Highly Enantioselective Hydration of α,β-unsaturated Imides by Al- Catalyzed Conjugate Addition of Oxime Nucleophiles

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1 ighly Enantioselective ydration of α,β-unsaturated Imides by Al- Catalyzed Conjugate Addition of xime ucleophiles Christopher D. Vanderwal and Eric. Jacobsen * Department of Chemistry and Chemical Biology, arvard University, Cambridge, Massachusetts Supporting Information General: All reactions were carried out in flame-dried glassware under an atmosphere of 2 unless otherwise specified. Tetrahydrofuran, acetonitrile, and dichloromethane were distilled from sodium and calcium hydride, respectively. Cyclohexane (mnisolv, EMD Chemicals) and ethanol (200 proof) were used as received. Commercial reagents of high purity were purchased and used without further purification. Reactions were monitored by thin-layer chromatography (TLC) on 0.25mm EMD Chemicals silica gel plates (60 F 254 ) using UV light as a visualizing agent and aqueous potassium permanganate and heat as developing agents. Silica gel 60 ( mesh) from EMD Chemicals was used for flash chromatography. Instrumentation: FT-IR infrared spectra were recorded on a Mattson Galaxy Series FTIR 3000 spectrometer. uclear magnetic resonance (MR) spectra were taken on a Varian Inova-500 and a Bruker DMX MR and 13 C MR spectra were recorded in deuterated chloroform (CDCl 3 ) at 500 Mz and 125 Mz, respectively. Proton chemical shifts are reported in parts per million downfield from tetramethylsilane and are calibrated to the residual protium (7.26 ppm) in the CDCl 3 MR solvent. Carbon chemical shifts are reported in parts per million downfield from tetramethylsilane and are calibrated to the solvent peaks (77 ppm). The multiplicities are abbreviated as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad signal. ptical rotations were measured on a Jasco DIP 370 digital polarimeter using a 2 ml, 1 dm cell. Mass spectra were obtained using a Micromass Platform II Quadrupole Mass Spectrometer at the arvard University Mass Spectrometry Facility. Chiral PLC analysis was performed on a ewlett-packard 1050 instrument. Experimental: Catalyst 1c was prepared as described previously. 1 All α,β-unsaturated imides were prepared by orner-wadsworth-emmons olefinations 2 of the requisite aldehydes with phosphonate A. Imides 2a, 2b, and 2c are known compounds. 2a S-1

2 General Procedure for orner-wadsworth-emmons lefination (this procedure was adapted from reference 2a): P Et Et 1. n-buli (2.0) 2. RC R A 2.5 M solution of n-butyllithium in hexanes (4.0 ml, 10 mmol) was added dropwise to a solution of phosphonate (1.50 g, 5.0 mmol) in TF (20 ml) at 78 C. The resulting bright yellow solution was stirred at this temperature for 15 minutes. A solution of the requisite aldehyde (5.0 mmol) in TF (5 ml) was added via cannula, followed by a TF rinse (1 ml). The reaction mixture was stirred at 78 C for 1 hour, then it was warmed to 0 C. The reaction was quenched with 0.2 Cl (25 ml), and the resulting mixture was extracted with EtAc (2 x 25 ml). The combined organic extracts were washed with brine (25 ml), dried over MgS 4, and concentrated by rotary evaporation. The crude products typically consisted of a mixture of E and Z isomers in ratios of 20:1 to >50:1. Pure (E)-α,β-unsaturated imides were obtained by flash chromatography on silica gel in unoptimized yields of 50 to 96%. Synthesis of Imide 9 by the Masamune-Roush Modification of the orner- Wadsworth-Emmons lefination: P Et Et + MM C LiCl, DIPEA, MeC MM Freshly distilled acetonitrile (90 ml) was added to flame-dried lithium chloride (566 mg, mmol). osphonate (4.00 g, 13.4 mmol) was added, followed by diisopropylethylamine (1.94 g, 11.1 mmol), and the resulting mixture was stirred at ambient temperature for 1 hour. Aldehyde (8.9 mmol, crude from Swern oxidation of the corresponding alcohol) was added via cannula as a solution in acetonitrile (8 ml), follwed by an acetonitrile rinse (2 ml). The reaction mixture was stirred at ambient temperature for 24 hours. 0.5 Cl (200 ml) was added, and the mixture was extracted with EtAc (3 x 100 ml). The combined organic extracts were washed with brine (100 ml), dried over MgS 4, and concentrated by rotary evaporation. The crude product was purified by flash chromatography (Si 2, 3:1 hexanes/etac) to afford 1.37 g (56% over two steps including Swern oxidation) pure 9 as a clear, colorless, viscous oil. See below for physical data. S-2

3 General Procedure for the Two-Step ydration of α,β-unsaturated Imides: eq. 5 mol% [(R,R)-salen Al] M in cyclohexane, 48 h 2. 2, Pd() 2 /C, Ac, Et R R o precautions were taken to exclude moisture or air during the following procedure. The requisite α,β-unsaturated imide (0.50 mmol) and salicylaldoxime (82.3 mg, 0.60 mmol) were placed in a two-dram screw-cap vial containing a teflon-coated stirbar. Cyclohexane (1.0 ml) was added, followed by salen(al) catalyst (R,R)-1c (29.0 mg, mmol), and the resulting mixture (which was heterogeneous for most substrates) was stirred vigorously for 48 hours. The mixture was diluted with EtAc (1.0 ml) to achieve complete dissolution, and this solution was filtered through a plug of silica gel (2.5 x 0.8 cm in a Monstr-pette 4 ml capacity Pasteur pipette) eluting with a mixture of hexanes and EtAc (1:1, 20 ml). This filtration serves to remove the aluminum catalyst. This solution was concentrated by rotary evaporation, and the crude oxime ether product was redissolved in Et (5.0 ml). An aliquot (20 µl) was removed and concentrated for analysis of conversion and ee determination. To the remainder of the solution was added acetic acid (57 µl, 1.0 mmol) and 20% Pd() 2 /C (100 mg). The mixture was stirred vigorously under an atmosphere of hydrogen until the reaction was judged complete by TLC (generally 3 to 6 hours). Filtration through a celite plug with EtAc (20 ml) as eluent followed by concentration by rotary evaporation afforded the crude formal hydration products. Flash chromatography (Si 2, hexanes/etac/ac) afforded the purified β-hydroxy imides. The aliquot removed prior to hydrogenolysis was analyzed by 1 MR to determine conversion. The sample was partially purified (in cases where conversion was incomplete, the products could not be completely separated from remaining α,βunsaturated imide 2) by flash chromatography (approx. 1 ml Si 2, Pasteur pipet column) and the resulting product was used for ee determination by chiral PLC. Racemic samples used for analytical purposes were synthesized using racemic catalyst. otes: 1: The acetic acid used in the hydrogenolysis step is necessary for the suppression of side reactions involving the o-hydroxybenzylamine byproduct. In the absence of an acid source, significant aminolysis of the benzimide functionality occurs, leading to greatly diminished yields and product purities. Even with added acetic acid, this side reaction does occur to a small degree (ca. 5%). 2: The acetic acid used as coeluent in some of the chromatographic purifications is used to prevent streaking of the o-hydroxybenzylamine byproduct into the desired product. The use of 1% by volume of acetic acid completely prevents elution of this amine. Aqueous acid washes of the crude product were not feasible for many of the hydration S-3

4 products; decreased yields would result due to the water solubility of these polar compounds. 3: Some of the more polar products (esp. 4a, 4e, 6a, and 6b) were isolated contaminated with small quantities (1-5 mol%) of benzamide. The yields are corrected for this impurity, and pure samples could be obtained by preparative thin-layer chromatography. 4: The 48 hour reaction times for oxime additions are certainly not necessary in all cases. The fact that substrate and product co-elute on TLC of in this step, coupled with the heterogeneous nature of most reactions, rendered difficult accurate analysis of conversion during the course of the reaction. For example, highly reactive imide 4b had undergone 95% conversion at 24 hours. Imide reactivity appears to be a function of both the steric properties of the β-substituent and the solubility of the substrate. 5: To ensure that no erosion of optical purity was occurring during the hydrogenolysis step, product 4c was analyzed by chiral PLC. The enantiomeric excess of this product matched that of the intermediate oxime ether. The chiral PLC traces are included in this Supporting Information. xime Screen: A variety of commercially available or easily synthesized oximes was screened in the conjugate addition reaction. The results are shown in the following table: oxime (1.2 eq.) 1c (10 mol%) cyclohexane 0.5 M 23 C, 20 hours R R' oxime conv. oxime conv. oxime conv. 50% <10% >95%, clean reaction 96% isolated yield (also >95% with 5 mol% catalyst over 48 hours) none % 10% 2 Me 29% Me 2 none E and Z mix approx. 90% (3:1 ratio of nitrone and oxime ether) 56% 80-85% none Me F 3 C <10% 30% none Me 2 S-4

5 ysical Data for ew Compounds: The rather small molecular ion peaks observed in the mass spectra of the products are a result of the fragmentation of these benzimides with release of [C 2 +] + ; thus the base peak in all spectra was at Previously Unreported α,β-unsaturated Imides: 2d: TLC: R f = 0.34 (2:1 hexanes/etac); IR (film) 3284, 1729, 1681, 1644 cm -1 ; 1 MR (500 Mz, CDCl 3 ) δ 9.00 (br, 1), 7.89 (d, J = 7.3 z, 2), 7.59 (t, J = 7.3 z, 1), 7.49 (t, J = 7.8 z, 2), (m, 2), 5.02 (heptet, J = 6.3 z, 1), (m, 2), (m, 2), 1.23 (d, J = 6.3 z, 6); 13 C MR (125 Mz, CDCl 3 ) δ 171.7, 167.4, 165.8, 149.1, 133.1, 132.9, (2C), (2C), 123.4, , 27.7, 21.8 (2C). 2e: MM TLC: R f = 0.47 (1:1 hexanes/etac); IR (film) 3282, 1728, 1681, 1645 cm -1 ; 1 MR (500 Mz, CDCl 3 ) δ 9.05 (br, 1), 7.89 (d, J = 7.8 z, 2), 7.59 (t, J = 7.5 z, 1), 7.49 (t, J = 7.8 z, 2), (m, 2), 4.63 (s, 2), 3.70 (t, J = 6.3 z, 2), 3.36 (s, 3), (dd, J = 6.3, 5.9 z, 2); C MR (125 Mz, CDCl 3 ) δ 167.4, 165.9, 147.9, 133.1, 132.9, (2C), (2C), 124.3, 96.4, 65.8, 55.2, 33.0; MS (AP-CI) calculated for [M+a] , found (12 %). 2f: TBS TLC: R f = 0.45 (3:1 hexanes/etac); IR (film) 3274, 1723, 1676, 1633 cm -1 ; 1 MR (500 Mz, CDCl 3 ) δ 8.80 (br, 1), 7.88 (d, J = 7.4 z, 2), 7.60 (t, J = 7.7 z, 1), 7.50 (t, J = 7.8 z, 2), 7.20 (dt, J = 15.1, 6.3 z, 1), 7.15 (d, J = 15.1 z, 1), 3.63 (m, 2), 2.33 (m, 2), (m, 4), 0.89 (s, 9), 0.05 (s, 6); 13 C MR (125 Mz, CDCl 3 ) δ 167.5, 165.8, 151.9, 133.1, 133.0, (2C), (2C), 122.7, 62.7, 32.5, 32.3, 25.9 (3C), 24.4, 18.3, -5.3 (2C); MS (AP-CI) calculated for [M+] , found (7 %), calculated for [M+a] , found (13 %). S-5

6 5: MM TLC: R f = 0.53 (1:1 hexanes/etac); IR (film) 3275, 1725, 1680, 1643 cm -1 ; 1 MR (500 Mz, CDCl 3 ) δ 9.03 (br, 1), 7.90 (d, J = 7.4 z, 2), 7.59 (t, J = 7.6 z, 1), 7.49 (t, J = 7.8 z, 2), (m, 2), 4.69 (d, J = 7.1 z, 1), 4.63 (d, J = 7.1 z, 1), 3.88 (m, 1), 3.35 (s, 3), 2.53 (m, 1), 2.48 (m, 1), 1.23 (d, J = 5.9 z, 3); 13 C MR (125 Mz, CDCl 3 ) δ 167.4, 165.9, 147.6, 133.1, 132.9, (2C), (2C), 124.8, 94.9, 71.9, 55.3, 40.0, 20.3; [α] 23 D = +5.5 (c = 1.0, C 2 Cl 2 ); MS (AP-CI) calculated for [M+a] , found (7%). 7: TLC: R f = 0.32 (3:2 hexanes/etac); IR (film) 3288, 1724, 1679, 1645 cm -1 ; 1 MR (500 Mz, CDCl 3 ) δ 9.03 (br, 1), 7.90 (d, J = 7.3 z, 2), 7.60 (t, J = 7.3 z, 1), 7.50 (t, J = 7.8 z, 2), 7.24 (d, J = 15.1 z, 1), 7.17 (dt, J = 15.1, 6.8 z, 1), 4.27 (quintet, J = 6.3 z, 1), 4.08 (dd, J = 8.3, 5.9 z, 1), 3.62 (dd, J = 7.8, 6.8 z, 1), 2.62 (m, 1), 2.56 (m, 1), 1.43 (s, 3), 1.36 (s, 3); 13 C MR (125 Mz, CDCl 3 ) δ 167.2, 165.9, 146.1, 133.2, 132.8, (2C), (2C), 125.1, 109.3, 74.2, 68.8, 36.8, 26.8, 25.5; [α] 23 D = -5.8 (c = 1.0, C 2 Cl 2 ); MS (AP-CI) calculated for [M+] , found (5%), calculated for [M+a] , found (18%). 9: MM TLC: R f = 0.53 (1:1 hexanes/etac); IR (film) 3278, 1725, 1680, 1644 cm -1 ; 1 MR (500 Mz, CDCl 3 ) δ 8.92 (br, 1), 7.89 (d, J = 8.3 z, 2), 7.59 (t, J = 7.3 z, 1), 7.50 (t, J = 7.8 z, 2), (m, 2), 4.63 (s, 2), 3.53 (d, J = 6.3 z, 2), 3.35 (s, 3), 2.75 (m, 1), 1.16 (d, J = 6.8 z, 3); 13 C MR (125 Mz, CDCl 3 ) δ 167.5, 165.9, 153.5, 133.1, 133.0, (2C), (2C), 122.4, 96.5, 71.4, 55.2, 37.1, 16.1; [α] 23 D = (c = 1.0, C 2 Cl 2 ); MS (AP-CI) calculated for [M+a] , found (15%). The enantiomeric excess of this substrate was determined to be 97.7% by chiral PLC (ChiralPak AD column, 15% Et/hexanes, 1.0 ml/min, 254 nm, rt minor 21.2 min, rt major 32.6 min). S-6

7 Representative xime Ether Intermediate: TLC: R f = 0.43 (2:1 hexanes/etac); IR (film) 3273, 3176, 1714, 1683 cm -1 ; 1 MR (500 Mz, CDCl 3 ) δ 9.80 (s, 1), 9.10 (br, 1), 8.14 (s, 1), 7.88 (d, J = 7.8 z, 2), 7.57 (t, J = 7.3 z, 1), 7.47 (t, J = 7.6 z, 2), 7.26 (t, J = 7.8 z, 1), 7.11 (dd, J = 7.8, 1.5 z, 1), 6.97 (d, J = 8.3 z, 1), 6.88 (t, J = 7.6 z, 1), 4.94 (m, 1), 3.52 (dd, J = 16.6, 7.3 z, 1), 3.20 (dd, J = 16.6, 5.2 z, 1), 1.46 (d, J = 6.3 z, 3); 13 C MR (125 Mz, CDCl 3 ) δ 173.4, 165.7, 157.3, 151.7, 133.3, 132.5, 131.2, 130.7, (2C), (2C), 119.6, 116.7, 76.1, 43.8, 19.7; [α] 23 D = (c = 1.0, C 2 Cl 2 ); MS (AP-CI) calculated for [M+a] , found (12%). The enantiomeric excess was determined to be 97% by chiral PLC (ChiralPak AD column, 20% i-pr/hexanes, 1.0 ml/min, 220 nm, rt minor 10.3 min, rt major 13.8 min). The enantiomeric excesses of the oxime ether addition products leading to compounds 4b-f were also analyzed under these exact conditions. The chiral PLC traces are included in this Supporting Information. Formal ydration Products: 4a: Purified by flash chromatography (60:39:1 hexanes/etac/ac), yield 80%; TLC: R f = 0.23 (1:2 hexanes/etac); IR (film) 3434, 3293, 1743, 1682 cm -1 ; 1 MR (500 Mz, CDCl 3 ) δ 9.47 (br, 1), 7.87 (d, J = 7.8 z, 2), 7.59 (t, J = 7.8 z, 1), 7.48 (t, J = 7.8 z, 2), 4.31 (m, 1), 3.35 (br, 1), 3.13 (dd, J = 17.6, 2.4 z, 1), 2.99 (dd, J = 17.6, 9.1 z, 1), 1.28 (d, J = 6.3 z, 3); 13 C MR (125 Mz, CDCl 3 ) δ 175.4, 165.8, 133.3, 132.5, (2C), (2C), 64.1, 46.0, 22.5; [α] 23 D = (c = 1.0, C 2 Cl 2 ); MS (AP-CI) calculated for [M+a] , found (4%). 4b: Purified by flash chromatography (66:33:1 hexanes/etac/ac), yield 93%; TLC: R f = 0.46 (1:2 hexanes/etac); IR (film) 3434, 3290, 1740, 1683 cm -1 ; 1 MR (500 Mz, CDCl 3 ) δ 9.32 (br, 1), 7.86 (d, J = 7.3 z, 2), 7.60 (t, J = 7.6 z, 1), 7.49 (t, J = 7.8 z, 2), 4.06 (m, 1), 3.17 (br, 1), 3.15 (dd, J = 17.6, 2.6 z, 1), 2.99 (dd, J = 17.6, 9.3 z, 1), (m, 2), 0.99 (t, J = 7.5 z, 3); 13 C MR (125 Mz, CDCl 3 ) δ 175.5, 165.7, 133.3, 132.5, (2C), (2C), 69.3, 44.2, 29.5, 9.8; [α] 23 D = (c = 1.0, C 2 Cl 2 ). S-7

8 4c: Purified by flash chromatography (75:24:1 hexanes/etac/ac), yield 81%; TLC: R f = 0.53 (1:2 hexanes/etac); IR (film) 3435, 3293, 1739, 1684 cm -1 ; 1 MR (500 Mz, CDCl 3 ) δ 9.26 (br, 1), 7.86 (d, J = 7.3 z, 2), 7.60 (t, J = 7.3 z, 1), 7.49 (t, J = 7.8 z, 2), 3.91 (m, 1), 3.12 (dd, J = 16.9, 2.2 z, 1), 3.05 (br, 1), 3.02 (dd, J = 16.9, 9.8 z, 1), 1.79 (m, 1), 0.99 (t, J = 6.8 z, 3); 13 C MR (125 Mz, CDCl 3 ) δ 175.8, 165.7, 133.3, 132.5, (2C), (2C), 72.7, 41.8, 33.3, 18.4, 17.7; [α] 23 D = (c = 1.0, C 2 Cl 2 ); MS (AP-CI) calculated for [M+a] , found (4%). The enantiomeric excess of this product was determined to be 98% by chiral PLC (ChiralCel D column, 5% Et/hexanes, 1.0 ml/min, 254 nm, rt minor 16.3 min, rt major 18.2 min). The chiral PLC traces are included in this Supporting Information. 4d: Purified by flash chromatography (2:1 3:2 hexanes/etac), yield 88%; TLC: R f = 0.23 (2:1 hexanes/etac); IR (film) 3431, 3289, 1731, 1684 cm -1 ; 1 MR (500 Mz, CDCl 3 ) δ 9.36 (br, 1), 7.86 (d, J = 7.8 z, 2), 7.60 (t, J = 7.3 z, 1), 7.48 (t, J = 7.3 z, 2), 5.00 (m, 1), 4.16 (m, 1), 3.52 (br, 1), 3.12 (dd, J = 17.1, 2.9 z, 1), 3.02 (dd, J = 17.1, 9.1 z, 1), (m, 2), (m, 2), 1.22 (d, J = 6.3 z, 3); 13 C MR (125 Mz, CDCl 3 ) δ 174.8, 173.4, 165.6, 133.3, 132.5, (2C), (2C), 67.9, 67.2, 44.7, 31.4, 30.9, 21.8, 21.7; [α] 23 D = (c = 1.0, C 2 Cl 2 ); MS (AP- CI) calculated for [M+a] , found (19%). 4e: MM Purified by flash chromatography (50:49:1 hexanes/etac/ac), yield 88%; TLC: R f = 0.13 (1:1 hexanes/etac); IR (film) 3433, 3286, 1743, 1683 cm -1 ; 1 MR (500 Mz, CDCl 3 ) δ 9.54 (br, 1), 7.86 (d, J = 7.8 z, 2), 7.58 (t, J = 7.3 z, 1), 7.47 (t, J = 7.3 z, 2), 4.62 (s, 2), 4.33 (m, 1), (m, 2), 3.63 (br, 1), 3.35 (s, 3), 3.06 (dd, J = 17.1, 3.4 z, 1), 3.01 (dd, J = 17.1, 8.8 z, 1), (m, 2); 13 C MR (125 Mz, CDCl 3 ) δ 174.2, 165.5, 133.2, 132.6, (2C), (2C), 96.5, 66.4, 65.1, 55.3, 44.8, 36.0; [α] 23 D = (c = 1.0, C 2 Cl 2 ); MS (AP-CI) calculated for [M+a] , found (15%). S-8

9 4f: TBS Purified by flash chromatography (5:1 3:1 hexanes/etac), yield 82%; TLC: R f = 0.21 (5:1 hexanes/etac); IR (film) 3433, 3287, 1740, 1683 cm -1 ; 1 MR (500 Mz, CDCl 3 ) δ 9.01 (br, 1), 7.85 (d, J = 7.8 z, 2), 7.62 (t, J = 7.3 z, 1), 7.51 (t, J = 7.8 z, 2), 4.16 (m, 1), 3.63 (t, J = 6.3 z, 2), 3.15 (dd, J = 17.1, 2.4 z, 1), 3.05 (br, 1), 3.02 (dd, J = 17.1, 9.3 z, 1), (m, 6), 0.89 (s, 9), 0.05 (s, 6); 13 C MR (125 Mz, CDCl 3 ) δ 175.3, 165.6, 133.3, 132.5, (2C), (2C), 67.8, 63.0, 44.7, 36.3, 32.5, 25.9 (3C), 21.8, 18.3, -5.3 (2C); [α] 23 D = (c = 1.0, C 2 Cl 2 ); MS (AP-CI) calculated for [M+a] , found (33%). 6a: MM Purified by flash chromatography (60:39:1 50:49:1 hexanes/etac/ac), yield 78%; TLC: R f = 0.18 (1:1 hexanes/etac); IR (film) 3429, 3285, 1742, 1683 cm -1 ; 1 MR (500 Mz, CDCl 3 ) δ 9.62 (br, 1), 7.85 (d, J = 7.8 z, 2), 7.57 (t, J = 7.3 z, 1), 7.47 (t, J = 7.3 z, 2), 4.69 (d, J = 6.8 z, 1), 4.64 (d, J = 6.8 z, 1), 4.40 (m, 1), 4.01 (m, 1), 3.76 (br, 1), 3.37 (s, 3), (m, 2), (m, 2), 1.21 (d, J = 6.3 z, 3); 13 C MR (125 Mz, CDCl 3 ) δ 174.0, 165.5, 133.1, 132.7, (2C), (2C), 95.4, 70.9, 64.5, 55.5, 44.9, 43.3, 20.5; [α] 23 D = (c = 1.0, C 2 Cl 2 ); MS (AP-CI) calculated for [M+a] , found (26%). 6b: MM Purified by flash chromatography (60:39:1 50:49:1 hexanes/etac/ac), yield 73%; TLC: R f = 0.18 (1:1 hexanes/etac); IR (film) 3436, 3288, 1742, 1687 cm -1 ; 1 MR (500 Mz, CDCl 3 ) δ 9.67 (br, 1), 7.86 (d, J = 7.8 z, 2), 7.57 (t, J = 7.3 z, 1), 7.46 (t, J = 7.3 z, 2), 4.63 (d, J = 6.8 z, 1), 4.32 (d, J = 6.8 z, 1), 4.31 (m, 1), 3.99 (br, 1), 3.98 (m, 1), 3.36 (s, 3), 2.97 (dd, J = 16.6, 3.9 z, 1), 2.93 (dd, J = 16.6, 7.8 z, 1), 1.85 (m, 1), 1.64 (m, 1), 1.21 (d, J = 6.3 z, 3); 13 C MR (125 Mz, CDCl 3 ) δ 173.2, 165.3, 133.1, 132.8, (2C), (2C), 94.6, 72.7, 67.0, 55.6, 45.0, 43.2, 20.2; [α] 23 D = (c = 1.0, C 2 Cl 2 ); MS (AP-CI) calculated for [M+a] , found (16%). S-9

10 8a: Purified by flash chromatography (60:39:1 50:49:1 hexanes/etac/ac), yield 88%; TLC: R f = 0.21 (1:1 hexanes/etac); IR (film) 3522, 3272, 1741, 1680 cm -1 ; 1 MR (500 Mz, CDCl 3 ) δ 9.47 (br, 1), 7.85 (d, J = 7.8 z, 2), 7.58 (t, J = 7.3 z, 1), 7.47 (t, J = 7.3 z, 2), (m, 2), 4.08 (m, 1), 3.56 (t, J = 7.8 z, 1), 3.52 (br, 1), 3.13 (dd, J = 17.1, 2.9 z, 1), 3.04 (dd, J = 17.1, 8.8 z, 1), 1.78 (t, J = 6.8 z, 2), 1.39 (s, 3), 1.34 (s, 3); 13 C MR (125 Mz, CDCl 3 ) δ 174.9, 165.7, 133.3, 132.5, (2C), (2C), 108.7, 73.2, 69.5, 65.3, 44.9, 39.8, 26.9, 25.6; [α] 23 D = (c = 1.0, C 2 Cl 2 ); MS (AP-CI) calculated for [M+a] , found (20%). 8b: Purified by flash chromatography (60:39:1 50:49:1 hexanes/etac/ac), yield 89%; TLC: R f = 0.20 (1:1 hexanes/etac); IR (film) 3467, 3292, 1742, 1685 cm -1 ; 1 MR (500 Mz, CDCl 3 ) δ 9.57 (br, 1), 7.86 (d, J = 7.3 z, 2), 7.59 (t, J = 7.3 z, 1), 7.48 (t, J = 7.3 z, 2), (m, 2), 4.11 (dd, J = 8.3, 5.9 z, 1), 3.88 (br, 1), 3.59 (dd, J = 7.3, 5.9 z, 1), (m, 2), (m, 2), 1.41 (s, 3), 1.36 (s, 3); 13 C MR (125 Mz, CDCl 3 ) δ 173.2, 165.3, 133.2, 132.7, (2C), (2C), 109.4, 74.7, 69.5, 66.9, 44.8, 39.7, 26.8, 25.7; [α] 23 D = (c = 1.0, C 2 Cl 2 ); MS (AP-CI) calculated for [M+a] , found (27%). 10a: MM Purified by flash chromatography (60:39:1 50:49:1 hexanes/etac/ac), yield 70%; TLC: R f = 0.22 (1:1 hexanes/etac); IR (film) 3436, 3284, 1741, 1685 cm -1 ; 1 MR (500 Mz, CDCl 3 ) δ 9.80 (br, 1), 7.86 (d, J = 7.3 z, 2), 7.56 (t, J = 7.3 z, 1), 7.46 (t, J = 7.8 z, 2), 4.61 (d, 2), 4.07 (m, 1), 3.97 (br, 1), 3.64 (dd, J = 9.7, 4.9 z, 1), 3.58 (dd, J = 9.7, 6.6 z, 1), 3.34 (s, 3), 3.03 (dd, J = 16.1, 2.4 z, 1), 2.94 (dd, J = 16.1, 8.8 z, 1), 1.95 (m, 1), 0.98 (d, J = 6.8 z, 3); 13 C MR (125 Mz, CDCl 3 ) δ 173.9, 165.5, 133.1, 132.7, (2C), (2C), 96.5, 71.2, 70.9, 55.3, 42.5, 38.3, 13.6; [α] 23 D = (c = 1.0, C 2 Cl 2 ); MS (AP-CI) calculated for [M+a] , found (32%). S-10

11 10b: MM Purified by flash chromatography (60:39:1 50:49:1 hexanes/etac/ac), yield 75%; TLC: R f = 0.21 (1:1 hexanes/etac); IR (film) 3467, 3292, 1740, 1685 cm -1 ; 1 MR (500 Mz, CDCl 3 ) δ 9.70 (br, 1), 7.87 (d, J = 7.3 z, 2), 7.56 (t, J = 7.3 z, 1), 7.45 (t, J = 7.8 z, 2), 4.60 (d, 2), 4.29 (dt, J = 10.3, 3.0 z, 1), (m, 2), 3.52 (br, 1), 3.34 (s, 3), 3.06 (dd, J = 16.6, 10.3 z, 1), 2.93 (dd, J = 16.6, 2.4 z, 1), 1.93 (m, 1), 0.99 (d, J = 6.8 z, 3); 13 C MR (125 Mz, CDCl 3 ) δ 174.7, 165.7, 133.1, 132.6, (2C), (2C), 96.5, 70.7, , 42.3, 38.1, 11.2; [α] 23 D = (c = 1.0, C 2 Cl 2 ); MS (AP-CI) calculated for [M+a] , found (20%). Correlation with ethyl hydroxybutyrate to confirm absolute sense of induction: Er(Tf) 3 Et Et ethyl (S)-hydroxybutyrate Product 4a of 97% ee was converted into ethyl (S)-hydroxybutyrate according to the following procedure: 1 Imide 4a (11.0 mg, mmol) was dissolved in Et (0.5 ml). Erbium triflate (1.6 mg, mmol) was added, and the reaction was stirred at 4 C for 20 hours. The mixture was diluted with EtAc (0.5 ml), filtered through a plug of Si 2 eluting with EtAc, and concentrated. The residue was purified by flash chromatography (Si 2, 1:1 pentane/et 2 ) to afford ethyl (S)-hydroxybutyrate (6.2 mg, 89%) as a clear, colorless liquid. Synthetic ethyl (S)-hydroxybutyrate exhibited identical MR spectra as a commercial source of ethyl (R)-hydroxybutyrate (Aldrich), with an opposite sign of specific rotation, thus confirming the absolute sense of induction. Representative procedure for imide ethanolysis of 4a, 4d, 4e, 8a, 8b: Er(Tf) 3, Et, 4 C R 4a,d,e 8a,b R Et 89-98% yield The β-hydroxy imide (0.10 mmol) was dissolved in Et (1.0 ml). Erbium triflate (3.1 mg, mmol) was added, and the reaction was stirred at 4 C until the starting material was completely consumed, as judged by TLC analysis (6 to 20 hours). The mixture was diluted with EtAc (1.0 ml), filtered through a plug of Si 2 eluting with EtAc, and concentrated. The residue was purified by flash chromatography (Si 2, pentane/et 2 ) to afford the β-hydroxy esters as clear, colorless oils in yields of 89-98%. These products were typically somewhat volatile, and extended exposure to high vacuum should be avoided in order to obtain maximum yields. S-11

12 Procedure for the conversion of β-hydroxy imide 4f to the Weinreb amide: Me 2 Al(Me)Me, TBS TBS TF/Me, -20 C 4f 88% yield Me,-dimethylhydroxylamine hydrochloride (293 mg, 3.0 mmol) was suspended in TF (1.5 ml) and cooled to 0 C. Trimethylaluminum (1.5 ml of a 2.0 M solution in toluene, 3.0 mmol) was added dropwise over 2 minutes. The resulting mixture was stirred for 15 minutes at 0 C followed by 15 minutes at ambient temperature. It was then recooled to 20 C, and a solution of the β-hydroxy imide 4f (379 mg, 1.0 mmol) in TF (1.5 ml) was added slowly via cannula, followed by a TF rinse (0.5 ml). The reaction was stirred at 20 C for one hour, at which point it was judged complete by TLC analysis. The mixture was poured into a vigorously stirred 0 C mixture of 0.1 Cl (10 ml) and C 2 Cl 2 (10 ml). The biphasic mixture was stirred until the phases clarified, approximately 20 minutes. The layers were separated, the aqueous layer was extracted with C 2 Cl 2 (3 x 10 ml), and the combined organic extracts were washed with brine, dried over MgS 4, and concentrated. Purification by flash chromatography (Si 2, 2:1 hexanes/etac) afforded the Weinreb amide (280 mg, 88%) as a clear, colorless oil. References: 1. Taylor, M. S.; Jacobsen, E.. J. Am. Chem. Soc. 2003, 125, (a) Myers, J. K.; Jacobsen, E.. J. Am. Chem. Soc. 1999, 121, ; (b) Goodman, S..; Jacobsen, E.. Adv. Synth. Catal. 2002, 344, S-12

13 Chiral Chromatographic Traces for Intermediate xime Ethers: Racemate: S-13

14 Racemate: S-14

15 Racemate: S-15

16 MM Racemate: S-16

17 Racemate: S-17

18 TBS Racemate: S-18

19 Representative - Cleaved (Formal ydration) Product 4c: Racemate: S-19