Trityl penicillin

The bulky triphenylmethyl group has been used to protect a variety of amines such as amino acids, penicillins, and cephalosporins. Esters of N-trityl a-amino acids are shielded from hydrolysis and require forcing conditions for cleavage. The a-proton s also shielded from deprotonation, which means that esters elsewhere in the molecule can be selectively deprotonated. 

In subsequent studies,22 Sheehan et al. demonstrated that the action of diisopropylcarbodiimide on penicilloate 24, prepared by protection of the free primary amino group in 23 with trityl chloride (see Scheme 6b), results in the formation of the desired -lactam 25 in a very respectable yield of 67 %. In this most successful transformation, the competing azlactonization reaction is prevented by the use of a trityl group (Ph3C) to protect the C-6 amino function. Hydrogenolysis of the benzyl ester function in 25, followed by removal of the trityl protecting group with dilute aqueous HC1, furnishes 6-aminopenicillanic acid (26), a versatile intermediate for the synthesis of natural and unnatural penicillins. 

Formation of p-Lactams, Peptides and Oligonucleotides. The intramolecular cyclization technology to form /8-lactams using DCC in the condensation reaction was used by Sheehan and Henery-Logan in the total synthesis of penicilline in 1957. They also found that N-trityl penicilloates are cyclized with diisopropylcarbodiimides. Other p-lactames, such as cephalothin lactone and (—)-thienamicin are similarly constructed. The latter synthesis proceeds in a stereospecific manner and DCC is used in combination with triethylamine to give a 93 % yield of the /3-lactam 661. 

The trityl group has proved particularly valuable for the protection of a-amino acids in peptide [186, 187] and penicillin [188] synthesis since its bulk shields not only the amino function but to some extent the groups which are a. to it... 

In addition to the S—C-2 bond cleavages described thus far, both S—C-5 and C-3—N bond cleavage have been explored in penicillin degradation. Chlorinolysis of penicillin effects S—C-5 cleavage, affording the 4-chloro-2-azetidinone (105 t,y), from which the cephalosporin disulphide (106 f,z) was prepared (Scheme 4). The structure and stereochemistry of (106) were determined by X-ray techniques. Chlorinolysis of an N-trityl-anhydropeni-cillintoluene-p-sulphonate (107 g) gave, after hydrolysis, a sulphur-free 2-azetidinone (108 z, R = NHi), which cyclized to the oxazoline (109) on reaction with chloroformate esters. Allylic bromination of (108 f, y) afforded a monobromide (110), from which the azacephem (111 f, y) was obtained by... 

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