total synthesis of (−)- lepenine
DESCRIPTION
Total Synthesis of (−)- Lepenine. Yiyun Peng 5/6/2014 doi.org/10.1021/ja503023h |J. Am. Chem. Soc. XXXX, XXX, XXX− XXX Yoshitake Nishiyama , Yuki Han- ya , Satoshi Yokoshima , and Tohru Fukuyama. Tohru Fukuyama’s Correction Crisis. Tohru Fukuyama’s Correction Crisis. Background. - PowerPoint PPT PresentationTRANSCRIPT
Total Synthesis of (−)-Lepenine
Yiyun Peng5/6/2014
doi.org/10.1021/ja503023h |J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Yoshitake Nishiyama, Yuki Han-ya, Satoshi Yokoshima, and Tohru Fukuyama
Tohru Fukuyama’s Correction Crisis
Tohru Fukuyama’s Correction Crisis
Background
Retrosynthesis
Me
H
H
HO
OH
OH
NEt
Me
H
O
NEt
OMe
OH
Me
H
OOMe
OH
ONHEt
H
MeO
OMe
OH
O
O
HO
OMe
OH
Forward synthesis
MeOOC Me
OH
O
MeOOC
OMe
Me
O
OMe
Me
OH
guaiacol, Ph3P, DEAD
toluene, 0 oC,
87%, >99% ee
i-Bu2AlH, Et2O, hexane, 78 to .40 oC;
vinylmagnesium chloride, THF, 40 to 0 oC
94% (1:1.6 mixture)
EtO NN OEt
O
O
:PPh3
EtO NN OEt
O
OPPh3
O
OCH3
H
EtO N
HN OEt
O
OPPh3
O
OCH3
EtO NH
HN OEt
O
O
MeOOC Me
OH
MeOOC Me
O
PPh3
O
OCH3O
MeOOC
OMe
Me
i-Bu2AlH
O
OHC
OMe
Me
MgClO
OMe
Me
OH
Mitsunobu Reaction
Forward synthesis
O
OMe
Me
OH
4-O2NC6H4OH (5 mol %), (EtO)3CMe, reflux, 9 d, 85%;
OH
OMe
Me
EtOOC OMs
OMe
EtOOC
OPiv
1) MsCl, Et3N, CH2Cl2, 0 oC, 85%
2) O3, CH2Cl2, MeOH, .78 oC; NaBH4, 78 to 0 oC, 86% 3) PivCl, pyridine, DMAP, CH2Cl2, rt, 80%, 91% ee
EtOOEt
OEtCH3
AcO H
EtOOEt
OEtMe
H
EtOOEt
CH3
R
OH
EtOO
CH3
OEt
ROAc
H
EtOO
CH3
OEt
R
H OAc
EtOO
CH2
OEt
R
HEtO
O
CH3
R
EtOO
R
HH H
OAcO
R
OEt
O
R
OEt
OH
NO2
OH
OMe
Me
EtOOC
O
OMe
Me
O
OEt
Johnson-Claisen Rearrangement
Claisen Rearrangement
Cl
O
Forward synthesisCOOH
Friedel-Crafts ReactionMechanism? Without AlCl3
OMs
OMe
EtOOC
OPiv
OMs
OMe
OPiv
O
1) aq LiOH, THF, MeOH, 0 oC;
2) TFAA, TFA, CH2Cl2, rt, 82% (two steps)
OMs
OMe
OPiv
1) vinylmagnesium chloride, THF, .40 oC, 85%;
2) AgOTf (5 mol %), toluene (20 mM), reflux, 1 h, 63%
Dehydration of tertiary alcohol
OMs
OMe
OMe
O
1) i-Bu2AlH, hexane, CH2Cl2, 0 oC, 89%
2) methacrylic acid, DCC, DMAP, CH2Cl2, rt, 85%
MeO
OMe
OMs
O
H
1) BHT, PhCN (20 mM), 160 oC, 6 h, 90%
2) crystallization from CHCl3/hexane (1:2), 84%
91% ee->99% ee
Replaced pivaloyl group with a methacryloyl group
OH
radical scavenger
MeO
OMe
OMs
O
H
HOH
Me
H
OHOMe
OMs
CHO
H
OH
BH3.THF, THF, rt; MeOH, 0 oC;
aq NaOH, aq H2O2, 97%i-Bu2AlH, hexane, CH2Cl2, 40 oC, 97%
Hydroboration occurred exclusively from the convex face
Forward synthesisReductive amination
Kagan's reagent
How?
Mannich Reaction
Me
H
OHOMe
OMs
CHO
H
OHMe
H
OHOMe
OMs
H
OHNEt
Alloc
Me
H
OOMe
OMs
H
CHO
NEt
Alloc
EtNH2.HCl, Et3N, AcOH, MeCN, rt;
NaBH(OAc)3; aq NaOH, 0 oC; AllocCl, 93% Dess.Martin periodinane, CH2Cl2, rt, 79%
Me
H
O
NEt
OMe
OMs
Me
H
OH
NEt
OMe
OHPd(PPh3)4, AcOH, CH2Cl2, reflux, 75%
KOH, MeOH, 60 oC, 3 h;
NaBH4, 0 oC, 95%
Me
H
OH
NEt
O
methyl red, AcCl, MeOH, rt;
PhI(OAc)2, 0 oC, 88%
OMe
OMe
Me
H
OH
NEt
O
OMe
OMeethylene (70 bar), CH2Cl2, 70 oC, 5 d, 84%
1) TBSOTf, 2,6-lutidine, CH2Cl2, rt, 91%;
2) SmI2, MeOH, THF, 0 oC, 96%
Me
H
OTBS
NEt
O
Diels-Alder reaction
Forward synthesisReductive amination
Me
H
OTBS
NEt
O
Me
H
OTBS
NEt
OH
Me
H
TBSO
NEt
OH
HO
HRed-Al, toluene, 0 oC, 88%
BH3.THF, THF, rt; H2O, 0 oC;
NaBO3.H2O, 0 oC to rt, 54%
Dess.Martin periodinane, TFA, CH2Cl2, rt, 72%
Me
H
TBSO
NEt
O
HO
H
Me
H
TBSO
NEt
O
HO
H
Me
H
OH
NEt
OH
HO
HHCO2Et, KHMDS, toluene, 70 oC;
aq HCHO, THF, 50 oC, 70%
1) NaBH4, CeCl3.7H2O, MeOH, 0 .C, 83%;
2) TBAF, THF, 65 oC, 93%
lepenine 2
O
R
HCO2Et, KHMDS
O
R
H aq HCHO
O
R
O
?
Luche ReductionSelectively reduce α, β-unsaturated ketone