Lignan Natural Products Baran Group Meeting Mike DeMartino

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.


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


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.


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'


November 18, 2005

-Synthesis of furofuran lignans (cont.) OO

Ar'

Ar


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%


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


November 18, 2005

-Synthesis of furofuran lignans (cont.) OO

Ar'

Ar


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


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.


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.


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


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.

Documents

Lignan Natural Products Baran Group Meeting Mike DeMartino