Expeditious Synthesis of Gem-Difluorinated Methylene(Bisphosphonate) Analogues of P1, P2-Pyrophosphates Diesters

S5.3 Oligosaccharide synthesis II
Location (hall): 
Start/end time: 
Tuesday, July 2, 2019 - 15:25 to 15:30

Vladimir Borodkin1, Daan van Aalten1

1University Of Dundee, Dundee, United Kingdom

P1, P2-pyrophosphate diester structural motif is embedded into the molecules of several classes of biologically important natural compounds such as nucleotide diphosphate sugars (NDPS), sugar diphospholipids, nicotinamide (NAD)/ flavin (FAD) dinucleotides, co-enzyme A, and ADP-ribose derivatives. Moreover, pyrophosphorylation has been recently recognised as a posttranslational modification of proteins on its own, whereas inositol pyrophosphates are on the list of major players in the inositol signalling pathways.

Chemical and enzymatic frailty of the pyrophosphate bond provides an impetus for design and synthesis of stable non-hydrolysable analogues of natural pyrophosphates that are highly sought after as molecular probes to assist in depth elucidation of the relevant enzymatic activities and as novel molecular scaffolds for the next generations of potent and selective inhibitors. Preparation of methylene(bisphosphonate) (meBP) analogues of nucleoside (poly)phosphates sporting the methylene bond either in α,β- (P1-pyrophosphate monoesters) or in γ,β-position is well documented [1]. Introduction of electron withdrawing substituents and particularly fluorine in the methylene linker of meBP’s furnishes bioisosteric pyrophosphate analogues (F/FF-meBP) closely resembling the natural pyrophosphate in terms of acidity as well as both of bond angles and lengths, and critically improves biological relevance of the pyrophosphate mimics [2]. Only handful of examples of synthesis of meBP/ FF-meBP analogues of P1, P2‐ pyrophosphate diesters have appeared in the literature over three recent decades [3].

Here we will report initial findings towards development of a generic synthetic strategy aiming preparation of FF-meBP analogues of natural P1, P2-pyrophosphate diesters. Starting from inexpensive starting materials a novel synthetic approach to the targeted compounds was developed making use of pseudo orthogonally protected mixed symmetric FF-meBP tetraesters to achieve crucial stepwise selective functionalization of the opposite termini of the bridging bisphosphonate bond. Notably, both esterification reactions were efficiently performed using standard Mitsunobu conditions. Ensuing global deprotection furnished representatives of novel non-hydrolysable analogues of some natural pyrophosphates in fair yields.

  1. V. D. Romanenko, V. P. Kukhar.Phosphonate analogues of nucleoside polyphosphates. Arkivoc. 2018:1-49.
  2. (a) G. M. Blackburn. Phosphonates as Analogs of Biological Phosphates. Chem Ind-London. 1981(5):134-138; (b) C. E. Mckenna, P. D. Shen. Fluorination of Methanediphosphonate Esters by Perchloryl Fluoride - Synthesis of Fluoromethanediphosphonic Acid and Difluoromethanediphosphonic Acid. J Org Chem. 1981;46(22):4573-4576.
  3. (a) M. M. Vaghefi, R. J. Bernacki, W. J. Hennen, R. K. Robins. Synthesis of Certain Nucleoside Methylenediphosphonate Sugars as Potential Inhibitors of Glycosyltransferases. J Med Chem. 1987;30(8):1391-1399; (b) K. W. Pankiewicz, K. Lesiak, K. A. Watanabe. Efficient synthesis of methylenebis(phosphonate) analogues of P-1,P-2-disubstituted pyrophosphates of biological interest. A novel plausible mechanism. Journal of the American Chemical Society. 1997;119(16):3691-3695; (c) H. Ikeda, E. Abushanab, V. E. Marquez. The assembly of beta-methylene-TAD, a metabolically stable analogue of the antitumor agent TAD, by the stepwise esterification of monodeprotected methylenebis(phosphonate) benzyl esters under Mitsunobu conditions. Bioorg Med Chem Lett. 1999;9(21):3069-3074; (d) V. S. Borodkin, M. A. J. Ferguson, A. V. Nikolaev. Synthesis of potential bisubstrate inhibitors of Leishmania elongating alpha-D-mannosyl phosphate transferase. Tetrahedron Lett. 2004;45(4):857-862; (e) S. B. Engelsma, N. J. Meeuwenoord, H. S. Overkleeft, G. A. van der Marel, D. V. Filippov. Combined Phosphoramidite-Phosphodiester Reagents for the Synthesis of Methylene Bisphosphonates. Angew Chem Int Edit. 2017;56(11):2955-2959.