Efficient Synthesis of Diethyl, Dialkyl α-Hydroxy-propylenebisphosphonates and Related 5-Phosphonoyl-1,2-oxaphospholane 2-Oxides

Abstract

A series of new dialkyl α-diethylphosphonoylethyl-α-hydroxy-ethylphosphonates were prepared using the Pudovik reaction of the corresponding γ-oxophosphonate with dialkyl phosphites performed on the surface of Al₂O₃/KF. The adducts revealed unexpected reactivity in the attempted O-acylation reaction, and provided the corresponding 5-phosphonoyl-1,2-oxaphospholane 2-oxides. On treatment with Cs₂CO₃, instead of the expected rearrangement a cyclization reaction leading to the same ring products took place. Three of the phosphonoylethyl-α hydroxy-ethylphosphonates, along with two phosphonoylmethyl analogues revealed significant and selective anticancer effect on A431 cells, and occasionally, on PC-3 and MDA-MB 231 cells.

Key words

γ-oxophosphonate - Pudovik reaction - α-hydroxy-propylenebisphosphonate - cyclization - phosphonoyl-1,2-oxaphospholane 2-oxide - anticancer effect

Publication History

Received: 27 April 2023

Accepted after revision: 03 July 2023

Accepted Manuscript online:
04 July 2023

Article published online:
17 August 2023

• References

• 1 Kategaonkar AH, Pokalwar RU, Sonar SS, Gawali VU, Shingate BB, Shingare MS. Eur. J. Med. Chem. 2010; 45: 1128
• 2 Pokalwar RU, Hangarge RV, Maske PV, Shingare MS. ARKIVOC 2006; (xi): 196
• 3 Reddy GS, Sundar CS, Prasad SS, Dadapeer ED, Raju CN, Reddy CS. Pharma Chem. 2012; 4: 2208
• 4 Naidu KR. M, Kumar KS, Arulselvan P, Reddy CB, Lasekan O. Arch. Pharm. Chem. Life Sci. 2012; 345: 957
• 5 Kalla RM. N, Lee HR, Cao J, Yoo JW, Kim I. New J. Chem. 2015; 39: 3916
• 6 Rádai Z, Windt T, Nagy V, Füredi A, Kiss NZ, Randelovic I, Tóvári J, Keglevich G, Szakács G, Tóth S. New J. Chem. 2019; 43: 14028
• 7 Kafarski P, Lejczak B. J. Mol. Catal. B: Enzymol. 2004; 29: 99
• 8 Patel DV, Rielly-Gauvin K, Ryono DE, Free CA, Rogers WL, Smith SA, DeForrest JM, Oehl RS, Petrillo EW. Jr. J. Med. Chem. 1995; 38: 4557
• 9 Fields SC. Tetrahedron 1999; 55: 12237
• 10 Rádai Z, Keglevich G. Molecules 2018; 23: 1493
• 11 Kumar KS, Reddy CB, Reddy CR, Rani CS, Reddy MV. N. Org. Commun. 2012; 5: 50
• 12 Mahmood T, Samad K, Zahra T, Ahmadreza B. Chin. J. Chem. 2012; 30: 827
• 13 Nandre KP, Nandre JP, Patil VS, Bhosale SV. Chem. Biol. Interface 2012; 2: 314
• 14 Kong D.-L, Liu R.-D, Li G.-Z, Zhang P.-W, Wu M.-S. Asian J. Chem. 2014; 26: 1246
• 15 Kulkarni MA, Lad UP, Desai UV, Mitragotri SD. C. R. Chim. 2013; 16: 148
• 16 Ramananarivo HR, Solhy A, Sebti J, Smahi A, Zahouily M, Clark J, Sebti S. ACS Sustainable Chem. Eng. 2013; 403
• 17 Santhisudha S, Sreelakshmi P, Jayaprakash SH, Kumar BV, Reddy CS. Phosphorus, Sulfur Silicon Relat. Elem. 2015; 190: 1479
• 18 Keglevich G, Rádai Z, Kiss NZ. Green Proc. Synth. 2017; 6: 197
• 19 Rádai Z, Szeles P, Kiss NZ, Hegedűs L, Windt T, Nagy V, Keglevich G. Heteroat. Chem. 2018; 29: e21436
• 20 Keglevich G, Tóth VR, Drahos L. Heteroat. Chem. 2011; 22: 15
• 21 Texier-Boullet F, Foucaud A. Tetrahedron Lett. 1980; 21: 2161
• 22 Texier-Boullet F, Foucaud A. Synthesis 1982; 165
• 23 Texier-Boullet F, Foucaud A. Synthesis 1982; 916
• 24 Texier-Boullet F, Lequitte M. Tetrahedron Lett. 1986; 27: 3515
• 25 Smahi A, Solhy A, Tahir R, Sebti S, Mayoral JA, García JI, Fraile JM, Zahouily M. Catal. Commun. 2008; 9: 2503
• 26 Varga PR, Hägele G, Keglevich G. Tetrahedron Lett. 2021; 68: 152902
• 27 Keglevich G, Sipos M, Takács D, Greiner I. Heteroat. Chem. 2007; 18: 226
• 28 Varga PR, Belovics A, Bagi P, Tóth S, Szakács G, Bősze S, Szabó R, Drahos L, Keglevich G. Molecules 2022; 27: 2067
• 29 Öhler E, Zbiral E. Liebigs Ann. Chem. 1991; 229
• 30 Kalchhauser H, Öhler E. Helv. Chim. Acta 1991; 74: 417
• 31 Rádai Z, Szabó R, Szigetvári Á, Kiss NZ, Mucsi Z, Keglevich G. Curr. Org. Chem. 2020; 24: 465