Lignan lactones, synthesis

Honda T, Kimura N et al (1994) Chiral synthesis of lignan lactones, (—)-hinokinin, (—)-deoxypodorhizone, (—)-isohibalactone and (—)-savinin by means of enantioselective deprotonation strategy. J Chem Soc Perkin Trans 1 1043-1046... 

More recent applications in target-oriented synthesis took advantage of the BVMO platform for the generation of enanhocomplementary lactones. In this context, butyrolactones represent appealing intermediates due to the facile availability of prochiral ketone substrates for enzyme-mediated desymmetrizations Scheme 21.7 indicates the potenhal in lignan total synthesis based on products obtained in a previous study [46]. The collechon of BVMOs exploited by our groups also allowed efficient access to various indole alkaloids via enanhocomplementary lactones obtained in the desymmetrizahon of fused bicycloketones [35]. 

There has been much interest in the synthesis of lignan lactones of the aryl tetralin type, induced by the antitumour activity of podophyllotoxin relatives, and some short oxidative routes into the series have been pursued. In a typical reaction, in which both Cp—Cp and Cp—Car couplings occur, the cinnamyl cinnamate (297) was treated for 30 s with chromium trioxide-fluoroboric acid in acetonitrile. Three tetracyclic products were obtained, the lactones (298 19%) and (299 7%), and ( )-isopodophyllotoxone... 

H Saito, H Yoshikawa, Y Nishimura, S Kondo, T Takeuchi, H Umezawa. Studies on lignan lactone antitumor agents.I. Synthesis of aminoglycosidic lignan variants related to podophyUotoxin. Chem Pharm Bull 34 3733-3740, 1986. 

Bisbenzocyclooctadienes The nonphenolic coupling used in the synthesis of lignan lactones is accomplished with Re207 in TFA-TFAA media. 

This reaction was a key step in the synthesis of the (+)-form of the dibenzocyclooctadiene lignan lactone steganacin (5).°... 

The reaction of enolates derived from lactones (121) with aromatic aldehydes has been used effectively in the synthesis of lignan lactones, e.g. (122) and... 

Extensive investigations by Doyle have resulted in the identification of a number of optimized chiral Rh catalysts to effect enantioselective C-H insertion processes. In this regard, several examples of intramolecular C-H insertions have efficiently provided access to optically active building blocks (Equations 29 and 30) [94], Such processes were illustrated in the synthesis of lignan lactones including 178 (Scheme 15.20) [95]. 

Two different classes of optically active a-hydroxylated lignans have been prepared from sugars by Yamauchi and co-workers lactone lignans [47, 48] and tetrahydrofuran lignans [49, 50]. In both cases, only model compounds were synthesized, such as lactone lignan 55 (Scheme 13), as a result of the synthetic strategy. The key intermediate for the synthesis of lactone lignan... 

The stereoselective introduction of both benzyl groups simultaneously in one step seemed to be particularly attractive for a short synthesis of a- hy-droxylated lactone lignans from malic acid (99). Such a simultaneous double alkylation requires the formation of a chiral l,3-diene-l,4-diolate, which was not known. On the other hand, achiral 1,3-diene-1,4-diolates (di-enolates) have been previously prepared by Garrett et al. [58] and subsequently employed for the synthesis of racemic lignans by Snieckus [59] and Pohmakotr [60]. With knowledge of the synthesis and reactivity of di-enolates, we planned to prepare chiral di-enolates from dioxolanones and to alkylate these di-enolates in a stereocontrolled manner (Scheme 22). For the development of the described double deprotonation/alkylation strategy, tert-hutyl... 

Hydrogenolysis of the benzylether of lactone 141 (H2, 10% Pd/C) quantitatively afforded (-)-wikstromol ent-3). The overall yield of ent-3 from diisopropyl malate 107 over six steps was 30% [62]. This strategy for the construction of optically-active lactone lignans provided a short and stereoselective synthesis with comparably good overall yield. 

Our strategy for the synthesis of a-hydroxylated lactone lignans might be extended to the general synthesis of a-hydroxylated lignans, when either of the alkylation steps is changed to an aldol addition. For example, berchemol... 

The chiral lactone (178) has been used for the synthesis of a variety of natural products, such as sugars, lignans, terpenes, alkaloids, and P-lactams as a chiral building block 182c,184). The use of (178) as a powerful inductor of asymmetry was mainly established by Takano et al. 181, 84> one can expect more highly interesting reports from this group. 

Regioselective hydrogenation of anhydrides to lactones. The last step in the synthesis of arylnaphthalene lignans is usually selective hydrogenation of an an-... 

Some approaches to the stereoselective synthesis of a-hydroxylated lactone lignans have been reported [59,60]. As a short and efficient example, the synthesis of a dibenzylbutyrolactone lignan wikstromol from two diastereo-selective alkylations of malic acid (+) has recently been reported [61]. In order to get high stereoselectivity, isoPr malate was chosen for the synthesis of (+)-wikstromol its formation in six steps with a 20% overall yield is shown in Fig. 10. 

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