Elsevier

Tetrahedron: Asymmetry

Volume 19, Issue 24, 12 December 2008, Pages 2789-2795
Tetrahedron: Asymmetry

Efficient asymmetric synthesis of the functionalized pyroglutamate core unit common to oxazolomycin and neooxazolomycin using Michael reaction of nucleophilic glycine Schiff base with α,β-disubstituted acrylate

https://doi.org/10.1016/j.tetasy.2008.11.036Get rights and content

Abstract

The functionalized pyroglutamate core unit, (2R,4R)-3, which could be converted into the β-lactone/pyrrolidine or γ-lactone/pyrrolidine ring system of oxazolomycin A 1 and neooxazolomycin 2, and which possesses an exomethylene group at C3 as a scaffold for the construction of their C3 polyene segment, was synthesized by the Michael reaction of a glycine Schiff base 4 with the α,β-disubstituted acrylate 8 as the key step.

Introduction

Oxazolomycin A 1, isolated in 1985 by Uemura et al.,1 from the fermentation broth of Streptomyces sp., exhibits potent antibiotic properties against various gram positive bacteria and Agrobacterium tumefaciens,2 strong anticancer activity,1, 3 and various antiviral activities.4 In addition, oxazolomycin A inhibits crown gall formation in plants.5 Due to its broad biological activity profile,1, 3 oxazolomycin A has received much attention as a candidate for antibiotic and anticancer drugs. Neooxazolomycin 2, structurally related to 1, has also been isolated from the same fermentation broth.6 The structural features common to both 1 and 2 are characterized by the highly functionalized 2,3,3,4-tetrasubstituted pyroglutamate core unit and the conjugate diene and triene segment attached to C3. Their novel structures as well as their important biological activity profiles have attracted significant attention as important synthetic target molecules. Although a number of research groups have developed and studied the polyene segment7 and the β-lactone/pyrrolidine or γ-lactone/pyrrolidine ring system8 in 1 and 2, an efficient construction of the functionalized pyroglutamate core unit remains a challenging target. Recently, Kende et al.9 and Hatakeyama et al.10 reported the total synthesis of neooxazolomycin 2, although a total synthesis of oxazolomycin 1 has not yet been achieved. We considered that the pyroglutamate core unit, such as 3, which possesses appropriate functional groups at C2 and C3, that is, the C2 hydroxymethyl substituent could readily cyclize to the β- or γ-lactone/pyrrolidine and the C3 exomethylene group would play a key role in assembling the polyene segment, can be viewed as a key synthetic intermediate of the total synthesis of these natural products. In this paper, we describe the synthesis of (2R,4R)-tert-butyl 2-(hydroxymethyl)-1,4-dimethyl-3-methylene-5-oxopyrrolidine-2-carboxylate 3 (Fig. 1).

Section snippets

Results and discussion

Recently, we have developed an operationally convenient methodology for the generalized asymmetric synthesis of various types of β-substituted pyroglutamates 7a (Scheme 1).11, 12 One of the methods involves the highly diastereoselective organic base-catalyzed Michael addition of the achiral glycine Schiff base derivative 4 with the chiral (R)- or (S)-N-(E-enoyl)-4-phenyl-1,3-oxazolidine-2-one 5a to give the addition product 6a as individual diastereoisomers in nearly quantitative yields in

Conclusion

In conclusion, we have developed a simple and diastereoselective access to the 3,4-disubstituted pyroglutamic acid 10a using the Michael addition of the achiral glycine Schiff base 4 with the chiral α,β-disubstituted acrylate derivative 8. The quarternalization of C2 followed by introduction of the exomethylene group at C3 was carried out by the internal nucleophilic trap of the carbonate 14 and lactone opening with the phenylselenide anion. The total number of processes included was 12 steps,

General remarks

All reagents and solvents were purchased from either Aldrich Chemical Company, Inc., Merck & Co., Inc., Nacalai Tesque Co., Ltd, Tokyo Kasei Kogyo Co., Ltd, or Wako Pure Chemical Industries, Ltd., Kanto Chemical Co., Ltd, and used without further purification unless otherwise indicated. Tetrahydrofuran and ethyl alcohol (EtOH) of anhydrous grade were used. Optical rotations were taken on a JASCO P-1030 polarimeter with a sodium lamp (D line). FT-IR spectra were measured on a JASCO FT/IR-420

Acknowledgments

This study was supported by Grants-in-Aid (16201045 and 19201045) for Scientific Research from the Japan Society for the Promotion of Science (JSPS).

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