Lignan natural products

Keywords a-Hydroxylated lignans Natural product synthesis Enantioselective hydrogenation Chiral building blocks Malic acid... 

A short and highly stereoselective route to lignan natural products ( )-dihydrosesamin and ( )-lariciresinol using radical methods has been reported [95JCS(P1)927]. These cyclizations proceed in good yields and the stereochemistry at two contiguous chiral centers are established. 

The 2-aryl-substituted 4-phenyloxazole 144 has been used in the synthesis of the pharmacologically active tetrahydrofuran lignan natural products (Fig. 3.43). Refluxing a mixture of 144 with 2-butyn-l,4-diol diacetate in the presence of sodium carbonate and hydroquinone for 22 h provided an 89% yield of the 2,3,4-trisub-stituted furan 145. Elaboration of 145 by hydrolysis of the diacetate and selective oxidation of the 4-carbinol then afforded the lignan 146 as a mixture of diaster-eomers after three additional steps. ... 

A recent and succinct approach to 2-aryltetrahydrofuran precursors to lignan natural products involves the cycloaddition of 2-aryM-phenyloxazoles with di-methylacetylene dicarboxylate. For example, 2,4-diphenyloxazole 273 (R = H) reacts with dimethylacetylene dicarboxylate in refluxing xylenes in the presence of sodium carbonate and hydroquinone to provide 2-phenyl-3,4-furandicarboxylic acid dimethyl ester 274 in 98% yield (Fig. 3.82). Not surprisingly, 4,5-diphenylox-azole and 2,4,5-triphenyloxazole gave lower yields of the corresponding furans... 

Scheme 14.20 Synthesis of Lignan natural products through fS.SI-rearrangemenLs nf JV-allyl hydrazones. ...

The Thomson group has also recendy adapted the iodonium-promoted rearrangement of N-allylic hydrazones to the synthesis of several naphthyl-type lignan natural products that display... 

The Pummerer rearrangement can also be carried in tandem with a Diels-Alder reaction. This sequence has been utilized in the syntheses of the arylnaphthalene lignan natural products. Sulphoxide 64 in acetic anhydride was slowly added to a solution of dimethyl maleate in acetic anhydride under reflux, resulting in cycloadduct 65 in 85% yield. 

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]... 

Hong and coworkers have taken advantage of hemiacetal reductions to synthesize lignan natural products. In the course of their studies, they discovered that the relative stereochemistiy of the products that come from the activatiOTi and reductimi of hemiketal 4 was dependent upon the conditions used to cany out the reaction (Scheme 2) [7]. Namely, they found that 2,5-c/s-tetrahydrofuran isomer 5, as needed for the synthesis of (—)-futokadsurin A and (—)-veraguensin, came from the rapid NaBHaCN reduction of the intermediate oxocarbenium ion that comes... 

Scheme 2 Synthesis of lignan natural products from lactol reductions by Hong et al. [7]...

Another group of natural products, namely the biologically active lignans of the aryltetralin series - for example, isopodophyllotoxone (2-59), picropodophyllone (2-60), and podophyllotoxin (2-61) (Scheme 2.13) [19] - have also been synthesized using a domino Michael/aldol process. 

Using this system, (Z)-hinokiresinol isolated from cultured cells of A. officinalis was determined to be the optically pure (75 )-isomer, while ( )-hinokiresinol isolated from cultured cells of C. japonica had 83.3% e.e. in favor of the (7S)-enantiomer (Table 12.1). The enzymatically formed (Z)-hinokiresinol obtained following incubation of p-coumaryl p-coumarate with a mixture of equal amounts of recZHRSa and recZHRSf) was found to be the optically pure (75)-isomer, which is identical to that isolated from A. officinalis cells (Table 12.1). A similar result was obtained with the crude plant protein from A. officinalis cultured cells, where the formed (Z)-hinokiresinol was almost optically pure, 97.2% e.e. in favor of the (75)-isomer (Table 12.1). In sharp contrast, when each subunit protein, recZHRSa or recZHRSP, was individually incubated with p-coumaryl p-coumarate, ( )-hinokiresinol was formed (Table 12.1). The enantiomeric compositions of ( )-hinokiresinol thus formed were 20.6% e.e. (with recZHRSa) and 9.0% e.e. (with recZHRSP) in favor of the (7S)-enantiomer (Table 12.1). Taken together, these results clearly indicate that the subunit composition of ZHRS controls not only cis/trans selectivity but also enantioselectivity in hinokiresinol formation (Fig. 12.3). This provides a novel example of enantiomeric control in the biosynthesis of natural products. Although the mechanism for the cis/trans selective and enantioselective reaction remains to be elucidated, for example by x-ray crystallography, the enantioselective mechanism totally differs from the enantioselectivity in biosynthesis of lignans, another class of phenylpropanoid compounds closely related to norlignans in terms of structure and biosynthesis. 

Upon treatment of diastereoisomerically pure ketone (R)-16 with MeLi an 8 1 mixture of compounds ent-6 and ent-5 was obtained in 85% yield (Scheme 3). The synthetic isoschzandrin was in all respects identical to (+)-isoschizandrin (6). However, both, (-)-schizandrin ent-5) and (-)-isoschizandrin ent-6) have the opposite sign of optical rotation from those of the natural products, establishing the absolute configuration of the schizandra lignans. 

The enantiomers of the naturally occurring lignans, schizandrin (5) and isoschizandrin (6), have been prepared from oxazoline 10 in 11 steps with 0.7% and 5.5% overall yield, respectively. Although both natural products are accessible by this strategy, the reported synthetic approach is basically a route to isoschizandrin (6). Schizandrin (5) was obtained only as minor congener and a selective synthesis of 5 has not been accomplished by the authors. 

Two classes of a-hydroxylated lignans have been enantioselectively prepared a) wikstromol (3) [10, 38] and related natural products [39] and b) gomisin A (1) and congeners [40, 41]. In both cases, chiral, non-racemic ita-conic acid derivatives have been synthesized as key compounds for the preparation of -benzyl-y-butyrolactones (either by resolution (g [32]) or by asymmetric hydrogenation (h [25])). 

Nishibe, S., H. Tsukamoto, I. Agata, S. Hisada, K. Shima, and T. Takemoto. Isolation of phenolic compounds from stems of Olea europaea. Shokugaku Zasshil981 35 251-254. Tsukamoto, H., S. Hisada, and S. Nishibe. Studies on the lignans from Oleaceae plants. Proc 26th Symposium on the Chemistry of Natural Products, Kyoto, Japan 1983 26 181—188. Paganuzzi, V. Use of silver nitrate TLC in the analysis of olive oil triterpene alcohols. I. Oils obtained from various anatomical parts of the olives. Riv Ital Sostanze Grasse 1981 58(8) 285-393. 

Abdel-Kader MS, Wisse J, Evans R, van der Werff H, Kingston DGI. Bioactive Iridoids and a New Lignan from Allamanda cathartica and Himatanthus fallax from the Suriname Rainforest. Journal of Natural Products 1997 60(12) 1294-1297. 

A large group of the lignane-type natural products characteristically contain a substituted y-lactone moiety. During attempts to synthesize these natural products the diastereoselective a-alkylation of a y-lactone was a central step in each of the chosen routes. 

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. 

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. 

The fully aromatic A,B-diheteropentalenes do not occur in nature. However, the reduced furofurans and pyrrolopyrroles are present in a variety of natural products such as lignans, fungal metabolites and alkaloids. It is beyond the scope of this chapter to present an exhaustive survey of these compounds. However, a few selected examples are presented in formulae (376)-(380). 

Lewis NG and Davin LB (1999) Lignans biosynthesis and function. Comprehensive Natural Products Chemistry, Vol 1. Elsevier, Amsterdam, pp 639-712. 

The lignans comprise a class of natural products, derived from cinnamic acid derivatives, which are related biochemically to phenylalanine metabolism. 

---