Masked ketene

But what do we do if we want the product of a ketene [4 + 2] cycloaddition We must use a compound that is not a ketene but that can be transformed into a ketone afterwards—a masked ketene or... 

A successful method for preparation of an isoquinuclidene related to 203 based on Diels-Alder reaction between dihydropyridine 131 and a ketene equivalent was developed. This approach involving preparation and zwit-terionic amino-Claisen rearrangement of the isoquinuclidene 203 to form the enone 202 followed by subsequent E-ring elaboration and Wenkert cycliza-tion ultimately culminated in a formal synthesis of deserpidine (3) (Scheme 3.32) (44). Mariano and his coworkers found that Diels-Alder reaction of the N-trichloroethoxycarbonyl-l,2-dihydropyridine (209) and the masked ketene equivalent, 210, reacted to afford the isoquinuclidene 211 as an epimeric mixture of 7-cyano-7- acetoxy isomers. The a-cyanoacetate functionality in... 

The synthetic utility of the D-A reaction can be expanded by the use of dienophiles that contain masked functionality and are the synthetic equivalents of unreactive or inaccessible compounds. (See Section 13.1.2 for a more complete discussion of the concept of synthetic equivalents.) For example, a-chloroacrylonitrile shows satisfactory reactivity as a dienophile. The a-chloronitrile functionality in the adduct can be hydrolyzed to a carbonyl group. Thus, a-chloroacrylonitrile can function as the equivalent of ketene, CH2=C=0,63 which is not a suitable dienophile because it has a tendency to react with dienes by [2 + 2] cycloaddition, rather than the desired [4 + 2] fashion. 

Catalysis with Ti(IV) Complexes and Boronates. Carreira has documented the addition of dienolsilane 105 to a broad range of aldehydes [28], Enolization of the commercially available acetone-ketene adduct 104 with LDA, followed by quenching with chlorotrimethyl silane, gave 105 in 78% yield as a clear colorless liquid that can be conveniently purified by distillation (Eq. 8B2.24). The addition reactions are conducted at 23°C utilizing 5 mol % 72 to give adducts with up to 94% ee (Eq. 8B2.25, Table 8B2.13). The aldol adducts 106 were isolated fully protected as the corresponding 0-silyl ethers with the P-keto ester masked in the form of a dioxinone. 

The sulfonyl group has also been incorporated into the vinyl sulfoxide moiety in order to increase both its reactivity and selectivity. Thus, (S)-l-f-butylsul-fonyl-1 -p-tolylsulfonyl ethene 65 was used as a masked chiral ketene equivalent... 

Oxazolidine 134 is a masked trifluoroacetaldehyde imine that generates in situ the corresponding imine 135 under Lewis acid catalysis conditions. Lewis acid-catalyzed reactions of 134 with TMS-cyanide and ketene silylacetal provide adducts 136 in high yields with good diastereoselectivities (see Scheme 9.29) [56]. Conventional chemical transformation of 137 produces 3-amino-4,4,4-trifluorobutanoic acid 138. Similarly, tri-fluoroacetone oxazolidine 139 is used for the synthesis of 2-trifluoromethylalanine 142... 

Ketene generator (K-1), 529 Lithium-alkylamine reduction (L-1), 580 Manipulation of a noxious solid with rubber gloves, a powder funnel, and a dust mask (N-3), 717 Mel-Temp apparatus (D-3), 243 Mercury seal for stirrer (G-3), 416 Model of the complex Coi(CO)g CuHaC— CCsHt (D-1) for construction of cobalt atoms, see L. F. Fieser, J- Chem. Ed., 42, 408 (1965), 111 Molecular sieve crystals (M-2), 704... 

Another catalytic application of chiral ketene enolates to [4 + 2]-type cydizations was the discovery of their use in the diastereoselective and enantioselective syntheses of disubstituted thiazinone. Nelson and coworkers described the cyclocondensations of acid chlorides and a-amido sulfones as effective surrogates for asymmetric Mannich addition reactions in the presence of catalytic system composed of O-TM S quinine lc or O-TMS quinidine Id (20mol%), LiC104, and DIPEA. These reactions provided chiral Mannich adducts masked as cis-4,5 -disubstituted thiazinone heterocycles S. It was noteworthy that the in situ formation of enolizable N-thioacyl imine electrophiles, which could be trapped by the nucleophilic ketene enolates, was crucial to the success of this reaction. As summarized in Table 10.2, the cinchona-catalyzed ketene-N-thioacyl-imine cycloadditions were generally effective for a variety of alkyl-substituted ketenes and aliphatic imine electrophiles (>95%ee, >95%cis trans) [12]. 

A similar transformation can be carried out under milder conditions by taking advantage of silyl ketene acetals, a masked form of the earboxylate dianion. When epichlorohydrin 53 was treated with the ketene acetal 79 in the presence of titanium(IV) chloride, a regioseleetive epoxide ring opening occurs at the less substituted carbon. Treatment of the crude reaction mixture with catalytic p-toluenesulfonic acid promoted a lactonization to the y-butanolide 80 in high overall yield <04T8957>. 

Silyloxycyclopropanecarboxylates are masked homoenolate equivalents which can also add to dimethyl(methylene)iminium salts. In one of several examples reported by Reissig and Lorey, methyl 2-f-butyl-2-(trimethylsilyloxy)cyclopropanecarboxylate and triflate salt (33) react to produce methylaminomethyl-y-oxo ester (64 Scheme 14). The reactive intermediate has not been precisely determined but is most likely a ring-opened enolate (63) or its silyl ketene acetal derivative. The reaction can also be performed using the chloride iminium salt (31) in the presence of TiCU, but the reproducibility is poor due to reduced solubility. The products of these reactions are convenient precursors to a-methylene-8-lactones and acrylic acid derivatives. 

The masked 1,3-dipole, thiatriazole (135), undergoes intramolecular cycloaddition with subsequent elimination of molecular nitrogen, smoothly in ethanol at 75 C to give (136). These reactions were studied in detail with iso thiocyanates, isocyanates, ketenes, and electrophilic nitriles <92T7505>. 

Two pyrimidine monomers containing masked ketone functionalities were synthesized in this way. One of the monomers featured a free ketone group, while the other contained a ketene dithioacetal moiety. Reaction between the ketone and ketene dithioacetal groups then led to the formation of... 

Kocienski et al. have used a vinyl silane as a masked vinyl alcohol in the synthesis of the C26 to C32 fragment of rapamycin (Scheme 4.82) [77]. Ireland-Claisen rearrangement of the vinylsilane glycolate ester via the Z-silyl ketene acetal yielded the corresponding anti pentenoic acid with high diastereoselectivity. Oxidative cleavage of the furyl substituent and Tamao oxidation then afforded the allyhc alcohol. 

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