eac short lit 9-23-08.pptx
TRANSCRIPT
Total Synthesis of (—)-Kendomycin Jason T. Lowe and James S. Panek
Formal Synthesis of (—)-Kendomycin Featuring a Prins-Cyclization To Construct the Macrocycle
Kevin B. Bahnck and Scott D. Rychnovsky
Org. Lett. 2008, 10, 3813
J. Am. Chem Soc., 2008, ASAP.
Short Literature Presentation Erika A. Crane
September 23, 2008
O
Me
HO
OMe
O
H MeMe H
Me
H
MeMe
OH
HO
(-)-kendomycin 1
• Isolated in 1996 by Funahashi from Streptomyces violaceuber
• Endothelian receptor antagonist activity
• Antiosteoporotic agent • Broad-spectrum antibacterial
activity • Potent cytotoxicity (GI50 < 100 nM)
through proteosome inhibition
Retrosynthesis of (—)-Kendomycin (Panek)
O
Me
HO
OMe
O
H MeMe H
Me
H
MeMe
OH
HO
(-)-kendomycin 1
O
Me
Me
TBSO
H
H
OMe
MeTBSO
OMe
OH
Me
Me
Me
Me
2
O
Me
Me
TBSO
H
H
OMe
MeTBSO
OMe
Br
MeMeMe
Me
3
O
O
Me
Me
TBSO
H
H
OMe
MeTBSO
OMe
OMOM
5
OHC
MeMe
I OTBS
6
OBn
!PPh3Br
4OMe
MeBnO
OMeOHC
CO2Me
OTMS
SiMe2PhMe
7
8
[4+2]
Negishi cross-coupling
Wittig olefination
SmI2 assistedcyclization
acid-catalystring closure
MeOH
OHO
!!
Br
OMe
Me
OMe
TBSO
O
Br
OMe
Me
OMe
TBSO
O
O Br
OMe
Me
OMe
TBSO
O
O
1. i-PrOTMS, TMSOTf CH2Cl2, 77%
2. Cp2TiMe2, THF 85%
Me2AlCl, CH2Cl2
85%
J. Am. Chem. Soc. 2005, 127, 6948.
Smith et al.
Lee et al.
J. Am. Chem. Soc. 2004, 126, 14720.
CHO
Me
Me
OHMe
OCO
Me
NO
O
BnN O
O
Bn
O
Me
O
Sc(OTf)2, TEA, CH2Cl2
82%, dr = 7:1
NaBH(OAc)3, AcOH
84%. dr = 20:1
Me
OMe
O
Me
O
Other Syntheses of the THP ring of (—)-Kendomycin
OMe
Me
OMe
OMe
Me
OMe
MeO
OMe
Me
OMe
O Me
O
OMe
Me
OMe
OH
AcCl, TiCl4
C6H6
95%
mCPBAcat. TsOH
CH2Cl291%
KOH
EtOH/H2O90%
Synthesis 2002, 4, 557.
Synthesis of Aldehyde 8 (Panek)
OMe
Me
OMe
BnO
OMe
MeBnO
OMeOHC
810
OMe
Me
OMe
HO
9
1. Et2AlCl, (CHO)n
CH2Cl2
2. BnBr, K2CO3 acetone 78% 2 steps
PCC, CH2Cl2
85%
HO
Me
OH
SiMe2Ph
MeOH
PhMe2SiLi, ZnEt2
CuCn, THF90%
SiMe2Ph
MeO
O
OPMB
DCC, DMAP
CH2Cl2, 91%
CO2Me
OTMS
SiMe2PhMe
7
CO2H
OPMB
SiMe2PhMe
HOOPMB
O
LiHMDS, THF;TMSCl90% dr > 30:1
1. [sat. NaHCO3]; Adogen, MeI
2. DDQ, CH2Cl2/H2O3. TMSOTf, CH2Cl2
O
O
PMBO
Me
SiMe2Ph
Me
Li+
Synthesis of Crotylsilane 7 (Panek)
Org. Lett., 2005, 7, 1529.
PhMe2SiLi ZnEt2 (PhMe2Si)2Zn PhMe2SiCu!Zn(CN)2
active species: monosilyl copper complex
1-5 mol% Cu cat.
Chem. Com. 2005, 311.
Synthesis of THP 5 (Panek)
OMe
MeBnO
OMeOHC
CO2Me
OTMS
SiMe2PhMe
78
O
Me
H
H
OMe
MeBnO
OMe
11
MeO2C
O
Me
H
OMe
MeBnO
OMe
12
MeO2C
Me
HO
O
Me
H
OMe
MeTBSO
OMe
13
MeO2C
Me
TBSO
O
Me
H
OMe
MeTBSO
OMe
14
MeO2C
Me
TBSO
O
Me
H
OMe
MeTBSO
OMe
5
OHC
Me
TBSO
OMOM
Me
TMSOTf, CH2Cl2
87%, dr > 20:1
OMe CO2Me
Ar
Me
O
HO
OCl
1. m-CPBA, CH2Cl22. K2CO3, MeOH 50 % 2 steps !:" = 1:3
1. H2, PtO2, MeOH
2. TBSOTf, 2,6-lut., CH2Cl2 84 % 2 steps
1. Br2, propylene oxide2. Pd(PPh3)4, toluene
(n-Bu)3Sn
82% 2 steps
1. O3, MeOH/CH2Cl2; NaBH4
2. MOMCl, 2,6-lut., CH2Cl23. DIBAL-H, Et2O 84% 3 steps
OBn
!PPh3Br
4
O
Me
H
H
OMe
MeTBSO
OMe
18
Me
TBSO
OMOM
OMe
O
Me
H
H
OMe
MeTBSO
OMe
19
Me
TBSO
OMOM
Me
Me
O
Me
H
H
OMe
MeTBSO
OMe
20
Me
TBSO
OMOM
Me I
Me
O
Me
Me
TBSO
H
H
OMe
MeTBSO
OMe
OMOM
MeMeMe
Me
21
OTBS
1. n-BuLi, THF, 5
2. Raney Ni, EtOH3. (COCl)2, DMSO, Et3N 79% 3 steps
1. CBr4, Zn, PPh3
2. n-BuLi, THF; MeI 88 % 2 steps
1. SnH(n-Bu)3, PCy3, Pd(OAc)22. NIS, CH3CN
tBuLi, Et2O, 6, ZnCl2;
Pd(PPh3)4, THF
Synthesis of Aryl THP 21 (Panek)
MeMe
I OTBS
6
N
Me Me
O
OH
Me
I OTBS
Me N
Me Me
O
OH
Me
OTBS
Me
15
16
17
LDA, LiCl, THF
95%, dr > 30:1
1. NH3-BH3, LDA, THF
2. PPh3, I2, imidazole 83% 2 steps
PdCl2(PPh3)2 + 2Bu3SnH
Pd(PPh3)2 + H2 + 2Bu3SnCl
generation of catalytic species in Pd(0)-mediated hydrostannation
J. Org. Chem. 1990, 55, 1857.
O
Me
Me
TBSO
H
H
OMe
MeTBSO
OMe
OMOM
MeMeMe
Me
21
OTBS
O
Me
Me
TBSO
H
H
OMe
MeTBSO
OMe
Br
MeMeMe
Me
3
O
O
Me
Me
TBSO
H
H
OMe
MeTBSO
OMe
OH
Me
Me
Me
Me
2
O
Me
Me
TBSO
H
H
O
MeO
OMe
O
Me
Me
Me
Me
22
1. MgBr2!Et2O, EtSH
2. PPh3, Br2, CH2Cl23. CSA, MeOH/CH2Cl24. (COCl)2, DMSO, Et3N 74% 4 steps
SmI2, THF
60%
1. TBAF, THF
2. Dess-Martin 61% 2 steps
Completion of the Synthesis (Panek)
Synthesis completed in 26 steps in a 1.51% overall yield
Completion of the Synthesis (Panek)
H
O
Me
Me
TBSO
H
H
O
MeO
OMe
O
Me
Me
Me
Me
H
aq. HFCH3CN
H2O
O
Me
Me
TBSO
H
H
O
MeO
OMe
O
Me
Me
Me
Me
H
H
O
Me
Me
TBSO
H
H
O
MeO
O
Me
Me
Me
Me
23
OH
+H+
-MeOH
O
OH
Me
O
O
OH
OH
Me
O
O
O
Me
O
O
H
H
O
OH
Me
O
HO
H
O
Me
Me
HO
H
H
O
MeHO
O
Me
Me
Me
Me
1
OH
OH
-H+
-H+
-TBS
O
Me
O
O
OHHH
H
-H+
+H+
OH
O
Me
Me
TBSO
H
H
O
MeO
OMe
O
Me
Me
Me
Me
22
O
Me
Me
HO
H
H
O
MeHO
O
Me
Me
Me
Me
1
OH
O
Me
Me
TBSO
H
H
OMe
MeHO
O
Me
Me
Me
Me
2
OHMe
Me
Me
Me
Me
3
Me
O
O
Me
OMePhO2SO
Me
O
Me
OMeTBSO
Me
I
5OHMe
Me
Me
Me
I
4
Prins-mediatedmacrocyclization
Suzuki-Miyaura coupling
Retrosynthesis of (—)-Kendomycin (Rychnovsky)
Retrosynthesis of (—)-Kendomycin (Rychnovsky)
OR
Me
HO
Me
OMe
Me
OMe
OMe
X
H
H
HH
HO
R
Me
HO
Me
OMe
Me
OMe
X
MeO
H
H
HH
H
NOE interactions observed at -40°C when X = H
A : BX = H 93 : 7X = Br 1 : 5
Me
OMe
OMe
O
Me
O
Me
O
Me
OTBDPS
MeOMe
Me
Me
OMe
OMe
O
Me
HO
Me
O
Me
OTBDPS
MeO
MeOH:HCl (0.2M), rt
6 h, 92%, ds = 97:3
OHMe
Me
Me
Me
I
4
Me
Me
OTBDPS
Me
OTBDPS
I
Me
Me
O
I
Me
1011 12 B
O
O Cy
CyMe
1. Cp2Zr(H)Cl, PhH;
2. I2, CH2Cl2 89%
1. TBAF, THF, 93%
2. pyr•SO3, DMSO, CH2Cl2 85%
hexane, 90%
J. Am. Chem. Soc. 2004, 126, 14720.
N
Me Me
O
OH
Me1. LDA, LiCl, THF
1. CBr4, Zn, PPh3 CH2Cl2, 83%
2. n-BuLi, THF; MeI 99 %
I
OTBDPS
2. LiAlH(OEt)3
O
H
OTBDPS
Me
Me
OTBDPS
Synthesis of Vinyl Iodide 4 (Rychnovsky)
R H
O
N2
Si
Me
Me
Me
Li
RH
O LiN2
Si
Me
Me
Me
-TMSOLiHR
Colvin Rearrangement:
Synlett. 1994, 107.
Synthesis of Alkyl Iodide 5 (Rychnovsky)
OBn
Me
O
Me
14
OBn
Me
Me
15
OMe
Me
OMe
HO
OAc
Me
OMe
AcO
IOAc
Me
OMe
AcO
OBn
Me
Me
Me
OMeHO
O
Me
Me
BnO
17
16
18
19
Me
O
Me
OMeTBSO
Me
I
5
LiC(N2)TMS, Et2O
72%
PdCl2(PPh3)2, CuI
NEt3, DMF, 94%
aq. CsOH, EtOH89%
1. TBSCl, imid., CH2Cl2, 94%
2. Pd(OH)2/C, H2, THF, 99%3. I2, PPh3, imid, CH2Cl2, 94%
1. CAN, CH3CN!H2O; aq. Na2S2O4;
2. Ac2O, pyr. 75 % 2 steps3. NIS, HOAc, cat. H2SO4, 95%
OHMe
Me
Me
Me
Me
20
Me
O
Me
OMeTBSO
Me
O
Me
OMeTBSO
Me
I
5OHMe
Me
Me
Me
I
4
OHMe
Me
Me
Me
Me
3
Me
O
O
Me
OMePhO2SO
5, tBuLi, Et2O, 9-(MeO)-BBN;
4, DMF, aq. K3PO4, PdCl2(dppf)90%
1. TBAF, THF, 93 %2. HMTA, H2O, HOAc 76 %3. PhSO2Cl, i-PrNEt2, CH2Cl2 85%
O
Me
Me
X
H
H
OMe
MeHO
O
Me
Me
Me
Me
AcOH, BF3•OEt2, CH2Cl2
22 X = OAc or F; 33% or 48% 2 X = OH
O
Me
Me
TBSO
H
H
O
MeHO
O
Me
Me
Me
Me
1
OH1. IBX, DMF, 62%
2. aq. HF, CH3CN
KOH, EtOH, 95%
J. Am. Chem. Soc. 2004, 126, 14720.
Completion of the Synthesis (Rychnovsky)
PI THP Synthesis Other Interesting Transformations # of Steps
Smith Petasis-Ferrier Reaction, Petasis-Tebbe Methylenation, LA-Catalyzed Rearrangement
Ring-Closing Metathesis, BF3OEt2 Coupling, Sharpless Reduction
24 steps (longest linear)
Lee Myersʼ Pseudoephedrine Alkylation, Reduction, Lactonization
Wittig Olefination, Suzuki Coupling Reaction, LA-Catalyzed O-macroglycosidation
24 steps (longest linear)
Rychnovsky Prins Macrocyclization Parikh-Doering Oxidation Hoffmannʼs Borane Reaction, Sonogashira Coupling Reaction, 5-endo-dig Cyclization, Colvin Rearrangement, Suzuki-Miyaura Coupling Reaction Hydrozirconation Reaction, Corey-Fuchs Reaction, Myersʼ Pseudoephedrine Alkylation
24 steps (longest linear)
Panek [4 + 2] Annulation SmI2-assisted Macrocyclization, Negishi Coupling Reaction, Wittig Olefination, LA-catalyzed Hydroxymethylation Myersʼ Pseudoephedrine Alkylation, Corey-Fuchs Reaction, Swern Oxidation, Pd-Catalyzed Hydrostannation Stille Coupling, Cu-Catalyzed Silyl Zincation, Claisen Rearrangement Ozonolysis
26 steps 1.51 % yield