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Protecting-Group-Free Enantioselective Synthesis of (-)-Pallavicinin and (+)-Neopallavicinin Huang, B., Guo, L., Jia, Y., ACIE 2015, 54, 13599-13603 Wipf Group Current Literature 11-21-15 James Johnson
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Pallavicinins • Isolated from Asian Liverworts (bryophytes)
Pallavicinia subciliata and P. ambigua
• Structures determined by X-ray diffraction and CD analysis.
• Contains a novel cagelike 6-5-5-5 tetracyclic skeleton with seven contiguous stereocenters
• Bioactivities include antipyretic properties, muscle regeneration, and detoxification
• Other similar diterpenoids exhibit 10 µM activity
towards leukemic K562/A02 cells.
• Only one example: (±) Pallavicinin and (±) Neopallavicinin (32 steps 0.1% and 0.007% overall yield)
Chem. Asian J. 2006, 1, 111 Chem. Pharm. Bull. 1998, 46, 178
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Wong’s Biomimetic Synthesis
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Chem. Asian J. 2006, 1, 111
O O
OH
HHH
HO
O O
OH
HHH
HO
Pallavicinin Neopallavicinin
O OH
H
H
H
H
O
OO
O O
H
H
O
HO
O
OHC
O
O
OHOMs
HO
O
OOMsHO
O
O
Grobfragmentation
O
O
Weiland-Miesher ketone
IntrmolecularAldol
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Wong’s Biomimetic Synthesis
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Chem. Asian J. 2006, 1, 111
O
O 1) NaBH4, EtOH, 0 °C 95%
2) BzCl, pyr, rt, 96% O
OBz 1) KOtBu, MeI, tBuOH, rt, 74%
2) Ethylene glycol, TsOH, C6H6 reflux 98%
O
O
OBz1) KOH, MeOH reflux 96%
2) TBSCl, Im, DMF, rt, 92%
O
O
OTBS
1) BH3THF, DCM, 0°C2) PDC, DCM, rt
3) NaOMe, THF, rt (56% 3 steps)
O
O
OTBS
HO
O
O
OTBS
HOBn
1) Na, NH3, THF/MeOH -78°C, 74%
2) NaH, BnBr, TBAI THF, reflux, 92%
1) TBAF, THF reflux, 93%
2) PDC, DCM rt, 85%
O
O
O
HOBn
O
OHOBn
O
O
OHOH
O
TBSO1) 9-BBN, DCM,rt, then NaOH, H2O2 76%
2) TBSCl, Im, DMF, rt, 84%3) H2, 10%Pd/C, EtOH rt, 97%
HO
O
OHC
O1) LDA, PhNTf2 THF, -78 °C, 86%
2) Pd(PPh3)4, K2CO3 THF, reflux, 84%
O(HO)2B
1) MsCl, Et3N, DMAP DCM, rt, 77%
2) TBAF, THF, rt3) KOtBu, 18-crown-6 tBuOH, 50°C 56% (2 steps)
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Wong’s Biomimetic Synthesis
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Chem. Asian J. 2006, 1, 111
1) TsOH, acetone, rt2) tBuONa (10%), tBuOH, 60°C
3) IBX, CH2Cl2, rt 56% (3 steps)
O O
H
H
O
O OH
H
HO
O
1) ethylene glycol TsOH, C6D6 reflux, 72%
2) MeLi, THF, -78°C then TMSCl, 54%
TMS
O OH
H
H
H
H
O
OO
1) CH3CO3H, NaOAc, 0°C
2) LDA,THF, 0°C HOAc 56% (2 steps)
4.4:1 drinseparable mixture
A
B
DBU
toluene, reflux43% A9.8% B
O O
H
HHH
HO
O
O
O O
H
HHH
HO
O
O
O O
H
HHH
HO
O
O
O O
OH
HHH
HO
O O
H
HHH
HO
O
O
O O
OH
HHH
HO
1) LDA, CH3CHO -78 °C
2) Et3N, MsCl DCM, 0 °C 38% (2 steps)
cat. TsOH
acetone, 0°C 80%
1) LDA, CH3CHO -78 °C
2) Et3N, MsCl DCM, 0 °C 31% (2 steps)
cat. TsOH
acetone, 0°C 30%
HO
O
OHC
O
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Title Paper
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Retrosynthesis
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O O
OH
HHH
HO
O O
OH
HHH
HO
Pallavicinin Neopallavicinin
O OH
H
H
H
H
OO O
H
H
O
TMS
OH
OHH
O
H
OTMS
O
H
H
TMS
O
OOH
O
O
TMS
O OH
O
H
O
O
OiBu
O
O
O
Pd-catalyzedasymmetric
decarboxylativeallylation
Pd-catalyzedoxidativecyclization
LiBHEt3-inducedfragmentation/protonation
ACIE, 2015, 54, 13599-13603
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Synthesis of Payne Precursor
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OL. 2010, 12, 2551–2553 ACIE, 2011, 50, 2756-2760 ACIE, 2015, 54, 13599-13603
PPh2 N
O
tBu(S)-tBu-PHOX
i-BuO
O
1) LDA, THF, -78 °C then
2) Cs2CO3, MeI CH3CN, 80 °C i-BuO
O O
ONC
O
OO
O
i-BuOH, TsOH
benzene, refluxovernight
93% 84% (2 steps)1 kg = $185
(S)-tBu-PHOXPd2(pmdba)3
toluene, 50 °C79% (85% ee) i-BuO
O
O
LiAlH4, Et2Ort, 30 min
then H2SO490% O
1) LDA, TBSCl HMPA, THF, -78 °C
2) Pd(OAc)2, O2 DMSO, 65 °C overnight 77% (2 steps)
MgBrCuBr•Me2S
THF, -40 °C, 5 min95% (d.r. = 10:1) O
NaH, MeI
DME, rt, 3 h 93% O
SeO2, TBHP
DCM, rtovernight
75%O
OH
O
OH
O
VO(acac)2, TBHP
DCM, rt, 30 min64% O
O
O
DMP
DCM, rt, 30 min79% (99% ee)
Ore-faceattack
2-TMS-furannBuLi
Et2O-40 °C, 5 min
72% O
O
TMS
O OH
H
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LiBHEt3-mediated Payne rearrangement
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R OOH
R1 Yb(OTf)3
CH2Cl2, rt, 1 h
H
OR
R1
OH
Ph
Ph O OH
Ph
PhO
THF, rt43%
66-97%
Cp2TiCl2, Zn
O
O
TMS
O OH
LiBHEt3
THF
30 °C
80%
60 °C
84%
0 °C
90%
OHH
O
H
OTMS
O
TMS
O
A
BOHHO
H
9:7 A:B
ACIE, 2015, 54, 13599-13603
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Proposed Mechanism
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O
O
TMS
O OH
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The Final Steps 11-21-15 11
OHH
O
H
OTMS
DMP
DCM, rt, 30 min89% O
H
OTMSO
MeMgBr (4 eq)
THF, -40 °C80% OH
HO
TMSO
m-CPBA
CH2Cl2, rt
OH
H
OOO OH
H
OOO
DBU
DCM, rt45% (2 steps)
O OO
H
HO
O OH
H
OH
O
O O
H
HHH
HO
O O
H
HHH
HO
O
O
O O
OH
HHH
HO
O O
OH
HHH
HO
Pallavicinin55% (2 steps)
Neopallavicinin12% (2 steps)
30%
15%1) LDA, CH3CHO THF, -78 °C
2) MsCl, Et3N DMAP, DCM
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Conclusions • Protecting group free asymmetric synthesis of (-)-
pallavicinin and (+)-neopallavicinin
• 15 steps. 1.3% and 0.1% for (-)-pallavicinin and (+)-neopallavicinin from known compound. Improved from previous synthesis.
• New example of a LiBHEt3 induced “Payne” rearrangement
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