Axial shielding of Pd(II) complexes enables perfect stereoretention in Suzuki-Miyaura cross-coupling of Csp3 boronic acids

Stereocontrolled Csp3 cross-coupling can fundamentally change the types of chemical structures that can be mined for molecular functions. Although considerable progress in achieving the targeted chemical reactivity has been made, controlling stereochemistry in Csp3 cross-coupling remains challenging. Here we report that ligand-based axial shielding of Pd(II) complexes enables Suzuki-Miyaura cross-coupling of unactivated Csp3 boronic acids with perfect stereoretention. This approach leverages key differences in spatial orientation between competing pathways for stereoretentive and stereoinvertive transmetalation of Csp3 boronic acids to Pd(II). We show that axial shielding enables perfectly stereoretentive cross-coupling with a range of unactivated secondary Csp3 boronic acids, as well as the stereocontrolled synthesis of xylarinic acid B and all of its Csp3 stereoisomers. We expect these ligand design principles will broadly enable the continued search for practical and effective methods for stereospecific Csp3 cross-coupling.


Supplementary Methods
Materials. Commercial reagents were purchased from Sigma-Aldrich, Fisher Scientific, Alfa Aesar, TCI America, Frontier Scientific, or Matrix Scientific, and were used without further purification, with the following exceptions. All commercially available aryl halides were purified by either column chromatography or silica gel filtration to remove baseline impurities, followed by concentration under vacuum. Ag2O was purchased from Sigma-Aldrich. A gift of Pd(P(o-tol)3)2 was donated by Johnson Matthey. Solvents were purified via passage through packed columns as described by Pangborn and coworkers 1 (THF, Et2O, CH3CN, CH2Cl2: dry neutral alumina; hexane, benzene, and toluene, dry neutral alumina and Q5 reactant; DMSO, DMF: activated molecular sieves). Acetone was dried by stirring 24 hours with boric anhydride followed by distillation. Anhydrous 1,4-dioxane was purchased from Sigma-Aldrich and used without further manipulation. All water was deionized prior to use.
General experimental procedures. Unless noted, all reactions were performed in round bottom flasks fitted with rubber septa or Teflon-lined screw-cap vials (vials: VWR catalog number 66022-300; vial caps: VWR catalog number 16198-911) under argon or nitrogen. Organic solutions were concentrated via rotary evaporation under reduced pressure with a bath temperature of 30°C unless otherwise noted. Reactions were monitored by analytical thin layer chromatography (TLC) performed using the indicated solvent on normal phase Merck silica gel 60 F254 plates (0.25mm) or reverse phase Merck silica gel 60 RP-18 F254s plates. Compounds were visualized by exposure to a UV lamp (λ = 254 nm), and/or a solution of KMnO4 and/or a solution of cerium ammonium molybdate followed by brief heating using a Varitemp heat gun. Normal phase column chromatography was performed using Merck silica gel grade 9385 60Å (230-400 mesh), and reverse phase column chromatography was performed with Luknova C-18 silica gel SGFLASHC18-1. Preparative HPLC was performed with a Waters SunFire TM Prep C18 OBD TM 5µm 30mm x 150mm column, Part No. 186002797. Chiral HPLC was performed with a Chiralcel® OD-H column (4.6mm x 250mm, 5µm particle size, part No. 14325), a Chiralcel® AD-H column (4.6mm x 250mm, 5µm particle size, part No. 19325), and a Chiralcel AD-RH column (4.6mm x 150mm, 5μm particle size, part No. 19724). Chiral GC was performed with a Cyclodex-B column (30m x 0.250mm, 0.25μm film, part. No. 112-2532).

A. Synthesis of MIDA and BIDA Boronates
To a 250-mL round-bottom flask with a stir bar was added (±)-1a (1.02 g, 10 mmol, 1.0 eq, obtained from Frontier Scientific), N-methyliminodiacetic acid (MIDA) (1.77 g, 12 mmol, 1.2 eq), DMSO (10 mL, 1.0 Molar in boronic acid), and toluene (90 mL, 0.11 Molar in boronic acid). The mixture was fitted with a Dean Stark trap, on top of which was fitted a reflux condenser. The mixture was heated to reflux and water was collected in the trap for 2 hours, at which point complete conversion of the boronic acid was confirmed by TLC (100% EtOAc, KMnO4). The toluene was then removed by rotary evaporation. H2O (75 mL) was added, and the mixture was extracted with EtOAc (5 x 75 mL). The combined organic phase was washed with H2O (5 x 75 mL). The organic phase was then dried over Na2SO4 and concentrated under vacuum to give (±)-6a as a white solid (1.49 g, 70%), which was used without purification. This material was stable in a capped vial under air on a bench top for at least 4 months.

C. Synthesis of Boronic Acids as Dioxane Solutions
Sodium alkyltrihydroxyborate (S)-7a (0.213 g, 1.50 mmol, 1.00 eq) was added to a 2 mL screw-cap vial with a stir bar. Anhydrous dioxane (1.15 mL, 1.3 Molar) was added and the slurry was vigorously stirred. BF3·OEt2 (0.185 mL, 0.213 g, 1.50 mmol, 1.00 eq) was added dropwise over 15 minutes under air. If the mixture became unstirrable, it was periodically capped and shaken by hand. After completion of the addition, the vial was capped and stirred for 20 minutes. The resulting thin suspension was filtered by passing through a Pasteur pipette containing 40 mg of Celite over a small cotton plug, using pressure from an applied air hose. The residue from the vial was washed through with additional dioxane (0.35 mL, 1.0 Molar theoretical concentration). The resulting homogeneous solution amounted to 1.15 mL. An aliquot of this solution (30 µl, 30 µmol theoretical) was combined with a standard solution DMSO-d6 and 1,4dimethoxybenzene (0.050 Molar, 0.60 mL, 30 µmol 1,4-dimethoxybenzene) in an NMR tube. The boronic acid was analyzed by 1 H-NMR with the relaxation delay (d1) set to 10 seconds. The concentration of boronic acid 1a was determined to be 1.07M, giving a yield of 82%. The only visible impurity was diethyl ether (see spectrum of (S)-1a and standard). This solution was diluted to 0.91 Molar by adding dioxane (0.20 mL) and was then transferred in a capped vial into a glovebox and used in the cross coupling step. In a stability test, this boronic acid solution was stored on the benchtop under air for 4 months and showed less than 10% decomposition.
This procedure proved to be scalable and could also be carried out in 7 mL vials using 3-4 mmol of the sodium alkyltrihydroxyborate.

D. Set-up of the Csp 3 Cross-Coupling Reaction Ligand Testing
To a stir bar-equipped 7 mL vial were added phosphine ligand (0.010 mmol, 10 mol%), Pd2dba3 (4.6 mg, 0.0050 mmol, 5 mol%), 4-bromobiphenyl 2a (23.3 mg, 0.100 mmol, 1.00 eq), and Ag2O (69.5 mg, 0.3 mmol, 3 eq). A dioxane solution of boronic acid 1a (0.91 Molar, 0.220 mL, 0.200 mmol, 2.00 eq) was added by pipette. The vial was tightly sealed with a teflon-lined screw cap and stirred at 200 rpm at 85°C for 24 hours. Upon completion, the reaction mixture was filtered through a silica gel plug in a Pasteur pipette, rinsing with HPLC grade hexanes. The filtrate was collected in a 25 mL volumetric flask and diluted with hexanes up to the mark. After thorough mixing, an aliquot of this solution was transferred to an HPLC vial and immediately subjected to HPLC analysis (OD-H chiral column, 2.0 mL/min, isocratic 100% hexanes, 214.4 nm absorbance). On each new day of HPLC analysis, a standard solution of the branched product standard was analyzed in duplicate to confirm the bulb brightness and to adjust response factors if necessary. If peak retention times drifted, standards were repeated as necessary to confirm the identity of the peaks.

Substrate Table
The reaction was assembled as described above, except using 1.5 equivalents of Ag2O (34.8 mg, 0.15 mmol). After 24 hours, the reactions were cooled and filtered through silica gel in a glass pipet, rinsing Et2O or EtOAc. An aliquot of the crude reaction mixture was first subjected to HPLC analysis to determine the branched/linear product ratio, comparing with an authentic sample of the linear product isomer. The crude reaction was then purified by column chromatography, and then the enantiospecificity was determined by chiral HPLC.
The next day, the mixture was filtered through celite, rinsing with EtOAc. The filtrate was concentrated thoroughly in vacuo to afford a viscous oil. Using formic acid (310 mL, 378 g, 8.21 mol, 26.7 eq), the crude product was transferred to a stir bar equipped 3-neck 3 liter round bottom flask. The flask was equipped with a Vigreux condenser and heated at 85°C for 2 hours. An aliquot of the reaction was examined by NMR, confirming that the deprotection was complete.
The reaction was thoroughly concentrated in vacuo to remove all formic acid. The resulting viscous red oil was dissolved in hot EtOH (1250 mL), creating a super saturated solution. Soon after, a white powder began to crash out. The mixture was cooled to 0°C and filtered through a medium porosity glass frit, rinsing with additional cold EtOH. The product was dried in vacuo to afford an offwhite powder (56.6 g, 184 mmol, 70% overall yield). Product characterization matched a previous report. 3 BIDA Recovery. After hydrolysis of BIDA boronates and the preparation of sodium alkyltrihydroxyborate salts, the BIDA ligand could be recovered in 85% yield. Specifically, BIDA boronate 5a (≥99:1 d.r., 0.933 g, 2.50 mmol) was converted to sodium alkyltrihydroxyborate salt (S)-7a by General Procedure B. After addition of saturated aqueous NH4Cl and MTBE extraction, the aqueous phase was acidified to pH 3 with 4 Molar HCl and then concentrated by rotary evaporation with a 40°C bath until precipitation began. The solution was then stirred in an ice bath for one hour. Filtration through a medium porosity glass frit followed by drying on high vacuum afforded BIDA as a white solid (0.651 g, 2.12 mmol).
Tris(2-ethylphenyl)phosphine L3. An oven dried, 50 mL 3-neck round bottom flask equipped with a stir bar was fitted with a thermometer adapter, a nitrogen inlet, and a rubber septum. The apparatus was vac-filled three times with nitrogen and charged with 1-bromo-2-ethylbenzene (0.55 mL, 740 mg, 4.0 mmol, 1.0 equiv.) and THF (6.5 mL, 1.6 Molar). The RBF was lowered into a dry ice/acetone bath and allowed to equilibrate for over 20 minutes. nbutyllithium (1.6 Molar in hexanes, 2.4 mL, 3.8 mmol, 0.95 equiv.) was added dropwise over 10 minutes, keeping temperature below -60°C. The reaction appearance changed from colorless to green. Following the addition, the reaction mixture was allowed to stir for one hour and 50 minutes in the dry ice / acetone bath.
An oven dried 40 mL vial equipped with a stir bar was backfilled with nitrogen and charged with phosphorus trichloride (0.36 mL, 0.565 g, 4.12 mmol) and THF (8.0 mL; 0.515 Molar). 2.1 mL of the resulting PCl3 solution (1.08 mmol, 0.27 eq) was transferred to the reaction mixture over 10 minutes (maintaining a temperature below -54°C). Following the addition, the reaction mixture was allowed to stir and warm to room temp overnight. The reaction mixture was cooled to 0°C in an ice / water bath and was quenched with 0.7mL water and 8mL NH4Cl following equilibration. The quenched solution was then transferred to a separatory funnel, rinsing with water and toluene. After removing the organic layer, the aqueous layer was extracted with toluene (2 x 10 mL). Combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated by rotary evaporation to afford a sticky white/yellow solid was allowed to dry overnight on high vac. The crude product was purified by normal phase column chromatography (4.5 x 9 cm silica gel column, isocratic 100% hexanes), affording the pure L3 as a white solid (251.4 mg, 0.7256 mmol, 67% yield). 1-benzyl-2-bromobenzene SI-1. This procedure was based on a previous report of the selective coupling of benzylic bromides. 4 While in an argon-filled atmosphere glovebox, Pd(PPh3)4 (0.6933 g, 0.600 mmol, 2 mol%) was massed out into a stir bar-equipped, 3-neck 500 mL round bottom flask. The flask was sealed with three septa, brought out into a fume hood, and then equipped with a reflux condenser attached to a nitrogen inlet. After the system was put under nitrogen, additional reagents and solvents were added by briefly removing a septum while under a positive nitrogen pressure. In this manner, ethanol (48 mL, 0.63 Molar), water (13 mL, 2.3 Molar), toluene (58 mL, 0.52 Molar), 2bromobenzyl bromide (7.498 g, 30.0 mmol, 1.00 eq), phenylboronic acid (3.66 g, 30.0 mmol, 1.00 eq), and an aqueous solution of sodium carbonate (3.58 g, 33.8 mmol, 1.13 eq in 34 mL H2O) were added to the reaction.
The reaction was heated to 80°C for 24 hours, cooled to room temperature, and then filtered through celite. After concentration, the crude material was diluted with H2O and extracted with Et2O. Combined organics were washed with brine, dried with Na2SO4, decanted, and reconcentrated. The product was purified by normal phase column chromatography (100% hexanes) followed by vacuum distillation using a kugelrohr, giving aryl bromide SI-1 as a clear colorless oil (4.189 g, 16.95 mmol, 56% yield). 1 Tris(2-benzyl-phenyl)phosphine L4. A flame dried, 250 mL, 1 neck round bottom flask was equipped with a stir bar, sealed with a septum, and put under nitrogen. To a separate, flame-dried 40 mL vial was added 2-benzyl-1-bromobenzene SI-1 (4.19 g, 16.95 mmol, 1.00 eq). The vial put under nitrogen, and THF (28 mL total) was used to transfer the aryl bromide to the reaction flask, with rinsing for quantitative transfer. The solution was cooled by submerging in a dry ice / acetone bath. To the -78°C mixture was added nbutyllithium (1.6 Molar in hexanes, 9.5 mL, 15.3 mmol, 0.90 eq) dropwise over 5-10 minutes, causing the reaction to turn a cloudy brownish/yellow. The reaction was allowed to stir for 1.5 hours at -78°C. Phosphorus trichloride (0.37 mL, 0.582 g, 4.24 mmol, 0.25 eq) was added neat in a dropwise manner over 2-3 minutes. The reaction was allowed to gradually warm to room temperature and stirred overnight.

SI-2.
In an argon-filled glovebox, a dry 40 mL vial was charged with LiAlD4 (84.0 mg, 2.00 mmol, 1.00 eq), followed by a stir bar. The vial was capped, brought out of the glovebox and into a fume hood, and put under nitrogen. Dry THF (1.0 mL) was added, and the mixture was cooled to 0°C in an ice/water bath. In a separate dry 40 mL vial under nitrogen, a solution was prepared of 2-bromobenzyl bromide (499.9 mg, 2.00 mmol, 1.00 eq) in dry THF (1.0 mL). This solution was then added to the LiAlD4 suspension dropwise over two minutes, rinsing with THF (1.0 mL) for quantitative transfer. After 10 minutes of stirring at 0°C, the reaction was allowed to warm to room temperature. The sides of the vial were rinsed with an additional 1.0 mL THF.
After another 10 minutes, the reaction was worked up by the Fieser method. 5 Et2O (5.3 mL) was added, and the reaction was cooled to 0°C. Deionized water (0.08 mL) was then added, followed by 15% NaOH (0.23 mL) and another portion of deionized water (0.08 mL). The mixture was then allowed to warm to room temperature and stir overnight. The next day, MgSO4 was added to soak up the remaining water. After 15 minutes of stirring, the mixture was filtered through a 2 cm long SiO2 plug, rinsing with pentane. The crude product was concentrated by rotary evaporation in a 0°C ice/water bath to retain the volatile product. This material was purified by normal phase silica gel chromatography using 100% pentane, followed by rotary evaporation in a 0°C ice/water bath to give pure product as a colorless oil of low viscosity (252. 5

L6.
A dry, stir bar-equipped 25 mL recovery flask was put under nitrogen. Aryl bromide SI-2 (224.0 mg, 1.30 mmol, 1.00 eq) was massed out in a separate dry 40 mL vial and put under nitrogen. Dry THF (1.0 mL) was added, and the solution of SI-2 was transferred to the reaction flask, using 1.2 mL THF for quantitative transfer. This solution was cooled with stirring to -78°C in a dry ice / acetone bath. nbutyllithium (1.6 M in hexanes, 0.73 mL, 1.17 mmol, 0.90 eq) was added dropwise over 5 minutes. The reaction appearance changed to cloudy and slightly off-white. After stirring for one hour and 45 minutes at -78°C, the reaction was treated with PCl3 (neat, 28.3 μL, 44.6 mg, 0.325 mmol, 0.25 eq, dropwise over 3-4 minutes). The reaction, which had turned bright orange, was allowed to stir overnight, gradually warming to room temperature over four hours.
The reaction was quenched with saturated aqueous NH4Cl (5 mL). The crude mixture was diluted with water (10 mL) and DCM (15 mL). The aqueous layer was extracted with DCM (3 x 15mL), and the combined organics were washed with brine (50 mL), dried with Na2SO4, decanted, and concentrated. The crude product was purified by normal phase column chromatography (2 cm diameter, 35 mL SiO2, isocratic 20/1 hexanes/DCM), giving the pure product as a free-flowing white powder (62.7 mg, 0.204 mmol, 63% yield).

SI-3.
In an argon-filled glovebox, a flame-dried, stir bar-equipped, 3-neck 100 mL round bottom flask was charged with LiAlD4 (420 mg, 10.0 mmol, 1.09 eq). The flask was sealed with a rubber septum, brought out of the glovebox and into a chemical fume hood, and put under nitrogen atmosphere. Dry THF (8 mL) was added, and the stirring suspension was cooled to 0°C. In a separate dry 40 mL vial under nitrogen, a solution was prepared of methyl 2-bromobenzoate (1.97 g, 9.16 mmol, 1.00 eq) and dry THF (3.5 mL). The solution was added to the LiAlD4 suspension dropwise over 5 minutes.
After stirring for an hour at 0°C, the reaction was worked up by the Fieser method. 5 Et2O (12 mL) was added. Deionized water (0.42 mL) was then added (dropwise over five minutes, causing bubbling), followed by 15% NaOH (0.42 mL) and another portion of deionized water (1.26 mL). The mixture was then allowed to warm to room temperature and stir overnight. The next day, MgSO4 was added to soak up the remaining water. After 15 minutes of stirring, the mixture was filtered through celite, rinsing with Et2O. After rotary evaporation, the crude product was purified by normal phase silica gel chromatography (3 cm diameter, 100 mL SiO2, isocratic 3/1 pentane/Et2O), giving the pure product as a fluffy white solid (1.563 g, 8

SI-4.
A flame-dried, stir bar-equipped 200 mL round bottom flask was charged with PPh3 (2.75 g, 10.5 mmol, 1.50 eq) and imidazole (0.715 g, 10.5 mmol, 1.50 eq) and put under nitrogen. Dry DCM (14 mL) was added, and the stirring mixture was cooled to 0°C. Bromine (0.54 mL, 1.68 g, 10.5 mmol) was added dropwise over five minutes, using DCM to rinse the sides of the flask. The reaction was allowed to warm to room temperature, stirred for an additional 10 minutes, and then cooled to 0°C again. A solution of the benzylic alcohol SI-3 (1.32 g, 7.00 mmol, 1.00 eq) in dry DCM (10 mL) was added dropwise over five minutes, causing a precipitate to form. Additional DCM (2.0 mL) was used to rinse for quantitative transfer of the alcohol. The reaction was allowed to warm to room temperature and stir for an additional 40 minutes.
At this point, the stir bar was removed, and the crude reaction was concentrated by rotary evaporation. Pentane (20 mL) was added to the crude product, and it was again concentrated. The crude material was purified by normal phase column chromatography (6 cm diameter, 400 mL SiO2, isocratic 100% pentane), giving the pure product as a colorless oil of low viscosity (981 mg, 3.89 mmol, 56% yield). SI-5. To a dry 40 mL vial was added LiAlH4 (56.9 mg, 1.50 mmol, 1.00 eq), followed by a stir bar. The vial was capped and put under nitrogen. Dry THF (1.0 mL) was added, and the stirring suspension was cooled to 0°C with an ice/water bath. In a separate dry 40 mL vial under nitrogen, a solution of benzylic bromide SI-4 (379 mg, 1.50 mmol, 1.00 eq) was prepared in dry THF (1.0 mL). This solution was added to the LiAlH4 vial dropwise over two minutes, using THF (1.0 mL) for quantitative transfer and THF (1.0 mL) to rinse the sides of the reaction vial.
After another 10 minutes of stirring, the reaction was worked up according the Fieser method. 5 Et2O (4.0 mL) was added. Deionized water (0.06 mL) was then added, followed by 15% NaOH (0.17 mL) and another portion of deionized water (0.06 mL). The mixture was then allowed to warm to room temperature and stir overnight. The next day, MgSO4 was added to soak up the remaining water. After 15 minutes of stirring, the mixture was filtered through a 2 cm long SiO2 plug, rinsing with pentane. The filtrate was concentrated by rotary evaporation in a 0°C ice/water bath to retain the volatile product, which was isolated without further purification as a colorless oil of low viscosity (250. 6

L7.
A dry, stir bar-equipped 25 mL recovery flask was put under nitrogen. Aryl bromide SI-5 (207.7 mg, 1.20 mmol, 1.00 eq) was massed out in a separate dry 40 mL vial and put under nitrogen. Dry THF (1.0 mL) was added, and the solution of SI-5 was transferred to the reaction flask, using 1.0 mL THF for quantitative transfer. This solution was cooled with stirring to -78°C in a dry ice / acetone bath. nbutyllithium (1.6 M in hexanes, 0.675 mL, 1.08 mmol, 0.90 eq) was added dropwise over 5 minutes. The reaction appearance changed to cloudy and slightly off-white. After stirring for one hour and 30 minutes at -78°C, the reaction was treated with PCl3 (neat, 26.2 μL, 41.2 mg, 0.300 mmol, 0.25 eq, dropwise over 3-4 minutes). The reaction, which had turned bright orange, was allowed to stir overnight, gradually warming to room temperature over four hours.
The reaction was quenched with saturated aqueous NH4Cl (5 mL). The crude mixture was diluted with water (10 mL) and DCM (15 mL). The aqueous layer was extracted with DCM (3 x 15mL), and the combined organics were washed with brine (50 mL), dried with Na2SO4, decanted, and concentrated. The crude product was purified by normal phase column chromatography (isocratic 100% hexanes), giving the pure product as a free-flowing white powder (53.0 mg, 0.169 mmol, 56% yield). SI-6. To a dry 40 mL vial was added LiAlD4 (63.0 mg, 1.50 mmol, 1.01 eq), followed by a stir bar. The vial was capped and put under nitrogen. Dry THF (1.0 mL) was added, and the stirring suspension was cooled to 0°C with an ice/water bath. In a separate dry 40 mL vial under nitrogen, a solution of benzylic bromide SI-4 (373 mg, 1.48 mmol, 1.00 eq) was prepared in dry THF (1.0 mL). This solution was added to the LiAlD4 vial dropwise over two minutes, using THF (1.0 mL) for quantitative transfer and THF (1.0 mL) to rinse the sides of the reaction vial.
After another 10 minutes of stirring, the reaction was worked up according the Fieser method. 5 Et2O (4.0 mL) was added. Deionized water (0.06 mL) was then added, followed by 15% NaOH (0.17 mL) and another portion of deionized water (0.06 mL). The mixture was then allowed to warm to room temperature and stir overnight. The next day, MgSO4 was added to soak up the remaining water. After 15 minutes of stirring, the mixture was filtered through a 2 cm long SiO2 plug, rinsing with pentane. The filtrate was concentrated by rotary evaporation in a 0°C ice/water bath to retain the volatile product, which was isolated without further purification as a colorless oil of low viscosity (238.2 mg, 1.368 mmol, 93% yield). L8. A dry, stir bar-equipped 25 mL recovery flask was put under nitrogen. Aryl bromide SI-6 (208.9 mg, 1.20 mmol, 1.00 eq) was massed out in a separate dry 40 mL vial and put under nitrogen. Dry THF (1.0 mL) was added, and the solution of SI-6 was transferred to the reaction flask, using 1.0 mL THF for quantitative transfer. This solution was cooled with stirring to -78°C in a dry ice / acetone bath. nbutyllithium (1.6 M in hexanes, 0.675 mL, 1.08 mmol, 0.90 eq) was added dropwise over five minutes. The reaction appearance changed to cloudy and slightly off-white. After stirring for one hour and 30 minutes at -78°C, the reaction was treated with PCl3 (neat, 26.2 μL, 41.2 mg, 0.300 mmol, 0.25 eq, dropwise over two minutes). The reaction, which had turned bright orange, was allowed to stir overnight, gradually warming to room temperature over four hours.
The reaction was quenched with saturated aqueous NH4Cl (5 mL). The crude mixture was diluted with water (10 mL) and DCM (15 mL). The aqueous layer was extracted with DCM (3 x 15mL), and the combined organics were washed with brine (50 mL), dried with Na2SO4, decanted, and concentrated. The crude product was purified by normal phase column chromatography (2 cm diameter, 50 mL SiO2, isocratic 100% hexanes), giving the pure product as a free-flowing white powder (53.0 mg, 0.169 mmol, 56% yield). Tris(2-methyl-4-dimethylaminophenyl)phosphine L10. This procedure was based on previously reported synthesis of this compound. 6 A dry, stir bar-equipped 50 mL 3-neck round bottom flask was fitted with a reflux condenser and put under nitrogen. N,N,3-trimethylaniline (1.45 mL, 1.352 g, 10.0 mmol, 3.03 eq) was added, followed by pyridine (5.0 mL), resulting in a clear, homogeneous, slightly yellow solution. The mixture was cooled to 0°C, and phosphorus tribromide (0.31 mL, 0.901 g, 3.33 mmol, 1.00 eq) was added in a neat fashion dropwise over three or four minutes. The reaction immediately changed to a yellow color and precipitate began to gradually form. After five minutes of stirring at 0°C, the reaction was heated to 125°C for one hour and then cooled to room temperature.
The crude reaction was diluted in benzene (50 mL) and washed with 6 N NaOH (20 mL), H2O (20 mL), and brine (20 mL). The organic layer was dried with Na2SO4, decanted, and concentrated on strong vacuum to remove all solvent. The crude material was then transferred to a small round bottom flask (50 mL) and dissolved in degassed acetone. After heating to boiling and stirring, a white powder was present that still would not dissolve. The mixture was cooled to room temperature and filtered through a medium porosity glass frit. The filtrate was reconcentrated and triturated again, and this process was repeated once more. The combined crystals were triturated with acetone and filtered again, this time under nitrogen. The crystalline product L10 was crushed to a white powder and stored under in an argon-filled glovebox (0.233 g, 0.537 mmol, 16% yield). Tris(4-isopropoxy-2-methylphenyl)phosphine L11. A solution of 1-bromo-4-isopropoxy-2methylbenzene (0.6874 g, 3.00 mmol, 1.00 eq) in dry THF (5.0 mL) in a three-neck, 100 mL round bottom flask was cooled to -78°C before adding nbutyllithium (1.6 Molar in hexanes, 1.84 mL, 2.94 mmol, 0.98 eq) dropwise over five minutes. The reaction was allowed to stir for 1 hour and 45 minutes at -78°C, resulting in a cloudy, orange/sherbet-colored suspension. A solution of phosphorus trichloride (78 μL, 0.124 g, 0.90 mmol, 0.30 eq) in THF (2.0 mL) was added to the reaction dropwise over about five minutes. The resulting clear, homogeneous orange-colored reaction was stirred for 40 minutes at -78°C and then allowed to warm to room temperature.
The reaction was quenched with saturated NH4Cl (10 mL), and diluted with H2O (20 mL) and DCM (30 mL). The aqueous layer was extracted with DCM (3x30 mL). The combined organics were washed with brine (100 mL), dried (MgSO4), filtered, and concentrated to afford a viscous yellow oil. The crude product was purified by normal phase column chromatography (5 cm diameter, 200 mL silica gel, isocratic 30/1 Hex/EtOAc), giving L11 as a white powder (0.1876 g, 0.3920 mmol, 44% yield). Tris(4-methoxy-2-methylphenyl)phosphine L12. This compound has been previously synthesized and characterized. 7 A dry, stir bar-equipped 100 mL recovery flask was charged with magnesium turnings (0.3975 g, 16.35 mmol, 1.01 eq) in an argon-filled glovebox. The flask was sealed with a septum, brought out into the hood, equipped with a reflux condenser, attached to a Schlenk line, and put under nitrogen. Dry THF (8 mL) was added, followed by 1-bromo-4-methoxy-2-methylbenzene (2.29 mL, 3.26 g, 16.2 mmol, 1.00 eq) dropwise over eight minutes. An additional 8 mL of dry THF was added. The reaction began to reflux without any external heat or initiating agent. In a separate round bottom flask, a solution of phosphorus trichloride (0.44 mL, 0.69 g, 5.0 mmol, 0.31 eq) in dry THF (14 mL) was prepared under nitrogen. After the Grignard had turned to a cloudy grey and most of the magnesium was gone (about one hour), the solution of phosphorus trichloride was added at 0°C dropwise over 10 minutes. The reaction was allowed to warm to room temperature and stirred overnight.
The next day, the reaction was quenched with addition of saturated NH4Cl (40 mL) and diluted with H2O (80 mL) and toluene (100 mL). The aqueous layer was extracted with toluene (3x100 mL), and the combined organics were washed with brine, dried with MgSO4, filtered, and concentrated. The crude product was purified by column chromatography (4 cm diameter, 130 mL silica gel, 30/1 Hex/EtOAc), giving L12 as a white powder (0.4652 g, 1.179 mmol, 24% yield). Tris(4-fluoro-2-methylphenyl)phosphine L14. A dry, stir bar-equipped 25 mL three neck round bottom flask was charged with magnesium turnings (0.1535 g, 6.314 mmol, 1.05 eq) in an argon-filled glovebox. The flask was sealed with septa, brought out into the hood, equipped with a reflux condenser, attached to a Schlenk line, and put under nitrogen. To a separate 10 mL pear flask under nitrogen was added 1-bromo-4-fluoro-2-methylbenzene (0.76 mL, 1.136 g, 6.011 mmol, 1.00 eq) and dry THF (6.0 mL). This solution was added in a dropwise fashion to the magnesium-containing flask, causing initiation of the Grignard reaction. After about 1.5 hours, the reaction had turned cloudy and a brownish/grey color and cooled to room temperature. The Grignard was added to a -78°C solution of phosphorus trichloride (0.155 mL, 0.243 g, 1.77 mmol, 0.295 eq) in THF (5.0 mL) in a 50 mL pear flask. The reaction was allowed to gradually warm to room temperature and stir overnight.
Separately, a solution of methyl 4-bromo-3-methylbenzoate (1.145 g, 5.00 mmol, 1.00 eq) in MeCN (3.0 mL) was prepared under nitrogen in a 10 mL recovery flask. A small amount of the aryl bromide solution (about 0.2 mL) was added to the zinc suspension and allowed to stir for 25 minutes at room temperature. The remainder of the aryl bromide solution was then added (dropwise over five minutes at room temperature, with rinsing 2x0.5 mL of MeCN for quantitative transfer).
After stirring at room temperature for 1 hour and 35 minutes, the reaction was monitored by NMR. A small aliquot (0.2 mL) was removed via needle and added to a solution of iodine in pentane. The vial was capped and shaken, and then 3 mL of saturated Na2S2O3 was added. The organic layer was removed, concentrated, and analyzed by 1 H-NMR in C6D6. No aryl bromide remained (complete conversion). There was approximately 75% of the aryl iodide and 25% protodehalogenated side product.
The arylzinc solution was filtered by the following procedure. First, a dry, stir bar-equipped 100 mL Schlenk flask was put under nitrogen. The arylzinc was drawn into a 24 mL syringe through a needle.
The needle was then quickly removed and replaced with a dry 0.2 micron HPLC filter with a needle on the end. The arylzinc was pushed through the filter and the needle into the receiving Schlenk flask.
To this room temperature stirring solution was added phosphorus trichloride (110 μL, 0.173 g, 1.25 mmol, 0.33 eq relative to the arylzinc as read out by NMR yield of the aryl iodide). During the addition, the reaction changed from an orange homogeneous solution to a yellow cloudy suspension. After the addition was complete, the reaction was heated to 45°C with vigorous stirring.
After one hour, the reaction was monitored by NMR. A small aliquot was removed, quenched by 1 M HCl, extracted with DCM, and concentrated. Only traces of product had formed, with most material converted to the protodehalogenated side product. The reaction was then heated to 65°C and allowed to stir overnight.
After 13 hours, the reaction was again monitored by NMR. Two aliquots were removed. One was quenched with 1 M HCl (to check for product formation), and the other was quenched with iodine (to check for consumption of the arylzinc reagent). By NMR analysis, there was a 5:5:1 ratio of arylzinc / protodehalogenated side product / triarylphosphine product. To accelerate the reaction by enhancing the nucleophilicity of the arylzinc reagent, 10,11 anhydrous lithium bromide beads (0.436 g, 5.00 mmol, 1.00 eq relative to original ArBr) in THF was added in one portion. The reaction changed from a pale, cream-colored suspension to an opaque, green/blue suspension. After another hour, the reaction was monitored by NMR using the same dual aliquot procedure. It was approximately 3:3:1 arylzinc / protodehalogenated side product / triarylphosphine product. The reaction was allowed to continue stirring at 65°C for another three hours and then cooled to room temperature. The reaction was quenched with 1 Molar HCl (30 mL) and extracted with DCM (3x30 mL). The combined organics were washed with H2O (100 mL) and brine (100 mL), dried with Na2SO4, decanted, and concentrated. The crude material was dried on high vac overnight.
The reaction was cooled to 0°C and quenched by addition of H2O (0.8 mL) while under nitrogen. The septum was then removed, and saturated NH4Cl (10 mL) was added. The reaction was diluted using H2O (20 mL) and toluene (20 mL). After extraction of the aqueous layer (3x30 mL toluene), the combined organics were washed with brine (100 mL), dried (MgSO4), filtered, and concentrated to afford a mixture of a yellow oil and white crystalline product. The crude reaction was purified by normal phase column chromatography (150 mL silica gel, isocratic 100% hexanes). The ligand was further purified via recrystallization by dissolving in a minimal amount of boiling MeOH, cooling to 0°C, and filtering, giving L17 a white crystalline product (0.2615 g, 0.5144 mmol, 34% yield). Tris(2-methyl-4-cyanophenyl)phosphine L18. To a dry 50 mL, 3-neck, stir bar-equipped round bottom flask was added 4-bromo-3-methylbenzonitrile (0.9803 g, 5.00 mmol, 1.00 eq). The aryl bromide was put under nitrogen, dry THF (5.0 mL) was added, and the stirring solution was cooled to 0°C in an ice/water bath. iPrMgCl • LiCl (1.3 Molar in THF, 3.85 mL, 5.00 mmol, 1.00 eq) was added (dropwise over 20 minutes), causing the reaction appearance to change to a cloudy, dark yellow. The reaction was allowed to continue stirring at 0°C. The reaction was monitored by NMR by removing a small aliquot and reacting with a mixture of iodine in pentane. After quenching with saturated Na2S2O4, the organic layer was separated and concentrated. 1 H NMR was used to quantify the aryl iodide (as a readout for the reactive organometallic reagent), remaining aryl bromide, and protodehalogenated side product.
After seven hours, the reaction was cooled to -78°C in a dry ice / acetone bath. Phosphorus trichloride (50 μL, 0.0785 g, 0.572 mmol, 0.24 eq relative to aryl Grignard as readout by NMR yield of corresponding aryl iodide) was added (neat, dropwise over 2 minutes). The reaction changed from an orange cloudy appearance to a yellow cloudy appearance. The reaction was allowed to warm to room temperature and stir overnight. Nine hours later, the crude reaction was filtered through celite (20 mL), rinsing with DCM (100 mL). The filrate was concentrated to give a viscous orange oil. The crude product was purified by normal phase column chromatography (5 cm diameter, 300 mL silica gel, isocratic 8/1 Hex), giving L18 as a white powder (40.4 mg, 0.106 mmol, 19% yield). 1 H NMR (500 MHz, C6D6) δ 6.80-6.76 (m, 6H), 6.27 (dd, J = 8.0, 3.8 Hz, 3H), 1.86 (s, 9H). Tris(4-chloro-2-methylphenyl)phosphine SI-7. A dry, stir bar-equipped 50 mL Schlenk flask was sealed with a rubber septum and vac-filled with nitrogen three times. In a separate dry 40 mL vial, 2-bromo-5chlorotoluene (2.055 g, 10.0 mmol, 1.00 eq) was massed out. The vial was likewise put under nitrogen, and dry THF (16.7 mL total, 0.60 Molar) was used to transfer the aryl bromide to the Schlenk flask. The solution was cooled with stirring to -78°C in a dry ice / acetone bath. To this stirring solution was added n-butyllithium (1.6 Molar in hexanes, 5.6 mL, 9.0 mmol, 0.90 eq, dropwise over 10 minutes), causing a change in the reaction appearance from clear / colorless to opaque / cream-colored. After additional stirring at -78°C for 1 hour and 50 minutes, PCl3 (0.218 mL, 0.343 g, 2.50 mmol, 2.50 eq) was added (neat, dropwise over 3-4 minutes). The now opaque orange suspension was allowed to gradually warm to room temperature with stirring.
The reaction was heated to 80°C for 12 hours and then filtered through celite, rinsing with Et2O. After concentration, the crude material was diluted with H2O (30 mL) and extracted with Et2O (3x30 mL). Combined organics were washed with brine (100 mL), dried with Na2SO4, decanted, and reconcentrated. The crude product was purified by normal phase column chromatography (5 cm diameter, 300 mL silica gel, isocratic 4/1 Hex/DCM, Rf = 0.27), giving SI-9 as a clear colorless oil (0.7136 g, 2.575 mmol, 52% yield). Tris(2-benzyl-4-methoxyphenyl)phosphine L20. A flame dried, 25 mL recovery flask was equipped with a stir bar, sealed with a septum, and put under nitrogen. To a separate, flame-dried 40 mL vial was added 2-benzyl-1-bromo-4-methoxybenzene (0.6762 g, 2.44 mmol, 1.00 eq). The vial put under nitrogen, and THF (4.1 mL total) was used to transfer the aryl bromide to the reaction flask, with rinsing for quantitative transfer. The solution was cooled to -78°C by submerging in a dry ice / acetone bath, and then nbutyllithium (1.6 Molar in hexanes, 1.37 mL, 2.20 mmol, 0.90 eq) was added dropwise over 5-10 minutes. The reaction was allowed to stir for 1.5 hours at -78°C. Phosphorus trichloride (53.2 μL, 83.8 mg, 0.610 mmol, 0.25 eq) was added neat in a dropwise manner over 2-3 minutes. The reaction was allowed to gradually warm to room temperature and stirred overnight.
The reaction was heated to 80°C for 12 hours and then filtered through celite, rinsing with Et2O. After concentration, the crude material was diluted with H2O (30 mL) and extracted with Et2O (3x30 mL). Combined organics were washed with brine (100 mL), dried with Na2SO4, decanted, and reconcentrated. The crude product was purified by normal phase column chromatography (5 cm diameter, 300 mL silica gel, isocratic 100% hexanes) followed by reverse phase column chromatography (3 cm diameter, 50 mL C18 silica gel, isocratic 3/1 MeCN/H2O, Rf = 0.25, extracting with 4x100 mL pentane and drying with Na2SO4), giving SI-11 as a clear colorless oil (0.5966 g, 2.250 mmol, 49% yield). Tris(2-benzyl-4-fluorophenyl)phosphine L21. A flame dried, 25 mL recovery flask was equipped with a stir bar, sealed with a septum, and put under nitrogen. To a separate, flame-dried 40 mL vial was added 2-benzyl-1-bromo-4-fluorobenzene (0.5583 g, 2.106 mmol, 1.00 eq). The vial put under nitrogen, and THF (3.5 mL total) was used to transfer the aryl bromide to the reaction flask, with rinsing for quantitative transfer. The solution was cooled by submerging in a dry ice / acetone bath. To the -78°C mixture was added nbutyllithium (1.6 Molar in hexanes, 1.18 mL, 1.895 mmol, 0.90 eq) dropwise over 5-10 minutes. The reaction was allowed to stir for 1.5 hours at -78°C. Phosphorus trichloride (45.9 μL, 72.3 mg, 0.527 mmol, 0.25 eq) was added neat in a dropwise manner over 2-3 minutes. The reaction was allowed to gradually warm to room temperature and stirred overnight.
The reaction was heated to 80°C for 15 hours and then filtered through celite, rinsing with Et2O. After concentration, the crude material was diluted with H2O and extracted with Et2O. Combined organics were washed with brine, dried with Na2SO4, decanted, and reconcentrated. The crude product was purified by normal phase column chromatography (isocratic 100% hexanes), giving SI-13 as a clear colorless oil (0.3895 g, 1.176 mmol, 36% yield). Tris(2-benzyl-4-(trifluoromethoxy)phenyl)phosphine L22. A flame dried, 25 mL recovery flask was equipped with a stir bar, sealed with a septum, and put under nitrogen. To a separate, flame-dried 40 mL vial was added 2-benzyl-1-bromo-4-(trifluoromethoxy)benzene (0.4368 g, 1.319 mmol, 1.00 eq). The vial put under nitrogen, and THF (2.2 mL total) was used to transfer the aryl bromide to the reaction flask, with rinsing for quantitative transfer. The solution was cooled by submerging in a dry ice / acetone bath. To the -78°C mixture was added nbutyllithium (1.6 Molar in hexanes, 0.74 mL, 1.19 mmol, 0.90 eq) dropwise over 5-10 minutes. The reaction was allowed to stir for 1.5 hours at -78°C. Phosphorus trichloride (28.8 μL, 45.3 mg, 0.330 mmol, 0.25 eq) was added neat in a dropwise manner over 2-3 minutes. The reaction was allowed to gradually warm to room temperature and stirred overnight.
At this point, TLC indicated that the reaction had gone to full conversion. The mixture was then filtered through celite (rinsing with hexanes) and concentrated in vacuo. The crude product was purified by normal phase column chromatography (isocratic 100% hexanes), giving SI-14 as a white solid (24.32 g, 77.2 mmol, 79% yield). Tris(2-benzyl-4-(trifluoromethyl)phenyl)phosphine L23. To a suspension of magnesium powder (0.170 g, 7.00 mmol, 1.02 eq) in THF (14 mL) in a dry 40 mL vial was added 2-benzyl-1-bromo-4-(trifluoromethyl)benzene. After addition of catalytic iodine and brief heating, the Grignard reaction initiated. The reaction was allowed to stir overnight at room temperature. The next day, a small aliquot was quenched with H2O and analyzed by TLC (100% hexanes), showing complete consumption of the aryl bromide. The reaction was submerged in a dry ice / acetone bath, and upon cooling to -78°C, phosphorus trichloride (0.198 mL, 0.3109 g, 2.20 mmol, 0.32 eq) was added dropwise. The reaction was stirred for one hour at -78°C and then at room temperature overnight.
The next day, an orange solid was visible in the reaction. TLC of a quenched aliquot (5% EtOAc in hexanes) showed complete consumption of the dehalogenated intermediate. Saturated NH4Cl and H2O were added, and the crude mixture was extracted with EtOAc twice. The combined organic layers were dried with Na2SO4 and concentrated to afford a red oil. This material was filtered through a plug of silica gel, rinsing with 5% EtOAc in hexanes to remove the red baseline side products. After concentration to an oil and application of high vac to remove solvent residue, the crude product was recrystallized from hot methanol (7 mL). After cooling for 30 minutes in an ice bath, the mixture was filtered through a medium porosity glass frit to give L23 as a white solid (0.530 grams, 0.720 mmol, 33% yield).

Determination of Response Factors
All standard solutions were prepared by dissolving the compounds in HPLC hexanes in 25  Cross-coupling reactions were assembled per general procedure D, using boronic acid (S)-1a in ≥99:1 e.r prepared by general procedure C. After 24 hours, the reactions were cooled to room temperature and filtered through a plug of silica gel in a glass pipet, rinsing with HPLC grade hexanes. The filtrate was collected in 25 mL volumetric flasks and further diluted with HPLC grade hexanes to the 25 mL mark. After thorough mixing, an aliquot of this solution was transferred to an HPLC vial and immediately subjected to HPLC analysis using the same conditions as above (OD-H chiral column, 2.0 mL/min, isocratic 100% hexanes, 214.4 nm absorbance). On each new day of HPLC analysis, a standard solution of the branched product standard was analyzed in duplicate to confirm the bulb brightness and to adjust response factors if necessary. If peak retention times drifted, standards were repeated as necessary to confirm the identity of the peaks. The BIDA boronate 5a, 99:1 d.r., was hydrolyzed to the boronic acid (S)-1a as in general procedure B. This boronic acid was then converted to the potassium (S)-2-butyltrifluoroborate (S)-1a' by a reported method. 14 The chiral trifluoroborate salt was cross-coupled using the reaction conditions recently reported to proceed with stereoinversion. 15 The trifluoroborate salt (94 mg, 0.57 mmol, 1.5 eq), 4-chlorobiphenyl (72 mg, 0.38 mmol, 1.0 eq), the palladacycle 16 (11 mg, 0.019 mmol, 5 mol%), toluene (0.76 mL, 0.5 M), H2O (0.38 mL, 1.0 M), and K2CO3 (157 mg, 1.14 mmol, 3.0 eq) were combined under argon in a 7 mL screw-cap vial with a stir bar. The vial was capped and stirred at 100°C for 24 hours. TLC (100% hexanes) showed complete conversion of the aryl chloride. The aqueous layer was extracted twice with hexanes. The combined organic layers were dried with sodium sulfate and concentrated under vacuum. The crude product was purified by silica column using 100% pentane, giving (R)-3a (65 mg, 0.309 mmol, 81% yield). NMR spectra were identical to those of the (S) enantiomer.
Using the potassium trifluoroborate salt made from BIDA boronate 5a of 99:1 d.r., the coupling product (R)-3a had an e.r. of 96:4 (94% enantiospecificity), as determined by Chiralcel OD-H column, 100% hexanes, 2.0mL/min., 210nm absorbance. The absolute configuration of the major enantiomer was identified as (R), having identified the retention time of the (S) enantiomer by independent synthesis. Minor: 5.7, Major: 9.3. This independently confirms that the cross-coupling conditions developed by Biscoe results in stereoinversion.

Synthesis and Characterization of Boron-Containing Compounds
MIDA Boronate SI-15. To zinc dust (3.24 g, 49.5 mmol, 3.41 eq) in a nitrogen-purged 40 mL vial with stir bar were added trimethylsilyl chloride (100 μL, 120 mg, 1.1 mmol, 8 mol%) and 1,2-dibromoethane (100 μL, 220 mg, 1.2 mmol, 8 mol%) by syringe. Anhydrous THF (16 mL) was added, followed by 1-iodo-3,3,3trifluoropropane (3.8 g, 17.0 mmol, 1.17 eq) portionwise at RT with stirring over 20 min, keeping the exotherm below 50 °C. The suspension was then stirred for 1 h at 50 °C. To a separate 100 mL round bottom flask purged with nitrogen containing a stir bar were added RuPhos (655 mg, 1.40 mmol, 10 mol%), Pd2dba3 (629 mg, 0.687 mmol, 5 mol%), and DMF (20 mL). This was stirred for 30 min at 23 °C. Trans-2-bromo-1-methylvinyl MIDA boronate (Aldrich cat. no. 763853, 3.79 g, 14.5 mmol, 1.00 eq) was then added to this solution in 13 mL DMF. The alkyl zinc suspension was filtered through a syringe filter and the filtrate was added to the DMF solution. The remaining alkylzinc solution was washed over with additional THF (2 mL). The reaction was then stirred for 24 h at 50 °C, after which time nearly complete conversion of the vinyl bromide was observed by TLC (C18 plate, 2:1 H2O:MeCN, KMnO4 stain). In a separatory funnel, the reaction was diluted with EtOAc and saturated aqueous NH4Cl was added. The aqueous phase was extracted twice with EtOAc. The combined organic phase was washed three times with H2O, each time adding a few mL of brine to break the emulsion. The organic phase was dried with Na2SO4, concentrated to a dark orange foam, then dissolved in DCM and adsorbed onto celite. The celite pad was loaded onto a C18 silica column of 100 mL volume, eluting with a gradient of 30% to 60% MeCN in H2O. The product-containing fractions were combined and solid NaCl was added to induce phase separation. The organic phase was separated and the aqueous layer extracted with EtOAc (×2). The combined organic phases were dried and concentrated to give SI-15 as a yellow solid (2.91 g, 9.93 mmol 68% yield).  3 g). The flask was sealed with a rubber septum and purged with nitrogen. Methanol (30 mL) was added via syringe. A balloon of hydrogen was affixed by needle and the headspace was purged with hydrogen. The balloon was refilled with hydrogen and affixed to the reaction again. The black suspension was stirred for two hours at 23°C. Monitoring the reaction by TLC (100% EtOAc, KMnO4) showed complete conversion. The headspace was purged with nitrogen and the reaction was filtered through a silica plug twice, washing with EtOAc. The flow-through was concentrated to give 6b as a white solid (2.34 g, 7.93 mmol, 90% yield). BIDA Boronate 5b. To a 100-mL round-bottom flask with a stir bar was added MIDA boronate (±)-6b (2.07 g, 7.01 mmol), THF (35 mL, 0.20 Molar) and freshly prepared 1M NaOH (35 mL, 5.0 eq). The mixture was stirred at 23 °C until complete conversion was confirmed by TLC (100% EtOAc, KMnO4). THF was removed under rotary evaporation (bath temperature 40°C). When most of the THF was removed, the receiving flask was emptied and dried and rotary evaporation was then continued until water condensation began to collect in the receiving flask. Saturated NH4Cl (35 mL) was added to the resulting aqueous solution and this was extracted with MTBE (4x35 mL) in a separatory funnel. The organic phase was dried over Na2SO4, filtered, and concentrated to an oil. The oil was combined with BIDA (2.15 g, 7.04 mmol, 1.0 eq), MgSO4 (2.0 g, 16.6 mmol, 2.4 eq), and anhydrous MeCN (14 mL, 0.50 Molar) in a 40 mL vial and stirred at 50 °C overnight. The reaction was filtered through fluorosil in a glass frit, rinsing with EtOAc. The filtrate was concentrate to a white foam. The two diastereomers were resolved by silica gel column (125 g silica, 1:1 Hex/EtOAc). The diastereomer with the higher Rf was isolated as 5b (1.19 g, 2.61 mmol, 37%). The stereochemistry of the C2 center of 5b was assigned by analogy to the other BIDA boronates resolved by silica gel column. 1 H-NMR in CDCl3 showed a diastereomeric ratio of ≥99:1 by integrating the methyl doublets of 5b and epi-5b at 0.87 and 0.98 ppm, respectively. The absolute stereochemistry at the boron-bearing carbon was tentatively assigned based on analogy to other BIDA boronates.   Pinacol boronic ester SI-16. The pinacol boronic ester was synthesized according to a modified literature procedure. 17 In an argon-filled glovebox, sodium tert-butoxide (9.652 g, 100.4 mmol, 3.15 eq) was added to a dry, stir bar-equipped 500 mL round bottom flask. In a separate dry 300 mL round bottom flask, a mixture was prepared containing Et(Bpin)2 (12.23 g, 43.37 mmol, 1.36 eq) and 5benzyloxypentyl bromide 18 (8.20 g, 31.9 mmol, 1.00 eq). Both flasks were sealed with rubber septa, brought out into a fume hood, and connected to nitrogen lines. To the flask containing NaOt-Bu was added anhydrous THF (97 mL), and the suspension was cooled to 0°C in an ice / water bath. Additional THF (25 mL) was added to the Et(Bpin)2 / alkyl bromide mixture, and the resulting solution was transferred (gradually over six minutes, using an additional 25 mL THF for quantitative transfer) into the flask containing NaOt-Bu. During this time, a precipitate began to form. The reaction was allowed to stir overnight, gradually warming to room temperature.
The next day, the reaction was diluted with Et2O (250 mL) and filtered through a pad of celite to remove salts. The filtrate was concentrated thoroughly in vacuo, giving a viscous orange oil. This crude product was purified by column chromatography (1 Liter silica gel, 10 cm diameter, isocratic 30:10:2 Hex/DCM/Et2O, Rf = 0.25), affording SI-16 as a clear colorless oil (7.68 g, 23.1 mmol, 72% yield). BIDA Boronate 5c. The pinacol boronic ester SI-16 (6.68 g, 20.1 mmol, 1.00 eq) was added to a stir barequipped 1 Liter round bottom flask. THF (84 mL, 0.24 M), H2O (30 mL, 0.68 M), and sodium periodate (21.5 g, 100.5 mmol, 5.00 eq) were added. To the resulting stirring mixture was added concentrated HCl (12 Molar, 4.2 mL, 50.4 mmol, 2.5 eq). The reaction was allowed to stir at room temperature for two hours. Monitoring the reaction by TLC showed the formation of boronic acid (with 1:1 Hex/EtOAc) and consumption of starting material (with 5/1 Hex/EtOAc). Solvent was removed by rotary evaporation. The aqueous mixture was diluted with addition water and extracted with methyl tert-butyl ether three times. Combined organic layers were washed with water six times to remove any traces of the oxidant before finally drying with Na2SO4 and performing a solvet switch to dry acetonitrile (200 mL, 0.10 Molar). To this solution was added a stir bar, magnesium sulfate (8.04 g, 66.8 mmol, 3.3 eq), and BIDA (6.18 g, 20.2 mmol, 1.00 eq). The reaction was sealed with a rubber septum and vac-filled with nitrogen (using brief cycles to avoid solvent evaporation). The reaction was stirred overnight at 60°C. The next day, the reaction was filtered through a pad of silica gel, rinsing with EtOAc. The crude product was resolved by normal phase column chromatography (1/1.3 Hex/EtOAc), giving a fraction of mostly the first diastereomer and another fraction of mostly the second diastereomer. The first diastereomer was repurified with two more columns (1/1.2 Hex/EtOAc and 1/1.1 Hex/EtOAc, Rf = 0.30), giving the pure product as a sticky foam (3.29 g, 6.31 mmol, 31% yield). 1 H-NMR in CDCl3 showed a diastereomeric ratio of ≥99:1 by integrating the methyl signals of 5c and epi-5c at 0.86 and 0.98 ppm, respectively. The absolute stereochemistry at the boron-bearing carbon was tentatively assigned based on analogy to other BIDA boronates.  BIDA Boronate 5d. AcOH (11.7 mL, 12.3 g, 204 mmol, 0.82 eq.) was added as a single portion to a slurry of NaIO4 (125 g, 584 mmol, 2.3 eq.) and pinacol boronic ester SI-17 19 (62.8 g, 249 mmol, 1.00 eq.) in THF (1.5 L, 0.17 Molar). The reaction mixture was stirred at room temperature, filtered to remove salts and the filter cake washed with Et2O (200 mL). The filtrate was concentrated in vacuo and then partitioned between H2O (500 mL) and methyl tert-butyl ether (1 L). The organic layer was separated, and then the aqueous phase was extracted with a MTBE (1 L). The combined organics were washed with water (5x300 mL) until free of peroxide (as determined by peroxide test strips). The organics were diluted with DMSO (196 mL, 1.3 Molar) and concentrated in vacuo to afford a DMSO solution of boronic acid. The DMSO solution was diluted with toluene (2.1 L, 0.12 Molar) and BIDA (50 g, 163 mmol, 0.65 eq.) was added. The reaction mixture was then heated at reflux with a Dean-Stark Trap for 3 hours. The reaction mixture was concentrated in vacuo to afford 90 g of crude material which was purified with the following gradient elution of hexanes/EtOAc (80:20 3L, 70:30 2L, 60:40 1L, 55:45 1L, 50:50 1L, 45:55 1L, 30:70 1L), affording the mostly resolved BIDA boronate (12.5 g, 28.3 mmol 17% yield, ~97:3 dr) after 5 columns. This material was then suspended in boiling hexanes (3 L), and a minimal amount of EtOAc (~90 mL) was added to effect dissolution. The mixture was cooled to room temperature, cooled in an ice bath for one hour, and then filtered to give the BIDA boronate. After a second crop was recrystallized, the product was isolated as a white powder (8.66 g, 20.1 mmol, 12% yield). 1 H-NMR in DMSO-d6 showed a diastereomeric ratio of ≥99:1 by integrating the methyl signals of 5d and epi-5d at 0.72 and 0.80 ppm, respectively.  was added dropwise, the reaction mixture was warmed to room temperature and stirred fro 30 mins at which point 300 mL 1M HCl was added. The organic layer was separated, and the aqueous layer extracted with Et2O (2 x 100 mL), the organics were combined, dried (Na2SO4) and decanted into a 500 mL RBF. DMSO (40 mL) was added to the flask and the Et2O was removed in vacuo. MIDA (1.47 g, 10 mmol) and benzene (95 mL) were added and the reaction mixture heated under dean-stark conditions for 3h. The reaction mixture was diluted with EtOAc (200 mL) and washed with water (4 x 50 mL), dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in the minimum amount of acetone and Et2O/Hexanes (1:1, 300 mL) was added causing precipitation of 6e which was collected by vacuum filtration on a fine porosity fritted glass funnel as a white crystalline solid (530 mg, 2.33 mmol, 23% yield).  The BIDA boronates corresponding to boronic acid 1g were not readily separable. Boronic acid 1g was prepared in non-racemic form through the following process.
Pinacol boronic ester (+)-SI-18. According to the procedure of Aggarwal and co-workers, 19 n-propyl carbamate 19 (3.29 g, 17.6 mmol, 1.2 eq.) and (-)-spartiene (4.20 mL, 17.6 mmol, 1.2 eq.) were dissolved in Et2O (86 mL) and s-BuLi (13.5 mL, 1.6M in cyclohexane, 21.6 mmol, 1.5 eq) was added dropwise at −78 °C. After five hours, n-PrBpin (2.50 g, 14.7 mmol, 1.0 eq.) was added dropwise. The reaction mixture was stirred for one more hour at −78 °C before warming to room temperature, and then a biphasic solution of MgBr2 MIDA boronate (+)-6g. A flame dried, stir bar-equipped 3-neck 500mL RBF was sealed with septa, fitted with a Schlenk adaptor, and put under nitrogen via three vac-fill cycles. Separately, pinacol boronic ester (+)-SI-18 (0.849 g, 4.00 mmol, 1.00 eq) was massed out into a dry 40 mL vial and likewise put under nitrogen. (+)-SI-18 was transferred to the RBF using DCM, and then additional DCM was added to reach 51 mL. The stirring solution was cooled to 0°C with an ice/water bath, and then BBr3 (1.0 M in DCM, 20.8 mL, 20.8 mmol, 5.2 eq) was added (dropwise over 10 minutes). The reaction was stirred for another 10 minutes a 0°C and then allowed to warm to room temperature and stirred for an additional hour.
At this point, TLC confirmed that the starting material was consumed (4/1 Hex/DCM) and that boronic acid was present (1/1 Hex/EtOAc). The reaction was cooled to 0°C and quenched with H2O (120 mL). Additional H2O (80 mL) and methyl tert-butyl ether (200 mL) were added, and the layers were mixed and separated. The organic layer was washed with 0.1 Molar HCl (200 mL) and then H2O (200 mL). The organic layer was then dried with Na2SO4, decanted, and partially concentrated to a volume of 20 mL. Toluene (21 mL) and DMSO (2 mL) were added, and then the remaining MTBE and DCM were removed by rotary evaporation. The resulting solution (in a 100 mL recovery flask) was charged with a stir bar and MIDA. The flask was then equipped with a Dean Stark trap and reflux condenser. After refluxing for 1.5 hours, TLC confirmed that the boronic acid was gone (1/1 Hex/EtOAc) and that MIDA boronate was present (100% EtOAc). The stir bar was removed, and then toluene was removed by rotary evaporation using the pump cart.
This crude ester (3S)-SI-20 was determined to be 97. 2  BIDA boronate (1S, 2S)-5l. 1.07 g (5 mmol) of racemic potassium trans-2-methylcyclohexyltrifluoroborate (95% purity, Frontier Scientific) was combined with 25 mL of H 2 O and 1.07 g of silica gel. The suspension was stirred at 23 °C for 20 min. 10mL of MTBE was added and the mixture was filtered through a pad of Celite with a washing of MTBE to remove the silica. The aqueous layer was extracted with MTBE and the combined organic layers were dried over sodium sulfate and concentrated under vacuum to 5 mL. This crude solution of boronic acid was used directly in the next step, forming 7l of ~1:1 d.r. by general procedure A. After work up, the crude material was subjected to resolution by silica column using a gradient of 10% to 70% EtOAc in hexanes. Fractions were analyzed by TLC using 1:1 EtOAc:hexanes and KMnO 4 stain. 620 mg (1.5 mmol) of the top diastereomer was isolated as a white foam in 30% yield. 1 H-NMR integration of the signals at 0.71 and 0.45 ppm showed none of the bottom diastereomer. The absolute configuration of the C1 and C2 stereocenters was assigned by x-ray crystal structure of the corresponding MIDA boronate.

Synthesis and Characterization of Cross-Coupled Products
Boronic acid (S)-1a (≥99:1 e.r.) was prepared in 77% yield by general procedure C and coupled to organohalide 2a to give product (+)-3a by general procedure D.  Boronic acid (S)-1c (≥99:1 e.r.) was prepared in 71% yield by general procedure C and coupled to organohalide 2a to give product (+)-3c by general procedure D.  Boronic acid 1e was prepared by general procedure C and coupled to organohalide 2a to give product 3e by general procedure D. The product was isolated in 25% yield (11 mg) by purification with normal phase flash chromatography (hexanes) as a mixture with unreacted aryl halide.
A duplicate run of the reaction gave an isolated yield of 30%. Boronic acid 1g (97.2:2.8 e.r.) was prepared in 76% yield by general procedure C and coupled to organohalide 2a to give product (+)-3g by general procedure D. The regioisomeric product ratio of the crude reaction (3-hexyl : 2-hexyl : 1-hexyl) was determined to be 220/4.7/1 by GC (Cyclodex-B column, isothermal 170°C). 3-hexyl = 13.5 minutes; 2-hexyl = 15.0 minutes; 1-hexyl = 20.3 minutes). The product was isolated in 54% yield (12  3i was made from 1i (prepared by general procedure C) and 2b by general procedure D in 44% yield (11.7 mg). The product was isolated by reverse-phase MPLC with 13 g of C18 silica using a gradient of 1: 3j was made from 1j (prepared by general procedure C) and 2b by general procedure D in 61% yield (17.1 mg). The product was isolated by reverse-phase MPLC with 13 g of C18 silica using a gradient of 1:1 MeCN:H2O to 100% MeCN. A 1 mmol scale reaction gave 3j in 42% NMR yield (118 mg) after partial purification using reverse-phase MPLC, which gave a mixture of the product with a small amounts of unidentified side products. The NMR yield of this partially purified product was obtained using 1,4dimethoxybenzene as an internal standard. 3k was made from 1k (prepared by general procedure C) and 2b by general procedure D in 68% yield (20.0 mg). The product was isolated by reverse-phase MPLC with 13 g of C18 silica using a gradient of 1: (1S, 2S)-3l was made from (1S, 2S)-1l and 2a by general procedure D in 28% yield (7.0 mg). The product was isolated by preparative HPLC using 80:20 MeOH:H2O with a 25 mL/minute flow rate. The retention time of the desired product was 30 minutes. The isomeric product was isolated in 9% yield. These were the two major coupling products seen in the reaction mixture. Their NMR spectra matched those previously reported. 14 When the crude reaction mixture was subjected to reverse-phase MPLC, a 42% yield of product isomers resulted. This mixture showed 5 peaks with the mass of the coupled product. In addition, 31% yield of biphenyl was detected by quantitative HPLC assay. This side product presumably arises from β-hydride elimination of the LnPd II (Alkyl)(Ar) followed by reductive elimination of the resulting LnPd II (Alkyl)(Ar).             The mixture was stirred until the solids dissolved and transferred to a separatory funnel with Et2O (10 mL). After phase separation, the aqueous layer was extracted with Et2O (2x30 mL). The organics were washed with H2O (30 mL), brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified on a silica gel column (isocratic 15% EtOAc in hexanes). Mixed fractions were combined for a second silica gel column purification, affording the product SI-22 as a colorless oil (2.92 g, 9.65 mmol, 65% yield).  (R)-SI-23. A solution of SI-22 (4.60 g, 15.2 mmol) in anhydrous DMF (6.5 mL) was prepared in a dry, stir bar-equipped 40 mL vial. This solution was then added to LiBr (1.98 g, 22.8 mmol, 1.5 eq) in another dry, stir bar-equipped 40 mL vial via syringe under nitrogen, rinsing with DMF (2x0.5 mL, total DMF = 7.5 mL = 2.0 Molar) for quantitative transfer. The reaction was stirred at 70 °C for one hour, then cooled to room temperature and transferred to two 50 mL centrifuge tubes, rinsing with DMF (3×0.5 mL). To each centrifuge tube was added H2O (40 mL). After shaking, the phases were separated by centrifugation (3000 rpm for three minutes, then 4000 rpm for three minutes). In both centrifuge tubes, the aqueous layer on top was removed by pipet and fresh H2O was added to the 40 mL mark. After mixing, the phases were again separated by centrifugation by the same procedure. The oil at the bottom of each centrifuge tube was removed and passed through a short pad of a mixture consisting of celite and Na2SO4 in a Pasteur pipette into a tared 7 mL vial, giving the (R)-SI-23 as a clear colorless oil (1.76 g, 11.6 mmol, 76% yield). NMR matches that reported in the literature. 21 (4R)-SI-24. The pinacol boronic ester was synthesized by a modified literature procedure. In an argonfilled glovebox, a stir bar-equipped 250 mL Schlenk flask was charged with NaOt-Bu (2.87 g, 29.8 mmol, 3.15 eq). A separate 40 mL vial was charged with (R)-1-bromo-2-methylbutane (R)-SI-23 (1.43 g, 9.47 mmol, 1.00 eq) and Et(Bpin)2 17 (3.63 g, 12.9 mmol, 1.36 eq). The Schlenk flask was sealed with a rubber septum, and the 40 mL was sealed with a septa cap. Both vessels were brought out of the glovebox and into a fume hood and connected to nitrogen lines. Anhydrous THF (29 mL) was added to the Schlenk flask, resulting in a cloudy, light yellow suspension. The mixture of alkyl bromide and Et(Bpin)2 was then added (at room temperature, dropwise over five minutes) to the Schlenk flask, using additional THF (2x7 mL, total THF = 43 mL = 0.22 Molar) for quantitative transfer. The reaction was stirred efficiently at room temperature overnight.
The next day, the reaction was diluted with Et2O (75 mL) and filtered through a pad of silica gel in a coarse glass frit. The filtrate was concentrated by rotary evaporation, giving a colorless oil of low viscosity. The crude product was purified by normal phase column chromatography (6 cm diameter, 250 mL silica gel, isocratic 4/1 Hex/DCM), giving (4R)-SI-24 as a colorless oil (1.34 g, 5.94 mmol, 63% yield).   NMR of (4S)-SI-24 matches that of (4R)-SI-24.
BIDA Boronates 5p and 5m. To a stir bar-equipped 300 mL round bottom flask was added the pinacol boronic ester (4R)-SI-24 (1.442 g, 6.37 mmol, 1.00 eq) followed by THF (43 mL, 0.15 M), H2O (6.1 mL), NaIO4 (6.02 g, 28.1 mmol, 3.00 eq), and 1 Molar HCl (4.3 mL, 4.3 mmol, 0.68 eq). After five hours, monitoring of the reaction by TLC (3/1 Hex/EtOAc) still showed a substantial amount of the starting boronic ester. Additional 5.5 Molar HCl (4.6 mL, 25.3 mmol, 4.0 eq) was added to increase the total amount of HCl (2 Molar, 4.7 eq). The reaction was stirred for another hour and 15 minutes, at which point TLC indicated full consumption of the pinacol boronic ester. The stir bar was removed, additional H2O (15 mL) was added, and THF was removed by rotary evaporation. The reaction was diluted with additional H2O (15 mL) and extracted with methyl tert-butyl ether (2x40 mL). Combined organics were washed repeatedly with H2O (10x35 mL) to remove any remaining oxidant and then once with brine (35 mL). After drying with MgSO4 and filtering through a glass frit into a 500 mL round bottom flask, the solution was partially concentrated (remaining volume of 5-10 mL) and then the solvent was switched to anhydrous MeCN (64 mL, 0.10 Molar). BIDA (2.01 g, 6.54 mmol, 1.03 eq) and MgSO4 (2.55 g, 21.2 mmol, 3.3 eq) were added, along with a stir bar. The reaction was sealed with a rubber septum and connected to a nitrogen line before stirring overnight at 60°C. The reaction mixture was filtered through a plug of silica gel, rinsing with EtOAc. The filtrate was concentrated by rotary evaporation, giving a red foam (2.06 g, 4.97 mmol, 78% crude yield). This material was subjected to normal phase column chromatography (15/1 MTBE/EtOAc or 1/1 Hex/EtOAc). Mixed fractions were repurified until the d.r. of both diastereomers was ≥99:1 as determined by a sequence of stereospecific oxidation to the alcohol and derivatization to the para-nitrobenzoate ester (described below). The higher Rf diastereomer (5p, R,S; 0.549 g, 1.32 mmol, 21% yield) was isolated as a white powder, and so was the lower Rf diastereomer (5m, R,R; 0.498 g, 1.20 mmol, 19% yield).  BIDA Boronates 5n and 5o. To a stir bar-equipped 300 mL round bottom flask was added the pinacol boronic ester (4S)-SI-24 (1.859 g, 8.22 mmol, 1.00 eq) followed by THF (55 mL, 0.15 M), NaIO4 (5.28 g, 24.7 mmol, 3.00 eq), and 2 Molar HCl (19 mL, 38 mmol, 6.0 eq). Once the reaction was complete by TLC (3/1 Hex/EtOAc), the stir bar was removed, additional H2O (20 mL) was added, and THF was removed by rotary evaporation. The reaction was diluted with more H2O (20 mL) and extracted with methyl tertbutyl ether (2x50 mL). Combined organics were washed repeatedly with H2O (10x45 mL) to remove any remaining oxidant and then once with brine (50 mL). After drying with MgSO4 and filtering through a glass frit into a 500 mL round bottom flask, the solution was partially concentrated (remaining volume of 5-10 mL) and then the solvent was switched to anhydrous MeCN (84 mL, 0.10 Molar). BIDA (2.53 g, 8.22 mmol, 1.00 eq) and MgSO4 (3.28 g, 27.3 mmol, 3.3 eq) were added, along with a stir bar. The reaction was sealed with a rubber septum and connected to a nitrogen line before stirring overnight at 60°C.
The next day, the reaction mixture was filtered through a plug of silica gel, rinsing with EtOAc. The filtrate was concentrated by rotary evaporation, giving a red foam. This material was subjected to normal phase column chromatography (gradient 1.2/1 Hex/EtOAc to 1/1.2 Hex/EtOAc). Mixed fractions were repurified until the d.r. of both diastereomers was ≥99:1 as determined by a sequence of stereospecific oxidation to the alcohol and derivatization to the para-nitrobenzoate ester (described below). The higher Rf diastereomer (5n, S,S; 0.8222 g, 1.98 mmol, 24% yield) was isolated as white powder, and so was the lower Rf diastereomer (5o, S,R; 1.2124 g, 2.92 mmol, 36% yield).  To a solution of the crude SI-25 in anhydrous DCM (0.5 mL, 0.05 Molar) in a stir bar-equipped 7 mL vial was added anhydrous pyridine (7 μL, 7 mg, 0.09 mmol, 1.8 eq), 4-nitrobenzoyl chloride (13 mg, 0.07 mmol, 1.4 eq) and 4-(dimethylamino)pyridine (0.6 mg, 0.005 mmol, 10 mol%). The vial was capped and stirred at room temperature overnight. The next day, the reaction mixture was passed through a pad of MgSO4 in a cotton-plugged glass pipet, and filtrate was concentrated in vacuo. The crude product was purified by normal phase column chromatography (1:1 Hex/DCM), giving the pure 4-nitrobenzoate ester SI-26. SI-32 was prepared following the same procedure as for SI-26. Using the same HPLC conditions as for SI-26, the d.r. was determined to be 99.3:0.7.
Sodium alkyltrihydroxyborate 7p was made from BIDA boronate (-)-5p in quantitative yield as a white solid using general procedure B by directly concentrating the suspension without filtration.  A duplicate run of the reaction gave a branched/linear product ratio of 600/1, isolated yield of 54%, and diastereospecificity of 99.0%. 1 H NMR matches that of (-)-3ac. 13 C NMR matches that of (-)-3ac. Boronic acid 1n (99.3:0.7 e.r.) was prepared in 73% yield by general procedure C and coupled to organohalide 2p to give product (-)-3ae by general procedure D. A duplicate run of the reaction gave a branched/linear product ratio of 669/1, isolated yield of 64%, and diastereospecificity of 99.8%. 1 H NMR matches that of (+)-3ab. 13 C NMR matches that of (+)-3ab.
[ Phenyl amide SI-33. 4-epi-xylarinic acid B (6.49 mg, 0.0352 mmol, 1.00 eq) was massed out in a stir barequipped 2 mL screw cap vial. Under nitrogen, anhydrous DCM (0.100 mL) was added, followed by a solution of oxalyl chloride in DCM (1.17 Molar, 60 μL, 0.0070 mmol, 2.0 eq) and a solution of DMF in DCM (1.3 Molar, 2.7 μL, 3.5 μmol, 10 mol%). The mixture was stirred under nitrogen for 20 minutes at room temperature, and then the volatiles (DCM and excess oxalyl chloride) were removed by a stream of nitrogen. Additional DCM (100 μL) was added, followed by a solution of aniline in DCM (0.548 Molar, 129 μL, 0.71 mmol, 2.0 eq). The reaction was stirred for 10 more minutes and then quenched by addition of 1M HCl (0.50 mL). The aqueous layer was extracted twice with DCM, and the extracts were passed through silica gel in a cotton-plugged glass pipet, rinsing with 10% EtOAc/hexanes. The filtrate was concentrated in vacuo. The d.r. of the crude phenyl amide was determined to be 99. 6

Absolute Configuration of BIDA Boronates
Determining the absolute configuration of the C2 stereocenter of 5a: The absolute stereochemistry of the 2-butyl stereocenter was determined by x-ray crystallography of crystals grown by slow diffusion of Et2O into an acetone solution of 5a at 23°C using the known stereocenters of the cyclopentyl ring as reference.
Determining the absolute configuration of the C2 stereocenter of 7d: The trihydroxyborate salt (-)-7d (synthesized from 5d using general procedure B) was treated with 1M NaOH (5 equiv) followed by 30% H2O2 (3 eq) dropwise, causing the product to oil out. The mixture was stirred for 1 h at 23 °C, then quenched with saturated aqueous sodium thiosulfate (10 equiv). The solution was extracted with DCM, dried with Na2SO4, and concentrated to give SI-37 an oil. The crude alcohol (4.0 mg, 0.028 mmol) thus obtained was dissolved in pyridine (50 μL, 0.056 Molar) and treated with (S)-(+)-αmethoxy-α-trifluoromethylphenylacetyl chloride (10 mg, 0.04 mmol, 1.4 eq) at 23 °C and stirred for three hours. 2M HCl was added and the mixture extracted with EtOAc twice. The organic phase was dried with Na2SO4 and concentrated under vacuum. The product SI-38 (7 mg, 0.020 mmol 70%) was obtained after purification by silica gel chromatography (2% EtOAc/hexanes). The 1 H NMR and 13 C NMR matched that of SI-38 independently synthesized from (S)-propylene oxide as described below, thus confirming that the configuration of the C2 stereocenter is (S). Independent synthesis of SI-37 and SI-38: Following a literature procedure, 24 a 7-mL vial was charged with Mg turnings (24 mg, 1 mmol, 1 eq) and I2 (1 mg, catalytic), followed by anhydrous THF (1 mL, 1 Molar) and bromocyclohexane (163 mg, 1 mmol, 1 eq) under nitrogen. The mixture was stirred at 50 °C until most of the Mg dissolved. CuI (24 mg, 0.13 mmol) was added. (S)-propylene oxide (Aldrich # 540021, 73 μL, 1.04 mmol) was then added dropwise at 23 °C. After stirring for 1 h, the black suspension was quenched with saturated aqueous NH4Cl, and the mixture extracted with EtOAc. The organics were dried with Na2SO4, filtered and concentrated. The crude product was purified by silica gel column (10% to 15% EtOAc/hexanes) to give SI-37 25 as a colorless oil. Spectra matched those reported previously.
A 7 mL vial equipped with a stir bar was charged with SI-37 (15.2 mg, 0.107 mmol, 1.0 eq), DCM (0.5 mL, 0.21 Molar) and pyridine (30 μL, 0.37 mmol, 3.5 eq). (S)-(+)-α-Methoxy-α-trifluoromethylphenylacetyl chloride (20 μL, 0.107 mmol, 1.0 eq) was added at 23 °C and the reaction stirred at the same temperature overnight. The solvent was removed under a stream of nitrogen and the crude product loaded onto a silica gel column with 4% Et2O/pentane. After silica gel purification (4% Et2O/pentane), a white crystalline solid was obtained as the desired product SI-38 (34.9 mg, 0.0974 mmol, 91%).  248 mg (0.6 mmol) of (1S, 2S)-5l was hydrolyzed and the boronic acid was obtained as a solution in MTBE after workup as described in general procedure B. The boronic acid solution was used directly in the complexation with MIDA ligand by general procedure A. 100 mg (0.4 mmol) of (1S, 2S)-6l was obtained as a white crystalline solid in 66% overall yield. X-ray crystals were grown by solvent layering of hexanes over a homogeneous solution of 6l in EtOAc. The absolute configuration was assigned by x-ray crystallography. In an unoptimized procedure, 2-chlorobutane (0.635 mL, 6 mmol, 1.0 eq) was added to a mixture of Mg (146 mg, 6 mmol, 1.0 eq), I2 (one crystal) and Et2O (6 mL, 1.0 Molar) dropwise at 23 °C. The reaction was stirred for 2.5 hours after the addition. The solution of the Grignard reagent was then added dropwise to a solution of (R)-propylene oxide (0.14 mL, 2 mmol, 0.33 eq) and Li2CuCl4 (1M in THF, 2 mL, 0.2 mmol, 0.033 eq) in THF (6 mL) at -50 °C. The reaction was warmed to room temperature and stirred overnight, then cooled to 0 °C. Saturated aqueous NH4Cl (12 mL) was added, and the mixture was stirred until most of the brown solids dissolved. The mixture was transferred to a separatory funnel with H2O and Et2O (10 mL). After mixing and phase separation, the aqueous layer was extracted with Et2O (10 mL). The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (30 to 40% Et2O/pentane) to give alcohol SI-41 (130 mg, 37%). The Mosher ester SI-42, which is a mixture of diastereomers with a stereodefined C2 stereocenter was synthesized from SI-41 using the procedure described above for the synthesis SI-40 from SI-39.

Absolute Configuration of Coupled Products
To determine the absolute stereochemistry of (+)-3a obtained from the coupling reaction of (S)-1a and 2a, (S)-3a was independently synthesized from (S)-3-phenylbutyric acid: SI-43. In a glovebox, lithium aluminum hydride powder (88 mg, 2.2 mmol) was added to a dry 3-neck flask. This was fitted with a reflux condenser and 2 septa. In a fume hood, dry THF (10 mL) was added and the mixture was stirred at 23°C. (+)-(S)-3-phenylbutyric acid (Sigma Aldrich 78240, Lot # BCBF9385V), was added dropwise as a solution in THF (3.5 mL) and the mixture was stirred at reflux for 12 hours. TLC (3:1 Hex/EtOAc, KMnO4) showed complete conversion. The reaction was quenched with 1M aqueous Rochelle salt and extracted three times with DCM. The combined DCM phase was dried over sodium sulfate and concentrated under vacuum. The crude material (310 mg) was used directly in the next step.
The crude alcohol (310 mg) was combined in a 7 mL vial with distilled pyridine (1.0 mL) and toluenesulfonyl chloride (0.419 g, 2.2 mmol) that had been recrystallized from hot hexanes. The reaction was capped and stirred at 23 °C until complete conversion of the alcohol as seen by TLC. At 5 h, 1M HCl was added and the mixture was extracted three times with Et2O. The combined Et2O phase was washed with 1M HCl, then H2O, then saturated NaHCO3. The solution was dried over sodium sulfate and concentrated under vacuum. The crude was purified by silica column using a gradient of 5% to 15% EtOAc in hexanes, giving the product SI-43 as a colorless oil (0.460 g, 1.51 mmol, 74% yield from (S)-3-phenylbutyric acid). SI-44. To a 20 mL vial with a septum cap and stir bar were added (S)-3-phenylbutyl 4methylbenzenesulfonate SI-45 (0.450 g, 1.45 mmol, 1.00 eq), followed by DMSO (8 mL) and NaBH4 (0.281 g, 7.43 mmol, 5.1 eq). The headspace was purged with nitrogen the reaction was stirred at 70°C, during which time the reaction became homogeneous. Monitoring of the reaction by TLC (4:1 Hex/EtOAc, KMnO4) showed complete conversion of the substrate at 20 hours. H2O (8 mL) was added and the solution was extracted four times with pentane. The combined pentane phase was washed twice with H2O, then with 3% H2O2, and again with H2O. The solution was dried over sodium sulfate and concentrated under light vacuum to give SI-44 as an oil (0.128 g, 0.770 mmol, 47% yield). This was used in the next step without purification. The spectral properties of sec-butylbenzene were identical to those reported previously. 26 Comparison of the optical rotation to the literature value showed a high level of enantiopurity. To the crude product from the above reaction in a 7 mL vial in a glove box were added Pd(PPh3)4 (1.7 mg, 1.5 µmol, 2.5 mol%), phenylboronic acid (12.1 mg, 0.10 mmol, 1.6 eq), K2CO3 (0.236 g, 1.9 mmol, 32 eq), and THF (0.8 mL, 0.08 Molar). In a fume hood, H2O (0.57 mL, 0.11 Molar) was added. The headspace was purged with nitrogen, capped and stirred 10 hours at 75°C. TLC (100% pentane, UV) showed product. The THF was removed under vacuum. The solution was then extracted three times with pentane. The pentane phase was dried over sodium sulfate, concentrated under vacuum, and purified by silica column with 100% pentane, giving (S)-3a as a colorless oil (12.3 mg, 0.0507 mmol, 32% yield).  The product (S)-3a had an e.r. of > 99.5:0.5 as determined using a Chiralcel OD-H column of 4.6 mm x 250 mm, hexanes, 2.0 mL/min., 210 nm absorbance. Major: 5.7, Minor: 9.3. The retention time of the (S)-3a obtained here matches that of the coupling product (+)-3a, thus confirming that the coupling reaction went with stereoretention.

SI-45
Intensity data were collected on a Bruker D8 Venture kappa diffractometer equipped with a Photon 100 CMOS detector. An Iµs microfocus Mo source (λ = 0.71073 Å) coupled with a multi-layer mirror monochromator provided the incident beam. The sample was mounted on a 0.3 mm loop with the minimal amount of Paratone-N oil. Data was collected as a series of φ and/or ω scans. Data was collected at 100 K using a cold stream of N2(g). The collection, cell refinement, and integration of intensity data was carried out with the APEX2 software. 28 A semi-empirical absorption correction was performed with SADABS. 29 The structure was phased with direct methods using SHELXS and refined with the full-matrix least-squares program SHELXL. 30 A structural model consisting of the host plus one highly disordered diethyl ether solvate molecule was developed; however, positions for the idealized solvate molecules were poorly determined. This model converged with wR2 = 0.1715 and R1 = 0.687 for 496 parameters with 645 restraints against 6325 data. Since positions for the solvate molecule were poorly determined a second structural model was refined with contributions from the solvate molecule removed from the diffraction data using the bypass procedure in PLATON. 31 No positions for the host network differed by more than two su's between these two refined models. The electron count from the "squeeze" model converged in good agreement with the number of solvate molecules predicted by the complete refinement.
One of the ligands was modeled as disordered over 2 sites. The C27/C27a pivot atom positions of bonded to the P atom were constrained to have the same position and same displacement parameters. The disordered ligands were restrained to have the same geometries (esd 0.01 Å). The terminal phenyl rings on the disordered ligands were also constrained to be perfect hexagons. Rigid-bond restraints (esd 0.006) were imposed on displacement parameters for all disordered sites.
H atom treatment -H atoms were included as riding idealized contributors and their U's were assigned as 1.2 times carrier Ueq.
3 low angle reflections were omited from the final refinements.

SI-46
Intensity data were collected on a Bruker D8 kappa diffractometer equipped with an APEXII CCD detector. An fine-focus Mo source (λ = 0.71073 Å) coupled with a graphite monochromator provided the incident beam. The sample was mounted on a 0.3 mm loop with the minimal amount of Paratone-N oil. Data was collected as a series of φ and/or ω scans. Data was collected at 100 K using a cold stream of N2(g). The collection, cell refinement, and integration of intensity data was carried out with the APEX2 software. 28 A semi-empirical absorption correction was performed with SADABS. 29 The structure was phased by intrinsic methods using SHELXS and refined with the full-matrix least-squares program SHELXL. 30 A structural model consisting of the target molecule, one ordered dichloromethane solvate molecule, and one disordered solvate molecule position in the asymmetric unit was developed; however, positions for the disordered solvate molecule was poorly determined. This model converged with wR2 = 0.2636 and R1 = 0.0783 for 956 parameters with 956 restraints against 14637 data. Since positions for the solvate molecules were poorly determined a second structural model was refined with contributions from the solvate molecules removed from the diffraction data using the bypass procedure in PLATON. 32 No positions for the host network differed by more than two su's between these two refined models. The electron count from the "squeeze" model converged in good agreement with the number of solvate molecules predicted by the complete refinement.
One of the phenyl rings of one phosphine ligand was found to be disordered over two orientations. Both disordered phenyl rings were constrained to be perfect hexagons. Similar displacement amplitudes (esd 0.01) were imposed on disordered sites overlapping by less than the sum of van der Waals radii. Similarity restraints (esd 0.01) were imposed on the C---C bonds joining the disordered phenyl ring to the ordered ligand carbon atom C73. The site occupancy of the two orientations was allowed to freely refine; at convergence the site occupancy ratio was 0.717(8):0.283 (8).
H atom treatment -Methyl H atom positions, R-CH3, were optimized by rotation about R-C bonds with idealized C-H, R--H and H--H distances. Remaining H atoms were included as riding idealized contributors. Methyl H atom U's were assigned as 1.5 times Ueq of the carrier atom; remaining H atom U's were assigned as 1.2 times carrier Ueq.
Due to the large unit cell and limitations on the instrument configuration, several reflections were completely or partially obscured by the beam stop in some orientations. These reflections were omitted from the final refinement.

CCDC: 1838474
5a Intensity data were collected on a Bruker D8 Venture kappa diffractometer equipped with a Photon 100 CMOS detector. An Iµs microfocus Cu source (λ = 1.54178 Å) coupled with a multi-layer mirror monochromator provided the incident beam. The sample was mounted on a 0.3 mm loop with the minimal amount of Paratone-N oil. Data was collected as a series of φ and/or ω scans. Data was collected at 100 K using a cold stream of N2(g). The collection, cell refinement, and integration of intensity data was carried out with the APEX2 software. 28 A semi-empirical absorption correction was performed with SADABS. 29 The structure was phased with direct methods using SHELXS 30 and refined with the full-matrix least-squares program SHELXL. 30 A structural model consisting of the target molecule was developed. There is no disorder in the structure.
Methyl H atom positions, R-CH3, were optimized by rotation about R-C bonds with idealized C-H, R--H and H--H distances. Remaining H atoms were included as riding idealized contributors. Methyl H atom U's were assigned as 1.5 times Ueq of the carrier atom; remaining H atom U's were assigned as 1.2 times carrier Ueq.
On the basis of 1548 unmerged Friedel opposites, the fractional contribution of the racemic twin was negligible. 33,34 The absolute structure parameter y was calculated using PLATON. 32 The resulting value was y=0.00 (5) indicating that the absolute structure has probably been determined correctly. 35
Supplementary Figure 10| X-ray structure of compound 5a (alternate angle). A solution of 1 mmol of (S)-1a, produced by hydrolysis of BIDA boronate 5a of ≥99:1 d.r. following general procedures B and C, was diluted to 0.5 Molar in dioxane in a 7 mL vial in an ice bath. To this was added 30% H2O2 (0.227 g, 2.0 mmol, 2.0 eq) and 1 Molar NaOH (2.0 mL, 2.0 mmol, 2.0 eq). The mixture was stirred until complete conversion of the boronic acid was seen by TLC (1:1 Hex/EtOAc, KMnO4). 1 Molar HCl (5 mL) and Et2O (5 mL) were then added, and the organic layer was washed with saturated sodium bisulfate, H2O, and brine. It was dried with sodium sulfate and concentrated to a 2mL volume (a small aliquot was removed, the Et2O was removed under an air stream, and the sample was analyzed by 1 H-NMR, showing the presence of 2butanol). To this solution was then added pyridine (0.242 mL, 0.238 g, 3.00 mmol, 3.00 eq) followed by the dropwise addition of acetyl chloride (0.213 mL, 0.234 g, 3.00 mmol, 3.00 eq). The heterogeneous mixture was capped and stirred 8 hours at 23 °C. The mixture was washed three times with 1 Molar HCl, once with saturated NaHCO3, and once with brine. The solvent was removed under light vacuum to yield 25 mg of 2-butylacetate (SI-47), confirmed by 1H NMR) as a colorless oil. This 2butylacetate (SI-47) was determined by chiral GC to be of ≥99:1 e.r.

XI. Assay to Test for Racemization of Boronic Acids
(Agilent chiral G-TA column was used, with 0.8mL/minute gas flow, 24°C to 55°C at 1°C/minute. Major: 20.6, Minor: 22.1), indicating that no racemization took place during the synthesis of (S)-1a.

XII. Stability Tests
The long-term bench top stability of these compounds was determined as follows. Two 2 mL Teflonlined screw-cap vials were each filled with 10 mg of MIDA boronate (±)-6a. Similarly, two of these vials were filled with 15 mg of BIDA boronate 5a of 99:1 dr and two were filled with 10 mg of trihydroxyborate salt (±)-7a. 0.5 mL of a solution of 1.15M (±)-1a in dioxane, prepared by general procedure C, was added to one vial. Each compound was initially quantified by adding 0.5 mL of DMSO-d6 with 0.10 Molar 1,4-dimethoxybenzene standard to one of the vials containing (±)-6a, 5a or (±)-7a. The solutions were transferred to NMR tubes. 50 µl of the solution of (±)-1a was also added to an NMR tube with 0.5 mL of DMSO-d6 with 0.1 Molar 1,4-dimethoxybenzene standard. Mmol of compound was determined by 1 H-NMR integration with a relaxation delay of 10 seconds. The remaining vials were tightly capped under air and stored on the bench top for 4 months. Then, the NMR quantification was repeated. All three solid compounds showed no decomposition. The concentration of (±)-1a decreased by <10% (1.05M), with small amounts of decomposition products present in the spectrum.