Efficient Synthesis of Glycoporphyrins by Microwave‐Mediated “Click” Reactions

Abstract

IntroductionGlycoporphyrins offer fascinating prospects for medicinal chemistry and glycobiology. [1a-1d] Carbohydrates not only improve the solubility of porphyrins in an aqueous environment but also offer improved targeting of porphyrin therapeutics.[2] For photodynamic therapy (PDT), [3] carbohydrates can bind to tumour associated lectins displayed on the surface of cancer cells therefore offering the potential for enhanced efficiency and improved selectivity in cancer treatment. Since lectin-carbohydrate interactions are relatively weak it would be advantageous to have access to a PDT photosensitiser with a defined cluster displaying more than one carbohydrate unit. Even more advantageous would be a defined system that displays more than one 'type' of carbohydrate. The synthesis of selectively modified, heterogeneous glycoporphyrins has not previously been reported. To date, the synthesis of glycoporphyrins has relied predominantly on the condensation reaction between a glycosylated aldehyde and a glycosylated aldehyde and a pyrrole.[4] This reaction is often low yielding and is unsuitable for systems where small quantities of a carbohydrate are available. A more general strategy involves the introduction of carbohydrates at specific sites predefined by a regioselective chemical modification. [5] A number of methodologies for the functionalisation of porphyrins with carbohydrates have been investigated including the use of Sonogashira [6] and olefin metathesis [7] cross coupling. Results and DiscussionFor this study we chose to investigate if the Cu(I)-catalysed 1,3-dipolar 'click' reaction [8] could be employed as a robust methodology to access a highly defined, multifunctionalised glycoporphyrin system. Click chemistry has previously been applied to the functionalisation of porphyrins, [9] but to date there is only one literature example describing a click reaction involving a monocarbohydrate modification of a chlorin [10] . 5,10,15,20-Tetraphenylporphyrin was chosen as a common starting material for all modifications. This symmetrical porphyrin can be readily accessed in good yield via a condensation reaction of benzaldehyde and pyrrole. Porphyrin (1), displaying a single azide was prepared according to the literature procedure.[11] The coupling reaction with commercially available β-propargyl glucose (2) (Scheme 1) was investigated under both conventional and microwave mediated heating. The use of MW heating conditions reduced the reaction time from 3 days to 20 mins. A range of reaction conditions were screened. The results of this initial study are outlined in Table 1. Scheme 1. Synthesis of mono-glycoporphyrin by microwave mediated 'click' reaction.It was found that copper chloride in toluene/water (4:1) at 120 o C for 20 mins furnished the desired mono-glycoporphyrin (5) in excellent yield (93%). THF/water (4:1) also gave a very good yield of 81% at a lower temperature but longer times (40 mins) were required for complete consumption of the starting material. It was found that zinc porphyrin was re...

Chemical Synthesis and Medicinal Applications of Glycoporphyrins

“…Various methods of linking carbohydrates to porphyrin scaffolds, for example by direct glycosylation to the porphyrin [30] , amide [31] , or triazole linkages [32] are available. The number and regiochemical arrangement of the sugar units gives scope for fine-tuning the hydrophobicity and hydrophilicity.…”

“…When introducing more expensive and synthetically relevant carbohydrates, it is preferably done in the later steps ensuring stability of the glycosidic linkage on large oligosaccharides. For example, our groups have published work using the CuAAC reaction under microwave and significantly less harsh conditions which are high yielding for the synthesis of homo-and heteroatom substituted tetraphenylporphyrins [32] . This allowed the synthesis of an extensive glycoporphyrin library which has been biologically evaluated and used to identify the intracellular localization of glycoporphyrins depending on the carbohydrate unit present [33] .…”

“…The substitution of the glycosyl group on the ortho position of the meso phenyl caused steric hindrance to metallation by zinc [160] . In extension of this work Maillard et al synthesized a range of tetraglycosylated TPP's containing glucopyranosyl, galactopyranosyl, maltosyl, and glucosaminosyl residues Olinked at the para position under Lindsey condensation conditions (29)(30)(31)(32)(33)(34)(35)(36) [162] . Similar compounds were prepared to determine the effect the glycosyl unit had on the singlet oxygen production for possible application in asymmetric photooxygenation.…”

“…Note, the click reaction can also be used to prepare suitable aldehydes for condensation reactions as exemplified in the synthesis of 472 (Scheme 20) [203] . A collaboration between our groups focused on the development of robust methodology for the synthesis of mono-, di-, tri-and tetra-modified glycoporphyrins (259-268) [32] . TPP was functionalized with an azido moiety and subsequently reacted with commercially available β-propargyl glucose and α-propargyl mannose either with acetylated or free hydroxyl groups under conventional and microwave-mediated heating conditions.…”

Ultrasound-assisted synthesis of glycoporphyrin conjugates bearing carbamate and thiocarbamate linkers.

“…In this field some molecules have already been elaborated through convergent synthesis strategies, specially bearing ether 1 , ester 2 and triazole 3,4 linkers. Nevertheless this type of linkage could not be considered ideal for the synthesis of glycoporphyrins since deglycosylation process and decreasing of biological activity 5 have already been associated with the nature of these linkers.…”