Rapid Access to 2,2-Disubstituted Indolines via Dearomative Indolic-Claisen Rearrangement: Concise, Enantioselective Total Synthesis of (+)-Hinckdentine A

The construction of 2,2-disubstituted indolines has long presented a synthetic challenge without any general solutions. Herein, we report a robust protocol for the dearomative Meerwein–Eschenmoser–Claisen rearrangement of 3-indolyl alcohols that provides efficient access to 2-substituted and 2,2-disubstituted indolines. These versatile subunits are useful for natural product synthesis and medicinal chemistry. The title [3,3] sigmatropic rearrangement proceeds in generally excellent yield and transfers the C3-indolic alcohol chirality to the C2 position with high fidelity, thus providing a reliable method for the construction of enantioenriched 2,2-disubstituted indolines. The power of this methodology is demonstrated through the concise and strategically unique total synthesis of the marine natural product hinckdentine A, which features a dearomative Claisen rearrangement, a diastereocontrolled hydrogenation of the alkene product, a one-pot amide-to-oxime conversion using Vaska’s complex, and a regioselective late-stage tribromination.

Room temperature refers to 22 °C. Higher temperatures were maintained using pre-heated oil baths; oil bath temperatures are reported. Lower temperatures were maintained using a cooling bath of acetone/dry ice (-78 °C), water/ice (0 °C), or NESLAB CB-80 Cryobath for all other temperatures in between. Similarly, reported temperature values are those of cooling baths.
Thin-layer chromatography (TLC) was performed using EMD Millipore silica gel 60 Å plates and visualization was achieved with either UV fluorescence quenching (254 nm), Hanessian's Stain (Cerium Ammonium Molybdate) with heat, or Seebach's stain (Ce(SO4)2 in phosphomolybdic acid) with heat. Flash column chromatography was performed on SiliCycle SiliaFlash P60 (40-63 μm particle size) using ACS grade solvents purchased from Fisher Scientific. Hexanes were freshly distilled prior to use to minimize H-grease content.
High-resolution mass spectral (HRMS) analyses were performed on Agilent Technologies 6224 TOF LC/MS using electrospray ionization (ESI) at the University of Chicago Mass Spectroscopy Core Facility. Optical rotations were measured on a Jasco DIP-1000 polarimeter using a 100 mm-path-length cell, c = g/100 mL. Infrared (IR) spectra were recorded on a Thermo Scientific Nicolet iS50 FT-IR spectrometer and are reported as a frequency of absorption (cm -1 ). Chiral high-performance liquid chromatography (HPLC) analyses were performed using an Agilent analytical chromatography system with commercial Chiralcel® columns equipped with a guard column.

Synthesis of Enatioenriched Alcohols
To a stirred solution (R)-MeCBS catalyst (37.5 mg, 0.13 mmol, 0.5 equiv) in THF (2.0 mL) at was added BH3·SMe2 (0.12 mL, 1.35 mmol, 5 equiv) at 0 °C. After stirring for 15 min, a solution of prochiral ketone 14 (0.27 mmol, 1 equiv) in THF (2 mL) was added dropwise over a period of 10 min. The reaction mixture was allowed to stir at 0 °C until TLC indicated complete consumption of the starting ketone (ca. 2 h). Then, it was quenched with MeOH (a few drops), 1 M aq. NaOH (2 mL), and diluted with EtOAc. The layers were separated, and the organic layer was washed with 1 M aq. NaOH 3-4 times (until washings were colorless), and then with brine. The organic layer was then dried over Na2SO4, filtered, and evaporated providing the crude product, which was purified using silica gel column chromatography (EtOAc/hexanes = 1:9 to 2:8) to afford enantioenriched 3-indolyl alcohol (S)-12.

Section 2: Hinckdentine A
Synthesis of Starting Material 1

SI
[2] Fischer Indole Synthesis Methanesulfonic acid (100 mL) was heated at 80 °C and P2O5 (14.4 g, 100 mmol, 2.2 equiv) was added. The mixture was stirred at 80 °C (occasionally mixing stuck P2O5 with a glass rod) until all P2O5 dissolved (ca. 2 h). To this solution was added solid SI-1 (10.0 g, 46.0 mmol) in small spatula-tip amounts over 10 min. When the addition was complete, the reaction mixture was allowed to stir for 30 min at 80 °C. Then, it was cooled to room temperature and poured over crushed ice (~ 200 mL). NaOH pellets (65 g) were then carefully added to neutralize the acid. 3 The precipitated beige-colored material was filtered, washed with excess H2O, washed with hexanes (50 mL), and used directly in the next step without further purification.
[3] Indoloquinazoline Synthesis A stirred solution of crude SI-2 in formic acid (70 mL) was heated at 90 °C for 1 h. Then, it was cooled to room temperature and poured over crushed ice. The precipitate was filtered, washed with excess water, then with chilled EtOAc (50 mL), and finally with pentane (20 mL) to provide the title indoloquinazoline 16 (8.9 g, 93% yield, 2 steps) as a cream-colored solid.

Total Synthesis of (+)-Hinckdentine A [1] Friedel-Crafts
To a stirred suspension of freshly sublimed AlCl3 (3.67 g, 27.5 mmol) in CH2Cl2 (50 mL) was dropwise added ethyl chlorooxoacetate (3.1 mL, 27.5 mmol) at 0 °C. Cold bath was removed, and the mixture was stirred until fully homogenized (ca. 10 min). Then, the reaction vessel was once again cooled to 0 °C, and indoloquinazoline 16 (2.0 g, 9.2 mmol) was added as a solid in small portions. After stirring for 2 h, the mixture was quenched with sat. aq. Roschelle's salt, and stirred until clear biphasic mixture was obtained. The layers were separated, and the aq. phase was extracted with CH2Cl2 once. The combined organic extract was washed with sat. aq. NaHCO3, dried over Na2SO4, filtered, and evaporated providing a yellow solid, which was washed with cold MeOH and dried to provide keto-ester 17 (2.6 g, 90% yield) as a yellow solid. [2] CBS reduction To a stirred suspension of (R)-MeCBS (9 mg, 0.031 mmol) in ether (5.7 mL) was dropwise added BH3·SMe2 (2.0 M in THF, 0.16 mL, 0.31 mmol) at 0 °C. After stirring for 5 min, a solution of prochiral keto-ester 17 (20 mg, 0.063 mmol) in CH2Cl2 (0.6 mL) was slowly added over 10 min using a syringe pump. After addition was complete, the reaction mixture was allowed to stir for 20 min, then MeOH (2 mL) was added, and stirring was continued for another 5 min. Then, a cold bath was removed, and a solution of DDQ (16 mg, 0.07 mmol) in CH2Cl2 (1.2 mL) was added dropwise over 10 min at room temperature. Then, the mixture was diluted with EtOAc, and washed with sat. aq. NaHCO3 three times, and once with brine. The organic layer was dried over Na2SO4, filtered, and evaporated providing crude material, which was purified using silica gel column chromatography (EtOAc/hexanes = 1:2 to 2:1) furnishing the desired allylic alcohol 18 (18 mg, 90% yield) as a white solid.
[3] Indole-Claisen To a stirred suspension of indolyl alcohol 18 (85 mg, 0.26 mmol) in toluene 4 (8.7 mL) was added DMAA (0.12 mL, 0.8 mmol) 5 at room temperature. The reaction mixture was placed in an oil bath preheated to 120 °C and stirred overnight. Then, it was cooled to room temperature, and 10% Pd/C (55 mg, 0.05 mmol) was added. The reaction vessel was sealed with a rubber septum, and purged with H2. After stirring at 60 °C under balloon pressure of H2 for 15 h, the mixture was filtered through a short Celite® pad. The filtrate was evaporated to provide a crude material, which was purified using silica gel column chromatography (acetone/hexanes = 1:4) to afford aminal 19 as a white solid. 6 This material was taken in minimal amount of acetone/hexanes = 1:9, and allowed to stand for a couple of hours. The racemate crystallized out; evaporation of the mother liquor provided enantiomerically pure material (74 mg, 70% yield).
Thus, isolation of carbamate SI-6 (see step 4, p. 15) provided an ideal model substrate for bromination experiments. Electrophilic aromatic substitution at C2 was found to be extremely challenging; none of the standard brominating agents (e.g. NBS, DBDMH; entries 2 and 4, respectively) could promote the desired transformation. Prolonged exposure of the substrate to electrophilic bromine source consistently resulted in a complex mixture formation, which did not contain any of the desired product (entries 3 and 5). Although, a number of Lewis base additives (not shown) provided the desired tribromide SI-9 in poor yields, ammonium cerium (IV) nitrate (CAN) catalyzed the bromination and furnished synthetically useful yields of SI-9 (entries 7-9, presumably via transient bromonium cerium (IV) nitrate). Finally, treatment of SI-6 with a much stronger brominating agent, namely N,N-dibromo-p-toluenesulfonamide (TsNBr2), 9 at low temperatures smoothly returned SI-9 in good yield (entries 12 and 13). Gratifyingly, bromination of caprolactam 21 turned out to be a much easier task compared to amide SI-6. 9 Preparation of TsNBr2: To a vigorously stirred suspension of chloramine-T trihydrate (3 g, 13.2 mmol) in H2O (43 mL) was dropwise added molecular Br2 (0.67 mL, 13.2 mmol) using a pipette. After addition was complete, the mixture was sonicated, then stirred for additional 5 min. The golden yellow suspension was filtered, thoroughly washed with H2O, washed with hexanes, and dried providing the desired brominating agent (3 g, 70% yield). A vial containing the material was wrapped with Al-foil and stored in a freezer to avoid degradation. Spectral data for TsNBr2 are in agreement with that previously reported. See: Saikia, I.; Chakraborty, P.; Sarma, M. J.; Goswami, M.; Phukan, P. Rapid and total bromination of aromatic compounds using TsNBr2 without any catalyst. Synth. Commun. 2015, 45,