Esters, phosphonate, from alcohols

Phosphonates have also been prepared from alcohols and (Ar0)2P(=0)Cl, NEts and a TiCl4 catalyst. ° The reaction of (R0)2P(=0)H and aryl iodides with a Cul catalyst leads to aryl phosphonates. " Polymer-bound phosphonate esters have been used for olefination. Dienes are produced when allylic phosphonate esters react with aldehydes. 

The construction of the alkenyl side chain and the control of the C9, CIO and Cll stereogenic centers was achieved from (5)-(+)-methyl 3-hydroxy-2-methylpropionate 1. (Scheme 21) This compound was transformed to aldehyde 99 in three steps. Bis(2,2,2)trifluoroethyl)[(methoxycabonyl)methyl]-phosphonate [23] was employed for the selective formation of the cA-a, 3-unsaturated ester 100. From this Z-unsaturated ester 100, the three consecutive asymmetric units were constructed via epoxide 101 (m-CPBA), which was selectively opened by lithium dimethylcuprate to produce 102. After deprotection-protection, the alcohol 102 was converted to the phosphonium iodide 103 via a tosylate intermediate(Scheme 21). 

It has recently been demonstrated in our own laboratory that negatively substituted olefins of the type known as dienophiles react smoothly with phosphite, phosphonite, and phosphinite esters in the presence of a suitable proton donor (123,127). With the use of phenol for this purpose, reactions are exceptionally clean and high yields may be realized. Some representative examples are included in Table I. While ethanol or methanol are often satisfactory substitutes for phenol, the yields of phosphonate are generally lower and side reactions often occur, possibly due to the lessened efficiency of alcohol as a protonating agent. Yields of phosphonate for reactions in ethanol are indicated in brackets in Table I. Thus, in addition to the expected phosphonate from reaction of acrylamide and triethyl phosphite in ethanol, there were also ob-... 

Compound 11 is, however, unexpectedly unreactive with Wittig-Horner reagents. Upon heating with the carbanion of ester phosphonates an addition across the allenic bond occurs [14]. In contrast, a slow normal 1,2-addition takes place [14] with the ylide from cyano-methylphosphonate but, unexpectedly, this proceeds with concomitant inversion at the chiral axis as shown in Scheme 3, to give a mixture of 6R or 6S, and (9E)- or (9Z)-isomers 12-15. However, a fast and very clean 1,2-addition occurs with the ethynyl ketone 18 to yield the esters 19 and 20 (Scheme 4). DIB AH reduction of the separated stereoisomers gives the allenic alcohols 21 and 22 in high yield. Mild oxidation to the aldehydes 23 and 24, followed by their condensation with the acetylenic Cio-bis-ylide 25, leads to the stereoisomeric 15,15 -didehydromimulaxanthins 26 and 28, respectively (Schemes 5 and 6). The optically active. 

Aluminum chloride Phosphonic acid esters from alcohols... 

Antibodies designed to catalyze the formation of a bond between two bound substrates suffer from the same problems of product inhibition as other enzyme mimics. Antibody 13D6.1, elicited through the phosphonate diester 161, catalyzed the transesteriflcation reaction (Figure 57) of ester 162 with alcohol 163 very efficiently with an effective molarity of s 10" -10 M but the formed product ester bound with a high affinity to the antibody ( diss = 18 uM) and thus inhibited turnover. " In favorable cases, the problem of product inhibition can be avoided by careful hapten design, as shown in the next example. 

Phosphonate esters can be readily prepared from alcohols and phosphonic acid derivatives. The selective phosphorylation of the 5 -hydroxy groups of thymidine and uridine was originally reported Mitsunobu s group in 1969. More recent examples include the modified derivative of the antitumor C-nucleoside tiazofurin (240) and an AZT triphosphate analog (241) shown... 

The strategy for the construction of 13 from aldehyde 16 with two units of phosphonate 15 is summarized in Scheme 12. As expected, aldehyde 16 condenses smoothly with the anion derived from 15 to give, as the major product, the corresponding E,E,E-tri-ene ester. Reduction of the latter substance to the corresponding primary alcohol with Dibal-H, followed by oxidation with MnC>2, then furnishes aldehyde 60 in 86 % overall yield. Reiteration of this tactic and a simple deprotection step completes the synthesis of the desired intermediate 13 in good overall yield and with excellent stereoselectivity. 

Mixed phosphonate acid esters can also be prepared from alkylphosphonate monoesters, although here the activation is believed occur at the alcohol.57... 

More recent developments in the field of the Pirkle-type CSPs are the mixed r-donor/ r-acceptor phases such as the Whelk-Of and the Whelk-02 phases.The Whelk-Of is useful for the separation of underiva-tized enantiomers from a number of families, including amides, epoxides, esters, ureas, carbamates, ethers, aziridines, phosphonates, aldehydes, ketones, carboxylic acids, alcohols and non-steroidal anti-inflammatory drugs.It has been used for the separation of warfarin, aryl-amides,aryl-epoxides and aryl-sulphoxides. The phase has broader applicability than the original Pirkle phases. The broad versatility observed on this phase compares with the polysaccharide-derived CSPs... 

The cyclic phosphonate may be intercepted with hydroxylamine to yield the corresponding hydroxamate. Importantly, the rate of hydroxylaminolysis is approximately the same as ethanol loss, thus it appears that the cyclic phosphonate and not a precursor pentacovalent species is being trapped. Insofar as the analogy is appropriate, hydroxylamine is trapping an acyclic acyl phosphate in the above case, albeit at a rate faster than benzyl alcohol loss. It is also noteworthy that for both the phosphonate and phosphate esters there is no net transfer of oxygen from the carboxyl to phosphorus during the entire course of hydrolysis, i.e. loss of two moles of alcohol. 

Several new routes involve formation of one carbon-carbon bond in pre-formed substrates. Palladium-catalyzed cyclization of /3-hydroxyenamine derivatives has been employed in a route to substituted pyrroles and 4,5,6,7-tetrahy-droindoles with multiple substituents by formation of the C-3-C-4 bond as the key feature, as illustrated by construction of the molecule 534 (Equation 146) <2006T8533>. Zinc perchlorate-catalyzed addition of alcohols to the nitrile functionality of a-cyanomethyl-/3-ketoesters, followed by annulation gave access to a series of substituted ethyl 5-alkoxypyrrole-3-carboxylates <2007T461>. Similar chemistry has also been used for synthesis of a related set of pyrrole-3-phosphonates <2007T4156>. A study on preparation of 3,5,7-functionalized indoles by Heck cyclization of suitable A-allyl substituted 2-haloanilines has also appeared <2006S3467>. In addition, indole-3-acetic acid derivatives have been prepared by base induced annulation of 2-aminocinnamic acid esters (available for instance from 2-iodoani-lines) <2006OL4473>. 

Apart from their behaviour as ligands in metal catalyst systems, studies of the reactivity of phosphites towards a wide variety of other substrates have attracted attention. New aspects and applications of the classical Michaelis-Arbuzov reaction and its variants continue to appear. Evidence of the thermal disproportionation of methyltriaryloxyphosphonium halides formed in the reactions of triarylphosphites with alkyl halides, together with the formation of P-O-P intermediates, has been reported. The Michaelis-Arbuzov reaction has been used in the synthesis of phosphonate-based styrene-divinylbenzene resins and polyphosphonated chelation therapy ligands.Treatment of electron-rich benzylic alcohols dissolved in triethylphosphite with one equivalent of iodine affords a low-temperature one-pot route to the related benzylic phosphonates, compounds which are otherwise difficult to prepare. Upper-rim chloromethylated thiacalix[4]arenes have also been shown to undergo phosphonation on treatment with a phosphite ester in chloroform at room temperature. The nickel(II)-catalysed reaction of aryl halides with phosphite esters in high boiling solvents, e.g., diphenyl ether, (the Tavs reaction), has also... 

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