Substrate enamide amides

A wide range of substrates have been reported to proceed successfully to conjugate addition products with the monobasic forms of phosphorous acids, including esters,371415416 amides,417-419 nitriles,415 420 acid chlorides,421 enamides,375 and nitro compounds.422-424... 

The low ee-values obtained with simple unsaturated acids as compared to the enamides of dehydroamino acid derivatives show that the oxygen atoms of the amide is a key to complex formation with the metal center. Knowles also proposed a quadrant model that has been adapted for many reactions [5, 22]. The mechanism of the reaction has been investigated, and it is known that the addition of the substrate to the metal is regioselective and that competing catalytic cycles can occur [5, 10, 22, 25, 27, 30-46]. 

Rhodium-BisP and -MiniPHOS catalysts are capable of high enantioselective reductions of dehydroamino acids in 96-99.9% ee.109 A variety of aryl enamides give optically active amides with 96-99% ee with the exception of ort/jo-substituted substrates.111 Despite the high enantio-selectivity, the rate of reaction in this transformation is slow. Rhodium-BisP and -MiniPHOS catalysts perform excellently in the asymmetric reduction of ( >P-(acylamino)acrylates to the corresponding protected-P-amino esters in 95-99% ee.112 Within the family of BisP and MiniPHOS, the ligands that contain t-Bu groups were found to be the most effective in a variety of asymmetric hydrogenations. 

Upon confronting the asymmetric carbon-nitrogen hydrogenation problem, we noted that, like a-enamides, A-acylhydrazones 32 possess an amide-like carbonyl oxygen that is similarly situated three atoms from the double bond to be reduced, and which could allow for chelation of the substrate to the catalytic Rh center. 

Enamides are successful substrates on account of their closely defined coordination geometry, since both the olefin and amide carbonyl group are available to bind at c/s-related sites. This must be necessary during the rate-determining stage, for species lacking the amide group (or a closely related functionality similarly sited) react much more slowly and with lower stereoselectivity. 

Enamide hydroformylation was evaluated as a new route to an l-DOPA precursor (Scheme 4.73). The required prochiral substrate was derived by a three-step sequence starting from vanillin. The asymmetric catalysis was conducted in a 0.15 g scale at 10 bar. Noteworthy, the chiral aldehyde obtained did not racemize during reduction with NaBH at low temperatures. Moreover, the authors claimed that also oxidation of the chiral a-formyl amides is possible without epimerization, since such compounds are stable even at temperatures of 100 °C [45]. However,... 

An interesting approach to the preparation of enamides entailed a formal vinyl transfer from vinyl ethers (Scheme 3.122) [130]. The reaction was catalyzed by palladium complexes bearing a phenanthroline derivative as the solubilizing/stabilizing ligand. Several secondary amides including cyclic and acyclic substrates were screened, and... 

One of the standard methods for preparing enantiomerically pure compounds is the enantioselective hydrogenation of olefins, a,/3-unsaturated amino acids (esters, amides), a,/3-unsaturated carboxylic acid esters, enol esters, enamides, /3- and y-keto esters etc. catalyzed by chiral cationic rhodium, ruthenium and iridium complexes ". In isotope chemistry, it has only been exploited for the synthesis of e.p. natural and nonnatural H-, C-, C-, and F-labeled a-amino acids and small peptides from TV-protected a-(acylamino)acrylates or cinnamates and unsaturated peptides, respectively (Figure 11.9). This methodology has seen only hmited use, perhaps because of perceived radiation safety issues with the use of hydrogenation procedures on radioactive substrates. Also, versatile alternatives are available, including enantioselective metal hydride/tritide reductions, chiral auxiliary-controlled and biochemical procedures (see this chapter. Sections 11.2.2 and 11.3 and Chapter 12). 

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