Abstract
A catalytic diastereoselective Prins reaction for hydroxymethylation and hydroxylation of 1,3-diarylpropene was successfully utilized to prepare various 1,3-dioxanes 7 in 14–88% yields. Take advantage of the synthetic intermediate 7h, the key B/C rings in brazilin core could be constructed by the sequential of Friedel–Crafts/Ullmann-Ma rather than Ullmann-Ma/Friedel–Crafts reactions.
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1 Introduction
The brazilin family of natural products is a group of homoisoflavonoids with oxo-6/5/6/6 fused tetracyclic tetrahydroindeno[2,1-c]chromene core from the traditional Chinese medicine ‘Sumu’ (Caesalpinia sappan L.) [1], of which brazilin (1) possesses antitumor, hypoglycemic, anti-inflammatory, and hepatoprotective pharmacological activities [2,3,4], and hematoxylin (2) exhibits c-Src inhibitory activity and is an excellent tyrosine kinase inhibitor [5] (Scheme 1). Organic chemists have extensively studied the total synthesis of such biologically active molecules. Representative routes mainly rely on the biogenetic precursors 3, [6,7,8,9] indane derivatives 4, [10,11,12,13,14] phenylpropanoid derivatives 5, [15, 16] and others [17, 18] as key intermediates. We propose that the generation of the tetracyclic brazilin core from 1,3-diol 6 through Ullmann-Ma (UM) and Friedel–Crafts (FC) reactions may present a new strategy for synthesizing this class of ring systems, and 1,3-dioxane 7 is an excellent precursor for the preparation of 1,3-diol 6 through the ring opening under the acid condition. Compound 7 can be prepared by the reaction of diarylpropene 8 with formaldehyde or paraformaldehyde (PF) via Prins reaction [19]. In this article, we report the synthesis of series 1,3-dioxane 7 through the TfOH-catalyzed diastereoselective Prins reaction of diarylpropene 8 with PF. We also explore the cyclization logic for the synthesis of brazilin core from 1,3-diol 6 via UM and FC reactions.
Synthetic routes to brazilin-type compounds
2 Results and discussion
Recently, List et al. reported the synthesis of chiral 1,3-dioxanes through the imino-imidodiphosphate (iIDP)-catalyzed asymmetric Prins reaction of styrene with paraformaldehyde (PF) [20]. However, we found both iIDP and N-triflyl phosphoramides (NTPAs) [21] were unable to catalyze the Prins reaction of diarylpropene 8a with PF (data not shown). Aiming at the preparation of 1,3-dioxane 7, we screened the conditions for the Prins reaction of diarylpropene 8a with formaldehyde or PF using Cu(OTf)2 [22] or TfOH (Table 1). Heating 8a with formaldehyde or PF in the presence of Cu(OTf)2 (5 mol%) generated the target product 7a in up to 36% yield, along with a small amount of ring-opening and subsequently FC cyclized products 11a and 11a′, while the reactions did not occurred at room temperature (Table 1, entries 1–4). Cu(BF4)2 gave a comparable yields of 7a to Cu(OTf)2 (entry 5), and DCM was seemed the optimal choice of solvent (entries 6–11). Replacement of Cu(OTf)2 with TfOH, no reaction was detected at 0 °C (entry 12), but at room temperature, TfOH could achieve similar results to Cu(OTf)2 (entry 13). Further increasing the loading of TfOH to 10 mol% resulted in the desired product 7a (79% yield) with excellent diastereoselective ratio (d.r.) > 20:1 and a small amount of 11a (entry 14). A large coupling constant of 9.8 Hz (3JH3–H4) indicated the trans-configuration of C3,C4 stereochemistry in 7a. The relative configuration of 11a was determined to be trans- through X-ray single-crystal diffraction of its methylated derivative 11a-1 (Scheme 2).
Synthesis of 1,3-dioxanes 7
After obtaining the optimal conditions (as shown in Table 1, entry 14), we investigated the substrate scope for this reaction (Scheme 2). The results indicated that only 8a and 8w (Z/E mixture, Additional file 1: Scheme S1) could directly produce the indane-type product 11 (type B). Specifically, 8a mainly led to 7a and 8w mainly generated 11b under the optimal conditions, while all of the other substrates produced the 1,3-dioxane-type product 7 (type A) with excellent diastereoselectivity (d.r. > 20:1). The reaction exhibited a certain range of substrate adaptation. The Ar1 fragment tolerated with ortho- or para-substituted electron-donating groups (EDGs) giving 7a, 11a, 11b, 7c, 7e–g, 7k-m, 7p in 10–79% yields, as well as ortho- or para-substituted electron-withdrawing groups (EWGs) delivering 7d, 7n, 7o, 7q–u in 14–88% yields (Scheme 2). However, the Ar2 fragment could only tolerate with the EDGs substitution, as the EWGs prevented the reaction from occurring (8 × in Additional file 1: Scheme S1). It is important to note that substrates 8i and 8j with four-carbon alkyl chain were equally capable of undergoing similar transformations (7i and 7j).
The mechanism of the reaction was postulated in Scheme 3. Given that the reaction yielded highly diastereoselective products 7 and 11 from substrate 8, it was hypothesized that the Prins reaction was a stepwise process [20]. Namely, the benzyl cation i was produced when 8 first underwent the Prins reaction with protonated formaldehyde. This step was significantly influenced by the electrical properties of Ar2 fragment, Ar2 with EDGs favoring the reaction and EWGs having the opposite effect. These results were consistent with those obtained in our experiments (Scheme 2). Then, by reacting with another molecular formaldehyde via the dominant transition state TS1, trans-7 was produced, while cis-7 resulting from the disfavored transition state TS2 was not detected. Alternatively, both products 11a and 11b could be generated simultaneously through further protonation ring-opening/FC reactions of trans-7a and 7b, as well as through the direct FC reaction of i (when strong EDGs were present in Ar1) [22, 23].
Proposed mechanism for the formation of 7 and 11
To construct the braziline core, we used 7b as a substrate (Scheme 4A). Under acidic conditions, 7b underwent ring-opening to give 1,3-diol 6b in quantitative yield. Subsequent UM reaction of 6b produced cyclization product 12a, which facilitated construction of the C-ring in the braziline core. A small amount of 12b was also observed as the debromination product of 6b. The X-ray single-crystal diffraction structure of 12b confirmed its relative configuration to be trans, which in turn verified the trans-configuration of 1,3-dioxane 7. However, treatment of 12a with various acids did not lead to the expected FC cyclization. The use of Lewis acids (BF3·OEt2, AlCl3, Cu(OTf)2, etc.) caused the decomposition of 12a, while Brönsted acids (HCl, pTSA, H3PO4, etc.) mainly produced the C4 racemized products 14a and 14b with a minor eliminated product 15. We hypothesized that the reason for the unsuccessful FC reaction of 12a may be attributed to the inert aryl rings A and D, which lack EDGs activation [17]. Specifically, aryl ring D cannot stabilize the benzylic cation ii, while aryl ring A is difficult to capture ii to form cyclized product. To address this issue, we utilized 7h as a substrate for further attempts, which contains three OMe groups on aryl ring D (Scheme 4B). Under acidic conditions, 7h was similarly converted to ring-opening product 6h but as a separable mixture of trans-6h and cis-6h in 85% yield (d.r. ~ 5:3). The subsequent UM reactions of trans-6h and cis-6h delivered the cyclized products trans-12h and cis-12h in 36% and 40% yield, along with debrominated products trans-12c and cis-12c, respectively. However, similar to 12a, attempts to achieve FC cyclization of both trans-12h and cis-12h using different acid catalysts were unsuccessful, the eliminated product 16 was obtained as a major product. Inspired by the formation of 11a in Scheme 2, we hypothesized whether the brazilin core could be constructed through the FC cyclization followed by UM ring closure from 7h, although this strategy was failed using ‘inert’ 7b. Namely, 7h was converted to the cyclized product 11h as a separable mixture (d.r. = 3:1) under the catalysis of H3PO4 in 13% yield (75% brsm). The UM reaction of 11h successfully enabled the C ring closure, resulting in the final tetracyclic product 17 albeit in 10% yield (73% brsm). It is worth noting that 17 is a first example with the trans-fused B/C rings in brazilin core.
Construction of the brazilin core from 7b and 7h
3 Conclusions
In summary, a catalytic diastereoselective Prins reaction for hydroxymethylation and hydroxylation of 1,3-diarylpropene was successfully utilized to prepare various 1,3-dioxanes 7. The construction of brazilin core was attempted using intermediates 7b and 7h. It was found that UM reaction smoothly achieved C-ring formation, but 7a could not undergo FC cyclization to construct the B-ring due to lack of EDG activation on aryl ring A. However, 7h containing the electron-rich aryl ring D was advantageous for the construction of the B-ring using FC reaction. This finding presents an alternative approach to synthesizing the brazilin core and provides insight into constructing B/C rings in similar tetracyclic structures.
4 Experimental section
4.1 General information
Unless otherwise noted, all reactions were conducted in oven-dried round-bottom flasks under an argon atmosphere. Solvents were dried and freshly distilled from Na (THF and 1,4-dioxane) under an argon atmosphere. All reagents were from commercial sources without further purification unless otherwise noted. The silica gel (200–300 mesh, Qingdao Marine Chemical Inc., Qingdao, China) was used for column chromatography. Thin layer chromatography (TLC) was carried out on GF plates (0.25 mm layer thickness, Qingdao Marine Chemical Inc.) and was visualized by ultraviolet light (254 nm, if applicable) and phosphomolybdic acid (50 g/L) in EtOH following heating as developing agents. Unless otherwise noted, yields reported were for isolated spectroscopically pure compounds.
1H, 13C, and 19F NMR spectra were recorded on ADVANCE III AM-400 MHz, ADVANCE III AM-500 MHz and ADVANCE III 600 MHz spectrometers (Bruker) at ambient temperature. The residue solvent protons (1H) or the solvent carbons (13C) were used as internal standards. 1H NMR data are presented as chemical shifts in parts per million downfield from tetramethylsilane [multiplicity, coupling constant (hertz), integration]. Chemical shifts (δ) are given in parts per million with reference to solvent signals [1H NMR: CDCl3 (7.26); 13C NMR: CDCl3 (77.16)]. The following abbreviations are used in reporting NMR data: s, singlet; brs, broad singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; ddd, doublet of doublet of doublets; dt, doublet of triplets; td, triplet of doublets; m, multiplet.
4.2 General procedure for preparation of 1,3-diarylpropenes 8a–8x
According to the literatures [24, 25], 1,3-diarylpropenes 8a–8 × were synthesized through Wittig reaction from commercially available benzaldehydes and the corresponding phosphonium salts. To a suspension of phosphonium salts (1.1 equiv) in THF (0.3 M) was added dropwise LiHMDS (1 M in THF, 1.1 equiv) at 0 °C, and the resulting mixture was stirred at 0 °C until a clear red solution formed (∼ 30 min); the reaction mixture was then placed in a − 78 °C cold bath. To this solution was added a THF (0.35 M) solution of benzaldehydes (1.0 equiv) over 5 min, and the resulting mixture was warmed to room temperature and stirred for 12 h. After consumption of the starting materials, the reaction was quenched by adding water at 0 °C, and the mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated under vacuum to give the crude product that was purified by flash column chromatography on silica gel (petroleum ether/dichloromethane, 1:0–2:1, v/v) to afford 8a–8x (for details about the structures, overall yields, and Z:E ratios, see Additional file 1: Scheme S1).
5-(3-(4-methoxyphenyl)allyl)benzo[d][1,3]dioxole (8a, 1:5 Z:E). yellow wax (477.0 mg, 87% yield); E isomer: 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 6.77 (d, J = 7.9 Hz, 1H), 6.75 (d, J = 1.2 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 6.40 (d, J = 15.7 Hz, 1H), 6.19 (dt, J = 15.7, 6.9 Hz, 1H), 5.93 (s, 2H), 3.81 (s, 3H), 3.45 (d, J = 6.8 Hz, 2H).; HRMS (ESI): m/z [M – H]– calcd for C17H15O3– 267.1027; found: 267.1025.
1-bromo-2-(3-phenylprop-1-en-1-yl)benzene (8b, 3:1 Z:E). colorless oil (51.3 mg, 75% yield); Z isomer: 1H NMR (600 MHz, CDCl3) δ 7.60 (dd, J = 8.0, 0.8 Hz, 1H), 7.31 (dd, J = 4.0, 2.4 Hz, 2H), 7.29 (s, 1H), 7.28 (d, J = 3.5 Hz, 1H), 7.21 (d, J = 6.5 Hz, 2H), 7.19 (s, 1H), 7.12 (td, J = 7.8, 1.6 Hz, 1H), 6.61 (d, J = 11.3 Hz, 1H), 5.96 (dt, J = 11.3, 7.6 Hz, 1H), 3.52 (d, J = 7.5 Hz, 2H); HRMS (ESI): m/z [M – H]– calcd for C15H12Br– 271.0128; found: 271.0125.
1-bromo-2-(3-(p-tolyl)prop-1-en-1-yl)benzene (8c, 5:4 Z:E). colorless oil (85.5 mg, 78% yield); Z isomer: 1H NMR (500 MHz, CDCl3) δ 7.60 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 7.4 Hz, 1H), 7.24 (overlapped, 1H), 7.12 (s, 1H), 7.10 (d, J = 3.6 Hz, 3H), 7.08 (d, J = 3.9 Hz, 1H), 6.60 (d, J = 11.2 Hz, 1H), 5.95 (dt, J = 11.3, 7.7 Hz, 1H), 3.48 (d, J = 7.5 Hz, 2H), 2.32 (s, 3H); HRMS (ESI): m/z [M – H]– calcd for C16H14Br– 285.0284; found: 285.0283.
1-bromo-2-(3-(4-chlorophenyl)prop-1-en-1-yl)benzene (8d, 5:2 Z:E). colorless oil (93.5 mg, 79% yield); Z isomer: 1H NMR (500 MHz, CDCl3) δ 7.60 (d, J = 8.0 Hz, 1H), 7.27 (s, 1H), 7.25 (d, J = 3.0 Hz, 2H), 7.18 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 4.9 Hz, 1H), 7.12 (s, 1H), 7.10 (s, 1H), 6.62 (d, J = 11.3 Hz, 1H), 5.91 (dt, J = 11.3, 7.6 Hz, 1H), 3.47 (d, J = 7.6 Hz, 2H); HRMS (ESI): m/z [M – H]– calcd for C15H11ClBr– 304.9738; found: 304.9736.
1-bromo-2-(3-(4-bromophenyl)prop-1-en-1-yl)benzene (8e, 5:2 Z:E). colorless oil (86.4 mg, 72% yield); Z isomer: 1H NMR (500 MHz, CDCl3) δ 7.61 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.28 (s, 1H), 7.27 (s, 1H), 7.15 (d, J = 4.0 Hz, 1H), 7.07 (d, J = 8.4 Hz, 2H), 6.63 (d, J = 11.3 Hz, 1H), 5.91 (dt, J = 11.3, 7.6 Hz, 1H), 3.46 (d, J = 7.6 Hz, 2H); HRMS (ESI): m/z [M – H]– calcd for C15H11Br2– 348.9233; found: 348.9231.
1-bromo-2-(3-(o-tolyl)prop-1-en-1-yl)benzene (8f, 2:1 Z:E). colorless oil (72.2 mg, 64% yield); Z isomer: 1H NMR (500 MHz, CDCl3) δ 7.61 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 7.4 Hz, 1H), 7.28 (d, J = 7.3 Hz, 1H), 7.19 (d, J = 7.5 Hz, 2H), 7.17 (d, J = 2.6 Hz, 1H), 7.14 (s, 2H), 6.63 (d, J = 11.3 Hz, 1H), 5.91 (dt, J = 11.3, 7.5 Hz, 1H), 3.49 (d, J = 7.4 Hz, 2H), 2.18 (s, 3H); HRMS (ESI): m/z [M – H]– calcd for C16H14Br– 285.0284; found: 285.0285.
5-(3-(2,5-bis(benzyloxy)-4-methoxyphenyl)allyl)benzo[d][1,3]dioxole (8g, 3:5 Z:E). yellow wax (75 mg, 65% yield); E isomer: 1H NMR (500 MHz, CDCl3) δ 7.43 (s, 2H), 7.42 (s, 1H), 7.40 (s, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.36 (t, J = 1.7 Hz, 1H), 7.34 (s, 2H), 7.31 (s, 1H), 7.30 (s, 1H), 7.03 (s, 1H), 6.74 (d, J = 4.4 Hz, 1H), 6.72 (dd, J = 4.1, 2.6 Hz, 2H), 6.70–6.66 (m, 1H), 6.54 (s, 1H), 6.10 (dt, J = 15.8, 6.9 Hz, 1H), 5.93 (s, 2H), 5.07 (s, 2H), 5.04 (s, 2H), 3.83 (s, 3H), 3.43 (d, J = 6.8 Hz, 2H); HRMS (ESI): m/z [M – H]– calcd for C31H27O5– 479.1864; found: 479.1861.
1-bromo-3,4,5-trimethoxy-2-(3-phenylprop-1-en-1-yl)benzene (8h, 3:2 Z:E). colorless oil (314.6 mg, 70% yield); Z isomer: 1H NMR (500 MHz, CDCl3) δ 7.31 (s, 1H), 7.29 (d, J = 1.7 Hz, 1H), 7.28 (s, 1H), 7.27 (s, 1H), 7.19 (s, 1H), 6.95 (s, 1H), 6.27 (dt, J = 11.0, 1.7 Hz, 1H), 5.97 (dt, J = 11.0, 7.2 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.78 (s, 3H), 3.32 (dd, J = 7.2, 1.2 Hz, 2H); HRMS (ESI): m/z [M – H]– calcd for C18H18O3Br– 361.0445; found: 361.0444.
(((2-methoxy-5-(4-phenylbut-1-en-1-yl)-1,4-phenylene)bis(oxy))bis(methylene)) dibenzene (8i, 2:3 Z:E). yellow wax (47.7 mg, 65% yield); E isomer: 1H NMR (500 MHz, CDCl3) δ 7.46 (s, 1H), 7.41 (s, 2H), 7.37 (s, 3H), 7.35 (s, 1H), 7.28 (s, 2H), 7.27 (s, 1H), 7.25 (s, 1H), 7.21 (d, J = 7.1 Hz, 3H), 7.14 (d, J = 7.1 Hz, 1H), 7.01 (s, 1H), 6.69 (d, J = 16.0 Hz, 1H), 6.53 (s, 1H), 6.04 (dt, J = 15.9, 6.9 Hz, 1H), 5.09 (s, 2H), 5.02 (s, 2H), 3.82 (s, 3H), 2.78–2.73 (m, 2H), 2.51 (dd, J = 14.6, 6.8 Hz, 2H); HRMS (ESI): m/z [M – H]– calcd for C31H29O3– 449.2122; found: 449.2125.
1-bromo-3,4,5-trimethoxy-2-(4-phenylbut-1-en-1-yl)benzene (8j, 1:1 Z:E). colorless oil (80.3 mg, 55% yield); Z/E mixture (1:1): 1H NMR (500 MHz, CDCl3) δ 7.29 (t, J = 7.4 Hz, 2H), 7.25 (overlapped, 4H), 7.19 (d, J = 7.2 Hz, 1H), 7.16 (d, J = 7.0 Hz, 3H), 6.90 (d, J = 7.4 Hz, 2H), 6.39–6.36 (overlapped, 2H), 6.17 (dt, J = 11.1, 1.5 Hz, 1H), 5.84 (dt, J = 11.1, 7.2 Hz, 1H), 3.86 (s, 3H), 3.85 (overlapped, 6H), 3.84 (s, 3H), 3.72 (s, 3H), 3.71 (s, 3H), 2.87 – 2.79 (m, 2H), 2.75–2.67 (m, 2H), 2.62–2.53 (m, 2H), 2.32–2.25 (m, 2H). HRMS (ESI): m/z [M – H]– calcd for C19H20O3Br– 375.0601; found: 375.0603.
4,4'-(prop-1-ene-1,3-diyl)bis(methoxybenzene) (8k, 3:5 Z:E). white wax (66.6 mg, 69% yield); Z isomer: 1H NMR (500 MHz, CDCl3) δ 7.47–7.44 (m, 1H), 7.30 (t, J = 2.9 Hz, 2H), 7.16 (dd, J = 5.0, 2.9 Hz, 2H), 6.91 (dd, J = 5.6, 3.2 Hz, 1H), 6.88 (d, J = 2.1 Hz, 1H), 6.83 (d, J = 2.1 Hz, 1H), 6.50 (d, J = 11.5 Hz, 1H), 5.75 (dt, J = 11.5, 7.5 Hz, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.62 (dd, J = 7.5, 1.5 Hz, 2H); HRMS (ESI): m/z [M – H]– calcd for C17H17O2– 253.1234; found: 253.1231.
1-methyl-2-(3-phenylallyl)benzene (8l, 2:1 Z:E). colorless oil (64 mg, 60% yield); Z isomer: 1H NMR (500 MHz, CDCl3) δ 7.35 (s, 1H), 7.34 (s, 2H), 7.33 (s, 2H), 7.20 (d, J = 1.9 Hz, 1H), 7.17 (d, J = 2.7 Hz, 1H), 7.16 (d, J = 2.9 Hz, 1H), 7.15 (s, 1H), 6.60 (d, J = 11.5 Hz, 1H), 5.79 (dt, J = 11.5, 7.3 Hz, 1H), 3.64 (dd, J = 7.3, 1.5 Hz, 2H), 2.22 (s, 3H); HRMS (ESI): m/z [M – H]– calcd for C16H15– 207.1179; found: 207.1175.
1-(3-(4-methoxyphenyl)allyl)-2-methylbenzene (8m, 2:3 Z:E). colorless oil (84.9 mg, 71% yield); E isomer: 1H NMR (500 MHz, CDCl3) δ 7.28 (s, 1H), 7.27 (s, 1H), 7.17 (d, J = 4.8 Hz, 2H), 7.15 (d, J = 2.2 Hz, 1H), 7.15 (s, 1H), 6.85–6.80 (m, 2H), 6.32 (d, J = 15.8 Hz, 1H), 6.19 (dt, J = 15.8, 6.5 Hz, 1H), 3.80 (s, 3H), 3.51 (d, J = 6.5 Hz, 2H), 2.34 (s, 3H); HRMS (ESI): m/z [M – H]– calcd for C17H17O– 237.1285; found: 237.1288.
1-chloro-4-(3-phenylallyl)benzene (8n, 2:1 Z:E). colorless oil (131.3 mg, 77% yield); Z isomer: 1H NMR (500 MHz, CDCl3) δ 7.45 (d, J = 8.6 Hz, 1H), 7.35 (d, J = 3.3 Hz, 2H), 7.34 (d, J = 1.8 Hz, 1H), 7.28–7.27 (overlapped, 2H), 7.16 (d, J = 3.1 Hz, 1H), 7.14 (s, 1H), 7.13 (d, J = 2.6 Hz, 1H), 6.61 (d, J = 11.5 Hz, 1H), 5.81 (dt, J = 11.5, 7.5 Hz, 1H), 3.46 (d, J = 5.5 Hz, 2H); HRMS (ESI): m/z [M – H]– calcd for C15H12Cl– 227.0633; found: 227.0630.
1-chloro-4-(3-(4-methoxyphenyl)allyl)benzene (8o, 4:5 Z:E). white wax (86 mg, 28% yield); E isomer: 1H NMR (500 MHz, CDCl3) δ 7.43 (d, J = 8.6 Hz, 1H), 7.31 (d, J = 2.7 Hz, 1H), 7.29 (d, J = 1.7 Hz, 1H), 7.27 (d, J = 1.9 Hz, 1H), 7.17 (d, J = 7.9 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.38 (d, J = 15.7 Hz, 1H), 6.16 (dt, J = 15.7, 6.9 Hz, 1H), 3.84 (s, 3H), 3.63 (d, J = 7.4 Hz, 2H); HRMS (ESI): m/z [M – H]– calcd for C16H14ClO– 257.0739; found: 257.0740.
1-(3-phenylallyl)naphthalene (8p, 2:1 Z:E). yellow oil (58.7 mg, 53% yield); Z isomer: 1H NMR (500 MHz, CDCl3) δ 7.90 (d, J = 9.0 Hz, 1H), 7.88 (dd, J = 6.5, 2.9 Hz, 1H), 7.50 – 7.48 (m, 1H), 7.48 (s, 1H), 7.48–7.46 (m, 1H), 7.43 (d, J = 3.4 Hz, 1H), 7.42 (s, 1H), 7.39 (d, J = 1.6 Hz, 2H), 7.38 (s, 1H), 7.30 (t, J = 2.0 Hz, 1H), 7.28 (s, 1H), 6.65 (d, J = 11.5 Hz, 1H), 5.95 (dt, J = 11.5, 7.2 Hz, 1H), 4.12 (dd, J = 7.2, 1.7 Hz, 2H); HRMS (ESI): m/z [M – H]– calcd for C19H15– 243.1179; found: 243.1178.
1-fluoro-2-(3-phenylallyl)benzene (8q, 3:2 Z:E). colorless oil (48.9 mg, 59% yield); Z isomer: 1H NMR (500 MHz, CDCl3) δ 7.37 (s, 1H), 7.35 (s, 2H), 7.34 (s, 1H), 7.23 (d, J = 7.2 Hz, 2H), 7.21 (s, 1H), 7.10 (dd, J = 4.5, 3.0 Hz, 1H), 7.08 (d, J = 7.5 Hz, 1H), 6.62 (d, J = 11.5 Hz, 1H), 5.83 (dt, J = 11.5, 7.5 Hz, 1H), 3.70 (d, J = 7.4 Hz, 2H); HRMS (ESI): m/z [M – H]– calcd for C15H12F– 211.0929; found: 211.0925.
1-bromo-2-(3-(2-fluorophenyl)prop-1-en-1-yl)benzene (8r, 5:1 Z:E). colorless oil (36.8 mg, 32% yield); Z isomer: 1H NMR (500 MHz, CDCl3) δ 7.61 (dd, J = 8.0, 0.9 Hz, 1H), 7.33 (dd, J = 7.6, 1.7 Hz, 1H), 7.31–7.28 (m, 1H), 7.20 (s, 1H), 7.19 (s, 1H), 7.15 (dd, J = 7.6, 1.7 Hz, 1H), 7.10–7.07 (m, 1H), 7.02 (dd, J = 13.4, 4.8 Hz, 1H), 6.63 (d, J = 11.3 Hz, 1H), 5.94 (dt, J = 11.3, 7.5 Hz, 1H), 3.54 (d, J = 7.6 Hz, 2H); HRMS (ESI): m/z [M – H]– calcd for C15H12FBr– 290.0112; found: 290.0110.
1-chloro-2-(3-phenylallyl)benzene (8s, 1:1 Z:E). colorless oil (56.6 mg, 65% yield); Z/E mixture (1:1): 1H NMR (400 MHz, CDCl3) δ 7.40–7.31 (overlapped, 6H), 7.30 (s, 2H), 7.28 (s, 2H), 7.26 (overlapped, 1H), 7.24 (s, 2H), 7.18 (overlapped, 5H), 6.63 (d, J = 11.5 Hz, 1H), 6.44 (d, J = 15.5 Hz, 1H), 6.39–6.27 (m, 1H), 5.86–5.73 (m, 1H), 3.76 (d, J = 7.3 Hz, 2H), 3.65 (d, J = 6.3 Hz, 2H); HRMS (ESI): m/z [M – H]– calcd for C15H12Cl– 227.0633; found: 227.0631.
1-bromo-2-(3-(2-chlorophenyl)prop-1-en-1-yl)benzene (8t, 5:1 Z:E). colorless oil (49.8 mg, 54% yield); Z isomer: 1H NMR (500 MHz, CDCl3) δ 7.64–7.58 (m, 1H), 7.35 (dd, J = 7.8, 1.2 Hz, 1H), 7.30 (d, J = 2.3 Hz, 1H), 7.24 (dd, J = 7.5, 2.0 Hz, 1H), 7.21 (dd, J = 7.2, 1.3 Hz, 1H), 7.18 (dd, J = 4.3, 1.9 Hz, 1H), 7.15 (t, J = 1.9 Hz, 1H), 7.14 (s, 1H), 6.66 (d, J = 11.3 Hz, 1H), 5.94 (dt, J = 11.3, 7.5 Hz, 1H), 3.62 (dd, J = 7.5, 1.3 Hz, 2H); HRMS (ESI): m/z [M – H]– calcd for C15H11ClBr– 304.9738; found: 304.9739.
1-fluoro-2-(3-(4-methoxyphenyl)allyl)benzene (8u, 4:5 Z:E). colorless oil (63.5 mg, 67% yield); E isomer: 1H NMR (500 MHz, CDCl3) δ 7.29–7.26 (m, 2H), 7.20 (ddd, J = 7.3, 6.2, 1.6 Hz, 2H), 7.09 (dd, J = 7.5, 1.3 Hz, 2H), 6.84 (dd, J = 8.7, 1.8 Hz, 2H), 6.41 (d, J = 15.7 Hz, 1H), 6.20 (dtd, J = 15.7, 6.9, 1.8 Hz, 1H), 3.80 (d, J = 1.2 Hz, 3H), 3.55 (d, J = 6.8 Hz, 2H); HRMS (ESI): m/z [M – H]– calcd for C16H14OF– 241.1034; found: 241.1036.
prop-1-ene-1,3-diyldibenzene (8v, 5:3 Z:E). yellow oil (77.9 mg, 80% yield); Z isomer: 1H NMR (500 MHz, CDCl3) δ 7.38 (s, 1H), 7.36 (s, 2H), 7.34 (s, 2H), 7.32 (d, J = 3.3 Hz, 2H), 7.24 (s, 2H), 7.22 (d, J = 1.7 Hz, 1H), 6.60 (d, J = 11.5 Hz, 1H), 5.87 (dt, J = 11.5, 7.5 Hz, 1H), 3.69 (d, J = 7.5 Hz, 2H); HRMS (ESI): m/z [M – H]– calcd for C15H13– 193.1023; found: 193.1022.
1,2-dimethoxy-4-(3-(4-methoxyphenyl)allyl)benzene (8w, 1:2 Z:E). white wax (87.8 mg, 72% yield); E isomer: 1H NMR (500 MHz, CDCl3) δ 7.30 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 6.81 (s, 1H), 6.79 (t, J = 2.1 Hz, 1H), 6.76 (d, J = 1.7 Hz, 1H), 6.39 (d, J = 15.7 Hz, 1H), 6.20 (dt, J = 15.7, 6.8 Hz, 1H), 3.87 (s, 3H), 3.87 (s, 3H), 3.80 (s, 3H), 3.47 (d, J = 6.7 Hz, 2H); HRMS (ESI): m/z [M – H]– calcd for C18H19O3– 283.1340, found: 283.1344.
2-bromo-3-(3-(3-methoxyphenyl)prop-1-en-1-yl)pyridine (8x, 5:2 Z:E). colorless oil (76.2 mg, 66% yield); Z isomer: 1H NMR (600 MHz, CDCl3) δ 8.28 (dd, J = 4.5, 1.5 Hz, 1H), 7.59 (dd, J = 7.4, 1.3 Hz, 1H), 7.25 (dd, J = 7.5, 4.8 Hz, 1H), 7.10 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 6.55 (d, J = 11.4 Hz, 1H), 6.05 (dt, J = 11.3, 7.7 Hz, 1H), 3.79 (s, 3H), 3.44 (d, J = 7.6 Hz, 2H); HRMS (ESI): m/z [M + H]+ calcd for C15H15ONBr+ 304.0332, found: 304.0336.
4.3 General procedure for Prins cyclization of 1,3-dioxanes 7
A reaction tube charged with a solution of (CHO)n (50 wt%), TfOH (10 mol%) in freshly distilled DCM (0.1 M) were stirred for 20 min at room temperature. Then the reaction mixture was cooled to 0 ℃ for 5 min, and was added of 8 (0.1 mmol, 1.0 equiv) in the DCM (0.5 M). The reaction was stirred at 0 ℃ for 4 h. Then the reaction mixture was warmed to room temperature for 20 h. The reaction was quenched with NaHCO3 saturated aqueous solution, and was extracted with dichloromethane. The combined organic layer was dried over Na2SO4, filtered, and concentrated to give the crude product that was further purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 25:1–2:1, v/v) to afford 7a–7v, 11a, 11a′ and 11b.
5-((trans-4-(4-methoxyphenyl)-1,3-dioxan-5-yl)methyl)benzo[d][1,3]dioxole (7a). yellow solid (25.9 mg, 79% yield): mp 112.4−113.0 °C; 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 8.5 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 6.66 (d, J = 7.8 Hz, 1H), 6.44 (s, 1H), 6.41 (d, J = 8.0 Hz, 1H), 5.89 (s, 2H), 5.15 (d, J = 6.2 Hz, 1H), 4.80 (d, J = 6.3 Hz, 1H), 4.21 (d, J = 9.9 Hz, 1H), 3.99 (dd, J = 11.4, 4.3 Hz, 1H), 3.83 (s, 3H), 3.43 (t, J = 11.1 Hz, 1H), 2.38 (dd, J = 13.8, 3.6 Hz, 1H), 2.35–2.23 (m, 1H), 2.00 (dd, J = 13.7, 10.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 159.8, 147.7, 146.0, 132.2, 131.5, 129.0, 129.0, 121.6, 114.1, 114.1, 109.1, 108.2, 101.0, 94.3, 84.5, 71.5, 55.4, 42.8, 34.4; HRMS (ESI): m/z [M + H]+ calcd for C19H21O5+ 329.1384, found: 329.1383.
(trans-5-(4-methoxyphenyl)-6,7-dihydro-5H-indeno[5,6-d][1,3]dioxol-6-yl)methanol (11a). yellow solid (3.0 mg, 10% yield): mp 167.1–169.1 ℃; 1H NMR (400 MHz, CDCl3) δ 7.09 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 6.72 (s, 1H), 6.34 (s, 1H), 5.89 (dd, J = 8.0, 1.0 Hz, 2H), 3.98 (d, J = 8.1 Hz, 1H), 3.83–3.76 (overlapped, 4H), 3.71 (dd, J = 10.6, 6.7 Hz, 1H), 3.08 (dd, J = 15.4, 8.0 Hz, 1H), 2.73 (dd, J = 15.4, 8.3 Hz, 1H), 2.65–2.54 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 158.5, 147.0, 146.8, 139.3, 136.7, 135.4, 129.4, 129.4, 114.1, 114.1, 105.7, 105.0, 101.0, 65.3, 55.4, 53.5, 53.2, 35.1; HRMS (ESI): m/z [M + H]+ calcd for C18H19O4+ 299.1278, found: 299.1278.
(cis-5-(4-methoxyphenyl)-6,7-dihydro-5H-indeno[5,6-d][1,3]dioxol-6-yl)methanol (11a′). The product was obtained under the conditions in Table 1, entry 3, as a yellow solid (4.2 mg, 14% yield): mp 98.5–100.1 ℃; 1H NMR (400 MHz, CDCl3) δ 7.05 (dd, J = 8.5, 4.3 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 6.69 (s, 1H), 6.33 (s, 1H), 5.89 (d, J = 7.3 Hz, 2H), 4.66 (s, 1H), 3.95 (t, J = 7.6 Hz, 1H), 3.79 (s, 3H), 3.70–3.52 (m, 2H), 3.03 (ddd, J = 14.9, 7.7, 2.4 Hz, 1H), 2.74–2.56 (overlapped, 2H); 13C NMR (100 MHz, CDCl3) δ 158.4, 146.9, 146.8, 139.2, 136.6, 135.7, 129.4, 129.4, 114.0, 114.0, 105.7, 105.0, 101.0, 69.9, 69.7, 55.4, 53.2, 51.1, 51.0, 35.6; HRMS (ESI): m/z [M + H]+ calcd for C18H19O4+: 299.1278; found: 299.1276.
((trans)-5,6-dimethoxy-1-(4-methoxyphenyl)-2,3-dihydro-1H-inden-2-yl)methanol (11b). yellow wax (15.7 mg, 50% yield); 1H NMR (400 MHz, CDCl3) δ 7.10 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 6.80 (s, 1H), 6.41 (s, 1H), 4.04 (d, J = 8.0 Hz, 1H), 3.88 (s, 3H), 3.83–3.78 (overlapped, 4H), 3.75–3.70 (overlapped, 4H), 3.12 (dd, J = 15.4, 8.1 Hz, 1H), 2.77 (dd, J = 15.4, 8.1 Hz, 1H), 2.64–2.49 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 158.4, 148.5, 148.4, 137.9, 136.9, 134.4, 129.4, 129.4, 114.1, 114.1, 108.2, 107.6, 65.4, 56.2, 56.2, 55.4, 53.5, 53.5, 35.1; HRMS (ESI): m/z [M + H]+ calcd for C19H23O4+ 315.1591, found: 315.1591.
trans-5-benzyl-4-(2-bromophenyl)-1,3-dioxane (7b). yellow oil (22.9 mg, 69% yield); 1H NMR (500 MHz, CDCl3) δ 7.63 (dd, J = 7.8, 1.5 Hz, 1H), 7.58 (dd, J = 8.0, 0.9 Hz, 1H), 7.41 (dd, J = 11.0, 4.1 Hz, 1H), 7.20 (td, J = 6.7, 2.8 Hz, 3H), 7.15 (t, J = 7.3 Hz, 1H), 6.97 (d, J = 7.2 Hz, 2H), 5.18 (d, J = 6.3 Hz, 1H), 4.96 (d, J = 9.9 Hz, 1H), 4.87 (d, J = 6.3 Hz, 1H), 3.98 (dd, J = 11.5, 4.2 Hz, 1H), 3.54 (t, J = 11.1 Hz, 1H), 2.48 (dd, J = 13.7, 3.4 Hz, 1H), 2.44–2.35 (m, 1H), 2.28 (dd, J = 13.7, 11.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 138.9, 138.4, 132.7, 129.9, 129.2, 128.7, 128.7,128.5, 128.5, 128.3, 126.4, 124.3, 94.4, 82.4, 71.4, 43.8, 34.1; HRMS (ESI): m/z [M + NH4]+ calcd for C17H21 O2NBr+ 350.0750, found: 350.0751.
trans-4-(2-bromophenyl)-5-(4-methylbenzyl)-1,3-dioxane (7c). colorless oil (17.7 mg, 51% yield); 1H NMR (500 MHz, CDCl3) δ 7.62 (dd, J = 7.8, 1.6 Hz, 1H), 7.58 (dd, J = 8.0, 1.1 Hz, 1H), 7.43–7.39 (m, 1H), 7.20 (td, J = 7.9, 1.7 Hz, 1H), 7.02 (d, J = 7.8 Hz, 2H), 6.85 (d, J = 7.9 Hz, 2H), 5.17 (d, J = 6.3 Hz, 1H), 4.94 (d, J = 9.9 Hz, 1H), 4.86 (d, J = 6.3 Hz, 1H), 3.98 (dd, J = 11.5, 4.2 Hz, 1H), 3.52 (t, J = 11.1 Hz, 1H), 2.44 (dd, J = 13.7, 3.4 Hz, 1H), 2.41–2.31 (m, 1H), 2.28 (s, 3H), 2.24 (dd, J = 13.7, 11.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 139.0, 135.9, 135.2, 132.8, 129.9, 129.2, 129.2, 129.2, 128.6, 128.6, 128.3, 124.4, 94.4, 82.5, 71.5, 43.8, 33.7, 21.1; HRMS (ESI): m/z [M – H]– calcd for C18H19O2ClBr– 381.0262, found: 381.0265.
trans-4-(2-bromophenyl)-5-(4-chlorobenzyl)-1,3-dioxane (7d). colorless oil (24.8 mg, 68% yield); 1H NMR (500 MHz, CDCl3) δ 7.64 – 7.57 (m, 2H), 7.42 (t, J = 7.5 Hz, 1H), 7.23 (dd, J = 7.8, 1.6 Hz, 1H), 7.21–7.17 (m, 2H), 6.91 (d, J = 8.3 Hz, 2H), 5.20 (d, J = 6.3 Hz, 1H), 4.96 (d, J = 9.7 Hz, 1H), 4.89 (d, J = 6.3 Hz, 1H), 3.98 (dd, J = 11.5, 4.1 Hz, 1H), 3.54 (t, J = 11.0 Hz, 1H), 2.46 (dd, J = 13.5, 3.4 Hz, 1H), 2.43–2.33 (m, 1H), 2.29 (dd, J = 13.4, 10.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 138.8, 136.9, 132.8, 132.2, 130.0, 130.0, 130.0, 129.2, 128.7, 128.7, 128.3, 124.2, 94.4, 82.36, 71.3, 43.8, 33.5; HRMS (ESI): m/z [M – H]– calcd for C17H15O2ClBr– 364.9949, found: 364.9948.
trans-5-(4-bromobenzyl)-4-(2-bromophenyl)-1,3-dioxane (7e). white solid (30 mg, 73% yield): mp 90.9–91.5 °C; 1H NMR (500 MHz, CDCl3) δ 7.58 (ddd, J = 13.2, 7.9, 1.3 Hz, 2H), 7.42 – 7.38 (m, 1H), 7.34–7.29 (m, 2H), 7.20 (td, J = 7.8, 1.7 Hz, 1H), 6.83 (d, J = 8.3 Hz, 2H), 5.17 (d, J = 6.3 Hz, 1H), 4.93 (d, J = 9.8 Hz, 1H), 4.86 (d, J = 6.3 Hz, 1H), 3.95 (dd, J = 11.5, 4.1 Hz, 1H), 3.51 (t, J = 11.0 Hz, 1H), 2.42 (dd, J = 13.5, 3.5 Hz, 1H), 2.33 (ddd, J = 13.8, 10.2, 5.0 Hz, 1H), 2.25 (dd, J = 13.5, 10.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 138.8, 137.4, 132.8, 131.6, 131.6, 130.4, 130.4, 130.0, 129.2, 128.3, 124.2, 120.2, 94.4, 82.4, 71.2, 43.7, 33.6; HRMS (ESI): m/z [M + Na]+ calcd for C17H15O2Br2Na+ 432.9409, found: 423.9607.
trans-4-(2-bromophenyl)-5-(2-methylbenzyl)-1,3-dioxane (7f). yellow oil (21.2 mg, 61% yield); 1H NMR (500 MHz, CDCl3) δ 7.61 (ddd, J = 20.9, 7.9, 1.4 Hz, 2H), 7.44–7.39 (m, 1H), 7.23–7.19 (m, 1H), 7.09–7.02 (m, 3H), 6.93–6.89 (m, 1H), 5.19 (d, J = 6.3 Hz, 1H), 5.01–4.96 (m, 1H), 4.89 (d, J = 6.3 Hz, 1H), 4.01 (dd, J = 11.6, 3.1 Hz, 1H), 3.63–3.55 (m, 1H), 2.44 (dd, J = 12.9, 7.1 Hz, 1H), 2.30 (overlapped, 2H), 1.96 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 139.1, 136.6, 136.0, 132.7, 130.6, 129.9, 129.6, 129.3, 128.2, 126.6, 125.9, 124.2, 94.4, 82.5, 71.6, 42.8, 31.5, 19.1; HRMS (ESI): m/z [M – H]– calcd for C18H18O2Br– 345.0496, found: 345.0494.
5-((trans-4-(2,5-bis(benzyloxy)-4-methoxyphenyl)-1,3-dioxan-5-yl)methyl)benzo [d][1,3]dioxole (7g). colorless oil (9.5 mg, 28% yield); 1H NMR (500 MHz, CDCl3) δ 7.49–7.29 (overlapped, 10H), 7.08 (s, 1H), 6.62 (d, J = 7.8 Hz, 1H), 6.56 (s, 1H), 6.32 (s, 1H), 6.30 (d, J = 7.9 Hz, 1H), 5.89 (dd, J = 4.3, 1.3 Hz, 2H), 5.18 (d, J = 12.1 Hz, 1H), 5.13 (s, 1H), 5.10 (d, J = 12.3 Hz, 1H), 5.06 (s, 2H), 4.81 (d, J = 10.0 Hz, 1H), 4.77 (d, J = 6.2 Hz, 1H), 3.91 (dd, J = 11.3, 4.2 Hz, 1H), 3.85 (s, 3H), 3.38 (t, J = 11.2 Hz, 1H), 2.29 (dd, J = 14.0, 3.8 Hz, 1H), 2.19–2.07 (m, 1H), 1.97 (dd, J = 14.0, 10.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 151.2, 150.5, 147.7, 146.0, 143.3, 137.5, 137.3, 132.5, 128.8, 128.8, 128.7, 128.7, 128.2, 128.0, 127.7, 127.7, 127.6, 127.6, 121.6, 120.3, 114.6, 109.2, 108.1, 100.9, 100.2, 99.7, 94.4, 72.1, 72.0, 71.6, 56.4, 43.1, 34.1; HRMS (ESI): m/z [M + H]+ calcd for C33H33O7+ 541.2221, found: 541.2221.
trans-5-benzyl-4-(6-bromo-2,3,4-trimethoxyphenyl)-1,3-dioxane (7h). yellow oil (32.1 mg, 76% yield); 1H NMR (500 MHz, CDCl3) δ 7.18 (t, J = 7.3 Hz, 2H), 7.11 (t, J = 7.3 Hz, 1H), 7.01 (d, J = 7.1 Hz, 2H), 6.89 (s, 1H), 5.19 (d, J = 6.1 Hz, 1H), 4.92 (d, J = 10.1 Hz, 1H), 4.82 (d, J = 6.2 Hz, 1H), 4.01 (dd, J = 11.3, 4.4 Hz, 1H), 3.94 (s, 3H), 3.85 (s, 3H), 3.83 (s, 3H), 3.44 (t, J = 11.1 Hz, 1H), 3.21 (s, 1H), 2.40 (dd, J = 14.0, 4.6 Hz, 1H), 2.18 (dd, J = 13.9, 9.9 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 154.4, 154.4, 154.0, 143.0, 138.9, 128.7, 128.7, 128.4, 128.4, 126.1, 124.4, 112.5, 94.6, 83.9, 72.2, 62.1, 60.9, 56.3, 39.1, 34.9; HRMS (ESI): m/z [M + H]+ calcd for C20H24O5Br+ 423.0786, found: 423.0786.
trans-4-(2,5-bis(benzyloxy)-4-methoxyphenyl)-5-phenethyl-1,3-dioxane (7i). yellow wax (34.7 mg, 68% yield); 1H NMR (500 MHz, CDCl3) δ 7.45 (d, J = 7.4 Hz, 2H), 7.39–7.27 (m, 8H), 7.20 (t, J = 7.4 Hz, 2H), 7.13 (t, J = 7.3 Hz, 1H), 6.99 (s, 1H), 6.95 (d, J = 7.3 Hz, 2H), 6.55 (s, 1H), 5.14 (d, J = 6.2 Hz, 1H), 5.11–4.98 (m, 4H), 4.82–4.75 (m, 2H), 4.23 (dd, J = 11.3, 4.4 Hz, 1H), 3.83 (s, 3H), 3.46 (t, J = 11.1 Hz, 1H), 2.45–2.35 (m, 1H), 2.21 (ddd, J = 13.9, 10.0, 6.6 Hz, 1H), 2.04–1.94 (m, 1H), 1.41–1.31 (m, 1H), 1.25–1.14 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 151.2, 150.4, 143.3, 141.9, 137.5, 137.3, 128.7, 128.7, 128.6, 128.6, 128.4, 128.4, 128.3, 128.3, 128.1, 127.9, 127.8, 127.8, 127.6, 127.6, 126.0, 120.5, 114.6, 99.7, 94.4, 75.5, 72.0, 72.0, 71.9, 56.4, 40.8, 32.8, 29.3; HRMS (ESI): m/z [M + H]+ calcd for C33H35O5+ 511.2478, found: 511.2478.
trans-4-(6-bromo-2,3,4-trimethoxyphenyl)-5-phenethyl-1,3-dioxane (7j). colorless oil (22.9 mg, 50% yield); 1H NMR (600 MHz, CDCl3) δ 7.21 (t, J = 7.5 Hz, 2H), 7.13 (t, J = 7.4 Hz, 1H), 7.03 (d, J = 7.3 Hz, 2H), 6.89 (s, 1H), 5.19 (d, J = 6.1 Hz, 1H), 4.87 (d, J = 10.2 Hz, 1H), 4.81 (d, J = 6.2 Hz, 1H), 4.28 (dd, J = 11.2, 4.5 Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.45 (t, J = 11.1 Hz, 1H), 2.94–2.83 (m, 1H), 2.49 (ddd, J = 14.1, 10.4, 5.6 Hz, 1H), 2.30 (ddd, J = 13.8, 10.2, 6.6 Hz, 1H), 1.42–1.32 (m, 1H), 1.34–1.26 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 154.6, 154.5, 154.0, 142.9, 142.0, 128.5, 128.5, 128.3, 128.3, 126.0, 124.6, 111.9, 94.5, 84.5, 72.2, 61.9, 60.9, 56.3, 37.2, 32.9, 30.1; HRMS (ESI): m/z [M + H]+ calcd for C21H26O5Br+ 437.0958, found: 437.0955.
trans-5-(4-methoxybenzyl)-4-(4-methoxyphenyl)-1,3-dioxane (7k). white solid (21.7 mg, 69% yield): mp 113.6–115.6 °C; 1H NMR (500 MHz, CDCl3) δ 7.40 – 7.33 (m, 2H), 6.94 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 6.76 (d, J = 8.6 Hz, 2H), 5.16 (d, J = 6.3 Hz, 1H), 4.81 (d, J = 6.3 Hz, 1H), 4.23 (d, J = 10.0 Hz, 1H), 3.98 (dd, J = 11.5, 4.3 Hz, 1H), 3.83 (s, 3H), 3.76 (s, 3H), 3.44 (t, J = 11.2 Hz, 1H), 2.42 (dd, J = 13.9, 3.6 Hz, 1H), 2.37–2.26 (m, 1H), 2.03 (dd, J = 13.9, 10.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 159.9, 158.2, 131.7, 130.5, 129.7, 129.7, 129.0, 129.0, 114.2, 114.2, 114.0, 114.0, 94.3, 84.6, 71.6, 55.5, 55.4, 42.8, 33.8; HRMS (ESI): m/z [M + Na]+ calcd for C19H22O4Na+ 337.1410, found: 337.1411.
trans-5-(2-methylbenzyl)-4-phenyl-1,3-dioxane (7l). white wax (17.1 mg, 64% yield); 1H NMR (500 MHz, CDCl3) δ 7.47 (d, J = 7.0 Hz, 2H), 7.41 (t, J = 7.2 Hz, 2H), 7.39–7.34 (m, 1H), 7.09–7.03 (overlapped, 3H), 6.94–6.89 (m, 1H), 5.20 (d, J = 6.2 Hz, 1H), 4.87 (d, J = 6.2 Hz, 1H), 4.33 (d, J = 9.9 Hz, 1H), 3.99 (dd, J = 11.4, 4.4 Hz, 1H), 3.53 (t, J = 11.1 Hz, 1H), 2.46 (dd, J = 13.9, 3.2 Hz, 1H), 2.38–2.25 (m, 1H), 2.12 (dd, J = 13.8, 11.5 Hz, 1H), 1.97 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 139.4, 136.6, 136.1, 130.6, 129.7, 128.7, 128.7, 128.7, 127.8, 127.8, 126.5, 125.9, 94.3, 85.3, 71.7, 41.6, 32.0, 19.1; HRMS (ESI): m/z [M + NH4]+ calcd for C18H24O2N+ 286.1802, found: 286.1806.
trans-4-(4-methoxyphenyl)-5-(2-methylbenzyl)-1,3-dioxane (7 m). colorless oil (20.0 mg, 67% yield); 1H NMR (500 MHz, CDCl3) δ 7.38 (d, J = 8.6 Hz, 2H), 7.08–7.02 (overlapped, 3H), 6.93 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 6.1 Hz, 1H), 5.17 (d, J = 6.2 Hz, 1H), 4.84 (d, J = 6.2 Hz, 1H), 4.26 (d, J = 9.9 Hz, 1H), 3.96 (dd, J = 11.5, 4.3 Hz, 1H), 3.83 (s, 3H), 3.51–3.47 (m, 1H), 2.45 (dd, J = 13.9, 3.2 Hz, 1H), 2.35–2.25 (m, 1H), 2.09 (dd, J = 13.8, 11.5 Hz, 1H), 2.00 (s, 3H).; 13C NMR (125 MHz, CDCl3) δ 159.9, 136.8, 136.1, 131.70, 130.6, 129.7, 129.0, 129.0, 126.5, 125.9, 114.1, 114.1, 94.3, 84.9, 71.8, 55.5, 41.6, 32.1, 19.3; HRMS (ESI): m/z [M + K]+ calcd for C19H22O3K+ 337.1201, found: 337.1200.
trans-5-(4-chlorobenzyl)-4-phenyl-1,3-dioxane (7n). white solid (16.1 mg, 56% yield): mp 100.7–102.0 °C; 1H NMR (500 MHz, CDCl3) δ 7.45–7.33 (overlapped, 5H), 7.18 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.3 Hz, 2H), 5.18 (d, J = 6.3 Hz, 1H), 4.83 (d, J = 6.3 Hz, 1H), 4.28 (d, J = 9.9 Hz, 1H), 3.95 (dd, J = 11.5, 4.3 Hz, 1H), 3.45 (t, J = 11.1 Hz, 1H), 2.43 (dd, J = 13.9, 3.7 Hz, 1H), 2.34 (dt, J = 10.0, 4.0 Hz, 1H), 2.09 (dd, J = 13.9, 10.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 139.2, 136.9, 132.2, 130.1, 130.1, 128.8, 128.8, 128.8, 128.7, 128.7, 127.8, 127.8, 94.3, 85.0, 71.3, 42.6, 34.0; HRMS (ESI): m/z [M + K]+ calcd for C17H17O2ClK+ 327.0549, found: 327.0547.
trans-5-(4-chlorobenzyl)-4-(4-methoxyphenyl)-1,3-dioxane (7o). white solid (20.3 mg, 64% yield): mp 123.5 − 126.9 °C; 1H NMR (500 MHz, CDCl3) δ 7.34 (d, J = 8.7 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.3 Hz, 2H), 5.15 (d, J = 6.2 Hz, 1H), 4.81 (d, J = 6.3 Hz, 1H), 4.22 (d, J = 9.9 Hz, 1H), 3.95 (dd, J = 11.4, 4.4 Hz, 1H), 3.83 (s, 3H), 3.44 (t, J = 11.1 Hz, 1H), 2.43 (dd, J = 13.9, 3.7 Hz, 1H), 2.31 (ddt, J = 10.6, 8.3, 5.2 Hz, 1H), 2.07 (dd, J = 13.9, 10.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 160.0, 137.0, 132.2, 131.4, 130.1, 130.1, 129.0, 129.0, 128.7, 128.7, 114.2, 114.2, 94.3, 84.5, 71.4, 55.5, 42.69, 34.1; HRMS (ESI): m/z [M – H]– calcd for C18H18O3Cl– 317.0950, found: 317.0951.
trans-5-(naphthalen-1-ylmethyl)-4-phenyl-1,3-dioxane (7p). yellow wax (4.2 mg, 14% yield); 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.56 (dd, J = 8.1, 1.3 Hz, 2H), 7.52 – 7.47 (m, 2H), 7.45 (dt, J = 5.0, 1.8 Hz, 1H), 7.41 (dd, J = 8.2, 1.3 Hz, 1H), 7.32 (ddd, J = 8.9, 6.8, 1.9 Hz, 2H), 7.26 (d, J = 8.3 Hz, 1H), 7.13 (d, J = 6.9 Hz, 1H), 5.19 (d, J = 6.2 Hz, 1H), 4.88 (d, J = 6.2 Hz, 1H), 4.42 (d, J = 9.4 Hz, 1H), 3.90 (dd, J = 11.3, 3.8 Hz, 1H), 3.61–3.52 (m, 1H), 3.01 (d, J = 11.3 Hz, 1H), 2.56–2.41 (overlapped, 2H); 13C NMR (100 MHz, CDCl3) δ 139.5, 134.5, 134.1, 131.7, 128.9, 128.9, 128.8, 128.8, 128.0, 128.0, 127.4, 126.9, 126.0, 125.7, 125.2, 123.7, 94.2, 85.2, 71.9, 41.9, 31.8; HRMS (ESI): m/z [M + NH4]+ calcd for C21H24O2N+ 322.1802, found: 322.1805.
trans-5-(2-fluorobenzyl)-4-phenyl-1,3-dioxane (7q). colorless oil (23.9 mg, 88% yield); 1H NMR (500 MHz, CDCl3) δ 7.45 (d, J = 7.0 Hz, 2H), 7.40 (t, J = 7.3 Hz, 2H), 7.38–7.33 (m, 1H), 7.14 (td, J = 7.4, 1.8 Hz, 1H), 7.01–6.88 (overlapped, 3H), 5.18 (d, J = 6.2 Hz, 1H), 4.85 (d, J = 6.2 Hz, 1H), 4.32 (d, J = 9.8 Hz, 1H), 3.98 (dd, J = 11.5, 4.2 Hz, 1H), 3.53 (t, J = 11.2 Hz, 1H), 2.42 (overlapped, 2H), 2.27 (dd, J = 13.8, 11.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 162.1, 160.1, 139.1, 131.0, 131.0, 128.7, 128.7, 128.2, 128.2, 127.9, 125.5, 125.4, 124.1, 124.1, 115.5, 115.3, 94.3, 85.2, 71.3, 41.7, 27.5, 27.5; 19F NMR (376 MHz, CDCl3) δ -117.6; HRMS (ESI): m/z [M + NH4]+ calcd for C17H21O2NF+ 290.1551, found: 290.1551.
trans-4-(2-bromophenyl)-5-(2-fluorobenzyl)-1,3-dioxane (7r). yellow oil (25.6 mg, 73% yield); 1H NMR (500 MHz, CDCl3) δ 7.59 (ddd, J = 16.4, 7.9, 1.3 Hz, 2H), 7.40 (t, J = 7.1 Hz, 1H), 7.20 (td, J = 7.9, 1.7 Hz, 1H), 7.16–7.10 (m, 1H), 6.99–6.90 (m, 3H), 5.17 (d, J = 6.3 Hz, 1H), 4.96 (d, J = 9.3 Hz, 1H), 4.88 (d, J = 6.3 Hz, 1H), 3.98 (dd, J = 11.4, 3.1 Hz, 1H), 3.59 (dd, J = 13.8, 7.6 Hz, 1H), 2.41 (overlapped, 3H); 13C NMR (125 MHz, CDCl3) δ 162.3, 159.9, 138.6, 132.7, 131.0, 131.0 130.0, 129.3, 128.3, 128.2, 125.5, 125.4, 124.4, 124.1, 124.1, 115.5, 115.3, 94.4, 82.4, 71.2, 42.7, 27.3; 19F NMR (376 MHz, CDCl3) δ-117.7; HRMS (ESI): m/z [M + Na]+ calcd for C17H16O2FBrNa+ 373.0210, found: 373.0210.
trans-5-(2-chlorobenzyl)-4-phenyl-1,3-dioxane (7s). white solid (24.8 mg, 86% yield): mp 61.6–62.0 °C; 1H NMR (500 MHz, CDCl3) δ 7.46 (d, J = 7.0 Hz, 2H), 7.39 (t, J = 7.3 Hz, 2H), 7.36 (d, J = 7.2 Hz, 1H), 7.27 (dd, J = 5.7, 3.5 Hz, 1H), 7.11 – 7.07 (m, 2H), 6.94 (dd, J = 5.7, 3.6 Hz, 1H), 5.19 (d, J = 6.2 Hz, 1H), 4.86 (d, J = 6.2 Hz, 1H), 4.33 (d, J = 9.6 Hz, 1H), 3.96 (dd, J = 11.4, 4.0 Hz, 1H), 3.57 (t, J = 11.0 Hz, 1H), 2.56–2.46 (overlapped, 2H), 2.35 (dd, J = 14.5, 11.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 139.0, 136.4, 134.1, 130.9, 129.8, 128.7, 128.7, 128.7, 127.9, 127.9, 127.9, 126.8, 94.3, 85.3, 71.3, 41.4, 32.1; HRMS (ESI): m/z [M + H]+ calcd for C17H18O2Cl+ 289.0990, found: 289.0990.
trans-4-(2-bromophenyl)-5-(2-chlorobenzyl)-1,3-dioxane (7t). yellow oil (25.6 mg, 70% yield); 1H NMR (500 MHz, CDCl3) δ 7.62 (dd, J = 7.8, 1.6 Hz, 1H), 7.58 (dd, J = 8.0, 1.1 Hz, 1H), 7.40–7.36 (m, 1H), 7.27 (dd, J = 3.2, 2.3 Hz, 1H), 7.21 – 7.17 (m, 1H), 7.12–7.06 (m, 2H), 6.97–6.94 (m, 1H), 5.18 (d, J = 6.3 Hz, 1H), 4.99 (d, J = 9.3 Hz, 1H), 4.89 (d, J = 6.3 Hz, 1H), 3.97 (dd, J = 11.3, 3.1 Hz, 1H), 3.66–3.58 (m, 1H), 2.58–2.43 (overlapped, 3H); 13C NMR (125 MHz, CDCl3) δ 138.6, 136.3, 134.0, 132.6, 131.0, 130.0, 129.8, 129.5, 128.2, 128.0, 126.7, 124.3, 94.4, 82.4, 71.3, 42.2, 31.8; HRMS (ESI): m/z [M + H]+ calcd for C17H17O2ClBr+ 367.0095, found: 367.0095.
trans-5-(2-fluorobenzyl)-4-(4-methoxyphenyl)-1,3-dioxane (7u). yellow oil (19.9 mg, 66% yield); 1H NMR (500 MHz, CDCl3) δ 7.37 (d, J = 8.7 Hz, 2H), 7.17–7.11 (m, 1H), 7.00–6.96 (m, 1H), 6.96–6.91 (overlapped, 4H), 5.16 (d, J = 6.2 Hz, 1H), 4.83 (d, J = 6.2 Hz, 1H), 4.26 (d, J = 9.8 Hz, 1H), 3.97 (dd, J = 11.4, 4.2 Hz, 1H), 3.83 (s, 3H), 3.51 (t, J = 11.1 Hz, 1H), 2.40 (overlapped, 2H), 2.23 (dd, J = 14.2, 11.3 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 162.1, 160.1, 159.9, 131.4, 131.0, 131.0, 129.1, 128.2, 128.1, 125.6, 125.5, 124.1, 124.1, 115.5, 115.3, 114.2, 94.3, 84.7, 71.4, 55.4, 41.7, 27.6; 19F NMR (376 MHz, CDCl3) δ − 117.5; HRMS (ESI): m/z [M + H]+ calcd for C18H20O3F+ 303.1391; found: 303.1391.
trans-5-benzyl-4-phenyl-1,3-dioxane (7v). white wax (19.4 mg, 77% yield); 1H NMR (500 MHz, CDCl3) δ 7.49–7.44 (m, 2H), 7.42 (t, J = 7.4 Hz, 2H), 7.37 (dd, J = 11.4, 4.2 Hz, 1H), 7.22 (t, J = 7.3 Hz, 2H), 7.16 (t, J = 7.3 Hz, 1H), 6.97 (d, J = 7.2 Hz, 2H), 5.19 (d, J = 6.2 Hz, 1H), 4.84 (d, J = 6.3 Hz, 1H), 4.31 (d, J = 9.9 Hz, 1H), 3.99 (dd, J = 11.5, 4.4 Hz, 1H), 3.48 (t, J = 11.2 Hz, 1H), 2.49 (dd, J = 13.8, 3.6 Hz, 1H), 2.44–2.33 (m, 1H), 2.11 (dd, J = 13.8, 10.9 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 139.3, 138.4, 128.8, 128.8, 128.8, 128.8, 128.7, 128.5, 128.5, 127.8, 127.8, 126.4, 94.3, 85.1, 71.5, 42.6, 34.6; HRMS (ESI): m/z [M – H]– calcd for C17H17O2– 253.1234, found: 235.1235.
4.4 Procedure for preparation of 11a-1
To a solution of 11a (20 mg, 0.067 mmol) in dry DMF (0.67 mL) was added NaH (4 mg, 0.101 mmol) at 0 ℃ and stirred for 30 min. The mixture was then allowed to warm up to room temperature, followed by the addition of MeI (4 mg, 0.101 mmol). The reaction mixture was stirred for 15 h. The reaction diluted with water and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated under vacuum to give the crude product that was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 10:2, v/v) to afford 11a-1.
trans-6-(methoxymethyl)-5-(4-methoxyphenyl)-6,7-dihydro-5H-indeno[5,6-d][1,3]dioxole (11a-1). white solid (18.5 mg, 88% yield): mp 156.7–157.5 ℃; 1H NMR (400 MHz, CDCl3) δ 7.08 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 6.71 (s, 1H), 6.34 (s, 1H), 5.89 (d, J = 7.6 Hz, 2H), 3.95 (d, J = 8.0 Hz, 1H), 3.80 (s, 3H), 3.49 (dd, J = 9.2, 5.1 Hz, 1H), 3.42 (t, J = 8.3 Hz, 1H), 3.33 (s, 3H), 3.07 (dd, J = 15.4, 7.9 Hz, 1H), 2.73 (dd, J = 15.4, 8.1 Hz, 1H), 2.68–2.55 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 158.4, 146.9, 146.7, 139.2, 136.7, 135.8, 129.4, 129.4, 114.0, 114.0, 105.7, 105.0, 101.0, 75.0, 59.0, 55.4, 53.1, 50.9, 35.6; HRMS (ESI): m/z [M + H]+ calcd for C19H21O4+ 313.1434, found: 313.1434.
4.5 Procedure for preparation of 6b, trans-6h, and cis-6h
Compound 7b or 7h (0.33 mmol, 1.0 equiv) was treated at 0 °C with glacial acetic acid added dropwise (5.0 equiv) and trifluoroacetic anhydride added dropwise (5.0 equiv). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was stopped by adding a cold saturated aqueous solution of NaHCO3 and then extracted with dichloromethane. The combined organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was dissolved in a 1N solution of NaOH (MeOH/H2O = 9:1, 0.2 M) and stirred for 40 min. After consumption of the starting materials, the reaction was quenched by adding water at 0 °C, and the mixture was extracted with ethyl acetate. The reaction mixture was then purified by flash chromatography (petroleum ether/dichloromethane/ethyl acetate, 20:10:2, v/v) to yield 6b, trans-6h, and cis-6h.
trans-2-benzyl-1-(2-bromophenyl)propane-1,3-diol (6b). light yellow oil (99.2 mg, quantitative yield); 1H NMR (400 MHz, CDCl3) δ 7.65 (dd, J = 7.8, 1.1 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.31–7.17 (overlapped, 5H), 7.14 (td, J = 7.8, 1.4 Hz, 1H), 5.17 (t, J = 4.1 Hz, 1H), 3.71 (d, J = 11.1 Hz, 1H), 3.53 (d, J = 11.0 Hz, 1H), 3.48 (d, J = 5.1 Hz, 1H), 2.93 (qd, J = 13.6, 7.8 Hz, 2H), 2.50 (s, 1H), 2.24–2.15 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 142.5, 140.1, 133.0, 129.4, 129.4, 129.1, 128.5, 128.5 128.1, 127.7, 126.3, 122.2, 76.8, 62.3, 45.9, 35.2; HRMS (ESI): m/z [M + Cl]– calcd for C16H17O2ClBr– 335.0106, found: 335.0104.
trans-2-benzyl-1-(6-bromo-2,3,4-trimethoxyphenyl)propane-1,3-diol (trans-6h). yellow oil (51 mg, 52% yield); 1H NMR (400 MHz, CDCl3) δ 7.20 (t, J = 7.4 Hz, 2H), 7.13 (t, J = 7.3 Hz, 1H), 7.02 (d, J = 7.2 Hz, 2H), 6.87 (s, 1H), 5.16 (t, J = 8.6 Hz, 1H), 4.01 (s, 3H), 3.89 (overlapped, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.76 (d, J = 9.9 Hz, 1H), 3.71 (dd, J = 11.1, 5.6 Hz, 1H), 2.92 (s, 1H), 2.55–2.36 (overlapped, 3H); 13C NMR (100 MHz, CDCl3) δ 153.7, 153.0, 141.9, 140.3, 129.0, 129.0, 128.4, 128.4, 126.9, 126.1, 117.8, 112.1, 78.0, 64.8, 61.9, 60.9, 56.3, 48.5, 34.4; HRMS (ESI): m/z [M + Na]+ calcd for C19H23 O5BrNa+ 433.0621, found: 433.0625.
cis-2-benzyl-1-(6-bromo-2,3,4-trimethoxyphenyl)propane-1,3-diol (cis-6h). yellow oil (32.5 mg, 33% yield); 1H NMR (400 MHz, CDCl3) δ 7.32–7.22 (overlapped, 4H), 7.19 (t, J = 6.9 Hz, 1H), 6.88 (s, 1H), 5.12 (t, J = 8.8 Hz, 1H), 4.02 (s, 3H), 3.85 (s, 3H), 3.83 (overlapped, 4H), 3.43 (s, 2H), 3.10 (dd, J = 13.4, 3.2 Hz, 1H), 2.92–2.78 (m, 1H), 2.34–2.23 (m, 1H), 1.89 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 153.4, 152.8, 141.8, 140.7, 129.5, 129.5, 128.5, 128.5, 126.6, 126.0, 116.5, 112.4, 76.1, 62.2, 62.0, 60.9, 56.3, 48.8, 32.8; HRMS (ESI): m/z [M + Na]+ calcd for C19H23O5BrNa+ 433.0621, found: 433.0623.
4.6 Procedure for preparation of 12a and 12b through UM reaction
A Schlenk tube was equipped with a magnetic stirring bar, and loaded with Cs2CO3 (200 mol %), CuI (20 mol %), ethane-1,2-diamine (22 mol %), 6b (1.0 equiv) and 1,4-dioxane (0.1 M) under air. The tube was sealed, evacuated, and refilled with argon. The reaction mixture was stirred at 120 °C for 12 h. Afterward, The mixture was filtered and the solid was washed with ethyl acetate, and the filtrates were concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/dichloromethane/ethyl acetate, 60:10:2—10:10:2 v/v) to give the product 12a and 12b.
trans-3-benzylchroman-4-ol (12a). white solid (4.8 mg, 21% yield, 34% brsm): mp 125.6 − 128.2 °C; 1H NMR (400 MHz, CDCl3) δ 7.36–7.31 (overlapped, 2H), 7.26 (overlapped, 3H), 7.24–7.18 (overlapped, 2H), 6.89 (t, J = 7.4 Hz, 1H), 6.85 (d, J = 8.6 Hz, 1H), 4.52 (d, J = 2.9 Hz, 1H), 4.11 (d, J = 2.8 Hz, 1H), 4.09 (s, 1H), 2.89 (dd, J = 13.6, 8.4 Hz, 1H), 2.73–2.62 (m, 1H), 2.39–2.27 (m, 1H), 1.68 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 154.5, 139.3, 130.3, 130.1, 129.3, 129.3, 128.7, 128.7, 126.5, 124.3, 120.7, 117.1, 65.1, 65.1, 40.1, 33.0; HRMS (ESI): m/z [M – H]– calcd for C16H15O2– 239.1078; found: 239.1075.
trans-2-benzyl-1-phenylpropane-1,3-diol (12b). white solid (3.9 mg, 17% yield, 20% brsm): mp 66.3 − 69.8 °C; 1H NMR (400 MHz, CDCl3) δ 7.37 (s, 2H), 7.36 (s, 2H), 7.32–7.27 (m, 1H), 7.25 (d, J = 7.5 Hz, 2H), 7.18 (t, J = 7.3 Hz, 1H), 7.13 (d, J = 7.4 Hz, 2H), 4.76 (d, J = 6.1 Hz, 1H), 3.75 (dd, J = 11.0, 2.1 Hz, 1H), 3.56 (dd, J = 11.0, 5.5 Hz, 1H), 3.18 (s, 1H), 2.71 (overlapped, 2H), 2.59 (dd, J = 13.8, 9.5 Hz, 1H), 2.10 (ddd, J = 8.9, 5.9, 2.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 143.5, 140.2, 129.2, 129.2, 128.6, 128.6, 128.5, 128.5, 127.8, 126.4, 126.4, 126.2, 78.1, 63.3, 48.5, 34.9; HRMS (ESI): m/z [M + Cl]– calcd for C16H18O2Cl– 277.1001, found: 277.1001.
4.7 Procedure for preparation of 14a, 14b and 15
A solution of 12a (1.0 equiv) in 17% HCl–MeOH (1:1, 0.05 M) was heated at 90 °C for 1 h. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure to give the crude residue, diluted with dichloromethane and water, and the layers were separated. The water layer was extracted with dichloromethane. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the residue which was purified by silica gel column chromatography (petroleum ether/dichloromethane, 8:1–0:1,v/v) to give 14a, 14b and 15.
cis-3-benzyl-4-methoxychromane (14a). yellow oil (2.1 mg, 16.5% yield); 1H NMR (400 MHz, CDCl3) δ 7.33 (overlapped, 2H), 7.22 (overlapped, 4H), 7.13–7.09 (m, 1H), 6.85 (d, J = 7.7 Hz, 2H), 4.20 (t, J = 10.7 Hz, 1H), 4.09 (ddd, J = 10.6, 3.9, 0.7 Hz, 1H), 3.92 (d, J = 2.9 Hz, 1H), 3.38 (s, 3H), 2.86 (dd, J = 13.5, 8.4 Hz, 1H), 2.66 (dd, J = 13.5, 7.2 Hz, 1H), 2.35 (tdd, J = 11.1, 7.1, 3.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 154.6, 139.6, 130.7, 130.0, 129.3, 129.3, 128.6, 128.6, 126.3, 121.2, 119.4, 117.0, 73.7, 65.8, 56.1, 39.3, 32.9; HRMS (ESI): m/z [M – H]– calcd for C17H17O2– 253.1234; found: 253.1236.
trans-3-benzyl-4-methoxychromane (14b). yellow oil (2.3 mg, 18% yield); 1H NMR (400 MHz, CDCl3) δ 7.34–7.27 (overlapped, 2H), 7.26 (overlapped, 1H), 7.25–7.20 (overlapped, 2H), 7.17 (d, J = 7.6 Hz, 2H), 6.94 (d, J = 7.4 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 4.26 (dd, J = 10.9, 2.2 Hz, 1H), 4.01 (d, J = 10.8 Hz, 1H), 3.96 (s, 1H), 3.36 (s, 3H), 2.58 (d, J = 2.5 Hz, 1H), 2.56 (s, 1H), 2.38–2.28 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 154.6, 139.5, 131.8, 129.2, 128.6, 129.2, 128.6, 126.4, 120.3, 119.9, 117.1, 75.9, 64.5, 55.8, 38.1, 34.7; HRMS (ESI): m/z [M – H]– calcd for C17H17O2– 253.1234; found: 253.1232.
3-benzyl-2H-chromene (15). colorless oil (2.4 mg, 21.6% yield); 1H NMR (400 MHz, CDCl3) δ 7.32 (t, J = 7.3 Hz, 2H), 7.24 (overlapped, 3H), 7.06 (td, J = 7.8, 1.6 Hz, 1H), 6.93 (dd, J = 7.4, 1.5 Hz, 1H), 6.84 (t, J = 7.4 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.16 (s, 1H), 4.65 (s, 2H), 3.43 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 153.0, 137.6, 134.1, 129.1, 129.1,128.7, 128.7, 128.6, 126.8, 126.3, 121.4, 120.5, 115.5, 68.2, 40.0; HRMS (ESI): m/z [M + Br]– calcd for C16H14OBr– 301.0234; found: 301.0235.
4.8 Procedure for preparation of trans-12h, cis-12h, trans-12c and cis-12c
Trans-12h, cis-12h, trans-12c and cis-12c were prepared using the same protocol as the preparation of 12a in trans-6h, and cis-6h. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate, 5:1–2:1, v/v) to give the product.
trans-3-benzyl-5,6,7-trimethoxychroman-4-ol (trans-12h). colorless oil (6 mg, 36% yield); 1H NMR (400 MHz, CDCl3) δ 7.36–7.20 (overlapped, 5H), 6.17 (s, 1H), 4.70 (s, 1H), 3.99 (d, J = 7.8 Hz, 2H), 3.96 (s, 3H), 3.80 (s, 3H), 3.78 (s, 3H), 2.97 (dd, J = 13.8, 7.6 Hz, 1H), 2.68 (dd, J = 13.8, 7.9 Hz, 1H), 2.28–2.18 (m, 1H), 2.15 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 154.6, 152.0, 150.9, 139.6, 135.4, 129.2, 129.2, 128.7, 128.7, 126.4, 110.6, 95.7, 65.1, 61.4, 61.1, 60.6, 56.0, 40.2, 33.1; HRMS (ESI): m/z [M + NH4]+ calcd for C19H26O5N+ 348.1805; found: 348.1806.
cis-3-benzyl-5,6,7-trimethoxychroman-4-ole (cis-12h). colorless oil (13.1 mg, 40% yield); 1H NMR (400 MHz, CDCl3) δ 7.31 (t, J = 7.4 Hz, 2H), 7.24 (d, J = 7.2 Hz, 1H), 7.20 (d, J = 7.7 Hz, 2H), 6.25 (s, 1H), 4.61 (s, 1H), 4.11 (dd, J = 11.0, 2.0 Hz, 1H), 3.99 (s, 3H), 3.93 (dd, J = 10.9, 2.4 Hz, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 2.65 (dd, J = 13.7, 6.9 Hz, 1H), 2.54 (overlapped, 2H), 2.22 (ddd, J = 9.2, 6.6, 2.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 154.4, 152.5, 150.6, 139.4, 135.6, 129.2, 129.2. 128.5, 128.5, 126.3, 109.1, 95.9, 64.4, 63.1, 61.3, 61.0, 55.89, 40.5, 34.6; HRMS (ESI): m/z [M + NH4]+ calcd for C19H26O5N+ 348.1805; found: 348.1803.
trans-2-benzyl-1-(2,3,4-trimethoxyphenyl)propane-1,3-diol (trans-12c). yellow oil (6.8 mg, 41% yield); 1H NMR (400 MHz, CDCl3) δ 7.26 (overlapped, 2H), 7.20–7.11 (m, 4H), 6.70 (d, J = 8.6 Hz, 1H), 4.96 (t, J = 4.8 Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.83 (s, 3H), 3.78 (d, J = 11.1 Hz, 1H), 3.57 (d, J = 11.1 Hz, 1H), 3.04 (d, J = 4.9 Hz, 1H), 2.78 (s, 1H), 2.74 (dd, J = 13.9, 5.9 Hz, 1H), 2.60 (dd, J = 13.8, 9.3 Hz, 1H), 2.20 (ddd, J = 8.7, 5.8, 2.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 153.3, 151.0, 142.0, 140.4, 129.2, 129.2, 128.8, 128.5, 128.5, 126.1, 121.8, 107.3, 73.6, 63.7, 61.1, 60.9, 56.1, 47.4, 34.9; HRMS (ESI): m/z [M + Na]+ calcd for C19H24O5Na+ 355.1516; found: 355.1515.
cis-2-benzyl-1-(2,3,4-trimethoxyphenyl)propane-1,3-diol (cis-12c). yellow oil (10.9 mg, 33% yield); 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 7.4 Hz, 2H), 7.15 (t, J = 9.0 Hz, 4H), 6.71 (d, J = 8.7 Hz, 1H), 5.19 (d, J = 5.2 Hz, 1H), 3.93 (s, 3H), 3.87 (s, 6H), 3.56 (dd, J = 11.2, 2.6 Hz, 1H), 3.51 (dd, J = 11.2, 4.1 Hz, 1H), 2.92 (s, 1H), 2.88 (dd, J = 13.7, 3.6 Hz, 1H), 2.74 (dd, J = 13.5, 11.1 Hz, 1H), 2.31 (s, 1H), 2.10–2.01 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 153.1, 150.6, 141.9, 141.1, 129.3, 129.3, 128.5, 128.4, 128.4, 125.9, 121.8, 107.4, 72.3, 63.1, 61.3, 60.9, 56.1, 48.7, 31.4; HRMS (ESI): m/z [M + Na]+ calcd for C19H24O5Na+ 355.1516; found: 355.1512.
4.9 Procedure for preparation of 16
To a solution of trans-12h or cis-12h (1.0 equiv) in dry benzene (0.05 M), then pTSA (5 mol%) was added at 0 ℃. The reaction was sealed and stirred at room temperature for 2 h. The reaction was quenched with NaHCO3 saturated aqueous solution, and was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4, filtered, and concentrated to give the crude product that was further purified by flash column chromatography on silica gel (petroleum ether/dichloromethane/ethyl acetate/ethyl acetate, 80:10:2, v/v) to afford 16.
3-benzyl-5,6,7-trimethoxy-2H-chromene (16). colorless oil (1.1 mg, quantitative yield); 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 6.9 Hz, 2H), 7.24 (d, J = 6.3 Hz, 3H), 6.45 (s, 1H), 6.19 (s, 1H), 4.53 (s, 2H), 3.88 (s, 3H), 3.80 (s, 6H), 3.46 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 153.2, 149.1, 149.4, 137.9, 130.5, 128.8, 128.8, 128.6, 128.6, 126.6, 115.3, 109.5, 95.9, 67.8, 61.5, 61.1, 56.0, 40.3, 32.0; HRMS (ESI): m/z [M + H]+ calcd for C19H21O4+ 313.1434; found: 313.1435.
4.10 Procedure for preparation of 11h
The contents of a reaction tube charged with a solution of 7h (1.0 equiv), H3PO4 (50 mol%) in freshly distilled dichloromethane (0.05 M) were stirred for 12 h at 80 ℃. The reaction was quenched with NaHCO3 saturated aqueous solution, and was extracted with dichloromethane. The combined organic layer was dried over Na2SO4, filtered, and concentrated to give the crude product that was further purified by flash column chromatography on silica gel (petroleum ether/dichloromethane/ethyl acetate, 10:10:2, v/v) to afford 11h.
(trans-1-(6-bromo-2,3,4-trimethoxyphenyl)-2,3-dihydro-1H-inden-2-yl)methanol (11h). colorless oil (24.2 mg, 13% yield, 75% brsm); trans-isomer: 1H NMR (400 MHz, CDCl3) δ 7.23 (t, J = 6.8 Hz, 1H), 7.13 (t, J = 7.4 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 6.91 (s, 1H), 6.88 (d, J = 4.0 Hz, 1H), 4.73 (d, J = 7.5 Hz, 1H), 3.86 (s, 3H), 3.83–3.78 (overlapped, 1H), 3.75 (overlapped, 4H), 3.32 (dd, J = 15.7, 8.8 Hz, 1H), 3.08 (s, 3H), 2.99 (dd, J = 15.0, 7.2 Hz, 1H), 2.88 (dd, J = 16.0, 7.5 Hz, 1H), 1.61 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 153.6, 153.0, 146.4, 142.8, 142.6, 130.5, 126.5, 126.2, 124.5, 123.5, 118.8, 111.0, 66.4, 60.6, 60.1, 56.2, 52.4, 49.0, 35.9; HRMS (ESI): m/z [M + H]+ calcd for C19H20O4Br+ 393.0696; found: 393.0693.
4.11 Procedure for preparation of 17
A Schlenk tube was equipped with a magnetic stirring bar, and loaded with Cs2CO3 (200 mol%), CuI (20 mol %), rac-cyclohexane-1,2-diamine (22 mol %), 11h (1.0 equiv) and 1,4-dioxane (0.1 M) under air. The tube was sealed, evacuated, and refilled with argon. The reaction mixture was stirred at 120 °C for 12 h. Afterward, the mixture was filtered and the solid was washed with ethyl acetate, and the filtrates were concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/dichloromethane/ethyl acetate/ethyl acetate, 80:10:2, v/v) to give the product 17.
trans-1,2,3-trimethoxy-6,6a,7,11b-tetrahydroindeno[2,1-c]chromene (17). yellow oil (3.9 mg, 10% yield, 73% brsm); 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 7.3 Hz, 1H), 7.28 (d, J = 7.1 Hz, 1H), 7.24–7.15 (overlapped, 2H), 6.27 (s, 1H), 4.46 (dd, J = 9.9, 3.4 Hz, 1H), 4.24 (t, J = 10.5 Hz, 1H), 3.97 (d, J = 11.8 Hz, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.82 (s, 3H), 2.92 (dd, J = 13.6, 5.5 Hz, 1H), 2.63 (t, J = 12.8 Hz, 1H), 2.54 (td, J = 12.0, 5.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 152.7, 152.5, 151.3, 144.3, 143.9, 136.3, 126.6, 126.5, 126.3, 124.6, 111.4, 97.1, 70.2, 61.5, 60.6, 56.0, 47.5, 46.8, 33.1; HRMS (ESI): m/z [M + H]+ calcd for C19H21O4+ 313.1434; found: 313.1432.
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References
Lin L-G, Liu Q-Y, Ye Y. Naturally occurring homoisoflavonoids and their pharmacological activities. Planta Med. 2014;80:1053–66.
Min BS, Cuong TD, Hung TM, Min BK, Shin BS, Woo MH. Compounds from the heartwood of Caesalpinia sappan and their anti-inflammatory activity. Bioorg Med Chem Lett. 2012;22:7436–9.
Moon C-K, Lee SH, Lee MO, Kim SG. Effects of brazilin on glucose oxidation, lipogenesis and therein involved enzymes in adipose tissues from diabetic KK-mice. Life Sci. 1993;53:1291–7.
Kim B, Kim S-H, Jeong S-J, Sohn EJ, Jung JH, Lee MH, Kim S-H. Brazilin induces apoptosis and G2/M arrest via inactivation of histone deacetylase in multiple myeloma U266 cells. J Agric Food Chem. 2012;60:9882–9.
Lin L-G, Xie H, Li H-L, Tong L-J, Tang C-P, Ke C-Q, Liu Q-F, Lin L-P, Geng M-Y, Jiang H, Zhao W-M, Ding J, Ye Y. Naturally occurring homoisoflavonoids function as potent protein tyrosine kinase inhibitors by c-Src-based high-throughput screening. J Med Chem. 2008;51:4419–29.
Javed U, Karim M, Jahng KC, Park J-G, Jahng Y. Enantioselective syntheses of (+)- and (−)-brazilin, Tetrahedron. Asymmetry. 2014;25:1270–4.
Jung Y, Kim I. Total synthesis of brazilin. J Org Chem. 2015;80:2001–5.
Jung Y, Kim I. A concise synthetic approach to brazilin via Pd-catalyzed allylic arylation. Org Biomol Chem. 2015;13:4331–5.
Gogoi D, Devi R, Pahari P, Sarma B, Das SK. cis-Diastereoselective synthesis of chroman-fused tetralins as B-ring-modified analogues of brazilin. Beilstein J Org Chem. 2016;12:2816–22.
Huang Y, Zhang J, Pettus TRR. Synthesis of (±)-brazilin using IBX. Org Lett. 2005;7:5841–4.
Pan C, Zeng X, Guan Y, Jiang X, Li L, Zhang H. Design and synthesis of brazilin-like compounds. Synlett. 2011;2011:425–9.
Wang X, Zhang H, Yang X, Zhao J, Pan C. Enantioselective total synthesis of (+)-brazilin, (−)-brazilein and (+)-brazilide A. Chem Commun. 2013;49:5405–7.
Yadav JS, Mishra AK, Das S. Formal synthesis of (±)-brazilin and total synthesis of (±)-brazilane. Tetrahedron. 2014;70:7560–6.
Arredondo V, Roa DE, Gutman ES, Huynh NO, Van Vranken DL. Total synthesis of (±)-brazilin using [4 + 1] palladium-catalyzed carbenylative annulation. J Org Chem. 2019;84:14745–59.
Lin C-C, Teng T-M, Tsai C-C, Liao H-Y, Liu R-S. Gold-catalyzed deoxygenative nazarov cyclization of 2,4-dien-1-als for stereoselective synthesis of highly substituted cyclopentenes. J Am Chem Soc. 2008;130:16417–23.
Huang S, Ou W, Li W, Xiao H, Pang Y, Zhou Y, Wang X, Yang X, Wang L. A total synthesis of (+)-brazilin. Tetrahedron Lett. 2020;61: 152052.
Wang X, Liu W, Duan S, Yang X, Zhang H. Research progress on the synthesis of brazilin-type natural products. Chin J Org Chem. 2015;35:1585–97.
Kim J, Kim I. Design and synthesis of a hybrid framework of indanone and chromane: total synthesis of a homoisoflavanoid, brazilane. Org Biomol Chem. 2018;16:89–100.
Grimm JAA, Zhou H, Properzi R, Leutzsch M, Bistoni G, Nienhaus J, List B. Catalytic asymmetric synthesis of cannabinoids and menthol from neral. Nature. 2023;615:634–9.
Díaz-Oviedo CD, Maji R, List B. The catalytic asymmetric intermolecular prins reaction. J Am Chem Soc. 2021;143:20598–604.
Peng B, Ma J, Guo J, Gong Y, Wang R, Zhang Y, Zeng J, Chen W-W, Ding K, Zhao B. A powerful chiral super brønsted C–H acid for asymmetric catalysis. J Am Chem Soc. 2022;144:2853–60.
Zhan R, Li D, Liu Y-L, Xie X-Y, Chen L, Shao L-D, Wang W-J, Chen Y-G. Structural elucidation, bio-inspired synthesis, and biological activities of cyclic diarylpropanes from Horsfieldia kingii. Tetrahedron. 2020;76: 131494.
Yang B, Dong K, Li X-S, Wu L-Z, Liu Q. Photoacid-enabled synthesis of indanes via formal [3 + 2] cycloaddition of benzyl alcohols with olefins. Org Lett. 2022;24:2040–4.
Zhang Z-J, Zhou X, Li D, Chen Y, Xiao W-W, Li R-T, Shao L-D. Aerobic copper-catalyzed intramolecular cascade oxidative isomerization/[4 + 4] cyclization of 2,2′-disubstituted stilbenes. J Org Chem. 2021;86:7609–24.
Wang M, Liu Y-L, Li D, Xiao W-W, Chen Y, Zhang H-L, Zhan R, Shao L-D. Biomimetic synthesis and anti-inflammatory effects of horsfiequinone A. Tetrahedron Lett. 2021;65: 152756.
Funding
The authors are grateful to the financial support from National Natural Science Foundation of China (82260683 and 22267024), Scientific and Technological Project of Yunnan Precious Metals Laboratory (YPML-2023050265 and YPML-2023050217), Yunnan Science and Technology Talent and Platform Program (202105AG070012), the Top Young Talent of Ten Thousand Talents Program of Yunnan Province (D. L. and L.-D. S.), the Start-up Fund of Yunnan University of Chinese Medicine (2019YZG03), and the Bioactive Ethnopharmacol Molecules Chemical Conversion and Application Innovation Team of Department of Education of Yunnan Province (2022).
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X.-T. H and Q.-Y. C were contributed equally; X.-T. H and Q.-Y. C carried out all experiments and wrote the manuscript. Y.-P. C assisted in the experimental operation. K. L and C.-X. Y involved in data analysis and figures preparation. D. L checked the manuscript. L.-D S supervised all work presented in this manuscript. All authors above reviewed this manuscript. All data were generated in-house, and no paper mill was used. All authors agree to be accountable for all aspects of work ensuring integrity and accuracy.
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Additional file 1: Scheme S1.
Copies of NMR spectra for all synthetic compounds, and X-ray crystallography data of compounds 11a-1 and 12b.
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Hu, XT., Cheng, QY., Chen, YP. et al. Hydroxymethylation hydroxylation of 1,3-diarylpropene through a catalytic diastereoselective Prins reaction: cyclization logic and access to brazilin core. Nat. Prod. Bioprospect. 14, 29 (2024). https://doi.org/10.1007/s13659-024-00450-2
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DOI: https://doi.org/10.1007/s13659-024-00450-2