Synthesis of (R)-dihydropyridones as key intermediates for an efficient access to piperidine alkaloids

Article abstract of DOI:10.3390/12040735

The efficient transformation of D-glucal to (2R)- hydroxymethyldihydropyridinone 5 in seven steps and 35 % overall yield is reported. Dihydropyridone 5 constitutes a versatile chiral building block for the synthesis of various piperidine alkaloids. In thi

Full text of DOI:10.3390/12040735

Molecules 2007, 12, 735-744
molecules
ISSN 1420-3049
© 2007 by MDPI
www.mdpi.org/molecules
Full Paper
Synthesis of (R)-Dihydropyridones as Key Intermediates for an
Efficient Access to Piperidine Alkaloids
Evangelia N. Tzanetou 1, Konstantinos M. Kasiotis 1, Prokopios Magiatis 2 and
Serkos A. Haroutounian 1,*
1
Chemistry Laboratory, Agricultural University of Athens, Iera odos 75, Athens 11855, Greece
2
Faculty of Pharmacy, Laboratory of Pharmacognosy and Natural Products Chemistry, University of
Athens, Panepistimiopolis Zografou, Athens 15771, Greece
* Author to whom correspondence should be addressed; E-mail: sehar@aua.gr
Received: 13 March 2007; in revised form: 25 March 2007 / Accepted: 27 March 2007 /
Published: 10 April 2007
Abstract: The efficient transformation of D-glucal to (2R)-hydroxymethyldihydro-
pyridinone 5 in seven steps and 35 % overall yield is reported. Dihydropyridone 5
constitutes a versatile chiral building block for the synthesis of various piperidine alkaloids.
In this regard, 5 was converted to piperidinol 13 and piperidinone 15, that may be further
elaborated for the syntheses of (+)-desoxoprosophylline (1) and deoxymannojirimycin (3) or
D-mannolactam (4), respectively.
Keywords: Dihydropyridones, piperidine alkaloids, azasugars, asymmetric synthesis
Introduction
Piperidine alkaloids comprise a large family of compounds that exhibit a large spectrum of
biological activities of medicinal interest. In particular, alkaloid lipids such as (+)-desoxoprosophylline
(1, Figure 1) [1] display significant anesthetic, analgesic and antibiotic activities [2-4], while their
corresponding iminosugars – exemplified by N-butyl–1–deoxynojirimycin (NB-DNJ, 2) which was
recently approved for the treatment of Gaucher disease [5] – constitute promising leads for the
development of immunosuppressive [6], antiviral [7], antidiabetic [8] and antitumour agents [9]. In

Molecules 2007, 12
736
addition, deoxymannojirimycin (3) and D-mannolactam (4, Figure 1) have also shown to inhibit
various enzymes that participate in the binding and processing of diverse glycoproteins, underlying
their possible therapeutic values [10-12].
Figure 1. Piperidine Alkaloids and Key Intermediate Dihydropyridone 5.
OH
OH
OH
HO
OH
HO
O
OH
( )
N
H
9
N
H
N
H
OH
OH
OH
(+)- Desoxoprosophylline Deoxymannojirimycin
D- Mannolactam
(4)
(1)
(3)
OH
O
HO
OH
OH
HOH2C
HO
HO
O
HO
N
Ts
5
N
OTBDPS
NB- DNJ
D-Glucal
2
As a result intense research efforts have been devoted to the development of methodologies and
synthetic strategies for the efficient preparation of these compounds and derivatives. Most of these
methods utilize sugars or amino acids as their chiral pool synthons [13-19] and suffer from a lack of
selectivity and applicability to diverse compounds. On the other hand, the optically active 1,6-dihydro-
2H-pyridin-3-ones represent flexible building blocks for the efficient access to diverse multi-
functionalized bioactive indolizines, quinolizidines and piperidine alkaloids [20]. Recently, we
reported the preparation of (2S)–hydroxymethyldihydropyridinone, [21] a chiral key intermediate for
the synthesis of various piperidine alkaloids such as (–)–desoxoprosophylline, allonojirimycin and
indolizidine alkaloids (e.g. swainsonine). The common structural feature of all the aforementioned
molecules is the (S)-configuration at C–2. Herein we present an efficient and highly enantioselective
route to its (R)−enantiomer 5 starting from the commercially available D-glucal. This molecule
represents a key intermediate for the synthesis of broad variety natural and unnatural piperidine
alkaloids and/or iminosugars displaying an (R)–configuration at C–2.
Results and Discussion
The key step for the implementation of the proposed synthetic sequence is the synthesis of chiral
(R)-N-[2-(tert-butyldiphenylsilyloxy)-1-furan-2-yl-ethyl]-4-methylbenzenesulfonamide (10), since all
final products retain that stereochemistry. Commercially available D-glucal was used as strarting
material for the synthesis of this intermediate. More specifically, D-glucal was reacted with HgSO4 (as
a solution in 0.002 M H2SO4) and subsequently its primary hydroxy group was protected with
TBDPSCl to provide the 2–furyl glycol (+)−6, according to a literature procedure reported by Hauser
et al. (Scheme 1) [22].

Molecules 2007, 12
737
The stereochemistry of compound 6 was efficiently inverted using the Mitsunobu protocol (DEAD,
Ph3P, benzoic acid) affording the (S)-ethyl-2-(tert-butyldiphenylsilanyloxy)-1-furan-2-yl-benzoate 7,
which was further saponified to afford (S)-1-furan-2-yl-ethanol 8. The displacement of the secondary
hydroxy group with azide with inversion of configuration was performed in high enantiomeric excess
(>98%) on treating 8 with DBU in toluene and DPPA. The enantiomeric excess was determined by
hydrogenating compound 9 over 10% Pd/C (4 mg) under 1 bar pressure for 40 min [23]. The mixture
was filtered over Celite® and the amine was then derivatized by adding Et3N and (−)-menthyl
chloroformate. The ratio of enantiomers was determined by reversed-phase HPLC [Kromasil 100-5, C-
18, H2O/MeOH/CH3CN gradient elution from 40:40:20 to 0:10:90, flow = 1.2 mL/min, UV detection
at 238 nm]; tR major 48 min (97%); and tR minor 49.4 min (3%).
Hydrogenation of 9 over Pd/C and tosylation of the resulting amine afforded the N-furfuryl-
sulfonamide (R)-10. Finally, oxidative cyclization of compound 10 using a modified version of the
standard aza-Achmatowich rearrangement conditions furnished the target dihydropyridone 5.
Scheme 1. Synthesis of Key Intermediate Dihydropyridone 5.
a, b
c
d
D-Glucal
OTBDPS
OTBDPS
OTBDPS
OTBDPS
92%
O
75%
O
80%
O
OH
OBz
OH
6
7
8
O
e
f
g
OTBDPS
O
O
HO
N
78%
94%
87%
Ts
N3
NHTs
OTBDPS
9
10
5
Reagents and Conditions. (a) HgSO4, H2SO4, MeOH; (b) TBDPSCl, imidazole, DMAP, DMF;
(c) DEAD, PPh3, PhCO2H, THF; (d) MeOH, aqueous NaOH; (e) DPPA, DBU, toluene, O °C; (f)
1. H2, Pd/C, EtOAc; 2. TsCl, Et3N, CH2Cl2; (g) m-CPBA, CH2Cl2.
1
The diastereomeric purity of the product was revealed by H-NMR and HPLC, since the presence
of the other diastereoisomer was not detected, while the stereochemistry of the newly formed
stereocenter was determined by 2D-NOESY spectroscopic analysis (the absolute configuration at C-2
derives from the starting material). Thus, the clear strong cross peak observed between the protons on
C-2 and C-6 is indicative of their cis pseudo-diaxial conformation (Figure 2). Furthermore, the
observed NOE between the aromatic protons of the tosyl group and the protons of tert-butyldiphenyl-
silanyloxymethyl group confirmed this configuration. Finally, the observed optical rotation value for
22
D
this compound (
–25.5) constitutes additional proof of the assigned configuration, since its
α
[ ]
22
enantiomer displays the opposite sign (
+27.9) [20b].
[ ]
α
D

Molecules 2007, 12
738
Figure 2. NOE Correlations in 5.
Ph
Ph
Si
O
H
Ts
N
OH
O
H
As depicted in Scheme 2, dihydropyridone 5 was treated with HC(OMe)3 in the presence of
BF3·OEt2 to furnish acetal 11, which under modified Luche reduction conditions (NaBH4, CeCl3) was
converted to allylic alcohol 12. Subsequent catalytic hydrogenation of alcohol 12 produced piperidinol
13, whose configuration 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 β H-2 and H-3
4
are indicative of the C1 chair conformation and the α equatorial disposition of the hydroxy group.
This intermediate may be incorporated into the stereoselective synthesis of (+)-desoxoprosophylline
(1), according to already published synthetic routes [1, 24].
Finally, oxidation of dihydropyridone 5 with Jones reagent produced in almost quantitative yield
the corresponding α,β-unsaturated-γ-keto-δ-lactam 14 (Scheme 3). The latter was diastereoselectively
reduced under modified Luche conditions (NaBH4 and CeCl3) to 5,6-dihydropyridin-2-one 15. This
product is the key substrate for the syntheses of deoxymannojirimycin (3) and D-mannolactam (4),
according to a recently published synthetic pathway [25].
Scheme 2. Synthesis of (+)-Desoxoprosophylline (1).
O
OH
OH
a
b
c
5
88%
88%
90%
O
N
O
N
O
N
Ts
Ts
Ts
OTBDPS
OTBDPS
OTBDPS
11
12
13
ref. 1, 23
OH
OH
( )
N
9
H
(+)- Desoxoprosophylline, 1
Reagents and Conditions. (a) HC(OMe)3, BF3·OEt2, 4Å molecular sieves, THF, O °C; (b)
CeCl3·7H2O, NaBH4, MeOH; (c) H2, Pd/C, MeOH.

Molecules 2007, 12
Scheme 3. Synthesis of Deoxymannojirimycin (3) and D-Mannolactam (4).
739
O
O
a
95%
HO
N
O
N
Ts
Ts
OTBDPS
OTBDPS
5
14
b 80%
OH
OH
OH
ref. 24
ref. 24
HO
OH
OH
HO
O
OH
OH
O
N
Ts
N
H
N
H
OTBDPS
15
Deoxymannojirimycin
D-Mannolactam
(4)
(3)
Reagents and conditions. (a) Jones Reagent, acetone, -10 ºC; (b) CeCl3·7H2O, NaBH4, MeOH.
Conclusions
In summary, we have demonstrated a concise synthetic route to (2R)-hydroxymethyl-
dihydropyridone 5, a chiral key intermediate useful in the synthesis of a variety of naturally occurring
bioactive piperidine alkaloids, such as (+)-desoxoprosophylline, deoxymannojirimycin and D-manno-
lactam.
Experimental
General
Air- and /or moisture sensitive reactions were carried out under an argon atmosphere in flame-
dried glassware. Solvents were distilled from the appropriate drying agents prior to use. All starting
materials were purchased from Aldrich (analytical reagent grades) and used without further
22
D
purification. 2-(tert-Butyldiphenylsilyloxy)-1-(2-furyl)ethanol (6,
+28.7, c 2.03, MeOH) was
[ ]
α
prepared according to a literature procedure [22]. All reactions were monitored by thin-layer
chromatography using TLC sheets coated with silica gel 60 F254 (Merck); spots were visualized with
UV light or/and an alcohol solution of anisaldehyde. Products were purified by flash chromatography
on Merck silica gel 60 (230-400 mesh ASTM). Melting points (uncorrected): Büchi melting point
apparatus. FT-IR: Nicolet Magna 750, series II. Samples were recorded as KBr pellets, unless
1
otherwise stated. Optical rotations were measured with a Perkin-Elmer-241 polarimeter. H-NMR
spectra were recorded on a Bruker DRX-400 (400 MHz) spectrometer, in CDCl3. Chemical shifts are
referenced to internal TMS. Coupling constants (J) are expressed in Hz. HPLC: 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.

Molecules 2007, 12
740
(S)-Ethyl-2-(tert-butyldiphenylsilanyloxy)-1-furan-2-yl benzoate (7). Diethyl azodicarboxylate
(DEAD) (0.91 g, 5.86 mmol) was added dropwise to solution of (R)-2-(tert-
a
butyldiphenylsilanyloxy)-1-furan-2-yl-ethanol 6 (1.8 g, 4.91 mmol), PPh3 (3.09 g, 11.76 mmol) and
benzoic acid (1.44 g, 11.52 mmol) in dry THF (15 mL). After the mixture was stirred for 1.5 h, the
solvent was evaporated. The residue was diluted with CH2Cl2 (150 mL) and washed with sat. aq.
NaHCO3 (60 mL), H2O (80 mL) and brine. The organic phase was separated and dried over MgSO4,
the solvent evaporated and the residue chromatographed (hexane/EtOAc 95:5, Rf = 0.70) yielding 1.73
−5.7 (c 1.00, EtOAc); 1H-NMR δ: 1.42 (s, 9H, C-CH3),
22
D
g (75%) of compound 7 as a colorless oil.
[ ]
α
4.53 (dd, J = 10.7, 4.8, 1H, CH2), 4.65 (dd, J = 10.7, 4.8, 1H, CH2), 6.78 (dd, J = 7.2, 4.9, 1H, CH),
6.88 (d, J = 6.8, 1H, H-3), 7.70-8.10 (m, 15H, Ph-H, H-4, H-5), 8.50 (d, J = 6.8, 2H, Ph-H); Anal.
Calcd. for C29H30O4Si (470.63) C, 74.01; H, 6.43. Found: C, 74.19; H, 6.30.
(S)-2-(tert-Butyldiphenylsilanyloxy)-1-furan-2-yl-ethanol (8). Aqueous NaOH (10%, 0.5 mL) was
added dropwise to a solution of compound 7 (1.2 g, 2.55 mmol) in MeOH (100 mL) and the reaction
was run at r.t. for 3 h. The resulting mixture was quenched with sat. aq. NH4Cl (3 mL) and extracted
with EtOAc (2×150 mL). The combined organic layers were washed with brine, dried over MgSO4
and concentrated under reduced pressure. Purification by flash chromatography (hexane/EtOAc 95:5,
22
D
R = 0.27) gave 0.75 g (80%) of the title compound 8 as a colorless oil.
–4.2 (c 1.03, EtOAc); IR
α
[ ]
f
-1
1
~
(neat): = 3350 (OH), 740, 1020 (furan) cm ; H-NMR δ: 1.07 (s, 9H, C-CH ), 3.95 (d, J = 1.4, 2H,
ν
3
CH2), 4.83 (m, 1H, CH), 6.27 (d, J = 3.2, 1H, H-3), 6.3 (dd, J = 5.0, 1.8, 1H, H-4), 7.3-7.6 (m, 11H,
Ph-H, H-5); Anal. Calcd. for C22H26O3Si (366.53): C, 72.09; H, 7.15. Found: C, 72.31; H, 7.02.
(R)-(2-Azido-2-furan-2-yl-ethoxy)-tert-butyldiphenylsilane (9). To an ice-cold solution of (2S)-2-furyl
glycol 8 (0.4 g, 1.09 mmol) and diphenylphosphoryl azide (0.23 mL, 1.09 mmol) in dry toluene (3 mL)
was added DBU (0.16 mL, 1.09 mmol) in small portions and the resulting mixture stirred for 2 h at 0
°C. The mixture was allowed to reach the room temperature, stirred for an additional 20 h and then
washed successively with H2O (2×3 mL) and 5% HCl (2 mL), dried over MgSO4 and the organic layer
concentrated under reduced pressure. Purification by silica gel chromatography (hexane/EtOAc 95:5,
22
D
~
R = 0.87) afforded 0.33 g (78%) of azide 9 as colorless oil.
+50.8 (c 1.01, EtOAc); IR (neat): =
ν
α
[ ]
f
2110 (N3), 742, 1020 (furan) cm-1; 1H-NMR δ: 1.10 (s, 9H, C-CH3), 4.01 (d, J = 6.7, 2H, CH2), 4.60 (t,
J = 5.5, 1H, CH), 6.37 (d, J = 1.8, 2H, H-3, H-4), 7.45 (m, 7H, H-5, Ph-H), 7.70 (m, 4H, Ph-H); Anal.
Calcd. for C22H25N3O2Si (391.54): C, 67.49; H, 6.44; N, 10.73. Found: C, 67.27; H, 6.52; N, 10.59.
(R)-N-[2-(tert-Butyldiphenylsilyloxy)-1-furan-2-yl-ethyl]-4-methylbenzenesulfonamide (10). Azide 9
(0.4 g, 1.02 mmol) was dissolved in EtOAc (10 mL) and hydrogenated over 10% Pd/C (0.04 g) under
1 bar pressure for 40 min. The reaction mixture was filtered over Celite® and concentrated in vacuo.
The residue was dissolved in CH2Cl2 (3 mL) and Et3N (0.2 mL, 1.5 mmol) was added. The resulting
solution was cooled to 0 °C and p-TsCl (0.28 g, 1.5 mmol) was added portionwise under stirring. The
reaction mixture was allowed to reach r.t., stirred for an additional 3 h. and then extracted successively
with sat. aq. NaHCO3 (2 mL) and brine, dried over MgSO4 and concentrated to dryness. The crude
product was chromatographed (hexane/EtOAc 4:1, Rf = 0.4) yielding 0.5 g (94%) of the desired
22
D
~
product 10 in pure crystalline form. M.p. 101-103 °C;
+5.5 (c 1.01, EtOAc); IR (neat): = 3285
ν
[ ]
α

Molecules 2007, 12
741
1
(N-H), 740, 1030 (furan), cm-1; H-NMRδ: 0.99 (s, 9H, C-CH3), 2.41 (s, 3H, PhCH3), 3.72 (dd, J =
10.1, 4.9, 1H, CH2), 3.85 (dd, J = 10.1, 4.9, 1H, CH2), 4.43 (m, 1H, CH), 5.2 (d, J = 7.6, 1H, NH), 6.13
(d, J = 3.11, 1H, H-3), 6.24 (dd, J = 3.1, 1.9, 1H, H-4), 7.20-7.52 (m, 13H, Ph-H, H-5), 7.22 (d, J =
8.3, 1H), 7.66 (d, J = 8.0, 2H, Ph-H); Anal. Calcd. for C29H33NO4SSi (519.73): C, 67.02; H, 6.40; N,
2.70. Found: C, 66.78; H, 6.30; N, 2.81.
(2R,6S)-2-(tert-Butyldiphenylsilyloxyphenyl)-6-hydroxy-1-(toluene-4-sulfonyl)-1,6-dihydropyridin-3-
(2H)-one (5). To a stirred solution of N-tosylfurfurylamine 10 (0.1 g, 0.19 mmol) in anhydrous CH2Cl2
(1 mL), m-chloroperbenzoic acid (70%, 0.08 g, 0.33 mmol) was added in small portions. The reaction
was run at r.t. for 4 h, then washed successively with 20% aq KI (1 mL), 30% Na2S2O3 (2 mL), sat. aq.
NaHCO3 (2 mL), H2O (3 mL) and brine. Concentration under reduced pressure gave a yellowish solid,
which was purified by flash chromatography (hexane/EtOAc 4:1, Rf = 0.28) providing 0.09 g (88%) of
the title compound 5 as a pale white solid. A small sample was crystallized from an Et2O/hexane
22
D
~
mixture as off white needles. M.p. 97-99 °C;
–25.5 (c 1.00, MeOH); IR (neat): = 3397 (OH),
ν
α
[ ]
1692 (C=O), 1595 (C=C) cm-1; H-NMR δ: 0.95 (s, 9H, C-CH3), 2.45 (s, 3H, PhCH3), 3.60 (dd, J =
10.7, 2.4, 1H, CH2), 3.90 (dd, J =10.7, 2.4, 1H, CH2 ), 4.55 (m, 1H, H-2), 4.96 (d, J = 11.5, 1H, OH),
6.10 (m, 1H, H-6), 6.22 (d, J = 10.4, 1H, H-4), 7.08 (dd, J = 10.4, 4.8, 1H, H-5), 7.3-7.5 (m, 12H, Ph-
H), 7.79 (d, J = 8.0, 2H, Ph-H); Anal. Calcd. for C29H33NO5SSi (535.73): C, 65.02; H, 6.21; N, 2.61.
Found: C, 65.17; H, 6.28; N, 2.68.
1
(2R,6S)-2-(tert-Butyldiphenylsilyloxyphenyl)-6-methoxy-1-(toluene-4-sulfonyl)-1,6-dihydropyridin-3-
(2H)-one (11). BF3·Et2O (0.23 mL) was added to an ice-cold solution of pyridone 5 (0.5 g, 0.93
mmol), trimethyl orthoformate (0.3 mL, 2.75 mmol) and 4Å molecular sieves (0.35 g) in dry THF (7
mL). The reaction mixture was stirred for 3 h at 0 °C, quenched with H2O (5 mL) and extracted with
Et2O (2×10 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
(hexane/EtOAc 4:1, Rf = 0.32) to furnish 0.45 g (88%) of desired product 11 as colorless fine needles.
-1
1
22
D
~
M.p. 84-86 °C;
−45 (c 1.02, EtOAc); IR (neat): = 1694 (C=O), 1596 (C=C) cm ; H-NMR δ:
ν
[ ]
α
1.07 (s, 9H, C-CH3), 2.39 (s, 3H, PhCH3), 3.54 (s, 3H, CH3), 3.97 (dd, J = 10.2, 6.6, 1H, CH2), 4.07
(dd, J = 10.2, 6.6, 1H, CH2), 4.47 (t, J = 6.9, 1H, H-2), 5.51 (d, J = 4.3, 1H, H-6), 5.74 (d, J = 10.36,
1H, H-4), 6.68 (dd, J = 10.3, 4.4, 1H, H-5), 7.24 (d, J = 7.4, 2H, Ph-H), 7.44 (m, 6H, Ph-H), 7.55 (d, J
= 8.2, 2H, Ph-H), 7.67 d, J = 7.4, 4H, Ph-H); Anal. Calcd. for C30H35NO5SSi (549.75): C, 65.54; H,
6.42; N, 2.55. Found: C, 65.69; H, 6.52; N, 2.44.
(2R,3S,6S)-2-(tert-Butyldiphenylsilyloxymethyl)-6-methoxy-1-(toluene-4-sulfonyl)-1,2,3,6-tetrahydro-
pyridin-3-ol (12). NaBH4 (23.5 mg, 0.62 mmol) was added portionwise to a stirred solution of
compound 11 (0.1 g, 0.18 mmol) and CeCl3·7H2O (33.1 mg, 0.09 mmol) in MeOH (2 mL) at –30 °C.
After 40 min of stirring at that temperature, the reaction was quenched with sat. aq. NaHCO3 (2 mL)
and extracted with Et2O (2×10 mL). The combined organic phases were washed with brine, dried
(MgSO4) and chromatographed (hexane/EtOAc 4:1, Rf = 0.3) to afford 90 mg (88%) of 12 as a
colorless oil, which crystallized in Et O/hexane as colorless fine needles. M.p. 106-107 °C; 2D2 −32.5
[ ]
3
α
2
-1
1
~
(c 0.98, EtOAc); IR (neat): = 3460 (OH), 1650 (C=C) cm ; H-NMR δ: 1.05 (s, 9H, C-CH ), 2.42 (s,
ν

Molecules 2007, 12
742
3H, PhCH3), 3.31 (s, 3H, CH3), 3.77 (dd, J = 10.6, 4.2, 1H, CH2), 3.95 (m, 1H, H-3), 4.17 (d, J = 6.85,
1H, OH), 4.2 (m, 1H, H-2), 4.4 (t, J = 10.3, 1H, CH2), 5.24 (m, 1H, H-6), 5.69 (m, 1H, H-5), 5.84 (m,
1H, H-4), 7.25 (t, J = 9.01, 2H, Ph-H), 7.4-7.5 (m, 6H, Ph-H), 7.6-7.7 (m, 6H, Ph-H); Anal. Calcd. for
C30H37NO5SSi (551.8): C, 65.30; H, 6.76; N, 2.54. Found: C, 65.55; H, 6.90; N, 2.63.
2-(tert-Butyldiphenylsilanyloxymethyl)-6-methoxy-1-(toluene-4-sulfonyl)-piperidin-3-ol (13). Allylic
alcohol 12 (0.52 g, 1 mmol) was dissolved in MeOH (15 mL) and hydrogenated over 10% Pd/C (52
mg) under 1 bar pressure for 2 h. The mixture was filtered over Celite®, evaporated and partitioned
between EtOAc and water. The aqueous layer was backwashed with EtOAc. The combined organic
extracts were washed with brine, dried over MgSO4 and concentrated. The yellowish slurry was
chromatographed (hexane/EtOAc 4:1, Rf = 0.29) to give 90 mg (90%) of compound 13 as an off-white
-1 1
22
D
~
solid. M.p. 98-100 °C;
−15.5 (c 1.02, EtOAc); IR (neat): = 3500 (OH) cm ; H-NMR δ: 1.07 (s,
ν
[ ]
α
9H, C-CH3), 1.65 (m, 2H, H-4), 1.9 (m, 2H, H-5), 2.4 (s, 3H, PhCH3), 3.1 (s, 3H, CH3), 3.44 (m, 1H,
H-3), 3.66 (m, 1H, CH2), 3.88 (dd, J = 10.2, 4.1, 1H, H-2), 4.35 (d, J = 6.26, 1H, OH), 4.5 (t, J = 10.4,
1H, CH2), 5.01 (m, 1H, H-6), 7.27 (t, J = 8.15, 2H, Ph-H), 7.3-7.5 (m, 6H, Ph-H), 7.6-7.7 (m, 6H, Ph-
H); Anal. Calcd. for C30H39NO5SSi (553.8): C, 65.07; H, 7.10; N, 2.53. Found: C, 65.31; H, 7.23; N,
2.42.
(6R)-6-(tert-Butyldiphenylsilyloxymethyl)-6-methoxy-1-(toluene-4-sulfonyl)-1,6-dihydropyridine-2,5-
dione (14). To an ice cold solution of compound 5 (0.1 g, 0.188 mmol) in acetone (1.3 mL) at –10 °C,
was added dropwise Jones reagent (0.1 mL). After being stirred for 20 min, the solid inorganic by
products were eliminated by decantation and the liquid layer was concentrated to a residue that was
partitioned in EtOAc (4 mL) and H2O (2 mL). The organic layer was separated, washed with brine,
dried over MgSO4, and evaporated. The residue was crystallized from cold Et2O/hexane to afford 95
22
D
mg (95%) of compound 14 as an off-white solid. M.p. 196-198 °C; R = 0.31 (hexane/EtOAc 1:4);
[α]
f
-1
1
~
−10.7 (c 1.00, EtOAc); IR (neat): = 1725 (C=O), 1692 (N-C=O) cm ; H-NMR δ: 0.92 (s, 9H, C-
ν
CH3), 2.44 (s, 3H, PhCH3), 4.11 (dd, J = 10.6, 1.6, 1H, CH2), 4.42 (dd, J =10.6, 1.6, 1H, CH2), 5.02 (s,
1H, H-6), 6.72 (d, J = 10.1, 1H, H-3), 6.8 (d, J = 10.1, 1H, H-4), 7.27 (d, J = 8.1, 2H, Ph-H), 7.3-7.55
(m, 10H, Ph-H), 7.94 (d, J = 8.3, 2H, Ph-H); Anal. Calcd. for C29H31NO5SSi (533.7): C, 65.26; H,
5.85; N, 2.62. Found. C, 65.01; H, 5.98; N, 2.49.
(5S,6R)-2-(tert-Butyldiphenylsilyloxymethyl)-5-hydroxy-1-(toluene-4-sulfonyl)-5,6-dihydropyridin-2-
one (15). NaBH4 (24 mg, 0.64 mmol) was added portionwise to a stirred solution of compound 14 (0.1
g, 0.187 mmol) and CeCl3⋅7H2O (34 mg, 0.092 mmol) in MeOH (2 mL) at –30 °C. After 40 min of
stirring at that temperature, the reaction was quenched with sat. aq. NaHCO3 (2 mL) and extracted
with Et2O (2×10 mL). The combined organic phases were washed with brine, dried (MgSO4) and
chromatographed (hexane/EtOAc 4:1, Rf = 0.4) to afford compound 15 (80 mg, 80%) as a pale white
-1
22
D
~
solid. M.p. 150-152 °C;
−2.7 (c 1.02, EtOAc); IR (neat): = 1450 (C=O), 1670 (N-C=O) cm ;
ν
α
[ ]
1H-NMR δ: 0.92 (s, 9H, C-CH3), 2.44 (s, 3H, PhCH3), 3.82 (dd, J = 10.6, 4.2, 1H, CH2), 4.02 (dd, J =
10.6, 4.2, 1H, CH2), 4.17 (d, J = 6.85, 1H, OH), 5.04 (m, 1H, H-5), 5.04 (m, 1H, H-5), 5.07 (m, 1H, H-
6), 5.60 (dd, J = 10.0, 4.2, 1H, H-4), 7.01 (dt, J = 10.2, 1.7, 1H, H-3), 7.2 (d, J = 7.2, 2H, Ph-H), 7.40-

Molecules 2007, 12
743
7.52 (m, 6H, Ph-H), 7.60 (dd, J = 7.5, 1.5, 2H, Ph-H), 7.7 (d, J = 8.4, 4H, Ph-H); Anal. Calcd. for
C29H31NO5SSi (533.7): C, 65.26; H, 5.85; N, 2.62. Found: C, 65.09; H, 5.71; N, 2.72.
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