Enantioselective tandem conjugate addition elimination reactions 5

Upon completion or after the indicated reaction time, the reaction was quenched by adding 1 M HCl solution 0.5 mL and extracted with ethyl acetate 2.0 mL × 2... The crude residue was pur

Chapter 5

Experimental

5.1 General procedures and methods

1H and 13C NMR spectra were recorded on a Bruker ACF300 (300 MHz),

DPX300 (300 MHz) or AMX500 (500 MHz) spectrometer Chemical shifts are reported in parts per million (ppm) The residual solvent peak was used as an internal reference Low resolution mass spectra were obtained on a VG Micromass 7035 spectrometer in EI mode, a Finnigan/MAT LCQ spectrometer in ESI mode, and a Finnigan/MAT 95XL-T mass spectrometer in FAB mode All high resolution mass spectra were obtained on a Finnigan/MAT 95XL-T spectrometer Infrared spectra were recorded on a BIO-RAD FTS 165 FTIR spectrometer Enantiomeric excesses

were measured via chiral HPLC analysis on Hewlett Packard Ti Series 1050 or a set

of Jasco HPLC units, including a Jasco DG-980-50 Degasser, a LG-980-02 Ternary Gradient Unit, a PU-980 Intelligent HPLC Pump, UV-975 Intelligent UV/VIS Detectors, and an AS-950 Intelligent Sampler Optical rotations were recorded on a Jasco DIP-1000 polarimeter Melting points were determined on a BÜCHI B-540 melting point apparatus Analytical thin layer chromatography (TLC) was performed with Merck pre-coated TLC plates, silica gel 60F-254, layer thickness 0.25 mm Flash chromatography separations were performed on Merck 60 (0.040 - 0.063 mm) mesh silica gel Toluene was distilled from sodium/benzophenone and stored under N2

atmosphere THF was freshly distilled from sodium/benzophenone before use

CH2Cl2 was freshly distilled from CaH2 MeOH was refluxed over magnesium turnings together with a small amount of iodine until the iodine disappeared and then distilled off Other distilled solvents such as CH3CN, ethyl acetate and CHCl3 were

stored under N2 All other reagents and solvents are commercial grade and were used

as supplied without further purification, unless otherwise stated

Crystals were grown from hexane and dichloromethane solutions and mounted on glass fibres X-ray data were collected with a Bruker AXS SMART APEX diffractometer, using Mo-Kα radiation at room temperature, with the SMART suite of Programs(1) Data were processed and corrected for Lorentz and polarisation effects with SAINT(2), and for absorption effect with SADABS(3) Structural solution and refinement were carried out with the SHELXTL, suite of programs (4) The structure was solved by direct methods to locate the heavy atoms, followed by difference maps for the light, non-hydrogen atoms All non-hydrogen atoms were generally given anisotropic displacement parameters in the final model All H-atoms were put at calculated positions

2 SAINT+ version 6.22a, 2001 Bruker AXS Inc., Madison, Wisconsin, USA

3 SADABS, version 2.10, 2001 G W Sheldrick, University of Göttingen

4 SHELXTL, Version 6.14, 2000, Bruker AXS Inc., Madison, Wisconsin, USA

5.2 Typical experimental procedures

5.2.1 Typical procedure for achiral tandem CA-E reactions

To a 5 mL round bottom flask containing 2- (bromomethyl) cyclopent-2-enone 3

(18 mg, 0.1 mmol) and S,S-di-tert-butyl dithiomalonate 16f (50 mg, 0.2 mmol, 2 eq.),

anhydrous CH2Cl2 (1 mL) followed by triethylamine (27.9 µL, 0.2 mmol, 2.0 eq.) were added and the mixture was stirred at room temperature Upon completion, the reaction mixture was directly loaded onto a silica gel column, followed by gradient elution with hexane/EA mixtures (20/1-4/1 ratio) After removing the solvent, the product was obtained as a white crystal in 95% yield DABCO was not used for this reaction as side products were observed by 1H NMR analysis

between 24a-j and S,S-di-tert-butyl dithiomalonate 16f

5.2.2 Typical procedure for asymmetric tandem CA-E reactions

To a 5 mL round bottom flask containing 2- (bromomethyl) cyclopent-2-enone 3

(18 mg, 0.1 mmol) and S,S-di-tert-butyl dithiomalonate 16f (50 mg, 0.2 mmol, 2 eq.),

anhydrous CH3CN (1 mL) followed by promoter 11h (53 mg, 0.15 mmol, 1.5 eq.)

were added and the mixture was stirred at room temperature Upon completion or after the indicated reaction time, the reaction was quenched by adding 1 M HCl solution (0.5 mL) and extracted with ethyl acetate (2.0 mL × 2) The aqueous layer was basified with 1 M NaOH (0.5 mL) and extracted with CH2Cl2 (2.0 mL × 2) to

recover the promoter 11h The combined organic layers were dried over anhydrous

Na2SO4, filtered and concentrated under vacuum The crude residue was purified by flash column chromatography on silica gel using hexane/ethyl acetate as eluent to

give the desired product 17f as a white crystal (97% yield, 90% ee) The enantiomeric

excess was determined by HPLC analysis using a chiral column

5.2.3 General procedure for the synthesis of chiral pyrrolidinyl sulfonamides (CPS)

5.2.3.1 Synthesis of CPS from chiral amino alcohols

OH

N NHTs

Bn N

Bn

Ts ii

11a

Reagents and conditions: (i) p-TsCl, Et3N, CH3CN; (ii) pyrrolidine, CH3CN, reflux

(i) Aziridines were prepared according to a reported procedure: W Ye, D Leow, L M

S Goh, C-T Tan, C-T Chian, C-T Tan, Tetrahedron Lett 2006, 47, 1007-1010

(ii) General procedure for the ring-opening of aziridines

To a dry sealed tube containing an N-benzyl aziridine (766 mg, 2.7 mmol) was

added anhydrous CH3CN (2 mL) Pyrrolidine (0.345 mL, 4.0 mmol, 1.5 eq.) was then added and the reaction mixture was refluxed (85oC oil bath) and monitored by TLC Upon completion, the solvent was removed under reduced pressure and the crude

product was purified by flash chromatography on silica gel to yield promoter 11a as

pale yellow oil (98% yield)

5.2.3.2 Synthesis of CPS from chiral amino acid

The synthesis of CPS from chiral amino acid was achieved according to the

following literatures

OH NHBoc

ii

tBu O N OH

(ii) E J Corey and M J Grogan, Org Lett 1999, 1, 157-160

(iii) G L Stahl, R Walter and C W Smith, J Org Chem., 1978, 43, 2285-2286

(iv) E J Corey and M J Grogan, Org Lett 1999, 1, 157-160

(v) L A Gandon, A G Russell, T Güveli, A E Brodwolf, B M Kariuki, N Spencer

and J S Snaith, J Org Chem., 2006, 71, 5198-5207

5.2.3.3 Preparation of polymer supported chiral pyrrolidinyl sulfonamide 37 (PS-CPS)

N

O O Cl

N NH

S O O

15

37

To a dry round bottom flask containing chiral diamine 15 (85.2 mg, 0.5 mmol, 5

eq.) in CH2Cl2 (1 mL) was added triethylamine (70 µL, 0.5 mmol, 5 eq.) followed by

50 mg polystyrene bound sulfonyl chloride (50 mg, 1.5-2.0 mmol/g) After shaking

for 5 days, the reaction mixture was filtered and washed with CH2Cl2 (2 mL) to

recover the chiral diamine 15 (67.1 mg, 0.39 mmol) The beads were washed with

DMF (2 mL × 2), H2O (2 mL × 2), EtOH (2 mL × 2), CH2Cl2 (2 mL × 2), diethyl ether

(2 mL × 2) and vacumm dried to afford 65.6 mg of 37

5.2.4 General procedure for the synthesis of chiral imidazoline (53a-j)

All chiral imidazoline promoters (53a-j) were synthesized through a reported protocol:

N A Boland, M Casey, S J Hynes, J W Matthews and M P Smyth, J Org Chem.,

2002, 67, 3919-3922

5.2.5 Typical procedure for asymmetric Baylis-Hillman reactions

Typical experimental procedure for chiral imidazoline promoted Baylis-Hillman

reaction between aldehydes and acrylates: To an oven-dried vial, promoter 53a (24.4

mg, 0.10 mmol, 1 eq.) was added This was followed by 4-nitrobenzaldehyde 54a (15.1 mg, 0.10 mmol) and methyl acrylate 55a (0.10 mL) The reaction was stirred at

room temperature and monitored by TLC Upon completion or after the indicated reaction time, the reaction was quenched by adding 2 M HCl solution (1.0 mL) and extracted with ethyl acetate (2.0 mL) The aqueous layer was basified with 2 M NaOH (1.0 mL) and extracted with CH2Cl2 (2.0 mL × 2) to recover the imidazoline 53a The

combined organic layers was dried over anhydrous MgSO4, filtered and concentrated under vacuum The crude residue was purified by flash column chromatography on silica gel using hexane/ethyl acetate as eluent to give the desired product The enantiomeric excess was determined by HPLC analysis using a chiral column

Typical experimental procedure for chiral imidazoline promoted Baylis-Hillman reaction between aldehydes and alkyl vinyl ketones: Similar as the reaction between aldehydes and acrylates, methyl vinyl ketone (30.0 µL, 0.36 mmol, 16 eq.) was added

to the toluene solution (0.1 mL) of 4-nitrobenzaldehyde (3.3 mg, 0.02 mmol) and

imidazoline promoter 53i (4.0 mg, 0.01 mmol, 50 mol%) at the indicated temperature

Upon completion or after the indicated reaction time, the reaction mixture was

purified directly via column chromatography using hexane/ethyl acetate as eluent to

yield the product (3.6 mg, 75% yield) and the recovered catalyst

NHTs

Pale yellow oil 1 H NMR (300 MHz, CDCl3, ppm) δ 1.51-1.64 (m, 4H), 2.00-2.08 (m,

2H), 2.11-2.18 (m, 3H), 2.39-2.47 (m, 4H), 2.73-2.80 (dd, 1H, J = 13.5, 7.9 Hz), 3.12-3.25 (m, 2H), 7.12-7.31 (m, 7H), 7.77 (d, 2H, J = 8.2 Hz); 13 C NMR (75 MHz,

Pale yellow crystal 1 H NMR (300 MHz, CDCl3, ppm) δ 0.88 (s, 9H), 1.52 (bs, 4H),

2.20-2.24 (m, 2H), 2.33-2.40 (m, 6H), 2.45-2.53 (m, 1H), 3.21 (dd, 1H, J = 9.1, 4.2 Hz), 7.22 (d, 2H, J = 8.3 Hz), 7.78 (d, 2H, J = 8.3 Hz); 13 C NMR (75 MHz, CDCl3,

ppm) δ 21.4, 23.4, 26.8, 34.3, 54.0, 56.8, 61.5, 127.0, 128.9, 139.5, 142.3; IR (KBr,

cm-1) 3433, 2969, 1600, 1457, 1321, 1153, 1086; LRMS (ESI) m/z 325.2 [M+H]+; HRMS (ESI) calcd for [C17H28N2O2S+H]+ requires m/z 325.1950 Found 325.1950

Pale yellow sticky liquid 1 H NMR (300 MHz, CDCl3, ppm) δ 0.84 (s, 9H), 1.33-1.39

(m, 6H), 2.11-2.19 (m, 3H), 2.27-2.34 (m, 3H), 2.38 (s, 3H), 3.27 (dd, 1H, J = 9.0, 4.8 Hz), 7.23 (d, 2H, J = 8.1 Hz), 7.80 (d, 2H, J = 8.1 Hz); 13 C NMR (75 MHz, CDCl3,

ppm) δ 21.4, 24.1, 25.5, 26.7, 34.3, 54.7, 59.4, 59.7, 127.0, 129.1, 139.5, 142.4; IR

(film, cm-1) 3395, 2940, 1600, 1475, 1316, 1155, 1094; LRMS (ESI) m/z 339.3

[M+H]+; HRMS (ESI) calcd for [C18H30N2O2S+H]+ requires m/z 339.2106 Found

δ 20.8, 23.0, 23.5, 26.8, 34.3, 54.1, 56.4, 61.4, 131.5, 136.8, 138.2, 141.1; IR (film,

cm-1) 3392, 2958, 1602, 1477, 1338, 1156, 1053; LRMS (ESI) m/z 353.3 [M+H]+; HRMS (ESI) calcd for [C19H32N2O2S+H]+ requires m/z 353.2263 Found 353.2260

[α] 24

D +57.7 (c = 4.79, CHCl3)

5.3.3 Characterization of tandem CA-E products

(17f) (S)-S,S'-di-tert-Butyl 2-(2-methylene-3-oxocyclopentyl) propanebis(thioate)

49.5, 49.6, 72.4, 119.5, 145.1, 192.4, 192.5, 205.2; IR (film, cm-1); 3021, 2926, 2855,

2401, 1690, 1216; LRMS (ESI) m/z 365.1 [M+Na]+; HRMS (ESI) calcd for

[C17H26O3S2Na]+ requires m/z 365.1221 Found 365.1222 [α]24

D -298 ( c = 0.52,

CHCl3); HPLC conditions: Chiralcel AD-H column (Diacel); 98/2

hexane/2-propanol; Flow rate 0.5 mL/min; λ = 210 nm; 17.2 min (minor), 18.4 min (major)

(21a) (S)-S,S'-bis(2,4,4-Trimethylpentan-2-yl) 2-(2-methylene-3-oxocyclopentyl)

propanebis(thioate)

O

O

O R

R

Yellow oil 94% ee; 1 H NMR (500 MHz, CDCl3, ppm) δ 1.00 (s, 9H), 1.02 (s, 9H),

1.53-1.59 (m, 14H), 1.70-1.80 (m, 3H), 1.87-1.91 (dd, 2H, J = 15.2, 5.7 Hz), 2.06-2.12 (m, 1H), 2.27-2.42 (m, 2H), 3.66 (d, 1H, J = 10.1 Hz), 3.69-3.74 (m, 1H), 5.31 (d, 1H, J = 1.9 Hz), 6.05 (d, 1H, J = 2.5 Hz); 13 C NMR (125 MHz, CDCl3, ppm)

δ 23.7, 29.1, 29.2, 29.5, 31.6, 32.6 (two peaks), 36.3, 41.3, 53.2, 53.3, 54.7 (two

peaks), 72.4, 119.6, 145.2, 192.0, 192.1, 205.4; IR (film, cm-1) 3021, 2401, 1688,

1216; LRMS (ESI) m/z 477.05 [M+Na]+; HRMS (ESI) calcd for [C17H26O3S2Na]+

requires m/z 477.2473 Found 477.2476 [α]25 D -23.1 ( c = 2.26, CHCl3); HPLC conditions: Two Chiralcel AD-H columns (Diacel); 95/5 hexane/2-propanol; Flow

rate 0.5 mL/min; λ = 210 nm; 22.8 min (minor), 23.6 min (major)

R

White solid 97% ee; Decomposes at 203.0-204.2 oC 1 H NMR (500 MHz, CDCl3,

ppm) δ 1.70-1.77 (m, 14H), 2.06-2.16 (m, 18H), 2.26-2.41 (m, 2H), 3.61 (d, 1H, J = 10.1 Hz), 3.65-3.69 (m, 1H), 5.33 (d, 1H, J = 1.9 Hz), 6.06 (d, 1H, J = 2.5 Hz); 13 C NMR (125 MHz, CDCl3, ppm) δ 23.7, 29.8, 36.2 (two peaks), 36.3, 41.4, 41.5, 52.6

(two peaks), 72.6, 119.6, 145.1, 192.1, 192.3, 205.3; IR (KBr, cm-1) 2906, 1689, 1451,

1259; LRMS (ESI) m/z 521.3 [M+Na]+; HRMS (ESI) calcd for [C29H38O3S2Na]+

requires m/z 521.2160 Found 521.2158 [α]25 D -40.4 ( c = 1.16, CHCl3); HPLC conditions: Chiralpak IA column (Diacel); 98/2 hexane/2-propanol; Flow rate 0.5

mL/min; λ = 210 nm; 23.9 min (major), 26.5 min (minor)

Pale yellow oil 94, 94% ee; d.r 3:2; 1 H NMR (300 MHz, CDCl3, ppm) δ (Mixture of

two diastereomers) 1.41 (d, 23 H, J = 3.1 Hz), 1.51-1.59 (m, 1H), 1.85-1.95 (m, 2H), 2.03-2.49 (m, 9H), 3.90-3.95 (m, 1H each for two diastereomers), 4.61 (d, 1H, J = 9.8

Hz, major diastereomer), 4.73 (d, 1H, J = 9.8 Hz, minor diastereomer), 5.03 (d, 1H, J

= 2.4 Hz, major diastereomer), 5.39 (d, 1H, J = 1.5 Hz, minor diastereomer), 5.92 (d, 1.5H, J = 2.4 Hz), 6.10 (d, 1H, J = 2.5 Hz), 7.46-7.52 (m, 6H), 7.58-7.61 (m, 3H),

8.01-8.05 (m, 6H); 13 C NMR (75 MHz, CDCl3, ppm) δ 23.7, 24.3, 29.5, 36.2, 36.6, 41.5, 41.6, 49.7, 66.1, 66.8, 119.0, 119.4, 128.8, 128.9, 133.9 (two peaks), 136.4,

136.5, 145.5, 145.9, 192.6, 192.8, 193.4 (two peaks), 205.4, 205.5; IR (film, cm-1)

3021, 1725, 1693, 1657, 1216; LRMS (ESI) m/z 353.0 [M+Na]+; HRMS (ESI) calcd

for [C19H22O3SNa]+ requires m/z 353.1187 Found 353.1183 [α]25 D -108 ( c = 0.54,

CHCl3); HPLC conditions: Chiralcel AD-H+AS-H columns (Diacel); 90/10

hexane/2-propanol; Flow rate 1.0 mL/min; λ = 254 nm; 16.6 min (minor), 17.8 min (minor), 24.2 (major), 41.3 (major)

OMe

Pale yellow oil 98, 95% ee, d.r 3:2; 1 H NMR (500 MHz, CDCl3, ppm) δ (Mixture of

two diastereomers) 1.41 (d, 26H, J = 6.3 Hz), 1.52-1.54 (m, 1H, major diastereomer),

1.84-1.90 (m, 1H, major diastereomer), 2.02-2.09 (m, 1H, minor diastereomer),

2.18-2.48 (m, 8H), 3.87-3.93 (m, 12H), 4.55 (d, 1H, J = 9.4 Hz, major diastereomer), 4.61 (d, 1H, J = 10.1 Hz, minor diastereomer), 5.02 (d, 1H, J = 2.5 Hz, major diastereomer), 5.38 (d, 1H, J = 1.9 Hz, minor diastereomer), 5.90 (d, 1H, J = 2.5 Hz, major diastereomer), 6.09 (d, 1H, J = 2.5 Hz, minor diastereomer), 6.94-6.97 (m, 5H),

8.01-8.04 (m, 5H); 13 C NMR (125 MHz, CDCl3, ppm) δ 23.8, 24.3, 29.5, 36.3, 36.6, 41.5, 41.6, 49.6, 55.5 (two peaks), 65.8, 66.5, 114.1 (two peaks), 119.0, 119.3, 129.4, 129.6, 131.3, 131.3, 145.7, 146.0, 164.2 (two peaks), 190.8, 191.0, 193.6, 193.7,

205.5, 205.6; IR (film, cm-1) 3015, 2963, 1740, 1689, 1597, 1511, 1459; LRMS (ESI)

m/z 360.8 [M]+; HRMS (ESI) calcd for [C20H24O4S]+ requires m/z 361.1474 Found

361.1478 [α] 25 D -11.3 ( c = 2.86, CHCl3); HPLC conditions: Chiralcel OD-H+IA

columns (Diacel); 90/10 hexane/2-propanol; Flow rate 1.0 mL/min; λ = 254 nm; 22.9 min (minor), 23.8 min (major), 26.6 (minor), 31.8 (major)

(21e) (S)-S-tert-Butyl 2-((S)-2-methylene-3-oxocyclopentyl)-3-oxobutanethioate

O

S O

Pale yellow oil 94, 94% ee, d.r 1:1; 1 H NMR (300 MHz, CDCl3, ppm) δ (Mixture of two diastereomers) δ = 1.47 (s, 9H), 1.48 (s, 9H), 1.57-1.61 (m, 1H), 1.73-1.81 (m,

1H), 2.04-2.39 (m, 16H), 3.64-3.73 (m, 3H), 3.74 (d, 1H, J = 9.5 Hz), 5.14 (d, 1H, J = 2.5 Hz), 5.31 (d, 1H, J = 1.9 Hz), 6.02 (d, 1H, J = 2.5 Hz), 6.06 (d, 1H, J = 2.5 Hz);

13 C NMR (125 MHz, CDCl3, ppm) δ 23.6, 24.0, 29.3, 29.4, 29.5 (two peaks), 29.9, 36.1, 36.3, 40.3, 40.4, 49.7, 49.8, 72.2, 72.6, 118.9, 119.6, 145.0, 145.8, 193.8, 194.3,

200.5, 200.6, 205.2, 205.4; IR (film, cm-1) 3021, 2967, 1724, 1671, 1217; LRMS

(ESI) m/z 267.0 [M]-; HRMS (ESI) calcd for [C14H20O3SNa]+ requires m/z 291.1031

Found 291.1036 [α] 25 D -464 ( c = 0.25, CHCl3); HPLC conditions: Chiralcel AS-H

column (Diacel); 80/20 hexane/2-propanol; Flow rate 1.0 mL/min; λ = 254 nm; 8.3 min (minor), 10.0 min (minor), 11.9 (major), 15.5 (major)

1H), 4.99 (d, 2H, J = 3.2 Hz), 5.20 (d, 1H, J = 1.9 Hz), 6.03 (d, 2H, J = 3.2 Hz), 6.11 (d, 1H, J = 1.9 Hz); 13 C NMR (125 MHz, CDCl3, ppm) δ 19.6 (two peaks), 22.3, 22.7, 25.6, 26.0, 26.1, 26.2, 36.2, 36.6, 39.4, 39.5, 43.1, 44.8, 72.0, 74.7, 118.4, 120.8,

144.3, 144.6, 201.8, 203.3, 204.9, 205.8, 214.1, 214.9; IR (film, cm-1) 3022, 2401,

1707, 1217; LRMS (ESI) m/z 237.9 [M+H2O]; HRMS (ESI) calcd for

[C13H16O3Na]+ requires m/z 243.0977 Found 243.1010 [α]25 D +29.1 ( c = 1.06,

CHCl3); HPLC conditions: Chiralcel OJ-H column (Diacel); 90/10

hexane/2-propanol; Flow rate 1.0 mL/min; λ = 210 nm; 20.5 min (minor), 21.6 min (major), 30.7 (major), 45.6 (minor)

(23a) (S)-S,S'-di-tert-Butyl 2-(2-methylene-3-oxocyclohexyl)propanebis(thioate)

Chiralcel AD-H column (Diacel); 98/2 hexane/2-propanol; Flow rate 0.5 mL/min; λ =

210 nm; 14.6 min (major), 16.6 min (minor)

IR (film, cm-1) 3019, 2400, 1642, 1216; LRMS (ESI) m/z 407.1 [M+Na]+; HRMS

(ESI) calcd for [C20H32O3S2Na]+ requires m/z 407.1691 Found 407.1685 [α]25 D

-59.2 ( c = 0.12, CHCl3); HPLC conditions: Chiralcel AS-H column (Diacel); 95/5

hexane/2-propanol; Flow rate 0.5 mL/min; λ = 210 nm; 7.3 min (minor), 12.8 min (major)