The first stereoselective total synthesis of a new antitumour and anti-inflammatory neolignan, surinamensinol A

Abstract

The stereoselective total synthesis of an antitumour and anti-inflammatory 8-O-4′-neolignan, surinamensinol A has been accomplished starting from two aldehydes, 3,4,5-trimethoxy benzaldehyde and vanillin. The key steps involve an asymmetric reduction using a chiral oxazaborolidine complex, a Sharpless asymmetric dihydroxyllation and a Mitsunobu reaction. This is the first report of the total synthesis of surinamensinol A.

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Surinamensinols A (1) and B (2), two new diastereomeric 8-O-4′-neolignans along with several other phenolics have recently been isolated from the rhizomes of the aquatic plant, Acorus gramineus (Araceae).¹ The first compound bears (7R, 8R) configuration while the latter (7S, 8R) (Fig. 1). Compounds 1 and 2 were found to possess potent cytotoxicity against the A549 cell line and moderate activity against the SK-OV-3, SK-MEL-2 and HCT-15 cell lines.¹ Both compounds 1 and 2 also exhibited impressive anti-inflammatory activity. They significantly inhibited the NO levels in LPS-stimulated BV-2 cells.¹ In continuation to our work² on the construction of natural products herein we disclose the total synthesis of 1. This is the first report of the synthesis of this molecule. The synthesis of some 8-O-4′-oxyneolignan derivatives have been reported,³ but earlier synthetic approaches were different compared to our present work. Our current approach involves two non-chiral easily available aldehydes as the starting materials. The reagents are also commercially available and the synthetic steps are limited.

Fig. 1 Surinamensinols A (1) and B (2).

The retrosynthetic analysis (Scheme 1) indicates that surinamensinol (1) can be synthesized from the chiral diol 3 and the TBS ether 4. Compounds 3 and 4 can, in turn, be obtained from 3,4,5-trimethoxy benzaldehyde (5) and vanillin (6), respectively.

Scheme 1 The retrosynthetic route for surinamensinol A.

For the synthesis of the chiral diol 3, 3,4,5-trimethoxy benzaldehyde (5) was treated with vinyl magnesium bromide to produce the alcohol 7 (Scheme 2).⁴ The alcohol 7 was oxidized with IBX and the corresponding ketone was subjected to chiral reduction using (R)-(+) 2-methyl-CBS-oxazaborolodine and BH₃SMe₂ to furnish the chiral alcohol 8 (ee 91%).⁵ The free hydroxyl group of 8 was protected as a Bn-ether (9) by treatment with BnBr and NaH. Compound 9 underwent a Sharpless asymmetric dihydroxylation⁶ with AD-mix β in t-BuOH : H₂O (1 : 1) to furnish the diol 10 along with its minor diastereomer (diastereomeric ratio 82 : 18) which was separated out. The primary hydroxyl group of 10 was tosylated with TsCl to form the mono-hydroxy compound 11. The subsequent reduction of 11 with LiAlH₄ afforded the desired fragment 3 in a high yield.⁷

Scheme 2 Reagents and conditions: (a) H₂C=CHMgBr, THF, 0 °C to room temperature, 85%; (b) (i) IBX, DMSO, CH₂Cl₂, 0 °C to room temperature; (ii) (R)-(+)-2-methyl-CBS-oxazaborolidine, BH₃·SMe₂, THF, −40 °C, 65% (ee 91%); (c) NaH, BnBr, THF, 0 °C to room temperature, 83%; (d) AD-mix β, t-BuOH : H₂O (1 : 1), 0 °C, 80% (82 : 18); (e) TsCl, Et₃N, DCM, DMAP, 0 °C to room temperature, 76%; (f) LiAlH₄, THF, 0 °C to reflux, 89%.

For the synthesis of another fragment 4, vanillin (6) was subjected to a Wittig reaction with Ph₃PCHCOOEt to form the unsaturated ester 12 (ref. 8) (Scheme 3) with an E : Z ratio of 92 : 8. The reduction of 12 with NaBH₄ in the presence of NiCl₂·6H₂O followed by the protection of the phenolic hydroxyl group by treatment with BnBr and NaH and subsequent reduction with LiAlH₄ afforded the saturated alcohol 13. The hydroxyl group of 13 was protected as a TBS ether (14) by using TBSCl and imidazole and compound 14 was then hydrogenated in the presence of 10% Pd–C to produce fragment 4.⁹

Scheme 3 Reagents and conditions: (a) Ph₃P=CHCO₂Et, benzene, reflux, 81%, (E/Z ratio 92 : 8); (b) NaBH₄, NiCl₂·6H₂O, MeOH, 0 °C to room temperature; (c) NaH, BnBr, THF 0 °C to room temperature; (d) LAH, dry THF, reflux, 67% (over 3 steps); (e) TBSCl, imidazole, DCM, 95%; (f) 10% Pd–C, H₂, EtOAc, room temperature, 91%.

Finally, the coupling of the two fragments 3 and 4 was carried out by a Mitsunobu reaction¹⁰ using Ph₃P and DEAD and the resulting product on treatment with p-TsOH in MeOH followed by hydrogenation in the presence of 10% Pd–C yielded the target molecule, surinamensinol A (1) (Scheme 4) with 90% ee. The physical and spectral properties of the compound were compared to those reported for the natural product.¹

Scheme 4 Reagents and conditions: (a) (i) Ph₃P, DEAD, dry THF, reflux; (ii) p-TsOH, MeOH, room temperature; (iii) 10% Pd–C, H₂, room temperature, 40%.

In conclusion, we have demonstrated the first stereoselective total synthesis of the bioactive neolignan, surinamensinol A starting from two easily available aldehydes, 3,4,5-trimethoxy benzaldehyde and vanillin. Chiral reduction, asymmetric dihydroxylation and the Mitsunobu reaction are the key steps in the present synthesis. The overall yield of 1 starting from 5 is 10% involving sixteen steps.

Acknowledgements

The authors thank CSIR and UGC, New Delhi for financial assistance. They are also thankful to NMR, Mass and IR divisions of CSIR-IICT for spectral recording.

References

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Footnotes

† Electronic supplementary information (ESI) available: experimental procedures, copies of ¹H and ¹³C NMR spectra of products. See DOI: 10.1039/c3ra45419c

‡ Part 68 in the series, synthetic studies on natural products.

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