4-Nitrophenyl chloroformate activation

Nitrophenyl chloroformate activation. The reaction of polysaccharides with chloroformates forming reactive carbonate derivatives has often been used to link bioactive compounds, such as affinity ligands and enzymes, onto polysaccharide matrixes. It was reported that upon reaction with ethyl chloroformate cyclic carbonate as well as ethyl-carbonate structures are formed (9-13). Activation with N-succinimi-do chloroformate (14), 2,4,5-trichloroformate (14) and 4-nitrophenyl chloroformate (14, 15) reportedly led to the introduction of pending carbonate moieties. 

On the other hand, polymeric carriers can also be modified to introduce reactive groups. Polysaccharides such as dextran and inulin may be activated [149] by periodate oxidation to create aldehyde groups, by succinic anhydride activation to create carboxylic groups, or by p-nitrophenyl chloroformate activation to create reactive ester groups. 

The nitric oxide donor SIN-1 13 (Section 5.03.12) reacts with 4-nitrophenyl chloroformate to give the N-acylated product that also acts as a potent nitric oxide donor. Further derivatives with trypanocidal activities may be prepared by transesterification with various alcohols <2003JHC943>. 

Eormation and subsequent cyclization of a hydroxyalkyl carbamate bearing an activating O-substituent can also be achieved in a one-pot procedure. When 2-(hydroxymethyl)aniline 394 was treated with -nitrophenyl chloroformate, the formation of the /)-nitrophenylcarbamate intermediate 395 was followed by in situ ring closure to give the 3,1-benzoxazin-2-one derivative efavirenz 250 in high yield and with high purity, free from the intermediate 395 (Scheme 74) <1998JOC8536>. 

The synthesis of pyrazolidine-2-carboxylic acid containing peptides is carried out following the standard procedures established for azaamino acid peptides as described in Section 10.4. Accordingly, l-(/< rt-butoxycarbonyl)pyrazolidine (which is the equivalent of 2-azaproline tert-butyl ester) is treated with 4-nitrophenyl chloroformate to generate (/ert-butoxy-carbonyl)pyrazolidine-2-carboxylic add 4-nitrophenyl ester.1 60 This active ester is then used... 

Amines can be linked to polymeric alcohols as carbamates. Carbamate attachment of amines can be achieved by reaction of isocyanates with alcohol linkers, or by treatment of alcohol linkers with phosgene [339,427,428] or a synthetic equivalent thereof, followed by exposure to the amine (Figure 3.26). The reagents most commonly used for the activation of alcohol linkers are 4-nitrophenyl chloroformate [69,429-436] and carbonyl diimidazole [427,437-440], The preparation of support-bound carbamates is discussed in Section 14.6. 

As alternatives to 4-nitrophenyl chloroformate, carbonyl diimidazole [100-102] or di-A-succinimidyl carbonate [103,104] can be used to convert polymeric alcohols into alkoxycarbonylating reagents suitable for the preparation of support-bound carbamates. Polystyrene-bound alkoxycarbonyl imidazole is less reactive than the corresponding 4-nitrophenyl carbonate, and sometimes requires heating to undergo reaction with amines. Additional activation of these imidazolides can be achieved by N-methylation (Entry 9, Table 14.7). 

Recently, the Klok group also prepared side-chain PEG-coated surfaces for protein immobilization [201], They employed surface-initiated ATRP for the synthesis. Terminal hydroxyl groups of the PEGs were activated with p-nitrophenyl chloroformate, and subsequently 06-benzylguanine was bound. The 06-benzylguanine-functionalized PEG brushes were used to chemoselectively immobilize 06-alkylguanine-DNA-alkyltransferase fusion proteins with a defined orientation and surface density. 

Recently we have reinvestigated (16) the activation of dextran with 4-nitrophenyl chloroformate (VII). The content of the 4-nitrophenyl carbonate groups in activated dextran can be easily determined... 

This data demonstrate that during the activation of dextran with 4-nitrophenyl chloroformate different types of carbonate groups are formed and that, depending on the reaction conditions, the degree of activation might be much higher than what one would conclude from the data obtained from the "conventional" alkaline hydrolysis and U.V. assay of the 4-nitrophenyl groups. 

Figure 4. Total carbamate content ( ) and 4-nitrophenyl carbamate content (O) during the activation of dextran with 4-nitrophenyl chloroformate [anhydro glucosides]0 =0.1 M [chlorofor-mate]Q = 50 mM.

Carbamate content, activation of dextran with 4-nitrophenyl chloroformate, 193,194/... 

A typical preparation of the polycarbonates is shown for polymer III in Scheme I. 1,4-Benzenedimethanol is activated by reaction with two equivalents of p-nitrophenyl chloroformate in pyridine and the resulting symmetrical dicarbonate is then used in a polycondensation with an equimolar amount of 2-cyclohexen-l,4-diol in a solid-liquid phase-transfer catalyzed reaction with 18-crown-6 as catalyst and solid anhydrous potassium carbonate as base. Alternately, the same polymer can be prepared by condensation of bis(4-nitrophenyl)-2-cyclohexen-1,4-ylene dicarbonate [12] with 1,4-benzenedimethanol or through a variety of similar polycondensations using diol biscar bonylimidazolides [13,14]. 

A second route (Method B in Scheme 36) involves the reaction of triphosgene with the deprotected terminal amine, providing chloroformamides that lose HCl to give isocyanates. A urea derivative is formed by adding an anthranilate or an an-thranilic acid derivative. Alternatively, an activated carbamate can be produced from p-nitrophenyl chloroformate as the reactive intermediate (Method C in Scheme 36). 

Hydrolysis of the galactosyl unit of 52 would produce a bis-carbamate intermediate. After release of C02, the resulting para-aminobenzylcarbamate, known to undergo spontaneous 1,6-elimination (52) under mild conditions, should lead to free doxorubicin (2) and another molecule of C02. Synthesis of prodrug 52 involved initial condensation of 2,3,4,6-tetra-O-acetyl-a-D-galactopyranose (49) with para-tolyl isocyanate in DMF to afford carbamate 53. Benzylic bromination of 53 to 54 was followed by solvolysis into primary alcohol 55. Activation of 55 to 56 was achieved by use of 4-nitrophenyl chloroformate. Further condensation of 56 with doxorubicin (2) in DMF gave 57 which was finally deprotected by transesterification to yield prodrug 52 [63]. 

Alternatively, Schultz and coworkers [59] have proposed an approach related to that of Burgess which utilizes azido 4-nitrophenyl carbamates 98 as activated monomers. Carbamates 98 were prepared in four steps from alcohol 95. Mesylation of 95 followed by azide displacement afforded the A-Boc-protected azide in high yield (80-90%). Boc deprotection and treatment of the resulting free amine with / -nitrophenyl chloroformate in the presence of pyridine in THF provided 98 (50-90% for the two steps). Solid-phase urea bond formation was performed on a Rink amide resin by coupling 98 (5 equiv.) in CH2CI2 in the presence of DIEA (7 equiv.) for 4 h at room temperature. Support-bound azide 99 was reduced in less than 2 h using... 

A group of activation reagents similar to GDI have been developed in Israel (11). They resemble phosgene and prodnce immobihzed enzymes with bonds identical to those produced by GDI. One of their advantages is that p-nitrophenyl chloroformate can be used to prepare an activated matrix that has the property of releasing the yellow p-nitrophenol anion as conphng occurs, thereby permitting one to easily monitor the reaction visnally ... 

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