Diastereoselective hydroxylation of 6-substituted piperidin-2-ones. An efficient synthesis of (2S,5R)-5-hydroxylysine and related α-amino acids

Article abstract of DOI:10.1021/jo025950c

The synthesis of (2S,5R)-5-hydroxy-6-oxo-1,2-piperidinedicarboxylates (5) and related (3S,6R)-3-hydroxy-6-alkyl-2-oxo-1-piperidinecarboxylates has been developed. The approach is based on the asymmetric hydroxylation of enolates generated from the corresponding N-protected-6-substituted piperidin-2-ones. The utility of 5a as a precursor in the synthesis of (2S,5R)-5-hydroxylysine (1), an amino acid unique to collagen and collagen-like proteins, has also been demonstrated. (2S)-6-oxo-1,2-piperidinedicarboxylates (6) required for hydroxylation studies were prepared in 38-74% yield, starting from conveniently protected aspartic acid as inexpensive chiral adduct. Hydroxylation of 6 to 5 proceeds in high yield and excellent diastereoselectivity by treatment of their Li-enolate with (+)-camphorsulfonyloxaziridine at -78 °C. Ring opening of di-tert-butyl (2S,5R)-6-oxo-1,2-piperidinedicarboxylate ((5R)-5a) under reductive conditions afforded the corresponding 1,2-diol (17) in 91%, which was further transformed to (2S,5R)-5-hydroxylysine in four steps (84%). 17 is also a versatile intermediate in the preparation of tert-butyl (2S,5R)-2-[(tert-butoxycarbonyl)amino]-5-hydroxy-6-iodohexanoate (3) and tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-[(2R)-oxiranyl]-butanoate (4), two amino acid derivatives used in the total synthesis of the bone collagen cross-link (+)-pyridinoline (2a).

Full text of DOI:10.1021/jo025950c

Dia ster eoselective Hyd r oxyla tion of 6-Su bstitu ted
P ip er id in -2-on es. An Efficien t Syn th esis of
(2S,5R)-5-Hyd r oxylysin e a n d Rela ted r-Am in o Acid s
J . Marin,†,‡ C. Didierjean,§ A. Aubry,§ J .-P. Briand,† and G. Guichard*,†
UPR 9021 CNRS, Immunologie et Chimie The´rapeutiques, Institut de Biologie Mole´culaire et Cellulaire,
15 rue Rene´ Descartes, F-67084 Strasbourg Cedex, France, Neosystem, 7 rue de Boulogne,
F-67100 Strasbourg, France, and ESA 7036 CNRS, LCM3B, Universite´ Henri Poincare´,
BP239, F-54509 Vandoeuvre, France
g.guichard@ibmc.u-strasbg.fr
Received May 29, 2002
The synthesis of (2S,5R)-5-hydroxy-6-oxo-1,2-piperidinedicarboxylates (5) and related (3S,6R)-3-
hydroxy-6-alkyl-2-oxo-1-piperidinecarboxylates has been developed. The approach is based on the
asymmetric hydroxylation of enolates generated from the corresponding N-protected-6-substituted
piperidin-2-ones. The utility of 5a as a precursor in the synthesis of (2S,5R)-5-hydroxylysine (1),
an amino acid unique to collagen and collagen-like proteins, has also been demonstrated. (2S)-6-
oxo-1,2-piperidinedicarboxylates (6) required for hydroxylation studies were prepared in 38-74%
yield, starting from conveniently protected aspartic acid as inexpensive chiral adduct. Hydroxylation
of 6 to 5 proceeds in high yield and excellent diastereoselectivity by treatment of their Li-enolate
with (+)-camphorsulfonyloxaziridine at -78 °C. Ring opening of di-tert-butyl (2S,5R)-6-oxo-1,2-
piperidinedicarboxylate ((5R)-5a ) under reductive conditions afforded the corresponding 1,2-diol
(17) in 91%, which was further transformed to (2S,5R)-5-hydroxylysine in four steps (84%). 17 is
also a versatile intermediate in the preparation of tert-butyl (2S,5R)-2-[(tert-butoxycarbonyl)amino]-
5-hydroxy-6-iodohexanoate (3) and tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-[(2R)-oxiranyl]-
butanoate (4), two amino acid derivatives used in the total synthesis of the bone collagen cross-
link (+)-pyridinoline (2a ).
In tr od u ction
among collagen types. Although the exact structural and
regulatory roles of hydroxylysines and hydroxylysine-
linked carbohydrate units have not been fully elucidated,
it is believed that these posttranslational modifications
play a major role in the regulation of collagen fibrillo-
genesis and in the morphology of fibrils.5 In addition, a
peptide derived from type II collagen (CII) and containing
a glycosylated hydroxylysyl residue has been identified
as an immunodominant T cell epitope involved in col-
lagen-induced arthritis (CIA), a mouse model of rheu-
matoid arthritis (RA).6
The structure of collagen is stabilized by intra- and
intermolecular (+)-pyridinoline (2a ) and (+)-deoxypyri-
dinoline (2b) cross-links formed between adjacent lysyl
and hydroxylysyl residues. Because of the usefulness of
2 for the diagnosis of osteoporosis and other metabolic
bone diseases, as well as difficulties in its isolation from
natural sources, a number of approaches to the synthesis
of 2a and 2b have been proposed in recent years.7 The
preparation of 2a involves either the use of 1 or the
related tert-butyl (2S,5R)-2-[(tert-butoxycarbonyl)amino]-
Collagen is the major structural protein in mammals
and plays an important role in the maintenance of the
structural integrity of tissues.1 Its biosynthesis requires
a series of posttranslational modifications such as the
hydroxylation of prolyl and lysyl residues and the gly-
cosylation of hydroxylysyl residues. (2S,5R)-5-Hydroxy-
lysine 1 is one of the amino acids unique to collagen and
collagen-like proteins.2,3 In collagen, hydroxylysine can
be glycosylated with either a â-D-galactopyrannosyl or
an R-D-glucopyrannosyl-(1f2)-â-D-galactopyrannosyl resi-
due.4 The extent of hydroxylation of lysyl residues and
glycosylation of hydroxylysyl residues varies markedly
* To whom correspondence should be addressed. Tel: +33388417025.
Fax: +33388610680.
† Institut de Biologie Mole´culaire et Cellulaire.
‡ Neosystem.
§ Universite´ Henri Poincare´.
(1) Traub, W.; Piez, K. A. Adv. Prot. Chem. 1971, 25, 243-352.
(2) 5-hydroxylysyl and dihydroxylysyl residues are also found in
styelin D, an antimicrobial peptide isolated from hemocytes of ascidian,
Styela clava: Taylor, S. W.; Craig, A. G.; Fischer, W. H.; Park, M.;
Lehrer, R. I. J . Biol. Chem. 2000, 275, 38417-38426.
(3) ꢀ-N,N,N-trimethyl-5-hydroxylysine, a (2S,5R)-hydroxylysine con-
taining a quaternary ammonium salt, is present in the sequence of
silaffin-1A1, a silica-precipitating peptide from diatom Cylindrotheca
fusiformis: Kro¨ger, N.; Deutzmann, R.; Sumper, M. J . Biol. Chem.
2001, 276, 26066-26070.
(5) Notbohm, H.; Nokelainen, M.; Myllyharju, J .; Fietzek, P. P.;
Mu¨ller, P. K.; Kivirikko, K. I. J . Biol. Chem. 1999, 274, 8988-8992.
(6) (a) Broddefalk, J .; Ba¨cklund, J .; Almqvist, F.; J ohansson, M.;
Holmdahl, R.; Kihlberg, J . J . Am. Chem. Soc. 1998, 120, 7676-7683.
(b) Corthay, A.; Ba¨cklund, J .; Broddefalk, J .; Micha¨elsson, E.; Gold-
schmidt, T. J .; Kihlberg, J .; Holmdahl, R. Eur. J . Immunol. 1998, 28,
2580-2590.
(4) (a) Butler, W. T.; Cunningham, L. W. J . Biol. Chem. 1966, 241,
3882-3888. (b) Spiro, R. G. J . Biol. Chem. 1969, 244, 602-612.
10.1021/jo025950c CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/06/2002
8440
J . Org. Chem. 2002, 67, 8440-8449

Hydroxylation of 6-Substituted Piperidin-2-ones
5-hydroxy-6-iodohexanoate 3 and tert-butyl (2S)-2-[(tert-
butoxycarbonyl)amino]-4-[(2R)oxiranyl]butanoate 4 as
intermediates.
R-amino acid to control the stereochemistry while the
second stereogenic center at C-5 is introduced. We
recently reported a short and stereoselective route to
optically active 1,4-disubstituted δ-amino acids that
allows the incorporation of various natural and nonnatu-
ral side chain functionalities at the R-position.13 The
method involved the alkylation of N-Boc-protected-6-alkyl
piperidin-2-ones readily prepared from N-Boc-protected
â3-amino acids via reduction of the keto functionality of
the corresponding â-aminoacyl Meldrum’s acid. The high
level of 1,4-asymmetric induction achieved during alky-
lation of the corresponding enolate anion is probably due
to the minimization of the allylic A(1,3) strain (see
conformation B).14,15 The ring substituent at the 6-posi-
tion would preferentially adopt an axial conformation,
thus providing a high diastereofacial bias in the alkyla-
tion step.
In the present study, we report an expedient stereo-
selective synthesis of (2S,5R)-5-hydroxylysine 1 starting
from aspartic acid as inexpensive chiral adduct; the
existing R-stereogenic center served for asymmetric
induction at C-5. The retrosynthetic analysis is shown
in Scheme 1.
Our strategy is based on asymmetric oxidation of
enolates generated from piperidinones 6 to the corre-
sponding R-hydroxy carbonyl compounds 5. We also
demonstrate that 5 can serve as a versatile intermediate
in the stereoselective synthesis of 3 and 4.
Although (2S,5R)-5-hydroxylysine (1) is commercially
available, it is expensive and requires lengthy procedures
for protection prior to its use in peptide synthesis (five
steps, 37%).8 (2S,5R)-5-Hydroxylysine (1) is commonly
produced by a tedious procedure starting from gelatine
acid hydrolysates.9 Only recently, a few stereoselective
approaches to the synthesis of 1 have been investigated.
In the strategy developed by Kunz et al.,10 two successive
asymmetric steps were used to create the two stereogenic
centers. The 1,2-amino alcohol structure was incorpo-
rated by Sharpless asymmetric aminohydroxylation into
a homoallyl glycine unit built using the Scho¨llkopf
methodology. Although the method was satisfactory for
the preparation of (2S,5S)-5-hydroxylysine, the yield and
diasteroselectivity in favor of 1 were poor. More recently,
a 10-step stereoselective synthesis involving the Williams’
glycine template methodology and (R)-hydroxynitrile
lyase for the introduction of the chirality at the 2- and
5-positions, respectively, afforded 1 in ca. 20% yield.11
Other reported strategies7a,12 utilized (S)-glutamic acid
as a starting material. Overall, these methods suffer from
limitations including the need for resolutions, lengthy
synthetic procedures, and/or separation of diastereomers.
None of the aforementioned syntheses has taken
advantage of the R-stereogenic center of the starting
Resu lts a n d Discu ssion
P ip er id in on e Syn th esis. Several (2S)-6-oxo-1,2-pi-
peridinedicarboxylates 6a -e varying at R2 or R1 were
synthesized for the purpose of studying the stereodirect-
ing effect of the ester substituent at C-2 and the influence
of the N-protecting groups. Piperidinones 6a -d were
prepared from the conveniently protected aspartic acid
derivatives 7a -d using a procedure similar to that
described previously for the synthesis of N-protected
6-alkyl piperidin-2-ones (Scheme 2).13,16
(13) Casimir, J . R.; Didierjean, C.; Aubry, A.; Rodriguez, M.; Briand,
J .-P.; Guichard, G. Org. Lett. 2000, 2, 895-897.
(14) For reviews on allylic 1,3-strain, see: (a) Hoffmann, R. H.
Angew. Chem., Int. Ed. Engl. 1992, 31, 1124-1134. (b) Hoffmann, R.
H. Chem. Rev. 1989, 89, 1841-1860.
(15) For utilization of allylic A(1,3) strain in the stereoselective
alkylation of enolates derived from (a) 1-acyl-1,3-imidazolidin-4-one
and N-acyl-oxazolidin-5-ones: Seebach, D.; Sting, A. R.; Hoffmann, M.
Angew. Chem., Int. Ed. Engl. 1996, 35, 2708-2748 and references
therein. (b) N-Acyl-oxazin-2-one: Dellaria, J . F.; Santarsiero, B. D. J .
Org. Chem. 1989, 54, 3916-3926. (c) N-Acylmorpholin-3-ones: Fritch,
P. C.; Kazmierski, W. M. Synthesis 1999, 112-116. Norman, B. H.;
Kroin, J . S. J . Org. Chem. 1996, 61, 4990-4998. Anthony, N. J .; Gomez,
R. P.; Holtz, W. J .; Murphy, J . S.; Ball, R. G.; Lee, T.-J . Tetrahedron
Lett. 1995, 36, 3821-3824. (d) Pyroglutamic acid derivatives: Najera,
C.; Yus, M. Tetrahedron: Asymmetry 1999, 10, 2245-2303 and
references therein.
(7) For the synthesis of 2a , see: (a) Adamczyk, M.; J ohnson, D. D.;
Reddy, R. E. Tetrahedron 1999, 55, 63-88. (b) Waelchli, R.; Beerli,
Ch.; Meigel, H.; Re´ve´sz, L. Bioorg. Med. Chem. Lett. 1997, 7, 2831-
2836. (c) Adamczyk, M.; J ohnson, D. D.; Reddy, R. E. Tetrahedron:
Asymmetry 2000, 11, 2289-2298; for the synthesis of 2b, see: (d)
Allevi, P.; Longo, A.; Anastasia, M. Chem. Commun. 1999, 559-560.
(e) Allevi, P.; Longo, A.; Anastasia, M. J . Chem. Soc., Perkin Trans. 1
1999, 2867-2868. (f) Adamczyk, M.; Akireddy, S. R.; Reddy, R. E.
Tetrahedron: Asymmetry 1999, 10, 3107-3110.
(8) Holm, B.; Broddefalk, J .; Flodell, S.; Wellner, E.; Kihlberg, J .
Tetrahedron 2000, 56, 1579-1586.
(9) Sheehan, J . C.; Bolhofer, W. A. J . Am. Chem. Soc. 1950, 72,
2466-2468.
(10) Lo¨hr, B.; Orlich, S.; Kunz, H. Synlett. 1999, 7, 1139-1141.
(11) van den Nieuwendijk, A. M. C. H.; Kriek, N. M. A. J .; Brussee,
J .; van Boom, J . H.; van der Gen, A. Eur. J . Org. Chem. 2000, 3683-
3691.
(12) Allevi, P.; Anastasia, M. Tetrahedron: Asymmetry 2000, 11,
3151-3160.
(16) This procedure was initially described for the synthesis of
pyrrolidin-2-one starting from N-protected R-amino acids: Smrcina,
M.; Majer, P.; Majerova´, E.; Guerassina, T. A.; Eissenstat, M. A.
Tetrahedron 1997, 53, 12867-12874.
J . Org. Chem, Vol. 67, No. 24, 2002 8441

Marin et al.
SCHEME 1. Retr osyn th esis of (2S,5R)-5-Hyd r oxylysin e 1
SCHEME 2a
responding enolate by treatment with 1.1 equiv of
LiHMDS or NaHMDS at -78 °C in THF for 2.5 h. The
results presented in Table 1 show the influence of the
counterion (Li+ or Na+) and the conjugated effects of
temperature and reaction time for the four electrophiles
mentioned above.
Initial oxidation studies with Vedejs’ reagent confirmed
the stereodirecting effect of the tert-butyl ester substitu-
ent. When the lithium enolate of 6a was treated with
MoOPH for 1 h, the corresponding hydroxylated adduct
5a was obtained in low yield with 76% diastereomeric
excess (de). The ratio between the two diastereomers was
determined by RP-HPLC of the crude product using a
C18 column. The major diastereomer, subsequently iden-
tified as (5R)-5a , (vide infra) was isolated in 20% yield
(Table 1, entry 1). Recovery of 73% of starting material
6a suggested that the low yield was attributable to a slow
oxidation rate. Attempts to improve the yield by a slow
increase of the temperature over a long period of time
(entry 2) did not give any hydroxylated product and
resulted in nearly complete degradation of 6a . Similarly,
no hydroxylation took place at -78 °C with the more
nucleophilic sodium enolate (entry 3). However, perform-
ing the experiment with Li-enolate at -50 °C during 0.5
h gave both a dramatic increase in yield and good
stereoselectivity (entry 4). Replacing LiHMDS by NaH-
MDS improved the yield but resulted in lower diastereo-
selectivity (entry 5 vs 4). In all cases, the remaining
starting material made the flash chromatography of 5a
difficult, and a nonnegligible amount of product was lost
during purification.
a
(a) Meldrum’s acid, EDC, DMAP, CH2Cl2; (b) NaBH4, CH2Cl2/
AcOH (10:1); (c) toluene, reflux; (d) H2, Pd/C, EtOH; (e) allyl
bromide, DBU, CH3CN.
The condensation of 7 with Meldrum’s acid afforded
8, which was used in the next step without further
purification. Treatment of 8 with NaBH4 in CH2Cl2/AcOH
at room temperature resulted in complete reduction of
its keto functionality to give 9. It is likely that 8 first
underwent reduction of its ketone functionality to the
â-hydroxy diester, and that this was followed by dehy-
dration to the unsaturated ester, which is further reduced
to 9 via Michael addition of hydride ion.16
Oxidation of the lithium enolate of 6a by (()-PPO for
1 h (entry 6) resulted in the formation of the imino-aldol
10 as the major product together with 5a in low yield
These compounds were obtained in excellent yield and
easily purified by crystallization with the exception of 9d ,
for which a flash chromatography was necessary. Decar-
boxylative ring closure of 9 in toluene at reflux afforded
lactams 6 in moderate to good yields after flash chroma-
tography. Additionally, we prepared the piperidinone 6e
in a two-step procedure starting from 6b. The quantita-
tive reduction of the benzyl ester gave the free carboxylic
acid, which was directly protected by reaction with allyl
bromide in the presence of DBU to yield 6e.
En ola te F or m a tion a n d r-Hyd r oxyla tion Stu d ies.
Initial oxidation studies were conducted on the enolate
of di-tert-butyl (2S)-6-oxo-1,2-piperidinedicarboxylate 6a .
Various oxidizing agents were evaluated, including Vede-
js’ MoOPH (MoO5‚HMPA‚pyridine) and Davis’ oxaziri-
dines [trans-(()-2-(phenylsulfonyl)-3-phenyloxaziridine
as well as the two antipodal (+)- and (-)-(10-camphor-
sulfonyl)oxaziridines].17,18 6a was converted to the cor-
but 94% de. The imino-aldol 10 was unambiguously
characterized by 1H NMR and resulted from the addition
of the enolate to the sulfonimine generated from (()-
PPO.17e-h,18 This side reaction is generally avoided by
using sodium enolates. However, in the case of 6a ,
replacing the lithium enolate by the sodium enolate
(entry 7 vs 6) did not eliminate the imino-aldol but only
reduced its amount to the advantage of 5a . Reduction of
the reaction time from 0.5 to 0.25 h (entries 8 vs 7)
8442 J . Org. Chem., Vol. 67, No. 24, 2002

Hydroxylation of 6-Substituted Piperidin-2-ones
TABLE 1. Cou n ter ion a n d Hyd r oxyla tin g Agen t Stu d y for P r ep a r a tion of 5
purified yield
of (5R)-5a , %
entry
base
electrophile
T, °C
-78
time, h
dra of 5a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
LiHMDS
LiHMDS
NaHMDS
LiHMDS
NaHMDS
LiHMDS
NaHMDS
NaHMDS
NaHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
MoOPHb
MoOPHb
MoOPHb
MoOPHb
MoOPHb
(()-PPOd
(()-PPOd
(()-PPOd
(()-PPOd
(+)-CSOe
(+)-CSOe
(+)-CSOe
(-)-CSOe
(-)-CSOe
(-)-CSOe
1.0
16.0
3.0
0.5
0.5
1.0
0.5
0.25
3.0
0.25
0.25
16.0
0.25
0.25
16.0
88:12
nd
-
20 (73)c
<5
0
77
83
<10
38
-78 f rt
-78
-50
-50
-78
-78
-78
-78
-78
-50
-78
-78
-50
-78
91:9
83:17
97:3
96:4
94:6
nd
99:1
97:3
98:2
99:1
97:3
98:2
48
<5
42 (53)c
77
92
21 (78)c
62
76
a
b
(5R)-5a :(5S)-5a ; ratio determined by analytical C18 RP-HPLC of the crude product. MoOPH ) MoO5‚pyridine‚HMPA. c % of recovered
starting material. PPO ) trans-2-(phenylsulfonyl)-3-phenyloxaziridine. e CSO ) (10-camphorsulfonyl)oxaziridine.
d
further improved the yield with only a slight decrease of
diastereoselectivity. Long reaction times (entry 9) were
detrimental for the reaction, and only a mixture of
degradation products and starting material was recov-
ered. In all these reactions the presence of the imino-
aldol 10 made the purification extremely difficult, and
the yields of isolated (5R)-5a (entries 6-8) do not reflect
the actual extent of the reaction. With the aim of
circumventing the problem of imino-aldol formation, we
next investigated (+)- and (-)-CSO as hydroxylating
agents.17g,h,18 The experiments with (+)- and (-)-CSO
were performed in parallel (entries 10-12 vs 13-15) and
resulted in very clean reactions (no degradation). In the
first series of experiments, the lithium enolate of 6a was
treated at -78 °C for 0.25 h with (+)-CSO or (-)-CSO
(entries 10 and 13). Excellent diastereoselectivities but
modest yields were obtained as a result of the steric
hindrance of CSO. Performing the reaction at -50 °C
resulted in better yield and only slightly lower de. The
reaction was brought to completion by performing the
oxidation at -78 °C overnight (entries 12 and 15). When
using (+)-CSO under these conditions (entry 12), the
hydroxylation reaction was found to proceed almost
F IGURE 1. Ortep plot of 6a .
quantitatively with a high diastereoselectivity (96% de):
(5R)-5a was isolated in 92% yield. From these experi-
ments with CSO, two general trends can be noted: on
one hand, yields are consistently higher with (+)-CSO
than with (-)-CSO. On the other hand, (+)- and (-)-CSO
do not have opposite effects on the stereochemical course
of the reaction.
Structural evidence for the high diasterofacial bias in
the hydroxylation reaction was obtained by determina-
tion of the X-ray crystal structure of 6a . The structure
shown in Figure 1 confirms the expected axial orientation
of the C-2 ring substituent resulting from the minimiza-
(17) For oxidations using MoOPH, see: (a) Vedejs, E. J . Am. Chem.
Soc. 1974, 94, 5944-5946. (b) Vedejs, E.; Engler, D. A.; Telschow, J .
E. J . Org. Chem. 1978, 43, 188-196. For
a comparison between
MoOPH and (()-PPO, see: (c) Davis, F. A.; Vishwakarma, L. C.;
Billmers, J . M. J . Org. Chem. 1984, 49, 3243-3244. (d) Natale, N. R.;
McKenna, J . I.; Nio, C.-S.; Borth, M. J . Org. Chem. 1985, 50, 5660-
5666. For oxidations using (()-PPO and/or (+)- and (-)-CSO, see: (e)
Evans, D. A.; Morrissey, M. M.; Dorow, R. L. J . Am. Chem. Soc. 1985,
107, 4346-4348. (f) Davis, F. A.; Wei, J .; Sheppard, A. C.; Gubernick,
S. Tetrahedron Lett. 1987, 28, 5115-5118. (g) Smith, A. B., III; Dorsey,
B. D.; Ohba, M.; Lupo, A. T., J r.; Malamas, M. S. J . Org. Chem. 1988,
53, 4314-1325. (h) Davis, F. A.; Sheppard, A. C.; Chen, B.-C.; Serajul
Haque, M. J . Am. Chem. Soc. 1990, 112, 6679-6690.
(18) For reviews on the chemistry of N-sulfonyloxaziridines, see: (a)
Davis, F. A.; Sheppard, A. C. Tetrahedron 1989, 45, 5703-5742. (b)
Davis, F. A.; Chen, B.-C. Chem. Rev. 1992, 92, 919-934.
J . Org. Chem, Vol. 67, No. 24, 2002 8443

Marin et al.
SCHEME 3a
TABLE 2. In flu en ce of th e P r otectin g Gr ou p s
p u r ified yield
of (5R)-5, %
compd
R1
tBu
tBu
TMSEt
tBu
R2
Bn
TCE
tBu
All
dra of 5
5b
5c
5d
5e
99:1
100:0
99:1
88
73
87
89
99:1
a
(5R)-5:(5S)-5; ratio determined by analytical C18 RP-HPLC of
the crude product.
tion of the allylic A(1,3) strain. Its enolate form is believed
to adopt a half-chair conformation with the metal coor-
dinating both oxygen atoms O2 and O5 (Figure 1).
The stereochemical outcome of the reaction was con-
firmed by X-ray crystal structure analysis of the major
diastereomer formed by hydroxylation of 6a , which was
unambiguously assigned to (5R)-5a .
The influence of R1 and R2 in 6a on the outcome of the
hydroxylation reaction was investigated under our opti-
mal conditions: Li-enolate/(+)-CSO/-78 °C/16 h. Results
shown in Table 2 indicate that the nature of the ester
group R2 has little influence on yield and stereoselectiv-
ity. Only in the case of the trichloroethyl ester protection
was the yield found to be consistently lower. The replace-
ment of Boc by Teoc (compound 5d ) had no significant
effect.
a
(a) LiHMDS, THF, -78 °C; (b) CSO, -78 °C, 16 h; (c)
preparation previously described by us (ref 13); (d) ratio deter-
mined by 1H NMR; (e) 14 is the only diastereomer detected; (f)
resulting from alkylation of 6a with MeI, equimolar mixture of
diastereomers; (g) ratio determined by C18 RP-HPLC of the crude
product.
SCHEME 4a
The hydroxylation reaction of the related 6-alkyl or 3,6-
disubstituted piperidinones 11, 13, and 15 (Scheme 3)
was investigated. When the ester group in 6a was
replaced by a s-Bu side chain (11), a significant decrease
in the diastereoselectivity was observed under our stan-
dard conditions with de ) 82%. This reaction was not
optimized for higher diastereoselectivities. Conversely,
high diastereofacial bias was obtained in the hydroxyla-
tion of the enolate generated from the piperidin-2-one 13.
The corresponding 3-alkylated-3-hydroxylated adduct 14
was obtained in 67% yield together with 18% of unreacted
13. In good agreement with the result obtained for 6a ,
hydroxylation of the mixture of diastereomers 15 pro-
ceeded in good yield and gave 16 as sole diastereomer
(dr ) 98:2) in 80% yield.
Syn th esis of (2S,5R)-5-Hyd r oxylysin e (1). With
pure hydroxylated piperidinone (5R)-5a in hand, the
transformation to the diol 17 then became the key step
in our approach to the synthesis of (2S,5R)-5-hydroxyl-
ysine (Scheme 4). We studied methods involving direct
ring-opening of (5R)-5a under reductive condition.19
Initially, we tried to reduce the lactam function using
lithium borohydride in the presence of 1 equiv of water.
This procedure, proposed by Penning et al.21 for the
reduction of sterically hindered and alkene-containing
acyloxazolidinones, failed to give us the desired product
a
(a) NaBH4, EtOH; (b) MsCl, collidine, CH2Cl2; (c) NaN3, DMF;
(d) H2, Pd/C, EtOH; (e) HCl, dioxane.
when starting from (5R)-5a . Protection of the secondary
alcohol prior to the reduction did not bring any improve-
ment. However, we found that the N-Boc-protected
lactam (5R)-5a could be opened using sodium borohydride
in ethanol, the 1,2-diol 17 being formed in high yield
(Scheme 4). The protection of the acidic function as the
tert-butyl ester was mandatory in this step. All attempts
to convert lactams 5b and 5e to the corresponding diols
under these conditions failed and gave degradation
(19) The two-step procedure consisting of ring opening of lactam
(5R)-5a by treatment with LiOH (ref 20) followed by reduction of the
newly formed acidic function to the expected diol 17 was not investi-
gated.
(20) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J . Org. Chem. 1983, 48,
2424-2426.
(21) Penning, T. D.; Djuric’, S. W.; Haack, R. A.; Kalish, V. J .;
Miyashiro, J . M.; Rowell, B. W.; Yu, S. S. Synth. Commun. 1990, 20,
307-312.
8444 J . Org. Chem., Vol. 67, No. 24, 2002

Hydroxylation of 6-Substituted Piperidin-2-ones
SCHEME 5
SCHEME 6a
a
(a) MsCl, collidine, CH2Cl2; (b) NaI, acetone; (c) K2CO3,
acetone.
transformed to the corresponding N-protected piperidi-
nones 6 in a simple three-step reaction sequence. Under
our optimal conditionssLi-enolate/(+)-CSO/-78 °C/16
hsthe hydroxylation reaction of 6 and of related N-pro-
tected-6-alkyl piperidinones was found to proceed almost
quantitatively with high diastereoselectivities (de ) 96%
in the case of 6a ). Avoidance of allylic A(1,3) strain that
forces the carboxylate substituent at C-2 to adopt an axial
disposition is believed to be the key factor governing the
stereochemical outcome of the reaction. The hydroxylated
lactam (5R)-5a represents a highly versatile chiral syn-
thon which has been used successfully in the synthesis
of (2S,5R)-5-hydroxylysine 1 (eight steps from 7a , 52%
overall yield), as well as in the synthesis of two inter-
mediates required in the total synthesis of bone collagen
cross-link (+)-pyridinoline 2a .
byproducts. The primary alcohol in 17 was selectively
mesylated in a very clean reaction,23 thus averting the
need for a purification before the following step. The
crude mesylate was quantitatively converted to the 1,2-
azido alcohol 18 by nucleophilic substitution with NaN3.
The reduction of the azide function gave the 1,2-amino
alcohol Boc-Hyl-OtBu (19), a known precursor of natural
hydroxylysine,7a in quantitative yield. The final depro-
tection of the Boc and tert-Butyl ester functional groups
afforded 1 in an overall yield of 52% starting from the
aspartic acid derivative 7a . The stereoisomeric purity of
5-hydroxylysine (1) prepared from (5R)-5a was deter-
mined after derivatization with 1-fluoro-2,4-dinitrophen-
yl-5-L-alanine amide (Marfey’s reagent),22 by RP-HPLC
analysis using a C18 column and a linear gradient of 0.1%
aqueous TFA and MeOH (30-65% MeOH in 35 min).
Under these conditions the four diastereomers of 5-hy-
droxylysine were baseline separated. Comparison with
a commercial sample of (2S,5R)-5-hydroxylysine revealed
that 5-hydroxylysine 1 was 97% pure.
Syn th esis of (+)-P yr id in olin e P r ecu r sor s 3 a n d
4. The total synthesis of (+)-pyridinoline 2a (Scheme 5),
described independently by Waelchli et al. and Adamczyk
et al.,7a,b involves the construction of an appropriately
functionalized 3-hydroxy-4,5-substituted pyridine deriva-
tive 20, followed by the quaternization of nitrogen with
the iodo compound 3. 20 was prepared starting from
epoxy amino acid 4 in a biomimetic pathway (Scheme
5). We found that diol 17 was a versatile precursor in
the synthesis of related amino acids 3 and 4, since
only two steps were required for the transformation
(Scheme 6).
Exp er im en ta l Section
Gen er a l. All reactions were performed under an atmo-
sphere of argon. THF was distilled from Na/benzophenone;
CH2Cl2 was distilled from CaH2; toluene was distilled over Na.
Flash column chromatography was carried out on silica gel
(0.063-0.200 mm). HPLC analysis was performed on a Nu-
cleosil C18 column (5 µm, 3.9 × 150 mm) by using a linear
gradient of A (0.1% TFA in H2O) and B (0.08% TFA in MeCN)
1
at a flow rate of 1.2 mL/min with UV detection at 214 nm. H
and 13C NMR spectra were recorded at 400 MHz in CDCl3 as
the solvent.
Ma ter ia ls. Amino acid derivatives were purchased from
Neosystem or Senn Chemicals. Boc-Asp-OBn (7b) is com-
mercially available. Boc-Asp-OtBu (7a ),24 Boc-Asp-OTCE (7c),
and Teoc-Asp-OtBu (7d )25 were prepared starting from the
commercially available Boc-Asp(Bn)-OH. The synthesis of
piperidin-2-ones 11 and 13 has already been described.13
MoOPH,26 (()-PPO,27 and (+)- and (-)-CSO28 were prepared
according to the published procedures.
Con clu sion
P r ep a r a tion of Meld r u m ’s Der iva tives 9a -d . EDC (1.5
equiv), DMAP (1.5 equiv), and Meldrum’s acid (1 equiv) were
added to a 0.25 M solution of PG1-Asp-OPG2 in CH2Cl2 at 0
We have reported an efficient methodology for synthe-
sizing enantiopure (2S,5R)-5-hydroxylysine 1 via the
hydroxylation of di-tert-butyl (2S)-6-oxo-1,2-piperidinedi-
carboxylate (6a ). Conveniently protected aspartic acid
derivatives 7 as inexpensive chiral adducts were first
(24) (a) Mathias, L. J . Synthesis 1979, 561-576. (b) Bergmeier, S.
C.; Cobas, A. A.; Rapoport, H. J . Org. Chem. 1993, 58, 2369-2376.
(25) Shute, R. E.; Rich, D. H. Synthesis 1987, 346-349.
(26) For the preparation of MoOPH, see: Mimoun, H.; Seree de
Roch, I.; Sajus, L. Bull. Soc. Chim. 1969, 5, 1481-1492.
(22) Marfey, P. Carlsberg Res. Commun. 1984, 49, 591-596.
(23) O’Donnell, C. J .; Burke, S. D. J . Org. Chem. 1998, 63, 8614-
8616.
(27) For the preparation of (()-PPO, see: Vishwakarma, L. C.;
Stringer, O. D.; Davis, F. A. Org. Synth. 1987, 66, 203-210.
J . Org. Chem, Vol. 67, No. 24, 2002 8445

Marin et al.
°C. The mixture was allowed to reach room temperature,
stirred for 3 h, and then washed with 1 N KHSO4. The organic
layer was dried over Na2SO4 and filtered prior to the addition
of CH2Cl2 (to afford a 0.05 M solution) and 10% v/v of acetic
acid. NaBH4 (3.0 equiv) was added portionwise to the previous
solution stirred at room temperature. After 48 h, the mixture
was diluted with brine, and the organic layer was washed
using water, dried over Na2SO4, filtered, and evaporated to
afford a residue which was purified by crystallization or by
flash chromatography.
solvent was evaporated and the residue dissolved in AcOEt
and washed with saturated NaHCO3, brine, and 1 N KHSO4.
The organic layer was dried over Na2SO4 and concentrated in
vacuo. The crude product was purified by flash column
chromatography (AcOEt/Hex, 2:8) to yield pure 6.
Di-ter t-b u t yl (2S)-6-Oxo-1,2-p ip er id in ed ica r b oxyla t e
(6a ). Purification of the crude product by flash column
chromatography gave 6a (2.03 g, yield ) 76%): HPLC tR 10.44
(linear gradient, 30-100% B, 20 min); white solid; [R]D ) -12.3
(c ) 1.1, MeOH); mp 46-48 °C; 1H NMR (400 MHz, CDCl3) δ
4.58 (dd, J ) 5.8, 3.6 Hz, 1H), 2.57 (ddd, J ) 17.5, 5.6, 4.5 Hz,
1H), 2.47 (ddd, J ) 17.4, 9.8, 7.0 Hz, 1H), 2.19-2.13 (m, 1H),
2.05-1.96 (m, 1H), 1.82-1.74 (m, 2H), 1.48 (s, 9H), 1.47 (s,
9H); 13C NMR (100 MHz, CDCl3) 170.6 (C), 170.4 (C), 152.3
(C), 83.2 (C), 82.1 (C), 59.0 (CH), 34.5 (CH2), 27.9 (6 CH3), 25.9
(CH2), 18.3 (CH2). Anal. Calcd for C15H25NO5: C, 60.18; H,
8.42; N, 4.68. Found: C, 60.30; H, 8.64; N, 4.65.
ter t-Bu tyl (2S)-2-[(ter t-Bu toxyca r bon yl)a m in o]-4-(2,2-
d im eth yl-4,6-d ioxo-1,3-d ioxa n -5-yl)bu ta n oa te (9a ). Re-
crystallization of the crude product from CH2Cl2/pentane gave
9a (5.44 g, yield ) 98%): HPLC tR 10.98 (linear gradient, 30-
100% B, 20 min); white crystals; [R]D ) +11.2 (c ) 1.0, CHCl3);
1
mp 100-102 °C; H NMR (400 MHz, CDCl3) δ 5.13 (bd, J )
7.1 Hz, 1H), 4.18 (bs, 1H), 3.77 (bs, 1H), 2.24-2.18 (m, 1H),
2.09-2.01 (m, 2H), 1.83-1.77 (m, 1H), 1.80 (s, 3H), 1.74 (s,
3H), 1.45 (s, 9H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCl3)
171.4 (C), 165.2 (2 C), 155.6 (C), 105.0 (C), 82.3 (C), 79.9 (C),
53.2 (CH), 45.4 (CH), 29.6 (CH2), 28.6 (CH3), 28.3 (3 CH3), 28.0
(3 CH3), 26.4 (CH3), 21.8 (CH2). Anal. Calcd for C19H31NO8:
C, 56.84; H, 7.78; N, 3.49. Found: C, 56.84; H, 7.92; N, 3.47.
Ben zyl (2S)-2-[(ter t-Bu t oxyca r b on yl)a m in o]-4-[(2,2-
d im eth yl-4,6-d ioxo-1,3-d ioxa n -5-yl)bu ta n oa te (9b). Re-
crystallization of the crude product from CH2Cl2/pentane gave
9b (6.34 g, yield ) 95%): HPLC tR 12.34 (linear gradient, 30-
100% B, 20 min); white crystals; [R]D ) +6.5 (c ) 1.0, CHCl3);
mp 94-96 °C; 1H NMR (400 MHz, CDCl3) δ 7.33-7.30 (m, 5H),
5.17 (m, 2H), 5.16 (m, 1H), 4.37 (m, 1H), 3.73 (m, 1H), 2.25-
2.18 (m, 1H), 2.16-2.07 (m, 2H), 1.86-1.81 (m, 1H), 1.80 (s,
3H), 1.74 (s, 3H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCl3)
172.2 (C), 165.1 (C), 165.0 (C), 156.0 (C), 135.3 (C), 128.7 (5
CH), 105.1 (C), 80.4 (C), 67.3 (CH2), 52.8 (CH), 45.4 (CH), 29.5
(CH2), 28.6 (CH3), 28.3 (3 CH3), 26.5 (CH3), 21.9 (CH2).
Tr ich lor oeth yl (2S)-2-[(ter t-Bu toxyca r bon yl)a m in o]-4-
(2,2-d im et h yl-4,6-d ioxo-1,3-d ioxa n -5-yl)b u t a n oa t e (9c).
Recrystallization of the crude product from CH2Cl2/pentane
gave 9c (3.66 g, yield ) 90%): HPLC tR 11.92 (linear gradient,
30-100% B, 20 min); white crystals; [R]D ) -8.8 (c ) 0.9,
2-Ben zyl 1-ter t-Bu tyl (2S)-6-Oxo-1,2-p ip er id in ed ica r -
boxyla te (6b). Purification of the crude product by flash
column chromatography gave 6b (3.19 g, yield ) 75%): HPLC
tR 11.09 (linear gradient, 30-100% B, 20 min); white solid;
[R]D ) -10.2 (c ) 1.0, CHCl3); mp 43-44 °C; 1H NMR (400
MHz, CDCl3) δ 7.32-7.29 (m, 5H), 5.22 (d, J ) 12.2 Hz, 1H),
5.14 (d, J ) 12.2 Hz, 1H), 4.73 (m, 1H), 2.55-2.49 (m, 1H),
2.44 (ddd, J ) 17.6, 9.9, 6.8 Hz, 1H), 2.18-2.11 (m, 1H), 2.06-
1.97 (m, 1H), 1.77-1.69 (m, 1H), 1.67-1.60 (m, 1H), 1.43 (s,
9H); 13C NMR (100 MHz, CDCl3) 171.4 (C), 170.2 (C), 152.2
(C), 135.3 (C), 128.7 (2 CH), 128.5 (CH), 128.4 (2 CH), 83.6
(C), 67.3 (CH2), 58.6 (CH), 34.5 (CH2), 27.9 (6 CH3), 25.9 (CH2),
18.3 (CH2). Anal. Calcd for C18H23NO5: C, 64.85; H, 6.95; N,
4.20. Found: C, 64.52; H, 7.01; N, 4.28.
2-Tr ich lor oeth yl 1-ter t-Bu tyl (2S)-6-Oxo-1,2-p ip e-
r id in ed ica r boxyla te (6c). Purification of the crude product
by flash column chromatography gave 6c (1.00 g, yield )
42%): HPLC tR 11.87 (linear gradient, 30-100% B, 20 min);
1
white solid; [R]D ) -1.0 (c ) 1.1, MeOH); mp 63-65 °C; H
NMR (400 MHz, CDCl3) δ 5.00 (d, J ) 11.9 Hz, 1H), 4.87 (dd,
J ) 6.0, 3.5 Hz, 1H), 4.68 (d, J ) 11.9 Hz, 1H), 2.63 (ddd, J )
17.5, 5.8, 4.4 Hz, 1H), 2.53 (ddd, J ) 17.5, 9.8, 7.2 Hz, 1H),
2.35-2.28 (m, 1H), 2.21-2.11 (m, 1H), 1.91-1.77 (m, 2H), 1.53
(s, 9H); 13C NMR (100 MHz, CDCl3) 170.1 (C), 169.8 (C), 152.5
(C), 94.5 (C), 84.0 (C), 74.5 (CH2), 58.3 (CH), 34.5 (CH2), 28.0
(3 CH3), 25.8 (CH2), 18.3 (CH2). Anal. Calcd for C13H18Cl3-
NO5: C, 41.68; H, 4.84; N, 3.74. Found: C, 41.78; H, 4.84; N,
3.81.
1
MeOH); mp 124-125 °C; H NMR (400 MHz, CDCl3) δ 5.15
(bd, J ) 7.7 Hz, 1H), 4.87 (d, J ) 11.8 Hz, 1H), 4.69 (d, J )
11.8 Hz, 1H), 4.44 (bs, 1H), 3.73 (bs, 1H), 2.29-2.24 (m, 1H),
2.24-2.15 (m, 2H), 1.90-1.85 (m, 1H), 1.81 (s, 3H), 1.74 (s,
3H), 1.43 (s, 9H); 13C NMR (100 MHz, CDCl3) 170.9 (C), 165.1
(2 C), 155.5 (C), 105.2 (C), 94.5 (C), 80.5 (C), 74.4 (CH2), 53.0
(CH), 45.5 (CH), 29.1 (CH2), 28.5 (CH3), 28.3 (3 CH3), 26.5
(CH3), 22.0 (CH2). Anal. Calcd for C17H24Cl3NO8: C, 42.83; H,
5.07; N, 2.94. Found: C, 43.04; H, 4.87; N, 2.90.
2-ter t-Bu tyl 1-[(Tr im eth ylsilyl)eth yl] (2S)-6-Oxo-1,2-
p ip er id in ed ica r boxyla te (6d ). Purification of the crude
product by flash column chromatography gave 6d (2.87 g, yield
) 71%): HPLC tR 13.74 (linear gradient, 30-100% B, 20 min);
ter t-Bu tyl (2S)-4-(2,2-Dim eth yl-4,6-d ioxo-1,3-d ioxa n -5-
y l )-2-({[(t r i m e t h y l s i l y l )e t h o x y ]c a r b o n y l}a m i n o )-
bu ta n oa te (9d ). Purification of the crude product by flash
column chromatography gave 9d (5.35 g, yield ) 98%): HPLC
tR 13.10 (linear gradient, 30-100% B, 20 min); colorless oil;
1
white solid; [R]D ) -10.1 (c ) 1.1, MeOH); mp 52-54 °C; H
NMR (400 MHz, CDCl3) δ 4.66 (dd, J ) 5.9, 3.5 Hz, 1H), 4.35-
4.30 (m, 2H), 2.59 (ddd, J ) 17.3, 5.8, 4.1 Hz, 1H), 2.48 (ddd,
J ) 17.3, 10.0, 7.1 Hz, 1H), 2.23-2.16 (m, 1H), 2.06-1.97 (m,
1H), 1.85-1.73 (m, 2H), 1.48 (s, 9H), 1.12-1.08 (m, 2H), 0.04
(s, 9H); 13C NMR (100 MHz, CDCl3) 170.4 (C), 170.3 (C), 154.4
(C), 82.3 (C), 65.6 (CH2), 59.1 (CH), 34.4 (CH2), 28.0 (3 CH3),
25.8 (CH2), 18.3 (CH2), 17.5 (CH2), -1.6 (3 CH3). Anal. Calcd
for C16H29NO5Si: C, 55.95; H, 8.51; N, 4.08. Found: C, 55.56;
H, 8.44; N, 4.09.
1
[R]D ) +12.4 (c ) 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ
5.27 (bd, J ) 5.3 Hz, 1H), 4.22 (bs, 1H), 4.14-4.09 (m, 2H),
3.69 (bs, 1H), 2.22-2.13 (m, 1H), 2.09-1.98 (m, 2H), 1.85-
1.76 (m, 1H), 1.79 (s, 3H), 1.73 (s, 3H), 1.45 (s, 9H), 0.98-0.94
(m, 2H), 0.00 (s, 9H); 13C NMR (100 MHz, CDCl3) 171.4 (C),
165.1 (2 C), 156.4 (C), 105.0 (C), 82.4 (C), 63.4 (CH2), 53.6 (CH),
45.5 (CH), 29.5 (CH2), 28.5 (CH3), 28.0 (3 CH3), 26.5 (CH3),
2-Allyl 1-ter t-Bu tyl (2S)-6-oxo-1,2-p ip er id in ed ica r box-
yla te (6e). Pd/C (150 mg, 10% w/w) was added to a solution
of 1.50 g (4.50 mmol) of 6b in 20 mL of AcOEt at room
temperature. The mixture was stirred for 2 h and filtered
through Celite. Evaporation of the solvent gave 1.10 g of the
free-acid intermediate. The free-acid derivative (1.00 g, 4.11
mmol) and allyl bromide (497 mg, 4.11 mmol) were dissolved
in 15 mL of acetonitrile. The mixture was cooled to 0 °C and
751 mg (4.93 mmol) of DBU was added. After stirring for 6 h,
acetonitrile was evaporated and the residue was dissolved in
AcOEt. The solution was washed with saturated NaHCO3,
brine, and 1 N KHSO4. Drying over Na2SO4 and evaporation
of the filtrate afforded pure 6e (1.15 g, yield ) 99% starting
21.8 (CH2), 17.7 (CH2), -1.4 (3 CH3). Anal. Calcd for C20H35
-
NO8Si: C, 53.91; H, 7.92; N, 3.14. Found: C, 54.15; H, 8.02;
N, 3.09.
P r ep a r a tion of P ip er id in -2-on es Der iva tives 6a -d . A
0.1 M solution of 9 in dry toluene was refluxed overnight. The
(28) For the preparation of (+)-CSO and (-)-CSO, see: (a) Bartlett,
P. D.; Knox, L. H. Organic Syntheses; Wiley: New York, 1973; Collect.
Vol. V, pp 196-198. (b) Towson, J . C.; Weismiller, M. C.; Sankar Lal,
G. Org. Synth. 1990, 69, 158-169. (c) Bulman Page, P. C.; Heer, J . P.;
Bethell, D.; Lund, A.; Collington, E. W.; Andrews, D. M. J . Org. Chem.
1997, 62, 6093-6094.
8446 J . Org. Chem., Vol. 67, No. 24, 2002

Hydroxylation of 6-Substituted Piperidin-2-ones
from 6b): HPLC tR 8.48 (linear gradient, 30-100% B, 20 min);
colorless oil; [R]D ) -8.9 (c ) 1.1, MeOH); 1H NMR (400 MHz,
CDCl3) δ 5.95-5.85 (m, 1H), 5.34 (dd, J ) 17.2, 1.4 Hz, 1H),
5.25 (dd, J ) 10.4, 1.4 Hz, 1H), 4.72 (dd, J ) 5.9, 3.8 Hz, 1H),
4.66-4.63 (m, 2H), 2.57 (ddd, J ) 17.5, 6.0, 4.3 Hz, 1H), 2.47
(ddd, J ) 17.5, 9.9, 6.8 Hz, 1H), 2.21-2.15 (m, 1H), 2.10-2.01
(m, 1H), 1.83-1.67 (m, 2H), 1.48 (s, 9H); 13C NMR (100 MHz,
CDCl3) 171.2 (C), 170.2 (C), 152.3 (C), 131.4 (CH), 119.0 (CH2),
83.6 (C), 66.1 (CH2), 58.6 (CH), 34.5 (CH2), 27.9 (3 CH3), 25.9
(CH2), 18.3 (CH2). Anal. Calcd for C14H21NO5: C, 59.35; H,
7.47; N, 4.94. Found: C, 59.62; H, 7.70; N, 5.01.
67.6 (CH2), 58.0 (CH), 27.8 (3 CH3), 26.7 (CH2), 22.7 (CH2).
Anal. Calcd for C18H23NO6: C, 61.88; H, 6.64; N, 4.01. Found:
C, 61.87; H, 6.88; N, 3.95.
2-Tr ich lor oeth yl 1-ter t-Bu tyl (2S,5R)-5-Hyd r oxy-6-oxo-
1,2-p ip er id in ed ica r boxyla te (5c). Using the procedure de-
veloped for (5R)-5a (Table 1, entry 12), 5c was obtained as a
yellowish oil which was purified by flash column chromatog-
raphy (181 mg, yield ) 73%): HPLC tR 9.45 (linear gradient,
30-100% B, 20 min); white solid; [R]D ) -17.3 (c ) 1.0,
1
MeOH); mp 91-92 °C; H NMR (400 MHz, CDCl3) δ 4.93 (d,
J ) 11.8 Hz, 1H), 4.93 (t, J ) 6.5 Hz, 1H), 4.64 (d, J ) 11.8
Hz, 1H), 4.15-4.10 (m, 1H), 3.59 (bs, 1H), 2.37-2.26 (m, 2H),
2.23-2.15 (m, 1H), 1.81-1.71 (m, 1H), 1.49 (s, 9H); 13C NMR
(100 MHz, CDCl3) 173.3 (C), 169.6 (C), 151.5 (C), 94.4 (C), 84.8
(C), 74.5 (CH2), 68.3 (CH), 57.6 (CH), 27.9 (3 CH3), 26.6 (CH2),
22.5 (CH2). Anal. Calcd for C13H18Cl3NO6: C, 39.97; H, 4.64;
N, 3.59. Found: C, 40.27; H, 4.65; N, 3.54.
Gen er a l Hyd r oxyla tion P r oced u r es.
En ola te Gen er a tion . The desired piperidinone derivative
was placed in an argon-filled round-bottom flask, dissolved in
anhydrous THF to give a ca. 0.3 M solution, and cooled to -78
°C. The indicated base (NaHMDS or LiHMDS; 1.1 equiv) was
introduced as a 1.0 M solution in THF via hypodermic syringe.
After being stirred for 2.5 h, the desired enolate was ready
for hydroxylation.
En ola te Hyd r oxyla tion . P r oced u r e A. To the cold eno-
late solution (-78 °C) prepared as described above was added
the indicated amount of crystalline MoOPH (2.0 equiv). The
temperature and duration of the hydroxylation reactions were
specific to each experiment. The reaction was quenched by
introducing a saturated solution of Na2SO3 (1 mL/mmol of
enolate). The resulting two-phase solution was vigorously
stirred for 15 min. The THF was evaporated under reduced
pressure and replaced with AcOEt which was washed with
water. The organic layer was dried over Na2SO4, concentrated,
and chromatographed on silica gel (AcOEt/Hex, 3:7).
2-ter t-Bu tyl 1-[(Tr im eth ylsilyl)eth yl] (2S,5R)-5-Hydr oxy-
6-oxo-1,2-p ip er id in ed ica r boxyla te (5d ). Using the proce-
dure developed for (5R)-5a (Table 1, entry 12), 5d was obtained
as a yellowish oil which was purified by flash column chro-
matography (90 mg, yield ) 87%): HPLC tR 11.99 (linear
gradient, 30-100% B, 20 min); colorless oil; [R]D ) -10.4 (c )
1
0.8, MeOH); H NMR (400 MHz, CDCl3) δ 4.76 (dd, J ) 6.3,
6.0 Hz, 1H), 4.37-4.32 (m, 2H), 4.12 (dd, J ) 9.1, 7.6 Hz, 1H),
3.60 (bs, 1H), 2.25-2.07 (m, 3H), 1.78-1.69 (m, 1H), 1.45 (s,
9H), 1.12-1.06 (m, 2H), 0.03 (s, 9H); 13C NMR (100 MHz,
CDCl3) 173.7 (C), 169.7 (C), 153.4 (C), 82.9 (C), 68.2 (CH), 66.6
(CH2), 58.3 (CH), 27.9 (3 CH3), 26.6 (CH2), 22.6 (CH2), 17.6
(CH2), -1.6 (3 CH3).
P r oced u r e B. To the cold enolate solution (-78 °C)
prepared as described above was added the indicated amount
of oxaziridine (1.5 equiv) dissolved in the minimum volume of
THF. The temperature and duration were specific to each
experiment. The reaction was quenched by introducing a
saturated aqueous solution of NH4Cl (1 mL/mmol of enolate),
and the THF was evaporated under reduced pressure and
replaced with AcOEt which was washed with water. The
organic layer was dried over Na2SO4, concentrated, and
chromatographed on silica gel (MeOH/CH2Cl2, 2:98).
2-Allyl 1-ter t-Bu tyl (2S,5R)-5-Hyd r oxy-6-oxo-1,2-p ip -
er id in ed ica r boxyla te (5e). Using the procedure developed
for (5R)-5a (Table 1, entry 12), 5e was obtained as a yellowish
oil which was purified by flash column chromatography (890
mg, yield ) 89%): HPLC tR 6.64 (linear gradient, 30-100%
B, 20 min); colorless oil; [R]D ) -9.0 (c ) 1.0, MeOH); 1H NMR
(400 MHz, CDCl3) δ 5.91-5.86 (m, 1H), 5.31 (dd, J ) 17.3, 1.4
Hz, 1H), 5.28 (dd, J ) 10.4, 1.4 Hz, 1H), 4.83 (t, J ) 6.5 Hz,
1H), 4.68-4.64 (m, 2H), 4.13 (dd, J ) 9.3, 6.4 Hz, 1H), 3.61
(bs, 1H), 2.32-2.24 (m, 2H), 2.18-2.05 (m, 1H), 1.82-1.74 (m,
1H), 1.52 (s, 9H); 13C NMR (100 MHz, CDCl3) 173.6 (C), 170.6
(C), 151.4 (C), 131.2 (CH), 119.4 (CH2), 84.5 (C), 68.3 (CH),
66.4 (CH2), 58.0 (CH), 27.9 (3 CH3), 26.7 (CH2), 22.7 (CH2).
Anal. Calcd for C14H21NO6: C, 56.18; H, 7.07; N, 4.68. Found:
C, 56.31; H, 7.19; N, 4.76.
Di-ter t-bu tyl (2S,5R)-5-Hydr oxy-6-oxo-1,2-piper idin edi-
ca r boxyla te ((5R)-5a ). Using the best conditions (Table 1,
entry 12), (5R)-5a was obtained as a yellowish oil which was
purified by flash column chromatography (640 mg, yield )
92%): HPLC tR 7.72 (linear gradient, 30-100% B, 20 min);
1
white solid; [R]D ) -12.1 (c ) 1.0, MeOH); mp 88-90 °C; H
ter t-Bu tyl (3S,6R)-3-Hyd r oxy-6-isobu tyl-2-oxo-1-p ip e-
r id in eca r boxyla te (12). Compound 12 was prepared accord-
ing to procedure B using (-)-CSO as oxidizing agent. The
solution was stirred at -78 °C during 16 h. After the workup,
flash column chromatography (MeOH/CH2Cl2, 2:98) of the
crude product afforded pure 12 (96 mg, yield ) 77%): HPLC
NMR (400 MHz, CDCl3) δ 4.68 (t, J ) 6.4 Hz, 1H), 4.11 (dd, J
) 9.7, 7.2 Hz, 1H), 3.61 (bs, 1H), 2.34-2.26 (m, 1H), 2.25-
2.16 (m, 1H), 2.13-2.04 (m, 1H), 1.78-1.68 (m, 1H), 1.52 (s,
9H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3) 173.8 (C), 169.8
(C), 151.6 (C), 84.2 (C), 82.7 (C), 68.3 (CH), 58.4 (CH), 27.9 (6
CH3), 26.8 (CH2), 22.7 (CH2). Anal. Calcd for C15H25NO6: C,
57.13; H, 7.99; N, 4.44. Found: C, 56.91; H, 8.20; N, 4.46.
Di-ter t-bu tyl (2S,5S)-5-h yd r oxy-6-oxo-1,2-p ip er id in ed i-
ca r boxyla te ((5S)-5a ): HPLC tR 7.48 (linear gradient, 30-
t
R 9.27 (linear gradient, 30-100% B, 20 min); colorless oil; [R]D
) +17.2 (c ) 1.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 4.33-
4.25 (m, 1H), 4.17 (t, J ) 7.9 Hz, 1H), 3.73 (bd, J ) 1.4 Hz,
1H), 2.41-2.30 (m, 1H), 2.06-1.99 (m, 1H), 1.77-1.65 (m, 2H),
1.65-1.58 (m, 1H), 1.52 (s, 9H), 1.43 (m, 2H), 0.92 (d, J ) 5.3
Hz, 3H), 0.90 (d, J ) 5.3 Hz, 3H);13C NMR (100 MHz, CDCl3)
174.3 (C), 170.6 (C), 151.9 (C), 83.8 (C), 67.7 (CH), 54.4 (CH),
43.8 (CH2), 27.8 (3 CH3), 26.8 (CH2), 25.0 (CH), 24.2 (CH2),
23.5 (CH3), 21.4 (CH3). Anal. Calcd for C14H25NO4: C, 61.97;
H, 9.29; N, 5.16. Found: C, 61.82; H, 9.05; N, 5.37.
1
100% B, 20 min); H NMR (400 MHz, CDCl3) δ 4.49 (m, 1H),
4.06 (dd, J ) 11.3, 6.2 Hz, 1H), 2.34-2.02 (m, 3H), 1.80-1.66
(m, 1H), 1.50 (s, 9H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3)
174.6 (C), 170.2 (C), 153.1 (C), 83.9 (C), 82.7 (C), 69.9 (CH),
59.9 (CH), 27.9 (6 CH3), 26.7 (CH2), 23.9 (CH2).
2-Ben zyl 1-ter t-bu tyl (2S,5R)-5-h yd r oxy-6-oxo-1,2-p ip -
er id in ed ica r boxyla te (5b). Using the procedure developed
for (5R)-5a (Table 1, entry 12), 5b was obtained as a yellowish
oil which was purified by flash column chromatography (1.81
g, yield ) 88%): HPLC tR 8.39 (linear gradient, 30-100% B,
20 min); colorless oil; [R]D ) -7.8 (c ) 1.2, MeOH); mp 88-90
ter t-Bu tyl (3S,6R)-3-Hyd r oxy-6-isobu tyl-3-(2-m eth yla -
llyl)-2-oxo-1-p ip er id in eca r boxyla te (14). Compound 14 was
prepared according to procedure B using (-)-CSO as oxidizing
agent. The solution was stirred at -78 °C during 16 h. After
the work up, flash column chromatography (MeOH/CH2Cl2,
2:98) of the crude product afforded pure 14 (73 mg, yield )
67%): HPLC tR 14.68 (linear gradient, 30-100% B, 20 min);
colorless crystals; [R]D ) -31.6 (c ) 1.0, CHCl3); mp 42-43
°C; 1H NMR (400 MHz, CDCl3) δ 4.89 (dd, J ) 2.2, 1.5 Hz,
1H), 4.73 (dd, J ) 2.0, 0.8 Hz, 1H), 3.99-3.92 (m, 1H), 3.57
(bs, 1H), 2.39 (d, J ) 10.1 Hz, 1H), 2.32 (d, J ) 10.2 Hz, 1H),
1
°C; H NMR (400 MHz, CDCl3) δ 7.33-7.29 (m, 5H), 5.22 (d,
J ) 12.1 Hz, 1H), 5.15 (d, J ) 12.2 Hz, 1H), 4.83 (t, J ) 6.3
Hz, 1H), 4.08 (dd, J ) 9.6, 6.9 Hz, 1H), 2.27-2.19 (m, 2H),
2.12-2.06 (m, 1H), 1.77-1.68 (m, 1H), 1.46 (s, 9H); 13C NMR
(100 MHz, CDCl3) 173.7 (C), 170.7 (C), 151.4 (C), 135.0 (C),
128.8 (CH), 128.7 (2 CH), 128.4 (2 CH), 84.5 (C), 68.3 (CH),
J . Org. Chem, Vol. 67, No. 24, 2002 8447

Marin et al.
2.06-2.00 (m, 1H), 1.75 (s, 3H), 1.72-1.68 (m, 3H), 1.45 (s,
9H), 1.32-1.21 (m, 1H), 1.18-1.05 (m, 1H), 0.86 (m, 6H); 13C
NMR (100 MHz, CDCl3) 176.3 (C), 153.8 (C), 140.5 (C), 115.7
(CH2), 83.8 (C), 72.4 (C), 60.9 (CH), 46.8 (CH2), 36.7 (CH3),
30.5 (CH2), 27.6 (3 CH3), 25.8 (CH2), 24.0 (CH), 18.6 (CH2),
12.8 (CH3), 12.0 (CH3). Anal. Calcd for C18H31NO4: C, 66.43;
H, 9.60; N, 4.30. Found: C, 66.37; H, 9.82; N, 4.38.
1,2-diol 17 in 90 mL of CH2Cl2 at ambient temperature. The
solution was cooled to 0 °C and 568 mg (4.96 mmol) of MsCl
dissolved in 5.5 mL of CH2Cl2 was added. After being stirred
for 20 h at 0 °C, the reaction was quenched with water (35
mL), the phases were separated, and the aqueous layer was
extracted with CH2Cl2. The combined organic extracts were
washed with 1 N KHSO4, dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was dissolved in 20 mL of
DMF. NaN3 (586 mg, 9.02 mmol) was added to the solution,
which was heated to 80 °C for 8 h. After being allowed to cool
to room temperature, water was added to the solution, which
was extracted twice with AcOEt. The combined organic layers
were washed with water, dried over Na2SO4, filtered, and
evaporated in vacuo. The crude product was purified by flash
column chromatography (AcOEt/Hex, 3:7) to yield pure 18
(1.37 g, yield ) 88%): HPLC tR 10.07 (linear gradient, 30-
100% B, 20 min); colorless oil; [R]D ) +13.8 (c ) 1.0, CHCl3);
1H NMR (400 MHz, CDCl3) δ 5.25 (bd, 1H), 4.21-4.14 (m, 1H),
3.76 (bs, 1H), 3.39-3.36 (m, 1H), 3.26 (dd, J ) 12.4, 4.0 Hz,
1H), 3.21 (dd, J ) 12.4, 6.6 Hz, 1H), 1.96-1.87 (m, 1H), 1.69-
Di-ter t-bu tyl (2S)-5-Meth yl-6-oxo-1,2-p ip er id in ed ica r -
boxyla te (15). 6a (100 mg, 0.334 mmol) was placed in an
argon-filled round-bottomed flask, dissolved in 2.0 mL of
anhydrous THF, and cooled to -78 °C. A 1 N solution (0.334
mL) of LiHMDS in THF was introduced by means of a
hypodermic syringe. After 2.5 h, 142 mg (1.0 mmol) of MeI
was added via a hypodermic syringe. After being stirried at
-78 °C during 16 h, the reaction was quenched by adding 0.35
mL of a saturated aqueous solution of NH4Cl. THF was
evaporated under reduced pressure and replaced with AcOEt
which was washed with water. The organic layer was dried
over Na2SO4, concentrated, and chromatographed on silica gel
(AcOEt/Hex, 2:8) to give 15 (97 mg, yield ) 92%) as an
equimolar mixture of diastereomers: HPLC tR 11.32 (linear
gradient, 30-100% B, 20 min); yellowish oil; [R]D ) -14.8 (c
) 1.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 4.54 (dd, J ) 6.2,
5.0 Hz, 1H), 4.46-4.45 (m, 1H), 2.51-2.44 (m, 1H), 2.43-2.35
(m, 1H), 2.14-1.80 (m, 8H), 1.45 (s, 9H), 1.44 (s, 9H), 1.40 (s,
9H), 1.40 (s, 9H), 1.18 (d, J ) 2.2 Hz, 3H), 1.17 (d, J ) 2.4 Hz,
3H); 13C NMR (100 MHz, CDCl3) 174.1 (C), 173.9 (C), 170.8
(C), 170.7 (C), 153.1 (C), 152.7 (C), 83.1 (C), 82.9 (C), 82.0 (C),
82.0 (C), 59.8 (CH), 58.9 (CH), 39.3 (2 CH), 38.1 (CH), 38.0
(CH), 28.0 (3 CH3), 28.0 (3 CH3), 27.9 (6 CH3), 27.2 (CH2), 26.3
(CH2), 25.7 (CH2), 23.6 (CH2), 17.5 (CH3), 16.9 (CH3). Anal.
Calcd for C16H27NO5: C, 61.32; H, 8.68; N, 4.47. Found: C,
61.44; H, 8.93; N, 4.52.
Di-ter t-bu tyl (2S,5R)-5-Hyd r oxy-5-m eth yl-6-oxo-1,2-p i-
p er id in ed ica r boxyla te (16). Compound 16 was prepared
according to procedure B using (+)-CSO as oxidizing agent.
The solution was stirred at -78 °C during 16 h. After the
workup, flash column chromatography (MeOH/CH2Cl2, 2:98)
of the crude product afforded pure 16 (84 mg, yield ) 80%):
HPLC tR 8.57 (linear gradient, 30-100% B, 20 min); colorless
oil; [R]D ) +44.5 (c ) 0.9, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 4.56 (t, J ) 5.7 Hz, 1H), 3.12 (bs, 1H), 2.25-2.13 (m, 1H),
2.04-1.91 (m, 2H), 1.84-1.79 (m, 1H), 1.49 (s, 9H), 1.46 (s,
9H), 1.46 (s, 3H); 13C NMR (100 MHz, CDCl3) 176.0 (C), 170.1
(C), 151.9 (C), 131.2 (CH), 83.8 (C), 82.3 (C), 72.6 (C), 59.8 (CH),
32.3 (CH3), 28.1 (CH2), 27.9 (3 CH3), 22.9 (CH2). Anal. Calcd
for C16H27NO6: C, 58.34; H, 8.26; N, 4.25. Found: C, 58.33;
H, 8.44; N, 4.06.
ter t-Bu tyl (2S,5R)-2-[(ter t-Bu toxyca r bon yl)a m in o]-5,6-
d ih yd r oxyh exa n oa te (17). NaBH4 (935 mg, 24.75 mmol) was
added to a solution of 1.56 g (4.95 mmol) of R-hydroxy lactam
(5R)-5a in 20 mL of absolute ethanol at 0 °C. The mixture was
allowed to reach room temperature and stirred for 4 h. After
being quenched with water, the mixture was stirred for a
further 10 min. Evaporation of the solvent gave a solid, which
was dissolved in AcOEt. The solution was washed with water
and dried over Na2SO4. Evaporation of the filtrate afforded
an oil which was subjected to filtration through a silica pad
(AcOEt/AcOH, 99:1). Pure 17 was recovered (1.44 g, yield )
91%): HPLC tR 5.85 (linear gradient, 30-100% B, 20 min);
[R]D ) +12.2 (c ) 1.1, CHCl3); waxy white solid; 1H NMR (400
MHz, CDCl3) δ 5.33 (bd, 1H), 4.15-4.10 (m, 1H), 3.92 (bs, 2H),
3.69-3.63 (m, 1H), 3.56 (dd, J ) 11.0, 2.9 Hz, 1H), 3.38 (dd, J
) 11.0, 7.3 Hz, 1H), 1.93-1.86 (m, 1H), 1.68-1.59 (m, 1H),
1.47-1.42 (m, 2H), 1.41 (s, 9H), 1.39 (s, 9H); 13C NMR (100
MHz, CDCl3) 172.0 (C), 155.8 (C), 82.0 (C), 79.9 (C), 71.7 (CH),
66.6 (CH2), 53.8 (CH), 29.3 (CH2), 28.7 (CH2), 28.3 (3 CH3),
28.0 (3 CH3). Anal. Calcd for C15H29NO6: C, 56.41; H, 9.15; N,
4.39. Found: C, 56.20; H, 9.42; N, 4.35.
1.58 (m, 1H), 1.53-1.48 (m, 2H), 1.42 (s, 9H), 1.40 (s, 9H); 13
C
NMR (100 MHz, CDCl3) 171.7 (C), 155.8 (C), 82.2 (C), 80.0
(C), 70.4 (CH), 57.0 (CH2), 53.5 (CH), 29.8 (CH2), 29.6 (CH2),
28.3 (3 CH3), 28.0 (3 CH3). Anal. Calcd for C15H28N4O5: C,
52.31; H, 8.19; N, 16.27. Found: C, 52.32; H, 8.42; N, 16.09.
(2S,5R)-5-Hyd r oxylysin e Dih yd r och lor id e (1). Palla-
dium on activated carbon (5 mg, 10% Pd) was added to a
solution of 100 mg (0.29 mmol) of 18 in 2 mL of ethanol. The
mixture was vigorously stirred at room temperature for 4 h
under an atmosphere of hydrogen and filtered through Celite.
Evaporation of the solvent gave 19 in quantitative yield as a
colorless oil. The residue was dissolved in 2 mL of a 4 N
solution of HCl in dioxane and stirred at room temperature
for 2 h. Evaporation of the solvent gave 1 (65 mg, yield ) 95%),
a white solid.
Deter m in a tion of th e Ster eom er ic P u r ity of 1. Com-
pound 1 (1 mg) was dissolved in 1 mL of 50% (v/v) aqueous
acetonitrile containing 0.4% (v/v) of triethylamine. A 200 µL
aliquot of this solution was mixed with 200 µL of Marfey’s
reagent in acetone (2.5 mg in 1 mL). The mixture was
thermostated at 40 °C for 2 h and diluted to 1.0 mL with water
prior to injection. The same procedure was repeated using the
commercially available (2S,5R)-5-hydroxylysine and a com-
mercial mixture of the four diastereoisomers. HPLC analysis
was performed on a Nucleosil C18 column (5 µm, 3.9 × 150
mm) by using a linear gradient (30-65% B, 35 min) of A (0.1%
TFA in H2O) and B (MeOH) at a flow rate of 1.0 mL/min
with UV detection at 214 nm: D,L-5-hydroxy-D,L-lysine, tR
23.93, 25.92, 27.57, 28.36 min; commercial 1, tR 27.59 min;
synthesized 1, tR 27.59 min.
ter t-Bu tyl (2S,5R)-2-[(ter t-Bu toxyca r bon yl)a m in o]-5-
h yd r oxy-6-iod oh exa n oa te (3). Collidine (0.83 mL, 6.26
mmol) was added to a solution of 200 mg (0.626 mmol) of 17
in 11.0 mL of CH2Cl2 at ambient temperature. The solution
was cooled to 0 °C and 79.0 mg (6.88 mmol) of MsCl dissolved
in 0.75 mL of CH2Cl2 was added. After being stirred for 20 h
at 0 °C, the reaction was quenched with water, the phases were
separated, and the aqueous layer was extracted with CH2Cl2
(5 mL). The combined organic extracts were washed with 1 N
KHSO4, dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was dissolved in 10 mL of acetone, and 188 mg
(1.252 mmol) of NaI was added to the solution, which was
refluxed for 16 h. Acetone was evaporated and replaced by
AcOEt. The solution was washed with water, dried over
Na2SO4, filtered, and evaporated under vacuo. The crude
product was purified by flash column chromatography (AcOEt/
Hex, 2:8) to yield pure 3 (210 mg, yield ) 78%): HPLC tR 10.82
(linear gradient, 30-100% B, 20 min); colorless oil; [R]D
)
+14.7 (c ) 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.23 (bd,
1H), 4.18-4.14 (m, 1H), 3.55-3.49 (m, 1H), 3.26 (m, 2H), 3.18
(dd, J ) 10.1, 5.9 Hz, 1H), 1.94-1.86 (m, 1H), 1.68-1.51 (m,
3H), 1.41 (s, 9H), 1.38 (s, 9H); 13C NMR (100 MHz, CDCl3)
ter t-Bu t yl (2S,5R)-6-Azid o-2-[(ter t-Bu t oxyca r b on yl)-
a m in o]-5-h yd r oxyh exa n oa te (18). Collidine (6.0 mL, 45.10
mmol) was added to a solution of 1.44 g (4.51 mmol) of the
8448 J . Org. Chem., Vol. 67, No. 24, 2002

Hydroxylation of 6-Substituted Piperidin-2-ones
171.6 (C), 155.7 (C), 82.2 (C), 79.9 (C), 70.6 (CH), 53.5 (CH),
31.9 (CH2), 29.7 (CH2), 28.4 (3 CH3), 28.1 (3 CH3), 15.4 (CH2).
Anal. Calcd for C15H28INO5: C, 41.97; H, 6.57; N, 3.26.
Found: C, 42.04; H, 6.69; N, 3.28.
100% B, 20 min); white solid; [R]D ) +18.3 (c ) 1.0, CHCl3);
mp 43-45 °C; 1H NMR (400 MHz, CDCl3) δ 5.11 (bd, 1H),
4.15-4.12 (m, 1H), 2.88-2.84 (m, 1H), 2.70 (dd, J ) 4.9, 4.0
Hz, 1H), 2.43 (dd, J ) 4.9, 2.7 Hz, 1H), 1.95-1.87 (m, 1H),
1.72-1.63 (m, 1H), 1.60-1.52 (m, 2H), 1.40 (s, 9H), 1.38 (s,
9H); 13C NMR (100 MHz, CDCl3) 171.6 (C), 155.4 (C), 82.0 (C),
79.6 (C), 53.7 (CH), 51.7 (CH), 47.0 (CH2), 29.2 (CH2), 28.4
(CH2), 28.3 (3 CH3), 28.0 (3 CH3). Anal. Calcd for C15H27NO5:
C, 59.78; H, 9.03; N, 4.65. Found: C, 59.64; H, 9.30; N, 4.91.
ter t-Bu tyl (2S)-2-[(ter t-Bu toxyca r bon yl)a m in o]-4-[(2R)-
oxir a n yl]bu ta n oa te (4). Collidine (0.83 mL, 6.26 mmol) was
added to a solution of 200 mg (0.626 mmol) of 17 in 11.0 mL
of CH2Cl2 at ambient temperature. The solution was cooled to
0 °C and 79.0 mg (6.88 mmol) of MsCl dissolved in 0.75 mL of
CH2Cl2 was added. After being stirred for 20 h at 0 °C, the
reaction was quenched with water, the phases were separated,
and the aqueous layer was extracted with CH2Cl2 (5 mL). The
combined organic extracts were washed with 1 N KHSO4, dried
over Na2SO4, filtered, and concentrated in vacuo. The residue
was dissolved in 3 mL of methanol. K2CO3 (173 mg, 1.252
mmol) was added to the solution, which was stirred at room
temperature during 4 h. The mixture was filtered, and the
solvent was evaporated and replaced by AcOEt. The solution
was washed with water and brine, dried over Na2SO4, filtered,
and evaporated under vacuo. The crude product was purified
by filtration through a plug of silica (AcOEt/Hex, 3:7) to yield
4 (132 mg, yield ) 70%): HPLC tR 9.93 (linear gradient, 30-
Ack n ow led gm en t. J .M. thanks the CNRS and
Neosystem for a predoctoral fellowship.
Su p p or tin g In for m a tion Ava ila ble: Ortep plot of com-
pound (5R)-5a . X-ray crystallographic file of (5R)-5a and 6a .
1H and 13C spectra for all compounds reported. RP-HPLC
traces of (5S)-5a and 5d . RP-HPLC traces of 1, commercial
(2S,5R)-5-hydroxylysine, and 5-hydroxylysine (four diastere-
omers) after derivatization with Marfey’s reagent. This mate-
rialis availablefreeofchargevia theInternet at http://pubs.acs.org.
J O025950C
J . Org. Chem, Vol. 67, No. 24, 2002 8449