Dimethyl phosphonate-4-substituted

The effect of the leaving group was briefly examined, but cinnamyl bromide gave a substantially lower ee (38%). Cinnamyl dimethyl phosphonate, or acetate, gave very poor results. The cyclohexyl-substituted allylic acetate 21, on the other hand, afforded a completely y-selective reaction, but the product turned out to be racemic. Changing the Grignard reagent halide from bromide to either chloride or iodide resulted in very low ees. 

As noted in the discussion of ( )-selective alkene formation, Kishi has found that a-substituted aldehydes reacted with trimethylphosphonopropionate and KOBu to produce the (Z)-alkene selectively. A strongly dissociating base is critical to this approach. In addition to the examples already presented in the discussion of ( )-alkene formation, the (Z)-selective reaction has recently been applied to the synthesis of macrolide antibiotics. In this example, a trisubstituted alkene was formed and closed to the lactone (148 equation 33). In an application to diterpenoids. Piers encountered an example of how substrate-specific the alkene formation can be. With a-dimethoxyphosphonyl-y-butyrolactone (150), the reactions with simple aldehydes proceeded with very high selectivity [(Z) ( ) = 99 1]. On application of the reaction to the more complex aldehyde (149) the (Z) ( ) stereoselectivity dropped to 3 1 in 58% yield (equation 34). No selectivity was observed on reaction with benzaldehyde. Although for hindered substrates, strongly basic conditions with a dimethyl phosphonate can be a simple and effective method for the synthesis of (Z)-isomers, the reaction is not general. In 1983, Still and coworkers introduced methodology that used bis(trifluoroethyl)phosphonoesters (153) to provide a facile approach to (Z)-aIkenes (154) when reacted with aldehydes (equation 35). " ... 

The first diastereoselective total synthesis of 5-substituted morpholine-3-phosphonic acids (416) has been reported by Ordonez. Nucleophilic addition of trimethyl phosphite in the presence of BFsxOEtj to 3-methoxylated (5S)-5-phenyl- and (5S)-5-benzylmorpholine (413) via the intermediacy of N-acyliminium cation (414) allowed the construction of cyclic a-aminophosphonates (415) from L-amino acids (412). Finally, the N-Boc cleavage and hydrolysis of the dimethyl phosphonate (415) produced desired (31 ,55 )-5-phenyl- and (31 ,55 )-5-benzylmorpholine-3-phosphonic acids (416) in almost quantitative yields (Scheme 125). ... 

Bioisosterism is an important aspect in designing bioactive compounds. For example, phosphinate unit is often used to replace the phosphonate unit to obtain a more active compound. Bailie et al. s SAR analyses showed that the replacement of methoxyl in acylphosphonate (1-1) by methyl to produce acylphosphinate (1-2), would significantly improve the inhibitory potency and herbicidal activity. Therefore, we were interested in examining herbicidal activity of the alkylphosphinates. On the basis of (9,(9-dimethyl 1-(substituted phenoxyacetoxy)alkylphosphonates IC, several novel series of (9-methyl [1-(substituted phenoxyacetoxy)alkyl]meth-ylphosphinates lllA-lllG including 54 compounds were designed and synthesized (Scheme 1.29). 

A series of novel f-butylaminium (9-methyl 1-(substituted phenoxyacetoxy)alkyl phosphonates IIJ including 28 compounds were selectively synthesized by the demethylation of dimethyl 1-(substituted phenoxyacetoxy)alkylphosphonates IC with f-butylamine. This reaction was mild, easy, clean, and good-yielding for the synthesis of f-butylaminium phosphonates. 

Shingare and co-workers have presented for the first time a successful implementation of ultrasound irradiation for the rapid synthesis of a-hydroxy phosphonates (521) and a-amino phosphonates (525) under solvent-free conditions from triethyl phosphite (524), aromatic aldehydes (523) and amines (522) using camphor sulfonic acid (CSA) (Scheme 130). One-pot, three-component Kabachnik-Fields synthesis of a-aminophos-phonates (529) from carbonyl compounds (526), primary amines (527), and dibenzyl/dimethyl/diethyl substituted phosphites (528) has been carried out in high yields, using H-beta zeolite as a reusable catalyst (Scheme 131). Zhang and co-workers have developed the nickel-catalysed Arbuzov type phosphonylation to afford phenyl substituted phosphonates (532) in the reaction of aryl triflates (530) with triethyl phosphite (531), in which KBr, as an additive, promoted the Sn2 catalytic step (Scheme 132). ... 

A modification of the Pomeranz-Fritsch synthesis <1983JCXI3344> is used in the preparation of thieno[2,3- l-pyridine and its 2-substituted derivatives. An aryl aldehyde undergoes condensation with aminoacetaldehyde dimethyl acetal giving a Schiff base which cyclizes to form an imine product. The imine is treated with ethyl chloroformate followed by triethyl phosphate to form an intermediate carbonate-phosphonate, which then cyclizes to the thienopyr-idine product (Scheme 22) <2004S1935>. Very low product yields (2-17%) are obtained for alkyl- and phenyl-substituted thieno[2,3- ]pyridines however, the unsubstituted product and 2-halogenated derivatives give moderate yields (28-44%). 

The reaction of nitronaphthalenes and nitroisoquinolines with dimethyl phosphite in MeONa/MeOH (equation 27), proceeded via nucleophilic substitution of hydrogen according to a redox stoichiometry and gave substituted dimethyl naphthalene- and isoquinoline-phosphonates and benzazepines.214... 

An attractive alternative to the direct preparation of enamines from mono-substituted phosphonate reagents is the use of dimethyl diazomethylphosphonate (Me0)2P(0)CH= N2. Treatment of this diazo compound with t-BuOK (or with LiOH or K2C03), followed by various ketones in the presence of secondary amines, delivered the corresponding enamines251-253 (equation 17). In the presence of amines, (MeO)2P(0)CH= N2 and RCHO afforded the terminal acetylenes RC=CH. 

Similar transformations using diphenylphosphine oxide and diethyl thio-phosphite have also been performed. Rhodium prolinate second generation complex Rh2(S-TISP)2 has been used as a very effective catalyst promoting conversion of dimethyl aryldiazomethyl phosphonates (192) into the stereo-chemically defined donor/acceptor substituted rhodium carbenoid intermediates. The latter are capable of cyclopropanation of various styrene derivatives affording cyclopropylphosphonates (193) in high yields (85-96%), diastereo-selectivity (>98% de), and enantioselectivity (76-92% ee) ( Scheme 52). A... 

Because of the commercial importance of fosfomycin, it is not surprising that several important and attractive synthetic methods are reported in patents. They include, for example, precursors such as dimethyl hydroxymethylphosphonate, dimethyl, dibenzyl, and diallyl formylphosphonate, trimethyl phosphite and 2-cyano-1-hydroxypropene, 9 trialkyl phosphite and 2-chloro-propionaldehyde or 2-acetoxypropionaldehydc, diethyl chloromethylphosphonate, dibenzyl phosphite, and 1-chloro-1,2-propylene oxide,2 propynylphosphonic acid, propenylphos-phonic acid,2 2-chloro-(czT-l,2-epoxypropyl)phosphonic acid, and extrusion reactions on thermolysis. The resolution of racemic acids has also been reported. In search of new effective antibiotics, a large variety of substituted epoxyethylphosphonic acids have been pre-pared.249... 

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