Acyl vinylogous

Scheme 11. Construction of the A/-acyl vinylogous urea and synthesis of natural palytoxin (1).

Photochemical equilibration of the 3 2 stereoisomeric mixture of N-acyl vinylogous ureas in DMF by irradiation at 300 nm in a Ray-onet reactor equipped with a stannous chloride filter solution at 37 °C for 4 h leads to a 6 1 mixture of trans-Aa b and c .v-Aa b paly-toxins. The total synthesis of palytoxin (1) is now complete. 

The total synthesis of palytoxin (1) is a landmark scientific achievement. It not only extended the frontiers of target-oriented synthesis in terms of the size and complexity of the molecules, but also led to new discoveries and developments in the areas of synthetic methodology and conformational analysis. Among the most useful synthetic developments to emerge from this synthesis include the refinement of the NiCh/CrC -mediated coupling reaction between iodoolefins and aldehydes, the improvements and modifications of Suzuki s palladium-catalyzed diene synthesis, and the synthesis of A-acyl vinylogous ureas. 

The photochemistry of 2-acyl-vinylogous amides has also been investigated by Tamura and coworkers, who reported that irradiation of 142 (R1 = CH2R R2 = H R1 = R2 = CH2R) through a quartz filter in methylene chloride led to the formation of the dealkylated product 143, albeit in modest yield (equation 19), both in the case of... 

A series of carbapenams have been generated using the sulfide-contraction reaction to construct the constituent -amino acid segment. The thiopyroglutamate derivative (143) was condensed with ethyl 2-bromoacetoacetate in the presence of sodium bicarbonate to afford the a-acyl vinylogous carbamate (144 Scheme 31). The use of sodium bicarbonate in the sulfide contraction was critical in this particular... 

Additional examples of the DMP-mediated oxidations of nitrogen substrates include the synthesis of 2-substituted benzothiazoles 903 via oxidative cyclization of thioanilides 902 [445] and the synthesis of imldes (e.g., 904), N-acyl vinylogous carbamates and ureas and nitriles by the oxidation of amides and amines with DMP (Scheme 3.362) [1292],... 

For the synthesis of A-acyl vinylogous carbamic acids and ureas see Han et al. [151]. 

Acyl carbonates (234), alkoxyquinones (235) as vinylogous esters, imino ethers (236), and diketene (237) react with ethyleneimine to give the corresponding acylated ethyleneimines. 

Dicarboxylic acid dichlorides with less than seven carbon atoms do not react to give tetraketones similar to 117, but instead undergo an intramolecular acylation (72) to give on hydrolysis the vinylogous acid anhydride (118), e.g., from succinyl chloride and the enamine (113). 

Alkylation of enamines with epoxides or acetoxybromoalkanes provided intermediates for cyclic enol ethers (668) and branched chain sugars were obtained by enamine alkylation (669). Sodium enolates of vinylogous amides underwent carbon and nitrogen methylation (570), while vicinal endiamines formed bis-quaternary amonium salts (647). Reactions of enamines with a cyclopropenyl cation gave alkylated imonium products (57/), and 2-benzylidene-3-methylbenzothiazoline was shown to undergo enamine alkylation and acylation (572). A cyclic enamine was alkylated with methylbromoacetate and the product reduced with sodium borohydride to the key intermediate in a synthesis of the quebrachamine skeleton (57i). 

Acylation of the vinylogous pyrrolidine amide of dimedone with acetic anhydride or acetyl chloride led (possibly indirectly) to the carbon acylation product, whereas trichloroacetyl chloride gave rise to products derived from attack of chloride at the oxygenated double bond position in an initial 0-acylation product (401-404). 

While esters do not usually react with enamines and can, in fact, be substituents in the azeotropic preparation of enamines, they can be used in acylation reactions when these involve intramolecular cyclizations. Such reactions have been observed even at room temperature when they lead to the formation of five- and six-membered vinylogous lactams (362). Applications to precursors for azasteroids (40S) and alkaloids (309,406) are key steps in synthetic sequences. 

The acylation of enamines derived from cyclic ketones, which can lead to the acyl ketone or ring expansion (692-694), was studied by NMR and mass spectroscopic analysis of the products (695,696). In a comparative study of the rates of diphenylketene addition to olefins, a pronounced activation was observed in enamines (697). Enamine N- and C-acylation products were obtained from reactions of Schiff s bases (698), vinylogous urethanes (699), cyanamides (699), amides (670,700), and 2-benzylidene-3-methylbenzothiazoline (672) with acid chlorides, anhydrides, and dithio-esters (699). 

The intermediacy of ketenes in some enamine acylation reactions using acid chlorides was described above (386,387). Direct addition of ketene to enamines was studied simultaneously by several groups (414-420). The initially formed aminocyclobutanone products could be isolated in some instances, depending on the substitution of the initial enamine. Opening to give either the acylated enamine or the alternative vinylogous amide was found to occur spontaneously or on heating, particularly in adducts derived from enamines with an olefinic proton. 

The reactions of vinylogous amides and vinylogous urethanes with excess ketene were found to give a-pyrones (421), which could also be obtained from further reactions of acylated enamines with ketene (383,421). 

One of the extensively investigated applications of enamines to heterocyclic syntheses is based on the bifunctional character of enamine acylation products. Thus the vinylogous ureas and thiorueas obtained from enamines and phenylisocyanate and phenylisothiocyanate (-433) have been converted to aminopyrazoles and thiouracils with hydrazine (566) and phenylisocyanate (567). 

The formation of five- (362) and six- (581) membered vinylogous lactams and pyrroles by intramolecular enamine acylations has been accomplished in some examples by formation of the cyclization precursor through an initial enamine exchange (362). 

Having retraced the remarkably efficient sequences of reactions which led to syntheses of key intermediates 14 and 15, we are now in a position to address their union and the completion of the synthesis of the spiroketal subunit (Scheme 6b). Regiocontrolled deprotonation of hydrazone 14 with lithium diisopropylamide (LDA), prepared from diisopropylamine and halide-free methyl-lithium in ether, furnishes a metalloenamine which undergoes smooth acylation when treated with A-methoxy-A-methylcarboxa-mide 15 to give the desired vinylogous amide 13 in 90% yield. It is instructive to take note of the spatial relationship between the... 

Diastereoselective synthesis of lactones.1 Acylation of the enolate (LDA) of the vinylogous urethane (1) results in a product (2) that on reduction with LiBH[CH(CH3)C2H5]3 (3) forms the anft-lactone (4) exclusively (equation I). This two-step synthesis of lactones is the equilvalent of an aldol condensation between... 

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