Synthesis of diastereomeric 3-hydroxy-4-pyrrolidinyl derivatives of nucleobases
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
References and notes (36)
- et al.
Bioorg. Med. Chem. Lett.
(2004) - et al.
Tetrahedron Lett.
(1988) - et al.
Tetrahedron Lett.
(1988) - et al.
Tetrahedron
(1998) - et al.
Tetrahedron Lett.
(1991) - et al.
Tetrahedron
(1998) - et al.
Tetrahedron
(1998) - et al.
Tetrahedron
(2006) - et al.
Tetrahedron Lett.
(1990) - et al.
Tetrahedron: Asymmetry
(1997)
Tetrahedron
Curr. Med. Chem.
J. Med. Chem.
J. Med. Chem.
J. Med. Chem.
Nucleosides Nucleotides
J. Med. Chem.
Can. J. Chem.
Cited by (46)
Recent advances in the synthesis of 4′-truncated nucleoside phosphonic acid analogues
2022, Carbohydrate ResearchCitation Excerpt :Removal of diisopropyl ester groups with TMSBr produced the target 4′-truncated N-phosphonocarbonyl-pyrrolidine-based guanine nucleoside phosphonic acid analogues 306a and 306b (Scheme 46). The synthesis of diastereomeric hydroxypyrrolidine derivatives of guanine 309a-d started from fully protected 3,4-dihydroxypyrrolidines 307a-d [118]. The mesyl group of these compounds was converted into an azido group by NaN3 in DMF.
Synthesis and α-glucosidase inhibition activity of dihydroxy pyrrolidines
2017, Bioorganic and Medicinal Chemistry Letters1-((3S,4S)-4-Amino-1-(4-substituted-1,3,5-triazin-2-yl) pyrrolidin-3-yl)-5,5-difluoropiperidin-2-one inhibitors of DPP-4 for the treatment of type 2 diabetes
2011, Bioorganic and Medicinal Chemistry LettersA study on the racemization step in the synthesis of pyrrolidinols via cyclic α-hydroxyimides
2011, Tetrahedron Asymmetry