The Enantioselective Synthesis and Biological Evaluation of Chimeric Promysalin Analogs Facilitated by Diverted Total Synthesis

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1 S1 The Enantioselective Synthesis and Biological Evaluation of Chimeric Promysalin Analogs Facilitated by Diverted Total Synthesis Kyle W. Knouse and William M. Wuest* Department of Chemistry, Temple University, Philadelphia, PA Supporting Information Table of Contents 1. Tables and Figures S2 2. Synthesis of Compounds 2.1 Instrumentation and General Notes S3 2.2 Experimental Procedures and Data S3-S References S21 3. Biological Information 3.1 Bacterial strains and culture conditions S IC 50 Assay S22 4. Appendix A: Spectral Data S23-S55

2 S2 1. Tables and Figures IC50 (µm) Compound P. fluorescens P. putida PAO1 PA14 (-)-3S > >455 (+)-3R > > (-)-4S >455 >455 > (+)-4R > (-)-5S >455 >455 >455 >455 (+)-5R >455 >455 >455 >455 (-)-13S,S >455 >455 >455 >455 (-)-13R,S >455 >455 >455 >455 (-)-14S,S >455 >455 >455 >455 (+)-14R,S >455 >455 >455 >455 (-)-12S,S 455 > >455 (+)-12R,S Table S1. IC 50 values (in µm) based on OD 595 after 5 days. Compounds highlighted in gray showed significant bioactivity. (µm) Figure S1. Representative results for PA14 growth after day 2 of 5 day trial. The red box highlights the nonlethal phenotypic effects of (-)-13R,S and (-)14R,S.

3 S3 2. Synthesis of Compounds 2.1 Instrumentation and General Notes Instrumentation and General Notes NMR spectra were recorded using the following spectrometers: Bruker Advance 500 (500/125 MHz) or Bruker Advance 400 (400/100 MHz). Chemical shifts are quoted in ppm relative to tetramethylsilane and with the indicated solvent as an internal reference. The following abbreviations are used to describe signal multiplicities: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). Accurate mass spectra were recorded on an Agilent 6520 Accurate-Mass Q-TOF LC/MS, infrared spectra were obtained using a Thermo Nicolet Nexus 670 FTIR spectrophotometer and specific rotation measurements were made with a 1 dm path length using a Perkin Elmer 341 Polarimeter. Non-aqueous reactions were performed under an atmosphere of argon, in flame- dried glassware, with HPLC-grade solvents dried by passage through activated alumina. Brine refers to a saturated aqueous solution of sodium chloride. Degassing was performed by piercing the septum of the reaction flask with a syringe filled with a cotton plug and drierite (CaSO4), and a long needle attached to a Schlenk line that was submerged into the solvent through which dry argon gas was bubbled for the indicated amount of time. After this was done, the long needle was replaced with a shorter one, the syringe was removed, and argon was switched to static pressure. All TBAF and DMPU were dried over 3 Å molecular sieves that were dried at 120 C in an oil bath under vacuum for 12 hours, for a minimum of 12 hours before use. 2.2 Experimental Procedures and Data (S)-undec-1-en-4-ol ( )-7S To a stirred solution of 1 M TiCl 4 in CH 2 Cl 2 (0.64 ml, 6.4 mmol) in DCM (20 ml) dried Ti(OPri) 4 (0.55 ml, 1.92 mmol) was added at 0 C. The solution was allowed to warm up to room temperature. After 1 h, silver (I) oxide (297 mg, 1.2 mmol) was added at room temperature, and the whole mixture was stirred for 5 h under exclusion of direct light. The mixture was diluted with

4 S4 CH 2 Cl 2 (10 ml), and treated with (R)-binaphthol (733 mg, 2.5 mmol) at room temperature for 2 h to furnish chiral bis-ti(iv) oxide (R,R)-I. The in situ generated (R,R)- I was cooled to -15 C, and treated sequentially with octanal (1.95 ml, 12.8 mmol) and allyltributyltin (4.4 ml, 14 mmol) at - 15 C. The whole mixture was allowed to warm to 0 C and stirred for 12 h. The reaction mixture was quenched with saturated NaHCO 3 and extracted with CH 2 Cl 2. Combined organics were washed with brine, dried (Na 2 SO 4 ) filtered and concentrated. The crude yellow oil was distilled under vacuum (ca. 5 torr, 100 C) yielding ( )-7S (1.54 g, 72%), with spectroscopic data identical to that previously described. 1 (R)-undec-1-en-4-ol (+)-7R Following the same procedure as ( )-7S; with the exception that (S)-BINOL was used as the catalyst. Yielding (+)-7R(1.40 g, 67%), with spectroscopic data identical to that previously described. 1 (S)-4-methoxyundec-1-ene( )-S1S To a solution of ( )-7S (215 mg, 1.26 mmol) in THF (5 ml) at 0 C was added NaH (60% dispersion in mineral oil, 101 mg, 2.53 mmol). The solution was stirred for 30 minutes at 0 C before MeI (0.156 ml, 2.53 mmol) was added. The reaction was allowed to warm to room temperature and stir for 16 hours. The reaction was quenched by the addition of saturated aqueous NH 4 Cl (5 ml). The aqueous layer was extracted with EtOAc (3 x 25 ml). Combined organics were washed with brine, dried (Na 2 SO 4 ) filtered and concentrated. The resulting oil was purified via column chromatography (5% Et 2 O: 95% Hexane) yielding ( )-S1S (200 mg, 86%), with spectroscopic data identical to that previously described. 1 (R)-4-methoxyundec-1-ene (+)-S1R

5 S5 Following the same procedure as ( )-S1S; (+)-7S (0.200 g, 1.17 mmol) in THF (5 ml), NaH (0.1 g, 2.35 mmol), MeI (0.15 ml, 2.35 mmol) yielding (+)-S1R (0.185 g, 86%), with spectroscopic data identical to that previously described. 1 (S,E)-7-methoxytetradec-4-enoic acid ( )-3S To a solution of ( )-S1S (0.100 g, 0.50 mmol) in CH 2 Cl 2 (5mL) was added 4-pentenoic acid (0.163g, 1.6 mmol) followed by Grubbs II Catalyst (23 mg, mmol). The reaction refluxed for 4.5 hours before being cooled to 0 C for 15 minutes. The solids were removed by filtration and the filtrate concentrated. The resulting crude oil was purified by column chromatography (15% Et 2 O : 85% Hexane) yielding ( )-3S (72 mg, 52%), R f (50% Et 2 O : 50 % Hexane) = 0.50, with spectroscopic data identical to that previously described. 1 (R,E)-7-methoxytetradec-4-enoic acid (+)-3R Following the same procedure as ( )-3S; (+)-S1R (85 mg, 0.46 mmol), 4-pentenoic acid (0.139 g, 1.4 mmol), CH 2 Cl 2 (5 ml), Grubbs II Catalyst (20 mg, mmol) yielding (+)-3R (56 mg, 47%) with spectroscopic data identical to that previously described. 1 (S,E)-7-methoxy-N-phenethyltetradec-4-enamide ( )-4S To a solution of ( )-3S (35 mg, mmol), DMAP (5 mg, mmol) and Et 3 N (0.042 ml, 0.3 mmol) in CH 2 Cl 2 (1 ml) was added pivaloyl chloride (0.017 ml, mmol). The resulting solution was stirred for 1 hour at room temperature before 2-phenylethyl amine (0.019 ml, mmol) was added, after stirring overnight at room temperature the reaction was quenched with 1 M HCl (5 ml). The aqueous was extracted with CH 2 Cl 2 (3 x 5mL), the combined organics washed with 0.1 M NaHCO 3 (5 ml) and dried (Na 2 SO 4 ), filtered and concentrated. The crude oil was purified via silica gel chromatography (20% EtOAc : 80% Hexane) to (40% EtOAc : 60 %

6 S6 Hexane) =, yielding ( )-4S (41 mg, 84%), with spectroscopic data identical to that previously described. 1 (R,E)-7-methoxy-N-phenethyltetradec-4-enamide (+)-4R To a solution of (+)-3R (20 mg, 0.08 mmol), HATU (36 mg, 0.09 mmol) and 2-phenylethyl amine hydrochloride (15 mg, 0.09 mmol) in NMP (1 ml) was added diisopropylethylamine (0.054 ml, 0.31 mmol). After stirring at room temperature overnight, the reaction was quenched with NH 4 Cl (5 ml). The aqueous was extracted with EtOAc (3 x 5 ml). The combined organics washed with 1 M HCl (3 x 5 ml) followed by NaHCO 3 (5 ml), dried (Na s SO 4 ) filtered and concentrated. The crude oil was purified by column chromatography (70 % Et 2 O : 30% Hexane), yielding (+)-4R (24 mg, 86%), R f (70 % Et 2 O : 30% Hexane) = 0.40 with spectroscopic data identical to that previously described. 1 (S,E)-N-(2-(1H-indol-3-yl)ethyl)-7-methoxytetradec-4-enamide ( )-5S Following the same procedure as ( )-4S; ( )-3S (25 mg, mmol), DMAP (3.5 mg, mmol), Et 3 N (0.03 ml, mmol), pivaloyl chloride (0.011 ml, mmol) and tryptamine (17 mg, mmol) yielding ( )-5S (16 mg, 42%) with spectroscopic data identical to that previously described. 1 (R,E)-N-(2-(1H-indol-3-yl)ethyl)-7-methoxytetradec-4-enamide (+)-5R Following the same procedure as ( )-4S; (+)-3R (20 mg, 0.08 mmol), HATU (36 mg, 0.09 mmol), tryptamine (15.mg, 0.09 mmol), NMP (1 ml), diisopropylethylamine (0.054 ml, 0.31

7 S7 mmol). The crude oil was purified via silica gel chromatography (100 % Et 2 O) yielding (+)-5R (20 mg, 64%), R f (100% Et 2 O) = 0.49 with spectroscopic data identical to that previously described. 1 (S,E)-7-hydroxytetradec-4-enoic acid (+)-8S To a solution of (+)-7R (127 mg, 0.75 mmol) in EtOAc (1.5 ml) was added 4-pentenoic acid (15 mg, 0.15 mmol). The solution was degassed with Argon for 20 minutes before 2 nd Generation Hoyveda-Grubbs catalyst (9.4 mg, mmol) was added. Degassing was continued for 20 minutes before switching to static pressure. After 2 hours the reaction was concentrated and purified by silica gel chromatography (10% Et 2 O: 90% CH 2 Cl 2 ) yielding (+)-8S as a tan solid (26 mg, 72%). R f (70% EtOAc: 30% Hexane) =0.1, with spectroscopic data identical to that previously described. 2 (R,E)-7-hydroxytetradec-4-enoic acid ( )-8R To a solution of ( )-7S (340 mg, 2.0 mmol) in EtOAc (5 ml) was added 4-pentenoic acid (50 mg, 0.50 mmol). The solution was degassed with Argon for 20 minutes before 2 nd Generation Hoyveda-Grubbs catalyst (31 mg, 0.05 mmol) was added. Degassing was continued for 20 minutes before switching to static pressure. After 2 hours the reaction was concentrated and purified by silica gel chromatography (10% Et 2 O: 90% CH 2 Cl 2 ) yielding ( )-8R as a tan solid (82 mg, 67%). R f (70% EtOAc: 30% Hexane) =0.1; 1 H NMR (400 MHz, CDCl 3 ) δ 5.52 (ddd, J = 9.0, 7.3, 5.6 Hz, 2H), (m, 1H), (m, 4H), 2.24 (dt, J = 8.8, 5.1 Hz, 1H), (m, 1H), 1.43 (s, 3H), 1.27 (s, 10H), 0.87 (t, J = 6.8 Hz, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ , , , 71.16, 40.58, 36.79, 33.98, 31.96, 29.75, 29.41, 27.90, 25.79, 22.79, 14.23; [α] D (c 0.28, CHCl 3 ); IR (film); 3310 (br O-H), 2924, 2854, 2360, 2342, 1715 (C=O), 1260, 1074, 969, 816, 668; HRMS Accurate mass (ES+): Found (+0 ppm), C 14 H 26 O 3 [M+Na] + requires

8 S8 (2-(trimethylsilyl)ethoxy)methyl (S,E)-7-hydroxytetradec-4-enoate (+)-S2S To a solution of (+)-8S (14.6 mg, mmol) in THF (0.6 ml) was added SEMCl (11.2 μl, mmol). After cooling the solution to 0 C, triethylamine (9.6 μl, mmol) was added. After stirring for 1.5 hr at 0 C the reaction was concentrated. The crude reaction was dissolved in CHCl 3 (5 ml) and saturated aqueous NH 4 Cl (5 ml) was added. The aqueous was extracted with CHCl 3 (3x 5 ml). The combined organics were washed with brine (5 ml) dried (Na 2 SO 4 ), filtered, concentrated and purified by silica gel chromatography (10% EtOAc: 90% Hexane è 30% EtOAc: 70% Hexane) to yield (+)-S2S as a clear oil (14 mg, 65%). Rf (30% EtOAc: 70% Hexane) =0.64; 1 H NMR (500 MHz, CDCl 3 ) δ (m, 2H), (m, 2H), (m, 2H), (m, 1H), (m, 2H), (m, 2H), 2.23 (ddd, J = 9.7, 5.6, 2.5 Hz, 1H), (m, 1H), 1.43 (s, 3H), 1.28 (s, 10H), (m, 2H), 0.88 (t, J = 7.0 Hz, 3H), (m, 9H); 13 C NMR (101 MHz, CDCl 3 ) δ , , , 89.25, 71.19, 68.21, 40.97, 37.12, 34.50, 32.16, 29.97, 29.62, 28.18, 26.04, 22.99, 18.37, 14.44, -1.10; [α] D (c 0.4, CHCl 3 ); IR (film) 3000 (br O-H), 2924, 2854, 1738 (C=O), 1248, 1101, 937, 850, 757, 693; HRMS Accurate mass (ES+): Found (-0.5 ppm), C 20 H 40 O 4 Si [M+Na] + requires (2-(trimethylsilyl)ethoxy)methyl (R,E)-7-hydroxytetradec-4-enoate ( )-S2R To a solution of ( )-8R (25 mg, mmol) in THF (1.0 ml) was added SEMCl (19 μl, mmol). After cooling the solution to 0 C, triethylamine (16 μl, mmol) was added. After stirring for 1.5 hr at 0 C the reaction was concentrated. The crude reaction was dissolved in CHCl 3 (5 ml) and saturated aqueous NH 4 Cl (5 ml) was added. The aqueous was extracted with CHCl 3 (3x 5 ml). The combined organics were washed with brine (5 ml) dried (Na 2 SO 4 ), filtered, concentrated and purified by silica gel chromatography (10% EtOAc: 90% Hexane è 30% EtOAc: 70% Hexane) to yield ( )-S2R as a clear oil (11.5 mg, 30%). Rf (30% EtOAc: 70% Hexane) =0.64; 1 H NMR (500 MHz, CDCl 3 ) δ (m, 2H), (m, 2H), (m, 2H), 3.59 (s, 1H), (m, 4H), 2.24 (dt, J = 9.7, 4.4 Hz, 1H), (m, 1H), 1.44 (s, 3H), 1.29 (d, J = 3.6 Hz, 10H), (m, 2H), 0.89 (t, J = 7.0 Hz, 3H), 0.04 (s, 9H); 13 C NMR (101 MHz, CDCl 3 ) δ , , , 89.06, 71.00, 68.02, 40.78, 36.93, 34.31, 31.97, 29.78, 29.43, 27.99, 25.85, 22.80, 18.18, 14.25, -1.29; [α] D 25-4 (c 0.24, CHCl 3 ); IR (film); 3310 (br O-H), 2925, 2855, 2360, 2342, 1739 (C=O), 1249, 1102, 967, 835, 693; HRMS Accurate mass (ES+): Found (-0.1 ppm), C 20 H 40 O 4 Si [M+Na] + requires

9 S9 (S,E)-7-hydroxy-N-phenethyltetradec-4-enamide (+)-10S To a solution of (+)-8S (12 mg, mmol), HATU (23 mg, mmol) and 2-phenylethyl amine hydrochloride (10 mg, mmol) in NMP (1 ml) was added diisopropylethylamine (0.035 ml, mmol). After stirring at room temperature overnight, the reaction was quenched with NH 4 Cl (5 ml). The aqueous was extracted with EtOAc (3 x 5 ml). The combined organics washed with 1 M HCl (3 x 5 ml) followed by NaHCO 3 (5 ml), dried (Na s SO 4 ) filtered and concentrated. The crude oil was purified by column chromatography (50 % Et 2 O : 50% CHCl 3 ), yielding (+)-10S (10 mg, 59%), R f (50 % Et 2 O : 50% CHCl 3 ) = 0.24 with spectroscopic data identical to that previously described. 2 (R,E)-7-hydroxy-N-phenethyltetradec-4-enamide ( )-10R To a solution of ( )-8R (16 mg, mmol) in NMP (1 ml) was added HATU (31 mg, mmol), PhEtNH 2 HCl (13 mg, mmol) and diisopropylethylamine (46 μl, 0.26 mmol). The resulting bright yellow solution was allowed to stir at room temperature overnight. The reaction was diluted with EtOAc (5 ml) and saturated aqueous NaHCO 3 (5 ml) was added. The aqueous was extracted with EtOAc (3x 5 ml). The combined organics were washed with 1 M HCl (3x 5 ml) followed by brine (3x 5mL). The organics were dried (Na 2 SO 4 ), filtered and concentrated. Purification by silica gel chromatography (50%CHCl 3 : 50% Et 2 O) yielded ( )-10R as a white solid (17 mg, 73%). Rf (50%CHCl 3 : 50% Et 2 O) = 0.24; 1 H NMR (500 MHz, CDCl 3 ) δ 7.31 (t, J = 7.4 Hz, 2H), (m, 1H), (m, 2H), (m, 3H), 3.51 (ddd, J = 12.8, 6.9, 2.0 Hz, 3H), 2.80 (t, J = 6.9 Hz, 2H), 2.32 (dd, J = 13.6, 6.8 Hz, 2H), 2.20 (t, J = 6.9 Hz, 3H), (m, 1H), 1.42 (s, 3H), (m, 10H), 0.88 (t, J = 7.0 Hz, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ , , , , , , , 72.92, 42.69, 42.61, 38.94, 38.54, 37.79, 33.92, 31.74, 31.39, 30.82, 27.82, 24.76, 16.20; [α] D 25-3 (c 0.53, CHCl 3 ); IR (film); 3307 (br O-H), 2920, 2851, 2360, 2342, 1639 (C=O), 1548, 1455, 1353, 1081, 961, 873, 697; HRMS Accurate mass (ES+): Found (+0.9 ppm), C 22 H 35 NO 2 [M+H] + requires

10 S10 (S,E)-N-(2-(1H-indol-3-yl)ethyl)-7-hydroxytetradec-4-enamide (+)-11S To a solution of (+)-8S (25 mg, 0.1 mmol), HATU (48 mg, 0.12 mmol) and tryptamine (20 mg, 0.12 mmol) in NMP (1.5 ml) was added diisopropylethylamine (0.072 ml, 0.4 mmol). After stirring at room temperature overnight, the reaction was quenched with NH 4 Cl (5 ml). The aqueous was extracted with EtOAc (3 x 5 ml). The combined organics washed with 1 M HCl (3 x 5 ml) followed by NaHCO 3 (5 ml), dried (Na s SO 4 ) filtered and concentrated. The crude oil was purified by column chromatography (70 % EtOAc : 30% Hexane), yielding (+)-11S (27 mg, 70%), R f (5 % MeOH : 95% CH 2 Cl 2 ) = 0.52, with spectroscopic data identical to that previously described. 2 (R,E)-N-(2-(1H-indol-3-yl)ethyl)-7-hydroxytetradec-4-enamide ( )-11R To a solution of ( )-8R (16 mg, mmol) in NMP (1 ml) was added HATU (31 mg, mmol), tryptamine (13 mg, mmol) and diisopropylethylamine (46 μl, 0.26 mmol). The resulting bright yellow solution was allowed to stir at room temperature overnight. The reaction was diluted with EtOAc (5 ml) and saturated aqueous NaHCO 3 (5 ml) was added. The aqueous was extracted with EtOAc (3x 5 ml). The combined organics were washed with 1 M HCl (3x 5 ml) followed by brine (3x 5mL). The organics were dried (Na 2 SO 4 ), filtered and concentrated. Purification by silica gel chromatography (80% EtOAc: 20% Hexane) yielded ( )- 11R as a tan solid (22 mg, 88%). Rf (5% MeOH: 95% CH 2 Cl 2 ) = 0.52; 1 H NMR (400 MHz, CDCl 3 ) δ 8.18 (s, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.13 (t, J = 7.4 Hz, 1H), 7.04 (s, 1H), (m, 3H), (m, 3H), 2.97 (t, J = 6.6 Hz, 2H), 2.31 (dd, J = 13.2, 6.5 Hz, 2H), 2.18 (t, J = 7.0 Hz, 3H), (m, 1H), 1.37 (d, J = 25.7 Hz, 3H), 1.27 (s, 10H), 0.88 (t, J = 6.6 Hz, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ , , , , , , , , , , 70.98, 40.67, 39.73, 36.98, 36.58, 31.95, 29.83, 29.78, 29.42, 28.84, 25.85, 25.43, 22.78, 14.23; [α] D 25-2 (c 0.5, CHCl 3 ); IR (film); 3384 (N-H), 3260 (br O-H), 2921, 2850, 2360, 2342, 1628 (C=O), 1550, 1456, 1340, 1074, 960, 739; HRMS Accurate mass (ES+): Found (+0.5 ppm), C 24 H 36 N 2 O 2 [M+H] + requires

11 S11 (S)-1-(2-((2-(trimethylsilyl)ethoxy)methoxy)benzoyl)-2,3-dihydro-1H-pyrrole-2-carboxylic acid ( )-6S Compound was prepared as previously reported. 3 (S)-1-(2-((2-(trimethylsilyl)ethoxy)methoxy)benzoyl)-2,3-dihydro-1H-pyrrole-2-carboxylic acid (S,E)-1-oxo-1-((2-(trimethylsilyl)ethoxy)methoxy)tetradec-4-en-7-yl (S)-1-(2-((2- (trimethylsilyl)ethoxy)methoxy)benzoyl)-2,3-dihydro-1h-pyrrole-2-carboxylate ( )-9S,S Acid ( )-6S (14 mg, mmol), MNBA (24 mg, mmol) and DMAP (1 mg, mmol) were dissolved in CH 2 Cl 2 (1 ml). After stirring for 10 minutes, a solution of (+)-7 (10 mg, mmol) in CH 2 Cl 2 (1 ml) was added. After stirring overnight, the reaction was diluted with CH 2 Cl 2 (5 ml) and saturated aqueous NaHCO 3 (5 ml) was added. The aqueous was extracted with CH 2 Cl 2 (3x 5 ml). The combined organics were washed with brine (5 ml) dried (Na 2 SO 4 ), filtered, concentrated and purified by silica gel chromatography (5% Et 2 O: 95% CH 2 Cl 2 ) to yield ( )-9S,S as a clear oil (16 mg, 84%). Rf (10% Et 2 O: 90% CH 2 Cl 2 ) =0.80; 1 H NMR (400 MHz, CDCl 3 ) δ (m, 2H), 7.21 (d, J = 8.9 Hz, 1H), 7.05 (t, J = 7.4 Hz, 1H), (m, 1H), 5.48 (dd, J = 9.3, 5.4 Hz, 2H), (m, 5H), (m, 3H), (m, 4H), (m, 1H), 2.67 (d, J = 16.9 Hz, 1H), 2.33 (ddd, J = 14.5, 13.5, 5.2 Hz, 6H), 1.59 (d, J = 9.4 Hz, 3H), 1.26 (s, 11H), 0.96 (dd, J = 16.5, 7.3 Hz, 4H), 0.87 (t, J = 6.4 Hz, 3H), (m, 18H); 13 C NMR (101 MHz, CDCl 3 ) δ , , , , , , , , , , , , , 93.55, 89.21, 74.96, 68.17, 66.83, 58.32, 37.62, 34.56, 34.44, 33.87, 32.14, 30.04, 29.76, 29.50, 28.02, 25.47, 22.97, 18.37, 14.44, -1.08; [α] D (c 0.34, CHCl 3 ); IR (film); 2918, 2850, 1741 (C=O), 1620 (C=O), 1601 (C=O), 1455, 1405, 1230, 1086, 971, 834, 754, 694; HRMS Accurate mass (ES+): Found (+0.4 ppm), C 38 H 63 NO 8 S i2 [M+H] + requires

12 S12 (S)-1-(2-((2-(trimethylsilyl)ethoxy)methoxy)benzoyl)-2,3-dihydro-1H-pyrrole-2-carboxylic acid (R,E)-1-oxo-1-((2-(trimethylsilyl)ethoxy)methoxy)tetradec-4-en-7-yl (S)-1-(2-((2- (trimethylsilyl)ethoxy)methoxy)benzoyl)-2,3-dihydro-1h-pyrrole-2-carboxylate (+)-9R,S Acid ( )-6S (13 mg, mmol), MNBA (22 mg, mmol) and DMAP (1 mg, mmol) were dissolved in CH 2 Cl 2 (1 ml). After stirring for 10 minutes, a solution of ( )-S2R (9 mg, mmol) in CH 2 Cl 2 (1 ml) was added. After stirring overnight, the reaction was diluted with CH 2 Cl 2 (5 ml) and saturated aqueous NaHCO 3 (5 ml) was added. The aqueous was extracted with CH 2 Cl 2 (3x 5 ml). The combined organics were washed with brine (5 ml) dried (Na 2 SO 4 ), filtered, concentrated and purified by silica gel chromatography (5% Et 2 O: 95% CH 2 Cl 2 ) to yield (+)-9R,S as a clear oil (12 mg, 70%). Rf (10% Et 2 O: 90% CH 2 Cl 2 ) =0.80; 1 H NMR (400 MHz, CDCl 3 ) δ 7.35 (d, J = 7.5 Hz, 2H), 7.20 (d, J = 8.0 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 6.16 (dt, J = 4.3, 2.1 Hz, 1H), 5.49 (q, J = 5.6 Hz, 2H), (m, 4H), (m, 3H), (m, 4H), (m, 1H), (m, 1H), (m, 6H), 1.59 (s, 3H), 1.25 (s, 11H), (m, 4H), 0.86 (t, J = 6.8 Hz, 3H), (m, 18H); 13 C NMR (101 MHz, CDCl 3 ) δ , , , , , , , , , , , , , 93.36, 88.99, 74.81, 67.95, 66.64, 58.24, 37.33, 34.39, 34.26, 33.48, 31.93, 29.84, 29.56, 29.32, 27.83, 25.35, 22.77, 18.17, 14.23, -1.28; [α] D (c 0.38, CHCl 3 ); IR (film); 2953, 2925, 2857, 2360, 2342, 1739 (C=O), 1653 (C=O), 1621 (C=O), 1456, 1405, 1339, 1088, 971, 857, 835, 754; HRMS Accurate mass (ES+): Found (+1.7 ppm), C 38 H 63 NO 8 Si 2 [M+H] + requires

13 S13 (S,E)-1-oxo-1-(phenethylamino)tetradec-4-en-7-yl (S)-1-(2-((2- (trimethylsilyl)ethoxy)methoxy)benzoyl)-2,3-dihydro-1h-pyrrole-2-carboxylate ( )-S3S,S Acid ( )-6S (15 mg, mmol), MNBA (26 mg, mmol), DMAP (1 mg, mmol) and Et 3 N (0.014 ml, mmol) were dissolved in CH 2 Cl 2 (1 ml). After stirring for 10 minutes, a solution of (+)-10S (10 mg, mmol) in CH 2 Cl 2 (1 ml) was added. After stirring overnight, the reaction was diluted with CH 2 Cl 2 (5 ml) and saturated aqueous NaHCO 3 (5 ml) was added. The aqueous was extracted with CH 2 Cl 2 (3x 5 ml). The combined organics were washed with brine (5 ml) dried (Na 2 SO 4 ), filtered, concentrated and purified by silica gel chromatography (70% EtOAc : 30% Hexane) to yield ( )-S3S,S (16 mg, 82%). Rf (70% EtOAc : 30% Hexane) = 0.74; 1 H NMR (500 MHz, CDCl3) δ (m, 4H), (m, 4H), 7.04 (ddd, J = 8.4, 5.8, 0.9 Hz, 1H), 6.15 (dt, J = 4.2, 2.1 Hz, 1H), 6.02 (s, 1H), 5.45 (qd, J = 15.4, 8.2 Hz, 2H), (m, 2H), 5.03 (dd, J = 4.4, 2.2 Hz, 1H), (m, 2H), (m, 2H), (m, 2H), 3.12 (ddd, J = 14.3, 10.4, 5.9 Hz, 1H), (m, 3H), 2.24 (ddd, J = 37.1, 10.3, 4.5 Hz, 6H), 1.63 (t, J = 19.2 Hz, 3H), 1.25 (s, 10H), (m, 2H), 0.86 (dd, J = 8.8, 5.2 Hz, 3H), (m, 9H); 13 C NMR (126 MHz, CDCl3) δ , , , , , , , , , , , , , , , , 93.13, 74.93, 66.50, 58.09, 40.49, 37.25, 35.93, 35.62, 34.35, 33.84, 31.71, 29.64, 29.33, 29.11, 28.25, 25.10, 22.57, 17.98, 14.03, 0.96, -1.47; [α] D (c 0.44, CHCl 3 ); IR (film); 3308 (br N-H), 2924, 2855, 2360, 1734 (C=O), 1645 (C=O), 1618 (C=O), 1514, 1455, 1409, 1248, 1192, 1086, 983, 835, 752, 698; HRMS Accurate mass (ES+): Found (+1.8 ppm), C 40 H 58 N 2 O 6 Si [M+H] + requires

14 S14 (R,E)-1-oxo-1-(phenethylamino)tetradec-4-en-7-yl (S)-1-(2-((2- (trimethylsilyl)ethoxy)methoxy)benzoyl)-2,3-dihydro-1h-pyrrole-2-carboxylate ( )-S3R,S Acid ( )-6S (25 mg, mmol), MNBA (44 mg, mmol), DMAP (1 mg, mmol) and Et 3 N (0.023 ml, mmol) were dissolved in CH 2 Cl 2 (1 ml). After stirring for 10 minutes, a solution of ( )-10R (10 mg, mmol) in CH 2 Cl 2 (1 ml) was added. After stirring overnight, the reaction was diluted with CH 2 Cl 2 (5 ml) and saturated aqueous NaHCO 3 (5 ml) was added. The aqueous was extracted with CH 2 Cl 2 (3x 5 ml). The combined organics were washed with brine (5 ml) dried (Na 2 SO 4 ), filtered, concentrated and purified by silica gel chromatography (70% EtOAc : 30% Hexane) to yield ( )-S3R,S (25 mg, 74%). Rf (70% EtOAc : 30% Hexane) = 0.74; 1 H NMR (400 MHz, CDCl 3 ) δ (m, 2H), (m, 4H), (m, 3H), 6.17 (dd, J = 4.3, 2.1 Hz, 1H), 5.49 (ddd, J = 22.2, 18.3, 11.1 Hz, 2H), 5.21 (dd, J = 15.0, 7.1 Hz, 2H), (m, 1H), (m, 1H), 4.95 (dd, J = 11.6, 4.6 Hz, 1H), (m, 2H), (m, 2H), (m, 1H), (m, 1H), 2.60 (t, J = 7.6 Hz, 2H), (m, 5H), 1.58 (t, J = 18.4 Hz, 2H), 1.26 (d, J = 8.9 Hz, 9H), (m, 5H), (s, 9H); 13 C NMR (101 MHz, CDCl 3 ) δ , , , , , , , , , , , , , , , , , 93.32, 75.19, 66.72, 57.98, 40.77, 37.60, 36.32, 35.73, 34.52, 34.41, 31.90, 29.85, 29.53, 29.31, 28.74, 25.53, 22.77, 18.15, 14.24, -1.28; [α] D (c 0.76, CHCl 3 ); IR (film); 3295 (br N-H), 2925, 2855, 2359, 2341, 1733 (C=O), 1644 (C=O), 1617 (C=O), 1540, 1456, 1417, 1247, 1194, 1086, 973, 834, 752, 695; HRMS Accurate mass (ES+): Found (+1.8 ppm), C 40 H 58 N 2 O 6 Si [M+H] + requires

15 S15 (S,E)-1-((2-(1H-indol-3-yl)ethyl)amino)-1-oxotetradec-4-en-7-yl (S)-1-(2-((2- (trimethylsilyl)ethoxy)methoxy)benzoyl)-2,3-dihydro-1h-pyrrole-2-carboxylate ( )-S4S,S Acid ( )-6S (14 mg, mmol), MNBA (25 mg, mmol), DMAP (1 mg, mmol) and Et 3 N (0.013 ml, mmol) were dissolved in CH 2 Cl 2 (1 ml). After stirring for 10 minutes, a solution of (+)-11S (11 mg, mmol) in CH 2 Cl 2 (1 ml) was added. After stirring overnight, the reaction was diluted with CH 2 Cl 2 (5 ml) and saturated aqueous NaHCO 3 (5 ml) was added. The aqueous was extracted with CH 2 Cl 2 (3x 5 ml). The combined organics were washed with brine (5 ml) dried (Na 2 SO 4 ), filtered, concentrated and purified by silica gel chromatography (70% EtOAc : 30% Hexane) to yield ( )-S4S,S (17 mg, 81%). Rf (70% EtOAc : 30% Hexane) = 0.64; 1 H NMR (500 MHz, CDCl3) δ 8.69 (s, 1H), 7.57 (d, J = 7.5 Hz, 1H), (m, 1H), 7.33 (dd, J = 7.5, 1.6 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), (m, 1H), (m, 2H), 7.00 (d, J = 2.3 Hz, 1H), (m, 1H), 5.86 (s, 1H), 5.37 (ddd, J = 21.8, 15.3, 8.8 Hz, 2H), (m, 2H), (m, 1H), 4.98 (dd, J = 11.6, 5.0 Hz, 1H), (m, 1H), (m, 2H), 3.56 (dd, J = 12.5, 6.5 Hz, 2H), (m, 1H), 2.93 (t, J = 6.6 Hz, 2H), (m, 1H), (m, 7H), 1.65 (d, J = 5.7 Hz, 3H), 1.24 (d, J = 6.8 Hz, 10H), 0.92 (t, J = 4.6 Hz, 2H), 0.86 (t, J = 7.0 Hz, 3H), (m, 9H); 13 C NMR (101 MHz, CDCl3) δ , , , , , , , , , , , , , , , , , , , , , 93.32, 66.73, 58.45, 39.61, 37.37, 36.34, 34.50, 33.66, 31.90, 29.51, 29.31, 28.54, 25.29, 25.23, 22.76, 18.16, 14.24, -1.29; [α] D (c 0.32, CHCl 3 ); IR (film); 3295 (br N- H), 2951, 2925, 2855, 2359, 2341, 1738 (C=O), 1644 (C=O), 1617 (C=O), 1600, 1549, 1456, 1417, 1229, 1194, 1152, 1086, 973, 834, 739; HRMS Accurate mass (ES+): Found (+1.5 ppm), C 42 H 59 N 3 O 6 Si [M+H]+ requires

16 S16 (R,E)-1-((2-(1H-indol-3-yl)ethyl)amino)-1-oxotetradec-4-en-7-yl (S)-1-(2-((2- (trimethylsilyl)ethoxy)methoxy)benzoyl)-2,3-dihydro-1h-pyrrole-2-carboxylate ( )-S4R,S Acid ( )-6S (21 mg, mmol), MNBA (37 mg, mmol), DMAP (1 mg, mmol) and Et 3 N (0.019 ml, mmol) were dissolved in CH 2 Cl 2 (1 ml). After stirring for 10 minutes, a solution of ( )-11R (16 mg, mmol) in CH 2 Cl 2 (1 ml) was added. After stirring overnight, the reaction was diluted with CH 2 Cl 2 (5 ml) and saturated aqueous NaHCO 3 (5 ml) was added. The aqueous was extracted with CH 2 Cl 2 (3x 5 ml). The combined organics were washed with brine (5 ml) dried (Na 2 SO 4 ), filtered, concentrated and purified by silica gel chromatography (70% EtOAc : 30% Hexane) to yield ( )-S4R,S (20 mg, 64%). Rf (70% EtOAc : 30% Hexane) = 0.64; 1 H NMR (500 MHz, CDCl 3 ) δ 8.67 (s, 1H), 7.52 (d, J = 8.1 Hz, 1H), (m, 2H), 7.20 (d, J = 8.0 Hz, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 2H), (m, 2H), 5.08 (dt, J = 4.8, 2.5 Hz, 1H), 4.94 (td, J = 11.7, 5.7 Hz, 2H), (m, 2H), 3.50 (dd, J = 12.7, 6.2 Hz, 1H), (m, 1H), 2.86 (t, J = 6.8 Hz, 1H), (m, 1H), (m, 5H), (m, 3H), (m, 10H), 0.90 (dd, J = 21.0, 4.2 Hz, 5H), (m, 9H); 13 C NMR (126 MHz, CDCl 3 ) δ , , , , , , , , , , , , , , , , , , , , , 93.36, 75.30, 66.73, 58.14, 39.57, 37.43, 36.45, 34.34, 34.00, 31.91, 29.52, 29.32, 28.70, 25.50, 25.19, 22.77, 18.16, 14.24, -1.30; [α] 25 D -14 (c 0.51, CHCl 3 ); IR (film); 3308 (br N-H), 2952, 2924, 2855, 2360, 2342, 1739 (C=O), 1652 (C=O), 1617 (C=O), 1456, 1418, 1193, 1087, 974, 857, 835, 753; HRMS Accurate mass (ES+): Found (+1.9 ppm), C 42 H 59 N 3 O 6 Si [M+H] + requires

17 S17 (S,E)-7-(((S)-1-(2-hydroxybenzoyl)-2,3-dihydro-1H-pyrrole-2-carbonyl)oxy)tetradec-4-enoic acid ( )-12S,S To a solution of ( )-9S,S (12.2 mg, mmol) in DMPU (0.17 ml) was added TBAF (1 M in THF) (.17 ml, 0.17 mmol). After stirring at room temperature for 2 hours, the reaction was diluted with EtOAc (5 ml) and washed with 1 M NH 4 Cl (5 x 5 ml) followed by 1 M LiCl (5 x 5mL) The organic layer was dried (Na 2 SO 4 ), filtered, concentrated, and purified by column chromatography (70% EtOAc : 30% Hexane) yielding ( )-12S,S (5.7 mg, 75%). Rf (70% EtOAc : 30% Hexane) = 0.50; 1 H NMR (400 MHz, CDCl 3 ) δ (m, 2H), 7.00 (d, J = 8.3 Hz, 1H), 6.88 (t, J = 7.3 Hz, 1H), 6.80 (s, 1H), 5.45 (dd, J = 19.1, 13.4 Hz, 2H), 5.26 (d, J = 4.3 Hz, 1H), 5.01 (dd, J = 11.3, 5.0 Hz, 1H), 4.95 (s, 1H), (m, 1H), 2.69 (d, J = 17.1 Hz, 1H), 2.32 (dd, J = 37.1, 6.4 Hz, 6H), 1.25 (s, 12H), 0.86 (d, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ , , , , , , , , , , , , 99.98, 75.53, 59.73, 37.52, 33.91, 33.82, 32.11, 29.70, 29.52, 27.88, 25.49, 22.99, 14.45, ; [α] D (c 0.18, CHCl 3 ); IR (film); 2925, 2856, 2360, 2342, 1734 (C=O), 1646 (C=O), 1616 (C=O), 1541, 1456, 1419, 1251, 1192, 1087, 970, 838, 756, 701; HRMS Accurate mass (ES+): Found (+0.4 ppm), C 26 H 35 NO 6 [M+H] + requires (R,E)-7-(((S)-1-(2-hydroxybenzoyl)-2,3-dihydro-1H-pyrrole-2-carbonyl)oxy)tetradec-4-enoic acid (+)-12R,S

18 S18 To a solution of (+)-9R,S (9 mg, mmol) in DMPU (0.2 ml) was added TBAF (1 M in THF) (.2 ml, 0.2 mmol). After stirring at room temperature for 15 minutes, the reaction was diluted with EtOAc (5 ml) and washed with 1 M NH 4 Cl (5 x 5 ml) followed by 1 M LiCl (5 x 5mL) The organic layer was dried (Na 2 SO 4 ), filtered, concentrated, and purified by column chromatography (70% EtOAc : 30% Hexane) yielding (+)-12R,S (5.1 mg, 89%). Rf (70% EtOAc : 30% Hexane) = 0.50, 1 H NMR (400 MHz, CDCl 3 ) δ 7.38 (dd, J = 15.6, 7.4 Hz, 2H), 7.00 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.70 (s, 1H), 5.49 (s, 2H), 5.29 (d, J = 7.6 Hz, 2H), 5.12 (s, 1H), 5.00 (d, J = 11.4 Hz, 1H), 3.35 (s, 1H), (m, 1H), 2.70 (d, J = 17.1 Hz, 1H), 2.35 (s, 6H), 1.25 (s, 12H), 0.86 (d, J = 7.0 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ , , , , , , , , , , , , , 75.81, 59.09, 56.13, 37.27, 34.27, 31.86, 29.84, 29.52, 29.27, 28.16, 25.27, 22.76, 14.23; [α] D (c 0.16, CHCl 3 ); IR (film); 3308 (br O-H), 2952, 2924, 2854, 2360, 2342, 1733 (C=O), 1717 (C=O), 1616 (C=O), , 757; HRMS Accurate mass (ES+): Found (+1.2 ppm), C 26 H 35 NO 6 [M+H] + requires (S)-1-(2-hydroxybenzoyl)-2,3-dihydro-1H- (S,E)-1-oxo-1-(phenethylamino)tetradec-4-en-7-yl pyrrole-2-carboxylate ( )-13S,S To a solution of ( )-S3S,S (15.3 mg, mmol) in DMPU (0.217 ml) was added TBAF (1 M in THF, ml, mmol). After stirring for 15 minutes at room temperature, the reaction was quenched by the addition of saturated NH 4 Cl (5 ml). The aqueous layer was extracted with Et 2 O (3 x 5 ml). The combined organics were washed with 1 M NH 4 Cl (5 x 2 ml) followed by 1 M LiCl (5 x 2 ml). The organics were dried (Na 2 SO 4 ) filtered and concentrated. The crude oil was purified by silica gel chromatography (40% EtOAc : 60 % CHCl 3 ) yielding ( )-13S,S (9.1 mg, 73%). Rf (40% EtOAc : 60 % CHCl 3 )) = 0.4; 1 H NMR (500 MHz, CDCl 3 ) δ 9.80 (s, 1H), (m, 1H), 7.35 (dd, J = 11.2, 4.4 Hz, 1H), (m, 2H), (m, 3H), 6.97 (dd, J = 11.9, 4.5 Hz, 1H), 6.89 (t, J = 7.0 Hz, 1H), 6.78 (s, 1H), 5.56 (s, 1H), (m, 2H), (m, 1H), (m, 2H), 3.51 (dd, J = 12.9, 6.9 Hz, 2H), 3.10 (dd, J = 17.0, 11.2 Hz, 1H), 2.81 (t, J = 6.9 Hz, 2H), 2.69 (d, J = 16.9 Hz, 1H), (m, 5H), 2.11 (t, J = 7.6 Hz, 1H), 1.26 (s, 11H), (m, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ ,

19 S , , , , , , , , , , , , , 75.43, 59.60, 40.72, 40.68, 37.30, 36.32, 35.86, 33.79, 31.89, 29.85, 29.50, 29.31, 28.57, 28.46, 25.43, 25.29, 22.77, 14.23; [α] D (c 0.16, CHCl 3 ); IR (film); 3291 (br N/O-H), 2951, 2926, 2856, 2360, 2342, 1734 (C=O), 1718 (C=O), 1616 (C=O), 1456, 1419, 1193, 1017, 969, 859, 752, 699; HRMS Accurate mass (ES+): Found (+0.8 ppm), C 34 H 44 N 2 O 5 [M+H] + requires (S)-1-(2-hydroxybenzoyl)-2,3-dihydro-1H- (R,E)-1-oxo-1-(phenethylamino)tetradec-4-en-7-yl pyrrole-2-carboxylate (-)-13R,S To a solution of ( )-S3R,S (23.6 mg, mmol) in DMPU (0.342 ml) was added TBAF (1 M in THF, ml, mmol). After stirring for 15 minutes at room temperature, the reaction was quenched by the addition of saturated NH 4 Cl (5 ml). The aqueous layer was extracted with Et 2 O (3 x 5 ml). The combined organics were washed with 1 M NH 4 Cl (5 x 2 ml) followed by 1 M LiCl (5 x 2 ml). The organics were dried (Na 2 SO 4 ) filtered and concentrated. The crude oil was purified by silica gel chromatography (40% EtOAc : 60 % CHCl 3 ) yielding ( )-13R,S (11.6 mg, 61%). R f (40% EtOAc : 60 % CHCl 3 )) = 0.4; 1 H NMR (500 MHz, CDCl 3 ) δ 9.71 (d, J = 97.8 Hz, 1H), (m, 2H), (m, 2H), (m, 3H), (m, 1H), (m, 1H), 6.75 (s, 1H), 5.95 (s, 1H), (m, 2H), 5.26 (dd, J = 4.3, 2.5 Hz, 1H), 4.97 (dd, J = 11.4, 4.7 Hz, 2H), 3.48 (ddd, J = 27.8, 13.1, 7.0 Hz, 2H), (m, 1H), (m, 2H), 2.69 (d, J = 17.2 Hz, 1H), (m, 6H), 1.66 (s, 1H), 1.22 (s, 10H), 0.87 (dd, J = 7.7, 6.4 Hz, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ , , , , , , , , , , , , , , , , , 75.69, 59.35, 40.71, 37.44, 36.36, 35.87, 34.02, 33.71, 31.86, 29.48, 29.26, 28.56, 25.42, 22.75, 14.22; [α] D (c 0.42, CHCl 3 ); IR (film); 3291 (br N/O-H), 2951, 2926, 2856, 2360, 2342, 1734 (C=O), 1718 (C=O), 1616 (C=O), 1456, 1419, 1193, 1017, 969, 859, 752, 699; HRMS Accurate mass (ES+): Found (+2.9 ppm), C 34 H 44 N 2 O 5 [M+H] + requires

20 S20 (S,E)-1-((2-(1H-indol-3-yl)ethyl)amino)-1-oxotetradec-4-en-7-yl dihydro-1h-pyrrole-2-carboxylate ( )-14S,S (S)-1-(2-hydroxybenzoyl)-2,3- To a solution of ( )-S4S,S (13 mg, mmol) in DMPU (0.18 ml) was added TBAF (1 M in THF, 0.18 ml, 0.18 mmol). After stirring for 15 minutes at room temperature, the reaction was quenched by the addition of saturated NH 4 Cl (5 ml). The aqueous layer was extracted with Et 2 O (3 x 5 ml). The combined organics were washed with 1 M NH 4 Cl (5 x 2 ml) followed by 1 M LiCl (5 x 2 ml). The organics were dried (Na 2 SO 4 ) filtered and concentrated. The crude oil was purified by silica gel chromatography (3% MeOH : 97 % CH 2 Cl 2 ) yielding ( )-14S,S (5.3 mg, 50%); 1 H NMR (400 MHz, CDCl 3 ) δ 9.79 (s, 1H), 8.26 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), (m, 3H), 7.19 (dd, J = 11.1, 4.1 Hz, 1H), (m, 1H), (m, 2H), 6.88 (t, J = 7.1 Hz, 1H), 6.77 (s, 1H), 5.64 (s, 1H), (m, 3H), 4.98 (dd, J = 11.3, 5.1 Hz, 1H), 4.90 (s, 1H), 3.60 (dd, J = 5.9, 4.3 Hz, 2H), (m, 1H), 2.97 (t, J = 6.6 Hz, 2H), 2.67 (d, J = 16.8 Hz, 1H), (m, 6H), 1.68 (s, 3H), 1.27 (d, J = 12.3 Hz, 10H), 0.86 (t, J = 5.9 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ , , , , , , , , , , , , , , , , , , , 75.53, 59.60, 39.65, 37.24, 36.36, 33.64, 31.88, 29.85, 29.48, 29.31, 28.45, 25.41, 25.28, 22.77, 14.24; [α] D (c 0.22, CHCl 3 ; IR (film); 3292 (br N/O-H), 2923, 2853, 2360, 2342, 1733 (C=O), 1645 (C=O), 1616 (C=O), 1540, 1457, 1429, 1252, 1195, 1098, 970, 859, 740, 705; HRMS Accurate mass (ES+): Found (+0.8 ppm), C 36 H 45 N 3 O 5 [M+H] + requires

21 S21 (R,E)-1-((2-(1H-indol-3-yl)ethyl)amino)-1-oxotetradec-4-en-7-yl dihydro-1h-pyrrole-2-carboxylate (+)-14R,S (S)-1-(2-hydroxybenzoyl)-2,3- To a solution of (-)-S4R,S (19 mg, mmol) in DMPU (0.26 ml) was added TBAF (1 M in THF, 0.26 ml, 0.26 mmol). After stirring for 15 minutes at room temperature, the reaction was quenched by the addition of saturated NH 4 Cl (5 ml). The aqueous layer was extracted with Et 2 O (3 x 5 ml). The combined organics were washed with 1 M NH 4 Cl (5 x 2 ml) followed by 1 M LiCl (5 x 2 ml). The organics were dried (Na 2 SO 4 ) filtered and concentrated. The crude oil was purified by silica gel chromatography (3% MeOH : 97 % CH 2 Cl 2 ) yielding (+)-14R,S (6.6 mg, 43%); 1 H NMR (400 MHz, CDCl 3 ) δ 9.63 (s, 1H), 8.24 (s, 1H), 7.58 (d, J = 8.1 Hz, 1H), (m, 3H), 7.18 (t, J = 7.8 Hz, 1H), 7.11 (d, J = 7.1 Hz, 1H), (m, 2H), 6.88 (t, J = 7.3 Hz, 1H), 6.74 (s, 1H), 5.89 (s, 1H), 5.43 (s, 2H), 5.25 (s, 1H), 4.94 (d, J = 25.5 Hz, 2H), 3.57 (d, J = 6.2 Hz, 2H), 3.10 (s, 1H), 2.93 (s, 2H), 2.70 (s, 1H), (m, 7H), 1.51 (s, 2H), 1.25 (s, 10H), 0.87 (d, J = 6.6 Hz, 3H); 13C NMR; [α] D (c 0.11, CHCl 3 ); IR (film); 3293 (br N/O-H), 2954, 2921, 2852, 2360, 2342, 1734 (C=O), 1717 (C=O), 1653 (C=O), 1615, 1457, 1419, 1193, 1018, 968, 858, 758, 698; HRMS Accurate mass (ES+): Found (+1.7 ppm), C 36 H 45 N 3 O 5 [M+H] + requires References 1. De Oliveira, E. O., Synthesis and evaluation of hermitamides A and B as human voltagegated sodium channel blockers. Bioorg. Med. Chem (2011). 2. Reddy, G. V., Novel malyngamide structural analogs: synthesis and biological evaluation. Med. Chem. Res (2013). 3. Steele, A. D., Knouse, K. W., Keohane, C. E., Wuest, W. M. Total Synthesis and Biological Investigation of ( )-Promysalin. J. Am. Chem. Soc. 137, (2015).

22 S22 3. Biological Data 3.1 Biological Procedures Pseudomonas putida KT2440, Pseudomonas fluorescens WCS365, and Pseudomonas aeruginosa PAO1 and PA14 were grown from freezer stocks overnight with shaking at 37 C in Tryptic Soy Broth (TSB). 3.1 IC 50 Assay Compounds were serially diluted in TSB media from DMSO stock solutions to yield twelve test concentrations. Overnight cultures were diluted to ca CFU/mL in TSB media, and 100 μl were inoculated into each well of a 96-well plate containing 100 μl of compound solution in triplicate. Plates were incubated statically at 37 C for 48 hours, upon which time growth was evaluated visually. After an additional 72h, the OD of each well was measured at 595 nm using a plate reader (POLARstar Omega, BMG Labtech). IC 50 values were assigned to the lowest concentration which resulted in a mean OD value of half of the mean of the DMSO control wells. 4. Appendix A: Spectral Data

23 S23

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25 S25

26 S26

27 S27

28 S28

29 S29

30 S30

31 S31

32 S32

33 S33

34 S34

35 S35

36 S36

37 S37

38 S38

39 S39

40 S40

41 S41

42 S42

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44 S44

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Supporting Information. Table of Contents. 1. General Notes Experimental Details 3-12

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