Modified Julia–Kocienski Reagents for a Stereoselective Introduction

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Note Cite This: J. Org. Chem. 2018, 83, 5323−5330

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Modified Julia−Kocienski Reagents for a Stereoselective Introduction of Trisubstituted Double Bonds: A Formal Total Synthesis of Limazepine E and Barmumycin Guna Sakaine and Gints Smits* Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia S Supporting Information *

ABSTRACT: A formal total synthesis of pyrrolo[1,4]benzodiazepine anticancer antibiotic family member limazepine E is described. The synthesis features a stereoselective introduction of a trisubstituted double bond using novel sterically demanding Julia−Kocienski reagents, allowing the number of linear steps to be significantly reduced. The potential of the newly developed reagents has also been demonstrated by the formal total synthesis of barmumycin.

L

method for an E-selective introduction of trisubstituted double bond was introduced on the basis of stereoselective Ireland− Claisen rearrangement;11,19 however, the desired 3-ethylideneproline building block was obtained in a linear sequence of nine steps. Herein, we report a concise formal total synthesis of limazepine E employing new sterically demanding Julia− Kocienski reagents for a stereoselective introduction of the C2 alkylidene substituent. Our retrosynthetic analysis (Scheme 1) was based on a latestage introduction of the trisubstituted double bond followed by selective C11 carbonyl reduction. The prerequisite ketone 8 could be easily constructed from inexpensive and readily available starting materials, isovanillic acid and trans-4-hydroxyL-proline, followed by an oxidation of the intermediate dilactam 9. The synthesis started with conversion of isovanilic acid into the corresponding nitrobenzoic acid 10 (Scheme 2). The latter was coupled with trans-4-hydroxy-L-proline to produce the intermediate 11 in a good yield.18 Hydrogenation of the amide 11, followed by treatment with benzaldehyde dimethyl acetal at elevated temperature, furnished the alcohol 12 which after oxidation gave the ketone 12 necessary for C2 olefination studies. With the ketone 13 in hand, we began our studies for the stereoselective introduction of the trisubstituted double bond at the C2 position (Table 1).

imazepine E (6) was isolated in 2009 from Micrococus sp. strain ICBB 81771 and belongs to a broad and expanding family of pyrrolo[1,4]benzodiazepine (PBD) natural products. Many PBD class members possess anticancer activity owing to their ability to covalently bind to the minor groove of DNA.2−4 A number of PBDs as well as their antibody drug conjugates (ADC) have been evaluated as anticancer agents and are currently undergoing clinical trials.5 Most PBDs possess a right-hand twisted three-ring system. Furthermore, several naturally occurring PBDs contain a C2 alkylidene group; some examples are shown in Figure 1.1,6−9

Figure 1. Representative examples of PBD natural products containing a C2 alkylidene group.

Importantly, it has been shown that a C2 double bond significantly increases anticancer activity.10 Although total syntheses of limazepine E11 (6) and several related (E)-2ethylidene PBDs12−15 have been reported, a stereoselective introduction of the C2 alkylidene group still poses a considerable challenge. Moreover, the classical olefination methods (Wittig and Julia−Kocienski) lack selectivity or give the undesired Z-isomer predominantly.12,16−18 An alternative © 2018 American Chemical Society

Received: March 12, 2018 Published: April 11, 2018 5323

DOI: 10.1021/acs.joc.8b00643 J. Org. Chem. 2018, 83, 5323−5330

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The Journal of Organic Chemistry Scheme 1. Retrosynthetic Analysis of Limazepine E

Table 1. Julia−Kocienski Reagent Screening for the Olefination of Ketone 3a

Our previous studies18 determined the high potential of Julia−Kocienski olefination20,21 for this transformation. To find the optimal olefination reagents, the classical benzothiazolyl sulfone 14a,22 2-pyridyl sulfone 14b,23 and tetrazole sulfones24 14c25 and 14d were synthesized and subjected to olefination reaction with the ketone 13 in the presence of three different bases: Li, Na, and KHMDS (Table 1). Whereas sulfones 14a and 14b (entry 1−6) lack stereoselectivity and reactivity (yields 0−66%), the tetrazole sulfones 14c and 14d delivered the desired product 15 in 53−75% yield and good stereoselectivity using KHMDS as a base (entries 9 and 12). To fine-tune the reaction conditions, we further focused on the solvent screening (Table 2). Out of five different solvents examined, only DCM (entry 3) delivered stereoselectivity comparable to that of the previously employed THF (Table 1, entry 12), although it was accompanied by a decrease in reactivity. Next, we speculated that the sterical effect of the Julia− Kocienski reagent 14 may have a decisive impact on the stereochemical outcome of the reaction. To verify this hypothesis, we synthesized several undescribed bulky Julia− Kocienski reagents and subjected them to the olefination reaction (Table 3). To our delight, all sulfones except 14h produced the desired alkene 15 with good stereoselectivity. The lack of reactivity on the part of 14h was attributed to the excessive steric build-up. The best result in olefination of ketone 13 was obtained with (2,4,6-tricyclohexylphenyl)tetrazole sulfone 14j (entry 6) to

a

Key: 13, 0.055 mmol; 14, 0.110 mmol; base, 0.110 mmol, THF (0.3 mL), −78 °C to rt. bDetermined by 1H NMR. cDetermined by HPLC.

furnish the desired alkene 15 with an E-/Z- ratio as high as 97:3. With the dilactam 15 in hand, the total synthesis of limazepine E (6) could be accomplished in one step according to the published route.11 Importantly, the newly developed methodology allows us to obtain Limazepine E (6) in nine steps (LLS) compared to the 12 steps previously reported11 and enables late-stage modification of the C2 position.

Scheme 2. Synthesis of Ketone 13

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DOI: 10.1021/acs.joc.8b00643 J. Org. Chem. 2018, 83, 5323−5330

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The Journal of Organic Chemistry Table 2. Solvent Screeninga

entry

solvent

yield (%)

E-/Z-a

1 2 3 4 5

DMF DME DCM toluene Et2O

53 10 34 44 24

77:26 84:16 89:11 60:40 82:18

Our newly developed modification of the Julia−Kocienski olefination was further applied to the formal total synthesis of barmumycin (19) (Scheme 3). The formal total synthesis was started with an oxidation of the known prolinol derivative 1626 to give the desired ketone 17 in high yield. Next, the Julia−Kocienski olefination of the substrate 18 was examined with the newly developed sulfone 14j and the classical 14c as a reference. Gratifyingly, 14j provided significantly higher stereoselectivity (E-/Z- 3:1) than 14c (E-/Z- 2:1). The obtained prolinole derivative 18 can be further converted into barmumycin by a known sequence.27 In summary, we have developed a new modification of the Julia−Kocienski olefination employing novel sterically demanding aryltetrazole sulfones for a stereoselective introduction of trisubstituted double bonds. The superiority of these modified Julia−Kocienski reagents over the known sulfones has been demonstrated in the formal total syntheses of limazepine E (6)

a

Key: 13, 0.055 mmol; 14d, 0.110 mmol; KHMDS, 0.110 mmol, solvent (0.3 mL), −78 °C to rt. bDetermined by HPLC.

Table 3. Alternative Julia−Kocienski Reagent Screening for the Olefination of Ketone 13a

a

Key: 13, 0.055 mmol; 14, 0.110 mmol; KHMDS, 0.110 mmol, THF (0.3 mL), −78 °C to rt. bDetermined by HPLC. 5325

DOI: 10.1021/acs.joc.8b00643 J. Org. Chem. 2018, 83, 5323−5330

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The Journal of Organic Chemistry Scheme 3. Formal Total Synthesis of Barmumycin 19

was added dropwise, and the reaction mixture was stirred for 4 h at this temperature followed by 16 h at room temperature. Then, 1.4 mL of concd HCl was diluted with 4 mL of H2O, and the resulting solution was added dropwise to the reaction mixture. Volatiles were evaporated, and the crude product was partitioned between water and DCM. Organics were separated, and the aqueous layer was extracted with DCM (3×). The combined organic extracts were dried over anhyd Na2SO4, filtered, and concentrated in vacuo. The crude 1-tert-butyl-1H-tetrazole-5-thiol was dissolved in EtOH (7 mL), KOH (615 mg, 10.995 mmol, 1.20 equiv) was added, and the resulting mixture was stirred for 30 min at room temperature. Then, EtBr (1572 mg, 10.079 mmol, 1.10 equiv) was added dropwise, and stirring was continued for 16 h at room temperature. The reaction mixture was then evaporated and the crude product partitioned between water and DCM. Organics were separated, and the aqueous layer was extracted with DCM (3×). The combined organic extracts were dried over anhyd Na2SO4, filtered, and concentrated in vacuo. The crude 1-tert-butyl-5-(ethylthio)-1H-tetrazole was dissolved in DCM (22 mL), and NaHCO3 (3.848 g, 45.81 mmol, 5.00 equiv) was added followed by slow addition of 70% mCPBA (6.79 g, 27.49 mmol, 3.00 equiv) under vigorous stirring. The resulting slurry was stirred at room temperature for 16 h and then quenched by addition of saturated aqueous solution of Na2S2O3 and NaHCO3. The obtained biphasic mixture was stirred vigorously for 2 h, the organics were separated, and the aqueous phase was extracted twice with DCM. The combined organic extracts were dried over anhyd Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (eluent: EtOAc/petroleum ether 0:1 → 1:2). The title compound was obtained as a yellowish solid (800 mg, 40% in three steps): 1H NMR (400 MHz, CDCl3) δ 3.84 (2H, q, J = 7.4), 1.86 (9H, s), 1.55 (3H, t, J = 7.4); 13C NMR (100 MHz, CDCl3) δ 154.6, 65.4, 51.5, 29.6, 7.1; IR (film) 2997, 2933, 1329, 1158 cm−1; HRMS (+ESI) calcd for C7H14N4O2NaS [M + Na] 241.0735 found 241.0732; mp 53−55 °C. 1-((3s,5s,7s)-Adamantan-1-yl)-5-(ethylsulfonyl)-1H-tetrazole 14e. Compound 14e was synthesized starting from commercially available 1-isothiocyanatoadamantane. NaN3 (168 mg, 2.586 mmol, 1.00 equiv) was dissolved in H2O (1 mL) and heated to 100 °C. Then a suspension of 1-isothiocyanatoadamantane (500 mg, 2.586 mmol, 1.00 equiv) in i-PrOH (1 mL) was added dropwise, and the reaction mixture was stirred 4 h at this temperature followed by 16 h at room temperature. Additional NaN3 (168 mg, 2.586 mmol, 1.00 equiv), H2O (2 mL), and dioxane (2 mL) were added, and the reaction mixture was stirred overnight at 100 °C and then cooled. Then 0.35 mL of concd HCl was diluted with 1 mL of H2O, and the resulting solution was added dropwise to the reaction mixture. Volatiles were evaporated, and the crude product was partitioned between water and DCM. Organics were separated, and aqueous layer was extracted with DCM (3×). The combined organic extracts were dried over anhyd Na2SO4, filtered, and concentrated in vacuo. The crude 1-((3s,5s,7s)-adamantan-1-yl)-1H-tetrazole-5-thiol was dissolved in EtOH (15 mL), KOH (189 mg, 3.362 mmol, 1.30 equiv) was added, and the resulting mixture was stirred for 30 min at room temperature. Then EtBr (338 mg, 3.104 mmol, 1.20 equiv) was added dropwise, and stirring was continued for 16 h at room temperature.

and barmumycin (19). Further studies on the scope of the described olefination are ongoing in our laboratory.

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EXPERIMENTAL SECTION

General Experimental Details. All reactions were performed under an atmosphere of argon unless otherwise indicated. Reagents and starting materials were obtained from commercial sources and used as received. The solvents were purified and dried by standard procedures prior to use; petroleum ether of boiling range 60−80 °C was used. Flash chromatography was carried out using Merck Kieselgel (230−400 mesh). NMR spectra were recorded on Varian Mercury (400 MHz) and Bruker (300 MHz) spectrometers. Chemical shift values are referenced against residual protons in the deuterated solvents, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad). J values are reported in hertz. Infrared spectra were recorded in the range 4000−500 cm−1 as a film. HRMS were obtained on a Micromass AutoSpec Ultima Magnetic sector mass spectrometer (TOF). Optical rotations were measured using a PerkinElmer 141 polarimeter. Melting points were determined using a Stanford Research System MPA100 automated melting point apparatus and are uncorrected. Chromatographic analyses were performed on a Waters 2695 Separations Module (UV-vis detector Waters 2489), Chiralpak IC-1 column (4.6 × 250 mm), 30% IPA/70% Hex, flow rate 1 mL/min. (8R,9aS)-8-Hydroxy-3-methoxy-1-phenyl-7,8,9,9a-tetrahydro-1H2-oxa-6a,10a-diazabenzo[cd]cyclopenta[g]azulene-6,10-dione (12). The title compound was prepared according the literature procedure starting from 10, 1.52 g (45% in three steps):18 1H NMR (300 MHz, CDCl3) δ 7.57 (1H, d, J = 8.9 Hz), 7.32−7.46 (6H, m), 6.84 (1H, d, J = 8.9 Hz), 4.53−4.59 (1H, m), 4.41 (1H, t, J = 7.7 Hz), 4.25 (1H, td, J = 12.7, 2.2 Hz), 3.97 (3H, s), 3.53 (1H, dd, J = 12.7, 4.0 Hz), 2.78−2.88 (1H, m), 2.25−2.35 (1H, m); 13C NMR (100 MHz, CDCl3) δ 169.4, 166.3, 146.7, 137.8, 136.5, 130.0, 128.9, 128.3, 126.0, 124.0, 113.7, 110.8, 95.5, 68.7, 58.0, 56.8, 54.9, 35.9; IR (film) 3397, 1685, 1636 cm−1; mp 110−113 °C; [α]D20 = 338.40 (c = 0.1, CHCl3); HRMS (+ESI) calcd for C20H19N2O5 [M + H+] 367.1294, found 367.1295. (9aS)-3-Methoxy-1-phenyl-9,9a-dihydro-1H-2-oxa-6a,10adiazabenzo[cd]cyclopenta[g]azulene-6,8,10(7H)-trione (13). The title compound was prepared according the literature procedure from 12, 1.320 g (82%):18 1H NMR (400 MHz, CDCl3) δ 7.63 (1H, d, J = 8.8 Hz), 7.34−7.46 (6H, m), 6.90 (1H, d, J = 8.8 Hz), 4.68 (1H, dd, J = 10.7, 4.4 Hz), 4.49 (1H, d, J = 20.2 Hz), 4.00 (3H, s), 3.86 (1H, d, J = 20.2 Hz), 3.65 (1H, dd, J = 20.2, 4.4 Hz), 2.92 (1H, dd, J = 20.2, 10.7 Hz); 13C NMR (100 MHz, CDCl3) δ 206.8, 168.1, 165.9, 147.2, 137.9, 136.2, 130.2, 129.0, 128.2, 125.9, 124.2, 113.0, 111.3, 95.4, 56.8, 56.4, 53.4, 37.3; IR (film) 1762, 1694, 1635 cm−1; mp 116−119 °C; [α]D20 = 403.20 (c = 0.1, CHCl3); HRMS (+ESI) calcd for C20H17N2O5 [M + H+] 365.1137 found 365.1138. 1-tert-Butyl-5-(ethylsulfonyl)-1H-tetrazole (14d). Compound 14d was synthesized starting from commercially available tert-butyl isothiocyanate. NaN3 (596 mg, 9.163 mmol, 1.00 equiv) was dissolved in H2O (4 mL) and heated to 100 °C. Then a solution of tert-butyl isothiocyanate (1056 mg, 9.163 mmol, 1.00 equiv) in i-PrOH (4 mL) 5326

DOI: 10.1021/acs.joc.8b00643 J. Org. Chem. 2018, 83, 5323−5330

Note

The Journal of Organic Chemistry Additional KOH (145 mg, 2.586 mmol, 1.00 equiv) and EtBr (282 mg, 2.586 mmol, 1.00 equiv) were added, and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was then evaporated and the crude product partitioned between water and DCM. Organics were separated, and the aqueous layer was extracted with DCM (3×). The combined organic extracts were dried over anhyd Na2SO4, filtered, and concentrated in vacuo. The crude 1-((3s,5s,7s)-adamantan-1-yl)-5-(ethylthio)-1H-tetrazole was dissolved in DCM (15 mL), and NaHCO3 (1.09 g, 12.93 mmol, 5.00 equiv) was added followed by slow addition of 70% mCPBA (1.91 g, 7.76 mmol, 3.00 equiv) under vigorous stirring. The resulting slurry was stirred at room temperature for 16 h and then quenched by addition of a saturated aqueous solution of Na2S2O3 and NaHCO3. The obtained biphasic mixture was stirred vigorously for 2 h, organics were separated, and the aqueous phase was extracted twice with DCM. The combined organic extracts were dried over anhyd Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (eluent: EtOAc/petroleum ether 1:9 → 1:1). The title compound was obtained as a white solid (435 mg, 57% in three steps): 1H NMR (400 MHz, CDCl3) δ 3.84 (2H, q, J = 7.4), 2.48 (6H, d J = 3.1), 2.31 (3H, s), 1.75−1.85 (6H, m), 1.55 (3H, t, J = 7.4); 13C NMR (100 MHz, CDCl3) δ 153.9, 66.3, 51.7, 41.9, 35.6, 29.9, 7.30; IR (film) 2943, 2916, 1339 cm−1; HRMS (+ESI) calcd for C13H21N4O2S [M + H+] 297.1385, found 297.1371; mp104−107 °C. 1-(2,6-Diisopropylphenyl)-5-(ethylsulfonyl)-1H-tetrazole (14f). Compound 14f was synthesized starting from commercially available 1,3-diisopropyl-2-isothiocyanatobenzene. NaN3 (299 mg, 4.582 mmol, 1.00 equiv) was dissolved in H2O (2 mL) and heated to 100 °C. Then a solution of 1,3-diisopropyl-2-isothiocyanatobenzene (1005 mg, 4.582 mmol, 1.00 equiv) in i-PrOH (2 mL) was added dropwise, and the reaction mixture was stirred 4 h at this temperature followed by 16 h at room temperature. Then, 0.7 mL of concd HCl was diluted with 2 mL of H2O, and the resulting solution was added dropwise to the reaction mixture. Volatiles were evaporated, and the crude product was partitioned between water and DCM. Organics were separated, and the aqueous layer was extracted with DCM (3×). The combined organic extracts were dried over anhyd Na2SO4, filtered, and concentrated in vacuo. The crude 1-(2,6-diisopropylphenyl)-1H-tetrazole-5-thiol was dissolved in EtOH (6 mL), KOH (308 mg, 5.498 mmol, 1.20 equiv) was added, and the resulting mixture was stirred for 30 min at room temperature. Then EtBr (549 mg, 5.040 mmol, 1.10 equiv) was added dropwise, and stirring was continued for 16 h at room temperature. The reaction mixture was then evaporated and the crude product partitioned between water and DCM. Organics were separated, and the aqueous layer was extracted with DCM (3×). The combined organic extracts were dried over anhyd Na2SO4, filtered, and concentrated in vacuo. The crude 1-(2,6-diisopropylphenyl)-5-(ethylthio)-1H-tetrazole was dissolved in DCM (20 mL), and NaHCO3 (1.92 g, 22.91 mmol, 5.00 equiv) was added followed by slow addition of 70% mCPBA (3.39 g, 13.75 mmol, 3.00 equiv) under vigorous stirring. The resulting slurry was stirred at room temperature for 16 h and then quenched by addition of saturated aqueous solution of Na2S2O3 and NaHCO3. The obtained biphasic mixture was stirred vigorously for 2 h, organics were separated, and the aqueous phase was extracted twice with DCM. The combined organic extracts were dried over anhyd Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (eluent: EtOAc/petroleum ether 0:1 → 1:5). The title compound was obtained as a beige solid (900 mg, 61% in three steps): 1H NMR (400 MHz, CDCl3) δ 7.57 (1H, t, J = 7.8), 7.33 (2H, d J = 7.8), 3.71 (2H, q, J = 7.4), 1.97−2.07 (2H, m), 1.52 (3H, t, J = 7.4), 1.24 (6H, d, J = 7.0), 1.08 (6H, d, J = 7.0); 13C NMR (100 MHz, CDCl3) δ 154.3, 146.2, 132.4, 128.6, 124.3, 50.7, 29.2, 25.3, 22.2, 6.9; IR (film) 2978, 2936, 1154 cm−1; HRMS (+ESI) calcd for C15H22N4O2NaS [M + Na] 345.1361 found 345.1369; mp 90−93 °C. 1-(3,5-Di-tert-butylphenyl)-5-(ethylsulfonyl)-1H-tetrazole (14g). Compound 14g was synthesized starting from commercially available 3,5-di-tert-butylaniline. To a solution of 3,5-di-tert-butylaniline (230 mg, 1.12 mmol, 1.00 equiv) in DCM (6 mL) was added saturated

aqueous NaHCO3 (6 mL), and the resulting mixture was cooled to 0 °C. After addition of thiophosgene (167 mg, 1.456 mmol, 1.30 equiv), the reaction mixture was allowed to warm to room temperature and vigorously stirred for 5 h. Then water was added, the organic layer separated, and aqueous layer extracted with DCM (3× ). The combined organic extracts were dried over anhyd Na2SO4, filtered, and concentrated in vacuo. The crude 1,3-di-tert-butyl-5-isothiocyanatobenzene was used in the next step without further purification. NaN3 (146 mg, 2.240 mmol, 2.00 equiv) was dissolved in H2O (3 mL) and heated to 100 °C. Then a solution of 1,3-di-tert-butyl-5isothiocyanatobenzene (277 mg, 1.120 mmol, 1.00 equiv) in dioxane (3 mL) was added dropwise, and the reaction mixture was stirred 4 h at this temperature followed by 16 h at room temperature. Then 0.2 mL of concd HCl was diluted with 0.6 mL of H2O, and the resulting solution was added dropwise to the reaction mixture. Volatiles were evaporated, and the crude product was partitioned between water and DCM. Organics were separated, and the aqueous layer was extracted with DCM (3×). The combined organic extracts were dried over anhyd Na2SO4, filtered, and concentrated in vacuo. The crude 1-(3,5-di-tert-butylphenyl)-1H-tetrazole-5-thiol was dissolved in EtOH (7 mL), KOH (144 mg, 2.576 mmol, 2.30 equiv) was added, and the resulting mixture was stirred for 30 min at room temperature. Then EtBr (268 mg, 2.464 mmol, 2.20 equiv) was added dropwise, and stirring was continued for 16 h at room temperature. The reaction mixture was then evaporated and the crude product partitioned between water and DCM. Organics were separated, and the aqueous layer was extracted with DCM (3×). The combined organic extracts were dried over anhyd Na2SO4, filtered, and concentrated in vacuo. The crude 1-(3,5-di-tert-butylphenyl)-5-(ethylthio)-1H-tetrazole was dissolved in DCM (10 mL), and NaHCO3 (470 mg, 5.60 mmol, 5.00 equiv) was added followed by slow addition of 70% mCPBA (828 mg, 3.36 mmol, 3.00 equiv) under vigorous stirring. The resulting slurry was stirred at room temperature for 16 h and then quenched by addition of saturated aqueous solution of Na2S2O3 and NaHCO3. The obtained biphasic mixture was stirred vigorously for 2 h, organics were separated, and the aqueous phase was extracted twice with DCM. The combined organic extracts were dried over anhyd Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (eluent: EtOAc/petroleum ether 0:1 → 1:9. The title compound was obtained as a yellow solid (160 mg, 41% in four steps): 1H NMR (400 MHz, CDCl3) δ 7.63 (1H, s), 7.54 (2H, s), 3.77 (2H, q, J = 7.4), 1.56 (3H, t, J = 7.4), 1.37 (18H, s); 13C NMR (100 MHz, CDCl3) δ 153.3, 153.0, 132.8, 125.3, 119.4, 51.0, 35.4, 31.4, 7.1; IR (film) 2965, 1341, 1153 cm−1; HRMS (+ESI) calcd for C17H26N4O2NaS [M + Na] 373.1674, found 373.1680; mp 55−57 °C. 5-(Ethylsulfonyl)-1-(2,4,6-tri-tert-butylphenyl)-1H-tetrazole (14h). Compound 14h was synthesized starting from 1,3,5-tri-tert-butyl-2isothiocyanatobenzene.28 NaN3 (321 mg, 4.942 mmol, 5.00 equiv) was dissolved in H2O (3 mL), 1,3,5-tri-tert-butyl-2-isothiocyanatobenzene (300 mg, 0.988 mmol, 1.00 equiv) and dioxane (6 mL) were added, and the obtained mixture was stirred for 16 h at 150 °C. After the mixture was cooled to ambient temperature, an aqueous solution of HCl (prepared from 0.5 mL of concd HCl and 1.5 mL of H2O) was added. Volatiles were evaporated, and the crude product was partitioned between water and DCM. Organics were separated, and the aqueous layer was extracted with DCM (3×). The combined organic extracts were dried over anhyd Na2SO4, filtered, and concentrated in vacuo. The crude 1-(2,4,6-tri-tert-butylphenyl)-1H-tetrazole-5-thiol was dissolved in EtOH (3 mL), KOH (83 mg, 1.482 mmol, 1.50 equiv) was added, the resulting mixture was stirred for 30 min at room temperature. Then EtBr (140 mg, 1.284 mmol, 1.30 equiv) was added dropwise, and stirring was continued for 16 h at room temperature. Additional KOH (83 mg, 1.482 mmol, 1.50 equiv) and EtBr (140 mg, 1.284 mmol, 1.30 equiv) were added, and the reaction mixture was stirred for 4 h at room temperature. The reaction mixture was then evaporated and the crude product partitioned between water and DCM. Organics were separated, and the aqueous layer was extracted 5327

DOI: 10.1021/acs.joc.8b00643 J. Org. Chem. 2018, 83, 5323−5330

Note

The Journal of Organic Chemistry with DCM (3×). The combined organic extracts were dried over anhyd Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using petroleum ether and EtOAc as eluents. 5-(Ethylthio)-1-(2,4,6-tri-tert-butylphenyl)-1Htetrazole (212 mg, 57% in two steps) was isolated. The 5-(ethylthio)-1-(2,4,6-tri-tert-butylphenyl)-1H-tetrazole (212 mg, 0.566 mmol, 1.00 equiv) was dissolved in DCM (10 mL), and NaHCO3 (238 mg, 2.830 mmol, 5.00 equiv) was added followed by slow addition of 70% mCPBA (418 mg, 1.698 mmol, 3.00 equiv) under vigorous stirring. The resulting slurry was stirred at room temperature for 16 h. Additional NaHCO3 (238 mg, 2.830 mmol, 5.00 equiv) and mCPBA (418 mg, 1.698 mmol, 3.00 equiv) were added, and the stirring was continued overnight. Additional NaHCO3 (238 mg, 2.830 mmol, 5.00 equiv), mCPBA (418 mg, 1.698 mmol, 3.00 equiv), and DCM (15 mL) were added, and the reaction mixture was stirred for 3 h at room temperature and then quenched by addition of saturated aqueous solution of Na2S2O3 and NaHCO3. The obtained biphasic mixture was stirred vigorously for 2 h, organics were separated, and the aqueous phase was extracted twice with DCM. The combined organic extracts were dried over anhyd Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (eluent: EtOAc/petroleum ether 0:1 → 1:5). The title compound was obtained as a beige solid (124 mg, 54%). The structure of the title compound was confirmed by X-ray crystallography: 1H NMR (400 MHz, CDCl3) δ 7.53 (2H, s), 3.69 (2H, q, J = 7.4), 1.54 (3H, t, J = 7.4), 1.36 (9H, s), 1.05 (18H, s); 13C NMR (100 MHz, CDCl3) δ 156.6, 153.1, 146.8, 125.3, 125.1, 51.2, 37.9, 35.3, 32.1, 31.3, 6.5; IR (film) 2964, 1367, 1154 cm−1; HRMS (+ESI) calcd for C21H35N4O2S [M + H+] 407.2481, found 407.2475; mp 104−106 °C. 5-(Ethylsulfonyl)-1-(2,4,6-tricyclopentylphenyl)-1H-tetrazole (14i). Compound 14i was synthesized starting from 2,4,6-tricyclopentylaniline.29 To a solution of 2,4,6-tricyclopentylaniline (460 mg, 1.546 mmol, 1.00 equiv) in DCM (8 mL) was added saturated aqueous NaHCO3 (8 mL), and the resulting mixture was cooled to 0 °C. After addition of thiophosgene (231 mg, 2.010 mmol, 1.30 equiv), the reaction mixture was allowed to warm to room temperature and vigorously stirred 5 h. Then water was added, the organic layer separated, and aqueous layer extracted with DCM (3×). The combined organic extracts were dried over anhyd Na2SO4, filtered, and concentrated in vacuo. The crude 1,3,5-tricyclopentyl-2isothiocyanatobenzene was used in the next step without further purification. NaN3 (201 mg, 3.092 mmol, 2.00 equiv) was dissolved in H2O (4 mL), a solution of 1,3,5-tricyclopentyl-2-isothiocyanatobenzene (525 mg, 1.546 mmol, 1.00 equiv) in dioxane (4 mL) was added, and the reaction mixture was stirred 4 h at 100 °C and then cooled. Additional NaN3 (201 mg, 3.092 mmol, 2.00 equiv), H2O (4 mL), and dioxane (4 mL) were added, and the reaction mixture was stirred for 16 h at 100 °C and then cooled. Then 1 mL of concd HCl was diluted with 3 mL of H2O, and the resulting solution was added dropwise to the reaction mixture. Volatiles were evaporated, and the crude product was partitioned between water and DCM. Organics were separated, and the aqueous layer was extracted with DCM (3×). The combined organic extracts were dried over anhyd Na2SO4, filtered, and concentrated in vacuo. The crude 1-(2,4,6-tricyclopentylphenyl)-1H-tetrazole-5-thiol was dissolved in EtOH (6 mL), KOH (120 mg, 2.146 mmol, 2.30 equiv) was added, and the resulting mixture was refluxed for 1 h and then cooled. Then EtBr (224 mg, 2.053 mmol, 2.20 equiv) was added dropwise, and the mixture was refluxed for 16 h. The reaction mixture was then evaporated, and the crude product was partitioned between water and DCM. Organics were separated, and the aqueous layer was extracted with DCM (3×). The combined organic extracts were dried over anhyd Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using petroleum ether and EtOAc as eluents. 5-(Ethylthio)-1-(2,4,6-tricyclopentylphenyl)1H-tetrazole (406 mg, 64% in was steps) was isolated. The 5-(ethylthio)-1-(2,4,6-tricyclopentylphenyl)-1H-tetrazole (400 mg, 0.974 mmol, 1.00 equiv) was dissolved in DCM (20 mL), and

NaHCO3 (409 mg, 4.871 mmol, 5.00 equiv) was added followed by slow addition of 70% mCPBA (720 mg, 2.922 mmol, 3.00 equiv) under vigorous stirring. The resulting slurry was stirred at room temperature for 2 h. An additional 10 mL of DCM, NaHCO3 (205 mg, 2.436 mmol, 2.50 equiv), and mCPBA (360 mg, 1.461 mmol, 1.50 equiv) were added, and the reaction mixture was stirred at room temperature for 16 h and then quenched by addition of saturated aqueous solution of Na2S2O3 and NaHCO3. The obtained biphasic mixture was stirred vigorously for 2 h, then organics were separated and aqueous phase extracted twice with DCM. The combined organic extracts were dried over anhyd Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (Eluent: EtOAc/petroleum ether 0:1 → 1:5). The title compound was obtained as a beige solid (150 mg, 35%): 1H NMR (400 MHz, CDCl3) δ 7.14 (2H, s), 3.69 (2H, q, J = 7.4), 2.99−3.08 (1H, m), 1.32−2.17 (26H, m), 1.51 (3H, t, J = 7.4); 13C NMR (100 MHz, CDCl3) δ 154.5, 150.7, 143.9, 127.8, 123.5, 50.7, 46.4, 40.8, 36.6, 34.7, 33.9, 25.9, 25.9, 25.6, 6.8; IR (film) 2955, 1346, 1153 cm−1; HRMS (+ESI) calcd for C24H34N4O2NaS [M + Na] 465.2300 found 465.2285; mp 119−121 °C. 5-(Ethylsulfonyl)-1-(2,4,6-tricyclohexylphenyl)-1H-tetrazole (14j). Compound 14j was synthesized starting from 2,4,6-tricyclohexylaniline.29 To a solution of 2,4,6-tricyclohexylaniline (1490 mg, 4.388 mmol, 1.00 equiv) in DCM (23 mL) was added saturated aqueous NaHCO3 (23 mL), and the resulting mixture was cooled to 0 °C. After addition of thiophosgene (656 mg, 5.714 mmol, 1.30 equiv), the reaction mixture was allowed to warm to room temperature and stirred vigorously 5 h. Then water was added, the organic layer separated, and aqueous layer extracted with DCM (3×). The combined organic extracts were dried over anhyd Na2SO4, filtered and concentrated in vacuo. The crude (2-isothiocyanatobenzene-1,3,5-triyl)tricyclohexane was used in the next step without further purification. NaN3 (570 mg, 8.776 mmol, 2.00 equiv) was dissolved in H2O (11 mL), a solution of crude (2-isothiocyanatobenzene-1,3,5-triyl)tricyclohexane in dioxane (11 mL) was added, and the reaction mixture was stirred 4 h at 100 °C and then cooled. Additional NaN3 (570 mg, 8.776 mmol, 2.00 equiv), H2O (11 mL), and dioxane (11 mL) were added, and the reaction mixture was stirred at 100 °C for 16 h and then cooled. Then 3 mL of concd HCl was diluted with 9 mL of H2O, and the resulting solution was added dropwise to the reaction mixture. Volatiles were evaporated, and the crude product was partitioned between water and DCM. Organics were separated, and the aqueous layer was extracted with DCM (3×). The combined organic extracts were dried over anhyd Na2SO4, filtered, and concentrated in vacuo. The crude 1-(2,4,6-tricyclohexylphenyl)-1H-tetrazole-5-thiol was dissolved in EtOH (30 mL), KOH (566 mg, 10.092 mmol, 2.30 equiv) was added, and the resulting mixture was refluxed for 1 h and then cooled. Then EtBr (1052 mg, 9.654 mmol, 2.20 equiv) was added dropwise, and the reaction mixture was refluxed for 16 h. The reaction mixture was then evaporated and the crude product partitioned between water and DCM. Organics were separated, and the aqueous layer was extracted with DCM (3×). The combined organic extracts were dried over anhyd Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using petroleum ether and EtOAc as eluents. 5-(Ethylthio)-1-(2,4,6tricyclohexylphenyl)-1H-tetrazole (1646 mg, 83% in three steps) were isolated. The 5-(ethylthio)-1-(2,4,6-tricyclohexylphenyl)-1H-tetrazole (1646 mg, 3.636 mmol, 1.00 equiv) was dissolved in DCM (100 mL), and NaHCO3 (1527 mg, 18.180 mmol, 5.00 equiv) was added followed by slow addition of mCPBA (2689 mg, 10.908 mmol, 3.00 equiv) under vigorous stirring. The resulting slurry was stirred at room temperature for 16 h. An additional 40 mL of DCM, NaHCO3 (764 mg, 9.090 mmol, 2.50 equiv), and mCPBA (1345 mg, 5.454 mmol, 1.50 equiv) were added, and the reaction mixture was stirred at room temperature for 16 h and then quenched by addition of saturated aqueous solution of Na2S2O3 and NaHCO3. The obtained biphasic mixture was stirred vigorously for 2 h, organics were separated, and the aqueous phase 5328

DOI: 10.1021/acs.joc.8b00643 J. Org. Chem. 2018, 83, 5323−5330

Note

The Journal of Organic Chemistry extracted twice with DCM. The combined organic extracts were dried over anhyd Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (eluent: EtOAc/ petroleum ether 1:10 → 1:4). The title compound was obtained as a beige solid (600 mg, 34%): 1H NMR (400 MHz, CDCl3) δ 7.10 (2H, s), 3.70 (2H, q, J = 7.4), 2.52−2.61 (1H, m), 0.95−1.98 (32H, m), 1.49 (3H, t, J = 7.4); 13C NMR (100 MHz, CDCl3) δ 154.2, 151.9, 144.6, 126.5, 123.4, 50.6, 44.9, 40.0, 35.7, 34.4, 32.4, 27.0, 26.9, 26.7, 26.2, 26.0, 7.1; IR (film) 2929, 1348, 1150 cm−1; HRMS (+ESI) calcd for C27H40N4O2NaS [M + Na] 507.2770 found 507.2779; mp 155− 158 °C. 5-(Ethylsulfonyl)-1-(5′-phenyl-[1,1′:3′,1″-terphenyl]-4′-yl)-1H-tetrazole (14k). Compound 14k was synthesized starting from commercially available 2,4,6-triphenylaniline. To a solution of 2,4,6-triphenylaniline (300 mg, 0.933 mmol, 1.00 equiv) in DCM (5 mL) was added saturated aqueous NaHCO3 (5 mL), and the resulting mixture was cooled to 0 °C. After addition of thiophosgene (140 mg, 1.213 mmol, 1.30 equiv), the reaction mixture was allowed to warm to room temperature and vigorously stirred 5 h. Then water was added, the organic layer separated, and aqueous layer extracted with DCM (3×). The combined organic extracts were dried over anhyd Na2SO4, filtered, and concentrated in vacuo. The crude 2′isothiocyanato-5′-phenyl-1,1′:3′,1″-terphenyl was used in the next step without further purification. NaN3 (121 mg, 1.866 mmol, 2.00 equiv) was dissolved in H2O (3 mL), a solution of crude 2′-isothiocyanato-5′-phenyl-1,1′:3′,1″terphenyl in dioxane (3 mL) was added, and the reaction mixture was stirred 4 h at 100 °C followed by 16 h at room temperature. Then 0.2 mL of concd HCl was diluted with 0.6 mL of H2O, and the resulting solution was added dropwise to the reaction mixture. Volatiles were evaporated, and the crude product was partitioned between water and DCM. Organics were separated, and the aqueous layer was extracted with DCM (3×). The combined organic extracts were dried over anhyd Na2SO4, filtered, and concentrated in vacuo. The crude 1-(5′-phenyl-[1,1′:3′,1″-terphenyl]-2′-yl)-1H-tetrazole-5thiol was dissolved in EtOH (6 mL), KOH (120 mg, 2.146 mmol, 2.30 equiv) was added, the the resulting mixture was stirred for 30 min at room temperature. Then EtBr (224 mg, 2.053 mmol, 2.20 equiv) was added dropwise, and stirring was continued for 16 h at room temperature. The reaction mixture was then evaporated and the crude product partitioned between water and DCM. Organics were separated, and the aqueous layer was extracted with DCM (3×). The combined organic extracts were dried over anhyd Na2SO4, filtered, and concentrated in vacuo. The crude 5-(ethylthio)-1-(5′-phenyl-[1,1′:3′,1″-terphenyl]-2′-yl)1H-tetrazole was dissolved in DCM (10 mL), and NaHCO3 (392 mg, 4.665 mmol, 5.00 equiv) was added followed by slow addition of 70% mCPBA (690 mg, 2.799 mmol, 3.00 equiv) under vigorous stirring. The resulting slurry was stirred at room temperature for 16 h and then quenched by addition of saturated aqueous solution of Na2S2O3 and NaHCO3. The obtained biphasic mixture was stirred vigorously for 2 h, organics were separated, and the aqueous phase was extracted twice with DCM. The combined organic extracts were dried over anhyd Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (eluent: EtOAc/petroleum ether 1:9 → 1:1). The title compound was obtained as a white solid (345 mg, 79% in four steps). 1H NMR (400 MHz, CDCl3) δ 7.77 (2H, s), 7.70−7.74 (2H, m), 7.41−7.53 (3H, m), 7.24−7.33 (10 H, m), 2.83 (2H, q, J = 7.4), 0.97 (3H, t, J = 7.4); 13C NMR (100 MHz, CDCl3) δ 153.6, 144.6, 141.2, 139.2, 136.8, 129.2, 129.1, 128.9, 128.7, 128.6, 128.5, 128.3, 127.6, 50.6, 6.1; IR (film) 1348, 1152 cm−1; HRMS (+ESI) calcd for C27H23N4O2S [M + H+] 467.1542 found 467.1534; mp 118−121 °C. (9aS)-8-Ethylidene-3-methoxy-1-phenyl-7,8,9,9a-tetrahydro-1H2-oxa-6a,10a-diazabenzo[cd]cyclopenta[g]azulene-6,10-dione (15). General procedure for the olefination of ketone 13: To a solution of the sulfone 14 (0.110 mmol, 2.00 equiv) in dry THF (0.3 mL) under Ar atmosphere was added KHMDS (1 M solution in THF, 0.11 mL, 0.110 mmol, 2.00 equiv) at −78 °C, the resulting mixture was stirred for 15 min at this temperature, and then a solution of the

ketone 13 (20 mg, 0.055 mmol, 1.00 equiv) in dry THF (0.4 mL) was added dropwise. The reaction mixture was stirred for 40 min at −78 °C and then warmed to room temperature (∼15 min), quenched with saturated aqueous NH4Cl, and extracted with DCM (3×). The combined organic extracts were dried over anhyd Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (eluent: EtOAc/petroleum ether 4:6 → 7:3). Major isomer (E-15): 1H NMR (400 MHz, CDCl3) δ 7.58 (1H, d, J = 9.0 Hz), 7.32−7.45 (6H, m), 6.85 (1H, d, J = 9.0 Hz), 5.48−5.57 (1H, m), 4.52 (1H, d, J = 15.5 Hz), 4.33 (1H, dd, J = 9.8, 3.1 Hz), 4.07 (1H, d, J = 15.5 Hz), 3.98 (3H, s), 3.57 (1H, d, J = 15.5 Hz), 2.68− 2.80 (1H, m), 1.72 (3H, d, J = 7.0 Hz); Minor isomer (Z-15): 1H NMR (400 MHz, CDCl3) δ 7.59 (1H, d, J = 9.0 Hz), 7.31−7.46 (6H, m), 6.85 (1H, d, J = 9.0 Hz), 5.47−5.60 (1H, m), 4.44 (1H, d, J = 15.5 Hz), 4.26 (1H, dd, J = 9.8, 3.1 Hz), 4.15 (1H, d, J = 15.5 Hz), 3.98 (3H, s), 3.45 (1H, d, J = 15.5 Hz), 2.82− 2.90 (1H, m), 1.64 (3H, d, J = 7.0 Hz) (S)-tert-Butyl 2-(((tert-Butyldiphenylsilyl)oxy)methyl)-4-oxopyrrolidine-1-carboxylate (17). To a solution of tert-butyl (2S,4R)-2(((tert-butyldiphenylsilyl)oxy)methyl)-4-hydroxypyrrolidine-1-carboxylate30 16 (1.24 g, 2.721 mmol, 1.00 equiv) in DCM (35 mL) was added DMP (1.73 g, 4.082 mmol, 1.50 equiv), and the resulting mixture was stirred at room temperature for 4 h. Additional DMP (577 mg, 1.361 mmol, 0.50 equiv) was added, and the mixture was stirred for 16 h. After being quenched by addition of an aqueous solution of Na2S2O3, the obtained biphasic mixture was stirred vigorously for 10 min, organics were separated, and the aqueous phase was extracted twice with DCM. The combined organic extracts were dried over anhyd Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (Eluent: EtOAc/petroleum ether 4:1 → 2:1). The title compound was obtained as a yellowish solid (1.14 g, 92%): 1H NMR (400 MHz, CDCl3) δ 7.53−7.68 (4H, m), 7.33−7.48 (6H, m), 4.41 (0.5H, d, J = 9.4)4.37 (0.5H, d, J = 9.4), 3.80−4.15 (3H, m), 3.52 (1H, t, J = 11.3), 2.65−2.83 (1H, m), 2.54 (1H, t, J = 19.2), 1.51 and 1.47 (together 9H, both s), 1.00 (9H, s); 13 C NMR (100 MHz, CDCl3 (rotomers): δ 211.0, 210.3, 135.7, 132.8, 130.0, 128.0, 80.5, 66.5, 66.2, 55.8, 55.3, 54.3, 53.7, 41.0, 40.5, 28.6, 26.8, 19.2; IR (film) 2962, 2931, 1764, 1165, 1106 cm−1; [α]D20 = 11.84° (c = 1, CHCl3); HRMS (+ESI) calcd for C26H35NO4NaSi [M + Na] 476.2233 found 476.2234; mp 99−102 °C. The olefination of ketone 17 was conduced according to general olefination procedure, and the obtained intermediate olefin was further subjected to TBDPS protecting group cleavage: To a solution of olefin in THF (3 mL) was added TBAF·3H2O (139 mg, 0.440 mmol, 2 equiv), and the resulting mixture was stirred at room temperature for 16 h, loaded on silica, and purified by flash column chromatography (eluent: EtOAc/petroleum ether 1:1 → 1:0). The title compound was isolated as a yellow wax: 29 mg (58% in two steps) using sulfone 14c; 31 mg (62% in two steps) using sulfone 14j.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00643. General scheme for the synthesis of sulfones 14, ORTEP diagram of 14h, representative examples of HPLC plots used for determination of E-/Z- ratio in Julia−Kocienski olefination of ketone 13 with sulfones 14, and NMR spectra (PDF) X-ray data for compound 14h (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Gints Smits: 0000-0001-5044-4169 5329

DOI: 10.1021/acs.joc.8b00643 J. Org. Chem. 2018, 83, 5323−5330

Note

The Journal of Organic Chemistry Notes

(18) Sakaine, G.; Smits, G.; Zemribo, R. Late Stage Fe(CO)5 Promoted Double Bond Migration: Total Synthesis of Limazepines C and D. Tetrahedron Lett. 2015, 56, 4767−4769. (19) Smits, G.; Kinens, A.; Zemribo, R. Ireland−Claisen Rearrangement of 6-Methylene-1,4-Oxazepan-2-Ones. Eur. J. Org. Chem. 2015, 2015, 6701−6709. (20) Dumeunier, R.; Markó, I. E. The Julia Reaction. In Modern Carbonyl Olefination; Takeda, T., Ed.; Wiley-VCH, 2003; pp 104−150. (21) Plesniak, K.; Zarecki, A.; Wicha, J. The Smiles Rearrangement and the Julia−Kocienski Olefination Reaction. In Sulfur-Mediated Rearrangements II; Topics in Current Chemistry; Springer: Berlin, 2006; pp 163−250. (22) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. A direct synthesis of olefins by reaction of carbonyl compounds with lithio derivatives of 2-[alkyl- or (2′-alkenyl)- or benzyl-sulfonyl]-benzothiazoles. Tetrahedron Lett. 1991, 32, 1175−1178. (23) Baudin, J. B.; Hareau, G.; Julia, S. A.; Lorne, R.; Ruel, O. Bull. Soc. Chim. Fr. 1993, 130, 856−878. (24) Blakemore, P. R.; Cole, W. J.; Kocieński, P. J.; Morley, A. A Stereoselective Synthesis of trans-1,2-Disubstituted Alkanes Based on the Condensation of Aldehydes with Metallated 1-Phenyl-1H-tetrazol5-yl Sulfones. Synlett 1998, 1998, 26−28. (25) Hoefle, G.; Richter, W. Novel Macrocycles for the Treatment of Cancer. WO2004007492(A1), Jan 22, 2004. (26) Vermote, A.; Brackman, G.; Risseeuw, M. D. P.; Coenye, T.; Van Calenbergh, S. Novel hamamelitannin analogues for the treatment of biofilm related MRSA infections-A scaffold hopping approach. Eur. J. Med. Chem. 2017, 127, 757−770. (27) Lorente, A.; Pla, D.; Cañedo, L. M.; Albericio, F.; Á lvarez, M. Isolation, Structural Assignment, and Total Synthesis of Barmumycin. J. Org. Chem. 2010, 75, 8508−8515. (28) Habib, N. S.; Rieker, A. Metathesis of Aryl Isothiocyanates: A Novel Method for the Synthesis of Sterically Hindered Aryl Isothiocyanates. Synthesis 1984, 1984, 825−827. (29) Savka, R.; Plenio, H. Metal Complexes of Very Bulky N,N′Diarylimidazolylidene N-Heterocyclic Carbene (NHC) Ligands with 2,4,6-Cycloalkyl Substituents. Eur. J. Inorg. Chem. 2014, 2014, 6246− 6253. (30) Vermote, A.; Brackman, G.; Risseeuw, M. D. P.; Coenye, T.; Van Calenbergh, S. Novel Hamamelitannin Analogues for the Treatment of Biofilm Related MRSA Infections−A Scaffold Hopping Approach. Eur. J. Med. Chem. 2017, 127, 757−770.

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge the Latvian Institute of Organic synthesis internal grant for G. Sakaine (IG-2017-05) and ERDF (PostDoc Latvia) project No.1.1.1.2/VIAA/1/16/243 for G. Smits. We also thank Dr. S. Belyakov (LIOS) for X-ray crystallographic analyses.

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REFERENCES

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DOI: 10.1021/acs.joc.8b00643 J. Org. Chem. 2018, 83, 5323−5330