Synthesis and comparative study of homoisofagomines and analogues as glycosidase inhibitors

Article abstract of DOI:10.1002/ejoc.201301279

The synthesis of polyhydroxyazepanes and their corresponding lactams has been carried out by use of Grubbs cyclisation, to yield the azepane scaffolds, as a key step. A comparative study of glycosidase inhibition by the azepanes and the corresponding lactams with varying stereochemical dispositions, number of hydroxy groups, and side chain structures was carried out.

Full text of DOI:10.1002/ejoc.201301279

FULL PAPER
DOI: 10.1002/ejoc.201301279
Synthesis and Comparative Study of Homoisofagomines and Analogues as
Glycosidase Inhibitors
Ranjan Kumar Basak[a] and Yashwant D. Vankar*[a]
Keywords: Inhibitors / Azasugars / Heterocycles / Michael addition / Metathesis
The synthesis of polyhydroxyazepanes and their correspond-
ing lactams has been carried out by use of Grubbs cycli-
sation, to yield the azepane scaffolds, as a key step. A com-
parative study of glycosidase inhibition by the azepanes and
the corresponding lactams with varying stereochemical dis-
positions, number of hydroxy groups, and side chain struc-
tures was carried out.
Introduction
The marketing of glycosidase-inhibitor-based drugs[1]
such as miglustat (1, Figure 1), against Gaucher’s disease,
and miglitol (2), against type 2 diabetes, has provided great
incentive for the design and synthesis of better glycosidase
inhibitors.[2,3] Design of glycosidase inhibitors is based on
mimicking the half-chair conformation and the charge on
the oxocarbenium ion at the glycosidase active site.[4] Many
of these glycosidase inhibitors are piperidine- and pyrrol-
idine-derived molecules and are referred to as azasugars (or
iminosugars).[5]
Figure 2. Examples of isofagomines, lactam counterparts and
higher analogues.
Figure 1. Examples of marketed drugs.
Although the synthesis of tetrahydroxylated and tri-
hydroxylated azepanes was reported[4a] as early as 1967,
glycosidase inhibition studies have been carried out only in
the last two decades. Enzyme inhibition studies on poly-
hydroxylated azepanes have recently grown in impor-
tance[6a,6b] as a consequence of the flexible azepane skel-
eton, which is believed to allow greater number of confor-
mations and the formation of greater numbers of (and
stronger) hydrogen bonds at the active sites of en-
zymes.[6c,6d] Polyhydroxyazepanes have also found use as
DNA minor groove binding ligands (MGBLs).[7] This ap-
plication has also been attributed to the greater flexibility
of the azepane ring skeleton.
Almost all synthetic endeavours pertaining to azasugars
have been directed towards pyrrolidines, piperidines and
their conjugates.
These studies have led to a number of excellent enzyme
inhibitors, such as isofagomine (3, Figure 2) and the amide
counterparts 4 and 5.[3g] Higher analogues of piperidines in
the form of polyhydroxyazepanes 6,[4h] 7[4k] and 8[4i,4j] have
also been reported to be good glycosidase inhibitors.[4]
[a] Department of Chemistry, Indian Institute of Technology,
Kalyanpur, Kanpur 208016, U.P., India
E-mail: vankar@iitk.ac.in
Here we report the synthesis of a number of poly-
hydroxylated azepanes and their lactam counterparts, to-
gether with a comparative inhibition study. To the best of
www.iitk.ac.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301279.
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Homoisofagomines and Analogues as Glycosidase Inhibitors
Scheme 1. Retrosynthesis of the planned polyhydroxyazepanes and their lactam counterparts.
our knowledge no such study directed towards comparing mediated N-allylation/acryolylation. Further, the nitro ole-
glycosidase inhibition by azasugars and by their lactam fin 9 was readily available from d-mannitol by a reported
counterparts based on the same skeleton, with compounds procedure.[9]
possessing varying numbers and stereochemical disposi-
tions of hydroxy groups, has been reported. For this pur-
pose we chose to explore the inhibition profiles of higher
congeners of the isofagomine-type skeleton. The excellent
Results and Discussion
selective enzyme inhibition activity (against β-glucosidases)
shown by isofagomine (3) was first reported by Bols et al.[8a]
Syntheses of isofagomine and its analogues, including of
Michael addition of allylmagnesium chloride to the con-
their lactam counterparts,[8] have been reported in the lit- jugated nitro olefin 9 at –30 °C led to the formation of a
erature; a few of these compounds have shown excellent in- diastereomeric mixture of nitro olefins 10 and 11
hibition profiles.
(Scheme 2), which could not be easily separated at this
In this study we planned to keep the number of hydroxy stage. Reduction of the mixture of nitro olefins 10 and 11
groups the same as that in isofagomine, but on an azepane and subsequent Boc protection furnished the chromato-
scaffold. The hydroxymethyl side chain has already been graphically separable diastereomeric mixture of carbamates
shown to be a moiety of importance, because it appears 12 and 13 in an approximate ratio of 1.6:1.
prominently in glycosidase inhibitors such as fagomine, iso-
N-Allylation of carbamate 12 furnished the diene 14,
fagomine, its analogues and various aminocyclitols. We which underwent facile ring-closing metathesis in the pres-
were interested in finding out how the molecules would be- ence of the first-generation Grubbs catalyst to provide the
have if an extra –CH2OH group were attached to the al- unsaturated azepene 16. Similarly, the carbamate 13 fur-
ready existing –CH2OH group. For this purpose we chose nished the cyclised product 17 via diene 15 in excellent
to use protected (R)-glyceraldehyde, derived from (+)-d- yield.
mannitol, as a precursor to the side chain on the azepanes
The cyclised products 16 and 17 were each exposed to a
and on the corresponding lactams. We planned to use the catalytic amount of OsO4 in the presence of NMO
Michael adducts 10 and 11 (Scheme 2, below), obtained (Scheme 3) to yield diastereomeric cis-dihydroxylated
from glyceraldehyde-derived nitro olefin 9 (Scheme 1), as azepane mixtures 18 and 19, respectively. The diol moieties
the common precursors to all of the azepanes and the cor- of the diastereomeric diol mixtures 18 and 19 were sepa-
responding lactams.
rately protected to form the corresponding acetonides: 20
The retrosynthetic analysis is shown in Scheme 1. The and 21 from 18, and 22 and 23 from 19. On the other hand,
final target molecules E and F, each with an extra –CH2OH non-hydroxylated azepenes 16 and 17 were hydrogenated in
group, and I and J, without one, should be obtainable from the presence of Pd(OH)2/C to yield the corresponding satu-
the common precursors A and B. The azepane skeletons rated products 24 and 25, respectively.
should be accessible through ring-closing metathesis (RCM)
The protected hydroxy azepanes 20, 21, 22, 23, 24 and
of the corresponding dienes in the presence of the Grubbs 25 were hydrolysed in acidic medium to generate the corre-
catalysts. The dienes should be reachable from the nitro ole- sponding free polyhydroxyazepanes 26, 28, 30, 32, 34 and
fin 9 through sequential Michael addition of an allyl group, 35 (Scheme 4) as their hydrochloride salts. These salts were
reduction of the nitro group to an amino group and base- neutralised by passage through basic resin (Dowex-50).
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Scheme 2. Synthesis of azepane scaffolds.
Scheme 3. Dihydroxylation and reduction of polyhydroxyazepanes.
The relative stereochemistry at the newly generated chiral
For compound 29 (Figure 3), irradiation of either one of
centres was confirmed by spectral analysis of the peracetyl- the protons H-4 and H-6 did not enhance the signals of the
ated products 27, 29, 31 and 33 obtained from 26, 28, 30 other, but irradiation of the signal for H-6 at δ = 2.45–
and 32, respectively. The relative stereochemistry of the 2.57 ppm enhanced only the signal for Hb-7 at δ = 3.92–
newly generated chiral centres (at C-3 and C-4) was deter- 4.00 ppm and not that for Ha-7. Irradiation of the signal
mined through nOe irradiation studies. The absolute stereo- for H-4 at δ = 5.26 ppm, however, enhanced only the signal
chemistry at the chiral centre C-6, on the other hand, was for Ha-7 at δ = 3.12 ppm and not that for Hb-7. The protons
deduced on the basis of the crystal structure of the cyclised H-4 and H-6 are thus anti-oriented with respect to one an-
lactam 85 (Scheme 13 and Figure 6, below).
other.
Irradiation of H-6 of compound 27 at δ = 2.18–2.28 ppm
For diastereomer 31, irradiation of either one of the sig-
thus led to enhancement of the combined signals for Hb- nals for H-4 at δ = 5.24–5.26 ppm and H-6 at δ = 2.35–
7 and Hb-2 at δ = 3.65–3.72 ppm, whereas only negligible 2.46 ppm did not enhance the signal of the other (Figure 3).
enhancement (1.2%) of the signal for Ha-7 (Figure 3) was
In the case of diastereomer 33, however, irradiation of
observed. Irradiation of the H-3 signal at δ = 5.24 ppm led the H-6 signal at δ = 2.26–2.36 ppm led to enhancement of
to 3.5% enhancement of the Hb-2 signal at δ = 3.65– the H-4 signal at δ = 5.02 ppm. The absolute configurations
3.72 ppm, whereas only 1.2% enhancement of the signal for of the stereocentres in 31 and 33 are thus as shown in Fig-
Ha-2 at δ = 3.48 ppm was observed. The protons H-6, Hb- ure 3.
7, Hb-2, H-3, and H-4 are thus syn-oriented with respect to
one another.
Further, the dihydroxyethyl side chains were cleaved to
afford the corresponding trihydroxyazepanes. For this, se-
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Homoisofagomines and Analogues as Glycosidase Inhibitors
moiety proved futile because they also simultaneously ef-
fected the removal of the N-Boc protecting group. Oxidative
cleavage of the dihydroxyethyl side chain with NaIO4 gave
the desired aldehyde 38 in excellent yield. Similarly, the
other cyclised product 17 furnished 37 in 95% yield (based
on recovered starting material), and this was converted into
the corresponding aldehyde 39. Reduction of these alde-
hydes with NaBH4 yielded the alcohols 40 and 41, respec-
tively.
Acetylation of the alcohols 40 and 41 led to the acetates
42 and 43 (Scheme 6), which were dihydroxylated with
OsO4/NMO to yield 44 and 45, respectively, each as an in-
separable mixture of diastereomers. Protection of the diol
systems as cyclohexylidene acetals led to the separation of
the diastereomers 46 and 47 (from 44) and of the dia-
stereomers 48 and 49 (from 45).
Non-hydroxylated azepanes 50 and 51 were obtained
upon hydrogenation of 40 and 41, respectively.
The newly generated hydroxyazepanes 46, 47, 48, 49, 50
and 51 underwent acidic hydrolysis to yield poly-
hydroxyazepanes 52, 54, 56, 58, 60 and 61 (Scheme 7),
respectively. The relative stereochemistry of 52, 54, 56 and
58 at C-3 and C-4 was determined by spectral analysis
(nOe) of the peracetylated products 53, 55, 57 and 59,
respectively. For compound 53 (Figure 4), irradiation of the
signals for H-4 (δ = 4.96–5.01 ppm) and for H-6 (δ = 2.23–
2.30 ppm) led in each case to enhancement of the signal of
the other proton, whereas in 55, irradiation of the H-4 sig-
nal (δ = 5.26–5.31 ppm) did not lead to enhancement of the
H-6 signal (δ = 2.39–2.48 ppm). Protons H-4 and H-6 are
thus syn oriented with respect to one another in 53 but anti
oriented in 55. Similarly, irradiation of the signals for H-4
(δ = 5.26–5.28 ppm) and H-6 (δ = 2.41–2.48 ppm) in 57 did
not in either case show enhancement in the signal of the
other proton, whereas for 59 they showed positive corre-
lation between the protons H-4 (δ = 4.96–5.01 ppm) and H-
6 (δ = 2.22–2.31 ppm).
Scheme 4. Hydrolysis of polyhydroxyazepanes and their peracetyl-
ation.
Figure 3. Representation of nOe correlations.
The lactam counterparts of the polyhydroxyazepanes
were also prepared by starting from the mixture of nitro
olefins 10 and 11. Reduction of the nitro functionality with
LiAlH4 and subsequent acryoylation led to amides 62 and
63 in a ratio of 1.6:1 (Scheme 8).
lective hydrolysis of the dioxolane ring of compound 16
with 40 mol-% p-toluenesulfonic acid (pTsA) in methanol
was first performed to afford compound 36 (Scheme 5) in
99% yield (based on recovered starting material) after 8 h
Surprisingly, cyclisation of the diene amides 62 and 63
at room temperature. Other reported methods utilising failed in the presence of either the first- or the second-gen-
camphorsulfonic acid,[9a] 0.1 n HCl in methanol[9b] or tri- eration Grubbs catalysts. Use of Ti(OiPr)4,[10] to reduce the
fluoroacetic acid[9c] for the hydrolysis of the cyclohexylidene electron density at the carbonyl group and thus allow cycli-
Scheme 5. Synthesis of side-chain-shortened azepanes.
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Scheme 6. Synthesis of side-chain-shortened azepanes.
Scheme 8. Synthesis of diene amides.
led to the cyclised products 66 and 67, respectively, but only
in moderate yields (Scheme 9). However, when a less
strongly electron-donating substituent (benzyl group) was
used, the major diene 68 and minor diene 69 cyclised to
give the unsaturated lactams 70 and 71, respectively, in
good yields.
Scheme 7. Synthesis of side-chain-shortened azepanes and their
peracetylation.
Scheme 9. Synthesis of azepane lactam scaffolds.
Figure 4. Representation of nOe correlations.
Further, cis dihydroxylation of lactam 70 led to diols 72
sation of the diene, also met with failure. Protection of the and 73 in almost equal ratio (Scheme 10). However, cis di-
secondary amides 62 and 63 with p-methoxybenzyl groups hydroxylation of 71 led to diastereomers 74 and 75, which
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Homoisofagomines and Analogues as Glycosidase Inhibitors
could only be partially separated chromatographically. Hy- (δ = 1.54–1.59 ppm). H-6 is thus oriented syn to Ha-5 but
drogenation of 70 and 71 led to saturated lactams 76 and anti to Hb-5. Similarly, H-4 is oriented syn to Hb-5 but anti
77, respectively, in excellent yields.
to Ha-5. Protons H-4 and H-6 are therefore oriented anti
to one another.
For compound 75 (Figure 5), irradiation of the signal for
H-6 (combined signals for H-6 and H-5) at δ = 1.88–
1.98 ppm led to enhancement of the Ha-7 signal (δ = 3.49–
3.55 ppm), whereas negligible enhancement was seen for the
Hb-7 signal at δ = 3.79–3.84 ppm. Similarly, irradiation of
the H-3 signal at δ = 4.45 ppm led only to enhancement of
the signal for Ha-7 at δ = 3.49–3.55 ppm together with a
small enhancement in the signal for H-6 at δ = 1.92–
1.98 ppm. Protons H-3, Ha-7 and H-6 are therefore ori-
ented syn with respect to one another.
Removal of the benzyl group under hydrogenolysis con-
ditions[11a,11b,11c,11d] was also attempted, in the presence of
10% Pd/C or 20% Pd(OH)2/C with or without acid; all met
with failure. Apart from hydrogenolysis, other methods
using conc. H2SO4, aq. HBr,[11e] pTsA,[11f] methanesulfonic
acid,[11g] TFA (reflux)[11h,11i] or NBS[11j] were tried without
any success. However, one recently reported procedure uti-
lising NBS and N-methylacetamide[11k] as a radical source
in CHCl3 indeed furnished the debenzylated product 78
(Scheme 11) but only in Ͻ5% yield from 77. It was there-
fore not possible to proceed further with such low yield.
Scheme 10. Synthesis of polyhydroxyazepane lactams.
The relative stereochemistry of the newly generated chi-
ral centres was determined by nOe irradiation. For com-
pound 72 (Figure 5), irradiation of the H-6 signal (δ = 1.77–
1.83 ppm) led to enhancement of the signals for H-4 (δ =
4.19 ppm) and for H-3 (δ = 4.50 ppm), whereas irradiation
of the signals for H-4 and H-3 also led to the enhancement
of the signal for H-6. For compound 73, however, irradia-
tion of signals for H-4 (δ = 4.09 ppm) and H-6 (δ = 1.83–
1.87 ppm) did not in either case lead to enhancement of the
signal of the other proton. The absolute configurations of
the stereocentres are therefore as shown in Figure 5.
Scheme 11. Radical-mediated debenzylation.
A recent report by Withers et al.[12] suggesting the inter-
action of the iminol tautomer of an amide group with the
active site of the enzyme provided the required impetus to
Figure 5. Representations of nOe correlations.
For compound 74 (Figure 5), irradiation of the H-4 sig- go further with the synthesis and enzyme assay, so we pro-
nal (δ = 4.21 ppm) and the H-6 signal (δ = 1.88–1.99 ppm, ceeded with the deprotection of the azepane lactams. The
combined signals for H-6 major rotamer, H-5 minor rot- polyhydroxyazepanes 72, 73, 74, 75, 76 and 77 were hydro-
amer, H-6 minor rotamer) did not in either case lead to lysed in acidic medium to yield N-benzylated azepanes 79,
enhancement of the signal of the other proton. Irradiation 80, 81, 82, 83 and 84, respectively (Scheme 12).
of the signal for H-6 (combined signals for both rotamers)
The side-chain lengths of the azepane lactams were re-
did, however, lead to a 3.6% enhancement in the signal for duced (Scheme 13) by use of a synthetic sequence similar to
Ha-5 (δ = 2.16–2.20 ppm), whereas negligible enhancement that employed for azepanes. The major and minor unsatu-
was observed for the Hb-5 signal (δ = 1.54–1.59 ppm). Irra- rated azepane lactams 70 and 71 were hydrolysed under
diation of the H-4 signal (δ = 4.13–4.18 ppm, combined sig- acidic conditions, leading to diols 85 and 86, respectively
nal for H-8 major rotamer, H-8 minor rotamer, H-4 minor (Scheme 13). The absolute stereochemistry at C-6 was de-
rotamer) led to only 0.6% enhancement in the signal for termined with the aid of single-crystal X-ray crystallo-
Ha-5 but around 1.8% enhancement in the signal for Hb-5 graphic data for the free diol 85 (Figure 6). Oxidative cleav-
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Scheme 14. Dihydroxylation of azepane lactams.
Scheme 12. Hydrolysis of azepane lactams.
The relative stereochemistry of the newly generated chi-
ral centres was determined with the aid of nOe irradiation.
For compound 91 (Figure 7), irradiation of the H-3 signal
at δ = 4.46 ppm led to enhancement of the combined signals
for Hb-5 and H-6 at δ = 1.95–2.04 ppm but did not show
any enhancement for the Ha-5 signal at δ = 2.09–2.13 ppm.
Irradiation of the Ha-5 signal, however, led to the enhance-
ment of the signal for H-8 at δ = 3.64–3.67 ppm, but no
enhancement for the H-3 signal at δ = 4.46 ppm was ob-
served. In addition, irradiation of the combined signal of
Hb-5 and H-6 led to enhancement of the H-3 signal. Ha-5
and H-8 are therefore oriented syn with respect to one an-
age of the diols yielded aldehydes 87 and 88, reduction of
which to alcohols 89 and 90, respectively, was carried out
with NaBH4.
Figure 6. ORTEP diagram of compound 85.[13]
cis Dihydroxylation of the unsaturated ring led to the
partially separable diastereomeric pair of trihydroxy-
azepanes 91 and 92 from alcohol 89 (Scheme 14) and to
another pair of trihydroxyazepanes 93 and 94 from alcohol
90. The combined yield of 91 and 92 was found to be 80%
whereas that for 93 and 94 was 78%.
Figure 7. Representation of nOe correlations.
Scheme 13. Synthesis of side-chain-shortened azepane lactams.
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Homoisofagomines and Analogues as Glycosidase Inhibitors
other whereas H-3 and Ha-5 are oriented anti. Moreover,
In the case of compound 92 (Figure 7), however, irradia-
Hb-5, H-6 and H-3 are oriented syn with respect to one tion of the signals for H-4 (δ = 4.19 ppm) and H-6 (δ =
another. The absolute configurations of the stereocentres 1.98–2.04 ppm, combined signal for Ha-5 and H-6) did not
are hence as shown in Figure 7.
in either case lead to enhancement of the signal of the other
Table 1. IC50 values (mm) of polyhydroxyazepanes.
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proton. For the pair of diastereomers 93 and 94, irradiation coffee beans), α-glucosidase (yeast), α-glucosidase (rice), β-
of the H-6 signal at δ = 2.01–2.04 ppm (combined signal glucosidase (almonds), α-mannosidase (jack beans) and β-
for Hb-5 and H-6) did not lead to enhancement in the signal galactosidase (bovine liver). Comparison of the IC50 values
of H-4 at δ = 4.20–4.24 ppm in the case of compound 93, for the dihydroxyethyl azepanes 26, 28, 30 and 32 with
whereas irradiation of the H-6 signal at δ = 1.99–2.04 ppm those for the corresponding hydroxymethyl azepanes 52, 54,
(combined signal for Ha-5 major rotamer, Ha-5 minor rot- 56 and 58 (Table 1) shows that the latter group of com-
amer, H-6 major rotamer) led to enhancement of the H-4 pounds were better inhibitors than the former. Among
signal at δ = 4.19 ppm in the case of compound 94. These them, azepanes 54, 56 and 58 showed IC50 values of
observations led to the assignment of absolute configura- 0.082 mm, 0.054 mm and 0.085 mm, respectively, against α-
tions of compounds 93 and 94 as shown in Figure 7.
The fully deprotected polyhydroxyazepanes and the N-
mannosidase (jack beans).
The same trend of better inhibition activity of hy-
benzylated polyhydroxyazepane lactams were subjected to droxymethyl azepane lactams (91, 92, 93 and 94) could be
enzyme inhibition studies (Table 1 and Table 2) against the observed on comparison with dihydroxyethyl azepane lact-
six commercially available enzymes α-galactosidase (green ams (79, 80, 81 and 82) as shown in Table 2. It can thus
Table 2. IC50 values (mm) of polyhydroxyazepane lactams.
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Homoisofagomines and Analogues as Glycosidase Inhibitors
be inferred that the dihydroxyethyl side chain is not only tution of NH with some suitable substituent for the devel-
ineffective in enhancing the enzyme inhibition profile for opment of better inhibitors, as has already been observed
azepanes but in fact lowers the activity of the hy- in the cases of miglitol and miglustat.
droxymethyl azepanes (isofagomine homologues). Further,
the IC50 values of compounds 54, 56 and 58 were compared
with the reported values[4k] for azepanes 95 and 96 (Fig-
ure 8), which have a close structural resemblance with an
General Considerations: FT-IR spectra were recorded as thin films
extra –OH group at C-5. Interestingly, the absence of the
or as KBr pellets and are expressed in cm–1. Proton (400 or
Experimental Section
extra –OH group at C-5 both in 54 and in 58 made them
better α-mannosidase inhibitors than 95 and 96. On the
other hand, 96 is a non-selective but strong inhibitor of α-
galactosidase (coffee beans). Out of compounds 54, 56 and
58, azepane 56 is the most active and selective inhibitor of
α-mannosidase. This suggests that better selectivity might
possibly be achieved by changing the stereochemistry of
the –OH and –CH2OH groups at C-3, C-4 and C-6.
500 MHz) and 13C (100 or 125 MHz) NMR spectra were recorded
with CDCl3 and/or D2O as solvents. Chemical shifts are reported
in δ values downfield from tetramethylsilane. Coupling constants
are reported and expressed in Hz, and splitting patterns are desig-
nated as br (broad), s (singlet), d (doublet), dd (double doublet), q
(quartet), m (multiplet). Optical rotations were measured with a
polarimeter at 28 °C. Freshly distilled and dried solvents were used
for all the reactions. The visualisation of spots on TLC plates was
achieved by exposure to iodine or by spraying with H2SO4 (10%)
followed by charring. Column chromatography was performed on
silica gel (100–200 Mesh) with hexane and ethyl acetate as eluents.
Mass spectra were obtained with a high-resolution ESI mass spec-
trometer.
General Procedure for Ring-Closing Metathesis (A): The first-gener-
ation Grubbs catalyst was added to a stirred solution of a diene
(1 mmol) in dry CH2Cl2 (5 mL) and the mixture was stirred for
the time interval given in the appropriate scheme. The solvent was
removed under reduced pressure and the crude product was puri-
fied by silica gel column chromatography using EtOAc/hexane
[either 5–10% (for azepanes) or 30–50% (for lactams)].
Figure 8. Structures of literature polyhydroxyazepanes.[4k]
The azepanes 34, 35, 60 and 61, without hydroxy groups
on their rings (Table 1), in general exhibit low affinities for
enzyme inhibition. This may be attributed to the smaller
extent of binding possible at the active sites of the glycosid-
ases, due to the presence of fewer hydroxy groups. The hy-
droxymethyl azepanes 34 and 35 (Table 1) show very little
inhibition, but the corresponding amides 83 and 84 were
not soluble in water and so inhibition studies could not be
done.
Of the lactams, only one compound – compound 94
(Table 2) – showed an inhibition value in the micromolar
range (0.074 mm, Entry 8), for β-galactosidase (bovine
liver). The same compound also showed inhibition very
close to the micromolar range for α-mannosidase (jack be-
ans). The other four lactams (81, 91, 92 and 94) also
showed inhibitions close to the micromolar range
(0.234 mm to 0.100 mm) both for α-mannosidase (jack be-
ans) and for β-galactosidase (bovine liver). The azepanes
reported in this paper thus appear not only to be better
inhibitors than their lactam counterparts but also to be
more selective.
General Procedure for Dihydroxylation (B): NMO (1.2 equiv. for
azepanes and 4 equiv. for lactams) and a catalytic amount of OsO4
dissolved in tBuOH were added to a stirred solution of an alkene
(1 mmol) in a tBuOH/H2O mixture (1.4:1, 6 mL) and stirring was
continued for 18 h (for azepanes) or for 24 h (for lactams). At the
end of the reaction, sodium sulfite (0.5 equiv. for azepanes or
3 equiv. for lactams) was added and the mixture was stirred for a
further 30 min, followed by extraction with EtOAc (4ϫ 20 mL),
washing with brine and drying over anhydrous Na2SO4. The crude
product was purified by silica gel column chromatography with
EtOAc/hexane (50%).
General Procedure for Acetonide Protection (C): 2,2-Dimethoxy-
propane (1.1 mL, 9 mmol) was added at room temperature to a
stirred solution of a diol (1 mmol) in dry acetone (10 mL), followed
by PPTS (50 mg, 0.2 mmol), and the mixture was stirred for 2 h.
Acetone was removed under reduced pressure and column chroma-
tographic purification was carried out on silica gel with EtOAc/
hexane (5–15%).
General Procedure for Hydrogenation (D): Pd(OH)2/C (20%, 15 mg)
was added to a stirred solution of an alkene (1 mmol) in MeOH
(5 mL) and the mixture was stirred under hydrogen at normal pres-
sure for 2 h. The reaction mixture was filtered through celite pad
and MeOH was removed under reduced pressure. The crude prod-
uct was purified by silica gel column chromatography with EtOAc/
hexane (5–10% for azepanes and 20–30% for lactams).
Conclusions
In general it is found that the azepanes are better inhibi-
tors than the corresponding azepane lactams, as well as be-
ing more selective. Further, the azepane-scaffold-based in-
hibitors (viz., 54¸ 56 and 58) were observed to be more active
towards α-mannosidase (jack beans) than towards other
glycosidases. This study also shows that the inhibition of
glycosidases by tertiary amides is comparable to the inhibi-
General Procedure for Hydrolysis (E): A solution of protected com-
pound (1 mmol) in a mixture of 1 n HCl/MeOH (1:1, 2 mL) was
stirred for 6 h. The solvent was removed under reduced pressure
and the reaction mixture in MeOH was passed through Dowex-50
resin to obtain pure product.
General Procedure for Acetylation (F): Ac2O (0.08 mL) and Et3N
tion profiles of azasugars. This might find utility in substi- (0.08 mL) were added to a stirred solution of an alcohol (1 mmol)
Eur. J. Org. Chem. 2014, 844–859
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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853

R. K. Basak, Y. D. Vankar
in dry CH2Cl2 (3 mL) and stirring was continued for 6 h. CH2Cl2 at –30 °C in a dropwise fashion over a period of 20 min to a suspen-
FULL PAPER
was removed under reduced pressure and the crude product was
purified by silica gel column chromatography with EtOAc/hexane
(25%).
sion of allylmagnesium chloride (3 equiv.) in THF (6 mL). The re-
action mixture was allowed to stir for 15 min and quenched by
addition of satd. NH4Cl solution. It was extracted with EtOAc (3ϫ
30 mL), washed with brine and dried with anhydrous Na2SO4. The
crude product was purified by silica gel column chromatography
with EtOAc/hexane (1–4%). Compounds 10 and 11 were obtained
in a combined yield of 1.55 g (65%), from which 380 mg of pure
compound 10 was obtained as a colourless viscous oil. Rf = 0.75
General Procedure for Peracetylation (G): Ac2O (3 mL) was added
to a solution of fully deprotected azepane (1 mmol) in pyridine
(3 mL) and the mixture was stirred at room temperature for 8 h.
The solvent was removed under reduced pressure and the crude
product was purified by silica gel column chromatography with
EtOAc/hexane (50–100%).
1
in EtOAc/hexane (10%). [α]D = +1.2 (c = 1.3, CH2Cl2). H NMR
(CDCl3, 400 MHz): δ = 1.39–1.40 (m, 2 H), 1.56–1.63 (m, 8 H),
2.11–2.16 (m, 1 H), 2.27–2.31 (m, 1 H), 2.63–2.66 (m, 1 H), 3.65
(dd, J = 8.5, 6.8 Hz, 1 H), 4.03 (dd, J = 8.6, 6.6 Hz, 1 H), 4.20 (dd,
J = 11.7, 6.6 Hz, 1 H), 4.32 (dd, J = 12.9, 6.3 Hz, 1 H), 4.47 (dd,
J = 12.9, 6.8 Hz, 1 H), 5.11–5.15 (m, 2 H), 5.76–5.83 (m, 1 H) ppm.
13C NMR (CDCl3, 100 MHz): δ = 23.7, 23.9, 25.1, 32.1, 34.3, 35.9,
General Procedure for Cyclohexylidene Deprotection (H): pTsA
(40 mol-%, 69 mg) was added at room temperature to a stirred
solution of protected compound (1 mmol) in MeOH (8.5 mL) and
stirring was continued for 8 h. The reaction mixture was quenched
with saturated Na2CO3 solution and extracted with EtOAc (5ϫ
20 mL), washed with brine and dried with anhydrous Na2SO4. The
crude product was purified by silica gel column chromatography
with EtOAc/hexane (50–70%).
39.4, 65.7, 74.8, 75.8, 109.9, 118.5, 134.2 ppm. IR (neat): ν = 2934,
˜
1553, 1100 cm–1. HRMS (ESI): calcd. for C13H21NO2 [M + H]+
256.1548; found 256.1549.
General Procedure for Vicinal Diol Cleavage (I): NaIO4 (1.2 mmol)
was added to an ice-cooled solution of a diol (1 mmol) in a MeCN/
H2O mixture (1.4:1, 4.5 mL) and the mixture was stirred for
30 min. The reaction mixture was filtered through a celite pad fol-
lowed by extraction with EtOAc (3ϫ 20 mL), washed with brine
and dried with anhydrous Na2SO4. The crude product was purified
by silica gel column chromatography with EtOAc/hexane (20%).
tert-Butyl (S)-2-[(S)-1,4-Dioxaspiro[4.5]decan-2-yl]pent-4-enylcarb-
amate (12): A mixture of compounds 10 and 11 (2 g, 7.84 mmol),
dissolved in THF (7 mL), was added over a period of 30 min to an
ice-cold suspension of LiAlH4 (745 mg, 19.6 mmol) in THF (7 mL)
and the reaction mixture was allowed to attain room temp. grad-
ually and stirred at r.t. for 6 h. It was quenched at 0 °C with a
mixture of EtOAc/H2O (9:1), filtered through a celite pad and dried
with anhydrous Na2SO4. The crude product was dissolved in dry
CH2Cl2 (5 mL) and cooled to 0 °C. Et3N (1.3 mL, 9.1 mmol) and
(Boc)2O (2.2 g, 10.3 mmol) were then added sequentially in drop-
wise fashion and the mixture was stirred at the same temperature
for 1 h. Water (10 mL) was added and the compound was extracted
with CH2Cl2 (3ϫ 20 mL), washed with brine and dried with anhy-
drous Na2SO4. The crude product was purified by silica gel column
chromatography with EtOAc/hexane (2–5 %) to afford 12 as a
colourless viscous oil, yield 1.01 g (40%); Rf = 0.6 in EtOAc/hexane
(10 %). [α]D = –1.32 (c = 2.5, CH2Cl2). 1H NMR (CDCl3,
400 MHz): δ = 1.44 (br. s, 11 H), 1.58–1.62 (m, 8 H), 1.70–1.73 (m,
1 H), 1.95–2.10 (m, 2 H), 3.10–3.16 (m, 1 H), 3.36–3.42 (m, 1 H),
3.64 (t, J = 7.8 Hz, 1 H), 3.96 (dd, J = 13.6, 7.6 Hz, 1 H), 4.07 (dd,
J = 7.8, 6.1 Hz, 1 H), 5.04–5.09 (m, 2 H), 5.56 (br. s, 1 H), 5.72–
5.82 (m, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 23.8, 23.9,
25.1, 28.4, 33.9, 35.0, 36.2, 42.0, 42.2, 67.9, 78.4, 78.8, 109.4, 117.2,
General Procedure for Aldehyde Reduction (J): NaBH4 (1 mmol)
was added to an ice-cooled solution of an aldehyde (1 mmol) in
MeOH (2.5 mL) and the reaction mixture was stirred at this tem-
perature for 30 min. Aqueous saturated NH4Cl solution was added
to the mixture, which was extracted with EtOAc (4ϫ 20 mL). The
organic layer was washed with brine and dried with anhydrous
Na2SO4. The crude product was purified by silica gel column
chromatography with EtOAc/hexane (30–50%).
General Procedure for Cyclohexylidene Protection (K): Cyclohexan-
one (2.5 mmol) was added to a stirred solution of diol (1 mmol) in
dry CH2Cl2 (3 mL), followed by the addition of camphorsulfonic
acid (10 mol-%), and the mixture was stirred for 2 h. Dichloro-
methane was removed under reduced pressure and the crude prod-
uct was purified by silica gel column chromatography with EtOAc/
hexane (5–10%).
General Procedure for Enzyme Inhibition: All the enzymes and their
corresponding substrates (p-nitrophenyl glycosides) were procured
from Sigma–Aldrich Chemical Co. The enzymes and substrate
solutions were prepared as 0.025 m solutions in the appropriate pH
buffer solutions of the corresponding enzyme. Solutions of com-
pounds were made separately in water in the 1 to 5 mm range and
added to enzyme solutions. The mixture of enzyme and compound
was allowed to incubate at 37 °C for 1 h. An equal amount of the
substrate solution was added to this mixture and incubation was
continued for 10 min. Control experiments without the test com-
pound were carried out simultaneously. The reaction was arrested
by addition of excess 0.05 m borate solution. The percentage inhibi-
tion of the inhibitor for each enzyme was determined by comparing
the absorption of the released nitrophenol in the test reaction and
in the control reaction at 405 nm wavelength with a UV/Vis spec-
trophotometer (Perkin–Elmer Lambda-20). The IC50 values were
calculated from the percentage inhibition, as the concentrations of
the test compounds required to effect 50% inhibition of the en-
zyme.
135.4, 156.1 ppm. IR (neat): ν = 3363, 2934, 1715, 1166 cm–1
.
˜
HRMS (ESI): calcd. for C18H31NO4 [M + H]+ 326.2331; found
326.2336.
tert-Butyl (S)-2-[(S)-1,4-Dioxaspiro[4.5]decan-2-yl]pent-4-enyl(all-
yl)carbamate (14): NaH (553 mg, 3 mmol, 60% in oil) was added
to an ice-cold solution of carbamate 12 (1.5 g, 4.6 mmol) in dry
DMF (5 mL) and the mixture was stirred for 10 min, followed by
the addition of allyl bromide (0.6 mL, 6.9 mmol) and further stir-
ring for 30 min. Subsequently, H2O (10 mL) was added and the
reaction mixture was extracted with Et2O (3ϫ 20 mL), washed with
brine and dried with anhydrous Na2SO4. The crude product was
purified by silica gel column chromatography with EtOAc/hexane
(5%) to give a light cream-coloured viscous oil; 1.53 g (91%); Rf =
0.8 in EtOAc/hexane (10%). [α]D = –8.8 (c = 1.7, CH2Cl2). 1H
NMR (CDCl3, 400 MHz): δ = 1.39 (br. s, 2 H), 1.45 (br. s, 9 H),
1.56–1.60 (m, 8 H), 1.69–1.71 (m, 1 H), 1.91–2.04 (m, 2 H), 2.16–
2.21 (m, 1 H), 3.28 (br. s, 2 H), 3.62–3.66 (m, 1 H), 3.75–3.87 (m,
2 H), 3.99–4.05 (m, 2 H), 5.00–5.13 (m, 4 H), 5.75–5.81 (m, 2
H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 23.8, 23.9, 25.2, 28.4,
32.9, 34.8, 36.2, 40.4, 47.2, 49.9, 66.9, 76.4, 79.6, 109.1, 116.6,
(S)-2-[(S)-1-Nitropent-4-en-2-yl]-1,4-dioxaspiro[4.5]decane (10): Ni-
tro olefin 9 (2 g, 9.4 mmol), dissolved in THF (2.5 mL), was added
134.1, 136.2, 155.8 ppm. IR (neat): ν = 2975, 1695, 1163 cm–1
.
˜
854
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 844–859

Homoisofagomines and Analogues as Glycosidase Inhibitors
HRMS (ESI): calcd. for C21H35NO4 [M + H]+ 366.2644; found
366.2641.
1164 cm–1. HRMS (ESI): calcd. for C22H37NO6 [M + H]+
412.2699; found 412.2697.
tert-Butyl (S)-3-[(S)-1,4-Dioxaspiro[4.5]decan-2-yl]azepane-1-carb-
oxylate (24): Hydrogenation of 16 (40 mg, 0.12 mmol) was per-
formed as described in General Procedure D. Compound 24 was
obtained as a colourless viscous oil, yield 39 mg (97%); Rf = 0.6 in
EtOAc/hexane (10%). [α]D = –2.7 (c = 0.75, CH2Cl2). 1H NMR
(CDCl3, 400 MHz, rotamer ratio 1:1.3): δ = 0.86 (t, J = 7.6 Hz, 1
H minor rotamer), 0.92 (t, J = 7.6 Hz, 1 H major rotamer), 1.14–
1.43 (m, 6 H, 3 H major rotamer, 3 H minor rotamer), 1.46 (br. s,
9 H minor rotamer), 1.47 (br. s, 9 H major rotamer), 1.53–1.60 (m,
20 H, 10 H major rotamer, 10 H minor rotamer), 1.65 (br. s, 2 H,
1 H major rotamer, 1 H minor rotamer), 1.74–1.84 (m, 4 H, 2 H
major rotamer, 2 H minor rotamer), 2.93 (dd, J = 14.5, 9.8 Hz, 1
H major rotamer), 3.02 (dd, J = 13.9, 10.2 Hz, 1 H minor rotamer),
3.15–3.28 (m, 2 H, 1 H major rotamer, 1 H minor rotamer), 3.36–
3.48 (m, 2 H, 1 H major rotamer, 1 H minor rotamer), 3.59–3.69
(m, 3 H, 2 H major rotamer, 1 H minor rotamer), 3.80–3.91 (m, 3
H, 1 H major rotamer, 2 H minor rotamer), 3.94–4.05 (m, 2 H, 1
H major rotamer, 1 H minor rotamer) ppm. 13C NMR (CDCl3,
100 MHz): δ = 22.8, 23.8, 23.9, 24.8, 25.2, 25.5, 27.8, 28.4, 28.5,
29.3, 29.6, 30.4, 34.9, 35.0, 36.3, 42.4, 43.5, 46.9, 47.5, 48.6, 48.7,
tert-Butyl (S)-3-[(S)-1,4-Dioxaspiro[4.5]decan-2-yl]-2,3,4,7-tetra-
hydro-1H-azepine-1-carboxylate (16): General Procedure A for
ring-closing metathesis was followed with diene 14 (500 mg,
1.37 mmol) in the presence of the first-generation Grubbs catalyst
(22 mg, 2 mol-%) over 2 h. Compound 16 was obtained as a colour-
less viscous oil, yield 455 mg (99%); Rf = 0.7 in EtOAc/hexane
(10 %). [α]D = +6.08 (c = 1.15, CH2Cl2). 1H NMR (CDCl3,
400 MHz, rotamer ratio 2:1): δ = 1.39 (br. s, 4 H, 2 H major isomer,
2 H minor rotamer), 1.44 (br. s, 9 H minor rotamer), 1.47 (br. s, 9
H major rotamer), 1.56–1.61 (m, 16 H, 8 H major rotamer, 8 H
minor rotamer), 1.99–2.17 (m, 6 H, 3 H major rotamer, 3 H minor
rotamer), 3.32 (dd, J = 13.9, 7.8 Hz, 1 H major rotamer), 3.39 (dd,
J = 12.0, 11.2 Hz, 1 H minor rotamer), 3.64–4.12 (m, 12 H, 6 H
major rotamer, 6 H minor rotamer), 5.67 (br. s, 4 H, 2 H major
rotamer, 2 H minor rotamer) ppm. 13C NMR (CDCl3, 100 MHz):
δ = 23.8, 23.9, 25.2, 27.8, 27.9, 28.5, 35.1, 36.4, 41.3, 42.3, 47.0,
49.1, 49.3, 67.3, 67.5, 77.7, 79.3, 79.5, 109.4, 127.8, 128.8, 128.9,
155.4 ppm. IR (neat): ν = 2934, 1695, 1165 cm–1. HRMS (ESI):
˜
calcd. for C19H31NO4 [M + H]+ 338.2331; found 338.2333.
tert-Butyl (S)-6-[(S)-1,4-Dioxaspiro[4.5]decan-2-yl]-3,4-dihydrox-
yazepane-1-carboxylate (18): General Procedure B was used for di-
hydroxylation of diene 16 (590 mg, 1.75 mmol). Compound 18 was
obtained as a colourless viscous oil, yield 507 mg (78%); Rf = 0.2
in EtOAc/hexane (50%). 1H NMR (CDCl3, 400 MHz): δ = 1.40
(br. s, 4 H, 2 H major isomer, 2 H minor isomer), 1.46 (br. s, 18
H, 9 H major isomer, 9 H minor isomer), 1.56–1.61 (m, 16 H, 8 H
major isomer, 8 H minor isomer), 1.91–1.96 (m, 2 H, 1 H major
isomer, 1 H minor isomer), 2.15–2.20 (m, 2 H, 1 H major isomer,
1 H minor isomer), 2.34–2.42 (m, 2 H, 1 H major isomer, 1 H
minor isomer), 2.63–2.76 (m, 2 H, 1 H major isomer, 1 H minor
isomer), 3.10–3.21 (m, 2 H, 1 H major isomer, 1 H minor isomer),
3.35–3.48 (m, 4 H, 2 H major isomer, 2 H minor isomer), 3.52–
3.56 (m, 1 H minor isomer), 3.63–3.69 (m, 3 H, 2 H major isomer,
1 H minor isomer), 3.78 (br. s, 1 H major isomer), 3.96–4.06 (m, 4
H, 1 H major isomer, 3 H minor isomer), 4.09 (br. s, 1 H major
67.4, 67.7, 69.9, 72.2, 78.0, 78.2, 109.3, 155.5 ppm. IR (neat): ν =
˜
2931, 2861, 1694 cm–1. HRMS (ESI): calcd. for C19H33NO4 [M +
H]+ 340.2488; found 340.2483.
(3S,4R,6S)-6-[(S)-1,2-Dihydroxyethyl]azepane-3,4-diol (26): Hydrol-
ysis of 20 (120 mg, 0.29 mmol) was performed as described in Ge-
neral Procedure E. This gave compound 26 as a colourless viscous
1
oil, yield 55 mg (quantitative). [α]D = –17.3 (c = 2.3, MeOH). H
NMR (CDCl3, 400 MHz): δ = 1.56 (d, J = 13.9 Hz, 1 H), 1.67–
1.77 (m, 1 H), 1.90–1.95 (m, 1 H), 3.00–3.06 (m, 2 H), 3.11–3.17
(m, 2 H), 3.34–3.39 (m, 1 H), 3.43 (dt, J = 11.7, 3.9 Hz, 1 H), 3.52–
3.56 (m, 1 H), 3.64–3.68 (m, 1 H), 4.01 (br. s, 1 H) ppm. 13C NMR
(D2O, 100 MHz): δ = 31.9, 34.4, 46.2, 47.2, 63.8, 68.1, 73.3,
74.8 ppm. IR (neat): ν = 3391, 2928 cm–1. HRMS (ESI): calcd. for
˜
C8H17NO4 [M + H]+ 192.1236; found 192.1237.
(3S,4R,6S)-1-Acetyl-6-[(S)-1,2-diacetoxyethyl]azepane-3,4-diyl Di-
acetate (27): General Procedure G was followed for peracetylation
of 26 (25 mg, 0.13 mmol), and compound 27 was obtained as a
colourless viscous oil, yield 48 mg (91%); Rf = 0.2 in EtOAc/hexane
(50%). [α]D = –4.2 (c = 1.75, CH2Cl2). 1H NMR (CDCl3, 400 MHz,
rotamer ratio 1:2): δ = 1.60–1.72 (m, 2 H, Hb-5 major rotamer, Hb-
5 minor rotamer), 1.90–1.98 (m, 2 H, Ha-5 major rotamer, Ha-5
minor rotamer), 2.01–2.13 (series of singlets, 30 H, 8 OAc, 2 NAc),
2.13–2.19 (m, 1 H, H-6 minor rotamer), 2.18–2.28 (m, 1 H, H-6
major rotamer), 3.13–3.18 (m, 2 H, Hb-2 minor rotamer, Ha-7
minor rotamer), 3.33 (dd, J = 14.2, 8.3 Hz, 1 H, Ha-7 major rot-
amer), 3.48 (dd, J = 15.4, 4.6 Hz, 1 H, Ha-2 major rotamer), 3.65–
3.72 (m, 3 H, Hb-7 minor rotamer, Hb-7 major rotamer, Hb-2 major
rotamer), 4.04–4.07 (m, 2 H, Hb-9 major rotamer, Hb-9 minor rot-
amer), 4.28–4.38 (m, 3 H, Ha-9 major rotamer, Ha-9 minor rotamer,
Ha-2 minor rotamer), 4.88–4.92 (m, 1 H, H-4 minor rotamer),
4.94–5.01 (m, 3 H, H-4 major rotamer, H-8 major rotamer, H-8
minor rotamer), 5.24 (br. s, 1 H, H-3 major rotamer), 5.34 (br. s, 1
H, H-3 minor rotamer) ppm. 13C NMR (CDCl3, 100 MHz): δ =
20.6, 20.8, 21.1, 21.3, 28.9, 29.3, 35.5, 38.2, 46.2, 46.9, 49.6, 50.4,
62.7, 63.1, 70.6, 71.2, 71.8, 72.2, 72.5, 72.9, 169.7, 169.8, 169.9,
isomer) ppm. IR (neat): ν = 3433, 2934, 1689, 1164 cm–1. HRMS
˜
(ESI): calcd. for C19H33NO6 [M + H]+ 372.2386; found 372.2386.
tert-Butyl (3aS,7S,8aR)-7-[(S)-1,4-Dioxaspiro[4.5]decan-2-yl]-2,2-
dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]azepine-5(4H)-carboxyl-
ate (20): General Procedure C for acetonide protection was fol-
lowed for 18 (300 mg, 0.81 mmol). This gave compound 20 as a
colourless viscous oil, yield 130 mg (39%); Rf = 0.8 EtOAc/hexane
(15 %). [α]D = +2.3 (c = 3.75, CH2Cl2). 1H NMR (CDCl3,
400 MHz, approximately rotamer ratio is 1:1.25): δ = 1.32–1.34 (m,
6 H, 3 H major rotamer, 3 H minor rotamer), 1.39 (br. s, 4 H, 2 H
major rotamer, 2 H minor rotamer), 1.42–1.46 (m, 24 H, 12 H
major rotamer, 12 H minor rotamer), 1.56–1.65 (m, 18 H, 9 H
minor rotamer, 9 H minor rotamer), 1.71–1.79 (m, 4 H, 2 H major
rotamer, 2 H minor rotamer), 2.48 (dd, J = 12.9, 10.7 Hz, 1 H
major rotamer), 2.56 (dd, J = 13.1, 10.5 Hz, 1 H minor rotamer),
2.79 (dd, J = 13.2, 11.0 Hz, 1 H major rotamer), 2.88 (dd, J = 13.4,
10.5 Hz, 1 H minor rotamer), 3.63–3.71 (m, 2 H, 1 H major rot-
amer, 1 H minor rotamer), 3.79–3.84 (m, 1 H major rotamer), 3.86–
3.91 (m, 1 H minor rotamer), 3.99–4.09 (m, 3 H, 2 H major rot-
amer, 1 H minor rotamer), 4.19–4.31 (m, 4 H, 2 H major rotamer,
2 H minor rotamer), 4.34–4.44 (m, 2 H, 1 H major rotamer, 1 H
minor rotamer), 4.54–4.60 (m, 1 H major rotamer) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 23.8, 23.9, 24.6, 25.1, 27.5, 28.4, 33.3, 33.9,
34.9, 36.2, 36.5, 39.6, 41.4, 48.0, 51.3, 52.8, 67.0, 67.4, 74.0, 74.9,
170.3, 170.5, 170.6 ppm. IR (neat): ν = 2926, 1742, 1647,
˜
1242 cm–1. HRMS (ESI): calcd. for C18H27NO9 [M + H]+
402.1764; found 402.1765.
tert-Butyl (S)-3-[(S)-1,2-Dihydroxyethyl]-2,3,4,7-tetrahydro-1H-
77.2, 78.1, 79.9, 108.9, 109.8, 154.7 ppm. IR (neat): ν = 2926, 1697, azepine-1-carboxylate (36): General Procedure H for cyclohexylid-
˜
Eur. J. Org. Chem. 2014, 844–859
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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855

R. K. Basak, Y. D. Vankar
FULL PAPER
ene deprotection of 16 (590 mg, 1.75 mmol) was followed. This gave
36 as a colourless viscous oil, yield 358 mg (99% based on recovery
of starting material; 114 mg of starting material recovered); Rf =
reaction mixture was quenched at 0 °C with a mixture of EtOAc/
H2O (9:1), filtered through a celite pad and dried with anhydrous
Na2SO4. The crude product was dissolved in dry CH2Cl2 (5 mL)
0.2 in EtOAc/hexane (50%). [α]D = –20.0 (c = 0.75, CH2Cl2). 1H and cooled to 0 °C. Et3N (1.3 mL, 9.1 mmol) and acryloyl chloride
NMR (CDCl3, 400 MHz, approximate rotamer ratio 1:1): δ = 1.41
(br. s, 9 H), 1.43 (br. s, 9 H), 1.82–1.86 (m, 2 H), 2.21–2.26 (m, 4
H), 2.68 (br. s, 2 H), 3.05 (dd, J = 6.8, 3.6 Hz, 1 H), 3.07 (dd, J =
6.8, 3.6 Hz, 1 H), 3.34–3.42 (m, 2 H), 3.46–3.51 (m, 6 H), 3.67 (br.
(1.3 mL) were added sequentially in dropwise fashion and the mix-
ture was stirred at the same temperature for 30 min. Water (10 mL)
was added, and the reaction mixture was extracted with CH2Cl2
(3ϫ 20 mL). The organic layer was washed with brine and dried
s, 2 H), 4.23–4.28 (m, 4 H), 4.79–4.82 (m, 2 H), 5.69–5.77 (m, 4 with anhydrous Na2SO4. The crude product was purified by silica
H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 28.3, 28.7, 39.7, 47.1,
gel column chromatography with EtOAc/hexane (20–30%) to pro-
vide compound 62 as a colourless viscous oil, yield 761 mg (36%);
Rf = 0.2 in EtOAc/hexane (30%). [α]D = +0.32 (c = 62.5, CH2Cl2).
1H NMR (CDCl3, 400 MHz): δ = 1.40–1.44 (m, 2 H), 1.55–1.64
(m, 8 H), 1.73–1.81 (m, 1 H), 1.98–2.11 (m, 2 H), 3.22 (ddd, J =
13.8, 8.3, 3.9 Hz, 1 H), 3.65 (t, J = 8.0 Hz, 1 H), 3.73 (ddd, J =
13.8, 7.1, 3.9 Hz, 1 H), 4.01 (dt, J = 7.8, 6.1 Hz, 1 H), 4.11 (dd, J
= 8.0, 6.1 Hz, 1 H), 5.06–5.07 (m, 1 H), 5.09–5.11 (m, 1 H), 5.62
(dd, J = 10.2, 1.5 Hz, 1 H), 5.77 (ddt, J = 17.1, 10.0, 7.3 Hz, 1 H),
6.06 (dd, J = 17.1, 10.2 Hz, 1 H), 6.24 (dd, J = 17.1, 1.2 Hz, 1 H),
6.66 (br. s, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 23.9, 24.2,
25.1, 34.3, 35.0, 36.3, 41.6, 41.7, 68.2, 79.0, 109.6, 117.5, 125.5,
49.4, 64.4, 71.2, 80.5, 129.0, 130.0, 156.7 ppm. IR (neat): ν = 3406,
˜
2927, 1667 cm–1. HRMS (ESI): calcd. for C13H23NO4 [M + H]+
258.1705; found 258.1706.
tert-Butyl (S)-3-Formyl-2,3,4,7-tetrahydro-1H-azepine-1-carboxyl-
ate (38): General Procedure I was followed for vicinal diol cleavage
of 36 (330 mg, 1.28 mmol). Compound 38 was obtained as a
colourless viscous oil, yield 274 mg (95%); Rf = 0.6 in EtOAc/hex-
ane (30%). [α]D = +6.96 (c = 1.15, CH2Cl2). 1H NMR (CDCl3,
400 MHz, rotamer ratio approximately 1:1): δ = 1.40 (br. s, 9 H),
1.41 (br. s, 9 H), 2.38–2.41 (m, 4 H), 2.71–2.82 (m, 2 H), 3.63 (dd,
J = 14.7, 7.3 Hz, 1 H), 3.71 (dd, J = 14.2, 5.9 Hz, 1 H), 3.77–3.82
(m, 3 H), 3.89–3.97 (m, 2 H), 4.07–4.11 (m, 1 H), 5.55–5.60 (m, 2
H), 5.66–5.75 (m, 2 H), 9.68 (s, 2 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 23.7, 24.5, 28.4, 45.3, 47.8, 50.9, 51.3, 80.0, 80.5,
131.4, 136.0, 165.3 ppm. IR (neat): ν = 2935, 1659, 1551,
˜
1102 cm–1. HRMS (ESI): calcd. for C16H25NO3 [M + H]+
280.1912; found 280.1917.
N-{(S)-2-[(S)-1,4-Dioxaspiro[4.5]decan-2-yl]pent-4-enyl}-N-(4-meth-
oxybenzyl)acrylamide (64): NaH (430 mg of 60% NaH) was added
in a portionwise fashion to an ice-cold solution of 62 (500 mg,
1.79 mmol) in THF (6 mL), followed by dropwise addition of p-
methoxybenzyl chloride (0.32 mL, 2.32 mmol), and the reaction
mixture was allowed to attain room temperature gradually and
stirred at r.t. for 2 h. The mixture was cooled to 0 °C; this was
followed by addition of saturated aqueous NH4Cl solution and ex-
traction with EtOAc (3ϫ 20 mL). The organic layer was washed
with brine and dried with anhydrous Na2SO4. Column chromato-
graphic purification of the crude product over silica gel with
EtOAc/hexane (10%) gave compound 64 as a colourless viscous
126.3, 127.6, 129.1, 129.3, 155.1, 155.6, 202.2 ppm. IR (neat): ν =
˜
2975, 1727, 1694 cm–1. HRMS (ESI): calcd. for C12H19NO3 [M +
H]+ 226.1443; found 226.1443.
tert-Butyl (S)-3-(Hydroxymethyl)-2,3,4,7-tetrahydro-1H-azepine-1-
carboxylate (40): General Procedure J was followed for reduction
of aldehyde 38 (260 mg, 1.16 mmol). Compound 40 was obtained
as a colourless viscous oil, yield 244 mg (93%); Rf = 0.2 in EtOAc/
1
hexane (30%). [α]D = –11.6 (c = 1.2, CH2Cl2). H NMR (CDCl3,
400 MHz, rotamer ratio approximately 1:3): δ = 1.46 (br. s, 9 H),
1.48 (br. s, 9 H), 2.05–2.11 (m, 3 H, 1 H major rotamer, 2 H minor
rotamer), 2.25–2.29 (m, 3 H, 2 H major rotamer, 1 H minor rot-
amer), 3.15 (dd, J = 14.4, 4.0 Hz, 1 H major rotamer), 3.34–3.39
(m, 2 H minor rotamer), 3.46–3.54 (m, 4 H, 2 H major rotamer, 2
H minor rotamer), 3.79–3.84 (m, 2 H, 1 H major rotamer, 1 H
minor rotamer), 4.06–4.14 (m, 2 H, 1 H major rotamer, 1 H minor
rotamer), 4.24–4.29 (m, 1 H major rotamer), 5.69–5.75 (m, 4 H, 2
H major rotamer, 2 H minor rotamer) ppm. 13C NMR (CDCl3,
100 MHz): δ = 28.3, 28.7, 39.7, 40.7, 47.2, 47.3, 49.4, 63.4, 64.8,
oil, yield 392 mg (55%); Rf = 0.7 in EtOAc/hexane (30%). [α]D
=
1
–9.63 (c = 4, CH2Cl2). H NMR (CDCl3, 400 MHz, rotamer ratio
approximately 1:2): δ = 1.38 (br. s, 4 H, 2 H major rotamer, 2 H
minor rotamer), 1.54–1.58 (m, 16 H, 8 H major rotamer, 8 H minor
rotamer), 1.97–2.10 (m, 5 H, 3 H major rotamer, 2 H minor rot-
amer), 2.18–2.23 (m, 1 H minor rotamer), 3.31 (dd, J = 15.2,
8.5 Hz, 1 H minor rotamer), 3.47–3.58 (m, 3 H, 2 H major rotamer,
1 H minor rotamer), 3.64–3.69 (m, 1 H minor rotamer), 3.78 (br.
s, 1 H major rotamer), 3.79 (s, 3 H major rotamer), 3.81 (s, 3 H
minor rotamer), 3.90–3.96 (m, 1 H minor rotamer), 4.00–4.07 (m,
3 H, 2 H major rotamer, 1 H minor rotamer), 4.51–4.74 (m, 4 H,
2 H major rotamer, 2 H minor rotamer), 4.99–5.08 (m, 4 H, 2 H
major rotamer, 2 H minor rotamer), 5.64–5.83 (m, 4 H, 2 H major
rotamer, 2 H minor rotamer), 6.35–6.44 (m, 2 H, 1 H major rot-
amer, 1 H minor rotamer), 6.57 (dd, J = 16.7, 10.5 Hz, 1 H major
rotamer), 6.70 (dd, J = 16.6, 10.5 Hz, 1 H minor rotamer), 6.83–
6.89 (m, 4 H, 2 H major rotamer, 2 H minor rotamer), 7.08 (m, 2
H, 1 H, major rotamer, 1 H minor rotamer), 7.21 (d, J = 8.3 Hz,
1 H major rotamer), 7.29 (d, J = 8.3 Hz, 1 H minor rotamer) ppm.
13C NMR (CDCl3, 100 MHz): δ = 23.8, 23.9, 25.2, 33.3, 34.8, 36.2,
40.3, 41.9, 47.2, 47.5, 48.8, 51.1, 55.2, 64.9, 67.1, 67.6, 76.4, 76.8,
109.1, 109.4, 113.9, 114.2, 116.7, 117.8, 127.7, 128.0, 128.1, 128.5,
80.2, 128.4, 128.7, 130.2, 156.6 ppm. IR (neat): ν = 3404, 2927,
˜
1692, 1669, 1167 cm–1. HRMS (ESI): calcd. for C12H21NO3 [M +
H]+ 228.1600; found 228.1608.
(3S,4R,6S)-6-(Hydroxymethyl)azepane-3,4-diol (52): General Pro-
cedure E was adopted for hydrolysis of 46 (60 mg, 0.16 mmol). It
gave 52 as a colourless viscous oil, yield 23 mg (92%); Rf = 0.5 in
MeOH/EtOAc (50%). [α]D = –11.0 (c = 0.5, MeOH). 1H NMR
(D2O, 500 MHz): δ = 1.48 (d, J = 13.0 Hz, 1 H), 1.56–1.63 (m, 1
H), 1.68–1.76 (m, 1 H), 2.35 (dd, J = 13.8, 10.0 Hz, 1 H), 2.64 (dd,
J = 14.5, 6.0 Hz, 1 H), 2.71 (d, J = 18.0 Hz, 1 H), 2.76 (dd, J =
13.0, 5.5 Hz, 1 H), 3.25–3.30 (m, 2 H), 3.71 (d, J = 10.5 Hz, 1 H),
3.80 (br. s, 1 H) ppm. 13C NMR (D2O, 125 MHz): δ = 30.8, 37.6,
48.6, 49.6, 64.9, 71.6, 72.8 ppm. IR (neat): ν = 3373, 2930 cm–1.
˜
HRMS (ESI): calcd. for C7H15NO3 [M + H]+ 162.1130; found
162.1130.
128.9, 129.6, 134.7, 136.0, 159.1, 166.7, 167.3 ppm. IR (neat): ν =
˜
N-{(S)-2-[(S)-1,4-Dioxaspiro[4.5]decan-2-yl]pent-4-enyl}acrylamide
(62): A mixture of compounds 10 and 11 (2 g, 7.84 mmol) dissolved
in THF (7 mL) was added over a period of 30 min to an ice-cooled
suspension of LiAlH4 (745 mg, 19.6 mmol) in THF (7 mL), allowed
gradually to attain room temperature and stirred at r.t. for 6 h. The
2929, 1648, 1611, 1248 cm–1. HRMS (ESI): calcd. for C24H33NO4
[M + H]+ 400.2488; found 400.2486.
(S)-6-[(S)-1,4-Dioxaspiro[4.5]decan-2-yl]-1-(4-methoxybenzyl)-6,7-
dihydro-1H-azepin-2(5H)-one (66): General Procedure A for ring-
856
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 844–859

Homoisofagomines and Analogues as Glycosidase Inhibitors
closing metathesis was followed with 64 (400 mg, 1.0 mmol) in the
presence of the first-generation Grubbs catalyst (58 mg, 7 mol-%)
and with stirring for 24 h. This gave compound 66 as a colourless
viscous oil, yield 260 mg (70%); Rf = 0.2 in EtOAc/hexane (50%).
[α]D = –2.0 (c = 1, CH2Cl2). 1H NMR (CDCl3, 400 MHz): δ =
1.38–1.41 (m, 2 H), 1.53–1.61 (m, 8 H), 1.94–2.01 (m, 2 H), 2.17–
2.28 (m, 1 H), 3.34–3.46 (m, 3 H), 3.75–3.79 (m, 1 H), 3.79 (s, 3
H), 3.95 (dd, J = 8.0, 6.1 Hz, 1 H), 4.39 (d, J = 14.4 Hz, 1 H), 4.85
(d, J = 14.4 Hz, 1 H), 6.06 (d, J = 11.7 Hz, 1 H), 6.16–6.21 (m, 1
H), 6.85 (d, J = 8.8 Hz, 2 H), 7.26 (d, J = 8.3 Hz, 2 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 23.8, 25.1, 29.9, 34.9, 36.4, 44.8,
47.9, 50.5, 55.2, 67.4, 76.6, 109.6, 113.9, 127.4, 129.8, 129.9, 135.9,
(m, 2 H), 1.52–1.60 (m, 8 H), 1.95–2.03 (m, 2 H), 2.21–2.30 (m, 1
H), 3.41–3.45 (m, 3 H), 3.78 (q, J = 6.6 Hz, 1 H), 3.95 (dd, J =
8.0, 6.6 Hz, 1 H), 4.49 (d, J = 14.4 Hz, 1 H), 4.91 (d, J = 14.6 Hz,
1 H), 6.08 (d, J = 11.7 Hz, 1 H), 6.18–6.23 (m, 1 H), 7.26–7.33 (m,
5 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 23.8, 25.1, 29.7, 34.9,
36.3, 44.7, 48.8, 51.2, 67.4, 76.7, 109.7, 127.2, 127.5, 128.4, 128.6,
136.2, 137.7, 168.7 ppm. IR (neat): ν = 2933, 1654, 1607 cm–1
.
˜
HRMS (ESI): calcd. for C21H27NO3 [M + H]+ 342.2069; found
242.2065.
(3S,4S,6S)-1-Benzyl-6-[(S)-1,4-dioxaspiro[4.5]decan-2-yl]-3,4-di-
hydroxyazepan-2-one (72): Dihydroxylation of 70 (100 mg,
0.29 mmol) was carried out by General Procedure B. Compound
72 was obtained as a colourless viscous oil, yield 47 mg (42%); Rf
159.1, 168.6 ppm. IR (neat): ν = 2931, 1654, 1609, 1512, 1246 cm–1.
˜
HRMS (ESI): calcd. for C22H29NO4 [M + H]+ 372.2175; found
372.2176.
1
= 0.2 in EtOAc/hexane (60%). [α]D = +8.33 (c = 0.6, CH2Cl2). H
NMR (CDCl3, 500 MHz): δ = 1.41–1.44 (m, 2 H, cyclohexylidene),
1.49–1.56 (m, 6 H), 1.60–1.66 (m, 3 H, 2ϫ cyclohexylidene, H-5),
1.77–1.83 (m, 1 H, H-6), 1.89–1.94 (m, 1 H, H-5Ј), 2.49 (br. s, OH),
3.18 (dd, J = 15.5, 9.9 Hz, 1 H, H-7), 3.36 (dd, J = 8.3, 6.5 Hz, 1
H, H-9), 3.53 (d, J = 15.3 Hz, 1 H, H-7Ј), 3.66 (dd, J = 13.6, 6.5 Hz,
1 H, H-8), 3.90 (dd, J = 8.2, 6.5 Hz, 1 H, H-9Ј), 4.19 (br. s, 1 H,
H-4), 4.50 (br. s, 1 H, H-3), 4.61 (d, J = 14.5 Hz, 1 H, OCH2Ph),
4.75 (br, OH), 4.78 (d, J = 15.0 Hz, 1 H, OCH2Ph), 7.25–7.35 (m,
5 H, Ar-H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 26.4, 27.4,
28.8, 38.3, 39.7, 40.3, 52.9, 56.1, 70.9, 74.3, 77.0, 113.4, 131.4,
N-{(S)-2-[(S)-1,4-Dioxaspiro[4.5]decan-2-yl]pent-4-enyl}-N-benzyl-
acrylamide (68): NaH (344 mg, 14.3 mmol of 60% NaH or 206 mg,
8.6 mmol of pure NaH) was added portionwise to an ice-cold solu-
tion of 62 (400 mg, 1.4 mmol) in THF (5 mL), followed by addition
of PhCH2Br (0.22 mL, 1.86 mmol) in a dropwise fashion, and the
reaction mixture was allowed to attain room temperature gradually
and stirred at r.t. for 2 h. The reaction mixture was cooled to 0 °C,
followed by addition of saturated NH4Cl and extraction with
EtOAc (3ϫ 20 mL), washed with brine and dried with anhydrous
Na2SO4. Column chromatographic purification of the crude prod-
uct over silica gel with EtOAc/hexane (15%) gave compound 68 as
a colourless viscous oil, yield 299 mg (56%); Rf = 0.6 in EtOAc/
132.1, 132.3, 139.9, 175.9 ppm. IR (neat): ν = 3402, 2925, 2854,
˜
1650 cm–1. HRMS (ESI): calcd. for C21H27NO5 [M + H]+
376.2124; found 376.2122.
1
hexane (30%). [α]D = –14.0 (c = 0.5, CH2Cl2). H NMR (CDCl3,
(S)-1-Benzyl-6-[(S)-1,4-dioxaspiro[4.5]decan-2-yl]azepan-2-one (76):
Compound 76 was obtained by hydrogenolysis of compound 70
(70 mg, 0.21 mmol) as described in General Procedure D, as a
colourless viscous oil, yield 64 mg (91%); Rf = 0.5 in EtOAc/hexane
(50%). [α]D = –1.6 (c = 2.5, CH2Cl2). 1H NMR (CDCl3, 400 MHz):
δ = 1.33–1.71 (m, 14 H), 1.84–1.90 (m, 1 H), 2.60–2.65 (m, 2 H),
3.32 (dd, J = 15.2, 8.6 Hz, 1 H), 3.45–3.53 (m, 2 H), 3.75 (dd, J =
15.0, 6.6 Hz, 1 H), 3.96 (dd, J = 8.0, 6.1 Hz, 1 H), 4.52 (d, J =
14.4 Hz, 1 H), 4.73 (d, J = 14.4 Hz, 1 H), 7.24–7.33 (m, 5 H) ppm.
13C NMR (CDCl3, 100 MHz): δ = 22.2, 24.0, 24.2, 25.2, 32.7, 35.1,
36.5, 36.9, 42.8, 50.2, 51.2, 67.8, 76.4, 109.7, 127.4, 128.5, 128.6,
400 MHz, rotamer ratio approximately 2:3): δ = 1.38 (br. s, 4 H, 2
H major rotamer, 2 H minor rotamer), 1.55–1.58 (m, 16 H, 8 H
major rotamer, 8 H minor rotamer), 1.96–2.08 (m, 5 H, 2 H major
rotamer, 3 H minor rotamer), 2.18–2.23 (m, 1 H major rotamer),
3.53–3.58 (m, 4 H, 2 H major rotamer, 2 H minor rotamer), 3.66–
3.68 (m, 1 H major rotamer), 3.90–3.95 (m, 1 H minor rotamer),
4.03–4.08 (m, 3 H, 2 H major rotamer, 1 H minor rotamer), 4.58–
4.71 (m, 3 H, 2 H major rotamer, 1 H minor rotamer), 4.79–4.82
(m, 1 H minor rotamer), 4.99–5.07 (m, 4 H, 2 H major rotamer, 2
H minor rotamer), 5.63–5.81 (m, 4 H, 2 H major rotamer, 2 H
minor rotamer), 6.35–6.45 (m, 2 H, 1 H major rotamer, 1 H minor
rotamer), 6.54 (dd, J = 16.7, 10.4 Hz, 1 H major rotamer), 6.72
(dd, J = 16.4, 10.7 Hz, 1 H minor rotamer), 7.15–7.34 (m, 10 H, 5
H major rotamer, 5 H minor rotamer) ppm. 13C NMR (CDCl3,
100 MHz): δ = 23.7, 23.8, 23.9, 25.0, 25.1, 33.2, 33.3, 34.7, 34.9,
36.2, 40.3, 42.0, 47.6, 47.8, 49.5, 51.7, 67.1, 67.6, 76.3, 76.8, 109.2,
109.4, 116.9, 117.9, 126.4, 127.3, 127.6, 127.8, 128.1, 128.4, 128.5,
137.9, 175.8 ppm. IR (neat): ν = 2930, 2857, 1646 cm–1. HRMS
˜
(ESI): calcd. for C21H29NO3 [M + H]+ 344.2225; found 344.2221.
(R)-6-[(S)-1,4-Dioxaspiro[4.5]decan-2-yl]azepan-2-one (78): NBS
(124 mg, 0.69 mmol) was added at room temperature, together with
N-methylacetamide (NMA, 2 mg, cat. amount), to a stirred solu-
tion of 77 (48 mg, 0.13 mmol) in CHCl3 (2 mL) and the mixture
was allowed to stir in the open air and in the presence of light for
4 d. The reaction mixture was then stirred with NaOH (0.1 n,
1 mL) for 5 min and extracted with CH2Cl2 (4ϫ 10 mL), washed
with brine and dried with anhydrous Na2SO4. Column purification
of the crude product over silica gel with EtOAc/hexane (15–40%)
gave compound 78 as a colourless viscous oil, yield 2 mg (Ͻ 5%);
128.8, 134.7, 135.9, 137.0, 137.4, 166.8, 167.3 ppm. IR (neat): ν =
˜
2935, 1650, 1613 cm–1. HRMS (ESI): calcd. for C23H31NO3 [M +
H]+ 370.2382; found 370.2382.
Note: Strangely enough, during the benzylation (and also in the
case of p-methoxybenzylation) the reactions needed 6 equiv. of
NaH (60% in oil) to start, taking 2 h for completion. If done other-
wise (i.e., by using the base in lesser equivalents initially and adding
it subsequently to make it up to 6 equiv. or even more) there was
only slight progress in the reaction, which never reached comple-
tion.
1
Rf = 0.2 in EtOAc/hexane (70%). H NMR (CDCl3, 400 MHz): δ
= 1.33–1.61 (m, 13 H), 2.00–2.04 (m, 2 H), 2.47–2.49 (m, 2 H),
3.12–3.20 (m, 3 H), 3.98–4.02 (m, 2 H), 5.81 (br. s, NH) ppm. IR
(neat): ν = 3312, 2925, 1725, 1668 cm–1. HRMS (ESI): calcd. for
˜
C14H23NO3 [M + H]+ 254.1756; found 254.1753.
(S)-1-Benzyl-6-[(S)-1,4-dioxaspiro[4.5]decan-2-yl]-6,7-dihydro-1H-
azepin-2(5H)-one (70): General Procedure A for ring-closing me-
tathesis was followed with 68 (400 mg, 1.08 mmol) in the presence
of the first-generation Grubbs catalyst (27 mg, 3 mol-%) and with
stirring for 8 h. This gave compound 70 as a colourless viscous oil,
yield 336 mg (91%); Rf = 0.2 in EtOAc/hexane (50%). [α]D = –6.7
(c = 0.16, CH2Cl2). 1H NMR (CDCl3, 400 MHz): δ = 1.36–1.40
(3S,4S,6S)-1-Benzyl-6-[(S)-1,2-dihydroxyethyl]-3,4-dihydroxyazepan-
2-one (79): General Procedure E was followed for hydrolysis of 72
(31 mg, 0.08 mmol). Compound 79 was obtained as a colourless
viscous oil, yield 21 mg (86%); Rf = 0.6 in MeOH/EtOAc (20%).
[α]D = –37.0 (c = 0.7, MeOH). H NMR (D2O, 400 MHz, rotamer
ratio approximately 1:2): δ = 1.78–1.82 (m, 1 H minor rotamer),
1
1.86–1.98 (m, 3 H, 1 H major rotamer; 2 H minor rotamer), 2.02–
Eur. J. Org. Chem. 2014, 844–859
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
857

R. K. Basak, Y. D. Vankar
2.09 (m, 1 H major rotamer), 2.19–2.28 (m, 1 H major rotamer), (3R,4R,6S)-1-Benzyl-3,4-dihydroxy-6-(hydroxymethyl)azepan-2-one
FULL PAPER
3.23–3.67 (m, 9 H, 5 H major rotamer, 4 H minor rotamer), 3.98–
4.00 (m, 1 H minor rotamer), 4.21 (d, J = 15.2 Hz, 1 H minor
rotamer), 4.42 (d, J = 15.2 Hz, 1 H major rotamer), 4.57–4.60 (m,
3 H, 1 H major rotamer, 3 H minor rotamer), 5.02 (d, J = 14.4 Hz,
1 H minor rotamer), 5.88 (d, J = 11.0 Hz, 1 H major rotamer),
6.34–6.40 (m, 1 H major rotamer), 7.18–32 (m, 10 H, 5 H major
(91): Dihydroxylation of 89 (65 mg, 0.28 mmol) was performed as
described in General Procedure B. This led to compounds 91 and
92 (60 mg, 80% combined yield). Column chromatographic purifi-
cation was done with EtOAc/2% MeOH/EtOAc; pure compound
91 was obtained as a colourless viscous oil (although only 20 mg);
1
Rf = 0.1 in EtOAc. [α]D = –70 (c = 0.4, MeOH). H NMR (D2O,
rotamer, 5 H minor rotamer) ppm. 13C NMR (D2O, 100 MHz): δ 500 MHz): δ = 1.70–1.75 (m, 1 H), 1.81 (br. s, 1 H), 1.87–1.94 (m,
= 31.4, 34.5, 38.2, 43.8, 48.7, 49.4, 52.2, 52.9, 64.1, 64.6, 71.3, 72.1,
1 H), 3.37 (dd, J = 10.9, 5.2 Hz, 1 H), 3.39–3.47 (m, 3 H), 3.94–
3.95 (m, 1 H), 4.16 (d, J = 14.9 Hz, 1 H), 4.58 (br. s, 1 H), 4.91
(d, J = 15.2 Hz, 1 H), 7.16–7.29 (m, 5 H) ppm. 13C NMR (D2O,
125 MHz): δ = 34.0, 36.9, 47.9, 52.4, 62.8, 70.4, 127.7, 127.8, 128.9,
73.8, 128.8, 129.8, 137.5, 142.3, 171.9, 174.5 ppm. IR (neat): ν =
˜
3372, 2923, 2853, 1641, 1592 cm–1. HRMS (ESI): calcd. for
C15H21NO5 [M + H]+ 296.1498; found 296.1499.
136.5, 173.8 ppm. IR (neat): ν = 3428, 2925, 1639 cm–1. HRMS
˜
(S)-1-Benzyl-6-[(S)-1,2-dihydroxyethyl]azepan-2-one (83): Hydroly-
sis of compound 76 (32 mg, 0.09 mmol) as described in General
Procedure E led to compound 83 as a colourless viscous oil, yield
25 mg (quantitative); Rf = 0.3 in EtOAc. [α]D = –3.7 (c = 0.12,
MeOH). 1H NMR (CDCl3, 400 MHz): δ = 1.38–1.47 (m, 2 H),
1.53–1.62 (m, 1 H), 1.84–1.89 (m, 1 H), 1.94–2.01 (m, 1 H), 2.24
(br, OH), 2.55–2.64 (m, 2 H), 3.23 (d, J = 15.4 Hz, 1 H), 3.32–3.38
(m, 2 H), 3.47–3.53 (m, 2 H), 4.56 (d, J = 14.6 Hz, 1 H), 4.60 (d,
J = 14.6 Hz, 1 H), 7.26–7.35 (m, 5 H) ppm. 13C NMR (CDCl3,
125 MHz): δ = 22.9, 31.1, 36.7, 42.2, 50.5, 50.9, 63.6, 74.1, 127.5,
(ESI): calcd. for C14H19NO4 [M + H]+ 266.1392; found 266.1394.
Compound 91: 1H NMR (CDCl3, 500 MHz): δ = 1.95–2.04 (m, 2
H, H-5, H-6), 2.09–2.13 (m, 1 H, H-5Ј), 3.41–3.51 (m, 2 H, H-7,
H-7Ј), 3.64–3.67 (m, 1 H, H-8), 3.76–3.80 (m, 1 H, H-8Ј), 4.13 (br.
s, 1 H, H-4), 4.19 (d, J = 14.9 Hz, 1 H, OCH2Ph), 4.46 (br. s, 1 H,
H-3), 4.73–4.75 (m, OH), 5.31 (d, J = 14.9 Hz, 1 H, OCH2PhЈ),
7.25–7.34 (m, 5 H, Ar-H) ppm.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details and spectral data of new compounds;
1
copies of H and 13C NMR spectra and additional NMR spectra
128.5, 128.6, 137.5, 175.6 ppm. IR (neat): ν = 3392, 2928, 1615,
˜
1451 cm–1. HRMS (ESI): calcd. for C15H21NO3 [M + H]+
264.1600; found 264.1602.
for stereochemical analysis.
(R)-1-Benzyl-6-[(S)-1,2-dihydroxyethyl]-6,7-dihydro-1H-azepin-
2(5H)-one (86): Hydrolysis of 71 (213 mg, 0.62 mmol) as described
in General Procedure E gave compound 86 as a colourless viscous
oil, yield 163 mg (quantitative); Rf = 0.2 in EtOAc. [α]D = –33.5 (c
Acknowledgments
The authors thank the Department of Science and Technology
(DST), New Delhi, for a J. C. Bose National Fellowship (JCB/SR/
S2/JCB-26/2010) to Y. D. V. and the Council of Scientific and In-
dustrial Research (CSIR), New Delhi for financial support [grant
number: 02(0124)/13/EMR-II]. R. K. B. thanks CSIR for a Senior
Research Fellowship.
1
= 1.7, MeOH). H NMR (CDCl3, 400 MHz): δ = 1.96 (br. s, 1 H),
2.32–2.36 (m, 2 H), 3.19 (d, J = 12.9 Hz, 1 H), 3.32–3.37 (m, 2 H),
3.46–3.49 (m, 2 H), 4.52 (d, J = 14.6 Hz, 1 H), 4.83 (d, J = 14.6 Hz,
1 H), 6.04 (d, J = 12.0 Hz, 1 H), 6.24–6.29 (m, 1 H), 7.29–7.33 (m,
5 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 29.2, 42.9, 49.4, 51.1,
64.3, 73.3, 126.1, 127.6, 128.3, 128.7, 137.3, 138.4, 168.8 ppm. IR
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C15H19NO3 [M + H]+ 262.1443; found 262.1443.
(S)-1-Benzyl-7-oxo-2,3,4,7-tetrahydro-1H-azepine-3-carbaldehyde
(87): Compound 87 was obtained from 85 (270 mg, 1.03 mmol) by
General Procedure I for vicinal diol cleavage as a colourless viscous
oil, yield 200 mg (85%); Rf = 0.6 in EtOAc. [α]D = +13.3 (c = 0.6,
CH2Cl2). 1H NMR (CDCl3, 400 MHz): δ = 2.49–2.59 (m, 2 H),
2.70–2.77 (m, 1 H), 3.54–3.56 (m, 2 H), 4.44 (d, J = 14.6 Hz, 1 H),
4.94 (d, J = 14.4 Hz, 1 H), 6.13 (d, J = 11.7 Hz, 1 H), 6.25–6.31
(m, 1 H), 7.26–7.36 (m, 5 H), 9.46 (s, 1 H) ppm. 13C NMR (CDCl3,
125 MHz): δ = 26.5, 45.2, 50.9, 53.1, 127.9, 128.0, 128.5, 128.9,
135.2, 137.2, 168.7, 200.2 ppm. IR (neat): ν = 2927, 1723, 1647,
˜
1600 cm–1. HRMS (ESI): calcd. for C14H15NO2 [M + H]+
230.1181; found 230.1186.
(S)-1-Benzyl-6-(hydroxymethyl)-6,7-dihydro-1H-azepin-2(5H)-one
(89): General Procedure J for aldehyde reduction with 87 (145 mg,
0.63 mmol) gave compound 89 as a colourless viscous oil, yield
111 mg (76%); Rf = 0.35 in EtOAc. [α]D = –1.5 (c = 2, CH2Cl2).
1H NMR (CDCl3, 500 MHz): δ = 1.98–2.10 (m, 2 H), 2.31 (dt, J
= 16.5, 5.7 Hz, 1 H), 3.23–3.36 (m, 3 H), 3.41 (dd, J = 10.7, 5.4 Hz,
1 H), 4.55 (d, J = 14.6 Hz, 1 H), 4.77 (d, J = 14.6 Hz, 1 H), 6.03
(d, J = 11.9 Hz, 1 H), 6.21–6.25 (m, 1 H), 7.27–7.33 (m, 5 H) ppm.
13C NMR (CDCl3, 125 MHz): δ = 30.2, 43.1, 48.4, 51.2, 64.3,
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858
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: August 25, 2013
Published Online: November 26, 2013
Eur. J. Org. Chem. 2014, 844–859
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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