silver-catalyzed enantioselective propargylic c–h bond ...€¦ · s1 supplementary information...

doi.org/10.26434/chemrxiv.12373262.v3

Silver-Catalyzed Enantioselective Propargylic C–H Bond AminationThrough Rational Ligand Designminsoo ju, Emily Zerull, Jessica Roberts, Minxue Huang, Jennifer Schomaker

Submitted date: 29/05/2020 • Posted date: 01/06/2020Licence: CC BY-NC-ND 4.0Citation information: ju, minsoo; Zerull, Emily; Roberts, Jessica; Huang, Minxue; Schomaker, Jennifer (2020):Silver-Catalyzed Enantioselective Propargylic C–H Bond Amination Through Rational Ligand Design.ChemRxiv. Preprint. https://doi.org/10.26434/chemrxiv.12373262.v3

Asymmetric C–H amination via nitrene transfer (NT) is a powerful tool for the preparation of enantioenrichedamine building blocks from abundant C–H bonds. Herein, we report a highly regio- and enantioselectivesynthesis of -alkynyl -amino alcohol motifs via a silver-catalyzed propargylic C–H amination. The protocolwas enabled by development of a new bis(oxazoline) (BOX) ligand through a rapid structure-activityrelationship (SAR) analysis. The method utilizes readily accessible carbamate ester substrates bearing-propargylic C–H bonds and furnishes versatile products in good yields and with excellent enantioselectivity(90–99% ee). A putative Ag–nitrene intermediate is proposed to undergo an enantiodetermininghydrogen-atom transfer (HAT) during the C–H amination event. Density functional theory (DFT) calculationswere performed to investigate the origin of enantioselectivity in the HAT step.

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http://doi.org/10.26434/chemrxiv.12373262.v3

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S1

Supplementary Information for

Silver-Catalyzed Enantioselective Propargylic C–H Bond Amination Through Rational Ligand Design

Minsoo Ju, Emily E. Zerull, Jessica M. Roberts, Minxue Huang, Ilia A. Guzei, Jennifer M. Schomaker*

Department of Chemistry, University of Wisconsin-Madison 1101 University Avenue, Madison, WI 53706, USA

*Corresponding author. Email: [email protected]

S2

Table of Contents

I. General information ..................................................................................... S3

II. Synthesis of carbamate ester substrates ..................................................... S4

III. Synthesis of novel Min-BOX ligand ......................................................... S15

IV. Procedure for reaction development ......................................................... S18

V. Asymmetric amination of propargylic C–H bonds .................................. S20

VI. LFER studies evaluating steric effects on enantioselectivity .................. S37

VII. VT NMR studies of silver complexes ........................................................ S38

VIII. Computational studies ................................................................................ S42

IX. X-ray crystallography data of compound 16 ........................................... S48

X. References .................................................................................................... S60

XI. NMR spectral data ...................................................................................... S63

XII. HPLC chromatograms ............................................................................ S116

S3

I. General information.

All glassware was either oven-dried overnight at 130 °C or flame-dried using a Bunsen burner. All

glassware was then allowed to cool to room temperature in a desiccator filled with DrieriteTM as a

desiccant or under a stream of dry nitrogen prior to use. Unless otherwise specified, reagents were

used as obtained from Sigma-Aldrich, Oakwood Products, Alfa Aesar, Tokyo Chemical Industry,

Combi-Blocks, Acros Organics or Cayman Chemicals and directly used without further

purification. Diethyl ether (Et2O) was freshly distilled from Na/benzophenone ketyl.

Tetrahydrofuran (THF) was either freshly distilled from Na/benzophenone ketyl or passed through

an alumina column before use. Dichloromethane (CH2Cl2) was either dried over calcium hydride

(CaH2) and freshly distilled before use or passed through an alumina column before use.

Acetonitrile (CH3CN), toluene and benzene were all dried over CaH2 and freshly distilled before

use. All other solvents were purified using accepted procedures from the sixth edition of

“Purification of Laboratory Chemicals”.1 Air- and moisture-sensitive reactions were performed

using standard Schlenk techniques under a nitrogen atmosphere. Analytical thin layer

chromatography (TLC) was performed utilizing pre-coated silica gel 60 F24 plates containing a

fluorescent indicator, while preparative chromatography was performed using SilicaFlash P60

silica gel (230-400 mesh) via Still’s method.2 Column chromatography was typically run using a

gradient method employing mixtures of hexanes and ethyl acetate (EtOAc). Various stains were

used to visualize reaction products, including p-anisaldehyde, KMnO4, ceric ammonium

molybdate (CAM stain) and iodine powder. 1H NMR and 13C NMR spectra were obtained using

Bruker Avance-400 (400 and 100 MHz) and Bruker Avance-500 (500 and 125 MHz)

spectrometers. Chemical shifts were reported in accordance to residual protiated solvent peaks

(note: CDCl3 referenced at δ 7.26 and 77.16 ppm, respectively). High-performance liquid

S4

chromatography (HPLC) analyses were performed using Shimadzu LC-20AB and Waters

ACQUITY UPC2 systems, respectively. A CHIRALPAK® AD-H (0.46 cm diameter x 25 cm) or

CHIRALCEL® OJ-H column (0.46 cm diameter x 25 cm) was employed, maintained at a

temperature of 40 °C, using iPrOH/hexane mobile phase. Accurate mass measurements were

acquired at the University of Wisconsin-Madison using a Micromass LCT (electrospray ionization,

time-of-flight analyzer or electron impact methods). The following instrumentation in the Paul

Bender Chemistry Instrumentation Center was supported by: Thermo Q ExactiveTM Plus by NIH

1S10 OD020022-1; Bruker Quazar APEX2 and Bruker Avance-500 by a generous gift from Paul

J. and Margaret M. Bender; Bruker Avance-600 by NIH S10 OK012245; Bruker Avance-400 by

NSF CHE-1048642 and the University of Wisconsin-Madison; Varian Mercury-300 by NSF CHE-

0342998.

II. Synthesis of carbamate ester substrates.

General procedure A for TCI-mediated carbamate synthesis. Trichloroacetyl isocyanate (TCI,

1.43 mL, 12 mmol, 1.2 equiv) was slowly added dropwise to a solution of alcohol (10 mmol, 1.0

equiv) in 20 mL of dry CH2Cl2 at 0 °C. The reaction was warmed to room temperature and stirred

until TLC indicated complete consumption of the starting alcohol (1–6 h). The solvent was then

removed under reduced pressure and the crude reaction mixture was dissolved in 17 mL of MeOH.

K2CO3 (0.14 g, 1 mmol, 0.1 equiv) was added and the mixture was stirred overnight. The mixture

was diluted with CH2Cl2 (10 mL) and quenched by careful addition of saturated aqueous NH4Cl

S5

(15 mL). The aqueous layer was extracted with CH2Cl2 (3 x 15 mL). The combined organic layers

were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure.

IMPORTANT NOTE: The trichloroacetamide contaminant must be removed in order to achieve

reproducibility in silver-catalyzed nitrene transfer reactions. This was accomplished by re-

dissolving the crude mixture in CH2Cl2 (150 mL) and stirring vigorously with a 1 M aqueous

NaOH solution (75 mL) for 30 min. The phases were separated, and the aqueous layer was

extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine, dried

over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified

by silica gel column chromatography.

General procedure B for CDI-mediated carbamate synthesis. To a solution of alcohol (10

mmol, 1.0 equiv) in 60 mL of dry toluene was added carbonyl-diimidazole (CDI, 1.96 g, 12.0

mmol, 1.2 equiv) at room temperature. Upon complete consumption of starting alcohol indicated

by TLC (3–5 h), solvent was evaporated under reduced pressure. The residue was dissolved in 25

mL of dry THF and the resulting solution was stirred for 1 h before the addition of aqueous NH4OH

(28–30%, 1.2 mL). Stirring was continued overnight, then the mixture diluted with EtOAc (50

mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under

reduced pressure. The crude product was purified by silica gel column chromatography.

S6

General procedure C for carbamate synthesis via Sonogashira coupling. Pent-4-ynyl

carbamate (3 mmol, 1.5 equiv) was added to a mixture of bis(triphenylphosphine)palladium (II)

dichloride (PdCl2(PPh3)2, 1 mol %) and aryl bromide (2 mmol, 1 equiv) dissolved in Et3N (0.25

M). The solution was warmed to 40 °C and stirred for 15 minutes. CuI (2 mol %) was then added

to the reaction and was warmed to 80 °C and stirred overnight. After cooling to ambient

temperature, the solution was diluted with EtOAc and quenched with 1 M HCl. The mixture was

extracted with three portions of EtOAc. The combined organic phases were washed with brine,

dried over Mg2SO4, and concentrated under reduced pressure. The crude product was purified by

silica gel column chromatography.

Compound 1. Carbamate ester 1 was prepared from 4-hexyn-1-ol according to the general

procedure A on a 9.7 mmol scale. Purification was carried out by silica gel column

chromatography (0→50% EtOAc/hexanes) to yield a white solid (1.14 g, 83% yield); Rf = 0.47

(50% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 4.66 (s, 2H, br), 4.16 (t, J = 6.4 Hz, 2H),

2.23 (tq, J = 7.1, 2.5 Hz, 2H), 1.83 – 1.76 (m, 5H); 13C NMR (126 MHz, CDCl3) δ 156.9, 77.7,

76.3, 64.0, 28.3, 15.4, 3.5; HRMS (ESI) m/z calcd. for C7H11NO2 [M+H]+: 142.0863, found:

142.0862.

Compound S1. Carbamate ester S1 was prepared from 4-decyn-1-ol according to the general

procedure A on a 5.0 mmol scale. Purification was carried out by silica gel column


S7


2.25 (tt, J = 7.0, 2.4 Hz, 2H), 2.13 (tt, J = 7.2, 2.4 Hz, 2H), 1.81 (p, J = 6.7 Hz, 2H), 1.48 (p, J =

7.1 Hz, 2H), 1.40 – 1.25 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 156.8,

81.2, 78.5, 64.0, 31.1, 28.8, 28.5, 22.2, 18.7, 15.4, 14.0; HRMS (ESI) m/z calcd. for C11H19NO2

[M+H]+: 198.1489, found: 198.1490.

Compound S2. Carbamate ester S2 was prepared from 6-methyl-4-heptyn-1-ol according to the

general procedure A on a 5.1 mmol scale. Purification was carried out by silica gel column



2.51 (dpdd, J = 9.1, 6.8, 4.5, 2.2 Hz, 1H), 2.24 (td, J = 7.0, 2.2 Hz, 2H), 1.80 (p, J = 7.0, 6.5 Hz,

2H), 1.13 (d, J = 6.9 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 157.0, 87.0, 77.9, 64.1, 28.6, 23.5,

20.6, 15.5; HRMS (ESI) m/z calcd. for C9H15NO2 [M+H]+: 170.1176, found: 170.1174.

Compound S3. Carbamate ester S3 was prepared from 6,6-dimethyl-4-heptyn-1-ol according to

the general procedure A on a 6.5 mmol scale. Purification was carried out by silica gel column



2.24 (t, J = 7.0 Hz, 2H), 1.79 (p, J = 6.7 Hz, 2H), 1.19 (s, 9H); 13C NMR (126 MHz, CDCl3) δ

S8

157.0, 89.9, 77.1, 64.1, 31.5, 28.7, 27.5, 15.5; HRMS (ESI) m/z calcd. for C10H17NO2 [M+H]+:

184.1332, found: 184.1330.

Compound S4. Carbamate ester S4 was prepared from 5-(trimethylsilyl)-4-pentyn-1-ol according

to the general procedure B on a 10 mmol scale. Purification was carried out by silica gel column



2.32 (t, J = 7.1 Hz, 2H), 1.84 (p, J = 6.7 Hz, 2H), 0.14 (s, 9H); 13C NMR (126 MHz, CDCl3) δ

156.9, 106.0, 85.4, 63.9, 28.2, 16.7, 0.2; HRMS (ESI) m/z calcd. for C9H17NO2Si [M+Na]+:

222.0921, found: 222.0919.

Compound S5. Following a literature procedure reported by Tresse et al.,3 a pre-dried 100-mL

round-bottom flask was charged with CuI (0.86 g, 4.5 mmol, 1.5 equiv), K2CO3 (1.24 g, 9.0 mmol,

3.0 equiv), TMEDA (0.68 mL, 4.5 mmol, 1.5 equiv), and dry DMF (14 mL). The resulting deep

blue mixture was vigorously stirred at room temperature under an atmosphere of air (balloon) for

15 min. TMFCF3 (0.89 mL, 6.0 mmol, 2.0 equiv) was added and the resulting deep green mixture

was stirred for an additional 5 min under air atmosphere. After cooling to 0 °C, a solution of pent-

4-ynyl carbamate (0.38 g, 3.0 mmol, 1.0 equiv) and TMFCF3 (0.89 mL, 6.0 mmol, 2.0 equiv) in

dry DMF (14 mL), previously cooled to 0 °C, was then added in one portion. Under air atmosphere,

the reaction mixture was stirred at 0 °C for 30 min, and then at room temperature for 40 h. The

S9

reaction mixture was diluted with E2O and washed with H2O. The aqueous layer was extracted

with E2O three times. The combined organic layer was washed with H2O (three times) and brine,

dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was

purified by silica gel column chromatography (0→70% EtOAc/hexanes) to afford the desired

trifluoromethylated alkyne S5 as a white solid (0.26 g, 44% yield); 1H NMR (500 MHz, CDCl3) δ

4.68 (s, 2H, br), 4.16 (t, J = 6.1 Hz, 2H), 2.43 (tq, J = 7.3, 3.7 Hz, 2H), 1.92 (p, J = 7.0, 6.3 Hz,

2H); 13C NMR (126 MHz, CDCl3) δ 156.7, 114.2 (q, J = 256.3 Hz), 88.0 (q, J = 6.3 Hz), 69.0 (q,

J = 52.1 Hz), 63.5, 27.0 (q, J = 1.5 Hz), 15.2 (q, J = 1.6 Hz); 19F NMR (377 MHz, CDCl3) δ -49.6;

HRMS (ESI) m/z calcd. for C7H8F3NO2 [M+H]+: 196.0580, found: 196.0581.

Compound S6. Carbamate ester S6 was prepared from bromobenzene according to the general

procedure C on a 3.0 mmol scale. Purification was carried out by silica gel column chromatography

(0→30% EtOAc/hexanes) to yield a white solid (0.47 g, 76% yield); 1H NMR (500 MHz, CDCl3)

δ 7.42 – 7.36 (m, 2H), 7.28 (dd, J = 5.0, 2.0 Hz, 3H), 4.57 (s, 2H, br), 4.23 (t, J = 6.3 Hz, 2H), 2.52

(t, J = 7.0 Hz, 2H), 1.94 (p, J = 6.7 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 156.6, 131.5, 128.2,

127.6, 123.6, 88.6, 81.2, 63.9, 28.1, 16.1.

Compound S7. Carbamate ester S7 was prepared from 4-bromotoluene according to the general


(EtOAc/hexanes) to yield an off-white solid (0.37 g, 86% yield); 1H NMR (500 MHz, CDCl3) δ

S10

7.28 (d, J = 7.8 Hz, 2H), 7.08 (d, J = 7.8 Hz, 2H), 4.79 (s, 2H, br), 4.22 (t, J = 6.3 Hz, 2H), 2.50

(t, J = 7.0 Hz, 2H), 2.32 (s, 3H), 1.92 (p, J = 6.7 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 157.01,

137.69, 131.43, 128.97, 120.60, 87.86, 81.28, 63.93, 28.20, 21.40, 16.14; HRMS (ESI) m/z calcd.

for C13H15NO2 [M+Na]+: 240.0995, found: 240.0994.

Compound S8. Carbamate ester S8 was prepared from 4-bromobenzotrifluoride according to the

general procedure C on a 2.0 mmol scale. Purification was carried out by silica gel column

chromatography (EtOAc/hexanes) to yield an off-white solid (0.52 g, 96% yield); 1H NMR (500

MHz, CDCl3) δ 7.54 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H), 4.59 (s, 2H, br), 4.23 (t, J = 6.3

Hz, 2H), 2.54 (t, J = 7.1 Hz, 2H), 1.99 – 1.91 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 156.8, 132.0,

129.5 (q, J = 32.7 Hz), 127.7 (q, J = 1.4 Hz), 125.3 (q, J = 3.8 Hz), 123.1 (q, J = 272.0 Hz). 91.6,

80.3, 64.0, 28.1, 16.3; HRMS (ESI) m/z calcd. for C13H12F3NO2 [M+Na]+: 294.0712, found:

294.0710.

Compound S9. Carbamate ester S9 was prepared from 4-bromoanisole according to the general



7.35 – 7.30 (m, 2H), 6.83 – 6.79 (m, 2H), 4.55 (s, 2H, br), 4.23 (t, J = 6.3 Hz, 2H), 3.80 (s, 3H),

2.50 (t, J = 7.0 Hz, 2H), 1.93 (p, J = 6.7 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 159.2, 156.7,

S11

132.9, 115.9, 113.9, 87.0, 81.0, 64.0, 55.27, 28.24, 16.14; HRMS (ESI) m/z calcd. for C13H15NO3

[M+Na]+: 256.0944, found: 256.0944.

O

O NH2

.

OMe

Compound S10. Carbamate ester S10 was prepared from 5-(3-methoxyphenyl)pent-4-yn-1-ol

according to the general procedure A on a 5.0 mmol scale. Purification was carried out by silica

gel column chromatography (0→40% EtOAc/hexanes) to yield a white solid (0.62 g, 35% yield);

Rf = 0.58 (40% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.19 (t, J = 7.9 Hz, 1H), 6.99 (dt,

J = 7.6, 1.3 Hz, 1H), 6.93 (dd, J = 2.7, 1.5 Hz, 1H), 6.84 (ddd, J = 8.3, 2.6, 1.0 Hz, 1H), 4.57 (s,

2H, br), 4.23 (t, J = 6.3 Hz, 2H), 3.79 (s, 3H), 2.51 (t, J = 7.1 Hz, 2H), 1.94 (p, J = 6.7 Hz, 2H);

13C NMR (126 MHz, CDCl3) δ 159.7, 157.1, 129.7, 125.1, 124.5, 116.8, 114.7, 88.9, 81.6, 64.3,

55.7, 28.5, 16.5.

Compound S11. Carbamate ester S11 was prepared from 2-bromotoluene according to the general



7.36 (d, J = 7.5 Hz, 1H), 7.20 – 7.14 (m, 2H), 7.10 (dq, J = 8.4, 4.0 Hz, 1H), 4.58 (s, 2H, br), 4.25

(t, J = 6.3 Hz, 2H), 2.56 (t, J = 7.0 Hz, 2H), 2.41 (s, 3H), 1.96 (p, J = 6.7 Hz, 2H); 13C NMR (126

MHz, CDCl3) δ 156.7, 140.0, 131.9, 129.3, 127.7, 125.5, 123.5, 92.6, 80.1, 64.0, 28.3, 20.7, 16.3;

HRMS (ESI) m/z calcd. for C13H15NO2 [M+Na]+: 240.0995, found: 240.0993.

S12

Compound S12. Carbamate ester S12 was prepared from 5-furan-2-yl-pent-4-yn-1-ol according

to the general procedure A on a 0.4 mmol scale. No further purification was necessary and a white

solid was obtained (89.9 mg, quant. yield); 1H NMR (500 MHz, CDCl3) δ 7.33 (dd, J = 1.9, 0.8

Hz, 1H), 6.48 (d, J = 3.4 Hz, 1H), 6.35 (dd, J = 3.4, 1.9 Hz, 1H), 4.60 (s, 2H, br), 4.21 (t, J = 6.2

Hz, 2H), 2.54 (t, J = 7.1 Hz, 2H), 1.94 (p, J = 6.6 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 156.7,

142.9, 137.4, 114.0, 110.7, 93.2, 71.6, 63.8, 27.8, 16.3; HRMS (ESI) m/z calcd. for C10H11NO3

[M+Na]+: 216.0631, found: 216.0630.

Compound S13. Carbamate ester S13 was prepared from 3-bromothiophene according to the

general procedure C on a 2.0 mmol scale. Purification was carried out by silica gel column

chromatography (EtOAc/hexanes) to yield an off-white solid (0.26 g, 61% yield); 1H NMR (500

MHz, CDCl3) δ 7.35 (dd, J = 3.0, 1.1 Hz, 1H), 7.23 (dd, J = 5.0, 3.0 Hz, 1H), 7.06 (dd, J = 5.0, 1.2

Hz, 1H), 4.69 (s, 2H. br), 4.21 (t, J = 6.3 Hz, 2H), 2.49 (t, J = 7.1 Hz, 2H), 1.92 (p, J = 6.7 Hz,

2H); 13C NMR (126 MHz, CDCl3) δ 156.7, 130.0, 127.8, 125.1, 122.6, 88.2, 76.3, 63.9, 28.1, 16.1;

HRMS (ESI) m/z calcd. for C10H11NO2S [M+Na]+: 232.0403, found: 232.0400.

S13

Compound S14. Carbamate ester S14 was prepared from 5-tert-butyldiphenylsilyl-4-pentyn-1-ol

according to the general procedure B on a 7.44 mmol scale. Purification was carried out by silica

gel column chromatography (0→50% EtOAc/hexanes) to yield a colorless oil (2.50 g, 92% yield);

Rf = 0.35 (40% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.82 – 7.76 (m, 4H), 7.43 – 7.33

(m, 6H), 4.55 (s, 2H, br), 4.24 (t, J = 6.3 Hz, 2H), 2.51 (t, J = 7.1 Hz, 2H), 1.97 (p, J = 6.7 Hz, 2H),

1.07 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 156.8, 135.7, 133.9, 129.5, 127.8, 110.2, 80.5, 64.1,

28.4, 27.2, 18.6, 17.1; HRMS (ESI) m/z calcd. for C22H27NO2Si [M+Na]+: 388.1703, found:

388.1695.

Compound S15. Carbamate ester S15 was prepared from 7-methoxy-4-heptyn-1-ol according to

the general procedure A on a 0.8 mmol scale. No further purification was necessary and a white

solid was obtained (0.13 g, 89% yield); 1H NMR (500 MHz, CDCl3) δ 4.62 (s, 2H, br), 4.15 (t, J

= 6.3 Hz, 2H), 3.47 (t, J = 6.9 Hz, 2H), 3.37 (s, 3H), 2.43 (tt, J = 6.8, 2.4 Hz, 2H), 2.26 (tt, J = 7.0,

2.4 Hz, 2H), 1.81 (p, J = 6.7 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 156.8, 79.8, 77.5, 71.2, 64.0,

58.6, 28.2, 19.9, 15.5; HRMS (ESI) m/z calcd. for C9H15NO3 [M+Na]+: 226.0605, found:

226.0606.

Compound S16. Carbamate ester S16 was prepared from 1-chloro-8-hydroxyoct-4-yne according

to the general procedure A on a 1.0 mmol scale. No further purification was necessary and a white

solid was obtained (0.19 g, 91% yield); 1H NMR (500 MHz, CDCl3) δ 4.61 (s, 2H, br), 4.15 (t, J

S14

= 6.3 Hz, 2H), 3.65 (t, J = 6.4 Hz, 2H), 2.34 (tt, J = 6.8, 2.4 Hz, 2H), 2.25 (tt, J = 7.0, 2.4 Hz, 2H),

1.93 (p, J = 6.6 Hz, 2H), 1.81 (p, J = 6.7 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 156.9, 79.9,

79.1, 64.1, 43.9, 31.8, 28.5, 16.3, 15.5; HRMS (ESI) m/z calcd. for C9H14ClNO2 [M+Na]+:

208.0944, found: 208.0944.

Compound S17. Carbamate ester S17 was prepared from 2,2-dimethyl-5-phenyl-pent-4-yn-1-ol

according to the general procedure A on a 2.0 mmol scale. Purification was carried out by silica

gel column chromatography (0→30% EtOAc/hexanes) to yield a white solid (0.32 g, 68% yield);

1H NMR (500 MHz, CDCl3) δ 7.44 – 7.37 (m, 2H), 7.28 (dd, J = 5.2, 2.0 Hz, 3H), 4.60 (s, 2H, br),

3.97 (s, 2H), 2.39 (s, 2H), 1.08 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 156.9, 131.6, 128.2, 127.7,

123.8, 87.1, 82.7, 72.2, 34.8, 29.7, 24.1; HRMS (ESI) m/z calcd. for C14H17NO2 [M+Na]+:

254.1152, found: 254.1150.

Compound S18. Carbamate ester S18 was prepared from 1,1-dimethyl-5-phenyl-pent-4-yn-1-ol

according to the general procedure A on a 2.0 mmol scale. No further purification was necessary

and a white solid was obtained (0.38 g, 83% yield); 1H NMR (500 MHz, CDCl3) δ 7.38 (dh, J =

5.6, 2.3 Hz, 2H), 7.31 – 7.26 (m, 3H), 4.41 (s, 2H, br), 2.52 – 2.44 (m, 2H), 2.14 – 2.07 (m, 2H),

1.51 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 155.8, 131.5, 128.2, 127.6, 123.9, 89.9, 80.9, 80.5,

40.0, 26.0, 14.4; HRMS (ESI) m/z calcd. for C14H17NO2 [M+Na]+: 254.1152, found: 254.1150.

S15

III. Synthesis of novel Min-BOX ligand.

Compound S19. The title compound was prepared according to a 2-step asymmetric

hydroformylation–reduction procedure reported by the Landis group,4 using 3,5-di-tert-

butylstyrene on a 3.0 mmol scale. Silica plug eluting with CH2Cl2 afforded the desired alcohol S19

as a colorless oil (0.78 g, quant. yield over 2 steps); Rf = 0.37 (20% EtOAc/hexanes); 1H NMR

(500 MHz, CDCl3, OH signal not visible) δ 7.31 (t, J = 1.8 Hz, 1H), 7.07 (d, J = 1.8 Hz, 2H), 3.71

(t, J = 6.6 Hz, 2H), 2.95 (h, J = 6.9 Hz, 1H), 1.33 (s, 18H), 1.29 (d, J = 7.1 Hz, 3H); 13C NMR (126

MHz, CDCl3) δ 151.1, 142.6, 121.7, 121.0, 69.1, 43.1, 35.0, 31.7, 17.8; HRMS (ESI) m/z calcd.

for C17H28O [M–H2O+H]+: 231.2107, found: 231.2106.

Compound S20. The title compound was prepared according to the general procedure A on a 3.0

mmol scale. Silica gel column chromatography (0→40% EtOAc/hexanes) afforded the desired

carbamate ester S20 as a colorless oil (0.98 g, quant. yield); Rf = 0.21 (20% EtOAc/hexanes); 1H

NMR (500 MHz, CDCl3) δ 7.29 (t, J = 1.8 Hz, 1H), 7.06 (d, J = 1.8 Hz, 2H), 4.56 (s, 2H, br), 4.20

S16

– 4.13 (m, 2H), 3.08 (h, J = 7.1 Hz, 1H), 1.34 – 1.29 (m, 21H); 13C NMR (126 MHz, CDCl3) δ

157.0, 150.8, 142.4, 121.6, 120.8, 70.5, 39.7, 35.0, 31.7, 18.3; HRMS (ESI) m/z calcd. for

C18H29NO2 [M+NH4]+: 309.2537, found: 309.2530.

Compound S21. The title compound was prepared according to a literature procedure reported by

the Schomaker group,5 using carbamate ester S20 on a 3.0 mmol scale. Silica gel column

chromatography (0→50% EtOAc/hexanes) followed by recrystallization from hexanes afforded

the desired oxazolidinone S21 as a white solid (0.50 g, 58% yield, 98% ee); Rf = 0.30 (30%

EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.39 (t, J = 1.8 Hz, 1H), 7.19 (d, J = 1.7 Hz, 2H),

5.77 (s, 1H, br), 4.41 – 4.33 (m, 2H), 1.77 (s, 3H), 1.33 (s, 18H); 13C NMR (126 MHz, CDCl3) δ

159.1, 151.7, 142.5, 122.3, 118.9, 78.5, 60.9, 35.2, 31.6, 28.0; HRMS (ESI) m/z calcd. for

C17H27NO2 [M+H]+: 290.2115, found: 290.2109.

Compound S22. To a round-bottom flask containing compound S21 (0.50 g, 1.73 mmol, 1 equiv)

were added EtOH (4.3 mL), H2O (2.2 mL), and NaOH (277 mg, 6.92 mmol, 4 equiv). The resulting

mixture was refluxed at 80 °C until TLC indicated reaction completion (30 h). After cooling to

room temperature, EtOH was evaporated under reduced pressure and the residue extracted with

CH2Cl2 three times. The combined organic phase was washed with brine and the brine layer

extracted with CH2Cl2 three times again. The total combined organic phase was dried over Na2SO4

and concentrated under reduced pressure to afford the desired β-amino alcohol S22 as a white solid

(0.45 g, 99% yield); 1H NMR (500 MHz, CDCl3) δ 7.34 (d, J = 1.5 Hz, 1H), 7.29 (d, J = 1.5 Hz,

2H), 3.64 (s, 2H, br), 1.69 (s, 3H, br), 1.49 (s, 3H), 1.34 (s, 18H); 13C NMR (126 MHz, CDCl3) δ

150.9, 145.2 (br), 121.2, 119.5, 72.0 (br), 56.6 (br), 35.2, 31.7, 27.5 (br); HRMS (ESI) m/z calcd.

for C17H29NO [M+H]+: 264.2322, found: 264.2324.

*Due to intermolecular proton exchange, broadened signals were observed on the NMR.

S17

Min-BOX. Following a literature procedure reported by Cornejo et al.,6 a 25-mL three-necked

round-bottom flask fitted with a reflux condenser was charged with 2,2-dimethylmalononitrile (43

mg, 0.457 mmol, 1.0 equiv) and Zn(OTf)2 (166 mg, 0.684 mmol, 1.5 equiv). The system was

purged with N2 and freshly distilled toluene (9 mL) was added. The system was stirred for 5 min

and β-amino alcohol S22 (0.24 g, 0.911 mmol, 2.0 equiv) was added in one portion. The solution

was refluxed at 110 °C for 80 h. The system was allowed to cool to room temperature, diluted

with EtOAc, and washed with brine. The brine layer was extracted with EtOAc three times. The

combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The

crude material was purified by silica gel column chromatography (0→30% EtOAc/hexanes) to

afford the desired Min-BOX as a yellow solid (0.14 g, 52% yield); Rf = 0.13 (10%

EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.29 (t, J = 1.8 Hz, 2H), 7.22 (d, J = 1.8 Hz, 4H),

4.31 – 4.24 (m, 4H), 1.67 (d, J = 5.0 Hz, 12H), 1.31 (s, 36H); 13C NMR (126 MHz, CDCl3) δ

168.4, 150.7, 146.0, 121.0, 119.8, 81.6, 72.8, 38.8, 35.1, 31.7, 28.5, 24.8; HRMS (ESI) m/z calcd.

for C39H58N2O2 [M+H]+: 587.4571, found: 587.4564.

S18

IV. Procedure for reaction development.

General procedure for ligand optimization. A pre-dried 1-dram vial equipped with a magnetic

stir bar was charged with AgClO4 (4.2 mg, 0.02 mmol, 0.2 equiv) and a BOX ligand (10 mol %,

see Table S1). Dry CH2Cl2 (2 mL) was added to the vial and the reaction mixture stirred vigorously

for 15 min. Powdered 4 Å molecular sieves (100 mg, 1 g of sieves/mmol of substrate) were added,

followed by carbamate ester 1 (14.1 mg, 0.1 mmol, 1.0 equiv). Iodosobenzene (44 mg, 0.2 mmol,

2.0 equiv) was added in one portion and the reaction mixture was stirred at room temperature

overnight (8–12 h). The mixture was filtered through a pad of Celite® rinsing with CH2Cl2, and the

filtrate concentrated under reduced pressure. The yield of oxazinanone 2 was obtained by 1H NMR

spectroscopic analysis of the crude reaction mixture (relative to mesitylene as an internal standard).

The ee value was determined by chiral HPLC analysis of compound 2a obtained by benzylation

of oxazinanone 2 (see section V for the benzylation procedure) in comparison with an authentic

sample of racemic material.

S19

Table S1. BOX ligand optimization with carbamate ester 1.

General procedure for further optimization. A pre-dried 13 x 100 mm glass test tube equipped

with a magnetic stir bar was charged with AgClO4 (x mol %), Min-BOX ligand (y mol %), and

dry CH2Cl2 (2 mL). The test tube was capped with a rubber septum and the reaction mixture was

stirred vigorously for 15 min at room temperature. Powdered 4 Å molecular sieves (100 mg, 1 g

of sieves/mmol of substrate) were added, followed by carbamate ester S6 (20.3 mg, 0.1 mmol, 1.0

equiv). After adjusting the reaction temperature using a chiller, iodosobenzene (44 mg, 0.2 mmol,

2.0 equiv) was added in one portion and the reaction mixture was stirred for 12–72 h. The mixture

S20

was filtered through a pad of Celite® rinsing with CH2Cl2, and the filtrate concentrated under

reduced pressure. The yield of oxazinanone 8 was obtained by 1H NMR spectroscopic analysis of

the crude reaction mixture (relative to mesitylene as an internal standard). The ee value was

determined by chiral HPLC analysis of oxazinanone 8 in comparison with an authentic sample of

racemic material.

Table S2. Further reaction optimization with carbamate ester S6.

V. Asymmetric amination of propargylic C–H bonds.

General procedure D for Ag-catalyzed asymmetric C–H amination. A pre-dried 16 x 100 mm

glass test tube equipped with a magnetic stir bar was charged with AgClO4 (2.1 mg, 10 μmol, 5

mol %), Min-BOX ligand (2.9 mg, 5 μmol, 2.5 mol %), and dry CH2Cl2 (4 mL). The test tube was

capped with a rubber septum and the reaction mixture was stirred vigorously for 15 min at room

temperature. Powdered 4 Å molecular sieves (200 mg, 1 g of sieves/mmol of substrate) were

added, followed by carbamate ester substrate (0.2 mmol, 1.0 equiv). After adjusting the reaction

temperature to –10 °C using a chiller, iodosobenzene (88 mg, 0.4 mmol, 2.0 equiv) was added in

S21

one portion and the reaction mixture was stirred at –10 °C for 36–48 h. The mixture was filtered

through a pad of Celite® rinsing with CH2Cl2, and the filtrate concentrated under reduced pressure.

The crude C–H amination product was purified by silica gel column chromatography.

General procedure E for benzylation of C–H amination product. To a solution of oxazinanone

(1.0 equiv) in anhydrous THF (0.05 M) were added KOtBu (2.0 equiv) and BnBr (1.5 equiv). The

reaction mixture was stirred at room temperature overnight and diluted with EtOAc and washed

with saturated aqueous NH4Cl. The aq. layer was extracted with EtOAc three times. The combined

organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced

pressure. The crude material was purified by silica gel column chromatography.

Compound 2. The title compound was obtained from carbamate ester 1 following the general

procedure D. Silica gel column chromatography (0→100% EtOAc/hexanes) afforded oxazinanone

2 as a white solid (23.0 mg, 83% yield); Rf = 0.17 (80% EtOAc/hexanes); 1H NMR (500 MHz,

CDCl3) δ 5.88 (s, 1H, br), 4.47 (ddd, J = 11.2, 8.2, 3.2 Hz, 1H), 4.34 – 4.20 (m, 2H), 2.18 (dddd,

J = 13.6, 8.3, 5.2, 3.4 Hz, 1H), 1.99 (dtd, J = 13.4, 6.4, 3.1 Hz, 1H), 1.83 (d, J = 2.1 Hz, 3H); 13C

NMR (126 MHz, CDCl3) δ 153.1, 80.8, 77.2, 64.8, 42.4, 28.1, 3.4; HRMS (ESI) m/z calcd. for

C7H9NO2 [M+H]+: 140.0706, found: 140.0705.

S22

The ee value (90%) was determined by chiral HPLC analysis of compound 2a obtained by

benzylation of compound 2 in comparison with an authentic sample of racemic material

(CHIRALPAK® AD-H, 5→30% iPrOH/hexane gradient over 22 min, 0.7 mL/min, 210 nm): tR =

14.6 min (minor), 16.5 min (major).

Compound 2a. The title compound was prepared from oxazinanone 2 according to the general

procedure E on a 0.079 mmol scale. Purification was carried out by silica gel column

chromatography (0→70% EtOAc/hexanes) to yield a yellow oil (12.1 mg, 67% yield); Rf = 0.54

(80% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.26 (m, 5H), 5.26 (d, J = 15.0 Hz,

1H), 4.55 (td, J = 11.2, 2.6 Hz, 1H), 4.26 (dtd, J = 11.0, 3.7, 1.4 Hz, 1H), 4.12 (d, J = 15.0 Hz,

1H), 4.00 (ddq, J = 5.4, 3.5, 2.0 Hz, 1H), 2.20 – 2.07 (m, 1H), 1.98 (dq, J = 13.9, 3.0 Hz, 1H), 1.85

(d, J = 2.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 153.3, 136.8, 128.8, 128.5, 127.8, 81.4, 76.5,

64.2, 50.3, 45.3, 28.9, 3.6; HRMS (ESI) m/z calcd. for C14H15NO2 [M+H]+: 230.1176, found:

230.1174.

Compound 3. The title compound was obtained from carbamate ester S1 following the general


3 as a colorless oil (34.4 mg, 88% yield); Rf = 0.21 (70% EtOAc/hexanes); 1H NMR (500 MHz,

CDCl3) δ 5.53 (s, 1H, br), 4.46 (ddd, J = 11.1, 8.0, 3.2 Hz, 1H), 4.31 (tt, J = 5.4, 2.2 Hz, 1H), 4.25

(ddd, J = 10.8, 6.9, 3.3 Hz, 1H), 2.22 – 2.14 (m, 3H), 1.99 (dtd, J = 13.5, 6.5, 3.2 Hz, 1H), 1.49 (p,

J = 7.2 Hz, 2H), 1.37 – 1.26 (m, 4H), 0.89 (t, J = 7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ

152.9, 85.6, 78.1, 65.0, 42.6, 31.1, 28.4, 28.3, 22.3, 18.6, 14.1; HRMS (ESI) m/z calcd. for

C11H17NO2 [M+H]+: 196.1332, found: 196.1333.

S23


benzylation of oxazinanone 3 in comparison with an authentic sample of racemic material






CDCl3) δ 5.43 (s, 1H), 4.45 (ddd, J = 11.2, 8.0, 3.1 Hz, 1H), 4.30 (ddd, J = 7.6, 5.1, 2.2 Hz, 1H),

4.25 (ddd, J = 10.9, 7.0, 3.3 Hz, 1H), 2.55 (heptd, J = 6.9, 1.8 Hz, 1H), 2.18 (dddd, J = 13.4, 8.3,

5.2, 3.3 Hz, 1H), 1.98 (dtd, J = 13.5, 6.4, 3.3 Hz, 1H), 1.14 (d, J = 6.9 Hz, 6H); 13C NMR (126

MHz, CDCl3) δ 152.9, 90.9, 77.4, 65.0, 42.6, 28.4, 22.9, 20.5; HRMS (ESI) m/z calcd. for

C9H13NO2 [M+H]+: 168.1019, found: 168.1019.



S24





chromatography (0→60% EtOAc/hexanes) to yield a colorless oil (11.5 mg, 59% yield); Rf = 0.31

(40% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.35 – 7.27 (m, 5H), 5.22 (d, J = 15.0 Hz,

1H), 4.53 (td, J = 11.1, 2.5 Hz, 1H), 4.25 (dtd, J = 11.0, 3.8, 1.4 Hz, 1H), 4.15 (d, J = 15.1 Hz,

1H), 4.03 (ddt, J = 5.1, 3.2, 1.6 Hz, 1H), 2.57 (heptd, J = 6.9, 1.8 Hz, 1H), 2.15 (dddd, J = 13.9,

11.3, 5.5, 3.9 Hz, 1H), 1.99 (dq, J = 13.9, 3.2 Hz, 1H), 1.17 (d, J = 6.9 Hz, 6H); 13C NMR (126

MHz, CDCl3) δ 153.3, 136.8, 128.8, 128.5, 127.8, 91.5, 76.4, 64.2, 50.4, 45.5, 29.1, 23.0, 23.0,

20.6; HRMS (ESI) m/z calcd. for C16H19NO2 [M+H]+: 258.1489, found: 258.1488.




CDCl3) δ 5.26 (s, 1H, br), 4.45 (ddd, J = 11.1, 7.8, 3.2 Hz, 1H), 4.32 – 4.28 (m, 1H), 4.25 (ddd, J

= 10.9, 7.1, 3.2 Hz, 1H), 2.18 (dddd, J = 13.3, 8.2, 5.2, 3.3 Hz, 1H), 1.98 (dtd, J = 13.8, 6.9, 3.2

Hz, 1H), 1.20 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 152.8, 93.8, 76.6, 65.0, 42.7, 31.0, 28.4,

27.4; HRMS (ESI) m/z calcd. for C10H15NO2 [M+H]+: 182.1176, found: 182.1175.

S25







chromatography (0→50% EtOAc/hexanes) to yield a white solid (21.9 mg, 83% yield); 1H NMR

(500 MHz, CDCl3) δ 7.36 – 7.27 (m, 5H), 5.20 (d, J = 15.0 Hz, 1H), 4.52 (td, J = 11.1, 2.6 Hz,

1H), 4.25 (dtd, J = 11.0, 3.8, 1.4 Hz, 1H), 4.17 (d, J = 15.0 Hz, 1H), 4.02 (ddd, J = 5.5, 3.3, 1.3

Hz, 1H), 2.15 (dddd, J = 13.9, 11.1, 5.6, 3.9 Hz, 1H), 1.99 (dtd, J = 13.8, 3.6, 2.6 Hz, 1H), 1.21 (s,

9H); 13C NMR (126 MHz, CDCl3) δ 153.3, 136.8, 128.8, 128.5, 127.8, 94.4, 75.7, 64.2, 50.4, 45.5,

31.0, 29.1, 27.5; HRMS (ESI) m/z calcd. for C17H21NO2 [M+H]+: 272.1645, found: 272.1643.




CDCl3) δ 5.38 (s, 1H, br), 4.47 (ddd, J = 11.3, 8.2, 3.2 Hz, 1H), 4.33 (td, J = 5.7, 2.3 Hz, 1H), 4.27

(dddd, J = 11.0, 6.7, 3.4, 0.8 Hz, 1H), 2.21 (dddd, J = 13.8, 8.5, 5.4, 3.4 Hz, 1H), 2.09 – 1.99 (m,

1H), 0.17 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 152.6, 103.1, 89.8, 64.9, 43.1, 27.9, -0.1; HRMS

(ESI) m/z calcd. for C9H15NO2Si [M+Na]+: 220.0764, found: 220.0761.

S26


benzoylation of oxazinanone 6 in comparison with an authentic sample of racemic material



Compound 6a. To a stirred solution of oxazinanone 6 (17.2 mg, 0.087 mmol, 1.0 equiv) in dry

CH3CN (1 mL) at 0 °C were sequentially added Et3N (0.11 mL 0.785 mmol, 9.0 equiv) and BzCl

(46 μL, 0.392 mmol, 4.5 equiv). The reaction mixture was stirred at room temperature until TLC

indicated complete consumption of the starting material (67 h). Upon reaction completion, the

mixture was diluted with CH2Cl2 and washed with saturated aqueous NH4Cl. The aq. layer was

extracted with CH2Cl2 three times. The combined organic layer was dried over Na2SO4, filtered,

and concentrated under reduced pressure. The crude material was purified by silica gel column

chromatography (0→40% EtOAc/hexanes) to afford the desired benzoylation product 6a as an

orange solid (24.4 mg, 93% yield); Rf = 0.29 (30% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3)

δ 7.65 – 7.58 (m, 2H), 7.55 – 7.48 (m, 1H), 7.42 (dd, J = 8.4, 7.0 Hz, 2H), 5.36 (dt, J = 5.6, 2.0

Hz, 1H), 4.77 (td, J = 11.4, 3.0 Hz, 1H), 4.47 (dddd, J = 11.0, 4.3, 2.5, 1.6 Hz, 1H), 2.35 (dddd, J

= 16.3, 11.9, 5.6, 4.3 Hz, 1H), 2.27 (dq, J = 14.2, 2.8 Hz, 1H), 0.14 (s, 9H); 13C NMR (126 MHz,

CDCl3) δ 172.6, 150.5, 135.6, 132.2, 128.4, 128.1, 101.7, 90.2, 65.4, 45.2, 28.4, -0.1; HRMS (ESI)

m/z calcd. for C16H19NO3Si [M+H]+: 302.1207, found: 302.1200.

S27



7 as a white solid (19.6 mg, 51% yield); Rf = 0.34 (100% EtOAc); 1H NMR (500 MHz, CDCl3) δ

6.40 (s, 1H, br), 4.53 – 4.45 (m, 2H), 4.37 (dddd, J = 11.6, 4.9, 3.7, 1.0 Hz, 1H), 2.33 (dddd, J =

13.7, 9.5, 5.7, 3.7 Hz, 1H), 2.18 – 2.11 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 152.5, 113.8 (q, J

= 258.3 Hz), 84.9 (q, J = 6.4 Hz), 71.9 (q, J = 53.4 Hz), 64.4, 41.7, 26.6; 19F NMR (377 MHz,

CDCl3) δ -50.8; HRMS (ESI) m/z calcd. for C7H6F3NO2 [M+H]+: 194.0423, found: 194.0424.

The ee value (94%) was determined by chiral HPLC analysis of oxazinanone 7 in comparison with

an authentic sample of racemic material (CHIRALCEL® OJ-H, 5→10% iPrOH/hexane gradient

over 22 min then 10% iPrOH/hexane isocratic for 5 min, 0.7 mL/min, 200 nm): tR = 20.2 min

(major), 22.2 min (minor).




CDCl3) δ 7.44 – 7.40 (m, 2H), 7.38 – 7.30 (m, 3H), 5.68 (s, 1H, br), 4.61 – 4.52 (m, 2H), 4.33

(ddd, J = 10.7, 6.5, 3.4 Hz, 1H), 2.31 (dddd, J = 13.7, 8.5, 5.3, 3.4 Hz, 1H), 2.15 (dtd, J = 13.5,

6.1, 3.0 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 152.8, 131.9, 129.0, 128.6, 121.9, 86.8, 84.7,




over 22 min, 0.7 mL/min, 235 nm): tR = 19.1 min (major), 20.5 min (minor).

S28



9 as a white solid (28.4 mg, 66% yield); 1H NMR (500 MHz, CDCl3) δ 7.30 (d, J = 7.9 Hz, 2H),

7.12 (d, J = 7.9 Hz, 2H), 5.68 (s, 1H, br), 4.59 – 4.51 (m, 2H), 4.32 (ddd, J = 10.8, 6.7, 3.4 Hz,

1H), 2.35 (s, 3H), 2.30 (dddd, J = 13.7, 8.6, 5.2, 3.3 Hz, 1H), 2.14 (dtd, J = 13.6, 6.2, 3.1 Hz, 1H);

13C NMR (126 MHz, CDCl3) δ 152.9, 139.3, 131.7, 129.3, 118.8, 86.1, 84.9, 65.0, 43.1, 28.1, 21.6;

HRMS (ESI) m/z calcd. for C13H13NO2 [M+H]+: 216.1019, found: 216.1017.



over 22 min, 0.7 mL/min, 235 nm): tR = 19.1 min (major), 20.5 min (minor)



10 as a white solid (48.4 mg, 90% yield); 1H NMR (500 MHz, CDCl3) δ 7.59 (d, J = 8.3 Hz, 2H),

7.52 (d, J = 8.1 Hz, 2H), 5.88 (s, 1H, br), 4.60 (td, J = 5.5, 2.3 Hz, 1H), 4.55 (ddd, J = 11.5, 8.5,

3.1 Hz, 1H), 4.35 (ddd, J = 10.9, 6.4, 3.4 Hz, 1H), 2.33 (dddd, J = 13.8, 8.7, 5.4, 3.5 Hz, 1H), 2.16

(ddt, J = 13.5, 6.1, 3.0 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 152.7, 132.0, 130.7 (q, J = 32.8

S29

Hz), 125.6, 125.4 (q, J = 3.8 Hz), 123.8 (q, J = 272.3 Hz), 89.0, 83.2, 64.8, 42.8, 27.7; HRMS (ESI)

m/z calcd. for C13H10F3NO2 [M+H]+: 270.0736, found: 270.0734.

The ee value (92%) was determined by chiral HPLC analysis of oxazinanone 10 in comparison

with an authentic sample of racemic material (CHIRALCEL® OJ-H, 5→50% iPrOH/hexane

gradient over 22 min, 0.7 mL/min, 246 nm): tR = 15.5 min (major), 16.9 min (minor).



11 as a white solid (32.3 mg, 70% yield); 1H NMR (500 MHz, CDCl3) δ 7.37 – 7.33 (m, 2H), 6.87

– 6.82 (m, 2H), 5.53 (s, 1H, br), 4.58 – 4.51 (m, 2H), 4.32 (ddd, J = 10.7, 6.6, 3.3 Hz, 1H), 3.81

(s, 3H), 2.29 (dddd, J = 13.7, 8.4, 5.3, 3.4 Hz, 1H), 2.13 (dtd, J = 13.5, 6.4, 3.1 Hz, 1H); 13C NMR

(126 MHz, CDCl3) δ 160.2, 152.8, 133.3, 114.2, 113.9, 85.4, 84.7, 65.0, 55.5, 43.2, 28.2; HRMS

(ESI) m/z calcd. for C13H13NO3 [M+H]+: 232.0968, found: 232.0967.



gradient over 17 min then 50% iPrOH/hexane isocratic for 10 min, 0.7 mL/min, 246 nm): tR = 23.0

min (major), 25.8 min (minor).

S30



12 as a yellow oil (35.2 mg, 76% yield); 1H NMR (500 MHz, CDCl3) δ 7.23 (t, J = 8.0 Hz, 1H),

7.01 (dt, J = 7.6, 1.3 Hz, 1H), 6.94 (dd, J = 2.7, 1.4 Hz, 1H), 6.91 (ddd, J = 8.3, 2.7, 0.9 Hz, 1H),

5.52 (s, 1H, br), 4.60 – 4.52 (m, 2H), 4.33 (ddd, J = 10.8, 6.6, 3.4 Hz, 1H), 3.81 (s, 3H), 2.31 (dddd,

J = 13.8, 8.5, 5.3, 3.4 Hz, 1H), 2.15 (dtd, J = 13.6, 6.3, 3.1 Hz, 1H); 13C NMR (126 MHz, CDCl3)

δ 159.5, 152.7, 129.7, 124.3, 122.8, 116.7, 115.7, 86.5, 84.7, 65.0, 55.5, 43.1, 28.1.







13 as a yellow oil (29.2 mg, 68% yield); Rf = 0.21 (80% EtOAc/hexanes); 1H NMR (500 MHz,

CDCl3) δ 7.38 (dd, J = 7.7, 1.4 Hz, 1H), 7.24 (dd, J = 7.5, 1.4 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H),

7.14 (td, J = 7.4, 1.5 Hz, 1H), 5.68 (s, 1H, br), 4.62 (td, J = 5.5, 2.3 Hz, 1H), 4.56 (ddd, J = 11.4,

8.4, 3.1 Hz, 1H), 4.35 (ddd, J = 10.4, 6.4, 3.2 Hz, 1H), 2.40 (s, 3H), 2.33 (dddd, J = 13.8, 8.6, 5.3,

3.5 Hz, 1H), 2.19 – 2.13 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 152.8, 140.4, 132.2, 129.7, 129.1,

125.8, 121.6, 90.6, 83.7, 65.0, 43.2, 28.3, 20.8.

S31






14 as a yellow oil (23.3 mg, 61% yield); 1H NMR (500 MHz, CDCl3) δ 7.39 (dd, J = 1.9, 0.7 Hz,

1H), 6.61 (dd, J = 3.5, 0.8 Hz, 1H), 6.39 (dd, J = 3.4, 1.9 Hz, 1H), 5.59 (s, 1H, br), 4.60 (td, J =

5.5, 2.4 Hz, 1H), 4.54 (ddd, J = 11.6, 8.6, 3.1 Hz, 1H), 4.36 – 4.31 (m, 1H), 2.31 (dddd, J = 13.9,

8.7, 5.4, 3.4 Hz, 1H), 2.20 – 2.11 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 152.5, 144.2, 135.9,

116.3, 111.1, 91.1, 75.2, 64.9, 43.1, 27.7; HRMS (ESI) m/z calcd. for C10H9NO3 [M+H]+: 192.0655,

found: 192.0655.







S32

15 as a colorless oil (26.5 mg, 64% yield); 1H NMR (500 MHz, CDCl3) δ 7.46 (dd, J = 3.0, 1.2

Hz, 1H), 7.28 (dd, J = 5.0, 3.0 Hz, 1H), 7.09 (dd, J = 5.0, 1.2 Hz, 1H), 5.57 (s, 1H, br), 4.58 – 4.50

(m, 2H), 4.32 (ddd, J = 10.4, 6.5, 3.2 Hz, 1H), 2.30 (dddd, J = 13.8, 8.5, 5.3, 3.4 Hz, 1H), 2.18 –

2.10 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 152.7, 129.8, 129.8, 125.8, 120.9, 86.4, 80.0, 65.0,

43.1, 28.0; HRMS (ESI) m/z calcd. for C10H9NO2S [M+H]+: 208.0427, found: 208.0428.








CDCl3) δ 7.73 (dt, J = 6.7, 1.6 Hz, 4H), 7.45 – 7.36 (m, 6H), 5.52 (s, 1H, br), 4.56 (ddd, J = 11.4,

8.4, 3.1 Hz, 1H), 4.51 (td, J = 5.5, 2.4 Hz, 1H), 4.37 – 4.31 (m, 1H), 2.33 (dddd, J = 13.9, 8.7, 5.4,

3.5 Hz, 1H), 2.17 (dtd, J = 14.5, 6.1, 3.1 Hz, 1H), 1.08 (s, 9H); 13C NMR (126 MHz, CDCl3) δ

152.5, 135.6, 132.6, 132.6, 130.0, 129.9, 128.0, 107.1, 85.5, 64.9, 43.3, 28.1, 27.2, 18.6; HRMS

(ESI) m/z calcd. for C22H25NO2Si [M+Na]+: 386.1547, found: 386.1542.




S33

The corresponding free 1,3-amino alcohol was obtained by adding 1,3-diaminopropane (84 μL,

0.1 mmol, 20 equiv) to a solution of oxazinanone 16 in dry THF (0.5 mL) and refluxing at 65 °C

for 3 d. After cooling to room temperature, the reaction mixture was concentrated under reduced

pressure. The yield (92%) was determined by 1H NMR spectroscopic analysis of the crude reaction

mixture (relative to mesitylene as an internal standard).



17 as a white solid (33.3 mg, 91% yield); 1H NMR (500 MHz, CDCl3) δ 5.51 (s, 1H, br), 4.47 (ddd,

J = 11.3, 8.1, 3.2 Hz, 1H), 4.33 (tq, J = 4.5, 2.0 Hz, 1H), 4.26 (ddd, J = 10.7, 6.8, 3.4 Hz, 1H), 3.48

(t, J = 6.7 Hz, 2H), 3.37 (s, 3H), 2.48 (td, J = 6.7, 2.0 Hz, 2H), 2.19 (dddd, J = 13.6, 8.5, 5.2, 3.4

Hz, 1H), 2.01 (dtd, J = 13.5, 6.4, 3.2 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 152.8, 82.3, 79.2,

70.6, 64.9, 58.9, 42.6, 28.2, 20.0; HRMS (ESI) m/z calcd. for C9H13NO3 [M+Na]+: 206.0788,

found: 206.0787.



S34





chromatography (0→80% EtOAc/hexanes) to yield a colorless oil (12.6 mg, 57% yield); 1H NMR


1H), 4.26 (dtd, J = 11.0, 3.8, 1.3 Hz, 1H), 4.15 (d, J = 15.0 Hz, 1H), 4.04 (dh, J = 6.0, 2.1 Hz, 1H),

3.48 (t, J = 6.8 Hz, 2H), 3.38 (s, 3H), 2.48 (td, J = 6.8, 2.0 Hz, 2H), 2.15 (dddd, J = 11.3, 9.5, 5.6,

3.9 Hz, 1H), 2.01 (dq, J = 13.9, 3.2 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 153.2, 136.7, 128.8,

128.5, 127.8, 82.8, 78.3, 70.7, 64.2, 58.9, 50.4, 45.5, 28.9, 20.0; HRMS (ESI) m/z calcd. for

C16H19NO3 [M+H]+: 274.1438, found: 274.1435.



18 as a colorless oil (33.8 mg, 84% yield); 1H NMR (500 MHz, CDCl3) δ 5.52 (s, 1H, br), 4.46

(ddd, J = 11.3, 8.0, 3.2 Hz, 1H), 4.32 (td, J = 5.6, 2.3 Hz, 1H), 4.26 (ddd, J = 10.8, 6.9, 3.3 Hz,

1H), 3.62 (t, J = 6.2 Hz, 2H), 2.40 (td, J = 6.9, 2.0 Hz, 2H), 2.20 (dddd, J = 13.5, 8.3, 5.2, 3.4 Hz,

1H), 2.01 (ddt, J = 10.1, 6.9, 3.1 Hz, 1H), 1.95 (p, J = 6.6 Hz, 2H); 13C NMR (126 MHz, CDCl3)

δ 152.8, 83.5, 79.2, 64.9, 43.6, 42.6, 31.2, 28.3, 16.1; HRMS (ESI) m/z calcd. for C9H12ClNO2

[M+H]+: 202.0629, found: 202.0629.

S35







chromatography (0→60% EtOAc/hexanes) to yield a colorless oil (16.1 mg, 66% yield); 1H NMR


1H), 4.27 (dtd, J = 11.1, 3.7, 1.4 Hz, 1H), 4.16 (d, J = 15.0 Hz, 1H), 4.05 (dh, J = 5.3, 1.8 Hz, 1H),

3.61 (t, J = 6.3 Hz, 2H), 2.41 (td, J = 6.9, 2.0 Hz, 2H), 2.17 (dddd, J = 13.8, 11.3, 5.5, 3.9 Hz, 1H),

2.00 (dq, J = 13.9, 3.3 Hz, 1H), 1.94 (p, J = 6.7 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 153.2,

136.7, 128.8, 128.5, 127.9, 83.9, 78.4, 64.2, 50.5, 45.5, 43.6, 31.2, 29.0, 16.2; HRMS (ESI) m/z

calcd. for C16H18ClNO2 [M+H]+: 292.1099, found: 292.1095.



19 as a white solid (43.1 mg, 94% yield); 1H NMR (500 MHz, CDCl3) δ 7.45 – 7.41 (m, 2H), 7.38

– 7.31 (m, 3H), 5.44 (s, 1H, br), 4.22 (d, J = 1.5 Hz, 1H), 4.10 (d, J = 11.0 Hz, 1H), 3.95 (d, J =

11.0 Hz, 1H), 1.24 (s, 3H), 1.17 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 152.4, 131.9, 129.1, 128.6,

S36

121.9, 86.5, 84.6, 75.1, 53.8, 32.2, 22.5, 19.8; HRMS (ESI) m/z calcd. for C14H15NO2 [M+H]+:

230.1176, found: 230.1173.






procedure D (2x higher catalyst loading). Silica gel column chromatography (0→80%

EtOAc/hexanes) afforded oxazinanone 20 as a white solid (44.8 mg, 98% yield); 1H NMR (500

MHz, CDCl3) δ 7.42 – 7.39 (m, 2H), 7.36 – 7.30 (m, 3H), 5.57 (s, 1H, br), 4.61 (dd, J = 10.2, 5.3

Hz, 1H), 2.16 (ddd, J = 13.9, 5.4, 1.2 Hz, 1H), 2.07 (dd, J = 13.9, 10.3 Hz, 1H), 1.51 (s, 3H), 1.43

(s, 3H); 13C NMR (126 MHz, CDCl3) δ 152.8, 131.8, 129.0, 128.5, 121.9, 86.4, 84.8, 78.5, 41.0,






VI. LFER studies evaluating steric effects on enantioselectivity.

Table S3. Enantiomeric ratio (er) data and corresponding Charton’s steric parameters.

S37

ν value for n-C5H11 group was predicted from the ν value (0.68) for n-(CH2)nCH3 (n = 2, 3, 8, 10, 12, 14, 16) groups.7,8

1.0

1.2

1.4

1.6

1.8

2.0

0 0.2 0.4 0.6 0.8 1 1.2 1.4

Figure S1. LFER studies with Ag(Min-BOX)ClO4 catalyst using a modified Taft equation.

VII. VT NMR studies of silver complexes.

R (S ) (R ) er log(er ) ν (Charton)

Me 1570944 30281420 19.27594 1.285016 0.52

Ph 1641394 44344994 27.01667 1.431632 0.57

n ‐C5H11 917445 27842922 30.34833 1.482135 0.68

i ‐Pr 828535 32487865 39.21122 1.59341 0.76

t ‐Bu 665628 34473345 51.79071 1.714252 1.24

S38

Representative procedure for synthesis of Ag-BOX complexes. To a flame-dried 1/2-dram vial

containing a magnetic stir bar were added AgOTf (1.3 mg, 5 µmol, 1 equiv), and BOX ligand (1

equiv), and CD2Cl2 (1 mL). The mixture was stirred until complete dissolution (1–2 h). Variable

temperature (VT) NMR studies were carried out on generated Ag-BOX complexes and the data

summarized below in Figures S2–S5.

Figure S2. 1H NMR spectra of Ag(Ph-BOX)OTf complex at varying concentrations in CD2Cl2.

S39

Figure S3. VT NMR studies of Ag(Ph-BOX)OTf complex in CD2Cl2 (5 mM).

S40

10 °C

24 °C

20 °C

20 °C

17.5 °C

15 °C

10 °C

0 °C

30 °C

40 °C

50 °C

70 °C

90 °C

Figure S4. VT NMR studies of Ag(L7)OTf complex in CD2Cl2 (5 mM).

S41

Figure S5. VT NMR studies of Ag(L9)OTf complex in CD2Cl2 (5 mM).

VIII. Computational studies.

A. Computational methods

All calculations were conducted using the Orca 4.0.0.2 software package.9 The resolution of

identity with the chain-of-sphere approximation (RICOSX) was applied to the Hartree-Fock (HF)

exchange integrals and the Density Functional Theory (DFT) Coulomb integrals. Molecular

graphics were visualized using UCSF Chimera.10

S42

Ground state geometry optimizations. Geometry optimizations were conducted using the

unrestricted hybrid-GGA B3LYP level of theory11 with dispersion correction (D3BJ) reported by

Grimme.12 Def2-TZVPP basis was applied to Ag metal centers, utilizing parameters from

TurboMole 7.0.2, while def2-SVP basis was applied to all other atoms.13 These methods have

been shown in previous studies to reproduce experimental selectivities and crystal structure

geometries observed in Ag systems.5,14 Final optimizations were run with the numerical grid

increased to “grid 4” and the HF exchange grid increased to “grid x4” in Orca. Frequency

calculations were performed on resultant optimized structures at the same level of theory and no

imaginary frequencies were observed, confirming that these geometries are indeed local minima.

Vibrational frequencies below 10 cm-1 were omitted during all frequency analyses.

Transition state geometry optimizations. Geometry optimizations utilized the same methodology

as the ground state geometry optimizations. Relaxed surface scans were conducted along the N–

H bond which is formed during the C–H amination. Geometries exhibiting the highest energy in

these scans were then subjected to subsequent transition state optimizations. Frequency

calculations were conducted to confirm the presence of a single imaginary frequency with the

corresponding vibration leading to product formation.

Figure S6. Mono-oxazoline models to investigate the influence of substitution on the barrier of

rotation for the aryl ring.

S43

B. Conformational analysis

Conformational analyses were conducted on model mono-oxazoline ligands in order to investigate

the effects of substitution on the barrier of rotation for the aryl ring (Figure S6). Relaxed surface

scans were conducted, stepping the N–C–C–C dihedral angle (highlighted in blue) in 10°

increments for a total of 36 steps. ΔGrot values were determined based on comparison of the lowest

and highest energy conformers along each respective relaxed surface scan. The relaxed surface

scan of M1 indicated a 1.3 kcal mol-1 energetic penalty for rotation of the aryl ring; comparison of

the highest (step 26) and lowest (step 34) energy conformers suggest this barrier is likely due in

part to steric interactions between the aryl ring and the protons present on the ligand scaffold

(Figure S7-A). Introduction of the α-Me in M2 accounts for a larger rotation barrier, with a 1.1

kcal mol-1 increase relative to M1. In this case, the heightened energy penalty originates from the

addition of steric interactions between the aryl ring and the α-Me group (Figure S7-B).

Introduction of meta substitution on the aryl ring further increases ΔGrot, and the dependence on

steric profile can be seen moving from M3 (Figure S8-A, 3.1 kcal mol-1) to M4 (Figure S8-B, 7.8

kcal mol-1).

S44

0

0.5

1

1.5

2

2.5

3

‐200 ‐100 0 100 200

Grel

Dihedral angle

0

0.2

0.4

0.6

0.8

1

1.2

1.4

‐200 ‐100 0 100 200

Grel

Dihedral angle

Figure S7. Relaxed surface scans of N–C–C–C dihedral angle in (A) M1 and (B) M2 models.

S45

0

1

2

3

4

5

6

7

8

9

‐200 ‐100 0 100 200

Grel

Dihedral angle

0

0.5

1

1.5

2

2.5

3

3.5

‐200 ‐100 0 100 200

Grel

Dihedral angle

Figure S8. Relaxed surface scans of N–C–C–C dihedral angle in (A) M3 and (B) M4.

S46

C. Absolute energies

Table S3. Absolute energies, zero-point vibrational energy, and entropy for γ C–H insertion the intermediate (INT), reactant complexes (RC) and transition states (TS) with trigonal planar Ag coordination geometries at the triplet spin state. Energy unit is Eh.

Complex E D3 ZPVE+Thermala Sb

INTL8 -1931.173925 -0.215295 0.752963 0.120778

RCL8,pro-R -1931.176120 -0.223561 0.752430 0.119634

TSL8,pro-R -1931.169235 -0.225775 0.746385 0.115942

RCL8,pro-S -1931.179797 -0.229746 0.752590 0.119087

TSL8,pro-S -1931.169227 -0.229852 0.745232 0.115121

aZero-point vibrational energy + thermal correction to vibrational, rotational, and translational states at 298.15 K. bEntropy at 298.15 K.

Table S4. Activation barriers (∆E≠, ∆H≠, and ∆G≠) for γ C–H insertion with trigonal planar Ag coordination geometries at the triplet spin state (298.15 K). Calculated from the difference between RC and TS energies. Energy unit is kcalꞏmol-1.

Pathway Ligand ∆E≠ ∆H≠ ∆G≠b ∆∆E≠ ∆∆H≠ ∆∆G≠b

TSL8,pro-R L8

4.32 0.53 2.84 2.31 1.49 1.66

TSL8,pro-S 6.63 2.02 4.50

S47

D. Molecular parameters for geometry optimized structures

Table S5. Selected bond lengths and angles for γ C–H insertion the intermediate (INT), reactant complexes (RC), and transition states (TS) with trigonal planar Ag coordination geometries at the triplet spin state. Bonds are in units of Å and angles are in units of °.

Complex Ag–Nnitrene Ag–O Nnitrene–H C–H Nnitrene–H–C

INTL8 2.011 3.310 N/A N/A N/A

RCL8,pro-R 2.018 3.334 2.273 1.105 125.0

TSL8,pro-R 2.052 3.423 1.405 1.267 158.3

RCL8,pro-S 2.042 3.383 2.542 1.103 110.7

TSL8,pro-S 2.070 2.887 1.399 1.261 161.7

E. Transition state frequencies

Complex Frequency (cm-1)

TSL8,pro-R -1127.31

TSL8,pro-S -1195.09

F. Mulliken spin populations

Table S6. Group spin populations in γ C–H insertion intermediate (INT), reactant complexes (RC), and transition states (TS) with trigonal planar Ag coordination geometries at the triplet spin state.

Complex ρ(Ag) ρ(Nnitrene) ρ(C)

INTL8 0.217384 1.415627 -0.000302

RCL8,pro-R 0.176734 1.400203 0.016104

TSL8,pro-R 0.123204 1.149723 0.337282

RCL8,pro-S 0.138327 1.420662 0.005456

TSL8,pro-S 0.178182 1.045839 0.348106

S48

IX. X-ray crystallography data of compound 16.

Data Collection

The data for Compound 16 were deposited with the CCDC as Deposition Number 2005980. A

colorless crystal with approximate dimensions 0.34 × 0.25 × 0.2 mm3 was selected under oil under

ambient conditions and attached to the tip of a MiTeGen MicroMount©. The crystal was mounted

in a stream of cold nitrogen at 100(1) K and centered in the X-ray beam by using a video camera.

The crystal evaluation and data collection were performed on a Bruker D8 VENTURE PhotonIII

four-circle diffractometer with Cu Kα (λ = 1.54178 Å) radiation and the detector to crystal distance

of 4.0 cm.15 The initial cell constants were obtained from a 180° φ scan conducted at a 2θ = 50°

angle with the exposure time of 1 second per frame. The reflections were successfully indexed by

an automated indexing routine built in the APEX3 program. The final cell constants were

calculated from a set of 9229 strong reflections from the actual data collection. The data were

collected by using the full sphere data collection routine to survey the reciprocal space to the extent

of a full sphere to a resolution of 0.78 Å. A total of 43118 data were harvested by collecting 42

sets of frames with 0.7–1.0º scans in and φ with an exposure time 0.5–5 sec per frame. These

highly redundant datasets were corrected for Lorentz and polarization effects. The absorption

correction was based on fitting a function to the empirical transmission surface as sampled by

multiple equivalent measurements.16

Structure Solution and Refinement

The systematic absences in the diffraction data were consistent for the space groups P1̄ and P1.

The E-statistics strongly suggested the non-centrosymmetric space group P1 that yielded

chemically reasonable and computationally stable results of refinement.17-22 A successful solution

by the direct methods provided most non-hydrogen atoms from the E-map. The remaining non-

hydrogen atoms were located in an alternating series of least-squares cycles and difference Fourier

maps. All non-hydrogen atoms were refined with anisotropic displacement coefficients. All

hydrogen atoms except H1(N1) and H1a(N1a) were included in the structure factor calculation at

idealized positions and were allowed to ride on the neighboring atoms with relative isotropic

displacement coefficients. There are two symmetry-independent molecules with identical

compositions but different conformations in the unit cell. The absolute configuration was

S49

unequivocally established by anomalous scattering effect as C4 – R, C4a – R. The crystal is an

inversion twin with the minor component contribution of 0.036(17). The final least-squares

refinement of 484 parameters against 8029 data resulted in residuals R (based on F2 for I≥2σ) and

wR (based on F2 for all data) of 0.0268 and 0.0712, respectively. The final difference Fourier map

was featureless.

Summary

Crystal data for compound 16 (C22H25NO2Si, M = 363.52 g/mol): triclinic, space group P1 (no.

1), a = 7.2340(6) Å, b = 11.5016(9) Å, c = 12.5242(10) Å, α = 78.190(6)°, β = 76.949(5)°, γ =

88.671(9)°, V = 993.35(14) Å3, Z = 2, T = 100.0 K, μ(CuKα) = 1.157 mm-1, Dcalc = 1.215 g/cm3,

43118 reflections measured (7.402° ≤ 2Θ ≤ 159.368°), 8029 unique (Rint = 0.0285, Rsigma = 0.0246)

which were used in all calculations. The final R1 was 0.0268 (I > 2σ(I)) and wR2 was 0.0712 (all

data).

Figure S9. A molecular drawing of the first symmetry-independent molecule of compound 16

shown with 50% probability ellipsoids.

S50

Figure S10. A molecular drawing of the second symmetry-independent molecule of compound 16

shown with 50% probability ellipsoids.

S51

Figure S11. A molecular drawing of a superposition of the two symmetry-independent molecules

of compound 16 shown with 50% probability ellipsoids. All H atoms are omitted.

Table S7. Crystal data and structure refinement for compound 16. Identification code Compound 16 Empirical formula C22H25NO2Si Formula weight 363.52 Temperature/K 100.0 Crystal system triclinic Space group P1 a/Å 7.2340(6) b/Å 11.5016(9) c/Å 12.5242(10) α/° 78.190(6) β/° 76.949(5) γ/° 88.671(9) Volume/Å3 993.35(14) Z 2

S52

ρcalcg/cm3 1.215 μ/mm-1 1.157 F(000) 388.0 Crystal size/mm3 0.34 × 0.25 × 0.2 Radiation CuKα (λ = 1.54178) 2Θ range for data collection/° 7.402 to 159.368 Index ranges -8 ≤ h ≤ 9, -14 ≤ k ≤ 14, -15 ≤ l ≤ 15 Reflections collected 43118 Independent reflections 8029 [Rint = 0.0285, Rsigma = 0.0246] Data/restraints/parameters 8029/4/484 Goodness-of-fit on F2 1.060 Final R indexes [I>=2σ (I)] R1 = 0.0268, wR2 = 0.0711 Final R indexes [all data] R1 = 0.0270, wR2 = 0.0712 Largest diff. peak/hole / e Å-3 0.32/-0.14 Flack parameter 0.036(17) Table S8. Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for compound 16. Ueq is defined as 1/3 of of the trace of the orthogonalised UIJ tensor. Atom x y z U(eq) Si1 316.1(6) 8513.4(4) 2667.9(4) 15.55(11) O1 6208(2) 6011.4(14) 6154.3(14) 30.0(3) O2 3530(2) 5201.5(14) 7222.3(15) 33.7(4) N1 3503(2) 6976.4(15) 5972.8(14) 22.8(3) C1 4473(3) 6055.0(18) 6420.1(17) 21.6(4) C2 1470(3) 5219.1(19) 7530.4(18) 27.5(4) C3 664(3) 5706.2(18) 6523.5(16) 23.0(4) C4 1438(3) 6975.0(17) 6063.5(15) 21.0(4) C5 1036(3) 7471.6(18) 4964.8(17) 21.8(4) C6 732(3) 7872.6(18) 4060.8(16) 21.4(4) C7 1750(3) 9939.2(17) 2152.4(16) 18.2(4) C8 1929(3) 10659.3(19) 2901.3(18) 23.5(4) C9 2894(3) 11749(2) 2532(2) 28.9(5) C10 3718(3) 12135(2) 1404(2) 29.2(5) C11 3586(3) 11433(2) 646.5(19) 26.8(4) C12 2609(3) 10335.8(19) 1018.9(17) 21.7(4) C13 1165(3) 7430.8(18) 1744.7(17) 21.8(4) C14 796(5) 7576(2) 673(2) 40.5(6) C15 1412(5) 6759(3) 1(2) 52.1(8) C16 2397(4) 5768(2) 383(2) 43.3(6) C17 2810(3) 5625(2) 1420(2) 34.4(5)

S53

C18 2204(3) 6444.6(18) 2100.2(19) 24.9(4) C19 -2314(3) 8825.4(18) 2829.6(16) 18.3(4) C20 -3003(3) 9410(2) 3837.5(19) 27.6(4) C21 -2666(3) 9672(2) 1784(2) 35.5(6) C22 -3446(3) 7662(2) 3031(2) 34.4(5) Si1A 9611.6(6) 1517.7(4) 7187.7(4) 15.40(11) O1A 3822(2) 4966.9(15) 4352.9(15) 35.4(4) O2A 5350(2) 3712.1(15) 3359.9(14) 31.2(3) N1A 6875(3) 4607.5(16) 4421.1(15) 26.6(4) C1A 5287(3) 4452.7(18) 4072.9(17) 26.3(4) C2A 6945(3) 2935(2) 3204.3(19) 31.2(5) C3A 8779(3) 3611(2) 3050.4(17) 30.2(5) C4A 8718(3) 4067.9(18) 4115.7(16) 23.3(4) C5A 9018(3) 3134.1(18) 5061.5(16) 20.6(4) C6A 9202(3) 2419.1(18) 5872.3(16) 20.3(4) C7A 8817(3) 2448.9(17) 8277.7(16) 18.3(4) C8A 7519(3) 3351.1(18) 8112.3(17) 21.6(4) C9A 6993(3) 4096.6(19) 8874.5(19) 26.8(4) C10A 7757(3) 3955(2) 9811.9(19) 30.0(5) C11A 9015(3) 3050(2) 10009.1(18) 27.8(4) C12A 9524(3) 2297.4(18) 9250.8(17) 22.1(4) C13A 8178(3) 97.3(17) 7588.4(16) 18.2(4) C14A 7354(3) -389.2(19) 8712.8(18) 22.9(4) C15A 6444(3) -1499(2) 9028(2) 29.9(5) C16A 6347(3) -2147.9(19) 8222(2) 30.4(5) C17A 7123(3) -1679(2) 7101(2) 29.0(5) C18A 8026(3) -566.3(19) 6786.7(18) 23.1(4) C19A 12233(3) 1167.5(18) 6941.7(16) 19.6(4) C20A 13421(3) 2288(2) 6857(2) 30.4(5) C21A 12629(3) 172(2) 7879.9(19) 28.3(4) C22A 12843(3) 733(2) 5834.5(19) 28.3(4) Table S9. Anisotropic Displacement Parameters (Å2×103) for compound 16. The Anisotropic displacement factor exponent takes the form: -2π2[h2a*2U11+2hka*b*U12+…]. Atom U11 U22 U33 U23 U13 U12 Si1 15.4(2) 17.2(2) 14.6(2) -2.57(17) -5.22(17) 3.08(18) O1 19.8(7) 35.9(8) 41.2(8) -16.6(7) -13.8(6) 6.6(6) O2 28.6(8) 27.1(8) 45.6(9) 6.4(7) -21.0(7) -2.5(6) N1 21.3(8) 22.0(8) 24.6(8) 0.3(6) -8.3(6) -0.6(6) C1 22.0(10) 21.3(9) 25.8(10) -9.4(7) -10.6(8) 3.6(7) C2 29.3(11) 25.8(9) 26.5(10) 2.5(8) -10.8(8) -4.0(8)

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C3 21.3(9) 25.0(9) 22.6(9) -3.3(7) -6.4(7) -0.2(8) C4 19.4(9) 23.7(9) 19.3(9) -2.5(7) -5.1(7) 3.0(7) C5 17.0(9) 24.2(9) 22.4(9) -2.1(7) -3.4(7) 3.3(7) C6 17.7(9) 25.3(9) 20.2(9) -2.0(7) -5.2(7) 3.2(7) C7 13.1(9) 21.2(9) 21.0(9) -3.6(7) -6.3(7) 2.7(7) C8 18.1(10) 29.2(10) 23.8(9) -8.5(8) -3.3(7) -0.9(8) C9 21.7(10) 27.3(10) 41.4(12) -13.9(9) -8.6(9) 0.5(8) C10 19.1(10) 22.8(10) 43.0(12) -0.1(9) -7.3(8) -0.7(8) C11 19.8(10) 29.8(11) 26.9(10) 4.4(8) -6.5(8) 0.9(8) C12 19.1(10) 27.2(10) 18.2(9) -0.7(7) -6.7(7) 1.5(8) C13 19.8(9) 22.6(9) 23.2(9) -6.7(7) -3.2(7) 1.8(8) C14 59.2(17) 38.3(13) 30.1(12) -15.3(10) -16.8(11) 17.2(12) C15 78(2) 52.5(17) 35.0(13) -25.9(12) -18.4(14) 18.6(16) C16 46.6(15) 37.2(13) 49.1(15) -27.8(12) -0.2(12) 5.8(11) C17 28.5(11) 24.4(10) 50.5(14) -13.8(10) -4.3(10) 4.9(9) C18 19.7(10) 21.4(9) 32.6(11) -5.9(8) -3.9(8) 1.7(8) C19 15.4(9) 21.1(9) 18.5(9) -2.4(7) -5.8(7) 1.3(7) C20 20.7(10) 33.1(11) 31.1(11) -12.6(9) -5.5(8) 7.4(9) C21 21.4(11) 52.6(14) 26.0(10) 7.8(10) -7.5(8) 10.8(10) C22 24.6(12) 30.8(12) 46.4(14) -12.0(10) -0.6(10) -7.6(9) Si1A 14.8(2) 16.7(2) 15.6(2) -2.84(17) -5.89(17) 1.25(17) O1A 30.1(8) 36.5(8) 38.4(9) -6.6(7) -7.3(7) 13.3(7) O2A 29.0(8) 31.5(8) 37.4(8) -10.0(7) -14.2(7) 4.8(6) N1A 30.4(9) 25.1(8) 26.5(9) -4.8(7) -12.4(7) 9.2(7) C1A 27.2(10) 22.4(9) 26.3(10) 1.4(7) -6.0(8) 4.2(8) C2A 39.6(13) 30.8(11) 27.4(10) -11.8(9) -11.8(9) 8.0(9) C3A 30.4(11) 40.0(12) 18.2(9) -2.6(8) -5.1(8) 9.1(9) C4A 22.4(10) 24.4(9) 21.9(9) 0.6(7) -7.6(7) 1.5(8) C5A 19.0(9) 22.8(9) 20.9(9) -5.2(7) -5.9(7) 2.2(7) C6A 18.7(9) 22.9(9) 20.4(9) -4.4(7) -7.1(7) 2.0(7) C7A 16.3(9) 18.1(8) 19.8(9) -4.4(7) -2.1(7) -2.2(7) C8A 17.9(9) 20.8(9) 25.3(9) -4.0(7) -3.8(7) -1.1(7) C9A 23.4(10) 21.1(9) 32.1(11) -5.6(8) 1.6(8) 3.0(8) C10A 31.6(11) 27.8(10) 27.3(10) -10.7(8) 4.5(8) -2.1(9) C11A 31.8(11) 31.4(10) 19.8(9) -7.0(8) -3.0(8) -3.4(9) C12A 23.6(10) 23.1(9) 19.1(9) -3.7(7) -4.6(7) 1.0(8) C13A 16.0(9) 19.5(8) 20.3(9) -2.9(7) -8.2(7) 2.3(7) C14A 24.8(10) 23.2(10) 22.9(10) -3.3(7) -11.2(8) -0.1(8) C15A 29.9(12) 27.0(10) 29.4(11) 5.2(8) -9.7(9) -2.4(9) C16A 26.3(11) 19.1(9) 46.5(13) -3.9(9) -12.1(9) -1.3(8) C17A 23.0(11) 28.1(11) 40.3(12) -15.7(9) -8.0(9) 0.7(9)

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C18A 20.5(10) 26.1(10) 25.0(10) -9.8(8) -5.6(7) 0.5(8) C19A 16.0(9) 23.2(9) 20.2(9) -4.6(7) -5.5(7) 3.5(7) C20A 17.3(10) 34.2(12) 40.8(13) -11.5(10) -5.3(9) -2.3(9) C21A 25.4(11) 34.1(11) 26.4(10) -4.6(8) -10.4(8) 10.2(9) C22A 23.2(10) 38.5(12) 25.5(10) -13.8(9) -4.6(8) 6.3(9) Table S10. Bond Lengths for compound 16. Atom Atom Length/Å Atom Atom Length/Å Si1 C6 1.838(2) Si1A C6A 1.840(2) Si1 C7 1.878(2) Si1A C7A 1.886(2) Si1 C13 1.870(2) Si1A C13A 1.872(2) Si1 C19 1.901(2) Si1A C19A 1.898(2) O1 C1 1.226(3) O1A C1A 1.218(3) O2 C1 1.325(3) O2A C1A 1.348(3) O2 C2 1.453(3) O2A C2A 1.446(3) N1 C1 1.353(3) N1A C1A 1.345(3) N1 C4 1.472(3) N1A C4A 1.462(3) C2 C3 1.508(3) C2A C3A 1.508(3) C3 C4 1.524(3) C3A C4A 1.522(3) C4 C5 1.468(3) C4A C5A 1.479(3) C5 C6 1.199(3) C5A C6A 1.200(3) C7 C8 1.400(3) C7A C8A 1.399(3) C7 C12 1.400(3) C7A C12A 1.403(3) C8 C9 1.389(3) C8A C9A 1.395(3) C9 C10 1.387(4) C9A C10A 1.386(3) C10 C11 1.385(3) C10A C11A 1.387(3) C11 C12 1.400(3) C11A C12A 1.397(3) C13 C14 1.404(3) C13A C14A 1.402(3) C13 C18 1.398(3) C13A C18A 1.404(3) C14 C15 1.388(4) C14A C15A 1.391(3) C15 C16 1.389(4) C15A C16A 1.387(3) C16 C17 1.375(4) C16A C17A 1.387(4) C17 C18 1.395(3) C17A C18A 1.391(3) C19 C20 1.530(3) C19A C20A 1.538(3) C19 C21 1.531(3) C19A C21A 1.536(3) C19 C22 1.532(3) C19A C22A 1.538(3)

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Table S11. Bond Angles for compound 16. Atom Atom Atom Angle/˚ Atom Atom Atom Angle/˚ C6 Si1 C7 106.52(9) C6A Si1A C7A 105.69(9) C6 Si1 C13 107.62(10) C6A Si1A C13A 110.71(9) C6 Si1 C19 108.13(9) C6A Si1A C19A 107.29(9) C7 Si1 C19 110.23(9) C7A Si1A C19A 113.80(9) C13 Si1 C7 110.83(9) C13A Si1A C7A 109.94(8) C13 Si1 C19 113.22(9) C13A Si1A C19A 109.33(9) C1 O2 C2 119.46(16) C1A O2A C2A 118.40(17) C1 N1 C4 125.01(17) C1A N1A C4A 127.82(18) O1 C1 O2 118.55(19) O1A C1A O2A 119.0(2) O1 C1 N1 122.4(2) O1A C1A N1A 123.1(2) O2 C1 N1 118.94(18) N1A C1A O2A 117.86(19) O2 C2 C3 111.06(17) O2A C2A C3A 110.45(18) C2 C3 C4 107.17(16) C2A C3A C4A 107.79(17) N1 C4 C3 108.51(15) N1A C4A C3A 107.89(17) C5 C4 N1 109.69(15) N1A C4A C5A 109.96(16) C5 C4 C3 112.22(16) C5A C4A C3A 113.52(17) C6 C5 C4 179.1(2) C6A C5A C4A 176.0(2) C5 C6 Si1 178.58(19) C5A C6A Si1A 171.19(18) C8 C7 Si1 120.09(15) C8A C7A Si1A 119.85(15) C12 C7 Si1 121.77(15) C8A C7A C12A 117.76(18) C12 C7 C8 118.10(19) C12A C7A Si1A 122.37(16) C9 C8 C7 121.2(2) C9A C8A C7A 120.9(2) C10 C9 C8 119.9(2) C10A C9A C8A 120.3(2) C11 C10 C9 120.1(2) C9A C10A C11A 119.9(2) C10 C11 C12 120.0(2) C10A C11A C12A 119.6(2) C7 C12 C11 120.69(19) C11A C12A C7A 121.4(2) C14 C13 Si1 121.60(18) C14A C13A Si1A 120.95(15) C18 C13 Si1 120.88(16) C14A C13A C18A 117.68(19) C18 C13 C14 117.5(2) C18A C13A Si1A 121.16(15) C15 C14 C13 121.1(3) C15A C14A C13A 121.3(2) C14 C15 C16 120.5(3) C16A C15A C14A 119.9(2) C17 C16 C15 119.2(2) C17A C16A C15A 120.0(2) C16 C17 C18 120.7(2) C16A C17A C18A 120.1(2) C17 C18 C13 120.9(2) C17A C18A C13A 121.1(2) C20 C19 Si1 109.43(13) C20A C19A Si1A 110.33(14) C20 C19 C21 108.40(18) C20A C19A C22A 108.48(17) C20 C19 C22 108.47(17) C21A C19A Si1A 111.06(14) C21 C19 Si1 110.50(14) C21A C19A C20A 110.09(18) C21 C19 C22 109.92(19) C21A C19A C22A 107.59(18)

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C22 C19 Si1 110.07(15) C22A C19A Si1A 109.21(14) Table S12. Hydrogen Bonds for compound 16. D H A d(D-H)/Å d(H-A)/Å d(D-A)/Å D-H-A/° C3 H3A O11 0.99 2.48 3.358(2) 148.2 C3 H3B O1A 0.99 2.55 3.374(3) 140.8 C9 H9 O2A2 0.95 2.58 3.363(3) 139.4 C18 H18 O1A 0.95 2.57 3.414(3) 148.1 N1A H1A O1 0.90(3) 2.01(3) 2.912(2) 175(4) C17A H17A O13 0.95 2.42 3.260(3) 147.1 1-1+X,+Y,+Z; 2+X,1+Y,+Z; 3+X,-1+Y,+Z Table S13. Torsion Angles for compound 16. A B C D Angle/˚ A B C D Angle/˚ Si1 C7 C8 C9 -176.40(17) C1A O2A C2A C3A -45.6(2) Si1 C7 C12 C11 176.55(16) C1A N1A C4A C3A 18.3(3) Si1 C13 C14 C15 -179.1(2) C1A N1A C4A C5A -106.0(2) Si1 C13 C18 C17 178.87(17) C2A O2A C1A O1A -168.1(2) O2 C2 C3 C4 -61.0(2) C2A O2A C1A N1A 13.4(3) C1 O2 C2 C3 34.6(3) C2A C3A C4A N1A -47.0(2) C1 N1 C4 C3 -11.5(3) C2A C3A C4A C5A 75.1(2) C1 N1 C4 C5 -134.38(19) C4A N1A C1A O1A -178.08(19) C2 O2 C1 O1 -178.42(18) C4A N1A C1A O2A 0.3(3) C2 O2 C1 N1 5.5(3) C6A Si1A C7A C8A 22.72(17) C2 C3 C4 N1 48.2(2) C6A Si1A C7A C12A -155.37(16) C2 C3 C4 C5 169.57(17) C6A Si1A C13A C14A -142.90(17) C4 N1 C1 O1 166.17(18) C6A Si1A C13A C18A 42.53(19) C4 N1 C1 O2 -17.9(3) C6A Si1A C19A C20A 71.82(16) C6 Si1 C7 C8 -37.02(18) C6A Si1A C19A C21A -165.82(14) C6 Si1 C7 C12 145.26(16) C6A Si1A C19A C22A -47.33(16) C6 Si1 C13 C14 170.5(2) C7A Si1A C13A C14A -26.49(19) C6 Si1 C13 C18 -9.72(19) C7A Si1A C13A C18A 158.94(17) C7 Si1 C13 C14 -73.4(2) C7A Si1A C19A C20A -44.73(17) C7 Si1 C13 C18 106.38(17) C7A Si1A C19A C21A 77.63(16) C7 C8 C9 C10 -0.7(3) C7A Si1A C19A C22A -163.87(14) C8 C7 C12 C11 -1.2(3) C7A C8A C9A C10A 0.1(3) C8 C9 C10 C11 -0.2(3) C8A C7A C12A C11A -2.6(3) C9 C10 C11 C12 0.4(3) C8A C9A C10A C11A -1.6(3) C10 C11 C12 C7 0.3(3) C9A C10A C11A C12A 0.9(3) C12 C7 C8 C9 1.4(3) C10A C11A C12A C7A 1.2(3) C13 Si1 C7 C8 -153.81(16) C12A C7A C8A C9A 1.9(3)

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C13 Si1 C7 C12 28.48(19) C13A Si1A C7A C8A -96.79(16) C13 C14 C15 C16 0.6(5) C13A Si1A C7A C12A 85.12(17) C14 C13 C18 C17 -1.4(3) C13A Si1A C19A C20A -168.07(14) C14 C15 C16 C17 -2.1(5) C13A Si1A C19A C21A -45.71(16) C15 C16 C17 C18 1.8(4) C13A Si1A C19A C22A 72.78(16) C16 C17 C18 C13 -0.1(3) C13A C14A C15A C16A 0.2(3) C18 C13 C14 C15 1.1(4) C14A C13A C18A C17A -1.3(3) C19 Si1 C7 C8 80.05(18) C14A C15A C16A C17A -1.3(4) C19 Si1 C7 C12 -97.66(17) C15A C16A C17A C18A 1.1(3) C19 Si1 C13 C14 51.1(2) C16A C17A C18A C13A 0.3(3) C19 Si1 C13 C18 -129.15(17) C18A C13A C14A C15A 1.1(3) Si1A C7A C8A C9A -176.25(15) C19A Si1A C7A C8A 140.20(15) Si1A C7A C12A C11A 175.53(16) C19A Si1A C7A C12A -37.89(19) Si1A C13A C14A C15A -173.68(17) C19A Si1A C13A C14A 99.12(18) Si1A C13A C18A C17A 173.42(17) C19A Si1A C13A C18A -75.46(18) O2A C2A C3A C4A 62.2(2) Table S14. Hydrogen Atom Coordinates (Å×104) and Isotropic Displacement Parameters (Å2×103) for compound 16. Atom x y z U(eq) H1 4220(40) 7500(20) 5380(20) 35(7) H2A 1072.76 5716.28 8097.3 33 H2B 961.22 4402.28 7867.95 33 H3A -740.24 5699.31 6741.56 28 H3B 1051.28 5217.05 5949.03 28 H4 842.36 7483.78 6601.06 25 H8 1380.91 10397.63 3676.45 28 H9 2988.31 12229.88 3051.18 35 H10 4373.78 12881.14 1150.05 35 H11 4158.04 11695.28 -125.3 32 H12 2528.15 9855.7 496.8 26 H14 112.34 8245.69 402.43 49 H15 1157.43 6877.78 -724.91 62 H16 2781.13 5195.04 -68.03 52 H17 3515.44 4961.22 1676.91 41 H18 2501.01 6330.75 2815.02 30 H20A -2819.26 8870.24 4517.93 41 H20B -4354.37 9583.14 3913.89 41 H20C -2278.18 10151.28 3726 41 H21A -2359.72 9277.49 1144.75 53 H21B -1861.05 10388.38 1626.15 53

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H21C -4002.95 9892.45 1912.51 53 H22A -3204.78 7121.7 3696.96 52 H22B -3055.38 7291.33 2379.47 52 H22C -4804.15 7827.72 3146.36 52 H1A 6740(60) 5060(30) 4940(30) 60(10) H2AA 6973.86 2590.81 2538.19 37 H2AB 6801.88 2274.2 3864.74 37 H3AA 8921.66 4285.05 2401.11 36 H3AB 9870.08 3084.09 2912.12 36 H4A 9731.37 4697.26 3952.46 28 H8A 6987.14 3457.81 7472.05 26 H9A 6107.43 4703.96 8750.43 32 H10A 7420.67 4477.51 10318.71 36 H11A 9527.24 2942.71 10656.46 33 H12A 10366.55 1669.59 9397.19 27 H14A 7418.15 48.02 9270.51 27 H15A 5890.46 -1812.5 9793.95 36 H16A 5749.56 -2913.32 8437.03 36 H17A 7036.96 -2117.86 6548.08 35 H18A 8547.65 -250.6 6016.9 28 H20D 13078.91 2937.5 6301.26 46 H20E 14772.29 2123.77 6628.52 46 H20F 13168.78 2516.44 7587.7 46 H21D 11924.57 -551.5 7897.58 42 H21E 12223.92 416.66 8600.72 42 H21F 13991.26 17.17 7739.86 42 H22D 12067.81 33.52 5865.74 42 H22E 14183.29 521.48 5718.68 42 H22F 12665.81 1365.72 5213.43 42

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X. References.

1. Armarego, W. L. F.; Chai, C. L. L. Purification of Laboratory Chemicals, 6th ed., Elsevier:

Burlington, MA, 2009.

2. Still, W. C.; Kahn, M.; Mitra, A. J. Rapid Chromatographic Technique for Preparative

Separations with Moderate Resolution. J. Org. Chem. 1978, 43, 2923–2925.

3. Tresse, C.; Guissart, C.; Schweizer, S.; Bouhoute, Y.; Chany, A.-C.; Goddard, M.-L.;

Blanchard, N.; Evano, G. Practical Methods for the Synthesis of Trifluoromethylated

Alkynes: Oxidative Trifluoromethylation of Copper Acetylides and Alkynes. Adv. Synth.

Catal. 2014, 356, 2051–2060.

4. Watkins, A. L.; Hashiguchi, B. G.; Landis, C. R. Highly Enantioselective Hydroformylation

of Aryl Alkenes with Diazaphospholane Ligands. Org. Lett. 2008, 10, 4553–4556.

5. Ju, M.; Huang, M.; Vine, L. E.; Dehghany, M.; Roberts, J. M.; Schomaker, J. M. Tunable

Catalyst-Controlled Syntheses of β- and γ-Amino Alcohols Enabled by Silver-Catalysed

Nitrene Transfer. Nat. Catal. 2019, 2, 899–908.

6. Cornejob, A.; Frailea, J. M.; García, J. I.; Gilb, M. J.; Martínez-Merinob, V.; Mayorala, J. A.;

Pires, E.; Villalba, I. An Efficient and General One-Pot Method for the Synthesis of Chiral

Bis(oxazoline) and Pyridine Bis(oxazoline) Ligands. Synlett 2005, 2321–2324.

7. Charton, M. Steric Effects. III. Bimolecular Nucleophilic Substitution. J. Am. Chem. Soc.

1975, 97, 3694–3697.

8. Charton, M. Steric Effects. 7. Additional ν Constants. J. Org. Chem. 1976, 41, 2217–2220.

9. Neese, F., The ORCA program system. Wiley Interdiscip. Rev.: Comput. Mol. Sci. 2012, 2,

73–78.

10. Pettersen, E. F; Goddard, T. D.; Huang, C. C.; Couch, G. S.; Greenblatt, D. M.; Meng, E. C.;

S61

Ferrin, T. E., UCSF Chimera—a visualization system for exploratory research and analysis.

J. Comput. Chem. 2004, 13, 1605–1612.

11. Lee, C. T.; Yang, W. T.; Parr, R. G., Development of the Colle-Salvetti correlation-energy

formula into a functional of the electron density. Phys. Rev. B 1988, 37, 785–789.

12. (a) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H., A consistent and accurate ab initio

parameterization of density functional dispersion correction (DFT-D) for the 94 elements H-

Pu. J. Chem. Phys. 2010, 132, 154104. (b) Grimme, S.; Ehrlich, S.; Goerigk, J., Effect of the

damping function in dispersion corrected density functional theory. J. Comput. Chem. 2011,

32, 1456–1465.

13. (a) Dolg, M.; Stoll, H.;Preuss, H., Energy-adjusted ab initio pseudopotentials for the rare earth

elements. J. Chem. Phys. 1989, 90, 1730–1734. (b) Weigend, F.; Ahlrichs, R., Balanced basis

sets of split valence, triple zeta valence and quadruple zeta valence quality for H to Rn: Design

and assessment of accuracy. Phys. Chem. Chem. Phys. 2005, 7, 3297.

14. (a) Dolan, N. S.; Scamp, R. J.; Yang, T.; Berry, J. F.; Schomaker, J. M., Catalyst-controlled

and tunable, chemoselective silver-catalyzed intermolecular nitrene transfer: Experimental

and computational studies. J. Am. Chem. Soc. 2016, 138, 14658–14667. (b) Huang, M.; Yang,

T.; Paretsky, J.; Berry, J. F.; Schomaker, J. M., Inverting steric effects: Using ‘attractive’ non-

covalent interactions to direct silver-catalyzed nitrene transfer. J. Am. Chem. Soc. 2017, 139,

17376–17386.

15. Bruker-AXS (2018). APEX3. Version 2018.1-0. Madison, Wisconsin, USA.

16. Krause, L.; Herbst-Irmer, R.; Sheldrick, G. M.; Stalke, D. Comparison of silver and

molybdenum microfocus X-ray sources for single-crystal structure determination. J. Appl.

Cryst. 2015, 48. 3–10.

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17. Sheldrick, G. M. (2013b). XPREP. Version 2013/1. Georg-August-Universität Göttingen,

Göttingen, Germany.

18. Sheldrick, G. M. (2013a). The SHELX homepage, http://shelx.uni-ac.gwdg.de/SHELX/.

19. Sheldrick, G. M. (2015a). Acta Cryst. A, 71, 3–8.

20. Sheldrick, G. M. (2015b). Acta Cryst. C, 71, 3–8.

21. Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.; Puschmann, H. OLEX2: a

complete structure solution, refinement and analysis program. J. Appl. Crystallogr. 2009, 42,

339–341.

22. Guzei, I. A. (2007-2013). Programs Gn. University of Wisconsin-Madison, Madison,

Wisconsin, USA.

XI. NMR spectral data

S63

1H NMR (500 MHz, CDCl3) and 13C NMR (126 MHz, CDCl3) spectra for compound 1.

S64

1H NMR (500 MHz, CDCl3) and 13C NMR (126 MHz, CDCl3) spectra for compound S1.

S65


S66


S67


S68


S69

19F NMR (377 MHz, CDCl3) spectrum for compound S5.

S70


S71


S72


O

O NH2

.

F3C

S73


O

O NH2

.

MeO

S74


S75


O

O NH2

.

Me

S76


S77


S78


S79


S80


O

O NH2

.

Cl

S81


S82


S83


S84


S85


S86


S87

1H NMR (500 MHz, CDCl3) and 13C NMR (126 MHz, CDCl3) spectra for Min-BOX.

S88


S89

1H NMR (400 MHz, CDCl3) and 13C NMR (101 MHz, CDCl3) spectra for compound 2a.

S90


S91


S92


S93


S94


S95


S96


S97


S98

19F NMR (377 MHz, CDCl3) spectrum for compound 7.

S99


S100


S101


S102


S103


S104


S105


S106


S107


S108


S109


S110


S111


S112


S113


XII. HPLC chromatograms.

S114

HPLC analysis for compound 2a (CHIRALPAK® AD-H, 5→30% iPrOH/hexane gradient over

22 min, 0.7 mL/min, 210 nm): tR = 14.6 min (minor), 16.5 min (major); 90% ee.

Racemic 2a

Peak # Retention Time Area Area % 1 14.834 23292912 49.9 2 16.736 23407994 50.1

Enantioenriched (R)-2a


13.0 14.0 15.0 16.0 17.0 18.0 19.0 min

500

1000

1500

2000

2500

3000mV

Detector A Ch2:210nm

23

29

29

12

23

40

79

94

13.0 14.0 15.0 16.0 17.0 18.0 19.0 min

500

1000

1500

2000

2500

3000mV


15

70

94

4

30

28

14

20

S115



Racemic 3a




10.0 11.0 12.0 13.0 14.0 15.0 min

0

250

500

750

1000

1250

1500

1750

2000

mVDetector A Ch2:210nm

17

80

54

91

17

37

52

14

10.0 11.0 12.0 13.0 14.0 15.0 min

0

500

1000

1500

2000

2500


91

74

45

27

84

29

22

S116



Racemic 4a




11.0 12.0 13.0 14.0 15.0 16.0 min

0

250

500

750

1000

1250


97

93

11

7

97

61

13

3

11.0 12.0 13.0 14.0 15.0 16.0 min

0

500

1000

1500

2000

2500


82

85

35

32

48

78

65

S117



Racemic 5a




11.0 11.5 12.0 12.5 13.0 13.5 14.0 14.5 15.0 15.5 min

0

250

500

750

1000

1250

1500mV

Detector A Ch2:210nm 1

56

63

05

9

15

80

93

18

11.0 11.5 12.0 12.5 13.0 13.5 14.0 14.5 15.0 15.5 min

0

500

1000

1500

2000

2500

3000mV


66

56

28

34

47

33

45

S118



Racemic 6a




13.0 13.5 14.0 14.5 15.0 15.5 16.0 16.5 17.0 17.5 min

0

250

500

750

1000

1250


12

80

33

93

12

82

00

91

13.0 13.5 14.0 14.5 15.0 15.5 16.0 16.5 17.0 17.5 min

0

500

1000

1500

2000

2500


63

91

65

31

31

57

05

S119

HPLC analysis for compound 7 (CHIRALCEL® OJ-H, 5→10% iPrOH/hexane gradient over

22 min then 10% iPrOH/hexane isocratic for 5 min, 0.7 mL/min, 200 nm): tR = 20.2 min

(major), 22.2 min (minor); 94% ee.

Racemic 7


Enantioenriched (R)-7


18.0 19.0 20.0 21.0 22.0 23.0 24.0 25.0 26.0 min

100

125

150

175

200

225

250

275mV


16

56

34

3

16

33

41

2

18.0 19.0 20.0 21.0 22.0 23.0 24.0 25.0 26.0 min

125

150

175

200

225

250

275


36

30

58

2

10

90

30

S120


22 min, 0.7 mL/min, 235 nm): tR = 19.1 min (major), 20.5 min (minor); 93% ee.

Racemic 8




17.0 18.0 19.0 20.0 21.0 22.0 23.0 min

0

500

1000

1500

2000

2500mV


23

33

91

20

23

32

94

13

16.0 17.0 18.0 19.0 20.0 21.0 22.0 23.0 min

0

500

1000

1500

2000

2500

3000

3500

4000mV


44

34

49

94

16

41

39

4

S121



Racemic 9




16.0 17.0 18.0 19.0 20.0 21.0 22.0 23.0 24.0 25.0 26.0 min

0

250

500

750

1000

1250

1500

1750

2000mV


15

77

28

6

21

56

54

05

16.0 17.0 18.0 19.0 20.0 21.0 22.0 23.0 24.0 25.0 26.0 min

0

500

1000

1500

2000

2500

3000

3500

4000mV


52

52

89

44

19

50

41

5

S122



Racemic 10




13.0 14.0 15.0 16.0 17.0 18.0 19.0 min

0

250

500

750

1000

1250mV


90

30

72

6

90

48

32

6

13.0 14.0 15.0 16.0 17.0 18.0 19.0 min

0

500

1000

1500

2000

2500

3000


37

53

64

94

16

12

91

5

S123




Racemic 11




21.0 22.0 23.0 24.0 25.0 26.0 27.0 28.0 min

0

250

500

750

1000

1250

1500


15

67

51

06

15

67

96

24

21.0 22.0 23.0 24.0 25.0 26.0 27.0 28.0 min

0

500

1000

1500

2000

2500

3000


41

58

17

34

14

17

26

2

S124




Racemic 12




20.0 21.0 22.0 23.0 24.0 25.0 26.0 min

0

250

500

750

1000

1250

1500

1750mV


22

25

64

00

22

01

94

41

20.0 21.0 22.0 23.0 24.0 25.0 26.0 min

0

500

1000

1500

2000

2500

3000

3500mV


50

56

65

00

17

91

27

4

S125



Racemic 13




15.0 16.0 17.0 18.0 19.0 20.0 21.0 22.0 23.0 24.0 min

0

250

500

750

1000

1250

1500

1750mV


18

74

84

66

18

97

25

49

15.0 16.0 17.0 18.0 19.0 20.0 21.0 22.0 23.0 24.0 min

0

500

1000

1500

2000

2500

3000

3500mV


35

71

66

96

20

60

16

6

S126




Racemic 14




17.0 18.0 19.0 20.0 21.0 22.0 23.0 24.0 25.0 26.0 27.0 min

0

500

1000

1500

2000

2500


24

52

64

52

24

58

49

00

17.0 18.0 19.0 20.0 21.0 22.0 23.0 24.0 25.0 26.0 27.0 min

0

500

1000

1500

2000

2500

3000

3500


48

76

40

47

19

43

36

2

S127




Racemic 15




18.0 19.0 20.0 21.0 22.0 23.0 24.0 25.0 26.0 27.0 min

0

250

500

750

1000

1250


12

85

38

95

12

83

64

34

18.0 19.0 20.0 21.0 22.0 23.0 24.0 25.0 26.0 27.0 min

0

500

1000

1500

2000

2500

3000

3500mV


42

49

57

39

16

52

98

3

S128



Racemic 16




13.0 14.0 15.0 16.0 17.0 18.0 19.0 min

250

500

750

1000

1250

1500mV


20

86

31

20

20

35

29

08

13.0 14.0 15.0 16.0 17.0 18.0 19.0 min

250

500

750

1000

1250

1500

1750

2000


28

78

43

08

19

31

19

S129

HPLC analysis for compound 17a (CHIRALPAK® AD-H, 5→30% iPrOH/hexane gradient

over 22 min, 0.7 mL/min, 210 nm): tR = 15.6 min (minor), 17.1 min (major); 94% ee.

Racemic 17a




14.5 15.0 15.5 16.0 16.5 17.0 17.5 18.0 min

0

250

500

750

1000

1250

1500


14

66

24

12

14

64

37

12

14.5 15.0 15.5 16.0 16.5 17.0 17.5 18.0 min

0

500

1000

1500

2000

2500


10

48

33

3

31

62

73

81

S130

HPLC analysis for compound 18a (CHIRALPAK® AD-H, 5→30% iPrOH/hexane gradient

over 22 min, 0.7 mL/min, 210 nm): tR = 16.4 min (minor), 18.0 min (major); 92% ee.

Racemic 18a




14.0 15.0 16.0 17.0 18.0 19.0 20.0 min

0

250

500

750

1000

1250

1500

1750

2000

2250mV


20

95

49

96

19

52

90

97

14.0 15.0 16.0 17.0 18.0 19.0 20.0 min

0

500

1000

1500

2000

2500


12

02

51

4

28

68

27

30

S131




Racemic 19




17.5 20.0 22.5 25.0 27.5 min

0

250

500

750

1000

1250

1500


19

21

53

73

19

17

24

68

17.5 20.0 22.5 25.0 27.5 min

0

500

1000

1500

2000

2500

3000


47

52

81

33

10

85

27

3

S132




Racemic 20




18.0 19.0 20.0 21.0 22.0 23.0 24.0 25.0 min

0

250

500

750

1000

1250mV


41

83

76

9

14

15

99

43

18.0 19.0 20.0 21.0 22.0 23.0 24.0 25.0 min

0

500

1000

1500

2000

2500

3000

3500mV


49

43

67

75

96

72

87

download fileview on ChemRxivSilver-Catalyzed Enantioselective Propargylic C–H Bond A... (3.88 MiB)



Silver-Catalyzed Enantioselective Propargylic C–H Bond Amination

Through Rational Ligand Design

Minsoo Ju, Emily E. Zerull, Jessica M. Roberts, Minxue Huang, and Jennifer M. Schomaker*

Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, WI 53706, USA

ABSTRACT: Asymmetric C–H amination via nitrene transfer (NT) is a powerful tool for the preparation of enantioenriched amine building blocks from abundant C–H bonds. Herein, we report a highly regio- and enantioselective synthesis of -alkynyl -amino alcohol motifs via a silver-catalyzed propargylic C–H amination. The protocol was enabled by development of a new bis(oxazoline) (BOX) ligand through a rapid structure-activity relationship (SAR) analysis. The method utilizes readily acces-sible carbamate ester substrates bearing -propargylic C–H bonds and furnishes versatile products in good yields and with excellent enantioselectivity (90–99% ee). A putative Ag–nitrene intermediate is proposed to undergo an enantiodetermining hydrogen-atom transfer (HAT) during the C–H amination event. Density functional theory (DFT) calculations were performed to investigate the origin of enantioselectivity in the HAT step.

Enantioselective syntheses of γ-amino alcohols is an attrac-tive goal, as diverse biologically active molecules contain this motif,1 including the antibiotics negamycin and nikko-mycin Z,1a-c and the HIV treatments lopinavir and ri-tonavir.1e-g γ-Amino alcohols are valuable precursors to β-amino acids, which can be incorporated into peptides as a strategy to modulate their drug-like properties,2 and are also convenient sources of chirality for diverse asymmetric transformations.3 A popular strategy to prepare enantioen-riched γ-amino alcohols involves formation of chiral imine or carbonyl intermediates, followed by diastereoselective reduction of the C=X (X = N or O) bond.4-9 However, these asymmetric Mannich-based4-6 or chiral auxiliary-directed7-9 strategies require additional chemical steps. The direct asymmetric transformation of C–H to C–N bonds via transi-tion metal-catalyzed nitrene transfer (NT) offers the poten-tial for streamlined access to γ-amino alcohols from simple, abundant alcohol precursors.10 In 2008, the Blakey and Du Bois groups independently reported the first examples of asymmetric amination of benzylic and allylic C–H bonds to furnish enantioenriched -amino alcohols in good ee using chiral Ru and Rh catalysts, respectively (Scheme 1a).11,12

Since He’s first reports of Ag-catalyzed NT,13 we and oth-ers have exploited the diverse coordination of Ag(I) species supported by sp2 N-coordinating ligands to achieve tunable and predictable NT reactions with excellent control over chemo- and site-selectivity.14,15 The flexibility of ligands ca-pable of supporting Ag-catalyzed NT make this metal an ideal platform for developing general catalysts for asym-metric NT reactions. In 2017, we reported the first exam-ples of chemoselective, Ag-catalyzed asymmetric aziridina-tion using a 2,2ʹ-isopropylidenebis[(4S)-4-tert-butyl-2-oxa-zoline] ((S,S)-tBu-BOX) ligand,15e while Bach recently dis-closed a site- and enantioselective C–H amination of 2-quin-olones and 2-pyridones catalyzed by a heteroleptic Ag(I) bis(phenanthroline) complex.16 In this communication, we

describe coupling the flexibility of silver-catalyzed NT with the rational design of new ligands for the asymmetric ami-nation of propargylic C–H bonds (Scheme 1b) to enantioen-riched -alkynyl -amino alcohol building blocks.

Several factors were considered in our ligand design. One important issue is site-selectivity, as the putative metal nitrene generated from a carbamate precursor can engage a β- or -C(sp3)–H bond (Scheme 1c) to form either a 5- or 6-member heterocycle en route to 1,2- or 1,3-amino alcohol products. We previously demonstrated that ligand choice is key to achieving tunable catalyst control over ring size, with

Scheme 1. Prior and proposed asymmetric C–H bond amination.

a bidentate, achiral 2,2ʹ-isopropylidenebis[4,4-dimethyl-2-oxazoline] (dmBOX) ligand showing a strong preference for -C–H bond amination.15i A second concern involved mini-

mizing dynamic behavior of the Ag(I) complex in solution to ensure good transfer of stereochemical information from catalyst to product. Previous diffusion-ordered spectros-copy (DOSY) and variable temperature (VT) NMR studies of a silver complex formed from dmBOX and AgClO4 revealed no equilibrium between monomeric and dimeric species, and no fluxional behavior of the ligand.15i Finally, the chal-lenges inherent in differentiating between two prochiral hy-drogen atoms on a carbon adjacent to the linear, compact alkyne group required a modular, readily tunable ligand scaffold. Given these considerations, BOX ligands were a logical choice to investigate to achieve our goal of site- and enantioselective propargylic C–H bond amination.

Studies were initiated with carbamate ester 1, bearing two activated propargylic C–H bonds at the γ-position. A variety of chiral BOX ligands were explored (Figure 1, full details in the Supporting Information) using simple structure-activity

0

10

20

30

40

50

60

70

80

90

100

Figure 1. SAR between BOX ligand modification and enantioselec-tivity in Ag-catalyzed propargylic C–H bond amination of 1.

relationships (SAR) to rapidly identify a promising candi-date. Subjecting 1 to conditions for enantioselective aziridi-nation with commercially available (S,S)-tBu-BOX ligand,15e resulted in a good yield of oxazinanone 2, but in only 13% ee. Interestingly, when the tBu was substituted with a Ph group ((S,S)-Ph-BOX), a significant enhancement to 42% ee was observed. This was a promising lead, as the aryl-substi-tuted BOX scaffold is highly modular and the steric and elec-tronic features of the ligand can be readily tuned.17 Elec-tronic modifications to the aryl groups in L1 and L2 were used to probe if substrate-ligand π–π or metal-ligand cat-ion–π interactions might influence ee.15f,18 Neither electron-donating (L1) nor electron-withdrawing groups (L2) at the para position had much impact, giving 47% and 38% ee, re-spectively. BOX ligands substituted with a 2-naphthyl (L3) or 1-naphthyl group (L4) indicated increasing steric bulk at the meta position of the aryl group (L3) had a positive im-pact on the ee of 2 (48% ee), while substitution at the ortho position of the aryl group (L4) decreased the ee to 39%. In-deed, installation of meta-Me and tBu groups on the aro-matic ring of BOX ligands L5 and L6 improved the ee signif-icantly, up to 70% ee in the case of L6. Replacing the hydro-gens at the chiral carbons of (S,S)-Ph-BOX with Me groups to yield fully substituted carbon centers in L7 improved ee from 42% to 58%. Gratifyingly, combining the features that improve ee into a single Min-BOX ligand gave 86% ee and a near-quantitative yield of 2 at room temperature. The ee was further improved at lower temperatures, furnishing up to 90% ee at –10 °C (see the SI for details of optimization).

The beneficial effect of additional substitution at the ste-reocenter α to the coordinating N atoms in L7 and Min-BOX ligands was at first counterintuitive, as replacing H with Me should reduce facial discrimination in the NT event. We hy-pothesized this modification suppressed detrimental dy-namic behavior of the complex by increasing the steric con-gestion near the silver center.19 Previous observations showed certain N-chelating ligands for Ag(I) lead to equili-brating mixtures of mono- vs. bis-ligated species, as well as monomeric vs. dimeric complexes;15a,15i,19c the presence of multiple potential catalytic species leads to a loss of selec-tivity. Indeed, NMR studies of silver complexes supported by L7 and Min-BOX did not show any equilibrium between mono- and bis-ligated species (see the SI for details). Ra-ther, the data suggested the presence of altered conformer populations in the Ag(L7)OTf complex at different temper-atures (Figure 2a). The VT 1H NMR spectra of Ag(L7)OTf in CD2Cl2 (5 mM) showed substantial changes in the chemical shifts of the diastereotopic protons Ha and Haʹ and the aro-matic protons as the temperature was decreased, while no changes in chemical shift were observed in Ag complexes supported by BOX ligands lacking a fully substituted carbon center. Although individual conformer signals of Ag(L7)OTf were not resolved even at –90 °C, this implies a relatively high energy barrier for the rotations around single bond(s).20 DFT calculations were carried out on truncated mono-oxazoline models to shed further insight into the in-fluence of the fully substituted carbon center on bond rota-tion (Figure 2b, see the SI for details). Relaxed surface scans were conducted by rotating the N–C–C–C dihedral angle (10° increments, 36 steps) to assess the energetic penalty of rotating the aromatic ring (ΔGrot). Installation of the α-Me group (M2) increases bond rotation energy relative to the

Figure 2. Effect of the additional Me substitution in the ligand. (a) VT-NMR studies of [Ag(L7)]OTf complex. (b) Increased rotational barrier (ΔGrot) for the Ar group, as supported by DFT calculations.

M1 model (ΔΔGrot = +1.1 kcal/mol from M1 to M2). Success-ful bond rotation with this increased steric hindrance in-volves placing the ortho-proton within ~2.2–2.4 Å from two of the α-Me protons. In agreement with the observed ee en-hancement, introduction of meta-Me substitution on the aryl ring increased the bond rotation energy to 3.1 kcal/mol (M3). Further steric crowding with meta-tBu groups gave a 7.8 kcal/mol bond rotation energy (M4), nearly 6.5 kcal/mol greater than the M1 model. We postulate the in-creased rotational barrier introduced by the α-Me group substitution and the restricted rotation of the aryl ring in BOX ligands L7 and Min-BOX rigidify the enantiodetermin-ing transition state (TS) and enhance asymmetric induction.

With optimized conditions in hand, the scope of the reac-tion was explored (Figure 3). In general, substrates contain-ing bulky alkyl or aryl substitution at the distal carbon of the alkyne gave excellent yields and ee. For example, altering

the distal R group from the initial methyl group in 2 to bulk-ier substituents, such as n-pentyl (3), i-propyl (4) or t-butyl groups (5), resulted in increased ee to 94–96%. Notably, the enantioselectivities were not affected by electronic modifi-cations to the alkyne precursors. Both 6 (R = TMS) and 7 (R = CF3) gave excellent ee, although an increased catalyst load-ing was required for the CF3-substituted alkyne 7, due to slow conversion. These results helped to rule out the possi-bility of alkyne–Ag interactions playing a critical role in the enantiodetermining step. Carbamate esters containing a Ph group attached to the distal alkyne carbon (8), as well as de-rivatives possessing both electron-donating (9 and 11) and an electron-withdrawing groups (10) at the para-position were successfully transformed into the corresponding oxa-zinanones in high ee (92–93%). Addition of –OMe at the meta-position of the Ar substituent was tolerated (12), while ortho-Me-substitution slightly diminished the ee (13). Alkynes bearing heterocyclic groups, such as a furan (14) and a thiophene (15), were also tolerated under the reac-tion conditions.

The impact of the steric bulk of the substituents at the dis-tal carbon of the alkyne precursors on ee was further exam-ined through linear free-energy relationships (LFER) using the steric parameters and modified Taft equation developed by Charton.21 The equation log(k/k0) = ψν describes a rela-tionship between the relative rate (k/k0) and steric param-eters (ν), with ν defined from measuring steric effects in the rates of methyl ester hydrolysis. The k/k0 is equal to the en-antiomeric ratio (er) when evaluating an asymmetric reac-tion; therefore, log(er) is proportional to the product of ψ (the sensitivity factor) and ν.22 A LFER with a good correla-tion (R2 = 0.82) was observed when log(er) was plotted vs. ν values for 2–5 and 8. The positive sensitivity factor ψ and high correlation with Charton’s steric parameters indicate that larger groups on the distal alkyne carbon should yield higher ee. To test this prediction, a substrate containing an alkyne protected with a t-butyldiphenylsilyl (TBDPS) group was prepared and subjected to asymmetric C–H amination to give 16 in 99% ee. The oxazinanone 16 was subjected to a mild ring-opening conditions to give a 92% NMR yield of the corresponding -amino alcohol, while preserving the TBDPS group. The absolute configuration of 16 was deter-mined to be (R) by X-ray crystallography; other product configurations assigned by analogy to 16. Additionally, sub-strates bearing an alkyl ether (17) or an alkyl chloride (18) were well-tolerated in this chemistry, furnishing excellent ee of 93% and 92%, respectively. Substitution in the tether was also possible at both the α- and β-positions and had no detrimental effect on the enantioselectivity of the reaction (19–20, 95–96% ee). The carbamate ester precursor to 20 is particularly noteworthy, as it is derived from a tertiary alcohol that does not effectively form the sulfamate precur-sor required for Ru- and Rh-catalyzed NT.11,12 While α-sub-stitution in 20 led to a drop in conversion under standard conditions, a higher catalyst loading restored reactivity; this approach is also effective for substrates with electron-poor propargylic C–H bonds, such as the precursor to 7.

Previously reported experimental and computational studies on Ag-catalyzed NT reactions suggest the mechanis-tic pathway proposed in Figure 4a. The carbamate ester

1.0

1.2

1.4

1.6

1.8

2.0

0 0.2 0.4 0.6 0.8 1 1.2 1.4

Figure 3. Substrate scope and LFER study of Ag-catalyzed enantioselective amination of propargylic C–H bonds

nitrene precursor A initially undergoes ligand exchange with the iodosobenzene (PhIO) oxidant to form an iminoio-dinane species B (Figure 4a).15e,23 A silver–nitrene complex C is generated by reacting the iminoiodinane species with a chiral Ag(I) catalyst. According to our previous DFT studies, the reactive intermediate C is best described as Ag(II)–nitrene radical anion, which abstracts a prochiral propar-gylic hydrogen in a hydrogen atom transfer (HAT) step, fol-lowed by a rapid radical recombination (RR) step.14d,14f,18c The radical species is not a stationary point on the potential energy surface, as the RR step displays no energy barrier; experimentally, no radical intermediates are intercepted or trapped. Previous observations confirm the C–H amination is stereoretentive, further supporting the rapid nature of the RR step15i-j,19b and suggesting the initial HAT is the enan-tiodetermining step in the asymmetric C–H bond amination.

In order to probe the origin of enantioselectivity in the HAT, TS modeling of the two prochiral pathways was con-ducted on the propargylic C–H amination of carbamate es-ter 1 using a silver catalyst supported by a model BOX lig-and L8 (truncated from Min-BOX: meta-tBu→Me) (Figure 4b). The silver complex Ag(L8)+ in the calculations was sup-ported by a single BOX ligand, as DOSY NMR experiments show Ag-BOX complexes in solution are monomeric.15i,24 We were delighted to find the DFT calculations successfully pre-dicted the observed (R) absolute configuration, with the

pro-R pathway favored by 1.7 kcal/mol. The pro-R TS places the substrate tail in close proximity to the para-position of the aryl ring (2.794 Å ) to avoid steric interactions with the fully substituted carbon center. The alkyne position faces away from the ligand scaffold, with an alkyne substitu-ent⋯meta-Me distance of (2.778 Å ). Conversely, the disfa-vored pro-S TS places the alkyne tail near the ortho-proton of the aryl ring (2.546 Å ), with an alkyne Me⋯meta-Me dis-tance of 3.235 Å . This alkyne orientation introduces steric interactions between the substrate tail and the α-Me group of the fully substituted carbon center (2.884 Å ), which is ab-sent in the pro-R pathway. Though these TS models differ in their steric interactions, near-linear N⋯H⋯C geometries were observed for both the pro-R (158.3°) and pro-S (161.7°) TS in the HAT, consistent with our previous com-putational studies.15i In accordance with the anticipated ri-gidity of L8, the aryl ring rotations from pro-R to pro-S only deviate up to 7.5°; indeed, introduction of the fully substi-tuted carbon center and the meta alkyl substitution in the aryl ring of the Min-BOX reduces the ability of the ligand scaffold to minimize steric interactions in the disfavored pro-S pathway.

In conclusion, we report the first general catalyst for in-tramolecular, enantioselective propargylic C–H amination proceeding via an Ag-catalyzed NT pathway. A new Min-BOX ligand was rationally designed to transform carbamate

Figure 4. (a) Proposed mechanism of Ag-catalyzed enantioselec-tive propargylic C–H amination. (b) B3LYP-D3/def2-SVP/def2-TZVPP transition state models of pro-R and pro-S HAT pathways employing substrate 1 and Ag(L8)+ complex.

ester substrates bearing two prochiral γ-propargylic C–H bonds to γ-amino alcohol motifs in good yields and ee. Char-ton’s modified Taft equation and steric parameters estab-lished a LFER between the size of groups on the distal al-kyne carbon and the ee of the NT. DFT calculations further validated that the design features introduced into Min-BOX effectively differentiate between the pro-R and pro-S pro-tons during the enantiodetermining HAT step. The oxazi-nanones generated from this method are easily deprotected and derivatized to enantioenriched amino alcohols that can serve as useful building blocks for diverse molecules, in-cluding the platelet aggregation inhibitor, Xemilofiban,25 anti-malarial falcipain-2 inhibitors,26 and other amines.

ASSOCIATED CONTENT

Characterization data, optimization tables, and additional sub-strates/catalysts are included in the supplementary materials, which are available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION

* [email protected]

Author Contributions

The manuscript was written through contributions of all au-thors. All authors have given approval to the final version of the manuscript.

Funding Sources

J.M.S. is grateful to the NSF 1664374 for financial support of this research. The Paul Bender Chemistry Instrumentation

Center was supported by: Thermo Q ExactiveTM Plus by NIH 1S10 OD020022-1; Bruker Quazar APEX2 and Bruker Avance-500 by a generous gift from Paul J. and Margaret M. Bender; Bruker Avance-600 by NIH S10 OK012245; Bruker Avance-400 by NSF CHE-1048642 and the University of Wisconsin-Madi-son; Varian Mercury-300 by NSF CHE-0342998.

ACKNOWLEDGMENT

Dr. Charles G. Fry and Dr. Heike Hofstetter at UW-Madison are thanked for valuable discussions about NMR techniques. Dr. Martha M. Vestling at UW-Madison is thanked for help with mass spectrometry characterization. UCSF Chimera is devel-oped by the Resource for Biocomputing, Visualization, and In-formatics at the University of California, San Francisco (sup-ported by NIH P41-GM103311).

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25. a) Boys, M. L. A synthesis of the platelet aggregation inhibitor xemilofiban from L-aspartic acid. Confirmation of the absolute con-figuration. Tetrahedron Lett. 1998, 39, 3449-3450. b) Cossy, J.; Schmitt, A.; Cinquin, C.; Buisson, D.; Belotti, D. A very short, efficient and inexpensive synthesis of the prodrug form of SC-54701A a platelet aggregation inhibitor. Bioorg. Med. Chem. Lett. 1997, 7, 1699-1700. c) Awasthi, A. K.; Boys, M. L.; Cain-Janicki, K. J.; Colson, P. J.; Doubleday, W. W.; Duran, J. E.; Farid, P. N. Practical enantiose-lective synthesis of β-substituted-β-amino esters. J. Org. Chem. 2005, 70, 5387-97.

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Silver-Catalyzed Enantioselective Propargylic C–HBond Amination Through Rational Ligand DesignMinsoo Ju, Emily E. Zerull, Jessica M. Roberts, Minxue Huang, and Jennifer M. Schomaker*

Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, WI 53706, USA

ABSTRACT: Asymmetric C–H amination via nitrene transfer (NT) is a powerful tool for the preparation ofenantioenriched amine building blocks from abundant C–H bonds. Herein, we report a highly regio- andenantioselective synthesis of -alkynyl -amino alcohol motifs via a silver-catalyzed propargylic C–Hamination. The protocol was enabled by development of a new bis(oxazoline) (BOX) ligand through arapid structure-activity relationship (SAR) analysis. The method utilizes readily accessible carbamateester substrates bearing -propargylic C–H bonds and furnishes versatile products in good yields andwith excellent enantioselectivity (90–99% ee). A putative Ag–nitrene intermediate is proposed toundergo an enantiodetermining hydrogen-atom transfer (HAT) during the C–H amination event. Densityfunctional theory (DFT) calculations were performed to investigate the origin of enantioselectivity in theHAT step.

Enantioselective syntheses of γ-amino alcohols isan attractive goal, as diverse biologically activemolecules contain this motif,1 including theantibiotics negamycin and nikkomycin Z,1a-c andthe HIV treatments lopinavir and ritonavir.1e-g γ-Amino alcohols are valuable precursors to β-amino acids, which can be incorporated intopeptides as a strategy to modulate their drug-likeproperties,2 and are also convenient sources ofchirality for diverse asymmetric transformations.3

A popular strategy to prepare enantioenriched γ-amino alcohols involves formation of chiral imineor carbonyl intermediates, followed bydiastereoselective reduction of the C=X (X = N orO) bond.4-9 However, these asymmetric Mannich-based4-6 or chiral auxiliary-directed7-9 strategiesrequire additional chemical steps. The directasymmetric transformation of C–H to C–N bondsvia transition metal-catalyzed nitrene transfer(NT) offers the potential for streamlined access toγ-amino alcohols from simple, abundant alcoholprecursors.10 In 2008, the Blakey and Du Boisgroups independently reported the first examplesof asymmetric amination of benzylic and allylic C–H bonds to furnish enantioenriched -aminoalcohols in good ee using chiral Ru and Rhcatalysts, respectively (Scheme 1a).11,12

Since He’s first reports of Ag-catalyzed NT,13 weand others have exploited the diversecoordination of Ag(I) species supported by sp2 N-

coordinating ligands to achieve tunable andpredictable NT reactions with excellent controlover chemo- and site-selectivity.14,15 The flexibilityof ligands capable of supporting Ag-catalyzed NTmake this metal an ideal platform for developinggeneral catalysts for asymmetric NT reactions. In2017, we reported the first examples ofchemoselective, Ag-catalyzed asymmetricaziridination using a 2,2ʹ-isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline] ((S,S)-tBu-BOX) ligand,15e

while Bach recently disclosed a site- andenantioselective C–H amination of 2-quinolonesand 2-pyridones catalyzed by a heteroleptic Ag(I)bis(phenanthroline) complex.16 In thiscommunication, we describe coupling theflexibility of silver-catalyzed NT with the rationaldesign of new ligands for the asymmetricamination of propargylic C–H bonds (Scheme 1b)to enantioenriched -alkynyl -amino alcoholbuilding blocks.

Several factors were considered in our liganddesign. One important issue is site-selectivity, asthe putative metal nitrene generated from acarbamate precursor can engage a β- or -C(sp3)–H bond (Scheme 1c) to form either a 5- or 6-member heterocycle en route to 1,2- or 1,3-aminoalcohol products. We previously demonstratedthat ligand choice is key to achieving tunablecatalyst control over ring size, with

Scheme 1. Prior and proposed asymmetric C–H bondamination.

a bidentate, achiral 2,2ʹ-isopropylidenebis[4,4-dimethyl-2-oxazoline] (dmBOX) ligand showinga strong preference for -C–H bond amination.15i

A second concern involved mini-mizingdynamic behavior of the Ag(I) complex insolution to ensure good transfer ofstereochemical information from catalyst toproduct. Previous diffusion-orderedspectroscopy (DOSY) and variable temperature(VT) NMR studies of a silver complex formedfrom dmBOX and AgClO4 revealed noequilibrium between monomeric and dimericspecies, and no fluxional behavior of theligand.15i Finally, the challenges inherent indifferentiating between two prochiral hydrogenatoms on a carbon adjacent to the linear,compact alkyne group required a modular,readily tunable ligand scaffold. Given theseconsiderations, BOX ligands were a logicalchoice to investigate to achieve our goal ofsite- and enantioselective propargylic C–H bondamination.

Studies were initiated with carbamate ester1, bearing two activated propargylic C–H bondsat the γ-position. A variety of chiral BOX ligandswere explored (Figure 1, full details in theSupporting Information) using simple structure-activity

Figure 1. SAR between BOX ligand modification andenantioselectivity in Ag-catalyzed propargylic C–Hbond amination of 1.

relationships (SAR) to rapidly identify apromising candidate. Subjecting 1 to conditionsfor enantioselective aziridination withcommercially available (S,S)-tBu-BOX ligand,15e

resulted in a good yield of oxazinanone 2, butin only 13% ee. Interestingly, when the tBu wassubstituted with a Ph group ((S,S)-Ph-BOX), asignificant enhancement to 42% ee wasobserved. This was a promising lead, as thearyl-substituted BOX scaffold is highly modularand the steric and electronic features of theligand can be readily tuned.17 Electronicmodifications to the aryl groups in L1 and L2were used to probe if substrate-ligand π–π ormetal-ligand cation–π interactions mightinfluence ee.15f,18 Neither electron-donating (L1)nor electron-withdrawing groups (L2) at thepara position had much impact, giving 47% and38% ee, respectively. BOX ligands substitutedwith a 2-naphthyl (L3) or 1-naphthyl group (L4)

indicated increasing steric bulk at the metaposition of the aryl group (L3) had a positiveimpact on the ee of 2 (48% ee), whilesubstitution at the ortho position of the arylgroup (L4) decreased the ee to 39%. Indeed,installation of meta-Me and tBu groups on thearomatic ring of BOX ligands L5 and L6improved the ee significantly, up to 70% ee inthe case of L6. Replacing the hydrogens at thechiral carbons of (S,S)-Ph-BOX with Me groupsto yield fully substituted carbon centers in L7improved ee from 42% to 58%. Gratifyingly,combining the features that improve ee into asingle Min-BOX ligand gave 86% ee and anear-quantitative yield of 2 at roomtemperature. The ee was further improved atlower temperatures, furnishing up to 90% ee at–10 °C (see the SI for details of optimization).

The beneficial effect of additionalsubstitution at the stereocenter α to thecoordinating N atoms in L7 and Min-BOXligands was at first counterintuitive, asreplacing H with Me should reduce facialdiscrimination in the NT event. Wehypothesized this modification suppresseddetrimental dynamic behavior of the complexby increasing the steric congestion near thesilver center.19 Previous observations showedcertain N-chelating ligands for Ag(I) lead toequilibrating mixtures of mono- vs. bis-ligatedspecies, as well as monomeric vs. dimericcomplexes;15a,15i,19c the presence of multiplepotential catalytic species leads to a loss ofselectivity. Indeed, NMR studies of silvercomplexes supported by L7 and Min-BOX didnot show any equilibrium between mono- andbis-ligated species (see the SI for details).Rather, the data suggested the presence ofaltered conformer populations in the Ag(L7)OTfcomplex at different temperatures (Figure 2a).The VT 1H NMR spectra of Ag(L7)OTf in CD2Cl2(5 mM) showed substantial changes in thechemical shifts of the diastereotopic protons Ha

and Haʹ and the aromatic protons as thetemperature was decreased, while no changesin chemical shift were observed in Agcomplexes supported by BOX ligands lacking afully substituted carbon center. Althoughindividual conformer signals of Ag(L7)OTf werenot resolved even at –90 °C, this implies arelatively high energy barrier for the rotationsaround single bond(s).20 DFT calculations werecarried out on truncated mono-oxazolinemodels to shed further insight into theinfluence of the fully substituted carbon centeron bond rotation (Figure 2b, see the SI fordetails). Relaxed surface scans were conductedby rotating the N–C–C–C dihedral angle (10°increments, 36 steps) to assess the energeticpenalty of rotating the aromatic ring (ΔGrot).Installation of the α-Me group (M2) increasesbond rotation energy relative to the

Figure 2. Effect of the additional Me substitution inthe ligand. (a) VT-NMR studies of [Ag(L7)]OTfcomplex. (b) Increased rotational barrier (ΔGrot) forthe Ar group, as supported by DFT calculations.

M1 model (ΔΔGrot = +1.1 kcal/mol from M1 toM2). Successful bond rotation with thisincreased steric hindrance involves placing theortho-proton within ~2.2–2.4 Å from two of theα-Me protons. In agreement with the observedee enhancement, introduction of meta-Mesubstitution on the aryl ring increased the bondrotation energy to 3.1 kcal/mol (M3). Furthersteric crowding with meta-tBu groups gave a7.8 kcal/mol bond rotation energy (M4), nearly6.5 kcal/mol greater than the M1 model. Wepostulate the increased rotational barrierintroduced by the α-Me group substitution andthe restricted rotation of the aryl ring in BOXligands L7 and Min-BOX rigidify theenantiodetermining transition state (TS) andenhance asymmetric induction.

With optimized conditions in hand, the scopeof the reaction was explored (Figure 3). In

general, substrates containing bulky alkyl oraryl substitution at the distal carbon of thealkyne gave excellent yields and ee. Forexample, altering the distal R group from theinitial methyl group in 2 to bulkier substituents,such as n-pentyl (3), i-propyl (4) or t-butylgroups (5), resulted in increased ee to 94–96%.Notably, the enantioselectivities were notaffected by electronic modifications to thealkyne precursors. Both 6 (R = TMS) and 7 (R =CF3) gave excellent ee, although an increasedcatalyst loading was required for the CF3-substituted alkyne 7, due to slow conversion.These results helped to rule out the possibilityof alkyne–Ag interactions playing a critical rolein the enantiodetermining step. Carbamateesters containing a Ph group attached to thedistal alkyne carbon (8), as well as derivativespossessing both electron-donating (9 and 11)and an electron-withdrawing groups (10) at thepara-position were successfully transformedinto the corresponding oxazinanones in high ee(92–93%). Addition of –OMe at the meta-position of the Ar substituent was tolerated(12), while ortho-Me-substitution slightlydiminished the ee (13). Alkynes bearingheterocyclic groups, such as a furan (14) and athiophene (15), were also tolerated under thereaction conditions.

The impact of the steric bulk of thesubstituents at the distal carbon of the alkyneprecursors on ee was further examined throughlinear free-energy relationships (LFER) usingthe steric parameters and modified Taftequation developed by Charton.21 The equationlog(k/k0) = ψν describes a relationship betweenthe relative rate (k/k0) and steric parameters(ν), with ν defined from measuring steric effectsin the rates of methyl ester hydrolysis. The k/k0

is equal to the enantiomeric ratio (er) whenevaluating an asymmetric reaction; therefore,

log(er) is proportional to the product of ψ (thesensitivity factor) and ν.22 A LFER with a goodcorrelation (R2 = 0.82) was observed whenlog(er) was plotted vs. ν values for 2–5 and 8.The positive sensitivity factor ψ and highcorrelation with Charton’s steric parametersindicate that larger groups on the distal alkynecarbon should yield higher ee. To test thisprediction, a substrate containing an alkyneprotected with a t-butyldiphenylsilyl (TBDPS)group was prepared and subjected toasymmetric C–H amination to give 16 in 99%ee. The oxazinanone 16 was subjected to amild ring-opening conditions to give a 92%NMR yield of the corresponding -aminoalcohol, while preserving the TBDPS group. Theabsolute configuration of 16 was determined tobe (R) by X-ray crystallography; other productconfigurations assigned by analogy to 16.Additionally, substrates bearing an alkyl ether(17) or an alkyl chloride (18) were well-tolerated in this chemistry, furnishing excellentee of 93% and 92%, respectively. Substitutionin the tether was also possible at both the α-and β-positions and had no detrimental effecton the enantioselectivity of the reaction (19–20, 95–96% ee). The carbamate esterprecursor to 20 is particularly noteworthy, as itis derived from a tertiary alcohol that does noteffectively form the sulfamate precursorrequired for Ru- and Rh-catalyzed NT.11,12 Whileα-substitution in 20 led to a drop in conversionunder standard conditions, a higher catalystloading restored reactivity; this approach is alsoeffective for substrates with electron-poorpropargylic C–H bonds, such as the precursor to7.

Previously reported experimental andcomputational studies on Ag-catalyzed NTreactions suggest the mechanistic pathwayproposed in Figure 4a. The carbamate ester

Figure 3. Substrate scope and LFER study of Ag-catalyzed enantioselective amination of propargylic C–H bonds

nitrene precursor A initially undergoes ligandexchange with the iodosobenzene (PhIO)oxidant to form an iminoiodinane species B(Figure 4a).15e,23 A silver–nitrene complex C isgenerated by reacting the iminoiodinanespecies with a chiral Ag(I) catalyst. According toour previous DFT studies, the reactiveintermediate C is best described as Ag(II)–nitrene radical anion, which abstracts aprochiral propargylic hydrogen in a hydrogenatom transfer (HAT) step, followed by a rapidradical recombination (RR) step.14d,14f,18c Theradical species is not a stationary point on thepotential energy surface, as the RR stepdisplays no energy barrier; experimentally, noradical intermediates are intercepted ortrapped. Previous observations confirm the C–Hamination is stereoretentive, further supportingthe rapid nature of the RR step15i-j,19b andsuggesting the initial HAT is theenantiodetermining step in the asymmetric C–Hbond amination.

In order to probe the origin ofenantioselectivity in the HAT, TS modeling ofthe two prochiral pathways was conducted onthe propargylic C–H amination of carbamateester 1 using a silver catalyst supported by amodel BOX ligand L8 (truncated from Min-

BOX: meta-tBu→Me) (Figure 4b). The silvercomplex Ag(L8)+ in the calculations wassupported by a single BOX ligand, as DOSY NMRexperiments show Ag-BOX complexes insolution are monomeric.15i,24 We were delightedto find the DFT calculations successfullypredicted the observed (R) absoluteconfiguration, with the pro-R pathway favoredby 1.7 kcal/mol. The pro-R TS places thesubstrate tail in close proximity to the para-position of the aryl ring (2.794 Å) to avoid stericinteractions with the fully substituted carboncenter. The alkyne position faces away from theligand scaffold, with an alkyne substituent⋯meta-Me distance of (2.778 Å). Conversely, thedisfavored pro-S TS places the alkyne tail nearthe ortho-proton of the aryl ring (2.546 Å), withan alkyne Me⋯meta-Me distance of 3.235 Å.This alkyne orientation introduces stericinteractions between the substrate tail and theα-Me group of the fully substituted carboncenter (2.884 Å), which is absent in the pro-Rpathway. Though these TS models differ in theirsteric interactions, near-linear N⋯H⋯Cgeometries were observed for both the pro-R(158.3°) and pro-S (161.7°) TS in the HAT,consistent with our previous computationalstudies.15i In accordance with the anticipated

rigidity of L8, the aryl ring rotations from pro-Rto pro-S only deviate up to 7.5°; indeed,introduction of the fully substituted carboncenter and the meta alkyl substitution in thearyl ring of the Min-BOX reduces the ability ofthe ligand scaffold to minimize stericinteractions in the disfavored pro-S pathway.

In conclusion, we report the first generalcatalyst for intramolecular, enantioselectivepropargylic C–H amination proceeding via anAg-catalyzed NT pathway. A new Min-BOXligand was rationally designed to transformcarbamate

Figure 4. (a) Proposed mechanism of Ag-catalyzedenantioselective propargylic C–H amination. (b)B3LYP-D3/def2-SVP/def2-TZVPP transition statemodels of pro-R and pro-S HAT pathways employingsubstrate 1 and Ag(L8)+ complex.

ester substrates bearing two prochiral γ-propargylic C–H bonds to γ-amino alcoholmotifs in good yields and ee. Charton’smodified Taft equation and steric parametersestablished a LFER between the size of groupson the distal alkyne carbon and the ee of theNT. DFT calculations further validated that thedesign features introduced into Min-BOXeffectively differentiate between the pro-R andpro-S protons during the enantiodeterminingHAT step. The oxazinanones generated fromthis method are easily deprotected andderivatized to enantioenriched amino alcoholsthat can serve as useful building blocks fordiverse molecules, including the plateletaggregation inhibitor, Xemilofiban,25 anti-malarial falcipain-2 inhibitors,26 and otheramines.

ASSOCIATED CONTENT Characterization data, optimization tables, andadditional substrates/catalysts are included in thesupplementary materials, which are available freeof charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION* [email protected]

Author ContributionsThe manuscript was written through contributionsof all authors. All authors have given approval tothe final version of the manuscript.

Funding SourcesJ.M.S. is grateful to the NSF 1664374 for financialsupport of this research. The Paul BenderChemistry Instrumentation Center was supportedby: Thermo Q ExactiveTM Plus by NIH 1S10OD020022-1; Bruker Quazar APEX2 and BrukerAvance-500 by a generous gift from Paul J. andMargaret M. Bender; Bruker Avance-600 by NIHS10 OK012245; Bruker Avance-400 by NSF CHE-1048642 and the University of Wisconsin-Madison;Varian Mercury-300 by NSF CHE-0342998.

ACKNOWLEDGMENT Dr. Charles G. Fry and Dr. Heike Hofstetter at UW-Madison are thanked for valuable discussionsabout NMR techniques. Dr. Martha M. Vestling atUW-Madison is thanked for help with massspectrometry characterization. UCSF Chimera isdeveloped by the Resource for Biocomputing,Visualization, and Informatics at the University ofCalifornia, San Francisco (supported by NIH P41-GM103311).

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