The first stereospecific synthesis of L-tetrahydrodipicolinic acid; A key intermediate of diaminopimelate metabolism

Article abstract of DOI:10.1039/b105091p

L-Tetrahydrodipicolinic acid 1, a key intermediate of diaminopimelate metabolism has been prepared in 6 steps and 23% overall yield from L-allylglycine 4. The key step during this synthesis involves a base mediated cyclisation of dimethyl (2RS,6S)-2-[N-(b

Full text of DOI:10.1039/b105091p

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The first stereospecific synthesis of L-tetrahydrodipicolinic acid†;
a key intermediate of diaminopimelate metabolism
Jennifer F. Caplan, Andrew Sutherland and John C. Vederas*
1
Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2, Canada.
E-mail: john.vederas@ualberta.ca
Received (in Cambridge, UK) 11th June 2001, Accepted 25th July 2001
First published as an Advance Article on the web 23rd August 2001
-Tetrahydrodipicolinic acid 1, a key intermediate of diaminopimelate metabolism has been prepared in 6 steps and
23% overall yield from -allylglycine 4. The key step during this synthesis involves a base mediated cyclisation of
dimethyl (2RS,6S)-2-[N-(benzyloxycarbonyl)-N-(p-tolylsulfonyl)amino]-6-[N-(benzyloxycarbonyl)amino]heptane-
1,7-dioate 8 to give (2S)-N-(benzyloxycarbonyl)-1,2,3,4-tetrahydropyridine-2,6-dicarboxylic acid 9. 1H NMR studies
show this one pot transformation involves four steps; base elimination of toluene-p-sulfinic acid, intramolecular
nucleophilic attack of the 6-benzyloxycarbonylamino group on the resulting imine, followed by hydrolysis of the
esters and elimination of benzyl carbamate under acidic work-up to give the cyclic enamine 9.
acylation of -THDP 1, followed by transamination and
deacylation to give -DAP 2 which is then transformed to
meso-DAP 3 using DAP epimerase. In the less common path-
way, meso-DAP 3 is produced directly from -THDP 1 by DAP
Introduction
The recurring emergence of bacterial resistance to current anti-
biotics continues to stimulate strategies to disrupt microbial
cell wall biosynthesis.1,2 The peptidoglycan cell wall layer in
dehydrogenase.
bacterial cells provides numerous targets for further antibiotic
Although -THDP 1 is a key intermediate in the DAP path-
development.3 Crucially most bacteria require either lysine, or
way, the only reliable source of this compound to date, is the
its biosynthetic precursor, meso-diaminopimelic acid (DAP), as
oxidative deamination of meso-DAP 3 using DAP dehydro-
the key cross-linking amino acid of the peptidoglycan cell wall
genase.6 Two synthetic methods have been reported for the
layer. Since mammals lack the biosynthetic pathway to DAP
synthesis of racemic THDP,7,8 but there is as yet no reported
and require -lysine in their diet, there has been substantial
stereoselective or stereospecific synthesis of -THDP 1.
interest in the specific inhibition of enzymes involved in this
In the present study we report the first stereospecific synthesis
pathway.4
of -THDP 1 from -allylglycine 4 in 6 steps and 23% overall
yield. One of the key reactions during this synthesis involves an
One of the key intermediates in the DAP biosynthetic
pathway is -tetrahydrodipicolinic acid (-THDP) 1 which is
unusual one pot, four step formation of a tetrahydropyridine-
formed in two steps from aspartate semialdehyde and pyruvate
2,6-dicarboxylate derivative. Examination of this reaction
(Scheme 1). After formation of -THDP 1 the pathway then
mechanism by 1H NMR spectroscopy is also described.
Results and discussion
The first stage of the synthesis required the efficient preparation
of a fully protected diaminopimelic acid derivative. We sought
to achieve this using an intramolecular ene reaction between a
protected allylglycine and methyl glyoxylate,9 followed by a
Mitsunobu reaction using a nitrogen nucleophile.10 Thus, com-
mercially available -allylglycine 4 was treated with chloro-
trimethylsilane and methanol followed by triethylamine and
benzyl chloroformate in a one pot process to give the protected
derivative 5 in 91% yield (Scheme 2). Reaction of 5 with freshly
distilled methyl glyoxylate (prepared by oxidation of dimethyl
tartrate11) in the presence of tin tetrachloride at Ϫ78 ЊC
afforded the ene adduct 6 as a 1 : 1 mixture of diastereomers in
79% yield.
Rhodium metal has been shown to catalyse the hydrogen-
ation of double bonds without the hydrogenolysis observed
with palladium.12 Thus, ene adduct 6 was hydrogenated in the
presence of a catalytic amount of 5% rhodium on carbon
in ethyl acetate to give the saturated compound 7 in 86%
yield (Scheme 2). Treatment of the saturated alcohol 7 with
N-(benzyloxycarbonyl)toluene-p-sulfonamide13 under standard
Mitsunobu conditions gave the protected diaminopimelic acid
derivative 8 in 75% yield.
Scheme 1
splits into two main routes, both of which have been identified
in different bacterial species.5 The main route proceeds via
The base mediated cyclisation of DAP derivative 8 was
initially attempted using non-hydrolytic bases in an effort to
† The IUPAC name for tetrahydrodipicolinic acid is 2,3,4,5-tetra-
hydropyridine-2,6-dicarboxylic acid.
DOI: 10.1039/b105091p
J. Chem. Soc., Perkin Trans. 1, 2001, 2217–2220
This journal is © The Royal Society of Chemistry 2001
2217

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Scheme 2 Reagents and conditions: i, a) TMSCl, MeOH, b) BnO-
COCl, Et3N; ii, MeO2CCHO, SnCl4, CH2Cl2; iii, H2, Rh/C, EtOAc;
iv, TsNHCbz, DEAD, PPh3, THF; v, LiOH, MeCN, H2O.
prepare the di-methyl ester analogue of 9. It seemed that purifi-
cation of such a compound might be more readily achieved
than that of the corresponding di-acid derivative. However,
attempted cyclisation using either diethylamine or sodium bis-
(trimethylsilyl)amide returned only starting material. Thus,
DAP derivative 8 was treated with three equivalents of lithium
hydroxide in aqueous acetonitrile. Purification of the reaction
mixture by reversed phase HPLC gave the tetrahydropyridine-
2,6-dicarboxylic acid derivative 9 in 76% yield (Scheme 2). The
structure of this compound was confirmed by a HMQC NMR
experiment, which showed coupling of the alkene proton
signals (H-5) at 6.14 ppm to a carbon signal (C-5) at 123.9 ppm.
The success of this cyclisation reaction prompted an investi-
gation of the mechanism by 1H NMR spectroscopy. One
equivalent of lithium hydroxide in D2O was added to a solution
of the acyclic DAP derivative 8 in CD3CN and the reaction was
monitored at specific intervals. After 1 hour, loss of the H-2
proton signals and the appearance of signals corresponding
to toluene-p-sulfinic acid were observed. This suggested that
the first step involved deprotonation of the H-2 proton by
hydroxide followed by elimination of the tosyl group to give
imine 10 (Scheme 3). This unstable N-acyl imine is then readily
attacked by the 6-benzyloxycarbonylamino group to give
the cyclic compound 11. After 17 hours no further change was
noted, hence a second equivalent of lithium hydroxide was
added. This led to only partial hydrolysis of both esters and so
the third equivalent of lithium hydroxide was added to yield the
di-acid 12 after a further 6 hours. Subsequent exposure of the
reaction mixture to a 20% solution of DCl in D2O resulted in
the formation of benzyl carbamate and the cyclic enamine 9.
However, signals corresponding to the alkene proton (H-5)
were not observed. This was attributed to deuterium exchange
of the H-5 proton in the presence of the deuterated solvents.
This was confirmed by repeating the reaction as described
above, except that the deuterated solvents were removed before
Scheme 3
Scheme 4 Reagents and conditions: i, a) LiOH, MeOH, H2O, b) Li,
NH3 (l).
followed by reaction with lithium and liquid ammonia to give
the target compound as an equilibrium mixture of tautomers in
66% yield after flash chromatography. The H NMR spectrum
showed the presence of -THDP 1 along with its two equi-
librium products,8 enamine 13 and the acyclic keto acid 14 in a
1 : 1 : 1 mixture. The proton and carbon NMR signals of all
three compounds were assigned using a combination of COSY,
TOCSY, HMQC and HMBC NMR experiments.
1
1
acidic work-up. As expected, the resulting H NMR spectrum
showed the presence of the H-5 signals at 6.14 ppm, demon-
strating that elimination of benzyl carbamate to yield the cyclic
enamine 9 is acid catalysed (Scheme 3).
The synthesis of -THDP 1 was completed using a two step
process as shown in Scheme 4. The di-lithium salt of cyclic
enamine 9 was prepared using lithium hydroxide, which was
The structure and stereochemistry of -THDP 1 was further
confirmed by incubation of the compound with NADPH
and DAP dehydrogenase, which was isolated and purified from
2218
J. Chem. Soc., Perkin Trans. 1, 2001, 2217–2220

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the organism Bacillus sphaericus IFO 3525 as previously
reported.6,14 Monitoring of the reaction using a continuous
spectrophotometric assay at 340 nm14 showed consumption of
the co-factor thus confirming that, as expected, the synthetic
-THDP 1 is a substrate for the enzyme and has the correct
stereochemistry.
and 6.1 Hz, 2-H), 5.07–5.18 (4H, m, 5-H2 and PhCH2), 5.32
(1H, d, J 8.0 Hz, NH), 5.67 (1H, m, 4-H), 7.22–7.39 (5H, m,
Ph); δC (75.5 MHz, CDCl3) 36.6 (C-3), 52.2 (OMe), 53.3 (C-2),
66.9 (PhCH2), 119.2 (C-5), 127.9, 128.1, 128.4 (aromatics),
132.0 (C-4), 136.2 (quaternary aromatic C), 155.7 (OCON),
172.1 (CO2Me); m/z (EI) 263.1155 (Mϩ). C14H17NO4 requires
263.1157.
In summary, we have described the first stereospecific
synthesis of -THDP 1 in six steps from -allylglycine 4. This
synthesis involves three key steps; an ene reaction using tin
tetrachloride as the Lewis acid, a Mitsunobu reaction to insert
the second nitrogen functionality and a lithium hydroxide
mediated cyclisation. Deprotection of the resulting tetrahydro-
pyridine-2,6-dicarboxylic acid 9, gives the target compound 1
which is shown by 1H NMR spectroscopy to be in equilibrium
with the cyclic enamine 13 and the acyclic keto acid 14 as
described by Robins and co-workers during their synthesis of
racemic THDP.8 The structure of the final product is confirmed
by turnover of the DAP dehydrogenase enzyme using a UV
spectrophotometric assay. Studies on the synthesis and inter-
action of other DAP analogues with enzymes in the pathway to
-lysine are currently in progress.
Dimethyl (2RS,6S)-2-hydroxy-6-[N-(benzyloxycarbonyl)-
amino]hept-4-ene-1,7-dioate 6
Tin tetrachloride (24.9 cm3, 212 mmol) was added to a solution
of freshly distilled methyl glyoxylate (4.23 g, 47.9 mmol) in
dichloromethane (65 cm3) at Ϫ55 ЊC. After 10 min, the reaction
mixture was cooled to Ϫ78 ЊC and a solution of methyl (2S)-2-
[N-(benzyloxycarbonyl)amino]pent-4-enoate 5 (5.23 g, 19.9
mmol) in dichloromethane (25 cm3) was added dropwise. The
resulting white suspension was warmed to Ϫ25 ЊC and stirred
for 5 h. The reaction mixture was then poured into 1 M hydro-
chloric acid (250 cm3) and extracted with dichloromethane
(4 × 200 cm3). The combined organic layers were dried (NaSO4)
and concentrated in vacuo. The resulting yellow oil was purified
by flash column chromatography (40% ethyl acetate in hexane)
to give the title compound 6 (5.5 g, 79%) as a colourless oil
(Found: C, 57.75; H, 6.05; N, 3.85. C17H21NO7 requires C, 58.1;
H, 6.0; N, 4.0%); νmax (CHCl3)/cmϪ1 3355 (NH), 2953 (CH),
Experimental
All reactions were done under dry Ar. All solvents were purified
and distilled according to Perrin et al.15 Progress of reactions
was monitored by TLC on commercial silica gel plates (Merck
60F-254) using UV fluorescence, ninhydrin or potassium per-
manganate for visualization. Flash chromatography employed
silica gel 60 (Silicycle, 230–420 mesh) and was performed
according to the Still procedure.16 HPLC separations were per-
formed on a Beckman System equipped with a 166 variable
wavelength UV detector and an Altex 210A injector. HPLC
separations were monitored at a wavelength of 219 nm. Mps
were determined on a Büchi apparatus using open-end capillary
tubes and are uncorrected. NMR spectra were recorded on
Inova Varian 300 and 500 MHz instruments. IR spectra were
determined with a Nicolet Magna 750 FT-IR spectrometer.
Mass spectra (MS) were recorded with either a Micromass
ZabSpec Hybrid Sector-TOF instrument (electrospray ioniz-
ation (ES)) or a MS-50 high resolution (HR) mass spectrometer
(chemical ionization (CI) NH3). Optical rotations were meas-
ured on a Perkin-Elmer 241 polarimeter at 26 ЊC with a micro
cell (100 mm; 0.9 cm3) or a standard cell (100 mm, 8 cm3)
1738 (ester C᎐O), 1520, 1266; δ (300 MHz, CDCl ) 2.34–2.59
᎐
H
3
(2H, m, 3-H2), 3.72 (6H, s, 2 × OMe), 4.23 (1H, m, 2-H), 4.85
(1H, m, 6-H), 5.10 (2H, s, PhCH2), 5.60–5.65 (2H, m, NH and
5-H), 5.72–5.82 (1H, m, 4-H), 7.29–7.39 (5H, m, Ph); δC(75.5
MHz, CDCl3) 36.9 (C-3), 52.5 (OMe), 52.7 (OMe), 55.5 (C-6),
67.0 (PhCH2), 69.8 (C-2), 128.0, 128.1, 128.5, 128.6 (C-4, C-5
and aromatics), 136.2 (quaternary aromatic C), 155.5 (OCON),
171.1, 174.4 (2 × CO2Me); m/z (EI) 351.1319 (Mϩ). C17H21NO7
requires 351.1318.
Dimethyl (2RS,6S)-2-hydroxy-6-[N-(benzyloxycarbonyl)-
amino]heptane-1,7-dioate 7
A solution of dimethyl (2RS,6S)-2-hydroxy-6-[N-(benzyloxy-
carbonyl)amino]hept-4-ene-1,7-dioate 6 (2.48 g, 7.07 mmol) in
ethyl acetate (20 cm3) was treated with 5% rhodium on carbon
(0.2 g) and stirred under hydrogen at atmospheric pressure
for 2 d. The reaction mixture was filtered through a pad of
Celite and concentrated in vacuo. Purification by flash column
chromatography eluting with 40% ethyl acetate in hexane
gave dimethyl (2RS,6S)-2-hydroxy-6-[N-(benzyloxycarbonyl)-
amino]heptane-1,7-dioate 7 (2.15 g, 86%) as a colourless oil
(Found: C, 57.8; H, 6.7; N, 3.95. C17H23NO7 requires C, 57.8; H,
6.6; N, 4.0%); νmax (CHCl3)/cmϪ1 3354 (NH), 2953 (CH), 1737
respectively. [α]D Values are given in units of 10Ϫ1 deg cm2 gϪ1
.
Microanalyses were completed at the University of Alberta
Microanalytical Laboratory. All literature compounds had IR,
1H NMR and mass spectra consistent with assigned structures.
-Allylglycine was purchased from Sigma-Aldrich and methyl
glyoxylate was generated by standard literature procedures.11
(ester C᎐O), 1525, 740, 698; δ (300 MHz, CDCl ) 1.40–1.95
᎐
H
3
(6H, m, 3-H2, 4-H2 and 5-H2), 2.75 (1H, br s, OH), 3.75 (3H, s,
OMe), 3.76 (3H, s, OMe), 4.16 (1H, m, 2-H), 4.37 (1H, m, 6-H),
5.10 (2H, s, PhCH2), 5.36 (1H, br s, NH), 7.29–7.39 (5H, m,
Ph); δC(75.5 MHz, CDCl3) 20.6 (C-4), 32.3 (C-5), 33.6 (C-3),
52.4 (OMe), 52.6 (OMe), 53.7 (C-6), 67.1 (PhCH2), 70.1 (C-2),
128.1, 128.2, 128.6 (aromatics), 136.3 (quaternary aromatic C),
155.9 (OCON), 172.8, 175.4 (2 × CO2Me); m/z (EI) 353.1478
(MHϩ).C17H23NO7 requires 353.1474.
Methyl (2S)-2-[N-(benzyloxycarbonyl)amino]pent-4-enoate 5
To a stirred suspension of -allylglycine 4 (0.51 g, 4.35 mmol) in
methanol (10 cm3) at 0 ЊC was added chlorotrimethylsilane (1.7
cm3, 13.05 mmol). After 2 h, the reaction mixture was warmed
to room temperature and left stirring overnight. The reaction
mixture was then cooled to 0 ЊC and triethylamine (2.5 cm3,
17.40 mmol) and benzyl chloroformate (0.91 g, 5.22 mmol)
were added. After 3 h, the reaction mixture was concentrated in
vacuo. The resulting residue was dissolved in 2 M hydrochloric
acid (50 cm3) and extracted with ethyl acetate (2 × 40 cm3). The
combined organic layers were dried (MgSO4) and evaporated
under reduced pressure to leave a colourless oil. Purification by
flash column chromatography, eluting with 30% ethyl acetate in
hexane gave methyl (2S)-2-[N-(benzyloxycarbonyl)amino]pent-
4-enoate 5 (1.06 g, 91%) as a colourless oil; [α]D ϩ16.4 (c 4.0,
CHCl3) [lit.14 [α]D ϩ15.3 (c 1.6, CHCl3)]; νmax(CHCl3)/cmϪ1 3340
Dimethyl (2RS,6S)-2-[N-(benzyloxycarbonyl)-N-( p-tolyl-
sulfonyl)amino]-6-[N-(benzyloxycarbonyl)amino]heptane-1,7-
dioate 8
A solution of dimethyl (2RS,6S)-2-hydroxy-6-[N-(benzyloxy-
carbonyl)amino]heptane-1,7-dioate 7 (2.17 g, 6.15 mmol) in
THF (15 cm3) was added to a solution of triphenylphosphine
(2.66 g, 10.1 mmol) and N-(benzyloxycarbonyl)toluene-p-sulf-
onamide (2.87 g, 9.4 mmol) in THF (25 cm3) at 0 ЊC. Diethyl
azodicarboxylate (1.64 g, 9.4 mmol) was then added drop-
wise. After 5 h at room temperature, the reaction mixture was
(NH), 1723 (ester C᎐O), 1525, 739, 698; δH (300 MHz, CDCl3)
᎐
2.38–2.62 (2H, m, 3-H2), 3.68 (3H, s, OMe), 4.45 (1H, dd, J 7.4
J. Chem. Soc., Perkin Trans. 1, 2001, 2217–2220
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concentrated in vacuo. The resulting residue was purified by
flash column chromatography eluting with 25% ethyl acetate in
hexane to give dimethyl (2RS,6S)-2-[N-(benzyloxycarbonyl)-N-
(p-tolylsulfonyl)amino]-6-[N-(benzyloxycarbonyl)amino]hept-
ane-1,7-dioate 8 (2.95 g, 75%) as a colourless oil (Found:
C, 59.6; H, 5.6; N, 4.3. C32H36N2O10S requires C, 60.0; H, 5.7;
N, 4.4%); νmax (CHCl3)/cmϪ1 3360 (NH), 2952 (CH), 1735 (ester
tion mixture was warmed to room temperature. The reaction
mixture was then acidified to pH 7 by the addition of 0.1 M
hydrochloric acid (2 cm3) and concentrated in vacuo. The resi-
due was then purified by flash column chromatography to
remove trace impurities by eluting with 15% ammonia in
isopropanol (propan-2-ol) to give the title compound 1 (0.033 g,
66%) as a white solid; νmax (Nujol mull)/cmϪ1 3432 (NH), 2924
C᎐O), 1596, 1520, 1455, 1218; δ (300 MHz, CDCl ) 1.54 (2H,
(CH), 2852 (OH), 1735 (C᎐O), 1641 (C᎐C), 1454, 1377, 1209;
᎐
᎐ ᎐
H
3
m, 4-H2), 1.82 (2H, m, 5-H2), 2.12 (2H, m, 3-H2), 2.35 (3H, s,
CH3), 3.56 (3H, s, OMe), 3.74 (3H, s, OMe), 4.38 (1H, q, J 6.3
Hz, 6-H), 5.00–5.15 (5H, m, 2 × PhCH2O and 2-H), 5.40 (1H,
br d, J 6.3 Hz, NH), 7.06–7.36 (12H, m, 2 × OCH2Ph, 3-CH
and 3Ј-CH), 7.77 (2H, d, J 9.3 Hz, 2-CH and 2Ј-CH); δC(75.5
MHz, CDCl3) 21.6 (CH3), 22.1 (C-4), 29.3 (C-5), 31.8 (C-3),
52.3 (OMe), 52.4 (OMe), 53.6 (C-6), 59.3 (C-2), 66.9, 69.1 (2 ×
OCH2Ph), 128.0, 128.4, 128.5, 128.9, 129.0 (aromatics), 134.2,
135.7, 136.3, 144.6 (4 × quaternary aromatic C), 151.3, 155.9
(2 × OCON), 169.9, 172.8 (2 × CO2Me); m/z (ES) 663.1993
(MNaϩ). C32H36N2O10SNa requires 663.1988.
δH (500 MHz, D2O) 1.70–1.88 (6H, m, 3-H2 of imine, 4-H2 of
enamine, 4-H2 of keto), 2.00–2.26 (6H, m, 4-H2 of imine, 3-H2
of enamine, 3-H2 of keto), 2.42 (2H, m, 5-H2 of imine), 2.55
(2H, t, J 7.4 Hz, 5-H2 of keto), 4.10 (1H, dd, J 11.7, 3.1 Hz, 2-H
of imine), 4.17 (1H, t, J 6.6 Hz, 2-H of keto), 4.46 (1H, dd,
J 7.4, 5.1 Hz, 2-H of enamine); δC (125 MHz, D2O) 21.6 (C-4
of enamine), 22.5 (C-3 of imine), 22.6 (C-4 of keto), 24.7
(C-4 of imine), 27.6 (C-3 of enamine), 27.8 (C-5 of imine), 31.9
(C-3 of keto), 35.8 (C-5 of keto), 55.6 (C-2 of keto), 57.5 (C-2
of enamine), 59.9 (C-2 of imine), 131.5 (C-5 of enamine), 149.3
(C-6 of enamine), 155.9 (C-6 of imine), 166.9, 169.3, 171.1,
174.2, 174.8, 180.5 (C᎐O), 204.1 (C-6 of keto); m/z (ES)
᎐
(2S)-N-(Benzyloxycarbonyl)-1,2,3,4-tetrahydropyridine-2,6-
170.04467 (M Ϫ H). C7H8NO4 requires 170.04478.
dicarboxylic acid 9
A solution of lithium hydroxide monohydrate (0.21 g, 4.99
mmol) in water (5 cm3) was added to a solution of dimethyl
(2RS,6S)-2-[N-(benzyloxycarbonyl)-N-(p-toluenesulfonyl)-
Acknowledgements
These investigations were supported by the Natural Sciences
and Engineering Research Council of Canada (scholarship to
J. F. C.), and the Alberta Heritage Foundation for Medical
Research (postdoctoral fellowship for A. S.). The work is also
supported by the Canada Research Chair in Bioorganic and
Medicinal Chemistry (J. C. V.).
amino]-6-[N-(benzyloxycarbonyl)amino]heptane-1,7-dioate
8
(0.51 g, 1.61 mmol) in acetonitrile (10 cm3). After stirring for
8 h at room temperature, the reaction mixture was concen-
trated in vacuo. The resulting residue was dissolved in water
(10 cm3), extracted with ethyl acetate (2 × 15 cm3). The aqueous
layer was acidified to pH 2 with 2 M hydrochloric acid (10 cm3)
and extracted with ethyl acetate (2 × 15 cm3). The combined
organic layers were dried (MgSO4) and concentrated in vacuo.
The residue was purified by reversed phase HPLC (C18 Bond-
pak, gradient elution: 0–100% MeCN in water over 20 min) to
afford (2S)-N-(benzyloxycarbonyl)-1,2,3,4-tetrahydropyridine-
2,6-dicarboxylate 9 (0.18 g, 76%) as a white solid; mp
90–92 ЊC (from methanol); [α]D Ϫ66.7 (c 1.0, MeOH); νmax
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(MeOH)/cmϪ1 3415 (OH), 2952 (CH), 1732 (C᎐O), 1716
᎐
(C᎐O), 1695 (C᎐C), 1455; δ (300 MHz, CD3OD) 1.88–2.40
᎐
᎐
H
(4H, m, 3-H2 and 4-H2), 5.00 (1H, dd, J 5.3, 2.7 Hz, 2-H),
5.11 (2H, 2 × d, J 12.8 Hz, PhCH2), 6.14 (1H, t, J 4.0 Hz,
5-H), 7.26–7.38 (5H, m, Ph); δC (75.5 MHz, CD3OD) 21.4
(C-3), 27.2 (C-4), 58.1 (C-2), 69.1 (PhCH2), 123.9 (C-5), 128.7,
128.9, 129.0, 129.4 (aromatics), 135.1 (C-6), 137.3 (quaternary
aromatic C), 155.9 (OCON), 170.0, 176.8 (CO2H); m/z (ES)
328.0793 (MNaϩ). C15H15NO6Na requires 328.0797.
(2S)-2,3,4,5-Tetrahydrodipicolinic acid 1
(2S)-N-(Benzyloxycarbonyl)-1,2,3,4-tetrahydropyridine-2,6-
dicarboxylic acid 9 (0.088 g, 0.29 mmol) was dissolved in
methanol (5 cm3) and a solution of lithium hydroxide mono-
hydrate (0.024 g, 0.58 mmol) in water (1 cm3) was added. After
5 min, the reaction mixture was concentrated in vacuo. To the
resulting residue was added predistilled liquid ammonia (15
cm3). The reaction mixture was then cooled to Ϫ78 ЊC and
freshly cut lithium metal (0.025 g) was added until a blue colour
persisted. After 15 min, water (3 cm3) was added and the reac-
15 D. D. Perrin, W. L. F. Armarego and D. R. Perrin, Purification
of Laboratory Chemicals, Pergamon Press, New York, 2nd edn.,
1980.
16 W. C. Still, M. Kahn and A. Mitra, J. Org. Chem., 1978, 43, 2923.
2220
J. Chem. Soc., Perkin Trans. 1, 2001, 2217–2220