Enantioselective Spirocyclopropanation of para-Quinone Methides Using Ammonium Ylides

The use of Cinchona alkaloid-based chiral ammonium ylides allows for the first highly enantioselective and broadly applicable spirocyclopropanation reactions of para-quinone methides. This strategy provides a straightforward protocol toward the chiral spiro[2.5]octa-4,7-dien-6-one skeleton, which is a frequently found structural motif in important biologically active molecules.

To palladium on C (10 wt %, powder, 0.35 g, 0.05 equiv) under an atmosphere of H2 was added a solution of SI2 (2.05 g, 9.0 mmol, 1.0 equiv) in EtOH (14 ml). The reaction mixture was stirred overnight at rt and filtered through a pad of celite. The solvent was evaporated to yield SI3 as yellow oil (1.76 g, 92%) in sufficient purity for further reactions.
A mixture of SI5 (5.71 g, 17.6 mmol, 1.0 equiv) and HMDS (5.68 g, 35.2 mmol, 2.0 equiv) was refluxed and anhydrous THF (44 ml) for 5 h. Afterwards the solvent was evaporated and the crude residue redissolved in anhydrous THF (44 ml) and cooled to -78 °C. To the stirred solution, a solution of n-BuLi (1.6 M in hexanes, 11 ml, 17.6 mmol 1.0 equiv) was added dropwise. The reaction was stirred at -78 °C for 1 h and then at rt for 2 h. Afterwards the reaction mixture was quenched with sat. NH4Cl, extracted with EtOAc and the combined organic phases were washed with brine, dried over Na2SO4, the solvent evaporated and the residue dried in vacuo to yield SI6 as slightly yellow residue (5.30 g, 16.7 mmol, 95%) in sufficient purity for further reactions.
A mixture of SI6 (5.30 g, 16.7 mmol, 1.0 equiv) and TMSCl (2.72 g, 25.0 mmol, 1.5 equiv) and Et3N (2.53 g, 25.0 mmol, 1.5 equiv) in anhydrous THF (56 ml) was stirred at rt for 1 h. Then the mixture was cooled to -78 °C and a solution of n-BuLi (1.6 M in hexanes, 10.4 ml, 16.7 mmol, 1.0 equiv) was added dropwise. The reaction was stirred at -78 °C overnight and then quenched with sat. NH4Cl, extracted with EtOAc and the combined organic phases were washed with brine, dried over Na2SO4, the solvent evaporated and the residue dried in vacuo to yield SI7 as slightly yellow residue (4.41 g, 14.2 mmol, 85%) in sufficient purity for further reactions. SI7 (4.41 g, 14.2 mmol, 1.0 equiv) was dissolved in acetone (142 ml) and pTsOHxH2O (270 mg, 1.42 mmol, 0.1 equiv) was added. The reaction was stirred for 1 h at rt and then diluted with H2O and EtOAc. After extraction with EtOAc the combined organic phases were washed with brine, dried over Na2SO4, the solvent evaporated and the residue dried in vacuo to yield SI8 as slightly yellow residue (3.71 g, 14.2 mmol, 98%) in sufficient purity for further reactions.
To a cooled (0 °C) solution of SI8 (3.71 g, 14.2 mmol, 1.0 equiv) in anhydrous THF (28 ml) was added a solution of PhMgBr (1.0 M in THF, 57 ml, 57 mmol, 4.0 equiv) and the reaction mixture was refluxed for 2 h and cooled to 0 °C again and quenched with sat. NH4Cl. The mixture was filtered over a pad of celite and the solution extracted with Et2O, the combined organic phases were dried over Na2SO4, the solvent evaporated and the residue dried in vacuo to yield SI9 as slightly yellow residue (3.82 g, 11.1 mmol, 78%) in sufficient purity for further reactions.
Acetamide SI13: According to literature 10 , to a cooled to solution (0 °C) of N,Odimethylhydroxylamine hydrochloride (0.49 g, 5.0 mmol, 1 equiv) and triethylamine (504 mg, 5.0 mmol, 1 equiv) in DCM (20 ml) was added dropwise a solution of bromoacetyl bromide (1.01 g, 5.0 mmol, 1 equiv) in DCM (10 ml). The reaction mixture was continued to stir further at rt for 1 h. The resulting mixture was poured into water, extracted with DCM (3 times) and washed with 1 N HCl, sat. NaHCO3 solution and brine. The resulting organic phase was dried over Na2SO4, the solvent evaporated and the residue dried in vacuo, yielding SI13 (901 mg, 5.0 mmol, 99%) as orange oil which was used without further purification. Analytical data were in accordance to literature 10 . 1  Acetamide SI14: In analogy to literature 11 , to a cooled to solution (0 °C) of dibenzylamine (985 mg, 5.0 mmol, 1 equiv) and triethylamine (502 mg, 5.0 mmol, 1 equiv) in DCM (20 ml) was added dropwise a solution of bromoacetyl bromide (1.01 g, 5.0 mmol, 1 equiv) in DCM (10 ml). The reaction mixture was continued to stir further at 0 °C for 30 min. The resulting mixture was poured into water, extracted with DCM (3 times), dried over Na2SO4, the solvent evaporated and the residue dried in vacuo, yielding SI14 in (1.56 g, 4.9 mmol, 98%) as a brown oil which was used without further purification. Analytical data were in accordance to literature 12 . 1

Synthesis of chiral amines
Amine Q2: In analogy to literature 13 , KH (0.96 g, 7.2 mmol, 1.2 equiv, 30% suspension in mineral oil) was washed three times with pentanes, cooled to 0 °C and suspended in DMF (6.7 ml). Quinine (1.95 g, 6.0 mmol, 1 equiv) was added and the mixture stirred at 0 °C for 1 h before MeI (937 mg, 6.6 mmol, 1.1 equiv) was added. The mixture was allowed to warm to rt and further stirred for 2 h. Excess MeI was removed under reduced pressure and the resulting mixture carefully quenched with ice-cold water. The obtained solution was extracted 4 times with EtOAc, dried over Na2SO4, the solvent evaporated and the residue dried in vacuo, yielding Q2 after column chromatography (silica gel, EtOAc:MeOH = 3:2) as a colourless oil (1.38 g, 4.1 mmol, 68%). Analytical data were in accordance to literature 14 . 1  Amine QD2: In analogy to literature 13 , KH (802 mg, 6.0 mmol, 1.2 equiv, 30% suspension in mineral oil) was washed three times with pentanes, cooled to 0 °C and suspended in DMF (5.6 ml). Quinidine (1.62 g, 5.0 mmol, 1 equiv) was added and the mixture stirred at 0 °C for 1 h before MeI (746 mg, 5.3 mmol, 1.1 equiv) was added. The mixture was allowed to warm to rt and further stirred for 2 h. Excess MeI was removed under reduced pressure and the resulting mixture carefully quenched with ice-cold water. The obtained solution was extracted 4 times with EtOAc, dried over Na2SO4, the solvent evaporated and the residue dried in vacuo, yielding QD2 after column chromatography (silica gel, EtOAc:MeOH = 3:2) as a colourless oil (1.59 g, 4.7 mmol, 93%). Analytical data were in accordance to literature 15 . 1  Amine Q3: In analogy to literature 16 , KH (1.10 g, 8.2 mmol, 1.4 equiv, 30% suspension in mineral oil) was washed three times with pentanes, cooled to 0 °C and suspended in THF (25 ml). Cinchonidine (1.47 g, 5.0 mmol, 1 equiv) was added and the mixture stirred at 0 °C for 1 h, and further stirred at 50 °C for 2 h. The resulting orange suspension was cooled to 0 °C and MeI (746 mg, 5.3 mmol, 1.05 equiv) was added.
The mixture was allowed to warm to rt and stirred overnight. Excess MeI was removed under reduced pressure and the resulting mixture carefully quenched with ice-cold water. The obtained solution was extracted 4 times with EtOAc, washed with brine, dried over Na2SO4, the solvent evaporated and the residue dried in vacuo, yielding Q3 as orange oil (1.52 g, 4.9 mmol, 98%) in sufficient purity for further reactions. Analytical data were in accordance to literature 17 . 1  Amine QD3 According to literature 16 , KH (1.10 g, 8.2 mmol, 1.4 equiv, 30% suspension in mineral oil) was washed three times with pentanes, cooled to 0 °C and suspended in THF (25 ml). Cinchonine (1.47 g, 5.0 mmol, 1 equiv) was added and the mixture stirred at 0 °C for 1 h, and further stirred at 50 °C for 2 h. The resulting orange suspension was cooled to 0 °C and MeI (746 mg, 5.3 mmol, 1.05 equiv) was added. The mixture was allowed to warm to rt and stirred overnight. Excess MeI was removed under reduced pressure and the resulting mixture carefully quenched with ice-cold water. The obtained solution was extracted 4 times with EtOAc, washed with brine, dried over Na2SO4, the solvent evaporated and the residue dried in vacuo, yielding QD3 as orange oil (1.40 g, 4.5 mmol, 91%) in sufficient purity for further reactions. Analytical data were in accordance to literature 16 . 1  Amine Q4: According to literature 18 , Quinine (1.62 g, 5.0 mmol, 1 equiv) was dissolved in dry DCM (170 ml) and cooled to -78 °C. A Solution of BBr3 (1.0 M in DCM, 20 ml, 20 mmol, 4 equiv) was added dropwise, the reaction mixture was slowly warmed to rt and afterwards refluxed for 1 h. After cooling the mixture again to 5 °C, a 10 wt % solution of aqueous NaOH (50 ml) was added and the resulting phases separated. The aqueous phase was washed 2 times with DCM and then acidified by addition of 4 N HCl to pH = 8.5. The resulting cloudy liquid was extracted 5 times with DCM and the combined organic phases dried over Na2SO4, the solvent evaporated and the residue dried in vacuo, yielding Q4 as yellow solid (1.  Amine QD4: According to literature 18 , Quinidine (1.62 g, 5.0 mmol, 1 equiv) was dissolved in dry DCM (170 ml) and cooled to -78 °C. A Solution of BBr3 (1.0 M in DCM, 20 ml, 20 mmol, 4 equiv) was added dropwise, the reaction mixture was slowly warmed to rt and afterwards refluxed for 1 h. After cooling the mixture again to 5 °C, a 10 wt % solution of aqueous NaOH (50 ml) was added and the resulting phases separated. The aqueous phase was washed 2 times with DCM and then acidified by addition of 4 N HCl to pH = 8.5. The resulting cloudy liquid was extracted 5 times with DCM and the combined organic phases dried over Na2SO4, the solvent evaporated and the residue dried in vacuo, yielding QD4 as yellow solid (1.21 g, 3.9 mmol, 78%) in sufficient purity for further reactions. Analytical data were in accordance to literature 19 . 1

Synthesis of ammonium salts
General procedure B (for achiral ammonium salts): In analogy to literature 20 , 1.5 equiv of trimethylamine (33% solution in EtOH) was added to 1 equiv of -bromo amide in THF (10 ml/g amide) and stirred for 24 h at room temperature. The resulting suspension was filtered and the solid washed 3 times with ether and dried in vacuo to yield pure ammonium salt.
General procedure C (for chiral ammonium salts): According to literature 21 , 1 equiv of amine was added to 1 equiv of -bromo amide in THF (10 ml/g amide) and stirred for 24 h at room temperature. The solvent evaporated, the residue dried in vacuo and the crude product was subjected to column chromatography as stated below.

Spirocyclopropanation reactions
General racemic procedure D: 1 equiv of achiral ammonium salt 5 (NR3 = NMe3) and 1.5 equiv of quinone methide 1 were placed in a Schlenk tube and pre-dried in vacuo. After suspension in anhydrous DCM (0.1 M), Cs2CO3 (5 equiv) was added and the mixture was stirred for 24 h at room temperature. Afterwards the mixture was filtered over a pad of Na2SO4, the solvent evaporated and the residue dried in vacuo. The resulting crude product was subjected to careful column chromatography as stated below.

X-Ray Analysis of 3l
Single-crystal structure analyses were carried out on a Bruker Smart X2S diffractometer operating with Mo-Kα radiation (λ= 0.71073 Å). Further crystallographic and refinement data can be found in Table 1. The structures were solved by direct methods   22 and refined by full-matrix least squares on F 2 (SHELXL-97). 23 The H atoms were calculated geometrically, and a riding model was applied in the refinement process. The presence of the bromine atom allowed for the determination of the absolute configuration of 3l by refining the Flack parameter [0.041 (10)]. CCDC 1513618 contains the supplementary crystallographic data for compound 3l. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre at www.ccdc.cam.ac.uk.