Neolignan synthesis

Zanarotti, A. Synthesis and reactivity of lignin model quinone methides. Biomimetic synthesis of 8.0.4 neolignans. J. Chem. Res., Synop. 1983, 306-307. 

When the alkynyl substrate possesses a nucleophilic functionality, intramolecular solvomercuration reactions can sometimes be observed. These reactions, which result in the formation of a heterocycle, have been used in the total synthesis of natural products. For example, reaction of 114 with Hg(OAc)2 affords the benzofuran derivative 115, which is an important intermediate for the synthesis of various neolignans (Equation (42)).154 155... 

Other examples of the iodonium ylide-based syntheses of furan derivatives involve cycloaddition reactions with alkenes or alkynes. Although the majority of these syntheses involve stable iodonium ylides (86JOC3453 94T11541) (e.g., Eqs. 16 and 17), in some cases the ylides are unstable and are generated in situ (92JOC2135) (e.g., Eq. 18). In the case of alkenes, dihydrofuran derivatives are obtained (Eqs. 16-18). This synthetic route is especially useful for the synthesis of dihydrobenzofuran derivatives that are related to the neolignan family of natural products (Eq. 18). 

On the other hand, PIFA-induced oxidation of p-methoxy-substituted phenols (15) in the presence of electron-rich styrene derivatives (16) resulted in new carbon-carbon bond formation via an intermolecular 1,3-cycloaddition to afford frazzs-dihydrobenzofurans (17) stereoselectively [35,36] [Eq. (4)]. A formal synthesis of neolignans such as kadsurenone (18) and denudatin B (19) was achieved by this methodology. 

Irradiation of 2,2-dimethyl chromene through Pyrex using a 550-W Hanovia lamp initiates a retro 4 + 2 reaction to form the extended quinone methide 4, which reacts with methanol to form a pair of methyl ethers (Scheme 6A).18 Flash photolysis of coniferyl alcohol 5 generates the quinone methide 6 (Scheme 6B) by elimination of hydroxide ion from the excited-state reaction intermediate.19 The kinetics for the thermal reactions of 6 in water were characterized,20 but not the reaction products. These were assumed to be the starting alcohol 5 from 1,8-addition of water to 6 and the benzylic alcohol from 1,6-addition of water (Scheme 6). A second quinone methide has been proposed to form as a central intermediate in the biosynthesis of several neolignans,21a and chemical synthesis of neolignans has been achieved... 

In 2005, Baxendale et al. reported the first enantioselective synthesis of 2-aryl-2,3-dihydro-3-benzofurancarboxamide neolignan (grossamide) 260 conducted under continuous flow conditions. As illustrated in Scheme 73, the first step of the reaction involved the synthesis of amide 261 via the coupling of ferulic acid 262 and tyramine 171, in the presence of PS-HOBt 263. Monitoring reaction progress by LC-MS, the authors were able to optimize this step to afford the amide 261 in 90% conversion however, prior to performing the second reaction step it was imperative to remove any residual tyramine 171. As Scheme 74 illustrates, this was achieved by... 

Scheme 6. Arylation with an organolead compound as a key step in the synthesis of nor-neolignan.

A stereocontrolled synthesis of the biologically active neolignan (+)-dehydrodiconiferyl alcohol, which was isolated from several Taxus species, was achieved via Evans asymmetric aldol condensation [58] using ferulic acid amide derived from D-phenylalanine. The reaction steps are shown in Fig. 9. This stereocontrolled reaction is also useful for preparing the enantiomer of (+)-dehydroconiferyl alcohol using chiral auxiliary oxazolidinone prepared from L-phenylalanine. This reaction also enables the syntheses of other natural products that possess the same phenylcoumaran framework. 

Zacchino, S.A. and Badano, H. (1991) Enantioselective synthesis and absolute configuration assignment of erythro-(3,4-methylenedioxy-7-hydroxy-1 -allyl-3, 5 -dimethoxy)-8-0-4 -neolignan and its acetate, isolated from nutmeg (Myristica fragrans). Journal of Natural Products 54(1), 155-1 60. 

Benzo[/][l,2]oxasilepines, which are available by RCM, have been employed in the synthesis of as- and trans-dihydrobenzoMfuran neolignans (Equation 145) <2005SL3011>. A mechanistic proposal for the stereochemical outcome of this variant of the Hosomi-Sakurai reaction has been given <2007CEJ557>. 

Amoldi A, Merlini L (1985) Asymmetric Synthesis of 3-Methyl-2-phenyl-l,4-benzodiox-anes. Absolute Configuration of the Neolignan Eusiderin and Euseridin C and D. J Chem Soc Perkin Trans I 2555... 

In an analogous fashion, use of the 7r-bonds of vinyl ethers, vinyl sulfides, and electron-rich styrenes as nucleophiles has been developed as a surprisingly versatile anodic C-C bond-forming reaction, particularly for the synthesis of complex neolignan structures. Early controlled-potential electrolysis studies on pam-methoxyphenol and vinyl ethers gave the corresponding dihydrobenzofuran acetals in what is formally a [3 2]-... 

The anodic method, which often gives superior yields, has been effectively used in the total synthesis of a number of natural products, as in the preparation of Aniba neolignan (LII) in 81% yield [52] ... 

From the viewpoint of organic synthesis, nature provides us with a number of target molecules, which have novel structures and a variety of biological activities. As already shown in Section II.A, electrochemical oxidation of phenols has been applied successfully to natural products synthesis. Hypervalent (diacyloxyiodo)benzenes have also been proved to be effective for natural products synthesis. Generally, oxidation of o- and p-methoxyphenols in MeOH provides the corresponding o- and p-quinone monoketals, respectively. They are utilized as promising synthons for natural products and related bioactive compounds, as demonstrated by Swenton . Recently, these quinone monoketals have been utilized for syntheses of terpenoids, neolignans, anthraquinones, alkaloids and related compounds. 

SCHEME 93. Synthesis of dibenzocyclooctadiene-type neolignans and spirodienones... 

SCHEME 96. Synthesis of guianin, burechelUn and related neolignans... 

Of phenolic oxidations using vanadium compounds, intramolecular oxidative phenolcoupling reactions are quite attractive from the viewpoint of natural products synthesis. A number of benzylisoquinoline alkaloids, lignans and neolignans are well known to be produced, in a key step, by oxidative radical coupling of open phenolic precursors. 

Lunarine (26), a constituent of Lunaria biennis M., is a member of neolignans (see Scheme 4). Biomimetic synthesis of tetrahydrolunarine (720) was performed by K3Fe(CN)e-promoted oxidation of methyl p-hydroxyphenylpropionate (721) as a key step. 721 was oxidized with K3Fe(CN)e in aq. Na2C03 (0 °C, 3.5 h) to give in 14% yield an ortho-para coupled product 722, which was further converted to the target molecule 720 (Scheme 142) . ... 

The benzo[/][l,2]oxasilepme 212 (formed by a RCM reaction from 211) was used in a concise synthesis of some neolignans <05SL3011>. 

In 2006, Ley reported the application of a continuous flow-through platform for the preparation of the neolignan natural product Grossamide (Scheme 8.48) [63], This was the first report of the enantioselective total synthesis of Grossamide utilizing a fully automated and scalable flow reactor with supported-reagents and scavengers. This principle has a wider impact on multiple step assembly of libraries and natural products. 

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