Lignan Natural Products Baran Group Meeting November 18, 2005 Mike Demartino

Lignan Natural Products Baran Group Meeting November 18, 2005 Mike DeMartino

-Classification of lignan natural products: -Biosynthesis: Ar O -This topic nicely bridges two other Baran Group meeting topics, meaning Ar OH Ar O O O Ar that these will not be detailed in this lecture. In the most general sense, Ar' OH Ar' O Ar' the biosynthesis if lignans can be thought of as such: Ar'

dibenzylbutan(diol)e tetrahydrofuran tetrahydrofuran dibenzylbutyrolactone Carbohydrates --> Shikimic acid pathway --> Aromatic a.a.'s --> Cinnamic acids --> Lignans (Steganes)

OH OH O O RO See Group Meeting: See Group Meeting: Ambhaikar, (2005) Zografos, (2004) RO O O RO O http://www.scripps.edu/chem/baran/html/meetingschedule.html O R'O Ar Ar CO2H CO2H

tetralin naphthalene dibenzocyclooctadiene NH2 (stegane) cinnamic -Provisional statement acid Lignans are an extremely large class of natural products; for reasons detailed below, this lecture will focus on (bio)synthesis. That said, L-Phe O2 Shikimic NADPH neolignans (see next page) will not be discussed in detail. This is not Acid

meant to give a comprehensive coverage of all synthetic routes to CO2H CO2H CO2H CO2H CO2H CO2H lignans, but rather a representitive sampling thereof. NH 2 O O 2 SAM 2 -Pharmacological properties NADPH NADPH SAM

Because of the high structural diversity of this class of natural HO MeO MeO OH MeO OMe products, there is obviously an extraordinary range of medicinal OH OH OH OH OH OH properties and this area continues to be a fruitful research topic. L-Tyr 4-coumaric acid caffeic ferulic sinapic Many lignan containing plants have been used for centuries, (p-coumaric acid) acid acid acid 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 OH OH OH 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.

-Key References MeO MeO OMe 1. Ayres, D.C., Loike, J.D. In Lignans Chemical, Biological, and Clinical Properties; OH OH OH 4-hydroxycinnamyl alcohol coniferyl sinapyl Cambridge University Press: Cambridge, 1990. (p-coumaryl alcohol) alcohol alcohol 2. Dewick, P.M. Medicinal Natural Products, 2nd Ed.; John Wiley & Sons, LTD, W. Sussex, 2002. Polymers 3. Barton, D., Nakanishi, K. Comprehensive Natural Products Chemistry, Vol 3, x 2 x n PergamonPress. 4. Lewis, N.G. et. al. Phytochemical Reviews 2003, 2, 257. Lignans Lignin 5. Muhammad, S. et. al. Nat. Prod. Rep. 2005, ASAP. Lignan Natural Products Baran Group Meeting November 18, 2005 Mike DeMartino

Lignins vs. Lignans -One-electron oxidation followed by free radical resonance Ar distribution, leads to oxidative phenol coupling products Ar OH O Ar' OH Ar'

OH OH OH OH OH dibenzylbutan(diol)e tetrahydrofuran

peroxidases Ar O + Ar –H O O O Ar' –e- Ar' tetrahydrofuran dibenzylbutyrolactone MeO MeO MeO MeO MeO OH OH O O OH O O O O RO O RO O coniferyl alcohol C2-C2 Ar Ar NEOLIGNANS LIGNANS [O] coup. tetralin naphthalene radical pairing in any fasion H+ RO (excluding C2-C2); can also O O be classified as lignans O OMe R'O OH O dibenzocyclooctadiene (stegane) OH Picture taken from: http://honeybee.helsinki.fi/MMSBL/Gerberalab/lignin_structure_gosta.html H H OMe quinonemethide intenal quench -Related because they are made up of the same starting materials; outside of the O synthetic literature, it is difficult to find one term without the other. HO HO (+)-pinoresinol MeO -Lignin is a complex aromatic biopolymer formed of hydroxycinnamyl alcohols, which MeO are connected to each other with various linkages . It is three-dimensional in structure likely occurs through O and is formed between other constituents of the cell wall, having covalent linkages to quinonemethide/ NADPH H+ reduction cellulose, hemicelluloses and proteins. Lignans (and neolignans) are dimers of hydroxy cinnamyl alcohols. OH MeO OH O -The most important function of lignin is to strengthen the cell walls of plants; lignan H H OMe NAD+ HO function in plants not well understood. O lactonization HO -Lignin is the 2nd most abundant source of organic material on the earth (cellulose). HO (–)-secoisolariciresinol MeO matairesinol MeO Note: ortho- -Lignin has no ordered, repeating structure, but has secondary structure. hydroxymethylether is the OH biogenic precursor to the aryl methylenedioxy moiety -Lignin is racemic, or mosty racemic, polymer on the order of 10K Daltons; lignans are OH modifications always chiral owing to a stereocontrolled oxidative coupling. O O O O O O -Still not much known with regards to the assemblage process of lignin; significantly O O cyclization O more about lignans is known. through O O O hydroxylation quinone- -Monomeric constitution of lignin highly dependant on specific plant, but mostly methide p-coumaryl, coniferyl, and sinapyl alcohols. MeO OMe MeO OMe MeO OMe OH podophyllotoxin OH desoxypodophyllotoxin OH yatein -Lignans are differrentiated after oxidative coupling. Lignan Natural Products Baran Group Meeting November 18, 2005 Mike DeMartino

Ar OH Ar -Synthesis of dibenzylbutan(diol)e lignans -Synthesis of tetrahydrofuran O Ar' OH Ar' lignans

1. Ar'CH MgCl, Br 2 Ar NiCl (dppp) Me ArCH2ZnBr 2 Ar Pd(PPh3)4 O ONa 2. Raney Ni Ar' MeO OMe Br Br Me S Me Me O O MeO OMe Br S MeO MeO Me Me Me Me 1. ArMgBr OMe OMe 1. MeMgBr Pd(PPh ) Me NiCl (dppp) 3 4 Ar 2 Pd/C 2. Br2, AcOH Br 2. Ar'MgCl, Ar' S Br Me H2 NiCl2(dppp) low cat. 3. Raney Ni loading 60%

Kumada, M., et. al. Tetrahedron Letters 1980, 21, 4017. MeO OMe O

MeO OMe Me Me veraguensin Biftu, T., et. al. J. Chem. Soc. Perk. Trans. 1 1978, 1147. O ONa MeO OMe Me Me O O 1. Ac2O, Et3N, 98% O MeO OMe 2. NaH, Br O 1. (Me)2NH O MeO MeO OH (OEt) POCH CO Et B 7% BnO O 2 2 2 n O OMe OMe Me Me OH 83% 2. Swern; HO NMe2 Pd/C O 3. H2SO4, MeOH, 90% O ArMgBr O OH H2 OH 4. Pd/C, H2, 97% 68% high cat. 5. Ag2O, BnBr, 81% loading ~50% TsOH 69% MeO OMe O O MeO OMe O 1. Dibal OBn 2. Et3SiH 1. LHMDS; O Me Me HO BF3•Et2O O piperonal 64% 91% TBSO dihydroguaiaretic acid O O O 3. Pd (black) 2. TBSOTf O Biftu, T., et. al. J. Chem. Soc. Perk. Trans. 1 1978, 1147. HCO H 2,6-lut. O 4-epidihydrosesamin 2 O 60% OBn 93% O O *Note* This class have certainly been made many other different ways, but these are all O en route to higher oxidation state lignan natural products. O Yoda, H.T., et. al. Synlett 2001, 400. Lignan Natural Products Baran Group Meeting November 18, 2005 Mike DeMartino

Ar PhS SPh OMe -Synthesis of tetrahydrofuran lignans (cont.) O MeO OH Ar' n-BuLi PhS SPh H ArCHO OMe *MenthO O MeO Me2 MeO O OH Si 62% O 1. Allyldimethyl O OMe *MenthO O chlorosilane ArCHO FMe2Si Et3N BF3•Et2O 1. HgO, O BF3•Et2O 2. LAH 2. Grubbs I dr = 9:1 THF/H2O 67% O O 73% Ar 89% O OMe O OMe O MeO OH HO BF3•Et2O O O OMe 1. OsO (cat) MeO H H OMe 4 44% MeO HO O NMO O 2. NaIO O HO OH 4 MeO (–)-eudesmin O 3. NaBH4 O 93% O O Feringa, B.L., et. al. J. Org. Chem. 1994, 59, 5999. O 4-epidihydrosesamin O O Miles, S.M., et. al. J. Org. Chem. 2004, 69, 6874. O OH 1. ArCHO ArCH(Cl)OMe Ar ZnCl2, Et3N Et3N O OMe O O O -Synthesis of furofuran lignans O O O 2. BH3•DMS O 58% 60% Recent review: Brown, R.C.D., et. al. Syn. 2004, 6, 811. O Ar' O O O HO O OH O C. fumago O air LDA, H H OMe TMSCl MeO O ~5% O 92% OMe O pinoresinol O HO H H O OH O O O O Pare, P.W., et. al. Tetrahedron Letters 1994, 35, 4731 O aptosimon TMSOTf OMe O Et N O OH O 3 O OMe OH O H H dr = 1.4:1 FeCl3, O2 O O Ar O O O 47% aq. ROH; 1. LAH O OMe O OTMS H H MeO H H O O O H SO 2. 220°C asarinin LAH; H H 2 4 O O 73% Ar O O 0.05 Torr. O HCl, MeO OMe O HO MeOH O O OH syringaresinol 62% O MeO Freudenberg, K., et. al. Chem. Ber. 1955, 88, 16. Whiting, D.A., et. al. J. Chem. Soc., Chem. Comm. 1984, 59, 590. Lignan Natural Products Baran Group Meeting November 18, 2005 Mike DeMartino

Ar

MeO2C -Synthesis of furofuran lignans (cont.) O O LDA; O Br FVP ArCHO O 500°C Recent review: Brown, R.C.D., et. al. Syn. 2004, 6, 811. Ar' CO Me O O 2 70% 0.04 mbar O CO2Me 66% O

1. LAH 98% 2. ArCH(OMe)2 O Ph TMSOTf, 55% SO2Ph O Ph Cl TMS TMS 1. CsF H H O O O Et SiH O 2. TBAF Ph O CsF 3 Ph O BF3•Et2O O 64% 18% O H H H H TMS Cl O O 70% OMe Ph O O O O O

Hojo, M., et. al. Synlett 1996, 234. a-Ar: asarinin b-Ar: diasesamin a:b = 1:3 Steel, P.G. et. al. Org. Lett. 2002, 4, 1159.

O Me O O O Me MeO2C SO2Ph Me HO2C HO 1. NaH Cl N O O NaOH 210°C, TBSO 2. Na/Hg I– Me H2O PhMe, O O OH O 3. KOH Et3N TBAI Et N O HO 50% 51% A O 3 O O O O O 95% 90% O Br O O O O O O 1. LDA O TMSCl mCPBA 2. MeOH; 78% CH2N2 O OH 1. LAH MeO2C 2. OsO4, H H H Me NaIO4 H Ar TMSO O O OH O O O 25% (53%) TsOH 1. O3, py O O O O O O from A H OH O O samin O 63% O O 2. NaBH4 O O O O O 62% Knight, D.W.J., et. al. J. Chem. Soc. Chem. Comm. 1991, 1641. O O O neopaulownin O O

Mikami, K., et. al. Synlett 1993, 235. Lignan Natural Products Baran Group Meeting November 18, 2005 Mike DeMartino

O C5H11

O C5H11 O Pd(OAc) O 2 OH O 1. OsO O O BTAC TMSOTf 4 O NMO 1. LDA; CH O Hunig's Base O O NaBH 2 H 4 O O 2. PTSA I 2. ArCH2(C=NH)CCl3 dr = 25:1 OH 3. PCC O O 45% O CSA, 21% O O 57% O C5H11 O O O O hn O O PhH 68% 3. NaOMe, 1. OsO4, MeOH NMO 4. TBSCl, O 2. NaIO4 Im. O 86% O H OH O O O O OTBS O O TMSBr; H H O H H O paulownin O ArMgBr O Kraus, G.A., et. al. J. Am. Chem. Soc. 1990, 112, 3464. O asarinin 82% O O

Br Ar' Takano S., et. al. Synlett 1993, 785. O O O Ar' Cp2TiCl2; NaH OMe OMe H H 72-84% I2, 60-90% Ar OH Ar O O Tf2O O OMe Ar' Ar OMe OMe O O 2,6-DTBP Multiple examples K2CO3; 1. H2O2, Roy, S.C., et. al. J. Org. Chem. 2002, 67, 3242. OMe A; AcOH O N2 O A O NR2 NaHCO3 (aq.) 2. Et3N p-NO C H SO N OTBS 43% 2 6 4 2 3 OTBS O O OTBS O O O Et HO *ArSe • O • Ph SnH OH 3 O O AIBN 58% O Rh2(OAc)4 OMe SeTf MeO 40% MeO cat. OMe 81% OMe MeO

1. OsO4 2. H5IO6 OMe OMe NMO 42% O O 1. LAH O H H OMe H H OMe OMe OH O O O 2. MsCl, py O O O ArMgBr O 60% O H H fargesin 1 diastereomer O O MeO MeO (+)-membrine MeO Brown R. C., et. al. J. Org. Chem. 2001, 96, 122. MeO Wirth, T., et. al. J. Org. Chem. 1996, 61, 2686. Lignan Natural Products Baran Group Meeting November 18, 2005 Mike DeMartino

Ar

BnO OBn BnO -Synthesis of furofuran lignans (cont.) O O H O Recent review: Brown, R.C.D., et. al. Syn. 2004, 6, 811. O O O Ar' H H CHO Meldrum's MgCl2, Acid O wet DMA Me H H O Me DMAP O O 58% O O Me Mn(OAc)3 Me Cu(OAc) O D O 2 O O O O H O O O Ar OH Me O Me 92% Ar O O KOAc Me AcOH Ar O O 1. LDA, MoOPH 4. NaBH4 67% 5. BuLi, Ar'CH OH O 2. NaBH4 2 O TsCl, 48% Mg(ClO ) 3. NaIO4 O 4 2 54% O OH OBn O Me O OH 1. H2, Pd(OH)2 O Ar'H2CO NaN3, Tf2O, Ar'H2CO O H 1. ArMgBr H OsO4, H 2. MsCl, Et3N H N2 TBAB, H H O H H NaIO 3. NaI, MEK 2N NaOH, H 2. PPTS H 4 H H O O 54% O 97% O 4. Zn, MeOH O Ar O O 88% Ar O O MeO 48% (+)-xanthoxylol O O O O O O O (–)-sesamin (–)-samin Brown, R.C.D., et. al. Chem. Comm. 2002, 2042. O Takano, S., J. Chem. Soc. Chem. Comm. 1988, 189. OMe O OMe O A (0.86 eq) OMe CO Bn O 2 O B (1.33 eq) 1. (R)-B-methyl OMe py, CH Cl O O OH H H 2 2 CBS cat. CO2Bn 1. Br2 Br catechol borane SnBu3 reflux/ H H BnO2C A B sonication BnO C 2. Et N 2 Also 16%, 15% 3 2. t-BuLi, SnBu3Cl O Pb(OAc)3 Pb(OAc)3 33% of the symmet- O 70% O 71% O Generated though the action of O rically subst. O O O Pb(OAc)4 on the aryl stannane O core respectively Pd(PPh3)4 O CuCl, CuCl2 DMSO 1. H2, Pd/C 2. 2N HCl AcOH AcOH O 82% dr = 2:1 80°C O O 55% b,b:a,a-Ar,Ar' O HO OMe H 1. VO(acac)2 t-BuOOH O O HO O OMe HO OH O I O O 1. mCPBA 1. HgO-I Ar 2. PPTS NaBH Ar 2 Ar K CO O 4 CH Cl 2 3 O 35% OH H H H H 2 2 H H H H 15% 2. Dibal O (–)-wodeshiol O Ar' 2. hn Ar' O from C 56% Ar' O O I O methyl piperitol O O C OH O O H Han, X.J., Corey, E.J., Org. Lett. 1999, 1, 1871. Orito, K., et. al. J. Org. Chem. 1995, 60, 6208. Lignan Natural Products Baran Group Meeting November 18, 2005 Mike DeMartino

O 1. Cl3CCOCl 1. Simpkin's Ar POCl3, Zn–Cu Base -Synthesis of dibenzylbutyrolactone lignans O O OTES Ar' O O O 2. Zn, AcOH Et SiCl, 77% O 61% O 3 O

O3, MeOH; -By FAR, the most commonly used method for constructing symmetric and + unsymmetric lignan lactones is through use of (enantiopure) b-substituted O NaBH4; H 75% g-butyrolactones (right). These strategies will be mostly excluded as the b- O O substituted g-butyrolactones are generated through either chiral pool or O LDA; O resolution chemistry and most of this is easily understood. Late stage ArCH2Br manipulations are genrerally diastereoselective alkyltions, aldol, and O O O O olefination/hydrogenation reactions to complete the syntheses. Included in Ar' (–)-deoxypodorhizone 74% the sentiment are conjugate additions to (4-aux)-2-butenolides wherein the O Aux* struture to the right could even be an intermedite in a vicinal MeO OMe difunctionalization. For an impressive example of this, see Enders' work OMe which employed a chiral a-aminonirtile conjugate addition to access a variety of the lignan classes (Enders, D. et. al. Syn. 2002, 4, 515). Honda, T. et. al. J. Chem. Soc. Perk. Trans. 1 1994, 1043. O CO H One particularly famous way of accomplishing this is through the Stobbe 2 condesation: O O O O 1. LDA; CO2R CO H CHO Base CO2R O 2 O TiCl4 1. Ac2O R R O N O O O CO H 2 CO2H 2. LiOOH 2. NaBH4 i-Pr 75% dr = 5.6:1 O O It is also important to note that many of the furofuran syntheses proceeded 55% O (–)-hinokinin O through butyrolactones and, as such, yielded syntheses of lignan lactones. Kise, N. et. al. J. Org. Chem. 1994, 60, 1043.

OH OH CN *Note* Many symmetrical lignan lactones have been made with oxidative homodimerization (various conditions; the unsymmetrical variant has not yet been solved! O O 1. Isobutene (EtO)2OP NH 1. (CH ) SO Br + CO t-Bu 2 3 2 4 H 2 OMe OMe O 2. NaNO2/KBr 2. NaH O H SO Sm(OTf)3 O 1. NaHMDS OH 2 4 OMe NCCH2PO(OEt)2 OMe O OMe O OMe O N CO2Et ArCH2Br Ar'CH2Br, 60 %

O N CO2Et HO CO2Et L-dopa OH OMe OMe Bu SnH 2. LiOOH Ph 3 OMe Et B/O 74% NaH Ph 3 2 Ph ArCHO 80% Ph OBn MeO OMe MeO OMe O MeO O MeO MeO OMe 1. BH O CN CN O 3 MeO 1. TFA, Dibal 2. PPTS, 90% HCl OH 0°C OMe MeO CO t-Bu 2 (–)-isoarctigenin 3. H2, Pd/C 2. H2, 82% Pd/C OMe OMe OMe OMe OMe OH OMe OMe Sibi, M. et. al. J. Org. Chem. 2002, 67, 1738. Suarez, A. et. al. Syn. Comm. 1993, 23, 1991. Lignan Natural Products Baran Group Meeting November 18, 2005 Mike DeMartino

O OH O Ar -Synthesis of dibenzylbutyrolactone O -Synthesis of tetralin lignans lignans (cont.) Ar' RO O

Ar

O O O O OTBSO O O O O 1. Bu BOTf, 1. Tl(TFA) , 2 CO Et 3 CO Et MeO Et N; A 2 DCE, 84°C; 2 NBS (4 eq.) CO2Et N O H 3 N O O O O "bisulfite [H]" H2O (1 eq.) CO2Et CO2Et CO Et A 2. TBSOTf, 2 Me Bn MeO MeO Bn "20 min. 2,6-lut. 2. Me2SO4, OMe irr. w/GE 92% K2CO3 MeO OMe MeO OMe sunlamp MeO OMe S 55% OH OMe 90% OMe 2. py, O Cl NaOH 1. NaBH4 MeOH 85% D, 67% OMe O O OH O 88% H OTBS O O O O O 37% H CO OH OTBS 2 H O Jones; H+ O 5% NaOH O CO H H 2 1. (Me3Si)3SiH, O O O AIBN, 80°C O 71% 59% MeO 44% MeO S H MeO OMe MeO OMe MeO OMe OMe O OMe O 2. TBAF OMe OMe OMe (–)-7(S)-hydroxyarctigenin AcOH, 86% picropodophyllone OMe TBSO Kende, A.S., et. al. J. Am. Chem. Soc. 1977, 99, 7082. OH OMe

Fischer, J. Org. Lett. 2004, 6,1345. O OH OMe MeO MeO MeO CO Me H 1. MeOH, DCM 2 SO2, PhH SO2 TsOH (cat.) hn MeO MeO D, 98% MeO CO2Me dr = 1.9:1 2. ZnO, 67% Diethyl fumarate PhH, , 82% MeO MeO D MeO OMe OMe OMe

MeO OH 1. H , Pd/C OH 2 *Note* Also made enantiopure [(+)] by MeO 96% by resolving with (R)-1-phenylethanol at methyl etherification stage. isolariciresinol 2. LAH, dimethyl ether 100% MeO OMe Charlton, J.L., et. al. J. Org. Chem. 1986, 51, 3490. Lignan Natural Products Baran Group Meeting November 18, 2005 Mike DeMartino

NC OTBDMS OH O OTBDMS -Synthesis of tetralin lignans (cont.) O O RO O LDA; TFA, D CN 2-butenolide; O 12 hr O O O O O Ar O ArCHO 71% O (2 steps) NIS, MeO MeO allyl O OMe Li Ot-Bu O O OMe OMe alcohol O N taiwanin C O Me O O >95% 81% I O O Ot-Bu O Ot-Bu Ogiku, T. et. al. J. Org. Chem. 1995, 60, 4585.

DLP (0.5 eq) DLP (3 eq) O NaHCO3 NaHCO MeO CO2Et D, 76% 3 MeO D, 48% H H H + 6% A O O H MeO 1. NaH; O NaOEt MeO CO Et 1. ArLi, LiCl 2 O 1. 3N HCl O O OH BuLi; ArCHO MeO 0°C 2. PCC 53% O O O O MeO Br 2. PCC CO Et H O 50% H Ot-Bu 2. KH, 59% 2 A H Ot-Bu O PhSeCH2Cl , O O dr = 1:1 O O (EtO)2OP CO2Et MeO OMe MeO OMe 68% 73% OMe OMe TMSOK; HCl dehydrodeoxypodophyllotoxin 93% Renaud, P. et. al. Syn. 2005, 9, 1459. O a) BH3•DMS MeO MeO MeO CO2H HClEtOH O O OH O OR MeO MeO MeO CO2Et -Synthesis of napthalene lignans O b) NaH, LiBH RO O 4 D; 0.5N HCl

Ar O O O O O O MeO MeO Justicidin B Retrojusticidin B O Pd/C O NH4OCHO Conditions BnO HO a) 76% trace O O b) 28% 67% BnO daurinol Harrowven, D.C., et. al. Tetrahedron Letters 2001, 42, 6973. MeO O O xylenes O O O D, 5 hr O O MeO Pd/C MeO O RO O O NH4OCHO O -Synthesis of dibenzocyclooctadiene O BnO HO (stegane) lignans O O For a summary of the work done in this field, R'O retrochinensin please see 2004 group meeting seminar by O O Alex Zografos: Stegane Natural Products O O Anastas, P. et. al. J. Nat. Prod. 1991, 6, 1687. http://www.scripps.edu/chem/baran/html/meetinschedule.html Lignan Natural Products Baran Group Meeting November 18, 2005 Mike DeMartino

Lignan Me RO structural -Synthesis of miscellaneous lignans rearrangement/ modification O RO O

New Lignan The eupomatilones Scaffold HO Me HO Me Me Me Me RO O RO Me RO O Me OH RO Me RO O O RO OH O RO O RO O OR RO

O 1,4-benzodioxane lignans OH O OH oxygenated eupomatilone diarylbenzylbutane reigning biosynthetic hypothesis skelaton OH OH OH OH O CO H Carroll, A.R., et. al. Aust. J. Chem. 1991, 44, 1615. 2 Carroll, A.R., et. al. Aust. J. Chem. 1991, 44, 1705. Horse radish O OH O For syntheses of the eupomatilone 6, a representative member of the family, see: peroxidase Coleman, R.S., et. al. Org. Lett. 2004, 6, 4025. O CO2H HO2C OH Hutchinson, J.M., et. al. J. Org. Chem. 2004, 69, 4185. Hong, S.-p., et. al. Org. Lett. 2002, 4, 19. CO2H 8% 10% HO2C

Me 1. TMSCHN 2 Me 2. Dibal 3. LAH H O O H OH O O OH O OH O carpanone O Me O OH Me Me O PdCl2 H HO O KOt-Bu O (0.5 eq) O O O OH H HO OH DMSO O OH O OH NaOAc O O americanol isoamericanol 62% O carpanone O Chapman, O.L., Engel, M.R., Springer, J.P., Clardy, J.C. J. A. Chem. Soc. 1971, 93, 6696. Matsumoto, K.M., et. al. Tetrahedron Letters 1999, 40, 3185. For solid phase synthesis, see: For other syntheses of 1,4-benzodioxane lignans, see: Shair, M.D., et. al. J. Am. Chem. Soc. 2000, 122, 422. Gu, W., et. al. Tetrahedron Letters 2000, 41, 6079. For synthesis using solid phase reagents, see: Merlini, L., et. al. J. Chem. Soc. Perk. Trans.1 1980, 775. Ley, S.V., et. al. J. Chem. Soc. Perk. Trans. 1 2002, 1850.