A-Acylsulfonamides

After the peptide-chain assembly was complete, the A-acylsulfonamide-resin (8 pmol) was washed with NMP, and then NMP (2.2 mL), DIPEA (82 pL, 0.48 mmol), and ICHjCN (174 pL, 2.4 mmol), previously filtered through an alumina basic plug, were added to a final concentration of 1M. After stirring on a rotary plate for 24 h, the resin was washed with NMP (5 x 3mL) and DMF (5 x 3mL). The peptide was cleaved from the resin using 1M ethyl 3-sulfanylpropanoate in either DMF or CHjQj, with or without a catalytic amount of NaSPh.bh After 24 h at rt, the resin was removed by filtration and the filtrate was concentrated in vacuo. Alternatively, BzlSH in THF was utilized for the cleavage by Bertozzi et al.0 1... 

Catalytic resnlts are well correlated with the acid strength of the active species irrespective of their natnre (Lewis or Bronsted). On the other hand, there is no clear correlation between the density of the active sites and the catalytic performances. While the FS03H/Si02 catalyst is very active (yields 99.5 -100%, Table 48.2), AICI3/MCM shows only moderate yields (14.3-20.1%) to N-acylsulfonamide, even if both samples exhibit a similar density (25 x lO , Table 48.1). 

As we expected, the nature of the acylating agents has a great influence on the N-acylsulfonamide yields, the highest yields being obtained with acetic anhydride irrespective of the catalyst s nature. The acylation with acetic acid... 

Generally, N -acylsulfonamides are less effective than those having a single N -aryl group. One such acyl analogue, sulfabenzamide (130) is prepared simply from sulfanilamide (128) by bisbenzamide formation (to 129) using benzoyl chloride and pyridine,... 

Asymmetric cyclopropanol formation has been achieved with olefmic acylsulfonamides, which act like olefmic esters. Thus, their reaction with 1 provides a method for synthesizing cyclopropanols in an optically active form. As represented by Eq. 9.41, alkylation of Oppolzer s camphor sultam and reaction of the resulting unsaturated acylsulfonamides with 1 provides optically active bicyclic cyclopropanols having exclusively the structure shown in the equation [76],... 

B. J. Backes, A. A. Virgilio, J. A. Ellman, Activation Method to Prepare a Highly Reactive Acylsulfonamide... 

Scheme 2.40 Facile acylsulfonamide preparation using a sequence of immobilized reagents.

Thiol esters RC(0)SR have been prepared by nucleophilic cleavage of polystyrene-bound /V-acylsulfonamides with mixtures of a thiol and sodium thiophenolate [377] or LiBr [378], or by treatment of Wang or PAM resin bound carboxylic esters with ethanethiol in the presence of a Lewis acid (AlMe2Cl or AlMe3, DCM, 20 °C, 3 h [379,380]). The latter method can also give rise to the formation of orthoesters RC(SEt)3 and ketene thioacetals, which can, however, be hydrolyzed to the desired thiol esters by treatment with TFA [379]. 

The final example in this section features a rare instance where the electrophilic center is s -hybridized carbon, as most cyclative cleavages involve the attack of carbonyl derivatives. Oxazolidinones are formed cyclatively18 by the displacement of a sulfonate ester by an acylsulfonamide (Fig. 5). In a variant19 of this cyclization, a quasi-meso bis-sulfonate partitions into a pair of quasi-enantiomeric sulfonates, one resin bound and the other cleaved, depending on the direction of intramolecular cyclization. The resin-bound enantiomer can then be displaced by an external nucleophile. 

Backes BJ, Virgilio AA, Ellman JA, Activation method to prepare a highly reactive acylsulfonamide safety-catch linker for solid-phase synthesis, J. Am. Chem. Soc., 118 3055-3056, 1996. 

The ability of the pharmacophore method to identify and focus on features important for drug-receptor interactions was important for this result for example, the assignment of the acidic feature to the acylsulfonamide group increases the overlap by about a third (acids were also considered as general hydrogen-bond acceptors for this analysis). 

The sensitivity of thioester groups to aminolysis by piperidine has prevented the use of thioester-based linkers for Fmoc SPPS. Two groups d have adapted a modified form of Kenner s acylsulfonamide safety-catch linkerf for the synthesis of C-terminal thioester peptides using Fmoc protocols (Scheme 8). This approach is promising and future studies will more fully analyze the limitations of the method. 

To overcome the problems associated with these reaction conditions, Backes et al. developed an alkanesulfonamide safety-catch linker for solid-phase s)rnthesis [34]. In this method, acylation of a sulfonamide support affords a support-bound iV-acylsulfonamide that is able to withstand the basic and strongly nucleophilic reaction conditions required for Fmoc-based SPPS. On completion of the solid-phase synthesis sequence, iodoacetonitrile treatment yields iV-cyanomethyl derivatives that can be cleaved under mild nucleophilic reaction conditions to afford the target compounds. Coupling conditions of alkanesulfonamide resin with Boc- and Fmoc-amino acids were developed to minimize the racemization. Using this method, a short synthesis sequence, followed by iodoacetonitrile activation and nucleophilic displacement is able to form dipeptide products from a number of support-bound amino acids incorporating diverse side-chain functionalities. 

This compound is derived from acylation of the sulfonamide moiety of valdecoxib, followed by treatment with sodium hydroxide. The acidic acylsulfonamide forms a water-soluble sodium salt that is stable for administration but cleanly delivQS valedecoxib once in plasma. 

Direct derivatives of carboxylic acids are different functional groups which maintain an acidic proton and a hydrogen bond acceptor (the carbonyl) in order to have similar specific interactions with the receptor. Among the most common direct derivatives can be listed the hydroxamic acids (R—CO— NH—OH), the acylcyanamides (R—CO— NH—CN) and the acylsulfonamides (R—CO— NH—SO2—R ) (Table 15.11). 

K., Lancaster, M. E., Lee, F, Hart, R., Paulik, M. A., Sherman, B. W, True, T., Cowan, C. Synthesis and evaluation of potent and selective beta(3) adrenergic receptor agonists containing acylsulfonamide, sulfonylsulfonamide, and sulfonylurea carboxylic acid isosteres. J. Med. Chem. 2002,45(3), 567-583. 

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). 

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