A. Mastitski, Siret Niinepuu, Tõiv Haljasorg
Jul 4, 2018
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Organic Preparations and Procedures International
Abstract
Organic derivatives of hydrazine are used for synthesis of various heterocyclic compounds, pharmaceutical substances, agricultural chemicals and modified peptides. In the structure of aza-peptides at least one amino acid residue is substituted by a hydrazino acid and this modification greatly improves the proteolytic stability of a peptide, which, in turn, makes aza-peptides promising drug candidates. Due to the instability of aza-amino acids (carbazic acids), incorporation of hydrazino acids into the peptide sequences requires protected alkylhydrazines corresponding to the natural amino acids. Major approaches to protected alkylhydrazines include direct alkylation of protected hydrazines, reductive alkylation of hydrazines by aldehydes or ketones, and incorporation of protective groups into commercially available alkylhydrazines. To overcome the drawbacks of each of these methods, improvements have been made. For example, efficient alkylation of hydrazine anions was reported. In further studies, anions generated from conjugated hydrazones were alkylated by various halogenides and applied to the synthesis of aza-peptides. Thereafter the potassium iodide catalyzed direct alkylation of protected hydrazines was studied and reported by our group. Recently, we developed a convenient one-pot synthesis of protected alkylhydrazines from acetals and ketals that allowed us to avoid deprotection steps and separation of intermediates. 29,30 Encouraged by these results we extended this method to the synthesis of protected benzylic hydrazines, which were previously obtained from protected hydrazines by direct or KI catalyzed alkylation, as well as by reductive alkylation of protected hydrazines with benzaldehyde or substituted benzaldehydes. However, the formed hydrazones are conjugated and their reduction requires Pd(OH)2, 10 or Pd/C catalyzed hydrogenation. In the case of 2-(3,5-dimethoxyphenyl)propan-2-yloxycarbonyl (Ddz) protected hydrazones, NaBH3CN was successfully applied for reduction of the conjugated -CH1⁄4Nbond. Moreover, aromatic aldehydes, such as benzaldehyde, oxidize to carboxylic acids very easily and should be purified prior to use. Storage of these compounds in protected form (usually as the acetal) is thus much more favorable. This, in turn, requires an additional deprotection step. In the present study a set of five protected hydrazines carrying 9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), benzoyl (Bz), 3-nitrobenzoyl (3-NO2Bz) and 3,4-dimethoxybenzoyl (3,4-(OCH3)2Bz) groups was studied. Benzaldehyde dimethyl