Novel enantiopure δ-thiolactones: synthesis, structural characterization, and reactivity studies

Abstract

A new series of chiral δ-thiolactone derivatives have been prepared. These compounds exemplify the acetalic N-C-S reversibility of fused thiazolidines toward the thermodynamic product. The stereochemistry of the synthesized compounds was elucidated using X-ray crystallography, NOESY spectroscopy, and DFT calculations. The aminolysis reaction of the δ-thiolactone was studied with various alkyl amines, which can open the thioester to yield amido thiols in a single step. This reaction has the potential to be applied in the synthesis of bioactive compounds, polymer chemistry, and dynamic combinatorial chemistry, among others fields.

Fig. 1. Biologically relevant γ, δ and ε-thiolactones.

Fig. 2. Synthesis of δ-thiolactones 1a–c starting from bisthiazolidine 2, method A.

Fig. 3. Molecular and ORTEP diagram of δ-thiolactones: (a) 1a and (b) 1b showing the conformations of the respective enantiomers and the C–H⋯O, C–H⋯N and C–H⋯S hydrogen interactions. Atom color code: C (gray), H (white), O (red), N (purple), S (yellow).

Fig. 4. Hartree free energy of compounds 1a–d and their interconversion calculated using DFT calculations (B3LYP 311+G(d,p) level of theory).

Fig. 5. (i) In(OTf)₃ (10% molar), AcOEt, MW, 40 °C, 10 min, 54%; (ii) DIPEA (1.1 eq.) AcOEt, MW, 65 °C, 35 min, 60%.

Fig. 6. Thiolactone amine ring opening conditions: (TA-A) R¹NH₂ (2eq.), MeCN AgOTf (1 eq.) DABCO (1.2 eq.); (TA-B) R¹NH₂ (1.1 eq.), THF, n-PropSH (30 eq.); (TA-C) R¹NH₂ (1.2 eq.), MeCN, β-ME (2 eq.); (TA-D) R¹NH₂ (1.2 eq.), 4-DMAP (5%) n-PropSH (30 eq.) MeCN; (TA-E) R¹NH₂ (1.2 eq.), DTT (2 eq.), MeCN.

Fig. 7. Thiolactone amine ring opening conditions: (TA-B) R¹NH₂: p-Cl-Bn-NH₂ (1.1 eq.), THF, n-PropSH (30 eq.), 8a (34%); (TA-D) R¹NH₂: l-H₂N-Gly-OEt (1.2 eq.), 4-DMAP (5%) n-PropSH (30 eq.) MeCN, no reaction.

Fig. 8. Thiolysis of δ-thiolactones 1c and 4a. Condition TT-A: Gly (1.2 eq.), MeCN : DMF (3 : 1), gave: 9a 74%, dr (87 : 13); condition TT-B: Gly (1.2 eq.), H₂O : AcOEt (1 : 1), gave: 9b 75%, dr (100 : 0).

Fig. 9. Three component reaction of δ-thiolactones 1c, benzylamines and, methylmaleimide.