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. 2024 Dec 24;14(54):40287-40298.
doi: 10.1039/d4ra07780f. eCollection 2024 Dec 17.

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

Magdalena Rodríguez Saravia  1   2 , Verónica Martínez  1 , Franco Vairoletti  1   2 , Mario Macías  3 , Danilo Davyt  1 , Gonzalo Hernández Dossi  4 , Graciela Mahler  1
Affiliations

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

Magdalena Rodríguez Saravia et al. RSC Adv. .

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.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. Biologically relevant γ, δ and ε-thiolactones.
Fig. 2
Fig. 2. Synthesis of δ-thiolactones 1a–c starting from bisthiazolidine 2, method A.
Fig. 3
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
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
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
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
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
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
Fig. 9. Three component reaction of δ-thiolactones 1c, benzylamines and, methylmaleimide.
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