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Discussion MeetingMechanisms
Stereoselective Construction of the Tricyclic Core of Neoliacinic Acid
Clark, J. S.; Baxter, C. A.; Dossetter, A. G.; Poigny, S.; Castro, J. L.; Whittingham, W. G.
J. Org. Chem. ASAP.
O O
O
HH
H
OH
OH
O
CO2H
Neoliacinic Acid
January 22nd, 2008
Université de Montréal
Retrosynthetic Analysis
Clark, J. S.; Baxter, . A.; Dossetter, A. G.; Poigny, S.; Castro, J. L.; Whittingham, W. G. J. Org. Chem. ASAP. 2
O O
O
HH
H
OH
OH
O
CO2H
Neoliacinic Acid
O
OH
HH
OH
OH
OR
OHAcO
OSiR3
OHH
OR
AcO
OSiR3
OHH
AcO
OSiR3
O
OHH
AcO
OSiR3
O
OOSiR3O
N2
H H
AcO
OOSiR3
OR
H H
O
OOSiR3
OR
H
O
N2
OHOSiR3
OR
H
Br
OO
H
+
Synthesis of Allylbromide
Clark, J. S.; Baxter, . A.; Dossetter, A. G.; Poigny, S.; Castro, J. L.; Whittingham, W. G. J. Org. Chem. ASAP. 3
O
OMeHO
Roche EsterAldrich: 5 g = 129.50 $
MeO2C
OTIPS OTIPS
TMSi) TMS MgCl
CeCl3, THF-78 °C - rt
SiO2ii)
90 %
OTIPS
BrNH
O 3.HBr
THF, Py-10 °C - rt
85 %
NH
O 3.HBr3
Pyrrolidone hydrotribromideAldrich: 100 g = 62.80 $
Mechanism of Allylsilane Formation (Miguel)
Clark, J. S.; Baxter, . A.; Dossetter, A. G.; Poigny, S.; Castro, J. L.; Whittingham, W. G. J. Org. Chem. ASAP. 4
MeO2C
OTIPS OTIPS
TMSi) TMS MgCl
CeCl3 (3.3 equiv)THF, -78 °C - rt
NH4Clii)
90 %
3 equiv
SiO2iii)
TIPSO
TMS MgCl
SiO2
TMS CeCl2THF-78 °C
CeCl3
O
MeO
OTIPS
TMS
OMeO
Cl2CeOTIPS
TMS
OMeO
Cl2Ce
OTIPS
TMS
O
TMS
CeCl2
OTIPSOHTMS
NH4Cl
OTIPS
SiO2 (H+)
TMSTMS
Peterson Olefination
Synthesis of Diazoketone
Clark, J. S.; Baxter, . A.; Dossetter, A. G.; Poigny, S.; Castro, J. L.; Whittingham, W. G. J. Org. Chem. ASAP. 5
NaH, THFreflux
OTIPS
Br
1,2:5,6-Di-O-isopropylidene-D-mannitolAldrich: 5 g = 52.50 $
1) NaIO4, H2ODCM, rt
2)
93 %
75 %
O
OPMB
H
OO
H
OH
OPMB
H
OO
H
OTIPSMgBr OPMB
CuI, THF-78 °C - rt
OHH
OO
HHO
H
OO
H
O
OPMB
HOTIPS
1) PPTS, (CH2OH)2THF, DCM, reflux
2)
88 %
NaIO4, H2OTHF, rt
Me2CCHMe, t-BuOH, H2O, rt
NaClO2,NaH2PO4
O H
O
OPMB
HOTIPS
O OH
O
OPMB
HOTIPS
ON2 i) i-BuO2CCl
Et3N, Et2O
ii)
94 % / 2 steps
CH2N2, Et2O, 0 °C
OO
H
HO
Oxidative Cleavage Mechanism (Sébas)
Clark, J. S.; Baxter, . A.; Dossetter, A. G.; Poigny, S.; Castro, J. L.; Whittingham, W. G. J. Org. Chem. ASAP. 6
R R
HO OH
IO O
O O- Na+
R R
O OH
IHOO
O O- Na+
R R
O O
IHO OHO O- Na+
PT PT
IO O
O O-
R R
O O
IHO OH
O O-
I (VII) I (V)
Na+ Na+
NaIO4, H2ODCM, rt
OH
OO
HOH
H
OO
HHO
H
OO
H
Grignard Addition Mechanism (Angélique)
Clark, J. S.; Baxter, . A.; Dossetter, A. G.; Poigny, S.; Castro, J. L.; Whittingham, W. G. J. Org. Chem. ASAP. 7
H
O
O
OH
H
O
O
O
H
O
O
O
MgBr OPMBCuI, THF
-78 °C
Cu
PMBO
+ MgBrI
H
O
O
O
BrIMg
O
O
O
BrIMgCu
Cu OPMB
H
OPMB
HO
O
O
H
OPMB
H
O
O
HOH
HPMBO
OH
OPMB
H
OO
HMgBr OPMB
CuI (1.65 equiv)DMS (excess)
THF, -78 °C - rt
OO
H
HO
1.5 equiv
Synthesis of Diazoketone
Clark, J. S.; Baxter, . A.; Dossetter, A. G.; Poigny, S.; Castro, J. L.; Whittingham, W. G. J. Org. Chem. ASAP. 8
NaH, THFreflux
OTIPS
Br
1,2:5,6-Di-O-isopropylidene-D-mannitolAldrich: 5 g = 52.50 $
1) NaIO4, H2ODCM, rt
2)
93 %
75 %
O
OPMB
H
OO
H
OH
OPMB
H
OO
H
OTIPSMgBr OPMB
CuI, THF-78 °C - rt
OHH
OO
HHO
H
OO
H
O
OPMB
HOTIPS
1) PPTS, (CH2OH)2THF, DCM, reflux
2)
88 %
NaIO4, H2OTHF, rt
Me2CCHMe, t-BuOH, H2O, rt
NaClO2,NaH2PO4
O H
O
OPMB
HOTIPS
O OH
O
OPMB
HOTIPS
ON2 i) i-BuO2CCl
Et3N, Et2O
ii)
94 % / 2 steps
CH2N2, Et2O, 0 °C
OO
H
HO
Oxidation Mechanism (G. Pelletier)
Zhao, M.; Li, J.; Mano, E.; Song, Z.; Tschaen, D. M.; Grabowski, E. J. J.; Reider, P. J. J. Org. Chem. 1999, 64, 2564-2566. 9
R OH
N
O
TEMPO
7 mol%
Phosphate buffer pH = 6-7MeCN
O
OHR
NaOCl (2 mol%)NaClO2 (2 equiv)
Oxidation Mechanism
Zhao, M.; Li, J.; Mano, E.; Song, Z.; Tschaen, D. M.; Grabowski, E. J. J.; Reider, P. J. J. Org. Chem. 1999, 64, 2564-2566. 10
N
O
TEMPO
NaO
Cl HO
Cl
Phosphate bufferpH = 6-7 N
OX
Cl
X=Cl, OH
N+OX-
RHO
Phosphate bufferpH = 6-7
+H
-H
NH
OO
R
N+O
H-O
R
andor
N
OH
Phosphate bufferpH = 6-7
HO
Cl
O
H R
H2O
H R
HO OH
R
OH
NaO
ClO
HO
ClO
Phosphate bufferpH = 6-7
Phosphate bufferpH = 6-7
OCl
O-H
HOO
HO R
R OH
N
O
TEMPO
cat.
Phosphate buffer pH = 6-7MeCN
O
OHR
NaOCl (cat.)NaClO2 (2 equiv)
Synthesis of Second Diazoketone
Clark, J. S.; Baxter, . A.; Dossetter, A. G.; Poigny, S.; Castro, J. L.; Whittingham, W. G. J. Org. Chem. ASAP. 11
1) Rh2(tfacam)4THF, reflux
2)
56 %
MeMgCl, THF-78 °C - rt
DDQDCM, H2O
rt100 %
DMPDCM
0 °C - rt90 %
O
OPMB
HOTIPS
ON2
OOTIPS
OPMB
H H
HO Ac2ODMAP
90 %
OOTIPS
OPMB
H H
AcO
TEAEt2O, rt
OOTIPS
H H
AcO
OOTIPS
H H
AcO
OOTIPS
H H
AcO
O
1) 2)
Me2CCHMe, t-BuOH, H2O, rt
NaClO2,NaH2PO4
O
H
O
OH
i) NaOMeMeOH, rt
ii)
75 % (2 steps)
(COCl)2C6H6, rt
iii) CH2N2Et2O, 0 °C
N2
Synthesis of Second Diazoketone (Vincent)
Clark, J. S.; Baxter, . A.; Dossetter, A. G.; Poigny, S.; Castro, J. L.; Whittingham, W. G. J. Org. Chem. ASAP. 12
Rh2(tfacam)4 (0.4 mol%)THF, refluxO
OPMB
HOTIPS
ON2
OOTIPS
OPMB
H H
O
Synthesis of Second Diazoketone (Vincent)
Clark, J. S.; Baxter, . A.; Dossetter, A. G.; Poigny, S.; Castro, J. L.; Whittingham, W. G. J. Org. Chem. ASAP. 12
Rh2(tfacam)4 (0.4 mol%)THF, refluxO
OPMB
HOTIPS
ON2
OOTIPS
OPMB
H H
O
O
OPMB
HOTIPS
O
Rh
H
O+
OPMB
HOTIPS
O -Rh+
ConcertedC-H Insertion
O+
OPMB
HOTIPS
O-
Rh+
O
OOTIPS
OPMB
H H
HH
Red. Elim.
Diazoketone Key Cyclization (Maude)
Clark, J. S.; Baxter, . A.; Dossetter, A. G.; Poigny, S.; Castro, J. L.; Whittingham, W. G. J. Org. Chem. ASAP.
Cu(hfacac)22 mol%
69 %(3:2, E:Z)
DCM, reflux
OOTIPS
H H
AcO
O
N2
OHH
AcO
OTIPS
O
OHH
O
H
AcO
OTIPS
+
16 %
13
Clark, J. S.; Baxter, . A.; Dossetter, A. G.; Poigny, S.; Castro, J. L.; Whittingham, W. G. J. Org. Chem. ASAP.
Cu(hfacac)22 mol%
69 %(3:2, E:Z)
DCM, reflux
OOTIPS
H H
AcO
O
N2
OHH
AcO
OTIPS
O
OHH
O
H
AcO
OTIPS
+
16 %
O+
OTIPS
HAcO
H-
O
Diazoketone Key Cyclization
14
Clark, J. S.; Baxter, . A.; Dossetter, A. G.; Poigny, S.; Castro, J. L.; Whittingham, W. G. J. Org. Chem. ASAP.
EtSH, AIBN
(3:2, E:Z)
OHH
AcO
OTIPS
O
C6H6, refluxO
HHAcO
OTIPS
O
m-CPBA
DCM, refluxO
HHAcO
OTIPS
O
O
OHH
AcO
OTIPSO
Cp2TiMe2THF, reflux
81 %
81 % (2 steps)
Al(Oi-Pr)3PhMe, refluxO
HHHO
OTIPSOH
OH
OH
OTIPS
HO
39 % 60 %
+
Mechanismand
CommentsJames M.
Oxygen Insertions
15
Clark, J. S.; Baxter, . A.; Dossetter, A. G.; Poigny, S.; Castro, J. L.; Whittingham, W. G. J. Org. Chem. ASAP.
OHH
AcO
OTIPS
O
N NCN
CN
C6H6, reflux
-N2
CN
CN
S EtH
SEt
OHH
AcO
OTIPS
O
OHH
AcO
OTIPS
O
SEtH
SEt
OHH
AcO
OTIPS
O SEt
Oxygen Insertions (Fred)
16
EtSH, AIBN
(3:2, E:Z)
OHH
AcO
OTIPS
O
C6H6, refluxO
HHAcO
OTIPS
O
Clark, J. S.; Baxter, . A.; Dossetter, A. G.; Poigny, S.; Castro, J. L.; Whittingham, W. G. J. Org. Chem. ASAP.
Al-Mediated Rearrangement (Louis)
17
Al(Oi-Pr)310 equiv
PhMe, reflux OHH
HO
OTIPSOH
OH
OH
OTIPS
HO
39 %60 %
+O
HHAcO
OTIPSO
Clark, J. S.; Baxter, . A.; Dossetter, A. G.; Poigny, S.; Castro, J. L.; Whittingham, W. G. J. Org. Chem. ASAP.
OHH
AcO
OTIPSO
O+
HOTIPS
RO
OHH
RO
OTIPSO+
Al-Oi-Pr
i-PrOi-PrO
O+
HHRO
OTIPSO
Ali-PrO
Oi-Pr
-Oi-Pr
H
OAl
Oi-Pr
Oi-Pr-Oi-Pr
OH
OTIPS
ROO+Al-
O
H
Oi-Pr
Oi-Pr
MeMe
OH
OTIPS
HOOH
Al-Mediated Rearrangement
18
Clark, J. S.; Baxter, . A.; Dossetter, A. G.; Poigny, S.; Castro, J. L.; Whittingham, W. G. J. Org. Chem. ASAP.
TESOTf2,6-lutidine
DCM, -78 °C
OsO4, NMO
Acetone, H2Ort, 80 %
m-CPBADCM, 0 °C
86 %
OHH
HO
OTIPSOH
OHH
TESO
OTIPSOTES
OHH
TESO
OTIPSOTES
OHOH
OHH
TESO
OTIPSOTES
OHOH
98 %
O
TEMPO, TBABNaOCl, NaHCO3
NaCl, 0 °C
1)
2) NaClO2,NaH2PO4
Me2CCHMe, t-BuOH, H2O, rt
OHH
TESO
OTIPSOTES
OHO
O
OH
OHH
TESO
OTIPS
O
OTES
+
44 %
CSADCM, rtO
HH
TESO
OTIPSTESO
OH O
OH
O 37 % (3 steps)
H
Final Cyclization
19
Clark, J. S.; Baxter, . A.; Dossetter, A. G.; Poigny, S.; Castro, J. L.; Whittingham, W. G. J. Org. Chem. ASAP.
O
HH
TESO
OTIPSTESO
OH O
OH
O
HO O
O
HH
H
OH
OH
O
CO2H
Neoliacinic Acid
Most Advanced Precursor
20
