Enantioselective Synthesis of Acyclic Orthogonally Functionalized Compounds Bearing a Quaternary Stereocenter Using Chiral Ammonium Salt Catalysis

Abstract We herein report an asymmetric protocol to access a series of orthogonally functionalized acyclic chiral target molecules containing a quaternary stereogenic center by carrying out the enantioselective α‐alkylation of novel orthogonally functionalized dioxolane‐containing cyanoacetates under chiral ammonium salt catalysis. By using just 1 mol % of Maruoka's spirocyclic ammonium salt catalysts enantioselectivities up to e.r.=97.5 : 2.5 could be achieved and further functional group manipulations of the products were carried out as well.

The reaction mixture is allowed to cool to r.t. first and is then subsequently cooled with an ice bath and overlaid with Et2O (around 1 mL per mmol 1). By gentle addition of 2N HCl the pH value of the reaction mixture is set to pH 6. The separated aqueous phase is extracted 5x with Et2O. The combined organic phases are washed once with H2O, dried over Na2SO4, filtered over cotton and the solvent is evaporated.
Note: Analysis of the crude reaction mixture by 1 H NMR shows in situ yields of 30-60% (based on the limiting agent) besides unreacted starting materials 1 and 2. Longer reaction times result in higher conversions but also increased sideproduct formation. For the subsequent asymmetric reaction clean product 3 is beneficial and purification of 3 becomes more difficult with increasing amounts of impurities.
The crude product is carefully purified by column chromatography using heptane/EtOAc 20/1 as the mobile phase and only the clean fractions (judged by 1 H NMR) were used for the asymmetric transformations while the impure fractions were repurified again. Product spots on TLC plates are made visible by iodine staining.

Asymmetric a-alkylation
General procedure B: A solution of starting material 3 (0.10 mmol) in 1.2 mL toluene is cooled to 0 °C (Ar-atmosphere). Subsequently, catalyst C1 (1 mol-%, 1.1 mg), aq. KOH50% (30 eq, 227 µL) and electrophile 4 (0.12 mmol, 1.2 eq.) are added and the reaction mixture is stirred for 20 h (slow warm up to r.t.). Then 3.0 mL diethyl ether and 1.5 mL water are added and the phases are separated. The aqueous layer is extracted 5x with 2 mL Et2O each and the combined org. phases are washed with 7 mL brine. The org. phase is dried over Na2SO4, filtered over cotton and evaporated to dryness. Purification of the crude products is performed by column chromatography using heptane/EtOAc 20/1 to 10/1.

Analytical details of products 5a-5q
5a: Prepared according to the general procedure B (LG=Br) and obtained as an almost colorless oil in 86% yield and with e.r. = 96.5:3.5.

Follow-up transformations
2.3.1. Procedure for conversion of the nitrile functionality into a primary amide In accordance to a modified literature procedure, [2]2 1 eq (0.10 mmol, 31.7 mg) of compound 5a are dissolved in 2 mL EtOH and 5 eq (0.50 mmol, 53.0 mg) Na2CO3 are suspended in the solution. The mixture is cooled to 0 °C and 2 mL 35% aq. H2O2 solution is slowly added. The reaction mixture is stirred at r.t. for 69 h. [3 The reaction is quenched by addition of 4 mL H2O and extracted 5x with 3 mL DCM. The organic phases are combined and twice washed with 4 mL H2O; dried over Na2SO4, filtered over cotton and the solvent is evaporated.
The obtained crude product is purified by column chromatography using heptane/EtOAc 10/1 to 0/1, from which the product 6 is received as almost colorless oil in 87% isolated yield (29.3 mg, 0.087 mmol). The product 7 is isolated as a white solid in 38% yield (10.0 mg, 0.038 mmol) after purification by column chromatography using heptane/DCM 1/4 and further purification by preparative TLC (silica gel plate; heptane/EtOAc 3/4). Applying modified literature procedure, [4] 1 eq (0.164 mmol, 52.0 mg) of substance 5a is dissolved in 4 mL dry THF. At 0 °C, a suspension of 10 eq (1.823 mmol, 69.2 mg) LiAlH4 in 3 mL dry THF is added dropwise and the reaction mixture is stirred for 4 h. The reaction is quenched by careful addition of 6 mL EtOAc and 6 mL H2O and solids are removed by filtration over Celite. The phases of the filtrate are separated and the aqueous phase is extracted 3x with 8 mL EtOAc. The combined organic phases are washed with 8 mL water and the solvent is evaporated. To the obtained residue 2 mL pyridine and 5 eq (82.0 µL) acetic anhydride are added and the reaction mixture is stirred at 70 °C for 17 h. The reaction mixture is concentrated in vacuo, the obtained residue is dissolved in 15 mL DCM and twice washed with 5 mL sat. Na2CO3-solution (aq.). DCM is evaporated, from which the crude product is received. Purification is performed by column chromatography using heptane/EtOAc 10/1 to 2/1 to 0/1, from which the diacetylated product 8 is isolated as yellowish oil in 85% yield (46.8 mg, 0.140 mmol).