Macrocyclic phosphonate

Macrocyclic phosphonates have been reported as kinase inhibitors (P12WO074951). In a representative synthesis, 4-chloropyrimidine 31 was reacted with the aminoisoindolone 32 leading to the 2,4-diaminopyrimidine 33 in 79% yield (Scheme 7). Selective monodeprotection of phosphonate followed by coupling using PyBOP in h h dilution conditions afforded... 

Intramolecular condensation of phosphonate carbanions with carbonyl groups carried out under conditions of high dilution have been utilized in macrocycle syntheses. Entries 7 and 8 show macrocyclizations involving the Wadsworth-Emmons reaction. Entries 9 to 11 illustrate the construction of new double bonds in the course of a multistage synthesis. The LiCl/amine conditions are used in Entries 9 and 10. 

Phosphonate-based cyclization has been increasingly used in macrocyclic terpene synthesis. In a synthesis of the marine cembranoid (+)-desepoxyasperidiol the cyclization of the phosphonate (192) was attempted under a variety of conditions without success. 

Table 3.20 lists examples of the preparation of oxygen-containing heterocycles by RCM. Further examples, including lactones [895], pyrans [896,897], chromenes [839], tetrahydrofurans [838], phosphonates [898], and oxepines [856,899-902], have been reported. For references to macrocyclizations see Scope and Limitations in this section. 

The sulfone moiety was reductively removed and the TBS ether was cleaved chemoselectively in the presence of a TPS ether to afford a primary alcohol (Scheme 13). The alcohol was transformed into the corresponding bromide that served as alkylating agent for the deprotonated ethyl 2-(di-ethylphosphono)propionate. Bromination and phosphonate alkylation were performed in a one-pot procedure [33]. The TPS protecting group was removed and the alcohol was then oxidized to afford the aldehyde 68 [42]. An intramolecular HWE reaction under Masamune-Roush conditions provided a macrocycle as a mixture of double bond isomers [43]. The ElZ isomers were separated after the reduction of the a, -unsaturated ester to the allylic alcohol 84. Deprotection of the tertiary alcohol and protection of the prima-... 

Intramolecular condensation of phosphonate carbanions with carbonyl groups carried out under conditions of high dilution has been utilized in macrocycle synthesis (entries 8 and 9 in Scheme 2.17)... 

Intramolecular ketophosphonate-aldehyde condensation25 has been used by Nicolaou and co-workers as a cyclization release strategy to form macrocycles in the muscone series of natural products (Scheme 5).26 A highlight of this work was development of a unique phosphonate resin. 

Russian workers83 84 have synthesized a series of phosphorus-containing crowns utilizing O—P—O bonds in the macrocycle, i.e. cyclic phosphonate esters (7). One of these is claimed to have been prepared in 40% yield (equation 29). 

This review groups the information published on degradation of the main families of extractants studied in the frame of long-lived minor-actinide and fission-product recovery (1-4) (see Chapter 1) alkyl-phosphorus compounds (phosphates, phosphonic acids, bifunctional compounds like CMPO), amide compounds (dialkyl-amides, malonamides, and diglycolamides), N-donor compounds, and macrocycles like crown ethers and calixarenes (Table 8.1). The multicomponent systems based on the chlorinated cobalt dicarbollide process have not been considered. 

In order to prepare these macrocycles it was necessary to synthesize the previously unknown o -bis(phosphino)benzene (IV). Lithium aluminum hydride reduction of the o-bis(phosphonate) III gave IV in 50% yield (31P NMR, 6 -123.8 ppm, Jpy = 207 Hz). The phosphonate III could be obtained in modest yields by the photo-activated nucleophilic aromatic substitution by sodium diethyl-phosphite on o-chloroiodobenzene in liquid ammonia solution (4). 

The 14-membered ring phosphonate 208 was synthesized via cyclization of the acyclic precursor 207 using the Mitsunobu reaction. Macrocycle 208 was obtained in 82% yield as a mixture of two diastereomers (5 1). The phenyl moiety in 208 was substituted with iV-Cbz-protected aminopentanol, followed by hydrogenolysis in EtOH with hydrogen and 10% Pd/C to afford amine 209 in 50% yield <20010L643, 2002CJC1643>. 

Durette et al. [74] have achieved the total synthesis of the hexadepsipeptide antibiotic L-156,602 128) using the mixed phosphonic anhydride method as key macrolactamization step. As shown in Scheme 43, treatment of the linear depsipeptide 126 with n-propylphosphonic anhydride and DMAP in dichloro-methane at high dilution afforded the macrocycle 127 in more than 57% yield. 

The first total synthesis of sarcophytol A (3), which was reported by Takayanagi et al. in 1990, ° was achieved in a highly stereo- and enantioselective manner starting from , -famesol (91) it included (1) a newly developed Z-selective (Z > 35 1) Horner-Emmons reaction with a phosphonate nitrile, (2) modified cyanohydrin macrocyclization, and (3) enantioselective (93% ee) reduction of macrocyclic ketone 100 as its key steps (Scheme 6-1). 

Phosphonoacetate cycHzation. Intramolecular cyclization of keto phosphonates can be used for construction of macrocyclic a, -unsaturated lactones. Stork s laboratory found that use of lithium isopropoxide or lithium hexamethyidisilazide in THF containing 1% HMPT minimized formation of cyclic dilactones. Use of sodium or potassium counterions was much less satisfactory. An example is shown in equation (I). 

A very different kind of tetrapyrrolic expanded porphyrin is the [22]annulenoquinone 4.201. This tetrafuran-containing macrocycle was prepared in 10% yield via a Wittig condensation between the ketodialdehyde 4.198 and the phosphonate salt 4.200 (Scheme 4.6.5). A related difuran-dithiophene-containing [22]annulenoquinone 4.202 was likewise prepared via reaction of the corresponding ketodialdehyde 4.199 with 4.200. 

Se, N-Ph, or NPh) have been prepared. A full paper has appeared on the synthesis of nitrogen-containing macrocyclic compounds from phosphoric (as well as phosphonic) dihydrazides and... 

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