Synthesis and characterisation of novel α-functionalised phosphoryl derivatives

Sanganee, Mahesh Jayantilal (2001) Synthesis and characterisation of novel α-functionalised phosphoryl derivatives. Doctoral thesis, University of North London.


This thesis focuses on the synthesis and study of α-aminoalkylphosphinic acids, α-aminoalkylphosphonic acids and macrocycles containing these sub-units.

There are two broad types of macrocyclic systems that are targeted:

(i) C-functionalised α-aminophosphonic acids; and
(ii) N-functionalised α-aminophosphonic acids.

A novel N-functionalised macrocycle ring that includes four pendant methylenephosphonates with embedded pyridine has been successfully prepared. The strategy employed involved the synthesis of the macrocycle prior to addition of the pendant arms. However, the synthesis of analogous systems containing thiophene failed principally due to the very poor solubility of the intermediate Schiff base.

The N-functionalised macrocycle with embedded pyridine was synthesised via the Mannich reaction. The protonation behaviour of this macrocycle has been followed by P and H NMR spectroscopy. The initial protonation pattern of the N-functionalised macrocycle is rather like its corresponding macrocyclic amine. The proton NMR spectrum of its lanthanum (III) complex in aqueous solution indicates that the complex adopts only one of the five possible configurations, SSSS/RRRR. The crystal structure of the novel N-functionalised macrocycle shows an extended hydrogen-bonded structure in the solid state. The macrocycle has an unusual conformation with the pendant arms alternating ‘up’ and ‘down’ around the ring. The La3+ complex has a unique ten-co ordinate geometry with all pendant arms co-ordinated to the La3+ ion, which is in the plane of the six-macrocyclic nitrogen donors.

The synthesis of C-functionalised macrocycles with embedded pyridine or thiophene involved a strategy in which the macrocyclisation occurred after the phosphonic acid groups were introduced. The synthesis proved to be problematic in both the thiophene and pyridine systems. In the case of the pyridine system the synthetic route was achieved to the penultimate step at which point the key macrocyclisation step failed to occur. In the case of the thiophene systems problems arose during the deprotection step, which prevented progress with this synthetic route.

Another aspect of this thesis was to investigate synthetic procedures aimed at thiophene bis [α-aminoalkylphosphinic] acids. During this work a reaction of 2,5- thiophenedialdehyde with PI12CHNH2 and hypophosphorous acid yields novel α-hydroxy- or α-amino-methylphosphinic derivatives depending on reaction conditions: the X-ray structure analysis of diphenylmethylammonium 5-formyl-2-thienyl (hydroxy) methylphosphinate provides the first direct structural information on the a- hydroxyalkylphosphinate class of compounds. Key compounds prepared in the course of this work were submitted for screening in anti-cancer programmes and in no case was significant anti-cancer activity observed.

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