The Stereoselective Synthesis of Neolignans

REVIEW 2595

The Stereoselective Synthesis of Neolignans TheMichael Stereoselective Synthesis of Neolignans Sefkow Universität Potsdam, Institut für Chemie, Karl-Liebknecht-Straße 24-25, 14476 Golm, Germany. Fax +49(331)9775067; E-mail: [email protected]. Received 5 September 2003

cohol (2), or isoeugenol (3) (see Scheme 3).4 The Abstract: Neolignans, dehydrodimers of phenylpropenes, are important natural products with high structural diversity and various classification of dehydrodimers of phenylpropenes into biological properties. Several diastereo- and enantioselective syn- lignans and neolignans is based on their coupling pattern: thesis of neolignans have been developed in the past, either specific lignans are connected between C(8) and C(8¢) whereas all for each of the various neolignan skeletons or randomized. This re- other possible dimerization products of phenylpropenes view summarizes the efforts towards the synthesis of chiral neolig- are called neolignans.5 nans, racemic and optically active, and provides a brief outlook for future developments. The initial step of the oxidative dimerization is the gener- ation of a radical by the abstraction of a proton and an 1 Introduction 2 8,5¢-Neolignans with Dihydrobenzofuran Skeleton electron. This radical is highly stabilized by resonance, 2.1 Diastereoselective Synthesis of Dihydrobenzofuran Neolig- represented by the formulas A–E (Scheme 1). The subse- nans quent C–C bond-forming reaction is usually described as 2.2 Enantioselective Synthesis of Dihydrobenzofuran Neolign- the coupling of two radicals although evidence for this ans mechanism is still lacking.6 The newly created C–C bond 3 8,3¢-Neolignans can be positioned between different carbons of either of ¢ 4 8,1 -Neolignans the phenylpropenes affording structurally diverse cou- 5 8-O-4¢-Neolignans 5.1 Diastereoselective Synthesis of 8-O-4¢-Neolignans pling products, e.g. AA, AB, BB, or AD. Some prominent 5.2 Enantioselective Synthesis of 8-O-4¢-Neolignans examples of possible lignan and neolignan skeletons, 6 Benzodioxane-Neolignans found in natural products (e. g. steganacin, conocarpan, 6.1 Diastereoselective Synthesis of Benzodioxane-Neolignans diferulic acid, kadsurenone) are displayed in Figure 1. 6.2 Enantioselective Synthesis of Benzodioxane-Neolignans 1 7 Bicyclo[3.2.1]Octane-Neolignans An alternative mechanism for the formation of lignans 8 Conclusion and Outlook and neolignans is shown in Scheme 2. It is based on the consideration that highly reactive radicals are usually gen- Key words: natural products, neolignans, stereoselective synthesis, dihydrobenzofurans, enantioselective synthesis erated in low concentrations and on the finding that structures AB–AE but not BB are the most abundant substructures in lignins.7 If this is taken into account then it is more likely that the dimerization process involves the 1 Introduction electrophilic attack of a radical to a phenylpropene. This mechanism is further supported by the fact that the in vitro Lignans and neolignans are important secondary plant dimerization of phenylpropenes either with metal salts or metabolites possessing a variety of different biological ac- with enzymes yields dimers such as AB or AC as major tivities.1,2 Since the pioneering work of Erdtman3 it is products, which can be explained by the formation of a widely accepted that both, lignans and neolignans stabilized benzyl radical when the double bond is attacked (Figure 1), are produced in nature by oxidative dimeriza- at C(8) (Scheme 2). tion of phenylpropenes, e.g. ferulic acid (11), coniferyl al-

CO2H CO2H CO2H CO2H CO2H CO2H

-H+

-e− MeO MeO MeO MeO MeO MeO OH O O O O O ferulic acid (1) A B C D E

Scheme 1 Stabilized radical derived from ferulic acid (1) with resonance structures A–E.

SYNTHESIS 2003, No. 17, pp 2595–2625xx.xx.2003 Advanced online publication: 21.11.2003 DOI: 10.1055/s-2003-42482; Art ID: E09803SS © Georg Thieme Verlag Stuttgart · New York 2596 M. Sefkow REVIEW

Figure 1 Lignans and neolignans with different skeletons.

Many reviews and accounts have been published on the 2 8,5¢-Neolignans with Dihydrobenzofuran stereo- and enantioselective synthesis of lignans1,2 but Structure only a few gave an overview on the strategies for the synthesis of neolignans.8 It is the aim of this article to close 8,5¢-Neolignans containing a dihydrobenzofuran skeleton this gap. Several neolignans (e. g. benzofuran-neolignans) are the most abundant neolignans in nature. One reason are achiral compounds. The synthesis of these compounds may be the mechanism of their biosynthesis (Scheme 2). will not be reviewed in this article. It is restricted to the As mentioned, enzymatic or metal salt induced oxidative synthesis of chiral neolignans, in particular 8,5¢-, 8,3¢-, dimerization of several phenylpropenes afford predomi- 8,1¢-, 8-O-4¢-, benzodioxane-, and bicyclo[3.2.1]octane- nantly the dihydrobenzofuran neolignans. The ubiquitary neolignans. occurrence and the various biological properties of dihy-

-e− -H+ MeO -H+ MeO MeO MeO O O HO OMe HO OMe

MeO OH O OH MeO OH Scheme 2 Possible mechanism of the oxidative dimerization of phenylpropenes.

Biographical Sketch

Michael Sefkow (born vard University with Prof. include the stereoselective 1966, Berlin, Germany) D. A. Evans (1994–1995), synthesis of lignans and studied chemistry at the he went to GBF (1996– neolignans, the transition Technical University of 1997) working the epo- metal catalyzed cyclo- Berlin. He obtained his PhD thilones. In 1998 he started additions, and the reactivity in 1994 from the ETH his independent research at of non-solvated carbenium Zürich under the guidance the University of Potsdam ions. of Prof. D. Seebach. After funded by a DFG-fellow- postdoctoral study at Har- ship. His research interests

Synthesis 2003, No. 17, 2595–2625 © Thieme Stuttgart · New York REVIEW The Stereoselective Synthesis of Neolignans 2597

X drobenzofuran neolignans make them attractive for syn- X thesis. In fact, about 50% of all publications concerned with the synthesis of neolignans describe the preparation X 9 of 8,5¢-neolignans. oxidizing

agent Y O Y 2.1 Diastereoselective Synthesis of Dihydroben- OH OH zofuran Neolignans 3 X = CH3, Y = OMe 14 13 X = CH2OH, Y = H 15 Y 2 X = CH2OH, Y = OMe 16 Many diastereoselective syntheses of neolignans with di- 4 X = CO2H, Y = H 17 hydrobenzofuran skeleton have been published.2,9 The 9 X = CO2Me, Y = H 18 5 X = CO2H, Y = OH 19 vast majority of these syntheses is based on the biomimet- 10 X = CO2Me, Y = OH 20 ic oxidation of phenylpropenes, following Erdtman’s pro- 11 X = CO2Et, Y = OH 21 3 12 X = CO2tBu, Y = OH 22 cedure. Since the oxidative dimerization requires a 1 X = CO2H, Y = OMe 23 phenolic hydroxy group in the para position, only a few 6 X = CO2Me, Y = OMe 24 7 X = CO2Et, Y = OMe 25 phenylpropenes can been used as substrates. In fact, 8 X = CO2Ara, Y = OMe 26 ferulic (1), coumaric (4), and caffeic acid (5), their esters 6–12, coumaryl (13), coniferyl alcohol (2), and isoeu- Scheme 3 Ara = arabinosyl. genol (3) were the only phenylpropenes, which have been employed for the diastereoselective oxidative coupling nans and benzodioxane-neolignans were the predominant (Scheme 3). In all cases, the dihydrobenzofurans with side product. Evidently, benzodioxanes can only be pro- trans-configuration, compounds 14–26, were isolated, duced when o-dihydroxy-phenylpropenes have been em- this is also found in nature. A few neolignans were deter- ployed (see chapter 6). mined to have a cis-configuration.10 The structures of most of these neolignans had to be revised after analysis Two less common propenylphenols were also used for the 55 of a pure cis-8,5¢-neolignan which was prepared by hydro- oxidative dimerization: 4-hydroxy-phenyl-propene 27 56 genation of a benzofuran.11 and 4-hydroxy-2-methoxycinnamate 28. Compound 27 was oxidized by FeCl3 to insecticidal conocarpan (29) in Various oxidation reagents have been used for the dimer- 27% yield. Oxidation of compound 28 afforded the 8,5¢- ization of phenylpropenes, most of them based on two neolignan 30 alongside several other dimers and higher general strategies: (a) enzymatic oxidation (peroxidases,12 13 14 oligomers (Scheme 4). The yields were dependent on the laccases ) and (b) oxidation with metal salts (Ag2O, 15 16 oxidizing agent. Oxidation of 28 with K3Fe(CN)6–K2CO3 FeCl3 ). Other oxidizing agents were nitrous acid, oxy- produced the dihydrobenzofuran in 31% yield, whereas n 17 18 19 gen/h , stable radicals, and periodinanes (with this oxidation with Ag O gave only 21% of dimer 30. reagent, presumably a cationic mechanism is involved). In 2 recent years advances have been made to control the class R' of neolignans20 and to optimize the yield of the desired 12 product. However, the oxidative dimerization of phenyl- R' propenes produced in all cases several neolignans and R 21 higher oligomers with various ratios. The combined FeCl3 for 27 R yields of all dimers were, with few exceptions, in the R' K Fe(CN) range of 10–70%.3,12–54 Interestingly, Lewis et al. reported 3 6 O or Ag2O for 28 that the dimerization of isoeugenol (3) with horseradish OH R peroxidase/H2O2 (HRP/H2O2) gave dimer 14 in 99% yield.32 A summary of reaction conditions, starting mate- 27 R = H, R' = Me 29 (27%) OH rials and 8,5¢-neolignans is given in Table 1. 28 R = OMe, R' = CO2Me 30 (31/21%) As shown in Table 1, the dihydrobenzofuran-neolignans, Scheme 4 prepared by oxidative dimerization, were in most cases accompanied by substantial amounts of 8-O-4¢-neolig- Several dihydrobenzofuran-neolignans have been pre- nans no matter which phenylpropene was used as sub- pared involving alternative strategies. The strategies for strate or which oxidation method was employed. It was the diastereoselective construction of trans-dihydroben- observed that the ratio of 8-O-4¢- vs. 8,5¢-neolignans, ob- zofurans are based on a few principle reactions: the tained by enzyme catalyzed oxidation of phenylpropenes, Schmid rearrangement, the rearrangement of chalcone ep- was dependent on the pH value of the solution. The opti- oxides, and the acid catalyzed cycloaddition of properly mal yield and ratio for the synthesis of 8,5¢-neolignans functionalized quinoids to phenylpropenes. Furthermore, was achieved at pH 5.48 On the other hand, by varying the an anionic and a radical-based approach have been devel- reaction conditions the 8-O-4¢-neolignans were formed as oped for the synthesis of 8,5¢-neolignans. the major product.20 In some cases lignans, 5,5¢-neolig-

Synthesis 2003, No. 17, 2595–2625 © Thieme Stuttgart · New York 2598 M. Sefkow REVIEW

Table 1 Substrates and Conditions for the Oxidative Dimerization Table 1 Substrates and Conditions for the Oxidative Dimerization of Propenylphenols to Dihydrobenzofurans of Propenylphenols to Dihydrobenzofurans (continued)

a a C6C3 Conditions Prod- Yield Other References C6C3 Conditions Prod- Yield Other References uct % Productsb uct % Productsb

c ¢ 22,23 14,15,42,49,50 3 UV/solvent 14 8–10 8-O-4 6 Ag2O 24 38–50

d e ¢ 18 51 3 radical 14 (70) 8-O-4 6 UV/dye/O2 24 6 many prod.

f ¢ 17,24,25 ¢ 15 3 UV/dye 14 15–42 8-O-4 (42) 6 FeCl3 24 34 8,8 (30)

g h ¢ h 26,27,31,32 12,52 3 HRP/H2O2 14 19–99 8-O-4 (22) 7 HRP/H2O2 25 21–50 8,8¢ (13) 53 7 Ag2O 25 28–50 many prod. 16 3 HNO2 14 38 54 8 Ag2O 26 55 many prod. 3i 800mV, solv. 14 28 8-O-4¢ (20)j 28,29 a C6C3 = starting phenylpropene. ¢ j3,30 b 3 FeCl3 14 53 8,8 (2) Percent yield in parentheses. c In the absence of oxygen. k ¢ l 20,31 3 Ag2O 14 - 8-O-4 (59) d Radical = 2,4,6-Tri-tert-butylphenoxyl radical. e m 31 Combined yield based on recovered starting material. 3 Mn(III)/Ox. 14 10 f Proflavin;17 methylene blue.24,25 g ¢ ¢ 27 3 laccasen 14 43 8-O-4¢ (22) 13 With (Z)-3:8,5 -neolignan (22%), 8-O-4 -neolignan (53%). h Yields of 8,5¢- and 8-O-4¢-neolignans variable, depending on the 19 solvent. 3 PhI(OAc)2 14 35 i With (Z)-3:8,5¢-neolignan (5%); 8-O-4¢-neolignan (32%). ¢ 33 j 13 HRP/H2O2 15 24 8-O-4 (6) In addition to several other by-products. 8,8¢ (24) k Yields not reported. l Major product: 8,5¢-neolignan (in benzene); 8-O-4¢-neolignan (in 2 Ag O 16 47–50 8-O-4¢ (32) 34 2 CH2Cl2). 8,8¢ (5) m Ox. = iodosylbenzene. n From Rhus vernicifera. ¢ o 31,35 2 HRP/H2O2 16 18–24 8-O-4 (36) o 8-O-4¢-neolignan,31 8,8¢-neolignan.35 ¢ 8,8 (10) p The ratio varied from 3:3:1 to 1:1:1.5 (8,5¢:8,8¢:8-O-4¢). q 2 C. fumago 16 13 8,8¢ (12) 36 Combined yield of dimeric products (benzo. = benzodioxanes). r Benzodioxanes (17%) and lignans (18%) are the major products. s 2 Mn(III) 16 -k,p 8-O-4¢k,p 37 Nitroaromatic phenylpropenes and degradation compounds are the 8,8¢k,p major products. t Laccase (1.10.3.1). 2 laccasen 16 31 8-O-4¢ (11) 13 u Ratio of 8,5¢- vs. 8-O-4¢-neolignan depending on the pH value of the 8,8¢ (12) reaction mixture.

¢ 21 2 Cu(OAc)2 16 88-O-4 (33) 8,8¢ (9) The Schmid rearrangement57 is an abnormal Claisen rearrangement, which takes place when phenylcinnamyl ether 38 4 B. megaterium 17 9 are heated over 200 °C in diethylaniline or other high boil- 38 4 Na3Fe(CN)6 17 19 ing solvents (Scheme 5). The yields of dihydrobenzofurans are about 20–40%. The Schmid rearrangement was 39 9 Na3Fe(CN)6 18 57 first used by Gottlieb and Aiba for the synthesis of licarin 58 59 14 B (31), an immunosuppressive neolignan, and later by 9 Ag2O 18 23 Ponpipom et al. for the construction of dihydrobenzofuran q ¢ 40 5 O2 19 (18) benzo.; 8,8 32, an intermediate in the synthesis of the PAF-anatago- 60 5 HRP/H O 19 2,5 many prod.r41 nist kadsurenone (chapter 3). The same key reaction was 2 2 also used for the preparation of kadsurenin M (33)61 and a 14,42,43 62 10 Ag2O 20 33 bicyclo[3.2.1]octane neolignan (chapter 7). The yields 10 NO –, pH 1 20 20 many prod.s44 of the desired rearrangement products were ca. 40%. Oth- 2 er products, accompanying the major compound, were 45 11 Ag2O 21 29 benzo. (6) typically regioisomers thereof. The major drawback of this strategy was the preparation of the phenylallylether, 12 Ag O 22 28 benzo. (5) 46 2 such as 34, which was obtained only by a low yielding (ca. ¢ 47 1 HRP/H2O2 23 38 8,8 (25) 25%) etherification reaction under Mitsunobu conditions.60 Better yields of similar ethers have been accom- t k,u ¢k,u 48 1 laccase 23 - 8-O-4 plished in the reaction of 3,4-dimethoxycinnamyl chloride 31 61 6 HRP/H2O2 24 50 with the sodium salt of vanillin in DMF (60%). Chalcone epoxides, easily prepared by nucleophilic epoxidation, rearranges upon treatment with Lewis acids to Synthesis 2003, No. 17, 2595–2625 © Thieme Stuttgart · New York REVIEW The Stereoselective Synthesis of Neolignans 2599 afford the corresponding b-dicarbonyl compounds Heck reaction of 41 produced 8,5¢-neolignan 43 in 30% (Scheme 6). These compounds are not configurationally yield (Scheme 7). Removal of the protecting groups gave stable. Therefore, they were immediately treated with a 39 and reduction of 39 afforded 38.66 reducing agent (NaBH4), affording the corresponding 1,3- The acid catalyzed [3+2] cycloaddition of phenylprope- diols in reasonable yields (26–57% yield), but with mod- nes with quinones to dihydrobenzofurans was used as an erate diastereoselectivities (ca. 4:1). The 1,3-diols were alternative route for the construction of 8,5¢-neolignans. transformed into the dihydrobenzofurans by acid cata- The initial reaction between the phenylpropene and the lyzed cyclization after cleavage of the phenol protecting 63 quinone derivative is regarded as a cationic [5+2] cy- group. The acid-catalyzed rearrangement of chalcone cloaddition affording a bicyclo[3.2.1]octenyl carbocation, epoxides into dihydrobenzofurans was used for the syn- which rearranges to the more stable benzyl cation. Subse- thesis of silychristin, a flavonolignan containing the dihy- quent cyclization and proton abstraction then afforded the drobenzofuran skeleton 35,64 and for the lignin model 63 65 dihydrobenzofuran in 22–75% yield and with diastereo- compounds 36 and 37. Most recently, Antus et al. used meric ratios of ca. 95:5 (trans:cis). This reaction was ac- this protocol for the synthesis of balanophonin 38 and a 68 66 complished with p-diphenols at the stage of a quinone, related neolignan, 39, from dihydrobenzofuran 40. They of a quinone monoacetal,69 and of a quinone monoimide70 calculated that a selective functionalization at C(5) of (Scheme 8). Lewis acids [TiCl /Ti(i-PrO) and BF ·Et O] compound 40 should be possible with electrophilic re- 4 4 3 2 67 or protic acids were employed to catalyze this reaction. agents. In fact, bromination of 40 occurred exclusively For example, (E)-isosafrole reacted with 2-allyl-3,4,4-tri- at C(5) providing compound 41 in 80% yield. Compound methoxy-cyclohexa-2,5-dienone under the influence of 41 was functionalized by halogen metal exchange to give trinitrobenzenesulfonic acid to furnish dihydrobenzofuran the lithiated intermediate, which upon formylation and neolignan 44, the constituent of an Aniba species,71 in Wittig reaction provided 42 in 21% yield. Alternatively, 60% yield (Scheme 8).69

1,5-homo- Ar sigmatropic Ar ∆ H-shift O Claisen Ar O H O O

O MeO MeO CHO O MeO MeO O O OH O

31OMe 32 33 OMe

MeO O O

MeO 34 Scheme 5 The Schmid rearrangement.

Scheme 6 The chalcone epoxide rearrangement.

Synthesis 2003, No. 17, 2595–2625 © Thieme Stuttgart · New York 2600 M. Sefkow REVIEW

Br 5 Recently, Itoh et al. reported that 3 mol% iron(III) per- chlorate in the presence of Al2O3 effected the cycloaddition of phenylpropenes 45–47 with p-benzoquinone 48 to OMe Br2 OMe the dihydrobenzofurans 49–51. Excellent yields (91– AcO O AcO O AcOH 94%) and good diastereomeric ratios 8–30:1 (trans:cis) 80% have been achieved within a reaction time of 2–4 hours (Scheme 9).72 Even better results were obtained when the AcO OMe reaction was carried out in an ionic liquid (butylmethylim- AcO OMe 40 41 midazolium hexafluorophosphate, [bmim]PF6) and with Pd(OAc)2 iron(II) tetrafluoroborate as catalyst. Under these condi- CO Me 30% 1) OH 2 R = Ac 2) MOMCl tions dihydrobenzofuran 51 was produced within 3 min- 3) BuLi utes in 98% yield and a diastereomeric ratio of 8:1 Li (trans:cis). It was assumed that the redox system Fe(II)/ 1) DMF Fe(III) transfer one electron from the phenylpropene to 2) Wittig OMe the quinone affording a radical cation and a radical anion 21% from 41 RO O OMe which dimerize to the corresponding dihydrobenzofuran R = MOM MOMO O (Scheme 9). The proposed mechanism is supported by the observation that both, iron(II) and iron(III) salts catalyze the reaction. Similarly, 10 mol% InCl3 effected the [3+2] RO OMe cyclization of 45–47 with quinone 48 in 89–94% yield.73 42 R = MOM MOMO OMe 43 R = Ac OH O Scheme 7 72 Fe(ClO4)3 73 or InCl3 + 89 − 94% O X R' O X R (Lewis) R 48 R' acid R' R' + 45 R = OMe, R' = H 49 R = OMe, R' = H O 46 R,R' = OCH2O 50 R,R' = OCH2O 47 R,R' = OMe 51 R,R' = OMe O R O X = (OMe)2 X = OMe R III X = NSO2Ph X = NHSO2Ph Fe X = O X = OH O O FeII

O O XLA H R R' Scheme 9 LA R' X O The dihydrobenzofuran 52, derived from the BF3 cata- R lyzed [3+2] cycloaddition of 3,4-methylenedioxy-propenylbenzene and N-(3-methoxy-4-oxo-cyclohexa-2,5- O OMe dienylidene)-benzenesulfonamide, was used for the syn- O thesis of licarin B (31).70 Compound 52 was deprotected O OH at the amino group providing aniline 53, which was sub- 44 (60%) sequently converted to the iodide 54 in 48% overall yield from 52. Stille coupling of propenyltributyltin and iodide 54 catalyzed by Pd2(dba)3 afforded licarin B (31) in 85% Scheme 8 yield (Scheme 10).

PhSO2 1) (Boc)2O 1) NaNO2/HOAc NH NH2 I 2) Na/anthracene 2) Et2NH/K2CO3 3) F3CCO2H 3) NaI/Me3SiCl SnBu3 31 48% from 52 Pd2(dba)3 O OMe O OMe O OMe 85%

O O O 52 53 54 O O O Scheme 10

Synthesis 2003, No. 17, 2595–2625 © Thieme Stuttgart · New York REVIEW The Stereoselective Synthesis of Neolignans 2601

A somewhat different strategy to effect the cycloaddition A OMe OH of a quinone derivative is the base mediated reaction of PhI(O2CCF3)2 methylquinol 55 with phenylpropene 47. The reagent of 71% 47 + choice for the cycloaddition procedure was mesyl chlo- or O ride/triethylamine to produce dihydrobenzofuran 56, al- E , LiClO4 OMe 65% beit in low yield (15%) (Scheme 11).74 Other classes of MeO 60 59 B neolignans, such as 8,3¢- and 7,3¢-neolignans, can be pre- OMe pared as well using this approach. Scheme 13

OH OMe ployed in the directed a-metalation, then functionalized as OMe 78b MsCl/Et3N carbamates. Watanabe et al. found that the directed a- + 47 15% O metalation was effectively accomplished with arylphos- O phamidates as the directing metalation group (DMG).80 55 MeO 56 This methodology was later used for the synthesis of car- OMe inatol (61).81 Phosphamidate 62, prepared in 3 steps (94% Scheme 11 yield) from eugenol, was metalated at the benzylic methylene group ortho to the phosphamidoyl group and reacted with dimethoxybenzaldehyde (DMB) to give carbinol A radical-based cycloaddition was the key reaction in the 63 in 71% yield. The diastereomeric ratio was low 77:23 synthesis of conocarpan (29) by Snider et al.75 (anti:syn). The phosphamidoyl group was reductively re- (Scheme 12). Reaction of cyclohexenone 57 with anethol moved to afford phenol 64 (53% yield), which was subse- (45) by means of Mn(OAc) afforded dihydrobenzofuran 3 quently cyclized under acidic conditions to carinatol (61) 58. However, the yields achieved with various cyclohex- in 41% yield (Scheme 14). anones were rather low (0–31%) and double bonds in the side chain of the cyclohexenones were incompatible with the reaction conditions.

Cl Cl

>4 Mn(OAc)3 45 + 25% O O 57 MeO 58 1) KOtBu 2) LiPPh2

conocarpan (29)

Scheme 12

Electron-rich phenylpropenes, such as 47, have been oxidatively coupled with phenols (e.g. 59) induced either by iodobenzene bisacetates (method A) or by anodic oxida- Scheme 14 DMB = 3,4-Dimethoxybenzaldehyde tions (method B).76 Following these approaches, dihydrobenzofuran 60 was isolated in 71% (method A) and The first non-dimerizative synthesis of dehydrodiconifer- 65% (method B) yield (Scheme 13). Furthermore, neolig- 82 nan 32 (see Scheme 5), the key precursor of kadsurenone ylalcohol 16 was reported by Nakatsubo and Higuchi. A (see chapter 3), was prepared in 28% yield. Starting material for both aryl groups, present in 16, was vanillin. This was converted to O-benzyl vanillin and to 77 Benlow et al. recently published a new intramolecular iodo benzene 65. Formylation, treatment with methyl me- cyclization strategy but this method was not used for the thylthiomethyl sulfoxide (FAMSO), hydrolysis and re- stereoselective construction of dihydrobenzofurans con- protection afforded methylester 66 in 70% yield. The key taining two stereocenters. reaction of this strategy was the coupling of 66 with O- The directed metalation of phenol or aniline derivatives is benzyl vanillin. This reaction was accomplished after a widely used method for the functionalization of arenes deprotonation of 66 with LDA affording the threo product ortho to the oxygen or the nitrogen.78 In contrast, very few 67 in 80% yield (Scheme 15). Reduction of the ester moi- examples are known in which directed metalation occurs ety gave alcohol 68 (85% yield). Hydrogenolysis fol- 78,79 at a benzylic methylene group. When phenols are em- lowed by BF3-mediated cyclization provided dihydro-

Synthesis 2003, No. 17, 2595–2625 © Thieme Stuttgart · New York 2602 M. Sefkow REVIEW benzofuran 69 in 85% yield. Chain extension at C(5) of sponding sulfoxide, sulfoxide–lithium exchange, and ad- dihydrobenzofuran 69 was achieved by Wittig reaction. dition of the desired electrophile. The oxidation was Deprotection and reduction, completed the synthesis of achieved with MCPBA in almost quantitative yields. The dehydrodiconiferylalcohol (16) (85% yield from 69). subsequent replacement of the sulfoxide moiety was best accomplished with PhLi. Addition of the electrophile 1) BuLi/DMF gave the substituted dihydrobenzofurans in 52–93% yield. CH(OMe)2 2) FAMSO CH(OMe)2 3) HCl/MeOH The key precursor for the synthesis of liliflol B and + 4) CH(OMe)3, H kadsurenone, compound 70 (Scheme 16), was synthe- 70% sized in 26% from phenylpropene 47. I OMe OMe In contrast to the many naturally occuring trans-dihy- OBn MeO2C OBn 65 66 drobenzofuran neolignans, only a few cis-dihydrobenzofurans were identified in nature. However, in 1997, Wallis LDA, 80% benzyl- et al. reported that all of the known cis-dihydrobenzofuran vanillin natural products were misassigned. Their studies were

OBn OBn based on the stereoselective synthesis of cis-dihydroben- OMe OMe zofurans by the Pd-catalyzed hydrogenation of the corre- CH(OMe)2 1) Me3SiCl CH(OMe)2 sponding benzofurans (Scheme 17). Comparison of the 2) LiAlH4 NMR data of the cis- and trans-dihydrobenzofurans with 85% those reported for the ‘cis-8,5¢-neolignans’ revealed sev- HO OMe HO OMe eral differences between true and previously assigned cis- 11 OBn MeO2C OBn HO neolignans. 68 67

1) H2, Pd/C R' R' 85% . 2) BF3 Et2O

H2 HO 1) DHP, H+ 2) Wittig O Pd/C 5% O CHO OMe OMe 3) 10% HCl HO 4) NaBH4 R R O 16 85% Scheme 17 MeO OMe 69

Scheme 15 FAMSO = methyl methylthiomethylsulfoxide. Meanwhile one cis-dihydrobenzofuran neolignan, epi- conocarpan (71) has been isolated from Piper regnellii,84 A new type of oxidative [3+2] cycloaddition via an aro- whose relative configuration was further confirmed by its 85 matic Pummerer reaction (Scheme 16) was described by preparation (Scheme 18). Kita et al.83 Their strategy required the use of an aromatic A key reaction for the synthesis of epi-conocarpan (71) sulfoxide which upon treatment with Ac2O gave a sulfur- was the cis-selective carbene insertion using ruthenium substituted, cationic S,O-benzoquinone intermediate. This porphyrin complexes as catalysts. The carbene precursor, highly reactive intermediate added to the double bond of tosylhydroazone 73, was prepared from acetophenone 72 a phenylpropene and produced diastereoselectively thio- in two steps (85% yield). Tosylhydrazone 73 was metalat- ether-substituted trans-dihydrobenzofurans in good to ex- ed with NaOMe and treated with catalytic amounts of cellent yields (46–90%). The thioether could be replaced [RuII(TPP)(CO)] [TPP = meso-tetrakis(p-tolyl)porphy- + – by various electrophiles upon oxidizing it to the corre- rine] in the presence of BnEt3N Cl as phase transfer cat-

X SPh E OH O R'

Ac2O PhLi R R R R O E+ O − S S X = 2e Ph O Ph R' X = O R'

MeO

MeO O OMOM 70 (26% from 47)

Scheme 16

Synthesis 2003, No. 17, 2595–2625 © Thieme Stuttgart · New York REVIEW The Stereoselective Synthesis of Neolignans 2603

NNHTs 2.2 Enantioselective Syntheses of Dihydrobenzo- O Br furan Neolignans Br 1) PMBCl 2) TsNHNH 2 The asymmetric synthesis of dihydrobenzofuran neolig- 85% O OH nans is not highly developed. Up to now only a few re- 72 73 OMe ports on the synthesis of optically active 8,5¢-neolignans appeared in the literature. Obviously, one approach was 77% 1) MeONa 2) Ru(II)(TPP)(CO) the asymmetric biomimetic oxidative coupling of achiral phenylpropenes. Other strategies were the oxidative cou- 1) BuLi/DMF Br pling using chiral phenylpropenes, a chiral Lewis acid 2) Wittig mediated cycloaddition, the ring contraction of chiral fla- 3) PdCl2 4) LiPPh2 vanones, and more recently, a chiral aldol reaction approach based on Evans’ auxiliaries. O 30% O Early efforts at the biomimetic asymmetric dimerization 71 74 OH OMe of two achiral phenylpropenes using enzymes, such as Scheme 18 TPP = triphenylphosphane. peroxidase, have revealed that this process provided racemic dimers.88 Only when external chiral compounds such as sugars were added, a low asymmetric induction was ob- 89 alyst. The metal carbene inserted into the benzylic C–H served (0–10%). A similar result was obtained when isoeugenol (3) was oxidized with Cu(II) salts in an asym- bond providing dihydrobenzofuran 74 in 77% yield and a with a cis:trans ratio of >98:2. Dihydrobenzofuran 74 was metric environment such as -methylbenzylamine. Under these conditions licarin A (14) was produced in 21% yield converted to epi-conocarpan (71) by formylation, chain 90 extension, and deprotection. The yield for the conversion albeit in poor optical purity. Since the naturally occur- of 74 to 71 was 30% (Scheme 18).85 ring dehydrodimers are optically active, it is assumed that the oxidases need an agent to help control the stereospeci- Treatment of flavanones (e.g. 75) with trimethylorthofor- fity. A protein was identified with which coniferyl alcohol + 86 87 mate (TMOF)/H and Pb(OAc)4 or Tl(NO3)3 also pro- (2) was dimerized with good stereocontrol. However, the vided the cis-dihydrobenzofurans (e.g. 76) in good yields stereocontrol was only observed for the lignan-type via ring contraction (Scheme 19). The mechanism is pro- dimers, e.g. pinoresinol, whereas dehydrodiconiferyl al- posed to proceed via fragmentation of C–Pb or C–Tl in- cohol (16) was still produced as a racemate.91 On the other termediates, which were formed from acetal 77 by hand, an enzyme fraction from the leaves of Piper regnel- elimination of MeOH and addition of the metal salt to the lii converted 4-hydroxyphenylpropene (27) to conocarpan electron-rich vinyl ether. (29) (see Scheme 4) in 85% ee,55 whereas oxidation of coniferyl alcohol (2) using the cell-free extracts of Eucom- mia ulmoides provided racemic dehydrodiconiferyl O Ph OPh alcohol (16) and an optically active 8-O-4¢-dehy- 92 HC(OMe)3 drodimer. HClO4 An alternative approach, in which chiral auxiliaries, co- MeO OMe O valently bonded to phenylpropenes, were prepared and di- 75 77 astereoselectively dimerized, was developed by Orlandi et

-MeOH MXn+1 al. Following their strategy, ferulic acid (1) was reacted with phenyl- and benzyloxazolidinones,93 with camphor 6,93 6,94 OPh O Ph sultam and with alanine ethylester affording the chiral amides 78–81. These amides were subjected to the

M(X)n−1 oxidative dimerization by either horseradish peroxidase/ MeO OMe M(X)n H O or Ag O. In order to examine whether the peroxi- X MeOH OMe 2 2 2 X dase reacted differently with the two phenylpropene enan- M = Tl(III), X = NO3 tiomers, both antipodes of oxazolidinones 78 and 79 were M = Pb(IV), X = OAc prepared and dimerized. The dehydrodimers 82–85 and the corresponding minor diastereoisomers 86–89 were O Ph O obtained in 35–70% yield and in diastereomeric ratios of H2O Ph up to 92:8 (Scheme 20). No effect on yield or diastereo- Tl(III) 75% selectivity was observed when different enantiomers of OMe Pb(IV) 85% MeO CO2Me the phenylpropenes were employed in the oxidative 76 dimerization with HRP/H2O2. The auxiliaries were re- Scheme 19 moved by hydrolysis to afford dehydrodimer 24. This dehydrodimer was further transformed to optically active dehydrodiconiferyl alcohol (16). The ee of 16 was in the range of 18–84%.

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COXN COXN

COXN LiBH4 HRP/H2O2 or 1 − 6 steps or Ag2O XNOC XNOC LiOOH LiAlH4 1 3 + 3 24 16 55 − 70% − CH N 35 70% 2 2 2 2 (18 − 84% ee) O OMe O OMe OMe OH HO HO 78 − 81 OMe OMe

86 − 89 1 : 1.4 − 11.5 82 − 85

O O H 78,82,86 XN = N O 79,83,87 XN = N O 80,84,88 XN = N 81,85,89 XN = NCO2Et O S Bn Ph O both enantiomers were prepared

Scheme 20

Engler et al. have shown that the cationic [5+2] cycload- ether. Interestingly, this reaction provided directly the di- dition of a p-benzoquinone and a phenylpropene, induced hydrobenzofuran 98 without the need of an acid catalyzed by stoichiometric amounts of a Lewis acid, such as cyclization. The authors speculated that the bromine at Ti(i-PrO)4/TiCl4, is a versatile method for the construction C(5) might have activated the molecule. Chain extension of dihydrobenzofurans (Scheme 8). As a logical conse- at C(5) was carried out by formylation and Horner–Wads- quence the same group demonstrated that the asymmetric worth–Emmons (HWE) reaction to afford compound 99 Lewis acid induced cycloaddition of phenylpropene 47 in 71% yield. Finally deprotection and reduction provided and quinone 90 using TiCl4/Ti(i-PrO)4 and one equivalent (+)-16 in 61% yield and >99% ee (Scheme 22). The over- of TADDOL (91) gave dihydrobenzofuran 92 in 95% all yield over 16 steps was 15% (average yield 89%). 95 yield and with up to 82% ee (Scheme 21). Another approach for the synthesis of optically active dihydrobenzofurans is the use of natural chiral precursors. Ph Ph OH As shown in Scheme 19, flavanones rearrange to the dihy- Ph O + OH OMe drobenzofurans by means of trimethyl orthoformate/H , Me OH O O and a two electron oxidizing agent, such as Pb(IV) or 91 Ph Ph OMe Tl(III). In analogy to this approach, enantiomerically pure TiCl4/Ti(OiPr)4 47 + O flavanone 100 rearranged to dihydrobenzofuran 101 (40% −78 °C r.t. yield) upon treatment with iodobenzene diacetate and sul- 95% 99,100 O furic acid in trimethyl orthoformate (Scheme 23). It is 90 92 (82% ee) important to note that under these conditions the trans-di- MeO OMe hydrobenzofuran was obtained as single isomer. This is Scheme 21 particularly interesting since under metal-mediated conditions the cis-isomer was obtained exclusively (Scheme 19). Whether the different conditions produced The C(2)–C(3) bond of the dihydrobenzofuran moiety of ¢ different isomers or the stereochemical assignment of this 8,5 -neolignans can be constructed by an aldol reaction as or the previous work is incorrect is not clear at present. described by Nakatsubo and Higuchi82 (see Scheme 15). ¢ The Evans aldol synthesis is a reliable strategy for the Optically active 8,5 -neolignans have also been obtained asymmetric aldol reaction.96 The first application of this by resolution of the racemic mixture. The resolution was methodology to the synthesis of dihydrobenzofurans was achieved either by HPLC on a chiral stationary phase 50 reported for the asymmetric construction of the dihy- (Chiralcel OD) (even in preparative scale) or by deriva- drobenzofuran moiety 93 of the antiperspirant ephedra- tization with chiral auxiliaries, such as (–)-camphanic ac- 101 102 32 dine.97 Recently the synthesis of (+)-dehydrodiconiferyl id, menthoxyacetic acid acid or Mosher acid, alcohol (16) was published by Okazaki and Shuto em- followed by chromatographic separation. Recently, 103 ploying the same strategy.98 Starting from guajacol (94), Lemière et al. reported the kinetic resolution of dihy- allylphenol 95 was prepared in 65% yield (4 steps). The drodehydroconiferyl alcohol 102 by lipase-catalyzed chiral precursor, acyl oxazolidinone 96, was constructed monoacetylation. Lipases from various sources were ex- in 83% yield by oxidative cleavage of the double bond, amined. In all cases, acetylation was achieved at the hy- oxidation, and amide formation. Aldol reaction of 96 with droxypropyl group hence far away from the stereocenters. O-benzyl vanillin gave alcohol 97 (86% yield). Reductive As a result, monoacyl derivative (2S,3R)-103 was obtained with low ee (12–34%) at ca. 50% conversion. Two removal of the auxiliary was effected with LiBH4. The re- sulting triol was subjected to hydrogenolysis of the benzyl Candida species catalyzed a second acylation [at C(3)–

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Br 1) Br2 1) OsO4, NaIO4 Br 2) C3H5Br 2) NaClO2, H2O2 Bu2BOTf ∆ Br 3) (COCl) O Bn 3) 2 O Bn benzyl- 4) BnBr 4) Li-oxazolidinone vanillin OH N 65% OBn 83% MeO N 86% OMe OBn O OMe OBn O O O MeO 94 95 96 OH

BnO 97

1) LiBH 73% 4 CO2Et 2) H2, Pd/C H2N CO2tBu Br 1) TBSCl HO2C 1) TBAF TBSO 2) tBuLi, FP HO 2) DIBALH 3) HWE (+)-16 MeO 61% MeO MeO O OMe (>99% ee) O OMe 71% O OMe

MeO 93 TBSO 99 HO 98

Scheme 22 FP = 1-formylpiperidine, HWE = Horner–Wadsworth–Emmons olefination.

OR OR PhI(OAc) 5 5 2 AcO HO O O HC(OMe)3 2 3 3 2 2 H2SO4 3 O OMe O OMe 40% CO2Me O 64 − 99% ee 69 − 99% ee MeO MeO 100 101 (+)-(2S,3S) Figure 2 Scheme 23

¢ CH2OH] and the double acylated product 104 was isolated 38,3-Neolignans in up to 50% ee. Interestingly, the ee of the remaining starting material (2R,3S)-102 was 100% at 85% conver- The most important 8,3¢-neolignans are kadsurenone sion, though the yield was only 15% (Scheme 24). (105), an extraordinary potent platelate activating factor In fact, most recent results, reported by Itoh et al.104 under- antagonists (PAF-antagonists), and its diastereoisomer line the importance of ommiting the hydroxy group in the denudatin B (106). For this reason most of the syntheses ¢ side chain. Dihydrobenzofurans, having a protected hy- of 8,3 -neolignans were related to the synthesis of these droxy group at C(5) instead of the propyl alcohol side compounds (Figure 3). chain, can only be acylated at the hydroxymethylene Four different approaches to obtain kadsurenone (105) group which is much closer to the stereocenters. In this were reported. Two of these were the cycloaddition of ap- case, the Novozyme 435 catalyzed acylation with vinylac- propriate starting materials, which afforded directly kad- etate afforded the acylated (2S,3S)-enantiomer in up to surenone and/or denudatin, and two were based on the 99% ee (Figure 2). The remaining non-acylated (2R,3R)- oxidative conversion of dihydrobenzofurans, prepared by enantiomer was isolated in 69–99% ee, depending on the any of the routes described in chapter 2, to their corre- protecting group R.104 sponding 8,3¢-neolignans.

Scheme 24

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ductive removal of MeOH followed by oxidation with Tl(NO3)3 in MeOH provided o-quinone monoacetal 113 MeO in 90% yield. O

MeO Quinone 113 was reacted with trans-3,4-dimethoxypro- O pene (47) in the presence of SnCl to provide denutadin B α-OMe: kadsurenone (105) 4 β (106) in 45% yield alongside the bicyclo[3.2.1]octane 116 MeO -OMe: denudatin B (106) (5%). Interestingly, when the same transformation was Figure 3 carried out with cis-3,4-dimethoxyphenylpropene (117), a mixture of kadsurenone (105) (7% yield), the correspond- Shizuri et al. reported105 that anodic oxidative coupling of ing cis-isomer 118 (10% yield) and bicyclo[3.2.1]octane 2-allyl-4,5-dimethoxyphenol (107), prepared in two steps 119 (25% yield) were obtained (Scheme 26). 106 from 3,4-dimethoxyphenol, with phenylpropenes, ei- The approaches of Engler et al. and of Ponpipom et al. for ther 46 or 47, afforded the dimers 108 and 109, albeit in the synthesis of kadsurenone (105) are already described low yields (ca. 4%). Saponification of the acetic acid ester in chapter 2.1 since both strategies were based on the gave immediately the cyclized products 110 and 111, preparation of dihydrobenzofuran 32 as the central inter- which upon treatment with Ac2O/camphorsulfonic acid mediate (Scheme 5). A key reaction in the Ponpipom ap- (CSA) provided the natural products 112 and denatudin proach was the Schmid rearrangement (Scheme 5) of (106) (quantitatively from 108 and 109 (Scheme 25). phenylallyl ether 34, which was prepared from allyl alco- Horne et al. used a similar strategy for the synthesis of hol 120 and phenol 121 in 25% yield (Scheme 27).60 kadsurenone (105) and analogous natural products by The Engler approach proceeded via a Lewis acid induced which the Lewis acid induced cycloaddition of a quinone cycloaddition of quinone 122 and phenylpropene 47.68 with a phenylpropene was the key reaction 107 This reaction afforded dihydrobenzofuran 123 and cy- (Scheme 26). A suitable o-quinone mono-acetal, 113, clobutane 124 in 60% and 24%, respectively. Cyclobu- required for the cycloaddition, was obtained from quinone tane 124 was quantitatively converted into 123 upon monoacetal 114108 in 3 steps. Allylation of 114 with allyl- treatment with H2SO4. Thus the combined yield of 123 trimethylsilane and TiCl4 afforded 115 (92% yield). Re- from 122 was 84%. The allyl side chain was introduced by

OMe OMe OMe AcO MeO MeO anodic O O 46 oxidation KOH Ac2O + 47 HO ~4% O EtOH CSA OMe O OMe O quant. RO RO RO OR OR OR 107 108 R = −CH − 2 110 R = −CH2− 112 R = −CH2− 109 R = Me 111 R = Me 106 R = Me

Scheme 25

O O O O OMe OMe OMe OMe OMe

AllylSiMe3 1) Zn/HCl SnCl4 + 47 106 + MeO TiCl4 MeO 2) Tl(NO ) MeO (45%) 3 3 O MeO OMe 92% MeO MeOH/ 114 HC(OMe)3 113 90% MeO 115 116 (5%) + OMe SnCl4

105 + MeO + OMe (7%) O MeO MeO O OMe O O 117 118 (10%) 119 (25%) MeO OMe MeO Scheme 26

Synthesis 2003, No. 17, 2595–2625 © Thieme Stuttgart · New York REVIEW The Stereoselective Synthesis of Neolignans 2607 triflation of the hydroxy group and palladium-catalyzed the construction of 8,3¢-neolignans. Quinol 125 was treat- allylation with allyltributyltin. BF3-Mediated removal of ed with MsCl and Et3N to give in situ the arenium mesyl- the benzyl group afforded 32 in 60% yield from 123 ate 126, which in turn reacted with phenylpropene 47 to (Scheme 27). give a cationic, bicyclic intermediate A. This intermediate + Oxidation of 32 to kadsurenone (105) was effected by lost Et (pathway a) furnishing bicyclo[3.2.1]octane 127 ¢ Pb(OAc) in MeOH. However, this procedure was not ef- (41% yield) or rearranged to the 8,3 -neolignan precursor 4 B, providing after loss of Et+ compound 128 in 15% yield ficient, producing 105 and 106 in 10% and 15–19% yield, 74 respectively. The major products were the corresponding (Scheme 28). 3¢-acetoxy epimers. Other metal salts were even less ef- fective. Recently, iodobenzene diacetate (PIDA) was em- O O OEt OEt ployed as oxidizing agent, providing 105 and 106 in 20% MsCl and 50% yield, respectively.62 The avoidance of heavy Et N EtO 3 EtO metals and better yields were the major advantages of this OMs HO Bu Bu oxidizing agent. 126 125

Ponpipom approach 47

O MeO Bu OH + HO O EtO OEt MeO 1,3-shift 121 120 OEt b Bu 25% DEAD/Ph P b 3 O+ O Et MeO a MeO MeO OO MeO OMe BAOMe 34 a ~35% 225 °C O Pb(OAc)4 Bu or PIDA 105 EtO OH OEt 105 MeOH O MeO O Bu O 32 O MeO MeO 1) Tf O 128 (15%) MeO 2 OMe 127 (41%) 60% 2) AllylSnBu3 OMe 3) BF3 OH Scheme 28

OBn An enantioselective synthesis of a 8,3¢-neolignan has not MeO O 123 been reported yet. However, since some methods for the enantioselective synthesis of dihydrobenzofuran neolig- MeO nans are available, the synthesis of optically active 8,3¢- neolignans via conversion of suitable 8,5¢-neolignans Ti(IV) 60% quant. H+ should be in principle possible. O O H OBn OBn Ti(IV) 47 + 24% 48,1¢-Neolignans H O O MeO Only a few reports appeared in the literature on the selec- 122 124 OMe tive synthesis of 8,1¢-neolignans. The majority of the re- Engler approach cent strategies to 8,1¢-neolignans used the cationic Scheme 27 PIDA = phenyliodonium diacetate, DEAD = diethyl- cycloaddition as the key reaction. An elegant synthesis of 109 azodicarboxylate 8,1¢-model compounds was described by Grieco et al. They reacted quinone 129 with isosafrole (46) in the presence of TMSOTf and LiClO , which within 5 minutes af- As mentioned in chapter 2.1, the base-mediated cycload- 4 forded the 8,1¢-neolignan 130 in 89% yield (Scheme 29). dition of a quinol with a phenylpropene was also used for

Synthesis 2003, No. 17, 2595–2625 © Thieme Stuttgart · New York 2608 M. Sefkow REVIEW

OMe (Scheme 31). The quinone derivative 138 was prepared O Me 112 TMSOTf Me from sesamol in 3 steps. Me O LiClO4 + 46 5 min MeO O MeO OMe 89% 129O 130 O Scheme 29

Earlier, a similar approach was used by Engler et al. for the synthesis of burchellin (131). A key reaction was the SnCl4 induced cycloaddition of benzoquinone 132 with isosafrole (46). The combined yield of the 8,1¢-neolignan 133 and its tautomer was in the range of 69–78%, depending on the reaction conditions.110 Methylation of neolignan 133 produced burchellin (131) in 80% yield. Other 8,1¢-neolignans have been prepared as well according to this procedure. Noteworthy is the influence of the Lewis Scheme 31 acid.111 As described in chapter 2.1, titanium-based Lewis acids afforded exclusively the 8,5¢-neolignans, while tin- based Lewis acids produced the 8,5¢-neolignans at –78 °C The acid catalyzed cycloaddition was used by Angle et al. and the 8,1¢-neolignans upon warming to –30 °C for the synthesis of futoenone (139) from (Z)-isosafrole 113 (Scheme 30). Additionally, exposure of trans-propenyl- (137) (Figure 4). The anodic oxidation of 2-allyl-4,5- benzene to the same reaction conditions provided the bi- dimethoxyphenol in the presence of (E)- or (Z)-isosafrole 114 cyclo[3.2.1]octane 134 in 71% yield.110 A similar afforded burchellin (131) in moderate yield. compound, the methyl ether 135, was quantitatively obtained from quinone 129 and trans-propenylbenzene un- O der the Lewis acid conditions described by Grieco et al.109 Me O The bicyclo[3.2.1]octanes were only isolated when un- OMe O substituted propenylbenzenes were employed indepen- futoenone (139) dent from the functionality of the quinones. O 64% from (Z)-isosafrole (137) Figure 4

O OR The stereoselective synthesis of porosin (140), a bioactive SnCl4 Me ¢ 115 + 46 O 8,1 -neolignan was described by Matsumoto et al. They −78 −30 °C BnO developed a new route, which was different to the previ- O a O 69% ous cycloaddition strategies. Darzens reaction of -chlo- 132 ropropionate with aldehyde 141 provided epoxide 142 in O O 90% yield. Epoxide 142 was oxidatively opened to afford a-acetoxyketone 143 (89%). Conversion of 143 to lactone K CO 133 R = H 80% 2 3 MeI 131 R = Me 144 was achieved in two steps by malonester alkylation O followed by acidic transesterification. trans-Hydrogena- tion of 144 was effected with NaBH4 furnishing the dias- Me R' tereoisomers 145 and 146 in 48% yield (from 143) and in a 14:1 ratio. Alkylation of the major isomer 145 with me- 110 OR 134 R = H, R' = allyl (71%) thylvinylketone followed by decarboxylation, allylation, 135 R = R' = Me (99%)109 O and cyclization provided cyclohexenone 147 (37% yield), which upon a-oxygenation (LHMDS, TMSCl, then MCP- BA, NaHCO3, TBAF) gave a 9:1 mixture of alcohols 148 Scheme 30 and 149 in 99% yield (Scheme 32). Treatment of the major isomer 148 with CH2N2 in the presence of SiO2 gave Background for the above mentioned acid catalyzed cy- porosin 140 in 81% yield. The overall yield over 15 steps cloaddition reactions was the pioneering work of Büchi et was 10%. al.,112 who discovered in 1977 the acid catalyzed synthesis Two important 8,1¢-neolignans having no benzofuranoid of burchellin (131) from (E)-isosafrole (46), and its dia- skeleton are megaphone (150) and megaphyllone acetate stereoisomer 136 from (Z)-isosafrole (137) using tri- (151) (Figure 5).116 These natural products became attrac- fluoromethanesulfonic acid (TfOH) as a proton source

Synthesis 2003, No. 17, 2595–2625 © Thieme Stuttgart · New York REVIEW The Stereoselective Synthesis of Neolignans 2609

OR Even more steps were required for the synthesis of mega- 119 RO phone (150) following the strategy of Zoretic et al. Me 150 R,R = Me, R' = H Starting material was the Michael acceptor 156, which OMe (megaphone) MeO 151 R,R = −CH2−, R' = Ac was converted to compound 157 in 4 steps. From com- OR' (megaphyllone acetate) pound 157, ketal 158 was available in a further 8 steps. O The megaphone precursor 159 was synthesized in 7 steps Figure 5 from 158 (Scheme 34). From 159, megaphone (150) was prepared in 2 steps according to the procedure of Büchi. The longest linear sequence was 21 steps and the overall tive target molecules for a synthesis because they possess yield was 0.3%. 116,117 strong cytotoxic activities. Matsumoto et al. achieved the syntheses of megaphone Three groups have completed the synthesis of racemic (150)120 and megaphyllone acetate (151)121 following the megaphone (150). Büchi et al.106 used the acid catalyzed strategy developed for the synthesis of porosin (140). cycloaddition of quinone acetal 152 with (Z)-3,4,5-tri- However, the key intermediates, ketones 162 and 163, methoxyphenylpropene (153) (SnCl4, –30 °C) to afford were in this case realized by addition of metalated 2-me- the dihydrobenzofuran 154 in 48% yield (Scheme 33). thyl-1,3-dithiane to benzaldehydes 160 and 161, respec- The mesyloxypropyl side chain was necessary because tively, followed by oxidative cleavage of the dithiane the cationic cycloaddition was not successful with quino- moiety (Scheme 35). The synthesis of neolignans 164 and nes containing an allyl group in the side chain. Neolignan 165 was achieved from 162 and 163 according to the re- 154 was stereo- and regioselectively hydrogenated at the action sequence described in Scheme 32. Ring opening of 106 C(4)=C(5) double bond using 5% Rh/C affording 155 in the furan moiety according to the Büchi sequence pro- 33% yield. Elimination of methanesulfonic acid118 fol- vided 150 and 151. lowed by reduction of the carbonyl group with DIBALH Megaphone (150) is the only 8,1¢-neolignan, which has 122 and rearrangement (MsCl, Et3N, then H2O) yielded mega- also been prepared enantioselectively. The enantiomer- phone (150) (23%, 4% overall from 152) (Scheme 33). ically pure starting material for its synthesis was g-lactone

CO2Me Me OAc O O CHO O 1) Darzens CO2Na 1) DMM, TiCl4 O 2) NaOH Pb(OAc)4 2) HCl Me Me MeO 89% MeO 89% MeO MeO OMe OMe OMe OMe 141 142 143 144

48% NaBH4 OMe R CO2Me CO2Me Me Me Me Me O O CH N 2 2 O O SiO2 8 steps O O O + O 81% to 147 MeO 140 MeO MeO MeO OMe OMe OMe OMe 14 1) LHMDS 147 R = H (37%) 145: 1 146 2) MCPBA 148 R = α-OH (88%) 3) TBAF 149 R = β-OH (11%) Scheme 32 DMM = dimethyl malonate

OMs OMs 1) Sharpless OMe OMe OMe elimination118 MeO 2) MsCl, Et N OMe MeO OMe H2, 3 153 OMe Me 5% Rh/C Me then H2O O O 150 SnCl4 −30 °C 33% 23% MeO MeO 48% O O O MeO MeO OMs 152 154 155 OMe OMe Scheme 33

Synthesis 2003, No. 17, 2595–2625 © Thieme Stuttgart · New York 2610 M. Sefkow REVIEW

O O 1) SS OAc 4 steps Li MeO2C MeO CHO MeO O 46% then Ac2O OiBu 2) NCS Me 156 157 R R R ~60% R 9% 8 steps 160 R,R = OMe 162 R,R = OMe 161 R,R = OCH O 163 R,R = OCH O OMe 2 2

Me OH O O 7 steps MeO O OH 9% OH Me MeO O O 106 O 159 150 Büchi OMe 158 151 MeO O 71% 2 steps R 150 R 164 R,R = OMe 165 R,R = OCH2O Scheme 34 Scheme 35 166 which was converted to the Michael acceptor 167 in 3 steps (48% yield). Stereoselective conjugate addition An elegant method for the enantioselective synthesis of and subsequent alkylation, followed by desilylation af- intermediate 172 was reported by Marino et al.123 using forded 168 in 58% yield as a single isomer (Scheme 36). optically active sulfinic acid esters (Scheme 37). This compound was transformed to aldehyde 169 in 4 Sulfoxide 173 was prepared in 71% from bromide 174 steps (46% overall). Intramolecular aldol condensation and a menthyl sulfinate. Addition of dichloroketene to was achieved with NaHCO3. In addition to the cycliza- 173 yielded a zwitterionic species A. [3,3]-Sigmatropic tion, epimerization of the methoxy group was effected, rearrangement gave intermediate B, which cyclizes to b providing the thermodynamically favored -epimer as the yield the Pummerer-type reaction product 175 (76%). a b major product. The -/ -ratio was 1:4.5. Aldehyde 170 Dechlorination and desulfurization afforded lactone 176 was obtained after HgCl2 induced desulfurization. Addi- (44%, 2 steps), which was subsequently converted to op- tion of trimethoxybenzyllithium to 170 furnished a 1.8:1 tically pure 172 in 50% yield (Scheme 37). mixture of megaphone (150) and its epimer 171 in 74% yield from which pure megaphone was obtained by crys- tallization (Scheme 36). 58-O-4¢-Neolignans Compound 172 (Scheme 37) was identified as an important intermediate for the synthesis of porosin (140) or Dehydrodimers of phenylpropenes having an 8-O-4¢ con- megaphone (150) according to the synthetic strategy de- nectivity, such as virolin (177)124 (Figure 6), have been veloped by Matsumoto et al. It was prepared as a racemic recognized for a long time as a class of natural products mixture through Michael addition of 145 to methylvi- with distinct biological properties.2 The same substruc- nylketone as shown in Scheme 32. tures of phenylpropene coupling products are widely dis-

MeS Ph CO Ph CO Ph CO 1) KOH,KH, MeI 3 3 1) Li TBS 3 1) LDA, CH3CHO 2) MeLi 2) MsCl MeS 3) HCl Me 3) NaHCO3 2) C3H5Br 4) DMSO,SO3 MeS OMe O O O 48% 3) TBAF 46% Me MeS CHO O O 58% O O Me 169 166 SMe 167 MeS 168 54% 1) NaHCO3 2) HgCl2

MeO OMe MeO MeO Li Me Me OMe MeO OMe MeO + megaphone (150) 74% 4.5 : 1 OH 1 : 1.8 O 171 O O 170

Scheme 36

Synthesis 2003, No. 17, 2595–2625 © Thieme Stuttgart · New York REVIEW The Stereoselective Synthesis of Neolignans 2611

generally both the erythro- and the threo-isomers of the 8- 1) sBuLi O O-4¢-neolignans are isolated. Of these the erythro-isomers O 2) S S are favored over the threo-isomer by ca. 3:1. Br Tol OMenthyl MeO 71% MeO OMe OMe 173 174 Cl3CCOCl Zn(Cu)

Ar Cl Ar Cl

Ar' O Ar' S Cl S O Cl

B O A O

76% Scheme 38

¢ R CO2Me The 8-O-4 -neolignans were exclusively formed when a R 1) LDA, DMC propenylphenol with 2,6-disubstitution, such as com- MeO 2) MVK, Et3N O O pound 182, was employed in the oxidative coupling. It O O 50% O was even possible to isolate and characterize quinone me- MeO R' 125 thide 183 when Ag2O was used as oxidizing agent. Re- 1) Al(Hg) 175 R = Cl, MeO action of 183 with various nucleophiles furnished the 8-O- 2) Raney-Ni R' = STol OMe 176 R,R' = H 172 4¢-neolignans in 45–95% yield (Scheme 39). Other oxi- 44% 126 127 dizing agents (FeCl3, photooxidation) were used as Scheme 37 DMC = dimethyl carbonate, MVK = methylvinyl- well but they were less efficient. ketone. tributed in lignin.7 Both the biological properties of the dimers and the structural relation of these compounds with lignin made them attractive for chemical synthesis.

OMe

4' 8 O OMe OMe OH virolin (177)

Figure 6

5.1 Diastereoselective Synthesis of 8-O-4¢-Neolig- Scheme 39 nans ¢ It has been excessively demonstrated that 8-O-4¢-neolig- One of the first non-biomimetic approaches to 8-O-4 - nans can be synthesized by oxidative coupling of the phe- neolignans was based on the nucleophilic substitution of a nylpropenes 2 and 3 (see Table 1 in chapter 2.1). This -halogenated propiophenones with phenolates followed biomimetic synthesis afforded the 8-O-4¢-neolignans by reduction of the carbonyl group with boranates or alu- 128 a which are generally accompanied by 8,5¢-neolignans and minumhydrides. The -halogenated propiophenones lignans (Scheme 38). It was already mentioned that the could be prepared by Fries rearrangement of the corre- a 129 oxidative coupling of 2 or 3 involving Mn(salen)37 or oth- sponding phenol propionates and -bromination. How- er metal salts,21,35 silver oxide,20,34 laccase13 or peroxi- ever, this route generally delivered mixtures of erythro- dase,27,31 photooxidation,17,24 anodic oxidation,28,29 or and threo-isomers (Scheme 40). active radicals18 as oxidizing agents gave 8,5¢-neolignans Recently, Antus et al. described that the stereochemical as the major products. The 8-O-4¢-neolignans 178–181 outcome of the reduction was very much dependent on the were obtained as the minor congeners. However, in some reducing agent.130 When a-aryloxypropiophenones ¢ 1 cases it was possible to synthesize the 8-O-4 -neolignans (R = Me) were reduced by means of NaBH4 in the pres- in up to 59% yield.31 The substitution pattern at C(7) was ence of 15-crown-5131 then the threo-isomer was the ma- dependent on the solvent employed: the alcohols 178 and jor product. This selectivity was also found in earlier 180 were formed in water, the methoxy analogs 179 and studies on the synthesis of lignin model compounds.132 On 181 in MeOH. Under the biomimetic reaction condition,

Synthesis 2003, No. 17, 2595–2625 © Thieme Stuttgart · New York 2612 M. Sefkow REVIEW

the other hand, reduction of the same starting materials us- strategies by which two C6C3 units were coupled, one of ing LiAlH4 gave predominantly the erythro-isomer. the phenylpropene moieties was stereoselectively discon- nected between C(7) and C(8) (Scheme 41). O M OMe O 2 O O MeO2COAr 5 7 R4 R1 4 1 R R HO R R 6 + R MeO O OH 1 Br R3 Ar O R3 2 OH R R7 HO R2 erythro- & threo-178

R5 R6 Scheme 41 reduction (e.g. with NaBH4, LiAlH4) Aldol reaction of a-phenoxy acetate 184, prepared in two steps from vanillin (98% yield), and O-benzylvanillin af- OH OH forded an approximately 70:30 mixture of the erythro- R4 R1 R4 R1 + and threo-isomer, 185 and 186. This result is in accor- O R7 O R7 dance with the rationale assuming that a six-membered, 3 3 R R chair-like transition state is involved in the aldol addition, R2 R2 R6 R6 in which the bulky substituents are facing away from each R5 R5 other. The same results have been obtained in the synthe- 136 threo-isomer erythro-isomer sis of lignin model compounds using a similar strategy. Reduction, removal of the protecting group, and cleavage Scheme 40 of the acetal yielded aldehydes 187 and 188 (66% from 184). The ratio between compounds 185 and 186 re- Helm and Ralph found that the reduction of a-aryloxy-b- mained unchanged. Since neither 185/186 nor 187/188 1 hydroxypropiophenones (R =CH2OH) with Zn(BH4)2 were separable by chromatography the further reactions proceeded with low stereoselectivity when the b-hydroxy proceeded with the mixture of both stereoisomers. Protec- group was not protected.133 The authors assumed that in tion of all hydroxy groups and Knoevenagel condensation this case the Zn cation could competitively complex be- provided the corresponding cinnamic acids, which were tween the carbonyl-oxygen and either the aryloxy-oxy- subsequently reduced to the alcohols 189 and 190 in 54% gen, which afford the erythro-isomer, or the hydroxy- yield. Direct conversion of 189/190 to erythro-178 and its oxygen, which gave rise to the threo-isomer (Figure 7). threo-isomer did not proceed well. Therefore, oxidation b Similar results have been achieved with other reducing with MnO2 and deprotection gave the guaiacylglycerol- - agents which have an even lower complexation ability coniferaldehyde ethers. Borohydride reduction of the car- 134 (NaBH4). When the hydroxy group was ‘protected’ bonyl group furnished 178 in 73% yield from 189/190 with electron withdrawing groups (esterified) or bulky (Scheme 42). groups (e.g. TBS-ether) then complexation between the Erythro-configured lignin model compounds with 8-O-4¢ carbonyl and the hydroxy group prevailed and the connectivity were prepared by borane reduction of a-ary- Zn(BH ) reduction proceeded with good stereoselectivity 4 2 loxy-substituted cinnamic acids, such as 191.137 These ac- (up to 97% of the erythro-isomer).135 ids were synthesized by condensation of an aldehyde with a-aryloxy acetates using sodium, followed by saponifica- Ar2O tion. When isomerically pure cinnamic acids were em- H O ployed, isomerically pure erythro lignin model Ar1 O ZnR threo-isomer 2 compounds, such as 192 were obtained (Scheme 43). The electrophilic addition of borane to the double bond oc- H " H " cured after reduction of the acid moiety. Evidence for the H order of reduction is (1) the occurrence of cinnamyl alco- Ar2 O hols when the reaction was carried out at low temperature Ar1 O ZnR2 erythro-isomer and (2) the electrophilic attack occured exclusively at C(7), which should not be possible at the electron-poor b- HO position of Michael acceptors. Figure 7 Recently, Pan et al. reported a new stereoselective synthesis of erythro-8-O-4¢-neolignans, which was based on an unusual reaction of electron-rich arylpropenes with MCP- Another general strategy was developed by Nakatsubo et BA.138 When 4-benzyloxy-3-methoxy-cinnamyl alcohol al. for the synthesis of erythro- and threo-guaiacyl-glycer- (193), prepared in 3 steps from 1 (80% yield), was reacted ol-b-coniferylether (178).135 In contrast to the previous with MCPBA, not the expected epoxide but the b-hydroxy

Synthesis 2003, No. 17, 2595–2625 © Thieme Stuttgart · New York REVIEW The Stereoselective Synthesis of Neolignans 2613

Scheme 42 Knoevenagel = Knoevenagel condensation benzoyl ester 194 was isolated in 74% yield (Scheme 44). Ar O Ar O Selective protection of the primary hydroxy group and O O OH OH etherification under Mitsunobu conditions gave the eryth- OH OH ro-configured compound 195 (62% yield). Deprotection δ+ δ− of 195 afforded the erythro 8-O-4¢-neolignan 196 in 75% O O yield. R R Scheme 45

¢ MeO MeO 5.2 Enantioselective Syntheses of 8-O-4 -Neolig- . 1) BH3 Me2S nans HO2C O O 2) NaOH, H2O2 HO Plants produce 8-O-4¢-neolignans, like other neolignans, 50% H OH in general as enantiomerically pure compounds. There- ¢ OBn BnO fore, the asymmetric synthesis of 8-O-4 -neolignans is an OMe OMe important issue. So far, only a few reports on the enanti- 191 192 oselective synthesis of 8-O-4¢-neolignans have appeared. Scheme 43 The development of powerful synthetic strategies is com- plicated by the fact that natural 8-O-4¢-neolignans exists in two diastereomeric forms, requiring selective strategies The unusual reactivity of p-alkoxy-substituted phenylpro- for each of the two diastereomers. penes towards MCPBA may be attributed to the polariza- tion of the double bond, effected by the electron donation The oxidative coupling of coniferyl alcohol (2) by cell- of the alkoxy group. MCPBA attacks the polarized double free extracts of Eucommia ulmoides provided (+)-erythro- 139 bond at the electron-rich b-position rather than in a [2+1]- 178 in 38% ee and (–)-threo-178 in 34% ee. The ratio ¢ type addition providing a benzyl cation, which is highly of diastereomers was ca. 5:4 (erythro:threo). The 8-O-4 - stabilized (Scheme 45). As soon as the benzoyl anion is neolignans were accompanied by dehydrodiconiferyl al- liberated it reacts with the benzyl cation from the same cohol (16) and pinoresinol, both as a racemic mixture. The site as the initial electrophilic attack occur, furnishing ex- authors assumed that either both, erythro- and threo-178 clusively the threo-product (Scheme 45). were enantioselectively synthesized by the enzymes (and the opposite enantiomers derived from a non-specific ox-

CHO MeO CHO HO HO 1) BzCl O 2) vanillin, O 1) K CO OH OMe HO Cl 2 3 MCPBA Ph3P, DEAD BzO O 2) H2, Pd/C O O Cl 74% 62% 75% O HO MeO OMe OBn OBn OMe OH 193 194 OBn OMe (80% from 1) 195 196 Scheme 44

Synthesis 2003, No. 17, 2595–2625 © Thieme Stuttgart · New York 2614 M. Sefkow REVIEW idative coupling induced by peroxidase), or they were (reacetylation of the optically enriched bromohydrin 203, produced as racemic mixtures, followed by the metabo- followed by enzyme-catalyzed hydrolysis) increased the lization of one enantiomer and accumulation of the other. ee of 203 up to 79%. Base-catalyzed ring-closure of 203 However, no evidence was provided to support either of provided epoxide 204 in 95% yield. Regioselective ep- the assumptions. oxide opening at C(8) was achieved with deprotonated isoeugenol in refluxing dioxane providing (–)-virolin Based on the ‘classic’ etherification approach (see 142 Scheme 40), Badano and Zacchino140 used binaphthol- or (177) in 87% yield and 78% ee (Scheme 47). N-methylephedrine-modified lithium aluminum hydride reagents to prepare optically active erythro-8-O-4¢-neolignans by kinetic resolution. Ketones 197 and 198 were synthesized in high yields by aryloxy-substitution of the corresponding a-bromopropiophenones. Reduction of the ketones provided in all cases the erythro-configured products, 199 and 200, with good diastereoselectivity (Scheme 46). The ee was in the range of 80–82% with BINOL-modified hydrides (ca. 48% yield) and 60–68% ee with ephedrine-modified hydrides (51–54% yield). A limitation of this approach was the yield, which could not exceed 50% without the loss of optical purity since one stereocenter was already implemented and a dynamic isomerization of the initial stereocenter did not proceed during the reduction. Recently it was demonstrated that the asymmetric reduction of the carbonyl group, of a-aryloxypropiophenones, could also be achieved with intact Fusarium solani cells.141

Scheme 47

MeO OMe MeO OMe A recent approach towards enantiomerically pure 8-O-4¢- Me O Me O conditions neolignan model compounds was reported by Helm and 143,144 X X Li. Chiral starting material was diethyl tartrate 205, O OH which was converted to the mesylate 206 in five steps RO RO (62% yield) using well established procedures. Nucleo- OR OR philic substitution with a caesium phenoxylate cleanly 197 R = Me, X = OMe 199 R = Me, X = OMe provided 207 (76% yield). Removal of the protecting − − − − 198 R = CH2 , X = H 200 R = CH2 , X = H groups and diol cleavage gave aldehyde 208. Subsequent

a arylation with phenyllithium afforded a 1:1 mixture of s.m. cond. prod. yield ee 209 and 210 (Scheme 48) in 72% yield (from 207). 197 A 199 52 62.5 198 A 200 −b 65 Most recently, Pan et al. reported a new enantioselective 198 B 200 49 82 synthesis of erythro 8-O-4¢-neolignans.145 Since this ap- a LiAlH4 and A: (S)-BINOL, MeOH, B: proach is based on their previously described route devel- (−)-N-methylephedrine, N-ethylaniline b yield not reported. oped for the synthesis of optically active benzodioxane Scheme 46 neolignans, the synthesis will be discussed in the following chapter (chapter 6.2). Reduction of the carbonyl group of a-aryloxy-propiophenones with chiral hydrides afforded exclusively the eryth- 6 Benzodioxane-Neolignans ro-8-O-4¢-neolignans. For the construction of threo- ¢ configured 8-O-4 -neolignans, such as virolin (177), an- Benzodioxane-neolignans are a relatively rare subgroup other approach via resolution was developed based on the within the neolignans. However, they exhibit interesting a enzymatic hydrolysis of racemic acetates (Scheme 47). - pharmacological properties, such as antitumor promoting Bromopropiophenone 201 was reduced with NaBH4 and and antihypertensive activities. The most important ben- acetylated to give threo-202 in 70% yield after separation zodioxane-neolignans are those from Phytolacca ameri- from the minor erythro-isomer. The enantioselective hy- cana L. and the eusiderins (Figure 8). Furthermore, drolysis of one enantiomer of 202 was achieved with several bioactive flavonolignans, such as the hepatopro- Rhizopus nigrans. Bromohydrin 203 was obtained with tective silybin (211), and some sesquilignans contain a 65% ee (41% yield). Repetition of this procedure

OMe 6.1 Diastereoselective Synthesis of Benzodiox- ane-Neolignans OMe It is obvious, that biosynthetically at least one o-dihydrox- OBn MeO yphenylpropene unit is required for the construction of the HO CO2Et O OBn OCs benzodioxane skeleton. Indeed, benzodioxane-neolignans O 62% 18-crown-6 OBn are often synthesized using the biomimetic oxidative HO CO2Et O 76% dimerization approach. Both biomimetic approaches, the 205 OMe MsO homo and the cross-coupling has been extensively exam- OBn ined. 206 207 The synthesis of americanol (212) and isoamericanol 1) H2, Pd/C (213) as well as that of isoamericanin (214) was carried 2) Pb(OAc) 4 out by the homo-coupling of 3,4-dihydroxycinnamyl al- HO HO O H cohol (215). The initial oxidative dimerization of 215, OH + OH which was prepared in two steps from caffeic acid (5) O O OH 146 PhLi O (57% yield), was effected either by HRP/H2O2 or by OMe OMe 147 OMe Ag O. With the latter reagent only isoamericanol (213) 72% 2 from 207 was obtained in 85% yield. On the other hand, the HRP/ 1 : 1 H O induced oxidative dimerization of 215 furnished 210 209 208 2 2 212 and 213 in 82% yield and in a ca. 1:3 ratio Scheme 48 (Scheme 49). Isoamericanin 214 was prepared from 213 by regioselective oxidation of the allylic alcohol with 147 MnO2 in the presence of silica gel in 75% yield. Caffeic benzodioxane skeleton. Therefore not only the synthesis 146,148 149 of benzodioxane-neolignans but also that of the benzo- acid (5) or its ethyl ester (11) were also subjected to the enzyme catalyzed oxidation but the yields of benzodioxane moiety of more complex natural products is of in- 146 terest. dioxanes were low (6–18%). In recent years, the cross-coupling of two differently func- OMe tionalized phenylpropenes was used for the preparation of

R' OCH2OH O several eusiderins. This strategy, developed by Merlini and Zanarotti, was also used for the first synthesis of a OH OMe 150 R O C3 O benzodioxane-neolignan. The precursors 216–219, necessary for the synthesis of eusiderins, were prepared in OH OR 5–6 steps from pyrogallol (220) (Scheme 50). OMe americanins/isoamericanins eusiderins All eusiderins were synthesized using compound 216 as R = C3, R' = H the phenylpropene moiety. This was prepared by perme- R = H, R' = C3 OCH2OH thylation of pyrogallol (220) with dimethyl sulfate, regioselective demethylation with ZnCl2, and allylation HO O OH O affording intermediate 221 in 78% yield. Claisen rearrangement and Pd catalyzed double bond transposition OH OH gave 216 in 88% yield. OH O silybin (211) The second coupling partner, the o-diphenols 217–219, were also prepared from pyrogallol (220). Diol 217151 was Figure 8 obtained in 3 steps by selective monomethylation using a catecholboranate complex for the in situ protection of two

OH OH

O O OH OH O MnO OH OH 2 OH + O O OH SiO OH O 2 OH 75% OHC OH OH OH OH 215 212 213 214

Ag2O: 0 : 85 HRP/H2O2: 22 : 60 Scheme 49

The cross-coupling of electrophilic radicals, derived from caffeic acid esters, with electron-rich phenylpropenes, OH 1) Me2SO4 OMe OMe 2) ZnCl ∆ HO 2 O 1) HO such as coniferyl alcohol (2), was the key reaction for the 3) C H Br 3 5 2) PdCl2 regioselective synthesis of americanol and isoamericanol 78% 88% HO MeO MeO methyl ethers and the corresponding aldehydes (228– 220 221 216 231). The regioselectivity in the formation of benzodiox-

1) Na2B4O7/Me2SO4 ane-neolignans of either the americanol-type or the 82% 2) C3H5Br isoamericanol-type was achieved by using different oxi- ∆ 3) dizing agents (Scheme 52). OMe OMe OH 1) Ac2O With Ag2O in benzene–acetone, benzodioxanes 232 and HO HO 2) SeO2 MeO OMe 233 (R = CO Et) were obtained in 56% yield and in a 1:20 PdCl2 3) NaHCO3 2 ratio.155 On the other hand, K Fe(CN) in buffered water 88% 65% 3 6 HO HO produced 232 and 233 in 80% yield and in a 9:1 ratio.155 The use of 10 as the diphenol precursor was less efficient. 217 218 Ag2CO3 mediated oxidative coupling of 10 and 2 afforded 219 CHO 234 and 235 (R = CO2Me) in 40% yield 156,157 Scheme 50 (234:235 = 1:30) and coupling with K3Fe(CN)6 gave exclusively 234 in 31% yield.158 Reduction of the ester group of 234 and 235 provided 228 and 229 in 82% and of the three hydroxy groups, followed by monoallylation 75% yield, respectively. Oxidation of the allylic alcohol and Claisen rearrangement (82% yield). Double bond then furnished 230 and 231 in 60% and 80% yield, respec- 152 transposition gave diol 218 (88% yield). Allylic oxidatively (Scheme 52).156–158 tion was achieved with SeO2 after protection of the diol moiety. Subsequent deprotection produced 219153 in 65% No explanation was provided by the authors for the differ- yield from 218 (Scheme 50). ent regioselectivity in the cross-coupling induced by silver and by iron salts. However, one possible explanation The oxidative cross-coupling of phenylpropene 216 with might be as follows: basic silver salts suspended in aprotic diols 217–219 was achieved with Ag2O as the oxidizing organic solvents slowly deprotonates the phenol groups 151–154 agent in benzene–acetone (5–50:1) as solvent. Eu- prior to the electron abstraction. The more acidic proton at siderin K (222) and E (223), and compound 224 were iso- C(4)–O is deprotonated faster than the less acidic at C(3)– lated as single isomers in ca. 40% yield. Methylation of O. After formation of the phenolate, a fast and irreversible the remaining phenol group gave the eusiderins J, F, and electron transfer occurs. The regioisomeric O-radicals G (225–227) in 95% yield (Scheme 51). then attack the double bond of the phenylpropene at C(8) in a similar mechanism as that described in Scheme 2. OMe This produces a mixture of 232 and 233 in a ratio which OMe 217 Ag2O corresponds to the acidity of the phenols. 216 + 218 219 benzene/ OMe It is well known that Fe(III) salts give strong complexes acetone R O 159 5 : 1 with catechols. Therefore, it is likely, that complex A OR' ~40% (Scheme 53) is an intermediate in the Fe(III) induced OMe cross-coupling. The oxidation potential of Fe(III) is less 222 R = allyl, R' = H than that of quinones72 and may be similar to that of 223 R = propenyl, R' = H 224 R = CH=CH−CHO, R' = H quinonemethides. As a result of the similar oxidation po- MeI, KOH 225 R = allyl, R' = Me tentials of Fe(II)/Fe(III) and of O·/O– of catechols the two 95% 226 R = propenyl, R' = Me 227 R = CH=CH−CHO, R' = Me regioisomeric radicals B and C can equilibrate via complex A (Scheme 53). Since radical B is less reactive than Scheme 51 radical C the latter predominantly couples with the double

Ag CO K Fe(CN) O 2 3 3 6 O 232 OH or Ag2O 11 NaOAc OMe 233 + 2 + + 234 OMe benzene/ 10 acetone/ OH 235 R O acetone water R O − 2 : 1 1 : 1 9 : 0 1 1 : 20 − 30 OH 40 − 56% 31 − 80% 233 R = CO2Et 232 R = CO2Et 235 R = CO Me 234 R = CO Me LiAlH , AlCl 75% 2 LiAlH , AlCl 82% 2 4 3 229 R = CH OH 4 3 228 R = CH OH MnO , SiO 85% 2 2 2 2 231 R = CHO MnO2, SiO2 60% 230 R = CHO Scheme 52

bond of the phenylpropene providing preferentially com- a-Bromopropiophenones 237–239 upon treatment with pounds 232 and 234, respectively. This is also the case catechol 240 in the presence of NaHCO3 furnished the when other cinnamyl alcohols were employed as phenyl- ethers 241–243 in 71–82% yield. The etherification pro- propene moiety, which was demonstrated in the synthesis ceeded with complete regioselectivity at C(4)–O due to 160 161 of flavonolignan sinaicitin. Interestingly flavanones the higher acidity of this hydroxy group. NaBH4 reduction and flavones162 were also suitable substrates for the cross- of the carbonyl group provided alcohols 244–246 in 48– coupling with coniferyl alcohol (2) affording the corre- 96% yield. The alcohols were mixtures of diastereomers sponding flavonolignans, such as silybin (211) (Figure 8), with a preference for the erythro-isomer. Treatment of al- in one step! cohols 244–246 (as a mixture of isomers) with sulfuric acid or Amberlyst 15 gave the benzodioxanes 247–249 in O ca. 85% yield (Scheme 54). Fe(III) The regioisomer of benzodioxane 248 was prepared by RO2C O condensation of propiophenone 238 with m-phenol 250. A Reduction, cyclization, and methylation afforded benzodioxane 251 in good overall yield (Scheme 55).168

O O MeO CO2Me Fe(II) Fe(II) CO2Me RO2C O RO2C O O 5 steps B C 238 + O HO Scheme 53 O O MeO Ph Ph OMe The regioselectivity in the formation of benzodioxanes 250 251 was not only dependent on the oxidizing agent but also on Scheme 55168 the substitution pattern of the catechol. It was found that good regioselectivities were achieved in the Ag O in- 2 The eusiderins G (227) and M (236) were obtained from duced cross-coupling when electron-donating substitu- benzodioxane 247. Conversion of the ester group of 247 ents (e.g. alkyl groups) were attached to the catechol. gave aldehyde 252. This was either accomplished by a With electron withdrawing substituents, such as carbonyl common reduction/re-oxidation sequence or by fragmen- groups, mixtures of regioisomeric benzodioxanes were al- tation of the hydrazide with K Fe(CN) . High yields were ways isolated.161 The stereochemical course of all of these 3 6 achieved in both cases. Olefination or olefination/reduc- cross-coupling reactions was unambiguously determined tion then provided 227 and 236, respectively by x-ray crystallography of a model compound and corre- (Scheme 56). A drawback of this synthesis was the Wittig lation of the NMR data.163 reaction, which proceeded in low yield (36–52%). Another general approach to benzodioxane-neolignans is 2-Bromo-3-oxopropionates (e. g. 256, 257) were also suit- based on a-bromopropiophenones in which the bromine able substrates for a regioselective synthesis of benzo- was substituted by phenolates.164 This approach is similar dioxanes.169 These starting materials were used for the to that for the synthesis of 8-O-4¢-neolignans (Scheme 40) synthesis of silybin (211)170 and insecticidal sesquilign- but it requires the presence of a second phenol group ortho ans,171,172 such as haedoxan A (253)171 (Scheme 57). Thus, to the phenolate, either protected or unprotected. This ap- phenol 254 was reacted with oxopropionate 256 to give proach was recently used for the synthesis of eusiderin G benzodioxane 258, which was further transformed to sily- (227),165 M (236)166 and several analogs.166–168

CO2Me CO2Me CO2Me

CO2Me

HO OMe HO OMe OMe O O OH O OMe X HO X O X O X O Br + 240 OH NaBH4 H 2 R ~85% RO NaHCO3 RO 48 − 96% RO RO OR 71 − 82% OR OR OR 237 X = OMe, R = Me 241 X = OMe, R = Me 244 X = OMe, R = Me 247 X = OMe, R = Me 238 X = H, R = Me 242 X = H, R = Me 245 X = H, R = Me 248 X = H, R = Me 239 X = H, R = −CH2− 243 X = H, R = −CH2− 246 X = H, R = −CH2− 249 X = H, R = −CH2− Scheme 54

CHO OMOM OH CO2R' O O OH + Br N2H4/K3Fe(CN)6 O OMe R ROAr or LiAlH4/DDQ Ar 247 MeO O 1 1 86 − 92% 254 R = CHO 256 R' = Et, Ar = Ar 258 R = CHO, Ar = Ar 255 R = OMe 257 R' = Me, Ar = Ar2 259 R = OMe, Ar = Ar2 MeO 252 Ar1 = OBn , Ar2 = OMe O OMe O from 258 HO 1) Wittig 27% 52% Wittig CHO from 2) LiAlH4 259 OMe silybin (211) O O

O HO H O OMe O OMe OMe O O MeO O MeO O O OMe O MeO O MeO MeO O OMe OMe haedoxan A (253) eusiderin M (236) eusiderin G (227) Scheme 57 Scheme 56 Recently, Krupadanam et al. synthesized the basic skeleton of americanol-type neolignans using a similar route to bin (211). Benzodioxane 259 was prepared in a similar that described in Scheme 58.174 However, they achieved a manner from 255 and 257. Intermediate 259 was then major simplification by an one step formation of the ben- transformed to haedoxan A (253) after several steps. zodioxane skeleton from bromoepoxide 271. This precur- Americanin (260) and isoamericanin (214) were synthe- sor was obtained from allylbenzene through allylic sized on an alternative route developed by Ito et al.173 The bromination and subsequent epoxidation (53% yield).175 key step was the condensation of epoxide 261 [4 steps The reaction of 271 with the unsymmetrically substituted (57% yield) from caffeic acid (5)] either with phenol 262 catechol 272 provided regio- and stereoselectively the or with its regioisomer 263 affording the diols 264 and americanol-type benzodioxane 273 in 70% yield, which 265 in ca. 80% yield. Subsequent formation of the ep- was further transformed to neolignan 274 (Scheme 59). oxides 266 and 267 was accomplished in 72% yield. The The preferred attack of the p-hydroxy group was in accor- cyclization to the dihydrobenzofurans 268 and 269 was dance with that of other EWG-substituted cathechols in achieved in 83% yield. The reagent of choice for the the reaction with bromopropiophenones (Scheme 54). In HWE-reaction was phosphonate 270 containing a masked their initial report,175 Krupadanam et al. proposed the re- carbonyl group. Olefination with 270 and deprotection of gioisomer as the reaction product. The regioisomeric out- the remaining MOM-ethers provided 260 and 214 in 65– come was revised upon x-ray crystallography of 68% yield (Scheme 58). benzodioxane 273.

R OBn R OBn R OBn

O R' OH R' O R' O MOMO 262 R = CHO, R' = H 1) MsCl OH 263 R = H, R' = CHO MOMO OH 2) K2CO3 MOMO O MOMO ~80% ~72% MOMO OH MOMO 261 264 R = CHO, R' = H 266 R = CHO, R' = H 4 steps from 5 (57%) 265 R = H, R' = CHO 267 R = H, R' = CHO

1) H , Pd/C ~83% 2 2) K2CO3

R O O R O OH (EtO)2PCH−CH=N− OH OH 270 OMOM R' O R' O then hydrolysis

OH 65 − 68% OMOM 260 R = CH=CH−CHO, R' = H 268 R = CHO, R' = H 214 R = H, R' = CH=CH−CHO 269 R = H, R' = CHO

Scheme 58

CHO 6.2 Enantioselective Synthesis of Benzodioxane-

Br HO Neolignans O O HO 272 As demonstrated in Schemes 58 and 59, epoxides are attractive starting materials for the synthesis of benzodiox- 70% OH R O anes, hence optically active epoxides should be ideal for 271 273 R = CHO the enantioselective synthesis of benzodioxanes. Indeed, 53% from allylbenzene 48% − 274 R = CH=CH CH2OH two of the three enantioselective syntheses of benzodiox- Scheme 59 ane-neolignans, are based on enantiomerically pure epoxides as key intermediates. The first enantioselective synthesis of a benzodioxane- A second group of important benzodioxane-neolignans neolignan model compound was reported by Merlini and belongs to the coumarinolignans, namely propacin (275), Arnoldi.181 They used (+)-epoxide 283 which was ob- daphneticin (276), and the cleomiscosins A–D (277–280) tained from ephedrine as a chiral non-racemic precursor. (Figure 9). Some of these compounds attracted chemists Evidently, only model compounds could be prepared ac- since they exhibit strong cytotoxic activities among other cording to this route. In fact, benzodioxane 284 was only important biological properties. All coumarinolignans used to determine the absolute configuration of naturally- were prepared from the commercially available catechols occurring benzodioxane-neolignans by comparison of fraxetin (281) or daphnetin (282) either by cross-coupling their CD-spectra (Scheme 60). according to Scheme 51 or by stepwise condensation as Recently, Pan et al. reported the enantioselective synthe- shown in Scheme 57. sis of isoamericanol (213) and isoamericanin (214)182 fol- The cross-coupling of 281 or 282 with isoeugenol or an lowing a strategy developed in their laboratory for the appropriate cinnamyl alcohol induced by Ag2O or HRP synthesis of rac-benzodioxane-neolignans. Thus cin- gave mixtures of the natural products and the correspond- namyl alcohol 285 (91% from 5) was dihydroxylated in ing regioisomers in low yield 1–22%,176,177 except for pro- 88% yield using the Sharpless AD-mix methodology to pacin (275). This natural product was obtained in 87% as give triol 286 in 92% ee. The triol 286 was converted to 177a a single isomer with HRP/H2O2 as oxidizing agent. epoxide 287 (72% yield), which was subsequently con- Since the coupling induced by silver salts or enzymes pro- densed with phenol 263 under stereoinversion using the ceeded with low yields, Ito et al. introduced diphenyl se- Mitsunobu reaction. Benzylaryl ether 288 was obtained in lenoxide as an alternative oxidizing agent for the 81% yield. Removal of the benzylic protecting group and 178 preparation of coumarinolignans. The propacin-type K2CO3-mediated cyclization yielded the benzodioxane neolignans were prepared with this reagent in 18–55% carbaldehyde 289. Knoevenagel condensation with mo- yield and with good regio- and stereocontrol. noethyl malonate provided ester 290, which upon reduc- Monoprotection of either the C(7)–OH or the C(8)–OH of tion with LiAlH4/AlCl3 gave (2R,3R)-isoamericanol A 281 and 282 and condensation of these derivatives with a- (213). Re-oxidation with MnO2/SiO2 furnished (2R,3R)- bromopropiophenones179 or a-bromo-b-oxo-esters180 also isoamericanin A (214) (Scheme 61). provided regioselectively the coumarinolignans in reasonable overall yields. O OMe 3 2 Me O

1 MeO 283 R from ephedrine (2S,3S)-284

Scheme 60 O O O O O O R2 O HO O The same group used this strategy to prepare the benzo- HO R3 dioxane framework of silybin, compound 291 183 184 OMe (Scheme 61), and daphneticin (276) in optically ac- R OMe 1 2 3 tive form. 275 R = OMe, R = H, R = H OH 276 R1 = H, R2 = OMe, R3 = OH 277 R1 = OMe, R2 = H, R3 = OH 279 R = H The enantioselective synthesis of a regioisomeric analog 278 R1 = OMe, R2 = OMe, R3 = OH 280 R = OMe of benzodioxane 291, compound 292, as well as the naturally occurring 8-O-4¢-neolignan 196 was recently report- R ed.145 Starting material was (7S,8S)-triol 293, which was converted in two steps into a separable mixture of dioxane HO O O 294 and dioxolane 295 (ratio: 4:1). Etherification of the OH remaining hydroxy group of 294 with vanillin or with 4- 281 R = OMe benzyloxy-3-hydroxy-benzaldehyde under Mitsunobu 282 R = H conditions afforded 296 and 297 in 70% and 41% yield, Figure 9 respectively. Removal of the protecting groups of 296 af-

Scheme 61

Ph Ph OH OH 1) PhCH(OMe) phenol MeO 2 O O O O 2) TsCl Ph3P, DEAD MeO MeO OH BnO H 70% (296) H OH 41% (297) O R'' 293 BnO BnO 294 (67%) 4 RO R' CHO : + Ph 296 R = Me, R' = CHO, R'' = H 83% 1 O 297 R = Bn, R' = H, R'' = CHO 1) H+ 2) H , Pd/C MeO O 2 53% 36% HCl MeO H H OH O BnO OTs HO 295 O MeO OMe OH OH OHC O HO 292 196

Scheme 62 forded 8-O-4¢-neolignan 196 in 83% yield. Treatment of 7 Bicyclo[3.2.1]octane-Neolignans 297 with concentrated aqueous HCl provided benzodioxane 292 in one step and in 53% yield (Scheme 62). Several neolignans contain a bicyclo[3.2.1]octane skele- The insecticidal sesquilignan (+)-haedoxan A (253) was ton. They are divided into two subgroups depending on ¢ prepared by resolution.185 The resolution of racemic ben- the connectivity of the two phenylpropenes. The 8,1 -con- zodioxane 259, previously applied for the synthesis of nected bicyclo[3.2.1]octane-neolignans, such as 300 rac-253, was accomplished via the chiral phenylethyl car- (Figure 10), are the so-called guianin-type neolignans and ¢ bamates 298 and 299, providing (2R,3R)-259 in optically the 8,3 -connected neolignans, such as kadsurenine C pure form (Scheme 63). (301), are the macrophyllin-type neolignans.

O O

ON H OMe O OMe 3 (2R,3R)-259 2 O O MeO O O HO O O MeO (2R,3R)-298 O OMe (2S,3S)-299 guianin (300) kadsurenin C (301)

Scheme 63 Figure 10

So far only two syntheses of naturally-occuring bicyc- The bicyclo[3.2.1]octane-neolignans can be converted to lo[3.2.1]octane-neolignans62,112 alongside some anal- 8,3¢- or 8,1¢-neolignans with the dihydrobenzofuran skel- ogs106 and model compounds74,109,110 were completed. In eton upon acid treatment, but the reverse reaction, the all cases, with one exception,62 a formal cationic [5+2]- conversion of an 8,3¢-dihydrobenzofuran-neolignan into a cycloaddition was used for the construction of the bicyclic bicyclo[3.2.1]octane-neolignan, is also possible.187 Gen- skeleton (Scheme 64). erally, the guianin-type neolignans are transformed by acid treatment into burchellin-type neolignans, whereas O the kadsurenone-type neolignans rearrange into the macrophyllin-type neolignans under the same conditions (Scheme 66). This clearly shows that the equilibrium of O R' such acid catalyzed interconversions is dependent on the -R+ R' O bicyclic system formed by this reaction. It is assumed that O R R'' steric interactions are responsible for this observation, R'' which can be explained as follows: upon protonation, the burchellin-type and the guianin-type neolignans decom- Scheme 64 pose into cationic intermediate A whereas acid treatment of the macrophyllin-type and the kadsurenone-type neo- The cationic species was prepared using either (Lewis) ac- lignans give intermediate B. In both cationic species the ids (see Scheme 30), or bases (see Scheme 28) or by an- methyl group adjacent to the benzyl cation is forcing the odic oxidation. In most cases, the bicyclo[3.2.1]octane- aryl group into a transoid configuration, which reduces neolignans were accompanied by other classes of neolig- the number of possible stereoisomers. Intramolecular at- nans, although it was possible to synthesize the bicy- tack of the benzylic cation of intermediate A to the oxygen clo[3.2.1]octane-neolignans regioselectively in up to 99% (path a) produces the burchellin-type neolignans and at- yield depending on the conditions.109 tack at the enol (path b) give the bicyclo-[3.2.1]octane- For example, the reaction of phenol 302 with 3,4- neolignans. dimethoxy-phenylpropene (47) gave selectively the bicy- The formation of the guianin-type neolignan from inter- clo[3.2.1]octane-neolignan model compound 303 in 80% mediate A requires the approaching of the aryl and the cy- yield (Scheme 65).186 clohexadienyl group which is sterically less favored than the formation of burchellin-type neolignans, in which the O aryl and the cyclohexadienyl group occupies pseudo- OH equatorial positions. The opposite is true for the macro- Me E , AcOH, Ac2O phyllin/kadsurenone-type neolignan rearrangement. For + 47 Bu4NBF4 OMe the intramolecular attack of the benzyl cation of interme- OMe ¢ 80% O diate B to the carbonyl oxygen (path a ) a close proximity OMe of the aryl and the methoxy group (embolden) is neces- 302 MeO sary. On the other hand, intramolecular reaction of the OMe enol and the cation produces a bicycle, in which the aryl 303 and the methoxy group are in pseudo-equatorial positions, far away from each other. In this case, the formation of the Scheme 65

O OR Me Me Me O OMe MeO Me OMe O O O O O R O R a R b burchellin-type guianin-type macrophyllin-type b´ R kadsurenone-type a´ Me Me O a a O OMe R MeO H R b OH O b AB

Scheme 66

Synthesis 2003, No. 17, 2595–2625 © Thieme Stuttgart · New York 2622 M. Sefkow REVIEW bicyclic neolignan is sterically favored over the formation 8 Conclusion and Outlook of the dihydrobenzofuranoid neolignan (path b¢). After submitting the manuscript, I became aware of two Neolignans are natural products with high structural di- new approaches to neolignans which are different from versity. Representatives of all classes of neolignans exhib- those reviewed herein.188,189 They are briefly discussed in it important biological activities. Therefore they are the following: an enantioselective synthesis of the dihy- interesting targets for a synthesis. Most (but not all) of the drobenzofuran backbone of ephedradine was reported by neoligans contain one or more stereocenters. This review Fukuyama et al.188 Their strategy is based on the asym- presented an overview of the efforts on the diastereo- and/ metric Rh-catalyzed C–H insertion reaction developed by or enantioselective synthesis of stereocenter-containing Davies et al.190 In the case of the achiral a-diazo ester 304 neolignans. By far the majority of syntheses of neolignans the ratio (trans:cis) was 40:60 and the ee of trans-dihy- described herein concern the dihydrobenzofuran-neolig- drobenzofuran 305 was only 32%. On the other hand, re- nans (about the half of all cited publications). It is furthermore shown, that the diastereoselective synthesis of action of the chiral diazo ester 306 with Rh2(OAc)4 produced 307 and corresponding trans-diastereoisomer in neolignans is well developed. Several interesting new re- a 3:1 ratio. The trans:cis ratio was remarkably improved actions were designed for and/or applied to the synthesis by using chiral rhodium catalysts (up to 13:1) of neolignans. Despite the fact that, natural neolignans (Scheme 67). The diastereomerically pure dihydrobenzo- were generally isolated as optically active compounds, the furan 307 was subsequently converted to ephedradine.188b enantioselective synthesis of any class of neolignans is underrepresented. It is therefore expected that future developments in the field of neolignan synthesis will focus on the preparation of enantiomerically pure neolignans and bioactive analogs (e. g. via transition metal catalyzed reactions192).

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