Diastereoselective Access to anti-β-Hydroxy Sulfoxides from ­Chiral Epoxides and Prochiral Sulfenate Anions: Mechanistic ­Insights, Scope, and Limitation

Abstract

Reported herein is a stereoselective route to anti-β-hydroxy sulfoxides through the reaction of epoxides with sulfenate anions. Extensive experimental/computational studies revealed the dual special roles of MgBr₂·OEt₂, serving to generate the bromohydrin alkoxide intermediate, which undergoes nucleophilic attack on the prochiral sulfenate in a diastereoselective manner. The present study has opened a general stereoselective synthetic route to anti-β-hydroxy sulfoxides.

Key words

epoxides - diastereoselectivity - nucleophilic substitution - sulfenate anions - hydroxy sulfoxides

Publication History

Received: 24 September 2023

Accepted after revision: 23 October 2023

Accepted Manuscript online:
23 October 2023

Article published online:
21 November 2023

• References and Notes

• 1a Kosugi H, Hoshino K, Uda H. Phosphorus, Sulfur Silicon Relat. Elem. 1994; 95: 401
• 1b Kosugi H, Hoshino K, Uda H. Tetrahedron Lett. 1997; 38: 6861
• 1c Kosugi H, Abe M, Hatsuda R, Uda H, Kato M. Chem. Commun. 1997; 1857
• 2a Broutin P.-E, Colobert F. Org. Lett. 2003; 5: 3281
• 2b Salom-Roig X, Bauder C. Synthesis 2020; 52: 964 ; and references therein
• 3a Carreño MC, Pérez-González M, Ribagorda M, Somoza Á, Urbano A. Chem. Commun. 2002; 3052
• 3b Fernández de la Pradilla R, Viso A, Castro S, Fernández J, Manzano P, Tortosa M. Tetrahedron 2004; 60: 8171
• 3c Bauder C, Martínez J, Salom-Roig X.-J. Curr. Org. Synth. 2013; 10: 885 ; and references therein
• 4a Solladié G, Greck C, Demailly G, Solladié-Cavallo A. Tetrahedron Lett. 1982; 23: 5047
• 4b Solladié G, Greck C, Demailly G. J. Org. Chem. 1985; 50: 1552
• 4c Solladié G, Greck C, Demailly G. Tetrahedron Lett. 1985; 26: 435
• 4d Kosugi H, Konta H, Uda H. J. Chem. Soc., Chem. Commun. 1985; 211
• 5a Miokowski C, Solladié G. J. Chem. Soc., Chem. Commun. 1977; 162
• 5b Miokowski C, Solladié G. Tetrahedron 1980; 36: 227
• 5c Demailly G, Greek C, Solladié G. Tetrahedron Lett. 1984; 25: 4113
• 5d Solladié G, Moine G. J. Am. Chem. Soc. 1984; 106: 6097
• 6a Riddell AB, Smith MR. A, Schwan AL. J. Sulfur Chem. 2022; 43: 540
• 6b Saito F. Synthesis 2023; in press DOI: 10.1055/a-2155-3498.
• 7 Betkekar VV, Suzuki K, Ohmori K. Org. Biomol. Chem. 2022; 20: 7419
• 8 Caupéne C, Boudou C, Perrio S, Metzner P. J. Org. Chem. 2005; 70: 2812
• 9 The relative stereochemistry of the major diastereomer of 7a was determined by comparison with an authentic sample of anti-7a prepared by another method. For details, see the Supporting Information and Ref. 4d.
• 10 The use of other Lewis acids such as ZnBr₂, AlBr₃, InBr₃, ScBr₃, Sc(OTf)₃, In(OTf)₃, or Zn(OTf)₂ met with failure. For details, see the Supporting Information.
• 11 (R_S *,2S*)-1-Phenyl-3-(phenylsulfinyl)propan-2-ol (anti-7a); Typical Procedure A solution of sulfoxide 1a (0.800 mmol, 2.0 equiv) in THF (3 mL) was added to a solution of LiTMP (0.800 mmol, 2.0 equiv) in THF (3 mL) at –78 °C, and the mixture was stirred at –78 °C for 20 min to give the corresponding sulfenate anion PhS(O)Li (2a). MgBr₂.OEt₂ (207 mg, 0.800 mmol, 2.0 equiv) and LiI (11.0 mg, 0.0800 mmol, 0.2 equiv) were then added at –78 °C, and the mixture was stirred for 20 min. A solution of epoxide 6 (0.400 mmol, 1.0 equiv) in THF (2 mL) was then at –78 °C. The cooling bath was removed, the temperature was raised to RT, and the mixture was stirred for 9 h. The mixture was then poured into 1 M aq HCl (40 mL) at 0 °C, and the products were extracted with CH₂Cl₂ (3 × 50 mL). The combined organic layers were dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, hexane–EtOAc) to give a diastereomeric mixture of 7a [yield: 90 mg (86%), dr = 9:1 (assessed by ¹H NMR peak integration of the mixture)]. Further purification by flash chromatography [silica gel, hexane–EtOAc (2:3)] and crystallization from CH₂Cl₂–hexane (1:5) gave the major diastereomer anti-7a as a white powder; mp 88–90 °C; R_f = 0.4 (hexane–EtOAc, 1:1). IR (neat): 3630, 3030, 2927, 2825, 1580, 1477, 1452, 1059, 1050, 765 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ = 7.56–7.54 (m, 2 H), 7.53–7.50 (m, 3 H), 7.25 (t, J = 7.8 Hz, 2 H), 7.21–7.19 (m, 1 H), 7.09 (d, J = 7.2 Hz, 2 H), 4.44–4.40 (m, 1 H), 3.64 (d, J = 3.0 Hz, 1 H), 3.03 (dd, J = 13.8, 9.6 Hz, 1 H), 2.87 (dd, J = 13.8, 7.2 Hz, 1 H), 2.78 (dd, J = 13.8, 6.6 Hz, 1 H), 2.70 (dd, J = 13.2, 1.2 Hz, 1 H). ¹³C NMR (150 MHz, CDCl₃): δ = 142.9, 137.0, 131.1, 129.5, 129.4, 128.7, 126.9, 124.1, 67.8, 60.7, 43.4. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₅H₁₇O₂S: 261.0944; found: 261.0945.
• 12 For details of the TLC analyses, see the Supporting Information.

The few examples that have so far been reported on the diastereoselective alkylation of prochiral sulfenate anions using a chiral electrophile are limited to the pioneering studies by Schwan and co-workers, who used enantiopure chiral β-aminoalkyl iodides to obtain the corresponding diastereomeric β-amino sulfoxides, for selected examples, see:
• 13a Schwan AL, Verdu MJ, Singh SP, O’Donnell JS, Ahmadi AN. J. Org. Chem. 2009; 74: 6851
• 13b Söderman SC, Schwan AL. Org. Lett. 2011; 13: 4192
• 13c Söderman SC, Schwan AL. J. Org. Chem. 2013; 78: 1638

For selected recent examples of the enantioselective alkylation of prochiral sulfenate anions, see:
• 14a Zong L, Ban X, Kee CW, Tan C.-H. Angew. Chem. Int. Ed. 2014; 53: 11849
• 14b Jia T, Zhang M, McCollom SP, Bellomo A, Montel S, Mao J, Dreher SD, Welch CJ, Regalado EL, Williamson RT, Manor BC, Tomson NC, Walsh PJ. J. Am. Chem. Soc. 2017; 139: 8337
• 14c Wang L, Chen M, Zhang P, Li W, Zhang J. J. Am. Chem. Soc. 2018; 140: 3467
• 15 We deduced that the deprotonation of the halohydrins 8a and 8b to form the corresponding magnesium alkoxide occurred due to the co-existence of 2,2,6,6-tetramethylpiperidine (HTMP), generated together with the formation of the sulfenate species 2a.
• 16 To simplify the computational calculation, we employed MgBr₂·OMe₂ instead of MgBr₂·OEt₂.
• 17 The relative configuration of 17b was determined based on single-crystal X-ray diffraction analyses. For details, see the Supporting Information.
• 18 The relative stereochemistry was not determined.
• 19 The poor diastereoselectivity might be attributable to the following reason. The key interactions between the leaving bromo atom and the magnesium atom were inhibited by the presence of the strongly coordinative sulfinyl group initially introduced by the reaction, which might coordinate with the magnesium atom. This could also account for the low diastereoselectivity in the reaction of compound 6 shown next.
• 20 The relative configuration of 19b was determined by single-crystal X-ray diffraction analyses. For details, see the Supporting Information. CCDC 2280543, 2280545, 2280547, and 2280548 contain the supplementary crystallographic data for compounds anti-7d, anti-7f, anti-17b and 19b. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures17b