Towards phase-transfer catalysts with a chiral anion: Inducing asymmetry in the reactions of cations

Article abstract of DOI:10.1016/S0957-4166(03)00367-7

The ability of chiral anions, for example bis[1,1′-bi-2-naphtholato]borate, to induce asymmetry in the reactions of prochiral cations was investigated. Ion-pairing of a borate anion with an aziridinium ion was demonstrated by NMR spectroscopy. The additio

Full text of DOI:10.1016/S0957-4166(03)00367-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1995–2004
Towards phase-transfer catalysts with a chiral anion: inducing
asymmetry in the reactions of cations
Christabel Carter,a Sarah Fletcherb and Adam Nelsona,*
aDepartment of Chemistry, University of Leeds, Leeds LS2 9JT, UK
bSyngenta, Leeds Road, Huddersfield HD2 1FF, UK
Received 1 April 2003; accepted 2 May 2003
Abstract—The ability of chiral anions, for example bis[1,1%-bi-2-naphtholato]borate, to induce asymmetry in the reactions of
prochiral cations was investigated. Ion-pairing of a borate anion with an aziridinium ion was demonstrated by NMR
spectroscopy. The addition of N-methyl indole to an iminium ion (benzylidenedimethylammonium) and the ring-opening of an
aziridinium ion (1,2-diphenyl-3-azonia-spiro[2.4]heptane) with benzylamine were studied. Low, but significant, (<15%) enantiose-
lectivities were induced in the formation of the diamine benzyl-(1%,2%-diphenyl-2-pyrrolidin-1-yl-ethyl)-amine. The counterion of the
additive was found to have a remarkable effect on the yield and the sense of enantioselectivity of these reactions. © 2003 Elsevier
Ltd. All rights reserved.
1. Introduction
the phase-transfer catalyst. For example, cinchona
alkaloid-derived catalysts induce the highest levels of
enantioselectivity (up to 94% e.e.2) only when the
bridgehead nitrogen is quaternised with a 9-anthra-
cenylmethyl group.
Asymmetric phase-transfer catalysis provides an
extremely powerful and versatile means for inducing
asymmetry in reactions of prochiral anions.1 For exam-
ple, cinchondinium (e.g. 1) and cinchoninium (e.g. 2)
salts have been shown to induce high levels of enan-
tioselectivity in a wide range of reactions including
enolate alkylation,2–4 Michael,5 nucleophilic epoxida-
tion,6 cyclopropanation7 and oxidative cyclisation reac-
tions.8 In this regard, the cinchona alkaloids may be
considered to be ‘charmed’ templates for the design of
effective phase-transfer catalysts.
Corey has proposed a model which explains the sense
of the enantioselective alkylation of the enolate 5 (Fig.
1), and the importance of the size of the substituent on
the quaternised nitrogen atom.2 The enolate 5 is
believed to be in close contact with the least hindered
face of an imaginary tetrahedron formed by the four
atoms surrounding the quaternary nitrogen atom.
Scheme 1.
Asymmetric alkylations of the glycine derivative 3 have
been widely studied (Scheme 1), and have been
exploited in the synthesis of unnatural amino acid
derivatives.4,9 The enantioselectivity of this process can
depend critically on the detailed substitution pattern of
* Corresponding author. E-mail: adamn@chem.leeds.ac.uk
Figure 1.
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00367-7

1996
C. Carter et al. / Tetrahedron: Asymmetry 14 (2003) 1995–2004
In addition, we chose to study the effect of D3-sym-
metrical anions such as the hexacoordinate phosphate
17 in asymmetric reactions of cations. These anions
are highly symmetrical and have been found to be
highly effective chiral shift reagents for, for example,
chiral cationic complexes11 and phosphonium salts.12
It was felt that these reagents might, therefore, be
able to selectively stabilise one of an enantiomeric
pair of transition states.
Three of the faces are blocked by the bicyclic quinu-
clidine framework, the allyloxymethyl group and the
anthracene substituent. The enolate 5 contacts with
the remaining, open face, and alkylation of its less
hindered face leads to the observed enantiomer of the
product 4.
Ooi has exploited C2 symmetry in the design of effec-
tive chiral phase-transfer catalysts, and the most
exciting results were obtained with the rigid spiro
quaternary ammonium salt 6.10 The rate and enan-
tioselectivity of the benzylation of 3 was found to
depend critically on the substitution pattern: with 1
mol% 6, the reaction was complete within 30 min at
0°C, and gave the amino acid derivative (R)-4 with
95% e.e.
Herein, we describe our efforts to establish that stereo-
chemical information could be transmitted between a
chiral anion and a reacting cation. This goal would
be the first step in the development of asymmetric
phase-transfer catalysed processes. The success of
some chiral quaternary ammonium salts as phase-
transfer catalysts suggested that it should be possible
to identify a similarly potent chiral anion.
We have investigated the possibility of inducing
asymmetry in two classes of model reaction. Both of
these reactions proceed under neutral conditions
under which the D2-symmetric borate 7 was expected
to be chemically stable. Firstly, we have investigated
ring-openings of prochiral aziridinium ions (such as 8)
with amine nucleophiles; in the case of the aziri-
dinium 8, ring-opening would be expected to occur
trans-diaxially to give the trans-1,2-diamine 10. Sec-
ondly, we have investigated the reaction of the
iminium ion 11 with N-methylindole to give the ter-
tiary amine 13. In each case, selective stabilisation of
one of the enantiomeric transition states (9‡/ent-9‡ or
12‡/ent-12‡) by the chiral anion would give an enan-
tiomerically enriched product.
In terms of Corey’s model, the C2 symmetry element
of 6 means that the imaginary tetrahedron surround-
ing its nitrogen atom has two pairs of identical faces.
The success of Ooi’s catalyst may stem from its C2
symmetry: only one design feature would be needed
to block two faces of the imaginary tetrahedron.
Close contact of the enolate 5 with either of the
remaining faces, and asymmetric alkylation, would
lead to the amino acid derivative 4.
The aim of this research was to design chiral anions
which would induce asymmetry in reactions involving
prochiral, cationic intermediates. We felt that it might
be possible to exploit some of the design features
which have been found to underlie the success of the
best cationic phase transfer catalysts. In particular,
we chose to exploit symmetry in the design of chiral
anions. The borate 7 is D2 symmetric: it has three
mutually perpendicular C2 axes [the third C2 axis is
perpendicular to the plane of the paper (axis not
shown)]. The faces of the imaginary tetrahedron sur-
rounding the central boron atom are all identical,
meaning that the same level of asymmetry would be
induced if the reacting cation contacted any of its
faces.

C. Carter et al. / Tetrahedron: Asymmetry 14 (2003) 1995–2004
1997
2. Synthesis of salts with a chiral anion
ment of the amino alcohols 18 and 23 with
methanesulfonyl chloride and triethylamine gave the
chloroamines 19 and 24 as single diastereoisomers with
overall retention of configuration;19 the trans configura-
tion of 19 was established by measurement of the
vicinal coupling constant between CHCl and CHN
(3J=10.1 Hz).
The binaphthols (R)- and (S)-14 were prepared by
classical resolution13 and were shown to have >99% e.e.
by chiral analytical HPLC. Treatment of the binaph-
thols (R)- or (S)-14 with boric acid and an amine in
refluxing acetonitrile gave the borates (R,R)- or (S,S)-
15a–c (Scheme 2 and Table 1).14 Similarly, treatment
with (R)- or (S)-14 with sodium tetraborate and
sodium hydroxide in THF–water15 gave the borates
(R,R)- or (S,S)-15d. The silver salts (R,R)- and (S,S)-
15e were prepared by reaction of (R)- or (S)-14 with
Treatment of the chloroamines 19 and 24 with benzyl-
amine in a refluxing mixture of toluene and THF gave
the diamines 20 and 25, respectively.20 The observation
of overall retention of configuration for the transforma-
tions 19“20 and 24“25 confirmed the intermediacy of
a meso-aziridinium ion in each case (8 and 26, respec-
tively).19,20 We preferred to synthesise the diamine 25
directly from the amino alcohol 23: the diamine 25 was
isolated in 78% yield over two steps for this one-pot20
procedure (Scheme 3).
monobromoborane
methylsulfide
complex
in
dichloromethane, evaporation, suspension in acetonit-
rile, and treatment with silver carbonate.16 The tributyl-
ammonium TRISPHAT salt (M)-17 was resolved clas-
sically by selective precipitation of the cinchonidinium
(P) TRISPHAT salt.11,17
The aziridinium trifluoromethanesulfonate 21 was pre-
pared either by treatment of the chloroamine 19 with
silver trifluoromethanesulfonate, of by treatment of the
amino alcohol 18 with trifluoromethanesulfonic anhy-
dride and triethylamine. We were unable to prepare the
trifluoromethanesulfonate salt of the aziridinium ion 26
using either of these methods, presumably reflecting its
greater electrophilicity.
The 1,1-diamine 27, prepared from benzaldehyde, was
treated with acetyl chloride, and gave the iminium
chloride21 28 in 85% yield, which was stored in the
freezer until required. A racemic sample of the amine
13 was prepared in 82% yield by treatment of the
iminium salt 28 with N-methyl indole (Scheme 4).22
3. Synthesis of starting materials
The amino alcohols 18 and 23 were prepared by ring-
opening of the corresponding meso-epoxides.18 Treat-
Scheme 2.
Table 1. Preparation of salts 15 with the chiral counterion 7
Entry
Starting material
Conditions
Amine
Product
[h]2D0 (c in DMSO)
Yield (%)
1a
1b
2a
2b
3a
3b
4
(R)-14
(S)-14
(R)-14
(S)-14
(R)-14
(S)-14
(R)-14
(R)-14
A
A
A
A
A
A
B
Et2NH
Et2NH
Et3N
Et3N
(R)-16
(R)-16
−
(R,R)-15a
(S,S)-15a
(R,R)-15b
(S,S)-15b
(R,R)-15c
(S,S)-15c
(R,R)-15d
(R,R)-15e
−265 (1.10)
+271 (1.09)
−232 (1.01)
+249 (0.92)
−239 (1.06)
+321 (1.05)
+174 (1.04)
+136 (1.05)
88
84
82
85
31
37
42
15
5
C
−
A: B(OH)3, amine, MeCN, D, 12 h; B: Na2B4O7·10H2O, NaOH, THF–H2O; C: 1. BH2Br·Me2S, CH2Cl2; 2. Ag2CO3, MeCN.

1998
C. Carter et al. / Tetrahedron: Asymmetry 14 (2003) 1995–2004
The chemical shifts of the protons HA, HB and HC and
the carbons CA and CC were found to vary linearly with
the amount of (R,R)-15c present (Figs. 2 and 3). This
trend may indicate that the aziridinium ion 8 forms an
ion pair with the borate anion 7. However, there was
no evidence for splitting of the enantiotopic pairs of
protons HA/HA%, HB/HB% and HC/HC%, suggesting that
the enantiotopic sides of the aziridinium ion were not
being effectively distinguished by the chiral anion. Pre-
viously, some chiral anions have been shown to ion pair
diastereoselectively with chiral cations,23 and to have
value as chiral shift reagents.11,12,24
5. Effect of chiral additives on the reaction of
N-methyl indole with an iminium ion
We adopted a screening approach to study the reaction
of N-methyl indole with the iminium salt 28 (Scheme
5). The effect of solvent and 10 mol% of the chiral salt
(R,R)-15b on the yield of the amine 13 was investigated
(Table 2). Reactions were performed in parallel on a
0.076 mmol scale at 25°C in a Radley’s carousel reac-
tion station; in each case, the initial concentration of
the iminium ion was 1.19 M, and the reaction time was
2 h. The products of the reactions were analysed, and
the yields determined, by analytical HPLC.
Scheme 3.
In preliminary experiments, the solvent was found to
have a profound effect on the yield of the amine 13. In
the absence of the additive (R,R)-15b, the yield of the
amine 13 was significantly higher in the chlorinated
solvents dichloromethane and chloroform than in ace-
tonitrile, hexane or ethyl acetate. In none of these
reactions were any by-products isolated; therefore, the
yields of the products may give a reasonable guide to
relative rates of each reaction. In the case of solvents
with an intermediate dielectric constant, such as THF
(m=7.6) and dichloromethane (m=9.1), the addition of
10 mol% (R,R)-15b increased the yield of 13. This
result suggests that the presence of the additive may
reduce the activation energy of the reaction, pre-
sumably by selective stabilisation of its cationic transi-
tion state.
Scheme 4.
4. Investigation into ion-pairing between an aziridinium
and a borate ion
The possibility of ion pairing between the aziridinium
ion 8 and the borate anion 7 was investigated by NMR
spectroscopy. A sample of the aziridinium salt 21 was
dissolved in CDCl3, and 0.1 equiv. of the salt (R,R)-15c
were successively added until the solution was satu-
The reaction was investigated further in THF, chloro-
form and dichloromethane. In each case, the reactions
were performed in parallel with 10 mol% of a chiral
additive, and the yields were determined, by analytical
HPLC. In general, the reactions were performed in
duplicate using both (R,R) and (S,S) additives. For
reactions which proceeded in >20% yield, the enan-
tiomeric excesses were determined by chiral analytical
HPLC by comparison with a racemic sample of the
amine 13.
1
rated; at each stage, the 300 MHz H and the 75 MHz
13C NMR spectra were recorded. The first indication
that there was a favourable interaction was that the salt
(R,R)-15c dissolved in the presence of the aziridinium
salt 21; previously the borate (R,R)-15c had been solu-
ble only in DMSO-d6.

C. Carter et al. / Tetrahedron: Asymmetry 14 (2003) 1995–2004
1999
Figure 2.
Figure 3.
The cationic counterion of the chiral additive had a
remarkable effect on the yield of the product 13 (Table
2). Furthermore, the optimal counterion depended on
the solvent which was used; in general, however, the
salts with the more lipophilic ammonium ions—either
the triethylammonium 15b and (R)-a-methylbenzylam-
monium 15c salts—gave the best yields of the amine 13.
Scheme 5.

2000
C. Carter et al. / Tetrahedron: Asymmetry 14 (2003) 1995–2004
Table 2. Effect of solvent and additives on the yield and e.e. of the amine 13
Solvent
THF
CH2Cl2
CHCl3
Yielda (%)
Yielda (%)
Yielda (%)
Additive
(R,R) additive
(S,S) additive
(R,R) additive
(S,S) additive
(R,R) additive
(S,S) additive
[e.e. (%)]b
[e.e. (%)]b
[e.e. (%)]b
[e.e. (%)]b
[e.e. (%)]b
[e.e. (%)]b
None
15a
23
58
31
12c
22c
35c
[+3]
[−5]
[−6]
[−3]
[+8]
–
[−6]
[+3]
[+1]
[−1]
[+4]
15b
15c
15d
15e
38d
62d
–
32c
98e
0c
[−3]
–
52c
22d
28c
14e
28e
[−10]
[−11]
[+3]
[−8]
–
–
[+3]
f
f
[+11]
–
3e
20e
f
f
–
[−3]
–
a Determined by analytical HPLC.
b Determined by chiral analytical HPLC.
c Average yield for reactions with (R,R) and (S,S) additives.
d Yield for reactions with (R,R) additive.
e Yield for reactions with (R,R) additive.
f Enantiomeric excess not determined.
In each reaction, the iminium salt 28 was insoluble in
the reaction mixture, and the reaction gradually became
more homogeneous as the reaction proceeded.
The reaction 24“26“25 was investigated in parallel in
THF–toluene at four different temperatures, and the
yield of each reaction was determined by analytical
HPLC (see Table 3). The presence of 50 mol% of the
chiral borates 15 generally increased the yield of the
diamine 25, particularly at elevated temperature (40–
100°C). The effect of the counterion was rather less
pronounced in this case, though the yields were better
with the substituted alkylammonium 15a–c and sodium
15d salts. The tributylammonium TRISPHAT salt (M)-
17 improved the yield of the diamine 25, particularly at
higher temperatures (60 or 100°C).
The enantiomeric excesses of the product 13 were,
however, extremely disappointing. Few of the products
isolated had enantiomeric excesses which were signifi-
cantly higher than the estimated experimental error (ca.
5%). In order to recognise inherent systematic errors,
the reactions were generally performed using both the
(R,R) and the (S,S) additives. In the case of the addi-
tives 15a–b and 15d–e, the (R,R) and (S,S) additives
were enantiomeric:† in these cases, the enantiomeric
excesses measured were low, and were clearly close to
the limits of experimental error since equal and oppo-
site values were rarely observed. In view of the low
enantiomeric excesses, the absolute configuration of the
products was not determined.
The enantiomeric excesses (Fig. 4) were determined by
chiral analytical HPLC for the reactions at 100°C
which gave >20% yield of the diamine 25. These reac-
tions were, in general, performed with both enan-
tiomeric additives in order to recognise systematic
errors associated with each measurement. It is esti-
mated that the random error associated with each
enantiomeric excesses measurement was 3%.
6. Effect of chiral additives on the yield and enantio-
selectivity of ring-opening of an aziridinium ion
The chiral additives 15a–d and (M)-17 did have a
significant effect on the enantioselectivity of the ring-
opening of the aziridinium ion 26. Although, the
observed enantioselectivities were low (<ca. 15%), the
enantiomeric excesses measured were generally higher
than the inherent errors associated with each measure-
ment. Furthermore, approximately equal levels of
opposite senses of induction were observed for enan-
tiomeric catalysts (R,R)- and (S,S)-15a–b and 15d.
Remarkably, the role of the substituted ammonium
counterion in the additives is not simply as a bystander:
The influence of chiral additives on the yield and the
enantioselectivity of ring-opening of prochiral azirid-
inium ions was also investigated. Preliminary experi-
ments showed that the ring-opening of the aziridinium
ion 8 was rather sluggish, particularly at low tempera-
ture, and efforts were, therefore, focused on the ring-
opening of the aziridinium ion 26 with benzylamine
(Scheme 6).
the salts (R,R)-15a (A+=Et2NH2 ) and 15b (A+=
+
Et3NH+) induce opposite senses, although low levels, of
asymmetry in the ring-opening of the aziridinium ion
26 (Fig. 4).
† The salts (R,R)- and (S,S)-15c are diastereoisomers. With these
salts, equal and opposite enantiomeric excesses would not necessar-
ily be expected, and were not, in fact, observed.

C. Carter et al. / Tetrahedron: Asymmetry 14 (2003) 1995–2004
2001
detrimental) effect. A surprising observation was that
the cationic counterion of the chiral additive could have
a very pronounced effect on the yield of the reaction.
Unfortunately, all of the observed enantioselectivities
were low (<15% e.e.). However, in the case of the
ring-opening of the aziridinium ion 26 with benzyl-
amine, low, but significant, enantioselectivities were
induced. Nonetheless, the levels of induction compare
well the other studies in this area.16,25 Remarkably, the
chiral counterion was shown to have an effect on the
sense, as well as the level, of the induction. The enan-
tioselectivity may stem from selective stabilisation of
one of the enantiomeric transition states by ion-pairing
Scheme 6.
Table 3. Yields of the diamine 25 in THF–toluene as a
function of temperature
Temperature 25°C
40°C
60°C
100°C
Additive
Yielda (%) Yielda (%) Yielda (%) Yielda (%)
1
with the chiral anion present. H NMR spectroscopy
None
15a
15b
15c
15d
22
15
10
15
was used to show that the salt (R,R)-15c did interact
with the aziridinium ion 8; however, no evidence was
obtained for enantioselective recognition of one of the
enantiotopic sides of the ion 8. The absence of enan-
tioselective recognition in this case helps rationalise the
low levels of enantioselectivities observed. The princi-
ples which have been used to design a ‘first generation’
of chiral anions may be applied in the future to help
identify salts which are effective phase transfer catalysts
for inducing asymmetry in reactions of cations.
21b
15b
15b
13
26b
28b
21b
15d
28c
7
12b
13b
16b
17d
20b
37
18b
25b
30b
12d
27b
22
15e
(M)-17
15b
18
a Determined by analytical HPLC.
b Average yield for reactions with (R,R) and (S,S) additives.
c Yield for reactions with (R,R) additive.
d Yield for reactions with (S,S) additive.
8. Experimental
7. Conclusion
General experimental procedures have been described
previously. The borates (R,R)-15c14 and 15e,16 the
TRIPHAT salt (M)-17,11,17 the iminium chloride21 28,
the tertiary amine22 13 and the diamine20 20 were
prepared as has been previously described. Analytical
HPLC was conducted on a Gynkotek HPLC system
with diode array detection; unless otherwise stated, the
column oven was set at 24°C. A Chiracel OD column
The influence of chiral salts on reactions which involve
cationic meso intermediates was investigated. Efforts
were focused on two different classes of reaction: the
addition of N-methyl indole to a prochiral iminium ion,
and the ring-opening of a prochiral aziridium ion with
an amine nucleophile. The addition of these chiral
additives often had a very significant (beneficial or
Figure 4. Enantiomeric excesses of the diamine 25 prepared at 100°C.

2002
C. Carter et al. / Tetrahedron: Asymmetry 14 (2003) 1995–2004
(4.6×250 mm) and a ChirobioticV (4.6×250 mm)
column were used for chiral analytical HPLC and an
XTerra C18 (5 mm, 4.6×50 mm) column for analytical
HPLC; samples were calibrated against external stan-
dard samples.
mg, 45%) as colourless plates, mp >300°C; [h]2D0 +320.9
(c 1.05, DMSO); wmax/cm−1 (Nujol mull) 2920, 1463,
1377, 1247, 1070 and 1007; lH (300 MHz; DMSO-d6)
7.7 (4H, d, J 8.5, 3-H), 7.46 (4H, d, J 8.5, 4-H), 7.22
(4H, t, J 6.9), 7.11–7.02 (8H, m), 6.89 (4H, m, 8-H),
3.48 (1H, q, J 6.6, CH-NH3), 2.94 (3H, brs, NH3), 0.74
(3H, d, J 6.6, CH3-NH3); lC (75 MHz; DMSO-d6)
156.4, 153.4, 146.8, 133.2, 129.3, 128.6, 128.4, 127.1,
126.3, 126.2, 125.2, 124.8, 124.7, 122.8, 122.6, 122.2,
50.8 and 25.3; lB (250 MHz; DMSO-d6) 9.01; m/z
(FAB) 702.4 (23, MH+), 580.1 (10), 286.1 (8), 122.0 (55)
and 104.9 (100).
8.1. Diethylammonium bis[(R)-1,1%-bi-2-naphtholato]
borate (R,R)-15a
(R)-1,1%-Bi-2-naphthol (2.5 g, 8.73 mmol) was added to
the stirred solution of boric acid (270 mg, 4.37 mmol)
and diethylamine (1.35 ml, 13.1 mmol) in acetonitrile
(18 ml). The reaction mixture was refluxed 16 h. The
reaction mixture was cooled to rt then filtered. The
precipitate was then dried under vacuum to leave the
borate salt (R,R)-15a (5.01 g, 88%) as colourless plates,
mp >300°C; [h]2D0 −265.3 (c 1.10, DMSO); (found: MH+
8.4. Sodium bis[(R)-1,1%-bi-2-naphtholato] borate (R,R)-
15d
(R)-(−)-1,1%-Bi-2-naphthol (1 g, 3.5 mmol) in tetra-
hydrofuran (15 ml) was added to the stirred solution of
sodium tetraborate (180 mg, 0.46 mmol) and sodium
hydroxide (40 mg, 1 mmol) in water (4 ml). The reac-
tion mixture was stirred at rt 16 h. The phases were
separated and the organic layer was washed with satu-
rated aqueous sodium chloride solution (2 ml) and the
concentrated under reduced pressure to approx. 7 ml.
The solution was cooled to 0°C and the precipitate was
filtered to give the borate salt26 (R,R)-15d (886 mg,
42%) as yellow plates, [h]2D0 +173.6 (c 1.04, DMSO).
, 653.2815. C44H36BNO4 requires MH, 653.2815); wmax
/
cm−1 (Nujol mull) 1605, 1575, 1485, 1310, 1230, 800
and 730; lH (300 MHz; DMSO-d6) 7.95 (8H, m, 3 and
4-H), 7.26–7.34 (8H, m, 5 and 8-H), 7.15 (8H, m, 6 and
7-H), 2.86 (4H, q, J 7.3, CH2N), 1.10 (6H, t, J 7.3,
2×CH3); lC (75 MHz; DMSO-d6) 156.4, 133.1, 129.3,
128.5, 128.4, 126.1, 125.2, 124.9, 122.8, 122.2, 41.8 and
11.5; lB (250 MHz; DMSO-d6) 8.96; m/z (FAB) 727.2
(100%, MNH2Et2 ), 653.1 (13, M+) and 580 (82).
+
By the same method, (S)-1,1%-bi-2-naphthol 123 (2.5 g,
8.73 mmol) gave the borate salt (S,S)-15a (4.79 g, 84%)
as colourless plates, [h]2D0 +271.0 (c 1.09, DMSO), spec-
troscopically identical to the enantiomeric salt obtained
previously.
8.5. General method for the screening methods for the
synthesis of 13
N-Methylindole 13 (98 ml, 0.76 mmol) was added
slowly to a stirred solution of the iminium salt 28 (160
mg, 0.91 mmol) and the additive in a solvent (640 ml).
The reaction mixture was stirred at rt for 2 h. The
precipitate formed was filtered off and washed with
acetonitrile. The precipitate was redissolved in DCM (5
ml), 5% aqueous ammonia (3 ml) added and the layers
separated. The organic layer was washed with water,
dried (MgSO4), filtered and evaporated under reduced
pressure to give a crude product which was analysed by
chiral HPLC (Chiralcel OD column; eluent: 99.99:0.001
hexane–triethylamine; retention times: 13, 14.5 min;
ent-13, 18.5 min; N-methylindole, 21.5 min).
8.2. Triethylammonium bis[(R)-1,1%-bi-2-naphtholato]
borate (R,R)-15b
By the same general method, (R)-1,1%-bi-2-naphthol
(2.15g, 7.51 mmol) gave borate salt (R,R)-15b (4.19 g,
82%) as colourless crystals, [h]2D0 −232.4 (c 1.01,
DMSO); (found MH+, 682.3128. C46H40BNO4 requires
MH, 681.3128); wmax/cm−1 (Nujol mull) 1463 (CꢀC),
1377 (C-O) and 1071 (C-O); lH (300 MHz; DMSO-d6)
7.91 (4H, d, J 8.5, 3-H), 7.87 (4H, d, J 8.5, 4-H), 7.47
(4H, d, J 8.6, 5-H), 7.29 (4H, m, 6-H), 7.15 (4H, m,
7-H), 7.13 (4H, d, J 7.4, 8-H), 2.66 (6H, q, J 7.3 and
6.8, CH2NH), 0.83 (9H, t, J 7.2, CH2CH3); lC (75
MHz; DMSO-d6) 153.32, 133.2, 129.2, 128.9, 128.4,
126.2, 125.2, 124.9, 122.8, 122.2, 46.1 and 31.1; lB (250
MHz; DMSO-d6) 8.98; m/z (FAB) 681 (40%, MH+),
603 (100) and 580 (40).
8.6. 1,1-Pyrrolidinyl-2,3-cyclohexenylaziridinium trifluoro-
methanesulfonate 21
Triethylamine (2.2 ml, 15.2 mmol) was added dropwise
to a stirred solution of the amino alcohol 18 (2.0 g, 11.8
mmol) in dichloromethane (210 ml). The reaction mix-
ture was cooled to −78°C, trifluoromethanesulfonic
anhydride (2.2 ml, 13.2 mmol), warmed slowly to 0°C
over 90 min, saturated aqueous sodium hydrogen car-
bonate solution (150 ml) added and the layers sepa-
rated. The aqueous layer was washed with
dichloromethane (100 ml) and the combined organic
layers were dried (MgSO4), filtered, and evaporated
to give the aziridinium salt 21 (2.34 g, 66%) as
brown needles, mp 29.1–30.7°C, Rf 0.79; wmax/cm−1
3436, 3076, 2943, 2866, 2252, 1453, 1361, 1279, 1224,
1163, 1081, 1030, 913, 732 and 689 (CF); lH (300 MHz;
CDCl3) 3.57 (4H, t, J 6.8, (CH)CHNCH2), 3.23 (2H,
By the same general method, (S)-(−)-1,1%-bi-2-naphthol
123 (2.5g, 8.73 mmol) gave the borate salt (S,S)-15b
(5.06 g, 85%) as colourless crystals, [h]2D0 +249 (c 0.92,
DMSO), spectroscopically identical to the enantiomeric
salt obtained previously.
8.3. (R)-a-Methylbenzylamine bis[(S)-1,1%-bi-2-naphtho-
lato] borate (S,S)-15c
By the same general method, (S)-1,1%-bi-2-naphthol
(500 mg, 1.75 mmol) and (R)-(+)-a-methylbenzylamine
(300 ml, 2.62 mmol) gave the borate salt (S,S)-15c (545

C. Carter et al. / Tetrahedron: Asymmetry 14 (2003) 1995–2004
2003
t, J 6.8, NCH2), 2.25 (4H, t, J 7.3, CH2CH2), 2.12 (4H,
q, J 7.3), 1.36 (4H, t, J 7.3); lC (75 MHz; CDCl3) 123.0
(CF3), 64.8, 49.3, 47.4, 25.0, 24.2, 18.9 and 18.0; m/z
301 (12%, M+), 151 (26, C10H17N), 110 (31, C7H12N),
81 (49, C6H9), 69 (56, C4H7N), 43 (100, C2H5N).
chloroamine 24 (500 mg, 1.75 mmol) in toluene (5 ml)
and THF (5 ml). The reaction mixture was refluxed for
24 h, cooled to rt, washed with saturated aqueous sodium
bicarbonate solution (3×5 ml), dried (Na2SO4), filtered
and evaporated to leave the crude product, which was
purified by flash chromatography, eluting with 2:8 ethyl
acetate–petrol, to give the diamine 25 (512 mg, 82%) as
an orange oil, Rf 0.85; (found: MH+, 357.2331. C25H28N2
requires MH, 357.2331); wmax/cm−1 3299, 3061, 3027,
2821, 1602 and 1584; lH (300 MHz; CDCl3) 7.32–7.39
(2H, m), 7.21–7.31 (5H, m), 7.03–7.17 (6H, m), 6.95 (2H,
dt, J 6.2 and 1.8), 4.07 (1H, d, J 10.2, PhCHaHb), 4.00
(1H, d, J 10.2, PhCHaHb), 3.78 (1H, d, J 13.6, 1%- or 2%-H),
3.45 (1H, d, J 13.6, 2%- or 1%-H), 2.28–2.45 (4H, m) and
1.62 (4H, m); lC (75 MHz, CDCl3) 141.4, 140.9, 140.8,
130.2, 128.9, 128.4, 128.3, 128.0, 127.8, 127.7, 127.3,
126.9, 70.1 (CH-NH), 61.9 (CH-N), 51.0 (CH2-Ph), 47.7
(CH2-N), 22.7 (CH2); m/z (ES) 357 (100%, MH+), 286
(77) and 250 (62).
8.7. 1,1-Pyrrolidinyl-2,3-cyclohexenylaziridinium trifl-
uoromethanesulfonate 21
Silver trifluoromethanesulfonate (2.05 g, 7.99 mmol) was
added to a stirred solution of the chloroamine 19 (1.5 g,
7.99 mmol) in ethyl acetate (75 ml). The reaction mixture
was stirred for 1 h at rt, filtered and the filtrate was
evaporated under reduced pressure to give the aziri-
dinium salt 21 (2.41 g, 100%) as needles, spectroscopically
identical to that previously obtained.
8.8. (R*,R*)-1,2-Diphenyl-2-pyrrolidin-1-yl-ethanol 23
Pyrrolidine (159 ml, 1.91 mmol) was added to the stirred
solution of (R*,S*)-2,3-diphenyl oxirane27 (250 mg, 1.27
mmol) in toluene (2 ml). The reaction mixture was
refluxed for 24 h, cooled to rt, evaporated under reduced
pressure to give a crude product which crystallised to give
the amino alcohol 23 (326 mg, 96%), mp 88.5–89.4°C; Rf
0.18; (found: C, 80.6; H, 8.0; N, 5.2; C18H21NO requires
C, 80.9; H, 7.90; N, 5.2%); wmax/cm−1 3210, 1320, 1280,
1100 and 1060; lH (300 MHz; CDCl3) 7.08–7.28 (10H,
m, Ar-H), 5.29 (1H, br s, OH), 5.00 (1H, d, J 10.0,
CH-OH), 3.82 (1H, d, J 10.0, CH-N), 2.64 (2H, m), 2.47
(2H, m), 1.62–1.78 (4H, m); lC (75 MHz; CDCl3) 142.2,
130.6, 128.4, 128.2, 127.9, 127.7, 127.6, 72.3, 72.0, 48.4
and 23.1; m/z 268 (33%, MH+), 267 (10, M+), 266 (40),
160 (100), 105 (7) and 70 (15).
8.11. General method for the screening methods for the
synthesis of 25
Benzylamine (19 ml, 0.17 mmol) and triethylamine (24 ml,
0.17 mmol) were added to a stirred solution of the
chloroamine 24 (25 mg, 0.09 mmol) in toluene (2 ml) and
THF (2 ml). The reaction mixture was refluxed for 24 h,
cooled to rt and washed with saturated aqueous sodium
bicarbonate solution (2×2 ml), dried (Na2SO4), filtered
and evaporated under reduced pressure to give the crude
product which was analysed by analytical HPLC (Waters
XTerra column; gradient elution: 0.1:0.1:19.8:80“
0.1:0.1:99.8:0 triethylamine–acetic acid–methanol–water
over 15 min; retention time: 8.72 min) and chiral HPLC
(Waters XTerra column in series with Chirabiotic V
column;
gradient
elution:
0.1:0.1:19.8:80“
0.1:0.1:49.8:50 triethylamine–acetic acid–methanol–
water over 8.75 min, followed by 0.1:0.1:99.8:0
triethylamine–acetic acid–methanol–water for 16.25 min;
retention times: 25, 19.4 min; ent-25; 21.3 min).
8.9. (R*,R*)-1-Chloro-1,2-diphenyl-2-pyrrolidin-1-yl-eth-
ane 24
Methanesulfonyl chloride (650 ml, 8.4 mmol) and triethyl-
amine (1.2 ml, 8.4 mmol) were added to the stirred
solution of the amino alcohol 23 (1.5 g, 5.6 mmol) in
dichloromethane (25 ml) at 0°C. The reaction mixture
was slowly warmed to rt over 2 h, washed with saturated
aqueous sodium bicarbonate solution (2×25 ml) and the
organic layer dried (Na2SO4), filtered and evaporated
under reduced pressure to leave the chloroamine 220 (1.6
g, 99%) as a brown oil; Rf 0.84; (found: MH+, 286.1352.
C18H20NCl requires MH, 286.1363); wmax/cm−1 3025,
2950, 1610, 1480, 1445 and 710; lH (300 MHz; CDCl3)
7.11 (8H, s, Ar-H), 6.96 (2H, m, Ar-H), 5.42 (1H, d, J
7.5, CH-Cl), 4.06 (1H, d, J 7.5, CH-N), 2.65 (2H, m, CHa
and CHc), 2.56 (2H, m, CHb and CHd), 1.71 (4H, m,
CH2CH2); lC (75 MHz; CDCl3) 139.3, 136.6, 130.2,
128.7, 128.4, 128.2, 127.8, 127.5, 74.7, 64.6, 51.2 and 23.6;
m/z (ES) 286.2 (100%, MH+), 268.2 (83) and 250.2 (41).
References
1. (a) Nelson, A. Angew. Chem., Int. Ed. 1999, 38, 1583; (b)
Carter, C.; Nelson, A. In Organic Synthesis Highlights V;
Schmaltz, H.-G.; Wirth, T., Eds.; Wiley: Weinheim, 2003.
2. Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997,
119, 12414.
3. (a) O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem.
Soc. 1989, 111, 2353; (b) Lygo, B.; Wainwright, P. G.
Tetrahedron Lett. 1997, 38, 8595; (c) Corey, E. J.; Bo, Y.;
Busch-Petersen, J. J. Am. Chem. Soc. 1998, 120, 13000.
4. Lygo, B.; Crosby, J.; Peterson, J. A. Tetrahedron 2001, 57,
6447.
5. (a) Corey, E. J.; Noe, M. C.; Xu, F. Tetrahedron Lett. 1998,
39, 5347; (b) Kim, D. Y.; Huh, S. C.; Kim, S. M.
Tetrahedron Lett. 2001, 42, 6299.
6. (a) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1998, 39,
1599; (b) Alcaraz, L.; MacDonald, G.; Ragot, J.; Lewis,
N. J.; Taylor, R. J. K. Tetrahedron 1999, 55, 3707; (c) Arai,
S.; Shioiri, T. Tetrahedron Lett. 1998, 39, 2145.
7. Arai, S.; Nakayama, K.; Ishida, T.; Shioiri, T. Tetrahedron
Lett. 1999, 40, 4215.
8.10.
(R*,R*)-Benzyl-(1%,2%-diphenyl-2-pyrrolidin-1-yl-
ethyl)-amine 25
Benzylamine (287 ml, 2.62 mmol) and triethylamine (488
ml, 3.5 mmol) were added to the stirred solution of the

2004
C. Carter et al. / Tetrahedron: Asymmetry 14 (2003) 1995–2004
16. Llewellyn, D. B.; Adamson, D.; Arndtsen, B. Org. Lett.
8. Brown, R. C. D.; Kelly, J. F. Angew. Chem., Int. Ed. 2001,
40, 4496.
2000, 2, 4165.
17. Lacour, J.; Ginglinger, C.; Grivet, C.; Bernardinelli, G.
9. (a) Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka, K. J.
Am. Chem. Soc. 2000, 122, 5228; (b) Belokon, Y. N.; North,
M.; Kublitski, V. S.; Ikonnikov, N. S.; Krasik, P. E.;
Maleev, V. I. Tetrahedron Lett. 1999, 40, 6105; (c) Belokon,
Y. N.; Davies, R. G.; North, M. Tetrahedron Lett. 2000,
41, 7245; (d) Belokon, Y. N.; Kochetkov, K. A.; Churkina,
T. D.; Ikonnikov, N. S.; Chesnokov, A. A.; Larionov, O.
V.; Parma´r, V. S.; Kumar, R.; Kagan, H. B. Tetrahedron:
Asymmetry 1998, 9, 851.
10. Ooi, T.;Kameda, M.;Maruoka, M. J. Am. Chem. Soc. 1999,
121, 6519.
11. Lacour, J.; Ginglinger, C.; Favarger, F.; Torche-Haldi-
mann, S. Chem. Commun. 1997, 2285.
Angew. Chem., Int. Ed. 1997, 36, 609.
18. Shapiro, S. L.; Soloway, H.; Shapiro, H. J.; Freeman, L.
J. Am. Chem. Soc. 1959, 81, 3993.
19. Anderson, S. R.; Ayers, J. T.; Vries, K. M.d.; Ito, F.;
Mendenhall, D.; Vanderplas, B. C. Tetrahedron: Asymme-
try 1999, 10, 2655.
20. O’Brien, P.; Poumellec, P. Tetrahedron Lett. 1996, 37, 5619.
21. Betschart, C.; Schmidt, B.; Seebach, D. Helv. Chim. Acta
1988, 71, 1999.
22. Grumbach, H. J.; Arend, M.; Risch, N. Synthesis 1996, 7,
883.
23. Lacour, J.; Jodry, J. J.; Ginglinger, C.; Torche-Haldimann,
S. Angew. Chem., Int. Ed. 1998, 37, 2379.
24. (a) Chen, Y.-X.; Metz, M. V.; Li, L.; Stern, S. L.; Marks,
T. J. J. Am. Chem. Soc. 1998, 120, 6287; (b) Lacour, J.;
Ginglinger, C.; Favarger, F. Tetrahedron Lett. 1998, 39,
4825.
12. Ginglinger, C.; Jeannerat, D.; Lacour, J.; Juge´, S.; Uziel,
J. Tetrahedron Lett. 1998, 39, 7495.
13. Cai, D.; Hughes, D. L.; Verhoeven, T. R.; Reider, P. J.
Tetrahedron Lett. 1995, 36, 7991.
14. Perisamy, M.; Venkatraman, L.; Sivakumar, S.; Sam-
pathkumar, N.; Ramanathan, C. R. J. Org. Chem. 1999,
64, 7643.
15. Matteson, D. S.; Ray, R.; Rocks, R. R.; Tsai, D. J.
Organometallics 1983, 2, 1536.
25. Lacour, J.; Monchaud, D.; Marsol, C. Tetrahedron: Asym-
metry 2002, 43, 8257.
26. Arai, T.; Yamada, Y. M. A.; Yamamoto, N.; Sasai, H.;
Shibasaki, M. Chem. Eur. J. 1996, 2, 1368.
27. Lusinchi, X.; Hanquet, G. Tetrahedron 1997, 53, 13727.