General Procedure for Allylic Alkylation of Imidazolidinones

1.5 Experimental Section

1.5.2 Experimental Procedures

1.5.2.4 General Procedure for Allylic Alkylation of Imidazolidinones

CDCl

3

) δ 7.73 (s, 1H), 7.55 (s, 1H), 7.34 – 7.27 (m, 6H), 7.20 – 7.09 (m, 3H), 7.04 – 6.92 (m, 2H), 6.11 (ddt, J = 17.6, 10.4, 7.3 Hz, 1H), 5.26 – 5.12 (m, 2H), 4.24 – 4.07 (m, 1H), 3.96 (dd, J = 17.1, 14.4 Hz, 1H), 3.90 – 3.75 (m, 1H), 3.70 – 3.40 (m, 4H), 3.38 – 3.12 (m, 2H), 2.99 – 2.80 (m, 2H), 2.43 – 2.38 (m, 2H), 2.38 – 2.33 (m, 2H);

¹³

C NMR (100 MHz, CDCl

3

) δ 170.7, 170.5, 170.0, 163.0, 147.2, 144.4, 138.7, 138.6, 138.5, 136.9, 135.9, 135.8, 135.8, 135.7, 135.7, 135.6, 135.6, 134.2, 133.9, 133.8, 133.6, 133.5, 133.2, 132.9, 130.9, 130.8, 130.6, 130.6, 130.4, 130.4, 129.9, 129.5, 129.5, 129.0, 129.0, 128.3, 128.3, 128.2, 128.2, 128.2, 128.1, 128.1, 126.6, 126.6, 122.2, 122.0, 121.9, 120.5, 120.5, 119.2, 119.1, 119.0, 116.3, 116.3, 109.3, 109.2, 56.2, 56.1, 55.5, 54.3, 52.9, 52.2, 49.5, 49.3, 49.2, 48.9, 47.6, 45.0, 43.5, 43.1, 42.4, 42.2, 42.0, 41.8, 39.5, 39.5, 37.6, 21.0, 21.0, 20.9; IR (Neat Film, NaCl) 3431, 2923, 2854, 2356, 1644, 1634, 1574, 1568, 1538, 1505, 1462, 1454, 1428, 1372, 1308, 1251, 1216, 1172, 1054, 952, 921, 852, 822, 794, 737, 704 cm

^–1

; HRMS (MM: ESI-APCI): m/z calc’d for C

32

H

32

ClN

6

O

2

[M+H]

⁺

: 567.2270, found 567.2294;

[α]

_D^22.24

+41.90 (c 1.0, CHCl

3

).

(CF

3

)

3

-t-BuPHOX (10 mol %) were suspended in 2:1 hexanes:PhMe (2 mL) in a 20 mL glass vial. After stirring for 20 minutes at 25 °C, the appropriate imidazolidinone (1.0 equiv) and 2:1 hexanes:PhMe (5.1 mL, total substrate concentration 0.014 M) were added to the pre-stirred catalyst solution. The vial was then sealed and heated to the appropriate temperature in a heating block. After full consumption of starting material, as monitored by TLC, the reaction mixture was exposed to air. The crude reaction mixture was loaded directly onto a flash column and the product was isolated by silica gel flash chromatography.

tert-butyl (R)-5-allyl-3-benzoyl-5-benzyl-4-oxoimidazolidine-1-carboxylate (35a)

Prepared according to the general procedure with allyl ester 34a (49.0 mg, 0.105 mmol, 1.0 equiv), Pd

₂

(pmdba)

₃

(4.4 mg, 0.004 mmol, 4 mol %), and (S)-(CF

3

)

3

-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %) at 40 °C for 50 h. Purified by silica gel flash chromatography (10% EtOAc/hexanes) to provide benzyl imidazolidinone 35a as a colorless oil (33.7 mg, 0.0801 mmol, 76% yield, 92% ee);

¹

H NMR (400 MHz, CDCl

3

; compound exists as a 2:1 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by

^#

) δ 7.52 (dtd, J = 9.6, 6.5, 2.5 Hz, 1H), 7.44 – 7.30 (m, 4H), 7.31 – 7.23 (m, 3H), 7.12 (ddt, J = 8.8, 7.2, 2.0 Hz, 2H), 5.77 – 5.56 (m, 1H), 5.27 – 5.13 (m, 2H), 4.93 (d, J = 7.6 Hz, 1H

^#

), 4.85 (d, J = 7.4 Hz, 1H*), 4.31 (d, J = 7.6 Hz, 1H

^#

), 4.18 (d, J = 7.4 Hz, 1H*), 3.62 (d, J = 13.4 Hz, 1H*), 3.40 (d, J = 13.5 Hz, 1H

^#

), 3.27 (dd, J = 13.6, 7.7 Hz, 1H*), 3.02 (dd, J = 13.8, 7.4 Hz, 1H

^#

), 2.95 (dd, J = 13.5, 4.4

BzN NBoc

O Bn

Hz, 1H), 2.69 – 2.52 (m, 1H), 1.65 (s, 9H

^#

), 1.54 (s, 9H*);

¹³

C NMR (100 MHz, CDCl

3

) δ 171.5, 171.4, 168.4, 168.1, 152.6, 151.9, 135.9, 135.3, 133.3, 133.3, 132.6, 132.5, 131.9, 131.5, 130.0, 129.9, 128.9, 128.9, 128.8, 128.6, 127.9, 127.9, 127.8, 127.6, 120.6, 120.5, 82.2, 81.3, 71.5, 71.1, 61.3, 61.3, 41.7, 40.9, 40.6, 39.7, 28.8, 28.5; IR (Neat Film, NaCl) 2927, 1758, 1707, 1390, 1368, 1295, 1167, 702, 660 cm

^–1

; HRMS (MM: ESI-APCI): m/z calc’d for C

₂₅

H

₂₉

N

₂

O

₄

[M+H]

⁺

: 421.2122, found 421.2108; [α]

_D^21.7

+19.50 ( c 1.0, CHCl

₃

);

SFC (AD-H, IPA/CO

2

= 7/93, flow rate = 2.5 mL/min, λ = 210 nm) t

R

= 5.13 min (major),

6.29 min (minor).

tert-butyl (R)-5-allyl-3-benzoyl-4-oxo-5-(4-(trifluoromethyl)benzyl)imidazolidine-1-

carboxylate (35b)

Prepared according to the general procedure with allyl ester 34b (53.8 mg, 0.101 mmol, 1.0 equiv), Pd

₂

(pmdba)

₃

(4.4 mg, 0.004 mmol, 4 mol %), and (S)-(CF

3

)

3

-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %) at 60 °C for 23 h. Purified by silica gel flash chromatography (10% EtOAc/hexanes) to provide 4-trifluorobenzyl imidazolidinone 35b as a colorless oil (37.7 mg, 0.0772 mmol, 76% yield, 89% ee);

¹

H NMR (400 MHz, CDCl

3

; compound exists as a 3:1 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by

^#

) δ 7.60 – 7.52 (m, 3H), 7.47 – 7.37 (m, 3H), 7.36 – 7.22 (m, 3H), 5.82 – 5.59 (m, 1H), 5.31 – 5.19 (m, 2H), 4.96 (d, J = 7.7 Hz, 1H

^#

), 4.89 (d, J = 7.5 Hz, 1H*), 4.42 (d, J = 7.7 Hz, 1H

^#

), 4.34 (d, J = 7.5 Hz, 1H*), 3.72 (d, J = 13.4 Hz, 1H*), 3.48 (d, J = 13.5 Hz, 1H

^#

), 3.29 (ddt, J = 13.7, 7.8, 1.0 Hz, 1H), 3.05 (dd, J

= 13.3, 1.8 Hz, 1H), 2.72 – 2.55 (m, 1H), 1.67 (s, 9H

^#

), 1.56 (s, 9H*);

¹³

C NMR (100 MHz, CDCl

3

) δ 171.1, 171.1, 168.3, 168.0, 152.5, 152.0, 140.2, 139.6, 133.1, 133.1, 132.8, 132.8, 131.5, 131.1, 130.4, 130.4, 130.0, 129.7, 128.9, 128.0, 128.0, 125.7, 125.7, 125.6, 125.5, 125.5, 125.4, 125.4, 122.9, 121.1, 121.0, 82.5, 81.7, 71.3, 70.9, 61.4, 61.4, 41.4, 41.1, 40.3, 39.9, 28.8, 28.5; IR (Neat Film, NaCl) 2977, 1754, 1707, 1391, 1369, 1326, 1294, 1263, 1226, 1165, 1126, 1068, 1019, 858, 700, 662 cm

^–1

; HRMS (MM: ESI-APCI): m/z calc’d for C

26

H

31

F

3

N

3

O

4

[M+NH

⁴

]

⁺

: 506.2261, found 506.2254; [α]

_D^21.5

+25.45 ( c 1.0, CHCl

₃

);

SFC (OJ-H, IPA/CO

2

= 10/90, flow rate = 2.5 mL/min, λ = 254 nm) t

R

= 1.55 min (major),

BzN NBoc

O p-CF3-Ph

1.71 min (minor).

tert-butyl (S)-5-allyl-3-benzoyl-5-methyl-4-oxoimidazolidine-1-carboxylate (35c)

Prepared according to the general procedure with allyl ester 34c (40.7 mg, 0.105 mmol, 1.0 equiv), Pd

₂

(pmdba)

₃

(4.4 mg, 0.004 mmol, 4 mol %), and (S)-(CF

3

)

3

-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %) at 60 °C for 19 h. Purified by silica gel flash chromatography (15% EtOAc/hexanes) to provide methyl imidazolidinone 35c as a colorless oil (31.3 mg, 0.0909 mmol, 88% yield, 86% ee);

¹

H NMR (400 MHz, CDCl

3

; compound exists as a 4:3 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by

^#

) δ 7.65 – 7.50 (m, 3H), 7.43 (t, J = 7.6 Hz, 2H),

BzN NBoc

O Me

5.70 (ddt, J = 17.3, 9.9, 7.5 Hz, 1H), 5.25 – 5.13 (m, 3H), 5.07 (dd, J = 13.8, 7.7 Hz, 1H), 3.16 (dd, J = 13.7, 7.8 Hz, 1H*), 2.90 (dd, J = 13.8, 7.2 Hz, 1H

^#

), 2.56 – 2.38 (m, 1H), 1.63 – 1.48 (m, 12H);

¹³

C NMR (100 MHz, CDCl

3

) δ 172.7, 168.8, 168.6, 152.8, 151.7, 133.3, 132.7, 132.1, 131.9, 129.1, 128.1, 120.5, 81.8, 81.3, 66.2, 65.8, 60.9, 60.8, 41.3, 40.0, 28.6, 28.5, 23.6, 22.7; IR (Neat Film, NaCl) 3076, 2977, 2931, 1759, 1702, 1602, 1477, 1450, 1388, 1368, 1297, 1263, 1227, 1168, 1124, 1059, 998, 965, 928, 906, 879, 859, 823, 792, 774, 733, 704, 662, 614 cm

^–1

; HRMS (MM: ESI-APCI): m/z calc’d for C

₁₉

H

₂₅

N

₂

O

₄

[M+H]

⁺

: 345.1809, found 345.1805; [α]

_D^21.6

+4.82 ( c 1.0, CHCl

₃

); SFC (AD-H, IPA/CO

2

= 7/93, flow rate = 2.5 mL/min, λ = 210 nm) t

R

= 3.40 min (major), 3.04 min (minor).

tert-butyl (R)-5-allyl-3-benzoyl-5-(3-methylbut-2-en-1-yl)-4-oxoimidazolidine-1-

carboxylate (35d)

Prepared according to the general procedure with allyl ester 34d (42.2 mg, 0.0954 mmol, 1.0 equiv), Pd

₂

(pmdba)

₃

(4.4 mg, 0.004 mmol, 4 mol %), and (S)-(CF

3

)

3

-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %) at 60 °C for 24 h. Purified by silica gel flash chromatography (10% EtOAc/hexanes) to provide prenyl imidazolidinone 35d as a colorless oil (30.3 mg, 0.0760 mmol, 80% yield, 80% ee);

¹

H NMR (400 MHz, CDCl

3

; compound exists as a 3:2 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by

^#

) δ 7.62 – 7.50 (m, 3H), 7.42 (td, J = 7.7, 4.8 Hz, 2H), 5.75 – 5.58 (m, 1H), 5.24 – 4.96 (m, 5H), 3.17 (dd, J = 13.6, 7.8 Hz, 1H*), 3.06 (dd, J = 14.3, 7.9 Hz, 1H*), 2.90 (dd, J = 13.8, 7.2 Hz, 1H

^#

), 2.78 (dd, J = 14.4, 6.9 Hz, 1H

^#

), 2.58 – 2.36 (m, 2H), 1.73 (d, J = 1.5 Hz, 3H), 1.64 (d, J = 1.4 Hz, 3H), 1.56 (s, 9H

^#

), 1.51 (s, 9H*);

¹³

C NMR (100 MHz, CDCl

3

) δ 172.1, 168.7, 168.5, 152.7, 151.7, 137.3, 137.2, 133.3, 132.7, 132.7, 132.1, 131.7, 129.1, 129.1, 128.0, 128.0, 120.4, 120.3, 117.3, 117.0, 81.8, 81.2, 70.4, 70.0, 61.7, 61.6, 40.6, 39.4, 35.3, 34.3, 28.6, 28.5, 26.4, 26.3, 18.3, 18.2; IR (Neat Film, NaCl) 2976, 1758, 1702, 1449, 1396, 1368, 1305, 1264, 1223, 1168, 1143, 924, 858, 772, 702, 665 cm

^–1

; HRMS (MM: ESI-APCI): m/z calc’d for C

₂₃

H

₃₀

N

₂

O

₄

[M+H]

⁺

: 399.2278, found 399.2275; [α]

_D^21.7

–3.75 ( c 1.0, CHCl

₃

); SFC (OJ-H, IPA/CO

2

= 1/99, flow rate = 2.5 mL/min, λ = 254 nm) t

R

= 2.98 min (major), 3.34 min (minor).

BzN NBoc

O Me

Me

tert-butyl (R)-5-allyl-3-benzoyl-5-cinnamyl-4-oxoimidazolidine-1-carboxylate (35e)

Prepared according to the general procedure with allyl ester 34e (47.6 mg, 0.0970 mmol, 1.0 equiv), Pd

₂

(pmdba)

₃

(4.4 mg, 0.004 mmol, 4 mol %), and (S)-(CF

3

)

3

-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %) at 40 °C for 48 h. Purified by silica gel flash chromatography (10% EtOAc/hexanes) to provide cinnamyl imidazolidinone 35e as a colorless oil (41.9 mg, 0.0938 mmol, 97% yield, 85% ee);

¹

H NMR (400 MHz, CDCl

3

; compound exists as a 1.8:1 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by

^#

) δ 7.61 – 7.48 (m, 3H), 7.42 – 7.35 (m, 2H), 7.35 – 7.29 (m, 4H), 7.25 (dtd, J = 6.6, 3.5, 1.5 Hz, 1H), 6.60 – 6.48 (m, 1H), 6.14 – 6.00

BzN NBoc

O Ph

(m, 1H), 5.79 – 5.64 (m, 1H), 5.27 – 5.17 (m, 2H), 5.17 – 4.99 (m, 2H), 3.30 (ddd, J = 13.7, 7.6, 1.3 Hz, 1H*), 3.18 (dd, J = 13.6, 7.8 Hz, 1H*), 3.05 (ddd, J = 13.8, 6.8, 1.4 Hz, 1H

^#

), 2.93 (dd, J = 13.8, 7.4 Hz, 1H

^#

), 2.71 – 2.45 (m, 2H), 1.62 (s, 9H

^#

), 1.53 (s, 9H*);

¹³

C NMR (100 MHz, CDCl

3

) δ 171.8, 168.6, 168.4, 152.7, 151.8, 137.0, 136.7, 135.6, 135.5, 133.2, 132.8, 132.7, 131.8, 131.4, 129.1, 129.1, 128.9, 128.8, 128.0, 128.0, 127.9, 126.4, 126.3, 122.8, 122.3, 120.8, 120.7, 82.0, 81.4, 70.4, 70.0, 61.6, 61.6, 40.7, 40.1, 39.5, 38.9, 28.7, 28.5; IR (Neat Film, NaCl) 2974, 1755, 1703, 1398, 1296, 1172, 703 cm

^–1

; HRMS (MM:

ESI-APCI): m/z calc’d for C

₂₇

H

₃₄

N

₃

O

₄

[M+NH

⁴

]

⁺

: 464.2544, found 464.2521; [α]

_D^21.6

+30.48 (c 1.0, CHCl

₃

); SFC (AD-H, IPA/CO

2

= 10/90, flow rate = 2.5 mL/min, λ = 210

nm) t

R

= 5.15 min (major), 4.77 min (minor).

tert-butyl (R)-5-allyl-3-benzoyl-4-oxo-5-(prop-2-yn-1-yl)imidazolidine-1-carboxylate (35f)

Prepared according to the general procedure with allyl ester 34f (43.8 mg, 0.106 mmol, 1.0 equiv), Pd

₂

(pmdba)

₃

(4.7 mg, 0.00425 mmol, 4 mol %), and (S)-(CF

3

)

3

-t- BuPHOX (6.3 mg, 0.0106 mmol, 10 mol %) at 60 °C for 45 h. Purified by silica gel flash chromatography (20% EtOAc/hexanes) to provide propargyl imidazolidinone 35f as a colorless oil (18.1 mg, 0.0491 mmol, 46% yield, 91% ee);

¹

H NMR (400 MHz, CDCl

3

; compound exists as a 1.8:1 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by

^#

) δ 7.75 – 7.61 (m, 2H), 7.60 – 7.50 (m, 1H), 7.49 – 7.38 (m, 2H), 5.81 – 5.59 (m, 1H), 5.32 – 5.03 (m, 4H), 3.39 – 2.75 (m, 2H), 2.66 (dd, J = 16.7, 2.6 Hz, 1H

^#

), 2.59 (dd, J = 16.7, 2.6 Hz, 1H*), 2.52 – 2.36 (m, 1H), 2.09 (t, J = 2.6 Hz, 1H

^#

), 2.06 (t, J = 2.6 Hz, 1H*), 1.57 (s, 9H

^#

), 1.53 (s, 9H*);

¹³

C NMR (100 MHz, CDCl

3

) δ 171.0, 170.9, 168.6, 168.4, 152.4, 151.8, 133.1, 132.8, 132.8, 131.4, 131.1, 129.3, 129.2, 128.1, 128.1, 121.0, 120.9, 116.2, 82.2, 81.7, 79.1, 78.3, 72.0, 71.3, 69.6, 69.1, 62.2, 62.1, 40.1, 39.9, 38.7, 38.6, 28.6, 28.5, 28.5, 27.2, 25.9; IR (Neat Film, NaCl) 3276, 2980, 2930, 1760, 1704, 1642, 1602, 1478, 1449, 1392, 1369, 1306, 1266, 1228, 1172, 1091, 1015, 928, 878, 857, 768, 739, 704, 664 cm

^–1

; HRMS (MM: ESI-APCI): m/z calc’d for C

₂₁

H

₂₈

N

₃

O

₄

[M+NH

⁴

]

⁺

: 386.2074, found 386.2066; [α]

_D^21.4

–14.43 ( c 1.0, CHCl

₃

); SFC (OJ-H, IPA/CO

2

= 7/93, flow rate = 2.5 mL/min, λ = 210 nm) t

R

= 2.43 min (major), 2.11 min (minor).

BzN NBoc

O

tert-butyl (R)-3-benzoyl-5-benzyl-5-(2-methylallyl)-4-oxoimidazolidine-1-carboxylate (35g)

Prepared according to the general procedure with allyl ester 34g (48.1 mg, 0.101 mmol, 1.0 equiv), Pd

₂

(pmdba)

₃

(4.4 mg, 0.004 mmol, 4 mol %), and (S)-(CF

3

)

3

-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %) at 60 °C for 26 h. Purified by silica gel flash chromatography (10% EtOAc/hexanes) to provide benzyl imidazolidinone 35g as a colorless oil (36.4 mg, 0.0838 mmol, 83% yield, 89% ee);

¹

H NMR (400 MHz, CDCl

3

; compound exists as a 2.5:1 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by

^#

) δ 7.57 – 7.48 (m, 1H), 7.40 (d, J = 4.4 Hz, 3H), 7.35 – 7.22 (m, 4H), 7.16 – 7.08 (m, 2H), 4.98 – 4.75 (m, 3H), 4.36 (d, J = 7.7 Hz,

BzN NBoc

O BnMe

1H

^#

), 4.21 (d, J = 7.5 Hz, 1H*), 3.66 (d, J = 13.3 Hz, 1H*), 3.45 (d, J = 13.4 Hz, 1H

^#

), 3.22 (d, J = 13.5 Hz, 1H*), 3.01 – 2.88 (m, 1H), 2.62 (d, J = 13.7 Hz, 1H

^#

), 2.56 (d, J = 13.5 Hz, 1H*), 1.72 (s, 3H), 1.66 (s, 9H

^#

), 1.54 (s, 9H*);

¹³

C NMR (100 MHz, CDCl

3

) δ 171.5, 171.3, 168.5, 168.2, 152.6, 152.0, 140.7, 140.3, 135.8, 135.2, 133.5, 133.4, 132.5, 132.5, 130.0, 130.0, 128.9, 128.8, 128.6, 127.9, 127.9, 127.8, 127.6, 116.6, 116.4, 82.3, 81.3, 71.6, 71.1, 61.2, 61.1, 43.6, 42.5, 42.2, 41.1, 28.8, 28.6, 23.9, 23.8; IR (Neat Film, NaCl) 2974, 1755, 1708, 1450, 1397, 1368, 1295, 1216, 1171, 1141, 1076, 901, 703 cm

^–1

; HRMS (MM:

ESI-APCI): m/z calc’d for C

₂₆

H

₃₀

N

₂

NaO

₄

[M+Na]

⁺

: 457.2098, found 457.2083; [α]

_D^21.8

+26.68 (c 1.5, CHCl

₃

); SFC (OD-H, IPA/CO

2

= 10/90, flow rate = 2.5 mL/min, λ = 254

nm) t

R

= 3.79 min (major), 3.47 min (minor).

tert-butyl (R)-5-allyl-3-benzoyl-5-(2-chloroallyl)-4-oxoimidazolidine-1-carboxylate (35h)

Prepared according to the general procedure with allyl ester 34h (44.6 mg, 0.0994 mmol, 1.0 equiv), Pd

₂

(pmdba)

₃

(4.4 mg, 0.004 mmol, 4 mol %), and (S)-(CF

3

)

3

-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %) at 40 °C for 5.5 h. Purified by silica gel flash chromatography (10% EtOAc/hexanes) to provide alkenyl chloride 35h as a colorless oil (37.4 mg, 0.0924 mmol, 93% yield, 86% ee);

¹

H NMR (400 MHz, CDCl

3

; compound exists as a 2.7:1 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by

*, and the minor rotamer by

^#

) δ 7.64 (ddt, J = 8.5, 2.9, 1.7 Hz, 2H), 7.55 (ddt, J = 7.6, 6.9, 1.3 Hz, 1H), 7.46 – 7.38 (m, 2H), 5.75 – 5.60 (m, 1H), 5.38 – 5.28 (m, 2H), 5.27 – 5.08 (m, 4H), 3.40 (d, J = 14.3 Hz, 1H), 3.20 – 3.06 (m, 1H), 2.94 – 2.76 (m, 1H), 2.54 – 2.38 (m, 1H), 1.57 (s, 9H

^#

), 1.50 (s, 9H*);

¹³

C NMR (100 MHz, CDCl

3

) δ 170.9, 170.9, 168.4, 168.1, 152.2, 151.6, 136.7, 136.7, 133.2, 133.2, 132.6, 132.6, 131.1, 130.7, 129.0, 129.0, 127.9, 121.1, 121.0, 117.9, 117.8, 82.0, 81.3, 68.8, 68.6, 61.6, 61.5, 44.8, 44.1, 41.0, 39.6, 28.5, 28.3; IR (Neat Film, NaCl) 2976, 1758, 1707, 1394, 1368, 1295, 1266, 1140, 704 cm

^–1

; HRMS (MM: ESI-APCI): m/z calc’d for C

21

H

29

ClN

3

O

4

[M+NH

⁴

]

⁺

: 422.1841, found 422.1825. [α]

_D^21.7

–3.52 ( c 1.0, CHCl

₃

); SFC (OJ-H, IPA/CO

2

= 7/93, flow rate = 2.5 mL/min, λ = 210 nm) t

R

= 2.19 min (major), 1.99 min (minor).

BzN NBoc

OCl

tert-butyl (R)-5-allyl-3-benzoyl-5-((((benzyloxy)carbonyl)amino)methyl)-4-

oxoimidazolidine-1-carboxylate (35i)

Prepared according to the general procedure with allyl ester 34i (53.7 mg, 0.0100 mmol, 1.0 equiv), Pd

₂

(dba)

₃

(3.7 mg, 0.004 mmol, 4 mol %), and (S)-(CF

3

)

3

-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %) at 40 °C for 22 h. Purified by silica gel flash chromatography (25% EtOAc/hexanes) to provide carbamate 35i as a colorless foam (37.2 mg, 0.0754 mmol, 75% yield, 85% ee);

¹

H NMR (400 MHz, CDCl

3

; compound exists as a 2:1 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by

^#

) δ 7.73 – 7.59 (m, 2H), 7.55 (td, J = 7.3, 1.4 Hz, 1H), 7.42 (q, J =

BzN NBoc

O NHCbz

7.4 Hz, 2H), 7.36 – 7.27 (m, 5H), 5.75 – 5.55 (m, 1H), 5.26 – 4.97 (m, 6H), 3.80 – 3.62 (m, 2H), 3.02 (dd, J = 13.5, 8.0 Hz, 1H*), 2.85 (dd, J = 13.7, 7.3 Hz, 1H

^#

), 2.51 (dd, J = 13.8, 7.5 Hz, 1H

^#

), 2.41 (dd, J = 13.5, 7.0 Hz, 1H*), 1.58 (s, 9H

^#

), 1.50 (s, 9H*);

¹³

C NMR (100 MHz, CDCl

3

) δ 171.2, 170.8, 168.5, 168.2, 156.4, 156.3, 152.4, 152.2, 136.5, 136.2, 133.1, 133.0, 132.8, 132.7, 131.0, 130.7, 129.3, 129.2, 128.7, 128.4, 128.3, 128.0, 121.2, 82.6, 81.8, 69.5, 67.3, 67.2, 61.6, 61.5, 45.7, 45.5, 37.9, 37.1, 28.6, 28.4; IR (Neat Film, NaCl) 3347, 2977, 1704, 1519, 1449, 1392, 1369, 1304, 1166, 1073, 927, 858, 733, 698, 662 cm

^–1

; HRMS (MM: ESI-APCI): m/z calc’d for C

₂₇

H

₃₁

N

₃

NaO

₆

[M+Na]

⁺

: 516.2105, found 516.2087; [α]

_D^21.8

–18.93 ( c 1.0, CHCl

₃

); SFC (AD-H, IPA/CO

2

= 20/80, flow rate

= 2.5 mL/min, λ = 210 nm) t

R

= 6.15 min (major), 3.52 min (minor).

tert-butyl (S)-5-allyl-3-benzoyl-5-(2-cyanoethyl)-4-oxoimidazolidine-1-carboxylate (35j)

Prepared according to the general procedure with allyl ester 34j (41.4 mg, 0.0970 mmol, 1.0 equiv), Pd

₂

(dba)

₃

(3.7 mg, 0.004 mmol, 4 mol %), and (S)-(CF

3

)

3

-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %) at 40 °C for 22 h. Purified by silica gel flash chromatography (20% EtOAc/hexanes) to provide nitrile 35j as a colorless oil (37.2 mg, 0.0970 mmol, >99% yield, 95% ee);

¹

H NMR (400 MHz, CDCl

3

; compound exists as a 2.5:1 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by

^#

) δ 7.69 – 7.61 (m, 2H), 7.61 – 7.54 (m, 1H), 7.49 – 7.38 (m, 2H), 5.74 – 5.60 (m, 1H), 5.30 – 5.18 (m, 3H), 5.17 – 5.06 (m, 1H), 3.11 (dd, J = 13.6, 8.1 Hz, 1H*), 2.86 (dd, J = 13.7, 7.4 Hz, 1H

^#

), 2.63 (dt, J = 13.8, 6.8 Hz, 1H

^*

), 2.53 – 2.14 (m, 4H), 1.57 (s, 9H

^#

), 1.53 (s, 9H*);

¹³

C NMR (100 MHz, CDCl

3

) δ 170.7, 170.6, 168.2, 168.0, 152.2, 151.9, 133.0, 132.9, 132.8, 132.7, 130.5, 130.1, 129.0, 129.0, 128.0, 121.7, 121.6, 118.4, 118.2, 82.7, 82.1, 68.6, 68.3, 61.5, 61.5, 41.1, 39.7, 31.6, 30.4, 28.5, 28.3, 12.9, 12.7;

IR (Neat Film, NaCl) 2976, 1756, 1705, 1390, 1295, 1164, 704 cm

^–1

; HRMS (MM: ESI- APCI): m/z calc’d for C

21

H

29

N

4

O

4

[M+NH

⁴

]

⁺

: 401.2183, found 401.2182; [α]

_D^21.7

–33.24 (c 1.0, CHCl

₃

); SFC (IC, IPA/CO

2

= 15/85, flow rate = 2.5 mL/min, λ = 210 nm) t

R

= 5.49 min (major), 4.78 min (minor).

BzN NBoc

O CN

tert-butyl (S)-5-allyl-3-benzoyl-4-oxo-5-(3-oxobutyl)imidazolidine-1-carboxylate (35k)

Prepared according to the general procedure with allyl ester 34k (44.4 mg, 0.010 mmol, 1.0 equiv), Pd

₂

(dba)

₃

(3.7 mg, 0.004 mmol, 4 mol %), and (S)-(CF

3

)

3

-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %) at 60 °C for 19 h. Purified by silica gel flash chromatography (25% EtOAc/hexanes) to provide ketone 35k as a colorless oil (31.4 mg, 0.0784 mmol, 79% yield, 93% ee);

¹

H NMR (400 MHz, CDCl

3

; compound exists as a 1.3:1 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by

^#

) δ 7.67 – 7.60 (m, 2H), 7.59 – 7.52 (m, 1H), 7.44 (t, J = 7.7 Hz, 2H),

BzN NBoc

O Me

O

5.76 – 5.60 (m, 1H), 5.25 – 5.17 (m, 2H), 5.13 – 5.02 (m, 2H), 3.15 (dd, J = 13.6, 8.0 Hz, 1H*), 2.89 (dd, J = 13.8, 7.2 Hz, 1H

^#

), 2.59 – 2.27 (m, 4H), 2.21 – 2.00 (m, 4H), 1.54 (s, 9H

^#

), 1.51 (s, 9H*);

¹³

C NMR (100 MHz, CDCl

3

) δ 207.3, 206.6, 171.7, 171.6, 168.6, 168.3, 152.6, 151.7, 133.2, 133.1, 132.8, 132.7, 131.5, 131.2, 129.1, 129.1, 128.1, 121.0, 121.0, 82.3, 81.6, 69.0, 68.7, 61.5, 61.4, 41.2, 39.6, 39.0, 38.2, 30.5, 30.1, 29.6, 28.5, 28.5;

IR (Neat Film, NaCl) 2974, 1755, 1708, 1450, 1397, 1368, 1295, 1216, 1171, 1141, 1076,

901, 703 cm

^–1

; HRMS (MM: ESI-APCI): m/z calc’d for C

22

H

32

N

3

O

5

[M+NH

⁴

]

⁺

: 418.2336,

found 418.2347; [α]

_D^21.7

+3.65 ( c 1.0, CHCl

₃

); SFC (IC, IPA/CO

2

= 20/80, flow rate = 2.5

mL/min, λ = 210 nm) t

R

= 2.42 min (major), 3.23 min (minor).

Procedure for the large-scale preparation of compound 35a

In a N

2

filled glovebox, Pd

2

(pmdba)

3

(82 mg, 0.0744 mmol, 4 mol %) and (S)- (CF

3

)

3

-t-BuPHOX (110 mg, 0.186 mmol, 10 mol %) were suspended in 2:1 hexanes:PhMe (45 mL) in a 500 mL Schlenk flask. After stirring for 20 minutes at 25 °C, imidazolidinone 34a (864 mg, 1.86 mmol, 1.0 equiv) and 2:1 hexanes:PhMe (90 mL, total substrate concentration 0.014 M) were added to the pre-stirred catalyst solution. The flask was then sealed and heated at 40 °C in an oil bath for 64 h. The reaction mixture was then cooled to 23 °C and exposed to air. The crude reaction mixture was loaded directly onto a flash column and the product was isolated by silica gel flash chromatography (10%

EtOAc/hexanes) to provide 35a as a colorless oil (674 mg, 1.60 mmol, 86% yield, 95%

ee); All characterization data matched those reported above for compound 35a; [α]

_D^22.1

+21.69 (c 1.0, CHCl

₃

); SFC (AD-H, IPA/CO

2

= 7/93, flow rate = 2.5 mL/min, λ = 210 nm) t

R

= 5.07 min (major), 6.31 min (minor).

BzN NBoc

O Bn