A-Allenic acids

Another cycloaddition, in which this time the silyl enol ether functions as a dienophile, is the SnCl4-catalysed addition of butadiene to (180 R = Me) giving (181). If R = H in the starting material a 4 + 3 reaction takes place, producing the seven-membered ring (182). Flash-vacuum thermolysis of P-keto-trimethylsilyl enol ethers has been used in a substituted furan synthesis, and the same process has been used to prepare a-allenic acids (183) from siloxy-dienes. ... 

Conjugated terminal fluoroenynes add water to the double bond at -5 C to form a-fluoro allemc acid fluondes. At 20 C, the allenic acid fluorides and concentrated sulfunc acid give y- and 8-laaones (equation 1) In the presence of concentrated sulfuric acid, conjugated nontermmal fluoroenynes add water to the triple bond and then to the double bond to form a-fl uoro-P-diketones and exocyclic a-fluoroenones [/] (equation 2). 

Figure 15-12 is a schematic illustration of a technique known as acid volatile sulfides/ simultaneously extracted metals analysis (AVS/SEM). Briefly, a strong acid is added to a sediment sample to release the sediment-associated sulfides, acid volatile sulfides, which are analyzed by a cold-acid purge-and-trap technique (e.g., Allen et ai, 1993). The assumption shown in Fig. 15-12 is that the sulfides are present in the sediments in the form of either FeS or MeS (a metal sulfide). In a parallel analysis, metals simultaneously released with the sulfides (the simultaneously extracted metals) are also quantified, for example, by graphite furnace atomic absorption spectrometry. Metals released during the acid attack are considered to be associated with the phases operationally defined as "exchangeable," "carbonate," "Fe and Mn oxides," "FeS," and "MeS."... 

Accordingly, the cyclopropenylidene anthrones 190/198 were converted by ferric chloride in hydroxylic solvents to the allene ketal 466, whose hydrolysis gives the allenic ketone 46 7288. The dioxolane 468 was obtained from the alkyl-substituted quinocyclopropene 190 in glycol and the ketone 467 in methanol. Apparently FeCl3 served not only as an oxidant, but also as a Lewis acid assisting solvent addition to C1 2 of the triafulvene. 

Air-stable palladium(O) catalyst, [(Cy3P)2Pd(H)(H20)]BF4, catalyses carbonylation of propargylic alcohols to generate dienoic acids and esters (equation 167)286. Since propar-gyl alcohols are obtained from carbonyl compounds by acetyhde addition reactions, this sequence constitutes a three-carbon homologation. a-Allenic alcohols are converted to tt-vinylacrylic acids under similar conditions (equation 168)287. 

Acetylene is sufficiently acidic to allow application of the gas-phase proton transfer equilibrium method described in equation l7. For ethylene, the equilibrium constant was determined from the kinetics of reaction in both directions with NH2-8. Since the acidity of ammonia is known accurately, that of ethylene can be determined. This method actually gives A f/ acid at the temperature of the measurement. Use of known entropies allows the calculation of A//ac d from AG = AH — TAS. The value of A//acij found for ethylene is 409.4 0.6 kcal mol 1. But hydrocarbons in general, and ethylene in particular, are so weakly acidic that such equilibria are generally not observable. From net proton transfers that are observed it is possible sometimes to put limits on the acidity range. Thus, ethylene is not deprotonated by hydroxide ion whereas allene and propene are9 consequently, ethylene is less acidic than water and allene and propene (undoubtedly the allylic proton) are more acidic. Unfortunately, the acidity of no other alkene is known as precisely as that of ethylene. 

If the alkenes and acetylenes that are subjected to the reaction mediated by 1 have a leaving group at an appropriate position, as already described in Eq. 9.16, the resulting titanacycles undergo an elimination (path A) as shown in Eq. 9.58 [36], As the resulting vinyltitaniums can be trapped by electrophiles such as aldehydes, this reaction can be viewed as an alternative to stoichiometric metallo-ene reactions via allylic lithium, magnesium, or zinc complexes (path B). Preparations of optically active N-heterocycles [103], which enabled the synthesis of (—)-a-kainic acid (Eq. 9.59) [104,105], of cross-conjugated trienes useful for the diene-transmissive Diels—Alder reaction [106], and of exocyclic bis(allene)s and cyclobutene derivatives [107] have all been reported based on this method. 

Extracts from Clavularia viridis and also many other coral species convert arachidonic acid to the prostanoid preclavulone-A via 8-(i )-hydroperoxy-5,l 1,14(Z), 9(A)-cicosatetraenoic acid. The carbocyclization is considered to occur from allene oxide and oxidopentadienyl cation intermediates. An enantioselective total synthesis of preclavulone-A was developed to assist the biosynthetic research. 

Scheme 2.31 Synthesis of a-allenic a-amino acid derivatives 90 by 1,6-cuprate addition. Boc = tert-butoxycarbonyl.

When the terminal alkynes 96 are treated with the trimethylsilylalkyne 97 in the presence of HfCl4 as a Lewis acid, the silylated vinylallenes 98 are produced in acceptable yields. In an intramolecular variant of this process, 100 was obtained from the diyne 99 [32]. Vinylallenes, incorporated into a cyclic framework and hence of restricted conformational mobility, are of interest for photochemical studies [33] and are among the photoproducts in ring-enlargement reactions of polycyclic allenes [34]. 

Allenic esters react with cydopentadiene to give the two [4+2]-cycloadducts endo-and exo-102 in high yields (Table 12.5) [28, 91]. The use of a Lewis acid lowers the reaction temperature and improves the yield and endo selectivity. 

Intramolecular [4 + 2]-cycloaddition reactions of allenic acids and esters proceeded in refluxing toluene to give bicyclic compounds with the exo-isomer predominating (Table 12.9) [120]. When a Lewis acid was used as a promoter, the [4 + 2]-cydoaddi-tion occurred at 0 °C and the endo-isomer was favored. 

The efficiency of chirality transfer of chiral 2,3-allenic acids can be much increased by switching the Jt-allylpalladium mechanism to a coordinative cycliza-tion-reductive elimination route (Scheme 16.25) [30]. 

A novel Ni(cod)2-catalyzed allene/alkene cyclization has been utilized in the synthesis of (-)-a-kainic acid (Scheme 16.88) [96], A stereocontrolled metallacycle would be generated via coordination of Ni(0) species to both an alkene of the enone and a proximal allenyl double bond followed by oxidative cyclization of the Ni(0) complex. The metallacycle would be transformed into the product through transmetallation of Me2Zn and ensuing reductive elimination. 

The reaction of an allene with an aryl- or vinylpalladium(II) species is a widely used way of forming a Jt-allyl complex. Subsequent nucleophilic attack on this intermediate gives the product and palladium(O) (Scheme 17.1). Oxidative addition of palladium ) to an aryl or vinyl halide closes the catalytic cycle that does not involve an overall oxidation. a-Allenyl acids 27, however, react with palladium(II) instead of with palladium(O) to afford cr-vinylpalladium(II) intermediates 28 (Scheme 17.12). These cr-complexes than react with either an allenyl ketone [11] or with another alle-nyl acid [12] to form 4-(3 -furanyl)butenolides 30 or -dibutenolides 32, respectively. 

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]. 

The first syntheses of a-allenic a-amino acids [131,133] took advantage of Steg-lich s [134] protocol for the oxazole-Claisen rearrangement of unsaturated N-ben-zoylamino acid esters (Scheme 18.46). Thus, treatment of the propargylic ester 143 with triphenylphosphine and tetrachlormethane furnished the allenic oxazolone 144, which was converted into the amino acid derivative 145 by methanolysis. Stepwise deprotection finally led to the allenic DOPA analog 146, which shows a much higher decarboxylase-inhibiting activity than a-vinyl- and a-ethynyl-DOPA [133],... 

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

Further variations of the Claisen rearrangement protocol were also utilized for the synthesis of allenic amino acid derivatives. Whereas the Ireland-Claisen rearrangement led to unsatisfactory results [133b], a number of variously substituted a-allenic a-amino acids were prepared by Kazmaier [135] by chelate-controlled Claisen rearrangement of ester enolates (Scheme 18.47). For example, deprotonation of the propargylic ester 147 with 2 equiv. of lithium diisopropylamide and transmetallation with zinc chloride furnished the chelate complex 148, which underwent a highly syn-stereoselective rearrangement to the amino acid derivative 149. 

Additional routes to a-allenic-a-amino acids were described more recently and utilize radical [136] or transition metal-catalyzed [137] allenylations, in addition to copper-promoted Michael additions [15b]. Thus, sterically demanding amino acid derivatives (e.g. 151) are accessible via a 1,6-addition reaction of lithium di-tert-butyl-cyanocuprate with acceptor-substituted enynes of type 150 (Scheme 18.48). 

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]. 

In many cases, allenes are used as creative solutions to problems encountered using more saturated counterparts. This is the situation in Chevliakov and Montgomery s approach to (-)-a-kainic acid (131) [31]. They reported a late-stage common intermediate 132 that could be taken on to both (-)-a-kainic acid (131) and (+)-a-allokainic acid (133) (Scheme 19.25). Intermediate 132 was to be obtained from enyne 134. Indeed, treatment of 134 to conditions developed in their laboratories afforded the desired carboannulation to give 135. However, this pyrrole could only be taken on to (+)-a-allokainic acid (133) owing to reduction of the olefin affording... 

In the same research group the cationic hydridopalladium complex [Pd(H)(H20)(PCy3)2] [BF4] has been shown to catalyze the hydroxycarbony-lation of triple bonds. As a representative example the dehydration occurring to give the dienoic acid is displayed in Scheme 3 [35]. The same cationic complex is able to activate a carbon oxygen bond in a-allenic alcohols to provide dienoic acids but with the COOH group in the branched position (Scheme 3) [36]. 

Hulme C, Ma L, Kumar NV, Krolikowski PH, Allen AC, Labaudiniere R (2000) Novel applications of resin bound a-amino acids for the synthesis of benzodiazepines (via Wang resin) and ketopiperazines (via hydroxymethyl resin). Tetrahedron Lett 41 1509-1514... 

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