Sulfonamide ligands from chiral aziridines - Application to the titanium-mediated addition of diethylzinc to benzaldehyde

Article abstract of DOI:10.1002/1099-0690(200209)2002:18<3179::AID-EJOC3179>3.0.CO;2-A

A modular approach was developed for the preparation of chiral, enantiopure sulfonamide ligands with C₁, C₂, and C₃ symmetry by ring opening of chiral N-sulfonylaziridines with ammonia, primary amines, and diamines. The new ligands were assessed in the titanium-mediated addition of diethylzinc to benzaldehyde, giving the product with selectivities up to 76% ee. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200209)2002:18<3179::AID-EJOC3179>3.0.CO;2-A

FULL PAPER
Sulfonamide Ligands from Chiral Aziridines ؊ Application to the Titanium-
Mediated Addition of Diethylzinc to Benzaldehyde
Fredrik Lake[a] and Christina Moberg*[a]
Keywords: Sulfonamides / Aziridines / Enantioselective / Diethylzinc / Titanium
A modular approach was developed for the preparation of
chiral, enantiopure sulfonamide ligands with C1, C2, and C3
symmetry by ring opening of chiral N-sulfonylaziridines with
ammonia, primary amines, and diamines. The new ligands
were assessed in the titanium-mediated addition of di-
ethylzinc to benzaldehyde, giving the product with selectivit-
ies up to 76% ee.
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
2002)
Introduction
ines are conveniently accessible from amino alcohols,[45,46]
in turn obtained from synthetic or naturally occurring am-
ino acids. We realized that this synthetic method should
permit extensive facile structural variations as suitable
building blocks can be combined in various ways. Thus,
amines with various structures can be used for the ring
opening of aziridines with different substituents in 2-posi-
tion and different N-activating groups (Scheme 1). With this
synthetic methodology efficient screening of the ligands as
catalysts should be possible.
Chiral sulfonamides are known to serve as versatile li-
gands for a variety of catalytic applications. Thus, high en-
antioselectivity has been achieved in titanium-mediated ad-
ditions of diethylzinc to aldehydes catalysed by
bis(sulfonamides),[1Ϫ11] copper-catalysed Michael additions
of diethylzinc,[12Ϫ14] cyclopropanations[15] by zinc bis(sul-
fonamide) complexes,[16Ϫ25] aluminium bis(sulfonamide)
catalysed ketene aldehyde[26Ϫ28] and DielsϪAlder
cycloadditions,[29Ϫ31] and in transfer hydrogenations of ke-
tones catalysed by ruthenium sulfonamide complexes.[32]
Furthermore, magnesium sulfonamide compounds have
been successfully employed for the merged enolisation
and enantioselective amination of N-acyloxazolidinones,[33]
lanthanide sulfonamide complexes for the Mukaiyama al-
dol reaction,[34] and boron sulfonamides for the enantiose-
lective allylation of aldehydes[35] and IrelandϪClaisen re-
arrangement of esters.[36]
The sulfonamides are usually prepared in high yields by
treatment of chiral amines with the appropriate sulfonyl
chloride or other suitable sulfonic acid derivatives.[37Ϫ40] In
order to allow for efficient screening of catalysts for the
optimization of catalytic processes, it is desirable to have
easy access to synthetic methods permitting facile structural
variation of the ligands.[41,42] Of special interest are
methods built on a modular approach, allowing the pre-
paration of ligands in few high-yielding steps employing
methods that allow simple variation of ligand structures.
We have recently applied nucleophilic ring opening of
chiral activated aziridines for the preparation of ligands car-
rying sulfonamido functionalities.[43,44] The required azirid-
Scheme 1
To test the usefulness of this idea, the methodology previ-
ously developed has now been extended to include new
types of primary amines, primary amines carrying addi-
tional functional groups, primary diamines, and ammonia.
We present here the synthesis of a range of ligands, most of
which on the experimental timescale have C2 symmetry,
with the chirality due to the presence of stereogenic centres,
axes or planes together with an improved procedure for pre-
viously described C3-symmetric ligands.[44] The new ligands
were assessed as catalysts in the titanium-mediated addition
of diethylzinc to benzaldehyde.
Results and Discussion
Preparation of Ligands
[a]
Department of Chemistry, Organic Chemistry, Royal Institute
of Technology,
Aziridines with electron-withdrawing groups on the ni-
trogen atom readily undergo ring opening when treated
with nucleophiles.[45,46] The nucleophilic attack generally
10044 Stockholm, Sweden
Fax: (internat.) ϩ 46-8/791-2333
E-mail: kimo@orgchem.kth.se
Eur. J. Org. Chem. 2002, 3179Ϫ3188  WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0918Ϫ3179 $ 20.00ϩ.50/0
3179

F. Lake, C. Moberg
FULL PAPER
occurs at the sterically least hindered carbon atom. Second- with 1-methyl-1-phenylethylamine, 1,1-diphenylmethyl-
ary amines yield monosulfonamides by reaction with 1 amine, and (9-anthrylmethyl)amine in 65, 82, and 39% yield,
equiv. of the corresponding aziridine,[47,48] while respectively. It was interesting to note that the ring-opening
monosulfonamides,[47Ϫ51] as well as bis(sulfonamides) may reaction could be stopped after the addition of 1 equiv. of
be isolated from reactions with primary amines.[43,52Ϫ54] Re- the aziridine, provided that a large excess of amine was
action of 3 equiv. of the aziridine with ammonia yields C3- used.[55] Thus, the reaction using an excess of benzylamine
symmetric tris(sulfonamides),[44] but the reactions can be (9.5 equiv.) resulted in the mono- and bis(adducts) 8 and 2
stopped after the introduction of merely 1[55] or 2 equiv. of in a ratio of 10:1. In contrast, when bulky amines such as
the aziridine, and thus afford mono- as well as bis(sulfon- tritylamine or tert-butylamine were employed, no bis(ad-
amides) (Scheme 2). Furthermore, from diamines tetradent- ducts) were formed and the reaction stopped after the first
ate amines are accessible by reaction with 2 equiv. of the step, allowing the isolation of the monoadducts 9 and 10 in
aziridine; reaction with additional aziridine was not ob- 100 and 66% yield, respectively. Starting from ammonia,
served. Occasionally, a Lewis acid is employed in order to conditions favouring mono- or tris(adduct) formation can
accelerate the process. Thus, for example ytterbium() tri- be found, using an excess of either ammonia or the azirid-
flate has been used for the ring opening of N-tosylaziridines ine, but a problem arises when the bis(adduct) is the desired
with primary and secondary amines.[56]
product. However, the bis(adduct) 11 was obtained as the
major product in 31% yield by using 0.65 equiv. of aziridine
1a, together with 21% of the C1-symmetric mono- and 8%
of the C3-symmetric tris(adduct) (Scheme 4). Compound 12
was obtained in a one-pot reaction starting from (S)-alani-
nol by the ring opening of aziridine 1b in 20% yield [based
on (S)-alaninol]; aziridine 1b is susceptible to polymeriz-
ation and has to be treated in situ directly after preparation.
(S)-2-Isopropyl-N-tosylaziridine (1c) is less reactive than
the corresponding N-trifluoromethylsulfonyl analogue 1a
and heating at 55 °C in methanol was required for its reac-
tion with benzylamine to form bis(adduct) 13 (Scheme 5).
Scheme 2
The reaction of benzylamine with 2 equiv. of (S)-2-iso-
propyl-N-(trifluoromethylsulfonyl)aziridine (1a) has previ-
ously been shown to yield bis(sulfonamide) 2,[43] which
serves as a versatile ligand in the titanium-mediated addi-
tion of diethylzinc to benzaldehyde,[43,57] as well as in the
aluminium-catalysed ketene aldehyde cycloadditions.[26,27]
The synthetic approach used for the preparation of 2 allows
for wide structural variations of the product, as both azirid-
ines with different substituents and a variety of primary
amines can be used in the process. Thus, ligand 3, con-
taining an additional stereocentre, was prepared in the same
manner as 2 by exchanging benzylamine for (R)-1-phenyl-
ethylamine (Scheme 3). Highest yield (83%) was obtained
when dichloromethane was used as solvent, acetonitrile,
methanol, and tert-butyl alcohol/2-propanol (70:30) provid-
ing the same compound in yields of 63, 58, and 64%, re-
spectively. However, the reaction was considerably slower in
dichloromethane, requiring a reaction time of about 40 h
for completion, compared to around 16 h for the other
three solvent systems. In the alcoholic solvents, small
amounts of a by-product resulting from ring opening of the
aziridine by the solvent were formed. Use of (S)-1-phenyl-
thylamine as the nucleophile gave the diastereomer 4 in 76%
yield. Ligands 5Ϫ7, with more bulky substituents at the
Scheme 3
benzylic position, were obtained from the reaction of 1a Scheme 4
3180
Eur. J. Org. Chem. 2002, 3179Ϫ3188

Sulfonamide Ligands from Chiral Aziridines
FULL PAPER
Scheme 7
Scheme 5
that these aromatic amines are sufficiently reactive to open
1a. No further reaction of the secondary amine moieties in
compounds 19Ϫ24 was observed, probably due to steric
hindrance.
Next, ligands containing additional functional groups
were prepared. Compound 14 was obtained by treatment of
1a with (Ϫ)-norephedrine, whereas 15 and 16 were prepared
analogously using 2-hydroxy- and 2-methoxybenzylamine,
respectively, as nucleophile (Scheme 6). As the latter ligands
contain a prostereogenic aryl group, the preparation of li-
gands possessing planar chirality is possible. Upon reaction
with tricarbonyl(naphthalene)chromium,[58] 16 afforded
two diastereomeric chromium compounds with planar chir-
ality, 17 and 18. The diastereomers, which were obtained
as best in a ratio of 1:1.33, could be separated by column
chromatography to yield the pure stereoisomers. The com-
plexes were unstable and gave rise to broad signals in their
NMR spectra, which unfortunately hampered their charac-
terization.
Exchanging the primary amines for ammonia gives access
to C3-symmetric tripodal tris(sulfonamides) (Scheme 8).[44]
These ligands were previously obtained by reaction of the
aziridine with ammonia in methanol in a rather sluggish
process, tosyl derivative 25 requiring 4 d at 50 °C for com-
pletion (70% yield). We have now developed an improved
procedure, resulting in higher yield within shorter time, em-
ploying microwave irradiation.[59] It was found that after
30 min at 160 °C, a 3.1:1 ratio of aziridine 1c and ammonia
afforded 25 in 60% yield along with 16 and 20% of the bis-
and the mono(tosyl)amines 26 and 27 (Table 1, Entry 1).
Extending the reaction time to 75 min did not significantly
improve the yield of 25 (61%, Entry 2). Use of larger
amounts of the aziridine relative to ammonia resulted in
higher yields of the product, however. Thus, reactions at
160 °C between 1c and ammonia in ratios of 3.5:1 and 4:1
gave 25 in 68 and 77% yield after 45 min along with de-
creasing amounts of bis- and mono(tosyl)amines. Using a
ratio of 4:1 and extending the reaction time to 75 min im-
proved the yield of 25 to 85% (Entry 5), while an increase
Scheme 8
Table 1. Microwave-assisted ring opening of aziridine 1c with
ammonia at 160 °C (Scheme 8)
Scheme 6
The present methodology could also be employed for the
preparation of tetradentate ligands by exchanging the prim-
ary amines for C2-symmetric primary diamines. Thus, from
(R,R)- and (S,S)-1,2-diamino-1,2-diphenylethane diastere-
omeric ligands 19 and 20 were obtained in 84 and 79%
yield, respectively, whereas the two enantiomers of 1,2-di-
aminocyclohexane afforded 21 and 22 in 64 and 67% yield,
respectively (Scheme 7). Finally, tetradentate ligands with
axial chirality, 23 and 24, were obtained from (R)- and (S)-
Entry
Time [min]
1c/NH3
25 [%][a]
26 [%][a]
27 [%][a]
1
2
3
4
5
6
30
75
45
45
75
45
3.1:1
3.1:1
3.5:1
4:1
4:1
4.5:1
60
61
16
14
7
Ϫ
6
20
23
15
9
7
Ϫ
68
77[b]
85
88[c]
Ϫ
[a]
[c]
Isolated yields. [b] 13% of 1c was recovered. 12% of 1c was re-
binaphthylamine in 58 and 61% yield, respectively, showing covered.
Eur. J. Org. Chem. 2002, 3179Ϫ3188
3181

F. Lake, C. Moberg
FULL PAPER
of the ratio to 4.5:1 afforded the best yield, 88%, after tion, the addition of diethylzinc to benzaldehyde in the pres-
45 min at 160 °C.
ence of Ti(OiPr)4 was investigated (Scheme 9). We have pre-
viously demonstrated that the enantioselectivity as well as
the reactivity vary considerably with the reaction condi-
tions.[57] The amount of Ti(OiPr)4 employed in the process
was found to be particularly crucial. In the present study,
the conditions found to result in highest enantioselectivity
of the product for ligand 2 were employed, although op-
timal conditions probably have to be determined for each
particular ligand. Thus, best conditions for ligand 2 were
previously found to be a ligand/Ti(OiPr)4/Et2Zn ratio of
0.06:1.48:1.20, affording a 90% yield of the (S) product with
72% ee within 45 min at Ϫ35 °C (Entry 1, Table 2). The
introduction of a methyl group, and thus an additional ste-
Titanium-Mediated Addition of Diethylzinc to
Benzaldehyde
In order to assess the importance of the structure of the
sulfonamide ligands for the outcome in a catalytic applica-
Scheme 9
Table 2. Titanium-mediated addition of diethylzinc to benzaldehyde (Scheme 9)
Entry
Ligand
Time[a] [h]
ee [%][b]
(abs. conf.)
Yield[b]
[%]
Conversion[b]
[%]
Conversion[c]
15 min [%]
1
2
3
4
5
6
7
8
9
2
3
0.75
0.25
0.25
0.25
1
72 (S)
75 (S)
76 (S)
48 (S)
55 (S)
56 (S)
69 (S)
56 (S)
63 (S)
63 (S)
0
90
97
93
97
97
99
42
89
95
96
73
96
98
44
94
100
95
11
67
89
100
18
65
99
30
96
93
98
95
94
29
73
87
87
94
95
92
93
20
96
29
91
95
97
90
97
99
4
5
5
5[d]
6
2.5
91
93
42
96
0.25
0.25
1.25
2.33
0.25
1.33
2.7
19
0.25
1.5
7
7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
7
98
73
11
11
11
8
8 (S)
10 (S)
3 (S)
100
88
44
6
12
12
12
12
13
13
13
14
14
15[e]
16
17
18
19
19
19[e]
20[e]
21[f]
22
23
24
25
25
28
28
28
28[g]
7 (S)
17 (S)
23 (S)
19 (S)
31 (R)
49 (R)
50 (R)
41 (S)
29 (S)
20 (S)
61 (S)
65 (S)
65 (S)
80 (R)
65 (R)
59 (R)
12 (R)
0
3.5
19.3
0.25
1
4.5
0.25
18
97
99
11
18
92
90
90
78
78
30
22
86
74
76
4.5
1.67
1.67
1.67
0.25
1.67
5
5.25
18.25
18
3.67
3.33
0.25
18
0.25
1.75
2.67
3.3
79
87
89
95
83
84
29
27
5
4
25
35
0
9 (R)
5 (R)
25 (R)
31 (R)
17 (R)
9 (S)
91
20
10 (S)
11 (S)
89
29
[a]
[b]
[c]
[d]
Reaction time at Ϫ35 °C. Determined by chiral GLC. Determined by chiral GLC after 15 min at Ϫ35 °C. 12% ee of the (S)
product was obtained at 14% conversion after 15 min when the reaction was performed in THF (THF was used to solubilize the ligand).
[e]
[f]
5% of the ligand was used. Similar results were obtained when THF was used as the solvent (in which the ligand is completely
[g]
soluble). THF (0.30 mL) was added to dissolve the ligand.
3182
Eur. J. Org. Chem. 2002, 3179Ϫ3188

Sulfonamide Ligands from Chiral Aziridines
FULL PAPER
reogenic centre, at the benzylic position had only a minor tial part of the reaction (80% ee at 29% conversion, Entry
effect on the enantioselectivity, the absolute configuration 28), but the enantiomeric excess decreased as the reaction
at that centre also being of minor importance (3 and 4, proceeded (59% ee at 87% conversion, Entry 30). The dia-
Entries 2 and 3, Table 2). The reactions catalysed by ligands stereomer 20 gave a product with the same absolute config-
3 and 4 turned out to be slightly faster than the reaction uration, although the enantioselectivity was lower (12% ee,
catalysed by 2 and full conversion was achieved after only Entry 31). 1,2-Diaminocyclohexane derivatives 21 and 22
15 min at Ϫ35 °C. A lower selectivity, 48% ee, was observed afforded racemic products, and binaphthyl ligands 23 and
when the sterically more demanding ligand 5, containing 24 exhibited low selectivity, (9 and 5% ee, respectively, Ent-
one additional methyl group at the benzylic position, was ries 34 and 35). It is interesting to note that ligands derived
employed as a catalyst, although the selectivity increased from diamines, e.g. 19, 20, 23, and 24, gave the (R) enanti-
slightly over time (to 56% ee, Entries 4Ϫ6). Due to the poor omer of the product, and that the absolute configuration
solubility of the ligand in toluene, the reaction was also thus is determined by the configuration of the part in the
run in THF. In this solvent a lower ee (12%) was observed, ligand originating from aziridine 1a. Finally, the C3-sym-
however. The reason for the increase in enantioselectivity metric ligands 25 and 28 exhibited low selectivity in the
over time is unclear, but it has been previously observed catalytic reaction. In analogy to what was observed for li-
that the addition of for example chiral alcohols affects the gands 2 and 13, the tosyl derivative gave a product where
stereoselectivity of the reaction.[57] That steric bulk in the the (R) enantiomer dominated (31% ee) whereas the trifluo-
side chain did not improve the stereoselectivity was further romethylsulfonyl-substituted ligand gave a product where
demonstrated by use of ligand 6 (69% ee, Entry 7), which the (S) enantiomer dominated (11% ee), although the (R)
bears two phenyl groups at the benzylic position, and ligand product dominated at low conversion (Entries 38Ϫ41).
7 (63% ee, Entry 10), which contains an anthracene group
at the same position. The reaction catalysed by ligand 6
proved to be as fast as those catalysed by 3 and 4, and full
conversion was achieved after 15 min. For ligand 7 a small
change in the enantioselectivity over time was observed
(from 56 to 63% ee, Entries 8Ϫ10). The absence of a side
chain had a detrimental effect on the selectivity, as shown
Conclusion
by ligand 11 (10% ee, Entries 11Ϫ13). Likewise, the absence
of one coordinating arm resulted in a ligand exhibiting
poor enantioselectivity and low reaction rate (8, 3% ee,
Entry 14). Ligand 12, derived from aziridine 1b, induced
considerably lower enantioselectivity (19% ee) in the cata-
lytic reaction than the isopropyl analogue 2 (72% ee), al-
though the selectivity increased over time, and the reaction
was slower (Entries 15Ϫ18). A slow catalytic process was
also observed for the bis(tosylated) ligand 13 (Entries
19Ϫ21), which, surprisingly, afforded a product with a con-
figuration opposite to that obtained using the N-trifluoro-
methylsulfonyl ligands. Also when ligand 13 was employed
in the catalytic reaction the enantioselectivity increased over
time (from 31 to 50% ee). The presence of a hydroxy group
seemed to be unfavourable for the stereoselectivity, as use
of ligands 14 and 15 resulted in formation of products with
moderate enantioselectivity (29 and 20% ee, Entries 23 and
24, respectively). Higher selectivity was achieved when O-
methyl-substituted derivative 16 was used (61% ee, Entry
25). One reason might be that the hydroxy functions take
part in coordination to the metal ion, thereby changing the
structure of the catalytic intermediates in an unfavourable
manner. The diastereomeric chromium complexes 17 and
18 afforded results very similar to those of 16 (65% ee, Ent-
ries 26 and 27). This might be due to instability of the com-
plexes or that the planar chirality is situated too remote
from the catalytic centre.
A large variety of sulfonamide ligands were prepared by
ring opening of aziridines with amines. The methodology
developed gives access to libraries useful for optimization
of catalytic processes. Use of the ligands in the titanium-
mediated addition of diethylzinc to benzaldehyde demon-
strated that the substitution pattern had a profound effect
on the enantioselectivity and the rate of the catalytic reac-
tion. Bis(sulfonamides) prepared from primary amines had
properties superior to bis(sulfonamides) prepared from
ammonia and also to a ligand prepared from a primary
amine and 1 equiv. of the aziridine. Furthermore, ligands
derived from aziridines bearing an isopropyl group induced
higher selectivity than those derived from aziridines bearing
a methyl substituent. Tetradentate ligands obtained from
diamines were inferior to bis(sulfonamides) obtained from
monoamines. Ligands containing a hydroxy group did not
lead to improved results in the catalytic reaction. Finally,
use of a tosylamide resulted in a product with different ab-
solute configuration than that obtained using and the ana-
logous trifluoromethylsulfonamide. With these ligands in
hand, other catalytic processes are to be tested.
Experimental Section
General: 1H and 13C NMR spectra were recorded with a Bruker
DMX 500 instrument or with a Bruker Avance 400 instrument at
25 °C in CDCl3, using the residual signals from CHCl3 (1H: δ ϭ
7.26 ppm; 13C: δ ϭ 77.2 ppm) as internal standard. Optical rota-
Major differences in the selectivity were observed be-
tween diastereomers of the tetradentate ligands. Use of li-
gand 19, synthesised from (R,R)-1,2-diamino-1,2-dipheny-
lethane, resulted in quite high enantioselectivity in the ini- tions were recorded with a PerkinϪElmer 343 polarimeter at the
Eur. J. Org. Chem. 2002, 3179Ϫ3188 3183

F. Lake, C. Moberg
51.2, 57.2, 58.6, 119.8 (q, JC,F ϭ 327 Hz, CF3), 128.0, 128.69,
FULL PAPER
sodium D line at ambient temperature. Analytical TLC was per-
1
formed on SDS silica gel 60 F254 plates. The plates were visualized 128.71, 140.0 ppm. C20H31F6N3O4S2 (555.60): calcd. C 43.24, H
using a 5% ethanolic solution of phosphomolybdic acid. Flash
chromatography and MPLC (medium pressure liquid chromato-
graphy) were carried out using SDS silica gel 60 (40Ϫ63 µm). Melt-
ing points are uncorrected and were determined in open capillary
tubes using an Electrothermal instrument. Microwave heating was
performed in a SmithCreatorTM single-mode microwave cavity
from Personal Chemistry AB, Sweden. Elemental analyses were
performed by Analytische Laboratorien, Lindlar, Germany. En-
antiomeric excesses and yields were determined by GLC using a
Chrompack CP-cyclodextrin β-2,3,6-M-19 50-m column [110Ϫ140
°C, 2 °C/min, 5 min at 140 °C, 20 psi, benzaldehyde t: 8.6 min,
naphthalene (external standard) t: 14.7 min, (R) enantiomer tR:
18.0 min, (S) enantiomer tS: 18.3 min]. The assignment of the abso-
lute configuration of (R)- and (S)-1-phenylpropanol was made ac-
cording to our previous work.[43] All reactions were perfomed in
flame-dried glassware under argon. Toluene, THF, and diethyl
ether were distilled from Na/benzophenone and CH2Cl2 was dis-
tilled from CaH2. Benzaldehyde and Ti(OiPr)4 were freshly distilled
prior to use. A 1.1  solution of Et2Zn in toluene was used. All
amines were obtained from Aldrich, Lancaster or Tokyo Kasei (1-
methyl-1-phenylethylamine) and used as received except for (9-
anthrylmethyl)amine which was prepared according to a literature
procedure,[60] and 2-(aminomethyl)phenol which was prepared
from 2-cyanophenol by a procedure similar to that published.[61]
The concentration of the ammonia in methanol solution was deter-
mined by titration using a 0.0978  solution of HCl with methyl red
as indicator. Aziridine 1a was prepared according to our published
method, except that ice-cold solutions of 0.1  HCl and Na2CO3
(sat.) were used during a fast workup procedure;[44] 1a is quite un-
stable and was therefore used directly without further purification.
Aziridine 1b was prepared by the same procedure as that used for
1a but polymerized upon evaporation of the solvent; it should
therefore be used in situ. Aziridine 1c was prepared in a similar
way to that described in the literature.[52] Compounds 2[43] and
28[44] were prepared by our previous methods.
5.62, N 7.56; found C 43.09, H 5.61, N 7.40.
Compound 4: For purification, see ligand 3. Colourless crystals.
Yield: 76%. M.p. 157Ϫ158 °C. [α]2D0 ϭ Ϫ47.7 (c ϭ 0.61, MeOH).
Rf ϭ 0.43 (20% EtOAc in hexanes). 1H NMR (500 MHz): δ ϭ 0.85
(d, 3J ϭ 7.0 Hz, 6 H, iPr CH3), 0.87 (d, 3J ϭ 7.1 Hz, 6 H, iPr CH3),
1.34 (d, 3J ϭ 7.0 Hz, 3 H, CHCH3), 2.02 [d of sept, J ϭ 7.0, 3J ϭ
3
3.9 Hz, 2 H, CH(CH3)2], 2.51 (ABX system, 2J ϭ 13.7, 3J ϭ
2
10.8 Hz, 2 H, NCHH), 2.53 (ABX system, J ϭ 13.7, 3J ϭ 7.9 Hz,
2 H, NCHH), 3.59Ϫ3.64 (m, 2 H, CHNHTf), 4.22 (q, 3J ϭ 6.8 Hz,
1 H, CbenzylicH), 4.99 (br. s, 2 H, NHTf), 7.29 (t, 3J ϭ 7.3 Hz, 1 H,
3
3
Hpara), 7.38 (app t, J ϭ 7.5 Hz, 2 H, Hmeta), 7.47 (d, J ϭ 7.5 Hz,
2 H, Hortho) ppm. 13C NMR (125.8 MHz) 10.4, 17.4, 18.0, 30.3,
50.2, 56.7, 58.1, 119.7 (q, 1JC,F ϭ 327 Hz, CF3), 128.1, 128.9, 129.0,
142.0 ppm. C20H31F6N3O4S2 (555.60): calcd. C 43.24, H 5.62, N
7.56; found C 43.43, H 5.77, N 7.56.
Compound 5: For purification, see ligand 3. White crystals. Yield
65%. M.p. 142.5Ϫ143 °C. [α]2D0 ϭ Ϫ16.6 (c ϭ 0.37, MeOH). Rf ϭ
1
0.56 (20% EtOAc in hexanes). H NMR (500 MHz): δ ϭ 0.66 (d,
3
3J ϭ 6.9 Hz, 6 H, iPr CH3), 0.89 (d, J ϭ 6.9 Hz, 6 H, iPr CH3),
1.43 (s, 3 H, CbenzylicCH3), 1.45 (s, 3 H, CbenzylicCH3), 2.18 [d of
3
3
sept, J ϭ 6.9, J ϭ 2.2 Hz, 2 H, CH(CH3)2], 2.61 (ABX system,
2J ϭ 14.0, 3J ϭ 6.3 Hz, 2 H, NCHH), 2.65 (ABX system, 2J ϭ
3
14.0, J ϭ 8.6 Hz, 2 H, NCHH), 3.47Ϫ3.50 (m, 2 H, CHNHTf),
4.55 (br. s, 2 H, NHTf), 7.25 (t, 3J ϭ 7.2 Hz, 1 H, Hpara), 7.35 (app
t, 3J ϭ 7.5 Hz, 2 H, Hmeta), 7.47 (d, 3J ϭ 7.6 Hz, 2 H, Hortho) ppm.
13C NMR (125.8 MHz) 15.8, 18.7, 23.9, 25.7, 27.9, 54.8, 60.9, 62.3,
1
119.5 (q, JC,F ϭ 327 Hz, CF3), 123.3, 126.6, 127.4, 128.8, 148.0
ppm. C21H33F6N3O4S2 (569.63): calcd. C 44.28, H 5.84, N 7.38;
found C 44.35, H 5.85, N 7.30.
Compound 6: MPLC (gradient 1Ϫ40% EtOAc in hexanes) gave a
white powder. Yield. 82%. M.p. 134.5Ϫ135.5 °C. [α]2D0 ϭ 5.3 (c ϭ
0.34, MeOH). Rf ϭ 0.40 (20% EtOAc in hexanes). 1H NMR
(500 MHz): δ ϭ 0.70 (d, 3J ϭ 7.0 Hz, 6 H, CH3), 0.82 (d, 3J ϭ
2
6.9 Hz, 6 H, CH3), 1.95Ϫ2.00 [m, 2 H, CH(CH3)2], 2.61 (dd, J ϭ
3
2
3
General Procedure for the Preparation of Compounds 3؊7, 9؊10,
and 14؊16: The amine (1.03 mmol) was added to a 10-mL flask
and dissolved in dichloromethane (0.80 mL). The solution was co-
oled to 0 °C and aziridine 1a (0.80 g, 3.68 mmol, ca. 85% pure
according to 1H NMR) was added dropwise. The cooling bath was
removed after 30 min and the mixture was stirred at room temper-
ature for 48Ϫ72 h. SiO2 (5 g) and dichloromethane (10 mL) were
added, the solvent was evaporated and the residue was purified
by chromatography.
13.6, J ϭ 5.1 Hz, 2 H, NCHH), 2.74 (dd, J ϭ 13.6, J ϭ 9.7 Hz,
2 H, NCHH), 3.64Ϫ3.65 (m, 2 H, CHNHTf), 5.12 (br. s, 2 H,
NHTf), 5.30 (s, 1 H, CHbenzylic), 7.27Ϫ7.37 (m, 6 H, Haromatic),
7.38Ϫ7.42 (m, 4 H, Haromatic) ppm. 13C NMR (125.8 MHz) 17.4,
1
17.5, 30.3, 51.4, 58.2, 68.5, 122.0 (q, JC,F ϭ 327 Hz, CF3), 127.8,
128.0, 128.8, 128.9, 129.6, 129.7, 138.3, 140.2 ppm.
C25H33F6N3O4S2 (617.67): calcd. C 48.61, H 5.39, N 6.80; found
C 48.64, H 5.56, N 6.60.
Compound 7: Flash chromatography (2.5% EtOAc in hexanes) fol-
lowed by recrystallisation from first toluene/hexanes and then
EtOAc/hexanes gave a white powder. Yield: 39% (along with 23%
of the monoadduct). M.p. 157Ϫ159 °C. [α]2D0 ϭ Ϫ44.4 (c ϭ 0.47,
MeOH). Rf ϭ 0.43 (10% EtOAc in hexanes). 1H NMR (400 MHz):
δ ϭ 0.38 (d, 3J ϭ 7.0 Hz, 6 H, CH3), 0.75 (d, 3J ϭ 6.9 Hz, 6 H,
General Procedure for the Preparation of Compounds 19؊24: The
same procedure as that described above was used, except that
2.5 mmol of 1a (ca 85% pure) per mmol of diamine was used.
Compound 3: Purification by MPLC (gradient 1Ϫ40% EtOAc in
hexanes) followed by recrystallization from a mixture of EtOAc/
3
CH3), 1.86 [d of sept, J ϭ 7.0, 3J ϭ 3.1 Hz, 2 H, CH(CH3)2], 2.66
hexanes gave colourless crystals. Yield: 83%. M.p. 136Ϫ138 °C. (ABX system, 2J ϭ 13.4, 3J ϭ 5.8 Hz, 2 H, NCHH), 2.69 (ABX
[α]D20 ϭ Ϫ45.7 (c ϭ 0.74, MeOH). Rf ϭ 0.38 (20% EtOAc in hexanes). system, J ϭ 13.4, J ϭ 4.6 Hz, 2 H, NCHH), 3.60Ϫ3.66 (m, 2 H,
2
3
2
2
1H NMR (500 MHz): δ ϭ 0.72 (d, 3J ϭ 7.0 Hz, 6 H, iPr CH3),
CHNHTf), 4.58 (d, J ϭ 12.8 Hz, 1 H, CbenzylicHH), 4.73 (d, J ϭ
0.98 (d, 3J ϭ 6.9 Hz, 6 H, iPr CH3), 1.44 (d, 3J ϭ 6.9 Hz, 3 H, 12.8 Hz, 1 H, CbenzylicHH), 4.76 (br. s, 2 H, NHTf), 7.50 (app dt,
CHCH3), 2.01Ϫ2.07 [m, 2 H, CH(CH3)2], 2.36 (dd, 2J ϭ 13.6, 3J ϭ 3J ϭ 7.3, J ϭ 0.8 Hz, 2 H, Hanthryl), 7.58 (app dt, J ϭ 8.1, J ϭ
4
3
4
3
7.0 Hz, 2 H, NCHH), 2.62 (dd, 2J ϭ 13.5, 3J ϭ 7.8 Hz, 2 H,
1.5 Hz, 2 H, Hanthryl), 8.02 (br. d, J ϭ 8.4 Hz, 2 H, Hanthryl), 8.34
NCHH), 3.59Ϫ3.63 (m, 2 H, CHNHTf), 4.08 (q, 3J ϭ 6.9 Hz, 1 (br. d, 2 H, Hanthryl), 8.47 (s, 1 H, Hanthryl) ppm. 13C NMR
3
1
H, CbenzylicH), 5.20 (br. s, 2 H, NHTf), 7.20 (d, J ϭ 7.1 Hz, 2 H, (125.8 MHz) 15.9, 18.8, 28.9, 51.4, 56.6, 58.9, 119.8 (q, JC,F
ϭ
3
3
Hortho), 7.28 (t, J ϭ 7.3 Hz, 1 H, Hpara), 7.35 (app t, J ϭ 7.1 Hz, 327 Hz, CF3), 124.6, 125.5, 126.9, 128.2, 128.8, 129.7, 131.7,
2 H, Hmeta) ppm. 13C NMR (125.8 MHz) 15.4, 16.8, 18.8, 29.6,
131.7 ppm.
3184
Eur. J. Org. Chem. 2002, 3179Ϫ3188

Sulfonamide Ligands from Chiral Aziridines
FULL PAPER
Compound 8: Benzylamine (2.50 mL, 22.9 mmol) was disolved in
MeOH (2.5 mL). The solution was cooled to 0 °C and aziridine 1a
(0.62 g, 2.85 mmol, ca 85% pure) was added dropwise during
20 min. After 1 h, the reaction mixture was brought to room tem-
was washed with cold 0.1  HCl (2 ϫ 60 mL) and with cold sat.
Na2CO3 (2 ϫ 60 mL). The organic phase was dried with MgSO4
and filtered into a 50-mL flask which was cooled to Ϫ40 °C.
Benzylamine (0.25 mL, 2.32 mmol, the yield of 1b was assumed to
perature and stirred for 20 h. The benzylamine was distilled off and be 75%) was added dropwise to the mixture and the flask was left
the crude mixture was concentrated onto 3 g of silica and purified
by MPLC (gradient 1Ϫ100% EtOAc in hexanes) giving (0.59 g,
in the warming bath. The crude mixture was concentrated onto
2.4 g of silica and purified by flash chromatography (12.5% EtOAc
in hexanes) followed by a second flash chromatography (gradient
5Ϫ25% of diethyl ether in hexanes) giving 0.30 g of a sticky oil
which eventually solidified to a white powder. Yield: 20% [calcu-
1.82 mmol) of a white powder. Yield: 75%. M.p. 126 °C. [α]2D0
ϭ
1
Ϫ5.4 (c ϭ 0.63, MeOH). Rf ϭ 0.59 (80% EtOAc in hexanes). H
3
NMR (400 MHz): δ ϭ 0.93 (d, J ϭ 6.8 Hz, 3 H, CH3), 0.98 (d,
3J ϭ 6.8 Hz, 3 H, CH3), 1.85Ϫ1.94 [m, 1 H, CH(CH3)2], 2.67 (dd, lated on (S)-alaninol]. M.p. 86Ϫ87 °C. [α]2D0 ϭ Ϫ68.6 (c ϭ 0.47,
3
2
2J ϭ 12.9, J ϭ 4.8 Hz, 1 H, NCHH), 2.91 (dd, J ϭ 12.9, 3J ϭ MeOH). Rf ϭ 0.36 (20% EtOAc in hexanes). 1H NMR (400 MHz):
4.7 Hz, 1 H, NCHH), 3.31Ϫ3.36 (m, 1 H, CHNHTf), 3.42 (br. s, δ ϭ 1.21 (d, 3J ϭ 6.5 Hz, 6 H, CH3), 2.39 (dd, 2J ϭ 13.5, 3J ϭ
2 H, NHTf and NH), 3.78 (AB q, 2J ϭ 13.3 Hz, 1 H, CbenzylicHH), 4.1 Hz, 2 H, NCHHCH), 2.55 (dd, J ϭ 13.5, J ϭ 10.2 Hz, 2 H,
2
3
3.81 (AB q, J ϭ 13.3 Hz, 1 H, CbenzylicHH), 7.27Ϫ7.37 (m, 5 H, NCHHCH), 3.22 (d, 2J ϭ 13.0 Hz, 1 H, CbenzylicHH), 3.80Ϫ3.88
2
H
aromatic) ppm. 13C NMR (100.6 MHz) 19.0, 19.4, 30.8, 49.3, 54.4,
(m, 2 H, CHNHTf), 4.02 (d, 2J ϭ 13.0 Hz, 1 H, CbenzylicHH), 5.26
61.6, 120.1 (q, JC,F ϭ 321 Hz, CF3), 127.8, 128.5, 129.0, 139.8 (br. s, 2 H, NHTf), 7.28Ϫ7.39 (m, 5 H, Haromatic) ppm. 13C NMR
1
ppm. C13H19F3N2O2S (324.36): calcd. C 48.14, H 5.90, N 8.64;
found C 48.28, H 5.89, N 8.54.
(125.8 MHz) 20.3, 49.5, 58.6, 60.2, 119.8 (q, 1JC,F ϭ 327 Hz, CF3),
128.3, 129.2, 129.9, 137.5 ppm. C15H21F6N3O4S2 (485.47): calcd. C
37.11, H 4.36, N 8.66; found C 37.27, H 4.20, N 8.55.
Compound 9: MPLC (gradient 1Ϫ80% EtOAc in hexanes) followed
by recrystallization from EtOAc/hexanes gave a white powder.
Yield: 100%. M.p. 116.5Ϫ119.5 °C. [α]2D0 ϭ Ϫ6.4 (c ϭ 0.57,
MeOH). Rf ϭ 0.77 (20% EtOAc in hexanes). 1H NMR (500 MHz):
Compound 13: Benzylamine (75 µL, 0.68 mmol) was added to aziri-
dine 1c (0.33 g, 1.37 mmol) in methanol (0.9 mL) in a 10-mL flask
at 0 °C. The flask was kept at 0 °C for 10 min and at room temper-
ature for 10 min. The flask was then heated at 45 °C for 21 h and
55 °C for 14 h. The flask was placed at Ϫ30 °C until a white powder
formed. The powder was collected and washed with hexane giving
3
δ ϭ 0.75 (d, J ϭ 6.8 Hz, 3 H, CH3), 0.91 (d, 3J ϭ 6.8 Hz, 3 H,
CH3), 1.87 [app oct, 1 H, CH(CH3)2], 2.20 (dd, 2J ϭ 12.5, 3J ϭ
5.3 Hz, 1 H, NCHH), 2.45 (br. d, 2J ϭ 11.8 Hz, 1 H, NCHH), 3.37
(br. s, 1 H, CHNHTf), 5.15 (br. s, 1 H, NHTf), 7.21 (t, 3J ϭ 7.3 Hz,
(0.52 g, 0.43 mmol). Yield: 63%. Melts partly at 69Ϫ70 °C. [α]2D0
ϭ
1
3
3
Ϫ79.6 (c ϭ 0.50, MeOH). Rf ϭ 0.20 (20% EtOAc in hexanes). H
3 H, Haromatic), 7.29 (t, J ϭ 8.0 Hz, 6 H, Haromatic), 7.45 (d, J ϭ
7.4 Hz, 6 H, Haromatic) ppm. 13C NMR (125.8 MHz) 18.7, 18.8,
30.5, 45.1, 62.0, 70.8, 119.8 (q, 1JC,F ϭ 327 Hz, CF3), 126.8, 128.2,
128.4, 145.4 ppm.
3
NMR (400 MHz): δ ϭ 0.63 (d, J ϭ 6.9 Hz, 6 H, iPr CH3), 0.66
(d, 3J ϭ 7.0 Hz, 6 H, iPr CH3), 1.86 [d of sept, 3J ϭ 6.9, 3J ϭ
4.0 Hz, 2 H, CH(CH3)2], 2.31 (dd, 2J ϭ 13.2, 3J ϭ 5.6 Hz, 2 H,
2
3
NCHH), 2.40 (s, 6 H, CH3para), 2.47 (dd, J ϭ 13.2, J ϭ 9.0 Hz,
2 H, NCHH), 3.27 (d, 3J ϭ 13.3 Hz, 1 H, CbenzylicH), 3.44Ϫ3.50
Compound 10: MPLC (gradient 2.5Ϫ100% EtOAc in hexanes) gave
a white powder. Yield: 66%. M.p. 166Ϫ168 °C. [α]2D0 ϭ Ϫ32.9 (c ϭ
0.49, MeOH). Rf ϭ 0.22 (80% EtOAc in hexanes). 1H NMR
3
(m, 2 H, CHNHTs), 3.73 (d, J ϭ 13.2 Hz, 1 H, CbenzylicH), 5.21
(d, 3J ϭ 6.5 Hz, 2 H, NHTs), 7.23 (d, 3J ϭ 8.1 Hz, 6 H, Hmeta),
7.79 (d, 3J ϭ 8.3 Hz, 4 H, Hortho) ppm. 13C NMR (100.6 MHz)
17.6, 18.0, 21.7, 29.9, 54.2, 56.1, 56.5, 127.1, 127.4, 128.5, 129.6,
129.7, 137.9, 138.9, 143.1 ppm. C31H43N3O4S2 (585.83): calcd. C
63.56, H 7.40, N 7.17; found C 63.56, H 7.38, N 7.15.
3
(500 MHz): δ ϭ 0.94 (d, 3J ϭ 6.8 Hz, 3 H, iPr CH3), 1.02 (d, J ϭ
3
6.8 Hz, 3 H, iPr CH3), 1.18 (s, 9 H, tBu CH3), 1.78 [app oct, J ϭ
6.9 Hz, 1 H, CH(CH3)2], 2.74 (dd, 2J ϭ 12.4, 3J ϭ 4.3 Hz, 1 H,
NCHH), 2.95 (dd, 2J ϭ 12.5, 3J ϭ 5.7 Hz, 1 H, NCHH), 3.22Ϫ3.26
(m, 1 H, CHNHTf), 3.59 (br. s, 2 H, NH and NHTf) ppm. 13C
NMR (125.8 MHz) 20.7, 21.3, 29.1, 33.2, 44.7, 54.8, 60.8, 119.6 (q,
1JC,F ϭ 314 Hz, CF3) ppm. C10H21F3N2O2S (290.35): calcd. C
41.37, H 7.29, N 9.65; found C 41.36, H 7.36, N 9.64.
Compound 14: MPLC (gradient 1Ϫ60% EtOAc in hexanes) and
recrystallization from EtOAc/hexanes gave colourless crystals.
Yield: 41%. M.p. 147Ϫ148 °C. [α]2D0 ϭ Ϫ31.8 (c ϭ 0.49, MeOH).
Rf ϭ 0.29 (20% EtOAc in hexanes). 1H NMR (500 MHz): δ ϭ 0.88
3
3
Compound 11: Aziridine 1a (0.52 g, 2.39 mmol, ca 85% pure) was
added dropwise to ammonia in methanol (1.6 mL of a 2.0  solu-
tion, 3.2 mmol) in a 10-mL flask at 0 °C. The cooling bath was
removed after 1 h and the mixture was stirred at room temperature
for 27 h. The crude mixture was concentrated onto 2 g of silica and
purified by MPLC (gradient 1Ϫ100% EtOAc in hexanes) giving
0.139 g (0.31 mmol) of a white powder. Yield: 31% [along with 21%
(d, J ϭ 6.8 Hz, 3 H, CH3), 0.94 (d, J ϭ 7.0 Hz, 6 H, iPr CH3),
3
0.98 (d, J ϭ 6.9 Hz, 6 H, iPr CH3), 2.04 (br. s, 1 H, OH), 2.07 [d
of sept, 3J ϭ 7.0, 3J ϭ 3.8 Hz, 2 H, CH(CH3)2], 2.53 (dd, 2J ϭ
3
2
13.8, J ϭ 4.5 Hz, 2 H, NCHH), 2.87 (app t, J ϭ 11.1 Hz, 2 H,
3
3
NCHH), 2.91 (dq, J ϭ 6.8, J ϭ 2.7 Hz, 1 H, CHNCH3), 3.59Ϫ
3.61 (m, 2 H, CHNHTf), 5.32 (d, 3J ϭ 2.4 Hz, 1 H, CbenzylicH),
5.99 (br. s, 2 H, NHTf), 7.28Ϫ7.29 (m, 1 H, Haromatic), 7.35Ϫ7.39
(m, 4 H, Haromatic) ppm. 13C NMR (125.8 MHz) 15.1, 17.0, 18.1,
of the mono- and 8% of the tris(adduct)]. M.p. 107Ϫ109 °C. [α]2D0
ϭ
1
1
Ϫ7.2 (c ϭ 0.47, MeOH). Rf ϭ 0.67 (80% EtOAc in hexanes). H
30.4, 51.7, 58.4, 58.7, 79.5, 119.5 (q, JC,F ϭ 327 Hz, CF3), 126.0,
3
NMR (400 MHz): δ ϭ 0.98 (d, J ϭ 6.8 Hz, 6 H, CH3), 0.99 (d,
128.0, 128.7, 142.4 ppm. C21H33F6N3O5S2 (585.63): calcd. C 43.07,
H 5.68, N 7.18; found C 43.16, H 5.65, N 7.03.
3
3J ϭ 6.8 Hz, 6 H, CH3), 1.85 [oct, J ϭ 6.8 Hz, 2 H, CH(CH3)2],
2.78 (ABX system, 2J ϭ 13.0, 3J ϭ 4.2 Hz, 2 H, NCHH), 2.82
(ABX system, 2J ϭ 13.0, 3J ϭ 6.7 Hz, 2 H, NCHH), 3.33Ϫ3.38
(m, 2 H, CHNHTf) ppm; NHTf and NH signals were not visible.
13C NMR (100.6 MHz) 19.0, 19.4, 30.9, 51.6, 61.9, 119.9 (q,
1JC,F ϭ 320 Hz, CF3) ppm. C12H23F6N3O4S2 (451.45): calcd. C
31.93, H 5.14, N 9.31; found C 32.07, H 5.01, N 9.18.
Compound 15: Purification by first MPLC (gradient 1Ϫ100%
EtOAc in hexanes) and then flash chromatography through a short
column (gradient 0Ϫ100% CH2Cl2 in hexanes) gave a white pow-
der. Yield: 41%. M.p. 102Ϫ103 °C. [α]2D0 ϭ Ϫ55.0 (c ϭ 0.75,
MeOH). Rf ϭ 0.63 (20% EtOAc in hexanes). 1H NMR (400 MHz):
δ ϭ 0.82 (d, 3J ϭ 6.7 Hz, 6 H, CH3), 0.94 (d, 3J ϭ 6.7 Hz, 6 H,
Compound 12: Aziridine 1b was prepared in analogy with 1a start-
CH3), 1.56 (br. s, 1 H, OH), 1.99Ϫ2.07 [m, 2 H, CH(CH3)2], 2.65
2
ing from (S)-alaninol (0.46 g, 6.18 mmol). The cold crude mixture (ABX system, J ϭ 13.8, 3J ϭ 7.0 Hz, 2 H, NCHH), 2.72 (ABX
Eur. J. Org. Chem. 2002, 3179Ϫ3188
3185

F. Lake, C. Moberg
FULL PAPER
2
3
1
system, J ϭ 13.7, J ϭ 6.7 Hz, 2 H, NCHH), 3.64Ϫ3.68 (m, 2 H, 69.6, 119.7 (q, JC,F ϭ 314 Hz, CF3), 127.3, 127.9, 128.3, 141.2
CHNHTf), 3.69 (d, 2J ϭ 13.4 Hz, 1 H, CbenzylicH), 3.89 (d, 2J ϭ ppm. C26H36F6N4O4S2 (646.71): calcd. C 48.29, H 5.61, N 8.66;
13.4 Hz, 1 H, CbenzylicH), 6.83Ϫ6.87 (m, 2 H, C3ЈH and C5ЈH), 7.04 found C 48.45, H 5.74, N 8.57.
3
3
4
(d, J ϭ 7.3 Hz, 1 H, C6ЈH), 7.21 (d app t, J ϭ 7.6, J ϭ 1.6 Hz,
Compound 20: MPLC (gradient 1Ϫ60% EtOAc in hexanes) gave a
white powder. Yield: 79%. M.p. 124Ϫ125 °C. [α]2D0 ϭ Ϫ6.0 (c ϭ
0.53, MeOH). Rf ϭ 0.36 (20% EtOAc in hexanes). 1H NMR
(400 MHz): δ ϭ 0.80 (d, 3J ϭ 6.8 Hz, 6 H, CH3), 0.94 (d, 3J ϭ
1 H, C4ЈH) ppm; NHTf signal not visible. 13C NMR (125.7 MHz)
1
16.4, 18.6, 29.7, 56.5, 58.5, 58.6, 116.4, 119.5 (q, JC,F ϭ 321 Hz,
CF3), 120.4, 121.5, 129.8, 130.0, 156.1 ppm. C19H29F6N3O5S2
(557.57): calcd. C 40.93, H 5.24, N 7.54, S 11.50; found C 40.66,
H 5.19, N 7.40, S 11.65.
2
6.8 Hz, 6 H, CH3), 1.85Ϫ1.95 [m, 2 H, CH(CH3)2], 2.63 (dd, J ϭ
3
2
3
13.3, J ϭ 4.0 Hz, 2 H, NCHH), 2.75 (dd, J ϭ 13.1, J ϭ 5.0 Hz,
2 H, NCHH), 3.28Ϫ3.34 (m, 2 H, CHNHTf), 3.73 (s, 2 H, Cbenzyl-
icH), 3.95 (br. s, 4 H, NHTf and NH), 7.04 (d, 3J ϭ 7.3 Hz, 4
Compound 16: For purification, see ligand 3. White crystals. Yield:
65%. M.p. 85Ϫ86 °C. [α]2D0 ϭ Ϫ58.9 (c ϭ 0.54, MeOH). Rf ϭ 0.55
(20% EtOAc in hexanes). H NMR (400 MHz): δ ϭ 0.82 (d, J ϭ
1
3
H, Hortho), 7.12Ϫ7.18 (m, 6 H, Hpara and Hmeta) ppm. 13C NMR
3
1
6.9 Hz, 6 H, CH3), 0.89 (d, J ϭ 6.8 Hz, 6 H, CH3), 2.01Ϫ2.05 [m,
(100.6 MHz) 18.8, 19.5, 30.1, 48.4, 61.7, 68.6, 119.8 (q, JC,F
ϭ
2
3
2 H, CH(CH3)2], 2.61 (ABX system, J ϭ 13.8, J ϭ 6.5 Hz, 2 H,
NCHH), 2.67 (ABX system, 2J ϭ 13.8, 3J ϭ 7.0 Hz, 2 H, HCHH),
3.52Ϫ3.57 (m, 2 H, CHNHTf), 3.73 (AB q, 2J ϭ 13.3 Hz, 1 H,
321 Hz, CF3), 127.6, 127.8, 128.4, 140.0 ppm. C26H36F6N4O4S2
(646.71): calcd. C 48.29, H 5.61, N 8.66; found C 48.12, H 5.44,
N 8.50.
C
benzylicH), 3.77 (AB q, 2J ϭ 13.3 Hz, 1 H, CbenzylicH), 3.86 (s, 3
H, OCH3), 5.50 (br. s, 2 H, NHTf), 6.93 (d, 3J ϭ 8.0 Hz, 1 H,
C3ЈH), 6.96 (app t, 3J ϭ 7.4 Hz, 1 H, C5ЈH), 7.21 (dd, 3J ϭ 7.4,
Compound 21: MPLC (gradient 2.5Ϫ100% EtOAc in hexanes) gave
a white powder. Yield: 64%. M.p. 185Ϫ186 °C. [α]2D0 ϭ Ϫ60.9 (c ϭ
0.40, MeOH). Rf ϭ 0.18 (60% EtOAc in hexanes). 1H NMR
(400 MHz): δ ϭ 0.93 (d, 3J ϭ 6.8 Hz, 6 H, CH3), 0.98 (d, 3J ϭ
6.8 Hz, 6 H, CH3), 1.24Ϫ1.29 (m, 2 H, C4ЈHH and C5ЈHH),
1.33Ϫ1.38 (m, 2 H, C3ЈHH and C6ЈHH), 1.80Ϫ1.82 (m, 2 H,
C4ЈHH and C5ЈHH), 1.90Ϫ1.95 [m, 2 H, CH(CH3)2], 2.14 (br. d,
2J ϭ 12.6 Hz, 2 H, C3ЈHH and C6ЈHH), 2.50Ϫ2.52 (m, 2 H,
4J ϭ 1.5 Hz, 1 H, C6ЈH), 7.31 (d app t, J ϭ 7.8, J ϭ 1.7 Hz, 1
3
4
H, C4ЈH) ppm. 13C NMR (125.8 MHz) 17.6, 18.1, 29.5, 54.3, 55.3,
1
55.6, 59.2, 111.1, 119.6 (q, JC,F ϭ 314 Hz, CF3), 121.0, 125.1,
129.6, 132.1, 158.1 ppm. C20H31F6N3O5S2 (571.60): calcd. C 42.02,
H 5.47, N 7.35; found C 41.87, H 5.32, N 7.28.
2
3
Compounds 17 and 18: Compound 16 (101 mg, 0.177 mmol) and
tricarbonyl(naphthalene)chromium (114 mg, 0.432 mmol) were ad-
ded to a vial. The vial was sealed and THF (0.05 mL) and ether
(1.35 mL) were added. The vial was heated at 90 °C in an oil bath
for 5.25 h. CAUTION: High pressure! The crude mixture was puri-
fied by MPLC (gradient 0Ϫ80% EtOAc in hexanes) giving a 1:1.3
mixture of the diastereoisomers according to 1H NMR. The two
diastereoisomers were separated by flash chromatography (gradient
30Ϫ70% CH2Cl2 in pentane) giving 36.0 mg (0.051 mmol, 29%) of
the early isomer as a yellow oil, Rf ϭ 0.21 (50% CH2Cl2 in pent-
ane), and 47.0 mg (0.066 mmol, 38%) of the late isomer as a yellow
oil, Rf ϭ 0.05 (50% CH2Cl2 in pentane). 1H NMR (400 MHz) from
the crude mixture (some signals could not be assigned definitely).
Early: δ ϭ 0.90 (d, 3J ϭ 6.8 Hz, 6 H, iPr CH3), 0.92 (d, 3J ϭ
6.8 Hz, 6 H, iPr CH3), 1.84Ϫ1.95 [m, 2 H, CH(CH3)2], 3.04 (d, 2J ϭ
11.3 Hz, 1 H, CbenzylicH), 3.07 (d, 2J ϭ 11.6 Hz, 1 H, CbenzylicH),
3.45Ϫ3.57 (m, 4 H, NCH2), 3.63Ϫ3.66 (m, 2 H, CHNHTf), 3.77
CHN), 2.82 (dd, J ϭ 12.2, J ϭ 8.5 Hz, 2 H, NCHH), 3.02 (dd,
3
3
2J ϭ 12.2, J ϭ 4.4 Hz, 2 H, NCHH), 3.27 (app dt, J ϭ 8.0, 3J ϭ
2.7 Hz, 2 H, CHNHTf), 4.20 (br. s, 4 H, NHTf and NH) ppm. 13
C
NMR (100.6 MHz) 18.7, 19.7, 24.7, 30.4, 30.6, 48.0, 60.4, 61.7,
120.6 (q, JC,F ϭ 323 Hz, CF3) ppm. C18H34F6N4O4S2 (548.60):
calcd. C 39.41, H 6.25, N 10.21; found C 39.20, H 6.08, N 10.05.
1
Compound 22: MPLC (gradient 2.5Ϫ100% EtOAc in hexanes) fol-
lowed by recrystallization from EtOAc/hexanes gave white crystals.
Yield: 67%. M.p. 146Ϫ147 °C. [α]2D0 ϭ Ϫ5.4 (c ϭ 0.63, MeOH).
Rf ϭ 0.38 (80% EtOAc in hexanes). 1H NMR (400 MHz): δ ϭ 0.92
(d, 3J ϭ 6.6 Hz, 6 H, CH3), 1.01 (d, 3J ϭ 6.6 Hz, 6 H, CH3),
1.11Ϫ1.13 (m, 2 H, C3ЈHH and C6ЈHH), 1.22Ϫ1.27 (m, 2 H,
C4ЈHH and C5ЈHH), 1.79Ϫ1.81 (m, 2 H, C4ЈHH and C5ЈHH),
1.85Ϫ1.92 [m, 2 H, CH(CH3)2], 2.18 (br. d, 2J ϭ 12.2 Hz, 2 H,
2
C3ЈHH and C6ЈHH), 2.45Ϫ2.47 (m, 2 H, CHN), 2.68 (br. d, J ϭ
12.2 Hz, 2 H, NCHH), 3.11 (dd, 2J ϭ 12.6, 3J ϭ 4.4 Hz, 2 H,
NCHH), 3.23Ϫ3.25 (m, 2 H, CHNHTf), 4.85 (br. s, 4 H, NHTf
3
3
(s, 3 H, OCH3), 4.97 (t, J ϭ 5.9 Hz, 1 H, Haromatic), 5.83 (d, J ϭ
5.9 Hz, 1 H, Haromatic), 5.07 (app t, 3J ϭ 6.8 Hz, 2 H, Haromatic).
Late: δ ϭ 0.98 (d, 3J ϭ 7.0 Hz, 6 H, iPr CH3), 1.00 (d, 3J ϭ 6.9 Hz,
6 H, iPr CH3), 1.97Ϫ2.03 [m, 2 H, CH(CH3)2], 2.67Ϫ2.80 (m, 4 H,
NCH2), 3.31 (d, 2J ϭ 13.9 Hz, 1 H, CbenzylicH), 3.35 (d, 2J ϭ
14.9 Hz, 1 H, CbenzylicH), 3.72 (s, 3 H, OCH3), 3.75Ϫ3.77 (m, 2 H,
CHNHTf), 5.12 (d, 3J ϭ 6.7 Hz, 1 H, Haromatic), 5.56 (t, 3J ϭ
and NH) ppm. 13C NMR (100.6 MHz) 19.2, 20.0, 24.5, 29.9, 30.6,
1
47.7, 60.9, 60.9, 120.9 (q, JC,F
ϭ 324 Hz, CF3) ppm.
C18H34F6N4O4S2 (548.60): calcd. C 39.41, H 6.25, N 10.21; found
C 39.61, H 6.26, N 10.27.
Compound 23: MPLC (gradient 1Ϫ100% EtOAc in hexanes) gave
a white solid which was treated with pentane. The solution was
placed at Ϫ30 °C until a white solid formed. The solid was collected
and washed with a small amount of cold pentane. Yield: 58%.
Melts partly at 73Ϫ77 °C. [α]2D0 ϭ 69.5 (c ϭ 0.54, MeOH). Rf ϭ
3
6.2 Hz, 1 H, Haromatic), 6.40 (d, J ϭ 6.3 Hz, 1 H, Haromatic) ppm;
the signal of one aromatic proton is probably hidden under the
signals of naphthalene.
Compound 19: Purification by MPLC (gradient 1Ϫ60% EtOAc in 0.29 (20% EtOAc in hexanes). 1H NMR (500 MHz): δ ϭ 0.93 (app
3
hexanes) followed by recrystallization from EtOAc/toluene/hexanes
t, J ϭ 6.6 Hz, 12 H, CH3), 1.83Ϫ1.86 [m, 2 H, CH(CH3)2], 3.20
(d, 2J ϭ 11.3 Hz, 2 H, NCHH), 3.26Ϫ3.30 (m, 2 H, NCHH),
3.35Ϫ3.38 (ABX system, 2 H, CHNHTf), 3.88 (br. s, 2 H, NH),
gave a white powder. Yield: 84%. M.p. 162Ϫ163 °C. [α]2D0 ϭ Ϫ25.2
1
(c ϭ 0.59, MeOH). Rf ϭ 0.43 (20% EtOAc in hexanes). H NMR
3
3
(500 MHz): δ ϭ 0.89 (d, 3J ϭ 5.1 Hz, 6 H, CH3), 0.90 (d, 3J ϭ 5.74 (d, J ϭ 8.7 Hz, 2 H, NHTf), 6.95 (br. d, J ϭ 8.4 Hz, 2 H,
5.2 Hz, 6 H, CH3), 1.78 [app oct, 3J ϭ 5.3 Hz, 2 H, CH(CH3)2], Hbinaphthyl), 7.16 (app dt, J ϭ 6.7, J ϭ 1.2 Hz, 2 H, Hbinaphthyl),
3
4
3
3
4
2.57 (ABX system, 2J ϭ 12.0, 3J ϭ 9.5 Hz, 2 H, NCHH), 2.61 7.19 (d, J ϭ 9.0 Hz, 2 H, Hbinaphthyl), 7.21 (app dt, J ϭ 7.3, J ϭ
(ABX system, 2J ϭ 12.0, 3J ϭ 4.2 Hz, 2 H, NCHH), 3.39Ϫ3.43
1.0 Hz, 2 H, Hbinaphthyl), 7.82 (d, 3J ϭ 7.8 Hz, 2 H, Hbinaphthyl), 7.93
(m, 2 H, CHNHTf), 3.55 (s, 2 H, CbenzylicH), 3.88 (br. s, 2 H, NH), (d, 3J ϭ 9.0 Hz, 2 H, Hbinaphthyl) ppm. 13C NMR (125.8 MHz) 17.7,
7.01 (d, 3J ϭ 6.1 Hz, 4 H, Hortho), 7.09Ϫ7.15 (m, 6 H, Hpara and 18.7, 31.7, 44.5, 60.8, 112.2, 113.7, 119.3 (q, 1JC,F ϭ 319 Hz, CF3),
Hmeta) ppm. 13C NMR (125.8 MHz) 18.4, 19.1, 31.0, 48.6, 62.6,
122.0, 124.1, 126.7, 128.1, 128.4, 129.9, 134.0, 144.2 ppm.
3186
Eur. J. Org. Chem. 2002, 3179Ϫ3188

Sulfonamide Ligands from Chiral Aziridines
FULL PAPER
C32H36F6N4O4S2 (718.21): calcd. C 53.47, H 5.05, N 7.79; found
C 53.44, H 5.03, N 7.79.
[1]
[2]
L. Pu, H.-B. Yu, Chem. Rev. 2001, 101, 757Ϫ824.
M. Yoshioka, T. Kawakita, M. Ohno, Tetrahedron Lett. 1989,
30, 1657Ϫ1660.
H. Takahashi, T. Kawakita, M. Ohno, M. Yoshioka, S. Kobay-
ashi, Tetrahedron 1992, 48, 5691Ϫ5700.
J. Qiu, C. Guo, X. Zhang, J. Org. Chem. 1997, 62, 2665Ϫ2668.
C.-D. Hwang, B.-J. Uang, Tetrahedron: Asymmetry 1998, 9,
3979Ϫ3984.
S. Pritchett, D. H. Woodmansee, P. Gantzel, P. J. Walsh, J. Am.
Chem. Soc. 1998, 120, 6423Ϫ6424.
Compound 24: For purification, see ligand 23. Yield: 61%. Melts
partly at 74Ϫ77 °C. [α]2D0 ϭ 16.4 (c ϭ 0.54, MeOH). Rf ϭ 0.65
(40% EtOAc in hexanes). 1H NMR (500 MHz): δ ϭ 0.67 (app t,
3J ϭ 6.6 Hz, 12 H, CH3), 1.28Ϫ1.33 [m, 2 H, CH(CH3)2],
3.37Ϫ3.45 (m, 6 H, NCHH and CHNHTf), 3.64 (br. s, 2 H, NH),
5.59 (d, 3J ϭ 8.7 Hz, 2 H, NHTf), 7.02 (d, 3J ϭ 8.3 Hz, 2 H,
[3]
[4]
[5]
3
4
[6]
[7]
Hbinaphthyl), 7.22 (m, 2 H, Hbinaphthyl), 7.28 (app dt, J ϭ 7.5, J ϭ
1.1 Hz, 2 H, Hbinaphthyl), 7.33 (d, 3J ϭ 9.0 Hz, 2 H, Hbinaphthyl),
3
3
J.-Q. Wang, M. Zhong, G.-Q. Lin, Chin. J. Chem. 1998, 16,
65Ϫ77.
7.84 (d, J ϭ 8.0 Hz, 2 H, Hbinaphthyl), 7.97 (d, J ϭ 9.0 Hz, 2 H,
Hbinaphthyl) ppm. 13C NMR (125.8 MHz) 17.4, 19.1, 28.8, 45.9,
[8]
[9]
L. A. Paquette, R. Zhou, J. Org. Chem. 1999, 64, 7929Ϫ7934.
1
60.4, 113.8, 114.8, 119.6 (q, JC,F ϭ 321 Hz, CF3), 123.2, 123.9,
´
O. Prieto, D. J. Ramon, M. Yus, Tetrahedron: Asymmetry 2000,
127.3, 128.61, 128.64, 130.6, 133.7, 143.5 ppm. C32H36F6N4O4S2
(718.21): calcd. C 53.26, H 5.15, N 7.64; found C 53.44, H 5.03,
N 7.79.
11, 1629Ϫ1644.
[10]
[11]
[12]
[13]
[14]
[15]
[16]
J. Balsells, P. J. Walsh, J. Am. Chem. Soc. 2000, 122,
1802Ϫ1803.
P. Knochel, J. J. A. Perea, P. Jones, Tetrahedron 1998, 54,
8275Ϫ8319.
I. Chataigner, C. Gennari, U. Piarulli, S. Ceccarelli, Angew.
Chem. Int. Ed. 2000, 39, 916Ϫ918.
I. Chataigner, C. Gennari, S. Ongeri, U. Piarulli, S. Ceccarelli,
Chem. Eur. J. 2001, 7, 2628Ϫ2634.
S. Ongeri, U. Piarulli, R. F. W. Jackson, C. Gennari, Eur. J.
Org. Chem. 2001, 803Ϫ807.
Review cyclopropanation: W. A. Donaldson, Tetrahedron 2001,
57, 8589Ϫ8627.
S. E. Denmark, S. P. O’Connor, S. R. Wilson, Angew. Chem.
Int. Ed. 1998, 37, 1149Ϫ1151; Angew. Chem. 1998, 110,
1162Ϫ1165.
S. E. Denmark, B. L. Christenson, S. P. O’Connor, Tetrahedron
Lett. 1995, 36, 2219Ϫ2222.
S. E. Denmark, B. L. Christenson, D. M. Coe, S. P. O’Connor,
Tetrahedron Lett. 1995, 36, 2215Ϫ2218.
S. E. Denmark, S. P. O’Connor, J. Org. Chem. 1997, 62,
3390Ϫ3401.
Compound 25: Aziridine 1c (0.50 g, 2.09 mmol) was added to a
SmithProcessVialTM, the vial was sealed and charged with a solu-
tion of ammonia (0.27 mL, 2.1  in methanol, 0.57 mmol) and
methanol (0.20 mL). The vial was placed in the microwave cavity
for 75 min at 160 °C. CAUTION: High pressure! The mixture was
cooled in an ice bath and the white crystals were collected and
washed with cold methanol, giving 0.35 g (0.48 mmol, 85%) of 25.
M.p. 187Ϫ188 °C. [α]2D0 ϭ 108 (c ϭ 0.80, CHCl3). Rf ϭ 0.43 (40%
EtOAc in hexanes). 1H NMR (400 MHz): δ ϭ 0.77 (d, 3J ϭ 6.8 Hz,
3
9 H, iPr CH3), 0.80 (d, J ϭ 6.9 Hz, 9 H, iPr CH3), 1.66Ϫ1.73 [m,
2
3
3 H, CH(CH3)2], 2.15 (dd, J ϭ 12.6, J ϭ 4.6 Hz, 3 H, NCHH),
2
3
2.38 (s, 9 H, CH3para), 2.96 (app t, J ϭ 12.2, J ϭ 12.2 Hz, 3 H,
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
NCHH), 3.79Ϫ3.86 (m, 3 H, CHNHTs), 6.20 (d, 3J ϭ 7.0 Hz,
3
H, CHNHTs), 7.23 (d, 3J
ϭ
8.1 Hz,
6
H, Hmeta),
7.83 (d, 3J ϭ 8.3 Hz,6 Hz, Hortho) ppm. 13C NMR (100.6 MHz)
18.3, 18.5, 21.6, 31.6, 52.1, 55.3, 58.1, 126.7, 129.4, 139.8, 142.6
ppm. C36H54N4O6S3 (735.03): calcd. C 58.83, H 7.40, N 7.62;
found C 58.64, H 7.33, N 7.48.
S. E. Denmark, S. P. O’Connor, J. Org. Chem. 1997, 62,
584Ϫ594.
General Procedure for the Addition of Diethylzinc to Benzaldehyde:
Ligand (0.06 mmol) was added to a 10-mL flask. The flask was
evacuated during 2 min and filled with argon, and the cycle was
repeated twice. The ligand was dissolved in toluene (1.0 mL) and
Ti(OiPr)4 (1.48 mmol, 0.44 mL) was added. The mixture was co-
oled to Ϫ78 °C and Et2Zn (1.20 mmol, 1.09 mL) was added drop-
wise after 20 min. The temperature of the cooling bath was allowed
to reach Ϫ20 °C during 1 h, whereafter the flask was kept at 0 °C
for 15 min followed by 140 min at room temperature and then co-
oled to Ϫ78 °C. Benzaldehyde (1 mmol, 101.6 µL) was added after
15 min at this temperature. The flask was placed at Ϫ35 °C after
20 min. The mixture was maintained at this temperature and
aliqouts were removed with a syringe and quenched with 0.3 
HCl, extracted with ether, filtered through a short pad of silica
(around 0.5 cm), eluted with ether, and injected on a chiral GLC
column. The reaction was quenched with 0.3  HCl when all alde-
hyde was consumed. The aqueous phase was extracted four times
with ether and the combined organic phases were dried with
Na2SO4 and filtered, and the solvent was evaporated. The yield
and entiomeric excess were determined by GLC using naphthalene
as external standard.
N. Imai, K. Sakamoto, M. Maeda, K. Kouge, K. Yoshizane, J.
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C. Schneider, Angew. Chem. Int. Ed. 2002, 41, 744Ϫ746; Angew.
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E. J. Corey, S. Sarshar, J. Am. Chem. Soc. 1992, 114,
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A. Fujii, S. Hashiguchi, N. Uematsu, T. Ikariya, R. Noyori, J.
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1995, 6, 71Ϫ74.
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Acknowledgments
This work was supported financially by the Göran Gustafsson
Foundation for Research in Sciences and Medicine. The authors
are grateful to Ms. Pooja Gupta for studies of microwave-mediated
preparation of ligands.
Eur. J. Org. Chem. 2002, 3179Ϫ3188
3187

F. Lake, C. Moberg
FULL PAPER
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[O02254]
3188
Eur. J. Org. Chem. 2002, 3179Ϫ3188