Elsevier

Tetrahedron

Volume 67, Issue 48, 2 December 2011, Pages 9265-9272
Tetrahedron

A biomimetic synthesis of (−)-ascorbyl phloroglucinol and studies toward the construction of ascorbyl-modified catechin natural products and analogues

https://doi.org/10.1016/j.tet.2011.09.102Get rights and content

Abstract

A method for appending the ascorbyl moiety onto the framework of phenolic natural products has been developed. This reaction proceeds in two steps from l-ascorbic acid and employs acetic acid catalysis. Excellent stereoselectivity is observed during C–C bond formation between the phenolic compound and dehydroascorbic acid, and the process is also chemoselective for phenol derivatives bearing electron-donating substituents in each of the 1, 3, and 5 positions. Further, good regioselectivity was also observed when phenols lacking an axis of C2 symmetry were employed. This method has led to the synthesis of (−)-ascorbyl phloroglucinol as well as the tetracyclic core of ascorbyl-modified catechin natural products.

Introduction

Polyphenols produced by tea plants are well known to have a range of interesting and medicinally relevant bioactivities. Members of this class of molecules have been reported to be potent antiobesigens,1 antivirals,2 antioxidants,3, 4, 5 and anticarcinogens,6 and also display other desirable properties.6, 7, 8, 9 Many of these activities have been ascribed to catechin-derived molecules, and a series of ascorbyl-modified catechins have been reported. These natural products display a range of complexity from the simple ascorbylated phloroglucinol, (−)-ascorbyl phloroglucinol (1a), to more complex ascorbylated catechins (Fig. 1).10 While the full spectrum of biological activities displayed by molecules of this class have not been fully explored, 8-C-ascorbyl-(−)-epigallocatechin 2a has been shown to be effective in stopping the replication of HIV in vivo with an EC50 of 8.33 μM and for inhibiting pancreatic lipases in vitro with an IC50 of 0.646 μM.

(−)-Ascorbyl phloroglucinol 1a has previously only been isolated as the corresponding peracetate derivative 3. Prior work has also not been able to unambiguously assign the stereochemical configuration at the tertiary and hemiacetal carbons (C2′ and C3′) for any ascorbylated phenols, although modeling has suggested that the SSRS configuration for C2′–5′, respectively, is the most stable for 3.11 These intriguing biological data coupled with the interesting structures and open questions concerning the stability and stereochemistry of these molecules led us to pursue the development of a synthetic strategy to construct the tricyclic core of this set of related compounds.

Section snippets

Retrosynthetic analysis and design rationale

We reasoned that a late-stage introduction of the ascorbyl moiety onto the trioxyarene would be desirable for the construction of these natural products and analogous structures. After observing the structural similarity for the ascorbylated natural products, it became obvious that all of these compounds could be constructed by a similar route in which the C–C bond between the ascorbyl group and the arene were formed if a suitable electrophilic version of ascorbic acid was used (Scheme 1). The

Conclusion

A method utilizing readily available 4 for the biomimetic ascorbylation of phenolic natural products has been reported herein. This reaction was found to be stereo-, chemo-, and regioselective, and a synthesis of the natural product, (−)-ascorbyl phloroglucinol (1a), was accomplished. Data obtained from the crystal structure of 1b corroborate previous theoretical assignment of the configuration for the stereocenters at the ascorbyl–phenol junction in compounds of this type. Further, the

Materials and general methods

All reagents and solvents were purchased from Fisher Scientific and used without further purification unless noted. Silica gel (60 Å, 40–63 μm, 230×400 mesh) and polyester backed thin-layer chromatography (TLC) plates (Silica G w/UV, 200 μM) were purchased from Sorbent Technologies. All reactions were carried out under nitrogen unless otherwise stated. All 1D 1H and 13C spectra were recorded using a 300 MHz Varian Mercury or 500 MHz Varian INOVA spectrometer. Deuterated solvents used for NMR

Acknowledgements

The authors would like to acknowledge several colleagues from the University of Tennessee, Knoxville. We thank Drs. David C. Baker and Michael D. Best for helpful discussion, as well as Jessica R. Gooding and Amanda L. May (University of Tennessee, Knoxville) for assistance in preparing this manuscript. We are also grateful to Julia K.C. Abbott and Dr. Zheng Lu for assistance in obtaining crystallographic data. Support for this work was provided by start-up funds from the University of Tennessee

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