lignan natural products baran group meeting mike demartino
TRANSCRIPT
MeO
Mike DeMartinoBaran Group MeetingLignan Natural Products
November 18, 2005
OHOHAr'
ArO
Ar
Ar'OO
Ar'
Ar
O
OAr
Ar'
O
O
Ar
RO
OH
O
O
Ar
RO
OH
OO
RO
R'O
dibenzylbutan(diol)e tetrahydrofuran tetrahydrofuran dibenzylbutyrolactone
tetralin naphthalene dibenzocyclooctadiene(stegane)
-Classification of lignan natural products:
-Pharmacological propertiesBecause of the high structural diversity of this class of naturalproducts, there is obviously an extraordinary range of medicinalproperties and this area continues to be a fruitful research topic.Many lignan containing plants have been used for centuries,particualrly in Asian communities, as cures and remedies for variousailments. This subject will not be further elaborated upon as the sheer magnitude of the topic warrants more than this particualr avenue ofdiscussion. For interesting case studies on some of the more prolificmedicinally relavant lignans, see Ref 1 below. Ref 5 also hasexecllent discussions on the bioactivites of plant lignans.
-Biosynthesis:-This topic nicely bridges two other Baran Group meeting topics, meaning that these will not be detailed in this lecture. In the most general sense,the biosynthesis if lignans can be thought of as such:
Carbohydrates --> Shikimic acid pathway --> Aromatic a.a.'s --> Cinnamic acids --> Lignans (Steganes)
See Group Meeting:Ambhaikar, (2005)
See Group Meeting:Zografos, (2004)
http://www.scripps.edu/chem/baran/html/meetingschedule.html
CO2H
NH2
CO2H
NH2
OH
Shikimic Acid
CO2H
CO2H
OH
O2NADPH
CO2H
OH
CO2H
OH
CO2H
OH
CO2H
OHMeO
O2NADPH
O2NADPHSAM SAM
HO OH MeO OMe
L-Phe
L-Tyr
cinnamic acid
4-coumaric acid(p-coumaric acid)
caffeic acid
ferulic acid
sinapicacid
OH OHMeO
OHMeO OMe
OH OH OH
4-hydroxycinnamyl alcohol(p-coumaryl alcohol)
coniferylalcohol
sinapylalcohol
Polymersx 2 x n
Lignans Lignin
-Key References1. Ayres, D.C., Loike, J.D. In Lignans Chemical, Biological, and Clinical Properties; Cambridge University Press: Cambridge, 1990.2. Dewick, P.M. Medicinal Natural Products, 2nd Ed.; John Wiley & Sons, LTD, W. Sussex, 2002.3. Barton, D., Nakanishi, K. Comprehensive Natural Products Chemistry, Vol 3, PergamonPress.4. Lewis, N.G. et. al. Phytochemical Reviews 2003, 2, 257.5. Muhammad, S. et. al. Nat. Prod. Rep. 2005, ASAP.
-Provisional statementLignans are an extremely large class of natural products; for reasonsdetailed below, this lecture will focus on (bio)synthesis. That said,neolignans (see next page) will not be discussed in detail. This is not meant to give a comprehensive coverage of all synthetic routes tolignans, but rather a representitive sampling thereof.
Mike DeMartinoBaran Group MeetingLignan Natural Products
November 18, 2005
OH
OHMeO
OH
OMeO
OH
OMeO
OH
OMeO
OH
OMeO
–H+
–e-
coniferylalcohol
-One-electron oxidation followed by free radical resonance distribution, leads to oxidative phenol coupling products
OH
OMeO
HO
OOMe
H+
H+
O
O
OH
OMe
HO
MeO
quinonemethideintenal quench
(+)-pinoresinol
NEOLIGNANSradical pairing in any fasion (excluding C2-C2); can also
be classified as lignans
C2-C2[O]
coup.
HH
OH
HO
OH
OMe
HO
MeO(–)-secoisolariciresinol
HH
NADPHlikely occurs through
quinonemethide/reduction
O
O
MeO
HO
MeOOH
lactonization
O
O
MeOOH
OMe
O
O
OHOMeMeO
O
O
OHOMeMeO
OH
matairesinol
yateindesoxypodophyllotoxinpodophyllotoxin
arylmodifications
NAD+
cyclization through
quinone-methide
hydroxylation
peroxidases
-Related because they are made up of the same starting materials; outside of the synthetic literature, it is difficult to find one term without the other.
-Lignin is a complex aromatic biopolymer formed of hydroxycinnamyl alcohols, which are connected to each other with various linkages . It is three-dimensional in structure and is formed between other constituents of the cell wall, having covalent linkages to cellulose, hemicelluloses and proteins. Lignans (and neolignans) are dimers of hydroxy cinnamyl alcohols.
-The most important function of lignin is to strengthen the cell walls of plants; lignan function in plants not well understood.
-Lignin is the 2nd most abundant source of organic material on the earth (cellulose).
-Lignin has no ordered, repeating structure, but has secondary structure.
-Lignin is racemic, or mosty racemic, polymer on the order of 10K Daltons; lignans are always chiral owing to a stereocontrolled oxidative coupling.
-Still not much known with regards to the assemblage process of lignin; significantly more about lignans is known.
-Monomeric constitution of lignin highly dependant on specific plant, but mostly p-coumaryl, coniferyl, and sinapyl alcohols.
-Lignans are differrentiated after oxidative coupling.
Lignins vs. Lignans
Picture taken from:http://honeybee.helsinki.fi/MMSBL/Gerberalab/lignin_structure_gosta.html
O
O
O
O
O
O
Note: ortho-hydroxymethylether is the biogenic precursor to the methylenedioxy moiety
OHOHAr'
Ar OArAr'
OOAr'
Ar
OO
ArAr'
OO
Ar
RO
OH
OO
Ar
RO
OH
OO
RO
R'O
dibenzylbutan(diol)e tetrahydrofuran
tetrahydrofuran dibenzylbutyrolactone
tetralin naphthalene
dibenzocyclooctadiene(stegane)
LIGNANS
Mike DeMartinoBaran Group MeetingLignan Natural Products
November 18, 2005
-Synthesis of dibenzylbutan(diol)e lignans OHOHAr'
Ar
S
Br Br
ArCH2ZnBrPd(PPh3)4
1. MeMgBrNiCl2(dppp)2. Br2, AcOH
S
Br
S
Me Me
Br Br
Ar 1. Ar'CH2MgCl,NiCl2(dppp)
2. Raney Ni
Me
MeAr'Ar
1. ArMgBrPd(PPh3)4
2. Ar'MgCl,NiCl2(dppp)3. Raney Ni
Me
MeAr'Ar
Kumada, M., et. al. Tetrahedron Letters 1980, 21, 4017.
O
Br
MeONa
Me
MeMe
O O
MeOOMe
MeOOMe
MeO
MeO OMe
OMe
MeMe
MeO
MeO OMe
OMe
Pd/CH2
high cat. loading~50%
dihydroguaiaretic acidBiftu, T., et. al. J. Chem. Soc. Perk. Trans. 1 1978, 1147.
*Note* This class have certainly been made many other different ways, but these are all en route to higher oxidation state lignan natural products.
O
Br
MeONa
Me
MeMe
O O
MeOOMe
MeOOMe
MeO
MeO OMe
OMe
MeMe
Pd/CH2
low cat. loading
60%
veraguensinBiftu, T., et. al. J. Chem. Soc. Perk. Trans. 1 1978, 1147.
OMeO
MeO
OMe
OMe
-Synthesis of tetrahydrofuran lignans
OAr
Ar'
O
OOH
OH
OHHO
1. Ac2O, Et3N, 98%2. NaH, (OEt)2POCH2CO2Et 83%
3. H2SO4, MeOH, 90%4. Pd/C, H2, 97%5. Ag2O, BnBr, 81%
O O
1. (Me)2NH7%
2. Swern;ArMgBr
68%
OBn O
NMe2
BnO
OH
OO
O O
OBn
OO
TsOH69%
O
O
O
O
1. LHMDS;piperonal
91%
2. TBSOTf2,6-lut.93%OBn
TBSO
OO
1. Dibal2. Et3SiHBF3•Et2O
64%
3. Pd (black)HCO2H
60%
O
OO
HO O
O
4-epidihydrosesamin
Yoda, H.T., et. al. Synlett 2001, 400.
Mike DeMartinoBaran Group MeetingLignan Natural Products
November 18, 2005
-Synthesis of furofuran lignans OO
Ar'
Ar
Recent review: Brown, R.C.D., et. al. Syn. 2004, 6, 811.
HO
OHOMe O
O
H H
OH
OMeMeO
HO
C. fumagoair
~5%
Pare, P.W., et. al. Tetrahedron Letters 1994, 35, 4731
O OH
OHOMeMeO O
O
Ar
Ar
H H
O
O
1. LAH
2. 220°C0.05 Torr.
FeCl3, O2aq. ROH;
H2SO473% O
O
H H
OH
OMeMeO
HO
MeO
OMe
syringaresinol
Freudenberg, K., et. al. Chem. Ber. 1955, 88, 16.
H
SPhPhS
MeOOMe
O O*MenthO
n-BuLiArCHO
62%O O*MenthO
PhS SPh OH
MeO
MeO
OMe
OMe
HO
MeO
MeO
OMe
OMe
1. HgO,BF3•Et2OTHF/H2O
89%
2. LAH67%
OH
OHHO
BF3•Et2O
44%O
O
H H
OMe
OMeMeO
MeO(–)-eudesmin
Feringa, B.L., et. al. J. Org. Chem. 1994, 59, 5999.
O OO
1. ArCHOZnCl2, Et3N
2. BH3•DMS60%
O O
OO
OH
O O
OO
OOMe
O
O
ArCH(Cl)OMeEt3N
58%
O OTMS
OO
OOMe
O
O
TMSOTfEt3N
dr = 1.4:147%
O
O
H H O
O
O
OO
O
O
H H O
O
O
OO
O
O
H H O
O
O
O
aptosimon
asarinin LAH;HCl,
MeOH62%
LDA,TMSCl92%
OH
OO
O
Me2Si
O
O
1. Allyldimethylchlorosilane
Et3N
2. Grubbs IO
FMe2Si
Ar
ArCHOBF3•Et2O
dr = 9:173%
O
OO
O
O
O
OO
HO O
O
4-epidihydrosesamin
1. OsO4 (cat)NMO
2. NaIO4
3. NaBH493%
Miles, S.M., et. al. J. Org. Chem. 2004, 69, 6874.
pinoresinol
Whiting, D.A., et. al. J. Chem. Soc., Chem. Comm. 1984, 59, 590.
-Synthesis of tetrahydrofuran lignans (cont.) OArAr'
Mike DeMartinoBaran Group MeetingLignan Natural Products
November 18, 2005
-Synthesis of furofuran lignans (cont.) OO
Ar'
Ar
Recent review: Brown, R.C.D., et. al. Syn. 2004, 6, 811.
SO2Ph
TMS
Ph
TMS
O
Cl
1. CsF
2. TBAF64% O
O
O
Ph
TMS
O
Cl
PhH H
Ph
Ph
Hojo, M., et. al. Synlett 1996, 234.
SO2PhMeO2C
OO
TBSO
HO
1. NaH2. Na/Hg
3. KOH50%
O
HO2C HO
OO
O
O
O
OO
NClMeI–
Et3N51%
1. LDATMSCl2. MeOH;CH2N2
O
O
HH Ar
TMSOO
MeO2C
(53%)OO
O
O
H H
OH
OO
1. LAH2. OsO4,
NaIO4
25% from A
A
samin
Knight, D.W.J., et. al. J. Chem. Soc. Chem. Comm. 1991, 1641.
Br
CO2Me OCO2Me
OO
O
MeO2C
OO
1. LAH98%2. ArCH(OMe)2TMSOTf, 55%
LDA;ArCHO
70%
FVP500°C
0.04 mbar66%
O
O
H HO
O
O
O
OMeO
O
H HO
O
O
O
a-Ar: asarininb-Ar: diasesamin
a:b = 1:3
Et3SiHBF3•Et2O
70%
Steel, P.G. et. al. Org. Lett. 2002, 4, 1159.
Me
OH
OO Br
O
OMe
O
OO
O
O
O
Me
NaOHH2O
TBAI95% O
O
OO
210°C,PhMe,
Et3N90%
O
Me
OO
OO
O
O OO
OO
O
OH
O
O
H OHO
O
O
O
mCPBA78%
1. O3, py
2. NaBH462%
TsOH
63%
Mikami, K., et. al. Synlett 1993, 235.
neopaulownin
CsF18%
Mike DeMartinoBaran Group MeetingLignan Natural Products
November 18, 2005
OH
O
O O
O
OO
1. OsO4NMO
2. PTSA3. PCC
57%O
O
OO
OO
O
1. LDA; CH2O
2. ArCH2(C=NH)CCl3CSA, 21%
O
O
H OHO
O
O
O
hnPhH68%
paulowninKraus, G.A., et. al. J. Am. Chem. Soc. 1990, 112, 3464.
O
Ar OH
Br
Ar'
NaH
72-84%O
H H
OO
Ar O
Ar'
Ar
Ar'Cp2TiCl2;
I2, 60-90%
Multiple examplesRoy, S.C., et. al. J. Org. Chem. 2002, 67, 3242.
OTBS
OMeOMe SeTf
Et
OH•
58%
HO •
O
*ArSe
MeOOMe
OTBS
O
OTBS
MeO
MeO
Ph3SnH
AIBN40%
OMeO
MeO
1. OsO4NMO
2. H5IO642%
ArMgBr
O
H H
OOMe
MeO
MeOWirth, T., et. al. J. Org. Chem. 1996, 61, 2686.
(+)-membrine
O O
OO
Pd(OAc)2BTAC
Hunig's Base O O
OO
C5H11
I
C5H11
TMSOTfNaBH4
dr = 25:145% O
OO
OHC5H11
1. OsO4,NMO2. NaIO4
3. NaOMe,MeOH
4. TBSCl,Im.
86%
O
O
H H
OTBS
O
OO
O
H HO
O
O
O
TMSBr;
ArMgBr82%asarinin
Takano S., et. al. Synlett 1993, 785.
O
NR2
OO
Tf2O2,6-DTBP
K2CO3;A;
NaHCO3 (aq.)43%
O
OMe
OMe
A O
O OMe
OMe
O OO O
N2
O
OMe
OMe
OO
1. H2O2, AcOH
2. Et3Np-NO2C6H4SO2N3
O
O
H HO
O
Rh2(OAc)4cat.81%
OMe
OMe
O1 diastereomer
1. LAH
2. MsCl, py60%O
O
H HO
O
OMe
OMe
fargesin
Brown R. C., et. al. J. Org. Chem. 2001, 96, 122.
H
O OH
Mike DeMartinoBaran Group MeetingLignan Natural Products
November 18, 2005
-Synthesis of furofuran lignans (cont.) OO
Ar'
Ar
Recent review: Brown, R.C.D., et. al. Syn. 2004, 6, 811.
Brown, R.C.D., et. al. Chem. Comm. 2002, 2042.
Ar OH O
O
O
MeMeMe
D
92% Ar O O
O
MeMn(OAc)3Cu(OAc)2
KOAcAcOH67%
O O
Me
OH
Ar
O O
Me
OH
Ar
Ar'H2CO
Ar'CH2OHMg(ClO4)2
54%
NaN3, Tf2O,TBAB,
2N NaOH,88%O O
H
Ar
Ar'H2CON2
O
O
HH
OO
MeO(+)-xanthoxylol
O
OO
1. Br2
2. Et3N70%
O
OO
Br
1. (R)-B-methyl CBS cat.
catechol borane
2. t-BuLi, SnBu3Cl71%
OH
OO
SnBu3
OH
HO
O
O
O
O1. VO(acac)2
t-BuOOH
2. PPTS35%O
O
OHHO
OO
OO
Han, X.J., Corey, E.J., Org. Lett. 1999, 1, 1871.
(–)-wodeshiol
Pd(PPh3)4CuCl, CuCl2
DMSO82%
O
CO2Bn
BnO2C
HH
O Pb(OAc)3
OMeOMe O
O
Pb(OAc)3
Generated though the action of Pb(OAc)4 on the aryl stannane
A B
A (0.86 eq)B (1.33 eq)py, CH2Cl2
reflux/sonication
33%
O
CO2Bn
BnO2CHH
O
OMe
OMe
O
O
Also 16%, 15% of the symmet-rically subst.
core respectively
1. H2, Pd/CAcOH
dr = 2:1b,b:a,a-Ar,Ar'
2. 2N HClAcOH80°C55%
O
HH
O
Ar'
ArO
O
Ar
Ar'
OH
HOO
O
Ar
Ar'
HO
I
HO
I
HH HH
O
O
HH
OMe
OMe
OO
1. mCPBAK2CO3
2. Dibal56%
1. HgO-I2CH2Cl2
2. hn
NaBH4
15% from C
C
Orito, K., et. al. J. Org. Chem. 1995, 60, 6208.
BnO
CHO
OH
O
O O
OH
HMe
Me
O
OO O
O
OBn
Meldrum's Acid
DMAP OO
OH
H
OO
BnO
MgCl2,wet DMA
58%
4. NaBH45. BuLi, TsCl, 48%
1. LDA,MoOPH2. NaBH43. NaIO4
OH
HO
O
O
1. H2, Pd(OH)22. MsCl, Et3N
3. NaI, MEK4. Zn, MeOH
48%
OHH
HO
O
O
OH
H
OH
O
O
O
OH
HO
O O
OO
OBnOsO4,
NaIO497%
1. ArMgBr
2. PPTS54%
(–)-sesamin (–)-samin
Takano, S., J. Chem. Soc. Chem. Comm. 1988, 189.
methyl piperitol
Mike DeMartinoBaran Group MeetingLignan Natural Products
November 18, 2005
Suarez, A. et. al. Syn. Comm. 1993, 23, 1991.
-Synthesis of dibenzylbutyrolactone lignans O
OAr
Ar'
-By FAR, the most commonly used method for constructing symmetric andunsymmetric lignan lactones is through use of (enantiopure) b-substitutedg-butyrolactones (right). These strategies will be mostly excluded as the b-substituted g-butyrolactones are generated through either chiral pool orresolution chemistry and most of this is easily understood. Late stagemanipulations are genrerally diastereoselective alkyltions, aldol, andolefination/hydrogenation reactions to complete the syntheses. Included in the sentiment are conjugate additions to (4-aux)-2-butenolides wherein thestruture to the right could even be an intermedite in a vicinaldifunctionalization. For an impressive example of this, see Enders' workwhich employed a chiral a-aminonirtile conjugate addition to access avariety of the lignan classes (Enders, D. et. al. Syn. 2002, 4, 515).
One particularly famous way of accomplishing this is through the Stobbecondesation:
It is also important to note that many of the furofuran syntheses proceededthrough butyrolactones and, as such, yielded syntheses of lignan lactones.
O
O
Ar'Aux*
CHO
CO2H
CO2RR R
CO2H
CO2RBase
OHO
NH2
OH
OH
1. (CH3)2SO4
2. NaNO2/KBrH2SO4
OHO
Br
OMe
OMe
L-dopa
CO2t-Bu
OMe
OMe
CN(EtO)2OP1. Isobutene
H+
2. NaHNCCH2PO(OEt)2
NaHArCHO
CO2t-Bu
OMe
OMe
CN
MeO
MeO
OMe
OMe
OMe
CN
MeO
MeO
OMe
OHO
O
OMe
OMe
MeO
MeO
MeO
Dibal0°C
1. TFA,HCl
2. H2,Pd/C
OO
1. Cl3CCOClPOCl3, Zn–Cu
2. Zn, AcOH61%
OO
O1. Simpkin's
Base
Et3SiCl, 77% OO
OTES
O
O
O
O
O3, MeOH;NaBH4; H+
75%LDA;
ArCH2Br
74%
O
O
O
O
MeOOMe
OMe
(–)-deoxypodorhizone
Honda, T. et. al. J. Chem. Soc. Perk. Trans. 1 1994, 1043.
O N
O O
i-Pr
O
O1. LDA;
TiCl4
2. LiOOH dr = 5.6:1
55%
CO2H
CO2HOO
OO
1. Ac2O
2. NaBH475%
OO
OO
O
O
(–)-hinokinin
*Note* Many symmetrical lignan lactones have been made with oxidativehomodimerization (various conditions; the unsymmetrical variant has not yet been solved!
Kise, N. et. al. J. Org. Chem. 1994, 60, 1043.
O N
O O
PhPh
CO2EtSm(OTf)3ArCH2Br
Bu3SnHEt3B/O2
80%
O N
O O
PhPh
CO2Et
OMe
OMe 1. NaHMDSAr'CH2Br, 60 %
2. LiOOH74%
HO
O
CO2Et
OMe
OMe
OMe
OBn
1. BH32. PPTS, 90%
3. H2, Pd/C82%
O
OOMe
OMeOH
OMe(–)-isoarctigenin
Sibi, M. et. al. J. Org. Chem. 2002, 67, 1738.
Mike DeMartinoBaran Group MeetingLignan Natural Products
November 18, 2005
-Synthesis of dibenzylbutyrolactone lignans (cont.)
O
OAr
Ar'
ON
OO
Me Bn
O
H
MeO
MeOON
OO
Bn
OTBS
MeOOMe
1. Bu2BOTf, Et3N; A
2. TBSOTf,2,6-lut.92%
A
OTBSOMe
O Cl
S
1. NaBH485%
2. py,
88%
OTBS
MeOOMe
O
OS
TBSO
1. (Me3Si)3SiH, AIBN, 80°C
44%
2. TBAFAcOH, 86%
OH
MeOOMe
O
O
OHOMe
OMe
H
H
(–)-7(S)-hydroxyarctigenin
Fischer, J. Org. Lett. 2004, 6,1345.
-Synthesis of tetralin lignansO
O
Ar
RO
OH
CO2Et
CO2Et
MeOOH
OMe
1. Tl(TFA)3,DCE, 84°C;"bisulfite [H]"
2. Me2SO4, K2CO355%
CO2Et
CO2Et
MeOOMe
OMe
CO2Et
CO2Et
MeOOMe
OMe
O
NBS (4 eq.)H2O (1 eq.)
"20 min. irr. w/GE sunlamp
90%
O
O
O
O
O
O
CO2H
MeOOMe
OMe
O
O
O37% H2CO5% NaOH
59%
MeOOMe
OMe
O
O
OO
O
OH
MeOOMe
OMe
O
O
OO
OJones; H+
71%
H
H
NaOHMeOHD, 67%
picropodophylloneKende, A.S., et. al. J. Am. Chem. Soc. 1977, 99, 7082.
MeO
MeO
OMe
MeO
MeOH
O
SO2
OH
SO2, PhHhn
dr = 1.9:167%
OMeMeO MeO
1. MeOH, DCMTsOH (cat.)
D, 98%
2. ZnO,Diethyl fumarate
PhH, D, 82%
MeO
MeOOMe
OMeMeO
CO2Me
CO2Me
1. H2, Pd/C96%
2. LAH,100%
MeO
MeO
OMeMeO
OHOH
isolariciresinol dimethyl ether
*Note* Also made enantiopure [(+)] by by resolving with (R)-1-phenylethanol at methyl etherification stage.
Charlton, J.L., et. al. J. Org. Chem. 1986, 51, 3490.
Mike DeMartinoBaran Group MeetingLignan Natural Products
November 18, 2005
Renaud, P. et. al. Syn. 2005, 9, 1459.
-Synthesis of tetralin lignans (cont.)O
O
Ar
RO
OH
O
O N
OMe
OMe Li Ot-Bu
>95%
O
O
O Ot-Bu
O
O
O
O
I Ot-Bu
NIS,allyl
alcohol
81%
DLP (0.5 eq)NaHCO3D, 76%+ 6% A
DLP (3 eq)NaHCO3D, 48%
O
O
O
O
H Ot-Bu
H
A
1. ArLi, LiCl53%
2. KH,PhSeCH2Cl ,
dr = 1:168%
O
OO
H Ot-Bu
H
OMeOMe
MeO
O
OO
H
H
OMeOMe
MeO
1. 3N HCl2. PCC
50%
dehydrodeoxypodophyllotoxin
-Synthesis of napthalene lignansO
O
Ar
RO
OH
OTBDMS
CN
OO
LDA;2-butenolide;
ArCHO
O
O
NC OTBDMS
OO
OMeMeO
O
OO
O
OMeMeO
TFA, D12 hr
71%(2 steps)
taiwanin C
Ogiku, T. et. al. J. Org. Chem. 1995, 60, 4585.
MeO
BnO
O
OO
O
O
xylenesD, 5 hr
O
OO
O
OO
MeO
BnO
MeO
BnOO
O
O
OO
O
OO
MeO
HO
MeO
HOO
Pd/CNH4OCHO
Pd/CNH4OCHO
daurinol
retrochinensin
Anastas, P. et. al. J. Nat. Prod. 1991, 6, 1687.
MeO
MeO
OH
Br
1. NaH;BuLi; ArCHO
2. PCC59%
MeO
MeO
H
O
O
OO
MeO
MeO
OO
CO2Et
CO2EtNaOEt0°C
CO2Et
CO2Et(EtO)2OP73%
MeO
MeO
OO
CO2H
CO2Et
TMSOK;HCl93%
MeO
MeO
OO
MeO
MeO
OO
OO
O
O a) BH3•DMSHClEtOH
OR
b) NaH, LiBH4D; 0.5N HCl
a) 76%b) 28%
trace67%
ConditionsJusticidin B Retrojusticidin B
Harrowven, D.C., et. al. Tetrahedron Letters 2001, 42, 6973.
-Synthesis of dibenzocyclooctadiene (stegane) lignans
OO
RO
R'OFor a summary of the work done in this field, please see 2004 group meeting seminar by Alex Zografos: Stegane Natural Productshttp://www.scripps.edu/chem/baran/html/meetinschedule.html
O
Mike DeMartinoBaran Group MeetingLignan Natural Products
November 18, 2005
-Synthesis of miscellaneous lignans
Matsumoto, K.M., et. al. Tetrahedron Letters 1999, 40, 3185.
For other syntheses of 1,4-benzodioxane lignans, see: Gu, W., et. al. Tetrahedron Letters 2000, 41, 6079. Merlini, L., et. al. J. Chem. Soc. Perk. Trans.1 1980, 775.
Lignanstructural
rearrangement/modification
New LignanScaffold
O
O OO
O
OH
HMe
Me
carpanone
O
O OH
KOt-Bu
DMSO
O
O
Me
OH
O
O OO
O
OH
HMe
Me
carpanone
PdCl2 (0.5 eq)
NaOAc62%
Chapman, O.L., Engel, M.R., Springer, J.P., Clardy, J.C. J. A. Chem. Soc. 1971, 93, 6696.
For solid phase synthesis, see: Shair, M.D., et. al. J. Am. Chem. Soc. 2000, 122, 422.For synthesis using solid phase reagents, see: Ley, S.V., et. al. J. Chem. Soc. Perk. Trans. 1 2002, 1850.
The eupomatilones
O
RO
RO O
Me
RO
HO Me
Me
O
RO
OH
RO
HO Me
Me
O
ORO
RO
Me
Me
O
OHRO
OO
RO
RO O
Me
Me
OHeupomatilone
skelatonoxygenated diarylbenzylbutane
1,4-benzodioxane lignans
O
OOH
RO
OR
OHOH
CO2H
O
O CO2H
HO2C
OH
OH
Horse radish
peroxidaseO
O
HO2C
CO2H
OHOH
8% 10%
1. TMSCHN22. Dibal3. LAH
O
O
OH
OHO
O
OHOH
HO
HO
OH
OH
americanol isoamericanol
reigning biosynthetic hypothesisCarroll, A.R., et. al. Aust. J. Chem. 1991, 44, 1615.Carroll, A.R., et. al. Aust. J. Chem. 1991, 44, 1705.
For syntheses of the eupomatilone 6, a representative member of the family, see: Coleman, R.S., et. al. Org. Lett. 2004, 6, 4025. Hutchinson, J.M., et. al. J. Org. Chem. 2004, 69, 4185. Hong, S.-p., et. al. Org. Lett. 2002, 4, 19.