Extension of the "ring switch" approach to glutamate antagonists to δ-lactam urethanes

Article abstract of DOI:10.1039/b207936d

The versatile "ring switching" approach to antagonists of glutamate receptors has been extended to the use of δ-lactam urethanes. Three different types of δ-lactam urethane aldehydes 17, 26 and 59 have been used successfully in this approach. Altering dia

Full text of DOI:10.1039/b207936d

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Extension of the “ring switch” approach to glutamate antagonists
to ꢀ-lactam urethanes
Diane Coe,a Martin Drysdale,†a Oliver Philps,‡b Robert Westa and Douglas W. Young*b
1
a GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts,
UK SG1 2NY
b Sussex Centre for Biomolecular Design and Drug Development, CPES, University of Sussex,
Falmer, Brighton, UK BN1 9QJ
Received (in Cambridge, UK) 14th August 2002, Accepted 5th September 2002
First published as an Advance Article on the web 18th October 2002
The versatile “ring switching” approach to antagonists of glutamate receptors has been extended to the use of
δ-lactam urethanes. Three different types of δ-lactam urethane aldehydes 17, 26 and 59 have been used successfully
in this approach. Altering diastereoisomeric ratios in the synthesis by use of a hindered proton source has allowed
homochiral products with two chiral centres to be obtained. Although the δ-lactam urethane system did not prove
to be as versatile as the corresponding pyroglutamate or β-lactam urethanes, a variety of homologues of glutamate
antagonists have been prepared.
The known activity of the natural product ibotenic acid 11 gave
impetus to the synthesis of analogous compounds consisting of
a heterocyclic ring system fused to the α-carbon atom of a
glycine moiety and of homologous compounds such as AMPA
2 with a heterocyclic ring fused to the β-carbon atom of
-alanine. These and other compounds were found to mimic
to be less reactive than the corresponding β-lactam and pyro-
glutamate derivatives. We therefore prepared the methyl ester 14
using the method of Moloney,10 § and converted it into the
urethane 1511 in 85% yield by reaction with di-tert-butyl
dicarbonate and DMAP in acetonitrile as shown in Scheme 2.
Reaction of the urethane 15 with four equivalents of tert-
butoxybis(dimethylamino)methane in refluxing tetrahydro-
furan gave the enaminone 16 in 48% yield (60% based on
recovered starting material). Hydrolysis was achieved by main-
taining the pH of a methanolic solution of the enaminone 16 at
4.0 by addition of 0.1 N aq. HCl and the reaction was judged to
be complete after two days when λmax 319 nm in the UV spec-
trum for the enaminone 16 had been entirely replaced by λmax
261 for the enol of the aldehyde 17. Hydrazine was added to the
solution of the resultant aldehyde 17 in situ and the “ring
switched” product, the pyrazole 18, was obtained in 34% over-
all yield from the enaminone 16. The product exhibited a singlet
at δ 7.18 ppm for the proton H-3Ј and an exchangeable doublet
at δ 5.43 ppm for NHBoc. Other spectroscopic and analytical
data were in agreement with the structural assignment. When
methylhydrazine was used, then the pyrazole 19 was obtained
in 32% overall yield from the enaminone 16. Phenylhydrazine
and para-nitrophenylhydrazine gave no useful products in this
reaction.
It was later found that it was not necessary to hydrolyse the
enaminone 16 to effect “ring switching” with hydrazine and
methylhydrazine, since addition of one equivalent of acid to the
enaminone 16, followed immediately by addition of hydrazine
or methylhydrazine gave the pyrazoles 18 or 19 in much the
same yields as in the reaction where the enaminone had been
hydrolysed. Presumably the electrophile in the ring switching
reaction was the protonated enaminone 22. The overall yield of
the process could be enhanced by preparing the crude aldehyde
17 from the urethane 15 using LHMDS and methyl formate
in THF and treating it with hydrazine or methylhydrazine
in methanol. Overall yields for the two steps were 46% (18)
and 40% (19) from the urethane 15 by this route, compared to
20% and 18% for the alternative three-step process. Reaction of
the aldehyde 17 with 2-aminopyridine, which had given access
to adducts useful in “ring switching” reactions when a pyro-
glutamate, the fast excitatory receptor in the brain, but to have
activity at specific and different ionotropic and metabotropic
glutamate receptor sub-types.2 The glutamate receptors have a
variety of rôles in the central nervous system3 and antagonists
have been identified as potential drugs for variety of illnesses,
including persistent pain,4 Alzheimer’s disease,5 epilepsy6 and
ischaemia.7
We have discovered a versatile and economical synthesis for
the preparation of a large variety of homochiral compounds in
which a heterocyclic ring system is fused to the β-carbon atom
of -alanine.8 This methodology has recently been extended to
encompass the preparation of analogues of the lower homo-
logue, ibotenic acid.9 The synthesis, shown in Scheme 1, involves
reaction of bisnucleophiles with an aldehyde of a pyroglutamic
acid derivative 3 (n = 1) or an aldehyde of a β-lactam 3 (n = 0)
or with their homologues 11. It has the advantage of allowing a
large variety of relevant, homochiral products to be obtained in
a minimum number of steps. We have referred to this powerful
synthetic tool as a “ring switching” reaction.8a
It was of interest to see whether the method might be applied
to preparation of homologues with an additional carbon atom
in the chain separating the heterocyclic and amino acid moieties
by using the aldehydes 3 and 11 (n = 2) of 6-oxopiperidine-2-
carboxylate in the synthesis. These compounds were expected
† Present address: RiboTargets plc, Granta Park, Abington,
Cambridge, UK CB1 2JP
‡ Present address: Vertex Pharmaceuticals, 88 Milton Park, Abingdon,
Oxon, UK OX14 4RY
§ We thank Dr Moloney for his advice in optimizing our yields in this
synthesis.
DOI: 10.1039/b207936d
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Scheme 1 n = 0, 1.
Scheme 2 (i) (Boc)2O–DMAP–CH3CN (85%); (ii) tBuOCH(NMe2)2 (48%); (iii) pH 4.0; (iv) LHMDS–THF–HCO2Me; (v) RNHNH2,
[(iii) ϩ (v) 18, 34%; 19, 32%], [(iv) ϩ (v) 18, 46%; 19, 40%]; (vi) 6 N HCl–reflux (20, 57%; 21, 40%).
glutamate aldehyde had been used, gave no isolable products.
The free amino acids 20 and 21 were obtained in 57% and 40%
yields respectively from the urethane esters 18 and 19 by heating
in 6 N aq. HCl at reflux.
followed by reduction of the ozonide with triphenylphosphine
gave the aldehyde 26 in 72% yield. When the aldehyde 26 was
reacted with hydrazine hydrate in methanol, a single product
was obtained in 62% yield, as shown in Scheme 4. This com-
pound had spectroscopic properties expected of the pyridazine
32. This result was different from that found in the correspond-
ing reaction in both the pyroglutamate series and β-lactam
series, where carbinolamines corresponding to 31 were a major
product. None of the carbinolamine 31 was obtained in this
reaction. A possible explanation for this result is that the dimin-
ished electrophilicity of the ring carbonyl group in the six
membered ring compared to that in the four and five membered
rings, makes cyclisation to the carbinolamine 31 (Step [a]
in Scheme 4) slower than dehydration of the intermediate
carbinolamine 29 to the hydrazone 30, (Step [b] in Scheme 4).
Presumably the enhanced electrophilicity of the ring carbonyl
group in the carbinolamine 33 in the β-lactam and pyro-
glutamate series allows for trapping of the carbinolamine by
“ring switching”, before dehydration can occur. The pyridazine
32 was converted into the free amino acid 34 in 33% yield by
heating to reflux in 6 N aq. HCl. The corresponding N-methyl-
pyridazine 35 was obtained in 40% yield by reacting the
aldehyde 26 with methylhydrazine.
Our next target as a substrate for “ring switching” reactions
was the homologous aldehyde 26. In our first attempt to
synthesise this compound, we reacted the urethane 15 with
LHMDS in THF followed by benzyl bromoacetate, as shown in
Scheme 3. This reaction gave the diester 23, which, on hydro-
genolysis, afforded the monoacid 24. Reduction to the alcohol
25 using H3BؒSMe2 gave a product in which the alcohol 25
was contaminated with the lactone 27. The amount of
lactone 27 increased with time and it was evidently produced
by a spontaneous “ring switching” reaction of the alcohol
25. Oxidation of the mixture of the alcohol and the lactone
using oxalyl chloride and DMSO gave the aldehyde in only
20% yield.
It was evident that an alternative synthesis would be required
to access the homologous aldehyde in good yield. The urethane
15 was, therefore, alkylated using LHMDS and allyl bromide to
give the product 28 as a 1:1 mixture of diastereoisomers in 45%
yield. These could not be separated by column chromatography.
Ozonolysis of the product 28 in dichloromethane at Ϫ78 ЊC,
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Scheme 3 (i) LHMDS–BrCH2CO2Bn (56%); (ii) H2–Pd-C (88%); (iii) H3BؒSMe2 (55%) (iv) ClCOCOCl–DMSO (20%); (vi) LHMDS–allylBr–THF
(45%); (vii) O3–Ph3P (72%).
Scheme 4 (i) H2NNH2–MeOH (62% 32 from 26).
Because yields of amino acids were lower than we had come
to expect in the pyroglutamic acid series where we had used tert-
butyl esters, and because we wished to use a range of nucleo-
philes, some of which might react with the methyl ester, we
decided that the hindered tert-butyl ester 41 might be a more
useful substrate for our “ring switching” reactions. Attempts
to hydrolyse the methyl ester 14 to (2S )-6-oxopiperidine-2-
carboxylic acid 36 using acid gave low yields and use of LiOH
was accompanied by racemisation, and so we opted for a more
indirect approach. (2S )-Piperidine-2-carboxylic acid 38 was
prepared in 28% yield from the racemate 37 by resolution via
the salt with -tartaric acid.12,13 This was converted into the
tert-butyl ester 39 in 54% yield, as shown in Scheme 5, using
tert-butyl acetate and perchloric acid. The ester was converted
into the urethane 40 in 85% yield using tert-butyl dicarbon-
ate and triethylamine in methanol. Oxidation to the desired
δ-lactam urethane 41 was finally achieved in 83% yield using
ruthenium trichloride and sodium periodate. The product 41
was shown to be present in > 99% ee using chiral HPLC com-
parison with a racemic sample prepared from the racemate 37
by an identical route.
To compare the effect of using the tert-butyl ester 41 rather
than the methyl ester 15 in the “ring switching”–deprotection
sequence, we prepared the pyrazolones 43 and 44 by first react-
ing the ester 41 with LHMDS and methyl formate and then
reacting the resultant aldehyde 42 in situ with either hydrazine
or methylhydrazine. The pyrazolones 43 and 44 were obtained
in 46% and 42% yields respectively and these could be depro-
tected by brief exposure to 6 N HCl at room temperature to
give the amino acids 20 and 21 in 89% and 91% yields respect-
ively. As before, no useful products were obtained when
the aldehyde 42 was reacted with phenylhydrazine or para-
nitrophenylhydrazine.
The homologous aldehydes 46 were obtained as in Scheme 6
via the allyl derivatives 45 in much the same way as the
corresponding methyl esters 26 had been prepared. The allyl
derivatives 45 were obtained in 59% yield as a 1:1 mixture of
diastereoisomers and, when these were treated with LHMDS
followed by the hindered proton source 2,6-di-tert-butylphenol,
a 9:1 mixture of cis:trans isomers of 45 was obtained in
84% yield. Ozonolysis of the olefin in dichloromethane at
Ϫ78 ЊC, followed by reduction of the ozonide using triphenyl-
phosphine gave the diastereoisomeric tert-butyl esters 46. The
predominant (2S,5R)-diastereoisomer 46a could be obtained in
pure form by column chromatography. Although the stereo-
chemistry of the predominant isomer was expected to be
(2S,5R) due to protonation of the anion of the allyl deriv-
ative 45 from the less hindered face, this was confirmed by
decoupling and NOE experiments on the product 46a, shown in
Fig. 1. Irradiation of the signal for H-2 at δ 4.57 ppm led to
decoupling not only of the two signals for H-3 but also to the
signal at δ 1.97 ppm. The latter was therefore assigned as H-4R,
undergoing long range W-coupling with H-2, as shown in
Fig. 1a. The NOE experiments, summarised in Figs. 1b and 1c
and described in the experimental section, indicated that the
proton H-3S which had the larger NOE to H-2 also showed
enhancement when H-5 was irradiated. Further, H-4R, defined
by the W-coupling experiment, showed enhancement when
H-5 was irradiated. These data were all compatible with the
(2S,5R)-stereochemistry shown in 46a. The (2S,5R)-isomer 46a
was reacted with hydrazine hydrate in methanol to give the
pyridazine 47 in 88% yield. Again none of the carbinolamine
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Scheme 5 (i) tBuOAc–HClO4 (54%); (ii) Boc2O–NaHCO3 (85%); (iii) (a) RuCl3ؒH2O (b) NaIO4–EtOAc–H2O (83%), (ee >99%); (iv) LHMDS–
HCO2Me; (v) RNHNH2–MeOH [43 46%, 44 42% for (iv) ϩ (v)]; (vi) 6 N aq. HCl (20, 89%, 21 91%).
Fig. 1 Decoupling and NOE experiments on the diastereoisomer 46a.
an ethanolic solution of the enol ether 48 with formamidine
acetate, acetamidine acetate, benzamidine hydrochloride or
guanidine carbonate in the presence of potassium carbonate
gave the pyrimidinones 49, 50, 51 and 52 in 43%, 83%, 59% and
19% yields respectively. These compounds had the expected
analytical and spectroscopic properties and the pyrimidinones
50 and 51 were hydrolysed to the free amino acid hydro-
chlorides 53 and 54 in 97% and 98% yields respectively, using
6 N HCl at room temperature.
We had so far carried out our “ring switching” approach to
glutamate antagonists via aldehydes prepared by α-substitution
of β-, γ- and δ-lactam urethanes. We now decided to investigate
the possibility of preparing these compounds via β-substituted
lactam urethanes. We therefore prepared the α,β-unsaturated
compound 56, as shown in Scheme 8. The urethane ester 41 was
treated with LHMDS at Ϫ30 ЊC followed by phenylselenyl
chloride at Ϫ78 ЊC to give the monoselenide 55 as a 6:1 mixture
of diastereoisomers in 64% yield. Oxidation using 30% aq.
H2O2 gave the dehydro derivative 56 in 62% yield. Reaction with
vinylmagnesium bromide and CuBrؒSMe2 gave the diastereo-
isomeric products 57 in 43% yield and in a ratio of 2:1 as
deduced from integration of the signals for H-2. Since it had
been suggested11 that trans-4-substituted-6-oxopiperidine-2-
carboxylates have J2,3 2 and 4 Hz and the corresponding cis-
isomers have J2,3 6 and 10 Hz, we assigned the major isomer
(J2,3 2.7 and 5.8 Hz) as the trans (2S,4R)-isomer and the minor
Scheme 6 (i) LHMDS–allylBr (59%, 1:1 cis:trans); (ii) (a) LHMDS,
(b) 2, 6-di-tert-butylphenol (84% 9:1 cis:trans); (iii) (a) O3–CH2Cl2
Ϫ78 ЊC, (b) PPh3 (85%); (iv) separate; (v) H2NNH2–MeOH (88%);
(vi) 6 N HCl (94%).
corresponding to 31 was present in the product. An attempt to
achieve the corresponding reaction with methylhydrazine was
unsuccessful. Hydrolysis of the pyridazine 47 with 6 N HCl at
room temperature gave the amino acid hydrochloride 34a in
94% yield.
Because the racemic compound 41a, prepared in the same
way as the (2S )-compound 41, was more readily available,
we used this to test the applicability of the “ring switching”
method when bisnucleophiles other than substituted hydrazines
were used. The δ-lactone urethane 41a was therefore converted
into the aldehyde 42a as before and this was reacted with tri-
methylsilyldiazomethane in diethyl ether at 0 ЊC to afford the
enol ether 48 in 52% overall yield from 41a (Scheme 7). Heating
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and also to the aldehyde 59. Although not as versatile as
the corresponding syntheses in the pyroglutamate (n = 1)8 and
β-lactam (n = 0)11 series, useful homologues of glutamate
antagonists have been prepared. Versatility in the synthesis
seems to follow the order of the reactivity of the lactam
carbonyl group in these reactions, with (n = 0) > (n = 1) >
(n = 2).
Experimental
Melting points were determined on a Kofler hot-stage and are
uncorrected. Optical rotations (in units of 10Ϫ1 deg cm2 gϪ1
)
were measured on a Perkin–Elmer PE241 polarimeter using a
1 dm pathlength cell. IR spectra were recorded on a Perkin–
Elmer 1720 Fourier-transform instrument. UV spectra were
recorded on a ATI Unicam UV2–100 Fourier-transform scan-
1
ning spectrometer. H NMR spectra were recorded on Bruker
DPX 300 (300 MHz) and Bruker DPX 400 (400 MHz) Fourier-
transform instruments. J values are given in Hz. NOe spectra
were recorded on a Bruker AMX 500 Fourier-transform
instrument (500 MHz). 13C NMR spectra were recorded on
Bruker DPX 300 (75.48 MHz) and Bruker DPX 400 (100.61
MHz) Fourier transform instruments. DEPT experiments were
used to assign 13C resonances where necessary. Low resolution
mass spectra were recorded by Dr A. Abdul Sada on a Kratos
MS80RF and MS25 double focusing spectrometers. Accurate
mass measurements were obtained from the EPSRC Central
Mass spectrometry Service at Swansea and from GlaxoSmith-
Kline, Stevenage. Microanalyses were carried out by Medac
Ltd. Column chromatography was carried out using Fluka
Kieselgel 60 (220–440 mesh). Petroleum ether refers to the
fraction of alkanes of bp 60–80 ЊC.
Scheme 7 (i) LHMDS–HCO2Me; (ii) TMSCH2N2 [52% for (i) ϩ (ii)];
(iii) RC(᎐NH)NH2–Na2CO3–EtOH [49 43%; 50 83%; 51 59%; 52 19%;
᎐
(iv) 6 N HCl (53 97%, 54 98%).
Methyl (2S )-N-tert-butoxycarbonyl-6-oxopiperidine-2-
carboxylate (15)
isomer (J2,3 6.6 and 9.5 Hz) as the cis (2S,4S )-isomer.14 Reac-
tion of the dehydro derivative 56 with dimethylvinylmagnesium
bromide and CuBrؒSMe2 gave a 5:1 mixture of diastereo-
isomers 58. Neither of the diastereoisomeric mixtures 57 nor 58
could be separated. Ozonolysis of the olefins 57 and 58, fol-
lowed by reaction of the ozonides with triphenylphosphine gave
the aldehyde 59 as an inseparable mixture of diastereoisomers.
This was reacted immediately with hydrazine in methanol to
give the pyridazine 60 in 80% overall yield from the starting
olefin. We were unable to obtain useful products from this reac-
tion using methylhydrazine. Deprotection of the pyridazine 60
was effected by 6 N aq. HCl at room temperature, giving the
amino acid hydrochloride 61 in 79% yield.
Di-tert-butyl dicarbonate (903 mg, 4.14 mmol) was added to
a mixture of methyl (2S )-6-oxopiperidine-2-carboxylate 1410
(500 mg, 3.18 mmol) and 4-dimethylaminopyridine (DMAP)
(39 mg, 0.318 mmol) in acetonitrile (5 ml) under nitrogen at
0 ЊC. The mixture was allowed to warm to room temperature
and was stirred for a further 3 h. The solvent was removed in
vacuo to give a brown residue which was purified by column
chromatography on silica gel using petroleum ether–ethyl
acetate (3:1) as eluent to afford methyl (2S)-N-tert-butoxy-
carbonyl-6-oxopiperidine-2-carboxylate 15 as a yellow solid
25
(696 mg, 85%); mp 52–54 ЊC; [α]D ϩ9.4 (c 1.00, CHCl3);
Found: C, 56.25; H, 7.55; N, 5.4. C12H19NO5 requires C, 56.0;
H, 7.4; N, 5.4%; m/z [ϩve FAB, 3-NBA] 258 [M ϩ H]ϩ and 280
[M ϩ Na]ϩ; νmax (KBr)/cmϪ1 1766 and 1677 (C᎐O); δ (300
We have therefore successfully applied our “ring switching”
strategy shown in Scheme 1 to the aldehydes 3 and 11 (n = 2)
᎐
H
Scheme 8 (i) LHMDS–PhSeCl–THF Ϫ78ЊC (64%); (ii) H2O2–EtOAc (62%); (iii) R2C᎐CHMgBr–CuBr.Me2S (57, 43%; 58, 38%); (iv) (a) O3,
᎐
(b) Ph3P (80%); (v) H2NNH2–MeOH (80% for (iv) ϩ (v)); (vi) 6 N HCl (79%).
J. Chem. Soc., Perkin Trans. 1, 2002, 2459–2472
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MHz, C2HCl3) 4.58 (1H, dd, J2,3A 3.8, J2,3B 6.1, H-2), 3.70 (3H,
s, OCH3), 2.67–2.35 (2H, m, H-5), 2.22–1.93 (2H, m, H-3),
1.85–1.70 (2H, m, H-4) and 1.49 [9H, s, C(CH3)3]; δC (75 MHz,
C2HCl3) 172.03 (C-6), 170.16 (ester), 152.21 (urethane), 83.59
[OC(CH3)3], 58.49 (C-2), 52.53 (OCH3), 34.51 (C-5), 27.85
[C(CH3)3], 25.83 (C-3) and 18.24 (C-4).
34%). All spectra were identical to those of the product from
Method A.
Method C. Lithium hexamethyldisilazide (1 M in THF,
7.0 ml, 7.0 mmol) was added to a stirred solution of methyl
(2S )-N-tert-butoxycarbonyl-6-oxopiperidine-2-carboxylate 15
(1.50 g, 5.83 mmol) in THF (15 ml) at Ϫ78 ЊC under nitrogen.
The solution was allowed to warm to Ϫ30 ЊC over a period of
30 min to ensure enolate formation and cooled to Ϫ78 ЊC.
Methyl formate (0.719 ml, 12 mmol) was added and the solu-
tion was stirred for 5 min at Ϫ78 ЊC, warmed to 0 ЊC, and
stirred for a further 90 min. Saturated aqueous ammonium
chloride (5 ml) was added at 0 ЊC and the solvent was removed
in vacuo to give an orange residue. The residue was partitioned
between ethyl acetate (10 ml) and saturated aqueous ammo-
nium chloride (5 ml). The organic layer was separated and the
aqueous layer was extracted with ethyl acetate (2 × 5 ml). The
combined organic layers were dried (MgSO4) and the solvent
was removed in vacuo to give a yellow oil. The crude oil was
dissolved in methanol (15 ml) and hydrazine hydrate (55% aq.,
0.446 ml, 7.9 mmol) was added. The solution was stirred at
room temperature for 30 h and the solvent was removed in
vacuo to give a yellow residue. Column chromatography on
silica gel using ethyl acetate as eluent afforded methyl (2S)-2-N-
tert-butoxycarbonylamino(5-hydroxypyrazol-4-yl)butyrate 18 as
a colourless oil (807 mg, 46%). All spectra were identical to
those obtained by the previous methods.
Methyl (2S )-N-tert-butoxycarbonyl-5-dimethylaminomethylene-
6-oxopiperidine-2-carboxylate (16)
A mixture of tert-butoxybis(dimethylamino)methane (1.60 ml,
7.77 mmol) and methyl (2S )-N-tert-butoxycarbonyl-6-oxo-
piperidine-2-carboxylate 15 (500 mg, 1.94 mmol) in tetrahydro-
furan (5 ml) was heated under nitrogen at 70 ЊC for 18 h. The
solvent was removed in vacuo to give a brown residue which
was purified by column chromatography on silica gel using
ethyl acetate–petroleum ether (4:1) as eluent to afford methyl
(2S)-N-tert-butoxycarbonyl-5-dimethylaminomethylene-6-oxo-
25
piperidine-2-carboxylate 16 as a yellow oil (289 mg, 48%); [α]D
ϩ49.0 (c 1.0, CHCl3); m/z [CI] Found 313.1759 [M ϩ H]ϩ,
[C15H24N2O5 ϩ H]ϩ requires 313.1763; m/z [ϩve FAB, 3-NBA]
313 [M ϩ H]ϩ; νmax (film)/cmϪ1 1750, 1699 and 1678 (C᎐O); λ
᎐
max
(MeOH)/nm 319 (log ε 4.24); δH (300 MHz, C2HCl3) 7.54 [1H, s,
᎐CHN(CH ) ], 4.77 (1H, t, J 4.7, H-2), 3.73 (3H, s, OCH3),
᎐
3
2
2,3
3.02 [6H, s, N(CH3)2], 2.65 (1H, m, H-3), 2.46 (1H, m, H-3),
2.18 (1H, m, H-4A), 1.97 (1H, m, H-4B) and 1.49 [9H, s,
OC(CH3)3]; δC (75 MHz, C2HCl3) 172.23 (C-6), 167.00 (ester),
153.28 (urethane), 150.59 [᎐CHN(CH ) ], 94.99 (C-5), 82.27
᎐
3
2
[OC(CH3)3], 57.58 (C-2), 52.25 (OCH3), 43.19 [N(CH3)2], 28.01
[OC(CH3)3], 25.58 (C-3) and 21.07 (C-4).
Methyl (2S )-2-N-tert-butoxycarbonylamino(1-methyl-5-
hydroxypyrazol-4-yl)butyrate (19)
Methyl (2S )-2-N-tert-butoxycarbonylamino(5-hydroxypyrazol-
4-yl)butyrate (18)
Method A. Methyl (2S )-N-tert-butoxycarbonyl-5-dimethyl-
aminomethylene-6-oxopiperidine-2-carboxylate 16 (100 mg,
0.320 mmol) was dissolved in methanol (10 ml) and 0.1 N
hydrochloric acid was added dropwise to the solution, main-
taining the pH of the solution at 4.00, until its UV spectrum
showed the reaction to be complete (ca. 0.384 mmol). Methyl-
hydrazine (0.025 ml, 0.48 mmol) was added at room temper-
ature and the solution was stirred for a further 30 h. The solvent
was removed in vacuo to give a yellow residue which was
purified by column chromatography on silica gel using ethyl
acetate as eluent to afford methyl (2S)-2-N-tert-butoxycarbonyl-
amino(1-methyl-5-hydroxypyrazol-4-yl)butyrate 19 as a colour-
Method A. Methyl (2S )-N-tert-butoxycarbonyl-5-dimethyl-
aminomethylene-6-oxopiperidine-2-carboxylate 16 (120 mg,
0.384 mmol) was dissolved in methanol (10 ml) and 0.1 N
aqueous hydrochloric acid was added dropwise to the solution
with stirring, maintaining the pH of the solution at 4.0, until its
UV spectrum showed reaction to be complete (ca. 0.461 mmol).
Hydrazine hydrate (55% aq., 0.045 ml, 0.79 mmol) was added
to the solution at room temperature and stirring was continued
for a further 30 h. The solvent was removed in vacuo to give a
yellow residue which was purified by column chromatography
on silica gel using ethyl acetate as eluent to afford methyl (2S)-
2-N-tert-butoxycarbonylamino(5-hydroxypyrazol-4-yl)butyrate
18 as a colourless oil (39 mg, 34%); [α]D25 ϩ6.5 (c 0.98, CHCl3);
m/z [ϩve FAB, PEGH–NOBA] Found 299.1477 [M]ϩ, C13H21-
N3O5 requires 299.1481; m/z [ϩve FAB, 3-NBA] 300 [M ϩ H]ϩ;
νmax (film)/cmϪ1 3300 (OH, NH), 1740 and 1691 (C᎐O); λ
25
less oil (32 mg, 32%); [α]D ϩ12.1 (c 0.9, CHCl3); m/z [ϩve
FAB, PEGH–NOBA] Found 314.1697 [M ϩ H]ϩ, [C14H23-
N3O5 ϩ H]ϩ requires 314.1716; m/z [ϩve FAB, 3-NBA] 314
[M ϩ H]ϩ; νmax (film)/cmϪ1 3400 (OH, NH), 1740 and 1689
(C᎐O); λ
᎐
(MeOH)/nm 235 (log ε 3.86); λmax (MeOH–HCl)/
max
nm 239 (log ε 3.94); λmax (MeOH–NaOH)/nm 256 (log ε 3.86);
δH (300 MHz, C2HCl3) 8.37 (1H, br s, OH, exchangeable with
2H3CO2H), 6.99 (1H, s, H-3Ј), 5.16 (1H, d, J 8.3, NH,
᎐
max
(MeOH)/nm 227 and 249 (log ε 3.66 and 3.45); λmax (MeOH–
HCl)/nm 232 (log ε 3.88); λmax (MeOH–NaOH)/nm 241 (log ε
3.90); δH (300 MHz, C2HCl3) 9.49 (1H, br s, OH, exchangeable
2
exchangeable with H3CO2H), 4.31 (1H, m, H-2), 3.71 (3H, s,
2
with H3CO2H), 7.18 (1H, s, H-3Ј), 5.43 (1H, d, J 8.3, NH,
NCH3), 3.68 (3H, s, OCH3), 2.48–2.32 (2H, m, H-4), 2.11–
1.82 (2H, m, H-3) and 1.44 [9H, s, C(CH3)3]; δC (75 MHz,
C2HCl3) 173.32 (ester), 159.94 (C-4Ј), 155.48 (urethane), 130.61
(C-3Ј), 103.12 (C-5Ј), 79.85 [OC(CH3)3], 52.78 (C-2), 52.19
(OCH3), 38.06 (NCH3), 32.71 (C-4), 28.27 [C(CH3)3] and 18.08
(C-3).
2
exchangeable with H3CO2H), 4.23 (1H, m, H-2), 3.67 (3H, s,
OCH3), 2.45–2.36 (2H, m, H-4), 2.05–1.79 (2H, m, H-3) and
1.41 [9H, s, C(CH3)3]; δC (75 MHz, C2HCl3) 173.49 (ester),
160.63 (C-4Ј), 155.69 (urethane), 129.46 (C-3Ј), 103.38 (C-5Ј),
79.92 [OC(CH3)3], 52.89 (C-2), 52.23 (OCH3), 32.45 (C-4),
28.23 [C(CH3)3] and 18.25 (C-3).
Method B. 1 M aqueous hydrochloric acid (0.320 ml, 0.320
mmol) was added to a stirred solution of methyl (2S )-N-tert-
butoxycarbonyl-5-dimethylaminomethylene-6-oxopiperidine-
2-carboxylate 16 (100 mg, 0.320 mmol) in methanol (10 ml) at
room temperature followed by immediate addition of methyl-
hydrazine (0.025 ml, 0.480 mmol). After stirring for 30 h the
solvent was removed in vacuo to give a yellow residue. Column
chromatography on silica gel using ethyl acetate as eluent
afforded methyl (2S)-2-N-tert-butoxycarbonylamino(1-methyl-
5-hydroxypyrazol-4-yl)butyrate 19 as a colourless oil (32 mg,
32%). All spectra were identical to the product from Method A.
Method B. 1 N aqueous hydrochloric acid (0.304 ml, 0.304
mmol) was added to a stirred solution of methyl (2S )-N-tert-
butoxycarbonyl-5-dimethylaminomethylene-6-oxopiperidine-
2-carboxylate 16 (95 mg, 0.304 mmol) in methanol (10 ml) at
room temperature followed by immediate addition of hydrazine
hydrate (55% aq., 0.027 ml, 0.478 mmol). After stirring for
30 h, the solvent was removed in vacuo to give a yellow residue.
Column chromatography on silica gel using ethyl acetate
as eluent afforded methyl (2S)-2-N-tert-butoxycarbonylamino-
(5-hydroxypyrazol-4-yl)butyrate 18 as a colourless oil (31 mg,
2464
J. Chem. Soc., Perkin Trans. 1, 2002, 2459–2472

View Article Online
Method C. Lithium hexamethyldisilazide (1 M in THF, 7.00
ml, 7.00 mmol) was added to a stirred solution of methyl
(2S )-N-tert-butoxycarbonyl-6-oxopiperidine-2-carboxylate 15
(1.50 g, 5.83 mmol) in THF (15 ml) at Ϫ78 ЊC under nitrogen.
The solution was allowed to warm to Ϫ30 ЊC over a period of
30 min to ensure enolate formation and was cooled to Ϫ78 ЊC.
Methyl formate (0.719 ml, 12 mmol) was added and the solu-
tion was stirred for 5 min at Ϫ78 ЊC, warmed to 0 ЊC and stirred
for a further 90 min. Saturated aqueous ammonium chloride
(5 ml) was added at 0 ЊC and the solvent was removed in vacuo
to give an orange residue. The residue was partitioned between
ethyl acetate (10 ml) and saturated aqueous ammonium chlor-
ide (5 ml). The organic layer was separated and the aqueous
layer was extracted with ethyl acetate (2 × 5 ml). The combined
organic layers were dried (MgSO4) and the solvent was removed
in vacuo to give a yellow oil. The crude oil was dissolved in
methanol (15 ml) and methylhydrazine (0.419 ml, 7.9 mmol)
was added. The solution was stirred at room temperature for
30 h and the solvent was removed in vacuo to give a yellow
residue. Column chromatography on silica gel using ethyl acet-
ate as eluent afforded methyl (2S)-2-N-tert-butoxycarbonyl-
amino(1-methyl-5-hydroxypyrazol-4-yl)butyrate 19 as a colour-
less oil (731 mg, 40%). All spectra were identical to those of the
product from Method A.
1.17 mmol) in THF (5 ml) at Ϫ78 ЊC under nitrogen. The solu-
tion was allowed to warm to Ϫ30 ЊC over a period of 30 min to
ensure enolate formation and cooled to Ϫ78 ЊC. Benzyl
bromoacetate (0.203 ml, 1.28 mmol) was added and stirring was
continued for a further 90 min. Saturated aqueous ammonium
chloride (5 ml) was added at Ϫ78 ЊC and the solvent was
removed in vacuo to give an orange residue. The residue was
partitioned between ethyl acetate (10 ml) and saturated aqueous
ammonium chloride (5 ml). The organic layer was separated
and the aqueous layer was extracted with ethyl acetate (2 ×
5 ml). The combined organic layers were dried (MgSO4) and the
solvent was removed in vacuo to give a yellow oil. Column
chromatography on silica gel using petroleum ether–ethyl
acetate (1:1) as eluent afforded methyl (2S,5RS)-N-tert-butoxy-
carbonyl-5-benzyloxycarbonylmethyl-6-oxopiperidine-2-carb-
oxylate 23 as a 1:1 mixture of diastereoisomers (266 mg,
56%); m/z [CI] Found 406.1862 [M ϩ H]ϩ, [C21H27NO7 ϩ H]ϩ
requires 406.1866; m/z [ϩve FAB, 3-NBA] 428 [M ϩ Na]ϩ and
406 [M ϩ H]ϩ; νmax (film)/cmϪ1 1778 and 1727 (C᎐O); δ (300
᎐
H
MHz, C2HCl3) 7.41–7.28 (5H, m, ArH), 5.15 and 5.13 (2H,
2 × m, OCH2Ph), 4.77 (0.5H, t, J 6.4, H-2), 4.68 (0.5H, m, H-2),
3.76 (3H, s, OCH3), 3.19–2.83 (2H, m, H-5 ϩ H-7A), 2.57 and
2.39 (1H, 2 × m, H-7B), 2.27–1.91 (3H, m, H-3 ϩ H-4A), 1.65
(1H, m, H-4B) and 1.50 [9H, s, C(CH3)3]; δC (75 MHz, C2HCl3)
172.03 and 171.88 (C-6), 171.78 and 171.75 (ester), 171.59 and
171.53 (ester), 152.01 (urethane), 136.70–128.15 (Ar), 83.78 and
83.61 [OC(CH3)3], 66.45 and 66.40 (OCH2Ph), 58.82 and 58.10
(C-2), 52.60 (OCH3), 41.20 and 39.80 (C-5), 35.94 and 35.83
(C-7), 27.82 [C(CH3)3], 25.48 and 24.70 (C-3), and 24.55 and
24.21 (C-4).
(2S )-2-Amino(5-hydroxypyrazol-4-yl)butyric acid hydrochloride
(20)
A solution of methyl (2S )-2-N-tert-butoxycarbonylamino-
(5-hydroxypyrazol-4-yl)butyrate 18 (475 mg, 1.59 mmol) in 6 N
aqueous hydrochloric acid (15 ml) was heated to reflux for 18 h.
The solvent was removed in vacuo and residual water was
removed using a freeze dryer to afford (2S)-2-amino(5-hydroxy-
pyrazol-4-yl)butyric acid hydrochloride 20 as a glassy solid (200
mg, 57%); mp >250 ЊC; [α]D25 ϩ27.6 (c 1.03, H2O); m/z [ϩve es]
Found 186.0875 [M ϩ H]ϩ, [C7H11N3O3 ϩ H]ϩ requires
Methyl (2S,5RS )-N-tert-butoxycarbonyl-5-carboxymethyl-6-
oxopiperidine-2-carboxylate (24)
Methyl (2S,5RS )-N-tert-butoxycarbonyl-5-benzyloxycarbonyl-
methyl-6-oxopiperidine-2-carboxylate 23 (210 mg, 0.518 mmol)
and 5% palladium on carbon catalyst (21 mg) were stirred in
ethyl acetate (5 ml) in an atmosphere of hydrogen at room
temperature for 3 h. The catalyst was removed by filtration
through Celite® and the solvent was removed in vacuo to give a
yellow residue. Column chromatography on silica gel using
ethyl acetate as eluent afforded methyl (2S,5RS)-N-tert-but-
oxycarbonyl-5-carboxymethyl-6-oxopiperidine-2-carboxylate 24
as a colourless oil (143 mg, 88%); m/z [CI] Found 316.1394
[M ϩ H]ϩ, [C14H21NO7 ϩ H]ϩ requires 316.1396; m/z [ϩve FAB,
3-NBA] 316 [M ϩ H]ϩ and 338 [M ϩ Na]ϩ; νmax (film)/cmϪ1
1775 and 1724 (C᎐O); δ (300 MHz, C2HCl3) 8.05 (1H, br s,
186.0878; νmax (KBr)/cmϪ1 3300 (OH, NH) and 1723 (C᎐O);
᎐
λmax (MeOH)/nm 232 and 252 (log ε 3.70 and 3.54); λmax
(MeOH–HCl)/nm 231 (log ε 3.87); λmax (MeOH–NaOH)/nm
243 (log ε 3.83); δH (300 MHz,2H2O–2HCl) 7.45 (1H, s, H-3Ј),
3.74 (1H, t, J2,3 6.5, H-2), 2.26 (2H, m, H-4) and 1.86 (2H, m,
H-3); δC (75 MHz,2H2O–2HCl) 171.60 (acid), 154.24 (C-4Ј),
134.22 (C-3Ј), 103.60 (C-5Ј), 52.11 (C-2), 29.38 (C-4) and 17.14
(C-3).
(2S )-2-Amino(1-methyl-5-hydroxypyrazol-4-yl)butyric acid
hydrochloride (21)
᎐
H
OH, exchangeable with 2H3CO2H), 4.78 (0.5H, t, J2,3 6.4, H-2),
4.68 (0.5H, m, H-2), 3.78 (3H, s, OCH3), 3.13–2.81 (2H, m,
H-5 ϩ H-7A), 2.55 and 2.43 (1H, 2 × m, H-7B), 2.31–1.94 (3H,
m, H-3 ϩ H-4A), 1.65 (1H, m, H-4B) and 1.50–1.49 [9H, 2 × s,
C(CH3)3]; δC (75 MHz, C2HCl3) 177.24 and 176.98 (acid),
172.00 and 171.89 (C-6), 171.81 (ester), 152.48 and 151.94
(urethane), 84.00 and 83.84 [OC(CH3)3], 58.87 and 58.13 (C-2),
52.68 and 52.63 (OCH3), 41.00 and 39.63 (C-5), 35.78 and
35.66 (C-7), 27.81 [C(CH3)3], 25.47 and 24.67 (C-3), and 24.25
and 21.03 (C-4).
A solution of methyl (2S )-2-N-tert-butoxycarbonylamino(1-
methyl-5-hydroxypyrazol-4-yl)butyrate 19 (365 mg, 1.16 mmol)
in 6 N aqueous hydrochloric acid (15 ml) was heated to reflux
for 18 h. The solvent was removed in vacuo and residual water
was removed using a freeze dryer to afford (2S)-2-amino-
(1-methyl-5-hydroxypyrazol-4-yl)butyric acid hydrochloride 21
25
as a colourless gum (110 mg, 40%); [α]D ϩ15.9 (c 1.6, H2O);
m/z [ϩve es] Found 200.1039 [M ϩ H]ϩ, [C8H13N3O3 ϩ H]ϩ
requires 200.1035; νmax (KBr)/cmϪ1 3400 (OH–NH) and 1716
(C᎐O); λmax (MeOH)/nm 235 and 263 (sh) (log ε 3.77 and 3.17);
᎐
λmax (MeOH–HCl)/nm 239 (log ε 3.88); λmax (MeOH–NaOH)/
nm 257 (log ε 3.76); δH (300 MHz,2H2O–2HCl) 7.35 (1H, s,
H-3Ј), 3.72 (1H, t, J2,3 6.5, H-2), 3.46 (3H, s, NCH3), 2.25 (2H,
m, H-4) and 1.83 (2H, m, H-3); δC (75 MHz,2H2O–2HCl) 171.65
(acid), 154.31 (C-4Ј), 136.83 (C-3Ј), 103.48 (C-5Ј), 52.11 (C-2),
37.24 (NCH3), 29.50 (C-4) and 17.16 (C-3).
Methyl (2S,5RS )-N-tert-butoxycarbonyl-5-(2-hydroxyethyl)-6-
oxopiperidine-2-carboxylate (25)
Borane–dimethyl sulfide complex (1 M in THF, 0.380 ml, 0.761
mmol) was added to a stirred solution of methyl (2S,5RS )-N-
tert-butoxycarbonyl-5-carboxymethyl-6-oxopiperidine-2-carb-
oxylate 24 (200 mg, 0.634 mmol) in THF (6 ml) at 0 ЊC under
nitrogen. The mixture was allowed to warm to room temper-
ature and stirred for 30 min. Methanol (2 ml) was added and,
after stirring for 2 min, the solvents were removed in vacuo to
yield a mixture of the alcohol 25 and the lactone 27 (106 mg,
55%); m/z [ϩve es] Found 319.1871 [M ϩ NH4]ϩ, [C14H23NO6 ϩ
NH4]ϩ requires 319.1869; m/z [ϩve FAB, 3-NBA] 302 [M ϩ H]ϩ
Methyl (2S,5RS )-N-tert-butoxycarbonyl-5-benzyloxycarbonyl-
methyl-6-oxopiperidine-2-carboxylate (23)
Lithium hexamethyldisilazide (1 M in THF, 1.40 ml, 1.40
mmol) was added to a stirred solution of methyl (2S )-N-tert-
butoxycarbonyl-6-oxopiperidine-2-carboxylate 15 (300 mg,
J. Chem. Soc., Perkin Trans. 1, 2002, 2459–2472
2465

View Article Online
and 324 [M ϩ Na]ϩ; νmax (film)/cmϪ1 1771, 1747 and 1721
ether–ethyl acetate (1:1) as eluent afforded methyl (2S,5RS)-N-
(C᎐O). Methyl (2S,5RS)-N-tert-butoxycarbonyl-5-(2-hydroxy-
tert-butoxycarbonyl-5-allyl-6-oxopiperidine-2-carboxylate 28 as
a 1:1 mixture of diastereoisomers (1.30 g, 45%); m/z [CI] Found
298.1656 [M ϩ H]ϩ, [C15H23NO5 ϩ H]ϩ requires 298.1654; m/z
[ϩve FAB, 3-NBA] 298 [M ϩ H]ϩ and 320 [M ϩ Na]ϩ; νmax
᎐
ethyl)-6-oxopipecolate 25; δH (300 MHz, C2HCl3 recorded
immediately) 4.68 (1H, m, H-2), 3.74 (3H, s, OCH3), 3.74 (2H,
m, CH2OH), 2.90 (1H, br s, OH, exchangeable with 2H3CO2H),
2.62 (1H, m, H-7A), 2.32–1.50 (6H, m, H-3, H-4, H-5 ϩ H-7B)
and 1.47 [9H, s, C(CH3)3]; δC (75 MHz, C2HCl3) 174.35 (C-6),
172.15 and 171.94 (ester), 152.20 (urethane), 83.70 and 83.61
[OC(CH3)3], 60.52 and 60.44 (CH2OH), 58.78 and 58.33 (C-2),
52.56 (OCH3), 41.97 and 40.76 (C-5), 34.66 and 34.33 (C-7),
28.18 [C(CH3)3], 25.29 and 24.85 (C-3), and 24.39 and 23.63
(C-4). Methyl (2S,4RS)-2-tert-butoxycarbonylamino-4-(2-oxo-
tetrahydrofuran-3-yl)butyrate 27; δH (300 MHz, C2HCl3,
recorded after 1 week in C2HCl3) 5.17 (1H, d, J 7.9, NH,
exchangeable with 2H3CO2H), 4.64 (1H, m, H-2), 4.38–4.03
(2H, m, CH2O), 3.71 (3H, s, OCH3), 2.53 (1H, m, H-4A), 2.39
(1H, m, H-4B), 2.31–1.50 (5H, m, H-3, H-3Јϩ H-4Ј) and 1.44
and 1.43 [9H, 2 × s, C(CH3)3]; The 13C NMR spectrum was too
complex to assign.
(film)/cmϪ1 1777, 1749 and 1722 (C᎐O); δH (300 MHz, C2HCl3)
᎐
5.74 (1H, m, CH᎐), 5.05 (2H, m, ᎐CH ), 4.77 (1H, 2 × m, H-2),
᎐
᎐
2
3.75 (3H, s, OCH3), 2.74–1.49 (7H, m, H-3, H-4, H-7 ϩ H-5)
and 1.48 [9H, s, C(CH3)3]; δC (75 MHz, C2HCl3) 172.84 and
172.40 (C-6), 172.11 and 172.04 (ester), 152.41 (urethane),
135.48 and 135.37 (CH᎐), 117.43 and 117.17 (᎐CH ), 83.51 and
᎐
᎐
2
83.42 [OC(CH3)3], 58.79 and 58.26 (C-2), 52.52 and 52.45
(OCH3), 43.60 and 42.73 (C-5), 35.85 and 35.47 (C-7), 27.83
[C(CH3)3], 23.70 and 23.34 (C-3), and 22.79 (C-4).
Methyl (2S,5RS )-N-tert-butoxycarbonyl-5-(2-oxoethyl)-6-
oxopiperidine-2-carboxylate (26)
Method 2. A solution of methyl (2S,5RS )-N-tert-butoxy-
carbonyl-5-allyl-6-oxopiperidine-2-carboxylate 28 (855 mg,
2.86 mmol) in dichloromethane (30 ml) was cooled to Ϫ78 ЊC
and oxygen was passed through the solution for 5 min, followed
by ozone for 15 min, during which time it turned blue. Triphe-
nylphosphine (905 mg, 3.42 mmol) was added at Ϫ78 ЊC and
the solution was allowed to warm slowly to room temperature.
The solvent was removed in vacuo and the oil was purified by
column chromatography on silica gel using petroleum ether–
ethyl acetate (1:1) as eluent to afford methyl (2S,5RS)-N-tert-
butoxycarbonyl-5-(2-oxoethyl)-6-oxopiperidine-2-carboxylate
26 (622 mg, 72%) as a 1:1 mixture of diastereoisomers. The
spectra were identical to those of the sample prepared by
Method 1.
Methyl (2S,5RS )-N-tert-butoxycarbonyl-5-(2-oxoethyl)-6-
oxopiperidine-2-carboxylate (26)
Method 1. Oxalyl chloride (0.014 ml, 0.16 mmol) was dis-
solved in dichloromethane (2 ml) and the stirred solution was
cooled to Ϫ60 ЊC under nitrogen. Dimethyl sulfoxide (0.023 ml,
0.327 mmol) was added dropwise and the solution was stirred
for 3 min. A solution of methyl (2S,5RS )-N-tert-butoxy-
carbonyl-5-hydroxyethyl-6-oxopiperidine-2-carboxylate 25 (45
mg, 0.149 mmol) in dichloromethane (1 ml) was added. Stirring
was continued for a further 15 min and triethylamine (0.104 ml,
0.747 mmol) was added. Stirring at Ϫ60 ЊC was continued for
5 min and the solution was allowed to warm to room temper-
ature. Water (2 × 5 ml) was added and the organic layer was
separated. The aqueous layer was extracted with dichloro-
methane (2 × 5 ml). The combined organic layers were washed
with brine (5 ml) and dried (MgSO4). The solvent was removed
in vacuo to give a yellow residue. Column chromatography on
silica gel using ethyl acetate as eluent afforded methyl
(2S,5RS)-N-tert-butoxycarbonyl-5-(2-oxoethyl)-6-oxopiper-
idine-2-carboxylate 26 (8 mg, 20%) as a 1:1 mixture of dia-
stereoisomers; m/z [ϩve FAB, 3-NBA] 300 [M ϩ H]ϩ and 322
[M ϩ Na]ϩ; νmax (film)/cmϪ1 1775, 1747 and 1722 (C᎐O); δ (300
Methyl (2S,4RS )-2-tert-butoxycarbonylamino-4-(3-oxo-2,3,4,5-
tetrahydropyridazin-4-yl)butyrate (32)
Hydrazine hydrate (55% aq., 0.052 ml, 0.919 mmol) was added
to
a stirred solution of methyl (2S,5RS )-N-tert-butoxy-
carbonyl-5-(2-oxoethyl)-6-oxopiperidine-2-carboxylate 26 (275
mg, 0.919 mmol) in methanol (6 ml) under nitrogen. The solu-
tion was stirred at room temperature for 2 h and the solvent was
removed in vacuo to give a yellow residue. Column chrom-
atography on silica gel using ethyl acetate–petroleum ether
(4:1) as eluent afforded methyl (2S,4RS)-2-tert-butoxycarbonyl-
amino-4-(3-oxo-2,3,4,5-tetrahydropyridazin-4-yl)butyrate (32)
as a colourless oil (179 mg, 62%); m/z [CI] Found 314.1718
[M ϩ H]ϩ, [C14H23N3O5 ϩ H]ϩ requires 314.1716; m/z [ϩve
FAB, 3-NBA] 314 [M ϩ H]ϩ; νmax (film)/cmϪ1 1739, 1693 and
᎐
H
MHz, C2HCl3, mixed diastereoisomers) 9.80 (1H, d, J 8.5,
CH᎐O), 4.78 and 4.68 (1H, 2 × m, H-2), 3.77 (3H, s, OCH ),
᎐
3
3.17–2.93 (2H, m, H-5 ϩ H-7A), 2.56 (1H, m, H-7B), 2.31–1.91
(3H, m, H-3 ϩ H-4A), 1.73–1.50 (1H, m, H-4B) and 1.49 [9H s,
C(CH3)3]; δC (75 MHz, C2HCl ) 200.19 and 199.80 (CH᎐O),
᎐
3
1634 (C᎐O); λ
(MeOH)/nm 239 (log ε 3.60); δH (300 MHz,
᎐
171.94 and 171.91 (C-6), 171.75 (ester), 151.93 (urethane),
83.91 and 83.77 [OC(CH3)3], 58.76 and 58.05 (C-2), 52.64 and
52.60 (OCH3), 44.98 (C-7), 39.45 and 38.22 (C-5), 27.78
[C(CH3)3], 25.44 and 24.93 (C-3), and 25.60 and 24.43 (C-4).
max
C2HCl3) 8.75 (1H, br s, NH, exchangeable with 2H3CO2H), 7.14
(1H, t, J 2.8, H-6Ј), 5.26 (1H, d, J 7.6, NH, exchangeable with
2H3CO2H), 4.20 (1H, m, H-2), 3.74 (3H, s, OCH3), 2.62 (1H, m,
H-5ЈA), 2.43 (1H, m, H-4Ј), 2.27 (1H, m, H-5ЈB), 1.98–1.69
(3H, m, H-3 ϩ H-4A), 1.51 (1H, m, H-4B) and 1.43 [9H, s,
C(CH3)3]; δC (75 MHz, C2HCl3) 172.88 (C-3Ј), 169.64 (ester),
155.40 (urethane), 144.39 (C-6Ј), 79.95 [OC(CH3)3], 53.03
(C-2), 52.39 (OCH3), 34.94 (C-4Ј), 30.01 (C-5Ј), 28.25
[C(CH3)3], 27.81 (C-3) and 25.66 (C-4).
Methyl (2S,5RS )-N-tert-butoxycarbonyl-5-allyl-6-oxopiper-
idine-2-carboxylate (28)
Lithium hexamethyldisilazide (1 M in THF, 11.66 ml, 12 mmol)
was added to a stirred solution of methyl (2S )-N-tert-butoxy-
carbonyl-6-oxopipecolate 15 (2.50 g, 9.72 mmol) in THF (25
ml) at Ϫ78 ЊC under nitrogen. The solution was allowed to
warm to Ϫ30 ЊC over 30 min to ensure enolate formation and
cooled to Ϫ78 ЊC. Allyl bromide (3.36 ml, 39 mmol) was added
and stirring was continued for a further 90 min. Saturated
aqueous ammonium chloride (15 ml) was added at Ϫ78 ЊC and
the solvent was removed in vacuo to give an orange residue. The
residue was partitioned between ethyl acetate (25 ml) and satur-
ated aqueous ammonium chloride (20 ml). The organic layer
was separated and the aqueous layer was extracted with ethyl
acetate (2 × 15 ml). The combined organic layers were dried
(MgSO4) and the solvent was removed in vacuo to give a yellow
oil. Column chromatography on silica gel using petroleum
(2S,4RS )-2-Amino-4-(3-oxo-2,3,4,5-tetrahydropyridazin-4-yl)-
butyrate hydrochloride (34)
A solution of methyl (2S,4RS )-2-tert-butoxycarbonylamino-4-
(3-oxo-2,3,4,5-tetrahydropyridazin-4-yl)butyrate 32 (89 mg,
0.284 mmol) in 6 N aqueous hydrochloric acid (5 ml) was
heated to reflux for 18 h. The solvent was removed in vacuo and
residual water was removed using a freeze dryer to afford
(2S,4RS)-2-amino-4-(3-oxo-2,3,4,5-tetrahydropyridazin-4-yl)-
butyrate hydrochloride 34 as a foam (22 mg, 33%); m/z [ϩve es]
Found 200.1043 [M ϩ H]ϩ, [C8H13N3O3 ϩ H]ϩ requires
200.1035; νmax (KBr)/cmϪ1 3400 (NH–OH), 1734 and 1653
2466
J. Chem. Soc., Perkin Trans. 1, 2002, 2459–2472

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(C᎐O); λmax (MeOH)/nm 233 (log ε 2.35); δH (300 MHz, 2H2O–
[M ϩ H]ϩ, [C15H27NO4 ϩ H]ϩ requires 286.2018; m/z [ϩve FAB,
᎐
2HCl) 6.76 (1H, m, H-6Ј), 3.52 (1H, m, H-2) and 2.67–0.97 (7H,
3-NBA] 286 [M ϩ H]ϩ; νmax (film)/cmϪ1 1772, 1736 and 1698
2
m, H-3, H-4, H-4Ј ϩ H-5Ј); δC (75 MHz, H2O–2HCl) 171.58
(C᎐O); δ (400 MHz, C2HCl3, rotamers present) 4.80 and 4.62
᎐
H
(C-3Ј), 165.88 (acid), 144.76 (C-6Ј), 52.55 (C-2), 33.41 (C-4Ј),
30.74 (C-5Ј), 28.88 (C-4) and 26.73 (C-3).
(1H, 2 × m, H-2), 4.00 (1H, m, H-6A), 2.95 (1H, m, H-6B), 2.20
(1H, m, H-3A), 1.79–1.60 (4H, m, H-3B, H-4A ϩ H-5), 1.48
[18H, 2 × s, 2 × C(CH3)3] and 1.26 (1H, m, H-4B); δC (100 MHz,
C2HCl3) 170.96 (ester), 155.14 (urethane), 81.65 and 80.06
[2 × OC(CH3)3], 55.92 (C-2), 41.76 (C-6), 28.49 [2 × OC(CH3)3],
27.24 (C-5), 25.60 (C-3) and 21.60 (C-4).
Methyl (2S,4RS )-2-tert-butoxycarbonylamino-4-(2-methyl-3-
oxo-2,3,4,5-tetrahydropyridazin-4-yl)butyrate (35)
Methylhydrazine (0.049 ml, 0.92 mmol) was added to a stirred
solution of methyl (2S,5RS )-N-tert-butoxycarbonyl-5-(2-oxo-
ethyl)-6-oxopiperidine-2-carboxylate 26 (275 mg, 0.919 mmol)
in methanol (6 ml) under nitrogen. The solution was stirred at
room temperature for 2 h and the solvent was removed in vacuo
to give a yellow residue. Column chromatography on silica gel
using ethyl acetate–petroleum ether (4:1) as eluent afforded
methyl (2S,4RS)-2-tert-butoxycarbonylamino-4-(2-methyl-3-
oxo-2,3,4,5-tetrahydropyridazin-4-yl)butyrate 34 as a colour-
less oil (120 mg, 40%); m/z [CI] Found 328.1872 [M ϩ H]ϩ,
[C15H25N3O5 ϩ H]ϩ requires 328.1872; m/z [ϩve FAB, 3-NBA]
328 [M ϩ H]ϩ; νmax (film)/cmϪ1 1742, 1695 and 1657 (C᎐O); λ
tert-Butyl (2S )-N-tert-butoxycarbonyl-6-oxopiperidine-2-
carboxylate (41)
A solution of tert-butyl (2S )-N-tert-butoxycarbonylpiperidine-
2-carboxylate 40 (2.02 g, 7.07 mmol) in ethyl acetate (60 ml) was
added at room temperature to a vigorously stirred solution of
ruthenium() chloride hydrate (368 mg, 1.8 mmol) and sodium
periodate (6.05 g, 28 mmol) in water (60 ml). The solution was
stirred for 18 h. The aqueous layer was extracted with ethyl
acetate (4 × 25ml), the organic layers were combined and the
excess ruthenium tetroxide was destroyed by stirring for 2 h
with isopropyl alcohol (1.5 ml). The precipitate was removed by
filtration through Celite®. The filtrate was dried (MgSO4) and
the solvent was removed in vacuo to give an orange residue.
Column chromatography on silica gel using petroleum ether–
ethyl acetate (3:1) as eluent afforded tert-butyl (2S)-N-tert-
butoxycarbonyl-6-oxopiperidine-2-carboxylate 41 as a white
᎐
max
(MeOH)/nm 247 (log ε 3.60); δH (300 MHz, C2HCl3) 7.13 (1H,
t, J 3.1, H-6Ј), 5.24 (1H, d, J 8.0, NH, exchangeable with
2H3CO2H), 4.26 (1H, m, H-2), 3.70 (3H, s, OCH3), 3.30 (1H, s,
NCH3), 2.55 (1H, m, H-5ЈA), 2.37 (1H, m, H-4Ј), 2.23 (1H,
m, H-5ЈB), 1.96–1.58 (4H, m, H-3 ϩ H-4), and 1.40 [9H, s,
C(CH3)3]; δC (75 MHz, C2HCl3) 172.81 (C-3Ј), 167.93 (ester),
155.32 (urethane), 144.12 (C-6Ј), 79.79 [OC(CH3)3], 53.01
(C-2), 52.27 (OCH3), 36.32 (NCH3), 35.20 (C-4Ј), 29.93 (C-5Ј),
28.17 [C(CH3)3], 28.05 (C-3) and 25.72 (C-4).
25
solid (1.76 g, 83%); mp 80–82 ЊC; [α]D 0.00 (c 1.5, CHCl3);
m/z [ϩve es] Found 300.1819 [M ϩ H]ϩ, [C15H25NO5 ϩ H]ϩ
requires 300.1811; m/z [ϩve FAB, 3-NBA] 300 [M ϩ H]ϩ and
322 [M ϩ Na]ϩ; νmax (KBr)/cmϪ1 1777 and 1723 (C᎐O); δH (400
᎐
MHz, C2HCl3) 4.58 (1H, dd, J2,3 3.6 and 6.2, H-2), 2.62–2.42
(2H, m, H-5), 2.17 (1H, m, H-3A), 1.99 (1H, m, H-3B), 1.85–
1.66 (2H, m, H-4), 1.51 [9H, s, C(CH3)3] and 1.47 [9H, s,
C(CH3)3]; δC (100 MHz, C2HCl3) 170.52 (C-6), 170.48 (ester),
152.19 (urethane), 83.22 and 82.13 [2 × OC(CH3)3], 58.98 (C-2),
34.48 (C-5), 27.89 [2 × C(CH3)3], 25.82 (C-3) and 18.17 (C-4);
HPLC on a Chiracel OD-H chiral column using 2% EtOH in
heptane, flow rate 1.0 ml minϪ1 at room temperature gave a
single peak, Rt 9.14 min whereas a racemic sample prepared
from (2RS )-piperidine-2-carboxylic acid showed two peaks, Rt
7.14 and 9.4 min under these conditions.
tert-Butyl (2S )-piperidine-2-carboxylate (39)
Perchloric acid (70%) was added dropwise to a vigorously
stirred suspension of (2S )-piperidine-2-carboxylic acid 3812,13
(2.78 g, 22 mmol) in tert-butyl acetate (30 ml) until the suspen-
sion had completely dissolved. The solution was stirred for a
further 10 min and the pH was adjusted to 9 using saturated
aqueous sodium hydrogen carbonate. The organic layer was
separated and the aqueous layer was extracted with ethyl acet-
ate (3 × 50 ml). Brine (50 ml) was added to the aqueous layer,
which was further extracted with ethyl acetate (2 × 50 ml). The
combined organic layers were dried (MgSO4) and the solvent
was removed in vacuo to afford tert-butyl (2S)-piperidine-2-
tert-Butyl (2S )-2-N-tert-butoxycarbonylamino(5-hydroxy-
pyrazol-4-yl)butyrate (43)
25
carboxylate 39 as a colourless oil (2.15 g, 54%); [α]D Ϫ2.1
(c 1.5, CHCl3); m/z [ϩve es] Found 186.1492 [M ϩ H]ϩ,
[C10H19NO2 ϩ H]ϩ requires 186.1494; νmax (film)/cmϪ1 3600
Lithium hexamethyldisilazide (1 M in THF, 5.51 ml, 5.51
mmol) was added to a stirred solution of tert-butyl (2S )-N-tert-
butoxycarbonyl-6-oxopiperidine-2-carboxylate 41 (1.50 g, 5.01
mmol) in THF (15 ml) at Ϫ78 ЊC under nitrogen. The solution
was allowed to warm to Ϫ30 ЊC over 30 min to ensure enolate
formation and cooled to Ϫ78 ЊC. Methyl formate (0.618 ml,
10 mmol) was added. The solution was stirred for 5 min at
Ϫ78 ЊC, warmed to 0 ЊC and stirred for a further 90 min. Satur-
ated aqueous ammonium chloride (5 ml) was added at 0 ЊC and
the solvent was removed in vacuo to give an orange residue. The
residue was partitioned between ethyl acetate (10 ml) and satur-
ated aqueous ammonium chloride (5 ml). The organic layer was
separated and the aqueous layer was extracted with ethyl acet-
ate (2 × 5 ml). The combined organic layers were dried (MgSO4)
and the solvent was removed in vacuo to give a yellow oil. The
crude oil was dissolved in methanol (15 ml) and hydrazine
hydrate (55% aq., 0.446 ml, 15 mmol) was added. The solution
was stirred at room temperature for 30 h and the solvent was
removed in vacuo to give a yellow residue. Column chromato-
graphy on silica gel using ethyl acetate afforded tert-butyl (2S)-
2-N-tert-butoxycarbonylamino(5-hydroxypyrazol-4-yl)butyrate
43 as a colourless oil (786 mg, 46%); [α]D25 ϩ6.0 (c 0.2, CHCl3);
m/z [CI] Found 342.2029 [M ϩ H]ϩ, [C16H27N3O5 ϩ H]ϩ
requires 342.2029; m/z [ϩve FAB, 3-NBA] 342 [M ϩ H]ϩ and
364 [M ϩ Na]ϩ; νmax (film)/cmϪ1 1713 and 1695 (C᎐O); λ
(OH, NH) and 1734 (C᎐O); δ (400 MHz, C2HCl ) 6.24 (1H, br
᎐
H
3
2
s, NH, exchangeable with H3CO2H), 3.90 (1H, m, H-2), 3.64
(1H, m, H-6A), 3.20 (1H, m, H-6B), 2.26 (1H, m, H-3A), 1.99–
1.80 (4H, m, H-3B, H-4A ϩ H-5), 1.62 (1H, m, H-4B) and 1.51
[9H, s, C(CH3)3]; δC (100 MHz, C2HCl3) 167.49 (ester), 85.13
[2 × OC(CH3)3], 57.93 (C-2), 44.96 (C-6), 27.93 and 27.93
[2 × OC(CH3)3], 25.77 (C-3), 21.71 (C-5) and 21.62 (C-4).
tert-Butyl (2S )-N-tert-butoxycarbonylpiperidine-2-carboxylate
(40)
Di-tert-butyl dicarbonate (2.74 g, 13 mmol) and triethylamine
(1.75 ml, 13 mmol) were added to a solution of tert-butyl (2S )-
piperidine-2-carboxylate 39 (1.55 g, 8.37 mmol) in methanol
(650 ml) at room temperature under nitrogen. The solution was
stirred for 12 h and the solvent was removed in vacuo to give a
yellow residue. The residue was partitioned between ethyl acet-
ate (20 ml) and water (10 ml). The organic layer was washed
with water (2 × 5 ml) and dried (MgSO4). The solvent was
removed in vacuo to give a yellow oil. Column chromatography
on silica gel using petroleum ether–ethyl acetate (3:1) as eluent
afforded the product tert-butyl (2S)-N-tert-butoxycarbonyl-
piperidine-2-carboxylate 40 as a colourless oil (2.02 g, 85%);
25
[α]D Ϫ28.8 (c 1.45, CHCl3); m/z [ϩve es] Found 286.2020
᎐
max
J. Chem. Soc., Perkin Trans. 1, 2002, 2459–2472
2467

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(MeOH)/nm 226 and 252 (log ε 3.55 and 3.26); λmax (MeOH–
HCl)/nm 230 (log ε 3.70); λmax (MeOH–NaOH)/nm 241 (log ε
3.64); δH (300 MHz, C2HCl3) 9.95 (1H, br s, OH, exchangeable
was removed using a freeze dryer to afford (2S)-2-amino(5-
hydroxy-1-methylpyrazol-4-yl)butyric acid hydrochloride (21) as
a glassy solid (94 mg, 91%). The spectra were identical with
those of the sample prepared from the corresponding methyl
ester 19.
2
with H3CO2H), 7.18 (1H, s, H-3Ј), 5.30 (1H, d, J 8.3, NH,
2
exchangeable with H3CO2H), 4.17 (1H, m, H-2), 2.44 (2H, t,
J 7.2, H-4), 2.05–1.77 (2H, m, H-3) and 1.43 [18H, s, C(CH3)3];
δC (75 MHz, C2HCl3) 172.11 (ester), 160.77 (C-4Ј), 155.66
(urethane), 129.14 (C-3Ј), 103.76 (C-5Ј), 81.84 and 79.69 [2 ×
OC(CH3)3], 53.58 (C-2), 32.93 (C-4), 28.27 and 27.91 [2 ×
C(CH3)3] and 18.19 (C-3).
tert-Butyl (2S,5RS )-N-tert-butoxycarbonyl-5-allyl-6-oxopiper-
idine-2-carboxylate (45)
Lithium hexamethyldisilazide (1 M in THF, 12.03 ml, 12 mmol)
was added to a stirred solution of tert-butyl (2S )-N-tert-
butoxycarbonyl-6-oxopiperidine-2-carboxylate 41 (3.00 g, 10
mmol) in THF (30 ml) at Ϫ78 ЊC under nitrogen. The solution
was allowed to warm to Ϫ30 ЊC over 30 min to ensure enolate
formation and cooled to Ϫ78 ЊC. Allyl bromide (3.47 ml, 40
mmol) was added and stirring was continued for a further
90 min. Saturated aqueous ammonium chloride (15 ml) was
added at Ϫ78 ЊC and the solvent was removed in vacuo to give
an orange residue. The residue was partitioned between ethyl
acetate (25 ml) and saturated aqueous ammonium chloride (20
ml). The organic layer was separated and the aqueous layer was
extracted with ethyl acetate (2 × 15 ml). The combined organic
layers were dried (MgSO4) and the solvent was removed in
vacuo to give a yellow oil. Column chromatography on silica gel
using petroleum ether–ethyl acetate (3:1) as eluent afforded tert-
butyl (2S,5RS)-N-tert-butoxycarbonyl-5-allyl-6-oxopiperidine-
2-carboxylate 45 as a 1:1 mixture of cis/trans diastereoisomers
(2.01 g, 59%); m/z [CI] Found 340.2127 [M ϩ H]ϩ, [C18H29NO5
ϩ H]ϩ requires 340.2124; m/z [ϩve FAB, 3-NBA] 340 [M ϩ H]ϩ
and 362 [M ϩ Na]ϩ; νmax (film)/cmϪ1 1776, 1740 and 1722
(C᎐O); δ (400 MHz, C2HCl ) 5.76 (1H, m, CH᎐), 5.06 (2H, m,
tert-Butyl (2S )-2-N-tert-butoxycarbonylamino(5-hydroxy-1-
methylpyrazol-4-yl)butyrate (44)
Lithium hexamethyldisilazide (1 M in THF, 5.51 ml, 5.51
mmol) was added to a stirred solution of tert-butyl (2S )-N-tert-
butoxycarbonyl-6-oxopiperidine-2-carboxylate 41 (1.50 g, 5.01
mmol) in THF (15 ml) at Ϫ78 ЊC under nitrogen. The solution
was allowed to warm to Ϫ30 ЊC over 30 min to ensure enolate
formation and cooled to Ϫ78 ЊC. Methyl formate (0.618 ml,
10 mmol) was added. The solution was stirred for 5 min at
Ϫ78 ЊC, warmed to 0 ЊC, and stirred for a further 90 min.
Saturated aqueous ammonium chloride (5 ml) was added at
0 ЊC and the solvent was removed in vacuo to give an orange
residue. The residue was partitioned between ethyl acetate
(10 ml) and saturated aqueous ammonium chloride (5 ml). The
organic layer was separated and the aqueous layer was
extracted with ethyl acetate (2 × 5 ml). The combined organic
layers were dried (MgSO4) and the solvent was removed
in vacuo to give a yellow oil. The crude oil was dissolved in
methanol (15 ml) and methylhydrazine (0.359 ml, 6.7 mmol)
was added. The solution was stirred at room temperature for
30 h and the solvent was removed in vacuo to give a yellow
residue. Column chromatography on silica gel using ethyl
acetate as eluent gave tert-butyl (2S)-2-N-tert-butoxycarbonyl-
amino(5-hydroxy-1-methylpyrazol-4-yl)butyrate 44 as a colour-
less oil (748 mg, 42%); [α]D25 ϩ2.3 (c 1.0, CHCl3); m/z [ϩve es]
Found 356.2187 [M ϩ H]ϩ, [C17H29N3O5 ϩ H]ϩ requires
356.2185; νmax (film)/cmϪ1 1713 and 1640 (sh) (C᎐O); λ
᎐
᎐
H
3
᎐CH ), 4.59 (0.5H, t, J 5.6, H-2), 4.52 (0.5H, m, H-2), 2.65 (1H,
᎐
2
m, H-7A), 2.54–1.77 (5H, m, H-3, H-4A, H-5 ϩ H-7B), 1.60
(1H, m, H-4B), 1.50 [9H, s, C(CH3)3] and 1.46 [9H, s, C(CH3)3];
δC (100 MHz, C2HCl3) 173.10 and 172.60 (C-6), 170.68 and
170.59 (ester), 152.77 and 152.55 (urethane), 135.65 and 135.56
(CH᎐), 117.30 and 117.09 (᎐CH ), 83.18, 83.08 and 82.09
᎐
᎐
2
[2 × OC(CH3)3], 59.52 and 58.83 (C-2), 43.63 and 42.70 (C-5),
35.93 and 35.59 (C-7), 27.89 and 27.86 [2 × C(CH3)3], 25.54 and
23.83 (C-3), and 23.53 and 22.75 (C-4).
᎐
max
(MeOH)/nm 233 (log ε 3.62); λmax (MeOH–HCl)/nm 240 (log ε
3.64); λmax (MeOH–NaOH)/nm 254 (log ε 3.55); δH (300 MHz,
C2HCl3) 8.62 (1H, br s, OH, exchangeable with 2H3CO2H), 6.88
(1H, s, H-3Ј), 5.10 (1H, d, J 8.1, NH, exchangeable with
2H3CO2H), 4.15 (1H, m, H-2), 3.58 (3H, s, NCH3), 2.34 (2H, t,
J 6.9, H-4), 2.05–1.77 (2H, m, H-3) and 1.45 [18H, s, C(CH3)3];
δC (75 MHz, C2HCl3) 171.97 (ester), 160.19 (C-4Ј), 155.46
(urethane), 130.22 (C-3Ј), 103.36 (C-5Ј), 81.71 and 79.53 [2 ×
OC(CH3)3], 53.48 (C-2), 38.02 (NCH3), 33.03 (C-4), 28.21 and
27.91 [2 × C(CH3)3] and 17.97 (C-3).
Altering the ratio of diastereoisomers in (45) by quenching with
2,6-di-tert-butylphenol
Lithium hexamethyldisilazide (1 M in THF, 1.41 ml, 1.41
mmol) was added to a stirred solution of tert-butyl (2S,5RS )-
N-tert-butoxycarbonyl-5-allyl-6-oxopiperidine-2-carboxylate
45 (300 mg, 0.884 mmol) as a 1:1 cis/trans mixture in THF
(5 ml) at Ϫ78 ЊC under nitrogen. The solution was allowed to
warm to Ϫ30 ЊC over 30 min to ensure enolate formation and
cooled to Ϫ78 ЊC. 2,6-Di-tert-butylphenol (365 mg, 1.77 mmol)
was added and stirring was continued at Ϫ78 ЊC for a further
90 min. Saturated aqueous ammonium chloride (5 ml) was
added at Ϫ78 ЊC and the solvent was removed in vacuo to give
an orange residue. The residue was partitioned between ethyl
acetate (10 ml) and saturated aqueous ammonium chloride
(5 ml). The organic layer was separated and the aqueous layer
was extracted with ethyl acetate (2 × 10 ml). The combined
organic layers were dried (MgSO4) and the solvent was removed
in vacuo to give a yellow residue. Column chromatography on
silica gel using petroleum ether–ethyl acetate (6:1) as eluent
afforded tert-butyl (2S,5RS)-N-tert-butoxycarbonyl-5-allyl-6-
oxopiperidine-2-carboxylate 45 (252 mg, 84%) as a 9:1 mixture
of cis/trans diastereoisomers as judged by the integration of
H-2, δH (300 MHz, C2HCl3) 4.58 (0.1H, t, J 5.6, H-2A), 4.52
(0.9H, dd, J2,3 2.1 and 5.1, H-2B),
(2S )-2-Amino(5-hydroxypyrazol-4-yl)butyric acid hydrochloride
(20)
A suspension of tert-butyl (2S )-2-N-tert-butoxycarbonylamino-
(5-hydroxypyrazol-4-yl)butyrate (43) (135 mg, 0.395 mmol) in 6
N aqueous hydrochloric acid (3 ml) was stirred for 90 min at
room temperature. After 30 min the suspension had dissolved.
The solvent was removed in vacuo and residual water was
removed using a freeze dryer to afford (2S)-2-amino(5-
hydroxypyrazol-4-yl)butyric acid hydrochloride 20 as a glassy
solid (78 mg, 89%). The spectra were identical with those of the
sample prepared from the corresponding methyl ester 18.
(2S )-2-Amino(5-hydroxy-1-methylpyrazol-4-yl)butyric acid
hydrochloride (21)
A suspension of tert-butyl (2S )-2-N-tert-butoxycarbonylamino-
(5-hydroxy-1-methylpyrazol-4-yl)butyrate 44 (156 mg, 0.439
mmol) in 6 N aqueous hydrochloric acid (3 ml) was stirred for
90 min at room temperature. After 30 min the suspension had
dissolved. The solvent was removed in vacuo and residual water
tert-Butyl (2S,5R)-N-tert-butoxycarbonyl-5-(2-oxoethyl)-6-
oxopiperidine-2-carboxylate (46a)
A solution of tert-butyl (2S,5RS )-N-tert-butoxycarbonyl-5-
allyl-6-oxopiperidine-2-carboxylate 45 (560 mg, 1.65 mmol) in
2468
J. Chem. Soc., Perkin Trans. 1, 2002, 2459–2472

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dichloromethane (15 ml) was cooled to Ϫ78 ЊC and oxygen was
passed through the solution for 5 min followed by ozone for
15 min, during which time it turned blue. Triphenylphosphine
(519 mg, 1.98 mmol) was added at Ϫ78 ЊC and the solution was
allowed to warm slowly to room temperature. The solvent was
removed in vacuo to give a yellow oil. Partial separation of the
two stereoisomers was achieved by column chromatography on
silica gel using petroleum ether–ethyl acetate (6:1) as eluent.
The cis-product, tert-butyl (2S,5R)-N-tert-butoxycarbonyl-5-
(2-oxoethyl)-6-oxopiperidine-2-carboxylate 46a (148 mg, 26%),
was obtained together with a mixture of the cis- and trans-
products (331 mg, 59%). tert-Butyl (2S,5R)-N-tert-butoxy-
carbonyl-5-(2-oxoethyl)-6-oxopiperidine-2-carboxylate 46a was
cmϪ1 3400 (OH–NH), 1734 and 1655 (C᎐O); λmax (MeOH)/nm
᎐
233 (log ε 2.35); δH (300 MHz, 2H2O) 6.76 (1H, m, H-6Ј),
3.54 (1H, m, H-2) and 2.73–0.95 (7H, m, H-3, H-4, H-4Ј ϩ H-
5Ј).
tert-Butyl (2RS )-N-tert-butoxycarbonyl-5-methoxymethylene-
6-oxopiperidine-2-carboxylate (48)
Lithium hexamethyldisilazide (1 M in THF, 12.03 ml, 12 mmol)
was added to a stirred solution of tert-butyl (2RS )-N-tert-
butoxycarbonyl-6-oxopiperidine-2-carboxylate 41a (3.00 g, 10
mmol) in THF (30 ml) at Ϫ78 ЊC under nitrogen. The solution
was allowed to warm to Ϫ30 ЊC over 30 min to ensure enolate
formation and cooled to Ϫ78 ЊC. Ethyl formate (1.62 ml, 20
mmol) was added. The solution was stirred for 5 min at Ϫ78 ЊC,
warmed to 0 ЊC and stirred for a further 90 min. Saturated
aqueous ammonium chloride (15 ml) was added at 0 ЊC and the
solvent was removed in vacuo to give an orange residue. The
residue was partitioned between ethyl acetate (20 ml) and satur-
ated aqueous ammonium chloride (10 ml). The organic layer
was separated and the aqueous layer was extracted with ethyl
acetate (2 × 15 ml). The combined organic layers were dried
(MgSO4) and the solvent was removed in vacuo to give a yellow
oil. The crude oil was dissolved in diethyl ether (30 ml) and
trimethylsilyldiazomethane (2 M in hexanes, 5.01 ml, 10 mmol)
was added. The reaction was allowed to stand overnight. The
solvent was removed with a stream of nitrogen to give a brown
oil. Column chromatography on silica gel using ethyl acetate as
eluent afforded the product tert-butyl (2RS)-N-tert-butoxy-
carbonyl-5-methoxymethylene-6-oxopiperidine-2-carboxylate 48
as a pale yellow oil (1.78 g, 52%); m/z (ϩve es) 342 [M ϩ H]ϩ;
25
an oil, [α]D ϩ 24.8 (c 0.5, CHCl3); m/z [ϩve es] Found
342.1922 [M ϩ H]ϩ, [C17H27NO6 ϩ H]ϩ requires 342.1917; νmax
(film)/cmϪ1 1773 and 1723 (C᎐O); δ (500 MHz, C2HCl3) 9.84
᎐
H
(1H, t, J 1.3, CH᎐O), 4.57 (1H, ddd, J2,4S 1.2, J2,3R 2.4, J2,3S 5.7,
᎐
H-2), 3.11 (1H, ddd, J7A,8 1.3, J7A,5 5.6, J7A,7B 17.5, H-7A), 3.02
(1H, m, H-5), 2.52 (1H, ddd, J7B,8 1.3, J7B,5 5.6, J7B,7A 17.5, H-7),
2.23 (1H, m, H-3R), 2.11 (1H, m, H-3S ), 1.97 (1H, m, H-4R),
1.57 (1H, m, H-4S ), 1.51 [9H, s, C(CH3)3] and 1.48 [9H, s,
C(CH3)3]; irradiation of H-2 at δ 4.57 ppm gave enhancement to
H-3R at δ 2.23 ppm (2.6%) and H-3S at δ 2.11 ppm (3.6%);
irradiation of H-5 at δ 3.02 ppm gave enhancement to H-7B at
δ 2.52 ppm (2.7%), H-3S at δ 2.11 ppm (3%) and H-4R at δ 1.97
ppm (3.0%); irradiation of H-7B at δ 2.52 ppm gave enhance-
ment to H-7A at δ 3.11(21%) and H-5 at δ 3.02 ppm (3%); δC (75
MHz, C2HCl ) 200.37 (CH᎐O), 172.17 (C-6), 170.61 (ester),
᎐
3
152.53 (urethane), 83.49 and 82.37 [2 × OC(CH3)3], 59.54 (C-2),
45.15 (C-7), 39.58 (C-5), 27.90 [2 × C(CH3)3], 25.62 (C-3) and
25.10 (C-4).
δH (300 MHz, C2HCl ) 7.44 (1H, s, CH᎐), 4.69 (1H, t, J 4.6
᎐
3
2,3
and 10.2, H-2), 3.85 (3H, s, OCH3), 2.52 (1H, m, H-4A), 2.22
(1H, m, H-4B), 2.13 (1H, m, H-3A), 1.95 (1H, m, H-3B), 1.52
[9H, s, OC(CH3)3] and 1.47 [9H, s, OC(CH3)3]; δC (75 MHz,
C2HCl3) 170.04 (C-6), 165.16 (ester), 158.60 (C-7), 152.24
(urethane), 107.97 (C-5), 82.72 and 81.83 [2 × OC(CH3)3], 61.46
(OCH3), 58.13 (C-2), 27.80 [2 × OC(CH3)3], 24.22 (C-3) and
18.27 (C-4).
tert-Butyl (2S,5R)-2-tert-butoxycarbonylamino-4-(3-oxo-
2,3,4,5-tetrahydropyridazin-4-yl)butyrate (47)
Hydrazine hydrate (55% aq., 0.008 ml, 0.14 mmol) was added
to a stirred solution of tert-butyl (2S,5R)-N-tert-butoxy-
carbonyl-5-(2-oxoethyl)-6-oxopiperidine-2-carboxylate 53a (50
mg, 0.146 mmol) in methanol (10 ml) under nitrogen. The solu-
tion was stirred at room temperature for 2 h, and the solvent
was removed in vacuo to give a yellow residue. Column chrom-
atography on silica gel using ethyl acetate–petroleum ether (2:1)
as eluent afforded tert-butyl (2S,5R)-2-tert-butoxycarbonyl-
amino-4-(3-oxo-2,3,4,5-tetrahydropyridazin-4-yl)butyrate 47 as
tert-Butyl (2RS )-2-tert-butoxycarbonylamino-4-(6-oxopyrim-
idin-5-yl)butyrate (49)
tert-Butyl (2RS )-N-tert-butoxycarbonyl-5-methoxymethylene-
6-oxopiperidine-2-carboxylate 48 (100 mg, 0.293 mmol), form-
amidine acetate (122 mg, 1.17 mmol) and potassium carbonate
(162 mg, 1.17 mmol) were heated in absolute ethanol (10 ml)
at reflux for 18 h. The solvent was removed in vacuo to give
a yellow residue which was partitioned between 5% aqueous
citric acid (10 ml) and dichloromethane (10 ml). The
aqueous layer was separated and extracted with dichloro-
methane (2 × 5 ml). The combined organic phases were washed
with brine (10 ml), dried (MgSO4), and the solvent was removed
in vacuo to give a pale yellow residue. Column chromatography
on silica gel using methanol–ethyl acetate (5:95) as eluent
afforded tert-butyl (2RS)-2-tert-butoxycarbonylamino-4-(6-
oxopyrimidin-5-yl)-butyrate (49) as a pale white foam (42 mg,
43%); m/z [ϩve es] Found 354.2040 [M ϩ H]ϩ, [C17H27N3O5 ϩ
H]ϩ requires 354.2029; νmax (film)/cmϪ1 3400 (OH–NH), 1737
25
a colourless oil (46 mg, 88%); [α]D ϩ46.8 (c 1.0, CHCl3); m/z
[CI] Found 356.2181 [M ϩ H]ϩ, [C17H29N3O5 ϩ H]ϩ requires
356.2185; m/z [ϩve FAB, 3-NBA] 356 [M ϩ H]ϩ; νmax (film)/
cmϪ1 1696 and 1680 (C᎐O); λ (MeOH)/nm 241 (log ε 3.67);
᎐
max
δH (300 MHz, C2HCl3) 8.5 (1H, br, NH), 7.12 (1H, m, H-6Ј),
5.27 (1H, d, J 7.7, NH, exchangeable with 2H3CO2H), 4.15 (1H,
m, H-2), 2.56 (1H, m, H-5ЈA), 2.40 (1H, m, H-4Ј), 2.24 (1H, m,
H-5ЈB), 1.99–1.60 (3H, m, H-3A ϩ H-4), 1.51 (1H, m, H-3B),
1.43 [9H, s, C(CH3)3] and 1.41 [9H, s, C(CH3)3]; δC (75 MHz,
C2HCl3) 171.39 (C-6), 169.63 (ester), 155.30 (urethane), 144.21
(C-6Ј), 81.93 and 79.60 [2 × OC(CH3)3], 53.62 (C-2), 34.94
(C-4Ј), 29.38 (C-5), 28.21 and 27.88 [2 × C(CH3)3], 27.32 (C-4)
and 24.96 (C-3).
(2S,5R)-2-amino-4-(3-oxo-2,3,4,5-tetrahydropyridazin-4-yl)-
butyric acid hydrochloride (34a)
(sh) and 1651 (C᎐O); λmax (MeOH)/nm 228 and 271 (log ε 3.83
᎐
and 3.70); λmax (MeOH–HCl)/nm 231 and 261 (log ε 3.89 and
3.62); λmax (MeOH–NaOH)/nm 234 and 272 (log ε 3.97 and
3.70); δH (300 MHz, C2HCl3) 12.91 (1H, br s, NH, exchangeable
with 2H3CO2H), 8.11 (1H, s, H-2Ј), 7.92 (1H, s, H-4Ј), 5.35 (1H,
d, J 8.2, NH, exchangeable with 2H3CO2H), 4.21 (1H, m, H-2),
2.55 (2H, t, J 7.6, H-4), 2.14–1.84 (2H, 2 × m, H-3), 1.46 [9H, s,
OC(CH3)3] and 1.44 [9H, s, OC(CH3)3]; δC (75 MHz, C2HCl3)
171.64 (C-6Ј), 163.93 (ester), 155.46 (urethane), 152.46 (C-2Ј),
147.12 (C-4Ј), 128.31 (C-5Ј), 82.02 and 79.70 [2 × OC(CH3)3],
53.64 (C-2), 30.99 (C-4), 28.29 and 27.94 [2 × C(CH3)3] and
23.65 (C-3).
A
suspension of tert-butyl (2S,5R)-2-tert-butoxycarbonyl-
amino-4-(3-oxo-2,3,4,5-tetrahydropyridazin-4-yl)butyrate 47
(220 mg, 0.619 mmol) was stirred in 6 N aqueous hydrochloric
acid (3 ml) at room temperature for 90 min. After 30 min the
suspension had dissolved. The solvent was removed in vacuo
and residual water was removed using a freeze dryer to afford
(2S,5R)-2-amino-4-(3-oxo-2,3,4,5-tetrahydropyridazin-4-yl)-
butyric acid hydrochloride 34a as a white foam (137 mg,
25
94%); [α]D ϩ9.9 (c 0.94, H2O); m/z [ϩve es] Found 200.1043
[M ϩ H]ϩ, [C8H13N3O3 ϩ H]ϩ requires 200.1035; νmax (KBr)/
J. Chem. Soc., Perkin Trans. 1, 2002, 2459–2472
2469

View Article Online
tert-Butyl (2RS )-2-tert-butoxycarbonylamino-4-(2-methyl-6-
oxopyrimidin-5-yl)butyrate (50)
guanidine carbonate (158 mg, 0.87 mmol), and potassium
carbonate (162 mg, 1.17 mmol) were heated in absolute ethanol
(10 ml) at reflux for 18 h. The solvent was removed in vacuo
to give a yellow residue which was partitioned between 5%
aqueous citric acid (10 ml) and dichloromethane (10 ml). The
aqueous layer was separated and extracted with dichloro-
methane (2 × 5 ml). The combined organic phases were washed
with brine (10 ml) and dried (MgSO4). The solvent was
removed in vacuo to give a pale yellow residue. Column chrom-
atography on silica gel using methanol–dichloromethane (1:9)
as eluent afforded tert-butyl (2RS)-2-tert-butoxycarbonyl-
amino-4-(2-amino-6-oxopyrimidin-5-yl)butyrate 52 as a pale
white foam (20 mg, 19%) m/z [ϩve es] 369 [M ϩ H]ϩ; νmax (film)/
tert-Butyl (2RS )-N-tert-butoxycarbonyl-5-methoxymethylene-
6-oxopiperidine-2-carboxylate 48 (100 mg, 0.293 mmol), acet-
amidine acetate (111 mg, 1.17 mmol) and potassium carbonate
(162 mg, 1.17 mmol) were heated in absolute ethanol (10 ml)
at reflux for 18 h. The solvent was removed in vacuo to give
a yellow residue which was partitioned between 5% aqueous
citric acid (10 ml) and dichloromethane (10 ml). The
aqueous layer was separated and extracted with dichloro-
methane (2 × 5 ml). The combined organic phases were washed
with brine (10 ml) and dried (MgSO4). The solvent was
removed in vacuo to give a pale yellow residue. Column chrom-
atography on silica gel using methanol–ethyl acetate (5:95) as
eluent afforded tert-butyl (2RS)-2-tert-butoxycarbonylamino-4-
(2-methyl-6-oxopyrimidin-5-yl)butyrate 50 as a pale white solid
(89 mg, 83%); mp 175–177 ЊC; m/z [ϩve es] Found 368.2190
[M ϩ H]ϩ, [C18H29N3O5 ϩ H]ϩ requires 368.2185; νmax (KBr)/
cmϪ1 3400 (OH–NH), 1744 (sh) and 1645 (C᎐O); λmax (MeOH)/
᎐
nm 226 and 291 (log ε 4.13 and 3.90); λmax (MeOH–HCl)/nm
220 and 260 (log ε 4.09 and 3.88); λmax (MeOH–NaOH)/nm 232
and 280 (log ε 4.09 and 3.85); δH (400 MHz, C2HCl3) 7.39 (1H,
s, H-4Ј), 5.60 (1H, d, J 8.4, NH, exchangeable with 2H3CO2H),
4.13 (1H, m, H-2), 2.37 (2H, m, H-4), 2.04–1.80 (2H, m, H-3),
1.46 [9H, s, OC(CH3)3] and 1.44 [9H, s, OC(CH3)3.
cmϪ1 3400 (OH–NH), 1737 (sh) and 1645 (C᎐O); λmax (MeOH)/
᎐
nm 226 and 275 (log ε 3.54 and 3.47); λmax (MeOH–HCl)/nm
230 and 260 (log ε 3.59 and 3.39); λmax (MeOH–NaOH)/nm 232
and 272 (log ε 3.63 and 3.43); δH (300 MHz, C2HCl3) 13.19 (1H,
(2RS )-2-amino-4-(2-methyl-6-oxopyrimidin-5-yl)butyrate
hydrochloride (53)
2
s, NH, exchangeable with H3CO2H), 7.83 (1H, s, H-4Ј), 5.36
2
(1H, d, J 8.2, NH, exchangeable with H3CO2H), 4.21 (1H, m,
A suspension of tert-butyl (2RS )-2-tert-butoxycarbonylamino-
4-(2-methyl-6-oxopyrimidin-5-yl)butyrate 50 (52 mg, 0.142
mmol) in 6 N aqueous hydrochloric acid (1 ml) was stirred at
room temperature for 90 min. After 30 min the suspension had
dissolved. The solvent was removed in vacuo and residual water
was removed using a freeze dryer to afford (2RS)-2-amino-4-
(2-methyl-6-oxopyrimidin-5-yl)butyrate hydrochloride 53 as a
glassy solid (34 mg, 97%); mp softens at 199 ЊC; m/z [ϩve es]
Found 212.1032 [M ϩ H]ϩ, [C9H13N3O3 ϩ H]ϩ requires
212.1035; νmax (KBr)/cmϪ1 3400 (OH–NH), 1739 and 1687
H-2), 2.59–2.46 (2H, t, J 7.6, H-4), 2.46 (3H, s, CH3), 2.12–1.82
(2H, 2 × m, H-3), 1.46 [9H, s, OC(CH3)3] and 1.44 [9H, s,
OC(CH3)3]; δC (75 MHz, C2HCl3)), 171.71 (C-6Ј), 164.99
(ester), 157.41 (C-2Ј), 155.43 (urethane), 152.88 (C-4Ј), 124.42
(C-5Ј), 81.86 and 79.62 [2 × OC(CH3)3], 53.65 (C-2), 31.28
(C-4), 28.30 and 27.96 [2 × C(CH3)3], 23.20 (C-3) and 21.41
(CH3).
tert-Butyl (2RS )-2-tert-butoxycarbonylamino-4-(6-oxo-2-
phenylpyrimidin-5-yl)butyrate (51)
(C᎐O); λmax (MeOH)/nm 226 and 273 (log ε 3.39 and 3.32); λmax
᎐
(MeOH–HCl)/nm 230 and 260 (log ε 3.47 and 3.26); λmax
(MeOH–NaOH)/nm 233 and 272 (log ε 3.48 and 3.30); δH (300
tert-Butyl (2RS )-N-tert-butoxycarbonyl-5-methoxymethylene-
6-oxopiperidine-2-carboxylate 48 (100 mg, 0.293 mmol), benz-
amidine hydrochloride (183 mg, 1.17 mmol), and potassium
carbonate (162 mg, 1.17 mmol) were heated in absolute ethanol
(10 ml) at reflux for 18 h. The solvent was removed in vacuo
to give a yellow residue which was partitioned between 5%
aqueous citric acid (10 ml) and dichloromethane (10 ml). The
aqueous layer was separated and extracted with dichloro-
methane (2 × 5 ml). The combined organic phases were washed
with brine (10 ml) and dried (MgSO4). The solvent was
removed in vacuo to give a pale yellow residue. Column chrom-
atography on silica gel using methanol–ethyl acetate (5:95) as
eluent afforded tert-butyl (2RS)-2-tert-butoxycarbonylamino-4-
(6-oxo-2-phenylpyrimidin-5-yl)-butyrate 51 as a pale white solid
(74 mg, 59%); mp 186–188 ЊC; m/z [ϩve es] Found 430.2347
[M ϩ H]ϩ, [C23H31N3O5 ϩ H]ϩ requires 430.2342; νmax (KBr)/
2
MHz, H2O) 7.29 (1H, s, H-4Ј), 3.51 (1H, t, J 6.4, H-2), 2.31–
1.92 (5H, s ϩ m, CH3 ϩ H-4) and 1.56 (2H, m, H-3); δC (75
MHz, 2H2O) 171.30 (acid), 161.89 (C-2Ј), 161.37 (C-6Ј), 138.57
(C-4Ј), 126.16 (C-5Ј), 52.12 (C-2), 27.51 (C-4), 22.61 (C-3) and
17.60 (CH3).
(2RS )-2-amino-4-(6-oxo-2-phenylpyrimidin-5-yl)butyrate
hydrochloride (54)
A suspension of tert-butyl (2RS )-2-tert-butoxycarbonylamino-
4-(6-oxo-2-phenylpyrimidin-5-yl)butyrate 51 (44 mg, 0.102
mmol) in 6 N aqueous hydrochloric acid (1 ml) was stirred at
room temperature for 90 min. After 30 min the suspension had
dissolved. The solvent was removed in vacuo and residual water
was removed using a freeze dryer to give (2RS)-2-amino-4-
(6-oxo-2-phenylpyrimidin-5-yl)butyrate hydrochloride 54 as a
glassy solid (31 mg, 98%); mp >250 ЊC, m/z [ϩve es] Found
274.1185 [M ϩ H]ϩ, [C14H15N3O3 ϩ H]ϩ requires 274.1192; νmax
(KBr)/cmϪ1 3400 (OH–NH), 1737 (sh) and 1700 (C᎐O); λ
cmϪ1 3400 (OH–NH), 1733 (sh) and 1651 (C᎐O); λmax (MeOH)/
᎐
nm 239 and 297 (log ε 4.16 and 4.05); λmax (MeOH–HCl)/nm
241 and 280 (log ε 4.15 and 4.11); λmax (MeOH–NaOH)/nm 233,
252 and 285 (log ε 4.29, 4.00 and 3.92); δH (300 MHz, C2HCl3)
13.04 (1H, s, NH, exchangeable with 2H3CO2H), 8.17–8.24 (2H,
m, ArH), 8.04 (1H, s, H-4Ј), 7.63–7.52 (3H, m, ArH), 5.25 (1H,
d, J 8.4, NH, exchangeable with 2H3CO2H), 4.28 (1H, m, H-2),
2.60 (2H, m, H-4), 2.18–1.99 (2H, m, H-3) and 1.44 [18H, s,
2 × OC(CH3)3]; δC (75 MHz, C2HCl3) 171.78 (C-6Ј), 164.73
(ester), 155.75 (C-2Ј), 155.52 (urethane), 152.90 (C-4Ј), 125.38
(C-5Ј), 127.31–131.81 (Ar), 81.97 and 79.69 [2 × OC(CH3)3],
53.83 (C-2), 31.31 (C-4), 28.29 and 27.96 [2 × C(CH3)3] and
24.06 (C-3).
᎐
max
(MeOH)/nm 245 and 280 (log ε 3.68 and 3.72); λmax (MeOH–
HCl)/nm 242 (sh), 252 (sh) and 276 (log ε 3.67, 3.70 and 3.78);
λmax (MeOH–NaOH)/nm 234, 260 and 277 (log ε 3.76, 3.67 and
3.67); δH (300 MHz, 2H2O) 7.73 (1H, s, H-4Ј), 7.57–7.29 (5H, m,
ArH), 3.95 (1H, t, J 7.1, H-2), 2.41 (2H, m, H-4) and 1.93 (2H,
m, H-3); δC (75 MHz, 2H2O) 171.28 (acid), 161.77 (C-2Ј), 159.54
(C-6Ј), 139.02 (C-4Ј), 135.53 (C-5Ј), 129.91–124.30 (Ar), 52.15
(C-2), 27.54 (C-4) and 22.77 (C-3).
tert-Butyl (2S,5RS )-N-tert-butoxycarbonyl-6-oxo-5-phenyl-
selenylpiperidine-2-carboxylate (55)
tert-Butyl (2RS )-2-tert-butoxycarbonylamino-4-(2-amino-6-
oxopyrimidin-5-yl)butyrate (52)
Lithium hexamethyldisilazide (1 M in THF, 13.36 ml, 13 mmol)
was added to a stirred solution of tert-butyl (2S )-N-tert-
butoxycarbonyl-6-oxopiperidine-2-carboxylate 41 (2.00 g, 6.68
tert-Butyl (2RS )-N-tert-butoxycarbonyl-5-methoxymethylene-
6-oxopiperidine-2-carboxylate 48 (100 mg, 0.293 mmol),
2470
J. Chem. Soc., Perkin Trans. 1, 2002, 2459–2472

View Article Online
mmol) in THF (20 ml) at Ϫ78 ЊC under nitrogen. The solution
was allowed to warm to Ϫ30 ЊC over 30 min to ensure enolate
formation and cooled to Ϫ78 ЊC. Phenylselenyl chloride (1.41 g,
7.35 mmol) was added and stirring was continued for 90 min.
Saturated aqueous ammonium chloride (5 ml) was added at
Ϫ78 ЊC and the solvent was removed in vacuo to give an orange
residue. The residue was partitioned between ethyl acetate
(5 ml) and saturated aqueous ammonium chloride (5 ml). The
organic layer was separated and the aqueous layer was
extracted with ethyl acetate (2 × 10 ml). The combined
organic layers were dried (MgSO4) and the solvent was removed
in vacuo to give a yellow oil. Column chromatography on silica
gel using petroleum ether–diethyl ether (2:1) as eluent afforded
yellow oil. Column chromatography on silica gel using petrol-
eum ether–ethyl acetate (3:1) as eluent afforded tert-butyl
(2S,4RS)-N-tert-butoxycarbonyl-4-vinyl-6-oxopipecolate 57 as
a 2:1 mixture of trans/cis diastereoisomers (58 mg, 43%); m/z
[CI] Found 326.1966 [M ϩ H]ϩ, [C17H27NO5 ϩ H]ϩ requires
326.1967; m/z [ϩve FAB, 3-NBA] 348 [M ϩ Na]ϩ; νmax (film)/
cmϪ1 1779, 1737 (sh) and 1723 (C᎐O); δ (300 MHz, C2HCl3)
᎐
H
5.67 (1H, m, CH᎐), 5.04 (2H, m, ᎐CH ), 4.58 (0.66H, dd, J2,3 2.7
᎐
᎐
2
and 5.8, H-2), 4.46 (0.33H, dd, J2,3 6.6 and 9.5, H-2), 2.70–2.42
(2H, m, H-5), 2.36–2.17 (2H, m, H-3), 1.82 (1H, m, H-4), 1.48
[9H, s, C(CH3)3] and 1.45 [9H, s, C(CH3)3]; δC (75 MHz,
C2HCl3) 170.40 (C-6), 169.52 (ester), 151.98 (urethane), 139.27
and 138.92 (CH᎐), 115.00 and 114.84 (᎐CH ), 83.47, 83.26,
᎐
᎐
2
tert-butyl
(2S,5RS)-N-tert-butoxycarbonyl-6-oxo-5-phenyl-
82.23 and 82.08 [2 × OC(CH3)3], 58.55 and 58.36 (C-2), 39.93
(C-5), 34.80 and 33.67 (C-4), 31.72 and 31.39 (C-3), and 27.81
and 27.76 [C(CH3)3].
selenylpiperidine-2-carboxylate 55 as a 6:1 mixture of trans/cis
diastereoisomers (1.94 g, 64%); m/z [CI] Found 456.1250,
[C21H29NO5Se ϩ H]ϩ requires 456.1289; m/z [ϩve FAB, 3-NBA]
455 [M]ϩ and 478 [M ϩ Na]ϩ; νmax (film)/cmϪ1 1774, 1740 (sh)
and 1723 (C᎐O); δ (300 MHz, C2HCl3) 7.70–7.60 (2H, m,
tert-Butyl (2S,4RS )-N-tert-butoxycarbonyl-4-(2-methyl-1-
propenyl)-6-oxopiperidine-2-carboxylate (58)
᎐
H
ArH), 7.37–7.22 (3H, m, ArH), 4.50 (1H, m, H-5), 4.00 (1H, m,
H-2), 2.18 (1H, m, H-3A), 2.10–1.80 (3H, m, H-3B, H-4), 1.51
[9H, s, C(CH3)3] and 1.47 [9H, s, C(CH3)3]; δC (75 MHz,
C2HCl3) 169.97 (C-6), 169.67 (ester), 152.51 (urethane), 135.75–
128.01 (Ar), 83.43 and 82.30 [2 × OC(CH3)3], 59.26 (C-2), 44.11
(C-5), 27.85 and 27.80 [2 × C(CH3)3], 26.97 (C-3) and 25.66
(C-4).
2-Methyl-1-propenylmagnesium bromide (0.5 M in THF, 26.91
ml, 13 mmol) was added slowly to a suspension of copper
bromide–dimethyl sulfide complex (1.39 g, 6.72 mmol) at
Ϫ25 ЊC under nitrogen. The mixture was stirred for 15 min at
Ϫ25 ЊC and cooled to Ϫ78 ЊC. A solution of tert-butyl (2S )-N-
tert-butoxycarbonyl-6-oxo-1,2,3,6-tetrahydropyridine-2-carb-
oxylate 56 (400 mg, 1.35 mmol) and trimethylsilyl chloride
(0.342 ml, 2.69 mmol) in THF (5 ml) was added. The mixture
was stirred for a further 90 min at Ϫ78 ЊC and saturated aque-
ous ammonium chloride (15 ml) was added. The organic layer
was separated and the aqueous layer was extracted with ethyl
acetate (3 × 20 ml). The combined organic layers were washed
with saturated aqueous ammonium chloride (3 × 20 ml) and
brine (2 × 20 ml) and dried (MgSO4). The solvent was removed
in vacuo to give a pale yellow oil. Column chromatography on
silica gel using petroleum ether–ethyl acetate (6:1) as eluent
afforded tert-butyl (2S,4RS)-N-tert-butoxycarbonyl-4-(2-
methyl-1-propenyl)-6-oxopipecolate 58 as a 5:1 mixture of trans/
cis diastereoisomers (181 mg, 38%); m/z [CI] Found 354.2284
[M ϩ H]ϩ, [C19H31NO5 ϩ H]ϩ requires 354.2280; m/z [ϩve FAB,
3-NBA] 354 [M ϩ H]ϩ; νmax (KBr)/cmϪ1 1778, 1737 (sh) and
1723 (C᎐O); δ (300 MHz, C2HCl ) 4.88 (1H, d, J 8.7, CH᎐),
tert-Butyl (2S )-N-tert-butoxycarbonyl-3,6-dihydro-6-oxo-
pyridine-2-carboxylate (56)
Hydrogen peroxide (30%, 3.30 ml, 29 mmol) was added to a
stirred solution of tert-butyl (2S,5RS )-N-tert-butoxycarbonyl-
5-phenylselenyl-6-oxopipecolate 55 (494 mg, 1.09 mmol) in
ethyl acetate (10 ml) at 0 ЊC. The solution was allowed to warm
to room temperature and stirred for 3 h. The aqueous layer was
separated and the organic layer was washed with saturated
aqueous sodium hydrogen carbonate (3 × 15 ml). The com-
bined organic layers were washed with brine (2 × 10 ml) and
dried (MgSO4). The solvent was removed in vacuo to give a
yellow residue. Column chromatography on silica gel using pet-
roleum ether–ethyl acetate (3:1) as eluent afforded tert-butyl
(2S)-N-tert-butoxycarbonyl-6-oxo-1,2,3,6-tetrahydropyridine-2-
carboxylate 56 as a white solid (200 mg, 62%); mp 47–49 ЊC;
᎐
᎐
H
3
4.57 (0.83H, dd, J2,3 2.5 and 5.8, H-2), 4.46 (0.17H, dd, J2,3 6.7
and 9.6, H-2), 2.79–2.45 (2H, m, H-5), 2.28–2.01 (2H, m, H-3),
1.89–1.65 (4H, m ϩ s, CH3 ϩ H-4), 1.50 (3H, s, CH3), 1.49 [9H,
s, C(CH3)3] and 1.47 [9H, s, C(CH3)3]; δC (75 MHz, C2HCl3)
170.62 (C-6), 170.08 (ester), 152.14 (urethane), 133.56
25
[α]D ϩ14.1 (c 1.0, CHCl3); Found: C, 60.4; H, 7.9; N, 4.7.
C15H23NO5 requires C, 60.6; H, 7.8; N; 4.7%; m/z [ϩve FAB,
3-NBA] 298 [M ϩ H]ϩ and 320 [M ϩ Na]ϩ; νmax (film)/cmϪ1
1771, 1717 (sh) 1696 and 1640 (C᎐O); δ (300 MHz, C2HCl3)
᎐
H
6.60 (1H, m, H-4), 5.97 (1H, dd, J5,3 2.4, J5,4 9.8, H-5), 4.90 (1H,
dd, J2,3 1.9 and 6.5, H-2), 2.92–2.68 (2H, m, H-3), 1.55 [9H, s,
C(CH3)3] and 1.43 [9H, s, C(CH3)3]; δC (75 MHz, C2HCl3)
169.62 (C-6), 162.59 (ester), 152.17 (urethane), 139.76 (C-5),
126.59 (C-4), 83.26 and 82.65 [2 × OC(CH3)3], 56.22 (C-2),
27.97 and 27.78 [2 × C(CH3)3] and 27.25 (C-3).
(C᎐), 126.12 (CH᎐), 83.23 and 82.12 [2 × OC(CH ) ], 58.69
᎐ ᎐
3 3
(C-2), 41.10 (C-5), 32.22 (C-3), 29.28 (C-4), 27.88 and 27.84
[2 × C(CH3)3], and 25.57 and 17.80 (CH3).
tert-Butyl (2S,4ЈRS )-2-tert-butoxycarbonylamino-3-(6-oxo-
1,4,5,6-tetrahydropyridazin-4-yl)propionate (60)
A solution of tert-butyl (2S,4RS )-N-tert-butoxycarbonyl-4-(2-
methyl-1-propenyl)-6-oxopiperidine-2-carboxylate 58 (112 mg,
0.317 mmol) in dichloromethane (15 ml) was cooled to Ϫ78 ЊC
and oxygen was passed through the solution for 5 min. Ozone
was passed through the solution for 15 min during which time it
turned blue. Triphenylphosphine (100 mg, 0.38 mmol) was
added at Ϫ78 ЊC and the solution was allowed to warm slowly
to room temperature. The solvent was removed in vacuo to give
a yellow oil. Column chromatography on silica gel using petrol-
eum ether–ethyl acetate (1:1) as eluent afforded the aldehyde 59
as a 5:1 mixture of trans/cis products. The aldehyde was dis-
solved in methanol (5 ml) and hydrazine hydrate (55% aq.,
0.024 ml, 0.42 mmol) was added. The solution was stirred for
2 h and the solvent was removed in vacuo to give a yellow resi-
due. Column chromatography on silica gel using ethyl acetate as
eluent afforded tert-butyl (2S,4ЈRS)-2-tert-butoxycarbonyl-
amino-3-(6-oxo-1,4,5,6-tetrahydropyridazin-4-yl)propionate 60
tert-Butyl (2S,4RS )-N-tert-butoxycarbonyl-4-vinyl-6-oxopiper-
idine-2-carboxylate (57)
Vinyl magnesium bromide (1 M in THF, 4.17 ml, 4.17 mmol)
was added slowly to a suspension of copper bromide–dimethyl
sulfide complex (429 mg, 2.09 mmol) at Ϫ25 ЊC under nitrogen.
The mixture was stirred for 15 min at Ϫ25 ЊC and cooled to
Ϫ78 ЊC. A solution of tert-butyl (2S )-N-tert-butoxycarbonyl-6-
oxo-1,2,3,6-tetrahydropyridine-2-carboxylate 56 (124 mg, 0.417
mmol) and trimethylsilyl chloride (0.106 ml, 0.834 mmol) in
THF (5 ml) was added. The mixture was stirred for a further
90 min at Ϫ78 ЊC. Saturated aqueous ammonium chloride
(5 ml) was added and the organic layer was separated. The
aqueous layer was extracted with ethyl acetate (3 × 10 ml). The
combined organic layers were washed with saturated aqueous
ammonium chloride (3 × 10 ml) and brine (2 × 10 ml) and dried
(MgSO4). The solvent was removed in vacuo to give a pale
J. Chem. Soc., Perkin Trans. 1, 2002, 2459–2472
2471

View Article Online
as a colourless oil (87 mg, 80%); m/z [ϩve es] Found 342.2034
[M ϩ H]ϩ, [C16H27N3O5 ϩ H]ϩ requires 342.2029; νmax (KBr)/
cmϪ1 3400 (OH–NH), 1735 (sh), 1685 and 1654 (C᎐O); λ
References
1 C. H. Eugster, Progress in the Chemistry of Organic Natural
Products, 1969, 27, 261.
2 H. Bräuner-Osborne, J. Egebjerg, E. Ø. Nielson, U. Madsen and
P. Krogsgaard-Larsen, J. Med. Chem., 2000, 43, 2609.
3 E. K. Michaelis, Progress in Neurobiology, 1998, 54, 369.
4 M. Zhuo, Drug Discovery Today, 2002, 7, 259.
5 R. J. Bridges, J. W. Geddes, D. T. Monaghan and C. W. Cotman,
in “Excitatory Amino Acids in Health and Disease, Ed. D. Lodge,
John Wiley, New York, 1988, p. 321.
6 S. Patel, A. G. Chapman, M. H. Millan and B. S. Meldrum,
in “Excitatory Amino Acids in Health and Disease, Ed. D. Lodge,
John Wiley, New York, 1988, p. 353.
᎐
max
(MeOH)/nm 228 (log ε 3.35); δH (300 MHz, C2HCl3) 8.77 (1H,
2
br s, NH, exchangeable with H3CO2H), 7.11 (1H, d, J 2.3,
2
H-3Ј), 5.25 (1H, d, J 8.1, NH, exchangeable with H3CO2H),
4.32 (1H, m, H-2), 2.86–2.42 (2H, m, H-4Јϩ H-5ЈA), 2.41–2.16
(1H, m, H-5ЈB), 2.05–1.73 (2H, m, H-3) and 1.60 and 1.45 [18H,
2 × s, 2 × C(CH3)3]; δC (75 MHz, C2HCl3) 171.02 (C-6Ј), 166.88
(ester), 156.26 (urethane), 147.60 (C-3Ј), 82.86 and 80.23
[OC(CH3)3], 51.73 (C-2), 35.95 (C-4Ј), 31.76 (C-3), 30.61 (C-5Ј),
and 28.23 and 27.92 [C(CH3)3].
7 G. K. Steinberg, J. Saleh, D. Kunis, R. DeLaPaz and S. R. Zarnegar,
Stroke, 1989, 20, 1247.
(2S,4ЈRS )-2-Amino-3-(6-oxo-1,4,5,6-tetrahydropyridazin-4-yl)-
8 (a) A. N. Bowler, P. M. Doyle and D. W. Young, J. Chem. Soc.,
Chem. Commun., 1991, 314; (b) A. Dinsmore, P. M. Doyle and
D. W. Young, Tetrahedron Lett., 1995, 36, 7503; (c) A. N. Bowler,
A. Dinsmore, P. M. Doyle and D. W. Young, J. Chem. Soc.,
Perkin Trans. 1, 1997, 1297; (d ) A. Dinsmore, P. M. Doyle,
P. B. Hitchcock and D. W. Young, Tetrahedron Lett., 2000, 41,
10153; (e) A. Dinsmore, P. M. Doyle and D. W. Young, J. Chem.
Soc., Perkin Trans., 1, 2002, 155; ( f ) A. Dinsmore, P. M. Doyle,
M. Steger and D. W. Young, J. Chem. Soc., Perkin Trans. 1, 2002, 613.
9 K. Papadopoulos and D. W. Young, Tetrahedron Lett., 2002, 43,
3951.
propionic acid hydrochloride (61)
A suspension of tert-butyl (2S,4ЈRS )-2-tert-butoxyamino-3-(6-
oxo-1,4,5,6-tetrahydropyridazine-4-yl)propionate 60 (60 mg,
0.169 mmol) was stirred in 6 N aqueous hydrochloric acid
(2 ml) at room temperature for 90 min. After 30 min the suspen-
sion had dissolved. The solvent was removed in vacuo and
residual water was removed using a freeze dryer to afford
(2S,4ЈRS)-2-amino-3-(6-oxo-1,4,5,6-tetrahydropyridazin-4-yl)-
propionic acid hydrochloride 61 as a colourless oil (30 mg, 79%);
m/z [ϩve FAB, glycerol] 185 [M]ϩ; νmax (KBr)/cmϪ1 3400 (OH–
10 C. E. Davies, T. D. Heightman, S. A. Hermitage and M. G. Moloney,
Synth. Commun., 1996, 26, 687.
NH), 1724 and 1636 (C᎐O); λmax (MeOH)/nm 217 (log ε 3.13);
᎐
11 The synthesis of this compound has recently been independently
reported by M. Muller, A. Schoenfelder, B. Didier, A. Mann and
C.-G. Wermuth, J. Chem. Soc., Chem. Commun., 1999, 683.
12 V. W. Rodwell, Methods Enzymol., 1971, 17(Part B), 174.
13 T. Shiraiwa, K. Shinjo and H. Kurokawa, Bull. Chem. Soc. Jpn.,
1991, 64, 3251.
14 recently S. Hanessian, W. A. L. van Otterlo, I. Nilsson and U. Bauer,
Tetrahedron Lett., 2002, 43, 1995 have noted trans specificity in
additions to the methyl ester corresponding to 56.
δH (300 MHz,2H2O–2HCl) 6.94 (1H, d, J 2.1, H-3Ј), 3.75 (1H, m,
H-2) and 2.82–1.37 (5H, m, H-4Ј, H-5Ј ϩ H-3).
Acknowledgements
We thank the DTI, EPSRC, GlaxoSmithKline and Tocris
Cookson for an Asymmetric Synthesis LINK Award.
2472
J. Chem. Soc., Perkin Trans. 1, 2002, 2459–2472