Total Synthesis of Verruculogen and Fumitremorgin A Enabled by Ligand-Controlled C H Borylation

Transcription

1 Total Synthesis of Verruculogen and Fumitremorgin A Enabled by Ligand-Controlled C H Borylation Yu Feng, Dane Holte, Jochen Zoller, Shigenobu Umemiya, Leah R. Simke, and Phil S. Baran* Department of Chemistry, The Scripps Research Institute, North Torrey Pines Road, La Jolla, California SUPPORTING INFORMATION Part 1: Experimental Procedures and Characterization Data Table of Contents General Experimental...page S3 Experimental Procedures and Characterization Data...page S4 S73 Compound 4...page S4 Compound 7...page S9 Compounds 8, 9, and 10...page S10 Compounds 11 and 13...page S11 Compound 14...page S12 Compounds 7a and 8a...page S15 Compounds 9a and 10a...page S16 Compounds 11a and 13a...page S17 Compound 14a...page S18 Structural determination for the mixture of 14a and 14b page S18 Compounds 6 and 23...page S20 Compound S1...page S23 Compound S2...page S24 Compound 24...page S25 Compound S4...page S26 Compound S5...page S27 Compound 19a...page S28 X-ray crystallography data for 19a...page S29 Compound 21a...page S39 X-ray crystallography data for 21a...page S40 Compound 3...page S52 S1

2 Compounds 25 and 25a...page Compound 25b...page Compound 19b...page Compound 21b...page Compound 27...page HPLC data for 27...page Compound 28...page Compound 29...page Compound 2...page Compound 1...page References...page S55 S56 S57 S58 S59 S61 S63 S64 S65 S71 S75 S2

3 General Experimental. All reactions were carried out under an inert nitrogen atmosphere with dry solvents under anhydrous conditions unless otherwise stated. Dry acetonitrile (MeCN), dichloromethane (DCM), diethyl ether (Et 2O), tetrahydrofuran (THF), toluene (PhMe) and triethylamine (Et 3N) were obtained by passing the previously degassed solvents through activated alumina columns. Reagents were purchased at the highest commercial quality and used without further purification, unless otherwise stated. Yields refer to chromatographically and spectroscopically ( 1 H-NMR) homogeneous material, unless otherwise stated. Reactions were monitored by thin layer chromatography (TLC) carried out on 0.25 mm E. Merck silica plates (60F-254), using UV light as the visualizing agent and an acidic solution of p-anisaldehyde and heat, ceric ammonium molybdate and heat, or KMnO 4 and heat as developing agents. Flash silica gel chromatography was performed using E. Merck silica gel (60, particle size mm), flash alumina chromatography was performed using Brockmann Grade 1 aluminum oxide (activated, basic, 58 Å, 60 mesh powder), and flash Florisil chromatography was conducted using Acros magnesium silicate (activated, mesh). Chiral HPLC was performed using a Hitachi LaChrom Elite HPLC system. NMR spectra were recorded on Bruker DRX-600 and AMX-400 instruments and were calibrated using residual undeuterated solvent as an internal reference (CHCl 7.26 ppm 1 H- NMR, ppm 13 C-NMR). The following abbreviations were used to explain NMR peak multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. High-resolution mass spectra (HRMS) were recorded on an Agilent LC/MSD TOF mass spectrometer by electrospray ionization timeof-flight (ESI-TOF) reflectron experiments. IR experiments were recorded on a Perkin-Elmer Spectrum 100 FT-IR spectrometer. Optical rotations were obtained on a Perkin-Elmer 341 polarimeter. Melting points were recorded on a Fisher-Johns melting point apparatus and are uncorrected. S3

4 methyl N a -(tert-butoxycarbonyl)-1-(triisopropylsilyl)-l-tryptophanate (4) This compound was synthesized according to the literature: Lesma, G.; Cecchi, R.; Cagnotto, A.; Gobbi, M.; Meneghetti, F.; Musolino, M.; Sacchetti, A.; Silvani, A. J. Org. Chem. 2013, 78, To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(1H-indol-3-yl)propanoate (6.09 g, mmol) in anhydrous THF (100 ml) cooled to 78 C under nitrogen atmosphere was added dropwise LiHMDS (1 M in THF, ml, mmol). After 1 h, triisopropylsilyl chloride (4.06 ml, mmol) was added dropwise at 78 C, and the solution was allowed to warm to ambient temperature. After 1 h, water (100 ml) and EtOAc (100 ml) were then added to the reaction mixture. The organic phase was separated, dried over Na 2SO 4, and the solvent was evaporated in vacuo. The crude residue was purified by silica gel chromatography (0 10% EtOAc/hexanes) to afford the pure product 4 (8.04 g, 89%). Physical state: yellow oil; TLC: R f = 0.50 (8:1 hexanes/etoac); Optical rotation: 20 D = º (c = 0.25, EtOAc); 1 H NMR (500 MHz, CDCl 3) δ 7.53 (d, J = 7.5 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), (m, 2H), 7.03 (s, 1H), 5.06 (d, J = 8.2 Hz, 1H), (m, 1H), 3.63 (s, 3H), 3.27 (dd, J = 5.8, 3.0 Hz, 2H), 1.68 (p, J = 7.5 Hz, 3H), 1.43 (s, 9H), 1.14 (dd, J = 7.6, 1.9 Hz, 18H); 13 C NMR (126 MHz, CDCl 3) δ 172.9, 155.3, 141.4, 131.2, 129.9, 121.8, 119.8, 118.8, 114.1, 112.2, 79.9, 54.3, 52.3, 28.5, 28.3, 18.2, 18.2, 18.1, 17.9, 13.0; HRMS (m/z): calcd for C 26H 42N 2NaO 4Si [M+Na] ; found S4

5 Figure S1. Literature summary: selected methods for the synthesis of 6-methoxytryptophan A. Direct C H oxidation from a tryptophan derivative 6-Methoxylation of Moc-DL-Trp-OMe in 4 steps, 33% overall yield, but with a stoichiometric lead reagent. Ref: Hino and co-workers, J. Am. Chem. Soc. 1978, 100, ; Hino and co-workers, Heterocycles 1979, 12, ; Hino and co-workers, Chem. Pharm. Bull. 1984, 32, N H CO 2 Me NHCO 2 Me 85% H 3 PO 4 then Ac 2 O (81% of an isomeric mixture) H 1) Pb(OAc) 4 CO 2 Me (1.2 eq.), TFA CO 2 Me MeO N 2) MeI, K N 2 CO 6 N 3 Ac H CO 2 Me 7 N Ac H CO 2 Me * This second step was desired 6-OMe product: 42% done primarily because + 5-OMe product (17%) the OH products are + 5-OH product (2%) difficult to separate + 6-OH product (2%) + 7-OH product (4%) B. 6-Methoxytryptophan derivatives by ring synthesis i. Japp Klingemann/Fischer indole synthesis followed by Schöllkopf amino acid synthesis in 8 steps. Ref: Cook and co-workers, J. Org. Chem. 1997, 62, ) NaOH, heat Me Me 2) Cu, heat 1) NaNO 2, HCl 3) Boc 2 O MeO MeO 2) HCl, heat NH CO 2 Et 2 Ac (73%, 10:1 desired:undesired) N H CO 2 Et 4) NBS, AIBN, heat 5) BuLi, Schöllkopf D-ligand 6) HCl, THF; HCl, MeOH (6 steps, 54%) 5 MeO H N H 10% H 2 SO 4 in MeOH ii. Larock indole synthesis using an alkyne that has incorporated a Schöllkopf auxiliary. Ref: Cook and co-workers, Tetrahedron Lett. 1999, 40, ; Cook and co-workers, J. Org. Chem. 2001, 66, EtO EtO MeO NH 2 I + 2 steps from 2-nitro-4-methoxyaniline TES N N OEt ipr 3 steps from propargyl alcohol, one of the steps including L-ligand iv. Iodoaniline/ketone cyclization. Ref: Zhu and co-worker, Synlett 2005, CO 2 Me I + MeO NH 2 2 steps from 2-nitro-4-methoxyaniline N(Boc) 2 O 4 steps from Glu-OH Pd(OAc) 2 (1 mol%), Na 2 CO 3, LiCl DMF, 100 C (77%) Pd(OAc) 2 (5 mol%), DABCO DMF, 85 C (58%) MeO MeO N H N H N TES N OEt CO 2 Me N(Boc) 2 i Pr (98%) CO 2 Et NH 2 2N HCl EtOH, THF (86%) iii. Iodoaniline/ketone cyclization. Ref: Baran and co-workers, Angew. Chem. Int. Ed. 2005, 44, ; Baran and co-workers, J. Am. Chem. Soc. 2006, 128, CO 2 Me CO 2 Me TsO NH 2 2 steps from 3-aminophenol I + NCbz OH 2 steps from Cbz-Glu-OMe Pd(OAc) 2 (5 mol%), DABCO, Bu 4 NI DMF, 105 C (75%) C. 6-Methoxytryptophan derivatives by C3-substitution of 6-methoxyindole i. C3-Formylation then hydantoin condensation. Ref: Harvey and co-worker, J. Chem. Soc. 1938, MeO N H KOH, CHCl 3 heat MeO N H CHO ii. C3-Aminomethylation then displacement with malonate. Ref: Bergmann and co-worker, J. Chem. Soc. 1962, EtO 2 C HCHO, NMe 2 Me 2 NH AcHN MeO MeO N H AcOH (59%) N H 1) hydantoin, piperidine, heat TsO N H 2) H 2 S, pyridine, heat N H O OEt NaOH, PhMe, heat (68%) MeO MeO iii. C3-Formylation, reduction, then displacement with Schöllkopf auxiliary. Ref: Cook and co-worker, Synth. Commun. 1992, 22, ) POCl 3, CHO DMF (95%) 1) NaBH 4 (97%) MeO MeO MeO N H 2) PhSO 2 Cl, NaH (89%) N SO2 Ph 2) Ph 3 PBr 2 (93%) iv. C3-Substitution using serine and acetic anhydride, followed by resolution. Ref: Sanderson and co-workers, Tetrahedron Lett. 2008, 49, CO 2 H MeO N H L-Ser Ac 2 O, AcOH (77%) MeO N H NHAc acylase resolution (32%; 91% ee) MeO N H EtO 2 C N SO2 Ph N H HN NHCbz O NH O CO 2 Et NHAc Br CO 2 H NH 2 detosylation and methylation (was not performed in publication) deprotection (was not performed in publication) NH 4 OH heat 1) NaOH, heat 2) H 2 O, heat 3) NaOH, heat (27%) 1) BuLi, L-ligand (93%) 2) 2N HCl (quant.) MeO N MeO OEt N ipr N H N H CO 2 Me NHCO 2 Me OEt OEt D-ligand L-ligand prepared from D-valine or L-valine in 3 steps MeO MeO MeO MeO MeO First step occurs via: AcO CO 2 H NHAc :Nu O N H N H N H N H N SO2 Ph :Nu CO 2 H Me NH N OEt N CO 2 Et NH 2 CO 2 Me NHCbz CO 2 Me NH 2 CO 2 H NH 2 CO 2 H NH 2 CO 2 Et NH 2 ipr CO 2 H NHAc :Nu S5

6 Optimization of ligand-controlled borylation on tryptophan ester derivative 4 1. Conditions Screening Table S1. Optimization of the C H borylation reaction on tryptophan derivative 4 a Figure S2. Ligand structures General Procedure: The iridium dimer catalyst, ligand, and B 2Pin 2 were placed in an oven-dried vial under an argon atmosphere. After dissolving in solvent (0.5 ml), HBPin was added in one portion followed by the addition of a solution of substrate (0.1 mmol) in solvent ( µl). The vial was sealed with parafilm and stirred for the indicated time at the indicated temperature. The reaction mixture was poured into a separatory funnel, diluted with EtOAc (1.5 ml), and washed with sat. NaHCO 3 (1.5 ml). The aqueous S6

7 phase was extracted with EtOAc (1.5 ml 3). The combined organic phase was dried over anhydrous Na 2SO 4, filtered, and the solvents were concentrated in vacuo. The crude residue was purified by silica gel chromatography. 2. Additional Ligands Screening a,b Table S2. Additional Ligands Screening for regioselective C6-borylation a, b S7

8 Figure S3. Additional ligand Structures S8

9 Substrates preparation for borylation: General method: To a solution of substrate (1.0 mmol) in THF (10 ml), was added base (1.1 eq) slowly at 0 o C. After stirring for 15 minutes, TIPSCl (1.2 mmol, 257 µl) was added in one portion. The cooling bath was then removed and the reaction was allowed to stir for an additional 1 hour at ambient temperature. Water (10 ml) and EtOAc (10 ml) were then added to the reaction mixture, and the organic phase was separated, dried over Na 2SO 4, and the solvent was evaporated in vacuo. The crude residue was purified by silica gel chromatography (0 5% EtOAc/hexanes) to afford the pure product. methyl 1-(triisopropylsilyl)-1H-indole-3-carboxylate (7) Using LiHMDS as base, yielded 299 mg of 7 (90% yield) as colorless oil; TLC: R f = 0.65 (8:1 hexanes/etoac); 1 H NMR (600 MHz, CDCl 3) δ 8.20 (d, J = 6.0 Hz, 1H), 7.98 (s, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.21 (t, J = 8.4 Hz, 1H), 3.92 (s, 3H), 1.73 (h, J = 7.6 Hz, 3H), 1.16 (d, J = 7.6 Hz, 18H); 13 C NMR (151 MHz, CDCl 3) δ 166.0, 141.6, 138.9, 129.2, 122.9, 122.2, 121.8, 114.5, 110.9, 51.3, 18.0, 12.6; HRMS(m/z): calcd for C 19H 30NO 2Si [M+H] , found [M+H] S9

10 3-methyl-1-(triisopropylsilyl)-1H-indole (8) Using LiHMDS as base, yielded 264 mg of 8 (92% yield) as colorless oil; TLC: R f = 0.70 (8:1 EtOAc/hexanes); 1 H NMR (500 MHz, CDCl 3) δ 7.58 (d, J = 7.58 Hz, 1H), 7.49 (m, 1H), 7.15 (ddt, J = 10.2, 7.0, 3.7 Hz, 2H), 7.15 (s, 1H), 2.36 (s, 3H), 1.72 (h, J = 7.5 Hz, 3H), 1.17 (d, J = 7.6 Hz, 18H); 13 C NMR (126 MHz, CDCl 3) δ 141.6, 132.2, 128.7, 121.6, 119.5, 118.9, 114.1, 113.7, 18.5, 13.2, 10.1; HRMS (m/z) calcd for C 18H 30NSi [M+H] , found (2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(triisopropylsilyl)-1H-indole (9) Using nbuli as base, yielded 363 mg of 9 (84% yield) as colorless oil; TLC: R f = 0.60 (8:1 hexanes/etoac); 1 H NMR (500 MHz, CDCl 3) δ 7.56 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), (m, 2H), 7.08 (s, 1H), 3.89 (t, J = 7.2 Hz, 2H), 2.98 (d, J = 7.2 Hz, 2H), 1.68 (h, J = 7.5 Hz, 3H), 1.14 (d, J = 7.5 Hz, 18H), 0.89 (s, 9H); 13 C NMR (126 MHz, CDCl 3) δ 141.5, 131.6, 129.3, 121.5, 119.5, 119.0, 115.4, 114.2, 99.9, 64.2, 29.5, 26.4, 18.7, 13.2; HRMS(m/z): calcd for C 25H 46NOSi 2 [M+H] , found [M+H] S10

11 4-(triisopropylsilyl)-1,2,3,4-tetrahydrocyclopenta[b]indole (10) Using nbuli as base, yielded 250 mg of 10 (80% yield) as colorless oil; TLC: R f = 0.70 (8:1 hexanes/etoac); 1 H NMR (600 MHz, CDCl 3) δ 7.51 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), (m, 1H), (m, 1H), (m, 2H), 2.79 (ddt, J = 7.2, 5.5, 1.5 Hz, 2H), (m, 2H), 1.78 (h, J = 7.5 Hz, 3H), 1.15 (d, J = 7.6 Hz, 18H); 13 C NMR (151 MHz, CDCl 3) δ 149.9, 147.0, 128.0, 123.7, 120.4, 119.8, 118.4, 114.9, 30.1, 28.8, 23.8, 18.7, 13.5; HRMS (m/z): calcd for C 20H 32NSi [M+H] ; found [M+H] (triisopropylsilyl)-1H-indole-3-carbonitrile (11) Using nbuli as base, yielded 259 mg of 11 (87% yield) as white foam; TLC: R f = 0.60 (8:1 hexanes/etoac); 1 H NMR (600 MHz, CDCl 3) δ (m, 1H), 7.73 (s, 1H), (m, 1H), (m, 2H), 1.70 (dtd, J = 8.7, 7.6, 6.2 Hz, 3H), 1.15 (d, J = 7.6, 18H); 13 C NMR (151 MHz, CDCl 3) δ 140.3, 139.4, 130.2, 124.0, 122.5, 120.1, 116.4, 115.0, 89.9, 18.3, 13.0; HRMS (m/z): calcd for C 18H 27N 2Si [M+H] ; found [M+H] (triisopropylsilyl)-9H-carbazole (13) Using nbuli as base, yielded 304 mg of 13 (94% yield) as colorless oil; S11

12 TLC: R f = 0.55 (8:1 hexanes/etoac); 1 H NMR (600 MHz, CDCl 3) δ 8.07 (d, J = 7.7 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.36 (t, J = 8.5 Hz, 2H), 7.23 (t, J = 7.8 Hz, 2H), 2.01 (h, J = 7.5 Hz, 3H), 1.21 (d, J = 7.6 Hz, 18H); 13 C NMR (151 MHz, CDCl 3) δ 145.4, 126.8, 125.6, 120.0, 119.8, 114.4, 19.0, 14.2; HRMS (m/z): calcd for C 21H 30NSi [M+H] ; found ; 3-ethyl-9-(triisopropylsilyl)-9H-carbazole (14) Using LiHMDS as base, yielded 333 mg (95% yield) as colorless oil; TLC: R f = 0.50 (8:1 hexanes/etoac); 1 H NMR (600 MHz, CDCl 3) δ 8.05 (d, J = 7.6, 1H), 7.88 (s, 1H), 7.67 (d, J = 8.5, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.34 (ddt, J = 8.3, 7.1, 1.2 Hz, 1H), (m, 2H), 2.82 (q, J = 7.6 Hz, 2H), 2.00 (h, J = 7.3, 3H), 1.35 (t, J = 7.6, 1.0 Hz, 3H), 1.20 (dd, J = 7.6, 1.0 Hz, 18H); 13 C NMR (151 MHz, CDCl 3) δ 145.7, 143.7, 135.7, 126.9, 126.8, 125.9, 125.4, 119.9, 119.6, 118.7, 114.4, 114.2, 28.9, 19.0, 16.5, 14.2; HRMS (m/z): calcd C 23H 34NSi [M+H] ; found S12

13 General Procedure for Borylation: Hexanes were freshly distilled over CaH 2 before use. An oven-dried vial under an argon atmosphere was charged with the catalyst [Ir(cod)(OMe)] 2 (3.3 mg, 5 mol%), 1,10-phenanthorline (1.9 mg, 10 mol%), and B 2Pin 2 (102 mg, 0.4 mmol). After dissolution in hexanes (0.5 ml), HBPin (3.6 μl, 25 mol%) was added in one portion followed by the addition of a solution of the substrate (0.1 mmol) in hexanes (100 µl). The vial was sealed with parafilm and stirred for 24 h at 80 o C. During the process, the green solution turned black. The reaction mixture was poured into a separatory funnel, diluted with EtOAc (15 ml), and washed with sat. NaHCO 3 (15 ml). The aqueous phase was extracted with EtOAc (15 ml 3). The combined organic phase was dried over anhydrous Na 2SO 4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography. S13

14 Figure S4. General operation process for C6-borylation Step 1: Solvent distillation Step 2: Place catalyst, ligand and B2Pin2 in an oven-dried tube Step 3: a. Solvent addition; b. HBPin addition; c. Substrate addition. Step 4: Cap exchange/reseal; stirring for o C S14

15 methyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(triisopropylsilyl)-1H-indole-3-carboxylate (7a) Using L3 as ligand, 7a was obtained as the major product (totally 38.4 mg, 84% yield, a 14:1 mixture of C6 and C5 products). Physical State: slightly yellow oil; TLC: R f = 0.60 (8:1 hexanes/etoac); 1 H NMR (600 MHz, CDCl 3) δ 8.16 (d, J = 8.0 Hz, 1H), 8.00 (s, 1H), 7.95 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 3.92 (s, 3H), 1.75 (m, 3H), 1.36 (s, 12H), 1.16 (d, J = 7.6 Hz, 18H); 13 C NMR (151 MHz, CDCl 3) δ 166.0, 141.3, 139.9, 131.6, 128.2, 121.3, 121.0, 110.9, 83.9, 51.4, 25.3, 18.4, 13.0; HRMS (m/z): calcd C 25H 41BNO 4Si [M+H] ; found methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(triisopropylsilyl)-1H-indole (8a) Using L3 as ligand, 8a was obtained as the major product (totally 31.0 mg, 75% yield, a 9:1 mixture of C6 and C5 products). Physical state: slightly yellow oil; TLC: R f = 0.65 (8:1 hexanes/etoac); 1 H NMR (600 MHz, CDCl 3) δ 7.92 (s, 1H), 7.55 (dd, J = 3.1, 0.8 Hz, 2H), 7.06 (s, 1H), 2.32 (d, J = 1.1 Hz, 3H), 1.70 (dq, J = 15.5, 7.7 Hz, 3H), 1.35 (s, 12H), 1.15 (d, J = 7.5 Hz, 18H); 13 C NMR (151 MHz, CDCl 3) δ 141.3, 134.6, 130.2, 125.5, 121.0, 118.2, 113.8, 83.6, 25.3, 18.6, 13.2, 10.1; S15

16 HRMS(m/z) calcd C 24H 41BNO 2Si [M+H] ; found (2-((tert-butyldimethylsilyl)oxy)ethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- (triisopropylsilyl)-1h-indole (9a) Using L3 as ligand, 9a was obtained as the major product (totally 45.1 mg, 81% yield, a 8:1 mixture of C6 and C5 products). Physical state: slightly yellow oil; TLC: R f = 0.55 (8:1 hexanes/etoac); 1 H NMR (600 MHz, CDCl 3) δ 7.92 (s, 1H), (m, 2H), 7.13 (s, 1H), 3.87 (t, J = 7.0 Hz, 2H), 2.97 (t, J = 5.6 Hz, 2H), (m, 3H), 1.35 (s, 12H), 1.14 (d, J = 7.7Hz, 18H), 0.88 (d, J = 2.6 Hz, 9H), 0.01 (s, 3H), 0.01 (s, 3H); 13 C NMR (151 MHz, CDCl 3) δ 141.2, 134.0, 130.8, 125.5, 121.1, 118.2, 115.4, 83.6, 64.1, 29.4, 26.4, 25.2, 18.6, 13.2; HRMS (m/z): calcd C 31H 57BNO 3Si [M+H] ; found [M+H] (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(triisopropylsilyl)-1,2,3,4- tetrahydrocyclopenta[b]indole (10a) Using L3 as ligand, 10a was obtained as the major product (totally 33.4 mg, 76% yield, a 6:1 mixture of C6 and C5 products). Physical state: slightly yellow oil; S16

17 TLC: R f = 0.65 (8:1 hexanes/etoac); 1 H NMR (600 MHz, CDCl 3) δ 7.97 (s, 1H), 7.50 (d, J = 5.4 Hz, 1H), 7.39 (d, J = 5.4 Hz, 1H), 2.98 (q, J = 7.4 Hz, 2H), 2.78 (t, J = 7.1 Hz, 2H), 2.48 (h, J = 6.8, 6.1 Hz, 2H), (m, 3H), 1.35 (s, 12H), 1.14 (d, J = 8.0 Hz, 18H); 13 C NMR (151 MHz, CDCl 3) δ 151.7, 146.7, 130.2, 125.9, 124.0, 121.8, 117.7, 114.4, 83.5, 30.0, 28.8, 25.2, 23.7, 18.7, 13.5; HRMS (m/z): calcd C 26H 43BNO 2Si [M+H] ; found (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(triisopropylsilyl)-1H-indole-3-carbonitrile (11a) Using L3 as ligand, 11a was obtained as the major product (totally 22.9 mg, 54% yield, a 8:1 mixture of C6 and C5 products). Physical state: white foam; TLC: R f = 0.55 (8:1 hexanes/etoac); 1 H NMR (600 MHz, CDCl 3) δ 7.97 (d, J = 0.9 Hz, 1H), 7.77 (s, 1H), 7.75 (dd, J = 7.9, 0.7 Hz, 1H), 7.70 (dd, J = 7.9, 0.8 Hz, 1H), (m, 3H), 1.35 (s, 12H), 1.15 (d, J = 7.6 Hz, 18H); 13 C NMR (151 MHz, CDCl 3) δ 140.1, 139.8, 132.4, 128.2, 121.4, 119.1, 116.2, 89.7, 83.9, 25.1, 18.1, 12.8; HRMS (m/z): calcd C 24H 38BN 2O 2Si [M + H] , found (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9-(triisopropylsilyl)-9H-carbazole (13a) Using L3 as ligand, 13a was obtained as the major product (totally 38.6 mg, 67% yield). S17

18 Physical state: slightly yellow oil; TLC: R f = 0.50 (8:1 hexanes/etoac); 1 H NMR (600 MHz, CDCl 3) δ 8.19 (s, 1H), 8.08 (d, J = 7.7 Hz, 1H), 7.66 (d, J = 7.7Hz, 1H), (m, 3H), 1.37 (s, 12H), 1.21 (d, J = 7.5 Hz, 18H); 13 C NMR (151 MHz, CDCl 3) δ 145.4, 132.5, 128.9, 125.6, 121.3, 119.7, 25.3, 19.0, 14.0; HRMS (m/z): calcd C 33H 52B 2NO 4Si [M+H] ; found ethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9-(triisopropylsilyl)-9H-carbazole (14a) Using L3 as ligand, 14a was obtained as the major product (totally 42.6 mg, 89% yield, a 5.5:1 mixture of C7 and C6 products). Physical state: slightly yellow oil; TLC: R f = 0.45 (8:1 hexanes/etoac); 1 H NMR (600 MHz, CDCl 3) δ 8.16 (t, J = 2.3 Hz, 1H), (m, 1H), 7.91 (d, J = 2.9 Hz, 1H), 7.65 (dt, J = 8.3, 4.6 Hz, 1H), (m, 1H), (m, 1H), 2.82 (q, J = 8.1 Hz, 2H), 2.00 (dtt, J = 15.7, 7.9, 3.4 Hz, 3H), (m, 15H), 1.20 (q, J = 7.0 Hz, 18H); 13 C NMR (151 MHz, CDCl 3) δ 145.2, 144.2, 135.6, 131.8, 129.1, , 126.5, , , , , , 28.92, 25.30, 18.99, 16.43, 14.08; HRMS (m/z): calcd C 29H 45BNO 2Si [M+H] ; found S18

19 Structure Determination for the mixture of 14a and 14b Figure S5. 1 H NMR for mixture 14a and 14b ( ppm) S19

20 Figure S6. HN-HMBC for mixture 14a and 14b methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- (triisopropylsilyl)-1h-indol-3-yl)propanoate (6) Gram-scale preparation procedure: The largest scale for this borylation was carried out on a 10 gram (21.1 mmol) scale. The procedure was the same as described above. In this reaction, [Ir(cod)(OMe)] 2 (669 mg, 1.05 mmol, 5 mol%), 1,10-phenanthroline (379 mg, 2.10 mmol, 10 mol%), HBPin (765 µl, 5.27 mmol, 25 mol%), B 2Pin 2 (21.42 g) and hexanes (70 ml) were used. Silica gel chromatography yielded compounds 6 and 5 as an inseparable mixture (8.86 g, 6:5 = 8:1) in 70% yield. S20

21 Physical state: pale red oil; TLC: R f = 0.46 (8:1 hexanes/etoac); Optical rotation: 20 D = º (c = 0.09, CDCl 3); 1 H NMR (500 MHz, CDCl 3) δ 7.92 (s, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.08 (s, 1H), 5.04 (d, J = 8.1 Hz, 1H), (m, 1H), 3.62 (s, 3H); 3.27 (d, J = 5.5 Hz, 2H), (m, 3H), 1.43 (s, J = 6.3 Hz, 9H), 1.35 (s, 12H), 1.13 (d, J = 7.2 Hz, 18H); 13 C NMR (151 MHz, CDCl 3) δ 172.7, 155.2, 141.0, 133.6, 131.4, 125.7, 121.0, 118.0, 113.5, 112.2, 83.5, 79.8, 54.3, 52.3, 28.5, 28.1, 25.0, 18.3, 13.0; HRMS (m/z): calcd for C 32H 54BN 2O 6Si [M+H] ; found (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(6-methoxy-1-(triisopropylsilyl)-1H-indol-3- yl)propanoate (23) The 6-borylated tryptophan methyl ester 6 (3.2 g, 5.33 mmol, containing C5-borylated tryptophan) was dissolved in MeOH (50 ml) followed by the addition of Cu(OAc) 2 (2.1 g, mmol) and Et 3N (2.97 ml, mmol). Oxygen was bubbled into the flask for hours at ambient temperature. The solution was filtered through a coarse sintered glass frit and concentrated in vacuo. The crude residue was purified by silica gel chromatography (1:20 1:4, EtOAc/hexanes) to give 6-methoxy tryptophan methyl ester 23 (2.15 g, 90% yield). Physical state: yellow oil; TLC: R f = 0.45 (8:1 hexanes/etoac); Optical rotation: 20 D = º (c = 0.13, EtOAc); S21

22 1 H NMR (500 MHz, CDCl 3) δ 7.39 (d, J = 8.6 Hz, 1H), 6.98 (d, J = 2.2 Hz, 1H), 6.91 (s, 1H), 6.79 (dd, J = 8.7, 2.2 Hz, 1H), 5.05 (d, J = 8.2 Hz, 1H), 4.62 (d, J = 8.1 Hz, 1H), 3.83 (s, 3H), 3.63 (s, 3H), 3.23 (d, J = 5.6 Hz, 2H), (m, 3H), 1.50 (s, 9H), 1.14 (dd, J = 7.6, 2.0 Hz, 18H); 13 C NMR (126 MHz, CDCl 3) δ 172.9, 156.2, 155.3, 142.2, 128.7, 125.7, 119.1, 112.1, 108.8, 98.7, 79.9, 56.0, 54.2, 52.3, 28.5, 28.5, 18.3, 13.0; HRMS (m/z): calcd for C 27H 44N 2O 5SiNa [M+Na] ; found One Pot Synthesis of 6-methoxy N-TIPS, N-Boc tryptophan methyl ester (23) from N-TIPS, N-Boc tryptophan methyl ester (4) One-Pot Procedure: Hexanes were freshly distilled over CaH 2 before use. The catalyst [Ir(cod)(OMe)] 2 (33 mg, 5 mol%), 1,10-phenanthorline (18.8 mg, 10 mol%), and B 2Pin 2 (1.02 g, mmol) were placed in an oven-dried vial under an argon atmosphere. Hexanes (18 ml) were added, followed by the addition of HBPin (36 μl, 25 mol%) A solution of substrate 4 (1.50 g, 3.16 mmol) in hexanes (10 ml, 0.1 M) was then added to the vial, followed by the addition of HBpin (36 μl, 25 mol%). The vial was sealed with parafilm and stirred for 24 h at 80 o C. During the process, the green solution turned black. The reaction mixture was poured into a round-bottomed flask and concentrated in vacuo. The crude residue was then dissolved in MeOH (40 ml) followed by the addition of Cu(OAc) 2 (1.26 g, 6.32 mmol) and Et 3N (1.76 ml, mmol). Oxygen was bubbled into the flask for 36 hours at ambient temperature. The solution was filtered through celite to remove the solids and concentrated in vacuo. The crude residue was purified by silica gel chromatography (5% 20%, EtOAc/hexanes) to yield 23 as the major product (totally 1.08 g, 65% yield, a 8:1 mixture of C6 and C5 products). S22

23 Scheme S1. Synthesis of aldehyde 24 Procedures: ((4,4-diethoxy-2-methylbutan-2-yl)peroxy)triethylsilane (S1) To a solution of 3-methylbut-2-enal (20, 5.0 g, 59.4 mmol) in EtOH (17.5 ml) was added KHSO 4 (0.4 g, 2.97 mmol) followed by (EtO) 3CH (8.8 g, 59.4 mmol) at 0 o C. The mixture was allowed to stirred for 30 minutes at 0 o C and was then stirred for an additional 30 minutes at ambient temperature. After filtration through a coarse sintered glass frit, the solids were washed with EtOH (3 ml). K 2CO 3 was then added and the mixture was stirred for 2 hours at ambient temperature. The solution was then filtered through a coarse sintered glass frit and concentrated in vacuo. The crude liquid was used for next step without further purification. (The crude compound can be stored over K 2CO 3 for a couple of months.) Oxygen was bubbled through a solution of above compound (1.0 g, 6.32 mmol), Co(modp) 2 (341 mg, mmol, 10 mol%), and triethylsilane (3.0 ml, mmol) in 1,2-dichloroethane for 1 hour. The reaction mixture was then stirred under static oxygen pressure for 24 hours. The mixture was then concentrated in vacuo, placed on high vacuum for 1 hour, and then purified immediately by silica gel chromatography (hexanes to 2% hexanes/etoac) to give TES-peroxide S1 (1.42 g, 73%). S23

24 Note: the catalyst Co(modp) 2 was prepared according to the literature: Wang et al. Can. J. Chem. 2009, 87, 328. Physical state: colorless oil; TLC: R f = 0.65 (10% EtOAc/hexanes); 1 H NMR (400 MHz, C 6D 6) δ 4.83 (t, J = 5.5 Hz, 1H), 3.58 (dq, J = 9.1, 7.0 Hz, 2H), 3.43 (dq, J = 9.2, 7.1 Hz, 2H), 2.16 (d, J = 5.2, 2H), 1.33 (s, 3H), 1.13 (t, J = 7.1 Hz, 6H), 1.05 (t, J = 8.0 Hz, 9H), 0.73 (q, J = 8.0 Hz, 6H); 13 C NMR (101 MHz, C 6D 6) δ 100.6, 81.7, 60.7, 42.6, 25.2, 15.6, 7.1, 4.3; HRMS (m/z): calcd for C 15H 34O 4SiNa [M+Na] , found tert-butyl((4,4-diethoxy-2-methylbutan-2-yl)peroxy)diphenylsilane (S2) TBAF (6.13 ml, 1.0 M in THF) was added to the TES-peroxide (S1, 1.88 g, 6.13 mmol) in THF (61 ml, 0.1 M) at 0 ºC. The reaction was complete in less than 15 minutes and was diluted with Et 2O (120 ml) and washed with NH 4Cl (sat. aq.). The aqueous phase was extracted with Et 2O (60 ml 3). The organic phases were combined, washed with brine, dried over MgSO 4, and concentrated in vacuo. The free peroxide was then dissolved in CH 2Cl 2. To this mixture was added imidazole (0.626 g, 9.20 mmol) and TBDPSi-Cl (2.07 ml, 1.3 equiv). The reaction as stirred for 4 hours and then the solids were removed by filtration. The crude material was concentrated in vacuo and purified by silica gel chromatography (0 2% EtOAc/hexanes) to afford the TBDPS-protected peroxide S2 (2.23g, 84%). Physical state: colorless oil; TLC: R f = 0.60 (10% EtOAc/hexanes); S24

25 1 H NMR (500 MHz, C 6D 6) δ (m, 4H), (m, 6H), 4.71 (t, J = 5.1 Hz, 1H), 3.50 (dq, J = 9.3, 7.0 Hz, 2H), 3.32 (dq, J = 9.3, 7.1 Hz, 2H), 2.10 (d, J = 5.1 Hz, 2H), 1.26 (s, 6H), 1.24 (s, 9H), 1.08 (t, J = 7.1 Hz, 6H); 13 C NMR (126 MHz, C 6D 6) δ 136.4, 133.7, 130.1, 127.9, 100.5, 82.7, 60.8, 42.9, 27.7, 25.2, 19.8, 15.6; HRMS (m/z): calcd for C 25H 38O 4SiNa [M+Na] , found ((tert-butyldiphenylsilyl)peroxy)-3-methylbutanal (24) TFA (181 µl, 2.37 mmol) was added to a stirred solution of diethyl acetal (680 mg, 1.58 mmol) and H 2O (1.14 ml, 63.2 mmol) in CHCl 3 (15.8 ml). After three hours, the reaction was quenched with NaHCO 3 (sat. aq.) and extracted with EtOAc (10 ml 3). The organic phase was separated, washed with brine, dried over Na 2SO 4, and concentrated in vacuo. The crude aldehyde was used immediately without further purification (560 mg, 100%). Physical state: colorless oil; TLC: R f = 0.50 (10% EtOAc/hexanes); 1 H NMR (400 MHz, C 6D 6) δ 9.60 (t, J = 2.7 Hz, 1H), (m, 4H), (m, 6H), 2.29 (d, J = 2.7 Hz, 2H), 1.19 (s, 9H), 1.01 (s, 6H). Scheme S2. Endoperoxide formation on model substrate S25

26 methyl (1S,3S)-1-(2-((tert-butyldiphenylsilyl)peroxy)-2-methylpropyl)-2,3,4,9-tetrahydro-1Hpyrido[3,4-b]indole-3-carboxylate (S4) Aldehyde 24 (462 mg, 1.3 mmol), L-tryptophan methyl ester (S3, 218 mg, 1.0 mmol), and 3 Å molecular sieves (300 mg) were stirred in CHCl 3 (10 ml) under argon for an hour. Then TFA (1.15 ml, 15.0 mmol) was added quickly. The reaction was stirred for 30 minutes and slowly quenched with NaHCO 3 (sat. aq. 10 ml). The biphasic mixture was filtered through a coarse sintered glass frit and then the aqueous phase was extracted with CH 2Cl 2 (10 ml 3). The combined organic phases were then dried over MgSO 4 and concentrated in vacuo. The crude residue was used in the next step without further purification. S26

27 methyl 1H-pyrido[3,4-b]indole-3-carboxylate (S5) Acetyl chloride (130 µl, 5 equiv) was added to a vigorously stirred solution of amine S4 in CH 2Cl 2 (3.6 ml, 0.1 M) and sat. aq. NaHCO 3 (3.6 ml, 0.1 M). The reaction was stirred for 14 hours and the phases were separated. The aqueous phase was extracted with CH 2Cl 2 (4 ml 3), and the organic layers were combined, dried over MgSO 4, and concentrated in vacuo. The crude compound was purified by silica gel chromatography (15% 30% EtOAc/hexanes) to afford amide S5 (186 mg, 87%). Physical state: white solid foam; TLC: R f= 0.75 (50% EtOAc/hexanes); Optical rotation: 20 D = (c = 0.85, EtOAc); 1 H NMR (500 MHz, CDCl 3) δ 7.83 (t, J = 7.6 Hz, 4H), 7.71 (s, 1H), (m, 4H), 7.40 (q, J = 7.6, 6.1 Hz, 3H), (m, 2H), (m, 1H), 5.03 (s, 1H), 3.91 (dd, J = 11.2, 4.0 Hz, 1H), 3.75 (s, 3H), 3.23 (dd, J = 15.7, 11.2 Hz, 1H), 2.93 (dd, J = 15.8, 4.1 Hz, 1H), 2.33 (dd, J = 15.0, 4.3 Hz, 1H), (m, 1H), 1.89 (s, 3H), 1.39 (s, 3H), 1.28 (s, 3H), 1.24 (s, 9H); 13 C NMR (151 MHz, CDCl 3) δ 171.3, 170.5, 136.1, 136.0, 135.9, 134.7, 132.3, 132.2, 130.7, 130.7, 128.3, 128.2, 126.6, 122.1, 119.7, 118.2, 111.1, 108.6, 83.2, 54.1, 52.3, 51.7, 45.1, 27.5, 26.7, 24.2, 22.0, 21.9, 19.8; HRMS (m/z): calcd for C 35H 43N 2O 5Si [M + H] , found methyl (1S,3S)-2-acetyl-1-(2-((tert-butyldiphenylsilyl)peroxy)-2-methylpropyl)-2,3,4,9-tetrahydro- (1S,3S)-2-acetyl-1-(2-hydroperoxy-2-methylpropyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-3-carboxylate (19a) S27

28 TBAF (0.22 ml, 1 M in THF) was added to a solution of protected peroxide S5 (130 mg, 0.22 mmol) and AcOH (12.6 µl, 1 equiv) in DMF (4.4 ml, 0.05 M) at 0 ºC. The reaction was done within 5 minutes and H 2O (10 ml) and EtOAc (10 ml) were added. The aqueous phase was extracted with EtOAc (5 ml 3). The organic phases were combined, dried over MgSO 4, washed sequentially with H 2O and NaCl (sat. aq.), and concentrated in vacuo. The crude mixture was purified by silica gel chromatography (30% 50% EtOAc/hexanes) to afford free peroxide 19a (67 mg, 85%). Physical state: white solid; TLC: R f = 0.20 (50% EtOAc/hexanes); Optical rotation: 20 D = (c = 0.27, EtOAc); 1 H NMR (600 MHz, CDCl 3) δ 9.27 (s, 1H), 7.95 (s, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 5.19 (d, J = 9.8 Hz, 1H), 4.11 (dd, J = 11.8, 3.8 Hz, 1H), 3.84 (s, 3H), (m, 1H), (m, 1H), 2.59 (dd, J = 15.6, 10.0 Hz, 1H), 2.25 (s, 3H), 1.88 (d, J = 15.6 Hz, 1H), 1.43 (d, J = 1.7 Hz, 6H); 13 C NMR (151 MHz, CDCl 3) δ 172.6, 171.0, 136.5, 133.6, 126.8, 122.8, 120.3, 118.6, 111.1, 110.3, 81.5, 53.7, 52.9, 41.8, 29.9, 25.9, 24.7, 22.8, 22.3; HRMS calcd for C 19H 25N 2O 5 [M + H] , found X-ray crystallographic data for 19a: Table S3. Crystal data and structure refinement for CCDC # S28

29 Identification code Empirical formula C19 H24 N2 O5 Formula weight Temperature 100(2) K Crystal system Monoclinic Space group P2(1) Unit cell dimensions a = (4) Å b = (4) Å c = (5) Å Volume (4) Å 3 Z 2 Z, Z Z: 0 Z': 0 Unit cell angles α = β = (2) γ = Theta range for data collection 4.55 to Absorption correction Multi-scan Table S4. Bond lengths [Å] for CCDC # Number Atom1 Atom2 Type Polymeric Cyclicity Length SybylType 1 O1 C1 Unknown no acyclic 1.438(2) 1 2 O1 C2 Unknown no acyclic 1.347(2) 1 3 O2 C2 Unknown no acyclic 1.194(2) 2 4 O3 C14 Unknown no acyclic 1.237(2) 2 5 O4 O5 Unknown no acyclic 1.463(2) 1 6 O4 C17 Unknown no acyclic 1.436(2) 1 7 O5 H5 Unknown no acyclic 0.87(3) 1 8 N1 H1 Unknown no acyclic 0.88(2) 1 9 N1 C11 Unknown no cyclic 1.381(2) 1 10 N1 C12 Unknown no cyclic 1.381(2) 1 11 N2 C3 Unknown no cyclic 1.467(2) 1 12 N2 C13 Unknown no cyclic 1.492(2) 1 13 N2 C14 Unknown no acyclic 1.360(2) un 14 C1 H1A Unknown no acyclic C1 H1B Unknown no acyclic S29

30 16 C1 H1C Unknown no acyclic C2 C3 Unknown no acyclic 1.530(2) 1 18 C3 H3A Unknown no acyclic C3 C4 Unknown no cyclic 1.532(3) 1 20 C4 H4A Unknown no acyclic C4 H4B Unknown no acyclic C4 C5 Unknown no cyclic 1.485(2) 1 23 C5 C6 Unknown no cyclic 1.434(3) un 24 C5 C12 Unknown no cyclic 1.359(2) un 25 C6 C7 Unknown no cyclic 1.403(2) un 26 C6 C11 Unknown no cyclic 1.407(2) un 27 C7 H7A Unknown no acyclic C7 C8 Unknown no cyclic 1.383(3) un 29 C8 H8A Unknown no acyclic C8 C9 Unknown no cyclic 1.404(2) un 31 C9 H9A Unknown no acyclic C9 C10 Unknown no cyclic 1.381(3) un 33 C10 H10A Unknown no acyclic C10 C11 Unknown no cyclic 1.395(3) un 35 C12 C13 Unknown no cyclic 1.501(3) 1 36 C13 H13A Unknown no acyclic C13 C16 Unknown no acyclic 1.556(2) 1 38 C14 C15 Unknown no acyclic 1.506(2) 1 39 C15 H15A Unknown no acyclic C15 H15B Unknown no acyclic C15 H15C Unknown no acyclic C16 H16A Unknown no acyclic C16 H16B Unknown no acyclic C16 C17 Unknown no acyclic 1.536(2) 1 45 C17 C18 Unknown no acyclic 1.527(2) 1 46 C17 C19 Unknown no acyclic 1.519(3) 1 47 C18 H18A Unknown no acyclic C18 H18B Unknown no acyclic C18 H18C Unknown no acyclic C19 H19A Unknown no acyclic C19 H19B Unknown no acyclic C19 H19C Unknown no acyclic S30

31 Table S5. Bond angles [deg] for CCDC # Number Atom1 Atom2 Atom3 Angle 1 C1 O1 C (1) 2 O5 O4 C (1) 3 O4 O5 H5 95(2) 4 H1 N1 C11 125(1) 5 H1 N1 C12 126(1) 6 C11 N1 C (1) 7 C3 N2 C (1) 8 C3 N2 C (1) 9 C13 N2 C (1) 10 O1 C1 H1A O1 C1 H1B O1 C1 H1C H1A C1 H1B H1A C1 H1C H1B C1 H1C O1 C2 O (2) 17 O1 C2 C (1) 18 O2 C2 C (2) 19 N2 C3 C (1) 20 N2 C3 H3A N2 C3 C (1) 22 C2 C3 H3A C2 C3 C (1) 24 H3A C3 C C3 C4 H4A C3 C4 H4B C3 C4 C (1) 28 H4A C4 H4B H4A C4 C H4B C4 C C4 C5 C (2) 32 C4 C5 C (2) 33 C6 C5 C (1) 34 C5 C6 C (2) 35 C5 C6 C (1) S31

32 36 C7 C6 C (2) 37 C6 C7 H7A C6 C7 C (2) 39 H7A C7 C C7 C8 H8A C7 C8 C (2) 42 H8A C8 C C8 C9 H9A C8 C9 C (2) 45 H9A C9 C C9 C10 H10A C9 C10 C (2) 48 H10A C10 C N1 C11 C (1) 50 N1 C11 C (2) 51 C6 C11 C (2) 52 N1 C12 C (1) 53 N1 C12 C (1) 54 C5 C12 C (2) 55 N2 C13 C (1) 56 N2 C13 H13A N2 C13 C (1) 58 C12 C13 H13A C12 C13 C (1) 60 H13A C13 C O3 C14 N (2) 62 O3 C14 C (2) 63 N2 C14 C (2) 64 C14 C15 H15A C14 C15 H15B C14 C15 H15C H15A C15 H15B H15A C15 H15C H15B C15 H15C C13 C16 H16A C13 C16 H16B C13 C16 C (1) S32

33 73 H16A C16 H16B H16A C16 C H16B C16 C O4 C17 C (1) 77 O4 C17 C (1) 78 O4 C17 C (1) 79 C16 C17 C (1) 80 C16 C17 C (1) 81 C18 C17 C (1) 82 C17 C18 H18A C17 C18 H18B C17 C18 H18C H18A C18 H18B H18A C18 H18C H18B C18 H18C C17 C19 H19A C17 C19 H19B C17 C19 H19C H19A C19 H19B H19A C19 H19C H19B C19 H19C Table S6. Atoms Information for CCDC # Number Label Charge SybylType Xfrac + ESD Yfrac + ESD Zfrac + ESD Symm. op. 1 O1 0 O (15) (13) (10) x,y,z 2 O2 0 O (17) (14) (12) x,y,z 3 O3 0 O (15) (13) (11) x,y,z 4 O4 0 O (15) (15) (11) x,y,z 5 O5 0 O (17) (16) (12) x,y,z 6 H5 0 H 1.148(3) 0.932(3) 0.878(2) x,y,z 7 N1 0 N (18) (16) (12) x,y,z 8 H1 0 H 0.865(2) 0.912(2) (15) x,y,z 9 N2 0 N.am (17) (16) (12) x,y,z 10 C1 0 C (2) (2) (17) x,y,z 11 H1A 0 H x,y,z 12 H1B 0 H x,y,z S33

34 13 H1C 0 H x,y,z 14 C2 0 C (2) (19) (15) x,y,z 15 C3 0 C (2) (18) (15) x,y,z 16 H3A 0 H x,y,z 17 C4 0 C (2) (19) (15) x,y,z 18 H4A 0 H x,y,z 19 H4B 0 H x,y,z 20 C5 0 C (2) (18) (14) x,y,z 21 C6 0 C (2) (18) (14) x,y,z 22 C7 0 C (2) (2) (14) x,y,z 23 H7A 0 H x,y,z 24 C8 0 C (2) (2) (15) x,y,z 25 H8A 0 H x,y,z 26 C9 0 C (2) (2) (16) x,y,z 27 H9A 0 H x,y,z 28 C10 0 C (2) (2) (16) x,y,z 29 H10A 0 H x,y,z 30 C11 0 C (2) (19) (14) x,y,z 31 C12 0 C (2) (17) (14) x,y,z 32 C13 0 C (2) (18) (14) x,y,z 33 H13A 0 H x,y,z 34 C14 0 C (2) (19) (14) x,y,z 35 C15 0 C (2) (2) (17) x,y,z 36 H15A 0 H x,y,z 37 H15B 0 H x,y,z 38 H15C 0 H x,y,z 39 C16 0 C (2) (18) (14) x,y,z 40 H16A 0 H x,y,z 41 H16B 0 H x,y,z 42 C17 0 C (2) (19) (14) x,y,z 43 C18 0 C (2) (2) (15) x,y,z 44 H18A 0 H x,y,z 45 H18B 0 H x,y,z 46 H18C 0 H x,y,z 47 C19 0 C (2) (2) (16) x,y,z 48 H19A 0 H x,y,z 49 H19B 0 H x,y,z S34

35 50 H19C 0 H x,y,z Table S7. Crystal atoms torsion for CCDC # Number Atom1 Atom2 Atom3 Atom4 Torsion 1 C2 O1 C1 H1A C2 O1 C1 H1B C2 O1 C1 H1C C1 O1 C2 O2-1.8(2) 5 C1 O1 C2 C (1) 6 C17 O4 O5 H5 166(2) 7 O5 O4 C17 C (1) 8 O5 O4 C17 C (2) 9 O5 O4 C17 C (2) 10 H1 N1 C11 C6 172(1) 11 H1 N1 C11 C10-7(1) 12 C12 N1 C11 C6 2.8(2) 13 C12 N1 C11 C (2) 14 H1 N1 C12 C5-172(1) 15 H1 N1 C12 C13 12(1) 16 C11 N1 C12 C5-2.8(2) 17 C11 N1 C12 C (2) 18 C13 N2 C3 C2 71.3(2) 19 C13 N2 C3 H3A C13 N2 C3 C4-54.9(2) 21 C14 N2 C3 C2-97.8(2) 22 C14 N2 C3 H3A C14 N2 C3 C (2) 24 C3 N2 C13 C (2) 25 C3 N2 C13 H13A C3 N2 C13 C (2) 27 C14 N2 C13 C (1) 28 C14 N2 C13 H13A C14 N2 C13 C (2) 30 C3 N2 C14 O (2) 31 C3 N2 C14 C15-3.5(2) 32 C13 N2 C14 O3 6.5(2) S35

36 33 C13 N2 C14 C (1) 34 O1 C2 C3 N2 44.8(2) 35 O1 C2 C3 H3A O1 C2 C3 C (1) 37 O2 C2 C3 N (2) 38 O2 C2 C3 H3A O2 C2 C3 C4-12.5(3) 40 N2 C3 C4 H4A N2 C3 C4 H4B N2 C3 C4 C5 45.0(2) 43 C2 C3 C4 H4A C2 C3 C4 H4B C2 C3 C4 C5-81.1(2) 46 H3A C3 C4 H4A H3A C3 C4 H4B H3A C3 C4 C C3 C4 C5 C (2) 50 C3 C4 C5 C (2) 51 H4A C4 C5 C H4A C4 C5 C H4B C4 C5 C H4B C4 C5 C C4 C5 C6 C7-4.1(3) 56 C4 C5 C6 C (2) 57 C12 C5 C6 C (2) 58 C12 C5 C6 C11 0.1(2) 59 C4 C5 C12 N (2) 60 C4 C5 C12 C13-0.7(3) 61 C6 C5 C12 N1 1.7(2) 62 C6 C5 C12 C (2) 63 C5 C6 C7 H7A C5 C6 C7 C (2) 65 C11 C6 C7 H7A C11 C6 C7 C8 0.9(3) 67 C5 C6 C11 N1-1.8(2) 68 C5 C6 C11 C (2) 69 C7 C6 C11 N (2) S36

37 70 C7 C6 C11 C10-0.7(3) 71 C6 C7 C8 H8A C6 C7 C8 C9-0.4(3) 73 H7A C7 C8 H8A H7A C7 C8 C C7 C8 C9 H9A C7 C8 C9 C10-0.3(3) 77 H8A C8 C9 H9A H8A C8 C9 C C8 C9 C10 H10A C8 C9 C10 C11 0.5(3) 81 H9A C9 C10 H10A H9A C9 C10 C C9 C10 C11 N (2) 84 C9 C10 C11 C6 0.0(3) 85 H10A C10 C11 N H10A C10 C11 C N1 C12 C13 N (1) 88 N1 C12 C13 H13A N1 C12 C13 C (2) 90 C5 C12 C13 N2-3.0(2) 91 C5 C12 C13 H13A C5 C12 C13 C (2) 93 N2 C13 C16 H16A N2 C13 C16 H16B N2 C13 C16 C (1) 96 C12 C13 C16 H16A C12 C13 C16 H16B C12 C13 C16 C (2) 99 H13A C13 C16 H16A H13A C13 C16 H16B H13A C13 C16 C O3 C14 C15 H15A O3 C14 C15 H15B O3 C14 C15 H15C N2 C14 C15 H15A N2 C14 C15 H15B 59.2 S37

38 107 N2 C14 C15 H15C C13 C16 C17 O4-74.5(2) 109 C13 C16 C17 C (1) 110 C13 C16 C17 C (2) 111 H16A C16 C17 O H16A C16 C17 C H16A C16 C17 C H16B C16 C17 O H16B C16 C17 C H16B C16 C17 C O4 C17 C18 H18A O4 C17 C18 H18B O4 C17 C18 H18C C16 C17 C18 H18A C16 C17 C18 H18B C16 C17 C18 H18C C19 C17 C18 H18A C19 C17 C18 H18B C19 C17 C18 H18C O4 C17 C19 H19A O4 C17 C19 H19B O4 C17 C19 H19C C16 C17 C19 H19A C16 C17 C19 H19B C16 C17 C19 H19C C18 C17 C19 H19A C18 C17 C19 H19B C18 C17 C19 H19C S38

39 methyl (2S,3aS,8R)-3-acetyl-5,5-dimethyl-8-(2-methylprop-1-en-1-yl)-1,2,3,3a,4,5-hexahydro-8H- 6,7-dioxa-3,8a-diazacycloocta[jk]fluorene-2-carboxylate (21a) Free peroxide 19a (33.9 mg, mmol) was added to a stirred solution of 3-methyl-2-butenal (45 μl, 0.47 mmol) and 4 Å molecular sieves (20 mg). To this was added BF 3OEt 2 (94 μl, mmol) slowly, and the reaction was stirred at room temperature for 28 minutes. The acid was then quenched with a few drops of 1:1 Et 3N/MeOH and concentrated in vacuo. The crude mixture was purified by silica gel chromatography (2% 5%, CH 2Cl 2/Et 2O) to afford endoperoxide 21a (16.9 mg, 42%). Physical State: off white solid foam; TLC: R f= 0.45 (50% hexanes/etoac); Optical rotation: 1 H NMR (600 MHz, CDCl 3) 20 D = (c = 0.21, EtOAc); rotamer A: δ (m, 1H), (m, 2H), (m, 1H), 6.71 (dd, J = 7.9, 2.7 Hz, 1H), (m, 1H), (m, 1H), 4.92 (dd, J = 7.4, 1.3 Hz, 1H), 4.81 (dq, J = 7.9, 1.4 Hz, 1H), 4.69 (dp, J = 7.8, 1.3 Hz, 1H), 3.68 (s, 3H), 3.59 (dd, J = 15.7, 1.4 Hz, 1H), (m, 1H), 2.34 (s, 3H), 2.21 (dd, J = 14.3, 1.1 Hz, 1H), (m, 1H), 1.95 (s, 3H), 1.80 (dd, J = 13.7, 10.2 Hz, 1H), 1.71 (s, 3H), 1.05 (s, 3H); rotamer B: (m, 1H), (m, 2H), (m, 1H), 6.71 (dd, J = 7.9, 2.7 Hz, 1H), (m, 1H), (m, 1H), 4.92 (dd, J = 7.4, 1.3 Hz, 1H), 4.81 (dq, J = 7.9, 1.4 Hz, 1H), 4.69 (dp, J = 7.8, 1.3 Hz, 1H), 3.69 (s, 3H), 3.43 (dd, J = 15.9, 3.4 Hz, 1H), (m, 1H), 2.40 (s, 3H), 2.21 (dd, J = 14.3, 1.1 Hz, 1H), (m, 1H), 1.98 (s, 3H), 1.80 (dd, J = 13.7, 10.2 Hz, 1H), 1.70 (s, 3H), 1.09 (s, 3H). 13 C NMR (151 MHz, CDCl 3) rotamer A: δ 171.9, 170.9, 142.6, 136.5, 134.2, 127.7, 122.1, 119.9, 118.8, 118.4, 110.5, 106.3, 86.8, 81.8, 53.6, 52.6, 49.3, 47.4, 27.3, 25. 7, 24.0, 22.9, 21.7, 18.9; S39

40 rotamer B: δ 172.7, 170.2, 143.8, , 133.3, 127.4, 122.4, 120.1, 118.7, 118.4, 110.1, 107.5, 86.6, 81.2, 52.30, 51.4, 50.5, 49.1, 29.9, 27.4, 25.8, 24.7, 21.0, 19.0; HRMS (m/z): calcd for C 24H 31N 2O 5 [M+H] ; found X-ray crystallographic data for 21a: Table S8. Crystal data and structure refinement for CCDC # Identification code Empirical formula C24 H30 N2 O5 Formula weight Temperature 100(2) K Crystal system Monoclinic Space group P 1 Unit cell dimensions a = (3) Å b = (5) Å c = (5) Å Volume (4) Å 3 Z, Z Z: 0 Z': 0 Unit cell angles α = (2) β = (2) γ = (2) Absorption correction Multi-scan Table S9. Bond lengths [Å] for CCDC # Number Atom1 Atom2 Type Polymeric Cyclicity Length SybylType S40

41 1 O1' C1' Unknown no acyclic 1.450(3) 1 2 O1' C2' Unknown no acyclic 1.331(3) 1 3 O2' C2' Unknown no acyclic 1.195(3) 2 4 O3' C14' Unknown no acyclic 1.216(3) 2 5 O4' O5' Unknown no cyclic 1.474(2) 1 6 O4' C17' Unknown no cyclic 1.447(3) 1 7 O5' C20' Unknown no cyclic 1.405(3) 1 8 N1' C11' Unknown no cyclic 1.381(3) un 9 N1' C12' Unknown no cyclic 1.390(3) un 10 N1' C20' Unknown no cyclic 1.474(2) 1 11 N2' C3' Unknown no cyclic 1.467(2) 1 12 N2' C13' Unknown no cyclic 1.493(2) 1 13 N2' C14' Unknown no acyclic 1.350(4) un 14 C1' H1'A Unknown no acyclic C1' H1'B Unknown no acyclic C1' H1'C Unknown no acyclic C2' C3' Unknown no acyclic 1.527(3) 1 18 C3' H3' Unknown no acyclic C3' C4' Unknown no cyclic 1.524(4) 1 20 C4' H4'A Unknown no acyclic C4' H4'B Unknown no acyclic C4' C5' Unknown no cyclic 1.487(3) 1 23 C5' C6' Unknown no cyclic 1.431(4) un 24 C5' C12' Unknown no cyclic 1.360(2) un 25 C6' C7' Unknown no cyclic 1.400(4) un 26 C6' C11' Unknown no cyclic 1.405(2) un 27 C7' H7' Unknown no acyclic C7' C8' Unknown no cyclic 1.376(4) un 29 C8' H8' Unknown no acyclic C8' C9' Unknown no cyclic 1.394(3) un 31 C9' H9' Unknown no acyclic C9' C10' Unknown no cyclic 1.383(4) un 33 C10' H10' Unknown no acyclic C10' C11' Unknown no cyclic 1.401(4) un 35 C12' C13' Unknown no cyclic 1.504(4) 1 36 C13' H13' Unknown no acyclic C13' C16' Unknown no cyclic 1.552(3) 1 S41

42 38 C14' C15' Unknown no acyclic 1.510(3) 1 39 C15' H15D Unknown no acyclic C15' H15E Unknown no acyclic C15' H15F Unknown no acyclic C16' H16C Unknown no acyclic C16' H16D Unknown no acyclic C16' C17' Unknown no cyclic 1.515(2) 1 45 C17' C18' Unknown no acyclic 1.515(5) 1 46 C17' C19' Unknown no acyclic 1.534(4) 1 47 C18' H18D Unknown no acyclic C18' H18E Unknown no acyclic C18' H18F Unknown no acyclic C19' H19D Unknown no acyclic C19' H19E Unknown no acyclic C19' H19F Unknown no acyclic C20' H20' Unknown no acyclic C20' C21' Unknown no acyclic 1.502(3) 1 55 C21' H21' Unknown no acyclic C21' C22' Unknown no acyclic 1.320(3) un 57 C22' C23' Unknown no acyclic 1.505(4) 1 58 C22' C24' Unknown no acyclic 1.485(4) 1 59 C23' H23D Unknown no acyclic C23' H23E Unknown no acyclic C23' H23F Unknown no acyclic C24' H24D Unknown no acyclic C24' H24E Unknown no acyclic C24' H24F Unknown no acyclic Table S10. Bond angles [deg] for CCDC # Number Atom1 Atom2 Atom3 Angle 1 C1' O1' C2' 114.8(2) 2 O5' O4' C17' 105.9(2) 3 O4' O5' C20' 107.3(1) 4 C11' N1' C12' 107.6(2) 5 C11' N1' C20' 121.0(2) 6 C12' N1' C20' 129.4(2) S42

43 7 C3' N2' C13' 118.4(2) 8 C3' N2' C14' 123.5(2) 9 C13' N2' C14' 117.6(2) 10 O1' C1' H1'A O1' C1' H1'B O1' C1' H1'C H1'A C1' H1'B H1'A C1' H1'C H1'B C1' H1'C O1' C2' O2' 124.1(2) 17 O1' C2' C3' 111.4(2) 18 O2' C2' C3' 124.5(2) 19 N2' C3' C2' 112.0(2) 20 N2' C3' H3' N2' C3' C4' 110.5(2) 22 C2' C3' H3' C2' C3' C4' 111.8(2) 24 H3' C3' C4' C3' C4' H4'A C3' C4' H4'B C3' C4' C5' 109.7(2) 28 H4'A C4' H4'B H4'A C4' C5' H4'B C4' C5' C4' C5' C6' 128.3(2) 32 C4' C5' C12' 124.5(2) 33 C6' C5' C12' 107.2(2) 34 C5' C6' C7' 133.1(2) 35 C5' C6' C11' 106.7(2) 36 C7' C6' C11' 120.2(2) 37 C6' C7' H7' C6' C7' C8' 118.6(2) 39 H7' C7' C8' C7' C8' H8' C7' C8' C9' 120.8(2) 42 H8' C8' C9' C8' C9' H9' S43

44 44 C8' C9' C10' 122.0(3) 45 H9' C9' C10' C9' C10' H10' C9' C10' C11' 117.3(2) 48 H10' C10' C11' N1' C11' C6' 108.4(2) 50 N1' C11' C10' 130.6(2) 51 C6' C11' C10' 121.0(2) 52 N1' C12' C5' 110.1(2) 53 N1' C12' C13' 125.5(2) 54 C5' C12' C13' 124.3(2) 55 N2' C13' C12' 107.3(2) 56 N2' C13' H13' N2' C13' C16' 110.2(2) 58 C12' C13' H13' C12' C13' C16' 113.8(2) 60 H13' C13' C16' O3' C14' N2' 121.3(2) 62 O3' C14' C15' 120.7(2) 63 N2' C14' C15' 118.0(2) 64 C14' C15' H15D C14' C15' H15E C14' C15' H15F H15D C15' H15E H15D C15' H15F H15E C15' H15F C13' C16' H16C C13' C16' H16D C13' C16' C17' 118.2(2) 73 H16C C16' H16D H16C C16' C17' H16D C16' C17' O4' C17' C16' 111.3(2) 77 O4' C17' C18' 111.2(2) 78 O4' C17' C19' 100.7(2) 79 C16' C17' C18' 112.9(2) 80 C16' C17' C19' 109.5(2) S44

45 81 C18' C17' C19' 110.5(2) 82 C17' C18' H18D C17' C18' H18E C17' C18' H18F H18D C18' H18E H18D C18' H18F H18E C18' H18F C17' C19' H19D C17' C19' H19E C17' C19' H19F H19D C19' H19E H19D C19' H19F H19E C19' H19F O5' C20' N1' 111.1(2) 95 O5' C20' H20' O5' C20' C21' 103.7(2) 97 N1' C20' H20' N1' C20' C21' 111.3(2) 99 H20' C20' C21' C20' C21' H21' C20' C21' C22' 126.7(2) 102 H21' C21' C22' C21' C22' C23' 120.8(2) 104 C21' C22' C24' 124.9(3) 105 C23' C22' C24' 114.3(3) 106 C22' C23' H23D C22' C23' H23E C22' C23' H23F H23D C23' H23E H23D C23' H23F H23E C23' H23F C22' C24' H24D C22' C24' H24E C22' C24' H24F H24D C24' H24E H24D C24' H24F H24E C24' H24F S45

46 Table S11. Atoms Information for CCDC # Number Label Charge SybylType Xfrac + ESD Yfrac + ESD Zfrac + ESD Symm. op. 1 O1' 0 O (17) (14) (14) x,y,z 2 O2' 0 O (18) (15) (14) x,y,z 3 O3' 0 O (2) (2) (17) x,y,z 4 O4' 0 O (19) (14) (14) x,y,z 5 O5' 0 O (16) (13) (13) x,y,z 6 N1' 0 N.am (19) (15) (15) x,y,z 7 N2' 0 N.am (19) (15) (15) x,y,z 8 C1' 0 C (3) (2) (3) x,y,z 9 H1'A 0 H x,y,z 10 H1'B 0 H x,y,z 11 H1'C 0 H x,y,z 12 C2' 0 C (2) (19) (18) x,y,z 13 C3' 0 C (2) (18) (18) x,y,z 14 H3' 0 H x,y,z 15 C4' 0 C (2) (18) (19) x,y,z 16 H4'A 0 H x,y,z 17 H4'B 0 H x,y,z 18 C5' 0 C (2) (17) (18) x,y,z 19 C6' 0 C (2) (18) (19) x,y,z 20 C7' 0 C (3) (19) (2) x,y,z 21 H7' 0 H x,y,z 22 C8' 0 C (3) (2) (2) x,y,z 23 H8' 0 H x,y,z 24 C9' 0 C (3) (3) (2) x,y,z 25 H9' 0 H x,y,z 26 C10' 0 C (3) (2) (2) x,y,z 27 H10' 0 H x,y,z 28 C11' 0 C (2) (19) (19) x,y,z 29 C12' 0 C (2) (16) (17) x,y,z 30 C13' 0 C (2) (18) (17) x,y,z 31 H13' 0 H x,y,z 32 C14' 0 C (3) (2) (2) x,y,z 33 C15' 0 C (4) (3) (2) x,y,z 34 H15D 0 H x,y,z 35 H15E 0 H x,y,z S46

47 36 H15F 0 H x,y,z 37 C16' 0 C (2) (18) (19) x,y,z 38 H16C 0 H x,y,z 39 H16D 0 H x,y,z 40 C17' 0 C (3) (2) (2) x,y,z 41 C18' 0 C (3) (2) (3) x,y,z 42 H18D 0 H x,y,z 43 H18E 0 H x,y,z 44 H18F 0 H x,y,z 45 C19' 0 C (4) (2) (3) x,y,z 46 H19D 0 H x,y,z 47 H19E 0 H x,y,z 48 H19F 0 H x,y,z 49 C20' 0 C (2) (19) (19) x,y,z 50 H20' 0 H x,y,z 51 C21' 0 C (2) (19) (19) x,y,z 52 H21' 0 H x,y,z 53 C22' 0 C (3) (2) (2) x,y,z 54 C23' 0 C (3) (3) (3) x,y,z 55 H23D 0 H x,y,z 56 H23E 0 H x,y,z 57 H23F 0 H x,y,z 58 C24' 0 C (4) (4) (3) x,y,z 59 H24D 0 H x,y,z 60 H24E 0 H x,y,z 61 H24F 0 H x,y,z Table S12. Crystal atoms torsion for CCDC # Number Atom1 Atom2 Atom3 Atom4 Torsion 1 C2' O1' C1' H1'A C2' O1' C1' H1'B C2' O1' C1' H1'C C1' O1' C2' O2' 3.9(3) 5 C1' O1' C2' C3' (2) 6 C17' O4' O5' C20' (2) 7 O5' O4' C17' C16' 73.3(2) S47

48 8 O5' O4' C17' C18' -53.6(2) 9 O5' O4' C17' C19' (2) 10 O4' O5' C20' N1' 76.8(2) 11 O4' O5' C20' H20' O4' O5' C20' C21' (2) 13 C12' N1' C11' C6' -1.3(2) 14 C12' N1' C11' C10' 179.2(2) 15 C20' N1' C11' C6' (2) 16 C20' N1' C11' C10' 13.6(3) 17 C11' N1' C12' C5' 1.2(2) 18 C11' N1' C12' C13' 176.7(2) 19 C20' N1' C12' C5' 165.2(2) 20 C20' N1' C12' C13' -19.4(3) 21 C11' N1' C20' O5' (2) 22 C11' N1' C20' H20' C11' N1' C20' C21' 68.0(2) 24 C12' N1' C20' O5' 21.0(3) 25 C12' N1' C20' H20' C12' N1' C20' C21' -94.1(2) 27 C13' N2' C3' C2' 64.3(2) 28 C13' N2' C3' H3' C13' N2' C3' C4' -61.0(2) 30 C14' N2' C3' C2' (2) 31 C14' N2' C3' H3' C14' N2' C3' C4' 126.6(2) 33 C3' N2' C13' C12' 42.0(2) 34 C3' N2' C13' H13' C3' N2' C13' C16' -82.3(2) 36 C14' N2' C13' C12' (2) 37 C14' N2' C13' H13' C14' N2' C13' C16' 90.5(2) 39 C3' N2' C14' O3' 172.2(2) 40 C3' N2' C14' C15' -10.2(3) 41 C13' N2' C14' O3' -0.2(3) 42 C13' N2' C14' C15' 177.4(2) 43 O1' C2' C3' N2' 50.9(2) 44 O1' C2' C3' H3' S48

49 45 O1' C2' C3' C4' 175.5(2) 46 O2' C2' C3' N2' (2) 47 O2' C2' C3' H3' O2' C2' C3' C4' -5.8(3) 49 N2' C3' C4' H4'A N2' C3' C4' H4'B N2' C3' C4' C5' 44.0(2) 52 C2' C3' C4' H4'A C2' C3' C4' H4'B C2' C3' C4' C5' -81.4(2) 55 H3' C3' C4' H4'A H3' C3' C4' H4'B H3' C3' C4' C5' C3' C4' C5' C6' 159.9(2) 59 C3' C4' C5' C12' -18.4(3) 60 H4'A C4' C5' C6' H4'A C4' C5' C12' H4'B C4' C5' C6' H4'B C4' C5' C12' C4' C5' C6' C7' -0.1(4) 65 C4' C5' C6' C11' (2) 66 C12' C5' C6' C7' 178.5(2) 67 C12' C5' C6' C11' -0.2(2) 68 C4' C5' C12' N1' 178.0(2) 69 C4' C5' C12' C13' 2.5(3) 70 C6' C5' C12' N1' -0.6(2) 71 C6' C5' C12' C13' (2) 72 C5' C6' C7' H7' C5' C6' C7' C8' (2) 74 C11' C6' C7' H7' C11' C6' C7' C8' -0.6(3) 76 C5' C6' C11' N1' 0.9(2) 77 C5' C6' C11' C10' (2) 78 C7' C6' C11' N1' (2) 79 C7' C6' C11' C10' 1.6(3) 80 C6' C7' C8' H8' C6' C7' C8' C9' -0.4(4) S49

50 82 H7' C7' C8' H8' H7' C7' C8' C9' C7' C8' C9' H9' C7' C8' C9' C10' 0.4(4) 86 H8' C8' C9' H9' H8' C8' C9' C10' C8' C9' C10' H10' C8' C9' C10' C11' 0.5(4) 90 H9' C9' C10' H10' H9' C9' C10' C11' C9' C10' C11' N1' 177.9(2) 93 C9' C10' C11' C6' -1.5(3) 94 H10' C10' C11' N1' H10' C10' C11' C6' N1' C12' C13' N2' 173.1(2) 97 N1' C12' C13' H13' N1' C12' C13' C16' -64.8(3) 99 C5' C12' C13' N2' -12.1(3) 100 C5' C12' C13' H13' C5' C12' C13' C16' 110.1(2) 102 N2' C13' C16' H16C N2' C13' C16' H16D N2' C13' C16' C17' (2) 105 C12' C13' C16' H16C C12' C13' C16' H16D C12' C13' C16' C17' 91.9(2) 108 H13' C13' C16' H16C H13' C13' C16' H16D H13' C13' C16' C17' O3' C14' C15' H15D O3' C14' C15' H15E O3' C14' C15' H15F N2' C14' C15' H15D N2' C14' C15' H15E N2' C14' C15' H15F C13' C16' C17' O4' -61.1(3) 118 C13' C16' C17' C18' 64.8(3) S50

51 119 C13' C16' C17' C19' (2) 120 H16C C16' C17' O4' H16C C16' C17' C18' H16C C16' C17' C19' H16D C16' C17' O4' H16D C16' C17' C18' H16D C16' C17' C19' O4' C17' C18' H18D O4' C17' C18' H18E O4' C17' C18' H18F C16' C17' C18' H18D C16' C17' C18' H18E C16' C17' C18' H18F C19' C17' C18' H18D C19' C17' C18' H18E C19' C17' C18' H18F O4' C17' C19' H19D O4' C17' C19' H19E O4' C17' C19' H19F C16' C17' C19' H19D C16' C17' C19' H19E C16' C17' C19' H19F C18' C17' C19' H19D C18' C17' C19' H19E C18' C17' C19' H19F O5' C20' C21' H21' O5' C20' C21' C22' 108.0(3) 146 N1' C20' C21' H21' N1' C20' C21' C22' (2) 148 H20' C20' C21' H21' H20' C20' C21' C22' C20' C21' C22' C23' (2) 151 C20' C21' C22' C24' 4.3(4) 152 H21' C21' C22' C23' H21' C21' C22' C24' C21' C22' C23' H23D C21' C22' C23' H23E S51

52 156 C21' C22' C23' H23F C24' C22' C23' H23D C24' C22' C23' H23E C24' C22' C23' H23F C21' C22' C24' H24D C21' C22' C24' H24E C21' C22' C24' H24F C23' C22' C24' H24D C23' C22' C24' H24E C23' C22' C24' H24F CO 2 Me MeO N H 3 NH 2 (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(5-methoxy-1-(triisopropylsilyl)-1H-indol-3- yl)propanoate (3) To a solution of N-TIPS, N-Boc 6-methoxy tryptophan methyl ester 23 (1.53 g, 3.04 mmol) in EtOAc (20 ml) was added aq. HCl (4N solution, 15 ml). The mixture was stirred for 3 hours at 60 o C. A sat. NaHCO 3 solution (30 ml) was added carefully followed by the addition of EtOAc (20 ml). The organic phase was dried over Na 2 SO 4 and concentrated in vacuo. The crude residue was then dissolved in THF (20 ml), and TBAF (3.64 ml, 1.0 M in THF) was added at ambient temperature. After stirring for 1 hour, the reaction was then quenched with sat. NaHCO 3 solution (20 ml). The aqueous phase was extracted with EtOAc (10 ml 3). The combined organic phase was dried over Na 2 SO 4 and concentrated in vacuo. The crude residue was purified by silica gel chromatography (25% 100%, EtOAc/hexanes) to give compound 3 (686 mg, 91%). Physical state: yellow oil; TLC: R f = 0.15 (EtOAc); 20 Optical rotation: [ α] = º (c = 0.17, EtOAc); D S52

53 1 H NMR (600 MHz, CDCl 3) δ 8.15 (s, 1H), 7.47 (d, J = 8.6 Hz, 1H), 6.92 (s, 1H), 6.83 (s, 1H), 6.79 (dd, J = 8.7, 2.2 Hz, 1H), 3.83 (s, 3H), 3.81 (m, 1H), 3.71 (s, 3H), 3.24 (dd, J = 14.4, 4.8 Hz, 1H), 3.02 (dd, J = 14.4, 7.7 Hz, 1H); 13 C NMR (151 MHz, CDCl 3) δ , , , , , , , , 94.76, 55.66, 54.88, 52.11, 30.76; HRMS (m/z): calcd C 13H 17N 2O 3 [M+H] ; found Pictet Spengler Cyclization Conditions screening: Table S13. Conditions screening for Pictet-Spengler cyclization a Procedure for entries 1, 3, 5: L-tryptophan methyl ester 3 (0.2 mmol), aldehyde 24 (0.24 mmol), and 4 Å molecular sieves (130 mg) were stirred in solvent (1.5 ml) at 0 o C for 1 hour. Then TFA (1.48 µl, 0.02 mmol) was added and the solution was allowed to stir for an additional 24 hours. The reaction mixture was then filtered through a coarse sintered glass frit, and the solution was concentrated in vacuo. The crude residue was purified by silica gel chromatography (10% 50%, EtOAc in hexanes) to yield the diastereomers (25 and 25a) as a yellow foam. The diastereomers were separated via PTLC (100:100:2, S53

54 hexanes/ch 2ClCH 2Cl/MeOH) to deliver 1,3-cis isomer 25 (upper band in PTLC, R f = 0.30) and 1,3-trans isomer 25a (lower band in PTLC, R f = 0.20). Procedure for entries 2, 4, 6: L-tryptophan methyl ester 3 (0.2 mmol), aldehyde 24 (0.24 mmol), and 4 Å molecular sieves (130 mg) were stirred in solvent (1.5 ml) at 0 o C for 24 hours. Then the reaction mixture was filtered through a coarse sintered glass frit, and the solution was concentrated in vacuo. The crude residue was purified by silica gel chromatography (10% 50%, EtOAc in hexanes) to yield the diastereomers (25 and 25a) as yellow foam. The diastereomers were separated via PTLC (100:100:2, hexanes/ch 2ClCH 2Cl/MeOH) to deliver 1,3-cis isomer 25 (upper band in PTLC, R f = 0.30) and 1,3-trans isomer 25a (lower band in PTLC, R f = 0.20). Scale up for entry 5: L-tryptophan methyl ester 3 (246 mg, 1.0 mmol), aldehyde 24 (427 mg, 1.2 mmol), and 4 Å molecular sieves (600 mg) were stirred in DCE (8 ml) at 0 o C for 1 hour. Then TFA (7.4 µl) was added and the solution was stirred for an additional 24 hours. Then the reaction mixture was filtered through a coarse sintered glass frit, and the solution was concentrated in vacuo. The crude residue was purified by silica gel chromatography (10% 50%, EtOAc in hexanes) to yield a mixture of diastereomers (246 mg, 42% yield) as yellow foam. The diastereomers were separated via PTLC (100:100:2, hexanes/ch 2ClCH 2Cl/MeOH) to deliver 1,3-cis isomer 25 (161 mg, upper band in PTLC) and 1,3-trans isomer 25a (79 mg, lower band in PTLC). methyl (1S,3S)-1-(2-((tert-butyldiphenylsilyl)peroxy)-2-methylpropyl)-7-methoxy-2,3,4,9- tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate (25) Physical state: pale yellow foam; TLC: R f = 0.45 (1:1 EtOAc/hexanes); S54

55 Optical rotation: 20 D = (c = 0.07, CDCl 3); 1 H NMR (500 MHz, CDCl 3) δ 8.45 (s, 1H), 7.80 (d, J = 7.7 Hz, 2H), 7.71 (d, J = 7.2 Hz, 2H), (m, 4H), 7.28 (d, J = 7.5 Hz, 2H), 7.23 (d, J = 9.3 Hz, 2H), 6.66 (d, J = 8.1, 2.1 Hz, 1H), 6.00 (d, J = 2.2 Hz, 1H), (m, 1H), 3.76 (s, 3H), 3.71 (s, 3H), 3.64 (dd, J = 11.2, 4.3 Hz, 1H), 2.98 (ddd, J = 15.1, 4.5, 1.9 Hz, 1H), 2.70 (ddd, J = 14.5, 11.3, 2.6 Hz, 1H), 2.30 (dd, J = 15.4, 6.0 Hz, 1H), 1.68 (dd, J = 15.4, 2.6 Hz, 1H), 1.31 (s, 3H), 1.21 (s, 3H), 1.15 (s, 9H); 13 C NMR (126 MHz, CDCl 3) δ 174.1, 156.2, 136.5, 136.3, 136.1, 135.6, 132.8, 132.4, 130.6, 130.6, 128.3, 128.1, 121.6, 118.4, 109.2, 106.6, 94.9, 84.1, 57.2, 56.2, 52.4, 49.3, 46.3, 27.8, 26.8, 26.3, 23.3, 20.0; HRMS (m/z): calcd for C 34H 43N 2O 5Si [M+H] , found methyl (1R,3S)-1-(2-((tert-butyldiphenylsilyl)peroxy)-2-methylpropyl)-7-methoxy-2,3,4,9- tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate (25a) Physical state: yellow foam; TLC: R f = 0.45 (1:1 EtOAc/hexanes); Optical rotation: 20 D = (c = 0.12, CDCl 3); 1 H NMR (500 MHz, CDCl 3) δ 7.99 (s, 1H), (m, 4H), (m, 7H), 7.25 (d, J = 2.3 Hz, 1H), 6.70 (dd, J = 8.5, 2.3 Hz, 1H), 6.15 (d, J = 2.2 Hz, 1H), 4.31 (s, 1H), (m, 1H), 3.76 (s, 3H), 3.74 (s, 3H), 3.02 (dd, J = 15.3, 4.9 Hz, 1H), (m, 1H), 2.21 (dd, J = 15.5, 4.5 Hz, 1H), 1.85 (dd, J = 15.1, 4.5 Hz, 1H), 1.34 (s, 3H), 1.18 (s, 9H), 1.13 (s, 3H); S55

56 13 C NMR (126 MHz, CDCl 3) δ 174.4, 156.1, 136.2, 136.1, 135.4, 132.8, 132.5, 130.5, 130.4, 129.8, 128.1, 128.1, 121.4, 118.3, 108.9, 105.8, 95.0, 84.0, 56.0, 53.1, 52.2, 46.7, 46.4, 27.7, 26.3, 25.5, 23.4, 19.9; HRMS (m/z): calcd for C 34H 43N 2O 5Si [M+H] , found methyl (1S,3S)-2-acetyl-1-(2-((tert-butyldiphenylsilyl)peroxy)-2-methylpropyl)-7-methoxy-2,3,4,9- tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate (25b) Acetyl chloride (130 µl, 5 equiv) was added to a vigorously stirred solution of amine 25 in CH 2Cl 2 (3.6 ml, 0.1 M) and sat. aq. NaHCO 3 (3.6 ml, 0.1 M). The reaction was stirred for 14 hours and the phases were separated. The aqueous phase was extracted with CH 2Cl 2 (4 ml 3), and the combined organic phase was dried over MgSO 4, and concentrated in vacuo. The crude was purified by silica gel chromatography (15% 30% EtOAc/hexanes) to afford amide 25b (181 mg, 80%). Physical state: slight yellow foam; TLC: R f= 0.75 (50% EtOAc/hexanes); Optical Rotation: 20 D = (c = 0.47, EtOAc); 1 H NMR (500 MHz, CDCl 3) δ 8.56 (s, 1H), (m, 2H), (m, 2H), (m, 2H), (m, 2H), (m, 1H), 7.33 (dd, J = 8.0, 6.6 Hz, 2H), 7.22 (d, J = 8.5 Hz, 1H), 6.63 (dd, J = 8.6, 2.3 Hz, 1H), 5.47 (dt, J = 8.2, 1.5 Hz, 1H), 4.83 (dd, J = 6.3, 1.5 Hz, 1H), 3.66 (s, 3H), 3.59 (s, 3H), 3.39 (dd, J = 15.4, 1.5 Hz, 1H), 2.88 (ddd, J = 15.4, 6.2, 2.0 Hz, 1H), 2.23 (s, 3H), 2.12 (dd, J = 15.5, 1.4 Hz, 1H), (m, 1H), 1.75 (s, 3H), 1.27 (s, 3H), 1.12 (s, 9H); S56

57 13 C NMR (151 MHz, CDCl 3) δ 171.6, 170.1, 156.1, 136.6, 136.0, 135.9, 132.5, 132.2, 130.6, 130.5, 128.3, 128.1, 120.5, 118.3, 109.3, 103.6, 94.5, 85.4, 56.1, 55.6, 52.6, 47.4, 46.9, 27.5, 27.4, 27.4, 23.4, 23.3, 23.1, 19.9; HRMS (m/z): calcd for C 36H 45N 2O 6Si [M + H] ; found methyl (1S,3S)-2-acetyl-1-(2-hydroperoxy-2-methylpropyl)-7-methoxy-2,3,4,9-tetrahydro-1Hpyrido[3,4-b]indole-3-carboxylate (19b) TBAF (0.10 ml, 1 M in THF) was added to a solution of protected peroxide 25b (63 mg, 0.10 mmol) and AcOH (5.7 µl, 1 equiv) in DMF (2.0 ml, 0.05 M) at 0 ºC. The reaction was done within 5 minutes and was diluted with H 2O (10 ml) and EtOAc (10 ml). The aqueous phase was extracted with EtOAc (5 ml 3). The organic phases were combined, dried over MgSO 4, washed sequentially with H 2O and NaCl (sat. aq.), and concentrated in vacuo. The crude mixture was purified by silica gel chromatography (30% 70% EtOAc/hexanes) to afford free peroxide 19b (31.2 mg, 80%). Physical state: white foam; TLC: R f= 0.15 (50% EtOAc/hexanes); Optical Rotation: 20 D = (c = 0.19, EtOAc); 1 H NMR (600 MHz, CDCl 3) δ 8.94 (s, 1H), 8.45 (s, 1H), 7.35 (d, J = 8.5 Hz, 1H), 6.85 (d, J = 2.2 Hz, 1H), 6.77 (dd, J = 8.6, 2.2 Hz, 1H), 5.65 (d, J = 8.6 Hz, 1H), 4.87 (d, J = 6.4 Hz, 1H), 3.83 (s, 3H), 3.65 (s, 3H), (m, 1H), 2.92 (dd, J = 15.2, 6.4 Hz, 1H), 2.27 (s, 3H), 2.17 (m, 2H), 1.61 (s, 3H), 1.39 (s, 3H); S57

58 13 C NMR (151 MHz, CDCl 3) δ 195.1, 171.5, 170.8, 156.6, 137.1, 131.8, 120.9, 118.8, 109.4, 104.8, 95.1, 83.4, 55.9, 55.5, 52.7, 47.2, 44.5, 26.7, 23.3, 23.1; HRMS (m/z): calcd for C 20H 27N 2O 6 [M+H] , found methyl (2S,3aS,8R)-3-acetyl-10-methoxy-5,5-dimethyl-8-(2-methylprop-1-en-1-yl)-1,2,3,3a,4,5- hexahydro-8h-6,7-dioxa-3,8a-diazacycloocta[jk]fluorene-2-carboxylate (21b) Free peroxide 19b (31.2 mg, mmol) was added to a stirred solution of 3-methyl-2-butenal (38 μl, 0.40 mmol) and 4 Å molecular sieves (20 mg) in DCE (1.0 ml). To this was added BF 3OEt 2 (80 µl, 1.0 M in DCE, mmol) slowly, and the reaction was stirred at 0 o C for 15 minutes. The mixture was then quenched with a few drops of 1:1 Et 3N/MeOH and concentrated in vacuo. The crude mixture was purified by silica gel chromatography (2% 5%, CH 2Cl 2/Et 2O) to afford endoperoxide 21b (8.4 mg, 23%). Physical state: white foam; TLC: R f= 0.45 (50% EtOAc/hexanes); Optical Rotation: 1 H NMR (600 MHz, CDCl 3) 20 D = (c = 0.10, EtOAc); Rotamer A: δ 7.42 (d, J = 8.6 Hz, 1H), 6.82 (dd, J = 8.4, 2.2 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 6.61 (dd, J = 9.9, 2.2 Hz, 1H), 6.44 (d, J = 10.2 Hz, 1H), 4.92 (d, J = 7.1 Hz, 1H), 4.72 (dt, J = 8.0, 1.6 Hz, 1H), 3.86 (s, 3H), 3.70 (s, 3H), 3.56 (dd, J = 15.6, 1.4 Hz, 1H), 3.42 (dd, J = 15.8, 3.0 Hz, 1H), 3.09 (dtd, J = 15.7, 7.9, 1.5 Hz, 1H), 2.36 (s, 3H), 1.97 (d, J = 1.3 Hz, 3H), 1.73 (d, J = 3.7 Hz, 3H), 1.66 (d, J = 1.4 Hz, 3H), 1.08 (s, 3H); S58

59 Rotamer B: δ 7.44 (d, J = 8.4 Hz, 1H), 6.83 (dd, J = 8.2, 2.2 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 6.61 (dd, J = 9.9, 2.2 Hz, 1H), 5.87 (dd, J = 8.1, 3.1 Hz, 1H), 5.81 (d, J = 10.7 Hz, 1H), 4.83 (d, J = 8.0 Hz, 1H), 3.86 (s, 3H), 3.71 (s, 3H), 3.56 (dd, J = 15.6, 1.4 Hz, 1H), 3.42 (dd, J = 15.8, 3.0 Hz, 1H), 3.09 (dtd, J = 15.7, 7.9, 1.5 Hz, 2H), 2.41 (s, 3H), 2.01 (s, 3H), 1.73 (d, J = 1.7 Hz, 3H), 1.68 (s, 3H), 1.12 (s, 3H). 13 C NMR (151 MHz, CDCl 3) Rotamer A: 172.0, 170.9, 156.5, 142.5, 137.4, 133.0, 122.2, 118.9, 118.7, 109.1, 95.2, 86.8, 81.9, 55.9, 53.6, 52.6, 49.4, 47.5, 29.9, 27.3, 25.9, 25.7, 22.9, 19.0; Rotamer B: 172.7, 170.2, 156.7, 143.6, 137.0, 132.0, 122.1, 119.3, 118.3, 107.5, 94.9, 86.6, 81.6, 53.5, 52.3, 51.4, 50.6, 49.0, 29.5, 27.4, 24.7, 22.9, 21.7, 21.0; HRMS (m/z): calcd for C 25H 33N 2O 6 [M+H] , found methyl (1S,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)-L-prolyl)-1-(2-((tert- butyldiphenylsilyl)peroxy)-2-methylpropyl)-7-methoxy-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole- 3-carboxylate (27) To a solution of (((9H-fluoren-9-yl)methoxy)carbonyl)-L-proline (337 mg, 1.0 mmol) in CH 2Cl 2 (10 ml) was added oxalyl chloride (348 μl, 4 mmol) and a catalytic amount of DMF (5 µl) at 0 ºC. After stirring at ambient temperature for 2 h, the reaction mixture was concentrated in vacuo. The resulting acid chloride 26 was dried on a vacuum pump for 1 hour and dissolved in CH 2Cl 2 (5 ml) to give a 0.2 M solution of acid chloride. Free amine 25 (150 mg, mmol) in CH 2Cl 2 (2.5 ml) was added to a vigorously stirred emulsion of fresh prepared acid chloride 26 solution in CH 2Cl 2 (0.30 mmol, 0.15 ml) and sat. NaHCO 3 (2.5 ml). The biphasic solution was stirred for 5 hours at ambient temperature. The organic phase was separated and the S59

60 aqueous phase was extracted with CH 2Cl 2 (4 ml 3). The organic phases were combined, dried over Na 2SO 4, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (5% 30% EtOAc/hexanes) to yield amide 27 (202 mg, 87%). Physical state: yellow foam; TLC: R f = 0.65 (1:1 EtOAc/hexanes); Optical rotation: 20 D = (c = 0.09, EtOAc); HRMS (m/z): calcd for C 54H 60N 3O 8Si [M + H] , found Note: Due to the rotamers issue, both 1 H and 13 C NMR are complex. For details, please see the attached corresponding spectra. S60

61 HPLC data for compound 27: S61

62 S62

63 (12S,14aS)-12-(2-((tert-butyldiphenylsilyl)peroxy)-2-methylpropyl)-9-methoxy-1,2,3,11,12,14ahexahydro-5H, 14H-pyrrolo[1'',2'':4',5']pyrazino[1',2':1,6]pyrido[3,4-b]indole-5,14-dione (28) To a solution of ester 27 (100 mg, 0.11 mmol) in CH 2Cl 2 (1 ml) was added nitrosobenzene (30 mg, 0.28 mmol) followed by ZrCl 4 (26 mg, 0.11 mmol) at 0 o C. The resulting brown solution was allowed to stir for an additional 3 hours at ambient temperature. The reaction was then quenched with Et 3N/MeOH (0.2 ml/0.2 ml) and concentrated in vacuo. The crude residue was purified by silica gel chromatography (10% 40% EtOAc/hexanes) to afford the unsaturated ester (75 mg, 76%) as pale yellow foam (R f = 0.60; 1:1 EtOAc/hexanes). Et 2NH (35 µl, 0.33 mmol) was added to a stirred solution of unsaturated ester (60 mg, mmol) in THF (0.5 ml) and was stirred at 40 ºC. The reaction was concentrated in vacuo and purified by silica gel chromatography (10% 50% EtOAc/hexanes) to afford pentacycle 28 (39 mg, 91% yield). Physical state: off-white foam; TLC: R f = 0.25 (1:1 EtOAc/hexanes); Optical rotation: 20 D = (c = 0.19, EtOAc); 1 H NMR (600 MHz, C 6D 6) δ 8.01 (d, J = 6.8 Hz, 2H), 7.82 (d, J = 6.5 Hz, 2H), 7.37 (m, 2H), (m, 2H), (m, 2H), (m, 2H), 6.96 (dd, J = 8.6, 2.3 Hz, 1H), 6.22 (s, 1H), 5.82 (dd, J = 10.0, 3.4 Hz, 1H), 3.58 (dd, J = 15.7, 5.1 Hz, 1H), 3.53 (s, 3H), 3.41 (dd, J = 11.8, 5.0 Hz, 1H), (m, 2H), (m, 1H), 3.12 (ddd, J = 11.9, 8.2, 4.0 Hz, 1H), 2.46 (dd, J = 13.7, 3.5 Hz, 1H), (m, 1H), 1.90 (dtd, J = 13.1, 7.0, 3.9 Hz, 1H), 1.60 (s, 3H), 1.24 (s, 9H), 0.72 (s, 3H); S63

64 13 C NMR (151 MHz, C 6D 6) δ 169.4, 166.4, 157.5, 137.2, 136.9, 134.0, 133.9, 133.1, 131.4, 131.0, 129.2, 128.9, 128.7, 121.8, 119.5, 110.4, , 96.3, 84.5, 59.7, 57.6, 56.0, 49.7, 48.0, 45.8, 29.1, 28.1, 26.5, 26.1, 23.7, 22.6, 20.3; HRMS (m/z): calcd for C 38H 44N 3O 5Si [M+H] , found (5aR,6S,12S,14aS)-12-(2-((tert-butyldiphenylsilyl)peroxy)-2-methylpropyl)-5a,6-dihydroxy-9- methoxy-1,2,3,5a,6,11,12,14a-octahydro-5h,14h-pyrrolo[1'',2'':4',5']pyrazino[1',2':1,6]pyrido[3,4- b]indole-5,14-dione (29) To a solution of pentacycle 28 (30 mg, 46 µmol) in MeCN/acetone/H 2O (150µL/150µL/75µL) was added OsO 4 (45 µl, 2.5% in tbuoh) followed by NMO (N-Methylmorpholine N-oxide, 22 µl, 50% in water) at ambient temperature. The reaction was stirred for 8 hours and then quenched with sat. NaHSO 3 (150 µl) and stirred for an additional 30 minutes. The reaction mixture was diluted with H 2O (1 ml) and EtOAc (2 ml) and extracted with EtOAc (2 ml 3). The organic phases were combined, and dried over MgSO 4. After concentration in vacuo, the crude residue was purified by silica gel chromatography (20% 60%, EtOAc/hexanes) to afford diol 29 (25 mg, 79% yield). Physical state: pale yellow foam; TLC: R f = 0.40 (EtOAc); Optical rotation: 20 D = (c = 0.06, EtOAc); 1 H NMR (600 MHz, C 6D 6) δ 7.94 (d, J = 6.6 Hz, 2H), 7.86 (d, J = 6.8 Hz, 2H), 7.36 (td, J = 7.3, 6.7, 1.1 Hz, 2H), (m, 4H), 6.97 (d, J = 8.2 Hz, 1H), 6.21 (dd, J = 8.2, 2.3 Hz, 1H), 5.72 (d, J = 2.2 Hz, S64

65 1H), 5.27 (s, 1H), 5.04 (s, 1H), 4.19 (dd, J = 12.9, 3.2 Hz, 1H), 3.88 (s, 1H), 3.37 (t, J = 7.9 Hz, 1H), 3.32 (s, 3H), 3.21 (dt, J = 11.5, 7.8 Hz, 1H), (m, 2H), 2.76 (s, 1H), 2.39 (dd, J = 15.0, 13.0 Hz, 1H), 2.05 (dt, J = 18.6, 8.4 Hz, 1H), 1.98 (dd, J = 15.3, 4.4 Hz, 1H), (m, 1H), 1.54 (s, 3H), 1.19 (s, 9H), 0.87 (s, 3H); 13 C NMR (151 MHz, C 6D 6) δ 169.6, 167.0, 163.3, 150.8, 137.1, 136.9, 133.6, 133.3, 131.1, 131.0, 129.0, 128.9, 128.7, 128.5, 125.3, 125.1, 105.2, 96.1, 93.3, 84.2, 75.1, 59.9, 55.7, 53.2, 52.9, 45.6, 34.8, 28.9, 28.1, 27.1, 23.8, 20.3; HRMS (m/z): calcd for C 38H 46N 3O 5Si [M+H] , found (5R,10S,10aR,14aS,15bS)-10,10a-dihydroxy-7-methoxy-2,2-dimethyl-5-(2-methylprop-1-en-1-yl)- 1,10,10a,12,13,14,14a,15b-octahydro-5H,15H-3,4-dioxa-5a,11a,15a-triazacycloocta[lm]indeno[5,6- b]fluorene-11,15(2h)-dione (Verruculogen, 2) To a solution of silyl peroxide 29 (19.5 mg, 29 µmol) in DMF (0.5 ml) was added acetic acid (1.7 µl, 30 µmol) followed by TBAF (36 µl, 1.0 M in THF) at 0 ºC. The reaction was stirred for 10 minutes, and was subsequently poured into brine (1 ml) and EtOAc (1 ml). The organic phase was separated and the aqueous phase was extracted with EtOAc (2 ml 2). The organic phases were combined, and dried over Na 2SO 4, and concentrated in vacuo. The crude residue free peroxide was dissolved in CH 2ClCH 2Cl (0.5 ml) and cooled to -20 ºC. 3-methyl-2-butenal (14 µl, 148 µmol), and 4 Å molecular sieves (25 mg) were added followed by dropwise addition of BF 3OEt 2 (3.7 µl, 29 µmol) in CH 2ClCH 2Cl (100 µl). The reaction was quenched after 15 minutes with Et 3N/MeOH (150 µl/150 µl) and was allowed to warm to S65

66 room temperature. The reaction mixture was concentrated in vacuo and purified by preparatory TLC (50% EtOAc/hexanes) to afford verrucologen 2 (4.5 mg, 30% over 2 steps). Physical state: white foam; TLC: R f = 0.3 (1:1 hexanes/etoac); Optical rotation: 20 D = 3.8 (c = 0.20, EtOAc, synthetic sample); 20 D = 5.8 (c = 0.34, EtOAc, natural sample); 1 H NMR (600 MHz, CDCl 3) δ 7.90 (d, J = 8.7 Hz, 1H), 6.83 (dd, J = 8.8, 2.2 Hz, 1H), 6.64 (d, J = 8.1 Hz, 1H), 6.60 (d, J = 2.2 Hz, 1H), 6.05 (d, J = 10.1 Hz, 1H), 5.66 (m, 1H), 5.05 (d, J = 8.3 Hz, 1H), 4.77 (d, J = 2.6 Hz, 1H), 4.48 (dd, J = 9.7, 6.8 Hz, 1H), 4.03 (s, 1H), 3.83 (s, 3H), 3.62 (q, J = 7.2, 6.4 Hz, 2H), 2.51 (dt, J = 13.1, 6.7 Hz, 1H), (m, 2H), (m, 1H), 1.99 (s, 3H), (m,1 H), 1.74 (s, 3H), 1.73 (s, 3H), 1.68 (dd, J = 13.4, 1.2 Hz, 1H), 1.01 (s, 3H); 13 C NMR (151 MHz, CDCl 3) δ 170.9, 166.4, 156.5, 143.3, 136.3, 131.7, 121.8, 121.1, 118.6, 109.6, 105.8, 94.1, 86.0, 82.7, 82.2, 68.8, 58.8, 56.0, 51.3, 49.0, 45.4, 29.2, 27.2, 25.7, 24.4, 22.8, 19.0; HRMS (m/z): calcd for C 27H 34N 3O 7, [M + H] , found S66

67 Natural verruculogen: Figure S7. Initial spore growth of Pennicilium verruculosum in a 1 L Erlenmeyer flask (left), Subsequent generations were grown on 12 x12 petri dishes (right). Potatoes (900 g) were boiled in H 2O (3 L) for 1 hour. The resulting solution was filtered through cheesecloth and buffered with NaOAc/HCl to ph 4.8. The solution was heated in an autoclave and transferred to a clean hood. Agar and dextrose were added and the substrate was plated onto 12 x12 square petri dishes. A spore of Penicillium verruculosum was suspended in H 2O for 3 hours then streaked onto the prepared potato dextrose agar plates. The plates were transferred to a dark place at room temperature for 1 3 months. After the fungus had grown, the agar was chopped and transferred to a 4 L Erlenmeyer flask. The solids were extracted with sonication using 10-20% MeOH:CH 2Cl 2 (3x). The combined extracts were washed with NaCl (sat. aq.) and the aqueous phase was back extracted with DCM. The combined organic phases were dried with Na 2SO 4 and concentrated in vauco. The resulting yellow solid was dry loaded onto silica gel and purified by silica gel chromatography (silica gel, 0 70% EtOAc/hexanes) and verruculogen (2) was isolated as a white solid foam. Physical state: Off-white solid; S67