Stereoselective Synthesis of Lower and Upper rim Functionalized Tetra-α Isomers of Calix[4]pyrroles

Stereoselective Synthesis of Lower and Upper rim Functionalized Tetra-α Isomers of Calix[4]pyrroles Alejandro Díaz-Moscoso, Daniel Hernández-Alonso, Luis Escobar, Frank A. Arroyave, and Pablo Ballester*,, Institute of Chemical Research of Catalonia (ICIQ); The Barcelona Institute of Science and Technology (BIST), Avda. Països Catalans 16, 43007 Tarragona, Spain ICREA, Passeig Lluís Companys 23, 08010 Barcelona, Spain Supporting Information - Table of Contents Page S2: General methods Pages S3-S7: Synthetic procedures and characterization data for new compounds Pages S8-S20: 1 H and 13 C{ 1 H} NMR spectra of new compounds Pages S21-S23: Crystallographic data S1

General experimental information. Reagents and solvents were purchased from commercial sources and used without further purification unless otherwise stated. When required, dried and deoxygenated solvents supplied by Sigma-Aldrich Solvent Purification System (SPS-200-6) were employed. THF was dried over Na/benzophenone and distilled. Starting ketones 1a-c and HCl 4.0 M in dioxane are commercially available. Pyrrole was freshly distilled under vacuum prior to use. Methyltribuylammonium chloride (TBMACl) was purchased as aqueous solution, dried under vacuum and employed as a solid. Thin-layer chromatography (TLC) was performed with DC-Alufolien Kieselgel 60 F254 (Merck). Silica gel 60Å for chromatography (SDS) was employed in flash column chromatography. 1 H NMR, 13 C NMR, COSY, HSQC and HMBC spectra were recorded at 400 MHz using a Bruker 400 UltrashieldTM or a 500 MHz Bruker Avance 500 UltrashieldTM spectrometer. Usual JOC spectral abbreviation are employed with the addition of quin for quintet and app for apparent. Residual solvent peaks were employed for calibration of the spectra. Mass spectrometry experiments were performed on a LCT Premier, Waters-Micromass ESI. FTIR measurements were carried out on a Bruker Optics ATR FTIR Alpha-p spectrometer equipped with a DTGS detector, KBr beam splitter at 4 cm -1 resolution. Melting points were measured in a Büchi Melting Point B-540 device with a 5 C min -1 gradient. Method A. General procedure for the preparation of bifunctionalised meso-tetraalkyl meso-tetraaryl calix[4]pyrroles. In a typical reaction, the starting ketone and pyrrole (1 equiv) were dissolved in dry CH2Cl2 under Ar and covered with aluminium foil. Then, the corresponding methyltrialkylammonium chloride (3 equiv) was added. After stirring for 10 min (under Ar and in the dark), HCl (3 equiv; 4.0 M in dioxane) was added dropwise over 15 min (the solution turns dark). The reaction was stirred under Ar in the dark for 18 h. Then, it was diluted with an adequate organic solvent and the mixture washed twice with water and once with brine. The organic phase was dried (Na2SO4), filtered and concentrated under vacuum. A silica-gel filter was carried out in order to remove Aliquat 336 when necessary (in case of adding TBMACl, it was washed away with water). The mixture was purified by column chromatography or precipitation. S2

Ketone 2a (The synthesis involves 3 steps). Step 1: Glutaric anhydride (4 g, 35.1 mmol) was dissolved in 70 ml of anhydrous THF under Ar atmosphere at 0 ºC. 3-Methoxyphenylmagnesium bromide (1M solution in THF, 36.8 ml, 36.8 mmol, 1.05 equiv) was slowly added under vigorous stirring over 30 min. After addition, the reaction was left to slowly reach rt for 18 h. Next day, the reaction mixture was quenched with 50 ml of water and acidified until ph 1 with HCl (10% aq). The aqueous phase was extracted with EtOAc (3 x 50mL). The EtOAc extracts were combined, dried (Na2SO4), filtered and concentrated to dryness, yielding a yellow syrup. 20 ml of water were added and the mixture sonicated yielding a solid. The solid was filtered, washed with water (2 x 20 ml) and dried by passing air through it. Once the solid was dried, it was washed with hexane (2 x 20 ml) yielding desired product 5 as a white solid (5.4 g, 24.3 mmol, 69%). If necessary, the product was crystallised from boiling water. 1 H NMR (400 MHz, acetone-d6, 298 K): δ (ppm) = 10.59 (br s, 1H, COOH); 7.59 (ddd, 1H, 3 JHe- Hd= 7.6 Hz; 4 JHe-Hc= 1.5 Hz; 4 JHe-Ha= 1.0 Hz, He); 7.51 (dd, 1H, 4 JHc-Ha= 2.6 Hz, Hc); 7.42 (app t, 1H, app 3 JHd- Ha= 3 JHd-He= 7.9 Hz, Hd); 7.17 (ddd, 1H, 3 JHa-Hd= 8.2 Hz, Ha); 3.86 (s, 3H, OCH3); 3.11 (t, 2H, 3 JHh-Hi= 7.3 Hz, Hh), 2.43 (t, 2H, 3 JHj-Hi= 7.3 Hz, Hj), 1.98 (app quin, 2H, Hi). 13 C{ 1 H} NMR (100.6 MHz, acetone-d6, 298 K): δ (ppm) = 199.7 (Cg); 174.5 (Ck); 160.9 (Cb); 139.5 (Cf); 130.6 (Cd); 121.2 (Ce); 119.8 (Ca); 113.3 (Cc); 55.7 (OCH3); 38.2 (Ch); 33.3 (Cj); 20.3 (Ci). HRMS (ESI-TOF): m/z Calcd for C12H13O4 [M-H] - = 221.0819; Found = 221.0820. Step 2: 5-(3-methoxyphenyl)-5-oxopentanoic acid 5 (13.28 g, 59.8 mmol) was dissolved in a mixture of 80 ml of acetic acid and 80 ml of HBr (48% aq solution). The mixture was refluxed for 6h. Then it was cooled down to rt and diluted with water (typically 100 ml). The crude was extracted with EtOAc (3 x 60 ml). The EtOAc extracts were combined, dried (Na2SO4), filtered and concentrated to dryness, yielding the desired product 6 as a brown solid (10.4 g, 50.2 mmol, 84%). 1 H NMR (500 MHz, acetone-d6, 298 K): δ (ppm) = 10.57 (br s, 1H, COOH); 8.75 (br s, 1H, OH); 7.49 (ddd, 1H, 3 JHe-Hd= 7.7 Hz; 4 JHe-Hc= 1.6 Hz; 4 JHe-Ha= 1.0 Hz, He); 7.44 (dd, 1H, 4 JHc-Ha= 2.5 Hz, Hc); 7.33 (app t, 1H, app 3 JHd-Ha= 3 JHd-He= 7.9 Hz, Hd); 7.07 (ddd, 1H, 3 JHa- Hd= 8.1 Hz, Ha); 3.07 (t, 2H, 3 JHh-Hi= 7.3 Hz, Hh), 2.42 (t, 2H, 3 JHj-Hi= 7.3 Hz, Hj), 1.98 (app quin, 2H, Hi). 13 C{ 1 H} NMR (125.7 MHz, acetone-d6, 298 K): δ (ppm) = 199.7 (Cg); 174.6 (Ck); 158.6 (Cb); 139.5 (Cf); 130.6 (Cd); 120.8 (Ca); 120.1 (Ce); 115.1 (Cc); 38.2 (Ch); 33.3 (Cj); 20.3 (Ci). HRMS (ESI-TOF) m/z: Calcd for C11H11O4 [M-H] - = 207.0663; Found = 207.0662. Step 3: To a solution of 5-(3-hydroxyphenyl)-5-oxopentanoic acid 6 (8.5 g, 40.8 mmol) dissolved in absolute EtOH (400 ml), H2SO4 (1.1 ml, 96%, 20.4 mmol, 0.5 equiv) was added, and the mixture was refluxed for 1.5 h. The mixture was concentrated under reduced pressure. The crude was redissolved in CH2Cl2 (100 ml) and washed with NaHCO3 (aq sat) until complete neutralisation of the acid. The CH2Cl2 solution was dried (Na2SO4), filtered and concentrated to dryness. The product was purified by column chromatography on silica gel (CH2Cl2:EtOAc 95:5 CH2Cl2:EtOAc 9:1). Ketone 2a was isolated as a white solid (8.2 g, 34.7 mmol, 85% yield). Rf = 0.39 (9:1 CH2Cl2:EtOAc). 1 H NMR (400 MHz, acetone-d6, 298 K): δ (ppm) = 8.63 (br s, 1H, OH); 7.49 (ddd, 1H, 3 JHe-Hd= 7.7 Hz; 4 JHe-Hc= 1.6 Hz; 4 JHe-Ha= 1.0 Hz, He); 7.43 (ddd, 1H, 4 JHc-Ha= 2.5 Hz, 4 JHc-Hd= 0.4 Hz, Hc); 7.34 (br app t, 1H, app 3 JHd-Ha= 3 JHd-He= 7.9 Hz, Hd); 7.08 (ddd, 1H, 3 JHa-Hd= 8.1 Hz, Ha); 4.09 (q, 2H, 3 JHl-Hm= 7.1 Hz, Hl); 3.06 (t, 2H, 3 JHh-Hi= 7.2 Hz, Hh), 2.41 (t, 2H, 3 JHj-Hi= 7.4 Hz, Hj), 1.97 (app quin, 2H, app 3 JHi-Hh= 3 JHi-Hj= 7.3 Hz, Hi); 1.21 (t, 3H, Hm). 13 C{ 1 H} NMR (125.7 MHz, acetone-d6, 298 S3

K): δ (ppm) = 199.6 (Cg); 173.5 (Ck); 158.5 (Cb); 139.5 (Cf); 130.6 (Cd); 120.8 (Ca); 120.2 (Ce); 115.1 (Cc); 60.6 (Cl); 38.1 (Ch); 33.8 (Cj); 20.3 (Ci); 14.6 (Cm). HRMS (ESI-TOF) m/z: Calcd for C13H15O4 [M-H] - = 235.0976; Found = 235.0984. FTIR (ATR): ῡ (cm-1) = 3324, 2983, 2965, 2942, 2907, 1688, 1674, 1446, 1266, 1203, 1168. M.p.: 48-50 ºC. Ketone 2b (The synthesis involves 3 steps). Step 1: Bromo-3,5-dimethoxybenzene (5 g, 23.03 mmol) was dissolved in 150 ml of anhydrous THF and cooled to -78 o C. BuLi (2.5 M in hexanes, 9.67 ml, 24.19 mmol, 1.05 equiv) was added dropwise and the mixture was stirred for 90 min. Magnesium bromide ethyl etherate (6.25 g, 29.19 mmol, 1.05 equiv) was added in small portions at -78 ºC. The reaction mixture was stirred for 10 min and allowed to warm up to 0 o C. Glutaric anhydride (3.42 g, 29.9 mmol, 1.3 equiv) was added and the mixture warmed up to rt and stirred for 12 h. Then the solvent was removed by rotary evaporation and the resulting mixture was stirred in HCl (0.3 M, 200 ml) for 30 min, extracted with CH2Cl2, dried (Na2SO4), filtered and concentrated under vaccum. Purification by column chromatography on silica, (CH2Cl2:EtOAc 2:1 1:1), and further recrystallisation from CH2Cl2:hexanes produced 7 as a white solid (1.47 g, 5.8 mmol, 25% yield). 1 H NMR (500 MHz, DMSO-d6, 298 K): δ (ppm) = 12.07 (s, 1H, COOH); 7.06 (d, 2H, 3 JHa-Hc= 2.3 Hz, Hc); 6.75 (t, 1H, Ha); 3.80 (s, 6H, OCH3); 3.02 (t, 2H, 3 JHh-Hi= 7.2 Hz, Hh); 2.29 (t, 2H, 3 JHj-Hi= 7.4 Hz, Hj); 1.81 (app quin, 2H, app 3 JHi-Hh= 3 JHi- Hj= 7.3 Hz, Hi). 13 C{ 1 H} NMR (125.7 MHz, DMSO-d6, 298 K): δ (ppm) = 199.3 (Cg); 174.2 (Ck); 160.6 (Cb); 138.7 (Cf); 105.6 (Cc); 104.9 (Ca); 55.5 (OCH3); 37.3 (Ch); 32.8 (Cj); 19.4 (Ci). HRMS (ESI-TOF) m/z: Calcd for C13H15O5 [M-H] - = 251.0925; Found = 251.0924. FTIR (ATR): ῡ (cm 1 ) = 3106, 3032, 2966, 2917, 2895, 2839, 1708, 1678, 1592, 1453, 1425, 1352, 1295, 1271, 1199, 1153, 1063, 1051, 921, 858, 840, 751. Step 2. 5-(3,5-dimethoxyphenyl)-5-oxopentanoic acid 7 (1.4 g, 5.5 mmol) was dissolved in a mixture of glacial acetic (50 ml) acid and HBr (48% aq solution) (15.7 ml, 139 mmol, 25 equiv.). The mixture was stirred at 125 o C for 12 h, then the solvent was removed by rotary evaporation and the resulting solid was partitioned between EtOAc (100 ml) and water (150 ml). The organic layer was washed with water (2x), dried over Na2SO4 and filtered. Removal of the solvent produced 8 as a brown solid (1.1 g, 4.9 mmol, 88% yield). 1 H NMR (400 MHz, DMSO-d6, 298 K): δ (ppm) = 12.05 (s, 1H, COOH); 9.57 (s, 2H, OH); 6.77 (br d, 2H, Hc); 6.44 (br t, 1H, Ha); 2.92 (t, 2H, 3 JHh-Hi= 7.2 Hz, Hh); 2.27 (t, 2H, 3 JHj-Hi= 7.4 Hz, Hj); 1.78 (app quin, 2H, app 3 JHi-Hh= 3 JHi-Hj= 7.3 Hz, Hi). 13 C{ 1 H} NMR (100.6 MHz, DMSO-d6, 298 K): δ (ppm) = 199.3 (Cg); 174.3 (Ck); 158.6 (Cb); 138.6 (Cf); 107.1 (Ca); 105.8 (Cc); 37.1 (Ch); 32.8 (Cj); 19.3 (Ci). HRMS (ESI-TOF): m/z Calcd for C11H11O5 [M-H] - = 223.0612, Found = 223.0614. FTIR (ATR): ῡmax (cm 1 ) = 3325, 1700, 1667, 1593, 1445, 1332, 1279, 1148, 994, 825, 667. Step 3: 5-(3,5-dihydroxyphenyl)-5-oxopentanoic acid 8 (0.95 g, 4.24 mmol) (from step 2) was dissolved in 150 ml of absolute EtOH. Sulfuric acid (0.11 ml, 2.12 mmol, 0.5 equiv) was added and the mixture was stirred at reflux (90 o C) for 2 h. The reaction was allowed to cool to 40 o C, then the ph was increased to 5 by adding NaHCO3 (aq sat). The solvent was removed under reduced pressure and the mixture partitioned between water and EtOAc (60 ml). The organic layer was dried (Na2SO4) and filtered through silica. The solvent was removed by rotary evaporation, the resulting solid was dispersed in 200:1 CH2Cl2:Et2O S4

and collected by filtration. Ketone 2b was obtained as an off-white solid (0.7 g, 2.8 mmol, 66% yield). 1 H NMR (500 MHz, CDCl3:DMSO-d6 5:1, 298 K): δ (ppm) = 8.80 (s, 2H, OH); 6.73 (d, 2H, 3 JHa-Hc= 2.2 Hz, Hc); 6.40 (t, 1H, Ha); 3.93 (q, 3 JHa-Hc= 7.1 Hz, Hl); 2.76 (t, 2H, 3 JHh-Hi= 7.3 Hz, Hh); 2.20 (t, 2H, 3 JHj-Hi= 7.3 Hz, Hj); 1.82 (app quin, 2H, Hi); 1.06 (t, 2H, Hm). 13 C{ 1 H} NMR (100.6 MHz, CDCl3:DMSO-d6 5:1, 298 K): δ (ppm) = 199.2 (Cg); 172.9 (Ck); 158.3 (Cb); 138.4 (Cf); 107.6 (Ca); 106.3 (Cc); 59.9 (Cl); 37.2 (Ch); 33.1 (Cj); 19.1 (Ci); 13.9 (Cm). HRMS (ESI-TOF): m/z Calcd for C13H15O5 [M-H] = 251.0925, Found 251.0933. FTIR (ATR): ῡmax (cm 1 ) = 3264, 2973, 2905, 1683, 1663, 1600, 1377, 1352, 1287, 1160, 1005, 865, 684. Ketone 2c. 4-iodoacetophenone (20 g, 81 mmol) was dissolved in piperidine (40 ml, 406 mmol, 5 equiv) and hexane (500 ml) was added. The mixture was stirred at 0 ºC for 10 min. Then, TiCl4 (5.4 ml, 48 mmol, 0.6 equiv) was added slowly during 5 min. The reaction was stirred for 30 min more at 0 ºC and 24 h at rt. Then, the solids were filtered off and washed with hexane (200 ml). The combined organic phases were concentrated under vacuum. The resulting enamine was obtained as brown oil (22.5 g, 71.8 mmol, 88% yield). The enamine (18 g, 57.47 mmol) was dissolved in dried EtOH (180 ml). The solution was stirred under Ar atmosphere at rt and methyl acrylate (10.35 ml, 115 mmol, 2 equiv) was added. After six days, methanol (50 ml), water (50 ml) and acetic acid (27 ml) were added and the reaction was heated at 45 ºC for 1 h. The organic solvent was evaporated and EtOAc (100 ml) was added. The organic phase was washed with HCl 1N (2 x 100 ml) and water (100 ml), dried (Na2SO4), filtered and concentrated to dryness. The product was purified by column chromatography on silica gel (CH2Cl2:Hexane 8:2 CH2Cl2:Hexane:Et2O 8:1.9:0.1) to afford the product as a white solid (5.5 g, 16.56 mmol, 26% yield). Rf = 0.3 (8:1.9:0.1 CH2Cl2:Hexane:Et2O). 1 H NMR (400 MHz, CDCl3, 298 K): δ (ppm) = 7.83-7.80 (AA XX system, 2H, 3 JHb-Hc = 8.6 Hz; 4 JHb-Hb = 2.0 Hz, Hb); 7.67-7.64 (AA XX system, 2H, 4 JHc-Hc = 2.0 Hz, Hc); 3.67 (s, 3H, Hl); 3.00 (t, 2H, 3 JHh-Hi = 7.1 Hz, Hh); 2.43 (t, 2H, 3 JHj-Hi = 7.1 Hz, Hj); 2.05 (app quin, 2H, Hi). 13 C{ 1 H} NMR (75.5 MHz, CDCl3, 298 K): δ (ppm) = 198.8 (Cg); 173.8 (Ck); 138.1 (Cb); 136.2 (Cf); 129.6 (Cc); 101.2 (Ca); 51.8 (Cl); 37.5 (Ch); 33.1 (Cj); 19.3 (Ci). HRMS (ESI-TOF): m/z Calcd for C12H13INaO3 [M+Na] + = 354.9802, Found = 354.9818. FT-IR (ATR): ῡ (cm -1 ) = 2944; 2883; 1731; 1675; 1579; 1437; 1358; 1313; 1217; 1169; 1004; 874; 807; 714. M.p. = 70-71 ºC. Ketone 2d. 4-Nitroacetophenone (20 g, 121 mmol) was dissolved in piperidine (60 ml, 606 mmol, 5 equiv) and hexane (500 ml) was added. The mixture was stirred at 0 ºC for 10 min. Then, TiCl4 (8 ml, 72.7 mmol, 0.6 equiv) was added slowly during 5 min. The reaction was stirred for 30 min more at 0 ºC and then 24 h at rt. Then, the solids were filtered off and washed with hexane (200 ml). The combined organic phases were concentrated under vacuum. The resulting enamine was obtained as brown oil (24.3 g, 105 mmol, 87% yield). The enamine (20 g, 86 mmol) was dissolved in dried EtOH (40 ml). The solution was stirred under Ar atmosphere at rt and ethyl acrylate (11.3 ml, 103 mmol, 1.2 equiv) was added. Then, the reaction was stirred at rt for 7 days. After that, water (100 ml), acetic acid (27 ml) and EtOAc (40 ml) were added and the reaction was heated at 45 ºC for 1 h. Then, more EtOAc (60 ml) was added, and the phases separated. The organic phase was washed with HCl 1N (2 x 100 ml) and water (100 ml). The organic layer was dried (Na2SO4), filtered and concentrated. The product was purified by column chromatography on silica gel (CH2Cl2 CH2Cl2:TBME 99:1) affording a brown solid (5.58 g, 18.36 mmol, 21% yield). Rf = 0.5 (9:0.1 CH2Cl2:TBME). 1 H NMR (400 MHz, CDCl3, 298 K): δ (ppm) = 8.31 (AA XX system, 2H, 3 JHb-Hc= 8.9 Hz; 4 JHb-Hb = 2.1 Hz, Hb); 8.12 (AA XX system, 2H, 4 JHc-Hc = 2.1 Hz, Hc); 4.14 (q, 2H, 3 JHl-Hm = 7.2 Hz, Hl); 3.11 (t, 2H, 3 JHh-Hi= 7.2 Hz, Hh); 2.45 (t, 2H, 3 JHj-Hi= 7.0 Hz, Hj); 2.09 (app quin, 2H, app 3 JHi-Hh= 3 JHi-Hj= 7.1 Hz, Hi); 1.26 (t, 3H, Hm). 13 C{ 1 H} NMR (100.6 MHz, CDCl3, 298 K): δ (ppm) = 198.0 (Cg); 173.2 (Ck); 150.5 (Cf); 141.3 (Ca); 129.2 (Cc); 124.0 (Cb); 60.6 (Cl); 38.2 (Ch); 33.2 (Cj); 19.2 (Ci); 14.4 (Cm). HRMS (ESI-TOF): m/z Calcd for S5

C13H15NNaO5 [M+Na] + = 288.0851, Found = 288.0851. FTIR (ATR): ῡ (cm -1 ) = 3101; 3071; 3049; 2950; 1727; 1682; 1602; 1521; 1345; 1318; 1202; 1184; 1154; 871; 854; 744. M.p. = 46-47 ºC. Calix[4]pyrrole 3a. Ketone 1a (0.5 g, 2.47 mmol) in 5 ml of CH2Cl2 was subjected to Method A with TBMACl. Then, EtOAc (50 ml) was added and the mixture washed with water (2 x 50 ml) and then with brine (50 ml). The organic phase was dried (Na2SO4), filtered and concentrated under vacuum. The crude was purified by column chromatorgraphy on silica gel (CH2Cl2 CH2Cl2:EtOAc 2:1 1:1 1:2). The fraction containing the target compound was concentrated and redissolved in 10 ml of CH2Cl2 and sonicated to afford a white solid that was filtered off and washed with CH2Cl2. α,α,α,α isomer: (190 mg, 0.19 mmol, 31% yield). Rf = 0.54 (1:2 CH2Cl2:EtOAc). 1 H NMR (500 MHz, DMSO-d6, 298 K): δ (ppm) = 9.33 (br s, 4H, OH); 9.22 (br t, 4H, NH); 6.69 (m, 16H, Hc, Hb); 5.89 (d, 8H, 3 JHa-NH = 2.2 Hz, Hβ); 3.48 (t, 8H, 3 JHj-Hi = 6.5 Hz, Hj); 2.29 (m, 8H, Hh); 1.39 (m, 8H, Hi). 13 C{ 1 H} NMR (125.7 MHz, acetone-d6, 298 K): δ (ppm) = 157.0 (Ca); 138.1 (Cα); 137.2 (Cf); 130.9 (Cc); 115.8 (Cb); 105.6 (Cβ); 48.2 (Cg); 46.3 (Cj); 38.8 (Ch); 29.4 (Ci). HRMS (ESI-TOF): m/z Calcd for C56H56Cl4N4NaO4 [M+Na] + = 1011.2948, Found = 1011.2938. FT-IR (ATR): ῡ (cm -1 ) = 3392, 2957, 2866, 1681, 1661, 1611, 1593, 1509, 1441, 1236, 1175, 840, 817, 770, 697, 529. M.p. > 120 ºC (decompose). Calix[4]pyrrole 3b. Ketone 1b (0.5 g, 2.74 mmol) in 5 ml of CH2Cl2 was subjected to Method A with TBMACl. Then, more CH2Cl2 (50 ml) was added and the mixture washed with water (2 x 50 ml) and then with brine (50 ml). The organic phase was dried (Na2SO4), filtered and concentrated under vacuum. The crude was purified by column chromatorgraphy on silica gel (Hexane:CH2Cl2 1:1). The fraction containing the target compound was concentrated and redissolved in the minimum amount of CH2Cl2, 20 ml of MeCN were added and the solution sonicated to afford a white solid that was filtered off and washed with MeCN. α,α,α,α isomer: (120 mg, 0.13 mmol, 19% yield). Rf = 0.32 (1:1 CH2Cl2:Hexane). 1 H NMR (500 MHz, CDCl3, 298 K): δ (ppm) = 7.39 (br t, 4H, NH); 7.2-7.1 (m, 20H, Hb, Ha, Hc); 5.90 (d, 8H, 3 JH -NH = 2.7 Hz, Hβ); 3.49 (t, 8H, 3 JHj-Hi = 6.3 Hz, Hj); 2.44 (m, 8H, Hh); 1.73 (m, 8H, Hi). 13 C{ 1 H} NMR (125.7 MHz, CDCl3, 298 K): δ (ppm) = 144.3 (Cf); 135.5 (Cα); 128.4 (Cc); 127.9 (Cb); 126.8 (Ca); 106.5 (Cβ); 48.6 (Cg); 45.7 (Cj); 37.5 (Ch); 28.7 (Ci). HRMS (ESI-TOF): m/z Calcd for C56H57Cl4N4 [M+H] + = 925.3332, Found = 925.3357. FTIR (ATR): ῡ (cm -1 ) = 3414, 3406, 2960, 2925, 2867, 2245, 1575, 1486, 1447, 1423, 1283, 1043, 1029, 911, 779, 766, 704, 649, 558, 505. M.p. > 187 ºC (decompose). Calix[4]pyrrole 3c. Ketone 1c (0.5 g, 1.91 mmol) in 5 ml of CH2Cl2 was subjected to Method A with TBMACl. Then, more CH2Cl2 (50 ml) was added and the mixture washed with water (2 x 50 ml) and then with brine (50 ml). The organic phase was dried (Na2SO4), filtered and concentrated under vacuum. The crude was purified by column chromatorgraphy on silica gel (Hexane:CH2Cl2 1:1). The fraction containing the target compound was concentrated and redissolved in the minimum amount of CH2Cl2 followed by addition of MeOH (20 ml) to get a white powder that was filtered off and washed with MeOH (mixture of α,α,α,β and α,α,β,β isomers). The filtrate was concentrated and redissolved in MeCN (5 ml), sonicated for 5 min and cooled at -25 ºC for 18 h to afford an off-white solid that was filtered off and washed with cold MeCN (α,α,α,α isomer). α,α,α,α isomer: (30 mg, 0.024 mmol, 5% yield). Rf = 0.57 (1:1 CH2Cl2:Hexane). 1 H NMR (500 MHz, acetone-d6, 298 K): δ (ppm) = 8.41 (br t, 4H, NH); 7.56 (AA XX system, 8H, 3 JHb-Hc = 8.6 Hz; 4 JHb-Hb = 2.4 Hz, Hb); 6.98 (AA XX system, 8H, 4 JHc-Hc = 2.4 Hz, Hc); 6.07 (d, 8H, 3 JHa-NH = 2.7 Hz, Hβ); 3.58 (t, 8H, 3 JHi- Hj = 6.6 Hz, Hj); 2.53 (m, 8H, Hh); 1.58 (m, 8H, Hi). 13 C{ 1 H} NMR (125.7 MHz, acetone-d6, 298 K): δ (ppm) = 146.0 (Cf); 137.3 (Cα); 132.1 (Cb); 131.8 (Cc); 121.4 (Ca); 106.7 (Cβ); 48.7 (Cg); 46.0 (Cj); 38.4 (Ch); 29.5 S6

(Ci). HRMS (ESI-TOF): m/z Calcd for C56H51Br4Cl4N4 [M-H] - = 1234.9586, Found = 1234.9607. FTIR (ATR): ῡ (cm -1 ) = 3425, 3415, 2959, 2945, 2920, 2868, 1578, 1485, 1454,1425, 1397, 1287, 1076, 1010, 8282, 813, 774, 715, 665, 646, 511. M.p. > 155 ºC (decompose). Unseparable mixture of α,α,α,β and α,α,β,β isomers (262 mg, 0.21 mmol, 44% yield). Rf = 0.59 (1:1 CH2Cl2:Hexane). Calix[4]pyrrole 4a. Ketone 2a (2 g, 8.46 mmol) in 17 ml of CH2Cl2 was subjected to Method A with TBMACl. Then, more CH2Cl2 (40 ml) was added and the mixture washed with NaHCO3 (aq sat) (2 x 50 ml). The aqueous phase was extracted with CH2Cl2 (2 x 40 ml). The organic extracts were combined, dried (Na2SO4), filtered and concentrated under vacuum. The crude was passed through a short column of silica (CH2Cl2:EtOAc 7:3). Then, it was further purified by column chromatography on silica gel (CH2Cl2:Acetone 9:1). The fraction containing the target compound was concentrated and recrystallized from CH2Cl2:Hexane yielding pure product as a light yellow solid. α,α,α,α isomer: (0.55 g, 0.49 mmol, 23%). Rf = 0.3 (7:1 CH2Cl2:EtOAc). 1 H NMR (400 MHz, acetoned6, 298 K): δ (ppm) = 8.58 (br t, 4H, NH); 8.16 (br s, 4H, OH); 7.09 (app t, 4H, app 3 JHd-Ha= 3 JHd-He= 7.9 Hz, Hd); 6.59 (ddd, 4H, 3 JHa-Hd= 8.1 Hz; 4 JHa-Hc= 2.5 Hz; 4 JHa-He= 1.0 Hz, Ha); 6.52 (ddd, 4H, 3 JHe-Hd= 7.7 Hz; 4 JHe- Hc= 1.7 Hz, He); 6.48 (dd, 4H, Hc); 6.01 (d, 8H, 4 JHβ-NH= 2.7 Hz, Hβ); 4.05 (q, 8H, 3 JHl-Hm= 7.1 Hz, Hl); 2.35 (m, 8H, Hh); 2.23 (t, 8H, 3 JHj-Hi= 7.3 Hz, Hj); 1.40 (m, 8H, Hi); 1.19 (t, 12H, Hm). 13 C{ 1 H} NMR (100.6 MHz, acetone-d6, 298 K): δ (ppm) = 173.7 (Ck); 157.5 (Cb); 148.7 (Cf); 137.9 (Cα); 129.9 (Cd); 121.6 (Ce); 116.9 (Cc); 114.5 (Ca); 105.7 (Cβ); 60.4 (Cl); 49.1 (Cg); 40.7 (Ch); 34.7 (Cj); 21.6 (Ci); 14.6 (Cm). HRMS (ESI- TOF): m/z Calcd for C68H75N4O12 [M-H] - = 1139.5387; Found = 1139.5364. FTIR (ATR): ῡ (cm -1 ) = 3409, 2974; 1701; 1596, 1582; 1445; 1196; 769. M.p.: >110 ºC (decompose). Calix[4]pyrrole 4b. Ketone 2b (0.35 g, 1.39 mmol) in 3 ml of CH2Cl2 was subjected to Method A with TBMACl. The solvent was removed to dryness and the resulting mixture was partitioned between EtOAc (50 ml) and KHSO4 (aq 0.2%) (60 ml). The EtOAc layer was washed with water (2x), dried (Na2SO4) and filtered. After removal of the solvent, the product was purified by column chromatography on silica gel (5:1 EtOAc:MeOH). The resulting solid was dissolved in 15 ml of a 100:1 CH2Cl2:Et2O. Then, 1:1 CH2Cl2:Hexane was added until a solid precipitated. The solid was filtered and washed with the CH2Cl2:Hexanes mixture, air dried, and placed under vacuum. Calix[4]pyrrole 2g was obtained as a pale brown solid. α,α,α,α isomer: (0.248 g, 0.2 mmol, 62% yield). 1 H NMR (500 MHz, DMSO-d6, 298 K): δ (ppm) = 9.33 (br t, 4H, NH); 8.62 (s, 8H, OH); 5.95 (t, 4H, 4 JHa-Hc= 2.1 Hz, Ha); 5.93 (d, 8H, Hc); 5.86 (d, 8H, 4 JHβ-NH= 2.6 Hz, Hβ); 4.03 (q, 8H, 3 JHl-Hm= 7.1 Hz, Hl); 2.22 (t, 8H, 3 JHj-Hi= 7.4 Hz, Hj); 2.18 (m, 8H, Hh); 1.25 (m, 8H, Hi); 1.16 (t, 12H, Hm). 13 C{ 1 H} NMR (100.6 MHz, DMSO-d6, 298 K): δ (ppm) = 173.0 (Ck); 157.5 (Cb); 148.3 (Cf); 136.5 (Cα); 107.0 (Cc); 104.0 (Ca); 100.8 (Cβ); 59.7 (Cl); 47.6 (Cg); 39.8 (Ch); 33.6 (Cj); 20.6 (Ci); 14.2 (Cm). HRMS (ESI-TOF): m/z Calcd for C68H75N4O16 [M - H] = 1203.5184, Found = 1203.5211. FTIR (ATR): ῡmax (cm 1 ) = 3369, 2976, 1704, 1600, 1442, 1332, 1147, 998, 767. S7

1 H NMR (400 MHz, acetone-d6, 298 K) of 5 (intermediate towards ketone 2a). 13 C{ 1 H} NMR (100.6 MHz, acetone-d6, 298 K) of 5 (intermediate towards ketone 2a). S8

1 H NMR (500 MHz, acetone-d6, 298 K) of 6 (intermediate towards ketone 2a). 13 C{ 1 H} NMR (125.7 MHz, acetone-d6, 298 K) of 6 (intermediate towards ketone 2a). S9

1 H NMR (500 MHz, acetone-d6, 298 K) of compound 2a. 13 C{ 1 H} NMR (125.7 MHz, acetone-d6, 298 K) of compound 2a. S10

1 H NMR (500 MHz, DMSO-d6, 298 K) of 7 (intermediate towards ketone 2b). 13 C{ 1 H} NMR (125.7 MHz, DMSO-d6, 298 K) of 7 (intermediate towards ketone 2b). S11

1 H NMR (400 MHz, DMSO-d6, 298 K) of 8 (intermediate towards ketone 2b). 13 C{ 1 H} NMR (100.6 MHz, DMSO-d6, 298 K) of 8 (intermediate towards ketone 2b). S12

1 H NMR (500 MHz, CDCl3:DMSO-d6 5:1, 298 K) of compound 2b. 13 C{ 1 H} NMR (100.6 MHz, CDCl3:DMSO-d6 5:1, 298 K) of compound 2b. S13

1 H NMR (400 MHz, CDCl3, 298 K) of compound 2c. 13 C{ 1 H} NMR (75.5 MHz, CDCl3, 298 K) of compound 2c. S14

1 H NMR (400 MHz, CDCl3, 298 K) of compound 2d. 13 C{ 1 H} NMR (100.6 MHz, CDCl3, 298 K) of compound 2d. S15

1 H NMR (500 MHz, DMSO-d6, 298 K) of compound 3a (α,α,α,α isomer). 13 C{ 1 H} NMR (125.7 MHz, acetone-d6, 298 K) of compound 3a (α,α,α,α isomer). S16

1 H NMR (500 MHz, CDCl3, 298 K) of compound 3b (α,α,α,α isomer). 13 C{ 1 H} NMR (125.7 MHz, CDCl3, 298 K) of compound 3b (α,α,α,α isomer). S17

1 H NMR (500 MHz, acetone-d6, 298 K) of compound 3c (α,α,α,α isomer). 13 C{ 1 H} NMR (125.7 MHz, acetone-d6, 298 K) of compound 3c (α,α,α,α isomer). S18

1 H NMR (500 MHz, CDCl3, 298 K) of compound 4a (α,α,α,α isomer). 13 C{ 1 H} NMR (125.7 MHz, CDCl3, 298 K) of compound 4a (α,α,α,α isomer). S19

1 H NMR (500 MHz, CDCl3, 298 K) of compound 4b (α,α,α,α isomer). 13 C{ 1 H} NMR (125.7 MHz, CDCl3, 298 K) of compound 4b (α,α,α,α isomer). S20

Crystallographic data Table S1. Crystal data and structure refinement for 3a (α,α,α,α isomer). Identification code mo_cadm10_0m Empirical formula C83.88 H93 Cl4 N4 O6 Formula weight 1394.92 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P2(1)/n Unit cell dimensions a = 23.5226(8)Å = 90. b = 21.9096(9)Å = 102.0600(11). c = 30.3857(11)Å = 90. Volume 15314.3(10) Å 3 Z 8 Density (calculated) 1.210 Mg/m 3 Absorption coefficient 0.209 mm -1 F(000) 5922 Crystal size 0.40 x 0.30 x 0.05 mm 3 Theta range for data collection 1.000 to 25.414. Index ranges -28<=h<=23,-26<=k<=26,-32<=l<=36 Reflections collected 148987 Independent reflections 28146[R(int) = 0.0422] Completeness to theta =25.414 99.6% Absorption correction Multi-scan Max. and min. transmission 0.990 and 0.762 Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 28146/ 3367/ 2343 Goodness-of-fit on F 2 1.044 Final R indices [I>2sigma(I)] R1 = 0.0699, wr2 = 0.1983 R indices (all data) R1 = 0.1058, wr2 = 0.2277 Largest diff. peak and hole 0.953 and -1.086 e.å -3 S21

Table S2. Crystal data and structure refinement for 3b (α,α,α,α isomer). Identification code mo_cadm14-05 Empirical formula C58 H59 Cl4 N5 Formula weight 967.90 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P2(1) Unit cell dimensions a = 21.1993(19)Å = 90. b = 8.9364(9)Å = 108.488(3). c = 27.249(3)Å = 90. Volume 4895.8(8) Å 3 Z 4 Density (calculated) 1.313 Mg/m 3 Absorption coefficient 0.287 mm -1 F(000) 2040 Crystal size 0.40 x 0.40 x 0.10 mm 3 Theta range for data collection 1.013 to 26.388. Index ranges -25<=h<=25,0<=k<=11,0<=l<=33 Reflections collected 10188 Independent reflections 10188[R(int) =?] Completeness to theta =26.388 98.6% Absorption correction Empirical Max. and min. transmission 0.972 and 0.471 Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 10188/ 153/ 687 Goodness-of-fit on F 2 1.130 Final R indices [I>2sigma(I)] R1 = 0.0859, wr2 = 0.2221 R indices (all data) R1 = 0.0978, wr2 = 0.2297 Largest diff. peak and hole 1.181 and -0.601 e.å -3 S22

Table S3. Crystal data and structure refinement for 3c (α,α,α,α isomer). Identification code CADM17aaa_twin1_hklf4 Empirical formula C60 H58 Br4 Cl4 N6 Formula weight 1324.56 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Tetragonal Space group P4/n Unit cell dimensions a = 14.2293(2)Å = 90. b = 14.2293(2)Å = 90. c = 14.5334(4)Å = 90. Volume 2942.62(12) Å 3 Z 2 Density (calculated) 1.493 Mg/m 3 Absorption coefficient 2.960 mm -1 F(000) 1332 Crystal size 0.15 x 0.15 x 0.02 mm 3 Theta range for data collection 2.024 to 30.677. Index ranges -19<=h<=20,-19<=k<=19,-19<=l<=19 Reflections collected 53682 Independent reflections 4347[R(int) = 0.0701] Completeness to theta =30.677 95.0% Absorption correction Multi-scan Max. and min. transmission 0.943 and 0.725 Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 4347/ 0/ 174 Goodness-of-fit on F 2 1.034 Final R indices [I>2sigma(I)] R1 = 0.0342, wr2 = 0.0948 R indices (all data) R1 = 0.0408, wr2 = 0.0989 Largest diff. peak and hole 1.010 and -0.402 e.å -3 S23