Synthesis uncatalyzed reactions

W. R. Roush in Allylorganometallics The Uncatalyzed Reaction of Allylorganometallics with C = X Electrophiles in Comprehensive Organic Synthesis, C. H. Heathcock, Ed., Vol. 2, Perga-mon. Oxford 1991. 

The aqueous aza-Diels-Alder reaction of an aldehyde and an amine hydrochloride with a diene is catalyzed by lanthanide(III) trifluoromethane sulfonates (Ln(OTf)3, triflates [24]). Some examples are reported in Schemes 6.12 and 6.13. With respect to uncatalyzed reactions, the lanthanide catalyst allows milder reaction conditions, increases the reaction yield and does not affect the diaster-eoselectivity of the reaction, but influences the regiochemistry as in the cycloaddition of 25 with 1,3-dimethyl-1,3-butadiene (Schemes 6.10 and 6.12). These results have been applied [24b-d] to the synthesis of azasugars (Scheme 6.14). 

While in the uncatalyzed reaction of l-ethyleneimino-2-hydroxy-3-butene in THF, refluxing for four hours was necessary to produce 70% of the ester, in the presence of NaNH2 a 90% yield was achieved at room temperature after only five minutes.[13 14] An especially interesting example of the use of the imidazolide method for ester synthesis is illustrated by the total synthesis of actinomycin C3.[15],[16] Working with N-protected L-TV-methylvaline and CDI, esterification of the hydroxyl group on the threonine residue proved successful whereas this could not be accomplished by any of the conventional methods. 

In contrast to thermal uncatalyzed reactions of /V-acylsulfinylamines with aryl isocyanates which give rise to azoarenes,188 the cobalt or iron carbonyl-catalyzed process gives additionally 3,5-dioxo-l,2,4-triphenyl-1,2,4-triazolidine (Scheme 124).189 The only possible restriction on this simple urazole synthesis would be the expectation that the substituents on the reactants must be the same to prohibit exchange. 

It has since been shown that the cycloaddition is catalyzed by transition metal salts (78JOC667). Although the yields are generally lower than irr the uncatalyzed reaction, this is outweighed by the advantages of shorter reaction times and a lower cyclization temperature. Illustrative examples of the formation of 2-alkoxy-3,4-dihydro-2//-pyrans are presented in Table 3, which includes a comparison of the two methods of synthesis. 

Interestingly, the uncatalyzed reaction takes place at 80°C and is a rare case of a thermal [2+2] cycloaddition. However, the catalytic process offers advantages in terms of higher cis/trans ratios. It should be noted that the turns isomer can be isomerized into the thermodynamically favored cis product by extended heating to 80°C in acetonitrile. The utility of the products was demonstrated by the synthesis of amino acid 20 (Scheme 2.6). 

Menger et al. (33) also reported a similar polymeric library to identify catalysts for the hydrolysis of a phosphate ester (102), where a 30,000-fold increase versus the uncatalyzed reaction rate was obtained. Miller and Ford (103) reported the synthesis of a 32-member discrete polymer library based on anion-exchange latexes and its screening for the alkaline hydrolysis of p-nitrophenylalkane carboxylates. The reported efforts may represent just the tip of an iceberg in terms of opportunities granted by polymeric catalysts, and an expansion of knowledge derived from further efforts is to be expected in the near future. 

An important aspect of the metal catalyzed hydroboration reaction is its ability to selectively reduce certain functionalities within a molecule. For instance, a key step in the synthesis of a tripeptide derivative containing the Phe-Arg hydroxyethy-lene dipeptide iosostere is the selective rhodium-catalyzed hydroboration of a lactone. The use of disiamylborane, 9-H-BBN, dicyclohexylborane, and (.9)-alpmeborane, however, gave only low to variable yields of the alcohol due to competitive reduction of the y-lactone to the hemiacetal (equation 8). In another example, hydroboration of the diene illustrated in equation (9) with HBcat and RhCl(PPh3)3 gave exclusive formation of the terminal alcohol derived from reaction of the less substituted alkene. Interestingly, uncatalyzed reactions failed to hydroborate this substrate selectively. ... 

Although yields are not always high, the introduction of acid-catalyzed reactions has generally extended the scope of this route.A typical example, which mirrors the cyclobutadiene addition, is provided by the synthesis of 3,3-dimethyl-2,4-diphenyl-e rfo-tricyclo[3.3.0.0 > ]oct-6-ene (12). ° Further examples of both catalyzed and uncatalyzed reactions are given in Table 8. 

Chemistry A reliable synthesis of CS was reported in 1928 by Corson and Stoughton. The procedure involved condensation of a starting aldehyde with malononitiile and was catalyzed with base. Even uncatalyzed reactions eventually were successful, although significantly slower. 

In an attempt to avoid problems with the phosphate groups from the CoA moiety, the penultimate intermediate in the synthesis of the bisubstrate inhibitor, A-bromoacetyltryptamine, was tested as a possible affinity label inhibitor or as a substrate for the in situ enzymatic synthesis of the bisubstrate inhibitor through an acylation mechanism. N-Bromoacetyltryptamine did act as an inhibitor of the enzyme, but inhibition could be reversed by dialysis suggesting that the inhibition was not due to a covalent adduct. It was shown that the enzyme catalyzed the acylation of A-bromoacetyltryptamine by CoASH to form compound 6a with a rate enhancement of 3.3 x 10 relative to the uncatalyzed reaction. Ultimately, it was shown that the acylation reaction occurs at the same active site as the acetylation activity. A closer inspection of the kinetics of inhibition by tbe bisubstrate analog 6a resulted in the observation of slow-onset inhibition over the first few minutes of the reaction with a A) value of 84nmol 1 . Owing to its neutrality, A-bromoacetyltryptamine was tested as an inhibitor in vivo. The analog precursor was shown to inhibit melatonin production in norepinephrine-stimulated pinealocytes in a concentration-dependent manner and with low cytotoxicity. 

Catalytic antibodies - These interesting molecules are antibodies with a very specific binding site to the transition state of an enzymatic reaction. The resulting molecules, called abzymes, act like antibodies. In some cases, abzymes can speed up reaction rates as much as lO -fold over the uncatalyzed reaction. The stereospecificity of enzymes (including abzymes) may provide a tremendous aid to the synthesis of stereospecific compounds in organic chemistry. 

Reports of uncatalyzed reactions in liquid polymers continue to appear occasionally. For a recent example, a synthesis of homoallylic amines by a Barbier-type reaction in dried PPG [Eq. (1)] was recently reported by Andrews et al. [47]. Indium powder was used in stoichiometric quantities. The yields were comparable to those in VOC solvents. The products were isolated by vacuum distillation from the polymer, which was subsequently washed by water and dried by MgS04 before reuse. 

---