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. 2024 Oct 15;29(20):4885.
doi: 10.3390/molecules29204885.

Serendipitous Conversion of an Acetylamino Dideoxy-Octonic Acid Derivate into a Functionalized Carbohydrate-Pyrazole Conjugate and Investigation of the Method´s General Applicability

Jelena K Berl  1 , Christian Czaschke  1 , Ann-Kathrin Pramor  1 , Christian B W Stark  1 , Joachim Thiem  1
Affiliations

Serendipitous Conversion of an Acetylamino Dideoxy-Octonic Acid Derivate into a Functionalized Carbohydrate-Pyrazole Conjugate and Investigation of the Method´s General Applicability

Jelena K Berl et al. Molecules. .

Abstract

By treatment of the peracetylated methylester of 4-acetylamino-2,4-dideoxy-d-glycero-d-galacto-octonic acid (ADOA-PAE) with nitrosyl tetrafluoroborate, a serendipitous formation of a highly functionalized carbohydrate-pyrazole conjugate was observed in 95% yield. This observation is remarkable, as it involves a five-step one-pot synthesis that proceeds via an 1,3-acyl shift and a 1,5-electrocyclization, which usually requires thermal conditions; however, the reaction occurred at a temperature of 0 °C. Additionally, the excellent yield of the carbohydrate-decorated pyrazole and the regiospecificity of the cyclization are of particular interest, as regioselectivity is always a challenge in pyrazole synthesis. Subsequently, this novel access to pyrazoles starting from N-acetyl-allyl amides via nitrosation and electrocyclization was investigated. In addition, mechanistic studies for the formation of substituted pyrazoles of type were carried out.

Keywords: ADOA; pyrazole synthesis; sialic acid derivate.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structure of the biologically active compounds celecoxib (1), compound (2), rimonabant (3) and sildenafil (4) [11,12,13,14,15].
Scheme 1
Scheme 1
The preparation of 4-acetylamino-2,4-dideoxy-d-glycero- d-galacto-octonic acid (ADOA, 6) starting from N-acetylneuraminic acid (Neu5Ac, 5) as well as the synthesis of the peracetylated methyl ester of 3-deoxy-d-glycero-d-galacto-nonulosonic acid (10) starting from the peracetylated methyl ester of Neu5Ac (8) [20,21,22].
Scheme 2
Scheme 2
Formation of pyrazole (11) starting from ADOA-PAE (7).
Scheme 3
Scheme 3
Known syntheses of pyrazoles starting from N-nitroso compounds [27,28,29,30].
Scheme 4
Scheme 4
Formation of pyrazole (11) starting from ADOA-PAE (7) in a one-pot five step synthesis.
Scheme 5
Scheme 5
1,3-Acyl shift of N-nitroso amides and formation of diazo compounds via deprotonation [33].
Figure 2
Figure 2
Stabilization of in situ generated diazonium ion by donor function of acetate/acetate and ester.
Scheme 6
Scheme 6
Proposed mechanism of pyrazole formation.
See this image and copyright information in PMC

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