Synthesis of aminocyclopentanols: α-D-galacto configured sugar mimics

Article abstract of DOI:10.1039/b501824b

Four aminocyclopentanols, as mimics of putative intermediates in the hydrolysis of α-D-galactosides, have been synthesized through a number of stereoselective transformations using the cis-fused cyclopentane-1,4-lactone (1R, 5S, 7R, 8R)-7,8-dihydroxy-2-ox

Full text of DOI:10.1039/b501824b

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A R T I C L E
Synthesis of aminocyclopentanols: a-D-galacto configured
sugar mimics
Marie Bøjstrup and Inge Lundt*
Department of Chemistry, Technical University of Denmark, Building 201, DK-2800,
Kgs. Lyngby, Denmark. E-mail: il@kemi.dtu.dk; Fax: +45 45933968; Tel: +45 45252133
Received 4th February 2005, Accepted 15th March 2005
First published as an Advance Article on the web 1st April 2005
Four aminocyclopentanols, as mimics of putative intermediates in the hydrolysis of a-D-galactosides, have been
synthesized through a number of stereoselective transformations using the cis-fused cyclopentane-1,4-lactone (1R,
5S, 7R, 8R)-7,8-dihydroxy-2-oxabicyclo[3.3.0]oct-3-one 1 as a chiral building block. The compounds were tested
towards various glycosidases but showed no anomer selectivity in the inhibition of a- and b-galactosidases.
Introduction
Glycosidases are enzymes which very efficiently play a range of
roles in biological systems. As a consequence of this, glycosidase
inhibitors are used in the treatment and investigation of a wide
range of diseases such as diabetes, viral infections and cancer.1
The interest in the design of potent and selective glycosidase
inhibitors has dramatically emerged since the first naturally
occurring gylcosidase inhibitors were isolated in the late 1970s.2
One of these was 1-deoxynojirimycin, which was shown to be
a good a-glucosidase inhibitor. Since then a range of naturally
occurring glycosidase inhibitors have been isolated from natural
sources. The differences in structures of these inhibitors reflect
the marked substrate specificity of most glycosidases and their
structures have often been an inspiration for the design of
synthetic analogues in order to improve their efficiency.
The mechanism of enzymatic cleavage of glycosides has been
continuously under debate and the design of new inhibitors has
been based on the structural similarity of putative intermediates
Fig. 2 Aminocyclopentanols as glycosidase inhibitors.
or transition states (Fig. 1), like the oxocarbenium ion D or
species C, having some carbonium ion character at C-1.3
tent a-mannosidase inhibitor “Merrell Dow cyclopentylamine”
(MDC),7 which can be seen as a ring-contracted analogue of
a-D-mannose where the ring-oxygen is missing. The authors
showed in a modelling study that this aminocyclopentanol has
a conformation in which the amino group is positioned at the
a-face between the ring oxygen and C-1 of the mannosyl cation,
thus mimicking either the modelled “flap-up” mannosyl cation8
or the glycoside precursor protonated at the exocyclic oxygen.
This concept, where an aminocyclopentanol has a substitu-
tion pattern similar to common carbohydrates, was recently
expanded by Reymond9 and Ja¨ger10 and their coworkers, who
synthesized a selection of aminocyclopentanols with fuco,
manno, galacto and gluco configurations. The configuration
at the carbon, having the amino substituent mimicking either
the a- or b-anomer, was especially considered. They found a
close relationship between the configuration of the substitution
pattern and the activity towards the relevant glycosidases,
indicating that the amino group might be a mimic of the
positively charged exocyclic oxygen. The available data seemed
to indicate an anomer selectivity in the inhibitory activity for
amino cyclopentanols with a gluco configuration, while the
manno configured mimics did not show this difference.10a In the
series of galacto mimics only b-configured aminocyclopentanols
were available and they showed a tendency towards anomeric
inhibitory selectivity.10b
In order to have a comparative study of both “anomers” we
found a short synthesis of the a-D-galacto configured aminocy-
clopentanol based on the bicyclic cis-fused cyclopentane lactone
chemistry, which was developed in our group.11
This strategy was based on the use of carbohydrate starting
materials. A short and efficient method leads to bicyclic cis-fused
Fig. 1 1-Deoxynojirimycin and suggested intermediates or transition
states of the glycosidic cleavage.
Iminodeoxy sugars of the piperidine or pyrrolidine type
have been synthesized to mimic the substrate or one of the
aforementioned intermediary species in the hydrolytic cleavage
and have been shown to act as glycosidase inhibitors. Recently,
the aminocyclopentanols have drawn considerable attention
as potent glycosidase inhibitors.4 The interest in this class
of compounds began with the isolation of the potent a-
mannosidase inhibitor mannostatin A (Fig. 2), an amino-
(thiomethyl)cyclopentanol from the microorganism Streptover-
ticillium verticillus.5 The overlap of the OH-groups in manno-
statin with the OH-2 and OH-3 groups in the MO-optimized
“flap-up”-conformation of the mannosyl cation reported by
Winkler,6 suggests mannostatin to be a mimic of this intermedi-
ary specie. The mechanism of its action is however not yet fully
understood. In 1990 Farr and coworkers synthesized the po-
1 7 3 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 7 3 8 – 1 7 4 5
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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cyclopentane lactones, like 1 (Fig. 3), by stereoselective radical
induced carbocyclisations of x-bromodeoxy-a,b-unsaturated
heptonolactones. These bicyclic lactones can be converted into
carbapentofuranoses functionalised at four of the five carbons
in the ring11,12 or at all five carbons13 via the unsaturated
bicyclic lactone 2. For the synthesis of the aminocyclopentanols
described in the present paper, we likewise took advantage of
the unsaturated bicyclic lactone 2.
Fig. 4 Retrosynthetic analysis of aminocyclopentanols from 2.
coworkers published similar and identical compounds with an
a-D-galacto configuration.14
Results and discussion
By choosing the bicyclic lactone 2 as a starting compound, the
side chain in the final cyclopentane will be a two-carbon chain.
We have prepared the a-D-galacto mimics having both the two-
carbon chain, as well as having the usual hydroxymethyl side
chain. The cleavage of the carbon–carbon bond was performed
by a Sua´rez fragmentation.
Fig. 3 Carbapentofuranoses from 1.
Dihydroxylation of the allylic alcohol 2 has been shown to
proceed with a higher diastereoselectivity using the O-protected
compound.13 The benzyl protecting group was chosen for this
protection as this showed acceptable selectivity in the dihydrox-
ylation. Benzylation using benzyl trichloroacetimidate under
acidic conditions15 gave better yields and easier purification
than benzylation under basic conditions and was therefore the
method of choise for preparation of 3 in a high yield. Dihydrox-
ylation using OsO4 under standard Upjohn conditions followed
by isopropylidene protection, gave the two stereoisomers 4a
and 4b in a 7 : 1 relationship, where the desired compound 4a
Retrosynthetic analysis (Fig. 4) revealed that introduction of
the amino substituent at C-6 of compound 2 would lead to
mimics of L-sugars, while introduction at C-1 would lead to
corresponding mimics in the D-sugar series.
Following the second strategy (Scheme 1 and Scheme 2), we
describe in this paper the synthesis of four aminocyclopentanols
which are mimics of a-D-galactose. Their inhibitory activity
towards several glycosidases were tested in order to contribute
to the elucidation of possible anomeric selectivity by this type
of compounds. During the course of this study Reymond and
Scheme 1 Synthesis of aminocyclopentanols 15 and 16. Reagents and conditions: a) BnOCNCCl3, dioxane, triflic acid, 0 ◦C. 10 min (81%); b)
OsO4(s), NMO, CH2Cl2, 25 ◦C, overnight; c) acetone, 2,2-dimethoxypropane, H2SO4, 25 ◦C, 30 min (71% 4a); d) DIBAL–H, CH2Cl2, −78 ◦C, 1.5 h
(88%); e) DIB, I2, cyclohexane, 250 W, 25 ◦C, 40 min; f) Na2CO3, MeOH, H2O, 25 ◦C, 2.5 h (61%); g) CsOAc, DMF, 65 ◦C, overnight (61% 8, 17%
9); h) MsCl, DMAP, pyridine, CH2Cl2, 25 ◦C, overnight (87%); i) Pd/C (5%), MeOH, EtOAc, 25 ◦C, overnight (90%); j) benzylisocyanate, Et3N,
CH2Cl2, 25 ◦C, overnight (96%); k) KOtBu, THF, 25 ◦C, 35 min, then H2O (72%); l) NaOH (2 M), ethanol, 65 ◦C, 2 h; m) HCl, H2O, 60 ◦C, 5 h
(65%); n) Pd/C (10%), EtOH, 25 ◦C, overnight (quant).
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 7 3 8 – 1 7 4 5
1 7 3 9

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Scheme 2 Synthesis of aminocyclopentanols 24 and 25. Reagents and conditions: a) LiAlH4, THF, 0 ◦C, 5 min (84%); b) TBDMSCl, DMAP, CH2Cl2,
25 ◦C, overnight (95%); c) MsCl, DMAP, CH2Cl2, pyridine, 25 ◦C, overnight (94%); d) Pd(OH)2 (10% on charcoal), EtOAc, 25 ◦C, 4.5 h (79%); e)
benzylisocyanate, Et3N, CH2Cl2, 25 ◦C, overnight (98%); f) KOtBu, THF, 25 ◦C, 15 min (87%); g) NaOH (2 M), ethanol, 65 ◦C, 2 h (76%); h) HCl
(conc.), H2O, 60 ◦C, 5 h (76%); i) Pd/C (10%), EtOH, 25 ◦C, overnight (quant.).
could be isolated by flash chromatography. For the C–C bond
cleavage, the lactone 4a was initially reduced with DIBAL–
H to give the lactol 5, followed by a Sua´rez fragmentation
with diacetoxyiodobenzene (DIB) and iodide under activation
by light.16 Subsequent basic hydrolysis of the initially formed
formate 6 gave the desired iodo compound 7 in a modest yield.
Substitution of the iodide with an oxygen nucleophile proved
to be difficult, as elimination partly took place. Several acetate
salts were tried, resulting in the use of CsOAc in DMF as the
nucleophile to give 8 in a modest yield. Even after optimisation,
a substantial amount of the elimination product 9 was formed
during the reaction.
In order to obtain an analogue to a D-sugar (Fig. 4), the
free secondary hydroxy group of 8 should be converted into an
amino group. Thus, mesylation of 8 to 10 gave the possibility
of an intermolecular substitution with a nitrogen nucleophile
like N3−. Unfortunately, reacting 10 with NaN3 in DMF
resultedprimarily inelimination and therefore an intramolecular
substitution was considered. Removal of the benzyl group by
catalytic hydrogenation gave 11, which was treated with benzyl
isocyanate to give the carbamate 12. This molecule was now set
up for an intramolecular substitution. Thus, treatment of 12 with
KOtBu gave only the desired isoxazoline 13 with no elimination
observed. Basic hydrolysis at an elevated temperature to cleave
the isoxazoline and final deprotection of the isopropylidene
group with aq. HCl gave the hydrochloric salt of the desired
a-D-galacto configured aminocyclopentanol as the N-benzyl
derivative 15. The benzyl group could be removed by standard
hydrogenation to give the unsubstituted aminocyclopentanol 16.
In order to investigate the influence of the side chain on the
inhibitory activity, we also prepared the analogues keeping the
two-carbon side chain. Following a similar protocol 4a was
reduced to the corresponding hydroxy substituted cyclopentane
17 (Scheme 2). For selective introduction of an amino sub-
stituent, the primary hydroxy group was selectively protected
with TBDMSCl to 18, followed by mesylation of the free
secondary hydroxy group to give 19. Transformation of 19 into
the two a-D-galacto configured aminocyclopentanols 24 and 25
was performed as described above for 15 and 16.
The four aminocyclopentanols, 15, 16, 24 and 25, all having
an a-D-galacto configuration, were assayed for inhibition of a
selection of glycosidases (Table 1). This revealed that only 15 and
16 showed activity towards a-galactosidase (green coffee beans).
All four compounds showed activity towards b-galactosidase
(bovine liver) as expected from the configuration of the side
chain and hydroxy groups, but not from the configuration of the
amino group. The compounds 24 and 25, having a side chain one
carbon longer than the parent carbohydrate, had a significantly
lower activity for both a- and b-galactosidases than both 15 and
16. This indicates that the hydroxymethyl group side chain is
essential for optimal inhibition of these enzymes. Furthermore,
it is interesting to note that the a-D-galacto configured inhibitors
15 and 16 are also powerful inhibitors of b-glucosidase from
almonds. This cross-reactivity for inhibitors with the hydroxy
groups in a galacto configuration is well known and is discussed
in detail by Reymond and coworkers.14
Inhibitory activities for the b-D-galacto configured inhibitors
26 and 27 (Fig. 5), published by Ja¨ger and coworkers, are shown
Fig. 5 b-D-galacto configured inhibitors from ref. 10b.
Table 1 Ki values (lM) obtained from inhibition data on glycosidases
Compound
a-Glucosidase (b.y.)
b-Glucosidase (a)
a-Galactosidase (g.c.b.)
b-Galactosidase (b.l.)
a-Mannosidase (a)
15
16
24
25
26
27
N.i.
94.2
N.i.
N.i.
0.53
0.15
N.i.
1.08
1.39a
2.2a
2.26
24.3
N.i.
1.01
5.31
20.7
N.i.
N.i.
N.i.
N.i.
N.i.
31.6
N.i.a
12.0a
0.006a
3.3a
a From ref. 10b. (B.y.): baker’s yeast; (a): almonds; (g.c.b.): green coffee beans; (b.l.): bovine liver; N.i.: no inhibition.
1 7 4 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 7 3 8 – 1 7 4 5

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in Table 1 for comparrison.10b The compounds 16 and 27, having
a primary amino group mimicking the a- and b-configuration,
respectively, show very similar inhibitory activity towards both
a- and b-galactosidases. The N-benzylated aminocylopentanol
15 has a slightly enhanced activity towards both a- and
b-galactosidases, but the selectivity between these two enzymes
is low. The N-benzylated aminocyclopentanol 26, mimicking
the b-D-galacto configuration, has a markedly enhanced activity
towards b-galactosidases. Furthermore, the selectivity between
the inhibition of a- and b-galactosidases had increased, as almost
no activity was observed towards the a-galactosidase.
p-nitrophenolate formed was measured by UV spectroscopy at
405 nm every 30 s.
After the initial test, the inhibitors with a Ki < 50 lM
determined from a Lineweaver–Burk plot were assayed as
described above with four different concentrations (0.03, 0.04,
0.06 and 0.12 mM) of inhibitor in order to obtain a Dixon plot
for a more precise determination of the inhibition constant Ki.
Ki values were determined with a Sigma Plot program
(Enzyme kinetics module 1.1) from a Lineweaver–Burke plot
(initial experiments) or a Dixon plot.
(1R, 5R, 8R)-8-Benzyloxy-2-oxabicyclo[3.3.0]oct-6-en-3-one
(3). To an ice-cooled solution of the allylic alcohol 2 (500 mg,
3.57 mmol) and benzyl trichloroacetimidate (1.18 g, 4.67 mmol)
in anhydrous dioxane (10 mL) was added TfOH (10 drops). The
mixture was stirred at 0 ◦C for 10 min, then diluted with diethyl
ether (20 mL) and washed with half-saturated NaHCO3 (20 mL)
and water (10 mL). The organic phase was dried (MgSO4),
concentrated and purified by flash chromatography (EtOAc–
hexane, 1 : 1) to give the title compound as colourless crystals
(670 mg, 81%); mp 65–67 ◦C. Recrystallization from EtOAc–
Conclusions
These results indicate that aminocyclopentanols with an a-
or b-D-galacto configuration are mimics of the oxocarbenium
ion intermediate of the glycosidic cleavage and therefore show
similar inhibitory activity for the N-unsubstituted inhibitors
16 and 27. The anomer selectivity seen for the b-D-galacto
configured N-alkylated inhibitor 26 is probably due to the
position of the benzyl group on the b-face of the ring, where
hydrophobic interactions with the aglycon site will contribute
to the binding. These hydrophobic interactions are not as
important for the a-D-galacto configured inhibitor 15. This was
also noted by Reymond and coworkers, who drew attention
to the fact that the N-alkyl aminocyclopentanols might not be
suitable for providing a-selective inhibitors.14
◦
hexane gave mp 73–74 C. [a]2D0 −147 (c 1.0 in CHCl3); found:
1
C, 72.73; H, 6.18. Calc. for C14H13O3: C, 73.03; H, 6.13%. H
NMR (500 MHz, CDCl3): dH 7.36–7.30 (5H, m, Ar–H), 5.95–
5.90 (2H, m, H-7, H-8), 4.94 (1H, d, J = 6.0, H-1), 4.69–4.60 (2H,
m, PhCH2O), 3.71 (1H, m, H-5), 2.77 (1H, dd, J = 10.1, 18.2,
H-4), 2.38 (1H, dd, J = 2.7, 18.2, H-4ꢀ);13C NMR (126 MHz,
CDCl3): dC 175.7 (CO), 137.5, 137.1 (C-6, C-7), 130.5, 128.5,
127.9, 127.9 (Ar–C), 87.3, 85.7 (C-1, C-8), 71.7 (PhCH2O), 43.6
(C-5), 32.4 (C-4).
Experimental
1H NMR spectra were recorded on a Bruker AM 500 and 13C
NMR spectra on Varian Mercury 300 instruments. Chemical
shifts were measured in d (ppm) and coupling constants J
in Hz. For NMR spectra in deuterated solvents, the solvent
peak was used as reference (CDCl3: d = 7.26 for 1H, 76.93
for 13C; MeOH-d4: d = 3.31 for 1H, 49.00 for 13C). Where
necessary, NMR data were assigned using HH- and CH-
correlated spectra. Melting points are uncorrected. Specific
rotations were measured on a Perkin-Elmer 241 polarimeter.
Elemental analyses were performed by the Institute of Physical
Chemistry, Vienna. HR-MS was performed by BioCentrum,
DTU. TLC was performed on Merck 60 F254 precoated silica
plates and spots were generally detected by spraying with a
solution of 1.5% NH4Mo2O2, 1% Ce(IV)SO4 and 10% H2SO4,
followed by charring. Flash chromatography was performed
with silica gel 60 (Merck, 40–63 (lm). Concentrations were
performed on a rotary evaporator at a temperature below
40 ◦C. All solvents were distilled before use. Celite refers to
Filter Aid from Celite Corporation.
(1R, 5R, 6S, 7S, 8S)-8-Benzyloxy-6,7-isopropylidenedioxy-
2-oxabicyclo[3.3.0]oct-3-one (4a). Compound
3 (190 mg,
0.83 mmol) was dissolved in dry CH2Cl2 (10 mL) and NMO·H2O
(167 mg, 1.23 mmol) was added together with a catalytic amount
of OsO4(s). The mixture was stirred under N2 at rt overnight.
Na2SO3 was added and the mixture stirred for 30 min at rt. The
mixture was concentrated in vacuo and coevaporated three times
with toluene. Dry acetone (5 mL), 2,2-dimethoxypropane (4 mL)
and conc. H2SO4 (7 drops) were added and the mixture stirred
for 30 min. The mixture was then neutralised with NaHCO3(s),
filtered and evaporated in vacuo to give the title compound and
its stereoisomer in a 7 : 1 relationship. Purification by flash
chromatography (EtOAc–heptane, 1 : 3) gave the title compound
as colourless crystals (180 mg, 71%); mp 117–118 ◦C. [a]D20 −57.9
(c 1.1 in EtOAc); found; C, 67.12; H, 6.74%. Calc. for C17H20O5;
C, 67.09; H, 6.62%; 1H NMR (500 MHz, CDCl3): dH 7.39–7.30
(5H, m, Ar–H), 4.78 (1H, d, J = 5.8, H-1), 4.76 (1H, dd, J =
6.1, 6.1, H-6), 4.73 (1H, d, J = 5.7, H-7), 4.65, 4.60 (2H, d, J =
11.5, PhCH2O), 4.20 (1H, s, H-8), 3.10 (1H, m, H-5), 2.78 (1H,
d, J = 17.5, H-4), 2.57 (1H, dd, J = 9.3, 17.5, H-4ꢀ), 1.419, 1.298
(2 × 3H, s, [(CH3)2C]);13C NMR (75.4 MHz, CDCl3): dC 176.1
(CO), 136.9, 128.5, 128.1, 127.7 (Ar–C), 111.8 [(CH3)2C], 88.6
(C-1), 86.2 (C-7), 84.6 (C-8), 80.9 (C-6), 72.1(PhCH2O), 42.1
(C-5), 30.1 (C-4), 25.4, 23.9 [(CH3)2C].
Enzymatic assay
Inhibitory activities of the synthesized compounds were de-
termined on a Labsystem iEMS reader MF. The residual
hydrolytic activities of the glycosidases were measured spectro-
metrically of the corresponding p-nitrophenyl glycosides in the
presence of the synthesized compounds. The following enzymes
were purchased from Sigma: a-glucosidase (baker’s yeast), b-
glucosidase (almonds), a-galactosidase (green coffee beans), b-
galactosidase (bovine liver) and a-mannosidase (almonds). A
typical enzymatic assay (final volume 0.3 ml) contains 0.08–
0.17 units ml−1 of the enzyme (1 unit = 1 enzyme unit liberating
1 lmol of glycoside per minute from p-nitrophenyl glycoside).
Each assay was performed with the 4-nitrophenyl glycoside
derivatives of the appropriate sugar as substrate in a phosphate
buffer (0.12 mM, pH 6.8). The assays were performed with four
different concentrations of the substrates (1, 2, 3 and 4 mM in
the aq. buffer solution). Enzyme and inhibitor (0.1 mM) were
preincubated for 1–2 min at 25–35 ◦C dependent on the enzyme
and the reaction was started by addition of the substrate. The
(1R, 5S, 6S, 7S, 8S)-8-Benzyloxy-6,7-isopropylidenedioxy-
2-oxabicyclo[3.3.0]oct-3-ol (5). Compound 4a (4.187 g,
13.7 mmol) was dissolved in dry CH2Cl2 (50 mL) and cooled
to −78 ◦C under an N2 atmosphere. DIBAL–H (1 M in CH2Cl2,
38 mL) was added over 5 min and the mixture was stirred
at −78 ◦C for 1.5 h. Saturated Rochelles salt (100 mL) was
carefully added and the mixture was stirred for 15 min. CH2Cl2
(100 mL) was added and the phases separated. The water
phase was re-extracted with CH2Cl2 (2 × 50 mL) and the
organic phases were pooled and washed with brine (30 mL),
dried (MgSO4), filtered and concentrated in vacuo to give the
a crude product (4.07 g, 96.6%). The residue was purified by
flash chromatography (EtOAc–hexane, 1 : 1) to give the title
compound as colourless crystals (3.69 g, 88%); mp 55–59 ◦C.
[a]2D0 −24.4 (c 1.0 in EtOAc); found; C, 66.77; H, 7.30%. Calc.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 7 3 8 – 1 7 4 5
1 7 4 1

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for C17H22O5; C, 66.65; H, 7.24%;13C NMR (75.5 MHz, CDCl3):
dC 137.4, 128.3, 127.7, 127.6 (Ar–C), 112.2 [C(CH3)2], 100.1 (C-
3), 90.5, 90.2, 88.7, 81.2 (C-1, C-6, C-7, C-8), 71.8 (PhCH2O),
43.2 (C-5), 35.5 (C-4), 26.4, 24.6 [C(CH3)2]. 137.5, 128.3, 127.7,
127.6 (Ar–C), 111.4 [C(CH3)2], 100.8 (C-3), 88.2, 87.4, 86.3, 80.5
(C-1, C-6, C-7, C-8), 71.7 (PhCH2O), 45.3 (C-5), 34.5 (C-4), 26.4,
24.6 [C(CH3)2].
d, J = 4.7, H-1), 3.81 (1H, dd, J = 3.1, 4.9, H-2), 1.48, 1.36
(2 × 3H, s, [C(CH3)2]);13C NMR (75.5 MHz, CDCl3): dC 148.4
(C-5), 137.5, 128.3, 127.7, 127.7 (Ar–C), 114,4 ( = CH2), 112.1
[C(CH3)2], 87.8 (C-2), 82.5 (C-3), 78.7 (C-4), 77.5 (C-1), 71.7
(PhCH2O), 27.0, 24.7 [C(CH3)2].
(1R, 2R, 3S, 4S, 5R)-1-O-Mesyl-2-O-benzyl-3,4-O-isoprop-
ylidene-5-acetoxymethyl-cyclopentane-1,2,3,4-tetrol (10). Com-
pound 8 (420 mg, 1.25 mmol) was dissolved in dry CH2Cl2
(6 mL) and dry pyridine (6 mL). DMAP (18 mg, cat.) was added
followed by MsCl (0.5 mL, 6.4 mmol) which was added dropwise.
The mixture was stirred under N2 at rt, overnight. H2O (20 mL)
was added and the mixture stirred for 30 min. CH2Cl2 (20 mL)
was then added and the phases separated. The organic phase was
washed with aq. HCl (1 M, 2 × 20 mL), sat. NaHCO3 (20 mL)
and brine (20 mL). The organic phase was dried, filtered and
evaporated in vacuo to give a crude residue (quant.). The residue
was purified by flash chromatography (EtOAc–heptane, 1 : 2)
to give the title compound as a colourless syrup (450 mg, 87%).
[a]2D0 +20.9 (c 0.7 in EtOAc); found; C, 55.29; H, 6.37%. Calc. for
C19H26O8S; C, 55.06; H, 6.32%;1H NMR (500 MHz, CDCl3): dH
7.39–7.30 (5H, m, Ar–H), 5.03 (1H, d, J = 4.4, H-1), 4.77 (1H,
dd, J = 5.8, 5.8, H-4), 4.65–4.63 (3H, m, H-3, PhCH2O), 4.43
(1H, dd, J = 9.0, 11.7, CH2OAc), 4.37 (1H, dd, J = 6.3, 11.4,
CH2OAc), 4.19 (1H, s, H-2), 2.98 (3H, s, CH3SO2), 2.72 (1H, m,
H-5), 2.08 (3H, s, CH3CO), 1.46, 1.29 (2 × 3H, s, [C(CH3)2]);
13C NMR (75.5 MHz, CDCl3): dC 170.8 (CH3CO), 137.0, 128.5,
128.0, 127.7 (Ar–C), 111.8 [C(CH3)2], 85.0 (C-2), 84.4 (C-3), 82.2
(C-1), 79.7 (C-4), 72.0 (PhCH2O), 59.1 (C-6), 44.6 (C-5), 38.2
(CH3SO2), 25.7, 23.7 [C(CH3)2], 20.9 (CH3CO).
(1R, 2S, 3S, 4S, 5S)-2-O-Benzyl-3,4-O-isopropylidene-5-
iodomethyl-cyclopentane-1,2,3,4-tetrol (7). Compound
5
(500 mg, 1.63 mmol) was suspended in dry cyclohexane
(20 mL). (Diacetoxyiodo)benzene (608 mg, 1.88 mmol) and
I2 (438 mg, 1.73 mmol) were added and the mixture treated
with a 250 W lamp for 40 min at rt, H2O (10 mL) added and
the phases separated. The water phase was re-extracted with
diethyl ether (2 × 10 mL). The organic phases were pooled and
washed with sat. Na2S2O4 (20 mL), dried (Na2SO4), filtered and
evaporated in vacuo to give a colourless oil. This was purified
by flash chromatography (EtOAc–heptane, 1 : 4) to give (1R,
2S, 3S, 4S, 5R)-1-formyloxy-2-benzyloxy-3,4-isopropylidene-
5-iodomethyl-1,2,3,4-cyclopentane tetrol (6) as a colourless
oil (437 mg, 62%). This oil was dissolved in MeOH–H2O (2 :
1, 7 mL), Na2CO3 (600 mg) was added and the mixture
stirred at rt for 2.5 h. The mixture was partly evaporated to
remove MeOH. H2O (10 mL) and CH2Cl2 (15 mL) were added
and the phases separated. The water phase was re-extracted
with CH2Cl2 (10 mL), the organic phases were pooled, dried
(Na2SO4), filtered and evaporated in vacuo. The residue was
purified by flash chromatography (EtOAc–heptane, 1 : 3) to
give the title compound as a colourless syrup (400 mg, 60.7%).
[a]2D0 −1.4 (c 1.0 in EtOAc); found; C, 47.82; H, 5.40%. Calc. for
1
(1R, 2R, 3R, 4S, 5R)-1-O-Mesyl-3,4-O-isopropylidene-5-
acetoxymethyl-cyclopentane-1,2,3,4-tetrol (11). Compound 10
(425 mg, 1.03 mmol) was suspended in MeOH–EtOAc (1 : 1,
10 mL). Pd/C (5%, 200 mg) was added and the mixture stirred in
an H2 atmosphere at rt, overnight. The mixture was then filtered
through Celite and evaporated in vacuo to give a colourless
oil (quant.). The residue was purified by flash chromatography
(EtOAc–heptan, 1 : 1) to give the title◦compound as colourless
crystals (300 mg, 90.4%); mp 98–99 C; [a]2D0 +25.1 (c 1.0 in
EtOAc); found; C, 44.55; H, 6.34; S, 9.78%. Calc. for C12H20O8S;
C, 44.44; H, 6.22; S, 9.88%;1H NMR (500 MHz, CDCl3): dH
4.88 (1H, d, J = 4.6 Hz, H-1), 4.78 (1H, dd, J = 5.3, 5.6 Hz,
H-4), 4.54 (1H, dd, J = 1.3, 5.8, H-3), 4.46 (1H, br s, H-2),
4.43 (1H, dd, J = 8.3, 11.3, CH2OAc), 4.36 (1H, dd, J = 6.3,
11.8, CH2OAc), 3.03 (3H, s, CH3SO2), 2.77 (1H, m, H-5), 2.39
(1H, br s, OH), 2.08 (3H, s, CH3CO), 1.45, 1.29 (2 × 3H, s,
[C(CH3)2]);13C NMR (75.5 MHz, CDCl3): dC 170.91 (CH3CO),
111.72 [C(CH3)2], 85.92 (C-3), 84.59 (C-4), 79.76 (C-3), 78.28 (C-
2), 59.13 (CH2OAc), 44.15 (C-5) 38.18 (CH3SO2), 25.64, 23.71
[C(CH3)2], 20.87 (CH3CO).
C16H21O4I; C, 47.53; H, 5.24%; H NMR (500 MHz, CDCl3):
dH 7.37–7.29 (5H, Ar–H), 4.76 (1H, dd, J = 5.2, 5.2, H-4), 4.66
(1H, dd, J = 1.5, 5.5, H-3), 4.58 (2H, s, PhCH2O), 4.16 (1H,
dd, J = 4.2, 11.0, H-1), 3.97 (1H, s, H-2), 3.45 (2H, d, J = 8.4,
H-6, H-6ꢀ), 2.55 (1H, m, H-5), 2.25 (1H, d, J = 11.0, OH), 1.48,
1.33 (2 × 3H, s, [C(CH3)2]);13C NMR (75.5 MHz, CDCl3): dC
137.3, 128.4, 127.9, 127.6 (Ar–C), 110.9 [C(CH3)2], 86.1 (C-2),
84.2 (C-3), 81.2 (C-4), 78.2 (C-1), 71.6(PhCH2O), 49.3(C-5),
26.3, 22.1 [C(CH3)2], −0.9 (C-6).
(1R, 2S, 3S, 4S, 5S)-2-O-Benzyl-3,4-O-isopropylidene-5-
acetoxymethyl-1,2,3,4-cyclopentane tetrol (8) and (1R, 2S, 3S,
4S)-2-O-benzyl-3,4-O-isopropylidene-5-methylene-cyclopentane-
1,2,3,4-tetrol (9). Compound 7 (881 mg, 2.18 mmol) was
dissolved in dry DMF (5 mL), CsOAc (2.01 g, 11.4 mmol) was
added and the mixture heated to 65 ◦C under N2 overnight.
After cooling to rt diethyl ether (60 mL) was added and the
organic phase washed with water (3 × 30 mL). The organic
phase was dried (MgSO4), filtered and evaporated in vacuo to
give a mixture of two major products as a colourless oil. The
residue was purified by flash chromatography (EtOAc–heptane,
1 : 4), to give the title compound as a colourless oil (450 mg,
61%); [a]2D0 −18.2 (c 0.5 in EtOAc); found; C, 64.48; H, 7.30%.
(1R, 2R, 3S, 4S, 5R)-1-O-Mesyl-2-O-(benzylcarbamoyl)-3,4-O-
isopropylidene-5-acetoxymethyl-cyclopentane-1,2,3,4-tetrol (12).
Compound 11 (200 mg, 0.62 mmol) was suspended in dry
CH2Cl2 (7 mL). Et3N (0.1 mL) and benzyl isocyanate (0.1 mL,
0.8 mmol) was added and the mixture stirred overnight at rt.
Conc. aq. NH4Cl (25 mL) and diethyl ether (25 mL) were added
and the phases separated. The water phase was re-extracted twice
with diethyl ether (2 × 10 mL). The organic phases were pooled,
dried (Na2SO4), filtered and evaporated in vacuo. This gave a
crude product, which was purified by flash chromatography
(Et2O) to give the title compound as a colourless foam (270 mg,
95.7%); [a]2D0 −9.1 (c 1.0 in EtOAc); found; C, 52.54; H, 6.14;
S, 6.72; N, 3.10%. Calc. for C20H27O9SN; C, 52.51; H, 5.95;
S, 7.01; N, 3.06%;1H NMR (500 MHz, CDCl3): dH 7.37–7.27
(5H, m, Ar–H), 5.13 (1H, s, H-2), 4.99 (2H, br s, NH, H-1),
4.76 (1H, dd, J = 5.5, 5.5, H-4), 4.61 (1H, d, J = 5.6, H-3),
4.48–4.31 (4H, m, CH2OAc, PhCH2N), 3.16 (3H, s, CH3SO2),
2.61 (1H, m, H-5), 2.07 (3H, s, COCH3), 1.49, 1.24 (2 × 3H, s,
[C(CH3)2]);13C NMR (75.5 MHz, CDCl3): dC 171.2 (CH3CO),
1
Calc. for C18H24O6; C, 64.27; H, 7.19%;. H NMR (500 MHz,
CDCl3): dH 7.36–7.26 (5H, Ar–H), 4.77 (1H, dd, J = 5.3, 5.3,
H-4), 4.62 (1H, dd, J = 1.2, 6.1, H-3), 4.59 (2H, s, PhCH2O),
4.52 (1H, dd, J = 8.1, 11.5, CH2OAc), 4.40 (1H, dd, J = 7.1,
11.3, CH2OAc), 4.14 (1H, dd, J = 4.5, 10.5, H-1), 3.94 (1H, s,
H-2), 2.48 (1H, m, H-5), 2.40 (1H, d, J = 10.8, OH), 2.08
(3H, s, CH3CO), 1.47, 1.32 (2 × 3H, s, [C(CH3)2]);13C NMR
(75.5 MHz, CDCl3): dC 171.0 (CO), 137.4, 128.4, 127.8, 127.5
(Ar–C), 111.0 [C(CH3)2], 86.3 (C-2), 84.1 (C-3), 80.6 (C-4),
76.7 (C-1), 71.5 (PhCH2O), 59.9 (CH2OAc), 45.0 (C-5), 26.3,
22.9 [C(CH3)2], 20.9 (CH3CO), foll◦owed by 9 as colourless
crystals (100 mg, 17%); mp 69–72 C; [a]2D0 −17.4 (c 0.4 in
EtOAc); found; C, 69.33; H, 7.21%. Calc. for C16H20O4; C,
1
69.54; H, 7.30%; H NMR (500 MHz, CDCl3): dH 7.36–7.29
=
(5H, m, Ar–H), 5.45 (2H, br s, C CH2), 4.92 (1H, br d, J =
6.5, H-4), 4.72 (1H, d, J = 11.9, PhCH2O), 4.63 (1H, d, J =
11.8, PhCH2O), 4.53 (1H, dd, J = 2.3, 6.6, H-3), 4.40 (1H,
1 7 4 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 7 3 8 – 1 7 4 5

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154.6 (CO, carbamate), 137.8, 129.1, 128.1, 127.9 (Ar–C), 112.5
[C(CH3)2], 84.4 (C-3), 83.1 (C-1), 80.3 (C-2), 79.6 (C-4), 59.1
(CH2OAc), 45.2 (PhCH2N), 44.9 (C-5), 38.4 (CH3SO2), 25.7,
23.8 [C(CH3)2], 20.9 (CH3CO)
which resulted in precipitation of salts. The mixture was filtered
and evaporated in vacuo. The residue was purified by flash
chromatography (EtOAc–heptane, 1 : 1, then EtOAc–heptane,
2 : 1) to give the title compound as a colourless oil (130 mg, 84%);
[a]2D0 +1.3 (c 1.25 in EtOAc); found; C, 65.92; H, 7.81%. Calc. for
C17H24O5; C, 66.21; H, 7.84%;1H NMR (500 MHz, CDCl3): dH
7.34–7.26 (5H, Ar–H), 4.72 (1H, dd, J = 5.0, 5.0, H-4), 4.62–4.55
(3H, m, PhCH2O, H-3), 4.06 (1H, d, J = 4.2, H-1), 3.93 (1H, s,
H-2), 3.81 (2H, m, CH2CH2OH), 2.34 (1H, m, H-5), 1.99 (2H,
m, CH2CH2OH), 1.45, 1.33 (2 × 3H, s, [C(CH3)2]); 13C NMR
(75.5 MHz, CDCl3): dC 137.6, 128.4, 127.8, 127.5 (Ar–C), 110.6
[C(CH3)2], 87.1 (C-2), 84.1 (C-3), 82.3 (C-4), 78.2 (C-1), 71.5
(PhCH2O), 61.5 (CH2CH2OH), 42.9 (C-5), 26.9 (CH2CH2OH),
26.5, 23.1 [C(CH3)2]).
(1S, 2S, 3S, 4S, 5S)-4-N -Benzyl-5-acetoxymethyl-7,8-
isopropylidenedioxy-2-oxa-4-azabicyclo[3.3.0]oct-3-one (13).
Compound 12 (260 mg, 0.57 mmol) was suspended in dry
THF (8 mL), KtOBu (197 mg, 1.8 mmol) was added in two
portions, the mixture was stirred at rt for 35 min and thereafter
quenched with a few drops of water. EtOAc (15 mL) and brine
(15 mL) were added and the phases separated. The aqueous
phase was reextracted with EtOAc (2 × 15 mL). The organic
phases were pooled, dried (Na2SO4), filtered and evaporated
in vacuo to give slightly yellow crystals. These were purified
by flash chromatography (EtOAc–heptane, 1 : 1) to give the
title ◦compound as colourless crystals (130 mg, 71.5%); mp 112–
114 C; [a]2D0 +63.6 (c 0.6 in EtOAc); found; C, 64.05; H, 6.66;
N, 4.33%. Calc. for C17H21O5N; C, 63.94; H, 6.63; N, 4.39%;1H
NMR (500 MHz, CDCl3): dH 7.38–7.30 (5H, m, Ar–H), 4.79
(1H, dd, J = 5.5, 5.5, H-1), 4.76 (1H, d, J = 15.3, PhCH2N), 4.74
(1H, d, J = 4.9, H-2), 4.68 (1H, d, J = 8.1 Hz, H-3), 4.25 (1H, d,
J = 14.7, PhCH2N), 4.11 (1H, dd, J = 7.2, 7.2, H-4), 3.82 (1H,
dd, J = 4.9, 11.8, CH2OH), 3.72 (1H, m, CH2OH), 2.35 (1H, m,
H-5), 1.40, 1.30 (2 × 3H, s, [C(CH3)2]); 13C NMR (75.5 MHz,
CDCl3): dC 156.9 (CO, carbamate), 135.9, 128.8, 128.0, 128.0
(Ar–C), 112.0 [C(CH3)2], 84.3 (C-2), 84.1 (C-3), 82.3 (C-1), 61.0
(CH2OH), 60.2 (C-4), 50.4 (C-5), 46.7 (PhCH2N), 26.6, 24.2
[C(CH3)2].
(1R, 2S, 3S, 4S, 5S)-2-O-Benzyl-3,4-O-isopropylidene-5-
(2-O-TBDMS-hydroxyethyl)-cyclopentane-1,2,3,4-tetrol (18).
Compound 17 (850 mg, 2.76 mmol) was dissolved in dry CH2Cl2
(20 mL), DMAP (743 mg, 6.08 mmol) and TBDMSCl (461 mg,
3.06 mmol) was added and the mixture stirred at rt under N2,
overnight. H2O (20 mL) and CH2Cl2 (10 mL) were then added
and the phases separated. The organic phase was washed with
aq. HCl (1 M, 2 × 20 mL), aq. sat. NaHCO3 (10 mL) and brine
(10 mL). The organic phase was dried (Na2SO4), filtered and
evaporated in vacuo to give a crude product as a syrup. The
residue was purified by flash chromatography (EtOAc–heptane,
1 : 2) to give the title compound as a colourless syrup (1.11 g,
95%); [a]2D0 +4.4 (c 1.0 in EtOAc); found; C, 65.52; H, 9.07%.
Calc. for C23H38O5Si; C, 65.36; H, 9.06%;. 1H NMR (500 MHz,
CDCl3): dH 7.36–7.26 (5H, m, Ar–H), 4.70 (1H, dd, J = 5.0,
5.0, H-4), 4.58–4.56 (3H, m, PhCH2O, H-3), 4.06 (1H, dd,
J = 4.2, 10.2, H-1), 3.92 (1H, s, H-2), 3.78 (2H, t, J = 6.3,
CH2CH2O), 2.50 (1H, d, J = 10.2 Hz, OH), 2.37 (1H, m, H-5),
1.94 (2H, m, CH2CH2O), 1.47, 1.32 (2 × 3H, s, [C(CH3)2]),
0.90 (9H, s, [C(CH3)3]), 0.07 (6H, s, 2 × CH3Si);13C NMR
(75.5 MHz, CDCl3): dC 137.7, 128.3, 127.6, 127.4 (Ar–C), 110.5
([C(CH3)2]), 87.4 (C-2), 84.2 (C-3), 82.6 (C-4), 77.8 (C-1), 71.4
(C-7), 54.3 (PhCH2O), 42.5 (C-5), 26.8 (C-6), 26.4 ([C(CH3)2]),
25.8 ([C(CH3)3]), 23.1 ([C(CH3)2]), 18.2 ([C(CH3)3]), −5.4, −5.5
(2 × CH3Si).
(1R, 2R, 3S, 4S, 5R)-1-O-Mesyl-2-O-benzyl-3,4-O-isopropyli-
dene-5-(2-O-TBDMS-hydroxyethyl)-cyclopentane-1,2,3,4-tetrol
(19). Compound 18 (1.05 g, 2.48 mmol) was suspended in dry
CH2Cl2 (10 mL) and dry pyridine (10 mL). DMAP (30 mg,
0.25 mmol) and MsCl (1 mL) were added and the mixture
stirred at rt under N2, overnight. H2O (20 mL) was added
and the phases separated. The organic phase was washed
with aq. HCl (1 M, 2 × 20 mL), sat. aq. NaHCO3 (20 mL)
and brine (20 mL), dried (MgSO4), filtered and evaporated
in vacuo to give a yellow syrup. The residue was purified by
flash chromatography (EtOAc–heptane, 1 : 3) to give the title
compound as a colourless syrup (1.17 g, 94%); [a]2D0 +10.3
(c 1 in EtOAc); found; C, 57.99; H, 8.34; S, 6.19%. Calc. for
C24H40O7SiS; C, 57.57; H, 8.05; S, 6.40%; 1H NMR (300 MHz,
CDCl3): dH 7.38–7.26 (5H, m, Ar–H), 4.98 (1H, d, J = 4.8,
H-1), 4.70 (1H, dd, J = 5.5, 5.5, H-4), 4.63 (2H, dd, J = 3.3,
PhCH2O), 4.59 (1H, d, J = 5.9, H-3), 4.12 (1H, s, H-2), 3.75
(2H, dd, J = 6.3, 5.8, CH2CH2O), 2.95 (3H, s, CH3SO2), 2.61
(1H, m, H-5), 1.94–1.83 (2H, m, CH2CH2O), 1.44, 1.29 (2 ×
3H, s, [C(CH3)2]), 0.90 (9H, s, [C(CH3)3]), 0.07 (6H, s, 2 ×
CH3Si);13C NMR (75.5 MHz, CDCl3): dC 137.2, 128.4, 127.9,
127.7 (Ar–C), 111.1 ([C(CH3)2]), 85.1 (C-2), 84.6 (C-1), 84.3
(C-3), 81.0 (C-4), 71.8 (CH2CH2O), 60.7 (PhCH2O), 41.9 (C-5),
38.5 (SO2CH3), 26.8 (CH2CH2O), 25.9 [C(CH3)3], 25.8, 23.8
(2 × [C(CH3)2]), 18.2 [C(CH3)3], −5.4 (2 × CH3Si).
(1S, 2S, 3S, 4S, 5R)-4-Benzylamino-5-hydroxymethyl-cyclo-
pentane-1,2,3-triol (15). Compound 13 (110 mg, 0.35 mmol)
was dissolved in aq. NaOH (2 M, 5 mL) and ethanol (5 mL),
the mixture was heated to 65 ◦C for 2 h and then evaporated
in vacuo and purified by flash chromatography (EtOAc then
EtOAc–MeOH–TEA, 10 : 1 : 0.3) to give 14 as a colourless oil
(65 mg, 64%). The oil was dissolved in H2O (3 mL) and conc.
HCl (1 mL), the mixture was heated to 60 ◦C for 5 h and then
evaporated in vacuo to give the title compound as yellow crystals
(64 mg, 65%); mp 140–142 ◦C; [a]2D0 −27.8 (c 0.7 in MeOH); 1H
NMR (500 MHz, D–MeOD): dH 7.53–7.45 (5H, m, Ar–H), 4.33
(1H, dd, J = 3.8, 8.4, H-1), 4.31 (1H, d, J = 13, PhCH2N), 4.24
(1H, d, J = 13.2, PhCH2N), 4.21 (1H, dd, J = 4.3, 6.4, H-3), 3.96
(1H, dd, J = 4.3, 4.3, H-2), 3.86 (1H, dd, J = 5.7, 10.6, CH2OH),
3.76 (1H, dd, J = 7.7, 10.6 Hz, CH2OH), 3.66 (1H, dd, J = 7.1,
7.3, H-4), 2.37 (1H, m, H-5);13C NMR (75.5 MHz, D–MeOD):
dC 132.8, 130.9, 130.6, 130.3 (Ar–C), 79.7 (C-2), 73.2 (C-3), 72.0
(C-1), 61.6 (C-4), 61.4 (CH2OH), 51.3 (PhCH2N), 46.4 (C-5);
HR-ESI–MS calculated for C13H19O4NCl [M − 1]: 288.1003;
found 288.1019.
(1S, 2S, 3S, 4S, 5R)-4-Amino-5-hydroxymethyl-cyclopentane-
1,2,3-triol (16). Compound 15 (40 mg, 0.14 mmol) was dis-
solved in EtOH (10 mL), Pd/C (10%, 30 mg) was added and the
mixture stirred under an H2 atmosphere at rt, overnight. The
mixture was filtered through celite and evaporated in vacuo to
give the title compound as a hygroscopic oil (28 mg, quant.);
1
[a]2D0 −8.8 (c 0.8 in MeOH); H NMR (500 MHz, D–MeOD):
dH 4.24 (1H, dd, J = 4.8, 4.8, H-1), 4.15 (1H, dd, J = 5.3, 7.4,
H-3), 3.93 (1H, dd, J = 5.2, 5.2, H-2), 3.86 (1H, dd, J = 6.1,
10.9, CH2OH), 3.78 (1H, dd, J = 6.9, 10.4, CH2OH), 3.57 (1H,
dd, J = 8.0, 8.0, H-4), 2.25 (1H, m, H-5);13C NMR (75.5 MHz,
D–MeOD): dC 79.7 (C-2), 74.4 (C-3), 72.0 (C-1), 61.2 (CH2OH),
54.4 (C-4), 47.7 (C-5); HR-ESI–MS; calc. for C6H13O4NCl
[M − 1] 198.0533; found 198.0578.
(1R, 2S, 3S, 4S, 5S)-2-O-Benzyl-3,4-O-isopropylidene-5-(2-
hydroxyethyl)-cyclopentane-1,2,3,4-tetrol (17). Compound 4a
(153 mg, 0.50 mmol) was dissolved in dry THF (5 mL) and
cooled to 0 ◦C. LiAlH4 (36 mg, 0.95 mmol) was added and
the mixture stirred under N2 at 0 ◦C for 5 min. H2O (4 drops),
aq. NaOH (15%, 4 drops) and H2O (8 drops) were then added
(1R, 2R, 3R, 4S, 5R)-1-O-Mesyl-3,4-O-isopropylidene-5-(2-O-
TBDMS-hydroxyethyl)-cyclopentane-1,2,3,4-tetrol (20). Com-
pound 19 (200 mg, 0.4 mmol) was suspended in EtOAc
(5 mL), Pd(OH)2/C (10%, 43 mg,) was added and the mixture
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 7 3 8 – 1 7 4 5
1 7 4 3

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stirred under H2 for 4.5 h. The mixture was filtered through
celite and evaporated in vacuo. The residue was purified by
flash chromatography (EtOAc–heptane, 1 : 1) to give the title
compound as a colourless syrup (130 mg, 79%); [a]2D0 +5.2
(c 1.0 in EtOAc); found; C, 49.57; H, 8.57; S, 7.35%. Calc. for
C17H34O7SiS; C, 49.72; H, 8.35; S, 7.80%;. 1H NMR (500 MHz,
CDCl3): dH 4.79 (1H, d, J = 4.8, H-1), 4.71 (1H, dd, J = 5.5,
5.5, H-4), 4.49 (1H, d, J = 5.7, H-3), 4.41 (1H, s, H-2), 3.75
(2H, t, J = 6.0, CH2CH2O), 3.02 (3H, s, CH3SO2), 2.64 (1H,
m, H-5), 1.92, 1.81 (2H, m, CH2CH2O), 1.45, 1.29 (2 × 3H, s,
([C(CH3)2]), 0.90 (9H, s, [C(CH3)3]), 0.06 (6H, s, 2 × CH3Si);13C
NMR (75.5 MHz, CDCl3): dC 111.0 ([C(CH3)2]), 87.3 (C-1), 85.8
(C-3), 80.9 (C-4), 78.3 (C-2), 60.8 (CH2CH2O), 41.4 (C-5), 38.4
(CH3SO2), 26.7 (CH2CH2O), 25.9 [C(CH3)3], 25.7, 23.8 (2 ×
[C(CH3)2]), 18.2 [C(CH3)3], −5.4, −5.5 (2 × CH3Si).
(1R, 2R, 3S, 4S, 5R)-1-O-Mesyl-2-O-(benzylcarbamoyl)-3,4-
O-isopropylidene-5-(2-O-TBDMS-hydroxyethyl)-cyclopentane-
1,2,3,4-tetrol (21). Compound 20 (469 mg, 1.14 mmol)
was suspended in dry CH2Cl2 (6 mL). Et3N (0.2 mL) and
benzylisocyanate (0.2 mL, 1.6 mmol) were added under N2 and
the mixture stirred at rt, overnight. NH4Cl (20 mL) and CH2Cl2
(20 mL) were added, the phases separated and the aq. phase
reextracted with CH2Cl2 (10 mL). The organic phases were
pooled, dried (Na2SO4), filtered and evaporated in vacuo. The
residue was purified by flash chromatography (EtOAc–heptane,
1 : 2) to give the title compound as a colourless syrup (610 mg,
98%); [a]2D0 −2.4 (c 1.0 in EtOAc);1H NMR (500 MHz, CDCl3):
dH 7.40–7.30 (5H, Ar–H), 5.07 (1H, s, H-2), 4.96 (1H, t, J =
6, PhCH2NH), 4.87 (1H, d, J = 4.7, H-1), 4.70 (1H, dd, J =
5.5, 5.5, H-4), 4.57 (1H, d, J = 5.7, H-3), 4.41 (1H, dd, J = 5.8,
14.5, PhCH2N), 4.33 (1H, dd, J = 5.7, 14.9, PhCH2N), 3.75
(2H, t, J = 6, CH2CH2O), 2.49 (1H, m, H-5), 1.96–1.87 (2H,
m, CH2CH2O), 1.48, 1.28 (2 × 3H, s, ([C(CH3)2]), 0.88 (9H, s,
[C(CH3)3]), 0.05 (6H, s, 2 × CH3Si);13C NMR (75.5 MHz,
CDCl3): dC 154.6 (CO), 137.6, 128.7, 127.7, 127.5 (Ar–C), 111.6
([C(CH3)2]), 85.5 (C-1), 83.9 (C-3), 80.9 (C-4), 80.6 (C-2), 60.3
(C-7), 45.1 (PhCH2N), 42.1 (C-5), 38.4 (CH3SO2), 26.7 (C-6),
25.8 [C(CH3)3], 25.8, 23.9 (2 × [C(CH3)2]), 18.2 [C(CH3)3], −5.5
(2 × CH3Si).
ethanol (8 mL) and the mixture was heated to 70 ◦C for 2 h.
The mixture was evaporated in vacuo. EtOAc (20 mL) and H2O
(10 mL) were added and the phases separated. The water phase
was reextracted with EtOAc (3 × 15 mL), the organic phases
were pooled, dried (Na2SO4), filtered and evaporated in vacuo.
The residue was purified by flash chromatography (EtOAc then
EtOAc–MEOH, 10 : 1, then EtOAc–MEOH–TEA, 10 : 1 : 0.3)
to give (1S, 2R, 3S, 4S, 5S)-1,2-isopropylidene-4-benzylamino-
5-(2-hydroxyethyl)-1,2,3-cyclopentanetriol (23) as a colourless
oil (130 mg, 76%);13C NMR (75 MHz, D–MeOD): dC 140.4,
129.6, 129.5, 128.3 (Ar–C), 110.8 [C(CH3)2], 85.2 (C-2), 81.3 (C-
1), 72.4 (C-3), 63.7 (C-4), 62.6 (CH2CH2OH), 52.9 (PhCH2N),
46.4 (C-5), 32.6 (CH2CH2OH), 26.3, 23.9 [2 × C(CH3)2]. This
oil was disso◦lved in H2O (6 mL) and conc. HCl (2 mL) and
heated to 60 C for 4.5 h. The mixture was then evaporated in
vacuo and coevaporated several times with toluene to give the
title compound as a colourless hygroscopic oil (130 mg, 76%);
[a]2D0 −35.9 (c 1.0 in MeOH); 1H NMR (500 MHz, D–MeOD):
dH 7.46 (5H, m, Ar–H), 4.35 (1H, d, J = 12.9, PhCH2N), 4.29
(1H, dd, J = 4.7, 7.1, H-3), 4.13 (1H, d, J = 12.9, PhCH2N),
4.06 (1H, dd, J = 4.4, 4.4, H-1), 3.97 (1H, dd, J = 4.3, 4.3,
H-2), 3.84 (1H, ddd, J = 4.3, 4.3, 10.6, CH2CH2OH), 3.55 (1H,
ddd, J = 2.3, 10.6, 10.6, CH2CH2OH), 3.46 (1H, dd, J = 8.7,
8.7, H-4), 2.13 (1H, m, H-5), 1.95 (1H, m, CH2CH2OH), 1.75
(1H, m, CH2CH2OH);13C NMR (75 MHz, D–MeOD): dC 133.1,
130.8, 130.6, 130.3 (Ar–C), 81.0 (C-2), 74.0 (C-1), 73.8 (C-3),
63.8 (C-4), 62.1 (CH2CH2OH), 51.9 (PhCH2N), 45.3 (C-5), 32.4
(CH2CH2OH); HR-ESI–MS; calc. for C14H21O4NCl [M − 1]
302.1159, found 302.1111.
(1S, 2S, 3S, 4S, 5S)-4-Amino-5-(2-hydroxyethyl)-cyclo-
pentane-1,2,3-triol hydrochloride (25). Compound 24 (120 mg,
0.395 mmol) was dissolved in EtOH (20 mL). Pd/C (50 mg,
10%) was added and the mixtures stirred at rt under an H2
atmosphere overnight. The mixture was filtered through celite
and evaporated in vacuo. In order to ease the purification the
crude product was acetylated by treatment with CH2Cl2 (1 mL),
pyridine (1 mL) and Ac2O (0.7 mL) and left overnight at rt.
The mixture was evaporated in vacuo and purified by flash
chromatography to give the acetylated product as an oil (70 mg,
0.18 mmol). This was suspended in aq. HCl (4 M, 5 mL) and
◦
(1S, 2S, 3S, 4S, 5S)-4-N-Benzyl-6-(2-O-TBDMS-hydroxy-
ethyl)-7,8-isopropylidenedioxy-2-oxa-4-azabicyclo[3.3.0]octan-3-
one (22). Compound 21 (550 mg, 1.01 mmol) was suspended
in dry THF (15 mL). KOtBu (200 mg, 1.8 mmol) was added and
the mixtures stirred at rt under N2 for 15 min. CH2Cl2 (20 mL)
and brine (20 mL) were added and the phases separated. The
water phase was re-extracted with CH2Cl2 (20 mL), the organic
phases were pooled, dried (Na2SO4), filtered and evaporated
in vacuo to give a crude product as slightly yellow crystals
(quant.). The residue was purified by flash chromatography
(EtOAc–heptane, 1 : 3), to give the title compound as colourless
the mixture was heated to 60 C for 4.5 h, then evaporated in
vacuo and coevaporated three times with toluene to give the title
compound as an hygroscopic oil (39 mg, 46%); [a]2D0 −24.6 (c 1.1,
MeOH);1H NMR (500 MHz, D–MeOD): dH 4.17 (1H, dd, J =
6.4, 7.7, H-3), 4.04 (1H, dd, J = 4.1, 4.1, H-1), 3.93 (1H, dd, J =
4.7, 4.7, H-2), 3.81 (1H, ddd, J = 4.9, 4.9, 10.0, CH2CH2OH),
3.61 (1H, ddd, J = 3.8, 10.1, 10.1, CH2CH2OH), 3.39 (1H, dd,
J = 8.5, 8.5, H-4), 2.10 (1H, m, H-5), 1,92 (1H, m, CH2CH2OH),
1.79 (1H, m, CH2CH2OH);13C NMR (75 MHz, D–MeOD): dC
80.5 (C-2), 74.5 (C-3), 73.1 (C-1), 61.5 (CH2CH2OH), 56.6 (C-4),
44.7 (C-5); HR-EI–MS; calc. for C7H15O4NCl [M − 1] 212.0690,
found 212.0687.
◦
crystals (390 mg, 86.5%); mp 114–116 C; [a]2D0 +38.9 (c 1.0
in EtOAc); found; C, 64.14; H, 8.32; N, 3.03%. Calc. for
C24H37O5SiN; H, 8.33; C, 64.40; N, 3.13%;1H NMR (500 MHz,
CDCl3): dC 7.38–7.26 (5H, m, Ar–H), 4.87 (1H, d, J = 15.8,
PhCH2N), 4.69–4.65 (2H, m, H-1, H-2), 4.62 (1H, d, J = 8.2,
H-3), 4.14 (1H, d, J = 15.7, PhCH2N), 3.79 (1H, dd, J = 8.2,
8.2, H-4), 3.67–3.59 (2H, m, CH2CH2OH), 2.34 (1H, m, H-5),
1.86 (1H, m, CH2CH2OH), 1.70 (1H, m, CH2CH2OH), 1.36,
1.28 (2 × 3H, s, [C(CH3)2]), 0.91 (9H, s, [C(CH3)3]), 0.07, 0.06
(2 × 3H, s, 2 × CH3Si);13C NMR (75.5 MHz, CDCl3): dH 157.0
(CO), 135.7, 128.8, 127.9, 127.7 (Ar–C), 111.3 [C(CH3)2], 84.5
(C-3), 84.2, 80.9 (C-1, C-2), 63.0 (C-4), 60.8 (CH2CH2OH), 46.5
(PhCH2N), 45.5 (C-5), 31.9 (CH2CH2OH), 26.9 [C(CH3)2], 25.9
[C(CH3)3], 24.6 [C(CH3)2], 18.2 [C(CH3)3], −5.4 (CH3Si), −5.5
(CH3Si).
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