Synthesis of pyrrolidine-based imino sugars as glycosidase inhibitors

Article abstract of DOI:10.1002/ejoc.200700719

Two pyrrolidine-based imino sugars have been synthesized in an efficient manner, using regiospecific amination, ring closing metathesis, and diastereospecific dihydroxylations as key steps. These azasugars are found to be moderate inhibitors of glycosidas

Full text of DOI:10.1002/ejoc.200700719

FULL PAPER
DOI: 10.1002/ejoc.200700719
Synthesis of Pyrrolidine-Based Imino Sugars as Glycosidase Inhibitors
Venkata Ramana Doddi[a] and Yashwant D. Vankar*[a]
Keywords: Regiospecific amination / Ring closing metathesis / Diastereospecific dihydroxylation
Two pyrrolidine-based imino sugars have been synthesized
in an efficient manner, using regiospecific amination, ring
closing metathesis, and diastereospecific dihydroxylations as
key steps. These azasugars are found to be moderate inhibi-
tors of glycosidases.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Among the pyrrolidine-based azasugars,[5] 1,4-dideoxy-
1,4-iminohexitols, 1a, 1b, 1c, 1d (Figure 1) are more potent
glycosidase inhibitors[6,7] and the biological activity varies
depending on substitution patterns of the hydroxy groups.
Thus, while compounds 1a,[8a] 1b[8b,8c] and 1c[8d,8e] are in-
hibitors of α-mannosidases, a stereochemical analog 1d[8f]
acts as a potent inhibitor of α-galactosidases. One of the
characteristic features that these molecules possess is the
presence of 1,2-dihydroxyethyl side chain. Likewise, some
of the potent glycosidase inhibitors such as trehazolamine
2a,[9] 1-epitrehazolamine 2b,[9] valiolamine 3a,[10] voglibose
Introduction
Biosynthesis of oligosaccharides and glycoconjugates is
controlled by glycosidases and glycosyltransferases.[1] These
oligosaccharides and glycoconjugates play a major role in
various cellular functions such as cell adhesion, cell-cell dif-
ferentiation, metastasis and other metabolic disorders and
diseases. Therefore, development of inhibitors of such en-
zymes is of immense importance, and as a result there has
been explosive growth in the design, synthesis and bio-
logical evaluation of new glycosidase inhibitors.[2]
Among many glycosidase inhibitors, polyhydroxylated
nitrogen-containing heterocycles have been the subject of
immense interest in recent years.[3] Some of them such as
N-hydroxyethyl-1-deoxynojirimycin (miglitol) and N-butyl-
1-deoxynojirimycin are already marketed against type II di-
abetes and Gaucher’s disease, respectively. Besides these,
many other polyhydroxylated five- and six-membered, and
bicyclic aza heterocycles and their analogs are potent gly-
cosidase inhibitors. In addition to the use of such inhibitors
as potential drugs for the treatment of viral infections, can-
cer, HIV-AIDS, diabetes, Gaucher’s disease and other meta-
bolic disorders,[4,2b] analysis of their structures vis-à-vis the
associated biological activities may provide new mechanistic
insight into the glycoside cleavage and formation processes.
Many of these glycosidase inhibitors have therefore been
designed[2] to mimic the shape, configuration and charge
distribution of the cation liberated during the enzyme-cata-
lyzed processes.
[a] Department of Chemistry, Indian Institute of Technology,
Kanpur 208 016, India
Fax: +91-512-259-7436
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.
Figure 1. Some of the important glycosidase inhibitors.
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 5583
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V. R. Doddi, Y. D. Vankar
FULL PAPER
3b[11] (3S,4R,5S)-3,4,5-trihydroxy-5-(hydroxymethyl)piper- volved the use of the Baylis–Hillman adduct 6, obtained
idine 4a[12a,12b] and its enantiomer,[12c] (3S,4R,5R)-3,4,5-tri- from the aldehyde 5 as a masked diol, and ring closing me-
hydroxy-5-(hydroxymethyl)piperidine 4b[12a] and its enanti- tathesis to form the key five-membered ring core.
omer[12d] (Figure 1) contain quaternary carbons bearing a
Accordingly, the Baylis–Hillman reaction of (R)-2,3-O-
hydroxy and a hydroxymethyl group[12e] as key features.
isopropylidene-glyceraldehyde (5)[14] (Scheme 1) with ethyl
acrylate in the presence of DABCO gave 6 as a mixture of
two diastereomers[15] which was acetylated to obtain a mix-
ture of diastereomeric acetates 7. Treatment of 7 with p-
Results and Discussions
As part of on going research project in our laboratory toluenesulfonamide and DABCO underwent successive
towards the synthesis of natural and unnatural azasugars SN2Ј–SN2Ј displacement reactions regiospecifically to give
and hybrid sugars,[13] we became interested in synthesizing the amine 8 whose treatment with allyl bromide yielded two
new pyrrolidine-based azasugars with combined structural chromatographically separable dienes 9 and 10 in 58:42 ra-
features as pointed above viz. having 1,2-dihydroxyethyl tio in 86% yield. Separation of the dienes by column
side chains and a quaternary C atom holding a hydroxy and chromatography led to the isolation of the more polar com-
a hydroxymethyl group. This was perceived from the point pound 9 as a crystalline solid and subsequent recrystalli-
of view in finding out if these combined features make any zation from CH2Cl2 and hexane (1:9) at 0 °C followed by
difference in selective and/or improved inhibition. Thus, we X-ray analysis permitted its structural characterization.[16]
wish to report the synthesis of two new polyhydroxylated Based on the structure of 9, the other diastereomer was
azasugars 18 and 26. The key steps in their synthesis in- assigned structure 10. Reduction of the unsaturated ester 9
Scheme 1. Synthesis of imino sugar 18.
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Pyrrolidine-Based Imino Sugars as Glycosidase Inhibitors
with DIBAL-H at –30 °C gave the primary alcohol 11 in compound 17 revealed that they are in cis relationship.
76% yield which was characterized as its acetate 12. Likewise, protons H-7 and H-6 and H-5 were also found to
Alcohol 11 was subjected to detosylation with sodium be cis to each other which indicated that the carbon side
naphthalenide solution in DME[17] followed by acetylation chains are cis to each other and oriented in β-fashion
to form the diacetate 13.
whereas the acetoxy groups at C-3 and C-4 are α-oriented.
Initially the diacetate 13 was treated with catalytic This obviously confirms that the dihydroxylation had taken
amount of Grubbs’ first-generation ruthenium complex place on the face opposite to the acetonide moiety. In a
A,[16] but no reaction was observed even not in refluxing similar fashion, the structure of compound 25 was estab-
toluene. On the other hand, treatment of diene 13 with the lished for which the NOE correlations are shown in Fig-
more reactive second-generation Grubbs’ catalyst B[16] ure 2.
(5 mol-%) in toluene at 60 °C for 3 h gave one single prod-
uct 14 in 89% yield. Dihydroxylation of 14 was performed
by using a catalytic amount of OsO4 in the presence of
NMO which afforded exclusively one diastereomeric diol
15. It appears that the bulky acetonide group blocks the β-
face of the trisubstituted double bond of the pyrrolidine
ring and is responsible for high diastereoselectivity. Subse-
quent cleavage of the acetonide group gave the tetrahydroxy
compound 16 which was subjected to acetylation affording
hexaacetate 17. Treatment of this hexaacetate with 6  HCl
followed by treatment with basic Dowex gave the expected
product 18 in quantitative yield.
Figure 2. NOE correlations of compounds 17 and 25.
Likewise, the diastereomer 26 was synthesized from the
The inhibitory activity of iminosugars 18 and 26 were
diene 10 similar to the synthesis of compound 18 (from tested against a few glycosidases[18] and the same is shown
compound 9) using the same synthetic sequence and reac- in Table 1. Thus, pyrrolidine 18 was specifically found to
tion conditions as shown in Scheme 2. Since the stereocen- show moderate inhibition of β-galactosidase and showed
ters at C-2 and C-7 of compound 18 were already estab- no inhibition of α-glucosidase, β-glucosidase, α-galactosid-
lished by the X-ray crystal structure of compound 9, the ase and α-mannosidase. On the other hand, pyrrolidine 26
overall stereochemistry of both 18 and 26 was confirmed showed no inhibition of α-glucosidase, β-glucosidase and β-
from the COSY and NOE (Figure 2) experimental data[16] glactosidase but reasonable inhibition of α-glactosidase and
of the corresponding pentaacetates viz. 17 and 25, respec- α-mannosidase at 0.1 and 0.22 m concentrations, respec-
tively. Thus, the NOE correlation between H-4 and H-5 of tively.
Scheme 2. Synthesis of imino sugar 26.
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V. R. Doddi, Y. D. Vankar
FULL PAPER
was added DABCO (985 mg, 8.8 mmol). Tosylamide (759 mg,
4.4 mmol) was then added slowly and stirred it for 4 h at room
temperature. Usual workup and column chromatographic purifica-
tion gave 8 as a mixture of two diastereomers (58:42) (1.06 g, 69%
yield). 1H NMR (400 MHz, CDCl3): δ = 7.47 (d, major, J =
8.32 Hz, 2 H, Ar-H), 7.64 (d, minor, J = 8.32 Hz, 2 H, Ar-H), 7.28–
7.22 (m, both isomers, 4 H, Ar-H), 6.25 (s, 1 H, major), 6.03 (s, 1
H, minor), 5.80 (s, 1 H, major), 5.75 (d, J = 10.24 Hz, 1 H, minor),
5.51 (s, 1 H, minor), 5.35 (d, J = 7.56 Hz, 1 H, major), 4.26–4.05
(m, 3 H, both isomers), 3.99–3.87 (m, 2 H, both isomers), 3.52 (dd,
J = 8.56, 5.12 Hz, 1 H, major), 2.41 (s, 3 H, Ar-CH3, minor), 2.40
(s, 3 H, ArCH3, major), 1.36 [s, 3 H, C(CH3)2, major], 1.34 [s, 3
H, C(CH3)2, minor], 1.29–1.21 [m, 3 H, C(CH3)2, 3 H, OCH2CH3,
both isomers] ppm. 13C NMR (100 MHz, CDCl3): δ = 165.6, 143.4,
137.6, 137.2, 137.1, 135.1, 130.0, 129.6, 129.5, 129.4, 128.4, 127.2,
110.2, 109.8, 76.2, 75.6, 67.4, 66.2, 61.1, 59.9, 55.8, 26.7, 26.2, 25.0,
24.7, 21.5, 14.0, 13.9 ppm. ESMS: m/z = 406 [M + Na]+.
C18H25NO6S (383.46): calcd. C 56.38, H 6.57, N 3.65, O 25.03, S
8.36; found C 56.41, H 6.58, N 3.67.
Table 1. IC50 values for compounds 18 and 26.
Enzyme
18
26
α-Glucosidase (rice)
NI[a]
NI[a]
β-Glucosidase (almonds)
α-Galactosidase (coffee beans)
β-Galactosidase (bovine liver)
α-Mannosidase (jack beans)
NI[a]
NI[a]
NI[a]
0.1 m
0.28 m
NI[a]
NI[a]
0.22 m
[a] NI: no inhibition at 3 m concentration, inhibition studies were
carried out at 0.1 m concentrations, optimal pH of the enzymes,
at 37 °C.
It is noteworthy that a compound similar to that of 18
but devoid of the hydroxymethyl side chain at C-3
showed[19a] inhibition against α-mannosidase at 0.12 m
concentration. Likewise, a similar analog of 26 devoid of
hydroxymethyl side chain at C-3 was reported[19b] to be
active against β-glucosidase at 0.32 m concentration.
Similarly, 5-hydroxy-ribo-isofagomine and its enantiomer,
each bearing a quaternary carbon bonded to a hydroxy and
a hydroxymethyl group have been reported[12a] to inhibit α-
and β-glucosidases whereas compounds 18 and 26 show no
inhibition of these enzymes. Clearly there is a change both
in terms of specificity as well as the inhibition constant val-
ues as a result of the combination of the structural features
as aimed in the present studies.
Procedure for the Allylation of Compound 8: A mixture of 8
(900 mg, 0.42 mmol) and allyl bromide (0.042 mL, 0.5 mmol) in
3 mL of dry DMF was treated with K2CO3 (115 mg, 0.84 mmol)
and stirred at room temperature for 2 h. Usual workup and column
chromatographic purification gave a mixture of two diastereomers
(9:10, 58:42) (854 mg, 86% yield).
Ethyl
2-{(R)-(N-Allyl-4-methylphenylsulfonylamino)[(4S)-2,2-di-
methyl-1,3-dioxolan-4-yl]methyl}acrylate (9): White crystalline so-
lid. [α]2D8 = +36.25 (c = 0.8, CH2Cl2), m.p. 154 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.76 (d, J = 8.32 Hz, 2 H, Ar-H), 7.23 (d,
J = 8.32 Hz, 2 H, Ar-H), 6.41 (s, 1 H, 1-H), 5.92 (s, 1 H, 1-H),
5.74 (merged tdd, J = 10.24, 17.08, 4.16 Hz, 1 H, 2Ј-H), 5.10 (dd,
J = 17.32, 1.48 Hz, 1 H, 3Ј-H), 5.03 (dd, J = 10.24, 1.24 Hz, 1 H,
3Ј-H), 4.82 (d, J = 9.28 Hz, 1 H), 4.77–4.71 (m, 1 H, 5-H), 4.14 (q,
J = 7.32 Hz, 2 H, OCH2CH3), 3.99–3.95 (m, 3 H), 3.55 (dd, 1 H,
8.54, 6.84), 2.40 (s, 3 H, Ar-CH3), 1.39 [s, 3 H, C(CH3)2], 1.33 [s,
3 H, C(CH3)2], 1.29 (t, J = 7.28 Hz, 3 H, OCH2CH3) ppm. 13C
NMR (100 MHz, CDCl3): δ = 166.0, 142.8, 138.1, 137.6, 135.6,
129.8, 129.0, 128.0, 117.1, 109.9, 74.9, 67.5, 61.3, 59.6, 49.1, 26.4,
25.3, 21.4, 14.0 ppm. ESMS: m/z = 446 [M + Na]+. C21H29NO6S
(423.52): calcd. C 59.55, H 6.90, N 3.31, O 22.67, S 7.57; found C
59.89, H 6.92, N 3.34.
Conclusions
In conclusion, we have described efficient methods for
the synthesis of iminosugars 18 and 26 which are moderate
inhibitors of β-galactosidase, and α-glacto- and α-manno-
sidases, respectively. It is expected that further structural
variations of these pyrrolidines could improve inhibition
values.
Experimental Section
(R)-Ethyl 2-[Acetoxy(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]acrylate
(7): To a solution of 6 (1 g, 4.34 mmol) in 3 mL of dry CH2Cl2
were added Ac2O (0.5 mL, 5.2 mmol), Et3N (0.9 mL, 5.2 mmol)
and catalytic amount of DMAP. After stirring for 3 h at ambient
temperature, usual workup with water and CH2Cl2 gave a crude
product which was purified by column chromatography to give 7
Ethyl
2-{(S)-(N-Allyl-4-methylphenylsulfonylamino)[(4S)-2,2-di-
methyl-1,3-dioxolan-4-yl]methyl}acrylate (10): White solid. [α]2D8
=
+180 (c = 1.15, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.64
(d, J = 8.32 Hz, 2 H, Ar-H), 7.23 (d, J = 8.32 Hz, 2 H, Ar-H), 6.46
(s, 1 H, 1-H), 5.98 (s, 1 H, 1-H), 5.86–5.78 (m, 1 H, 2Ј-H), 5.24–
5.16 (m, 2 H), 4.75 (br. s, 2 H), 4.16–4.08 (m, 2 H), 4.05–3.98 (m,
2 H), 3.91 (dd, J = 6.56, 1.00 Hz, 2 H), 2.40 (s, 3 H, Ar-CH3), 1.37
[s, 3 H, C(CH3)2], 1.33 [s, 3 H, C(CH3)2], 1.98 (t, J = 7.32 Hz, 3 H,
OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.3, 143.1,
137.4, 135.9, 135.2, 130.0, 129.2, 127.7, 118.8, 109.9, 74.9, 67.5,
61.0, 58.5, 49.8, 26.8, 25.7, 21.4, 14.0 ppm. ESMS: m/z = 446 [M
+ Na]+. C21H29NO6S (423.52): calcd. C 59.55, H 6.90, N 3.31, O
22.67, S 7.57; found C 59.01, H 6.92, N 3.30.
1
as a mixture of two diastereomers (69:31) (1.15 g, 98% yield). H
NMR (400 MHz, CDCl3): δ = 6.40 (s, 1 H, both isomers), 5.90 (s,
1 H, minor), 5.88 (s, 1 H, major), 5.78 (d, J = 4.16 Hz, 1 H, major),
5.68 (d, J = 5.12 Hz, 1 H, major), 4.45–4.40 (m, 1 H, both isomers),
4.27–4.22 (m, 2 H, both isomers), 4.01–3.96 (m, 1H both isomers),
3.89 (dd, J = 8.80, 5.88 Hz, 1 H, major), 3.80 (dd, J = 8.52,
5.88 Hz, 1 H, minor), 2.12 (s, 3 H, minor), 2.11 (s, 3 H, major),
1.46 (s, 3 H, minor), 1.40 (s, 3 H, minor), 1.35–1.25 (m, 6 H, both
isomers) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.4, 164.9,
137.1, 137.0, 127.9, 127.6, 110.1, 109.9, 76.0, 75.9, 71.7, 70.9, 65.7,
65.2, 61.1, 26.3, 26.1, 25.4, 25.2, 20.1, 20.0, 14.1 ppm. ESMS: m/z
= 295 [M + Na]+. C13H20O6 (272.29): calcd. C 57.34, H 7.40, O
35.25; found C 57.35, H 7.42.
(3R)-3-(N-Allyl-4-methylphenylsulfonylamino)-3-[(4S)-2,2-dimethyl-
1,3-dioxolan-4-yl]-2-methylenepropyl Acetate (12): A solution of un-
saturated ester 9 (800 mg, 1.891 mmol) in 10 mL of dry CH2Cl2
was cooled to –78 °C under N2 before slowly adding DIBAL
(5.67 mL, 1  in toluene, 5.67 mmol). After addition of DIBAL,
Ethyl (S)-2-[(2,2-Dimethyl-1,3-dioxolan-4-yl)(4-methylphenylsulfon- the temperature was slowly raised to –30 °C and stirred at that
ylamino)methyl]acrylate (8): To a stirred solution of the Baylis–Hill- temperature for 30 min. The reaction mixture was quenched by
man acetate 7 (1.1 g, 4.04 mmol) in 5 mL of dry CH2Cl2 at 0 °C slow addition of MeOH until evolution of gas bubbles ceased, con-
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Pyrrolidine-Based Imino Sugars as Glycosidase Inhibitors
centrated at reduced pressure followed by column chromatographic
purification to get the desired product 11 (595 mg, 83% yield).
To the solution of 11 (50 mg, 0.13 mmol) in 1 mL of dry CH2Cl2
were added Ac2O (0.015 mL, 0.156 mmol), Et3N (0.021 mL,
0.156 mmol) and catalytic amount of DMAP. After stirring for 2 h
at ambient temperature, usual workup gave the crude product
which was purified by column chromatography to give 12 colorless
oil (53.28 mg, 96% yield). [α]2D8 = –53.3 (c = 0.15, CH2Cl2). 1H
minor) 5.88 (s, 1 H, 4-H, major), 5.09 (s, 1 H, 2-H, major), 4.81
(d, major, J = 14.16 Hz, 1 H, 6-H), 4.72 (d, major, J = 14.16 Hz,
1 H, 6Ј-H), 4.63 (td, major, J = 2.92, 6.84 Hz, 1 H, 7-H), 4.48 (d,
major, J = 17.36 Hz, 1 H, minor), 4.36 (m, 1 H, minor), 4.24 (d,
major, J = 14.64 Hz, 1 H, 5-H), 4.15 (dd, major, J = 1.92, 14.64 Hz,
1 H, 5Ј-H), 3.95 (dd, major, J = 6.60, 8.32 Hz, 1 H, 8-H), 3.74
(merged dd, major, J = 7.32, 8.28 Hz, 1 H, 8Ј-H), 3.62 (merged dd,
major, J = 7.32, 8.04 Hz, 1 H, minor), 2.18 (s, 3 H, COCH3, minor),
NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 8.32 Hz, 2 H, Ar-H), 2.11 (s, 3 H, COCH3, minor), 2.09 (s, 3 H, COCH3, major), 2.07
7.24 (d, J = 8.32 Hz, 2 H, Ar-H), 5.69–5.62 (m, 1 H, 2Ј-H), 5.37
(s, 1 H, 1-H), 5.12 (s, 1-H), 5.07 (dd, J = 1.44, 17.32 Hz, 1 H, 3Ј-
(s, 3 H, COCH3, major), 1.44 [s, 3 H, C(CH3)2, minor], 1.39 [s, 3
H, C(CH3)2, major], 1.34 [s, 3 H, C(CH3)2, minor], 132 [s, 3 H,
H), 4.97 (dd, J = 1.24, 10.00 Hz, 1 H, 3Ј-H), 4.56–4.50 (m, 4 H, C(CH3)2, major] ppm. 13C NMR (100 MHz, CDCl3): δ = 170.1,
2H-CH2OAc, 3-H, 4-H), 4.05–3.97 (m, 2 H, 5-H, 1Ј-H), 3.77 (dd, 170.0,136.5, 132.7, 108.8, 74.6, 65.2, 63.3, 60.9, 54.5, 25.9, 24.7,
J = 1.44, 16.8 Hz, 1 H, 1Ј-H), 3.54 (dd, J = 8.52, 6.8 Hz, 1 H, 5- 22.4, 20.8 ppm. ESMS: m/z = 306 [M + Na]+. C14H21NO5 (283.32):
H), 2.41 (s, 3 H, Ar-CH3), 2.11 (s, 3 H, COCH3), 1.58 [s, 3 H,
C(CH3)2], 1.37 [s, 3 H, C(CH3)2] ppm. 13C NMR (100 MHz,
CDCl3): δ = 170.4, 143.0, 140.0, 138.1, 135.2, 129.0, 128.1, 117.8,
117.1, 109.6, 73.9, 68.0, 65.4, 60.34, 47.2, 26.4, 25.0, 21.5, 20.9 ppm.
ESMS: m/z = 446 [M + Na]+. C21H29NO6S (423.52): calcd. C
59.55, H 6.90, N 3.31, O 22.67, S 7.57; found C 59.57, H 6.91, N
3.30.
calcd. C 59.35, H 7.47, N 4.94, O 28.24; found C 59.41, H 7.39, N
4.98.
(2S,3R,4R)-3-(Acetoxymethyl)-1-acetyl-2-[(1S)-1,2-diacetoxyethyl]-
pyrrolidine-3,4-diyl Diacetate (17): To a stirred solution of com-
pound 14 (100 mg, 0.353 mmol) in acetone/water/tBuOH (1:1:0.4)
at room temperature, were added NMO·H2O (57 mg, 0.423 mmol)
and OsO4 (4 µL, 0.004 equiv.). The reaction mixture was stirred for
16 h and then treated with Na2S2O5 (80.4 mg, 0.423 mmol). The
reaction mixture was stirred for further 1 h and extracted with Ac-
OEt (2 ϫ 15 mL). The organic layer was washed with 1  HCl,
water and finally with brine. Usual workup thereafter gave a crude
product which was purified by column chromatography to give the
diol 15 (94 mg, 84 % yield). To a solution of diol 15 (60 mg,
0.189 mmol) in 2 mL of MeOH was added catalytic amount of
HCl, stirred for 5 min and then passed the reaction mixture
through DOWEX (50X) basic resin column. Concentration under
reduced pressure to get the tetrahydroxy compound followed by
acetylation with excess of triethylamine and Ac2O (1:1, 4 mL) and
catalytic amount of DMAP at room temperature for 8 h gave a
crude product which was purified by column chromatography to
give hexaacetate 17 (76 mg, 91% yield two steps) as colorless oil.
(3R)-3-(N-Allylacetamido)-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-
2-methylenepropyl Acetate (13): To a solution of naphthalene
(512 mg, 4 mmol) in 10 mL of dry DME was added Na (85.2 mg,
4 mmol) and solution stirred at room temperature for 2 h under N2
atmosphere to give sodium naphthalenide solution (0.4 ). To a
solution of 11 (500 mg, 1.31 mmol) in 3 mL of dry DME was added
freshly prepared sodium naphthalenide solution (7 mL, 2.8 mmol)
was added at –78 °C until decolorization of reagent stops in solu-
tion. After stirring at –78 °C for 5 min, the solution was quenched
with saturated NH4Cl solution and the organic layer was washed
with brine, and dried with Na2SO4. After removal of the solvent
the residue was subjected to acetylation in 5 mL of dry CH2Cl2
using Ac2O (0.47 mL, 5 mmol), Et3N (0.7 mL, 5 mmol) and cata-
lytic amount of DMAP. After stirring for 8 h at ambient tempera-
ture, usual workup and chromatographic purification gave 13 as a
[α]2D8 = +20.01 (c = 0.45, CH2Cl2). H NMR (400 MHz, CDCl3): δ
1
colorless oil (195 mg, 63% overall yield for 2 steps). [α]2D8 = –40.923
= mixture of rotamers (87:13): δ = 5.59 (dd, J = 8.32, 8.28 Hz, 1
1
(c = 3.25, CH2Cl2). H NMR (400 MHz, CDCl3): δ = mixture of H, 4-H), 5.34–5.33 (m, 1 H, 7-H), 5.07 (d, J = 1.48 Hz, 1 H, 2-H),
rotamers (67:33): δ = 5.87–5.80 (m, 1 H, 2Ј-H), 5.43 (s, 1 H, 1-H,
minor), 5.35 (s, 1 H, 1-H), 5.23–5.03 (m, 4 H, 1-H, 3-H, 3Ј-H),
4.53–4.40 (m, 3 H, CH2OAc, 4-H), 4.41 (d, J = 5.4 Hz, 1 H, 4-H,
minor), 4.13 (dd, J = 8.52, 6.56 Hz, 1 H, 5-H, minor), 4.08 (dd, J
= 8.52, 6.32 Hz, 1 H, 5-H), 3.91–3.88 (m, 2 H, 1Ј-H), 3.63 (dd, J
= 8.56, 6.60 Hz, 1 H, 5-H), 3.51 (dd, J = 8.52, 7.08 Hz, 1 H, 5-H
4.84 (d, J = 12.68 Hz, 1 H, 6-H), 4.51 (d, J = 12.7 Hz, 1 H, 6Ј-H),
4.33 (dd, J = 11.72, 4.88 Hz, 1 H, 8-H), 4.05–3.96 (m, 2 H, 5-H,
8Ј-H), 3.41 (dd, J = 9.52, 8.04 Hz, 1 H, 5Ј-H) ppm. 2.15 (s, 3 H,
COCH3), 2.11 (s, 3 H, COCH3), 2.08 (s, 3 H, COCH3), 2.05 (s, 3
H, COCH3), 2.03 (br. s, 6 H, COCH3). 13C NMR (100 MHz,
CDCl3): δ = 171.0, 170.5, 170.1, 169.7, 169.6, 169.3, 85.6, 71.6,
minor), 2.25 (s, 3 H, COCH3, minor), 2.17 (s, 3 H, COCH3), 2.09 (s, 70.3, 63.8, 60.7, 60.6, 49.4, 21.9, 21.6, 21.1, 20.7, 20.6, 20.5 ppm.
3 H, COCH3, minor), 2.09 (s, 3 H, COCH3), 1.45 [s, 3 H, C(CH3)2,
minor], 1.42 [s, 3 H, C(CH3)2], 1.34 [s, 3 H, C(CH3)2], 1.33 [s, 3 H,
C(CH3)2, minor] ppm. 13C NMR (400 MHz, CDCl3): δ = 172.2,
170.5, 141.0, 135.0, 116.9, 116.8, 109.5, 74.4, 67.3, 65.2, 54.9, 47.9,
26.4, 25.2, 22.3, 20.9 ppm. Minor isomer: 171.6, 170.2, 139.9, 134.9,
118.1, 116.1, 109.4, 73.5, 67.8, 65.6, 61.8, 44.3, 24.4, 22.0 ppm.
ESMS: m/z = 334 [M + Na]+. C16H25NO5 (311.37): calcd. C 61.72,
H 8.09, N 4.50, O 25.69; found C 61.76, H 8.10, N 4.79.
ESMS: m/z = 468 [M + Na]+. C19H27NO11 (445.42): calcd. C 51.23,
H 6.11, N 3.14, O 39.51; found C 51.13, H 6.25, N 3.00.
N-Allyl-N-{(S)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(ethoxy-
methyl)allyl}-4-methylbenzenesulfonamide (20): A solution of unsat-
urated ester 10 (800 mg, 1.891 mmol) in 10 mL of CH2Cl2 was co-
oled to –78 °C under N2 before slowly adding of DIBAL (5.67 mL,
1  in toluene, 5.67 mmol). After addition of DIBAL, the tempera-
ture was slowly raised to –30 °C and stirred at that temperature for
30 min. The reaction mixture was quenched by slow addition of
MeOH until evolution of gas bubbles ceased, concentrated at re-
duced pressure followed by column chromatographic purification
to get the desired product 19 (544 mg, 1.48 mmol, 76% yield). To
the solution of 19 (50 mg, 0.13 mmol) in 1 mL of dry CH2Cl2 were
added Ac2 O (0.015 mL, 0.156 mmol), Et3 N (0.021 mL,
0.156 mmol) and catalytic amount of DMAP. After stirring for 2 h
at ambient temperature, usual workup gave the crude product
which was purified by column chromatography to give 20
(53.28 mg, 0.125 mmol, 96% yield). [α]2D8 = +48.4 (c = 2.05,
{(2R)-1-Acetyl-2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,5-dihydro-
1H-pyrrol-3-yl}methyl Acetate (14): To a stirred solution of com-
pound 13 (150 mg, 0.482 mmol) in dry toluene at room tempera-
ture was added the Grubbs’ 2nd generation catalyst (5 mol-%). The
mixture was heated up to 60 °C and stirred for 3 h and after com-
pletion of the reaction, the solvent was evaporated under reduced
pressure and the crude product purified by column chromatog-
raphy to obtain compound 14 (116 mg, 86% yield) as a viscous
liquid. [α]2D8 = +70.40 (c = 2.94, CH2Cl2). 1H NMR (400 MHz,
CDCl3): δ = [mixture of rotamers (89:11)]: δ = 6.00 (s, 1 H, 4-H,
Eur. J. Org. Chem. 2007, 5583–5589
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5587

V. R. Doddi, Y. D. Vankar
FULL PAPER
CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.71 (d, J = 8.32 Hz,
C(CH3)2, minor], 1.30 [s, 3 H, C(CH3)2, major] ppm. 13C NMR
1
2 H, Ar-H), 7.31 (d, J = 8.32 Hz, 2 H, Ar-H), 5.78–5.68 (m, 1 H, (100 MHz, CDCl3): δ = 170.4, 169.4, 137.3, 127.1, 123.8, 109.1,
2Ј-H), 5.48 (s, 1 H, 1-H), 5.41 (s, 1 H, 1Ј-H), 5.15–5.10 (m, 2 H, 67.4, 64.9, 61.4, 53.8, 26.1, 24.9, 22.3, 20.8 ppm. ESMS: m/z = 306
3Ј-H), 4.51–4.50 (m, 2 H, 3-H, 4-H), 4.26 (d, J = 13.40 Hz, 1 H,
CH2OAc), 4.12–4.06 (m, 2 H, 5-H), 4.02 (d, J = 13.40 Hz, 1 H,
CH2OAc), 3.91 (dd, J = 5.12, 16.12 Hz, 1 H, 1Ј-H), 3.58 (dd, J =
8.32, 16.12 Hz, 1 H, 1Ј-H), 2.43 (s, 3 H, Ar-CH3), 2.05 (s, 3 H,
COCH3), 1.42 [s, 3 H, C(CH3)2], 1.35 [s, 3 H, C(CH3)2] ppm. 13C
NMR (100 MHz, CDCl3): δ = 170.1, 143.8, 138.1, 137.3, 135.5,
129.7, 127.4, 119.5, 118.4, 110.0, 74.5, 67.5, 65.5, 59.7, 47.4, 26.7,
25.7, 21.5, 20.8 ppm. ESMS: m/z = 446 [M + Na]+. C21H29NO6S
(423.52): calcd. C 59.55, H 6.90, N 3.31, O 22.67, S 7.57; found C
59.59, H 6.91, N 3.35.
[M + Na]+. C14H21NO5 (283.32): calcd. C 59.35, H 7.47, N 4.94,
O 28.24; found C 59.79, H 7.96, N 4.86.
(2R,3S,4S)-3-(Acetoxymethyl)-1-acetyl-2-[(1S)-1,2-diacetoxyethyl]-
pyrrolidine-3,4-diyl Diacetate (25): To a stirred solution of com-
pound 22 (100 mg, 0.353 mmol) in acetone/water/tBuOH (1:1:0.4)
at room temperature, were added NMO·H2O (57 mg, 0.423 mmol)
and OsO4 (4 µL, 0.004 equiv.). The reaction mixture was stirred for
16 h and then it was treated with Na2S2O5 (80.4 mg, 0.423 mmol).
The reaction mixture was stirred for further 1 h and extracted with
AcOEt (2ϫ15 mL). The organic layer was washed with 1  HCl,
water and finally with brine. Usual workup thereafter gave a crude
product which was purified by column chromatography to give the
diol 23 (91.8 mg, 0.289 mmol, 82% yield). To the solution of diol
23 (60 mg, 0.189 mmol) in 2 mL of MeOH was added catalytic
amount of HCl and stirred for 5 min and then passed the reaction
mixture through DOWEX (50X) basic resin column and concen-
trate under reduced pressure to get the tetra hydroxy compound
followed by acetylation with excess of triethylamine and Ac2O (1:1,
4 mL) and catalytic amount of DMAP at room temperature for
8 h. The usual workup gave a crude product which was purified by
column chromatography to give hexaacetate 25 (79.8 mg,
0.179 mmol, 95% yield two steps). Colorless oil, [α]2D8 = –5.01 (c =
(3S)-3-(N-Allylacetamido)-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-
2-methylenepropyl Acetate (21): To a solution of naphthalene
(512.8 mg, 4 mmol) in 10 mL of dry DME was added Na (85.2 mg,
4 mmol) and solution stirred at room temperature for 2 h under N2
atmosphere to give sodium naphthalenide solution (0.4 ). To a
solution of 19 (500 mg, 1.31 mmol) in 3 mL of dry DME was added
freshly prepared sodium naphthalenide solution (7 mL, 2.8 mmol)
at –78 °C until decolorization of reagent stops in solution. After
stirring at –78 °C for 5 min, the solution was quenched with satu-
rated NH4Cl solution and the organic layer was washed with brine,
and dried with Na2SO4. After removal of the solvent the residue
was subjected to acetylation in 5 mL of dry CH2Cl2 using Ac2O
(0.47 mL, 5 mmol), Et3N (0.7 mL, 5 mmol) and catalytic amount
of DMAP. After stirring for 8 h at ambient temperature, usual
workup and chromatographic purification gave 21 as a colorless oil
(195 mg, 0.627 mmol, 63% overall yield for 2 steps). [α]2D8 = +45.07
1
0.6, CH2Cl2). H NMR (400 MHz, CDCl3): δ = [mixture of rota-
mers (95:5)]: δ = 5.55 (t, 1 H, 4-H), 5.41 (m, 1 H, 7-H), 5.02 (d, J
= 5.36 Hz, 1 H, 2-H), 4.85 (d, J = 12.2 Hz, 1 H, 6-H), 4.73 (d, J =
12.2 Hz, 1 H, 6Ј-H), 4.30 (dd, J = 12.2, 4.16 Hz, 1 H, 8-H), 4.14
(dd, J = 11.96, 7.32 Hz, 1 H, 8Ј-H), 3.92 (dd, J = 9.52, 8.52 Hz, 1
H, 2-H), 3.37 (dd, J = 9.28, 9.00 Hz, 1 H, 5Ј-H), 2.11–2.04 (6 s, 18
H, 6OAc) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.5, 170.5,
169.9, 169.8, 169.6, 169.4, 85.0, 71.6, 70.2, 63.1, 61.0, 60.8, 48.1,
22.0, 21.6, 20.9, 20.7, 20.6, 20.5 ppm. ESMS: m/z = 468 [M +
Na]+. C19H27NO11 (445.42): calcd. C 51.23, H 6.11, N 3.14, O 39.5;
found C 51.10, H 6.20, N 3.12.
1
(c = 3.15, CH2Cl2). H NMR (400 MHz, CDCl3): δ = [mixture of
rotamers (78:22)]: δ = 5.82–5.79 (m, 1 H, 2Ј-H, minor), 5.78–5.68
(m, 1 H, 2-H, major), 5.56 (s, 1 H, minor), 5.48 (s, 1 H, 1-H, major),
5.47 (s, 1 H, 1-H, major), 5.24–5.07 (m, 3 H, 3Ј-H, 3-H, major),
4.53–4.40 (m, 3 H, CH2OAc, 4-H, major), 4.02 (dd, major, J =
8.32, 6.12 Hz, 1 H, 5-H), 3.83–3.79 (m, 5-H, 1Ј-H, major), 2.23 (s,
3 H, COCH3, minor), 2.11 (s, 3 H, COCH3, major), 2.08 (s, 3 H,
COCH3, major), 2.07 (s, 3 H, COCH3, minor), 1.38 [s, 3 H,
C(CH3)2, major], 1.37 [s, 3 H, C(CH3)2, minor], 1.32 [s, 3 H,
C(CH3)2, minor], 1.30 [s, 3 H, C(CH3)2, major] ppm. 13C NMR
(100 MHz, CDCl3): δ = 171.8, 170.5, 139.6, 134.2, 117.9, 117.8,
109.9, 74.3, 67.3, 65.1, 56.3, 47.7, 26.5, 25.4, 22.1, 20.8 ppm. Minor
isomer: 170.8, 170.1, 138.7, 134.4, 119.4, 117.4, 110.3, 74.3, 66.5,
65.9, 60.8, 45.1, 27.2, 25.2, 25.1, 21.8 ppm. ESMS: m/z = 334 [M
+ Na]+. C16H25NO5 (311.37): calcd. C 61.72, H 8.09, N 4.50, O
25.69; found C 61.78, H 8.11, N 4.6.
(2S,3R,4R)-2-[(1S)-1,2-Dihydroxyethyl]-3-(hydroxymethyl)pyrrol-
idine-3,4-diol (18): To the solution of hexaacetate 17 (50 mg,
0.111 mmol) in 3 mL of MeOH was added concd. HCl (0.5 mL)
and stirred for 12 h and then passed the reaction mixture through
DOWEX (50X) basic resin column and concentrate under reduced
pressure to get the imino sugar 18 in quantitative yield. Light
1
brownish solid, [α]2D8 = +3.06 (c = 0.1, H2O). H NMR (400 MHz,
D2O): δ = 4.07 (br. s, 1 H), 3.80 (br. s, 1 H), 3.56–3.47 (m, 4 H),
3.20 (br. s, 1 H), 2.89 (br. m, 1 H), 2.59 (br. s, 1 H) ppm. ESMS:
m/z = 194 [M + H]+. C7H15NO5 (193.20): calcd. C 43.52, H 7.83,
N 7.25, O 41.4; found C 43.23, H 7.97, N 7.19.
{(2S)-1-Acetyl-2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,5-dihydro-
1H-pyrrol-3-yl}methyl Acetate (22): To a stirred solution of com-
pound 21 (150 mg, 0.482 mmol) in dry toluene at room tempera-
ture was added the Grubbs’ 2nd generation catalyst (5 mol-%). The
mixture was heated up to 60 °C and stirred for 3 h and after com-
pletion of the reaction, the solvent was evaporated under reduced
pressure and the crude product was purified by column chromatog-
raphy to obtain compound 22 (116 mg, 0.409 mmol, 86% yield) as
a viscous liquid. [α]2D8 = –55.93 (c = 2.95, CH2Cl2). 1H NMR
(400 MHz, CDCl3): δ = [mixture of rotamers (80:20)]: δ = 5.95 (s,
1 H, H-4, minor), 5.85 (s, 1 H, H-4, major), 4.90 (d, 1 H,CHHOAc,
J = 13.40 Hz, major), 4.83 (br. s, 1 H, H-2, major), 4.63 (d, 1 H,
CHHOAc, J = 13.9 Hz, major), 4.35 (dd, 1 H, H-7, J = 6.36,
4.88 Hz, major), 4.23 (m, 2 H, H-5, major), 4.09 (dd, 1 H, H-8, J
= 6.84, 9.04 Hz, major), 4.01 (dd, 1 H, H-8Ј, J = 6.36, 9.28 Hz,
major), 2.23 (s, 3 H, minor), 2.12 (s, 3 H, COCH3, minor), 2.09 (s,
(2R,3S,4S)-2-[(1S)-1,2-Dihydroxyethyl]-3-(hydroxymethyl)pyrrol-
idine-3,4-diol (26): To the solution of hexaacetate 25 (50 mg,
0.111 mmol) in 3 mL of MeOH was added concd. HCl (0.5 mL)
and stirred for 12 h and then passed the reaction mixture through
DOWEX (50X) basic resin column and concentrate under reduced
pressure to get the imino sugar 26 in quantitative yield. white solid,
1
[α]2D8 = –2.32 (c = 0.1, H2O). H NMR (400 MHz, D2O): δ = 3.80
(t, J = 5.36 Hz, 1 H), 3.69 (d, J = 12.20 Hz, 1 H), 3.58 (m, 2 H),
3.43 (d, J = 12.44 Hz, 1 H), 3.40 (m, 1 H), 3.05 (dd, J = 11.96,
6.12 Hz, 1 H), 2.86 (d, J = 9.52 Hz, 1 H), 2.58 (dd, J = 11.96,
4.88 Hz, 1 H) ppm. ESMS: m/z = 194 [M + H]+. C7H15NO5
(193.20): calcd. C 43.52, H 7.83, N 7.25, O 41.4; found C 43.27, H
7.89, N 7.30.
3 H, COCH3, major), 2.07 (s, 3 H, COCH3, major), 1.38 [s, 3 H, CCDC-646079 (for compound 9) contains the supplementary crys-
C(CH3)2, major], 1.37 [s, 3 H, C(CH3)2, minor], 1.32 [s, 3 H, tallographic data for this paper. These data can be obtained free
5588
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5583–5589

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of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Supporting Information (see also the footnote on the first page of
this article): X-ray data for compound 9, copies of spectra for all
new compounds 7, 8, 9, 10, 12, 13, 14, 17, 18, 20, 21, 22, 25, 26.
Acknowledgments
We thank the Department of Science and Technology (DST), New
Delhi, for financial support to Y. D. V. in the form of Ramanna
Fellowship. D. V. R. thanks the Council of Scientific and Industrial
Research (CSIR), New Delhi, for senior research fellowship.
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Received: July 31, 2007
Published Online: September 25, 2007
Eur. J. Org. Chem. 2007, 5583–5589
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5589