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 im- portant 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 struc- tures 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 syn- thesis 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 11 56 genation of a benzofuran. 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.