Pergamon Tetrahedron Letters 39 (1998) 8031-8034 TETRAHEDRON LETTERS A Facile and Convenient Solid-Phase Procedure for Synthesizing Nucleoside Hydroxamic Acids Shoeb I. Khan and Mark W. Grinstaff* Departmentof Chemistry,P.M. GrossChemicalLaboratory,Duke University, Durham, NC 27708 USA. http://www.chem.duke.edu/~mwg Received 19 June 1998; revised 5 August 1998; accepted 19 August 1998 Abstract: The solid-phasesynthesisof a nucleoside hydroxamicacid is accomplishedby the Pd(0) cross-coupling of 5-iodouridine and an O-linked hydroxylamine alkyne bound to 2- chlorotritylchloridepolystyrene resin. © 1998ElsevierScienceLtd. All rights reserved. Hydroxamates are know to possess a wide spectrum of biological activities including antibacterial, anticancer, and antifungal,t-3 The hydroxamic acid functionality is an effective metal ion (e.g., zinc) chelator. 4,5 Consequently, compounds containing this functionality can be potent inhibitors of metalloenzymes such as thermolysin, 6'7 angiotensin-converting enzyme (ACE), 8 and matrix metalloproteases (MMPs) 9-11. Hydroxamic acids are also observed to inhibit ribonucleoside diphosphate reductase (RDPR), 1215 a key enzyme involved in the rate-determining step of DNA biosynthesis. For example, hydroxyurea is clinically used and believed to be efficacious by trapping the free tyrosyl radical present in the RDPR active site. 16,17 However, the weak in vivo effectiveness of hydroxyurea has prompted additional synthetic studies towards other RDPR hydroxamic acid inhibitors. Specifically, the hydroxamic acid nucleosides and analogues are of interest for RDPR inhibition, yet the current synthetic procedures to these derivatives are limited. 18,19 Herein, we report a facile strategy for the preparation of a nucleoside hydroxamic acid on solid-support. A number of requirements must be met to successfully synthesize nucleoside hydroxamic acid derivatives on solid support and demonstrate the utility of this synthetic method. The goals in this initial study are to: 1) identify a suitable linker and reaction conditions for optimal nucleoside modification, 2) capitalize on the obvious advantages of solid-phase synthesis,2° and 3) design a strategy amenable to combinatorial library synthesis. Presently, nucleoside hydroxamic acids are synthesized by a solution phase method via acylation of hydroxylamine with activated carboxylic acid derivatives, and reports of a solid-phase procedure are not known. 18A9 Solid-phase procedures for synthesizing peptide and peptidomimetic hydroxamic acids using either resin bound N -21 or O-linked hydroxylamines are described in the literature. 2227 The O-linked hydroxylamine can be used if subsequent solid-phase reactions do not alter the unprotected amine (pKa --10). With these issues in mind, we decided to use the 2-chlorotrityl chloride polystyrene resin as solid support, an O-linked 0040-4039/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved. PII: S0040-4039(98)01794-8