Bisphosphonic acid substituted

Hertzog, K., Naumann, P., and Schuelke, U., Combined Production of Substituted w-Alkyl l-a,a-Bisphosphonic Acids and Alkyl Phosphites, East German Patent 222,599, 1985. 

Enantioselective hydrogenation of prochiral ketones has rarely been studied in aqueous biphasic media. In addition to the chiral bisphosphonic acid derivatives of 1,2-cyclohexanediamine [130], the protonated 4,4 -, 5,5 -, and 6,6 -amino-methyl-substituted BINAP (diamBINAP 2HBr) ligands (Scheme 38.7) served as constituents of the Ru(II)-based catalysts in the biphasic hydrogenations of ethyl acetoacetate [131, 132]. These catalysts were recovered in the aqueous phase and used in at least four cycles, with only a marginal loss of activity and enantio-selectivity. 

Studies Based on Molecular Mechanics Theory. - Amino-imino tautomerism in thiazolium-substituted alkylidene-l,l-bisphosphonic acids (11) has been studied by spectroscopy and pKa measurements. The effects of pH, steric and electronic effects on the conversion of amino to imino tautomers (and on the spectra) have been confirmed by molecular mechanics calculations of their optimised molecular geometries and PPP spectra. ... 

The reaction of isonitriles (259) with triethyl phosphites in the presence of hydrogen chloride gave tetraallgrl iV-substituted aminomethy-lenebisphosphonates (261) via iV-methylideneaminium (isonitrilium) salts (260). Hydrolysis or dealkylation of these tetraall l esters (261) gave the corresponding JV-substituted bisphosphonic acids (262) in 77-98% yields (Scheme 92). ... 

The steroidal a-(isocyanomethyl)phosphonates (130) and (133) have been synthesized by methylation of the carbanions (129) and (132), respectively.66 Compounds (130) and (133) behave as N,P-ketals in that they can be hydrolysed to the corresponding ketones (131) and (134) (Scheme 10). A range of a-substituted a-aminophosphonic acids (136) have been prepared in moderate to excellent yield by the alkylation of the protected a-aminophosphonate (135) with alkyl and aryl halides and Michael acceptors under phase transfer catalysis (Scheme 11).67 The reactions of the lithium carbanion of diethyl prop-2-enyIphosphonate (137) with a,P-unsaturated ketones and esters have been investigated.6S Attack can be at the a- or y-positions in the phosphonate although in all cases Michael addition to the a, p-unsaturated carbonyl is preferred to attack at carbonyl carbon. In some examples simple adducts (138) are formed, but in more complex cases addition is followed by cyclisation to give (139) (Scheme 12). The bisphosphonate (141), which is a potent inhibitor of myo-inositol monophosphatase, has been prepared with the phosphonylation of the carbanion of (140) as a key step.6 9... 

Substitution of oxygen to carbon makes them resistant to rapid hydrolysis by phosphatase, an enzyme with widespread distribution in the body. More importantly, the replacement of the oxygen atom between the two phosphonic acid moieties of pyrophosphate by a carbon atom opened up the possibility of attaching side chains. The nature of the groups attached to the central carbon atom is the key to the optimization of bisphosphonates as potent inhibitors of osteoclastic bone resorption. The action of the bisphosphonates on calcium salts is similar to the action of pyrophosphates. They exhibit the following actions ... 

Macrocychc bisphosphonates 165 and 166 were prepared from 2, 3 -0-isopropyhdene-5 -tosyladenosine 158 or -mesyladenosine 159 precursors, and the bis(tetrabutylammonium) salt of nicotinamide riboside 5 -methylbis (phosphonate) 160 (05JMC4177). Nucleophilic substitution of the precursors afforded the acyclic pyrophosphate 161 or 162 in modest yields. After deprotection with an aqueous hydrochloric acid solution, nicotinamide... 

Haelters and co-workers have reported the synthesis of a series of new functionalized tetraethyl methylenebisphosphonates (105) with long chain aliphatic groups in order to increase their lipophilicity and bioavailability Subsequent allylation of the latter with allyl bromide afforded the corresponding bisphosphonates (106) (Scheme 35). The reactivity of the allyl group was further utilized to give access to other substituted bisphosphonates (107), functionalized by diverse groups including alcohol, aldehyde, carboxylic acid, epoxide and amine. 

A new approach to a-amino acid containing a geminal bisphosphonate moiety (578) has been developed. A two-step reaction sequence utilised the Michael addition of a-substituted azlactones (576) to a vinylidene bisphosphonate (577) followed hy azalactone ring opening under acidic conditions (Scheme 166). Initial attempts to develop an enantioselective version of this reaction have been also demonstrated. ... 

Enantioselective total synthesis of ((47J,5iS)-5-Amino-4-(2,4,5-tri-fluorophenyl) cyclohex- l-enyl)-(3-(trifluoromethyl)-5,6-dihydro-[l, 2,4]tri-azolo[4,3-a]pyrazin-7(877)-yl)methanone ABT-341 (708), a DPP4 (dipeptidyl peptidase IV) inhibitor, has been completed in diphenylprolinol silyl ether (707), in the one-pot, multicomponent, reaction of nitroalkene (704), acetaldehyde (703), vinyl phosphonate (706) and amine (705) (Scheme 178) A novel, catalytic, asymmetric Michael addition of azomethine ylide (710) with p-substituted tetraethyl alkyhdene bisphosphates (709) has been realised in the presence of a chiral copper(I)/TF-Bipham-Phos (712) complex. This system provided enantioenriched unnatural i -amino acid derivatives (711) containing gem-bisphosphonates in high yields with... 

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