Bifunctional Iminophosphorane Organocatalysts for Enantioselective Synthesis: Application to the Ketimine Nitro-Mannich Reaction

The design, synthesis, and development of a new class of modular, strongly basic, and tunable bifunctional Brønsted base/H-bond-donor organocatalysts are reported. These catalysts incorporate a triaryliminophosphorane as the Brønsted basic moiety and are readily synthesized via a last step Staudinger reaction of a chiral organoazide and a triarylphosphine. Their application to the first general enantioselective organocatalytic nitro-Mannich reaction of nitromethane to unactivated ketone-derived imines allows the enantioselective construction of β-nitroamines possessing a fully substituted carbon atom. The reaction is amenable to multigram scale-up, and the products are useful for the synthesis of enantiopure 1,2-diamine and α-amino acid derivatives.


General information Solvents and Reagents
Concentration under reduced pressure was performed by rotary evaporation at the appropriate pressure and temperature. Reagents used were obtained from commercial suppliers or purified according to standard procedures. Petroleum ether (PE) refers to distilled light petroleum of fraction 30 -40 °C. Anhydrous toluene, tetrahydrofuran, dichloromethane and diethyl ether were dried by filtration through activated alumina (powder ~150 mesh, pore size 58 Å, basic, Sigma-Aldrich) columns. Dimethyl sulfoxide and dimethylformamide were used as supplied. Deuterated solvents were used as supplied.

Chromatography
Reactions were monitored by thin layer chromatography (TLC) using Merck silica gel 60 F 254 plates and visualized by fluorescence quenching under UV light. In addition, TLC plates were stained with potassium permanganate solution. Chromatographic purification was performed on VWR 60 silica gel 40 -63 μm using technical grade solvents that were used as supplied.

Instrumentation
Melting points were obtained on a Leica Galen III Hot-stage melting point apparatus and

tert-Butyl [(2S)-1-azido-3-phenylpropan-2-yl]carbamate, 12
To a solution of compound 11 (1.25 g, 3.08 mmol) in DMF (10 mL), NaN 3 (220 mg, 3.39 mmol) was added at rt and the resulting suspension was stirred at 45 ºC for 7 h. After cooling to rt, H 2 O (15 ml) was added to the reaction mixture and it was extracted with Et 2 O (3 x 40 mL). The combined organics were dried over Na 2 SO 4 , filtered and concentrated. The resulting crude was purified by flash column chromatography (PE/Et 2 O 7:3) to yield 12 (460 mg, 54%) as a colorless solid. to obtain 13 (447 mg, 71% over 2 steps) as a colorless solid. Compounds 24, 9 25, 10 and 26 11 were synthesized according to literature procedures and their physical and spectroscopic properties are in agreement to those reported.
Its spectroscopic properties are in agreement to those of 2.

amide, 5l
Obtained according to general procedure B using 1-

Synthesis and characterization of nitro-Mannich addition products 6a -6q
General procedure C for the catalyst optimization studies (Table 1) To a stirred solution of the azide precursors to catalysts 4a, 4d -4r (0.02 mmol) in Et 2 O (0.1 mL) in a closed vial was added triphenylphosphine (5.2 mg, 0.020 mmol, 1 eq) and stirred at rt for 24 h.

General procedure D for the synthesis of racemic nitro-Mannich addition products
To a stirred suspension of the corresponding ketimine 5a -5q (0. The conversion to 6a using cinchonine-derived catalyst I was 0% after 32 h under identical reaction conditions.

Large scale synthesis of nitro-Mannich addition product 6a
To ketimine 5a ( (synthesized according to general procedure D).

Conversion of addition product 6a into amino acid 8 and determination of absolute
configuration (See Supplementary Figure 11).