Chichibabin and IsoChichibabin Pyridinium Syntheses of Isodesmosine, Desmosine, and their Derivatives

Abstract

Isodesmosine and desmosine are 1,2,3,5‐tetrasubstituted and 1,3,4,5‐tetrasubstituted pyridinium amino acids that crosslink elastin and exist naturally in a 1:1 ratio. In this work, starting from the corresponding aldehyde and amine, we achieved the selective Chichibabin pyridinium syntheses of isodesmosine and desmosine with protecting groups using 50 mol‐% Pr(OTf)3 in H2O/DMF (2:1) and H2O/CH2Cl2 (1:6), respectively. It is important to note that selective desmosine synthesis (herein called isoChichibabin pyridinium synthesis) has been discovered and reported for the first time. Meanwhile, the reaction of aldehyde and amine bearing one alanine using the same conditions as above afforded the protected isodesmosine‐(Ala)4 and desmosine‐(Ala)4 with no selectivity, suggesting that these reactions imitated the formation of the elastin crosslinkers in nature.

An efficient and scalable synthesis of Isodesmosine

“…S C H E M E 1 Concise retrosynthetic approach for the synthesis of Isodesmosine (2) In summary, we have developed an efficient and scalable synthesis of Isodesmosine from readily available starting material, cost effective reagents, mild and simple reaction conditions with 35.3% overall yield. This accomplishment ought to add to the elucidation of the other pyridinium polyfunctional cross-links structure of elastin.…”

“…Elastin found to be present in extracellular matrix, is an insoluble protein located which plays a vital role in producing resilience of internal organs, the elasticity, and tissues such as tendons, ligaments, arteries, lungs, and skin [2,3]. Elastin comprises of dissolvable antecedent tropoelastin monomers crosslinked extracellularly by amino acids generating two amino acid isoforms [4] that is, Desmosine (1) and Isodesmosine (2) along with other pyridinium polyfunctional cross-links such as Isodesmopyridine [5] (3) and Desmopyridine [5] (4), Neodesmosine [6] (5) (Figure 1). Their contents may be used to estimate the quantitative insoluble elastin formation [7].…”

Isotope-dilution LC-MS/MS Analysis of the Elastin Crosslinkers Desmosine and Isodesmosine in Acute Cerebral Stroke Patients

“…In the present study, we chemically synthesized isotopically labeled isodesmosine-13 C 3 , 15 N 1 (Fig. 1) [19] via praseodymium-promoted Chichibabin pyridinium synthesis, as we reported the total synthesis of desmosine and isodesmosine [20,21]. Using isotopically labeled isodesmosine-13 C 3 , 15 N 1 as an internal control, we established an isotopedilution LC-MS/MS method.…”

Preparation of Protected 13Cn-Labeled Isodesmosines: Mechanistic Insight of Isodesmosine Formation

“…The preparation of protected 13 C-labeled allysine aldehyde 9 12 and protected lysine hydrochloride 10 was conducted according to literature procedures. 13 Pr(OTf) 3 -protmoted Chichibabin pyridinium synthesis [13][14][15][16][17][18] was then carried out to obtain the 13 C n -labeled isodesmosines with protecting groups on amino acids as shown in Scheme 2. Four equivalents of 4/9 (with different ratios) and 1 equivalent of 10 were used in this reaction under the conditions of 50 mol% Pr(OTf) 3 in H 2 O at room temperature for 24 hours.…”

“…Pr(OTf) 3 -protmoted Chichibabin pyridinium synthesis 13 -18 was then carried out to obtain the 13 C n -labeled isodesmosines with protecting groups on amino acids as shown in Scheme 2. Four equivalents of 4 / 9 (with different ratios) and 1 equivalent of 10 were used in this reaction under the conditions of 50 mol% Pr(OTf) 3 in H 2 O at room temperature for 24 hours.…”