Diastereoselective Synthesis of b-Piperonyl-g-Butyrolactones from Morita-Baylis-Hillman Adducts . Highly Efficient Synthesis of ( ± )-Yatein , ( ± )-Podorhizol and ( ± )-epi-Podorhizol

Starting from a Morita-Baylis-Hillman adduct we describe a simple and very efficient method for the diastereoselective preparation of hydroxylated β-Piperonyl-γ-Butyrolactones. To exemplify the efficiency of this approach we also describe a highly efficient synthesis for the biologically active lignans (±)-yatein, (±)-podorhizol and (±)-epi-podorhizol.


Introduction
Lignans are natural products originated from a coupling reaction between C6-C3 units (phenylpropionate).These secondary metabolites are widely encountered in plant kingdom and present a huge structural diversity normally associated with interesting biological effects, such as antitumoral, fungicide and anti-viral. 1,2Furthermore, they also show other biological activities against insects and some vertebrates (Figure 1). 3  Trachelogenin amide A (1, Figure 1) is a dibenzylbutane lignan, isolated from the leaves and stems of Trachelospermum jasminoides.This plant is used in chinese folk medicine to treat rheumatic arthralgia, aching of loins and knees, and traumatic injuries. 4Actaelactone (2, Figure 1), is a dibenzylbutyrolactone lignan isolated from back cohosh (Actaea racemosa). 5Actaealactone showed antioxidant activity in the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free-radical assay, with an IC 50 value of 26 µmol L -1 .It also exhibited a small stimulating effect on the growth of MCF-7 breast cancer cells.9a-Angloyloxypinoresinol (3) has displayed inhibitory activity against HIV reverse transcriptase and was isolated from the roots and rhizomes of the chinese plant Ligularia kanaitizensis. 6,7 Kadsuralignan J (4) was isolated from roots of the chinese plant Kadsura coccinea and presents a moderate nitric oxide inhibitory activity. 8Beilschmin A (5) was isolated from the stems of chinese plant Beilschmiedia tsangii.This lignan was found to exhibit significant in vitro cytotoxicity against P-388 and HT-29 cell lines, with IC 50 values of 1.2 and 5.0 mg mL -1 , respectively. 9The most prominent member of the aryltetralin lignan class is podophyllotoxin (6).This compound and some analogues have been isolated from American Mayapple (Podophyllum peltatum). 10 Podophyllotoxin (6) has long been known to possess antimitotic activity with early clinical trials showing it to be highly efficacious but also quite toxic.Driven by the desire to enhance this biological profile, there have been many synthetic modifications to the podophyllotoxin structure, including the generation of potent anticancer agents.It is possible to include the following agents, as the actually marketed medicines Etoposide and Teniposide. 10  The structural diversity and complexity associated with biological effects exhibit by lignans have stimulated the development of several synthetic approaches to prepare them, both in racemic and enantiomeric pure forms. 11Most of the synthetic methodologies are based on a b-aryl-gbutyrolactone.This key intermediate is very important in the synthesis of butyrolactone lignans, which are used as plataform for the preparation of other lignans. 12 Some years ago, Enders et al. 13 elegantly demonstrated that hydroxylated b-aryl-g-butyrolactone is a central intermediate from which several different types of lignans can be synthesized (Figure 2). 13,14

Results and Discussion
Morita-Baylis-Hillman is an amazing chemical transformation capable of efficiently providing highly dibenzyilbutanediols functionalized b-hydroxy-a-methylene carbonyl derivatives. 15,16The adducts formed in this reaction have been used as substrate for the synthesis of natural products and drugs. 17 Some years ago we reported, for the first time, a strategy which allowed the preparation of b-aryl-gbutyrolactone using Morita-Baylis-Hillman adduct as Vol. 21, No. 12, 2010 intermediates. 14This simple and straightforward strategy provided access to syn-and anti-hydroxylated b-aryl-gbutyrolactone (8 and 9, respectively) in good yield.The diastereoselectivity for the syn isomer was acceptable (4:1), but for the anti was very poor (1:1.5).In this case, the presence of regioisomeric lactone 10 was also detected, thus compromising the whole efficiency of the synthetic methodology (Scheme 1).
Basically, a diastereoselective Michael addition of a cyanide to the double bond of a Morita-Baylis-Hillman gave 7a/b, as a mixture of diastereoisomers.Reduction of the ester group followed by basic hydrolysis of the nitrile group and in situ cyclisation, afford the desired butyrolactones in good yield.Unfortunately, this strategy had two major drawbacks.The first one was concerning the poor diastereoselectivity observed for the anti isomer.This isomer is particularly important for the synthesis of aryltetralin lactones, such as podophillotoxin.Second, an undesired regioisomeric butyrolactone (10) is formed, which renders the chromatographic separation laborious.
The butyrolactones can be prepared by direct oxidation of lactol 14, which in turn can be synthesized in one step from cyanide-ester 7, using reductive conditions.The preparation of 7 can be secured by a diastereoselective Michael addition reaction with a suitable Morita-Baylis-Hillman adduct, such as 16.Based on our previous results, we anticipated good diastereoselective control could be achieved in the Michael step, mainly in the preparation of the syn diastereoisomer. 14 In order to improve the diastereoselectivity in the preparation of anti isomer, we thought that b-ketoesters 15 could be used as substrate in a diastereoselective reduction step.Based on a careful conformational analysis of 15, we likely assume that A is the most stable conformer (Scheme 3).We can thus expect that hydride attack should preferentially occur on the less hindered side, leading to the anti diastereoisomer as the major product.
Taking in to account these preliminary considerations, we commenced with the synthesis of b-hydroxy-ester 16 by coupling of methyl acrylate with piperonal.Electronrich aldehyde piperonal is very resistant to Morita-Baylis-Hillman reaction and normally rate, conversion and yield are very low.Searching to circumvent this problem we carried out a reaction using an excess of acrylate (30 equiv.) in the presence of catalytic amount of an ionic liquid [bmim]PF 6 (1-butyl-3-methylimidazolium hexafluorophosphate) and ultrasound.Under these conditions, adduct 16 was obtained after 80 h, in 89% yield (Scheme 4).
The mixture was easily characterized by measuring the coupling constant (J) of the carbinolic proton in 1 H NMR spectrum.A doublet resonance at 5.10 ppm (J 4.4 Hz) was attributed to the syn diastereomer, while the doublet resonance at 4.95 ppm (J 7.6 Hz) was attributed to the anti isomer.The spectral data are consistent with those previously reported in literature. 14 The preparation of b-ketoester 15 was unexpectedly troublesome.We tested several different oxidizing reagents.The results are summarized in Table 1.
Depending on experimental conditions used the b-ketoester 15 was contaminated with the decarboxylation product 17 (entries 1 and 2, Table 1).It is known that hypervalent reagent can hydrolyse esters and acetals. 23 Then, we believe that the large excess of 2-iodoxybenzoic acid (IBX) used in the reaction has favored the hydrolysis of our keto ester, which subsequently loss CO 2 .The best result was achieved when Jones reagent was used in acetone at 0 °C. 24Under these conditions, b-ketoester 15 was obtained as a sole product in 94% yield (entry 6, Table 1).
Having ketoester 15 in our hands, we subjected it to a set of different reductive conditions.The results are summarized in Table 2.
In all cases, diastereoselectivity was better than that achieved by conjugate addition of cyanide to the double bond of Morita-Baylis-Hillman adduct.Moreover, the highest selectivity was attained when employing NaBH 4 at room temperature and using methanol as solvent (syn:anti;1 :10).The difference between the diastereoselectivity for the oxidation-reduction approach and the Michael addition of sodium cyanide Michael addition is remarkable (Figure 4).After a simple chromatographic purification, anti-(±)-7b was obtained as a sole diastereoisomer in 75% yield.To accomplish our goal, it was necessary to protect the secondary  hydroxyl group of anti-cyanide 7b.Then, compound 7b was treated with tert-butyldimethylsilyl chloride (TBSCl) and imidazole in anhydrous dimethyl formamide (DMF) to afford the silylether 18 in 78% yield.A dichloromethane solution of 18 was then treated with a solution of diisobutylaluminium hydride (DIBAL-H) (3 equiv.), at -78 °C for 3 h to give the lactol 14 in 91% (Scheme 5).DIBAL-H reduces the ester group to the primary alcohol and nitrile to an imine, which is quenched at this stage.During the aqueous workup, imine is hydrolyzed to the aldehyde, which reacts with the alcohol to give lactol 14 (Scheme 5).The NMR analysis of lactol 14 was tedious, since the temporary appearance of a third stereogenic center excessively complicates the spectrum.Thus, 14 was directly treated with tetrapropylammonium perruthenate (TPAP) in the presence of N-methylmorpholine-N-oxide (NMO) and molecular sieve (MS, 4 Å) to afford silylated antibutyrolactone 19 in 92%. 28 Removal of the protecting group with tetra-nbutylammonium fluoride (TBAF) in MeOH gave anti-bpiperonyl-g-butyrolactone 9 in 94% (Scheme 5).
All spectroscopic data are compatible with the proposed structure.The anti-b-piperonyl-g-butyrolactone 9 was prepared in a highly diastereoselective approach in 36% overall yield, in 8 steps starting from piperonal.To demonstrate the feasibility of this strategy we also prepared syn-butyrolactone (8), using a similar synthetic sequence.To direct the diastereoselectivity towards the formation of the syn isomer, the secondary hydroxyl group of Morita-Baylis-Hillman adduct should be protected before the cyanide addition.The enhanced presence of the silyl group alters the course of the Michael addition leading to the syn isomer as the major product (Scheme 6).
Initially adduct 16 was silylated to afford the silyl ether 20 in 95%.Michael addition reaction yielded cyanideesters 18a/b as a mixture of diastereoisomers in which the syn isomer is the major one (4:1).This stereochemical ratio is certainly defined during the protonation of the enol intermediate formed after the addition of cyanide (Scheme 7).This protonation should likely occur in the enol face in opposite to the silyl group.However, the preference for this face seems to be not so high.A careful analysis of the proposed conformers clearly shows that we have a steric enhancement in both faces, although one side (opposite to TBDS group) being most accessible than other.This observation can explain the moderate selectivity attained.
We made several attempts to separate these diasteroisomers by column chromatography at this stage, however, only slight enrichment of the mixture in favor of the syn isomer was realized.DIBAL-H reduction afford the lactol, which was immediately oxidized to the corresponding silylated lactone in 84% yield over two steps.The silyl group was removed to provide syn-hydroxylated b-piperonyl-g-butyrolactone (8) in 95%.Unfortunately, lactone syn was already contaminated with a small amount of the anti isomer (7:1).The syn-butyrolactone was prepared in an overall yield of 56% in 7 steps from piperonal.

Conclusions
In summary we have described an alternative and efficient strategy for the synthesis of lignans from Morita-Baylis-Hillman adduct.This simple and straighforward sequence allows the diastereoseletive synthesis of anti and syn hydroxylated b-piperonyl-g-butyrolactone in good overall yield.As far as we know this is the first report concerning the total synthesis of lignans from a Morita-Baylis-Hillman adduct.Due to the ease to which different Morita-Baylis-Hillman adducts were obtained, this approach can be used to furnish lignans of greater molecular diversity.Finally, we have demonstrated that Morita-Baylis-Hillman adducts can be considered as a valuable substrate to prepare lignans.

General
The 1 H and 13 C NMR spectra were recorded with a Varian GEMINI BB at 300 and 75.4 MHz and Bruker at 250 and 62.5 MHz, respectively, or on an Inova Instrument at 500 and 125 MHz, respectively.The mass spectra were recorded using a HP model 5988A GC/MS with a High Resolution Autospec/EBE.IR were obtained with a Nicolet model Impact 410.Diastereoselectivities were determined from GC analysis on a HP6890 with flame ionization detector, using a HP-5 capillary (cross linked 5% phenyl methyl siloxane, 28 m) column or by NMR.Manipulations and reactions were not performed under a dry atmosphere or employing dry solvents, unless otherwise specified.Purifications and separations by column chromatography were performed on silica gel, using normal or flash chromatography.Thin-layer chromatography (TLC) visualization was achieved by spraying with 5% ethanolic phosphomolybdic acid and heating.Morita-Baylis-Hillman reactions were sonicated in an UNIQUE model GA 1000 ultrasonic bath (1000 W, 25 kHz).Ice was added occasionally to avoid increasing the temperature of the water of the ultrasonic bath, which was maintained between 30 and 40 °C.Reagents were purchased from Aldrich, Acros or Lancaster, and were used without prior purification.
Preparation of (±)-podorhizol ( 12) and (±)-epi-podorhizol (13) To a solution of 21 (0.1 g, 0.44 mmol) in anhydrous THF (5 mL), at -78 °C and under an inert gas atmosphere, was added a solution of freshly prepared lithium diisopropylamine (LDA, 0.2 mol L -1 , 0.26 mL, 0.42 mmol).The resulting solution was allowed to warm to 0 °C during 30 min.After the solution was cooled again to -78 °C and stirred after 30 min.Then a solution of 3,4,5-trimethoxybenzaldehyde (0.08 g, 0.44 mmol) in anhydrous THF (2 mL) was added.The resulting solution was stirred after 1 h, at -78 °C.Then the reaction was quenched with a saturated solution of ammonium chloride (10 mL) and warmed to the room temperature.The medium was extracted with ethyl acetate (30 mL) and the organic phase was washed with distilled water (2 × 10 mL) and dried over anhydrous Na 2 SO 4 .The isomers were separated by flash silica gel column chromatography (CH 2 Cl 2 :MeOH, 98:2, v/v) to afford 12 and 13 in a combined yield of 80%.

Figure 1 .
Figure 1.Types and examples of biological active lignans.

Figure 4 .
Figure 4. Determining the stereochemical ratio of cyano-ester 7a/b. A. Diastereoisomeric ratio (syn:anti; 1:2) obtained by direct addition of cyanide on the double bond of the adduct.Signal centered at 5.08 ppm was atributted to the syn isomer (J 2.8 and 5.1 Hz), while that centered at 4.92 ppm (J 3.5 and 7.8 Hz) was atributted to the anti one.In both cases the minor coupling constants are due to the coupling with the hydroxyl hydrogen.B. Diastereoisomeric ratio obtained just after ketoester reduction with NaBH 4 .

Table 1 .
Preparation of b-keto ester 15 a Yields refer to isolated and purified products; b all spectral data ( 1 H NMR,13C NMR, IR, HRMS) are compatible with the proposed structures; c see reference22.

Table 2 .
Diastereoselective reduction of b-keto ester 17 a Yields refer to isolated and purified products; b all spectral data ( 1 H NMR,13C NMR, IR, HRMS) are compatible with the proposed structures; c see reference 25; (d) see reference 26.