Aza-Claisen rearrangement of 2-C-hydroxymethyl glycals as a versatile strategy towards synthesis of isofagomine and related biologically important azasugars

Article abstract of DOI:10.1039/c2ob06851f

Synthesis of isofagomine has been achieved by implementation of aza-Claisen rearrangement of 2-C-hydroxymethyl glycals as a key step. The above rearrangement has also been utilized in the synthesis of biologically important polyhydroxylated piperidine frameworks such as isogalactofagomine, ent-isogalactofagomine and their analogues and some other azasugars as glycosidase inhibitors. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob06851f

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PAPER
Aza-Claisen rearrangement of 2-C-hydroxymethyl glycals as a versatile
strategy towards synthesis of isofagomine and related biologically important
azasugars†
Y. Suman Reddy, Pavan K. Kancharla, Rashmi Roy and Yashwant D. Vankar*
Received 3rd November 2011, Accepted 12th January 2012
DOI: 10.1039/c2ob06851f
Synthesis of isofagomine has been achieved by implementation of aza-Claisen rearrangement of 2-C-
hydroxymethyl glycals as a key step. The above rearrangement has also been utilized in the synthesis of
biologically important polyhydroxylated piperidine frameworks such as isogalactofagomine, ent-
isogalactofagomine and their analogues and some other azasugars as glycosidase inhibitors.
Introduction
Since the discovery of 1-deoxynojirimycin1 1 (DNJ), design and
synthesis of polyhydroxylated piperidines, also called aza sugars
or iminosugars, have gained huge importance in recent times.2,3
These molecules have been targets for possible therapeutic uses
ranging from diabetes,4 cancer,5 HIV6 and other metabolic dis-
orders.7 Among them Miglitol 2 (N-hydroxylethyl-1-deoxynojir-
imycin) and Zavesca 3 (N-butyl-1-deoxynojirimycin) are being
used as drugs in the treatment of type II diabetes and type I Gau-
cher’s disease respectively (Fig. 1). Isofagomine 4A is also
another important polyhydroxylated piperidine analogue,
designed by Bols et al.8 and is a selective and strong inhibitor of
β-glucosidase [Ki = 0.11 μM, sweet almonds].8,9 The rationale
behind the design of isofagomine is the fact that it could act as
an apparent transition state analogue that mimics the oxycarbe-
nium ion-like transition state in which the positive charge resides
at the anomeric carbon.9 The tartrate salt of isofagomine is a
designed drug for the treatment of Gaucher’s disease,10,11 which
apparently12 failed in phase III clinical trials. It is an active-site
inhibitor, and it increases GlcCerase activity by 3.0 0.6 fold in
N370S fibroblasts by several mechanisms.13 Furthermore, isoga-
lactofagomine 5, a stereoisomer of isofagomine, has been
reported to be a selective and potent inhibitor of β-galactosidases
[Ki = 0.004 μM, Aspergillus oryzae].14 Likewise, the L-fucosi-
dase inhibitor 6 was synthesized by Bols et al.15 and found to be
active in micromolar range (Ki = 6.4 μM, Human placenta). Ichi-
kawa et al16 have reported the synthesis of galactose-type
Fig. 1 Piperidine based imino- and azasugars.
azasugar 8 (Fig. 2), with an extra hydroxyl group at C-3, which
is a specific and potent inhibitor against β-galactosidase (Ki =
5.7 μM). Owing to the above mentioned importance and selec-
tive inhibition activities there has been an increased interest
towards the development of general and flexible methodologies
for the synthesis of such polyhydroxylated frameworks through a
common precursor.17
Aza-Claisen rearrangement (or Overman rearrangement) con-
stitutes a mild and powerful tool for the synthesis of several
nitrogen containing natural products in organic as well as in
medicinal chemistry.18 In this rearrangement the reaction of an
allylic alcohol with trichloroacetonitrile is carried out either
under thermal conditions or by Hg(II) or Pd(II) catalysis to form
allylic trichloroacetamide via the rearrangement of the corre-
sponding trichloroacetimidate.17d This rearrangement has also
been explored in the area of carbohydrate chemistry.18d,19,20
Thus, Nguyen et al.19 have utilized palladium-catalyzed aza-
Department of Chemistry, Indian Institute of Technology, Kanpur 208
016, India. E-mail: vankar@iitk.ac.in; Fax: +0091-512-259 7492;
Tel: +91-512-2597169
†Electronic supplementary information (ESI) available: Copies of 1H
NMR and 13C NMR spectra for all new compounds, and 2D-COSY,
NOE, DEPT-135 spectras of some selected compounds. See DOI:
10.1039/c2ob06851f
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Fig. 2 Strategy for the construction of biologically important azasugars.
Scheme 1 One-pot rearrangement of 2-hydroxyglycals.
Claisen rearrangement of glycals as a key step for the synthesis
of glycosyl urea derivatives. In these reactions, the C-3 free
hydroxyl group was reacted with trichloroacetonitrile under pal-
ladium catalysis to afford stereoselectively the 2,3-unsaturated α-
and β-N-glycosyl amides by introducing the nitrogen atom at the
anomeric center. It is well known that the presence of a nitrogen
atom at the anomeric carbon permits easy access towards the
synthesis of monocyclic21a,b,c and bicyclic iminosugars.21d,e
More recently, we reported21a the aza-claisen rearrangement of
gluco and galacto derived C-2 hydroxymethyl glycals (vide
infra) en route to some iminosugars. Thus, when 3,4,6-tri-O-
benzyl-2-C-hydroxymethyl galactal 13 (Scheme 1) was treated
with trichloroacetonitrile and NaH at room temperature, we
observed the formation of the rearranged trichloroacetamide 16
instead of the expected trichloroacetimidate 15. Clearly, the
imidate formation and subsequent rearrangement seem to occur
in the same pot without any catalysis or need of high tempera-
ture. We have shown the utility of these rearranged products in
the synthesis of L-allo-deoxynojirimycin and two new azasugars,
viz. 5-(hydroxymethyl) analogues of L-altro- and L-ido-deoxyno-
jirimycin21a and these were found to be moderate glycosidase
inhibitors. Our continued interest in developing newer
approaches towards the synthesis of glycosidase inhibitors,22,23
and the importance of isofagomine and its analogs (vide supra)
led us to explore the potential of the aza-Claisen rearrangement
of 2-C-hydroxymethyl glycals derived from D-arabinal, L-arab-
inal and D-xylal to synthesise isofagomine and related azasugars.
The retrosynthetic analysis for our approach is shown in
Scheme 2.
Results and discussion
Thus, our synthesis emanated from 3,4-di-O-benzyl-D-arabinal
18 (Table 1), derived from D-arabinose, which upon Vilsmeier–
Haack formylation using phosphoryl chloride and N,N-dimethyl-
formamide yielded the corresponding 2-formyl pentose glycal
19 in good yield which was characterised by its spectral data.
1
Thus, in its H NMR spectrum a sharp singlet around δ 9.35,
and in the 13C NMR spectrum a peak at δ 189 were observed.
Furthermore, in the IR spectrum a sharp band at 1621 cm−1 for
the conjugated formyl group was visible which asserted the for-
mation of the desired product. Reduction of aldehyde 19 with
sodium borohydride in methanol furnished the 2-C-hydroxy-
methyl 3,4-di-O-benzyl-D-arabinal 20 in 85% yield. The
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Scheme 2 Retrosynthetic analysis for the synthesis of common intermediate A.
Table 1 Conversion of 2-C-hydroxymethyl glycals into rearranged products
Entry
1
Glycal
Aldehyde
C-2 hydroxy glycal
1-Azido sugar
2
3
disappearance of the corresponding –CHO group signals in the
1H and 13C NMR spectra of compound 20 confirmed the for-
mation of the reduced product which was subjected to the aza-
Claisen rearrangement. Thus, treatment of 2-C-hydroxymethyl
3,4-di-O-benzyl-D-arabinal 20 with trichloroacetonitrile and NaH
in dichloromethane at room temperature provided an inseparable
mixture of α/β-N-glycosyl trichloroacetamidate 21a/b in 8.5 : 1.5
ratio and in 88% yield, as confirmed from the spectral data (see
Experimental section and ESI†).
Likewise, 3,4-di-O-benzyl-L-arabinal 22 and 3,4-di-O-benzyl-
D-xylal 26 were subjected to formylation24 followed by reduction
and treatment with trichloroacetonitrle to lead to rearrangement
furnishing the trichloroacetamides 25 and 29 respectively in
good yields.
With these rearranged products (glycosyl amides) in hand, we
turned our attention towards the conversion of these products
into polyhydroxylated sugar intermediates. For this purpose,
reduction of amide accompanied by ring opening was executed.
Thus, reaction of amide 21a/b with NaBH4 in EtOH resulted in
the formation of the corresponding free amine which was
immediately treated with di-tert-butyl dicarbonate to obtain Boc-
protected amine 30 (Scheme 3) in 80% yield. Mesylation of the
amino alcohol 30 proceeded smoothly affording 31 in good
yield. In our earlier report,21a we employed intramolecular SN2
cyclization that was triggered by the deprotection of –NHBoc
group using CF3COOH in CH2Cl2 followed by treatment with
K2CO3. But in the present study, to reduce the number of steps
and to retain the –NHBoc group for synthetic manipulations, we
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Scheme 3 Synthesis of azasugar 5.
have carried out one pot, intramolecular SN2 cyclization with
t-BuOK to obtain the cyclized product 32 in 90% yield. The
structure of the product was confirmed by spectral analysis. In its
1H-NMR spectrum the absence of –OMs peak at δ 2.91 and
appearance of [M + Na]+ peak at 432.2154 (calculated
432.2145) in its high resolution mass spectrum confirmed that
cyclization had occurred. It is expected that synthon 32 could be
easily converted into various targets by suitably functionalizing
the exocyclic double bond. In the present study, compound 32
was subjected to hydroboration–oxidation with 9-BBN/H2O2 to
lead to the monohydroxy compound 33 in 87% yield as a single
diastereomer. However, because of the presence of rotamers, the
determination of exact stereochemistry was difficult at this stage.
Thus, acetylation of 33 followed by removal of the NHBoc pro-
tection gave compound 34 whose spectral data, including COSY
and NOE experiments, permitted the assignment of the stereo-
chemistry at the newly generated stereocenter. Thus, in an NOE
experiment, irradiation of signal for H-5 at δ 3.54 enhanced the
signal H-3 at δ 1.99 and there was no enhancement of H-7and
H-7′ at δ 4.10. This confirmed the absolute configuration at the
newly generated stereocenter to be ‘R’. The reason for the selec-
tivity may be attributed to the selective hydroboration of 32 from
the β-face, possibly due to the preferential low energy equatorial
orientation of the bulky bicyclic boron in the four membered
transition state. Finally, deprotection of compound 33 was
carried out in two steps viz. hydrogenolysis of benzyl groups
using catalytic Pd(OH)2/C–H2 and deprotection of NHBoc
employing acidic conditions that gave the deprotected compound
5 in 89% yield. Spectral data for 5 were in complete agreement
with those reported in literature.14
These have also been found to be moderate glycosidase inhibi-
tors.26 We realized that olefin 32 could be an ideal precursor for
the synthesis of this molecule. Thus, compound 32 was sub-
jected to dihydroxylation using a catalytic amount of osmium
tetroxide and NMO to afford a diol 35 as a single diastereomer
(Scheme 4). It was oxidatively cleaved with sodium periodate
affording the corresponding ketone 36 whose reduction with
sodium borohydride followed by acetylation of the crude product
gave 37 as a single diastereomer. Deprotection of N-Boc was
carried out by using TFA in methylene chloride affording the
free amine in quantitative yield. The stereochemistry of the
newly generated hydroxyl group was confirmed by the COSY
and NOE experiments of 38 (Scheme 4). Thus, irradiation of the
signal for H-3 led to the enhancement of the signal for H-5
proton confirming the absolute configuration at the newly gener-
ated center to be S. These correlations revealed that the reduction
had only occurred from the less hindered side of the carbonyl
moiety. Finally, compound 37 was subjected to hydrogenolysis
under catalytic Pd(OH)2/C–H2 conditions, followed by treatment
with aq. 6 N HCl for the removal of acetate and –NHBoc protec-
tions to provide triol 7 which was characterized as its hydrochlo-
ride salt. Its spectral data were in complete agreement with those
reported in literature.26c,d
Compound 8 is a selective potent inhibitor (vide supra) and in
the present study we have achieved its synthesis from diol 35.
Thus, diol 35 was subjected to hydrogenolysis followed by
acid treatment to provide the polyhydroxylated azasugar 8
(Scheme 4) in 91% yield. The spectral data is in absolute match
with the literature data16 for it. Likewise, when compound 32
was subjected to hydrogenolysis and acid treatment it provided
the azasugar 9, which is a mirror image of the fucosidase inhibi-
tor 6, in 81% yield and the data was in complete agreement with
the previously reported data (Scheme 4).27
Kusano and co-workers isolated the piperidine triol25 7 and its
analogues from the Eupatoriumfortunei TURZ and found them
to be active components of the extracts of this plant.25 These are
traditionally used in Japanese and Chinese and folk medicines as
diuretic, antidiabetic, emmenagogue, and antipyretic agents.25
Likewise, glycosyl amides 29a/b were transformed into isofa-
gomine 4A and 5-epi-isofagomine 4B (Scheme 5). The reaction
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Scheme 4 Synthesis of azasugars 7, 8, 9.
of an anomeric mixture of 29a/b with NaBH4 in ethanol afforded
the ring opened free amine, –NHBoc protection of which furn-
ished 39 in 78% yield. Mesylation of this amino alcohol fol-
lowed by cyclization provided the expected product 41 in 95%
yield.14 Hydroboration of 41 with 9-BBN gave 42 as a mixture
of two epimers with D-gluco and L-idose configurations in quan-
titative yield.14 This mixture was subjected to hydrogenolysis
which resulted in the removal of the benzyl groups and upon
acid treatment the resulting product furnished isofagomine 4A
and 5-epi-isofagomine 4B in 89% yield (Scheme 5). Each of
these isomers was successfully separated by silica gel chromato-
graphy with 2-propanol–water–NH4OH (7 : 2 : 1, v/v) to afford
the faster moving isofagomine 4A and the slower moving 5-epi-
isofagomine 4B in a ratio of 8 : 2. Spectral data for 4A and 4B
were in complete agreement with those reported in literature.14,28
Further, azasugar 10 (Fig. 2, Scheme 6) is known to be a mod-
erate inhibitor of β-glucosidase.29a We realized that 41 could be
easily transformed into 10. Thus, compound 41 upon dihydroxy-
lation using a catalytic amount of osmium tetroxide and NMO
afforded a separable mixture of diastereomeric diols 43 and 44
in 9 : 1 ratio. Deprotection of the major isomer 43 was finally
carried out in two steps viz. hydrogenolysis of benzyl groups
using Pd(OH)2/C–H2 and NHBoc deprotection employing acidic
conditions gave the deprotected compound 10 in 80% yield
(Scheme 6). Spectral data for 10 was in complete agreement
with those reported in literature.29b
Similarly, glycosyl amide 25a/b was transformed into 2-
hydroxymethyl analogue and subsequent reactions gave the cor-
responding polyhydroxylated frameworks viz. ent-isogalactoiso-
fagomine 11 and its analogue 12 and fucosidase inhibitor 614
(Scheme 7) following the same sequence of reactions as
employed above for manipulating compound 32.
Conclusion
In summary, we have reported the facile aza-Claisen rearrange-
ment of 2-C-hydroxymethyl glycals to prepare α/β-N-glycosyltri-
chloroacetamidates. These sugar-derived trichloroacetamidates
were converted into biologically important polyhydroxylated
piperidine frameworks. The synthesis of isofagomine has been
achieved with modest (4 : 1) selectivity.
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Scheme 5 Synthesis of isofagomine 4A and 5-epi-isofagomine 4B.
Scheme 6 Synthesis of azasugar 10.
(3R,4S)-3,4-bis(Benzyloxy)-3,4-dihydro-2H-pyran-5-
carbaldehyde (19)
Experimental
Infrared spectra were recorded on Bruker FT/IR Vector 22 spec-
trophotometer. 1H and 13C NMR spectra were recorded on a
JEOL LA-400 (400 and 100 MHz respectively) spectrometer or
JEOL ECX-500 spectrometer (500 and 125 MHz respectively)
in solutions of CDCl3 using tetramethylsilane as the internal
standard. The mass spectra were recorded on a Waters HAB 213
Q Tof Premier Micromass spectrometer. Optical rotations were
recorded on an Autopol II automatic polarimeter at the wave-
length of sodium D-line (589 nm) at 28 °C. Column chromato-
graphy was performed on silica gel (100–200 mesh) and thin
layer chromatography (TLC) was performed on silica gel plates
made by using grade G silica gel obtained from s.d.fine-chem
Ltd., Mumbai or on Merck silica gel pre-coated plates. All sol-
vents and common reagents were purified by established
procedures.
POCl3 (5.17 g, 33.71 mmol) was added dropwise to a stirred sol-
ution of di-O-benzyl-D-arabinal 18 (2.5 g, 8.43 mmol) in dry
DMF (30 mL) at 0 °C under N2 atmosphere. The reaction
mixture was stirred for 30 min at the same temperature, brought
to room temperature and stirred for 18 h. After completion of the
reaction (TLC monitoring) the reaction mixture was transferred
to another round bottom flask containing aq. saturated sodium
bicarbonate and stirred vigorously for 2 h. The reaction mixture
was extracted with ethyl acetate (3 × 30 mL). The combined
organic extracts were washed with water, brine, dried over
Na2SO4 and the solvent was removed to obtain the crude vinyl
aldehyde 19 which was purified column chromatography. Yield:
73% (2.01 g), Rf: 0.4 (hexane : ethyl acetate, 4 : 1), yellow liquid,
[α]2D8 = +193.0 (c 1.0, CH2Cl2). IR(neat) νmax cm−1: 3063, 3031,
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Scheme 7 Synthesis of sugar some other azasugars.
2872, 1721, 1621, 1496, 1453, 1407, 1376, 1301, 1270, 1229,
1202, 1092, 972, 939, 779, 740, 713. 1H NMR (400 MHz,
CDCl3): δ 9.35 (s, 1H), 7.41–7.24 (m, 11H, ArH, H-2), 4.75
(dd, 2H, J = 11.48 Hz, 11.72 Hz, –OCHPh), 4.69–4.68 (m, 1H),
4.64 (d, 1H, J = 11.96 Hz, –OCHPh), 4.49 (d, 1H, J = 11.96 Hz,
–OCHPh), 4.30 (t, 1H, J = 10.96 Hz), 4.23–4.19 (m, 1H),
3.68–3.63 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 189.0,
166.1, 138.6, 137.4, 128.4–127.4 (m, Ar–C), 119.3, 72.2, 70.9,
64.9, 63.6 HRMS (ESI): calcd for C20H20NaO4 [M + Na]+
347.1254; found 347.1255.
then quenched by the addition of saturated NH4Cl solution
(10 mL). Methanol was removed in vacuo, and the reaction
mixture was extracted with CH2Cl2 (3 × 15 mL). The combined
organic extracts were washed with water, brine, dried over
Na2SO4 and the solvent was removed to obtain the crude alcohol
20 which was purified by column chromatography. Yield: 85%
(1.28 g), Rf: 0.4 (hexane : ethyl acetate, 7 : 3), yellow liquid,
[α]2D8 = +49.0 (c 1.0, CH2Cl2). IR(neat) νmax cm−1: 3423, 3087,
3063, 3030, 2876, 1724, 1700, 1663, 1619, 1496, 1454, 1377,
1
1345, 1312, 1229, 1204, 1170, 1100, 1026, 739, 698. H NMR
(400 MHz, CDCl3): δ 7.38–7.29 (m, 10H, ArH), 6.42 (s, 1H),
4.94 (d, 1H, J = 11.24 Hz, –OCHPh), 4.71 (s, 2H, –OCHPh),
4.65 (d, 1H, J = 11.44 Hz, –OCHPh), 4.23 (d, 1H, J = 3.44 Hz),
4.05–3.93 (m, 4H), 3.83–3.78 (m, 1H), 1.65 (s, 1H). 13C NMR
(100 MHz, CDCl3): δ 144.7, 138.6, 137.9, 128.5–127.5 (m, Ar–
C), 111.9, 74.2, 73.3, 71.6, 69.7, 62.8, 61.9. HRMS (ESI): calcd
for C20H22NaO4 [M + Na]+ 349.1410; found 349.1417.
((3R,4S)-3,4-bis(Benzyloxy)-3,4-dihydro-2H-pyran-5-yl)
methanol (20)
NaBH4 (703 mg, 0.68 mmol) was added portionwise to a stirred
solution of aldehyde 19 (1.5 g, 4.62 mmol) in dry methanol
(25 mL) at 0 °C. The reaction mixture was stirred for 30 min and
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822, 740, 699, 678. 1H NMR (500 MHz, CDCl3, mixture of
anomers): δ 8.66 (d, J = 8.25 Hz, 0.2H), 7.39–7.28 (m, 12H,
ArH), 7.00 (d, 1H, J = 9.20 Hz), 5.87 (d, 1H, J = 9.20 Hz), 5.77
(d, 0.2H, J = 8.55 Hz), 5.33 (s, 0.2H), 5.23 (s, 1H), 5.17 (s,
0.2H), 5.10 (s, 1H), 4.73 (d, 1H, J = 12.55 Hz, –OCHPh), 4.68
(d, 0.2H, J = 13.75 Hz, –OCHPh), 4.58–4.55 (m, 1.2H), 4.44
(dd, 2H, J = 12.20 Hz, 12.25 Hz), 4.31 (d, 0.2H, J = 2.75 Hz),
4.27 (d, 1H, J = 2.75 Hz), 4.11 (t, 1H, J = 10.70 Hz), 4.01 (t,
0.2H, J = 11.00 Hz), 3.88 (dd, 1H, J = 11.00, 4.90 Hz),
3.80–3.75 (m, 0.2H), 3.67–3.61 (m, 0.2H), 3.60–3.57 (m, 1H).
13C NMR (125 MHz, CDCl3, mixture of anomers): δ 161.5,
161.2, 140.2, 137.8, 137.6, 137.4, 136.8, 128.6–127.7 (m, Ar–
C), 118.1, 114.1, 92.3, 79.0, 77.5, 77.4, 76.0, 75.9, 75.5, 75.0,
71.6, 71.3, 70.9, 69.5, 64.4, 58.6. HRMS (ESI): calcd for
C22H22Cl3NNaO4 [M + Na]+ 492.0507; found 492.0527.
N-((4S,5R)-4,5-bis(Benzyloxy)-3-methylenetetrahydro-2H-pyran-
2-yl)-2,2,2-trichloroacetamide (21a/b)
A
solution of 2-C-hydroxymethyl glycal 20 (500 mg,
1.53 mmol) in dichloromethane (12 mL) was cooled to 0 °C.
Trichloroacetonitrile (2.29 mmol, 332 mg) was added to it, fol-
lowed by the addition of NaH (1.83 mmol, 44 mg) in small por-
tions. The resulting mixture was stirred at 0 °C for 30 min. The
cooling bath was removed and stirring continued for 12 h. The
reaction mixture was quenched by adding saturated NH4Cl sol-
ution and extracted with dichloromethane (2 × 20 mL). The
combined organic extracts were washed with water and brine sol-
ution, dried over sodium sulfate, filtered and concentrated.
Column chromatography of the crude reaction mixture afforded
N-glycosyl trichloroacetamides 21a/b in 88% (635 mg) Yield.
α : β = 9 : 1, Rf: 0.45 (hexane : ethyl acetate, 9 : 1). IR (neat) νmax
cm−1: 3317, 3063, 3031, 2877, 1723, 1660, 1513, 1454, 1257,
1226, 1082, 1028, 932, 840, 822, 740, 699, 678. 1H NMR
(400 MHz, CDCl3, mixture of anomers): δ 8.54 (d, J = 8.5 Hz,
0.2H), 7.39–7.25 (m, 12H, ArH), 7.00 (d, 1H, J = 9.04 Hz),
5.87 (d, 1H, J = 9.28 Hz), 5.77 (d, 0.2H, J = 8.56 Hz), 5.34 (s,
0.2H), 5.24 (s, 1H), 5.18 (s, 0.2H), 5.11(s, 1H), 4.74 (d, 1H, J =
12.44 Hz, –OCHPh), 4.68 (d, 0.2H, J = 12.72 Hz, –OCHPh),
4.58–4.55 (m, 1.2H), 4.43 (dd, 2H, J = 12.20 Hz, 12.44 Hz),
4.30 (d, 0.2H, J = 3.00 Hz), 4.27 (d, 1H, J = 2.92 Hz), 4.12 (t,
1H, J = 10.72 Hz), 4.02 (t, 0.2H, J = 10.72 Hz), 3.88 (dd, 1H, J
= 10.96, 4.92 Hz), 3.80–3.75 (m, 0.2H), 3.67–3.61 (m, 0.2H),
3.60–3.57 (m, 1H). 13C NMR (125 MHz, CDCl3, mixture of
anomers): δ 161.3, 161.2, 137.8, 137.7, 137.6, 137.5, 136.8,
128.6–127.7 (m, Ar–C), 119.0, 114.1, 92.3, 79.0, 78.3, 77.5,
77.4, 76.0, 75.6, 75.1, 71.7, 71.3, 71.0, 69.6, 64.4, 58.6. HRMS
(ESI): calcd for C22H22Cl3NNaO4 [M + Na]+ 492.0507; found
492.0515.
((3R,4R)-3,4-bis(Benzyloxy)-3,4-dihydro-2H-pyran-5-yl)
methanol (28)
Compound 28 (806 mg, 80% yield) was obtained as a viscous
liquid from 27 (1.0 g, 3.08 mmol) using the same procedure
which was used to obtain 20. Rf: 0.4 (hexane : ethyl acetate,
7 : 3), yellow liquid, [α]2D8 = −70.8 (c 1.2, CH2Cl2). IR(neat)
νmax cm−1: 3432, 3062, 3030, 2868, 1666, 1604, 1496, 1454,
1399, 1348, 1304, 1249, 1204, 1171, 1094, 1058, 1027, 1001,
1
928, 738, 698. H NMR (500 MHz, CDCl3): δ 7.38–6.59 (m,
10H, ArH), 6.60 (s, 1H), 4.66–4.51 (m, 4H), 4.15–4.12 (m, 1H),
4.06–3.93 (m, 3H), 3.87 (d, 1H, J = 11.60 Hz), 3.70 (s, 1H),
1.71 (br s, 1H). 13C NMR (125 MHz, CDCl3): δ 145.2, 137.8,
137.6, 128.5–127.8 (m, Ar–C), 111.3, 71.8, 71.7, 71.2, 71.0,
63.7, 62.9. HRMS (ESI): calcd for C20H26NO4 [M + NH4]+
344.1856; found 344.1862.
N-((4R,5R)-4,5-bis(Benzyloxy)-3-methylenetetrahydro-2H-
((3S,4R)-3,4-bis(Benzyloxy)-3,4-dihydro-2H-pyran-5-yl)
pyran-2-yl)-2,2,2-trichloroacetamide (29a/b)
methanol (24)
Compound 29a/b (563 mg, 78% yield) was obtained as a
viscous liquid from 28 (500 mg, 1.53 mmol) using the same pro-
cedure which was used to obtain 21a/b. α : β = 1 : 1, Rf: 0.4
(hexane : ethyl acetate, 9 : 1). IR (neat) νmax cm−1: 3366, 2917,
Compound 24 (1.28 g, 85% yield) was obtained as a viscous
liquid from 23 (1.5 g, 4.62 mmol) using the same procedure
which was used to obtain 20. Rf: 0.4 (hexane : ethyl acetate,
7 : 3), yellow liquid, [α]D28 = −66.0 (c 1.25, CH2Cl2). IR(neat)
νmax cm−1: 3412, 3087, 3063, 3030, 2981, 2930, 2875, 1662,
1618, 1496, 1454, 1378, 1342, 1296, 1229, 1198, 1168, 1135,
1
1722, 1620, 1497, 1453, 1049, 822, 738, 697, 670. H NMR
(500 MHz, CDCl3, mixture of anomers): δ 8.43 (d, 1H, J = 8.25
Hz), 7.36–7.25 (m, 21H, ArH, –NHCOCl3), 5.91 (d, 1H, J =
9.20 Hz), 5.87 (d, 1H, J = 8.55 Hz), 5.45 (s, 1H), 5.39 (s, 1H),
5.25 (s, 1H), 5.23 (s, 1H), 4.66–4.55 (m, 6H), 4.49 (d, 1H, J =
11.60 Hz, –OCHPh), 4.34 (d, 1H, J = 11.90 Hz, –OCHPh),
4.15–4.07 (m, 3H), 3.99 (dd, 2H, J = 9.75 Hz, 12.85 Hz), 3.81
(d, 1H, J = 13.10 Hz), 3.63 (br s, 1H), 3.57 (br s, 1H). 13C NMR
(125 MHz, CDCl3, mixture of anomers): δ 161.4, 161.3, 139.0,
137.6, 137.6, 137.4, 136.5, 136.0, 128.7–127.6 (m, Ar–C),
119.3, 115.8, 92.5, 92.4, 79.4, 77.8, 77.4, 75.5, 74.4, 71.5, 71.3,
71.3, 71.2, 70.0, 65.8, 59.0. HRMS (ESI): calcd for
C22H22Cl3NNaO4 [M + Na]+ 492.0507; found 492.0510.
1
1101, 1051, 1025, 738, 698. H NMR (500 MHz, CDCl3): δ
7.39–7.25 (m, 10H, ArH), 6.42 (s, 1H), 4.95 (d, 1H, J = 11.20
Hz, –OCHPh), 4.71 (s, 2H, –OCHPh), 4.66 (d, 1H, J = 11.45
Hz, –OCHPh), 4.24 (d, 1H, J = 3.15 Hz), 4.04–3.93 (m, 4H),
3.83–3.79 (m, 1H), 1.68 (s, 1H). 13C NMR (125 MHz, CDCl3):
δ 144.8, 138.6, 138.0, 128.6–127.7 (m, Ar–C), 111.9, 74.2,
73.9, 71.7, 69.8, 62.9, 61.9. HRMS (ESI): calcd for
C20H22NaO4 [M + Na]+ 349.1410; found 349.1412.
N-((4R,5S)-4,5-bis(Benzyloxy)-3-methylenetetrahydro-2H-pyran-
2-yl)-2,2,2-trichloroacetamide (25a/b)
tert-Butyl (3S,4R)-3,4-bis(benzyloxy)-5-hydroxy-2-
methylenepentylcarbamate (30)
Compound 25a/b (635 mg, 88% yield) was obtained as a liquid
from 24 (500 mg, 1.53 mmol) using the same procedure which
was used to obtain 21a/b. α : β = 9 : 1, Rf: 0.45 (hexane : ethyl
acetate, 9 : 1). IR(neat) νmax cm−1: 3321, 3063, 3031, 2878,
1723, 1660, 1513, 1454, 1259, 1227, 1087, 1028, 932, 841,
NaBH4 (162 mg, 4.24 mmol) was added portionwise to a stirred
solution of compound 21a/b (500 mg, 1.06 mmol) in dry
ethanol (10 mL) at 0 °C. The reaction mixture was stirred for 2 h
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and then quenched by addition of saturated NH4Cl solution
(10 mL). Ethanol was removed in vacuo, and the crude reaction
mixture was extracted with ethyl acetate (3 × 30 mL). The com-
bined organic extracts were washed with water, brine, dried over
Na2SO4 and the solvent removed to obtain the crude amino
alcohol which was subjected to subsequent reaction without any
further purification. Thus, amino alcohol was taken in ethyl
acetate (10 mL) and cooled to 0 °C. It was then treated with satu-
rated NaHCO3 solution (10 mL) followed by Boc2O (0.28 mL,
1.48 mmol) and allowed the reaction mixture to stir for 4 h. It
was extracted with ethyl acetate (3 × 25 mL), washed with water,
brine, and dried over Na2SO4. Solvent evaporation followed by
purification through column chromatography gave compound 30
in 80% (365 mg, over 2 steps) yield as viscous liquid. Rf: 0.5
(hexane : ethyl acetate, 3 : 2), colorless liquid, [α]2D8 = +23.7 (c
1.2, CH2Cl2). IR (neat) νmax cm−1: 3423, 3063, 3031, 2976,
2928, 2872, 1696, 1510, 1454, 1391, 1366, 1250, 1207, 1169,
1071, 1028, 911, 737, 698. 1H NMR (500 MHz, CDCl3): δ
7.34–7.25 (m, 10H, ArH), 5.29 (s, 1H), 5.24 (s, 1H), 4.75 (br s,
1H), 4.61–4.55 (m, 3H, 3 × –OCHPh), 4.31 (d, 1H, J = 11.60
Hz, –OCHPh), 4.00 (d, 1H, J = 7.00 Hz), 3.75 (br s, 4H), 3.60
(br s, 1H), 2.22 (br s, 1H), 1.43 (s, 9H, –C(CH3)3). 13C NMR
(125 MHz, CDCl3): δ 155.9, 143.3, 137.9, 137.7, 128.5–127.9
(m, Ar–C), 115.8, 81.1, 80.0, 79.4, 72.7, 70.8, 61.9, 42.4, 28.5.
HRMS (ESI): calcd for C25H33NNaO5 [M + Na]+ 450.2251;
found 450.2255.
added to this reaction mixture. After stirring for 2 h at room
temperature, it was extracted with ethyl acetate (3 × 20 mL),
washed with water and brine, and dried over Na2SO4. Solvent
evaporation followed by purification through column chromato-
graphy gave compound 32 (183 mg, 90%) as viscous liquid. Rf:
0.6 (hexane : ethyl acetate, 4 : 1), colorless liquid, [α]2D8 = +9.2 (c
1.3, CH2Cl2). IR (neat) νmax cm−1: 3064, 3031, 2976, 2930,
2871, 1694, 1454, 1416, 1367, 1257, 1231, 1204, 1164, 1119,
1
1069, 1027, 737, 698. H NMR (500 MHz, CDCl3, mixture of
rotamers): δ 7.37–7.25 (m, 20H, ArH), 5.17 (br s, 1H), 5.11 (br
s, 1H), 5.02 (s, 2H), 4.63 (d, 3H, J = 12.50 Hz, –OCHPh), 4.57
(br s, 3H, –OCHPh), 4.40 (d, 2H, J = 12.55 Hz, –OCHPh), 4.17
(br s, 1H), 4.07 (s, 3H), 3.98 (br s, 1H), 3.74–3.70 (m, 3H),
3.46–3.43 (m, 4H), 1.44 (s, 18H). 13C NMR (125 MHz,
CDCl3): δ 154.7, 154.6, 139.6, 138.3, 128.4–127.6 (m, Ar–C),
115.3, 114.4, 80.0, 77.2, 75.6, 70.5, 69.6, 69.0, 45.7, 43.3, 42.0,
28.5. HRMS (ESI): calcd for C25H31NNaO4 [M + Na]+
432.2145; found 432.2154.
(3R,4S,5R)-tert-Butyl 3,4-bis(benzyloxy)-5-(hydroxymethyl)
piperidine-1-carboxylate (33)
a 0.5 M solution of 9-BBN (1.2 mL, 1.2 mmol) in THF was
added dropwise to a stirred solution of 32 (100 mg, 0.24 mmol)
in THF (4 mL) at 0 °C, and the reaction mixture was stirred for
20 h at room temperature and then cooled to 0 °C. To the cooled
mixture were successively added water (0.3 mL), 1 N NaOH sol-
ution (0.3 mL), and 30% H2O2 solution (0.3 mL) at 0 °C, and
the reaction mixture stirred for 12 h at room temperature. It was
diluted with water and extracted with EtOAc (3 × 15 mL). The
combined extracts were successively washed with water and
brine, dried, and concentrated. The residue was chromatographed
on silica gel to give 33 (91 mg, 87%) as a colorless liquid. Rf:
0.5 (hexane : ethyl acetate, 1 : 1), [α]2D8 = −16.9 (c 1.3, CH2Cl2).
IR (neat) νmax cm−1: 3438, 3063, 3030, 2975, 2927, 2875, 1690,
1454, 1426, 1366, 1239, 1168, 1141, 1097, 1065, 1027, 883,
(2R,3S)-2,3-bis(Benzyloxy)-4-((tert-butoxycarbonylamino)
methyl)pent-4-enyl methanesulfonate (31)
Et3N (0.19 mL, 1.4 mmol) was added to a solution of amino
alcohol 30 (300 mg, 0.70 mmol) in CH2Cl2 (6 mL) cooled to
0 °C. Methanesulfonyl chloride (0.08 mL, 1.05 mmol) was
added dropwise to the reaction mixture and then allowed to stir
for 2 h at same temperature. The reaction mixture was quenched
by the addition of saturated NaHCO3 solution, extracted with
CH2Cl2 (3 × 20 mL). The combined organic extracts were
washed with water and brine and dried over anhydrous Na2SO4.
Solvent removal followed by column chromatography afforded
the mesylated compound 31 (306 mg, 86%) as a colorless liquid.
Rf: 0.6 (hexane : ethyl acetate, 3 : 2), [α]2D8 = +15.62 (c 1.6,
CH2Cl2). IR (neat) νmax cm−1: 3418, 3064, 3031, 2977, 2933,
1710, 1510, 1454, 1391, 1356, 1249, 1174, 1092, 1027, 966,
1
736, 698. H NMR (500 MHz, CDCl3): δ 7.37–7.25 (m, 10H,
ArH), 4.91–4.70 (m, 2H), 4.62 (d, 4H, J = 11.60 Hz, –OCHPh),
3.97 (br s, 2H), 3.68 (br s, 2H), 3.50 (br s, 1H), 3.38–3.16 (m,
1H), 1.90–1.80 (m, 2H), 1.43 (s, 9H). 13C NMR (125 MHz,
CDCl3): δ 155.2, 138.5, 138.2, 128.3–127.2 (m, Ar–C), 79.8,
75.3, 73.2, 72.8, 71.0, 62.2, 61.2, 43.7, 41.8, 28.3. HRMS (ESI):
calcd for C25H33NNaO5 [M + Na]+ 450.2251; found 450.2258.
1
819, 740, 699, 528. H NMR (500 MHz, CDCl3): δ 7.34–7.25
(m, 10H, ArH), 5.31 (s, 1H), 5.25 (s, 1H), 4.72 (br s, 1H), 4.65
(d, 1H, J = 11.30 Hz, –OCHPh), 4.55 (dd, 2H, J = 11.60 Hz,
11.30 Hz, –OCHPh), 4.50 (dd, 1H, J = 11.00 Hz, 11.00 Hz),
4.34 (dd, 1H, J = 5.20 Hz, 5.20 Hz), 4.30 (d, 1H, J = 11.30 Hz,
–OCHPh), 3.96 (d, 1H, J = 5.55 Hz), 3.74 (d, 3H, J = 5.80 Hz),
2.91 (s, 3H), 1.43 (s, 9H). 13C NMR (125 MHz, CDCl3): δ
155.7, 142.7, 137.4, 137.3, 128.4–127.8 (m, Ar–C), 116.2, 79.3,
79.0, 78.0, 72.9, 70.6, 68.7, 42.2, 37.4, 28.3. HRMS (ESI):
calcd for C26H35NNaO7S[M + Na]+ 528.2026; found 528.2038.
((3R,4S,5R)-4,5-bis(Benzyloxy)piperidin-3-yl)methyl acetate (34)
Ac2O (0.01 mL, 0.16 mmol), Et3N (0.02 mL, 0.16 mmol) and a
catalytic amount of DMAP were added to a stirred solution of
compound 33 (50 mg, 0.11 mmol) in dry CH2Cl2 (4 mL) cooled
to 0 °C. After stirring for 2 h at room temperature, the usual
workup and chromatographic purification afforded the corre-
sponding acetate which was directly used for further reaction.
The residue was taken in CH2Cl2 (1 mL), cooled to 0 °C and
trifluroacetic acid (0.05 mL) was added. After stirring for 2 h,
the reaction mixture was neutralized with aq. Na2CO3 solution,
and extracted with CH2Cl2 (3 × 10 mL). Purification through
column chromatography afforded pure compound 34 (35 mg,
81%) as a colourless liquid. Rf: 0.2 (ethyl acetate) [α]2D8 = −6.45
(3R,4S)-tert-Butyl 3,4-bis(benzyloxy)-5-methylenepiperidine-1-
carboxylate (32)
Compound 31 (250 mg, 0.58 mmol) was dissolved in THF
(10 mL) and cooled to 0 °C. t-BuOK (130 mg, 1.16 mmol) was
2768 | Org. Biomol. Chem., 2012, 10, 2760–2773
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(c 1.55, CH2Cl2). IR (neat) νmax cm−1: 3441, 3063, 3030, 2924,
(d, 2H, J = 11.60 Hz, 2 × –OCHPh), 4.29 (br d, 2H, J = 18.30
Hz), 4.18–4.10 (m, 4H), 3.90 (d, 2H, J = 13.75 Hz), 3.76 (d,
2H, J = 12.50 Hz, 2 × –OCHPh), 3.64 (t, 2H, J = 14.40 Hz),
1.43 (s, 18H). 13C NMR (125 MHz, CDCl3): δ 202.8, 154.5,
137.5, 137.2, 128.4–127.6 (m, Ar–C), 82.5, 82.3, 80.9, 80.8,
74.3, 73.8, 72.5, 72.4, 71.9, 71.7, 53.4, 52.3, 47.4, 46.0, 28.2.
HRMS (ESI): calcd for C24H29NNaO5 [M + Na]+ 434.1938;
found 434.1945.
2854, 1739, 1606, 1496, 1453, 1367, 1245, 1093, 1064, 1028,
1
737, 699. H NMR (500 MHz, CDCl3): δ 7.34–7.25 (m, 10H,
ArH), 4.88 (d, 1H, J = 11.15 Hz, –OCHPh), 4.66 (s, 2H,
–OCHPh), 4.58 (d, 1H, J = 11.70 Hz, –OCHPh), 4.10 (br s, 2H,
H-7, H-7′), 3.92 (br s, 1H, H-4), 3.55–3.53 (m, 1H, H-5), 3.08
(dd, 1H, J = 9.45 Hz, 9.15 Hz, H-6), 2.98–2.96 (m, 1H, H-6′),
2.79 (t, 1H, J = 10.30 Hz, H-2), 2.72 (dd, 1H, J = 4.00 Hz, 8.35
Hz, H-2′), 2.63 (s, 1H, H-1), 2.00–1.95 (m, 4H, H-3, –OAc).
13C NMR (125 MHz, CDCl3):
δ
170.9, 138.7, 138.4,
(3S,4R,5R)-tert-Butyl 3-acetoxy-4,5-bis(benzyloxy)piperidine-1-
128.4–127.3 (m, Ar–C), 78.3, 74.4, 73.2, 71.2, 63.1, 45.2, 43.2,
40.3, 29.6, 20.9. HRMS (ESI): calcd for C22H28NO4 [M + H]+
370.2013; found 370.2018.
carboxylate (37)
To a stirred solution of compound 36 (100 mg, 0.24 mmol) in
methanol (3 mL) cooled to 0 °C was added NaBH4 (14 mg,
0.36 mmol). The reaction mixture was stirred at same tempera-
ture for 30 min and then quenched with saturated NH4Cl sol-
ution. The reaction mixture was concentrated under high vacuum
to remove methanol. Aqueous phase was extracted with ethyl
acetate (3 × 10 mL), combined organic extracts were washed
with water and brine and dried over anhydrous Na2SO4. After
concentration, crude residue was directly subjected to acetylation
in dry CH2Cl2 (2 mL) using Ac2O, Et3N and a catalytic amount
of DMAP. After stirring for 4 h at room temperature, usual
workup and chromatographic purification afforded acetate 37
(100 mg, 90%) as a colorless liquid. Rf: 0.6 (hexane : ethyl
acetate, 3 : 1), [α]D28 = −12.94 (c 0.85, CH2Cl2). IR (neat) νmax
cm−1: 3064, 3030, 2976, 2930, 1739, 1697, 1496, 1454, 1417,
1367, 1320, 1229, 1167, 1100, 1047, 1028, 987, 953, 911, 882,
(3S,4R,5R)-tert-Butyl 4,5-bis(benzyloxy)-3-hydroxy-3-
(hydroxymethyl)piperidine-1-carboxylate (35)
To a stirred solution of compound 32 (200 mg, 0.48 mmol) in
acetone : water: t-BuOH (4 mL, 1 : 1 : 0.5) at room temperature
were added NMO (66 mg, 0.56 mmol) and OsO4 (25 mg mL−1
solution in t-BuOH, 0.02 mL, 0.002 mmol). The reaction
mixture was stirred for 48 h and then treated with Na2S2O5
(106 mg, 0.56 mmol). The reaction mixture was stirred for
further 0.5 h and extracted with ethyl acetate (3 × 20 mL). The
combined organic extracts were washed with water and finally
with brine. Evaporation of the organic layer followed by purifi-
cation through column chromatography gave compound 35
(206 mg, 95%). Rf: 0.5 (hexane : ethyl acetate, 1 : 1), white solid,
[α]2D8 = −32.25 (c 1.55, CH2Cl2). IR (neat) νmax cm−1: 3432,
3088, 3064, 3029, 3005, 2975, 2929, 1670, 1495, 1455, 1429,
1367, 1306, 1272, 1239, 1209, 1163, 1118, 1090, 1073, 1041,
1
738, 698. H NMR (400 MHz, CDCl3): δ 7.38–7.25 (m, 10H,
ArH), 4.84 (d, 1H, J = 11.96 Hz, –OCHPh), 4.70–4.55 (m, 4H),
4.12 (br s, 1H), 3.95–3.82 (m, 1H), 3.46 (br s, 3H), 3.25–3.10
(m, 1H), 2.01 (s, 3H), 1.44 (s, 9H). 13C NMR (125 MHz,
CDCl3): δ 170.2, 154.8, 138.8, 138.1, 128.5–127.4 (m, Ar–C),
80.3, 75.5, 74.8, 74.7, 74.1, 71.2, 69.7, 41.2, 28.4, 21.1. HRMS
(ESI): calcd for C26H33NNaO6 [M + Na]+ 478.2206; found
478.2208.
1
1027, 879, 737, 698. H NMR (400 MHz, CDCl3): δ 7.34–7.25
(m, 10H, ArH), 4.79 (d, 1H, J = 11.30 Hz, −OCHPh),
4.64–4.57 (m, 3H, 3 × –OCHPh), 3.83 (br s, 2H), 3.71 (br d,
4H, J = 14.00 Hz), 3.50 (br s, 2H), 3.26 (br s, 1H), 3.01 (br s,
1H), 1.41 (s, 9H). 13C NMR (125 MHz, CDCl3): δ 156.2, 155.6,
138.4, 138.1, 128.3–127.2 (m, Ar–C), 80.3, 79.4, 79.3, 79.2,
74.3, 74.0, 73.6, 73.2, 73.1, 71.1, 65.6, 64.7, 47.0, 44.3, 28.4.
HRMS (ESI): calcd for C25H33NNaO6 [M + Na]+ 466.2200;
found 466.2205.
(3S,4R,5R)-4,5-bis(Benzyloxy)piperidin-3-yl acetate (38)
Compound 38 (32 mg, 82% yield) was obtained from 37
(50 mg, 0.10 mmol) using the procedure which was used to
obtain 34. Rf: 0.2 (ethyl acetate), [α]2D8 = +25.33 (c 0.75,
CH2Cl2). IR (neat) νmax cm−1: 3329, 3063, 3030, 2930, 2867,
1738, 1496, 1453, 1365, 1242, 1160, 1095, 1048, 1028, 981,
(3R,4R)-tert-Butyl 3,4-bis(benzyloxy)-5-oxopiperidine-1-
carboxylate (36)
1
946, 738, 698. H NMR (500 MHz, CDCl3): δ 7.33–7.25 (m,
10H, ArH), 4.80 (d, 1H, J = 12.05 Hz, –OCHPh), 4.73–4.69 (m,
2H, H-2, H-3), 4.69–4.55 (m, 3H, –OCHPh) 4.05 (br s, 1H,
H-1), 3.47 (br s, 1H, H-5), 3.05–3.00 (m, 2H, H-2′, H-6′), 2.03
(s, 3H, –OAc). 13C NMR (125 MHz, CDCl3): δ 170.4, 138.8,
138.3, 128.6–127.3 (m, Ar–C), 75.2, 73.6, 73.4, 71.2, 71.0,
44.8, 44.3, 21.1. HRMS (ESI): calcd for C21H26NO4 [M + H]+
356.1856; found 356.1860.
NaIO4 (106 mg, 0.49 mmol) dissolved in water was added to a
solution of diol 35 (150 mg, 0.33 mmol) in methanol (3 ml) at
0 °C. The reaction mixture was stirred for 30 min at room temp-
erature. Water was added to the reaction mixture and solvent
evaporated in vacuo. The residue was extracted with ethyl
acetate (3 × 10 mL) and the combined organic layers were
washed with brine and concentrated. The residual oil was
purified by silica gel chromatography to give the ketone 36
(134 mg, 96%) as a colorless liquid. Rf: 0.7 (hexane : ethyl
acetate, 7 : 3), [α]D28 = +15.55 (c 1.35, CH2Cl2). IR (neat) νmax
cm−1: 3064, 3032, 2977, 2931, 1739, 1698, 1455, 1395, 1368,
tert-Butyl (3R,4R)-3,4-bis(benzyloxy)-5-hydroxy-2-
methylenepentylcarbamate (39)
1
1251, 1206, 1156, 1027, 738, 698. H NMR (500 MHz, CDCl3,
mixture of rotamers): δ 7.35–7.25 (m, 20H, ArH), 4.90 (dd, 2H,
J = 12.50 Hz, 11.95 Hz), 4.74–4.64 (m, 4H, 4 × –OCHPh), 4.67
Compound 39 (355 mg, 78% yield) was obtained as a colorless
liquid from 29a/b (500 mg, 1.06 mmol) using the same pro-
cedure which was used to obtain 30. Rf: 0.5 (hexane : ethyl
This journal is © The Royal Society of Chemistry 2012
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acetate, 3 : 1), colorless liquid, [α]2D8 = −9.4 (c 0.85, CH2Cl2). IR
(neat) νmax cm−1: 3423, 3063, 3030, 2976, 2929, 2871, 1696,
1511, 1454, 1391, 1281, 1251, 1169, 1088, 1071, 1028, 912,
1314, 1249, 1158, 1097, 1027, 895, 736, 698. 1H NMR
(400 MHz, CDCl3, rotameric mixture of 42 and 42′): δ
7.36–7.25 (m, 10H, ArH), 4.90–4.80 (m, 1H), 4.71–4.64 (m,
2H), 4.58 (d, 1H, J = 11.72 Hz, –OCHPh), 3.80–3.47 (m, 8H),
1.90–1.69 (m, 2H), 1.43 (br s, 9H). 13C NMR (125 MHz,
CDCl3, rotameric mixture of 42 and 42’): δ 155.2, 155.4, 138.2,
138.0, 128.5–127.6 (m, Ar–C), 80.0, 79.8, 78.8, 79.7, 77.8,
73.5, 72.1, 71.7, 61.6, 61.1, 44.8, 44.5, 42.9, 42.6, 42.2, 41.3,
38.4, 28.3, 14.1. HRMS (ESI): calcd for C25H34NO5 [M + H]+
428.2431; found 428.2437.
1
736, 698. H NMR (500 MHz, CDCl3): δ 7.33–7.25 (m, 10H,
ArH), 5.23 (d, 2H, J = 13.75 Hz), 4.81 (d, 2H, J = 11.65 Hz),
4.65 (d, 1H, J = 11.65 Hz), 4.59 (d, 1H, J = 11.60 Hz), 4.35 (d,
1H, J = 11.90 Hz), 4.04 (d, 1H, J = 6.40 Hz), 3.77–3.51 (m,
5H), 2.22 (br s, 1H), 1.43 (s, 9H, –C(CH3)3). 13C NMR
(125 MHz, CDCl3): δ 155.8, 142.8, 138.2, 137.9, 128.4–127.7
(m, Ar–C), 115.1, 82.9, 80.7, 79.4, 73.7, 70.8, 61.9, 42.0, 28.3.
HRMS (ESI): calcd for C25H34NO5 [M + H]+ 428.2431; found
428.2435.
(4S,5R)-tert-Butyl 4,5-bis(benzyloxy)-3-hydroxy-3-
(hydroxymethyl)piperidine-1-carboxylate
(2R,3R)-2,3-bis(Benzyloxy)-4-((tert-butoxycarbonylamino)
methyl)pent-4-enyl methanesulfonate (40)
Compound 43 (89 mg, 82%) and compound 44 (10 mg, 10%)
were obtained from 41 (100 mg, 0.24 mmol) using the procedure
which was used to obtain 35.
Compound 40 (313 mg, 88% yield) was obtained as a colorless
liquid from 39 (300 mg, 0.7 mmol) using the same procedure
which was used to obtain 31. Rf: 0.6 (hexane : ethyl acetate,
3 : 1), [α]2D8 = −2.97 (c 1.0, CH2Cl2). IR (neat) νmax cm−1: 3396,
2922, 2851, 1592, 1461, 1384, 1119, 1092, 1037. 1H NMR
(500 MHz, CDCl3): δ 7.33–7.25 (m, 10H, ArH), 5.24 (d, 2H,
J = 11.00 Hz), 4.71 (dd, 2H, J = 11.60 Hz, 11.30 Hz), 4.59
(d, 1H, J = 11.95 Hz), 4.33 (d, 2H, J = 11.60 Hz), 4.20–4.16
(m, 1H), 4.02 (d, 1H, J = 5.80 Hz), 3.87 (br s, 1H), 3.75–3.72
(m, 2H), 2.89 (s, 3H), 1.43 (s, 9H, –C(CH3)3). 13C NMR
(125 MHz, CDCl3): δ 155.9, 142.5, 137.7, 128.5–127.9 (m, Ar–
C), 115.4, 80.7, 79.6, 78.3, 74.2, 71.1, 69.7, 42.1, 37.3, 28.4.
HRMS (ESI): calcd for C26H35NNaO7S [M + Na]+ 528.2026;
found 528.2032.
(3R,4S,5R)-tert-Butyl 4,5-bis(benzyloxy)-3-hydroxy-3-
(hydroxymethyl)piperidine-1-carboxylate (43)
(Major isomer) Rf: 0.5 (hexane : ethyl acetate, 1 : 1), viscous
liquid, [α]D28 = −18.82 (c 0.85, CH2Cl2). IR (neat) νmax cm−1
:
3467, 3063, 3031, 2975, 2925, 2690, 1455, 1427, 1393, 1366,
1
1274, 1249, 1167, 1144, 1094, 1028, 888, 736, 698. H NMR
(500 MHz, CDCl3, mixture of rotamers): δ 7.34–7.25 (m, 20H,
ArH), 4.81(d, 1H, J = 11.00 Hz, –OCHPh), 4.68 (br s, 1H), 4.61
(br s, 4H), 4.51(d, 1H, J = 10.70 Hz, –OCHPh), 4.44 (d, 1H, J =
11.00 Hz, –OCHPh), 4.28 (br s, 3H), 3.95 (br s, 1H), 3.87 (d,
1H, J = 12.20 Hz, –OCHPh), 3.68–3.62 (m, 8H), 3.52–3.35 (m,
2H), 3.21–3.10 (m, 3H), 2.48 (br s, 1H), 2.24 (br s, 1H), 1.45
(br s, 18H). 13C NMR (125 MHz, CDCl3): δ 155.7, 155.6,
137.9, 137.7, 137.1, 128.6–127.9 (m, Ar–C), 127.6, 80.1, 80.1,
77.2, 76.1, 74.2, 73.9, 73.7, 73.6, 73.4, 72.6, 71.6, 71.3, 65.1,
64.5, 48.2, 47.1, 43.4, 41.0, 28.4. HRMS (ESI): calcd for
C25H33NNaO6 [M + Na]+ 466.2200; found 466.2202.
(3R,4R)-tert-Butyl 3,4-bis(benzyloxy)-5-methylenepiperidine-1-
carboxylate (41)
Compound 41 (192 mg, 95% yield) was obtained as a colorless
liquid from 40 (250 mg, 0.58 mmol) using the same procedure
which was used to obtain 32. Rf: 0.55 (hexane : ethyl acetate,
4 : 1), colorless liquid, [α]2D8 = +5.8 (c 1.15, CH2Cl2). IR (neat)
νmax cm−1: 3064, 3031, 2976, 2929, 1694, 1454, 1420, 1366,
(3S,4S,5R)-tert-Butyl 4,5-bis(benzyloxy)-3-hydroxy-3-
(hydroxymethyl)piperidine-1-carboxylate (44)
1
1236, 1165, 1123, 1072, 1028, 913, 872, 737, 698. H NMR
(500 MHz, CDCl3, mixture of rotamers): δ 7.34–7.25 (m, 20H,
ArH), 5.25 (br s, 2H), 5.12 (br s, 2H), 4.70 (br s, 2H, –OCHPh),
4.60 (d, 2H, J = 11.95 Hz, –OCHPh), 4.57 (d, 2H, J = 11.95 Hz,
–OCHPh), 4.45 (br s, 2H, –OCHPh), 4.19–4.11 (m, 2H),
3.95–3.86 (m, 4H), 3.76–3.71 (m, 2H), 3.54 (br s, 4H), 1.43 (s,
18H). 13C NMR (100 MHz, CDCl3): δ 154.8, 138.2, 138.1,
128.3–127.5 (m, Ar–C), 115.1, 114.9, 80.0, 79.7, 71.1, 70.9,
47.9, 46.8, 43.9, 42.7, 28.3. HRMS (ESI): calcd for C25H32NO4
[M + H]+ 410.2326; found 410.2338.
(Minor isomer) Rf: 0.3 (hexane : ethyl acetate, 1 : 1), viscous
liquid, [α]D28 = − 12.41 (c 0.45, CH2Cl2). IR (neat) νmax cm−1
:
3436, 3063, 3030, 2975, 2927, 1682, 1455, 1430, 1392, 1366,
1252, 1164, 1099, 1028, 897, 844, 817, 737, 698. 1H NMR
(500 MHz, CDCl3, mixture of rotamers): δ 7.36–7.25 (m, 20H,
ArH), 4.78–4.75 (m, 2H), 4.65–4.28 (m, 10H), 3.76–3.33 (m,
12H), 2.77 (br s, 1H), 2.68 (br s, 1H), 1.93 (br s, 1H), 1.78 (br s,
1H), 1.44 (br s, 9H), 1.40 (br s, 9H). 13C NMR (125 MHz,
CDCl3): δ 155.7, 155.6, 137.8, 137.6, 128.5–127.3 (m, Ar–C),
80.1, 78.7, 75.1, 74.3, 73.5, 72.0, 71.5, 70.2, 65.7, 65.1, 64.6,
64.1, 48.5, 47.0, 44.3, 44.3, 28.2. HRMS (ESI): calcd for
C25H33NNaO6 [M + Na]+ 466.2200; found 466.2209.
(3R,4R)-tert-Butyl 3,4-bis(benzyloxy)-5-(hydroxymethyl)
piperidine-1-carboxylate (42)
Compound 42 (104 mg, quantitative, concomitant with 42′) was
obtained as a colorless liquid from 41 (100 mg, 0.24 mmol)
using the same procedure which was used to obtain 33. Rf: 0.5
(hexane : ethyl acetate, 1 : 1). IR (neat) νmax cm−1: 3447, 3063,
3030, 2975, 2927, 2875, 1692, 1495, 1453, 1426, 1392, 1366,
tert-Butyl (3R,4S)-3,4-bis(benzyloxy)-5-hydroxy-2-
methylenepentylcarbamate (45)
Compound 45 (365 mg, 80% yield, over 2 steps) was obtained
as a viscous liquid from 25a/b (500 mg, 1.06 mmol) using the
2770 | Org. Biomol. Chem., 2012, 10, 2760–2773
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same procedure which was used to obtain 30. Rf: 0.5 (hexane :
ethyl acetate, 3 : 2), colorless liquid, [α]2D8 = −17.0 (c 0.85,
CH2Cl2). IR (neat) νmax cm−1: 3423, 3063, 3031, 2976, 2927,
2871, 1696, 1510, 1500, 1454, 1391, 1366, 1250, 1207, 1169,
1071, 1028, 911, 737, 698. 1H NMR (500MHz, CDCl3): δ
7.33–7.25 (m, 10H, ArH), 5.28 (s, 1H), 5.24 (s, 1H), 4.76 (br s,
1H), 4.61–4.56 (m, 3H, 3x-OCHPh), 4.31 (d, 1H, J = 11.65 Hz,
–OCHPh), 4.00 (d, 1H, J = 7.00 Hz), 3.75 (br s, 4H), 3.60 (br s,
1H), 2.23 (br s, 1H), 1.43 (s, 9H, –C(CH3)3). 13C NMR
(125 MHz, CDCl3): δ 155.9, 143.3, 138.0, 137.7, 128.5–127.4
(m, Ar–C), 115.9, 81.1, 80.0, 79.4, 72.7, 70.8, 61.9, 42.4, 28.5.
HRMS (ESI): calcd for C25H33NNaO5 [M + Na]+ 450.2251;
found 450.2203.
which was used to obtain 33. Rf: 0.5 (hexane : ethyl acetate,
1 : 1), [α]2D8 = +22.3 (c 0.65, CH2Cl2). IR (neat) νmax cm−1
:
3438, 3063, 3030, 2975, 2927, 2875, 1690, 1454, 1426, 1366,
1
1239, 1168, 1141, 1097, 1065, 1027, 883, 736, 698. H NMR
(500 MHz, CDCl3): δ 7.37–7.25 (m, 10H, ArH), 4.93–4.69 (m,
2H), 4.62 (d, 4H, J = 11.72 Hz, –OCHPh), 3.97 (br s, 2H), 3.68
(br s, 2H), 3.50 (br s, 1H), 3.38–3.16 (m, 1H), 1.90–1.80 (m,
2H), 1.43 (s, 9H). 13C NMR (125 MHz, CDCl3): δ 155.2, 138.7,
138.3, 128.5–127.4 (m, Ar–C), 80.0, 75.5, 73.3, 72.9, 71.2,
62.5, 61.4, 43.8, 41.9, 28.4. HRMS (ESI): calcd for
C25H33NNaO5 [M + Na]+ 428.2431; found 428.2437.
(3R,4S,5S)-tert-Butyl 4,5-bis(benzyloxy)-3-hydroxy-3-
(hydroxymethyl)piperidine-1-carboxylate (49)
(2S,3R)-2,3-bis(Benzyloxy)-4-((tert-butoxycarbonylamino)
methyl)pent-4-enyl methanesulfonate (46)
Compound 49 (206 mg, 95% yield) was obtained as a white
solid from 47 (200 mg, 0.48 mmol) using the same procedure
which was used to obtain 35. Rf: 0.5 (hexane : ethyl acetate,
1 : 1), white solid, [α]D28 = +34.48 (c 1.45, CH2Cl2). IR (neat)
νmax cm−1: 3423, 3088, 3063, 3030, 2975, 2928, 1670, 1455,
1429, 1367, 1272, 1240, 1208, 1163, 1118, 1092, 1044, 1027,
881, 736, 698. 1H NMR (400 MHz, CDCl3): δ 7.34–7.25
(m, 10H, ArH), 4.78 (d, 1H, J = 11.44 Hz, –OCHPh), 4.64–4.58
(m, 3H, 3x-OCHPh), 3.83 (br s, 2H), 3.74–3.69 (m, 4H), 3.48
(br s, 2H), 3.19 (br s, 1H), 2.93 (br s, 1H), 1.41 (s, 9H). 13C
NMR (125 MHz, CDCl3): δ 156.2, 155.6, 138.4, 138.1,
128.3–127.2 (m, Ar–C), 80.7, 79.4, 79.3, 79.2, 74.3, 74.0, 73.6,
73.2, 73.1, 71.6, 71.2, 65.7, 64.7, 48.5, 47.0, 43.3, 42.7, 28.4.
HRMS (ESI): calcd for C25H33NNaO6 [M + Na]+ 466.2200;
found 466.2207.
Compound 46 (306 mg, 86% yield) was obtained as a yellow
liquid from 45 (300 mg, 0.70 mmol) using the same procedure
which was used to obtain 31. Rf: 0.6 (hexane : ethyl acetate,
3 : 2), [α]2D8 = −18.18 (c 0.55, CH2Cl2). IR (neat) νmax cm−1
:
3421, 3064, 3031, 2977, 2933, 1710, 1505, 1454, 1391, 1357,
1249, 1210, 1174, 1075, 1051, 1027, 967, 819, 740, 699, 528.
1H NMR (500 MHz, CDCl3): δ 7.34–7.25 (m, 10H, ArH), 5.31
(s, 1H), 5.25 (s, 1H), 4.72 (br s, 1H), 4.65 (d, 1H, J = 11.30 Hz,
–OCHPh), 4.55 (dd, 2H, J = 11.30 Hz, 11.30 Hz, –OCHPh),
4.50 (dd, 1H, J = 11.00 Hz, 11.00 Hz), 4.34 (dd, 1H, J = 5.20
Hz, 5.20 Hz), 4.30 (d, 1H, J = 11.30 Hz, –OCHPh), 3.96 (d, 1H,
J = 5.50 Hz), 3.74 (d, 3H, J = 5.80 Hz), 2.91 (s, 3H), 1.42 (s,
9H). 13C NMR (125 MHz, CDCl3): δ 155.7, 142.8, 137.4,
137.3, 128.4–127.8 (m, Ar–C), 116.2, 79.3, 79.0, 78.1, 73.0,
70.7, 68.7, 42.2, 37.4, 28.3. HRMS (ESI): calcd for
C26H36NO7S[M + H]+ 506.2207; found 506.2214.
(3R,4R)-5-(Hydroxymethyl)piperidine-3,4-diol
Hydrogenolysis (20% Pd(OH)2/C) of 42 (150 mg, 0.35 mmol)
in methanol gave debenzylated compound, which was passed
through a pad of Celite and the filtrate concentrated. The residue
was dissolved in methanol (2 mL) and added conc. HCl
(0.15 mL) to it and stirred for 6 h at room temperature. After
completion of the reaction, the reaction mixture was concentrated
and the residue chromatographed on silica gel with 2-propanol–
H2O–NH4OH (7 : 2 : 1) to give pure 4A and 4B in 8 : 2 ratio
respectively (89%, combined yield).
(3S,4R)-tert-Butyl 3,4-bis(benzyloxy)-5-methylenepiperidine-1-
carboxylate (47)
Compound 47 (183 mg, 90% yield) was obtained as a liquid
from 46 (250 mg, 0.58 mmol) using the same procedure which
was used to obtain 32. Rf: 0.6 (hexane : ethyl acetate, 4 : 1), col-
orless liquid, [α]D28 = −7.8 (c 0.75, CH2Cl2). IR (neat) νmax
cm−1: 3064, 3031, 2976, 2930, 2871, 1694, 1454, 1416, 1367,
1
1257, 1231, 1204, 1164, 1119, 1069, 1027, 737, 698. H NMR
(500 MHz, CDCl3, mixture of rotamers): δ 7.37–7.25 (m, 20H,
ArH), 5.17 (br s, 1H), 5.11 (br s, 1H), 5.02 (s, 2H), 4.63 (d, 3H,
J = 12.55 Hz, –OCHPh), 4.56 (br s, 3H, –OCHPh), 4.40 (d, 2H,
J = 12.50 Hz, –OCHPh), 4.17 (br s, 1H), 4.07 (s, 3H), 3.98 (br
s, 1H), 3.74–3.70 (m, 3H), 3.46–3.44 (m, 4H), 1.44 (s, 18H).
13C NMR (125 MHz, CDCl3): δ 154.6, 154.5, 139.5, 139.2,
138.1, 128.2–127.5 (m, Ar–C), 115.2, 114.4, 79.8, 77.2, 75.4,
70.4, 69.4, 46.8, 45.6, 43.2, 42.2, 28.3. HRMS (ESI): calcd for
C25H31NNaO4 [M + Na]+ 432.2145; found 432.2156.
(3R,4R,5R)-5-(Hydroxymethyl)piperidine-3,4-diol (4A)
Major isomer (70%, 36 mg), (Rf 0.37 in 2-propanol–H2O–
NH4OH, 7 : 2 : 1), [α]2D8 = +13.3 (c 1.5, CH3OH), lit.28 [α]2D5
=
1
+25.4 (c 1.30, EtOH). H NMR (500 MHz, D2O): δ 3.63 (br s,
1H), 3.51–3.41 (m, 2H), 3.22 (t, J = 8.90 Hz, 1H), 3.11 (m, 2H),
2.43 (m, 1H), 1.63 (m, 1H). 13C NMR (125 MHz, CDCl3): δ
72.7, 70.6, 59.9, 48.3, 45.7, 43.1. HRMS calcd for C6H14NO3
[M + H]+ 148.0968, found: 148.0976.
(3S,4R,5S)-tert-Butyl 3,4-bis(benzyloxy)-5-(hydroxymethyl)
(3R,4R,5S)-5-(Hydroxymethyl)piperidine-3,4-diol (4B)
piperidine-1-carboxylate (48)
Minor isomer (19%, 10 mg), (Rf 0.26 in 2-propanol–H2O–
Compound 48 (91 mg, 87% yield) was obtained as a colorless
liquid from 47 (100 mg, 0.24 mmol) using the same procedure
NH4OH, 7 : 2 : 1), [α]2D8 = −5.0 (c 0.5, CH3OH), lit.30 [α]2D0
=
− 10.3 (c 0.5, MeOH). 1H NMR (500 MHz, D2O): δ 3.91
Org. Biomol. Chem., 2012, 10, 2760–2773 | 2771
This journal is © The Royal Society of Chemistry 2012

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1
(s, 1H), 3.85 (s, 1H), 3.58–3.43 (m, 2H), 3.19 (dd, 1H, J =
13.70, 13.15 Hz, 1H), 3.10 (d, 1H, J = 12.90 Hz, 1H),
2.88–2.82 (m, 1H), 2.27–2.24 (m, 1H). 13C NMR (125 MHz,
CDCl3): δ 65.2, 65.1, 60.2, 44.2, 40.6, 34.9. HRMS calcd for
C6H14NO3 [M + H]+ 148.0968, found: 148.0972.
lit.26d [α]D20 = 0.0 (c 0.8, MeOH). H NMR (500 MHz, D2O): δ
3.97–3.96 (m, 2H), 3.92 (br s, 1H), 3.15–3.07 (m, 4H). 13C
NMR (125 MHz, D2O): δ 68.2, 65.4, 44.1. HRMS (ESI): calcd
for C5H12NO3 [M + H]+ 134.0812; found 134.0818.
(3S,4R,5R)-3-(Hydroxymethyl)piperidine-3,4,5-triol (8)
(3R,4S,5R)-5-(Hydroxymethyl)piperidine-3,4-diol (5)
Compound 8 (25 mg, 91% yield) was obtained as a viscous
liquid from 35 (75 mg, 0.17 mmol) using the same procedure
which was used to obtain 5. Rf: 0.3 (iPrOH : H2O : NH4OH
A solution of 33 (75 mg, 0.17 mmol) in methanol (5 mL) was
stirred under H2 in the presence of 20% Pd(OH)2–C (35 mg) for
36 h. After completion of the reaction, the reaction mixture was
filtered through the pad of Celite and the filtrate concentrated.
The residue was dissolved in methanol (2 mL), added conc. HCl
(0.15 mL) and stirred for 8 h. After completion of the reaction,
the reaction mixture was concentrated and the residue passed
through Dowex (50×) basic resin column and concentrated under
reduced pressure to get the azasugar 5 (23 mg, 89% yield) as a
viscous liquid. Rf: 0.2 (ethyl acetate : methanol, 4 : 1), [α]2D8 = +
1
7 : 2 : 1), [α]2D8 = −15.83 (c 1.2, MeOH). H NMR (400 MHz,
D2O): δ 4.08–4.05 (m, 1H, H-3), 3.72 (br s, 1H, H-4), 3.52 (d,
1H, J = 11.90 Hz, H-6), 3.44 (d, 1H, J = 12.20 Hz, 1H, H-6′),
3.04–3.01 (dd, 1H, J = 4.90, 11.90 Hz, H-2), 2.85 (s, 2H, H-7,
H-7′), 2.78 (t, 1H, J = 12.25 Hz, H-2′). 13C NMR (125 MHz,
D2O): δ 72.8, 68.4, 63.8, 63.4, 44.4, 42.5. HRMS (ESI): calcd
for C6H14NO4 [M + H]+ 164.0917; found 164.0924.
1
2.35 (c 1.7, MeOH), lit.31 [α]D22 = +2.5 (c 1.0, H2O). H NMR
(500 MHz, D2O): δ 3.93 (br s, 1H, H-4), 3.76–3.72 (m, 1H,
H-3), 3.53 (dd, 1H, J = 6.70, 11.30 Hz, H-7), 3.43 (dd, 1H, J =
7.35, 11.00 Hz, H-7′), 3.06–2.98 (m, 2H, H-2, H-6), 2.82 (t, 1H,
J = 11.95 Hz, H-6′), 2.67 (t, 1H, J = 12.50 Hz, H-2′), 1.93–1.89
(m, 1H, H-5). 13C NMR (125 MHz, D2O): δ 66.0, 65.7, 60.0,
42.1, 39.7, 39.1. HRMS (ESI): calcd for C6H14NO3 [M + H]+
148.0968; found 148.0973.
(3S,4R,5R)-5-Methylpiperidine-3,4-diol (9)
Compound 9 (13 mg, 81% yield) was obtained as a viscous
liquid from 32 (50 mg, 0.12 mmol) using the same procedure
which was used to obtain 6. Rf: 0.4 (ethyl acetate : methanol,
4 : 1), [α]2D8 = −1.05 (c 0.65, MeOH), 1H NMR (500 MHz,
D2O): δ 3.85–3.81 (m, 2H, H-3, H-4), 3.12 (dd, 1H, J = 4.30
Hz, 12.30 Hz, H-2), 2.96 (dd, 1H, J = 4.25 Hz, 12.60 Hz, H-2′),
2.87 (t, 1H, J = 11.45 Hz, H-6), 2.69 (t, 1H, J = 12.60 Hz, H-6′)
1.94–1.89 (m, 1H, H-5), 0.90 (d, 3H, J = 6.85 Hz, H-7).13C
NMR (125 MHz, D2O): δ 69.3, 65.9, 42.8, 41.5, 31.5, 13.5.
HRMS (ESI): calcd for C6H14NO2 [M + H]+ 132.1019; found
132.1027.
(3R,4S,5S)-5-Methylpiperidine-3,4-diol (6)
To a stirred solution of compound 47 (50 mg, 0.12 mmol) in
methanol was initially treated with 10% Pd–C (5 mg) under
hydrogen atmosphere. After stirring for 3 h additional amount of
10% Pd–C (30 mg) was added and stirring continued for 24 h.
After completion of the reaction, the reaction mixture was
filtered through a pad of Celite and filtrate concentrated. The
residue was dissolved in methanol (2 mL), treated with conc.
HCl (0.15 mL) and stirred for 8 h. After completion of the reac-
tion, reaction mixture was concentrated and the residue was
passed through Dowex (50×) basic resin column and concen-
trated under reduced pressure to get the azasugar 6 (13 mg, 81%
yield) as a white liquid. Rf: 0.4 (ethyl acetate : methanol, 4 : 1),
[α]D28 = −3.75 (c 0.65, MeOH), lit.15 [α]D20 = −6.3 (c 0.75, H2O).
1H NMR (500 MHz, D2O): δ 3.85–3.82 (m, 1H, H-3), 3.81 (s,
1H, H-4), 3.12 (dd, 1H, J = 4.30 Hz, 12.30 Hz, H-2), 2.96 (dd,
1H, J = 4.25 Hz, 12.60 Hz, H-2′), 2.87 (t, 1H, J = 11.45 Hz,
H-6), 2.69 (t, 1H, J = 12.60 Hz, H-6′) 1.94–1.89 (m, 1H, H-5),
0.90 (d, 3H, J = 6.85 Hz, H-7).13C NMR (125 MHz, D2O): δ
69.3, 65.9, 42.8, 41.5, 31.5, 13.5. HRMS (ESI): calcd for
C6H13NaO2 [M + Na]+ 154.0838; found 154.0845.
(3R,4S,5R)-3-(Hydroxymethyl)piperidine-3,4,5-triol (10)
Compound 10 (22 mg, 80% yield) was obtained as a viscous
liquid from 43 (75 mg, 0.17 mmol) using the same procedure
which was used to obtain 5. Rf: 0.2 (methanol : ethyl acetate,
1 : 4), [α]2D8 = +13.04 (c 1.15, CH3OH), lit.29b [α]2D5 = +11.0 (c
1
0.2, EtOH). H NMR (400 MHz, D2O): δ 3.93 (d, 1H, J = 3.92
Hz), 3.68 (d, 1H, J = 4.40 Hz), 3.50 (dd, 2H, J = 11.96, 11.96
Hz), 3.26 (dd, 1H, J = 13.68, 13.44 Hz) 3.18–3.11 (m, 2H), 2.99
(d, 1H, J = 13.10 Hz). 13C NMR (125 MHz, D2O): δ 71.6, 67.8,
66.5, 63.5, 46.0, 45.2. HRMS (ESI): calcd for C6H14NO4
[M + H]+ 164.0917; found 164.0925.
(3S,4R,5S)-5-(Hydroxymethyl)piperidine-3,4-diol (11)
Compound 11 (23 mg, 89% yield) was obtained as a viscous
liquid from 48 (75 mg, 0.17 mmol) using the same procedure
which was used to obtain 5 as a viscous liquid. Rf: 0.2 (ethyl
acetate : methanol, 4 : 1), [α]2D8 = +2.35 (c 1.5, MeOH), lit.28
(3R,4S,5S)-Piperidine-3,4,5-triol hydrochloride (7)
1
Hydrogenolysis (20% Pd(OH)2–C) of 37 (75 mg, 0.16 mmol) in
methanol gave debenzylated compound, which was passed
through a pad of Celite, and the filtrate was concentrated to
obtain a residue. It was dissolved in 6 N aqueous HCl (3 mL)
and stirred for 4 h. Solvent removal afforded 7 (24 mg, 86%). Rf:
0.4 (ethyl acetate : methanol, 4 : 1), [α]2D8 = 0.0 (c 0.8, MeOH),
[α]2D5 = +3.5 (c 1.02, EtOH). H NMR (400 MHz, D2O): δ 3.91
(br s, 1H, H-4), 3.71–3.69 (m, 1H, H-3), 3.49 (dd, 1H, J = 6.84,
11.20 Hz, H-7), 3.39 (dd, 1H, J = 7.08, 11.20 Hz, H-7′),
3.02–2.94 (m, 2H, H-2, H-6), 2.79 (t, 1H, J = 11.72 Hz, H-6′),
2.63 (t, 1H, J = 12.72 Hz, H-2′), 1.90–1.85 (m, 1H, H-5). 13C
NMR (125 MHz, D2O): δ 66.3, 66.2, 60.1, 42.4, 39.8, 39.6.
2772 | Org. Biomol. Chem., 2012, 10, 2760–2773
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HRMS (ESI): calcd for C6H14NO3 [M + H]+ 148.0968; found
148.0973.
10 (a) G. Horne, F. X. Wilson, J. Tinsley, D. H. Williams and R. Storer,
Drug Discovery Today, 2011, 16, 107–118; (b) C. Dulsat and N. Mealy,
Drugs Future, 2009, 34, 23–25.
11 http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/
2009/10/WC500006482.pdf
(3R,4S,5S)-3-(Hydroxymethyl)piperidine-3,4,5-triol (12)
12 We thank one of the reviewers for bringing this point to our notice.
13 R. A. Steet, S. Chung, B. Wustman, A. Powe, H. Do and S. A. Kornfeld,
Proc. Natl. Acad. Sci. U. S. A., 2006, 103, 13813–13818.
14 Y. Ichikawa, Y. Igarashi, M. Ichikawa and Y. Suhara, J. Am. Chem. Soc.,
1998, 120, 3007–3018.
Compound 12 (25 mg, 91% yield) was obtained as a viscous
liquid from 49 (75 mg, 0.17 mmol) using the same procedure
which was used to obtain 5. Rf: 0.3 (iPrOH : H2O : NH4OH
1
7 : 2:1), [α]2D8 = +19.23 (c 0.65, MeOH). H NMR (500 MHz,
15 A. Hansen, T. M. Tagmose and M. Bols, Chem. Commun., 1996, 2649–
2650.
D2O): δ 4.02–3.98 (m, 1H, H-3), 3.70 (d, 1H, J = 2.75 Hz, H-4),
3.51 (d, 1H, J = 12.25 Hz, H-6), 3.42 (d, 1H, J = 12.20 Hz, 1H,
H-6′), 2.93 (dd, 1H, J = 4.90, 11.90 Hz, H-2), 2.78–2.67 (m, 3H,
H-7, H-7′, H-2′). 13C NMR (125 MHz, D2O): δ 73.1, 68.8, 64.1,
64.0, 44.7, 43.0. HRMS (ESI): calcd for C6H14NO4 [M + H]+
164.0917; found 164.0922.
16 M. Ichikawa and Y. Ichikawa, Bioorg. Med. Chem., 1995, 2, 161–165.
17 (a) M. M. Matin, T. Sharma, S. G. Sabharwal and D. D. Dhavale, Org.
Biomol. Chem., 2005, 3, 1702–1707; (b) V. H. Lillelund, H. Liu,
X. Liang, H. Søhoel and M. Bols, Org. Biomol. Chem., 2003, 1, 282–
287; (c) G. Zhao, U. C. Deo and B. Ganem, Org. Lett., 2001, 3, 201–
203; (d) G. Mehta and N. Mohal, Tetrahedron Lett., 2000, 41, 5747–
5751.
18 (a) F. Gianfranco and P. A. Palumbo, Tetrahedron Lett., 2011, 52, 884–
886; (b) R. K. Boeckman Jr., N. E. Genung, K. Chen and T. R. Ryder,
Org. Lett., 2010, 12, 1628–1631; (c) L. E. Overman, J. Am. Chem. Soc.,
1974, 96, 597–598; (d) For a comprehensive review, see: L. E. Overman
and N. E. Carpenter, Organic Reactions, Wiley-VCH, Weinheim, 2005,
Vol. 66, pp. 1–107.
19 (a) J. Yang, G. J. Mercer and H. M. Nguyen, Org. Lett., 2007, 9, 4231–
4234; (b) G. J. Mercer, J. Yang, M. J. McKay and H. M. Nguyen, J. Am.
Chem. Soc., 2008, 130, 11210–11218.
Acknowledgements
We thank the Department of Science and Technology, New
Delhi, for J. C. Bose National Fellowship (JCB/SR/S2/JCB-26/
2010) to Y. D. V. and the Council of Scientific and Industrial
Research, New Delhi, for financial support [Grant No. 01(2298)/
09/EMR-II]. Y. S. R. thanks to the Council of Scientific Indus-
trial Research, New Delhi, for Senior Research Fellowship, and
K. P. K. and R. R thank the University Grant Commission, New
Delhi, for Senior Research Fellowship.
20 P. L. Armstrong, I. C. Coull, A. T. Hewson and M. J. Slater, Tetrahedron
Lett., 1995, 36, 4311–4314.
21 (a) P. Gupta and Y. D. Vankar, Eur. J. Org. Chem., 2009, 1925–1933;
(b) N. Kumari, B. G. Reddy and Y. D. Vankar, Eur. J. Org. Chem., 2008,
160–169; (c) J. L. O’brein, M. Tosin and P. V. Murphy, Org. Lett., 2001,
3, 3353; (d) L. Cronin and P. V. Murphy, Org. Lett., 2005, 7, 2691–2693;
(e) N. Kumari and Y. D. Vankar, Org. Biomol. Chem., 2009, 7, 2104–
2109.
22 (a) Y. S. Reddy, A. P. John Pal, P. Gupta, A. A. Ansari and Y. D. Vankar,
J. Org. Chem., 2011, 76, 5972–5984; (b) A. P. John Pal and Y.
D. Vankar, Tetrahedron Lett., 2010, 51, 2519–2524; (c) A. P. John Pal,
P. Gupta, Y. S. Reddy and Y. D. Vankar, Eur. J. Org. Chem., 2010, 6957–
6966.
23 (a) K. Jayakanthan and Y. D. Vankar, Tetrahedron Lett., 2006, 47, 8667–
8671; (b) B. Gopal Reddy and Y. D. Vankar, Angew. Chem., Int. Ed.,
2005, 44, 2001–2004 and references cited therein.
24 A. Bari, H. Feist, D. Michalik, M. Michalik and K. Peseke, Synthesis,
2004, 2863–2868.
Notes and references
1 M. Yagi, T. Kouno, Y. Aoyagi and H. Murai, The structure of moranoline,
a piperidine alkaloid from Morus species, Nippin Nougei Kagaku Kaishi,
1976, 50, 571–572.
2 (a) P. E. Compain and O. R. Martin, Iminosugars. From Synthesis to
Therapeutic Applications, Wiley-VCH, Weinheim, 2007; (b) A. E. Stutz,
Iminosugars as Glycosidase Inhibitors. Nojirimycin and Beyond, Wiley-
VCH, Weinheim, 1999.
3 (a) N. Asano, Cell. Mol. Life Sci., 2009, 66, 1479–1492; (b) K. Afarinka
and A. Bahar, Tetrahedron: Asymmetry, 2005, 16, 1239–1287;
(c) M. S. M. Pearson, M. Mathé-Allaimat, V. Fargeas and J. Lebreton,
Eur. J. Org. Chem., 2005, 2159–2191; (d) N. Asano, R. J. Nash, R.
J. Molyneux and G. W. J. Fleet, Tetrahedron: Asymmetry, 2000, 11,
1645–1680; (e) L. Cipolla, B. La Ferla and F. Nicotra, Curr. Top. Med.
Chem., 2003, 3, 485–511 and references cited therein (f) P. Gupta,
S. Dharuman and Y. D. Vankar, Tetrahedron: Asymmetry, 2011, 21,
2966–2972.
4 L. Somsak, V. Nagya, Z. Hadady, T. Dosca and P. Gergely, Curr. Pharm.
Des., 2003, 9, 1177–1189.
5 M. Weiss, S. Hettmer, P. Smith and S. Ladish, Cancer Res., 2003, 63,
3654–3658.
6 (a) G. B. Karlsson, T. D. Butters, R. A. Dwek and F. M. Platt, J. Biol.
Chem., 1993, 268, 570–576; (b) J. E. Groopmann, Rev. Infect. Dis.,
1990, 12, 931–937.
7 T. D. Butters, R. A. Dwek and F. M. Platt, Chem. Rev., 2000, 100, 4683–
4696.
25 T. Sekioka, M. Shibano and G. Kusano, Nat. Med. (Tokyo, Jpn.), 1995,
49, 332.
26 (a) H. Ouchi, Y. Mihara and H. Takahata, J. Org. Chem., 2005, 70,
5207–5214; (b) R. C. Bernotas, G. Papandreou, J. Urbach and B. Ganem,
Tetrahedron Lett., 1990, 31, 3393–3396; (c) M. Godskesen, I. Lundt,
R. Madsen and B. Winchester, Bioorg. Med. Chem., 1996, 4, 1857–1865;
(d) N. T. Patil, S. John, S. G. Sabharwal and D. D. Dhawale, Bioorg.
Med. Chem., 2002, 10, 2155–2160.
27 L. Chen, D. P. Dumas and C.-H. Wong, J. Am. Chem. Soc., 1992, 114,
741–748.
28 Y. Mihara, H. Ojima, T. Imahori, Y. Yoshimura, H. Ouchi and
H. Takahata, Heterocycles, 2007, 72, 633–645.
29 (a) G. Pandey, M. Kapur, M. S. Khan and S. M. Gaikwad, Org. Biomol.
Chem., 2003, 1, 3321–3326; (b) G. Pandey and M. Kapur, Org. Lett.,
2002, 4, 3883–3886.
30 (a) Ch. Schneider and U. Kazmaier, Eur. J. Org. Chem., 1998, 1155–
1159; (b) U. Kazmaier and Ch. Schneider, Tetrahedron Lett., 1998, 39,
817–818.
8 T. M. Jespersen, W. Dong, M. R. Sierks, T. Skrydstrup, I. Lundt and
M. Bols, Angew. Chem., Int. Ed. Engl., 1994, 33, 1778–1779.
9 A. Bülow, I. W. Plesner and M. Bols, J. Am. Chem. Soc., 2000, 122,
8567–8568.
31 X. Liang, A. Lohse and M. Bols, J. Org. Chem., 2000, 65, 7432–
7437.
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