thieme · synthesis of amino urea catalysts representative procedure for the preparation of amino...

Thieme

Supporting Information for DOI: 10.1055/s-0037-1611860

Catalytic Asymmetric Intramolecular Bromolactonization of

α,β-Unsaturated Ketones

Shenghui Liu,a Hailong He,

b Min Gan,

a Peng Yi,

a Xiaojian Jiang*

* chemjxj2015@jnu.edu.cn

Table of Contents

GENERAL METHODS

General procedures -------------------------------------------------------------------------------------------------------- 2

Materials -------------------------------------------------------------------------------------------------------------------- 2

Instrumentation ------------------------------------------------------------------------------------------------------------ 2

SYNTHESIS OF AMINO UREA CATALYSTS

Representative Procedure for the Preparation of Amino Urea Catalyst -------------------------------------------- 3

SYNTHESIS OF α, β-UNSATURATED ACID SUBSTRATES

Representative Procedure for the Preparation of α, β-Unsaturated Ketone -------------------------------------------- 9

SYNTHESIS OF BROMOLACTONE PRODUCTS

General Procedure for Bromolactonization --------------------------------------------------------------------------- 14

Synthetic Application ---------------------------------------------------------------------------------------------------- 27

X-ray of 4b----------------------------------------------------------------------------------------------------------------- 29

References ----------------------------------------------------------------------------------------------------------------- 30

13C Spectra ------------------------------------------------------------------------------------------------------------ 31

a International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug

Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, Guangzhou

510632, China

b Guangzhou Wanglaoji Pharmaceutical Company Limited, Guangzhou 510450, China

GENERAL METHODS

General Procedures

All reactions were generally performed open air or in dried glassware under an atmosphere of dry N2.

Reaction mixtures were stirred magnetically unless otherwise indicated and monitored by thin layer

chromatography (TLC) on Merck precoated glass-backed silica gel 60 F-254 0.25 mm plates with

visualization by fluorescence quenching at 254 nm. TLC plates were stained using potassium permanganate.

Chromatography purification of products (flash column chromatography) was performed on silica gel 60

(70−230 mesh, Merck) using a forced flow of eluent at 0.3−0.5 bar. Concentration of reaction product

solutions and chromatography fractions under reduced pressure was performed by rotary evaporation at

35−45oC at the appropriate pressure and then at rt, ca. 10 mmHg (vacuum pump) unless otherwise indicated.

Materials

All chemicals, including dry solvents were purchased from Aldrich, Fluka, Acros, TCI, Merck, Strem, or

Alfa Aesar and used as such unless stated otherwise. Yields given refer to chromatographically purified

compounds unless otherwise demonstrated.

Instrumentation

Melting points were determined on a Sinoinstructment melting point apparatus. 1H NMR spectra was

recorded on Bruker 300 MHz or Bruker 400 MHz spectrometer. 13

C NMR spectra was recorded on Bruker

75 MHz or Bruker 100 MHz spectrometer. 13

C NMR chemical shifts are expressed in parts per million ()

downfield from tetramethylsilane (with the central peak of CHCl3 at 77.16 ppm used as standard). 1H NMR

chemical shifts are expressed in parts per million () downfield from tetramethylsilane (with the peak of

CHCl3 at 7.26 ppm used as standard; with the peak of benzene at 7. 36 ppm used as standard). All 13

spectra were measured with complete proton decoupling. NMR coupling constants (J) are reported in Hertz

(Hz), and splitting patterns are indicated as follows: br, broad; s, singlet; d, doublet; dd, doublet of doublet;

ddd, doublet of doublet of doublet; dt, doublet of triplet; t, triplet; q, quartet; m, multiplet. High resolution

mass spectrometric measurements (HRMS) were performed by the AB SCIEX, Triple TOF 5600+.

Enantiomeric excesses were determined by HPLC analysis on Shimadzu HPLC units, including the

following instruments: pump, LC-16; detector, SPD-16; column, Daicel Chiralpak AD-H.

SYNTHESIS OF AMINO UREA CATALYSTS

Representative Procedure for the Preparation of Amino Urea Catalyst1

To a solution of A (1.0 mmol, 1.0 eq) in THF (5 mL) was added phenyl isocyanate (1.0 mmol, 1.0 eq) in one

portion at room temperature. The reaction was stirred for 16 h. After evaporation of THF, the residue was

purified by flash column chromatography (MeOH/EtOAc 1:10) to afford amino urea catalyst 5a 384.5 mg,

87% yield; pale yellow solid; MP 136-137°C; []

D25= 35.0 (c 1.0, MeOH); exist as rotamers, and the main

signals were assigned: 1H NMR (300 MHz, Chloroform-d) δ 8.71 – 8.73 (m, 1H), 8.00 – 8.05 (m, 2H), 7.76

(s, 1H), 7.28 – 7.40 (m, 4H), 7.17 – 7.22 (m, 2H), 6.94 – 6.99 (m, 1H), 6.81 – 6.83 (m, 1H), 5.58 – 5.70 (m,

1H), 5.55 (s, broad, 1H), 3.99 – 4.02 (m, 4H), 3.37 – 3.56(m, 2H), 3.08 – 3.16 (m, 1H), 2.65 – 2.73 (m, 2H),

2.28 – 2.35 (m, 2H), 1.52 – 1.73 (m, 4H), 0.92 – 0.98 (m, 1H). 13

C NMR (101 MHz, CDCl3) δ 158.22,

155.50, 147.53, 144.76, 144.41, 139.56, 139.15, 131.64, 128.91, 128.29, 122.77, 122.12, 119.43, 115.67,

101.87, 59.73, 55.83, 55.07, 41.19, 38.35, 27.07, 26.58, 25.84; HRMS (TOF+) calcd. for C27H31N4O2

[M+H]+ 443.2442, found 443.2421.

375.7 mg, 85% yield; pale yellow solid; MP 134-136°C; []

D25= –68.5 (c 1.0, MeOH); exist as rotamers, and the

main signals were assigned: 1H NMR (300 MHz, Chloroform-d) δ 8.80 – 8.66 (m, 2H), 7.90 – 7.63 (m,

3H),7.45 (d, J = 2 Hz, 2H), 7.32 – 7.12 (m, 3H), 6.92 – 6.89 (m, 1H), 5.90 – 5.85 (m, 1H), 5.76 – 5.68 (m,

1H), 5.09 – 5.05 (m, 2H), 4.65 – 4.32(m, 2H), 3.99 (s, 3H), 3.57 – 3.13(m, 3H), 2.49 (s, broad, 1H), 1.98 –

1.80 (m, 3H), 1.03 – 1.00 (m, 1H). 13

C NMR (75 MHz, CDCl3) δ 158.53, 155.43, 147.69, 144.61, 142.64,

139.48, 137.16, 131.49, 128.81, 128.08, 122.56, 122.36, 118.94, 117.04, 101.38, 59.90, 55.83, 49.11, 45.85,

36.73, 26.53, 24.79, 23.95; HRMS (TOF+) calcd. for C27H31N4O2 [M+H]

+ 443.2442, found 443.2423.

358 mg, 87%, white solid; MP 117-119°C; []

D25= 114.1 (c 1.0, MeOH); exist as rotamers, and the main signals

were assigned: 1H NMR (300 MHz, Chloroform-d) δ 8.85 (d, J = 6 Hz, 1H), 8.39 – 8.42 (m, 1H), 8.14 (d, J =

6 Hz, 1H), 8.06 (s, 1H), 7.59– 7.75 (m, 2H), 7.33 – 7.47 (m, 2H), 7.27 – 7.33 (m, 1H), 7.17 – 7.23 (m, 5H),

6.94 – 6.99 (m, 2H), 5.80 – 5.91 (m, 1H), 5.54 (s, broad, 1 H), 5.15 – 5.23 (m, 2H), 4.00 (s, broad, 1H), 2.71

– 3.24 (m, 5H), 2.24 – 2.36 (m, 1H), 1.65 (s, 1H), 1.23-1.25 (m, 1H), 0.90 – 0.99 (m, 1H). 13

C NMR (75

MHz, CDCl3) δ 155.70, 150.17, 148.51, 139.19, 139.04, 130.31, 129.46, 129.36, 128.90, 126.99, 123.38,

122.72, 119.44, 115.76, 48.92, 46.64, 38.44, 27.04, 25.62, 24.90; HRMS (TOF+) calcd. for C26H29N4O

[M+H]+ 413.5793, found 413.5791.

D25= 52.5 (c 1.0, MeOH); exist as rotamers, and the

main signals were assigned: 1H NMR (300 MHz, Chloroform-d) δ 8.84 – 8.85(m, 1H), 8.37 (d, J = 9 Hz, 1H),

8.00 – 8.29 (m, 2H)，7.42 – 7.73 (m, 4H), 7.21– 7.24 (m, 2H), 6.72 – 6.75 (m, 2H), 5.66 – 6.06 (m, 4H), 5.19

– 5.26 (m, 2H), 3.71 (s, 3H), 3.47 – 3.50 (m, 1H), 3.22 – 3.29 (m, 1H), 3.04 – 3.08 (m, 1H), 2.77 – 2.93 (m,

2H), 2.32 – 2.35 (m, 1 H), 2.01 (s, 1H), 1.54 – 1.68 (m, 3H), 1.24 – 1.31 (m, 1H), 0.98 – 1.07 (m, 1H). 13

NMR (75 MHz, CDCl3) δ 155.95, 155.50, 150.24, 148.41, 146.29, 138.17, 132.25, 130.22, 129.47, 127.18,

127.03, 123.38, 121.65, 116.37, 114.12, 60.22, 55.47, 48.78, 46.16, 37.68, 26.78, 24.84, 24.66; HRMS

(TOF+) calcd. for C27H31N4O2 [M+H]

+ 443.2442, found 443.2420.

main signals were assigned: 1H NMR (300 MHz, Chloroform-d) δ 8.81 – 8.83 (m, 1H), 8.35 – 8.38 (m, 2H),

8.05 – 8.08 (m, 1H), 7.52 – 7.69 (m, 3H), 7.19 – 7.22 (m, 2H), 6.70 (d, J = 9 Hz, 1H), 5.67 – 5.83 (m, 2H),

5.34 – 5.44 (m, 3H), 5.15 – 5.21 (m, 2H), 3.84 – 3.91 (m, 2H), 3.44 – 3.54 (m, 1H), 3.30 (s, 1H), 2.74 – 3.30

(m, 4H)), 2.28 – 2.36 (m, 1H),1.97 (s, 1H), 1.50 – 1.62 (m, 3H), 1.29 – 1.33 (m, 3H), 0.97 – 1.24 (m, 3H).

13C NMR (75 MHz, CDCl3) δ 155.97, 154.69, 150.26, 148.30, 138.29, 132.28, 130.08, 129.45, 127.15,

123.43, 121.40, 116.22, 114.75, 63.65, 60.17, 48.83, 46.24, 45.50, 37.69, 26.79, 24.83, 14.83, 9.02; HRMS

(TOF+) calcd. for C28H33N4O2 [M+H]

+ 457.3726, found 457.3725.

main signals were assigned: 1H NMR (300 MHz, Chloroform-d) δ 8.82 (d, J = 6 Hz, 1H), 8.42 (s, 1H), 8.30 (d,

J = 9 Hz, 1H), 8.01 (d, J = 9 Hz, 1H), 7.54– 7.66 (m, 3H), 7.42– 7.44 (m, 1H), 7.03 (s, 1H), 6.75 – 6.78 (m,

1H), 6.53 – 6.59 (m, 3H), 5.66 – 5.77 (m, 2H), 5.16 – 5.22 (m, 2H), 3.74 – 3.78 (m, 1H), 3.68 (s, 6H), 3.44

(s, 1H)), 3.20 (s, 1H), 2.95 – 3.01 (m, 1H), 2.79 – 2.81 (m, 1H), 2.24 – 2.38 (m, 1H), 1.88 (s, 1H), 1.51 –

1.63 (m, 3H), 1.02 – 1.24 (m, 3H). 13

C NMR (75 MHz, CDCl3) δ 155.63, 150.38, 148.96, 148.27, 145.38,

144.66, 137.46, 132.97, 130.12, 129.55, 127.32, 126.86, 123.27, 116.74, 111.57, 104.77, 60.34, 56.11, 55.87,

48.90, 46.05, 41.70, 37.09, 26.59, 24.36, 24.15, 21.00, 14.15, 11.60, 11.07; HRMS (TOF+) calcd. for

C28H33N4O3 [M+H]+ 473.6011, found 473.6012.

main signals were assigned: 1H NMR (300 MHz, Chloroform-d) δ 8.90 (d, J = 3 Hz, 1H), 8.33 – 8.47 (m, 2H),

8.06(d, J = 9 Hz, 1H), 8.01 (d, J = 9 Hz, 1H), 7.59 – 7.75 (m, 3H), 7.41 – 7.44 (m, 1H), 7.09 – 7.13 (m, 1H),

6.81 – 6.85 (m, 1H), 6.63 – 6.66 (m, 1H), 5.70 – 5.99 (m, 2H), 5.25– 5.36 (m, 5H), 3.88 – 4.00(m, 5H), 3.58

– 3.64 (m, 1H), 3.18 – 3.42 (m, 2H)), 2.97 – 3.07 (m, 1H), 2.40 – 2.52 (m, 1H), 1.30 – 1.34 (m, 6H), 1.20 –

1.26 (m, 2H). 13

C NMR (75 MHz, CDCl3) δ 155.56, 150.51, 149.07, 148.33, 144.63, 144.23, 137.00, 133.25,

130.17, 129.63, 127.47, 126.81, 123.27, 119.69, 117.16, 114.54, 111.65, 106.53, 65.12, 64.61, 60.39, 49.11,

46.04, 36.75, 26.54, 24.34, 23.79, 14.89, 14.78; HRMS (TOF+) calcd. for C30H37N4O3 [M+H]

+ 501.7148,

found 501.7149.

D25= 81.5.0 (c 1.0, MeOH); exist as rotamers, and the

main signals were assigned: 1H NMR (300 MHz, Chloroform-d) δ 8.85 (d, J = 6 Hz, 1H), 8.51 (s, 1H), 8.31 (d,

J = 6 Hz, 1H), 8.02 – 8.05 (m, 1H), 7.56 – 7.73 (m, 3H), 7.41 – 7.44 (m, 1H), 7.07 (s, 1H), 6.85 (s, broad,

1H), 6.66 – 6.69 (m, 1H), 6.52 – 6.55 (m, 1H), 5.68 – 5.89 (m, 4H), 5.22 – 5.30 (m, 2H), 4.00 – 4.08 (s, 1H),

3.63 (s, 1H), 3.62 (s, 1H), 2.83 – 2.98 (m, 3H)), 2.45 – 2.47 (m, 1H), 1.99 (s, 1H), 1.86 (s, 1H), 1.65 – 1.73

(m, 3H), 1.18 – 1.30 (m, 5H). 13

C NMR (75 MHz, CDCl3) δ 178.48, 171.15, 155.60, 150.43, 148.31, 147.51,

144.60, 142.83, 137.04, 133.72, 130.12, 129.63, 127.50, 126.82, 123.24, 117.08, 112.28, 107.90, 102.29,

100.86, 60.36, 60.29, 49.07, 45.92, 41.88, 36.72, 26.55, 24.36, 23.83, 21.02, 14.16, 11.11; HRMS (TOF+)

calcd. for C27H29N4O3 [M+H]+ 457.6172, found 457.6171.

D25= 102.5.0 (c 1.0, MeOH); exist as rotamers, and

the main signals were assigned: 1H NMR (300 MHz, Chloroform-d) δ 8.88 (d, J = 3 Hz, 1H), 8.33 – 8.49 (m,

2H), 8.05 – 8.08 (m, 1H), 7.46 – 7.71 (m, 4H), 7.02 (s, 1H), 6.86 – 6.88 (m, 1H), 6.57 (s, broad, 3H), 5.71 –

6.01 (m, 2H), 5.25 – 5.38 (m, 2H), 3.96 – 4.13 (m, 5H), 3.62 – 3.69 (m, 1H), 3.25 – 3.40 (m, 2H), 2.87 –

2.89 (m, 1H), 2.49 – 2.51 (m, 1H), 2.20 (s, 1H), 1.90 (s, 1H), 1.66 – 1.76 (m, 3H), 1.21 – 1.34 (m, 3H). 13

NMR (75 MHz, CDCl3) δ 155.53, 150.69, 148.39, 144.50, 143.31, 139.04, 137.00, 133.24, 130.19, 129.61,

127.49, 126.84, 123.28, 119.62, 117.18, 116.96, 113.03, 108.90, 64.38, 64.19, 60.32, 49.08, 45,89, 41,87,

36.67, 26.58, 24.39, 23.81, 14.18, 11.15; HRMS (TOF+) calcd. for C28H31N4O3 [M+H]

+ 471.3940, found

471.3941.

8.09 – 8.15 (m, 2H), 7.59 – 7.74 (m, 3H), 6.67 (s, 1H), 6.55 (s, 1H), 5.75 – 5.86 (m, 2H), 5.25 – 5.30 (m,

4H), 4.07 – 4.21 (m, 4H), 3.76 (s, 3H), 2.88 – 3.48 (m, 4H), 2.40 – 2.50 (m, 1H), 2.00 (d, J = 9 Hz, 1H),

1.64 – 1.76 (m, 3H), 1.11 – 1.37 (m, 3H). 13

C NMR (75 MHz, CDCl3) δ 155.48, 150.35, 148.78, 148.42,

145.33, 143.81, 137.46, 132.39, 130.26, 129.57, 128.86, 127.35, 126.87, 123.28, 116.92, 101.27, 97.31,

64.40, 60.34, 56.12, 48.90, 46.03, 37.21, 26.68, 24.51, 24.30, 14.18; HRMS (TOF+) calcd. for C29H33N4O4

[M+H]+ 501.7145, found 501.7146.

8.05 – 8.07 (m, 1H), 7.51 – 7.70 (m, 5H), 7.37 – 7.50 (m, 1H), 6.59 – 6.61 (m, 2H), 5.70 – 5.86 (m, 4H),

5.22 – 5.30 (m, 2H), 3.90 (q, J = 6 Hz, 3H), 2.78 – 3.49 (m, 4H), 2.33 – 2.47 (m, 1H), 2.10 (s, 3H), 1.61 –

1.73 (m, 3H), 1.32 (t, J = 3 Hz, 3 H), 1.20 – 1.26 (m, 2H). 13

C NMR (75 MHz, CDCl3) δ 156.42, 155.87,

150.41, 148.37, 145.14, 137.34, 132.99, 130.13, 129.58, 127.38, 126.94, 125.64, 123.44, 119.57, 116.89,

116.39, 112.07, 63.53, 60.09, 48.99, 45.85, 36.93, 26.58, 24.49, 24.11, 18.40, 14.85; HRMS (TOF+) calcd.

for C29H35N4O2 [M+H]+ 471.6349, found 471.6350.

8.05 – 8.07 (m, 1H), 7.51 – 7.69 (m,5H), 7.28 – 7.34 (m, 1H), 6.57 – 6.61 (m, 2H), 5.71 – 5.81 (m, 4H), 5.21

– 5.27 (m, 2H), 3.90 (q, J = 6 Hz, 2H), 3.52 – 3.70 (m, 1H), 2.78 – 2.24 (m, 3H), 2.28 – 2.45 (m,1H), 2.09 (s,

3H), 1.57 – 1.70 (m, 3H), 1.29 (t, J = 9 Hz, 3 H), 1.11 – 1.26 (m, 3H). 13

C NMR (75 MHz, CDCl3) δ 156.45,

155.91, 150.34, 148.34, 145.52, 137.58, 133.06, 130.11, 129.56, 127.29, 126.96, 125.70, 123.45, 119.56,

116.70, 116.40, 112.09, 63.52, 60.37, 60.02, 48.88, 45.87, 37.11, 26.62, 24.53, 24.30, 21.02, 18.32, 14.84,

14.17; HRMS (TOF+) calcd. for C29H35N4O2 [M+H]

+ 471.6347, found 471.6349.

8.04 – 8.07 (m, 1H), 7.56 – 7.70 (m, 4H), 7.22 (s, 1H), 6.50 (s, 1H), 6.23 (s, broad, 2H), 5.70 – 5.93 (m, 2H),

5.23 – 5.30 (m, 2H), 3.99 – 4.12 (m, 1H), 3.90 (q, J = 6 Hz, 2H), 2.95 – 3.59 (m, 4H), 2.34 – 2.50 (m, 1H),

2.08 – 2.11 (m, 6H), 1.89 – 1.94 (m, 1H), 1.35 – 1.48 (m, 3H), 1.32 (s, 2H), 1.30 (t, J = 6 Hz, 3 H), 1.22 –

1.25 (m, 3H). 13

C NMR (75 MHz, CDCl3) δ13

C NMR (101 MHz, CDCl3) δ 156.76, 155.81, 154.62, 151.88,

150.24, 148.49, 146.58, 145.59, 138.46, 137.84, 134.61, 130.31, 129.31, 128.62, 127.90, 127.60, 127.07,

126.94, 124.79, 123.48, 123.21, 119.53, 116.12, 113.56, 83.03, 63.91, 60.30, 48.87, 46.46, 38.01, 27.68,

26.95, 25.14, 24.73, 18.12, 15.80, 14.97.; HRMS (TOF+) calcd. for C30H37N4O2 [M+H]

+ 485.7133, found

485.7131.

8.07 – 8.09 (m, 1H), 7.57 – 7.72 (m, 4H), 7.32 (s, 1H), 7.10 – 7.13 (m, 1H), 6.56 – 6.59 (m, 1H), 5.74 – 5.83

(m, 1H), 5.50 (s, broad, 2H), 5.21 – 5.29 (m, 2H), 3.91 (q, J = 6 Hz, 2H), 3.29 – 3.45 (m, 2H), 2.75 – 3.00

(m, 2H), 2.31 – 2.44 (m, 1H), 2.02 – 2.08 (m, 6H), 1.61 – 1.72 (m, 3H), 1.30 (t, J = 9 Hz, 3 H), 1.22 – 1.24

(m, 3H). 13

C NMR (75 MHz, CDCl3) δ 156.87, 154.63, 150.38, 148.39, 145.53, 137.60, 133.26, 130.16,

129.51, 129.09, 127.25, 127.02, 125.90, 123.83, 123.53, 119.58, 116.71, 109.42, 64.08, 60.05, 48.95, 45.99,

41.77, 37.24, 26.71, 24.57, 24.37, 14.98, 14.58, 12.28, 11.05; HRMS (TOF+) calcd. for C30H37N4O2 [M+H]

485.7132, found 485.7130.

8.05 – 8.07 (m, 1H), 7.55 – 7.70 (m, 4H), 7.39 (s, 1H), 7.12 – 7.20 (m, 1H), 6.53 – 6.56 (m, 1H), 5.69 – 5.82

(m, 5H), 5.21 – 5.29 (m, 2H), 3.90 – 4.03 (m, 1H), 3.69 (s, 3H), 3.38 – 3.55 (m, 2H), 2.89 – 3.07 (m, 2H),

2.31 – 2.46 (m, 1H), 2.00 – 2.03 (m, 6H), 1.63 – 1.72 (m, 3H), 1.20 – 1.26 (m, 3H). 13

C NMR (75 MHz,

CDCl3) δ 156.80, 155.16, 150.43, 148.35, 145.15, 137.31, 133.16, 130.09, 129.56, 129.21, 127.34, 126.98,

125.44, 123.77, 123.53, 119.60, 116.87, 107.96, 60.02, 55.68, 49.02, 45.84, 36.94, 26.61, 24.50, 24.10,

14.55, 12.17; HRMS (TOF+) calcd. for C29H35N4O2 [M+H]

+ 471.6346, found 471.6348.

D25= 66.0 (c 1.0, MeOH);

1H NMR (400 MHz,

Chloroform-d) δ 9.10 (s, broad, 1H), 8.93 (d, J = 4 Hz, 1H), 8.43 – 8.19 (m, 2H), 7.82 –7.76 (m, 3H), 7.68 –

7.40 (m, 3H), 6.84 (s, broad, 1H), 5.90–5.81 (m, 1H), 5.18–5.06 (m, 2H), 3.48 (s, 1H), 2.98 – 2.62 (m, 5H),

2.26 – 2.21 (m, 1H), 1.62 – 1.27 (m, 4H), 0.95 – 0.88 (m, 1H). 13

C NMR (100 MHz, CDCl3) δ 155.2, 149.9,

148.4, 141.1, 139.5, 132.5 (q, J = 32 Hz), 130.1, 129.6, 127.1, 124.6, 123.4, 121.9, 118.0, 115.3, 48.8, 46.8,

38.8, 27.1, 26.0, 25.0; HRMS (TOF+) calcd. for C28H27F6N4O [M+H]

+ 549.4127, found 549.4129.

SYNTHESIS OF α, β-UNSATURATED ACID SUBSTRATES

Representative Procedure for the Preparation of α, β-Unsaturated Ketone1, 2

Step-1: To a solution of benzaldehyde (1.06 g, 10 mmol, 1.0 equiv) in THF (20 ml ) was added CuI (38 mg,

2 mmol , 0.2 equiv) at -20 °C under nitrogen. After stirring for 10 min, vinylmagnesium bromide (6 mL 2

mol/L, 1.2 equiv) was slowly added to the mixture and stirred at the same temperature for 3 h.2 The reaction

was quenched with saturated aqueous NH4Cl. After filtration, the combined organic layers were dried over

Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on

silica gel (hexane/EtOAc=10:1) to provide 1-phenylprop-2-en-1-ol, 1.09g, 81% yield.

Step-2: To a solution of 1-phenylprop-2-en-1-ol (1.34g, 10 mmol ,1.0 equiv) in DMF (20 ml ) was removed

to a sealable reaction tube , Pd(OAc)2 (44.9 mg, 0.2 mmol, 0.02 equiv), X-PHOS (190.6 mg, 0.4 mmol, 0.04

equiv) , NaHCO3 (2.1 g, 24 mmol, 2.4 equiv) and methyl 2-bromobenzoate (2.14g, 10 mmol ,1.0 equiv) was

added. The tube was sealed with a Teflon-lined septum and heated to 120 oC with vigorous stirring for 16 h.

The resulting suspension was cooled to room temperature, diluted with EtOAc, and filtered through a pad of

Celite. The filtrate was concentrated in vacuo to afford the crude product, which was purified by flash

column chromatography on silica gel (hexane/EtOAc=10:1) to provide the key intermediate 3a-1 1.7g, 65%

yield, colorless oil; 1H NMR (300 MHz, Chloroform-d) δ 8.02 – 7.86 (m, 3H), 7.56 – 7.46 (m, 1H), 7.46 –

7.37 (m, 3H), 7.37 – 7.31 (m, 1H), 7.31 – 7.22 (m, 1H), 3.87 (s, 3H), 3.44 – 3.28 (m, 4H). 13

C NMR (75

MHz, CDCl3) δ 199.26, 167.72, 143.36, 136.88, 132.94, 132.27, 131.44, 130.87, 129.43, 128.52, 128.09,

126.32, 51.98, 40.56, 29.35; HRMS (TOF+) calcd for C17H17O3 [M+H]

+ 269.1099, found 269.1098.

Step-3: To a solution of 3a-1 (1.34g, 5.0 mmol, 1.0 equiv.) in acetic acid (15 mL) was added dilute

hydrochloric acid solution (5 ml 3mol/L, 3.0 equiv) and the mixture was then stirred for 12 h at 120oC. After

evaporation of acetic acid, water and EtOAc were added. The organic layer was washed with water, and

dried over magnesium sulfate. Concentration of the organic layer offered the crude product that was further

purified by flash column chromatography (hexane/EtOAc=6:1) to provide 3a-2 540 mg, 56% yield, white

solid; MP 89-91°C; 1H NMR (300 MHz, Chloroform-d) δ 10.23 (s, broad，1H), 8.14 – 8.08 (m, 1H), 8.06 –

7.96 (m, 2H), 7.57 – 7.30 (m, 6H), 3.52 – 3.44 (m, 2H), 3.43 – 3.35 (m, 2H). 13

C NMR (75 MHz, CDCl3) δ

199.74, 172.92, 144.26, 136.78, 133.29, 133.09, 131.92, 131.71, 130.20, 128.57, 128.20, 126.53, 40.57,

29.58; HRMS (TOF−) calcd for C16H13O3 [M−1]

−: 253.0943; found 253.0945..

Step-4: To a solution of 3a-2 (756 mg, 3.0 mmol, 1.0 equiv) in acetic acid ( 6 mL) was added piperidine

(0.1 mL, 1.2 mmol, 0.4 equiv) and formaldehyde solution (36.5-38% in H2O, 1mL, 13.2 mmol, 4.4 equiv) at

room temperature. The mixture was then stirred for 48 h at 90oC.

1 After evaporation of acetic acid, water

and EtOAc were added. The organic layer was washed with water, and dried over magnesium sulfate.

Concentration of the organic layer offered the crude product that was further purified by flash column

chromatography (hexane/EtOAc=6:1) to provide 3a 482 mg, 86%, white solid; MP 76-78°C; 1H NMR (300

MHz, Chloroform-d) δ 10.60 (s, broad, 1H), 8.16 – 8.05 (m, 1H), 7.86 – 7.74 (m, 2H), 7.61 – 7.47 (m, 2H),

7.46 – 7.32 (m, 4H), 5.65 (s, 1H), 5.52 (s, 1H), 4.22 (s, 2H). 13

C NMR (75 MHz, CDCl3) δ 198.22, 172.74,

147.71, 141.25, 137.56, 133.20, 132.34, 132.28, 131.97, 129.63, 128.72, 128.18, 126.88, 126.59, 36.54;

HRMS (TOF−) calcd for C17H13O3 [M−1]

−: 265.0870; found 265.0860.

654 mg, 89% yield, white solid; MP 126-128°C; 1H NMR (300 MHz, Chloroform-d) δ 10.03 (s, broad, 1H),

8.28 – 8.02 (m, 2H), 8.00 – 7.78 (m, 2H), 7.64 – 7.34 (m, 7H), 5.70 (s, 1H), 5.60 (s, 1H), 4.36 (s, 2H). 13

NMR (75 MHz, CDCl3) δ 199.41, 172.76, 149.67, 141.45, 136.49, 133.59, 133.27, 132.47, 132.09, 130.88,

130.84, 129.89, 128.74, 128.27, 127.21, 127.12, 126.94, 126.34, 125.55, 124.27, 35.61; HRMS (TOF−)

calcd for C21H15O3 [M−1] −

: 315.1027; found 315.1022.

8.29 (s, 1H), 8.06 (d, J = 7.7 Hz, 1H), 8.00 – 7.76 (m, 4H), 7.61 – 7.29 (m, 5H), 5.69 (s, 1H), 5.53 (s, 1H),

4.26 (s, 2H). 13

C NMR (75 MHz, CDCl3) δ 198.19, 172.71, 147.94, 141.27, 135.23, 134.73, 133.19, 132.40,

132.24, 132.01, 131.39, 129.47, 128.76, 128.17, 128.14, 127.71, 126.89, 126.63, 126.09, 125.48, 36.79;

−: 315.1027; found 315.1022.

462 mg, 91% yield, white solid; MP 92-94°C;1H NMR (300 MHz, Chloroform-d) δ 11.15 (s, broad, 1H),

8.14 (dd, J = 8.2, 1.5 Hz, 1H), 7.56 (td, J = 7.6, 1.4 Hz, 1H), 7.45 – 7.35 (m, 2H), 7.35 – 7.25 (m, 2H), 7.25

– 7.14 (m, 2H), 5.66 (s, 1H), 5.57 (s, 1H), 4.25 (s, 2H), 2.34 (s, 3H).13

C NMR (75 MHz, CDCl3) δ 200.06,

172.86, 149.08, 141.40, 138.80, 136.27, 133.19, 132.40, 132.00, 130.73, 129.85, 129.73, 128.78, 128.07,

126.87, 125.04, 35.26, 19.67; HRMS (TOF−) calcd for C18H15O3 [M−1]

−: 279.1027; found 279.1022.

454 mg, 89% yield, brown oil; 1H NMR (300 MHz, Chloroform-d) δ 9.12 (s, broad, 1H), 8.08 (d, J = 8.0 Hz,

1H), 7.64 – 7.46 (m, 3H), 7.44 – 7.23 (m, 4H), 5.65 (s, 1H), 5.52 (s, 1H), 4.21 (s, 2H), 2.38 (s, 3H). 13

NMR (75 MHz, CDCl3) δ 198.36, 172.61, 147.75, 141.25, 138.00, 137.63, 133.13, 133.02, 132.29, 131.91,

130.01, 128.80, 127.98, 126.91, 126.83, 126.51, 36.53, 21.32; HRMS (TOF−) calcd for C18H15O3 [M−1]

279.1027; found 279.1022.

578 mg, 92% yield, white solid; MP 113-115°C; 1H NMR (300 MHz, Chloroform-d)

1H NMR (400 MHz,

Chloroform-d) δ 8.12 – 8.01 (m, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.53 (td, J = 7.7, 1.4 Hz, 1H), 7.42 – 7.33 (m,

2H), 7.21 (d, J = 7.9 Hz, 2H), 5.63 (s, 1H), 5.52 (s, 1H), 4.19 (s, 2H), 2.38 (s, 3H). 13

C NMR (75 MHz,

CDCl3) δ 197.89, 172.59, 147.73, 143.07, 141.20, 134.77, 133.09, 132.25, 131.88, 129.86, 128.87, 126.81,

125.74, 36.67, 21.56; HRMS (TOF−) calcd for C18H15O3 [M−1]

−: 279.1027; found 279.1022.

8.21 – 8.10 (m, 1H), 7.61 – 7.51 (m, 1H), 7.45 – 7.26 (m, 4H), 7.25 – 7.14 (m, 2H), 5.66 (s, 1H), 5.58 (s,

1H), 4.26 (s, 2H), 2.34 (s, 3H). 13

C NMR (75 MHz, CDCl3) δ 200.08, 172.88, 149.10, 141.42, 138.80,

136.27, 133.21, 132.42, 132.02, 130.74, 129.87, 129.74, 128.78, 128.08, 126.88, 125.06, 35.27, 19.69;

−: 295.0976; found 295.0974.

8.08 (d, J = 8.0 Hz, 1H), 7.60 – 7.47 (m, 1H), 7.45 – 7.22 (m, 5H), 7.16 – 6.99 (m, 1H), 5.66 (s, 1H), 5.52 (s,

1H), 4.20 (s, 2H), 3.80 (s, 3H). 13

C NMR (75 MHz, CDCl3) δ 197.87, 172.61, 159.40, 147.66, 141.20,

138.86, 133.15, 132.31, 131.94, 129.13, 128.76, 126.86, 126.48, 122.33, 118.65, 113.99, 55.34, 36.57;

−: 295.0976; found 295.0974.

8.14 – 8.01 (m, 1H), 7.87 – 7.73 (m, 2H), 7.58 – 7.47 (m, 1H), 7.42 – 7.30 (m, 2H), 6.94 – 6.83 (m, 2H),

5.55 (s, 1H), 5.42 (s, 1H), 4.19 (s, 2H), 3.80 (s, 3H). 13

C NMR (75 MHz, CDCl3) δ 197.05, 172.67, 163.19,

147.78, 141.15, 133.12, 132.33, 132.12, 131.86, 129.90, 128.85, 126.83, 124.42, 113.47, 55.39, 36.96;

−: 295.0976; found 295.0974.

589 mg, 88% yield, colorless oil; 1H NMR (400 MHz, Chloroform-d) δ 8.88 (s, 1H), 8.08 (dd, 1H), 7.52 (td,

J = 7.6, 1.2 Hz, 1H), 7.45 – 7.31 (m, 3H), 7.31 – 7.21 (m, 1H), 7.00 – 6.85 (m, 2H), 5.75 (s, 1H), 5.65 (s,

1H), 4.24 (s, 2H), 4.03 (q, J = 7.0 Hz, 2H), 1.33 (t, J = 7.0 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 198.1,

172.5, 156.4, 148.6, 141.5, 132.8, 131.9, 131.7, 131.3, 129.3, 129.2, 129.0, 126.5, 120.2, 112.4, 64.1, 34.9,

14.6; HRMS (TOF−) calcd for C19H17O4 [M−1]

−: 309.1132; found 309.1130.

8.09 (d, J = 7.7 Hz, 1H), 7.92 – 7.72 (m, 2H), 7.55 (t, J = 7.3 Hz, 1H), 7.37 (d, J = 6.8 Hz, 2H), 7.09 (td, J =

8.7, 2.2 Hz, 2H), 5.59 (s, 1H), 5.48 (s, 1H), 4.18 (s, 2H). 13

C NMR (75 MHz, CDCl3) δ 196.67, 172.72,

166.99 (d, J = 252.00 Hz), 147.73, 141.13, 133.69(d, J = 3.0 Hz), 133.29, 132.41(d, J = 9.8 Hz), 132.16(d, J

= 11.3 Hz), 128.55, 126.98, 125.75, 115.46, 115.17, 36.68; HRMS (TOF−) calcd for C17H12FO3 [M−1]

283.0776; found 283.0780.

8.15 – 8.05 (m, 1H), 7.78 – 7.66 (m, 2H), 7.62 – 7.48 (m, 1H), 7.42 – 7.32 (m, 4H), 5.60 (s, 1H), 5.49 (s,

1H), 4.18 (s, 2H). 13

C NMR (75 MHz, CDCl3) δ 196.83, 172.72, 147.65, 141.14, 138.68, 135.77, 133.30,

132.42, 132.06, 131.05, 128.51, 127.01, 126.18, 36.57; HRMS (TOF−) calcd for C17H12ClO3 [M−1]

299.0480; found 299.0499.

545 mg, 85% yield, white solid; MP 107-109°C; 1H NMR (300 MHz, Chloroform-d) δ

1H NMR (400 MHz,

Chloroform-d) δ 8.10 (dd, J = 7.7, 1.1 Hz, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 7.57 (td, J

= 7.5, 1.4 Hz, 1H), 7.47 – 7.34 (m, 2H), 5.64 (s, 1H), 5.56 (s, 1H), 4.19 (s, 2H).13

C NMR (75 MHz, CDCl3)

δ 196.83, 172.64, 147.70, 141.11, 140.71, 134.87, 133.40, 132.47, 132.14, 130.56, 129.74, 128.37, 127.32,

127.09, 125.21 (q, J = 3.8 Hz), 36.33; HRMS (TOF−) calcd for C18H12F3O3 [M−1]

−: 333.0744; found

333.0751.

745 mg, 83% yield, white solid; MP 120-124°C; 1H NMR (400 MHz, Chloroform-d) δ 8.06 (dd, J = 7.8, 1.2

Hz, 1H), 7.57 – 7.24 (m, 12H), 7.00 (d, J = 7.1 Hz, 1H), 5.58 (s, 1H), 5.37 (s, 1H), 4.04 (s, 2H). 13

(100 MHz, CDCl3) δ 200.02, 172.51, 148.70, 141.10, 140.73, 139.09, 132.90, 132.17, 131.66, 130.13,

129.99, 129.86, 128.95, 128.88, 128.53, 128.46, 127.33, 126.98, 126.56, 34.76; HRMS (TOF−) calcd for

C23H17O3 [M−1] −

: 341.1183; found 341.1189.

346mg, 76% ,white solid; MP 106-108°C; 1H NMR (400 MHz, Chloroform-d) δ 9.86 (s, broad, 1H), 8.05 (d,

J = 7.8 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 6.03 (s, 1H), 5.42

(s, 1H), 4.01 (s, 2H), 3.03 (t, J = 10.8 Hz, 1H), 1.78 (d, J = 10.0 Hz, 4H), 1.69 (d, J = 11.7 Hz, 1H), 1.53 –

1.06 (m, 5H). 13

C NMR (100 MHz, CDCl3) δ 205.43, 172.54, 147.43, 141.47, 132.84, 131.87, 131.71,

128.99, 126.60, 124.02, 45.10, 35.55, 29.51, 25.89, 25.80 ; HRMS (TOF−) calcd for C17H13O3 [M−1]

271.0870; found 271.0860.

8.15 – 8.00 (m, 1H), 7.71 – 7.58 (m, 2H), 7.57 – 7.47 (m, 1H), 7.41 – 7.30 (m, 2H), 7.07 (dd, J = 4.9, 3.8 Hz,

1H), 5.82 (s, 1H), 5.41 (s, 1H), 4.18 (s, 2H). 13

C NMR (75 MHz, CDCl3) δ 189.65, 172.67, 147.91, 143.15,

140.90, 134.26, 134.14, 133.17, 132.25, 131.91, 128.76, 127.88, 126.91, 123.85, 36.88; HRMS (TOF−)

calcd for C15H12O3S [M−1]−: 271.0434; found 271.0428.

545 mg, 89% yield, white solid; MP 105-107°C;

1H NMR (300 MHz, Chloroform-d) δ 7.92 (d, J = 7.1 Hz,

1H), 7.84 – 7.77 (m, 2H), 7.58 – 7.49 (m, 1H), 7.48 – 7.39 (m, 3H), 7.29 (t, J = 7.7 Hz, 1H), 5.59 (s, 1H),

5.26 (s, 1H), 4.18 (s, 2H), 2.40 (s, 3H). 13

C NMR (75 MHz, CDCl3) δ 198.42, 146.60, 138.90, 137.67,

135.00, 132.26, 129.66, 129.46, 128.19, 126.59, 125.38, 32.33, 19.90; HRMS (TOF−) calcd for C18H15O3

[M−1] −

: 279.1027; found 279.1022.

531 mg, 84% yield, white solid; MP 106-108°C; 1H NMR (300 MHz, Chloroform-d) δ

1H NMR (400 MHz,

Chloroform-d) δ 9.58 (s, broad, 1H), 8.09 – 7.95 (m, 1H), 7.85 – 7.69 (m, 2H), 7.55 – 7.48 (m, 1H), 7.45 –

7.36 (m, 2H), 7.24 – 7.03 (m, 2H), 5.62 (s, 1H), 5.50 (s, 1H), 4.17 (s, 2H), 2.41 (s, 3H). 13

C NMR (75 MHz,

CDCl3) δ 198.29, 172.66, 147.88, 144.03, 141.43, 137.64, 133.23, 132.24, 129.65, 128.17, 127.66, 126.31,

125.75, 36.59, 21.57; HRMS (TOF−) calcd for C18H15O3 [M−1]

−: 279.1027; found 279.1022.

532 mg, 85% yield, white solid; MP 112-114°C; 1H NMR (300 MHz, Chloroform-d)

1H NMR (400 MHz,

Chloroform-d) δ 9.58 (s, broad, 1H), 8.09 – 7.95 (m, 1H), 7.85 – 7.69 (m, 2H), 7.55 – 7.48 (m, 1H), 7.45 –

7.36 (m, 2H), 7.24 – 7.03 (m, 2H), 5.62 (s, 1H), 5.50 (s, 1H), 4.17 (s, 2H), 2.41 (s, 3H). 13

C NMR (75 MHz,

CDCl3) δ 198.27, 172.99, 147.90, 138.13, 137.64, 136.59, 133.98, 132.43, 132.30, 132.22, 129.65, 128.51,

128.17, 126.47, 36.19, 20.88; HRMS (TOF−) calcd for C18H15O3 [M−1]

−: 279.1027; found 279.1022.

7.42 – 7.31 (m, 2H), 7.30 – 7.23 (m, 2H), 7.02 – 6.87 (m, 2H), 5.69 (s, 1H), 5.59 (s, 1H), 4.17 (s, 2H), 3.78

(s, 3H), 2.40 (s, 3H). 13

C NMR (100 MHz, CDCl3) δ 198.03, 172.67, 157.15, 148.99, 138.24, 136.30, 133.67,

132.14, 132.07, 131.39, 129.21, 128.97, 128.82, 120.19, 111.39, 55.64, 34.70, 20.84; HRMS (TOF−) calcd

for C19H17O4 [M−1]−: 309.1132; found 309.1130.

SYNTHESIS OF BROMOLACTONE PRODUCTS

General Procedure for Bromolactonization. To a PhMe/CHCl3 (4 mL/1 ml) solution of α, β-unsaturated

ketone (0.1 mmol, 1.0 equiv) and catalyst (7.1 mg, 0.15 mmol, 0.15 equiv), at 15oC, in dark under nitrogen

was added halogen source (0.13 mmol, 1.3 equiv). The resulting mixture was stirred at 15oC and monitored

by TLC. The reaction was quenched with saturated Na2SO3 (1 mL) at 15oC and then was warm to room

temperature. The solution was diluted with water (3 mL) and extrated with EtOAc, dried over MgSO4 and

concentrated in vacuo. The residue was purified by flash column chromatography (hexane/EtOAc=3:1) to

yield the corresponding lactone.

34.0 mg, 98% yield, white solid; MP 109-111°C; []

D25= 34.5 (c 1.0, MeOH, 15:85 er);

1H NMR (300 MHz,

Chloroform-d) 1H NMR (400 MHz, Chloroform-d) δ 8.06 – 7.96 (m, 2H), 7.90 – 7.80 (m, 1H), 7.61 – 7.50

(m, 2H), 7.47 – 7.38 (m, 2H), 7.32 (t, J = 7.2 Hz, 2H), 4.05 (d, J = 11.1 Hz, 1H), 3.84 (d, J = 11.1 Hz, 1H),

3.76 (d, J = 16.1 Hz, 1H), 3.50 (d, J = 16.0 Hz, 1H). 13

C NMR (75 MHz, CDCl3) δ 197.55, 162.84, 136.78,

134.58, 134.51, 133.53, 130.07, 129.88, 128.58, 128.03, 127.99, 124.00, 88.81, 35.09, 34.65; HRMS (TOF+)

calcd. for C17H14BrO3 [M+H]+ 345.0048, found 345.0053; HPLC (Daicel Chiralpak AD-H, i-PrOH/Hexane

= 10/90, 1.0 mL/min, 254 nm) t1 = 18.4 min (minor), t2 = 19.4 min (major).

D25= –17.7 (c 1.0, MeOH, 14:86 er);

1H NMR (300 MHz,

Chloroform-d) δ 8.12 (dd, J = 7.3, 1.0 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.57 –

7.42 (m, 3H), 7.42 – 7.35 (m, 1H), 7.34 – 7.17 (m, 3H), 7.09 (t, J = 7.6 Hz, 1H), 4.21 (d, J = 11.1 Hz, 1H),

3.96 (d, J = 11.2 Hz, 1H), 3.74 (d, J = 15.9 Hz, 1H), 3.61 (d, J = 15.9 Hz, 1H). 13

C NMR (75 MHz, CDCl3)

δ 202.44, 163.00, 135.40, 134.42, 133.50, 132.56, 129.86, 129.72, 128.36, 128.19, 127.97, 127.70, 127.38,

126.12, 124.91, 124.02, 88.90, 36.06, 35.44; HRMS (TOF+) calcd. for C21H16BrO3 [M+H]

+ 395.0277, found

395.0280; HPLC (Daicel Chiralpak AD-H, i-PrOH/Hexane = 10/90, 2.0 mL/min, 254 nm) t1 = 7.9 min

(minor), t2 = 11.0 min (major).

39.0 mg, 98% yield, colorless oil; []

D25= 30.5 (c 1.0, MeOH, 21:79 er);

1H NMR (300 MHz, Chloroform-d)

1H NMR (400 MHz, Chloroform-d) δ 8.77 (s, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.94 (dd, J = 8.7, 1.8 Hz, 1H),

7.89 – 7.76 (m, 3H), 7.71 – 7.50 (m, 3H), 7.39 – 7.23 (m, 2H), 4.14 (d, J = 11.2 Hz, 1H), 3.92 (d, J = 11.2

Hz, 1H), 3.84 (d, J = 16.0 Hz, 1H), 3.55 (d, J = 16.0 Hz, 1H). 13

C NMR (100 MHz, CDCl3) δ 197.10, 162.94,

136.99, 135.51, 134.65, 132.52, 132.27, 131.53, 130.19, 130.17, 129.18, 128.42, 128.03, 127.62, 126.95,

125.07, 123.89, 89.10, 35.39, 34.70 HRMS (TOF+) calcd. for C21H16BrO3 [M+H]

+ 395.0277, found

395.0280 ; HPLC (Daicel Chiralpak AD-H, i-PrOH/Hexane = 10/90, 2.0 mL/min, 254 nm) t1 = 7.5 min

D25= –7.5 (c 1.0, MeOH, 11:89 er);

1H NMR (300 MHz,

Chloroform-d) δ 7.83 (dd, J = 7.5, 1.5 Hz, 1H), 7.72 (d, J = 7.1 Hz, 1H), 7.54 (td, J = 7.5, 1.3 Hz, 1H), 7.37

– 7.25 (m, 4H), 7.04 (d, J = 7.0 Hz, 1H), 4.12 (d, J = 11.2 Hz, 1H), 3.89 (d, J = 11.2 Hz, 1H), 3.67 – 3.50 (m,

2H), 1.67 (s, 3H). 13

C NMR (75 MHz, CDCl3) δ 203.14, 162.81, 137.93, 135.69, 134.93, 134.37, 131.50,

131.22, 129.81, 128.66, 128.32, 127.80, 125.19, 124.97, 88.74, 35.89, 35.53, 19.04; HRMS (TOF+) calcd.

for C18H16BrO3 [M+H] +

359.0277, found 359.0278; HPLC (Daicel Chiralpak AD-H, i-PrOH/Hexane =

10/90, 1.0 mL/min, 254 nm) t1 = 9.3 min (minor), t2 = 10.9 min (major).

D25= 6.5 (c 1.0, MeOH, 18:82 er);

1H NMR (300 MHz,

Chloroform-d) δ 7.86 (d, J = 7.1 Hz, 2H), 7.75 (s, 1H), 7.61 – 7.50 (m, 1H), 7.40 – 7.27 (m, 4H), 4.05 (d, J

= 11.1 Hz, 1H), 3.91 – 3.66 (m, 2H), 3.50 (d, J = 16.0 Hz, 1H), 2.38 (s, 3H). 13

C NMR (75 MHz, CDCl3) δ

197.56, 162.85, 138.44, 136.87, 134.52, 134.46, 134.36, 130.25, 130.08, 128.44, 127.97, 127.10, 124.03,

88.80, 35.18, 34.62, 21.33; HRMS (TOF+) calcd. for C18H16BrO3 [M+H]

+ 359.0277, found 359.0278;

HPLC (Daicel Chiralpak AD-H, i-PrOH/Hexane = 10/90, 1.0 mL/min, 254 nm) t1 = 8.5 min (minor), t2 =

10.1 min (major).

D25= 25.5 (c 1.0, MeOH, 17:83 er);

δ 7.98 – 7.93 (m, 2H), 7.87 (dd, J = 8.0, 1.2 Hz, 1H), 7.55 (td, J = 7.6, 1.3 Hz, 1H), 7.32 (t, J = 7.0 Hz, 2H),

7.22 (d, J = 8.1 Hz, 2H), 4.05 (d, J = 11.1 Hz, 1H), 3.88 – 3.72 (m, 2H), 3.50 (d, J = 16.0 Hz, 1H), 2.39 (s,

3H). 13

C NMR (101 MHz, CDCl3) δ 196.68, 162.95, 144.75, 137.05, 134.54, 131.75, 130.19, 130.10, 129.33,

128.00, 127.94, 123.92, 88.86, 35.29, 34.56, 21.70; HRMS (TOF+) calcd. for C18H16BrO3 [M+H]

+ 359.0277,

found 359.0278; HPLC (Daicel Chiralpak AD-H, i-PrOH/Hexane = 10/90, 1.0 mL/min, 254 nm) t1 = 11.6

min (minor), t2 = 13.8 min (major).

D25= 42.0 (c 1.0, MeOH, 10:90 er);

1H NMR (400 MHz,

Chloroform-d) δ 7.83 (dd, J = 7.7, 1.4 Hz, 1H), 7.75 – 7.69 (m, 1H), 7.54 (td, J = 7.5, 1.3 Hz, 1H), 7.37 –

7.22 (m, 5H), 7.04 (d, J = 7.5 Hz, 1H), 4.11 (d, J = 11.2 Hz, 1H), 3.88 (d, J = 11.2 Hz, 1H), 3.67 – 3.50 (m,

2H), 1.67 (s, 3H). 13

C NMR (100 MHz, CDCl3) δ 203.05, 162.74, 137.92, 135.71, 134.98, 134.33, 131.46,

131.21, 129.81, 128.64, 128.28, 127.78, 125.18, 124.99, 88.70, 35.85, 35.50, 19.04; HRMS (TOF+) calcd.

for C18H16BrO4 [M+H] +

375.0154, found 375.0152; HPLC (Daicel Chiralpak AD-H, i-PrOH/Hexane =

D25= 6.8 (c 1.0, MeOH, 19:81 er);

1H NMR (300 MHz, Chloroform-d) δ

7.87 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.56 (td, J = 7.6, 1.3 Hz, 1H), 7.49 – 7.43 (m, 1H), 7.38 –

7.27 (m, 3H), 7.10 (dd, J = 7.9, 3.0 Hz, 1H), 4.05 (d, J = 11.1 Hz, 1H), 3.84 (d, J = 12.7 Hz, 4H), 3.76 (d, J

= 16.0 Hz, 1H), 3.49 (d, J = 16.0 Hz, 1H). 13

C NMR (75 MHz, CDCl3) δ 197.19, 162.86, 159.49, 136.79,

135.52, 134.59, 130.13, 129.64, 128.05, 127.97, 123.97, 122.47, 120.36, 114.14, 88.84, 55.45, 35.19, 34.73;

HRMS (TOF+) calcd. for C18H16BrO4 [M+H]

+ 375.0154, found 375.0152; HPLC (Daicel Chiralpak AD-H,

i-PrOH/Hexane = 10/90, 1.0 mL/min, 254 nm) t1 = 12.8 min (minor), t2 = 13.7 min (major).

D25= 50.7 (c 1.0, MeOH, 14:86 er);

δ 8.16 – 8.06 (m, 2H), 7.87 (dd, J = 8.0, 1.1 Hz, 1H), 7.54 (td, J = 7.6, 1.3 Hz, 1H), 7.35 – 7.27 (m, 2H),

6.94 – 6.85 (m, 2H), 4.05 (d, J = 11.2 Hz, 1H), 3.86 (s, 3H), 3.85 – 3.73 (m, 2H), 3.49 (d, J = 16.0 Hz, 1H).

13C NMR (75 MHz, CDCl3) δ 195.01, 163.94, 163.09, 137.31, 134.59, 132.84, 130.10, 128.03, 127.90,

+ 375.0154,

D25= 25.3 (c 1.0, MeOH, 80:20 er);

1H NMR (400 MHz,

Chloroform-d) δ 7.79 – 7.72 (m, 1H), 7.55 (td, J = 7.5, 1.3 Hz, 1H), 7.40 – 7.30 (m, 2H), 7.26 (d, J = 7.6 Hz,

1H), 6.89 (dd, J = 8.5, 0.8 Hz, 1H), 6.78 (td, J = 7.5, 0.9 Hz, 1H), 6.61 (dd, J = 7.6, 1.7 Hz, 1H), 4.34 (d, J =

11.3 Hz, 1H), 4.23 – 4.01 (m, 2H), 3.84 (d, J = 11.3 Hz, 1H), 3.70 – 3.54 (m, 2H), 1.41 (t, J = 7.0 Hz, 3H).

13C NMR (100 MHz, CDCl3) δ 204.57, 162.85, 156.27, 135.95, 134.10, 133.01, 129.71, 128.73, 127.94,

127.90, 127.63, 124.97, 120.44, 112.04, 88.19, 64.48, 35.95, 34.84, 14.64; HRMS (TOF+) calcd. for

C19H18BrO4 [M+H] +

389.0383, found 389.0381; HPLC (Daicel Chiralpak AD-H, i-PrOH/Hexane = 10/90,

2.0 mL/min, 254 nm) t1 = 4.9 min (major), t2 = 6.6 min (minor).

D25= 32.3 (c 1.0, MeOH, 16:84 er);

δ 8.10 (dd, J = 8.8, 5.5 Hz, 2H), 7.86 (d, J = 7.7 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.32 (t, J = 8.8 Hz, 2H),

7.09 (t, J = 8.6 Hz, 2H), 4.02 (d, J = 11.1 Hz, 1H), 3.85 – 3.69 (m, 2H), 3.47 (d, J = 16.0 Hz, 1H).13

(100 MHz, Chloroform-d) δ 195.95 , 165.82 (d, J = 257.1 Hz), 162.71 , 136.78 , 134.69 , 133.02 (d, J = 9.5

Hz), 130.79 (d, J = 3.3 Hz), 130.14 , 128.10 , 128.02 , 123.82 , 115.85 (d, J = 21.8 Hz), 88.83 , 34.98 ,

34.64 ; HRMS (TOF+) calcd. for C17H13BrFO3 [M+H]

+ 363.0003, found 363.0001; HPLC (Daicel Chiralpak

AD-H, i-PrOH/Hexane = 10/90, 2.0 mL/min, 254 nm) t1 = 6.4 min (minor), t2 = 8.6 min (major).

D25= 50.4 (c 1.0, MeOH, 16:84 er);

1H NMR (400 MHz,

Chloroform-d) δ 8.02 – 7.96 (m, 2H), 7.86 (d, J = 7.8 Hz, 1H), 7.55 (td, J = 7.6, 1.2 Hz, 1H), 7.42 – 7.36 (m,

2H), 7.36 – 7.29 (m, 2H), 4.00 (d, J = 11.1 Hz, 1H), 3.84 – 3.69 (m, 2H), 3.47 (d, J = 16.1 Hz, 1H). 13

NMR (100 MHz, CDCl3) δ 196.48, 162.62, 140.26, 136.67, 134.70, 132.76, 131.48, 130.18, 128.95, 128.14,

128.01, 123.83, 88.79, 34.86, 34.63; HRMS (TOF+) calcd. for C17H13BrClO3 [M+H]

+ 378.9731, found

378.9735; HPLC (Daicel Chiralpak AD-H, i-PrOH/Hexane = 10/90, 2.0 mL/min, 254 nm) t1 = 6.7 min

D25= 18.5 (c 1.0, MeOH, 19:81 er);

1H NMR (400 MHz,

Chloroform-d) δ 8.11 (d, J = 8.2 Hz, 2H), 7.89 – 7.83 (m, 1H), 7.69 (d, J = 8.3 Hz, 2H), 7.58 (td, J = 7.6, 1.3

Hz, 1H), 7.39 – 7.30 (m, 2H), 4.01 (d, J = 11.1 Hz, 1H), 3.85 – 3.70 (m, 2H), 3.48 (d, J = 16.1 Hz, 1H). 13

NMR (100 MHz, CDCl3) δ 197.34, 162.44, 137.48, 136.33, 134.80, 134.75, 134.42, 130.22, 128.29, 128.01,

125.61 (q, J = 303 Hz), 123.86, 88.69, 34.67, 34.51; HRMS (TOF+) calcd. for C18H13BrF3O3 [M+H]

412.9995, found 412.9996; HPLC (Daicel Chiralpak AD-H, i-PrOH/Hexane = 10/90, 2.0 mL/min, 254 nm)

t1 = 9.3 min (minor), t2 = 12.3 min (major).

D25= 7.5 (c 1.0, MeOH, 12:88 er);

1H NMR (400 MHz,

Chloroform-d) δ 7.79 – 7.72 (m, 1H), 7.56 (td, J = 7.5, 1.3 Hz, 1H), 7.46 (td, J = 7.6, 1.3 Hz, 1H), 7.40 –

7.28 (m, 5H), 7.24 – 7.16 (m, 2H), 7.11 (d, J = 9.5 Hz, 2H), 6.94 – 6.85 (m, 1H), 3.58 – 3.42 (m, 2H), 3.22

(d, J = 16.2 Hz, 1H), 3.03 (d, J = 11.4 Hz, 1H). 13

C NMR (100 MHz, CDCl3) δ 205.68, 162.28, 140.98,

140.59, 136.89, 135.77, 134.26, 130.89, 130.16, 129.88, 129.55, 128.35, 128.08, 127.94, 127.90, 127.71,

126.82, 124.91, 88.23, 36.19, 35.24; HRMS (TOF+) calcd. for C23H18BrO3 [M+H]

+ 421.0434, found

421.0439; HPLC (Daicel Chiralcel AD-H, i-PrOH/Hexane = 10/90, 2.0 mL/min, 254 nm) t1 = 4.3 min

33.1 mg, 95%, colorless oil; MP 119-121°C; []

D25= 14.5 (c 1.0, MeOH, 36:64 er);

1H NMR (400 MHz,

Chloroform-d) δ 8.10 (d, J = 7.8 Hz, 1H), 7.57 (td, J = 7.5, 1.3 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.26 (d, J =

7.6 Hz, 1H), 3.76 (d, J = 11.1 Hz, 1H), 3.58 (d, J = 11.1 Hz, 1H), 3.46 (d, J = 16.5 Hz, 1H), 3.33 (d, J = 16.5

Hz, 1H), 3.12 – 2.94 (m, 1H), 1.94 – 1.74 (m, 2H), 1.71 – 1.63 (m, 2H), 1.49 – 1.05 (m, 6H). 13

C NMR (100

MHz, CDCl3) δ 210.78, 162.94, 136.16, 134.60, 130.28, 128.24, 128.00, 124.02, 87.60, 45.42, 34.29, 33.41,

28.95, 28.78, 25.52, 25.35; HRMS (TOF+) calcd. for C17H14BrO3 [M+H]+ 351.0048, found 351.0053;

HPLC (Daicel Chiralcel AD-H, i-PrOH/Hexane = 5/95, 1.0 mL/min, 254 nm) t1 = 10.2 min (minor), t2 =

10.8 min (major).

34,2 mg, 98% yield, white solid; MP 124-126°C; []

D25= 27.5 (c 1.0, MeOH, 25:75 er);

1H NMR (300 MHz,

Chloroform-d) δ 8.31 (dd, J = 4.0, 1.0 Hz, 1H), 7.98 (d, J = 7.2 Hz, 1H), 7.73 (dd, J = 5.0, 1.0 Hz, 1H), 7.58

(td, J = 7.5, 1.3 Hz, 1H), 7.42 – 7.30 (m, 2H), 7.19 (dd, J = 4.9, 4.0 Hz, 1H), 3.99 (d, J = 11.2 Hz, 1H), 3.85

– 3.73 (m, 2H), 3.52 (d, J = 16.2 Hz, 1H). 13

C NMR (100 MHz, CDCl3) δ 188.80, 162.86, 139.73, 137.08,

136.44, 136.35, 134.75, 130.38, 128.94, 128.14, 128.04, 123.57, 87.99, 35.50, 33.55; HRMS (TOF+) calcd.

for C15H11BrO3S [M+H]+ 350.9685, found 350.9667; HPLC (Daicel Chiralpak AD-H, i-PrOH/Hexane =

D25= 25.5 (c 1.0, MeOH, 13:87 er);

1H NMR (300 MHz,

Chloroform-d) δ 8.07 – 7.97 (m, 2H), 7.72 (d, J = 7.6 Hz, 1H), 7.61 – 7.52 (m, 1H), 7.43 (t, J = 7.7 Hz, 3H),

7.21 (t, J = 7.7 Hz, 1H), 4.06 (d, J = 11.1 Hz, 1H), 3.90 – 3.74 (m, 2H), 3.32 (d, J = 16.3 Hz, 1H), 2.40 (s,

3H). 13

C NMR (75 MHz, CDCl3) δ 197.54, 163.28, 135.94, 135.91, 135.48, 134.38, 133.60, 129.95, 128.62,

+ 359.0277,

D25= 29.5 (c 1.0, MeOH, 86:14 er);

1H NMR (300 MHz,

Chloroform-d) δ 8.08 – 7.96 (m, 2H), 7.74 (d, J = 8.4 Hz, 1H), 7.62 – 7.48 (m, 1H), 7.48 – 7.36 (m, 2H),

7.11 (d, J = 5.6 Hz, 2H), 4.04 (d, J = 11.1 Hz, 1H), 3.82 (d, J = 11.1 Hz, 1H), 3.71 (d, J = 16.0 Hz, 1H), 3.44

(d, J = 16.0 Hz, 1H), 2.40 (s, 3H). 13

C NMR (75 MHz, CDCl3) δ 197.61, 162.99, 145.85, 136.85, 134.45,

133.56, 130.15, 129.96, 128.98, 128.58, 128.50, 121.23, 88.73, 35.16, 34.55, 21.86; HRMS (TOF+) calcd.

for C18H16BrO3 [M+H]+ 359.0277, found 359.0278; HPLC (Daicel Chiralpak AD-H, i-PrOH/Hexane =

D25= 26.8 (c 1.0, MeOH, 14:86 er);

1H NMR (300 MHz,

Chloroform-d) δ 8.06 – 7.97 (m, 2H), 7.67 (s, 1H), 7.59 – 7.51 (m, 1H), 7.42 (t, J = 7.6 Hz, 2H), 7.38 – 7.32

(m, 1H), 7.19 (d, J = 7.8 Hz, 1H), 4.04 (d, J = 11.1 Hz, 1H), 3.83 (d, J = 11.1 Hz, 1H), 3.72 (d, J = 16.0 Hz,

1H), 3.44 (d, J = 16.0 Hz, 1H), 2.32 (s, 3H). 13

C NMR (75 MHz, CDCl3) δ 197.60, 163.17, 138.01, 135.56,

134.47, 133.76, 133.55, 130.29, 129.94, 128.58, 127.87, 123.65, 88.86, 35.13, 34.27, 20.95; HRMS (TOF+)

calcd. for C18H16BrO3 [M+H]+ 359.0277, found 359.0278; HPLC (Daicel Chiralpak AD-H, i-PrOH/Hexane

= 10/90, 1.0 mL/min, 254 nm) t1 = 5.1 min (minor), t2 = 5.8 min (major).

D25= 67.8 (c 1.0, MeOH, 30:70 er);

1H NMR (400 MHz,

Chloroform-d) δ 7.62 (s, 1H), 7.44 – 7.33 (m, 2H), 7.16 (d, J = 7.7 Hz, 1H), 6.87 (dd, J = 16.9, 7.9 Hz, 2H),

6.80 (dd, J = 7.6, 1.8 Hz, 1H), 4.18 (d, J = 11.2 Hz, 1H), 3.81 (d, J = 11.2 Hz, 1H), 3.77 (s, 3H), 3.63 – 3.48

(m, 2H), 2.36 (s, 3H).13

C NMR (100 MHz, CDCl3) δ 203.93, 163.11, 156.63, 137.88, 134.98, 132.93,

132.80, 129.86, 128.51, 127.81, 127.42, 124.61, 120.58, 111.38, 88.16, 55.78, 35.76, 34.25, 20.94; HRMS

(TOF+) calcd. for C19H18BrO4 [M+H]

+ 389.0383, found 389.0381; HPLC (Daicel Chiralpak AD-H,

i-PrOH/Hexane = 10/90, 2.0 mL/min, 254 nm) t1 = 8.1 min (minor), t2 = 10.1 min (major).

Synthetic Application.

To a solution of 4g (37mg, 0.1 mmol, 1.0 equiv) in DMF ( 3 mL) was added NaN3 (19.5 mg, 0.3 mmol, 3 equiv), The

mixture was then stirred for 4 h at 60oC. The solution was diluted with water (1.5 mL) and extrated with EtOAc, dried over

MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (hexane/EtOAc=10:1) to

yield the corresponding azide derivative 7 32.0 mg, 99% yield, white solid; MP 91-93°C; []

D25= 9.8 (c 1.0, MeOH,

10:90 er); 1H NMR (400 MHz, Chloroform-d) δ 7.77 – 7.67 (m, 2H), 7.53 (td, J = 7.5, 1.2 Hz, 1H), 7.37 –

7.23 (m, 4H), 7.03 (d, J = 7.0 Hz, 1H), 4.12 (d, J = 12.9 Hz, 1H), 3.85 (d, J = 12.9 Hz, 1H), 3.57 – 3.38 (m,

2H), 1.58 (s, 3H). 13

C NMR (100 MHz, CDCl3) δ 204.72, 162.63, 137.48, 135.62, 135.41, 134.27, 131.30,

131.08, 129.85, 128.43, 128.31, 127.78, 125.17, 125.15, 89.70, 56.92, 34.23, 18.65; HRMS (TOF+) calcd.

for C18H16N3O4 [M+H]+ 337.10063, found 337.1060; HPLC (Daicel Chiralpak AD-H, i-PrOH/Hexane =

To a solution of 4g (37mg, 0.1 mmol, 1.0 equiv) in EtOH ( 3 mL) was added NaHCO3 (17 mg, 0.2 mmol, 2

equiv), The mixture was then stirred for overnight at 70oC. The solution was diluted with water (1.5 mL)

and extrated with EtOAc, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash

column chromatography (hexane/EtOAc=10:1) to yield the corresponding chiral ether derivative 8 32.3 mg,

95% yield, colorless oil; []

D25= 12.3 (c 1.0, MeOH, 10:90 er);1H NMR (400 MHz, Chloroform-d) δ 7.89 (dd,

J = 7.8, 1.1 Hz, 1H), 7.49 – 7.41 (m, 2H), 7.38 – 7.30 (m, 3H), 7.20 (t, J = 6.9 Hz, 2H), 4.37 (q, J = 7.1 Hz,

2H), 4.05 (d, J = 14.6 Hz, 1H), 3.79 (d, J = 14.7 Hz, 1H), 2.70 (d, J = 5.2 Hz, 1H), 2.57 (d, J = 5.2 Hz, 1H),

2.31 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 203.43, 167.60, 137.36, 136.13,

135.52, 132.40, 131.57, 131.51, 130.83, 130.68, 130.36, 128.10, 127.01, 124.94, 62.39, 60.94, 49.76, 33.20,

19.79, 14.28; HRMS (TOF+) calcd. for C20H21O5 [M+H]

+ 341.1131, found 341.1129; HPLC (Daicel

Chiralpak AD-H, i-PrOH/Hexane = 10/90, 1.0 mL/min, 254 nm) t1 = 5.9 min (minor), t2 = 6.9 min (major).

X-ray of 4b

References

1. Tay, D. W.; Jong, H.; Lim, Y. H.; Wu, W.; Chew, X.; Robins, E. G.; Johannes, C. W. J. Org. Chem. 2015, 80, 4054.

2. Jiang, X.; Liu, S.; Yang, S.; Jing, M.; X, L.; Yu, P.; Wang, Y.; Yeung, Y.-Y. Org. Lett. 2018, 20, 3259.

13C Spectra

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