In situ preactivation

In situ preactivation of thioglycosides with BSP/Tf20, initially developed by Crich for the synthesis of /i-mannosides 21 was applied to expeditious oligosaccharide synthesis by van der Marel and co-workers.20 For a representative example, see the synthesis110 of 106 depicted in Scheme 19. The thiogalactosyl donor 102 was preactivated with BSP/Tf20 and then allowed to react with thiomannoside 103 to yield disaccharide 104 in 73% yield. The latter then reacted with glycosyl acceptor... 

Activation of the carboxylic acid can be carried out either in situ immediately prior to the reaction, with coupling reagents, or before the reaction with the formation of an activated species that is isolated, purified, and characterized. As discussed below, the precise experimental conditions, e.g. organic solvent, preactivation step (when applicable), presence of base, temperature, time, and concentration, are often critical and should be considered carefully. 

A number of other pathways have been developed, which include in situ utilization of 0-pentenyl glycosides117143 and selenoglycosides.137 The versatility of the two-step preactivation concept was further expanded by development of a one-pot procedure based on the preactivation of tolyl thioglycosides. This strategy is discussed18137 in Section VI. 1. 

The formation of guanidino side products is not critical for the stepwise solid-phase synthesis of standard peptides, in which a preactivation of reactive amino acids is conducted. However, if activation in situ is carried out or activation of hindered amino acids, protected peptides, or a carboxylic moiety before a cycli-zation step is performed, the use of phosphonium salts may be more efficient. For slow activation reactions, the addition of more coupling reagent (e.g., PyAOP) during the course of the reaction is advisable because the coupling derivative is hydrolyzed after a few minutes. 

Boc-Amipo Adds via Phosphonium and Aminium Salts with In Situ Neutralization. The previously described procedure was used except that 8-12 equiv. of base was added during preactivation. When this procedure is performed for sequences susceptible to DKP formation, the use of 8 equiv. of base is preferred. 

In 2013, Chen reported the homopolymerisation of both yMBL and yMMBL by using the bidentate half-salen titanium trisbenzyl complex 114 preactivated with B(C6F5)3 leading to the putative cationic active species 115 (Scheme e.lS)." The in situ activation of 114 in toluene allowed up to 87% of yMBL and 98% of yMMBL to be converted in 24 h at 25 °C, and afforded mainly syndio-biased atactic PyMBL and PyMMBL (39.3% rr and 47.8 to 57% rr, respectively), which are still far less active and stereoselective than cationic zirconocene catalysts." ... 

To avoid hydrolysis of the no-carrier-added F-labeled active esters in aqueous buffered solution, the acylation route can be inverted, i.e., radiolabeled amines are prepared and coupled with activated carboxyls at the peptide (O Table 42.9, amidation). Oxytocin was successfully coupled with 2-[ F]fluoroethylamine in yields >90% hy both preactivation (NHS, 4-nitrophenyl and pentafluorophenyl esters) and in situ activation of the C-terminus (TBTU) (Jelinski et al. 2002). 

Although peptides normally are assembled by in situ activation, i.e., by activation of the carboxylic acid immediately prior to coupling or (Figs. 7, 8, and 9) in the presence of the free amine, preactivated amino acid building blocks are also a viable possibility. Thus, pentafluorophenyl (Pfp) [34] esters of some Fmoc-amino acids are commercially available or can be prepared easily. For these couplings, an auxfliary nucleophile such as HOBt is added, which... 

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