2-((3R,9bS)-5,5-Dioxido-2,3-dihydro-9bH-benzo[4,5]isothiazolo[3,2-b]oxazol-3-yl)-1-phenylethan-1-one

Abstract

A highly efficient method has been developed for preparing 2-((3R,9bS)-5,5-dioxido-2,3-dihydro-9bH-benzo[4,5]isothiazolo[3,2-b]oxazol-3-yl)-1-phenylethan-1-one. This enantioenriched title compound was obtained via an organocatalytic asymmetric [3+2]-cycloaddition of benzo[d]isothiazole 1,1-dioxide with (E)-4-hydroxy-1-phenylbut-2-en-1-one, using a bifunctional squaramide-based chiral catalyst. The reaction yielded 99% of the product with high enantioselectivity and diastereoselectivity (89:11 er and >20:1 dr). The structure of the newly synthesized compound was confirmed by ¹H-, ¹³C-NMR, IR and mass spectral data.

1. Introduction

Benzosultam derivatives, N-heterocycles featuring sulfonamide functionality within their ring structure, are highly valued due to their wide-ranging bioactivities [1,2,3,4,5,6]. These frameworks are frequently encountered in a variety of biologically active natural products, pharmaceuticals, and agrochemicals, making them important for drug discovery (Figure 1). In addition to their bioactive potential, benzosultams are versatile tools in organic chemistry, functioning as chiral auxiliaries in asymmetric synthesis, protecting groups, and directed metalation groups [7]. As a result, benzosultams are not only promising targets for new drug development but also serve as crucial intermediates in synthetic methodologies. In addition, oxazolidine N,O-heterocycles are notable as crucial building blocks in natural products, displaying a wide range of important biological activities [8,9,10,11,12]. Building on our research interest in the stereoselective synthesis of N,O-heterocycles using γ-hydroxy-α,β-unsaturated carbonyl compounds [13,14], we considered that cyclic N-sulfonyl ketimine and γ-hydroxy-α,β-unsaturated phenyl ketone would be suitable substrates for a cycloaddition reaction, potentially leading to the synthesis of enantioenriched benzosultam-fused oxazolidine derivatives.

2. Results and Discussion

In our previous study [15], bifunctional cinchona-squaramide has proven to be an efficient catalyst for asymmetric [3+2]- and [4+2]-cycloaddition reactions involving cyclic N-sulfimines. Building on this, we anticipated that the cinchona-squaramide-catalyzed [3+2]-cycloaddition of cyclic N-sulfonyl ketimine with γ-hydroxy-α,β-unsaturated phenyl ketone would yield an enantioenriched benzosultam-fused oxazolidine. And we carried out an asymmetric [3+2]-cycloaddition between benzo[d]isothiazole 1,1-dioxide (1) and (E)-4-hydroxy-1-phenylbut-2-en-1-one (2) using the quinine-derived squaramide I (Figure 2) as a catalyst in ClCH₂CH₂Cl at room temperature. This reaction successfully produced the desired enantioenriched benzosultam-fused oxazolidine 3 with an excellent yield (99%) and high diastereoselectivity and enantioselectivity (>20:1 dr and 89:11 er) (Scheme 1). The structure of compound 3 was confirmed by ¹H- and ¹³C-NMR, IR, and mass spectral data, all of which were consistent with the proposed structure.

The structure of compound 3 was confirmed by ¹H- and ¹³C-NMR, IR, and mass spectral data, all of which were consistent with the proposed structure. The diastereoselective ratio value was determined by ¹H NMR analysis and the enantioselective ratio value was determined by chiral HPLC of the major diastereomer. All data are available in the Supplementary Materials File (Figures S1–S4 and Table S1).

3. Materials and Methods

3.1. General

All reagents were used as received without further purification. Chromatographic purification of title compound 3 was accomplished using forced-flow chromatography on ICN 60 32–64 mesh silica gel 63 (Merck, Darmstadt, Germany). Thin-layer chromatography (TLC) (Merck, Darmstadt, Germany) was performed on EM Reagents 0.25 mm silica gel 60-F plates. Developed chromatograms were visualized by fluorescence quenching and anisaldehyde stain. ¹H- and ¹³C-NMR spectra were recorded on 400 MHz instrument (Bruker BioSpin GmbH, Karlsruhe, Germany) as noted, and are internally referenced to residual proton solvent signals. Data for ¹H NMR are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet), integration, coupling constant (Hz), and assignment. Data for ¹³C-NMR are reported in terms of chemical shift. IR spectra were recorded on a Perkin–Elmer 1600 FT-IR spectrometer (Bruker Optics GmbH, Ettlingen, Germany), and reported in terms of frequency of absorption (cm⁻¹). High-resolution mass spectrometry data were recorded on a JEOL JMS-700 M Station mass spectrometer (JEOL, Tokyo, Japan). Enantiomeric excesses were determined using an HPLC instrument with Chiralpak columns, as indicated.

3.2. Synthesis of 2-((3R,9bS)-5,5-Dioxido-2,3-dihydro-9bH-benzo[4,5]isothiazolo[3,2-b]oxazol-3-yl)-1-phenylethan-1-one (3)

A solution of benzo[d]isothiazole 1,1-dioxide (1, 0.15 mmol, 1.5 equiv) and catalyst I (0.01 mmol, 0.1 equiv) in ClCH₂CH₂Cl (1.0 mL, 0.1 M) was stirred for 10 min at 0 °C and then added (E)-4-hydroxy-1-phenylbut-2-en-1-one (2, 0.10 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature for 24 h. Then, the resulting mixture was concentrated in vacuo and was purified by flash column chromatography with EtOAc/CH₂Cl₂/hexanes (1/5:4) as eluent to afford desired product 3 (99%, 45 mg). The enantiomeric excess was determined using HPLC analysis. >20:1 dr, ${\left[\alpha \right]}_{\mathrm{D}}^{24}$ = −72.0 (c = 1.32, CHCl₃); 78% ee; white solid; m.p. 136–138 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.04–7.95 (m, 2H), 7.85–7.77 (m, 1H), 7.74–7.65 (m, 2H), 7.65–7.58 (m, 2H), 7.49 (dd, J = 8.3, 7.0 Hz, 2H), 6.15 (s, 1H), 4.89–4.73 (m, 1H), 4.38 (dd, J = 9.0, 6.2 Hz, 1H), 3.91 (dd, J = 9.1, 5.2 Hz, 1H), 3.71 (dd, J = 18.0, 4.5 Hz, 1H), 3.39 (dd, J = 18.0, 9.5 Hz, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 197.1, 136.1, 134.3, 133.8, 133.6, 131.6, 128.7(two peaks overlapping), 128.0, 125.5, 121.6, 91.7, 73.0, 55.6, 42.9; IR (neat) 2934, 2895, 2850, 1681, 1597, 1450, 1371, 1306, 1207, 1167, 1073 cm⁻¹; HRMS (EI) m/z calcd for [M]⁺ C₁₇H₁₅NO₄S: 329.0722 found the following: 329.0721; Chiralpak OJ-H column and OJ-H guard column (50% EtOH:hexanes, 1.0 mL/min flow, λ = 254 nm); minor-isomer t_r = 37.9 min and major-isomer t_r = 46.4 min.