Aldehyde-ketene

While diketene remains a very important synthetic precursor, there has been increasing interest in the chemistry of a-methylene-/3-lactones, 3-methylene-2-oxetanones. However, unlike diketene, which can be readily synthesized by the dimerization of aldehydic ketenes, there are few methods for the synthesis of a-methylene-/3-lactones in the literature. Recent strategies for the preparation of the compounds are discussed in Section 2.05.9.2. The kinetic resolution of racemates of alkyl-substituted a-methylene-/3-lactones has been carried out via a lipase-catalyzed transesterification reaction with benzyl alcohol (Equation 21) <1997TA833>. The most efficient lipase tested for this reaction was CAL-B (from Candida antarctica), which selectively transesterifies the (A)-lactone. At 51% conversion, the (R)-f3-lactone, (R)-74, and (A)-/3-hydroxy ester, (S)-75, were formed in very high enantio-selectivities (up to 99% ee). 

Lipstatin is a natural product that exhibits potent inhibitor activity of the pancreatic lipase, and therefore it is a potential lead for the development of antiobesity agents. P.J. Kocienski developed a synthesis for this compound that incorporates an aldehyde-ketene cycloaddition as the key step. The reaction between the aldehyde and silylketene derivative was carried out in the presence of EtAICIs that served as the Lewis acid activator. This transformation led to the formation of four diastereomers in 91% yield, but after desilylation, the desired stereoisomer could be isolated in 64% yield from the mixture. 

A very good example of the enormous benefits that DFT computations of IR spectra have brought to matrix-isolation studies giving the technique a veritable new lease of life in the study of organic reactive intermediates - has been provided by a study of the photolysis of a-pyrone (32) and its 4,6-dimethyl derivative (Breda et al.. Chapter 6). The photochemistry of a-pyrone was the subject of some of the earliest matrix-isolation studies of organic species, but the use of DFT computations has now allowed a virtually complete identification of the individual rotamers of the ring opened aldehyde-ketene (33)-(36). 

Acyl Halide-Aldehyde Cyclocondensation (AAC) Reactions. Treatment of ( -symmetric ligand bis(sulfonamide) A with 1 equiv of trimethylaluminum generated the triamine-Al complex (C), which catalyzed the aldehyde ketene [2 + 2] cyclad-dition. 

Some cyclic ketones undergo a-cleavage followed by intramolecular hydrogen abstraction to form unsaturated aldehydes. Usually abstraction of hydrogen takes place from 5-carbon. In addition to aldehyde, ketene is also formed involving another path in some cyclic ketones. The following examples [9, 10] are illustrative ... 

Next, the application of ketene silyl acetals was tried in the above aqueous reactions of silyl enolates with aldehydes. Ketene silyl acetals are useful ester enolate equivalents that can be isolated [27, 28], and the aldol-type reaction of ketene silyl acetals with aldehydes is among the most important and mildest methods of carbon-carbon bond formation [29]. Disappointingly, no aldol adduct was obtained when the ketene silyl acetal derived from methyl 2-methylpropionate (3) was employed as a representative ketene silyl acetal (structure 3 is shown later in Table 8.10). In aqueous media, hydrolysis of the ketene silyl acetal preceded the desired aldol reaction. 

Romo and coworkers were able to expand on their tetrahydrofuran synthesis by finding conditions for a three-component cascade sequence that resulted in 2,5-cis-tetrahydrofurans from keto-aldehydes, ketene acetals, and EtaSiH (Scheme 8) [11]. Optimal conditions required an excess of ZnCh and Et3SiH to give tetrahydrofurans in high diastereoselectivity. The two-step yields, with alkyl ketones, were in the 42-54 % range with the lowest yield of 13 % coming from the use of a benzylic ketone (R = Ph). The authors found it easier to isolate the products after reduction of the crude reaction mixture. 

Lewis acid promoted condensation of silyl ketene acetals (ester enolate equiv.) with aldehydes proceeds via "open" transition state to give anti aldols starting from either E- or Z- enolates. 

A more eflicient and general synthetic procedure is the Masamune reaction of aldehydes with boron enolates of chiral a-silyloxy ketones. A double asymmetric induction generates two new chiral centres with enantioselectivities > 99%. It is again explained by a chair-like six-centre transition state. The repulsive interactions of the bulky cyclohexyl group with the vinylic hydrogen and the boron ligands dictate the approach of the enolate to the aldehyde (S. Masamune, 1981 A). The fi-hydroxy-x-methyl ketones obtained are pure threo products (threo = threose- or threonine-like Fischer formula also termed syn" = planar zig-zag chain with substituents on one side), and the reaction has successfully been applied to macrolide syntheses (S. Masamune, 1981 B). Optically pure threo (= syn") 8-hydroxy-a-methyl carboxylic acids are obtained by desilylation and periodate oxidation (S. Masamune, 1981 A). Chiral 0-((S)-trans-2,5-dimethyl-l-borolanyl) ketene thioketals giving pure erythro (= anti ) diastereomers have also been developed by S. Masamune (1986). 

Silyl enol ethers are other ketone or aldehyde enolate equivalents and react with allyl carbonate to give allyl ketones or aldehydes 13,300. The transme-tallation of the 7r-allylpalladium methoxide, formed from allyl alkyl carbonate, with the silyl enol ether 464 forms the palladium enolate 465, which undergoes reductive elimination to afford the allyl ketone or aldehyde 466. For this reaction, neither fluoride anion nor a Lewis acid is necessary for the activation of silyl enol ethers. The reaction also proceed.s with metallic Pd supported on silica by a special method[301j. The ketene silyl acetal 467 derived from esters or lactones also reacts with allyl carbonates, affording allylated esters or lactones by using dppe as a ligand[302]... 

Aldehydes and Ketenes Text Nucleephilic Additien te the Carbenyl Greup... 

Simple olefins do not usually add well to ketenes except to ketoketenes and halogenated ketenes. Mild Lewis acids as well as bases often increase the rate of the cyclo addition. The cycloaddition of ketenes to acetylenes yields cyclobutenones. The cycloaddition of ketenes to aldehydes and ketones yields oxetanones. The reaction can also be base-cataly2ed if the reactant contains electron-poor carbonyl bonds. Optically active bases lead to chiral lactones (41—43). The dimerization of the ketene itself is the main competing reaction. This process precludes the parent compound ketene from many [2 + 2] cyclo additions. Intramolecular cycloaddition reactions of ketenes are known and have been reviewed (7). 

Ketene can also be added to trihalosubstituted aldehydes or ketones (12) to form 4-trihalomethyloxetanones. If this addition is performed in the presence of optically active bases such as quinine [130-95-0] chiral lactones are obtained (41,42). 

Carbonyl Compounds. Cychc ketals and acetals (dioxolanes) are produced from reaction of propylene oxide with ketones and aldehydes, respectively. Suitable catalysts iaclude stannic chloride, quaternary ammonium salts, glycol sulphites, and molybdenum acetyl acetonate or naphthenate (89—91). Lactones come from Ph4Sbl-cataly2ed reaction with ketenes (92). 

The reaction of ketene itself with tettaalkyl titanates followed by a ketone R R C=0 gives P-hydroxy-esters, R R C0HCH2C02R. Polyinsertion of ketene and aldehyde into the Ti—O bond leads to di-, tri-, and tetraesters, eg, H0CR R CH2C02CR R CH2C02R (200). 

The aromatic primary and secondary stibines are readily oxidized by air, but they are considerably more stable than their aHphatic counterparts. Diphenylstibine is a powerful reducing agent, reacting with many acids to Hberate hydrogen (79). It has also been used for the selective reduction of aldehydes and ketones to the corresponding alcohols (80). At low temperatures, diphenylstibine undergoes an addition reaction with ketene (81) ... 

In 1959 Carboni and Lindsay first reported the cycloaddition reaction between 1,2,4,5-tetrazines and alkynes or alkenes (59JA4342) and this reaction type has become a useful synthetic approach to pyridazines. In general, the reaction proceeds between 1,2,4,5-tetrazines with strongly electrophilic substituents at positions 3 and 6 (alkoxycarbonyl, carboxamido, trifluoromethyl, aryl, heteroaryl, etc.) and a variety of alkenes and alkynes, enol ethers, ketene acetals, enol esters, enamines (78HC(33)1073) or even with aldehydes and ketones (79JOC629). With alkenes 1,4-dihydropyridazines (172) are first formed, which in most cases are not isolated but are oxidized further to pyridazines (173). These are obtained directly from alkynes which are, however, less reactive in these cycloaddition reactions. In general, the overall reaction which is presented in Scheme 96 is strongly... 

In stepwise additions, ketenes are usually the nucleophilic component, so that such additions can be catalyzed by Lewis acids, such as the additions of trimethylsilylketenes to aldehydes, catalyzed by BF3 (Scheme 14) (79JOC733). However, the roles can be reversed, such as in the addition of chlorocyanoketene to benzaldehyde (79JA5435). 

The photochemical addition of azirines to the carbonyl group of aldehydes, ketones, and esters is also completely regiospecific (77H(6)143). Besides the formation of the isomeric oxazolines (50) from (39) and ethyl cyanoformate, there is also formed the imidazole (51) from addition to C=N in the expected regioselective manner. Thioesters lead to thiazolines (52), while isocyanates and ketenes produce heterocycles (53). 

The most efficient intramolecular secondary processes competing with the acyl-alkyl diradical recombination in five-membered and larger cyclic ketones are hydrogen shifts resulting in the disproportionation of the diradical to either ketenes or unsaturated aldehydes [cf. (5) (4) (6)]. 

Acyl-AlkyI Diradical Disproportionations to Ketenes and Unsaturated Aldehydes... 

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