Transformation of D-glucal to (2S)-hydroxymethyl-dihydropyridones as intermediates to piperidine alkaloids

Article abstract of DOI:10.1055/s-1999-3604

The efficient transformation of D-glucal to (2S)-hydroxymethyl- dihydropyridone 1 in five steps and 61% overall yield is reported. The latter is used as chiral building block for the synthesis of piperidine alkaloids. The preparation of piperidinol 8, whi

Full text of DOI:10.1055/s-1999-3604

PAPER
1889
Transformation of D-Glucal to (2S)-Hydroxymethyl-dihydropyridones as
Intermediates to Piperidine Alkaloids
Sofia D. Koulocheri, Serkos A. Haroutounian*
Chemistry Laboratory, Agricultural University of Athens, Iera odos 75, Athens 11855 Greece
Fax +30(1)5294265; E-mail: sehar@aua.gr
Received 4 June 1999; revised 27 July 1999
O
Abstract: The efficient transformation of D-glucal to (2S)-hy-
droxymethyl-dihydropyridone 1 in five steps and 61% overall yield
is reported. The latter is used as chiral building block for the synthe-
sis of piperidine alkaloids. The preparation of piperidinol 8, which
may be elaborated to the synthesis of (–)-desoxoprosophylline 9, is
also presented.
HOH2C
azasugars
piperidine alkaloids
pipecolic acid deriv.
O
HO
HO
HO
N
Ts
OTBDPS
2
1
Scheme 1
Key words: dihydropyridone, piperidine alkaloids, asymmetric
synthesis, D-glucal
one 1, as an entry to piperidines with the S-configuration
on C2. Key step for the implementation of this synthetic
route is the transformation of commercially available D-
glucal 2 to chiral, nonracemic N-furfurylsulfonamide 5,
since all the final products retain its stereochemistry. Fur-
thermore, since the inversion of stereochemistry of parent
2-furyl glycol 3 by a Mitsunobu protocol has already de-
scribed,12 this synthetic route provides efficient access to
both enantiomeric forms of these building blocks.
Naturally occurring or synthetically derived multifunc-
tionalized piperidines are particularly attractive synthetic
targets, because of their significant biological activity of
medicinal interest, including glycosidase inhibition,1 tu-
mor growth inhibition,2 and anti-HIV behavior.3 In addi-
tion, their usefulness as chiral building blocks for the
asymmetric synthesis of many indolizidine alkaloids is
well documented.4 Thus, intense research activity target-
ing the synthesis of these compounds has been initiated,
producing a large number of elegant and efficient routes
based on carbohydrate5 and noncarbohydrate6 starting
materials. Most of these synthetic methods, however, suf-
fer from excessive length or lack of selectivity and are not
generally applicable.
a, b
c
2
OTBDPS
OTBDPS
O
O
92%
84%
N3
OH
4
3
O
Recently, a general approach to this class of compounds
was introduced by the synthesis of optically active 1,6-di-
hydropyridin-3(2H)-ones which serve as flexible building
blocks for the synthesis of various azasugars7 and pipe-
ridines.8 These intermediates were prepared by oxidative
rearrangement of the corresponding chiral N-furfurylsul-
fonamides using MCPBA. This transformation was firstly
reported by Ciufolini9 and is similar to the well-known re-
arrangement of furfuryl alcohols (Achmatowicz rear-
rangement).10 By this methodology, the total synthesis of
several natural and unnatural multifunctionalized pipe-
ridines was accomplished.7,11 It is noteworthy, however,
that all these preparations concern products with the R-
configuration at C2 of the piperidine ring. By contrast, the
synthesis of the corresponding S-enantiomers, which in-
cludes many biologically interesting compounds such as
(–)-desoxoprosophylline, allonojirimycin derivatives, and
indolizidine alkaloids (e.g. swainsonine), is less docu-
mented. Thus, we were interested in developing a synthet-
ic route for the efficient preparation of the corresponding
building blocks.
d
e
OTBDPS
HO
N
O
87%
91%
Ts
NHTs
5
OTBDPS
1
Reagents and conditions: (a) HgSO4, H2SO4, MeOH; (b) TBDMSCl,
imidazole, DMAP, DMF; (c) DPPA, DBU, toluene, 0 °C to r.t.; (d) 1.
H2, Pd/C, MeOH; 2. TsCl, Et3N, CH2Cl2; (e) MCPBA, CH2Cl2.
Scheme 2
According to our reaction sequence, depicted in Scheme
2, D-glucal 2 by reaction with HgSO4 (solution in 0.002 M
H2SO4)12 and subsequent selective protection of the pri-
mary hydroxy group with TBDPSCl furnished the 2-furyl
glycol (+)-3. Displacement of the secondary hydroxy
group with azide by inversion of configuration was
achieved in high enantiomeric excess (>98%) on treating
3 with DBU in toluene and DPPA. Hydrogenation of 4
over Pd/C and tosylation of the resulting amine afforded
the desired N-furfurylsulfonamide (S)-5. This compound,
by reaction with MCPBA underwent an oxidative rear-
rangement furnishing the target dihydropyridone 1.
In this report we wish to present a short and highly enan-
tioselective route to (2S)-hydroxymethyl-dihydropyrid-
Synthesis 1999, No. 11, 1889–1892 ISSN 0039-7881 © Thieme Stuttgart · New York

1890
S. D. Koulocheri, S. A. Haroutounian
PAPER
Flash column chromatography was performed on silica gel 60 (230–
400 mesh).
As shown in Scheme 3, compound 1 was protected by re-
action with HC(OEt)3 in the presence of BF3•OEt2 and
subsequently reduced (NaBH4, CeCl3) and hydrogenated
over Pd/C to give stereoselectively compound 7 as the
sole product. Finally, Mitsunobu reaction (DEAD, Ph3P,
PhCO2H) of 7 provided the protected piperidinol 8, an in-
termediate that may be elaborated in the stereoselective
synthesis of (–)-desoxoprosophylline 9 according to re-
cently published synthetic routes.13 The formation of 2,6-
cis-disubstituted compound 6 is in accordance with
Speckamp's results,8b implying that the A(1,3) strain be-
tween the tosyl and tert-butyldiphenylsilyloxymethyl
groups force the latter to adopt a pseudo-axial orientation.
Thus, the tosyl group shields the opposite side of the mol-
ecule, favoring the formation of the cis-product. The ste-
reochemisty of C2, C3 and C6 of compound 8 was
established based on its 1H NMR spectrum and COSY ex-
periments. Furthermore, the chemical shift of H4 of com-
pound 6 in CDCl3 is 5.73, revealing its cis configuration.8b
(S)-2-(tert-Butyldiphenylsilyloxy)-1-(2-furyl)ethyl Azide (4)
To an ice-cold solution of alcohol 3 (15.0 g, 41 mmol) and diphe-
nylphosphoryl azide (10.6 mL, 49 mmol) in dry toluene (100 mL)
was added DBU (7.3 mL, 49 mmol) in small portions and stirred for
2 h at 0 °C and additional 20 h at r.t. Then the mixture was washed
successively with H2O (2 × 50 mL) and 5% HCl (40 mL) and the
organic phase was collected. After removal of solvent, the residue
obtained was purified by chromatography (hexane/EtOAc 95:5) to
22
afford the azide 4 as a colorless oil; yield: 13.2 g (84%); [α]D
87.5 (c 1.2, hexane).
–
IR: ν = 2110 cm–1 (N3).
1H NMR: δ = 1.10 (s, 9H, C-CH3), 4.02 (d, J = 6 Hz, 2H, CH2), 4.62
(tr, J = 6.6 Hz, 1H, CH), 6.37 (d, J = 1.8 Hz, 2H, H-3, H-4), 7.45
(m, 7H, H-5, Ph-H), 7.72 (m, 4H, Ph-H).
Anal calcd for C22H25N3O2Si (391.5): C, 67.49; H, 6.44; N, 10.73.
Found: C, 67.66; H, 6.19; N, 10.55.
The enantiomeric excess was determined after hydrogenation of a
sample of 4 (40 mg) over 10% Pd/C (4 mg) under 1 bar pressure for
40 min.14 The mixture was filtered over Celite and the amine was
then derivatized by adding Et3N (150 µL) and (–)-menthyl chloro-
formate (100 µL). The ratio of enantiomers was determined by re-
versed-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 48.9 min (96.2%); and tR minor 49.45
min (3.8%).
(S)-2-(tert-Butyldiphenylsilyloxy)-1-(2-furyl)-N-tosylethyl-
amine (5)
Azide 4 (4.50 g, 11.5 mmol) was dissolved in MeOH (100 mL) and
hydrogenated over 10% Pd/C (0.45 g) under 1 bar pressure for 40
min. The mixture was filtered over Celite and concentrated in vac-
uo. The residue was dissolved in CH2Cl2 (30 mL) and Et3N (2.0 mL,
15 mmol) was added. The resulting solution was cooled to 0 °C and
TsCl (2.85 g, 15 mmol) was added portionwise under stirring. The
reaction was allowed to reach r.t. and stirred for an additional 3 h.
Then, the mixture was extracted successively with sat. aq NaHCO3
(20 mL) and brine, dried (MgSO4) and concentrated to dryness. The
crude product was purified by chromatography employing EtOAc/
hexane (1:4) to give 5 in pure crystalline form; yield: 5.22 g (87%);
[α]D22 –18.7 (c 1.35, MeOH); mp 107–108 °C (EtOAc/hexane).
Reagents and conditions:(a) HC(OEt)3, BF3•OEt2, 4Å molecular sie-
ves, THF, 0 °C; (b) 1. NaBH4, CeCl3•7 H2O, MeOH, –30 °C; 2. H2,
Pd/C, EtOAc; (c) DEAD, Ph3P, PhCO2H, THF, rt.
Scheme 3
In summary, the asymmetric synthesis of 1, well known to
be carried forward to several azasugars and piperidine al-
kaloids such as 9, was accomplished in only five steps
(61% overall yield from D-glucal). Key step of this syn-
thetic route is the transformation of 2-furyl glucol (+)-3 to
azide (–)-4 by inversion of configuration (>98% ee). Sub-
sequent reports will describe the application of this trans-
formation to the synthesis of other members of these
biologically important systems.
IR: ν = 3281 cm–1 (N–H).
1H NMR: δ = 0.98 (s, 9H, C-CH3), 2.40 (s, 3H, PhCH3), 3.71 (dd,
J = 10.5, 4.8 Hz 1H, CH2), 3.85 (dd, J = 10.5, 4.8 Hz 1H, CH2), 4.52
(m, 1H, CH), 5.24 (d, J = 7.7 Hz, 1H, NH), 6.13 (d, J = 3.1 Hz, 1H,
H-3), 6.23 (dd, J = 3.1, 1.8 Hz, 1H, H-4), 7.20–7.64 (m, 15H Ph-H,
H-5).
Anal calcd for C29H33NO4SSi (519.7): C, 67.02; H, 6.40; N, 2.70.
Found: C, 67.28; H, 6.21; N, 2.55.
(2S,6S)-2-(tert-Butyldiphenylsilyloxymethyl)-6-hydroxy-1-to-
syl-1,6-dihydropyridin-3(2H)-one (1)
All reactions (except hydrogenations) were carried out under argon.
Solvents were dried by distillation prior to use. Starting materials
were purchased from Aldrich (analytical reagent grades) and used
without further purification. 2-(tert-Butyldiphenylsilyloxy)-1-(2-
furyl)ethanol 3 ([α]D22 +28.7 (c 2.03, MeOH) was prepared accord-
ing to a literature procedure.12 Mps were determined on a Büchi
melting point apparatus and are uncorrected. IR spectra were re-
To a stirred solution of N-tosylfurfurylamine 5 (1.143 g, 2.20 mmol)
in anhyd CH2Cl2 (10 mL) maintained below 10 °C, MCPBA (70%,
0.80 g, 3.25 mmol) was added in small portions. The mixture was
stirred for 3 h, then washed successively with 20% aq KI (10 mL),
30% Na2S2O3 (15 mL), concd NaHCO3 (15 mL), water, and brine
and evaporated to a yellowish solid which was chromatographed
(EtOAc/hexane 1:4) to give 1 as white solid which was crystallized
1
corded on a Nicolet Magna 750, series II spectrometer. H NMR
spectra were recorded on a Bruker AC-200 spectrometer in CDCl3
using TMS as internal standard. Optical rotations were measured
with a Perkin–Elmer-241 polarimeter. Elemental analyses were
provided by the University of Illinois microanalytical service lab.
22
from Et2O/hexane; yield: 1.07 g (91%); [α]D +27.9 (c 0.98,
MeOH); mp 97–98 °C.
IR: ν = 3356 (OH), 1696 cm–1 (C=O).
Synthesis 1999, No. 11, 1889–1892 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
(2S)-Hydroxymethyl-dihydropyridones as Intermediates to Piperidine Alkaloids
1891
1H NMR: δ = 0.91 (s, 9H, C-CH3), 2.43 (s, 3H, PhCH3), 3.60 (dd,
J = 10.6, 2.4 Hz, 1H, CH2α), 3.89 (dd, J = 10.6, 2.4 Hz, 1H, CH2β),
4.54 (m, 1H, H-2), 4.90 (br, 1H, OH), 6.09 (m, 1H, H-6), 6.19 (d,
J = 10.4 Hz, 1H, H-4), 7.07 (dd, J = 10.4, 4.8 Hz, 1H, H-5), 7.32 (m,
12H, Ph-H), 7.78 (d, J = 8 Hz, 2H, Ph-H).
1H NMR: δ = 0.9 (tr, J = 7 Hz, 3H, CH3), 1.09 (s, 9H, C-CH3), 1.6-
2.0 (m, 4H, H-4, H-5), 2.11 (s, 3H, PhCH3), 3.34-3.56 (m, 2H, CH2),
3.92 (dd, J = 10.3, 4,8 Hz, 1H, CH2a), 3,98 (tr, J = 10.3 Hz, 1H,
CH2b), 4.1 (dd, J = 10.3, 4.8 Hz, 1H, H-2), 5.28 (s, 1H, H-6), 5.54
(s, 1H, H-3), 6.96 (d, J = 8.4 Hz, 2H, Ph-H), 7.27-7.75 (m, 17H, Ph-
H).
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.
Anal calcd for C38H45NO6SSi (671.9): C, 67.93; H, 6.75; N, 2.08.
Found: C, 68.09; H, 6.66; N, 2.15.
(2S,6R)-2-(tert-Butyldiphenylsilyloxymethyl)-6-ethoxy-1-tosyl-
1,6-dihydropyridin-3(2H)-one (6)
Acknowledgement
To an ice-cold solution of 1 (2.75 g, 5.13 mmol), triethyl orthofor-
mate (1.70 mL, 10.25 mmol) and 4Å molecular sieves (0.40 g) in
dry THF (30 mL) was added BF3•OEt2 (15 drops). The reaction was
run for 3 h at 0 °C, quenched with water and extracted with Et2O (2
× 30 mL). The combined organic layers were washed with brine,
dried (MgSO4) and concentrated under reduced pressure to give a
yellowish solid which was chromatographed (EtOAc/hexane 1:4)
yielding 6 in pure crystalline form; yield: 2.34g (81%); [α]D22 +100
(c 1.0 MeOH); mp 83–84 °C (Et2O/hexane).
This work was supported by a grant from the Board of Research of
the Agricultural University of Athens (gr. no. 23.20.212). S.D.K.’s
scholarship from I.K.Y., Greece, is also gratefully acknowledged.
References
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IR: ν = 1692 cm–1 (C=O).
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(2S,3S,6R)-2-(tert-Butyldiphenylsilyloxymethyl)-6-ethoxy-1-
tosylpiperidin-3-ol (7)
To a stirred solution of 6 (1.00 g, 1.78 mmol) and CeCl3•7 H2O (331
mg, 0.89 mmol) in MeOH (20 mL) at –30 °C was added portionwise
NaBH4 (235 mg, 6.23 mmol). After 40 min of stirring at –30 °C, the
reaction was quenched with sat. aq NH4Cl (15 mL) at –10 °C and
extracted with EtOAc (3 × 20 mL). The combined organic phases
were washed with brine, dried (MgSO4) and chromatographed
(EtOAc/hexane 15:85) to afford (0.796g, 79%) of allylic alcohol
which was dissolved in EtOAc (20 mL) and hydrogenated over 10%
Pd/C (0.07 g) under 1 bar pressure for 40 min. The mixture was fil-
tered over Celite and evaporated to a yellowish solid which was
chromatographed (EtOAc/hexane 1:4) to give 7 as a white solid
which was crystallized from Et2O/hexane; yield: 0.76 g (95%);
[α]D22 +60.4 (c 0.90, MeOH); mp 111–112 °C.
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IR: ν = 3476 cm–1 (OH).
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1H NMR: δ = 0.87 (tr, J = 7 Hz, 3H, CH3), 1.07 (s, 9H, C-CH3),
1.26–1.96 (m, 4H, H-4, H-5), 2.43 (s, 3H, PhCH3), 3.34 (m, 3H,
CH2, CH2b) 3.79 (dd, J = 10.3, 3.7 Hz, 1H, CH2a), 4.18 (m, 1H, H-
3), 4.38 (d, J = 7 Hz, 1H, OH), 4.54 (t, J = 10.5 Hz, 1H, H-2), 5.07
(m, 1H, H-6), 7.29–7.74 (m, 14H, Ph-H).
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Synthesis 1999, No. 11, 1889–1892 ISSN 0039-7881 © Thieme Stuttgart · New York

1892
S. D. Koulocheri, S. A. Haroutounian
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1437-210X,E;1999,0,11,1889,1892,ftx,en;H03799SS.pdf
Synthesis 1999, No. 11, 1889–1892 ISSN 0039-7881 © Thieme Stuttgart · New York