Facile aza-Claisen rearrangement of glycals: Application in the synthesis of 1-deoxy-l-iminosugars

Article abstract of DOI:10.1002/ejoc.200801301

2-C-Methylene-N-glycosyl amides have been obtained from 2-(hydroxymethyl)glycals through a facile aza-Claisen rearrangement. This rearrangement has also been utilized in the synthesis of L-allo- deoxynojirimycin, a moderate inhibitor of human lysosomal α-

Full text of DOI:10.1002/ejoc.200801301

FULL PAPER
DOI: 10.1002/ejoc.200801301
Facile Aza-Claisen Rearrangement of Glycals: Application in the Synthesis of
1-Deoxy- -iminosugars
L
Preeti Gupta[a] and Yashwant D. Vankar*[a]
Dedicated to Professor Dr. Hans-Ulrich Reißig on the occasion of his 60th birthday
Keywords: Carbohydrates / Iminosugars / Azasugars / Rearrangement / Enzymes / Inhibitors
2-C-Methylene-N-glycosyl amides have been obtained from
2-(hydroxymethyl)glycals through a facile aza-Claisen re-
arrangement. This rearrangement has also been utilized in
new C-5-(hydroxymethyl) analogues of
mycin and -ido-deoxynojirimycin.
L-altro-deoxynojiri-
L
the synthesis of
of human lysosomal α-mannosidase (IC50 = 64 µM), and two
L
-allo-deoxynojirimycin, a moderate inhibitor
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
eoselectively by a palladium-catalyzed aza-Claisen re-
arrangement of glycals, which were later transformed into
glycosyl ureas.[11]
Introduction
The design and synthesis of glycosidase inhibitors have
gained huge momentum in recent years along with develop-
ments in the field of glycobiology.[1] Such inhibitors are not
only useful as potential drugs for a variety of carbohydrate-
mediated diseases, but can also provide interesting insights
into the mechanism of enzymatic glycoside hydrolysis.[2]
Polyhydroxylated piperidines (commonly known as aza- or
iminosugars) are an important class of glycosidase inhibi-
tors[3] with possible therapeutic uses in the treatment of dia-
betes,[4] cancer,[5] HIV,[6] and other metabolic disorders.[7]
Ever since the discovery of 1-deoxynojirimycin (1; DNJ), a
potent α-glucosidase inhibitor, the synthesis and biological
evaluation of naturally occurring as well as synthetic aza-
sugars have received considerable attention.[8] Notable con-
tributions in this area have led to the development of migli-
tol (2; N-hydroxyethyl-1-deoxynojirimycin) and miglustat
(3; N-butyl-1-deoxynojirimycin) for use in patients with
type II diabetes and type I Gaucher’s disease, respectively
(Figure 1). In recent years, research efforts have been di-
rected towards the development of general and flexible
methodologies for accessing a variety of azasugars through
common precursors.[9] With this in mind, we decided to ex-
plore the aza-Claisen rearrangement[10] (or Overman re-
arrangement), which has been widely used in the synthesis
of several nitrogen-containing natural products. Very re-
cently, α- and β-N-glycosyl amides have been obtained ster-
Figure 1. Piperidine-based iminosugars.
Following on from our previous work on glycals and
their use in the synthesis of biologically important mole-
cules,[12] we expected that such rearrangements of 2-(hy-
droxymethyl)glycals would afford N-glycosyl amides with
an exo-methylene unit at C-2. Although Ramesh and Balas-
ubramanian[13] described the introduction of a nitrogen
functionality at C-1, they exploited the Mitsunobu reaction
employing phthalimide as the nucleophile. We perceived
that glycosyl amides obtained by the rearrangement reac-
tion would not only be important in the synthesis of glyco-
peptides, but they could also provide access to azasugars by
suitable manipulations of the carbohydrate scaffold. Thus,
we report herein a facile aza-Claisen rearrangement of 2-
(hydroxymethyl) glycals and its application to the synthesis
of -allo-deoxynojirimycin (4) and two new azasugars,
namely 5-(hydroxymethyl) analogues of -altro- and -ido-
deoxynojirimycin, 5 and 6, respectively (Figure 1).
[a] Department of Chemistry, Indian Institute of Technology,
Kanpur 208016, India
Fax: +91-512-259-0007
E-mail: vankar@iitk.ac.in
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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(Scheme 1). The structures of all the glycosyl amides were
confirmed by 1D and 2D NMR and by NOE experiments
(see the Supporting Information for details).
Results and Discussion
The aza-Claisen rearrangement involves the reaction of
allylic alcohol with trichloroacetonitrile to give the tri-
With the glycosyl amides in hand, we focused our atten-
chloroacetimidate, which then rearranges to give allylic tri- tion on their conversion into azasugar intermediates. For
chloroacetamide. These rearrangements are either carried this purpose, hydrolysis of the amide followed by ring-open-
out thermally or by HgII or PdII catalysis. Thus, when 3,4,6- ing was required. Attempts to hydrolyze the amides under
tri-O-benzyl-2-C-(hydroxymethyl)galactal (7) was subjected basic[18a,18b] as well as acidic[18c] conditions gave poor yields
to the conditions for imidate preparation using NaH and of the free amine and therefore deprotection was achieved
trichloroacetonitrile, we did not observe the formation of by using NaBH4.[18d] Thus, reaction of an anomeric mixture
the expected imidate; instead we isolated the rearranged of glycosyl amides 9a and 9b with NaBH4 in ethanol led to
product 9a/b. Clearly, the formation of the imidate and sub- the reduction of the amide followed by ring-opening to pro-
sequent rearrangement seems to occur in the same pot with- vide the corresponding free amine, which was immediately
out any catalysis or high temperature required. Although treated with di-tert-butyl pyrocarbonate to give the Boc-
such a facile rearrangement is being observed for the first protected amine 15 in 75% yield. As a stereocenter is lost at
time with pyran glycals, such a rearrangement has been re- this stage, an anomeric mixture of 9a and 9b was employed
ported previously in the case of furan glycals.[14] Thus, the directly without any need for their separation. Mesylation
galactal derivative 7[15] afforded a separable mixture of α- of the amino alcohol 15 proceeded smoothly to afford 16
and β-N-glycosyltrichloroacetamidates 9a and 9b in a 9:1 in good yield (Scheme 2). Removal of the NHBoc group
ratio. The 1H and 13C NMR spectra were in complete using CF3COOH in CH2Cl2 followed by intramolecular
agreement with their structures. The configuration of 9a SN2 cyclization induced by K2CO3 gave the cyclized prod-
was confirmed by NOE experiments wherein irradiation of uct 17 in 70% yield with an inversion of the stereochemistry
the signal of 1-H led to an enhancement of the signal of at C-2.[19] A coupling constant value of J2,3 = 10.0 Hz was
1
one of the olefinic protons, whereas no enhancement was observed in its H NMR spectrum, which indicates a trans
seen of the signal of 5-H. Reaction with glucal derivative diaxial orientation of 2-H and 3-H, thus supporting the
8[15] afforded an inseparable mixture of α- and β-N-glycos- existence of a 1C4 conformation. It is expected that synthon
yltrichloroacetamidates 10a and 10b in a 3.7:1 ratio. The 17 can be easily converted into various targets by suitably
minor isomer was isolated as a mixture with the major iso- functionalizing the exocyclic double bond.[9d,20] Protection
mer. However, a pure sample of the major isomer could be of the secondary amine as an N-benzyl derivative gave 18.
obtained by column chromatography. By employing glucal Dihydroxylation using catalytic osmium tetroxide and
derivative 11,[16] a 3-deoxy derivative, an inseparable mix- NMO afforded 19 as a single diastereomer. In the 1H NMR
ture of α/β-trichloroacetamidate 12 was obtained in a 1:1.2 spectrum of 19, the signal for 3-H appears as a doublet of
ratio. Clearly the absence of a substituent at C-3 appears to doublets with coupling constants of J2,3 = 9.4 Hz and J3,4
be responsible for the observed low stereoselectivity. With = 2.9 Hz. This indicates a trans diaxial orientation of 2-H
glycal derivative 13,[17] in which the configuration at the C- and 3-H and the existence of a 1C4 conformation in 19. The
3 center is inverted, the α anomer was obtained exclusively stereochemistry at the newly generated quaternary center
Scheme 1. One-pot rearrangement of the 2-hydroxyglycals.
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Facile Aza-Claisen Rearrangement of Glycals
Scheme 2. Synthesis of iminosugar 5.
C-5 was adjudged on the basis of NOE experiments spectroscopic data of which, including COSY and NOE
(Scheme 2). Irradiation of the signal of one of the CH2 hy- data, permitted the assignment of the stereochemistry at the
drogen atoms attached to the quaternary center, that is, 8- newly generated stereocenter. The major isomer 24 was fi-
H, led to an enhancement of the signal of the 4-H proton, nally deprotected in two steps, namely, hydrogenolysis of
whereas irradiation of the signal of the other CH2 hydro- the benzyl groups using catalytic Pd/C and H2 and NHBoc
gen, that is, 8Ј-H, led to an enhancement of the signal of deprotection under acidic conditions, to give the depro-
the axial hydrogen at C-6. No enhancement of the signal of tected compound 6 in 90% yield.
3-H was observed when 8-H and 8Ј-H were irradiated.
It has been recently reported that -allo-deoxynojirimy-
These correlations support the stereochemical outcome of cin (4; -allo-DNJ) is a moderate inhibitor of human lyso-
19 with the dihydroxylation occurring only from the less somal α-mannosidase with an IC50 value of 64 µ.[21] How-
hindered side of the double bond with the hydroxy group ever, very few syntheses of this azasugar have been reported
occupying an α orientation (axial) and the hydroxymethyl in the literature.[9b,21,22] We realized that 19 could be an
group a β orientation (equatorial) in the obtained diol. Hy- ideal precursor for the synthesis of this molecule. Thus, for
drogenolysis of 19 with 10% Pd/C and H2 in ethanol con- the synthesis of -allo-DNJ, the diol in compound 19
taining hydrochloric acid gave the deprotected compound, (Scheme 4) was cleaved with sodium periodate to afford the
which afforded the deprotected C-5-(hydroxymethyl)--al- corresponding ketone, which was rather unstable and hence
tro-DNJ (5) after passing through a basic Dowex column. immediately subjected to sodium borohydride reduction.
Compound 5 was characterized by spectroscopy.
Direct acetylation of the crude product afforded 28 as an
Similarly, glycosyl amides 10a and 10b were transformed inseparable mixture in an 80:20 diastereomeric ratio. This
into 5-(hydroxymethyl)--ido-DNJ (6; Scheme 3). Reaction failure forced us to revert back to synthon 17, which on
of the anomeric mixture of 10a and 10b with NaBH4 in Boc protection instead of benzyl protection gave compound
ethanol afforded the ring-opened free amine, which on 29. Dihydroxylation with OsO4/NMO afforded the diol 30.
NHBoc protection furnished 20 in 50% yield. Mesylation Sodium periodate oxidation of 30 gave the desired ketone
of this amino alcohol gave 21, which on NHBoc deprotec- 31, which was reduced with sodium borohydride. Acety-
tion followed by cyclization provided the expected product lation of the crude product gave 32 as a separable mixture
1
22. The appearance in its H NMR spectrum of a doublet in a 90:10 diastereomeric ratio. The stereochemistry of the
at δ = 3.95 ppm for 4-H with a small coupling constant of newly generated hydroxy group was confirmed by COSY
J3,4 = 3.1 Hz indicates the diequatorial disposition of the 3- and NOE experiments (see the Supporting Information).
1
H and 4-H protons, thus confirming the C4 conformation Finally, deprotection of the benzyl groups under catalytic
of 22. Protection of the amine with a benzyl group followed Pd/C-H2, followed by treatment with 6  aq. HCl allowed
by dihydroxylation afforded an inseparable mixture of dia- the removal of the acetate and NHBoc protecting groups
stereomeric diols. Hence we changed the protecting group to provide -allo-deoxynojirimycin (4), which was charac-
and instead of benzyl protection, Boc protection of the terized as its hydrochloride salt. The spectral data of 4 were
amine in 22 gave 23, which on dihydroxylation gave a sepa- in complete agreement with those reported in the litera-
rable mixture of diastereomeric diols 24 and 25 in a 3:1 ture.[9b]
ratio. However, because of the presence of rotamers the de-
The azasugar inhibitory activities of analogues 5 and
termination of the exact stereochemistry was difficult at this 6 towards a few commercially available glycosidases were
stage. Thus, acetylation of the major diol 24 followed by evaluated at millimolar concentrations (Table 1). The par-
removal of the NHBoc protection gave compound 26 the ent -altro-DNJ is known to inhibit α-glucosidase (rice) at
Eur. J. Org. Chem. 2009, 1925–1933
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P. Gupta, Y. D. Vankar
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Scheme 3. Synthesis of iminosugar 6.
Scheme 4. Synthesis of iminosugar 4.
a concentration of 0.45 m (IC50).[21] Its hydroxymethyl its parent azasugar -ido-DNJ is not known to inhibit any
analogue 5 not only showed inhibition against α-gluco- of the studied enzymes.[21] These studies indicate that al-
sidase, but also showed inhibition towards α-galactosidase though 5 showed inhibition against various glycosidases, 6
(coffee beans) and moderate inhibition towards β-galacto- is not only selective, but a better inhibitor than the parent
sidase (bovine liver; entries 1, 3, and 4). Similarly, the hy- compound. It further suggests that structural variations of
droxymethyl analogue
6 showed selective inhibition these molecules could further promote glycosidase inhibi-
against α-galactosidase (coffee beans; entry 3), although tion.
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Facile Aza-Claisen Rearrangement of Glycals
Table 1. IC50 values for compounds 5 and 6.[a]
olefinic), 4.79 (d, J = 11.9 Hz, 1 H, OCH2Ph), 4.64–4.53 (m, 3 H,
OCH2Ph), 4.46 (d, J = 11.9 Hz, 1 H, OCH2Ph), 4.40 (d, J =
11.7 Hz, 1 H, OCH2Ph), 4.20 (br. s, 1 H, 3-H), 4.09 (dt, J = 2.4,
6.1 Hz, 1 H, 5-H), 3.95 (t, J = 2.4 Hz, 1 H, 4-H), 3.71 (dd, J = 6.3,
[b]
Entry Enzyme
IC50 [m]
5
6
10.2 Hz, 1 H, 6Ј-H), 3.67 (dd, J = 6.3, 10.0 Hz, 1 H, 6-H) ppm. 13
C
1
2
3
4
α-glucosidase (rice)
1.0
NI
29
NI
NI
8.5
NI
β-glucosidase (almonds)
α-galactosidase (coffee beans)
β-galactosidase (bovine liver)
NMR (100 MHz, CDCl3): δ = 161.0, 138.9, 138.3, 138.0, 137.7,
128.5, 128.4, 128.3, 128.0, 127.9, 127.7, 127.5, 114.7, 92.5, 79.7,
74.8, 74.1, 73.5, 73.5, 73.4, 71.2, 68.1 ppm. HRMS (ESI): calcd. for
C30H30Cl3NO5 [M – H]– 588.1112; found 588.1110.
0.76
[a] Inhibition studies were carried out at millimolar concentrations,
the optimal pH of the enzymes and 37 °C. [b] NI = no inhibition
at Ͻ1.0 m concentration of the inhibitor.
N-(3,4,6-Tri-O-benzyl-2-deoxy-2-C-methylene-β-D-lyxo-hexopyr-
anosyl)trichloroacetamide (9b): Compound 9b (11 mg, 8.31% yield)
was obtained as a colorless liquid from glycal 7 (100 mg,
0.22 mmol) by following the general procedure described above
over 6 h. Rf = 0.4 (hexane/ethyl acetate, 9:1). [α]2D5 = –42.6 (c = 2.5,
Conclusions
We have developed a new route to -azasugars and their
analogues by the aza-Claisen rearrangement of glycals. The
new azasugar analogue 6 proved to be a more potent inhibi-
tor than the parent sugar. Further variations of these mole-
cules and their inhibitory studies can provide new insights
into the inhibitory activities of -azasugars.
CH Cl ). IR (neat): ν = 3335, 1721, 1662 cm–1 1H NMR
.
˜
2
2
(400 MHz, CDCl3): δ = 7.58 (d, J = 6.8 Hz, 1 H, NHCOCl3), 7.37–
7.23 (m, 15 H, ArH), 5.69 (d, J = 8.2 Hz, 1 H, 1-H), 5.55 (s, 1 H,
olefinic), 5.27 (s, 1 H, olefinic), 4.90 (d, J = 11.4 Hz, 1 H,
OCH2Ph), 4.70–4.61 (m, 3 H, OCH2Ph), 4.47 (d, J = 11.7 Hz, 1
H, OCH2Ph), 4.42 (d, J = 11.7 Hz, 1 H, OCH2Ph), 4.13 (br. s, 1
H, 3-H), 4.03 (br. s, 1 H, 5-H), 3.88 (m, 1 H, 4-H), 3.57 (m, 2 H,
6-H, 6Ј-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 161.0, 140.2,
138.0, 137.8, 137.7, 128.5, 128.3, 128.2, 127.8, 127.5, 110.0, 92.6,
79.7, 79.2, 75.9, 74.4, 74.1, 73.5, 71.8, 68.6 ppm. HRMS (ESI):
calcd. for C30H30Cl3NO5 [M – H]– 588.1112; found 588.1111.
Experimental Section
General: Infrared spectra were recorded with a Bruker FT/IR Vec-
tor 22 spectrometer. H and 13C NMR spectra were recorded with
1
a JEOL LA-400 (400 and 100 MHz, respectively) 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 with a Waters HAB 213 Q Tof Premier
Micromass or Micromass Quattro II triple Quadrupole Mass spec-
trometer. Optical rotations were recorded with an Autopol II auto-
matic polarimeter at the wavelength of the sodium D line (589 nm)
at 25 °C. Elemental analyses were carried out with a Thermoquest
CE-instruments EA-1110 CHNS analyzer. Column chromatog-
raphy 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 precoated on aluminium plates. Melting
points were determined with a Fischer-John melting point appara-
tus and are uncorrected. All solvents and common reagents were
purified by established procedures.
N-(3,4,6-Tri-O-benzyl-2-deoxy-2-C-methylene-α-D-arabino-hexopyr-
anosyl)trichloroacetamide (10a): Compound 10a/b (100 mg, 75.5%
yield) was obtained as a 3.7:1 mixture of α and β anomers, respec-
tively, from glycal 8 (100 mg, 0.22 mmol) by following the general
procedure described above over 10 h. The pure sample of α anomer
10a was obtained as a colorless solid by column chromatography.
Rf = 0.4 (hexane/ethyl acetate, 9:1); m.p. 64 °C. [α]2D5 = +43.1 (c =
1.6, CH Cl ). IR (neat): ν = 3337, 1722 cm–1. 1H NMR (400 MHz,
˜
2
2
CDCl3): δ = 7.35–7.17 (m, 16 H, ArH, NHCOCCl3), 6.06 (d, J =
7.5 Hz, 1 H, 1-H), 5.43 (s, 1 H, olefinic), 5.41 (s, 1 H, olefinic),
4.75–4.66 (m, 2 H, OCH2Ph), 4.60–4.47 (m, 4 H, OCH2Ph), 4.14
(d, J = 5.6 Hz, 1 H, 3-H), 3.87–3.85 (m, 1 H, 5-H), 3.77–3.73 (m,
2 H, 6Ј-H, 4-H), 3.68 (dd, J = 3.6, 10.7 Hz, 1 H, 6-H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 161.1, 139.6, 138.0, 137.6, 137.5,
128.4, 128.3, 128.0, 127.8, 127.6, 116.6, 92.4, 79.3, 79.1, 78.2, 74.1,
73.6, 73.5, 71.9, 69.1 ppm. HRMS (ESI): calcd. for C30H30Cl3NO5
[M + H]+ 588.1112; found 588.1115.
General Procedure for the Synthesis of N-Glycosyltrichloroacet-
amides: A solution of glycal (0.22 mmol, 1 equiv.) in dichlorometh-
ane (2 mL) was cooled to 0 °C. Trichloroacetonitrile (0.33 mmol,
1.5 equiv.) was added to it, followed by the addition of NaH
(0.26 mmol, 1.2 equiv.) in small portions. The resulting mixture was
stirred at 0 °C for 30 min. Then the cooling bath was removed and
stirring was continued for a period of time, as indicated by TLC
analysis. The reaction was quenched by adding a saturated NH4Cl
solution. The reaction mixture was then extracted with dichloro-
methane (2ϫ20 mL), the combined organic extracts were washed
with water and brine solution, dried with sodium sulfate, filtered,
and concentrated. Column chromatography of the crude reaction
mixture afforded the N-glycosyltrichloroacetamides.
N-(4,6-Di-O-benzyl-2,3-dideoxy-2-C-methylene-α/β-D-threo-hexo-
pyranosyl)trichloroacetamide (12a/b): Compound 12a/b (124 mg,
87% yield) was obtained as a 1:1.2 mixture of α and β anomers,
respectively, from glycal 11 (100 mg, 0.29 mmol) by following the
general procedure described above over 6 h. Rf = 0.4 (hexane/ethyl
acetate, 9:1). Colorless liquid. [α]2D5 = –20.0 (c = 1.0, CH2Cl2). IR
1
(neat): ν = 3373, 1726 cm–1. H NMR (400 MHz, CDCl , mixture
˜
3
of anomers): δ = 7.95 (d, J = 8.5 Hz, 1 H, NHCOCl3, α anomer),
7.35–7.22 (m, 21 H, ArH, both α and β anomers, NHCOCl3, β
anomer), 6.02 (d, J = 8.5 Hz, 1 H, 1-H, α anomer), 5.65 (d, J =
9.2 Hz, 1 H, 1-H, β anomer), 5.15 (s, 1 H, olefinic, α anomer), 5.13
(s, 1 H, olefinic, α anomer), 5.00 (s, 2 H, olefinic, β anomer), 4.65–
N-(3,4,6-Tri-O-benzyl-2-deoxy-2-C-methylene-α-D-lyxo-hexopyr- 4.42 (m, 8 H, OCH2Ph, both α and β anomers), 3.98 (dd, J = 4.16,
anosyl)trichloroacetamide (9a): Compound 9a (99 mg, 74.8% yield)
was obtained as a colorless solid from glycal 7 (100 mg, 0.22 mmol)
by following the general procedure described above over 6 h. Rf =
0.4 (hexane/ethyl acetate, 9:1); m.p. 90 °C. [α]2D5 = +37.0 (c = 2.1,
8.32 Hz, 1 H, 5-H, α anomer), 3.89 (m, 1 H, 4-H, α anomer), 3.77–
3.72 (m, 4 H, 4-H, 5-H, 6-H, 6Ј-H, β anomer), 3.67 (dd, J = 4.6,
10.4 Hz, 1 H, 6Ј-H, α anomer), 3.57 (dd, J = 4.8, 10.4 Hz, 1 H, 6-
H, α anomer), 2.98 (dd, J = 4.6, 13.6 Hz, 1 H, 3Ј-H, β anomer),
CH Cl ). IR (neat): ν = 3334, 1725, 1664 cm–1 1H NMR 2.69 (br. d, J = 11.7 Hz, 1 H, 3Ј-H, α anomer), 2.62 (dd, J = 5.1,
.
˜
2
2
(400 MHz, CDCl3): δ = 7.31–7.20 (m, 16 H, ArH, NHCOCl3), 5.99
(d, J = 7.0 Hz, 1 H, 1-H), 5.45 (s, 1 H, olefinic), 5.35 (s, 1 H,
11.7 Hz, 1 H, 3-H, α anomer), 2.35 (br. t, J = 12.4 Hz, 1 H, 3-H,
β anomer) ppm. 13C NMR (100 MHz, CDCl3, mixture of ano-
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P. Gupta, Y. D. Vankar
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mers): δ = 161.3, 161.1, 140.3, 137.9, 137.3, 128.4, 128.1, 127.7,
forded the mesylated compound 16 (148 mg, 86.5% yield) as a col-
114.7, 110.4, 92.5, 92.3, 80.0, 79.7, 78.3, 73.8, 73.6, 73.1, 71.3, 70.9, orless liquid. Rf = 0.6 (hexane/ethyl acetate, 3:1). [α]2D5 = +5.64 (c
69.8, 68.7, 37.1, 31.7 ppm. HRMS (ESI): calcd. for C23H24Cl3NO4
= 3.0, CH Cl ). IR (neat): ν = 3419, 3031, 1713, 1392 cm–1. 1H
˜
2 2
[M + H]+ 484.0849; found 484.0847.
NMR (400 MHz, CDCl3): δ = 7.38–7.21 (m, 15 H, ArH), 5.33 (s,
1 H, olefinic), 5.28 (s, 1 H, olefinic), 5.14 (m, 1 H, 5-H), 4.83 (br.
s, 1 H, NHBoc), 4.65 (d, J = 11.0 Hz, 1 H, OCH2Ph), 4.51–4.39
(m, 5 H, OCH2Ph), 4.07 (d, J = 7.6 Hz, 1 H, 3-H), 3.81–3.75 (m,
3 H, 1-H, 1Ј-H, 4-H), 3.74 (dd, J = 10.7, 7.0 Hz, 1 H, 6Ј-H), 3.54
(dd, J = 10.7, 4.1 Hz, 1 H, 6-H), 2.95 (s, 3 H, SO2CH3), 1.42 [s, 9
H, C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δ = 155.8, 143.2,
137.8, 137.5, 137.3, 128.4, 128.3, 127.9, 127.7, 116.5, 80.3, 80.1,
79.2, 78.8, 74.9, 73.3, 70.7, 69.4, 42.4, 38.6, 28.4 ppm. HRMS
(ESI): calcd. for C34H43NO8S [M + H]+ 626.2787; found 626.2781.
N-(4,6-Di-O-benzyl-3-O-methyl-2-deoxy-2-C-methylene-α/β-D-xylo-
hexopyranosyl)trichloroacetamide (14): Compound 14 (99 mg,
71.2 % yield) was obtained as a viscous liquid from glycal 13
(100 mg, 0.27 mmol) by following the general procedure described
above over 8 h. Rf = 0.5 (hexane/ethyl acetate, 9:1). [α]2D5 = +32.8
(c = 1.3, CH Cl ). IR (neat): ν = 3373, 1726 cm–1 1H NMR
.
˜
2
2
(400 MHz, CDCl3): δ = 8.41 (d, J = 8.5 Hz, 1 H, NHCOCl3), 7.27–
7.18 (m, 10 H, ArH), 5.83 (d, J = 8.5 Hz, 1 H, 1-H), 5.39 (s, 1 H,
olefinic), 5.13 (s, 1 H, olefinic), 4.51 (s, 2 H, OCH2Ph), 4.47 (d, J
= 11.7 Hz, 1 H, OCH2Ph), 4.38 (d, J = 11.7 Hz, 1 H, OCH2Ph),
4.21 (t, J = 6.3 Hz, 1 H, 5-H), 3.69 (d, J = 2.9 Hz, 1 H, 4-H), 3.61–
3.55 (m, 2 H, 6Ј-H, 3-H), 3.53 (dd, J = 9.5, 5.6 Hz, 1 H, 6-H), 3.24
(s, 3 H, OCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.9,
138.0, 137.7, 135.5, 128.4, 128.3, 128.1, 128.0, 127.8, 127.6, 119.8,
93.2, 79.8, 79.4, 74.3, 73.5, 73.0, 68.4, 67.1, 56.7 ppm. HRMS
(ESI): calcd. for C24H26Cl3NO5 [M + H]+ 514.0955; found
514.0957.
(2S,3S,4R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-5-methylene-
piperidine (17): Trifluoroacetic acid (1.5 mL) was added dropwise
to a solution of the mesylate 16 (500 mg, 0.80 mmol) in CH2Cl2
(6 mL) at 0 °C over 5 min while stirring. The reaction mixture was
then stirred at room temperature for 45 min. Upon cooling the re-
action mixture to 0 °C again and diluting with CH2Cl2 (5 mL), a
2  K2CO3 solution (10 mL) was added carefully. This mixture was
partitioned and the aqueous phase was extracted with DCM
(15 ϫ 3 mL). The combined organic extracts were washed with
water and brine, dried with anhydrous Na2SO4, and the solvents
removed. The residue was dissolved in CH3CN (30 mL) and
K2CO3 (553 mg, 4 mmol) was added. After stirring for 4 h at room
temperature, the reaction mixture was heated up to 70 °C and
stirred for a further 4 h. The reaction mixture was cooled to room
temperature, filtered, and concentrated in vacuo. The residue was
extracted with ethyl acetate (3ϫ15 mL), washed with water and
brine, and dried with Na2SO4. Solvent evaporation followed by pu-
rification by column chromatography gave compound 17 (242 mg,
70.5% yield) as a viscous liquid. Rf = 0.4 (hexane/ethyl acetate,
tert-Butyl (3R,4S,5R)-3,4,6-Tris(benzyloxy)-5-hydroxy-2-methylene-
hexylcarbamate (15): NaBH4 (258 mg, 0.68 mmol) was added por-
tionwise to a stirred solution of compound 9a/b (100 mg,
0.17 mmol) in dry ethanol (2 mL) at 0 °C. The reaction mixture
was stirred for 2 h and then quenched by the addition of a saturated
NH4Cl solution (2 mL). Ethanol was removed in vacuo and the
reaction mixture was extracted with ethyl acetate (3ϫ10 mL). The
combined organic extracts were washed with water, brine, dried
with Na2SO4, and the solvent was removed to obtain the crude
amino alcohol, which was submitted to subsequent reaction with-
out any further purification. Thus, the amino alcohol was taken in
ethyl acetate (2 mL) and cooled to 0 °C. Then a saturated NaHCO3
solution (2 mL) was added followed by Boc2O (0.04 mL,
0.19 mmol) and the reaction mixture was stirred for 4 h. Then it
was extracted with ethyl acetate, washed with water and brine, and
dried with Na2SO4. Solvent evaporation followed by purification
by column chromatography gave compound 15 (0.070 g, 75.5%) as
1:1). [α]2D5 = –40.9 (c = 1.4, CH Cl ). IR (neat): ν = 3318, 2864,
˜
2
2
1
1453 cm–1. H NMR (400 MHz, CDCl3): δ = 7.37–7.21 (m, 15 H,
ArH), 5.02 (s, 1 H, olefinic), 4.85 (s, 1 H, olefinic), 4.64 (d, J =
12.4 Hz, 1 H, OCH2Ph), 4.51–4.42 (m, 3 H, OCH2Ph), 4.34–4.30
(m, 2 H, OCH2Ph), 4.15 (d, J = 2.9 Hz, 1 H, 4-H), 3.76 (dd, J =
9.0, 4.1 Hz, 1 H, 7-H), 3.66 (dd, J = 9.0, 2.6 Hz, 1 H, 7Ј-H), 3.49
(d, J = 13.6 Hz, 1 H, 6Ј-H), 3.43 (dd, J = 10.0, 2.9 Hz, 1 H, 3-H),
3.33 (m, 1 H, 2-H), 3.21 (d, J = 13.6 Hz, 1 H, 6-H), 2.01 (br. s, 1
H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 144.2, 138.3,
128.3, 128.2, 127.9, 127.7, 127.6, 127.4, 113.0, 79.0, 76.5, 73.4, 70.5,
70.3, 69.0, 54.5, 47.5 ppm. HRMS (ESI): calcd. for C28H31NO3 [M
+ H]+ 430.2382; found 430.2382.
a viscous liquid. Rf = 0.5 (hexane/ethyl acetate, 3:1). [α]2D5 = –20.9
1
(c = 1.9, CH Cl ). IR (neat): ν = 3361, 3031, 1713 cm–1. H NMR
˜
2
2
(400 MHz, CDCl3): δ = 7.34–7.21 (m, 15 H, ArH), 5.28 (s, 1 H,
olefinic), 5.27 (s, 1 H, olefinic), 4.72 (br. s, 1 H, NHBoc), 4.60–4.53
(m, 5 H, OCH2Ph), 4.30 (d, J = 11.4 Hz, 1 H, OCH2Ph), 4.11–4.07
(m, 2 H, 3-H, 5-H), 3.76 (m, 2 H, 1-H, 1Ј-H), 3.66 (m, 1 H, 4-H),
3.51–3.48 (m, 2 H, 6-H, 6Ј-H), 2.79 (br. s, 1 H, OH), 1.43 [s, 9 H,
C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δ = 155.8, 143.7,
138.1, 137.9, 137.8, 128.4, 128.3, 128.2, 128.1, 127.9, 127.8, 127.7,
127.6, 127.1, 115.5, 80.7, 79.2, 74.1, 73.4, 71.2, 70.9, 69.6, 42.7,
28.4 ppm. HRMS (ESI): calcd. for C33H41NO6 [M + H]+ 548.3012;
found 548.3012.
(2S,3S,4R)-1-Benzyl-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-5-meth-
ylenepiperidine (18): Compound 17 (250 mg, 0.58 mmol) was dis-
solved in CH3CN (5 mL) and cooled to 0 °C. K2CO3 (161 mg,
1.16 mmol) was added to the reaction mixture followed by BnBr
(109 mg, 0.08 mL, 0.64 mmol). After stirring for 4 h at room tem-
perature, the reaction mixture was filtered, the solvent was evapo-
rated, and purification by column chromatography gave the title
compound 18 (251 g, 83.0% yield) as a colorless liquid. Rf = 0.6
(hexane/ethyl acetate, 4:1). [α]2D5 = –10.8 (c = 0.9, CH2Cl2). IR
tert-Butyl (3R,4R,5R)-3,4,6-Tris(benzyloxy)-5-(methylsulfonyloxy)-
2-methylenehexylcarbamate (16): Et3N (54.6 mg, 0.08 mL,
0.54 mmol) was added to a solution of the amino alcohol 15
(150 mg, 0.27 mmol) in CH2Cl2 (4 mL) cooled to 0 °C. Then meth-
anesulfonyl chloride (47 mg, 0.03 mL, 0.41 mmol) was added drop-
(neat): ν = 2922, 1495 cm–1 1H NMR (400 MHz, CDCl3): δ =
.
˜
7.15–7.27 (m, 20 H, ArH), 4.92 (s, 1 H, olefinic), 4.90 (s, 1 H,
olefinic), 4.53 (d, J = 12.4 Hz, 1 H, OCH2Ph), 4.43 (m, 3 H,
wise to the reaction mixture. A catalytic amount of 4-(dimeth- OCH2Ph), 4.29 (d, J = 11.4 Hz, 1 H, OCH2Ph), 4.23 (d, J =
ylamino)pyridine was also added. The reaction mixture was stirred
for 2 h at the same temperature. The reaction was quenched by the
addition of a saturated NaHCO3 solution. The reaction mixture
was extracted with CH2Cl2 (3ϫ10 mL) and the combined organics
were washed with water and brine, and dried with anhydrous
Na2SO4. Solvent removal followed by column chromatography af-
12.7 Hz, 1 H, OCH2Ph), 4.02 (d, J = 3.2 Hz, 1 H, 4-H), 3.88 (d, J
= 13.4 Hz, 1 H, NCH2Ph), 3.79 (dd, J = 10.4, 2.9 Hz, 1 H, 7Ј-H),
3.74 (dd, J = 10.4, 4.4 Hz, 1 H, 7-H), 3.61 (dd, J = 9.2, 3.2 Hz, 1
H, 3-H), 3.50 (d, J = 13.4 Hz, 1 H, NCH2Ph), 3.17–3.13 (m, 1 H,
2-H), 3.02 (d, J = 12.6 Hz, 1 H, 6Ј-H), 2.93 (d, J = 12.6 Hz, 1 H,
6-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 140.6, 139.4, 138.4
1930
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1925–1933

Facile Aza-Claisen Rearrangement of Glycals
(2 peaks), 129.1, 128.2, 127.9, 127.8, 127.4, 126.7, 114.7, 76.6, 76.0,
73.3, 71.0, 68.9, 68.0, 60.1, 55.7, 52.8 ppm. HRMS (ESI): calcd. for
C35H37NO3 [M + H]+ 520.2851; found 520.2855.
was obtained from 20 (100 mg, 0.18 mmol) using the procedure
that was used to obtain 16. Rf = 0.6 (hexane/ethyl acetate, 3:1).
[α]2D5 = +15.8 (c = 1.5, CH Cl ). IR (neat): ν = 3424, 3031, 1712,
˜
2
2
1
1392 cm–1. H NMR (400 MHz, CDCl3): δ = 7.33–7.25 (m, 15 H,
ArH), 5.25 (s, 1 H, olefinic), 5.11 (s, 1 H, olefinic), 4.90 (br. s, 1 H,
5-H), 4.80 (br. s, 1 H, NHBoc), 4.75 (br. s, 2 H, OCH2Ph), 4.56–
4.45 (m, 3 H, OCH2Ph), 4.32 (d, J = 11.4 Hz, 1 H, OCH2Ph), 4.05
(br. s, 1 H), 3.95 (br. d, J = 6.6 Hz, 1 H, 3-H), 3.82–3.72 (m, 4
H), 2.98 (s, 3 H, SO2CH3), 1.45 [s, 9 H, C(CH3)3] ppm. 13C NMR
(100 MHz, CDCl3): δ = 155.8, 142.9, 138.0, 137.8, 137.6, 128.4,
128.3, 128.2, 128.1, 128.0, 127.8, 127.7, 127.6, 115.7, 82.7, 82.5,
81.5, 79.3, 75.5, 73.2, 71.0, 68.3, 41.5, 38.2, 28.4 ppm. HRMS
(ESI): calcd. for C34H43NO8S [M + H]+ 626.2787; found 626.2784.
(2S,3S,4S,5R)-1-Benzyl-2-(benzyloxymethyl)-3,4-bis(benzyloxy)-5-
(hydroxymethyl)piperidin-5-ol (19): NMO (66 mg, 0.56 mmol) and
OsO4 (25 mg/mL solution in tBuOH, 0.02 mL, 0.002 mmol) were
added to a stirred solution of compound 18 (250 mg, 0.48 mmol)
in acetone/water/tBuOH (5 mL, 1:1:0.5) at room temperature. The
reaction mixture was stirred for 48 h and then it was treated with
Na2S2O5 (106 mg, 0.56 mmol). The reaction mixture was stirred for
a further 30 min and then extracted with ethyl acetate (3ϫ20 mL).
The combined organic extracts were washed with water and finally
with brine. Evaporation of the organic layer followed by purifica-
tion by column chromatography gave the compound 19 (198 mg,
74.4% yield, based on starting material recovered 93.0% yield) as
a viscous liquid along with the recovered starting material (50 mg,
20.0% yield). Rf = 0.5 (hexane/ethyl acetate, 1:1). [α]2D5 = +11.6 (c
(2S,3R,4R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-5-methylene-
piperidine (22): Compound 22 (82 mg, 59.8% yield) was obtained
from 21 (200 mg, 0.32 mmol) using the procedure that was used to
obtain 17. Rf = 0.4 (hexane/ethyl acetate, 1:1). [α]2D5 = +26.5 (c =
= 1.8, CH Cl ). IR (neat): ν = 3436, 2921, 1096 cm–1. 1H NMR 0.7, CH Cl ). IR (neat): ν = 3317, 2866, 1457 cm–1 1H NMR
.
˜
˜
2
2
2
2
(400 MHz, CDCl3): δ = 7.35–7.21 (m, 20 H, ArH), 4.83 (d, J = (500 MHz, CDCl3): δ = 7.34–7.21 (m, 15 H, ArH), 5.14 (s, 1 H,
11.4 Hz, 1 H, OCH2Ph), 4.69 (d, J = 11.4 Hz, 1 H, OCH2Ph), 4.51 olefinic), 4.94 (s, 1 H, olefinic), 4.57–4.52 (m, 3 H, OCH2Ph), 4.45–
(m, 2 H, OCH2Ph), 4.43 (s, 2 H, OCH2Ph), 4.18 (d, J = 13.2 Hz, 4.42 (m, 2 H, OCH2Ph), 4.26 (d, J = 12.0 Hz, 1 H, OCH2Ph), 3.95
1 H, NCH2Ph), 3.98 (dd, J = 9.4, 2.9 Hz, 1 H, 3-H), 3.86 (d, J =
2.9 Hz, 1 H, 4-H), 3.80–3.77 (m, 2 H, 7-H, 7Ј-H), 3.57 (d, J =
10.4 Hz, 1 H, 8Ј-H), 3.40 (d, J = 11.2 Hz, 1 H, 8-H), 3.27 (d, J =
13.2 Hz, 1 H, NCH2Ph), 2.86 (br. d, J = 9.2 Hz, 1 H, 2-H), 2.49
(d, J = 3.1 Hz, 1 H, 4-H), 3.68 (dd, J = 3.1, 1.1 Hz, 1 H, 3-H), 3.52
(d, J = 13.4 Hz, 1 H, 6Ј-H), 3.49 (dd, J = 8.0, 6.3, Hz, 1 H, 7Ј-H),
3.45–3.38 (m, 2 H, 2-H, 7-H), 3.32 (d, J = 13.7 Hz, 1 H, 6-H), 1.9
(br. s, 1 H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 142.2,
(d, J = 11.7 Hz, 1 H, 6-H), 2.44 (d, J = 11.7 Hz, 1 H, 6Ј-H) ppm. 138.2, 128.1, 127.7, 127.4, 115.1, 77.1, 76.5, 73.2, 72.0, 70.5, 69.2,
13C NMR (100 MHz, CDCl3): δ = 138.9, 138.7, 138.2, 138.1, 128.8, 54.2, 48.2 ppm. HRMS (ESI): calcd. for C28H31NO3 [M + H]+
128.3, 128.2, 127.8, 127.7, 127.6, 127.5, 127.0, 76.1, 74.3, 73.2, 72.3,
72.2, 66.4, 65.6, 61.5, 56.8, 53.2 ppm. HRMS (ESI): calcd. for
C35H39NO5 [M + H]+ 554.2906; found 554.2903.
430.2382; found 430.2385.
tert-Butyl (2S,3R,4R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-5-
methylenepiperidine-1-carboxylate (23): Compound 22 (100 mg,
0.23 mmol) was dissolved in CH2Cl2 (2 mL) and cooled to 0 °C.
(2S,3S,4S,5R)-2,5-Bis(hydroxymethyl)piperidine-3,4,5-triol (5): A
solution of 19 (100 mg, 0.18 mmol) in ethanol (5 mL) containing Et3N (25 mg, 0.04 mL, 0.25 mmol) was added followed by Boc2O
conc. HCl (0.04 mL) was stirred under H2 in the presence of 10%
Pd/C (50 mg) for 3 d. After completion of the reaction, the mixture
was filtered through a Celite pad, the filtrate was concentrated, and
the residue was passed through a Dowex (50X) basic resin column
and concentrated under reduced pressure to give the iminosugar 5
(32 mg, 91.7% yield) as a viscous liquid. Rf = 0.3 (ethyl acetate/
methanol, 4:1). [α]2D5 = –9.68 (c = 0.6, MeOH). 1H NMR
(400 MHz, D2O): δ = 3.93 (br. d, J = 10.72 Hz, 1 H), 3.87–3.81
(m, 1 H), 3.73–3.66 (m, 2 H), 3.53 (d, J = 12.9 Hz, 1 H), 3.45 (d,
(55 mg, 0.06 mL, 0.25 mmol) and the reaction mixture was stirred
for 4 h. It was then extracted with CH2Cl2 (3ϫ10 mL), washed
with water and brine, and dried with Na2SO4. Solvent evaporation
followed by purification by column chromatography gave com-
pound 23 (99 mg, 80.4% yield) as a viscous liquid. Rf = 0.6 (hex-
ane/ethyl acetate, 4:1). [α]2D5 = +18.5 (c = 0.8, CH2Cl2). IR (neat):
ν = 2925, 1694, 1110 cm–1. 1H NMR (400 MHz, CDCl ): δ = 7.35–
˜
3
7.24 (m, 15 H, ArH), 5.21 (s, 1 H, olefinic), 5.04 (s, 1 H, olefinic),
4.72–4.64 (m, 5 H), 4.57 (br. d, J = 11.9 Hz, 1 H), 4.46 (d, J =
J = 12.9 Hz, 1 H), 3.19–3.11 (m, 1 H), 3.02 (d, J = 13.2 Hz, 1 H), 12.2 Hz, 1 H), 4.28 (br. d, J = 8.7 Hz, 1 H), 3.87 (br. s, 1 H), 3.77
2.97 (d, J = 13.2 Hz, 1 H) ppm. 13C NMR (125 MHz, D2O): δ = (br. s, 1 H), 3.68–3.60 (m, 3 H), 1.43 [s, 9 H, C(CH3)3] ppm. 13C
72.5, 68.5, 64.0, 63.6, 58.2, 55.6, 44.5 ppm. HRMS (ESI): calcd. for
C7H15NO5 [M + H]+ 194.1028; found 194.1026.
NMR (100 MHz, CDCl3): δ = 154.7, 141.3, 138.5, 138.3, 128.2,
127.6, 127.5, 127.4, 127.3, 110.4, 80.6, 80.0, 79.9, 73.3, 73.2, 72.9,
66.9, 53.8, 46.3, 28.3 ppm. HRMS (ESI): calcd. for C33H39NO5 [M
+ H]+ 530.2906; found 530.2904.
tert-Butyl (3R,4R,5R)-3,4,6-Tris(benzyloxy)-5-hydroxy-2-methyl-
enehexylcarbamate (20): Compound 20 (46 mg, 50% yield) was ob-
tained from 10a/b (100 mg, 0.17 mmol) by following the same pro-
cedure as that used to obtain 15. Rf = 0.5 (hexane/ethyl acetate,
Piperidine-1-carboxylates 24 and 25: Compound 23 (100 mg,
0.19 mmol) was dihydroxylated using the same procedure as that
used to obtain 19 to give 24 and 25 in a ratio of 3:1 (100 mg, 94%
yield), which were separated by silica gel column chromatography
(hexane/ethyl acetate, 3:2).
3:1). [α]2D5 = +14.7 (c = 1.5, CH Cl ). IR (neat): ν = 3427, 2922,
˜
2
2
1
1713, 1093 cm–1. H NMR (400 MHz, CDCl3): δ = 7.35–7.24 (m,
15 H, ArH), 5.24 (s, 1 H, olefinic), 5.23 (s, 1 H, olefinic), 4.70 (br.
s, 1 H, NHBoc), 4.63–4.50 (m, 5 H, OCH2Ph), 4.30 (d, J = 11.4 Hz,
1 H, OCH2Ph), 4.10 (d, J = 3.8 Hz, 1 H, 3-H), 3.94 (br. s, 1 H, 5-
H), 3.74 (m, 2 H, 1-H, 1Ј-H), 3.66 (m, 1 H, 4-H), 3.59 (m, 2 H, 6-
H, 6Ј-H), 2.67 (br. s, 1 H, OH), 1.44 [s, 9 H, C(CH3)3] ppm. 13C
NMR (100 MHz, CDCl3): δ = 155.9, 143.4, 138.2, 138.0, 137.8,
128.3, 128.2, 127.9, 127.8, 127.7, 114.5, 81.0, 80.7, 79.3, 74.5, 73.4,
71.2, 71.0, 70.4, 42.7, 28.4 ppm. HRMS (ESI): calcd. for
C33H41NO6 [M + H]+ 548.3012; found 548.3010.
tert-Butyl (2S,3R,4S,5R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-5-
hydroxy-5-(hydroxymethyl)piperidine-1-carboxylate (24): Yield:
75 mg, 70.7%. Viscous liquid. Rf = 0.5 (hexane/ethyl acetate, 1:1).
[α]2D5 = –6.5 (c = 1.2, CH Cl ). IR (neat): ν = 3443, 2974, 1670,
˜
2
2
1
1101 cm–1. H NMR (400 MHz, CDCl3): δ = 7.27–7.19 (m, 15 H,
ArH), 4.77 (d, J = 11.0 Hz, 1 H, OCH2Ph), 4.71 (br. s, 1 H,
OCH2Ph), 4.58 (br. s, 2 H, OCH2Ph), 4.53 (d, J = 12.2 Hz, 1 H,
OCH2Ph), 4.43 (d, J = 12.2 Hz, 1 H, OCH2Ph), 3.88–3.75 (m, 4
H), 3.71 (dd, J = 10.7, 3.9 Hz, 1 H), 3.59 (br. s, 1 H), 3.40 (br. d,
J = 11.9 Hz, 1 H), 3.06 (br. s, 1 H), 2.94 (br. s, 1 H), 1.37 [s, 9 H,
tert-Butyl (3R,4S,5R)-3,4,6-Tris(benzyloxy)-5-methylsulfonyloxy-2-
methylenehexylcarbamate (21): Compound 21 (91 mg, 79.8% yield)
Eur. J. Org. Chem. 2009, 1925–1933
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1931

P. Gupta, Y. D. Vankar
FULL PAPER
C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δ = 155.4, 138.4,
138.1, 137.8, 128.4, 128.3, 127.8, 127.7, 127.5, 127.4, 84.4, 80.8,
77.9, 76.1, 73.3, 73.2, 72.8, 65.8, 63.8, 52.8, 44.5, 28.3 ppm. HRMS
(ESI): calcd. for C33H41NO7 [M + H]+ 564.2961; found 564.2962.
0.58 mmol) by following the same procedure as that used to obtain
23. Rf = 0.6 (hexane/ethyl acetate, 4:1). [α]2D5 = +21.6 (c = 0.5,
CH Cl ). IR (neat): ν = 2925, 1693, 1412 cm–1 1H NMR
.
˜
2
2
(400 MHz, CDCl3): δ = 7.36–7.19 (m, 15 H, ArH), 5.22 (s, 1 H,
olefinic), 5.13 (s, 1 H, olefinic), 4.64–4.56 (m, 5 H), 4.46–4.40 (m,
3 H), 4.16 (br. s, 1 H), 3.91 (br. s, 1 H), 3.58–3.53 (m, 3 H), 1.42
[s, 9 H, C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δ = 155.0,
139.6, 138.4, 138.0, 128.2, 127.8, 127.3, 111.0, 79.8, 76.4, 74.5, 73.0,
71.4, 70.6, 68.7, 54.2, 46.3, 28.4 ppm. HRMS (ESI): calcd. for
C33H39NO5 [M + H]+ 530.2906; found 530.2904.
tert-Butyl (2S,3R,4S,5S)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-5-
hydroxy-5-(hydroxymethyl)piperidine-1-carboxylate (25): Yield:
25 mg, 23.5%. Viscous liquid. Rf = 0.5 (hexane/ethyl acetate, 1:1).
[α]2D5 = –11.4 (c = 1.0, CH Cl ). IR (neat): ν = 3446, 2927, 1681,
˜
2
2
1
1100 cm–1. H NMR (400 MHz, CDCl3, mixture of rotamers): δ =
7.23–7.17 (m, 15 H, ArH), 4.83 (d, J = 11.0 Hz, 1H, OCH2Ph),
4.62–4.52 (m, 3 H, OCH2Ph), 4.46–4.37 (m, 2 H, OCH2Ph), 4.04–
3.97 (m, 2 H), 3.87–3.69 (m, 3 H), 3.37 (br. s, 1 H), 3.16 (br. s, 1
H), 3.06 (br. s, 1 H), 2.44 (br. s, 1 H), 1.46 [br. s, 9 H, C(CH3)
3] ppm. 13C NMR (100 MHz, CDCl3): δ = 155.7, 138.1, 138.0,
137.9, 137.8, 128.4, 128.3, 128.0, 127.8, 127.7, 127.5, 127.4, 80.1,
77.8, 75.1, 73.9, 73.1, 73.0, 67.2, 65.8, 53.3, 51.2, 46.4, 45.2
28.3 ppm. HRMS (ESI): calcd. for C33H41NO7 [M + H]+ 564.2961;
found 564.2960.
tert-Butyl (2S,3S,4S,5R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-5-
hydroxy-5-(hydroxymethyl)piperidine-1-carboxylate (30): Diol 30
(263 mg, 98.8% yield) was obtained as a viscous liquid from com-
pound 29 (250 mg, 0.47 mmol) using the same procedure as that
used to obtain 19. Rf = 0.5 (hexane/ethyl acetate, 1:1). [α]2D5 = +61.4
1
(c = 0.9, CH Cl ). IR (neat): ν = 3433, 2925, 1685, 1100 cm–1. H
˜
2
2
NMR (400 MHz, CDCl3): δ = 7.33–7.22 (m, 15 H, ArH), 4.64–
4.62 (m, 1 H, OCH2Ph), 4.47–4.40 (m, 5 H, OCH2Ph), 4.03 (br. d,
J = 13.6 Hz, 1 H), 3.88 (br. s, 1 H), 3.70 (d, J = 2.9 Hz, 1 H), 3.57–
(2S,3R,4S,5R)-2,5-Bis(hydroxymethyl)piperidine-3,4,5-triol (6): A
solution of 24 (75 mg, 0.13 mmol) in methanol (5 mL) was stirred
under H2 in the presence of 10% Pd/C (35 mg) for 36 h. After com-
pletion of the reaction, the reaction mixture was filtered through a
pad of Celite and the filtrate concentrated. The residue was dis-
solved in methanol (2 mL), conc HCl (0.15 mL) was added and
the mixture heated at 80 °C. After completion of the reaction, the
reaction mixture was concentrated and the residue was passed
through a Dowex (50X) basic resin column and concentrated under
reduced pressure to give the iminosugar 6 (23 mg, 89.5% yield) as
3.50 (m, 2 H), 2.67–2.60 (m, 5 H), 1.39 [s, 9 H, C(CH3)3] ppm. 13
C
NMR (100 MHz, CDCl3): δ = 155.2, 138.1, 137.8, 128.5, 128.4,
128.3, 127.8, 127.7, 127.5, 81.6, 80.6, 74.1, 73.3, 73.2, 72.7, 71.9,
68.1, 64.9, 54.8, 46.0, 28.2 ppm. HRMS (ESI): calcd. for
C33H41NO7 [M + H]+ 564.2961; found 564.2963.
tert-Butyl (2S,3S,4S)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-5-
oxopiperidine-1-carboxylate (31): NaIO4 (57 mg, 0.27 mmol) dis-
solved in water was added to a solution of diol 30 (100 mg,
0.18 mmol) in methanol (2 mL) at 0 °C. The reaction mixture was
stirred for 30 min at room temperature. Water was added to the
reaction mixture and the solvent was evaporated in vacuo. The resi-
due was extracted with ethyl acetate (3ϫ10 mL) and the combined
organic layers were washed with brine and concentrated. The resid-
ual oil was purified by silica gel chromatography to give the ketone
31 (95 mg, 95%) as a colorless oil. Rf = 0.7 (hexane/ethyl acetate,
a viscous liquid. Rf = 0.2 (ethyl acetate: methanol, 4:1). [α]2D5
=
1
+75.0 (c = 0.24, MeOH). H NMR (500 MHz, D2O): δ = 3.80 (m,
1 H), 3.72 (d, J = 3.5 Hz, 1 H), 3.62–3.69 (m, 2 H), 3.50 (d, J =
12.0 Hz, 1 H), 3.36 (d, J = 12.0 Hz, 1 H), 3.21 (dt, J = 6.0, 1.5 Hz,
1 H), 2.91 (s, 2 H) ppm. 13C NMR (125 MHz, D2O): δ = 74.7, 70.6,
69.4, 66.6, 62.3, 58.4, 48.8 ppm. HRMS (ESI): calcd. for
C7H15NO5 [M + H]+ 194.1028; found 194.1026.
7:3). [α]2D5 = +17.1 (c = 0.4, CH Cl ). IR (neat): ν = 1740, 1696,
˜
2
2
1
1120 cm–1. H NMR (400 MHz, CDCl3): δ = 7.37–7.21 (m, 14 H,
ArH), 7.14 (d, J = 7.5 Hz, 1 H, ArH), 4.83 (d, J = 12.4 Hz, 1 H,
OCH2Ph), 4.64 (br. s, 2 H), 4.54 (d, J = 12.4 Hz, 1 H, OCH2Ph),
4.49–4.39 (m, 2 H), 4.36 (br. s, 3 H), 4.10 (br. s, 1 H), 3.82 (br. d,
J = 16.3 Hz, 1 H), 3.64 (br. s, 1 H), 3.57 (dd, J = 3.2, 9.7 Hz, 1 H),
1.42 [s, 9 H, C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δ =
202.6, 154.5, 137.7, 137.6, 137.5, 128.5, 128.4, 128.3, 127.8, 127.6,
127.4, 80.8, 79.6, 76.6, 73.4, 72.5, 71.8, 69.2, 54.0, 28.3 ppm.
HRMS (ESI): calcd. for C32H37NO6 [M + H]+ 532.2699; found
532.2696.
(2S,3R,4S,5R)-[5-Acetoxy-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-
piperidin-5-yl]methyl Acetate (26): Ac2O (0.012 mL, 0.13 mmol),
Et3N (0.02 mL, 0.13 mmol), and a catalytic amount of DMAP
were added to a stirred solution of compound 24 (25 mg,
0.04 mmol) in dry CH2Cl2 (2 mL) cooled to 0 °C. After stirring for
2 h at room temperature, the usual work-up and chromatographic
purification afforded the diacetate, which was used directly for fur-
ther reaction. The residue was taken in CH2Cl2 (1 mL), cooled to
0 °C, and trifluoroacetic acid (0.05 mL) was added. After stirring
for 2 h, the reaction mixture was neutralized with aq. Na2CO3 and
extracted with CH2Cl2. Purification by column chromatography af-
forded the pure compound 26 (20.5 mg, 84.3% yield) as a colorless
tert-Butyl (2S,3S,4R,5R)-5-Acetoxy-3,4-bis(benzyloxy)-2-(benzyl-
oxymethyl)piperidine-1-carboxylate (32): NaBH4 (22 mg,
0.57 mmol) was added to a stirred solution of compound 31
(200 mg, 0.38 mmol) in methanol (4 mL) cooled to 0 °C. The reac-
tion mixture was stirred at same temperature for 30 min and then
quenched with a saturated NH4Cl solution. The reaction mixture
was concentrated under high vacuum to remove methanol. The
aqueous phase was extracted with ethyl acetate (3ϫ10 mL) and the
combined organic extracts were washed with water and brine and
dried with anhydrous Na2SO4. After concentration, the crude resi-
due was directly subjected to acetylation in dry DCM (2 mL) using
Ac2O, Et3N, and a catalytic amount of DMAP. After stirring for
4 h at room temperature, the usual work-up and chromatographic
purification afforded acetate 32 (173 mg, 80%) as a colorless liquid.
liquid. R = 0.4 (hexane/ethyl acetate, 1:2). IR (neat): ν = 3427,
˜
f
2922, 1713, 1093 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.35–7.18
(m, 15 H, ArH), 4.69 (d, J = 2.5 Hz, 1 H, 4-H), 4.68 (d, J =
12.0 Hz, 1 H), 4.56–4.51 (m, 3 H), 4.47 (d, J = 12.0 Hz, 1 H), 4.39
(d, J = 11.0 Hz, 1 H), 4.37 (d, J = 12.0 Hz, 1 H), 4.30 (d, J =
11.0 Hz, 1 H), 3.55–3.46 (m, 3 H, 3-H, 7-H, 7Ј-H), 3.27 (t, J =
5.5 Hz, 1 H, 2-H), 3.09 (d, J = 14.0 Hz, 1 H, 6e-H), 2.93 (d, J =
14 Hz, 1 H, 6a-H), 2.0 (s, 3 H, COCH3), 1.6 (s, 3 H, COCH3) ppm.
13C NMR (125 MHz, CDCl3): δ = 171.0, 170.6, 138.1, 137.7, 137.3,
128.4, 128.3, 128.2, 128.1, 128.0, 127.7, 127.6, 78.2, 73.5, 73.3, 73.2,
72.7, 63.8, 53.8, 48.2, 21.8, 20.7 ppm. HRMS (ESI): calcd. for
C32H37NO7 [M + H]+ 548.2648; found 548.2645.
tert-Butyl (2S,3S,4R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-5-
methylenepiperidine-1-carboxylate (29): Compound 29 (258 mg,
83.7% yield) was obtained as a viscous liquid from 27 (250 mg,
Rf = 0.6 (hexane/ethyl acetate, 3:1). [α]2D5 = +12.4 (c = 0.8, CH2Cl2).
1
IR (neat): ν = 1736, 1696, 1244, 1172 cm–1. H NMR (400 MHz,
˜
CDCl3): δ = 7.40–7.17 (m 15 H, ArH), 5.12 (br. s, 1 H, 5-H), 4.75
1932
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1925–1933

Facile Aza-Claisen Rearrangement of Glycals
R. J. Nash, R. J. Molyneux, G. W. J. Fleet, Tetrahedron: Asym-
metry 2000, 11, 1645–1680; d) L. Cipolla, B. La Ferla, F. Nico-
tra, Curr. Top. Med. Chem. 2003, 3, 485–511, and references
cited therein.
(br. s, 1 H, 2-H), 4.69–4.65 (m, 2 H, OCH2Ph), 4.61 (d, J = 12.4 Hz,
1 H, OCH2Ph), 4.53 (d, J = 12.4 Hz, 1 H, OCH2Ph), 4.40–4.39 (m,
2 H, OCH2Ph), 4.33 (br. d, J = 15.2 Hz, 1 H, 6Ј-H), 3.85 (t, J =
2.6 Hz, 1 H, 3-H), 3.76 (t, J = 3.6 Hz, 1 H, 4-H), 3.50–3.49 (m, 2
H, 7-H, 7Ј-H), 3.08 (br. d, J = 14.8 Hz, 1 H, 6-H), 2.04 (s, 3 H,
OCH3), 1.41 [s, 9 H, C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3):
δ = 181.1, 171.1, 155.5, 138.9, 138.2, 137.8, 128.4, 128.3, 128.0,
127.7, 127.6, 127.5, 127.4, 127.3, 127.2, 79.9, 74.1, 73.7, 73.2, 71.6,
71.0, 69.4, 67.4, 53.9, 43.5, 28.3, 21.2 ppm. HRMS (ESI): calcd. for
C34H41NO7 [M + H]+ 576.2961; found 576.2961.
[9] For selected references, see: a) M. Ruiz, T. M. Ruanova, O.
Blanco, F. Núñez, C. Pato, V. Ojea, J. Org. Chem. 2008, 73,
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(2S,3S,4R,5R)-2-(Hydroxymethyl)piperidine-3,4,5-triol Hydrochlo-
ride (4): Hydrogenolysis (10 % Pd/C) of compound 32 (50 mg,
0.09 mmol) in methanol gave the debenzylated compound, which
was passed through a pad of Celite. The filtrate was concentrated
and the residue was dissolved in 6  aqueous HCl and refluxed for
4 h. Solvent removal afforded 4 (15 mg, 86%) as a white solid. Rf
= 0.4 (ethyl acetate/methanol, 4:1); m.p. 165 °C. [α]2D5 = –37.5 (c =
[11] a) J. Yang, G. J. Mercer, H. M. Nguyen, Org. Lett. 2007, 9,
4231–4234; b) G. J. Mercer, J. Yang, M. J. McKay, H. M.
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2008, 49, 4728–4730; b) A. Kumar, G. K. Rawal, Y. D. Vankar,
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1
1.0, MeOH). H NMR (500 MHz, D2O): δ = 4.03 (t, J = 2.5 Hz,
1 H), 3.87 (ddd, J = 2.5, 5.0, 11.5 Hz, 1 H), 3.80 (dd, J = 3.0,
13.0 Hz, 1 H), 3.72 (dd, J = 5.5, 13.0 Hz, 1 H), 3.69 (dd, J = 2.5,
11.0 Hz, 1 H), 3.17–3.21 (m, 1 H), 3.12 (dd, J = 5.5, 12.5 Hz, 1 H),
2.98 (t, J = 11.5 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ
= 72.4, 67.8, 67.0, 60.1, 57.2, 44.0 ppm. HRMS (ESI): calcd. for
C6H14ClNO4 [M + H]+ 164.0923; found 164.0923.
[13] N. G. Ramesh, K. K. Balasubramanian, Tetrahedron 1995, 51,
Supporting Information (see also the footnote on the first page of
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respectively, by Vilsmeir–Haack formylation followed by re-
duction: N. G. Ramesh, K. K. Balasubramanian, Tetrahedron
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Acknowledgments
We thank the Department of Science and Technology (DST), New
Delhi for financial support to Y. D. V. in the form of a Ramanna
Fellowship (Grant No. SR/S1/RFOC-04/2006). P. G. thanks the
University Grants Commission, New Delhi for a Senior Research
Fellowship.
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Received: December 31, 2008
Published Online: March 5, 2009
Eur. J. Org. Chem. 2009, 1925–1933
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1933