Asymmetric synthesis of (2R,3S)-3-hydroxypipecolic acid δ-lactam derivatives

Article abstract of DOI:10.1016/S0040-4020(02)00674-9

A practical synthetic scheme that incorporates an amide functionality into the rigid framework of (2S,3R)-3-hydroxypipecolic acid to produce novel hydroxylated δ-lactam derivatives is reported. The reaction sequence includes the transformation of chiral furanylazide to a 2S-hydroxymethyldihydro pyridone, which was reduced diasteroselectively, protected and oxidized to two corresponding δ-lactam derivatives. Asymmetric dihydroxylation and oxidation of the latter compounds afforded two chiral (2R,3S)-3-hydroxypipecolic acid δ-lactam derivatives.

Full text of DOI:10.1016/S0040-4020(02)00674-9

Tetrahedron 58 (2002) 6665–6671
Asymmetric synthesis of (2R,3S)-3-hydroxypipecolic acid
d-lactam derivatives
Sofia D. Koulocheri,a Prokopios Magiatis,b Alexios-Leandros Skaltsounisb
and Serkos A. Haroutouniana
,
*
aChemistry Laboratory, Agricultural University of Athens, Iera odos 75, Athens 11855, Greece
bDepartment of Pharmacy, University of Athens, Panepistimiopolis Zografou, Athens 15771, Greece
Received 23 April 2002; revised 28 May 2002; accepted 20 June 2002
Abstract—A practical synthetic scheme that incorporates an amide functionality into the rigid framework of (2S,3R)-3-hydroxypipecolic
acid to produce novel hydroxylated d-lactam derivatives is reported. The reaction sequence includes the transformation of chiral furanylazide
to a 2S-hydroxymethyldihydro pyridone, which was reduced diasteroselectively, protected and oxidized to two corresponding d-lactam
derivatives. Asymmetric dihydroxylation and oxidation of the latter compounds afforded two chiral (2R,3S)-3-hydroxypipecolic acid
d-lactam derivatives. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
blocks used in nature, has already been represented by a
special class of compounds called sugar amino acids
(Saa).12
3-Hydroxypipecolic acid derivatives constitute the common
structural sub-units of a wide variety of naturally occurring
alkaloids1 and drugs.2 Compounds with this unnatural
amino acid scaffold are known to possess a broad range of
significant pharmacological properties3 and medicinal
chemists often incorporate their structural motif in the
design and synthesis of novel biologically active molecules.
Over the past years, the 3-hydroxypipecolic acid framework
has been incorporated in the preparation of compounds with
diverse activities, such as immunosupressants,4 enzyme
inhibitors,5 NMDA antagonists,6 anticancer7 and anti-HIV8
agents. Furthermore, there are many current reports
concerning the use this core structure, as conformationally
constrained a-amino b-hydroxy acid, in the synthesis of
peptidomimetics.9 Thus, the development of synthetic
strategies, which would provide enantioselective access to
novel derivatives of 3-hydroxypipecolic acid, is highly
desired and the subject of significant research activity.10
In this report we present the incorporation of an amide
functional group into the rigid heterocyclic framework of
(2S,3R )-3-hydroxypipecolic acid to produce novel
hydroxylated d-lactam derivatives. The latter belong to a
class of compounds which recently has received consider-
able attention13 due to their significant biological properties,
such as anti-inflammatory activity14 and inhibition of
glucosidases15 or cancer cell metastasis.16 To date, sodium
D-glucaro-d-lactam (ND-2001, 2) a derivative of (2S,3S )-3-
hydroxypipecolic acid, is the only example in the literature
of a compound with such a structural framework.17 This
compound is a potent inhibitor of b-glucurodinase, with
98.5% inhibition at 0.1 mM and also exhibits significant
antimetastatic activity on a pulmonary model of mouse
melanoma B16, with 91.8% metastatic inhibition at 10 mg/
mL.18
Surprisingly, among the four possible isomers of 3-hydroxy-
pipecolic acid, the synthesis of the (2R,3S)-enantiomer (1)
is less documented, since there are only limited examples of
its synthesis and derivatization.11 This has captured our
research interest, which was further stimulated by the
potential of these molecules to induce a secondary structure
in a short sequence. Example of such a hybrid design that
amalgamates in a single molecule the structural frameworks
of a sugar and an amino acid, two fundamental building
2. Results and discussion
Our synthetic approach relies on chiral furanylazide 3,
which provides the stereogenic center for the enantioselec-
tive elaboration of the piperidine ring. This compound was
efficiently prepared in high enantiomeric excess from the
Keywords: pipecolic acid; d-lactam; 2-pyridone.
*
Corresponding author. Tel.: þ30-10-5294247; fax: þ30-10-5294265;
e-mail: sehar@aua.gr
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00674-9

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S. D. Koulocheri et al. / Tetrahedron 58 (2002) 6665–6671
Figure 1. Spatial view of the osmium tetroxide attack on compound 15.
Scheme 1. (a) DPPA, DBU, toluene, 08C; (b) (i) H2, Pd/C, MeOH; (ii) TsCl,
˚
Et3N, CH2Cl2; (c) m-CPBA, CH2,Cl2; (d) HC(OMe)3, BF3·OEt3, 4 A
molecular sieves, THF, 08C.
15. The next step of the synthetic route called for the
diastereoselective dihydroxylation of the double bond. In
that regard, treatment of 15 with OsO4 and 4-methyl-
morpholine N-oxide afforded the dihydroxy piperidine
derivative 16 as a single diastereomer. The high diastereo-
selectivity of this reaction may be rationalized considering
that the addition occurred from the less sterically hindered si
face of the molecule, since the opposite side (re ) is
effectively shielded by the sterically demanding tert-butyl-
dimethyl-silyl group (Fig. 1). The diastereomeric purity of
readily available D-glucal, according to a recently reported
method.19 Subsequent hydrogenation and oxidative cycli-
zation furnished the 2S-hydroxymethyl-dihydropyridone 5,
which was further protected to compound 6, the key
intermediate for the construction of the target 3-hydroxy-
pipecolic acid d-lactam derivatives (Scheme 1).
1
the product was revealed by HPLC and H NMR spectro-
Reduction of intermediate 6 under modified Luche con-
ditions20 resulted in the formation of alcohol 7 as a single
diastereomer, which has the 3-hydroxy group with an
equatorial disposition. Benzoylation of the hydroxy
group and subsequent oxidation afforded smoothly the
a,b-unsaturated-d-lactam 9, which subsequently was hydro-
genated to produce the saturated d-lactam 10. At this stage,
it is necessary to point out that it is essential to use the
protected substrate, since catalytic hydrogenation of the
unprotected 5-hydroxy-d-lactam led to the exclusive
formation of the corresponding g-lactone, via a ring opening
and in situ intramolecular acylation mechanism. The silyl-
protecting group was efficiently cleaved by treatment with
TBAF, while subsequent attempt to oxidize the hydroxy-
methyl moiety using Jones reagent proved troublesome,
since it led to the formation of a variety of unidentified
products. Thus, the oxidation was performed using
ruthenium tetroxide (prepared in situ from ruthenium
trichloride and sodium periodate), while cleavage of the
protecting groups provided the target (2R,3S)-3-hydroxy-
pipecolic acid d-lactam derivative 13 (Scheme 2).
scopic analyses, since no traces of any other diastereomer
was detected. The cis configuration, including the 3-axial
and 4-equatorial orientation of the hydroxy groups, was
elucidated unambiguously by diagnostic coupling constants
and 2D-NOESY spectroscopy of compound 16. More
specifically, the strong NOE signals between the protons
of methylene group of hydroxymethyl moiety and H-3 are
indicative of the axial orientation of the hydroxy group of
carbon atom C-3. This assignment was reinforced by the
NOE enhancement between the said hydroxy proton and
H-5. On the other hand, the intense NOE signals between
H-4 and the protons of methylene group of hydroxymethyl
Figure 2. NOE Correlations in 16.
Scheme 2. (a) NaBH4, CeCl3·H2O, MeOH, 2308C; (b) BzCl, Et3N,
CH2Cl2; (c) m-CPBA, BF3·Et2O, THF; (d) H2, Pd/C, MeOH; (e) TBAF,
THF; (f) RuCl3, NaIO4, H2O/CCl4/CH3CN; (g) Na, naphthalene, THF.
Accordingly, the synthesis of the polyhydroxylated
2R-pipecolic acid d-lactam derivative started with the
benzylation of compound 7, which by oxidation was
transformed to the corresponding a,b-unsaturated-d-lactam
Scheme 3. (a) NaH, BnBr, Bu4NI, THF; (b) m-CPBA, BF3·Et2O, THF;
(c) OsO4, NMO, t-BuOH/acetone (1:1); (d) (CH3)2C(OCH3)2, p-TsOH·
H2O, aceton; (e) TBAF, THF, (f) RuCl3, NaIO4, H2O/CCl4/CH3CN; (g) (i)
H2, Pd/C, EtOH; (ii) p-TsOH·H2O, MeOH; (h) Na, naphthalene, THF.

S. D. Koulocheri et al. / Tetrahedron 58 (2002) 6665–6671
6667
moiety or the benzylic protons, proved the equatorial
orientation of the hydroxy group of carbon atom C-4.
Finally, the large coupling constant (10.5 Hz) observed
between H-4 and H-5 is consistent with the axial orien-
tation of H-4 reinforcing the previous assignment (Fig. 2,
Scheme 3).
4.5 Hz, 1H), 4.52 (dd, J¼7.0, 4.5 Hz, 1H), 6.35 (m, 2H),
7.37 (s, 1H). Anal. calcd for C12H21N3O2Si (267.4): C,
53.90; H, 7.92; N, 15.71. Found: C, 54.21; H, 7.84; N, 15.79.
3.1.2. (S)-N-[2-(tert-Butyl-dimethyl-silyloxy)-1-furan-2-yl-
ethyl]-4-methyl-benzenesulfonamide (4). Azide 3 (2 g,
7.48 mmol) was dissolved in EtOAc (50 mL) and hydro-
genated over 0.2 g of Pd/C (10%) under 1 bar pressure for
40 min. The reaction mixture was filtered over celite and
concentrated in vacuo. The residue was dissolved in CH2Cl2
(20 mL) and triethylamine (1.3 mL, 9.75 mmol) was added.
The resulting solution was cooled to 08C and p-toluene-
sulfonyl chloride (1.86 g, 9.75 mmol) was added portion-
wise under stirring. The reaction allowed to reach rt and
stirred for additional 3 h. Then, the mixture was extracted
successively with NaHCO3, brine and the solvent was
evaporated. The resulting solid was chromatographed
(EtOAc/hexane 1:4, Rf 0.4) yielding the desired product 4
as colorless fine needles (2.57 g, 87%). Mp 55–578C
(Et2O/hexane); [a ]2D2¼231.1 (c 1.15, EtOAc); IR (neat):
Acetalization of diol 16 and subsequent cleavage of the
silyl-protecting group gave compound 18, which was
oxidized with ruthenium tetroxide to produce the protected
pipecolic acid-d-lactam derivative 19. Finally, hydro-
genolysis of the benzyl ether and subsequent sequential
removal of the acetonide and tosyl protective groups
provided the target (2R,3R,4S,5S )-trihydroxypipecolic
acid d-lactam derivative 21 in 12 steps and 20% overall
yield from furanylazide 3.
In conclusion, we have described a simple and efficient
synthetic route that allows the incorporation of an amide
functionality into the rigid framework of 3-hydroxy
pipecolic acid to produce novel chiral hydroxylated
pipecolic acid d-lactam derivatives.
nmax 3293 (N–H), 741, 1019 (furan) cm21 1H NMR
;
(400 MHz, CDCl3): dH 0.07 (s, 6H), 0.80 (s, 9H), 2.39 (s,
3H), 3.69 (dd, J¼10.1, 4.8 Hz, 1H), 3.82 (dd, J¼10.1,
4.8 Hz 1H), 4.45 (dt, J¼7.5, 4.8 Hz, 1H), 5.18 (d, J¼7.5 Hz,
1H), 6.10 (d, J¼3.1 Hz, 1H), 6.19 (dd, J¼3.1, 1.8 Hz, 1H),
7.19 (d, J¼1.8 Hz, 1H), 7.22 (d, J¼8.3 Hz, 1H), 7.66 (d,
J¼8.3 Hz, 1H). Anal. calcd for C19H29NO4SSi (395.6): C,
57.69; H, 7.39; N, 3.54. Found: C, 57.41; H, 7.22; N, 3.71.
3. Experimental
3.1. General comments
1H and 2D NMR spectra were recorded on Bruker DRX-400
or AC-200 spectrometers (400 and 200 MHz, respectively).
IR spectra were obtained on a Nicolet Magna 750, series II
spectrometer. Melting points were determined on a Bu¨chi
melting point apparatus and are uncorrected. Optical
rotations were measured with a Perkin–Elmer 241 polari-
meter at ambient temperature. HPLC separations were
performed using a Hewlett Packard 1100 series instrument
with a variable wavelength UV detector and coupled to HP
Chem-Station utilizing the manufacturer’s 5.01 software
package. TLC was conducted on Merck glass plates coated
with silica gel 60 F254. Flash column chromatography was
performed using Merck silica gel 60 (230–400 mesh
ASTM).
3.1.3. (2S,6R )-2-(tert-Butyl-dimethyl-silyloxymethyl)-6-
hydroxy-1-(toluene-4-sulfonyl)-1,6-dihydro-2H-pyridin-
3-one (5). To a stirred solution of N-tosylfurfurylamine
4 (2.31 g, 5.84 mmol) in anhydrous CH2Cl2 (30 mL),
m-chloroperbenzoic acid 70% (2.08 g, 8.8 mmol) was
added. The reaction mixture was stirred at rt for 4 h, then
washed successively with 20% KI, 30% Na2S2O3, sat.
NaHCO3, water, brine and concentrated under reduced
pressure to a yellowish solid. Purification by flash chroma-
tography (EtOAc/hexane 1:4, Rf 0.33) gave the title
compound as a pale white solid (2.21 g, 92%). A small
sample was recrystallized from Et2O/hexane mixture as
off white needles. Mp 101–1038C; [a]2D2¼226.7 (c 0.84,
EtOAc); IR (neat): nmax 3362 (OH), 1698 (CvO), 1639
(CvC) cm21; 1H NMR (400 MHz, CDCl3): dH 0.01 (s, 6H),
0.72 (s, 9H), 2.37 (s, 3H), 3.54 (d, J¼10.6 Hz, 1H), 3.89 (dd,
J¼10.6 Hz, 1H), 4.48 (s, 1H), 4.92 (d, J¼11.4 Hz, 1H), 5.94
(dd, J¼11.4, 5.1 Hz, 1H), 6.05 (d, J¼10.5 Hz, 1H), 6.92
(dd, J¼10.5, 5.1 Hz, 1H), 7.25 (d, J¼8.5 Hz, 2H), 7.75 (d,
J¼8.5 Hz, 2H). Anal. calcd for C19H29NO5SSi (411.6): C,
55.44; H, 7.10; N, 3.40. Found: C, 55.68; H, 7.35; N, 3.51.
All reactions (except hydrogenations) were carried out
under argon atmosphere. Solvents were dried by distillation.
Tetrahydrofuran was distilled from sodium-benzophenone
and methylene chloride over CaH2 immediately prior to use.
Starting materials were purchased from Aldrich (analytical
reagent grades) and used without further purification.
3.1.1. (S )-(2-Azido-2-furan-2-yl-ethoxy)-tert-butyl-di-
methyl-silane (3). To an ice-cold solution of (2R)-2-furyl
glycol (2.4 g, 10 mmol) and diphenylphosphorazide
(2.7 mL, 12 mmol) in dry toluene (25 mL), DBU (1.8 mL,
12 mmol) was added. After stirring for 10 h at that
temperature, the reaction mixture was washed successively
with H2O (2£15 mL), sat. NH4Cl (20 mL) and the organic
layer was concentrated under reduced pressure. Purification
by silica gel chromatography (EtOAc/hexane 5:95, Rf 0.83)
afforded azide 4 as colorless oil (2.14 g, 80%). [a]2D2¼
240.6 (c 1.1, EtOAc); IR (neat): nmax 2109 (N3), 742, 1017
(furan) cm21; 1H NMR (400 MHz, CDCl3): dH 0.09 (s, 6H),
0.9 (s, 9H), 3.93 (dd, J¼10.1, 7.0 Hz, 1H), 4.00 (dd, J¼10.1,
3.1.4. (2S,6R )-2-(tert-Butyl-dimethyl-silyloxymethyl)-6-
methoxy-1-(toluene-4-sulfonyl)-1,6-dihydro-2H-pyridin-
3-one (6). To an ice-cold solution of azapyranone 5 (1.53 g,
3.72 mmol), trimethyl orthoformate (0.8 mL, 7.44 mmol)
˚
and 4 A molecular sieves (0.35 g) in dry THF (25 mL),
BF3·Et2O (0.7 mL) was added. The reaction mixture was
stirred for 3 h at 08C, then quenched with water and
extracted with Et2O (2£30 mL). The combined organic
layers were washed with brine, dried over MgSO4 and
concentrated under reduced pressure to give a yellowish
solid which was chromatographed (EtOAc/hexane 1:4, Rf
0.35) to furnish the desired product 6 (1.49 g, 94%) as

6668
S. D. Koulocheri et al. / Tetrahedron 58 (2002) 6665–6671
colorless fine needles. mp 68–708C (Et2O/hexane); [a ]2D2¼
þ106 (c 0.51, EtOAc); IR (neat): nmax 1695 (CvO), 1637
(CvC) cm21; 1H NMR (400 MHz, CDCl3): dH 0.05 (s, 6H),
0.89 (s, 9H), 2.40 (s, 3H), 3.58 (s, 3H), 3.94 (dd, J¼10.1,
7.3 Hz 1H), 4.00 (dd, J¼10.1, 7.5 Hz, 1H), 4.39 (t, J¼
7.3 Hz, 1H), 5.55 (dd, J¼4.4, 0.9 Hz, 1H), 5.78 (d, J¼
10.1 Hz, 1H), 6.74 (dd, J¼10.1, 4.4 Hz, 1H), 7.25 (d, J¼
8.3 Hz, 2H), 7.59 (d, J¼8.3 Hz, 2H). Anal. calcd for
C20H31NO5SSi (425.6): C, 56.44; H, 7.34; N, 3.29. Found:
C, 56.55; H, 7.11; N, 3.34.
extracted with Et2O (2£20 mL). The combined organic
layers were washed with brine, dried over MgSO4 and
concentrated under reduced pressure to give a yellowish
solid which was chromatographed (EtOAc/hexane 1:4, Rf
0.50) to furnish the desired product 9 as an off-white solid
(0.67 g, 92%); mp 77–788C (Et2O/hexane); [a]2D2¼þ56.8
(c 0.7, EtOAc); IR (neat): nmax 1645 (CvC), 1676
(N–CvO), 1710 (CvO) cm21 1H NMR (400 MHz,
;
CDCl3): dH 0.05 (s, 6H), 0.82 (s, 9H), 2.38 (s, 3H), 4.15
(m, 2H), 4.32 (m, 1H), 4.78 (m, 1H), 5.68 (dd, J¼10.2,
2.4 Hz, 1H), 6.69 (dt, J¼10.2, 1.7 Hz, 1H), 7.25 (d, J¼
8.2 Hz, 2H), 7.35 (m, 2H), 7.46 (m, 1H), 7.65 (d, J¼8.2 Hz,
2H), 7.92 (m, 2H). Anal. calcd for C26H33NO6SSi (515.7):
C, 60.55; H, 6.45; N, 2.72. Found: C, 60.71; H, 6.33; N, 2.57.
3.1.5. (2S,6R )-2-(tert-Butyl-dimethyl-silyloxymethyl)-6-
methoxy-1-(toluene-4-sulfonyl)-1,2,3,6-tetrahydro-pyri-
din-3-ol (7). To a stirred solution of compound 6 (0.76 g,
1.80 mmol) and CeCl3·7H2O (0.33 g, 0.90 mmol) in metha-
nol (20 mL) at 2308C, NaBH4 (0.24 g, 6.23 mmol) was
added portionwise. After 40 min of stirring at that
temperature, the reaction was quenched with sat. NH4Cl
(15 mL) and extracted with EtOAc (3£20 mL). The
combined organic phases were washed with brine, dried
(MgSO4) and chromatographed (EtOAc/hexane 1:4, Rf 0.3)
to afford 7 as colorless oil (0.68 g, 89%). [a ]2D2¼þ60 (c 0.9,
EtOAc); IR (neat): nmax 3445 (OH), 1650 (CvC) cm21; 1H
NMR (400 MHz, CDCl3): dH 0.05 (s, 6H), 0.84 (s, 9H), 2.40
(s, 3H), 3.45 (s, 3H), 3.66 (dd, J¼10.5, 3.9 Hz), 3.82 (m,
1H), 4.04 (dt, J¼10.1, 5.3 Hz, 1H), 4.3 (m, 2H), 5.24 (s,
1H), 5.66 (dt, J¼10.3, 2.2 Hz, 1H), 5.77 (d, J¼10.3 Hz, 1H),
7.25 (d, J¼8.3 Hz, 2H), 7.66 (d, J¼8.3 Hz, 2H). Anal. calcd
for C20H33NO5SSi (427.6): C, 56.17; H, 7.78; N, 3.28.
Found: C, 56.35; H, 7.89; N, 3.11.
3.1.8. (2S,3S)-Benzoic acid 2-(tert-butyl-dimethyl-silyl-
oxymethyl)-6-oxo-1-(toluene-4-sulfonyl)-piperidin-3-yl
ester (10). Olefin 9 (0.52 g, 1 mmol) was dissolved in
MeOH (15 mL) and hydrogenated over 10% Pd/C (51 mg)
under 1 bar pressure for 2 h. The mixture was filtered
through celite and partitioned between EtOAc and water.
The aqueous layer was washed with EtOAc and the
combined organic extracts were washed with brine, dried
over MgSO4 and concentrated. The yellowish slurry was
chromatographed (EtOAc/hexane 1:4, Rf 0.52) to give
compound 10 (0.46 g, 89%) as an off-white solid. Mp 85–
868C (Et2O/hexane); [a ]2D2¼þ63.6 (c 0.3, EtOAc); IR
(neat): nmax 1692 (N–CvO), 1725 (CvO) cm21; 1H NMR
(400 MHz, CDCl3): dH 0.05 (s, 6H), 0.83 (s, 9H), 1.71 (dd,
J¼12.8, 2.41 Hz, 1H), 1.90 (m, 1H), 2.39 (s, 3H), 2.42 (m,
1H), 2.55 (dd, J¼12.0, 1.7 Hz, 1H), 4.21 (m, 2H), 4.56 (m,
1H), 4.71 (m, 1H), 7.18 (d, J¼8.0 Hz, 2H), 7.40–7.47 (m,
3H), 7.68 (d, J¼8.0 Hz, 2H), 7.89 (m, 2H). Anal. calcd for
C26H35NO6SSi (517.7): C, 60.32; H, 6.81; N, 2.71. Found:
C, 60.50; H, 6.85; N, 2.58.
3.1.6. (2S,3S)-Benzoic acid 2-(tert-butyl-dimethyl-silyl-
oxymethyl)-6-methoxy-1-(toluene-4-sulfonyl)-1,2,3,6-tetra-
hydro-pyridin-3-yl ester (8). To a stirred ice-cold solution
of 7 (0.65 g, 1.52 mmol), and triethylamine (0.24 mL,
1.82 mmol) in dry CH2Cl2 (10 mL), BzCl (0.21 mL,
1.82 mmol) was added dropwise under stirring. The reaction
allowed to reach the rt and stirred for additional 1 h. The
mixture was extracted successively with sat. NH4Cl
(10 mL), brine and the solvent was evaporated. The
resulting solid was chromatographed (EtOAc/hexane 1:4,
Rf 0.48) to yield the desired product 8 as colorless oil
(0.78 g, 87%). [a ]D22¼þ72.3 (c 0.7, EtOAc); IR (neat): nmax
3.1.9. (2S,3S)-Benzoic acid 2-hydroxymethyl-6-oxo-1-
(toluene-4-sulfonyl)-piperidin-3-yl ester (11). To a solu-
tion of 10 (0.45 g, 0.87 mmol) in THF (7 mL), TBAF (1.0 M
solution in THF, 1.25 mL) was added. The mixture was
stirred for 2 h and the solvent was evaporated under reduced
pressure. The yellowish slurry was purified by chroma-
tography (EtOAc/hexane 1:4, Rf 0.21) to give alcohol 11
(0.33 g, 93%) as a colorless oil. [a ]2D2¼þ37.5 (c 0.3,
EtOAc); IR (neat): nmax 3444 (OH), 1690 (N–CvO), 1720
1645 (CvC), 1710 (CvO) cm21 1H NMR (400 MHz,
;
CDCl3): dH 0.05 (s, 6H), 0.85 (s, 9H), 2.41 (s, 3H), 3.45 (s,
3H), 4.08 (m, 2H), 4.35 (m, 1H), 4.84 (m, 1H), 5.24 (s, 1H),
5.75 (dt, J¼10.0, 2.1 Hz, 1H), 5.80 (d, J¼10.0 Hz, 1H), 7.18
(d, J¼8.1 Hz, 2H), 7.37 (m, 2H), 7.46 (m, 1H), 7.60 (d,
J¼8.1 Hz, 2H), 7.92 (m, 2H). Anal. calcd for C27H37NO6-
SSi (531.7): C, 60.99; H, 7.01; N, 2.63. Found: C, 61.24; H,
6.93; N, 2.51.
1
(CvO) cm21; H NMR (400 MHz, CDCl3): dH 1.69 (m,
1H), 1.92 (m, 1H), 2.44 (s, 3H), 2.44 (m, 1H), 2.59 (m, 1H),
3.80 (m, 1H), 3.98 (m, 1H), 4.02 (m, 1H), 4.95 (m, 1H), 7.18
(d, J¼8.3 Hz, 2H), 7.40–7.47 (m, 3H), 7.59 (d, J¼8.3 Hz,
2H), 7.89 (m, 2H). Anal. calcd for C20H21NO6S (403.5): C,
59.54; H, 5.25; N, 3.47. Found: C, 59.41; H, 5.32; N, 3.64.
3.1.7. (2S,3S)-Benzoic acid 2-(tert-butyl-dimethyl-silyl-
oxymethyl)-6-oxo-1-(toluene-4-sulfonyl)-1,2,3,6-tetra-
hydro-pyridin-3-yl ester (9). To a solution of 5 (0.75 g,
3.1.10. (2R,3S )-3-Benzoyloxy-6-oxo-1-(toluene-4-sulfo-
nyl)-piperidine-2-carboxylic acid (12). To a stirred
solution of alkene 11 (0.35 g, 0.87 mmol) in H2O/CCl4/
CH3CN (1.5:1:1 v/v, 6 mL), NaIO4 (0.74 g, 3.49 mmol) and
a catalytic amount of RuCl3 (3.8 mg, 0.015 mmol) were
added. The mixture was stirred for 2 h, quenched with
propan-2-ol and filtered through a celite pad. The filtrate
was evaporated to a yellowish slurry which was purified by
chromatography (CHCl3/MeOH 3:2 Rf 0.45) yielding 12
(0.29 g, 80%) as a foamy solid. [a]2D2¼þ122.9 (c 0.3,
CHCl3); IR (neat): nmax 1660 (N–CvO), 1740, 1720
˚
1.41 mmol) and 4 A molecular sieves (0.54 g) in dry
CH2Cl2 (7 mL) at 2158C, m-chloroperbenzoic acid 70%
(0.4 g, 1.65 mmol) dissolved in dry CH2Cl2 (3 mL) and
freshly distilled BF3·Et2O (0.2 mL, 1.65 mmol) were added.
The reaction was allowed to proceed the rt and stirred for
2 h. Then the reaction was quenched with sat. NaHCO3
(2 mL) and the resulting mixture was filtered through a pad
of celite. The filtrate was poured into 15 mL of water and

S. D. Koulocheri et al. / Tetrahedron 58 (2002) 6665–6671
6669
1
(CvO) cm21; H NMR (200 MHz, CDCl3): dH 1.75 (m,
reduced pressure to give a yellowish solid which was
chromatographed (EtOAc/hexane 1:4, Rf 0.27) to furnish
the desired product 15 (0.84 g, 93%) as colorless oil.
[a ]2D2¼þ39.3 (c 0.65, EtOAc); IR (neat): nmax 1675
1H), 1.87 (m, 1H), 2.42 (s, 3H), 2.44 (m, 1H), 2.56 (m, 1H),
3.95 (m, 1H), 4.68 (m, 1H), 7.18 (d, J¼8.3 Hz, 2H), 7.40–
7.47 (m, 3H), 7.59 (d, J¼8.3 Hz, 2H), 7.89 (m, 2H). Anal.
calcd for C20H19NO7S (417.4): C, 57.55; H, 4.59; N, 3.36.
Found: C, 57.81; H, 4.41; N, 3.42.
1
(N–CvO) cm21; H NMR (400 MHz, CDCl3): dH 0.05
(s, 6H), 1.04 (s, 9H), 2.41 (s, 3H), 3.95 (dd, J¼11.4, 3.2 Hz,
1H), 4.14 (dd, J¼11.4, 3.9 Hz, 1H), 4.56 (d, J¼11.5 Hz,
1H), 4.63 (d, J¼11.5 Hz, 1H), 4.73 (dt, J¼7.0, 2.0 Hz, 1H),
5.04 (m, 1H), 5.75 (dd, J¼10.1, 2.9 Hz, 1H), 6.63 (d, J¼
10.1 Hz, 1H), 7.17 (dd, J¼5.7, 3.5 Hz, 2H), 7.21 (d, J¼
8.3 Hz, 2H), 7.30 (m, 3H), 7.70 (d, J¼8.3 Hz, 2H). Anal.
calcd for C26H35NO5SSi (501.7): C, 62.24; H, 7.03; N, 2.79.
Found: C, 62.08; H, 6.91; N, 2.88.
3.1.11. (2R,3S)-3-Hydroxy-6-oxo-piperidine-2-carboxylic
acid (13). To a stirred solution of naphthalene (71 mg,
0.55 mmol) in freshly distilled THF (2.5 mL), sodium
(13 mg, 0.53 mmol) was added. After 45 min of stirring at
ambient temperature (dark-green color), the mixture was
cooled to 2788C and a solution of compound 12 (200 mg,
0.48 mmol) in THF (2 mL) was added. The reaction mixture
was stirred at that temperature for 30 min, quenched with
sat. aqueous NH4Cl (15 mL) and extracted with CHCl3
(2£20 mL). The combined organic layers were dried
(MgSO4) and evaporated to give the target molecule 13
(47 mg, 62%). An analytically pure sample was obtained as
white prisms by crystallization from MeOH/Et2O. Mp 220–
2258C (decomp.); [a]2D2¼þ36.5 (c 0.3, MeOH); IR (neat):
3.1.14. (3S,4S,5R,6S )-5-Benzyloxy-6-(tert-butyl-di-
methyl-silyloxymethyl)-3,4-dihydroxy-1-(toluene-4-sul-
fonyl)-piperidin-2-one (16). To a stirred solution of alkene
15 (0.81 mg, 1.62 mmol), in a mixture of t-BuOH/acetone
(1:1 v/v, 20 mL), NMO (0.6 g, 2.75 mmol) and catalytic
amount of solution OsO4 (1 mL) were added. The reaction
mixture was run for 6 h, then quenched with Na2SO3
(0.42 g, 3 mmol), stirred for 30 min and extracted with
EtOAc (2£30 mL). The combined organic extracts were
washed with brine, dried (MgSO4) and evaporated to a
yellowish slurry which was purified by chromatography
(EtOAc/hexane 1:1, Rf 0.3) yielding 16 (0.83 g, 96%) as
colorless oil. [a]D22¼þ67.3 (c 0.65, EtOAc); IR (neat): nmax
nmax 3420 (OH), 1650 (N–CvO), 1735 (CvO) cm21; H
1
NMR (400 MHz, D2O): dH 1.80 (m, 2H), 2.38 (m, 2H), 3.91
(m, 1H), 4.67 (s br, 1H). Anal. calcd for C6H9NO4 (159.1):
C, 54.28; H, 5.70; N, 8.80. Found: C, 54.39; H, 5.82; N, 8.73.
3.1.12. (2S,3S,6R )-3-Benzyloxy-2-(tert-butyl-dimethyl-
silyloxymethyl)-6-methoxy-1-(toluene-4-sulfonyl)-1,2,3,6-
tetrahydro-pyridine (14). To an ice-cold solution of
compound 7 (0.94 g, 2.20 mmol) in dry THF (3.5 mL),
sodium hydride (63 mg, 2.64 mmol) was added in portions
under stirring. The reaction mixture was allowed to reach
the rt and stirred for 30 min. Then, a catalytic amount of
Bu4NI (40 mg, 0.11 mmol) and benzyl bromide (0.37 mL,
3.31 mmol) were added. After 2 h of stirring, the reaction
was quenched with sat. aq NH4Cl (8 mL) and extracted with
EtOAc (3£10 mL). The combined organic extracts were
washed with brine, dried (MgSO4) and evaporated to a
yellowish slurry which was purified by chromatography
(EtOAc/hexane 1:4, Rf 0.55) yielding 14 (1.04 g, 91%) as
colorless oil. [a ]D22¼þ106.2 (c 0.3, EtOAc); 1H NMR
(400 MHz, CDCl3): 1H NMR: dH 0.05 (s, 6H), 1.04 (s, 9H),
2.41 (s, 3H), 3.50 (s, 3H), 3.97 (dd, J¼11.1, 3.2 Hz, 1H),
4.01 (m, 1H), 4.15 (m, 2H), 4.53 (d, J¼11.5 Hz, 1H), 4.60
(d, J¼11.5 Hz, 1H), 5.24 (s,1H), 5.66 (dt, J¼10.2, 2.2 Hz,
1H), 5.75 (d, J¼10.2 Hz, 1H), 7.21 (d, J¼7.9 Hz, 2H), 7.25
(d, J¼8.3 Hz, 2H), 7.34 (m, 3H), 7.67 (d, J¼8.3 Hz, 2H).
Anal. calcd for C27H39NO5SSi (517.8): C, 62.63; H, 7.59;
N, 2.71. Found: C, 62.48; H, 7.38; N, 2.55.
1
3420 (OH), 1670 (N–CvO) cm21; H NMR (400 MHz,
CDCl3): dH 0.05 (s, 6H), 0.90 (s, 9H), 2.30 (d, J¼2.2 Hz,
1H), 2.43 (s, 3H), 2.48 (d, J¼2.2 Hz, 1H), 3.40 (m, 1H),
3.82 (dd, J¼ 10.5, 5.7 Hz, 1H), 3.95 (dt, J¼10.5, 5.5 Hz,
1H), 4.01 (dd, J¼10.5, 6.1 Hz, 1H), 4.08 (m, 1H), 4.16 (dt,
J¼10.7, 5.7 Hz, 1H), 4.23 (d, J¼11.4 Hz, 1H), 4.65 (d,
J¼11.4 Hz, 1H), 7.16 (dd, J¼5.7, 3.5 Hz, 2H), 7.27 (d,
J¼8.3 Hz, 2H), 7.30 (m, 3H), 7.83 (d, J¼8.3 Hz, 2H). Anal.
calcd for C26H37NO7SSi (535.7): C, 58.29; H, 6.96; N, 2.61.
Found: C, 58.37; H, 7.11; N, 2.54.
3.1.15. (1S,3S,6S,7R)-7-Benzyloxy-6-(tert-butyl-dimethyl-
silanyloxymethyl)-2,2-dimethyl-5-(toluene-4-sulfonyl)-
tetrahydro-[1,3]dioxolo[4,5-c ]-pyridin-4-one (17). To a
stirred solution of piperidin-2-one 16 (0.73 g, 1.36 mmol)
and 2,2-dimethoxypropane (0.84 mL, 6.8 mmol) in dry
acetone (2 mL), p-TsOH (5 mg, 0.02 mmol) was added. The
reaction was run for 5 h, then quenched with sat. NaHCO3
(10 mL) and extracted with EtOAc (2£20 mL). The com-
bined organic extracts were washed with brine, dried
(MgSO4) and evaporated to a yellowish slurry which was
purified by chromatography (EtOAc/hexane 1:4, Rf 0.55)
yielding 17 (0.71 g, 90%) in pure white crystalline form. Mp
118–1198C (Et2O/hexane); [a ]2D2¼þ44.1 (c 0.3, EtOAc);
3.1.13. (5S,6S )-5-Benzyloxy-6-(tert-butyl-dimethyl-silyl-
oxymethyl)-1-(toluene-4-sulfonyl)-5,6-dihydro-1H-pyri-
˚
din-2-one (15). A solution of 14 (0.93 g, 1.8 mmol) and 4 A
1
IR (neat): nmax 1670 (N–CvO) (CvO) cm21; H NMR
(200 MHz, CDCl3): dH 0.03 (s, 6H), 0.88 (s, 9H), 1.34 (s,
3H), 1.39 (s, 3H), 2.23 (s, 3H), 3.50 (m, 1H), 3.69 (m, 1H),
3.80–3.92 (m, 2H), 4.01 (m, 2H), 4.36 (d, J¼11.8 Hz, 1H),
4.60 (d, J¼11.8 Hz, 1H), 7.15 (d, J¼7.5 Hz, 2H), 7.23 (d,
J¼8.3 Hz, 2H), 7.31 (m, 3H), 7.60 (d, J¼8.3 Hz, 2H). Anal.
calcd for C29H41NO7SSi (575.8): C, 60.49; H, 7.18; N, 2.43.
Found: C, 60.74; H, 7.40; N, 2.29.
molecular sieves (0.65 g) in dry CH2Cl2 (10 mL) was
cooled at 2158C and a solution m-chloroperbenzoic acid
70% (0.48 g, 1.98 mmol) in dry CH2Cl2 (4 mL) and freshly
distilled BF3·Et2O (0.25 mL, 2 mmol) were added. The
reaction allowed to reach the rt and stirred for 2 h. Then
the reaction was quenched with NaHCO3 (2.5 mL) and the
resulting mixture was filtered through a pad of celite. The
filtrate was poured into 18 mL of water and extracted with
Et2O (2£20 mL). The combined organic layers were
washed with brine, dried (MgSO4) and concentrated under
3.1.16. (1S,3S,6S,7R )-7-Benzyloxy-6-hydroxymethyl-
2,2-dimethyl-5-(toluene-4-sulfonyl)-tetrahydro-[1,3]-
dioxolo[4,5-c ]pyridin-4-one (18). To a solution of 17

6670
S. D. Koulocheri et al. / Tetrahedron 58 (2002) 6665–6671
(0.66 g, 1.15 mmol) in THF (13 mL), TBAF (1.0 M solution
in THF, 1.7 mL) was added. The mixture was stirred for 2 h,
and the solvent was evaporated under reduced pressure. The
resulting yellowish slurry was purified by chromatography
(EtOAc/hexane 3:2, Rf 0.25) to give alcohol 18 (0.48 g,
92%) as a white solid. Mp 155–1568C (decomp.); [a ]2D2¼
1H NMR (400 MHz, CDCl3): dH 1.34 (s, 3H), 1.39 (s, 3H),
2.30 (s, 3H), 3.10 (d, J¼6.2 Hz, 1H), 3.47 (m, 1H), 3.67 (dd,
J¼10.1, 6.2 Hz, 1H), 3.79 (m, 1H), 3.92–4.01 (m, 3H), 4.36
(d, J¼11.8 Hz, 1H), 4.60 (d, J¼11.8 Hz, 1H), 7.15 (d,
7.5 Hz, 2H), 7.23 (d, J¼8.3 Hz, 2H), 7.31 (m, 3H), 7.60 (d,
J¼8.3 Hz, 2H). Anal. calcd for C23H27NO7S (461.5): C,
59.85; H, 5.90; N, 3.03. Found: C, 59.73; H, 5.66; N, 3.15.
obtained as white prisms by crystallization from MeOH/
Et2O. Mp 260–2658C (decomp.). [a ]2D2¼þ103.5 (c 0.3,
MeOH); IR (neat): nmax 3420–3370 (OH), 3250 (NH), 1670
(N–CvO), 1725 (CvO) cm21; 1H NMR (400 MHz, D2O):
dH 4.19 (m, 1H), 4.25 (dd, J¼2.8, 4.8 Hz, 1H), 4.40 (d,
J¼3.5 Hz, 1H), 4.80 (s br, 1H). Anal. calcd for C6H9NO6
(191.1): C, 65.54; H, 6.42; N, 2.55. Found: C, 65.39; H,
6.44; N, 2.71.
þ76.8 (c 0.3, EtOAc); IR (neat): nmax 1665 (CvO) cm21
;
Acknowledgments
S. D. K.’s scholarship from I.K.Y., Greece, is gratefully
acknowledged.
3.1.17. (1S,3S,6R,7R )-7-Benzyloxy-2,2-dimethyl-4-oxo-
5-(toluene-4-sulfonyl)-hexahydro[1,3]dioxolo[4,5-c]pyri-
din-6-carboxylic acid (19). To a stirred solution of 18
(0.46 g, 1 mmol) in a mixture of H2O/CCl4/CH3CN (1.5:1:1
v/v, 7.5 mL), NaIO4 (0.84 g, 4.0 mmol) and RuCl3 (4.5 mg,
0.018 mmol) catalyst were added. The mixture was stirred
for 2 h, quenched with propan-2-ol and filtered through a
celite pad. The filtrate was evaporated to a yellowish slurry
which was purified by chromatography (CHCl3/MeOH 3:2
Rf 0.4) yielding 19 (0.42 g, 85%) as a foamy solid. [a ]2D2¼
þ41.1 (c 0.3, MeOH); IR (neat): nmax 1735 (CvO), 1670
(N–CvO) cm21; 1H NMR (400 MHz, CHCl3): dH 1.36 (s,
3H), 1.40 (s, 3H), 2.39 (s, 3H), 3.72 (m, 1H), 3.95–4.08 (m,
2H), 4.36 (d, J¼12.0 Hz, 1H), 4.45 (d, J¼12.0 Hz, 1H), 4.98
(m, 1H), 7.18 (d, J¼7.9 Hz, 2H), 7.25 (d, J¼8.3 Hz, 2H),
7.39 (m, 3H), 7.68 (d, J¼8.3 Hz, 2H). Anal. calcd for
C24H27NO8S (489.5): C, 58.88; H, 5.56; N, 2.86. Found: C,
58.67; H, 5.51; N, 2.96.
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cm21; H NMR (400 MHz, DMSO): dH 2.40 (s, 3H), 3.50
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