A-Acyl ureas

In its original form the DCC procedure for peptide synthesis has one basic disadvantage, which you have already learned about as side reaction B —> E in Figure 6.15 When acyl isoureas are exposed to a poor nucleophile, they rearrange to form unreactive A-acyl ureas. These mismatched reactivities characterize the situation encountered in the peptide syntheses in Figures 6.31 and 6.32. The example given in Figure 6.31 uses 0,0-di-fert-butylserine as a... 

Reactions are carried out at room temperature in dichloromethane which is an excellent swelling agent for polystyrene supports. Dimethylformamide can be added to increase the solubility of some amino acid derivatives e.g. Boc-Arg(N02), Boc-Arg(Tos), Boc-His(Tos), Boc-Trp, and Boc-Asn(Xan), but it increases the rate of undesirable rearrangement of O-acylisourea to A-acylurea which is not reactive.P The principal limitations in using car-bodiimides are racemization, rearrangement of O-acylisourea to A-acylurea 5, and dehydration of Asn and Gin side-chain carboxamide groups. Fortunately this dehydration problem is completely avoided by the use of additives such as A-hydroxysuccinimide (HOSu) and 1,2,3-benzotriazol-l-ol (HOBt). Additives also reduce racemization and A-acyl-urea formation. Other carbodiimides have also been used in SPPS such as or N-tert-... 

RCO2H, R OH, DCC/DMAP, EtjO, 25°C, l-24h, 70-95% yield. This method is suitable for a large variety of hindered and unhindered acids and alcohols. The use of Sc(OTf)3 as a cocatalyst improves the esterification of 3° alcohols. Carboxylic acids that can form ketenes with DCC react preferentially with aliphatic alcohols in the presence of phenols whereas those that do not show the opposite selectivity. In some sterically congested situations the 0-acyl urea will migrate to an unreactive A-acyl urea in competition with esterification. Carbodi-imide I was developed to make the urea by-product water soluble and thus easily washed out. Isoureas are prepared from a carbodiimide and an alcohol which upon reaction with a carboxylic acid give esters in excellent yield. A polymer supported version of this process has been developed. This process has been reviewed. Note that DCC is a potent skin irritant in some individuals. 

The application of additives was investigated in order to suppress or diminish side reactions (A-acyl urea formation and racemization). Al-Hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HoBt), and ethyl l-hydroxy-lH-l,2,3-triazole-4-carboxylate are potential additives in the DCC-based coupling synthesis. Solid-phase peptide synthesis (SPPS) is a variant of the linear (stepwise) coupling of amino acids in the C N direction using two major protection groups Boc/Bzl (iert-butoxycarbonyl/benzyl) and Fmoc/tBu (/9-fluorenylmethoxycarbonyl/ieri-butyl). The synthetic scheme for peptides on a polymer (Atherton and Sheppard, 1989 Fields, 1997) is illustrated in Figure 8.1. 

Then N-Boc-O-benzylserine is coupled to the free amino group with DCC. This concludes one cycle (N° -deprotection, neutralization, coupling) in solid-phase synthesis. All three steps can be driven to very high total yields (< 99.5%) since excesses of Boc-amino acids and DCC (about fourfold) in CHjClj can be used and since side-reactions which lead to soluble products do not lower the yield of condensation product. One side-reaction in DCC-promoted condensations leads to N-acylated ureas. These products will remain in solution and not reaa with the polymer-bound amine. At the end of the reaction time, the polymer is filtered off and washed. The times consumed for 99% completion of condensation vary from 5 min for small amino acids to several hours for a bulky amino acid, e.g. Boc-Ile, with other bulky amino acids on a resin. A new cycle can begin without any workup problems (R.B. Merrifield, 1969 B.W. Erickson, 1976 M. Bodanszky, 1976). 

Phosgenation. Reaction of phosgene with arylamines to form ureas, and with reactive aryl species to form substituted hen zophen ones, are special cases of acylation. They are dealt with separately siace a more specialized plant is required than for other acylations. Urea formation takes place readily with water-soluble arylamines by simply passiag phosgeae through a slightly alkaline solutioa. An important example is carbonyl-J-acid from J-acid. 

Schollenberger added 2% of a polycarbodiimide additive to the same poly(tetra-methylene adipate) urethane with the high level of acid (AN = 3.66). After 9 weeks of 70°C water immersion, the urethane was reported to retain 84% of its original strength. Carbodiimides react quickly with residual acid to form an acyl urea, removing the acid catalysis contributing to the hydrolysis. New carbodiimides have been developed to prevent hydrolysis of polyester thermoplastics. Carbodiimides are also reported to react with residual water, which may contribute to hydrolysis when the urethane is exposed to high temperatures in an extruder [90]. 

Scheme 11. Construction of the A/-acyl vinylogous urea and synthesis of natural palytoxin (1).

The total synthesis of palytoxin (1) is a landmark scientific achievement. It not only extended the frontiers of target-oriented synthesis in terms of the size and complexity of the molecules, but also led to new discoveries and developments in the areas of synthetic methodology and conformational analysis. Among the most useful synthetic developments to emerge from this synthesis include the refinement of the NiCh/CrC -mediated coupling reaction between iodoolefins and aldehydes, the improvements and modifications of Suzuki s palladium-catalyzed diene synthesis, and the synthesis of A-acyl vinylogous ureas. 

Poor nucleophiles react with acyl isoureas B so slowly that the latter start to decompose. In some sense they acylate themselves. The N atom designated with the positional number 3 intramolecularly substitutes the O-bound leaving group that is attached to the carboxyl carbon Cl. A four-membered cyclic tetrahedral intermediate is formed. When the Cl -Ol bond in this intermediate opens up, the N-acyl urea E is produced. Because compound E is an amide derivative it is no longer an acylating agent (cf. Section 6.2). 

When the less hindered 2,4-tolylene diisocyanate is reacted with a phospholene oxide catalyst linear oligomeric carbodiimides are obtained which have been reacted with a variety of nucleophiles to give poly(ureas), poly(acyl ureas), poly(formamidines) and poly-(guanidines) by addition across the N=C=N group. Also, reaction of the oligomeric carbodiimides with acrylic or methacrylic acid affords linear polymers, which can be further polymerized by free-radical type processes. Also, reaction of the carbodiimide oligomers obtained from 2,4-TDI with adipic acid in DMF produces a polyureid. ... 

Both straight-chain and branched acyl halides successfully acylate urea to the mono- and di-acyl derivatives. Yields of 75 85% of either derivative may be obtained. A review of four additional methods for the preparation of acylureas has been made. ... 

These esters (see Tables 10 and 11) are obtained by the usual procedure. The benzotriazolyl esters are rarely isolated because they are too reactive for routine use but are often prepared and subjected to aminolysis immediately.The latter is the case in solid-phase synthesis where DIG is used in preference to DCC because the urea is soluble.P l Benzotriazolyl esters possess the unique feature of existing in two forms in solution, ester 46 being in equilibrium with A -acylated A -oxide 47 (Scheme 9), readily distinguishable by their absorbances in the infrared spectrum at 1827 and 1725 cm respectively.The two forms are stable, the form... 

The yields in the former reactions were generally higher. Intramolecular cyclization of o-unsubstituted aniline derivatives to give quinazolin-2(lH)-ones had never been reported. Recently, however, V-phenyl-V -acyl ureas (21) lacking in ortho-substituents in the benzene ring were cyclized to 4-substituted quinazolin-2(l//)-ones in polyphosphoric acid at 90°-130°C. 4-Aminoquinazolin-2(l//)-ones were prepared by a Chichibabin reaction (NaNHj) from quinazolin-2(l//)-ones. ... 

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