phd allylation project
TRANSCRIPT
Enantioselective Synthesis of Substituted Tetrahydrofurans from
Homoallylic Alcohols
Ondřej Kysilka
THFs in Natural Products
O
Galbacin
O R4R1
R2 R3
O O OO
HO
COONa
OMe
H H O
OHOHMonensin
O
R
OMe
O
Amphidinolide K fragment
OOMe
OMe
Caloptin
OMeO
MeO
MeO
OO
OMeHO O
O
OOHHO
MeO OMe
OMeO
MeO
OO
MeO OMe
Virgatusin
O
O
OO
O
O
2
Allylation with Trichlorosilane
R2 SiCl3
R1 H
O
R1
OHLewis base
R2 Lewis acid
R3 H
O
R3R2OH
R1 H
O+
**
*+
R1
O
R3
OHR1
O
R2
R3
+
R2
:
NO
OMe
MeO
METHOX
+
- OMeN
O-OMe
+
QUINOX
Chiral Lewis bases:
Malkov, A. V.; Kočovský, P. Eur. J. Org. Chem. 2007, 29-36. 3
Allylation with Bifunctional Disilane
Peng, F.; Hall D. G. J. Am. Chem. Soc. 2007, 129, 3070-3071.
SiCl3Me3Si
R1 H
O
R1
OHLewis base
Lewis acid
R2 H
O
R1
O
R2
+
+ **
Me3Si
R1
O
R2
+
Me3Si
O R2R1
* **
R1
O
R2
OH
Me3Si
Me3Si
:
SiCl3Me3Si
activated by Lewis base
activated by Lewis acid
4
Disilane - Synthesis
Me3SiOH
OTHP n-BuLi, then OTHP
Me3Si
PPTS, EtOH
(98%)
(83%)SiMe3I
OH
Me3Si
LiAlH4
(48%)
Me3SiCl
(Cl3C)2COPh3Por
NCS, Ph3P(80%)
(SOCl2; SOCl2 / amines; MsCl / LiCl; NCS / Me2S; Ph3P / CCl4 )
Cl3SiH, CuClEt3N, Et2O
(60%)(E)
Me3SiSiCl3
OH
Me3Si
H2
Lindlar cat.
Me3Si
OH
(Z)Me3Si
ClNCS, Ph3P
Cl3SiH, CuClEt3N, Et2O
Me3Si
SiCl3
5
Allylation with Bifunctional Disilane
Tol
SiMe3
OHO TolTol
+THF, 90 oC
syn anti
TolCH=O(TfO)2Sn(10 mol%)
* * **
*O TolTol
**
*
Tol
SiMe3
O
* *
OH
Tol
:
Tol
SiMe3
O
Tol+
Tol
SiMe3
O
Tol+
(TfO)2SnTfOCuTfOAgZnI2ZnCl2AlCl3Ph3SiClMe3SiOTfTfOH< 25 : 1
hexanebenzeneCCl4CH2Cl2CHCl3Et2O
THFAcOEtMeOHDMFDMSO
H
O OH
* *Me3SiSiCl3
X X SiMe3DMF, MeCN
X = H, Me, F, CF3, NO2 (85-92%; de > 98 : 2)
6
Allylation with Disilanes
Ar1
SiMe3
OHO Ar2Ar1
+THF
90 oC to 60 oCsyn anti
Ar2CH=O(TfO)2Sn
* * **
*O Ar2Ar1
**
*
< 25 : 1 to 1 : 3
OAr1
Ar2+
SiMe3
Ar1
SiMe3
O
Ar2
+
Ar1
SiMe3
O
Ar2
+
* *
* OAr1
Ar2
HMe3Si
+* O Ar2Ar1
**
*
Me3Si
+
O Ar2Ar1
syn
**
*
* *
kinetic
OHAr1
Ar2+
*
Me3Si
O Ar2Ar1**
*
Me3Si
+
O Ar2Ar1
anti
**
*
thermodynamic 7Malkov, A. V.; Kabeshov, M. A.; Barłóg, M.; Kočovský, P. Chem. Eur. J. 2009, 15, 1570-1573.
Enantioselective Allylation
R1
OSiCl3 R1
OH
-35 oC *+ * Catalyst*
Me3Si
SiMe3
R1 catalyst (loading %) yield (%) ee (%)
Ph KENPHOS (10) 37 16
Ph KENAMIDE (10) 23 10
p-F-C6H4 PINDIOX (10) 20 30
p-F-C6H4 PINDY (30) 0 n/a
p-F-C6H4 QUINDIOX (5) 4 69
N
ONP
H
HO
KENPHOS N
ONMeO
H
H
KENAMIDE
NO
NO
PINDIOX10
N N
PINDY11
N
N
OO
QUINDIOX 8
Enantioselective AllylationR1 catalyst (loading %) time yield (%) ee (%)
Ph METHOX (20) 7d 52 93
4 FC‑ 6H4 METHOX (15) 7d 45 97
4 CF‑ 3C6H4 METHOX (15) 7d 55 90
4 NO‑ 2C6H4 METHOX (20) 7d 46 94
3 MeOC‑ 6H4 METHOX (15) 7d 41 96
4-F-C6H4 QUINOX (20) 9d 45 89
4-CF3-C6H4 QUINOX (20) 9d 50 88
Ph ANET-RR (10) 12h 80 90
3 MeOC‑ 6H4 ANET-RR (5) 12h 73 77
4 CF‑ 3C6H4 ANET-RR (5) 12h 73 97
C5H11 ANET-RR (5) 12h 80 73
C3H7CH=CH ANET-RR (5) 12h 83 98
Ph ANET-SR (10) 12h 82 96
Ph ANET-SR (1) 24h 70 91
3 MeOC‑ 6H4 ANET-SR (5) 12h 71 87
4 CF‑ 3C6H4 ANET-SR (5) 12h 79 94
NO-OMe
+
QUINOX
N N-O -O
+ +
PhOANET-SR
N N-O -O
+ +
PhO
ANET-RR
NO
OMe
MeO
METHOX
+
- OMe
9
Tetrahydrofurans by Allylation
OF
95% ee (from 97% ee)94%
OF3C
90% ee (from 90% ee)95%
OO2N
91%
OO2N
80%
O
85%
O
88%
O
95% ee (from 98% ee)92%
OO
81%10
Tetrasubstituted Tetrahydrofurans
Me3SiSiCl3
R1
SiMe3
OHO R4R1
11
Tetrasubstituted Tetrahydrofurans
Me3SiOH
OTHP n-BuLi, then OTHP
Me3Si
PPTS, EtOH 55oC, 24 h
(10%)
(88%)SiMe3I
OH
Me3Si
LiAlH4
(60%)
Me3SiCl
NCS, Ph3P(82%)
Cl3SiH, CuClEt3N, Et2O
(0%)(E)
Me3SiCl Me3Si
OHOH
Me3Si
Me3SiBr
Mg/TMSCl
1)BuLi2)MeCHO
LiAlH4
(54%)NCS, Ph3P
(81%)
Mg/SiCl4
(38%)
(40%)
(0%)
Me3SiSiCl3
12
Tetrasubstituted Tetrahydrofurans
R1
SiMe3
OHCO2MeR1
SiMe3
OH?
CO2Me, Grubbs catalyst 1st generation
CO / MeOH / PdCl2 / Cu(OAc)2
CO2Me, Grubbs catalyst 2nd generation
Ph
SiMe3
O
CO2Me
O
no reaction
20-30% yield
13Forman, S.G.; Tooze, R. P. J. Organomet. Chem. 2005, 690, 5863-5866.
Tetrahydrofuran Targets
OMeO
MeO
OMeOMeMeO
OMe
Beilschmin B(cytotoxic)
OMeO
MeO
OO
MeO OMe
Virgatusin (antibacterial)
O
Ochnone (cytotoxic)
OHHO
O
O
HO
OH
HO
OH
OMeO
MeO
MeO
OO
OMeHO O
O
(cytotoxic)
OMeO
MeO
OOMeO
OMe
Beilschmin A(cytotoxic)
OO
O
Galbacin(hepatoprotective)
O
O
OMeO
HO
OHOMe
Verrucosin(antifungal)
OOMe
OMe
Caloptin(antiprotozoal)
O
O
14
Other Disilanes
OH
OTHP n-BuLi, then OTHPMe3Si
PPTS, EtOH 55oC, 24 h
(97%)
(90%)
Me3SiCl
OHMe3Si
LiAlH4
(71%)
Me3SiCl
(COCl)2DMF
Cl3SiH, CuClEt3N, Et2O
(60%)(E)
Me3Si85%
R1
SiMe3
OHR2CHOSn(OTf)2
R1CHO
TMSCl
R1
SiMe3
OTMS R2CHOSn(OTf)2
R1
OH
R2
OH95%
88%
SiCl3Me3Si
R1
90%
O R2R1
0%
Flamme, E. M.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 13644-13645.15
Other Disilanes
LiAlH4
(71%)
Cl3SiH, CuClEt3N, Et2O
MeO2C CO2MeNaH
(86%)SiMe3I
MeO2C CO2Me
SiMe3SiMe3
OH
SiMe3
Cl
NCS Ph3P
R1
OHSiMe3 R1CHO
R2CHOSn(OTf)2
O R2R1
82%
79%
90%
89%
SiMe3
SiCl3
Trost, B. M.; King S. A. J. Am. Chem. Soc. 1990, 112, 408-422. 16
Summary
SiMe3
SiCl3SiCl3Me3SiMe3SiSiCl3
R1
OHSiMe3
O R2R1
R1
SiMe3
OH
R1
OH
R2
OH
R1
OH
Me3Si
O R2R1
17
AcknowledgementsPavel KočovskýAndrei Malkov
Colin RobinsonIvana LuštickáJiří MikušekJoanna PhilipsLucie PotuckáMaciej BarłógMichal MájekMikhail KabeshovSigitas Stoncius
Thank you, for your attention!
18
syn/anti alcohol
19