Intramolecular Lactones of Sialic Acids

Abstract

The so-called "sialo-chemical-biology" has become an attractive research area, as an increasing number of natural products containing a sialic acid moiety have been shown to play important roles in biological, pathological, and immunological processes. The intramolecular lactones of sialic acids are a subclass from this crucial family that could have central functions in the discrimination of physiological and pathological conditions. In this review, we report an in-depth analysis of the synthetic achievements in the preparation of the intramolecular lactones of sialic acids (1,4-, 1,7- and γ-lactones), in their free and/or protected form. In particular, recent advances in the synthesis of the 1,7-lactones have allowed the preparation of key sialic acid derivatives. These compounds could be used as authentic reference standards for their correct determination in biological samples, thus overcoming some of the limitations of the previous analytical procedures.

Keywords: biomarker; heptafluoro derivatives; lactone; sialic acid; tumor.

Figure 1

Representation of the three principal sialic acids (Neu5Ac 1a, Neu5Gc 1b, and KDN 1c), the general structure of modified Sias linked to the glycoconjugate chain, and the three cytidine mononucleotide Sias (CMP)-Sias (2a–c).

Figure 2

Representation of the 1,4-bicyclic lactone 3a, the six 1,7-bicyclic lactones 4a–f, the 1,5-bicyclic lactame 5 and the 2,3-unsaturated derivative DANA 6.

Scheme 1

Synthesis of the free 1,4-bicyclic lactone 3a starting from Neu5Ac 1a [16].

Scheme 2

Synthesis of the peracetylated 1,7-bicyclic lactone 8 as by-product of Neu5Ac 1a classical acetylation [71,72,73].

Scheme 3

(A) Synthesis of the protected 1,4-bicyclic lactones 10, 12 and the 1,7-bicyclic lactones 11a–d, 13 and 14a–c starting from Neu5Ac 1a [70]; (B) proposed mechanism of intramolecular lactonization [70].

Scheme 3

(A) Synthesis of the protected 1,4-bicyclic lactones 10, 12 and the 1,7-bicyclic lactones 11a–d, 13 and 14a–c starting from Neu5Ac 1a [70]; (B) proposed mechanism of intramolecular lactonization [70].

Scheme 4

(A) Synthesis of the saccharopeptides 18 and 19 via the protected 1,4-bicyclic lactones 10 and 16 [67]; (B) synthesis of the protected ¹³C-labeled 1,4-bicyclic lactones 10-¹³C and 16-¹³C and the 1,7-bicyclic lactones 11a-¹³C and 17-¹³C [68].

Scheme 5

Protected 1,7-byciclic lactones 20a–c and 21a–c and synthesis of the β-2,8-unnatural saccharides 23a–c [75].

Scheme 6

(A) Synthesis of the free 1,7-bicyclic lactone of Neu5Ac 4a starting from Neu5Ac 1a [17]; (B) isotopically labeled 1,7-byciclic lactones 4a-d₃ and 4a-d₅ derived from the corresponding Sias 1a-d₃ and 1a-d₅ [18].

Scheme 6

(A) Synthesis of the free 1,7-bicyclic lactone of Neu5Ac 4a starting from Neu5Ac 1a [17]; (B) isotopically labeled 1,7-byciclic lactones 4a-d₃ and 4a-d₅ derived from the corresponding Sias 1a-d₃ and 1a-d₅ [18].

Scheme 7

(A) Synthesis of the peracetylated 1,7-bicylclic lactone of KDN 26 [79]; (B) synthesis of the protected 1,7-bicylclic lactone of KDN 29 [80].

Scheme 7

(A) Synthesis of the peracetylated 1,7-bicylclic lactone of KDN 26 [79]; (B) synthesis of the protected 1,7-bicylclic lactone of KDN 29 [80].

Scheme 8

(A) Synthesis of the free 1,7-bicyclic lactone of Neu5Gc 4d and of KDN 4f, starting from Neu5Gc 1b and KDN 1c, respectively [19]; (B) isotopically labeled 1,7-byciclic lactones 4d-d₂ and 4d-d₄ derived from the corresponding Sias 1b-d₂ and 1b-d₄ [18].

Scheme 9

(A) Synthesis of Neu5Ac 1a starting from N-acetylmannosamine 34 [83]; (B) synthesis of Neu5Ac 1a and Neu5Gc 1b starting from the protected compounds 36 and 37, respectively [83,84].

Scheme 10

Synthesis of protected γ-lactone 41 [88].

Scheme 11

(A) Synthesis of protected γ-lactones 44–46 and the proposed reaction mechanism [89]; (B) alternative synthesis of compound 44 [70].

Scheme 11

(A) Synthesis of protected γ-lactones 44–46 and the proposed reaction mechanism [89]; (B) alternative synthesis of compound 44 [70].

Scheme 12

Synthesis of the free γ-lactone 33 starting from the methyl ester 47 [85].

Scheme 13

Synthesis of the free γ-lactone 33 starting from the bicyclic 1,7-lactone 4a [78].

Scheme 14

Synthesis of the protected γ-lactone 48 starting from the corresponding bicyclic 1,7-lactone 4b [78].

Scheme 15

The three fundamental steps of Zanetta’s gas chromatography–mass spectrometry (GC-MS) method. From the hydrolysis of the glycoconjugates with acetic acid (AcOH), different Sias and their lactones are produced. Here, by way of example, the structures of Neu5Ac 1a and its lactone 4a have been reported [60].

Scheme 16

General two-steps hydrolysis of compound 4a (see Table 1 for reaction conditions) [78].

Scheme 17

Reactivity of 1,7-lactones 4a, 4b and 4c under acidic conditions (AcOH, 80 °C) [78].

Scheme 18

Derivatization conditions with HFBAA explored by Allevi’s group [66].