首页   按字顺浏览 期刊浏览 卷期浏览 The Reaction of 2′-Deoxynucleosides withN-(2-Chloro-1,1,2-trifluoroethyl)diethyla...
The Reaction of 2′-Deoxynucleosides withN-(2-Chloro-1,1,2-trifluoroethyl)diethylamine: Mechanisms ofO2,3′-Anhydro-2′-deoxynucleoside and By-product Formation

 

作者: Raj K. Sehgal,  

 

期刊: Journal of Chemical Research, Synopses  (RSC Available online 1998)
卷期: Volume 0, issue 1  

页码: 24-25

 

ISSN:0308-2342

 

年代: 1998

 

DOI:10.1039/a705686i

 

出版商: RSC

 

数据来源: RSC

 

摘要:

N HN O O R O HO HO N F ClFCH Et Et + F – , DMF N HN O O R O O HO ClFCH N Et Et F – + 5 N HN O O R O O O ClFCH N Et Et N N O O R O HO 7 (60%) 6 (15–20%) Major path b 1 Minor path a a R = Me b R = H N N O O R O O O F N O Me Me 13 N N O O R O O O F Cl H N N O O R O O ClFCH N Et Et 12 8 F N N O O R O O ClFCH N Et Et OH 11 N N O O R O O ClFCH N Et Et + F – N N O O R O HO 7 a R = Me b R = H N N O O R O F 9 10 24 J. CHEM. RESEARCH (S), 1998 J. Chem. Research (S), 1998, 24–25 J. Chem. Research (M), 1998, 0301–0326 The Reaction of 2p-Deoxynucleosides with N-(2-Chloro- 1,1,2-trifluoroethyl)diethylamine: Mechanisms of O2,3p-Anhydro-2p-deoxynucleoside and By-product Formation Raj K.Sehgal* and Joseph G. Turcotte Department of Medicinal Chemistry, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881, USA Reaction mechanisms consistent with the formation of isopropylidene-like trans-furanose-3p,5p-[2-(R)(S)-aminochloro- fluoromethyl-1,3-dioxanyl]-2p-deoxynucleoside intermediates 6, O2,3p-anhydro-2p-deoxynucleosides 7 and other minor reaction products and the yield-limiting effect of 6 on the cyclization of 7 are proposed.In our ongoing efforts to develop anti-HIV liponucleotides with distinct biophysical properties, the synthesis of the immediate anhydro precursors (7a, 7b) of azidothymidine and azidodeoxyuridine via reaction of 2p-deoxynucleoside series of compounds with N-(2-chloro-1,1,2-trifluoroethyl)- diethylamine (CTFDA) was investigated in detail.5a,7,9 We herein report our preliminary findings on the reaction mechanism underlying the formation of O2,3p-anhydronucleosides and by-product analysis envisaged to optimize the reaction conditions for this intriguing transformation. The main features of the proposed mechanism as outlined in Schemes I and II are an equilibrium between the transfuranose intermediates 6 and 5, with the latter iminium species undergoing intramolecular cyclization to form anhydronucleosides 7.To rationalize the formation of the minor novel product *To receive any correspondence. †This is a Short Paper as defined in the Instructions for Authors, Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is therefore no corresponding material in J. Chem. Research (M). Scheme I Scheme IIN HN O O R O TsO N3 16 N HN O O R O HO N3 N HN O O R O N3 N3 15 14 N HN O R O HO N3 + O 7 N N O O R O O N N O O R O O ClFCH N Et Et 9 LiN3, DMF N N O O R O O ClFCH N Et Et OH LiN3, DMF O ClFCH N Et Et N N O O R O HO 11 6 a R = Me b R = H – N3 + 17 J.CHEM. RESEARCH (S), 1998 25 13a, analogous intermediates 8a, 9a and 12a are invoked. The extremely acidic hydrogen atom of the chlorofluoromethyl group of 12a is readily removed via base, with the resulting intermediate fluorocarbene inserting into the C·H bond of the solvent (DMF); elimination of hydrogen chloride to the enolate gives rise to the isolated ester 13a (preferred keto form).Azide displacements on the stable bicyclic intermediates 6 with lithium azide in DMF afforded the corresponding disubstituted derivatives 17 (Scheme III) via the likely intermediates 11 and 9. The stereochemical course of the resulting diazido nucleosides having the 3p-a-stereochemistry was ascertained and confirmed by an independent synthetic route. The products of reaction of 2p-deoxycytidine with CTFDA proved too unstable to isolate chromatographically (silica gel). Techniques used: 1H NMR, MS, IR References: 18 Schemes: 4 Received, 5th August 1997; Accepted, 30th September 1997 Paper E/7/05686I References cited in this synopsis 5 (a) R. P. Glinski, M. S. Khan and R. L. Kalamas, J. Org. Chem., 1973, 38, 4299. 7 G. Kowollik, K. Gaertner and P. Langen, Tetrahedron Lett., 1969, 3863. 9 R. L. Rideout, D. W. Barry, S. F. Lehrman, M. H. St. Clair, P. A. Furman, L. M. Beecham II, H. S. LeBlanc and G. A. Freeman, Eur. Pat. Appl., 86301896.6, 1986. Scheme III

 



返 回