeAllylO

N

N

OAc

Me

OO

S

OO

CNH

HH

H

H

Alloc

TrocHN

1. n-Bu3SnH, PdCl2(PPh3)2, AcOH, CH2Cl2, rt,

2. NaBH3CN, AcOH, HCHO, rt,

84%;

OMe

MeHO

N

N

OAc

Me

OO

S

OO

CNH

HH

H

H

Me

TrocHN

NO

Me

PhSO3

1. AcOH, Zn, rt,2. A, DMF-CH2Cl2, rt;DBU; citric acid

48%

A

OMe

MeHO

N

N

OAc

Me

OO

S

OO

CNH

HH

H

H

Me

O

NaOAc, EtOH, rt,

97%+

HO

MeONH2

OMe

MeHO

N

N

OAc

Me

OO

S

OO

NHMeO

HO

CNH

HH

H

H

Me

AgNO3, CH3CN-H2O, rt

93% Ecteinascidin_743

Page 15: Enantioselective Total Synthesis of Ecteinascidin 743 Nan Li

15

Fukuyama, T. Total Synthesis of Ecteinascidin 743

OMe

MeHO

N

N

OAc

Me

OO

S

OO

NHMeO

HO

OHH

HH

H

H

OMe

MeRO

N

N

OH

Me

OO CN

H

HH

H

OH

HO

R

Me

OMe

MeRO

N

N

OH

Me

OO O

H

HH

H

O

O

R

OMe

MeRO

N

N

OH

HH

R

Me

O

O

OR

Me

O

O

OR

N N

+

OMe

MeRO

N

N

OH

HH

R

OMe

OTfTfO

N

HN

OH

HH

Boc

MeO2C

OBn

OMe

OBn

NBoc

AcN

O

O

H

MeO2CAcN

NAc

O

O

MeO2C

H

+

OBn

OMe

OBn

O

Page 16: Enantioselective Total Synthesis of Ecteinascidin 743 Nan Li

16

OH

Me

OO

1. PhI(OAc)2,

MeOH, 0 oC;

2. NaCN,DMF/H2O,

0 oC to rt

37%

OH

Me

OO

CN

OBn

Me

OO O

NH2

1. BnBr, K2CO3, DMF, rt;

2. aq H2O2, K2CO3, DMSO, rt

1. PhI(OAc)2,

MeOH, 0 oC;

2. LiOH, EtOH/H2O, reflux, 83%

OBn

Me

OO

NH2

HN

NH

O

O

MeO2C

H Ac2O,

130 oC,

80% AcN

NAc

O

O

MeO2C

H

+

OBn

OMe

OBn

O

1. t-BuOK,THF,

-78 to 0 oC; DBU, 0 oC;

2. Boc2O, DMAP, THF, rt, quant

OBn

OMe

OBn

NBoc

AcN

O

O

H

MeO2C

1. H2 (750 psi), Pd/C, EtOAc,

2. H2NNH2H2O,

THF, rt; evaporation;

NaBH4, MeOH, 0 oC,

57%

OH

OMe

OH

NBoc

HN

OH

O

H

MeO2C

TFA, CF3CH2OH, rt; evaporation;

PhNTf2, DMAP, Cs2CO3, MeCN,rt,

88%

OMe

OTfTfO

N

HN

OH

HH

Boc

MeO2C

trimethylboroxine,

Pd(PPh3)4, K3PO4,

1,4-dioxane, 100 oC,

92%

Page 17: Enantioselective Total Synthesis of Ecteinascidin 743 Nan Li

17

OMe

MeTfO

N

HN

OH

HH

Boc

MeO2C

HCl, EtOAc, rt; ClCO2Me,

NaHCO3, H2O, 0 oC

91%

OMe

MeTfO

N

HN

OH

HH

CO2Me

MeO2C

1. L-Selectride,

THF, -42 oC;

2. CSA, tol, reflux. 55%

OMe

MeTfO

N

N

OH

HH

CO2Me

aq KOH, 1,4-dioxane, rt;

MOMCl, 0 oC,

95%

OMe

MeMOMO

N

N

OH

HH

CO2Me

OBn

Me

OO

NH2

+ BF3 OEt2, t-BuONO,

THF, -15 to 0 oC;

Pd2(dba)3, NaOAc,

MeCN/THF, 0 oC to rt;

OMe

MeMOMO

N

N

OH

HH

CO2Me

OO

Me

BnO

OsO4, K3[Fe(CN)6],K2CO3, quinuclidine HCl, MeSO2NH2,

t-BuOH, H2O, rt,

93%

H5IO6,

THF, 0 oC.

87%;

OMe

MeMOMO

N

N

OH

HH

CO2MeO

OH

HO

O

O

Me

OBn

H2, Pd/C, MeOH, rt;

OMe

MeMOMO

N

N

OH

HH

CO2MeO

OH

HO

O

O

Me

OH

m-xylene, 120 oC;

Red-Al, .-42 to 60 oC

76%

OMe

MeMOMO

N

N

OH

HH

CO2Me

OO

Me

BnO

HO

HO

Page 18: Enantioselective Total Synthesis of Ecteinascidin 743 Nan Li

18

OMe

MeMOMO

N

N

OH

Me

OO

H

HH

H

OH

Me

O

KCN, AcOH, rt,

98%

OMe

MeMOMO

N

N

OH

Me

OO

H

HH

H

OH

Me

CNHO

1. EDCI HCl, DMAP, CH2Cl2, rt,

NHAlloc

CO2HAcS+

2. H2NNH2H2O, MeCN, rt,85%

OMe

MeMOMO

N

N

OH

Me

OO

H

HH

H

OH

Me

CNO

O

NHAlloc

HS

TFA, CF3CH2OH, 25 oC; tol,

evaporation; Ac2O, pyridine, rt,;

55%

OMe

MeMOMO

N

N

OAc

Me

OO

S

OO

CNH

HH

H

H

Me

AllocHN

1. TFA, CH2Cl2,

2. (Ph3P)2PdCl2, AcOH, n-Bu3SnH,CH2Cl2, rt,

61%

OMe

MeHO

N

N

OAc

Me

OO

S

OO

CNH

HH

H

H

Me

H2N

DMF-CH2Cl2, rt;DBU; citric acid

54%

NO

Me

PhSO3

OMe

MeHO

N

N

OAc

Me

OO

S

OO

CNH

HH

H

H

Me

O

NaOAc, EtOH, rt.

MeO

HO

NH3Cl

96%

OMe

MeHO

N

N

OAc

Me

OO

S

OO

NHMeO

HO

CNH

HH

H

H

Me

Page 19: Enantioselective Total Synthesis of Ecteinascidin 743 Nan Li

19

Curtius rearrangement

R OH

O

+P

O

OPh

N3PhOR N3

OR

N C O

BnOHR

HN OBn

O

R N

O

NN

R N

O

NN

RN C O

Strecker reaction

R H

O KCN

NH4Cl R CN

NH2 H+

R CO2H

NH2

R1 R2

O+

R3

HN

R4R1 R2

NR3 R4 CN

R1 R2

NR3 R4

CN

Page 20: Enantioselective Total Synthesis of Ecteinascidin 743 Nan Li

20

DMSO, Tf2O, -40 oC;

i-Pr2NEt, 0 oC;

t-BuOH, 0 oC;

79%

OMe

MeMOMO

N

H

H

Me

CN

N

Me

O

OO

OOH

O

SNH

AllylO

O

F3C O

O

CF3

O

SOMe

Me

F3C O

O

CF3

O

O

S

F3C O

S

O

OH

R1R2

R3

+

HO

SOF3C

O

MeMe

R3

R1

R2

-CF3CO2H S

O R3

H

R1R2

S

O

CH2

R1R3

H

R2 R3

R1 R2

OMe

MeMOMO

N

H

H

Me

CN

N

Me

O

OO

O

O

SNH

AllylO

O

(Me2N)2CN-t-Bu

OMe

MeMOMO

N

H

H

Me

CN

N

Me

O

OO

O

O

SNH

AllylO

O

Ac2O

OMe

MeMOMO

N

N

OAc

Me

OO

S

OO

CNH

HH

H

H

Me

NHAllylO

O

i-Pr2NEt

Page 21: Enantioselective Total Synthesis of Ecteinascidin 743 Nan Li

Rapoport, H. J. Am. Chem. Soc. 1982, 104, 4446.

N

O

CH3PhSO3

+NH2

R2R1

N

N

CH3

R2R1

DBU

N

N

CH3

R2R1

- H+

N

N

CH3

R2R1

N

R2R1

N

Me

+H+

N

N

CH3

R2R1

N

NH2

CH3

+O

R2R1

OMe

MeHO

N

N

OAc

Me

OO

S

OO

CNH

HH

H

H

Me

TrocHN

NO

Me

PhSO3

DMF-CH2Cl2, rt;DBU; citric acid

70%

OMe

MeHO

N

N

OAc

Me

OO

S

OO

CNH

HH

H

H

Me

O

Page 22: Enantioselective Total Synthesis of Ecteinascidin 743 Nan Li

22

ArNH2

RONO

BF3

ArN2 BF4

N2BF4

OMe

+ OR

O

Pd/C (1 mol%)

MeOH

OMe

CO2R

OMe

MeMOMO

N

N

OH

HH

CO2Me

OBn

Me

OO

NH2

+ BF3 OEt2, t-BuONO,

THF, -15 to 0 oC;

Pd2(dba)3, NaOAc,

MeCN/THF, 0 oC to rt;

OMe

MeMOMO

N

N

OH

HH

CO2Me

OO

Me

BnO

1. Doyle, M. P. J. Org. Chem. 1979, 44, 1572.2. Beller, M. Synlett, 1995, 441.

Page 23: Enantioselective Total Synthesis of Ecteinascidin 743 Nan Li

23

Pictet-Spengler reaction

R1

R3

NH2

R2

+R4 R5

O protic or Lewis acid

protic or aproticsolvent, heat

R1

R3

N

R2

R4

R5R1

R3

NH

R2

R4 R5