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Theoretical Synthesis of Biyouyanagin A
Maryon GinistyKim Laberge
Miguel St-OngeDavid Marcoux
Guillaume Barbe
Université de MontréalMarch 20th 2007
O
OO
Ph O
Biyouyanagin A
Retrosynthetic Analysis
[2+2]O
OO
Ph O
O
O
O
O
Ph O
O
O
OTBDPS
O
O OR
IO
O
OTBDPS
O
O
O
H
+OI
O
O
OTBDPS
OTMSO
OP
OMeO
MeO
O
NMe
Me
OH
Ph
N
O
O
Ph
RMyers
Meyers
NHK
HWE
R1
R2R3
R4 R5
Synthesis of R4
OH
P rice:111 $ f or 100 g
i) nBuLi, T MEDA,
Et2O, 0°C to rt
ii)
Et 2O , -78°C to rt
Br
Jones Reagent,
acet one, 0°C
OH O
OH1 2 3
Yong H. K., Lotoski J. A., Chong J. M .J . O rg. C hem . 2001 , 66 , 8248-8251.
OH
Jones Reag ent,
acetone, 0°CO
OH
S mith A. B., Toder B . H., Branca S. J., Dieter R. K.J . A m. C hem . Soc. 1981 , 103 , 1996-2008.
84 %
86 %
Synthesis of R4
O
OH
i) SOCl2, DMF, heating
ii)
TEA, THF, 0 °C
O
3
4
NH
Ph
OH
Me
Me MeN Me
HO Ph(R,R)-(-)-Pseudiephedrine
150$ / kilo
NH
Ph
OH
Me
Me
O
Cl Ph
TEA, THF, 0 °C
83 %
NMe
Ph
OH
Me O
Ph
mp = 102-104 °C
Myers, A. G., Yang, B. H., Chen, H., McKinstry, L., Kopecky, D. J., Gleason, J. L.J. Or g. Chem. 2001, 66 , 8248-8251.
Synthesis of R4
O
LDA, LiCl
THF, 0 °C
OH
O
HO-CH2-CH2- OH,
cat. d -tart ar ic acid,
AcOE t, reflux
90 %OH
Br2, PPh3, CH3CN,
- 10°C to 0°C to rt
75 %
O O
Br
O O
I
O O
1
4
O
5
O
O
Petrosk i R. J . S y nth. C om m. 2002 , 32 , 449-455.
6 7
7
MeN Me
HO Ph
M yers , A . G., Yang, B . H., Chen, H., M cK instry , L ., Kopeck y, D. J ., Gleason, J. L.J . Or g. C hem. 2001 , 66 , 8248-8251.
MeN
Ph
Me
HO
OH
5
O
O
LiH2NBH3
THF, 0 °C
Synthesis of R4
O
LDA, LiCl
THF, 0 °C
I
O O
4
O
5
O
O
7
MeN Me
HO Ph
M yers , A . G., Yang, B . H., Chen, H., M cK instry , L ., Kopeck y, D. J ., Gleason, J. L.J . Or g. C hem. 2001 , 66 , 8248-8251.
MeN
Ph
Me
HO
OH
5
O
O
LiH2NBH3
THF, 0 °C
IPh
L DA, LiClT HF, 0 °C
83 %
NMe
Ph
O H
Me O
MeNMe
Ph
OH
Me O
Me
Ph
95 % de
Synthesis of R4
O
LDA, LiCl
THF, 0 °C
I
O O
4
O
5
O
O
7
MeN Me
HO Ph
M yers , A . G., Yang, B . H., Chen, H., M cK instry , L ., Kopeck y, D. J ., Gleason, J. L.J . Or g. C hem. 2001 , 66 , 8248-8251.
MeN
Ph
Me
HO
OH
5
O
O
LiH2NBH3
THF, rt
THF, rt
91 %
NMe
Ph
OH
Me O
Me
OTIPS
97 % de
LiH2NBH3HO
Me
OTIPS
>95 % ee
Synthesis of R4
Hoveyda, A. H., E vans, D. A ., Fu, G . C. C hem . R ev. 1993 , 93 , 1307-1370.
OH
5
O
O
Rh+OH
5
O
O
OH
5
O
OH2
OH
Me Ph
OH
Me Ph
Me
7:1
OH
iPr CONHMe10:1
Me
OH
iP r CONHMe
Me
Me
PPh 2Ph2PRh+
BF4-
Synthesis of R4
Hoveyda, A. H., Evans, D. A., Fu, G. C. Chem. Rev. 1993, 93 , 1307-1370.
MO
H
OOH
(ent)
Synthesis of R4
Stork G ., Zhao K . T etr ahedr on Lett . 1989 , 30 , 2173-2174.
O
10
O
O
(COCl)2, DMSO
E t3N
11
Ph3PI
THF, HMPAOH
9
O
O DCM , - 78 °C to rt
OTBS
CHO
OPMB 73 % (Z:E= 13:1)
OTBS
OPMB
I
Ph3PI
THF, HMPA
I
O
i)
ii) aq. HClacetone
Synthesis of R5
H2N N
O
O i. LDA, THF, - 78 °Cii. MeI
N
OPh
O
HO
OHO
OH
Ph
OTsOH
Heat
Ph
1)
i. LDA, THF, - 78 °Cii. (CH2=O)n
2)
Meyers, A. I.; Brengel, G. P. Chem. Commun. 1997, 1-8.Meyers, A. I.; Harre, M.; Garland, R. J. Am. Chem. Soc. 1984, 1-8.
TBDPSCl, ImidazoleDCM
H2SO4
1)
BH3-DMSTHF
2)
BuOH
O
O
Ph
OHHO
O
Ph
OHOTBDPS
Synthesis of R5
B oya, B .; P ar ades, M. D.; Oz or es , L.; Alonso, R. J . O r g. C hem . 2000 , 65, 5960.
O
Ph
OHm-CPBA
OH
O
OPh
O
O
OTBDPS
OTBDPSO TBDPS
NaH(CH2O)n
O
O
OTBDPS
H+
THF
OO
NOMe
OO
O
OO
NOMe
OO
O80 %
NaH(CH2O)n
THF
Synthesis of R5
Ish ibas hi, F.; Taniguchi, E. Phy tochemi str y 1998, 49 , 613.
O
O
OTBDPS
O
O
OTBDPS
HOHO
O
O
OT BDPS
OTMSO
OP
OMeO
MeO
TMSCl, ImidazoleDCM
1)
2)
HO
O
POMe
O
OMe
CDC, DCM
OO
H
TBDMSOH
OO
H
TBDMSOH
HOHO
99 %
OsO 4, NMO
acetone/H2O
OsO4, NMO
acet one/H2O
Synthesis of R5
OsO4, NMO
O
O
OTBDPS
acet one/H2O O
O
OTBDPS
HOHO
O
O
OT BDPS
OTMSO
OP
OMeO
MeO
TMSCl, ImidazoleDCM
1)
2)
HO
O
POMe
O
OMe
CDC, DCM
N
H OOH SePh
HO
O
POMe
O
OMe
CDC, DCM
N
H OO SePh
O
PMeO
OMeO
Han, G .; LaP orte, M . G.; Folm er , J . J .; Werner, K. M.; Weinreb, S . M. J. Or g. Chem. 2000 , 65 , 6293.
88 %
Synthesis of R3
+NaH, THF
O
OMe
OMe
OMe
OMe(O Et)2P (O)CH2CO 2E t
NaH, THF
96%
Maloney, D. J.; Hec ht, S. M . Or g. Lett. 2005 , 7 , 4297-4300 .
HEW :
I
O
OI
O
O
OTBDPS
OTMSO
OP
OMeO
MeO
IO
O
OTBDPS
O
TMSO
O
O Et
O
6:1 t rans :cis
Synthesis of R3
aq. HCl
IO
O
OTBDPS
O
TMSO
O
1)
DMSO, (COCl) 2E t3N, DCM
-78oC to rt
2) IO
O
OTBDPS
O
O
O
H
Synthesis of R2
IO
O
OTBDPS
O
O
O
O
O
OTBDPS
O
O OR
O
O
OTBS
CHOI
OTBS
O
O
OTBS
OTBSHO
NHK:CrCl2/NiCl2 (0 .5%),
DMF 0.005 M
V ic tor, M . M .; de Meijere, A.; Pi lli , R. A . J .Or g. C hem . 2005, 65 , 5910-5916.
CrCl2/NiCl2 (0 .5%)DMF 0.005 M
H 1)
TBSCl, ImidazoleDCM
2)
R = TBS
74 %
Synthesis of R1
O
O
OTBDPS
O
O O R
Th ermodynamicor
Kinet icEno late Formation
1)
T f2O or PhNTf22)
R = TBS
O
O
O TBDPS
O
TfO OR
R = TBS
• Thermodynamic enolization– All cis configuration
– Tri-substituted alkene
• Kinetic enolization (system conformation)– The conformation of the system may position suitably a methylene
proton for kinetic cis,cis diene formation
Synthesis of R1
O
O
O TBDPS
O
Ph OR
R = TBS
O
O
OTBDPS
O
TfO O R
R = TBS
O O
Ph2CuLi
THF/Hex-40 °C
82 %
Ts us hima, K.; Mura i, A. C hem . Lett. 1990 , 5 , 761-764.
Ph2CuLi
THF/Hex-40 °C
OTf
Synthesis of R1
O
O
O
O
Ph O
O
O
OTBDPS
O
Ph OR
R = TBS
TBAF, THF1)
PDC, DCM2)
Synthesis of Biyouyanagin A
O
OO
Ph O1)
O
O
O
O
Ph O
Et2AlCl (0.2 mol%)DCM, -78 °C
2)
2+2
OTBS
OCH2CF3
O
+
OTBSCO2CH2CF3
Takusu, K.; Nagao, S.; Ihara, M. T etr ahedr on Let t. 2005, 46, 1005-1008.
93 %
93 : 7
Et2AlCl (0.2 mol%)DCM, -78 °C
Ph3P=CH2
Synthesis of Biyouyanagin A
O
OO
Ph O1)
O
O
O
O
Ph O
Et2AlCl (0.2 mol%)DCM, -78 °C
2)
2+2
OTBS
OCH2CF3
O
+
OTBSCO2CH2CF3
Takusu, K.; Nagao, S.; Ihara, M. T etr ahedr on Let t. 2005, 46, 1005-1008.
93 %
93 : 7
Et2AlCl (0.2 mol%)DCM, -78 °C
Ph3P=CH2
Synthesis of Biyouyanagin A
O
OO
Ph O1)
O
O
O
O
Ph O
Tf2NH (1 mol%)DCM, -78 °C
2)
2+2
OTBS
OMe
O
+
OTBSCO2Me
Inanaga, K.; Takusu, K.; Ihara, M. J . Am. Chem. Soc. 2005, 127, 3668-3669.
70 %
80 : 20
Tf2NH (1 mol%)DCM, -78 °C
Ph3P=CH2
• Theoric total synthesis in 22 linear steps• Key Steps include NHK macrocyclisation and transannular
[2+2] cycloaddition• Chiral auxiliaries approach (Myers and Meyers)
Conclusion
O
OO
Ph O
Biyouyanagin A
