Polymer-supported reagents coupling

Weik and Rademann have described the use of phosphoranes as polymer-bound acylation equivalents [65]. The authors chose a norstatine isostere as a synthetic target and employed classical polymer-bound triphenylphosphine in their studies (Scheme 7.54). Initial alkylation of the polymer-supported reagent was achieved with bromoacetonitrile under microwave irradiation. Simple treatment with triethyl-amine transformed the polymer-bound phosphonium salt into the corresponding stable phosphorane, which could be efficiently coupled with various protected amino acids. In this acylation step, the exclusion of water was crucial. 

When a sample containing a polymer-supported reagent is subjected to electromagnetic irradiation, it is possible for the energy to be directly coupled to polar functional groups. It then takes a defined period of time for the absorbed energy to dissipate... 

As mentioned in the introduction, polymer-supported reagents can be used in excess to drive a reaction to completion, without a penalty in terms of purification. However, in many coupling reactions, it is not only an excess of coupling reagent, e.g., a carbodiimide moiety such as 10 (Scheme 2), that is required to drive the reaction to completion, but also an excess of one of the coupling partners. Consequently, new methods have been developed to separate these excess quantities from the product by simple filtration processes (Fig. 3). These techniques are described in more detail in Chapter 1. 

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]. 

A convergent synthesis of the potent selective inhibitor of the enzyme phosphodiesterase sildenafil (Viagra) has been based on polymer supported reagents [134], In this synthesis, the HOBt-supported resin 126 has been used for the isolation and preparation of the resin-bound active ester 128, performed by coupling polymer 126 with the benzoic acid sulfonamide derivative 127 by means of PyBrop (Scheme 7.40). Subsequent reaction of active ester 128 with aminopyrazole 129 gave rise to the clean synthesis of amide 130, which has been transformed into sildenafil (131) after a base-promoted pyrimidinone formation. 

Wang resin served as the polymer support. Reagent 16 is a very effective coupling reagent for the synthesis of esters (17) and amides (18). 

The polymeric imide could then be reacted with primary amines or ammonia to form ammonium salts for a subsequent reactions with a carboxylic acid in the presence of a coupling reagent. It could then be converted to amides or functionalized as a uranium salt for use as polymer-supported peptide coupling. In addition, the anhydride was also reacted with di(2-pyrldyl)methylamine and formed a recoverable palladium catalyst for cross-coupling reactions that could take place in water. 

SCHEME 6.22 Coupling the three epothilone fragments in the synthesis of epothilone A using polymer-supported reagents. 

As an alternative approach, instead of performing the process with educts coupled to the support, polymer-supported reagents (PSRs) can be brought into contact with the educt dissolved in an appropriate solvent. In this case, the polymer support can be easily isolated from the product solution by filtration. Moreover, it is possible to apply a surplus of the PSR, and this frequently leads to higher product yields. Microwave heating has also been used to improve the PSR method, and some typical microwave-assisted reactions are shown in Scheme 1.9. More detailed information on this topic, and some appropriate references, are provided in Ref [14]. 

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