Use of Prolyl Sulfonimidamides in Solvent-Free Organocatalytic Asymmetric Aldol Reactions

Abstract

Prolyl-substituted sulfonimidamides have been synthesized and applied as organocatalysts in solvent-free asymmetric aldol reactions.

Keywords

aldehyde - aldol reaction - amino acids - ketone - organocatalysis - sulfonimidamide

References and Notes

• Selected reviews:
• 1a Palomo C. Oiarbide M. García JM. Chem. Soc. Rev.  2004,  33:  65 
• 1b Guillena G. Nájera C. Ramón DJ. Tetrahedron: Asymmetry  2007,  18:  2249 
• 1c Mlynarski J. Paradowska J. Chem. Soc. Rev.  2008,  37:  1502 
• For recent reviews, see:
• 2a Kotsuki H. Ikishima H. Okuyama A. Heterocycles  2008,  75:  493 
• 2b Kotsuki H. Ikishima H. Okuyama A. Heterocycles  2008,  75:  575 
• 3 Berkessel A. Koch B. Lex J. Adv. Synth. Catal.  2004,  346:  1141 
• 4 Cobb AJA. Shaw DM. Longbottom DA. Gold JB. Ley SV. Org. Biomol. Chem.  2005,  3:  84 
• 5a Bellis E. Vasilatou K. Kokotos G. Synthesis  2005,  2407 
• 5b Tsandi E. Kokotos CG. Kousidou S. Ragoussis V. Kokotos G. Tetrahedron  2009,  65:  1444 
• 6 For the use of a ketone/aldehyde ratio of 3:1, see: Wu Y. Zhang Y. Yu M. Zhao G. Wang S. Org. Lett.  2006,  8:  4417 
• 7 Yang H. Carter RG. Org. Lett.  2008,  10:  4649 
• 8a Di Chenna PH. Robert-Peillard F. Dauban P. Dodd RH. Org. Lett.  2004,  6:  4503 
• 8b Fruit C. Robert-Peillard F. Bernardinelli G. Müller P. Dodd RH. Dauban P. Tetrahedron: Asymmetry  2005,  16:  3484 
• In an unoptimized ball milling experiment (at 400 rpm) the aldol reaction between ketone 11 (5 equiv) and aldehyde 12a catalyzed by 10 mol% of (S,R)-10 led to 35% conversion of 12a after 5.3 h, giving 13a with 66% ee (anti/syn, 88:12) in 31% yield. For recent guiding reviews in this area, see:
• 12a Rodriguez B. Rantanen T. Bruckmann A. Bolm C. Adv. Synth. Catal.  2007,  349:  2213 
• 12b Bruckmann A. Krebs A. Bolm C. Green Chem.  2008,  10:  1131 

9

Syntheses of (2 S )-benzyl 2-(N-tosyl-4-tolylsulfonimid-oylcarbamoyl)pyrrolidine-1-carboxylates 9; General Procedure: To a solution of Cbz-l-proline (l-7, 374 mg, 1.50 mmol), sulfonimidamide 8 (487 mg, 1.50 mmol) and DMAP (46 mg, 0.375 mmol) in CH₂Cl₂ (9 mL), was added EDC (233 mg, 263 µL, 1.50 mmol). After stirring of the reaction mixture at room temperature for 24 h, EtOAc (30 mL) was added. The resulting mixture was then sequentially washed with 1 M HCl (10 mL) and half-saturated brine (10 mL). Drying the organic phase over MgSO₄ and concentra-tion under reduced pressure gave white solids that were used without further purification.
For analytical data of (S,R)-9 and (S,R)-9 see Supporting Information.
Syntheses of (2 S )- N -( N -tosyl-4-tolylsulfonimidoyl)pyr-rolidine-2-carboxamides 10; General Procedure: To a solution of (2S)-benzyl 2-(N-tosyl-4-tolylsulfonimidoyl-carbamoyl)pyrrolidine-1-carboxylate (9; 800 mg, 1.44 mmol) in CH₂Cl₂ (32 mL), was added 10% Pd/C (86 mg). The mixture was stirred for 24 h at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through a pad of Celite^® and silica and rinsed with CH₂Cl₂-MeOH (9:1, 30 mL). The solvent was removed under reduced pressure and the residue was purified by column chromatography (CH₂Cl₂-MeOH, 9:1). Products 10 were isolated as white solids.
For analytical data of (S,R)-10 and (S,R)-10 see Supporting Information.

10

The use of solvents such as dimethylsulfoxide, methanol, tetrahydrofuran, and dichloromethane led to low catalyst activity and stereoselectivity.

11

Aldol Reaction; General Procedure: A vial was charged with sulfonimidamide 10 (10 mol%), ketone (5.0 equiv, 3.0 mmol) and aldehyde (1.0 equiv, 0.6 mmol) and sealed. The mixture was stirred at 30 ˚C for the indicated period of time. After the addition of ethyl acetate (5 mL) the reaction mixture was filtered thought a pad of silica gel, then the solvent was removed in vaccuo, and purified by column chromatography on silica gel to afford the corresponding aldol products.

13

The catalyst performance in the reaction of acetone and 4-nitrobenzaldehyde was poor. The product was isolated after 6 d at 30 ˚C with 49% ee in 23% yield.