Total synthesis of L-(+)-swainsonine and other indolizidine azasugars from D-glucose

Article abstract of DOI:10.1002/ejoc.200800649

A total synthesis of L-(+)-swainsonine, a potent and specific inhibitor of naringinase, along with the syntheses of six unnatural indolizidine azasugars are reported by starting from D-glucose. L-(+)-Swainsonine was synthesized in 14 steps in 17% overall yield. Further, two of the indolizidine analogues were found to be good glycosidase inhibitors at micromolar concentrations. In all of these syntheses, the key step was an intramolecular S_N2 reaction. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800649

FULL PAPER
DOI: 10.1002/ejoc.200800649
Total Synthesis of
L
-(+)-Swainsonine and Other Indolizidine Azasugars from
-Glucose
D
Mohammad Abrar Alam,[a] Amit Kumar,[a] and Yashwant D. Vankar*[a]
Keywords: Nitrogen heterocycles / Azasugars / Epoxides / Nucleophilic substitution
A total synthesis of
inhibitor of naringinase, along with the syntheses of six un-
natural indolizidine azasugars are reported by starting from
L
-(+)-swainsonine, a potent and specific
were found to be good glycosidase inhibitors at micromolar
concentrations. In all of these syntheses, the key step was an
intramolecular SN2 reaction.
D
-glucose.
L
-(+)-Swainsonine was synthesized in 14 steps in
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
17% overall yield. Further, two of the indolizidine analogues
Introduction
Since 1966 more than 100 azasugars have been isolated
from various plants and microorganisms.[1] Owing to their
potent glycosidase inhibition activity, a large number of
structural analogues[2] have also been prepared and tested
as therapeutically potent inhibitors. Two of these synthetic
analogues, polyhydroxylate piperidines Miglitol[3] and Mig-
lustat,[4] have been approved as drugs against Type-2 diabe-
tes and Gaucher’s disease, respectively. Among these aza-
sugars, the indolizidine class of glycosidase inhibitors has
attracted much attention due to their potent and selective
glycosidase inhibition activities. Thus, whereas -(–)-swain-
sonine (1; Figure 1) shows anticancer activity,[5] (+)-cas-
tanospermine is a potent antiviral agent[6] and (+)-lentigi-
nosine is an amyloglucosidase inhibitor.[7] To obtain more-
potent as well as more-selective inhibitors, a large number
of swainsonine analogues have been synthesized[8] and
evaluated for their glycosidase inhibition activity. It is well
established that changes in the configuration of chiral cen-
ters change the inhibition activity of the resultant molecule;
for example, -(+)-swainsonine is a potent inhibitor of nar-
inginase at submicromolar concentration, whereas -(–)-
swainsonine does not inhibit naringinase.[9] Similarly, ad-
dition of a substituent in the indolizidine core of swainson-
Figure 1. Enantiomers of swainsonine.
It is believed that inhibitors of naringinase, which process
nonmammalian sugars, might be useful in controlling dis-
eases caused by mycobacteria.[13] Although a number of
molecules[2c,8,14] have been reported as naringinase inhibi-
tors, only a few of them (Figure 2) show good inhibition
activity. While we were preparing this manuscript, Fleet[14e]
et al. reported the total synthesis of -(+)-swainsonine
along with the synthesis of an analogue showing inhibition
activity at nanomolar concentrations. Apart from this, Fleet
et al.[9] earlier synthesized -(+)-swainsonine from octanol-
actone, whereas Hirama et al.[15] synthesized it from substi-
tuted butyrolactone. Recently, O’Doherty et al.[16] reported
the de novo synthesis of this molecule from furan and bu-
ine changes its selectivity as well as its potency.[10] Pearson
[11]
et al.
reported the synthesis and glycosidase inhibition
study of -(–)-swainsonine analogues with an additional
substituent in the indolizidine core, and they found that
some of the analogues were more potent than -(–)-swain-
sonine in their ability to inhibit jack bean α-mannosidase.
Many other analogues are documented in the literature.[12]
[a] Department of Chemistry, Indian Institute of Technology,
Kanpur 208016, India
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 2. Naringinase inhibitors.
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-(+)-Swainsonine and Other Indolizidine Azasugars from -Glucose
tyrolactone. In addition, a racemic synthesis of swainsonine
is also reported in literature.[17] In continuation of our ef-
forts to obtain pharmacologically promising glycosidase in-
hibitors[18] and our interest in the functionalization of
sugars[19] in an effort to obtain glycosidase inhibitors, we
hereby report the synthesis of -(+)-swainsonine and a few
analogues of swainsonine with an additional hydroxymethyl
substituent. It was reported that an extra hydroxymethyl
substituent in azasugars enhances the interaction with the
active site of glycosidases, and it provides conformational
flexibility to the molecule as well.[20]
Retrosynthetic analysis for -(+)-swainsonine (2) is
shown in Scheme 1. This involves two crucial intramolecu-
lar SN2 cyclizations leading to the formation of two rings
successively. The stereochemically significant epoxide 4
could be readily assembled from -(+)-glucose following
the manipulation of the exocylic 1,2-diol unit.
Scheme 1. Retrosynthetic analysis.
As outlined in Scheme 2, diol 3 was obtained from -
glucose following literature procedures.[21a,21b,22a,22b] How-
ever, the configuration at C-5 needed to be inverted, and (Scheme 2), which was characterized by the presence of an
this was achieved by converting diol 3 into epoxide 4 in internal olefinic proton at δ = 5.81 ppm and the C-1 proton
1
69% overall yield[23] through sequential treatment of this at δ = 5.72 ppm in its H NMR spectrum apart from other
diol with pivaloyl chloride (to form the ester of the primary spectroscopic data.[25] The free hydroxy group was pro-
alcohol), followed by treatment with mesyl chloride/Et3N. tected as a benzyl ether by using NaH/benzyl bromide[22a]
The corresponding mesylate was then treated with K2CO3 to give 6 in 97% yield. Removal of the isopropylidene group
in methanol.
and introduction of a methoxy group at the anomeric car-
Regiospecific ring opening[24] of epoxide 4 with allylmag- bon atom was carried out by treating 6 with 10% HCl in
nesium chloride at –10 °C gave alcohol 5 in 95% yield MeOH, which afforded 7 in excellent yield. Again, the free
Scheme 2.
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4973

M. A. Alam, A. Kumar, Y. D. Vankar
FULL PAPER
hydroxy group so liberated was protected as a benzyl ether
The spectral and analytical data of -(+)-swainsonine
and compound 8 was obtained in 80% yield. The acetal were in complete agreement with the literature data. The
1
group in compound 8 was deprotected by using 3  HCl in structure was further confirmed by analyzing the H and
refluxing dioxane followed by the reduction of the hemiace- 13C NMR, COSY, and nOe spectroscopic data of its acetate
tal group with NaBH4 to form diol 9 in 88% yield.[26] For- derivative 15. In the nOe experiment (Figure 3), irradiation
1
mation of the diol was confirmed from its H NMR spec- of the H-5 proton did not show any enhancement in the H-
troscopic data, which showed the disappearance of the 2, H-3, or H-4 protons. In contrast, irradiation of the H-3
OMe peak and further indicated the formation of a single proton enhanced the signal for the H-2 and H-4 protons.
diastereomer. Diol 9 was converted into dimesylate 10 with These observations confirmed the absolute stereochemistry
mesyl chloride and Et3N in an excellent yield, which was of -(+)-swainsonine triacetate and consequently that of -
characterized by the presence of two mesyl peaks as a sing- (+)-swainsonine.
let at δ = 2.93 ppm. The double bond was cleaved with
OsO4 and NaIO4[27] to give the corresponding aldehyde. Re-
duction of this aldehyde with NaBH4 gave hydroxy dimesyl-
ate 11 in 90% yield. Initially, it was anticipated that treat-
ment of trimesylate 12, obtained from dimesylate 11 upon
treatment with MsCl/Et3N, with benzylamine would di-
rectly afford[28] desired bicyclic moiety 13. However, this re-
action was not clean, and it led to the formation of several
products from which we could not isolate any pure com-
pound. We therefore decided to proceed with compound 11
in two steps. Thus, 11 was heated with neat benzylamine at
90 °C for 12 h, which afforded compound 14 in 91% yield.
Disappearance of the two mesylate group signals and inte-
gration of the phenyl protons in its 1H NMR spectrum
along with other spectroscopic data[25] confirmed the for-
mation of the pyrrolidine ring. This cyclization, as a conse-
quence of the intramolecular SN2 reaction, inverted[29] the
configuration at the stereocenter of the secondary mesylate.
This was further confirmed by nOe experiments of bicyclic
triacetate 15 obtained later (vide infra). In order to con-
struct the second ring, alcohol 14 was treated with MsCl/
Et3N in CH2Cl2; a very polar compound, most likely a qua-
Figure 3. nOe correlations.
A known analogue of swainsonine, viz. 26, having a trans
1,2-diol unit in the pyrrolidine ring and a 5β-OH group is
known to be an inhibitor of cytosolic β--galactosidase of
human liver.[32] We hereby report its new synthesis, as
shown in Scheme 3, from epoxide 16 having the β-configu-
ration, which was obtained from -glucose according to a
literature procedure.[31] The sequence of reactions followed
were essentially the same as that used for the synthesis of
-(+)-swainsonine (Scheme 2). The structures of the inter-
mediate products and 26 were confirmed by H and 13C
1
NMR, COSY, and nOe spectroscopic analysis.[25]
In order to obtain the indolizidine azasugars with an ad-
ternary ammonium chloride salt,[30] was isolated, which ditional hydroxymethyl substituent, dimesylate 23 was
upon hydrogenolysis[16] with 10% Pd/C in MeOH at 5 atm heated in neat benzylamine at 90 °C for 15 h to afford pyr-
H2 gave desired compound 2 in 78% yield.
rolidine derivative 27 (Scheme 4) in 85% yield. The primary
Scheme 3.
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-(+)-Swainsonine and Other Indolizidine Azasugars from -Glucose
Scheme 4.
hydroxy group of 27 was protected as a trityl ether followed was further supported by the nOe interactions between the
by mesylation of the secondary hydroxy group. Treatment pseudoequatorial H-1a and H-8 protons and the pseudo-
of mesylate 29 with a half-weight equivalent of 10% Pd/C axial H-1b and H-9 protons.
in methanol under 1 atm H2 afforded two diastereomeric
To obtain the other set of isomers, epoxide 37 (Scheme 5)
cyclized products 30 and 31. These diastereomers were with the inverted configuration at C-5 was prepared. For
chromatographically separated and separately detritylated this purpose, diol 36 was treated with pivaloyl chloride fol-
and hydrogenolyzed in one pot by treating with 10% Pd/C lowed by treatment with mesyl chloride to get the corre-
in TFA/MeOH (2:3) at 5 atm H2 for 30 h to afford 32 and sponding mesyl ester, which was treated with K2CO3 in
33, respectively. The absolute stereochemistry and struc- methanol to afford desired epoxide 37 in 69% overall yield.
tures of these molecules were confirmed from the spectro- By using the same sequence of reactions as employed for
scopic data of their acetate derivatives 34 and 35,[25] respec- the synthesis of 26, dimesylate 44 was obtained from 37 in
tively.
excellent yield. Upon treatment with benzylamine at 90 °C,
In the case of 34, nOe interactions between the H-4 and dimesylate 44 gave pyrrolidine-derived diol 45 in 91% yield,
H-9 protons confirmed the S configuration of the newly which was cleaved by treating with NaIO4 followed by re-
generated chiral center, which was further confirmed by the duction with NaBH4 to give 47 in 95% yield. This hydroxy
nOe between the H-1a and H-9 protons. So, the configura- derivative of pyrrolidine was treated with MsCl/Et3N fol-
tion of the newly generated chiral center of 35 is R. This lowed by hydrogenolysis with Pd/C at 5 atm H2 to give 48
Scheme 5.
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M. A. Alam, A. Kumar, Y. D. Vankar
FULL PAPER
1
in 78% yield, which was characterized by the H and 13C ingly, the same enzyme was not inhibited by 26. Thus, the
NMR, COSY, and nOe spectroscopic data of its acetate de- extra hydroxymethyl substituent plays an important role in
rivative 49.[25]
the inhibition activity of the indolizidine azasugars.
The other set of isomers with a hydroxymethyl substitu-
ent viz. 54 and 55 were obtained from compound 44 in an
analogous manner to that shown in Scheme 6.[25]
Conclusion
In conclusion, short and efficient syntheses of -(+)-
swainsonine and indolizidine azasugars were achieved from
-glucose, a cheap and commercially available starting ma-
terial. Enzyme inhibition activities showed the significance
of the extra hydroxymethyl substituent.
Experimental Section
(3aR,6R,6aR)-6-Benzyloxy-2,2-dimethyl-5-[(2S)-oxiran-2-yl]tetra-
hydrofuro[2,3-d][1,3]dioxole (4): To a solution of diol 3 (5 g,
16.1 mmol) in CH2Cl2 (50 mL) was added pyridine (1.9 mL,
24.2 mmol) and PivCl (2.3 mL, 18.7 mmol) at 0 °C. The mixture
was stirred at ambient temperature for 8 h and then diluted with
Et2O (50 mL). The organic layer was washed with 1  HCl (30 mL),
saturated aqueous NaHCO3 (30 mL), and brine (50 mL), dried
with MgSO4, filtered, and concentrated in vacuo. The crude prod-
uct was dissolved in CH2Cl2 (50 mL) and treated with triethylamine
(4.4 mL, 31.7 mmol) at 0 °C, followed by the addition of MsCl
(2.5 mL, 32.1 mmol) and DMAP (0.09 g, 0.078 mmol). The mix-
ture was stirred overnight at room temperature and then poured
into saturated aqueous NH4Cl and extracted with CH2Cl2
(3ϫ50 mL). The combined organic layer was washed with brine
(50 mL), dried with MgSO4, filtered, and concentrated in vacuo.
The crude mesylate was dissolved in methanol (100 mL) and
K2CO3 (4.8 g, 35.0 mmol) was added, and the mixture was stirred
overnight at room temperature. The mixture was concentrated and
diluted with brine (100 mL), extracted with Et2O (3 ϫ100 mL),
dried with MgSO4, and concentrated in vacuo. Purification by col-
umn chromatography gave 4 (3.24 g, 69% overall yield) as a color-
Scheme 6.
The absolute stereochemistry of the molecules was con-
firmed from the spectroscopic data of their acetate deriva-
tives 56 and 57. Thus, in the case of 56, nOe interactions
between the H-1b and H-8 protons confirmed the R config-
uration of the newly generated chiral center, which was fur-
ther supported by the nOe interaction between the H-1a
and H-9 protons. Similarly, in 57 nOe interactions between
the H-1b and H-9 protons confirmed the reverse S configu-
ration of the newly generated chiral center, which was fur-
ther confirmed by the nOe interaction between the pseu-
doaxial H-1a and H-8 protons.
The inhibitory activities of compounds 32, 33, 54, and
55, all of which have an extra hydroxymethyl substituent,
towards six commercially available enzymes were then
evaluated (Table 1). Of these four indolizidine azasugars,
compounds 33 and 55 showed good inhibition activity
against α-glucosidase obtained from baker’s yeast. Interest-
less semisolid. [α]2D5 = +32 (c = 0.5, CH Cl ). IR (thin film): ν =
˜
2
2
3031, 2988, 1496, 1455, 1252, 860 cm–1
.
1H NMR (400 MHz,
CDCl3): δ = 7.38–7.28 (m, 5 H), 5.69 (d, J = 3.6 Hz, 1 H), 4.79 (d,
J = 11.9 Hz, 1 H), 4.62 (d, J = 11.9 Hz, 1 H), 4.56 (t, J = 3.8,
7.8 Hz, 1 H), 4.03 (dd, J = 3.9, 9.0 Hz, 1 H), 3.78 (dd, J = 4.4,
9.0 Hz, 1 H), 3.08 (m, 1 H), 2.87 (dd, J = 2.6, 5.4 Hz, 1 H), 2.78
(dd, J = 4.4, 5.6 Hz, 1 H), 1.58 (s, 3 H), 1.35 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 137.3, 128.5, 128.1, 128.0, 113.2,
104.1, 79.0, 72.4, 51.0, 44.2, 29.6, 26.8, 26.4 ppm. HRMS (ESI):
calcd. for C16H20O5 [M + Na]+ 315.1208; found 315.1201.
(1S)-1-{(3aR,6R,6aR)-6-Benzyloxy-2,2-dimethyltetrahydrofuro[2,3-
d][1,3]dioxol-5-yl}pent-4-en-1-ol (5): To a stirred suspension of a
mixture of Mg (65.73 mg, 27.39 mmol) in THF (10 mL) and a cata-
lytic amount of I2 at 0 °C was added allyl chloride (0.66 mL,
8.21 mmol). After disappearance of the iodine color, the solution
was further cooled to –10 °C and epoxide 4 (2.0 g, 6.84 mmol) in
THF (5 mL) was added dropwise. After 1 h of stirring, the reaction
mixture was quenched with aqueous NH4Cl (15 mL) and extracted
with ethyl acetate (2ϫ15 mL). The combined organic layers was
washed with brine (15 mL), dried with MgSO4, concentrated in
vacuo, and purified by silica gel chromatography to obtain colorless
viscous liquid 5 (2.17 g, 95%). [α]2D5 = +61.3 (c = 0.75, CH2Cl2). IR
Table 1. IC50 values for compounds 32, 33, 54 and 55.[a]
Enzymes
32
33
54
55
α-Mannosidase (Jack beans)
β-Glucosidase (Almonds)
α-Galactosidase (Green coffee)
α-Glucosidase (Baker’s yeast)
β-Galactosidase (Bovine liver)
NI
NI
NI
NI
NI
NI
NI
NI
56 µ
NI
NI
NI
NI
NI
NI
NI
NI
NI
30.15 µ
NI
(thin film): ν = 3435, 3065, 2985, 2933, 1640, 1454, 1373, 1309,
˜
1217, 1130, 1024, 912, 886, 739, 699 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 7.40–3.29 (m, 5 H), 5.85–5.76 (m, 1 H), 5.73 (d, J =
3.4 Hz, 1 H), 5.07–4.96 (m, 2 H), 4.76 (d, J = 11.7 Hz, 1 H), 4.59
[a] NI: no inhibition at a concentration of 3 m; optimal pH of the
enzymes at 37 °C.
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-(+)-Swainsonine and Other Indolizidine Azasugars from -Glucose
(d, J = 11.7 Hz, 1 H), 4.56 (d, J = 3.9 Hz, 1 H), 3.98 (dd, J = 2.4,
7.38–7.25 (m, 15 H), 5.81–5.74 (m, 1 H), 5.01–4.92 (m, 3 H), 4.69
9.0 Hz, 1 H), 3.86 (dd, J = 4.4, 9.0 Hz, 1 H), 3.62 (m, 1 H), 2.26– (d, J = 12.2 Hz, 1 H), 4.59–4.56 (m, 2 H), 4.49 (d, J = 11.7 Hz, 1
2.11 (m, 2 H), 1.72–1.61 (m, 2 H), 1.59 (s, 3 H), 1.36 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 138.1, 137.5, 128.4, 128.0, 114.9,
113.1, 104.2, 80.8, 76.6, 72.3, 69.3, 33.7, 29.9, 26.9, 26.5 ppm.
HRMS (ESI): calcd. for C19H26O5 [M + H]+ 335.1858; found
335.1849.
H), 4.32 (d, J = 11.7 Hz, 1 H), 4.22 (dd, J = 5.4, 7.5 Hz 1 H), 4.01
(dd, J = 4.4, 7.5 Hz, 1 H), 3.85 (d, J = 4.3 Hz, 1 H), 3.43–3.38 (m,
2 H), 3.32 (s, 3 H), 2.33–2.12 (m, 2 H), 1.70–1.67 (m, 2 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 138.9, 138.5, 137.7, 128.4, 128.1,
128.0, 127.8, 127.6, 127.3, 114.6, 105.7, 82.8, 79.2, 78.0, 72.3, 72.3,
55.0, 29.8, 29.5 ppm. HRMS (ESI): calcd. for C31H36O5 [M + H]+
489.2641; found 489.2638.
(3aR,6R,6aR)-6-Benzyloxy-5-[(1S)-1-benzyloxypent-4-enyl]-2,2-di-
methyltetrahydrofuro[2,3-d][1,3]dioxole (6): NaH (60% suspension
in paraffin oil, 0.29 g, 11.97 mmol) was added in small portions to
(2S,3R,4R,5S)-2,3,5-Tribenzyloxynon-8-en-1,4-diol (9): Compound
a stirred solution of 5 (2.00 g, 5.98 mmol) in DMF (40 mL). After 8 was dissolved in p-dioxane (30 mL). To this solution was added
30 min, benzyl chloride (0.82 mL, 6.58 mmol) was added dropwise,
and the reaction mixture was stirred for 4 h at room temperature.
The reaction mixture was poured into ice, and it was then extracted
3  HCl (10 mL). The reaction mixture was heated at reflux over-
night and then neutralized with solid NaHCO3 at 0 °C. The aque-
ous layer was extracted with ethyl acetate (3 ϫ 50 mL), and the
with diethyl ether (60 mL) followed by washing with water combined organic layer was dried with MgSO4 and concentrated
(3ϫ50 mL), dried with MgSO4 and concentrated in vacuo, which
gave a crude product. Purification of the crude product by column
chromatography gave colorless semi solid 6 (2.46 g, 97 % yield).
in vacuo. The hemiacetal product was dissolved in methanol
(30 mL) and cooled to 0 °C. To this solution was added NaBH4
(0.31 g, 7.02 mmol), and the reaction mixture was stirred at room
temperature for 2 h. The mixture was then diluted with water
(40 mL) and extracted with ethyl acetate (3ϫ50 mL). The com-
[α]2D5 = +94 (c = 0.5, CH Cl ). IR (thin film): ν = 3030, 2983, 2930,
˜
2
2
1
1640, 1495, 1375, 1214, 1167, 1072, 1023, 1167, 738, 698 cm–1. H
NMR (400 MHz, CDCl3): δ = 7.36–7.23 (m, 10 H), 5.78 (m, 2 H), bined organic layer was dried with MgSO4 and concentrated in
5.03–4.95 (m, 2 H), 4.68 (d, J = 11.7 Hz, 1 H), 4.56 (t, J = 3.9 Hz,
1 H), 4.53 (d, J = 11.7 Hz, 1 H), 4.43 (d, J = 11.7 Hz, 1 H), 4.38
(d, J = 11.7 Hz, 1 H), 4.10 (dd, J = 2.6, 8.8 Hz, 1 H), 3.83 (dd, J
= 4.4, 8.8 Hz, 1 H), 3.54 (dt, J = 2.6, 6.5 Hz, 1 H), 2.14 (m, 2 H),
1.84–1.75 (m, 2 H), 1.58 (s, 3 H), 1.35 (s, 3 H) ppm. 13C NMR
vacuo. Purification by silica gel column chromatography afforded
9 (1.45 g, 88% yield) as a viscous liquid. [α]2D5 = +54 (c = 0.5,
CH Cl ). IR (thin film): ν = 3434, 3063, 3030, 2929, 1720, 1639,
˜
2
2
1605, 1496, 1398, 1271, 1068, 912, 735, 698 cm–1
.
1H NMR
(400 MHz, CDCl3): δ = 7.35–7.25 (m, 15 H), 5.77 (m, 1 H), 5.03–
(100 MHz, CDCl3): δ = 138.5, 138.2, 137.6, 128.3, 128.2, 128.1, 4.96 (m, 2 H), 4.78 (d, J = 11.2 Hz, 1 H), 4.79–4.69 (d, J = 11.7 Hz,
128.0, 127.9, 127.5, 114.8, 112.7, 104.1, 79.9, 76.6, 76.3, 72.3, 71.9,
30.0, 29.7, 26.8, 26.6 ppm. HRMS (ESI): calcd. for C26H32O5 [M
+ H+] 425.2328; found 425.2313.
1 H), 4.63 (d, J = 11.7 Hz, 1 H), 4.57 (d, J = 11.3 Hz, 1 H), 4.35
(d, J = 11.4 Hz, 1 H), 4.26 (d, J = 11.4 Hz, 1 H), 3.93 (m, 1 H),
3.88 (br. s, 2 H), 3.72 (dd, J = 2.6, 8.0 Hz, 1 H), 3.66 (dt, J = 2.2,
6.3 Hz, 1 H), 2.60 (br. s, 2 H), 2.10 (m, 2 H), 1.73 (m, 2 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 138.3, 138.0, 128.4, 128.3, 127.9,
127.8, 127.7, 114.9, 79.8, 79.6, 73.4, 72.2, 72.0, 71.9, 61.2, 29.9,
29.4 ppm. HRMS (ESI): calcd. for C30H36O5 [M + H]+ 477.2641;
found 477.2639.
(3R,4S)-4-Benzyloxy-5-[(1S)-1-benzyloxypent-4-enyl]-2-methoxy-
tetrahydrofuran-3-ol (7): A solution of 6 (2.30 g, 5.42 mmol) in 10%
HCl in methanol (50 mL) was stirred at room temperature for 3 h.
The reaction mixture was quenched by adding NaHCO3 (5 g), and
the mixture was then concentrated in vacuo followed by the ad-
dition of ice water to the residue. The residue was then extracted
with ethyl acetate (3 ϫ30 mL), dried with MgSO4, and concen-
trated in vacuo. Purification of the product by column chromatog-
raphy afforded colorless thick oil 7 (2.11 g, 98% yield). [α]2D5 = –4.06
(2S,3S,4R,5S)-2,3,5-Tribenzyloxynon-8-en-1,4-diyl Dimethanesul-
fonate (10): To a stirred solution of diol 9 (1.3 g, 2.73 mmol) in
CH2Cl2 (15 mL) at 0 °C was added Et3N (0.832 mL, 6.00 mmol)
followed by MsCl (0.41 mL, 5.73 mmol) and a catalytic amount of
DMAP. After 2 h, aqueous NaHCO3 (20 mL) was added, and the
organic layer was washed with water (2ϫ20 mL), followed by brine
(10 mL), dried with MgSO4, and concentrated in vacuo. Purifica-
(c = 0.25, CH Cl ). IR (thin film): ν = 3464, 3064, 3030, 2925, 1640,
˜
2
2
1605, 1496, 1362, 1257, 1103, 737, 698 cm–1. H NMR (400 MHz,
1
CDCl3): δ = 7.35–7.21 (m, 10 H), 5.78 (m, 1 H), 5.02 (d, J = 1.7 Hz,
2 H), 4.87 (s, 1 H), 4.64–4.46 (m, 5 H), 4.18–4.06 (m, 2 H), 4.02 (s, tion by silica gel column chromatography afforded colorless viscous
1 H), 3.46–3.40 (m, 2 H), 3.36 (s, 3 H), 2.61 (br. s, 1 H), 2.24–2.12
liquid 10 (1.65 g, 96% yield). [α]2D5 = –28 (c = 0.25, CH2Cl2). IR
(m, 2 H), 1.64–1.59 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): (thin film): ν = 3064, 3031, 2936, 1745, 1640, 1496, 1355, 1174,
˜
δ = 138.4, 128.6, 128.3, 128.2, 127.9, 127.7, 127.5, 127.4, 114.7,
107.9, 84.0, 82.8, 79.5, 79.0, 76.6, 72.8, 72.7, 72.5, 29.7, 29.5 ppm.
HRMS (ESI): calcd. for C24H30O5 [M + H]+ 399.2179; found
399.2172.
1069, 938, 825, 747, 699 cm–1. 1H NMR (400 MHz, CDCl3): δ =
7.35–7.25 (m, 15 H), 5.77 (m, 1 H), 5.04 (dd, J = 1.9, 7.8 Hz, 1 H),
4.95 (d, J = 1.4 Hz, 1 H), 4.90 (m, 1 H), 4.76 (d, J = 10.9, 1 H),
4.71 (d, J = 10.7, 1 H), 4.64 (d, J = 2.2 Hz, 1 H), 4.57 (d, J = 11.2,
1 H), 4.51 (d, J = 1.7 Hz, 1 H), 4.48 (d, J = 1.9, 1 H), 4.42–4.36
(m, 2 H), 3.90 (m, 1 H), 3.81–3.76 (m, 2 H), 2.93 (s, 6 H), 2.03 (m,
2 H), 1.59 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ = 137.9,
137.7, 136.6, 128.7, 128.5, 128.3, 128.2, 128.0, 127.7, 115.1, 84.2,
76.2, 75.8, 73.1, 72.6, 67.8, 38.9, 37.6, 30.3, 28.6 ppm. HRMS
(ESI): calcd. for C39H40O9S2 [M + Na]+ 656.2011; found 656.2010.
(3R,4R)-3,4-dibenzyloxy-2-[(1S)-1-benzyloxypent-4-enyl]-5-meth-
oxytetrahydrofuran (8): NaH (60 % suspension in paraffin oil,
0.361 g, 15.04 mmol) was added in small portions to a stirred solu-
tion of 7 (2.0 g, 5.02 mmol) in DMF (40 mL). After 30 min, benzyl
bromide (0.60 mL, 6.58 mmol) was added dropwise, and the reac-
tion mixture was stirred overnight at room temperature. The reac-
tion mixture was poured into ice and extracted with diethyl ether
(3ϫ30 mL) followed by washing with water (3ϫ50 mL). The solu-
tion was then dried with MgSO4 and concentrating in vacuo. The
crude product was purified by column chromatography to afford
colorless semisolid 8 (1.96 g, 80% yield). [α]2D5 = +24 (c = 0.5,
(2S,3S,4R,5S)-2,3,5-Tribenzyloxy-8-hydroxyoctan-1,4-diyl Dimeth-
anesulfonate (11): To a stirred solution of 10 (1.50 g, 2.37 mmol)
in THF/H2O (4:1, 10 mL) was added NMO (0.305 g, 2.60 mmol)
followed by a catalytic amount of OsO4 at room temperature. The
reaction mixture was stirred for 20 h, and the volatile substances
CH Cl ). IR (thin film): ν = 3063, 3029, 1639, 1496, 1359, 1258, were then removed in vacuo to afford a crude brown oil product,
˜
2
2
1103, 1027, 912, 736, 697 cm–1. H NMR (400 MHz, CDCl3): δ = which was used in the next step without further purification. To a
1
Eur. J. Org. Chem. 2008, 4972–4980
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4977

M. A. Alam, A. Kumar, Y. D. Vankar
FULL PAPER
mixture of diol and MeOH/H2O (6:1, 20 mL) at 0 °C was added
NaIO4(0.56 g, 2.63 mmol), and the solution was stirred for 1 h. The
reaction mixture was filtered followed by evaporation of methanol
in vacuo and then H2O (10 mL) was added. The aqueous layer was
extracted with ethyl acetate (3ϫ15 mL). The combined organic
layer was washed with brine (20 mL), dried with MgSO4, and con-
centrated in vacuo to afford a brownish viscous liquid. This crude
product was dissolved in MeOH (20 mL) and cooled to 0 °C fol-
lowed by the addition of NaBH4 (0.16 g, 3.5 mmol). The reaction
(1R,2S,8S,8aS)-Octahydroindolizin-1,2,8-triol (2): To a stirred solu-
tion of 14 (0.60 g, 1.08 mmol) in DCM (10 mL) at 0 °C was added
Et3N (0.16 mL, 6.00 mmol) followed by MsCl (0.15 mL,
5.73 mmol). After 1 h, aqueous NaHCO3 (10 mL) was added, and
the aqueous layer was extracted with CH2Cl2 (2 ϫ10 mL). The
combined organic layer was washed with brine (10 mL), dried with
MgSO4, and concentrated in vacuo. The crude product was dis-
solved in 40% CF3CO2H in MeOH and 10% Pd/C (300 mg) was
added. The reaction mixture was subjected to 5 atm H2 for 30 h at
mixture was stirred for 1 h at room temperature followed by the room temperature. The catalyst was filtered off through Celite, and
addition of a saturated aqueous solution of NH4Cl (10 mL) and
then extraction with ethyl acetate (3ϫ20 mL). The combined or-
ganic layer was washed with brine(30 mL), dried with MgSO4, and
concentrated in vacuo to afford a colorless viscous liquid, which
was purified by silica gel column chromatography to get 11 (1.35 g,
concentrated in vacuo followed by purification by passing through
anion exchange resin to afford 2 (149 mg, 78% yield). [α]2D5 = +81
(c = 0.85, MeOH) {ref.[16] [α]2D5 = +75 (c = 0.92, MeOH); ref.[15]
[α]2D5 = +84.3 (c = 1.02, H2O)}. M.p. 142–143 °C (lit.[9] m.p. 143–
144 °C). IR (thin film): ν = 3305, 2937, 2858, 1578, 1413, 1342,
˜
90% yield). [α]2D5 = –50 (c = 0.1, CH Cl ). IR (thin film): ν = 3563,
1261, 1219, 1143, 1085, 1024, 933 cm–1
CD3OD): δ = 4.34 (td, J = 2.9, 5.6 Hz, 1 H), 2.27 (dd, J = 3.4,
1065, 936, 824, 746, 700 cm–1. 1H NMR (400 MHz, CDCl3): δ = 5.8 Hz, 1 H), 3.85 (ddd, J = 4.6, 9.5, 10.9, 1 Hz), 3.12–3.05 (m, 2
.
1H NMR (400 MHz,
˜
2
2
3444, 3088, 3031, 2937, 2873, 1666, 1496, 1454, 1352, 1211, 1172,
7.36–7.25 (m, 15 H), 5.07 (dd, J = 1.7, 8.0 Hz, 1 H), 4.77 (d, J =
11.0 Hz, 1 H), 5.72 (d, J = 11.7 Hz, 1 H), 4.64 (dd, J = 1.9, 11.4 Hz,
1 H), 4.59 (d, J = 11.2 Hz, 1 H), 4.47 (d, J = 10.5 Hz, 1 H), 4.40
(d, J = 11.2 Hz, 1 H), 4.39 (dd, J = 3.2, 11.2 Hz, 1 H), 3.89 (dt, J
= 2.4, 4.9, 7.8 Hz, 1 H), 3.82 (m, 2 H), 3.47 (m, 2 H), 2.95 (s, 3 H),
2.93 (s, 3 H), 1.49 (m, 4 H) ppm. (100 MHz, CDCl3): δ = 137.9,
136.8, 136.7, 128.7, 128.5, 128.4, 128.3, 128.2, 128.0, 127.7, 84.2,
77.6, 76.3, 75.7, 72.9, 72.7, 72.5, 67.8, 62.1, 39.0, 37.7, 27.4,
27.1 ppm. HRMS (ESI): calcd. for C31H40O10S2 [M + H]+
637.2141; found 637.2138.
H), 2.77 (dd, J = 7.8, 11.0 Hz, 1 H), 2.23 (dt, J = 3.4, 12.4 Hz, 1
H), 2.15 (m, 1 H), 2.06 (m, 1 H), 1.77 (m, 1 H), 1.66 (qt, J = 4.2,
8.8 Hz, 1 H), 1.34–1.25 (m, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 77.9, 73.4, 72.8, 69.3, 65.3, 56.0, 36.6, 26.9 ppm.
HRMS (ESI): calcd. for C8H15NO3 [M + H]+ 174.1130; found
174.1125.
(1R,2S,8S,8aS)-Octahydroindolizine-1,2,8-triyl Triacetate (15): To a
stirred solution of 2 (50 mg, 0.28 mmol) in pyridine (2 mL) was
added Ac2O (0.1 mL, 1.10 mmol) and a catalytic amount of
DMAP. The reaction mixture was stirred for 12 h at room tempera-
ture. Pyridine was removed in vacuo followed by workup with water
(5 mL) and extraction with ethyl acetate (3ϫ5 mL). The combined
organic layer was washed with brine (5 mL), dried with MgSO4,
and concentrated in vacuo followed by purification by silica gel
chromatography to afford pure triacetate 15 (84.68 mg, 98% yield).
(2S,3S,4R,5S)-2,3,5-Tribenzyloxyoctan-1,4,8-triyl Trimethanesul-
fonate (12): Prepared by the same procedure as that used for the
preparation of compound 11. Yield: 96%. [α]2D5 = –40 (c = 0.25,
CH Cl ). IR (thin film): ν = 3099, 3031, 2936, 1497, 1351, 1205,
˜
2
2
1
973, 701 cm–1. H NMR (400 MHz, CDCl3): δ = 7.34–7.26 (m, 15
H), 4.90 (t, J = 5.1 Hz, 1 H), 4.70–4.63 (m, 3 H), 4.52 (dt, J = 7.0,
11.7 Hz, 2 H), 4.45–4.38 (m, 2 H), 4.28 (dd, J = 4.4, 11.2 Hz, 1 H),
4.12 (m, 2 H), 3.93 (t, J = 4.8 Hz, 1 H), 3.86–3.83 (m, 1 H), 3.62
(m, 1 H), 2.95 (s, 3 H), 2.95 (s, 3 H), 2.91 (s, 3 H), 1.71–1.64 (m, 4
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 137.6, 136.6, 136.4,
128.8, 128.6, 128.4, 128.1, 127.8, 84.2, 75.9, 75.4, 73.3, 72.7, 72.3,
69.7, 67.2, 60.3, 42.8, 39.0, 37.6, 31.5, 27.0, 24.3, 14.3 ppm. HRMS
(ESI): calcd. for C32H42O12S3[M + H]+ 715.1838; found 715.1833.
[α]2D5 = +28 (c = 0.25, CH Cl ). IR (thin film): ν = 2944, 2854,
˜
2
2
2802, 11743, 1374, 1256, 1045, 901 cm–1
.
1H NMR (400 MHz,
CDCl3): δ = 5.52 (dd, J = 4.4, 6.6 Hz, 1 H), 5.21 (dt, J = 1.7,
8.0 Hz, 1 H), 4.95 (m, 1 H), 3.16 (dd, J = 1.6, 11.2 Hz 1 H), 3.05
(br. td, J = 2.9, 5.8, 10.7 Hz, 1 H), 2.58 (dd, J = 7.8, 11.2 Hz, 1
H), 2.16–2.08 (m, 1 H), 2.08 (s, 3 H), 2.03 (s, 3 H), 1.99 (s, 3 H),
1.94–1.89 (m, 1 H), 1.78–1.71 (m, 3 H), 1.28–1.18 (m, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 170.1, 169.9, 70.1, 69.7, 69.2,
68.0, 59.2, 51.7, 29.7, 23.2, 20.9, 20.5, 20.4 ppm. HRMS (ESI):
calcd. for C14H21NO6 [M + H]+ 300.1147; found 300.1143.
(4S)-4-[(3R,4S)-1-Benzyl-3,4-dibenzyloxypyrrolidin-2-yl]-4-benzyl-
oxybutan-1-ol (14): Dimesylate 11 (1.0 g, 1.57 mmol) was dissolved
in benzylamine (5 mL) and stirred for 12 h at 90 °C. To this reac-
tion mixture was added 1  HCl (10 mL), and the mixture was then
extracted with CH2Cl2 (3ϫ15 mL). The combined organic layer
was washed with saturated aqueous NaHCO3 (25 mL) and brine
(20 mL), dried with MgSO4, and concentrated in vacuo. The crude
product was purified by silica gel column chromatography to afford
colorless semisolid 14 (0.78 g, 91% yield). [α]2D5 = +30 (c = 0.5,
(2S,3R,4R,5R)-2,3,5-Tribenzyloxy-8,9-dihydroxynonane-1,4-diyl Di-
methanesulfonate (23): To a stirred solution of 22 (3.0 g, 5.74 mmol)
in THF/H2O (4:1, 20 mL) was added NMO (0.71 g, 5.20 mmol)
followed by a catalytic amount of OsO4 at room temperature. The
reaction mixture was stirred for 20 h and then treated with
Na2S2O5 (1.36 g, 6.88 mmol). The reaction mixture was further
stirred for 1 h and then extracted with EtOAc (2ϫ50 mL). The
combined organic layer was washed with 1  HCl, water, and fi-
CH Cl ). IR (thin film): ν = 3429, 3061, 2929, 2865, 1604, 1495, nally brine, and it was then dried with MgSO4 and concentrated in
˜
2
2
1453, 1263, 1210, 1144, 1062, 1027, 734, 698 cm–1
(400 MHz, CDCl3): δ = 7.34–7.25 (m, 20 H), 4.76 (d, J = 11.7 Hz,
1 H), 4.60 (d, J = 7.0 Hz, 1 H), (d, J = 8.0 Hz,1 H), 4.44 (m, 3 H), [α]2D5 = +3.6 (c = 0.6, CH Cl ). IR (thin film): ν = 3434, 3063, 2927,
.
1H NMR vacuo to give a crude product that was purified by silica gel column
chromatography to afford vacuous liquid 23 (3.09 g, 98% yield).
˜
2
2
4.30 (d, J = 13.6 Hz, 1 H), 4.11 (dd, J = 4.8, 7.4 Hz, 1 H), 3.95 (q,
J = 4.1, 8.5 Hz, 1 H), 3.85 (m, 1 H), 3.54 (t, J = 6.8 Hz, 2 H) 3.38 (400 MHz, CDCl3): δ = 7.31 (m, 15 H), 5.20 (m, 1 H), 4.85 (dd, J
(d, J = 13.6 Hz, 1 H), 3.21 (dd, J = 3.4, 7.8 Hz, 1 H), 3.12 (dd, J = 3.6, 11.2 Hz, 1 H), 4.68 (dd, J = 4.6, 11.4 Hz, 1 H), 4.60 (d, J =
= 3.8, 11.0 Hz, 1 H), 2.31 (m, 2 H), 1.76–1.65 (m, 4 H) ppm. 13C 11.0 Hz, 1 H), 4.52 (d, J = 11.2 Hz, 1 H), 4.46 (d, J = 11.4 Hz, 1
2870, 1605, 1495, 1453, 1355, 1208, 1096, 1027, 912 cm–1. 1H NMR
NMR (100 MHz, CDCl3): δ = 139.5, 138.8, 138.4, 128.4, 128.2,
H), 4.40 (d, J = 4.6 Hz, 2 H), 4.29 (t, J = 11.4 Hz, 1 H), 3.80 (m,
128.1, 127.7, 127.5, 126.7, 80.0, 79.6, 72.6, 71.7, 71.4, 65.6, 62.7,
1 H), 3.74 (m, 1 H), 3.63 (m, 1 H), 3.52 (m, 1 H), 3.44 (m, 1 H),
60.7, 54.4, 49.4, 27.4 ppm. HRMS (ESI): calcd. for C36H41NO4 [M 3.31 (m, 1 H), 3.00 (s, 3 H), 2.93 (s, 3 H), 2.02 (br. s, 2 H), 1.63
+ H]+ 552.3114; found 552.3111. (m, 3 H), 1.55 (m, 1 H) ppm. 13C NMR (100 MHz): δ = 137.3,
4978
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4972–4980

-(+)-Swainsonine and Other Indolizidine Azasugars from -Glucose
137.2, 136.9, 128.6, 128.5, 128.4, 128.2, 128.1, 127.9, 82.2, 78.5,
76.3, 75.0, 72.8, 72.0, 71.2, 67.8, 66.6, 39.1, 37.3, 28.9, 28.3, 25.9,
25.2 ppm. HRMS (ESI): calcd. for C32H42O11S2 [M + H]+
667.2247; found 667.2232.
methanol (30 mL) was stirred under an atmosphere of H2 in the
presence of 10% Pd/C (560 mg) at room temperature for 1 h. The
reaction mixture was filtered through Celite to remove the catalyst
and then concentrated in vacuo. At this stage, diastereomers 30
and 31[26] were separated by silica gel chromatography to give pure
bicyclic product 30 (0.43 g, 38% yield). [α]2D5 = +5.3 (c = 0.6,
(5R)-5-[(3S,4S)-1-Benzyl-3,4-dibenzyloxypyrrolidin-2-yl]-5-benzyl-
oxypentan-1,2-diol (27): Prepared by the same procedure as that
used for the preparation of 14. Yield: 3.00, 85%. [α]2D5 = +25 (c =
CH Cl ). IR (thin film): ν = 3366, 3060, 3030, 2926, 1600, 1492,
˜
2
2
1450, 1359, 1206, 1152, 1089, 1028, 744, 698 cm–1 1H NMR
.
1.0, CH Cl ). IR (thin film): ν = 3411, 3086, 3062, 3029, 2923,
˜
2
2
1670, 1495, 1453, 1393, 1092, 1072, 736, 698 cm–1 1H NMR
.
(400 MHz, CDCl3): δ = 7.44–7.11 (m, 30 H), 4.53 (d, J = 12.4 Hz,
1 H), 4.50 (d, J = 11.9 Hz, 1 H), 4.37–4.28 (m, 3 H), 4.21 (d, J =
11.2 Hz, 1 H), 4.08 (dd, J = 2.6, 9.2 Hz, 1 H), 3.83 (dd, J = 2.6,
6.1 Hz, 1 H), 3.66 (br. s, 1 H), 3.28 (dd, J = 5.4, 9.2 Hz, 1 H), 3.17
(d, J = 10.7 Hz, 1 H), 3.08 (dd, J = 6.1, 15.6 Hz, 1 H), 2.34 (dd, J
= 6.8, 10.5 Hz, 1 H), 2.23 (m, 1 H), 2.10–2.03 (m, 2 H), 1.70 (m, 1
H), 1.57 (m, 1 H), 1.28 (m, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 137.2, 137.0, 125.5, 128.3, 128.1, 127.9, 127.7, 127.5,
126.7, 79.4, 79.3, 76.2, 75.6, 74.4, 73.2, 72.1, 71.1, 68.8, 39.3, 38.6,
37.2, 29.6, 22.0 ppm. HRMS (ESI): calcd. for C49H49NO4
[M + H]+ 716.3740; found 716.3732.
(400 MHz, CDCl3): δ = 7.35–7.24 (m, 20 H), 4.73 (dd, J = 1.9,
11.2 Hz, 1 H), 4.54–4.43 (m, 6 H), 4.02 (dd, J = 2.9, 8.0 Hz, 1 H),
3.95 (dd, J = 3.4, 13.1 Hz, 1 H), 3.88 (d, J = 4.1 Hz, 1 H), 3.55–
3.44 (m, 4 H), 3.35 (m, 1 H), 3.15 (dd, J = 4.8, 10.4 Hz, 1 H), 3.05
(d, J = 3.6 Hz, 1 H), 2.59 (dd, J = 4.4, 10.7 Hz, 1 H), 2.02 (m, 1
H), 1.52–1.41 (m, 4 H) ppm. 13C NMR (100 MHz): δ = 138.2,
128.7, 128.3, 128.1, 127.6, 127.0, 84.5, 81.0, 72.0, 71.6, 71.4, 70.6,
66.6, 60.1, 57.6, 30.2, 26.6, 26.4 ppm. HRMS (ESI): calcd. for
C37H43NO5 [M + H]+ 582.3219; found 582.3206.
(5R)-5-[(3S,4S)-1-Benzyl-3,4-dibenzyloxypyrrolidin-2-yl]-5-benzyl-
oxy-1-trityloxypentan-2-ol (28): A solution of diol 27 (1.5 g, (1S,2S,5S,8R,8aS)-5-(Hydroxymethyl)octahydroindolizine-1,2,8-
1.82 mmol) in CH2Cl2 (20 mL) was treated with TrCl (0.75 mL,
2.73 mmol) and Et3N (0.76 mL, 5.65 mmol). The reaction mixture
was stirred for 8 h and then H2O (20 mL) was added. The reaction
mixture was extracted with CH2Cl2 (2ϫ20 mL). The combined or-
ganic layer was washed with brine(30 mL), dried with MgSO4, and
concentrated in vacuo to afford the crude tritylated product, which
was purified by silica gel chromatography to give a colorless viscous
tritylated product (1.7 g, 80% yield). [α]2D5 = +1.50 (c = 0.4,
triol (32): The indolizidine derivative (0.4 g, 0.55 mmol) in 40%
TFA methanol (30 mL) was stirred under 5 atm of H2 in the pres-
ence of 10% Pd/C (300 mg) at room temperature for 30 h. The
reaction mixture was filtered through Celite to remove the catalyst
and concentrated in vacuo. The residue was purified by passing
through a Dowex basic resin (109 mg, 90% yield). [α]2D5 = +19.2 (c
= 1.0, MeOH). IR (thin film): ν = 3397, 3031, 2929, 1665, 1415,
˜
1336, 1278, 1211, 1059, 738, 699 cm–1. 1H NMR (400 MHz, D2O):
CH Cl ). IR (thin film): ν = 3582, 3445, 3085, 30360, 3029, 2923, δ = 4.14 (m, 3 H), 3.88 (br. d, J = 4.1 Hz, 1 H), 3.72 (dd, J = 4.6,
˜
2
2
2866, 2794, 1670, 1598, 1493, 1450, 1367, 1212, 1092, 1074, 1028,
12.6 Hz, 1 H), 3.64 (m, 1 H), 3.59 (s, 1 H), 3.27 (s, 1 H), 3.13 (br.
901, 737, 698 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.43–7.21 d, J = 11.7 Hz, 1 H), 1.91 (t, J = 5.8 Hz, 1 H), 1.73 (m, 2 H), 1.62
(m, 35 H), 4.74 (dd, J = 1.3, 11.2 Hz, 1 H), 4.51–4.40 (m, 5 H), (dd, J = 5.6, 14.6 Hz, 1 H) ppm. 13C NMR (100 MHz, D2O): δ =
3.98 (d, J = 12.9 Hz, 2 H), 3.85 (s, 1 H), 3.46 (d, J = 12.9 Hz, 2
H), 3.11–2.99 (m, 4 H), 2.55 (dd, J = 3.2, 6.1 Hz, 1 H), 2.02–1.94
76.6, 74.4, 67.4, 63.4, 59.8, 58.9, 56.7, 24.8, 20.9 ppm. HRMS
(ESI): calcd. for C9H17NO4 [M + H]+ 204.1236; found 204.1224.
(m, 1 H), 1.56–1.54 (m, 1 H), 1.40 (m, 2 H), 1.25 (s, 1 H) ppm. 13
C
(1S,2S,5R,8R,8aS)-5-(Acetoxymethyl)octahydroindolizine-1,2,8-
triyl Triacetate (34): Polyhydroxy derivative 32 (50 mg, 0.24 mmol)
in pyridine and acetic anhydride (1:0.5, 2 mL) was stirred for 20 h
at room temperature The reaction mixture was dissolved in CH2Cl2
(5 mL) and washed with water (2ϫ4 mL) and brine (3 mL), dried
with MgSO4, concentrated in vacuo, and purified by silica gel
chromatography to give the pure tetraacetate derivative (84 mg,
NMR (100 MHz, CDCl3): δ = 144.0, 128.7, 128.3, 128.0, 127.8,
127.6, 127.5, 126.9, 1269, 86.5, 81.1, 72.1, 71.7, 71.4, 70.5, 60.2,
57.5, 30.6 ppm. HRMS (ESI): calcd. for C56H57NO5 [M + H]+
824.4315; found 824.4305.
(5R)-5-[(3S,4S)-1-Benzyl-3,4-dibenzyloxypyrrolidin-2-yl]-5-benzyl-
oxy-1-trityloxypentan-2-yl Methanesulfonate (29): To a stirred solu-
tion of 28 (1.50 g, 1.82 mmol) in CH2Cl2 (30 mL) at 0 °C was added
Et3N (0.29 mL, 2.17 mmol) followed by MsCl (0.15 mL,
2.00 mmol) and a catalytic amount of DMAP. After 4 h, aqueous
NaHCO3 (20 mL) was added, and the organic layer was washed
with H2O (2 ϫ 40 mL) followed by brine (20 mL), dried with
MgSO4, and concentrated in vacuo. Purification by silica gel col-
umn chromatography afforded a colorless viscous liquid (1.51 g,
97% yield). [α]2D5 = +2.3 (c = 0.3, CH Cl ). IR (thin film): ν = 2960,
˜
2
2
2927, 2855, 1739, 1651, 1551, 1428, 1374, 1260, 1104, 1028 cm–1.
1H NMR (400 MHz, CDCl3): δ = 5.06 (dd, J = 2.9, 6.8 Hz, 1 H),
5.03 (d, J = 2.6 Hz, 1 H), 4.99 (m, 1 H), 4.29 (dd, J = 5.8, 11.4 Hz,
1 H), 4.08 (dd, J = 6.1, 11.4 Hz,1 H) 3.25 (dd, J = 6.8, 10.9 Hz, 2
H), 3.05 (dd, J = 2.2, 11.0 Hz, 1 H), 2.88 (dd, J = 2.4, 6.8 Hz, 1
H), 2.16 (s, 3 H), 2.09 (s, 3 H), 2.07 (s, 3 H), 2.06 (s, 3 H), 1.90 (m,
2 H), 1.56 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.8,
170.7, 170.5, 170.0, 77.4, 76.1, 66.2, 61.9, 60.3, 55.2, 52.9, 23.6,
21.1, 21.0, 20.8, 20.7 ppm. HRMS (ESI): calcd. for C17H25NO7
[M + H]+ 372.1658; found 372.1638.
92% yield). [α]2D5 = +6.0 (c = 0.9, CH Cl ). IR (thin film): ν = 3060,
˜
2
2
3030, 2928, 1702, 1493, 1451, 1362, 1265, 1090, 1027, 907, 739,
1
698 cm–1. H NMR (400 MHz, CDCl3): δ = 7.43–7.21 (m, 35 H),
4.69 (dd, J = 3.4, 11.4 Hz, 2 H), 4.49–4.35 (m, 6 H), 3.94 (m, 2 H),
3.81 (d, J = 3.9 Hz, 1 H), 3.46 (dd, J = 4.8, 13.2 Hz, 1 H), 3.13 (m,
1 H), 3.00 (d, J = 10.5 Hz, 1 H), 2.81 (s, 3 H), 2.54 (dd, J = 4.1,
10.4 Hz, 1 H), 1.93 (m, 2 H), 0.84 (m,1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 143.5, 142.6, 142.4, 139.2, 138.4, 138.2,
138.1, 128.9, 128.6, 128.3, 128.0, 127.8, 127.7, 127.6, 127.5, 127.1,
126.9, 86.9, 84.9, 84.8, 83.2, 82.8, 80.8, 79.3, 78.9, 72.2, 72.2, 72.1,
71.6, 71.5, 71.4, 71.3, 70.5, 65.1, 60.1, 57.6, 38.5, 29.0, 28.8, 26.4,
26.2 ppm. HRMS (ESI): calcd. for C56H57NO7S [M + H]+
902.4090; found 902.4078.
Supporting Information (see footnote on the first page of this arti-
cle): All spectroscopic data for the remaining unknown com-
pounds; detailed experimental procedure for the evaluation of en-
zyme inhibition activity of 32, 33, 54, and 55.
Acknowledgments
We thank the Department of Science and Technology, New Delhi,
for financial support to one of us in the form of a Ramanna Fel-
lowship (Grant No. SR/S1/RFOC-04/2006). M. A. A. thanks IIT,
(1S,2S,5R,8R,8aS)-1,2,8-Tribenzyloxy-5-trityloxymethyloctahy-
droindolizine (30): Mesylate derivative 29 (1.4 g, 1.55 mmol) in
Eur. J. Org. Chem. 2008, 4972–4980
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4979

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Received: July 1, 2008
Published Online: September 9, 2008
4980
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4972–4980