Recent Advances on the Synthesis and Application of α,α-Difluoro-β-aminophosphonates

doi:10.6023/cjoc202405013

Abstract

α,α-Difluoro-β-aminophosphonates can be looked as structural analogies with α-amino acids, which have attracted great attention in biological and medicinal chemistry during the past decades. Furthermore, these compounds also belong to an important type of organic building blocks for the rapid synthesis of difluoromethylenephosphonate-containing molecules. Thus, the preparation and application of α,α-difluoro-β-aminophosphonates are hot research topics in organic phosphine chemistry. A comprehensive summary of the literature reports related to α,α-difluoro-β-aminophosphonates in recent years is presented. And aspects of synthesis and applications of α,α-difluoro-β-aminophosphonates are discussed, in order to provide critical guidance for the further development of reactions and applications for the synthesis of difluoromethylenephosphonate derivatives.

Key words: aminophosphonate, α,α-difluoro-β-aminophosphonate, carbene, diazo compound, amine, bioactive compound

Cite this article

Youlong Du, Qian Wang, Haibo Mei, Romana Pajkert, Gerd-Volker Röschenthaler, Jianlin Han. Recent Advances on the Synthesis and Application of α,α-Difluoro-β-aminophosphonates[J]. Chinese Journal of Organic Chemistry, 2024, 44(12): 3686-3701.

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Fig. & Tab. 24

Figure 1. Examples of biologically active difluorinated aminophosphonates and phosphonic acids

Scheme 1. Synthetic route to 2-amino-1,1-difluorophosphonic acid

Scheme 2. General strategies for the synthesis of α,α-difluoro-β-aminophosphonates

Scheme 3. Classical synthetic routes to LiCF2P(O)(OR)2 and TMSCF2P(O)(OR)2

Scheme 4. Diastereoselective synthesis of α,α-difluoro-β-aminophosphonates

Scheme 5. Synthesis of N-protected α,α-difluoro-β-aminophosphonates

Scheme 6. Synthesis of N-phenyl α,α-difluoro-β-aminophosphonate

Scheme 7. Stereoselective synthesis of 1-C-phosphonodifluoromethyl iminosugars

Scheme 8. Addition of LiCF2P(O)(OEt)2 to furanosylamines

Scheme 9. Addition of TMSCF2P(O)(OEt)2 to benzylidene-methylimine

Scheme 10. Addition of TMSCF2P(O)(OEt)2 to selected ena- mines

Scheme 11. Addition of TMSCF2P(O)(OEt)2 to chiral N-tert- butanesulfinyl imines

Scheme 12. Difluorophosphorylation of tetrahydroisoquinoline

Scheme 13. Reaction of difluoromethylphosphonate imine with N-protected indoles

Scheme 14. Preparation of α,α-difluoro-β-aminophosphonates via reduction of α,α-difluoro-β-iminophosphonates

Scheme 15. Synthetic route to α,α-difluoro-β-aminophosphonates via reduction of α,α-difluoro-β-iminophosphonate

Scheme 16. Petasis boronic acid Mannich reaction of α,α-difluoro-β-aminophosphonates

Scheme 17. O—H insertion reaction of (β-diazo-α,α-difluoroethyl)phosphonates

Scheme 18. Application of in situ generated (β-diazo-α,α-difluoroethyl)phosphonates in [3＋2] cycloadditions

Scheme 19. Halogenation reaction of (β-diazo-α,α-difluoroeth- yl)phosphonates

Scheme 20. One-pot reaction of (β-amino-α,α-difluoroethyl)phosphonates via aza-Wittig reagent

Scheme 21. Possible mechanism for the aza-Wittig reaction of (β-amino-α,α-difluoroethyl)phosphonates

Scheme 22. Rh-catalyzed cascade carbonylation/C—F bond cleavage reaction of (β-diazo-α,α-difluoroethyl)phosphonates

Scheme 23. Ru-catalyzed reaction of (β-diazo-α,α-difluoroethyl)phosphonates with Hantzsch esters

References 51

[1]	(a) Kukhar V. P.; Hudson H. R. Aminophosphonic and Aminophosphinic Acids: Chemistry and Biological Activity, Wiley, Chichester, UK, 2000. pmid: 19229586
	(b) Kafarski P.; Lejczak B. Phosphorus, Sulfur Silicon Relat. Elem. 1991, 63, 193. pmid: 19229586
	(c) Naydenova E. D.; Todorov P. T.; Troev K. D. Amino Acids 2010, 38, 23. doi: 10.1007/s00726-009-0254-7 pmid: 19229586
	(d) Galezowska J.; Gumienna-Kontecka E. Coord. Chem. Rev. 2012, 256, 105. pmid: 19229586
	(e) Mucha A.; Kafarski P.; Berlicki Ł. J. Med. Chem. 2011, 54, 5955. pmid: 19229586
[2]	(a) Palacios F.; Alonso C.; Santos J. M. Chem. Rev. 2005, 105, 899.
	(b) Ma J. A. Chem. Soc. Rev. 2006, 35, 630.
	(c) Cao H. Q.; Li J. K.; Zhang F. G.; Cahard D.; Ma J. A. Adv. Synth. Caltal. 2021, 363, 688.
[3]	Kudzin Z. H.; Kudzin M. H.; Drabowicz J.; Stevens V. C. Curr. Org. Chem. 2011, 15, 2015.
[4]	(a) Wardle N. J.; Bligh S. W.; Hudson H. R. Curr. Org. Chem. 2007, 11, 1635.
	(b) Ordonez M.; Rojas-Cabrera H.; Cativiela C. Tetrahedron 2009, 65, 17.
	(c) Soloshonok V. A.; Belokon Y. N. N.; Kuzmina A.; Maleev V. I.; Svistunova N. Y.; Solodenko V. A.; Kukhar V. P. J. Chem. Soc., Perkin Trans. 1 1992, 1525.
[5]	(a) Ojima I. Fluorine in Medicinal Chemistry and Chemical Biology, Wiley-Blackwell, Chichester, 2009.
	(b) Uneyama K. Organofluorine Chemistry, Blackwell Publishing Ltd, Oxford, 2006.
	(c) Wang Q.; Bian Y.; Dhawan G.; Zhang W.; Sorochinsky A. E.; Makarem A.; Soloshonok V.; Han J. Chin. Chem. Lett. 2024, 35, 109780.
	(d) He J.; Li Z.; Dhawan G.; Zhang W.; Sorochinsky A. E.; Butler G.; Soloshonok V. A.; Han J. Chin. Chem. Lett. 2023, 34, 107578.
	(e) Hagmann W. K. J. Med. Chem. 2008, 51, 4359.
	(f) Yu Y.; Liu A.; Dhawan G.; Mei H.; Zhang W.; Izawa K.; Soloshonok V. A.; Han J. Chin. Chem. Lett. 2021, 32, 3342.
[6]	O’Hagan D.; Rzepa H. S. Chem. Commun. 1997, 645.
[7]	(a) Turcheniuk K. V.; Kukhar V. P.; Röschenthaler G. V.; Aceña J. L.; Soloshonok V. A.; Sorochinsky A. E. RSC Adv. 2013, 3, 6693.
	(b) Makhaeva G. F.; Aksinenko A. Y.; Sokolov V. B.; Baskin I. I.; Palyulin V. A.; Zefirov N. S.; Hein N. D.; Kampf J. W.; Wijeye- sakere S. J.; Richardson R. J. Chem. Biol. Interact. 2010, 187, 177.
	(c) Cytlak T.; Kaźmierczak M.; Skibińska M.; Koroniak H. Phosphorus, Sulfur Silicon Relat. Elem. 2017, 192, 602.
[8]	(a) Shevchuk M.; Wang Q.; Pajkert R.; Xu J.; Mei H.; Röschenthaler G.-V.; Han J. Adv. Synth. Catal. 2021, 363, 2912. pmid: 16967924
	(b) Romanenko V. D.; Kukhar V. P. Chem. Rev. 2006, 106, 3868. pmid: 16967924
[9]	(a) Burke T.; Smyth M.; Otaka A.; Nomizu M.; Roller P.; Wolf G.; Case R.; Shoelson S. Biochemistry 1994, 33, 6490. pmid: 10888338
	(b) Chen L.; Wu L.; Otaka A.; Smyth M.; Roller P.; Burke T.; Hertog J.; Zhang Z. Biochem. Biophys. Res. Commun. 1995, 216, 976. pmid: 10888338
	(c) Chen H.; Cong L.; Li Y.; Yao Z.; Wu L.; Zhang Z.; Burke T.; Quon M. Biochemistry 1999, 38, 384. pmid: 10888338
	(d) Higashimoto Y.; Saito S.; Tong X.; Hong A.; Sakaguchi K.; Appela E.; Anderson C. J. Biol. Chem. 2000, 275, 23199. doi: 10.1074/jbc.M002674200 pmid: 10888338
	(e) Yokomatsu T.; Murano T.; Akiyama T.; Koizumi J.; Shibuya S.; Tsuji Y.; Soeda S.; Shimeno H. Bioorg. Med. Chem. Lett. 2003, 13, 229. pmid: 10888338
	(f) Gautier-Lefebvre I.; Behr J.-B.; Guillerm G.; Ryder N. Bioorg. Med. Chem. Lett. 2000, 10, 1483. pmid: 10888338
	(g) Pfund E.; Lequeux T.; Masson S.; Vazeux M.; Cordi A.; Pierre A.; Serre V.; Hervé G. Bioorg. Med. Chem. 2005, 13, 4921. pmid: 10888338
	(h) Hakogi T.; Yamamoto T.; Fujii S.; Ikeda K.; Katsumura S. Tetrahedron Lett. 2006, 47, 2627. pmid: 10888338
	(i) Koga Y.; Okuda T.; Watanuki S.; Kamikubo T.; Hirayama F.; Moritomo H.; Fujiyasu J.; Kageyama M.; Uemura T.; Takasaki J. WO 2007105751, 2007. pmid: 10888338
	(j) Wu L.; Zhan Z.; Qian Y.; Wang J.; Chen S. WO 2021058024, 2021. pmid: 10888338
[10]	Chambers R. D.; O’Hagan D.; Lamont R. B.; Jain S. C. J. Chem. Soc., Chem. Commun. 1990, 1053.
[11]	(a) Xu Y.; Aoki J.; Shimizu K.; Umezu-Goto M.; Hama K.; Takanezawa Y.; Yu S.; Mills G. B.; Arai H.; Qian L.; Prestwich G. D. J. Med. Chem. 2005, 48, 3319.
	(b) Wang J.; Fei X.; Gardner T. A.; Hutchins G. D.; Zheng Q. Bioorg. Med. Chem. 2005, 13, 549.
[12]	(a) Behr J.-B.; Evina C.; Phung N.; Guillerm G. J. Chem. Soc., Perkin Trans. 1 1997, 1597. pmid: 28221798
	(b) Cocaud C.; Nicolas C.; Poisson T.; Pannecoucke X.; Legault C. Y.; Martin O. R. J. Org. Chem. 2017, 82, 2753. doi: 10.1021/acs.joc.6b03071 pmid: 28221798
[13]	(a) Röschenthaler G.-V.; Kukhar V.; Barten J.; Gvozdovska N.; Belik M.; Sorochinsky A. Tetrahedron Lett. 2004, 45, 6665.
	(b) Röschenthaler G.-V.; Kukhar V. P.; Belik M. Y.; Mazurenko K. I.; Sorochinsky A. E. Tetrahedron 2006, 62, 9902.
[14]	Cherkupally P.; Beier P. J. Fluorine Chem. 2012, 141, 76.
[15]	Henry-dit-Quesnel A.; Toupet L.; Pommelet J.-C.; Lequeux T. Org. Biomol. Chem. 2003, 1, 2486. pmid: 12956065
[16]	Van Tran T.; Désiré J.; Auberger N.; Blériot Y. J. Org. Chem. 2022, 87, 7581.
[17]	Kosobokov M. D.; Dilman A. D.; Struchkova M. I.; Belyakov P. A.; Hu J. J. Org. Chem. 2012, 77, 2080. doi: 10.1021/jo202669w pmid: 22283481
[18]	Das M.; O’Shea D. F. Chem.-Eur. J. 2015, 21, 18717.
[19]	Chen Q.; Zhou J.; Wang Y.; Wang C.; Liu X.; Xu Z.; Lin L.; Wang R. Org. Lett. 2015, 17, 4212.
[20]	Xie C.; Zhang L.; Mei H.; Pajkert R.; Ponomarenko M.; Pan Y.; Röschenthaler G.-V.; Soloshonok V. A.; Han J. Chem.-Eur. J. 2016, 22, 7036.
[21]	(a) Rapp M.; Szewczyk M. Z.; Koroniak H. J. Fluorine Chem. 2014, 167, 152.
	(b) Szewczyk M. Z.; Rapp M.; Virieux D.; Pirat J.-L.; Koroniak H. New J. Chem. 2017, 41, 6322.
[22]	Xie J.; Zhang T.; Chen F.; Mehrkens N.; Rominger F.; Rudolph M.; Hashmi A. S. K. Angew. Chem., Int. Ed. 2016, 55, 2934.
[23]	Obayashi M.; Kondo K. Tetrahedron Lett. 1982, 23, 2327.
[24]	(a) Waschbüsch R.; Samadi M.; Savignac P. A. J. Organomet. Chem. 1997, 529, 267.
	(b) Alexandrova A. V.; Beier P. J. Fluorine Chem. 2009, 130, 493.
[25]	Czerwiński P. J.; Furman B. Chem. Commun. 2019, 55, 9436.
[26]	(a) Escorihuela J.; Fustero S. Chem. Rec. 2023, 23, e202200262.
	(b) Bégué J. P.; Bonnet-Delpon D.; Crousse B.; Legros J. Chem. Soc. Rev. 2005, 34, 562.
	(c) Mei H.; Han J.; Fustero S.; Román R.; Ruzziconi R.; Soloshonok V. A. J. Fluorine Chem. 2018, 216, 57.
[27]	Dilman A. D.; Levin V. V. Eur. J. Org. Chem. 2011, 2011, 831.
[28]	(a) Froidevaux V.; Negrell C.; Caillol S.; Pascault J. P.; Boutevin B. Chem. Rev. 2016, 116, 14181. pmid: 32064858
	(b) Pelckmans M.; Renders T.; Van de Vyver S.; Sels B. F. Green Chem. 2017, 19, 5303. pmid: 32064858
	(c) Cabré A.; Verdaguer X.; Riera A. Chem. Rev. 2022, 122, 269. pmid: 32064858
	(d) Compain P. Adv. Synth. Catal. 2007, 349, 1829. pmid: 32064858
	(e) Yin Q.; Shi Y.; Wang J.; Zhang X. Chem. Soc. Rev. 2020, 49, 6141. pmid: 32064858
	(f) Trowbridge A.; Walton S. M.; Gaunt M. J. Chem. Rev. 2020, 120, 2613. doi: 10.1021/acs.chemrev.9b00462 pmid: 32064858
[29]	((a) Serafini M.; Cargnin S.; Massarotti A.; Pirali T.; Genazzani A. A. J. Med. Chem. 2020, 63, 10170. doi: 10.1021/acs.jmedchem.0c00415 pmid: 32352778
[30]	(a) Nagaraaj P.; Vijayakumara V. Org. Chem. Front. 2019, 6, 2570. doi: 10.1039/c9qo00387h pmid: 36218331
	(b) Berger K. J.; Levin M. D. Org. Biomol. Chem. 2021, 19, 11. pmid: 36218331
	(c) Yamamoto Y.; Kodama S.; Nomotoa A.; Ogawa A. Org. Biomol. Chem. 2022, 20, 9503. doi: 10.1039/d2ob01421a pmid: 36218331
[31]	Shevchuk M. V.; Sorochinsky A. E.; Khilya V. P.; Romanenko V. D.; Kukhar V. P. Synlett 2010, 73.
[32]	(a) Li P.; Jia X. Synthesis 2018, 50, 711.
	(b) Dahiya A.; Sahoo A. K.; Alam T.; Patel B. K. Chem.-Asian J. 2019, 14, 4454.
[33]	(a) Ciszewski Ł. W.; Rybicka-Jasińska K.; Gryko D. Org. Biomol. Chem. 2019, 17, 432. doi: 10.1039/c8ob02703j pmid: 26854865
	(b) Xiao Q.; Zhang Y.; Wang J. Acc. Chem. Res. 2013, 46, 236. pmid: 26854865
	(c) Fulton J. R.; Aggarwal V. K.; de Vicente J. Eur. J. Org. Chem. 2005, 2005, 1479. pmid: 26854865
	(d) Maas G. Angew. Chem., Int. Ed. 2009, 48, 8186. pmid: 26854865
	(e) Candeias N. R.; Paterna R.; Gois P. M. P. Chem. Rev. 2016, 116, 2937. doi: 10.1021/acs.chemrev.5b00381 pmid: 26854865
[34]	Mix K. A.; Aronoff M. R.; Raines R. T. ACS Chem. Biol. 2016, 11, 3233.
[35]	(a) Mertens L.; Koenigs R. M. Org. Biomol. Chem. 2016, 14, 10547. pmid: 27722720
	(b) Sivaguru P.; Bi X. Sci. China: Chem. 2021, 64, 1614. pmid: 27722720
	(c) Hock K. J.; Mertens L.; Metze F. K.; Schmittmann C.; Koenigs R. M. Green Chem. 2017, 19, 905. pmid: 27722720
[36]	Mei H.; Liu J.; Pajkert R.; Wang L.; Röschenthaler G. V.; Han J. Org. Chem. Front. 2021, 8, 767.
[37]	Liu J.; Xu J.; Pajkert R.; Mei H.; Röschenthaler G. V.; Han J. Acta Chim. Sinica 2021, 79, 747 (in Chinese).
	(刘江, 徐敬成, Romana Pajkert, 梅海波, Gerd-Volker Röschenthaler, 韩建林, 化学学报, 2021, 79, 747.) doi: 10.6023/A21030096
[38]	Li Z.; Yao X.; Zhang X.; Mei H.; Han J. J. Org. Chem. 2022, 87, 15483.
[39]	Mei H.; Wang L.; Pajkert R.; Wang Q.; Xu J.; Liu J.; Röschenthaler G. V.; Han J. Org. Lett. 2021, 23, 1130.
[40]	Wang Q.; Wang L.; Pajkert R.; Hajdin I.; Mei H.; Röschenthaler G. V.; Han J. J. Fluorine Chem. 2021, 251, 109899.
[41]	Zhai S. J.; Cahard D.; Zhang F. G.; Ma J. A. Chin. Chem. Lett. 2022, 33, 863.
[42]	(a) Khanal H. D.; Thombal R. S.; Maezono S. M. B.; Lee Y. R. Adv. Synth. Catal. 2018, 360, 3185.
	(b) Schnaars C.; Hennum M.; Bonge-Hansen T. J. Org. Chem. 2013, 78, 7488.
[43]	Liu J.; Pajkert R.; Wang L.; Mei H.; Röschenthaler G. V.; Han J. Chin. Chem. Lett. 2022, 33, 2429.
[44]	Lu Y.; Huang C.; Liu C.; Guo Y.; Chen Q. Y. Eur. J. Org. Chem. 2018, 2018, 2082.
[45]	Zhang F. G.; Lv N.; Zheng Y.; Ma J. A. Chin. J. Chem. 2018, 36, 723.
[46]	Zhang F. G.; Zeng J. L.; Tian Y. Q.; Zheng Y.; Cahard D.; Ma J. A. Chem.-Eur. J. 2018, 24, 7749.
[47]	Wang Q.; Liu J.; Wang N.; Pajkert R.; Mei H.; Röschenthaler G. V.; Han J. Adv. Synth. Catal. 2022, 364, 1969.
[48]	Wang Q.; Pajkert R.; Mei H.; Röschenthaler G. V.; Han J. J. Fluorine Chem. 2024, 273, 110226.
[49]	Wang Q.; Liu J.; Mei H.; Pajkert R.; Röschenthaler G. V.; Han J. Adv. Synth. Catal. 2023, 365, 2883.
[50]	Zhang X.; Zhang X.; Song Q.; Sivaguru P.; Wang Z.; Zanoni G. Bi X. Angew. Chem., Int. Ed. 2022, 61, e202116190.
[51]	Wang Q.; Liu J.; Mei H.; Pajkert R.; Kessler M.; Röschenthaler G. V.; Han J. Org. Lett. 2022, 24, 8036.

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