Intramolecular reductive cyclization strategy to the synthesis of (-)-6-methyl-3-hydroxy-piperidine-2-carboxylic acid, (+)-6-methyl-(2- hydroxymethyl)-piperidine-3-ol and their glycosidase inhibitory activity

Article abstract of DOI:10.1016/j.bmc.2010.09.055

The first stereoselective synthesis of (2S,3R,6S)-6-methyl-3-hydroxy- piperidine-2-carboxylic acid (-)-6 and (2R,3R,6S)-6-methyl-(2-hydroxymethyl)- piperidine-3-ol (+)-7 was achieved starting from readily available d-glucose in 14 steps with 17% overall y

Full text of DOI:10.1016/j.bmc.2010.09.055

Bioorganic & Medicinal Chemistry 18 (2010) 7799–7803
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Intramolecular reductive cyclization strategy to the synthesis
of (ꢀ)-6-methyl-3-hydroxy-piperidine-2-carboxylic acid,
(+)-6-methyl-(2-hydroxymethyl)-piperidine-3-ol and their glycosidase
inhibitory activity
Vishwas U. Pawar a, Sanjay T. Chavan b, Sushma G. Sabharwal b, Vaishali S. Shinde a,
⇑
a Garware Research Centre, Department of Chemistry, University of Pune, Pune 411007, India
b Division of Biochemistry, Department of Chemistry, University of Pune, Pune 411007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The first stereoselective synthesis of (2S,3R,6S)-6-methyl-3-hydroxy-piperidine-2-carboxylic acid (ꢀ)-6
and (2R,3R,6S)-6-methyl-(2-hydroxymethyl)-piperidine-3-ol (+)-7 was achieved starting from readily
available D-glucose in 14 steps with 17% overall yield for both the compounds. The key feature of the
present strategy includes the Wittig-olefination for the preparation of required conjugated keto-azide
9 and construction of 2,3,6-trisubstituted piperidine skeleton 11 by applying intramolecular reductive
cyclization of conjugated keto-azide intermediate. The glycosidase inhibitory activity of compounds 6
and 7 towards several glycosidases has been evaluated.
Received 12 August 2010
Revised 21 September 2010
Accepted 22 September 2010
Available online 21 October 2010
Keywords:
Tri-substituted piperidines
Pipecolic acid
Ó 2010 Elsevier Ltd. All rights reserved.
Iminosugars
Glycosidase inhibitors
1. Introduction
In view of wide-range of biological and synthetic applications of
these alkaloids, a number of synthetic methods for alkyl substi-
Pipecolic acid 1 (piperidine-2-carboxylic acid)—a conforma-
tionally constrained non-proteinogenic amino acid and its alkyl
substituted derivatives are naturally occurring and present
in a number of biologically active compounds. For example,
(2S,5S,6S)-6-methyl-5-hydroxypipecolic acid 2a ( Fig. 1) and
(2S,5R,6S)-6-methyl-5-hydroxypipecolic acid 2b were isolated
from the fruits of Fagus silvatica.1 Alkyl pipecolic acid derivatives
are known to be thrombin inhibitor,2 dihydropicolinic acid syn-
tuted hydroxy piperidines have been developed.11,12 Recently,
Vankar and co-workers11a reported the syntheses of deoxopro-
sophylline (ꢀ)-3b, (+)-2-epideoxoprosopinine 5, and (2R,3R)- and
(2R,3S)-3-hydroxypipecolic acids starting from
D
-glycal with
HO
HO
4
5
6
3
2
thase inhibitors,3 N-methyl- -aspartic acid receptor agonist,4
D
1
OH
OH
OH
OH
N
N
H3C
H3C
N
H
2a
and antagonist.5 cis-6-Alkylpipecolic acids have also attracted
the attention of synthetic chemists because of their use as a
building block in the synthesis of biologically active molecules.6
3-Hydroxy, alkyl substituted pipecolic acid derivatives and their
reduced analogs such as prosophylline 3a, deoxoprosophylline
3b7,8 and b-1-C-butyl-galactonojirimycin 49 constitute the
common structural unit of a wide variety of natural alkaloids
and drugs. In fact, 3a, 3b, and 4 fall under the category of imi-
nosugars and are known to be potent glycosidase inhibitors,9
acetylcholinesterase inhibitors,10a antibacterial,10b–e antimy-
cotic,10b,d and DNA binding agents.10f
H
O
H
O
O
1
2b
OH
OH
OH
OH
HO
OH
R
R
N
H
N
H
OH
C4H9
N
H
4
(+)-5,
(+)-3a, R = (CH2)9COEt
(+)-3b, R = C12H25
R = (CH2)9COEt
OH
OH
O
OH
OH
H3C
H3C
N
H
N
H
(−)-6
(+)-7
⇑
Corresponding author. Tel.: +91 20 25601395; fax: +91 20 25691728.
E-mail address: vsshinde@chem.unipune.ac.in (V.S. Shinde).
Figure 1. Pipecolic acid and analogs.
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2010.09.055

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V. U. Pawar et al. / Bioorg. Med. Chem. 18 (2010) 7799–7803
chemoselective saturation of olefins and reductive aminations as
key steps. Purkayastha et al.12e,12f developed a novel, acid catalyzed
cascade of reactions for the synthesis of all-cis 6-tert-butyl-4-oxo-
pipecolic acid derivatives.
Most of the synthetic methods for pipecolic acid derivatives
starts from chiral amino acids, carbohydrates and also includes
asymmetric syntheses using expensive chiral ligands and transi-
tion metals. However, only one group reported the synthesis of
methyl substituted hydroxy pipecolic acids from protected threose
derivative.12g To the best of our knowledge, the syntheses of all-cis-
6-methyl-3-hydroxy-pipecolic acid 6 and its reduced analog 7
starting from carbohydrate precursor, are not available in the liter-
The conversion of 9 to piperidine ring skeleton is a one pot four
step sequence that probably involves reduction of carbon–carbon
double bond and azide functionality to get amine. Subsequently,
intramolecular aminocyclization gave cyclic imine 10 which
undergoes concomitant imine reduction to give piperidine analog
as a single diastereomer (based on the 1H NMR of crude sample)
which was isolated as N-Cbz protected derivative 11.
The stereochemical outcome in 11 was unambiguously assigned
on the basis of 1H–1H COSY (Supplementary Fig. 5-S7) and 2D-
NOESY (Supplementary Fig. 6-S8) correlation studies. The chemical
shift assignments and coupling constant values were obtained
from decoupling as well as 1H–1H COSY and 1H NMR, respectively,
and are given in Table 1.
ature. In present work, we utilized D-glucose for the synthesis of
all-cis configured (2S,3R,6S)-6-methyl-3-hydroxy-piperidine-2-
carboxylic acid 6 and (2R,3R,6S)-6-methyl-(2-hydroxymethyl)-
piperidine-3-ol 7 using intramolecular reductive aminocyclization
of azido-ketone 9 as a key step. The glycosidase inhibitory activity
of 6 and 7 was evaluated.
In the 2D-NOESY spectrum, C-7 methyl showed cross peaks
with the H-1, H-2 and each one of the proton from H-5/H-6 indi-
cating their close spatial proximity.
The formation of compound 11 could be explained from the
cyclic imine 10 as shown in Figure 2. The attack from the b-face
is hindered due to bulky furanose ring, hence hydrogen approaches
from less hindered
a-face to make C-7 methyl b-orientated with
2. Results and discussion
‘7S’ absolute configuration. To achieve the synthesis of target mol-
ecules, 1,2-acetonide group in 11 was hydrolyzed with TFA/H2O
(3:2) to afford anomeric mixture of hemiacetals that on oxidative
2.1. Synthesis of (ꢀ)-6 and (+)-7
cleavage using NaIO4 afforded
a-aminal 12 which was noticed to
As shown in Scheme 1, our synthetic strategy begins with
be unstable and directly used it for further reactions. Thus, com-
pound 12 on treatment with sodium chlorite and hydrogen perox-
ide gave N-Cbz protected pipecolic acid 13. In the final step,
hydrogenolysis in presence of catalytic amount of 10% Pd/C at
80 psi in methanol afforded 6-methyl-3-hydroxy-piperidine-2-car-
boxylic acid 6.
known azido-aldehyde 8 that was easily obtained from
D-glu-
cose according to known procedure.13 Treatment of 8 with the
1-(triphenylphosphoranylidene)-2-propanone14 in THF at 0 °C
afforded
a,b-unsaturated methyl ketone 9 as a mixture of E
and Z isomers in the ratio 09:91 as evident from the 1H NMR
of crude product.15 In the next step, hydrogenation of 9 in the
presence of 10% Pd/C in MeOH for 12 h at variety of pressure
conditions (80, 150, and 200 psi) afforded a complex mixture
of products. However, at 260 psi we observed a single product
(as evident from the TLC) that on treatment with CbzCl and
NaHCO3 gave 11.
Targeting the synthesis of hydroxymethyl derivative 7, a-aminal
12 was reduced with sodium borohydride in methanol to afford
N-Cbz protected diol 14 in good yield. Finally hydrogenolysis with
10% Pd/C in MeOH at 80 psi afforded the 6-methyl-(2-hydroxy-
methyl)-piperidine-3-ol 7 as a white solid. All the compounds were
characterized by spectral and analytical techniques, and the data
were found to be in good agreement with the assigned structures.
D-glucose
ref. 13
2.2. Glycosidase inhibitory activity
O
O
After the successful synthesis of 6 and 7, the inhibitory activities
of these compounds were studied against various glycosidases viz.
O
O
H
H3C
(c)
(a)
O
O
O
a
-galactosidase, b-galactosidase, b-glucosidase,
N-acetyl-b- -glucosaminidase (isolated from almond seeds),
-galactosidase (isolated from Geobacillus toebii BK 1) and -gluco-
a-mannosidase,
N3
N3
D
O
O
9
(b)
8
a
a
sidase from Baker’s yeast (Sigma Chemical Co.). The results are
summarized in Table 2.
OCHO
H
O
1
5
6
7
4
Compound 6 exhibited strong competitive inhibition of
cosidase from Baker’s yeast with Ki = 71 M and IC50 = 1150
On the other hand compound 6 showed non-competitive inhibi-
tory activity against -Galactosidase ( G. toebii BK 1) with
Ki = 26 M and IC50 = 180 M. However, compound 6 showed no
a-glu-
2
3
H3C
H3C
l
lM.
N
N
Cbz
Cbz
O
O
11
12
a
single diastereomer
l
l
inhibition against remaining five enzymes and also compound 7
showed no inhibition against any of the glycosidases screened.
Substitution of carboxylic acid group by hydroxymethyl group
(d)
(e)
OH
OH
O
OH
OH
H3C
N
H3C
N
Cbz
Cbz
Table 1
14
13
d and J values from 1H NMR spectrum of 11
(f)
(+)-7
(f)
(−)-6
Proton
d
J (Hz)
H-1
H-2
5.89 (d)
4.56 (d)
3.9 (J1,2
3.9 (J2,1
)
)
Scheme 1. Reagents and conditions: (a) CH3COCH@PPh3, THF, 0 °C, 2 h, 87%. (b)
(i) H2, Pd/C, MeOH, rt, 12 h, 260 psi, (ii) CbzCl, NaHCO3, MeOH/H2O (9:1), rt, 6 h,
91%. (c) TFA/H2O (3:2), 0 °C to rt, 1 h then NaIO4, acetone/water (8:2), 0 °C to rt,
1.5 h. (d) NaClO2, NaH2PO4, 30% H2O2, aq MeCN, 0 °C to rt, 10 h, 87%. (e) NaBH4,
MeOH, 0 °C, 1 h, 89%. (f) H2, Pd/C, MeOH, rt, 80 psi, 12 h, 97% for (ꢀ)-6, 93% for (+)-7.
H-3
H-4
H-7
C-7-methyl
4.46 (d)
7.2 (J3,4), 0 (J3,2)
—
—
4.63–4.68 (m)
4.08–4.12 (m)
1.16 (d)
6.3 (Jvicinal)

V. U. Pawar et al. / Bioorg. Med. Chem. 18 (2010) 7799–7803
7801
β-face
5
H
O
4
O
H
O
H
O
6
7
H
1
O
H
3
O
O
H
O
H3C
H3C
N
H3C
N
2
H
Cbz
Cbz
O
N
β-face addition
product
α-face addition product
10
(observed)
(not observed)
α-face
Figure 2. Facial selectivity and observed NOESY of 11.
Table 2
Inhibitory potencies of piperidines 6 and 7
Enzyme
6
7
a
a
IC50
(
lM)
Kib
(l
M)
IC50
(
lM)
Kib
(lM)
a
-Galactosidase
NI
NI
NI
NI
NI
1150
180
NI
NI
NI
NI
NI
71
26
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
b-Galactosidase
b-Glucosidase
a
-Manosidase
N-Acetyl-b- -glucosaminidase
-Glucosidase (Baker’s yeast)
-Galactosidase (Geobacillus toebii BK 1)
D
a
a
NI: no inhibition.
a
Less than 50% inhibition at 1 mM concentration of inhibitor.
No inhibition at 1 mM concentration of inhibitor. Data is average of three sets of assay performed.
b
(as in 7) led to complete loss in inhibitory activity against the given
enzymes.
with 3.5% solution of 2,4-dinitrophenylhydrazine in ethanol/
H2SO4 or with basic aqueous potassium permanganate solution.
4.1.1. 3-Azido-1,2-O-isopropylidene-3,5,6,8-tetradeoxy-
xylo-oct-5-(E:Z)-ene-furanos-7-ulose (9)
a-D-
3. Conclusion
To a stirred solution of azido aldehyde 8 (3.2 g, 15 mmol) in dry
THF (40 mL) was added the Wittig reagent (5.26 g, 16 mmol) at
0 °C. The reaction mixture was stirred for 2 h at the same temper-
ature. After completion of reaction (monitored by TLC), THF was
vacuum evaporated. 1H NMR of crude product showed Z as a major
isomer in 91:09 ratio. Column purification afforded mixture 9
(3.24 g, 85%) from which we have isolated the pure Z-isomer as
thick liquid and used for characterization. Data of the Z-isomer is
given below: Rf = 0.48 (ethyl acetate/hexane, 1.5:8.5); IR (thin film)
In conclusion, starting from readily available D-glucose and fol-
lowing a practical sequence of reactions, efficient synthetic route
to enantiopure and new compounds 6 and 7 have been developed.
This method is expected to be attractive alternative to the existing
methods for the synthesis of the similar piperidine alkaloids (e.g.,
alkaloids from Cassia and Prosopis species) having all syn configura-
tions by simply changing the Wittig reagent. Our work in this
direction is in progress. Among the title compounds, pipecolic acid
derivative (ꢀ)-6 showed a significant inhibitory activity against
2109, 1693, 1622 cmꢀ1 1H NMR (300 MHz, CDCl3) d 1.33 (s, 3H),
;
a
-glucosidase (Baker’s yeast) and a-galactosidase (G. toebii BK 1).
1.53 (s, 3H), 2.28 (s, 3H), 4.46 (d, J = 3.3 Hz, 1H), 4.64 (d,
J = 3.6 Hz, 1H), 5.48–5.51 (m, 1H), 5.94 (d, J = 3.9 Hz, 1H), 6.17
(dd, J = 6.0, 11.7 Hz, 1H), 6.40 (dd, J = 1.8, 11.7 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 26.3, 26.7, 31.1, 68.1, 78.4, 84.0, 104.7, 112.2,
128.3, 142.2, 198.4; Elem. Anal. Calcd for C11H15N3O4: C, 53.52;
H, 7.11; N, 16.59. Found: C, 53.61; H, 7.19; N, 16.73.
This finding could be a potential lead to further chemotherapeutic
applications.
4. Experimental
4.1. General
4.1.2. 2,2-Dimethylperhydro[1,3]dioxolo-N-benzyloxycarbonyl-
[40,50:4,5]furo[3,2-b]-7-methyl-pyridine (11)
Melting points were recorded with Thomas Hoover Capillary
melting point apparatus and are uncorrected. IR spectra were re-
corded with Shimadzu FTIR-8400 as a thin film or using KBr pellets
A solution of 9 (1.6 g, 6.3 mmol) in dry MeOH (20 mL) and 10%
Pd/C (0.05 g) was hydrogenated at 260 psi for 12 h at 25 °C. After
completion of the reaction, it was filtered through a Celite pad,
washed with MeOH, and concentrated on a rotavapor to give
amine as a single diastereomer (determined by 1H NMR of crude
sample), (crude wt 1.5 g). This crude amine was dissolved in
MeOH/H2O (41 mL; 9:1) and cooled to 0 °C. To this NaHCO3
(1.1 g, 12.7 mmol) was added followed by dropwise addition of
CbzCl (50% solution in toluene; 2.7 mL, 9.5 mmol). Reaction mix-
ture was stirred for 6 h at rt. Solvent was evaporated under re-
duced pressure and thick residue thus obtained was extracted in
ethyl acetate. Evaporation of solvent and column purification
(ethyl acetate/hexane, 1:9) afforded Cbz protected piperidine 11
and are expressed in cmꢀ1 1H (300 MHz) and 13C (75 MHz) NMR
.
spectra were recorded with Varian Mercury instrument using
CDCl3 or D2O as the solvent. Chemical shifts were reported in d unit
(ppm) with reference to TMS as an internal standard and J values
are given in hertz. 1H–1H COSY and decoupling experiments con-
firmed the assignments of the signals wherever required. Elemen-
tal analyzes were carried out with Thermo-Electron Corporation
CHNS analyzer Flash-EA 1112. Optical rotations were measured
using Jasco P1020 polarimeter with sodium light (589.3 nm) at
25 °C. Thin layer chromatography was performed on pre-coated
plates (0.25 mm, silica gel 60 F254). Visualization was made by
absorption of UV light or by thermal development after spraying

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V. U. Pawar et al. / Bioorg. Med. Chem. 18 (2010) 7799–7803
as a thick liquid (1.99 g, yield 91%): Rf = 0.38 (ethyl acetate/hexane,
acetate = 6.5/3.5 gave 14 as a thick liquid (0.32 g, 74% from 11):
2:8); ½a 2D5
ꢁ
+9 (c 1.23, CHCl3); IR (thin film) 1704, 1452 cmꢀ1
;
1H
Rf = 0.49 (ethyl acetate/hexane, 3:7); ½a D25
ꢁ
+16 (c 4.8, CHCl3); IR
NMR (300 MHz, CDCl3) d 1.16 (d, J = 6.3 Hz, 3H), 1.32 (s, 3H),
1.52–1.58 (m, 5H), 1.82–1.90 (m, 2H), 4.08–4.12 (m, 1H), 4.46 (d,
J = 7.2 Hz, 1H), 4.56 (d, J = 3.9 Hz, 1H), 4.63–4.68 (m, 1H), 5.19 (s,
2H), 5.89 (d, J = 3.9 Hz, 1H), 7.28–7.41 (m, 5H); 13C NMR
(75 MHz, CDCl3) d 22.3, 22.9, 23.5, 26.5, 27.1, 46.4, 60.5, 67.1,
73.5, 87.7, 104.8, 111.7, 126.8, 127.7, 127.8, 128.3, 136.5, 141.1,
156.1; Elem. Anal. Calcd for C19H25NO5: C, 65.69; H, 7.25; N,
4.03. Found: C, 65.89; H, 7.31; N, 4.16.
(thin film) br 3352, 1702 cmꢀ1 1H NMR (300 MHz, CDCl3) d 1.12
;
(t, J = 7.2 Hz, 3H),16 1.54–1.84 (m, 4H), 3.52–3.64 (m, 1H), 3.71–
3.81 (br s, 2H, D2O Ex.), 3.89–4.21 (m, 2H), 4.27–4.31 (m, 1H),
4.53–4.58 (m, 1H), 5.19 (s, 2H), 7.29–7.43 (m, 5H); 13C NMR
(75 MHz, CHCl3) d 20.2, 23.2, 28.1, 45.1, 55.4, 62.6, 67.4, 69.7,
127.72–136.44, 156.1; Elem. Anal. Calcd for C15H21NO4: C, 64.50;
H, 7.58; N, 5.01. Found: C, 64.52; H, 7.48; N, 5.13.
4.1.6. (2R,3R,6S)-6-Methyl-2-hydroxymethylpiperidin-3-ol (7)
The same procedure was adopted for the synthesis of 7 as used
to obtain 6. Column purification with methanol/chloroform (1:9)
afforded (+)-7 as a white solid. (0.072 g, 93%): mp 164–166 °C;
4.1.3. (2S,3R,6S)-N-Benzyloxycarbonyl-6-methyl-3-hydroxypip-
eridine-2-carboxylic acid (13)
An ice-cold solution of 11 (0.53 g, 1.5 mmol) in TFA-H2O
(5.0 mL, 3:2) was stirred for 1 h. Trifluoroacetic acid was co-evap-
orated with toluene using high vacuum to afford hemiacetal as a
thick liquid (crude wt 0.46 g) that was dissolved in acetone/water
(10 mL, 9:1), cooled to 0 °C. Sodium metaperiodate (0.48 g,
2.2 mmol) was added and reaction mixture was stirred for 1.5 h
at 25 °C. After completion of reaction, ethylene glycol (0.2 mL)
was added and solvent was evaporated. The residue thus obtained
Rf = 0.46 (methanol/chloroform, 3:7); ½a D25
ꢁ
+3 (c 2.1, MeOH); IR
(KBr, disk): 3374, 2934, 1048 cmꢀ1 1H NMR (300 MHz, D2O) d
;
1.36 (d, J = 6.3 Hz, 3H), 1.80 (m, 3H), 1.98 (m, 1H), 3.31 (m, 2H),
3.77 (dd, J = 8.7, 12.3 Hz, 1H), 3.86 (dd, J = 4.8, 11.8 Hz, 1H), 4.17
(br s, 1H); 13C NMR (75 MHz, D2O) d 18.2, 24.5, 28.7, 53.3, 59.8,
60.8, 61.9; Elem. Anal. Calcd for C7H15NO2: C, 57.90; H, 10.41; N,
9.65. Found: C, 57.81; H, 10.32; N, 9.77.
was extracted with chloroform (3 ꢂ 10 mL) to get
a-aminal 12 as a
thick liquid (crude wt 0.415 g). To a stirred solution of 12 (0.24 g,
0.87 mmol) in acetonitrile (6 mL) was added the solution of so-
dium dihydrogen phosphate (0.03 g, 0.17 mmol) in water (2 mL)
and 30% H2O2 (0.13 mL, 0.95 mmol). The mixture was cooled to
0 °C, and NaClO2 (0.12 g, 1.4 mmol) in water (3.5 mL) was added
dropwise over 30 min. The reaction mixture was stirred at 15 °C
and monitored by the evolution of oxygen with a bubbler con-
nected to the apparatus. After 10 h, the reaction was decomposed
by addition of a small amount of Na2SO4 (0.10 g) and extracted
with ethyl acetate (3 ꢂ 10 mL). Evaporation of solvent and column
purification with methanol/chloroform (0.5:9.5) gave 13 as a sticky
gum (0.23 g, 67% from 11): Rf = 0.41 (methanol/chloroform, 2:8);
Acknowledgment
We gratefully acknowledge University of Pune, Pune for finan-
cial support (BCUD/OSD/184-2009). We are grateful to Professor
M.S. Wadia for insightful discussions. VUP and STC are thankful
to UGC and CSIR (New Delhi, INDIA), respectively, for fellowships
in the form of SRF.
Supplementary data
This material can be found in the online version. Contained in
this are general experimental and inhibition assay methods, exper-
imental details for 9 and 1H and 13C NMR spectra of compounds 9,
11, 13, 14, (ꢀ)-6, and (+)-7, 1H–1H COSY and 2D-NOESY spectrum
½
a 2D5
ꢁ
ꢀ36 (c 3.2, CHCl3); IR (thin film) 1708, 1452 cmꢀ1
;
1H NMR
(300 MHz, CDCl3) d 1.15 (d, J = 7.2 Hz, 3H), 1.58–1.63 (m, 1H),
1.69–1.90 (m, 3H), 3.77–3.84 (m, 1H), 4.38 (m, 1H), 5.00 (d,
J = 5.9 Hz, 1H), 5.18 (s, 2H), 5.82–6.23 (br s, 2H, D2O Ex.),
7.31–7.39 (m, 5H); 13C NMR (75 MHz, CDCl3) d 17.9, 24.9, 28.8,
46.5, 54.8, 68.1, 68.5, 127.83–136.01, 156.7, 174.2; Elem. Anal.
Calcd for C15H19NO5: C, 61.42; H, 6.53; N, 4.78. Found: C, 61.53;
H, 6.65; N, 4.86.
of compounds 11, Lineweaver–Burk plot of 6 with
a-glucosidase
and a-galactosidase. Supplementary data associated with this arti-
cle can be found, in the online version, at doi:10.1016/
j.bmc.2010.09.055.
References and notes
1. (a) Kristensen, I.; Larsen, P. O.; Sorensen, H. Phytochemistry 1974, 13, 2803; (b)
Kristensen, I.; Larsen, P. O.; Olsen, C. E. Tetrahedron 1976, 32, 2799; (c) Kasai, T.;
Larsen, P. O.; Sorensen, H. Phytochemistry 1978, 17, 1911.
4.1.4. (2S,3R,6S)-3-Hydroxy-6-methylpiperidine-2-carboxylic
acid (ꢀ)-6
A solution of 13 (0.20 g, 0.68 mmol) and 10% Pd/C (0.025 g) in
methanol (8 mL) was stirred under H2 atmosphere at 80 psi for
12 h at 25 °C. The catalyst was filtered through pad of Celite. Sol-
vent evaporation afforded (ꢀ)-6 as a thick liquid (0.10 g, 97%):
2. (a) Okamoto, S.; Hijikata, A.; Kikumoto, R.; Tonomura, S.; Hara, H.; Ninomiya,
K.; Maruyama, A.; Sugano, M.; Tamao, Y. Biochem. Biophys. Res. Commun. 1981,
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Rf = 0.51 (methanol); ½a D25
ꢀ36 (c 2, H2O); IR (thin film); br 3352,
ꢁ
1702 cmꢀ1 1H NMR (300 MHz, D2O) d 1.39 (d, J = 6.4 Hz, 3H),
;
1.77–1.86 (m, 3H), 2.00–2.05 (m, 1H), 3.27–3.33 (m, 1H), 3.73 (br
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4.1.5. (2R,3R,6S)-N-Benzyloxycarbonyl-6-methyl-2-hydroxyme-
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major product, we obtained Z-isomer as a major product. The same Wittig
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could be attributed to lower reaction temperature (0 °C). See Ref. 14.
16. 1H and 13C NMR of the compound 14 showed a doubling of signals due to
restricted rotation around the C–N bond of N-Cbz functionality.