Lignans asymmetric synthesis

Highly substituted 2,3-dihydrofurans 44 (Scheme 1.3.18) would make particularly interesting starting materials for the asymmetric synthesis of tetrahydrofu-rans, structural motifs which can be found in many important natural products, including polyether antibiotics, lignans, and nucleosides [30]. Not only the activated double bond but also the vinylic silyl group of 44 should allow useful synthetic transformations. 

Asymmetric synthesis of lignans may involve the use of several approaches like a tandem conjugate addition reaction, a Diels-Alder reaction or a radical carboxyarylation reaction, as mentioned above. 

Modified chiral biphosphinic dioxolane ligands and their use in the asymmetric synthesis of natural lignans 92H(33)435. 

A broad range of biaryl structures, as is often encountered in various classes of naturally occurring compounds, such as alkaloids, lignans, and tannins, can be prepared by oxidative arylic coupling. Oxidative couplings have also been used to build non-natural skeletons, such as the binaphthol derivatives that play an important role in asymmetric synthesis. 

Other methods of preparation and diastereoselective alkylation of chiral butyrolactones (44) are summarized in the recent review of asymmetric synthesis of lignans (16). 

Scheme (10). Asymmetric synthesis of lignans by Charlton and co-workers...

As the previous chapters have demonstrated, chiral auxiliaries have found a widespread application in the asymmetric synthesis of lignans. Among them, chiral oxazolidinones have been used extensively due to their ability to produce excellent diastereoselectivities in aldol as well as in numerous other reactions. For example, Kise et al. reported the use of (5)-4-isopropyl-3-(phenylacetyl)-2-oxazolidinone (141) in oxidative homocoupling reactions and its application in the asymmetric synthesis of dibenzylbutyrolactones and dibenzylbutandiols, Scheme (26) [86,87]. Treatment of 3-arylpropanoic acid derivative 142 with LDA in the presence of TiCU yielded a mixture of the dimeric compounds 143 in a ratio of 85 15 to 87 13. The major product having (R,R) configuration was converted into dibenzylbutyrolactones 145 in a three step sequence... 

Scheme (38). Asymmetric synthesis of samin-type lignan by Yamauchi...

Synthesis and asymmetric synthesis, reviewing important synthetic routes to lignans... 

As already demonstrated tra 5-dibenzylbutyrolactones are valuable as precursors for the synthesis of a wide range of lignans. For example, the keto-lactones (90) and (91), which have both been prepared by tandem conjugate addition reactions, provide key intermediates for the synthesis and asymmetric synthesis respectively of lignans of the furofuran type (scheme 30) [85,86]. 

Butenolides substituted with a chiral sulphoxide moiety are also good substrates, as shown by the short asymmetric synthesis of (-)-podorhizon (91), a lignan natural product.t35]... 

Meyers reported an important extension of the method to the asymmetric synthesis of chiral biphenyl derivatives [76]. In this regard, the Grignard reagent derived from aryl bromide 60 underwent addition to oxazoline 61 to furnish chiral biaryl derivative 62 (dr=88 12. Scheme 12.8) [77]. After removal of the oxazoline auxiliary, the chiral biphenyl served as a key intermediate in the total synthesis of the antileukemic lignan steganone (63). 

Asymmetric catalysis with Rh2(4Y-MPPIM)4 has been used to prepare a wide variety of lignans such as (+)-isodeoxypodophyllotoxin 70 (Equation (62))202,203 and (—)-enterolactone 71 (Equation (63)).194 The chemistry has also been utilized in the synthesis of (A)-(+)-imperanene 72 (Equation (64))197 and (R)-(—)-baclofen 73 (Equation (65)).198 Enantioselectivities of 91-96% ee have been obtained for a broad range of applications. 

C-H activation at a primary benzylic site was the key step in very short syntheses of lig-nans 206 and 207 (Scheme 14.27) [138]. Even though both the substrate 203 and the vinyl-diazoacetate 204 contain very electron-rich aromatic rings, C-H activation to form 205 (43% yield and 91% ee) is still possible because the aromatic rings are sterically protected from electrophilic aromatic substitution by the carbenoid. Reduction of the ester in (S)-205 followed by global deprotection of the silyl ethers completes a highly efficient three-step asymmetric total synthesis of (-i-)-imperanene 206. Treatment of (R)-205 in a more elaborate synthetic sequence of a cascade Prins reaction/electrophilic substitution/lacto-nization results in the total synthesis of a related lignan, (-)-a-conidendrin 207. 

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