Organocatalysis with Cysteine Derivatives: Recoverable and Cheap Chiral Catalyst for Direct

Organocatalysis with Cysteine Derivatives: Recoverable and Cheap Chiral Catalyst for direct Aldol Reactions

Shi Li · Xiangkai Fu[(] · Chuanlong Wu

Experimental

General information

All reagents were commercial products. The reactions were monitored by TLC (thin layer chromatography). The column and preparative TLC purification were carried out using silica gel. Flash column chromatography was performed on silica gel (200-300 mesh). NMR spectra were recorded on a 300 MHz instrument. Chemical shifts (d) are given in ppm relative to TMS as the internal reference, coupling constants (J) in Hz. IR spectra were recorded on a spectrometer. Melting points were measured on a digital melting point apparatus. Mass spectra (MS) were measured with a spectrometer. Analytical high performance liquid chromatography (HPLC) was carried out on Agilent 1200 instrument using Chiralpak AD (4.6 mm × 250 mm), Chiralcel OD-H (4.6 mm × 250 mm) or Chiralcel OJ-H (4.6 mm× 250 mm) columns. Optical rotations were measured on a JASCO P-1010 Polarimeter at λ = 589 nm.

General Procedure for the Preparation of Catalysts 1a-1f[1]:

A 500 mL round bottom flask was charged with CF3CO2H (20 mL) and placed in 0 oC. L-cysteine (5.00 g, 41.3 mmol) was added in small portions under vigorous stirring to give a viscous solution. The reaction mixture was stirred for 40 min, and then acyl chloride (82.6 mmol) was added in one portion. After 10 min of stirring, and then removed from the ice/water bath. The reaction flask was fitted with a loose glass stopper, and the reaction mixture was stirred at room temperature for 12 h. The reaction flask was then cooled in 0 oC, and Et2O (400 mL) was added under vigorous stirring over a period of 20 min, slowly at first. The resulting white suspension was stirred at 0 oC for 30 min after completed addition, and then at room temperature for 5 h and filtered by vacuum. The crystals were washed with four portions of Et2O and dried at 70 oC for 24 h in a ventilated hood to give S-acyl-L-cysteine hydrochloride1, as a fine white powder. This essentially pure material was used for the next step without further purification, and then S-acylation cysteine hydrochloride1 dissolved in water, added an equivalent amount of diethylethanamine (Et3N), the resulting white suspension was stirred at room temperature for 10 min after completed addition, and then filtered by vacuum. The white crystals were washed with two portions of H2O and dried to give S-acylation cysteine-based organocatalysts. This essentially pure material was used for the next step without further purification.

(S)-S-(n- Benzoyl)-L-cysteine (1a):

White solid; Yield: 89%; [α]D20= -33.1 (c = 1, MeOH); 1H NMR (300 MHz, DMSO): δ = 3.23-3.48 (d, J = 5.5Hz, 2H), 4.17 (br. s, 1H), 7.45 (d, J = 4.5Hz, 2H), 7.58 (br. s, 1H), 7.97 (d, J = 6Hz, 2H) ppm; 13C NMR (75 MHz, DMSO): δ = 33.2, 54.0, 128.1, 128.1, 129.0, 129.0, 134.2, 134.7, 174.9, 191.5 ppm; MS (ESI) m/z calcd. for C10H11NO3S 225.05 found 225.74.

(S)-S-(1-naphthoyl)-L-cysteine (1b):

White solid; Yield: 89%; [α]D20= -28.9 (c = 1, MeOH); 1H NMR (300 MHz, DMSO): δ = 3.13-3.39 (d, J = 5.8Hz, 2H), 4.25 (br. s, 1H)， 7.42-7.88 （m, 6H）, 8.72 (br. s, 1H) ppm; 13C NMR (75 MHz, DMSO): δ = 33.2, 54.0, 120.3,127.3, 127.4, 129.8, 130.1, 131.4, 132.8, 134.2, 195.6 ppm; MS (ESI) m/z calcd. for C14H13NO3S 275.06 found 275.69.

(S)-S-(n-cyclohexoyl)-L-cysteine (1c):

White solid; Yield: 92%; [α]D20= -30.0 (c = 1, MeOH); 1H NMR (300 MHz, DMSO): δ = 1.46-1.93 (m, 10H), 2.37 (m, 1H), 3.42-3.49 (d, J = 5.7 Hz, 2H), 4.09 (br. s, 1H) ppm; 13C NMR (75 MHz, DMSO): δ = 25.3, 25.3, 28.0, 29.9, 29.9, 33.7, 50.9, 54.1, 180.9, 211.7 ppm; MS (ESI) m/z calcd. for C10H17NO3S 231.09 found 231.81.

(S)-S-(n-adamantanoyl)-L- cysteine (1d):

White solid; Yield: 93%; [α]D20= -27.2 (c = 1, MeOH); 1H NMR (300 MHz, DMSO): δ = 1.17-1.83 (m, 13H), 3.38-3.44 (d, J = 5.3 Hz, 2H), 4.24 (br. s, 1H) ppm; 13C NMR (75 MHz, DMSO): δ = 28.5, 30.5, 30.5, 34.2, 37.8, 37.8, 37.8, 39.6, 39,6, 39.6, 45.7, 54.8, 180.1, 207.4 ppm; MS (ESI) m/z calcd. for C14H21NO3S 283.12 found 283.47.

(S)-S-(n-Cinnamoyl)-L- cysteine (1e):

White solid; Yield: 86%; [α]D20= -23.0 (c = 1, MeOH); 1H NMR (300 MHz, DMSO): δ = 3.46-3.48 (d, J = 5.8 Hz, 2H), 4.17 (br. s, 1H), 7.01 (d, J = 3 Hz, 1H), 7.17-7.43 (m, 5H), 7.64 (d, J = 3 Hz, 1H) ppm; 13C NMR (75 MHz, DMSO): δ =33.7, 54.9, 126.7, 127.4, 129.3, 129.7, 129.9, 136.3, 177.2, 189.1ppm; MS (ESI) m/z calcd. for C12H13NO3S 251.06 found 251.67.

(S)-S-(t-Butoyl)-L- cysteine (1f):

White solid; Yield: 83%; [α]D20= -13.1 (c = 1, MeOH); 1H NMR (300 MHz, DMSO): δ = 1.19 (br.s, 9H), 3.36-3.38 (d, J = 5.4 Hz, 2H), 4.06 (d, J = 5.1Hz, 1H) ppm; 13C NMR (75 MHz, DMSO): δ= 27.2, 28.2, 46.5, 51.9, 169.4, 204.6 ppm; MS (ESI) m/z calcd. for C8H15NO3S 205.08 found 205.89.

General procedure for the preparation of aldol products

Representative procedure for asymmetric stiochiometric anti-aldol reactions of ketone with aldehydes

To a mixture of catalyst 1c (0.1 mmol) and ketone (1.0 mmol) were added aldehyde (1.0 mmol), ClCH2CH2Cl. The resulting mixture was stirred at room temperature. The reaction was monitored by TLC. It was then quenched with 5 mL saturated NH4Cl solution, extracted with EtOAc (3×5 mL), and dried over Na2SO4. Purification by flash chromatography afforded the corresponding pure aldol products.

The crude product before SiO2 chromatography was submitted to 1H NMR analysis to determine diastereomeric ratio. The product after SiO2 chromatography was analyzed by HPLC to determine the enantiomeric as well as the diastereomeric ratios; the latter matched, within allowable limits, the values determined by 1HNMR analysis. The syn and anti diastereomers of the aldols were readily distinguished in 1HNMR spectroscopy by the diagnostic chemical shifts of –CHOH– proton, cf. SI for the chemical shift data.

(2S, 10R)-2-(Hydroxy-(4-nitrophenyl) methyl)-cyclohexan-1-one 2a[2]

Yield 85%, anti/syn >99, enantiomeric excess: 99% of anti-diastereomer determined by HPLC (Dicael Chiralpak AD-H column; i-PrOH/Hexane = 20:80; flow rate 0.5 mL/min, 20 oC, λ = 254 nm; tR = 42.5 min (anti, major), tR = 32.8 min (anti, minor)). 1H NMR(300 MHz, CDCl3): δ = 8.21 (d, 2H, J = 8.7 Hz), 7.51 (d, 2H, J = 8.7 Hz), 4.90 (dd, 1H, J = 8.4, 3.0 Hz), 4.09 (d, 1H, J = 3.0 Hz), 2.65-2.45 (m, 2H), 2.36 (td, 1H, J = 13.2, 5.7 Hz), 2.17-2.06 (m, 1H), 1.87-1.78 (m, 1H), 1.67-1.51 (m, 3H), 1.45-1.31 (m, 1H).

(2S, 10R)-2-(Hydroxy-(2-nitrophenyl) methyl)-cyclohexan-1-one 2b[2]

Yield 89%, anti/syn = 90:10, enantiomeric excess: 93% of anti-diastereomer determined by HPLC (Dicael Chiralpak OD-H column; i-PrOH/Hexane=5:95; flow rate 0.5 mL/min, 20 oC, λ = 254 nm; tR = 41.9 min (anti, major), tR = 50.7 min (anti, minor)). 1H NMR(300 MHz, CDCl3): δ = 7.84 (d, 1H, J = 8.1 Hz), 7.77 (d, 1H, J = 7.8 Hz), 7.63 (t, 1H, J = 7.5 Hz), 7.43 (t, 1H, J = 7.8 Hz), 5.45 (d, 1H, J = 6.6 Hz), 3.90 (br., 1H), 2.82-2.70 (m, 1H), 2.50-2.40 (m, 1H), 2.34 (td, 1H, J = 12.3, 5.7 Hz), 2.15-2.06 (m, 1H), 1.90-1.55 (m, 4H).

(2S, 10R)-2-(Hydroxy-(3-nitrophenyl) methyl)-cyclohexan-1-one 2c[2]

Yield 83%, anti/syn = 95:5, enantiomeric excess: 91% of anti-diastereomer determined by HPLC (Dicael Chiralpak AD-H column; i-PrOH/Hexane=20:80; flow rate 0.5 mL/min, 20 oC, λ = 254 nm; tR = 41.9 min (anti, major), tR = 32.4 min (anti, minor)). 1H NMR(300 MHz, CDCl3): δ = 8.21(d, 2H, J = 8.7 Hz), 7.51(d, 2H, J = 8.7 Hz), 4.90 (dd, 1H, J = 8.4, 3.0 Hz), 4.09 (d, 1H, J = 3.0 Hz), 2.65-2.45 (m, 2H), 2.36 (td, 1H, J = 13.2, 5.7 Hz), 2.17-2.06 (m, 1H), 1.87-1.78 (m, 1H), 1.67-1.51 (m, 3H), 1.45-1.31 (m, 1H).

(2S, 10R)-2-(Hydroxy-(2, 4-dinitro-phenyl) methyl) cyclohexan-1-one 2d[2]

Yield 80%, anti/syn = 97:3, enantiomeric excess: 92% of anti-diastereomer determined by HPLC (Dicael Chiralpak AD-H column; i-PrOH/Hexane=5:85; flow rate 1.0 mL/min, 20 oC, λ = 254 nm; tR = 27.6 min (anti, major), tR = 24.5 min (anti, minor)). 1H NMR(300 MHz, CDCl3): δ = 8.75 (d, J = 2.4 Hz, 1H), 8.48 (dd, J = 8.4, 2.0 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 5.53(s, 1H), 4.31(d, J = 4.0 Hz, 1H) 2.31-2.82 (m, 3H), 2.11-2.16 (m, 1H), 1.63-1.94 (m, 5H).

(2S, 10R)-2-(Hydroxy-(4-cyanophenyl) methyl) cyclohexan-1-one 2e[2]

Yield 88%, anti/syn= 95:5, enantiomeric excess: 95% of anti-diastereomer determined by HPLC (Dicael Chiralpak AD-H column; i-PrOH/Hexane=20:80, flow rate 0.5 mL/min, 20 oC, λ = 254 nm; tR = 22.5 min (anti, major), tR= 18.1 min (anti, minor)). 1H NMR(300 MHz, CDCl3): δ = 7.65 (d, 2H, J = 8.1 Hz), 7.45 (d, 2H, J = 8.1 Hz), 4.85 (dd, 1H, J = 8.1, 3.0 Hz), 4.11 (d, 1H, J = 3.0 Hz), 2.65-2.44 (m, 2H), 2.37 (td, 1H, J = 12.9, 6.0 Hz), 2.17-2.06 (m, 1H), 1.88-1.77 (m, 1H), 1.72-1.47 (m, 3H), 1.44-1.31 (m, 1H).

(2S, 10R)-2-(Hydroxy-(4-(trifluoromethyl)methyl) cyclohexan-1-one 2f

Yield 88%, anti:syn=97:3, enantiomeric excess: 98% of anti diastereomer determined by HPLC(Dicael Chiralpak AD-H column; i-PrOH:Hexane=10:90; flow rate 0.5 mL/min, 20oC,λ=254 nm; tR=34.4 min (anti, major), tR=26.9 min (anti, minor)). 1H NMR (300 MHz, CDCl3): δ 7.74–7.55 (m, 3H), 7.40 (t, 1H, J = 7.2 Hz), 5.30 (d, 1H, J = 9.3 Hz), 4.03 (t, 1H, J = 3.0 Hz), 2.81–2.69 (m, 1H), 2.55–2.45 (m, 1H), 2.37 (td, 1H, J = 12.9, 4.8 Hz), 2.15–2.03 (m, 1H), 1.81–149 (m, 3H), 1.48–1.23 (m, 1H).

(2S, 10R)-2-(Hydroxy-(4-bromophenyl) methyl) cyclohexan-1-one 2g[2]

Yield 90%, anti/syn = 97:3, enantiomeric excess: 94% of anti-diastereomer determined by HPLC (Dicael Chiralpak AD-H column; i-PrOH/Hexane=10:90; flow rate 0.8 mL/min, 20 oC, λ = 221 nm; tR = 27.0 min (anti, major), tR = 22.4 min (anti, minor)). 1H NMR(300 MHz, CDCl3): δ = 7.47 (d, 2H, J = 8.1 Hz), 7.20 (d, 2H, J = 8.7 Hz), 4.75 (dd, 1H, J = 8.7, 2.7 Hz), 3.99 (d, 1H, J = 3.0 Hz), 2.61-2.44 (m, 2H), 2.35 (td, 1H, J = 12.9, 6.3 Hz), 2.15-2.04 (m, 1H), 1.85-1.75 (m, 1H), 1.70-1.50 (m, 3H), 1.37-1.20 (m, 1H).

(2S, 10R)-2-(Hydroxy-(4-chlorophenyl) methyl) cyclohexan-1-one 2h[2]

Yield 92 %, anti/syn = 93:7, enantiomeric excess: 96 % of anti-diastereomer determined by HPLC (Dicael Chiralpak AD-H column; i-PrOH/Hexane=10:90; flow rate 0.5 mL/min, 20 oC, λ = 221 nm; tR = 39.2 min (anti, major), tR = 33.4 min (anti, minor)). 1H NMR(300 MHz, CDCl3): δ = 7.29 (dd, 4H, J = 20.4, 8.4 Hz), 4.76 (dd, 1H, J = 8.7, 2.7 Hz), 3.99 (d, 1H, J = 3.0 Hz), 2.61-2.44 (m, 2H), 2.35 (td, 1H, J = 12.9, 5.4 Hz), 2.15-2.05 (m, 1H), 1.85-1.75 (m, 1H), 1.70-1.50 (m, 3H), 1.37-1.20 (m, 1H).

(2S, 10R)-2-(Hydroxy-(2-chlorophenyl) methyl) cyclohexan-1-one 2i[2]

Yield 86%, anti/syn = 90:10, enantiomeric excess: 97 % of anti-diastereomer determined by HPLC (Dicael Chiralpak OD-H column; i-PrOH/Hexane=5:95; flow rate 1.0 mL/min, 20 oC, λ = 221 nm; tR = 9.7 min (anti, major), tR = 12.3 min (anti, minor)). 1H NMR(300 MHz, CDCl3): δ = 7.56 (d, 1H, J = 8.4 Hz,) 7.20-7.34 (m, 3H), 5.35 (d, 1H, J = 8.0 Hz), 2.65-2.71 (m, 1H), 3.88 (s, 1H), 2.46-2.49 (m, 1H), 2.31-2.39 (m, 1H), 2.05-2.13 (m, 1H), 1.53-1.84 (m, 5H).

(2S, 10R)-2-(Hydroxy-(4-tolyl) methyl) cyclohexan-1-one 2j[2]

Yield 70%, anti/syn >99, enantiomeric excess: 97% of anti-diastereomer determined by HPLC (Dicael Chiralpak AD-H column; i-PrOH/Hexane=10:90; flow rate 0.5 mL/min, 20 oC, λ = 221 nm; tR = 32.8 min (anti, major), tR = 44.5 min (anti, minor)). 1H NMR(300 MHz, CDCl3): δ = 7.18 (dd, 4H, J = 17.1, 8.4 Hz), 4.75 (dd, 1H, J = 9.0, 2.7 Hz), 3.91 (d, 1H, J = 2.7 Hz), 2.66-2.54 (m, 1H), 2.51-2.43 (m, 1H), 2.35 (td, 1H, J = 13.2, 6.0 Hz), 2.34 (s, 3H), 2.14-2.03 (m, 1H), 1.82-1.72 (m, 1H), 1.70-1.50 (m, 3H), 1.38-1.18 (m, 1H).

(2S, 10R)-2-(Hydroxy-(4-methoxy-phenyl) methyl) cyclohexan-1-one 2k[2]

Yield 77 %, anti/syn = 95:5, enantiomeric excess: 95 % of anti-diastereomer determined by HPLC (Dicael Chiralpak AD-H column; i-PrOH/Hexane = 10:90; flow rate 0.8 mL/min, 20 oC, λ = 221 nm; tR = 32.5 min (anti, major), tR = 30.8 min (anti, minor)). 1H NMR(300 MHz, CDCl3): δ = 7.27 (dd, J = 13.2, 8.4 Hz, 3H), 6.90 (d, J = 8.8 Hz, 3H), 4.76 (d, J = 7.6 Hz, 1H), 3.94 (s, 1H), 3.83 (s, 3H), 2.34-2.65 (m, 3H), 2.08-2.14 (m, 1H), 1.55-1.82 (m, 6H), 1.20-1.40 (m, 2H).

(2S, 10R)-2-(Hydroxy-(3-methoxy-phenyl) methyl) cyclohexan-1-one 2l[2]

Yield 65%, anti/syn = 91:9, enantiomeric excess: 96 % of anti-diastereomer determined by HPLC (Dicael Chiralpak AD-H column; i-PrOH/Hexane = 10:90; flow rate 0.5 mL/min, 20 oC, λ = 221 nm; tR= 56.3 min (anti, major), tR = 51.1 min (anti, minor)). 1H NMR (300 MHz, CDCl3): δ = 7.28-7.33 (m, 1H), 6.80–7.00 (m, 3H), 4.80 (d, J = 8.7 Hz, 1H), 3.85 (s, 3H), 2.30-2.75 (m, 3H), 2.00-2.15 (m, 1H), 1.55-1.90 (m, 4H), 1.20-1.40 (m, 1H).

(2S, 10R)-2-(Hydroxy-(2-naphthyl) methyl) cyclohexan-1-one 2m[2]

Yield 76%, anti/syn = 98:2, enantiomeric excess: 94 % of anti-diastereomer determined by HPLC (Dicael Chiralpak OD-H column; i-PrOH/Hexane=10:90; flow rate 1.0 mL/min, 20 oC, λ = 221 nm; tR = 15.7 min (anti, major), tR = 22.2 min (anti, minor)). 1H NMR (300 MHz, CDCl3): δ = 7.70-7.90 (m, 4H), 7.40-7.55 (m, 3H), 5.01 (d, J = 8.7 Hz, 1H), 4.10 (s, 1H), 2.71-2.78 (m, 1H), 2.37-2.55 (m, 2H), 2.09-2.14 (m, 1H), 1,52-1.80 (m, 5H), 1.28-1.42 (m, 2H).

(2S, 10R)-2-(Hydroxy-(1-naphthyl) methyl) cyclohexan-1-one 2n [2]

Yield 74%, anti/syn >99, enantiomeric excess: 90 % of anti-diastereomer determined by HPLC (Dicael Chiralpak AD-H column; i-PrOH/Hexane=5:95; flow rate 1.0 mL/min, 20 oC, λ = 221 nm; tR = 45.9 min (anti, major), tR = 36.7 min (anti, minor)). 1H NMR (300 MHz, CDCl3): δ = 8.24-8.27 (m, 1H), 7.84-7.89 (m, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.57 (d, J = 6.3 Hz, 1H), 7.45-7.53 (m, 3H), 5.58 (dd, J = 8.7, 2.9 Hz, 1H), 4.15 (d, J = 2.9 Hz, 1H), 2.95-3.04 (m, 1H), 2.49-2.54 (m, 1H), 2.35-2.45 (m, 1H), 2.05-2.12 (m, 1H), 1.61-1.74 (m, 2H), 1.33-1.51 (m, 3H).