Scavenging nucleophiles

Kaldor [49 i, 55] demonstrated the advantages of applying solid-supported scavengers to the preparation of parallel arrays in a multi-step fashion. In these studies he examined the clean-up of multiple amine alkylation and acylation reactions using a variety of immobilized electrophilic and nucleophilic scavenger reagents including an amine, isocyanate, aldehyde and acid chloride (Tab. 2.1). 

Some rather interesting custom made electrophilic resins that have been developed lately as nucleophile scavenging materials are the acid chloride (25) and arenesulfonyl chloride (26) resin shown in Fig. 9. Resin 26 is stable to various reaction conditions over resin 18 and can be used while conducting subsequent chemical steps.62... 

Fig. 9. Acid chloride (25) and arenesulfonyl chloride (26)-based custom made nucleophilic scavenging resins.

Two complementary procedures have been developed for alkylation of secondary amines [11] - both of which involve the use an excess of amine to drive the reaction to completion. The remaining amine was removed from the required tertiary amine using a polymer supported isocyanate 5 as a nucleophilic scavenger (under thermodynamic control) (Table 1 entry 2). The use of this amine scavenger has subsequently been applied in the purification of urea-based libraries prepared by solid-phase organic synthesis [12],... 

It should be noted that several groups have utilized the nucleophilic scavenging of radical cations by alcohols for synthetic processes [28, 61]. 

Benzyl-type linkers are the most common anchoring groups for various kinds of functionality. Esters, amides, amines, alcohols, and thiols, in particular, can be immobilized by this linker family. This was demonstrated by Merrifield [2] and Wang [19] and is the starting point of modern linker development. Benzylic linkers are typically cleaved by strong acids (for example trifluoroacetic acid, TFA), which cause protonation and subsequent elimination. A nucleophilic scavenger usually quenches the resonance-stabilized cation thus formed. 

Song, G., Cai, Y., and Peng, Y. (2005) Amino-functionalized ionic liquid as a nucleophilic scavenger in solution phase combinatorial synthesis./. Comb. Chem., 7, 561-566. 

Allyl alk-2-ynoates can be readily converted into alk-2-ynoic acids by reaction with morpholine as the nucleophilic scavenger and Pd2(dba>3 as catalyst together with l, 3-diphenylphosphtnopropane as associated ligand, thereby enabling deprotection of allyl esters of 2,2,3,3-tetradehydro-PGE derivatives [Scheme 6.64]. 

Additional tests such as the addition of nucleophilic scavengers (e.g., thiols such as dithiothreitol or j8-mercaptoethanol) can provide further evidence for the presence of a free, reactive electrophilic species. The scavengers should quench all of the free reactive species, thereby protecting the enzyme from inhibition. Unfortunately, this method cannot exclude the possibility that a nucleophilic thiol may even attack the bound reactive species at the active site of the enzyme (which would also give rise to protection from inactivation). However, the use of a bulky thiol, such as reduced glutathione, should limit that possibility. An alternative scenario occurs wherein the released reactive species returns and reacts faster with an active-site nucleophile than with the added thiol. Clearly this is a complex problem and, consequently,it is advisable to use several different tests to avoid misleading conclusions. 

Electrophilic scavengers contain a reactive electrophilic functional group and, hence, can react with a compatible nucleophile, allowing for its sequestration and subsequent removal. Electrophilic scavengers are also referred to as nucleophile scavengers. Several electrophilic/nucleophile scavengers have been developed to date and are summarized in Table 8.1. 

Table 8.1 Summary of electrophilic/nucleophile scavengers developed to date.

Conventional polystyrene isocyanates have been successfully utilized for nucleophile scavenging in the synthesis of pharmaceutically attractive molecules. Player and coworkers have reported the use of conventional resin-bound isocyanates in the scavenging of amines in the synthesis of an 80-member library of triazolo-pyrimidines with purities greater than 90% (Scheme 8.2) [6]. 

Scheme 8.25 Utilization of oligomeric anhydride for nucleophile scavenging.

Several electrophile/nucleophilic scavengers have been developed to date and are summarized in Table 8.2. 

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