Unusual stereoselectivity in the alkylation of pyroglutamate ester urethanes

Article abstract of DOI:10.1039/b106451g

Previous studies on the alkylation of pyroglutamate ester urethanes have led to a consensus that alkylation at C-4 occurs to give a mixture of diastereoisomers, the major isomer of which usually has the alkyl group trans to the ester group at C-2. We have now discovered that this generalisation is not invariably correct and that, although for S_N1-type electrophiles stereoselectivity is in fact trans, S_N2-type electrophiles can give the thermodynamically less stable cis compounds as the predominant products. Use of the bulky proton source 2,6-di-tert-butylphenol to quench these reactions yields the cis isomers as the only products in good yield, thus making direct alkylation of pyroglutamic acid derivatives a useful alternative to our hydrogenation approach to these synthons.

Full text of DOI:10.1039/b106451g

View Article Online / Journal Homepage / Table of Contents for this issue
Unusual stereoselectivity in the alkylation of pyroglutamate ester
1
urethanes
Jean-Damien Charrier, James E. S. Duffy, Peter B. Hitchcock and Douglas W. Young*
1
Sussex Centre for Biomolecular Design and Drug Development, CPES, University of Sussex,
Falmer, Brighton, UK BN1 9QJ
Received (in Cambridge, UK) 19th July 2001, Accepted 8th August 2001
First published as an Advance Article on the web 7th September 2001
Previous studies on the alkylation of pyroglutamate ester urethanes have led to a consensus that alkylation at
C-4 occurs to give a mixture of diastereoisomers, the major isomer of which usually has the alkyl group trans to
the ester group at C-2. We have now discovered that this generalisation is not invariably correct and that, although
for S 1-type electrophiles stereoselectivity is in fact trans, S 2-type electrophiles can give the thermodynamically
N
N
less stable cis compounds as the predominant products. Use of the bulky proton source 2,6-di-tert-butylphenol to
quench these reactions yields the cis isomers as the only products in good yield, thus making direct alkylation of
pyroglutamic acid derivatives a useful alternative to our hydrogenation approach to these synthons.
Protected pyroglutamic acid derivatives have been used as
homochiral starting materials in the synthesis of a variety of
interesting natural products. At first, derivatives in which the
ester at C-2 had been converted to a protected alcohol were
2
used, presumably due to fears that the centre C-2 might prove
configurationally unstable under some of the reaction con-
ditions. However, subsequent work using the esters themselves
has shown that these fears are largely groundless and reactions
have been carried out using the anion at C-4 of protected pyro-
glutamate esters without loss of stereochemical integrity at C-2.
3
However, 4-alkylation has rarely been fully diastereoselective,
except in the case of 4-benzylation in which alkylation gives
only that diastereoisomer where the benzyl group is trans to the
4
ester group at C-2.
Results and discussion
Our interest in discovering the alignment of the diastereotopic
t
Scheme 1 (i) HC(O Bu)(NMe ); (ii) (a) DIBAL-H
3, R = H; or (b)
5
2
methyl groups in leucine residues in proteins, led us to develop
RMgBr
3, R = alkyl, aryl vinyl; (iii) H –Pd-C.
2
2
6
a
synthesis of (2S,4R)-[5,5,5- H ]leucine. Methodology
3
developed in this work was extended to provide a general
method for stereospecific synthesis of 4-alkylpyroglutamic ester
urethanes, which reliably gave the product in which the alkyl
7
group was always cis to the ester at C-2. In this method, shown
in Scheme 1, the pyroglutamic ester urethane 1 was reacted with
Bredereck’s reagent to yield the enaminone 2. On reaction with
7
DIBAL-H or Grignard reagents this gave a variety of alkyl-
idene derivatives 3. Catalytic reduction of these compounds
then led to addition from the less hindered side of the molecule
to afford the single diastereoisomer 4, which could be converted
into diastereoisomerically pure (2S,4S)-4-alkylglutamic acids
7
and (2S,4S)-4-alkylprolines. Cuprate addition to the enone
7
3
(R = H), although only 80% diastereoselective, afforded
access to the epimeric (2S,4R)-series of compounds from the
7
product 5.
1
9
Use of F NMR spectroscopy to study protein conformation
has been under-exploited except in the case of fluoroaromatic
amino acid residues. We have, therefore, adapted our gen-
eral synthesis of 4-alkylpyroglutamate derivatives to provide
were to be exploited to the full in molecular recognition studies,
then larger quantities would be required.
This meant that our synthesis would have to be improved.
The stereoselective methylation in our synthesis involved two
steps: reaction of the protected pyroglutamate 1 with the costly
Bredereck’s reagent to obtain the enaminone 2, followed by
8,9
stereochemically pure (2S,4S)-5-fluoroleucine 6, which we
incorporated into the enzyme dihydrofolate reductase using
9
biological methods. Although useful quantities were obtained,
we realised that if the potential of this fluorinated amino acid
DOI: 10.1039/b106451g
J. Chem. Soc., Perkin Trans. 1, 2001, 2367–2371
This journal is © The Royal Society of Chemistry 2001
2367

View Article Online
treatment of this with hydrogen and large amounts of catalyst
to give the cis-methyl compound 7 as the sole product by a
process involving reduction, elimination and reduction. We
therefore decided to reinvestigate direct alkylation of the pro-
tected pyroglutamic ester 1 as a way of preparing our key syn-
thetic intermediate 7 or its trans epimer 8. Reports of direct
methylation of pyroglutamate ester urethanes were not promis-
4
ing as Baldwin et al. had not been successful in attempting to
methylate a pyroglutamate enolate using methyl iodide and
3
Ezquerra et al. obtained yields of less than 10% when this
electrophile was used. However, when we treated the protected
ester 1 with lithium hexamethyldisilazide in THF at Ϫ78 ЊC,
followed by reaction with methyl iodide, we obtained a mixture
of monoalkylated products in 67% yield together with 10% of
the dialkylated compound 9.
The monoalkylated products were present in a diastereo-
isomeric ratio of 5 : 1 and could be separated by chroma-
tography. To our surprise, the major isomer was spectroscopi-
6
cally identical to the cis isomer 7, which we had prepared by
Fig. 1 X-Ray structure of the major isomer 15, from alkylation of the
ester urethane 1 with tert-butyl bromoacetate.
the route outlined in Scheme 1. We had assigned stereo-
chemistry to this product on the basis of NOE studies, and the
coupling constants were in keeping with the considerable
6
number of examples in the literature. Further, the rationale of
hydrogenation occurring from the less hindered side of the
intermediate 3 (R = H) was in keeping with the result. Sub-
10
sequently, Coudert et al. confirmed our stereochemical
assignments by preparing the methyl ester 10 from the corre-
sponding enaminone using our method, and converting it to
an authentic sample of (2S,4S)-4-methylglutamic acid 11.
This compound had previously been degraded to -α-
11
methylsuccinic acid, the absolute configuration of which had
been confirmed by the solution of the X-ray structure of ergo-
flavin by anomolous dispersion methods, -α-methylsuccinic
12
acid being a degradation product of this fungal metabolite.
Although these results seemed unassailable, the alkylations
3
reported by Ezquerra et al. had all given the trans isomer as
the major product and so we confirmed our assignment by
single crystal X-ray structure determination on the major
isomer.†
major isomer was therefore the cis isomer 15 and this was con-
firmed by a single crystal X-ray structure as shown in Fig. 1.
As improving the yield and diastereoselectivity of the
methylation reaction had been our first objective, we next used
methyl triflate as the electrophile in the reaction. This resulted
in monoalkylation in increased yield (75%) and with no
dialkylation. The cis : trans ratio of 5 : 1 was unaltered. The
“contra-steric” cis stereoselectivity found in methylation and in
alkylation using tert-butyl bromoacetate might be due to the
1
3
Interestingly, Langlois and Rojas had noted that treatment
of the protected pyroglutamate 12 with LiHMDS followed by
reaction with tert-butyl bromoacetate had given a 3 : 1 mixture
in which the cis isomer 13 was the major product, although
3
Ezquerra reported a 2 : 1 ratio in favour of the trans isomer 14
when he treated the protected ester 1 with LiHMDS followed
by reaction with ethyl bromoacetate. When we reacted our
pyroglutamic ester urethane 1 with 1.5 equivalents of LiHMDS
at Ϫ78 ЊC, followed by addition of 1.2 equivalents of tert-
butyl bromoacetate at the same temperature, a mixture of the
diastereoisomeric monoalkylated products 15 and 16 was
obtained in 70% yield in a 4 : 1 ratio, together with a 16% yield
of the 4,4-dialkyl derivative 17. The major monoalkylated
product 15 showed an NOE at H-3S (2.62 ppm) and at H-4
fact that these electrophiles imply an S 2 mechanism and so
N
chelation of the leaving group via lithium with the ester at C-2
might account for suprafacial alkylation. Such an explanation
would not apply to electrophiles which are more likely to
operate in an S 1 manner and when we used benzyl bromide in
N
the reaction, the sole product observed was the trans product
1
8, obtained in 72% yield. This result is in keeping with that
4
observed by Baldwin et al. When the methylation reaction
using LiHMDS and methyl triflate was repeated in toluene as
solvent, a 77% yield of the monoalkylated product was
obtained with a cis : trans ratio of 17 : 1. Chelation therefore
seems a reasonable explanation. Interestingly, Armstrong and
(
2.93 ppm) when H-2 (4.39 ppm) was irradiated and an NOE at
H-3R (1.65 ppm) when H-6 (2.36 ppm) was irradiated. The
†
The X-ray data for this compound were reported in our preliminary
14
DeMattei noted that alkylation of the enolate of the bicyclic
communication (ref. 1) and the atomic coordinates were lodged with
the Cambridge Crystallography Data Centre, University Chemical
Laboratory, Lensfield Road, Cambridge, CB2 1EW. They are available
on request from the Director of the CCDC at the above address, quot-
ing CCDC reference code POYBAG.
compound 19 with methyl iodide gave kinetic endo alkylation,
15
and Meyers et al. have explained such alkylation as a prefer-
ence for attack by small electrophiles anti to a pseudopyrimidal
lone pair on the amide nitrogen.
2
368
J. Chem. Soc., Perkin Trans. 1, 2001, 2367–2371

View Article Online
1
7.5 mmol) was dissolved in THF (50 ml) under nitrogen with
stirring. The solution was cooled to Ϫ78 ЊC and LiHMDS
1.0 M in THF, 20.17 ml, 20.17 mmol) was added. After stirring
(
for 1 h at Ϫ78 ЊC methyl iodide (1.31 ml, 21.05 mmol) was
added dropwise and stirring was continued at Ϫ78 ЊC for a
further 2 h. The reaction was quenched with saturated aqueous
ammonium chloride and allowed to warm to room temper-
ature. The crude product was extracted into ethyl acetate, the
combined organic layers were washed with water and brine,
and dried (Na SO ). The solvent was removed in vacuo to give
2
4
an orange oil, which was purified by column chromatography
on silica gel using a gradient of EtOAc (5–25%) in petroleum
ether as eluant. tert-Butyl (2S)-N-(tert-butoxycarbonyl)-4,4-
dimethylpyroglutamate 9 eluted first as a yellow solid (0.55 g,
2
0
1
0%), mp 100–102 ЊC; [α]
D
3
Ϫ26.24 (c 1.0, CHCl ) (Found:
C, 61.3; H, 8.7; N, 4.5. C H NO requires C, 61.3; H, 8.7;
1
6
27
5
ϩ
Ϫ1
N, 4.5%); m/z [ϩ FAB, NBA] 314 [M ϩ H] ; ν
785 (imide/urethane) and 1714 (ester); δ (300 MHz, C HCl )
.21 (6H, s, 2 × CH ), 1.48 [9H, s, C(CH ) ], 1.52 [9H, s,
(KBr)/cm
2
max
1
1
H
3
Alkylation of pyroglutamate ester urethanes at C-4 is not
as simple a process as had been previously thought and it is
evident from the variation between our results and those of
Ezquerra, that subtle changes in reaction conditions can alter
diastereoisomeric ratios considerably. However, although we
had improved cis diastereoselectivity by using solvents of
low relative permittivity, we had yet to achieve complete dia-
stereoselectivity in these reactions except in the case of the
trans specificity previously discovered by Baldwin et al. for the
3
3 3
C(CH ) ], 1.92 (1H, dd, J 13.3, J3R,2 4.3, H3R), 2.19 (1H, dd,
3
3
3R,3S
J3S,3R 13.3, J3S,2 9.7, H-3S), 4.41 (1H, dd, J 9.7, J2,3R 4.3, H-2);
2,3S
2
δ (75.5 MHz, C HCl ) 25.1 (CH ), 25.7 (CH ), 27.7 [C(CH ) ],
C
3
3
3
3 3
3
1
6.5 (C-3), 41.4 (C-4), 56.3 (C-2), 82.0 and 83.0 [2 × OC(CH ) ],
49.6 (urethane), 170.5 (ester) and 178.2 (C-5). tert-Butyl
3 3
(
2S,4R)-N-(tert-butoxycarbonyl)-4-methylpyroglutamate 8 was
the second compound from the column, a white solid (0.63 g,
2
2
4
12%), mp 62–64 ЊC; [α]
D
Ϫ16.9 (c 1.0, CHCl
3
); m/z [ϩ FAB,
benzylation reaction. We were finally able to achieve total cis
ϩ
Ϫ1
NBA] 300 [M ϩ H] ; ν
(film)/cm 1793 (imide/urethane)
max
diastereoselectivity by recourse to the hindered proton source
2
16,17
and 1742 (ester); δ
H
(300 MHz, C HCl ) 1.21 (3H, d, J 7.0,
3
2
,6-di-tert-butylphenol.
When the trans-methylpyroglut-
CH ), 1.48 [9H, s, C(CH ) ], 1.51 [9H, s, C(CH ) ], 1.89 (1H, m,
3
3
3
3 3
amate 8 was reacted with LiHMDS at Ϫ78 ЊC and quenched
with 2,6-di-tert-butylphenol, then the sole product was the cis
epimer 7, obtained in 89% yield. Amending the conditions of
the trans-specific benzylation reaction was now investigated and
the pyroglutamate ester urethane 1 was treated with 1.15
equivalents of LiHMDS and 1.2 equivalents of benzyl bromide
followed by addition of a further 1.3 equivalents of LiHMDS.
H-3R), 2.24 (1H, ddd, J3S,3R 13.5, J3S,4 8.7, J3S,2 1, H-3S), 2.65
2
(
1H, m, H-4), 4.42 (1H, d, J2,3 9.5, H-2); δ (75.5 MHz, C HCl )
C
3
1
8
5.0 (CH ), 27.7 [C(CH ) ], 30.4 (C-3), 36.2 (C-4), 57.4 (C-2),
3 3 3
2.0 and 82.9 [2 × OC(CH ) ], 149.2 (urethane), 170.1 (ester)
3
3
and 175.7 (C-5). Irradiation at the methyl resonance (1.21 ppm)
caused enhancement of H-3S (2.24 ppm) and the same reson-
ance was enhanced on irradiation at H-2 (4.42 ppm). The third
compound from the column was tert-butyl (2S,4S)-N-(tert-
butoxycarbonyl)-4-methylpyroglutamate 7 which was obtained
2
,6-Di-tert-butylphenol was finally added and the sole
monoalkylated product of the reaction, obtained in 63% yield
was now the cis product 20 accompanied by ca. 9% of the
dialkylated product 21.
2
2
as a white solid (2.88 g, 55%), mp 68–69 ЊC; [α] Ϫ44.8 (c 1.12,
D
6
b
18
CHCl ) [lit. mp 54–56 ЊC, [α]D Ϫ6.1; lit. mp 69–71 ЊC,
[
3
1
13
α] Ϫ44.8 (c 1.12, CHCl )].‡ The H and C NMR spectra of
D 3
Experimental
Melting points were determined on a Kofler hot-stage appar-
this compound were identical to those of a sample obtained
using the method in Scheme 1 and NOE experiments were
6
also in keeping with the structure. A single crystal X-ray struc-
ture for this compound has been reported in our preliminary
atus and are uncorrected. Optical rotations (given in units of
Ϫ1
Ϫ2
Ϫ1
1
0
deg cm g ) were measured on a Perkin-Elmer PE241
1
communication and lodged with the CCDC.†
polarimeter using a 1 dm path length micro cell. IR spectra
were recorded on a Perkin-Elmer 1720 Fourier transform
1
Alkylation of tert-butyl (2S,4S)-N-tert-
butoxycarbonylpyroglutamate 1 with tert-butyl bromoacetate
instrument. H NMR spectra were recorded on Bruker
DPX300 (300 MHz) and AMX500 (500 MHz) Fourier trans-
13
6
form instruments. J values are given in Hz. C NMR spectra
tert-Butyl (2S)-N-tert-butoxycarbonylpyroglutamate 1 (0.200
1
(
(
broad band H decoupled) were recorded on a Bruker DPX300
75.5 MHz) Fourier transform instrument. Distortionless
g, 0.70 mmol) was dissolved in tetrahydrofuran (2 ml) under
nitrogen with stirring. The solution was cooled to Ϫ78 ЊC and
LiHMDS (1.0 M in tetrahydrofuran, 0.77 ml, 0.77 mmol) was
added. After stirring for 1 h at Ϫ78 ЊC, tert-butyl bromoacetate
(0.125 ml, 0.84 mmol) was added dropwise and stirring was
continued at Ϫ78 ЊC for a further 2 h. The reaction was
quenched with saturated aqueous ammonium chloride and
allowed to warm to room temperature. The crude product was
extracted into ethyl acetate, the combined organic layers were
washed with water and saturated aqueous sodium chloride, and
enhancement polarisation transfer (DEPT) experiments were
13
used to help assign C NMR resonances. Either tetramethyl-
silane (0.00 ppm) or residual solvent peaks were used as internal
references in the NMR spectra unless otherwise stated. Mass
spectra were recorded on Kratos MS80F and MS25 double
focusing spectrometers by Dr A. Abdul-Sada (Sussex). 3-NBA
refers to 3-nitrobenzyl alcohol. Accurate mass measurements
were recorded by the EPSRC National Mass Spectrometry
Service, Swansea. Microanalyses were performed by Medac Ltd
(
Brunel). Column chromatography was performed using Fluka
silica gel 60 (200–400 mesh ASTM). Petroleum ether refers to
that fraction boiling between 60–80 ЊC.
6
‡
We reported mp 54–56 ЊC, [α] Ϫ6.1 (c 1.12, CHCl ) for a sample of
D
3
18
the cis isomer 7 prepared as in Scheme 1. Subsequently we found that
a sample of this compound, prepared by the method of Scheme 1 had
Alkylation of tert-butyl (2S)-N-tert-
butoxycarbonylpyroglutamate 1 with methyl iodide in THF
mp 69–71 ЊC, [α]D Ϫ44.8 (c 1.12, CHCl ). Both samples were prepared
3
from samples of enaminone 2 with comparable [α] values and had
D
identical spectra. We assume that our rotation in ref. 6 was quoted in
error.
6
tert-Butyl (2S)-N-tert-butoxycarbonylpyroglutamate 1 (5 g,
J. Chem. Soc., Perkin Trans. 1, 2001, 2367–2371
2369

View Article Online
2
19
dried (Na SO ). The solvent was removed in vacuo to give an
Refined on F using SHELXL-93. Final R = 0.060 for 1768
2
4
1
orange oil, which was purified by column chromatography on
silica gel using a gradient of ethyl acetate (5–25%) in petroleum
ether as eluant.
reflections with I > 2σ(I ), wR2 = 0.169 for all reflections.§
Alkylation of tert-butyl (2S)-N-tert-butoxycarbonylpyro-
glutamate with methyl triflate in THF
tert-Butyl (2S)-4,4-bis(tert-butoxycarbonylmethyl)-N-tert-
butoxycarbonylpyroglutamate 17 eluted first as a white crystal-
6
25
tert-Butyl (2S)-N-tert-butoxycarbonylpyroglutamate 1 (5 g,
line solid (58 mg, 16%); mp 89.5–91.0 ЊC; [α]
D
ϩ16.5 (c 1.0,
1
7.5 mmol) was dissolved in THF (50 ml) under nitrogen with
CHCl ) (Found: C, 60.7; H, 8.6; N, 2.7. C H NO requires C,
3
26 43
9
Ϫ1
stirring. The solution was cooled to Ϫ78 ЊC and LiHMDS
(1.0 M in THF, 20.17 ml, 20.17 mmol) was added. After stirring
for 1 h at Ϫ78 ЊC, methyl triflate (2.38 ml, 21.05 mmol) was
added dropwise and stirring was continued at Ϫ78 ЊC for a fur-
ther 2 h. The reaction was quenched with saturated aqueous
ammonium chloride and allowed to warm to room temper-
ature. The crude product was extracted into ethyl acetate, and
the combined organic layers were washed with water and brine,
and dried (Na SO ). The solvent was removed in vacuo to give
6
0.8; H, 8.4; N, 2.7%); νmax (KBr)/cm 1761 (imide/urethane)
and 1723 (ester); δH (300 MHz, C HCl ) 1.37, 1.39, 1.45 and
2
3
1
3
1
.47 [4 × 9H, 4 × s, OC(CH ) ], 2.23 (1H, dd, J
.4, H-3S), 2.40 (1H, d, J6A,6B 16.1, H-6A), 2.49 (1H, dd, J3R,3S
4.0, J3R,2 11.0, H-3R), 2.59 (1H, d, J6B,6A 16.1, H-6B), 2.69 (1H,
14.0, J3S,2
3
3
3S,3R
d, J6ЈA,6ЈB 17.0, H-6ЈA), 2.77 (1H, d, J6ЈB,6ЈA 17.0, H-6ЈB) and
2
4
.45 (1 H, dd, J2,3R 11.0, J2,3S 3.4, H-2); δ (75.5 MHz, C HCl )
C
3
2
8.3 [2 × OC(CH ) ], 28.4 [2 × OC(CH ) ], 30.2 (C-3), 41.1
3
3
3 3
2
4
(
8
C-6), 42.0 (C-6Ј), 45.7 (C-4), 57.3 (C-2), 81.8, 81.9, 82.5 and
3.7 [4 × OC(CH ) ], 149.7 (urethane), 169.9, 170.1 and 171.4
an orange oil which was purified by column chromatography on
silica gel using a gradient of ethyl acetate (5–25%) in petroleum
ether as the eluant to give the trans isomer 8 (0.68 g, 13%), and
the cis isomer 7 (3.25 g, 62%) with spectra identical to those of
the compounds prepared above.
3
3
(
esters) and 176.0 (C-5).
tert-Butyl (2S,4S)-N-tert-butoxycarbonyl-4-tert-butoxycarb-
onylmethylpyroglutamate 16 eluted second as a clear oil (39 mg,
2
5
1
4%), mp 81.0–82.0 ЊC; [α] Ϫ20.8 (c 1.0, CHCl ); m/z [CI]
D
3
ϩ
Found: 400.2335. [C H NO ϩ H] requires 400.2341; m/z
ϩve FAB, (3-NBA)] 422 [M ϩ Na] ; ν
imide/urethane) and 1733 (ester); δH (500 MHz, C HCl )
26
33
7
ϩ
Ϫ1
Alkylation of tert-butyl (2S)-N-tert-butoxycarbonylpyro-
glutamate with methyl triflate in toluene
[
(
(film)/cm 1781
max
2
3
6
1
.43 [9H, s, OC(CH ) ], 1.48 [9H, s, O(CH ) ], 1.50 [9H, s,
tert-Butyl (2S)-N-tert-butoxycarbonylpyroglutamate 1 (0.5 g,
3
3
3 3
OC(CH ) ], 2.03 (1H, ddd, J 13.2, J3S,4 11.8, J3S,2 9.8, H-3S),
1.75 mmol) was dissolved in toluene (5 ml) under nitrogen with
stirring. The solution was cooled to Ϫ78 ЊC and LiHMDS
(1.0 M in THF, 2.02 ml, 2.02 mmol) was added. After stirring
for 1 h at Ϫ78 ЊC, methyl triflate (0.238 ml, 2.11 mmol) was
added dropwise and stirring was continued at Ϫ78 ЊC for a
further 2 h. The reaction was quenched with saturated aqueous
ammonium chloride and allowed to warm to room temper-
ature. The crude product was extracted into ethyl acetate, and
the combined organic layers were washed with water and brine,
and dried (Na SO ). The solvent was removed in vacuo to give
3
3
3S,3R
2
.30 (1H, ddd, J3S,2 13.2, J3R,4 8.8, J3R,2 1.3, H-3R), 2.38 (1H,
dd, J6A,6B 17.0, J6A,4 8.8, H-6A), 2.80 (1H, dd, J6B,6A 17.0, J6B,4
3
3
.9, H-6B), 2.96 (1H, dddd, J4,3S 11.8, J4,3R 8.8, J4,6A 8.8, J4,6B
.9, H-4) and 4.43 (1H, dd, J 1.3, J2,3S 9.8, H-2); δC
2,3R
2
(
75.5 MHz, C HCl ) 28.3 [OC(CH ) ], 28.5 [OC(CH ) ], 28.9
3 3 3 3 3
(
C-3), 31.4 [OC(CH ) ], 36.3 (C-6), 38.8 (C-4), 58.2 (C-2),
3 3
8
1.6, 82.8 and 83.8 [3 × OC(CH ) ], 149.7 (urethane), 170.6
3 3
and 170.8 (2 × ester) and 174.5 (C-5). Selective irradiation of
H-3S (2.03 ppm) led to a 24.2% enhancement in H-3R (2.30
ppm), a 2.8% enhancement in H-6A (2.38 ppm) and a 10.0%
enhancement H-2 (4.43 ppm). Selective irradiation of H-6B
2
4
an orange oil. The crude product was purified by column
chromatography on silica gel using a gradient of ethyl acetate
(5–25%) in petroleum ether as eluant to give the trans isomer 8
(0.022 g, 4%) and the cis isomer 7 (0.382 g, 73%) with spectra
identical to those of the compounds prepared above.
(
2.80 ppm) led to a 27.3% enhancement in H-6A (2.38 ppm)
and a 6.0% enhancement in H-4 (2.96 ppm). Selective irradi-
ation of H-2 (4.43 ppm) led to a 4.8% enhancement in H-3S
(
2.03 ppm).
tert-Butyl (2S,4R)-N-tert-butoxycarbonyl-4-tert-butoxycarb-
Epimerisation of tert-butyl (2S,4R)-N-(tert-butoxycarbonyl)-4-
methylpyroglutamate
onylmethylpyroglutamate 15 eluted last as a white crystalline
2
5
solid (156 mg, 56%), mp 114–119 ЊC; [α]
D
ϩ2.7 (c 1.0, CHCl3)
tert-Butyl (2S,4R)-N-(tert-butoxycarbonyl)-4-methylpyroglut-
amate 8 (0.175 g, 0.585 mmol) was dissolved in THF (5 ml)
under nitrogen with stirring. The solution was cooled to Ϫ78 ЊC
and LiHMDS (1.0 M in THF, 0.80 ml, 0.80 mmol) was added.
After stirring for 1 h at Ϫ78 ЊC, 2,6-di-tert-butylphenol (0.25 g,
(
8
Found: C, 59.9; H, 8.3; N, 3.4. C H NO requires C, 60.1; H,
20
33
7
ϩ
.3; N, 3.5%); m/z [ϩ FAB (3-NBA)] 422 [M ϩ Na] ; ν (film)/
max
Ϫ1
cm 1764 (imide), 1744 (ester) and 1715 (urethane); δ (500
MHz, C HCl ) 1.43 [9H, s, OC(CH ) ], 1.47 [9H, s, O(CH ) ],
H
2
3
3
3
3 3
1
6
.50 [9H, s, OC(CH ) ], 1.65 (1H, ddd, J
13.4, J3R,4 8.1, J3R,2
3
3
3R,3S
1
.23 mmol) was added and stirring was continued at Ϫ78 ЊC for
.8, H-3R), 2.36 (1H, dd, J6A,6B 16.6, J6A,4 3.8, H-6A), 2.62 (1H,
ddd, J3S,3R 13.4, J3S,4 9.2, J3S,2 8.9, H-3S), 2.83 (1H, dd, J6B,6A
a further 30 min. Saturated aqueous ammonium chloride was
added to the mixture and the reaction was allowed to warm to
room temperature. The crude product was extracted into ethyl
acetate and the combined organic layers were washed with
water and brine, and dried (Na SO ). The solvent was removed
1
8
6.6, J6B,4 10.4, H-6B), 2.93 (1H, dddd, J4,6B 10.4, J4,3S 9.2, J4,3R
.1, J4,6A 3.8, H-4) and 4.39 (1H, dd, J 8.9, J2,3R 6.8, H-2);
2,3S
2
δ (75.5 MHz, C HCl ) 28.3 [3 × OC(CH ) ], 28.5 (C-3), 37.9
C
3
3 3
2
4
(
C-6), 39.9 (C-4), 58.5 (C-2), 81.7, 82.7 and 84.0 [3 ×
in vacuo to give an orange oil. The crude product was purified
by column chromatography on silica gel using a gradient of
ethyl acetate (5–25%) in petroleum ether as eluant to give the cis
isomer 7 (0.156 g, 89%) as the sole product of the reaction.
OC(CH ) ], 149.8 (urethane), 170.7 and 171.0 (2 × ester) and
3
3
1
1
74.5 (C-5). Selective irradiation of H-6A (2.36 ppm) led to a
.7% enhancement in H-3R (1.65 ppm), a 26.8% enhancement
in H-6B (2.83 ppm) and a 1.0% enhancement in H-4 (2.93
ppm). Selective irradiation of H-2 (4.39 ppm) led to a 5.0%
enhancement in H-3S (2.62 ppm) and a 1.8% enhancement in
H-4 (2.93 ppm).
Reaction of tert-butyl (2S)-N-tert-butoxycarbonylpyroglutamate
with benzyl bromide
Method A—without 2,6-di-tert-butylphenol. tert-Butyl (2S)-
6
N-tert-butoxycarbonylpyroglutamate 1 (0.5 g, 1.75 mmol) was
dissolved in THF (5 ml) under nitrogen with stirring. The
Crystal data—compound 15. C H NO , M = 399.5, mono-
20
33
7
clinic, space group P21, a = 5.634(7),3 b = 16.312(6), c =
1
1.909(6) Å, β = 94.20(9)Њ, V = 1092(2) Å , Z = 2, D = 1.22
calc
§
CCDC reference number 167665. See http://www.rsc.org/suppdata/
Ϫ3
Ϫ1
Mg m , µ(Mo-Kα) = 0.09 mm , T = 173 K. Nonius CAD4,
2
p1/b1/b106451g/ for crystallographic files in .cif or other electronic
format.
196 total reflections measured; 1998 unique (Rint = 0.061).
2
370 J. Chem. Soc., Perkin Trans. 1, 2001, 2367–2371

View Article Online
2
2
7c
solution was cooled to Ϫ78 ЊC and LiHMDS (1.0 M in THF,
.02 ml, 2.02 mmol) was added. After stirring for 1 h at Ϫ78 ЊC,
D
3
(0.416 g, 63%), mp 127–129 ЊC; [α] ϩ50.8 (c 1.01, CHCl ) [lit.
22
2
D
3
mp 130–131 ЊC, [α] ϩ66 (c 0.2, CHCl )]. The spectra were
7c
benzyl bromide (0.25 ml, 2.1 mmol) was added dropwise and
stirring was continued at Ϫ78 ЊC for a further 2 h. Saturated
aqueous ammonium chloride was added and the mixture was
allowed to warm to room temperature. The crude product was
extracted into ethyl acetate and the combined organic layers
were washed with water and brine, and dried (Na SO ). The
identical with those of an authentic sample.
Acknowledgements
We thank the BBSRC/EPSRC for a fellowship (to J.-D. C.);
the EPSRC for a studentship (to J. E. S. D), Dr A. Abdul
Sada for low resolution mass spectra, the EPSRC National
Mass Spectrometry Service, Swansea for accurate mass
measurements and Dr A. G. Avent for 500 MHz NMR spectra.
2
4
solvent was removed in vacuo to give an orange oil. The crude
product was purified by column chromatography on silica gel
using a gradient of ethyl acetate (5–25%) in petroleum ether as
eluant to give tert-butyl (2S,4R)-N-(tert-butoxycarbonyl)-4-
benzylpyroglutamate 18 (0.495 g, 72%), as white crystals, mp
2
2
4
References
1
[
25–126 ЊC; [α]
D
D
Ϫ52.6 (c 1.02, CHCl ) [lit. mp 125.5–126.5,
3
22
α] Ϫ49.2 (c 0.9, CHCl )]. The spectra were in keeping with
those reported in the literature.
3
1 Part of this work has been reported in preliminary form in J.-D.
Charrier, J. E. S. Duffy, P. B. Hitchcock and D. W. Young,
Tetrahedron Lett., 1998, 39, 2199.
4
2
3
4
See for example J. K. Thottathill, J. L. Moniot, R. H. Mueller,
M. K. Y. Wong and T. P. Kissick, J. Org. Chem., 1986, 51, 3140.
J. Ezquerra, C. Pedregal, A. Rubio, B. Yruretagoyena, A. Escribano
and F. Sanchez-Ferrando, Tetrahedron, 1993, 49, 8665.
J. E. Baldwin, T. Miranda, M. Moloney and T. Hokelek,
Tetrahedron, 1989, 45, 7459.
Method B—with 2,6-di-tert-butylphenol. tert-Butyl (2S)-N-
tert-butoxycarbonylpyroglutamate 1 (0.5 g, 1.75 mmol) was
dissolved in THF (5 ml) under nitrogen with stirring. The
solution was cooled to Ϫ78 ЊC and LiHMDS (1.0 M in THF,
.02 ml, 2.02 mmol) was added. After stirring for 1 h at Ϫ78 ЊC,
benzyl bromide (0.25 ml, 2.1 mmol) was added dropwise and
stirring was continued at Ϫ78 ЊC for a further 2 h. LiHMDS
1.0 M in THF, 2.28 ml, 2.28 mmol) was added and the reaction
was stirred for 1 h at Ϫ78 ЊC. 2,6-Di-tert-butylphenol (0.724 g,
.51 mmol) was added and stirring was continued at Ϫ78 ЊC for
6
2
5 G. Ostler, A. Soteriou, C. M. Moody, J. A. Khan, B. Birdsall, M. D.
Carr, D. W. Young and J. Feeney, FEBS Lett., 1993, 318, 177.
6
(a) R. A. August, J. A. Khan, C. M. Moody and D. W. Young,
Tetrahedron Lett., 1992, 33, 4617; (b) R. A. August, J. A. Khan,
C. M. Moody and D. W. Young, J. Chem. Soc., Perkin Trans. 1, 1996,
(
3
5
07.
a further 30 min. Saturated aqueous ammonium chloride was
added and the reaction was allowed to warm to room temper-
ature. The crude product was extracted into ethyl acetate and
the combined organic layers were washed with water and brine,
and dried (Na SO ). The solvent was removed in vacuo to give
an orange oil, which was purified by column chromatography
on silica gel using a gradient of ethyl acetate (5–25%) in petrol-
eum ether as eluant. tert-Butyl (2S)-N-(tert-butoxycarbonyl)-
7 (a) C. M. Moody and D. W. Young, Tetrahedron Lett., 1993, 34,
4667; (b) C. M. Moody and D. W. Young, Tetrahedron Lett., 1994,
3
5, 7277; (c) C. M. Moody and D. W. Young, J. Chem. Soc., Perkin
Trans. 1, 1997, 3519.
8
9
C. M. Moody, B. A. Starkmann and D. W. Young, Tetrahedron Lett.,
2
4
1
994, 35, 5485.
(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;
and its accompanying supplementary material.
4
,4-dibenzylpyroglutamate 21 eluted first as a yellow oil (0.073
22
10 E. Coudert, F. Acher and R. Azerad, Synthesis, 1997, 863.
g, 9%); [α]
D
3
Ϫ18.8 (c 0.47, CHCl ) (Found [CI] 466.2593.
ϩ
1
1
1 H. M. Kagan and A. Meister, Biochemistry, 1966, 5, 2423.
2 A. T. McPhail, G. A. Sim, J. D. M. Asher, J. M. Robertson and J. V.
Silverton, J. Chem. Soc. (B), 1966, 18.
[
[
C H NO ϩ H] requires 466.2592); m/z [ϩ FAB, NBA] 488
28 35 5
ϩ ϩ Ϫ1
M ϩ Na] and 466 [M ϩ H] ; ν
(KBr)/cm 1788 (imide/
max
2
urethane), 1737 (ester) and 1723; δH (300 MHz, C HCl ) 1.22
13 N. Langlois and A. Rojas, Tetrahedron Lett., 1993, 34, 2477 and
3
[
9H, s, C(CH ) ], 1.39 [9H, s, C(CH ) ], 1.85 (1H, dd, J
13.5,
corrigendum N. Langlois and A. Rojas, Tetrahedron Lett., 1993, 34,
3
3
3
3
3R,3S
6
156.
4 R. W. Armstrong and J. A. DeMattei, Tetrahedron Lett., 1991, 32,
749.
J3R,2 7.7, H-3R), 2.17 (1H, dd, J3S,3R 13.5, J3S,2 9.4, H-3S),
1
1
2
.60 (1H, d, JAB 13.1, 4-CH H C H ), 2.75 (1H, d, J 13.7,
A
B
6
5
CD
5
4
-CH H C H ), 3.17 (1H, dd, J
9.4, J2,3R 7.7, H-2), 3.18
C
D
6
5
2,3S
5 A. I. Meyers, M. A. Seefeld, B. A. Lefker, J. F. Blake and P. G.
Willard, J. Am. Chem. Soc., 1998, 120, 7429.
16 S. Takano, W. Uchida, S. Hatakeyama and K. Ogasawara, Chem.
Lett., 1982, 733.
(
1H, d, JAB 13.1, 4-CH H C H ), 3.32 (1H, d, J
13.7,
A
B
6
5
CD
4
-CH H C H ) and 7.16–7.31 (10H, m, ArH); δ (75.5 MHz,
C
D
6
5
C
2
C HCl ) 27.5 and 27.7 [2 × C(CH ) ], 28.1 (C-3), 42.8 (4-
3
3 3
1
7 S. Hanessian, U. Reinhold and G. Gentile, Angew. Chem., Int. Ed.
Engl., 1997, 36, 1881.
CH C H ), 45.0 (4-CH C H ), 52.1 (C-4), 56.8 (C-2), 81.5 and
2
6
5
2
6
5
8
2.9 [2 × OC(CH ) ], 126.7, 127.0, 128.3, 128.4, 129.7, 130.6,
3 3
1
1
8 B. A. Starkmann, DPhil Thesis, University of Sussex, 1996.
9 SHELXL-93—Program for Crystal Structure Refinement G. M.
Sheldrick, Institut für Anorganische Chemie der Universität,
Tammanstrasse 4, D-3400 Göttingen, Germany, 1993.
1
36.0 and 136.6 (8 × ArC), 148.6 (urethane), 170.0 (ester)
and 176.8 (C-5). Finally, tert-butyl (2S,4S)-N-(tert-butoxy-
carbonyl)-4-benzylpyroglutamate 20 eluted as white crystals
J. Chem. Soc., Perkin Trans. 1, 2001, 2367–2371
2371