Improved and efficient synthesis of chiral N,P-ligands via cyclic sulfamidates for asymmetric addition of butyllithium to benzaldehyde

Article abstract of DOI:10.1021/ol701504c

A robust and scaleable route to chiral 1-isopropylamino-2- (diphenylphosphino)ethanes is described via the ring-opening of chiral, cyclic sulfamidates with potassium diphenylphosphide (KPPh₂). The novel protocol offers a robust access to gram q

Full text of DOI:10.1021/ol701504c

Supporting information
Improved and Efficient Synthesis of Chiral N,P-
Ligands via Cyclic Sulfamidates for Asymmetric
Addition of Butyllithium to Benzaldehyde
Petra Rönnholm, Mikael Södergren, Göran Hilmersson
Kemivägen 10, SE-412 96 Göteborg, Sweden
hilmers@chem.gu.se
Contents
1
2
4
. General Experimental
S2-S3
. Synthesis of chiral amines, experimental and spectroscopic data
. 1H and 13C NMR spectra
S4-S9
S10-S25
S1

Experimental
General
NMR spectra were recorded on a Varian 400 MHz spectrometer using CDCl as
3
solvent. Optical rotations were measured using Perkin-Elmer 324 LC polarimeter. IR
spectra were recorded on a Perkin-Elmer 1600 Series FTIR spectrometer. Melting
points points were determined using a Büchi Melting Point B-545 and are
uncorrected. GC analyses were carried out using a Varian Star 3400 CX gas
chromatograph equipped with a chiral stationary phase column (CP-Chirasil-DEX
CB, 25 m, 0.32 mm) from Chrompack. Analysis were done using H (1.5 ml /min) as
2
carrier gas (injector 225°C, detector 250°C). Dried solvents were distilled from
sodium/benzophenone. Column chromatography were performed with SiO -60 (40-
2
6
3 µm) from Fluka at ambient/atmospheric pressure. TLC were SiO -60 F254, Merck
2
and visualized by UV light at 254 nm and by staining with a solution of
H [P(Mo O ) ] · xH O (10 g) in 95% EtOH (100 mL). MS were recorded on a
3
3
10 4
2
Micromass LCTP using ESI+ as ionization mode and gradient of 5% ACN to 95%
ACN in 6 minutes in a buffered solution of 40 mM ammonia and 5 mM carbonate
(pH 10).
Glassware and syringes were dried at 150°C in a vacuum oven before transfer into a
glovebox (Braun equipped with a gas purification system that removes oxygen and
moisture) containing a nitrogen atmosphere. Typical moisture content was less than
1
.5 ppm. Ether solvents were distilled under nitrogen from sodium/benzophenone and
were kept over 4Å molecular sieves in septum sealed flasks inside the glove box.
General procedure for the addition of BuLi to benzaldehyde
BuLi (0.30 mmol, 120 µL, 2.5 M in hexanes) was added dropwise, over a period of 5
min, to a solution of the chiral aminophosphine (0.20 mmol, 4.0 eq.) in dry Et O/THF
2
1
:1 (2.0 mL) at –78 °C under N . After 15 minutes, the solution was cooled to –116
2
°
C, using an Et O/liquid nitrogen cooling bath, and after a further 15 minutes at this
2
temperature, a solution of benzaldehyde (1.0 M in hexane, containing n-decane as an
S2

internal standard, 50 µL, 0.05 mmol, 1.0 eq.) was added dropwise, during ca 5 min.
The mixture was allowed to react for another 15 minutes before methanol (1.0 mL)
was added to quench the remaining organolithum species. The resulting mixture was
allowed to warm up to room temperature and aqueous HCl (1M, 1.0 mL) and MTBE
(2.0 mL) were added, followed by rigorous stirring during 5 min. The stirring was
discontinued and an aliquot of the organic phase was diluted with MTBE and
analysed using chiral stationary phase gas chromatography.
S3

Syntheses of the chiral amines
(4R)-3-isopropyl-4-phenyl-1,2,3-oxothiazolidine S-oxide (4c)
CH2Cl2
Imidazole
SOCl2
Et3N
HN
OH
N
O
S
Chemical Formula: C11H17NO
Molecular Weight: 179,26
O
Chemical Formula: C11H15NO2S
Molecular Weight: 225,31
A solution of (R)-N-isopropyl-phenylglycinol (47.0 g, 0.26 mol), imidazole (72 g, 1.1
mmol), and Et N (73 mL, 0.52 mol) in dry CH Cl (800 mL) was cooled on an ice
3
2
2
bath. To the stirred yellow solution, SOCl (28 mL, 0.39 mol) was added dropwise
2
over ca 20 min, keeping the internal temperature below +10 °C. After complete
addition the ice bath was removed and the resulting mixture allowed to warm to rt
overnight, and then filtrated through a short pad of silica gel, washed with brine, dried
over MgSO , and concentrated to give 4c (58.0 g, 98% crude) as a yellowish oil,
4
which solidified upon standing. The crude product, which was used in the next step
1
without further purification, was judged >95% pure by H NMR and GC. If needed,
the mixture of sulfamidites can be purified, but not easily separated into the individual
diastereomers, using silica gel chromatography (silica, hexane / EtOAc 9:1 to 3:1).
Filtration and concentration in vacuo gave the crude product as a brown solid. NMR
of the crude product shows the desired sulfamidites as a mixture of two
diastereoisomers.
1
H NMR (CDCl ): ꢀ 1.16 (d J=6.6 Hz, 6H), 1.34 (d, J = 6.8 Hz, 3 H), ), 1.39 (d, J =
3
6
.8 Hz, 3 H), 3.3-3.4 (m, 1H), 4.2 (dd, J=3.8 Hz, 1H), 4.5-4.6 (m, 2H), 4.74 (dd,
J=3.8 Hz, 1H), 4.86 (dd, J=6.8 Hz, 1H), 5.07 (dd, J=7.8 Hz, 1H), 7.3-7.6 (m, 5H).
1
3
C NMR (CDCl ): δ 21.0, 21.9, 22.1, 23.0, 46.7, 48.2, 60.0, 65.9, 76.0, 127.9, 128.1,
3
1
28.5, 129.1, 137.1, 138.0.
(4S)-3-isopropyl-4-isopropyl-1,2,3-oxothiazolidine S-oxide (4a)
Using the procedure described for 4c, (S)-N-isopropylvalinol (28 g, 0.20 mol) gave
4
a as a 1:1 mixture of inseparable diastereoisomers (36.5 g, 97%), as a yellow oil,
which solidified upon standing. The crude product thus obtained was directly used in
the next step without further purification.
S4

1
H NMR (CDCl ): ꢀ 0.82 (d, J=6.9 Hz, 3H), 0.92 (d, J=7.0 Hz, 3H), 0.98 (d, J=6.8
3
Hz, 3H), 1.20 (d, J=6.9 Hz, 3H), 1.21 (d, J=6.6 Hz, 3H), 1.3 (d, J=6.6 Hz, 3H), 1.36
d, J=6.9 Hz, 3H), 1.47 (d, J=6.9 Hz, 3H), 3.25 (q, J=7.57 Hz, 1H), 3.38 (q, J=6.70
Hz, 1H), 3.52 (q, J=6.70 Hz, 1H), 3.68-3.74 (m, 1H), 4.24 (dd, J=8.80 Hz, 1H), 4.49
(
(dd, J=7.37 Hz, 1H), 4.57 (dd, J=8.42 Hz, 1H), 4.70 (dd, J=7.74 Hz, 1H).
13
C NMR (CDCl ): δ 15.02, 18.37, 19.62, 20.40, 21.07, 21.43, 22.26, 23.11, 28.64,
3
3
1.95, 46.86, 50.85, 60.41, 67.26, 69.60, 72.34.
(4S)-3-isopropyl-4-benzyl-1,2,3-oxothiazolidine S-oxide (4b)
Using the procedure described for 4c, (S)-N-isopropyl-phenylalaninol (6.5 g, 34
mmol) gave 4b s a 1:1 mixture of inseparable diastereoisomers (7.5 g, 87%), as a
brown oil, which solidified upon standing. The crude product thus obtained was
directly used in the next step without further purification.
(S)-phenylalanine cyclic sulfamidite, mixture of 1:1 epimers at sulfur:
1
H NMR (CDCl ): ꢀ 1.21 (d, J = 6.7 Hz, 3 H), 1.35 (d, J = 6.7 Hz, 6 H), 1.35 (d, J =
3
6
1
1
.7 Hz, 3 H), 2.56 (dd, J = 9.8, 13.5 Hz, 1 H), 2.91-3.04 (m, 2H), 3.23 (dd, J = 5.8,
3.5 Hz, 1 H), 3.46 (sept, J = 6.7 Hz, 1 H), 3.61 (sept, J = 6.7 Hz, 1 H), 3.69-3.79 (m,
H), 3.93-4.02 (m, 1 H), 4.16 (t, J = 4.0, 8.6 Hz, 1 H), 4.29-4.37 (m, 1H), 4.54-4.66
(m, 2H).
1
3
C NMR (CDCl ): δ 21.5, 22.0, 22.20, 22.7, 39.5, 40.7, 47.0, 48.5, 57.4, 61.5, 72.9,
3
7
5.6, 126.9, 127.1, 128.9, 129.2, 137.2, 138.0.
(4R)-3-isopropyl-4-phenyl-1,2,3-oxothiazolidine S,S-dioxide (5c)
RuCl3
H2O
N
O
NaIO4
wet silica gel
N
O
S
S
O
O O
Chemical Formula: C11H15NO2S
Molecular Weight: 225,31
Chemical Formula: C11H15NO S
3
Molecular Weight: 241,31
RuCl (0.7 mg, 0.15 mol%) was added to water (1.25 ml) yielding a black solution.
3
This solution was stirred at a brisk pace and small portions of NaIO (1.19 g, 5.55
4
mmol) were then added, the black solution immediately turned yellow (RuO ). Note
4
that only the amount of NaIO that dissolved was added. The RuO solution and the
4
4
remaining NaIO was added directly to silica gel (2.5 g) in a 100 ml round bottom
4
flask with a magnetic stirring bar. The rate of stirring was increased and the solid was
S5

stirred until a free flowing white solid was obtained. EtOAc (9 ml) was added to the
wet silica gel and put on an ice bath. The sulfamidite (500 mg, 2.22 mmol) was
dissolved in EtOAc (9 ml), a few drops of CH Cl was added to dissolve all of the
2
2
sulfamidite. The solution of the substrate was added dropwise to the slurry of silica
gel at 0 °C. After complete addition the ice bath was removed and stirred at a brisk
pace throughout the reaction. A white slurry is formed and stirred until TLC (silica,
hexane/EtOAc 3:1) indicated complete consumption of the starting material,
Typically this requires 10 min-2 h depending on sulfamidite. The slurry was filtrated
through a short pad of silica gel, dried over Na SO , filtrated and concentrated in
2
4
vacuo to give 5c (503.3 mg, 2.086, mmol 95% crude) as a colourless oil as crude
product, which solidifies upon standing. In most cases, the crude product was
essentially pure (>95% by NMR and GC) and used in the next step without further
purification. Occasionally, however, the crude product contains traces of the Ru
catalyst (brown to black). This may be removed by re-dissolving in hexane/EtOAc
(4:1) and filtering again through a silica plug (ca 5 cm), followed by evaporation.
1
H NMR (CDCl ): δ 1.13 (d, J=6.73 Hz 3H), 1.37 (d, J=6.89 Hz 3H), 3.7-3.6 (m, 1H),
3
4
.24-4.30 (dd, J=8.17, 8.17 Hz 1H), 4.64-4.70 (dd, J=15.52, 15.52 Hz, 1H), 4.80-4.86
(dd, J=7.33, 7.33 Hz, 1H), 7.39-7.47 (m, 5H).
1
3
C NMR (CDCl ): δ 19.82, 20.12, 49.09, 60.73, 72.49, 127.40, 129.44, 129.51,
3
1
36.90.
-1
νmax (neat): 2981, 2359, 1604, 1456, 1338, 1194 cm .
2
0
[
ꢀ] = -87.3° (c=1.00, CDCl
3
).
D
+
HRMS (FAB): MH , found 242.0856, C H NO S requires 242.0853.
11
16
3
(4S)-3-isopropyl-4-isopropyl-1,2,3-oxothiazolidine S,S-dioxide (5a)
Following the procedure described for 5c, sulfamidate 4a (2.00 g, 10.5 mmol) was
oxidized to give 5a (2.02 g, 93%) as a colourless oil.
1
H NMR (CDCl ): δ 0.97 (dd, J=7.38 Hz, 6H), 1.29 (d, J=6.83 Hz, 3H), 1.36 (d,
3
J=6.83 Hz, 3H), 2.03 (sext, 1H), 3.50 (sext, 1H), 3.70 (q, 1H), 4.25 (dd, J=8.82 Hz,
1
H), 4.40 (m, 1H).
1
3
C NMR (CDCl ): δ 16.49, 18.89, 19.64, 20.57, 30.87, 50.63, 61.44, 67.93.
3
-1
νmax (neat): 2969, 2359, 1718, 1469, 1338, 1196 cm .
2
0
[
ꢀ] = -12.11 (c=1.14, CDCl
).
3
D
S6

+
HRMS (FAB): MH , found 208.1011, C H NO S requires 208.1009.
8
18
3
(4S)-3-isopropyl-4-benzyl-1,2,3-oxothiazolidine S,S-dioxide (5b)
Following the procedure described for 5c, sulfamidate 4b (5.49 g, 28.76 mmol) was
oxidized to give 5b (6.39 g, 93%) as a colourless oil.
1
H NMR (CDCl ): δ 1.11 (d, J=6.79 Hz 3H), 1.32 (d, J=6.82 Hz 3H), 2.85-2.95 (m,
3
1
H), 3.10-3.20 (m, 1H), 3.68 (sext, J=6.8 Hz, 1H), 3.90-4.00 (m, 1H), 4.20-4.30 (m,
1
H), 4.20-4.35 (m, 1H), 7.20-7.45 (m, 5H).
1
3
C NMR (CDCl ): 19.28, 20.66, 39.75, 50.13, 57.36, 70.68, 127.20, 128.78, 129.38,
3
1
35.90
-1
νmax (neat): 2979, 2257, 1604, 1455, 1338, 1189 cm .
(R)-2-isopropylamino-2-phenyl-1-(diphenylphosphino)ethane (6c)
acidic silica gel
KPPh2
N
O
THF
N
S
PPh2
NH PPh2
S
O
O
O
O
Chemical Formula: C23H26NP
Molecular Weight: 347,43
O
Chemical Formula: C11H15NO3S
Molecular Weight: 241,31
Chemical Formula: C23H25NO3PS-
Molecular Weight: 426,49
To a solution of 5c (1.0 g, 4.14 mmol) in dry THF (5 mL) at -78 °C, a solution of
KPPh (0.5 M in THF, 8.7 mL, 4.35 mmol) was added dropwise, over 15 min, to give
2
a red solution. After complete additon the ice bath was removed and stirred for
another 5 min, when TLC (hexane/EtOAc/Et N, 10:1:0.1) indicated complete
3
disappearance of the starting material (5-45 min depending on the sulfamidate and
concentration in the reaction mixture). Acidic silica (2g silica and 0.8 mL 2 M aq.
H SO , evenly mixed to a white powder) was added portionwise until pH1. The
2
4
resulting white slurry was stirred at rt during 40 min, followed by the addition of
saturated aqueous NaHCO (35 mL). The mixture was filtered off and washed with
3
brine (2 x 10 mL). The combined aqueous layers were extracted with CH Cl (3 x 10
2
2
mL) and the combined organic layers were dried over Na SO and evaporated under
2
4
reduced pressure to give a white solid (1.75 g, 122% crude), which was purified by
column chromatography (hexane/EtOAc/Et N, 10:1:0.1) to yield 6c (1.17 g, 81%) as
3
a colourless oil, which solidified upon standing.
1
H NMR (CDCl ): δ 0.94 (t, J=5.52 Hz, 6H), 1.6 (bs, 1H), 2.44 (d, 2H, J=6.93 Hz),
3
2
.50-2.60 (m, 1H), 3.75-3.80 (q, J=7.13 Hz, 1H), 7.20-7.50 (m, 15H).
S7

1
3
C NMR (CDCl ): δ 22.0, 24.26, 38.99, 39.13, 45.87, 57.44, 57.59, 126.80, 126.98,
3
1
1
28.31, 128.38, 128.75, 132.47, 132.66, 133.06, 133.25, 138.05, 138.18, 138.77,
38.89, 145.15, 145.21.
3
1
P NMR (CDCl ): δ -22.30
3
-1
νmax (neat): 3314, 3055, 2960, 1952, 1883, 1811, 1585, 1477, 1433, 1378, 1169 cm .
20
[
ꢀ] = -60.12° (c=1.60, THF).
D
+
HRMS (FAB): MH , found 348.1883, C H NP requires 348.1912.
23
27
(S)-2-isopropylamino-3-metyl-1-(diphenylphosphino)butane (6a)
Using the procedure described for the synthesis of 6b, starting from 5a (0.79 g, 3.83
mmol) was phosphinated to yield 6a (0.55 g, 46% yield) as a colourless syrup.
1
H NMR (CDCl ): δ 0.83 (d, J=6.86 Hz, 3H, 0.89 (d, J=6.86 Hz, 3H), 0.93 (t, J
3
=6.86 Hz, 6H), 1.94–2.05 (m, 2H), 2.23 (m, 1H), 2.48 (m, 1H), J=4.26 Hz), 2.77 (m,
1
H), 7.35-7.50 (m, 10H).
1
3
C NMR (CDCl ): δ 17.20, 18.13, 23.11, 23.73, 30.52, 30.60, 30.86, 30.99, 45.96,
3
5
1
6.85, 56.97, 128.22, 128.29, 128.35, 128.63, 132.43, 132.61, 133.06, 133.25, 138.45,
38.48, 139.50, 139.63.
3
1
P NMR (CDCl ): δ -21.68
3
-1
νmax (neat): 3314, 3053, 2957, 1952, 1883, 1810, 1585, 1477, 1434, 1377, 1169 cm .
20
[
ꢀ] = +37.04° (c =1.73, THF).
D
+
HRMS (FAB): MH , found 314.2015, C H NP requires 314.2039.
20
29
(
S)-2-isopropylamino-3-phenyl-1-(diphenylphosphino)propane (6b)
Using the procedure described for the phosphination of 6c, sulfamidate 5b (0.79 g,
.83 mmol) was converted into 6b (1.10 g, 4.3 mmol, 80% yield) as a viscous,
3
colourless oil.
1
H NMR (CDCl ): δ 0.86 (d, J=6.27 Hz, 3H), 0.91 (d, J=6.27 Hz, 3H), 1.1-1.2 (bs,
3
1
H), 2.11 (t, J=6.6 Hz, 1H), 2.23 (m, 1H), 2.76-2.92 (m, 4H).
1
3
C NMR (CDCl ): δ 22.76, 23.97, 33.58, 34.29, 42.30, 42.40, 45.94, 52.19, 52.22,
3
1
1
26.54, 128.80, 129.78, 130.65, 130.75, 130.95, 131.04, 131.78, 132.50, 133.47,
33.70, 134.68, 138.79.
3
1
P NMR (CDCl ): δ -22.97
3
S8

-1
νmax (neat): 3314, 3056, 2960, 1951, 1882, 1810, 1585, 1478, 1434, 1377, 1171 cm .
20
[
ꢀ] = +25.74° (c=2.02, THF).
D
+
HRMS (FAB): MH , found 362.2043, C H NP requires 362.2039.
24
29
S9

1
H NMR (4R)-3-isopropyl-4-phenyl-1,2,3-oxothiazolidine S-oxide (4c)
S10

1
3
C NMR (4R)-3-isopropyl-4-phenyl-1,2,3-oxothiazolidine S-oxide (4c)
S11

1
H NMR (4S)-3-isopropyl-4-isopropyl-1,2,3-oxothiazolidine S-oxide (4a)
S12

1
3
C NMR (4S)-3-isopropyl-4-isopropyl-1,2,3-oxothiazolidine S-oxide (4a)
S13

1
H NMR (4S)-3-isopropyl-4-phenyl-1,2,3-oxothiazolidine S,S-dioxide (5c)
S14

1
3
C NMR (4S)-3-isopropyl-4-phenyl-1,2,3-oxothiazolidine S,S-dioxide (5c)
S15

1
H NMR (4S)-3-isopropyl-4-isopropyl-1,2,3-oxothiazolidine S,S-dioxide (5a)
S16

1
3
C NMR (4S)-3-isopropyl-4-isopropyl-1,2,3-oxothiazolidine S,S-dioxide (5a)
S17

1
H NMR (4S)-3-isopropyl-4-benzyl-1,2,3-oxothiazolidine S,S-dioxide (5b)
S18

1
3
C NMR (4S)-3-isopropyl-4-benzyl-1,2,3-oxothiazolidine S,S-dioxide (5b)
S19

1
H NMR (R)-1-isopropylamino-1-phenyl-2-(diphenylphosphino)ethane (6c)
S20

1
3
C NMR (R)-1-isopropylamino-1-phenyl-2-(diphenylphosphino)ethane (6c)
S21

1
H NMR (S)-2-isopropylamino-3-metyl-1-(diphenylphosphino)butane (6a)
S22

1
3
C NMR (S)-2-isopropylamino-3-metyl-1-diphenylphosphinobutane (6a)
S23

1
H NMR (S)-2-isopropylamino-2-phenyl-1-(diphenylphosphino)ethane (6b)
S24

1
3
C NMR (S)-2-isopropylamino-2-phenyl-1-(diphenylphosphino)ethane (6b)
S25