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Hong Ren
The Wulff Group 04‐19‐09
O
O
O
O
O
O
O
O
O
O OO
O
O
O
O
HO
CO2H
H
H
H
H
H
H
H
H
H
H
Jackson, K. L.; Henderson, J. A.; Motoyoshi, H.; Phillips, A. J. Angew. Chem. Int. Ed. 2009, 48, 2346‐2350.
What is Norhalichondrin B?
O
O
O
O
O
O
O
O
O
O OO
O
O
O
O
HO
CO2H
H
H
H
H
H
H
H
H
H
H
Isolated from Halichondrin Okadai Kadota in 1986
Structure Elucidated in 1986
Exits Extraordinary in vitro and in vivo AnVtumor AcVvity
Halichondrin (Pacific Ocean in Japan)
Uemura, D.; Takahashi, K.; Yamamoto, T.; Katayama, C.; Tanaka, J.; Okumura, Y. J .Am. Chem. Soc. 1985, 107, 4796‐4798. Hirata, Y.; Uemura, D. Pure Appl. Chem. 1986, 58, 701‐710.
Strategy‐Level Analysis Showing Key DisconnecVons
O
O
O
O
O
O
O
O
O
O OO
O
O
O
O
HO
CO2H
H
H
H
H
H
H
H
H
H
H
Horner Wadswort Emmons
MacrolactonizaVon
Cross Metathesis
2 3
1
Jackson, K. L.; Henderson, J. A.; Motoyoshi, H.; Phillips, A. J. Angew. Chem. Int. Ed. 2009, 48, 2346‐2350.
O
O
TBSOH
HCO2Me
TBSO
CHO
PMB
+
O
O
O
O
O OO
O
O
O
O
H
H
H
H
H
H H
(MeO)2PO
TBSO
O
3
MacrolactonizaVon
Cross Metathesis
Strategy‐Level Analysis Showing Key DisconnecVons
Jackson, K. L.; Henderson, J. A.; Motoyoshi, H.; Phillips, A. J. Angew. Chem. Int. Ed. 2009, 48, 2346‐2350.
O
O
OPMB
O
O
H
H
H
H
TBSO
TBSO
O
OO
H
TBSO
OTBS
MeO2C
OHH H
Nozaki Hiyama Kishi
Tandem Ring‐opening/Ring‐closing Metathesis
4
5
O
O
O
O
O OO
O
O
O
O
H
H
H
H
H
H H
(MeO)2PO
TBSO
O
Strategy‐Level Analysis Showing Key DisconnecVons
O
O
OPMB
O
O
H
H
H
H
TBSO
TBSO
O
Nozaki Hiyama Kishi
O
OTBSO
H
H
H
H
OPMBTBSO
CHO
O
OPIv
IOMs
+
Jackson, K. L.; Henderson, J. A.; Motoyoshi, H.; Phillips, A. J. Angew. Chem. Int. Ed. 2009, 48, 2346‐2350.
4
6 7 Achmatowicz [O]‐Kishi [H]
Key ReacVons for the Synthesis of Compound 7
Jackson, K. L.; Henderson, J. A.; Motoyoshi, H.; Phillips, A. J. Angew. Chem. Int. Ed. 2009, 48, 2346‐2350.
O
OPIv
IOMs
Noyori Asymmetric HydrogenaVon of β ‐ ketoester
R
O O
OMe
RuCl2[(R)-BINAP] (0.05 mol%)
H2, MeOH R
OH O
OMe
FormaVon of THF Ring by Copper Catalyzed [2, 3] Sigmatropic Rearr.
O
O
N2
R2
R1
metal
- N2O
O
R2
R1 O
O
R1
R2
Kishi’s Protocol of Coupling ReacVon mediated by Cr(II)
O
CHO
OTIPS
20
(0.5 equiv) 22, Co–phthalocyanine, Mn,
Et3N·HCl, LiCl, TMSCl, DME, r. t. then TBAF
O
OH
21
OHI
+
I
I23
N
O
N Cr(Cl)2(THF)
SO2Me
22
Synthesis of Compound 7
Jackson, K. L.; Henderson, J. A.; Motoyoshi, H.; Phillips, A. J. Angew. Chem. Int. Ed. 2009, 48, 2346‐2350.
O
OPIv
IOMs
EtO2C OTIPS
O
14
1) [(S)-binapRuBr2], EtOH, 50°C,H2
2) allyl ethylcarbonate, (2.5 mol %) [Pd2(dba)3] , dppb, THF, 60 °C,
EtO2C OTIPS
O
1) LiOH, MeOH/THF (2 :3)
50%
2) (COCl)2, DMF, THF then CH2N2, Et3N, Et2O,
OTIPS
O
15
17
O
N2
60%
[Cu(acac)2] , THF, reflux
O
O
OTIPS
1891%
MePPh3Br, tBuOK, THF, r. t.
O
OTIPS
1999%
1) Sia2BH, THF then NaOH, H2O2,
2) Dess–Martin, NaHCO3, CH2Cl2,
O
CHO
OTIPS
2084%
Synthesis of Compound 7
Jackson, K. L.; Henderson, J. A.; Motoyoshi, H.; Phillips, A. J. Angew. Chem. Int. Ed. 2009, 48, 2346‐2350.
O
OPIv
IOMs
O
CHO
OTIPS
2084%
23 (2 equiv), 22 (0.5 equiv), Co–phthalocyanine, Mn,
Et3N·HCl, LiCl, TMSCl, DME, r. t. then TBAF
O
OH
2152%
OHI
PvCl, DMAP, pyridine, CH2Cl2
O
OPv
2487%
OHI
Ms2O, Et3N, DMAP, CH2Cl2
O
OPv
799%
OMsI
N
O
N Cr(Cl)2(THF)
SO2Me
I
I22 23
Key ReacVons for the Synthesis of Compound 6
Jackson, K. L.; Henderson, J. A.; Motoyoshi, H.; Phillips, A. J. Angew. Chem. Int. Ed. 2009, 48, 2346‐2350.
O
OPIv
IOMs
Brown CrotylaVon
Achmatowicz OxidaVon and Kishi ReducVon
Nozaki‐Hiyama‐Kishi ReacVon
(E)-crotylboraneRCHO
then NaOH, H2O2
OH
R1XCrCl2, NiII, Mn0
Cp2ZrCl2
R2 R3
O
R1 R2
OHR3
O
OTBS
HO tBuOOH, [VO(acac)2],CH2Cl2 then Et3SiH, TFA
CH2Cl2, -40 °CO
O
TBSOH H
27 86%26
Synthesis of Compound 6 O
OTBSO
H
H
H
H
OPMBTBSO
CHO
O
OPIv
IOMs
+
Jackson, K. L.; Henderson, J. A.; Motoyoshi, H.; Phillips, A. J. Angew. Chem. Int. Ed. 2009, 48, 2346‐2350.
O3 then Me2S O
OTES
CHO
H H
H H
O
O
methyl-!-iodoacrylate,0.22 mol% 35, Cr2Cl2, proton sponge,
LiCl, Mn, [NiCl2(dppp)], 2,6 - lutidine, Cp2ZrCl2, MeCN, r .t.
34
O
O
H H
H H
O
O
34TES CO2Me
OH
75%
PMBOC(=NH)CCl3, BF3•OEt2
O
O
H H
H H
O
O
TES CO2Me
OPMB
TBAF, THFO
O
H H
H H
O
O
CO2Me
OPMB
36
37
PPTS, MeOH
50%
TBSOTf, Et3N, CH2Cl2
O
O
H H
H H
TBSO
TBSO
CO2Me
OPMB
3887%
1) LAH, Et2O, 0 °C
2) Dess-Martin PeriodinaneCH2Cl2
O
O
H H
H H
TBSO
TBSO
CHO
OPMB
6
O
OTES
H H
H H
O
O
33
90%
O2S
NH
O
N
35
Synthesis of Compound 6 O
OTBSO
H
H
H
H
OPMBTBSO
CHO
O
OPIv
IOMs
+
Jackson, K. L.; Henderson, J. A.; Motoyoshi, H.; Phillips, A. J. Angew. Chem. Int. Ed. 2009, 48, 2346‐2350.
6
OOHC
OTBS(-)-Ipc2-(Z)-crotylborane
then H2O2, NaOH
OOHCOH tBuOOH, [VO(acac)2],
CH2Cl2 then Et3SiH, TFA
CH2Cl2, -40 °C
O
O
TBSOH H
25 30
31
75%
90%
1) TFA, H2O, CH2Cl2, -37 °C
2) Jones reagent, acetone, 0 °C to r. t.
O
O
H H
63%
O
O
H
NaBH4, MeOH, -10 °CO
OH
H H
32 80%
O
O
H H
LiBH4, THF, r. t. O
OH
H H
H H
HO
HO
2, 2- DMP, PPTS, CH2Cl2O
OH
H H
H H
O
O
TESCl, imidazole O
OTES
H H
H H
O
O
33 75%
DMF
Key ReacVons for the Synthesis of Compound 5
Jackson, K. L.; Henderson, J. A.; Motoyoshi, H.; Phillips, A. J. Angew. Chem. Int. Ed. 2009, 48, 2346‐2350.
Davies Asymmetric Synthesis of 8‐Oxabicyclo[3.2.1] octene
OO
H
TBSO
OTBS
MeO2C
OHH H
N2
O
OO
O
+
O
[Rh2(OOct)4] (1 mol %), hexane, reflux
O
O
O
O
O8
9
Synthesis of Compound 5
Jackson, K. L.; Henderson, J. A.; Motoyoshi, H.; Phillips, A. J. Angew. Chem. Int. Ed. 2009, 48, 2346‐2350.
OO
H
TBSO
OTBS
MeO2C
OHH H
N2
O
OO
O
+
O
[Rh2(OOct)4] (1 mol %), hexane, reflux
O
O
O
O
O8
959%
1) NaOMe, MeOH then LiOH, MeOH/H2O (2 :1) ; 2) DPPA, Et3N, PhMe/CH3CN (2 :1) then H2O, reflux ; 3) L-Selectride, THF, -78 °C to r. t. ; 4) H2C=CHCH(OMe)2, PPTS, PhMe, 45 °C
OO
H
H
OMe
O
O
16%
OMe
10
Grubbs II (3 mol %), H2C=CH2, PhMe, r. t.,
1171%
Sia2BH, THF then NaBO3, H2O,
Synthesis of Compound 5
Jackson, K. L.; Henderson, J. A.; Motoyoshi, H.; Phillips, A. J. Angew. Chem. Int. Ed. 2009, 48, 2346‐2350.
OO
H
TBSO
OTBS
MeO2C
OHH H
OO
H
H
12
OMe
HO
Jones reagent, acetone then TMSCHN2, MeOH/PhMe (1:3)
OO
H
H
MeO2C
13O
68%
6 steps
17% ovrall
OO
H
TBSO
OTBS
MeO2C
OHH H
5
Synthesis of Compound 4
Jackson, K. L.; Henderson, J. A.; Motoyoshi, H.; Phillips, A. J. Angew. Chem. Int. Ed. 2009, 48, 2346‐2350.
O
O
OPMB
O
O
H
H
H
H
TBSO
TBSO
O
O
OTBSO
H
H
H
H
OPMBTBSO
CHO
O
OPIvI
OMs
+
6 7
1) 1 % NiCl2/CrCl2, THF/DMF (4 :1) , r. t.;
2) KHMDS, THF, 0 °C,
O
OTBSO
H
H
H
H
OPMBTBSO
O
O
OPv39
1. LAH, Et2O, 0 °C ; 2. Dess–Martin, NaHCO3, CH2Cl2, r. t.; 3. H2C= CHMgBr, THF, 0 °C ; 4. Dess–Martin, NaHCO3, CH2Cl2, r. t.
59%
O
O
OPMB
O
O
H
H
H
H
TBSO
TBSO
O
4
70%
Synthesis of Compound 3
Jackson, K. L.; Henderson, J. A.; Motoyoshi, H.; Phillips, A. J. Angew. Chem. Int. Ed. 2009, 48, 2346‐2350.
OO
H
TBSO
OTBS
MeO2C
OHH H
5
O
O
OPMB
O
O
H
H
H
H
TBSO
TBSO
O
4
+
41 (20 mol %), PhMe, 80 °C
O
O
OPMB
O
O
H
H
H
H
TBSO
TBSO
OO
H
TBSO
OTBS
MeO2C
OHH H
O
40
62%
TBAF, AcOH, THF, r. t.
O
O
O
O
O OO
O
O
O
O
H
H
H
H
H
H H
(MeO)2PO
TBSO
O
3
Ru
O
Cl
Cl
NNo-Tolylo-Tolyl
i-Pr41
Synthesis of Compound 3
Jackson, K. L.; Henderson, J. A.; Motoyoshi, H.; Phillips, A. J. Angew. Chem. Int. Ed. 2009, 48, 2346‐2350.
O
O
OPMB
O
O
H
H
H
H
HO
HO
OO
H
HO
O
MeO2C
OHH H
O
41
CaCO3, DOWEX 50WX8-400, MeOH as workup
O
O
OPMB
O
O
H
H
H
H
HO
HO
OO
H
O
O
MeO2C
H H
42
O
TBSOTf, Et3N, CH2Cl2, 0 °C
64%
DDQ, CH2Cl2, pH 7 phosphate buffer
O
O
O
O
O OO
O
O
O
O
H
H
H
H
H
H H
(MeO)2PO
TBSO
O
3
Synthesis of Compound 3
Jackson, K. L.; Henderson, J. A.; Motoyoshi, H.; Phillips, A. J. Angew. Chem. Int. Ed. 2009, 48, 2346‐2350.
O
O
O
O
O OO
O
O
O
O
H
H
H
H
H
H H
(MeO)2PO
TBSO
O
3
O
O
OH
O
O
H
H
H
H
TBSO
TBSO
OO
H
O
O
MeO2C
H H
O
44
65%
1 m LiOH, THF, r. t.
O
O
OH
O
O
H
H
H
H
TBSO
TBSO
OO
H
O
O
H H
O
45
100%
2,4,6- trichlorobenzoyl chloride, Et3N, THF, r. t. then DMAP, PhMe, 80 °C
Synthesis of Compound 3
Jackson, K. L.; Henderson, J. A.; Motoyoshi, H.; Phillips, A. J. Angew. Chem. Int. Ed. 2009, 48, 2346‐2350.
O
O
O
O
O OO
O
O
O
O
H
H
H
H
H
H H
TBSO
TBSO
46
92%
PPTS, MeOH
O
O
O
O
O OO
O
O
O
O
H
H
H
H
H
H H
HO
HO
97%
47
Dess–Martin, NaHCO3,
CH2Cl2, r. t.
O
O
O
O
O OO
O
O
O
O
H
H
H
H
H
H H
(MeO)2PO
TBSO
O
3
Synthesis of Compound 3
Jackson, K. L.; Henderson, J. A.; Motoyoshi, H.; Phillips, A. J. Angew. Chem. Int. Ed. 2009, 48, 2346‐2350.
O
O
O
O
O OO
O
O
O
O
H
H
H
H
H
H H
OHC
HO
89%
48
dimethyl(diazomethyl)phosphonate (20 equiv), SnCl2 (3 equiv), CH2Cl2, r. t.
O
O
O
O
O OO
O
O
O
O
H
H
H
H
H
H H
(MeO)2PO
TBSO
O
3
74%
O
O
O
O
O OO
O
O
O
O
H
H
H
H
H
H H
(MeO)2PO
TBSO
O
3
Synthesis of Compound 2
Jackson, K. L.; Henderson, J. A.; Motoyoshi, H.; Phillips, A. J. Angew. Chem. Int. Ed. 2009, 48, 2346‐2350.
O
O
TBSOH
HCO2Me
TBSO
CHO
PMB
OOHC
OTBS
25
(-)-Ipc2- (E)-crotylborane then H2O2, NaOH O
OTBS
HO
26 71%
tBuOOH, [VO(acac)2],CH2Cl2 then Et3SiH, TFA
CH2Cl2, -40 °CO
O
TBSOH H
27 86%
1) 29, tBuLi, Et2O, -78 °C ; 2) Dess–Martin, CH2Cl2, r.t,; 3) O3, MeOH, pyridine then Me2S
7 steps, 33% overall
CHOOTBSO
H
HCO2Me
TBS
O
O
TBSOH
HCO2Me
TBSO
CHO
PMB
2862%
2
I
OPMB
29
The Final Game
Jackson, K. L.; Henderson, J. A.; Motoyoshi, H.; Phillips, A. J. Angew. Chem. Int. Ed. 2009, 48, 2346‐2350.
O
O
TBSOH
HCO2Me
TBSO
CHO
PMB
2
O
O
O
O
O OO
O
O
O
O
H
H
H
H
H
H H
(MeO)2PO
TBSO
O
3
+
18 (1 equiv), K2CO3, 18-crown-6, PhMe, 60 °C
O
O
O
O
O OO
O
O
O
O
H
H
H
H H
O
TBS
O
O
O
TBSOH
HCO2Me
TBSO
PMB
4983%
O
O
OTIPS
18
The Final Game
Jackson, K. L.; Henderson, J. A.; Motoyoshi, H.; Phillips, A. J. Angew. Chem. Int. Ed. 2009, 48, 2346‐2350.
O
O
O
O
O OO
O
O
O
O
H
H
H
H H
O
TBS
O
O
O
TBSOH
HCO2Me
TBSO
PMB
49
1) TBAF, AcOH, MeOAc/THF (2 :1), r. t.; 2) DDQ, CH2Cl2/MeOH (10 :1);
3) LiOH, THF/H2O (3 :1),
O
O
O
O
O
O
O
O
O
O OO
O
O
O
O
HO
CO2H
H
H
H
H
H
H
H
H
H
H
1
38%
