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Construction of chiral α-tert-amine scaffolds via amine-catalyzed asymmetric Mannich reactions of alkyl-substituted ketimines

Stereoselective Mannich reactions of aldehydes with ketimines provide chiral β-amino aldehydes that bear an α-tert-amine moiety. However, the structural variation of the ketimines is limited due to the formation of inseparable E/Z isomers, low reactivity, and other synthetic difficulties. In this study, a highly diastereodivergent synthesis of hitherto difficult-to-access β-amino aldehydes that bear a chiral α-tert-amine moiety was achieved using the amine-catalyzed Mannich reactions of aldehydes with less-activated Z-ketimines that bear both alkyl and alkynyl groups.

In experiments requiring dry solvents, tetrahydrofuran (THF) was purchased from Kanto Chemical Co. Inc.
as "Dehydrated". All other solvents were purchased from FUJIFILM Wako Pure Chemical Corporation, Ltd.

◆ General procedure for preparation of amidines
To a mixture of an N-Boc-protected amide (1.0 eq.), triphenylphosphine (PPh3) (4.0 eq.), K2CO3 (2.0 eq.) and benzimidazole (4.0 eq.) in DCE (0.5 M) was added CBr4 (2.0 eq.) at room temperature. After stirring for 1 h at 50 or 60 ºC, the mixture was filtered through a Celite pad and washed with CH2Cl2. The filtrate was evaporated under reduced pressure. The crude mixture was purified by silica gel column chromatography with dry ice jacket (hexane/EtOAc = 7/1 ~ 2/1 as eluent) to give the desired product.

◆ General procedure for preparation of Z-ketimines
To a solution of a terminal alkyne (3-5 eq.) in THF was added n-butyllithium (n-BuLi) (1.56 M in hexane, 1.1-1.6 eq.) at 0 °C dropwise under a nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 30 min.
To the reaction mixture was added dropwise the amidine (1.0 eq.) in THF (1.0 M) at -40 °C or −78 ºC, and the solution was stirred for 3 h at the same temperature. The mixture was then quenched with saturated NH4Cl aq. and extracted with EtOAc. The combined organic layers were dried over Na2SO4, and concentrated in vacuo.
The residue was purified by flash column chromatography on silica gel with dry ice jacket (hexane/EtOAc = 40/1 ~ 20/1 cooled by ice as eluent) to afford the corresponding ketimine. All of N-Boc protected ketimines were stored under a nitrogen atmosphere at −78 °C because they gradually decompose at room temperature.
Spectroscopic data were in agreement with the ones previously reported in literature. 7
After stirring for 1 h at room temperature, 1-methylpiperazine (excess) was added. 9 After stirring for 1 h at room temperature, the mixture was then quenched with H2O and extracted with CH2Cl2. The combined organic layers were washed with 1 N HCl aq. and brine, dried with Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (hexane/EtOAc = 1/0 ~ 1/3 as eluent) to give the corresponding carbamate as a colorless oil (2.9 g, 7.6 mmol, 84% yield).

Synthesis of Phenylcyclopropane-Based Catalyst (S,R)-7 ◆ Improved synthesis of catalyst intermediate (S,R)-S2
(S,R)-S1 was synthesized according to the literature procedures. 10 To a mixture of (S,R)-S1 (860 mg, 2.0 mmol, 1.0 eq.), K2CO3 (276 mg, 2.0 mmol, 1.0 eq.) and NaI (29 mg, 0.2 mmol, 10 mol%) in acetone (10 mL) was added 4-nitrobenzyl bromide (432 mg, 2.0 mmol, 1.0 eq.). The reaction mixture was stirred at room temperature for 12.5 h. Water was added to quench the reaction, and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo. The product was used for the next reaction without purification. 11 To a solution of the obtained crude intermediate in THF (10 mL) was added NaH (60% in mineral oil, 400 mg, 10 mmol, 5 eq.) at 0 ºC. The mixture was warmed at room temperature, stirred for 1.5 h and then poured on ice. The mixture was then acidified with 2 M HCl aq. and washed with EtOAc. The aqueous layer was basified with Na2CO3 and 1 M NaOH aq. and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The product was used for the next reaction without purification.
To a solution of the crude intermediate in MeOH (10 mL) was added NaBH4 (151 mg, 4 mmol, 2 eq.) at 0 °C. After stirring at 0 ºC for 2 h, the reaction mixture was quenched with H2O, and then extracted with EtOAc.
The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The product was used for the next reaction without purification.

General Procedure for Benzoylation of Mannich Products
To a solution of 2 in CH2Cl2 (0.1 M) were added benzoyl chloride (2.0 eq.), triethylamine (TEA) (2.2 eq.) and DMAP (50 mol%) at 0 ºC. After stirring the mixture for 1-2.5 h at room temperature, the reaction mixture was quenched with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude mixture was purified by preparative thin layer chromatography (hexane/EtOAc = 7/1 or 3/1).

Crystal Structure Analysis of syn-2k
Single crystals of syn-2k were grown from Et2O and hexane at room temperature. The data were collected at -170 °C on a Rigaku Saturn Saturn70 CCD(system) with VariMax Mo Optics using graphite-monochromated Mo Kα radiation (λ = 0.71073 Å). The crystal structure was solved by direct methods using SHELXT 13

Determination of Absolute Configuration of Mannich Product 2a
To determine the absolute configuration of the Mannich product catalyzed by L-proline, Mannich product 2a' was epimerized.
To a mixture of obtained 2a' with impurities and pyrrolidine (8.2 μL, 0.1 mmol, 1 eq.) in CH2Cl2 was added p-toluenesulfonic acid monohydrate (3.8 mg, 0.02 mmol, 20 mol%). After stirring at 120 ºC for 2 h, 2 M HCl aq. (excess) was added. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried with Na2SO4 and concentrated in vacuo. The product was used for the next reaction without purification.
To the mixture of the obtained product in MeOH (ca. 2 mL) was added NaBH4 (excess) at 0 ºC. After stirring for 1 h, the reaction mixture was quenched with H2O and extracted with EtOAc. The organic layers were washed with brine, dried with Na2SO4 and concentrated in vacuo.
The absolute configuration of the obtained syn-2a was determined by comparison with syn-2a which is obtained from the reaction catalyzed by (S,R)-7.