total synthesis of cribrostatin iv and et-743
DESCRIPTION
Total Synthesis of Cribrostatin IV and ET-743. Literature Meeting Presented by Nancy Labbé-Giguère January 30 th , 2006 Danishefvsky, S. et al , J. Am. Chem. Soc. 2005 , 127 , 4596-4598. D-amino acid. What is the structure of Fremy Salt? Mechanism of the reaction?. X. - PowerPoint PPT PresentationTRANSCRIPT
Total Synthesis of Cribrostatin IV Total Synthesis of Cribrostatin IV and ET-743and ET-743
Literature Meeting
Presented by Nancy Labbé-Giguère
January 30th, 2006
Danishefvsky, S. et al, J. Am. Chem. Soc. 2005, 127, 4596-4598.
N
NMe
O OO
H
H H
HO
OMe
Me
OHO
Me
MeO
O
Me
Me
O
N
NMe
CNHH
HO
OMe
Me
OAc
MeH
HS
OO
NH
HO
MeOO
O
Outline
1. Introduction
1.1. Properties 1.2 Natural Alcaloids and derivatives
2. Total Synthesis of Cribrostatin IV (Danishefsky)
2.1 Retrosynthetic Analysis 2.2 Total Synthesis (First Approach) 2.3 Total Synthesis (Second Approach)
3. Total Synthesis of (-)-Renieramycin G (Williams)
3.1 Retrosynthetic Analysis 3.2 Total Synthesis
4. Total Synthesis of (-)-Saframycin A (Myers)
4.1 Retrosynthetic Analysis 4.2 Total Synthesis
5. Total Synthesis of ET-743 (Corey)
5.1 Introduction and Retrosynthesis 5.2 Total Synthesis 5.3 Danishefsky's Approach to the Bridge lactone.
Known Cribrostatins and Renieramycins
N
O
O Me
Me
H2NNH
O
O Me
Me
RO
O N
O
O
Me
RHN
O
O
Me
Me
Cribrostatin I R = Et, Cribrostatin IIR = Me, Mimosamycin
R = H, Cribrostatin IIIR = Me, Cribrostatin V
N
NMe
OO
H
H H
O
OMe
OMe
OO
Me
MeO
O
Me
Me
R3
H
R1 R2R1=R2=H, R3=OH, Renieramycin AR1=R2=O, R3=OH, Renieramycin CR1=R2=O, R3=OEt, Renieramycin DR1=R2=O, R3=H, Renieramycin GR1=R2=O, R3=O, Renieramycin H
Renieramycin, from Sponge Reniera sp
Pettit, G. R. et al, J. Nat. Prod. 2000, 63, 793-798.
Tetrahydroisoquinoline Core
N
NR'
XOP
H
H H
R
R
Y
Cribrostation IV
- The core appears is several series of alkaloids, including naphthyridinomycin, quinocarcinoids, saframycins, renerramycins and ecteinascidins.
- Isolated in 2000 by Pettit from a blue marine sponge, Cribrochalina, in the Republic of Maldives1.
- Is a potent cytotoxic and antitumor agent.
- Known to have potential for treatment of breast cancer and several types of sarcoma.
- Is isolated as a trace amount. Total synthesis is required for evaluation of biological activity.
1. Pettit, G. R. et al, J. Nat. Prod. 2000, 63, 793.
- Member of Ecteinascidins - Propeller caracter
- One of the most Potent Cytotoxin known.
- Evaluated in clinical trial for treatment of cancer.
- More active than Taxol.
- Isolation: Rinehart in 1990.
- Total Synthesis: Corey in 1996
Fukuyama in 2002
Zhu in 2006
N
NMe
OHHH
HO
OMe
Me
OAc
MeH
HS
OO
NH
HO
MeOO
O
Comparaison between Cribrostatin IV and ET-743
N
NMe
O OO
H
H H
HO
OMe
Me
OHO
Me
MeO
O
Me
Me
- Member of Cribrostatin.- Oxidized form- Potent Cytotoxic Agent (micromolar).- Isolation: Pettit in 2000.- Total Synthesis: Danishefsky in 2005
O
Cribrostatin IV ET-743
Synthetic Strategy
N
NMe
O OO
H
H H
HO
OMe
Me
OHO
Me
MeO
O
Me
Me
N
NMe
OOP
H H
RO
OR
Me
OH
R1
O HH
NR2HN
OOP
H H
OH
R1
O
R1NHR1
OH
OP
+
A A
AAO
R2HN
CO2H
R
E E
EE
B
B
Amide Bond
Mannich
BO
Functionalized Subunits
N
NMe
O OO
H
H H
HO
OMe
Me
OHO
Me
MeO
O
Me
Me
O N
NMe
MeO OOBn
H H
O
OMe
Me
OTBS
Me
MeO
HO
O
N
OBnOMe
MeO
Me
O OH
O
NMeBoc
HOBn
OMe
Me
OPMB
NH
OBnOMe
MeO
Me
O OH
+
OMe
MeBnO
PMBO
CO2H
N
HBoc
Me
Cribrostatin IV
Left Fragment Right Fragment
OMe
MeO
Me
1. Cl2CHOMe, TiCl4
OH
HO
Me
CHO
97%
1. Br2, NaOAc, AcOH
2. BBr3, MeOH 2. Me2SO4, Bu4NBr NaOH, CH2Cl2
OMe
MeO
Me
CHO
Br
76% (2 steps)
1. mCPBA, CHCl3
2. HCl, MeOH
OMe
MeO
Me
OH
Br
TBDPSCl, Et3N
DMAP, DMF
78% (2 steps) 89%OMe
MeO
Me
OTBDPS
Br
Left Fragment Synthesis
N
NMe
O OO
H
H H
HO
OMe
Me
OHO
Me
MeO
O
Me
Me
1. n-BuLi, (9:1) PhMe:THF, -78 °C
2.
N
O
OBnMe
OMe
80% (2 steps)
O
MeO
MeO
Me
OTBDPS
O
OBn
Left Fragment Synthesis
N
NMe
O OO
H
H H
HO
OMe
Me
OHO
Me
MeO
O
Me
Me
(RuCl2)2(p-cymene)2DMF/HCO2H/Et3N, 40 °C
89%, 95% ee
MeO
MeO
Me
OTBDPS
OH
OBnPh
NH2
Ph
TosHN
DPPA, DBU
(9:1) PhMe;DMF, 50 °C
82%, 95% ee
MeO
MeO
Me
OTBDPS
N3
OBn
H2, Pd/C, EtOAc
80%
MeO
MeO
Me
OTBDPS
NH2
OBn
1. (MeO)2CHCHO, AcOH NaBH3CN, MeOH
2. TBAF, THF99% (2 steps)
O
Left Fragment Synthesis
N
NMe
O OO
H
H H
HO
OMe
Me
OHO
Me
MeO
O
Me
Me
MeO
MeO
Me
OH
NH
OBn
NaH, Allyl bromide
87%
MeO
MeO
Me
O
NH
OBn
8.0M HCl, Dioxane
97%NH
OBnOMe
MeO
Me
O OH
OMe
OMeOMe
OMe
Left Fragment Synthesis20% (16 Steps)
O
Left Fragment Synthesis
N
NMe
O OO
H
H H
HO
OMe
Me
OHO
Me
MeO
O
Me
Me
MeO
MeO
Me
OH
NH
OBn
NaH, Allyl bromide
87%
MeO
MeO
Me
O
NH
OBn
8.0M HCl, Dioxane
97%NH
OBnOMe
MeO
Me
O OH
OMe
OMeOMe
OMe
Left Fragment Synthesis20% (16 Steps)
Name of the last Reaction?
O
Left Fragment Synthesis
N
NMe
O OO
H
H H
HO
OMe
Me
OHO
Me
MeO
O
Me
Me
MeO
MeO
Me
OH
NH
OBn
NaH, Allyl bromide
87%
MeO
MeO
Me
O
NH
OBn
8.0M HCl, Dioxane
97%NH
OBnOMe
MeO
Me
O OH
OMe
OMeOMe
OMe
Left Fragment Synthesis20% (16 Steps)
Name of the last Reaction?Pomeranz-Fritsch cyclization
Bobbitt modification
Bobbitt, J. M., Sih, J. C. J. Org. Chem. 1968, 33, 856-858.Bobbitt, J. M., Moore, T. E. J. Org. Chem. 1968, 33, 2958-2959.
O
Right Fragment Synthesis
N
NMe
O OO
H
H H
HO
OMe
Me
OHO
Me
MeO
O
Me
Me
OH
MeHO TsCl, Et3NOH
MeTsO
84%
ICl, AcOH
96%
OH
MeTsO
I
MeI, K2CO3
95%
OMe
MeTsO
I
Acetone
NaOH, EtOH
OMe
MeHO
I
90%
(CH2O)n Et2AlCl
CH2Cl21
86%
OMe
MeHO
I
HO
O
1. For ortho-Hydroxyalkylation, see: Casiraghi, G. et al, J. Org. Chem. 1985, 50, 5018-5022.
Right Fragment Synthesis
OMe
MeHO
I
HO
BnBr, K2CO3
Acetone85%
OMe
MeBnO
I
HO
NaH, PMBCl
THF:DMF99%
OMe
MeBnO
I
PMBOMeO2C NHBoc
OTs(o-tolyl)3P, Pd(OAc)2
Et3N, TBAB, CH3CN
87% (Z isomer only)
OMe
MeBnO
PMBO
CO2Me
NHBoc
N
NMe
O OO
H
H H
HO
OMe
Me
OHO
Me
MeO
O
Me
Me
O
For Jeffery Heck reaction, see: Jeffery, T. J. Chem. Soc. Chem. Commun. 1984, 19, 1287-1289.Heck reaction with dehydroalanine gave lower yield due to polymerization.
+
OMe
MeBnO
PMBO
CO2Me
NHBoc
Rh(COD)-S,S)-Et-Duphos+-OTf
100 psi H2, CH2Cl2:MeOH1
93%, 99% ee
OMe
MeBnO
PMBO
CO2Me
NHBoc
H
LiOH, MeOH
H2O:THF
93%
OMe
MeBnO
PMBO
CO2H
NHBoc
H
NaH, THF
MeI
OMe
MeBnO
PMBO
CO2H
N
HBoc
Me
82%
Right Fragment Synthesis
N
NMe
O OO
H
H H
HO
OMe
Me
OHO
Me
MeO
O
Me
Me
O
1. Burk, M. J. et al, J. Am. Chem. Soc. 1993, 115, 10125-10138.
Right Fragment Synthesis31% (11 steps)
Fragment Coupling: Formation of Amide Bond
NH
OBnOMe
MeO
Me
O OH
+
OMe
MeBnO
PMBO
CO2H
N
HBoc
Me
BOPCl, Et3N
CH2Cl2 N
OBnOMe
MeO
Me
O OH
O
NMeBoc
HOBn
OMe
Me
OPMB89%
DDQ, CH2Cl2
Buffer (pH=7) N
OBnOMe
MeO
Me
O OH
O
NMeBoc
HOBn
OMe
Me
OH
N
OBnOMe
MeO
Me
O O
O
NMeBoc
HOBn
OMe
Me
O
DMP
90%84%
Mannich Cyclization: Formation of Pentacyclic Core
Results from Preliminary Studies:
Danishefsky, S. J. et al, Tetrahedron Lett. 2000, 41, 2043-2046.
Syn Product
Mannich Reaction: Formation of Pentacyclic Core
Results from Preliminary Studies:
N
OBnOMe
MeO
Me
OMe O
O
NMeBoc
H
Me
OMeO
OMe
HCO2H100 °C
87% N
NMe
MeO OOR
H H
MeO
OMe
Me
OMe
Me
MeO
O HH
OMe
Danishefsky, S. J. et al, Tetrahedron Lett. 2000, 41, 2043-2046.
N
OBnOMe
MeO
Me
O O
O
NMeBoc
H
Me
OBn HCO2H100 °C
N
NMe
MeO OOBn
H H
BnO
OMe
Me
O
Me
MeO
O HH
59%
O
D-amino acid
Pentacycle Synthesis
N
NMe
MeO OOBn
H H
BnO
OMe
Me
O
Me
MeO
O HH
1. NaBH4 (8:1) THF:H2O
2. (Ph3P)2PdCl2, Bu3SnH AcOH, CH2Cl2 N
NMe
MeO OOBn
H H
BnO
OMe
Me
OH
Me
MeO
OH HH
98% (2 steps)
CSA
Benzene, 80 °C
N
NMe
MeO OOBn
H H
BnO
OMe
Me
OH
Me
MeO
H
80%
H2, 5% Pd/C
EtOAc90%
N
NMe
MeO OOBn
H H
HO
OMe
Me
OH
Me
MeO
H
Pentacyclic Core is obtained
What is the structure of Fremy Salt?Mechanism of the reaction?
Towards Cribrostatin IV
N
NMe
MeO OOBn
H H
HO
OMe
Me
OH
Me
MeO
H
SeO2
Dioxane, 100 °C1
87%
Fremy Salt, KH2PO4
CH3CN:H2O
84%
N
NMe
O OOBn
H H
O
OMe
Me
O
Me
MeO
HO
N
NMe
O OOBn
H H
O
OMe
Me
O
Me
MeO
HO
OH
DMP, CH2Cl2
99% N
NMe
O OOBn
H H
O
OMe
Me
O
Me
MeO
HO
O
NNMe
O OO
H
H H
HOOMe
Me
OHO
Me
MeO
OMe
Me
O
1. For allylic oxidation related to the Saframycins: Kubo, A. et al, Tetrahedron, 1990, 46, 7711-7728.
Fremy Salt Oxidation - The Teuber Reaction
NSO3O3S
O
2K - Radical Character
- Unstable compound
OH
R
Fremy Salt
O
O
R
O
OR = H, OR', R''
p-benzoquinoneR = H, OR'
o-benzoquinoneR = R''
Reaction: Oxidation of Phenol and Aniline (very mild condition)
OH
OH
ON(SO3K)2
O
OH
O
HO
ON(SO3K)2
O
ON(SO3K)2HO
H3O+
O
O
Mechanism:
Zimmer, H.; Lankin, D. C.; Horgan, S. W. Chem. Rev. 1971, 71, 229-246.
X
End of the Synthesis
N
NMe
O OOBn
H H
O
OMe
Me
O
Me
MeO
HO
O N
NMe
MeO OOH
H H
HO
OMe
Me
OTBS
Me
MeO
HOH
O
1. H2, 10% Pd/C2. Air, MeOH
N
NMe
MeO OOH
H H
HO
OMe
Me
OTBS
Me
MeO
HOH
O
N
NMe
O OO
H
H H
HO
OMe
Me
OHO
Me
MeO
O
Me
Me
O
Cl
O
Me
Me
- Substrate unstable to mildly basic conditions.- Ketone was attacked by nucleophile. Cleavage of the β-dicarbonyl bond was observed.
New Approach to Cribrostatin IV
N
NMe
MeO OOBn
H H
BnO
OMe
Me
OH
Me
MeO
H 1. TBSOTf, Et3N2. H2, 5% Pd/C
81% (2 steps) N
NMe
MeO OOBn
H H
HO
OMe
Me
OTBS
Me
MeO
H
SeO2
Dioxane, 100 °C87%
Fremy Salt, KH2PO4
CH3CN:H2O
84%
N
NMe
MeO OOBn
H H
O
OMe
Me
OTBS
Me
MeO
HO
N
NMe
MeO OOBn
H H
O
OMe
Me
OTBS
Me
MeO
HO
OH
DMP, CH2Cl2
99%
N
NMe
MeO OOBn
H H
O
OMe
Me
OTBS
Me
MeO
HO
O
H2, 10% Pd/C
MeOH
90% N
NMe
MeO OOH
H H
O
OMe
Me
OTBS
Me
MeO
HO
O
End of the Synthesis
N
NMe
MeO OOH
H H
O
OMe
Me
OTBS
Me
MeO
HO
O
Cl
O
Me
Me
1.
CH2Cl2
2. TBAF, AcOH;THF
75% (2 steps)
N
NMe
MeO OO
H H
O
OMe
Me
OH
Me
MeO
HO
O
OMe
Me
1. PIFA, CH3CN:H2O2. Zn, AcOH
3. Air, DMF, 24 hrs.
65% (3 steps)
N
NMe
O OO
H
H H
HO
OMe
Me
OHO
Me
MeO
O
Me
Me
Cribrostatin IV
OA
E
8% (17 steps, from amide coupling)1.6% (37 steps, longer linear synthesis)
85% (average yield by step)
- Enantioselective synthesis- Convergent Synthesis- Efficient differentation of the quinone and hydroquinone function.
For the selective oxidation of ring A, see: Conant, J. B.; Fieser, L. F. J. Am. Chem. Soc. 1924, 46, 1858.
PIFA ??PIFA ??
N
NMe
O OOR
H
H
OOMe
Me
OO
Me
MeO
H
(-)-Renieramycin G Synthesis
N
OH OOR
OMeMe
MeO NMeR
CHO
MeO
Me
OMe
OH
NH
OHOR
OMeMe
MeO
CHO
O NMeR
MeO Me
OMe
OH
HO
CH2OH
MeO
Me
OMe
OBn
PPh3, I2
Imidazolequant.
O
NBoc
OPh
PhCH2I
MeO
Me
OMe
OBnNaHMDS, THF
88%
MeO
Me
MeO OBn
O
BocN
O
Ph
Ph
1. H2, Pd/C, MeOH
2. IBCF, NMM then NaBH4
89% (2 steps)
OMe
Me
MeO
OH
BocN
OH
Ph
Ph
H 1. TFA, CH2Cl22. TBSCl, Et3N
3. EtO2C-CHO, 50 °C
OMe
Me
MeO
OH
N
OTBS
Ph
Ph
H
CO2Et81% (3 steps)
Williams, R. D. et al, J. Am. Chem. Soc. 2005, 127, 12684-12690.
OMe
Me
MeO
OH
N
OTBS
Ph
Ph
H
CO2Et
1. DBU, THF2. LiBH4, THF
89% dr 3.3:1
OMe
Me
MeO
OH
N
OTBS
Ph
Ph
H
OH
OMe
Me
MeO
AllylO
NH
OTBS
H
OAllyl
67% (3 steps)
(-)-Renieramycin G Synthesis
+
CO2H
HNFmoc
OTBS
OMe
Me
MeO(COCl)2, DMF
2,6-lutidine, CH2Cl2MeO
Me
MeO OAllyl
N
H
OAllyl
TBSO
O
NHFmoc
MeO
MeOMe
OTBS
93%
84% (3 steps)
OMeMe
MeO
AllylO
N
H
OAllyl
HO
ONHBoc
MeOMe
OMe
OTBS
1. DMP2. TBAF
N
NBoc
OAllylMeO
Me
MeO
OAllylO
HOH OH
OMe
MeMeO
92%
51% (7 steps fromthe same precursor)
N
NBoc
OAllylMeO
Me
MeO
OAllylO
HOH OH
OMe
MeMeO
(-)-Renieramycin G Synthesis
1. TFA, CH2Cl2 anisole
2. HCHO, NaBH3CNN
NMe
AllylO OOAllyl
H
H
HOOMe
Me
OMeOMe
Me
MeO
H
71% (2 steps)
1. Bu3SnH, Pd(Ph3)4, AcOH2. 2,4-6-trichlorobenzoyl chloride Et3N, toluene, 95 °C
N
NMe
HO O
H
H
HOOMe
Me
OMeOMe
Me
MeO
H
HO
OMe
Me
(-)-Renieramycin G
N
NMe
O OOR
H
H
OOMe
Me
OO
Me
MeO
H
DDQ
63%
65% (2 steps)
For a racemic synthesis of Renieramycin, see: Magnus, P. Matthews, K. S. J. Am. Chem. Soc. 2005, 127, 12476-12477.
O
O
Me
Me
8% (23 steps)Longer linear Synthesis
N
NMe
O CNNH
H
H H
OOMe
Me
OO
Me
MeO
OMe
O
H
(-)-Saframycin A
N
NMe
OH CNNHFmoc
H
H H
HOOMe
Me
OMeOMe
Me
MeO
H
NH2
OH
OMeMe
MeO
CHOOH
OMe
Me
OMe
NH2
OHC
HCN
CH2O
CHO
NHFmoc
Myers, A. G., Kung, D. W. J. Am. Chem. Soc. 1999, 121, 10828-10829.
MultipleCondensation
(-)-Saframycin A: Synthesis
Me
OMeMeO
TBSO
CHOFmocHNH
+
OMe
MeHO
NC N
OMe
H2N
H
H
O
96% ee 92% ee
i. Na2SO4, CH2Cl2ii. LiBr, DME, 35 °C
72%
OMe
MeHO
NC N
OMe
N
H
H
O
FmocHN
OMe
Me
MeO
TBSO
HN
NNC
O
FmocHN
H
H
H
OMe
Me
MeO
TBSOHO
OMe
Me
OMe
H
1. CH2O-H2O NaBH(OAc)3
2. AcOH, TBAF; DBU, CH2Cl23. FmocNHCH2CHO
57%N
NNC
O
H2N
H
H
H
OMe
Me
MeO
HOHO
OMe
Me
OMe
H
Me
Amino nitrile used asa masked aldehyde
18% overall yield (8 steps)
(-)-Saframycin A: Synthesis
1. ZnCl2, TMSCN CF3CH2OH-THF
86% NH
NMe
OH
H
H
HOOMe
Me
OMeOMe
Me
MeO
H
FmocHNN
O
N
NNC
O
NH
H
H
H
OMe
Me
MeO
HOHO
OMe
Me
OMe
H
MeFmocHN
N
NMe
OH CNNHFmoc
H
H H
HOOMe
Me
OMeOMe
Me
MeO
H1. DBU, CH2Cl2
2.
Cl
O
Me
OPhNEt2, CH2Cl2
52% (3 steps)
N
NMe
O CNNH
H
H H
OOMe
Me
OO
Me
MeO
OMe
O
H
3. PhIO, CH3CN-H2O
(-)-Saframycin A
ET-743 - Introduction
N
NMe
OHHH
HO
OMe
Me
OAc
MeH
HS
OO
NH
HO
MeOO
O Isolation: 1990, Caribbean tunicate Ecteinascidia turbinateTotal Synthesis: Corey, E.J. et al, J. Am. Chem. Soc. 1996, 118, 9202-9203. Fukuyama, T. et al, J. Am. Chem. Soc. 2002, 124, 652-6554. Zhu, J. et al, J. Am. Chem. Soc. 2006, 128, 87-89.Other Studies: Manzanares, I. et al, Org. Lett. 2000, 2, 2545-2548. Danishefsky, S. J. et al, Org. Lett. 2002, 4, 43-46. Williams, R. M. et al, Org. Lett. 2003, 5, 2095-2098.
Ecteinascidin 743
N
NMe
CNH
MOMOOMe
MeO
MeH
H
OO
OH
O
O
NHS
AllylO2C
N
NP5
NCH
P3OOMe
OTfOP2
MeH
H
OO
P4O
OO
HO
Me
NH
H
OO
OMe
OP2TBSO
HN
HO
HGP KCN
OO
OH
i. NaH, DMF:Et2Oii. MOMBr
OO
OMOM
i. n-BuLi, TMEDAii. MeI
OO
OMOM
Me i. n-BuLi, THFii. DMF
OO
MOMO
MeH
O
64%87%90%
CH3SO3H, CH2Cl2
OO
HO
MeH
Oi. NaH, DMFii. BnBr
OO
BnO
MeH
O
86%
Synthesis of Left Fragment of ET-743
O
O
O
O
OMe
OMe
1. Piperidine, AcOH, PhH
93% (2 steps)O
O
BnO
Me
H
O OH
O
O
OMe
OMeOO
BnO
MeH
O
2. Pd(Ph3)4, Et3NHCO2H
Synthesis of Left Fragment of ET-743
OO
BnO
Me
H
O OH
O
O
OMe
OMe
i. (PhO)2P(O)N3, Et3Nii. BnOH
93% OO
BnO
Me
H
HN
O
O
OMe
O
O
PhH2C
H2 (45 psi), CH3OH:CH2Cl2RhCOD)R,R-DIPAMPBF4-
OO
BnO
Me
HN
O
O
OMe
O
O
PhH2C
OMe
OMe97%, 96% ee
H i. BF3OEt2, H2O, CH2Cl2ii. BF3OEt2, CH2Cl2
OO
BnO
Me
N
H
CO2CH2Ph
OO
73%
H2, Pd/C, EtOAc
OO
HO
Me
NH
H
OO
Quant.
Left Fragment
26% (14 steps)
OMe
OHHO
OMeO
1. TBSCl, Et3N CH2Cl2, DMAP
2. Dibal-H, CH2Cl23. PDC, CH2Cl2
OMe
OTBSTBSO
HO97% (3 steps)
MonomethylmalonatePiperidine, AcOH, PhCH3
OMe
OTBSTBSO
HHO2C
OMeO
1. i. (PhO)2P(O)N3, Et3N ii. BnOH
2. H2 (45 psi), CH3OH:CH2Cl2 RhCOD)R,R-DIPAMPBF4-
OMe
OTBSTBSO
HN
OMeO
HBnO2C
89% (2 steps), 96% ee
1. H2, Pd/C, EtOAc2. AllylOCOCl, pyr
93% (3 steps)
OMe
OTBSTBSO
HN
HO
HAllylO2C3. Dibal-H, CH2Cl2
Synthesis of Right Fragment of ET-743
Right Fragment
80% (9 step)
Quant.
OMe
OTBSTBSO
HN
HO
HAllylO2C OO
HO
Me
NH
H
OO
+KCN, AcOH
OO
HO
Me
N
H
OO
CN
HN
H
TBSOOMe
OTBS
CO2Allyl61%
Formation of Pentacycle
1. Cs2CO3, Allyl bromide2. Dibal-H, PhCH3
3. KF2H2O, MeOH
87% (3 steps) OO
AllylO
Me
N
H
OHO
CN
HN
H
HOOMe
OH
CO2Allyl
CH3SO3H CH2Cl2
N
NCO2Allyl
CNH
H
HO
MeOOH
AllylO
Me
HH
O O
HO
55%
N
NCO2Allyl
NCH
HOOMe
OTfOAllyl
MeH
H
OO
1. Tf2NPh, Et3N2. TBDPSCl, CH2Cl2
64%
TBDPSO
MOMBr, DIPEA
N
NCO2Allyl
NCH
MOMOOMe
OTfOAllyl
MeH
H
OO
TBDPSO
92%
N
N
NCH
MOMOOMe
OTfOAllyl
MeH
H
OO
TBDPSO
1.Bu3SnH, Pd(Ph3)4, AcOH, CH2Cl22. CH2O, NaBH3CN, AcOH, MeCN
3. SnMe4, (Ph3P)PdCl2, LiCl, DMF
79% (3 steps)
N
NMe
NCH
MOMOOMe
MeOH
MeH
H
OO
TBDPSO
CO2Allyl
Formation of Pentacycle
N
NMe
OHHH
HO
OMe
Me
OAc
MeH
HS
OO
NH
HO
MeOO
O
1. (PhSeO)2O, CH2Cl2
2. TBAF, THFN
NMe
NCH
MOMOOMe
MeO
MeH
H
OO
HO
OH
75% (2 steps)
SCO2H
HNCO2Allyl
+EDCHCl, DMAP
91%
End of the Synthesis
N
NMe
CNH
MOMOOMe
MeO
MeH
H
OO
OH
O
O
NHS
AllylO2C
1. Tf2O, DMSO, -40 °C2. (i-Pr)2NEt3. t-BuOH4.
N-t-Bu
(Me)2N N(Me)25. Ac2O
79% N
NMe
CNHH
MOMOOMe
Me
OAc
MeH
HS
OO
O
O
NHH
CO2Allyl
N
NMe
OHHH
HO
OMe
Me
OAc
MeH
HS
OO
NH
HO
MeOO
O
1. Bu3SnH, PdCl2(PPh3)2
2. DBU, DMF, CH2Cl2
NH
O
Me
N
NMe
CNHH
MOMOOMe
Me
OAc
MeH
HS
OO
O
O
O
NH2
HO
MeO
1. Silica gel, EtOH2. TFA, THF:H2O3. AgNO3, H2O
ET-74384%
45% (4 steps)
I
0,71% (37 steps)
?
OO
NBoc
OTBS
OH
Me
OMe
+HO2C
NHAlloc
SPMB EDC, DMAP, CH2Cl2O
O
NBoc
TBSO
O
Me
MeO
OSPMB
NHAlloc
Hg(O2CCF3)2
95%
80%O
O
NBoc
OH
O
Me
MeO
O SH
NHAlloc
TFA
95%
N
H
MeO
Me
S
OO
NHAlloc
O
O
Boc
Danishefsky's Approach to ET-743 Bridge Macrolactone Formation
Danishefsky, S. J. et al, Org. Lett. 2002, 4, 43-46.
N
NMe
OHHH
HO
OMe
Me
OAc
MeH
HS
OO
NH
HO
MeOO
O
NH
H
MeO
Me
S
OO
NH
HO
MeOO
O
4 steps
54%