Synthesis of Biyouyanagin A Philippe Murphy Daniel Beaudoin Lucie Zimmer Christian Perreault
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Synthesis of Biyouyanagin A Philippe Murphy Daniel Beaudoin Lucie Zimmer Christian Perreault Capt’n Alex Introduction Introduction O O Ph O O
description
Introduction. Synthesis of Biyouyanagin A Philippe Murphy Daniel Beaudoin Lucie Zimmer Christian Perreault Capt’n Alex. Retrosynthesis. p -Allyl Substitution. Enolate C-Acylation. Retrosynthesis. p -Allyl Substitution. Enolate C-Acylation. p -Allyl Substitution. Radical Allylation. - PowerPoint PPT Presentation
Transcript of Synthesis of Biyouyanagin A Philippe Murphy Daniel Beaudoin Lucie Zimmer Christian Perreault
Synthesis of Biyouyanagin A
Philippe MurphyDaniel Beaudoin
Lucie ZimmerChristian Perreault
Capt’n Alex
IntroductionIntroduction
O O
Ph
O
O
RetrosynthesisRetrosynthesis
-Allyl Substitution
Enolate C-Acylation
O O
Ph
O
O
OPh
O
PGO
RetrosynthesisRetrosynthesis
-Allyl Substitution
Radical Allylation
-Allyl SubstitutionEnolate C-Acylation
O O
Ph
O
O
OPh
O
OO
O
PGO Ph O
OE
PGO
RetrosynthesisRetrosynthesis
-Allyl Substitution
Radical Allylation
-Allyl Substitution
O-Alkylation
Enolate C-AcylationC-H Insertion
O O
Ph
O
O
OPh
O
OO
O
PGO Ph O
OE
PGO
Ph
OPG
OO
O
PGO
RetrosynthesisRetrosynthesis
-Allyl Substitution
Radical Allylation
-Allyl Substitution
O-Alkylation
Diels-Alder
SuzukiCoupling
Enolate C-AcylationC-H Insertion
O O
Ph
O
O
OPh
O
OO
O
PGO Ph O
OE
PGO
Ph
OPG
OO
O
PGO
Ph
OPG
OO
O
Ph
OPG
OO
O
OTf
Bpin
+
TBDPSO Ph
HO
Ph1) Kinetic Résolution with Novozym 435. (41%, >99%ee)1
TBDPSO Ph
BCatecholborane, THF
2) TBDPSCl, imidazole, DMF
O O
1 Xu, D.; Li, Z.; Ma, S. Tetrahedron Lett. 2003, 44, 6343
Preparing the Diels-AlderPreparing the Diels-Alder
TBDPSO Ph
HO
Ph1) Kinetic Résolution with Novozym 435. (41%, >99%ee)1
TBDPSO Ph
BCatecholborane, THF
2) TBDPSCl, imidazole, DMF
O O
OTfOO
O
OOO
Oa) KHMDS, THF, -78oCb) Comins reagent, THF
O
N
HO
a) DCM, CDIb) MeMgBr, THF, -78oC
O
OH 1 a) SOCl2, DCM b) CH3ONHCH3.HCl, pyridine (litt: 94%)2
2- Beta-AD mix3 (litt: 91%, >94% ee)2
Me OMe
HO
N N(Tf)2
Cl
1 Xu, D.; Li, Z.; Ma, S. Tetrahedron Lett. 2003, 44, 63432 Smith, N. D.; Goodman, M. Org. Lett. 2003, 5, 10353 (DHQD)2-PHAL and K2OsO2(OH)4
Preparing the Diels-AlderPreparing the Diels-Alder
Pd(PPh3)4, K3PO4
Dioxane
OTfOO
O
TBDPSO Ph
OO
O
TBDPSO Ph
BO O
Diels-Alder key stepDiels-Alder key step
Pd(PPh3)4, K3PO4
Dioxane
OTfOO
O
TBDPSO Ph
OO
O
TBDPSO Ph
BO O
Ph
OTBDPS
OO
O
Ph
OTBDPS
OO
O
NC Cl
2-ChloroacrylonitrileNC
Cl
HPh
OTDBPSMe
O
OO
Diels-Alder key stepDiels-Alder key step
Pd(PPh3)4, K3PO4
Dioxane
OTfOO
O
TBDPSO Ph
OO
O
TBDPSO Ph
BO O
Ph
OTBDPS
OO
O
Ph
OTBDPS
OO
O
NC Cl
2-ChloroacrylonitrileNC
Cl
HPh
OTDBPSMe
O
OO
Diels-Alder key stepDiels-Alder key step
Me
OR
Me
Me
OR
Me
O
O
O
PhMe, 105°C, 14 h
OO O
Me
OR
Me
O
O
O
HH+
A BR
BnTBDPS
TESTBMS
A/B
11.59.55.13.9
Gung, B. W.; et al. Chirality 1995, 7, 96.
52%75%77%53%
Why the D-A should workWhy the D-A should work
Me
OTMS
i-Pr
Me
OTMS
i-Pr
PhH, 50°C, 36 h72%
H
OMOMCHO
OMOM
Endo : Exo 97 : 03
McDougal, P. G.; Rico, J. G.; VanDerveer, D. J. Org. Chem. 1986, 51, 4494.
OHC
Me
OR
Me
Me
OR
Me
N
O
O
PhH, RT, 10 d
NO O
Me
OR
Me
N
O
O
HH+
A BR
TMSMe
A/B
7.35.0
Franck, R. W.; Argade, S.; Subramaniam, C. S.; Frechet, D. M. Tetrahedron Lett. 1985, 26, 3187.
75%-
Ph
PhPh
Tripathy, R.; Franck, R. W.; Onan, K. D. J. Am. Chem. Soc. 1988, 110, 3257.
Pd(PPh3)4, K3PO4
Dioxane
OTfOO
O
TBDPSO Ph
OO
O
TBDPSO Ph
BO O
Ph
OTBDPS
OO
O
Ph
OTBDPS
OO
O
NC Cl
2-Chloroacrylonitrile
Ph
OTBDPS
OO
O
PMBO Me
1. KOH
2. a) MeMgBr b) PMBBr
O
BrOMe
OPh
O
OO
O
PMBO MeO
OMe
O
TBAF
Diels-Alder key stepDiels-Alder key step
RetrosynthesisRetrosynthesis
O O
Ph
O
O
OPh
O
OO
O
PGO Ph O
OE
PGO
Ph
OPG
OO
O
PGO
Ph
OPG
OO
O
Ph
OPG
OO
O
OTf
Bpin
+
O-Alkylation
C-H Insertion
Tetrahydrofuran Ring-ClosureTetrahydrofuran Ring-Closure
PMBO
O
Ph
O O
OMe
PMBO
O
Ph
O O
OMe
N2
PMBO PhO
ORh2(OAc)4TfN3, Et3N
MeCN, rt
OO
O
OO
O
OO
O
E
Ph
O
O O
OMeMsN3, Et3N
MeCN, rt47%
Ph
O
O O
OMe
N2 Rh(OAc)2, 0.5mol%
DCM, 0°C (trans)DCM, reflux (cis)59%
O
O
Ph
COOMe
Ye T.; McKervey, M. A.; Brandes, B. D., Doyle, M. P. Tetrahedron Lett. 1994, 35, 7269.
Ph
O O
OMe
TsN3, Et3N MeCN, rt87%
Ph
O O
OMe
N2
Rh2(OAc)4
DCM, rt, 30 min
O
COOMe
Ph
after decarboxylation56%, >98%ee
Müller, P.; Boléa, C. Hel. Chim. Acta 2002, 85, 483.
Tetrahydrofuran Ring-ClosureTetrahydrofuran Ring-Closure
PMBO
O
Ph
O O
OMe
PMBO
O
Ph
O O
OMe
N2
PMBO PhO
ORh2(OAc)4TfN3, Et3N
MeCN, rt
OO
O
OO
O
OO
O
E
RetrosynthesisRetrosynthesis
Radical Allylation
-Allyl Substitution
O O
Ph
O
O
OPh
O
OO
O
PGO Ph O
OE
PGO
Ph
OPG
OO
O
PGO
Ph
OPG
OO
O
Ph
OPG
OO
O
OTf
Bpin
+
O
HO
Ph
O
PMBO
EOO
O
PMBO Ph O
OEPd(dppe)2 (5 mol%)
Cyclobutane FormationCyclobutane Formation
MeO2C
CO2Me
O
Pd(dppe)2 (5 mol%)
THF, refluxCO2Me
CO2Me
HO
CO2MeMeO2C
OH
Exclusive productSyn:Anti = 4:1
+
Zucco, M.; Le Bideau, F.; Malacria, M. Tet. Lett. 1995, 36, 2487
O
HO
Ph
E O
O
HO
Ph
E O
H2,
[Rh(nbd)(diphos-4)]BF4
or
1) Sia2BH
2) AcOHPMBO PMBO
LiCl, DMSO,
O
HO
Ph
O
PMBO
Double Bond ReductionDouble Bond Reduction
O
HO
Ph
E O
O
HO
Ph
E O
H2,
[Rh(nbd)(diphos-4)]BF4
or
1) Sia2BH
2) AcOHPMBO PMBO
LiCl, DMSO,
O
HO
Ph
O
PMBO
H2, 800 psi[Rh(nbd)(diphos-4)]BF4
THF
Me
OH
Me
OHH
Hoveyda, A. H.; Evans, D. A.; Fu, G. C.; Chem. Rev. 1993, 93, 1307
(d.r., 70 : 1)
O
1) Me3SiCH2MgCl2) H3O+
3) Sia2BH4) H2O2, NaOH OH
OH
SiMe3
KHOH
Negishi, E-.I.; Boardman, L. D.; Tour, J. M.; Sawada, H.; Rand, C. L. J. Am. Chem. Soc. 1983, 105, 6344
Double Bond ReductionDouble Bond Reduction
RetrosynthesisRetrosynthesis
O O
Ph
O
O
OPh
O
OO
O
PGO Ph O
OE
PGO
Ph
OPG
OO
O
PGO
Ph
OPG
OO
O
Ph
OPG
OO
O
OTf
Bpin
+
-Allyl Substitution
Enolate C-Acylation
Putting the Side Chain in PlacePutting the Side Chain in Place
HOBr
(Bu3Sn)2, h
PhH, RT, 13 h74%
HO
SPh
Keck, G. E.; Byers, J. H. J. Org. Chem. 1985, 50, 5442.
OPh
O
PMBO
O
HO
Ph
O
PMBO
1. PPh3, I2, imidazole
2.
(Bu3Sn)2, h
SPh
OPh
O
1. DDQ2. Martin's Sulfurane
Final CyclizationFinal Cyclization
O
N
Me
OMe
OHHO
O
HOH
TBSO
OCO2MeONC
O
OCO2MeTBSO1) TBSCl, imidazole
2) LAH
1. MeOCOCl, Et3N
2. Ph3P=CH2
1) Pyr.HF2 a) COCl2 b) KCN
O
O
PhO
Ph
OO
O
OCO2Me
OOCO2Me
O
NC
1a) KH
b)
O O
Ph
O
OO
Ph
OO
O
OCO2MePd
OAc
CO2Et
CO2Et CO2EtCO2EtNaH, Pd(Ph3P)4
THF, 65°C, 6 h66%
Godleski, S. A.; Valpey, R. S. J. Org. Chem. 1982, 47, 383
O
O
OCO2MeO
MeOPd(OAc)2, DPPE
DMF, 60°C, 90 min61%
O
OMeO
O
TMS
TMS
Vitale, M.; Prestat, G.; Lopes, D.; Madec, D.; Poli, G. Synlett 2006, 14, 2231
Final CyclizationFinal Cyclization
RetrospectiveRetrospective
O
OO
O
BzO O
Ph
OH
O
MeO2C Br
O O
Ph
O
O
Bu3Sn
ONCCNCl
19 Steps in Total!19 Steps in Total!
Ph
OTBDPS
OO
O
O O
Ph
O
OO
Ph
OO
O
O
O
OPh
O
PMBO
O
HO
Ph
O
PMBO
O
HO
Ph
O
PMBO
OO
O
PMBO
Ph
OTBDPS
OO
O
NC Cl
Ph
O
OO
O
PMBO CO2Me
Ph
OTBDPS
OO
O
PMBO
O
Ph
1. KOH2. i. MeMgBr ii. PMBBr
O
CO2MeBr
1. TfN3, Base2. [Rh]
Ph O
OEPd
1. LiCl, DMSO, 2. H2, Cat.
1. PPh3, I2, imid.2. (Bu3Sn)2, h
SPh1. DDQ2. Martin Sulfurane
OCO2Me
E
OOCO2Me
O
NCKH,
Pd
TBAF
Cl
CN
