Chichibabin “isodesmopyridine” synthesis

doi:10.1016/j.tetlet.2019.02.038

Tetrahedron Letters

Volume 60, Issue 13, 28 March 2019, Pages 928-930

https://doi.org/10.1016/j.tetlet.2019.02.038 Get rights and content

Highlights

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First total synthesis of isodesmopyridine was achieved.
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The biomimetic synthesis involved Chichibabin pyridine synthesis.
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The synthesis was accomplished from allysine and ammonium acetate.

Abstract

2,3,5-Trisubstituted pyridine isodesmopyridine is one of the elastin crosslinking amino acid which was isolated from the acid hydrolysates of bovine ligamentum nuchae. Biosynthesis of isodesmopyridine is believed to undergo via Chichibabin pyridine synthesis starting from aldehydes and an ammonia. Herein, we report the first total synthesis of isodesmopyridine through Chichibabin pyridine synthesis from allysines with protecting groups and ammonium salts in the presence of 50 mol% Pr(OTf)₃ with the optimization of the reaction conditions.

Graphical abstract

Introduction

Isodesmopyridine (1, Fig. 1) and desmopyridine (2) are 2,3,5- and 3,4,5- trisubstituted pyridines, respectively, which were isolated from the hydrolysates of bovine ligamentum nuchae in 2001 by Suyama and co-workers, and are one of the crosslinking amino acids of elastin [1]. Elastin is the main component of elastic fibers existing in vertebrate tissues such as lung, skin, blood vessels and ligamentum [2]. Biosynthetically, 1 and 2 are considered to be formed through Chichibabin pyridine synthesis between dehydrolysinonorleucine and allysine [1]. It was suggested that the amount of 1 and 2 in human aorta elastin would gradually increase with age. Thus, 1 and 2 could be effective biomarkers for the aortic elastin damaged by ammonia.

Previously, our group achieved the first total synthesis of 2 starting from 4-aminopyridine over six steps via chemo- and regioselective palladium-catalyzed Sonogashira and Negishi cross-coupling reactions [3]. We also accomplished the synthesis of isodesmosine and desmosine, which are also known as elastin crosslinking amino acids [4], via Pr(OTf)₃-assisted Chichibabin pyridinium synthesis starting from allysine and lysine derivatives [5], [6]. Herein, we report the first total synthesis of 1 via Pr(OTf)₃-assisted Chichibabin pyridine synthesis from allysine derivatives and ammonium salts with optimization of the reaction conditions.

Section snippets

Results and discussion

We commenced the study with preparation of allysine derivative 3 according to the literature procedure [5a]. With 3 in hand, we firstly attempted the synthesis of 1 via Chichibabin pyridinium synthesis of 1,2,3,5-tetrasubstituted pyridinium 5. Four equivalents of allysine 3 and one equivalent of benzylamine hydrochloride 4 were reacted with 50 mol% Pr(OTf)₃ in H₂O at room temperature for 24 h to afford 5 in 19% yield (Scheme 1). Hydrogenolysis of 5 was attempted with H₂ gas in the presence of

Conclusion

In summary, the first total synthesis of isodesmopyridine (1) was accomplished via Pr(OTf)₃-assisted Chichibabin pyridine synthesis in maximum 30% yield starting from protected allysine 3 and NH₄OAc. This achievement might be helpful for the development of useful biomarkers for the aortic elastin damaged by ammonia. This could also lead to elucidation of the biosynthesis of 1 through Chichibabin pyridine synthesis.

Acknowledgments

This work was supported by JSPS KAKENHI Grant Numbers JP25750388 and JP17K01953. We are grateful to Ms. Daria A. Baut (Sophia University) for manuscript suggestion.

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