Lignan Natural Products
Baran Group Meeting
-Biosynthesis:
-Classification of lignan natural products:
Ar
Ar
OH
Ar
Ar'
OH
Ar'
Mike DeMartino
November 18, 2005
O
O
O
Ar
O
O
Ar'
-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:
Ar'
dibenzylbutan(diol)e
OH
tetrahydrofuran
OH
O
O
RO
tetrahydrofuran
dibenzylbutyrolactone
Carbohydrates --> Shikimic acid pathway --> Aromatic a.a.'s --> Cinnamic acids --> Lignans (Steganes)
O
See Group Meeting:
Ambhaikar, (2005)
RO
O
RO
Ar
tetralin
Ar
O
R'O
http://www.scripps.edu/chem/baran/html/meetingschedule.html
O
CO2H
naphthalene
See Group Meeting:
Zografos, (2004)
dibenzocyclooctadiene
(stegane)
CO2H
NH2
cinnamic
acid
-Provisional statement
Lignans are an extremely large class of natural products; for reasons
detailed 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 to
lignans, but rather a representitive sampling thereof.
Shikimic
Acid
O2
NADPH
L-Phe
CO2H
NH2
O2
NADPH
-Pharmacological properties
Because of the high structural diversity of this class of natural
products, there is obviously an extraordinary range of medicinal
properties 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 various
ailments. This subject will not be further elaborated upon as the sheer
magnitude of the topic warrants more than this particualr avenue of
discussion. For interesting case studies on some of the more prolific
medicinally relavant lignans, see Ref 1 below. Ref 5 also has
execllent discussions on the bioactivites of plant lignans.
CO2H
CO2H
HO
CO2H
O2
NADPH
SAM
MeO
OH
OH
OH
L-Tyr
4-coumaric acid
(p-coumaric acid)
caffeic
acid
ferulic
acid
OH
CO2H
SAM
MeO
OH
OH MeO
OH
OMe
OH
sinapic
acid
OH
-Key References
1. 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.
CO2H
OH
MeO
OH
4-hydroxycinnamyl alcohol
(p-coumaryl alcohol)
Polymers
OMe
OH
coniferyl
alcohol
x2
Lignans
MeO
OH
sinapyl
alcohol
xn
Lignin
Lignan Natural Products
Baran Group Meeting
Lignins
-One-electron oxidation followed by free radical resonance
distribution, leads to oxidative phenol coupling products
OH
Mike DeMartino
November 18, 2005
OH
OH
vs.
Lignans
Ar
Ar'
OH
OH
Ar
Ar'
OH
OH
tetrahydrofuran
dibenzylbutan(diol)e
peroxidases
–H+
Ar
O
O
Ar
Ar'
O
Ar'
–e-
tetrahydrofuran
MeO
MeO
MeO
OH
MeO
O
O
MeO
O
LIGNANS
radical pairing in any fasion
(excluding C2-C2); can also
be classified as lignans
H
C2-C2
[O]
coup.
H+
MeO
H+
O
NAD+
OMe
H
(–)-secoisolariciresinol
O
O
O
hydroxylation
OMe
OH podophyllotoxin
-Lignin has no ordered, repeating structure, but has secondary structure.
OH
aryl
modifications
O
O
MeO
matairesinol
-Lignin is racemic, or mosty racemic, polymer on the order of 10K Daltons; lignans are
always chiral owing to a stereocontrolled oxidative coupling.
O
O
O
-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).
Note: orthohydroxymethylether is the
biogenic precursor to the
methylenedioxy moiety
OH
dibenzocyclooctadiene
(stegane)
O
MeO
MeO
O
HO
lactonization
HO
HO
O
MeO
OH
OH
O
-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.
MeO
NADPH
O
-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.
HO
(+)-pinoresinol
H
R'O
Picture taken from:
http://honeybee.helsinki.fi/MMSBL/Gerberalab/lignin_structure_gosta.html
O
likely occurs through
quinonemethide/
reduction
naphthalene
RO
OMe
OH
O
Ar
O
quinonemethide
intenal quench
OMe
H
OH O
RO
Ar
tetralin
OH
O
dibenzylbutyrolactone
O
RO
NEOLIGNANS
O
OH O
O
coniferyl
alcohol
HO
O
MeO
OMe
OH
cyclization
through
quinonemethide
desoxypodophyllotoxin
O
O
-Still not much known with regards to the assemblage process of lignin; significantly
more about lignans is known.
O
MeO
OMe
OH
yatein
-Monomeric constitution of lignin highly dependant on specific plant, but mostly
p-coumaryl, coniferyl, and sinapyl alcohols.
-Lignans are differrentiated after oxidative coupling.
Lignan Natural Products
Baran Group Meeting
-Synthesis of dibenzylbutan(diol)e lignans
Br
Br
Br
Ar
ArCH2ZnBr
Pd(PPh3)4
S
Ar
OH
Ar'
OH
1. Ar'CH2MgCl,
NiCl2(dppp)
Ar
2. Raney Ni
Ar'
Br
Me
S
Br
1. ArMgBr
Pd(PPh3)4
O
ONa
Me
Me
Br
Ar'
MeO
OMe
Me
O O
MeO
OMe
MeO
OMe
Me
Ar
2. Ar'MgCl,
NiCl2(dppp)
3. Raney Ni
O
Ar'
Me
MeO
Me
Ar
-Synthesis of tetrahydrofuran
lignans
S
1. MeMgBr
NiCl2(dppp)
2. Br2, AcOH
Mike DeMartino
November 18, 2005
Me
OMe
Me
Pd/C
H2
low cat.
loading
60%
Me
MeO
Kumada, M., et. al. Tetrahedron Letters 1980, 21, 4017.
OMe
O
MeO
OMe
Me
O
Br
MeO
OMe
veraguensin
Biftu, T., et. al. J. Chem. Soc. Perk.
Trans. 1 1978, 1147.
ONa
Me
MeO
Me
OMe
Me
O O
MeO
OMe
MeO
Me
OMe
O
Me
HO
Pd/C
H2
high cat.
loading
~50%
MeO
OH
1. Ac2O, Et3N, 98%
2. NaH,
(OEt)2POCH2CO2Et
83%
OH
3. H2SO4, MeOH, 90%
4. Pd/C, H2, 97%
5. Ag2O, BnBr, 81%
O
OH
1. (Me)2NH
7%
O
B
n
O
O
O
O
BnO
2. Swern;
ArMgBr
68%
NMe2
OH
TsOH
69%
O
OMe
O
O
MeO
O
OMe
Me
O
HO
Me
dihydroguaiaretic acid
O
Biftu, T., et. al. J. Chem. Soc. Perk. Trans. 1 1978, 1147.
4-epidihydrosesamin
O
O
1. Dibal
2. Et3SiH
BF3•Et2O
64%
TBSO
3. Pd (black)
HCO2H
60%
O
2. TBSOTf
2,6-lut.
O
93%
OBn
O
*Note* This class have certainly been made many other different ways, but these are all
en route to higher oxidation state lignan natural products.
Yoda, H.T., et. al. Synlett 2001, 400.
OBn
1. LHMDS;
piperonal
91%
O
O
O
O
O
Lignan Natural Products
Baran Group Meeting
Ar
-Synthesis of tetrahydrofuran lignans (cont.)
OH
O
1. Allyldimethyl
chlorosilane
Et3N
PhS SPh
O
Ar'
*MenthO
MeO
O
*MenthO
dr = 9:1
73%
Ar
O
1. OsO4 (cat)
NMO
2. NaIO4
3. NaBH4
93%
O
4-epidihydrosesamin
O
H
MeO
OMe
H
OH HO
OMe
MeO
44%
O
OMe
MeO
BF3•Et2O
O
OH
HO
MeO
(–)-eudesmin
O
O
Feringa, B.L., et. al. J. Org. Chem. 1994, 59, 5999.
O
O
O
Miles, S.M., et. al. J. Org. Chem. 2004, 69, 6874.
OH
1. ArCHO
ZnCl2, Et3N
Ar
-Synthesis of furofuran lignans
O
O
O
Recent review: Brown, R.C.D., et. al. Syn. 2004, 6, 811.
O
O
ArCH(Cl)OMe
Et3N
O
O
2. BH3•DMS
60%
O
OMe
58%
O
Ar'
O
O
HO
O
O
C. fumago
air
~5%
H
MeO
pinoresinol
O
Pare, P.W., et. al. Tetrahedron Letters 1994, 35, 4731
OMe
O
H
OMe
H2SO4
73%
Ar
Ar
H
O
O
O
O
1. LAH
2. 220°C
0.05 Torr.
MeO
H
O
HO
syringaresinol
OH
MeO
Freudenberg, K., et. al. Chem. Ber. 1955, 88, 16.
H
OMe
O
H
H
O
O
H
O
TMSOTf
Et3N
O
O
O
O
asarinin
LAH; O
HCl,
MeOH
62% O
H
H
O
O
O
aptosimon
O
O
OH
O
H
O
OH
FeCl3, O2
aq. ROH;
O
O
HO
OH
LDA,
TMSCl
92%
OMe
H
O
OMe
MeO
O
O
OH
O
2. LAH
67%
OMe
O
O
O
O
O
1. HgO,
BF3•Et2O
THF/H2O
89%
O
O
O
OMe
MeO
62%
OMe
O
PhS SPh OH
FMe2Si
ArCHO
BF3•Et2O
HO
O
O
OMe
MeO
n-BuLi
ArCHO
H
Me2
Si
2. Grubbs I
O
Mike DeMartino
November 18, 2005
O
OMe
dr = 1.4:1
47%
O
O
O
O
Whiting, D.A., et. al. J. Chem. Soc., Chem. Comm. 1984, 59, 590.
O
OTMS
Lignan Natural Products
Baran Group Meeting
Mike DeMartino
November 18, 2005
Ar
-Synthesis of furofuran lignans (cont.)
O
O
Recent review: Brown, R.C.D., et. al. Syn. 2004, 6, 811.
Ar'
CO2Me
MeO2C
O
LDA;
ArCHO
Br
FVP
500°C
O
O
70%
0.04 mbar
66%
CO2Me
O
SO2Ph
2. TBAF
64%
TMS Cl
Ph
Ph
TMS
H
Ph
CsF
18%
O
O
1. LAH
98%
2. ArCH(OMe)2
TMSOTf, 55%
O
Cl
1. CsF
TMS
O
O
Ph
Ph
H
O
O
O
H
O
O
O
H
H
O
70%
O
O
O
O
Et3SiH
BF3•Et2O
OMe
O
O
O
H
a-Ar: asarinin
b-Ar: diasesamin
a:b = 1:3
Hojo, M., et. al. Synlett 1996, 234.
Steel, P.G. et. al. Org. Lett. 2002, 4, 1159.
O
MeO2C
SO2Ph
TBSO
HO2C
1. NaH
2. Na/Hg
HO
O
3. KOH
50%
HO
O
Me
O
O
Cl
I–
N
O
O
Me
Et3N
51%
O
O
O
O
A
O
NaOH
H2O
H
H
O
O
O
OH
samin
1. LAH
2. OsO4,
NaIO4
O
TBAI
95%
O
O
25%
from A
MeO2C
Br
O
H
TMSO
O
O
(53%)
O
Knight, D.W.J., et. al. J. Chem. Soc. Chem. Comm. 1991, 1641.
210°C,
PhMe,
OH
Et3N
90%
O
O
O
O
O
O
O
1. LDA
TMSCl
2. MeOH;
CH2N2
O
Me
O
Me
mCPBA
78%
Me
H Ar
O
O
O
O
O
H
OH
O
OH
O
TsOH
O
O
neopaulownin
1. O3, py
O
O
63%
O
O
O
2. NaBH4
62%
O
O
O
Mikami, K., et. al. Synlett 1993, 235.
O
O
O
Lignan Natural Products
Baran Group Meeting
Mike DeMartino
November 18, 2005
O
O
O
1. OsO4
NMO
O
OH
2. PTSA
3. PCC O
57%
O
C5H11
Pd(OAc)2
BTAC
Hunig's Base
O
H
O
O
dr = 25:1
45%
O
O
C5H11
O
O
O
O
O
OH
paulownin
H
O
O
Ar
OH
Ar'
O
NaH
72-84%
Ar'
Ar
O
Cp2TiCl2;
H
I2, 60-90%
O
Ar
O
O
OTBS
•
OMe
O
ArMgBr
O
Wirth, T., et. al. J. Org. Chem. 1996, 61, 2686.
O
O
O
Rh2(OAc)4
cat.
81%
OH
OMe
OMe
O
O
O
H
(+)-membrine
N2
2. Et3N
p-NO2C6H4SO2N3
MeO
O
MeO
O
O
OMe
O
OMe
OMe
O
O
1. OsO4 2. H5IO6
NMO
42%
H
OMe
O
AIBN
40% MeO
OMe
O
O
1. H2O2,
AcOH
NaHCO3 (aq.)
43%
O
OTBS
MeO
MeO
A
•
O
58%
SeTf
O
O
Ph3SnH
OH
OMe
Tf2O
2,6-DTBP
K2CO3;
A;
OMe
O
OMe
*ArSe
asarinin
OTBS
H
OMe
NR2
HO
O
ArMgBr
82%
H
Multiple examples
Et
H
Takano S., et. al. Synlett 1993, 785.
Ar'
Roy, S.C., et. al. J. Org. Chem. 2002, 67, 3242.
OTBS
O
TMSBr;
O
H
O
Br
O
O
Kraus, G.A., et. al. J. Am. Chem. Soc. 1990, 112, 3464.
O
3. NaOMe,
MeOH
4. TBSCl,
Im.
86%
1. OsO4,
NMO
2. NaIO4
O
O
O
O
O
H
O
O
hn
PhH
68%
O
OH
TMSOTf
NaBH4
O
I
2. ArCH2(C=NH)CCl3
CSA, 21%
O
O
O
1. LDA; CH2O
O
O
C5H11
H
O
H
O
fargesin
OMe
1. LAH
2. MsCl, py
60%
O
MeO
MeO
Brown R. C., et. al. J. Org. Chem. 2001, 96, 122.
O
O
H
H
O
OMe
O
1 diastereomer
Lignan Natural Products
Baran Group Meeting
Mike DeMartino
November 18, 2005
Ar
-Synthesis of furofuran lignans (cont.)
O
Recent review: Brown, R.C.D., et. al. Syn. 2004, 6, 811.
Ar
OH
Me
O
Ar
O
KOAc
AcOH
67%
O
O
Meldrum's
Acid
CHO
O
O
H
H
H
O
MeO
Ar
O
O
O
H
O
2N NaOH,
88%
O
Ar
H
H
O
1. ArMgBr
2. PPTS
54%
O
O
O
H
H
O
NaIO4
97%
O
(+)-xanthoxylol
O
Brown, R.C.D., et. al. Chem. Comm. 2002, 2042.
O
(–)-sesamin
H
O
3. NaI, MEK
4. Zn, MeOH
48%
O
O
(–)-samin
OBn
O
H 2. MsCl, Et3N
O
O
4. NaBH4
5. BuLi,
TsCl, 48%
1. H2, Pd(OH)2
OH
OsO4,
O
O
1. LDA,
MoOPH
2. NaBH4
3. NaIO4
OH
Me
Ar'H2CO
O
O
O
O
H
H
58%
O
O
O
N2
H
O
O
Ar
NaN3, Tf2O,
TBAB,
O
MgCl2,
wet DMA
O
O
O
Ar'H2CO
O
H
Me
Me
Ar'CH2OH
Mg(ClO4)2
54%
O
BnO
O
DMAP
H
92%
Me
Me
O
Me
Mn(OAc)3
Cu(OAc)2
O
D
O
OBn
H
Ar'
Me
O
BnO
O
H
H
O
O
Takano, S., J. Chem. Soc. Chem. Comm. 1988, 189.
OMe
O
OMe
CO2Bn
H
O
O
OMe
H
BnO2C
A
B
Pb(OAc)3
O
Pb(OAc)3
A (0.86 eq)
B (1.33 eq)
py, CH2Cl2
O
reflux/
H
sonication BnO2C
33%
Generated though the action of
Pb(OAc)4 on the aryl stannane
OMe
O
O
O
1. Br2
CO2Bn
H
Also 16%, 15%
of the symmetrically subst.
O
core respectively
Br
2. Et3N
70%
O
O
O
O
1. (R)-B-methyl
CBS cat.
catechol borane
2. t-BuLi, SnBu3Cl
71%
OH
SnBu3
O
O
Pd(PPh3)4
CuCl, CuCl2
DMSO
82%
O
OMe
H
I
O
H
methyl piperitol
O
O
O
NaBH4
Ar
15% Ar'
from C
O
HO
O
OMe
H
1. H2, Pd/C
AcOH
dr = 2:1
b,b:a,a-Ar,Ar'
H
H
2. hn
O
I
O
Ar
H
H
Orito, K., et. al. J. Org. Chem. 1995, 60, 6208.
1. mCPBA
K2CO3
H
O
OH
O
O
HO
1. VO(acac)2
t-BuOOH
O
OH
HO
H
O
O
O
Ar
2. Dibal
56% Ar'
Ar'
C
H
O
O
O
1. HgO-I2
CH2Cl2
2. 2N HCl
AcOH
80°C
55%
2. PPTS
35%
(–)-wodeshiol
O
O
Han, X.J., Corey, E.J., Org. Lett. 1999, 1, 1871.
O
OH
O
Lignan Natural Products
Baran Group Meeting
O
1. Cl3CCOCl
POCl3, Zn–Cu
Ar
-Synthesis of dibenzylbutyrolactone lignans
O
Ar'
O
-By FAR, the most commonly used method for constructing symmetric and
unsymmetric lignan lactones is through use of (enantiopure) b-substituted
g-butyrolactones (right). These strategies will be mostly excluded as the bsubstituted g-butyrolactones are generated through either chiral pool or
resolution chemistry and most of this is easily understood. Late stage
manipulations are genrerally diastereoselective alkyltions, aldol, and
olefination/hydrogenation reactions to complete the syntheses. Included in
the sentiment are conjugate additions to (4-aux)-2-butenolides wherein the
struture to the right could even be an intermedite in a vicinal
difunctionalization. For an impressive example of this, see Enders' work
which employed a chiral a-aminonirtile conjugate addition to access a
variety of the lignan classes (Enders, D. et. al. Syn. 2002, 4, 515).
O
R
O
O3, MeOH;
NaBH4; H+
75%
O
LDA;
ArCH2Br
O
O
(–)-deoxypodorhizone
Ar'
Aux*
O
O
O
74%
MeO
O
OMe
OMe
Honda, T. et. al. J. Chem. Soc. Perk. Trans. 1 1994, 1043.
O
CO2H
O
O
R
CO2H
OTES
O
Et3SiCl, 77%
O
O
O
CO2R
Base
O
O
One particularly famous way of accomplishing this is through the Stobbe
condesation:
CO2R
1. Simpkin's
Base
O
2. Zn, AcOH
61%
O
CHO
Mike DeMartino
November 18, 2005
O
O
N
CO2H
i-Pr
It is also important to note that many of the furofuran syntheses proceeded
through butyrolactones and, as such, yielded syntheses of lignan lactones.
O
1. LDA;
TiCl4
CO2H
O
1. Ac2O
O
2. LiOOH
dr = 5.6:1
55%
O
O
2. NaBH4
75%
(–)-hinokinin O
O
O
O
Kise, N. et. al. J. Org. Chem. 1994, 60, 1043.
OH
OH
O
1. (CH3)2SO4
NH2
OH
L-dopa
OMe
OH
(EtO)2OP
1. Isobutene
H+
Br
2. NaNO2/KBr
H2SO4
*Note*
Many symmetrical lignan lactones have been made with oxidative
homodimerization (various conditions; the unsymmetrical variant has not yet been solved!
CN
O
CO2t-Bu
OMe
O
2. NaH
NCCH2PO(OEt)2
OMe
OMe
Ph
OMe
MeO
Ph
O
MeO
OMe
Bu3SnH
Et3B/O2
80%
O
1. NaHMDS
Ar'CH2Br, 60 %
O
N
OMe
CO2Et
Ph
2. LiOOH
74%
O
HO
Ph
1. TFA,
HCl
OMe
MeO
CN
Dibal
0°C
OH
O
CN
OMe
CO2t-Bu
2. H2,
Pd/C
OMe
OMe
OMe
OMe
Suarez, A. et. al. Syn. Comm. 1993, 23, 1991.
OMe
OMe
CO2Et
OMe
OBn
O
MeO
MeO
O
OMe
OMe
O
MeO
Sm(OTf)3
CO2Et ArCH2Br
N
OMe
NaH
ArCHO
MeO
O
O
1. BH3
2. PPTS, 90%
3. H2, Pd/C
82%
(–)-isoarctigenin
OMe
OH
Sibi, M. et. al. J. Org. Chem. 2002, 67, 1738.
Lignan Natural Products
Baran Group Meeting
Mike DeMartino
November 18, 2005
O
OH
Ar
-Synthesis of dibenzylbutyrolactone
lignans (cont.)
-Synthesis of tetralin lignans
O
O
O
RO
Ar'
Ar
O
O
O
N
Me
O
O
MeO
A
MeO
Bn
1. Bu2BOTf,
Et3N; A
H
2. TBSOTf,
2,6-lut.
92%
N
MeO
O
O
OTBSO
CO2Et
O
O
CO2Et
Bn
OMe
MeO
S
OMe
OH
2. py, O
1. Tl(TFA)3,
DCE, 84°C;
"bisulfite [H]"
O
O
CO2Et
O
CO2Et
2. Me2SO4,
K2CO3
55%
MeO
NBS (4 eq.)
H2O (1 eq.) O
"20 min.
irr. w/GE
sunlamp
90%
OMe
OMe
MeO
OH
H
Cl
NaOH
MeOH
D, 67%
O
MeO
OMe
H
1. (Me3Si)3SiH,
AIBN, 80°C
44%
O
(–)-7(S)-hydroxyarctigenin
OMe
OH
2. TBAF
AcOH, 86%
O
OMe
OTBS
O
H
O
O
O
O
Jones; H
O
S
O
MeO
O
OMe
37% H2CO
5% NaOH
O
71%
O
MeO
O
O
+
H
OMe
OH
O
OTBS
OMe
OMe
1. NaBH4
85%
88%
CO2Et
CO2Et
MeO
O
59%
OMe
OMe
CO2H
MeO
OMe
OMe
OMe
picropodophyllone
TBSO
Kende, A.S., et. al. J. Am. Chem. Soc. 1977, 99, 7082.
OMe
Fischer, J. Org. Lett. 2004, 6,1345.
O
MeO
OMe
OH
H
MeO
MeO
SO2
SO2, PhH
hn
MeO
dr = 1.9:1
67%
MeO
MeO
OMe
1. MeOH, DCM
TsOH (cat.)
D, 98%
2. ZnO,
Diethyl fumarate
PhH, D, 82%
OMe
CO2Me
MeO
CO2Me
MeO
OMe
MeO
*Note* Also made enantiopure [(+)] by
by resolving with (R)-1-phenylethanol at
methyl etherification stage.
MeO
OH
OH
MeO
isolariciresinol
dimethyl ether
2. LAH,
100%
MeO
Charlton, J.L., et. al. J. Org. Chem. 1986, 51, 3490.
1. H2, Pd/C
96%
OMe
Lignan Natural Products
Baran Group Meeting
OH
-Synthesis of tetralin lignans (cont.)
NC
O
OMe
N
O
Me
O
>95%
O
H
O
O
MeO
1. 3N HCl
2. PCC
O
O
O
H
50%
OMe
MeO
OMe
Ot-Bu
OMe
O
TFA, D
12 hr
O
O
O
ArCHO
O
MeO
MeO
OMe
OMe
taiwanin C
O
81%
O
1. ArLi, LiCl
53%
2. KH,
PhSeCH2Cl ,
dr = 1:1
68%
I
Ot-Bu
Ogiku, T. et. al. J. Org. Chem. 1995, 60, 4585.
DLP (3 eq)
NaHCO3
D, 48%
O
MeO
MeO
H
OH
O
O
O
A
O
H
O
O
71%
(2 steps)
O
DLP (0.5 eq)
NaHCO3
D, 76%
+ 6% A
O
O
O
H
O
H
Ot-Bu
O
O
LDA;
2-butenolide;
CN
O
NIS,
allyl
alcohol
O
Ot-Bu
Li
OTBDMS
OTBDMS
O
RO
Ar
O
Mike DeMartino
November 18, 2005
MeO
1. NaH;
BuLi; ArCHO
NaOEt
0°C
O
MeO
2. PCC
59%
Br
Ot-Bu
MeO
CO2Et
MeO
CO2Et
H
CO2Et
O
O
(EtO)2OP
O
73%
O
CO2Et
TMSOK;
HCl
93%
OMe
dehydrodeoxypodophyllotoxin
O
Renaud, P. et. al. Syn. 2005, 9, 1459.
MeO
OH
-Synthesis of napthalene lignans
O
O
MeO
MeO
BnO
O
HO
O
BnO
O
daurinol
MeO
O
O
xylenes
D, 5 hr
O
Conditions
a)
b)
MeO
CO2H
MeO
CO2Et
b) NaH, LiBH4
D; 0.5N HCl
O
O
O
O
Justicidin B
Retrojusticidin B
76%
28%
O
trace
67%
Harrowven, D.C., et. al. Tetrahedron Letters 2001, 42, 6973.
O
O
O
O
MeO
MeO
Pd/C
O NH4OCHO
BnO
HO
O
O
Pd/C
NH4OCHO
a) BH3•DMS
HClEtOH
OR
MeO
O
Ar
O
O
O
O
RO
MeO
MeO
O
O
-Synthesis of dibenzocyclooctadiene
(stegane) lignans
RO
O
R'O
retrochinensin
O
O
O
Anastas, P. et. al. J. Nat. Prod. 1991, 6, 1687.
O
For a summary of the work done in this field,
please see 2004 group meeting seminar by
Alex Zografos: Stegane Natural Products
http://www.scripps.edu/chem/baran/html/meetinschedule.html
O
Lignan Natural Products
Baran Group Meeting
Mike DeMartino
November 18, 2005
Lignan
-Synthesis of miscellaneous lignans
Me
RO
structural
rearrangement/
modification
O
RO
New Lignan
Scaffold
O
The eupomatilones
HO
Me
HO
Me
Me
O
RO
RO
OH
O
O
RO
RO
OR
1,4-benzodioxane lignans
RO
O
Me
O
Me
O
OH
RO
O
O
O
OH
oxygenated
diarylbenzylbutane
OH
eupomatilone
skelaton
reigning biosynthetic hypothesis
OH
OH
OH
OH
Horse radish
O
OH
O
O
HO2C
CO2H
Carroll, A.R., et. al. Aust. J. Chem. 1991, 44, 1615.
Carroll, A.R., et. al. Aust. J. Chem. 1991, 44, 1705.
CO2H
O
peroxidase
CO2H
RO
Me
RO
Me
RO
Me
HO2C
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.
OH
10%
8%
Me
1. TMSCHN2
2. Dibal
3. LAH
Me
H
O
O
H
OH
O
HO
HO
americanol
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.
O
O
isoamericanol
O
O
Me
Me
OH
OH
OH
O
carpanone
O
O
O
O
OH
OH
KOt-Bu
OH
DMSO
Me
PdCl2
(0.5 eq)
O
H
O
O
H
O
OH
NaOAc
62%
O
O
O
O
carpanone
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.