N,N-Disuccinimidyl Carbonate

[74124-79-1]  · C9H8N2O7  · N,N-Disuccinimidyl Carbonate  · (MW 256.19)

(reagent for the preparation of (active) esters in peptide chemistry;1 b-eliminations2 and carbonyl insertions in heterocyclic and especially peptide chemistry;3 useful in preparation of some carbamates, ureas, and nitrosoureas4)

Alternate Name: DSC.

Physical Data: mp 211-215 °C (dec); prisms.5

Form Supplied in: white to off-white powder.

Preparative Methods: by treatment of N-Hydroxysuccinimide (HOSu) with Trichloromethyl Chloroformate (TCF, Cl3COCOCl) or using trimethylsilylated N-hydroxysuccinimide and phosgene, both giving DSC in good yield (eq 1).1

Handling, Storage, and Precautions: moisture sensitive; stable under refrigeration; irritant.

Active Ester Preparation in Peptide Chemistry.

Eq 2 shows the method for activating acids for subsequent reaction with amines, to give peptide bonds.1

Di(N-succinimidyl) Oxalate (DSO) has also been used as an alternative to DSC in the preparation of esters.8

Carbamate Preparation.

DSC reacts with primary and secondary amines to give carbamates (eq 3),4 in which the carbonyl group is activated by the electron withdrawal of the succinimidyl group. Further attack by the amino groups on the carbonyl of such active carbamates gives ureas. Such carbamates produced by DSC have been used in the preparation of chiral derivatizing agents for amino compounds6 and in the preparation of nucleoside analogs.7


b-Elimination of the hydroxy group of N-protected b-hydroxy-a-amino acids has been effected using DSC and Triethylamine.2 Reaction of Z-threonine with equimolar DSC/Et3N in acetonitrile gave exclusively the (Z)-isomer of Z-DBut-OMe (eq 4). Similarly, use of a 1:2 molar ratio of DSC gave the (Z)-isomer of Boc-DBut-OSuc, which on treatment with the methyl ester of alanine gave Z-DBut-Ala-OMe (eq 5).

Carbonyl Insertions.

DSC has been used as a replacement for Phosgene in the cyclization of N-aralkyl a-amino acids to N-carboxyanhydrides (eq 6).9 This method releases N-hydroxysuccinimide as a byproduct, which is only weakly acidic and so does not affect any acid sensitive groups, whereas phosgene releases 2 equiv of hydrogen chloride. Unlike in ester formation using carboxylates, where the central carbonyl group of DSC is released as CO2, with better nucleophiles, such as secondary a-amino functions, incorporation of the carbonyl group occurs. This is assumed to be by N-substitution by R-CO-, followed by intramolecular anhydride formation by tertiary amine. Similar carbonyl insertions by N,N-Carbonyldiimidazole (CDI) to give heterocycles10,11 leads to racemization. Use of DSC as a carbonyl insertion reagent has led to its use in the preparation of ureas and various heterocycles.3 Reaction with amines (to give ureas), 1,2-diamines (to give cyclic ureas), 1,2-aminothiols (to give cyclic thiocarbamates), and 1,2-hydroxyamines have all been observed. One simple example is the action of DSC on cyclohexylamine to give dicyclohexylurea. A series of (thio)carbamates used as muscle relaxants have also been prepared, e.g. chloroxazone (5-chloro-2-hydroxybenzoxazole) (eq 7). 3-(Benzoxazolyl, benzimidazolyl)pyrazole derivatives have also been made using DSC in MeCN.

1. Ogura, H.; Kobayashi, T.; Shimizu, K.; Kawabe, K.; Takeda, K. TL 1979, 49, 4745. Ogura, H.; Takeda, K. NKK 1981, 5, 836.
2. Ogura, H.; Sato, O.; Takeda, K. TL 1981, 22, 4817.
3. Takeda, K.; Ogura, H. SC 1982, 12, 213.
4. Takeda, K.; Akagi, Y.; Saika, A.; Tsukahara, T.; Ogura, H. TL 1983, 24, 4569.
5. Sigma-Aldrich Handbook of Chemical Safety Data, 2nd ed.; Lenga, R. E., Ed.; Aldrich: Milwaukee, WI, 1987.
6. Iwaki, K.; Yoshida, S.; Nimura, N.; Kinoshita, T.; Takeda, K.; Ogura, H. Chromatographia 1987, 23, 899.
7. McCormick, J. E.; McElhinney, R. S.; McMurray, T. B. H.; Maxwell, R. J. JCS(P1) 1991, 877.
8. Yamashina, T.; Higuchi, K.; Hirata, H. YZ 1991, 40, 155.
9. Halstrom, J.; Kovács, K. ACS(B) 1986, 462.
10. Wright, W. JHC 1965, 2, 41.
11. Kutney, J.; Ratcliffe, A. SC 1975, 5, 47.

Edwin C. Davison

University of Cambridge, UK

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