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An Enantioselective Total Synthesis of (+)-Duocarmycin SA Michael A. Schmidt, Eric M. Simmons, Carolyn S. Wei, Hyunsoo Park, and Martin D. Eastgate J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00285 • Publication Date (Web): 20 Mar 2018 Downloaded from http://pubs.acs.org on March 20, 2018

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The Journal of Organic Chemistry

An Enantioselective Total Synthesis of (+)-Duocarmycin SA Michael A. Schmidt*†, Eric M. Simmons†, Carolyn S. Wei†, Hyunsoo Park‡ and Martin D. Eastgate† †

Chemical & Synthetic Development, Bristol-Myers Squibb Company, 1 Squibb Dr. New Brunswick NJ, 08903 Drug Product Science Technologies, Material Science and Engineering, Bristol-Myers Squibb Company, 1 Squibb Dr. New Brunswick NJ, 08903 of carbon-carbon bond formation at the indoline C4 position. We ABSTRACT: An efficient, concise enantioselective total ‡

synthesis of the potent antitumor antibiotic (+)-duocarmycin SA is described. The invented route is based on a disconnection strategy that was devised to facilitate rapid and efficient synthesis of key core compounds to enable preclinical structure-activity relationship investigations. The key tricycle core was constructed with a highly enantioselective indole hydrogenation to set the stereocenter and a subsequent hitherto unexplored vicarious, nucleophilic-substitution/cyclization sequence to effectively forge a final indole ring. Additionally, development of a stable sulfonamide protecting group, capable of mild chemoselective cleavage greatly enhanced sequence yield and throughput. An understanding of key reaction parameters ensured a robust, reproducible sequence easily executable on decagram scales to this highly promising class of compounds. Introduction The duocarmycins represent a subset of potent antitumor antibiotics that were identified from Streptomyces strains in the late 1980’s.1 These molecules in general contain, or can form in vitro2 a cytotoxic 1,1a,2,3,-tetrahydro-5Hcyclopropa[c]indol-5-one (Figure 1A, light blue highlight) structural motif. Within this class, (+)-duocarmycin SA (DSA, 1) has an interesting property of being among the most potent in the group yet also among the most stable.3 Recently, there has been much work4 combining the potent cytotoxicity of the duocarmycins and their structural analogs with the cellular specificity of antibodies in the form of antibody-drug conjugate (ADC) based therapeutics. Within ADC development, significant work is devoted to systematically examining each of the parameters relating to the antibody and the linker attaching the cytotoxin,5 prompting a need of large quantities of materials which ideally would be accessed by an efficient, flexible total synthesis strategy. Herein, we describe an enantioselective route to 1 that can be carried out straightforwardly on the decagram scale which enables downstream ADC studies. The first total synthesis of 1 was achieved shortly after its discovery in 19903 by the Boger lab in 1992,6 and in the subsequent years, the extensive and thorough work from their lab helped establish a key understanding of the structure-activity relationship and biological association of this general class of alkylating agents.6 Additional, highly innovative syntheses from the Natsume & Muratake7, Fukuda & Terashima8, Fukuyama9 and Tietze10 labs were also reported shortly thereafter (Figure 1A). These syntheses differ considerably in how the core tricycle is made (Figure 1A) and pose many challenges. Excluding the creative route by Natsume and Muratake, a unifying strategy across the literature is to begin with an appropriate central arene, then sequentially build the chiral indoline and 2-carboxy ester indole moieties. Approaches which form the indoline ring last are racemic or require sensitive anionic cyclization conditions, outcomes likely complicated by the presence of the fragile indole 2-carboxy ester. Likewise, approaches that form the indole 2-carboxy ester last are lengthy and/or require large loadings of palladium due to the challenges

sought to develop an enantioselective synthetic strategy that would form the sensitive indole 2-carboxy ester last; a feature that would enable late stage diversification of ester analogs, overcome the challenges of indoline C4 functionaliztion, and utilize a rapid and efficient methodology for introduction of the chiral indoline.

Figure 1. A) Previous reports to 1, total yields and amounts prepared (NG = not given). B) Proposed retrosynthetic analysis. Results and Discussion Our proposed retrosynthesis (Figure 1B) installs the cytotoxic cyclopropane last and cleaves the trimethoxy indole to reveal the tricyclic core. We desired to forge the indole 2-carboxy ester leveraging an underutilized vicarious nucleophilic substitution (VNS) / cyclization strategy.11 This approach was considered risky, as it is absent from the DSA literature and

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examples of VNS in complex settings are particularly scarce, however are notable for the mild, transition metal-free conditions. This strategy was pursued due to the belief that prior introduction of the indole 2-carboxy ester was responsible for several challenges noted in the preceding work. We planned to form the

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preceding chiral indoline by an enantioselective indole hydrogenation12, a strategy that obviates the need to synthesize one of the most challenging heterocyclic rings asymmetrically late in the synthesis.

Scheme 1. Total Synthesis of (+)-Duocarmycin SA (1)a

a

Reagents and conditions: 1) 1.25 equiv. POCl3, DMF then NaOH, H2O; 2) 1.10 equiv. TsCl, 1.50 equiv. Et3N, 5 mol% DMAP, CH2Cl2; 3) 0.5 equiv. LiBH4 in THF, 2-MeTHF; 4) 1.20 equiv. TBSCl, 1.50 equiv. imidazole, DMF; 5) 0.20 mol% of [Rh(COD)(acac)], 0.22 mol% L1, 750 psig H2, i-PrOH, 65 °C; 6) 10-15 equiv. Mg, MeOH, PhMe; 7) 1.05 equiv. 4-CsCl, 1.20 equiv. i-Pr2NEt; 8) 1.30 equiv. fuming HNO3, CH2Cl2; 9) 1.15 equiv. chloromethyl phenyl sulfone, 2.30 equiv. KOt-Bu, THF,–25 °C; 10) 10 equiv. Zn, 10 equiv. AcOH, MeCN; 11) 2.00 equiv. methyl 2-hydroxy-2-methoxyacetate (8), EtOAc; 12) 5.00 equiv. Cs2CO3, DMSO, 50 °C; 13) 6.0 equiv. 1-dodecanethiol, 5.7 equiv. DBU, DMF; 14) 1.05 equiv. 11, 1.15 equiv. 2,6-lutidine, CH2Cl2; 15) 2.50 mol% Pd(OH)2 on carbon, 5.00 equiv. ammonium formate, MeOH, 50 °C; 16) 1.20 equiv. TBAF, THF, 35 °C, 17) 1.50 equiv ADDM, 1.50 equiv PBu3, THF; DMF = N,N-dimethylformamide, TsCl = p-toluenesulfonyl chloride, DMAP = 4-dimethyaminopyridine, THF = tetrahydrofuran, 2-MeTHF = 2methyltetrahydrofuran, TBSCl = tert-butyldimethylsilyl chloride, COD = 1,5-cyclooctadiene, acac = acetylacetonate, 4-CsCl = 4-cyanobenzenesulfonyl chloride, DBU = 1,8-diazabicyclo [5.4.0] undec-7-ene, DMSO = dimethylsulfoxide, TBAF = tetrabutylammonium fluoride, ADDM = azodicarbonyl dimorpholide. The majority of the hydrogen atoms of the X-ray structures were omitted for clarity; the ellipsoids represent 50% probability.

The route to 1 (Scheme 1) begins with a VilsmeierHaack formylation of commercially available 6-benzyloxyindole (2). The precipitated aldehyde was tosylated then reduced with substoichometric LiBH4, and the resulting alcohol was silylated with TBSCl in the presence of imidazole. Product 3 was isolated by crystallization from the DMF reaction stream by the addition of water. The key enantioselective indole hydrogenation was next explored. After surveying a variety of conditions and with multiple catalysts,13 success was only realized with the (S,S)(R,R)-PhTRAP ligand (L1) developed by Kuwano and coworkers.12 This ligand is not commercially available, however can be prepare via the known procedures. For convenience, we’ve compiled our synthesis in the experimental section. We discovered that the precatalyst generated by mixing [Rh(COD)(acac)] with L1 was highly sensitive to air and impurities in 3. However, with purified 3 we were able to lower

the catalyst loading while maintaining reaction efficiency, obtaining complete conversion of 3 with only 0.20 mol% rhodium and 0.22 mol% L1 (96% yield, 98.2% e.e. on a 30 g scale). The tosyl group was used to enable the hydrogenation and indoline N-protection of some capacity was necessary to facilitate the remainder of the synthesis, however we found that it was resistant to cleavage downstream of the eventual indole 2carboxy ester formation. For example, the Ts analog of 9 decomposed under a variety of reductive (Mg, SmI2), basic (NaOMe, thiols and DBU) or nucleophilic (hydrazine, hydroxylamine) conditions. The tosyl group of 4 however, was easily removed with excess magnesium in methanol and toluene and a wide variety of amide, carbamate and sulfonamide14 based protecting groups were screened. Unfortunately, we found none were acceptable, thus we developed a new amine protecting group, through subtly tuning arylsulfonyl electronic properties to

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The Journal of Organic Chemistry

enable a mild, functional group-tolerant cleavage. We discovered that the 4-cyanobenzensulfonamide (4-Cs)15 was an excellent protecting group in this context, not only compatible with the downstream chemistry, but also rendering intermediates in the sequence crystalline, facilitating purification, handling and storage. In practice, the tosyl group of 4 was removed with excess magnesium, then the crude stream was quenched into cold (~0 °C) 3 N HCl containing 10 wt% urea, a finding that greatly enhanced the aqueous solubility of the magnesium salts. The crude indoline was sulfonylated with 4-cyanobenzenesulfonyl chloride and Hunig’s base to afford 5 in 84% overall yield. Unfortunately, the 4-Cs group was not compatible with the initial chiral hydrogenation due to nitrile reduction, prompting this protecting group exchange. The regioselective nitration of 5 was most effectively carried out with red fuming nitric acid with the nitroarene 6 being isolated by crystallization from isopropanol in 78% yield. After extensive exploration, the second key transformation, the vicarious nucleophilic substitution of 6 was successfully performed with chloromethyl phenyl sulfone and potassium tert-butoxide affording sulfone 7. By performing the reaction at –25 °C in THF, 7 is obtained as a single regioisomer in 76% yield on a 50 g scale. Other VNS reagents11 failed to afford desired products such as O-methylhydroxylamine, trimethylsulfonium iodide, 1,1,1-trimethylhydrazinium iodide, diethyl (chloromethyl)phosphonate and ethyl bromopyruvate (Scheme 1), decomposition was instead observed. The nitro group was cleanly reduced with excess zinc and acetic acid to give the aniline as a foam, which was used directly in the subsequent reaction. The crude aniline was treated with 2.00 equivalents of methyl 2-hydroxy-2-methoxyacetate (8) in ethyl acetate, a reaction driven to completion by azeotropic removal of methanol and water below the reagent’s boiling point (~128 °C at 760 torr). The resulting imine was highly hydrolytically unstable, and as such was immediately used in the next cyclization reaction. Upon extensive screening, cesium carbonate in DMSO were by far the most effective conditions to form 9. After neutralization and an aqueous workup, the crude residue is heated in isopropanol affording beige crystals of 9 which were approximately 85 wt% quantitative NMR (73% corrected yield for three steps from 7). The 4-Cs group of 9 was removed under the previously reported conditions (1-dodecanethiol and DBU).15 We found this to be a strategic place to purify the product by proper flash column chromatography, and we isolated the stable, free indoline core 10 in 95% yield. The indoline 10 was treated with the acid chloride 11 in the presence of 2,6-lutidine to afford the amide 12 as a crude foam, which after removal of the benzyl group with Pearlman’s catalyst and ammonium formate afforded the crystalline phenol 12 in 95% overall yield. The acid 16 (Scheme 2), the precursor to 11, is commercially available on small scales and is costly. We elected to synthesize 11 by a modification of Fukuyama’s9 route. Specifically, instead of using a phosphonoglycine reagent and tetramethylguanidine base to form a dehydroaminoester derivative (e.g. 15), we elected to use an Erlenmeyer-Plöchl azlactone/methanolysis sequence which employs very inexpensive reagents. Secondly, we reduced the copper loading in the Ullmann reaction by 97%, facilitated by the addition of the ligand phenanthroline, and replaced the 7.00 equivalents of cesium acetate with 2.50 equivalents of potassium carbonate. This six-step sequence proceeds in 53% total yield and does not employ flash column chromatography.

Scheme 2. Synthesis of Acid Chloride 11a

a

Reagents and conditions: 1) 1.05 equiv. NBS, MeCN, 50 °C, 2) 1.10 equiv. N-Bz-glycine, 0.50 equiv. KOAc, 3.00 equiv. Ac2O, 60 °C, 3) 10 mol% Et3N, MeOH, 60 °C, 4) 5.0 mol% CuI, 7.5 mol% 1,10phenanthroline, 2.50 equiv. K2CO3, DMF, 80 °C, 5) 3.00 equiv. NaOH, THF, H2O, 60 °C, 6) 2.0 mol% DMF, 1.50 equiv. oxalyl chloride, THF.

Removal of the TBS group of 12 with TBAF in THF afforded the penultimate 13 in 95% yield after crystallization from DMF and water. Dehydration of 13 to 1 was effective under a variety of Mitsunobu conditions, however we chose azodicarbonyl dimorpholide (ADDM)16 and PBu3 based on the ease of byproduct removal. An aqueous wash removed the azoderived products and a hexanes wash removed phosphine-derived products. A final purification by flash chromatography afforded 1 in 94% yield, identical in all respects to the previously reported characterization data. Due to the highly toxic nature of 1, we limited this reaction to the 1 g scale. The structure of 1 was examined by X-ray diffraction, and consistent with expectations17, the nitrogen-carbon bond in the vinylogous amide is 0.06-0.07 Å shorter than the average bond length in the pyrrolidine ring indicating a stabilizing effect. The goal of this work was to develop a synthetic sequence that would be both flexible to allow analog study, but also concise and efficient to facilitate material throughput. This was accomplished by developing a strategy that begins with the conserved pharmacophore (Figure 1A, light blue highlight) and rapidly advances to core 10 using an enantioselective indole 2,3bond hydrogenation followed by a VNS/cyclization sequence. The synthesis proceeds in seventeen chemical transformations (longest linear sequence) and the overall yield from 2 to 1 was 24.1% with an average reaction efficiency of 92%. Four telescoped sequences in the route minimized isolations down 40% (10 out of 17 steps were isolated), a feat greatly enabled using a new nitrogen protecting group, the 4-cyanobenzenesulfonyl. The synthetic sequence was developed with late-stage diversification in mind; and compound 10 should find use in structure-activity relationship studies to further develop this important class of compounds.

Experimental Section All reactions were performed in round bottom flasks and stainless steel syringes were used to transfer liquids (unless noted otherwise). Flash column chromatography was performed using silica gel (20-40 µm). Organic solutions were concentrated on a rotary evaporator at ~20 torr at 25-35 ºC. Commercial reagents and solvents were used as received. All quantities expressed in the individual experiments are corrected for purity as specified by the vendor. Proton nuclear magnetic resonance (1H NMR) spectra were recorded with a 400 MHz spectrophotometer and are recorded in parts per million from internal tetramethylsilane on the δ scale and are referenced from the residual protium in the

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NMR solvent (CDCl3: CHCl3 δ 7.27, DMSO-d6: C2D5HSO δ 2.50, THF-d8: C4D7HO δ 3.58, 1.73, C6D6: C6D5H δ 7.16). Data are reported as follows: chemical shift [multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant(s) in Hertz, integration]. Phosphorous nuclear magnetic resonance (31P NMR) spectra were recorded with a 400 MHz spectrophotometer and are recorded in parts per million from external phosphoric acid on the δ scale (H3PO4: δ 0.00). Data are reported as follows: chemical shift [multiplicity (s = singlet), integration]. Carbon nuclear magnetic resonance (13C NMR) spectra were recorded with a 400 MHz spectrophotometer and are recorded in parts per million from internal tetramethylsilane on the δ scale and are referenced from the carbon resonances in the NMR solvent (CDCl3: δ 77.00, DMSO-d6: δ 39.51, THF-d8: δ 25.37, 67.57, C6D6: δ 128.39). Data are reported as follows: chemical shift. Infrared data (FTIR) were obtained with a Fourier-transform infrared spectrometer, and are reported as follows: [frequency of absorption (cm−1), intensity of absorption (a = apparent, s = strong, m = medium, w = weak, br = broad). Melting points were determined with a capillary melting point apparatus. High resolution mass spectrometry (HRMS) was collected on a TOF instrument. Optical rotations were measured on a polarimeter. Synthesis of (+)-Duocarmycin SA (1): 6-Benzyloxy-3-(tert-butyldimethylsilyloxymethyl)-1-tosyl-1Hindole (3): To a three-neck round bottomed flask equipped with a nitrogen inlet and thermocouple was added DMF (75 mL) and the flask was cooled to an internal temperature of +2.8 °C with an ice water bath. Phosphorous(V) oxychloride (12.7 mL, 137.2 mmol, 1.25 equiv.) was added dropwise, keeping the internal temperature below 5 °C (~1 h). Once the addition was complete, 6-benzyloxyindole (2) (25.0 g, 109.7 mmol, 1.0 equiv.) was added in ~1 g portions keeping the internal temperature below 5 °C (~1 h). The dark solution was warmed to room temperature and held for 1 h. A solution of sodium hydroxide (50 g) in water (250 mL) was prepared in a Morton flask and cooled to an internal temperature of 2.0 °C. The dark reaction mixture was slowly added to the cold caustic solution under vigorous stirring, keeping the internal temperature between 20–30 °C. A light beige solid separates (final pH ~ 14). The slurry was heated slowly up to an internal temperature of 70 °C (moderate off-gassing is observed at an internal temperature of ~70 °C. Use of a large vessel (2 x expected volume), strong agitation, adequate venting and a slow temperature ramp are encouraged) and held for 10-15 minutes under a light nitrogen sweep to remove evolving dimethylamine, then it is heated to an internal temperature of 90 °C and held for 15 min. Upon cooling to room temperature, the slurry was diluted with water (40 mL) and the solids were collected via filtration. The cake was washed with water (2 x 100 mL) and dried in a vacuum oven at 50 °C and 23 in Hg with a slight nitrogen sweep to constant weight to afford formylated indole (27.3 g) as a beige/tan solid which was identical in all respects with the previously reported literature.18 The product was used without further purification and was ground to a fine powder, if clumpy, before use in the next step. Rf (50% ethyl acetate in hexanes, silica gel): 2 0.88 (UV), formylated indole S1 0.35 (UV). M.p. (DMF/water): 211–212 °C (dec.). 1H NMR (400 MHz, DMSOd6) δ: 11.94 (br s), 9.87 (s, 1H), 8.15 (s, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.47 (d, J=7.2 Hz, 2H), 7.40 (app t, J=7.4 Hz, 2H), 7.33 (t, J=7.0 Hz, 1H), 7.08 (s, 1H), 6.95 (d, J=8.5 Hz, 1H), 5.15 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ: 184.7, 155.7, 137.9, 137.8, 137.2, 128.4, 127.7, 127.6, 121.4, 118.25, 118.23, 112.4, 96.9, 69.5. IR (KBr) (cm˗1): 1634 (s), 1526 (m), 1426 (m), 1385 (m),

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1159 (m). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H13NO2 252.1019; Found 252.1025. To a Morton flask was added the formylated indole S1 (50.00 g, 199.0 mmol, 1.00 equiv.), 4-dimethylaminopyridine (1.22 g, 9.95 mmol, 0.05 equiv.) and DCM (400 mL) to form a suspension. Triethylamine (42.0 mL, 298.4 mmol, 1.5 equiv.) was added followed by para-toluenesulfonyl chloride (42.15 g, 218.9 mmol, 1.10 equiv.). A remaining charge of dichloromethane (100 mL) was used to wash any solids down the sides of the flask. The reaction is exothermic, a ∆T of +7–10 °C was observed on this scale. The reaction mixture was vigorously stirred at room temperature for 1 h and had become mostly homogeneous. The mixture was washed with a 1.0 N aqueous solution of hydrochloric acid (500 mL), then a saturated aqueous solution of brine (500 mL). The mixture was dried over sodium sulfate, filtered and concentrated in vacuo to afford the tosylated indole-aldehyde as a dark solid (84.06 g) that was used without further purification. Rf (50% ethyl acetate in hexanes, silica gel): formylated indole S1 0.35 (UV), tosylated indole-aldehyde S2 0.73 (UV). The tosylated indole-aldehyde S2 (84.06 g) was slurried in a mixture of 2-methyltetrahydrofuran (375 mL) and THF (125 mL, water content of the system was approximately 0.22 wt% by Karl Fischer analysis) under nitrogen and was cooled to an internal temperature of 5 °C. A solution of lithium borohydride (2.0 M in THF, 50.0 mL, 99.48 mmol, 0.50 equiv.) was added slowly, keeping the internal temperature below 10 °C (approx. 30 min). Once the addition was complete, the reaction mixture was warmed to room temperature and stirred for 30 min. The light slurry was cooled to an internal temperature of 5 °C and acetone (50 mL) was added slowly such that the internal temperature did not exceed 15 °C (approx. 20 min). The mixture was warmed to room temperature, stirred for 60 min, washed with a 1.0 M aqueous solution of a pH 7 sodium phosphate buffer (500 mL), then a saturated aqueous solution of brine (250 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the hydroxymethylindole S3 as a dark red/brown viscous gel that was used without further purification. Rf (50% ethyl acetate in hexanes, silica gel): tosylated indole-aldehyde S2 0.73 (UV), hydroxymethylindole S3 0.54 (UV). The hydroxymethylindole S3 and imidazole (20.32 g, 298.4 mmol, 1.5 equiv.) were dissolved in DMF (200 mL, water content containing from 185.98 ppm to 0.366 wt% has been successfully used) with vigorous stirring using a mechanical stirrer. tert-Butyldimethylsilyl chloride (37.10 g, 238.8 mmol, 1.2 equiv.) was added followed by a remaining charge of DMF (50 mL) that was used to rinse down any solids down the sides of the flask. The reaction is exothermic, a ∆T of +10–13 °C was observed on this scale. The reaction mixture was stirred for 60 min, then water (25 mL) was added slowly over 30 min. The mixture was seeded with product (250 mg), then aged for 60 min whereupon a thick bed of short rods formed. Water (225 mL) was added over 1 h to form a very thick slurry. Additional water (200 mL) was added to complete the desaturation of the product and lighten the slurry. The solids were collected by filtration, washed with water (2 x 200 mL) and the brown wet cake (120 g) was dried in a vacuum oven at 50 °C and 100 torr with a slight nitrogen sweep to constant weight. The dry cake (95.0 g) was further passed through a plug of silica gel (10 to 15% ethyl acetate in hexanes gradient) to afford the silylated indole 3 as a white solid (90.0 g, 86% over four steps from 2). Rf (20% ethyl acetate in hexanes, silica gel): hydroxymethylindole 0.00 (UV), 3 0.62 (UV). Rf (50% ethyl acetate in hexanes, silica gel):

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The Journal of Organic Chemistry

hydroxymethylindole S3 0.54 (UV), 3 0.99 (UV). M.p. (ethyl acetate/hexanes): 91–92 °C. 1H NMR (400 MHz, DMSO-d6) δ: 7.67 (d, J=7.9 Hz, 2H), 7.40-7.52 (m, 7H), 7.38 (app t, J=6.6 Hz, 1H), 7.31 (d, J=7.8 Hz, 2H), 6.99 (d, J=8.7 Hz, 1H), 5.22 (s, 2H), 4.75 (s, 2H), 2.30 (s, 3H), 0.84 (s, 9H), 0.01 (s, 6H). 13C NMR (101 MHz, DMSO-d6) δ: 156.5, 145.3, 137.0, 135.7, 134.0, 130.1, 128.5, 127.8, 127.4, 126.5, 123.2, 123.1, 122.1, 120.9, 113.0, 98.8, 69.6, 57.1, 25.7, 21.0, 17.9, –5.4. IR (thin film) (cm˗1): 1619 (m), 1364 (s), 1170 (s), 1102 (s), 987 (m). HRMS (ESITOF) m/z: [M+H]+ Calcd for C29H36NO4SSi 522.2129; Found 522.2140. (S)-6-Benzyloxy-3-(tert-butyldimethylsilyloxymethyl)-1tosylindoline (4): To two 350 mL stainless-steel autoclaves were charged indole 3 (30.0 g, 57.5 mmol, 1.00 equiv. in each). In a nitrogen filled glovebox, a dark orange stock solution of [Rh(cod)(acac)] (72.0 mg, 0.230 mmol, 0.002 equiv.) and (S,S)(R,R)-PhTRAP benzene solvate L1 (221 mg, 0.253 mmol, 0.0022 equiv.) in dimethoxyethane (6.0 mL) was prepared19 by aging at room temperature for 20 min. The autoclave was brought into the glovebox and isopropanol (150 mL) was added to each autoclave, followed by 3 mL of the rhodium-catalyst solution. The autoclaves were then sealed under nitrogen, removed from glovebox and the atmosphere was replaced with hydrogen (purge, backfill five times). The autoclaves were pressurized with hydrogen to 750 psi, then heated 65 °C for 20 h, maintaining a hydrogen pressure of 750 psi. The atmosphere in the autoclaves was replaced with nitrogen (purge, backfill five times) at ambient pressure20, cooled to room temperature, their contents combined and concentrated in vacuo. The crude product was passed through a plug of silica gel (0 to 15% ethyl acetate in hexanes gradient) to remove the catalyst and afford the indoline 4 as a hard, white solid (57.63 g, 96%). The product was found to have an enantiomeric excess of 98.2% favoring the (S) configuration as determined by chiral stationary phase HPLC. The absolute stereochemistry was determined by single X-ray crystallography. Rf (20% ethyl acetate in hexanes, silica gel): 3 0.62 (UV), 4 0.57 (UV). M.p. (ethyl acetate/hexanes): 78–79 °C. [α]D22: +40.1 ° (c = 10.0 mg/mL, toluene). 1H NMR (400 MHz, DMSO-d6) δ: 7.56 (d, J=8.1 Hz, 2H), 7.49-7.44 (m, 2H), 7.41 (app t, J=7.4 Hz, 2H), 7.33-7.37 (m, 1H) 7.31 (d, J=8.1 Hz, 2H), 7.13, (d, J=1.7 Hz, 1H), 7.08 (d, J=8.2 Hz, 1H), 6.65 (dd, J=8.3, 2.1 Hz, 1H), 5.13 (s, 2H), 3.90 (dd, J=10.7, 8.8 Hz, 1H), 3.69 (dd, J=10.8, 4.3 Hz, 1H), 3.30-3.38 (m, 1H), 3.17-3.26 (m, 2H), 2.32 (s, 3H), 0.78 (s, 9H), – 0.08 (s, 3H), –0.12 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ: 158.5, 144.2, 142.6, 137.0, 133.0, 129.8, 128.4, 127.7, 127.4, 127.0, 125.9, 124.6, 110.0, 101.3, 69.3, 64.7, 52.9, 41.3, 25.6, 20.9, 17.8, –5.6, –5.8. IR (thin film) (cm˗1): 1614 (m), 1500 (m), 1349 (s), 1160 (s), 1096 (s). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C29H38NO4SSi 524.2285; Found 524.2295. (S)-6-Benzyloxy-3-(tert-butyldimethylsilyloxymethyl)-1-(4cyanobenzenesulfonyl)indoline (5): Caution!! This reaction produces hydrogen gas and should be performed in a wellventilated hood. A three-neck round bottomed flask was equipped with a nitrogen inlet, thermocouple and an outlet vent. The flask was charged with the indoline 4 (50.00 g, 95.46 mmol, 1.00 equiv.) and a mixture of toluene (250 mL) and methanol (250 mL) was added. The solution was sparged with nitrogen for approximately 10 min at room temperature, then kept under a small nitrogen sweep. The reaction is sensitive to water; the typical water content ranged between 143.651 and 176.047 ppm by Karl Fischer analysis. Magnesium turnings21 (2.32 g, 95.46

mmol, 1.00 equiv.) were added and the mixture stirred for 1 h whereupon an exotherm and off-gassing were noted. The internal temperature was maintained below 35 °C with an ice-water bath. Additional magnesium was added 1.00 equiv.22 at a time at approximately 1 h intervals, then the mixture was held overnight (or until all the solid magnesium reacted). The slurry was poured into a cold (0-5 °C) biphasic solution of toluene (500 mL) and 10 wt% urea in 3 N aqueous HCl, (1.00 L)23 and vigorously agitated. The quench is exothermic, a ∆T of +30-35 °C was observed on this scale. The pH of the aqueous layer should be 6. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the deprotected indoline as dark brown solid (37.81 g). Rf (20% ethyl acetate in hexanes, silica gel): 4 0.57 (UV), deprotected indoline S4 0.51 (UV). The crude deprotected indoline S4 was dissolved in ethyl acetate (500 mL, water content ranged between 59.4286 and 86.4664 ppm by Karl Fischer analysis) and cooled to an internal temperature of 0-5 °C. N,N-Diisopropylethylamine (20.0 mL, 114.54 mmol, 1.20 equiv.) was added followed by recrystallized15 4-cyanobenzenesulfonyl chloride (20.63 g, 100.23 mmol, 1.05 equiv.). A white precipitate forms over 15-20 min and the slurry was warmed to room temperature. The reaction mixture was stirred for 1 h, was washed with a 10 wt% aqueous solution of citric acid (250 mL), then was washed with a 1.0 M aqueous solution of a pH 7 sodium phosphate buffer (375 mL), ensuring the pH of the aqueous layer was >6; proceeding into the crystallization with an acidic stream can lead to cleavage of the TBS group. The red-orange stream was stirred over sodium sulfate and activated carbon (DARCO® G-60, 100 mesh, 25.0 g) for two hours, then was filtered over Celite (3.5” dia, 0.75” ht), rinsing the pad with ethyl acetate (2 x 25 mL). The light orange solution was concentrated in vacuo to afford a thick orange oil (55.27 g). To the oil was added isopropanol (500 mL) and the solvent level was marked.24 Additional isopropanol (500 mL) is added followed by dimethylethylamine (0.500 mL) and the oil is dissolved with mild heating at an internal temperature of ~35 °C, then was allowed to cool to room temperature under mechanical stirring. The solution was seeded with product (250 mg) and the mixture was stirred for 15 h. The slurry was concentrated slowly (on this scale, 45 min to 1 h, vacuum pressure 8) then the layers are separated and the organic layer is washed with a saturated aqueous solution of brine (125 mL) diluted with water (125 mL). The pH of the aqueous layer is typically >7. If the pH of the aqueous layer is 7. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to afford a dark red/brown gel. To the gel was added isopropanol (450 mL) and the mixture was heated to an internal temperature of 70 °C to dissolve, then the solution is cooled slowly (20 min) to an internal temperature of 50 °C and held for 30 min whereupon the product will begin to crystallize forming a large bed. The slurry was allowed to cool to room temperature and desaturate over 4 h. The crystals were collected by filtration, washed with 20 v% isopropanol in hexanes (2 x 250 mL) and the wet cake was dried in a vacuum oven at 50 °C and 100 torr with a slight nitrogen sweep to constant weight to afford nitroindoline 6 as dark yellow, thick plates (42.35 g, 78%). Rf (20% ethyl acetate in hexanes, silica gel): 5 0.53 (UV), 6 0.39 (UV). M.p. (isopropanol): 84–89 °C. [α]D22: +17.75 ° (c = 9.46 mg/mL, chloroform). 1H NMR (400 MHz, DMSO-d6) δ: 8.03 (d, J=8.8 Hz, 2H), 7.87 (d, J=8.6 Hz, 2H), 7.86 (s, 1H), 7.45-7.52 (m, 4H), 7.40 (tt, J=6.9, 2.0 Hz 1H), 7.34 (s, 1H), 5.44 (s, 2H), 4.08 (app t, J=9.7 Hz, 1H), 3.75 (dd, J=10.7, 4.7 Hz, 1H), 3.52-3.57 (m, 1H), 3.35-3.42 (m, 2H), 0.69 (s, 9H), –0.11 (s, 3H), –0.18 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ: 152.8, 146.1, 139.3, 136.0, 134.7, 133.8, 128.7, 128.1, 127.8, 127.0, 124.9, 123.2, 117.3, 116.7, 99.8, 70.5, 63.8, 52.9, 40.4, 25.5, 17.6, –5.6, –5.8. IR (thin film) (cm˗1): 2235 (w), 1624 (m), 1515 (s), 1365 (s), 1249 (s). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C29H34N3O6SSi 580.1932; Found 580.1931. (S)-6-Benzyloxy-3-(tert-butyldimethylsilyloxymethyl)-1-(4cyanobenzenesulfonyl)-5-nitro-4-(phenylsulfonylmeth-1yl)indoline (7): The nitroindoline 6 (50.00 g, 86.25 mmol, 1.00 equiv.) and chloromethyl phenyl sulfone (19.10 g, 99.19 mmol,

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1.15 equiv.) were dissolved in toluene (350 mL) and concentrated in vacuo to afford a dark oil. This is done as a safeguard to remove any residual traces of water or isopropanol from the previous step. The oil was dissolved in anhydrous tetrahydrofuran (300 mL, water content ranged between 31.3467 and 45.3390 ppm by Karl Fischer analysis), and cooled to an internal temperature of –25 ± 2 °C with a dry ice-acetonitrile bath. A solution of potassium tert-butoxide (1.0 M in THF, 198.4 mL, 198.4 mmol, 2.30 equiv.) was added dropwise at a rate that maintained the internal temperature at –25 ± 2 °C (~20 min). The dark solution was stirred at –25 ± 2 °C for 1 h, then quenched by the slow addition of a solution of acetic acid (14.83 mL, 258.8 mmol, 3.00 equiv.) in THF (35.2 mL) at a rate that maintained the internal temperature < –20 °C (~10 min). The light suspension was warmed to room temperature and poured into a 1.0 M aqueous solution of a pH 7 sodium phosphate buffer (250 mL) and extracted with isopropyl acetate (250 mL). The organic phase was washed with a saturated aqueous solution of brine (250 mL), then was dried over sodium sulfate, filtered and concentrated in vacuo to afford a dark crude gel. The gel was passed through a plug of silica gel (isocratic: 35% ethyl acetate in hexanes) and the fractions containing the product are pooled and concentrated in vacuo to afford a dark oil. The oil was dissolved in isopropyl acetate (250 mL) and if any solids are present at this point, the solution is polish filtered over a small plug of Celite (0.5” dia, 0.5” ht) before proceeding. Solids present at this point cause premature gelling during the crystallization. Heptane (250 mL) is added over 5 min then the dark solution is seeded with product (500 mg) and stirred for no less than 1 h. Heptane (50 mL) is added over 1 h and the mixture is stirred for no less than 1 h (preferably 2 h). This sequence is repeated four more times for a total of 250 mL of heptane added (at any place, the procedure can be held overnight). The mixture was stirred for 14 h, and the slurry thickened. Additional heptane (500 mL) was added slowly over 8 h, then held for an additional 15 h. The crystals were collected by filtration and the wet cake was dried in a vacuum oven at 50 °C and 100 torr with a slight nitrogen sweep to constant weight, affording product 7 as very small, beige crystalline rods (48.08 g, 76%). Rf (25% ethyl acetate in hexanes, silica gel): 6 0.50 (UV), 7 0.25 (UV). M.p. (isopropyl acetate/heptane): 114–118 °C. [α]D22: +65.04 ° (c = 9.46 mg/mL, chloroform). 1H NMR (400 MHz, DMSO-d6) δ: 8.11 (d, J=8.3 Hz, 2H), 7.86 (d, J=8.3 Hz, 2H), 7.65 (app t, J=7.5 Hz, 1H), 7.57 (d, J=7.3 Hz, 2H), 7.38-7.51 (m, 8H), 5.43 (ABq, J=12.8 Hz, ∆δAB=0.05, 2H), 4.84 (d, J=14.4 Hz, 1H), 4.59 (d, J=14.4 Hz, 1H), 3.80 (d, J=10.9 Hz, 1H), 3.28-3.38 (m, 2H), 3.01 (dd, J=10.0, 7.7 Hz, 1H), 2.87 (dd, J=13.9, 7.1 Hz, 1H), 0.69 (s, 9H), – 0.17 (s, 3H), –0.25 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ: 151.6, 143.2, 139.0, 137.5, 137.4, 135.7, 134.5, 133.9, 129.4, 128.8, 128.2, 128.0, 127.8, 127.0, 126.6, 120.2, 117.3, 116.8, 100.8, 70.6, 65.0, 55.1, 53.1, 40.028, 25.5, 17.7, –5.8, –6.0. IR (thin film) (cm˗1): 2235 (w), 1607 (m), 1534 (s), 1168 (s), 1088 (s). HRMS (ESI-TOF) m/z: [M+NH4]+ Calcd for C36H43N4O8S2Si 751.2286; Found 751.2289. Methyl (S)-4-Benzyloxy-8-(tert-butyldimethylsilyloxymethyl)6-(4-cyanobenzenesulfonyl)-3,6,7,8-tetrahydropyrrolo[3,2e]indole-2-carboxylate (9): To a solution of the nitroindoline 7 (30.00 g, 40.88 mmol, 1.00 equiv.) in anhydrous acetonitrile (300 mL, water content ranged between 39.9137 and 101.5740 ppm by Karl Fischer analysis) was cooled to an internal temperature of 5 °C and acetic acid29 (23.4 mL, 408.8 mmol, 10.0 equiv.) was added. The system was placed under a nitrogen atmosphere and

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The Journal of Organic Chemistry

zinc dust30,31 (280 °C, at 260 °C 13 darkens. [α]D22: +10.19 ° (c = 14.95 mg/mL, DMF). 1H NMR (400 MHz, DMSOd6) δ: 11.54 (d, J=1.5 Hz, 1H), 11.32 (d, J=1.3 Hz, 1H), 9.68 (s, 1H), 7.77 (br s, 1H), 7.13 (d, J=2.0 Hz, 1H), 6.99 (br d, J=1.8 Hz, 1H), 6.94 (s, 1H), 4.94 (t, J=5.2 Hz, 1H), 4.56 (br t, J=10.0 Hz, 1H), 4.34 (br dd, J=10.9, 3.8 Hz, 1H), 3.93 (s, 3H), 3.87 (s, 3H), 3.74-3.81 (m, 7H), 3.64-3.70 (m, 1H), 3.43-3.49 (m 1H). 13C NMR (101 MHz, DMSO-d6) δ: 161.7, 159.8, 149.2, 143.0, 139.8, 139.2, 137.9, 131.8, 127.8, 125.9, 125.2, 124.5, 123.4, 114.8, 106.8, 105.7, 100.9, 98.1, 63.4, 61.2, 61.0, 56.0, 54.5, 51.8, 43.2. IR (thin film) (cm˗1): 3436 (m), 3342 (br w), 1716 (m), 1583 (m), 1315 (s). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C25H26N3O8 496.1714; Found 496.1724. (+)-Duocarmycin SA (1): Caution!! (+)-Duocarmycin SA is a potent toxin!! Appropriate PPE and laboratory hygiene are necessary when performing this reaction and handling any samples of, reaction streams containing, or equipment/instruments in contact with 1. The following reaction was performed in a laboratory equipped for handling high potency compounds. To a flask containing 13 (1.00 g, 2.02 mmol, 1.00 equiv.) and ADDM16 (776 mg, 3.03 mmol, 1.50 equiv.) was added THF (15.0 mL) under nitrogen. To the slurry was added tri-n-butylphosphine (770 uL, 3.03 mmol, 1.50 equiv.) and after ~5 min the mixture became homogeneous. The solution was stirred for 2 h, then quenched by pouring into water (15 mL). The solution was extracted with dichloromethane (1 x 15 mL, then 2 x 10 mL). The combined organic extracts were concentrated in vacuo to afford a gel. To the gel was added 25 mL hexanes and was stirred vigorously until all the gel had converted into a solid (~15-20 min). The solids were collected by filtration and washed with additional hexanes (25 mL). The solids were dissolved off the filter back into the original flask with dichloromethane (35 mL) and concentrated in vacuo to afford a solid. The solids were dissolved in the minimum amount of dichloromethane (25 mL) and applied to a column of silica gel, pre-wetted with dichloromethane. Care was

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The Journal of Organic Chemistry

taken not to let the column go dry. If the column runs dry, or is locally concentrated, the product may precipitate. If this occurs, the compound will streak heavily on the column. The product will appear on the column as a bright yellow band. The product was eluted with a sharp gradient of 0 to 25% acetone in dichloromethane.35 Fractions containing the product were pooled and concentrated in vacuo to afford an orange gel (1.405 g). The gel was stirred vigorously with hexanes (10 mL) until completely converted to a light yellow-orange powder. The powder was collected by filtration and dried at ambient temperature under vacuum (100 torr) until a constant weight was achieved affording 1 as a light yellow-orange powder (912 mg, 94%) which was identical in all respects with the previously reported literature.6,9 Solid samples of (+)-duocarmycin SA (1) are stored under nitrogen at –20 °C. Rf (30% acetone in dichloromethane, silica gel): 13 0.16 (UV), 1 0.51 (UV, visual, yellow spot). M.p. (dichloromethane/acetone/hexanes): >250 °C, at 200 °C 1 darkens. [α]D22: +188.39 ° (c = 0.34 mg/mL, methanol). 1H NMR (400 MHz, DMSO-d6) δ: 9.95 (br s, 1H), 9.34 (br s, 1H), 7.05 (s, 1H), 6.97 (d, J=2.3 Hz, 1H), 6.80 (s, 1H), 6.62 (d, J=2.3 Hz, 1H), 4.49 (dd, J=10.4, 4.8 Hz, 1H), 4.41 (d, J=10.4 Hz, 1H), 4.09 (s, 3H), 3.96 (s, 3H), 3.93 (s, 3H), 3.91 (s, 3H), 2.81 (app dt, J=7.6, 4.8 Hz, 1H), 1.76 (dd, J=7.6, 4.6 Hz, 1H), 1.59 (app t, J=4.7 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ: 177.9, 161.5, 161.1, 160.9, 150.3, 141.0, 138.8, 131.5, 129.9, 128.4, 126.7, 126.3, 123.2, 112.5, 107.7, 107.5, 97.5, 61.4, 61.1, 56.2, 54.9, 52.1, 31.3, 26.0, 23.5. IR (thin film) (cm˗1): 3415 (br w), 3190 (br w), 1713 (m), 1640 (m), 1271 (s). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C25H24N3O7 478.1609; Found 478.1613. Synthesis of 11: 2-Bromo-3,4,5-trimethyoxybenzaldehyde (S8)36: To a three neck round bottomed flask equipped with a thermocouple was added 3,4,5-trimethoxybenzaldehyde (14, 50.00 g, 249.7 mmol, 1.00 equiv.) and acetonitrile (500 mL) then was allowed to stir until a homogeneous solution formed (~5 min). The flask was placed under nitrogen and N-bromosuccinimide (47.14 g, 262.2 mmol, 1.05 equiv.) was added in one portion. The mixture was heated to an internal temperature of 50 °C for 1 h, cooled to room temperature, and diluted with toluene (500 mL). The solution was washed with a half saturated, aqueous solution of sodium thiosulfate (500 mL), then with a saturated aqueous solution of brine (250 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford a dark solid. The solid was dissolved in a 25 v% solution of isopropanol in hexane (200 mL) at 50 °C, then cooled to 38–40 °C, and seeded with product (250 mg). The seed bed was stirred for 1 h, then cooled to room temperature (23 °C) and held for 15 h. The slurry was then further cooled to an internal temperature of 5 °C and held for 1 h. The crystals were isolated by filtration and the cake was washed with a 25 v% solution of isopropanol in hexanes (100 mL) then dried in a vacuum oven at 50 °C until constant weight, to afford bromide S8 as off-white needles (57.62 g, 84%) which was identical in all respects with the previously reported literature.36 Rf (20% ethyl acetate in hexanes, silica gel): 14 0.26 (UV), bromide S8 0.53 (UV). M.p. (isopropanol/hexanes): 58.5– 59.5 °C. 1H NMR (400 MHz, CDCl3) δ: 10.30 (s, 1H), 7.31 (s, 1H), 3.99 (s, 3H), 3.92 (s, 3H), 3.91 (s, 3H). 13C NMR (101 MHz, CDCl3) δ: 191.0, 153.0, 150.8, 148.7, 128.8, 115.6, 107.4, 61.24, 61.17, 56.2. IR (thin film) (cm˗1): 2942 (m), 2866 (m), 1691 (s), 1579 (m), 1107 (s). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C10H12O4Br 274.9914; Found 274.9919.

(Z)-4-(2-Bromo-3,4,5-trimethoxybenzylidene)-2-phenyloxazol5-one (S9): To a three neck round bottomed flask equipped with a thermocouple was added 2-bromo-3,4,5trimethoxybenzaldehyde (S8, 40.00 g, 145.4 mmol, 1.00 equiv.), freshly powdered potassium acetate (7.14 g, 72.7 mmol, 0.50 equiv.), THF (200 mL) and acetic anhydride (41.2 mL, 436.2 mmol, 3.00 equiv.). The light slurry was placed under nitrogen and heated to an internal temperature of 60 °C. Solid N-Bzglycine (29.54 g, 159.9 mmol, 1.10 equiv.) was added in small (~2.0 g) portions though a funnel, against a slight nitrogen flow from the round bottom flask, at a rate that maintained the internal temperature at 60±3 °C (~5 min, minor delayed exotherm). The light brown slurry becomes a red/orange slurry and is allowed to stir for 2 h at 60 °C. An addition funnel was attached, filled with a 10 v% solution of water in isopropanol (400 mL) and the solution was added at a rate that maintained the internal temperature at 55 °C (~1.25 h). The yellow/orange slurry was cooled to room temperature, then to an internal temperature of 5 °C, and held for 30 min. The crystals were isolated by filtration, then dried in a vacuum oven at 50 °C until constant weight, to afford oxazolone S9 as dense, yellow prisms (51.58 g, 85%). Rf (20% ethyl acetate in hexanes, silica gel): bromide S8 0.53 (UV), oxazolone S9 0.39 (UV, visual, yellow spot). M.p. (THF/aqueous isopropanol): 167–168 °C. 1H NMR (400 MHz, CDCl3) δ: 8.54 (s, 1H), 8.12 (d, J=7.8 Hz, 2H), 7.73 (s, 1H), 7.64 (t, J=7.4 Hz, 1H), 7.54 (t, J=7.7 Hz, 2H), 4.04 (s, 3H), 4.00 (s, 3H), 3.92 (s, 3H). 13C NMR (101 MHz, CDCl3) δ:37 167.2, 163.9, 152.5, 151.0, 145.8, 133.6, 129.4, 129.1, 128.3, 128.2, 125.4, 115.6, 111.9, 61.3, 61.0, 56.1. 1H NMR (400 MHz, THF-d8) δ: 8.60 (s, 1H), 8.13-8.16 (m, 2H), 7.65 (tt, J=7.3, 1.6 Hz, 1H), 7.59 (s, 1H), 7.53-7.58 (m, 2H), 3.99 (s, 3H), 3.93 (s, 3H), 3.86 (s, 3H). 13C NMR (101 MHz, THF-d8) δ: 167.3, 165.4, 154.0, 152.2, 147.1, 135.1, 134.6, 130.1, 129.24, 129.16, 128.5, 126.9, 115.7, 112.9, 61.4, 61.3, 56.6. IR (thin film) (cm˗1): 1797 (s), 1648 (m), 1482 (m), 1327 (s), 1170 (m). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C19H17O5NBr 418.0285; Found 418.0290. Methyl (Z)-2-Benzamido-3-(2-bromo-3,4,5trimethoxyphenyl)acrylate (15): To a three neck round bottomed flask equipped with a thermocouple was added the oxazolone S9 (40.00 g, 95.65 mmol, 1.00 equiv.), methanol (200 mL) and triethylamine (1.33 mL, 9.57 mmol, 0.10 equiv.). The yellow suspension was heated to an internal temperature of 60 °C, then held for 0.5 h, whereupon a light yellow homogeneous solution formed. Heptane (200 mL) was added, maintaining an internal temperature >50 °C. The biphasic mixture was cooled to an internal temperature of 40 °C, seeded with product (200 mg), and the mixture was stirred for 30 min before being cooled to room temperature. The solvents were concentrated in vacuo to approximately 200 mL, additional heptane (200 mL) was added, and the solvents were again concentrated to approximately 200 mL. The slurry was cooled to an internal temperature of 5 °C, held for 30 min, then the crystals were isolated by filtration and dried in a vacuum oven at 50 °C until constant weight, to afford the product 15 as dense, light yellow rods (42.3 g, 98%). Rf (40% ethyl acetate in hexanes, silica gel): oxazolone S9 0.61 (UV, visual, yellow spot), 15 0.41 (UV). M.p. (methanol/heptane): 139–140 °C. 1H NMR (400 MHz, CDCl3) δ: 7.82 (app d, J=7.3 Hz, 2H), 7.78 (br s, 1H), 7.60 (s, 1H), 7.54 (app tt, J=7.5, 1.4 Hz, 1H), 7.44 (app t, J=7.6 Hz, 2H), 6.92 (s, 1H), 3.89 (s, 3H), 3.88 (br s, 6H), 3.55 (s, 3H). 13C NMR (101 MHz, CDCl3) δ: 165.8, 165.4, 152.4, 150.9, 143.6, 133.2, 132.3, 130.2, 129.4, 128.8,

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127.2, 125.5, 111.9, 108.0, 61.1, 60.9, 55.8, 52.9. IR (thin film) (cm˗1): 3393 (m), 1725 (s), 1674 (s), 1470 (s), 1250 (m). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C20H21O6NBr 450.0547; Found 450.0550. Methyl 1-Benzoyl-5,6,7-trimethoxyindole-2-carboxylate (S10): To a three neck round bottom flask was added the dehydroamino ester 15 (30.00 g, 66.62 mmol, 1.00 equiv.), 1,10-phenanthroline (910 mg, 5.00 mmol, 0.075 equiv.), potassium carbonate (23.02 g, 166.6 mmol, 2.50 equiv.) and anhydrous DMF (150 mL, water content containing from 77.42 to 220.38 ppm was successfully used). The mixture was stirred and nitrogen was sparged though the suspension for 10 min, during which time the supernatant became bright yellow. Copper(I) iodide (634 mg, 3.33 mmol, 0.05 equiv.) was added and the mixture became deep red. The suspension was heated to an internal temperature of 80 °C under nitrogen, held for 2 h, then was cooled to an internal temperature of 5 °C. An addition funnel filled with water (450 mL) was attached, and water was added at a rate such that the internal temperature did not exceed 10 °C (~1.25 h). The crystals were isolated by filtration, washed with water (2 x 120 mL), and pulled dry with vacuum thoroughly for ~30 min to afford a dark colored crystals. The crystals were dissolved in THF (300 mL) with mild heating to afford a dark, slightly hazy suspension. Activated carbon (DARCO® G-60, 100 mesh, 3.0 g) was added and the mixture was stirred for 15 min before being filtered over a plug of Celite (1” dia, 0.5” ht). The plug was washed with additional THF (2 x 30 mL). The orange/brown filtrate and washings were concentrated in vacuo to afford a brown solid. To the solid was charged methanol (750 mL) and the mixture was heated to reflux for ~15 min to dissolve the vast majority of the solids. The mixture was allowed to cool slowly over 45 min to room temperature, the volume was carefully reduced in vacuo to approximately 120 mL then the slurry was cooled to 5 °C. The crystals were isolated by filtration38 and washed with cold (~5 °C) methanol (2 x 30 mL). To wash, suction was suspended, the cold methanol was charged to the filter, the cake was agitated carefully for 5-10 seconds, and then the wash was removed by suction. The white, granular crystals which were then dried in a vacuum oven at 50 °C until constant weight, to afford indole S10 (23.19 g, 94%). Rf (40% ethyl acetate in hexanes, silica gel): 15 0.41 (UV), indole S10 0.69 (UV). M.p. (methanol): 139–140 °C. 1H NMR (400 MHz, CDCl3) δ: 7.76 (app d, J=7.1 Hz, 2H), 7.60 (app tt, J=7.4, 1.1 Hz, 1H), 7.46 (app t, J=7.8 Hz, 2H), 7.27 (s, 1H)39, 6.89 (s, 1H), 3.93 (s, 3H), 3.85 (s, 3H), 3.76 (s, 3H), 3.53 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ: 171.0, 161.1, 150.8, 141.8, 139.6, 134.5, 133.8, 129.8, 129.1, 128.7, 128.3, 122.7, 111.6, 97.9, 61.1, 60.4, 56.2, 51.9. IR (thin film) (cm˗1): 1724 (s), 1709 (s), 1535 (m), 1454 (m), 1233 (s). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C20H20O6N 370.1285; Found 370.1284. 5,6,7-Trimethoxyindole-2-carboxylic Acid (16): To a suspension of the indole S10 (55.00 g, 148.9 mmol, 1.00 equiv.) in THF (275 ml) was added solution of aqueous sodium hydroxide (2.5 N, 180.0 mL, 446.7 mmol, 3.0 equiv.). The headspace was purged with nitrogen40 and the mixture was heated to an internal temperature of 60 °C and vigorously stirred for 3 h, becoming a homogeneous light yellow solution. The mixture was cooled to room temperature, then poured into an aqueous solution of hydrochloric acid (2.33 M, 275 mL, 640 mmol). The layers were separated and the aqueous layer was extracted with 2methyltetrahydrofuran (2 x 275 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in

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vacuo to afford an off white solid. To the solid was added methanol (110 mL) and the solvent line is marked.24 Additional methanol (715 mL) is added and the mixture is brought to reflux to dissolve the solids. The solution was cooled to an internal temperature of 40 °C and seeded with product (550 mg), and the mixture was cooled to room temperature and stirred for 15 h. The volume was carefully reduced in vacuo to approximately 110 mL (4.0 mL/g indole) then the slurry was cooled to 5 °C and held for 30 min. The crystals were isolated by filtration41 and washed with cold (~5 °C) methanol (2 x 110 mL). To wash, suction was suspended, the cold methanol was charged to the filter, the cake was agitated carefully for 5-10 seconds, and then the wash was removed by suction. The white, granular crystals which were then dried in a vacuum oven at 50 °C until constant weight, to afford the acid 16 (32.49 g, 87%) which was identical in all respects with the previously reported literature.9 Rf (75% hexanes, 20% ethyl acetate, 5% acetic acid, silica gel): indole S10 0.49 (UV), 16 0.25 (UV). M.p. (methanol): 220–221 °C. 1H NMR (400 MHz, DMSO-d6) δ: 12.73 (s, 1H), 11.57 (br s, 1H), 7.00 (d, J=2.0 Hz, 1H), 6.91 (s, 1H), 3.89 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ: 162.5, 149.2, 140.2, 139.3, 128.5, 126.7, 123.0, 108.3, 98.0, 61.1, 60.9. 55.9. IR (thin film) (cm˗1): 3281 (br s), 1657 (s), 1539 (m), 1504 (m), 1262 (s). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C12H14O5N 252.0866; Found 252.0870. 5,6,7-Trimethoxyindole-2-carbonyl Chloride (11): Carboxylic acid 16 (30.00 g, 119.4 mmol, 1.00 equiv.) and anhydrous THF (300 mL, water content by KF = 38.6576 ppm) were added to a round bottomed flask and stirred for 5 min forming a very light slurry. Anhydrous DMF (0.186 mL, 2.388 mmol, 0.020 equiv., water content by KF = 147.901 ppm) was added and the system was placed under nitrogen with a vent into a solution of 10 wt% aqueous potassium phosphate. Oxalyl chloride (15.5 mL, 179.1 mmol, 1.50 equiv.) was added dropwise over 20 min, forming a yellow solution and evolving gas mildly. The solution has held for an additional 1 h, then concentrated in vacuo to afford a deep yellow powder that was dissolved in methyl tert-butyl ether (600 mL) at reflux, leaving behind a small amount of a precipitate. The mixture was filtered hot over a 0.45 µm polypropylene filter and concentrated in vacuo to afford a yellow solid. The solids were dissolved in toluene (150 mL) at an internal temperature of 60 °C under mechanical stirring, and heptane (150 mL) was added slowly, maintaining the internal temperature at 60 °C (~20 min). The internal temperature was cooled to 50 °C and the product began to crystallize heavily. An additional charge of heptane (150 mL) was added, maintaining the internal temperature at 50 °C (~30 min), then the temperature is lowered to 5 °C over 30 min. The product was isolated by filtration and dried in a vacuum oven at 50 °C and 100 torr with a slight nitrogen sweep to constant weight to afford the acid chloride 11 as bright yellow needles (26.7 g, 92%) which was identical in all respects with the previously reported literature.9 This product was sealed under nitrogen and stored at –17 to –20 °C. Rf (20% ethyl acetate, 75% hexanes, 5% acetic acid, silica gel): 16 0.25 (UV), 11 0.42 (UV). M.p. (toluene/heptane): 120.5–121.5 °C. 1H NMR (400 MHz, C6D6)42 δ: 9.00 (s, 1H), 7.24 (d, J=2.3 Hz, 1H), 6.44 (s, 1H), 3.74 (s, 3H), 3.66 (s, 3H), 3.39 (s, 3H). 13C NMR (101 MHz, C6D6) δ: 159.2, 151.9, 143.4, 139.5, 130.1, 129.7, 123.6, 117.0, 98.5, 61.5, 61.2, 56.1. IR (thin film) (cm˗1): 1720 (s), 1495 (m), 1310 (m), 1112 (m), 826 (m). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C12H13O4NCl 270.0528; Found 270.0532.

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Synthesis of L1: (S)-(+)-N,N-Dimethylamino-1-ferrocenylethylammonium LTartrate (S14): To43 a 250 mL round-bottomed flask was added triethylamine (23.5 mL, 166.6 mmol, 4.0 equiv.) and dichloromethane (30 mL). The solution was cooled to an internal temperature of –20 °C and formic acid (98%, 17.7 mL, 461.5 mmol, 10.0 equiv.) was added dropwise, keeping the internal temperature below –15 °C, then the solution was warmed to room temperature. Acetylferrocene (S11, 10.0 g, 41.6 mmol, 1.0 equiv.) was added followed by RuCl[(S,S)-TsDPEN](mesitylene) (1.38 g, 2.08 mmol, 0.05 equiv.). A remaining charge of dichloromethane (20 mL) was used to wash any solids down into the reaction mixture (total volume: 50 mL). The flask was sealed with a septa and a 16 gauge needle was inserted to allow generated carbon dioxide to escape. The mixture was stirred for 5 days, then concentrated in vacuo, then down from toluene (50 mL) to afford a dark solid mass that was used without further purification. A small aliquot was purified by flash column chromatography over silica gel (0 to 30% ethyl acetate in hexanes gradient) for characterization purposes and was identical in all respects with the previously reported literature.43 The light orange powder was found to have an enantiomeric ratio of 99.26 to 0.74 favoring the (S) configuration as determined by chiral stationary phase HPLC. Rf (20% ethyl acetate in hexanes, silica gel): acetylferrocene 0.39 (UV), (S)-1-ferrocenylethanol (S12) 0.34 (UV), Rf (20% ethyl acetate in hexanes, basic alumina): acetylferrocene 0.49 (UV), (S)-1-ferrocenylethanol (S12) 0.21 (UV). M.p. (ethyl acetate/hexanes): 77–78 °C. [α]D22: +25.6 ° (c = 10.0 mg/mL, dichloromethane). 1H NMR (400 MHz, CDCl3) δ: 4.50-4.58 (app br s, 1H), 4.15-4.30 (m, 9H), 1.80-1.88 (app br s, 1H), 1.45 (br d, J=5.6 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ: 95.2, 68.6, 68.22, 68.18, 66.45, 66.35, 65.5, 23.6. IR (thin film) (cm˗1): 3340 (br s), 1455 (m), 1409 (m), 1233 (m), 1092 (s). HRMS (ESI-TOF) m/z: [M]+ Calcd for C12H14OFe 230.0389; Found 230.0393. The crude residue from the previous step was dissolved in dichloromethane (100 mL) and 4-dimethylaminopyridine (514 mg, 4.16 mmol, 0.10 equiv.) was added, followed by triethylamine (10.20 mL, 72.89 mmol, 1.75 equiv.) and acetic anhydride (6.69 mL, 70.81 mmol, 1.70 equiv.). The reaction mixture was allowed to stir for 1 h, then a solution of 1.0 N aqueous hydrochloric acid (100 mL) was added, the layers were separated, and the aqueous layer was extracted with methyl tertbutyl ether (3 x 100 mL, visualization of difficult-to-see phase splits were aided by using a flashlight or by the addition of small amounts of ice chips). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford the acylated product S13 as a dark red-brown solid (13.83 g) that was used without further purification. Rf (20% ethyl acetate in hexanes, basic alumina): (S)-1-ferrocenylethanol (S12) 0.25 (UV), acylated product S13 0.78 (UV). The crude acetate44 S13 (13.83 g) was dissolved in methanol (200 mL) and an aqueous solution of 40 wt% dimethylamine (28.0 mL, 221.6 mmol, 5.3 equiv.) was added. The mixture was stirred for 24 h and then the methanol was removed in vacuo to afford a dark aqueous solution. A solution of aqueous phosphoric acid (5.0 mL of an 85 wt% aqueous solution, diluted to a total of 50 mL with water) was added. The pH of the resulting solution was approximately 2. The mixture was washed with methyl tert-butyl ether (2 x 100 mL). Solid sodium hydroxide (5.0 g) was added slowly (Caution!! exothermic) and the resulting solution (pH >10) was extracted

with dichloromethane (3 x 75 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude amine S14 as a dark red oil (9.37 g). Rf (20% ethyl acetate in hexanes, basic alumina): acylated product S13 0.78 (UV), amine freebase S14-freebase 0.46 (UV, Rf can vary based on loading). The crude amine S14-freebase (9.37 g) was dissolved in methanol (20 mL) and the solution was heated to 60 °C. To a separate flask was dissolved L-(+)-tartaric acid (5.47 g, 36.43 mmol, 1.00 equiv. with respect to crude amine) in methanol (20 mL) at 60 °C. The hot acid solution was added to the solution of the amine, maintaining an internal temperature of 60 °C. Additional methanol (6.85 mL) was used to quantitate the transfer of the acid. Once the addition was complete, the mixture was seeded with product (20 mg) and cooled to room temperature slowly over 4.5 h, then held an additional 19.5 h. The crystals were collected by filtration and washed with a minimal amount of methanol (5 mL), then dried to afford salt S14 (12.45 g, 73% from acetylferrocene) as orange crystals which was similar with the previously reported literature44 and additionally characterized here. The product was found to have an enantiomeric ratio of 99.92 to 0.08 favoring the (S) configuration as determined by chiral stationary phase HPLC. M.p. (methanol): 158–163 °C. [α]D22: +9.0 ° (c = 10.0 mg/mL, DMF). 1H NMR (400 MHz, DMSO-d6) δ: 6.25-10.25 (br s, 4H), 4.43 (br s, 1H), 4.37 (br s, 1H), 4.28 (br s, 2H), 4.18-4.26 (m, 6H), 4.01 (s, 2H), 2.36 (s, 6H), 1.59 (d, J=6.7 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ: 174.6, 81.4, 72.1, 70.2, 68.9, 68.58, 68.50, 67.6, 59.8, 38.3, 14.2. IR (KBr) (cm˗1): 3494 (s), 3320 (s), 2639 (s), 1715 (m), 1408 (s). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C14H20NFe 258.0940; Found 258.0946. (R,R)-2,2”-Bis[(S)-1-diphenylphosphinylethyl]-1,1”biferrocene Toluene Solvate (S18)45: The tartrate salt S14 (50.0 g, 122.8 mmol, 1.0 equiv.) was partitioned between dichloromethane (250 mL), and an aqueous solution of sodium hydroxide (25.0 g dissolved in 250 mL water). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 x 250 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo, then concentrated down from benzene (2 x 50 mL) to afford the free base S14-freebase as a dark oil (32.91 g). A sample of S14-freebase was analyzed by polarimetry: [α]D22 – 12.9 ° (c = 15.0 mg/mL, absolute ethanol ). The oil was dissolved in diethyl ether (298 mL) and cooled to an internal temperature of +1.5 °C using an ice-water bath.46 A 1.4 M cyclohexane solution of sec-butyl lithium (100 mL, 140.0 mmol, 1.14 equiv.) was added at a rate maintaining an internal temperature below +5.0 °C (30 min). The solution was allowed to stir for 1 h, and then it was cooled to an internal temperature of –68 °C with a dry ice-acetone bath. A solution of iodine (35.9 g, 141.3 mmol, 1.15 equiv.) in THF (298 mL) was added dropwise, maintaining an internal temperature below –50 °C (approximately 50 min). The suspension was allowed to stir at –60 °C for 1 h, then was warmed to room temperature and washed with a half saturated, aqueous solution of sodium thiosulfate (250 mL). The aqueous layer was extracted with diethyl ether (2 x 100 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford a dark red oil. The red oil was passed through a plug of basic alumina (0 to 50% ethyl acetate in hexanes gradient) to afford the iodide as dark red crystals (40.99 g, 87%). Rf (10% ethyl acetate in hexanes, basic

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alumina): amine freebase S14-freebase 0.29 (UV, Rf can vary based on loading), iodide S15 0.43 (UV, Rf can vary based on loading). The iodide S15 (30.0 g, 78.3 mmol, 1.0 equiv.) was dissolved in acetone (150 mL) then cooled in an ice-water bath to an internal temperature of 1.0 °C and iodomethane (22.1 mL, 352.4 mmol, 4.50 equiv.) was added dropwise, maintaining an internal temperature below 15 °C (~5 min), whereupon a solid precipitated.47 The heavy slurry was allowed to stir at room temperature for 30 min and concentrated in vacuo (Caution!! iodomethane in headspace), then down from acetonitrile (2 x 60 mL) to afford the crude ammonium iodide salt S16. Separately, diphenylphosphine oxide (20.0 g, 94.0 mmol, 1.2 equiv.) was dissolved in anhydrous THF (210 mL) and cooled in an ice-water bath to an internal temperature of 0.9 °C. A 1.6 M solution of n-butyl lithium in hexanes (58.7 mL, 94.0 mmol, 1.20 equiv.) was added dropwise, maintaining an internal temperature below 10 °C (~45 min). The initially clear solution became cloudy with a white precipitate, and slowly developed an orange coloration near the end of the addition. The suspension was allowed to stir for 1.5 h, then was concentrated in vacuo to afford a light yellow residue. The ammonium iodide salt S16 was slurried in acetonitrile (400 mL) and transferred to the residue of the diphenylphosphine oxide anion. A remaining charge of acetonitrile (100 mL, total volume: 16.7 mL/g iodide S15) was used to quantitate the transfer. The slurry was heated to reflux and stirred for 2 h before being cooled to room temperature and concentrated in vacuo (Caution!! trimethylamine in headspace). The mass was partitioned between methyl tert-butyl ether (300 mL) and water (300 mL). The aqueous layer was extracted with methyl tert-butyl ether (300 mL) and the combined organic layers were washed with a solution of 5 wt% citric acid in a saturated aqueous solution of brine (90 mL), then a saturated aqueous solution of brine (90 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford a dark oil that was passed through a plug of silica gel (0 to 10% methanol in dichloromethane gradient) to afford the product phosphine oxide S17 as a viscous, dark red oil that was used without further purification (42.4 g). Rf (5% methanol in dichloromethane, silica gel): iodide S15 0.09 (UV, Rf can vary based on loading), phosphine oxide S17 0.45 (UV, Rf can vary based on loading). To an oven-dried round bottomed flask was added bis(triphenylphosphine)nickel(II) chloride (25.6 g, 39.2 mmol, 0.50 equiv.), tetraethylammonium iodine (20.6 g, 78.3 mmol, 1.00 equiv.) and freshly washed zinc dust (7.7 g, 117.5 mmol, 1.50 equiv.).31 Under a heavy flow of nitrogen, anhydrous DMF (156.5 mL) was added and the heavy slurry was vigorously stirred under nitrogen for 30 min. Initially, a deep blue suspension was formed, that faded to a deep green, then maroon color (all within ~10 min). Separately, the phosphine oxide S17 (42.4 g, 78.3 mmol, 1.00 equiv.) was dissolved in anhydrous DMF (78.3 mL) with heating. The dark red solution was cooled to room temperature and degassed by nitrogen sparging for 20 min, then transferred to the maroon catalyst mixture via cannula and heated in a 120 °C bath for 2 h. The reaction is then cooled to room temperature, and partitioned between dichloromethane (600 mL) and water (600 mL) forming a biphasic mixture with heavy precipitates, all of which was passed through a plug of Celite (4” dia, 3” ht, gentle agitation of the top layer of Celite with a spatula can maintain a good filtration rate) removing a sticky black film. The two layers of the filtrate were separated, and the aqueous

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layer was extracted with dichloromethane (2 x 90 mL). The combined organic layers were washed with a saturated aqueous solution of brine (2 x 300 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford a dark red oil. The oil was purified by flash column chromatography over silica gel (0 to 40% acetone in toluene) to afford a thick orange paste (42.6 g). The paste was dissolved in toluene (150 mL) at an internal temperature of 80 °C, then allowed to cool to room temperature for 15 h. The orange crystals were collected by filtration, washed with toluene (40 mL) and dried until constant weight to afford the dimer S18 as bright orange crystals (17.0 g, 44% from iodide) which was identical in all respects with the previously reported literature.45c The product was found to have an enantiomeric ratio of >99.9% favoring the (S,S)-(R,R) configuration as determined by chiral stationary phase HPLC. Rf (20% acetone in toluene, silica gel): phosphine oxide S17 0.28 (UV, Rf can vary based on loading), dimer S18 0.37 (UV, Rf can vary based on loading). M.p. (toluene): 153–156 °C. [α]D22: +138.0 ° (c = 10.0 mg/mL, chloroform). 1H NMR (400 MHz, CDCl3) δ: 7.79-7.91 (m, 4H), 7.68 (app dd, J=10.1, 8.3 Hz, 4H), 7.42-7.56 (m, 6H), 7.33 (td, J=7.5, 1.0 Hz, 2H), 7.25-7.31 (m, 6H, PhMe), 7.15-7.24 (m, 6H, partial PhMe), 7.06 (td, J=7.8, 2.8 Hz, 4H), 4.38 (m, 12H), 4.10 (t, J=2.5 Hz, 2H), 4.04 (br s, 2H), 3.78-3.91 (m, 2H), 2.37 (s, 5.6 H, PhMe), 1.68 (dd, J=16.7, 7.3 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ: 137.8, 133.9 (d, J=94.4 Hz), 132.2 (J=8.8 Hz), 132.0 (d, J=93.7 Hz), 131.3 (d, J=8.8 Hz), 131.2 (d, J=2.9 Hz), 130.9 (d, J=2.9 Hz), 129.0, 128.2, 128.16 (d, J=11.0 Hz), 128.0 (d, J=11.7 Hz), 125.3, 90.6, 84.4 (d, J=6.6 Hz), 72.6, 69.3, 68.3 (d, J=5.1 Hz), 65.4, 30.2 (d, J=68.1 Hz), 21.4, 19.1. 31P NMR (162.0 MHz, CDCl3) δ: 34.84. IR (thin film) (cm˗1): 3413 (br s), 2877 (m), 1618 (w), 1184 (s), 1171 (s). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C48H45O2Fe2P2 827.1588; Found 827.1603. (R,R)-2,2”-Bis[(S)-1-diphenylphosphinoethyl]-1,1”biferrocene Benzene Solvate (L1)48: To an autoclave was added the dimer S18 (20.00 g, 20.15 mmol, 1.00 equiv.), benzene (54 mL) and triethylamine (23.3 mL, 167.3 mmol, 8.3 equiv.). The headspace was blanketed with nitrogen, trichlorosilane (13.0 mL, 127.0 mmol, 6.3 equiv.) was added and the reactor was quickly sealed. The mixture was heated to an internal temperature of 100 °C for 19 h then was cooled to room temperature. The contents of the reactor were transferred cautiously to a room temperature solution of 30 wt% aqueous sodium hydroxide (40 g sodium hydroxide diluted to 133 g with water), using 400 mL of benzene to aid in the transfer (Caution!! exothermic and will produce wisps of a white precipitate in air, perform quench in a well ventilated hood). The mixture was heated to 60 °C for 30 min under nitrogen to dissolve the solid silicon species then cooled to room temperature affording a biphasic mixture. The layers were separated, and the organic layer was washed with water (100 mL), then a saturated aqueous solution of brine (100 mL). The mixture was dried over sodium sulfate, filtered and concentrated to approximately 50% volume in vacuo. The red oil was passed through a plug of basic alumina (3.25” dia, 1.5” ht) eluting with benzene until the eluent ran colorless (~1 L). The solution was concentrated in vacuo to afford an orange paste (16.98 g). The paste was dissolved in boiling benzene (60 mL) under a nitrogen atmosphere then cooled to room temperature. Absolute ethanol (200 proof, 40 mL) was added then the mixture was seeded with product (10 mg), additional ethanol (20 mL) was added and the slurry aged for 15 min to develop a seed bed. Additional ethanol (120 mL) was added slowly over 10 min and the slurry was aged for 1 h. The bright orange crystals were collected by filtration,

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The Journal of Organic Chemistry

washed with absolute ethanol (2 x 20 mL) and dried in vacuo at room temperature to afford the product L1 as bright orange crystals (10.05 g, 57%) which was identical in all respects with the previously reported literature.48 A sample that was stored on the benchtop in a vial sealed with parafilm showed no signs of aerial oxidation by 31P and 1H NMR over 15 months, however we typically store it in a nitrogen-filled glovebox. Rf (20% acetone in toluene, silica gel): dimer 0.37 (UV, Rf can vary based on loading), L1 0.98 (UV, Rf can vary based on loading). Rf (100% benzene, basic alumina): dimer 0.00, L1 0.95. M.p. (benzene/ethanol): 133–138 °C. [α]D22: +410.0 ° (c = 5.0 mg/mL, chloroform). 1H NMR (400 MHz, CDCl3) δ: 7.35 (br s, 6H), 7.10-7.30 (m, 20H), 4.55 (dd, J=2.3, 1.3 Hz, 2H), 4.29 (s, 10 H), 4.12 (t, J=2.4 Hz, 2H), 3.79 (m, 2H), 3.49 (q, J=6.8 Hz, 2H), 1.35 (app t, J=7.2 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ: 138.9 (app dd, J=10.2, 7.3 Hz), 136.0 (app dd, J=12.4, 9.5 Hz) 135.1 (m), 132.1 (m), 128.4, 128.3, 128.0 (t, J=2.2 Hz), 127.5 (t, J=3.3 Hz), 127.2, 93.1 (m), 84.4 (t, J=2.2 Hz), 71.7, 69.3, 68.0 (t, J=3.7 Hz), 65.4, 29.2 (m), 17.0. 31P NMR (162.0 MHz, CDCl3) δ: 1.52. IR (thin film) (cm˗1): 3413 (br s), 1618 (m), 1434 (m), 815 (s), 739 (s). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C48H45Fe2P2 795.1690; Found 795.1711.

Associated Content The Supporting Information is available free of charge Reference schemes, an expanded bibliography, analytical data (1H and 13C NMR) for all compounds, chiral HPLC methods, and spectra, methods for generating seeds for crystallizations as well as optimization details. crystal structures_4_duocarmycin.cif

Author Information Corresponding Author *[email protected]

Notes A provisional patent has been filed for this work.

Acknowledgments We’d like to thank Drs. David Kronenthal and Rob Waltermire for support of this work. Drs. Neil Strotman, Yi Xiao, Yichen Tan and Ms. Jeanne Ho for assistance with high pressure equipment. We’d like to thank Mr. Mike Peddicord and Mr. Jonathan Marshall for HRMS support and Mrs. Merrill Davies for HPLC support. We thank Mr. Tianhong Zhang for assistance obtaining infrared data and optical rotation data. We thank Dr. Adrian Ortiz for reviewing the manuscript. We thank Professor Phil Baran for helpful discussions on the composition of the manuscript.

1

For a summary see: Yasuzawa, T.; Muroi, K.; Ichimura, M.; Takahashi, K.; Ogawa, T.; Takahashi, K.; Sano, H.; Saitoh, Y. Chem. Pharm. Bull. 1995, 43, 378. 2 Ichimura, M.; Ogawa, T.; Takahashi, K.; Mihara, A.; Takahashi, I.; Nakano, H. Oncol. Res. 1993, 5, 165. 3 Ichimura, M.; Ogawa, T.; Takahashi, K.; Kawamoto, I.; Yasuzawa, T.; Takahashi, I.; Nakano, H. J. Antibiot. 1990, 43, 1037. 4 Research spans across multiple individual and collaborative academic and industrial labs. For example, contributions from the Tietze lab, Seattle Genetics, the Sinha lab, Bristol-Myers Squibb, Synthon

Biopharmaceuticals, Searcey & Novartis Labs. Please see the supporting information for a bibliography. 5 Beck, A.; Goetsch, L.; Dumontet, C.; Corvaïa, N. Nat. Rev. Drug Discov. 2017, 16, 315. 6 Boger, D. L.; Machiya, K. J. Am. Chem. Soc. 1992, 114, 10056. Tichenor, M. S.; Trzupek, J. D.; Kastrinsky, D. B.; Shiga, F.; Hwang, I.; Boger, D. L. J. Am. Chem. Soc. 2006, 128, 15683. 7 Muratake, H.; Matsumura, N.; Natsume, Chem. Pharm. Bull. 1998, 46, 559. 8 Fukuda, Y.; Terashima S. Tetrahedron Lett. 1997, 38, 7207. 9 Yamada, K.; Kurokawa, T.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2003, 125, 6630. 10 Tietze, L. F.; Haunert, F.; Feuerstein, T.; Herzig, T. Eur. J. Org. Chem. 2003, 562. 11 For a review see Mąkosza, M. Chem. Eur. J. 2014, 20, 5536. For relevant examples see: a) Mąkosza, M.; Glinka, T.; Kinowski, A. Tetrahedron, 1984, 40, 1863. b) Wojciechowski, K.; Mąkosza, M. Bull. Soc. Chim. Belg. 1986, 95, 671. 12 Kuwano, R.; Kashiwabara, M.; Sato, K.; Ito, T.; Kaneda, K.; Ito, Y. Tetrahedron: Asymmetry 2006, 17, 521. 13 Please see the supporting information for more details. 14 >20 protecting groups were explored, please see the supporting information for details. 15 Schmidt, M. A.; Stokes, R. W.; Davies, M. L.; Roberts, F. J. Org. Chem. 2017, 82, 4550. 16 Lanning, M. E.; Fletcher, S. Tetrahedron Lett. 2013, 54, 4624. 17 MacMillan, K. S.; Boger, D. L. J. Med. Chem. 2009, 52, 5771. 18 Becknell, N. C.; Hudkins, R. L. Preparation of pyridazino[4,5-b]indole derivatives with protein kinase inhibiting activity for treating angiogenic disorders and neurodegenerative diseases. Patent WO 2007/149557 A1, December 27, 2007. 19 This precatalyst solution is very air sensitive. If reaction stalling is observed, it has been demonstrated that an additional 0.001 equivalent charge of freshly prepared precatalyst solution can restore reactivity and with no loss of enantioselectivity. 20 The reaction can be examined for conversion here by sampling at 65 °C. At temperatures below 45 °C, the product can crystallize. Additionally, if at any point post-reaction completion the product crystallizes, it can be dissolved in dichloromethane for further manipulation. 21 A fresh bottle (purchased within 6 months) of ordinary magnesium turnings was used. “Activated” magnesium turnings, for example, prewashed with 0.5% aqueous HCl as in Brown, A. C.; Carpino, L .A. J. Org. Chem. 1985, 50, 1749, or with 5 v% TMSCl in THF (stirred for 30 min) also worked, but no significant difference was observed. 22 Total magnesium added can vary around 11-15 equiv. Initial charges of magnesium are more exothermic than the later charges. A magnesium charge rate that maintains the internal temperature below 35 °C is encouraged. After 10 equiv. of magnesium were added, any subsequent charges are accompanied with a 7 mL/g (with respect to Mg (i.e. 7 mL per 1 g magnesium)) charge of methanol. 23 The amount here is for ≤12 equiv. magnesium. If more magnesium is used, increase this quench amount to ensure the pH of the aqueous layer is