A new approach toward the total synthesis of (+)-batzellaside B

A new synthetic approach to (+)-batzellaside B from naturally abundant L-pyroglutamic acid is presented in this article. The key synthetic step involves Sharpless asymmetric dihydroxylation of an olefinic substrate functionalized with an acetoxy group to introduce two chiral centres diastereoselectively into the structure. Heterocyclic hemiaminal 4, which could be converted from the resulting product, was found to provide stereospecific access to enantiomerically enriched allylated intermediate, offering better prospects for the total synthesis of this natural product.


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General: All solvents and reagents were of reagent-grade quality from Wako Pure Chemicals and Tokyo Chemical Industry (TCI) and used without further purification.
The 1 H and 13 C nuclear magnetic resonance (NMR) spectra operating at the frequencies of 300 and 75 MHz, respectively, were recorded on a JEOL JNM-AL300 spectrometer in chloroform-d (CDCl 3 ) and methanol-d 4 (CD 3 OD). Chemical shifts are reported in parts per million (ppm) relative to TMS, the solvent was used as the internal standard, and the coupling constants are reported in hertz (Hz). and the resulting mixture was stirred at room temperature. After 10 min, the mixture was quenched by addition of saturated NH 4 Cl aq (10 mL) and concentrated in vacuo.

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Synthesis and characterization of 10: To a solution of 9 (43.9 mg, 0.122 mmol) in methanol (2.0 mL) was added a catalytic amount of p-toluenesulfonic acid (p-TsOH), and the resulting mixture was stirred at room temperature. After 3 h, the mixture was quenched by the addition of saturated NaHCO 3aq (30 mL), concentrated, and extracted with ethyl acetate (50 mL). The extracts were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was roughly separated by column chromatography on silica gel (eluent: hexane/ethyl acetate, 1/1) to provide the crude alcohol intermediate (   hexane/ethyl acetate, 4/1 to 2/1) to yield 14B (  General procedure for asymmetric dihydroxylation of 6a-d (Table 1, entries 1-9): To a suspension of AD-mix-α or AD-mix-β in 50% aqueous t-BuOH (0.080 M, 0.50 mol %) were successively added a solution of olefinic substrate 6 in 50% aqueous t-BuOH (0.020 M) and methanesulfonamide (100 mol %) at 0 °C, and the resulting mixture was stirred at the temperature as indicated in Table 1. Upon S11 completion of the reaction based on TLC analysis, the mixture was quenched by addition of saturated NaHSO 3aq (10 mL), and extracted with ethyl acetate (3 x 30 mL).

Dihydroxylation of 6a and characterization of 12a-A and 12a-B:
The extracts were dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo.
The residue was roughly separated by column chromatography on silica gel to yield the mixtures of 12-A and 12-B (diastereomeric ratios and combined yields are presented in Table 1).