Microwave-Assisted Synthesis of α-Amino Phosphonates Derived from Formylporphyrins of Natural Origin

Abstract

S y n t h e s i s o f a -A m i n o P h o s p h o n a t e s D e r i v e d f r o m F o r m y l p o r p h y r i n sAbstract: The first synthesis of a-amino phosphonates comprising porphyrin core was accomplished. Three methods of obtaining aamino phosphonates 5-8 were compared. Conventional heating of formylporphyrins 1-4 with t-BuNH 2 and (EtO) 2 P(O)H in various solvents was ultimately unsuccessful for preparing 5-8 whereas the use of microwave irradiation made it possible to obtain 5-8 in good yields. Regioselective preparation of 5-8 in excellent yields was achieved by combining microwave-assisting conditions and catalysis with CdI 2 . Efficient synthetic procedures of obtaining formylporphyrins 3,4 in large scale were also proposed.Extensive substituent manipulations on porphyrins derived from naturally occurring tetrapyrroles (e.g. heme and chlorocruoroheme) produce a number of phototherapeutic agents efficiently utilized in diverse medical fields including ophthalmology, oncology, gynecology, dermatology, urology, cardiology and immunology. 1-4 The method allowing tetrapyrroles to be used as photosensitizers (PSs) is called photodynamic therapy (PDT). Due to the basic concept of PDT, the combination of two therapeutic agents, a PS and light, which have low toxicity by themselves and being combined in the presence of oxygen lead to ultimate tissue destruction. [1][2][3][4] In order to construct porphyrin-based PSs capable of accumulating selectively in neoplastic (e.g. tumor) tissues a variety of synthetic approaches were elaborated. 1,2 Promising results were achieved by introducing pharmacophor units (e.g. alkoxy-, amino-, a-amino acid residues) into the side-chain positions of porphyrins. 1,2,5 An intriguing class of biologically active compounds are a-amino phosphonates. Due to their structural analogy with a-amino acids and transition state mimicking of peptides, a-amino phosphonates act as potent antibiotics, 6 peptide mimics, 6,7 enzyme inhibitors 6,8 and pharmacological agents. 9With the aim of combining in one molecule phototherapeutic potential of porphyrins and unique biological activity of a-amino phosphonates, we report the first synthesis of a-amino phosphonates comprising porphyrin moiety. It is well documented 10-14 that heterocyclic a-amino phosphonates could be efficiently prepared by the addition of phosphites to aldimine, generated from the corresponding amines and heterocyclic aldehydes. Although there is a broad variety of formylporphyrins derived from natural tetrapyrrols, 2,15 we chose to utilize namely 1-4 15,16 as aldehyde components since formyl group of 1-4 was reported to be an optimum site for designing potent pharmacological agents. 1,2,17-20 (EtO) 2 P(O)H and t-BuNH 2 were employed because they have been successfully used in obtaining various a-amino phosphonates and their motif could be easily detected by NMR. 21-23 Thus, this paper describes the synthesis of a-amino phosphonates 5-8 and synthetic approach to them is shortly depicted in Scheme 1.Our synthesis began from protopo...

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