Efficient synthesis of (-)-clausenamide

A new method for the synthesis of (-)-clausenamide was reported. (-)-Clausenamide was synthesized starting from the inexpensive trans-cinnamic acid. The synthesis was carried out over five steps, and the overall yields were 8.9% (99.9% ee). Compared with the multi-step asymmetric synthesis methods reported in the literature, the raw materials used in this method are inexpensive. The overall method is easy to carry out. Furthermore, the reaction takes place under very mild reaction conditions (25 °C). Anhydrous and very low temperature (-78 °C) conditions can be avoided. The column chromatography technique need not be conducted after each reaction step. Hence, this is a suitable method to carry out the large-scale synthesis of (-)-clausenamide. The structures were confirmed using the 1 H NMR, 13 C NMR, and MS techniques.

In the literature, two methods have been reported for the synthesis of (-)-clausenamide: asymmetric synthesis and resolution intermediate synthesis.To the best of our knowledge, the resolution of the starting material to synthesize (-)-clausenamide has not yet been reported.Two pathways can be followed to access (-)-clausenamide, following the asymmetric synthesis methods.One method involves the synthesis of the key intermediate amide (+)-4, followed by the cyclization of (+)-4 to afford (-)-clausenamidone (-)-5 in the presence of LiOH.The process also involves the reduction of (-)-5 with sodium borohydride to obtain the target product.Shi Yi'an 11 reported the synthesis of (-)-clausenamide using trans cinnamate (1a) as the starting material.The synthesis could be conducted over five steps.The overall yield was 18.9% (99% ee; Scheme1, route A).The disadvantage of this method was that the raw materials and chiral catalyst fructose derivatives need to be prepared by themselves.The yield of the chiral catalyst fructose derivatives was low, and its cost was high.In addition, ruthenium trichloride trihydrate sodium periodate was used during oxidation.The reaction mixture was filtered using diatomaceous earth prior to conducting the oxidation step.This resulted in the poor yields of the products.Xuan Yi-ning used cinnamaldehyde (1b) (Scheme 1, route B) 12 as the starting material during the synthesis of (-)-clausenamide.The yield of the product was 6.2% over six steps (99% ee).However, the esterification product and the intermediate epoxy cinnamaldehyde required needed to be separated by column chromatography.The yield of the product obtained after the first step was low.The chiral catalyst prolinol silyl ether derivative was unstable and needed to be prepared each time freshly.In addition, potassium permanganate-copper sulfate pentahydrate was used for oxidation.A viscous manganese dioxide was produced during the reaction, which was difficult to filter.This makes the large-scale synthesis of (-)-clausenamide difficult.(-)-Clausenamide can also be synthesized starting from (-)-3deshydroxyxanthoenamide (-)-6 as the common intermediate.The subsequent steps involve the treatment with Davis reagent to obtain (-)-clausenamide under alkaline conditions.Liu Di and workers synthesized (-)clausenamide starting from cinnamic aldehyde (1d) (Scheme 1, route C). 13 The overall yield of the eight-step synthesis of (-)-clausenamide was 11.5% (99% ee).This method is limited by the Sharpless asymmetric epoxidation of (2c), which needs harsh conditions (anhydrous environment and long-term low temperature).The column chromatography technique must be used to purify the compounds obtained at each step of the multi-step reactions.The Davis oxidant was used in the last step, making this process costly and unsuitable for the large-scale preparation of (-)-clausenamide.Tanda reported the synthesis of (-)-3deshydroxyxanthoenamide (-)-6 starting from phenylpropanhydroxime chloride 1d.(-)-6 was synthesized in 6.5% yield over twelve steps (99% ee). 14The synthesis of the starting material 1d was completed over multiple steps.Furthermore, this material is unstable and can only be stored at room temperature for a few days.At the same time, the reaction of (-)-3d with zinc borohydride could be conducted under low reaction temperature (-78 °C).

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(-)-Clausenamide can also be prepared following a second pathway: the intermediate (±)-clausenamidone (±)-5 (Scheme 2) was resolved using menthol oxyacetic acid to obtain menthoxyacetyclausenamidone (-)-6e.This compound was subjected to hydrolysis to furnish (-)-5, which was reduced with NaBH 4 to give (-)clausenamide in 11.5% yield (98% ee). 15As the diastereoisomeric products (-)-6e and (+)-6e need to be separated by column chromatography, and the enantiomer (+)-clausenamidone is not used for further reactions; the process does not conform to the concept of atom economy.Furthermore, the preparation of the resolving agent (-)-menthyloxyacetic acid requires the use of a large amount of sodium metal (solvent: toluene).The reaction mixture is refluxed for 60-70 h.Hence, the reaction conditions are not suitable for large-scale synthesis.Scheme 2. Chiral resolution of (±)-clausenamidone.

Results and Discussion
We designed a cost-effective method to synthesize the starting material, trans-cinnamic acid (1) (Scheme 3).First, trans-cinnamic acid (1) was treated with potassium persulfate to obtain the racemic epoxy cinnamic acid (±)-2.Following this, the resolution of (±)-2 was achieved using (R)-(+)-ꭤ-methylbenzylamine.(2S,3R)epoxycinnamic acid(R)-α-methylbenzylamine salt (+)-3 was obtained.The latter was treated with HCl (1M) in dichloromethane to give (+)-2, which was directly used in the next step without further purification.This compound was converted to the amide (+)-4 using 2-methylamino-1-phenyl-ethanol.Subsequent treatment with LiOH afforded lactam (-)-5.Finally, the reduction of (-)-5 with NaBH 4 furnished (-)-clausenamide in 8.9% yield over five steps (99.9% ee).Compared with the synthetic methods reported in the literature, the operational steps followed in the described procedure are simpler.Moreover, the reaction takes place under mild reaction conditions (25 °C).Anhydrous reaction conditions and very low-temperature temperature (-78 °C) can be avoided.The products obtained after each step need not be separated using the column chromatography technique.The reaction products obtained at each step can be purified by the process of recrystallization.The raw materials and solvents used in the reaction are cost-effective.The use of expensive chiral catalysts can be avoided.The solvent used is relatively safe (third-type organic solvent) and can be efficiently used in large-scale synthesis processes.Scheme 3. Synthesis of (-)-clausenamide.

Conclusions
In this work, a new method has been reported for the synthesis of (-)-clausenamide.The target compound can be synthesized over steps starting from the cheap starting material (trans-cinnamic acid).First, transcinnamic acid was oxidized using potassium persulfate to yield the racemic epoxy cinnamic acid 2. This was followed by the process of resolution in the presence of (R)-(+)-ꭤ-methylbenzylamine.(+)-(2S,3R)epoxycinnamic acid-(R)-α-methylbenzylamine salt (3) was obtained.
Following this, 3 was converted to the amide 4 using 2-methylamino-1-phenyl-1-ethanone.Base-catalyzed cyclization of 4 furnished lactam 5. Finally, reduction of 5 with sodium borohydride yielded (-)-clausenamide in 8.9% yield (99.9% ee).The advantage of this approach is that cheap raw materials can be used, and the reaction takes place under moderate reaction conditions (anhydrous reaction conditions and ultra-low reaction temperatures can be avoided).All reactions were carried out at room temperature, and the products were purified using the process of recrystallization.This method is suitable to carry out the large-scale synthesis of natural products.