Asymmetric α-substitution versus aza Diels-Alder reaction of electron deficient N-sulfonyl imines

Article abstract of DOI:10.1039/a909116e

Several N-arylsulfonylglycine esters have been brominated under photolytic conditions to provide the corresponding α-bromoglycine. These bromo esters can be treated with a range of bases to generate N-sulfonyl imino esters in situ; attempts to isolate the imines in a pure state were universally unsuccessful. Once generated, the imines can be trapped with cyclopcntadiene to provide the corresponding aza Diels-Alder adducts in varying yields, depending upon the base used. In addition, if organometallic bases were employed (alkyllithiums and alkylaluminium reagents), not only were aza Diels-Alder adducts formed, but addition to the imine was also observed. In the case of organoaluminium reagents, imine addition was the major product. This process could be transformed into a stoichiometric asymmetric version, by generating a chiral aluminium reagent in situ to form a trialkyl (or trialkoxy) aluminium reagent, which when reacted with an N-sulfonyl bromoglycinate resulted in 19 to 62% enantiomeric excess of the corresponding substituted glycinate product. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/a909116e

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Asymmetric ꢀ-substitution versus aza Diels–Alder reaction of
electron deficient N-sulfonyl imines
Paul E. Morgan,a Ray McCagueb and Andrew Whiting*a
1
a Department of Chemistry, Faraday Building, U.M.I.S.T., P.O. Box 88, Manchester,
UK M60 1QD
b ChiroTech Ltd., Cambridge Science Park, Milton Road, Cambridge, UK CB4 4WE
Received (in Cambridge, UK) 17th November 1999, Accepted 8th December 1999
Several N-arylsulfonylglycine esters have been brominated under photolytic conditions to provide the corresponding
α-bromoglycine. These bromo esters can be treated with a range of bases to generate N-sulfonyl imino esters in situ;
attempts to isolate the imines in a pure state were universally unsuccessful. Once generated, the imines can be trapped
with cyclopentadiene to provide the corresponding aza Diels–Alder adducts in varying yields, depending upon the
base used. In addition, if organometallic bases were employed (alkyllithiums and alkylaluminium reagents), not only
were aza Diels–Alder adducts formed, but addition to the imine was also observed. In the case of organoaluminium
reagents, imine addition was the major product. This process could be transformed into a stoichiometric asymmetric
version, by generating a chiral aluminium reagent in situ to form a trialkyl (or trialkoxy) aluminium reagent, which
when reacted with an N-sulfonyl bromoglycinate resulted in 19 to 62% enantiomeric excess of the corresponding
substituted glycinate product.
Introduction
The asymmetric synthesis of α-amino acids has been the focus
of considerable synthetic endeavour for many years and has
relied upon methods such as an asymmetric Strecker reaction,
asymmetric alkylation of glycinate derivatives, asymmetric
amination of chiral enolates and asymmetric hydrogenation.1
Amongst the various methods, the asymmetric addition of
nucleophiles to an imine double bond2 is important for access-
ing acyclic amino acid derivatives, while cyclic amino acid
derivatives may also be derived from the cycloaddition of a
diene to an imine, i.e. an aza Diels–Alder reaction.3
During studies related to the development of new methods
for catalysing asymmetric aza Diels–Alder reactions to derive
chiral synthons for the preparation of cyclic amino acid deriv-
atives,4 we examined the use of various methods for the gener-
ation of electron deficient imines, including imine 2, which can
be prepared via elimination of HBr from α-bromoglycinate 15
(Scheme 1). Of many methods investigated for the efficient gen-
eration of imine 2, organometallic reagents (RM, Scheme 1)
were employed. However, not only were Diels–Alder adducts 3
isolated, but often α-substitution products 4 were also isolated.6
In this paper, we discuss the full details of this investigation
and its application to the asymmetric synthesis of N-sulfonyl
α-amino acid derivatives.
Results and discussion
In order to develop new asymmetric Lewis-acid catalysed
entries to adducts of type 3, we wished to generate imines of
type 2 in a pure form and free from metal ligating by-products.
Scheme 1
We therefore extensively examined methods for the unambig-
uous formation of N-sulfonyl imines 2. It has been reported
that condensation of an aldehyde with a sulfonamide results in
the formation of an N-sulfonyl imine,7 however, we were unable
to isolate the extremely moisture sensitive imine 2b under the
reported conditions. Additionally, attempted in situ trapping
of the imine with cyclopentadiene to yield the cycloadduct 3b
resulted in low conversions (<23% yield). Similarly, using the
isocyanate method of Holmes,8 we were unable to cleanly
isolate the sulfonyl imine 2d in a pure state. An alternative
solution to the clean generation of N-sulfonyl imines 2 was
postulated using similar methods to those used by Jung and
co-workers for the preparation of N-acyl imines, i.e. via an aza-
Wittig reaction.9 It was envisaged that use of a sulfonyl chloride
6 with ylide 5, would provide the corresponding sulfonyl imine
2 (Scheme 2) after the aza-Wittig reaction.
Treatment of the N-trimethylsilylphosphinamide 5 with
4-nitrobenzenesulfonyl chloride 6a gave the corresponding
phosphorus ylide 7a in high yield. In contrast, the reaction
DDOI: 10.1039/a909116e
J. Chem. Soc., Perkin Trans. 1, 2000, 515–525
This journal is © The Royal Society of Chemistry 2000
515

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with benzenesulfonyl chloride 6b gave very poor yields (<25%)
of the corresponding phosphinamide 7b, due to the lack of
reactivity of the sulfonyl chloride. However, addition of sodium
fluoride and a catalytic amount of 18-crown-6 to the reaction
mixture in refluxing toluene effected clean generation of 7b
in 75% yield. The resulting N-sulfonylphosphinamides 7 were
column stable and readily handled in air. The ensuing aza-
Wittig reactions of ylides 7 proved less reactive than their acyl
imine counterparts, reported by Jung and co-workers.9 The
reaction of either of the N-sulfonylphosphinamides 7 with
ethyl glyoxylate 8 in refluxing toluene failed to yield the corres-
ponding imines 2 in a quantitative manner (Scheme 2) and
scale, presumably catalysed by traces of HBr. This was not,
however, observed for the 4-nitrophenylsulfonyl derivative 1c,
where the NH and CH signals were always distinct at δ 6.15 and
6.70.
Having prepared a range of α-bromoglycinates 1, suitable
conditions for generation of the corresponding imines were
examined. Of particular interest was the use of bases which
would induce clean elimination of HBr without producing by-
products which might inhibit the use of Lewis-acid catalysts.
Consequently, metal alkyl-type bases were employed, since they
offer the potential of producing a metal bromide and a neutral
species, e.g. an alkane. Thus the α-bromoglycinates were
screened against a variety of bases and solvents to determine
the best conditions for generation of imines 2 (Scheme 1). Due
to the hydrolytic sensitivity of imines 2, the efficiency of the
imine generation was determined by in situ trapping with
cyclopentadiene as before. The results of this exercise are
summarised in Table 1.
From observation of Table 1, it is apparent that the imines 2
were not generated in quantitative yields under most of the
conditions examined. The most efficient production of aza
Diels–Alder adduct 3 was obtained by using Hünig’s base; use
of lithium bases resulted in competing bromide substitution to
provide the α-substituted products 4, via imine generation and
alkyllithium addition to the resulting C᎐N bond (Scheme 1).
᎐
Additionally, different aryl substituents failed to have a pro-
found effect on the generation of the imines 2. Since the nitro
group is a potent electron withdrawing group, it should cause
an increase in the acidity of the sulfonyl NH of the bromo-
glycinate 1c and should be more rapidly deprotonated under
basic conditions. However, the resulting imine 2c will be more
electrophilic than unsubstituted systems and could result in
increased α-substitution if the alkylating agent is still present in
solution, rather than cycloaddition. Examination of the yields
of the cycloadduct 3c (Table 1) shows that there is little change
in the ratio of α-substitution reaction versus cycloaddition.
Thus the overall effect of the arylsulfonamide seems to be that
despite increased acidity of the NH function by addition of
an electron withdrawing group, the sensitivity of the resulting
imine towards addition compensates, resulting in little change
in product distribution. This point is reinforced by examination
of different aryl substituents. Although the methoxy group
of 1d, being electron donating, should cause a decrease in the
acidity of the NH, which by 1H NMR shows its virtual coinci-
dence with the α-CH, there is again no substantial change in
product distribution. The degree of conversion of the bromo-
glycinate 1d to the cycloadduct 3d (Table 1) differs to a minor
extent compared to the α-substituted product, with overall
increased yields and a slight improvement in the ratio of the
Diels–Alder cycloadduct to the α-substituted product. For final
comparison, the effects of the arylsulfonyl substituent were
compared with an N-methylsulfonyl substituent, i.e. 1e. As
before, the yield of the cycloadduct 3e was again compromised
by competing α-substitution products 4e and the yields and
product distribution were very similar to those obtained for the
arylsulfonyl systems.
Scheme 2
subsequent in-situ reaction with cyclopentadiene to yield the
cycloadducts 3 resulted in low (ca. 5–25%) yields.
Having been unable to generate N-sulfonyl imines 2 in high
yield and purity, an alternative method was examined based
on work reported independently by Prato5a and Holmes,5b as
summarised in Scheme 1, i.e. using a base mediated elimination
of HBr from a bromoglycinate 1. In order to probe the reactiv-
ity of N-sulfonyl imines generated by this method, a variety of
N-sulfonyl glycine systems 910 were prepared by reaction of the
glycine ester with the corresponding sulfonyl chloride.11 Sub-
sequent photobromination of glycines 9 [eqn. (1)] produced the
Since the amine bases efficiently produced the cycloadduct 3,
attempts were made to remove the ammonium hydrobromide
salt from the reaction mixture by filtration of the precipitate
from the reaction of bromide 1b with Hünig’s base (compare
with entry 10, Table 1). However, subsequent addition of
cyclopentadiene to the presumed intermediate imine 2b, pro-
duced a fall in the yield of the subsequent Diels–Alder reaction
to 56% from 95%. This may be attributed to the imine 2b being
insoluble and being removed with the amine hydrobromide
salt, however, mass spectral data of the precipitate showed
no evidence for this. Alternatively, the imine 2a may exist in
equilibrium with the ammonium sulfonamide salt 10 (Scheme 3)
which is likely to be insoluble and hence be removed by filtration,
thus lowering the yield of the subsequent Diels–Alder reaction.
corresponding bromides 1 in reasonably pure form by direct
crystallisation from the reaction mixture. The only exception
being tert-butyl ester 9f; exposure to the bromination condi-
tions caused cleavage of the tert-butyl ester.
The highly hydrolytically unstable bromoglycinates 1 all
appeared similar with respect to the sulfonamide and methine
hydrogen resonances by 1H NMR, with the exception of
p-nitrophenylsulfonyl derivative 1c, which exhibited a separ-
ation of 0.55 ppm between the NH and CH resonances. This
compares with 0.05 ppm for the remaining bromine derivative
1. Significantly, some batches of bromo compounds 1a, 1b and
1d–1e showed coalescence of the NH and CH resonances,
which strongly suggests proton exchange on the NMR time-
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J. Chem. Soc., Perkin Trans. 1, 2000, 515–525

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Table 1 Conversion of bromides 1 to cycloadducts 3 versus addition products 4
α-Bromo-
glycinate
Base
(equiv.)
Temp./
ЊC
Time/
min
Yield
3 (%)
Yield
4 (%)
Entry
Solvent
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1c
1c
1c
1c
1c
1c
1c
1d
1d
1d
1d
1d
1d
1d
1e
1e
1e
1e
1e
1e
1e
Et3N (1)
C7H8
C7H8
CH2Cl2
C7H8
C7H8
C7H8
C7H8
CH2Cl2
C7H8
C7H8
CH2Cl2
C7H8
C7H8
C7H8
C7H8
C7H8
CH2Cl2
C7H8
C7H8
C7H8
C7H8
CH2Cl2
C7H8
C7H8
C7H8
C7H8
C7H8
C7H8
CH2Cl2
C7H8
C7H8
C7H8
C7H8
C7H8
C7H8
CH2Cl2
C7H8
C7H8
C7H8
C7H8
RT
0
60
60
60
30
60
30
60
10
60
60
60
10
60
60
30
60
30
30
30
60
60
60
30
60
30
60
60
60
60
30
60
30
60
60
60
60
30
60
30
60
76
92
0
n/a
n/a
n/a
30
25
12
iPr2NEt (1)
DBU (1)
nBuLi (1)
nBuLi (1)
MeLi (1)
MeLi (1)
Et3N (3)
0
0
0
0
15
18
27
26
22
80
95
5
0
15
RT
0
n/a
n/a
n/a
n/a
32
27
47
12
13
12
0
Et3N (3)
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
iPr2NEt (1)
DBU (1)
nBuLi (1)
nBuLi (1)
nBuLi (1)
MeLi (1)
MeLi (1)
MeLi (1)
LiHMDS (1)
tBuLi (1)
Et3N (1)
0
0
0
0
12
5
5
Ϫ78
0
38
42
38
0
15
72
96
0
20
17
10
10
65
98
0
0
0
0
0
0
0
0
0
5
n/a
n/a
n/a
27
25
18
iPr2NEt (1)
DBU (1)
nBuLi (1)
nBuLi (1)
MeLi (1)
MeLi (1)
Et3N (1)
0
Ϫ78
0
RT
0
22
n/a
n/a
n/a
35
37
28
iPr2NEt (1)
DBU (1)
nBuLi (1)
nBuLi (1)
MeLi (1)
MeLi (1)
Et3N (1)
0
0
0
0
5
13
22
28
74
98
0
12
15
23
29
0
32
RT
0
n/a
n/a
n/a
22
37
22
iPr2NEt (1)
DBU (1)
nBuLi (1)
nBuLi (1)
MeLi (1)
MeLi (1)
0
0
0
Ϫ78
0
12
of these 1H NMR experiments may be explained by the mechan-
ism shown in Scheme 3, i.e. after initial abstraction of the acidic
NH, the ensuing ammonium glycinate sulfonamide appears as a
broad singlet at 8.20 ppm. After thirty minutes, the imine 2b is
generated, together with the hydrogen bromide salt of the
amine base. The HBr salt of Hünig’s base appears as the broad
singlet at 7.20 ppm at this concentration, with the remaining
two singlets corresponding to the imino CH resonances for the
E- and Z-imines. Obviously, the more thermodynamically
stable E-imine would be expected to predominate over the
Z-imine, which explains the observed resonance ratio. Finally,
the peak at δ 9.10 may well correspond to some aldehyde
derived from hydrolysis of the imine.
Having considered the fact that electronic alterations to the
α-bromoglycinates 1 produced minimal difference with respect
to generation of the imines 2, it was decided that removing the
possibility of α-substitution would be the logical answer to the
problem of the α-substitution reaction, while avoiding amine
bases. Therefore, the use of hydride based reagents was con-
sidered. The N-phenylsulfonyl derived α-bromoglycinate 1b was
therefore treated with a range of metal hydrides, to determine if
generation of the imine could be achieved in a quantitative
manner. The results of this exercise are shown in Table 2
(entries 1–6).
Scheme 3
Having achieved minimal success with respect to generation
of the imines 2 in a pure state, attempts were made to examine
the reaction by H NMR. Attempts to generate imines 2 with
1
alkyllithium bases in the 1H NMR tube failed to yield any
significant results. However, when Hünig’s base was used in
dry, degassed d-chloroform, a difference in the spectrum was
observed upon addition of the base. Acquisition of the 1H
NMR spectrum immediately after addition of the base to 1b
showed a complex set of signals, with peaks corresponding to
the base, bromoglycinate 1b and a rather broad peak at 8.20
ppm. However, acquisition of the spectrum some thirty minutes
later saw a shift in the broad peak from 8.20 to 7.20 ppm, and
the appearance of three sharp singlets at 8.15, 8.20 and 9.10
ppm, with an integration ratio of 1:2:2 respectively. The results
It can be clearly seen from Table 2 (entries 1–6) that the
cycloadduct 3b was produced in an almost quantitative man-
ner (except for entry 2), presumably with the imine 2b being
generated by a deprotonation–elimination sequence by the
addition of hydride reagents. However, a similar observation
J. Chem. Soc., Perkin Trans. 1, 2000, 515–525
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Table 2 Hydride-induced conversion of 1b to cycloadduct 3b
α-Bromo-
Temp./
ЊC
Time/
min
Yield of
3b (%)
Ee of
3b (%)
Entry
glycinate
Base
Lewis acid
Solvent
1
2
3
4
5
6
7
8
9
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
NaH
n/a
n/a
n/a
n/a
n/a
n/a
THF
THF
THF
THF
THF
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
0
10
10
10
10
10
10
15
15
15
15
95
56
98
96
97
89
86
92
94
75
n/a
n/a
n/a
0
n/a
n/a
0
0
0
n/a
NaHa
DIBAL-H
DIBAL-H/(R)-Binaphthol
K-Selectride
NaH
NaH
NaH
NaH
NaH
Ϫ78
Ϫ78
Ϫ78
Ϫ100
Ϫ100
Ϫ100
Ϫ100
Ϫ100
TiCl4/(R)-Binaphthol
Ti(OiPr)2Cl2/(R)-Binaphthol
Et2AlCl/(R)-Binaphthol
Ln(OTf)3
10
a Precipitate filtered before addition of the diene.
Table 3 Aluminium complex-mediated conversion of 1b to alkylated products 4b
α-Bromo-
glycinate
Temp./
ЊC
Product 1 4b,
R3 (Yield [%])
Ee
Product 2 4b,
R3 (Yield [%])
Entry
Reagent
(configuration)
1
2
3
4
5
6
7
8
9
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
Me3Al
Et3Al
Ϫ78
Ϫ78
0
Me (55)
Et (95)
EtO (76)
iPrO (97)
nBu (30)
tBu (0)
Me (55)
Et (90)
Et (95)
n/a
n/a
n/a
n/a
n/a
n/a
52 (S)
62 (S)
55 (S)
19
n/a
n/a
n/a
n/a
Et (21)
Et (18)
n/a
n/a
n/a
(EtO)3Al
(iPrO)3Al
0
0
0
Et2AlCl, nBuLi
Et2AlCl, tBuLi
Me3Al, (R)-binaphthol
Et3Al, (R)-binaphthol
Ϫ78
Ϫ78
RT
Ϫ78
RT
RT
10
11
12
(EtO)3Al, (R)-binaphthol
(iPrO)3Al, (R)-binaphthol
Et2AlCl, nBuLi, (R)-binaphthol
EtO (69)
iPrO (97)
nBu (35)
n/a
n/a
Et (12)
25
0
to that found for imine 2b generation with amine bases was
noted, i.e. filtration of the precipitate formed immediately
after addition of the base (NaH), caused a decrease in the
yield of the cycloadduct 3b formed after reaction with
cyclopentadiene (entry 2, Table 2). This reduction in the yield
(to 56%) can be explained in an analogous manner to that
described earlier, whereby the initial abstraction of the acidic
NH yields the partially insoluble intermediate sodium sul-
fonamide salt, which in turn may be in equilibrium with the
imine 2b. Hence, removal of the precipitate led to the reduc-
tion in the overall yield of the imine 2b and consequently the
cycloadduct 3b.
In the case of the DIBAL-H (entry 3 and 4, Table 2) induced
elimination of hydrogen bromide, the by-product of imine 2b
generation would presumably be diisobutylaluminium bromide,
which could in turn act as a Lewis acid for the resulting Diels–
Alder reaction. As a result, attempts to generate a chiral
aluminium Lewis acid, after addition of the hydride reagent,
were undertaken. This was carried out by addition of a
stoichiometric quantity of (R)-binaphthol, (Table 2, entry 4) to
the imine 2b–diisobutylaluminium bromide mixture, in the
hope that this would lead to enantioselection in the subsequent
Diels–Alder reaction. Only racemic Diels–Alder cycloadduct 3b
was isolated however, whether in the presence or absence of
molecular sieves, though yields were high.
There is a fundamental question about whether it is actually
possible to obtain asymmetric induction for the reaction of an
imine of type 2 with cyclopentadiene to derive 3. In order to
probe the reactivity of imine 2b in isolation, i.e. the thermal
cycloaddition process, bromide 1b was treated with sodium
hydride at Ϫ100 ЊC (Table 2, entry 6) in the presence of
cyclopentadiene. The reaction was complete in less than 10
minutes and produced an 89% yield of the cycloadduct 3b.
Clearly, this experiment shows the very high reactivity of imine
2b under thermal conditions12 and raises the likelihood that
even if a chiral Lewis acid were added to the reaction, it may
not result in sufficient imine activation to dominate the reaction
outcome. Thus, asymmetric induction using the addition of an
external Lewis acid catalyst to an imine 2 may be expected to be
highly unlikely. Indeed, these conclusions seem to be supported
by the results shown in Table 2, entries 7–9, where initial imine
generation with sodium hydride was followed by complexation
of the imine with a chiral Lewis acid, however, no asymmetric
induction was obtained (chiral HPLC). In addition, using a
lanthanide Lewis acid (Table 2, entry 10) after imine generation
failed to produce identifiable differences in the thermal
reaction.
A possible solution to this could be a slow generation of an
imine 2, using a Lewis acid to induce fragmentation of the
bromide, followed by deprotonation. It would then be possible
that the resulting Lewis acid complex, if closely associated with
the imine 2, may assist in producing asymmetric induction. We
therefore began to examine the effect of adding aluminium-
based Lewis acids to bromide 1b, however it was immediately
apparent from the first reaction attempted (Table 3, entry 2)
that rather than obtaining the cycloadduct 3b, only the
α-substituted products 4b were produced despite the presence
of cyclopentadiene. Following an exploration of different
achiral aluminium reagents (Table 3, entries 1–6), it was clear
that such reagents produced efficient substitution products,
except where attempts were made to generate n-butyl and tert-
butyl aluminium reagents (entries 5 and 6). The asymmetric
variant was therefore explored, whereby the trialkyl (or alkoxy)
aluminium reagents were treated with (R)-binaphthol and
subsequently added to the bromoglycinate 1b. The results are
shown in Table 3.
In order to generate an asymmetric version of the aluminium
species, the trialkyl or trialkyloxy aluminium species was first
treated with binaphthol. The resulting chiral reagent was then
reacted with the bromide 1b. In each case, the alkylaluminium
complexes (vide infra) converted bromide 1b through to the
α-amino acid analogue 4b with reasonable efficiency (Entries 7–
9, Table 3) and with moderate enantioselectivity at Ϫ78 ЊC (52–
62%). The ee was only marginally lowered by raising the tem-
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J. Chem. Soc., Perkin Trans. 1, 2000, 515–525

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perature to room temperature (entry 9, Table 3). Ee’s for the
alkoxy-derived reagents were much poorer (entries 10 and 11,
Table 3), however, the fact that such compounds are highly
hydrolytically sensitive means that any asymmetric induction is
fortuitous. Finally, attempts to generate an asymmetric variant
of the n-butylaluminium complex proved unrewarding, with
only low yields of the ethyl derivative 4b (R = Et) being
obtained.
attempted formation of the ester using HCl–ethanol yielded
predominately the amide 16 after sulfonylation.
It is possible to propose a mechanism for the process which
involves the initial formation of an aluminium complex 11 by
reaction of the aluminium species with binaphthol (Scheme 4).
For the alanine analogue, i.e. 4b, R = Me, (Table 3, entry 1),
the ee was determined by reduction to the alcohol and conver-
sion to the (ϩ)-Mosher ester 17 (Scheme 6). The de was then
Scheme 6 i; LiAlH4, Et2O. ii; (ϩ)-Mosher acid chloride, Et3N.
determined by comparison of the methylene signals by 1H
NMR and was reinforced by 19F NMR. The absolute con-
figuration of this product was determined by the comparison
1
with the H NMR spectrum of the (ϩ)-Mosher ester of the
product derived from commercially available -alanine, after
esterification, sulfonylation, and reduction (Scheme 7) to the
alcohol.
Scheme 4
After formation of this aluminate, dehalogenation of 1b could
afford imine 2b and the alkylaluminium bromide 12, which in
turn may act as a second Lewis acid. This complex may then
deliver a second alkyl group to the imine 2b to afford the
α-substituted glycine derivative 4b. Evidence for this mechan-
ism has been obtained by treatment of the binaphthol with
triethylaluminium, which produces only one molar equivalent
of ethane gas. The resulting activated aluminium complex
is therefore likely to be 11. In order to derive the observed
major enantiomeric products, attack of 12 [derived from (R)-
binaphthol] on 2b must occur from the Si-face. Examination of
approximate molecular mechanics based models suggest that
Re-face attack could be disfavoured due to steric repulsion
between the sulfonyl oxygens of 2b and the aluminium bromide
function, whereas Si-face attack is less sterically congested.
In order to determine the ee of the products 4b, chiral HPLC
was used for the isopropoxy, ethoxy and ethyl derivatives. In the
last case, the absolute configuration of the product was
determined by comparison of the HPLC of the same derivative
prepared from commercially available (S)-(ϩ)-2-aminobutyric
acid 14, after a) formation of the acid chloride; b) esterification
and c) subsequent sulfonylation (Scheme 5). Interestingly,
Scheme 7 i; HCl, EtOH, CH2Cl2. ii; PhSO2Cl, Et3N, CH2Cl2. iii;
LiAlH4, Et2O. iv; (ϩ)-Mosher acid chloride, Et3N.
Summary
α-Bromoglycinates 1 are readily prepared by photobromination
of the corresponding glycine. The ease of cycloaddition, versus
nucleophilic addition, of the imine derivatives 2 depends
entirely on the nucleophilicity versus basicity of the base system
used. Imines of type 2 are highly electron deficient and are
therefore difficult to isolate in a pure state using the bromo-
glycinate route, they can therefore react with dienes in the
absence of other reactive nucleophiles. However, alkyl or
alkyloxyaluminium based reagents are sufficiently nucleophilic
to override cycloaddition processes and produce efficient
α-substitution products 4b. This process can be made asym-
metric, but is stoichiometric in binaphthol and results in low to
moderate asymmetric induction. Further developments of this
work are underway to produce catalytic asymmetric variants of
the imine substitution process.
Experimental
All reagents which were not prepared as detailed later were
purchased from either Aldrich, Acrös Chimica, Avocado or
Lancaster. Aryl- and alkyl-sulfonyl glycinates were prepared
according to literature methods.10,11 All commercial reagents
were used without any further purification unless otherwise
stated. Solvents were all distilled before use over either
Scheme 5 i; SOCl2, CH2Cl2. ii; EtOH. iii; PhSO2Cl, CH2Cl2, Et3N.
J. Chem. Soc., Perkin Trans. 1, 2000, 515–525
519

View Article Online
benzophenone–sodium (THF) or calcium hydride (all remain-
ing solvents) under an atmosphere of argon. TLC was per-
formed on Merck plastic or aluminium sheets coated with silica
gel 60 F254 (Art. 5735); the chromatograms were initially exam-
ined under UV light and then developed either with iodine
vapour or a 10% ethanolic solution of molybdophosphoric acid
and visualised by heating with a heat gun. Column chromato-
graphy was achieved under medium pressure, using Acrös
Chimica silica gel, 0.035–0.07 nm (pore diameter: ca. 6 nm). All
anhydrous, low temperature reactions were carried out in
glassware which was dried prior to use by storage in a glass
oven maintained at 140 ЊC and cooled under a stream of argon.
Extractions were dried over magnesium sulfate. Evaporations
were carried out using a Büchi rotary evaporator or Büchi cold-
finger rotary evaporator, followed by drying in vacuo. Kugel-
röhr distillations were carried out using a Büchi GKR-51
Kugelröhr apparatus. Mps were determined using an Electro-
thermal melting point apparatus and are uncorrected. 1H NMR
spectra were recorded at 200 or 300 MHz on a Bruker AC200 or
AC300 spectrometer. 13C NMR spectra were recorded at 75.5
MHz on a Bruker AC300 spectrometer. 31P NMR spectra were
132.4 (Ar, quat); δP (81 MHz; CDCl3) 16.7; m/z (FAB) 835
(2Mϩ ϩ H), 418 (base peak, Mϩ ϩ H) [Found: m/z (FAB)
418.1024. Calc. for C24H20NSO2P: m/z, 418.1031].
Preparation of N,N-phthaloylglycine tert-butyl ester
A stirred mixture of toluene (150 ml), tert-butyl chloroacetate
(24.39 g, 0.16 mol), potassium phthalimide (30.00 g, 0.16 mol)
and hexadecyltributylphosphonium bromide (8.12 g, 16.00
mmol) was heated to reflux under argon. After 24 h, the cloudy
solution was cooled, filtered and washed with diethyl ether.
The combined organic filtrate was evaporated and chromato-
graphed on silica gel (diethyl ether as eluant). The first fraction
(1600 ml) was collected, washed with aqueous sodium hydrox-
ide solution (1 M) and water, dried (MgSO4) and evaporated to
yield N,N-phthaloylglycine tert-butyl ester11b as a white solid
(33.77 g, 81%): mp 90–92 ЊC (lit. 92–93 ЊC11b); νmax (KBr disc)/
cmϪ1 inter alia 1745 (s) C᎐O, 1710 (s) C᎐O, 1230 (m); δ (300
᎐
᎐
H
MHz; CDCl3) 1.45 [9H, s, C(CH3)3], 4.30 (2H, s, CH2), 7.70
(2H, m, ArH’s), 7.90 (2H, m, ArH’s); δC (75.5 MHz; CDCl3)
27.8 [C(CH3)3], 39.5 (CH2), 82.6 [C(CH3)3], 123.3 (Ar), 131.8
(Ar), 134.0 (Ar, quat), 166.1 and 167.4 (C᎐O, quat); m/z (FAB)
recorded at 81 MHz on a Bruker AC200 spectrometer. 1H, 13
C
᎐
523 (2Mϩ ϩ H), 262 (Mϩ ϩ H), 206 (base peak, Mϩ Ϫ C4H7)
[Found: C, 64.1; H, 5.7; N, 5.1. Calc. for C14H15NO4: C, 64.4;
H, 5.8; N, 5.4%].
and 31P spectra were recorded using either CDCl3 or DMSO
as internal standards respectively. J Values are measured in Hz.
IR spectra were recorded on a Perkin-Elmer 783 equipped
with a PE600 data station or a Perkin-Elmer 1605 FT-IR, and
UV spectra were recorded on a Perkin-Elmer l15 spectrometer.
Electron impact (EI) (70 eV) and chemical ionisation (CI)
spectra were recorded with a Kratos MS25. Fast atom bombard-
ment (FAB) spectra were recorded on a Kratos MS50, using a
m-nitrobenzylalcohol matrix and accurate mass determinations
were carried out on a Kratos Concept IS spectrometer. Micro-
analyses were performed using a Carlo-Erba 1106 elemental
analyser. Chiral HPLC was undertaken by the use of either a
Chiralpak AD, OD or Chiracel OF chiral column with a Pye
Unicam UV detector and pump. Optical rotations are given in
10Ϫ1 deg cm2 gϪ1 and were performed on an Optical Activity
AA-1000 polarimeter.
Preparation of N-phenylsulfonylglycine tert-butyl ester 9f
Hydrazine monohydrate (2.30 g, 46.00 mmol) was added to a
suspension of N,N-phthaloylglycine tert-butyl ester (12.00 g,
45.93 mmol) in ethanol (100 ml) with vigorous stirring.
The solution was heated to reflux for 4 h, cooled and filtered.
Benzenesulfonyl chloride (12.19 g, 69.00 mmol) was added to
the resulting solution, followed by triethylamine (6.98 g, 69.00
mmol) in a dropwise manner. The mixture was stirred for 24 h
before evaporation to yield a green solid. This solid was sus-
pended in dichloromethane (100 ml), washed with water (100
ml), dried (MgSO4) and evaporated. The residual solid was
recrystallised from dichloromethane–hexane to yield the N-
phenylsulfonylglycine tert-butyl ester10c 9f as a white solid
(11.78 g, 95%): mp 110–112 ЊC (lit. 117–117.510c); νmax (KBr
disc)/cmϪ1 inter alia 3200 (m) NH, 2920 (m) CH , 1745 (s) C᎐O,
Preparation of triphenyl(p-nitrophenylsulfonylimino)-
phosphorane 7a
᎐
3
1240 (s) C–O, 760 and 690 (m); δH (300 MHz; CDCl3) 1.45 [9H,
s, C(CH3)3], 3.80 (2H, d, J 7.5, CH2, collapses to a singlet upon
addition of D2O), 5.20 (1H, broad m, NH, disappears upon
addition of D2O), 7.65–7.69 (3H, m, ArH’s), 8.00–8.05 (2H, m,
ArH’s); δC (75.5 MHz; CDCl3) 27.9 [C(CH3)3], 44.9 (CH2),
83.0 [C(CH3)3], 127.3 (Ar), 129.3 (Ar), 133.0 (Ar), 139.4 (Ar,
p-Nitrobenzenesulfonyl chloride (0.634 g, 2.860 mmol) was
added to a stirred slurry of triphenyl(trimethylsilylimino)phos-
phorane 5 (1.000 g, 2.860 mmol) in toluene (150 ml), heated to
reflux under an atmosphere of argon. After heating for 24 h, the
solution was evaporated to yield a brown solid (1.119 g). The
solid was recrystallised from dichloromethane–hexane to yield
7a as a pale brown solid (1.110 g, 90%): mp 147–149 ЊC; νmax
(KBr disc)/cmϪ1 inter alia 1665 (s) N᎐P, 1527 (m) NO , 1377 (m)
N–SO2, 851 (w), 755 (w) and 722 (w); δH (300 MHz; CDCl3)
7.41–7.80 (17H, m, ArH’s), 8.05 (2H, d, J 10, ArH’s); δC (300
MHz; CDCl3) 123.4 (Ar), 127.2 (Ar, quat), 127.5 (Ar), 128.7 (Ar),
128.8 (Ar), 129.0 (Ar, quat), 132.0 (Ar), 132.9 (Ar, quat); δP (81
MHz; CDCl3) 16.8; m/z (FAB) 463 (base peak, Mϩ ϩ H) [Found:
m/z (FAB) 463.0882. Calc. for C24H20N2SO4P: m/z, 463.0881].
quat), 167.9 (C᎐O, quat); m/z (FAB) 431 (2Mϩ Ϫ 2C H ),
᎐
4
7
272 (Mϩ ϩ H), 216 (base peak, Mϩ Ϫ C4H7) [Found: C, 53.4;
H, 6.1; N, 5.5; S, 12.2. Calc. for C12H17NSO4: C, 53.1; H, 6.3;
N, 5.2; S, 11.8%].
᎐
2
General procedure for bromination of N-sulfonylglycine esters 1
Bromine (1 eq.) was added to a slurry of the alkyl N-aryl-
sulfonylglycinate 9 (1 eq.) in carbon tetrachloride under an
atmosphere of argon. The mixture was irradiated with UV light
(254 nm) while being heated under reflux for 2 h. After com-
pletion, the solvent was partially removed by distillation and
the resulting suspended residue was cooled under a stream
of argon to complete precipitation and left a brown sus-
pended solid, which was filtered under argon and used without
further purification. These solids could be stored in vacuo over
phosphorus pentoxide for several months.
Preparation of triphenyl(phenylsulfonylimino)phosphorane 7b
Benzenesulfonyl chloride (0.505 g, 2.860 mmol) was added to a
stirred slurry of triphenyl(trimethylsilylimino)phosphorane 5
(1.00 g, 2.86 mmol), sodium fluoride (0.120 g, 14.3 mmol) and
18-crown-6 (0.076 g, 0.286 mmol) in toluene (150 ml). The
resulting solution was heated to reflux under argon. After heat-
ing for 24 h, the solution was evaporated to yield a brown solid
(0.932 g). The solid was recrystallised from dichloromethane–
hexane to yield 7b as a pale brown solid (0.829 g, 75%): mp 137–
N-Phenylsulfonyl-ꢀ-bromoglycine methyl ester 1a. Bromine
(3.30 g, 41.00 mmol), N-phenylsulfonylglycine methyl ester 9a
(9.40 g, 41.00 mmol) and carbon tetrachloride (300 ml) accord-
ing to the general procedure produced a brown solid 1a (12.12
g, 96%): mp 79–81 ЊC; νmax (KBr disc)/cmϪ1 inter alia 3300 (s)
139 ЊC; νmax (KBr disc)/cmϪ1 inter alia 1657 (s) N᎐P, 1362 (m)
᎐
N–SO2, 755 (w) and 723 (w); δH (300 MHz; CDCl3) 7.39–7.78
(20H, m, ArH’s); δC (75.5 MHz; CDCl3) 123.4 (Ar), 125.7 (Ar,
quat), 127.8 (Ar), 128.8 (Ar), 128.8 (Ar), 128.9 (Ar), 132.0 (Ar),
520
J. Chem. Soc., Perkin Trans. 1, 2000, 515–525

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NH, 1740 (s) C᎐O, 1340 (s) C–O, 760 (m), 730 (m), 550 (m)
(0.403 g, 1.552 mmol), toluene (40 ml) and cyclopentadiene
᎐
C–Br; δH (300 MHz; CDCl3) 4.19 (3H, s, OCH3), 6.37 (2H, m,
CH and NH), 7.61–7.81 (3H, m, ArH’s), 8.07 (2H, d, J 10,
ArH’s); δC (75.5 MHz; CDCl3) 53.5 (OCH3), 53.8 (CHBr),
(0.256 ml, 3.104 mmol) according to the general procedure gave
a viscous orange oil (0.398 g) which was chromatographed to
yield the cycloadduct 3a (0.346 g, 76%) as a white solid: mp 64–
127.1 (Ar), 127.8 (Ar), 129.1 (Ar), 133.7 (Ar, quat), 165.9 (C᎐O,
65 ЊC; νmax (KBr disc)/cmϪ1 inter alia 1760 (m) C᎐O, 1220 (m)
᎐
᎐
quat); m/z (FAB) 536 (2Mϩ Ϫ Br), 228 (base peak, Mϩ Ϫ HBr)
[Found: C, 35.3; H, 3.9; N, 4.3; S, 10.1. Calc. for C9H10NSO4Br:
C, 35.1; H, 3.6; N, 4.6; S, 10.4%].
C–O, 745 and 692 (m) and 606 (s) C᎐C (cis); δ (300 MHz;
᎐
H
CDCl3) 1.73 (2H, ABq, J 9, septet, 115, CH2), 3.31 (1H, s,
COCHCH), 3.49 (1H, s, CHCO2CH3), 3.68 (3H, s, OCH3), 4.56
(1H, s, NCH), 6.12–6.23 (2H, m, HC᎐CH), 7.44–7.55 (3H, m,
᎐
ArH’s), 7.82–7.87 (2H, m, ArH’s); δC (75.5 MHz; CDCl3) 46.3
(CH2), 49.6 (COCHCH), 52.4 (CH3), 59.7 (COCH), 64.5
(NCH), 127.8 (Ar), 128.8 (Ar), 132.8 (Ar), 135.9 (Ar), 136.3
(HC᎐CH), 139.4 (Ar, quat), 171.2 (C᎐O, quat); m/z (FAB) 294
N-(p-Nitrophenylsulfonyl)-ꢀ-bromoglycine ethyl ester 1c.
Bromine (3.30 g, 41.00 mmol), N-p-nitrophenylsulfonylglycine
ethyl ester 9c (11.82 g, 41.00 mmol) and carbon tetrachloride
(300 cm3) according to the general procedure produced a brown
solid 1c (13.84 g, 92%): mp 89–91 ЊC; νmax (KBr disc)/cmϪ1 inter
᎐
᎐
(Mϩ ϩ H), 234 (Mϩ Ϫ C2O2H3), 228 (base peak, Mϩ Ϫ C6H5)
[Found: C, 57.2; H, 5.2; N, 4.7; S, 10.5. Calc. for C14H15NSO4:
C, 57.3; H, 5.2; N, 4.8; S, 10.9%].
alia 3250 (m) NH, 2980 (m) CH , 1740 (s) C᎐O, 1330 (s) NO ,
᎐
3
2
1240 (s) C–O, 850 (m) and 510 (m) C–Br; δH (300 MHz; CDCl3)
1.30 (3H, t, J 7.5, CH3CH2O), 4.30 (2H, q, J 7.5, OCH2CH3),
6.15 (1H, d, J 10, CHBr), 6.70 (1H, d, J 10, NH), 8.15 (2H, d,
J 10, ArH’s), 8.40 (2H, d, J 10, ArH’s); δC (75.5 MHz; CDCl3)
13.9 (CH3CH2O), 53.3 (CHBr), 63.5 (CH3CH2O), 124.5 (Ar),
Cyclopentadiene cycloadduct 3b. (i) Diisopropylethylamine
(0.282 ml, 1.62 mmol), N-phenylsulfonyl-α-bromoglycine ethyl
ester 1b (0.500 g, 1.620 mmol), toluene (40 ml) and cyclopenta-
diene (1.33 ml, 16.20 mmol) according to the general procedure
gave an orange oil (0.510 g) which was chromatographed to
yield the cycloadduct 3b (0.473 g, 95%) as a white solid: mp 67–
129.5 (Ar), 145.4 (Ar, quat), 150.4 (Ar, quat), 165.6 (C᎐O,
᎐
quat); m/z (FAB) 573 (2Mϩ Ϫ Br), 287 (base peak, Mϩ Ϫ Br)
[Found: C, 34.0; H, 3.2; N, 7.9; S, 8.8. Calc. for C10H11N2SO6Br:
C, 32.7; H, 3.0; N, 7.6; S, 8.7%].
69 ЊC; νmax (KBr disc)/cmϪ1 inter alia 1750 (m) C᎐O, 1220 (m)
᎐
C–O, 740 and 690 (m) and 610 (s) C᎐C (cis); δ (300 MHz;
᎐
H
CDCl3) 1.21 (3H, t, J 10, OCH2CH3), 1.72 (2H, ABq, J 10,
septet, 127, CH2), 3.32 (1H, s, COCHCH), 3.49 (1H, s, COCH),
4.12 (2H, q, J 7.5, OCH2CH3), 4.59 (1H, s, NCH), 6.04–6.21
N-(p-Methoxyphenylsulfonyl)-ꢀ-bromoglycine ethyl ester 1d.
Bromine (3.30 g, 41.00 mmol), N-(p-methoxyphenylsulfonyl)-
glycine ethyl ester 9d (11.20 g, 41.00 mmol) and carbon tetra-
chloride (300 ml) according to the general procedure gave a
yellow solid 1d (8.10 g, 56%): mp 106–108 ЊC; νmax (KBr disc)/
(2H, m, HC᎐CH), 7.47 (3H, m, ArH’s), 7.85 (2H, m, ArH’s);
᎐
δC (75.5 MHz; CDCl3) 14.0 (CH3CH2O), 46.1 (CH2), 49.5
(COCHCH), 59.7 (COCH), 61.1 (CH3CH2O), 64.5 (NCH),
128.7 (Ar), 127.7 (Ar), 132.7 (Ar), 136.2 (Ar), 136.4 (Ar, quat),
139.4 (HC᎐CH), 170.6 (C᎐O, quat); m/z (CI) 325 (Mϩ ϩ NH ),
cmϪ1 inter alia 3220 (s) NH, 1740 (s) C᎐O, 1350 (m) C–O, 840
᎐
(m) and 490 (m) C–Br; δH (300 MHz; CDCl3) 1.30 (3H, t, J 7.5,
CH3CH2O), 3.85 (3H, s, OCH3), 4.25 (2H, q, J 7.5, OCH2CH3),
6.15 (2H, m, NH and CH), 7.00 (2H, d, J 10, ArH’s), 7.85 (2H,
d, J 10, ArH’s); δC (75.5 MHz; CDCl3) 13.6 (CH3CH2O), 54.5
(CHBr), 55.5 (OCH3), 63.2 (OCH2CH3), 114.0 (Ar), 114.2 (Ar),
114.3 (Ar), 129.2 (Ar), 129.7 (Ar, quat), 130.1 (Ar, quat), 163.7
᎐
᎐
4
308 (Mϩ ϩ H), 61 (base peak, Mϩ Ϫ C13H8SO2) [Found: C,
58.3; H, 5.8; N, 4.3; S, 10.3. Calc. for C15H17NSO4: C, 58.6; H,
5.6; N, 4.6; S, 10.4%].
(ii) Sodium hydride (0.037 g, 1.552 mmol) was added to a
stirred solution of N-phenylsulfonyl-α-bromoglycine ethyl ester
1b (0.403 g, 1.552 mmol), dichloromethane (40 cm3) and cyclo-
pentadiene (0.256 ml, 3.104 mmol) and according to the general
procedure gave a viscous orange oil (0.522 g), which was
chromatographed to yield the cycloadduct 3b (0.453 g, 95%) as
a white solid and which was identical to that isolated in the
previous procedure.
(iii) n-Butyllithium (0.648 ml of a 2.5 M solution in hexanes,
1.620 mmol), N-phenylsulfonyl-α-bromoglycine ethyl ester 1b
(0.500 g, 1.620 mmol), toluene (40 ml) and cyclopentadiene
(1.334 ml, 16.20 mmol) according to the general procedure gave
an orange oil (0.347 g) which was chromatographed to yield the
cycloadduct 3b (0.134 g, 27%) as a white solid, which was identi-
cal to that isolated from the previous procedure, together with
the α-substituted glycine (0.024 g, 5%) 4b (R = nBu): mp 70 ЊC;
νmax (KBr disc)/cmϪ1 inter alia 3279 (s) NH, 2959 (s) CH3, 2873
(C᎐O, quat); m/z (FAB) 543 (2Mϩ Ϫ Br), 272 (Mϩ Ϫ Br), 171
᎐
(base peak, Mϩ Ϫ C4H6NO2Br) [Found: C, 37.8; H, 4.3; N, 4.3;
S, 8.9. Calc. for C11H14NSO5Br: C, 37.5; H, 4.0; N, 4.0; S, 9.1%].
N-Methylsulfonyl-ꢀ-bromoglycine ethyl ester 1e. Bromine
(3.30 g, 41.00 mmol), N-methylsulfonylglycine ethyl ester 9e
(7.43 g, 41.00 mmol) and carbon tetrachloride (300 ml) accord-
ing to the general procedure gave a yellow solid 1e (10.66 g,
100%): mp 108–110 ЊC; νmax (KBr disc)/cmϪ1 inter alia 3260 (m)
NH, 1730 (s) C᎐O, 1340 (s) C–O and 500 (m) C–Br; δ (300
᎐
H
MHz; CDCl3) 1.35 (3H, t, J 7.5, OCH2CH3), 3.15 (3H, s,
SO2CH3), 4.30 (2H, q, J 7.5, OCH2CH3), 6.25 (2H, m, NH and
CH); δC (75.5 MHz; CDCl3) 13.6 (CH3CH2O), 41.9 (SO2CH3),
54.8 (CHBr), 63.3 (CH CH O), 165.5 (C᎐O, quat); m/z (FAB)
᎐
3
2
359 (2Mϩ Ϫ Br), 180 (Mϩ Ϫ Br) [Found: C, 24.4; H, 4.3; N, 6.2;
S, 13.2. Calc. for C5H10NSO4Br: C, 23.0; H, 3.9; N, 5.4; S,
12.3%].
(s) CH , 1724 (s) C᎐O, 1216 (s) C–O, 755 (s) and 689 (s); δ (300
᎐
2
H
MHz; CDCl3) 0.79–0.89 (3H, m, CH2CH2CH3), 1.10 (3H, t,
J 7.5, OCH2CH3), 1.19–1.37 (4H, m, CH2CH2), 1.51–1.73 (2H,
m, CHCH2), 3.80–3.92 (3H, m, OCH2CH3 and CHNH), 5.25
(1H, d, J 10, NH), 7.47 (3H, m, ArH’s), 7.85 (2H, m, ArH’s); δC
(75.5 MHz; CDCl3) 14.0 (CH3CH2O), 14.0 (CH3CH2CH2), 21.9
(CH3CH2CH2), 25.4 (CH3CH2CH2), 32.0 (CH2CH), 55.7
(CHNH), 61.5 (OCH2), 127.4 (Ar), 128.9 (Ar), 132.3 (Ar),
General procedure for the preparation of cyclopentadiene
cycloadducts 3 and ꢀ-substituted products 4
Base (1 eq.) was added to a stirred solution of the N-sulfonyl-α-
bromoglycine 1 (1 eq.) in toluene (or other solvent as specified
below) at 0 ЊC. After 30 min cyclopentadiene (2 eq.) was added
and the mixture allowed to stir for 60 min. Water was
added, the layers separated and the organic layer extracted with
dichloromethane. The combined organic extracts were dried
(MgSO4) and evaporated to yield an orange oil. This oil was
chromatographed on silica gel (ethyl acetate–hexanes (1:9) as
eluant) to yield the cycloadducts 3.
139.7 (Ar, quat), 171.7 (C᎐O, quat); m/z (FAB) 599 (2Mϩ ϩ H),
᎐
300 (base peak, Mϩ ϩ H) [Found: m/z (FAB), 300.1263. Calc.
for C14H22NSO4: m/z, 300.1270].
Cyclopentadiene cycloadduct 3c. Triethylamine (0.225 ml,
1.62 mmol), N-4-nitrophenylsulfonyl-α-bromoglycine ethyl
ester 1c (0.59 g, 1.62 mmol), toluene (40 ml) and cyclopenta-
diene (1.334 ml, 16.2 mmol) according to the general procedure
gave an orange oil (0.467 g), which after chromatography gave
Cyclopentadiene cycloadduct 3a. Triethylamine (0.216 ml,
1.552 mmol), N-phenylsulfonyl-α-bromoglycine methyl ester 1a
J. Chem. Soc., Perkin Trans. 1, 2000, 515–525
521

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cycloadduct 3c (0.410 g, 72%) as a white solid: mp 105–106 ЊC;
νmax (KBr disc)/cmϪ1 inter alia 2920 (w) CH , 1730 (s) C᎐O,
1350 (s) NO2, 1250 (m) C–O, 850 (s) and 620 (s); δH (300 MHz;
CDCl3) 1.24 (3H, t, J 7.5, OCH2CH3), 1.49–1.98 (2H, ABq,
J 10, septet, 127.5, CH2 bridgehead), 3.40 (1H, s, COCHCH),
3.62 (1H, s, COCH), 4.17 (2H, q, J 7.5, OCH2CH3), 4.58 (1H, s,
hexanes (1:9) as eluant] to yield the cycloadduct 3b as a white
solid (0.458 g, 96%) which was identical to that isolated above.
The product was determined to be racemic by chiral HPLC
using a Chiralpak AD column [propan-2-ol–hexane (20:80) as
eluant], peaks at 582 and 534 s.
᎐
3
NCH), 6.30–6.36 (2H, m, HC᎐CH), 8.08 (2H, d, J 10, ArH’s),
(ii) Diethylaluminium chloride. Diethylaluminium chloride
(1.552 ml of a 1 M solution in hexanes, 1.552 mmol) was added
to a stirred colourless solution of (R)-binaphthol (0.444 g,
1.552 mmol) cooled to Ϫ78 ЊC in dichloromethane (10 ml) and
was allowed to stir for 30 min before cooling to Ϫ100 ЊC. This
solution was then added via cannula to a stirred mixture of
N-phenylsulfonyl-α-bromoglycine ethyl ester 1b (0.403 g, 1.552
mmol) and sodium hydride (0.037 g, 1.552 mmol) cooled to
Ϫ100 ЊC, which produced a pale yellow turbid solution. After
30 min, cyclopentadiene (0.256 ml, 3.104 mmol) was added and
after a further 15 min, water (50 ml) was added. The mixture
was extracted with dichloromethane (2 × 50 ml), separated,
dried (MgSO4) and evaporated to yield a viscous orange oil
(0.905 g). Purification by silica gel chromatography [ethyl
acetate–hexanes (1 : 9) as eluant] gave the cycloadduct 3b (0.448
g, 94%) as a white solid, which was identical to that isolated
above. The product was determined to be racemic by chiral
HPLC as above.
᎐
8.33 (2H, d, J 10, ArH’s); δC (75.5 MHz; CDCl3) 13.9
(OCH2CH3), 46.1 (CH2), 49.4 (COCHCH), 60.2 (COCH), 61.6
(OCH2CH3), 64.9 (NCH), 113.9 (Ar), 123.9 (Ar), 128.8 (Ar),
136.2 (Ar), 136.8 (Ar, quat), 145.6 (Ar, quat), 149.9 (HC᎐CH),
᎐
170.1 (C᎐O, quat); m/z (FAB) 706 (2Mϩ ϩ H), 353 (Mϩ ϩ H),
᎐
151 (base peak, Mϩ Ϫ C6H5N2SO4) [Found: C, 50.9; H, 4.9; N,
7.8; S, 9.5. Calc. for C15H16N2SO6: C, 51.1; H, 4.6; N, 8.0; S,
9.1%].
Cyclopentadiene cycloadduct 3d. Triethylamine (0.225 ml,
1.62 mmol), N-4-methoxyphenylsulfonyl-α-bromoglycine ethyl
ester 1d (0.57 g, 1.62 mmol), toluene (40 ml) and cyclopenta-
diene (1.334 ml, 16.20 mmol) according to the general procedure
gave an orange oil (0.402 g), which was chromatographed to
yield the cycloadduct 3d (0.356 g, 65%) as a white solid: mp
114–116 ЊC; νmax (KBr disc)/cmϪ1 inter alia 2990 (m) CH3, 2870
(m) OCH , 1750 (s) C᎐O, 1260 (s) C–O, 850 (s) and 600 (s);
᎐
3
δH (300 MHz; CDCl3) 1.24 (3H, t, J 10, OCH2CH3), 1.39–2.05
(2H, ABq, J 10, septet, 110, CH2 bridgehead), 3.28 (1H, s,
COCHCH), 3.42 (1H, s, COCH), 4.15 (2H, q, J 7.5, OCH2-
Preparation of N-phenylsulfonyl-ꢀ-methylglycine ethyl ester 4b
(R3 ؍ Me)13
CH ), 4.55 (1H, s, NCH), 6.01–6.21 (2H, m, HC᎐CH), 6.95 (2H,
᎐
3
Trimethylaluminium (0.776 ml of a 2 M solution in hexanes,
1.552 mmol) was introduced dropwise to a stirred solution of
N-phenylsulfonyl-α-bromoglycine ethyl ester 1b (0.500 g, 1.552
mmol) at Ϫ78 ЊC in dichloromethane (25 ml). The resulting
pale yellow solution was stirred for 30 min, allowed to warm to
RT and stirred for a further 8 h. Water (25 ml) was added, the
layers were separated, extracted with dichloromethane (3 × 20
ml), dried (MgSO4) and evaporated to yield the α-substituted
product 4b (R3 = Me) as a white solid (0.225 g). Purification by
silica gel chromatography [ethyl acetate–hexane (3:7) as eluant]
gave the product 4b (R3 = Me)13 as a white solid (0.220 g,
55%): mp 56–58 ЊC; νmax (KBr disc)/cmϪ1 inter alia 3300 (m)
d, J 9.5, ArH’s), 7.78 (2H, d, J 9.5, ArH’s); δC (75.5 MHz;
CDCl3) 14.1 (OCH2CH3), 46.1 (CH2), 49.6 (COCHCH), 55.5
(COCH), 55.7 (OCH3), 61.4 (OCH2CH3), 64.3 (NCH), 113.9
(Ar), 130.0 (Ar), 131.0 (Ar), 131.9 (Ar), 135.9 (Ar, quat),
136.154 (Ar, quat), 162.9 (HC᎐CH), 170.8 (C᎐O, quat); m/z
᎐
᎐
(FAB) 675 (2Mϩ ϩ H), 338 (Mϩ ϩ H), 171 (base peak, Mϩ Ϫ
C9H11NO2) [Found: C, 57.0; H, 6.0; N, 4.3; S, 9.9. Calc. for
C16H19NSO5: C, 57.0; H, 5.7; N, 4.2; S, 9.5%].
Cyclopentadiene cycloadduct 3e. Triethylamine (0.225 ml, 1.6
mmol), N-methylsulfonyl-α-bromoglycine ethyl ester 1e (0.500
g, 1.6 mmol), toluene (40 cm3) and cyclopentadiene (1.334 ml,
16.200 mmol) according to the general procedure gave an
orange oil (0.335 g), which was chromatographed to yield the
cycloadduct 3e (0.290 g, 74%): mp 99–101 ЊC; νmax (KBr disc)/
cmϪ1 inter alia 2980 (m) CH , 1755 (s) C᎐O, 1330 (m) C–O, 695
NH, 1735 (s) C᎐O, 1210 (w) C–O, 745 (m) and 690 (m); δ (300
᎐
H
MHz; CDCl3) 1.11 (3H, t, J 7, OCH2CH3), 3.91–3.98 (3H, m,
OCH2CH3 and NHCH, simplifies to a 2H, m upon addition
of D2O), 5.39 (1H, d, J 9, NH, disappears upon addition of
D2O), 7.46–7.59 (3H, m, ArH’s), 7.84 (2H, m, ArH’s); δC (75.5
MHz; CDCl3) 13.9 (CH3CH), 19.8 (OCH2CH3), 51.6 (CH3-
CH2CH), 61.8 (OCH2CH3), 127.2 (Ar), 129.1 (Ar), 132.5 (Ar),
᎐
3
(m); δH (300 MHz; CDCl3) 1.30 (3H, t, J 7.5, OCH2CH3), 1.51–
1.91 (2H, ABq, J 10, septet, 127.5, CH2 bridgehead), 2.97 (3H,
s, SO2CH3), 3.47 (1H, s, COCHCH), 3.62 (1H, s, COCH), 4.23
(2H, q, J 7.5, OCH2CH3), 4.63 (1H, s, NCH), 6.43–6.53 (2H, m,
139.8 (Ar, quat), 172.1 (C᎐O, quat); m/z (FAB) 258 (base peak,
᎐
Mϩ ϩ H) [Found: C, 51.1; H, 5.7; N, 5.4; S, 12.6. Calc. C, 51.3;
H, 5.9; N, 5.4; S, 12.5%].
HC᎐CH); δ (75.5 MHz; CDCl3) 14.3 (OCH2CH3), 41.6
᎐
C
(COCHCH), 46.7 (CH2), 49.7 (COCH), 61.0 (NCH), 61.5
(OCH CH ), 65.4 (SO CH ), 137.0 (HC᎐CH), 171.0 (C᎐O,
᎐
᎐
2
3
2
3
Preparation of N-phenylsulfonyl-ꢀ-ethylglycine ethyl ester 4b
(R3 ؍ Et)
quat); m/z (FAB) 246 (Mϩ ϩ H), 151 (base peak, Mϩ Ϫ SO2-
CH2) [Found: C, 49.2; H, 6.7; N, 5.5; S, 13.1. Calc. for C10H15-
NSO4: C, 49.0; H, 6.2; N, 5.7; S, 13.1%].
Triethylaluminium (1.552 ml of a 1 M solution in hexanes,
1.552 mmol) was introduced dropwise to a stirred solution of
N-phenylsulfonyl-α-bromoglycine ethyl ester 1b (0.50 g, 1.552
mmol) at Ϫ78 ЊC in dichloromethane (25 ml). The resulting
pale yellow solution was stirred for 30 min, allowed to warm to
RT and stirred for a further 8 h. Water (25 ml) was added, the
layers were separated, extracted with dichloromethane (3 × 20
ml), dried (MgSO4) and evaporated to yield the α-substituted
product 4b (R3 = Et) as a white solid (0.405 g). Purification by
silica gel chromatography [ethyl acetate–hexane (3:7) as eluant]
gave the product 4b (R3 = Et) as a white solid (0.400 g, 95%):
mp 43–45 ЊC; νmax (KBr disc)/cmϪ1 inter alia 3280 (m) NH, 1735
Attempted asymmetric preparation of cyclopentadiene
cycloadduct 3b
(i) DIBAL-H. DIBAL-H (0.220 cm3 of a 1 M solution in
toluene, 1.552 mmol) was added to a stirred solution of
N-phenylsulfonyl-α-bromoglycine ethyl ester (0.403 g, 1.552
mmol) in dichloromethane (40 ml) cooled to Ϫ78 ЊC. The solu-
tion, with a slight colourless precipitate, was stirred for 30 min
before the addition of (R)-binaphthol (0.444 g, 1.552 mmol).
The turbid solution was stirred for a further 15 min before the
addition of cyclopentadiene (0.256 ml, 3.104 mmol). After 10
mins, water (50 ml) was added, the mixture was extracted with
dichloromethane (2 × 50 ml), the phases were separated, dried
(MgSO4) and evaporated to yield a viscous orange oil (0.482 g).
This oil was chromatographed on silica gel [ethyl acetate–
(s) C᎐O, 1210 (w) C–O, 750 (m) and 690 (m); δ (300 MHz;
᎐
H
CDCl3) 0.90 (3H, t, J 7, CH2CH3), 1.06 (3H, t, J 7, OCH2CH3),
1.59–1.85 (2H, m, CH3CH2CH), 3.82–3.96 (3H, m, OCH2CH3
and NHCH, simplifies to a 2H, m upon addition of D2O),
5.25 (1H, d, J 9, NH, disappears upon addition of D2O), 7.45–
522
J. Chem. Soc., Perkin Trans. 1, 2000, 515–525

View Article Online
7.59 (3H, m, ArH’s), 7.84 (2H, m, ArH’s); δC (75.5 MHz;
CDCl3) 9.3 (CH3CH2), 13.9 (OCH2CH3), 26.7 (CH3CH2), 56.9
(CH3CH2CH), 61.6 (OCH2CH3), 127.5 (Ar), 129.0 (Ar), 132.7
solution was stirred at this temperature for 30 min, allowed to
warm to RT and stirred for a further 8 h. Water (25 cm3) was
added, the layers were separated, extracted with dichloro-
methane (3 × 20 cm3), dried (MgSO4) and evaporated to yield a
mixture of α-substituted products 4b (R3 = Et) and 4b (R3 =
nBu) as an off white solid (0.267 g). The components were sep-
arated by silica gel chromatography [ethyl acetate–hexane (3:7)
as eluant] and gave the α-ethyl derivative 4b (R3 = Et) (0.088 g,
21%) and the α-n-butyl derivative 4b (R3 = nBu) (0.144 g, 31%),
which were both identical to those products isolated above.
(Ar), 139.8 (Ar, quat), 171.5 (C᎐O, quat); m/z (FAB) 543
᎐
(2Mϩ ϩ H), 272 (Mϩ ϩ H), 198 (base peak, Mϩ Ϫ C3H4O2)
[Found: C, 53.1; H, 6.5; N, 5.3; S, 11.6. Calc. C, 53.1; H, 6.3;
N, 5.2; S, 11.8%].
Preparation of N-phenylsulfonyl-ꢀ-ethoxyglycine ethyl ester 4b
(R3 ؍ OEt)
Triethoxyaluminium (0.251 g, 1.552 mmol) was introduced to a
stirred solution of N-phenylsulfonyl-α-bromoglycine ethyl ester
1b (0.500 g, 1.552 mmol) at 0 ЊC in dichloromethane (25 ml).
The resulting pale yellow solution was stirred for 30 min,
allowed to warm to RT and stirred for a further 8 h. Water (25
ml) was added, the layers separated, extracted with dichloro-
methane (3 × 20 ml), dried (MgSO4) and evaporated to yield
the α-substituted product 4b (R3 = OEt) as a white solid (0.356
g). Purification by silica gel chromatography [ethyl acetate–
hexane (3:7) as eluant] gave the product as a white solid (0.339
g, 76%): mp 52–55 ЊC; νmax (KBr disc)/cmϪ1 inter alia 3275 (m)
Attempted preparation of N-phenylsulfonyl-ꢀ-tert-butylglycine
ethyl ester 4b (R3 ؍ tBu)
Diethylaluminium chloride (1.552 ml of a 1 M solution in
hexanes, 1.552 mmol) was added to a stirred solution of tert-
butyllithium (0.913 ml of a 1.7 M solution in hexanes, 1.552
mmol) in dichloromethane (5 ml) at 0 ЊC. After 30 min, the
solution was added dropwise to a stirred solution of N-phenyl-
sulfonyl-α-bromoglycine ethyl ester 1b (0.500 g, 1.552 mmol)
at 0 ЊC in dichloromethane (25 ml). After 30 min, the mixture
was allowed to warm to RT and stirred for a further 8 h. Water
(25 ml) was added, the layers separated, extracted with dichloro-
methane (3 × 20 ml), dried (MgSO4) and evaporated to yield
the α-ethyl substituted product 4b (R3 = Et) as an off-white
solid (0.225 g). Purification by silica gel chromatography [ethyl
acetate–hexane (3:7) as eluant] gave the α-ethyl derivative 4b
(R3 = Et) (0.075 g, 18%), which was identical to that isolated
above.
NH, 1735 (s) C᎐O, 1210 (w) C–O, 750 (m) and 690 (m); δ (300
᎐
H
MHz; CDCl3) 1.04 (3H, t, J 7, CH2CH3), 1.19 (3H, t, J 7,
OCH2CH3), 3.42–3.72 (2H, m, CH3CH2OCH), 4.16 (2H, m,
OCH2CH3), 5.06 (1H, d, J 9, CH, collapses to a singlet upon
addition of D2O), 5.93 (1H, d, J 9, NH, disappears upon addi-
tion of D2O), 7.45–7.61 (3H, m, ArH’s), 7.88 (2H, m, ArH’s);
δC (75.5 MHz; CDCl3) 11.3 (CH3CH2), 14.2 (OCH2CH3), 63.6
(OCH2CH3), 69.0 (CH3CH2OCH), 69.4 (CH3CH2), 127.5 (Ar),
128.5 (Ar), 133.0 (Ar), 139.6 (Ar, quat), 171.2 (C᎐O, quat); m/z
᎐
Preparation of (S)-(؉)-N-phenylsulfonyl-ꢀ-ethylglycine ethyl
ester 15 from (S)-(؉)-2-aminobutyric acid 14
(FAB) 288 (base peak, Mϩ ϩ H) [Found: m/z, 288.3371. Calc.
for C12H18NSO5 m/z, 288.3379].
(S)-2-Aminobutyric acid 14 (0.20 g, 1.93 mmol) was suspended
in dichloromethane (5 ml) and treated with thionyl chloride
(1.18 ml, 1.93 mmol). After 5 h, ethanol (10 ml) was added and
the mixture was evaporated to yield a brown oil, which was
resuspended in dichloromethane (5 ml) and treated with tri-
ethylamine (5.30 ml, 3.86 mmol) and phenylsulfonyl chloride
(0.230 g, 1.93 mmol). The resulting solution was stirred over-
night before the addition of water (15 ml). The organic phase
was extracted with dichloromethane (3 × 15 ml), dried
(MgSO4) and evaporated to yield a white solid (0.299 g). Purifi-
cation by column chromatography [ethyl acetate–hexane (3 : 7)
as eluant] gave N-phenylsulfonamide ethyl ester 15 as a white
solid (0.275 g, 53%): [α]2D0 ϩ15 (c = 1, THF). This product was
identical to that isolated above.
Preparation of N-phenylsulfonyl-ꢀ-isopropoxyglycine ethyl ester
4b (R3 ؍ OiPr)
Triisopropoxyaluminium (0.317 g, 1.552 mmol) was introduced
to a stirred solution of N-phenylsulfonyl-α-bromoglycine ethyl
ester 1b (0.500 g, 1.552 mmol) at 0 ЊC in dichloromethane (25
ml). After 30 min, the mixture was allowed to warm to RT and
stirred for a further 8 h. Water (25 ml) was added, the layers
separated, extracted with dichloromethane (3 × 20 ml), dried
(MgSO4) and evaporated to yield the α-substituted product 4b
(R3 = OiPr) as a colourless oil (0.502 g). Purification by silica gel
chromatography [ethyl acetate–hexane (3:7) as eluant] gave the
product 4b (R3 = OiPr) as an oil (0.479 g, 97%): νmax (KBr disc)/
cmϪ1 inter alia 3280 (m) NH, 1750 (s) C᎐O, 1210 (w) C–O, 740
᎐
(m), 690 (m); δH (300 MHz; CDCl3) 1.05 (3H, d, J 6, CHCH3),
1.10 (3H, d, J 6, CHCH3), 1.16 (3H, t, J 7, OCH2CH3), 3.92
(1H, septet, J 6, HC(CH3)2), 4.07 (2H, q, J 7, OCH2CH3), 5.07
(1H, d, J 9.5, NHCH, collapses to a singlet upon addition of
D2O), 5.77 (1H, d, J 9, NH, disappears upon addition of D2O),
7.47–7.59 (3H, m, ArH’s), 7.85 (2H, d, ArH’s); δC (75.5
MHz; CDCl3) 13.8 (CH3CH2), 21.5 (CHCH3), 22.4 (CH3CH),
62.2 (OCH2CH3), 70.1 (CHNH), 79.9 [(CH3)2CH], 126.8
Preparation of amide 16
(S)-(ϩ)-2-Aminobutyric acid 14 (0.050 g, 0.48 mol) was sus-
pended in ethanol (5 ml) and saturated with hydrogen chloride
gas. Evaporation gave a white solid which was suspended
in dichloromethane (20 ml) and treated with triethylamine
(1.99 ml, 1.45 mmol) and benzenesulfonyl chloride (0.084 g,
0.48 mmol). After 12 h, water (15 ml) was added, the layers
separated, extracted with dichloromethane (3 × 10 ml), dried
(MgSO4) and evaporated to yield a pale brown oil (0.173 g).
Purification by silica gel chromatography [ethyl acetate–hexane
(1:1) as eluant] gave a colourless oil which was crystallised from
dichloromethane–hexane to yield a white solid (0.065 g, 75%)
identified as the amide 16: [α]2D0 Ϫ9 (c = 1, THF); mp 127–
129 ЊC; νmax (KBr disc)/cmϪ1 inter alia 3260 (m) and 3360 (m)
(Ar), 129.0 (Ar), 132.8 (Ar), 140.9 (Ar, quat), 167.4 (C᎐O,
᎐
quat); m/z (CI) 319 (base peak, Mϩ ϩ NH4), 261 (Mϩ ϩ
NH4 Ϫ C3H7O) [Found: m/z, 319.1326. Calc. for C13H23N2SO5:
m/z, 319.1328].
Preparation of N-phenylsulfonyl-ꢀ-n-butylglycine ethyl ester 4b
(R3 ؍ nBu)
NH, 1740 (s) C᎐O (ester), 1650 (s) C᎐O (amide), 1210 (m) and
᎐
᎐
Diethylaluminium chloride (1.552 ml of a 1 M solution in hex-
anes, 1.552 mmol) was added to a stirred solution of n-
butyllithium (0.610 ml of a 2.5 M solution in hexanes, 1.552
mmol) in dichloromethane (5 ml) at 0 ЊC. After 30 min, this
solution was added dropwise to a stirred solution of N-phenyl-
sulfonyl-α-bromoglycine ethyl ester 1b (0.500 g, 1.552 mmol) at
0 ЊC in dichloromethane (25 cm3). The resulting pale yellow
1255 (m) C–O, 760 (w) and 690 (w); δH (300 MHz; CDCl3) 0.75
(3H, t, J 7, CH3CH2CHNH), 0.85 (3H, t, J 7, CH3CH2CH),
1.27 (3H, t, J 7, CH3CH2O), 1.56–1.83 (4H, m, 2 × CH3-
CH2CH), 3.64–3.78 (1H, q, J 7, NHCH, collapses to a t upon
addition of D2O), 4.18 (2H, m, CH3CH2O), 4.34 (1H, q, J 7,
COCH, collapses to a t upon addition of D2O), 5.61 (1H, d, J 7,
NHSO2, disappears upon addition of D2O), 6.45 (1H, d, J 7,
J. Chem. Soc., Perkin Trans. 1, 2000, 515–525
523

View Article Online
NHCO, disappears upon addition of D2O), 7.41–7.59 (3H, m,
ArH’s), 7.85 (2H, d, J 7, ArH’s); δC (75.5 MHz; CDCl3) 9.2
(CH3CH2CHNH), 9.4 (CH3CH2CH), 14.1 (CH3CH2O), 25.3
(CH3CH2CHNH), 27.0 (CH3CH2CH), 53.3 (CH3CH2CH),
57.7 (NHCH), 61.6 (CH3CH2O), 126.3 (Ar), 129.0 (Ar), 132.8
Asymmetric preparation of N-phenylsulfonyl-ꢀ-methylglycine
ethyl ester 4b (R3 ؍ Me)
Trimethylaluminium (0.776 ml of a 2 M solution in hexanes,
1.552 mmol) was added dropwise at Ϫ78 ЊC under argon to a
stirred solution of (R)-binaphthol (0.444 g, 1.552 mmol) in
dichloromethane (10 ml). The resulting solution was stirred for
30 min before dropwise addition via cannula, to a stirred solu-
tion of N-phenylsulfonyl-α-bromoglycine ethyl ester 1b (0.500
g, 1.552 mmol) at Ϫ78 ЊC in dichloromethane (25 ml). After 30
min, the mixture was allowed to warm to room temperature, left
for a further 4 h, quenched with sat. ammonium chloride solu-
tion (25 ml), extracted with dichloromethane (3 × 20 ml), dried
(MgSO4) and evaporated to yield the α-substituted product 4b
(R3 = Me)13 and binaphthol as a white solid (0.665 g). The
solid was purified by silica gel chromatography (ethyl acetate–
hexanes (3:7) as eluant) to afford 4b (R3 = Me) as a white solid
(0.220 g, 55%), which was identical to that isolated above.
Binaphthol was also recovered (0.434 g, 98%). This product
4b (R3 = Me) was reduced and converted to the (ϩ)-Mosher
ester 17, as outlined above and subsequent NMR analysis (by
comparison of the methylene signals at δ 3.49 and 3.55 and
reinforced by 19F NMR of the CF3 signals at δ 6.15 and 6.61)
showed that the sample had a de of 52%.
(Ar), 139.7 (Ar, quat), 170.2 (NHC᎐O, quat), 171.8 (C᎐O,
᎐
᎐
quat); m/z (FAB) 357 (Mϩ ϩ H), 283 (Mϩ Ϫ C3H5O2), 198
(Mϩ Ϫ C7H12NO3) [Found: m/z, 357.1489. Calc. for C16H25N2-
SO5: m/z, 357.1484].
Preparation of (؊)-2-N-benzenesulfonamidopropanol14
Lithium aluminium hydride (0.389 mol of a 1 M solution
in ether, 0.389 mmol) was added to a stirred solution of
(Ϫ)-N-phenylsulfonyl-α-methylglycine ethyl ester 4b (R3 = Me)
(0.10 g, 0.389 mmol) at Ϫ78 ЊC in THF (3 ml). The colourless
solution was stirred overnight and heated at 60 ЊC for 1 h.
Water (15 ml) was added, the layers separated, extracted with
dichloromethane (3 × 10 cm3), dried (MgSO4) and evaporated
to yield a yellow oil (0.075 g). The oil was purified by silica gel
chromatography [ethyl acetate–hexanes (1:1) as eluant] to
afford the alcohol14 (0.052 g, 63%) as a colourless oil: [α]2D0 Ϫ20
(c = 1.4, THF); bp 121 ЊC; νmax (KBr disc)/cmϪ1 inter alia 3510
(m) OH, 3280 (m) NH, 705 (s) and 695 (s); δH (300 MHz;
CDCl3) 0.95 (3H, d, J 7, CH3), 2.40 (1H, br s, OH, disappears
upon addition of D2O), 3.36 (2H, m, CH2), 3.53 (1H, m, CH),
5.18 (1H, d, J 7, NH), 7.41–7.59 (3H, m ArH’s), 7.81–7.86 (2H,
m, ArH’s); δC (75.5 MHz, CDCl3) 17.6 (CH3), 51.52 (CH), 66.1
(CH2), 126.962 (Ar), 129.1 (Ar), 132.7 (Ar), 140.485 (Ar, quat);
m/z (FAB) 216 (base peak, Mϩ ϩ H) [Found: m/z, 216.0688.
Calc. for C9H14NSO3: m/z, 216.0694].
Asymmetric preparation of N-phenylsulfonyl-ꢀ-ethylglycine
ethyl ester 4b (R3 ؍ Et)
Triethylaluminium (1.552 ml of a 1 M solution in hexanes,
1.552 mmol) was added dropwise at Ϫ78 ЊC under argon to a
stirred solution of (R)-binaphthol (0.444 g, 1.552 mmol) in
dichloromethane (10 ml). The resulting solution was stirred for
30 min before dropwise addition via cannula, to a stirred solu-
tion of N-phenylsulfonyl-α-bromoglycine ethyl ester 1b (0.500
g, 1.552 mmol) at Ϫ78 ЊC in dichloromethane (25 ml). After 30
min, the mixture was allowed to warm to room temperature,
stirred for a further 4 h, quenched with sat. ammonium chloride
solution (25 ml), extracted with dichloromethane (3 × 20 ml),
dried (MgSO4) and evaporated to yield the α-substituted prod-
uct 4b (R3 = Et) and binaphthol as a white solid (0.902 g). The
solid was purified by silica gel chromatography (ethyl acetate–
hexanes (3:7) as eluant) to afford the product 4b (R3 = Et) as a
white solid (0.378 g, 90%), which was identical to that reported
above. Binaphthol was also recovered (0.427 g, 96%). The
product 4b (R3 = Et) showed an ee of 62% by chiral HPLC
using a Chiralpak AD column [propan-2-ol–hexane (20:80) as
eluant] (peaks were observed at 11.14 and 12.56 min).
Preparation of (؉)-Mosher ester of 17
(Ϫ)-2-N-Benzenesulfonamidopropanol (0.050 g, 0.232 mmol)
was dissolved in dichloromethane (2 ml) and treated with (ϩ)-
Mosher’s acid chloride (0.059 g, 0.232 mmol), pyridine (0.474
ml, 0.464 mmol) and DMAP (0.010 g, 0.1 mmol). After 16
hours, the reaction was quenched with water (10 ml), extracted
with dichloromethane (2 × 5 ml), dried (MgSO4) and evapor-
ated to yield a white solid (0.170 g). The solid was purified
by silica gel chromatography [ethyl acetate–hexanes (4:6) as
eluant] to yield the ester 17 as a white solid (0.020 g, 20%):
mp 135–136 ЊC; νmax (KBr disc)/cmϪ1 inter alia 3300 (m) NH,
1750 (m) C᎐O, 1250 (w), C–O, 690 (w) and 720 (w); δ (300
᎐
H
MHz; CDCl3) 1.0 (3H, J 7, CH3), 3.49 (3H, s, OCH3), 3.65
(1H, m, CH), 4.10–4.29 (2H, m, CH2), 4.62 (1H, d, J 7, NH,
disappears upon addition of D2O), 7.41–7.61 (8H, m,
ArH’s), 7.83–7.85 (2H, m, ArH’s); δC (300 MHz; CDCl3) 18.0
(CH3), 48.3 (CH), 55.4 (OCH3), 68.8 (CH2), 126.82 (Ar),
127.3 (Ar), 128.6 (Ar), 129.2 (Ar), 132.8 (Ar, quat), 166.3
Asymmetric preparation of N-phenylsulfonyl-ꢀ-ethoxyglycine
ethyl ester 4b (R3 ؍ OEt)
Triethoxyaluminium (0.251 g, 1.552 mmol) was added at
Ϫ78 ЊC under argon to a stirred solution of (R)-binaphthol
(0.444 g, 1.552 mmol) in dichloromethane (10 ml). The result-
ing solution was stirred for 30 min before dropwise addition
via cannula, to a stirred solution of N-phenylsulfonyl-α-bromo-
glycine ethyl ester (0.500 g, 1.552 mmol) at Ϫ78 ЊC in dichloro-
methane (25 ml). The resulting pale yellow solution was stirred
at this temperature for 30 min, allowed to warm to room tem-
perature and stirred for a further 4 h. Sat. ammonium chloride
solution (25 ml) was added, the layers separated, extracted with
dichloromethane (3 × 20 ml) and the combined extracts dried
(MgSO4) and evaporated to yield the α-substituted product 4b
(R3 = OEt) and binaphthol as a white solid (0.802 g). The solid
was purified by silica gel chromatography using an eluant of
ethyl acetate–hexanes (3:7) to afford the product 4b (R3 = OEt)
as a white solid (0.307 g, 69%) and was found to be analytically
identical to that isolated above. Binaphthol was also recovered
(0.404 g, 90%). The product 4b (R3 = OEt) was determined
to have an ee of 19% by chiral HPLC using a Chiralpak OD
column with an eluant of propan-2-ol–hexane (30:70). Peaks
were observed at 7.26 and 8.12 min.
(C᎐O, quat); m/z (FAB) 432 (Mϩ ϩ H), 198 (base peak,
᎐
Mϩ Ϫ C10H8O3F3) [Found: m/z, 432.1097. Calc. for C19H20-
NSO5F3: m/z, 432.1092].
Preparation of N-phenylsulfonyl-ꢀ-methylglycine ethyl ester 4b
(R3 ؍ Me) from L-alanine
-Alanine (0.200 g, 2.24 mmol) was suspended in dichloro-
methane (25 ml) and saturated with hydrogen chloride gas
until the solution became homogeneous. After 5 h, ethanol (10
ml) was added, the solvent evaporated and the resulting pale
yellow oil was resuspended in dichloromethane (25 ml). This
solution was treated with triethylamine (6.15 ml, 4.480 mmol)
and benzenesulfonyl chloride (0.394 g, 2.24 mmol) and the
resulting solution was stirred overnight before the addition of
water (15 ml). Extraction with dichloromethane (3 × 15 ml),
drying (MgSO4) and evaporation gave a white solid (0.299 g).
The solid was purified by silica gel chromatography [ethyl
acetate–hexanes (3:7) as eluant] to afford the ester 4b (R3 =
Me)13 as a white solid (0.432 g, 75%): [α]2D0 Ϫ5 (c = 1, THF).
524
J. Chem. Soc., Perkin Trans. 1, 2000, 515–525

View Article Online
Chiral catalysed preparation of N-phenylsulfonyl-ꢀ-isopropoxy-
glycine ethyl ester 4b (R3 ؍ OiPr)
References
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Triisopropoxyaluminium (0.317 g, 1.552 mmol) was added to a
stirred solution of (R)-binaphthol (0.444 g, 1.552 mmol) in
dichloromethane (10 ml), cooled to Ϫ78 ЊC. The resulting solu-
tion was stirred for 30 min before dropwise addition via can-
nula, to a stirred solution of N-phenylsulfonyl-α-bromoglycine
ethyl ester 1b (0.500 g, 1.552 mmol) at Ϫ78 ЊC in dichloro-
methane (25 ml). The resulting pale yellow solution was stirred
at this temperature for 30 min; allowed to warm to room tem-
perature and stirred for a further 4 h. Sat. ammonium chloride
solution (25 ml) was added, the layers separated, extracted with
dichloromethane (3 × 20 ml) and the combined extracts dried
(MgSO4) and evaporated to yield the α-substituted product 4b
(R3 = OiPr) and binaphthol as a white solid (0.905 g). The solid
was purified by silica gel chromatography using an eluant of
ethyl acetate–hexanes (3:7) to afford the product 4b (R3 = OiPr)
as a colourless oil (0.478 g, 97%) and was found to be analytic-
ally identical to that isolated above. Binaphthol was also
recovered (0.424 g, 95%). The product 4b (R3 = OiPr) was
determined to have an ee of 25% by chiral HPLC using a
Chiralpak OD column with an eluant of propan-2-ol–heptane
(8:92). Peaks were observed at 8.33 and 12.65 min.
Chiral catalysed preparation of N-phenylsulfonyl-ꢀ-n-butyl-
glycine 4b (R3 ؍ nBu)
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Diethylaluminium chloride (1.552 ml of a 1 M solution in
hexanes, 1.552 mmol) was added dropwise to a stirred solution
of n-butyllithium (0.608 ml of a 2.5 M solution in hexanes,
1.552 mmol) in dichloromethane (10 ml), cooled to Ϫ78 ЊC.
The resulting solution was stirred for 30 min before the addition
of (R)-binaphthol (0.444 g, 1.552 mmol). The solution was
stirred for 30 min before the dropwise addition, via cannula, to
a stirred solution of N-phenylsulfonyl-α-bromoglycine ethyl
ester 1b (0.500 g, 1.552 mmol) at Ϫ78 ЊC in dichloromethane
(25 ml). The resulting pale yellow solution was stirred at this
temperature for 30 min; allowed to warm to room temperature
and stirred for a further 4 h. Saturated ammonium chloride
solution (25 ml) was added, the layers separated, extracted with
dichloromethane (3 × 20 ml) and the combined extracts dried
(MgSO4) and evaporated to yield a white solid (0.767 g). The
solid was purified by silica gel chromatography using an eluant
of ethyl acetate–hexanes (3:7) to afford the product 4b
(R3 = nBu) (0.161 g, 35%) and 4b (R3 = Et) (0.050 g, 12%),
each as a white solid and were analytically identical to that
isolated above. Binaphthol was also recovered (0.323 g, 73%).
The product 4b (R3 = nBu) was determined to be racemic by
chiral HPLC using a Chirocel OF column with an eluant of
propan-2-ol–heptane (10:90). Peaks were observed at 9.23
and 13.56 min.
Acknowledgements
We thank the EPSRC for a studentship (to P. E. M.) and
Chiroscience for additional funding.
14 A. Kretow and K. Abraschanowa, Zh. Obshch. Khim., 1958, 28, 2779
[Engl. Transl., 1958, 28, 2802].
Paper a909116e
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