Send Orders for Reprints to reprints@benthamscience.net Mini-Reviews in Organic Chemistry, 2014, 11, 000-000 1 1570-193X/14 $58.00+.00 © 2014 Bentham Science Publishers Cyclobutyl- and Cyclobutenylphosphonates: Synthesis, Transformations and Biological Activities Abed Al Aziz Al Quntar 1,3 *, Morris Srebnik 3 , Alexander O. Terent'ev 2 and Valery M. Dembitsky 2,3 1 Department of Material Engineering, Faculty of Engineering, Al Quds University, Jerusalem 2002, Palestine; 2 N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect 47, Moscow, 119991, Russia; 3 Institute for Drug Research, Hebrew University, Jerusalem 91120, Israel Abstract: The synthesis, chemical properties, transformations, and biological activities of mono- and multi- substituted cyclobutyl- and cyclobutenylphosphonates were broadly discussed in this article review. The synthesis of four-membered ring phosphonates was based either on phosphorylation of already constructed cyclobutyl moiety or on inter- and in- tramolecular cyclizations of phosphorus containing compounds. Also, emphasis was illustrated on the recent development in this field. Keywords: Four membered ring, cyclobutanes, cyclobutenes, phosphonates, phosphorylation, phosphonates biological activities. 1. INTRODUCTION Various phosphonate derivatives were found to be pharmacologically active in many fields [1-13]. For instance, they have been widely used in different bone diseases [14- 18], many others shown anticancer [9, 19-22], antiviral [7, 9, 23-25], and antibacterial [26-28] activities. Various synthetic routes to different types of phosphonates with distinct potency and pharmacological activity have been described [1, 2, 8, 29-31]. The presence or introduction of a cyclobutyl group into chemical structures may increase their biological activity potential in which their ring strain increases their reactivity [32-35]. Cyclobutanes are frequently observed functional groups in natural products, in which they shown a wide spectrum of applications, such as agrochemicals and pharmaceuticals in their natural product structures [36-40]. In addition to their biological interests, cyclobutane derivatives play an important role in organic synthesis, both as synthetic targets for natural products synthesis, such as terpenes which contain a cyclobutane groups, and as synthetic intermediates. A variety of useful and special transformations of this strained four-membered ring is very well documented [41-45]. This is the first review devoted to describe the synthesis, transformations, biological activity and future prospects of cyclobutylphosphonates. 2. CYCLOBUTYL- AND CYCLOBUTENYLPHOS- PHONATES 2.1. Synthesis via Arbusov Reactions Arbusov reaction is one of the most utilized methods for the phosphorylation of organic compounds. Accordingly, it has been widely used to prepare cyclobutyl- and cyclobu *Address correspondence to this author at the Department of Material Engineering, Faculty of Engineering, Al Quds University, Jerusalem 2002, Palestine and Institute for Drug Research, Hebrew University, Jerusalem 91120, Israel; Tel: ???????????; Fax: ??????????; E-mail: abedalaziz@eng.alquds.edu tenylphosphonates. For example, the structure and reactivity of multi-halogenated cyclobutenes with trialkyl phosphite [(RO) 3 P] were reported [46]. The stable phosphoranes intermediates of the Arbuzov reaction were detected in which upon a controlled decomposition of these inter- mediates multi fluorinated cyclobutenes substituted with bisphosphonic acid methyl and ethyl esters (1 and 2) respectively were formed (Scheme 1). Cl Cl F F F F P P F F F F O O P(OMe) 3 + 1 R = Me, 70% 2 R = Et, 30% ! OR RO OR RO Scheme 1. Synthesis of fluorinated cyclobutenyphosphonates 1 and 2. In a separate study, the radiation-induced addition reaction of dialkyl phosphites with multi-fluoro substituted cyclobutenes, such as perfluoro- (3a), 1,2-dichlorotetrafluoro- (3b), 1-chloro-2,3,3,4,4-pentafluoro- (3c), 1,3,3,4,4-penta- fluoro- (3d) and 1-chloro-3,3,4,4-tetra- (3e) fluorocyclobu- tenes was successfully carried out to produce the corre- sponding fluorinated cyclobutenylphosphonates adducts. Addition of two equiv. of dialkyphosphite to perfluoro- cyclobutene gave mixtures of dialkyl 2,3,3,4,4-pentafluoro- 1-cyclobutenylphosphonate and alkoxy-3,3,4,4-tetrafluoro-1- cyclobutenylphosphonate 4 and 5 respectively. However, when the addition was carried out with 1,2-dichloro- tetrafluorocyclobutene only traces of 1-chloro-2,3,3,4,4- pentafluoro-cyclobutenyl-phosphonate 6 were obtained, apparently due to steric interactions between the attacking phosphonyl radical and carbon attached to the chlorine atoms of the double bond. On the other hand, when 2,3,3,4,4- pentafluorocyclobutene 3e or 2-chloro-tetra-fluorocyclobu-