Palladium-Catalyzed Conjunctive Cross-Coupling with Electronically Asymmetric Ligands

Abstract

Palladium-catalyzed conjunctive cross-coupling can be accomplished with the use of chiral phosphine-oxazoline based ligand structures. Of note, the reaction can be conducted on Grignard-based boron ate complexes and operates without the use of halide-scavenging additives which are required for other catalyst systems.

Graphical Abstract

Chiral organoboron reagents are versatile building blocks in organic synthesis.¹ Their importance largely stems from the myriad of mild, stereospecific transformations that allow replacement of the organoboronic ester with new carbon-, nitrogen-, and oxygen-based functional groups.² As one route to address the enantioselective construction of organoboronic esters, we have developed a palladium-catalyzed three-component conjunctive cross-coupling reaction that combines boronic esters, organolithium or Grignard reagents, and C(sp²) electrophiles.^3–6 This process occurs by way of palladium-induced 1,2-metalate shift of an alkenylboron ate complex (Scheme 1). Since the initial reaction discovery^3a, the chiral bis(phosphine) ligand MandyPhos has proven to be much more effective than other ligands in controlling the chemoselectivity of the reaction (conjunctive coupling vs direct Suzuki coupling), as well as delivering the product in an efficient and enantioselective fashion. However, there are several shortcomings to conjunctive couplings that have prompted us to assess other ligand classes for their ability to effect catalysis. One limitation is that reactions involving MandyPhos–palladium(II) complexes appear to be inhibited by halides and thus conjunctive couplings require the addition of stoichiometric additives to sequester chloride, bromide or iodide that are present in Grignard reagents or generated during organolithium synthesis.^3b Similarly, the use of halogen-based electrophiles releases halide salts and these also must be sequestered. While modification of the electronic properties of the MandyPhos ligand framework might present a solution, the synthesis of MandyPhos congeners is made difficult by a challenging reaction between a ferrocenyllithium and phosphorous-based electrophiles. In this report,^7,8 we describe the utility of electronically non-symmetric phosphinooxazoline ligands in the conjunctive cross-coupling and show that these structures can provide efficient and selective reactions, and that the presence of halide contaminants is less problematic allowing simpler experimental procedures to suffice for successful outcomes.⁹

Scheme 1. Electronically-Asymmetric Ligands in Pd-Based Metalate Shifts.

In considering other ligands that might be effective for conjunctive coupling reactions, three dichotomous criteria remained at the fore: (1) the ligand should render the Pd center sufficiently electron-rich to facilitate oxidative addition of the palladium complex to a C(sp²) halide; (2) the ligand should facilitate subsequent heterolysis of the resulting Pd–X bond to furnish a cationic Pd center; (3) the ligand should also allow the palladium(II) intermediate to serve as a π-acid such that the ensuing metal-induced metallate rearrangement is facile. In this connection, it seemed plausible that electronically non-symmetric ligands, especially P–N based structures might fulfill the above-mentioned criteria wherein the phosphine group might render palladium sufficiently electron rich for oxidative addition, but the pyridine would provide a π-acidic site for alkene binding and reaction. To test this hypothesis, we carried out DFT calculations (B3LYP/LANL2DZ) to probe the energetics of Pd(II)-promoted metallate shift for a complex involving a diphosphine ligand in comparison to a prototypical pyridylphosphine ligand. As depicted in Scheme 1, the metallate shift involving the diphosphine (eq. 1) was calculated to have an 8.2 kcal/mol activation barrier for the 1,2-metallate shift. In contrast, the barrier for 1,2-metallate shift when employing the pyridylphosphine ligand is substantially lower (5.3 kcal/mol), so long as the alkenyl boronate binds to palladium trans to the pyridine group (eq. 3). Thus, the PN ligand framework appeared to be a suitable candidate for further studies.

Encouraged by the abovementioned calculations, studies were commenced to probe the ability of several electronically non-symmetric ligands to promote conjunctive coupling reaction between aryl triflate 2 and the alkenylboron “ate” complex 1 (Scheme 2). Reactions were conducted with 5 mol% Pd and 6 mol% ligand at 60 °C in THF for 12 hours followed by oxidative workup and isolation of the product 3. As the data in Scheme 2 suggests, ligands bearing a phosphine group and a basic sp² nitrogen donor were most promising (L4, L5, and L7), providing the conjunctive coupling product in appreciable yield and with encouraging levels of enantioselectivity. Of note, when the phosphine is replaced with thiooether (L6) or quinoline (L8), or if a less basic nitrogen is employed (L2), reactivity is significantly diminished, presumably as a consequence of inefficient oxidative addition.

Scheme 2. Analysis of Conjunctive Cross-Coupling with Chiral P-N Ligands.^a.

(a) Reaction conducted with the following stoichiometry: 1 (0.2 mmol), 2 (0.22 mmol), solvent (0.8 mL).

Amongst the most effective ligands in Scheme 2, the phosphine-oxazoline ligand structure¹⁰ (L5) is most readily synthesized, allowing the steric and electronic properties to be easily fine-tuned. As depicted in Table 1, the oxazoline substituent was modified first and found to have a modest effect on stereoselectivity of the reaction with methyl (L10) and phenyl (L11) substituted ligands providing highest selectivity, but with the phenyl-substituted version providing unparalleled reaction efficiency. With the phenyl-substituted oxazoline held constant, the phosphine portion of the ligand was examined. In general, enantioinduction remained good with most ligands but ligands bearing ortho-substituted aryl phosphines resulted in diminished reaction efficiency. Ultimately, for practical reasons, 3,5-xylyl-substituted ligand L16 was selected for further studies: compound L16 is an easily isolated and handled solid material at room temperature.

Table 1.

Optimization of Pd-Catalyzed Conjunctive Cross-Coupling employing Phosphinooxazoline Ligands.^a

ligand	R1	R	yield (%)b	erc
L5	i-Pr	Ph	71	95:5
L9	t-Bu	Ph	70	95:5
L10	Me	Ph	75	95:5
L11	Ph	Ph	83	97:3
L12	Ph	2-furyl	85	93:7
L13	Ph	mesityl	13	93:7
L14	Ph	o-tolyl	trace	NA
L15	Ph	Cy	55	94:6
L16	Ph	3,5-xylyl	84	97:3

^(a)1 (0.2 mmol), 2 (0.22 mmol), solvent (0.8 mL)

^(b)Yields are of ioslated material after column chromatography.

^(c)Enantiomer ratio determined by chiral SFC analysis.

With an effective ligand framework in hand, we set out to study its utility in practical conjunctive coupling reactions. Notably, with DMSO/THF as the solvent, it was found that commercially available organomagnesium halide reagents could be employed directly in the synthesis of the reactive boron ate complex, and the reaction did not require the addition of halide-scavenging additives (i.e. NaOTf) for effective reaction. Similarly, halogen-based electrophiles could also be employed in the process and the reaction was generally efficient and selective. As depicted in Scheme 3, in addition to aromatic electrophiles of varying electronic properties (products 4–8), heteroaryl electrophiles such as pyrimidines, pyridines, and thiophenes could be employed in the coupling reaction (9, 11–13, 15). Compounds 10 and 14 demonstrate effective coupling reactions with acyclic alkenyl halide substrates that may be useful in chemical synthesis. Also of note, a range of functionalized migrating groups (16–19) participated in the process and delivered the respective chiral organoboronate products with useful levels of selectivity.

Scheme 3. Pd/L16-Catalyzed Conjunctive-Coupling of Grignard-Derived Ate Complexes.^a.

(a) Reactions were carried out with 0.20 mmol of starting material; er values were determined by chiral chromatography (SFC) and have an error of ±1%. (b) Oxidative work-up omitted. (c) This experiment employed (R)-L16 as the ligand.

While reactions of Grignard reagents described above in Scheme 3 are simple to conduct, in some cases the requisite boronic ester may not be available and it may be of interest to conduct reactions using organolithium reagents instead. To examine the efficacy of such conjunctive couplings with Pd/L16, boronate complexes were prepared from vinylB(pin) and alkyllithium reagents. As shown in Scheme 4, these reactions proceed with yield and selectivity that is comparable to reactions of Mg-based boronate complexes (compare 22 in Scheme 3 vs. 4). One noteworthy example is the reaction of the methyl-lithium-derived complex to furnish compound 26; even though the yield for this reaction is modest, this example represents the first migration of a simple methyl group in Pd-catalyzed conjunctive coupling reactions and provides a simple route to important phenylethyl alcohol and phenethyl amine derivatives. In addition, for the synthesis of compound 24, it was demonstrated that these reactions can be conducted on millimole scale and still perform adequately. Lastly, the advantage of P-N ligand L16 was shown for the synthesis of 24 from 4-iodoanisole where the reaction employing Mandyphos ligand proceeds in only 14% yield.

Scheme 4. Pd/L9-Catalyzed Conjunctive-Coupling of Organolithium-Derived Ate Complexes.^a.

(a) Reactions were carried out with 0.20 mmol of starting material; er values were determined by chiral chromatography (SFC) and have an error of ±1%.

In summary, we have described the use of electronically non-symmetric phosphino-oxazoline ligands in conjunctive coupling reactions and find them to be easily tuned and able to offer levels of reactivity and selectivity that can rival MandyPhos ligands. Use of these ligands to address other challenges in conjunctive cross-coupling will be reported in due course.

EXPERIMENTAL SECTION

Unless otherwise stated, all reactions were conducted in oven-dried glassware under an inert atmosphere of nitrogen or argon. Commercially available reagents were used as received without further purification. Solvents were purified using Pure Solv MD-4 solvent purification system. NMR spectra were recorded on either a Varian Gemini-500 (500 MHz), or a Varian Gemini-600 (600 MHz) spectrometer and were reported in ppm with residual solvent resonance as the internal standard (¹H NMR CHCl₃ at 7.26 ppm; ¹³C {¹H} NMR CDCl₃ at 77.16 ppm)). ¹¹B NMR spectra were recorded on a Varian Inova-500 (128 MHz). ¹⁹F{1H} NMR spectra were recorded on a Varian Gemini600 (564 MHz) spectrometer. High-resolution mass spectrometry (Jeol AccuTOF DART) was performed at the Mass Spectrometry Facility, Boston College, Chestnut Hill, MA. Analytical chiral supercritical fluid chromatography (SFC) was performed on a TharSFC Method Station II equipped with Waters 2998 Photodiode Array Detector with isopropanol as the modifier. Analytical high performance liquid chromatography (HPLC) was performed on an Agilent 1260 Infinity II System equipped with Diode Array Detector HS with isopropanol as the modifier.

General Procedure for Conjunctive Cross Coupling Reactions using Grignard Reagents:

In a glovebox under argon, a 2-dram vial equipped with a magnetic stir bar was charged with the boronic ester (0.20 mmol, 1.0 equiv.), THF (0.1 mL), and dimethyl sulfoxide (0.1 mL), and sealed with a septum cap. The vial was removed from the glovebox, equipped with a positive-pressure N₂ line, and placed in a 0 °C bath. Vinylmagnesium bromide in THF (0.24 mmol, 1.2 equiv.) was added dropwise. The reaction vial was allowed to warm to room temperature and stir for 30 minutes before being returned to the glovebox. In the glovebox, a second oven-dried 2-dram vial equipped with a magnetic stir bar was charged with Pd₂(dba)₃ (2.0 μmol, 0.01 equiv.), ligand L16 (4.80 μmol, 0.024 equiv.) and THF (0.06 mL). The Pd₂(dba)₃/L16 solution was allowed to stir for 3 h at room temperature. The Pd₂(dba)₃/L16 solution was then transferred into the reaction vial, followed by dimethyl sulfoxide (0.2 mL, used to rinse the Pd₂(dba)₃/L16 vial), and aryl/vinyl halide (0.22 mmol. 1.1 equiv.). The reaction vial was sealed with a polypropylene cap, taped, and removed from the glovebox where it was allowed to stir in a 60 °C oil bath for 12 h. The reaction was quenched with saturated ammonium chloride solution, and the aqueous layer was extracted with diethyl ether. The combined organic layers were filtered through a silica plug, concentrated, and then diluted with THF (1 mL). The mixture was then cooled to 0 °C and 3 M NaOH (0.8 mL) was added, followed by 30% hydrogen peroxide (0.4 mL), dropwise. The reaction mixture was allowed to warm to room temperature, and stir for 3 h. The mixture was cooled to 0 °C and saturated sodium thiosulfate (2 mL) was added dropwise. After warming to room temperature, the aqueous layer was extracted with diethyl ether (8 × 2 mL). The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure and subsequently purified via silica gel column chromatography to provide the desired products.

General Procedure for Conjunctive Cross Coupling Reactions using Organolithium Reagents:

In a glovebox under argon, a 2-dram vial equipped with a magnetic stir bar was charged with the boronic ester (0.20 mmol, 1.0 equiv.), and diethyl ether (0.2 mL), and sealed with a septum cap. The vial was removed from the glovebox, equipped with a positive-pressure N₂ line, and placed in a 0 °C bath. Organolithium (0.20 mmol, 1.0 equiv.) was added dropwise. The reaction vial was allowed to warm to room temperature and stir for 30 minutes. Then the solvent was carefully removed under reduced pressure before being returned to the glovebox. In the glovebox, a second oven-dried 2-dram vial equipped with a magnetic stir bar was charged with Pd₂(dba)₃ (1.0 μmol, 0.005 equiv.), ligand L16 (2.40 μmol, 0.012 equiv.) and THF (0.06 mL). The Pd₂(dba)₃/L16 solution was allowed to stir for 3 h at room temperature. The Pd₂(dba)₃/L16 solution was then transferred into the reaction vial, followed by THF (0.54 mL, used to rinse the Pd₂(dba)₃/L16 vial), and aryl/vinyl halide (0.22 mmol. 1.1 equiv.). The reaction vial was sealed with a polypropylene cap, taped, and removed from the glovebox where it was allowed to stir in a 60 °C oil bath for 12 h. The reaction was diluted with diethyl ether and filtered through a silica plug, concentrated, and then diluted with THF (1 mL). The mixture was then cooled to 0 °C and 3 M NaOH (0.8 mL) was added, followed by 30% hydrogen peroxide (0.4 mL), dropwise. The reaction mixture was allowed to warm to room temperature, and stir for 3 h. The mixture was cooled to 0 °C and saturated sodium thiosulfate (2 mL) was added dropwise. After warming to room temperature, the aqueous layer was extracted with diethyl ether (8 × 2 mL). The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure and subsequently purified via silica gel column chromatography to provide the desired products.

Procedure for 1.0 mmol Conjunctive Cross Coupling Reactions:

In a glovebox under argon, a 3-dram vial equipped with a magnetic stir bar was charged with the boronic ester (1.0 mmol, 1.0 equiv.), and diethyl ether (1.0 mL), and sealed with a septum cap. The vial was removed from the glovebox, equipped with a positive-pressure N₂ line, and placed in a 0 °C bath. Organolithium in pentane (1.0 mmol, 1.0 equiv.) was added dropwise. The reaction vial was allowed to warm to room temperature and stir for 30 minutes. Then the solvent was carefully removed under reduced pressure before being returned to the glovebox. In the glovebox, a second oven-dried 2-dram vial equipped with a magnetic stir bar was charged with Pd₂(dba)₃ (5.0 μmol, 0.005 equiv.), ligand L16 (12.0 μmol, 0.012 equiv.) and THF (0.3 mL). The Pd₂(dba)₃/L16 solution was allowed to stir for 3 h at room temperature. The Pd₂(dba)₃/L16 solution was then transferred into the reaction vial, followed by THF (2.7 mL, used to rinse the Pd₂(dba)₃/L16 vial), and aryl/vinyl halide (1.1 mmol, 1.1 equiv.). The reaction vial was sealed with a polypropylene cap, taped, and removed from the glovebox where it was allowed to stir in a 60 °C oil bath for 12 h. The reaction was diluted with diethyl ether and filtered through a silica plug, concentrated, and then diluted with THF (5 mL). The mixture was then cooled to 0 °C and 3 M NaOH (4.0 mL) was added, followed by 30% hydrogen peroxide (2.0 mL), dropwise. The reaction mixture was allowed to warm to room temperature, and stir for 3 h. The mixture was cooled to 0 °C and saturated sodium thiosulfate (10 mL) was added dropwise. After warming to room temperature, the aqueous layer was extracted with diethyl ether (15 × 2 mL). The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure and subsequently purified via silica gel column chromatography to provide the desired products.

(R)-1,5-diphenylpentan-2-ol (4)

The reaction was performed according to general method using 4,4,5,5-tetramethyl-2-(3-phenylpropyl)-1,3,2-dioxaborolane (49.2 mg, 0.2 mmol, 1.0 equiv.), and iodobenzene (44.9 mg, 0.22 mmol, 1.1 equiv.). The crude product was purified by automated flash column chromatography (Biotage 2% → 28% ethyl acetate in n-hexane, stained in CAM) to afford a colorless oil (38.5 mg, 80% yield, 95:5 er). All spectral data were in accordance with the literature.^3d Chiral SFC (OJ-H, 9% IPA, 3ml/min, 100 bar, 35 °C, 210–270 nm) retention time 8.20 (major) and 8.89 min.

(R)-1-(4-Methoxyphenyl)-5-phenylpentan-2-ol (5)

The reaction was performed according to general procedure using 4,4,5,5-tetramethyl-2-(3-phenylpropyl)-1,3,2-dioxaborolane (49.2 mg, 0.2 mmol, 1.0 equiv.), 4-bromoanisole (41.2 mg, 0.22 mmol, 1.1 equiv.). The crude product was purified by automated flash column chromatography (Biotage 2% → 30% ethyl acetate in n-hexane, stained in CAM) to afford a colorless oil (45.4 mg, 84% yield, 95:5 er). ¹H NMR (600 MHz, CDCl₃) δ 7.33 – 7.27 (m, 2H), 7.23 – 7.18 (m, 3H), 7.13 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 3.81 (s, 3H), 3.80 – 3.77 (m, 1H), 2.78 (dd, J = 13.7, 4.2 Hz, 1H), 2.66 (ddd, J = 8.3, 6.7, 3.3 Hz, 2H), 2.59 (dd, J = 13.7, 8.4 Hz, 1H), 1.91 – 1.82 (m, 1H), 1.78 – 1.68 (m, 1H), 1.63 – 1.51 (m, 3H).; ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 158.4, 142.5, 130.54, 130.47, 128.5, 128.4, 125.8, 114.1, 72.7, 55.4, 43.2, 36.4, 36.0, 27.7.; IR (neat) ν_max 3415 (br), 2934 (s), 1611 (m), 1511 (s), 1246 (s), 1178 (m), 1035 (m), 818 (br), 699 (s) cm⁻¹.; HRMS (DART) m/z: [M+NH₄]⁺ Calc’d for C₁₈H₂₆NO₂ 288.1958; Found: 288.1961.; [α]²⁰_D −4.10 (c 1.0, CHCl₃); Chiral SFC (OD-H, 10% IPA, 3ml/min, 100 bar, 35 °C, 210–270 nm) retention time 10.26 (major) and 10.99 min.

(R)-5-Phenyl-1-(4-(trifluoromethyl)phenyl)pentan-2-ol (6)

The reaction was performed according to general procedure using 4,4,5,5-tetramethyl-2-(3-phenylpropyl)-1,3,2-dioxaborolane (49.2 mg, 0.2 mmol, 1.0 equiv.), 1-bromo-4-(trifluoromethyl)benzene (50.5 mg, 0.22 mmol, 1.1 equiv.). The crude product was purified by automated flash column chromatography (Biotage 2% → 25% ethyl acetate in n-hexane, stained in CAM) to afford a white solid (47.5 mg, 77% yield, 90:10 er). ¹H NMR (600 MHz, CDCl₃) δ 7.57 (d, J = 8.0 Hz, 2H), 7.31 (dd, J = 15.3, 7.8 Hz, 4H), 7.23 – 7.17 (m, 3H), 3.90 – 3.80 (m, 1H), 2.86 (dd, J = 13.6, 4.3 Hz, 1H), 2.73 (dd, J = 13.7, 8.3 Hz, 1H), 2.72 – 2.61 (m, 2H), 1.93 – 1.82 (m, 1H), 1.77 – 1.68 (m, 1H), 1.65 – 1.50 (m, 3H).; ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 143.0, 142.3, 129.9, 128.9 (q, ²J_C-F = 32.4 Hz), 128.53, 128.48, 126.0, 125.5 (q, ³J_C-F = 4.0 Hz), 124.4 (q, ¹J_C-F = 271.7 Hz), 72.4, 43.9, 36.6, 35.9, 27.6.; ¹⁹F{¹H} NMR (564 MHz, CDCl₃) δ −62.38.; IR (neat) ν_max 3380 (br), 3063 (w), 2937 (m), 2859 (m), 1418.06 (w), 1325 (s), 1122 (s), 1019 (s), 749 (w), 699 (m) cm⁻¹.; HRMS (DART) m/z: [M+H-H₂O]⁺ Calc’d for C₁₈H₁₈F₃ 291.1355; Found: 291.1364.; [α]²⁰_D −3.10 (c 1.0, CHCl₃); Chiral SFC (OJ-H, 7% IPA, 3ml/min, 100 bar, 35 °C, 210–270 nm) retention time 7.81 (major) and 8.49 min.

(R)-1-(4-Fluorophenyl)-5-phenylpentan-2-ol (7)

The reaction was performed according to general procedure using 4,4,5,5-tetramethyl-2-(3-phenylpropyl)-1,3,2-dioxaborolane (49.2 mg, 0.2 mmol, 1.0 equiv.), 1-bromo-4-fluorobenzene (38.5 mg, 0.22 mmol, 1.1 equiv.). The crude product was purified by automated flash column chromatography (Biotage 2% → 25% ethyl acetate in n-hexane, stained in CAM) to afford a white solid (40.8 mg, 79% yield, 93:7 er). ¹H NMR (600 MHz, CDCl₃) δ 7.30 (t, J = 7.5 Hz, 2H), 7.21 (t, J = 8.1 Hz, 3H), 7.16 (dd, J = 8.4, 5.5 Hz, 2H), 7.01 (t, J = 8.6 Hz, 2H), 3.82 – 3.79 (m, 1H), 2.79 (dd, J = 13.8, 4.3 Hz, 1H), 2.71 – 2.61 (m, 1H), 1.91 – 1.82 (m, 1H), 1.77 – 1.68 (m, 1H), 1.62 – 1.51 (m, 3H).; ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 161.8 (d, ¹J_C-F = 244.5 Hz), 142.4, 134.3 (d, ⁴J_C-F = 3.1 Hz), 130.9 (d, ³J_C-F = 7.7 Hz), 128.53, 128.45, 125.9, 115.4 (d, ²J_C-F = 21.1 Hz), 72.6, 43.2, 36.4, 35.9, 27.7.; ¹⁹F{¹H} NMR (564 MHz, CDCl3) δ −116.77.; IR (neat) ν_max 3350 (m), 3280 (br), 3027 (w), 2941 (m), 2858 (m), 1601 (w), 1509 (s), 1217 (s), 1090 (m), 851 (m), 764 (s), 697 (s), 567 (m) cm⁻¹.; HRMS (DART) m/z: [M+H-H₂O]⁺ Calc’d for C₁₇H₁₈F 241.1387; Found: 241.1393.; [α]²⁰_D −3.47 (c 1.0, CHCl₃); Chiral SFC (OD-H, 4% IPA, 3ml/min, 100 bar, 35 °C, 210–270 nm) retention time 23.36 and 24.06 (major) min.

(R)-1-(4-Chlorophenyl)-5-phenylpentan-2-ol (8)

The reaction was performed according to general procedure using 4,4,5,5-tetramethyl-2-(3-phenylpropyl)-1,3,2-dioxaborolane (49.2 mg, 0.2 mmol, 1.0 equiv.), 1-bromo-4-chlorobenzene (42.1 mg, 0.22 mmol, 1.1 equiv.). The crude product was purified by automated flash column chromatography (Biotage 2% → 28% ethyl acetate in n-hexane, stained in CAM) to afford a white solid (44.5 mg, 81% yield, 92:8 er). ¹H NMR (600 MHz, CDCl₃) δ 7.33 – 7.26 (m, 4H), 7.23 – 7.17 (m, 3H), 7.13 (d, J = 8.4 Hz, 2H), 3.82 – 3.77 (m, 1H), 2.78 (dd, J = 13.7, 4.3 Hz, 1H), 2.71 – 2.59 (m, 3H), 1.90 – 1.80 (m, 1H), 1.77 – 1.67 (m, 1H), 1.64 – 1.48 (m, 3H).; ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 142.4, 137.2, 132.4, 130.9, 128.7, 128.53, 128.45, 125.9, 72.5, 43.4, 36.5, 35.9, 27.6.; IR (neat) ν_max 3367 (br), 3026 (m), 2936 (s), 2858 (m), 1491 (s), 1453 (m), 1406 (w), 1088 (s), 1015 (m), 803 (m), 749 (s), 699 (s), 664 (w) cm⁻¹.; HRMS (DART) m/z: [M+H-H₂O]⁺ Calc’d for C₁₇H₁₈Cl 257.1092; Found: 257.1106.; [α]²⁰_D −2.47 (c 1.0, CHCl₃); Chiral SFC (AD-H, 10% IPA, 3ml/min, 100 bar, 35 °C, 210–270 nm) retention time 8.35 and 10.07 (major) min.

(R)-5-Phenyl-1-(2-(piperidin-1-yl)pyrimidin-5-yl)pentan-2-ol (9)

The reaction was performed according to general procedure (with the modification: the reaction was run with 5 % palladium loading instead of 2 %) using 4,4,5,5-tetramethyl-2-(3-phenylpropyl)-1,3,2-dioxaborolane (49.2 mg, 0.2 mmol, 1.0 equiv.), 5-bromo-2-(1-piperidinyl)pyrimidine (41.2 mg, 0.22 mmol, 1.1 equiv.). The crude product was purified by automated flash column chromatography (Biotage 5% → 45% ethyl acetate in n-hexane, stained in CAM) to afford a white solid (22.8 mg, 35% yield, 92:8 er). ¹H NMR (600 MHz, CDCl₃) δ 8.13 (s, 2H), 7.29 – 7.27 (m, 2H), 7.20 – 7.16 (m, 3H), 3.79 – 3.70 (m, 4H), 3.71 – 3.67 (m, 1H), 2.63 (ddd, J = 8.2, 6.8, 3.1 Hz, 2H), 2.57 (dd, J = 14.2, 4.2 Hz, 1H), 2.44 (dd, J = 14.3, 8.0 Hz, 1H), 1.93 – 1.76 (m, 2H), 1.72 – 1.46 (m, 9H).; ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 161.1, 158.5, 142.3, 128.51, 128.46, 125.9, 118.5, 72.3, 45.0, 37.7, 36.4, 35.9, 27.8, 25.8, 25.0.; IR (neat) ν_max 3385 (br), 2932 (s), 2853 (m), 1605 (s), 1500 (s), 1461 (m), 1304 (m), 1025 (m), 749 (m) cm⁻¹.; HRMS (DART) m/z: [M+H]⁺ Calc’d for C₂₀H₂₈N₃O 326.2227; Found: 326.2216.; [α]²⁰_D −7.10 (c 1.0, CHCl₃); Chiral SFC (OJ-H, 15% IPA, 3ml/min, 100 bar, 35 °C, 210–270 nm) retention time 9.77 (major) and 14.40 min.

Ethyl (R,E)-8-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oct-2-enoate (10)

The reaction was performed according to general procedure (with the modifications: the opposite enantiomer of the ligand was used, and the boronate ester product was directly isolated without further oxidation) using 4,4,5,5-tetramethyl-2-(3-phenylpropyl)-1,3,2-dioxaborolane (49.2 mg, 0.2 mmol, 1.0 equiv.), ethyl (E)-3-iodoacrylate (49.7 mg, 0.22 mmol, 1.1 equiv.). The crude product was purified by automated flash column chromatography (Biotage 2% → 10% ethyl acetate in n-hexane, stained in CAM) to afford a clear oil (44.7 mg, 60% yield, 86:14 er). ¹H NMR (500 MHz, CDCl₃) δ 7.28 – 7.24 (m, 2H), 7.20 – 7.13 (m, 3H), 7.03 – 6.87 (m, 1H), 5.80 (d, J = 15.6 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 2.66 – 2.53 (m, 2H), 2.35 – 2.18 (m, 2H), 1.69 – 1.57 (m, 2H), 1.54 – 1.39 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H), 1.22 (s, 12H).; ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 166.6, 149.1, 142.6, 128.3, 128.2, 125.6, 121.7, 83.2, 60.0, 36.1, 33.7, 30.8, 30.5, 24.79, 24.76, 14.3.; ¹¹B NMR (160 MHz, CDCl₃) δ 34.06.; IR (neat) ν_max 2975 (w), 2925 (w), 1717 (m), 1651 (w), 1380 (w), 1368 (m), 1141 (s) cm⁻¹.; HRMS (DART) m/z: [M+H]⁺ Calc’d for C₂₂H₃₄BO₄ 373.2545; Found: 373.2536.; Chiral SFC (OD-H, 3% IPA, 3ml/min, 100 bar, 35 °C, 210–270 nm) retention time 9.85 and 10.43 (major) min.

(R)-4-(5-Phenyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pentyl)pyridine (11)

The reaction was performed according to general procedure (with the modification: the boronate ester product was directly isolated without further oxidation) using 4,4,5,5-tetramethyl-2-(3-phenylpropyl)-1,3,2-dioxaborolane (49.2 mg, 0.2 mmol, 1.0 equiv.), 4-iodopyridine (45.1 mg, 0.22 mmol, 1.1 equiv.). The crude product was purified by automated flash column chromatography (Biotage 10% → 65% ethyl acetate in n-hexane, stained in CAM) to afford an orange solid (50.6 mg, 72% yield, 89:11). ¹H NMR (500 MHz, CDCl₃) δ 8.44 (d, 2H), 7.29 – 7.22 (m, 2H), 7.20 – 7.12 (m, 2H), 7.10 (d, J = 6.1 Hz, 3H), 2.77 – 2.51 (m, 4H), 1.73 – 1.59 (m, 2H), 1.56 – 1.35 (m, 3H), 1.15 (s, 6H), 1.13 (s, 6H).; ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 151.4, 149.6, 142.6, 128.5, 128.4, 125.8, 124.4, 83.4, 36.6, 36.1, 30.9, 30.8, 24.9, 24.8.; ¹¹B NMR (160 MHz, CDCl₃) δ 35.63.; IR (neat) ν_max 3024 (m), 2977 (m), 2928 (m), 1601 (s), 1495 (s), 1453 (m), 1414 (m), 1216 (s), 748 (m) cm⁻¹.; HRMS (DART) m/z: [M+H]⁺ Calc’d for C₂₂H₃₁BNO₂ 352.2442; Found: 352.2436.; [α]²⁰_D +31.4 (c 1.0, CHCl₃); Chiral HPLC (AD-H, 5% IPA, 1ml/min, 70 bar, 35 °C, 210–270 nm) retention time 6.492 (major) and 7.054 min.

(R)-3-(5-Phenyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pentyl)pyridine (12)

The reaction was performed according to general procedure (with the modification: the boronate ester product was directly isolated without further oxidation) using 4,4,5,5-tetramethyl-2-(3-phenylpropyl)-1,3,2-dioxaborolane (49.2 mg, 0.2 mmol, 1.0 equiv.), 3-iodopyridine (45.1 mg, 0.22 mmol, 1.1 equiv.). The crude product was purified by automated flash column chromatography (Biotage 10% → 65% ethyl acetate in n-hexane, stained in CAM) to afford a colorless oil (32.3 mg, 46% yield, 90:10 er). ¹H NMR (500 MHz, CDCl₃) δ 8.45 (s, 1H), 8.40 (dd, J = 4.8, 1.7 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.30 – 7.21 (m, 2H), 7.21 – 7.12 (m, 4H), 2.75 – 2.52 (m, 4H), 1.65 (d, J = 11.8 Hz, 2H), 1.57 – 1.43 (m, 2H), 1.42 – 1.32 (m, 1H), 1.15 (s, 6H), 1.12 (s, 6H).; ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 150.5, 147.3, 142.7, 137.6, 136.3, 128.5, 128.4, 125.7, 123.2, 83.3, 36.2, 34.5, 31.0, 30.9, 24.88, 24.85.; ¹¹B NMR (160 MHz, CDCl₃) δ 35.58.; IR (neat) ν_max 3061 (w), 3025 (m), 2977 (s), 2855 (m), 1386 (s), 1326 (m), 1256 (w), 1143 (s), 749 (m), 699 (w) cm⁻¹.; HRMS (DART) m/z: [M+H]⁺ Calc’d for C₂₂H₃₁BNO₂ 352.2442; Found: 352.2437.; [α]²⁰_D +7.13 (c 1.0, CHCl₃); Chiral HPLC (AD-H, 5% IPA, 1ml/min, 70 bar, 35 °C, 210–270 nm) retention time 6.262 and 6.696 (major) min.

(R)-5-Phenyl-1-(pyridin-2-yl)pentan-2-ol (13)

The reaction was performed according to general procedure using 4,4,5,5-tetramethyl-2-(3-phenylpropyl)-1,3,2-dioxaborolane (49.2 mg, 0.2 mmol, 1.0 equiv.), 2-iodopyridine (45.1 mg, 0.22 mmol, 1.1 equiv.). The crude product was purified by automated flash column chromatography (Biotage 10% → 75% ethyl acetate in n-hexane, stained in CAM) to afford a colorless oil (22.2 mg, 46% yield, 89:11 er). ¹H NMR (600 MHz, CDCl₃) δ 8.49 (d, J = 4.5 Hz, 1H), 7.61 (td, J = 7.7, 2.0 Hz, 1H), 7.30 – 7.26 (m, 2H), 7.22 – 7.08 (m, 5H), 5.12 (s, 1H), 4.11 – 4.03 (m, 1H), 2.90 (dd, J = 15.0, 2.7 Hz, 1H), 2.83 (dd, J = 15.0, 8.8 Hz, 1H), 2.66 (t, J = 7.7 Hz, 2H), 1.93 – 1.82 (m, 1H), 1.81 – 1.70 (m, 1H), 1.68 – 1.60 (m, 1H), 1.59 – 1.51 (m, 1H).; ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 160.5, 148.7, 142.7, 136.9, 128.6, 128.4, 125.8, 123.8, 121.6, 70.9, 43.4, 36.8, 36.0, 27.6.; IR (neat) ν_max 3403 (br), 3026 (m), 2930 (s), 2857 (s), 1595 (s), 1436 (s), 1089 (m), 749 (s), 699 (s) cm⁻¹.; HRMS (DART) m/z: [M+H]⁺ Calc’d for C₁₆H₂₀NO 242.1539; Found: 242.1545.; [α]²⁰_D +7.37 (c 1.0, CHCl₃); Chiral SFC (OD-H, 4% IPA, 3ml/min, 100 bar, 35 °C, 210–270 nm) retention time 14.68 and 15.44 (major) min.

(R)-7-Methyl-1-phenyloct-6-en-4-ol (14)

The reaction was performed according to general procedure using 4,4,5,5-tetramethyl-2-(3-phenylpropyl)-1,3,2-dioxaborolane (49.2 mg, 0.2 mmol, 1.0 equiv.), 1-bromo-2-methylprop-1-ene (29.7 mg, 0.22 mmol, 1.1 equiv.). The crude product was purified by automated flash column chromatography (Biotage 2% → 24% ethyl acetate in n-hexane, stained in CAM) to afford a colorless oil (23.1 mg, 53% yield, 94:6 er). ¹H NMR (600 MHz, CDCl₃) δ 7.28 (t, J = 7.6 Hz, 2H), 7.21 – 7.15 (m, 3H), 5.19 – 5.13 (m, 1H), δ 3.65 – 3.57 (m, 1H), 2.70 – 2.59 (m, 2H), 2.22 – 2.09 (m, 2H), 1.86 – 1.77 (m, 1H), 1.74 (s, 3H), 1.72 – 1.65 (m, 1H), 1.64 (s, 3H), 1.56 (d, J = 4.1 Hz, 1H), 1.55 – 1.47 (m, 2H).; ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 142.6, 135.4, 128.6, 128.4, 125.8, 120.2, 71.7, 36.5, 36.4, 36.1, 27.8, 26.1, 18.1.; IR (neat) ν_max 3362 (br), 3062 (m), 3026 (m), 2965 (s), 2857 (s),1496 (m), 1472 (s), 1453 (m), 1375 (m), 1083 (m), 875 (w), 748 (s), 698 (s) cm⁻¹.; HRMS (DART) m/z: [M+H-H₂O]⁺ Calc’d for C₁₅H₂₁ 201.1634; Found: 201.1638.; [α]²⁰_D −5.00 (c 1.0, CHCl₃); Chiral SFC (OJ-H, 5% IPA, 3ml/min, 100 bar, 35 °C, 210–270 nm) retention time 5.34 (major) and 6.12 min.

(R)-5-Phenyl-1-(thiophen-3-yl)pentan-2-ol (15)

The reaction was performed according to general procedure using 4,4,5,5-tetramethyl-2-(3-phenylpropyl)-1,3,2-dioxaborolane (49.2 mg, 0.2 mmol, 1.0 equiv.), 3-bromothiophene (35.9 mg, 0.22 mmol, 1.1 equiv.). The crude product was purified by automated flash column chromatography (Biotage 2% → 30% ethyl acetate in n-hexane, stained in CAM) to afford a colorless oil (24.6 mg, 50% yield, 91:9 er). ¹H NMR (600 MHz, CDCl₃) δ 7.29 (t, J = 7.6 Hz, 3H), 7.21 – 7.17 (m, 3H), 7.03 – 7.02 (m, 1H), 6.96 (d, J = 4.9 Hz, 1H), 3.86 – 3.81 (m, 1H), 2.84 (dd, J = 14.2, 4.1 Hz, 1H), 2.71 (dd, J = 14.2, 8.4 Hz, 1H), 2.65 (t, J = 7.6 Hz, 2H), 1.89 – 1.79 (m, 1H), 1.76 – 1.67 (m, 1H), 1.61 – 1.50 (m, 3H).; ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 142.5, 138.8, 128.8, 128.6, 128.5, 126.0, 125.9, 122.2, 71.9, 38.5, 36.4, 36.0, 27.7.; IR (neat) ν_max 3547 (w), 3383 (br), 3025 (m), 2935 (s), 2858 (m), 1495 (m), 1453 (s), 1082 (m), 774 (s), 749 (s), 699 (s), 636 (m), 478 (w) cm⁻¹.; HRMS (DART) m/z: [M+H-H₂O]⁺ Calc’d for C₁₅H₁₇S 229.1046; Found: 229.1056.; [α]²⁰_D −2.75 (c 1.0, CHCl₃); Chiral SFC (AD-H, 10% IPA, 3ml/min, 100 bar, 35 °C, 210–270 nm) retention time 8.89 and 9.65 (major) min.

(R)-1-(4-Methoxyphenyl)hex-5-en-2-ol (16)

The reaction was performed according to general procedure using 2-(but-3-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (36.4 mg, 0.2 mmol, 1.0 equiv.), 4-bromoanisole (41.2 mg, 0.22 mmol, 1.1 equiv.). The crude product was purified by automated flash column chromatography (Biotage 2% → 25% ethyl acetate in n-hexane, stained in CAM) to afford a colorless oil (33.2 mg, 80% yield, 95:5 er). ¹H NMR (600 MHz, CDCl₃) δ 7.18 – 7.08 (m, 2H), 6.90 – 6.79 (m, 2H), 5.84 (ddt, J = 16.9, 10.0, 6.7 Hz, 1H), 5.05 (dd, J = 17.1, 1.7 Hz, 1H), 4.98 (dd, J = 10.2, 1.2 Hz, 1H), 3.90 – 3.68 (m, 4H), 2.77 (dd, J = 13.7, 4.4 Hz, 1H), 2.61 (dd, J = 13.7, 8.3 Hz, 1H), 2.32 – 2.11 (m, 2H), 1.67 – 1.53 (m, 3H).; ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 158.4, 138.6, 130.52, 130.48, 114.9, 114.1, 72.3, 55.4, 43.2, 35.9, 30.3.; IR (neat) ν_max 3429 (br), 2996 (m), 2934 (m), 2836 (w), 1640 (w), 1512 (s), 1246 (s), 1178 (m), 1036 (m), 818 (w) cm⁻¹.; HRMS (DART) m/z: [M+H-H₂O]⁺ Calc’d for C₁₄H₁₉O 189.1274; Found: 189.1275.; [α]²⁰_D −9.03 (c 1.0, CHCl₃); Chiral SFC (OJ-H, 3% IPA, 3ml/min, 100 bar, 35 °C, 210–270 nm) retention time 8.83 and 9.71 (major) min.

Methyl (R)-4-hydroxy-5-phenylpentanoate (17)

The reaction was performed according to general procedure using methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propanoate (42.8 mg, 0.2 mmol, 1.0 equiv.), iodobenzene (44.9 mg, 0.22 mmol, 1.1 equiv.). The crude product was purified by automated flash column chromatography (Biotage 4% → 55% ethyl acetate in n-hexane, stained in CAM) to afford a colorless oil (23.7 mg, 57% yield, 96:4 er). ¹H NMR (500 MHz, CDCl₃) δ 7.35 – 7.28 (m, 2H), 7.26 – 7.17 (m, 4H), 3.89 – 3.81 (m, 1H), 3.67 (s, 3H), 2.82 (dd, J = 13.6, 4.6 Hz, 1H), 2.70 (dd, J = 13.5, 8.2 Hz, 1H), 2.57 – 2.42 (m, 2H), 1.91 (ddt, J = 14.3, 7.2, 3.6 Hz, 1H), 1.83 (s, 1H), 1.80 – 1.71 (m, 1H).; ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 174.6, 138.3, 129.5, 128.7, 126.7, 72.1, 51.8, 44.3, 31.7, 30.7.; IR (neat) ν_max 3460 (br), 3027 (w), 2949 (m), 1773 (m), 1734 (s), 1520 (w), 1257 (m), 1176 (m), 747 (m), 701 (s) cm⁻¹.; HRMS (DART) m/z: [M+H-H₂O]⁺ Calc’d for C₁₂H₁₇O₃ 209.1172; Found: 209.1174.; [α]²⁰_D −7.10 (c 1.0, CHCl₃); Chiral SFC (OD-H, 10% IPA, 3ml/min, 100 bar, 35 °C, 210–270 nm) retention time 4.45 and 4.99 (major) min.

(R)-5,5-Dimethoxy-1-phenylpentan-2-ol (18)

The reaction was performed according to general procedure using 2-(3,3-dimethoxypropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (46.0 mg, 0.2 mmol, 1.0 equiv.), 4-bromoanisole (41.2 mg, 0.22 mmol, 1.1 equiv.). The crude product was purified by automated flash column chromatography (Biotage 6% → 50% ethyl acetate in n-hexane, stained in CAM) to afford a colorless oil (28.2 mg, 63% yield, 96:4 er). All spectral data were in accordance with the literature.^3b Chiral SFC (OD-H, 10% IPA, 3ml/min, 100 bar, 35 °C, 210–270 nm) 4.51 and 4.86 (major) min.

tert-Butyl (S)-4-(1-hydroxy-2-(4-methoxyphenyl)ethyl)piperidine-1-carboxylate (19)

The reaction was performed according to general procedure using tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)piperidine-1-carboxylate (62.2 mg, 0.2 mmol, 1.0 equiv.), 4-bromoanisole (41.2 mg, 0.22 mmol, 1.1 equiv.). The crude product was purified by automated flash column chromatography (Biotage 2% → 45% ethyl acetate in n-hexane, stained in CAM) to afford a white solid (43.6 mg, 65% yield, 95:5 er). ¹H NMR (600 MHz, CDCl₃) δ 7.11 (d, J = 8.2 Hz, 2H), 6.84 (d, J = 8.1 Hz, 2H), 4.15 (s, 2H), 3.77 (s, 3H), 3.53 (s, 1H), 2.81 (dd, J = 13.8, 3.4 Hz, 1H), 2.66 (s, 2H), 2.52 (dd, J = 13.7, 9.5 Hz, 1H), 1.84 (d, J = 12.8 Hz, 1H), 1.75 – 1.61 (m, 2H), 1.56 – 1.49 (m, 1H), 1.45 (s, 9H), 1.37 – 1.22 (m, 2H).; ¹³C{¹H} NMR (151 MHz, CDCl3) δ 158.4, 154.9, 130.5, 130.4, 114.2, 79.4, 76.0, 55.3, 41.6, 39.9, 28.6, 24.9.; IR (neat) ν_max 3439 (br), 2974 (m), 2933 (m), 2857 (m), 1689 (s), 1670 (s), 1512 (s), 1426 (s), 1246 (s), 1169 (s), 1082 (m), 865 (w) cm⁻¹.; HRMS (DART) m/z: [M+H]⁺ Calc’d for C₁₉H₃₀NO₄ 336.2169; Found: 336.2171.; [α]²⁰_D −7.36 (c 1.0, CHCl₃); Chiral SFC (AD-H, 10% IPA, 3ml/min, 100 bar, 35 °C, 210–270 nm) retention time 6.58 and 9.41 (major) min.

(S)-1-Cyclopentyl-2-(4-methoxyphenyl)ethan-1-ol (20)

The reaction was performed according to general procedure using 2-cyclopentyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (39.2 mg, 0.2 mmol, 1.0 equiv.), 4-bromoanisole (41.2 mg, 0.22 mmol, 1.1 equiv.). The crude product was purified by automated flash column chromatography (Biotage 2% → 28% ethyl acetate in n-hexane, stained in CAM) to afford a colorless oil (30.0 mg, 68% yield, 93:7 er). ¹H NMR (600 MHz, CDCl₃) δ 7.15 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 3.79 (s, 3H), 3.62 – 3.54 (m, 1H), 2.85 (dd, J = 13.8, 3.5 Hz, 1H), 2.55 (dd, J = 13.8, 8.9 Hz, 1H), 1.92 (h, J = 8.2, 1H), 1.86 – 1.72 (m, 2H), 1.69 – 1.61 (m, 2H), 1.60 – 1.52 (m, 3H), 1.49 – 1.39 (m, 1H), 1.37 – 1.28 (m, 1H).; ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 158.3, 130.9, 130.5, 114.1, 76.8, 55.4, 45.7, 41.9, 29.5, 28.7, 25.9, 25.8.; IR (neat) ν_max 3421 (br), 2948 (m), 2865 (m), 2835 (m), 1611 (m), 1511 (s), 1300 (m), 1245 (s), 1177 (m), 1036 (m), 817 (m), 530 (s) cm⁻¹.; HRMS (DART) m/z: [M+H-H₂O]⁺ Calc’d for C₁₉H₃₀NO₄ 203.1430; Found: 203.1429.; [α]²⁰_D −8.76 (c 1.0, CHCl₃); Chiral SFC (OJ-H, 10% IPA, 3ml/min, 100 bar, 35 °C, 210–270 nm) retention time 5.13 and 5.42 (major) min.

(S)-1-(4-Methoxyphenyl)-3-methylbutan-2-ol (21)

The reaction was performed according to general procedure using 2-isopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (34.0 mg, 0.2 mmol, 1.0 equiv.), 4-bromoanisole (41.2 mg, 0.22 mmol, 1.1 equiv.). The crude product was purified by automated flash column chromatography (Biotage 2% → 30% ethyl acetate in n-hexane, stained in CAM) to afford a colorless oil (25.6 mg, 66% yield, 89:11 er). All spectral data were in accordance with the literature.¹¹ Chiral SFC (OJ-H, 5% IPA, 3ml/min, 100 bar, 35 °C, 210–270 nm) retention time 6.64 and 7.15 (major) min.

(S)-1,2-Diphenylethan-1-ol (22)

The reaction was performed according to general procedure using 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane (40.8 mg, 0.2 mmol, 1.0 equiv.), phenyl trifluoromethanesulfonate (49.8 mg, 0.22 mmol, 1.1 equiv.). The crude product was purified by automated flash column chromatography (Biotage 2% → 28% ethyl acetate in n-hexane, stained in CAM) to afford a white solid (30.1 mg, 76% yield, 96:4 er). All spectral data were in accordance with the literature.^3a Chiral SFC (OD-H, 5% IPA, 3ml/min, 100 bar, 35 °C, 210–270 nm) retention time 11.92 and 12.95 (major) min.

(S)-1-(Benzo[d][1,3]dioxol-5-yl)-2-phenylethan-1-ol (23)

The reaction was performed according to general procedure using 2-(benzo[d][1,3]dioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (49.6 mg, 0.2 mmol, 1.0 equiv.), phenyl trifluoromethanesulfonate (49.8 mg, 0.22 mmol, 1.1 equiv.). The crude product was purified by automated flash column chromatography (Biotage 2% → 25% ethyl acetate in n-hexane, stained in CAM) to afford a white solid (27.5 mg, 57% yield, 96:4 er). ¹H NMR (600 MHz, CDCl₃) δ 7.30 (t, J = 7.4 Hz, 2H), 7.24 (t, J = 7.4 Hz, 1H), 7.19 (d, J = 6.9 Hz, 2H), 6.90 (d, J = 1.6 Hz, 1H), 6.80 – 6.74 (m, 2H), 5.95 (d, J = 1.3 Hz, 2H), 5.01 – 4.66 (m, 1H), 3.19 – 2.74 (m, 2H), 1.94 (d, J = 2.8 Hz, 1H).; ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 147.9, 147.1, 138.1, 138.0, 129.6, 128.7, 126.8, 108.2, 106.6, 101.1, 75.4, 46.2.; IR (neat) ν_max 3385 (br), 3027 (w), 2893 (w), 1502 (s), 1487 (m), 1442 (s), 1244 (s), 1038 (s), 932 (m), 811 (m), 700 (m), 513 (w) cm⁻¹.; HRMS (DART) m/z: [M+H-H₂O]⁺ Calc’d for C₁₅H₁₃O₂ 225.0910; Found: 225.0904.; [α]²⁰_D +12.4 (c 1.0, CHCl₃); Chiral SFC (OD-H, 10% IPA, 3ml/min, 100 bar, 35 °C, 210–270 nm) retention time 6.99 and 7.41 (major) min.

(R)-1-(4-methoxyphenyl)hexan-2-ol (24)

The reaction was performed according to general procedure using 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (30.8 mg, 0.2 mmol, 1.0 equiv.), n-butyl lithium (2.5 M in diethyl ether, 0.08 mL, 0.20 mmol, 1.0 equiv.), 1-iodo-4-methoxy-benzene (54.2 mg, 0.22 mmol, 1.1 equiv.). The crude product was purified by automated flash column chromatography (Biotage 2% → 28% ethyl acetate in n-hexane, stained in CAM) to afford a colorless oil (31.7 mg, 76% yield, 95:5 er).¹H NMR (600 MHz, CDCl₃) δ 7.13 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 3.80 (s, 3H), 3.77 (tt, J = 8.8, 4.5 Hz, 1H), 2.78 (dd, J = 13.6, 4.3 Hz, 1H), 2.58 (dd, J = 13.7, 8.4 Hz, 1H), 1.58 – 1.42 (m, 4H), 1.43 – 1.28 (m, 3H), 0.92 (t, J = 7.2 Hz, 3H).; ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 158.4, 130.7, 130.5, 114.1, 72.9, 55.4, 43.2, 36.6, 28.1, 22.9, 14.2.; IR (neat) ν_max 3392 (br), 2994 (m), 2955 (m), 2859 (w), 1612 (m), 1512 (s), 1464 (m), 1246 (s), 1036 (m), 816 (m), 523 (w) cm⁻¹.; HRMS (DART) m/z: [M+H-H₂O]⁺ Calc’d for C₁₃H₁₉O:191.1430, Found: 191.1437.; [α]²⁰_D: −12.0 (c 1.0, CHCl₃); Chiral SFC (OJ-H, 5% IPA, 3ml/min, 100 bar, 35 °C, 210–270 nm) retention time 5.91 and 6.33 (major) min.

(R)-1-(benzo[b]thiophen-5-yl)hexan-2-ol (25)

The reaction was performed according to general procedure using 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (30.8 mg, 0.2 mmol, 1.0 equiv.), n-butyl lithium (2.5 M in diethyl ether, 0.08 mL, 0.20 mmol, 1.0 equiv.), 5-bromobenzothiophene (45.7 mg, 0.21 mmol, 1.05 equiv.). The crude product was purified by automated flash column chromatography (Biotage 4% → 30% ethyl acetate in n-hexane, stained in CAM) to afford a colorless oil (39.4 mg, 84% yield, 95:5 er). ¹H NMR (600 MHz, CDCl₃) δ 7.81 (d, J = 8.2 Hz, 1H), 7.67 (s, 1H), 7.43 (d, J = 5.4 Hz, 1H), 7.29 (dd, J = 5.4, 0.8 Hz, 1H), 7.20 (dd, J = 8.2, 1.7 Hz, 1H), 3.88 – 3.83 (m, 1H), 2.95 (dd, J = 13.6, 4.2 Hz, 1H), 2.75 (dd, J = 13.6, 8.4 Hz, 1H), 1.61 – 1.44 (m, 4H), 1.42 – 1.25 (m, 3H), 0.92 (t, J = 7.3 Hz, 3H).; ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 140.1, 138.1, 134.8, 126.9, 126.1, 124.3, 123.8, 122.6, 73.0, 44.1, 36.7, 28.1, 22.9, 14.2.; IR (neat) ν_max 3394 (br), 2954 (s), 2929 (s), 2858 (m), 1464 (w), 1455 (s), 1260 (w), 1050 (m), 1031 (m), 703 (s), 690 (s), 478 (m) cm⁻¹.; HRMS (DART) m/z: [M+H-H₂O]⁺ Calc’d for C₁₄H₁₇S: 217.1046, Found: 217.1043.; [α]²⁰_D: −7.80 (c 1.0, CHCl₃); Chiral SFC (OD-H, 10% IPA, 3ml/min, 100 bar, 35 °C, 210–270 nm) retention time 7.26 and 8.12 (major) min.

(R)-1-phenylpropan-2-ol (26)

The reaction was performed according to general procedure using 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (30.8 mg, 0.2 mmol, 1.0 equiv.), methyl lithium (1.6 M in diethyl ether, 0.125 mL, 0.20 mmol, 1.0 equiv.), bromobenzene (34.5 mg, 0.22 mmol, 1.1 equiv.). The crude product was purified by automated flash column chromatography (Biotage, 2% → 20% ethyl acetate in n-hexane, stained in CAM) to afford a colorless oil (10.9 mg, 40% yield, 95:5 er). All spectral data were in accordance with the literature.¹² Chiral SFC (OJ-H, 1% IPA, 3ml/min, 100 bar, 35 °C, 210–270 nm) retention time 11.85 and 12.52 (major) min.

Data Availability Statement

The data underlying this study are available in the published article and its online supplementary material.