Allocolchicinoid synthesis via direct arylation

Article abstract of DOI:10.1021/ol0505959

(Chemical Equation Presented) A formal enantioselective synthesis of allocolchicine and a synthesis of a C-ring analogue have been achieved by employing an intramolecular direct arylation of an aryl chloride to form the biaryl carbon-carbon bond and the s

Full text of DOI:10.1021/ol0505959

Assymmetric Synthesis of Allocolchicine and a C-Ring Analogue.
Mélissa Leblanc & Keith Fagnou*
Center for Catalysis Research and Innovation, University of Ottawa, Department
of Chemistry, 10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
Keith.Fagnou@science.uottawa.ca
Supporting Information
General Methods:
1
All experiments were carried out under an atmosphere of nitrogen. H and
1
3
C NMR were recorded in CDCl
3
or (CD
3
) SO solutions using a Bruker AVANCE
2
3
00 spectrometer with Me Si as an internal standard. High-resolution mass
4
spectra were obtained on a Kratos Concept IIH. Infra-Red analysis was
performed with a Bruker EQUINOX 55. HPLC analysis was performed on
Waters apparatus using photodiode array detector. HPLC Grade THF, Et
Benzene, Toluene and CH Cl are dried and purified via MBraun SP Series
solvent purification system. Triethylamine was freshly distilled from NaOH before
every use. Dimethylacetamide was degassed with N before every use.
2
O,
2
2
2
Palladium and Copper complexes were stored in a dessicator and were weighed
out to air unless otherwise specified. All other reagents and solvents were used
without further purification from commercial sources. Unless noted below, all
other compounds have been reported in the literature or are commercially
available.
1
Compound 4 was prepared as reported in the literature and exhibited identical
spectral data.
2
3
Compound 5 and 11 are commercially available or can be prepare as reported
4
in the literature and exhibited identical spectral data.
S1

1
-(5-bromo-2-chlorophenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-yn-1-one (7)5,6
O
O
O
O
Cl
Br
To freshly prepared 5-bromo-2-chlorobenzoyl chloride (5) (0.546 g, 2.15
mmol) under argon was added the 5-ethynyl-1,2,3-trimethoxybenzene (4) (0.275
g, 1.43 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (10.1 mg,
0.014 mmol) and copper iodide (9.0 mg, 0.047 mmol). THF (7.2 mL) was then
added followed by triethylamine (0.181 g, 0.25 mL, 1.79 mmol). The brown
solution was stirred at room temperature for 20h after which the solvent was
removed by rotary evaporator. DCM and water were added to the brown residue
and the organic phase was extracted three times with DCM. The organic layer
was dried over MgSO
column chromatography on silica gel using 20% AcOEt/hexane to give solid 7
0.543 g, 92%).
H NMR (300 MHz, CDCl
J= 2.5, 8.6 Hz), 7.37 (1H, d, J= 8.7 Hz), 6.89 (2H, s), 3.91 (3H, s), 3.89 (6H,s).
4
, filtered and concentrated. The brown oil was purified by
(
1
3
, 293K, TMS): δ 8.14 (1H, d, J= 2.4 Hz), 7.59 (1H, dd,
1
3
C NMR (75 MHz, CDCl
32.9, 132.3, 120.4, 114.2, 110.6, 95.8, 87.6, 61.1, 56.3.
HRMS calculated for C18 BrCl (M+) 407.9764; Found: 407.9754.
3
, 293K, TMS): 175.2, 153.3, 141.5, 137.4, 136.1, 134.7,
1
H
14
O
4
Melting point °C (ether): 114-116
IR: 2947, 2185, 1648, 1503, 1237, 1131, 822, 610.
1
-(2-bromophenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-yn-1-one (12)5,6
O
O
Br
O
O
S2

2-Bromo-benzoyl chloride (11) (0.522 g, 2.38 mmol) was added to a
solution of the 5-ethynyl-1,2,3-trimethoxybenzene (4) (0.305 g, 1.59 mmol),
trans-dichlorobis(triphenylphosphine) palladium (II) (10.9 mg, 0.016 mmol) and
copper iodide (9.1 mg, 0.048 mmol) in THF (8.0 mL) under argon. Triethylamine
(0.181 g, 0.25 mL, 1.79 mmol) was added and the brown solution was stirred at
room temperature for 20h. The solvent was then removed by rotary evaporator.
DCM and water were added to the brown residue and the organic phase was
extracted three times with DCM. The organic layer was dried over MgSO ,
4
filtered and concentrated. The brown oil was purified by column chromatography
on silica gel using 20% AcOEt/hexane to give solid 12 (0.470 g, 79%).
1
H NMR (100 MHz, CDCl , 293K, TMS): δ 8.05 (1H, dd, J= 1.6, 7.6 Hz), 7.70
3
(
1H, d, J= 7.8 Hz), 7.47-7.38 (2H, m), 6.89 (2H, s), 3.90 (3H, s), 3.88 (6H, s).
1
3
C NMR (75 MHz, CDCl
27.3, 121.0, 114.4, 110.4, 94.7, 87.4, 60.9, 56.2.
HRMS calculated for C18 Br (M+) 374.0154; Found: 374.0149.
Melting point °C (ether): 77.5-79.5
3
, 293K): 177.4, 153.1, 141.1, 137.4, 134.8, 133.2,
1
H
15
O
4
-1
IR (vmax/cm ): 2940, 2188, 1644, 1245, 1129, 1022, 631.
(
(
S)-1-(5-bromo-2-chlorophenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-yn-1-ol
8)
7
OH
Br
O
Cl
O
O
To a flame dried flask fitted with a condenser was added 9-BBN 0.5 M
solution in THF (5.9 mL, 2.93 mmol) and (S)-α-pinene (0.439 g, 0.5 mL, 3.22
mmol) under argon. The solution was stirred at reflux for 2.5h after which the
solution was cooled to room temperature and a solution of 1-(5-bromo-2-
chlorophenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-yn-1-one (7) (0.60 g, 1.46 mmol)
in THF was added via cannula. The resulting solution was stirred at room
S3

temperature overnight. A 10% solution of NaOH in water was then added and
the mixture was vigorously stirred for 1.5h. THF was removed by rotary
evaporator and the aqueous phase was extracted three times with a mixture of
EtOAc/Et
2
O (1/1). The organic layer was dried over MgSO , filtered and
4
concentrated. The brown oil was purified by column chromatography on silica
gel using 30% AcOEt/hexane to give yellow oil 8 (0.479 g, 80%).
1
H NMR (300 MHz, CDCl , 293K, TMS): δ 7.95 (1H, d, J= 2.4 Hz), 7.42 (1H, dd,
3
J= 2.3, 9.6 Hz), 7.27 (1H,d, J= 8.4 Hz), 6.69 (2H, s), 5.97 (1H, d, J= 4.5 Hz), 3.85
(
9H, s), 2.66 (1H, bs).
1
3
C NMR (75 MHz, CDCl
20.9, 116.9, 108.9, 86.8, 86.0, 61.8, 61.0, 56.1.
HRMS calculated for C18 BrCl (M+) 409.9920; Found: 409.9896
3
, 293K, TMS): 153.0, 139.8, 139.1, 132.5, 131.5, 131.2,
1
H
16
O
4
HPLC: 97.8% ee; column: chiralcel AS-H; flow rate: 0.8 mL/min; eluant: 10%
iPrOH/hexane: (minor) retention time: 25.87 min, 1.1%; (major) retention time:
3
1.55 min, 98.9%
2
2
[
α]
D
= -50.5 (c = 1, CH
2
Cl
2
)
-1
IR (vmax/cm ): 3430, 2938, 2229, 1579, 1237, 1129, 835, 756, 631.
(
S)-1-(2-bromophenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-yn-1-ol (13)7
OH
O
Br
O
O
To a dry flask fitted with a condenser under argon were added 9-BBN 0.5
M solution in THF (16 mL, 8.00 mmol) and (S)-α-pinene (1.198 g, 1.37 mL, 8.80
mmol). The solution was stirred at reflux for 2.5h after which the solution was
cooled to room temperature and a solution of 1-(2-bromophenyl)-3-(3,4,5-
trimethoxyphenyl)prop-2-yn-1-one (12) (1.50 g, 4.00 mmol) in THF was added
via cannula. The resulting solution was stirred at room temperature for 28h. A
saturated solution of NaHCO in water followed by a solution of peroxide 30%
3
were added and stirred for 1.5h. The white precipitate was filtered and THF was
S4

removed by rotary evaporator. The aqueous phase was extracted three times
with a mixture of EtOAc/Et O (1/1). The organic layer was dried over MgSO ,
2
4
filtered and concentrated. The brown oil was purified by column chromatography
on silica gel using 35% AcOEt/hexane to give a yellow solid 13 (1.189 g, 79%).
1
H NMR (300 MHz, CDCl , 293K, TMS): δ 7.83 (1H, d, J= 7.8 Hz), 7.56 (1H, d,
3
J= 8.1 Hz), 7.37 (1H, t, J= 7.5 Hz), 7.19 (1H, t, J= 7.5 Hz), 6.68 (2H, s), 6.00 (1H,
s), 3.84 (3H, s), 3.81 (6H, s), 3.14 (1H, s).
1
3
C NMR (75 MHz, CDCl
27.8, 122.5, 117.2, 108.8, 86.8, 86.3, 64.4, 60.8, 56.0.
HRMS calculated for C18 Br (M+) 376.0310; Found: 376.0305.
3
, 293K, TMS): 152.8, 139.5, 138.8, 132.8, 129.8, 128.5,
1
H
17
O
4
Melting point °C (ether): 97.2-100
HPLC: 98% ee; column: chiralcel AS-H; flow rate: 0.9 mL/min; eluant: 10%
iPrOH/hexane: (minor) retention time: 30.82 min, 1.0 %; (major) retention time:
3
4.33 min, 99.0 %.
2
2
[
α]
D
= +58.0 (c = 1, CH
2
Cl
2
)
-1
IR (vmax/cm ): 3472, 2938, 2230, 1579, 1237, 1129, 646.
(
S)-5-(3-(2-bromo-5-chlorophenyl)-3-(methoxymethoxy)prop-1-ynyl)-1,2,3-
trimethoxybenzene (9)
O
O
Cl
O
O
Br
O
To a solution of 8 (0.961 g, 2.33 mmol) in 12 mL of dry THF was added
sodium hydride 60% in mineral oil (0.107 g, 2.68 mmol) at 0°C. The resulting
mixture was stirred at room temperature for 1h. Bromo(methoxy)methane (0.356
g, 0.23 mL, 2.57 mmol) was added and the resulting mixture was stirred at 0°C
for 15 min before letting the solution warm to room temperature and stir overnight.
Water was added slowly and THF was removed under rotary evaporator. The
resulting thick oil was extracted twice with ether. The organic layer was dried
S5

over MgSO
chromatography on silica gel using 20% AcOEt/hexane to give white solid 9
0.996 g, 94%).
4
, filtered and concentrated. The resulting oil was purified by column
(
1
H NMR (300 MHz, CDCl
3
, 293K, TMS): δ 7.94 (1H, d, J= 2.4 Hz), 7.43 (1H, dd,
J= 8.7, 2.4 Hz), 7.27 (1H, d, J= 8.4 Hz), 6.70 (2H, s), 5.96 (1H, s), 5.12 (1H, d, J=
6
.9 Hz), 4.74 (1H, d, J= 6.9 Hz), 3.85 (9H, s), 3.47 (3H, s).
1
3
C NMR (75 MHz, CDCl
31.4, 121.3, 117.4, 109.6, 109.4, 94.7, 87.9, 84.6, 64.7, 61.4, 56.6, 56.6.
BrCl (M+) 454.0183; Found: 454.0212
3
, 293K, TMS): 153.4, 139.6, 138.8, 133.0, 132.5, 132.2,
1
HRMS calculated for C20
H
20
O
5
Melting point °C (ether): 56.5-57.4
HPLC: 96.6% ee; column: chiralcel AS-H; flow rate: 0.8 mL/min; eluant: 10%
iPrOH/hexane: (major) retention time 9.68 min, 98.3 %; retention time: 10.55 min,
1
.7 %.
D
2
2
[
α]
= -135.4 (c = 1, CH
IR (vmax/cm ): 2939, 2221, 1578, 1237, 1129, 1024, 833.
2
Cl
2
)
-1
(
S)-5-(3-(2-bromophenyl)-3-(methoxymethoxy)prop-1-ynyl)-1,2,3-trimethoxy
benzene (14)
O
O
O
O
Br
O
To a solution of 13 (1.07 g, 2.84 mmol) in 28 mL of dry THF was added
sodium hydride 60% in mineral oil (0.136 g, 3.41 mmol) at 0°C. The resulting
mixture was stirred at room temperature for 1h. Bromo(methoxy)methane (0.433
g, 0.28 mL, 3.13 mmol) was added and the resulting mixture was stirred at 0°C
for 15 min before letting the solution warm to room temperature and stir overnight.
Water was added slowly and THF was removed under rotary evaporator. The
resulting thick oil was extracted twice with ether. The organic layer was dried
S6

over MgSO
4
, filtered and concentrated. The colourless oil was purified by
column chromatography on silica gel using 30% AcOEt/hexane to give 14 (1.11 g,
9
3%).
1
H NMR (300 MHz, CDCl , 293K, TMS): δ 7.83 (1H, dd, J= 7.8, 1.6 Hz), 7.59
1H, dd, J= 8.0, 0.9 Hz), 7.40 (1H, t, J= 7.5 Hz), 7.22 (1H, dt, J= 7.7, 1.6 Hz),
3
(
6
.70 (2H, s), 6.01 (1H, s), 4.94 (2H, dd, J= 111, 6.9 Hz), 3.84 (9H, s), 3.48 (3H, s).
1
3
C NMR (75 MHz, CDCl
27.9, 123.1, 117.3, 109.0, 94.3, 87.3, 85.1, 67.2, 60.9, 56.2, 56.1.
(M+): 420.0572; Found: 420.0601.
3
, 293K, TMS): 153.0, 139.0, 138.0, 132.9, 130.0, 129.6,
1
HRMS calculated for C20
H21BrO
5
HPLC: 95.4% ee; column: chiralcel AS-H; flow rate: 0.9 mL/min; eluant: 10%
iPrOH/hexane: (minor) retention time: 10.23 min, 2.3 %; (major) retention time:
1
1.03 min, 97.7 %.
2
2
[
α]
D
= -22.5 (c = 1, CH
2
Cl
2
)
-1
IR (vmax/cm ): 2940, 2221, 1577, 1504, 1237, 1025, 757, 689.
(
R)-5-(3-(5-bromo-2-chlorophenyl)-3-(methoxymethoxy)propyl)-1,2,3-
8
trimethoxy benzene (10)
O
O
O
O
Br
Cl
O
To a refluxing solution of 9 (0.794 g, 1.75 mmol) and p-
toluenesulfonhydrazide (3.91 g, 20.99 mmol) in dimethoxyethane (17 mL) was
added a solution of sodium acetate (2.15 g, 26.23 mmol) in water (17 mL) over a
5h period. The solution was refluxed overnight. DME was concentrated under
rotary evaporator and Et O was added. The organic layer was washed three
2
times with water and then dried over MgSO , filtered and concentrated. The
4
colourless oil was purified by column chromatography on silica gel using 20%
AcOEt/hexane to give 10 (0.76 g, 95%).
S7

1H NMR (300 MHz, CDCl
J= 8.5, 2.4 Hz), 7.19 (1H, d, J= 8.4 Hz), 6.43 (2H, s), 5.04 (1H, t, J= 6.2 Hz), 4.58
2H, dd, J= 24.1, 6.8 Hz), 3.85 (6H, s), 3.82 (3H, s), 3.42 (3H, s), 2.86-2.64 (2H,
m), 2.05-1.98 (2H, m).
, 293K, TMS): δ 7.64 (1H, d, J= 2.4 Hz), 7.32 (1H, dd,
3
(
1
3
C NMR (75 MHz, CDCl
30.8, 130.5, 120.8, 105.1, 95.1, 73.9, 60.8, 56.0, 55.9, 38.1, 32.3.
HRMS calculated for C20 : (M+) 424.0885; Found: 424.0868.
3
, 293K, TMS): 153.0, 142.1, 137.1, 135.9, 131.4, 131.3,
1
H25BrO
5
HPLC: 97% ee; column: chiralcel AS-H; flow rate: 0.8 mL/min; eluant: 2%
iPrOH/hexane: (major) retention time: 13.43 min, 98.8 %; (minor) retention time:
1
5.417 min, 1.2 %.
2
2
[
α]
D
= 65.4 (c = 1, CH
2
Cl
2
)
-1
IR (vmax/cm ): 2938, 1590, 1240, 1129, 1025, 816, 667.
(
R)-5-(3-(2-bromophenyl)-3-(methoxymethoxy)propyl)-1,2,3-trimethoxy
8
benzene (15)
O
O
O
O
Br
O
To a refluxing solution of (14) (1.025 g, 2.43 mmol) and p-toluene
sulfonhydrazide (5.44 g, 29.20 mmol) in dimethoxyethane (25 mL) was added a
solution of sodium acetate (2.99 g, 36.50 mmol) in water (25 mL) over a 5h
period. The solution was refluxed overnight. DME was concentrated under
rotary evaporator and Et
times with water and then dried over MgSO
2
O was added. The organic layer was washed three
, filtered and concentrated. The
4
colourless oil was purified by column chromatography on silica gel using 25%
AcOEt/hexane to give 15 (1.005 g, 97%).
1
H NMR (300 MHz, CDCl , 293K, TMS): δ 7.51 (1H, dd, J= 8.0, 1.1 Hz), 7.50
3
(1H, dd, J= 7.8, 1.8 Hz), 7.33 (1H, t, J= 7.3 Hz), 7.13 (1H, dt, J= 7.7, 1.7 Hz),
6
3
.44 (2H, s), 5.07 (1H, t, J= 6.3 Hz), 4.57 (2H, dd, J= 18.3, 6.9 Hz), 3.85 (6H, s),
.82 (3H, s), 3.43 (3H, s), 2.87-2.65 (2H, m), 2.06-1.98 (2H, m).
S8

13C NMR (75 MHz, CDCl
1
, 293K, TMS): 153.0, 141.4, 137.5, 136.0, 132.7, 128.9,
27.8, 127.7, 122.8, 105.2, 95.0, 76.5, 60.9, 56.0, 56.0, 38.6, 32.6.
3
HRMS calculated for C20
H
25BrO (M+); 424.0885 Found: 424.0868.
5
HPLC: 98.4% ee; column: chiralcel AS-H; flow rate: 0.8 mL/min; eluant: 10%
iPrOH/hexane: (major) retention time: 13.48 min, 99.2 %; (minor) retention time:
1
9.12 min, 0.8 %.
2
2
[
α]
D
= +109.6 (c = 1, CH
2
Cl
2
)
-1
IR (vmax/cm ): 2939, 1590, 1463, 1240, 1027, 678.
(
R)-Methyl
4-chloro-3-(1-(methoxymethoxy)-3-(3,4,5-trimethoxy
phenyl)
9
propyl)benzoate (6)
O
O
O
O
CO Me
2
Cl
O
(
R)-5-(3-(2-bromophenyl)-3-(methoxymethoxy)propyl)-1,2,3-trimethoxy
benzene (10) (0.352 g, 0.77 mmol), potassium carbonate (0.318 g, 2.3 mmol)
and trans-dichlorobis(triphenylphosphine) palladium (II) (27.0, 0.039 mmol) were
placed in a schlenk tube. The tube was purged with carbon monoxide and DMF
(3.4 mL) was added. Carbon monoxide was bubbled into the solution for 30 min
then methanol was added (0.369 g, 0.47 mL, 11.52 mmol). The solution was
bubbled with carbon monoxide for an additional 10 min then the schlenk tube
was sealed and the solution was heated at 95°C overnight. The solution was
then cooled to room temperature, Et
washed 3 times with brine. The organic layer was dried over MgSO
2
O was added and the organic layer was
, filtered and
4
concentrated. The colourless oil was purified by column chromatography on
silica gel using 25% AcOEt/hexane to give 6 (0.277 g, 82%).
1
H NMR (300 MHz, CDCl , 293K, TMS) δ: 8.20 (1H, d, J= 2.1 Hz), 7.88 (1H, dd,
3
J= 8.3, 2.2 Hz), 7.40 (1H, d, J= 8.4 Hz), 6.42 (2H, s), 5.12 (1H, dd, J= 7.5, 5.1
Hz), 4.59 (2H, dd, J= 29.7, 6.6 Hz), 3.92 (3H, s), 3.85 (6H, s), 3.81 (3H, s), 3.42
S9

(
3H, s), 2.89-2.80 (1H, m), 2.70-2.2.62 (1H, m), 2.09-2.04 (2H, m).
1
3
C NMR (75 MHz, CDCl
29.7, 129.5, 129.1, 129.0, 105.2, 95.2, 74.1, 60.8, 56.1, 56.0, 52.3, 38.3, 32.5.
HRMS calculated for C22 (M+): 438.1445; Found: 438.1447.
3
, 293K, TMS): 166.3, 153.1, 140.5, 137.5, 137.3, 136.0,
1
H27ClO
7
HPLC: 97.4% ee; column: chiralcel AS-H; flow rate: 0.8 mL/min; eluant: 10%
iPrOH/hexane: (major) retention time: 10.033 min, 98.7 %; (minor) retention time:
1
1.38 min, 1.3%
2
2
[
α]
D
= +76.3 (c = 1, CH
2
Cl
2
)
-1
IR (vmax/cm ): 2950, 1725, 1590, 1242, 1025, 764.
(
R)-9,10,11-Trimethoxy-5-methoxymethoxy-6,7-dihydro-5H-dibenzo[a,c]
cyclo heptene-3-carboxylic acid methyl ester (16)
O
O
O
O
O
O
O
(
R)-Methyl
4-chloro-3-(1-(methoxymethoxy)-3-(3,4,5-trimethoxyphenyl)
propyl)benzoate (6) (87 mg, 0.20 mmol), potassium carbonate (57.8 mg, 0.40
mmol) 2-dicyclohexylphosphino-2’-(N,N-dimethylamino)biphenyl (19) (7.9 mg,
0.02 mmol) and palladium acetate (4.5 mg, 0.02 mmol) were placed in a flame
dried round bottom flask fitted with a condenser. The flask was purged with
argon for 10 min and DMA (3.3 mL) was added followed by heating at 145°C
overnight. DMA was then removed by short path distillation under vacuum and
the residual black precipitate was directly loaded on a silica gel column for
chromatography using 20% acetone/hexane to give colourless oil 16 as a 10:1
mixture of atropisomers (58 mg, 73%).
1
H NMR (300 MHz, CDCl , 293K, TMS) (Major atropisomer): 8.29 (1H, d, J= 1.2
3
Hz,), 8.01 (1H, dd, J= 8.1, 1.8 Hz), 7.54 (1H, d, J= 7.8 Hz), 6.60 (1H, s,), 4.71
(
(
1H, d, J= 6.9 Hz), 4.57 (1H, d, J= 6.6 Hz), 4.51 (1H, dd, J= 10.5, 7.2 Hz), 3.95
3H, s), 3.92 (6H, s), 3.63 (3H, s), 3.36 (3H, s), 2.63-2.39 (2.4H, m, mixture of
S10

atropisomers), 2.29-2.17 (1H, m,), 2.04-2.1.94 (1.1H, m).
Minor atropisomer): 7.93 (1H, dd, J= 1.5 Hz, minor), 7.62 (2H, d, J= 8.1 Hz),
.44 (1H, s), 4.85 (1H, d, J= 6.0 Hz,), 4.26-4.13 (2H, m), 3.85 (3H, s), 3.82 (2H,
s), 3.59 (3H, s,), 3.20 (3H, s).
(
6
1
3
C NMR (75 MHz, CDCl , 293K, TMS) (mixture of atropisomers): 167.3, 153.3,
3
153.0 (minor), 150.9, 141.0, 139.9, 138.7, 138.3 (minor), 136.1 (minor), 135.5,
132.2 (minor), 130.7 (minor), 129.5 (minor), 130.0, 128.7, 128.5 (minor), 127.6,
127.0 (minor), 124.7, 123.6 (minor), 107.7, 107.4 (minor), 105.2 (minor), 95.4,
95.0 (minor), 74.1, 61.1, 61.0, 60.9 (minor), 60.7 (minor), 56.0, 55.8 (minor), 55.6,
55.2 (minor), 52.1, 39.8, 38.4 (minor), 32.6 (minor), 30.2
HRMS calculated for C22
H
26
7
O (M+): 402.1679; Found: 402.1692.
HPLC: 96.8% ee; column: chiralcel AD-H; flow rate: 0.8 mL/min; eluant: 10%
iPrOH/hexane: (minor) retention time: 7.60 min, 1.6 %; (major) retention time:
1
0.75 min, 98.4 %
2
2
[
α]
D
= +162.4 (c = 1, CH
2
Cl
2
)
-1
IR (vmax/cm ): 2947, 1721, 1598, 1484, 1231, 1149, 1103, 1039, 648.
(
R)-1,2,3-Trimethoxy-7-methoxymethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclo
heptene (20)
O
O
O
O
O
(
R)-5-(3-(2-bromophenyl)-3-(methoxymethoxy)propyl)-1,2,3-trimethoxy
benzene (15) (257mg, 0.60 mmol), potassium carbonate (167 mg, 1.20 mmol) 2-
dicyclohexylphosphino-2’-(N,N-dimethylamino)biphenyl (19) (23.6 mg, 0.06 mmol)
and palladium acetate (13.5 mg, 0.06 mmol) were placed in a flame dried round
bottom flask fitted with a condenser. The flask was purged with argon for 10 min
and DMA (12.1 mL) was added. The solution was then heated at 145°C
overnight. After which the DMA was removed by short path distillation under
vacuum. The residual black precipitate was directly loaded on a silica gel column
for chromatography using 10% acetone/hexane to give colourless oil 20 as a
S11

1
5:1 mixture of atropisomers (143 mg, 69%).
1
H NMR (300 MHz, CDCl
3
, 293K, TMS) (major atropisomer): 7.60-7.58 (1H, m),
.47-7.44 (1H, m), 7.39-7.30 (2H, m), 6.58 (s, 1H), 4.62 (2H, dd, J= 29.7, 6.6 Hz),
.50 (2H, dd, J= 10.7, 7.1 Hz), 3.92 (3H, s), 3.91 (3H, s), 3.62 (3H, s), 3.35 (3H,
7
4
s), 2.60-2.39 (2.2H, m, mixture of atropisomers), 2.34-2.27 (1H, m), 1.99-1.95
(
(
1H, m).
Minor atropisomer): 7.39 (3H, m), 7.31 (1H, m), 6.44 (1H, s), 4.77 (2H, d, J= 6.3
Hz), 4.26 (1H, m), 3.89 (3H, s), 3.57 (3H, s), 3.21 (3H, s), 1.73-1.70 (2H, m).
1
3
C NMR (75 MHz, CDCl , 293K, TMS) (mixture of atropisomers): 152.7, 150.8,
3
141, 139.3, 135.5, 133.7, 132.0 (minor), 129.8, 127.1, 126.6 (minor), 126.4,
124.6, 123.1, 107.5, 95.3, 74.4, 61.1, 60.9, 60.6 (minor), 56.0, 55.8 (minor), 55.5,
55.2 (minor), 40.4 (minor), 40.0, 30.3.
HRMS calculated for C20
H
24
5
O (M+): 344.1624; Found: 344.1641.
HPLC: 98% ee; column:chiralcel AD-H; flow rate: 0.8 mL/min; eluant: 10%
iPrOH/hexane: (minor) retention time: 5.43 min, 1.0 %; (major) retention time:
5
.82 min 99.0 %
2
2
[
α]
D
= +132.4 (c = 1, CH
2
Cl
2
)
-1
IR (vmax/cm ): 2936, 1598, 1483, 1237, 1152, 2034.
(
R)-7-Hydroxy-1,2,3-trimethoxy-5,6-dihydro-5H-dibenzo[a,c]cycloheptene
-
1
0
9
-carboxylic acid methyl ester (21)
O
O
O
O
O
OH
To a solution of 16 (35 mg, 0.0.09 mmol) in methanol (1.7 mL) was added
.17 mL of concentrated hydrochloric acid. The resulting solution was refluxed
0
for 1h. Methanol was removed by rotary evaporator, DCM was added and the
solution was transferred into a separatory funnel. NaHCO was slowly added
3
and the organic layer was extracted three times with DCM. The organic layer
was dried over MgSO
4
, filtered and concentrated to give a white solid 21 as a
S12

1
1:1 mixture of atropisomers (29 mg, 94%).
1
H NMR (300 MHz, CDCl , 293K, TMS) (major atropisomer): 8.36 (1H, d, J=1.5
3
Hz), 8.01 (1H, dd, J= 8.1, 1.8 Hz), 7.54 (1H, d, J=8.1 Hz), 6.60 (1H, s), 4.65 (1H,
dd, J= 10.7, 7.4 Hz), 3.95 (3H, s), 3.92 (3.5 H, s, mixture of atropisomers), 3.91
(
(
(
(
3H, s), 2.62 (3H, s), 2.67-2.54 (1.2H, m, mixture of atropisomers), 2.49-2.39
1.2H, m, mixture of atropisomers), 2.33-2.22 (1H, m), 1.98-1.88 (1H, m), 1.77
1.10H, bs, mixture of atropisomers).
minor atropisomer): 8.04 (1H, d, J= 1.8 Hz), 7.90 (1H, d, J= 1.8 Hz), 7.63 (1H, d,
J= 8.4 Hz), 6.66 (1H, s), 4.86 (1H, d, J= 5.7 Hz), 3.85 (2H, s), 3.85 (1H, s), 2.60
3H, s),
(
1
3C NMR (75 MHz, CDCl
minor), 151.1 (minor), 150.9, 142.0, 141.5 (minor), 141.0, 140.0 (minor), 138.0,
37.4 (minor), 136.1 (minor), 135.7, 132.0 (minor), 130.0, 129.4 (minor), 129.1
minor), 128.7, 128.5 (minor), 127.6, 127.1 (minor), 124.0, 123.6, 107.9 (minor),
3
, 293K, TMS): 167.3, 167.0 (minor), 153.2, 153.1
(
1
(
1
5
07.5, 105.2 (minor), 70.1 (minor), 69.7, 61.2 (minor), 61.1, 61.0, 60.9 (minor),
6.0, 52.2 (minor), 52.1, 42.9 (minor), 41.3, 30.4, 29.7.
HRMS calculated for C20
H
22
6
O (M+): 358.1416; Found: 358.1404.
HPLC: 97.6 %ee; column: chiralcel AS-H; flow rate: 0.8 mL/min; eluant: 10%
iPrOH/hexane: (major) retention time: 18.52 min, 98.8 %; (minor) retention time:
2
0.03 min, 1.2 %.
2
2
[
α]
D
= +131.2 (c = 1, CH
2
Cl
2
)
-1
IR (vmax/cm ): 3481, 3938, 1720, 1292, 1231, 1097.
(
(
R)-7-Hydroxy-1,2,3-trimethoxy-5,6-dihydro-5H-dibenzo[a,c]cycloheptene
22)
O
O
OH
O
To a solution of 20 (109 mg, 0.316 mmol) in methanol (6.3 mL) was added
.63 mL of concentrated hydrochloric acid. The resulting solution was refluxed
0
for 1h. Methanol was removed by rotary evaporator, DCM was added and the
S13

solution was transferred into a separatory funnel. NaHCO
and the organic layer was extracted three times with DCM. The organic layer
was dried over MgSO , filtered and concentrated to give a white solid 22 as a
0:1 mixture of atropisomers (95 mg, 92%).
3
was slowly added
4
1
1
H NMR (300 MHz, CDCl
3
, 293K, TMS) (major atropisomer): 7.65 (1H, dd, J= 6.9,
1.5 Hz), 7.45 (1H, dd, J= 7.2, 1.8 Hz), 7.40-7.29 (2.3H, m, mixture of
atropisomers), 6.59 (1H, s), 4.61 (1H, dd, J= 10.7, 7.2 Hz), 3.90 (6.8H, s, mixture
of atropisomers), 3.60 (3H, s), 2.57-2.28 (3.8H, m, mixture of atropisomers), 2.09
(1H, bs), 1.94-1.84 (1.3H, s, mixture of atropisomers).
(Minor atropisomer): 7.53 (2H, dd, J= 7.5, 1.2 Hz), 7.19 (1H, dd, J= 7.4, 1.3 Hz),
6
.65 (1H, s), 4.75 (1H, d, J= 5.7), 3.83 (2H, s), 3.58 (3H, s), 2.16 (1H, s),
1
3
C NMR (75 MHz, CDCl
3
, 293K, TMS) (mixture of atropisomers): 152.7 (minor),
152.6, 151.1 (minor), 150.8, 141.6, 141.2 (minor), 141.2 (minor), 140.9, 136.1
(
(
minor), 135.6, 134.5 (minor), 132.9, 131.6 (minor), 129.7, 127.9 (minor), 127.4
minor), 127.2, 127.0 (minor), 126.3, 125.5 (minor), 124.5, 122.4, 107.8 (minor),
1
(
07.4, 75.2 (minor), 69.9, 61.2 (minor), 61.1, 60.9, 60.8 (minor), 56.0, 55.9
minor), 43.0 (minor), 41.4, 30.6 (minor), 30.5.
HRMS calculated for C18 (M+): 300.1362; Found: 300.1369.
H
20
O
4
HPLC: 98% ee; column: chiralcel OJ-H; flow rate: 0.8 mL/min; eluant: 10%
iPrOH/hexane: (minor) retention time: 12.72 min, 1.0 %; (major) retention time:
20.85 min, 99.0 %.
Melting point °C (ether): 140.6-141.9
2
2
[
α]
D
= +89.1 (c = 1, CH
2
Cl
2
)
-1
IR (vmax/cm ): 3439, 2935, 1598, 1453, 1234, 1095, 760.
(
S)-7-Deacetamido-7-azidoallocolchicine10
O
O
O
O
N3
O
S14

To a stirred solution of 21 (25 mg, 0.070 mmol) and triphenylphosphine
(
36.6 mg, 0.140 mmol) in anhydrous toluene (1.0 mL) under argon was added
1
1
Zn(N
3
) -2Py (16.0 mg, 0.052 mmol). Diisopropyl azadicarboxylate (28.2 mg, 27
2
µL, 0.140 mmol) was then added dropwise to the suspension. The suspension
was stirred at room temperature overnight. The solvent was then removed by
rotary evaporator, the residue was adsorbed onto silica gel for column
chromatography using 20 % acetone/hexane which gave colourless oil as a 8:1
mixture of atropisomers (23 mg, 86%). This compound exhibits spectral data
1
0
that is identical to that reported in the literature. .
1
H NMR (300 MHz, CDCl
.9 Hz), 8.04 (1H, dd, J= 4.8, 0.9 Hz), 7.56 (1H, d, J= 4.8 Hz), 6.61 (1H, s), 4.48
1H, dd, J= 6.9, 4.2 Hz), 3.96 (3H, s), 3.93 (3H, s), 3.92 (3.7H, s, mixture of
atropisomers), 3.66 (3H, s), 2.65-2.44 (2.6H, m, mixture of atropisomers), 2.33-
.23 (1.2H, m, mixture of atropisomers), 2.07-1.97 (1.2H, m, mixture of
3
, 293K, TMS ) (major atropisomer): 8.24 (1H, d, J =
3
0
(
2
atropisomers).
Minor atropisomer: 7.94-7.89 (2H, m), 7.70 (1H, d, J= 4.8 Hz), 6.59 (1H, s), 4.84
(
1H, d, J= 3.9 Hz), 3.95 (3H, s), 3.90 (2H, s), 3.62 (3H, s), 3.45 (2H, s).
HPLC: 93% ee; column: chiralcel AD-H; flow rate: 0.8 mL/min; eluant: 10%
iPrOH/hexane: (major) retention time 6.63 min, 96.5%; (minor) retention time:
7
.75 min, 3.5%.
2
2
[
α]
D
= -137.4 (c = 1, CH
2
Cl
2
)
-1
IR (vmax/cm ): 2936, 2101, 1598, 1455, 1237, 1112.
(
S)-7-Azido-1,2,3-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cycloheptene (23)
O
O
N3
O
To a stirred solution of 22 (80 mg, 0.266 mmol) and triphenylphosphine
(
139.7 mg, 0.533 mmol) in anhydrous toluene (1.6 mL) under argon was added
Zn(N
3
)
2
-2Py11 (61.2 mg, 0.200 mmol). Diisopropyl azadicarboxylate (107.7 mg,
103.2 µL, 0.533) was then added dropwise to the suspension. The suspension
S15

was stirred at room temperature overnight. The solvent was then removed by
rotary evaporator, the residue was adsorbed onto silica gel for column
chromatography using 10 % acetone/hexane which gave colourless oil 23 as a
5
:1 mixture of atropisomers. (65 mg, 76%).
1
H NMR (300 MHz, CDCl
3
, 293K, TMS) (major atropisomer):, 7.59-7.55 (1H, m),
.49-7.46 (1H, m), 7.42-7.30 (2H, m), 6.60 (1H, s), 4.46 (1H, dd, J= 11.3, 6.7 Hz),
.92 (6H, s,), 3.65 (3H, s), 2.61-2.44 (2.2H, m), 2.36-2.24 (1H, m), 2.04-1.96 (1H,
7
3
m).
(
(
Minor atropisomer): 7.81 (1H, d, J= 6.9 Hz), 7.61 (1H, d, J= 7.2 Hz), 7.34-7.30
2H, m), 6.58 (1H, s), 4.74 (1H, d, J= 6.6 Hz), 3.90 (3H, s), 3.90 (2H, s), 3.61 (2H,
s), 3.44 (2H, s), 3.08-3.01 (1H, m), 2.81-2.74 (1H, m)
1
3
C NMR (75 MHz, CDCl , 293K, TMS) (mixture of atropisomers): 152.9, 152.7
3
(minor), 152.2 (minor), 150.9, 141.1, 140.7 (minor), 140.4 (minor), 137.1, 136.5
(minor), 135.8 (minor), 134.8, 133.8, 132.3 (minor), 131.8 (minor), 130.1, 129.3
(minor), 128.9 (minor), 128.5(minor), 128.2(minor), 127.5, 126.9, 126.2 (minor),
1
(
24.9(minor), 126.5, 107.5, 105.6(minor), 65.2 (minor), 61.1, 61.0, 61.0, 60.6
minor), 56.0, 55.9 (minor), 39.0, 38.8 (minor), 33.4 (minor), 30.6 (minor), 30.4.
HRMS calculated for C18 (M+): 325.1426; Found: 325.1435.
H
19
N
3
O
3
HPLC: 96.2 % ee; column: chiralcel AS-H; flow rate: 0.8 mL/min; eluant: 10%
iPrOH/hexane: (minor) retention time: 6.55 min, 1.9 %; (major) retention time:
7
.38 min, 98.1 %.
2
2
[
α]
D
= -90.3 (c = 1, CH
2
Cl
2
)
-1
IR (vmax/cm ): 2936, 2101, 1598, 1454, 1237, 1112.
(
S)-7-amino-6,7-dihydro-1,2,3trimethoxy-7H-dibenzo[a,c]cycloheptene 12.
O
O
NH2
O
To a stirred solution of 23 (51 mg, 0.157 mmol) in dry THF (1.6 mL) under
argon was added a solution of LiAlH 1M in THF (0.24 mL, 0.235 mmol). The
4
resulting mixture was stirred at room temperature overnight. 5 ml of water was
then added dropwise followed by 5 mL of NaOH 10% followed by 5 mL of water.
S16

Ether was added and the aqueous phase was extracted. HCl 10 % was added to
the organic phase and the mixture was stirred for 15 min. It was then extracted
twice with ether. The organic layer was discarded and aqueous layer was
treated with 10 % aqueous NaOH solution until a pH 12 was reached. The
amine was extracted once with DCM and once with ether. The organic layers
were combined, dried over MgSO
4
, filtered and concentrated to give a solid as a
1
5:1 mixture of atropisomers (41 mg, 87%).
1
H NMR (300 MHz, CDCl , 293K, TMS) (major atropisomer):, 7.61 (1H, d, J= 7.2
3
Hz), 7.42 (1H, d, J= 7.2 Hz,), 7.40-7.30 (2.3H, m, mixture of atropisomers), 6.59
1H, s), 3.91 (6H, s), 3.62 (3H, s), 2.52-2.39 (2.2H, m, mixture of atropisomers),
.34-2.22 (1.2H, m, mixture of atropisomers), 1.87 (2H, bs), 1.79-1.69 (1.1H, m,
mixture of atropisomers).
Minor atropisomer): 7.74-7.70 (1H, m), 7.54-7.52 (2H, m), 6.65 (1H, s), 3.86-
(
2
(
3
.84 (6H, m), 2.17 (2H, s),
C NMR (75 MHz, CDCl , 293K, TMS): 152.6, 150.8, 142.5 (minor), 140.9,
1
3
3
135.9, 134.3, 131.8 (minor), 130.9 (minor), 129.9, 128.9 (minor), 128.3 (minor),
127.2, 126.7 (minor), 126.1, 124.9, 122.6, 107.8 (minor), 107.3, 68.1(minor), 61.1,
60.9, 60.6 (minor), 56.0, 50.8, 42.6, 31.2, 30.3 (minor), 28.9 (minor).
HRMS calculated for C18
H
21NO
3
(M+) 299.1521; Found: 299.1534.
): 91-93.5
Cl
IR (vmax/cm ): 3318, 2932, 1596, 1453, 1240, 1146, 1103.
Melting point °C (CHCl
3
2
2
[
α]
D
= -43.5 (c = 1, CH
2
2
)
-1
(
-)-(S)-7-acetamido-6,7-dihydro-1,2,3trimethoxy-7H-dibenzo[a,c]
12.
cycloheptene (3)
O
O
O
NHAc
To a stirred solution of (S)-7-amino-6,7-dihydro-1,2,3trimethoxy-7H-
dibenzo[a,c]cycloheptene (31 mg, 0.104 mmol) and DMAP (3 mg, 0.025 mmol) in
DCM (1.0 mL) under argon were added acetic anhydride (12.7 mg, 11.8 µL,
0.124 mmol) and triethylamine (21.0 mg, 28.9 µL, 0.207 mmol). After 36h of
S17

stirring at room temperature the mixture was quenched with water and extracted
twice with DCM. The organic layers were combined and washed with 10 %
aqueous HCl, dried over MgSO , filtered and concentrated. The residual solid
4
was purified by column chromatography on silica gel using 40% acetone/hexane
1
to give a white solid 3 as a 5:1 mixture of atropisomers (31.2 mg, 86%). H NMR
1
3
and C NMR in CDCl for the major atropisomer are identical are identical to that
3
1
2
report in the literature . The atropisomer ratio is known to be solvent dependant.
We were gratified to find that H NMR in (CD
1
3
2
) SO shows only one isomer
proving purity product.
1
H NMR (300 MHz, CDCl , 293K, TMS) (major atropisomer): 7.52-7.47 (1.5H, m,
3
mixture of atropisomers), 7.34-7.28 (3.4H, m, mixture of atropisomers), 6.57 (1H,
s), 5.99 (1H, bs), , 4.88-4.80 (1H, m), 3.93 (3.6H, s), 3.90 (3H, s), 3.51 (3H, s),
2
1
.51-2.37 (3.2H, m, mixture of atropisomers), 2.34-2.28 (1H, m), 2.04 (3H, s),
.86-1.82 (1H, m).
(Minor atropisomer): 7.38-7.34 (1H, m), 6.67 (1H, s), 6.62 (1H, s), 5.27 (1H, s),
5
.18-5.13 (1H, m), 3.94 (3H, s), 3.58 (3H, s), 3.55 (1H, s), 2.18 (3H, s),
1
H NMR (300 MHz, (CD
3
)
2
SO, 293K): 8.41 (d, J= 8.4 Hz, 1H), 7.34-7.30 (m, 4H),
.79 (s, 1H), 4.58-4.50 (m, 1H), 3.83 (s, 3H), 3.78 (s, 3), 3.48 (s, 2.6), 3.35 (s,
.2H), 2.27-1.97 (m, 2.2H), 1.87 (bs, 3.8H).
6
1
1
3
C NMR (75 MHz, CDCl , 293K, TMS) (mixture of atropisomers and rotameres):
3
169.3, 168.0 (minor), 153.0 (minor), 152.7, 151.2, 152.0 (minor), 141.4 (minor),
141.3, 139.1 (minor), 138.9, 138.7 (minor), 135.9, 134.8 (minor), 134.7, 134.4,
134.3 (minor), 134.0 (minor), 131.3, 130.4 (minor), 130.2, 129.0, 127.7 (minor),
127.5 (minor), 127.3 (minor), 127.2, 127.0 (minor), 126.5, 125.8 (minor), 124.9,
124.2 (minor), 122.9 (minor), 122.0, 107.9 (minor), 61.3, 61.2 (minor), 61.1, 60.8
(minor), 60.6 (minor), 56.1, 56.0 (minor), 53.3 (minor), 52.5, 49.2, 41.0 (minor),
4
2
0.4 (minor), 39.7, 30.8 (minor), 30.5, 30.4 (minor), 29.7 (minor), 29.3 (minor),
3.3.
HRMS calculated for C20
H
23NO (M+): 341.1627; Found: 341.1628.
4
HPLC: 96.2% ee; column: chiralcel OD-H; flow rate: 0.8 mL/min; eluant: 10%
iPrOH/hexane: (minor) retention time: 11.04 min, 1.9 %; (major) retention time:
13.88 min, 98.1 %.
Melting point °C (ether): 185.2-187.6
2
2
[
α]
D
= -25.4 (c = 1, CH
2
Cl
2
)
-1
IR (vmax/cm ): 3292, 2937, 1650, 1548, 1484, 1237, 1145, 1104.
S18

1
Lawrence, N.J.; Ghani, F.A.; Hepworth, L.A.; Hadfield, J.A.; McGown, A.T.; Pritchard,
R.G.; Synthesis, 1999, 9, 1656
2
Commercially available – CAS# 7454-66-7.
Commercially available – CAS# 21900-52-7.
Dubowchik, G. M.; Vrudhula, V. M.; Dasgupta, B.; Ditta, J.; Chen, T.; Sheriff, S.;
3
4
Sipman, K.; Witmer, M.; Tredup, J.; Vyas, D. M.; Verdoorn, T. A.; Bollini, S.; Vinitsky, A.;
Org. Lett., 2001, 3, 3987.
5
Cox, R.J; D J. Ritson, D.J.; Dane, T.A.; Berge, J.; Charmant, J.P.H.; Kantacha, A. ;
Chem. Commun., 2005, 8, 1037.
6
(
a) Tohda, Y; Sonogashira, K; Hagihara, N.; Synthesis, 1977, 11, 777. (b)Negishi, E.-I.;
Bagheri, V.; Chatterjee, S.; Luo, F.-T.; Miller, J.A.; Stoll, A.T; Tetrahedron Lett., 1983,
4
7, 5181. For recent review see Negishi, E.-I; Anastasia, L.; Chem Rev., 2003, 103,
1
979.
7
a) Midland, M.M.; McDowell, D.C.; Hatch, R.L; Tramontano, A.; J. Am. Chem. Soc.
980, 102, 867. (b) Midland, M.M; Tramontano, A.; kazubski, A; Graham, R.S.; Tsai,
1
D.J.S.; Cardin, D.B.; Tetrahedron, 1984, 40, 1371.
8
(
a) Evans, P.A.; Cui, J.; Gharpure, S.J.; Polosukhin, A.; Zhang, H.-R.; J. Am. Chem.
Soc., 2003, 125, 14702. (b) Hart, D. J.; Hong, W.-P.; Hsu, L.-Y.: J. Org. Chem., 1997,
6
2, 4665.
9
Adapted from (a) Ishiyama, T.; Kizaki, H.; Miyaura, N.; Suzuki, A.; Tetrahedron Lett.
993, 34, 7595. (b) Back, T. G.; Parvez, M.; Wulff, J. E.; J. Org. Chem., 2003, 68, 2223.
Vorogushin, A.V.; Predeus, A.V.; Wulff, W.D.; Hansen, H.J.; J. Org. Chem., 2003, 68,
826
1
1
0
5
11
Viaud, M.C.; Rollin, P.; Synthesis, 1990, 1990, 130.
1
2
Boyé, O., Brossi, A.; Can. J. Chem., 1992, 70, 1237.
S19

O
Br
O
O
Cl
O
9
8
7
6
5
4
3
2
1
0
S20

O
Br
O
O
Cl
O
180
170
160
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
S21

O
O
O
Br
O
9
8
7
6
5
4
3
2
1
0
S22

O
O
O
Br
O
180
170
160
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
S23

OH
Br
O
O
Cl
O
9
8
7
6
5
4
3
2
1
0
S24

OH
Br
O
O
Cl
O
170
160
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
S25

OH
O
O
Br
O
9
8
7
6
5
4
3
2
1
0
S26

OH
O
O
Br
O
180
170
160
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
S27

O
O
Br
O
O
Cl
O
9
8
7
6
5
4
3
2
1
0
S28

O
O
Br
O
O
Cl
O
180
170
160
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
S29

O
O
O
O
Br
O
9
8
7
6
5
4
3
2
1
0
S30