General Procedure for Allylic Alkylation of Diazepanones

1.5 Experimental Section

1.5.2 Experimental Procedures

1.5.2.1 General Procedure for Allylic Alkylation of Diazepanones

In a N

filled glovebox, Pd

(dba)

(4 mol %) or Pd

(pmdba)

(4 mol %) and (S)- (CF

)

-t-BuPHOX (10 mol %) were suspended in methylcyclohexane (2 mL) in a 20 mL glass vial. After stirring for 20 minutes at 25 °C, the appropriate diazepanone (1.0 equiv)

NBoc O R₁O

Pd₂(dba)₃ or Pd₂(pmdba)₃ (4 mol %) (S)-(CF3)3-t-BuPHOX (10 mol %)

methylcyclohexane, 40 °C RN

NBoc O R₁

P N

t-Bu F3C

(S)-(CF3)3-t-BuPHOX 2

CF3

and methylcyclohexane (5.2 mL, total substrate concentration 0.014 M) were added to the pre-stirred catalyst solution. The vial was then sealed and heated to 40 °C. 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 (S)-6-allyl-4-benzoyl-6-benzyl-5-oxo-1,4-diazepane-1-carboxylate (20a)

Prepared according to the general procedure with allyl ester 19a (51.2 mg, 0.104 mmol, 1.0 equiv), Pd

₂

(pmdba)

₃

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

)

-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %). Purified by silica gel flash chromatography (15%

EtOAc/hexanes) to provide benzyl diazepanone 20a as a colorless oil (43.4 mg, 0.0967 mmol, 93% yield, 90% ee);

H NMR (400 MHz, CDCl

) δ 7.56 – 7.40 (m, 3H), 7.40 – 7.32 (m, 2H), 7.32 – 7.19 (m, 3H), 7.19 – 7.00 (m, 2H), 5.88 (br s, 1H), 5.26 – 5.07 (m, 2H), 4.26 – 4.03 (m, 1H), 3.94 (d, J = 15.4 Hz, 1H), 3.73 (d, J = 42.2 Hz, 1H), 3.54 (d, J = 15.3 Hz, 1H), 3.40 (s, 2H), 3.09 (dd, J = 61.0, 13.7 Hz, 1H), 2.94 – 2.34 (m, 3H), 1.48 (s, 9H);

C NMR (100 MHz, CDCl

₃

) δ 179.2, 174.8, 156.0, 155.4, 136.6, 136.4, 133.0, 131.5, 130.8, 128.6, 128.4, 127.8, 127.1, 120.0, 119.7, 80.8, 54.3, 53.9, 49.1, 47.4, 46.9, 42.5, 42.0, 41.5, 40.3, 28.5; IR (Neat Film, NaCl) 3062, 2975, 2928, 1693, 1682, 1601, 1452, 1415, 1392, 1365, 1322, 1283, 1246, 1156, 1044, 978, 917, 865, 728, 697 cm

^–1

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

₂₇

H

₃₃

N

₂

O

₄

[M+H]

⁺

: 449.2435, found 449.2429; [α]

_D^22.4

BzN

NBoc O Bn

+14.19 (c 0.66, CHCl

₃

); SFC conditions: 20% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 210 nm, t

(min): major = 3.51, minor = 2.71.

tert-butyl (R)-6-allyl-4-benzoyl-6-methyl-5-oxo-1,4-diazepane-1-carboxylate (20b)

Prepared according to the general procedure with allyl ester 19b (39.0 mg, 0.0937 mmol, 1.0 equiv), Pd

₂

(pmdba)

₃

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

)

-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %). Purified by silica gel flash chromatography (20%

EtOAc/hexanes) to provide methyl diazepanone 20b as a colorless, waxy solid (32.3 mg, 0.868 mmol, 93% yield, 90% ee);

H NMR (400 MHz, CDCl

) δ 7.54 – 7.43 (m, 3H), 7.43 – 7.32 (m, 2H), 5.74 (ddt, J = 17.1, 9.9, 7.4 Hz, 1H), 5.19 – 5.06 (m, 2H), 4.30 – 3.89 (m,

BzN

NBoc O Me

3H), 3.85 – 3.69 (m, 1H), 3.66 – 3.34 (m, 2H), 2.63 – 2.20 (m, 2H), 1.50 (s, 9H), 1.30 (s,

3H);

¹³

C NMR (100 MHz, CDCl

) δ 180.8, 174.5, 155.4, 155.0, 136.3, 132.9, 131.4, 128.3,

127.5, 119.5, 80.7, 50.9, 49.9, 47.2, 46.5, 42.5, 42.1, 41.8, 28.4, 23.5, 23.1; IR (Neat Film,

NaCl) 2976, 2933, 1694, 1450, 1418, 1392, 1366, 1323, 1284, 1246, 1146, 1057, 983, 917,

868, 768, 729, 696 cm

^–1

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

H

N

O

[M+H]

⁺

:

373.2122, found 373.2117; [α]

_D^22.31

–12.69 (c 1.0, CHCl

₃

); SFC Conditions: 20% IPA, 2.5

mL/min, Chiralpak IC column, λ = 210 nm, t

(min): minor = 4.31, major = 5.68.

tert-butyl (R)-6-allyl-6-methyl-5-oxo-4-(4-(trifluoromethyl)benzoyl)-1,4-diazepane-1-

carboxylate (20c)

Prepared according to the general procedure with allyl ester 19c (55.3 mg, 0.114 mmol, 1.0 equiv), Pd

(dba)

(4.2 mg, 4.57 µmol, 4 mol %), and (S)-(CF

)

-t-BuPHOX (6.7 mg, 0.011 mmol, 10 mol %). Purified by silica gel flash chromatography (20%

EtOAc/hexanes) to provide methyl diazepanone 20c as a colorless oil (45.1 mg, 0.102 mmol, 90% yield, 92% ee);

H NMR (400 MHz, CDCl

) δ 7.64 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H), 5.71 (ddt, J = 17.2, 10.1, 7.4 Hz, 1H), 5.23 – 5.07 (m, 2H), 4.21 – 4.03 (m, 2H), 4.02 – 3.64 (m, 2H), 3.58 – 3.38 (m, 2H), 2.59 – 2.21 (m, 2H), 1.49 (s, 9H), 1.29 (s, 3H);

¹³

C NMR (100 MHz, CDCl

) δ 181.0, 180.8, 173.1, 155.4, 155.1 140.0, 132.8 (q, J

C-F

= 32.9 Hz), 132.7, 127.6, 125.5 (q, J

C-F

= 3.7 Hz), 123.7 (q, J

C-F

= 272.5 Hz), 119.9, 81.0, 50.9, 50.0, 47.2, 46.4, 42.4, 42.0, 41.8, 28.5, 23.6, 23.3; IR (Neat Film, NaCl) 3366, 3077, 2978, 2934, 1694, 1452, 1410, 1394, 1367, 1326, 1248, 1167, 1147, 1066, 1014, 984, 925, 852, 764 cm

^–1

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

H

F

N

O

[M+NH

]

⁺

: 458.2261, found 458.2250; [α]

_D^22.6

–12.32 (c 1.0, CHCl

₃

); SFC Conditions: 5%

IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 210 nm, t

(min): minor = 4.49, major = 5.86.

(p-F₃C-Bz)N

NBoc O Me

tert-butyl (R)-6-allyl-4-(4-methoxybenzoyl)-6-methyl-5-oxo-1,4-diazepane-1-

carboxylate (20d)

Prepared according to the general procedure with allyl ester 19d (45.8 mg, 0.103 mmol, 1.0 equiv), Pd

(dba)

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

)

-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %). Purified by silica gel flash chromatography (20%

EtOAc/hexanes) to provide methyl diazepanone 20d as a colorless oil (38.9 mg, 0.0966 mmol, 94% yield, 94% ee);

H NMR (400 MHz, CDCl

) δ 7.62 – 7.44 (m, 2H), 6.95 – 6.75 (m, 2H), 5.76 (m, 1H), 5.26 – 4.99 (m, 2H), 4.24 – 3.87 (m, 3H), 3.83 (s, 3H), 3.75 (m, 1H), 3.59 – 3.37 (m, 2H), 2.60 – 2.25 (m, 2H), 1.49 (s, 9H), 1.31 (s, 3H);

¹³

C NMR (100

AnN

NBoc O Me

MHz, CDCl

) δ 180.7, 180.6, 174.3, 162.5, 155.4, 155.0, 133.0, 130.1, 128.1, 119.4, 113.6,

80.7, 55.4, 50.8, 49.8, 47.4, 46.6, 42.7, 42.4, 28.4, 23.5, 23.1; IR (Neat Film, NaCl) 3352,

3076, 2975, 2932, 2841, 2568, 1690, 1605, 1579, 1542, 1511, 1458, 1420, 1392, 1366,

1322, 1284, 1256, 1214, 1168, 1146, 1056, 1032, 984, 924, 868, 842, 807, 762, 743, 736,

650, 633, 621, 608 cm

^–1

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

H

N

O

[M+H]

⁺

:

403.2227, found 403.2225; [α]

D22.45

–40.51 (c 1.0, CHCl

); SFC Conditions: 20% MeOH,

2.5 mL/min, Chiralpak IC column, λ = 210 nm, t

(min): minor = 5.11, major = 5.66.

tert-butyl (S)-6-allyl-6-benzyl-4-(4-methoxybenzoyl)-5-oxo-1,4-diazepane-1- carboxylate (20e)

Prepared according to the general procedure with allyl ester 19e (52.3 mg, 0.100 mmol, 1.0 equiv), Pd

(dba)

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

)

-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %). Purified by silica gel flash chromatography (20%

EtOAc/hexanes) to provide benzyl diazepanone 20e as a colorless oil (48.1 mg, 0.100 mmol, >99% yield, 89% ee);

H NMR (400 MHz, CDCl

) δ 7.51 – 7.44 (m, 2H), 7.32 – 7.20 (m, 3H), 7.18 – 7.09 (m, 2H), 6.87 – 6.81 (m, 2H), 5.93 (br s, 1H), 5.26 – 5.12 (m, 2H), 4.09 – 3.88 (m, 2H), 3.84 (s, 3H), 3.78 – 2.41 (m, 8H), 1.48 (s, 9H);

¹³

C NMR (100 MHz, CDCl

) δ 179.0, 174.6, 162.6, 156.0, 155.4, 136.7, 133.1, 130.8, 130.5, 128.5, 128.2, 127.0, 119.9, 119.6, 113.7, 80.9, 80.7, 55.5, 54.2, 53.8, 49.1, 47.5, 47.3, 42.4, 42.0, 41.2, 40.9, 40.0, 28.5; IR (Neat Film, NaCl) 3374, 2974, 2927, 1694, 1604, 1581, 1510, 1454, 1416, 1392, 1365, 1320, 1282, 1256, 1211, 1166, 1028, 979, 925, 838, 762, 742, 705, 678, 636, 610 cm

^–1

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

H

N

O

[M+H]

⁺

: 479.2540, found 479.2533; [α]

_D^22.81

+19.02 (c 1.0, CHCl

₃

); SFC Conditions: 20% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 210 nm, t

(min): minor = 3.94, major = 6.20.

AnN

NBoc O Bn

tert-butyl (S)-6-allyl-4-benzoyl-6-fluoro-5-oxo-1,4-diazepane-1-carboxylate (20f)

Prepared according to the general procedure with allyl ester 19f (43.2 mg, 0.103 mmol, 1.0 equiv), Pd

₂

(pmdba)

₃

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

)

-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %). Purified by silica gel flash chromatography (20%

EtOAc/hexanes) to provide alkyl fluoride 20f as a white, amorphous solid (32.6 mg, 0.0866 mmol, 84% yield, 90% ee);

H NMR (400 MHz, CDCl

) δ 7.61 – 7.53 (m, 2H), 7.53 – 7.45 (m, 1H), 7.45 – 7.34 (m, 2H), 5.94 – 5.72 (m, 1H), 5.34 – 5.17 (m, 2H), 4.58 – 4.38 (m, 1H), 4.26 – 4.02 (m, 2H), 3.99 – 3.74 (m, 1H), 3.39 – 3.10 (m, 2H), 2.96 – 2.74 (m, 1H), 2.73 – 2.43 (m, 1H), 1.47 (s, 9H);

¹³

C NMR (100 MHz, CDCl

) δ 173.9, 173.9 (d, J

C-F

= 26.3 Hz), 155.1, 135.2, 132.1, 130.3, 128.4, 128.2, 121.0, 97.7 (dd, J

C-F

= 193.9, 47.2 Hz), 81.1, 49.8 (dd, J

C-F

= 35.3, 23.1 Hz), 47.2, 46.6, 42.6, 39.7 (dd, J

C-F

= 27.6, 21.9 Hz), 28.3;

IR (Neat Film, NaCl) 2978, 2926, 1694, 1450, 1414, 1393, 1367, 1329, 1246, 1152, 1042, 999, 979, 926, 857, 766, 724, 694, 672, 648 cm

^–1

; HRMS (MM: ESI-APCI): m/z calc’d for

BzN

NBoc O F

C

H

FN

O

[M+NH

]

⁺

: 438.2035, found 438.2040; [α]

D22.85

+28.89 (c 1.0, CHCl

); SFC Conditions: 10% IPA, 2.5 mL/min, Chiralcel OD-H column, λ = 210 nm, t

(min): minor

= 6.26, major = 4.99.

tert-butyl (S)-6-allyl-6-fluoro-4-(4-methoxybenzoyl)-5-oxo-1,4-diazepane-1-

carboxylate (20g)

Prepared according to the general procedure with allyl ester 19g (60 mg, 0.133 mmol, 1.0 equiv), Pd

₂

(dba)

₃

(4.9 mg, 0.0053 mmol, 4 mol %), and (S)-(CF

)

-t-BuPHOX (7.9 mg, 0.013 mmol, 10 mol %). Purified by automated silica gel flash chromatography (0→50% acetone/hexanes) to provide alkyl fluoride 20g as a colorless oil (45 mg, 0.111 mmol, 84% yield, 83% ee);

H NMR (400 MHz, CDCl

) δ 7.61 – 7.53 (m, 2H), 6.92 – 6.84

AnN

NBoc O F

(m, 2H), 5.93 – 5.78 (m, 1H), 5.30 – 5.21 (m, 2H), 4.35 (t, J = 16.0 Hz, 1H), 4.22 – 4.02 (m, 2H), 3.96 – 3.85 (m, 1H), 3.84 (s, 3H), 3.40 – 3.19 (m, 2H), 2.94 – 2.78 (m, 1H), 2.71 – 2.48 (m, 1H), 1.47 (s, 9H);

¹³

C NMR (100 MHz, CDCl

₃

) δ 173.9, 173.7, 163.1, 155.3, 131.0, 130.6, 127.1, 121.0, 113.8, 97.8 (dd, J

C-F

= 193.7, 52.5 Hz), 81.2, 55.5, 49.8 (dd, J

C- F

= 33.5, 23.3 Hz), 47.5, 46.9, 43.2, 39.8 (dd, J

C-F

= 32.1, 21.8 Hz), 28.3; IR (Neat Film,

NaCl) 2977, 2932, 1696, 1603, 1578, 1511, 1448, 1413, 1366, 1327, 1256, 1169, 1152,

1029, 1000, 977, 923, 835, 766 cm

^–1

; HRMS (MM: ESI-APCI): m/z calc’d for

C

₂₁

H

₂₈

FN

₂

O

₅

[M+H]

⁺

: 407.1977, found 407.1973; [α]

_D^22.5

+46.99 (c 1.7, CHCl

₃

); SFC

conditions: 20% IPA, 2.5 mL/min, Chiralcel OD-H column, λ = 210 nm, t

(min): major =

2.69, minor = 3.25.

tert-butyl (S)-6-allyl-6-(2-chloroallyl)-4-(4-methoxybenzoyl)-5-oxo-1,4-diazepane-1-

carboxylate (20h)

Prepared according to the general procedure with allyl ester 19h (48.1 mg, 0.0949 mmol, 1.0 equiv), Pd

(dba)

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

)

-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %). Purified by silica gel flash chromatography (20%

EtOAc/hexanes) to provide alkenyl chloride 20h as a colorless oil (36.7 mg, 0.0793 mmol, 84% yield, 90% ee);

H NMR (400 MHz, CDCl

) δ 7.55 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 5.93 – 5.71 (m, 1H), 5.36 – 5.07 (m, 4H), 4.36 – 3.84 (m, 4H), 3.83 (s, 3H), 3.82 – 3.51 (m, 2H), 3.00 – 2.33 (m, 4H), 1.50 (s, 9H);

¹³

C NMR (100 MHz, CDCl

) δ 178.2, 174.6, 162.7, 155.8, 155.2, 137.5, 132.9, 130.5, 128.3, 120.1, 118.2, 113.7, 81.1, 80.9, 55.5, 52.6, 49.2, 47.7, 47.4, 47.0, 44.5, 43.8, 42.8, 42.0, 41.8, 40.3, 28.5; IR (Neat Film, NaCl) 2976, 2930, 1694, 1631, 1604, 1580, 1510, 1456, 1421, 1393, 1366, 1320, 1282, 1256, 1212, 1167, 1150, 1030, 980, 928, 840, 765, 682, 636, 610 cm

^–1

; HRMS (MM:

ESI-APCI): m/z calc’d for C

H

ClN

O

[M+H]

⁺

: 463.1994, found 463.2005; [α]

_D^22.68

– 24.10 (c 0.5, CHCl

₃

); SFC Conditions: 20% IPA, 2.5 mL/min, Chiralpak AD-H column, λ

= 210 nm, t

(min): minor = 2.52, major = 2.77.

AnN

NBoc Cl O

tert-butyl (S)-6-allyl-4-(4-methoxybenzoyl)-5-oxo-6-(prop-2-yn-1-yl)-1,4-diazepane-

1-carboxylate (20i)

Prepared according to the general procedure with allyl ester 19i (70.0 mg, 0.149 mmol, 1.0 equiv), Pd

(pmdba)

(5.4 mg, 4.9 µmol, 4 mol %), and (S)-(CF

)

-t-BuPHOX (8.8 mg, 0.015 mmol, 10 mol %) at 50 °C. Purification by automated silica gel flash chromatography (Teledyne ISCO, 0→40% acetone/hexanes) provided alkyne 20i as a colorless oil (28.0 mg, 0.0656 mmol, 44% yield, 94% ee);

H NMR (400 MHz, CDCl

) δ 7.59 (d, J = 8.2 Hz, 2H), 6.89 – 6.82 (m, 2H), 5.93 – 5.63 (m, 1H), 5.30 – 5.10 (m, 2H), 4.36 – 4.15 (m, 1H), 4.09 – 3.68 (m, 4H), 3.83 (s, 3H), 3.62 – 3.37 (m, 1H), 2.83 – 2.43 (m, 4H), 2.20 – 1.99 (m, 1H), 1.51 (s, 9H);

¹³

C NMR (100 MHz, CDCl

) δ 177.5, 174.6, 162.9, 155.6, 155.2, 132.1, 130.7, 127.9, 120.0, 113.7, 81.1, 80.9, 80.5, 72.1, 55.6, 52.7, 49.1, 46.9, 47.7, 43.0, 42.3, 39.1, 37.5, 28.5, 26.5, 25.9; IR (Neat Film, NaCl) 3283, 2972, 2922, 1692, 1603, 1511, 1454, 1418, 1365, 1322, 1255, 1169, 1031, 980, 926, 839, 766,

AnN

NBoc O

670 cm

^–1

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

₂₄

H

₃₁

N

₂

O

₅

[M+H]

⁺

: 427.2227, found 427.2238; [α]

D22.1

–7.69 (c 1.0, CHCl

₃

); SFC conditions: 10% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 210 nm, t

(min): major = 10.85, minor = 10.29.

tert-butyl (R)-6-allyl-6-(3-methoxy-3-oxopropyl)-4-(4-methoxybenzoyl)-5-oxo-1,4-

diazepane-1-carboxylate (20j)

Prepared according to the general procedure with allyl ester 19j (51.9 mg, 0.100 mmol, 1.0 equiv), Pd

(dba)

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

)

-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %). Purified by silica gel flash chromatography (33%

AnN

NBoc O

CO₂Me

EtOAc/hexanes) to provide methyl ester 20j as a white, amorphous solid (45.8 mg, 0.0965 mmol, 96% yield, 95% ee);

H NMR (400 MHz, CDCl

) δ 7.57 – 7.48 (m, 2H), 6.92 – 6.83 (m, 2H), 5.80 – 5.64 (m, 1H), 5.22 – 5.09 (m, 2H), 4.21 (ddd, J = 15.7, 6.6, 2.1 Hz, 1H), 4.13 – 3.85 (m, 3H), 3.83 (s, 3H), 3.62 (s, 3H), 3.51 (d, J = 15.2 Hz, 1H), 3.42 – 3.29 (m, 1H), 2.64 – 2.20 (m, 4H), 2.20 – 1.86 (m, 2H), 1.49 (s, 9H);

¹³

C NMR (100 MHz, CDCl

) δ 179.2, 174.7, 173.6, 173.4, 162.7, 155.4, 155.0, 132.7, 132.5, 130.3, 128.3, 120.0, 113.8, 81.1, 80.9, 55.5, 51.8, 50.1, 48.9, 47.6, 46.8, 43.2, 42.9, 40.3, 39.7, 29.3, 28.8, 28.5; IR (Neat Film, NaCl) 2975, 2360, 1736, 1694, 1605, 1580, 1510, 1426, 1393, 1366, 1321, 1283, 1254, 1167, 1031, 980, 927, 842, 811, 762, 647, 610 cm

^–1

; HRMS (MM: ESI-APCI):

m/z calc’d for C

H

N

O

[M+H]

⁺

: 475.2439, found 475.2438; [α]

D22.52

+7.73 (c 1.0,

CHCl

₃

); SFC conditions: 15% IPA, 2.5 mL/min, Chiralcel OD-H column, λ = 210 nm, t

(min): major = 5.27, minor = 4.84.

tert-butyl (R)-6-allyl-6-(2-cyanoethyl)-4-(4-methoxybenzoyl)-5-oxo-1,4-diazepane-1-

carboxylate (20k)

Prepared according to the general procedure with allyl ester 19k (62.2 mg, 0.128 mmol, 1.0 equiv), Pd

(dba)

(4.7 mg, 0.00512 mmol, 4 mol %), and (S)-(CF

)

-t-BuPHOX (7.6 mg, 0.0128 mmol, 10 mol %), using 9:1 methylcyclohexane-toluene as the reaction solvent. Purified by silica gel flash chromatography (33% EtOAc/hexanes) to provide nitrile 20k as a white, amorphous solid (48.6 mg, 0.110 mmol, 86% yield, 84% ee);

H NMR (400 MHz, CDCl

) δ 7.59 – 7.47 (m, 2H), 6.96 – 6.85 (m, 2H), 5.82 – 5.64 (m, 1H), 5.30 – 5.11 (m, 2H), 4.09 – 3.93 (m, 2H), 3.93 – 3.72 (m, 2H), 3.85 (s, 3H), 3.70 – 3.38 (m, 2H), 2.60 – 2.25 (m, 4H), 2.22 – 1.93 (m, 2H), 1.50 (s, 9H);

¹³

C NMR (100 MHz, CDCl

) δ 178.0, 174.5, 163.0, 155.6, 154.9, 131.7, 130.3, 127.9, 120.7, 119.7, 113.9, 81.4, 55.6, 52.2, 49.6, 48.0, 47.4, 46.8, 43.0, 42.6, 39.9, 39.0, 32.1, 31.5, 28.4, 12.4; IR (Neat Film, NaCl) 2975, 2931, 2361, 2246, 1690, 1604, 1579, 1510, 1456, 1419, 1366, 1321, 1256, 1168, 1148, 1031, 980, 926, 840, 811, 766, 607 cm

^–1

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

H

N

O

[M+NH

]

⁺

: 459.2602, found 459.2602; [α]

D22.4

+9.31 (c 0.5, CHCl

₃

); SFC conditions: 20% IPA, 2.5 mL/min, Chiralcel OD-H column, λ = 310 nm, t

(min): major = 8.33, minor = 6.18.

AnN

NBoc O

tert-butyl (S)-6-allyl-4-benzoyl-6-(((tert-butoxycarbonyl)amino)methyl)-5-oxo-1,4- diazepane-1-carboxylate (20l)

Prepared according to the general procedure with allyl ester 19l (53 mg, 0.0997 mmol, 1.0 equiv) and Pd

₂

(dba)

₃

. Purification by automated silica gel flash chromatography (0→50% EtOAc/hexanes) provided carbamate 20l as a white foam (37 mg, 0.0759 mmol, 76% yield, 93% ee).

H NMR (400 MHz, CDCl

) δ 7.55 – 7.44 (m, 3H), 7.44 – 7.35 (m, 2H), 5.74 (ddt, J = 15.7, 10.5, 7.4 Hz, 1H), 5.35 (br s, 0.5H), 5.21 – 5.06 (m, 2H), 4.79 (br s, 0.5H), 4.48 – 4.28 (m, 1H), 4.14 – 3.09 (m, 7H), 2.69 – 2.18 (m, 2H), 1.50 (s, 9H), 1.44 (s, 9H);

¹³

C NMR (100 MHz, CDCl

₃

) δ 179.3, 178.8, 174.5, 156.3, 155.9, 155.1, 136.3,

BzN

NBoc O BocHN

132.5, 132.1, 131.7, 128.5, 127.7, 120.1, 81.3, 81.1, 79.5, 54.8, 48.9, 47.3, 46.8, 46.3, 42.6, 41.1, 38.7, 37.1, 28.5, 28.5; IR (Neat Film, NaCl) 2977, 1687, 1502, 1422, 1391, 1365, 1322, 1282, 1245, 1168, 978, 916, 753 cm

^–1

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

₂₆

H

₃₇

N

₃

O

₆

[M+H]

⁺

: 488.2755, found 488.2747; [α]

_D^23.2

–3.70 ( c 1.85, CHCl

₃

); SFC conditions: 20% IPA, 2.5 mL/min, Chiralpak IC column, λ = 254 nm, t

(min): major = 5.85, minor = 4.65.

Procedure for the large-scale preparation of diazepanone 20e

To a 500 mL Schlenk flask was added Pd

(dba)

(37 mg, 0.04 mmol, 4 mol %), (S)- (CF

)

-t -BuPHOX (59 mg, 0.1 mmol, 10 mol %), and MeCy (20 mL). After stirring for 20

AnN

NBoc O Bn

minutes at 25 °C, allyl ester 19e (523 mg, 1.0 mmol, 1.0 equiv) and methylcyclohexane (52 mL, total substrate concentration 0.014 M) were added to the pre-stirred catalyst solution. After stirring for 23 h at 40 °C, the reaction mixture was directly loaded onto a flash column and purified by silica gel flash chromatography (20% EtOAc/hexanes) to provide benzyl diazepanone 20e as a colorless oil (393 mg, 0.82 mmol, 82% yield, 83%

ee); All characterization data matched those reported above for compound 20e; [α]

_D^21.96

+14.757 (c 1.0, CHCl

₃

); SFC Conditions: 20% IPA, 2.5 mL/min, Chiralpak AD-H column,

λ = 210 nm, t

(min): minor = 3.76, major = 5.90.

Dalam dokumen synthesis of organic building blocks and synthetic (Halaman 57-76)