Synthesis and conformational analysis of linear homo- and heterooligomers from novel 2-C-branched sugar amino acids (SAAs)

Abstract

Sugar amino acids (SAAs), as biologically interesting structures bearing both amino and carboxylic acid functional groups represent an important class of multifunctional building blocks. In this study, we develop an easy access to novel SAAs in only three steps starting from nitro compounds in high yields in analytically pure form, easily available by ceric (IV) mediated radical additions. Such novel SAAs have been applied in the assembly of total nine carbopeptoids with the form of linear homo- and heterooligomers for the structural investigations employing circular dichroism (CD) spectroscopy, which suggest that the carbopeptoids emerge a well-extended, left (or right)-handed conformation similar to polyproline II (PPII) helices. NMR studies also clearly demonstrated the presence of ordered secondary structural elements. 2D-ROESY spectra were acquired to identify ⁱ⁺¹ NH ↔ ⁱ C ₁ H, ⁱ C ₂ H correlations which support the conformational analysis of tetramers by CD spectroscopy. These findings provide interesting information of SAAs and their oligomers as potential scaffolds for discovering new drugs and materials.

Figure 1

Glucosaminuronic acid 1 & galactosaminuronic acid 2 and 2- C-branched glucosaminuronic acid 3 & galactosaminuronic acid 4.

Figure 2

Proposed synthesis of SAAs 3′ and 4′. Reagents and conditions: (a) H2, 10% Pd/C, MeOH; Boc2O, NaOH, MeOH/H2O (3:1), 64%; (b) TIPSCl, imidazole, DMF, 89%; (c) BnBr, 18-crown-6, KOH, THF, 71%; (d) TBAF, THF, 98%; (e) TEMPO, NaBr, TBABr, NaOCl; quan.; (f) ZnCl2, Ac2O/AcOH (2:1), 85%; (g) LiAlH4, THF; Boc2O, NaOH, MeOH/H2O (3:1), 64%; (e’) TEMPO, NaBr, TBABr, NaOCl; quan.; (f’) ZnCl2, Ac2O/AcOH (2:1), 77%; (g’) LiAlH4, THF; Boc2O, NaOH, MeOH/H2O (3:1), 46%.

Figure 3

A convenient method to access novel 2-C-branched sugar amino acids gluco-3′ and galacto-4′.

Figure 4

The synthetic linear homooligomers 16–21 and heterooligomers 22–24 with standard coupling method.

Figure 5

Normalized circular dichroism (CD) spectra of nine oligosaccharides (16–24) recorded in trifluoroethanol solution.

Figure 6

(A) Expanded ROESY spectrum of 17 in CDCl₃ (ca. 10 mM, 263 K). The nOes ²NH ↔ ¹C₁H, ¹C₂H, ³NH ↔ ²C₁H, ²C₂H and ⁴NH ↔ ³C₁H, ³C₂H are marked as 1–6; (B). Characteristic nOes of compound 17 in CDCl₃.

Figure 7

Solvent Titration plot of 17, 20 and 23.