DMAP scavenging

The coupling reaction with the amine usually requires an additional acid scavenger (often a base like triethylamine, DIEA, or NMM) to trap the formed HCl. The reaction can also be accelerated in the presence of a catalytic amount of DMAP (21), pyridine, or metallic zinc (22). 

A comparative study of the (3-menthyl (Men) ester of aspartic acid with other cycloalkyl esters showed that this ester is less susceptible to base-catalyzed aspartimide formation than the cPe, Cy, cHp, or cOc derivatives. Boc-Asp(OMen)-OH is prepared by esterification of Boc-Asp-OBzl with menth-l-ol by the DCC/DMAP procedure (see Section 2.2.2.5), followed by hydrogenolysis. The menthyl ester is stable to TFA treatment and is cleaved by HF or 1M TfOH/thioanisole in TFA within 60 min in an ice bath. For some syntheses, dependent on the peptide sequence, an excess (1.4 equiv) of Boc-Asp(OMen)-OSu has to be used, presumably owing to the bulkiness of the protected side chain. For the cleavage of the Men group, in some cases diphenyl sulfide (20 equiv) has to be added as a scavenger to the 1M TfOH/thioanisole/TFA mixture to facilitate its removal. However, acid-catalyzed aspartimide formation cannot be fully prevented. 

Recently, Djuric, Sauer and coworkers described the application of a silica-bound p-toluene sulfonic acid (Si-SCX) cartridge for scavenging of DMAP used in the synthesis of acylsulfonamides [51], Reactions were delivered to a packed SPE, allowing gravity elution to effectively remove the DMAP, providing the desired products in high purity by LC/MS (Scheme 8.38). 

Scheme 8.38 Scavenging of DMAP using a silica-bound p-toluene sulfonic acid (Si-SCX) cartridge.

Using these methods we more recently reported the synthesis of another isoquinoline alkaloid, (-)-norarmepavine (Scheme IS.IO). " This was accomplished by coupling the amine 26 with the ester 27 to give an intermediate amide (28). This was best done using focused microwave irradiation under solvent-free conditions. Next, 28 was converted to a Bischler-Napieralski product by using a combination of triflic anhydride and PS-DMAP. This was followed by scavenging with polymer-supported A(-(2-aminoelhyl)aminomethyl polystyrene to remove any excess anhydride. The intermediate triflate was then converted to the free base 29 with PS-BEMP (7), mentioned earlier. Finally, a proline-derived reductant... 

This reaction was initially reported by Einhorn and Hollandt in 1898. It is the acylation of alcohols using anhydride or acyl haUde in a tertiary amine such as pyridine. Therefore, this reaction is known as the Einhorn acylation, Einhorn reaction, and Deninger-Einhorn method." The function of tertiary amines in this reaction have been identified as both nucleophilic acylation catalyst and acid scavenger. The solid evidence of nucleophilic catalyst is to record the UV spectrum of the intermediate acetylpyridinium salt in water. Subsequently, a number of highly nucleophilic tertiary amines have been employed for the acylation of alcohols. These tertiary amines include triethylamine, 4-(dimethylamino)pyridine (DMAP), l,4-diazabicyclo[2.2.2]octane and... 

Intermolecular a-alkylation of aldehydes with 2-(bromomethyl)acrylates 18 were developed by the Palomo group [8]. The reaction was best catalyzed by diphenyl-prolinol TMS (6 )(Scheme 25.5) or dihexylprolinol triphenylsilyl ethers (Scheme 25.6), and required the presence of an acid scavenger, such as DABCO or DMAP. 

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