Allenic phosphates

If allenes bear a potential leaving group in the a-position to the cumulene system, they are very attractive substrates for palladium-catalyzed substitutions. Examples are a-allenic acetates and particularly a-allenic phosphates, which react under palladium(O) catalysis with carbanions derived from /3-diesters, /i-keto esters, a-phenylsulfonyl esters and glycine ester derivatives. They lead to /3-functionalized allenes such as 86, 89 and 93 (Eqs. 14.9-14.11) [45 18]. 

The stereochemical outcome can be rationalized by the mechanism illustrated in Scheme 14.22. The formation of an enantiomeric pair of allylpalladium complexes (Sp)/(RP)-99 offers two possibilities for the attack of the nucleophile in the subsequent addition leading to the formation of the stereoisomers (R)- and (S)-101. It should be mentioned that the structure of intermediate 102, prepared from a-allenic phosphate 91, could be proved by both NMR spectroscopy and single-crystal X-ray analysis and therefore serves as evidence for the formation of intermediate 100 (Scheme 14.22 and Eq. 14.12) [49]. 

In addition to the aforementioned allenic steroids, prostaglandins, amino acids and nucleoside analogs, a number of other functionalized allenes have been employed (albeit with limited success) in enzyme inhibition (Scheme 18.56) [154-159]. Thus, the 7-vinylidenecephalosporin 164 and related allenes did not show the expected activity as inhibitors of human leukocyte elastase, but a weak inhibition of porcine pancreas elastase [156], Similarly disappointing were the immunosuppressive activity of the allenic mycophenolic acid derivative 165 [157] and the inhibition of 12-lipoxygenase by the carboxylic acid 166 [158]. In contrast, the carboxyallenyl phosphate 167 turned out to be a potent inhibitor of phosphoenolpyruvate carboxylase and pyruvate kinase [159]. Hydrolysis of this allenic phosphate probably leads to 2-oxobut-3-enoate, which then undergoes an irreversible Michael addition with suitable nucleophilic side chains of the enzyme. 

Dialkyl (l-hydroxy-2-alkynyl)phosphonates [e.g. (64)], prepared by addition of lithium acetylides to acyl phosphonates, can be converted regioselectively into allenic phosphates via the phosphonate-phosphate rearrangement (e.g. Scheme 104). If sodium alkoxides in alcohols are used to effect the rearrangement, mixtures of allenic and acetylenic products are formed however, use of sodium bis(trimethylsilyl)amide in DMSO furnishes allenic phosphates almost exclusively. 

Zigmond, 1988). The ATP-hydrolysis that accompanies actin polymerization, ATP —> ADP + Pj, and the subsequent release of the cleaved phosphate (Pj) are believed to act as a clock (Pollard et ah, 1992 Allen et ah, 1996), altering in a time-dependent manner the mechanical properties of the filament and its propensity to depolymerize. Molecular dynamics simulations suggested a so-called back door mechanism for the hydrolysis reaction ATP ADP - - Pj in which ATP enters the actin from one side, ADP leaves from the same side, but Pj leaves from the opposite side, the back door (Wriggers and Schulten, 1997b). This hypothesis can explain the effect of the toxin phalloidin which blocks the exit of the putative back door pathway and, thereby, delays Pi release as observed experimentally (Dancker and Hess, 1990). 

Et4N F , CH3CN, 48 h, reflux. TMSF and allene are formed in the cleavage reaction. These conditions are not compatible with phenyl phosphates, which are cleaved preferentially with fluoride.Cleavage of a bis TMSP phosphate results in the cleavage of only one of the TMSP groups. 

A current area of interest is the use of AB cements as devices for the controlled release of biologically active species (Allen et al, 1984). AB cements can be formulated to be degradable and to release bioactive elements when placed in appropriate environments. These elements can be incorporated into the cement matrix as either the cation or the anion cement former. Special copper/cobalt phosphates/selenates have been prepared which, when placed as boluses in the rumens of cattle and sheep, have the ability to decompose and release the essential trace elements copper, cobalt and selenium in a sustained fashion over many months (Chapter 6). Although practical examples are confined to phosphate cements, others are known which are based on a variety of anions polyacrylate (Chapter 5), oxychlorides and oxysulphates (Chapter 7) and a variety of organic chelating anions (Chapter 9). The number of cements available for this purpose is very great. 

More recently copper phosphate cements have been suggested for use as controlled-release agents for supplying trace amounts of copper to cattle and sheep over an extended period (Allen et al., 1984 Mansion et al., 1985 Prosser et al., 1986). The cements were prepared with a Cu/P ratio of 1 1 to ensure that the matrix was an add phosphate and so subject to dissolution in aqueous solutions. They released copper at a constant rate for 90 days. 

Figure 3.89 Cyclic voltammograms of 500 pm cytochrome c at a gold electrode modified by (a) 2-mercaptopyridine, (b> 2-mercaptosuccinic acid, 4,4 -dithiobis(butanoic acid), (d) 4-mercaploaniline. pH 7.0 phosphate buffer +0.1 M NaC104. Scan rale 50mVs . From Allen...

Mikami and Yoshida extended the scope of this method considerably by using propargyl phosphates and chiral proton sources [94], The propargylic phosphates thereby have been found to be advantageous owing to their high reactivity towards palladium and the extremely low nudeophilicity of the phosphate group [95]. In some cases, it was even possible to obtain allenes from primary substrates, e.g. ester 194 (Scheme 2.60) [96]. A notable application of this transformation is the synthesis of the allenic isocarbacydin derivative 197 from its precursor 196 [97]. 

By employing chiral proton sources for the protonation of the intermediate samarium species 184/185, highly enantioenriched allenes were accessible in some cases [98]. Thus, in the reaction of propargylic phosphate 198, (R,Rj- 1,2-diphenyl-1,2-ethandiol (200) and (R)-pantolactone (201) were found to give the highest selec-tivities, affording allene 199 with up to 95% ee (Scheme 2.61). 

Reductions of propargyl bromides, mesylates and phosphates using LiAlH4, NaBH4 and LiBHEt3 as reductants were reported however, the selectivity towards allenic products was generally low [49, 50],... 

Palladium-catalyzed reduction of propargyl acetates is possible with Sml2 in the presence of a proton source (Scheme 3.17) [51]. The allene/alkyne selectivity is greatly influenced by the choice of the proton source. Propargyl phosphates were also converted into hydridoallenes by Pd-catalyzed reduction with Sml2 [52],... 

When the same reaction was performed with a phosphate 96 and nBuMgBr in the presence of a copper salt, a conjugated diene 97 was obtained exclusively and no allenic product was detected (Scheme 3.47) [91]. 

The enantioselective synthesis of an allenic ester using chiral proton sources was performed by dynamic kinetic protonation of racemic allenylsamarium(III) species 237 and 238, which were derived from propargylic phosphate 236 by the metalation (Scheme 4.61) [97]. Protonation with (R,R)-(+)-hydrobcnzoin and R-(-)-pantolactone provided an allenic ester 239 with high enantiomeric purity. The selective protonation with (R,R)-(+)-hydrobenzoin giving R-(-)-allcnic ester 239 is in agreement with the... 

In another reduction, the propargylic phosphate 64 is reduced with samarium(II) iodide in the presence of tetrakis(triphenylphosphine)palladium and tert-butanol as a proton source the allene 65 is produced almost exclusively, <1% of the isomeric alkyne 66 being present in the product mixture [19]. 

To prepare the other cross-conjugated allene, 4-methylene-l,2,5-hexatriene ( 2-allenyl-1,3-butadiene ) (23), the allene alcohol 215 was first converted into the phosphate 216, that readily underwent an SN2 -type substitution with allenylmagnesium bromide to yield the target hydrocarbon as a highly reactive allene derivative (Scheme 5.32) [76],... 

An enantioenriched propargylic phosphate was converted to a racemic allene under the foregoing reaction conditions (Eq. 9.152) [124]. It is proposed that the racemization pathway involves equilibration of the allenyl enantiomers via a propargylic intermediate (Scheme 9.37). Both the allenylpalladium precursor and the allenylsamarium reagent could racemize by this pathway. When a chiral alcohol was used as the proton source, the reaction gave rise to enantiomerically enriched allenes (Table 9.61) A samarium alcohol complex is thought to direct the protonolysis (Scheme 9.38). 

Gore and co-workers developed a convenient experimental procedure for the conversion of a-phosphate-substituted allene 103 to the preferentially formed E-config-ured 1,3-pentadiene 105 (Eq. 14.13) [46, 47, 51]. In a similar manner, Vermeer and co-workers converted a-acetate-substituted allenes 106 into the corresponding 1,3-dienes 107 in moderate to good yields by simple treatment with organozinc chlorides in the presence of Pd(0) catalyst (Eq. 14.14) [52]. 

The amino acid 26, which has been isolated from various Amanita fungi [35], is one of the few examples of a natural product with an achiral allene moiety (Scheme 18.10) and was prepared inter alia by Strecker synthesis and also substitution reactions of allenic bromides and phosphates [36]. Recently, even unfunctionalized allenes have been found in nature seven allenic hydrocarbons 27 with chain lengths ranging from C23 to C31 were isolated from the skin of the Australian scarab beetle Anti-trogus consanguineus and related species (Scheme 18.10) [37]. Also these allenes do not occur in enantiomerically pure form, but with enantiomeric excesses of86-89% ec. 

Allenic amino acids belong to the classical suicide substrates for the irreversible mechanism-based inhibition of enzymes [5], Among the different types of allenic substrates used for enzyme inhibition [128, 129], the deactivation of vitamin B6 (pyr-idoxal phosphate)-dependent decarboxylases by a-allenic a-amino acids plays an important role (Scheme 18.45). In analogy with the corresponding activity of other /3,y-unsaturated amino acids [102,130], it is assumed that the allenic amino acid 139 reacts with the decarboxylase 138 to furnish the imine 140, which is transformed into a Michael acceptor of type 141 by decarboxylation or deprotonation. Subsequent attack of a suitable nucleophilic group of the active site then leads to inhibition of the decarboxylase by irreversible formation of the adduct 142 [131,132]. 

Scheme 18.45 Postulated inhibition mechanism of pyridoxal phosphate-dependent decarboxylases by a-allenic a-amino acids.

In addition to a-allenic a-amino acids, the corresponding allenic derivatives of y-aminobutyric acid (GABA) have also been synthesized as potential inhibitors of the pyridoxal phosphate-dependent enzyme GABA-aminotransferase (Scheme 18.49) [131,138-142]. The synthesis of y-allenyl-GABA (152) and its methylated derivatives was accomplished through Crabbe reaction [131], aza-Cope rearrangement [138] and lactam allenylation [139], whereas the fluoroallene 153 was prepared by SN2 -reduc-tion of a propargylic chloride [141]. 

The rearrangements of 3-methylbut-l-ene oxides" and l,2-epoxybut-3-ene on lithium phosphate have been studied, and a detailed theoretical study of the rearrangement of allene oxide (342) to cyclopropanone (344), which shows that the transformation proceeds via an intermediate oxyallyl (343), has been presented. It has been shown that aldehydes, ketones, and cyclic ethers are all produced... 

J. W. Pettegrew, M. S. Keshavan, K. Panchalingam, S. Strychor, D. B. Kaplan, M. G. Tretta and M. Allen, Alterations in brain high-energy phosphate and membrane phospholipid metabolism in first episode, drug-naive schizophrenics. A pilot study of the dorsal prefrontal cortex by in vivo phosphorus 31 nuclear magnetic resonance spectroscopy. Arch. Gen. Psychiatry, 1991,48,563-568. 

There are many examples of U contamination in the environment, from U-mining sites to U production facilities (Bertsch et al. 1994 Abdelouas etal. 1999 Buck etal. 1996) and disposed U ordnance (Salbu et al. 2003). The major U-bearing phases found in soils at the former U-processing site at Femald in Ohio, USA, were Ca-meta-autunite, U-Ca-oxide, uraninite, and uranium (IV) meta-phosphate (U3PO4) (Buck et al. 1996). Bertsch et al. (1994) and Allen et al. (1994) used XAS to determine the oxidation state of U in bulk soil samples. The position of the U-Lm edge indicated that 80% of the U was hexavalent. 

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