Disulfides hydrazones

In comparison to abundant examples of noncovalent supramolecular assemblies,relatively few structures have been built with strong covalent bonds. This is due to the fact that normal covalent bonds are not easily broken and reformed. One can manipulate the temperature and conditions so that the formation of stable imines, esters, disulfides, hydrazones, and boronate esters is reversible. Some examples of these covalent self-assembled systems include disulfide hosts and covalent organic frameworks. ... 

Chloroformates or carbonyl chloride react with 2-piperidone hydrazones to give triazolopyridine-3-ones (86JAP(K)69776), and there are further examples of the production of 3-thiols from a hydrazine and carbon disulfide (83USP4419516, 88EUP254623). 

Hydrazine 835 underwent ring closure with one carbon cyclizing reagents to afford 837 and/or /V-acyl derivatives 836. The N-acyl derivatives underwent cyclization on treatment with phosphorus oxychloride. They were also prepared by the reaction of hydrazones 838 with thionyl chloride (84JHC1565). Compound 835 underwent ring closure with carbon disulfide and ethyl chloroformate to give 839 (Scheme 169). 

Figure 5.14 PDPH reacts with thiol-containing compounds through its pyridyl disulfide end to form reversible disulfide linkages. Its hydrazide end then may be subsequently conjugated with an aldehyde-containing molecule to form hydrazone bonds. Glycoproteins may be crosslinked using this approach after periodate activation to...

Figure 5.15 PDPH may be used to add a sulfhydryl group to an aldehyde-containing molecule. After reacting its hydrazide end with the aldehyde to form a hydrazone bond, the pyridyl disulfide may be reduced with DTT to create a free thiol.

The hydrazone bond can be reduced to stabilize the linkage by the addition of sodium cyanoborohydride to a final concentration of 50mM. React for 30 minutes at room temperature with mixing. All operations with cyanoborohydride should be done in a fume hood. If the glycoprotein being modified is sensitive to disulfide reduction and potential denaturation, then this step should be avoided. 

Semisynthetic proteins can involve the combination of a synthetic with a biosynthetic portion by either noncovalent or covalent bonds. Among covalent bonds, there are available for use disulfide bonds, peptide bonds, and other, completely unnatural, bonds such as oximes and hydrazones. 

A recent example of the noncovalent approach is that of Roy and Imperiali.M Earlier work on noncovalent and disulfide-bridge semisynthesis is dted in a review 2 and we limit ourselves in this chapter to the covalent preparation of semisynthetic proteins, using peptide bonds, oximes, hydrazones, and thiazolidines. 

Examples of polymeric carriers are presented in Table 1 and typical methods of covalent conjugation are shown below. Drugs may be bound to macromolecular carriers via, e.g., ester, amide, urethane, hydrazone, thioether, and disulfide... 

Compound 279, prepared from the corresponding chloro derivative, is converted into 280 upon treatment with ethyl orthoformate under mild conditions. Heating 2TO in neutral solvents gives 281 (81JCS(PI)2387). The hydrazine 279 (R = Me) is converted into 282 on treatment with carbon disulfide in DMF (77GEP2838029). The hydrazone 283 is formed from 284 and 5-nitrofuranal (76JMC512). 

Thermolysis of 3,6-diphenyl-l,4-di(phenylsulfonyl)-l,4-dihydro-l,2,4,5-tetrazine (127) in boiling toluene gives benzenesulfonic anhydride (128), phenyl benzenethiosulfonate (129), small amounts of diphenyl disulfide (130), 3,6-diphenyl-l,2,4,5-tetrazine (51) and a rearrangement product, 3,6-diphenyl-l,2-di(phenylsulfonyl)-l,2-dihydro-l,2,4,5-tetrazine (79) (79BCJ483). 3,6-Disubstituted hexahydro-1,2,4,5-tetrazines (132) afforded aldehyde hydrazones (133) when heated at their melting point (63AG1204). 

Replacement of the carbonyl oxygen atom by sulfur may be effected by heating with phosphorus pentasulfide (49JCS2142), boron sulfide or silicon disulfide which gives high yields under mild conditions, as, for example, in the synthesis of 7-methoxy-2-methylchromene-4-thione (438) (69JCS(C)2192). Such compounds are more easily converted into their oximes or hydrazones than the oxygen compounds. 

The reaction of the multisubstituted pyridine (329) with excess carbon disulfide in the presence of triethylamine at room temperature gave a product identified as the tricyclic compound (330) (Scheme 33) <90JMC656>. To block one mode of cyclization, the hydrazone (331) was prepared and condensed with one equivalent of carbon disulfide in the presence of triethylamine. In this case, no tricyclic product was formed but the products (332) and (333) were isolated in 15 and 36% yields, respectively. 

Disubstituted 4-phenyl-5-phenylimino-l,3,4-thiadiazolines (203 X = NPh) are prepared by the reaction of phenyl isothiocyanate with ketonic phenylhydrazones in DMF in the presence of sodium hydride. Replacing the isothiocyanate with carbon disulfide leads to (203 X = S). Aliphatic aldehydes react similarly however, benzaldehyde phenyl-hydrazone furnishes the thiosemicarbazone which on thermolysis yields the thiadiazoline (204). The structures of these compounds are supported by detailed spectroscopic measurements (80JCS(P1)574>. 

Rodriguez-Docampo Z, Otto S (2008) Orthogonal or simultaneous use of disulfide and hydrazone exchange in dynamic covalent chemistry in aqueous solution. Chem Commun 2008 5301-5303... 

The small-molecule-based machine conceived by von Delius, Geertsema, and Leigh [45] is a linear (for reviews, see [46], [100]) motor based on dynamic covalent chemistry [19-24] (forming, breaking, and reforming of dynamic covalent bonds with relatively fast equilibration in response to stimuli), namely on acyl-hydrazone and disulfide exchanges. The motor consists of a track that has four functional groups disposed alternately aldehyde-thiol-aldehyde-thiol which are the positions 1,2, 3, and 4 of the track, a walker NH2-NH-CO-(CH2)5-SH which has the feet A (hydrazide or acyl-hydrazine) and B (thiol), and a placeholder with a foot C of type thiol (Fig. 10). 

In the initial station 35, the walker is connected to the track through a hydrazone 1-A and a disulfide (for a hydrazone-disulfide macrocycle and its dynamic covalent ring-opening under acidic and basic conditions, see [47]) 2-B bond, while the placeholder HSCH2CH2COOCH3 (the source is the corresponding disulfide) is connected through a disulfide bond 4-C to the other thiol group of the track... 

Fig. 10 (a) Operation of a linear motor based on hydrazone and disulfide exchanges the conversion between 37 and 38 occurs in the same conditions as that between 35 and 36, and that between 35 and 38 in the same conditions as that between 36 and 37 (b) stylized representation of the operation of the linear motor... 

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