towards maoecrystal v: a comparison of recent strategiesccc.chem.pitt.edu/wipf/current...
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TowardsMaoecrystalV:AComparisonofRecentStrategies
CurrentLiterature:November14,2009MelissaSprachman
Reactant/Reagent
O
O
O
OO
O
Melissa Sprachman @ Wipf Group Page 1 of 14 12/28/2009
MaoecrystalV:StructuralRepresentaGons
X-Ray Crystallographic Structure
Org. Lett. 2004, 6, 4327-4330.
O
O
OO
O
O
H
OO
OO
Melissa Sprachman @ Wipf Group Page 2 of 14 12/28/2009
IsolaGonandStructuralInformaGon
• IsolatedfromtheleavesofIsodoneriocalyx(Chinesemedicinalherb)
• StructuralconfirmaGon:1Dand2DNMR,MS,X‐Ray• InhibitoryacGvitytowardHeLacells(IC50=0.02μg/mL)[Compare
tocis‐plaGn:IC50=0.99μg/mL)
O
O
OO
O
Copied from: Org. Lett. 2004, 6, 4327.
Melissa Sprachman @ Wipf Group Page 3 of 14 12/28/2009
Theent‐Kauranes(diterpenoids)ent -kaurene
H
For a review see Nat. Prod. Rep. 2006, 23, 673.
Related Structures:
O
H
O
O
CHOO
H
Epi-eriocalyxin A
O
H
O
O
CO2HO
H
Maoecrystal N
O
H
OCO2HO
H
Maoecrystal OOAc
O O
HAcO CHO
HOH
Maoecrystal Z
Org. Lett. 2006, 8, 4727.
Acta Botanica Yunnanica, 1997, 19, 191.
Proposed Biogenetic Pathways for Maoecrystal V and Maoecrystal Z from a common 7,20-epoxy-ent-kaurane:
O O
H CHO
HOH
O O
H
HHCO
O
O O
H
HCO2H
O
H OHOH
O
H
O
[O]
O OHCO2H
CHO-CO2H
O
H
OO
OO
Melissa Sprachman @ Wipf Group Page 4 of 14 12/28/2009
SummaryofRoutesDanishefsky: TL 2009, 50, 6586.
OMe
MOMO OHO
O+
OMe
Br
Me
MOMO H OTBS
O
O
H CO2MeIMDA
OO
O
CO2MeMOMO
HH
Baran (Li): Org. Lett. 2009, 11, 4744 and Org. Lett. 2009, 11, 4770.
OH
OTBSO
OMOMMeBi
3
Cl
Cl
+
TBSOO
O
O
HO
Oxidative Dearomatization
TBSO
O
O
O O MeOAc
IMDA
OO
OH
AcO Me
H O
H
OTBSMe
Nicolaou: Chem. Commun. Advance
OMe
OMe
O OMOM
O
OTBS
MeO2CO CO2Me
OOH
O
O OOH
OMeOMeO
Melissa Sprachman @ Wipf Group Page 5 of 14 12/28/2009
Danishefsky:“PaZernRecogniGon”
O
O
OO
O
OOPG
O
PGOOTBS
O
O
Pd(OAc)2ligand, K3PO4,THF, 80 oC, 12 h
91%+
OMe
Br
OMe
O
OMe
1.
2. TMSCHN2, DIPEACH3CN/MeOH, 9:1
quant.
1. Bu3SnCH2OMOM,BuLi, THF, -78 oC to -40 oC30 min, 0.5% HCl workup, 75%
2. HCl/MeOH, 50 oC, 75%3. PivCl, pyr, DCM, 12 h, 96%
O
OMeOPiv
1. NaBH4, CeCl3MeOH, 0 oC, 2 h, 93%
2. MOMCl,DIPEA, DCM, 12 h, 95%
MOMO
OMeOPiv
1. DIBALH, -78 oCDCM, 30 min, 95%
2. KH, 18-crown-6, ICH2SnBu3, 0 oC, THF, 6 h, 90%
MOMO
OMeO SnBu3
P(tBu)2
ligand =
“Pattern Recognition:” J. Org. Chem. 2007, 72, 4293.
Melissa Sprachman @ Wipf Group Page 6 of 14 12/28/2009
Danishefsky(cont.)
1 N HClTHF, MeOH, 10:10 oC, 8 h78% over 2 steps Me
MOMO H
O
HO
180 oCsealed tubetoluene, 12 h
OO
O
CO2MeMOMO
1.
2. TBAF, 0 oC, THF48% (2 steps)
MOMO
OMeO SnBu3
n-BuLi-78 oC to -20 oC,THF, 6 h, 88%
MOMO H
OMe
HO Li, NH3(l), t-BuOHTHF, -78 oc, 20 min,
Me
MOMO H
OMe
HO
α:β = 1 : 3
-33 oC, 40 min
Incorrect Facial Selectivity from IMDA:
MeO2CH
OCl
Me
MOMO HPyr, DCM, 0 oC, 72%
1.
2. TBSOTf, Et3N, DCM, 0 oC, 15 h, 81%
OTBS
O
O
H CO2Me
Melissa Sprachman @ Wipf Group Page 7 of 14 12/28/2009
Nicolaou:“CoreStructuresforEvaluaGon”
OMe
OMeCO2H
O
Pd(TFA)2Ag2CO3
DMF/DMSO (20:1)80 oC, 3 h, 89%
OMe
OMe
O1. BBr3CH2Cl2, -78 oC to 0 oC2 h, 98%2. MOMCl, THF, 0 oC, 2 h, 56%
OMOM
OH
O
1. TBSOTf, Et3NCH2Cl2, 0 oC, 2 h
OMOM
O
OTBS
MeO2C
2. K2CO3hydroquinonethen 1 N HCl (50%, 2 steps)3. 6 N HCl (aq), reflux, 3 h (83%)
O CO2Me
OOH
1. NaH, THF, then
NMeO2C
Br
THF, 0 to 23 oC, 8 h2. Na2CO3, MeI, MeOH,reflux, 2 h, 57%
OMOM
O
O
MeO2C
Melissa Sprachman @ Wipf Group Page 8 of 14 12/28/2009
Nicolaou(cont.)
O CO2Me
OOH PIFA
KHCO3, MeOH
0 to 23 oC, 0.5 h, 83%O CO2Me
OO
MeO OMe
H2, Pd/C
+
O CO2Me
O
MeO
OH
O CO2Me
OO
MeO OMe
H
H
PIFA
NaOH
O CO2H
OO
MeO OMe
H
H
ClCH2I, KOtBu18-crown-6
O
O OOH
OMeOMeO
O
O OOH
O
MeOOMe
42% (3 steps)
Melissa Sprachman @ Wipf Group Page 9 of 14 12/28/2009
Nicolaou:Simplifiedstructure/interesGngapproachtotheTHF
Rh2(OAc)2 (10 mol%)CH2Cl2, 23 oC 1 h
O
O
O
OMe
Silica gel
O
O
O
O
75%
H2, Pd/CEtOAc, 23 oC, 24 h (87%)
O
O
O
O
Tested three "core" structures against cell lines:
OO
O
O
OO
O
O
O
O OOH
OMeOMeO
A B C
Only “C” showed moderate (but non-selective) activity against human tumor cell lines.
O CO2Me
O
exo:endo: > 20:1
1. 1 N NaOH(aq)EtOH, 60 oC 5 h
2. (COCl)2, DMF, CH2Cl2reflux, 1 h3. TMSCHN2, THF/CH3CN, 1:10 oC, 2 h, 79% (3 steps)
O
O
ON2
OMeOMe
Melissa Sprachman @ Wipf Group Page 10 of 14 12/28/2009
Baran:OxidaGveDeramoGzaGonandIMDA
Cl
O
69% OTBSO
O OMOMMe
O
DIPEADMAPDCM-78 oC
OH
OTBSO
OMOMMeBi
3
Cl
Cl
DBU, toluene
67% (dr = 7:3 OTBSO
O OMOMMe
Li(t-BuO)3AlH
72% OTBSO
HO OMOMMe
THF, -78 oC
1. H2, Pd/C 97%
OO
OHH Me
H O
H
OTBS
MeMe2. SmI2
78% (dr = 17:3)
165 oC, o-DCBBHT
O O
O
HOAc
Me
HO
HTBSO
Me
MeOO
OH
AcO Me
H O
H
OTBS
MeMe79%
TFA, DCM, 0 oC
65% TBSOO
O
O
HOPb(OAc)4
AcOH, 81% (dr = 7:3)
TBSO
O
O
O O MeOAc
(Major)
Melissa Sprachman @ Wipf Group Page 11 of 14 12/28/2009
ReacGonsofNoteArylation with a Bi(V) species:
OBi ClAr Ar
O
Ar
TBSO
Ar2BiCl
OTBSO
O OMOMMe
OH
OTBSO
OMOMMeBi
3
Cl
Cl
DBU, toluene
Applications of Bi(V) species include phenol oxidation alpha-arylation:
Wessely oxidation/Diels Alder:
Tetrahedron 2006, 62, 10594.
Et OH
CO2EtPb(OAc)4, AcOH
Et O
CO2EtOAc140 oC
Et OOAc
EtO2C
(+/-)-coronafacic acid72% 89%
H
H
OEt
J. Chem. Soc., Chem. Commun. 1990, 739.
Melissa Sprachman @ Wipf Group Page 12 of 14 12/28/2009
Li(SameApproach?)
B(OH)2OMOM Pb(OAc)4
Hg(OAc)2CHCl3, 60 oC
Pb(OAc)3OMOM
OCO2Me
Pyr, CHCl3then H+
70%O
MeO O
OH
1. TMSCl, imid.CH2Cl2, 0 oC2. DIBAL-H, CH2Cl2-78 oC to rt, then HCl85% (2 steps)
O
HO
OH
OH
O
EDCI, DMAP
70% O
O
OH
O
Pb(OAc)4AcOH
92% OO
O
OMe OAc
(mixture of diastereomers;separated at this stage
toluene, 130 oC
OO O
Me OAcO
82%
H2, Pd/C90%
OO O
Me OAcO SmI2, THF
t-BuOH, rt
68%OO O
H MeO
+
OO O
Me HO
2 : 1(w/ free alcohol as substrate: 3.8 : 1
Melissa Sprachman @ Wipf Group Page 13 of 14 12/28/2009
SummaryandOutlook
• SeveralgroupshavereportedapproachestoMaoecrystalV,allinvolvingadearomaGzaGonandIMDAreacGons.
• OnlyNicolaouandcoworkershavesuccessfullyinstalledthekeyTHFmoeity.
• AlthoughBaranandcoworkersposeanenanGoselecGveapproach,theneedforimproveddiastereoselecGviGesisapparent.
• EventheadvancedMaoecrystalVintermediate(Nicolaou)didnotexhibitcomparablebiologicalacGvitytothatofthenaturalcompound;isaviabletotalsynthesisnecessaryformakingausefultherapeuGc?
Melissa Sprachman @ Wipf Group Page 14 of 14 12/28/2009