Enantioselective Synthesis of Spiroindenes by Enol-Directed Rhodium(III)-Catalyzed C–H Functionalization and Spiroannulation

Chiral cyclopentadienyl rhodium complexes promote highly enantioselective enol-directed C(sp2)-H functionalization and oxidative annulation with alkynes to give spiroindenes containing all-carbon quaternary stereocenters. High selectivity between two possible directing groups, as well as control of the direction of rotation in the isomerization of an O-bound rhodium enolate into the C-bound isomer, appear to be critical for high enantiomeric excesses.


Preparation of Substrate 1h
Ethyl 2-(N-benzyl-2-phenylacetamido)acetate (S10). To a suspension of NaH (60% in mineral oil, 1.99 g, 52.0 mmol) in THF (50 mL) at 0 °C was added a solution of S9 5 (5.02 g, 26.0 mmol) in THF (25 mL), and the mixture was stirred for 30 min. Phenylacetyl chloride (3.4 mL, 26.0 mmol) was added slowly and the mixture was stirred at room temperature for 3 h. The reaction was quenched carefully with 10% aqueous HCl solution and the aqueous layer was separated and extracted with CH 2 Cl 2 (2 × 50 mL).

Preparation of Substrate 1i
Ethyl
Purification of the residue by flash column chromatography (10% acetone/petrol) gave the lactam 1i as a yellow amorphous solid (
Purification of the residue by flash column chromatography (8% acetone/petrol) gave the amide S14 as a 1:0.9 mixture of rotamers (by 1 H NMR analysis) as a colorless viscous oil (4.60 g, 54%

1-Benzyl-4-hydroxy-6-methyl-3-phenyl-1,2-dihydropyridin-2-one (1p).
To a stirred solution of ester 1o (7.00 g, 19.3 mmol) in toluene (80 mL) was added aqueous 2 M NaOH solution (28.9 mL, 57.8 mmol) slowly, and the reaction mixture was stirred at 90 °C for 3 h. After cooling to room temperature, the aqueous layer was separated and washed with toluene (50 mL). The aqueous layer was acidified to pH (2-3) using aqueous 10% HCl solution and extracted with EtOAc (2 × 100 mL). The combined organic extracts were washed with water (100 mL), brine (100 mL), dried (Na 2 SO 4 ), and evaporated under reduced pressure to leave the carboxylic acid S15 as a pale brown solid which was used immediately in the next step without further purification.
Ph 2 O (80 mL) was added to the acid obtained above and the solution was heated at 220 °C for 3 h.
The mixture was cooled to room temperature, diluted with petrol, and stirred for 1 h which upon filtration afforded a light brown solid which was purification by trituration (20% acetone/petrol) to give the lactam 1p as a pale brown solid (3.97 g, 71%

Preparation of Alkynes
The following alkynes were purchased from commercial sources: The following alkynes were prepared according to literature procedures.

Preparation of Chiral Cyclopentadienyl Rh(I) Metal Complexes 13
The chiral Rh(I) complexes 3a-3f were prepared according to literature procedures, 13,14 with the following modifications to the routes: (R)-3,3'-Dimethoxy-2,2'-bis(methoxymethoxy)-1,1'-binaphthalene (S17) 14,15 Following a literature procedure: 14 To a solution of (R)-2,2'-bis(methoxymethoxy)-1,1'binaphthalene (7.00 g, 18.7 mmol) in THF (50 mL Modified workup procedure: At this stage, the workup procedure was changed slightly from the literature method, 14 which in our hands often gave unidentified material after the solvent was removed. Instead, we kept the product as a solution in benzene. The modified procedure is as follows: The reaction was quenched with H 2 O (20 mL), and the layers were separated. The organic layer was passed through a short pad of Na 2 SO 4 under nitrogen atmosphere and the aqueous layer was extracted with benzene (2 × 20 mL). The combined organic extracts were passed through a short pad of Na 2 SO 4 under nitrogen atmosphere, and then combined with the first organic layer to give a solution of 2,2'-bis(methoxymethoxy)-[1,1'-binaphthalene]-3,3'-diol (S16) in benzene which was used immediately in the next step. To a cold (0 °C) solution of 2,2'-bis(methoxymethoxy)-[1,1'-binaphthalene]-3,3'-diol obtained as described above was added K 2 CO 3 (7.75 g, 56.1 mmol) and acetone (100 mL), before iodomethane (5.8 mL, 93.5 mmol) was added dropwise. The mixture was then heated at 70 °C for 24 h. After cooling to room temperature, the mixture was filtered on a short pad of silica concentrated in vacuo.
Purification of the residue by flash column chromatography (4% EtOAc/hexane) to give the dimethyl ether S17 as a white solid (6.42 g, 79%) that displayed spectroscopic data consistent with those reported previously. 15 R f 0.41 (10% EtOAc/hexane).
After cooling the reaction mixture to 23 °C, EtOAc (100 mL) was added and washed with water (2 × 50 mL). The organic layer was dried (Na 2 SO 4 ), filtered, and concentrated in vacuo. Purification of the residue by flash column chromatography (2% EtOAc/petrol) gave the dibromide S19 as an offwhite solid (2.82 g, 97%) that displayed spectroscopic data consistent with those reported previously. 13 Use of unrecrystallized NBS in benzene often gave the aromatic dibromide S20 as an off-white solid which had the following NMR data: 1

3,5-Dihydrospiro[cyclohepta[1,2-a:7,6-a']dinaphthalene-4,1'-cyclopenta[2,4]diene]-2,6-diol (S22) 13
The following method was preferred over the literature procedure, 13 which uses toxic/malodorous reagents. The procedure was adapted from one contained in a University of Nottingham thesis. 16 To a solution of PPh 3 (4.97 g, 18.9 mmol) in THF (70 mL) at 0 °C was added lithium metal (262 mg, 37.8 mmol) in portions and the mixture was heated at 60 °C for 6 h to generate a mixture of lithium diphenylphosphine and phenyl lithium as a bright red-colored solution which was transferred via cannula to a solution of the dimethyl ether S21 13 (1.53 g, 3.79 mmol) in dry THF (10 mL) at ambient temperature. The mixture was heated at reflux for 6 h, cooled to 0 °C, quenched carefully with 10% aqueous HCl solution (50 mL) and extracted with Et 2 O (2 x 100 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered, and concentrated in vacuo. Purification of the residue by flash column chromatography (15% acetone/petrol) gave the diol S22 as a pale yellow solid (1.37 g, 96%) that displayed spectroscopic data consistent with those reported previously. 13

Stereochemical Determinations
The absolute stereochemistries of 4g, 4h, 4i, 4j, 4o, and 4r were determined by single crystal X-ray crystallography using a copper radiation source. All crystals were obtained by recrystallization from EtOAc/petroleum ether. The stereochemistries of the remaining products were assigned by analogy.
The CF 3 groups of 4g are rotationally disordered over two positions (see .cif file for further details).
Although the Falck and Hooft parameters of 4h did not unambiguously indicate the presence of a single enantiomer, the P2 and P3 analysis proves that a single enantiomer is present, and that the correct hand has been determined (see .cif file for further details).
The absolute configuration of 4j was confirmed by application of the Parsons quotient method as described in Acta Cryst. 2013, B69, 249-259 (see .cif file for further details).