Copper(II)salen catalysed, asymmetric synthesis of α,α- disubstituted amino acids

Article abstract of DOI:10.1016/j.tet.2003.12.031

Cu(salen) complex 1 was found to be a versatile catalyst for the asymmetric alkylation of a range of enolates derived from α-amino acids, leading to α,α-disubstituted amino acids. The enantioselectivity of the process decreases as the size of the amino ac

Full text of DOI:10.1016/j.tet.2003.12.031

Tetrahedron 60 (2004) 1849–1861
Copper(II)salen catalysed, asymmetric synthesis of
a,a-disubstituted amino acids
a
Yuri N. Belokon, Devayani Bhave, Daniela D’Addario, Elisabetta Groaz, Michael North
b
b
b
b,*
b
and Valeria Tagliazucca
a
A.N. Nesmeyanov Institute of Organo-Element Compounds, Russian Academy of Sciences, 117813 Moscow, Vavilov 28, Russian Federation
Department of Chemistry, King’s College London, Strand, London WC2R 2LS, UK
b
Received 10 October 2003; revised 24 November 2003; accepted 11 December 2003
Abstract—Cu(salen) complex 1 was found to be a versatile catalyst for the asymmetric alkylation of a range of enolates derived from
a-amino acids, leading to a,a-disubstituted amino acids. The enantioselectivity of the process decreases as the size of the amino acid
sidechain increases, but functionalized amino acids such as allylglycine and aspartic acid are substrates for the process. Benzylic bromides
are found to be more enantioselective alkylating agents than propargylic bromides. As an example of the utility of this chemistry, an
a-propargylic allylglycine derivative is prepared and subjected to ene–yne metathesis using Grubbs’ catalyst to give a non-racemic
cyclopentenyl amino acid.
q 2003 Elsevier Ltd. All rights reserved.
1
. Introduction
methyl group to quaternize the cinchona alkaloid resulted in
5
a catalyst that exhibited enhanced enantioselectivity. In
6
Phase transfer methodology offers many possibilities in
allowing otherwise unfavourable reactions to be carried
out. In particular, liquid–liquid phase transfer catalysis
allows reactions to be carried out involving reagents for
which no convenient mutual solvent is available. Solid–
liquid phase transfer catalysis is potentially even more
general as a solvent only needs to be found for one
component of a reaction.
addition to enolate alkylations, this catalyst will also
7
,8
9
catalyse Michael additions, aldol reactions, and enone
10
1
epoxidations. It can also be used in conjunction with
achiral palladium complexes to induce the asymmetric
1
1
allylation of enolates. However, only glycine derived
2
1
imines give products with high enantiomeric excesses.
8
,13
14
Recently, polymer supported
and oligomeric versions
of the cinchona derived phase transfer catalysts have been
developed and used for asymmetric amino acid synthesis.
The catalysts have also been used under micellar con-
Recently, there has been an upsurge of interest in
asymmetric phase transfer catalysis in which a chiral, non-
racemic phase transfer catalyst is used to induce the
enantioselective conversion of a prochiral substrate into an
enantiomerically enriched product. Most work in this area
has focused upon the asymmetric synthesis of a-amino
acids or a,a-disubstituted amino acids by the alkylation of
achiral enolates of glycine or alanine derivatives, though
other classes of reactions can also be catalysed. The first
reports in this area were due to O’Donnell who demon-
strated that quaternary ammonium salts derived from
cinchona alkaloids could catalyse the asymmetric alkylation
of a glycine enolate, leading to a-amino acids with
1
5
ditions.
Maruoka has developed a class of binaphthyl derived
quaternary ammonium salts and has shown that they act as
asymmetric phase transfer catalysts for both the alkylation
and dialkylation (with two different alkylating agents) of a
glycine derived imine, leading to both a-amino acids and
a,a-disubstituted amino acids with excellent enantiomeric
1
6
17
18
excesses. Aldol reactions, Michael additions, and the
1
9
alkylation of b-keto esters are also catalysed by this class
of asymmetric phase transfer catalysts. Other groups have
2
0
also investigated the use of synthetic ammonium and
21
2
22
moderate enantiomeric excesses. This chemistry was
3
guanidinium salts and crown ethers as asymmetric phase
transfer catalysts.
subsequently developed simultaneously by Lygo and
4
Corey, who both showed that the use of a 9-anthracenyl-
In 1998, Belokon’ and Kagan were the first to demonstrate
that a metal complex could act as an asymmetric phase
transfer catalyst. The sodium salt of TADDOL was found to
catalyse the alkylation of alanine derivatives leading to
Keywords: Cu(salen) complex; Phase transfer methodology; Alkylation.
*
Corresponding author. Tel.: þ44-207-848-1164; fax: þ44-870-131-3783;
e-mail address: michael.north@kcl.ac.uk
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.12.031

1850
Y. N. Belokon et al. / Tetrahedron 60 (2004) 1849–1861
a-methyl-a-amino acids with up to 82% enantiomeric
2
3
excess. It was subsequently shown that the sodium salts of
2
4
25
both NOBIN and BINOLAM could act as asymmetric
phase transfer catalysts for the same reaction.
Although chiral transition metal complexes have been used
to catalyse a wide range of asymmetric transformations, we
were the first to show that they could be used to catalyse the
asymmetric alkylation of amino acid enolates under phase
transfer conditions. In particular, we have shown that
copper(II)salen complex 1 will catalyse the asymmetric
alkylation of the enolate of alanine derivative 2 leading to a-
methyl, a-amino acids with up to 90% enantiomeric excess
2
6
as shown in Scheme 1. The key alkylation reaction is
carried out under solid–liquid phase transfer conditions
using solid sodium hydroxide as base, and toluene as the
solvent. One of the advantages of this chemistry compared
to the quaternary ammonium salt methodologies is the
ability to use the readily available and inexpensive methyl
ester of alanine as substrate, as the nature of the ester
appears to make no significant difference to the level of
asymmetric induction observed in the reactions. Although
the methyl ester is hydrolysed under the reaction conditions,
this appears to be slower than the enolate formation and
alkylation and the product can readily be re-esterified as part
2
7
of the work-up procedure. In this manuscript, we report
the extension of this chemistry to substrates derived from
2
8
amino acids other than alanine.
0
þ
Scheme 1. (i) NaOH/R X/1 (2 mol%), toluene, R.T (ii) H
3
O .
2
. Results and discussion
0
Scheme 2. (i) 4-ClC
6
H
MeOH/AcCl; (iii) SiO
4
CHO/MgSO
; (iv) excess (S)-PhCHMe-NvCvO, CDCl
4
; (ii) NaOH/R X/1, toluene, R.T., then
, RT.
2
3
The first substrate that we chose to investigate was amino-
butyric acid derivative 3a as this involved only a small
change in the sidechain from methyl to ethyl. Imine 3a was
prepared from (R,S)-aminobutyric acid methyl ester and
para-chlorobenzaldehyde (Scheme 2), and was then alkyl-
ated with allyl bromide under the standard conditions for the
use of catalyst 1, to give a-ethyl allylglycine methyl ester 4a
with 80% enantiomeric excess (Table 1 entry 1). By
doubling the amount of allyl bromide used to 2.4 equiv., the
yield of compound 4a increased to .50%, though at the
expense of a decrease in the enantiomeric excess (Table 1:
entry 2).
benzylisocyanate followed by analysis of the resulting
1
diastereomeric ureas 5 by H NMR spectroscopy. When
substrate 3a was alkylated using benzyl bromide to give
a-ethyl phenylalanine methyl ester 4b, the standard
conditions (Table 1: entry 3) gave a product with good
enantiomeric excess but in very low yield. Simply extending
the reaction time from 1 to 2 days increased the chemical
yield to .90% whilst leaving the enantiomeric excess of the
product essentially unchanged (Table 1: entry 4). The final
alkylating agent studied in conjunction with substrate 3a
was 4-nitrobenzyl bromide. In this case, the standard
conditions (Table 1: entry 5) again gave the product 4c with
ca. 80% enantiomeric excess but in low yield. Doubling
either the reaction time (Table 1: entry 6) or the amount of
The enantiomeric excess of all the a,a-disubstituted amino
esters prepared in this work was determined by reaction of a
sample of the amino ester with an excess of (S)-a-methyl

Y. N. Belokon et al. / Tetrahedron 60 (2004) 1849–1861
Table 1. Alkylation of amino acid derivatives 3a–i
1851
Entry
Substrate
Alkylating agent (equivalents) (product)
Catalyst (mol%)
Time (days)
Yield (%)
Enantiomeric excess (%)
1
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
3b
3b
3c
3c
3c
3c
3c
3c
3c
3c
3c
3d
3d
3d
3e
3e
3f
Allyl bromide (1.2) (4a)
Allyl bromide (2.4) (4a)
2
2
2
2
2
2
2
2
10
10
10
10
10
2
10
2
2
1
1
1
2
1
2
1
1
1
7
1
7
1
1
1
1
5
1
1
1
1
1
1
1
7
2
2
1
1
1
1
1
2
2
2
2
2
1
1
46
54
39
91
23
83
95
0
41
54
46
63
64
47
46
30
44
53
74
87
40
68
70
67
0
80
70
80
82
78
79
75
Benzyl bromide (1.2) (4b)
Benzyl bromide (1.2) (4b)
Para-nitro-benzyl bromide (1.2) (4c)
Para-nitro-benzyl bromide (1.2) (4c)
Para-nitro-benzyl bromide (2.4) (4c)
Benzyl bromide (1.2) (4d)
Benzyl bromide (1.2) (4d)
Benzyl bromide (1.2) (4d)
Para-nitro-benzyl bromide (1.2) (4e)
Para-nitro-benzyl bromide (1.2) (4e)
Para-nitro-benzyl bromide (2.4) (4e)
Para-nitro-benzyl bromide (2.4) (4e)
Allyl bromide (1.2) (4f)
Allyl bromide (1.2) (4g)
Allyl bromide (1.2) (4g)
Allyl bromide (2.4) (4g)
Allyl bromide (4.8) (4g)
Allyl bromide (4.8) (4g)
Allyl bromide (1.2) (4g)
Allyl bromide (1.2) (4g)
Allyl bromide (1.2) (4g)
Para-nitro-benzyl bromide (1.2) (4h)
Allyl bromide (2.4)
Allyl bromide (2.4)
Benzyl bromide (2.4)
Allyl bromide (1.2) (4i)
Benzyl bromide (1.2) (4j)
Benzyl bromide (1.2) (4k)
Benzyl bromide (2.4) (4k)
Benzyl bromide (1.2) (4k)
Para-nitro-benzyl bromide (1.2) (4l)
1-Bromo-but-2-yne (4m)
Propargyl bromide (4n)
1-Bromo-but-2-yne (4m)
Benzyl bromide (7)
Allyl bromide (1.2) (4o)
27
55
40
56
47
43
22
17
17
15
18
20
31
27
19
34
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
2
2
10
10
25
50
10
2
10
10
2
2
2
2
10
2
2
2
2
2
2
2
0
0
31
38
66
67
38
45
46
49
44
52
25
75
48
42
57
57
43
47
25
20
25
3f
3f
3f
3f
3f
3g
3h
3i
17
10
3i
Benzyl bromide (1.2) (4p)
4
-nitrobenzyl bromide used (Table 1: entry 7) increased the
enantiomeric excess (Table 1: entries 11–14). Employing
1.2 equiv. of the alkylating agent (Table 1: entries 11 and
12) gave results which are very similar to those obtained
when benzyl bromide was used as the alkylating agent, with
optimal yield and enantioselectivity being observed after a
reaction time of 7 days. However, by increasing the amount
of alkylating agent to 2.4 equiv., it was possible to reduce
the reaction time to one day (Table 1: entry 13) with no
reduction in the chemical yield, though the enantiomeric
excess of the product was slightly reduced. Subsequent
reduction of the amount of catalyst used back to 2 mol%
(Table 1: entry 14) did give compound 4e, all be it in
reduced chemical yield and with a lower enantiomeric
excess. Finally, allyl bromide reacted with substrate 3b to
give a-allyl leucine methyl ester 4f, though again the
reaction required 10 mol% of catalyst 1 and the
enantiomeric excess of the product was very low (Table 1:
entry 15).
chemical yield to .80% without significantly reducing the
enantiomeric excess of the product. Thus, by choice of
appropriate concentrations and/or reaction times it was
possible to convert imine 3a into a-ethyl amino acids in
high yield and with ca. 80% enantiomeric excess in each
case. Peptides incorporating a-ethyl amino acids have
recently been shown to adopt unique conformations. To
further extend the scope of the chemistry, leucine derivative
3
presence of a branch at the g-carbon makes this a more
hindered substrate than aminobutyric acid derivative 3a,
which was anticipated to affect the enantioselectivity of the
alkylation reaction. Under the standard conditions (Table 1:
entry 8) no reaction occurred when substrate 3b was treated
with benzyl bromide. Only by increasing the amount of
catalyst to 10 mol% (Table 1: entry 9) could a-benzyl
leucine methyl ester (4d) be isolated in moderate yield and
with low enantiomeric purity. Interestingly, increasing the
reaction time from 1 to 7 days (Table 1: entry 10) resulted in
only a small increase in the isolated yield of compound 4d,
but doubled its enantiomeric purity to a respectable 55%.
2
9
b was used as substrate (Scheme 2, R¼CH CHMe ). The
2
2
Phenylalanine derived substrate 3c also branches at the
g-position. The initial studies using this substrate were
carried out using allyl bromide as the alkylating agent
(
Table 1: entries 16–23). Despite numerous optimization
para-Nitrobenzyl bromide also reacted with substrate 3b,
giving a,a-disubstituted amino ester 4e with up to 56%
attempts in which the catalyst concentration, alkylating
agent concentration and reaction time were all varied, the

1852
Y. N. Belokon et al. / Tetrahedron 60 (2004) 1849–1861
highest enantiomeric excess observed for product 4g was
1%, and in a mediocre 40% yield. This enantiomeric
excess was observed using 10 mol% of catalyst 1 (Table 1:
over a direct alkylation of the enolates of compounds 6a,b in
that no dialkylation occurs.
3
entry 21), and use of a lower (Table 1: entry 16) or higher
(
Imine 3f was subsequently reacted with catalyst 1 and
benzyl bromide according to Scheme 2 to give a-allyl-
phenylalanine methyl ester 4k in 66% yield and with 57%
enantiomeric excess (Table 1: entry 30). Attempts to
increase the enantioselectivity and/or chemical yield with
this substrate by increasing the concentration of substrate or
catalyst were unsuccessful (Table 1: entries 31 and 32).
Optimal yields with all products derived from imines 3f and
3g were obtained by omitting the methanolic HCl treatment
at the end of the alkylation reaction. Presumably, the
products are sufficiently sterically hindered that ester
hydrolysis does not occur on the reaction timescale and
the methanolic HCl treatment reduces the isolated yield by
inducing addition reactions to the alkene and/or alkyne units
within products 4k–4n. Product 4k is constitutionally
identical to product 4g obtained by the allylation of
Table 1: entries 22 and 23) concentration of catalyst 1
resulted in reduced enantioselectivity. The only other
alkylating agent studied with substrate 3c was para-
nitrobenzyl bromide, and under the optimized conditions,
this gave product 4h with 34% enantiomeric excess (Table 1:
entry 24) which is essentially identical to that observed
using allyl bromide as the alkylating agent (Table 1:
entry 21).
Valine derived substrate 3d which is b-branched is amongst
the most hindered possible substrates for this type of
alkylation reaction. All attempts to react substrate 3d with
either allyl bromide (Table 1: entries 25 and 26) or benzyl
bromide (Table 1: entry 27) were totally unsuccessful. It
appears that substrate 3d is too hindered to be a substrate for
catalyst 1.
1
phenylalanine derivative 3c. However, analysis of the H
NMR spectra of the derived ureas 5g and 5k revealed that
the major stereoisomer formed in each case was different.
This implies that products 4g and 4k are enantiomeric, and
this is consistent with the alkylation occurring enantio-
selectively on the re-face of the enolate. Further evidence
for this hypothesis was obtained by hydrolysis of amino
ester 4g to give (þ)-a-allyl-phenylalanine, which is known
The final unfunctionalized substrate that we have investi-
gated is phenylglycine derivative 3e. This substrate was of
interest since although the sidechain branches at the
b-position, the enolate of compound 3e would be com-
pletely planar, unlike the enolates of compounds 3a–d.
Alkylation of substrate 3e with allyl bromide (Table 1: entry
3
2
28) gave a-phenyl allylglycine with 48% enantiomeric
excess. This enantioselectivity, whilst not comparable with
to correspond to the (S)-enantiomer of this amino acid.
that obtainable from aminobutyric acid derived substrate 31
Table 1: entry 1), is significantly higher than that obtained
Use of para-nitrobenzyl bromide as the alkylating agent
with substrate 3f (Table 1: entry 33) gave a-para-
nitrobenzyl-allylglycine 4l with similar enantiomeric excess
(47%) to that observed using benzyl bromide, though with a
lower isolated yield. However, use of 1-bromo-2-butyne as
the alkylating agent (Table 1: entry 34) gave a-but-2-ynyl-
allylglycine 4m with a much lower enantiomeric excess
(25%) and with propargyl bromide as the alkylating agent,
the enantioselectivity dropped still further (Table 1: entry
35). In this case, use of the para-chlorobenzylidene imine
3g did not increase the enantioselectivity of the alkylation
reaction (Table 1: entry 36). This result is consistent with
our previous results on substrate 2 where propargyl bromide
was found to give a product with lower enantiomeric excess
(
from either leucine or phenylalanine derived substrates 3b
and 3c (Table 1: entries 15 and 21). The alkylation of
substrate 3e by benzyl bromide was also investigated. In this
case, the enantioselectivity was lower than that obtained for
either substrate 3a or 3b, but the latter results are not strictly
comparable due to the different amounts of catalyst used.
Substrates 3a–e are all unfunctionalized but differ in their
steric properties. It appears that the enantioselectivity of the
alkylation of these substrates decreases as the substrate
becomes more sterically hindered. We next decided to study
more functionalized substrates to investigate the compati-
bility of the chemistry with functional groups. The first
substrates chosen for this work were allylglycine derivatives
2
6,27
than that observed using allylic or benzylic halides.
3
palladium catalysed allylation of glycine imines 6a and 6b
f and 3g. Compounds 3f and 3g were prepared by the
Glutamic acid derivative 3h was felt to be an interesting
substrate for this chemistry since alkylated glutamic acid
derivatives are known to be selective neurotransmitters. In
3
0,31
33
as shown in Scheme 3.
This method has the advantage
addition, since glutamic acid is branched only at the
d-carbon, it was expected to be a good substrate, and to
lead to a-substituted derivatives with high enantiomeric
excess. However, treatment of substrate 3h with benzyl
bromide in the presence of catalyst 1 (Table 1: entry 37)
gave not the expected a-benzyl glutamic acid dimethyl
ester, but a-benzyl-pyroglutamic acid methyl ester 7 as
shown in Scheme 4. It appears that the alkylation chemistry
works exactly as expected, but on work-up the a-substituted
glutamic acid diester spontaneously cyclises to lactam 7.
Unfortunately, compound 7 failed to react with a-methyl
benzylisocyanate, so we were unable to determine its
enantiomeric excess.
Scheme 3. (i) H
2
CvCHCH
2
OCO Me/Pd(dppe) (5 mol%).
2
To avoid the cyclisation problem encountered in the

Y. N. Belokon et al. / Tetrahedron 60 (2004) 1849–1861
1853
Scheme 4. (i) 1 (2 mol%)/NaOH/BnBr; (ii) MeOH/AcCl; (iii) SiO
2
.
Figure 1.
synthesis of a-substituted glutamic acid derivatives, we
turned to the lower homologue aspartic acid. Reaction of
imine 3i with allyl bromide gave a-allyl-aspartic acid
dimethyl ester (4o) (Table 1: entry 38), and the correspond-
ing reaction with benzyl bromide gave a-benzyl aspartic
acid dimethyl ester (4p) (Table 1: entry 39). However, the
enantiomeric excesses of products 4o/p were disappointing
re-face of the enolate. This model works well for glycine
2
6
and alanine substrates, both of which are alkylated with
high enantioselectivity. Other amino acid derived substrates
are more complicated as an additional factor needs to be
considered: rotation around the C –C -bond of the enolate.
a b
Thus, the R-group shown in Figure 1 could be located over
the re- (as shown) or si-face of the enolate. The former is
more likely since the R-group will be repelled by the same
features of the cyclohexane ring that direct alkylation to the
re-face of the enolate. If the R-group is over the re-face of
the enolate, then it will hinder the approach of the
electrophile to the re-face and this will result in a lower
enantioselectivity during the alkylation. The overall rate of
reaction will also decrease as the size of the R-group
increases. Thus, the model correctly predicts both the
absolute configuration of the product, and the general
relationship between the enantioselectivity of alkylation and
the size of the amino acid sidechain.
(10–20%), possibly reflecting the fact that the sidechain of
aspartic acid branches at the g-carbon.
To demonstrate the utility of this methodology in the
synthesis of complex amino acids, the further manipulation
of adducts 4m and 4n was investigated. Thus, amino esters
4
m and 4n were first protected with a Boc group, then
treated with Grubbs’ catalyst (5 mol%) under an ethene
atmosphere to induce ring-closing ene–yne metathesis to
give dienes 8a,b as shown in Scheme 5. Subsequent Diels–
Alder reaction of diene 8a with maleic anhydride gave
tricyclic amino acid derivative 9 as a 1:1 mixture of
diastereomers.
Substrate 3e derived from phenylglycine was included in
this study specifically to probe the stereochemical model
shown in Figure 1. Since the sidechain of this substrate
consists of just a phenyl ring, the enolate of substrate 3e
should be completely planar and there should be no
hindrance to alkylation on the preferred re-face of the
enolate. Thus, substrate 3e was expected to undergo highly
enantioselective alkylation despite being a b-substituted
amino acid. In the event, alkylation of enolate 3e by allyl
bromide (Table 1: entry 28) induced by catalyst 1 was not as
highly enantioselective (48%) as the alkylation of the
2
6,27
corresponding alanine
(
or aminobutyric acid derivatives
Table 1: entries 1 and 2) (70–80%). It was, however,
considerably more enantioselective than the allylation of
substrates 3b,c,i (Table 1: entries 15, 21, 38) (17–30% ee).
The reason for the lower than expected enantioselectivity
observed with substrate 3e is probably related to the highly
acidic nature of the a-proton of this substrate. Control
experiments have shown that substrates 3 undergo alkyl-
ation to give racemic products 4 under the reaction
conditions, even in the absence of catalyst 1. This
uncatalysed process is expected to be particularly facile in
the case of substrate 3e which will lower the observed
enantiomeric excess of the product, and account for the
enantiomeric excess observed with this substrate being
lower than would be predicted by the model shown in
Figure 1.
Scheme 5. (i) Boc
(iii) maleic anhydride.
2 3 2 2 2 2
O; (ii) (PCy ) Ru(Cl) vCHPh (5 mol%) /H CvCH ;
Our model for the alkylation of amino ester enolates
2
6,28
catalysed by complex 1 is shown in Figure 1.
The
enolate is coordinated to both the copper and sodium ions of
a bimetallic complex and is held orthogonal to the plane of
the salen ligand. Alkylation then occurs preferentially on the

1854
Y. N. Belokon et al. / Tetrahedron 60 (2004) 1849–1861
3. Conclusions
yellow oil. nmax (film) 2970 (m), 2878 (w), 1738 (s), 1643
(
m), 1596 (w) and 1573 cm2 (w); d (CDCl ) 0.79 (3H, t
1
H 3
Complex 1 has been shown to be a versatile catalyst for the
asymmetric alkylation of enolates derived from a range of
unhindered amino acids. Of the substrates studied, only the
valine derivative failed to react, though for other substrates
the enantioselectivity of the alkylation was found to
diminish as the size of the sidechain increased.
J¼7.4 Hz, CH CH ), 1.7–1.85 (1H, m, CH ), 1.9–2.0 (1H,
3
2
2
m, CH ), 3.61 (3H, s, OCH ), 3.78 (1H, t J¼5.5 Hz,
2 3
CHCH ), 7.24 (2H, d J¼8.4 Hz, ArCH), 7.59 (2H, d
2
J¼8.5 Hz, ArCH), 8.11 (1H, s, CHvN); d (CDCl ) 9.48
C
3
(CH CH ), 25.69 (CH ), 51.12 (OCH ), 73.73 (CHCH ),
3
2
2
3
2
126.91 (ArCH), 126.97 (ArCH), 127.16 (ArC), 128.77
ArC), 161.00 (NvCH), 171.81 (CO ); m/z (CI, NH ) 240
(
(MH , 80), 180 (100); [found: (ES) 240.0794 (MH ,
2
3
þ
þ
Further work on the mechanism of the catalysis using
complex 1 and the optimization of the catalyst for sterically
hindered substrates is in progress and will be reported in due
course.
3
C H NO Cl requires 240.0791)].
5
1
2
15
2
4.1.2. a-Ethyl-allylglycine methyl ester 4a. Imine 3a
0.24 g, 1.0 mmol) was dissolved in dry toluene (2.5 ml) and
(
copper(salen) complex 1 (7.7 mg, 0.02 mmol) was added.
Powdered sodium hydroxide (0.14 g, 3.5 mmol) and allyl
bromide (14.5 mg, 1.2 mmol) were added to the mixture.
The resulting solution was stirred overnight under an argon
atmosphere at room temperature. Then, methanol (2 ml)
followed by acetyl chloride (0.5 ml) were added dropwise to
the mixture. The mixture was stirred for four more hours
and the solvents were removed in vacuo. The residue was
purified by column chromatography using first ethyl acetate
and then a mixture of ethyl acetate and ethanol (4:1) as
eluent to give compound 4a (72.2 mg, 46%) as a colourless
4
. Experimental
4
.1. General
1
13
H NMR and C NMR spectra were recorded on a Bruker
1
13
Avance 360 Spectrometer, ( H 360 MHz and C 90 MHz)
The solvent for a particular spectrum is given in
parentheses. Spectra were referenced to TMS and chemi-
cal-shift (d) values, expressed in parts per million (ppm), are
reported downfield of TMS. The multiplicity of signals is
reported as singlet (s), doublet (d), triplet (t), quartet (q),
multiplet (m), broad (br) or a combination of any of these.
For C NMR spectra, the peak assignments were made with
the assistance of DEPT experiments. Infrared spectra were
recorded on a Perkin–Elmer FT-IR Paragon 1000 spec-
trometer, as a thin film between NaCl plates or as KBr disks.
The characteristic absorption is reported as broad (br),
strong (s), medium (m) or weak (w). Low and high
resolution mass spectra were recorded at the EPSRC
national service at the University of Wales, Swansea, or
on a 4.7T Bruker Apex III FTMS within the chemistry
department at King’s College. The sample was ionised by
electron ionisation (EI), chemical ionisation (CI) or
electrospray ionization (ES). The major fragment ions are
reported and only the molecular ions are assigned.
2
0
oil. [a]
¼þ1.6 (c¼1.85, CHCl
); nmax (film) 3372 (m),
3
D
3012 (w), 2978 (m), 2882 (m), 1732 (s), 1596 (s) and
1
3
21
1492 cm
CH CH
NH ), 1.7–1.8 (1H, m, CH
8.4 Hz, CH
CHv), 2.45 (1H, dd J¼13.5, 6.4 Hz,
CH CHv), 3.65 (3H, s, OCH ), 5.0–5.1 (2H, m, vCH ),
5.6–5.7 (1H, m, vCH); d (CDCl ) 8.68 (CH CH ), 33.22
(CH CH ), 44.36 (CH CHv), 52.46 (OCH ), 61.61
(NCCO ), 119.75 (vCH ), 133.23 (vCH), 177.64 (CO );
) 158 (MH , 100); [found: (ES) 158.1183
requires 158.1181)].
(m); d
), 1.4–1.6 (1H, m, CH
CH
), 2.15 (1H, dd J¼13.5,
(CDCl
) 0.79 (3H, t J¼7.5 Hz,
H
3
CH ), 1.54 (2H, br s,
3
2
2
3
2
2
3
2
2
3
2
C
3
3
2
3
2
2
3
2
2
2
þ
m/z (CI, NH
3
þ
(MH , C
H
16NO
8
2
4.1.3. a-Ethyl-phenylalanine methyl ester 4b. Imine 3a
(0.24 g, 1.00 mmol) was dissolved in dry toluene (2.5 ml)
and copper(salen) complex 1 (7.7 mg, 0.02 mmol) was
added. Powdered sodium hydroxide (0.14 g, 3.5 mmol) and
benzyl bromide (205 mg, 1.2 mmol) were added to the
mixture. The resulting solution was stirred for 2 days under
an argon atmosphere at room temperature. Then, methanol
(2 ml) followed by acetyl chloride (0.5 ml) were added
dropwise to the mixture. The mixture was stirred for four
more hours and the solvents were removed in vacuo. The
residue was purified by column chromatography using first
ethyl acetate and then a mixture of ethyl acetate and ethanol
(4:1) as eluent to give compound 4b (188 mg, 91%) as a
Optical rotations were recorded on a Perkin–Elmer 343
polarimeter in a thermostated cell of length 1 dm at 20 8C
using the sodium D-line, and a suitable solvent that is
reported along with the concentration (in g/100 ml). Melting
points are uncorrected.
Chromatographic separations were performed with silica
gel 60 (230–400 mesh) and thin-layer chromatography was
performed on polyester backed silica sheets, both supplied
by Merck.
2
0
yellow oil. [a] ¼þ20 (c¼1.75, CHCl ); n
(film) 3373
max
D
3
4.1.1. Methyl N-para-chlorobenzylidene-(R,S)-2-amino-
butyrate 3a. To a stirred suspension of methyl (R,S)-2-
(m), 2968 (m), 2880 (w), 1732 (s), 1603 (m), 1495 (w) and
1454 cm2 (m); d
1
(CDCl
), 1.46 (2H, br s, NH
), 1.8–2.0 (1H, m, CH
Ph), 3.11 (1H, d J¼13.2 Hz, CH
3.63 (3H, s, OCH ), 7.0–7.3 (5H, m, ArCH); d (CDCl
7.41 (CH CH ), 32.21 (CH CH ), 44.83 (CH Ph), 50.92
(OCH ), 61.62 (NCCO ), 125.90 (ArCH), 127.36 (ArCH),
) 0.82 (3H, t J¼7.5 Hz,
), 1.5–1.6 (1H, m,
CH ), 2.68 (1H, d
Ph),
H
3
aminobutyrate hydrochloride (18.1 g, 118.2 mmol) in
dichloromethane
CH
CH
3
2
CH
CH
2
3
2
(50 ml),
9.1 mmol), para-chlorobenzaldehyde (8.3 g, 59.1 mmol)
triethylamine
(8.5 ml,
2
3
5
J¼13.2 Hz, CH
2
2
and a small amount of magnesium sulphate were added. The
reaction mixture was stirred overnight, and was sub-
sequently filtered and evaporated in vacuo. The crude
product was then taken up in diethyl ether and washed with
water (5£30 ml), dried with magnesium sulphate and
evaporated to dryness to give imine 3a (8.47 g, 60%) as a
3
C
)
3
3
2
2
3
2
3
2
128.85 (ArCH), 135.44 (ArC), 175.99 (CO
þ
); m/z (CI, NH )
3
) 208.1338 (MH ,
2
þ
208 (MH , 100); [found: (CI, NH
C H18NO requires 208.1337)].
12 2
3

Y. N. Belokon et al. / Tetrahedron 60 (2004) 1849–1861
1855
4
.1.4. a-Ethyl-para-nitrophenylalanine methyl ester 4c.
Imine 3a (0.24 g, 1.00 mmol) was dissolved in dry toluene
2.5 ml) and copper(salen) complex 1 (7.7 mg, 0.02 mmol)
as a colourless oil. dH (CDCl ) 0.76 (3H, d J¼6.6 Hz,
3
CH CH), 0.89 (3H, d J¼6.6 Hz, CH CH), 1.46 (2H, br s,
3
3
(
NH ), 1.55 (1H, dd J¼13.7, 4.6 Hz, CH CH), 1.6–1.75 (1H,
2 2
2
2
was added. Powdered sodium hydroxide (0.14 g, 3.5 mmol)
and para-nitrobenzyl bromide (0.259 g, 1.2 mmol) were
added to the mixture. The resulting solution was stirred for
two days under an argon atmosphere at room temperature.
Then, methanol (2 ml) followed by acetyl chloride (0.5 ml)
were added in a dropwise manner to the mixture. The
mixture was stirred for four more hours and the solvents
were removed in vacuo. The residue was purified by column
chromatography using first ethyl acetate and then a mixture
of ethyl acetate and ethanol (4:1) as eluent to give
m, CHMe ), 1.82 (1H, dd J¼13.7, 4.6 Hz, CH CH), 2.64
(1H, d J¼13.1 Hz, CH Ph), 3.09 (1H, d J¼13.1 Hz,
2
CH Ph), 3.61 (3H, s, OCH ), 7.0–7.3 (5H, m, ArCH); d
2
3
C
(CDCl ) 24.28 (CH CH), 26.06 (CH CH), 26.45 (CHMe ),
3
3
3
2
49.24 (CH ), 50.73 (CH ), 53.51 (OCH ), 63.40 (NCCO ),
2
2
3
2
128.71 (ArCH), 130.11 (ArCH), 131.61 (ArCH), 137.87
þ
(ArC), 179.31 (CO ); m/z (CI, NH ) 236 (MH , 100).
2
3
4.1.7. a-para-Nitrobenzyl-leucine methyl ester 4e. Imine
3b (0.267 g, 1.0 mmol) was dissolved in dry toluene
2
0
compound 4c (209 mg, 83%) as a yellow oil. [a] ¼þ21
(2.5 ml) and copper(salen) complex
1
(38.5 mg,
D
(
and 1518 cm
c¼3.65, CHCl ); n
(film) 3370 (m), 1732 (s), 1604 (m),
max
0.10 mmol) was added. Powdered sodium hydroxide
(0.14 g, 3.5 mmol) and para-nitrobenzyl bromide (0.259 g,
1.2 mmol) were added to the mixture. The resulting solution
was stirred for 7 days under an argon atmosphere at room
temperature. Then, methanol (2 ml) followed by acetyl
chloride (0.5 ml) were added dropwise to the mixture. The
mixture was stirred for four more hours and the solvents
were removed in vacuo. The crude residue was purified by
column chromatography using first ethyl acetate and then a
3
1
2
(s); d (CDCl ) 0.83 (3H, t J¼7.5 Hz,
2 2 3
H
3
CH CH ), 1.41 (2H, br s, NH ), 1.5–1.6 (1H, m, CH CH ),
3
1
3
2
.8–2.0 (1H, m, CH CH ), 2.81 (1H, d J¼13.0 Hz, CH Ar),
2 3
2
3
2
.17 (1H, d J¼13.0 Hz, CH Ar), 3.64 (3H, s, OCH ), 7.27
(
2H, d J¼8.6 Hz, ArCH), 8.06 (2H, d J¼8.5 Hz, ArCH); d
C
(
CDCl ) 8.69 (CH CH ), 33.59 (CH CH ), 45.91 (CH Ar),
3 3 2 2 3 2
5
2.57 (OCH ), 62.99 (NCCO ), 123.77 (ArCH), 131.25
3 2
(
ArCH), 144.94 (ArC), 147.38 (ArC), 176.67 (CO ); m/z
2
þ
(CI, NH ) 253 (MH , 20), 223 (50), 116 (100); [found: (CI,
NH ) 253.1190 (MH , C H N O requires 253.1188)].
mixture of ethyl acetate and ethanol (4:1) as eluent to give
20
3
þ
compound 4e (176 mg, 63%) as a yellow oil. [a] ¼þ2.7
3
12 17
2
4
D
(
1733 (s), 1605 (s) and 1521 cm (s); d (CDCl ) 0.77 (3H,
c¼0.6, CHCl ); n
(film) 3390 (w), 2956 (s), 2872 (m),
max
3
2
1
4.1.5. N-para-Chlorobenzylidene (R,S)-leucine methyl
ester 3b. To a stirred suspension of (R,S)-leucine methyl
H
3
d J¼6.5 Hz, CH CH), 0.90 (3H, d J¼6.5 Hz, CH CH), 1.46
2 2
3
3
ester hydrochloride (9.43 g, 52.1 mmol) in dichloromethane
190 ml), triethylamine (5.26 g, 52.1 mmol), para-chloro-
(2H, br s, NH ), 1.60 (1H, dd J¼13.6, 4.5 Hz, CH CH),
(
1.7–1.8 (1H, m, CHMe ), 1.85 (1H, dd J¼13.6, 8.0 Hz,
2
benzaldehyde (7.32 g, 52.1 mmol) and a small amount of
magnesium sulphate were added. The reaction mixture was
stirred overnight, and was subsequently filtered and
evaporated in vacuo. The crude product was then taken up
in diethyl ether and washed with water (5£30 ml), dried
with magnesium sulphate and evaporated to dryness to give
CH CH), 2.82 (1H, d J¼13.0 Hz, CH Ar), 3.17 (1H, d
2
2
J¼13.0 Hz, CH Ar), 3.63 (3H, s, OCH ), 7.27 (2H, d
2
3
J¼8.6 Hz, ArCH), 8.07 (2H, d J¼8.6 Hz, ArCH); d
C
(CDCl ) 21.15 (CH CH), 22.88 (CH CH), 23.23 (CHMe ),
2
3
3
3
45.83 (CH ), 47.45 (CH ), 50.66 (OCH ), 60.32 (NCCO ),
2
2
3
2
122.03 (ArCH), 130.20 (ArCH), 142.75 (ArC), 145.67 (ArC),
175.49 (CO ); m/z (CI, NH ) 281 (MH , 70), 251 (100);
þ
[found: (ES) 281.1501 (MH ,C H N O requires 281.1501)].
compound 3b (9.06 g, 65%) as a yellow oil. n
(film) 2956
1
max
2
3
s), 2871 (m), 1742 (s), 1642 (m), 1596 (w) and 1572 cm2
w); d (CDCl ) 0.80 (3H, d J¼6.6 Hz, CH CH), 0.85 (3H,
þ
(
(
14 21 2 4
H
3
3
3
5
d J¼6.6 Hz, CH CH), 1.4–1.5 (1H, m, CHMe ), 1.73–1.75
4.1.8. a-Allyl-leucine methyl ester 4f. Imine 3b (0.267 g,
1.0 mmol) was dissolved in dry toluene (2.5 ml) and
copper(salen) complex 1 (38.5 mg, 0.10 mmol) was added.
Powdered sodium hydroxide (0.14 g, 3.5 mmol) and allyl
bromide (145 mg, 1.2 mmol) were added to the mixture.
The resulting solution was stirred overnight under an argon
atmosphere at room temperature. Then, methanol (2 ml)
followed by acetyl chloride (0.5 ml) were added dropwise to
the mixture. The mixture was stirred for four more hours
and the solvents were removed in vacuo. The residue was
purified by column chromatography using first ethyl acetate
and then a mixture of ethyl acetate and ethanol (4:1) as
eluent to give compound 4f (85 mg, 46%) as a colourless
oil. d (CDCl ) 0.75 (3H, d J¼6.2 Hz, CH CH), 0.87 (3H, d
3
2
(
(
(
1H, m, CHCH CH), 1.76–1.78 (1H, m, CHCH CH), 3.64
2 2
3H, s, OCH ), 4.22 (1H, dd J¼8.3, 6.1 Hz, NCHCO ), 7.28
3
2
2H, d J¼8.5 Hz, ArCH), 7.63 (2H, d J¼8.5 Hz, ArCH),
8
.16 (1H, s, NvCH); d (CDCl ) 21.85 (CH CH), 23.47
C
3
3
(
(
(
CH CH), 24.79 (CHMe ), 42.43 (CHCH CH), 52.51
3 2 2
OCH3), 71.83 (NCHCO2), 129.22 (ArCH), 130.09
ArCH), 134.50 (ArC), 137.45 (ArC), 162.12 (NvCH),
þ
68.1100 (MH , C H NO Cl requires 268.1104)].
1
2
73.06 (CO ); m/z (CI, NH ) 268 (MH , 100); [found: (ES)
2
3
þ
35
1
4
19
2
3
4,35
4
(
.1.6. a-Benzyl-leucine methyl ester 4d.
0.267 g, 1.0 mmol) was dissolved in dry toluene (2.5 ml)
Imine 3b
and copper(salen) complex 1 (38.5 mg, 0.10 mmol) was
added. Powdered sodium hydroxide (0.14 g, 3.5 mmol) and
benzyl bromide (0.14 ml, 1.2 mmol) were added to the
mixture. The resulting solution was stirred for 7 days under
an argon atmosphere at room temperature. Then, methanol
H
3
3
J¼6.3 Hz, CH CH), 1.4–1.5 (1H, m, CH CHMe ), 1.6–1.7
3
2
2
(1H, m, CH CHMe ), 2.14 (1H, dd J¼13.5, 8.6 Hz,
2
2
CH CHv), 2.39 (2H, br s, NH ), 2.48 (1H, dd J¼13.4,
2
2
6.5 Hz, CH CHv), 2.9–3.0 (1H, m, CHMe ), 3.64 (3H, s,
2
2
(
2 ml) followed by acetyl chloride (0.5 ml) were added
OCH ), 5.0–5.1 (2H, m, vCH ), 5.5–5.6 (1H, m, vCH);
3 2
m/z (CI, NH ) 186 (MH , 100).
3
þ
dropwise to the mixture. The mixture was stirred for four
more hours and the solvents were removed in vacuo. The
crude residue was purified by column chromatography using
first ethyl acetate and then a mixture of ethyl acetate and
ethanol (4:1) as eluent to give compound 4d (127 mg, 54%)
4.1.9. N-para-Chlorobenzylidene (R,S)-phenylalanine
3
6
methyl ester 3c. To a stirred suspension of (R,S)-
phenylalanine methyl ester hydrochloride (3.00 g,

1856
Y. N. Belokon et al. / Tetrahedron 60 (2004) 1849–1861
1
(
1
3.95 mmol) in dichloromethane (40 ml), triethylamine
1.28 g, 12.68 mmol), para-chlorobenzaldehyde (1.78 g,
2.68 mmol) and a small amount of magnesium sulphate
chloride were added and the mixture was stirred for 4 h. The
solvents were then removed in vacuo. The residue was
purified by column chromatography using ethyl acetate and
ethanol (4:1) as eluent to give compound 4h (210 mg, 67%)
were added. The reaction mixture was stirred overnight, and
was subsequently filtered and evaporated in vacuo. The
residue was then taken up in diethyl ether and washed with
water (5£30 ml), dried with magnesium sulphate and
evaporated to dryness to give compound 3c (3.82 g, 90%)
2
0
as light yellow oil. [a] ¼þ1.6 (c¼0.6, CHCl ); n
(KBr)
max
D
3
3028 (m), 2953 (m), 1951 (w), 1739 (s), 1603 (s) and
1520 cm2 (s); d (CDCl ) 1.63 (2H, br s, NH ), 2.79 (1H, d
1
H
3
2
J¼13.3 Hz, CH Ph), 2.88 (1H, d J¼12.9 Hz, CH Ph), 3.29
2
2
as yellow solid. Mp 63–65 8C; dH (CDCl ) 3.06 (1H, dd
3
(1H, d J¼13.0 Hz, CH ArNO ), 3.35 (1H, d J¼13.0 Hz,
CH ArNO ), 3.59 (3H, s, OCH ), 7.0–7.1 (2H, m, ArCH),
2 2 3
2
2
J¼13.5, 9.0 Hz, CH Ph), 3.28 (1H, dd J¼13.5, 4.9 Hz,
2
CH Ph), 3.67 (3H, s, OCH ), 4.08 (1H, dd J¼9.0, 4.9 Hz,
7.1–7.3 (3H, m, ArCH), 7.29 (2H, d J¼8.6 Hz, ArCH), 8.07
(2H, d J¼8.7 Hz, ArCH); d (CDCl ) 39.85 (CH ), 41.03
(CH ), 52.20 (OCH ), 64.45 (NCCO ), 123.07 (ArCH),
2 3 2
2
3
NCHCO ), 7.0–7.2 (5H, m, ArCH), 7.27 (2H, d J¼8.5 Hz,
2
C
3
2
ArCH), 7.53 (2H, d J¼8.5 Hz, ArCH), 7.76 (1H, s, CHvN);
d (CDCl ) 40.74 (CH Ph), 53.34 (OCH ), 75.93 (NCHCO ),
3
127.38 (ArCH), 128.17 (ArCH), 129.41 (ArCH), 130.1
(ArCH), 131.09 (ArC), 139.19 (ArC), 146.71 (ArC), 168.35
C
3
2
2
1
27.66 (ArCH), 129.36 (ArCH), 129.86 (ArCH), 130.66
ArCH), 130.76 (ArCH), 134.96 (ArC), 138.12 (ArC), 138.24
þ
(
(
(CO ); m/z (CI, NH ) 315 (MH , 58), 285 (100); [found:
2
3
ArC), 163.42 (NvCH), 172.98 (CO2).
(ES) 337.1141 (MþNaþ, C H N O Na requires
17
18 2 4
337.1159)].
3
7
4
(
.1.10. a-Allyl-phenylalanine methyl ester 4g. Imine 3c
0.301 g, 1.00 mmol) was dissolved in dry toluene (2.5 ml)
4.1.13. N-para-Chlorobenzylidene (R,S)-phenylglycine
4
0
and copper(salen) complex 1 (96.25 mg, 0.25 mmol) was
added. Powdered sodium hydroxide (0.14 g, 3.5 mmol) and
allyl bromide (0.145 g, 1.2 mmol) were added to the
mixture. The resulting solution was stirred overnight
under an argon atmosphere at room temperature. Then,
methanol (2 ml) followed by acetyl chloride (0.5 ml) were
added dropwise to the mixture. The mixture was stirred for
four more hours and the solvents were removed in vacuo.
The crude residue was purified by column chromatography
using first ethyl acetate and then a mixture of ethyl acetate
and ethanol (4:1) as eluent to give compound 4g (149 mg,
methyl ester 3e. To a stirred suspension of (R,S)-
phenylglycine methyl ester chloride (2.00 g, 9.92 mmol)
in dichloromethane (28 ml), triethylamine (0.84 g,
8.27 mmol), para-chlorobenzaldehyde (1.16 g, 8.27 mmol)
and a small amount of magnesium sulphate were added. The
reaction mixture was stirred overnight, and was sub-
sequently filtered and evaporated in vacuo. The crude
product was then taken up in diethyl ether and washed with
water (5£30 ml), dried with magnesium sulphate and
evaporated to dryness to give compound 3e (1.09 g, 46%)
as a yellow oil. d (CDCl ) 3.67 (3H, s, OCH ), 5.13 (1H, s,
H
3
3
6
2
8%) as a colourless oil. nmax (KBr) 3378 (w), 3030 (w),
955 (w), 1738 (s), 1634 (m) and 1604 cm2 (m); dH
NCH), 7.1–7.5 (7H, m, ArCH), 7.69 (2H, d J¼8.5 Hz,
1
ArCH), 8.22 (1H, s, CHvN).
(
CDCl ) 1.48 (2H, br s, NH ), 2.25 (1H, dd J¼13.5, 8.5 Hz,
3
2
4
1
CH CHv), 2.64 (1H, dd J¼13.4, 6.4 Hz, CH CHv), 2.71
2 2
4.1.14. a-Phenyl-allylglycine methyl ester 4i. Imine 3e
(0.200 g, 0.70 mmol) was dissolved in dry toluene (2 ml)
and catalyst 1 (5 mg, 0.014 mmol) was added. Finely
ground sodium hydroxide (0.097 g, 2.4 mmol) was then
added, followed by allyl bromide (101 mg, 0.83 mmol). The
mixture was allowed to stir for 24 h at room temperature
under an argon atmosphere. The solution was then filtered
and the solvent evaporated in vacuo to leave a residue to
which a mixture of methanol (1.3 ml) and acetyl chloride
(
CH Ph), 3.63 (3H, s, OCH ), 5.08–5.09 (2H, m, CH v),
1H, d J¼13.2 Hz, CH Ph), 3.11 (1H, d J¼13.2 Hz,
2
2
3
2
5
(
(
1
(
2
.6–5.7 (1H, m, vCH), 7.0–7.3 (5H, m, ArCH); dC
CDCl ) 42.32 (CH ), 43.79 (CH ), 53.04 (OCH ), 64.36
3
2
2
3
NCCO ), 121.98 (vCH ), 128.07 (ArCH), 129.23 (ArCH),
2 2
30.55 (ArCH), 131.07 (vCH), 134.47 (ArC), 173.00
þ
20.1337 (MH , C H NO requires 220.1337)].
CO ); m/z (CI, NH ) 220 (MH , 100); [found: (CI, NH )
2
3
3
þ
1
3
17
2
(
0.3 ml) was added. The resulting mixture was stirred at
3
8,39
4
.1.11. Hydrolysis of 4g to a-Allyl-phenylalanine.
A
room temperature for 4 h, then evaporated in vacuo. The
residue was added to a silica gel column and eluted with
EtOAc/EtOH (4:1) to give product 4i (43 mg, 31%) as a
colourless oil. nmax (KBr) 3389 (w), 3320 (w), 3070 (w),
3025 (w), 2952 (m), 1732 (s), 1640 (m) and 1600 cm2 (m);
dH (CDCl ) 1.97 (2H, br s, NH ), 2.59 (1H, dd J¼13.6,
sample of compound 4g was refluxed overnight in 2 M
hydrochloric acid. The solvent was evaporated as an
azeotrope with toluene to leave a-allyl-phenylalanine as a
white solid which was analysed without further purification.
1
2
5
[
HCl) for (S)-enantiomer.
a] ¼þ4.6 (c¼1, 1 M HCl) [a] ¼þ16 (c¼1, aqueous
D
D
3
2
3
9
d
(CD OD) 2.66 (1H, dd
3
7.8 Hz, CH CHv), 2.91 (1H, dd J¼13.6, 6.7 Hz,
H
2
J¼14.5, 7.6 Hz, CH CHv), 2.86 (1H, dd J¼14.5, 7.1 Hz,
CH CHv), 3.64 (3H, s, OCH ), 5.0–5.1 (2H, m, vCH ),
2
2
3
2
CH CHv), 3.16 (1H, d J¼14.3 Hz, CH Ph), 3.35 (1H, d
5.5–5.7 (1H, m, vCH), 7.2–7.5 (5H, m, ArCH); dC
(CDCl ) 45.05 (CH ), 52.92 (OCH ), 63.54 (NCCO ),
120.38 (vCH ), 125.79 (ArCH), 127.92 (ArCH), 128.83
2
2
2
J¼14.3 Hz, CH Ph), 5.3–5.4 (2H, m, vCH ), 5.7–5.9 (1H,
2
2
3
2
3
2
m, vCH), 7.2–7.4 (5H, m, ArCH).
(ArCH), 133.34 (vCH), 143.14 (ArC), 176.05 (CO ); m/z
(CI, NH ) 206 (MH , 20), 164 (97), 145 (81), 104 (100);
2
þ
[found: (ES) 206.1168 (MH , C H NO requires
206.1176)].
4
.1.12. a-(4-Nitrophenylmethyl)-phenylalanine methyl
3
þ
ester 4h. Imine 3c (0.301 g, 1.00 mmol) was dissolved in
dry toluene, then copper(salen) complex 1 (38.4 mg,
1
2
16
2
0
4
.1 mmol), powdered NaOH (140 mg, 3.5 mmol) and
-nitrobenzyl bromide (259.2 mg, 1.2 mmol) were added.
4
2
4.1.15. a-Phenyl-phenylalanine methyl ester 4j. Imine
3e (0.200 g, 0.70 mmol) was dissolved in dry toluene (2 ml)
and catalyst 1 (5 mg, 0.014 mmol) was added. Finely
The mixture was stirred overnight under an argon
atmosphere at room temperature. Methanol and acetyl

Y. N. Belokon et al. / Tetrahedron 60 (2004) 1849–1861
1857
ground sodium hydroxide (0.097 g, 2.4 mmol) was then
added, followed by benzyl bromide (143 mg, 0.83 mmol).
The mixture was allowed to stir for 24 h at room
temperature under an argon atmosphere. The solution was
then filtered and the solvent evaporated in vacuo to leave a
residue to which a mixture of methanol (1.3 ml) and acetyl
chloride (0.3 ml) was added. The resulting mixture was
stirred at room temperature for 4 h, then evaporated in
vacuo. The residue was added to a silica gel column and
eluted with EtOAc/EtOH (4:1) to give product 4j (67 mg,
(294 mg, 2.21 mmol). The mixture was allowed to stir for
48 h at room temperature under an argon atmosphere. The
solution was then filtered and the solvent evaporated in
vacuo to leave a residue which was added to a silica gel
column and eluted first with EtOAc and then with EtOAc/
EtOH (4:1) to give product 4m (154 mg, 46%). nmax (KBr)
3395 (w), 3063 (w), 2951 (w), 1733 (s), 1642 (s), 1601 (m)
and 1581 cm2 (m); dH (CDCl ) 1.71 (3H, t J¼2.5 Hz,
1
3
CuCCH ), 1.85 (2H, br s, NH ), 2.24 (1H, dd J¼13.4,
3
2
8.1 Hz, CH –CH), 2.34 (1H, dq J¼16.3, 2.5 Hz, CH –
2
2
3
8%) as a colourless oil. d (CDCl ) 1.61 (2H, br s, NH ),
H
CuCMe), 2.45 (1H, dd J¼13.4, 6.7 Hz, CH –CH), 2.55 (1H,
3
2
2
3
CH Ph), 3.66 (3H, s, OCH ), 7.0–7.5 (10H, m, ArCH); d
.08 (1H, d J¼13.3 Hz, CH Ph), 3.57 (1H, d J¼13.3 Hz,
dq J¼16.3, 2.5 Hz, CH –CuCMe), 3.67 (3H, s, OCH ), 5.0–
2
2
3
5.1 (2H, m, CHvCH ), 5.5–5.7 (1H, m, CHvCH ); d
2 2 C
2
3
C
(
CDCl ) 46.40 (CH ), 52.84 (OCH ), 64.88 (NCCO ),
2
(CDCl )2.5(CH CuC), 29.0(CH CuCMe), 42.6(CH CH),
3 3 2 2
3
2
3
1
25.94 (ArCH), 127.39 (ArCH), 128.01 (ArCH), 128.68
ArCH), 128.81 (ArCH), 130.83 (ArCH), 136.53 (ArC),
51.3 (OCH ), 59.7 (NCCO ), 72.9 (CuCCH ), 78.1
3 2 3
(
(CuCCH ), 118.5 (CH vCH), 131.4 (CHvCH ), 174.9
2 2 2
þ
100), 104 (100); [found: (ES) 256.1323 (MH , C H NO
þ
(CO ); m/z (CI, NH ) 182 (MH , 100); [found: (CI, NH )
2 3 3
1
75.72 (CO ); m/z (CI, NH ) 256 (MH , 20), 196 (90), 165
2
3
þ
þ
182.1181 (MH , C H NO requires 182.1180)].
10 16 2
(
requires 256.1338)].
1
6
18
2
4.1.19. a-But-2-ynyl-allylglycine methyl ester 4m from
3
7
4
(
.1.16. a-Allyl-phenylalanine methyl ester 4k. Imine 3f
0.4 g, 1.84 mmol) was dissolved in dry toluene (5 ml) and
imine 3g. Imine 3g (0.4 g, 1.59 mmol) was dissolved in dry
toluene (5 ml) and catalyst 1 (12 mg, 0.03 mmol) was
added. Finely ground sodium hydroxide (0.222 g,
5.57 mmol) was then added, followed by 1-bromo-2-butyne
(254 mg, 1.91 mmol). The mixture was allowed to stir for
48 h at room temperature under an argon atmosphere. The
solution was then filtered and the solvent evaporated in
vacuo to leave a residue which was added to a silica gel
column and eluted first with EtOAc and then with EtOAc/
EtOH (4:1) to give product 4m (124 mg, 44%).
catalyst 1 (14 mg, 0.04 mmol) was added. Finely ground
sodium hydroxide (0.258 g, 6.46 mmol) was then added
followed by benzyl bromide (0.26 ml, 2.21 mmol). The
mixture was allowed to stir for 48 h at room temperature
under an argon atmosphere. The solution was then filtered
and the solvent evaporated in vacuo to leave a residue which
was added to a silica gel column and eluted first with EtOAc
and then with EtOAc/EtOH (4:1) to give product 4k
2
0
20
(249 mg, 69%). [a] ¼247.0 (c¼0.3, CHCl ); other data as
reported for compound 4g.
[a] ¼227.3 (c¼0.3, CHCl ); other data as reported for
D
3
D
3
the same compound prepared from imine 3f.
4
.1.17. a-(4-Nitrophenylmethyl)-allylglycine methyl
4.1.20. a-Propargyl-allylglycine methyl ester 4n. Imine
3f (0.4 g, 1.84 mmol) was dissolved in dry toluene (5 ml)
and catalyst 1 (14 mg, 0.04 mmol) was added. Finely
ground sodium hydroxide (0.258 g, 6.46 mmol) was then
added, followed by propargyl bromide (263 mg,
2.21 mmol). The mixture was allowed to stir for 48 h at
room temperature under an argon atmosphere. The solution
was then filtered and the solvent evaporated in vacuo to
leave a residue which was added to a silica gel column and
eluted first with EtOAc and then with EtOAc/EtOH (4:1) to
4
3
ester 4l. Imine 3f (0.4 g, 1.84 mmol) was dissolved in
dry toluene (5 ml) and catalyst 1 (14 mg, 0.04 mmol) was
added. Finely ground sodium hydroxide (0.258 g,
6
.46 mmol) was then added, followed by para-nitrobenzyl
bromide (0.477 g, 2.21 mmol). The mixture was allowed to
stir for 48 h at room temperature under an argon
atmosphere. The solution was then filtered and the solvent
evaporated in vacuo to leave a residue which was added to a
silica gel column and eluted first with EtOAc and then with
EtOAc/EtOH (4:1) to give product 4l (365 mg, 75%).
2
0
give product 4n (150 mg, 49%). [a] ¼222.7 (c¼0.3,
D
2
0
[
(
(
a] ¼262.6 (c¼0.3, CHCl ); n
(KBr) 3367 (w), 3010
1
CHCl ); n
3
(KBr) 3301 (w), 2952 (w), 1736 (s), and
1641 cm (m); dH (CDCl ) 1.8–2.0 (2H, br, NH ), 2.00
3 2
D
3
max
max
21
2
w), 2957 (w), 1733 (s), 1604 (m) and 1519 cm (s); dH
CDCl ) 1.64 (2H, br s, NH ), 2.26 (1H, dd J¼13.0, 8.4 Hz,
(1H, t J¼2.8 Hz, H–Cu), 2.28 (1H, dd J¼13.5, 8.2 Hz,
3
2
CH CHv), 2.6–2.7 (1H, m, CH CHv), 2.84 (1H, d
2
CH –CHv), 2.41 (1H, dd J¼16.5, 2.6 Hz, CH –Cu), 2.48
2
2
2
J¼12.9 Hz, CH Ar), 3.18 (1H, d J¼12.8 Hz, CH Ar),
(1H, dd J¼13.5, 6.7 Hz, CH –CHv), 2.62 (1H, dd J¼16.5,
2
2
2
3
.65 (3H, s, OCH ), 5.1–5.2 (2H, m, CHvCH ), 5.5–5.7
2
2.6 Hz, CH –Cu), 3.69 (3H, s, OCH ), 5.0–5.2 (2H, m,
3
3
2
(
1H, m CHvCH ), 7.28 (2H, d J¼8.2 Hz, ArCH), 8.07 (2H,
CHvCH ), 5.5–5.7 (1H, m, CHvCH ); d (CDCl ) 29.9
2 2 C 3
(CH Cu), 43.8 (CH CHv), 52.9 (OCH ), 60.8 (NCCO ),
2 2 3 2
2
d J¼8.0 Hz, ArCH); d (CDCl ) 44.9 (CH CHv), 46.0
C
3
2
(
1
CH Ar), 52.7 (CH ), 64.4 (NCCO ), 120.8 (CH vCH),
2
72.0 (CuCH), 79.8 (CuCCH ), 120.3 (CH vCH), 132.4
2 2
3
2
2
þ
(CHvCH ), 174.8 (CO ); m/z (CI, NH ) 168 (MH , 100);
2 2 3
23.9 (ArCH), 131.6 (ArCH), 132.2 (CHvCH ), 132.9
2
þ
þ
[found: (CI, NH ) 168.1019 (MH , C H NO requires
3 9 14 2
(
ArC), 144.5 (ArC), 173.0 (CO ); m/z (CI, NH ) 265 (MH ,
2
3
þ
6
C H N O requires 265.1185)].
0), 235 (100); [found: (CI, NH ) 265.1188 (MH ,
3
168.1019)].
1
3 17 2 4
4.1.21. Dimethyl N-para-chlorobenzylidene (R,S)-gluta-
4
.1.18. a-But-2-ynyl-allylglycine methyl ester 4m from
mate 3h. To a suspension of dimethyl glutamate hydro-
chloride (10.0 g, 47.5 mmol) in dichloromethane (110 ml),
was added triethylamine (4.7 ml, 33.8 mmol), para-chloro-
benzaldehyde (5.53 g, 39.6 mmol) and magnesium sulphate
(4.0 g). The reaction was stirred overnight, filtered, and
imine 3f. Imine 3f (0.4 g, 1.84 mmol) was dissolved in dry
toluene (5 ml) and catalyst 1 (14 mg, 0.04 mmol) was
added. Finely ground sodium hydroxide (0.258 g,
6
.46 mmol) was then added, followed by 1-bromo-2-butyne

1858
Y. N. Belokon et al. / Tetrahedron 60 (2004) 1849–1861
evaporated in vacuo. The residue was redissolved in
dichloromethane (50 ml) and washed with water
mixture was allowed to stir for 24 h at room temperature
under an argon atmosphere. The solution was then filtered
and the solvent evaporated in vacuo to leave a residue to
which a mixture of methanol (1.3 ml) and acetyl chloride
(0.3 ml) was added. The resulting mixture was stirred at
room temperature for 4 h, then evaporated in vacuo. The
residue was added to a silica gel column and eluted with
EtOAc/EtOH (4:1) to give product 4o (35 mg, 25%) as a
(
3£50 ml). The organic layer was dried (MgSO ) and
4
evaporated in vacuo to leave imine 3h (6.5 g, 69%) as a
white solid. Mp 62–63 8C; nmax (KBr) 3004 (s), 2954 (m),
1
2
1
743 (s), 1642 (s) and 1593 cm (m); d (CDCl ) 2.1–2.5
H 3
(
4H, m, CH CH ), 3.67 (3H, s, OCH ), 3.77 (3H, s, OCH ),
2 2 3 3
4
.09 (1H, dd J¼7.5, 4.9 Hz, NCHCO ), 7.41 (2H, d
2
2
0
J¼8.7 Hz, ArCH), 7.73 (2H, d J¼8.5 Hz, ArCH), 8.27
colourless oil. [a] ¼þ0.9 (c¼0.8, CHCl ); n
(KBr)
max
D
3
2
1
(
1H, s, HCvN); dC (CDCl ) 28.67 (CH ), 30.53 (CH ),
3
3384 (w), 3002 (w), 2954 (m) and 1736 cm
(s); dH
2
2
5
2.08 (OCH ), 52.74 (OCH ), 72.04 (NCHCO ), 129.32
3
(CDCl ) 1.89 (2H, br s, NH ), 2.23 (1H, dd J¼13.2, 8.3 Hz,
CH CHv), 2.3–2.4 (1H, m, CH CHv), 2.48 (1H, d
2 2
3
2
3
2
(
1
ArCH), 130.18 (ArCH), 138.12 (ArC), 138.21 (ArC),
63.36 (HCvN), 172.36 (CO ), 174.58 (CO ); m/z (EI) 299
J¼16.7 Hz, CH CO Me), 2.91 (1H, d J¼16.6 Hz, CH -
CO Me), 3.61 (3H, s, OCH ), 3.66 (3H, s, OCH ), 5.0–5.2
2 3 3
2
2
2
2
2
þ 37
þ 35
(
M ( Cl), 23), 297 (M ( Cl), 42), 266 (40), 238 (100),
þ
3
5
2
C H NO ClNa requires 320.0662)].
24 (65), 178 (91); [found: (ES) 320.0636 (M( Cl)þNa ,
(2H, m, vCH ), 5.5–5.7 (1H, m, vCH); d (CDCl ) 43.57
2 C 3
(CH ), 44.87 (CH ), 52.17 (OCH ), 52.82 (OCH ), 59.20
2 2 3 3
3
5
1
4
16
4
(NCCO ), 120.52 (vCH ), 131.88 (vCH), 172.23 (CO );
m/z (EI) 202 (MH , 8), 160 (100), 142 (90), 128 (30);
2 2 2
þ
4
4
4
.1.22. a-Benzyl-pyroglutamic acid methyl ester 7.
Imine 3h (0.635 g, 2.13 mmol) was dissolved in dry toluene
5 ml) and catalyst 1 (16 mg, 0.043 mmol) was added.
þ
[found: (ES) 224.0891 (MþNa , C H NO Na requires
9
15
4
(
224.0893)].
Finely ground sodium hydroxide (0.298 g, 7.46 mmol) was
then added, followed by benzyl bromide (437 mg,
4.1.25. a-Benzyl-aspartic acid dimethyl ester 4p. Imine 3i
(0.222 g, 0.78 mmol) was dissolved in dry toluene (2 ml)
and catalyst 1 (6 mg, 0.043 mmol) was added. Finely
ground sodium hydroxide (0.298 g, 7.5 mmol) was then
added, followed by benzyl bromide (161 mg, 0.94 mmol).
The mixture was allowed to stir for 24 h at room
temperature under an argon atmosphere. The solution was
then filtered and the solvent evaporated in vacuo to leave a
residue to which a mixture of methanol (1.5 ml) and acetyl
chloride (0.4 ml) was added. The resulting mixture was
stirred at room temperature for 4 h, then evaporated in
vacuo. The residue was added to a silica gel column and
eluted with EtOAc/EtOH (4:1) to give product 4p (146 mg,
2
.56 mmol). The mixture was allowed to stir for 48 h at
room temperature under an argon atmosphere. The solution
was then filtered and the solvent evaporated in vacuo to
leave a residue to which a mixture of methanol (4 ml) and
acetyl chloride (1 ml) was added. The resulting mixture was
stirred at room temperature for 4 h, then evaporated in
vacuo. The residue was added to a silica gel column and
eluted with EtOAc/EtOH (4:1) to give product 7 (256 mg,
5
2
2%) as a colourless oil. nmax (KBr) 3221 (br), 3025 (w),
2
1
930 (m), 2859 (w), 1736 (s) and 1698 cm
(s); dH
(
CDCl ) 2.0–2.5 (4H, m, CH CH ), 2.85 (1H, d J¼13.4 Hz,
3
2
2
CH Ph), 3.18 (1H, d J¼13.4 Hz, CH Ph), 3.64 (3H, s, OCH ),
2 2 3
2
0
6
.33(1H, brs,NH),7.0–7.3(5H,m,ArCH);d (CDCl )28.73
3
75%) as a colourless oil. [a] ¼þ0.7 (c¼0.7, CHCl ); n
C
D
3
max
(
(
CH ), 29.53 (CH ), 43.92 (CH ), 51.64 (OCH ), 65.42
2
NCCO ), 126.48 (ArCH), 127.68 (ArCH), 128.78 (ArCH),
2
(KBr) 3386 (w), 3056 (w), 2925 (m), 2852 (m) and
2
2
3
1736 cm2 (s); dH (CDCl ) 1.98 (2H, br s, NH ), 2.51
1
3
2
1
33.75 (ArC), 172.63 (CO ), 175.82 (NCO).
2
(1H, d J¼16.7 Hz, CH CO Me), 2.77 (1H, d J¼13.2 Hz,
2
2
CH Ph), 2.95 (1H, d J¼13.2 Hz, CH Ph), 2.99 (1H, d
2
2
4
.1.23. Dimethyl N-para-chlorobenzylidene (R,S)-aspar-
J¼16.7 Hz, CH CO Me), 3.60 (6H, s, 2£ CO Me), 7.0–7.3
(5H, m, ArCH); d (CDCl ) 43.73 (CH ), 46.55 (CH ),
C 3 2 2
2
2
2
4
5
tate 3i. To a suspension of dimethyl aspartate hydro-
chloride (2.5 g, 12.8 mmol) in dichloromethane (35 ml),
was added triethylamine (2.5 ml, 17.9 mmol), para-chloro-
benzaldehyde (1.19 g, 8.4 mmol) and magnesium sulphate
52.15 (OCH ), 52.62 (OCH ), 60.47 (NCCO ), 127.67
3
3
2
(ArCH), 128.81 (ArCH), 130.10 (ArCH), 135.48 (ArC),
172.16 (CO ); m/z (EI) 252 (MH , 49), 192 (60), 160 (80),
þ
100 (100); [found: (ES) 252.1222 (MH , C H NO
requires 252.1230)].
2
þ
(
2.0 g). The reaction was stirred overnight, filtered, and
1
3
18
4
evaporated in vacuo. The residue was redissolved in
dichloromethane (50 ml) and washed with water
(
evaporated in vacuo to leave imine 3i (2.0 g, 84%) as a
3£50 ml). The organic layer was dried (MgSO ) and
4.1.26. N-Boc-a-but-2-ynyl-allylglycine methyl ester. A
solution of (BOC) O (12 mg, 0.056 mmol) in tert-butanol
4
2
yellow oil. dH (CDCl ) 2.89 (1H, dd J¼16.8, 7.8 Hz,
(0.2 ml) was added dropwise at room temperature to a
vigorously stirred solution of amine 4m (10 mg,
0.055 mmol) in tert-butanol (0.5 ml). After the addition
was complete, the reaction mixture was stirred at 30 8C for
3 h. The solvent was then evaporated in vacuo to leave a
yellow oil which was purified by column chromatography
on silica gel using EtOAc/hexane (4:1) as eluent to give
N-Boc-a-but-2-ynyl-allylglycine methyl ester (12 mg,
3
CH CO Me), 3.17 (1H, dd J¼16.8, 5.8 Hz, CH CO Me),
2
2
2
2
3
.68 (3H, s, OCH ), 3.77 (3H, s, OCH ), 4.49 (1H, dd
3 3
J¼7.8, 5.8 Hz, NCHCO Me), 7.40 (2H, d J¼8.5 Hz,
2
ArCH), 7.72 (2H, d J¼8.5 Hz, ArCH), 8.36 (1H, s,
þ 37
0), 226 (35), 224 (100); [found: (ES) 306.0488
þ 35
HCvN); m/z (EI) 285 (M ( Cl), 10), 283 (M ( Cl),
3
3
5
þ
35
(
M( Cl)þNa , C H NO ClNa requires 306.0505)].
1
3
14
4
2
0
8
0%) as a yellow oil. [a] ¼þ7 (c¼0.6, CHCl ); n
D
3
max
2
1
4
(
.1.24. a-Allyl-aspartic acid dimethyl ester 4o. Imine 3i
0.200 g, 0.71 mmol) was dissolved in dry toluene (2 ml)
(KBr) 3565 (s), 3287 (s), 2902 (s) and 1704 cm (m); d
(CDCl ) 1.37 (9H, s, (CH ) C), 1.70 (3H, t J¼5.0 Hz,
H
3
3 3
and catalyst 1 (5.4 mg, 0.043 mmol) was added. Finely
ground sodium hydroxide (0.298 g, 7.5 mmol) was then
added, followed by allyl bromide (102 mg, 0.85 mmol). The
CH CuC), 2.47 (1H, dd J¼13.7, 6.9 Hz, CH –CH), 2.6–
2 2
3
2
2.7 (1H, m, CH –Cu), 2.8–2.9 (1H, m, CH –CH), 2.9–
3.0 (1H, m, CH –Cu), 3.69 (3H, s, OCH ), 5.0–5.1 (2H,
2
3

Y. N. Belokon et al. / Tetrahedron 60 (2004) 1849–1861
1859
m, CHvCH ), 5.33 (1H, br s, NH), 5.5–5.7 (1H, m
2
3.69 (3H, s, OCH ), 4.9–5.1 (3H, m, vCH þ vHCCH ),
3
2
2
CHvCH ); d (CDCl ) 2.6 (CH ), 27.3 ((CH ) C), 28.7
3 3
5.55 (1H, br s, NH), 6.44 (1H, dd J¼17.4, 10.8 Hz,
2
C
3
3
(
CH C), 38.4 (CH CH), 51.7 (OCH ), 61.4 ((CH ) C), 72.6
2 2 3 3 3
H CvCH); d (CDCl ) 27.3 ((CH ) C), 34.6 (CH CHv),
2
C
3
3 3
2
(
CuCCH ), 84.2 (CuCCH ), 118.4 (CH vCH), 130.1
2
43.8 (CH Cv), 51.6 (OCH ), 63.2 (NCCO ), 84.2
2 3 2
3
2
(
2
(
CHvCH ), 153.2 (CONH), 171.7 (CO ); m/z (CI, NH )
2
((CH ) C), 114.1 (vCH ), 125.6 (vCH), 131.6 (CvCH),
3 3 2
2
3
þ
MH , C H NO requires 282.1700)].
82 (MH , 54), 225 (100); [found: (CI, NH ) 282.1698
3
145.7 (CHv), 154.2 (OCONH), 173.5 (CO Me); m/z (CI,
2
þ
þ
68.1547 (MH , C H NO requires 268.1543)].
NH ) 268 (MH , 54), 229 (100); [found: (CI, NH )
3
1
5
24
4
3
þ
2
1
4
22
4
4.1.27. N-Boc-a-Propargyl-allylglycine methyl ester. A
solution of (BOC) O (40 mg, 0.181 mmol) in tert-butanol
4.1.30. Diels–Alder adduct 9. To a solution of diene 8a
(10 mg, 0.036 mmol) in ethyl acetate (2 ml) at room
temperature was added maleic anhydride (8 mg,
0.078 mmol). The mixture was stirred at room temperature
overnight. The solvent was then removed in vacuo and the
residue was dissolved in dichloromethane and filtered twice
through a pad of Celite, leaving product 9 (8 mg, 62%) as a
2
(
0.5 ml) was added dropwise at room temperature to a
vigorously stirred solution of amine 4n (30 mg,
.179 mmol) in tert-butanol (2 ml). After the addition was
complete, the reaction mixture was stirred overnight at
0 8C. The solvent was then evaporated in vacuo to leave a
0
3
yellow oil which was purified by column chromatography
on silica gel using EtOAc/hexane (4:1) as eluent to give
N-Boc-a-propargyl-allylglycine methyl ester (36 mg, 75%)
1:1 mixture of diastereomers. n
(KBr) 2929 (m), 2855
max
(w), 2254 (w), 1850 (w) and 1779 cm2 (s); dH (CDCl3)
1
2
0
as a yellow oil. [a] ¼þ4 (c¼0.6, CHCl ); n
(KBr) 3430
1
1.37 (18H, s, 2£ (CH ) C), 1.6–1.7 (6H, m, 2£ CH ), 1.8–
D
3
max
3 3
3
(
(
s), 3305 (s), 2981 (s), 2123 (w), 1809 (s) and 1712 cm2
s); dH (CDCl ) 1.37 (9H, s, (CH ) C), 1.93 (1H, t
2.0 (4H, m, 2£ CH ), 2.2–2.3 (2H, m, 2£ CH), 2.4–2.6 (4H,
2
m, 2£ CH ), 2.6–2.7 (4H, m, 2£ CH ), 3.3–3.4 (4H, m, 4£
3
3 3
2
2
J¼2.5 Hz, H–Cu), 2.47 (1H, dd J¼13.7, 7.3 Hz, CH –
CH), 3.68 and 3.65 (3H, 2£ s, OCH ), 4.7–4.8 and 5.0–5.1
2
3
CHv), 2.7–2.8 (1H, m, CH –Cu), 2.8–2.9 (1H, m, CH –
2
(2H, 2£ br s, NH); d (CDCl ) 16.9 (CH ), 27.3 (C(CH ) ),
2
C
3
3
3 3
CHv), 3.0–3.1 (1H, m, CH –Cu), 3.71 (3H, s, OCH ),
3
28.8 (COCH), 31.2 (COCH), 36.0 (CH ), 38.2 (CH–Cv),
2
2
5
.0–5.1 (2H, m, CHvCH ), 5.35 (1H, br s, NH), 5.5–5.7
2
42.4 (CH ), 43.8 (CH ), 51.6 (OCH ), 63.2 (NCCO ), 84.2
2
2
3
2
(
(
7
1H, m, CHvCH ); dC (CDCl ) 25.9 (CH Cu), 27.8
2
(OCMe ), 133.6 (vCH), 142.2 (vC), 154.2 (OCONH),
3
3
2
þ
100), 380 (MH , 70); [found: (CI, NH ) 397.1971
(CH ) C), 40.0 (CH CHv), 53.2 (OCH ), 62.4 ((CH ) C),
3
167.7 (CO ), 173.6 (CO ); m/z (CI, NH ) 397 (MþNH ,
3
2
3
3 3
2
2
3
4
þ
1.4 (CuCH), 85.6 (CuCCH ), 120.2 (CH vCH), 131.9
2
2
3
þ
(
NH ) 268 (MH , 93), 229 (100); [found: (CI, NH )
2
CHvCH ), 147.2 (OCONH), 172.8 (CO Me); m/z (CI,
(MþNH , C H N O requires 397.1969)].
2
2
4
19 29 2 7
þ
68.1539 (MH , C H NO requires 268.1543)].
3
3
þ
4.2. Determination of enantiomeric excess
1
4
22
4
4
.1.28. Diene 8a. N-Boc-a-but-2-ynyl-allylglycine methyl
(S)-a-Methylbenzyl isocyanate (one or two drops) was
added to an NMR sample of a,a-disubstituted amino acid
methyl ester and left overnight to react completely with the
amino ester. The diastereomeric excess and therefore
enantiomeric excess was determined from the integration
ester (7 mg, 0.025 mmol) was dissolved in dry dichloro-
methane (2.5 ml) and Grubbs’ catalyst (1.0 mg, 5 mol%)
was added to the solution. The reaction mixture was stirred
overnight at room temperature under an ethene atmosphere.
The solvent was removed in vacuo, the residue redissolved
in dichloromethane and filtered through silica to remove the
catalyst. The eluent was evaporated in vacuo to leave diene
1
of the methylene or methyl ester region of the H NMR
spectrum of the resulting diastereomers.
8
a (10 mg, 100%) as a yellow oil. n
2
(KBr) 3364 (m),
max
1
2925 (s), 2854 (s), and 1715 cm (s); d (CDCl ) 1.36 (9H,
H 3
s, (CH ) C), 1.85 (3H, s, CH Cv), 2.6–2.7 (2H, m, CH ),
Acknowledgements
3
3
3
2
3
vCH ), 4.87 (1H, s, vCH ), 5.02 (1H, br s, NH), 5.57 (1H,
.1–3.2 (2H, m, CH ), 3.69 (3H, s, OCH ), 4.78 (1H, s,
2 3
The authors thank the EU for funding a Socrates exchange
visit (V.T.) and for funding this project through the
Descartes prize research grant. Mass spectra were recorded
by the EPSRC national service at the University of Wales,
Swansea.
2
2
s, CHv); dC (CDCl ) 19.3 (CH ), 27.3 ((CH ) C), 34.6
3
3
3 3
(
(
(
(
CH CH), 43.9 (CH C), 51.6 (OCH ), 63.4 (NCCO ), 84.2
2 2 3 2
(CH ) C), 112.4 (CH vCH), 122.5 (vCH), 138.0
3
3
2
CvCH), 140.3 (CHvCH ), 153.9 (CONH), 173.6
2
þ
81.1622 (M , C H NO requires 281.1628)].
CO ); m/z (EI) 281 (M , 18), 207 (100); [found: (EI)
2
þ
2
1
4
22
4
References and notes
4
.1.29. Diene 8b. N-Boc-a-propargyl-allylglycine methyl
ester (14 mg, 0.052 mmol) was dissolved in dry dichloro-
methane (5 ml) and Grubbs catalyst (2.1 mg, 5 mol%) was
added to the solution. The reaction mixture was stirred
overnight at room temperature under an ethene atmosphere.
The solvent was removed in vacuo, the residue redissolved
in dichloromethane and filtered through silica to remove the
catalyst. The eluent was evaporated in vacuo to leave diene
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1
2
933 (s), and 1715 cm
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(
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