Solution-phase reagents

The introduction of these alternative approaches has permitted the direct trans-ferral and smooth integration of many versatile solution phase reagents from mainstream chemistry catalogues straight into practical protocols for use in com-hinatorial parallel hbrary generation thus broadening the amenable chemistry base. As with aU procedures it is the flexibihty and synthetic scope provided by these simple operations that has enhanced their utility as alternative reaction conditions and purification strategies. 

Despite the breakthrough associated with Merrifield s approach, there are several limitations such as the discontinuous nature of the reaction, the need for large excesses of reagent and the mechanical instability of the polymer matrix. An early solution to the restrictions imposed by Merrifield s polystyrene supported batch process was the use of commercially available benzyl alcohol-functionalized silica (used for H PLC columns). This was initially derivatized with the first member of the peptide chain to be propagated. The synthesis of a tetrapeptide in flow was completed in half the time required for the equivalent batch mode assembly and required significantly smaller excesses of the solution-phase reagent [92],... 

A solution-phase reagent commonly employed for the transformation of carbonyl groups to thiocarbonyl analogues is Lawesson s reagent, which con-... 

The resin-supported carbodiimide 2 (R = Cy), related to the popular solution phase reagent dicyclohexylcarbodiimide (DCC), has been the most successfully employed polymeric carbodiimide of this series, especially in the presence of additives to accelerate the coupling reaction and avoid the acylisourea-unreactive acylurea rearrangement [2]. This carbodiimide has been used for esterification reactions, as exemplified in the reaction of dithiane-containing alcohol 3 with Fmoc-protected valine in the presence of a catalytic amount of N,N-dimethylami-nopyridine (DMAP) to give ester 4 [10] (Scheme 7.1). This polymer-supported reagent 2 (R = Cy) has also been used without any additive in the amidation reaction of 3,4-diaminocyclopentanol scaffolds with 2-(methylsulfanyl)acehc acid [11]. 

As an ultimate example of how polymer-supported reagents can be applied to alkaloid synthesis, their multiple applications in the synthesis of (+)-plicamine truly stands out (Scheme 18.17). In this synthesis, extensive use was made of parallel optimization methods in order to progress the forward route more rapidly. Again, microwave techniques worked especially well to achieve fast reaction times. The entire route, including optimization, was complete in just six weeks, without the need to rehearse the reactions using conventional solution-phase reagents or the requirement of separation methods. 

One solution to the challenges of mixing proteins in microfluidic systems is to immobilize proteins in microreactors [5]. These systems typically consist of chambers of enzymes immobilized on beads, micropillars [6], or porous polymer monoliths [7] (Fig. 2a and b). Such systems have large surface area-to-volume ratios, which minimize diffusion time for reactions with solution-phase reagents. Microreactors can be used either for the conversion of an analyte to another form that is more easily detected or for direct studies of the properties of enzymes and substrates. One of the most common uses is for the digestion of proteins for proteome profiling, but such systems can also be used for the removal of amino acid residues from peptides or proteins or for enzyme kinetic studies. 

Fig. 3 (A) The Pd catalyst remains site-isolated, allowing only solution phase reagents to participate in the reaction the resin-bound reagent does not react. (B) The Pd catalyst leaches out of the heterogeneous support, allowing both the solution-phase and the resin-bound reagents to react. Reproduced with the permission of ACS Publishing. (S. J. Broadwater and D. T. McQuade, J. Org. Chem., 2006, 71, 2131).

Catch-and-release Synthesis. Catch-and-release synthesis is a special case of solid-phase synthesis in which a small molecule is first immobilized on the solid support, then simultaneously transformed and released from the resin by reaction with a solution-phase reagent. PS-SO2CI resin 3 has been used in catch-and-release synthesis for the transformation of alcohols to secondary amines (eq 11), sulfides, and alkylated imidazoles via sulfonate resin 9.1 ... 

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