Stereoselective Michael addition of thiophenols, amino acids and hydrazoic acid to (2S)-hydroxymethyl-dihydropyridone as a convenient route to novel azasugar derivatives

Article abstract of DOI:10.1016/S0040-4020(00)00563-9

The outcome and stereochemical aspects of 1,4-conjugate addition of thiophenols, α-aminoacid derivatives and hydrazoic acid to chiral (2S)-hydroxymethyl-dihydropyridone 3 is presented. Subsequent reduction with NaBH₄ provided predominantly the kinetically favored axial 3-piperidinol adducts. The stereochemistry of the products, which depends on electrostatic interaction and steric hindrance, was revealed by ¹H NMR and 2D NOESY spectroscopic analysis. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00563-9

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 6135±6141
Stereoselective Michael Addition of Thiophenols, Amino Acids
and Hydrazoic Acid to (2S)-Hydroxymethyl-dihydropyridone as a
Convenient Route to Novel Azasugar Derivatives
So®a 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 31 March 2000; revised 25 May 2000; accepted 8 June 2000
AbstractÐThe outcome and stereochemical aspects of 1,4-conjugate addition of thiophenols, a-aminoacid derivatives and hydrazoic acid
to chiral (2S)-hydroxymethyl-dihydropyridone 3 is presented. Subsequent reduction with NaBH4 provided predominantly the kinetically
favored axial 3-piperidinol adducts. The stereochemistry of the products, which depends on electrostatic interaction and steric hindrance, was
1
revealed by H NMR and 2D NOESY spectroscopic analysis. q 2000 Elsevier Science Ltd. All rights reserved.
Naturally occurring and synthetic derivatives of piperidi-
nose type aminosugars are a well-known class of selective
inhibitors of the oligosaccharide processing enzymes known
as glycosidases.1 These compounds have attracted a great
deal of attention as synthetic targets, since they have been
used as probes for the study of the biological functions of
oligosaccharides2 and for the treatment of various carbohy-
drate-mediated diseases.3 Thus, a variety of natural and
synthetic azasugars are now ®nding clinical application as
anti-HIV,4 anticancer5 or antidiabetic agents6 and their
effectiveness has prompted considerable effort toward
their structural modi®cation targeting the development of
additional glycosidase inhibitors.7,8 The literature abounds
with methods concerning the ef®cient stereoselective synth-
esis of various piperidinol derivatives based on carbohy-
drate9 and non-carbohydrate10 building blocks.
pyridin-3(2H)-ones, which serve as ¯exible chiral building
blocks for the synthesis of various novel piperidinol type
azasugars and alkaloids.11 In this context, we have devel-
oped a new synthetic methodology for the stereoselective
transformation of d-glucal to (2S)-hydroxymethyl-dihydro-
pyridone 2.12 The latter allowed us to carry out an ef®cient
stereoselective total synthesis of (2)-prosophylline.13
As a part of our long-standing interest in the study of
Michael additions to heterocyclic a,b-unsaturated carbonyl
compounds14 and quinones,15 we envisaged the use of (2S)-
hydroxymethyl-dihydropyridone 3 as a suitable substrate
for the stereoselective synthesis of novel 5-amino- and 5-
thio-3,6-piperidinol derivatives. Available methods for the
preparation of similar compounds are few in number,16
despite the biological activity and ubiquity in nature of
their corresponding sugars.17 Thus, we report herein the
outcome and stereochemical aspects of 1,4-conjugate addi-
tion of various a-aminoacid derivatives, thiophenols and
hydrazoic acid to this chiral a,b-unsaturated system as a
Recently, a general approach to this class of compounds was
introduced by the application of the aza-Achmatowicz rear-
rangement for the synthesis of optically active 1,6-dihydro-
Ê
Scheme 1. (a) m-CPBA, CH2Cl2. (b) HC(OMe)3, BF3´OEt2, 4 A molecular sieves, THF, 08C.
Keywords: azasugar; Michael addition; amino acid; thiophenol; hydrazoic acid.
* Corresponding author. Tel: 130-1-5294247; fax: 130-1-5294265; e-mail: sehar@aua.gr
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00563-9

6136
S. D. Koulocheri et al. / Tetrahedron 56 (2000) 6135±6141
Figure 2.
dated.20 Another addition to this discussion is a recent paper
of Zhou,21 who revised his previous results and reported that
a (2R)-dihydropyridone prepared by similar oxidative cycli-
zation has the cis-con®guration (structure deduced by X-ray
analysis). Treatment of 2 with trimethyl orthoformate in the
Figure 1. The structure of (2S, 6R)-dihydropyridine-3-one 2 based on 2D
NOESY studies and Molecular Modeling (the observed NOE are indicated
by arrows).
²
presence of BF3´Et2O produced acetal 3 in very good yield.
convenient means for the preparation of asymmetric aza-
sugar conjugates of these compounds.
The 1H and 2D NMR data of this compound are comparable
with those of a similar 2,6-cis-disubstituted compound of
the literature,20 but not conclusive for an unequivocal
stereochemical assignment. On the other hand, reduction
of compound 3 with NaBH4 in the presence of CeCl3´7H2O
and subsequent hydrogenation (H2, Pd/C) produced stereo-
selectively compound 3a (Scheme 2), whose con®guration
was elucidated by 2D COSY and NOESY NMR studies.
Thus, the NOE correlation between the H-5ax and H-3ax
and the small coupling constant between the b H-2 and H-
Results and Discussion
(S)-2-(tert-Butyldiphenylsilyloxy)-1-(2-furyl)-N-tosylethyl-
amine 1 was prepared in excellent enantiomeric excess
(.98%), by stereoselective transformation of d-glucal
according to our previously reported method.12 Ef®cient
oxidative cyclization of this compound to (2S)-dihydropyr-
idone 2 was achieved using a modi®ed version of the stan-
4
3 are indicative of the C1 chair conformation and the a
equatorial disposition of the hydroxy group (Fig. 2).
Furthermore, the small coupling constants exhibited
between H-6 and the two H-5 are consistent with the b
equatorial orientation of H-6 and consequently the a axial
orientation of the methoxy group.
dard
(Scheme 1). The diastereomeric purity of the product was
aza-Achmatowich
rearrangement
conditions18
1
revealed by H NMR and HPLC, while the stereochemistry
of the newly formed stereocenter (C-6) was determined by 2D
NOESY spectroscopic analysis (the absolute con®guration at
C-2 derives from the starting material). Thus, the clear strong
cross peak observed between the hydroxy proton and the
protons of tert-butyldiphenylsilanyloxymethyl group is
indicative of the cis diaxial conformation. Furthermore,
the observed NOE between the aromatic protons of the
tosyl group and protons on C-2 and C-6 con®rmed this
con®guration, which is in good accordance with the theore-
tically calculated model using molecular mechanics calcu-
lations (Fig. 1). This formation of the cis isomer may be
rationalized considering that the A(1, 3) strain between the
tosyl and tert-butyldiphenylsilyloxymethyl groups force the
latter to adopt a pseudo-axial orientation and the tosyl group
shields the opposite side of the molecule, favoring the
formation of the cis-product. It is noticeable however, that
this assignment does not comply with previous literature
results, which have either reported that trans-dihydropyri-
done11,19 is the outcome of this oxidative cyclization, or the
con®guration of the product was not unequivocally eluci-
The optimal reaction conditions for the Michael addi-
tion of various nucleophiles to this dihydropyridone
system were determined considering previous experi-
mental procedures on the relative dihydropyranuloside
system.22 Thus, we were able to avoid undesirable
side reactions23 such as retro-Michael addition, self-
condensation and polymerisation which often limit the
utility of the method. The reaction was performed in a
polar solvent (CH3OH) in order to stabilize the enolate
anion, using a large excess of nucleophile. Moreover, a
slightly alkaline pH environment prevented the possibi-
lity of a retro-Michael reaction to occur. The results
²
In our hands this compound proved to be fairly stable and did not
undergo epimerization upon chromatography on silica gel, as was reported
previously for a similar compound by Altenbach,19b in an attempt to explain
the formation of the cis acetal product from the erroneously considered as
the trans dihydropyridone.
Scheme 2.

S. D. Koulocheri et al. / Tetrahedron 56 (2000) 6135±6141
6137
Scheme 3.
obtained for the 1,4-conjugate addition of various
nucleophiles to the examined (2S)-dihydropyridone
substrate are summarized in Scheme 3. The reaction
proved to be remarkably stereospeci®c, providing the
desired Michael adducts in pure diastereomeric form.
This may be attributed to the steric hindrance between
the pseudo-axially oriented 2,6-bulky substituents and
the equatorially approaching nucleophile (Scheme 4),
which explains the exclusive formation of the kineti-
cally favored axial 1,4-adduct. Similar experiments in
the literature using dihydropyranulosides as substrates
led to the formation of a mixture of diasteroisomers,22
presumably because the absence of the tosyl group
makes the molecules more ¯exible, permitting the attack
from the opposite side. Finally, the stereochemistry of
the in situ reduction of the carbonyl group was affected
by the existence of a bulky nucleophile on C-5, because
the syn-axial attack of the hydride anion was hindered,
leading to the formation of the kinetically favored axial
product. It is noticeable, however, that this selectivity
also depends on the nature of C-5 substituent. Thus,
when thiol was used as the nucleophile, NaBH4 reduc-
tion furnished exclusively the kinetically favored axial
product, while in the case of compounds with a carbon±
nitrogen bond at C-5, the formation of a small amount
of the thermodynamically favored equatorial product
was also detected.
Finally, the tosyl protective group may ef®ciently be
cleaved by reaction with sodium in liquid ammonia,21
furnishing the corresponding azasugar derivatives.
Structural analyses
The stereochemistry of the Michael addition products were
unambiguously assigned based on NMR spectroscopic
analysis. Thus, the H NMR data (con®rmed by 2D COSY
1
spectra) presented in the Experimental and the absence of
NOE interaction between H-6 and H-2, provided evidence
that all target compounds (4a±e and 5d,e) adopted the C1
4
chair conformation (Fig. 3), which disposes the a cis located
methoxy and tert-butyl-diphenyl-silanyloxy residues in
diaxial positions. Moreover, in the case of thiophenol addi-
tion product 4a, the small coupling constants between both
H-4 and H-3,5 in conjunction with the absence of a 1,3-
diaxial NOE interaction between the H-3 and H-5 are indi-
cative of a b diaxial orientation of the nucleophile and
hydroxy groups.
Since thiols are very effective nucleophiles, in the case of
p-amino-thiophenol and l-cysteine ethylester, the 1,4-conju-
gate addition resulted in the formation of a carbon±sulfur
bond furnishing compounds 4b and 4c. The stereochemistry
of the addition and reduction is similar, while the observed
positive enhancement between H-2 and the protons of the
Scheme 4. Spatial view of the nucleophile attack on 2-(tert-butyl-diphenyl-
silanyloxymethyl)-6-methoxy-1-(toluene-4-sulfonyl)-1,6-dihydro-2H-pyri-
din-3-one 3.
Figure 3.

6138
S. D. Koulocheri et al. / Tetrahedron 56 (2000) 6135±6141
amino acid supports the conclusion of the axial orientation of
the conjugate addition.
To a stirred solution of N-tosylfurfurylamine 1 (0.38 g,
0.73 mmol) in anhydrous CH2Cl2 (5 mL), was added
m-chloroperbenzoic acid 70% (0.26 g, 1.10 mmol). The
reaction was run at room temperature for 4 h, then washed
successively with 20% KI, 30% Na2S2O3, saturated
NaHCO3, water, brine and concentrated under reduced pres-
sure to a yellowish solid. Puri®cation by ¯ash chroma-
tography (ethyl acetate/hexane 1:4, Rf 0.23) gave the title
compound as a pale white solid (0.35 g, 94%). A small
sample was recrystallized from a diethylether/hexane
mixture as off white prisms; mp 97±988C; [a]2D2ˆ127.9,
(c 1.0, MeOH); IR (neat): nmax 3356 (OH), 1739 (CvO)
When nitrogen containing groups were used as nucleophiles
(glycine methylester and hydrazoic acid), the spectral data
of the products are similar with those reported for thiol
additions (Fig. 3) and are conclusive of an axial 1,4-conju-
gate addition. In this case, however, the ketone reduction
furnished a small amount of the thermodynamically favored
products 5d,e in addition to the predominantly formed
diaxial derivatives (4d,e). The equatorial orientation of the
hydroxy group on C-3 was revealed by the observed diaxial
coupling between H-4ax and H-3ax at 1H NMR (see Experi-
mental).
1
cm21; H NMR: dH 0.91 (s, 9H, C±CH3), 2.43 (s, 3H,
ArCH3), 3.60 (dd, Jˆ10.6, 2.4 Hz, 1H, CH2a), 3.89 (dd,
Jˆ10.6, 2.4 Hz, 1H, CH2b), 4.54 (m, 1H, H-2), 4.90 (d,
Jˆ7 Hz, 1H, OH), 6.09 (m, 1H, H-6), 6.19 (d, Jˆ10.4 Hz,
1H, H-4), 7.07 (dd, Jˆ10.4, 4.8 Hz, 1H, H-5), 7.32 (m, 12H,
ArH), 7.78 (d, Jˆ8 Hz, 2H, ArH). Anal. Calcd for
C29H33NO5SSi (535.7): C, 65.02; H, 6.21; N, 2.61. Found:
C, 64.97; H, 6.32; N, 2.57.
In summary, we have shown that the use of chiral (2S)-
hydroxymethyl-dihydropyridone 3 as substrate for the 1,4-
conjugate addition of various nucleophiles and in situ reduc-
tion provides a useful strategy for the preparation of novel
enantiomerically pure 5-amino- and 5-thio-3,6-piperidinol
derivatives. Further studies on synthetic applications and bio-
logical activity of these compounds are currently in progress.
(2S,6R)-2-(tert-Butyl-diphenyl-silanyloxymethyl)-6-
methoxy-1-(toluene-4-sulfonyl)-1,6-dihydro-2H-pyridin-
3-one 3. To an ice-cold solution of azapyranone 2 (2.00 g,
3.72 mmol), trimethyl orthoformate (0.8 mL, 7.44 mmol)
Experimental
Ê
and 4 A molecular sieves (0.35 g) in dry THF (25 mL)
was added BF3´Et2O (0.7 mL). The reaction mixture was
stirred for 3 h at 08C, quenched with water and extracted
with diethylether (2£30 mL). The combined organic layers
were washed with brine, dried over MgSO4 and concen-
trated under reduced pressure to give a yellowish solid
which was chromatographed (ethyl acetate/hexane 1:4, Rf
0.27) to furnish the desired product 2 (1.96 g, 95%) as color-
less ®ne needles; mp 83±848C (diethylether/hexane);
[a]2D2ˆ1122.9 (c 0.3, MeOH); IR(neat): nmax 1700
General comments
1H and 2D NMR spectra were recorded at 400 MHZ on a
Bruker DRX-400 spectrometer in CDCl3, using TMS as
internal standard. IR spectra were obtained on a Nicolet
Magna 750, series II spectrometer. Melting points were
determined on a BuÈchi melting point apparatus and are
uncorrected. Optical rotations were measured with a
Perkin±Elmer 241 polarimeter 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
manufactorer'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).
1
(CvO) cm21; H NMR: dH 1.06 (s, 9H, C±CH3), 2.38 (s,
3H, ArCH3), 3.53 (s, 3H, OCH3), 3.95 (dd, Jˆ10, 6.7 Hz,
1H, CH2a), 4.05 (dd, Jˆ10, 6.7 Hz, 1H, CH2b), 4.45 (t,
Jˆ6.7 Hz, 1H, H-2), 5.50 (d, Jˆ4.2 Hz, 1H, H-6), 5.74 (d,
Jˆ10.4 Hz, 1H, H-4), 6.66 (dd, Jˆ10.4, 4.2 Hz, 1H, H-5),
7.23 (d, Jˆ8 Hz, 2H, ArH), 7.35±7.47 (m, 6H, ArH), 7.54
(d, Jˆ8 Hz, 2H, ArH), 7.65 (d, Jˆ8 Hz, 4H, ArH). Anal.
Calcd for C30H35NO5SSi (549.8): C, 65.54; H, 6.42; N, 2.55.
Found: C, 65.39; H, 6.44; N, 2.71.
All reactions (except hydrogenation) were carried out under
argon atmosphere. Solvents were dried by distillation prior
to use. Starting materials were purchased from Aldrich
(analytical reagent grades) and used without further puri®-
cation. N-[2-(tert-Butyl-diphenyl-silanyloxy)-1-furan-2-yl-
(2S,6R)-2-(tert-Butyl-diphenyl-silanyloxymethyl)-6-
methoxy-1-(toluene-4-sulfonyl)-piperidin-3-ol 3a.
To a stirred solution of compound 3 (1.0 g, 1.78 mmol)
and CeCl3´7H2O (0.33 g, 0.89 mmol) in methanol (20 mL)
at 2308C was added portionwise NaBH4 (0.24 g,
6.23 mmol). After 40 min of stirring at that temperature,
the reaction was quenched with sat. aqueous NH4Cl
(15 mL) and extracted with ethyl acetate (3£20 mL). The
combined organic phases were washed with brine, dried
(MgSO4) and chromatographed (ethyl acetate/hexane 1:4)
to afford (0.8 g, 78%) of the allylic alcohol, which was
dissolved in ethyl acetate (20 mL) and hydrogenated over
10% Pd/C (0.07 g) under 1 bar pressure for 40 min. The
mixture was ®ltered over Celite and evaporated to a yellow-
ish solid which was chromatographed (ethyl acetate/hexane
1:4, Rf 0.23) to give compound 3a as a white solid which
was crystallized from diethylether/hexane (0.76, 94%); mp
105±1078C; [a]2D2ˆ181.2 (c 0.90, MeOH); IR (neat): nmax
ethyl]-4-methyl-benzenesulfonamide
according to a published procedure.12
1
was prepared
Molecular mechanics calculations were performed using the
MM1 force ®eld of the HyperChem program (HyperChem
is developed and licensed from Hypercube; the MM1 force
®eld used in this software for molecular mechanics calcula-
tions is an extension of MM2 using the MM2 (1991) para-
meters and atom types with the 1997 functional form). The
Polac±Ribiere (conjugate gradient) minimization method
with an energy convergence criterion of 0.01 kcal mol21
was used for geometry optimization.
(2S,6R)-2-(tert-Butyl-diphenylsilyloxymethyl)-6-hydroxy-
1-(toluene-4-sulfonyl)-1,6-dihydro-2H-pyridine-3-one 2.

S. D. Koulocheri et al. / Tetrahedron 56 (2000) 6135±6141
6139
1
3476 (OH) cm21; H NMR: dH 1.05 (s, 9H, C±CH3), 1.35
Jˆ5.1, 3.9, 1.5 Hz, 1H, H-5), 3.85 (d, Jˆ5.1 Hz, 1H,
CH2b), 3.86 (s br, 1H, H-2) 3.97 (d, Jˆ5.1 Hz, 1H, CH2a),
4.17 (s br, 1H, H-3) 5.21 (d, Jˆ1 Hz, 1H, H-6), 6.62 (d,
Jˆ8.5 Hz, 2H, ArH), 7.31±7.50 (m, 12H, ArH), 7.62±7.7
(m, 4H, ArH), 7.83 (d, Jˆ8 Hz, 2H, ArH). Anal. Calcd for
C36H44N2O5S2Si (676.96): C, 63.87; H, 6.55; N, 4.14.
Found: C, 63.91; H, 6.33; N, 4.10.
(tt, Jˆ14.4, 4 Hz, 1H, H-5ax), 1.66 (m, 1H, H-4eq), 1.85 (m,
1H, H-5eq), 1.92 (m, 1H, H-4ax), 2.40 (s, 3H, ArCH3), 3.20
(s, 3H, OCH3), 3.36 (m, 1H, H-3), 3.86 (dd, Jˆ10.4, 3.4 Hz,
1H, CH2a), 4.16 (dt, Jˆ10.4, 3.4 Hz, 1H, H-2), 4.36 (d,
Jˆ7.4 Hz, 1H, OH), 4.47 (t, Jˆ10.4 Hz, 1H, CH2b), 5.05
(d, Jˆ2.5 Hz, 1H, H-6), 7.25 (d, Jˆ8.3 Hz, 2H, ArH),
7.36±7.47 (m, 6H, ArH), 7.59±7.70 (m, 6H, ArH). Anal.
Calcd for C30H39NO5SSi (553.79): C, 65.07; H, 7.10; N,
2.53. Found: C, 64.95; H, 7.02; N, 2.39.
(20R, 30S, 50R, 60S)-2R-Amino-3-[60-(tert-butyl-diphenyl-
silanyloxymethyl)-50-hydroxy-20-methoxy-10-(toluene-4-
sulfonyl)-piperidin-30-ylsulfanyl]-propionic acid ethyl
ester 4c. This compound was obtained as an off white
hygroscopic solid (81%); Rf 0.48 (ethyl acetate/hexane
1:1); [a]2D2ˆ225 (c 0.25, CHCl3); IR (CHCl3 solution in
General procedure for the syntheses of 5-sulfanyl
piperidin-3-oles (4a±c)
ZnSe cells): nmax 3071 (NH2), 1735 (COO) cm21 1H
;
The pH of a methanolic (2 mL) solution of thiol derivative
(2.27 mmol) was adjusted to 8 by addition of triethylamine
(ca 3 drops) and a methanolic solution (2 mL) of azapyra-
none 3 (0.25 g, 0.45 mmol) was added. The resulting
mixture was stirred at room temperature until the Michael
addition was complete (monitored by TLC). Extractive
workup with ethyl acetate (3£15 mL) gave a yellowish oil
which was puri®ed by ¯ash chromatography (ethyl acetate/
hexane 1:4) furnishing the desired Michael adducts. Subse-
quently, these compounds were dissolved in ice-cold metha-
nol (3 mL) and sodium borohydride (0.09 g, 2.27 mmol)
was added portionwise under stirring. The pH of the reac-
tion was adjusted and maintained to 4±5 (by addition of
acetic acid) and stirring was continued at 08C for 40 min.
The reaction was quenched with saturated NH4Cl and
extracted with ethyl acetate (3£15 mL). The combined
organic layer was dried over MgSO4 and concentrated
under reduced pressure to give a yellowish solid. Flash
chromatographic puri®cation (ethyl acetate/hexane)
afforded the title compounds as white solids, which were
crystallized from diethylether/hexane.
NMR: dH 1.04 (s, 9H, C±CH3), 1.28 (t, Jˆ7.0 Hz, 3H,
CH2CH3), 1.61 (dt, Jˆ14.6, 3.0 Hz, 1H, H-40eq), 1.92(s br,
2H, NH2), 2.02 (dt, Jˆ14.6, 3.0 Hz, 1H, H-40ax), 2.41 (s, 3H,
ArCH3), 2.83 (dd, Jˆ13.0, 7.0 Hz, 1H, CH2S), 2.92 (dd,
Jˆ13.0, 4.5 Hz, 1H, CH2S), 3.05 (t, Jˆ3 Hz, 1H, H-50),
3.20 (s, 3H, OCH3), 3.64 (dd, Jˆ7, 4.5 Hz, 1H, CHNH2),
3.77 (s br, 1H, H-20) 3.79 (d, Jˆ6.1 Hz, 1H, CH2b), 3.91 (d,
Jˆ6.1 Hz, 1H, CH2a), 4.07 (s br, 1H, H-30) 4.2 (q, Jˆ7.0 Hz,
2H, CH2CH3) 5.16 (s, 1H, H-6), 7.26 (d, Jˆ6.7 Hz, 2H,
ArH), 7.34±7.48 (m, 6H, ArH), 7.58±7.66 (m, 4H, ArH),
7.77 (d, Jˆ8 Hz, 2H, ArH). Anal. Calcd for C35H48N2O7S2Si
(700.98): C, 59.97; H, 6.90; N, 4.00. Found: C, 59.69; H,
6.71; N, 3.89.
[6-(tert-Butyl-diphenyl-silanyloxymethyl)-5-hydroxy-
2-methoxy-1-(toluene-4-sulfonyl)-piperidin-3-ylamino]-
acetic acid methyl ester (4d and 5d). The pH of a stirred
solution of glycine methylester hydrochloride (0.46 g,
3.64 mmol) in absolute methanol (5 mL) was adjusted to
8.5 by addition of triethylamine (0.57 mL) and a methanolic
solution (5 mL) of azapyranone 3 (0.5 g, 0.91 mmol) was
added. The resulting mixture was stirred at room tempera-
ture until TLC analysis indicated that the Michael addition
was complete. Then, the reaction mixture was cooled to 08C
and sodium borohydride (0.17 g, 4.55 mmol) was added
portionwise, while the pH of the reaction was adjusted
and maintained to 7.5±8.5 (by addition of acetic acid).
After 40 min of stirring at that temperature, the reaction
mixture was quenched with saturated NH4Cl and extracted
with ethyl acetate (3£15 mL). The combined organic layers
were washed with brine, dried over MgSO4 and puri®ed by
¯ash chromatography (ethyl acetate/hexane 2:3, Rf 0.31) to
yield the title compound as mixture of diastereoisomers in
75% total yield (3R/3Sˆ7:3, determined by 1H NMR);
Separation by semi-preparative HPLC24 furnished as the
less mobile crop (retention timeˆ29.07) the major diastereo-
isomer (2S, 3R, 5S, 6R)-[6-(tert-butyl-diphenyl-silanyloxy-
methyl)-5-hydroxy-2-methoxy-1-(toluene-4-sulfonyl)-piper-
idin-3-ylamino]-acetic acid methyl ester 4d; white gum;
[a]2D2ˆ256.5 (c 1.0, MeOH); IR (®lm): nmax 3492 (OH),
3308 (NH), 1751 (COO) cm21; 1H NMR: dH 1.07 (s, 9H, C±
CH3), 1.65 (dt, Jˆ15.2, 3.0 Hz, 1H, H-4eq), 1.74 (dt, Jˆ15.2,
3.0 Hz, 1H, H-4ax), 2.42 (s, 3H, ArCH3), 2.90 (br s, 1H, H-
5), 3.21 (s, 3H, OCH3), 3.37 (s, 2H, CH2NH), 3.75 (s, 3H,
COOCH3), 3.85 (t, Jˆ10.4 Hz, 1H, CH2b), 3.89 (dd, Jˆ10.4,
4.1 Hz, 1H, H-2) 4.06 (dd, Jˆ10.4, 4.3 Hz, 1H, CH2a), 4.09
(s br, 1H, H-3), 5.03 (d, Jˆ1.8 Hz, 1H, H-6), 7.26 (d,
Jˆ6.7 Hz, 2H, ArH), 7.35±7.52 (m, 6H, ArH), 7.62±7.71
(2S, 3R, 5S, 6R)-2-(tert-Butyl-diphenyl-silanyloxymethyl)-6-
methoxy-5-phenyl sulfanyl-1-(toluene-4-sulfonyl)-piperi-
din-3-ol 4a. This compound was obtained as colorless
prisms (80%); mp 104±1068C (diethylether/hexane); Rf
0.43 (ethyl acetate/hexane 1:4); [a]2D2ˆ277.5 (c 0.78,
1
MeOH); IR (neat): nmax 3553 (OH) cm21; H NMR: dH
1.03 (s, 9H, C±CH3), 1.67 (dt, Jˆ15.2, 3.6 Hz, 1H, H-
4eq), 1.94 (ddd, Jˆ15.2, 3.0, 4.9 Hz, 1H, H-4ax), 2.41 (s,
3H, ArCH3), 2.89 (d, Jˆ9.7 Hz, 1H, OH), 3.12 (s, 3H,
OCH3), 3.12 (m, 1H, H-5), 3.79 (d, Jˆ5.3 Hz, 1H, CH2b),
3.80 (s br, 1H, H-2) 3.91 (d, Jˆ5.3 Hz, 1H, CH2a), 4.10 (s br,
1H, H-3) 5.19 (d, Jˆ1 Hz, 1H, H-6), 6.62 (d, Jˆ8.5 Hz, 2H,
ArH), 7.23±7.31 (m, 5H, ArH), 7.33±7.45 (m, 6H, ArH),
7.58±7.65 (m, 4H, ArH), 7.82 (d, Jˆ8 Hz, 2H, ArH). Anal.
Calcd for C36H43NO5S2Si (661.95): C, 65.32; H, 6.55; N,
2.12. Found: C, 65.15; H, 6.45; N, 2.22.
(2S, 3R, 5S, 6R)-5-(4-Amino-phenylsulfanyl)-2-(tert-
butyl-diphenyl-silanyloxymethyl)-6-methoxy-1-(toluene-
4-sulfonyl)-piperidin-3-ol 4b. This compound was
obtained as pale yellow needles (83%); mp 82±848C
(diethylether/hexane); Rf 0.34 (ethyl acetate/hexane 1:4);
[a]2D2ˆ276.9 (c0.55, MeOH); IR(neat): nmax 3492 (OH),
1
3375 (NH2) cm21; H NMR: dH 1.08 (s, 9H, C±CH3),
1.68 (dt, Jˆ15.2, 3.9 Hz, 1H, H-4eq), 2.08 (ddd, Jˆ15.2,
3.2, 5.1 Hz, 1H, H-4ax), 2.46 (s, 3H, ArCH3), 2.64 (d,
Jˆ8.8 Hz, 1H, OH), 3.18 (s, 3H, OCH3), 3.42 (ddd,

6140
S. D. Koulocheri et al. / Tetrahedron 56 (2000) 6135±6141
(m, 4H, ArH), 7.74 (d, Jˆ8 Hz, 2H, ArH). Anal. Calcd for
C33H44N2O7SSi (640.86): C, 61.85; H, 6.92; N, 4.37. Found:
C, 61.57; H, 6.81; N, 4.27.
(c0.4, MeOH); IR (solution in CHCl3): nmax 3533 (OH), 2111
1
(N3) cm21; H NMR: dH 1.03 (s, 9H, C±CH3), 1.92 (dt,
Jˆ14.3, 3.3 Hz, 1H, H-4eq), 2.04 (td, Jˆ14.3, 3.3 Hz, 1H,
H-4ax), 2.38 (s, 3H, ArCH3), 3.15 (s, 3H, OCH3), 3.73 (s br,
1H, H-5) 3.86 (dd, Jˆ10.4, 4.3 Hz, 1H, CH2a), 4.01(s br, 1H,
H-3), 4.22 (d, Jˆ6.5 Hz, 1H, H-2), 4.38 (t, Jˆ10.4 Hz, 1H,
CH2b), 4.89 (d, Jˆ1.8 Hz, 1H, H-6), 7.28 (d, Jˆ8 Hz, 2H,
ArH), 7.33±7.44 (m, 6H, ArH), 7.58±7.65 (m, 4H, ArH),
7.73 (d, Jˆ8 Hz, 2H, ArH); Anal. Calcd for C30H38N4O5SSi
(594.8): C, 60.58; H, 6.44; N, 9.42. Found: C, 60.51; H, 6.49;
N, 9.45.
The more mobile crop (retention timeˆ27.38) corresponded
to the minor diastereoisomer (2S, 3S, 5S, 6R)-[6-(tert-butyl-
diphenyl-silanyloxymethyl)-5-hydroxy-2-methoxy-1-(tol-
uene-4-sulfonyl)-piperidin-3-ylamino]-acetic acid meth-
yl ester 5d; clear oil; [a]2D2ˆ216.3 (c 1.0, MeOH); IR
(®lm): nmax 3490 (OH), 3310 (NH), 1748 (COO) cm21
;
1H NMR: dH 1.07 (s, 9H, C±CH3), 1.79 (dt, Jˆ14.5,
3.4 Hz, 1H, H-4eq), 2.09 (td, Jˆ14.5, 3.4 Hz, 1H, H-4ax),
2.44 (s, 3H, ArCH3), 2.98 (br s, 1H, H-5), 3.17 (s, 3H,
OCH3), 3.37 (d, Jˆ17 Hz, 1H, CH2NH), 3.45 (d,
Jˆ17 Hz, 1H, CH2NH), 3.75(s, 3H, COOCH3), 3.93 (m,
1H, H-3), 4.00 (dd, Jˆ10.2, 6.5 Hz, 1H, CH2b), 4.14 (d,
Jˆ6.5 Hz, 1H, H-2) 4.46 (t, Jˆ10.2 Hz, 1H, CH2a), 4.89
(d, Jˆ1.8 Hz, 1H, H-6), 7.26 (d, Jˆ6.7 Hz, 2H, ArH),
7.35±7.52 (m, 6H, ArH), 7.62±7.71 (m, 4H, ArH), 7.82
(d, Jˆ8 Hz, 2H, ArH). Anal. Calcd for C33H44N2O7SSi
(640.86): C, 61.85; H, 6.92; N, 4.37. Found: C, 61.61; H,
6.76; N, 4.31.
Acknowledgements
S. D. K.'s scholarship from I. K. Y., Greece is gratefully
acknowledged.
References
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1
determined by H NMR); Separation by semi-prepara-
tive HPLC24 furnished as the less mobile crop (reten-
tion timeˆ27.70 min) the major diastereoisomer (2S,
3R, 5S, 6R)-5-azido-2-(tert-butyl-diphenyl-silanyloxy-
methyl)-6-methoxy-1-(toluene-4-sulfonyl)-piperidin-3-
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mixture as colorless prisms; mp 105±1068C;
[a]2D2ˆ241.6 (c 0.4, MeOH); IR (solution in CHCl3):
1
nmax 3536 (OH), 2115 (N3) cm21; H NMR: dH 1.03 (s,
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9H, C±CH3), 1.67 (dt, Jˆ15.2, 3 Hz, 1H, H-4eq), 1.78
(dt, Jˆ15.2, 3 Hz, 1H, H-4ax), 2.40 (s, 3H, ArCH3), 3.2
(s, 3H, OCH3), 3.73 (t, Jˆ10.4 Hz, 1H, CH2b), 3.73 (s
br, 1H, H-5) 3.86 (dd, Jˆ10.4, 4.3 Hz, 1H, CH2a), 3.91
(dd, Jˆ10.4, 4.1 Hz, 1H, H-2), 4.01(s br, 1H, H-3) 5.05
(d, Jˆ1.8 Hz, 1H, H-6), 7.28 (d, Jˆ8 Hz, 2H, ArH),
7.33±7.44 (m, 6H, ArH), 7.58±7.65 (m, 4H, ArH),
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C30H38N4O5SSi (594.8): C, 60.58; H, 6.44; N, 9.42.
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24. Column: Kromasil 10-5C18 (25 cm£10 mm); Mobile phase:
H2O/CH3CN (9:1); Detector: UV l 254 nm; Flow: 4 ml/min; Load:
3 mg/200 mL solution in mobile phase.
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