enantioselective total synthesis of ecteinascidin 743 nan li
TRANSCRIPT
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.
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
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
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
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
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
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
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
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
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
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
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
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
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
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%
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
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
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
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
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
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.
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