Disuccinimidyl carbonate DSC

Dihydropyran (DHP) linker 45 is a common handle that couples an alcohol to a solid support with subsequent release upon mild TFA conditions (Fig. 12) [54]. An alternative approach is to prepare an active carbonate linker. TV,TV -Disuccinimidyl carbonate (DSC), a valuable reagent for converting hydroxymethyl-based supports to their corresponding carbonates, was reacted with 4-hydroxymethylpolystyrene 46 and 4-nitrobenzamido (Nbb) 47 resins to anchor alcohols and phenols (Scheme 17) [55]. The final products were released from the solid support by HF and photolysis, respectively. 

A modification of Zalipsky s method by Miron and Wilchek (1993) simplifies the creation of the SC-activated species. Instead of using highly toxic phosgene to form a chloroformate intermediate and then reacting with NHS, the new procedure utilizes either N-hydroxysuccinimidyl chloroformate or N,N -disuccinimidyl carbonate (DSC Chapter 4, Section 1.7) to produce the SC-PEG in one step (Figure 25.6). Since both activation reagents are commercially available, creating an amine-reactive PEG derivative has never been easier. 

The synthesis of darunavir (1) is shown in Scheme 12. Optically active bis-THF alcohol (-)-ll was converted to activated mixed carbonate 46 by treatment with N,N-disuccinimidyl carbonate (DSC) in the presence of triethylamine.30 For the synthesis of the hydroxyethylsulfonamide isostere, epoxide 38 was treated with isobutyl amine (47) in 2-propanol at reflux to provide the corresponding amino alcohol. Reaction of the resulting amino alcohol with p-nitrophenylsulfonyl chloride in the presence of aqueous NaHC03 afforded the sulfonamide derivative 48 in 95% yield for the two steps. This was converted to darunavir in a three-step process, involving (1) catalytic hydrogenation of nitro to an amine, (2) removal of the Boc group by exposure to trifluoroacetic acid in... 

PAC/HMPP supports (see Section V) with disuccinimidyl carbonate (DSC) and used to anchor amino acids as carbamates [106]. After further chain elongations using the Fmoc strategy, lactamization reactions were conducted on resin and the resulting cyclic peptides cleaved by treatment with TFA in the presence of cation scavengers. 

Disuccinimidyl (DS)-PEG, a crosslinker of hydrogel, has been synthesised by the reaction between N,N -disuccinimidyl carbonate (DSC) and the hydroxyl groups at both ends of PEG-diol. Firstly, DSC and triethylamine were added to anhydrous acetonitrile containing PEG-diol. The synthesised polymer was precipitated, filtered and then lyophilised in benzene. The molecular weight of the obtained polymers was then determined using gel permeation chromatography and H-nuclear magnetic resonance [83]. 

The 0-protection of A -protected amino acids 55 was achieved by decarboxylative esterification in solvent-free conditions by Colacino et al. (Scheme 4.13). It was found that the use of planetary ball mill was more effective than vibratory mill [8], Commonly used 0-activation reagents (diaUcyl dicarbonate (B0C2O), carbonate (A, A -disuccinimidyl carbonate, DSC), and alkyl chloroformates (ROCOCl, R=Bn, Et, allyl)) were employed in combination with DMAP as base. Reaction parameters had to be optimized for each individual reagent to achieve acceptable yields (selection of results. Table 4.3). Due to high reactivity of benzyloxy chloroformate (Z-Cl), the two-step cycled milling was executed by addition of Z-Cl in 2equiv. portions, so as to consume the chloroformate and reduce the formation of the undesired byproducts. Acidic workup with 10% aqueous citric acid of ether extracts eliminates DMAP and affords the A-protected amino ester derivatives 56 in good yields. 

Carbonates can be described as diester derivatives of carbonic acid, formed by condensation with hydroxyl compounds. However, carbo q lic acids do not possess the necessaiy reactivity to synthesize such products. Therefore bifunctional reactive molecules such as phosgene or carbonyldiimidazoles like N,N -carbonyldiimidazole (CDI) and disuccinimidyl carbonate (DSC) are commonly used (Scheme 1.13). These compounds readily react with nucleophiles to form stable conjugates. They react with hydro)q l-containing molecules to form the amino-reactive carbonate or carbamate intermediates. These intermediates react in a subsequent step with primaiy amines to form stable carbamate bonds (aliphatic urethanes). The reaction is usually carried out in alkaline media (pH 7-9) and in the absence of competing amino and... 

Bioreactive surfaces on gold were prepared by self-assembly of hydroxyl-terminated dendron thiols self-assembled on gold and subsequent bridging reactions using generation-two amine-terminated dendrimers. The hydroxylated SAM was activated by the homobifunctional cross-linker yV,yV-disuccinimidyl carbonate (DSC), and linked to amine-terminated dendrimers via bridging reactions. 

Another important reagent, particularly used for the coupling of functional groups, such as carboxylic groups, is N,N -disuccinimidyl carbonate (DSC) 904, which has been prepared from N-hydroxysuccinimide with triphosgene in 94% yield [653]. 

Typical procedure. N.N -Disuccinimidyl carbonate (DSC) 904 [653] In a dry 200-mL flask equipped with an Ar inlet adapter, a rubber septum, and a magnetic stirring bar were placed N-hydroxysuccinimide 903 (2.00 g, 17.4 mmol) and a solution of triphosgene (7.24 g, 24.4 mmol, 1.4 equiv.) in dry dichloromethane (50 mL). The mixture was cooled to 30 °C, whereupon DIPEA (2.24 g, 17.4 mmol, 1 equiv.) was added dropwise. The resulting mixture was stirred at 0 °C for 3 h, allowed to warm to 20 °C over a period of 6 h, and then refluxed for a further 2 h. It was concentrated under reduced pressure to leave a crystalline solid, which was suspended in THE (20 mL). The precipitate was collected by filtration, washed well with THF (2 x 20 mL), and then crystallized from MeCN. Yield 94% of DSC mp... 

An efficient method for the synthesis of various mixed succinimidyl carbonates 960, commonly used for the alkoxycarbonylation of amino acids, has been described. Disuccinimidyl carbonate (DSC) has been exclusively used as the reagent for the preparation of these carbonates from structurally diverse alcohols [677]. Thus, important reagents for the introduction of N-protective groups, such as Z-OSu, Boc-OSu, and Fmoc-OSu, can be prepared (Table 4.26), often in good yields. 

Another possibility to synthesize carbamates on a solid support is the addition of activating reagents that transform alcohols directly into (activated) carbamates Hke NAi-disuccinimidyl carbonate (DSC) or carbonyl diimidazole (CDI). These activated carbamates then are easily reacted to the target linker via addition of amines [193,194]. 

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