6-Membered P-Heterocycles: Ring-Condensed 1,3,2-Diheterophosphorinane 2-Chalcogenides

Abstract

Literature publications (up to the end of 2006) relating to the synthesis, biological significance and conformational behaviour of carbocycle-and heterocycle-condensed six-membered tetracoordinate P(V) 1,3,2-diheterophosphorinanes are reviewed. The replacement of carbon atoms of cyclohexane by P and O and/or N to form 1,3,2-dioxa-, 1,3,2-oxaza-or 1,3,2-diazaphosphorinanes introduces lone pair electrons instead of hydrogens and changes the bond angles and bond lengths, and can thereby lead to significantly different stereostructural preferences of the hetero ring as compared with those of cyclohexane. Although monocyclic 1,3,2-diheterophosphorinanes often exist in a chair conformation in both the solid and solution states, the existence of conformations other than a chair can predominate in some cases for steric and stereoelectronic reasons associated with the presence of bulky groups on the P-containing ring or in polycyclic rigid systems.After a brief account on the most important pharmacological and stereochemical features, involving the configuration assignment and conformation determination of P-diheterophosphorinanes, the present review mainly focuses on the synthesis and stereostructural studies of carbo-and heterocycle-condensed derivatives, where the fused ring may exert considerable effects on the conformational behaviour of the P-hetero ring.

Six-Membered Ring Phosphates and Phosphonates As Model Compounds for Cyclic Phosphate Prodrugs: Is the Anomeric Effect Involved in the Selective and Spontaneous Cleavage of Cyclic Phosphate Prodrugs?

“…One of the topics in physical−organic chemistry is the conformational and configurational analysis of six-membered ring phosphates (2-oxo-1,3,2-dioxaphosphorinanes) and derivatives. − The information extracted from such studies stimulated the Bentrude group to postulate an ingenious model of interaction between the active site of the enzyme and the dioxaphosphorinane ring of cyclic adenosine monophosphate (cAMP), also known as the second messenger for the cellular processes. On the basis of the empirical estimation of the Δ G ° for the chair ⇌ twist equilibrium of neutral model phosphates, they proposed that cAMP in a twisted conformation could be appropriate for such enzyme−cAMP interactions (Figure ) …”

Structure of Cyclic Nucleoside Phosphonate Ester Prodrugs: An Inquiry

“…Six-membered phosphonate rings constitute an essential structural feature of cyclic prodrug diesters derived from acyclic nucleoside phosphonates (ANPs), − which are dNMP analogues that are broadly active against DNA viruses and retroviruses. More generally, six-membered ring phosphates and related compounds have been a durable topic of interest in organic chemistry. − An example of a clinically important ANP is cidofovir ( 1 , ( S )-HPMPC, Vistide; Figure ), − which is used for the treatment of CMV retinitis in patients with AIDS . A well-known drawback of ANPs as antiviral drugs is their poor oral bioavailability, owing to the presence of a phosphonic acid group that ionizes at physiological pH.…”