Synthesis of γ-hydroxyalkyl substituted piperidine iminosugars from D-glucose

Article abstract of DOI:10.1021/jo800044r

(Chemical Equation Presented) D-Glucose was converted to synthetic equivalent of meso-pentodialdose, namely 3-C-(1′-aminoethyl)-α-D- ribo-pentodialdo-1,4-furanose 10 that gives an easy access to manipulate the aldehyde functionalities on either sides to g

Full text of DOI:10.1021/jo800044r

labeled these compounds as isofagomine 2a.4 The structure
activity relationship data indicates that the bioactivity of 1 and
2 is reliant on the position and orientation of the hydroxyalkyl
group in the piperidine iminosugars.5 For example, isofagomine
2a is stronger and more selective inhibitor of â-glucosidases;
however, its 5(S)-hydroxy (C5-hydrogen replaced by -OH)
substituted analogue 2b is a better inhibitor toward both R and
â-glucosidases6 whereas 5(R)-hydroxy isofagomine 2c is a mild
â-mannosidase inhibitor.4i,7d The N-alkyl derivatives of 2b
inhibit glycolipid biosynthesis6 with little inhibitory activity
against glycosidases. Although R/â-hydroxyalkyl substituted
piperidine iminosugars are known in the literature, the existence
of γ-hydroxyalkyl substituted pattern is not known. As a part
of our continuing efforts in this area,7 we are now reporting
hitherto unknown γ-1,2-dihydroxyethyl and hydroxymethyl
Synthesis of γ-Hydroxyalkyl Substituted
Piperidine Iminosugars from D-Glucose
Rajendra S. Mane, K. S. Ajish Kumar, and
Dilip D. Dhavale*
Department of Chemistry, Garware Research Centre, UniVersity
of Pune, Pune- 411 007, India
ddd@chem.unipune.ernet.in
ReceiVed January 9, 2008
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Am. Chem. Soc. 2007, 129, 2349-2352. (r) See the recent book on
iminosugars: Compain, P., Martin, O. R., Eds. Imunosugars: From
synthesis to therapeutic applications; Wiley: New York, 2007.
D-Glucose was converted to synthetic equivalent of meso-
pentodialdose, namely 3-C-(1′-aminoethyl)-R-D-ribo-pento-
dialdo-1,4-furanose 10 that gives an easy access to manipu-
late the aldehyde functionalities on either sides to get
enantiomeric pair of 3. Thus, reduction of C5-aldehyde
followed by hydrolysis of 1,2-acetonide functionality and
reductive aminocyclization with C1-aldehyde afforded γ-1,2-
dihydroxyethyl piperidine iminosugar 3. On the other hand,
first reductive aminocyclization with C5-aldehyde gave
piperidine ring skeleton 12 that on removal of 1,2-acetonide
and reduction of C1-aldehyde gave ent-3 while chopping of
C1-aldehyde in 12 and reduction afforded γ-hydroxymethyl
piperidine iminosugar 4.
Among six membered iminosugars, the nojirimycin 1a was
the first to be recognized as a glycosidase inhibitor;1 however,
it was noticed that 1a was highly unstable to the mild acidic/
basic conditions. This led to the discovery of a more stable and
promising glycosidase inhibitor, namely 1-deoxynojirimycin 1b,
that was synthesized first2a and then isolated.2b,c Later on, 1,2-
dideoxynojirimycin, commonly known as fagomine 1c, was
isolated and evaluated for biological studies.3 A common feature
in 1 is the presence of hydroxymethyl substituent at the
R-position with respect to the ring nitrogen atom. In an attempt
to find a classical variation in the position of hydroxymethyl
substituent in 1, Bols et al. synthesized â-hydroxymethyl
substituted hydroxylated piperidine iminosugars in which
nitrogen atom was shifted to the anomeric position of 1 and
(6) Ichikawa, M.; Igarashi, Y.; Ichikawa, Y. Tetrahedron Lett. 1995, 36,
1767-1770.
(7) (a) Dhavale, D. D.; Markad, S. D.; Karanjule, N. S.; PrakashaReddy,
J. J. Org. Chem. 2004, 69, 4760-4766. (b) Patil, N. T.; Tilekar, J. N.;
Dhavale, D. D. J. Org. Chem. 2001, 66, 1065-1074 and references cited
therein. (c) Markad, S. D.; Karanjule, N. S.; Sharma, T.; Sabharwal, S. G.;
Dhavale, D. D. Biorg. Med. Chem. 2006, 14, 5535-5539. (d) Matin, M.
M.; Sharma, T.; Sabharwal, S. G.; Dhavale, D. D. Org. Biomol. Chem.
2005, 3, 1702-1707. (e) Dhavale, D. D.; Matin, M. M.; Sharma, T.;
Sabharwal, S. G. Bioorg. Med. Chem. 2004, 12, 4039-4044. (f) Dhavale,
D. D.; Ajish Kumar, K. S.; Chaudhari, V. D.; Sharma, T.; Sabharwal, S.
G.; PrakashaReddy, J. Org. Biomol. Chem. 2005, 3, 3720-3726. (g) Ajish
Kumar, K. S.; Chaudhari, V. D.; Puranik, V. G.; Dhavale, D. D. Eur. J.
Org. Chem. 2007, 29, 4895-4901 and references cited therein.
(1) Ishida, N.; Kumagai, K.; Niida, T.; Tsuruoka, T.; Yumate, H. J.
Antibiot. 1967, 20, 66-71.
(2) (a) Bernotas, R. C.; Papandreou, G.; Urbach.J.; Ganem, B. Tetrahe-
dron Lett. 1990, 31, 3393-3396. (b) Murao, S.; Miyata, S. Agric. Biol.
Chem. 1980, 44, 219-221. (c) Yagi, M.; Kouno, T.; Aoyagi, Y.; Murai,
H. Nippon Nogei Kagaku Kaishi 1976, 50, 571-572.
(3) Koyama, M.; Aijima, T.; Sakamura, S. Agric. Biol. Chem. 1974, 38,
1467-1469.
10.1021/jo800044r CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/15/2008
3284
J. Org. Chem. 2008, 73, 3284-3287

SCHEME 2. Synthesis of 10
FIGURE 1. Piperidine iminosugars.
free (C5) and other protected aldehyde (C1) functionalities, and
(iii) the suitably placed ethylamine side chain at C3, required
for building the piperidine ring skeleton. The masked symmetry
of A is apparent in the meso-open structure of the 1,2-acetonide
cleavage product B wherein the C3 is achirotopic and stereo-
genic. The aldehyde functionalities on either side afford inherent
flexibility and could be manipulated elegantly to get the
enantiomeric pair of 3. For example, first reduction of C5-
aldehyde functionality in A will afford C that on 1,2-acetonide
removal and reductive aminocyclization with C1-aldehyde will
give 3. On the other hand, first reductive aminocyclization in
A with C5-aldehyde functionality to get piperidine ring skeleton
D and 1,2-acetonide removal following reduction of C1-
aldehyde will give an access to ent-3, whereas protection of
tertiary hydroxyl in D followed by acetonide removal, chopping
of the anomeric C1, and reduction will give 4. Our results in
this direction are reported herein.
SCHEME 1. Retrosynthesis of 3, ent-3, and 4
substituted piperidine iminosugars 3, ent-3, and 4. It is interest-
ing to note that such type of piperidine system (as in 3) is present
in the microbial metabolite 5, which is a potent and selective
inhibitor of bacterial tyrosyl tRNA synthetases (YRS) (see
Figure 1).8
In general, introduction of hydroxyalkyl moiety at the carbon
atom of the piperidine ring skeleton is difficult; however, we
thought of utilizing carbon skeleton of D-glucose to get the
required substituents while building the piperidine ring. Thus,
the common intermediate to the target molecules is the synthetic
equivalent of the meso-pentodialdose B, namely 3-C-(1′-
aminoethyl)-R-D-ribo-pentodialdo-1,4-furanose A, that could be
easily obtained from the D-glucose (Scheme 1).
As shown in Scheme 2, D-glucose was converted to the
known alcohol 6 as reported earlier.9 Dihydroxylation of 6 using
catalytic amount of K2OsO4‚2H2O (5 mol %) and NMO as a
cooxidant afforded triol which was directly subjected to
oxidative cleavage using sodium metaperiodate to give aldehyde
7.10 Reductive amination of 7 using benzylamine and sodium
cyanoborohydride in methanol followed by treatment with
benzyloxycarbonyl chloride and sodium bicarbonate in methanol-
water afforded N-Cbz protected amino alcohol 8.11 Selective
5,6-acetonide deprotection in 8 using 30% HClO4 in THF under
controlled conditions gave triol 9 that on treatment with sodium
metaperiodate afforded N-protected aminoaldehyde 10 in good
yield.
Attractive features of chiral template A are (i) the presence
of two differentially protected and stereochemically defined
hydroxylated C2 and C4 carbon atoms, (ii) the presence of one
While targeting the synthesis of 3 (Scheme 3), the C5-
aldehyde group in 10 was first reduced with sodium borohydride
to give N-protected aminoalcohol 11. Removal of 1,2-acetonide
group with TFA-water (to free the C1-aldehyde) and subsequent
reductive aminocyclization using ammonium formate and 10%
(8) (a) Stefanska, A. L.; Coates, N. J.; Mensah, L. M.; Pope, A. J.; Ready,
S. J.; Warr, S. R. J. Antibiot. 2000, 53, 345-350.(b) Walker, G.; Brown,
P.; Forrest, A. K.; O’Hanlon, P.; Pons, J. E. Recent AdVances in the
Chemistry of Anti-infectiVe Agents; Royal Society of Chemistry: London,
1993; p 106. (c) Houge-Frydrych, C. S. V.; Readshaw, S. A.; Bell, D. J. J.
Antibiot. 2000, 53, 351-356. (d) Berge, J. M.; Broom, N. J. P.; Houge-
Frydrych, C. S. V.; Jarvest, R. L.; Mensah, L.; McNair, D. J.; O’Hanlon,
P. J.; Pope, A. J.; Rittenhouse, S. J. Antibiot. 2000, 53, 1282-1292. (e)
Berge, J. M.; Copley, R. C. B.; Eggleston, D. S.; Hamprecht, D. W.; Jarvest,
R. L.; Mensah, L. M.; O’, Hanlon, P. J.; Pope, A. J. Bioorg. Med. Chem.
Lett. 2000, 10, 1811-1814. (f) Berge, J. M.; Catherine, S. V.; Houge-
Frydrych, C. S. V.; Jarvest, R. L. J. Chem. Soc., Perkin Trans. 1 2001, 20,
2521-2523.
(9) (a) Hotha, S.; Maurya, S. K.; Gurjar, M. K. Tetrahedron Lett. 2005,
46, 5329-5332.
(10) Compound 7 is reported using different methodology, see: Pinheiro,
J. M.; Ismael, M. I.; Figueiredo, J. A.; Silva, A. M. S. J. Heterocycl. Chem.
2004, 41, 877-882.
1
(11) The H and 13C NMR spectra of compounds 8, 9, 10, 11, 12, 13,
14, and 15 in which a N-Cbz group is present, showed doubling of signals.
This was due to restricted rotation around the N-CdO bond, see: (a)
Applications of NMR Spectroscopy in Organic Chemistry; Jackman, L. M.,
Sternhell, S., Eds.; Pergamon Press: Elmsford, NY, 1978; p 361.
J. Org. Chem, Vol. 73, No. 8, 2008 3285

SCHEME 3. Synthesis of 3
and hydroxymethyl functionalities at the γ-position of the
piperidine ring nitrogen to get new piperidine iminosugars 3,
ent-3, and 4. Another interesting aspect of present route is that
we have converted D-glucose to enantiomeric pair 3. Thus, a
single starting compound obtained from D-glucose has been used
to synthesize two enantiomers having several stereo-centers. The
new molecules are being studied for their inhibitory activity,
and the results will be published in due course.
SCHEME 4. Synthesis of ent-3 and 4
Experimental Section
1,2:5,6-Di-O-isopropylidene-3-C-(1′-(N-benzyl-N-benzyloxy-
carbonyl)aminoethyl)-r-D-allo-1,4-furanose (8). To a solution of
benzyl amine (0.79 mL, 7.28 mmol) and glacial acetic acid (0.02
mL) in dry methanol (20 mL) was added a solution of 7 (2.00 g,
6.62 mmol) in methanol (15 mL) over a period of 30 min at -20
°C and stirred for 1 h. Sodium cyanoborohydride (1.04 g, 16.55
mmol) was added in three portions (10 min), and the solution was
warmed to 0 °C and stirred for 2 h. Reaction mixture was quenched
by adding saturated aq NaHCO3 solution. Methanol was removed
under reduced pressure, and the residue was extracted with
chloroform (25 mL × 3) and concentrated to afford crude amine.
To a solution of crude amine (2.60 g, 6.61 mmol) in methanol-
water (25 mL, 9:1) at 0 °C was added sodium bicarbonate (1.66 g,
19.84 mmol) and benzyloxycarbonyl chloride (1.40 mL, 9.92
mmol). The reaction mixture was allowed to attain room temper-
ature and stirred for 3 h. Methanol was evaporated under reduced
pressure, and the residue was extracted with chloroform (25 mL ×
3) and concentrated. Purification by column chromatography (n-
hexane/ethyl acetate ) 4/1) gave 8 (2.90 g, 83% over two steps)
Pd/C in methanol at reflux afforded (3S, 4S)-3,4-dihydroxy-4-
((R)-1,2-dihydroxyethyl)piperidine (3) as a thick liquid. This
one-pot three-steps process involves hydrogenolysis of N-benzyl
and N-Cbz groups to give insitu formation of primary amine
that concomitantly undergoes reductive aminocyclization with
C1-aldehyde (equilibrium with hemiacetal) to give 3.
25
as a thick liquid: Rf 0.50 (n-hexane/ethyl acetate ) 2/3); [R]D
+11 (c 1.06, CHCl3); IR (CDCl3) 3525 (br), 1697 cm-1; 1H NMR
(300 MHz, CDCl3) δ 1.10-2.10 (m, 14H), 2.67 (br s, 1H), 3.20-
4.70 (m, 9H), 5.05-5.75 (m, 3H), 7.10-7.35 (m, 10H); 13C NMR
(75 MHz, CDCl3) δ 25.3, 26.4, 26.6 (s), 30.0, 42.3, 51.1, 67.2,
67.7, 73.0, 78.3, 80.4, 82.1, 103.5, 109.4, 112.4, 127.3 (s), 127.6,
127.8 (s), 128.1, 128.4 (s), 128.5 (s), 137.5 (s), 156.2. Anal. calcd
for C29H37NO8: C, 66.02; H, 7.07; Found: C, 65.95; H, 7.00.
(3S,4S)-3,4-Dihydroxy-4-((R)-1,2-dihydroxyethyl)piperidine
(3). A solution of 11 (0.10 g, 0.21 mmol) in TFA-water (2 mL,
3:1) was stirred for 3 h at 0 °C. TFA was coevaporated with toluene
at reduced pressure to furnish a hemiacetal as a thick liquid. To a
solution of hemiacetal (0.09 g, 0.21 mmol) in dry methanol (5 mL)
was added 10% Pd/C (0.05 g) and ammonium formate (0.07 g,
1.09 mmol), and the reaction mixture was refluxed for 1 h. On
cooling, the reaction mixture was filtered through celite, washed
with methanol, and the solvent was evaporated at reduced pressure.
Purification by column chromatography (methanol) gave 3 (0.03
g, 87% over two steps) as a thick liquid: Rf 0.18 (25% aq NH4-
To achieve the synthesis of ent-3, another strategy as
described in Scheme 1 was adopted. Thus as shown in Scheme
4, N-protected aminoaldehyde 10 was first subjected to reductive
aminocyclization (ammonium formate, 10% Pd/C, methanol at
reflux) to afford piperidine ring skeleton that on selective N-Cbz
protection gave bicyclic oxapiperidine 12 (85% yield over two
steps).12 In the next step, hydrolysis of 1,2-acetonide functional-
ity in 12 with TFA-water and reduction of C1-aldehyde with
sodium borohydride in THF-water yielded N-Cbz protected
piperidine 13. In the final step, hydrogenolysis of 13 using 10%
Pd/C in methanol at 80 psi afforded (3R, 4R)-3,4-dihydroxy-
4-((S)-1,2-dihydroxyethyl)piperidine (ent-3) as a thick liquid.
For the synthesis of γ-hydroxymethyl substituted piperidine
4, it was necessary to protect the tertiary hydroxyl functionality.
Thus, treatment of 12 with sodium hydride and benzyl bromide
in THF afforded benzylated product 14 (Scheme 4). In the next
step, removal of 1,2-O-isopropylidene functionality in 14 with
TFA-water followed by oxidative cleavage of the resultant
hemiacetal with NaIO4 and subsequent reduction using sodium
borohydride gave N-Cbz protected hydroxymethyl piperidine
15. Finally, hydrogenolysis of 15 (ammonium formate and 10%
Pd/C, methanol reflux) afforded (3R, 4S)-3,4-Dihydroxy-4-
hydroxymethyl piperidine (4) as a thick liquid.
25
OH/MeOH ) 1/9); [R]D +12 (c 0.65, MeOH); IR (neat) 3600-
2900 (br) cm-1; 1H NMR (300 MHz, D2O) δ 1.68-1.89 (m, 2H),
2.75-3.00 (m, 3H), 3.05 (dd, J ) 14.1, 1.8 Hz, 1H), 3.61 (br s,
1H), 3.62 (dd, J ) 11.1, 7.8 Hz, 1H), 3.72 (dd, J ) 7.8, 2.7 Hz,
1H), 3.85 (dd, J ) 11.1, 2.7 Hz, 1H); 13C NMR (75 MHz, D2O) δ
28.5, 39.7, 46.7, 61.2, 67.4, 72.3, 75.4. Anal. calcd for C7H15NO4:
C, 47.45; H, 8.53; Found: C, 47.70; H, 8.85.
(2R,3R,3aR,7aR)-2,3-O-Isopropylidene-3a-hydroxy-6-(benzyl-
oxycarbonyl) octahydrofuro[2,3-c]pyridine (12). Reductive ami-
nocyclization of 10 (0.10 g, 0.21 mmol), 10% Pd/C (0.05 g), and
ammonium formate (0.07 g, 1.09 mmol) in dry methanol (5 mL)
as described for 3 afforded crude amine as a thick liquid: Rf 0.30
(chloroform/methanol ) 1/1). Selective N-Cbz protection of amine
as described for 8 and purification by column chromatography (n-
hexane/ethyl acetate ) 9/1) gave 12 (0.065 g, 85% over two steps)
In conclusion, we have adroitly exploited the carbon skeleton
of D-glucose to introduce otherwise difficult 1,2-dihydroxyethyl
(12) While our work was in progress, Hanessian et al. have reported the
synthesis of 3a-methoxy-N-Bus bicyclic oxapiperidine, analogous to
compound 12, using different methodology, see: Loiseleur, O.; Ritson, D.;
Nina, M.; Crowley, P.; Wagner, T.; Hanessian, S. J. Org. Chem. 2007, 72,
6353-6363.
25
as a thick liquid: Rf 0.40 (n-hexane/ethyl acetate ) 1/1); [R]D
+1 (c 10.0, CHCl3); IR (neat) 3421, 1693 cm-1;1H NMR (300 MHz,
CDCl3) δ 1.35 (s, 3H), 1.40-1.78 (m, 2H), 1.55 (s, 3H), 1.80-
2.60 (br s, 1H), 2.83-3.21 (m, 2H), 3.58-3.68 (m, 1H), 3.86-
3286 J. Org. Chem., Vol. 73, No. 8, 2008

4.20 (br s, 2H), 4.34-4.56 (m, 1H), 5.00-5.23 (m, 2H), 5.72 (br
s, 1H), 7.30-7.42 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 26.2
(s), 29.8, 38.6, 42.0, 66.8, 73.6, 74.4, 82.3, 103.2, 112.1, 127.2,
127.4 (s), 128.0 (s), 136.2, 155.3. Anal. calcd for C18H23NO6: C,
61.88; H, 6.64; Found: C, 62.04; H, 6.90.
thick oil. Treatment of hemiacetal with sodium metaperiodate as
described for 10 afforded an aldehyde as a thick liquid: Rf ) 0.35
(n-hexane/ethyl acetate ) 4/1), which on subsequent sodium
borohydride reduction as describe for 13 and purification by column
chromatography (n-hexane/ethyl acetate ) 4/1) gave 15 (0.23 g,
68% over three steps) as a thick liquid: Rf 0.25 (n-hexane/ethyl
(3R,4R)-3,4-Dihydroxy-4-((S)-1,2-dihydroxyethyl)-N-benzyl-
oxycarbonyl Piperidine (13). A solution of 12 (0.10 g, 0.28 mmol)
in TFA-water (2 mL, 3:1) was stirred for 3 h at 0 °C. TFA was
coevaporated with toluene to furnish a thick liquid. To an ice-cooled
solution of hemiacetal (0.08 g, 0.28 mmol) in THF-water (4 mL,
4:1) was added sodium borohydride (0.01 g, 0.34 mmol) in two
portions and stirred for 30 min at 0 °C. The reaction mixture was
quenched with saturated aq NH4Cl solution. THF was evaporated
under reduced pressure, extracted with ethyl acetate (10 mL × 3),
and concentrated. Purification by column chromatography (n-
hexane/ethyl acetate ) 3/7) gave 13 (0.06 g, 70% over two steps)
25
acetate ) 1/1); [R]D -14 (c 2.30, CH2Cl2); IR (CH2Cl2) 3580-
2900 (br), 1691 cm-1; 1H NMR (300 MHz, CDCl3 + D2O) δ 1.51-
1.92 (m, 2H), 3.00-4.20 (m, 7H), 4.32-4.55 (m, 2H), 5.18 (br s,
2H), 7.18-7.28 (m, 10H); 13C NMR (75 MHz, CDCl3 + D2O) δ
24.7, 39.2, 62.5, 63.2, 67.1, 71.2, 76.2, 127.0, 127.5 (s), 127.7,
128.2 (s), 136.3, 138.1, 156. Anal. calcd for C21H25NO5: C, 67.91;
H, 6.78; Found: C, 68.10; H, 6.80.
(3R,4S)-3,4-Dihydroxy-4-hydroxymethyl Piperidine (4). Reac-
tion of 15 (0.10 g, 0.26 mmol) with 10% Pd/C (0.05 g) and
ammonium formate (0.05 g, 0.80 mmol) in dry methanol (5 mL)
as described for 3 and purification by column chromatography
(methanol) gave 4 (0.03 g, 84%) as a thick liquid: Rf 0.20 (25%
25
as a thick liquid: Rf 0.25 (n-hexane/ethyl acetate ) 0/10); [R]D
-24 (c 0.50, MeOH); IR (neat) 3600-2900 (br), 1691 cm-1; H
1
25
NMR (300 MHz, D2O) δ 1.82 (br s, 2H), 2.97-3.20 (m, 1H), 3.24-
3.42 (m, 1H), 3.60-3.80 (m, 3H), 3.82-4.15 (m, 3H), 5.16 (br s,
2H), 7.45 (br s, 5H); 13C NMR (75 MHz, D2O) δ 28.5, 39.3, 46.3,
61.3, 67.7, 68.0, 72.6, 75.2, 127.9 (s), 128.5, 128.9 (s), 136.5, 157.4.
Anal. calcd for C15H21NO6: C, 57.87; H, 6.80; Found: C, 58.16;
H, 7.04.
aq NH4OH/MeOH ) 1/9); [R]D -19 (c 0.50, MeOH); IR (neat)
1
3590-2900 (br) cm-1; H NMR (300 MHz, D2O) δ 1.42-1.53
(br d, J ) 14.4 Hz, 1H), 1.80 (ddd, J ) 14.4, 9.3, 5.7 Hz, 1H),
2.74-2.90 (m, 3H), 3.07 (dd, J ) 13.8, 2.1 Hz, 1H), 3.52 (d, J )
12.0 Hz, 1H), 3.65(br s, 1H), 3.68 (d, J ) 12.0 Hz, 1H); 13C NMR
(75 MHz, D2O) δ 28.9, 40.1, 46.9, 65.4, 68.3, 72.0. Anal. calcd
for C6H13NO3: C, 48.97; H, 8.90; Found: C, 49.17; H, 9.11.
(3R,4R)-3,4-Dihydroxy-4-((S)-1,2-dihydroxyethyl)piperidine
(ent-3). To a solution of 13 (0.08 g, 0.25 mmol) in dry methanol
(5 mL) was added 10% Pd/C (0.04 g), and the solution was
hydrogenated at 80 psi for 12 h. The catalyst was filtered, washed
with methanol, and the filtrate was concentrated. Purification by
column chromatography (methanol) gave ent-3 (0.03 g, 82%) as a
thick liquid: Rf 0.14 (25% aq NH4OH/MeOH ) 1/9); [R]D25 -11
Acknowledgment. We are grateful to Prof. M. S. Wadia
for helpful discussions. We are thankful to UGC, New Delhi,
for the Junior Research Fellowship to R.S.M., CSIR, New Delhi,
for the Senior Research Fellowship to A.K.S., and University
Seed Money, BCUD, University of Pune, Pune for the financial
support.
(c 0.65, MeOH); IR (Neat) 3600-2900 (br) cm-1 1H NMR (300
;
MHz, D2O) δ 1.58-1.78 (m, 2H), 2.66-2.88 (m, 3H), 2.95 (br d,
J ) 14.1 Hz, 1H), 3.51 (br s, 1H), 3.52 (dd, J ) 10.8, 8.4 Hz, 1H),
3.59 (dd, J ) 8.1, 2.4 Hz, 1H), 3.73 (dd, J ) 10.8, 2.4 Hz, 1H);
13C NMR (75 MHz, D2O) δ 28.4, 39.8, 46.7, 61.2, 67.3, 72.3, 75.4.
Anal. calcd for C7H15NO4: C, 47.45; H, 8.53; Found: C, 47.75;
H, 8.82.
Supporting Information Available: General experimental
methods, experimental procedure, spectral and analytical data for
1
compounds 7, 9, 10, 11, and 14, and copies of H and 13C NMR
spectra of compounds 7, 8, 9, 10, 11, 3, 12, 13, ent-3, 14, 15, and
4. This material is available free of charge via the Internet at
http://pubs.acs.org.
(3R,4S)-3,4-Dihydroxy-4-hydroxymethyl-N-benzyloxycarbo-
nyl Piperidine (15). Reaction of 14 (0.40 g, 0. 91 mmol) with
TFA-water (5 mL, 3:1) as described for 3 gave hemiacetal as a
JO800044R
J. Org. Chem, Vol. 73, No. 8, 2008 3287