Department of Chemistry, Michigan State University, East Lansing, Michigan Dow Agrosciences LLC, 9330 Zionsville Rd, Indianapolis, IN

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1 Supplemental Information ighly Regio- and Enantioselective Vicinal Dihalogenation of Allyl Amides Bardia Soltanzadeh, Arvind Jaganathan, Yi Yi, ajoon Yi, Richard J. Staples, and Babak Borhan* Department of Chemistry, Michigan State University, East Lansing, Michigan Dow Agrosciences LLC, 9330 Zionsville Rd, Indianapolis, I Table of Contents: I. General information... S2 II. General procedure for catalytic asymmetric dichlorination of unsaturated amides... S2 II.A. Procedure for gram scale scope analysis for catalytic asymmetric dichlorination of unsaturated amides in presence of 1% chiral catalyst... S3 III. ptimization of reaction variables... S3 III.A. Dichlorination of allyl amides in acetonitrile... S3 III.B. Influence of reaction concentration on the yield for the dichlorination of unsaturated aryl and trisubstituted amides... S4 III.C. ptimization of solvents and equivalants of lithium chloride in the chlorobromination reactions... S5 III.D. Enantioselective dihalogenation of unsaturated amides... S6 IV. Infuence of Li particle size on olefin dichlorination reactions... S7 V. Influence of 12-crown-4 in olefin dichlorination reactions... S8 VI. Product distribution arising due to substrate-control and catalyst-control for the dichlorination reactions... S9 VII. Analytical data for products... S10 VIIA. Analytical data for byproduct 6a... S22 VIIB. Analytical data for products in non-catalyzed reaction (9b, 10b, 11b)... S23 VIIC. Analytical data for substrate 4i... S24 VIII. References... S25 IX. MR spectra... S26 X. PLC traces... S74 S1

2 I. General information Commercially available reagents were purchased from Sigma-Aldrich or Alfa-Aesar and used as received. C 2 2 and acetonitrile were freshly distilled over Ca 2 prior to use. TF was distilled over sodium-benzophenone ketyl. All other solvents were used as purchased. Li and Li were purchased from Sigma-Aldrich; the particle size of Li and Li were <850 µm. 1 and 13 C MR were recorded on 500 Mz Varian MR machines using CD 3 as solvent and were referenced to residual solvent peaks. Flash silica gel (32-63 mm, Silicycle 60 Å) was used for column chromatography. The sieves for obtaining different mesh size of Li were purchased from &C sieving systems. Enantiomeric excess for all products was determined by PLC analysis using DAICEL CIRALCEL J- and D- or CIRALPAK IA and AD- columns. ptical rotations of all products were measured in chloroform. Allyl amides 4a-4n (except 4i) were synthesized as reported previously. 1 Analytical data for byproducts 7a and 8a were also reported in the same reference. 1 II. General procedure for catalytic asymmetric dichlorination of unsaturated amides The substrate (0.1 mmol, 1.0 equiv) and Li (420 mg, 10 mmol, 100 equiv, reagent grade, <850 µm particle size) were suspended in trifluoroethanol (TFE, 5.0 ml) in a screw-capped 20 ml vial equipped with a micro stir bar (7 2 mm). The resulting suspension was cooled to -30 C in an immersion cooler. (DQD) 2 PAL (7.8 mg, 10 mol%) was then introduced. After stirring for 2 min DCDM (39.5 mg, 0.2 mmol, 2.0 equiv) was added. The stirring at 300 RPM (as indicated by the stirrer) was continued at - 30 C till the reaction was complete (TLC). The reaction was quenched by the addition of saturated aq. a 2 S 3 (3 ml) and diluted with DCM (3 ml). The organics were separated and the aqueous layer was extracted with DCM (3 4 ml). The combined organics were dried over anhydrous a 2 S 4 and concentrated in the presence of small quantity of silica gel. Column chromatography (Si 2 /EtAc exanes gradient elution) gave the desired product. S2

3 IIA. Procedure for gram scale scope analysis for catalytic asymmetric dichlorination of unsaturated amides in presence of 1% of chiral catalyst 4a (1.0 g, 4.0 mmol, 1.0 equiv) and Li (17 g, 100 equiv) were suspended in trifluoroethanol (TFE, 20.0 ml) in a round-bottom flask equipped with a stir bar. The resulting suspension was cooled to -30 C in an immersion cooler. (DQD) 2 PAL (32.0 mg, 1.0 mol%) was then introduced. After stirring for 2 min DCDM (1500 mg, 8.0 mmol, 2.0 equiv) was added. The stirring in >300 RPM was continued at -30 C till the reaction was complete (TLC). The reaction was quenched by the addition of saturated aq. a 2 S 3 (20 ml) and diluted with DCM (15 ml). The organics were separated and the aqueous layer was extracted with DCM (3 15 ml). The combined organics were dried over anhyd. a 2 S 4 and concentrated in the presence of silica gel. Column chromatography (Si 2 /EtAc exanes gradient elution) gave the desired product in 91% yield and 98:2 enantioselectivity. III. ptimization of reaction variables III.A Dichlorination of allyl amides in acetonitrile Table S1: Dichlorination of allyl amides in acetonitrile R 1 R 2 4h-4j 2 10 mol% (DQD) 2 PAL 2.0 equiv DCDM 100 equiv Li, AC 0.02 M, -30 o C R 2 R 1 5h-5j 2 Entry R 1 R 2 Prod %Yield a /dr er b 1 Ph 5h 59/>6.3:1 91:9 2 C 3 7 5j 89/>99:1 61.5:38.5 a Combined yield, Determined by MR; b Determined by chiral PLC Using acetonitrile as the solvent for dichlorination of 4h produced the corresponding product 5h in moderate yield and stereoselectivity (entry 1, Table S1). Under the same conditions 5j was formed in high yield, diastereoselectivity (99:1 dr) albeit in low enantioselectivity (61.5:38.5 er, entry 2, Table S1). owever, performing the dichlorination reaction in trifluroethanol (TFE) gave a significant improvement in S3

4 stereoselectivity of 5h and 5j (>99:1 er and 93:7 er, respectively, see Table 2 in manuscript, entries 8 and 10). III.B. Influence of reaction concentration on the yield for the dichlorination of unsaturated aromatic and trisubstituted allyl amides The dichlorination of aromatic allyl amides (4h, 4m) in optimized concentration (0.02 M) produced the mixture of dichlorinated product and chloroetherification side product in moderate yield and high diastereoselectivity (entries 1 and 2, Table S2). Table S2: Dichlorination of aromatic and trisuststiuted allyl amides R mol% (DQD) 2 PAL 2.0 equiv DCDM R 2 2 R 2 2 R equiv Li, R 1 R 1 C 2 CF 3 TFE M, -30 o C 4h-4m-4n 5h-5m-5n 6h-6m-6n Entry R 1 R 2 Conc Prod %Yield a /dr 5:6 1 Ph h 55 c /10:1 4.2:1 2 Ph m 40 c /32:1 2.8:1 3 Me Me n 44 c /na 1:1.8 4 Ph 0.2 5h 62 c /15.6:1 15.6:1 5 Ph 0.2 5m 63 c /53:1 5.3:1 6 Me Me 0.2 5n 73 c /na 4.4:1 a Yield determined by MR; b Enantioselectivity determined by chiral PLC; c Rest of mass balance is TFE incorporated product The trisubstituted olefin 4n formed the desired product 5n in 44% yield (see entry 3, Table S2). The mass balance for these reactions was TFE-incorporated side product 6. In an attempt to increase the yield and chemoselectivity for these substrates (4h, 4m, 4n), the reaction was performed at a higher concentration (0.2 M). The higher concentration resulted in higher yields and diastereoselectivities of the desired products (see entries 4, 5 and 6, Table S2). S4

5 III.C. Influence of solvents and equivalents of lithium chloride in the chlorobromination reactions Table S3: ptimization of chlorobromination reactions C 3 7 4a 2 (DQD)2 PAL (0.10 equiv) BS (2.0 equiv) Li, Temp solvent (0.2 M) C C 3 7 9a 10 2 Entry Solvent Temp equiv of Li 9a:10 er (9a) 1 AC rt :1.0 76:24 2 AC :1.0 76:24 3 AC :1.0 76:24 4 TFE >99:1 98:2 c Combined yield, Determined by MR; b Determined by chiral PLC Treating allyl amide 4a in AC (0.2 M) with 30 equivalents of Li as chloride source and 2 equivalents of BS as bromenium source gave mixture of products 9a:10 in ratio of 1:1 with 76:24 er for the desired product 9a (entry 1, Table S3). Using higher equivalents of Li slightly increased the chemoselectivity in favor of dihalogenated product 9a (entries 2 and 3, Table S3). Interestingly, performing the chlorobromination reaction in TFE as solvent forms product 9a with exquisite chemoselectivity and enantioselectivity (98:2 er, entry 4, Table S3). S5

6 III.D. Enantioselective dihalogenation of unsaturated amides Table S4: Regio- and enantioselective dihalogenation 2 (DQD)2 PAL (0.10 equiv) X source (2.0 equive) C 3 7 X 2 2 C C 3 7 4a X source (100 equiv), TFE 0.4 M, -30 o C X 1 9a-9a ' TFE 6a Entry X - source X + source X 1 X 2 Prod %Conv %Yield a er b 1 Li BS 9a :2 2 Li BS 9a' :16 3 Li DCDM 9a' :23 4 LiF DCDM F nd nd 5 LiI IS I I - 0 nd nd 6 LiI DCDM I - 0 nd nd a Yield determined by MR; b Enantioselectivity determined by chiral PLC Treating 4a in TFE (0.2 M Conc) with 100 equivalents of Li as the chloride source and 2.0 equivalents of BS as the bromonium source produced 9a in 97% yield and 98:2 er. With this result in hand we attempted to form the other regioisomer by changing the X- source and X+ source. Using Li and BS formed dibrominated product 9a' in 90% yield and 84:16 er (Table S4, entry 2). Surprisingly, employing Li and DCDM led to the dibrominated product 9a' instead of the chlorobrominated product (Table S4, entry 3). Employing LiF as a fluoride source failed to yield chlorofluorinated product and instead returned the TFE incorporated product 6 in high yield (Table S4, entry 4). Lithium iodide does not lead to any product and starting material was recovered (Table S4, entries 4 and 5). S6

7 IV. Influence of Li particle size in olefin dichlorination reactions Table S5: Effect of Li particle size on product distribution of the dichlorination reaction Ph 2 10 mol% (DQD) 2 PAL 2.0 equiv DCDM Ph 50 equiv Li C 2 CF 3 TFE 0.04 M, rt 4m 5m 6m 2 Ph 2 Entry a Li particle size (µm) Ratio (5m:6m) c : : : :26 a For all reactions, 50% of the product was the intramolecularly cyclized compound; b Li was ground to powder and was sieved to obtain different particle sizes.; c Determined by MR The suggested role of solid Li in the reaction would presume that particle size should have an influence on reaction outcome. To probe the role of insoluble Li of the olefin dichlorination reaction, different particle sizes of lithium chloride were produced by sequential sieving through different mesh screens. This was accomplished by taking the salt particles that passed from a higher mesh size screen (for example 850 µm) and were trapped onto a smaller mesh size screen (such as 300 µm). In the latter example, the particle sizes are between 850 µm to 300 µm. The mesh ranges in Table S5 refer to sequential sieving with two different mesh screens as described above. The reactions were ran with 50 equivalents of Li in each case, since with larger excess the 5m:6m ratio would have been less pronounced (at 100 equivalents the majority of the product is the desired 5m). As anticipated for a reaction that is dependent on reaction at the solid interface, Li particle size makes a difference in the ratio of products. Entry 1, with the largest particle sizes yields the worst ratio of 5m:6m (62:38). As the particle sizes become progressively smaller, the ratio favors the desired 5m product, which is presumably aided by the reaction taking place at the solid interface. We would anticipate that the reaction to yield 6m (incorporation of the solvent) is independent of the solid and occurs in the soluble phase. These results are corroborate the RPM studies (Table 4 in the manuscript), which also highlights that the dichlorination reaction is aided by the S7

8 presence of the solid Li, suggestive of the fact that the reaction could occur on solidliquid interface. V. Influence of 12-crown-4 in olefin dichlorination reactions Table S6: Effect of 12-crown-4 ether on product distribution of dichlorination reactions 2 10 mol% (DQD) 2 PAL 2.0 equiv DCDM C C 3 7 C 3 7 Li, 12-crown-4 C 2 CF 3 TFE 0.02 M, rt 5a 6a 4a Entry Equiv of Li Equiv of Crown ether Ratio (5a:6a) a : : : : : :39 a Determined by MR 12-Crown-4 ether is a specific scavenger for lithium cation, yielding a more soluble chloride in the reaction mixture. In presence of 15 equivalents of Li at ambient temperature the desired product 5a was formed predominantly (5a:6a = 77:23, Table S6, entry 1). Adding 12-crown-4 ether formed 5a with diminished selectivity; in presence of 3 equivalents of 12-crown-4 ether the ratio of 5a:6a decreased to 68:32 (Table S6, entry 2). Employing 20 equivalents of crown ether in presence of 50 equivalants of Li gave a mixture of products in worse selectivity (61:39 5a:6a, Table S6, entry 6) These results in line with other control experiments (RPM studies, Li particle size) demonstrate that insoluble Li plays an important role for obtaining high selectivity for dichlorination reactions. S8

9 VI. Product distribution arising due to substrate-control and catalyst-control for the dichlorination reactions Table S7: Product distribution in catalyzed and non-catalyzed dichlorination reactions cat 2.0 equiv BS C 3 7 C 3 7 C 3 7 Li, (100 equiv) TFE 0.02 M, rt 9b 10b 4b (regioisomer of 9b) C b Entry a Catalyst Ratio (9b:10b:11b) c Regioselectivity er (9b) 1 one 52:24:24 2:1 50:50 2 (DQD) 2 PAL 90:5:5 18:1 94:6 a Determined by MR.; b Enantioselectivity determined by chiral PLC The dihalogenation reaction without any catalysts gave 3 major products. As shown in the MR trace for the crude reaction, along with the desired product 9b, the regioisomer 10b and the cyclized product 11b were also formed in a ratio of 52:24:24 (Table S7, entry 1). n the other hand, employing (DQD) 2 PAL as the chiral catalyst at ambient temperature gave the desired product in significantly higher selectivity with 94:6 enantioselectivity (Table S7, entry 2). These results demonstrate that the chiral catalyst is not only responsible for high enantioselectivity but also for the exquisite regioselectivity seen for reactions employing aliphatic substrates. Without (DQD) 2PAL 9b 11b 10b With (DQD) 2PAL Figure 1 MR trace for product distribution in catalyzed and non-catalyzed chlorobromination reaction S9

10 VII. Analytical data for products 5a: -((2S,3S)-2,3-dichlorohexyl)-4-nitrobenzamide 2 R f : 0.60 (30% EtAc in hexanes, UV) 1 MR (500 Mz, CD 3 ) δ 8.30 (d, J = 8.5 z, 2), 7.94 (d, J = 8.5 z, 2), 6.52 (br s, 1), (ddd, J = 9.5, 4.5, 2.5 z, 1), (ddd, J = 9.0, 4.5, 2.0 z, 1), (ddd, J = 14.0, 7.5, 4.5 z, 1), (ddd, J = 13.5, 8.5, 5.0 z, 1), (m, 2), (m, 1), (m, 1), 0.96 (t, J = 7.0 z, 3) 13 C MR (125 Mz, CD 3 ) δ , , , , , 63.49, 62.76, 44.92, 37.45, 19.67, RMS analysis (ESI): Calculated for [M+] + : C : ; Found: Resolution of enantiomers: DAICEL Chiralcel AD- column, 15% IPA-exanes, 1.0 ml/min, 254 nm, RT1 (major) = 8.3 min, RT2 (minor) = 10.8 min. 20 [α] D = (c 0.65, C 3, er = >99:1) Absolute stereochemistry was determined by single crystal X-ray diffraction (XRD). Crystals for XRD were obtained by crystallization from C 2 2 layered with hexanes in a silicone-coated vial. epi-5a: -((2R,3R)-2,3-dichlorohexyl)-4-nitrobenzamide 2 R f : 0.60 (30% EtAc in hexanes, UV) 94% yield with (DQ) 2 PAL S10

11 1 MR (500 Mz, CD 3 ) δ 8.30 (d, J = 8.5 z, 2), 7.94 (d, J = 8.5 z, 2), 6.52 (br s, 1), (ddd, J = 9.5, 4.5, 2.5 z, 1), (ddd, J = 9.0, 4.5, 2.0 z, 1), (ddd, J = 14.0, 7.5, 4.5 z, 1), (ddd, J = 13.5, 8.5, 5.0 z, 1), (m, 1), (m, 2), (m, 1), (m, 1), 0.96 (t, J = 7.0 z, 3) 13 C MR (125 Mz, CD 3 ) δ , , , , , 63.49, 62.76, 44.92, 37.45, 19.67, RMS analysis (ESI): Calculated for [M+] + : C : ; Found: Resolution of enantiomers: DAICEL Chiralcel AD- column, 15% IPA-exanes, 1.0 ml/min, 254 nm, RT1 (minor) = 8.6 min, RT2 (major) = 11.0 min. 20 [α] D = (c 1.0, C 3, er = 98:2) 5b: 4-bromo--((2S,3S)-2,3-dichlorohexyl)benzamide R f : 0.60 (30% EtAc in hexanes, UV) 1 MR (500 Mz, CD 3 ) δ 7.64 (d, J = 9.0 z, 2), 7.59 (d, J = 9.0 z, 2), 6.48 (br s, 1), (ddd, J = 9.0, 4.5, 2.5 z, 1), (ddd, J = 9.0, 4.5, 2.5 z, 1), (ddd, J = 14.0, 7.0, 4.5 z, 1), (ddd, J = 14.0, 8.5, 5 z, 1), (m, 2), (m, 1), (m, 1), 0.94 (t, J = 7.5 z, 3) 13 C MR (125 Mz, CD 3 ) δ , , , , , 63.62, 62.82, 44.82, 37.55, 19.66, RMS analysis (ESI): Calculated for [M+] + : C : ; Found: Resolution of enantiomers: DAICEL Chiralcel IA column, 15% IPA-exanes, 1.0 ml/min, 254 nm, RT1 (major) = 6.7 min, RT2 (minor) = 10.4 min. 20 [α] D = (c 0.8, C 3, er = >99:1) S11

12 5c: -((2S,3S)-2,3-dichloropentyl)-4-nitrobenzamide 2 R f : 0.50 (30% EtAc in hexanes, UV) 1 MR (500 Mz, CD 3 ) δ 8.30 (d, J = 8.5 z, 2), 7.95 (d, J = 8.5 z, 2), 6.61 (br s, 1), (ddd, J = 8.5, 4.0, 2.5 z, 1), (m, 2), (ddd, J = 14.0, 9.5, 5.5 z, 1), (m, 2), 1.06 (t, J = 7.5 z, 3) 13 C MR (125 Mz, CD 3 ) δ , , , , , 64.77, 63.17, 44.95, 28.94, RMS analysis (ESI): Calculated for [M+] + : C : ; Found: Resolution of enantiomers: DAICEL Chiralcel AD- column, 15% IPA-exanes, 1.0 ml/min, 254 nm, RT1 (major) = 9.9 min, RT2 (minor) = 11.3 min. 20 [α] D = (c 0.6, C 3, er = >99:1) 5d: -((2S,3S)-2,3-dichlorononyl)-4-nitrobenzamide 2 R f : 0.60 (30% EtAc in hexanes, UV) 1 MR (500 Mz, CD 3 ) δ 8.30 (d, J = 8.5 z, 2), 7.94 (d, J = 8.5 z, 2), 6.63 (br s, 1), (ddd, J = 9.0, 4.0, 2.0 z, 1), (m, 2), (ddd, J = 14.0, 9.0, 5.5 z, 1), (m, 2), (m, 1), (m, 7), 0.88 (t, J = 7.0 z, 3) 13 C MR (125 Mz, CD 3 ) δ , , , , , 63.46, 63.10, 44.93, 35.52, 31.52, 28.59, 26.37, 22.50, RMS analysis (ESI): Calculated for [M+] + : C ; Found: Resolution of enantiomers: DAICEL Chiralcel AD- column, 15% IPA-exanes, 1.0 ml/min, 254 nm, RT1 (major) = 6.6 min, RT2 (minor) = 8.0 min. 20 [α] D = (c 0.7, C 3, er = >99:1) S12

13 5e: -((2S,3S)-4-(benzyloxy)-2,3-dichlorobutyl)-4-nitrobenzamide 2 Bn R f : 0.50 (30% EtAc in hexanes, UV) 1 MR (500 Mz, CD 3 ) δ 8.28 (d, J = 9.0 z, 2), 7.90 (d, J = 9.0 z, 2), (m, 5), 6.65 (br s, 1), (ddd, J = 8.0, 5.0, 2.0 z, 1), 4.57 (s, 2), 4.29 (dt, J = 7.0, 2.5 z 1), (ddd, J = 14.0, 7.5, 5.0 z, 1), 3.78 (d, J = 6.5 z, 2), (ddd, J = 14.0, 8.5, 5.0 z, 1) 13 C MR (125 Mz, CD 3 ) δ , , , , , , , , , 73.77, 70.61, 60.12, 59.61, RMS analysis (ESI): Calculated for [M+] + : C : ; Found: Resolution of enantiomers: DAICEL Chiralcel AD- column, 15% IPA-exanes, 1.0 ml/min, 254 nm, RT1 (major) = 14.7 min, RT2 (minor) = 17.4 min. 20 [α] D = (c 0.55, C 3, er = 89:11) 5f: -((2S,3S)-5-((tert-butyldiphenylsilyl)oxy)-2,3-dichloropentyl)-4-nitrobenzamide TBDPS 2 R f : 0.60 (30% EtAc in hexanes, UV) 1 MR (500 Mz, CD 3 ) δ 8.29 (d, J = 9.0 z, 2), 7.93 (d, J = 9.0 z, 2), (m, 4), (m, 6), 6.57 (br s, 1), 4.60 (ddd, J = 9.0, 3.5, 2.5 z, 1), (ddd, J = 8.5, 5.0, 2.5 z, 1), (ddd, J = 14.5, 7.5, 5.5 z, 1), (m, 1), (m, 2), (m, 1), (m, 1), 0.98 (s, 9) 13 C MR (125 Mz, CD 3 ) δ , , , , , ,133.14, , , , , , , 63.38, 59.81, 59.49, 44.73, 38.29, 26.79, RMS analysis (ESI): Calculated for [M+] + : C Si: ; Found: S13

14 Resolution of enantiomers: DAICEL Chiralcel AD- column, 7% IPA-exanes, 0.8 ml/min, 254 nm, RT1 (minor) = 12.5 min, RT2 (major) = 13.3 min. [α] D 20 = (c 0.45, C 3, er = >99:1) Syn-5g: -((2S,3S)-2,3-dichloro-3-(p-tolyl)propyl)-4-nitrobenzamide 2 R f : 0.60 (30% EtAc in hexanes, UV) 1 MR (500 Mz, CD 3 ) δ 8.28 (d, J = 8.5 z, 2), 7.87 (d, J = 8.5 z, 2), 7.34 (d, J = 8.5 z, 2), 7.19 (d, J = 8.5 z, 2), 6.50 (br s, 1), 5.13 (d, J = 5.5 z, 1), (m, 1), (ddd, J = 14.5, 7.5, 4.0 z, 1), (ddd, J = 13.5, 9.0, 5.0 z, 1), 2.34 (s, 3) 13 C MR (125 Mz, CD 3 ) δ , , , , , , , , , 65.11, 64.35, 44.30, RMS analysis (ESI): Calculated for [M+] + : C : ; Found: Resolution of enantiomers: DAICEL Chiralcel AD- column, 15% IPA-exanes, 1.0 ml/min, 254 nm, RT1 (major) = 13.4 min, RT2 (minor) = 20.4 min. 20 [α] D = (c 0.4, C 3, er = 97:3) Anti-5g: -((2S,3R)-2,3-dichloro-3-(p-tolyl)propyl)-4-nitrobenzamide 2 R f : 0.60 (30% EtAc in hexanes, UV) 1 MR (500 Mz, CD 3 ) δ 8.30 (d, J = 8.5 z, 2), 7.91 (d, J = 8.5 z, 2), 7.31 (d, J = 8.5 z, 2), 7.19 (d, J = 8.5 z, 2), 6.50 (br s, 1), 4.99 (d, J = 8.0 z, 1), (m, 1), (ddd, J = 14.0, 6.5, 3.5 z, 1), (ddd, J = 13.5, 8.0, 5.0 z, 1), 2.34 (s, 3) 13 C MR (125 Mz, CD 3 ) δ , , , , , , , , , 64.08, 63.55, 43.90, S14

15 RMS analysis (ESI): Calculated for [M+] + : C : ; Found: Resolution of enantiomers: DAICEL Chiralcel AD- column, 15% IPA-exanes, 1.0 ml/min, 254 nm, RT1 (minor) = 14.9 min, RT2 (major) = 18.2 min. 20 [α] D = +4.0 (c 0.3, C 3, er = 91:9) 5h: -((2S,3S)-2,3-dichloro-3-phenylpropyl)-4-nitrobenzamide 2 R f : 0.50 (30% EtAc in hexanes, UV) 1 MR (500 Mz, CD 3 ) δ 8.29 (d, J = 9.0 z, 2), 7.88 (d, J = 9.0 z, 2), (m, 5), 6.50 (br s, 1), 5.18 (d, J = 5.0 z, 1), (m, 1), (ddd, J = 14.0, 7.5, 4.0 z, 1), (ddd, J = 14.0, 8.5, 4.5 z, 1) 13 C MR (125 Mz, CD 3 ) δ , , , , , , , , , 64.97, 64.25, RMS analysis (ESI): Calculated for [M+] + : C : ; Found: Resolution of enantiomers: DAICEL Chiralcel AD- column, 15% IPA-exanes, 1.0 ml/min, 254 nm, RT1 (major) = 13.5 min, RT2 (minor) = 27.6 min. 20 [α] D = (c 0.6, C 3, er = >99:1) 5i: -((2S,3S)-2,3-dichloro-3-(4-(trifluoromethyl)phenyl)propyl)-4-nitrobenzamide F 3 C 2 R f : 0.43 (30% EtAc in hexanes, UV) 1 MR (500 Mz, CD 3 ) δ 8.30 (d, J = 9.0 z, 2), 7.91 (d, J = 9.0 z, 2), 7.66 (d, J = 9 z, 2), 7.61 (d, J = 8.5 z, 2), 6.59 (br s, 1), 5.27 (d, J = 4.5 z, 1) (m, 1), (ddd, J = 14.5, 7.0, 4.0 z, 1), (ddd, J = 14.5, 8.5, 4.0 z, 1) S15

16 13 C MR (125 Mz, CD 3 ) δ , , , , (q, J CF = 32.2 z), , , (q, J CF = z), (q, J CF = 2.8 z), , 64.30, 63.03, RMS analysis (ESI): Calculated for [M+] + : C F 3 : ; Found: Resolution of enantiomers: DAICEL Chiralcel IA column, 15% IPA-exanes, 1.0 ml/min, 254 nm, RT1 (major) = 10.5 min, RT2 (minor) = 19.1 min. 20 [α] D = -5.2 (c 1.0, C 3, er = >99:1) 5j: -((2S,3R)-2,3-dichlorohexyl)-4-nitrobenzamide 2 R f : 0.56 (30% EtAc in hexanes, UV) 1 MR (500 Mz, CD 3 ) δ 8.31 (d, J = 8.5 z, 2), 7.95 (d, J = 8.5 z, 2), 6.55 (br s, 1), (ddd, J = 14.0, 7.0, 3.0 z, 1), (ddd, J = 10.0, 6.5, 3.0 z, 1), (ddd, J = 10.0, 6.5, 3.5 z, 1), (ddd, J = 14.0, 8.5, 5.0 z, 1), (m, 1), (m, 1), (m, 1), (m, 1), 0.97 (t, J = 7.0 z, 3) 13 C MR (125 Mz, CD 3 ) δ , , , , , 64.00, 63.59, 43.66, 37.21, 19.30, RMS analysis (ESI): Calculated for [M+] + : C : ; Found: Resolution of enantiomers: DAICEL Chiralcel IA column, 10% IPA-exanes, 1.0 ml/min, 254 nm, RT1 (major) = 13.0 min, RT2 (minor) = 14.5 min. 20 [α] D = (c 0.5, C 3, er = 92:7) epi-5j: -((2R,3S)-2,3-dichlorohexyl)-4-nitrobenzamide 2 R f : 0.56 (30% EtAc in hexanes, UV) 80% yield with (DQ) 2 PAL S16

17 1 MR (500 Mz, CD 3 ) δ 8.31 (d, J = 8.5 z, 2), 7.95 (d, J = 8.5 z, 2), 6.55 (br s, 1), (ddd, J = 14.0, 7.0, 3.0 z, 1), (ddd, J = 10.0, 6.5, 3.0 z, 1), (ddd, J = 10.0, 6.5, 3.5 z, 1), (ddd, J = 14.0, 8.5, 5.0 z, 1), (m, 1), (m, 1), (m, 1), (m, 1), 0.97 (t, J = 7.0 z, 3) 13 C MR (125 Mz, CD 3 ) δ , , , , , 64.00, 63.59, 43.66, 37.21, 19.30, RMS analysis (ESI): Calculated for [M+] + : C : ; Found: Resolution of enantiomers: DAICEL Chiralcel D- column, 5% IPA-exanes, 1.0 ml/min, 254 nm, RT1 (minor) = 13.0 min, RT2 (major) = 14.5 min. 20 [α] D = (c 1.0, C 3, er = 96:4) 5k: 4-bromo--((2S,3R)-2,3-dichlorohexyl)benzamide R f : 0.54 (30% EtAc in hexanes, UV) 1 MR (500 Mz, CD 3 ) δ 7.65 (d, J = 9.0 z, 2), 7.59 (d, J = 9.0 z, 2), 6.45 (br s, 1), (ddd, J = 14.0, 7.0, 3.0 z, 1), (m, 1), (ddd, J = 10.0, 6.5, 3.5 z, 1), (ddd, J = 13.5, 8.0, 4.0 z, 1), (m, 1), (m, 1), (m, 1), (m, 1), 0.95 (t, J = 7.0 z, 3) 13 C MR (125 Mz, CD 3 ) δ , , , , , 64.31, 63.70, 43.47, 37.18, 19.35, RMS analysis (ESI): Calculated for [M+] + : C : ; Found: Resolution of enantiomers: DAICEL Chiralcel AD- column, 15% IPA-exanes, 1.0 ml/min, 254 nm, RT1 (major) = 8.4 min, RT2 (minor) = 9.5 min. 20 [α] D = (c 0.9, C 3, er = 92:8) S17

18 5l: -((2S,3R)-4-(benzyloxy)-2,3-dichlorobutyl)-4-nitrobenzamide 2 R f : 0.50 (30% EtAc in hexanes, UV) 1 MR (500 Mz, CD 3 ) δ 8.26 (d, J = 8.5 z, 2), 7.86 (d, J = 8.5 z, 2), , 5), 6.63 (br s, 1), (dd, J = 22.5, 12.0 z, 2), (ddd, J = 10.5, 6.5, 4.5 z, 1), (m, 2), 3.88 (d, J = 5 z, 2), (ddd, J = 14.0, 8.0, 5.5 z, 1) 13 C MR (125 Mz, CD 3 ) δ , , , , , , , , 73.78, 70.75, 61.05, 60.37, RMS analysis (ESI): Calculated for [M+] + : C : ; Found: Resolution of enantiomers: DAICEL Chiralcel AD- column, 15% IPA-exanes, 1.0 ml/min, 254 nm, RT1 (minor) = 16.1 min, RT2 (major) = 17.6 min. 20 [α] D = +5.1 (c 0.3, C 3, er = 89:11) 5m:-((2S,3R)-2,3-dichloro-3-phenylpropyl)-4-nitrobenzamide 2 R f : 0.44 (30% EtAc in hexanes, UV) 1 MR (500 Mz, CD 3 ) δ 8.29 (d, J = 8.5 z, 2), 7.91 (d, J = 8.5 z, 2), (m, 5), 6.56 (br s, 1), 5.02 (d, J = 8 z, 1), (dt, J = 11, 3.5 z, 1), (ddd, J = 14.5, 7.0, 3.5 z, 1), (ddd, J = 13.5, 8.5, 5.0 z, 1) 13 C MR (125 Mz, CD 3 ) δ , , , , , , , , , 63.98, 63.55, RMS analysis (ESI): Calculated for [M+] + : C : ; Found: Resolution of enantiomers: DAICEL Chiralcel AD- column, 20% IPA-exanes, 1.0 ml/min, 254 nm, RT1 (minor) = 10.5 min, RT2 (major) = 11.6 min. 20 [α] D = +5.6 (c 1.0, C 3, er = 90:10) S18

19 5n: (S)--(2,3-dichloro-3-methylbutyl)-4-nitrobenzamide Me Me 2 R f : 0.50 (30% EtAc in hexanes, UV) 1 MR (500 Mz, CD 3 ) δ 8.30 (d, J = 9.0 z, 2), 7.95 (d, J = 9.0 z, 2), 6.63 (br s, 1), (ddd, J = 10.5, 7.5, 3.0 z, 1), 4.24 (dd, J = 9.5, 3.0 z, 1), (ddd, J = 14.5, 10.0, 4.5 z, 1), 1.78 (s, 3), 1.70 (s, 3) 13 C MR (125 Mz, CD 3 ) δ , , , , , 69.68, 69.44, 43.36, 31.29, RMS analysis (ESI): Calculated for [M+] + : C : ; Found: Resolution of enantiomers: DAICEL Chiralcel IA column, 2% IPA-exanes, 1.0 ml/min, 254 nm, RT1 (major) = min, RT2 (minor) = min. 20 [α] D = (c 0.8, C 3, er = 92:8) 9a: -((2S,3S)-2-bromo-3-chlorohexyl)-4-nitrobenzamide 2 R f : 0.52 (30% EtAc in hexanes, UV) 1 MR (500 Mz, CD 3 ) δ 8.31 (d, J = 8.5 z, 2), 7.95 (d, J = 8.5 z, 2), 6.62 (br s, 1), (ddd, J = 9.0, 4.0, 2.0 z, 1), (ddd, J = 15.0, 7.5, 4.5 z, 1), (m, 1), (ddd, J = 14.0, 9.0, 5.0 z, 1), (m, 2), (m, 1), (m, 1), 0.96 (t, J = 7.0 z, 3) 13 C MR (125 Mz, CD 3 ) δ , , , , , 62.70, 57.52, 45.25, 38.51, 19.67, RMS analysis (ESI): Calculated for [M+] + : C : ; Found: Resolution of enantiomers: DAICEL Chiralcel D- column, 10% IPA-exanes, 1.0 ml/min, 254 nm, RT1 (major) = 14.7 min, RT1 (minor) = 19.0 min S19

20 20 [α] D = (c 0.5, C 3, er = >99:1) Absolute stereochemistry was determined by single crystal X-ray diffraction (XRD). Crystals for XRD were obtained by crystallization from C 2 2 layered with hexanes in a silicone-coated vial. 9a': -((2S,3S)-2,3-dibromohexyl)-4-nitrobenzamide 2 R f : 0.60 (30% EtAc in hexanes, UV) 1 MR (500 Mz, CD 3 ) δ 8.31 (d, J = 8.5 z, 2), 7.94 (d, J = 8.5 z, 2), 6.61 (br s, 1), (ddd, J = 9.0, 4.0, 2.5 z, 1), (m, 2), (ddd, J = 14.5, 9.0, 5.5 z, 1), (m, 2), (m, 1), (m, 1), 0.96 (t, J = 7.5 z, 3) 13 C MR (125 Mz, CD 3 ) δ , , , , , 57.50, 56.06, 45.94, 38.68, 20.75, RMS analysis (ESI): Calculated for [M+] + : C : ; Found: Resolution of enantiomers: DAICEL Chiralcel IA column, 10% IPA-exanes, 1.0 ml/min, 254 nm, RT1 (major) = 14.7 min, RT2 (minor) = 17.9 min. 20 [α] D = (c 0.4, C 3, er = 83.0:17.0) 9g: -((2S,3S)-2-bromo-3-chloro-3-(4-(trifluoromethyl)phenyl)propyl)-4-nitrobenzamide F 3 C 2 R f : 0.60 (30% EtAc in hexanes, UV) S20

21 1 MR (500 Mz, CD 3 ) δ 8.29 (d, J = 8.0 z, 2), 7.91 (d, J = 8.0 z, 2), 7.66 (d, J = 9 z, 2), 7.61 (d, J = 8.5 z, 2), 6.63 (br s, 1), 5.29 (d, J = 4.0 z, 1) (m, 1), (ddd, J = 14.5, 7.0, 4.0 z, 1), (ddd, J = 14.5, 9.0, 5.0 z, 1), 13 C MR (125 Mz, CD 3 ) δ , , , , (q, J CF = 32.1 z), , , (q, J CF = z), (q, J CF = 3.7 z), , 63.03, 57.82, RMS analysis (ESI): Calculated for [M+] + : C : ; Found: Resolution of enantiomers: DAICEL Chiralcel AD- column, 15% IPA-exanes, 1.0 ml/min, 254 nm, RT1 (major) = 11.5 min, RT2 (minor) = 21.7 min. 20 [α] D = +2.5 (c 1.0, C 3, er = >99:1) 9j: -((2S,3R)-2-bromo-3-chlorohexyl)-4-nitrobenzamide 2 R f : 0.50 (30% EtAc in hexanes, UV) 1 MR (500 Mz, CD 3 ) δ 8.30 (d, J = 8.5 z, 2), 7.95 (d, J = 8.5 z, 2), 6.62 (br s, 1), (m, 2), (ddd, J = 10.0, 7.0, 3.5 z, 1), (ddd, J = 15.0, 10.0, 5.5 z, 1), (m, 1), (m, 1), (m, 1), (m, 1), (t, J = 7.5 z, 3) 13 C MR (125 Mz, CD 3 ) δ , , , , , 63.76, 57.32, 44.11, 38.22, 19.32, RMS analysis (ESI): Calculated for [M+] + : C : ; Found: Resolution of enantiomers: DAICEL Chiralcel IA column, 10% IPA-exanes, 1.0 ml/min, 254 nm, RT1 (major) = 13.7 min, RT2 (minor) = 15.0 min. 20 [α] D = +6.6 (c 1.0, C 3, er = 92:8) S21

22 9m: -((2S,3R)-2-bromo-3-chloro-3-phenylpropyl)-4-nitrobenzamide 2 R f : 0.50 (30% EtAc in hexanes, UV) 1 MR (500 Mz, CD 3 ) δ 8.30 (d, J = 8.5 z, 2), 7.93 (d, J = 8.5 z, 2), (m, 5), 6.57 (br s, 1), 5.08 (d, J = 9.5 z, 1), (dt, J = 12.0, 3.5 z, 1), (ddd, J = 14, 6.5, 3.0 z, 1), (ddd, J = 14.0, 8.0, 5.5 z, 1), 13 C MR (125 Mz, CD 3 ) δ , , , , , , , , , 63.62, 56.95, RMS analysis (ESI): Calculated for [M+] + : C : ; Found: Resolution of enantiomers: DAICEL Chiralcel AD- column, 20% IPA-exanes, 1.0 ml/min, 254 nm, RT1 (minor) = 11.4 min, RT2 (major) = 12.5 min. 20 [α] D = (c 0.7, C 3, er = 89:11) VIIA. Analytical data for byproduct 6a 6a: -(2-chloro-3-(2,2,2-trifluoroethoxy)hexyl)-4-nitrobenzamide 2 C 2 CF 3 R f : 0.60 (30% EtAc in hexanes, UV) 1 MR (500 Mz, CD 3 ) δ 8.30 (d, J = 8.5 z, 2), 7.93 (d, J = 8.5 z, 2), 6.68 (br s, 1), (m, 1), (ddd, J = 14.5, 7.0, 4.5 z, 1), (m, 2), (dt, J = 10.5, 3.5 z, 1), (ddd, J = 13.5, 9.0, 5.0 z, 1), (m, 1), (m, 1), (m, 2), 0.96 (t, J = 7.5 z, 3) 13 C MR (125 Mz, CD 3 ) δ , , , , (q, J CF = z), , 82.57, (q, J CF = 34.1 z), 60.76, 43.44, 32.18, 18.53, RMS analysis (ESI): Calculated for [M+] + : C F 3 : ; Found: S22

23 VIIB. Analytical data for products in non-catalyzed reaction (9b, 10b, 11b) 9b: 4-bromo--((2S,3S)-2-bromo-3-chlorohexyl)benzamide R f : 0.54 (30% EtAc in hexanes, UV) 1 MR (500 Mz, CD 3 ) δ 7.64 (d, J = 8.0 z, 2), 7.57 (d, J = 8.5 z, 2), 6.60 (br s, 1), (ddd, J = 8.5, 5.0, 2.5 z, 1), (m, 2), (ddd, J = 14, 9.0, 5.0 z, 1), (m, 2), (m, 1), (m, 1), 0.94 (t, J = 7.0 z, 3) 13 C MR (125 Mz, CD 3 ) δ , , , , , 62.74, 57.71, 45.15, 38.61, 19.65, RMS analysis (ESI): Calculated for [M+] + : C : ; Found: Resolution of enantiomers: DAICEL Chiralcel AD- column, 10% IPA-exanes, 1.0 ml/min, 254 nm, RT1 (major) = 10.2 min, RT2 (minor) = 20.8 min. 20 [α] D = (c 1.0, C 3, er = 94:6) 10b: 4-bromo--((2S,3S)-3-bromo-2-chlorohexyl)benzamide R f : 0.54 (30% EtAc in hexanes, UV) 1 MR (500 Mz, CD 3 ) δ 7.64 (d, J = 8.5 z, 2), 7.59 (d, J = 8.5 z, 2), 6.49 (br s, 1), (ddd, J = 9.0, 4.0, 2.5 z, 1), (ddd, J = 9.0, 4.5, 2.0 z, 1), (ddd, J = 14.0, 7.0, 4.5 z, 1), (ddd, J = 14.5, 9.0, 5,0 z, 1), (m, 2), (m, 1), (m, 1), 0.95 (t, J = 7.0 z, 3) 13 C MR (125 Mz, CD 3 ) δ , , , , , 63.57, 59.32, 45.80, 38.08, 20.72, RMS analysis (ESI): Calculated for [M+] + : C : ; Found: S23

24 11b: (S)-5-((S)-1-bromobutyl)-2-(4-bromophenyl)-4,5-dihydrooxazole C 3 7 R f : 0.30 (30% EtAc in hexanes, UV) 1 MR (500 Mz, CD 3 ) δ 7.80 (d, J = 8.5 z, 2), 7.55 (d, J = 8.5 z, 2), (m, 1), (dd, J = 15.0, 10.0 z, 1), (dt, J = 10.0, 3.5 z, 1), (dd, J = 15.0, 7.0 z, 1), (m, 1), (m, 1), (m, 1), (m, 1), 0.95 (t, J = 7.0 z, 3) 13 C MR (125 Mz, CD 3 ) δ , , , , , 81.21, 58.30, 56.36, 35.42, 20.78, RMS analysis (ESI): Calculated for [M+] + : C : ; Found: VIIC. Analytical data for substrate 4i 4i: (Z)-4-nitro--(3-(4-(trifluoromethyl)phenyl)allyl)benzamide F 3 C 2 R f : 0.39 (30% EtAc in hexanes, UV) 1 MR (500 Mz, CD 3 ) δ 8.20 (d, J = 8.5 z, 2), 7.88 (d, J = 8.5 z, 2), 7.58 (d, J = 7.5 z, 2), 7.34 (d, J = 7.5 z, 2), 6.67 (br s, 1), 6.63 (d, J = 12.0 z, 1), (m, 1), 4.32 (t, J = 6.0 z, 2) 13 C MR (125 Mz, CD 3 ) δ , , , , , , (q, J CF = 32.2 z), , , , (q, J CF = z), (q, J CF = 3.8 z), RMS analysis (ESI): Calculated for [M+] + : C F 3 : ; Found: S24

25 VIII. References (1) Soltanzadeh, B.; Jaganathan, A.; Staples, R. J.; Borhan, B. Angew. Chem. Int. Ed. 2015, 54, S25

26 ' 2 5a S26

27 ' 2 5a S27

28 5b S28

29 5b S29

30 2 5c S30

31 2 5c S31

32 2 5d S32

33 2 5d S33

34 Bn 2 5e S34

35 Bn 2 5e S35

36 TBDPS 2 5f S36

37 TBDPS 2 5f S37

38 2 Syn-5g S38

39 2 syn-5g S39

40 2 Anti-5g S40

41 2 Anti-5g S41

42 2 5h S42

43 2 5h S43

44 F 3 C 2 5i S44

45 F 3 C 2 5i S45

46 2 5j S46

47 2 5j S47

48 5k S48

49 5k S49

50 2 5i S50

51 2 5i S51

52 2 5m S52

53 2 5m S53

54 Me Me 2 5n S54

55 Me Me 2 5n S55

56 2 9a S56

57 2 9a S57

58 2 9a' S58

59 2 9a' S59

60 F 3 C 2 9g S60

61 F 3 C 2 9g S61

62 2 9j S62

63 2 9j S63

64 2 9m S64

65 2 9m S65

66 2 C 2 CF 3 6a S66

67 2 C 2 CF 3 6a S67

68 C 3 7 9b S68

69 C 3 7 9b S69

70 C b S70

71 C b S71

72 C b S72

73 C b S73

74 F 3 C 4i 2 S74

75 F 3 C 4i 2 S75

76 2 5a 5b S76

77 2 5c 2 5d S77

78 Bn 5e 2 TBDPS 2 5f S78

79 2 2 Syn-5g Anti-5g 2 2 Syn-5g Anti-5g S79

80 2 5h F 3 C 2 5i S80

81 2 5j 5k S81

82 5l 2 2 5m S82

83 Me Me 5n 2 2 9a S83

84 2 9a' F 3 C 2 9g S84

85 2 9j 2 9m S85