Stereospecific synthesis of naturally-occurring 4-alkylideneglutamic acids, 4-alkylglutamates and 4-alkylprolines

Article abstract of DOI:10.1039/a703489j

The enaminone 4, prepared from (2S)-pyroglutamic acid, has been found to react in an apparent 1,4-manner with DIBAL and Grignard reagents to afford a variety of alkylidene derivatives 8 which, except for the vinyl derivatives 8e, are formed only as the (E

Full text of DOI:10.1039/a703489j

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Stereospecific synthesis of naturally-occurring 4-alkylideneglutamic
1
acids, 4-alkylglutamates and 4-alkylprolines
Claire M. Moody and Douglas W. Young*
Sussex Centre for Biomolecular Design and Drug Development, CPES, University of Sussex,
Falmer, Brighton, UK BN1 9QJ
The enaminone 4, prepared from (2S)-pyroglutamic acid, has been found to react in an apparent 1,4-
manner with DIBAL and Grignard reagents to afford a variety of alkylidene derivatives 8 which, except
for the vinyl derivatives 8e, are formed only as the (E)-isomers. Three of these have been converted to the
4
-alkylideneglutamic acids, 1, 2 and 3, which are identical to known natural products, the synthesis
confirming 2 and 3 as the E-isomers. Catalytic reduction of the 4-alkylidenepyroglutamate derivatives 8 is
stereospecific and affords an effective route to (2S,4S)-4-alkylglutamic acids and (2S,4S)-4-alkylprolines.
Cuprate addition to the enone 5 affords access to the (2S,4R)-epimer 15 and carbene addition allows
cyclopropylglutamic acids 32 and 33 to be prepared.
In addition to the amino acids found in proteins, nearly one
thousand naturally occurring non-proteinogenic amino acids
H
H
H
H
H
H3C
CH3CH2
H2N
2,3
H
H
have now been discovered. There has recently been enormous
interest in these natural products and in unnatural synthetic
H2N
CO2H
H2N
CO2H
CO2H
4
HO2C
HO2C
HO2C
amino acids for their enzyme inhibitory and anti-metabolite
1
2
3
properties and their ability to impart protease resistance and to
induce conformation when incorporated into proteins. Our use
of such compounds in proteins has allowed us to probe the
N(CH3)2
H
5
3
H C
H
three dimensional structure of an enzyme. Substituted glu-
H
H
tamic acids are of particular interest because of their inter-
action with glutamate receptors in the central nervous system
H
H
H
O
O
O
N
CO2But
CO2But
N
t
N
CO2But
CO2But
CO Bu
CO2But
2
(
CNS) and their involvement in many other biological pro-
6
cesses. Proline and its analogues are constituent amino acids in
antibiotics,
enzyme inhibitors
7–10
and are of interest in angiotensin converting
4
5
6
1
1–13
and in providing conformational con-
Scheme 1
14
straint in proteins. We now report a method of synthesis of
optically pure (E)-4-alkylidenepyroglutamate derivatives which
is general and which we have used to gain access to three
naturally-occurring non-proteinogenic 4-alkylideneglutamic
acids, among other products. The synthesis has also been
adapted to provide a general and stereospecific synthesis of
ing such a general synthesis we have prepared the three 4-
alkylideneglutamic acid natural products 1, 2 and 3.
Our approach to 4-alkylidenepyroglutamic acid derivatives 8
30
was suggested by the fact that we had shown that, in spite of
its general tendency to react in a 1,2-fashion, DIBAL reduction
of the enamine 4 led to the exomethylene derivative 5 by what
appeared to be 1,4-addition followed by elimination. This sug-
gested that the enaminone 4 might react directly with Grignard
reagents to yield the alkylidene derivatives 8 as shown in
Scheme 2 and that the reaction might be considered as a 1,2-
(
2S,4S)-4-alkylglutamic acid and (2S,4S)-4-alkylproline de-
rivatives and to provide a further stereoselective route to
the (2S,4R)-epimers and to spiro cyclopropyl glutamic acid
derivatives.
4
-Methyleneglutamic acid 1 was first isolated as a product of
15
germinated peanuts and was then found in a variety of other
plants.
action, and, in peptides, to inhibit the vitamin K mediated γ-
16–24
It has been shown to exhibit strong CNS inhibitory
+
25
N(CH3)2
N(CH3)2
H
carboxylation of glutamic acid residues which is important in
H
26
H
H
the blood clotting process. 4-Ethylideneglutamic acid 2 is also
–
1
9–22,24,27
O
O
N
t
N
t
a widespread amino acid in plants,
and 4-propylidene-
CO Bu
CO2But
CO Bu
CO2But
2
2
20
glutamic acid 3 has been found in the fungus Mycena pura.
Synthesis of compounds 1 and 2 has previously been achieved
by reaction of substituted aziridines with stabilised Wittig
reagents followed by reaction of the ylide product with car-
4
4a
28
bonyl compounds.
Our interest in the stereospecific synthesis of amino acids
29
R
N(CH3)2
N
H3R
R
led us to consider 4-alkylidenepyroglutamic acids as possible
synthetic intermediates since we had shown in our synthesis of
H3S
H
H
H2
CO But
H
30
–
stereospecifically deuteriated leucine that the enaminone 4
and the enone 5 could be reduced stereospecifically to yield the
cis-4-methylpyroglutamate derivative 6 as shown in Scheme 1.
We therefore reasoned that a general synthesis of 4-alkylidene-
pyroglutamic acids might allow access to stereospecifically
alkylated derivatives of glutamic acid and proline. In develop-
O
O
N
CO But
2
2
CO2But
CO2But
8a R = Me
7
8
8
b R = Et
c R = Ph
8d R =
C
CH
Scheme 2
J. Chem. Soc., Perkin Trans. 1, 1997
3519

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addition to the resonance form 4a of the vinylogous amide. A
as the only isomer. Presumably in elimination of dimethylamine
search of the literature showed that other vinylogous amides
from the intermediate 7, steric interaction of the alkyl group, R,
and the imide carbonyl group must play an important role in
determining the stereochemistry of the product.
31,32
had been converted to alkylidene derivatives in this way.
The
danger of 1,2-attack to give ring-opened products was real,
however, since reaction of protected pyroglutamates with Grig-
nard reagents has been shown to proceed with ring opening to
Although reaction to yield the ring opened ketones 9 was not
a problem in our synthesis, we were interested in the possibility
of preparing these compounds in reasonable yields. The 4-
ethylidene derivative 8a was therefore reacted with MeMgBr at
room temperature when the ketone 9a was obtained in good
yield. The fact that no 1,4-addition was observed in this reac-
tion would suggest that the resonance form 4a is important in
achieving the original addition to the enaminone to yield the 4-
alkylidenepyroglutamate derivative 8. This might therefore sug-
gest that the reaction be regarded as 1,2-attack on the iminium
form 4a rather than 1,4-attack on the enaminone form 4.
Since 4-methyleneglutamic acid, 4-ethylideneglutamic acid
and 4-propylideneglutamic acid were known to be natural
products, a synthesis of these compounds required methods of
ring opening of the pyroglutamates 8. In previous studies, we
had found that the saturated pyroglutamate 6 could be con-
verted to the acid 11 by treatment with aqueous LiOH in
3
3,34
yield chain elongated amino acids.
However, should 1,4-
31,32
attack proceed as with other vinylogous amides,
the inter-
mediate 7 might not undergo elimination until the magnesium
salt was quenched and so ring opening would be prevented,
even if excess Grignard reagent were used.
30
When the enaminone 4 was reacted with 1.1 equiv. of
methylmagnesium bromide in Et O at Ϫ78 ЊC, the (E)-
2
ethylidene derivative 8a was obtained in 40% yield. Increasing
the amount of Grignard reagent to 2.5 equiv. caused the yield
to increase to 71%. Only a very small amount of the methyl
ketone 9a, formed by ring opening, was obtained. In keeping
33,34
with other work,
none of the alcohol which would result
from attack of the Grignard reagent on the ketone 9a was
obtained and no reaction with the ester group was observed.
The (E)-stereochemistry of the product 8a was assigned on the
basis of the observed nuclear Overhauser enhancement to H-
30
THF, but this was not successful with the less electrophilic
30
3
R when the methyl group of the ethylidene moiety† was irradi-
carbonyl group in the unsaturated compounds 8. When 5, 8a
and 8b were reacted with LiOMe in THF at Ϫ40 ЊC, however,
good yields of the esters 12h, 12a and 12b were obtained as
shown in Scheme 3. In addition to the ring opening reaction of
ated, H-3R and H-3S being assigned on the basis of the pres-
ence of an NOE between H-2 and H-3S.
H8E
H8Z
R
R
R
H8Z
H7
H3R
H3S
H8E
R
H6 H3R
H3S
H
H
H3R
H
H
H3S
H2
H6
H
H
H
H7
+
MeO2C
HN
H2
H2
O
O
N
CO2But
t
N
H
CO2But
CO Bu
2
R
O
O
CO2But
t
N
CO2But
N
O HN CO Bu
t
t
2
CO Bu
2
CO Bu
2
CO2But
CO2But
CO2But
5
, 8
12a R = Me
13a R = Me
13b R = Et
1
1
2b R = Et
2h R = H
8
e
8f
9a R = Me
9
c R = Ph
Scheme 3
Ph NHTs
H
H3C
HO2C
H
H
the ethylidene and propylidene compounds, removal of the N-
protecting group was observed and 13a and 13b were obtained
in small amounts as by-products in these reactions. The pro-
tected esters 12 were hydrolysed to the amino acids 1, 2 and 3
using 6  HCl. The acid 2 exhibited an NOE at both H-3 pro-
tons when the methyl group of the ethylidene moiety was
irradiated, and so the double bond had maintained the (E)-
stereochemistry in both the ring opening reaction and the
deprotection step.
6
4
H
H
O
N
t
HN
CO2CH2Ph
CO Bu
t
2
CO2But
CO Bu
2
1
0
11
Reaction of the enaminone 4 with EtMgBr, PhMgBr and
HC᎐CMgBr gave the products 8b, 8c and 8d in yields of 56, 78
and 59% respectively. (E)-Stereochemistry could be assigned to
b by observation of an NOE between the methylene of the
ethyl group and H-3S, and to 8c by an NOE between the aro-
matic protons and both H-3R and H-3S. The stereochemistry
of the single isomer of 8d was assigned by analogy, as no useful
NOE could be observed. A small amount of the by-product 9c
was obtained in the reaction with phenylmagnesium bromide.
When the enaminone 4 was treated with vinylmagnesium brom-
ide, the major product, obtained in 47% yield, was evidently the
E)-isomer 8e, since an NOE was observed between H and
both H-3R and H-3S. There was also a very small amount
1.6%) of the (Z)-isomer 8f which exhibited an NOE between
H-6 and H-3R.
The reaction proved to be general and remarkably stereo-
specific, the (E)-isomer being the preferred product in each
case. It was felt that this was not necessarily due to initial attack
of the Grignard reagent being stereospecific, since we showed in
our work on imine addition that base catalysed elimination
of both (6R)- and (6S)-isomers of the adduct 10 yielded the
benzyl ester corresponding to the (E)-benzylidene derivative 8c
᎐
The sample of synthetic 4-methyleneglutamic acid 1, [α]
D
8
24
ϩ13.2 (c 1, 3  HCl), {lit., [α]D ϩ13.2 (c 2, 3  HCl)} was
spectroscopically identical to a sample obtained from Lilium
24
maximowiczii, provided by Kasai et al. The synthetic sample
of 4-ethylideneglutamic acid 2, [α] ϩ27 (c 0.67, 3  HCl)
lit., [α] ϩ29.4 (c 1.4, 6  HCl)} was identical in all respects
with samples isolated from Tulipa gesueriana, provided by
Kasai et al., and from Mycena pura, provided by Hatanaka
and Katayama. The sample of 4-propylideneglutamic acid 3
obtained synthetically was identical to a sample isolated from
Mycena pura, provided by Hatanaka and Katayama, and the
synthesis defined the double bond geometry as (E).
Use of protected pyroglutamic acids is also attractive as a
potential route to stereospecifically alkylated glutamic acid and
proline derivatives, and reactions of the anion α to the amide
carbonyl group of pyroglutamic acid have been investigated as
possible routes to 4-substituted derivatives. Variable stereo-
D
2
4
{
D
2
4
20
(
7
20
(
29b
1
1,35,36
selectivity in syntheses using highly modified derivatives
and in aldol condensations at C-4 of simple protected pyro-
3
7,38
glutamates
have so far made such an approach less useful,
although we have achieved stereospecificity at C-4 in a high
yielding aldol-type reaction using activated imines as the elec-
trophiles and have also observed considerable stereoselectivity
at the second asymmetric centre to be generated in this reac-
1
13
†
For the purposes of H and C NMR spectral data the numbering
system shown in compound 8e below is used. The IUPAC nomenclature
system, using a different numbering, is used to construct names
however.
3
520
J. Chem. Soc., Perkin Trans. 1, 1997

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2
9
tion. Direct alkylation of the α-anion of protected pyro-
glutamate derivatives has proved to be unrewarding as a stereo-
specific route to non-proteinogenic amino acids except in the
and hydrogenolysis of the cis-isomer gave a sample of the acid
18, identical spectroscopically with the compound prepared by
oxidation of 17.
38
case of benzylation. Our discovery that the enone 5, which is
readily accessed from the corresponding protected pyro-
glutamic acid, can be catalytically hydrogenated from the less
hindered side to yield the 4-methylpyroglutamate 6 with cis-
To demonstrate that the synthetic cis-4-alkylpyroglutamic
acid derivatives could be converted to the corresponding
(2S,4S)-4-alkylglutamic acids, the ethyl derivative 14 was hydro-
lysed with aqueous LiOH in THF to give the acid 21 as a single
diastereoisomer in 68% yield. This and the corresponding
30
stereospecificity in spite of the reported lack of stereospeci-
10
30
ficity in reduction of 4-methyleneproline derivatives suggested
that catalytic reduction of 4-alkylidenepyroglutamic acid
derivatives would allow a more general synthesis of (2S,4S)-4-
alkylpyroglutamic acids to be developed. Access to the corres-
ponding (2S,4R)-4-alkylpyroglutamates might be gained by
conjugate addition of cuprates to the 4-alkylidenepyroglutamic
acid derivatives since the thermodynamically more stable trans
methyl derivative 11 were then treated with 6  HCl to yield
the hydrochlorides of (2S,4S)-4-methylglutamic acid 22a in
100% yield and (2S,4S)-4-ethylglutamic acid 22b in 85% yield.
The sample of 22a was different from an authentic sample of
the natural product supplied by Kasai et al. who isolated it from
a variety of plant sources and designated it (2S,4R)-4-
24
methylglutamic acid 23. The synthesis thus confirmed this
product at C would be expected. If attack of the cuprate were
assignment.
4
from the less hindered face, then a second new chiral centre
would be generated at C-6.
Et
CO2H
R
H
H
When the 4-ethylidene derivative 8b was hydrogenated using
t
H
Bu OCONH
H2N
CO2H
1
0% Pd–C in ethyl acetate, the product obtained in 99% yield
1
was a single diastereoisomer. Overlap in the H NMR spectra in
various solvents, however, precluded easy assignment of stereo-
chemistry. Although the (2S,4S)-product 14 was expected from
t
Bu O2C
HO2C
21
22a R = Me
2b R = Et
2
H
Et
H
Et H4 H3S
Pr
H
H3S
H3C
H3R
H
H3R
H
H
H2N
HO C
CO2H
H
O
O
O
N
CO2But
N
CO2But
N
CO2But
2
CO2But
CO2But
CO2But
2
3
1
4
15
16
The 4-alkylpyroglutamic acid derivatives were now converted
to the corresponding protected (2S,4S)-4-alkylprolines using
borane–dimethyl sulfide in THF. The methyl derivative 24a had
the reaction, this was proved when the (2S,4R)-isomer 15 was
prepared and its stereochemistry assigned unambiguously as
described below. The corresponding (2S,4S)-4-propylpyro-
glutamic acid derivative 16 was obtained as a single diastereo-
isomer by this route in 98% yield from the 4-propylidene-
pyroglutamate 8b.
5b
already been prepared in this way in 65% yield, and the ethyl
derivative 24b was now prepared in 53% yield, and the 4-propyl
derivative 24c in 66% yield. The amino alcohol 25 was obtained
as a single diastereoisomer as a by-product of reduction of
the 4-ethylpyroglutamate derivative 14. This would be the
(2S,4S,5S)-isomer if, as expected, attack of the borane were
Hydrogenation of the (E)-benzylidene derivative 8c using
0% Pd–C gave a 63% yield of a single diastereoisomer, the
1
1
(
2S,4S)-benzyl derivative 17, which exhibited a clear NOE
from the less hindered side, but the complication of the H
between H-3R and one of the benzyl protons and between H-2
and H-3S. This compound had possibilities for developing
functionality on the side chain, and, when it was oxidised with
ruthenium() chloride and sodium periodate, the acid 18 was
NMR spectrum due to the conformational isomerism did not
1
13
allow this to be verified. H and C NMR spectra of the pro-
tected prolines were complicated by conformational isomerism,
1
although the H NMR spectrum could be simplified by use of
variable temperature techniques. Deprotection of these deriv-
atives in 6  HCl gave the desired (2S,4S)-4-alkylprolines 26a
and 26c as the hydrochlorides in 94 and 89% yields respectively.
H4 H3S
H4 H3S
Ph
HO2C
H3R
H
H3R
H
O
O
N
CO2But
CO2But
N
CO But
CO2But
H
H
2
H
Et
R
R
H
H
H
1
7
18
HO
CO2But
N
t
N
H
N
2
CO Bu
H
CO2H
CO2But
CO2But
PhCH2O2C
H4
2
2
4a R = Me
4b R = Et
25
26a R = Me
26c R = Pr
H
H
O
O
24c R = Pr
N
CO2But
N
CO2But
CO2But
CO2But
cis-4-Methylproline 26a has been isolated from natural
42
sources but the reported [α] (Ϫ43 in 3  HCl) differed from
1
9
20
D
that found for our synthetic product ([α] Ϫ19). The analytical
D
obtained in 54% yield. The stereochemistry of this product was
confirmed as (2S,4S) by the observation of an NOE between H-
and spectroscopic data were, however, in keeping with our
structure, and an NOE between H-2 and H-3S and between the
methyl and H-3R confirmed the cis-stereochemistry.
3
S and H-4 and between H-2 and H-3S. In connection with
studies related to the synthesis of glutamate antagonists, we
have alkylated tert-butyl N-tert-butoxycarbonylpyroglutamate
Having succeeded in using pyroglutamic acid for the syn-
thesis of 4-alkylideneglutamic acids, 4-alkylglutamic acids and
4-alkylproline derivatives as single diastereoisomers, it was of
interest to investigate the synthesis of the isomeric series of
compounds which were epimeric at C-4. The enone 5 was there-
fore reacted with lithium dimethylcuprate in diethyl ether at
1
9 using benzyl bromoacetate and lithium hexamethyldisilazide
39
(
LHMDS) in THF. As was subsequently confirmed on related
40,41
compounds by other workers,
the reaction was non-stereo-
specific and led to a mixture of stereoisomers 20. Separation
J. Chem. Soc., Perkin Trans. 1, 1997
3521

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Ϫ78 ЊC. Although excellent control of stereochemistry had
been reported in 3-alkylation of endocyclic enones such as 27
(62.9 MHz) Fourier transform instruments. Insensitive nuclei
enhanced by polarisation transfer (INEPT) experiments were
36,43,44
13
with alkyl cuprates,
we obtained a mixture of two dia-
used to help assign C NMR resonances where necessary.
stereoisomers in 84% yield from the reaction of the exocyclic
Residual solvent peaks were used as an internal reference in
the NMR spectra. Mass spectra were recorded on Kratos
MS80RF, MS50 and MS25 spectrometers and accurate mass
measurements were recorded on Kratos MS80RF and V67070
spectrometers by Dr S. Chotai (Wellcome Research Laborator-
ies) and a VG/Fisons AutoSpec instrument by Dr A. Abdul-
Sada (Sussex). Microanalyses were performed by Mrs P Firmin
(Wellcome Research Laboratories), and Miss K. Plowman and
Miss M. Patel (Sussex). Thin layer chromatography was per-
formed using Merck Kieselgel 60 F254 pre-coated silica gel
plates of thickness 0.2 mm (ART 5554) and column chrom-
atography was performed using Merck Kieselgel 60 (230–400
mesh—ART 9385).
enone 5. The mixture consisted of 20% of the (2S,4S)-isomer
1
1
4, having an identical H NMR spectrum as the product from
hydrogenation of the enone 8a, and 80% of the (2S,4R)-isomer
5. The epimers were difficult to purify by flash chrom-
atography but a pure sample of the (2S,4R)-isomer 15 was
1
1
2
obtained, and its H NMR spectrum in [ H ]benzene was well
6
resolved. An NOE was observed between the protons H-3R
and H-4 and between the protons H-3S and H-2 of this
compound, confirming its stereochemistry. Thus, while our
synthesis of the cis-isomer 14 was completely stereoselective,
synthesis of the epimeric trans-isomer 15 was stereoselective to
the extent of 4:1 in favour of the (2S,4R)-isomer. Reaction of
the enone 5 with lithium diphenylcuprate gave a mixture of the
trans-isomer 28 and the cis-isomer 17 in a ratio of 6:1.
tert-Butyl (2S)-N-tert-butoxycarbonyl-4-ethylidenepyrogluta-
mate 8a
45
In view of the current interest in cyclopropyl amino acids,
carbene addition to the enones 8 seemed to afford a facile route
to spiro cyclopropyl glutamate derivatives. Reaction of the
enone 5 with diazomethane and palladium acetate gave the
crystalline product 29 in 67% yield. Ring opening to the acid 30
using LiOH–THF occurred in only 18% yield but LiOMe
treatment gave the diester 31 in 72% yield. Treatment of this
latter compound with 6  HCl at reflux then yielded the amino
acid 32 in 84% yield. An attempt was now made to see if add-
ition of carbene to the enone 8c would occur stereospecifically,
creating two new chiral centres. Reaction of this compound
with diazomethane and palladium acetate, however, yielded a
mixture of the four possible isomers in a ratio of 11:8:9:2.
Two of these compounds were isolated as white solids and were
assigned the trans structures 33a and 33b from their spectro-
scopic properties.
tert-Butyl (2S)-N-tert-butoxycarbonyl-4-dimethylaminomethyl-
30
enepyroglutamate 4 (1.00 g, 2.94 mmol) was dissolved in
diethyl ether (60 ml) and cooled to Ϫ78 ЊC under argon. Meth-
ylmagnesium bromide (3.0  in diethyl ether, 2.45 ml, 7.35
mmol) was added dropwise with stirring which was continued
at Ϫ78 ЊC for 1 h. The mixture was allowed to warm to room
temperature and stirring was continued for a further 3 h. The
reaction was quenched with saturated aqueous ammonium
chloride (60 ml) at room temperature, stirred overnight at room
temperature and extracted with diethyl ether (3 × 100 ml). The
combined organic layers were dried (Na SO ) and the solvent
2
4
was removed in vacuo to afford a pale yellow solid which was
purified by column chromatography on silica gel using light
petroleum (40–60 ЊC)–diethyl ether (1:1) as eluent to afford the
major product as a white solid and the minor product as a
colourless oil. The major product tert-butyl (2S)-N-tert-
butoxycarbonyl-4-ethylidenepyroglutamate 8a was recrystallised
from diethyl ether–light petroleum (40–60 ЊC) to give a white
H4 H3S
H3S
Ph
H
H3R
H
H3R
H
23
O
crystalline solid (653 mg, 71%), mp 120 ЊC; [α]D Ϫ16.0 (c 1,
N
O
O
N
CO2But
CO2But
N
t
CHCl ) (Found: C, 61.8; H, 8.1; N, 4.4. C H NO requires C,
3 16 25 5
ϩ
CO Bu
2
H
O
t
61.7; H, 8.0, N, 4.5%); m/z [ϩve FAB (3-NBA)] 312 [M ϩ H] ;
CO Bu
2
Ph
Ϫ1
νmax(KBr)/cm 1774 (‘imide’), 1739 (ester) and 1678 (C᎐C);
2
2
7
28
29
(MeOH)/nm 236 (ε 24 500); δ (360 MHz, C HCl ) 6.76
λmax
H
3
(
1H, m, J6,Me 7.2, J6,3S J6,3R 2.6, H-6), 4.48 (1H, dd, J2,3S 10.3,
J2,3R 3.4, H-2), 2.91 (1H, m, J3S,3R 17.3, J3S,2 10.3, J3S,Me 2, J3S,6
.6, H-3S), 2.53 (1H, m, J3R,3S 17.3, J3R,2 3.4, J3R,6 2.6, J3R,Me 1.8,
t
H
Bu OCONH
CO2H
t
H
Bu OCONH
CO2Me
2
H-3R), 1.79 (3H, m, JMe,6 7.2, JMe,3S JMe,3R 1.8, CH ), 1.50 [9H,
3
CO2But
CO2But
s, OC(CH ) ] and 1.45 [9H, s, OC(CH ) ]; irradiation of the
3
3
3 3
3
0
31
methyl resonance at δ 1.79 resulted in NOEs in the olefinic
2
proton at δ 6.76 and in H-3R at δ 2.53; δ (125.8 MHz, C HCl )
C
3
H
Ph
H3S
Ph
H
H3S
1
70.3 (1-CO ), 166.0 (CON), 149.9 (urethane), 133.8 (C-6),
2
1
29.6 (C-4), 83.0 [OC(CH ) ], 82.1 [OC(CH ) ], 56.3 (C-2), 27.8
3
3
3 3
H
H3R
H
H3R
H
H2N
HO2C
CO2H
[OC(CH ) ], 27.7 [OC(CH ) ], 25.4 (C-3) and 14.8 (CH ). The
3 3 3 3 3
minor product tert-butyl (2S)-2-tert-butoxycarbonylamino-4-
O
O
N
N
21
CO2R
CO2R
ethylidene-5-oxohexanoate 9a was an oil (39 mg, 4%), [α] Ϫ5.2
D
CO2But
CO2But
ϩ
(
c 1, CHCl ); m/z [ϩve FAB (3-NBA)] 328 [M ϩ H] ; νmax(film)/
3
Ϫ1
3
2
33a
33b
cm 3380 (br, NH), 1714 (ester) and 1669 (C᎐C); λmax(MeOH)/
᎐
2
nm 227 (ε 3200); δ (360 MHz, C HCl ) 6.85 (1H, m, J 7.1,
6,Me
H
3
J6,3S J6,3R 2.8, H-6), 5.20 (1H, d, JNH,2 7.9, exchangeable, NH),
.10 (1H, dd, J2,3A 14.4, J2,NH 8.3, H-2), 2.68 (2H, m, 2 × H-3),
2.30 (3H, s, COCH ), 1.94 (3H, d, J 7.1, CH ), 1.44 [9H, s,
Experimental
Melting points were determined on a Kofler hot-stage appar-
atus and are uncorrected. Optical rotations (given in units of
4
3
Me,6
3
2
OC(CH ) ] and 1.39 [9H, s, OC(CH ) ]; δ (125.8 MHz, C HCl )
3
3
3
3
C
3
Ϫ1
2
Ϫ1
1
0
deg cm g ) were measured on a Perkin-Elmer PE241
199.3 (5-CO), 171.3 (1-CO ), 155.4 (urethane), 141.4 (C-6),
2
polarimeter, using a 1 dm path length micro cell. IR Spectra
were recorded on a Perkin-Elmer 1720 Fourier transform
instrument, and UV spectra on a Philips PU8720 UV/VIS
139.1 (C-4), 81.7 [OC(CH ) ], 79.3 [OC(CH ) ], 53.8 (C-2), 28.3
3
3
3 3
[OC(CH ) ], 28.0 [OC(CH ) ], 28.0 (C-3), 18.4 (COCH ) and
3
3
3
3
3
15.0 (CH ).
3
1
scanning spectrophotometer. H NMR spectra were recorded
on Bruker WM 360 (360 MHz) and AMX 500 (500 MHz) Fou-
tert-Butyl (2S)-N-tert-butoxycarbonyl-4-propylidenepyrogluta-
mate 8b
13
rier transform instruments. J Values are given in Hz. C NMR
1
spectra (broad band H decoupled) were recorded on Bruker
tert-Butyl (2S)-N-tert-butoxycarbonyl-4-dimethylaminomethyl-
30
WM 360 (90.6 MHz), AMX 500 (125.8 MHz) and AC-P 250
enepyroglutamate 4 (100 mg, 0.294 mmol) was dissolved in
3
522
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
2
diethyl ether (15 ml) and cooled to Ϫ78 ЊC under argon. Ethyl-
magnesium bromide (3.0  in diethyl ether, 0.37 ml, 1.1 mmol)
was added dropwise with stirring which was continued at
Ϫ78 ЊC for 1 h. The mixture was allowed to warm to room
temperature and was stirred for a further 3 h and quenched with
saturated aqueous ammonium chloride (20 ml) at room tem-
perature. The mixture was stirred overnight at room temper-
ature and extracted with diethyl ether (3 × 25 ml). The organic
layers were dried (Na SO ) and the solvent was removed in
(C᎐C); δ (360 MHz, C HCl ) 7.81–7.46 (10H, m, ArH), 7.41
᎐
H 3
(1H, s, H-6), 5.17 (1H, d, JNH,2 8.5, exch., NH), 4.48 (1H, dd,
J2,3A 14.4, J2,NH 8.5, H-2), 3.16 (2H, m, H-3), 1.47 [9H, s,
OC(CH ) ] and 1.30 [9H, s, OC(CH ) ]; δ (125.8 MHz, C H )
198.3 (5-CO), 171.3 (1-CO ), 155.6 (urethane), 143.8 (C-6),
138.7 (C-4), 138.1–128.8 (C H ), 81.6 [OC(CH ) ], 79.2
2
6
3
3
3
3
C
6
2
6
5
3 3
[OC(CH ) ], 54.7 (C-2), 31.1 (C-3), 28.3 [OC(CH ) ] and 27.8
3
3
3 3
[OC(CH ) ].
3
3
2
4
vacuo to afford a pale yellow solid, which was purified by col-
umn chromatography on silica gel using light petroleum (40–
tert-Butyl (2S)-N-tert-butoxycarbonyl-4-(prop-2-yn-1-ylidene)-
pyroglutamate 8d
6
0 ЊC)–diethyl ether (1:1) as eluent to afford tert-butyl (2S)-N-
tert-Butyl (2S)-N-tert-butoxycarbonyl-4-dimethylaminomethyl-
30
tert-butoxycarbonyl-4-propylidenepyroglutamate 8b, which was
recrystallised from diethyl ether–light petroleum as a white
crystalline solid (53 mg, 56%), mp 69–70 ЊC; [α]D Ϫ8.5 (c 1,
CHCl ) (Found: C, 62.8; H, 8.6; N, 4.1. C H NO requires C,
enepyroglutamate 4 (1.0 g, 2.94 mmol) was dissolved in
diethyl ether (125 ml) and cooled to Ϫ78 ЊC under argon. Ethy-
nylmagnesium bromide (0.5  in diethyl ether, 17.6 ml, 8.8
mmol) was added dropwise with stirring which was continued
at Ϫ78 ЊC for 1 h. The mixture was allowed to warm to room
temperature, stirred for a further 5 h and quenched with satur-
ated aqueous ammonium chloride (125 ml) at room temper-
ature. After stirring overnight at room temperature, the mixture
was extracted with diethyl ether (3 × 100 ml). The organic
layers were dried (Na SO ) and the solvent was removed in
28
3
17 27
5
ϩ
6
2.8; H, 8.3; N, 4.3%); m/z [ϩve FAB (3-NBA)] 326 [M ϩ H] ;
Ϫ1
νmax(KBr)/cm 1776 (‘imide’), 1738 (ester) and 1675 (C᎐C);
λmax(MeOH)/nm 238 (ε 26 400); δ (360 MHz, C HCl ) 6.66
2
H
3
(
1H, m, J6,7 7.5, J6,3S 4.8, J6,3R 2.6, H-6), 4.45 (1H, dd, J2,3S 10.3,
J2,3R 3.4, H-2), 2.89 (1H, m, J3S,3R 17.3, J3S,2 10.3, J3S,6 4.8, J3S,7
1
2
OC(CH ) ], 1.45 [9H, s, OC(CH ) ] and 1.02 (3H, t, J 7.5, CH );
irradiation of the CH CH absorption at δ 2.11 resulted in an
.8, H-3S), 2.51 (1H, m, J3R,3S 17.3, J3R,2 3.4, J3R,6 2.6, H-3R),
2
4
.11 (2H, q, J7A,7B 15.4, J7,8 J7,6 7.5, 7-CH ), 1.50 [9H, s,
vacuo to afford tert-butyl (2S)-N-tert-butoxycarbonyl-4-(prop-2-
yn-1-ylidene)pyroglutamate 8d‡ as a pale brown oil, which was
purified by column chromatography on silica gel using pet-
roleum ether–diethyl ether (1:1) as eluent to give an orange oil
(554 mg, 59%); m/z (EI) found 321.159908. C H NO requires
2
3
3
3
3
3
3
2
NOE in H-3R at δ 2.51 and in H-3S at δ 2.89; δ (125.8 MHz,
C HCl ) 170.3 (1-CO ), 166.2 (CON), 150.0 (urethane), 140.2
C
2
3
2
17 23
5
Ϫ1
(
(
(
C-6), 128.1 (C-4), 83.1 [OC(CH ) ], 82.1 [OC(CH ) ], 56.5
C-2), 27.93 [OC(CH ) ], 27.86 [OC(CH ) ], 25.7 (C-3), 22.7
C-7) and 12.6 (CH ).
321.157623; νmax(film)/cm 1794, 1703 (‘imide’) and 1743
(ester); λmax(MeOH)/nm 263 (ε 11 000); δ (360 MHz, C HCl )
3
3
3 3
2
3
3
3
3
H
3
6.53 (1H, m, J6,3S 3.4, J6,3R J6,8 2.5, H-6), 4.52 (1H, dd, J2,3S 10.0,
J2,3R 3.2, H-2), 3.54 (1H, m, J8,6 2.5, J8,3S 1.2, J8,3R 1.0, H-8), 3.11
(1H, m, J3S,3R 19.1, J3S,2 10.0, J3S,6 3.4, J3S,8 1.2, H-3S), 2.77 (1H,
m, J3R,3S 19.1, J3R,2 3.2, J3R,8 1.0, H-3R), 1.53 [9H, s, OC(CH ) ]
3
tert-Butyl (2S)-N-tert-butoxycarbonyl-4-benzylidenepyrogluta-
mate 8c
tert-Butyl (2S)-N-tert-butoxycarbonyl-4-dimethylaminomethyl-
enepyroglutamate 4 (3.0 g, 8.82 mmol) was dissolved in
diethyl ether (150 ml) and cooled to Ϫ78 ЊC under argon. A
solution of phenylmagnesium bromide (3  in diethyl ether,
3
3
2
and 1.48 [9H, s, OC(CH ) ]; δ (125.8 MHz, C HCl ) 169.7 (1-
3 3 C 3
30
CO ), 164.6 (CON), 149.7 (urethane), 142.3 (C-4), 114.0 (C-6),
2
89.2 (C-8), 83.8 [OC(CH ) ], 82.6 [OC(CH ) ], 79.6 (C-7), 56.4
3
3
3 3
(C-2), 27.92 [OC(CH ) ], 27.88 [OC(CH ) ] and 27.6 (C-3).
3
3
3 3
3
.53 ml, 10.6 mmol) was added dropwise with stirring which
was continued at Ϫ78 ЊC for 1 h. The mixture was allowed to
warm to room temperature, stirring was continued for a further
tert-Butyl (2S)-N-tert-butoxycarbonyl-4-(prop-2-en-1-ylidene)-
pyroglutamate 8e and 8f
3
h and the reaction was quenched with saturated aqueous
tert-Butyl (2S)-N-tert-butoxycarbonyl-4-dimethylaminomethyl-
30
ammonium chloride (150 ml) at room temperature. The mixture
was stirred overnight at room temperature and extracted with
diethyl ether (3 × 100 ml). The organic layers were dried
enepyroglutamate 4 (4.0 g, 12 mmol) was dissolved in
diethyl ether (500 ml) and cooled to Ϫ78 ЊC under argon.
Vinylmagnesium bromide (1.0  in diethyl ether, 35.3 ml, 35
mmol) was added dropwise with stirring which was continued
at Ϫ78 ЊC for 1 h. The mixture was allowed to warm to room
temperature, stirred for a further 3 h, quenched with saturated
aqueous ammonium chloride (200 ml) at room temperature and
stirred overnight at room temperature. It was extracted with
diethyl ether (3 × 100 ml). The organic layers were dried
(Na SO ) and the solvent was removed in vacuo to afford a pale
(
Na SO ) and the solvent was removed in vacuo to afford a pale
2 4
yellow solid, which was purified by column chromatography on
silica gel using chloroform–ethyl acetate (97:3) as eluent to
afford the major product as a white solid and the minor product
as a colourless oil. The major product was recrystallised from
diethyl ether–chloroform to yield tert-butyl (2S)-N-tert-
butoxycarbonyl-4-benzylidenepyroglutamate 8c as a white crys-
2
4
25
talline solid (2.57 g, 78%), mp 158–159 ЊC; [α]D ϩ3.2 (c 0.5,
CHCl ); m/z (EI) found 373.18769; C H NO requires
yellow foam, which was purified by column chromatography on
silica gel using light petroleum (40–60 ЊC)–diethyl ether (1:1) as
eluent to afford two white solids. The major product was
recrystallised from diethyl ether–light petroleum (40–60 ЊC)
to yield tert-butyl (2S)-N-tert-butoxycarbonyl-4-(prop-2-en-1-
ylidene)pyroglutamate (E-isomer) 8e as a white crystalline
3
21 27
5
ϩ
3
73.188923; m/z [ϩve FAB (3-NBA)] 374 [M ϩ H] ; νmax(KBr)/
Ϫ1
cm 1775 (‘imide’), 1737 (ester) and 1654 (C᎐C); λmax(MeOH)/
2
nm 290 (ε 30 000); δ (360 MHz, C HCl ) 7.55 (1H, t, J J6,3R
H
3
6,3S
2
.8, H-6), 7.38 (5H, m, ArH), 4.59 (1H, dd, J2,3S 10.1, J2,3R 3.1,
H-2), 3.35 (1H, m, J3S,3R 17.9, J3S,2 10.1, J3S,6 2.8, H-3S), 2.92
1H, m, J3R,3S 17.9, J3R,2 3.1, J3R,6 2.8, H-3R), 1.55 [9H, s,
OC(CH ) ] and 1.46 [9H, s, OC(CH ) ]; irradiation of the
19
solid (1.79 g, 47%), mp 66–69 ЊC; [α]D ϩ1.4 (c 1, CHCl3)
(
(Found: C, 62.9; H, 7.7; N, 4.1. C H NO requires C, 63.1;
17
25
5
H, 7.7; N, 4.3%); m/z [ϩve FAB (3-NBA–CHCl )] 268
3
3
3
3
3
ϩ
Ϫ1
olefinic proton at δ 7.55 showed enhancement only to the aro-
matic protons but irradiation at H-3S at δ 3.35 gave an NOE in
H-3R at δ 2.92, in H-2 at δ 4.59 and in the phenyl protons at
[M Ϫ C H ϩ 2H] ; νmax(KBr)/cm 1786, 1719 (‘imide’) and
4 9
1752 (ester); λ (MeOH)/nm 271 (ε 26 000); δ (360 MHz,
max
H
2
C HCl ) 7.07 (1H, m, J 11.5, J6,3S J6,3R 2.7, H-6), 6.42 (1H, m,
3
6,7
2
δ 7.38; δ (125.8 MHz, C HCl ) 165.7 (1-CO ), 162.6 (CON),
J7,8A 16.8, J7,6 11.4, J7,8B 10.1, H-7), 5.65 (1H, d, J8A,7 16.8, H-
8A), 5.56 (1H, d, J8B,7 10.1, H-8B), 4.51 (1H, dd, J2,3S 10.1, J2,3R
3.4, H-2), 3.04 (1H, m, J3S,3R 17.9, J3S,2 10.1, J3S,6 2.7, H-3S),
C
3
2
1
45.4 (urethane), 130.5 (C-6), 130.2 (C-4), 125.6–122.8 (C H ),
6 5
7
8.9 [OC(CH ) ], 77.9 [OC(CH ) ], 52.2 (C-2), 23.5 (C-3), 23.4
3
3
3 3
[
OC(CH ) ] and 23.3 [OC(CH ) ]. The minor product tert-
3 3 3 3
butyl (2S)-2-tert-butoxycarbonylamino-4-benzylidene-4-benzoyl-
butanoate 9c (48 mg, 1.2%); m/z [ϩve FAB (3-NBA)] 452
‡
This compound is unstable on standing for prolonged periods at room
temperature. We thank Dr D. H.-S. Poon for preparing a further sample
of the compound for mass spectral analysis.
ϩ
Ϫ1
[
M ϩ H] ; νmax(film)/cm 3372 (br, NH), 1713 (ester) and 1649
J. Chem. Soc., Perkin Trans. 1, 1997
3523

View Article Online
2
.67 (1H, m, J3R,3S 17.9, J3R,2 J3R,6 2.9, H-3R), 1.52 [9H, s,
[OC(CH ) ], 53.3 (C-2), 52.0 (OCH ), 35.2 (C-3), 28.2
3 3 3
OC(CH ) ] and 1.46 [9H, s, OC(CH ) ]; irradiation of H-7 at δ
[OC(CH ) ] and 27.9 [OC(CH ) ].
3
3
3
3
3
3
3 3
6
3
.42 resulted in NOEs in H-6 at δ 7.07, in H-8B at δ 5.56, in H-
2
S at δ 3.04 and in H-3R at δ 2.67; δ (125.8 MHz, C HCl ) 169.9
1-tert-Butyl 5-methyl (2S)-N-tert-butoxycarbonyl-4-ethylidene-
glutamate 12a
C
3
(
1-CO ), 166.3 (CON), 149.5 (urethane), 133.9 (C-6), 131.4 (C-
2
7
5
), 128.7 (C-4), 126.0 (C-8), 83.0 [OC(CH ) ], 82.0 [OC(CH ) ],
tert-Butyl (2S)-N-tert-butoxycarbonyl-4-ethylidenepyrogluta-
mate 8a (75 mg, 0.241 mmol) was dissolved in tetrahydrofuran
(1.2 ml) and cooled to Ϫ40 ЊC under argon. A 1.0  solution of
lithium methoxide in methanol (0.289 ml, 0.289 mmol) was
added dropwise with stirring, and stirring was continued at
Ϫ40 ЊC for 50 min. The mixture was quenched with saturated
aqueous sodium chloride (10 ml) and ethyl acetate (10 ml) and
allowed to warm to room temperature. The aqueous layer was
separated and extracted with ethyl acetate (10 ml). The organic
layers were dried (Na SO ) and the solvent was removed in
3
3
3 3
6.3 (C-2), 27.64 [OC(CH ) ], 27.60 [OC(CH ) ] and 25.7 (C-3);
3
3
3 3
the minor product was tert-butyl (2S)-N-tert-butoxycarbonyl-4-
prop-2-en-1-ylidene)pyroglutamate (Z-isomer) 8f (58 mg, 1.5%),
mp79–82 ЊC;m/z[ϩveFAB(3-NBA–CHCl )]168[M Ϫ C H Ϫ
(
3
4
9
ϩ
ϩ
CO C H ϩ 3H] and 122 [M Ϫ (CO C H ) ϩ H] ; νmax(KBr)/
cm 1752, 1708 (‘imide’) and 1736 (ester); δ (360 MHz,
C HCl ) 7.82 (1H, m, J 17, J7,6 11.2, J7,8A 10, H-7), 6.42 (1H,
m, J6,7 11.2, J6,3S 2.5, J6,3R 1.9, H-6), 5.41 (1H, d, J8A,7 10, H-8A),
5
2
m, J3R,3S 17.3, H-3R), 1.51 [9H, s, OC(CH ) ] and 1.44 [9H, s,
OC(CH ) ]; irradiation at H-6 at δ 6.42 resulted in NOEs in H-7
at δ 7.82, in H-8B at δ 5.40 and in H-3R at δ 2.59; δ (125.8
MHz, C HCl ) 170.1 (1-CO ), 165.5 (CON), 150 (urethane),
2
Ϫ1
4
9
2
4
9 2
H
2
3
7,8B
.40 (1H, d, J8B,7 17, H-8B), 4.44 (1H, dd, J2,3S 10.1, J2,3R 3.2, H-
), 3.04 (1H, m, J3S,3R 17.3, J3S,2 10.1, J3S,6 2.5, H-3S), 2.59 (1H,
2
4
vacuo to afford a pale yellow oil, which was purified by column
chromatography on silica gel using light petroleum (60–80 ЊC)–
diethyl ether (2:1) as eluent to afford the major product as a
colourless oil and the minor product as a white crystalline solid.
The major product was 1-tert-butyl 5-methyl (2S)-N-tert-
3
3
3
3
C
2
3
2
2
3
1
38.7 (C-6), 131.6 (C-7), 126.5 (C-4), 124.7 (C-8), 83.3
butoxycarbonyl-4-ethylideneglutamate 12a (49 mg, 60%), [α]
D
[
OC(CH ) ], 82.2 [OC(CH ) ], 56.5 (C-2), 29.2 (C-3), 27.93
Ϫ0.75 (c 1.4, CHCl ) (Found: C, 59.9; H, 8.6; N, 4.3. C H NO
3 17 29 6
3
3
3
3
[
OC(CH ) ] and 27.86 [OC(CH ) ].
requires C, 59.5; H, 8.5; N, 4.1%); m/z [ϩve FAB (3-NBA)] 344
3
3
3 3
ϩ Ϫ1
[
M ϩ H] ; νmax(film)/cm 3377 (br, NH), 1718 (br, ester) and
2
tert-Butyl (2S)-2-tert-butoxycarbonylamino-4-ethylidene-5-
oxohexanoate 9a
tert-Butyl (2S)-N-tert-butoxycarbonyl-4-ethylidenepyrogluta-
mate 8a (100 mg, 0.322 mmol) was dissolved in diethyl ether
(
(
1650 (C᎐C); δ (360 MHz, C HCl ) 6.98 (1H, q, J
7.2, H-6),
6,Me
᎐
H
3
5.18 (1H, d, JNH,2 8.1, exchangeable, NH), 4.25 (1H, m, H-2),
3.73 (3H, s, OCH ), 2.71 (2H, m, J 14.0, J3A,2 5.7, 2 × H-3),
3
3A,3B
1.84 (3H, d, JMe,6 7.2, CH ), 1.43 [9H, s, OC(CH ) ] and 1.40
3
3 3
2
15 ml) and stirred under argon. Methylmagnesium bromide
3.0  in diethyl ether, 0.54 ml, 1.61 mmol) was added dropwise
[9H, s, O(CH ) ]; δ (125.8 MHz, C HCl ) 171.4 (CO ), 168.0
3 3 C 3 2
(CO ), 155.3 (urethane), 140.9 (C-6), 128.6 (C-4), 81.8
2
with stirring which was continued at room temperature over-
night. The mixture was quenched with saturated aqueous
ammonium chloride (15 ml) at room temperature, stirred at
room temperature for 6 h and extracted with diethyl ether
[OC(CH ) ], 79.5 [OC(CH ) ], 53.6 (C-2), 51.9 (OCH ), 29.4
3
3
3
3
3
(C-3), 28.2 [OC(CH ) ], 27.9 [OC(CH ) ] and 14.6 (7-CH ). The
3
3
3
3
3
minor product was tert-butyl (2S)-4-ethylidenepyroglutamate
2
2
13a (7 mg, 13%), mp 111–113 ЊC; [α] ϩ41.1 (c 1, CHCl ); m/z
D
3
ϩ
(
3 × 25 ml). The organic layers were dried (Na SO ) and the
[ϩve FAB (3-NBA)] 212 [M ϩ H] ; m/z (EI) found 211.12120.
C H NO requires 211.1208; νmax(KBr)/cm 3303 (br, NH),
2
4
Ϫ1
solvent was removed in vacuo to afford a pale yellow oil (78 mg,
1%), which was purified by column chromatography on silica
11
17
3
2
8
1741 (ester) and 1654 (C᎐C); δ (360 MHz, C HCl ) 6.54 (1H,
H
3
gel using light petroleum (40–60 ЊC)–diethyl ether (1:1) as elu-
ent to afford tert-butyl (2S)-2-tert-butoxycarbonylamino-4-
ethylidene-5-oxohexanoate 9a as a colourless oil (37 mg, 35%)
m, J6,Me 7.1, J6,3S J6,3R 2.6, H-6), 6.39 (1H, s, exchangeable, NH),
4.16 (1H, dd, J2,3S 9.5, J2,3R 4.6, H-2), 3.02 (1H, m, J3S,3R 17.3,
J3S,2 9.5, J3S,6 2.6, J3S,Me 1.9, H-3S), 2.80 (1H, m, J3R,3S 17.3, J3R,2
4.6, J3R,6 2.6, J3R,Me 1.9, H-3R), 1.78 (3H, m, JMe,6 7.1, JMe,3S
1
with a H NMR spectrum identical to that of the methyl ketone
9
a synthesised as a by-product of the reaction between methyl-
J
1.9, CH ) and 1.47 [9H, s, OC(CH ) ]; δ (125.8 MHz,
Me,3R 3 3 3 C
2
magnesium bromide and the enaminone 4 above.
C HCl ) 170.6 (1-CO ), 130.2 (C-4), 128.2 (C-6), 81.6
3
2
[
OC(CH ) ], 53.1 (C-2), 27.4 [OC(CH ) ], 27.3 (C-3) and 14.3
3
3
3
3
1
-tert-Butyl 5-methyl (2S)-N-tert-butoxycarbonyl-4-methylene-
(CH ).
3
glutamate 12h
tert-Butyl (2S)-N-tert-butoxycarbonyl-4-methylenepyrogluta-
1-tert-Butyl 5-methyl (2S)-N-tert-butoxycarbonyl-4-propylidene-
glutamate 12b
30
mate 5 (100 mg, 0.34 mmol) was dissolved in tetrahydrofuran
(
1.7 ml) and cooled to Ϫ40 ЊC under argon. A 1.0  solution of
tert-Butyl (2S)-N-tert-butoxycarbonyl-4-propylidenepyrogluta-
mate 8b (582 mg, 1.79 mmol) was dissolved in tetrahydrofuran
(9.0 ml) and cooled to Ϫ40 ЊC under argon. A 1.0  solution of
lithium methoxide in methanol (2.15 ml, 2.15 mmol) was added
dropwise with stirring which was continued at Ϫ40 ЊC for 1 h.
The reaction mixture was quenched with saturated aqueous
sodium chloride (10 ml) and ethyl acetate (10 ml) and allowed
to warm to room temperature. The aqueous layer was extracted
with ethyl acetate (2 × 10 ml). The organic layers were dried
(Na SO ) and the solvent was removed in vacuo to afford a pale
lithium methoxide in methanol (0.404 ml, 0.404 mmol) was
added dropwise with stirring, which was continued at Ϫ40 ЊC
for 30 min. The reaction mixture was quenched with saturated
aqueous sodium chloride (10 ml) and ethyl acetate (10 ml) and
allowed to warm to room temperature. The aqueous layer was
extracted with ethyl acetate (10 ml) and the combined organic
layers were dried (Na SO ). The solvent was removed in vacuo
to afford a pale yellow oil, which was purified by column chro-
matography on silica gel using petroleum (60–80 ЊC)–diethyl
ether (2:1) as eluent to afford 1-tert-butyl 5-methyl (2S)-N-tert-
butoxycarbonyl-4-methyleneglutamate 12h as a white crystalline
solid (66 mg, 60%), mp 81–84 ЊC; [α]D ϩ1.9 (c 1, CHCl ) (Found:
C, 58.2; H, 8.3; N, 4.2%. C H NO requires C, 58.3; H, 8.2; N,
4
3
C HCl ) 6.21 (1H, s, H-6A), 5.62 (1H, s, H-6B), 5.12 (1H, d,
JNH,2 8.0, exchangeable, NH), 4.33 (1H, m, H-2), 3.74 (3H, s,
OCH ), 2.75 (1H, dd, J
J3B,3A 14.0, J3B,2 8.2, H-3B), 1.41 [9H, s, OC(CH ) ], 1.38 [9H, s,
2
4
2
4
yellow oil, which was purified by column chromatography on
silica gel using light petroleum (40–60 ЊC)–diethyl ether (2:1) as
eluent to afford the major product as a colourless oil and the
minor product as a white crystalline solid. The major product
was 1-tert-butyl 5-methyl (2S)-N-tert-butoxycarbonyl-4-propyl-
23
3
1
6
27
6
ϩ
Ϫ1
.3%); m/z [ϩve FAB (3-NBA)] 330 [M ϩ H] ; νmax(KBr)/cm
346 (br, NH), 1709 (ester) and 1631 (C᎐C); δ (360 MHz,
25
ideneglutamate 12b (324 mg, 51%), [α]D Ϫ0.20 (c 2.0, CHCl3)
᎐
H
2
(Found: C, 60.1; H, 8.6; N, 4.0. C H NO requires C, 60.5;
3
18 31
6
ϩ
H, 8.7; N, 3.9%); m/z [ϩve FAB (3-NBA)] 358 [M ϩ H] ;
νmax(film)/cm 3377 (br, NH), 1718 (ester) and 1648 (C᎐C);
Ϫ1
14.0, J3A,2 5.7, H-3A), 2.60 (1H, dd,
3
3A,3B
2
δ (500 MHz, C HCl ) 6.79 (1H, t, J 7.5, H-6), 5.14 (1H, d,
3
3
H
3
6,7
2
OC(CH ) ]; δ (125.8 MHz, C HCl ) 171.0 (CO ), 167.1 (CO ),
1
JNH,2 8.3, exchangeable, NH), 4.18 (1H, m, J2,NH J2,3B 8.6, J2,3A
6.0, H-2), 3.66 (3H, s, OCH ), 2.66 (1H, m, J 13.8, J3A,2 6.0,
3
3
C
3
2
2
55.1 (urethane), 136.0 (C-6), 128.1 (C-4), 82.1 [O(CH ) ], 79.6
3 3
3
3A,3B
3
524
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
H-3A), 2.59 (1H, m, J3B,3A 13.8, J3B,2 8.7, H-3B), 2.17 (2H, quin-
tet, J7,6 J7,8 7.5, CH ), 1.36 [9H, s, OC(CH ) ], 1.33 [9H, s,
with 6  aqueous hydrochloric acid (5.0 ml) for 6 h. The sol-
vent was removed in vacuo to afford (2S)-4-propylideneglutamic
acid hydrochloride 3 as an off-white solid. Traces of residual
hydrochloric acid were removed by azeotropic distillation with
2
3 3
OC(CH ) ] and 0.98 (3H, t, J 7.5, CH ); δ (125.8 MHz,
3
3
8,7
3
C
2
C HCl ) 171.0 (CO ), 167.7 (CO ), 155.0 (urethane), 147.1 (C-
3
2
2
6
5
2
4
), 126.8 (C-4), 81.4 [OC(CH ) ], 79.0 [OC(CH ) ], 53.5 (C-2),
diethyl ether (118 mg, 85%); m/z [ϩve FAB (glycerol–CHCl )]
3
3
3
3
3
ϩ
1.5 (OCH ), 29.5 (C-3), 28.0 [OC(CH ) ], 27.7 [OC(CH ) ],
188 [free amino acid ϩ H] ; m/z (EI) found 187.08349.
3
3
3
3 3
Ϫ1
1.9 (C-7) and 12.9 (8-CH ). The minor product was tert-butyl
C H NO requires 187.0844; νmax(KBr)/cm 2900–3400 (br,
3
8
13
4
2
4
-propylidenepyroglutamate 13b (55 mg, 14%), mp 65–67 ЊC; [α]
NH and OH), 1736 (acid) and 1639 (C᎐C); δ (360 MHz,
᎐
H
2 2
D
ϩ
ϩ45 (c 1, CHCl ); m/z [ϩve FAB (3-NBA)] 226 [M ϩ H] ;
νmax(KBr)/cm 3386 (br, NH), 1750 (ester), 1700 and 1678
C H O H) 7.04 (1H, t, J 7.6, H-6), 4.08 (1H, t, J2,3B J2,3A ca. 7,
3 6,7
3
Ϫ1
H-2), 2.95 (1H, dd, J3A,3B 14.3, J3A,2 6.7, H-3A), 2.81 (1H, dd,
J3B,3A 14.3, J3B,2 7.5, H-3B), 2.27 (2H, quintet, J7,6 7.6, H-7)
2
(
C᎐C); δ (360 MHz, C HCl ) 7.27 (1H, s, exch., NH), 6.41 (1H,
J
7,8
2
᎐
H
3
2
m, J6,7 7.4, J6,3S J6,3R ca. 2, H-6), 4.13 (1H, dd, J2,3S 9.3, J2,3R 4.5,
H-2), 2.96 (1H, m, J3S,3R 17.3, J3S,2 9.3, J3S,6 ca. 2, H-3S), 2.73
and 1.08 (3H, t, J8,7 7.5, CH ); δ (500 MHz, 20% HCl– H O)
3
H
2
4.28 (1H, t, J2,3B J2,3A 7.2, H-2), 3.01 (2H, m, J3A,3B 14.3, J3,2 7.3,
2 × H-3), 2.29 (2H, m, J7,6 J7,8 7.6, 2 × H-7) and 1.06 (3H, t, J8,7
(
1H, m, J3R,3S 17.3, J3R,6 ca. 2, H-3R), 2.09 (2H, m, J7,8 J7,6 7.5,
CH ), 1.42 [9H, s, OC(CH ) ] and 1.01 (3H, t, J 7.5, CH );
7.4, CH ); the C-6 proton was masked by water at δ 7.18;
δ (125.8 MHz, C H O H) 171.6 (CO ), 171.1 (CO ), 151.2
C 3 2 2
2
3
3
8,7
3
3
2
2
2
δ (125.8 MHz, C HCl ) 170.9 (1-CO ), 170.8 (CON), 135.7 (C-
C
3
2
6
2
), 128.5 (C-4), 82.2 [OC(CH ) ], 53.3 (C-2), 27.8 [OC(CH ) ],
(C-6), 127.2 (C-4), 54.0 (C-2), 29.4 (C-3), 23.6 (C-7) and 13.8
3
3
3 3
7.7 (C-3), 22.5 (C-7) and 12.7 (CH ).
(CH ). The spectra were identical with those of a sample iso-
3
3
20
lated from M. pura by Hatanaka and Katayama.
(
1
2S)-4-Methyleneglutamic acid hydrochloride 1
-tert-Butyl 5-methyl (2S)-N-tert-butoxycarbonyl-4-methylene-
tert-Butyl (2S,4S)-N-tert-butoxycarbonyl-4-ethylpyroglutamate
14
glutamate 12h (238 mg, 0.723 mmol) was heated to reflux for
2
h with 6  aqueous hydrochloric acid (10 ml). The solvent was
tert-Butyl (2S)-N-tert-butoxycarbonyl-4-ethylidenepyrogluta-
mate 8a (300 mg, 0.965 mmol) was dissolved in ethyl acetate
(10 ml) and 10% palladium on carbon (30 mg, 10% w/w) was
added. The mixture was stirred under an atmosphere of hydro-
gen for four days at room temperature, filtered and the solvent
was removed in vacuo to afford a colourless oil which was puri-
fied by column chromatography on silica gel using light pet-
roleum (40–60 ЊC)–diethyl ether (1:1) as eluent to afford tert-
butyl (2S,4S)-N-tert-butoxycarbonyl-4-ethylpyroglutamate 14 as
removed in vacuo to afford an off-white solid. Traces of residual
hydrochloric acid were removed by azeotropic distillation with
diethyl ether. The solid was recrystallised from ethanol–diethyl
ether to yield (2S)-4-methyleneglutamic acid hydrochloride 1 as a
white crystalline solid (106 mg, 81%), mp 162–164 ЊC; [α]D
ϩ13.2 (c 1, 3  HCl) (Found: C, 36.7; H, 5.1; N, 6.7. C H -
23
6
10
NO Cl requires C, 36.8; H, 5.2; N, 7.2%); m/z [ϩve FAB
4
ϩ
Ϫ1
(
glycerol–ethanol)] 160 [free amino acid ϩ H] ; νmax(KBr)/cm
21
3
000–3500 (br, NH and OH), 1736, 1685 and 1638 (C᎐C);
a white crystalline solid (299 mg, 99%), mp 49–51 ЊC; [α] Ϫ32
᎐
D
2
2
δ (500 MHz, 20% HCl– H O) 6.49 (1H, s, H-6A), 6.08 (1H, s,
(c 0.2, CHCl ) (Found: C, 61.1; H, 8.4; N, 4.1. C H NO
H
2
3
16 27
5
H-6B), 4.42 (1H, dd, J2,3B 7.8, J2,3A 5.5, H-2), 3.11 (1H, dd,
J3A,3B 14.7, J3A,2 5.5, H-3A) and 2.97 (1H, dd, J 14.7, J3B,2 7.8,
requires C, 61.3; H, 8.6; N, 4.5%); m/z [ϩve FAB (3-NBA–
ϩ
Ϫ1
CHCl )] 314 [M ϩ H] ; νmax(KBr)/cm
1791 and 1727
3B,3A
3
2
2
2
H-3B); δ (125.8 MHz, 20% HCl– H O) 171.0 (CO ), 169.9
(‘imide’); δ (360 MHz, C H ) 4.19 (1H, dd, J 8.6, J2,3R 6.7,
C
2
2
H
6
6
2,3S
(
CO ), 134.1 (6-CH ), 133.3 (C-4), 52.8 (C-2) and 32.8 (C-3).
H-2), 1.90–1.67 (3H, m, H-4 and H-3), 1.43 [9H, s, OC(CH ) ],
2
1
2
3 3
The H NMR spectrum was identical to that of a sample pro-
vided by Kasai et al. and isolated from L. maximowiczii.
1.34 [9H, s, OC(CH ) ], 1.33 (2H, m, H-6) and 0.93 (3H, t, J
3 3 7,6
2
24
7.4, CH ); δ (360 MHz, C HCl ) 4.37 (1H, m, J 8.8, J2,3R 6.2,
3 H 3 2,3S
H-2), 2.44 (2H, m, 2 × H-3), 1.89 (1H, m, H-4), 1.54 (2H, m,
(
1
2S)-4-Ethylideneglutamic acid hydrochloride 2
-tert-Butyl 5-methyl (2S)-N-tert-butoxycarbonyl-4-ethylidene-
6-CH ), 1.50 [9H, s, OC(CH ) ], 1.47 [9H, s, CO C(CH ) ] and
2
3
3
2
3 3
2
0.96 (3H, t, J7,6 7.5, CH ); δ (125.8 MHz, C HCl ) 175.5
3
C
3
glutamate 12a (1.00 g, 2.92 mmol) was treated with 6  aqueous
hydrochloric acid (20 ml) and heated to reflux for 5 h. The
solvent was removed in vacuo to afford an off-white solid.
Traces of residual hydrochloric acid were removed by azeo-
tropic distillation with diethyl ether to afford (2S)-4-ethyl-
ideneglutamic acid hydrochloride 2 as a white solid (470 mg,
(CON), 170.6 (1-CO ), 149.6 (urethane), 83.2 [OC(CH ) ], 82.0
2 3 3
[OC(CH ) ], 58.0 (C-2), 44.0 (C-4), 27.8 [OC(CH ) ], 27.8
3
3
3 3
[OC(CH ) ], 26.9 (C-3), 24.2 (C-6) and 11.4 (CH ).
3
3
3
tert-Butyl (2S,4S)-N-tert-butoxycarbonyl-4-propylpyrogluta-
mate 16
18
7
4
6
7%), mp 181–184 ЊC; [α]D ϩ27 (c 0.67, 3  HCl) (Found: C,
tert-Butyl (2S)-N-tert-butoxycarbonyl-4-propylidenepyrogluta-
mate 8b (1.0 g, 3.1 mmol) was dissolved in ethyl acetate (20 ml)
and 10% palladium on carbon (100 mg, 10% w/w) was added.
The reaction was stirred under an atmosphere of hydrogen for
three days at room temperature, filtered and the solvent was
removed in vacuo to afford a white solid which was recrystal-
lised from light petroleum (40–60 ЊC)–diethyl ether to afford
tert-butyl (2S,4S)-N-tert-butoxycarbonyl-4-propylpyroglutamate
0.1; H, 5.7; N, 6.3. C H NO Cl requires C, 40.1; H, 5.7; N,
7
12
4
.7%); m/z [ϩve FAB (glycerol–CHCl )] 174 [free amino
3
ϩ
Ϫ1
acid ϩ H] ; νmax(KBr)/cm 2700–3300 (br, NH and OH), 1723
and 1672 (C᎐C); δ (360 MHz, C H O H) 7.17 (1H, q, J 7.3,
2
2
᎐
H
3
6,7
H-6), 4.08 (1H, dd, J2,3B 7.6, J2,3A 6.5, H-2), 2.98 (1H, dd, J3A,3B
4.3, J3A,2 6.5, H-3A), 2.83 (1H, dd, J3B,3A 14.3, J3B,2 7.6, H-3B)
1
and 1.88 (3H, d, J7,6 7.2, CH ); irradiation of the absorption
3
2
1
due to the methyl group at δ 1.88 resulted in NOEs in the olefin-
16 as a white crystalline solid (989 mg, 98%), mp 59–61 ЊC; [α]
D
ic absorption at δ 7.17, in H3A at δ 2.98, in H at δ 2.83 and in
Ϫ35 (c 0.3, CHCl ) (Found: C, 62.1; H, 8.9; N, 4.15. C H NO
3 17 29 5
3B
2
2
H at δ 4.08; δ (500 MHz, 20% HCl– H O) 7.26 (1H, q, J 7.3,
requires C, 62.4; H, 8.9; N, 4.3%); m/z [ϩve FAB (3-NBA–
2
H
2
6,7
ϩ Ϫ1
H-6), 4.29 (1H, t, J2,3B J2,3A ca. 7.0, H-2), 3.06 (1H, dd, J3A,3B
4.8, J3A,2 6.5, H-3A), 3.01 (1H, dd, J3B,3A 14.8, J 7.5, H-3B)
CHCl )] 328 [M ϩ H] ; ν (KBr)/cm 1795, 1709 (‘imide’)
3 max
2
1
and 1736 (ester); δ (500 MHz, C H ) 4.20 (1H, dd, J
8.8,
2,3S
3B,2
H
6
6
2
2
and 1.93 (3H, d, J7,6 7.3, CH ); δ (125.8 MHz, C H O H) 171.7
J2,3R 6.7, H-2), 1.91 (1H, m, J3R,3S 13.0, H-3R), 1.77 (1H, m,
J3S,3R 13, J3S,4 9.2, J3S,2 8.8, H-3S), 1.71 (1H, m, H-6A), 1.45 [9H,
s, OC(CH ) ], 1.36 [9H, s, OC(CH ) ], 1.34 (1H, m, H-4), 1.17
3
C
3
(
CO ), 171.0 (CO ), 144.7 (C-6), 128.8 (C-4), 53.9 (C-2), 29.1
2
2
(
C-3) and 15.3 (CH ). The spectra were identical with those of a
3
3
3
3 3
sample isolated from T. gesueriana and supplied by Kasai et
al.
(1H, m, H-6B), 1.10 (2H, m, H-7) and 0.68 (3H, t, J8 7.3, CH );
,7 3
2
24
δ (360 MHz, C HCl ) 4.27 (1H, m, H-2), 2.38 (2H, m, H-3),
H 3
1
.71 (1H, m, H-4), 1.47 (2H, m, H-6), 1.38 [9H, s, OC(CH ) ],
3 3
(
1
2S)-4-Propylideneglutamic acid hydrochloride 3
-tert-Butyl 5-methyl (2S)-N-tert-butoxycarbonyl-4-propylid-
eneglutamate 12b (223 mg, 0.625 mmol) was heated to reflux
1.36 [9H, s, OC(CH ) ], 1.27 (2H, m, H-7) and 0.79 (3H, t, J
3 3 8,7
2
7.4, CH ); δ (125.8 MHz, C H ) 173.4 (CON), 170.9 (1-CO ),
3 C 6 6 2
151.0 (urethane), 82.5 [OC(CH ) ], 81.2 [OC(CH ) ], 58.1 (C-2),
3
3
3 3
J. Chem. Soc., Perkin Trans. 1, 1997
3525

View Article Online
4
2.5 (C-4), 33.4 (C-6), 28.0 [OC(CH ) ], 27.8 [OC(CH ) ], 27.6
(3.0 ml) and 1  aqueous lithium hydroxide (1.04 ml) was added
3
3
3 3
(
C-3), 20.4 (C-7) and 13.8 (CH ).
dropwise at 0 ЊC with vigorous stirring over a period of 10 min.
Stirring was continued for a further 15 min at 0 ЊC. Ethyl acet-
ate (10 ml) and aqueous saturated sodium hydrogen carbonate
3
tert-Butyl (2S,4S)-N-tert-butoxycarbonyl-4-benzylpyrogluta-
mate 17
tert-Butyl (2S)-N-tert-butoxycarbonyl-4-benzylidenepyrogluta-
mate 8c (200 mg, 0.536 mmol) was dissolved in ethyl acetate
(
10 ml) were added and the organic layer was extracted with
aqueous saturated sodium hydrogen carbonate (10 ml). The
aqueous layers were carefully acidified to pH 5 at 0 ЊC with
stirring by the dropwise addition of 10% aqueous citric acid.
The aqueous layer was extracted with ethyl acetate (3 × 20 ml)
and the organic layers were dried (Na SO ) and the solvent was
(
70 ml) and 10% palladium on carbon (20 mg, 10% w/w) was
added. The reaction was stirred under an atmosphere of hydro-
gen for three days at room temperature, filtered and the solvent
was removed in vacuo to afford a white solid (188 mg, 93%)
which was purified by column chromatography on silica gel
using light petroleum (40–60 ЊC)–diethyl ether (1:1) to afford
tert-butyl (2S,4S)-N-tert-butoxycarbonyl-4-benzylpyroglutamate
2
4
removed in vacuo to afford 1-tert-butyl hydrogen (2S,4S)-N-
tert-butoxycarbonyl-4-ethylglutamate 21 as a white solid, which
was recrystallised from light petroleum (60–80 ЊC)–diethyl ether
22
(
196 mg, 68%), mp 90–92 ЊC; [α]D ϩ0.9 (c 0.23, CHCl ) (Found:
3
1
7 as a white crystalline solid (127 mg, 63%), mp 130–131 ЊC;
C, 57.5; H, 8.7; N, 4.2. C H NO requires C, 58.0; H, 8.8; N,
1
6
29
6
22
D
[
α] ϩ66 (c 0.2, CHCl ) (Found: C, 66.7; H, 8.0; N, 3.5.
ϩ
Ϫ1
3
4
3
4
1
.2%); m/z [ϩve FAB (3-NBA)] 332 [M ϩ H] ; ν (KBr)/cm
max
2 2
C H NO requires C, 67.2; H, 7.7; N, 3.7%); m/z [ϩve FAB
(
(
2
1
29
5
350 (br, NH), 1734 (ester), 1707 (acid); δ (500 MHz, C H O H)
H
3
ϩ
Ϫ1
3-NBA–CHCl )] 376 [M ϩ H] ; ν (KBr)/cm 1756, 1715
3
max
2
.00 (1H, dd, J2,3A 8.9, J2,3B 6.4, H-2), 2.36 (1H, m, J4,6 7.4, H-4),
.91 (1H, m, J3A,3B 16.4, J3A,2 8.9, J3S,4 7.4, H-3A), 1.85 (1H, dd,
imide), 1736 (ester); δ (360 MHz, C HCl ) 7.14–7.23 (5H, m,
H
3
ArH), 4.37 (1H, dd, J2,3S 9.2, J2,3R 5.8, H-2), 3.30 (1H, dd, J6A,6B
3.8, J6A,4 4.0, H-6A), 2.83 (1H, m, J4,6B 10.9, J4,3S 9.4, J4,3R 6.8,
J4,6A 4.0, H-4), 2.66 (1H, dd, J6B,6A 13.8, J6B,4 11.1, H-6B), 2.30
1H, dd, J3S,3R 13.3, J3S,2 J3S,4 9.4, H-3S), 1.67 (1H, m, J3R,3S 13.3,
J3R,2 5.8, J3R,4 6.8, H-3R), 1.51 [9H, s, OC(CH ) ] and 1.48 [9H,
J3B,3A 16.4, J3B,2 6.4, H-3B), 1.61 (2H, m, J6,7 J6,4 7.4, H-6), 1.46
1
[
7
8
9H, s, OC(CH ) ], 1.43 [9H, s, OC(CH ) ] and 0.92 (3H, t, J
.4, H-7); δ (125.8 MHz, C H O H) 179.2 (CO ), 173.6 (CO ),
C 3 2 2
3
3
3
3
7,6
2
2
(
2.8 [OC(CH ) ], 80.6 [OC(CH ) ], 54.2 (C-2), 44.7 (C-4), 34.3
3
3
3 3
3
3
(
(
C-3), 28.7 [OC(CH ) ], 28.2 [OC(CH ) ], 25.9 (C-6) and 11.6
3 3 3 3
s, OC(CH ) ]; irradiation of the absorption for H-2 at δ 4.37
gave an NOE in H-3S at δ 2.30; irradiation of H-6B at δ 2.66
gave NOEs in the absorption for H-6A at δ 3.30 and in H-3R at
δ 1.67; δ (125.8 MHz, C HCl ) 174.5 (CON), 170.6 (1-CO ),
1
3
3
CH ).
3
(
1
2S,4S)-4-Methylglutamic acid hydrochloride 22a
-tert-Butyl hydrogen (2S,4S)-N-tert-butoxycarbonyl-4-methyl-
2
C
3
2
49.5 (N-CO ), 138.6–126.6 (C H ), 83.4 [OC(CH ) ], 82.2
30
2
6
5
3 3
glutamate 11 (100 mg, 0.315 mmol) was dissolved in 6 
aqueous hydrochloric acid (3 ml) and stirred at room temper-
ature overnight. The solvent was removed in vacuo to afford an
off-white solid which was recrystallised from ethanol–diethyl
ether to yield (2S,4S)-4-methylglutamic acid hydrochloride 22a
[
OC(CH ) ], 58.1 (C-2), 44.5 (C-4), 36.9 (C-3), 28.0 [OC(CH ) ],
3
3
3
3
2
7.9 [OC(CH ) ] and 26.5 (C-6).
3 3
tert-Butyl (2S,4S)-N-tert-butoxycarbonyl-4-carboxymethylpyro-
glutamate 18
tert-Butyl (2S,4S)-N-tert-butoxycarbonyl-4-benzylpyrogluta-
mate 17 (1.0 g, 3.1 mmol) was dissolved in carbon tetrachloride
21
as a white solid (62 mg, 100%), mp 148–153 ЊC (decomp.); [α]
D
ϩ25.35 (c 1, 1  HCl) (Found: C, 36.5; H, 6.0; N, 6.8. C H -
6
12
NO Cl requires C, 36.5; H, 6.1; N, 7.1%); m/z [ϩve FAB (gly-
4
(
5 ml), acetonitrile (5 ml) and water (5 ml). Ruthenium trichlor-
ide hydrate (61 mg, 0.235 mmol) and sodium metaperiodate
5.02 g, 23.5 mmol) were added. The reaction mixture was stirred
ϩ
Ϫ1
cerol)] 162 [free amino acid ϩ H] ; νmax(KBr)/cm2 3300 (br,
2
NH and OH) and 1718 (acid); δ (500 MHz, 20% HCl– H O)
H
2
(
4
2
.23 (1H, t, J2,3A J2,3B ca. 7.0, H-2), 2.89 (1H, m, J4,CH3 7.1, H-4),
.30 (1H, m, J3A,3B 14.5, J3A,2 6.5, J3A,4 9.8, H-3A), 2.15 (1H, m,
overnight at room temperature and partitioned between ethyl
acetate (40 ml) and saturated aqueous sodium hydrogen car-
bonate (40 ml). The organic layer was washed with saturated
aqueous sodium hydrogen carbonate (40 ml). The aqueous
layers were carefully acidified to pH 4 at 0 ЊC with stirring by
the dropwise addition of 10% aqueous citric acid. The aqueous
layer was extracted with ethyl acetate (3 × 100 ml), the com-
bined organic layers were dried (Na SO ) and the solvent was
J3B,3A 14.5, J3B,2 7.2, J3R,4 5.6, H-3B) and 1.28 (3H, d, J
7.1,
3
CH ,4
2
2
CH ); δ (125.8 MHz, 20% HCl– H O) 181.6 (CO ), 173.3
3
C
2
2
(
CO ), 53.6 (C-2), 38.2 (C-4), 35.2 (C-3) and 19.4 (CH ).
2
3
(
1
2S,4S)-4-Ethylglutamic acid hydrochloride 22b
-tert-Butyl hydrogen (2S,4S)-N-tert-butoxycarbonyl-4-ethyl-
2
4
glutamate 21 (576 mg, 1.74 mmol) was dissolved in 6  aqueous
hydrochloric acid (10 ml) and stirred at room temperature over-
night. The solvent was removed in vacuo to afford an off-white
solid which was recrystallised from ethanol–diethyl ether to
yield (2S,4S)-4-ethylglutamic acid hydrochloride 22b as a white
removed in vacuo to afford a pale yellow solid, which was
recrystallised from ethanol–diethyl ether to afford 1-tert-butyl
(
1
(
2S,4S)-N-tert-butoxycarbonyl-4-carboxymethylpyroglutamate
8 as a white crystalline solid (219 mg, 24%), mp 125–127 ЊC
Found: C, 55.8; H, 7.0; N, 4.0. C H NO requires C, 55.95; H,
1
6
25
7
24
ϩ
solid (313 mg, 85%), mp 135–138 ЊC (decomp.); [α]D ϩ3.2 (c 1,
3  HCl) (Found: C, 39.5; H, 6.6; N, 6.5. C H NO Cl requires
7
.3; N, 4.1%); m/z [ϩve FAB (3-NBA–CHCl )] 344 [M ϩ H] ;
3
Ϫ1
7
14
4
νmax(KBr)/cm 3405 (OH, acid), 1785 (‘imide’), 1736 (ester);
δ (360 MHz, C H ) 4.10 (1H, t, J 9.2, J2,3R 5.8, H-2), 2.65
(
9
2
6
C, 39.7; H, 6.6; N, 6.6%); m/z [ϩve FAB (glycerol)] 176 [free
H
6
2,3S
ϩ Ϫ1
amino acid ϩ H] ; ν (KBr)/cm 3305 (br, NH and OH) and
max
1H, dd, J6A,6B 17.0, J6A,4 4.5, H-6A), 2.40 (1H, m, J4,3S 8.6, J4,6B
.2, J4,6A 4.5, H-4), 2.10 (1H, dd, J6B,6A 17.0, J6B,4 9.2, H-6B),
.95 (1H, m, J3S,3R 12.9, J3S,2 9.2, J3S,4 8.6, H-3S), 1.42 [9H, s,
2
2
1
8
708 (acid); δ (500 MHz, 20% HCl– H O) 4.19 (1H, dd, J
H 2 2,3B
.0, J2,3A 6.0, H-2), 2.77 (1H, m, J4,3A 10.0, H-4), 2.30 (1H, m,
1
J3A,3B 14.6, J3A,2 6.0, J3A,4 10.0, H-3A), 2.17 (1H, m, J3B,3A 14.6,
OC(CH ) ], 1.38 (1H, m, H-3R) and 1.35 [9H, s, OC(CH ) ];
irradiation of H-2 at δ 4.10 resulted in NOEs in H-3S at δ 1.95
and in H-4 at δ 2.40; irradiation at δ 1.95 of H-3S resulted in
NOEs at δ 2.40 for H-4 and in H-2 at δ 4.10; δ (125.8 MHz,
C HCl ) 176.0 (7-CO ), 173.9 (CON), 170.2 (1-CO ), 149.2
3
3
3 3
J3B,2 8.0, J3B,4 4.8, H-3B), 1.69 (2H, quintet, J6A,6B 14.5, J 7.5,
6,7
2
H-6) and 0.93 (3H, t, J7 7.5, CH ); δ (125.8 MHz, 20% HCl–
,6
3
C
2
H O) 181.2 (CO ), 173.3 (CO ), 53.8 (C-2), 45.0 (C-4), 33.3
2
2
2
C
2
(C-3), 27.6 (C-6) and 12.9 (CH ).
3
3
2
2
(
(
(
urethane), 83.8 [OC(CH ) ], 82.4 [OC(CH ) ], 58.0 (C-2), 39.0
3 3 3 3
tert-Butyl (2S,4S)-N-tert-butoxycarbonyl-4-ethylprolinate 24b
C-4), 35.2 (C-3), 27.76 [OC(CH ) ], 27.74 [OC(CH ) ] and 27.6
3
3
3 3
tert-Butyl
(2S,4S)-N-tert-butoxycarbonyl-4-ethylpyrogluta-
C-6).
mate 14 (500 mg, 1.60 mmol) was dissolved in tetrahydrofuran
(50 ml), cooled to 0 ЊC under argon with stirring and boraneؒ
dimethyl sulfide (BMS) (2.0  in tetrahydrofuran, 4 ml, 8 mmol)
was added dropwise. The solution was allowed to warm to
room temperature, stirred for four days, cooled to 0 ЊC and
1
-tert-Butyl hydrogen (2S,4S)-N-tert-butoxycarbonyl-4-ethyl-
glutamate 21
tert-Butyl
(2S,4S)-N-tert-butoxycarbonyl-4-ethylpyrogluta-
mate 14 (271 mg, 0.865 mmol) was dissolved in tetrahydrofuran
3
526
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
2
quenched with methanol (10 ml). The solvent was removed in
vacuo to afford a colourless oil, which was purified by column
chromatography on silica gel using light petroleum (60–80 ЊC)–
diethyl ether (3:1) to afford the major product as a colourless
oil and the minor product as a white crystalline solid. The
major product was tert-butyl (2S,4S)-N-tert-butoxycarbonyl-4-
δ (125.8 MHz, C H ) 172.4 and 171.6 (1-CO ), 154.0 and 153.5
C 6 6 2
(urethane), 80.1 and 80.0 [OC(CH ) ], 79.1 and 79.0
[OC(CH ) ], 60.4 and 60.0 (C-2), 52.7 and 52.6 (C-5), 38.4 and
37.6 (C-4), 37.5 and 36.3 (C-6), 35.2 and 35.1 (C-3), 28.5 and
28.0 [OC(CH ) ], 21.4 (CH ) and 14.2 and 14.1 (CH ).
3
3
3
3
3
3
3
3
22
ethylprolinate 24b (254 mg, 53%), [α]D Ϫ49 (c 1.0, CHCl3)
(2S,4S)-4-Methylproline hydrochloride 26a
tert-Butyl (2S,4S)-N-tert-butoxycarbonyl-4-methylprolinate
(
9
Found: C, 63.6; H, 9.8; N, 4.7. C H NO requires C, 64.2; H,
16
29
4
ϩ
5b
.7; N, 4.7%); m/z [ϩve FAB (3-NBA–CHCl )] 300 [M ϩ H]
24a (300 mg, 1.05 mmol) was dissolved in 6  aqueous hydro-
chloric acid (10 ml) and stirred at room temperature for five
days. The solvent was removed in vacuo to afford an off-white
solid which was recrystallised from ethanol–diethyl ether to
yield (2S,4S)-4-methylproline hydrochloride 26a as a white crys-
3
(
Found: 300.21536. C H NO requires 300.21742); ν (film)/
16 30 4 max
Ϫ1 2
cm 1745 (ester) and 1703 (urethane); δ (360 MHz, C H ,
H
6
6
complicated by conformational isomerism) 4.27 and 4.11 (1H,
t, J5A,5D J5A,4 8.2, H-5A; t, J5B,5C J5B,4 8.1, H-5B), 3.81 and 3.55
24
(
1H, dd, J2A,3S 10.0, J2A,3R 7.1, H-2A; dd, J2B,3S 9.9, J2B,3R 7.4, H-
talline solid (163 mg, 94%), mp 165–166 ЊC; [α]D Ϫ19 (c 0.1, 3 
2
9
B), 2.98 and 2.94 (1H, t, J5D,5A J5D,4 9.9, H-5D; t, J5C,5B J5C,4
.9, H-5C), 1.99 (1H, m, H-3), 1.51 and 1.47 [9H, 2s,
HCl) (Found: C, 43.2; H, 7.3: N, 8.2. C H NO Cl requires C,
6
12
2
43.5; H, 7.3; N, 8.5%); m/z [ϩve FAB (glycerol–water)] 130 [free
ϩ
Ϫ1
OC(CH ) ], 1.43 and 1.38 [9H, 2s, OC(CH ) ], 0.96 (2H, m, H-
6
amino acid ϩ H] ; ν (KBr)/cm 3375 (br, NH and OH) and
max
2 2
3
3
3
3
) and 0.57 and 0.54 (3H, t, J7,6 7.4, CH ; t, J 7.4, CH ); the
1742 (acid); δ (500 MHz, C H O H) 4.40 (1H, dd, J 9.4, J2,3R
H 3 2,3S
3
7,6
3
tert-butyl singlets masked two absorptions for C-3 and two
8.2, H-2), 3.50 (1H, dd, J5A,5B 11.0, J5A,4 7.4, H-5A), 2.91 (1H,
dd, J5B,5A 11.0, H-5B), 2.57 (1H, m, J3R,3S 12.7, J3R,4 7.5, H-3R),
2.51 (1H, m, H-4), 1.69 (1H, m, J3S,3R 12.7, J3S,2 J3S,4 ca. 9.8, H-
2
absorptions for C-4; δ (125.8 MHz, [ H ]-DMSO) 172.1 and
C
6
1
71.7 (1-CO ), 153.4 and 153.0 (urethane), 80.3, 80.1, 78.8 and
2
2
2
7
8.7 [OC(CH ) ], 59.6 and 59.2 (C-2), 51.9 and 51.7 (C-5), 36.3
3S) and 1.12 (3H, d, J6,4 6.5, CH ); δ (125.8 MHz, C H O H)
3
3
3 C 3
and 35.2 (C-4), 28.1 (C-3), 28.0 and 27.6 [OC(CH ) ], 25.3 (C-6)
171.4 (1-CO ), 60.8 (C-2), 50.0 (C-5), 37.6 (C-4), 34.4 (C-3) and
3
3
2
and 12.39 and 12.35 (CH ). The minor product was tert-butyl
16.9 (CH ).
3
3
(
(
2S,4S)-N-tert-butoxycarbonyl-4-ethyl-5-hydroxyprolinate
25
22
92 mg, 18%), [α] Ϫ29 (c 1.0, CHCl ) (Found: C, 60.65; H, 9.1;
(2S,4S)-4-Propylproline hydrochloride 26c
D
3
N, 4.45. C H NO requires C, 60.9; H, 9.2; N, 4.4%); m/z [ϩve
tert-Butyl
(2S,4S)-N-tert-butoxycarbonyl-4-propylprolinate
16
29
5
ϩ
Ϫ1
FAB (3-NBA–CHCl )] 298 [M Ϫ OH] ; νmax(KBr)/cm 3461
24c (300 mg, 0.958 mmol) was dissolved in 6  aqueous hydro-
chloric acid (10 ml) and stirred at room temperature for five
days. The solvent was removed in vacuo to afford an off-white
solid which was recrystallised from ethanol–diethyl ether to
yield (2S,4S)-4-propylproline hydrochloride 26c as a white crys-
talline solid (165 mg, 89%); m/z [ϩve FAB (glycerol–MeOH)]
3
2
(
OH), 1749 (ester) and 1699 (urethane); δ (360 MHz, C H )
H 6 6
5
5
.53 and 5.33 (1H, t, J5A,4 J5A,OH 3.8, H-5A; t, J5B,4 J5B,OH 5.1, H-
B), 4.23 and 4.04 (1H, t, J2A,3S J2A,3R 8.6, H-2A; dd, J2B,3S 9.7,
J2B,3R 7.9, H-2B), 3.73 and 3.28 (1H, exchangeable d, JOH,5A 3.3,
-OH ; exchangeable d, J 5.9, 5-OH ), 1.94 and 1.75 (2H,
5
A
OH,5B
B
ϩ
m, 3A-CH ; m, 3B-CH ), 1.57 (1H, m, H-4), 1.48 and 1.44 [9H,
158 [M Ϫ Cl] ; m/z (EI) found 157.1117. C H NO requires
2
2
8
15
2
2
2
s, OC(CH ) , s, OC(CH ) ], 1.39 and 1.36 [9H, s, OC(CH ) , s,
157.1103; δ (500 MHz, 20% HCl– H O) 4.53 (1H, t, J
J2,3A
3
3
3
3
3
3
H
2
2,3B
OC(CH ) ], 1.27 (2H, m, H-6) and 0.76 (3H, t, J 7.3, CH );
7.5, H-2), 3.61 (1H, br t, H-5A), 3.07 (1H, br t, H-5B), 2.67 (1H,
m, H-3A), 2.47 (1H, m, H-4), 1.80 (1H, m, H-3B), 1.45 (2H, m,
H-6), 1.34 (2H, m, H-7) and 0.89 (3H, t, J 6.7, CH ); δ (125.8
3
3
7,6
3
2
δ (125.8 MHz, C H ) 173.6 and 172.1 (1-CO ), 154.0 and 153.5
C
6
6
2
(
(
urethane), 82.5 and 82.4 (5-CHOH), 81.2 and 80.4 [OC-
CH ) ], 80.1 and 80.0 [OC(CH ) ], 60.0 and 59.8 (C-2), 46.7
8,7
3
C
2
2
MHz, 20% HCl– H O) 173.3 (1-CO ), 61.9 (C-2), 53.4 (C-5),
3
3
3
3
2
2
and 45.3 (C-4), 34.3 and 32.8 (C-3), 28.4 and 28.97 [OC(CH ) ],
40.1 (C-4), 36.6 (CH ), 35.8 (CH ), 22.8 (C-7) and 15.8 (CH ).
3
3
2
2
3
2
8.92 [OC(CH ) ], 22.0 and 21.7 (C-6) and 12.4 (CH ).
3
3
3
tert-Butyl (2S,4R)-N-tert-butoxycarbonyl-4-ethylpyroglutamate
15
tert-Butyl (2S,4S)-N-tert-butoxycarbonyl-4-propylprolinate 24c
tert-Butyl (2S,4S)-N-tert-butoxycarbonyl-4-propylpyrogluta-
mate 16 (500 mg, 1.53 mmol) was dissolved in tetrahydrofuran
Methyllithium (1.4  in diethyl ether, 4.33 ml, 6.06 mmol) was
added to a stirred slurry of purified copper iodide (513 mg, 2.69
mmol) in diethyl ether (2 ml) under argon at Ϫ78 ЊC. The mix-
ture was stirred for 1 h at Ϫ78 ЊC and tert-butyl (2S)-N-tert-
(
40 ml), cooled to 0 ЊC under argon with stirring and boraneؒ
dimethyl sulfide (BMS) (2.0  in tetrahydrofuran, 3.8 ml, 7.6
mmol) was added dropwise. The solution was allowed to warm
to room temperature and stirred for eight days. The solution
was then cooled to 0 ЊC and the reaction was quenched with
methanol (10 ml). The solvent was removed in vacuo to afford a
colourless oil, which was partitioned between diethyl ether (50
ml) and water (50 ml). The organic layer was washed with water
30
butoxycarbonyl-4-methylenepyroglutamate 5 (200 mg, 0.673
mmol) in diethyl ether (10 ml) was added. The solution was
stirred for 2 h at Ϫ78 ЊC and the reaction was quenched by
addition of saturated aqueous ammonium chloride (20 ml),
allowed to warm to room temperature and stirred overnight at
room temperature. The aqueous layer was extracted with
diethyl ether (3 × 25 ml). The combined organic layers were
washed with 10% aqueous citric acid (100 ml), saturated aque-
ous hydrogen carbonate (100 ml) and saturated aqueous
sodium chloride (100 ml) and dried (Na SO ). The solvent was
(
50 ml) and saturated aqueous sodium chloride (50 ml) and
dried (Na SO ). The solvent was removed in vacuo to afford a
2
4
colourless oil (450 mg, 85%), which was purified by column
chromatography on silica gel using light petroleum (40–60 ЊC)–
diethyl ether (3:1) as eluent to afford tert-butyl (2S,4S)-N-tert-
butoxycarbonyl-4-propylprolinate 24c as a colourless oil (314
2
4
removed in vacuo to afford a very pale yellow oil (178 mg, 84%)
which contained the trans- and cis-isomers 15 and 14 in a ratio
of 3:1. The oil was purified by column chromatography on
silica gel using light petroleum (40–60 ЊC)–diethyl ether (1:1) as
eluent. The trans-isomer tert-butyl (2S,4R)-N-tert-butoxy-
carbonyl-4-ethylpyroglutamate 15 was the major product as a
2
5
mg, 66%), [α] Ϫ52 (c 1.1, CHCl ); m/z [ϩve FAB (3-NBA–
D
3
ϩ
CHCl )] 314 [M ϩ H] ; m/z (EI) found 313.22728. C H NO
requires 313.2253; νmax(film)/cm
3
17 31
4
Ϫ1
1746 (ester) and 1703
2
6
(
urethane); δ (360 MHz, C H ) 4.27 and 4.11 (1H, t, J
H
6
5A,5D
J5A,4 8.2, H-5A; t, J5B,5C J5B,4 8.2, H-5B), 3.81 and 3.55 (1H, dd,
J2A,3S 10.4, J2A,3R 7.1, H-2A; dd, J2B,3S 10.0, J2B,3R 7.3, H-2B),
white solid, mp 78–79 ЊC; m/z [ϩve FAB (3-NBA–CHCl )]
3
ϩ
314 [M ϩ H] ; m/z (EI) found 313.19048. C H NO requires
16
27
5
Ϫ1
2
.97 and 2.93 (1H, t, J5C,5B J5C,4 10.0, H-5C; t, J5D,5A J5D,4 9.9, H-
D), 2.00 (1H, m, J3R,2 7.1, H-3R), 1.52 and 1.48 [9H, 2s,
313.1889; νmax(KBr)/cm 1791 (‘imide’), 1727 (ester); δ (500
MHz, C H ) 4.35 (1H, dd, J 9.6 J2,3R 1.5, H-2), 2.34 (1H, m,
H
2
6
5
6
2,3S
OC(CH ) ], 1.44 and 1.39 [9H, 2s, OC(CH ) ], 0.91 (4H, m, H-6
J4,3S 11.7, J4,3R 8.7, J4,6A 4.9, J4,6B 5.4, H-4), 1.77 (1H, m, J3R,3S
13.0, J3R,4 8.7, J3R,2 1.5, H-3R), 1.71 (1H, m, J6A,6B 13.8, J6A,7
7.5, J6A,4 4.9, H-6A), 1.44 [9H, s, OC(CH ) ], 1.34 [9H, s,
3
3
3 3
and H-7) and 0.68 (3H, m, J6,4 6.6, CH ); the tert-butyl singlets
3
masked two absorptions for H-3S and two absorptions for H-4;
3
3
J. Chem. Soc., Perkin Trans. 1, 1997
3527

View Article Online
2
OC(CH ) ], 1.24 (1H, m, J
13.0, J3S,4 11.7, J3S,2 9.6, H-3S),
MHz, C HCl ) 4.50 (1H, dd, J 9.9, J2,3R 2.9, H-2), 2.49 (1H,
3 2,3S
3
3
3S,3R
1
.11 (1H, m, J6B,6A 13.8, J6B,7 7.5, J6B,4 5.4, H-6A) and 0.61 (3H,
dd, J3S,3R 13.2, J3S,2 9.9, H-3R), 1.84 (1H, dd, J3R,3S 13.2, J3R,2
2.9, H-3R), 1.48 [9H, s, OC(CH ) ], 1.44 [9H, s, OC(CH ) ],
t, J7,6 7.5, CH ). Irradiation of the terminal methyl triplet at δ
3
3
3
3 3
0
1
1
.61 resulted in an NOE in both adjacent methylene protons (δ
.71 and 1.1), in H-4 at δ 2.34 and in each of the protons H-3 (δ
.77 and 1.24); irradiation of H-3S at δ 1.24 resulted in NOEs in
1.25 (1H, m, H-7A) and 1.18 (1H, m, H-7B); the tert-butyl
singlets masked two of the cyclopropyl protons (H-6A and H-
2
6
6B); δ (500 MHz, C H ) 4.39 (1H, dd, J 9.8, J2,3R 2.9, H-2),
H
6
2,3S
H-3R at δ 1.77, in H-2 at δ 4.35 and in the terminal methyl
group at δ 0.61; irradiation of H-3R at δ 1.77 resulted in NOEs
1.74 (1H, dd, J3S,3R 13.2, J3S,2 9.8, H-3S), 1.43 [9H, s,
OC(CH ) ], 1.39 (1H, dd, J 13.2, J3R,2 2.9, H-3R), 1.33 [9H,
3
3
3R,3S
2
in H-3S at δ 1.24 and H-4 at δ 2.34; δ (360 MHz, C HCl ) 4.42
s, OC(CH ) ], 1.15 (1H, m, J
10.2, J6A,7A 6.4, J6A,7B 3.8,
H
3
3
3
6A,6B
(
1H, dd, J2,3S 9.6, J2,3R 1.5, H-2), 2.52 (1H, m, J4,3R 8.7, J4,3S 4.6,
H-4), 2.16 (1H, m, J3R,3S 13.1, J3R,4 8.7, J3R,2 1.5, H-3R), 1.91
1H, m, J3S,3R 13.1, J3S,2 9.6, J3S,4 4.6, H-3S), 1.50 [9H, s,
OC(CH ) ], 1.47 [9H, s, OC(CH ) ], 1.45 (2H, m, H-6) and 0.95
6-CH ), 1.06 (1H, m, J
10.2, J6B,7B 6.7, J6B,7A 3.4, H-6B),
A
6B,6A
1.29 (1H, m, J7A,7B 10.2, J7A,6A 6.4, J7A,6B 3.4, H-7A) and 0.21
(1H, m, J 10.2, J7B,6B 6.7, J7B,6A 3.8, H-7B); δ (125.8 MHz,
(
7B,7A
C
2
6
C H ) 173.7 (CON), 170.8 (1-CO ), 150.7 (urethane), 82.3
3
3
3
3
6
2
2
(
3H, t, J7,6 7.5, CH ); δ (125.8 MHz, C HCl ) 175.1 (CON),
[OC(CH ) ], 81.2 [OC(CH ) ], 57.3 (C-2), 29.9 (C-3), 28.0
3
C
3
3 3 3 3
1
70.4 (1-CO ), 149.4 (urethane), 83.1 [OC(CH ) ], 82.1
[OC(CH ) ], 27.8 [OC(CH ) ], 22.8 (C-4), 16.9 (C-6) and 13.2
3 3 3 3
2
3
3
[
OC(CH ) ], 57.7 (C-2), 42.9 (C-4), 28.0 (C-3), 27.8 [OC(CH ) ],
(C-7).
3
3
3 3
2
7.8 [OC(CH ) ], 23.3 (C-6) and 11.1 (CH ). The minor product
3
3
3
was tert-butyl (2S,4S)-N-tert-butoxycarbonyl-4-ethylpyrogluta-
1-[(2S)-3-tert-butoxy-2-(tert-butoxycarbonylamino)-3-oxo-
propyl]cyclopropane-1-carboxylic acid 30
2
2
mate 14, δ (360 MHz, C H ) and δ (125.8 MHz, C HCl )
H
6
6
C
3
NMR spectra identical with those of the sample prepared by
the method described earlier.
Di-tert-butyl (6S)-4-oxo-5-azaspiro[2.4]heptane-5,6-dicarboxy-
late 29 (243 mg, 0.781 mmol) was dissolved in tetrahydrofuran
(
3.9 ml) and 1  aqueous lithium hydroxide (0.94 ml) was added
tert-Butyl (2S,4R)-N-tert-butoxycarbonyl-4-benzylpyrogluta-
mate 28
dropwise at 0 ЊC with vigorous stirring over a period of 5 min.
Stirring was continued for a further 20 min at 0 ЊC. Ethyl acet-
ate (10 ml) and saturated aqueous sodium hydrogen carbonate
(10 ml) were added to the mixture and the organic layer was
extracted with saturated aqueous sodium hydrogen carbonate
(10 ml). The combined aqueous layers were carefully acidified
to pH 5 at 0 ЊC with stirring by dropwise addition of ice cold
10% aqueous citric acid. The aqueous layer was extracted with
ethyl acetate (3 × 40 ml) and the organic layers were dried
(Na SO ) and filtered. The solvent was removed in vacuo to
Phenyllithium (1.8  in diethyl ether, 8.42 ml, 15 mmol) was
added to a stirred slurry of purified copper iodide (1.282 g, 6.73
mmol) in diethyl ether (10 ml) under argon at Ϫ78 ЊC. The
mixture was stirred for 1 h at Ϫ78 ЊC and tert-butyl (2S)-N-tert-
30
butoxycarbonyl-4-methylenepyroglutamate 5 (500 mg, 1.68
mmol) in diethyl ether (30 ml) was added. The solution was
stirred for 2 h at Ϫ78 ЊC and the reaction was quenched by
addition of saturated aqueous ammonium chloride (40 ml) and
allowed to warm to room temperature. After stirring overnight
at room temperature the aqueous layer was extracted with
diethyl ether (2 × 100 ml). The combined organic layers were
washed with 10% aqueous citric acid (200 ml), saturated aque-
ous hydrogen carbonate (200 ml) and saturated aqueous
sodium chloride (200 ml) and dried (Na SO ). The solvent was
2
4
afford
1-[(2S)-3-tert-butoxy-2-(tert-butoxycarbonylamino)-3-
oxopropyl]cyclopropane-1-carboxylic acid 30 as a white solid
18
(46 mg, 18%), mp 132–134 ЊC; [α]D Ϫ3.3 (c 0.3, CHCl ) (Found:
3
C, 58.2; H, 8.4; N, 4.1. C H NO requires C, 58.3; H, 8.2; N,
1
6
27
6
ϩ
4.25%); m/z [ϩve FAB (3-NBA–CHCl )] 330 [M ϩ H] ;
νmax(KBr)/cm 3350 (br, NH and OH), 1719 (acid) and 1703
(urethane); δ (500 MHz, C H ) 5.34 (1H, d, J
3
Ϫ1
2
4
2
removed in vacuo to afford a pale yellow oil. Column chrom-
atography proved unsuccessful, with inadequate separation and
poor recovery (587 mg, 93% crude). The trans- and cis-isomers
8.5,
H
6
6
NH,2
exchangeable, NH), 4.76 (1H, m, J2,3B 9.2, J2,NH 8.5, J2,3A 5.6, H-
2), 1.95 (1H, dd, J3A,3B 14.3, J3A,2 5.6, H-3A), 1.68 (1H, dd, J3B,3A
14.3, J3B,2 9.2, H-3B), 1.41 [9H, s, OC(CH ) ], 1.34 [9H, s,
2
8 and 17 were present in a ratio of 6:1. The major product was
tert-butyl (2S,4R)-N-tert-butoxycarbonyl-4-benzylpyrogluta-
mate 28, δ (360 MHz, C HCl ) 7.62–6.83 (5H, m, ArH), 4.35
3
3
OC(CH ) ], 1.26 (1H, overlapping with tert-butyl singlet, H-
3
3
2
6A), 1.18 (1H, m, J6B,6A 9.8, J6B,7B 6.5, J6B,7A 3.4, H-6B), 0.52
(1H, m, J7A,7B 10.2, J7A,6A 6.5, J7A,6B 3.4, H-7A) and 0.43 (1H, m,
H
3
(
1H, dd, J2,3S 8.4, J2,3R 2.9, H-2), 3.27 (1H, dd, H-6A), 2.93 (1H,
2
6
m, H-4), 2.71 (1H, dd, H-6B), 1.99 (2H, m, H-3), 1.52 [9H, s,
OC(CH ) ] and 1.45 [9H, s, OC(CH ) ]. The minor product was
J7B,7A 10.2, J7B,6B 6.5, J7B,6A 3.7, H-7B); δ (125.8 MHz, C H )
C
6
181.0 (5-CO ), 172.1 (1-CO ), 155.5 (urethane), 81.3
3
3
3
3
2
2
tert-butyl (2S,4S)-N-tert-butoxycarbonyl-4-benzylpyroglutamate
[OC(CH ) ], 79.2 [OC(CH ) ], 53.8 (C-2), 36.5 (C-3), 28.4
[OC(CH ) ], 27.8 [OC(CH ) ], 21.0 (C-4), 16.9 (C-6) and 16.1
3 3 3 3
3 3 3 3
2
1
7 with δ (360 MHz, C H Cl) identical with that of the sample
H
3
synthesised by hydrogenation.
(C-7).
Di-tert-butyl (6S)-4-oxo-5-azaspiro[2.4]heptane-5,6-dicarboxy-
late 29
Methyl 1-[(2S)-3-tert-butoxy-2-(tert-butoxycarbonylamino)-3-
oxopropyl]cyclopropanecarboxylate 31
Diazald (N-methyl-N-nitrosotoluene-p-sulfonamide) (20 g, 93
mmol) in diethyl ether (250 ml) was added dropwise to potas-
sium hydroxide (10 g, 178 mmol) in 2-ethoxyethoxyethanol (20
ml), water (15 ml) and diethyl ether (10 ml) at 60 ЊC. The yellow
ethereal solution of diazomethane generated by distillation was
added dropwise to tert-butyl (2S)-N-tert-butoxycarbonyl-4-
Di-tert-butyl (6S)-4-oxo-5-azaspiro[2.4]heptane-5,6-dicarboxy-
late 29 (1.00 g, 3.22 mmol) was dissolved in tetrahydrofuran
(16 ml) and cooled to Ϫ12 ЊC under argon. A 1.0  solution of
lithium methoxide in methanol (3.86 ml, 3.86 mmol) was added
dropwise with stirring which was continued at Ϫ12 ЊC for 30
min. The mixture was quenched with saturated aqueous sodium
chloride (20 ml) and diethyl ether (20 ml) and allowed to warm
to room temperature. The aqueous layer was extracted with
diethyl ether (20 ml). The combined organic layers were dried
(Na SO ) and the solvent was removed in vacuo to afford a pale
30
methylenepyroglutamate 5 (4.550 g, 15 mmol) and palladium
acetate (172 mg, 0.766 mmol) in diethyl ether (100 ml) at 0 ЊC. A
black precipitate was observed. The mixture was allowed to
warm to room temperature and stirred overnight at room tem-
perature. The black precipitate was removed by filtration and
the solvent was removed in vacuo to afford di-tert-butyl (6S)-4-
oxo-5-azaspiro[2.4]heptane-5,6-dicarboxylate 29 as a white crys-
2
4
yellow oil, which was purified by column chromatography on
silica gel using light petroleum (40–60 ЊC)–diethyl ether (2:1) as
eluent to afford methyl 1-[(2S)-3-tert-butoxy-2-(tert-butoxy-
carbonylamino)-3-oxopropyl]cyclopropanecarboxylate 31 as a
19
talline solid (3.186 g, 67%), mp 89–94 ЊC, [α]D Ϫ6.2 (c 1, CHCl3)
1
8
(
8
Found: C, 62.2; H, 8.25; N, 4.4. C H NO requires C, 61.7; H,
colourless oil (796 mg, 72%); [α]D ϩ4.25 (c 1, CHCl ); m/z [ϩve
16
25
5
3
Ϫ1
ϩ
ϩ
.0; N, 4.5%); m/z [ϩve FAB (3-NBA–CHCl )] 312 [M ϩ H] ;
FAB (3-NBA–CHCl )] 344 [M ϩ H] ; νmax(film)/cm 3377 (br,
NH) and 1719 (acid); δ (500 MHz, C H ) 5.46 (1H, d, J
3
3
Ϫ1
2
6
νmax(KBr)/cm 1782, 1701 (‘imide’) and 1741 (ester); δ (360
H
H
6
NH,2
3
528
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
8
5
.4, exchangeable, NH), 4.73 (1H, m, J2,3B 9.0, J2,NH 8.9, J2,3A
.6, H-2), 3.28 (3H, s, OCH ), 1.90 (1H, dd, J 14.3, J3A,2 5.6,
1.69) and the aromatic protons (δ 6.78) and H-3S (δ 1.60);
irradiation at δ 6.78 (ArH) resulted in NOEs at δ 2.69 (H-7B)
3
3A,3B
2
6
H-3A), 1.79 (1H, dd, J3B,3A 14.3, J3B,2 9.4, H-3B), 1.39 [9H, s,
OC(CH ) ], 1.32 [9H, s, OC(CH ) ], 1.19 (1H, m, J 9.9,
and δ 0.73 (H-6); δ (125.8 MHz, C H ) 172.9 (CON), 170.6 (1-
C
6
CO ), 150.7 (urethane), 136.7–126.7 (C H ), 82.5 [OC(CH ) ],
3
3
3
3
6A,6B
2
6
5
3 3
J6A,7A 6.4, J6A,7B 3.4, H-6A), 1.13 (1H, m, J6B,6A 9.8, J6B,7B 6.3,
J6B,7A 3.6, H-6B), 0.51 (1H, m, J7A,7B 9.6, J7A,6A 6.1, J7A,6B 3.8, H-
81.2 [OC(CH ) ], 56.8 (C-2), 32.4 (C-6), 30.9 (C-4), 28.0
3 3
[OC(CH ) ], 27.7 [OC(CH ) ], 24.6 (C-3) and 17.1 (C-7). The
3
3
3 3
7
A) and 0.43 (1H, m, J7
9.7, J7B,6B 6.3, J7B,6A 3.4, H-7B);
second trans product was di-tert-butyl (1S,3R,6R)-1-phenyl-4-
oxo-5-azaspiro[2.4]heptane-5,6-dicarboxylate 33b (37 mg, 14%),
B,7A
2
δ (125.8 MHz, C H ) 174.7 (CO ), 172.1 (CO ), 155.5
C
6
6
2
2
ϩ
(
(
(
urethane), 81.1 [OC(CH ) ], 79.0 [OC(CH ) ], 54.0 (C-2), 51.5
OCH ), 37.0 (C-3), 28.4 [OC(CH ) ], 27.9 [OC(CH ) ], 21.1
C-4), 16.3 (C-6) and 15.1 (C-7).
m/z [ϩve FAB (3-NBA–CHCl )] 388 [M ϩ H] ; δ (360 MHz,
3
3
3
3
3
H
2
C H ) 7.00 (3H, m, ArH), 6.65 (2H, m, ArH), 4.30 (1H, dd,
3
3
3
3
3
6 6
J2,3S 10.0, J2,3R 3.2, H-2), 2.74 (1H, dd, J7B,7A 9.4, J7B,6 7.1, H-
B), 1.63 (1H, dd, J7A,7B 9.4, J7A,6 4.9, H-7A), 1.44 [9H, s,
OC(CH ) ], 1.33 [9H, s, OC(CH ) ] and 0.91 (1H, dd, J 7.1,
7
1
-[(2S)-2-Amino-2-carboxyethyl]cyclopropanecarboxylic acid
3
3
3
3
6,7B
hydrochloride
J6,7A 4.9, H-6); the tert-butyl singlets masked the absorptions for
2
Methyl 1-[(2S)-3-tert-butoxy-2-(tert-butoxycarbonylamino)-3-
oxopropyl]cyclopropanecarboxylate 31 (661 mg, 1.93 mmol)
was heated to reflux with 6  aqueous hydrochloric acid (10 ml)
for three hours. The solvent was removed in vacuo to afford an
off-white solid. Traces of residual hydrochloric acid were
removed by azeotropic distillation with diethyl ether and the
residue was recrystallised from ethanol–diethyl ether to yield
the H-3S and H-3R protons; δ (125.8 MHz, C H ) 172.9
C
6
6
(CON), 170.9 (1-CO ), 150.7 (urethane), 136.6–126.8 (C H ),
2
6
5
82.5 [OC(CH ) ], 81.3 [OC(CH ) ], 57.2 (C-2), 30.6 (C-6), 29.9
3
3
3 3
(C-4), 28.0 [OC(CH ) ], 27.8 [OC(CH ) ], 26.6 (C-3) and 20.0
3
3
3 3
(C-7).
Acknowledgements
1
-[(2S)-2-amino-2-carboxyethyl]cyclopropanecarboxylic
acid
We thank the EPSRC for a studentship to (C. M. M.) and Dr
J. A. Khan and Dr P. Dieterich for useful discussions. We thank
Professor T. Kasai, Faculty of Agriculture, Hokkaido Univer-
sity, Japan for his kindness in providing us with samples of the
compounds 1, 2 and 23 and Professor S. Hatanaka, Depart-
ment of Biology, University of Tokyo, Japan for his kindness
in providing us with a sample of the compounds 2 and 3.
hydrochloride 32 as a white crystalline solid (340 mg, 84%), mp
22
5
7–61 ЊC; [α] ϩ14.8 (c 1, 1  HCl); m/z [ϩve FAB (glycerol–
D
ϩ ϩ
dilute HCl)] 174 [free amino acid ϩ H] ([M ϩ H] found
74.07482. C H NO ϩ H requires 174.07663); νmax(KBr)/
1
7
11
4
Ϫ1
cm 2900–3600 (br, NH and OH) and 1733 (acid); δ (500
H
2
2
MHz, C H O H) 4.25 (1H, t, J
J2,3A 6.9, H-2), 2.11 (2H, m,
3
2,3B
H-3), 1.37 (1H, m, J6A,6B 10.0, J6A,7A 6.3, J6A,7B 3.5, H-6A), 1.31
1H, m, J6B,6A 10.0, J6B,7B 6.3, J6B,7A 3.4, H-6B), 0.95 (1H, m,
J7A,7B 9.7, J7A,6A 6.3, J7A,6B 3.4, H-7A) and 0.88 (1H, m, J
(
References
7B,7A
2
2
9
.7, J7B,6B 6.3, J7B,6A 3.5, H-7B); δ (125.8 MHz, C H O H) 178.5
C
3
1
Part of this work has been reported in preliminary form in (a) C. M.
Moody and D. W. Young, Tetrahedron Lett., 1993, 34, 4667; and (b)
C. M. Moody and D. W. Young, Tetrahedron Lett., 1994, 35, 7277.
S. Hunt, in Methods in Plant Biochemistry, ed. L. J. Rogers,
Academic Press, New York, 1991, vol. 5, p.1.
S. Hunt, in Chemistry and Biochemistry of the Amino Acids, ed. G. C.
Barrett, Chapman and Hall, London, 1985, p. 55.
(
CO ), 171.8 (CO ), 58.3 (C-2), 53.4 (C-3), 21.7 (C-4), 17.0 (C-6)
2
2
and 16.5 (C-7).
2
3
Di-tert-butyl (6S)-1-phenyl-4-oxo-5-azaspiro[2.4]heptane-5,6-
dicarboxylate 33
Diazald (20 g, 93 mmol) in diethyl ether (250 ml) was added
dropwise to potassium hydroxide (10 g, 178 mmol) in 2-
ethoxyethoxyethanol (20 ml), water (15 ml) and diethyl ether
4
5
R. M. Williams, Aldrichimica Acta, 1992, 25, 11.
(a) J. Feeney, J. E. McCormick, C. J. Bauer, B. Birdsall, C. M.
Moody, B. A. Starkmann, D. W. Young, P. Francis, R. H. Havlin,
W. D. Arnold and E. Oldfield, J. Am. Chem. Soc., 1996, 118, 8700;
(
10 ml) at 60 ЊC. The yellow ethereal solution of diazomethane
(
b) ibid., supplementary material.
generated by distillation was added dropwise to tert-butyl (2S)-
N-tert-butoxycarbonyl-4-benzylidenepyroglutamate 8c (250
mg, 0.670 mmol) and palladium acetate (75 mg, 0.335 mmol) in
diethyl ether (50 ml) at 0 ЊC. A black precipitate was observed.
The mixture was allowed to warm to room temperature and
stirred overnight at room temperature. The black precipitate
was removed by filtration and the solvent was removed in vacuo
to afford a colourless oil (257 mg, 99% crude) which was a
mixture of diastereoisomers in the ratio 11:8:9:2 (cis:trans:
trans:cis). The oil was purified by column chromatography on
silica gel using light petroleum (30–40 ЊC)–diethyl ether (7:3) as
eluent. Column chromatography afforded pure samples of the
trans-isomers 33a and 33b as white solids and various fractions
containing diastereoisomeric mixtures of the trans- and cis-
isomers. The first trans product was di-tert-butyl (1S,3R,6S)-1-
phenyl-4-oxo-5-azaspiro[2.4]heptane-5,6-dicarboxylate 33a (28
6
7
For references see: A. N. Bowler, A. Dinsmore, P. M. Doyle and
D. W. Young, J. Chem. Soc., Perkin Trans. 1, 1997, 1297.
L. Radics, M. Kajtar-Peredy, C. G. Casinovi, C. Rossi, M. Ricci and
L. Tuttobello, J. Antibiot., 1987, 40, 714.
8 A. Isogai, A. Suzuki, S. Tamura, S. Higashikawa and S. Kuyama,
J. Chem. Soc., Perkin Trans. 1, 1984, 1405.
9
A. D. Argoudelis, J. A. Fox and T. E. Eble, Biochemistry, 1965, 4,
6
98.
1
1
0 B. J. Magerlein, R. D. Birkenmeyer, R. R. Herr and F. Kagan, J. Am.
Chem. Soc., 1967, 89, 2459.
1 J. K. Thottathil, J. L. Moniot, R. H. Mueller, M. K. Y. Wong and
T. P. Kissick, J. Org. Chem., 1986, 51, 3140.
12 J. K. Thottathil and J. L. Moniot, Tetrahedron Lett., 1986, 27, 151.
3 E. M. Smith, G. F. Swiss, B. R. Neustadt, E. H. Gold, J. A. Sommer,
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1
1
22
mg, 11%), mp 80–83 ЊC; [α]D ϩ6.9 (c 0.77, CHCl ) (Found: C,
15 J. Done and L. Fowden, Biochem. J., 1952, 51, 451.
16 R. M. Zacharius, J. K. Pollard and F. C. Steward, J. Am. Chem. Soc.,
1954, 76, 1961.
3
6
3
8.1; H, 7.6; N, 3.5. C H NO requires C, 68.2; H, 7.5; N,
22 29 5
ϩ
.6%); m/z [ϩve FAB (3-NBA–CHCl )] 388 [M ϩ H] ;
3
Ϫ1
17 B. Tschiersch, Phytochemistry, 1962, 1, 103.
νmax(KBr)/cm 1782, 1719 (‘imide’) and 1736 (ester); δ (360
MHz, C H ) 6.96 (3H, m, ArH), 6.78 (2H, m, ArH), 4.34 (1H,
H
1
1
8 J. Blake and L. Fowden, Biochem. J., 1964, 92, 136.
2
6
6
9 R. Watson and L. Fowden, Phytochemistry, 1973, 12, 617.
dd, J2,3S 10.5, J2,3R 2.1, H-2), 2.69 (1H, dd, J7B,7A 9.2, J7B,6 7.2,
H-7B), 1.69 (1H, dd, J7A,7B 9.2, J7A,6 5.1, H-7A), 1.60 (1H, dd,
J3S,3R 13.8, J3S,2 10.5, H-3S), 1.45 [9H, s, OC(CH ) ], 1.36 (1H,
20 S. Hatanaka and H. Katayama, Phytochemistry, 1975, 14, 1434.
21 C. S. Evans and E. A. Bell, Phytochemistry, 1978, 17, 1127.
22 P. R. Shewry and L. Fowden, Phytochemistry, 1976, 15, 1981.
3
3
2
2
3 L. K. Meier and H. Sorensen, Phytochemistry, 1979, 18, 1173.
4 T. Kasai, T. Nishitoba, Y. Shiroshita and S. Sakamura, Agric. Biol.
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6 E. Guibé, P. Decottignies-Le Maréchal, P. Le Maréchal and
R. Azerad, FEBS Lett., 1984, 177, 265.
dd, J3R,3S 13.8, J3R,2 2.1, H-3R), 1.15 [9H, s, OC(CH ) ] and 0.73
3
3
(
1H, dd, J6,7B7.2, J6,7A 5.1, H-6); irradiation of the resonance for
H-2 at δ 4.34 resulted in an NOE in H-3S at δ 1.60; irradiation of
H-3S at δ 1.60 resulted in NOEs in H-2 at δ 4.34 and in H-6 at δ
2
2
0
.73; irradiation of H-6 at δ 0.73 resulted in NOEs at H-7A (δ
J. Chem. Soc., Perkin Trans. 1, 1997
3529

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37 D. K. Dikshit and S. K. Panday, J. Org. Chem., 1992, 57, 1920.
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and F. Sanchez-Ferrando, Tetrahedron, 1993, 49, 8665.
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4387.
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2
7 L. Fowden, Biochem. J., 1966, 98, 57.
8 J. E. Baldwin, R. M. Adlington and N. G. Robinson, J. Chem. Soc.,
Chem. Commun., 1987, 153 and references cited therein.
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Tetrahedron Lett., 1991, 32, 2679; (b) A. N. Bowler, P. M. Doyle,
P. B. Hitchcock and D. W. Young, Tetrahedron, 1997, 53, 10 545.
0 (a) R. A. August, J. A. Khan, C. M. Moody and D. W. Young,
Tetrahedron Lett., 1992, 33, 4617; (b) ibid., J. Chem. Soc., Perkin
Trans. 1, 1996, 507.
2
3
3
3
3
1 E. Benary, Chem. Ber., 1931, 64, 2543.
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43 S. Hanessian and V. Ratovelomanana, Synlett, 1990, 501.
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2
091.
3
3
3
4 T. Ohta, A. Hosoi and S. Nozoe, Tetrahedron Lett., 1988, 29, 329.
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Paper 7/03489J
Received 20th May 1997
Accepted 31st July 1997
1
991, 32, 1379.
3
530
J. Chem. Soc., Perkin Trans. 1, 1997