Absolute and relative facial selectivities in organocatalytic asymmetric chlorocyclization reactions

For four related 1,1-disubstituted olefins, (DHQD)2PHAL-catalyzed asymmetric chlorocyclization delivers Cl+ uniformly to one π face, but cyclizes with strong but differing net syn vs. anti addition.

(DHQD) 2 PHAL (1.56 mg, 312 μL of a 5 mg/mL solution in TFE, 2 mol%) was introduced to a suspension of DCDPH (35 mg, 0.11 mmol, 1.1 equiv) in trifluoroethanol (TFE, 2.2 mL) in a screw capped vial equipped with a stir bar at -30 °C. After stirring vigorously for 10 min, the substrate (0.10 mmol, 1.0 equiv) was added in a single portion. The vial was capped and the stirring was continued at -30 °C till the reaction was complete (TLC). The reaction was quenched by the addition of 10% aq. Na 2 SO 3 (3 mL) and diluted with DCM (3 mL). The organics were separated and the aqueous layer was extracted with DCM (3 x 3 mL). The combined organics were dried over Na 2 SO 4 , concentrated and purified by column chromatography on silica gel using EtOAc-Hexanes as the eluent to give product 2a in 96% yield and 90% ee.  141.5, 131.5, 128.7, 128.4, 128.3, 128.2, 127.3, 124.9, 87.56, 64.93, 51.04 III. Procedure for the synthesis of unsaturated amide substrate 1b:

S-5, 2-phenylprop-2-en-1-amine
Allyl bromide S-4 (4.5 g, 22.96 mmol, 1.0 equiv) dissolved in THF (85 mL (1.79 g, 27.53 mmol, 1.2 equiv) at room temperature. After TLC analysis revealed the complete consumption of starting material (~ 3 h), PPh 3 (9.04 g, 34.46 mmol, 1.5 equiv) was added to the reaction vessel. After 2 h at ambient temperature, the reaction was concentrated to remove most of the THF. The resulting suspension was diluted with aq. HCl and extracted with ether (3x). The aqueous layer was then basified by adding solid KOH and extracted with ether (3x). The combined organics were dried (Na 2 SO 4 ) and concentrated to give the crude amine, which was usually pure enough to use in the next step. Analytical data for S-5: 1 4, 139.5, 132.3, 131.5, 128.3, 111.0, 45.8.

1b, N-(2-phenylallyl)benzamide
A solution of 2-phenylprop-2-en-1-amine S-5 (1.20 g, 9.0 mmol, 1.0 equiv), triethylamine (1.04 mL, 18.0 mmol, 2.0 equiv) and a catalytic amount of DMAP in DCM (50 mL) was cooled in an ice bath. To this solution, benzoyl chloride (1.57 mL, 13.5 mmol, 1.5 equiv) was added drop wise. After the completion of the reaction, it was allowed to warm to room temperature. It was quenched with water and extracted with DCM (3 x 25 mL). The combined organics were washed with brine (1 x 30 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to give the product as a colorless solid in 89% yield after column chromatography (10% EtOAc-Hexanes).

IV. Labeling studies of 1,1-unsaturated amide:
To explore the stereocontrol in chlorocyclization reactions, we replaced one of the vinylic protons with deuterium. This leads to diastereotopic products with two stereogenic carbons, the quaternary carbon and the carbon attached to the chlorine (Scheme S1). Having two stereocenters on the final product provides the opportunity to investigate the face selectivity in the chlorination and the subsequent attack of the  9, 134.2, 131.9, 123.5, 76.7, 71.5, 27.0.

1b-D, Deuterated N-(2-phenylallyl)benzamide
A solution of labeled 2-phenylprop-2-en-1-amine 6 (50 mg, 0.37 mmol, 1.0 equiv) and pyridine (63 mg, 0.74 mmol, 2.0 equiv) in DCM (2.5 mL) was cooled in an ice bath. To this, benzoyl chloride (80 mg, 0.57 mmol, 1.5 equiv.) was added drop wise. After the addition was complete, the reaction was allowed to warm to room temperature. After 3 h, the reaction was diluted with an equal amount of water and extracted with DCM (  This result suggests that the reaction does not go through a bridged chloronium intermediate, as two diastereomers resulting from syn and anti addition were observed in the absence of any catalyst. Other conditions such as changes in chlorenium source, solvent, and concentration were utilized to investigate the syn/anti diastereoselectivity.  (Table S1, entries 1-8). Change of solvent from TFE to CHCl 3 or MeCN led to similar diastereoselectivity (Table S1, entries 1, 10-11). Other solvents such as DCM, toluene, and CHCl 3 :Hex (1:1) yield more of the anti-cyclized product (Table S1, entries 9,12-13). Dilution plays an important role in the diastereoselectivity of this reaction.
Decreasing the concentration of both substrate and DCDPH in TFE led to the formation of more syn product (Table S1,

IV.b4. Changing the electronics of the aryl group and its effect on the diastereoselectivity of non-catalyzed chlorocyclization of unsaturated amide 1a-D:
Electronic properties of the benzoyl group with the labeled amide substrate were varied to see the effect of nucleophilicity on the diastereoselectivity of this reaction. Both electron donating and withdrawing groups yield more syn product as compared to substrate 1b-D (Table S2,  General procedure for the synthesis of labeled substrates 9b-D to 11b-D: Substrates 9b-D to 11b-D were synthesized similarly to that described for substrate 1b-D with the only difference being the choice of the amine protecting groups.

D:
Substrates 12a-D to 14b-D were synthesized similarly to that described for substrate 2b-D.

13b-D, Deuterated 5-(chloromethyl)-5-phenyl-2-(p-tolyl)-4,5-dihydrooxazole
Analytical data for 13b-D: 1   mg/mL solution in TFE, 2 mol%) was then introduced. After stirring vigorously for 10 min, unsaturated amide 1b-D (24 mg, 0.10 mmol, 1.0 equiv) was added in a single portion. The vial was capped and the stirring was continued at -30 °C till the reaction was complete (TLC). The reaction was quenched by the addition of 10% aq. Na 2 SO 3 (3 mL) and diluted with DCM (3 mL). The organics were separated and the aqueous layer was extracted with DCM (3 x 3 mL). The combined organics were dried over anhydrous Na 2 SO 4 . The pure product was isolated by column chromatography on silica gel using EtOAc-Hexanes (1:19) as the eluent in 93% yield. The resulting two enantiomers (ignoring the stereochemistry at the labeled carbon (C-6) as it is not distinguishable by chiral HPLC) were separated using a chiral pack OJ-H column (5% IPA in hexanes; 0.8 mL/min; 265 nm; RT 1 = 17.9 (S enantiomer) and RT 2 = 34.3 (R enantiomer)) and an R to S ratio of 93:7 was obtained. Analytical data for 2b-D: 1  In order to obtain the ratio of four isomeric products, two groups of products epimeric at C5 (5R versus 5S) were separated by chiral HPLC [with (93:7) er favoring R configuration at C-5 as determined by crystallography]. 3 Since HPLC does not separate deuterated from non-deuterated analogs, we obtained D1En2/D2En2 (set1) and D1En1/D2En1 (set2) after HPLC purification using OJ-H chiral column (Scheme S3). Set1 contains two diastereomers (5R,6R) and (5R,6S), while set2 has diastereomers (5S,6S) and (5S,6R). Note that each set contains epimeric C6 compounds, reflecting S23 the diastereomers engendered by the deuterium labels. 1 H NMR analysis of these two sets reveal a dr of (99:1) for set1 (obtained from chiral HPLC separation of the major enantiomer at C-5), and a dr of (73:27) for set2 (obtained from chiral HPLC separation of the minor enantiomer). These diastereomeric ratios are the finalized values after correction for the amount of non-labeled product and E/Z mixture of the starting material. The corrections are described below.
Steps toward the calculation of the final corrected dr numbers are as follows. The

S25
Assuming similar stereoselectivity of E and Z isomers, the major diastereomer (  ROESY and NOESY studies on the corresponding epoxy amide 3b show that H a (2.80 ppm) has a syn orientation with the phenyl group and H b (3.10 ppm) has an anti orientation with the phenyl group. After assignment of H a and H b , the labeled substrate 2b-D as a mixture (synthesized in the presence of the (DHQD) 2 PHAL) was reduced with BH 3 .THF, followed by base treatment to yield the desired labeled epoxy amide 3b-D. 1 H NMR analysis of the epoxy amide 3b-D shows only a peak at 3.10 ppm, which suggests that the deuterium has a cis orientation with respect to the phenyl group.
Based on this finding, the deuterated carbon is assigned as the R configuration in the corresponding epoxy amide 3b-D. Since the epoxy amide is formed through the S N 2

VI.a. General Procedure for the synthesis of epoxy alcohols 3b and 3b-D:
Oxazoline 2b or 2b-D (127 mg, 0.47 mmol, 1.0 equiv, 93:7 er after chiral chromatographic separation) was placed in a pre-dried flask. 1,4-Dioxane (10 mL) and 1N hydrochloric acid (10 mL) were added to the flask. The resulting mixture was stirred for 4 h at 50 °C. After it was cooled to room temperature, the reaction mixture was neutralized with saturated NaHCO 3 and subsequently extracted six times with EtOAc.

VII. General procedure for the synthesis of carbamate substrate 1c:
A solution of di-tert-butyl dicarbonate (0.71 g, 3.14 mmol, 1.1 equiv) in dry DCM (1 mL) was added under nitrogen at 0 °C to a solution of amine S-5 (0.5 g, 2.85 mmol, 1.0 equiv) and triethylamine (0.87 mL, 6.27 mmol, 2.2 equiv) in dry DCM (2 mL). The reaction mixture was stirred at room temperature for 24 h. The solvent was removed in vacuo, and the residue was dissolved with DCM (6 mL) and water (4 mL). The aqueous layer was extracted with DCM (3 × 5 mL). The combined organic extracts were washed with water (5 mL), dried with MgSO 4 , filtered, and concentrated. The resulting mixture was purified by flash chromatography on silica gel using 10% EtOAchexane to give carbamate 1c (tert-butyl (2-phenylallyl)carbamate) in 89% yield.
Analytical data for 1c: 1    Procedure for the synthesis of carbamates 2c-D and ent-2c-D is identical to the one reported for the non-labeled 2c and ent-2c (Section XI).

XIII. (DHQD) 2 PHAL catalyzed chlorocyclization of 1c-D monitored by 1 H NMR and HPLC:
To investigate the face selectivity of the chlorenium delivery, the labeled substrate 1c-D was cyclized under both optimized catalytic conditions (i.e. cyclization in n-PrOH and in CHCl 3 /Hexane) (see manuscript for details). Analysis of product ratios was accomplished using chiral HPLC and 1 H NMR spectroscopy (after the correction for considering the E:Z ratios) similar to that explained for amide substrate 1b-D and previously reported alkenoic acid 1a-D. 2b was protected with tosyl chloride and sodium hydride, followed by cesium carbonate treatment to yield the desired labeled epoxy sulfonamide ent-3c-D. 1 H NMR analysis of the epoxy sulfonamide ent-3c-D shows only a peak at 2.75 ppm, which suggests that the deuterium has an anti orientation with respect to the phenyl group. Based on this finding, the deuterated carbon is assigned the R configuration for the corresponding epoxy sulfonamide ent-3c-D (see Figure S2b). Since the epoxide is formed through the S N 2 ring opening of the corresponding chlorohydrin intermediate, substrate ent-3c-D (major product) is assigned as the S configuration on the labeled C6 center. Similar procedure was applied to substrate 2c-D to afford epoxide 3c-D ( Figure S2c).

XVI. E/Z ratios of recovered labeled starting materials
To ensure that various syn:anti addition ratios seen as a function of starting material and reaction conditions are independent of cis-trans isomerization of the starting olefin during the course of the reaction (for example, reversibility of a putative cationic species that could stereo-randomize the starting olefin, see Scheme 3 in the main text) a detailed analysis of the starting material geometry at various reaction conversions for each reaction was performed. The data in Table S2 clearly shows that the stereochemical integrity of the starting material for labeled substrates 1b-D and 1c-D recovered during the course of Reactions B, C, and C' do not change.
"Unimolecular" and "bimolecular"label refer to the number of substrate alkene molecules involved in the scheme, not total molecularity.

XVIII. Summaries of computational modeling (b)
(DHQD) 2 Phal-catalyzed reaction: (DHQD) 2 PHAL-catalyzed chlorocyclization reaction summary. This spreadsheet summarizes the catalyzed chlorocyclization energetics as computed at the B3LYP-D3/6-31G*//PM6 level of theory with further explorations of solvation effects. All calculations were performed with the Spartan '16 quantum chemistry package. Energies for each structure are listed in kcal/mol (except for the initial total electronic energies, which are also listed in atomic units (hartrees; 1 H = 627.51 kcal/mol). All derived energy differences are shown in kcal/mol. DCDMH = Dichlorodimethylhydantoin, the chlorenium delivery reagent. TFE = 2,2,2trifluoroethanol. Alkene substrate (PhCONHCH 2 CPh=CH 2 ) energies represent the most stable conformer as determined at the EDF2/6-31G* level. Monochlorohydantoin byproduct is the lowest energy tautomer, with H on the N from which Cl had been abstracted. "Unimolecular" and "bimolecular"labels refer to the number of substrate alkene molecules involved in the scheme, not total molecularity.