New Insights into the Chemistry of <i>gem</i>‐Bis(phosphonates): Unexpected Rearrangement of Michael‐Type Acceptors

Szajnman, Sergio H.; Liñares, Guadalupe Eugenia Garcia; Moro, Pablo; Rodríguez, Juan B.

doi:10.1002/ejoc.200500097

Cited by 23 publications

(19 citation statements)

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“…The title compounds 22 – 29 were straightforwardly prepared employing tetraethyl ethenylidenebisphosphonate (compound 13 ) as a Michael acceptor,37 which in turn was easily prepared from tetraethyl methylenebisphosphonate (compound 12 ) in two steps according to a slightly modified Degenhart protocol 38,39. Then, compound 13 was reacted with the corresponding n-alkylamine via a 1,4-conjugated addition reaction to afford the respective Michael adducts ( 14 – 21 ).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and biological evaluation of new 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase

Rosso

Szajnman

Malayil

et al. 2011

Bioorganic & Medicinal Chemistry

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The effect of long chain 2-alkylaminoethyl-1,1-bisphosphonates against proliferation of the clinically more relevant form of Trypanosoma cruzi, the etiologic agent of American trypanosomiasis (Chagas' disease), and against tachyzoites of Toxoplasma gondii was investigated. Particularly, compound 26 proved to be an extremely potent inhibitor against the intracellular form of T. cruzi, exhibiting IC 50 values at the nanomolar range. This cellular activity was associated with a strong inhibition of the enzymatic activity of T. cruzi farnesyl diphosphate synthase (TcFPPS), which constitutes a valid target for Chagas' disease chemotherapy. Compound 26 was an effective agent against T. cruzi (amastigotes) exhibiting an IC 50 value of 0.67 μM, while this compound showed an IC 50 value of 0.81 μM against the target enzyme TcFPPS. This drug was less effective against the enzymatic activity of T. cruzi solanesyl diphosphate synthase TcSPPS showing an IC 50 value of 3.2 μM. Interestingly, compound 26 was also very effective against T. gondii (tachyzoites) exhibiting IC 50 values of 6.23 μM. This cellular activity was also related to the inhibition of the enzymatic activity towards the target enzyme TgFPPS (IC 50 = 0.29 μM) As bisphosphonate-containing compounds are FDA-approved drugs for the treatment of bone resorption disorders, their potential low toxicity makes them good candidates to control different tropical diseases.The hemoflagellated protozoan parasite Trypanosoma cruzi is the etiological agent of Chagas' disease or American trypanosomiasis, which is an endemic disease widespread from southern United States to southern Argentina. It has been estimated that close to 18 million people are infected and over 40 million are at risk of infection by T. cruzi. 1 The central nervous system is the most frequently affected site in AIDS patients, with meningoencephalitis occurring approximately in 75% of cases. The next normally affected organ is the heart with myocarditis.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptBioorg Med Chem. Author manuscript; available in PMC 2012 April 1. In addition, since people migrate from endemic areas, the possibility for cases in developed nations will also escalate. Chemotherapy for Chagas' disease still remains unsatisfactory due to limited efficacy and common side effects of the currently available drugs such as nifurtimox (1), now discontinued, and benznidazole (2), which present toxicity associated with their continued use. [2][3][4] The parasite has a complex life cycle involving blood-sucking Reduv...

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Section: Resultsmentioning

confidence: 99%

Synthesis and biological evaluation of new 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase

Rosso

Szajnman

Malayil

et al. 2011

Bioorganic & Medicinal Chemistry

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“…[9] Among these, the Michael-type addition to ethylidene bisphosphonate esters is a common and effective procedure affording methylene bisphosphonate derivatives. Carbon nucleophiles, [10] as well as nitrogen, [3,11] oxygen, [11,12] sulphur [11,13] and phosphorus [14] nucleophiles undergo the Michael reaction in good yields. Surprisingly, despite the importance of enantiomerically pure compounds in the pharmaceutical industry, to our knowledge, only the report of Alexakis and co-workers presenting the conjugate addition of aldehydes to vinyl phosphonates, which has been published concurrently with the preparation of the present manuscript, deals with the synthesis of geminal bisphosphonate-based molecules, in an asymmetric fashion.…”

Section: Introductionmentioning

confidence: 99%

Highly Enantioselective Approach to Geminal Bisphosphonates by Organocatalyzed Michael‐Type Addition of β‐Ketoesters

Capuzzi

Perdicchia

Jørgensen

2007

Chemistry A European J

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A valuable organocatalyzed protocol has been developed for the asymmetric synthesis of bisphosphonate derivatives, a class of pharmaceutically important molecules. Cheap and commercially available dihydroquinine effectively catalyzed conjugate additions of cyclic beta-ketoesters to ethylidenebisphosphonate esters, leading to optically active geminal bisphosphonates, bearing an all-carbon substituted quaternary stereocenter, in high yields and enantioselectivities of up to 99 % ee. Further elaborations of Michael adducts to the corresponding bisphosphonic acids or vinyl phosphonates have also been successfully performed, with conservation of optical purity.

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“…The epoxide coming from PPh (PPhO) was reacted with a stoichiometric amount of organometals such as n-BuLi or PhMgBr, leading to the complete consumption of the starting PPhO epoxide and the appearance of a product whose 31 P{ 1 H} NMR spectrum showed two clearly different 31 P singlet resonances, one at 20.95 ppm and one at −1.51 ppm. The large up-field shift of one of the two P atoms is not compatible with the typical chemical shift for phosphonate units, but rather in agreement with the presence of a phosphate group [37].…”

Section: Resultsmentioning

confidence: 63%

Organocatalytic Stereoselective Epoxidation of Aryl-Substituted Vinylidenebisphosphonate Esters: On the Way to Chiral Anti-Osteoporosis Drugs

Chiminazzo¹,

Sperni²,

Scarso³

et al. 2017

Preprint

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Abstract:The synthesis of a new class of epoxide derivatives from prochiral vinylidene bisphosphonate (VBP) precursors is reported using hydrogen peroxide as the terminal oxidant. The reaction is carried out using a series of possible organic activators having a basic character, with the best results being observed using quinine and sparteine. These activators not only provide from good to excellent epoxide yields with a large variety of VBPs, but also interesting enantioselectivities in the 67%-96% ee range, at least in the case of the Ph and m-MeO-Ph VBP derivatives, opening the way to a number of chiral anti-osteoporosis potentially active pharmaceutical ingredients.

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New Insights into the Chemistry of gem‐Bis(phosphonates): Unexpected Rearrangement of Michael‐Type Acceptors

Cited by 23 publications

References 56 publications

Synthesis and biological evaluation of new 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase

Synthesis and biological evaluation of new 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase

Highly Enantioselective Approach to Geminal Bisphosphonates by Organocatalyzed Michael‐Type Addition of β‐Ketoesters

Organocatalytic Stereoselective Epoxidation of Aryl-Substituted Vinylidenebisphosphonate Esters: On the Way to Chiral Anti-Osteoporosis Drugs

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