université de montréal march 20th 2007
DESCRIPTION
Theoretical Synthesis of Biyouyanagin A Maryon Ginisty Kim Laberge Miguel St-Onge David Marcoux Guillaume Barbe. Université de Montréal March 20th 2007. Retrosynthetic Analysis. Synthesis of R4. Synthesis of R4. Synthesis of R4. Synthesis of R4. Synthesis of R4. Synthesis of R4. - PowerPoint PPT PresentationTRANSCRIPT
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