69451 Weinheim, GermanyTo a stirred suspension of N-9-anthracenylmethyl dihydrocinchoninium chloride...

Supporting Information © Wiley-VCH 2006

69451 Weinheim, Germany

1

Organocatalytic Enantioselective Nucleophilic

Vinylic Substitution

Thomas B. Poulsen, Luca Bernardi, Mark Bell and Karl Anker Jørgensen* The Danish National Research Foundation: Center for Catalysis

Department of Chemistry, Aarhus University, DK-8000 Aarhus C, Denmark e-mail: [email protected]

2

Table S1. Initial Screening Results – Ester Group.a

O

CO2R +Cl O

Phcat (mol%)

O

CO2R

OPh

(Z)-3a33% K2CO2 (aq.)

solv., temp.2 4

entry R temp./ time

solv. (M) cat.

(mol%) conv. (%)b

Z/Eb ee

(%)c

1 Et rt / 5.0h tol./CHCl3 (3:1) (0.15) 1e (10) 68 >95/5 13

2 Et rt / 4.7h tol./CHCl3 (3:1) (0.15) 1a (10) 59 >95/5 21

3 Et rt / 3.5h tol./CHCl3 (3:1) (0.15) 1g (10) 86 >95/5 42

4 tBu rt / 3.0h tol./CHCl3 (5:1) (0.15) 1g (10) 93 >95/5 64

5 tBu 0 oC / 4.3h tol./CHCl3 (7:1) (0.15) 1a (10) 25 >95/5 57

6 tBu 0 oC / 4.5h tol./CHCl3 (7:1) (0.15) 1g (10) 87 >95/5 74 a Performed with 0.12 mmol of (Z)-3a (0.15M) and 1.3 eq. of 2. b Determined by 1H NMR spectroscopy. c Of the (Z)-isomer determined by CSP-HPLC.

N

NO

HH

H

R'

X

R

1e: R' = Phenyl, R = H, X = Cl

1a: R' = 9-anthracenyl, R = H, X = Cl

1g: R' = 9-anthracenyl, R = allyl, X = Br

1h: R' = 9-anthracenyl, R = benzyl, X = Br

3

Table S2. Initial Screening Results - Conditions.a

O

CO2tBu +Cl O

Ph 1h (10 mol%)base (aq)

O

CO2tBu

OPh

solv., temp.

2a (Z)-3a 4a

Z/E >95/5

entry base (mL)

solv. (M)

temp/time (oC/h)

conv.

(%)b ee

(%)c

1 33% K2CO3 (0.4) CH2Cl2 (0.15) 0/3.5 45 38

2 33% K2CO3 (0.4) toluene (0.15) 0/4.5 67 76

3 33% K2CO3 (0.4) CHCl3 (0.15) 0/4.5 40 50

4 33% K2CO3 (0.4) 7:1 tol./CHCl3 (0.15) 0/3.2 83 77

5 33% K2CO3 (0.4) 7:1 tol./CHCl3 (0.08) 0/5.0 67 76

6 33% K2CO3 (0.4) 7:1 tol./CHCl3 (0.30) 0/5.0 96 73

7 33% K2CO3 (0.2) 7:1 tol./CHCl3 (0.15) 0/5.0 77 76

8 15% K2CO3 (0.4) 7:1 tol./CHCl3 (0.15) 0/5.0 72 77 a Performed with 0.12 mmol of (Z)-3a (0.15M) and 1.3 eq. of 2a. b Determined by 1H NMR spectroscopy. c Of the (Z)-isomer determined by CSP-HPLC.

N

NO

HH

H

R'

X

R

1e: R' = Phenyl, R = H, X = Cl

1a: R' = 9-anthracenyl, R = H, X = Cl

1g: R' = 9-anthracenyl, R = allyl, X = Br

1h: R' = 9-anthracenyl, R = benzyl, X = Br

4

Table S3. Catalyst Screening.a

O

CO2tBu +Cl O

Ph cat. (10 mol%)33% K2CO3 (aq)

O

CO2tBu

OPh

toluene/CHCl3(7:1)2a (Z)-3a 4a

entry R temp. (oC)

time (h)

conv. (%)b

Z/Eb ee

(%)c

1 allyl 0 4.5 87 > 95/5 74

2 benzyl 0 3.2 83 > 95/5 77

3 2-naphthomethyl 0 4.5 85 > 95/5 75

4 1-naphthomethyl 0 5.5 >95 > 95/5 76

5 2,4-dinitrophenyl 0 5.3 58 > 95/5 73

6 benzoyl 0 4.5 82 > 95/5 77

7 2-Cl-benzoyl 0 4.0 61 > 95/5 82

8 2-Cl-benzoyl -20 7.0 71 > 95/5 86

9 2,4,6-trimethylbenzoyl 0 6.5 >95 > 95/5 82

10 1-naphthoyl (5 mol%) 0 5.5 >95 > 95/5 81

11 2-naphthoyl 0 5.5 >95 > 95/5 76

12 p-Ts 0 5.7 9 > 95/5 42

13 pivaloyl 0 3.3 >95 > 95/5 86

14 pivaloyl -20 4.5 92 > 95/5 88

15 1-adamantoyl -20 5.0 97 > 95/5 88

16 neopentoyl -20 5.5 83 > 95/5 87 a Performed with 0.12 mmol of (Z)-3a (0.15M) and 1.3 eq. of 2a. b Determined by 1H NMR spectroscopy. c Of the (Z)-isomer determined by CSP-HPLC.

N

NO

HH

H

X

R

5

General Methods. NMR spectra were acquired on a Varian AS 400 spectrometer, running at 400 and 100 MHz for 1H and 13C,

respectively. Chemical shifts (δ) are reported in ppm relative to residual solvent signals (CHCl3, 7.26 ppm for 1H NMR, CDCl3,

77.0 ppm for 13C NMR; CHD2OD, 3.30 ppm for 1H NMR, CD3OD, 52.0 ppm for 13C NMR; C6D5H, 7.16 ppm for 1H NMR,

C6D6 128.1 ppm for 13C NMR). 13C NMR spectra were acquired on a broad band decoupled mode. Mass spectra were recorded

on a micromass LCT spectrometer using electrospray (ES+) ionization techniques. Analytical thin layer chromatography (TLC)

was performed using pre-coated aluminium-backed plates (Merck Kieselgel 60 F254) and visualized by ultraviolet irradiation

or KMnO4 dip. Melting points are uncorrected. Optical rotations were measured on a Perkin-Elmer 241 polarimeter. The

enantiomeric excess (ee) of the products was determined by chiral stationary phase HPLC (Daicel Chiralpak AS/AD or Daicel

Chiralcel OD/OJ columns).

Materials. Analytical grade solvents and commercially available reagents were used as received. CDCl3 was passed through a

short plug of neutral alumina. For flash chromatography (FC) silica gel was purchased from Fluka (Silica gel 60, 230-400

mesh). The tert-butyl ß-ketoesters 2 were either prepared by Claisen-condensation,i or from the corresponding methyl estersii

by Bu2SnO catalyzed transesterification with tert-BuOH in refluxing toluene.iii The β-halopropenones 3a-h and β-

halopropenoate 3i were prepared from the corresponding alkynes and a lithium halide.iv (E)-Ethyl β-chloro-α-iodopropenoate

was prepared following a procedure published recently.v N-9-anthracenylmethyl dihydrocinchoninium chloride 1a and N-9-

anthracenylmethyl dihydrocinchonidinium chloride were prepared following a literature procedure.vi Racemic samples were

prepared using TBAI as the catalyst.

O-1-Adamantoyl-N-9-anthracenylmethyl dihydrocinchoninium chloride (1d):

To a stirred suspension of N-9-anthracenylmethyl dihydrocinchoninium chloride 1a (261 mg,

0.5 mmol) in CH2Cl2 (5 mL), were sequentially added 1-adamantanecarbonyl chloride (299 mg,

2.5 mmol) and a 30% w/w NaOH solution (0.7 mL). After 30 minutes of vigorous stirring,

during which time all the solid dissolved, H2O and CH2Cl2 were added. The two layers were

separated and the aqueous layer extracted with CH2Cl2, the combined organic extracts were

dried over MgSO4, filtered and evaporated under reduced pressure. The crude product was

dissolved in CH2Cl2 (ca 1.5 mL), poured onto Et2O (15 mL) with stirring. The resulting precipitate was collected by suction

filtration, washed several times with Et2O, giving 1d as a yellow solid (285 mg, 83% yield). Mp 133-138 °C. 1H NMR

(CD3OD) δ 9.02 (d, J 4.7 Hz, 1H), 8.90 (s, 1H), 8.76 (d, J 8.4 Hz, 1H), 8.51 (d, J 8.4 Hz, 1H), 8.25 (t, J 6.6 Hz, 2H), 8.14 (dd,

J 8.4, 1.2 Hz, 1H), 8.01 (br s, 1H), 7.98-7.80 (m, 5H), 7.66 (dd, J 8.4, 6.5 Hz, 1H), 7.55 (dd, J 8.3, 6.5 Hz, 1H), 7.38 (ddd, J

8.8, 6.6, 1.0 Hz, 1H), 5.96 (d, J 14.0 Hz, 1H), 5.86 (d, J 14.0 Hz, 1H), 4.51 (br t, J 9.6 Hz, 1H), 4.19 (br t, J 11.6 Hz, 1H), 3.64-

3.58 (m, 1H), 3.42-3.36 (m, 1H), 2.80-2.70 (m, 2H), 2.30-2.20 (m, 3H), 2.25 (br s, 6H), 2.10-1.70 (m, 9H), 1.68-1.50 (m, 4H),

0.80 (t, J 6.8 Hz, 3H). 13C NMR (CD3OD) δ 179.8, 152.8, 150.2, 147.4, 137.3, 137.0, 136.9, 135.9, 135.7, 135.0, 134.4, 133.9,

132.5, 132.3, 132.1, 131.6, 129.5, 129.2, 128.6, 128.2, 127.1, 126.6, 123.2, 120.9, 72.2, 71.1, 61.9, 61.7, 59.7, 45.4, 43.1, 40.0,

39.6, 32.0, 28.5, 28.3, 27.9, 26.3, 14.2. HRMS calc.: C45H49N2O2 649.3789; found: 649.3788. [a]Drt +192 (c 0.49, CH3OH).

N

ON

O

H

Cl

6

O-1-Adamantoyl-N-9-anthracenylmethyl dihydrocinchonidinium chloride (1’d):

Starting from N-9-anthracenylmethyl dihydrocinchonidinium chloride and following the

procedure used for 1d, the title compound was obtained as a yellow solid in 73% yield. Mp

118-121 °C. 1H NMR (CD3OD) δ 8.98 (d, J 4.8 Hz, 1H), 8.91 (s, 1H), 8.59 (d, J 8.8 Hz, 1H),

8.49 (d, J 8.4 Hz, 1H), 8.28-8.24 (m, 2H), 8.20-8.10 (m, 3H), 7.89 (t, J 7.2 Hz, 1H), 7.86-

7.75 (m, 3H), 7.68-7.52 (m, 3H), 6.40 (d, J 14.0 Hz, 1H), 5.77 (d, J 14.0 Hz, 1H), 4.52-4.49

(m, 1H), 3.86 (br t, J 12.0 Hz, 1H), 3.50-3.46 (m, 1H), 3.30-3.22 (m, 1H), 2.92-2.80 (m, 1H),

2.61-2.52 (m, 1H), 2.25-2.12 (m, 10H), 1.96-1.80 (m, 8H), 1.74-1.54 (m, 2H), 1.30-1.20 (m,

2H), 0.65 (t, J 6.8 Hz, 3H). 13C NMR (CD3OD) δ 179.9, 152.9, 150.3, 147.5, 137.4, 137.1, 137.0, 136.0, 135.7, 135.1, 134.5,

134.0, 132.5, 132.3, 132.2, 131.7, 129.6, 128.7, 128.2, 127.2, 126.6, 123.3, 120.9, 72.2, 71.2, 61.9, 61.7, 59.7, 45.5, 43.2, 40.1,

39.9, 32.0, 28.6, 28.4, 27.9, 26.3, 14.2. [a]Drt -162 (c 0.27, CH3OH).

General Procedure for the Vinylic Substitution:

Method A:

To a sample vial equipped with a magnetic stirring bar was added 2a (36.8 mg, 0.20 mmol), o-xylene/CHCl3 (7:1) 1.3 mL, 3a

(36.7 mg, 0.22 mmol), and the catalyst 1d (3 mol%, 0.006 mmol, 4.1 mg). The mixture was stirred for a short time at ambient

temperature and was then placed at -20 oC. When the mixture had cooled, a cold (-20 oC) solution of 33% aq. K2CO3 (0.6 mL)

was added and the biphasic mixture was vigorously stirred for the time stated below (for 4a, 21 h). After the reaction was

judged to be complete by TLC analysis, the organic phase was collected, and the aqueous layer was extracted two times with

toluene. The combined organic fractions were loaded onto SiO2 and the product 4a (55.2 mg, 0.176 mmol, 89% yield, Z/E

>95/5) was obtained by FC eluting with Et2O in CH2Cl2 (0:100 to 3:97).

Method B:

To a sample vial equipped with a magnetic stirring bar was added 2a (36.8 mg, 0.20 mmol), o-xylene/CHCl3 (7:1) 0.65 mL, 3i

(53.8 mg, 0.40 mmol), and the catalyst 1d (6 mol%, 0.012 mmol, 8.2 mg). The mixture was stirred for a short time at ambient

temperature and was then placed at -20 oC. When the mixture had cooled, a cold (-20 oC) solution of 66% aq. Cs2CO3 (0.6 mL)

was added and the biphasic mixture was vigorously stirred for the time stated below (for 4i, 21 h). After the reaction was

judged to be complete by TLC analysis, the organic phase was collected, and the aqueous layer was extracted two times with

toluene. The combined organic fractions were loaded onto SiO2 and the product 4i (42.5 mg, 0.151 mmol, 75% yield, Z/E

>95/5) was obtained by FC eluting with Et2O in CH2Cl2 (0:100 to 3:97).

(S,Z)-2-Oxo-1-(3-oxo-3-phenyl-propenyl)-cyclopentanecarboxylic acid tert-butyl ester (4a):

The title compound was obtained according to the general procedure (method A, 21 h) as a viscous

colorless oil that solidified upon standing (89% yield). 1H NMR (CDCl3) δ 7.92 (d, J 7.8 Hz, 2H), 7.55 (t,

J 7.5 Hz, 1H), 7.45 (t, J 7.9 Hz, 2H), 7.03 (d, J 12.0 Hz, 1H), 6.86 (d, J 12.0 Hz, 1H), 2.76-2.86 (m, 1H),

2.51-2.61 (m, 2H), 2.35-2.43 (m, 1H), 2.14-2.26 (m, 2H), 1.46 (s, 9H). 13C NMR (CDCl3) δ 212.0, 190.2,

170.1, 145.7, 137.7, 133.0, 128.5 (2C), 128.3 (2C), 123.9, 82.7, 63.5, 38.4, 36.9, 27.7 (3C), 20.3. HRMS

calc.: C19H22NaO4 337.1416; found: 333.1416. The ee was determined by HPLC using a Chiralpak AD

column [hexane/iPrOH (97:3)]; flow rate 1.0 mL/min; τmajor = 12.2 min, τminor = 23.5 min (94% ee). [a]Drt +104.7 (c 0.51,

CH2Cl2).

N

O N

O ClH

OCO2tBu

O

7

(R,Z)-2-Oxo-1-(3-oxo-3-phenyl-propenyl)-cyclopentanecarboxylic acid tert-butyl ester (ent-4a):

The title compound was obtained according to the general procedure (method A, 24 h) using catalyst 1’d

derived from dihydrocinchonidine, as a viscous colorless oil (92% yield). Spectral data were identical to

compound 4a. The ee was determined by HPLC using a Chiralpak AD column [hexane/iPrOH (97:3)];

flow rate 1.0 mL/min; τmajor = 23.5 min, τminor = 12.2 min (84% ee). [a]Drt -94 (c 0.57, CH2Cl2).

(S,Z)-2-Oxo-1-[3-oxo-3-(4-trifluoromethyl-phenyl)-propenyl]-cyclopentane carboxylic acid tert-butyl ester (4b):

The title compound was obtained according to the general procedure (method A, 21 h) as an off-

white amorphous solid (89% yield). 1H NMR (CDCl3) δ 8.01 (d, J 8.6 Hz, 2H), 7.72 (d, J 8.2 Hz,

2H), 7.00 (d, J 12.0 Hz, 1H), 6.91 (d, J 11.9 Hz, 1H), 2.72-2.81 (m, 1H), 2.53-2.62 (m, 2H), 2.34-

2.42 (m, 1H), 2.15-2.23 (m, 2H), 1.46 (s, 9H). 13C NMR (CDCl3) δ 211.9, 189.4, 169.9, 147.2,

140.4, 134.3 (q, 2JC-F 32.6 Hz), 128.7 (2C), 125.6 (q, 3JC-F 3.6 Hz, 2C), 123.9, 123.5 (q, 1JC-F 277.6

Hz), 83.0, 63.7, 38.6, 37.0, 27.8 (3C), 20.3. HRMS calc.: C20H21F3NaO4 405.1290; found:

405.1283. The ee was determined by HPLC using a Chiralpak OD column [hexane/iPrOH (98:2)]; flow rate 1.0 mL/min; τmajor

= 9.5 min, τminor = 11.1 min (93% ee). [a]Drt +96.4 (c 0.51, CH2Cl2).

(S,Z)-1-[3-(4-Methoxy-phenyl)-3-oxo-propenyl]-2-oxo-cyclopentanecarboxylic acid tert-butyl ester (4c):

The title compound was obtained according to the general procedure (method A, 44 h) as a viscous

colorless oil that solidified upon standing (71% yield). 1H NMR (CDCl3) δ 7.91 (d, J 9.0 Hz, 2H),

6.99 (d, J 12.0 Hz, 1H), 6.91 (d, J 9.0 Hz, 2H), 6.80 (d, J 12.0 Hz, 1H), 3.86 (s, 3H), 2.75-2.84 (m,

1H), 2.49-2.58 (m, 2H), 2.35-2.43 (m, 1H), 2.12-2.20 (m, 2H), 1.44 (s, 9H). 13C NMR (CDCl3)

δ 212.1, 188.7, 170.2, 163.5, 144.7, 130.7 (2C), 127.4, 124.0, 113.7 (2C), 82.6, 63.4, 55.4, 38.4,

36.9, 27.8 (3C), 20.3. HRMS calc.: C20H24NaO5 367.1521; found: 367.1507. The ee was determined

by HPLC using a Chiralcel OD column [hexane/iPrOH (95:5)]; flow rate 1.0 mL/min; τmajor = 11.1 min, τminor = 16.3 min (93%

ee). [a]Drt +93.5 (c 0.48, CH2Cl2).

(S,Z)-2-Oxo-1-(3-oxo-3-thiophen-2-yl-propenyl)-cyclopentanecarboxylic acid tert-butyl ester (4d):

The title compound was obtained according to the general procedure (method A, 21 h) as an off-white

amorphous solid (87% yield). 1H NMR (CDCl3) δ 7.73 (dd, J 3.8, 1.1 Hz, 1H), 7.64 (dd, J 4.9, 1.1 Hz,

1H), 7.12 (dd, J 4.9, 3.8 Hz, 1H), 6.92 (d, J 11.9 Hz, 1H), 6.86 (d, J 11.9 Hz, 1H), 2.79-2.88 (m, 1H),

2.48-2.60 (m, 2H), 2.37-2.45 (m, 1H), 2.15-2.22 (m, 2H), 1.45 (s, 9H). 13C NMR (Benzene-d6) δ 210.0,

182.1, 170.4, 146.7, 146.1, 134.1, 132.2, 128.1, 123.6, 82.0, 63.7, 38.6, 37.2, 27.6 (3C), 20.7. HRMS

calc.: C17H20NaO4S 343.0980; found: 343.0973. The ee was determined by HPLC using a Chiralpak AD column

[hexane/iPrOH (92:8)]; flow rate 1.0 mL/min; τmajor = 10.5 min, τminor = 23.8 min (91% ee). [a]Drt +150.8 (c 0.50, CH2Cl2).

OCO2tBu

O

OCO2tBu

OF3C

OCO2tBu

OMeO

OCO2tBu

OS

8

The purified compound was allowed to crystallize from a mixture of CH2Cl2/EtOAc/n-heptane by slow evaporation of the

solvent affording crystals (mp = 118-120 oC) suitable for X-ray analysis. On this basis, the configuration of the formed

stereocenter could be assigned (S).

(S,Z)-1-(3-Naphthalen-1-yl-3-oxo-propenyl)-2-oxo-cyclopentanecarboxylic acid tert-butyl ester (4e):

The title compound was obtained according to the general procedure (method A, 25 h) as a

viscous colorless oil that solidified upon standing (86% yield). 1H NMR (CDCl3) δ 8.46 (d, J 8.4

Hz, 1H), 7.98 (d, J 8.2 Hz, 1H), 7.87 (d, J 9.5 Hz, 1H), 7.83 (d, J 7.2 Hz, 1H), 7.48-7.61 (m, 3H),

6.91 (d, J 11.9 Hz, 1H), 6.88 (d, J 11.9 Hz, 1H), 2.83-2.93 (m, 1H), 2.50-2.66 (m, 3H), 2.19-2.28

(m, 2H), 1.50 (s, 9H). 13C NMR (benzene-d6) δ 210.7, 194.3, 170.4, 145.4, 136.9, 134.2, 132.7,

130.8, 128.6 (2C), 128.2, 127.9, 126.6, 126.3, 124.6, 82.1, 63.7, 38.8, 37.3, 27.7 (3C), 20.8.

HRMS calc.: C23H24NaO4 387.1572; found: 387.1572. The ee was determined by HPLC using a

Chiralpak AD column [hexane/iPrOH (98:)]; flow rate 1.0 mL/min; τmajor = 11.5 min, τminor = 21.9 min (94% ee). [a]Drt +125.0

(c 0.50, CH2Cl2).

(S,Z)-2-Oxo-1-(3-oxo-but-1-enyl)-cyclopentanecarboxylic acid tert-butyl ester (4f):

The title compound was obtained according to the general procedure (method B, 21 h) as a

viscous colorless oil (87% yield, Z/E = 95:5). 1H NMR (benzene-d6) [signals of the Z isomer]

δ 6.72 (d, J 11.8 Hz, 1H), 5.75 (d, J 11.8 Hz, 1H), 2.77-2.87 (m, 1H), 2.23-2.48 (m, 3H), 1.85-

2.02 (m, 2H), 1.61 (s, 3H), 1.23 (s, 9H). 13C NMR (Benzene-d6) [signals of the Z isomer] δ 210.0,

197.4, 170.6, 144.0, 127.1, 82.0, 63.4, 38.7, 37.3, 30.7, 27.6 (3C), 20.7. HRMS calc.: C14H20NaO4

OCO2tBu

O

OCO2tBu

OMe

9

275.1259; found: 275.1252. The ee was determined by HPLC using a Chiralpak AD column [hexane/iPrOH (98:2)]; flow rate

1.0 mL/min; τmajor = 8.7 min, τminor = 15.3 min (91% ee).

After reduction of the C-C double bond [H2 (1 atm.), Pd/C, EtOH, rt, 0.5h, 92%] the optical rotation ([a]Drt -7.4 [c 0.88,

CHCl3], 90% ee) could be compared to a literature valuevii for the corresponding ®-enantiomer ([a]D20 +8.7 [c 0.41, CHCl3],

92% ee). Therefore the configuration of the stereocenter formed could be assigned to be (S).

(S,Z)-2-Oxo-1-(3-oxo-5-phenyl-pent-1-enyl)-cyclopentanecarboxylic acid tert-butyl ester (4g):

The title compound was obtained according to the general procedure (method A, cat. loading 6 mol%,

78 h) as a viscous colorless oil (78% yield). 1H NMR (CDCl3) δ 7.25-7.29 (m, 2H), 7.15-7.21 (m, 3H),

6.62 (d, J 11.8 Hz, 1H), 6.30 (d, J 11.8 Hz 1H), 2.74-2.90 (m, 5H), 2.51-2.59 (m, 1H), 2.41-2.47 (m,

1H), 2.22-2.30 (m, 1H), 2.12-2.19 (m, 2H), 1.46 (s, 9H). 13C NMR (CDCl3) δ 211.7, 199.0, 170.1,

144.1, 140.7, 128.3, 128.1 (2C), 126.3, 125.9 (2C), 82.6, 63.2, 45.4, 38.4, 36.9, 29.5, 27.7 (3C), 20.2.

HRMS calc.: C21H26NaO4 365.1729; found: 365.1729. The ee was determined by HPLC using a

Chiralpak AD column [hexane/iPrOH (97:3)]; flow rate 1.0 mL/min; τmajor = 10.6 min, τminor = 26.9 min (93% ee). [a]Drt

+102.4 (c 0.61, CH2Cl2).

(S,Z)-1-(4,4-Dimethyl-3-oxo-pent-1-enyl)-2-oxo-cyclopentanecarboxylic acid tert-butyl ester (4h):

The title compound was obtained according to the general procedure (method A, cat. loading 6 mol%,

23 h) as a viscous colorless oil (90% yield). 1H NMR (CDCl3) δ 6.66 (d, J 12.0 Hz, 1H), 6.56 (d, J

12.0 Hz, 1H), 2.68-2.77 (m, 1H), 2.43-2.56 (m, 2H), 2.25-2.33 (m, 1H), 2.11-2.19 (m, 2H), 1.45 (s,

9H), 1.12 (s, 9H). 13C NMR (CDCl3) δ 212.0, 205.2, 170.4, 144.4, 123.0, 82.6, 63.2, 43.3, 38.5, 37.0,

27.8 (3C), 25.9 (3C), 20.3. HRMS calc.: C17H26KO4 333.1468; found: 333.1469. The ee was

determined by HPLC using a Chiralpak AD column and a Chiralcel OD column combined in series [hexane/iPrOH (99:1)];

flow rate 1.0 mL/min; τmajor = 12.2 min, τminor = 15.3 min (96% ee). [a]Drt +99.3 (c 0.49, CH2Cl2).

(S,Z)-1-(2-Ethoxycarbonyl-vinyl)-2-oxo-cyclopentanecarboxylic acid tert-butyl ester (4i):

The title compound was obtained according to the general procedure (method B, 71 h) as a viscous

colorless oil (77% yield). 1H NMR (CDCl3) δ 6.72 (d, J 11.9 Hz, 1H), 5.95 (d, J 12.0 Hz, 1H), 4.11 (m,

2H), 2.61-2.70 (m, 1H), 2.48-2.58 (m, 2H), 2.32-2.40 (m, 1H), 2.08-2.19 (m, 2H), 1.45 (s, 9H), 1.25 (t,

J 7.1 Hz, 3H). 13C NMR (CDCl3) δ 212.4, 169.8, 165.5, 146.2, 121.0, 82.7, 63.1, 60.3, 38.0, 37.1, 27.8

(3C), 20.0, 14.1. HRMS calc.: C15H22NaO5 305.1365; found: 305.1359. The ee was determined by GC

using a Chrompack CP-Chirasil Dex CB (β-PM) column; τmajor = 24.7 min, τminor = 24.9 min (91% ee). [a]Drt +133.5 (c 0.48,

CH2Cl2).

OCO2tBu

O

OCO2tBu

O

OCO2tBu

OEtO

10

(R,Z)-1-(2-Ethoxycarbonyl-vinyl)-2-oxo-cyclopentanecarboxylic acid tert-butyl ester (ent-4i):

The title compound was obtained according to the general procedure (method B, 72 h) using catalyst

1’d derived from dihydrocinchonidine, as a viscous colorless oil (84% yield). Spectral data were

identical to compound 4i. The ee was determined by GC using a Chrompack CP-Chirasil Dex CB (β-

PM) column; τmajor = 24.9 min, τminor = 24.7 min (81% ee). [a]Drt -104.5 (c 0.49, CH2Cl2).

(S,Z)-1-Oxo-2-(3-oxo-3-phenyl-propenyl)-indan-2-carboxylic acid tert-butyl ester (4j):


viscous colorless oil (90% yield). 1H NMR (CDCl3) δ 7.98-7.92 (m, 2H), 7.78 (d, J 7.6 Hz, 1H),

7.64-7.52 (m, 2H), 7.48-7.44 (m, 3H), 7.38 (t, J 7.6 Hz, 1H), 7.11 (d, J 11.6 Hz, 1H), 6.85 (d, J

12.0 Hz, 1H), 4.15 (d, J 17.2 Hz, 1H), 3.14 (d, J 17.2 Hz, 1H), 1.30 (s, 9H). 13C NMR (CDCl3) δ

200.9, 190.4, 167.4, 153.6, 144.6, 137.6, 135.2, 135.0, 133.1, 128.6 (2C), 128.4 (2C), 127.5, 125.9,

125.4, 124.6, 82.4, 64.4, 40.4, 27.5 (3C). HRMS calc.: C23H22NaO4 385.1410; found: 385.1405.

The ee was determined by HPLC using a Chiralcel OJ column [hexane/iPrOH (80:20)]; flow rate 1.0 mL/min; τmajor = 16.5 min,

τminor = 14.5 min (90% ee). [a]Drt +133 (c 1.00, CH2Cl2).

(R,Z)-1-Oxo-2-(3-oxo-3-phenyl-propenyl)-indan-2-carboxylic acid tert-butyl ester (ent-4j):

The title compound was obtained according to the general procedure (method A, 24 h) using

catalyst 1’d derived from dihydrocinchonidine, as a viscous colorless oil (85% yield). Spectral

data were identical to compound 4j. The ee was determined by HPLC using a Chiralcel OJ

column [hexane/iPrOH (80:20)]; flow rate 1.0 mL/min; τmajor = 14.5 min, τminor = 16.5 min (89%

ee). [a]Drt -130 (c 0.85, CH2Cl2).

(S,Z)-5-Chloro-1-oxo-2-(3-oxo-3-phenyl-propenyl)-indan-2-carboxylic acid tert-butyl ester (4k):


viscous colorless oil (96% yield). 1H NMR (CDCl3) δ 7.94-7.78 (m, 2H), 7.69 (d, J 8.4 Hz, 1H),

7.58-7.52 (m, 1H), 7.48-7.42 (m, 3H), 7.35 (dd, J 8.0, 1.2 Hz, 1H), 7.12 (d, J 12.0 Hz, 1H), 6.85

(d, J 12.0 Hz, 1H), 4.05 (d, J 17.2 Hz, 1H), 3.13 (d, J 17.2 Hz, 1H), 1.29 (s, 9H). 13C NMR

(CDCl3) δ 199.2, 190.3, 167.4, 154.8, 144.0, 141.5, 137.4, 133.8, 133.2, 128.6 (2C), 128.4 (2C),

128.2, 126.0, 125.6, 125.4, 82.7, 64.4, 40.1, 27.5 (3C). HRMS calc.: C23H21ClNaO4 419.1021;

found: 419.1021. The ee was determined by HPLC using a Chiralpak AD column [hexane/iPrOH (90:10)]; flow rate 1.0

mL/min; τmajor = 15.3 min, τminor = 12.0 min (79% ee). [a]Drt +76 (c 1.00, CH2Cl2).

OCO2tBu

OEtO

OCO2tBu

O

OCO2tBu

O

OCO2tBu

OCl

11

(S,Z)-5,6-Dimethoxy-1-oxo-2-(3-oxo-3-phenyl-propenyl)-indan-2-carboxylic acid tert-butyl ester (4l):


white solid (95% yield). Mp 49-52 °C. 1H NMR (CDCl3) δ 7.93 (d, J 8.0 Hz, 2H), 7.54 (t, J 7.6

Hz, 1H), 7.44 (t, J 8.0 Hz, 2H), 7.15 (s, 1H), 7.05 (d, J 12.0 Hz, 1H), 6.84 (s, 1H), 6.78 (d, J

11.6 Hz, 1H), 4.10 (d, J 16.8 Hz, 1H), 3.93 (s, 3H), 3.87 (s, 3H), 3.05 (d, J 17.2 Hz, 1H), 1.30 (s,

9H). 13C NMR (CDCl3) δ 199.6, 190.5, 167.4, 155.9, 149.6, 149.4, 144.7, 137.5, 133.0, 128.6

(2C), 128.3 (2C), 127.0, 125.4, 106.8, 104.9, 82.2, 64.8, 56.2, 56.0, 40.0, 27.5 (3C). HRMS

calc.: C25H26NaO6 445.1622; found: 445.1618. The ee was determined by HPLC using a

Chiralpak AD column [hexane/iPrOH (90:10)]; flow rate 1.0 mL/min; τmajor = 53.5 min, τminor = 27.5 min (95% ee). [a]Drt +214

(c 0.780, CHCl3).

(S,Z)-2-Oxo-1-(3-oxo-3-phenyl-propenyl)-cyclohexanecarboxylic acid tert-butyl ester (4m):


viscous colorless oil (77% yield, Z/E = 90/10). 1H NMR (Benzene-d6) [signals of the Z isomer]

δ 7.81 (d, J 7.4 Hz, 2H), 6.98-7.10 (m, 3H), 6.84 (d, J 12.3, 1H), 6.61 (d, J 12.1 Hz, 1H), 2.53-

2.69 (m, 3H), 1.82-2.09 (m, 3H), 1.65-1.82 (m, 1H), 1.42-1.50 (m, 1H), 1.26 (s, 9H). 13C NMR

(CDCl3) [signals of the Z isomer] δ 204.3, 190.2, 170.2, 145.8, 137.7, 132.9, 128.5 (2C), 128.3

(2C), 124.0, 82.5, 63.4, 40.2, 36.5, 27.7 (3C), 25.2, 21.5. HRMS calc.: C20H24NaO4 351.1572;

found: 351.1567. The ee was determined by HPLC using a Chiralcel OJ column [hexane/iPrOH (95:5)]; flow rate 1.0 mL/min;

τmajor = 25.0 min, τminor = 28.7 min (89% ee).

(S)-1-Oxo-2-(3-oxo-3-phenyl-propenyl)-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid tert-butyl ester (4n):


viscous colorless oil (96% yield, Z/E = 95:5). 1H NMR (CDCl3) [signals of the Z isomer] δ 8.04 (d,

J 7.6 Hz, 1H), 7.93 (d, J 7.2 Hz, 2H), 7.54 (t, J 7.4 Hz, 1H), 7.48-7.41 (m, 3H), 7.31 (t, J 8.0 Hz,

1H), 7.23 (d, J 8.0 Hz, 1H), 7.05 (d, J 12.4 Hz, 1H), 6.60 (d, J 12.4 Hz, 1H), 3.13 (ddd, J 17.2,

11.6, 5.2 Hz, 1H), 2.95 (dt, Jd 16.8 Hz, Jt 4.8 Hz, 1H), 2.88-2.80 (m, 1H), 2.62 (dt, Jd 13.2 Hz, Jt

4.8 Hz, 1H), 1.38 (s, 9H). 13C NMR (CDCl3) [signals of the Z isomer] δ 192.6, 190.7, 170.2,

143.4, 142.3, 137.7, 133.0, 132.9, 132.8, 128.7, 128.5 (2C), 128.4 (2C), 127.9, 126.7, 126.1, 82.7, 61.1, 32.8, 27.7, 26.4 (3C).

HRMS calc.: C24H24NaO4 399.1567; found: 399.1552. The ee was determined by HPLC using a Chiralcel OJ column

[hexane/iPrOH (95:5)]; flow rate 1.0 mL/min; τmajor = 24.1 min, τminor = 28.3 min (95% ee).

OCO2tBu

OO

O

O

O

CO2tBu

O

O

CO2tBu

12

(S)-1-Oxo-2-(3-oxo-3-phenyl-propenyl)-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid tert-butyl ester (ent-4n):

The title compound was obtained according to the general procedure (method B, 48 h) using

catalyst 1’d derived from dihydrocinchonidine, as a viscous colorless oil (95% yield, Z/E = 92:8).

Spectral data were identical to compound 4n. The ee was determined by HPLC using a Chiralcel

OJ column [hexane/iPrOH (95:5)]; flow rate 1.0 mL/min; τmajor = 28.3 min, τminor = 24.1 min (94%

ee).

(S)-2-Oxo-1-(3-oxo-3-phenyl-propenyl)-cycloheptanecarboxylic acid tert-butyl ester (4o):

The title compound was obtained according to the general procedure (method B using 8 eq. of

solid Cs2CO3 as the base, 48 h) as a viscous colorless oil (81% yield, Z/E = 86:14). Pure (Z)-4o

can be obtained as a white solid by FC (pentane/Et2O 9:1). Mp 78-80 °C. 1H NMR (CDCl3)

δ [signals of the Z isomer] 7.97-7.94 (m, 2H), 7.60-7.52 (m, 1H), 7.46 (t, J 8.0 Hz, 2H), 6.98 (d, J

12.0 Hz, 1H), 6.75 (d, J 12.0 Hz, 1H), 2.98-2.90 (m, 1H), 2.66-2.54 (m, 2H), 2.35 (dd, J 14.8, 9.2 Hz, 1H), 1.96-1.86 (m, 1H),

1.85-1.70 (m, 2H), 1.66-1.54 (m, 3H), 1.30 (s, 9H). 13C NMR (CDCl3) δ [signals of the Z isomer] 208.1, 190.7, 168.2, 145.7,

137.8, 133.0, 128.6 (2C), 128.5 (2C), 124.3, 82.1, 67.2, 41.0, 34.5, 30.4, 27.6 (3C), 26.4, 25.2. HRMS calc.: C21H26NaO4

365.1723; found: 365.1725. The ee was determined by HPLC using a Chiralpak AD column [hexane/iPrOH (99:1)]; flow rate

1.0 mL/min; τmajor = 22.0 min, τminor = 16.6 min (75% ee). [a]Drt +30 (c 0.60, CH2Cl2).

(S,E)-1-(2-Ethoxycarbonyl-2-iodo-vinyl)-2-oxo-cyclopentanecarboxylic acid tert-butyl ester (4p):


viscous colorless oil (74% yield). 1H NMR (CDCl3) δ 7.25 (s, 1H), 4.17 (m, 2H), 2.56-2.62 (m,

1H), 2.36-2.53 (m, 2H), 2.25-2.33 (m, 1H), 2.00-2.16 (m, 2H), 1.43 (s, 9H), 1.29 (t, J 7.1 Hz, 3H). 13C NMR (CDCl3) δ 211.4, 168.1, 163.9, 151.1, 86.8, 83.1, 66.2, 62.5, 37.7, 36.1, 27.7 (3C), 19.8,

13.9. HRMS calc.: C15H21INaO5 431.0331; found: 431.0336. The ee was determined by HPLC

using a Chiralcel OD column [hexane/iPrOH (99:1)]; flow rate 1.0 mL/min; τmajor = 7.5 min, τminor = 8.7 min (91% ee). [a]Drt

+26.6 (c 0.55, CH2Cl2).

Preparative scale synthesis of 4p:

To a flask equipped with a magnetic stirring bar was added 2ª (931 mg, 5.05 mmol), o-xylene/CHCl3 (7:1) 16.6 mL, (E)-Ethyl

β-chloro-α-iodopropenoate (1.95 g, 7.50 mmol) and the catalyst 1d (5 mol%, 0.25 mmol, 171 mg). The mixture was stirred for

a short time at ambient temperature and was then placed at -20 oC. When the mixture had cooled, a cold (-20 oC) solution of

66% aq. Cs2CO3 (7 mL) was added and the biphasic mixture was vigorously stirred for 10h at which time the reaction was

judged to be complete by TLC analysis. Water and Et2O were added and the organic phase separated. The aqueous phase was

extracted with Et2O (2x), and the combined organic extracts were washed with brine, dried over MgSO4, filtered and

concentrated. The pure product 4p (1.67 g, 4.09 mmol, 81% yield, E/Z >95/5, 91% ee) was obtained by FC (eluent CH2Cl2/n-

hexane 1:4 then CH2Cl2 then Et2O/CH2Cl2 1:99).

O

O

CO2tBu

OCO2tBu

COPh

OCO2tBu

OEtO

I

13

Procedure for Isomerization of (Z)-4a to (E)-4a:

To an oven-dried flask equipped with a magnetic stirring bar was added (Z)-4ª (62.8 mg, 0.200 mmol). The flask was

evacuated and filled with nitrogen. Dry toluene (4 mL) was added and the mixture stirred for a few minutes. Tri-n-butyl

phosphine (10 mol%, 0.020 mmol, 4.9 µL) was added and the mixture stirred at ambient temperature for 30 min. After the

isomerization was judged to be complete by TLC-analysis, the mixture was concentrated and filtered through SiO2 (eluent

pentane/Et2O 4:1) affording (E)-4ª (55.0 mg, 0.175 mmol, 88% yield) as an amorphous white solid.

(S,E)-2-Oxo-1-(3-oxo-3-phenyl-propenyl)-cyclopentanecarboxylic acid tert-butyl ester (4a):

1H NMR (CDCl3) δ 7.90 (d, J 7.3 Hz, 2H), 7.55 (t, J 7.4 Hz, 1H), 7.45 (t, J 7.3 Hz, 2H), 7.03 (d, J

16.0 Hz, 1H), 6.92 (d, J 16.0 Hz, 1H), 2.68 (m, 1H), 2.47 (ddd, J 6.4, 8.8, 19.0 Hz, 1H), 2.20-2.37

(m, 2H), 2.03-2.13 (m, 1H), 1.92-2.02 (m, 1H), 1.45 (s, 9H). 13C NMR (CDCl3) δ 211.2, 190.7,

168.1, 143.6, 137.4, 132.9, 128.8 (2C), 128.5 (2C), 127.2, 83.1, 63.8, 37.6, 34.0, 27.8 (3C), 19.6.

HRMS calc.: C19H22NaO4 337.1416; found: 337.1416. The ee was determined by HPLC using a Chiralpak AD column

[hexane/iPrOH (97:3)]; flow rate 1.0 mL/min; τmajor = 17.4 min, τminor = 19.2 min (93% ee). [a]Drt +22.9 (c 1.00, CH2Cl2).

Catalytic Reactions With (E)-3a:

According to the general procedure (method A, 24h) using (E)-3a as the electrophilic reaction partner, (E)-4a and (E)-4l were

obtained in 85% yield (E/Z >95/5, 75% ee), and 94% yield (E/Z >95/5, 97% ee) respectively.

OCO2tBu

O

33

References:

i Cyclopentanone-core (2a) and cyclohexanone-core, see: (a) Bunnage, M. E.; Davies, S. G.; Parkin, R. M.; Roberts, P. M.;

Smith, A. D.; Withey, J. M. Org. Biomol. Chem. 2004, 2, 3337-3354. ii 1-Indanone-core and 6-chloro-1-indanone-core a) House, H. O.; Hudson, C. B. J. Org. Chem. 1970, 35, 674-651; 6,7-

dimethoxy-1-indanone-core: b) Fukushi, H.; Mabuchi, H.; Itoh, K.; Terashita, Z.-i.; Nishikawa, K.; Sugihara, H. Chem. Pharm.

Bull. 1994, 42, 541-550; 1-tetralone-core: c) Bennett, F.; Fenton, G.; Knight, D. W. Tetrahedron, 1994, 50, 5147-5158.

Cycloheptanone-core was purchased from Aldrich and used as received. iii a) Otera, J.; Yano, T.; Kawabata, A.; Nozaki, H. Tetrahedron Lett. 1986, 27, 2383-2386; b) Nakajima, M.; Yamamoto, S.;

Yamaguchi, Y.; Nakamura, S.; Hashimoto, S. Tetrahedron, 2003, 59, 7307-7313. iv Ma, S.; Lu, X.; Li, Z. J. Org. Chem. 1992, 57, 709-713. v Lemay, A. B.; Vulic, K. S.; Ogilvie, W. W. J. Org. Chem. 2006, 71, 3615-3618. vi Lygo, B.; Wainwright, P. G. Tetrahedron, 1999, 55, 6289-6300. vii Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 11240-11241.

69451 Weinheim, GermanyTo a stirred suspension of N-9-anthracenylmethyl dihydrocinchoninium chloride...

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Transcript of 69451 Weinheim, GermanyTo a stirred suspension of N-9-anthracenylmethyl dihydrocinchoninium chloride...