The importance of 1,2-anti-disubstitution in monotosylated diamine ligands for ruthenium(II)-catalysed asymmetric transfer hydrogenation

Article abstract of DOI:10.1016/j.tetasy.2004.05.025

The synthesis and applications to transfer hydrogenation of three derivatives of the popular TsDPEN are described. The results clearly demonstrate the importance of both disubstitution and the anti arrangement of substituents on this ligand. An explanatio

Full text of DOI:10.1016/j.tetasy.2004.05.025

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15(2004) 2079–2084
The importance of 1,2-anti-disubstitution in monotosylated diamine
ligands for ruthenium(II)-catalysed asymmetric transfer
hydrogenation
Aidan Hayes, Guy Clarkson and Martin Wills*
Department of Chemistry, The University of Warwick, Coventry CV4 7AL, UK
Received 18 May 2004; accepted 25May 2004
Available online
Abstract—The synthesis and applications to transfer hydrogenation of three derivatives of the popular TsDPEN are described. The
results clearly demonstrate the importance of both disubstitution and the anti arrangement of substituents on this ligand. An
explanation for the significance of these results is forwarded.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Table 1
1. Introduction
Ligand
Yield, %
Ee, %
R/S
Ref.
The asymmetric transfer hydrogenation of ketones has
been the subject of intense international research work
in recent years.1 This has been primarily due to the
discovery, by Noyori et al., of highly active catalysts
derived from ruthenium (II) complexes of b-amino
alcohols such as (1R,2S)-1,2-diphenyl-2-(N-methyl-
amino)-ethan-1-ol 12 and monotosylated 1,2-diamines
such as TsDPEN 2 (Scheme 1, Table 1).3
1
2
3
4
5
97
95a
70
90
97
56
97
91
94
42
S
S
S
S
S
2
3a
4a
5a
2
a Mesitylene complex used.
aminoindanol 34 and the 2-azanorbornyl derivative 4.5
When the diastereoisomer of ephedrine 1, that is, 5, is
employed as a ligand in the reduction, the resulting
alcohol product configuration is unchanged. This sug-
gests that the a-stereogenic centre is the predominant
one in controlling the absolute reduction stereochemis-
try.
Ph
Ph
OH
Ph
Ph
NH2
Ph
Ph
OH
OH
NH
OH
NH2
NHTs
NH2
NH2
4
2
5
1
3
In the case of b-aminoalcohols, several diverse types of
ligand4–6 have been successfully employed, including cis-
For b-aminoalcohol ligands, it has been proposed that
the reduction proceeds via the diastereoselective for-
mation of ruthenium hydride 6, from which hydrogen is
transferred to the ketone through the six membered
transition state illustrated in Figure 1. The resulting
OH
O
H
ligand 1-5
Ph
Ph
*
[Ru(p-cymene)Cl2]2
iPrOH, NaOH or iPrOK
Ru
Ru
Scheme 1.
Ru
H
H
H
O
O
O
Ph
Me
Ph
Me
H
N
NH
N
H
O CH3
Ph
H
6
7
Me
* Corresponding author. Tel.: +44-24-7652-3260; fax: +44-24-7652-
4112; e-mail: m.wills@warwick.ac.uk
Figure 1.
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.05.025

2080
A. Hayes et al. / Tetrahedron: Asymmetry 15 (2004) 2079–2084
‘16-electron’ species 7 is subsequently converted back
into 6 by hydrogen transfer (from isopropanol or formic
acid) through an analogous transition state.2b;5b
In the case of monotosylated 1,2-diamines, there are
very few examples in the literature, other than the
diaminocyclohexyl derivative 8,7 of effective ligands,
which deviate significantly in structure from TsDPEN 2.
However, there are a number of examples of ligands,
which bear alternative alkyl- or arylsulfonyl groups, and
functionalised aryl rings.8
We wished to investigate whether the anti orientation,
and the 1,2-disubstitution pattern of phenyl groups in
TsDPEN were critical to its effectiveness as a ligand in
asymmetric transfer hydrogenation. We were also
interested in determining which stereogenic centre in 2
was primarily responsible for the overall sense of
asymmetric induction during ketone reduction. Towards
this end we decided to prepare compounds 9–11 which
contain, respectively, a deleted phenyl group relative to
TsDPEN 2, and a syn-orientation between the phenyl
groups. To our knowledge, these ligands have not been
reported as ligands for the title application.
Figure 2. X-ray crystallographic structure of 9.
The synthesis of ligands 9 and 10 was completed by
reduction of the azide to amine using catalytic hydro-
genation. At this point the isomers could be separated
by flash chromatography on silica gel. In order to fully
confirm both the regiochemistry and absolute stereo-
chemistry of the products of this reaction, an X-ray
crystallographic structural analysis of 9 was completed
(Fig. 2). To confirm that no racemisation had taken
place during formation of 13 from 12 (i.e., no SN1
opening of intermediate 15) racemic 9 was synthesised
via the same route outlined in Scheme 2 using racemic
phenylglycinol. Subsequent HPLC analysis of 9 gave an
ee of 100%.
NH2
Ph
NH2
NH2
Ph
Ph
NH2
NHTs
NHTs
Ph
NHTs
NHTs
9
10
11
8
2. Results and discussion
Ligand 11 was prepared from amino alcohol 16 by the
route illustrated in Scheme 3, which was based on a
precedent in the patent literature.10 Tosylation of 16 to
give 17 was followed by mesylation to give 18. The
reaction of 18 with sodium azide resulted in formation
of 19, in excellent yield and with full diastereocontrol.
This reaction presumably proceeds via a C2-symmetric
aziridine, thus eliminating the requirement for regio-
selective ring opening. Reduction of 19 to 11 was
achieved using catalytic hydrogenation.
The approach that we designed for the synthesis of li-
gands 9 and 10 is outlined in Scheme 2. Tosylation of
commercially available (R)-phenylglycinol gave 12,9
which was converted to a 3:1 mixture of inseparable
isomers 13 and 14 upon reaction with sodium azide in
DMF. Whilst 14 may be produced by direct displace-
ment of the OTs group, the formation of 13 requires the
reaction to proceed via the formation of aziridine 15.
Attack of azide at the 1-position of the aziridine would
then be expected to take place with inversion of con-
figuration. Also, 15 was isolated as the major product
when R-phenylglycinol was tosylated in the presence of
triethylamine with no formation of 12 observed.
With ligands 9–11 in hand, we examined their applica-
tion to the asymmetric transfer hydrogenation of ace-
Ph
Ph
OH
Ph
Ph
OH
TsCl, NEt3
Ph
NH2
OH
2 equiv. TsCl
Ph
NHTs
NaN
DMF
3
CH2Cl2
94%
NH2
NHTs
Pyridine
59%
16
17
OTs
89%
12
N3
Ph
N3
Ph
OMs
H2/Pd/C
EtOH
NaN3
MsCl, NEt3
CH2Cl2
44%
+
DMF,
80%
NHTs
Ph
NHTs
Ph
NHTs
13:14 = 3:1
14
NH2
NHTs
18
13
Ph
NH2
R
Ph
Ph
NH2
NHTs
Ph
Ph
N3
H2/Pd/C
Ph
+
NHTs
NHTs
Ph
MeOH
86%
NHTs
S
(S)-9
(R)-10
87% wrt 14
15
19
(1S,2R)-11
81% wrt 13
Scheme 2.
Scheme 3.

A. Hayes et al. / Tetrahedron: Asymmetry 15 (2004) 2079–2084
2081
ꢀ
out routinely using 60 A silica gel (Merck). Reagents
were used as received from commercial sources unless
otherwise stated. NMR spectra were recorded on a
Bruker DPX (300 or 400 MHz) spectrometer. Chemical
shifts are reported in d units, parts per million downfield
from TMS. Coupling constants (J) are measured in
hertz. IR spectra were recorded on a Perkin–Elmer
Spectrum One FT-IR Golden Gate. Mass spectra were
recorded on a 7070E VG mass spectrometer. Melting
points were recorded on a Stuart Scientific SMP 1
instrument and are uncorrected. Optical rotations were
measured with an AA1000 polarimeter and are given
in 10ꢀ1 deg cm2 gꢀ1. Determination of enantiomeric
excesses by HPLC analysis was achieved using a Merck-
Hitachi L-6200A HPLC pump, Merck-Hitachi L-4000
UV absorbance detector, Axiomm 727 data module and
a Daicel Chiralcel OD 4.6 · 25cm column.
ligand 2, 9-11
HO
H OH
H
O
+
[Ru(p-cymene)Cl2]2
HCO2H.Et3N 5:2
Ph
Ph
Ph
R
S
Scheme 4.
Table 2
Ligand
Time
Conv., %
100
9569
Ee, %
98
R/S
(R,R)-2
(S)-9
(R)-10
22 h
48 h
R
S
R
S
13 day
220 h
46
32
33
70
(1S,2R)-11
tophenone (Scheme 4, Table 2). Since the new ligands
were all monotosylated diamines, the reduction was
carried out in a formic acid/triethylamine azeotrope,
which is known to give superior results and avoids
the problem of reaction reversibility. b-Aminoalcohol
ligands are not compatible with these conditions. Ligand
(R,R)-2 was also tested in order to provide a baseline for
comparison.
3.1. Representative procedure for test reduction of
acetophenone
A mixture of (p-cymene)ruthenium(II)chloride dimer
(7.7 mg, 0.0125mmol) and ( R,R)-TsDPEN 2 (9.2 mg,
0.0250 mmol) in formic acid/triethylamine 5:2 azeotrope
(2.5mL) was stirred in a flame dried Schlenk tube at
28 ꢁC for 30 min. Acetophenone (0.600 g, 5.00 mmol)
was added and the reaction mixture was stirred at 28 ꢁC,
following by TLC. After 22 h, the reaction mixture was
filtered (silica washed with ethyl acetate) and concen-
trated under vacuum to give the crude product. The
residue was purified by flash chromatography (5%
EtOAc/hexane to 10% EtOAc/hexane) to give
R-phenylethanol4a (0.586 g, 96%) as a clear liquid; 98%
ee (R) by HPLC [Chiralcel OD, 5% ethanol/hexane
(1.0 mL minꢀ1), R isomer 8.3 min, S-isomer 9.6 min];
The results obtained have an interesting and unexpected
pattern. Both centres direct reduction in the same sense.
With cis-11 the centres are mismatched, but the domi-
nant centre is the S centre adjacent to the NHTs group.
This is surprising because 9 gave a higher ee than 10,
suggesting that the a-NH2 centre in 11 would be
expected to be dominant. Also, the ee obtained using 11
was higher than that with either 9 or 10. Ligands 10 and
11 also induced much lower rate accelerations in the
reactions than either 2 or 9. It is clear that both sub-
stituents in monotosylated diamine ligands are required
to be present for optimal results in terms of both rate
and ee. In analogy with the b-aminoalcohol ligands, the
principal directing effect comes from the absolute con-
figuration of the stereogenic centre most distant from
the basic amine. However it is clear from the results that
the substituents on the stereogenic centre adjacent to
basic amine also contribute a vital directing role to the
reaction, possibly through a steric repulsion effect, or
possibly a p-attractive interaction with the substrate.
½aŠ ¼ þ49 (c 1.0, CHCl3); dH (300 MHz; CDCl3; Me4Si)
D
1.47 (3H, d, J 6.4, CH3), 2.04 (1H, br s, OH), 4.86 (1H,
q, J 6.4, PhCHCH3), 7.33–7.35(H5, m, Ph); dC
(75.5 MHz; CDCl3; Me4Si) 24.9 (q), 70.2 (d), 125.2
(2·d), 127.2 (d), 128.3 (2·d), 145.6 (s).
3.2. Synthesis of toluene-4-sulfonic acid (R)-2-phenyl-2-
(toluene-4-sulfonylamino)-ethyl ester 129
In conclusion, 2 is an ideal ligand for ruthenium-cata-
lysed transfer hydrogenation because (a) the stereogenic
centres are matched and (b) the trans orientation pro-
vides an extra element of overall stereocontrol and rate
enhancement.
To a stirred solution of R-phenyl glycinol (0.463 g,
3.38 mmol) in pyridine (6 mL) at 0 ꢁC was added para-
toluene sulfonyl chloride (1.415g, 7.42 mmol). The
reaction mixture was stirred overnight and then the
resulting dark brown solution was diluted with water
(20 mL), extracted with diethyl ether (5 · 10 mL),
washed with satd NaHCO3 solution (10 mL) and satd
NaCl solution (10 mL), dried (MgSO4), filtered and
concentrated under vacuum to give the crude product.
The residue was purified by flash chromatography (5%
EtOAc/hexane to 25% EtOAc/hexane) to give 12
3. Experimental section
All reactions, unless otherwise stated, were run under an
atmosphere of nitrogen at ambient temperature (18–
22 ꢁC). A temperature of 0 ꢁC refers to an ice slush bath.
Heated experiments were conducted using thermostati-
cally controlled oil baths. Reactions were monitored by
TLC using aluminium backed silica gel 60 (F254) plates,
visualised using UV 254 nm and phosphomolybdic acid,
ninhydrin, potassium permanganate or vanillin dips as
appropriate. Flash column chromatography was carried
(0.886 g, 59%) as a white solid; mp 114.0–114.5 ꢁC;
24
½aŠ ¼ ꢀ26:3 (c 1.60, CHCl3); dH (300 MHz; CDCl3;
D
Me4Si) 2.39 (3H, s, OTs-CH3), 2.44 (3H, s, NTs-CH3),
4.14 (2H, ABX system, J 16.0, 6.0 and 6.0, CHaHbOTs),
4.53 (1H, q, J 6.0, CHPhNHTs), 5.09 (1H, d, J 6.0,
NH), 7.02–7.26 (7H, m, ArH o to CH3 on NTs and Ph),

2082
A. Hayes et al. / Tetrahedron: Asymmetry 15 (2004) 2079–2084
7.29 (2H, d, J 8.2, ArH o to CH3 on NTs), 7.58 (2H, d, J
8.2, ArH o to SO2 on OTs), 7.64 (2H, d, J 8.2, ArH o to
SO2 on NTs); dC (100.6 MHz; CDCl3; Me4Si) 21.9 (q),
22.1 (q), 56.8 (d), 71.6 (t), 127.3 (2·d), 127.6 (2·d), 128.3
(2·d), 128.7 (d), 129.1 (2·d), 129.9 (2·d), 130.3 (2·d),
132.6 (s), 136.4 (s), 137.3 (s), 143.9 (s), 145.6 (s).
MeOH/DCM to 6% MeOH/DCM) giving first 9
(0.175g, 81% wrt amount of starting material containing
appropriate azide regioisomer) as a white solid (Found:
C, 61.65; H, 6.2; N, 9.45. C15H18N2O2S requires: C, 62.0;
H, 6.25; N, 9.65); mp 97–98 ꢁC; 100% ee (S) by HPLC
(Chiralcel OD, 10% ethanol/hexane (1.0 mL minꢀ1),
20
D
S-isomer 14.7 min, (R)-isomer 16.9 min); ½aŠ ¼ þ85( c
1.50, CHCl3); mmax/cmꢀ1 (solid) 3400 (NH), 3338 and
3.3. Synthesis of N-((S)-2-azido-2-phenyl-ethyl)-4-
methyl-benzenesulfonamide 13 and N-((R)-2-azido-1-
phenyl-ethyl)-4-methyl-benzenesulfonamide 14
3286 (NH2), 1598 (NH2), 1315and 1149 (SO N), 750
2
and 700 (Ph); dH (400 MHz; CDCl3; Me4Si) 1.35–2.08
(2H, br s, NH2), 2.42 (3H, s, NTs-CH3), 2.95(1H, ABX
system, J 12.7, 8.5and 2.5CH aHbNHTs), 3.15(1H,
ABX system, J 12.7, 5.0 and 2.5 CHaHbNHTs), 3.97
(1H, m, CHPhNH2), 7.20 (2H, d, J 8.1, ArH o to CH3
on NTs), 7.24–7.32 (5H, m, Ph), 7.71 (2H, d, J 8.1, ArH
o to SO2 on NTs); dC (100.6 MHz; CDCl3; Me4Si) 21.9
(q), 50.7 (t), 55.5 (d), 126.6 (2·d), 127.5(2 ·d), 128.2 (d),
129.2 (2·d), 130.1 (2·d), 137.3 (s), 143.0 (s), 143.8(s).
Found (EI): 291.1179 [M]þ, C15H18N2O2S requires
291.1167 (4.2 ppm error); m=z (EI) 291(Mþ, 5%), 155 (5),
106 (100), 91 (15), 79 (15), 69 (5). NH not observed in 1H
NMR.
Compound 12 (0.780 g, 1.75mmol) and sodium azide
(0.171 g, 2.63 mmol) were stirred in DMF (22 mL) at
85 ꢁC for 2.5h. The reaction mixture was cooled to room
temperature, diluted with water (22 mL) and extracted
with diethyl ether (5 · 15mL). The combined extracts
were washed with water (2 · 20 mL), saturated sodium
chloride solution (1 · 20 mL), dried (MgSO4), filtered
and concentrated under vacuum to give 13 and 14
(0.492 g, 89%) as an inseparable oil mixture in the ratio
1
13/14 ¼ 3:1 from H NMR; mmax/cmꢀ1 (thin film) 3286
(NH), 2100 (N3), 1319 and 1154 (SO2N), 812 (p-subst.
Ph), 751 and 699 (Ph); dH (400 MHz; CDCl3; Me4Si)
2.39 (minor isomer, 3H, s, CH3), 2.43 (major isomer,
3H, s, CH3), 3.08 (major isomer, 1H, ABX system, J
13.6, 5.0 and 4.0, CHCHaHbNH), 3.23 (major isomer,
1H, ABX system, J 13.6, 5.0 and 3.0, CHCHaHbNH),
3.57 (minor isomer, 2H, d, J 5.5, CH2CHNH), 4.46
(minor isomer, 1H, dt, J 6.0 and 5.5, CH2CHNH), 4.59
(major isomer, 1H, dd, J 9.0 and 5.0, CH2CH3), 4.75
(major isomer, 1H, br t, J 5.5, CH2NHSO2), 5.10 (minor
isomer, 1H, br d, J 6.0, CH2CHNH), 7.09–7.40 (both
isomers, 7H, m, Ph and ArH o to CH3), 7.62 (minor
isomer, 2H, d, J 8.5, ArH o to SO2), 7.73 (major isomer,
2H, d, J 7.7, ArH o to SO2); dC (100.6 MHz; CDCl3;
Me4Si) 21.9 (major isomer+minor isomer, 2·overlap-
ping q), 48.5(major isomer, t), 56.4 (minor isomer, t),
57.5 (minor isomer, d), 65.8 (major isomer, d), 127.2
(minor isomer, 2·d), 127.4 (major isomer, 2·overlap-
ping 2·d), 127.5(minor isomer, 2 ·d), 128.6 (minor
isomer, d), 129.1 (minor isomer, 2·d), 129.4 (major
isomer, d), 129.5(major isomer, 2 ·d), 129.9 (minor
isomer, 2·d), 130.3 (major isomer, 2·d), 136.7 (major
isomer, s), 137.3 (major isomer, s), 137.5(minor isomer,
s), 138.0 (minor isomer, s), 143.9 (minor isomer, s),
144.2 (major isomer, s). Found (EI): 317.1070 [MH]þ,
C15H17N4O2S requires 317.1072 (0.8 ppm error); m=z
(CI) 317 (MHþ, 5%), 274 (35), 260 (60), 184 (65), 155
(95), 106 (70), 91(100).
An X-ray crystal structure of 9 was undertaken.
C15H18N2O2S, M ¼ 290:37, orthorhombic, space
group P212121, a ¼ 5:6168ð12Þ, b ¼ 12:340ð2Þ, c ¼
3
ꢀ
ꢀ
21:000ð3Þ A, U ¼ 1455:5ð4Þ A (by least squares refine-
ment on 2442 reflection positions), T ¼ 180ð2Þ K,
F ð000Þ ¼ 616. l(MoK-a) ¼ 0.225mm ꢀ1. Crystal char-
ꢀ
k ¼ 0:71073 A,
Z ¼ 4,
DðcalÞ ¼ 1:325Mg m ꢀ3
,
acter:
colourless
block.
Crystal
dimensions
0.24 · 0.08 · 0.08 mm. The full data has been deposited
at the Cambridge Crystallographic Data Centre and
allocated the deposition number CCDC 235426.
Further elution gave 10 (0.066 g, 87% wrt amount of
starting material containing appropriate azide regio-
isomer) as a white solid (Found: C, 61.8; H, 6.25; N,
9.55. C15H18N2O2S requires: C, 62.0; H, 6.25; N, 9.65);
20
D
mp 109–110 ꢁC; ½aŠ ¼ ꢀ62 (c 0.85, CHCl3); mmax/cmꢀ1
(solid) 3408 (NH), 3343 and 3288 (NH2), 1602 (NH2),
1308 and 1149 (SO2N), 748 and 699 (Ph); dH (400 MHz;
CDCl3; Me4Si) 1.28–1.60 (2H, br s, NH2), 2.37 (3H, s,
NTs-CH3), 2.89 (2H, m, CHaHbNH2), 4.25(1H, t, J 6.0,
CHPhNHTs), 7.09 (2H, d, J 7.8, ArH o to CH3 on
NTs), 7.14–7.23 (5H, m, Ph), 7.58 (2H, d, J 7.8, ArH o
to SO2 on NTs); dC (100.6 MHz; CDCl3; Me4Si) 21.9
(q), 47.9 (t), 59.7 (d), 127.1 (2·d), 127.5(2 ·d), 127.9 (d),
128.8 (2·d), 130.1 (2·d), 137.8 (s), 139.4 (s), 143.5(s).
Found (EI): 291.1156 [M]þ, C15H18N2O2S requires
291.1167 (3.8 ppm error); m=z (EI) 291(Mþ, 10%), 260
(25), 155 (25), 106 (100), 91 (55). NH not observed in 1H
NMR.
3.4. Synthesis of N-((S)-2-amino-2-phenyl-ethyl)-4-meth-
yl-benzenesulfonamide 9 and N-((R)-2-amino-1-phenyl-
ethyl)-4-methyl-benzenesulfonamide 10
3.5. Synthesis of N-((1S,2R)-2-hydroxy-1,2-diphenyl-
ethyl)-4-methyl-benzenesulfonamide 17
To a stirred solution of 13 and 14 (0.316 g, 1.0 mmol) in
ethanol (15mL) was added 10% palladium on charcoal
(0.032 g). The reaction vessel was evacuated, filled with
H2 from a balloon and stirred overnight. The reaction
vessel was purged with N2, filtered (Celite) and con-
centrated under vacuum to give the crude products. The
residue was purified by flash chromatography (2%
To a solution of (1R,2S)-2-aminodiphenylethanol 16
(0.808 g, 3.79 mmol) and triethylamine (0.574 g,
5.69 mmol) in dichloromethane (15 mL) was added a
solution of para-toluene sulfonyl chloride (0.903 g,
4.74 mmol) in dichloromethane (5mL) and the reactants

A. Hayes et al. / Tetrahedron: Asymmetry 15 (2004) 2079–2084
2083
were stirred overnight. The solvent was removed from
the resulting precipitate under vacuum and the crude
solid was suspended in water (20 mL), filtered and
washed with water (2 · 20 mL) and dichloromethane
751 and 703 (Ph); dH (400 MHz; acetone-d6) 2.33 (3H, s,
NTs-CH3), 4.66 (1H, dd, J 7.5and 6.0, PhC HNH), 5.02
(1H, d, J 7.5, PhCH3), 7.11–7.32 (13H, m, 2·Ph, ArH o
to CH3 on NTs and NH), 7.43 (2H, d, J 8.3, ArH o to
SO2 on NTs); dC (100.6 MHz; acetone-d6) 21.7 (q), 63.4
(d), 71.2 (d), 128.0 (2·d), 128.7 (d), 129.0 (2· overlap-
ping 2·d), 129.5(2 ·d), 129.6 (overlapping d and 2·d),
130.4 (2·d), 138.0 (s), 139.0 (s), 140.0 (s), 143.8 (s).
Found (LSIMS): 393.1373 [MH]þ, C21H20N4O2S re-
quires 393.1385(3.0 ppm error); m=z (LSIMS) 393
(MHþ, 10%), 350 (15), 307 (40), 260 (30), 154 (100), 137
(70).
(10 mL) to give 17 (1.297 g, 94%) as a white solid; mp
19
D
207–209 ꢁC; ½aŠ ¼ ꢀ29:2 (c 0.55, acetone); mmax/cmꢀ1
(solid) 3458 (OH), 3323 (NH), 1311 and 1149 (SO2N),
746 and 699 (Ph); dH (400 MHz; DMSO-d6) 2.31 (3H, s,
NTs-CH3), 4.32 (1H, dd, J 9.4 and 6.7, PhCHNH),
4.45–4.90 (1H, br s, OH), 4.65 (1H, d, J 6.7, PhCHOH),
7.05–7.22 (12H, m, 2·Ph and ArH o to CH3 on NTs),
7.33 (2H, d, J 8.0, ArH o to SO2 on NTs), 8.14 (1H, d, J
9.4, NH); dC (100.6 MHz; DMSO-d6) 21.2 (q), 63.7 (d),
75.8 (d), 126.6 (2·d), 126.8 (d), 127.1 (2·d), 127.3 (d),
127.4 (2·d), 127.9 (2·d), 128.6 (2·d), 129.3 (2·d), 139.0
(s), 139.3 (s), 142.0 (s),143.1 (s). Found (LSIMS)
350.1211 [MH)H2O]þ, C21H20NO2S requires 350.1215
(1.0 ppm error); m=z (EI) 306 (80%), 260 (65), 201 (85),
106 (100), 91 (55), 77 (45).
3.8. Synthesis of N-((1S,2R)-2-amino-1,2-diphenyl-ethyl)-
4-methyl-benzenesulfonamide 11
To a solution of 19 (0.080 g, 0.21 mmol) in methanol
(4 mL) was added 10% palladium on charcoal (0.008 g).
The reaction vessel was evacuated, filled with H2 from a
balloon and stirred overnight. The reaction vessel was
purged with N2, filtered (Celite) and concentrated under
vacuum to give 11 (0.066 g, 86%) as a white solid
(Found: C, 68.45; H, 6.0; N, 7.35. C21H22N2O2S re-
quires: C, 68.8; H, 6.0; N, 7.65); mp 169–171 ꢁC; 100% ee
(1S,2R) by HPLC (Chiralcel OD, 10% ethanol/hexane
(1.0 mL minꢀ1), 1R,2S isomer 18.1 min, 1S,2R isomer
3.6. Synthesis of methanesulfonic acid (1R,2S)-1,2-
diphenyl-2-(toluene-4-sulfonylamino)-ethyl ester 18
To a suspension of 17 (0.404 g, 1.11 mmol) and trieth-
ylamine (0.168 g, 1.67 mmol) in dichloromethane (5mL)
was added a solution of methane sulfonyl chloride
(0.152 g, 1.33 mmol) in dichloromethane (2.5 mL). The
reaction mixture was stirred overnight, diluted with
water (10 mL) and extracted with dichloromethane
(2 · 10 mL). The combined extracts were washed with
water (10 mL) and concentrated under vacuum to give
the crude product. The residue was purified by flash
column chromatography (DCM to 5% MeOH/DCM) to
21.6 min); ½aŠ ¼ þ34:8 (c 0.65, CHCl3); mmax/cmꢀ1 3362
D
(NH), 3306 and 3262 (NH2), 1597 (NH2), 1321 and 1156
(SO2N), 755 and 696 (Ph); dH (400 MHz; CDCl3; Me4Si)
1.57 (2H, br s, NH2), 2.24 (3H, s, CH3), 4.04 (1H, d,
J 5.5, PhCHNH2), 4.39 (1H, d, J 5.5, PhCHNHTs), 5.60
(1H, br s, NH), 6.76 (2H, d, J 7.9, ArH o to CH3 on
NTs), 6.85–7.25 (10H, m, 2·Ph), 7.38 (2H, d, J 7.9, ArH
o to SO2 on NTs); dC (100.6 MHz; CDCl3; Me4Si) 21.8
(q), 60.8 (d), 63.4 (d), 127.4 (2·d), 127.5(2 ·d), 127.9 (d),
128.2 (overlapping d and 2·d), 128.3 (2·d), 128.8 (2·d),
129.7 (2·d), 137.2 (s), 137.7 (s), 141.3 (s), 143.4 (s).
Found (CI): 367.1465[MH] þ, C21H23N2O2S requires
367.1465(4.2 ppm error); m=z (EI) 367 (MHþ, 5%), 260
(20), 155 (15), 106 (100), 91 (25), 77 (15), 65 (10).
give 18 (0.216 g, 44%) as a white solid; mp 118–119 ꢁC;
19
½aŠ ¼ ꢀ34:5 (c 0.50, acetone); mmax/cmꢀ1 3266 (NH),
D
1341 and 1186 (SO2O), 1327 and 1167 (SO2N), 762 and
695(Ph); dH (400 MHz; acetone-d6) 2.33 (3H, s, NTs-
CH3), 2.65(3H, s, OMs-CH 3), 4.81 (1H, m,
PhCHNHTs), 5.81 (1H, d, J 6.8, PhCHOMs), 7.11–7.34
(13H, m, 2·Ph, ArH o to CH3 on NTs and NH), 7.44
(2H, d, J 8.3, ArH o to SO2 on NTs); dC (100.6 MHz;
acetone-d6) 21.7 (q), 38.9 (q), 63.3 (d), 86.2 (d), 128.0
(2·d), 128.7 (2·d), 129.0 (d), 129.2 (2·d), 129.5(2 ·d),
129.7 (2·d), 130.0 (d), 130.4 (2·d), (ipso carbons not
distinguishable). Found (LSIMS): 446.1092 [MH]þ,
C22H24NO5S2 requires 446.1096 (0.9 ppm error); m=z
(LSIMS) 446 (MHþ, 1%), 350 (20), 260 (10), 154 (100),
137 (70).
Acknowledgements
We thank the University of Warwick for support
(AMH). We would also like to thank Mr. Atsushi
Nagasawa for translation of the procedures relating to
the synthesis of 11. Professor D. Games and Dr. B. Stein
of the EPSRC National Mass Spectroscopic service
(Swansea) are thanked for HRMS analysis of certain
compounds. We also acknowledge the generous loan of
ruthenium salts by Johnson-Matthey limited and the use
of the EPSRC’s Chemical Database Service at Dares-
bury.11
3.7. Synthesis of N-((1S,2R)-2-azido-1,2-diphenyl-ethyl)-
4-methyl-benzenesulfonamide 19
To a solution of 18 (0.145g, 0.33 mmol) in dimethyl-
formamide (2 mL) was added sodium azide (0.064 g,
0.98 mmol) and the reactants were heated at 105 ꢁC for
4 h, cooled and stirred overnight. Water (5mL) was
added and the resulting precipitate was collected by fil-
tration and washed with water (5mL) and methanol
References and notes
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19
D
(solid) 3254 (NH), 2108 (N3), 1318 and 1161 (SO2N),
148–149 ꢁC; ½aŠ ¼ ꢀ62:8 (c 0.55, acetone); mmax/cmꢀ1
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