Synthesis of Tripeptide Derivatives with Three Stereogenic Centers and Chiral Recognition Probed by Tetraaza Macrocyclic Chiral Solvating Agents Derived from d-Phenylalanine and (1 S,2 S)-(+)-1,2-Diaminocyclohexane via 1H NMR Spectroscopy

Abstract

Enantiomers of a series of tripeptide derivatives with three stereogenic centers (±)-G1-G9 have been prepared from d- and l-α-amino acids as guests for chiral recognition by ¹H NMR spectroscopy. In the meantime, a family of tetraaza macrocyclic chiral solvating agents (TAMCSAs) 1a-1d has been synthesized from d-phenylalanine and (1 S,2 S)-(+)-1,2-diaminocyclohexane. Discrimination of enantiomers of (±)-G1-G9 was carried out in the presence of TAMCSAs 1a-1d by ¹H NMR spectroscopy. The results indicate that enantiomers of (±)-G1-G9 can be effectively discriminated in the presence of TAMCSAs 1a-1d by ¹H NMR signals of multiple protons exhibiting nonequivalent chemical shifts (ΔΔδ) up to 0.616 ppm. Furthermore, enantiomers of (±)-G1-G9 were easily assigned by comparing ¹H NMR signals of the split corresponding protons with those attributed to a single enantiomer. Different optical purities (ee up to 90%) of G1 were clearly observed and calculated in the presence of TAMCSAs 1a-1d, respectively. Intermolecular hydrogen bonding interactions were demonstrated through theoretical calculations of enantiomers of (±)-G1 with TAMCSA 1a by means of the hybrid functional theory with the standard basis sets of 3-21G of the Gaussian 03 program.

Figure 1.

Structures of TAMCSAs 1a–1d.

Figure 2.

X-ray crystal structures of TAMCSAs 1a·CHCl₃ (a) and 1b (b) drawn at 30% probability thermal ellipsoids.

Figure 3.

NOESY spectra of TAMCSAs 1c and 1d.

Figure 4.

¹H–¹H COSY (a) and HSQC (b) spectra of tripeptide derivative G1–2 in CDCl₃.

Figure 5.

Determination of enantiomeric excesses of G1, ee (%) = {(G1–2 – G1–1)/(G1–2 + G1–1)} × 100%. Overlaid ¹H NMR spectra of the TsNH proton of G1–1 and G1–2 in the presence of an equal amount of TAMCSAs 1a (a), 1b (b), 1c (c), and 1d (d), respectively. [G1] = 5 mM. Linear correlation between the theoretical (X) and observed (Y) ee (%) values of G1 with TAMCSAs 1a (a), 1b (b), 1c (c), and 1d (d), respectively.

Figure 6.

Proposed bonding models for the hydrogen bonding interactions between TAMCSA 1a and the enantiomers G1–1 (a) and G1–2 (b).

Figure 7.

Job plots for complexes of (±)-G1 and TAMCSA 1a. Δδ stands for chemical shift change of the NH proton (TsNH group) of G1–1 and G1–2 in the presence of TAMCSA 1a. X stands for the molar fraction of (±)-G1, (X = [(±)-G1]/[(±)-G1 + TAMCSA 1a]).

Figure 8.

ESI mass spectrum of (a) [(±)-G1 + H]: calcd for C₃₄H₃₆N₃O₆S [M + H]614.2319, found 614.2322; (b) [1a + H]calcd for C₃₈H₄₃N₄O₄ [M + H]619.3278, found 619.3275; (c) [(±)-G1 + 1a + H]calcd for C₇₂H₇₈N₇O₁₀S [M + H]1232.5525, found 1232.5558.

Chart 1.

Structures of Enantiomers of Tripeptide Derivatives G5–1–G9–2

Scheme 1.

Synthesis of TAMCSAs 1a–1d

Scheme 2.

Synthesis of G1–1–G4–2