enantioselective total synthesis of (-) jiadifenolide
DESCRIPTION
Enantioselective Total Synthesis of (-) Jiadifenolide. Pusheng Wang, 2011/04/09. Natural product isolated from the pericarps( 果壳 ) of Illicium jiadifengpi ( 假地枫皮 , 果形似八角茴香，有毒，切勿当八角茴香作调味品 ) by Fukuyama and co-workers - PowerPoint PPT PresentationTRANSCRIPT
Enantioselective Total Synthesis of (-) Jiadifenolide
Pusheng Wang, 2011/04/09
O
OH
O
O
OOH
OO
OH
O
OO
HO
O
O
OH
O
OHO
O
O
1: (-)-jiadifenolide 2: jiadifenoxolane A 3: jiadifenoxolane B 4: jiadifenin
A B
C
DE
O
OH
O
OO
HO CO2Me
Natural product isolated from the pericarps(果壳 ) of Illicium jiadifengpi(假地枫皮 ,果形似八角茴香，有毒，切勿当八角茴香作调味品 ) by Fukuyama and co-workers
Potent activities in promoting neurite( 突起 ) outgrowth in primary cultured rat cortical neurons(大脑皮层神经元 )
jiadifeninO
OH
O
OO
HO CO2MeWork by Samuel J. DanishefskyRef. JACS, 2004, 126, 14358-14359 JACS, 2006, 128, 1016-1022
Retrosynthetic strategy toward Jiadifenin
O
O
OOH
OH
O
O
OOH
OHO CO2Me
O
OH
O
O
O
O OTBS
EtO2CHWE
O
O
O
Claisen acylation
O
O
O
1. LHMDS, MeI,2. 10% KOH, HCHO, MeOH3. TBSOTf, 2,6-lutidine DCM 64%
O
O
O OTBS
LHMDS, THFAllyl bromide O
O
O OTBS73%
LDA, BrCH2CO2EtHMPA, THF O
O
O OTBS
EtO2C O
O
O OTBS
EtO2C+
Main (73%) 24%
O
O
O
Br CH2CO2Et
TBSO
O
O
O OTBS
EtO2C1. LiCH2P(O)(OMe)2, THF2. NaH, THF, Reflux
3. 2N HClHorner-Wadsworth-Emmons OH
O
O 1. ClCO2Et, Py DMAP, DCM
2. NaH, THF
O
O
O
HO
1. mCPBA, DCM2. NaBH4, THF-MeOH
O
O
OHO
OHO
OH
O
O
O
O
O OTBS
EtO2C1. LiCH2P(O)(OMe)2, THF2. NaH, THF, Reflux
3. 2N HClHorner-Wadsworth-Emmons OH
O
O
O
O
O OTBS
EtO2C LiCH2P(O)(OMe)2, THFO
O
O OTBSP
O
O
MeOMeO
NaH, THF, Reflux O
O
OTBSP
O
O
MeOMeO O
O
O
OTBS
O
OPMeO
MeOONa
OTBS
O
O 2N HCl
OH
O
O-ONa
PO
MeOMeO
O
O
OOH
OH1. LDA, MeI, HMPA, THF
2. O3, Sudan 7B Red3. Jones reagent
O
O
OOH
O
O
1. NaBH4, CeCl3.7H2O
2. NaHMDS, THFO
NSO
O
Davis oxaziridine
HO
O
OOH
O
OHO
Jones reagent
O
O
OOH
OHO CO2Me
MeOH
NaBH4 + CeCl3.7H2O Luche Reduction
O
NaBH4, CeCl3.7H2O
OH
99%O
CeBH
HHH
Luche, JACS, 1978, 100, 2226
Sudan 7B Red
NN
NN
NHEt
O
OH
O
O
OOH
O
(-)-jiadifenolide
A B
C
DE
Work by Emmanuel A. Theodorakis
Ref . Angew. Chem. Int. Ed. 2011, 50, 1 – 6
O
OH
O
O
OOH
OO
OHO
OTESO
O
O
OHO
OOH
O
O
O
OHO
TBSO O
O
OO
TBSO
O
O
(-)-1 7 8
91011
Scheme 1. Retrosynthetic strategy toward 1.
Key Step
O
OO
O
O
O O
O
TBSO
O
TBSO
OEtO
12 13 11
1415
63%
92%
Two steps 43%
1. [Pd(C3H5)Cl]2, PPh3, NaOAc BSA,THF, allyl acetate
2.O
D-prolinamide(30 mol%)PPTS (30 mol%)
MeCN, 40oC, 14 days74% (>90% ee)
1. NaBH4 (0.25 equiv) EtOH, 0oC, 1 h2. TBSCl,NH4NO3
DMF, RT, 12 hAvoid disilylated adduct
2. Et3O+BF4-, iPr2NEt
DCM, 0oC, 5 min;
1. TMSOTf, 2,6-lutidine DCM, 0oC to RT, 1 h 1. MMC, DMF, 130oC, 3 h
O
TBSO
O OEt
2. TBAF (1.0 equiv), MeI THF, -78oC to RT, 3 h,
MMC: methyl magnesium carbonate (Stiles's reagent)N
Si
SiO O
OMg
O
BSA:
2,6-lutidine:N
D-prolinamide:NH
O
NH2
OMg
OOMe
O
OOHMe
O
MgOMeOO
MgOMe
O
O
OH
OMg
MeO OMeHOMe
HOMe
O
O
MMC
O
O-t-Bu O-t-Bu
OHOMg
O
O-t-Bu
OHOMg
isomerization
Proposed Mechanism of Still's Reagent
O-t-Bu
O
MMC
O-t-Bu
O
Robert A. Micheli, JOC, 1975, 40, 675-681
O
MMC
O
O-t-Bu O-t-Bu
The success of the MMC reaction is most likely due to the enhanced stability of the resultant magnesium chelates produced (relative to the analogous sodium derivatives formed using the NaH-CO2 procedure) thus reducing the reversibility of the carbonation process. The regioselectivity observed in both carbonation procedures is apparently due to the preferance for heteroannular dienolate formation in indanones.
OHO
O
OH
Mg
Mg
O
O-t-Bu
O-t-Bu
O
OO
TBSO
O
TBSO
OEtO
O
TBSO
OTBS
10
1615
69%
1. LiAlH4, THF, 0oC to RT, 1 h2. TBSCl (1.0 equiv), imidazole, DCM, 0oC, 30 min3. IBX, DMSO, 80oC, 1 h
2. CO (1 atm), [Pd(PPh3)4] (1 mol%) MeOH, DMF, Et3N, 50oC, 2 h then TFA, DCM, RT, 5 h
1. KHMDS, PhNTf2, THF,-78oC, 1 h
85%
O
TBSO
OTBSOTf
TBSO
OTBSPd
TBSO
OTfPPh3
CO incert
Et3N, PPh3
TBSO
O
Pd PPh3PPh3
TBSO TfO
TBSO
O
TBSOOMe
16
O
O
TBSO
10
TBSOPPh3
-HEt3N+OTf -
Pd (0)
TFAMeOH
+
PdPPh3
PPh3
OTfH
Pd(0)
OO
TBSO
10O
O
TBSO
O
OO
TBSO
O
OH
O
OO
HO
O
OH
OO
O
O
OHO
O
OH
17 9
18
8
H2O2, 3M NaOHTHF, 0oC to RT, 5 h
99%
1. OsO4 (1 mol%), NaIO4 1,4-dioxane, H2O, RT, 12 h
2. Jones reagent acetone, 0oC, 30 min
TBAF, THF, RT30 min, 95%
70%
mCPBATHF, 50 oC, 3 h
OO
HO
O
OH
O
O
DMP, acetoneRT, 2 h
OO
O
O
OH
O
OH
H
Driving Force: formation of a thermodynamically favored five-membered ring lactone
mCPBA=
O
OOHCl
Jones reagent = CrO3 in diluted H2SO4
DMP=I
O
O
AcO OAcOAc
OO
O
OHO
O
OH
8
O
O
O
OHO
O
OTES
19
OO
OHO
O
OTES
7
O
OOHO
O
OTES
20
HO
O
OH
O
O
OOH
O
(-)-1
2. TESOTf, 2,6-lutidine THF, 0oC to RT, 30 min
1. 10% Pd/C (5 mol%) H2 (6 atm), MeOH RT, 24 h
90%
1. KHMDS Comins reagent THF, -78 oC, 1.5 h
2. [Pd(PPh3)4] (50 mol%) AlMe3, THF, RT, 2 h
NaHMDSTHF, -78oC to RT, 1.5 h
1. H2 (90 atm), PtO2 (20 mol%) MeOH, RT,24 h
OO
OHO
O
OTES
ONS
O
O
Jones reagentacetone, 0oC, 15 min
33% for 3 steps
57% for 2 steps
Davis oxaziridine
Comins reagent = NN
ClTf
Tf
OO
O
OHO
O
OTES
19O
OOHO
O
OTES
All these efforts (Wittig reaction, Ttanium or Zinc-based reagents) were unsuccessful,presumably because of the steric hindrance of the C1-carbonyl group.
Unwork
Titanium
Cp2TiCl
AlMe
Me[ Cp2Ti=CH2 ] R R
O
Cp2TiO
R
R
- Cp2Ti=OR R
可与酯键反应，等当量时优先与活泼羰基反应
1
Zn - CH2Br2 - TiCl4
Zinc-based reagents
[ Cl2Ti=CH2 ] R R
O
R R
Instantaneously react with aldehydes and ketones to give methylenated products with exceptional selectivity.
Steric hindrance
OO
OHO
O
OTES
20
HO
NaHMDS
OO
OHO
O
OTES
OO
OHO
ONa
OTES ON
SO
O
+
OO
OHO
O
OTES
O
NPhO2S
Na
OO
OHO
O
OTES
NaO
- PhSO2N=CHPhH2O
Thank you !