Stereoselective synthesis of (−)-diospongins A and B and their stereoisomers at C-5

doi:10.1016/j.tet.2007.06.081

Tetrahedron

Volume 63, Issue 37, 10 September 2007, Pages 9049-9056

J.U. dedicates this paper to Professor Yoshito Kishi on the occasion of his 70th birthday

https://doi.org/10.1016/j.tet.2007.06.081 Get rights and content

Abstract

Antiosteoporotic diarylheptanoids (−)-diospongins A (1) and B (2) were synthesized stereoselectively. The key steps in the synthesis include a stereospecific Pd^II-catalyzed cyclization of chiral 1,5,7-trihydroxy-2-heptenes, 6a and 6b, to form cis and trans tetrahydropyran rings and a regioselective Wacker oxidation of β-(tetrahydro-2H-pyran-2-yl)styrenes, 5a and 5b. Their C-5 epimers 3 and 4 were also synthesized.

Graphical abstract

Introduction

1,7-Diarylheptanoids including curcuminoids are a class of secondary plant metabolite and have been found in rhizomes of the Zingiberaceae family of plants.1, 1(a), 1(b), 1(c) Although 1,7-diarylheptanoids are relatively simple molecules, they exhibit various biological and pharmacological activities, such as anti-oxidant activity,2, 2(a), 2(b) anti-cancer activity,3, 3(a), 3(b), 3(c) inhibitory activity on nitric oxide production,4, 4(a), 4(b) anti-inflammatory activity,⁵ and DPPH-radical scavenging activity,^2b and so on.6, 6(a), 6(b) Particularly, cyclic 1,7-diarylheptanoids have been receiving considerable attention.7, 7(a), 7(b), 7(c), 7(d), 7(e), 7(f), 7(g), 8, 8(a), 8(b), 8(c) Diospongins A (1) and B (2) are cyclic 1,7-diarylheptanoids, as shown in Figure 1, that were isolated from rhizomes of Dioscorea spongiosa in 2004 by Kadota and co-workers.⁹ Diospongins A and B possess 2,6-cis and 2,6-trans tetrahydro-2H-pyran rings, respectively, and these rings are assumed to be formed by an intramolecular cyclization of 5,7-dihydroxy-1,7-diphenyl-2-hepten-1-one, in their biosynthesis. Although both compounds indicate an inhibitory activity against bone resorption induced by parathyroid hormone in a bone organ culture, diospongin B shows more potent antiosteoporotic activity than that of diospongin A due to their different configurations of tetrahydropyran rings. Recently, the synthesis of diospongin B has been reported by three groups.8, 10 We have been interested in studies of the synthesis of cyclic 1,7-diarylheptanoids as well as their biological activities not only because of their antiosteoporotic activity but also because of their inhibitory activity against nitric oxide production. In this paper, we report the total synthesis of diospongins A, B, and their C-5 epimers, 3 and 4.

Our retrosynthetic plan for 1 and 2 is outlined in Scheme 1. The key steps involve a stereospecific construction of chiral cis and trans tetrahydropyran rings of 5a and 5b from 6 by a Pd^II-catalyzed 1,3-chirality transfer reaction11, 11(a), 11(b), 11(c), 11(d) and a regioselective Wacker oxidation of 5a and 5b to 1 and 2. Acyclic precursors 6a and 6b could be derived by an enantioselective reduction of enone 7, which is readily prepared from the chiral homoallylalcohol 8¹² by the standard transformation steps.

Section snippets

Results and discussion

The synthesis of 7 is shown in Scheme 2. We commenced the synthesis from the known aldehyde 9,¹³ which was derived readily from ethyl (R)-(−)-mandelate. Since a simple allylation of 9 with non-chiral allylation reagents gave anti alcohol 8′, usually as a major product,14, 14(a), 14(b) enantioselective allylation must be employed in order to obtain the desired syn alcohol 8. Therefore, we chose Brown's chiral allylborane reagent, (+)-Ipc₂Ballyl,15, 15(a), 15(b) and compound 8 was obtained in 62%

Conclusions

In summary, the total syntheses of diospongins A and B were achieved in seven steps and nine steps, respectively, from the common intermediate 8. It is noteworthy that intramolecular Pd^II-catalyzed cyclizations are potentially useful for the stereospecific formation of oxacyclic natural products possessing cis and trans tetrahydropyran rings. Their stereoisomers 3 and 4 were also prepared in short steps. Syntheses of additional analogs and their biological tests are currently underway.

Asymmetric allylation of 9, preparation of (4S,6S)- and (4R,6S)-6-(tert-butyldimethylsilyl)oxy-4-hydroxy-6-phenyl-1-hexene (8) and (8′)

To a stirred solution of (−)-B-methoxydiisopinocamphenyl borane (360 mg, 1.1 mmol) in Et₂O (8 mL) at −78 °C was slowly added allylmagnesium bromide (1.1 mL, 1 M solution in ether) and the reaction mixture was stirred for 15 min at −78 °C and for 1 h at room temperature forming (+)-B-allyldiisopinocamphenyl borane in situ. After the addition of a solution of 9 (200 mg, 0.75 mmol) in Et₂O (6 mL), the reaction mixture was stirred for 3 h at −78 °C. Then, methanol (5 mL) and 8-hydroxyisoquinoline (220 mg, 1.5 mmol)

Acknowledgements

We thank Professor S. Kadota for generously providing a copy of ¹H NMR, ¹³C NMR spectra of natural (−)-diospongins A and B. This work was supported by Grant-in-Aid for Scientific Research on Priority Areas 17035084 and in part by the 21st COE Program from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.

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Stereoselective synthesis of (−)-diospongins A and B and their stereoisomers at C-5

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

Conclusions

Asymmetric allylation of 9, preparation of (4S,6S)- and (4R,6S)-6-(tert-butyldimethylsilyl)oxy-4-hydroxy-6-phenyl-1-hexene (8) and (8′)

Acknowledgements

J. Nat. Prod.

J. Nat. Prod.

Planta Med.

Biol. Pharm. Bull.

Phytochemistry

Phytochemistry

Chem. Pharm. Bull.

Planta Med.

Angew. Chem., Int. Ed.

Curr. Top. Med. Chem.

Org. Prep. Proced. Int.

J. Nat. Prod.

J. Nat. Prod.

J. Nat. Prod.

Bioorg. Med. Chem.

Oncol. Res.

Bioorg. Med. Chem.

Arch. Pharm. Res.

J. Pharmacol. Exp. Ther.

Biol. Pharm. Bull.

Chem. Pharm. Bull.