Synthesis of 4a-Carba-d-lyxofuranose Derivatives and Their Evaluation as Inhibitors of GH38 α-Mannosidases

Article abstract of DOI:10.1002/ejoc.201801586

A synthetic approach to 4a-carba-d-lyxofuranose derivatives starting from d-lyxose is described. The protected 4a-carba-β-d-lyxofuranose was employed as the key intermediate for the synthesis of 4a-carba-d-lyxofuranose derivatives including novel 1-amino-1-deoxy-4a-carba-d-lyxofuranoses. Synthesized 4a-carba-d-lyxofuranoses were evaluated as inhibitors of GH38 α-mannosidases, namely, the Golgi (GMIIb) and lysosomal (LManII) α-mannosidases from Drosophila melanogaster and commercial Jack bean α-mannosidase (JBMan) from Canavalia ensiformis. The biochemical evaluation revealed that only 1-amino-1-deoxy-4a-carba-β-d-lyxofuranose exhibited reasonable inhibitory activity against GMIIb (IC₅₀ = 200 μm). In addition, the results of biological evaluation were discussed by means of molecular modelling.

Full text of DOI:10.1002/ejoc.201801586

A Journal of
Accepted Article
Title: Synthesis of 4a-carba-D-lyxofuranose derivatives and their
evaluation as inhibitors of GH38 α-mannosidases
Authors: Mária Zajičková, Ján Moncoľ, Sergej Šesták, Juraj Kóňa,
Miroslav Koóš, and Maroš Bella
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801586
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10.1002/ejoc.201801586
European Journal of Organic Chemistry
FULL PAPER
Synthesis of 4a-carba-D-lyxofuranose derivatives and their
evaluation as inhibitors of GH38 α-mannosidases
Mária Zajičková,[a] Ján Moncoľ,[b] Sergej Šesták,[a] Juraj Kóňa,[a] Miroslav Koóš[a] and Maroš Bella*[a]
Abstract:
A
synthetic approach to 4a-carba-D-lyxofuranose
structure (Figure1).
derivatives starting from D-lyxose is described. The protected 4a-
carba-β-D-lyxofuranose was employed as the key intermediate for
the synthesis of 4a-carba-D-lyxofuranose derivatives including novel
1-amino-1-deoxy-4a-carba-D-lyxofuranoses. Synthesised 4a-carba-
D-lyxofuranoses were evaluated as inhibitors of GH38 α-
mannosidases, namely, the Golgi (GMIIb) and lysosomal (LManII) α-
mannosidases from Drosophila melanogaster and commercial Jack
bean α-mannosidase (JBMan) from Canavalia ensiformis. The
biochemical evaluation revealed that only 1-amino-1-deoxy-4a-
carba-β-D-lyxofuranose exhibited reasonable inhibitory activity
against GMIIb (IC50 = 200 µM). In addition, the results of biological
evaluation were discussed by means of molecular modelling.
Introduction
Densely hydroxylated cyclopentanes and cyclohexanes are
often referred to as carbasugars or pseudosugars as they
simulate monosaccharides in biological systems.[1] These
cyclitols can be considered as furanose or pyranose analogues
in which the endocyclic oxygen is replaced by a methylene
group.[2,3] The absence of an acetal function makes them
resistant to enzymatic hydrolysis in comparison with
carbohydrate derivatives, and therefore these compounds act as
effective inhibitors of glycosidases.[4] The inhibition of
glycosidases is closely related to a treatment of a vast number
of diseases such as metastatic cancer, bacterial and viral
infections including human immunodeficiency.[5] Due to strong
biological activities as well as interesting structural features,
(amino)cyclopentitols attract attention of both biologists and
organic chemists as potential therapeutics for the treatment of
carbohydrate-metabolism-related disorders.[6]
(Amino)cyclopentitols occur as a core structural motif in various
natural products such as mannostatin A (1),[7,8] salpantiol (2),[9,10]
trehazolin (3)[11] and their synthetic derivative Merrell-Dow’s
cyclopentylamine (4)[12] that display significant inhibition of
glycosidases (Figure 1). Carbocyclic nucleosides such as
neplanocin A (5),[13] aristeromycin (6)[14] and their numerous
analogues[15-19] exhibit antiviral, antibacterial and antitumor
activity. These compounds represent another class of
derivatives containing carbasugar framework within their
Figure 1. Examples of biologically active (amino)cyclopentitols
To date, many synthetic approaches have been developed in
order
to
provide
easy
and
effective
access
to
(amino)cyclopentitol derivatives with various stereochemistry,
substitution patterns and enhanced biological properties.[2-4,11,20]
However, the conversion of carbohydrates into cyclopentitols via
ring-closing metathesis (RCM) is among the most widely
employed routes.[21-23] Recently, several novel methodologies
have emerged, for example, Jung and co-workers described
divergent synthesis of new aminocyclopentitol derivatives via
diastereoselective
amination
of
benzylated
polyhydroxycyclopentenes with chlorosulfonyl isocaynate.[24]
Moreover, Padwal et al. developed the stereoselective synthesis
of aminocyclopentene derivative as a new scaffold for a two-
dimensional compound library for drug discovery.[25]
The synthetic methods based on ring-closing reactions
described previously include preparation of carba-D-
lyxofuranoses starting from carbohydrate[26] and non-
[a]
MSc. M. Zajičková, Dr. S. Šesták, Dr. J. Kóňa, Dr. M. Koóš,
Dr. M. Bella
carbohydrate[27]
carbafuranoses
substrates.
including
Recently,
4a-carba-β-D-lyxofuranose
preparation
of
by
Department of Glycochemistry,
employing CrCl2 mediated domino reaction and ring closing
metathesis was demonstrated.[28] Considering the biological
importance of (amino)cyclopentitols, effective methods for their
synthesis still remain highly desirable.
Institute of Chemistry, Slovak Academy of Sciences
Dúbravská cesta 9, SK-845 38, Bratislava, Slovakia
E-mail: maros.bella@savba.sk
http://www.chem.sk/index_en.php
Assoc. Prof. J. Moncoľ
[b]
In this contribution, stereoselective synthesis of novel 1-amino-
4a-carba-D-lyxofuranoses 19 and 25 starting from commercially
available D-lyxose is descrided. Protected 4a-carba-β-D-lyxo-
Department of Inorganic Chemistry, Faculty of Chemical and Food
Technology, Radlinského 9, SK-812 37 Bratislava, Slovakia
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201801586
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Scheme 1.
furanose 14,[27] as the key intermediate for synthesis of target
lyxofuranose 14 was commenced from D-lyxose which was
initially protected as lyxofuranose 7 according to recognized
procedures (Scheme 1).[35.36] Next, nucleophilic addition of
vinylmagnesium bromide to an aldehyde group of an open-chain
form of 7 afforded diastereomeric diols 8 in 3:1 ratio in almost
quantitative yield (Scheme 1). The diastereomeric ratio of diols 8
was determined by an integration of signals in 1H NMR spectrum.
Major anti-isomer 8a was separated by column chromatography
in 66% yield, and was used optically pure in the following
reaction sequence (Scheme 2). Standard silylation of sterically
less hindered hydroxy group in diol 8a furnished alcohol 9 in
81% yield. To incorporate another double bond for a ring-closing
metathesis (RCM), the hydroxy group in alcohol 9 was oxidized
with Dess-Martin periodinane (DMP) to yield ketone 10. Next,
ketone 10 was subjected to Wittig olefination to give diene 11 in
90% yield. The literature search indicated that RCM reactions on
substrates similar to diene 11 were unsuccessful due to
increased steric demands.[31] Therefore the t-butyldimethylsilyl
group in diene 11 was removed with tetrabutylammonium
fluoride to afford sterically less demanding diene 12. The latter
was smoothly converted into the polyhydroxycyclopentene 13 in
81% yield following the Grubbs’ protocol. Kasula et al.[32]
reported diastereoselective syn-hydrogenation of double bond in
compounds, was synthesised in
a nine-step reaction
sequence involving ring-closing metathesis and stereoselective
hydrogenation of double bond as the crucial steps. As 1-amino-
4a-carba-D-lyxofuranoses 19 and 25 can be considered as
mannostatin A analogues[8,29,30] they were evaluated together
with 4a-carba-D-lyxofuranose derivatives 15 and 18 as inhibitors
of GH38 α-mannosidases, more specifically, the Golgi (GMIIb)
and lysosomal (LManII) α-mannosidases from Drosophila
melanogaster and commercial Jack bean α-mannosidase
(JBMan) from Canavalia ensiformis. Moreover, the results of
biological evaluation are also discussed by means of molecular
modelling.
Results and Discussion
Synthesis
The synthetic approach leading to the key 4a-carba-D-
lyxofuranose 14 was based on the combination of literature
procedures that employ carbohydrates as the starting
materials.[31-34] In analogy, the preparation of 4a-carba-β-D-
Scheme 2. Synthesis of the key intermediate 14 and 4a-carba-β-D-lyxofuranose 15
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10.1002/ejoc.201801586
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Scheme 3. Syntheis of 1-amino-4a-carba-α-D-lyxofuranose 19
antipode of 13 on 10% Pd-C with Na2CO3 in EtOAc to give 4a-
carba-β-L-lyxofuranose in 95% yield. However, when these
Consequently, based on this information, the absolute
configuration of previous and subsequent products was
reaction conditions were applied on polyhydroxycyclopentene 13, confirmed. Simultaneous removal of trityl and acetonide
4a-carba-β-D-lyxofuranose 14[27] was isolated in about 50% yield. protecting groups from 14 under acidic conditions provided 4a-
Conventional catalytic hydrogenation of double bond in 13 on
10% Pd-C in EtOH led to unwanted hydrogenolysis of trityl
protecting group thus lowering the yields of 14 to about 40%. It
was found out that presence of Et3N during catalytic
hydrogenation of 13 on 10% Pd-C in EtOH slows down
hydrogenolysis of trityl protecting group. By this way, desired 4a-
carba-β-D-lyxofuranose 14 was isolated in almost 80% yield.
Moreover, the absolute configuration of 14 was unambiguously
confirmed by single-crystal X-ray analysis (Figure 2).[37]
carba-β-D-lyxofuranose 15[26-28] in almost quantitative yield
(Scheme2).
In the next progress, the attention was focused on preparation of
1-aminocarba-D-lyxofuranoses. First, 1-amino-4a-carba-α-D-
lyxofuranose 19 was accessed in four reaction steps starting
from 4a-carba-β-D-lyxofuranose 14 (Scheme 3).
Standard mesylation of 14 smoothly provided mesylate 16 in
almost quantitative yield. Nucleophilic substitution of mesylate in
16 with NaN3 in DMF at 130 °C yielded desired azide 17 in 87%
yield. Although catalytic hydrogenation of azide 17 on 10% Pd-C
in EtOH led to full conversion of starting material, the
corresponding amine was not isolated due to its rapid
decomposition during purification by column chromatography.
Therefore hydrolysis of trityl and acetonide protecting groups in
17 under acidic conditions was carried out to afford 1-azido-4a-
carba-α-D-lyxofuranose 18. Exposure of azide 18 to catalytic
hydrogenation on 10% Pd-C in MeOH resulted in a rapid
reduction of the azido group to give the final 1-amino-4a-carba-
α-D-lyxofuranose 19 in good yield (Scheme 3).
Figure 2. Crystal structure of compound 14 (OLEX2 drawing). Atomic
displacement ellipsoids are drawn at 50% probability level.
Scheme 4. Syntheis of 1-amino-4a-carba-β-D-lyxofuranose 25
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10.1002/ejoc.201801586
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The approach to 1-amino-4a-carba-β-D-lyxofuranose 25 relied
on a stereoselective reduction of a C=N double bond[38] from the
exo-face of the bicyclic skeleton with an appropriate hydride
donor. In this regard, free hydroxy group in protected 4a-carba-
β-D-lyxofuranose 14 was subjected to oxidation with DMP to
Table 1. Inhibitory activity of 4a-carba-β-D-lyxofuranose 15 and its derivatives
18, 19 and 25 against GH38 α-mannosidases (GMIIb, LManII and JBMan)
IC50 [M]
GMIIb
IC50 [M]
LManII
IC50 [M]
JBMan
Compound
furnish ketone 20[27] in high yield (Scheme 4). Direct reductive
[39]
amination of ketone 20 with NaBH(OAc)3
and a source of
mannostatin A
(137±13)×10−9
(3.7±0.4)×10−6
n.d.
ammonia (AcONH4, CF3COONH4) in a suitable solvent (EtOH,
THF) did not lead to desired amine 24. On the other hand,
reductive amination of ketone 20 with NaBH(OAc)3 and p-
anisidine in the presence of AcOH smoothly afforded p-
methoxyphenyl amine 21 in high yield (Scheme 4).[40] Despite
the successful synthesis of 21, a removal of p-methoxyphenyl
protecting group with ceric ammonium nitrate (CAN) under
standard conditions failed. Therefore another strategy based on
a reduction of appropriate oximes was considered. Within this
respect, oximes 22 and 23 were prepared by condensation of
ketone 20 with hydroxylamine and O-methylhydroxylamine,
respectively (Scheme 4). Reduction of oxime 22 with LiAlH4 or
NaBH4 in the presence of NiCl2·6H2O[41] did not provide desired
amine 24. Finally, treatment of O-methyl oxime 23 with BH3 in
anhydrous THF at 0 °C followed by heating at 55 °C and
subsequent basic work-up[42] accessed amine 24 in 72% yield.
During the reduction of O-methyl oxime 23, a corresponding O-
methylhydroxylamine was identified as the major by-product.
However, our attempts on improving the yields of amine 24 by
extending the reaction time or by employing more than three
equivalents of BH3 did not lead to success. Final acid hydrolysis
of trityl and acetonide protecting groups in 24 afforded 1-amino-
4a-carba-β-D-lyxofuranose 25 in 82% yield. Although an analysis
15
18
19
25
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
(200±20)×10−6
(1930±45)×10−6
(755±35)×10−6
n.i. no inhibition (inhibition below 20% at 2 mM); n.d. not determined
against GMIIb in comparison with mannostatin A (IC50 = 137 nM)
which was used as the standard in the biochemical assay. The
inhibitory activity of the compounds 15, 18, 19 and 25 against
GMIIb is further discussed together with the results of molecular
modelling in the following section.
Molecular modelling
The main goal of molecular modelling was to explain observed
inhibitory activity of the synthesised 4a-carba-D-lyxofuranoses
15, 18, 19 and 25 against GMIIb (Table 1). The numbering of
atoms in compounds discussed in this section is according to
IUPAC nomenclature. As synthesised compounds 15, 18, 19
and 25 can be considered as mannostatin A analogues lacking
methylthio moiety in the position C-5, and bearing
hydroxymethyl group in position the C-1 together with altered
functional groups and configurations at C-4, their structures and
inhibitory properties were compared with the available crystal
1
of H NMR spectrum of 24 indicated expected configuration, the
R-configuration at newly-built stereocenter in amine 24 was
confirmed by the comparison of spectroscopic and physical
properties of 1-amino-4a-carba-D-lyxofuranoses 19 and 25. As
amines 19 and 25 differ in their spectroscopic and physical
properties and the structure of amine 19 was indirectly
confirmed by X-ray analysis of 4a-carba-β-D-lyxofuranose 14,
the R-configuration at newly-built stereocenter in amine 24 is
undoubtedly correct.
structure of
a mannostatin A complex with Drosophila
melanogaster Golgi α-mannosidase II (dGMII) (PDB ID:2F7O).[8]
The compounds 15, 18, 19 and 25 were docked into the active
site of dGMII (Figure 3a and 3b). All structures are predicted to
bind in similar conformations except for derivative 19. In
derivative 19, a more planar arrangement of the cyclopentane
ring was found probably due to a different stereo configuration of
the amino group at the C-3 position. Binding positions of all
hydroxyl groups in studied 4a-carba-D-lyxofuranoses closely
correspond to those found in the crystal structure of the
mannostatin A with dGMII, i.e. they interact with Zn2+ ion co-
factor, Asp92 and Asp472 (Figure 3d).
Biochemical evaluation
As synthesised 4a-carba-β-D-lyxofuranose 15 and its derivatives
18, 19 and 25 can be considered as mannostatin A analogues,
they were evaluated against three GH38 α-mannosidases,
namely, the Golgi (GMIIb) and lysosomal (LManII) α-
mannosidases
from
Drosophila
melanogaster,[43]
and
commercial Jack bean α-mannosidase (JBMan) from Canavalia
ensiformis (Table 1). As can be seen from the results
summarized in Table 1, only 1-amino-4a-carba-β-D-lyxofuranose
25 showed reasonable inhibitory activity against GH38 α-
mannosidases. In case of compounds 15, 18 and 19, negligible
inhibitory activity (below 20% at 2 mM concentration) was
observed against the tested enzymes. Although the compound
As can be seen from the docking poses and the measured
inhibitory activity (Table 1), the presence of the amino group at
C-3 with an appropriate stereo configuration, mimicking the
stereo configuration of the amino group of mannostatin A,
seems to be crucial for maintaining biological activity of 25 at the
micromolar level. In Figure 3c, a schematic model of interactions
between the amino group of 25 and active-site amino acids is
proposed based on the docked calculations. The ammonium
form of the amino group of 25 may form two salt bridges with
two important amino acids, Asp341 (catalytic acid of dGMII) and
25 exhibited considerably higher activity against GMIIb (IC50
=
200 μM) compared to LManII (IC50 = 1930 μM) and JBMan (IC50
= 755 μM), it is still more than thousand times less effective
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10.1002/ejoc.201801586
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Figure 3. (a) and (b): The structures 15, 18, 19 and 25 docked into the active site of dGMII (PDB ID: 2F7O).[8] Carbon atoms are in yellow for 15, in magenta for
18, in green for 19 and in pink for 25. For sake of clarity, hydrogen atoms are omitted. (c) and (f): Schematic models of interactions between the amino and
hydroxyl groups of 25 and its 5-hydroxy analogue (PDB ID: 3DX1)[29] and the active-site amino acids of dGMII. The ammonium cation of 25 and its 5-hydroxy
analogue may form two salt bridges with Asp341 (catalytic acid) and Asp204 (catalytic nucleophile). (d): A binding pose of mannostatin A (in green) in X-ray
complex with dGMII (PDB ID: 2F7O)[8] as well as its pose from docking calculations (in magenta) and docked 25 (in pink). (e): A binding pose of 5-hydroxy
analogue of 25 (PDB ID: 3DX1)[29] (in green) and docked 25 (in pink).
Asp204 (catalytic nucleophile) in similar manner as it was found
in the crystal structure of mannostatin A with dGMII. In case of
compounds 15, 18 and 19, the two salt bridges are not formed
due to either inappropriate stereo configuration or different
chemical nature of the functional group at C-3.
4a-carba-β-D-lyxofuranose 14 was prepared from D-lyxose as
the key intermediate for synthesis of 4a-carba-D-lyxofuranose
derivatives. Biochemical evaluation of four synthesised 4a-
carba-D-lyxofuranoses 15, 18, 19 and 25 revealed that only 1-
aminocarba-β-D-lyxofuranose 25 exhibited reasonable inhibitory
activity against GMIIb (IC50 = 200 µM). Therefore 1-amino-4a-
carba-β-D-lyxofuranose 25 can be considered as a model
compound for a further development of more effective inhibitors
of GH38 α-mannosidases. In addition, the biochemical assay
along with docking calculations showed that the presence of the
amino group with the appropriate stereo configuration at the C-3
In all synthesized 4a-carba-D-lyxofuranoses 15, 18, 19 and 25, a
hydroxymethyl group is attached on the cyclopentane ring with
the same stereo configuration as a hydroxyl group at C-1 in
mannostatin A. The substitution of the hydroxyl by the
hydroxymethyl group at C-1 showed a little influence on potency
of the inhibitors since derivative 25 and its 5-hydroxy analogue
have similar inhibitory activities [Ki(dGMII) = 265 µM].[8,29] Indeed, position and neighbouring cis-diol are essential for biological
binding positions of the hydroxymethyl group in derivative 25
and hydroxyl group at C-1 in 5-hydroxy analogue (a comparison
of the docking pose for 25 with a crystal structure of its 5-
hydroxy analogue, PDB ID: 3DX1[29] (Figure 3e)) are similar
forming hydrogen bonds with Asp472 (Figure 3c and 3f).
activity of 25 against glycoside hydrolases from the GH family 38.
On the other hand, it should be mentioned that both C-2 epimers
of compounds 19 and 25 bearing trans-diol next to amino group
exhibited good inhibitory activity against Jack bean α-
mannosidase (JBMan).[44] These unexpected results point out
that the binding mode of aminocyclopentitols into the active site
of α-mannosidases is not completely understood. Nevertheless,
further improvement of inhibitory activity of 25 against the target
enzymes is required. This will be achieved by its structural
modification in cooperation with methods of molecular modelling.
Conclusions
In summary,
a stereoselective synthesis of 4a-carba-D-
lyxofuranose derivatives including novel 1-aminocarba-D-
lyxofuranoses 19 and 25 was developed. The partially protected
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[C(CH3)2]; IR (ATR) νmax: 3392, 1447, 1212, 1019, 753, 700 cm−1; HRMS:
m/z calcd for C29H32O5: 483.2142 [M+Na]+; found: 483.2130.
Experimental Section
Synthesis
(R)-1-((4S,5S)-5-((R)-1-(tert-butyldimethylsilyloxy)allyl)-2,2-dimethyl-
1,3-dioxolan-4-yl)-2-(trityloxy)ethanol (9): TBSCl (6.27 g, 41.60 mmol)
was added to a stirred solution of diol 8a (13.71 g, 29.77 mmol),
imidazole (6.07 g, 89.16 mmol) and DMAP (0.14 g, 1.14 mmol) in a
mixture of CH2Cl2 (180 mL) and DMF (22.5 mL) at 0 °C, and the reaction
mixture was stirred at room temperature overnight. Next, the reaction
mixture was washed with water (2×200 mL). The organic layer was
separated, dried with Na2SO4, and filtered, and the solvent was
evaporated under reduced pressure. The crude product was purified by
column chromatography on silica gel using EtOAc/hexanes (1:20, v/v) as
the eluent to afford silyl ether 9 (13.85 g, 81%) as a colourless oil. Rf =
0.20 (EtOAc/hexanes, 1:20); [α]D20 = −18.8 (c 1.00, CHCl3). 1H NMR (400
MHz, CDCl3): δ 7.47–7.40 (m, 6H, Ph), 7.32–7.17 (m, 9H, Ph), 5.82 (ddd,
J = 17.1, 10.4, 6.7 Hz, 1H, –CH=CH2), 5.33 (dt, J = 17.2, 1.4 Hz, 1H, –
CH=CH2-trans), 5.25 (dt, J = 10.4, 1.4 Hz, 1H, –CH=CH2-cis), 4.65 (ddt, J =
7.1, 6.1, 1.3 Hz, 1H), 4.41 (dd, J = 7.0, 1.1 Hz, 1H), 4.15 (dd, J = 7.0, 5.9
Hz, 1H), 4.03 (dddd, J = 7.4, 6.0, 4.9, 1.1 Hz, 1H), 3.29–3.16 (m, 3H),
1.45 and 1.36 [2s, each 3H, C(CH3)2], 0.90 [s, 9H, Si(CH3)2C(CH3)3], 0.14
and 0.09 [2s, each 3H, Si(CH3)2C(CH3)3]; 13C NMR (100 MHz, CDCl3): δ
144.1 (Ph), 137.5 (–CH=CH2), 128.7 (Ph), 127.6 (Ph), 126.8 (Ph), 117.5
(–CH=CH2), 107.9 [C(CH3)2], 86.6 (CPh3), 79.3, 76.3, 73.3, 68.1, 64.6,
26.4 and 24.9 [C(CH3)2], 25.8 [Si(CH3)2C(CH3)3], 18.2 [Si(CH3)2C(CH3)3],
−3.8 and −4.7 [Si(CH3)2C(CH3)3]; IR (ATR) νmax: 3465, 2929, 1252, 1072,
835, 704 cm−1; HRMS: m/z calcd for C35H46O5Si: 575.3187 [M+H]+;
found: 575.3190.
All reagents and anhydrous solvents were commercially sourced, and
were used as received. The starting lyxofuranose 7 was prepared from
D-lyxose according to published methods.[35,36] All solvents were of
technical grade, and were distilled before use. Dichloromethane (Slavus,
Slovakia) was heated at reflux with P2O5 for 1 h and distilled immediately
before use. Melting points were determined with a Boetius PHMK 05
microscope. Specific optical rotations were determined with a Jasco P-
2000 polarimeter. H and 13C NMR spectra were recorded with a Bruker
1
AVANCE III HD 400 spectrometer operating at 400 and 100 MHz working
frequencies, respectively. Chemical shifts are given in (δ), and were
calibrated using the residual signal of the deuterated solvent used (CDCl3,
CD3OD). Coupling constants are given in Hz. All given 13C spectra are
proton decoupled. High-resolution mass spectra were recorded with an
Orbitrap Elite (Thermo Scientific) mass spectrometer with ESI ionization
in positive mode. IR spectra (ATR) were measured with a Nicolet 6700
FTIR spectrometer. Thin-layer chromatography (TLC) was carried out on
glass plates pre-coated with TLC Silica gel 60 F254 (E. Merck). Plates
were visualized by immersing into phosphomolybdic acid (PMA; 10%
solution in ethanol), KMnO4 (3 g of KMnO4, 20 g, K2CO3, 2.5 mL of 10%
NaOH and 400 mL of water) or “Mo-stain” (5g of Ce(SO4)2·4H2O, 25 g of
(NH4)6Mo7O24·4H2O, 50 mL of H2SO4 and 450 mL of water) and heating
at ca 200 °C with a heat gun. Column chromatography was carried out as
flash chromatography on Silica gel 60 (E. Merck, 0.040–0.063 mm).
Solvents used for flash chromatography were of technical grade, and
were distilled before use. Data collection and cell refinement of 14 were
made on a Stoe StadiVari diffractometer using Pilatus3R 300K detector
and microfocused X-ray source Xenocs Genix3D Cu HF. The structure
was solved by the program SHELXT and refined by the full-matrix least-
squares procedure with SHELXL (version 2016/6).[45,46] The structure
was drawn using OLEX2 package.[47] The absolute structure and
configuration was determined. The Flack parameter was calculated by
the Parsons method.[48]
1-((4R,5S)-5-((R)-1-(tert-butyldimethylsilyloxy)allyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)-2-(trityloxy)ethanone (10): DMP (22.7 g, 53.49 mmol)
was added to a stirred solution of alcohol 9 (13.77 g, 23.95 mmol) in
CH2Cl2 (230 mL) at 0 °C, and the reaction mixture was stirred at room
temperature overnight. Next, the reaction mixture was cooled in an ice-
water bath, a mixture of saturated solution of NaHCO3 (100 mL) and
Na2S2O3 (25% aq.; 100 mL) was added, and the mixture was stirred until
effervescence ceased. Then, the organic layer was washed (2 ×) with a
mixture of saturated solution of NaHCO3 (100 mL) and Na2S2O3 (25%
aq.; 100 mL). The organic layer was separated, dried with Na2SO4, and
filtered, and the solvent was evaporated under reduced pressure. The
crude product was purified by column chromatography on silica gel using
(R)-1-((4R,5S)-5-((R)-1-hydroxy-2-(trityloxy)ethyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)prop-2-en-1-ol (8a):
A solution of vinylmagnesium
bromide (1M in THF, 225 mL, 225 mmol) was added dropwise to a stirred
solution of lyxofuranose 7 (19.50 g, 45.08 mmol) in anhydrous THF (280
mL) at 0 °C under a nitrogen atmosphere, and the mixture was stirred at
room temperature overnight. Next, the reaction mixture was cooled to
0 °C, and was carefully quenched with saturated aqueous solution of
NH4Cl (60 mL). Then, THF was evaporated under reduced pressure, and
the residue was partitioned between EtOAc (300 mL) and water (240 mL).
The organic layer was separated, and the aqueous layer was extracted
with EtOAc (100 mL). The combined extracts were dried with Na2SO4,
and filtered, and the solvent was evaporated under reduced pressure to
give a diastereoisomeric mixture of diols (8a-anti:8b-syn 3:1, 20.70 g,
99%). Three successive column chromatographies on silica gel using
EtOAc/hexanes (1:3, v/v) as the eluent afforded diol 8a-anti (13.71 g,
66%) as a white solid. M.p. 156-157 °C; Rf = 0.24 (EtOAc/hexanes, 1:3);
[α]D20 = +2.0 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.51–7.42 (m,
6H, Ph), 7.37–7.22 (m, 9H, Ph), 6.01 (ddd, J = 17.3, 10.6, 5.2 Hz, 1H, –
CH=CH2), 5.42 (dt, J = 17.3, 1.6 Hz, 1H, –CH=CH2-trans), 5.28 (dt, J =
10.6, 1.6 Hz, 1H, –CH=CH2-cis), 4.53–4.42 (m, 1H), 4.33 (dd, J = 6.3, 1.7
Hz, 1H), 4.18 (qd, J = 6.4, 1.7 Hz, 1H), 4.03 (dd, J = 7.7, 6.3 Hz, 1H),
3.36 (dd, J = 9.3, 6.4 Hz, 1H), 3.30 (dd, J = 9.3, 6.2 Hz, 1H), 3.10 (d, J =
4.9 Hz, 1H, OH), 2.84 (d, J = 6.9 Hz, 1H, OH), 1.49 and 1.38 [2s, each
3H, C(CH3)2]; 13C NMR (100 MHz, CDCl3): δ 143.8 (Ph), 137.5 (–
CH=CH2), 128.6 (Ph), 127.8 (Ph), 127.0 (Ph), 116.2 (–CH=CH2), 108.1
[C(CH3)2], 86.9 (CPh3), 79.5, 76.3, 70.7, 68.04, 65.2, 27.1 and 25.1
EtOAc/hexanes (1:15, v/v) as the eluent to afford ketone 10 (10.69 g,
20
78%) as a thick colourless oil. Rf = 0.21 (EtOAc/hexanes, 1:15); [α]D
=
+20.6 (c 1.00, CHCl3) (ref.[31] for antipode of 10 [α]D = −14.97 (c 1.00,
CHCl3). H NMR (400 MHz, CDCl3): δ 7.51–7.43 (m, 6H, Ph), 7.34–7.20
23
1
(m, 9H, Ph), 5.78 (ddd, J = 17.5, 10.5, 7.3 Hz, 1H, –CH=CH2), 5.09–5.06
(m, 2H, –CH=CH2), 4.54 (d, J = 7.0 Hz, 1H), 4.35–4.26 (m, 2H), 4.12 (d,
J = 17.7 Hz, 1H), 3.88 (d, J = 17.7 Hz, 1H), 1.34 and 1.27 [2s, each 3H,
C(CH3)2], 0.79 [s, 9H, Si(CH3)2C(CH3)3], −0.03 and −0.06 [2s, each 3H,
Si(CH3)2C(CH3)3]; 13C NMR (100 MHz, CDCl3): δ 204.6 (C=O), 143.5
(Ph), 137.2 (–CH=CH2), 128.6 (Ph), 127.8 (Ph), 127.1 (Ph), 117.9 (–
CH=CH2), 109.4 [C(CH3)2], 87.1 (CPh3), 82.4, 79.4, 73.0, 69.4, 26.2 and
24.7 [C(CH3)2], 26.0 [Si(CH3)2C(CH3)3], 18.3 [Si(CH3)2C(CH3)3], −4.3 and
−4.5 [Si(CH3)2C(CH3)3]; IR (ATR) νmax: 2952, 1735, 1213, 1042, 836, 702
;
cm−1 HRMS: m/z calcd for C35H44O5Si: 573.3031 [M+H]+; found:
573.3023.
tert-Butyl((R)-1-((4S,5S)-2,2-dimethyl-5-(3-(trityloxy)prop-1-en-2-yl)-
1,3-dioxolan-4-yl)allyloxy)dimethylsilane (11): A solution of nBuLi (1.6
M in hexanes, 55 mL, 88.00 mmol) was added to a stirred suspension of
triphenylmethylphosphonium bromide (32.98 g, 92.32 mmol) in
anhydrous THF (60 mL) at 0 °C under a nitrogen atmosphere, and the
mixture was stirred for 1.5 h at 0 °C. Next, a solution of ketone 10 (10.58
g, 18.47 mmol) in anhydrous THF (125 mL) was added via cannula to the
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801586
European Journal of Organic Chemistry
FULL PAPER
resulting mixture at 0 °C, and the reaction mixture was stirred at room
temperature overnight. The reaction mixture was cooled in an ice-water
bath, MeOH (30 mL) was added, and the mixture was stirred for 30 min.
The mixture was partitioned between ether (300 mL) and water (400 mL).
The organic layer was separated, and the aqueous layer was extracted
with ether (2×150 mL). The combined extracts were washed with water
(400 mL), dried with Na2SO4, and filtered, and the solvent was
evaporated under reduced pressure. The crude product was purified by
column chromatography on silica gel using EtOAc/hexanes (1:20, v/v) as
the eluent to afford diene 11 (9.54 g, 90%) as a thick colourless oil, which
crystallized in a refrigerator. M.p. 85-86 °C; Rf = 0.28 (EtOAc/hexanes,
1:20); [α]D20 = +41.3 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.50–
7.42 (m, 6H, Ph), 7.33–7.19 (m, 9H, Ph), 5.73–5.59 (m, 2H, –CH=CH2,
C=CH2), 5.37 (p, J = 1.4 Hz, 1H, C=CH2), 5.08 (ddd, 10.2, 1.8, 0.8 Hz,
1H, –CH=CH2-cis), 4.98 (ddd, J = 17.3, 1.8, 0.8 Hz, 1H, –CH=CH2-trans),
4.74 (d, J = 5.8 Hz, 1H), 3.95–3.85 (m, 2H), 3.72 (dt, J = 13.3, 1.6 Hz,
1H), 3.53 (dt, J = 13.3, 1.3 Hz, 1H), 1.29 and 1.25 [2s, each 3H, C(CH3)2],
0.78 [s, 9H, Si(CH3)2C(CH3)3], −0.07 and −0.08 [2s, each 3H,
Si(CH3)2C(CH3)3]; 13C NMR (100 MHz, CDCl3): δ 144.1 (Ph), 141.9
(C=CH2), 138.6 (–CH=CH2), 128.6 (Ph), 127.8 (Ph), 127.0 (Ph), 117.2 (–
CH=CH2), 113.5 (C=CH2), 107.9 [C(CH3)2], 86.7 (CPh3), 80.6, 78.7, 73.1,
64.7, 26.4 and 25.0 [C(CH3)2], 26.0 [Si(CH3)2C(CH3)3], 18.1
[Si(CH3)2C(CH3)3], −3.4 and −4.1 [Si(CH3)2C(CH3)3]; IR (ATR) νmax: 2928,
1255, 1207, 1068, 764, 708 cm−1; HRMS: m/z calcd for C36H46O4Si:
593.3058 [M+Na]+; found: 593.3052.
Rf = 0.19 (EtOAc/hexanes, 1:4); [α]D20 = −34.5 (c 1.00, CHCl3) (ref.[31] for
23
antipode of 13 [α]D = +33.21 (c 1.00, CHCl3), ref.[49] for antipode of 13
29
1
[α]D = +30.9 (c 1.00, CHCl3)). H NMR (400 MHz, CDCl3): δ 7.49–7.42
(m, 6H, Ph), 7.34–7.19 (m, 9H, Ph), 5.98 (dd, J = 2.6, 1.4 Hz, 1H, H-5),
4.88 (d, J = 5.5 Hz, 1H, H-6a), 4.74 (t, J = 5.5 Hz, 1H, H-3a), 4.62–4.54
(m, 1H, H-4), 3.88 (dt, J = 14.3, 1.7 Hz, 1H, CH2OTr), 3.71–3.63 (m, 1H,
CH2OTr), 2.72 (d, J = 10.0 Hz, 1H, OH), 1.36 [s, 6H, C(CH3)2]; 13C NMR
(100 MHz, CDCl3): δ 143.8 (Ph), 143.3 (C-6), 129.7 (C-5), 128.5 (Ph),
127.8 (Ph), 127.0 (Ph), 112.4 [C(CH3)2], 86.9 (CPh3), 83.3 (C-6a), 77.8
(C-3a), 73.4 (C-4), 60.8 (CH2OTr), 27.7 and 26.8 [C(CH3)2]; IR (ATR)
νmax: 3526, 2930, 1449, 1052, 707, 697 cm−1; HRMS: m/z calcd for
C28H28O4: 451.1880 [M+Na]+; found: 451.1879.
(3aR,4R,6R,6aS)-2,2-dimethyl-6-(trityloxymethyl)tetrahydro-3aH-
cyclopenta[d][1,3]dioxol-4-ol (14): Cyclopentene 13 (1.00 g, 2.33
mmol) was dissolved in EtOH (50 mL) while heating in a hot-water bath.
Et3N (0.65 mL, 0.47 g, 4.65 mmol) and Pd-C (10%; 100 mg) in EtOH (7
mL) were added to this solution at room temperature, and the mixture
was stirred under a hydrogen atmosphere (balloon) at room temperature
for 1 h. Next, the catalyst was removed by filtration through a pad of
Celite®, and a filter cake was washed with EtOH (40 mL), and the filtrate
was concentrated under reduced pressure. The crude product was
purified by column chromatography on silica gel using EtOAc/hexanes
(1:3, v/v/) as the eluent to afford cyclopentane 14 (0.77 g, 77%) as a
white solid. M.p. 134-135 °C (EtOAc/hexanes, 1:4); Rf
=
0.22
20
20
(EtOAc/hexanes, 1:3); [α]D = −12.7 (c 1.00, CHCl3) (ref.[27] [α]D
=
(R)-1-((4R,5S)-2,2-dimethyl-5-(3-(trityloxy)prop-1-en-2-yl)-1,3-
–11.7 (c 3.5, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.50–7.41 (m, 6H,
Ph), 7.33–7.17 (m, 9H, Ph), 4.65 (t, J = 4.9 Hz, 1H), 4.44 (t, J = 5.6 Hz,
1H), 3.84 (tt, J = 10.6, 5.9 Hz, 1H), 3.37 (dd, J = 8.8, 7.5 Hz, 1H), 3.09
(dd, J = 8.8, 6.5 Hz, 1H), 2.34 (d, J = 10.3 Hz, 1H, OH), 1.98–1.88 (m,
1H), 1.84 (m, 1H), 1.38 and 1.33 [2s, each 3H, C(CH3)2], 1.32–1.22 (m,
1H); 13C NMR (100 MHz, CDCl3): δ 144.2 (Ph), 128.7 (Ph), 127.6 (Ph),
126.8 (Ph), 110.3 [C(CH3)2], 86.4 (CPh3), 79.3, 78.6, 72.1, 62.0, 39.3,
33.6, 25.6 and 24.3 [C(CH3)2]; IR (ATR) νmax: 3553, 2932, 1450, 1088,
1063, 698 cm−1; HRMS: m/z calcd for C28H30O4: 453.2036 [M+Na]+;
found: 453.2043.
dioxolan-4-yl)prop-2-en-1-ol (12): A solution of TBAF (1M in THF, 30
mL, 30.00 mmol) was added to a stirred solution of silyl ether 11 (9.50 g,
16.64 mmol) in THF (60 mL), and the reaction mixture was stirred at
room temperature overnight. Next, silica gel (70 g) was added to the
reaction mixture, and the solvent was evaporated under reduced
pressure. The residue was loaded on a column of silica gel, and was
eluted with EtOAc/hexanes (1:10, v/v) to afford alcohol 12 (7.42 g, 98%)
20
as a colourless oil. Rf = 0.14 (EtOAc/hexanes, 1:10); [α]D = +67.2 (c
1.00, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.49–7.43 (m, 6H, Ph), 7.34–
7.21 (m, 9H, Ph), 5.94 (ddd, J = 17.2, 10.5, 5.4 Hz, 1H, –CH=CH2), 5.61
(q, J = 1.6 Hz, 1H, C=CH2), 5.51 (p, J = 1.2 Hz, 1H, C=CH2), 5.27 (dt, J =
17.2, 1.6 Hz, 1H, –CH=CH2-trans), 5.19 (dt, J = 10.5, 1.6 Hz, 1H, –
CH=CH2-cis), 4.59 (d, J = 6.0 Hz, 1H), 3.97 (dddt, J = 8.4, 5.5, 4.2, 1.4 Hz,
1H), 3.89 (dd, J = 8.6, 6.0 Hz, 1H), 3.77 (dt, J = 12.9, 1.5 Hz, 1H), 3.72
(dt, J = 12.9, 1.2 Hz, 1H), 2.16 (d, J = 4.2 Hz, 1H, OH), 1.37 and 1.29 [2s,
each 3H, C(CH3)2]; 13C NMR (100 MHz, CDCl3): δ 143.6 (Ph), 142.1
(C=CH2), 137.6 (–CH=CH2), 128.6 (Ph), 127.9 (Ph), 127.1 (Ph), 116.0 (–
CH=CH2), 113.8 (C=CH2), 108.1 [C(CH3)2], 87.5 (CPh3), 80.5, 77.8, 70.2,
65.3, 27.1 and 25.1 [C(CH3)2]; IR (ATR) νmax: 3467, 2986, 1448, 1213,
1043, 700 cm−1; HRMS: m/z calcd for C30H32O4: 479.2193 [M+Na]+;
found: 479.2195.
(1R,2R,3S,4R)-4-(hydroxymethyl)cyclopentane-1,2,3-triol (15):
A
solution of HCl (20% aq.; 2 mL) was added to a stirred suspension of
cyclopentane 14 (200 mg, 0.46 mmol) in MeOH (4 mL) at 0 °C, and the
mixture was heated at 50 °C for 5 h. Next, the reaction mixture was
cooled in an ice-water bath, and was carefully basified with solid Na2CO3
(0.95 g). The resulting mixture was filtered, and a filter cake was washed
with MeOH (5 mL), and the filtrate was concentrated under reduced
pressure. The crude product was purified by column chromatography on
silica gel using MeOH/CHCl3 (1:3, (v/v) containing 0.5% (v/v) of concd.
aqueous NH3) as the eluent to afford tetraol 15 (65 mg, 95%) as a thick
colourless oil. Rf = 0.16 (MeOH/CHCl3, 1:3 containing 0.5% (v/v) of concd.
aqueous NH3); [α]D20 = −15.6 (c 1.00, MeOH) (ref.[26] [α]D20 = –21.3 (c 1.0,
20
20
(3aR,4R,6aS)-2,2-dimethyl-6-(trityloxymethyl)-4,6a-dihydro-3aH-
cyclopenta[d][1,3]dioxol-4-ol (13): Grubbs catalyst (1.31 g, 1.59 mmol,
1st gen.) was added to a stirred solution of diene 12 (7.30 g, 15.98 mmol)
in CH2Cl2 (300 mL) under a nitrogen atmosphere, and the mixture was
stirred at room temperature overnight. Next, silica gel (65 g) was added
to the reaction mixture, and the solvent was evaporated under reduced
pressure. The residue was loaded on a column of silica gel, and was
eluted with EtOAc/hexanes (1:10→1:6, v/v) to afford cyclopentene 13 as
an off-white solid. Then, charcoal (0.5 g) was added to a stirred solution
of cyclopentene 13 in a mixture of EtOAc/hexanes (1:1, v/v, 70 mL), and
the mixture was stirred for 30 min. The resulting suspension was filtered
through a pad of silica gel, and was washed with a mixture of
EtOAc/hexanes (1:1, v/v, 100 mL), and the filtrate was concentrated
under reduced pressure to afford cyclopentene 13 (5.60 g, 81%) as a
white solid. M.p. 127-129 °C (ref.[49] m.p. 132-134 °C for antipode of 13);
MeOH), ref.[27] [α]D = –12.9 (c 1.0, MeOH), ref.[28] [α]D = –8 (c 0.4,
MeOH)). 1H NMR (400 MHz, CD3OD): δ 4.07 (t, J = 4.7 Hz, 1H), 4.05–
3.99 (m, 1H), 3.81–3.72 (m, 2H), 3.61 (dd, J = 10.6, 5.6 Hz, 1H), 2.16–
1.99 (m, 2H), 1.52 (ddd, J = 13.0, 8.6, 4.8 Hz, 1H); 13C NMR (100 MHz,
CD3OD): δ 75.5, 74.4, 72.6, 62.9, 42.5, 35.0; IR (ATR) νmax: 3288, 3154,
2931, 1397, 1110, 1009 cm−1; HRMS: m/z calcd for C6H12O4: 149.0808
[M+H]+; found: 149.0809.
(3aS,4R,6R,6aS)-2,2-dimethyl-6-(trityloxymethyl)tetrahydro-3aH-
cyclopenta[d][1,3]dioxol-4-yl methanesulfonate (16): MsCl (78 µL,
115 mg, 1.00 mmol) was added to a stirred solution of alcohol 15 (300
mg, 0.69 mmol), Et3N (0.28 mL, 203 mg, 2.00 mmol) and DMAP (26 mg,
0.21 mmol) in CH2Cl2 (6.5 mL) at 0°C, and the mixture was stirred at
room temperature overnight. Next, the reaction mixture was diluted with
CH2Cl2 (25 mL), and was washed with brine (25 mL). The aqueous layer
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801586
European Journal of Organic Chemistry
FULL PAPER
was extracted with additional CH2Cl2 (25 mL). The combined extracts
were dried with Na2SO4, and filtered, and the solvent was evaporated
under reduced pressure. The crude product was purified by column
chromatography on silica gel using EtOAc/hexanes (1:3, v/v) as the
eluent to afford mesylate 16 (333 mg, 94%) as a thick colourless oil. Rf =
(4:1, (v/v), containing 1% (v/v) of concd. aqueous NH3) as the eluent.
Amine 19 was dissolved in MeOH (0.5 mL), and the resulting mixture
was filtered through a PTFE syringe filter (45 µm). The clear filtrate was
concentrated under reduced pressure to afford amine 19 (24 mg, 66%)
as a thick brownish oil. Rf = 0.11 (MeOH/ACN, 4:1 containing 1% (v/v) of
concd. aqueous NH3); [α]D20 = +30.2 (c 1.00, MeOH). 1H NMR (400 MHz,
CD3OD): δ 4.05 (t, J = 4.2 Hz, 1H), 3.71 (dd, J = 10.7, 7.4 Hz, 1H), 3.65
(dd, J = 8.0, 3.9 Hz, 1H), 3.55 (dd, J = 10.7, 6.3 Hz, 1H), 3.30–3.23 (m,
1H), 2.25 (dtt, J = 9.5, 4.0, 2.0 Hz, 1H), 1.88 (ddd, J = 13.7, 9.8, 8.2 Hz,
1H), 1.49 (ddd, J = 13.7, 10.0, 6.5 Hz, 1H); 13C NMR (100 MHz, CD3OD):
δ 82.2, 74.5, 62.9, 56.4, 42.1, 32.5; IR (ATR) νmax: 3324, 3054, 2942,
1480, 1088, 951 cm−1; HRMS: m/z calcd for C6H13NO3: 170.0788
[M+Na]+; found: 170.0786.
20
0.21 (EtOAc/hexanes, 1:3); [α]D = +7.3 (c 1.00, CHCl3). 1H NMR (400
MHz, CDCl3): δ 7.48–7.42 (m, 6H, Ph), 7.34–7.20 (m, 9H, Ph), 4.64 (td, J
= 3.9, 2.7, 1.5 Hz, 3H), 3.41 (dd, J = 9.0, 7.1 Hz, 1H), 3.16–3.11 (m, 1H),
3.08 (s, 3H, OSO2CH3), 2.07 (dtd, J = 12.1, 5.3, 1.7 Hz, 1H), 1.95–1.83
(m, 1H, H-6), 1.78–1.66 (m, 1H), 1.37 and 1.30 [2s, each 3H, C(CH3)2];
13C NMR (100 MHz, CDCl3): δ 144.0 (Ph), 128.7 (Ph), 127.6 (Ph), 126.9
(Ph), 111.1 [C(CH3)2], 86.5 (CPh3), 79.0, 78.6, 77.5, 61.8, 38.8, 38.7,
30.4, 25.6 and 24.3 [C(CH3)2]; IR (ATR) νmax: 2929, 1355, 1175, 965, 869,
698 cm−1; HRMS: m/z calcd for C29H32O6S: 531.1812 [M+Na]+; found:
531.1823.
(3aS,6R,6aS)-2,2-dimethyl-6-(trityloxymethyl)dihydro-3aH-
cyclopenta[d][1,3]dioxol-4(5H)-one (20): DMP (856 mg, 2.01 mmol)
was added to a stirred solution of alcohol 14 (669 mg, 1.55 mmol) in
CH2Cl2 (20 mL) at room temperature, and the mixture was stirred for 1 h.
Next, the reaction mixture was washed (2 ×) with a mixture of saturated
solution of NaHCO3 (10 mL) and Na2S2O3 (25% aq.; 10 mL). The organic
layer was separated, dried with Na2SO4, and filtered, and the solvent was
evaporated under reduced pressure. The crude product was purified by
column chromatography on silica gel using EtOAc/hexanes (1:4, v/v) as
(3aR,4S,6R,6aS)-4-azido-2,2-dimethyl-6-(trityloxymethyl)tetrahydro-
3aH-cyclopenta[d][1,3]dioxole (17): NaN3 (151 mg, 2.32 mmol) was
added to a stirred solution of mesylate 16 (330 mg, 0.65 mmol) in DMF
(6.5 mL), and the mixture was heated at 130 °C overnight. Next, the
solvent was evaporated under reduced pressure, and the residue was
portioned between EtOAc (20 mL) and water (20 mL). The aqueous layer
was extracted with EtOAc (2×20 mL). The combined extracts were dried
with Na2SO4, and filtered, and the solvent was evaporated under reduced
pressure. The crude product was purified by column chromatography on
silica gel using EtOAc/hexanes (1:20, v/v) as the eluent to afford azide 17
the eluent to afford ketone 20 (624 mg, 93%) as a white solid. M.p. 149-
20
151 °C (EtOAc/hexanes, 1:5); Rf = 0.31 (EtOAc/hexanes, 1:4); [α]D
=
+88.5 (c 1.00, CHCl3) (ref.[27] [α]D20 = +54.7 (c 5.5, CH2Cl2). 1H NMR (400
MHz, CDCl3): δ 7.51–7.41 (m, 6H, Ph), 7.34–7.21 (m, 9H, Ph), 4.87 (t, J
= 4.3 Hz, 1H), 4.22 (d, J = 4.8 Hz, 1H), 3.52 (dd, J = 9.0, 7.6 Hz, 1H),
3.24 (dd, J = 9.0, 6.6 Hz, 1H), 2.53–2.39 (m, 1H), 2.30 (ddd, J = 18.5, 7.9,
1.5 Hz, 1H), 2.19 (ddd, J = 18.4, 12.5, 1.2 Hz, 1H), 1.36 and 1.34 [2s,
each 3H, C(CH3)2]; 13C NMR (100 MHz, CDCl3): δ 213.8 (C=O), 143.9
(Ph), 128.7 (Ph), 127.7 (Ph), 127.0 (Ph), 112.3 [C(CH3)2], 86.6 (CPh3),
80.2, 77.6, 62.9, 37.0, 36.0, 26.8 and 25.1 [C(CH3)2]; IR (ATR) νmax: 2935,
1746, 1217, 1061, 746, 694 cm−1; HRMS: m/z calcd for C28H28O4:
467.1619 [M+K]+; found: 467.1616.
(232 mg, 87%) as
a white solid. M.p. 97-99 °C, Rf = 0.31
(EtOAc/hexanes, 1:20); [α]D20 = +9.3 (c 1.00, CHCl3). 1H NMR (400 MHz,
CDCl3): δ 7.50–7.43 (m, 6H, Ph), 7.33–7.19 (m, 9H, Ph), 4.72 (t, J = 5.1
Hz, 1H), 4.41 (dd, J = 5.4, 1.5 Hz, 1H), 3.88 (d, J = 4.7 Hz, 1H), 3.41 (dd,
J = 8.9, 7.4 Hz, 1H), 3.08 (dd, J = 8.9, 6.8 Hz, 1H), 2.36–2.26 (m, 1H),
1.77 (dd, J = 13.2, 5.8 Hz, 1H), 1.64 (td, J = 13.2, 4.9 Hz, 1H), 1.31 and
1.27 [2s, each 3H, C(CH3)2]; 13C NMR (100 MHz, CDCl3): δ 144.2 (Ph),
128.8 (Ph), 127.6 (Ph), 126.8 (Ph), 110.3 [C(CH3)2], 86.5 (CPh3), 84.5,
79.8, 65.7, 62.0, 42.3, 31.1, 25.9 and 24.0 [C(CH3)2]; IR (ATR) νmax: 2083,
1447, 1209, 1066, 767, 696 cm−1; HRMS: m/z calcd for C28H29N3O3:
478.2101 [M+Na]+; found: 478.2111.
(3aR,4R,6R,6aS)-N-(4-methoxyphenyl)-2,2-dimethyl-6-
(trityloxymethyl)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-amine
(21): NaBH(OAc)3 (296 mg, 1.39 mmol) was added to a stirred solution of
ketone 20 (200 mg, 0.46 mmol) and p-anisidine (114 mg, 0.93 mmol) in
1,2-dichloroethane (1.5 mL), followed by AcOH (53 µL, 56 mg, 0.92
mmol), and the mixture was stirred at room temperature overnight. Next,
the reaction mixture was partitioned between ether (15 mL) and 1N
NaOH (15 mL). The aqueous layer was extracted with ether (3×20 mL).
The combined extracts were dried with Na2SO4, and filtered, and the
solvent was evaporated under reduced pressure. The crude product was
purified by column chromatography on silica gel using EtOAc/hexanes
(1:6, v/v) as the eluent to afford amine 21 (218 mg, 87%) as a yellowish
solid. M.p. 146-147 °C, Rf = 0.20 (EtOAc/hexanes, 1:6); [α]D20 = −36.7 (c
1.00, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.53–7.45 (m, 6H, Ph), 7.36–
7.21 (m, 9H, Ph), 6.83–6.76 (m, 2H, NHPMP), 6.68–6.61 (m, 2H,
NHPMP), 4.70 (t, J = 5.1 Hz, 1H, H-6a), 4.62 (t, J = 5.3 Hz, 1H, H-3a),
3.77 (s, 3H, OCH3), 3.53 (dt, J = 11.2, 5.5 Hz, 1H, H-4), 3.42 (dd, J = 8.8,
7.3 Hz, 1H, CH2OTr), 3.12 (dd, J = 8.8, 6.8 Hz, 1H, CH2OTr), 2.11 (dt, J
= 11.3, 5.5 Hz, 1H, H-5‘), 1.99 (tdd, J = 12.5, 7.0, 5.1 Hz, 1H, H-6), 1.40
and 1.33 [C(CH3)2], 1.27–1.15 (m, 1H, H-5); 13C NMR (100 MHz, CDCl3):
δ 152.1 (Ar), 144.2 (Ar), 141.6 (Ar), 128.8 (Ar), 127.6 (Ar), 126.8 (Ar),
115.0 (Ar), 114.8 (Ar), 109.8 [C(CH3)2], 86.4 (CPh3), 79.1 (C-6a), 79.0 (C-
3a), 62.2 (CH2OTr), 56.9 (C-4), 55.8 (OCH3), 41.2 (C-6), 31.3 (C-5), 25.7
and 24.1 [C(CH3)2]; IR (ATR) νmax: 3387, 2916, 1510, 1237, 1074, 1018
(1S,2R,3S,5R)-3-azido-5-(hydroxymethyl)cyclopentane-1,2-diol (18):
A solution of HCl (20% aq.; 2.5 mL) was added to a stirred suspension of
azide 17 (200 mg, 0.48 mmol) in MeOH (5 mL) at 0 °C, and the mixture
was heated at 50 °C for 20 h. Next, the reaction mixture was cooled in an
ice-water bath, and was carefully basified with solid Na2CO3 (1.0 g). The
resulting mixture was filtered, and a filter cake was washed with MeOH (3
mL), and the filtrate was concentrated under reduced pressure. The
crude product was purified by column chromatography on silica gel using
MeOH/CHCl3 (1:10, (v/v), containing 0.5% (v/v) of concd. aqueous NH3
as the eluent to afford triol 18 (61 mg, 73%) as a white solid. M.p. 49-
50 °C Rf = 0.18 (MeOH/CHCl3, 1:10 containing 0.5% (v/v) of concd.
20
aqueous NH3); [α]D = +60.7 (c 1.00, MeOH). 1H NMR (400 MHz,
CD3OD): δ 4.04 (t, J = 4.0 Hz, 1H), 3.91– 3.79 (m, 2H), 3.71 (dd, J = 10.7,
7.3 Hz, 1H), 3.55 (dd, J = 10.7, 6.3 Hz, 1H), 2.27–2.15 (m, 1H), 1.93 (dt,
J = 14.1, 9.0 Hz, 1H), 1.65 (ddd, J = 14.1, 9.8, 5.3 Hz, 1H); 13C NMR
(100 MHz, CD3OD): δ 80.7, 74.1, 66.8, 62.6, 42.4, 30.7; IR (ATR) νmax
3424, 3333, 2111, 1260, 1120, 984 cm−1
HRMS: m/z calcd for
C6H11N3O3: 196.0693 [M+Na]+; found: 196.0691.
:
;
(1S,2R,3S,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diol (19):
A mixture of azide 18 (43 mg, 0.25 mmol) and Pd-C (10%; 4 mg) in
MeOH (6 mL) was stirred under a hydrogen atmosphere (balloon) for 1 h
at room temperature. Next, the catalyst was removed by filtration through
a pad of Celite®, and a filter cake was washed with MeOH (3 mL), and
the filtrate was concentrated under reduced pressure. The crude product
was purified by column chromatography on silica gel using MeOH/ACN
;
cm−1 HRMS: m/z calcd for C35H37NO4: 536.2795 [M+H]+; found:
536.2767.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801586
European Journal of Organic Chemistry
FULL PAPER
(3aR,6R,6aS)-2,2-dimethyl-6-(trityloxymethyl)dihydro-3aH-
CD3OD): δ 7.50–7.42 (m, 6H, Ph), 7.33–7.17 (m, 9H, Ph), 4.66 (t, J = 5.2
Hz, 1H), 4.43 (t, J = 5.4 Hz, 1H), 3.38–3.30 (m, 1H), 3.08 (dd, J = 8.8, 6.9
Hz, 1H), 2.98 (dt, J = 11.3, 5.5 Hz, 1H), 2.05–1.93 (m, 1H), 1.81 (dt, J =
11.4, 5.7 Hz, 1H), 1.34 and 1.31 [2s, each 3H, C(CH3)2], 1.21 (q, J = 12.0
Hz, 1H); 13C NMR (100 MHz, CD3OD): δ 145.7 (Ph), 129.9 (Ph), 128.6
(Ph), 127.9 (Ph), 110.9 [C(CH3)2], 87.7 (CPh3), 81.5, 81.2, 63.6, 55.0,
42.6, 34.9, 25.9 and 24.2 [C(CH3)2]; IR (ATR) νmax: 3376, 2928, 1490,
1448, 1208, 1065 cm−1; HRMS: m/z calcd for C28H31NO3: 430.2377
[M+H]+; found: 430.2394.
cyclopenta[d][1,3]dioxol-4(5H)-one oxime (22): A mixture of ketone 20
(543 mg, 1.27 mmol), HONH2·HCl (420 mg, 6.1 mmol) and NaHCO3 (426
mg, 5.06 mmol) in a mixture of H2O (3 mL) and EtOH (3 mL) was stirred
at room temperature overnight. Next, the ethanol was evaporated under
reduced pressure, and the residue was partitioned between EtOAc (20
mL) and brine (20 mL). The aqueous layer was extracted with EtOAc
(2×20 mL). The combined extracts were dried with Na2SO4, and filtered,
and the solvent was evaporated under reduced pressure. The crude
product was purified by column chromatography on silica gel using
EtOAc/hexanes (1:3, v/v) as the eluent to afford oxime 22 as a mixture of
geometrical isomers in ≈3.5:1 ratio (536 mg, 95%, white foam). Rf = 0.15
(1S,2R,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diol (25):
A solution of HCl (20% aq.; 2.25 mL) was added to a stirred solution of
amine 24 (190 mg, 0.44 mmol) in MeOH (4.5 mL) at 0 °C, and the
mixture was heated at 50 °C overnight. Next, the volatile components
were evaporated under reduced pressure, and the residue was
partitioned between CHCl3 (20 mL) and distilled water (20 mL). The
organic layer was extracted with distilled water (20 mL). The combined
aqueous layers were neutralized with Amberlite IRA-400 (OH−) overnight.
The resin was removed by filtration, and was washed with distilled water
(20 mL), and the filtrate was lyophilized to afford aminotriol 25 (53 mg,
82%) as a colourless oil. Rf = 0.00 (MeOH/MeCN, 4:1 containing 0.5%
1
(EtOAc/hexanes, 1:3). H NMR (400 MHz, CDCl3): δ 7.50–7.42 (m, 29H,
Ph), 7.33–7.20 (m, 44H, Ph), 5.16 (d, J = 5.1 Hz, 1H), 4.85–4.80 (m, 3H),
4.78–4.75 (m, 4H), 3.50–3.46 (m, 4H), 3.22–3.16 (m, 4H), 2.89 (dd, J =
16.4, 6.8 Hz, 3H), 2.45 (dd, J = 15.7, 7.2 Hz, 1H), 2.34 (ddd, J = 15.7,
12.6, 1.4 Hz, 1H), 2.25–2.15 (m, 4H), 2.15–2.04 (m, 4H), 1.38, 1.36, 1.35
and 1.34 (4s, 28H, 2×C(CH3)2); 13C NMR (100 MHz, CDCl3): δ 162.6 and
162.0 (C=NOH), 144.1 (Ph), 144.0 (Ph), 128.7 (Ph), 127.7 (Ph), 126.9
(Ph), 126.9 (Ph), 111.8 and 111.6 [C(CH3)2], 86.5, 79.6, 79.2, 79.0, 74.3,
62.7, 62.6, 39.7, 30.2, 26.88, 26.81, 26.6, 25.1 and 24.9 [C(CH3)2]; IR
(ATR) νmax: 3290, 2928, 1490, 1448, 1211, 1069 cm−1; HRMS: m/z calcd
for C29H28NO4: 444.2169 [M+H]+; found: 444.2176.
20
(v/v) of concd. aqueous NH3); [α]D = −15.0 (c 1.00, MeOH). 1H NMR
(400 MHz, CD3OD): δ 4.11 (t, J = 4.2 Hz, 1H), 3.96 (dd, J = 6.3, 3.6 Hz,
1H), 3.76 (dd, J = 10.7, 7.0 Hz, 1H), 3.63 (dd, J = 10.7, 5.8 Hz, 1H), 3.39
(q, J = 6.6 Hz, 1H), 2.23 (dt, J = 13.6, 8.4 Hz, 1H), 2.16–2.05 (m, 1H),
1.50 (ddd, J = 13.6, 9.6, 5.5 Hz, 1H); 13C NMR (100 MHz, CD3OD): δ
74.6, 74.1, 62.4, 53.1, 42.8, 32.4; IR (ATR) νmax: 3342, 3235, 2928, 1476,
1296, 1116 cm−1; HRMS: m/z calcd for C6H13NO3: 148.0968 [M+H]+;
found: 148.0969.
(3aR,6R,6aS)-2,2-dimethyl-6-(trityloxymethyl)dihydro-3aH-
cyclopenta[d][1,3]dioxol-4(5H)-one O-methyl oxime (23): A mixture of
ketone 20 (350 mg, 0.82 mmol), MeONH2·HCl (325 mg, 3.8 mmol) and
NaHCO3 (273 mg, 3.2 mmol) in a mixture of H2O (2 mL) and EtOH (2
mL) was heated at reflux for 1 h. Next, the ethanol was evaporated under
reduced pressure, and the residue was partitioned between EtOAc (15
mL) and brine (15 mL). The aqueous layer was extracted with EtOAc
(2×15 mL). The combined extracts were dried with Na2SO4, and filtered,
and the solvent was evaporated under reduced pressure. The crude
product was purified by column chromatography on silica gel using
EtOAc/hexanes (1:6, v/v) as the eluent to afford O-methyl oxime 23 as a
mixture of geometrical isomers in 2:1 ratio (338 mg, 90%, white foam). Rf
= 0.22 (EtOAc/hexanes, 1:6). 1H NMR (400 MHz, CDCl3): δ 7.50–7.41 (m,
18H, Ph), 7.34–7.19 (m, 27H, Ph), 5.06 (dd, J = 5.1, 1.4 Hz, 1H), 4.84–
4.79 (m, 2H), 4.76–4.70 (m, 3H), 3.89 and 3.88 (2s, 9H, =NOCH3), 3.49–
3.44 (m Hz, 3H), 3.22–3.14 (m, 3H), 2.82 (dd, J = 16.6, 6.9 Hz, 2H), 2.46
(dd, J = 15.6, 7.1 Hz, 1H), 2.38–2.28 (m, 1H), 2.22–2.13 (m, 3H), 2.10–
2.03 (m, 2H), 1.37, 1.34 and 1.33 (3s, 18H, 2×C(CH3)2); 13C NMR (100
MHz, CDCl3): δ 160.9 and 160.4 (C=NOCH3), 144.1 (Ph), 144.0 (Ph),
128.7 (Ph), 127.71 (Ph), 127.70 (Ph), 126.95 (Ph), 126.92 (Ph), 111.7
and 111.6 [C(CH3)2], 86.5, 79.6, 79.3, 78.9, 74.5, 62.8, 62.7, 62.1, 61.9,
Biochemical assay
The isolation and purification of recombinant Drosophila melanogaster
Golgi (GMIIb) and lysosomal (LManII) α-mannosidases was carried out
as described previously.[43] The α-mannosidase from Canavalia
ensiformis (JBMan) was purchased from Sigma-Aldrich. Mannostatin A
hydrochloride as a standard was purchased from Enzo Life Sciences Inc.
The mannosidase activities of these enzyme preparations were
measured using p-nitrophenyl-α-D-mannopyranoside (pNP-Man; Sigma-
Aldrich; 100 mM stock in DMSO) as a substrate at 2 mM final
concentration in acetate buffer (50 mM) at the optimal pH (GMIIb at pH
6.0, JBMan at pH 5.0, and LManII at pH 5.2) and using 0.5 μL of enzyme
(0.05 µg of protein for JBMan), in a total volume of 50 μL for 1–2 h at
37 °C. GMIIb was assayed in the presence of CoCl2 (0.5 mM). The
inhibitor was pre-incubated with the enzyme in the buffer for 5 min at
room temperature, and the reaction was started by addition of the
substrate. The reactions were terminated with two volumes (0.1 mL) of
sodium carbonate (0.5 M), and the production of p-nitrophenol was
measured at 405 nm with a Mithras LB943 multimode reader (Berthold
Technologies). The averages of representative result of three
independent experiments performed in duplicate are presented. IC50
values were determined with pNP-Man (2 mM).
39.9, 39.8, 30.4, 27.4, 26.8, 26.6, 25.0 and 24.8 [C(CH3)2]; IR (ATR) νmax
:
2932, 1480, 1448, 1211, 1071, 1033 cm−1; HRMS: m/z calcd for
C29H31NO4: 496.1885 [M+K]+; found: 496.1888.
(3aR,4R,6R,6aS)-2,2-dimethyl-6-(trityloxymethyl)tetrahydro-3aH-
cyclopenta[d][1,3]dioxol-4-amine (24): A solution of BH3 (1M in THF,
1.9 mL, 1.9 mmol) was added to a stirred solution of O-methyl oxime 23
(290 mg, 0.63 mmol) in anhydrous THF (1.6 mL) at 0 °C under a nitrogen
atmosphere. Then, the mixture was heated at 55 °C for 4 h. Next, the
volatile components were evaporated under reduced pressure. The
residue was heated in a solution of KOH (10% aq.; 12 mL) at 95 °C
overnight. The mixture was diluted with water (20 mL), and was extracted
with CH2Cl2 (2×20 mL). The combined extracts were dried with Na2SO4,
and filtered, and the solvent was evaporated under reduced pressure.
The crude product was purified by column chromatography on silica gel
using EtOAc/MeOH (6:1, (v/v), containing 0.5% (v/v) of concd. aqueous
NH3) as the eluent to afford amine 24 (197 mg, 72%) as a thick
colourless oil. Rf = 0.31 (EtOAc/MeOH, 6:1 containing 0.5% (v/v) of
concd. aqueous NH3); [α]D20 = −14.0 (c 1.00, MeOH). 1H NMR (400 MHz,
Methods of molecular modelling
The crystal structures of a mannostatin A complex with dGMII (PDB ID:
2F7O)[8] was used as a 3D enzyme model of human GMII for docking of
synthesized compounds 15, 18, 19 and 25 with the GLIDE program[50,51]
of the Schrödinger package. In all docking calculations the catalytic acid
(Asp341 was modelled in the ionised form (COO−). The receptor box for
the docking conformational search was centred at the Zn2+ ion co-factor
at the bottom of the active site with a size of 25×25×25 Å using partial
atomic charges for the receptor from the OPLS2005 force field.[52] The
grid maps were created with no van der Waals radius and charge scaling
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801586
European Journal of Organic Chemistry
FULL PAPER
for the atoms of the receptor. Flexible docking in standard precision (SP)
was used. The partial charges of the ligands were calculated at the DFT
level (M06-2X/LACVP**)[53] using the Jaguar program[54] of the
Schrödinger package. The potential for non-polar parts of the ligands
was softened by scaling the van der Waals radii by a factor of 0.8 for
atoms of the ligands with partial atomic charges less than specified cut-
off of 0.15. The 5000 poses were kept per ligand for the initial docking
stage with scoring window of 100 kcal.mol−1 for keeping initial poses; the
best 400 poses were kept per ligand for energy minimization. The ligand
poses with RMS deviations less than 0.5 Å and maximum atomic
displacement less than 1.3 Å were discarded as duplicates. The post-
docking minimization for 10 ligand poses with the best docking score was
performed and optimized structures were saved for subsequent analyses.
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Acknowledgments
The financial support received from the Slovak Research and
Development Agency (Grant no. APVV-0484-12) and Scientific
Grant Agency (Grant no. VEGA 2/0064/15) is gratefully
acknowledged. This contribution is the result of the project
implementation: Centre of Excellence for Glycomics,
ITMS26240120031, supported by the Research & Development
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Carbasugars*
Mária Zajičková, Ján Moncoľ, Sergej
Šesták, Juraj Kóňa, Miroslav Koóš,
Maroš Bella *
Page No. – Page No.
4a-Carba-β-D-lyxofuranose and its three derivatives were synthesised and
evaluated as inhibitors of GH38 α-mannosidases. Only 1-amino-4a-carba-β-D-
lyxofuranose exhibited reasonable inhibitory activity (IC50 = 200 µM) against Golgi
α-mannosidase from Drosophila melanogaster (GMIIb). The inhibitory activity of 1-
amino-4a-carba-β-D-lyxofuranose against GMIIb was discussed by means of
molecular modelling.
Synthesis of 4a-carba-D-lyxofuranose
derivatives and their evaluation as
inhibitors of GH38 α-mannosidases
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