MeO Mike DeMartino Baran Group Meeting Lignan Natural Products November 18, 2005 OH OH Ar' Ar O Ar Ar' O O Ar' Ar O O Ar Ar' O O Ar RO OH O O Ar RO OH O O RO R'O dibenzylbutan(diol)e tetrahydrofuran tetrahydrofuran dibenzylbutyrolactone tetralin naphthalene dibenzocyclooctadiene (stegane) -Classification of lignan natural products: -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. -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 CO 2 H NH 2 CO 2 H NH 2 OH Shikimic Acid CO 2 H CO 2 H OH O 2 NADPH CO 2 H OH CO 2 H OH CO 2 H OH CO 2 H OH MeO O 2 NADPH O 2 NADPH SAM SAM HO OH MeO OMe L-Phe L-Tyr cinnamic acid 4-coumaric acid (p-coumaric acid) caffeic acid ferulic acid sinapic acid OH OH MeO OH MeO OMe OH OH OH 4-hydroxycinnamyl alcohol (p-coumaryl alcohol) coniferyl alcohol sinapyl alcohol Polymers x 2 x n Lignans Lignin -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. -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.
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MeO
Mike DeMartinoBaran Group MeetingLignan 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:
-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.
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.)
-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
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.