Synthesis of protected γ-carboxyglutamates and γ-acylglutamates by rearrangement of N,N-diacylglutamates

Article abstract of DOI:10.1039/b503900b

A new method for γ-acylation of protected glutamic acids, involving intramolecular rearrangement of an acyl urethane, has been devised to prepare the protected γ-carboxyglutamates 7, 9 and 11 and the protected 4-acylglutamates 15 and 22 from N,N-bisurethanes or N-acyl-N-urethanes of general structure 1. When the formylurethane 17 was used in the reaction, then the intermediate 18 in the intramolecular rearrangement was obtained. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b503900b

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A R T I C L E
Synthesis of protected c-carboxyglutamates and c-acylglutamates by
rearrangement of N,N-diacylglutamates†
Anthony G. Avent, Heather M. E. Duggan and Douglas W. Young*
Department of Chemistry, University of Sussex, Falmer, Brighton, UK BN1 9QJ
Received 17th March 2005, Accepted 20th April 2005
First published as an Advance Article on the web 19th May 2005
A new method for c-acylation of protected glutamic acids, involving intramolecular rearrangement of an acyl
urethane, has been devised to prepare the protected c-carboxyglutamates 7, 9 and 11 and the protected
4-acylglutamates 15 and 22 from N,N-bisurethanes or N-acyl-N-urethanes of general structure 1. When the formyl-
urethane 17 was used in the reaction, then the intermediate 18 in the intramolecular rearrangement was obtained.
chloride and triethylamine in acetone and thence into the N,N-
bisurethane 6 in 80% yield using di-tert-butyl dicarbonate and
DMAP in acetonitrile. The specific rotation of this compound
Introduction
Methods for direct c-alkylation of protected glutamates have
been remarkably stereoselective.1 c-Acylglutamates have been
was in accord with that of a sample prepared by an alternative
accessed by a variety of indirect methods involving the re-
route.6 We now reacted the bisurethane 6 with NaHMDS in THF
action of a malonate or acylacetate anion on an alanyl-b-
at −40 ◦C to obtain a mixture of diastereoisomers 7 in 53% yield.
carbocation equivalent2 and it has been shown that use of
a 9-(9-phenylfluorenyl)-protecting group will allow protected
The product was isomeric with the starting compound 6 but it
clearly showed an exchangeable NH proton at 4.92 ppm in the
glutamic acids to be directly c-acylated in good yields, using
1H NMR spectrum, and the two proton multiplet at 2.27 ppm
a variety of acyl halides.3 The ready reaction of pyroglutamate
1
for H-4 in the H NMR spectrum of the bisurethane 6 had
urethane esters with nucleophiles at the amide carbonyl group
has prompted us to consider the possibility of the preparation of
c-acylglutamates by intramolecular nucleophilic attack by a c-
glutamate anion 1 on an N-acylurethane group which should be
been replaced by a one proton multiplet at 3.35 ppm in the 1H
NMR spectrum of the product 7. The characteristic bisurethane
absorption at 1793 cm−1 was no longer present in the infra-red
spectrum. It was evident that rearrangement had occurred to
yield the protected c-carboxyglutamate 7.
expected to behave similarly to a mixed anhydride as in Scheme 1.
The bisurethane dimethyl ester 8 was now prepared by the
method of Kokotos et al.7 and reacted with NaHMDS in DMF
at −40 ◦C, as shown in Scheme 3, to give the rearranged product
9 as a mixture of diastereoisomers in 39% yield. The 1H NMR
spectrum of the product exhibited a one proton exchangeable
NH doublet at 4.97 ppm and, instead of the two proton multiplet
for H-4 at 2.40 ppm in the spectrum of the starting bisurethane
6, exhibited a one proton multiplet at 3.32 ppm. Further, the
bisurethane absorption at 1800 cm−1 in the infra-red spectrum
Scheme 1
of 8 was no longer present in the infra-red spectrum of 9. A
final orthogonally protected c-carboxyglutamate derivative was
prepared when the bisurethane 108 was reacted with NaHMDS
in DMF at −40 ◦C to give the product 11 in 58% yield
Results and discussion
1
Because of our interest4 in c-carboxyglutamic acid, formed
in the proteins of the blood clotting cascade, we elected to
test the method by first synthesising a series of orthogonally
protected derivatives of c-carboxyglutamate from symmetrical
N,N-bisurethanes. For our first substrate, we prepared the acid
4 by hydrolysis of the protected pyroglutamate 35 using 1 N
aqueous LiOH in THF, as shown in Scheme 2. The acid 4 was
converted into the c-benzyl ester 5 in 67% yield using benzyl
(Scheme 4). The H NMR spectrum of this compound again
showed an exchangeable NH doublet (4.9 ppm) and a one proton
multiplet for H-4 (3.29 ppm) (compared with a two proton
† Electronic supplementary information (ESI) available: all 1H, 13C
and COSY NMR spectra for compound 18. See http://www.rsc.org/
suppdata/ob/b5/b503900b/
Scheme 3 Reagents and conditions: (i) NaHMDS, DMF, THF, −40 ◦C,
5 h (39%).
Scheme 2 Reagents and conditions: (i) 1N aq LiOH, THF, 30 min, 0 ◦C (96%); (ii) PhCH2Cl, Et3N, acetone, reflux, 4 days (67%); (iii) Boc2O, DMAP,
CH3CN, rt, 72 h (80%); (iv) NaHMDS, THF, −40 ◦C, 2 h (53%).
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 2 7 – 2 3 3 2
2 3 2 7
©

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in a spin saturation transfer experiment, six signals at 4.08,
3.80, 3.44, 3.40, 3.30 and 3.12 ppm were affected and so were
evidently due to OH or NH protons. Further, an NOE was
observed for five signals integrating as one proton between 5.93
and 5.62 ppm in this experiment. Use of saturation transfer
experiments, irradiating the signals between 5.93 and 5.62 ppm
in turn, suggested that these signals were due to three pairs of
rotamers. There were six OMe signals at ca. 3.7 ppm integrating
for six protons. The data so far were compatible with structure
18 which might exist as four diastereoisomers, each having the
possibility of existing as two rotamers, a well known10 property
of proline-type urethanes. Three of these are apparent in the
1H NMR spectrum, each having a rotational isomer (labelled
1, 1ꢀ, 2, 2ꢀ and 3, 3ꢀ in spectrum 1 in the ESI†). An [(M −
H2O) + H]+ ion in the mass spectrum was in keeping with
the mass spectrum of a carbinolamine of this type which we
had prepared by reduction of a pyroglutamic acid derivative.11
When C2H3O2H was added to the C2HCl3 solution, the 1H
NMR spectrum simplified (spectrum 2 in ESI†) and 2D COSY
double quantum filtered spectra were run at 253 K (ESI, spectra
4–7†). These clearly showed that the carbinolamine signals
for proton H-5 were coupled to the signals assigned to H-
4 (spectrum 5), that the signals for H-4 were coupled to the
signals assigned to H-3A and H-3B (spectrum 6), and that
the signals assigned to H-2 were coupled to H-3A and H-3B
(spectrum 7). As expected for a compound with such possibilities
for rotational- and diastereoisomerism, the 13C NMR spectrum
(ESI, spectrum 3†) was very complex but the data, supported
by DEPT experiments, were in accord with the structure 18.
All of the data were in accord with the product of attempted
formyl migration being the compound 18, which is the structure
for the intermediate in the intramolecular acylation reaction.
This would imply that the intermediate is more stable when N-
formylurethane is the electrophile for the 4-anion and may be
due to steric considerations.
Scheme 4 Reagents and conditions: (i) NaHMDS, DMF, THF, −40 ◦C,
6 h (58%).
multiplet for H-4 at 2.34 ppm in 10). The bisurethane absorption
in the infra-red spectrum was no longer present.
Having shown the method to be viable for preparing c-
carboxyglutamates from N,N-bisurethanes, we now turned to
investigating the use of N-acylurethanes as substrates for the
reaction. Dimethyl N-acetylglutamate 13 was first prepared
from the dimethyl ester 129 and converted into the urethane
14 in 74% yield using di-tert-butyl dicarbonate and DMAP in
acetonitrile, as shown in Scheme 5. When this was reacted with
NaHMDS in DMF at −40 ◦C, the product 15 was obtained
1
in 20% yield. The H and 13C NMR spectra in C2HCl3 were
compatible with the keto structure 15a and there was no
2
chromophore in neutral methanol. However when H2O was
added to the C2HCl3 solution to exchange the NH group, the
spectrum underwent wholesale change, eventually giving a clean
spectrum which could be interpreted as being due to the enol
form 15b. The spectrum assigned to 15a had a one proton
multiplet at 5.18 ppm for H-4 which was not present in the
spectrum assigned to 15b. Most convincingly, there was long
range coupling between the acetate methyl and both protons H-
3 in the spectrum assigned to 15b. This suggested an intervening
double bond, and the 13C spectrum of 15b was in accord with
this, exhibiting a signal at 106.2, typical of a quaternary olefinic
carbon. A chromophore became evident (kmax 282 nm) when
sodium hydroxide was added to a methanolic solution of the
product.
Benzoylation of the diester 129 with benzoyl chloride and
triethylamine in acetonitrile gave the amide 20 in 51% yield,
as shown in Scheme 7. Urethanylation as before gave the
compound 21 in 91% yield. This was now subjected to a reaction
with NaHMDS in DMF at −40 ◦C to give a product in 32%
yield. This had the spectral characteristics expected of the
product 22 and had kmax (MeOH) 247 and 320 nm.
We have shown that the intramolecular route outlined in
Scheme 1 for the preparation of c-carboxyglutamates and 4-
acylglutamates is viable, although when the migrating group is
formyl, the intermediate 18 in the rearrangement is isolated.
Ready enolisation of the products has been shown by spec-
troscopic experiments. The method presents a new route to
For the precursor, 17, of the N-formyl compound 19, we
used the route outlined in Scheme 6. Formylation of dimethyl
glutamate 129 using formic acetic anhydride as solvent and
reagent gave the amide 16 in 47% yield and this was treated
with Boc2O and DMAP in acetonitrile to give 17 in 57% yield.
When the precursor 17 was treated with NaHMDS in DMF
at −40 ◦C, we could see no evidence for the presence of the
expected product 19, there being no formyl CH signal in the 1H
NMR spectrum. The 1H NMR spectrum in C2HCl3 (spectrum
1 in the ESI†) was complex but integration suggested that it
was an isomer of the starting material 17 and of the desired
product. When the signal due to water in C2HCl3 was irradiated
Scheme 5 Reagents and conditions: (i) (a) Et3N, CH3CN, rt, (b) CH3COCl, CH3CN, rt, overnight (44%); (ii) Boc2O, DMAP, CH3CN, rt, 3 days
(74%); (iii) NaHMDS, DMF, THF, −40 ◦C, 3 h (20%).
Scheme 6 Reagents and conditions: (i) (a) Et3N, CH2Cl2, (b) HCO2Ac, 0 ◦C, 15 min then rt, 2 h (47%); (ii) Boc2O, DMAP, CH3CN, rt, overnight
(57%); (iii) NaHMDS, DMF, −40 ◦C, 5 h (40%).
2 3 2 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 2 7 – 2 3 3 2

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Scheme 7 Reagents and conditions: (i) (a) Et3N, CH3CN, 0 ◦C, 15 min, (b) PhCOCl, 1 h, 0 ◦C then rt, 1 h (51%); (ii) Boc2O, DMAP, CH3CN, rt,
overnight (91%); (ii) NaHMDS, DMF, THF, −40 ◦C, 5 h (32%).
such compounds although yields are, so far, less synthetically
useful than the route3 involving direct acylation of 9-(9-
phenylfluorenyl)-protected glutamates.
heated at reflux for 4 days. The mixture was allowed to cool
and the white deposit was removed by filtration to give a yellow
solution. The solvent was removed in vacuo to give a brown
oil which was dissolved in ethyl acetate (200 ml) and extracted
with saturated aqueous sodium hydrogen carbonate (3 × 50 ml).
The aqueous layer was extracted with ethyl acetate (50 ml). The
combined organic layers were dried (Na2SO4) and the solvents
were removed in vacuo to give a yellow clear oil which was
purified by flash column chromatography on silica gel using
diethyl ether–petroleum ether (1 : 4) as eluent to give 1-tert-
butyl 5-benzyl (2S)-2-tert-butoxycarbonylaminopentanedioate
Experimental
Melting points were determined on a Kofler hot stage apparatus
and are uncorrected. Optical rotations (given in units of
10−1deg cm2 g−1) were measured on a Perkin Elmer PE241
polarimeter using a 1 dm path length cell. IR spectra were
recorded on a Perkin Elmer Spectrum 1710 FT-IR spectrometer
and UV spectra on a ATI Unicam UV2-00 Fourier transform
29
5
5 as a clear colourless oil (5.79 g, 67%); [a]D
+10.03 (c 1,
1
CHCl3), (lit13 [a]D +9 (c 1, CHCl3)); m/z [+ve FAB (3-NBA)]
394 ([M + H]+); mmax (nujol)/cm−1 3386 (NH), 1744 (ester) and
1720 (urethane); dH (300 MHz, C2HCl3) 7.27 (5H, s, ArH), 5.01
(3H, br s, OCH2Ar and NH), 4.14 (1H, dd, J2,NH 7.9, J2,3 12.9,
H-2), 2.37 (2H, m, H-4), 2.11 (1H, m, H-3A), 1.85 (1H, m,
H-3B), 1.38 (9H, s, C(CH3)3) and 1.31 (9H, s, C(CH3)3); dC
(75.5 MHz, C2HCl3) 173.1, 171.1 (ester), 156.9 (urethane), 136.2,
128.9, 128.6 and 128.6 (Ar), 82.6 and 80.2 (2 × OC(CH3)3),
66.8 (OCH2Ar), 53.7 (C-2), 30.7 (C-4), 28.7 (C(CH3)3), 28.4
(C(CH3)3) and 28.3 (C-3).
25
scanning spectrophotometer. H NMR spectra were recorded
on Bruker DPX300 (300 MHz) and AMX500 (500 MHz)
Fourier transform instruments. J values are given in Hertz.
13C NMR spectra (1H decoupled) were recorded on Bruker
DPX300 (75.5 MHz) and AMX500 (125.8 MHz) Fourier
transform instruments. DEPT experiments were used to help
assign 13C resonances where necessary. Low resolution mass
spectra were recorded by Dr A. Al Sada on Kratos MS-80RF
and MS25 double focusing spectrometers. High resolution mass
measurements were performed by the EPSRC Central Mass
Spectrometry Service at Swansea. Column chromatography was
performed using Fluka silica gel 60 (230–400 mesh). Petroleum
ether refers to that fraction of hexanes of bp 60–80 ◦C.
1-tert-Butyl 5-benzyl (2S)-2-(N,N-bis-tert-butoxycarbonyl)-
aminopentanedioate (6)
A solution of 1-tert-butyl 5-benzyl (2S)-2-tert-butoxycarbonyl-
aminopentanedioate 5 (159 mg, 0.404 mmol) in acetonitrile
(2 ml) was stirred at room temperature under nitrogen and
cooled to 0 ◦C. 4-Dimethylaminopyridine (14 mg, 0.115 mmol)
was added followed by a solution of di-tert-butyl dicarbonate
(115 mg, 0.525 mmol) in acetonitrile (1.8 ml). The mixture was
warmed to room temperature and stirred for 72 h. The solvent
was removed to give a dark brown oil which was purified by
flash column chromatography on silica gel, using diethyl ether–
petroleum ether (1 : 4) as eluent to give 1-tert-butyl 5-benzyl
(2S)-2-(N,N-bis-tert-butoxycarbonyl)-aminopentanedioate 6 as
1-tert-Butyl (2S)-2-tert-butoxycarbonylaminopentanedioate (4)
A
solution of 1,2-di-tert-butyl (2S)-5-oxopyrrolidinedi-
carboxylate 35 (6.77 g, 23.74 mmol) in THF (130 ml) was cooled
to 0 ◦C and 1 N aqueous lithium hydroxide (27.1 ml) was added
dropwise with vigorous stirring over 15 min. The reaction was
stirred for a further 15 min at 0 ◦C. Ethyl acetate (160 ml)
and saturated aqueous sodium hydrogen carbonate (160 ml)
were added. The organic layer was separated and extracted with
further saturated aqueous sodium hydrogen carbonate (40 ml).
The aqueous layers were combined and acidified at 0 ◦C to
pH 4–4.5 using 10% aqueous citric acid. The aqueous layer was
extracted with ethyl acetate (5 × 100 ml). The organic layer was
dried (MgSO4) and the solvent was removed in vacuo to give 1-
tert-butyl (2S)-tert-butoxycarbonylamino◦pentanedioate 4 as a
white solid (7.53 g, 96%); mp 103.3–105.5 C, (lit12 102–105 ◦C);
m/z [+ve FAB (3-NBA)] 327 ([M + Na]+) and 304 ([M + H]+);
22
a clear colourless oil (160 mg, 80%); [a]D −27.3 (c 1, CHCl3),
25
(lit6 [a]D −23.0 (c 1.3, EtOH)); m/z [+ve FAB (3-NBA)] 516
([M + Na]+) and 494 ([M + H]+); mmax (film)/cm−1 1793 (w,
bisurethane), 1739 (ester) and 1702 (urethane); dH (300 MHz,
C2HCl3) 7.26 (5H, s, ArH), 5.03 (2H, s, OCH2Ar), 4.72 (1H,
dd, J2,3A 9.3, J2,3B 3.6, H-2), 2.37 (3H, m, H-4 and H-3A), 2.09
(1H, m, H-3B), 1.43 (18H, s, 2 × C(CH3)3) and 1.36 (9H, s,
C(CH3)3); dC (75.5 MHz, C2HCl3) 173.0 and 169.6 (ester), 152.7
(urethane), 136.3, 128.9 and 128.5 (Ar), 83.3 (2 × OC(CH3)3),
81.7 (OC(CH3)3), 66.6 (OCH2Ar), 58.5 (C-2), 31.4 (C-4), 28.3
(2 × C(CH3)3), 28.3 (C(CH3)3) and 24.9 (C-3).
−1
mmax (nujol)/cm 3380 (NH), 1744 (ester) and 1701 (acid); dH
(300 MHz, C2HCl3) 10.40 (1H, br s, OH), 6.29, 5.25 (1H, d, JNH,2
8.0, NH), 4.15 (1H, dd, J2,NH 8.0, J2,3 13.0, H-2), 2.45–2.27 (2H,
m, H-4), 2.09 (1H, m, H-3A), 1.84 (1H, m, H-3B), 1.39 (9H, s,
OC(CH3)3) and 1.36 (9H, s, OC(CH3)3); dC (75.5 MHz, C2HCl3)
179.8, 172.4 (acid and ester), 156.2 (urethane), 82.8 and 81.2
(2 × OC(CH3)3), 53.6 (C-2), 30.5 (C-4 and C-3), 28.6 and 28.3
(2 × C(CH3)3).
1-Benzyl 5-tert-butyl (2S,4RS)-4-tert-butoxycarbonyl-2-tert-
butoxycarbonylaminopentanedioate (7)
A solution of 1-tert-butyl 5-benzyl (2S)-2-(N,N-bis-tert-butoxy-
carbonyl)-aminopentanedioate 6 (147 mg, 0.298 mmol) in
THF (1 ml) was stirred at −30 ◦C under nitrogen. Sodium
hexamethyldisilazide (1 M in THF, 0.596 ml, 0.596 mmol)
was added slowly over 30 min and the mixture was stirred
at −30 ◦C for a further 2 h. Ethyl acetate (3 ml) and 5%
aqueous sodium dihydrogen phosphate (5 ml) were added and
the reaction was allowed to warm to room temperature. The
1-tert-Butyl 5-benzyl (2S)-2-tert-butoxycarbonylamino-
pentanedioate (5)
Triethylamine (3.38 ml, 24.29 mmol) was added to a solution
of 1-tert-butyl (2S)-2-tert-butoxycarbonylaminopentanedioate
4 (6.7 g, 22.1 mmol) in acetone (45 ml) at room temperature
under nitrogen. The solution was stirred for 1 h. Benzyl chloride
(2.8 ml, 24.3 mmol) was added slowly and the solution was
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 2 7 – 2 3 3 2
2 3 2 9

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aqueous layer was extracted with ethyl acetate (3 × 5 ml).
The organic layers were combined and dried (Na2SO4), and the
solvent was removed in vacuo to give a clear oil. Purification by
flash chromatography on silica gel using diethyl ether–petroleum
ether (1 : 4) as eluent gave 1-benzyl 5-tert-butyl (2S,4RS)-4-tert-
butoxycarbonyl-2-tert-butoxycarbonylaminopentanedioate 7 as
a clear oil (77 mg, 53%); m/z [CI] (found 494.2759; [C26H39NO8 +
H]+ requires 494.2754); m/z [+ve FAB (3-NBA)] 517 ([M +
Na]+) and 494 ([M + H]+); mmax (film)/cm−1 3392 (NH) and
1727 (ester); dH (300 MHz, C2HCl3, mixture of diastereoisomers)
7.29 (5H, br, ArH), 5.10 (2H, 2 × overlapping AB, JAB 12,
OCH2Ar), 4.92 (1H, d, JNH,2 8.5, NH), 4.05 (1H, ddd, J2,NH 8.5,
J2,3A 6.3, J2,3B 1.7, H-2), 3.35 (1H, m, H-4), 2.37 (1H, ddd, J3A,3B
13.9, J3A,2 6.3, J3A,4 2.9, H-3A), 2.04 (1H, m, H-3B) and 1.39–
1.29 (27H, 5 × s, C(CH3)3); dC (75.5 MHz, C2HCl3, mixture of
diastereoisomers) 170.0, 168.3, 167.9, 166.9, 166.4 (ester), 154.7
and 154.2 (urethane), 134.4 and 134.3, 127.5, 127.4, 127.3 (Ar),
82.7, 81.2 and 78.7 (3 × OC(CH3)3), 66.1 (OCH2Ar), 51.6 and
51.3 (C-2), 48.8, 48.5 and 48.3 (C-4), 30.5 and 30.2 (C-3), 27.2,
26.9 and 26.7 (3 × C(CH3)3).
in dry dimethylformamide (1 ml) was stirred under nitro-
gen at −40 ◦C. Sodium hexamethyldisilazide (1 M in THF,
0.144 ml, 0.144 mmol) was slowly added and stirring was
continued at −40 ◦C for 6 h. Ethyl acetate (1 ml) and 5%
aqueous sodium dihydrogen phosphate (2 ml) were added
and the reaction was allowed to warm to room temperature.
The aqueous layer was extracted with ethyl acetate (3 ×
2 ml) and the combined organic layers were dried (Na2SO4),
and the solvent was removed in vacuo to give an orange
oil. This was purified by flash chromatography on silica gel
using ethyl acetate–petroleum ether (15 : 85) as eluent to
give 1-methyl 5-tert-butyl (2S,4RS)-4-tert-butoxycarbonyl-2-
tert-butoxycarbonylaminopentanedioate 11 as a clear colourless
oil (35 mg, 58%); m/z [CI] (found 418.2447; [C20H35NO8
+
H]+ requires 418.2441); m/z [+ve FAB (3-NBA)] 440 ([M +
Na]+) and 418 ([M + H]+); mmax (film)/cm−1 3379 (NH), 1728 (br,
ester) and 1708 (br, urethane); dH (300 MHz, C2HCl3, mixture of
diastereoisomers) 4.90 (1H, d, JNH,2 8.3, NH), 4.0 (1H, m, H-2),
3.66 and 3.65 (3H, 2 × s, OCH3), 3.29 (1H, dd, J4,3A 7.5, J4,3B
1.0, H-4), 2.35 (1H, m, H-3A), 2.03 (1H, m, H-3B), 1.38 (9H, s,
C(CH3)3), 1.37 (9H, s, C(CH3)3) and 1.34 (9H, s, C(CH3)3); dC
(75.5 MHz, C2HCl3, mixture of diastereoisomers) 171.4, 170.5,
170.0, 168.5 and 168.0 (esters), 155.7 (urethane), 82.6 and 80.1
(2 × OC(CH3)3), 52.9 and 52.7 (C-4), 50.1 and 49.9 (C-2), 32.0
and 31.6 (C-3), 28.6, 28.3 and 28.2 (3 × OC(CH3)3).
1,5-Dimethyl (2S,4RS)-4-tert-butoxycarbonyl-2-tert-
butoxycarbonylaminopentanedioate (9)
A
solution of 1,5-dimethyl (2S)-2-(N,N-bis-tert-butoxy-
carbonyl)-aminopentanedioate 87 (33 mg, 0.087 mmol) in dry
dimethylformamide (1 ml) was stirred at −40 ◦C under nitrogen.
Sodium hexamethyldisilazide (1 M in THF, 87 ll, 0.087 mmol)
was added slowly and the yellow solution was left stirring at
Dimethyl (2S)-2-acetylaminopentanedioate (13)
A solution of dimethyl (2S)-2-aminopentanedioate hydrochlo-
ride 129 (200 mg, 0.944 mmol) in acetonitrile (1 ml) was
stirred at room temperature under nitrogen. Triethylamine
(0.39 ml, 2.8 mmol) was added and the solution was cooled to
0 ◦C. Acetyl chloride (0.06 ml, 0.85 mmol) in acetonitrile (1 ml)
was added slowly and the solution was allowed to warm to room
temperature and stirred for 2 h. A further equivalent of acetyl
chloride (0.06 ml, 0.85 mmol) in acetonitrile (1 ml) was added
and the mixture was stirred overnight. The white precipitate
was removed by filtration and the solvent was removed in vacuo
to give a brown oil. The oil was dissolved in water (15 ml)
and extracted with ethyl acetate (3 × 5 ml). The aqueous layer
was acidified to pH 3 with 1 N aqueous hydrochloric acid and
extracted with ethyl acetate (3 × 5 ml). The combined organic
layers were dried (Na2SO4) and the solvent was removed in
vacuo giving dimethyl (2S)-2-acetylaminopentanedioate 13 as
◦
−40 C for 5 h. Ethyl acetate (1 ml) and 5% aqueous sodium
dihydrogen phosphate (1 ml) were added and the reaction was
allowed to warm to room temperature. The aqueous layer
was extracted with ethyl acetate (3 × 2 ml). The organic
layers were combined and dried (Na2SO4), and the solvent was
removed in vacuo to give a clear yellow oil. Purification by
flash column chromatography on silica gel using diethyl ether–
petroleum ether (1 : 4) as eluent gave 1,5-dimethyl (2S,4RS)-4-
tert-butoxycarbonyl 2-tert-butoxycarbonylaminopentanedioate
9 as a clear colourless oil (13 mg, 39%); m/z [CI] (found 376.1972;
[C17H29NO8 + H]+ requires 376.1971); m/z [+ve FAB (3-NBA)]
398 ([M + Na]+) and 376 ([M + H]+); mmax (film)/cm−1 3374
(NH) and 1730 (br, ester); dH (300 MHz, C2HCl3, mixture of
diastereoisomers) 4.97 (1H, d, JNH,2 6.7, NH), 4.30 (1H, m,
H-2), 3.68 (3H, s, OCH3), 3.67 (3H, s, OCH3), 3.32 (1H, dd,
J4,3A 7.1, J4,3B 5.8, H-4), 2.37 (1H, m, H-3A), 2.15 (1H, m, H-
3B), 1.39, 1.38 and 1.37 (18H, 3 × s, C(CH3)3); dC (75.5 MHz,
C2HCl3, mixture of diastereoisomers) 172.8, 169.9 and 167.9
(ester), 155.7 (urethane), 82.9 and 80.4 (2 × OC(CH3)3), 53.0,
52.9, 52.4 and 52.2 (C-2 and C-4), and 31.8 (C-3) and 28.2 (2 ×
C(CH3)3).
23
a colourless oil (91 mg, 44%), [a]D +25.89 (c 1.4, CHCl3); m/z
[ApcI+] (found 218.1029; [C9H15NO5 + H]+ requires 218.1028);
m/z [+ve FAB (3-NBA)] 218 ([M + H]+); mmax (film)/cm−1 3287
(NH), 1740 (ester) and 1658 (amide); dH (300 MHz, C2HCl3)
6.22 (1H, d, JNH,2 7.0, NH), 4.56 (1H, ddd, J2,3A 12.9, J2,NH 7.0,
J2,3B 5.1, H-2), 3.68 (3H, s, OCH3), 3.61 (3H, s, OCH3), 2.30
(2H, m, H-4), 2.09 (1H, m, H-3A) and 1.96–1.86 (4H, s + m,
CH3CON and H-3B); dC (75.5 MHz, C2HCl3) 171.8 and 170.9
(ester) 168.8 (urethane), 51.0 (OCH3), 50.3 (OCH3), 50.1 (C-2),
28.5 (C-4), 25.8 (C-3), and 21.6 (CH3CON).
1-tert-Butyl 5-methyl (2S)-2-(N,N-bis-tert-butoxycarbonyl)-
aminopentanedioate (10)
This was prepared by the method of Adamczyk8 as a clear
22
22
oil (94%), [a]D −21.0 (c 1, CHCl3), (lit8 [a]D −24.5 (c 1.46,
MeOH)); m/z [CI] (found 418.2446; [C20H35NO8 + H]+ requires
418.2441); m/z [+ve FAB (3-NBA)] 440 ([M + Na]+) and 418
([M + H]+); mmax (film)/cm−1 1793 (w, bisurethane), 1741 (ester)
and 1702 (urethane); dH (300 MHz, C2HCl3) 4.72 (1H, m, H-
2), 3.60 (3H, s, OCH3), 2.34 (3H, m, H-4 and H-3A), 2.11
(1H, m, H-3B), 1.43 (18H, s, 2 × C(CH3)3) and 1.37 (9H, s,
C(CH3)3); dC (75.5 MHz, C2HCl3) 174.9 and 170.9 (2 × ester),
153.9 (urethane), 84.5 and 83.0 (2 × OC(CH3)3), 59.7 (C-2), 53.2
(OCH3), 32.4 (C-4), 29.6 and 29.5 (2 × C(CH3)3) and 26.2 (C-3).
Dimethyl (2S) 2-(N-acetyl-N-tert-butoxycarbonyl)-
aminopentanedioate (14)
A solution of 1,5-dimethyl (2S)-2-acetylaminopentanedioate
13 (1.64 g, 7.57 mmol) in acetonitrile (50 ml) was stirred
under nitrogen at room temperature and di-tert-butyl dicar-
bonate (4.95 g, 22.72 mmol) in acetonitrile (50 ml), and 4-
dimethylaminopyridine (460 mg, 3.78 mmol) were added. The
mixture was stirred at room temperature for 3 days. The solvent
was removed in vacuo and the product was purified by flash
column chromatography on silica gel, using ethyl acetate–
petroleum ether (1 : 4) as eluent to give dimethyl (2S) 2-
(N-acetyl-N-tert-butoxycarbonyl)-aminopentanedioate 14 as a
1-Methyl 5-tert-butyl (2S,4RS)-4-tert-butoxycarbonyl-2-tert-
butoxycarbonylaminopentanedioate (11)
23
clear oil (1.78 g, 74%); [a]D −30.72 (c 1.1, CHCl3); m/z [CI]
A
solution of 1-tert-butyl 5-methyl (2S)-2-(N,N-bis-tert-
(found 318.1554; [C14H23NO7 + H]+ requires 318.1553); m/z
[+ve FAB (3-NBA)] 340 ([M + Na]+) and 318 ([M + H]+); mmax
butoxycarbonyl)-aminopentanedioate 10 (60 mg, 0.144 mmol)
2 3 3 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 2 7 – 2 3 3 2

View Article Online
(film)/cm−1 1741 (br, ester and urethane) and 1701 (br, amide);
dH (300 MHz, C2HCl3) 5.23 (1H, dd, J2,3A 9.0, J2,3B 4.8, H-2),
3.63 (3H, s, OCH3), 3.59 (3H, s, OCH3), 2.44 (3H, s, NCOCH3),
2.41–2.02 (4H, 3 × m, H-3 and H-4) and 1.42 (9H, s, C(CH3)3);
dC (75.5 MHz, C2HCl3) 172.0 and 171.8 (ester), 169.6 (amide),
150.9 (urethane), 83.2 (OC(CH3)3), 53.7 (C-2), 51.2 (OCH3),
50.6 (OCH3), 29.7 (C-4), 26.8 (C(CH3)3), 25.4 (CH3CON) and
23.9 (C-3).
br s, NH major), 6.45 (1H, br s, NH minor), 4.43 (1H, m, H-2
major), 4.33 (1H, m, H-2 minor), 3.49 (3H, s, OCH3), 3.40 (3H, s,
OCH3), 2.17 (2H, m, H-4), 2.00 (1H, m, H-3A) and 1.80 (1H,
m, H-3B); dC (75.5 MHz, C2HCl3) 172.9 and 171.6 (ester), 161.0
(amide), 52.5 (OCH3), 51.6 (OCH3), 49.9 (C-2), 29.7 (C-4) and
26.9 (C-3).
Dimethyl (2S)-2-(N-tert-butoxycarbonyl-N-formyl)-
aminopentanedioate (17)
Dimethyl (2S,4RS)-4-acetyl-2-tert-butoxycarbonyl-
A solution of dimethyl (2S)-2-formylaminopentanedioate 16
(200 mg, 0.98 mmol) in acetonitrile (3 ml) was stirred at room
temperature under nitrogen. Di-tert-butyl dicarbonate (644 mg,
2.95 mmol) in acetonitrile (3 ml) and 4-dimethylaminopyridine
(60 mg, 0.492 mmol) were added. The reaction was stirred
overnight. The solvents were removed in vacuo and the re-
sulting oil was purified by flash column chromatography on
silica gel, using ethyl acetate and petroleum ether (1 : 4)
as eluent. Dimethyl (2S)-2-(N-tert-butoxycarbonyl-N-formyl)-
aminopentanedioate 17 was isolated as a clear oil (171 mg,
aminopentanedioate (15)
A solution of dimethyl (2S)-2-(N-acetyl-N-tert-butoxycar-
bonyl)-aminopentanedioate 14 (52 mg, 0.163 mmol) in dry
dimethylformamide (4 ml) was stirred at −40 ◦C under ni-
trogen. Sodium hexamethyldisilazide (1 M in THF, 0.163 ml,
0.163 mmol) was added dropwise and stirring was continued at
◦
−40 C for 3 h. Ethyl acetate (4 ml) and 1 M aqueous sodium
dihydrogen orthophosphate (4 ml) were added to the mix-
ture which was allowed to warm to room temperature. The
aqueous layers were extracted with ethyl acetate (3 × 10 ml). The
combined organic layers were dried (Na2SO4) and the solvent
was removed to give an orange oil. Purification by flash column
chromatography on silica gel using ethyl acetate–petroleum
ether (3 : 7) as eluent gave dimethyl (2S,4RS)-4-acetyl-2-tert-
butoxycarbonylaminopentanedioate 15 as a clear oil (35 mg,
20%); m/z [CI] (found 318.1553; [C14H23NO7 + H]+ requires
318.1553); mmax (film)/cm−1 3372 (NH), 1741 (ester) and 1720
(ketone/urethane); kmax (MeOH–NaOH)/nm 282 (3,182); keto-
form 15a, dH (300 MHz, C2HCl3, mixture of diastereoisomers)
5.18 (1H, dd, J4,3A 9.0, J4,3B 4.8, H-4), 5.02 (1H, d, JNH,2 7.9,
NH), 4.21 (1H, br m, H-2), 3.62, 3.58, 3.55 and 3.54 (6H, 4 ×
s, 2 × OCH3), 2.39 (3H, s, CH3CO), 2.37–2.11 (2H, m, H-3), 1.36
and 1.31 (9H, 2 × s, C(CH3)3); dC (75.5 MHz, C2HCl3 mixture
of diastereoisomers) 174.5, 174.4, 174.2 and 172.0 (ester and
acetyl), 153.3 (urethane), 85.6 (OC(CH3)3), 56.1, 54.1, 53.7, 53.5,
53.1 and 53.0 (2 × OCH3, C-2 and C-4), 31.3 (C-3), 29.6 and
29.2 (C(CH3)3) and 27.8 (CH3CO); enol-form 15b, dH (500 MHz,
C2HCl3 and 2H2O) 4.66 (1H, dd, J2,3A 12.4, J2,3B 5.0, H-2),
3.75 (3H, s, OCH3), 3.69 (3H, s, OCH3), 3.06 (1H, ddq, with
overlap, J3A,2 12.4, J3A,3B 16.0, J3A,Me 2, H-3A), 2.69 (1H, ddq,
with overlap, J3B,3A 16.0, J3B,2 5.0, J3B,Me 1.2, H-3B), 2.62 (3H, s,
CH3) and 1.45 (9H, s, C(CH3)3)–decoupling at 2.62 ppm caused
the signal at 3.6 ppm to become an ABX system, J 16 and
12.3, and the signal at 2.69 ppm to become an ABX system, J
23
57%); [a]D +206.0 (c 1, CHCl3); m/z [CI] (found 304.1401,
[C13H21NO7 + H]+ requires 304.1396); m/z [+ve FAB (3-NBA)]
304 ([M + H]+); mmax (film)/cm−1 1741 (br, ester and urethane)
and 1697 (br,◦amide); dH (300 MHz, C2HCl3, 2 rotamers, ratio
89 : 11 at 26 C) 9.12 (1H, s, NCHO), 5.23 (1H, dd, J2,3A 9.0,
J
2,3B 4.7, H-2 minor), 4.95 (1H, dd, J2,3A 9.6, J2,3B 5.1, H-2 major),
3.65 (3H, s, OCH3), 3.59 (3H, s, OCH3), 2.43 (1H, m, H-3A),
2.28 (2H, m, H-4), 2.10 (1H, m, H-3B), 1.45 (9H, s, C(CH3)3
major) and 1.42 (9H, s, C(CH3)3 minor); dC (75.5 MHz, C2HCl3)
171.9 and 168.8 (ester), 161.6 (amide), 150.6 (urethane), 84.2
(OC(CH3)3), 51.5 (OCH3), 51.1 (C-2), 50.8 (OCH3), 29.5 (C-4),
26.9 (C(CH3)3) and 23.4 (C-3).
Methyl (2S,4RS,5RS)-N-tert-butoxycarbonyl-4-
methoxycarbonyl-5-hydroxypyrrolidine-2-carboxylate (18)
Sodium hexamethyldisilazide (1
M in THF, 0.564 ml,
0.564 mmol) was added dropwise to a solution of dimethyl
(2S)-2-(N-tert-butoxycarbonyl-N-formyl)-aminopentanedioate
17 (171 mg, 0.564 mmol) in dry dimethylformamide (2 ml)
with stirring at −40 ◦C under nitrogen. The solution was
allowed to stir for a further 2 h at −40 ◦C. Ethyl acetate (4 ml)
and 1 M aqueous sodium dihydrogen orthophosphate (4 ml)
were added to the mixture which was allowed to warm to
room temperature. The aqueous layer was extracted with ethyl
acetate (3 × 4 ml). The organic layers were combined and
dried (Na2SO4), and the solvent was removed in vacuo to give
an orange oil. Purification by flash column chromatography
on silica gel using ethyl acetate–petroleum ether (3 : 7) as
eluent gave methyl (2S,4RS,5RS)-N-tert-butoxycarbonyl-4-
methoxycarbonyl-5-hydroxypyrrolidine-2-carboxylate 18 as a
clear colourless oil (69 mg, 40%); m/z (EI) 286 ([M − OH]+);
the spectra of this compound are shown as seven documents in
the ESI† and are discussed in the results and discussion section.
16 and 5; dC (125.8 MHz C2HCl3 and H2O) 172.0 and 166.0
(ester), 151.2 (urethane), 106.2 (C-4), 82.3 (OC(CH3)3), 59.5 (C-
2), 52.3 (OCH3), 50.9 (OCH3), 31.9 (C-3), 20.0 (C(CH3)3) and
14.4 (CCH3).
2
Dimethyl (2S)-2-formylaminopentanedioate (16)
Triethylamine (1.22 ml, 8.7 mmol) was added to a solution of
dimethyl (2S)-2-aminopentanedioate hydrochloride 129 (1.69 g,
8.0 mmol) in dichloromethane (10 ml) and the solution was
stirred under nitrogen for 1 h. The white solid was filtered off
and the pale yellow filtrate was washed with water. The organic
layer was dried (Na2SO4) and the organic solvent was removed
in vacuo to give a yellow oil which was cooled to 0 ◦C, dissolved
in a large excess of formic acetic anhydride and stirred for
15 min. The reaction was allowed to warm to room temperature
and stirred for a further 2 h. The solvents were removed in
vacuo and the resulting oil was partitioned between water and
dichloromethane (20 ml). The aqueous layer was extracted with
dichloromethane (3 × 10 ml). The organic layers were combined
and dried (Na2SO4), and the solvent was removed in vacuo to give
dimethyl (2S)-2-formylaminopentanedioate 16 as a pale yellow
Dimethyl (2S)-2-benzoylaminopentanedioate (20)
A solution of dimethyl (2S)-2-aminopentanedioate hydrochlo-
ride 129 (1.00 g, 4.72 mmol) in acetonitrile (20 ml) was stirred
at 0 ◦C under nitrogen. Triethylamine (1.97 ml, 14.02 mmol)
was added and stirring was continued for 15 min. A solution of
benzoyl chloride (0.54 ml, 4.65 mmol) in acetonitrile (5 ml) was
added at 0 ◦C, whereupon a white gas evolved. The reaction was
◦
stirred for 1 h at 0 C, allowed to warm to room temperature
and stirred for a further 1 h. The white solid was removed by
filtration and the solvent was removed in vacuo to give an orange
oil. The resulting oil was partitioned between ethyl acetate and
water. The aqueous layer was extracted with ethyl acetate (3 ×
10 ml). The organic extracts were combined and dried (Na2SO4)
and the solvent was removed in vacuo to give an orange oil
which was recrystallised from diethyl ether to give dimethyl
30
oil (750 mg, 47%); [a]D +69.7 (c 1.4, CHCl3); m/z [+ve FAB
(3-NBA)] 407 ([2M + H]+) and 204 ([M + H]+); mmax (film)/cm−1
3353 (NH), 1740 (ester) and 1677 (amide); dH (300 MHz, C2HCl3
2 rotamers, ratio 82 : 18 at 26 ◦C) 7.95 (1H, s, NCHO), 6.69 (1H,
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 2 7 – 2 3 3 2
2 3 3 1

View Article Online
(2S)-2-benzoylaminopentanedioate 20 as a pale yellow solid.
32%); m/z [ES+] (found 402.1521; [C19H25NO7 + Na]+ requires
402.1529); m/z [+ve FAB (3-NBA)] 402 ([M + Na]+) and 380
([M + H]+), mmax (film)/cm−1 3217 (NH), complex carbonyl
region; kmax (MeOH)/nm 247 and 320 (e 5008 and 1153),
kmax (MeOH–NaOH)/nm 249 and 311 (e 3452 and 4788), kmax
(MeOH–HCl)/nm 252 and 299 (e 3961 and 4112); dH (300 MHz,
C2HCl3, mixture of diastereoisomers A and B, ratio 1 : 1 at 26 ◦C)
7.97 (2H, m, ArH), 7.59–7.34 (3H, 2 × m, ArH), 5.11 (0.5H, d,
JNH,2 8.4, NH isomerA), 5.00 (0.5H, d, JNH,2 8.3, NH isomerB),
4.65 (1H, m, H-2), 4.50 (0.5H, m, H-4 isomerA), 4.28 (0.5H, m,
H-4 isomerB), 3.68 (6H, m, 2 × OCH3), 2.63–2.04 (2H, m, H-3)
and 1.41 (4.5H, s, C(CH3)3 isomerA) and 1.40 (4.5H, s, C(CH3)3
isomerB); dC (75.5 MHz, C2HCl3 mixture of diastereoisomers
at 26 ◦C) 194.9, 194.3, 193.8 and 192.7 (benzoyl), 173.4, 172.7,
172.3, 171.8, 171.2, 170.3, 169.9 and 168.8 (ester), 149.5 and
147.2 (urethane), 136.1–127.0 (Ar), 84.6, 84.3, 84.2 and 80.5
(OC(CH3)3), 58.2, 57.7 and 57.1 (C-4), 53.2, 53.1, 53.0 and 52.9
(OCH3), 52.6, 52.2 and 51.9 (C-2), 28.6, 28.5, 28.3, 28.2 and 27.1
(C(CH3)3) and 24.9 and 24.8 (C-3).
(676 mg, 51%); mp 122–124 ◦C, [a]D +18.3 (c 1, CHCl3); m/z
22
[ES+] 343 ([M + 2Na]+), 302 ([M + Na]+) and 280 ([M + H]+);
mmax (film)/cm−1 1745 and 1731 (ester) and 1638 (amide); dH
(300 MHz, C2HCl3) 8.06–7.50 (5H, 2 × m, ArH), 7.30 (1H, d,
J
NH,2 7.3, NH), 5.06 (1H, ddd, J2,3A 12.6, J2,NH 7.3, J2,3B 5.0, H-2),
4.01 (3H, s, OCH3), 3.88 (3H, s, OCH3), 2.72 (2H, m, H-4), 2.55
(1H, m, H-3A) and 2.45 (1H, m, H-3B); dC (75.5 MHz, C2HCl3)
174.1 and 172.8 (2 × ester), 167.5 (amide), 147.3, 133.9, 133.2,
129.0 and 127.5 (Ar), 53.0 (OCH3), 52.6 (C-2), 52.3 (OCH3),
30.6 (C-4) and 27.5 (C-3).
Dimethyl (2S)-2-(N-benzoyl-N-tert-butoxycarbonyl)-
aminopentanedioate (21)
A solution of dimethyl (2S)-2-benzoylaminopentanedioate 20
(500 mg, 1.79 mmol) in acetonitrile (15 ml) was stirred at
room temperature under nitrogen. Di-tert-butyl dicarbonate
(780 mg, 3.575 mmol) in acetonitrile (7 ml) was added followed
by 4-dimethylaminopyridine (65 mg, 0.533 mmol) and the
reaction was stirred overnight. The solvent was removed in
vacuo and the product was purified by flash column chromatog-
raphy on silica gel using ethyl acetate–petroleum ether (1 : 4)
as eluent. Dimethyl (2S)-2-(N-benzoyl-N-tert-butoxycarbonyl)-
Acknowledgements
We thank Dr A. Abdul Sada for mass spectra and the EPSRC
Central Mass Spectrometry Service at Swansea for high resolu-
tion mass spectra.
23
aminopentanedioate 21 eluted as a clear oil (617 mg, 91%); [a]D
−37.3 (c 1, CHCl3); m/z [ES+] (found 402.1536; [C19H25NO7 +
Na]+ requires 402.1529); m/z [ES+] 402 ([M + Na]+); mmax
(film)/cm−1 1735 (br, ester) and 1676 (urethane/amide); dH
(300 MHz, C2HCl3) 7.55–7.31 (5H, 3 × m, ArH), 5.03 (1H,
dd, J2,3A 9.5, J2,3B 4.9, H-2), 3.70 (3H, s, OCH3), 3.61 (3H, s,
OCH3), 2.53 (1H, m, H-3A), 2.37 (2H, m, H-4), 2.24 (1H, m,
H-3B) and 1.08 (9H, s, C(CH3)3); dC (75.5 MHz, C2HCl3) 172.4
and 172.3 (ester), 170.0 (amide), 152.0 (urethane), 136.5, 130.8,
127.5 and 127.0 (Ar), 83.2 (OC(CH3)3), 56.4 (C-2), 51.9 (OCH3),
51.1 (OCH3), 30.1 (C-4), 26.6 (C(CH3)3) and 24.0 (C-3).
References
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A solution of dimethyl (2S)-2-(N-benzoyl-N-tert-butoxycar-
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dimethylformamide (2 ml) was stirred at −40 ◦C under ni-
trogen. Sodium hexamethyldisilazide (1 M in THF, 0.527 ml,
0.527 mmol) was added slowly to the solution which was
left stirring at −40 ◦C for 1 h. Ethyl acetate (4 ml) and
1 M aqueous sodium dihydrogen orthophosphate (4 ml) were
added and the reaction was warmed to room temperature.
The aqueous layer was extracted with ethyl acetate (3 ×
5 ml). The organic extracts were combined, washed with brine
and dried (Na2SO4). The solvents were removed in vacuo to
give a yellow oil which was purified by flash column chro-
matography on silica gel using ethyl acetate–petroleum ether
(1 : 4) as eluent to give dimethyl (2S,4RS)-4-benzoyl-2-tert-
butoxycarbonylaminopentanedioate 22 as a clear oil (65 mg,
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2 3 3 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 2 7 – 2 3 3 2