Carbamate-based linkers

Few examples have been described of nucleophilic cleavage of carbonate- or carbamate-linked alcohols from insoluble supports. A serine-based linker for phenols releases the phenol upon fluoride-induced intramolecular nucleophilic cleavage of an aryl carbamate (Entry 2, Table 3.36). A linker for oligonucleotides has been described, in which the carbohydrate is bound as a carbonate to resin-bound 2-(2-nitrophen-yl)ethanol, and which is cleaved by base-induced 3-elimination (Entry 3, Table 3.36). Trichloroethyl carbonates, which are susceptible to cleavage by reducing agents such as zinc or phosphines, have been successfully used to link aliphatic alcohols to silica gel (Entry 4, Table 3.36). These carbonates can also be cleaved by acidolysis (Table 3.22). 

Figure 13.18 Immobilization chemistry and its impact on enantioseparation selectivity of DNB-Leu, mandelic acid, and dichloroprop on cinchona 9-O-carbamate-based CSPs. Chromatographic conditions mobile phase MeOH 0.1 M NH4OAc AcOH 98 2 0.5 v/v/v, 1 ml/min, I = 10cm for Cll linkers [102], MeOH 0.1 M NH4OAc 80 20 v/v pHa 6, 1 ml/min, I = 15 cm for C9 linker [103],...

McKeown, S.C. Watson, S.P. Carr, R.A.E. Marshall, P.A. Photolabile Carbamate Based Dual Linker Analytical Construct for Facile Monitoring of Solid Phase Chemistry TLC for Solid Phase Tetrahedron Lett. 40, 2407-2410 (1999). 

Veerman JJN, Rutjes FPJT, Van Maarseveen JH, Hiemstra H. A novel acid stable/base labile carbamate linker for N-acyliminium ion reactions on solid support. Tetrahedron Lett 1999 40 6079-6082. 

It is also worthwhile to outline at this place the immobilization procedure that was used for the preparation of type I CSPs A bifunctional linker with a terminal isocyanate on one side and a triethoxysilyl group on the other end (3-isocyanatopropyl triethoxysilane) was reacted with the native cinchona alkaloids quinine and quinidine and subsequently the resultant carbamate derivative in a second step with silica [30], Remaining silanols have been capped with silane reagents, yet, are less detrimental for acidic solutes because of the repulsive nature of such electrostatic interactions. CSPs prepared in such a way lack the hydrophobic basic layer of the thiol-silica-based CSPs mentioned earlier, which may be advantageous for the separation of certain analytes. 

Allyl esters, carbonates, and carbamates readily undergo C-O bond cleavage upon reaction with palladium(O) to yield allyl palladium(II) complexes. These complexes are electrophilic and can react with nucleophiles to form products of allylic nucleophilic substitution. Linkers based on this reaction have been designed, which are cleavable by treatment with catalytic amounts of palladium complexes [165,166], For the immobilization of carboxylic acids, support-bound allyl alcohols have proven suitable (Figure 3.12, Table 3.7). 

Table 3.26 lists illustrative examples of cleavage reactions of support-bound N-aryl-carbamates, anilides, and /V-arylsulfonamidcs. /V-Arylcarbamatcs are more susceptible to attack by nucleophiles than /V-alkylcarbamates, and, if strong bases or nucleophiles are to be used in a reaction sequence, it might be a better choice to link the aniline to the support as an /V-bcnzyl derivative. Entry 7 (Table 3.26) is an example of a safety-catch linker for anilines, in which activation is achieved by enzymatic hydrolysis of a phenylacetamide to liberate a primary amine, which then cleaves the anilide. 

Alcohols and phenols can be attached to support-bound alcohol linkers as carbonates [467,665,666], although few examples of this have been reported. For the preparation of carbonates, the support-bound alcohol needs to be converted into a reactive carbonic acid derivative by reaction with phosgene or a synthetic equivalent thereof, e.g. disuccinimidyl carbonate [665], carbonyl diimidazole [157], or 4-nitrophenyl chloro-formate [467] (see Section 14.7). The best results are usually obtained with support-bound chloroformates. The resulting intermediate is then treated with an alcohol and a base (DIPEA, DMAP, or DBU), which furnishes the unsymmetrical carbonate. Carbonates are generally more resistant towards nucleophilic cleavage than esters, but are less stable than carbamates. Aryl carbonates are easily cleaved by nucleophiles and are therefore of limited utility as linkers for phenols. 

Alternatively, sulfonamides can also be prepared by oxidation of sulfinamides with periodate (Entry 3, Table 8.8) or with MCPBA [125]. Polystyrene-bound sulfonyl chlorides, which can be prepared from polystyrene-bound sulfonic acids by treatment with PCI5, SOCI2 [126-129], CISO3H [130], or SO2CI2/PPI13 [131], react smoothly with amines to yield the corresponding sulfonamides (Entry 4, Table 8.8). Support-bound carbamates of primary aliphatic or aromatic amines can be N-sulfonylated in the presence of strong bases, and can therefore be used as backbone amide linkers for sulfonamides (Entries 5 and 6, Table 8.8). 

The synthesis of peptides on a solid support, usually beads of either polystyrene (the Merrifield approach) or polyamide (the Sheppard approach) resins has become extremely important, because it allows peptides to be synthesized by machines, and a key feature of the Sheppard approach is the use of Fmoc-protected amino acid residues. The idea is that the C-terminus amino acid is tethered to the resin by means of a carbamate linker that is stable to mild acid or base. The peptide chain is then built up using the sorts of methods we have been discussing and, when complete, is released by cleaving the linker with strong acid. 

Dressman et a/. described an alternative solid-phase synthesis in which the amino acids were N-terminally linked to a hydroxymethyl resin through a carbamate linker. Amide formation gave products 273 which, after treatment with base cyclised to yield hydantoins of typ>e 274 Scheme 4.4.6). 

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