Synthesis of diastereomeric 3-hydroxy-4-pyrrolidinyl derivatives of nucleobases

doi:10.1016/j.tet.2006.11.047

Tetrahedron

Volume 63, Issue 5, 29 January 2007, Pages 1243-1253

https://doi.org/10.1016/j.tet.2006.11.047 Get rights and content

Abstract

The work deals with the synthesis of hydroxypyrrolidine analogs of nucleosides. Starting from the optically pure l- or d-tartaric acid, we improved the synthesis of enantiomeric trans-3,4-dihydroxypyrrolidines and elaborated a procedure for the synthesis of all possible diastereoisomers of 3-hydroxy-4-pyrrolidinyl derivatives of both purine and pyrimidine nucleobases. The prepared compounds were tested for cytostatic and antiviral properties but no significant activity was found.

Graphical abstract

Introduction

Sugar-modified nucleoside analogs form a large group of potential antimetabolites.¹ Thus, 1,3-oxothiolane,² 1,3-dioxolane,3, 4, 5, 6 and cyclobutane⁷ and cyclopentane8, 9, 10, 11, 12 ring-containing d- and l-nucleoside analogs have been synthesized and biologically evaluated. Among these analogs, potent compounds exhibiting remarkable antiviral and anticancer properties have been found.¹³

Replacement of the sugar moiety in nucleosides by a pyrrolidine ring seems to be one of the promising modifications, which could provide compounds possessing both diverse biological activities and the possibility of further derivatization, e.g., on the nitrogen atom of the pyrrolidine ring (Fig. 1).

The pyrrolidine nucleosides have attracted the attention of several laboratories.14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 Thus, Miyabe et al.²³ reported the total synthesis of 3-hydroxy-4-pyrrolidinyl derivatives of uracil, thymine, and adenine 1 via construction of both the pyrrolidine ring and the nucleobase moiety; in this case racemic mixtures were prepared. Richichi et al.²⁴ described the preparation of protected 3-hydroxypyrrolidinyl derivatives of uracil 2c and thymine 2d by Mitsunobu reaction of unprotected pyrimidine bases with appropriate N-benzylpyrrolidin-3,4-diols. Recently, we published the synthesis of 3-pyrrolidinyl derivatives of all four nucleobases mimicking 2′,3′-dideoxynucleosides, by nucleophilic displacement of the mesyloxy group for individual nucleobases under various conditions.25, 26

In this paper, we describe the synthesis of diastereomeric 3-hydroxy-4-pyrrolidinyl derivatives of thymine and adenine by nucleophilic displacement of mesyloxy group for nucleobase.

Section snippets

Results and discussion

The enantiomeric trans-3,4-dihydroxypyrrolidines 8a and 8b are known compounds and their synthesis starting from l- and d-tartaric acids (5a and 5b, respectively) was described in the literature many times.27, 28, 29, 30, 31, 32, 33, 34, 35 We prepared 8a and 8b from the appropriate tartaric acids via corresponding 2,5-diones 6a and 6b, the preparation of which was recently improved.²⁶ In short, the monobenzylammonium salt of tartaric acid prepared in aqueous methanol was refluxed, after

Conclusions

We reported the synthesis of novel nucleoside mimics, eight diastereoisomeric 3-hydroxy-4-pyrrolidinyl derivatives of adenine and thymine 1a,b, 2a,b, 3a,b, and 4a,b by a direct nucleophilic displacement of mesyloxy group in 16a,b and 19a,b for nucleobases. We improved the synthesis of key enantiomeric trans-1-N-benzyl-3,4-dihydroxypyrrolidines 8a and 8b to obtain reproducibly high yields of these compounds. We found that the N-benzyl protecting group in mesyloxy derivative 10 participated in

General

Unless stated otherwise, all used solvents were anhydrous. Final products were lyophilized from water, and dried over phosphorus pentoxide at 50–70 °C and 13 Pa. TLC was performed on silica gel pre-coated aluminum plates Silica gel/TLC-cards, UV 254 (Fluka), and the compounds were detected by UV light (254 nm), by heating (detection of dimethoxytrityl group; orange color), by spraying with 1% solution of ninhydrin to visualize amines, and by spraying with 1% solution of 4-(4-nitrobenzyl)pyridine

Acknowledgements

Support by grants # 203/02/D150 and 203/05/0827 (Czech Science Foundation), and Centre for Biomolecules and Complex Molecular Systems (LC512) under research project Z40550506 is gratefully acknowledged. Authors are indebted to the staff of the Department of Organic Analysis, Dr. Kvetoslava Kertisova, Dr. Blanka Kralova and Dr. Karel Ubik, for measurements of HRMS. Excellent technical assistance of Dr. Petr Simek and Mr. Jiri Strnad, both of Service laboratories of this Institute is also

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Synthesis of diastereomeric 3-hydroxy-4-pyrrolidinyl derivatives of nucleobases

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

Conclusions

General

Acknowledgements

Bioorg. Med. Chem. Lett.

Tetrahedron Lett.

Tetrahedron Lett.

Tetrahedron

Tetrahedron Lett.

Tetrahedron

Tetrahedron

Tetrahedron

Tetrahedron Lett.

Tetrahedron: Asymmetry

Tetrahedron

Curr. Med. Chem.

J. Med. Chem.

J. Med. Chem.

J. Med. Chem.

Nucleosides Nucleotides

J. Med. Chem.

Can. J. Chem.