Amines acylation with acidic chains

The acylation of OF and NH functions with acidic chains is probably the most popular mode of acidic solubilization. Alcohols and phenols are converted not only into halfesters such as hemisuccinates, hemiglutarates, hemiphta-lates meto-benzenesulfonates ° but also into phosphates or even sulfates (Figure 38.5). All these derivatives can give water-soluble sodium or amine salts. Similar acylation possibilities exist for amines, but peptide-like derivatives are often preferred because the enzymatic regeneration of the parent molecule in vivo is easier. 

In the first step, a resin-bound secondary amine is acylated with bromoacetic acid, in the presence of N,N-diisopropylcarbodiimide. Acylation of secondary amines is difficult, especially when coupHng an amino acid with a bulky side chain. The sub-monomer method, on the other hand, is facilitated by the use of bromoacetic acid, which is a very reactive acylating agent Activated bromoacetic acid is bis-reactive, in that it acylates by reacting with a nucleophile at the carbonyl carbon, or it can alkylate by reacting with a nucleophile at the neighboring ah-phatic carbon. Because acylation is approximately 1000 times faster than alkylation, acylation is exclusively observed. 

Reaction of 4-oxo l/7-chromene-3-sulfonyl chloride with an excess of 1,3-diaminopropane believed to proceed through acylation/ring-opening sequence. Open-chain intermediate 175 undergoes intramolecular cyclization accompanied by elimination of amine and formic acid to afford 1,2,6-thiadiazocine ring system 176 (Scheme 46 <1994AP819>). 

HMBA resin, an aminomethyl polystyrene resin acylated with 4-(hydro-xymethyl)benzoic acid. It is completely resistant towards treatment with acids (even liquid HE), and enables on-resin side-chain deprotection. The highly versatile linker is cleaved by a variety of nucleophiles such as hydroxide ions (to give peptide acids), alcohols (to give esters), ammonia or amines (to give amides), hydrazine (to give peptide hydrazides), or UBH4 (to give peptide alcohols) [R. C. Sheppard, B. J. Williams, Int.J. Pept. Protein Res. 1982, 20, 451]. 

Scheme 13 shows additional examples of constructions of four-carbon chains functionalized appropriately for condensation to pyrroles. Af,Af-bis(trimethylsilyl)propargyl amines can be converted to ketones or esters by lithiation and acylation. These compounds then undergo cuprate addition. The resulting allenyl silyl ethers cyclize to pyrroles on treatment with acid <93T4603). 

Compounds 265 were readily converted [125] into the iV-nitrosoimidazolidinones 267 (Scheme 76). Reduction to the amine 268 was somewhat troublesome since N-N bond cleavage occured very rapidly. However, with small quantities of zinc and very short reaction times, it was possible to obtain a mixture containing the amine 268, 267 and 265. Direct acylation with antibiotic side-chains yielded imidazolidinones 269. Deprotection of the PMB ester with formic acid gave the acids 269 (R = H). None of the compounds shows any antibiotic activity in vitro. 

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