Supporting Information. Copyright Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 2008

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1 Supporting Information Copyright Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 2008

2 Mechanistically Inspired Catalysts for Enantioselective Desymmetrizations via lefin Metathesis Pierre-André Fournier, Jolaine Savoie, Brice Stenne, Marion Bédard, Alain Grandbois and Shawn K. Collins* [a] [a] P.-A. Fournier, J. Savoie, M. Bédard, B. Stenne, A. Grandbois, Dr. S. K. Collins Department of Chemistry Université de Montréal C.P Station Downtown,, Montréal, Québec, CAADA H3C 3J7 Fax: 1-(514)

3 Mechanistically Inspired Catalysts for Enantioselective Desymmetrizations via lefin Metathesis. Pierre-André Fournier, Jolaine Savoie, Brice Stenne, Marion Bédard, Alain Grandbois and Shawn K. Collins* Département de chimie, Université de Montréal, P.. Box 6128, Station Downtown, Montréal, Québec, Canada H3C 3J7. SUPPRTIG IFRMATI General: All reactions that were carried out under anhydrous conditions were performed under an inert argon or nitrogen atmosphere in glassware that had previously been dried overnight at 120 o C or had been flame dried and cooled under a stream of argon or nitrogen. 1 All chemical products were obtained from Sigma- Aldrich Chemical Company or Strem Chemicals and were reagent quality. These products were used without further purification. The preparation of compounds 7-9 and have all been previously reported in detail. 2 The preparation of catalyst 4 and its evaluation in desymmetrization reactions has been previously described. 3 Technical solvents were obtained from VWR International Co. Anhydrous solvents (CH 2 2, Et 2, THF, Toluene, DMF and n-hexane) were dried and deoxygenated using a GlassContour system (Irvine, CA). Isolated yields reflect the mass obtained following flash column silica gel chromatography. rganic compounds were purified using the method reported by W. C. Still 4 and using silica gel obtained from Silicycle Chemical division (40-63 nm; mesh). Catalyst 5-6 was purified using silica gel 60 ( mesh) obtained from TSI Scientific (Cambridge, MA.). Analytical thin-layer chromatography (TLC) was performed on aluminum-backed silica gel 60 coated with a fluorescence indicator (Silicycle Chemical division, 0.25 mm, F 254.). Visualization of TLC plate was performed by UV (254 nm), ninhydrin or KMn 4 stains. All mixed solvent eluents are reported as v/v solutions. Concentration refers to removal of volatiles at low pressure on a rotary evaporator. Enantiomeric excesses were determined by chiral GC (Chiraldex G-TA, 30m 0.25mm or Chiraldex B- DM, 30m 0.25mm)) and were compared to racemic samples. All GC methods used were previously reported. 2,3 All reported compounds were homogeneous by thin layer chromatography (TLC) and by 1 H MR. MR spectra were taken in deuterated CD 3 using Bruker AV-400 and AV-500 instruments unless otherwise noted. Signals due to the solvent served as the internal standard. The acquisition parameters are shown on all spectra. The 1 H MR chemical shifts and coupling constants were determined assuming first-order behavior. Multiplicity is indicated by one or more of the following: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad); the list of couplings constants (J) corresponds to the order of the multiplicity assignment. The 1 H MR assignments were made based on chemical shift and multiplicity and were confirmed, where necessary, by homonuclear decoupling, 2D CSY experiments. The 13 C MR assignments were made on the basis of chemical shift and multiplicity and were confirmed, where necessary, by two dimensional correlation experiments (HSQC). Chemical shifts are reported in parts per million (ppm) downfield from H 3 P 4 for 31 P MR spectra. High resolution mass spectroscopy (HRMS) was done by the Centre régional de spectrométrie de masse at the Département de Chimie, Université de Montréal from an Agilent LC-MSD TF system using ESI mode of ionization. ( 1 ) Shriver, D. F.; Drezdon, M. A. in The Manipulation of Air-Sensitive Compounds; Wiley-VCH: ew York, ( 2 ) Funk, T.W.; Berlin, J.M.; Grubbs, R. H. J. Am. Chem. Soc. 2006, 126, ( 3 ) Fournier, P.-A.; Collins, S. K. rganometallics 2007, 26, ( 4 ) Still, W. C.; Kahn, M.; Mitra, M. A. J. rg. Chem. 1978, 43,

4 Preparation of Catalyst 9 : Me BF (F 6 )K PhMe, 60C, 6h. Me Major Me + 9 Minor In a glovebox, a seal tube was charged with 7 (122 mg, 0.30 mmol), potassium hexafluoro-t-butoxide (68 mg, 0.30 mmol), and toluene (2.5 ml). The resulting mixture is stirred at room temperature for 5 minutes. To the resulting yellow turbid solution is added ( ) 2 (=CH-o-iPrC 6 H 4 ) 2 (8) (125 mg, 0.20 mmol). The tube is sealed, taken out of the glovebox and heated at 60 C for 6h, after which time the mixture is directly loaded on a flash chromatography column packed with TSI silica gel (10 % Et 2 in hexanes) giving 30 mg (23 %) of 9 as a dark green solid. Catalyst 9 exists as a mixture of rotamers as observed by the two carbene proton singlets at and ppm (7.8:1) respectivly. 1 H MR (400 MHz, C 6 D 6 ) (only major rotamer reported) δ ppm (s, 1H), 9.34 (d, J = 7.5 Hz, 1H), (m, 2H), (m, 3H), 6.76 (t, J = 7.4, 7.4 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 4.60 (sept, 6.2 Hz, 1H), 3.95 (d, J = 1.6 Hz, 1H), 3.56 (s, 3H), 3.48 (sept, 6.9 Hz, 1H), 3.03 (d, J = 1.5 Hz, 1H), 1.67 (d, J = 6.1 Hz, 3H), 1.47 (d, J = 6.4 Hz, 6H), 1.29 (d, J = 6.9 Hz, 3H), 1.00 (s, 9H), 0.69 (s, 9H); 13 C MR (101 MHz, C 6 D 6 ) δ ppm 289.1, 216.7, 154.5, 145.6, 144.4, 144.3, 129.3, 129.1, 128.6, 122.4, 122.0, 113.8, 77.5, 74.6, 74.1, 42.3, 36.0, 35.6, 28.6, 27.5, 26.9, 24.3, 23.5, 22.4, 22.2; HRMS (ESI) m/z calculated for C 31 H [M] +, , found Preparation of Catalyst 5 : Me Me Br Me H 2 C, HC 2 H, a 2 S 4, CH 2 2, 24 h, r.t. H 2 H 2 Pd 2 (dba) 3, H 2 H Me A () 3 PHBF 4, atbu, B PhMe, 100 C, 48h C Me Me Me Me BF ) I 2, ahc 3, CH h 2) a 2 S 3, abf 4, CH h (4R,5R)-4,5-Di-tert-butyl-1-(2-isopropyl-4-methoxy-5-methyl-phenyl)-3-methyl-4,5-dihydro-3Himidazol-1-ium tetrafluoroborate (10) : In a glovebox, an oven-dried 100 ml sealed tube was charged with Pd 2 (dba) 3 (140 mg, 0.15 mmol), P(tBu) 3 HBF 4 (273 mg, 0.6 mmol), atbu (1.11 g, 11.6 mmol), (R,R)-1,2-diamino-1,2-di-tert-butylethane (500 mg, 2.9 mmol), 1-bromo-2-isopropyl-4-methoxy-5- methylphenyl [5] (775 mg, 3.19 mmol) and toluene (51 ml). The sealed tube was then sealed and taken out of the glove box. The reaction mixture was stirred at 110 C for 48 hours. The solution was then cooled to room temperature and filtered on a plug of silica gel (100% EtAc). Removal of the solvent in vacuo gave a yellow oil (A) that is normally carried on to the next step without additional purification. The crude oil is then transferred to a 250 ml round bottom flask, to which was added formaldehyde (37% in H 2, 4.7 ml, 29 mmol), a 2 S 4 (4.12 g, 58 mmol), formic acid (3 drops) and dichloromethane (40 ml). ( 5 )Berlin, J. M.; Goldberg, S. D.; Grubbs, R. H.; Angew.Chem., Int.Ed., 2006, 45,

5 The mixture was stirred at room temperature overnight, after which it was filtered and the solvent was evaporated. The resulting yellow oil was dissolved in dichloromethane and filtered on a plug of silica gel (100% EtAc). Removal the solvent in vacuo gave a yellow oil B. This oil can also be use in the next step without any further purification. The round bottom flask which contains the crude oil is charged with I 2 (740 mg, 2.9 mmol), K 2 C 3 (250 mg, 2.9 mmol) and dichloromethane (40 ml). The reaction mixture was stirred at rt. overnight. The reaction was quenched with a saturated solution of a 2 S 3 and an excess of solid abf 4. The mixture was stirred until complete decoloration of the organic phase. The organic phase was separated in a separatory funnel and the aqueous phase was extracted with ether (3 * 50 ml), dried over a 2 S 4 and the solvent was evaporated to give a pale yellow solid. The solid was purified by flash column silica gel chromatography (gradient of 1:4 EtAc:Hexane, 1:1 EtAc:Hexane and then 1:19 MeH: DCM) to give the desired salt as a pale yellow solid 1.11 g (86 % over 3 steps). [α] D 20 = (c , CH 2 2 ); 1 H MR (400 MHz, CD 3 ) δ ppm 8.36 (s, 1H), 7.01 (s, 1H), 6.72 (s, 1H), 4.16 (d, J = 3.2 Hz, 1H), 3.84 (s, 3H), 3.73 (d, J = 3.2 Hz, 1H), 3.53 (s, 3H), (m, 1H), 2.17 (s, 3H), 1.39 (d, J = 6.8 Hz, 3H), 1.22 (d, J = 6.7 Hz, 3H), 1.14 (s, 9H), 0.84 (s, 9H); 13 C MR (100 MHz, CD 3 ) δ ppm 158.8, 158.2, 141.3, 126.6, 108.4, 75.0, 73.6 (2C), 55.5, 37.7, 36,0 35.7, 29.0, 28.1, 26.5, 25.8, 24.1 (2C), 15.8; HRMS (ESI) m/z calculated for C 23 H 39 2, , found Me BF 4 10 Me Me Ph (F 6 )K PhMe, 60C, 6h. Me Me Me Ph Me Ph Me Me Major 5 Minor Catalyst 5 : In a glovebox, a sealed tube was charged with 10 (161 mg, 0.36 mmol), potassium hexafluoro-t-butoxide (79 mg, 0.36 mmol), ( ) 2 (=CHPh) 2 (200 mg, 0.24 mmol) and toluene (4 ml). The tube is then sealed and taken out of the glovebox and heated at 60 C for 6h. After cooling the mixture is purified by flash column silica gel chromatography (TSI silica gel) (5 % Et 2 in hexane) and the brown band is collected to give a brown solid. The resulting compound is isolated as an unseperable mixture of isomers (92:8, syn:anti) in an overall yield of 33% (71 mg). (ote: 10 was observed to decompose in CD 3 solution in a matter of minutes) 1 H MR (400 MHz, C 6 D 6 ) δ ppm major: (d, J = 7.4 Hz,1H), 8.88 (s, 1H), 7.40 (t, J = 7.3 Hz, 1H), 7.21 (t, J = 7.6 Hz, 2H), 7.15 (d, J = 1.3 Hz, 2H), 6.80 (s, 1H), (m, 1H), 3.86 (d, J = 2.3 Hz, 1H), 3.42 (s, 3H), 2.86 (d, J = 2.4 Hz, 1H), 2.57 (s, 3H), 2.49 (s, 3H), (m, 3H), (m, 3H), (m, 1H), 1.70 (d, J = 6.7 Hz, 3H), (m, 17H), 1.49 (d, J = 7.0 Hz, 3H), (m, 9H), 0.98 (s, 9H), 0.61 (s, 9H), selected resonances for the minor isomer: (s, 1H), 7.78 (s, 1H), 7.63 (dd, J = 3.3, 5.7 Hz, 1H), 6.98 (t, J = 7.9 Hz, 2H), 6.92 (dd, J = 3.4, 5.7 Hz, 1H), 6.21 (s, 1H), 6.01 (s, 1H), (m, 2H), 4.10 (s, 1H), 3.18 (s, 1H), 2.35 (s, 1H), 1.14 (s, 3H), 0.74 (s, 3H); 31 P MR (400 MHz, C 6 D 6 ) δ ppm major: 20.0, minor: 37.0 ; HRMS (ESI) m/z calculated for C 48 H P, , found

6 Preparation of Catalyst 6 : H 2 H 2 A Me Br Pd 2 (dba) 3, () 3 PHBF 4, atbu, PhMe, 100 C, 48h H 2 D H Me H 2 C, HC 2 H, a 2 S 4, CH 2 2, 24 h, r.t. E Me Me BF ) I 2, ahc 3, CH h 2) a 2 S 3, abf 4, CH h (4R,5R)-4,5-di-tert-butyl-3-(5-tert-butyl-2-isopropyl-4-methoxyphenyl)-1-methyl-4,5-dihydro-1Himidazol-3-ium tetrafluoroborate (11). In a glovebox, an oven-dried 100 ml sealed tube was charged with Pd 2 (dba) 3 (140 mg, 0.15 mmol), P(tBu) 3 HBF 4 (273 mg, 0.6 mmol), atbu (1.11 g, 11.6 mmol), (R,R)-1,2- diamino-1,2-di-tert-butylethane (500 mg, 2.9 mmol), 1-bromo-5-tert-butyl-2-isopropyl-4- methoxyphenyl (1) [3] (910 mg, 3.19 mmol) and toluene (51 ml). The sealed tube was then sealed and taken out of the glove box. The reaction mixture was stirred at 110 C for 48 hours. The solution was then cooled to room temperature and filtered on a plug of silica gel (100% EtAc). Removal of the solvent in vacuo gave a yellow oil D that is normally carried on to the next step without additional purification. The crude oil is then transferred to a 250 ml round bottom flask, to which was added formaldehyde (37% in H 2, 4.7 ml, 58 mmol), a 2 S 4 (4.12 g, 29 mmol), formic acid (3 drops) and dichloromethane (40 ml). The mixture was stirred at room temperature overnight, after which it was filtered and the solvent was evaporated. The resulting yellow oil E was dissolved in dichloromethane and filtered on a plug of silica gel (100% EtAc). Removal the solvent in vacuo gave a yellow oil. This oil can also be use in the next step without any further purification. The round bottom flask which contains the crude oil is charged with I 2 (740 mg, 2.9 mmol), K 2 C 3 (250 mg, 2.9 mmol) and dichloromethane (40 ml). The reaction mixture was stirred at rt overnight. The reaction was quenched with a saturated solution of a 2 S 3 and an excess of solid abf 4. The mixture was stirred until complete decoloration of the organic phase. The organic phase was separated in a separatory funnel and the aqueous phase was extracted with ether (3 * 50 ml), dried over a 2 S 4 and the solvent was evaporated to give a pale yellow solid. The solid was purified by flash column silica gel chromatography (gradient of 1:4 EtAc:Hexane, 1:1 EtAc:Hexane and then 1:19 MeH: DCM) to give the desired salt as a pale yellow solid 657 mg (64% over 3 steps). [α] D 20 = (c 0.001, CH 2 2 ); 1 H MR (400 MHz, CD 3 ) δ 8.32 (s, 1H), 7.02 (s, 1H), 6.75 (s, 1H), 4.10 (d, J = 3.2 Hz, 1H), 3.83 (s, 3H), 3.79 (d, J = 3.2 Hz, 1H), 3.52 (s, 3H), 3.05 (m, 1H), 1.35 (d, J = 6.8 Hz, 3H), 1.31 (s, 9H), 1.21 (d, J = 6.7 Hz, 3H), 1.11 (s, 9H), 0.82 (s, 9H); 13 C MR (100 MHz, CD 3 ) δ 158.7, 158.4, 141.3, 137.9, 126.5, 109.9, 75.1, 73.1, 55.1, 37.5, 35.8, 35.6, 34.7, 29.3, 29.0, 27.8, 26.4, 25.7, 24.1, 23.7; HRMS (ESI) m/z calculated for C 26 H 45 2, , found Me BF 4 11 Me Ph (F 6 )K PhMe, 60C, 6h. Me Me Ph Me Ph Me Major 6 Minor 4

7 Catalyst 6: In a glovebox, a sealed tube was charged with 11 (176 mg, 0.36 mmol), potassium hexafluoro-t-butoxide (79 mg, 0.36 mmol), ( ) 2 (=CHPh) 2 (200 mg, 0.24 mmol) and toluene (4 ml). The tube is then sealed and taken out of the glovebox and heated at 60 C for 6 h. After cooling the mixture is purified by flash column silica gel chromatography (TSI silica gel) (5 % Et 2 in hexane) and the brown band is collected to give a brown solid. The resulting compound is isolated as an unseperable mixture of isomers (79:21, syn:anti) in an overall yield of 44% (100 mg). (ote: 11 was observed to decompose in CD 3 solution in a matter of minutes. In addition, it began decomposing in C 6 D 6 solution after approximately 15 minutes. Due to the quantity of material prepared, it was extremely difficult to acquire accurate 13 C MR spectra) 1 H MR (400 MHz, C 6 D 6 ) δ ppm major: (d, J = 8.7 Hz, 1H), 8.59 (s, 1H), 7.41 (t, J = 7.3 Hz, 1H), 7.22 (t, J = 7.5 Hz, 2H), 7.16 (d, J = 0.9 Hz, 2H), 6.82 (s, 1H), (m, 1H), 3.81 (d, J = 2.8 Hz, 1H), 3.39 (s, 3H), 2.88 (d, J = 2.8 Hz, 1H), 2.48 (s, 3H), (m, 9H), 1.81 (s, 9H), 1.73 (d, J = 6.6 Hz, 3H), (m, 17H) 1.48 (d, J = 6.9 Hz, 3H), (m, 7H), 1.00 (s, 9H), 0.59 (s, 9H), selected resonances for the minor isomer: (s,1h), 8.13 (s, 1H), 7.00 (t, J = 7.9 Hz, 2H), 6.09 (s, 1H), 3.26 (s, 3H), 1.80 (s, 9H), 1.14 (d, J = 6.9 Hz, 3H), 1.12 (s, 9H), 0.93 (d, J = 6.8 Hz, 3H), 0.78 (s, 9H); HRMS (ESI) m/z calculated for C 51 H P, , found General procedure for the analysis of chiral heterocycles obtained via desymmetrization of meso trienes : Triene was added to a solution of catalyst 6 (2.5 mol %) in CH 2 2 (0.055 M), and the reaction stirred at 40 C for 2 h. The reaction was then quenched with ethylvinylether (approximately 0.1 ml) and cooled down to room temperature. The reaction mixture was then filtered on neutral alumina and the solvent was evaporated. Further purification by flash chromatography was performed if needed (1-5% Et 2 in pentane). 5

8 Me (2.5 mol%) CH 2 2, 40 C, 2 h Chiraldex G-TA, 1.0 ml/min, 60 C for 60 min. 6

9 Me (2.5 mol%) CH 2 2, 40 C, 2 h Chiraldex B-DA, 1.0 ml/min, 60 C for 120 min. 7

10 Me Ph (2.5 mol%) CH 2 2, 0 C, 2 h Chiraldex G-TA, 1.0 ml/min, 60 C for 60 min. 8

11 Me Me Ph (2.5 mol%) CH 2 2, 40 C, 2 h 9

12 Me (Me) 2 Si Me Ph (2.5 mol%) CH 2 2, 40 C, 2 h (Me) 2 Si Chiraldex G-TA, 1.0 ml/min, 60 C for 60 min. 10

13 Me Me Ph (2.5 mol%) CH 2 2, 40 C, 2 h Chiraldex B-DA, 1.0 ml/min, 60 C for 120 min. 11

14 Me Me Ph Si (Me) 2 (2.5 mol%) CH 2 2, 40 C, 2 h SiMe 2 Chiraldex G-TA, 1.0 ml/min, 60 C for 60 min. 12

15 Me Me Ph (2.5 mol%) CH 2 2, 0 C, 2 h Chiraldex G-TA, 1.2 ml/min, 60 C for 60 min. 13

16 Me (Me) 2 Si Me Ph (2.5 mol%) CH 2 2, 40 C, 2 h (Me) 2 Si Chiraldex G-TA, 1.0 ml/min, 50 C for 60 min. rac 36% ee 14

17 Me Me Ph (2.5 mol%) CH 2 2, 40 C, 2 h Chiraldex G-TA, 1.2 ml/min, 60 C for 60 min. 15

18 Me Me Me Ph (Me) 2 Si (2.5 mol%) CH 2 2, 40 C, 2 h (Me) 2 Si Chiraldex G-TA, 1.0 ml/min, 60 C for 60 min. 16

19 17

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23 Me Me Me Ph 21

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29 Me Me Major Minor 27

30 Me Me Major Minor 28

31 Me Me Major Minor 29