DMAP catalysis

Introducing the Tau residue into a peptide according to the first approach demands protection of the amino group, usually in the form of a Z-derivative and turning the sulfonic acid into sulfonyl chloride. Synthesis of (j-su Ifonamidopeptides via an iterative process, both in solution and in the solid phase, has been described.11201 Chiral methylene sulfinamide peptides can be synthesized both in solution and in the solid phase using the sulfonyl chlorides derived from enantiomerically pure 2-substituted taurines under mild coupling conditions (DMAP catalysis and excess methyl trimethylsilyl dimethylketene acetal as a proton trap).11261... 

Slow couplings (48 h) to the aromatic amino group of Abz-peptides are reported and the use of DMAP catalysis results in racemizationJ111 Fmoc amino acid chlorides can be coupled in good yield without any racemizationJ11 Similarly, Fmoc-Gly-Cl can be coupled to o-, m-,... 

Decarboxylation. Acid chlorides react with the sodium salt of 1 (DMAP catalysis) to form esters (2) derived from N-hydroxypyridine-2-thione. These esters undergo radical chain decarboxylation to the noralkane on heating with tri-n-butyltin hydride (equation I). ... 

A more complex hydroxy acid is lactonized in a synthesis of (9S)-9-dihydroerythronolide A, albeit in low yield (equation 128). By acid treatment (356) is deprotected to give the desired target molecule. The presence of jp -centers in the seco-acid obviously facilitates lactonization, as shown by the preparation of the mycinolide V precursor (357 equation 129). A mixed carbonate is used in the synthesis of the tylonolide precursor (358 equation 130). ° In general, DMAP catalysis is helpful in the ring closing step in most cases. 

CF3C02Et, EtjN, CH3OH, 25°C, 15-45h, 75-95% yield. A polymeric version of this approach has also been developed. This reagent selectively protects a primary amine in the presence of a secondary amine. With DMAP catalysis primary anilines are efficiently acylated (75-98% yield). ... 

DMAP acts as an efficient acyl transfer agent, so that alcohols resistant to acetylation hy Acetic Anhydride-Pyridine usually react well in the presence of DMAP. Sterically hindered phenols can be converted into salicylaldehydes via a benzofurandione prepared by DMAP catalysis (eq 2). ... 

DMAP Catalysis to Form Key Substructures. DMAP has been used as a catalyst in the Morita-Baylis-HiUinan (MBH) reaction. Conjugated nitroalkenes can be reacted with an amine base to form a zwitterionic species that can add to many types of ketones and aldehydes. Remarkably, only DMAP and imidazole were able to effectively catalyze this reaction, likely due to their small size and ability to stabilize the intermediate. In another example, a unique catalyst system involving 1 1 1 DMAP TMEDA Mgl2 (each in 10 mol %) allowed the MBH reaction to proceed in fairly high yields between aldehydes and a , -unsaturated ketones, esters, or a thioester. ... 

Cycloadditions Involving DMAP Catalysis. Bicyclic lactones containing a spirooxindole can be formed through a DMAP-catalyzed [4 + 2] Diels-Alder cycloaddition of pyrones and indole derivatives, resulting in both endo and exo products in approximately 2 1, 1 1, or 1 2 ratios in good yields. DMAP is proposed to abstract the proton on the pyrone, causing the initial cyclization to occur (eq 16). ... 

Muramatsu W, Kawabata T (2007) Regioselective acylation of 6-O-protected octyl p-d-glucopyranosides by DMAP catalysis. Tetrahedron Lett 48 5031-5033... 

Table 3. Comparison of Polymers Formed Using Et3N vs DMAP Catalysis.

The r-butoxycarbonylation of the sodium salt of thiourea does not require DMAP catalysis. The resulting N,N -bis t-butoxycarbonyl)thiourea reacts with amines to give bis(t-butoxycarbonyl)guanidines (eq 25). ... 

Pyridine is more nucleophilic than an alcohol toward the carbonyl center of an acyl chloride. The product that results, an acylpyridinium ion, is, in turn, more reactive toward an alcohol than the original acyl chloride. The conditions required for nucleophilic catalysis therefore exist, and acylation of the alcohol by acyl chloride is faster in the presence of pyridine than in its absence. Among the evidence that supports this mechanism is spectroscopic observation of the acetylpyridinium ion. An even more effective catalyst is 4-dimeftiyIaminopyridine (DMAP), which functions in the same wsy but is more reactive because of the electron-donating dimethylamino substituent. ... 

The combination of carboxyl activation by DCCI and catalysis by DMAP provides a useful method for in situ activation of carboxylic acids for reaction with alcohols. The reaction proceeds at room temperature.119... 

In 1967, (3) it was discovered that DMAP catalyzes the benzoylation of m-chloroaniline 10 times faster than pyridine. This enormous increase in reaction rate is unmatched by any other nucleophilic acylation catalyst (3. It was shown that the catalytic action of DMAP and PPY is not primarily due to their larger pKa s with respect to pyridine, but is a result of enhanced nucleophilic catalysis. 

In order to determine the efficiency of the polymers as reagents in nucleophilic catalysis, it was decided to study the rate of quaternization with benzyl chloride. Table I shows the second-order-rate constants for the benzylation reaction in ethanol. Comparison with DMAP indicates that poly(butadiene-co-pyrrolidinopyridine) is the most reactive of all the polymers examined and is even more reactive than the monomeric model. This enhanced reactivity is probably due to the enhanced hydrophobicity of the polymer chain in the vicinity of the reactive sites. 

Primary alcohols are selectively silylated by 1 and N(C,H5)j in CH,CU at 25°. Silylation of secondary alcohols is effected by catalysis with DMAP, and even tertiary alcohols can be silylated by 1 in DMF catalyzed by DMAP. 

Oxygen-based nucleophiles can also be employed for the catalysis of acyl transfer. For example, pyridine-A-oxide derivatives such as 4-DMAP-A-oxide have long been known as such catalysts although, interestingly, these catalophores are reportedly particularly efficient at mediating sulfonyl and phosphoryl transfer [229-230]. 

The Glaxo synthesis of zanamivir (2) started with the esterification of commercially available A-acetyl-neuraminic acid (88) with methanolic HCl to give the methyl ester as shown in Scheme 7.14 (Chandler and Weir, 1993 Chandler et ah, 1995 Patel, 1994 Weir et al., 1994). Global acetylation of all the hydroxyl groups with acetic anhydride in pyridine with catalysis by 4-(dimethylamino)pyridine (DMAP) led to the penta-acetoxy compound 89. Treatment of 89 with trimethylsilyl triflate in ethyl acetate at 52°C introduced the oxazoline as well as the 2,3-double bond to provide 86. Addition of trimethysilyl azide to the activated allylic oxazoline group led to the stereoselective introduction of azide at the C-4 position to afford 83 as in Scheme 7.13. 

Butenolides. The fmnal steps in a synthesis of jolkinolide E (4) involve formation of the butenolide ring by reaction of the a-hydroxy ketone 1 with the mixed anhydride of trichloroacetic acid amd a-(diethylphosphono)propionic acid (2) with catalysis by DMAP. The ester 3 undergoes an intramolecular Wittig-Horner reaction in the presence of NaH to give 4. ... 

The combination of carboxyl activation by a carbodiimide and catalysis by DMAP provides a useful method for in situ activation of carboxylic acids for reaction with alcohols.10 The reaction proceeds at room temperature. Carbodiimides are widely applied in the synthesis of polypeptides from amino acids. The proposed mechanism for this esterification reaction involves activation of the acid via isourea 28 followed by reaction with another acid molecule to form anhydride... 

You remember, of course, that esters can be made from carboxylic acids and alcohols under acid catalysis, so you might expect them to use this type of method. On a small scale, it s usually better to convert the acid to an acyl chloride before coupling with an alcohol, using pyridine (or DMAP + Et3N) as a base this type of reaction might have been a reasonable choice too. 

Dimethylaminopyridine (DMAP). Use of 4-dialkylaminopyridines for catalysis of acylation and alkylation has been reviewed (133 references). ... 

Use of DMAP to accelerate coupling reactions is another cause of racemization. DMAP has been most often used to accelerate coupling of the first protected annino acid to hydroxymethyl resins without catalysis, this reaction is often unacceptably slow. Use of an equivalent amount of DMAP in this situation can cause extensive racennization, especially of phenylalanine only a catalytic amount of the DMAP additive should be used.h l As a precautionary measure, optical purity of purchased amino acid derivatives should be ascertained before use by measuring their optical rotation. Optical purity of naturally occurring L-amino acids should not be a problem, since they are generally prepared biologically. However, o-amino acids are prepared chemically by resolution of racemic mixtures, and there are examples of suppliers mistakes in optical purity. 

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