Practical synthesis of both enantiomers of protected 4-oxopipecolic acid

Article abstract of DOI:10.1016/S0040-4020(01)00429-X

A new synthesis of both enantiomers of protected 4-oxopipecolic acid was achieved in six steps via 1,3-dipolar cycloaddition of C-ethoxycarbonyl N-(1R)-phenylethylnitrone to but-3-en-1-ol.

Full text of DOI:10.1016/S0040-4020(01)00429-X

TETRAHEDRON
Pergamon
Tetrahedron 57 *2001) 4995±4998
Practical synthesis of both enantiomers of protected
4-oxopipecolic acid
Fabrizio Machetti,p Franca M. Cordero, Francesco De Sarlo and Alberto Brandip
Centro di Studio sulla Chimica e la Struttura dei Composti Eterociclici e loro Applicazioni, Dipartimento di Chimica Organica `U. Schiff',
Á
C.N.R., Universita di Firenze, Via G. Capponi 9, I-50121 Firenze, Italy
Received 5 March 2001; revised 28 March 2001; accepted 12 April 2001
AbstractÐA new synthesis of both enantiomers of protected 4-oxopipecolic acid was achieved in six steps via 1,3-dipolar cycloaddition of
C-ethoxycarbonyl N-*1R)-phenylethylnitrone to but-3-en-1-ol. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
by condensation of N-benzylhydroxylamine and ethyl
glyoxylate, readily available from diethyl tartrate,7 accord-
ing to the literature.8
The *2S) enantiomer of 4-oxopipecolic acid *1) is a rare
non-proteinogenic amino acid present in some biologically
important cyclic peptides with antibiotic activity belonging
to the virginiamycin family.1 Owing to its use as a building
block in the syntheses of cyclopeptides, as an intermediate
in the preparation of N-methyl-d-aspartate *NMDA) recep-
tor antagonists,2 and as a precursor of 4-hydroxypipecolic
acid3,6f *a naturally occurring imino acid isolated from some
Acacia species in 19554), 1 has attracted a great deal of
synthetic attention leading to sixteen syntheses since its iso-
lation in 1959 from Staphylomycin.5 However, only a few
of the reported syntheses satisfy the enantio-controlled
construction of the 4-oxopipecolic skeleton, and do not
involve the oxidation of the corresponding enantiopure
4-hydroxypipecolic derivative.3b,6 We have recently
reported the preparation of the *2S)-4-oxopipecolic acid
via a domino process having as a key step the diastereo-
selective cycloaddition of a N-glycosylnitrone to methyl-
enecyclopropane followed by the thermal rearrangement
of the adduct.3b Continuing our study on the synthesis of
amino acids and derivatives employing chiral nitrones, we
investigated the use of C-ethoxycarbonyl-N-*1R)-phenyl-
ethylnitrone in the cycloaddition with but-3-en-1-ol as a
route to produce *2S) and *2R) protected 4-oxopipecolic
acids *Scheme 1).
Nitrone 2a was found to be a 1:1 mixture of E/Z isomers by
1H NMR analysis. Cycloaddition of the nitrone 2a to but-3-
en-1-ol gave 1:1 mixture of the cis and trans adducts 3a in
80% combined yield. Since both of them converge into
product 6a the next stepof the synthesis was carried out
with the above mixture and no attempt was made to isolate
the individual compounds. Upon treatment with MsCl in
pyridine, the adducts 3a gave the corresponding mesylates
Scheme 1.
2. Results and discussion
The approach was ®rst attempted with racemic inter-
mediates *Scheme 2, RˆBn). The nitrone 2a was prepared
Keywords: amino acid; cycloaddition; rearrangement; oxopipecolic acid;
nitrone.
p
Corresponding authors. Tel.: 139-055-2757610; fax: 139-055-2476964;
e-mail: machetti@uni®.it; brandi@chimorg.uni®.it
Scheme 2.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020*01)00429-X

4996
F. Machetti et al. / Tetrahedron 57 42001) 4995±4998
Scheme 3.
4a which could not be isolated because they undergo intra-
molecular nucleophilic displacement to give salts 5a. The
extraction of the bridgehead proton, according to a pro-
cedure investigated on similar salts,9 by DABCO in re¯ux-
ing MeCN was followed by the cleavage of the N±O bond,10
to afford the racemic oxopipecolic ester 6a. The synthetic
strategy described above was successfully applied to the
synthesis of *2R) and *2S)-4-oxopipecolic acid derivatives
using a nitrone which contains the chiral information at the
N-substituent *Scheme 2).
In summary a practical, multigram scale, six step synthesis
of both enantiomers of 4-oxopipecolic acid ethyl ester, has
been achieved in very good overall yield *20% for each,
including the synthesis of nitrone 2b) starting from inex-
pensive commercial materials.
3. Experimental
3.1. General
A large-scale preparation of nitrone 2b was performed by
condensation of ethylglyoxylate and *R)-*1)-N-phenyl-
ethylhydroxylamine, readily prepared in high yield from
*R)-*1)-phenylethylamine.11 Cycloaddition of nitrone 2b
to but-3-en-1-ol in re¯uxing CHCl3 gave an equimolecular
mixture of four diastereomeric adducts 3b in 98% combined
yield. The scale upof the synthesis was brought to the
synthesis of 65 g of adducts in one batch. The mixture of
isomers 3b was mesylated and no attempt was made to
separate the diastereoisomers. Treatment of the mixture of
mesylates 4b in re¯uxing MeCN in the presence of DABCO
gave the compounds *R,S)-6b and *R,R)-6b, epimers at
C*2), in nearly 1:1 ratio and 44% overall yield *Scheme 2).
Melting points are uncorrected. Chromatographic sepa-
rations *FCC) were performed on silica gel; Rf values
refer to TLC carried out on 25-mm silica gel plates
*Merck F254), with the same eluent indicated for the
1
column chromatography. H and 13C NMR spectra were
recorded at 200 and 50.33 MHz, respectively, unless other-
wise stated. Mass spectra were carried out in EI at 70 eV
ionizing voltage.
The *R)-*1)-N-phenylethylhydroxylamine oxalate was
prepared on a multigram scale as previously reported start-
ing from *R)-*1)-phenylethylamine.12
3.1.1. N-Benzyl-C-ethoxycarbonylnitrone 'E/Z) '2a). The
title compound was prepared as previously reported starting
from ethyl glyoxylate and N-benzylhydroxylamine.13
The separation of diastereomeric compounds *R,S)-6b and
*R,R)-6b was easily undertaken either by silica gel chroma-
tography or by repeated crystallization from Et2O. If the
direct crystallization failed occasionally a preliminary
chromatographic puri®cation on a short pad of silica gel
was necessary.
1
White solid. mp83±85 8C *Lit.13 84.0±85.68C). H NMR
*CDCl3) d 7.44±7.36 *m, 5H), 7.16 *E) and 7.09 *Z) *s,
1H), 5.68 *E) and 4.96 *Z) *s, 2H), 4.38±4.17 *m, 2H),
1.35±1.23 *m, 3H).
The stereochemical assignment of the diastereoisomers
*R,S)-6b and *R,R)-6b was done by chemical correlation
to the known product N-Boc-4-oxopipecolic acid ethyl
ester as outlined in Scheme 3. Hydrogenolysis of *R,S)-6b
in the presence Pd*OH)2 afforded the N-deprotected
compound *S)-7. Then, treatment with Boc2O and
i-Pr2NEt afforded the N-Boc-4-oxopipecolic acid ethyl
3.1.2. cis and trans 2-Benzyl-5-'2-hydroxy-ethyl)-isoxa-
zolidine-3-carboxylic acid ethyl ester '3a). A solution of
nitrone 2a *1.64 g, 7.9 mmol) and but-3-en-1-ol *0.82 ml,
9.5 mmol) in CHCl3 *10 mL) was heated to re¯ux for 6 h.
The solvent was evaporated and the residue puri®ed by FCC
*EtOAc±Petroleum ether 7:9, Rf 0.15 and 0.18) to give
adducts 3a *1.6 g, 6.4 mmol) in 81% yield. Clear oil. 1:1
Mixture of isomers. 1H NMR *CDCl3) d 7.42±7.20 *m, 5H),
4.50±4.00 *m, 4H), 3.80±3.44 *m, 3H), 2.80±2.52 *m, 1H),
2.24±2.05 *m, 1H), 2.00±1.64 *m, 3H), 1.31±1.18 *m, 3H).
13C NMR *CDCl3) d 170.8, 170.5, 136.1, 136.0, 129.2,
25
ester *S)-8 with [a]D ˆ211.4 *cˆ0.94, CHCl3) in agree-
ment to the previously reported value in the literature
23
*[a]D ˆ29.2, *cˆ0.91, CHCl3)).3b The same procedure
on diastereomeric *R,R)-6b gave the enantiomeric protected
oxopipecolic acid *R)-8 in similar yield.

F. Machetti et al. / Tetrahedron 57 42001) 4995±4998
4997
128.2, 128.1, 127.4, 76.1, 75.4, 66.5, 66.3, 62.2, 61.4, 61.2,
61.1, 38.6, 37.8, 36.6, 36.4, 14.1. IR *CDCl3) 3090, 2982,
1740 cm21. MS m/z *%) 279 *M1, ,1), 206 *9), 91 *100).
Anal. Calcd for C15H21NO4 *279.33): C, 64.50; H, 7.58; N,
5.01. Found: C, 64.47; H, 7.61; N, 5.29.
ethyl)-isoxazolidine-3-carboxylic acid ethyl ester '3b). A
solution of nitrone 2b *50 g, 226 mmol) and but-3-en-1-ol
*23.3 ml, 271 mmol) in CHCl3 *300 mL) was heated to
re¯ux for 18 h. The solvent and the excess of but-3-en-1-
ol were evaporated in vacuo to give adducts 3b *65 g,
270 mmol) in 98% yield and suf®ciently pure to be used
directly in the next step.
3.1.3. N-Benzyl-4-oxo-piperidine-2-carboxylic acid ethyl
ester '6a). MsCl *0.4 ml, 5.2 mmol) was added dropwise to
a solution of isoxazolidines 3a *0.726 g, 2.60 mmol) in pyri-
dine *18 mL) at 08C. The mixture was stirred at the same
temperature for 4 h then ®ltered. The solvent was removed
in vacuo and the solid residue was used without any puri®-
Mixture of isomers. 1H NMR *CDCl3) d 7.40±7.18 *m, 5H),
4.48±3.40 *m, 7H), 2.64±1.60 *m, 5H), 1.58±1.38 *m, 3H),
1.36±1.00 *m, 3H). 13C NMR *CDCl3) d 171.6 *s), 171.5 *s),
141.7 *s), 141.4 *s), 141.2 *s), 140.8 *s), 128.3 *d), 128.1 *d),
128.0 *d), 127.9 *d), 127.8 *d), 127.7 *d), 127.6 *d), 127.5
*d), 127.2 *d), 76.4 *d), 75.2 *d), 75.0 *d), 67.9 *d), 65.1 *d),
64.8 *d), 64.5 *d), 63.6 *d), 61.1 *t), 60.9 *t), 60.8 *t), 60.4 *t),
59.9 *t), 39.2 *t), 37.3 *t), 36.9 *t), 36.1 *t), 36.0 *t), 21.8 *q),
21.4 *q), 20.7 *q), 20.3 *q), 14.0 *q), 13.8 *q). MS m/z *%)
293 *M1, ,1), 220 *M12CO2Et, 4), 116 *27), 105 *100), 77
*20). IR *CDCl3) 3476, 2981, 1725 cm21. Anal. Calcd for
C16H23NO4 *293.36): C, 65.51; H, 7.90; N, 4.77. Found: C,
65.84; H, 7.66; N, 4.54.
1
cation in the next step. H NMR *CDCl3) d 7.60±7.22 *m,
5H), 6.00±5.80 and 5.60±5.42 *m, 1H), 5.42±5.20 *m, 1H),
4.42±4.00 *m, 2H12H), 3.64 *s, 2H), 3.60±3.40 *m, 1H),
2.81 *s, 3H), 2.75±2.40 *m, 2H), 2.30±2.00 *m, 1H), 1.40±
1.22 *t, Jˆ7.4 Hz, 3H).
A solution of crude 5a and DABCO *0.941 g, 8.4 mmol) in
freshly distilled MeCN *5 mL) was heated at 758C for 1 h.
The reaction mixture was ®ltered and the solvent was
evaporated under reduced pressure. The residue oil was
dissolved in Et2O *30 mL) and then washed with water.
The organic phase was dried over Na2SO4 and the solvent
was evaporated to give crude 6a. Puri®cation by FCC
*CH2Cl2±MeOHˆ100:1, Rfˆ0.32) afforded 0.292 g of 6a
3.1.6. '10R, 2S)-1-[10-Phenylethyl]-4-oxo-piperidine-2-
carboxylic acid ethyl ester ['R,S)-6b] and '10R, 2R)-1-
[10-Phenylethyl]-4-oxo-piperidine-2-carboxylic acid ethyl
ester ['R,R)-6b]. MsCl *10.0 ml, 129 mmol) was added
dropwise to a solution of isoxazolidines 3b *15.4 g,
52.5 mmol) in pyridine *170 mL) cooled to 08C. The
mixture was stirred at the same temperature for 4 h and
then ®ltered. The solvent was removed in vacuo and the
solid residue was used as crude in the next step.
1
as a dark oil *yield 43%). H NMR *CDCl3) d 7.44±7.16
*m, 5H), 4.19 *q, Jˆ6.8 Hz, 2H), 4.02 *m, 1H), 3.78 *s, 2H),
3.10±2.94 *m, 2H), 2.94±2.86 *m, 2H), 2.60±2.50 *m, 1H),
2.50±2.46 *m, 1H), 1.27 *t, Jˆ6.8 Hz, 3H). 13C NMR
*CDCl3) d 206.6 *s), 170.6 *s), 137.8 *s), 128.7 *d), 128.3
*d), 127.3 *d), 61.7 *d), 60.7 *t), 58.9 *t), 47.3 *t), 42.7 *t),
40.1 *t), 14.2 *q). IR *CDCl3) 3080, 3040, 2979, 2930,
1722 cm21. MS m/z *%) 261 *M1, ,1), 188 *M12CO2Et,
81), 91 *100). Anal. Calcd for C15H19NO3 *261.32): C,
68.94; H, 7.33; N, 5.36. Found: C, 68.66; H, 7.61; N, 5.29.
A solution of crude 4b and DABCO *13.9 g, 124 mmol) in
freshly distilled MeCN *140 mL) was heated at 758C for 1 h.
The reaction mixture was ®ltered and the solvent was
evaporated under reduced pressure. The residue oil was
subjected to chromatographic puri®cation over a short pad
of silica gel *AcOEt±Petroleum ether 1:7). The ®rst fraction
*Rfˆ0.24) containing *R,S)-6b was followed by a second
fraction containing *R,S)-6b and *R,R)-6b in nearly equi-
molecular ratio and a third fraction containing *R,R)-6b
*Rfˆ0.18). The intermediate fraction was subjected to dia-
stereomeric separation by repeated crystallization from
Et2O to give pure *R,S)-6b *3.29 g) and *R,R)-6b *3.08 g)
in 44% combined yield).
3.1.4.
N-['1R)-Phenylethyl]-C-ethoxycarbonylnitrone
'E/Z) '2b). TEA *52.2 mL, 373 mmol) was added dropwise
to an ice cooled mixture of N-*1R)-phenylethylhydroxyl-
amine oxalate *64.9 g, 285 mmol) and ethyl glyoxylate
*35.0 g, 342 mmol) in CH2Cl2 *360 mL) after which the
whole was stirred at 08C for 16 h. The reaction mixture
was washed with H2O *3£300 mL) and then the organic
phase dried over Na2SO4, ®ltered and the solvent evaporated
under reduced pressure. Two recrystallization from Et2O
afforded an analytical sample of 3 *53.1 g, 84%).
25
*R,S)-6b white solid. mp99±100 8C Rfˆ0.24. [a]D ˆ28.4
1
*c 0.5, CHCl3). H NMR *CDCl3) d 7.48±7.22 *m, 5H),
25
1
White solid. mp79±80 8C. [a]D ˆ193.0 *c 1, CHCl3). H
NMR *CDCl3) d *3:2 mixture of isomers) major isomer
7.59±7.26 *m, 5H), 7.14 *s, 1H), 5.09 *q, Jˆ7.0 Hz, 1H),
4.26±4.12 *m, 2H), 1.80 *d, Jˆ7.0 Hz, 3H), 1.32±1.21 *m,
3H) minor isomer 7.59±7.26 *m, 5H), 7.13 *s, 1H), 7.03 *q,
Jˆ7.0 Hz, 1H), 4.26±4.12 *m, 2H), 1.71 *d, Jˆ7.0 Hz, 3H),
1.32±1.21*m, 3H). 13C NMR *CDCl3) d 160.8 *s), 160.1 *s),
138.4 *s), 137.2 *s), 129.2 *d), 128.8 *d), 128.6 *d), 128.4
*d), 127.6 *d), 127.3 *d), 126.5 *d), 123.9 *d), 77.8 *d), 68.3
*d), 61.3 *t), 60.9 *t), 19.3 *q), 19.1 *q), 14.2 *q). IR *CDCl3)
1721, 1543 cm21. MS m/z *%): 204 *9), 176*4), 130*5), 105
*100), 77*43). Anal. Calcd for C12H15NO3 *221.25): C,
65.14; H, 6.83; N, 6.33. Found C, 65.38; H, 6.77; N, 6.37.
4.30±4.14 *m, 3H), 3.88 *q, Jˆ6.6 Hz, 1H), 2.94±2.82
*m, 2H), 2.80±2.56 *m, 2H), 2.50±2.22 *m, 2H), 1.45 *d,
Jˆ6.6 Hz, 3H), 1.31 *t, Jˆ7.2 Hz, 3H). 13C NMR *CDCl3) d
207.2 *s), 171.2 *s), 145.0 *s), 128.5 *d, 2 C), 127.1 *d, 2 C),
126.9 *d), 61.4 *d), 60.8 *t), 58.5 *d), 45.0 *t), 43.1 *t), 40.5
*t), 20.4 *q), 14.3 *q). MS m/z *%): 202 *M12CO2Et, 7), 105
*100), 98 *21), 79 *16), 77 *20). IR *CDCl3) 1716 cm21
.
Anal. Calcd for C16H21NO3 *275.34): C, 69.79; H, 7.69;
N, 5.09. Found: C, 69.37; H, 7.81; N, 5.21.
25
*R,R)-6b Clear oil. Rfˆ0.18. [a]D ˆ177.9 *c 0.8, CHCl3).
1H NMR *CDCl3) d 7.42±7.20 *m, 5H), 4.28±4.10 *m, 2H),
4.00 *q, Jˆ6.6 Hz, 1H), 3.76±3.66 *m, 1H), 3.32±3.18 *m,
1H), 3.16±3.00 *m, 1H), 2.72±2.28 *m, 4H), 1.43 *d, Jˆ
6.6 Hz, 3H), 1.29 *t, Jˆ7.4 Hz, 3H). 13C NMR *CDCl3) d
3.1.5. cis and trans '10R)-2-[10-Phenylethyl]-5-'2-hydroxy-

4998
F. Machetti et al. / Tetrahedron 57 42001) 4995±4998
207.1 *s), 171.3 *s), 143.8 *s), 128.4 *d, 2C), 127.3 *d, 2C),
126.9 *d), 60.8*d), 60.7 *t), 59.9 *d), 45.0 *t), 43.1 *t), 40.5
*t), 21.4 *q), 14.9 *q). MS m/z *%): 202 *M12CO2Et, 9), 105
Acknowledgements
Á
Authors thank MURST *Ministero dell'Universita e della
Ricerca Scienti®ca e Tecnologica-Rome) for ®nancial
*100), 98 *29), 79 *19), 77 *23). IR *CDCl3) 1718 cm21
.
Â
Anal. Calcd for C16H21NO3 *275.34): C, 69.79; H, 7.69;
N, 5.09. Found: C, 69.60; H, 7.78; N, 5.47.
support *Co®n 2000). Ms Anne-Cecile Moisan, Sokrates
student from the University of Rennes *France), is acknowl-
edged for carrying out several steps of the synthesis.
3.1.7. '2S)-4-Oxo-piperidine-2-carboxylic acid ethyl
ester ['S)-7]. The N-phenylethylamine *R,S)-6b *70 mg,
0.25 mmol) was dissolved in EtOH *2 mL), Pd*OH)2/C
*20%) *10 mg) was added and the apparatus ¯ushed three
times with H2. The reaction mixture was hydrogenated
under atmospheric pressure at room temperature for 24 h
®ltered through a pad of Celite *3£2 ml of EtOH rinse)
and then concentrated under reduced pressure to obtain
the amine *S)-7 *40 mg, 94%) that was suf®ciently pure to
be used in the next stepwithout puri®cation.
References
È
1. *a) Kessler, H.; KuÈhn, M.; Loschner, T. Liebigs Ann. Chem.
1986, 1±20. *b) Reed, J. W.; Purvis, M. B.; Kingston, I.; Biot,
Â
A.; Gossole, F. J. Org. Chem. 1989, 54, 1161±1165b.
*c) Molinero, A. A.; Kingston, D. G. I.; Reed, J. W. J. Nat.
Prod. 1989, 52, 99±108.
2. *a) Ornstein, P. L.; Schoepp, D. D.; Arnold, M. B.; Leander,
J. D.; Lodge, D.; Paschal, J. W.; Elzey, T. J. Med. Chem. 1991,
34, 90±97. *b) Hays, S. J.; Malone, T. C.; Johnson, G. J. Org.
Chem. 1991, 56, 4084±4086. *c) Pellicciari, R.; Marinizzi, M.;
Natalini, B.; Costantino, G.; Lankin, D. C.; Snyder, J. P.;
Monahan, J. B. Il Farmaco 1997, 52, 477±486.
Clear oil. [a]D ˆ227.5 *c 0.9, CHCl3). 1H NMR *CDCl3)
25
d 4.21 *q, Jˆ7.1 Hz, 2H), 3.68 *dd, Jˆ4.2 and 10.0 Hz, 1H),
3.44±3.32 *m, 1H), 3.02±2.88 *m, 1H), 2.73±2.61 *m, 1H),
2.58±2.38 *m, 3H), 1.27 *t, Jˆ7.1 Hz, 3H). 13C NMR
*CDCl3) d 206.8 *s), 171.5 *s), 61.4 *t), 58.5 *d), 44.5 *t),
44.2 *t), 42.2 *t), 14.1 *q). IR *CDCl3) 3154, 2983, 2965,
2937, 1722, 1378 cm21. Anal. Calcd for C8H13NO3
*171.20): C, 56.13; H, 7.65; N, 8.18. Found: C, 56.24; H,
7.36; N, 8.44.
3. Cis isomer: *a) Golubev, A.; Sewald, N.; Burger, K.
Tetrahedron 1996, 52, 14757±14776. *b) Machetti, F.;
Cordero, F. M.; De Sarlo, F.; Guarna, A.; Brandi, A.
Tetrahedron Lett. 1996, 37, 4205±4208. *c) Herdeis, C.;
Engel, W. Arch. Pharm. 4Weinheim) 1992, 419±424. Trans
protected isomer: *d) Ornstein, P. L.; Arnold, M. B.; Lunn,
W. H. W.; Heinz, L. J.; Leander, J. D.; Lodge, D.; Schoepp,
D. D. Biorg. Med. Chem. Lett. 1998, 8, 338±394.
3.1.8. '2S)-N-tert-Butoxycarbonyl-4-oxo-piperidine-2-car-
boxylic acid ethyl ester ['S)-8]. Boc2O *23 mg, 0.10 mmol)
was added portionwise to a solution of amine *S)-7 *18 mg,
0.10 mmol) and DIEA *0.017 mL, 0.10 mmol) in CH2Cl2±
EtOH 4:1 *1 mL). The mixture was stirred at room tempera-
ture for 3 days and then concentrated under reduced pres-
sure. The residue was partitioned between Et2O±CH2Cl2 2:1
and 10% NaHSO4. The aqueous layer was extracted with
Et2O±CH2Cl2 2:1. The solvent was evaporated and the resi-
due puri®ed by FCC on silica gel *CH2Cl2±MeOH 30:1, Rf
0.29) to give *S)-8 *24 mg, 0.089 mmol) in 86% yield.
4. Virtanen, A. I.; Kari, S. Acta Chem. Scand. 1955, 9, 170±171.
5. Vanderhaeghe, H.; Parmentier, G. J. Am. Chem. Soc. 1960, 82,
4415±4422.
6. *a) Jackson, R. F. W.; Graham, L. J.; Rettie, A. B. Tetrahedron
Lett. 1994, 35, 4417±4418. *b) Golubev, A.; Sewald, N.;
Burger, K. Tetrahedron 1996, 52, 14757±14776. *c) Skyles,
J. W.; Giannouis, P. P.; Fales, K. R. Biorg. Med. Chem. Lett.
1996, 6, 963±966. *d) Bousquet, Y.; Anderson, P. C.; Bogri,
T.; Duceppe, J.-S.; Grenier, L.; Guse, I. Tetrahedron 1997, 53,
Â
15671±15680. *e) Badorrey, R.; Cavitiela, C.; Dõaz-de-
Â
Villegas, M. D.; Galvez, J. A. Tetrahedron Lett. 1997, 38,
25
23
Clear oil. [a]D ˆ211.4, *c 0.94, CHCl3) *Lit.3b [a]D
ˆ
19.2, c 0.91, CHCl3). 1H NMR *CDCl3) d 5.05 and 4.80 *m,
1H, two conformers), 4.16 *q, Jˆ7.4 Hz, 2H), 4.02 *dt,
Jˆ14.0 and 5.8 Hz, 1H), 3.64 *m, 1H), 2.80 *m, 2H), 2.54
*m, 2H), 1.48 *s, 9H), 1.26 *t, Jˆ7.4 Hz, 3H). 13C NMR
*CDCl3) d 205.9 *s), 171.1 *s), 146.7 *s), 81.1 *s), 61.7 *t),
54.8 and 54.1 *d, two conformers), 41.1 *t), 40.46 and 39.33
*t, two conformers), 39.7 *t), 28.2 *q, 3 C), 14.1 *q). MS m/z
*%) 215 *1), 198 *16), 170 *24), 142 *61), 98 *100), 57 *100).
Anal. Calcd for C13H21NO5 *271.31): C, 57.57; H, 7.80; N,
5.16%. Found: C, 57.96; H, 7.54; N, 4.62%.
2547±2580. *f) Brooks, C. A.; Comins, D. L. Tetrahedron
Lett. 2000, 41, 3551±3553.
7. Kelly, T. R.; Schmidt, T. E.; Haggerty, J. G. Synthesis 1972,
544±545.
8. Inouye, Y.; Watanabe, Y.; Takahahi, S.; Kakisawa, H. Bull.
Chem. Soc. Jpn. 1979, 52, 3763±3764.
9. Cordero, F. M.; Machetti, F.; De Sarlo, F.; Brandi, A. Gazz.
Chim. Ital. 1997, 127, 25±29.
10. Murahashi, S.-I.; Kodera, Y.; Hosomi, T. Tetrahedron Lett.
1988, 29, 5949±5952.
11. *a) Polonski, T.; Chimiak, A. Tetrahedron Lett. 1974, 28,
2453±2456. *b) Polonski, T.; Chimiak, A. Bull. Acad. Pol.
Sci., Ser. Sci. Chim. 1979, 27, 459±464.
3.1.9. '2R)-4-Oxo-piperidine-2-carboxylic acid ethyl
25
ester ['R)-7]. [a]D ˆ125.8 *c 0.94, CHCl3). Spectral and
Â
12. Wovkulich, P. M.; Uskokovic, M. R. Tetrahedron 1985, 41,
analytical properties identical with *S)-7.
3455±3462.
13. Inouye, Y.; Watanabe, Y.; Takahashi, S.; Kakisawa, H. Bull.
Soc. Chem. Jpn. 1979, 52, 3763±3764.
3.1.10. '2R)-N-tert-Butoxycarbonyl-4-oxo-piperidine-2-
25
carboxylic acid ethyl ester ['R)-8]. [a]D ˆ110.8, *c
0.92, CHCl3). Spectral and analytical properties identical
with *S)-8.