Nucleophilic Additions to N‐Glycosylnitrones. Asymmetric Synthesis of α‐Aminophosphonic Acids

Abstract

Dedicated to Professor Dr. A . Eschenmoser on the occasion of his 60th birthday (6.V1.85)The hypothesis which explains the diastereoselectivity of the 1,3-dipolar cycloaddition of the N-glycosylnitrones 1-3 leading to the 5,s-disubstituted isoxazolidines 4 6 on the basis of a kinetic anomeric effect predicts that nucleophiles should add to N-glycosylnitrones with a high degree of diastereoselectivity. To test this prediction, the nucleophilic addition of lithium and potassium dialkylphosphites to the crystalline (Z)-nitrone 11, prepared from oxime 9 and (benzy1oxy)acetaldehyde has been examined. The addition of lithium phosphites gave the N-glycosyl-N-hydroxyaminophosphonates 12-16 (d. e. 78-92%) in high yields (Scheme 4). The addition of potassium phosphites showed a much lower diastereoselectivity. Glycoside cleavage, hydrogenolysis, and dealkylation of 12-16 gave (+)-(S)-phosphoserine (+)-19 (34-45 % from 9).Its absolute configuration was confirmed by an X-ray analysis of the N-(3,3,3-trifluoro-2-methoxy-2-phenylpropionyl) derivative 24. Similarly, the crystalline nitrone 25 gave the N-glycosyl-N-hydroxyaminophosphonate 26, which was transformed into ( +)-(S)-phosphovaline (+)-31 (42% from 9). The diastereoselectivity of the nucleophilic addition and the enantiomeric purity of ( + )-31 were determined by the analysis of the derivative 30 (d.e. 92%) and 32 (d.e. 93%), respectively. The addition of lithium diethyl phosphite to the nitrone 33, prepared in situ, gave the N-glycosyl-N-hydroxyaminophosphonate 34 (41 %;d.e. 91 YO), which was transformed in (+)-(S)-phosphoalanine (+)-37 (21 Sb from 9).

Synthesis of Amino‐L‐Lyxose Phosphonates as Fucosyl‐Phosphate Mimics

“…[19] By using this last condition (Scheme 2), the reaction of nitrone 4 with dialkyl esters 5a-c at 40°C gave the N-hydroxy-phosphonates 6a,b in quantitative yields whereas the bulky dibenzyl derivative 6c was only obtained in a moderate yield (47 %). Scheme 2. The N-OH group is generally reduced by hydrogenolysis over Pd/C, [15,18] and even better in the presence of aqueous HCl. [16,17] We have verified that this reduction also occurred by hydrogenolysis over Raney-nickel [20] but not over 5 % Pd/ C alone.…”

“…Addition of alkyl phosphites to nitrones has been carried out by Lewis acid catalysis, [15,16] with its anion [17,18] or in the absence of solvents. [19] By using this last condition (Scheme 2), the reaction of nitrone 4 with dialkyl esters 5a-c at 40°C gave the N-hydroxy-phosphonates 6a,b in quantitative yields whereas the bulky dibenzyl derivative 6c was only obtained in a moderate yield (47 %).…”

New strategy for the synthesis of functionalized phosphonic acids

“…(2) Addition of trimethylchlorosilane (TMSiCl), followed by immediate quenching with acid, furnished the ethenylidenebisphosphonate quantitatively, because TMSiCl reacted with lithium nitromethane to form the silyl nitronate, shifting the equilibrium to the right side completely. (3) Addition of TMSiCl followed by allowing the mixture to stand for two days and subsequent quenching with acid produced the SCHEME 29 SCHEME 30 2-isoxazoline-5,5-dilylbisphosphonate, resulting from 1,3-dipolar addition of the silyl nitronate to the ethenylidenebisphosphonate. Extension of this reaction to other nitroalkenes led to the development of a useful route to 3,4-disubstituted 4,5-dihydroisoxazole-5,5-diylbisphosphonates [59] (Scheme 23).…”

“…A number of syntheses have been developed to provide a convenient route to this class of compounds, including the controlled reduction of 1-nitroalkylphosphonates with zinc and ammonium chloride [28], the addition of a dialkyl phosphite to a 1-oxoaldoxime at an elevated temperature [29], the nucleophilic addition of a lithium or potassium dialkyl phosphite to N-glycosylnitrone followed by glycoside cleavage and hydrolysis [30], and the condensation of 1-(benzyloxyamino)alkylphosphonic acid with an O-alkylisourea, followed by treatment with boron tris(trifluoroacetate) [31]. These methods are, New Strategy for the Synthesis of Functionalized Phosphonic Acids 109 SCHEME 7 SCHEME 8 SCHEME 9 SCHEME 10 however, limited by their narrow scope, other competitive reactions, and relatively inaccessible starting materials.…”

Separation of aminoalkanephosphonic acid enantiomers by indirect UV detection capillary electrophoresis with application of cyclodextrins

“…Thus, a simple and versatile method for determination of enantiomeric purity of aminophosphonic acids is strongly desirable. In most cases the optical purity of these acids has been determined by NMR or chromatography and required derivatization prior to analysis [2][3][4][5][6][7][8]. The most common way of determinating the enantiomeric purity of aminophosphonic acids relies on the comparison of their specific optical rotation with the highest value given in the literature.…”