Design, synthesis and biological evaluation of bicyclic iminosugar hybrids: Conformational constraint as an effective tool for tailoring the selectivity of α-glucosidase inhibitors

Article abstract of DOI:10.1039/c4ob00486h

Principle guided design of glycan processing enzyme inhibitors involves embedding aromatic groups onto charge and shape mimics. Intramolecular azide-alkyne cycloaddition was used as a simple and versatile strategy for the synthesis of novel condensed bicyclic triazoles from carbohydrate derived Perlin aldehydes. These newly synthesised molecules were evaluated for glycosidase inhibition against 11 commercially available enzymes and were found to possess significant affinity (micromolar range) as well as high degree of selectivity for α-glucosidases. Conformational restriction was identified as an important tool to customize the selectivity of enzyme inhibition by five-membered iminosugars. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00486h

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
Design, synthesis and biological evaluation of
bicyclic iminosugar hybrids: conformational
constraint as an effective tool for tailoring the
selectivity of α-glucosidase inhibitors†
Cite this: Org. Biomol. Chem., 2014,
12, 6855
Inderpreet Arora,a Vivek Kr. Kashyap,b Alok Kumar Singh,b Arunava Dasgupta,b,c
Brijesh Kumard and Arun K. Shaw*a
Principle guided design of glycan processing enzyme inhibitors involves embedding aromatic groups
onto charge and shape mimics. Intramolecular azide–alkyne cycloaddition was used as a simple and ver-
satile strategy for the synthesis of novel condensed bicyclic triazoles from carbohydrate derived Perlin
aldehydes. These newly synthesised molecules were evaluated for glycosidase inhibition against 11 com-
mercially available enzymes and were found to possess significant affinity (micromolar range) as well as
high degree of selectivity for α-glucosidases. Conformational restriction was identified as an important
tool to customize the selectivity of enzyme inhibition by five-membered iminosugars.
Received 4th March 2014,
Accepted 8th July 2014
DOI: 10.1039/c4ob00486h
www.rsc.org/obc
Iminosugars, among the most important classes of glyco-
sidase inhibitors,2 are therapeutically relevant because of their
Introduction
Glycan processing enzymes are important targets for drug dis- ability to act as transition state analogs of carbohydrate proces-
covery amongst which glycosidases and glycosyltransferases sing enzymes.3 The first generation iminosugar therapeutics
hold prime importance. With the increasing knowledge of glyco- have attracted interest as anti-cancer, anti-diabetic and anti-
biology, it is now well established that the small molecule viral agents. Additionally, they are active against tuberculosis,
inhibitors possess the potential to modulate the activities of lysosomal storage disorder and cystic fibrosis.3,4 Apart from
glycan processing enzymes.1 The mode of action of most small Glyset and Zavesca (Fig. 1) being marketed for Type II diabetes
molecule inhibitors mainly involves the mimicry of the tran- and Gaucher’s disease, respectively, many other iminosugar
sition state of the enzyme catalysed reaction.1b Carbohydrate based drugs are currently under clinical trials.5
based inhibitors, built upon the knowledge of transition state
Recently, pyrrolidine iminosugars have attracted consider-
structures in enzyme inhibition, have proven not only to be able interest as inhibitors of glycoside hydrolases. The syn-
useful therapeutics but also as powerful tools to provide a thesis of five-membered iminosugars6 has attracted
deeper understanding of the mechanism of enzyme inhibition. heightened interest after the disclosure of the first X-ray crystal
The accumulating evidence suggests that a serious limitation structure of the pyrrolidine iminosugar, 2,5-imino-D-mannitol
associated with such carbohydrate based small molecule (DMDP) derivative, in complex with a retaining β-glucosidase.7
inhibitors is their ‘class promiscuity’ which is of major Despite an attractive biological profile,8 the full clinical poten-
concern in glycobiology because enzymes of the same class tial of pyrrolidine iminosugars has not yet been realised due to
harbour similar binding pockets.
the lack of specificity for a particular enzyme. For instance, the
natural product DGDP inhibits α-glucosidase, β-glucosidase,
β-galactosidase and trehalase. DMDP strongly inhibits β-gluco-
aDivision of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute,
BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
E-mail: akshaw55@yahoo.com
bMicrobiology Division, CSIR-Central Drug Research Institute, BS-10/1, Sector 10,
Jankipuram Extension, Sitapur Road, Lucknow 226031, India
cAcademy of Scientific and Innovative Research, New Delhi 110001, India
dSophisticated Analytical Instrumentation Facility, CSIR-Central Drug Research
Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031,
India
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4ob00486h
Fig. 1 Examples of some biologically active iminosugars.
Org. Biomol. Chem., 2014, 12, 6855–6868 | 6855
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
Organic & Biomolecular Chemistry
medicinal chemistry and an urge for the discovery of imino-
sugar based selective small molecule inhibitors motivated us
to synthesise the iminosugar triazole hybrids III.
Results and discussion
To synthesize these hydrophobically modified, conformation-
ally locked iminosugars, the triazole moiety turned out to be
of prime interest owing to the widespread applications of tri-
azoles as the privileged class of molecules in medicinal chem-
Fig. 2 Structural relationship between polyhydroxylated pyrrolidines I,
polyhydroxylated pyrrolizidines II and proposed triazole surrogates of
polyhydroxylated pyrrolizidines III. Fusing triazole to I results in hydro- istry,11 and their ease of installation via ‘click’ chemistry.12
phobically modified iminosugar III showing better activity and selectivity
towards α-glucosidases Ring A; and = Ring B.
A careful literature survey revealed that when triazoles were
annulated to piperidinoses,1b,13 they resulted in complete loss
of activity against β-glucosidases as compared to the parent
molecule. So, it seemed interesting to synthesise triazoles
annulated to pyrrolidinoses to know whether the activity
results could contribute to the distinction between confor-
sidases and α-galactosidases but shows weak inhibition of
α-glucosidases. DAB is a good inhibitor of many α-glucosidases
but also showed weak inhibition of β-glucosidases. Many struc-
mational behaviour of the piperidine and pyrrolidine rings in
the catalytic site of glucosidases and to predict the differences
in conformational changes of enzymes upon binding to the
inhibitor. On the basis of above discussions, herein we wish to
report bicyclic iminosugar hybrids (III) as α-glucosidase inhibi-
tors.14 For the synthesis of pyrrolidotriazoles, only three
reports from synthetic and structure elucidation point of view
have been published.15 The pyranoid glycal derived Perlin
aldehydes (VI) are versatile building blocks and have recently
been reviewed.16 In continuation of our interest to utilize
Perlin aldehydes to design the syntheses of small organic
molecules and natural products,16 we have now embarked
upon exploiting these chiral building blocks to synthesize
novel iminosugar constructs (III). Its retrosynthetic pathway
using intramolecular ‘click’ chemistry17 is depicted in
Scheme 1. The key intermediate (V) could be synthesised from
Perlin aldehyde (VI). The acetylene (V) could be converted to
azido-alkyne (IV) after silyl ether deprotection and could thus
serve as a template for intramolecular azide–alkyne cyclo-
addition to form III.
tural variants of these natural products have been synthesised
and a few inhibitors were realised which were both potent and
selective. However, these synthetic modifications were primar-
ily centred around either stereochemical variation or change in
the substitution pattern but rare efforts were made for tem-
plate modification of pyrrolidine iminosugars. Their lack of
specificity can be attributed to their existence as rapidly inter-
converting flexible envelope conformations.9 Hence, it is
highly desirable to synthesise flattened pyrrolidine sugars.
Pyrrolizidine alkaloids (II, Fig. 2) are generally good to
potent micromolar inhibitors of a range of glucosidases8,10 but
they are also less specific in their action probably because each
of their rings has its own conformational preferences and it is
difficult to predict the exact conformational outcome. With
these considerations we envisaged the synthesis of condensed
triazoles of general structure III where the replacement of ring
B of pyrrolizidine alkaloids by an aromatic triazole ring (Fig. 2)
would enforce planarity onto the polyhydroxylated pyrrolidine
core (ring A) so that it could adapt a conformation to mimic
the oxacarbenium ion like the transition state which is one of
the important pre-requisites for glycosidase inhibition. The
growing impact of hybrid molecules (Fig. 3) in the field of
Synthesis of C-3(R) configured precursors 9a, 9b and 9c for
the azide–alkyne cycloaddition is represented in Scheme 2.
The synthesis of acetylene precursors was achieved starting
from the Perlin aldehyde derived allylic alcohols 2a and 2b
which were readily prepared from pyranoid glycals in two steps
on a multi-gram scale.18 Protecting group manipulations
involved di-O-protection of hydroxyl functionalities at C1 and
C5 using TBDMSOTf followed by selective deprotection of
Fig. 3 Examples of some natural (above) and synthetic (below) hybrid
iminosugars.
Scheme 1 Retrosynthetic analysis.
6856 | Org. Biomol. Chem., 2014, 12, 6855–6868
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
Scheme 2 Synthesis of precursors 9a, 9b and 9c.
Scheme 3 Synthesis of precursors 14a and 14b.
primary TBS ether using SnCl2·2H2O19 affording compound 4
To overcome the drawbacks experienced during Mitsunobu
in good yield. The protected allylic alcohol 4 was subjected to azidation that could be due to the use of excess reagents, long
Sharpless asymmetric epoxidation20 with L-(+)-DET to provide reaction times, low yields and more importantly the risk of
(2S,3R) epoxide 5 which on chlorination with CCl4 in the pres- handling organic azides, the desired bicyclic triazoles were
ence of PPh3 and a catalytic amount of NaHCO3 under reflux obtained directly from their respective in situ generated azides.
yielded epoxy chloride 6. It was then fragmented by base Thus, a one-pot protocol for thermal tandem azidation/intra-
induced double elimination using 3 equiv. of n-BuLi at −60 °C molecular ‘click’ was tried. The acetylene 8a was subjected to
in dry THF under an argon atmosphere to furnish the desired chloromesylation to yield 9c in 84% yield which could serve as
chiral alkynol 7.21
an appropriate substrate for the tandem process to obtain the
In the subsequent step, the propargylic hydroxyl group of 7 title molecule. We were also interested to extend our study
(Scheme 2) was protected as benzyl ether which on desilylation with C-3(S) configured precursors 14a and 14b whose azide–
afforded the desired acetylene 8 which could now serve as an alkyne cycloaddition was completed in the same manner as
appropriate substrate for Mitsunobu azidation. Our initial described for 9b and 9c (Scheme 3). Having the alkynes 9 and
attempts for azidation under Mitsunobu conditions with 14 in our hand, we moved towards the synthesis of condensed
4 equiv. each of PPh3, DPPA (diphenylphosphoryl azide) and bicyclic triazoles 15 and 16. Thus, the azido acetylene 9a on
DIAD (diisopropyl azodicarboxylate) in dry THF under inert intramolecular 1,3 dipolar cycloaddition in dry degassed
conditions were futile.22 However, in the case of the D-galactal toluene under uncatalysed thermal conditions for 4.5 h
derived substrate 8a, it was observed that on increasing the afforded the condensed bicyclic triazole 15a as a single regio-
stoichiometry of the reagents to 8 equiv., the azido acetylene isomer in 78% yield (Scheme 4). Its detailed 1H, 13C, and
9a was obtained in 54% yield. Moreover, the reaction did not HSQC data analyses confirmed it to be a 1,5 regioisomer. The
take place with the alkyne 8b synthesized from D-glucal recently described one dimensional proton gated decoupled
derived epoxy chloride 6b.
13C NMR spectroscopy technique serves as a useful method for
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 6855–6868 | 6857

View Article Online
Paper
Organic & Biomolecular Chemistry
Scheme 4 Synthesis of fused bicyclic triazoles 17a, 17b, 18a and 18b. Reagents and conditions: (p) toluene, 100 °C, 4.5 h; (q) Cp*RuCl(PPh3)2,
toluene, 100 °C, 2 h; (r) NaN3, DMF, 120 °C, 4 to 6 h; (s) (1) NaN3, DMF, microwave heating, 80 °C, 2 h, (2) Cp*RuCl(PPh3)2, microwave heating,
120 °C, 20 min; (t) Pd(OH)2, MeOH, rt, 10 h. aTime taken and % yields vary for different isomers (Table 1).
structure assignment to 1,2,3 triazoles.23 On applying this secondary alkyl halides even at higher temperature despite the
method to our bicyclic system, the observed value of the coup- fact that secondary azides do participate in RuAAC reactions
ling constant was in fair agreement with those reported for albeit with slow reactivity compared to primary azides.26 Grati-
simple monocyclic 1,5 disubstituted triazoles (ESI†).
fyingly, in our case even the secondary chloromesylates reacted
This reaction was also carried out under ruthenium cata- readily to deliver the desired triazoles 15a, 15b, and 16a in
lyzed azide–alkyne cycloaddition (RuAAC) conditions develo- commendable yields. These results are indicative of the scope
ped by Fokin and Jia24 in the presence of 5 mol% Cp*RuCl- of using sterically hindered activated secondary alcohols as
(PPh3)2. The reaction was completed in lesser time (2 h) with substrates for RuAAC reaction. Debenzylation of 15a, 15b, 16a
better yield (88%) as compared to the uncatalysed reaction and 16b by hydrogenolysis using Pd(OH)2/C in MeOH furnished
described above. Here, it is worth mentioning that the Ru cata- triols 17a, 17b, 18a and 18b respectively in excellent yields.
lyst has been used for regioselective intermolecular AAC to
form 1,5-triazoles; our finding thus indicates that the RuAAC
can also be effectively applied to intramolecular ‘click’ reaction
to obtain condensed 1,5-triazoles with improved yield. When
Glycosidase inhibition
9c was refluxed with NaN3 in dry DMF at 120 °C under inert
conditions for the tandem one-pot azidation/1,3-dipolar cyclo-
addition, complete disappearance of the starting material was
observed on TLC in 4 h. The product was obtained in quanti-
tative yield and identified to be 15a whose synthesis has
already been discussed above. With these results in hand,
microwave (µw) assisted one-pot ruthenium catalysed ‘click’
reaction was also tried but it did not lead to the formation of
the desired triazole owing to deactivation of the catalyst by
sodium azide.25 In order to overcome this problem, the µw
assisted one-pot sequential ruthenium catalysed reaction as
developed by Johansson’s group26 was carried out whereby the
chloromesyl (instead of halide) was first allowed to convert
completely into the azido alkyne under µw conditions at 80 °C
for 2 h. This was then followed by the addition of the ruthe-
nium catalyst (5 mol%) and µw heating was further continued
at 120 °C for 30 min to obtain the triazole 15a in 90% yield. To
the best of our knowledge, this is the first example of µw
assisted intramolecular one-pot sequential RuAAC. Here, it is
worth mentioning that this reaction was not successful with
All the compounds were assayed against a panel of 11 carbo-
hydrate processing enzymes. The results are summarised in
Table 2. Three out of four compounds (17a, 17b and 18a) were
found to be potent and completely specific inhibitors of
α-glucosidase from rice and A. niger. However, in addition to
α-glucosidase inhibition, triazole 18b also displayed potent
inhibition (92% inhibition at 1000 µM) of α-L-fucosidase from
bovine kidney. These compounds were consistently active even
at concentrations as low as 400 µM (ESI†).
Compound 17b showed improved activity and selectivity
over known α-glucosidase inhibitors like monocyclic parent
compounds (natural product DGDP A and its L-ido configured
isomer B), pyrrolizidine alkaloids (3-epi-australine, D, and
3-epi-casuarine, E) and quaternary centered monocyclic ana-
logues (isoDGDP, C) (see Table 3). The natural product DGDP,
A, is a modest α-glucosidase inhibitor but is non-specific as it
also inhibits β-glucosidase, β-galactosidase and trehalase. This
study revealed that compound 17b is 6 times more potent than
DGDP and is highly selective for α-glucosidase (Table 3). The
enforced planarity imparted by the triazole ring to the pyrro-
6858 | Org. Biomol. Chem., 2014, 12, 6855–6868
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
Compound 18b also displayed potent inhibition although
the parent monocyclic pyrrolidines I and the N-alkylated ana-
logue, K, are completely inactive against rice α-glucosidase. K
is a selective rhamnosidase inhibitor with Ki of 13 µM. The
alteration in conformational flexibility could provide an oppor-
tunity for switching over the glucosidase inhibitory activity.
The triazole analogue (18b) of the monocyclic inhibitor LIL, J,
shows considerably improved selectivity profile.
As per literature precedence, grafting triazoles onto piperi-
dine iminosugars caused a complete loss of activity against
β-glucosidase,1b,13 leading to the conclusion that the hetero
atom attached to the anomeric carbon makes an important
interaction with the acid/base residue of the enzyme. However,
the increase in potency and specificity of pyrrolidotriazoles for
α-glucosidase indicates that an sp2 hybridised carbon attached
to the anomeric centre might be a feature specific to the cata-
lytic site of α-glucosidase (thus distinguishing it from other
enzymes) as also exemplified by natural products radicamines
and codonopsines (Table 3) which are potent α-glucosidase
inhibitors. Also, the triazole ring might promote an enzyme
dependent induced fit resulting in high favourable entropy for
binding. Further studies are required for such structural
insights to understand the mode of action of α-glucosidases
and to decipher the features responsible for the observed
results.
Table 1 Results for intramolecular ‘click’ reaction on different isomeric
alkynes under various conditions (Scheme 4)
Substrate
Product
Methoda
Yieldb (%)
t (h)
9a
9a
9c
9c
9b
9b
14a
14a
14b
15a
15a
15a
15a
15b
15b
16a
16a
16b
p
q
r
s
r
s
r
s
r
78%
88%
Quantitative
90%
81%
Quantitative
83%
82%
4.5
2
4–6
2.5
8
2.5
6
2.5
8–10
85%
a Methods p, q, r and s are as follows: p = uncatalysed from the azido-
alkyne substrate; q = Ru catalysed from the azido-alkyne substrate; r =
one pot uncatalysed from chloromesyl substrate; s = µw assisted one
pot sequential ruthenium catalysed from the chloromesyl substrate.
b The yield of the product isolated after column purification.
lidine core of DGDP seems to help in achieving selectivity with
enhanced potency.
The natural product DMDP (Fig. 1) is a strong inhibitor of
β-glucosidases and α-galactosidases but exhibits weak inhi-
bition of α-glucosidases. Its unnatural enantiomer L-DMDP, F,
was found to be highly specific and a potent inhibitor of α-gluco-
sidases (also inhibits α-trehalase with a IC50 value of 48 µM)
and LAB, G, is also a potent and specific inhibitor of α-glucosi-
dases with moderate inhibition of α-trehalase and β-galactosi-
dase. The activity profile of the triazole analogue 18a is
comparable to parent compounds L-DMDP, F, and LAB, G, yet
18a is more selective molecule with enhanced lipophilicity.
However Fleet’s C-branched analogue L-isoDMDP, H, has been
so far the most potent and the most specific for α-glucosidase
scaffolds with similar stereochemistry.
Conclusion
In summary, stereochemically pure polyhydroxylated bicyclic
triazoles 17a, 17b, 18a and 18b have been synthesised via
intramolecular ‘click’ reaction and proved to be a new class of
Table 2 Concentration of pyrrolidotriazoles giving 50% inhibitiona (IC50) of various glycosidases
IC50 in µM
Enzyme
17a
17b
18a
18b
α-glucosidase
Yeast
Rice
Aspergillus niger
β-Glucosidase
Almond
α-Galactosidase
Green coffee beans
β-Galactosidase
Bovine liver
α-Mannosidase
Jack bean
β-N-Acetyl glucosaminidase
Jack bean
Trehalase
NIb (3)c
NI (2)
20 [Ki = 24.87]
22 [Ki = 38.40]
NI (1)
8 [Ki = 11.48]
9 [Ki = 15.32]
NI (1)
13.75 [Ki = 15.75]
8 [Ki = 22.63]
40 [Ki = 38.37]d
47.5 [Ki = 49.00]
NI (1)
NI (7)
NI (7)
NI (1)
NI (2)
NI (5)
NI (3)
NI (1)
NI (13)
NI (7)
NI (8)
NI (6)
NI (7)
NI (4)
NI (3)
NI (0)
NI (3)
NI (5)
NI (6)
NI (4)
NI (2)
NI (1)
NI (4)
NI (1)
NI (2)
NI (6)
NI (3)
NI (1)
NI (1)
Porcine kidney
Amyloglycosidase
Aspergillus niger
α-L-Fucosidase
Bovine kidney
NI (2)
NI (4)
96.8 [Ki = 138]
a Inhibition was competitive in all cases. b NI: no inhibition (less than 50% inhibition) at 1000 µM. c ( ): inhibition% at 1000 µM. d Ki values are
given in square brackets.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 6855–6868 | 6859

View Article Online
Paper
Organic & Biomolecular Chemistry
Table 3 Comparative study of rice α-glucosidases inhibition by fused bicyclic triazoles 17b, 18a and 18b with known inhibitors of similar
stereochemistry
a NI = no inhibition at 1000 μm. b All % inhibition at 1000 μm.
potent and specific α-glucosidase inhibitors. Grafting of an synthesized compounds were recorded in CDCl3 at 25° at
aromatic residue led to attain selectivity without the loss of 300 MHz (1H) and 50, 75 MHz (13C) respectively. Chemical
potency and these results were consistent in all cases. These shifts are given on the δ scale and are referenced to the TMS at
molecules possibly act both as shape and charge mimics of 0.00 ppm for proton and 0.00 ppm for carbon. Reference
the transition state of the enzyme catalysed reaction as they CDCl3 for 13C NMR appeared at 77.20 ppm. Optical rotations
incorporate all three features1 that are supposed to be essential were determined using a 1 dm cell at 28 °C in chloroform as
for inhibition of a targeted enzyme. Additionally, in order to the solvent; concentrations mentioned are in g per 100 mL.
capture the aglycone binding energy, these molecules feature a Analytical TLC was performed on 2.5 × 5 cm plates coated with
site for appending a lipophilic group that is assumed to inter- a 0.25 mm thickness of silica gel (60F-254), and the spots were
act with the apparent aromatic residues that are close to the visualized with CeSO4 (1% in 2 N H2SO4) followed by charring
aglycone binding site of the enzyme. For pyrrolidine based over the hot plate. Silica gel (100–200 and 230–400 mesh) was
inhibitors, other structural modifications which aim at used for column chromatography. Low-temperature reactions
improving selectivity have led to either a decrease or complete were performed using an immersion cooler with ethanol as
loss of potency in some cases. Our findings thus indicate that the cooling agent.
embedding aromatic groups onto existing inhibitors or modifi-
General procedure for the enzyme inhibition assay
cation of the template so as to mimic the transition state
appears to be a more consistent approach to finely tune the
potency and selectivity of inhibition.
Our future efforts involve validation of this concept by
synthesising and analysing other conformationally restricted
hybrid iminosugars. Fine tuning of 18b for selective fucosidase
inhibition by constructing aglycone mimics is currently
underway.
All the enzymes and their corresponding substrates used in
this study were purchased from Sigma-Aldrich Chemical Co.
Inhibition studies of compounds (17a, 17b, 18a and 18b) were
determined by measuring residual hydrolytic activities of the
glycosidase. The substrate and enzymes were prepared as
50 mM solutions in the respective pH buffer solution of the
corresponding enzyme. In all cases, the substrates used were
the corresponding p-nitrophenyl glycopyranosides. The incu-
bation mixture consisted of 100 μL of enzyme solution, and
100 μL of (12.5 µM to 1000 µM) test compound in an appropri-
ate buffer solution of the optimum pH for the enzyme. After
incubation at the optimal temperature for 1 h, 100 μL of the
Experimental section
General methods
Organic solvents used in the present study were dried by stan- substrate solution was added and allowed to react for 1.5 h.
1
dard methods. All the products were characterized by H, 13C, The optimum temperature and respective buffer used for the
two-dimensional heteronuclear single quantum coherence enzyme are given in Table 1. The reaction was terminated by
(HSQC) and IR spectroscopy, and ESI-MS. NMR spectra of the addition of 1 M Na2CO3. In all cases, control experiments were
6860 | Org. Biomol. Chem., 2014, 12, 6855–6868
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
carried out simultaneously in the absence of the test com- 767; ESI-HRMS m/z [M + H]+: calcd for C32H52O4Si2 557.3477,
pound. A series of blank experiments for the substrate were measured 557.3038.
also carried out in the respective buffer solutions without the
(4R,5R,E)-4,6-Bis(benzyloxy)-5-(tert-butyldimethylsilyloxy)-
enzyme or test compounds. The absorbance of the liberated hex-2-en-1-ol (4a). To a stirred solution of compound 3a
p-nitrophenol in each reaction (both test and control reactions) (1.089 g, 1.96 mmol) in EtOH–H2O (10 mL + 1 mL) at room
was recorded using a spectrophotometer at 405 nm. Percen- temperature was added SnCl2·2H2O in small portions (200 mg,
tage inhibition was calculated as the ratio of the observed 0.88 mmol). The reaction mixture was allowed to stir at room
absorbances of the test and control reactions to the temperature for 45–50 minutes. On completion, the reaction
observed absorbance of the control reaction. Results have was quenched with aqueous NaHCO3 solution. The reaction
thus been reported as IC50 values, which is the concentration mixture was dissolved in ethyl acetate, and filtered through a
of the test compound that causes 50% inhibition of the Celite pad. The organic layer was then extracted with water.
enzyme.30,31
(8R,9R,E)-8-(Benzyloxy)-9-(benzyloxymethyl)-2,2,3,3,11,11,12,- reduced pressure to obtain clear oil which on column purifi-
12-octamethyl-4,10-dioxa-3,11-disilatridec-6-ene (3a). To cation yielded 4a (870 mg, 80% from 3a). Analytical data of 4a:
The organic layer was dried over Na2SO4 and evaporated under
a
stirred solution of compound 2a (540 mg, 1.646 mmol) in dry colorless oil, the eluent for column chromatography: EtOAc–
DCM at −78 °C were added 2,6-lutidine (1.6 mL, 13.7 mmol) hexane (9/91, v/v); [α]2D8 = +1.94 (c 0.89 CHCl3); Rf 0.50 (1/4,
and TBSOTf (1.2 mL, 5.23 mmol) under a N2 atmosphere. The EtOAc–hexane); 1H NMR (300 MHz, CDCl3): δ 0.03 (s, 3H,
mixture was allowed to stir for 2 h at −78 °C to room tempera- CH3), 0.05 (s, 3H, CH3), 0.88 (s, 9H, 3 × CH3), 3.40–3.45 (m,
ture. On completion, the reaction was quenched with aqueous 1H, 6-H), 3.62–3.66 (m, 1H, 6-H), 3.91–3.92 (m, 2H, 4-H + 5-H),
NaHCO3 solution. The reaction mixture was extracted with 4.14 (d, J = 4.9 Hz, 2H, 1-H), 4.41–4.63 (m, 4H, 2 × CH2Ph),
DCM. The extracted organic layer was dried over Na2SO4 and 5.65–5.73 (m, 1H, 3-H), 5.83–5.91 (m, 1H, 2-H), 7.26–7.33 (m,
evaporated under reduced pressure to obtain clear oil which 10H, ArH); 13C NMR (75 MHz, CDCl3): δ −4.53 (CH3, OTBS),
on column purification yielded 3a (865 mg, 94% from 2a). −4.40 (CH3, OTBS), 18.41 (Cq, OTBS), 26.07 (3 × CH3, OTBS),
Analytical data of 3a: colorless oil, the eluent for column 63.24 (CH2, 1-C), 71.00 (CH2, CH2Ph), 72.22 (CH2, 6-C), 73.51
chromatography: EtOAc–hexane (1/49, v/v); [α]2D8 = +0.41 (c 0.60 (CH2, CH2Ph), 74.26 (CH, 4-C), 80.75 (CH, 5-C), 127.59 (ArC),
CHCl3); Rf 0.50 (1/19, EtOAc–hexane); 1H NMR (300 MHz, 127.62–128.43 (ArC), 128.78 (CH, 3-C), 132.82 (CH, 2-C), 138.62
CDCl3): δ 0.01 (s, 3H, CH3), 0.03 (s, 3H, CH3), 0.06 (s, 6H, 2 × (ArCq), 138.82 (ArCq); IR (neat, cm−1) 3446, 2929, 2366, 1655,
CH3), 0.87 (s, 9H, 3 × CH3), 0.91 (s, 9H, 3 × CH3), 3.37–3.42 (m, 1219, 1100, 771; ESI-HRMS m/z [M + H]+: calcd for C26H38O4Si
1H, 6-H), 3.61–3.65 (m, 1H, 6-H), 3.89–3.90 (m, 2H, 4-H + 5-H), 443.2612, measured 443.2612.
4.19 (d, J = 4.0 Hz, 2H, 1-H), 4.37–4.64 (m, 4H, 2 × CH2Ph),
(4S,5R,E)-4,6-Bis(benzyloxy)-5-(tert-butyldimethylsilyloxy)-
5.64–5.71 (m, 1H, 3-H), 5.75–5.83 (m, 1H, 2-H), 7.25–7.32 (m, hex-2-en-1-ol (4b). The experimental procedure for synthesis
10H, ArH); 13C NMR (50 MHz, CDCl3): δ −5.01 (2 × CH3, of 4b is the same as that of compound 4a. Analytical data of
OTBS), −4.52 (CH3, OTBS), −4.40 (CH3, OTBS), 18.41 (Cq, 4b: colorless oil, the eluent for column chromatography:
OTBS), 18.58 (Cq, OTBS), 26.12 (6 × CH3, OTBS), 63.38 (CH2, EtOAc–hexane (9/91, v/v); [α]2D8 = +1.03 (c 0.10 CH3OH); Rf 0.50
1
1-C), 70.78 (CH2, CH2Ph), 72.39 (CH2, 6-C), 73.50 (CH2, (1/4, EtOAc–hexane); H NMR (300 MHz, CDCl3): δ 0.04 (s, 6H,
CH2Ph), 74.33 (CH, 4-C), 80.68 (CH, 5-C), 126.88 (CH, 3-C), 2 × CH3), 0.87 (s, 9H, 3 × CH3), 3.47–3.50 (m, 2H, 6-H),
127.55–128.40 (ArC), 133.25 (CH, 2-C), 138.72 (ArCq), 138.89 3.89–3.96 (m, 2H, 4-H + 5-H), 4.16 (bs, 2H, 1-H), 4.38–4.59 (m,
(ArCq); IR (neat, cm−1) 2932, 2858, 2366, 1676, 1217, 1108, 772; 4H, 2 × CH2Ph), 5.65–5.73 (m, 1H, 3-H), 5.78–5.86 (m, 1H,
ESI-HRMS m/z [M + H]+: calcd for C32H52O4Si2 557.3477, 2-H), 7.26–7.31 (m, 10H, ArH); 13C NMR (75 MHz, CDCl3):
measured 557.3480.
(8S,9R,E)-8-(Benzyloxy)-9-(benzyloxymethyl)-2,2,3,3,11,11,12,- 26.04 (3 × CH3, OTBS), 63.23 (CH2, 1-C), 70.83 (CH2, CH2Ph),
12-octamethyl-4,10-dioxa-3,11-disilatridec-6-ene (3b). The 72.08 (CH2, 6-C), 73.48 (CH2, CH2Ph), 74.24 (CH, 4-C), 80.87
δ −4.44 (CH3, OTBS), −4.35 (CH3, OTBS), 18.37 (Cq, OTBS),
experimental procedure for synthesis of 3b is the same as that (CH, 5-C), 127.50–129.02 (10 ArC + CH, 3-C), 133.89 (CH, 2-C),
of compound 3a. Analytical data of 3b: colorless oil, the eluent 138.54 (ArCq), 138.87 (ArCq); IR (neat, cm−1) 3399, 2932, 2365,
for column chromatography: EtOAc–hexane (1/49, v/v); [α]D28
=
1589, 771; ESI-HRMS m/z [M + H]+: calcd for C26H38O4Si
+ 17.28 (c 0.30 CH3OH); Rf 0.50 (1/19, EtOAc–hexane); 1H NMR 443.2612, measured 443.2612.
(300 MHz, CDCl3): δ 0.04 (s, 6H, 2 × CH3), 0.07 (s, 6H, 2 ×
(2S,3R)-3-((1R,2R)-1,3-Bis(benzyloxy)-2-(tert-butyldimethyl-
CH3), 0.86 (s, 9H, 3 × CH3), 0.91 (s, 9H, 3 × CH3), 3.47–3.49 (m, silyloxy)propyl oxiran-2-yl)methanol (5a). A solution of Ti(O-i-Pr)4
2H, 6-H), 3.87–3.96 (m, 2H, 4-H + 5-H), 4.14–4.24 (m, 2H, 1-H) (0.02 mL, 0.07 mmol) and L-(+)-diethyltartarate (0.01 mL,
4.34–4.60 (m, 4H, 2 × CH2Ph), 5.64–5.79 (m, 2H, 2-H + 3-H), 0.06 mmol) in dry DCM (5 mL) was stirred at −25 °C for 0.5 h
7.25–7.30 (m, 10H, ArH); 13C NMR (50 MHz, CDCl3): δ −5.02 in the presence of MS 4 Å. To this mixture, a solution of sub-
(CH3, OTBS), −4.39 (CH3, OTBS), 18.40 (Cq, OTBS), 18.57 (Cq, strate 4a (97 mg, 0.219 mmol) in dry DCM (5 mL) was added
OTBS), 26.13 (3 × CH3, OTBS), 63.31 (CH2, 1-C), 70.53 (CH2, and the mixture was stirred at the same temperature. After
CH2Ph), 72.20 (CH2, 6-C), 73.47 (CH2, CH2Ph), 74.24 (CH, 4-C), 0.5 h of stirring, a 6.0 M solution of t-BuOOH (0.09 mL,
80.93 (CH, 5-C), 127.14–128.44 (ArC + CH, 3-C), 134.59 (CH, 0.54 mmol) was added and the temperature of the reaction
2-C), 138.64 (ArCq), 138.99 (ArCq); IR (neat, cm−1) 3037, 1217, was raised to 0 °C and was left for stirring till the completion
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 6855–6868 | 6861

View Article Online
Paper
Organic & Biomolecular Chemistry
of the reaction. After completion, 10% solution of tartaric acid 3.34–3.67 (m, 5H, 1-H + 4-H + 6-H), 3.98 (dd, J = 4.5, 10.2 Hz,
(5 mL) was added to quench the reaction at 0 °C and stirred 1H, 5-H), 4.49–4.65 (m, 4H, 2 × CH2Ph), 7.25–7.31 (m, 10H,
for 0.5 h. The solution was filtered through a Celite pad. The ArH); 13C NMR (50 MHz, CDCl3, 25 °C): δ −4.83 (CH3, OTBS),
organic layer was extracted with DCM, concentrated, dissolved −4.38 (CH3, OTBS), 18.30 (Cq, OTBS), 26.03 (3 × CH3, OTBS),
in ether (7 mL) and again cooled to 0 °C. To this 4% NaOH in 44.63 (CH2, 1-C), 55.58 (CH, 2-C), 57.52 (CH, 3-C), 71.23 (CH2,
brine solution was added and stirred for 15–20 minutes. The 6-C), 72.24 (CH, 5-C), 73.61 (CH2, 2 × CH2Ph), 77.39 (CH, 1-C),
organic layer was extracted with ether, dried over Na2SO4, con- 127.75–128.53 (ArC), 138.38 (ArCq), 138.53 (ArCq); IR (neat,
centrated and evaporated under reduced pressure to obtain cm−1) 3948, 2364, 1217, 769; ESI-HRMS [M + H]+: calcd for
clear oil which on column purification yielded 5a (43 mg, 43% C26H37ClO4Si 477.2222, measured 477.2221.
from 4a). Analytical data of 5a: pale yellow oil, the eluent for
column chromatography: EtOAc–hexane (9/91, v/v); [α]D28
((1S,2R)-1,3-Bis(benzyloxy)-1-((2S,3R)-3-(chloromethyl)oxiran-
2-yl)propan-2-yloxy)(tert-butyl) dimethylsilane (6b). The experi-
=
+1.09 (c 0.10 CHCl3); Rf 0.46 (1/4, EtOAc–hexane); 1H NMR mental procedure for synthesis of 6b is the same as that of
(300 MHz, CDCl3): δ 0.04 (s, 3H, CH3), 0.05 (s, 3H, CH3), 0.89 compound 6a. Analytical data of 6b: colorless oil, the eluent
(s, 9H, 3 × CH3), 3.09 (bs, 1H, 2-H), 3.18–3.20 (m, 1H, 3-H), for column chromatography: EtOAc–hexane (1/99, v/v); [α]D28
=
1
3.48–3.53 (m, 3H, 1-H + 4-H + 6-H), 3.62–3.73 (m, 2H, 1-H + −20.01 (c 0.26 CH3OH); Rf 0.68 (1/4, EtOAc–hexane); H NMR
6-H), 3.94 (dd, J = 4.9, 9.3 Hz, 1H, 5-H), 4.50–4.59 (m, 4H, 2 × (300 MHz, CDCl3): δ 0.05 (s, 3H, CH3), 0.07 (s, 3H, CH3), 0.88
CH2Ph), 7.26–7.31 (m, 10H, ArH); 13C NMR (50 MHz, CDCl3): (s, 9H, 3 × CH3), 3.01–3.06 (m, 1H, 3-H), 3.16–3.19 (m, 1H,
δ −4.81 (CH3, OTBS), −4.38 (CH3, OTBS), 18.32 (Cq, OTBS), 2-H), 3.34–3.38 (m, 1H, 4-H), 3.48–3.52 (m, 4H, 1-H + 6-H),
26.04 (3 × CH3, OTBS), 54.93 (CH, 3-C), 56.65 (CH, 2-C), 61.71 4.01 (dd, J = 5.3 Hz, 9.7 Hz, 1H, 5-H), 4.43–4.77 (m, 4H, 2 ×
(CH2, 1-C), 71.20 (CH2, 6-C), 72.34 (CH, 5-C), 73.64 (CH2, CH2Ph), 7.26–7.33 (m, 10H, ArH); 13C NMR (75 MHz, CDCl3,
CH2Ph), 73.70 (CH2, CH2Ph), 77.80 (CH, 4-C), 127.80 (ArC), 25 °C): δ −4.54 (2 × CH3, OTBS), 18.28 (Cq, OTBS), 25.98 (3 ×
127.88 (ArC), 127.93 (ArC), 128.52 (ArC), 138.36 (ArCq), 138.75 CH3, OTBS), 44.60 (CH2, 1-C), 54.42 (CH, 2-C), 58.96 (CH, 3-C),
(ArCq); IR (neat, cm−1) 3450, 2927, 2342, 1622, 1218, 769; 71.35 (CH2, 6-C), 72.74 (CH2, CH2Ph), 72.88 (CH, 5-C), 73.54
ESI-HRMS m/z [M + H]+: calcd for C26H38O5Si 459.2561, (CH2, CH2Ph), 79.77 (CH, 4-C), 127.69–128.56 (ArC), 138.08
measured 459.2562.
(ArCq), 138.42 (ArCq); IR (neat, cm−1
) 3423, 1637, 772;
(2S,3R)-3-(1S,2R)-1,3-Bis(benzyloxy)-2-(tert-butyldimethylsilyl- ESI-HRMS m/z [M + H2O]+: calcd for C26H37ClO4Si 494.2250,
oxy)propyl(oxiran-2-yl) methanol (5b). The experimental pro- measured 494.2481.
cedure for synthesis of 5b is the same as that of compound 5a
(3R,4R,5R)-4,6-Bis(benzyloxy)-5-(tert-butyldimethylsilyloxy)-
Analytical data of 5b: pale yellow oil, the eluent for column hex-1-yn-3-ol (7a). To a stirred solution of epoxy chloride 6a
chromatography: EtOAc–hexane (9/91, v/v); [α]2D8 = −5.53 (c 0.26 (160 mg, 0.34 mmol) in dry THF (7.5 mL) at −60 °C was added
CH3OH); Rf 0.33 (1/4, EtOAc–hexane); 1H NMR (300 MHz, n-BuLi (1.8 mL, 3.6 mmol) dropwise in 3 lots at an interval of
CDCl3): δ 0.05 (s, 3H, CH3), 0.07 (s, 3H, CH3), 0.88 (s, 9H, 3 × 0.5 h between successive additions. The mixture was allowed
CH3), 2.95–2.98 (m, 1H, 3-H), 3.19–3.22 (m, 1H, 2-H), 3.35–3.39 to stir at −35 °C for additional 2 h. The reaction mixture was
(m, 1H, 4-H), 3.52–3.60 (m, 3H, 6-H + 1-H), 3.82 (d, J = 12.3 Hz, quenched with saturated aqueous solution of NH4Cl (5 mL)
1H, 1-H), 3.99 (dd, J = 5.0, 9.9 Hz, 1H, 5-H), 4.44–4.78 (m, 4H, and THF was removed under reduced pressure. The aqueous
2 × CH2Ph), 7.24–7.32 (m, 10H, ArH); 13C NMR (75 MHz, layer was extracted with ethyl acetate, dried with Na2SO4 and
CDCl3): δ −4.55 (CH3, OTBS), −4.49 (CH3, OTBS), 18.29 (Cq, concentrated. The residue was purified by silica gel column
OTBS), 26.00 (3 × CH3, OTBS), 55.47 (CH, 3-C), 56.42 (CH, 2-C), chromatography to furnish alkyne 7a as clear oil (80 mg, 50%
61.69 (CH2, 1-C), 71.53 (CH2, 6-C), 72.82 (CH2, CH2Ph), 73.00 from 6a). Analytical data of 7a: colorless oil, the eluent for
(CH, 5-C), 73.62 (CH2, CH2Ph), 80.37 (CH, 4-C), 127.67–128.55 column chromatography: EtOAc–hexane (1/39, v/v); [α]D28
=
(ArC), 138.11 (ArCq), 138.54 (ArCq); IR (neat, cm−1) 3439, 2367, −6.29 (c 0.20 CHCl3); Rf 0.36 (1/9, EtOAc–hexane); 1H NMR
1634, 772; ESI-HRMS m/z [M + H]+: calcd for C26H38O5Si (300 MHz, CDCl3): δ 0.07 (s, 3H, CH3), 0.11 (s, 3H, CH3), 0.90
459.2561, measured 459.2557.
(s, 9H, 3 × CH3), 2.46 (d, J = 2.3 Hz, 1H, 1-H), 3.60 (d, J =
((1R,2R)-1,3-Bis(benzyloxy)-1-((2S,3R)-3-(chloromethyl)oxiran- 3.8 Hz, 2H, 6-H), 3.75–3.79 (m, 1H, 5-H), 4.03–4.08 (m, 1H,
2-yl)propan-2-yloxy)(tert-butyl)dimethylsilane (6a). A stirred 4-H), 4.51 (s, 2H, CH2Ph), 4.59–4.61 (m, 1H, 3-H), 4.69 (d, J =
mixture of epoxy alcohol 5a (44 mg, 0.09 mmol), PPh3 (61 mg, 11.0 Hz, 1H, CH2Ph), 4.83 (d, J = 11.0 Hz, 1H, CH2Ph),
0.23 mmol) and NaHCO3 (2 mg, 4.5 wt%) in CCl4 (0.62 mL) 7.30–7.32 (m, 10H, ArH); 13C NMR (75 MHz, CDCl3): δ −4.76
was heated at reflux, under a N2 atmosphere for 7–8 h. After (CH3, OTBS), −4.24 (CH3, OTBS), 18.25 (Cq, OTBS), 26.03 (3 ×
completion of the reaction, CCl4 was removed under pressure CH3, OTBS), 61.49 (CH, 3-C), 71.26 (CH2, 6-C), 71.83 (CH, 4-C),
and the residue was purified by silica gel column chromato- 73.53 (CH2, CH2Ph), 73.73 (CH, 1-C),74.78 (CH2, CH2Ph), 81.24
graphy to furnish epoxy chloride 6a as a colorless liquid (CH, 5-C), 83.73 (Cq, 2-C), 127.82–128.59 (ArC), 137.97 (ArCq),
(20 mg, 46% from 5a). Analytical data of 6a: colorless oil, the 138.18 (ArCq); IR (neat, cm−1
) 3457, 2357, 1092, 773;
eluent for column chromatography: EtOAc–hexane (1/99, v/v); ESI-HRMS m/z [M + H]+: calcd for C26H36O4Si 441.2456,
[α]2D8 = −0.75 (c 0.20 CHCl3); Rf 0.68 (1/4, EtOAc–hexane); measured 441.2456.
1H NMR (300 MHz, CDCl3): δ 0.03 (s, 3H, CH3), 0.05 (s, 3H,
(3R,4S,5R)-4,6-Bis(benzyloxy)-5-(tert-butyldimethylsilyloxy)-
CH3), 0.88 (s, 9H, 3 × CH3), 3.13–3.19 (m, 2H, 2-H + 3-H), hex-1-yn-3-ol (7b). The experimental procedure for synthesis of
6862 | Org. Biomol. Chem., 2014, 12, 6855–6868
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
7b is the same as that of compound 7a. Analytical data of 7b: 4-C), 80.28 (CH, 1-C), 80.57 (Cq, 2-C) 127.88–128.10 (ArC),
colorless oil, the eluent for column chromatography: EtOAc– 128.34–128.59 (ArC), 137.37 (ArCq), 138.22 (ArCq); IR (neat,
hexane (1/39, v/v); [α]2D8 = −5.37 (c 0.06 CHCl3); Rf 0.36 (1/9, cm−1) 3429, 1636, 1217, 765; ESI-HRMS m/z [M + H]+: calcd for
EtOAc–hexane); 1H NMR (300 MHz, CDCl3): δ 0.07 (s, 3H, C27H28O4 417.2060, measured 417.2060.
CH3), 0.11 (s, 3H, CH3), 0.90 (s, 9H, 3 × CH3), 2.47 (d, J = 3.5
(2S,3R,4R)-1,3,4-Tris(benzyloxy)hex-5-yn-2-yl azide (9a). To a
Hz, 1H, 1-H), 2.97, 3.60 (d, J = 5.7 Hz, 2H, 6-H), 3.75–3.80 (m, stirred solution of compound 8a (114 mg, 0.273 mmol) and
1H, 4-H), 4.01–4.08 (m, 1H, 5-H), 4.51 (s, 2H, CH2Ph), PPh3 (574 mg, 2.19 mmol) in anhydrous THF (24 mL) were
4.57–4.64 (m, 1H, 3-H), 4.66–4.86 (m, 2H, CH2Ph), 7.30–7.35 added DEAD (0.43 mL, 2.18 mmol) and DPPA (0.47 mL,
(m, 10H, ArH); 13C NMR (75 MHz, CDCl3): δ −4.74 (CH3, 2.18 mmol) at −20 °C. The stirring was continued at −20 °C
OTBS), −4.23 (CH3, OTBS), 18.25 (Cq, OTBS), 26.04 (3 × CH3, for 6 h and then the reaction mixture was gradually brought to
OTBS), 61.52 (CH, 3-C), 71.40 (CH2, 6-C), 71.93 (CH, 5-C), 73.56 room temperature and stirred overnight. On complete disap-
(CH2, CH2Ph), 73.71 (CH, 1-C), 74.80 (CH2, CH2Ph), 81.53 (CH, pearance of the starting material on TLC, the solvent was evap-
4-C), 83.80 (CH, 2-C), 127.80–128.58 (ArC), 138.06 (ArCq), orated under reduced pressure and the residue was subjected
138.25 (ArCq); IR (neat, cm−1) 3438, 1632, 772; ESI-HRMS m/z to flash column chromatography to give 9a as a brown syrup
[M + H]+: calcd for C26H36O4Si 441.2456, measured 441.2446.
(61.56 mg, 54% from 8a). Analytical data of 9a: brown syrup,
the eluent for column chromatography: EtOAc–hexane (1/49,
(2R,3S,4R)-1,3,4-Tris(benzyloxy)hex-5-yn-2-ol
(8a). To
a
stirred solution of compound 7a (49 mg, 0.11 mmol) in dry v/v); [α]2D8 = −23.02 (c 0.0.43 CHCl3); Rf 0.66 (3/17, EtOAc–
1
THF (1 mL), sodium hydride (8 mg, 60% suspension in hexane); H NMR (300 MHz, CDCl3): δ 2.49 (d, J = 2.2 Hz 1H,
mineral oil), benzyl bromide (0.013 mL, 0.11 mmol) and TBAI 1-H), 3.55–3.60 (m, 1H, 6-H), 3.66–3.76 (m, 3H, 4-H, 5-H, 6-H),
(catalytic amount) were added at 0 °C and stirred at room 4.33–4.35 (m, 1H, 3-H), 4.42–4.55 (m, 4H, 2 × CH2Ph),
temperature for 6 to 8 h. After completion of the reaction, THF 4.76–4.81 (m, 2H, CH2Ph), 7.22–7.26 (m, 15H, ArH); 13C NMR
was evaporated, extracted with CHCl3, dried over Na2SO4, con- (75 MHz, CDCl3): δ 61.84 (CH, 5-C), 69.68 (CH2, 6-C), 70.34
centrated and evaporated under reduced pressure to obtain (CH, 3-C), 71.25 (CH2, CH2Ph), 73.51 (CH2, CH2Ph), 74.64
the crude product. This was dissolved in dry THF, cooled to (CH2, CH2Ph), 76.20 (CH, 1-C), 79.67 (CH, 4-C), 79.78 (Cq, 2-C),
0 °C and TBAF (0.18 mmol, 1.0 M solution in THF) was slowly 127.82–128.61 (ArC), 137.46 (ArCq), 138.00 (ArCq); IR (neat,
added. The mixture was allowed to stir at room temperature cm−1) 3425, 2924, 2102, 1218, 766; ESI-HRMS m/z [M + H]+:
for 2 h. After completion of the reaction, the reaction mixture calcd for C27H27N3O3 442.2125, measured 442.2125.
was quenched with water, THF was evaporated, extracted with
(2R,3S,4R)-1,3,4-Tris(benzyloxy)hex-5-yn-2-yl chloro(oxo)-
CHCl3, dried over Na2SO4 and concentrated under reduced methanesulfinate (9b). A solution of compound 8b (89 mg,
pressure. The residue on purification by silica gel column 0.21 mmol) and chloromethanesulphonyl chloride (0.02 mL,
chromatography afforded 8a as a clear liquid (33.32 mg, 68% 0.22 mmol) in pyridine (1.5 mL) was stirred at rt for 7 to
from 7a over two steps). Analytical data of 8a: colorless oil, the 10 minutes. On completion of the reaction, the mixture was
eluent for column chromatography: EtOAc–hexane (1/19, v/v); diluted with ethyl acetate and washed with water and brine
[α]2D8 = −31.02 (c 0.20 CHCl3); Rf 0.31 (3/17, EtOAc–hexane); and dried over Na2SO4. The compound on purification by
1H NMR (300 MHz, CDCl3): δ 2.54 (d, J = 1.9 Hz, 1H, 1-H), column chromatography yielded 9b as a clear oil (100 mg,
3.46–3.56 (m, 2H, 6-Ha, 6-Hb), 3.70–3.79 (m, 1H, 4-H), 4.13 88.5% from 8b). Analytical data of 9b: reddish brown oil, the
(s, 1H, 5-H), 4.39–4.43 (m, 1H, 3-H), 4.47–4.56 (m, 4H, 2 × eluent for column chromatography: EtOAc–hexane (1/49, v/v);
CH2Ph), 4.83–4.89 (m, 2H, CH2Ph), 7.29–7.35 (m, 15H, ArH); [α]2D8 = +15.12 (c 0.07 CHCl3); Rf 0.46 (3/17, EtOAc–hexane)
13C NMR (50 MHz, CDCl3): δ 69.21 (CH, 3-C), 69.65 (CH, 5-C), 1H NMR (75 MHz, CDCl3): δ 2.57 (d, J = 2.1 Hz, 1H, 1-H),
70.95 (CH2, 6-C), 71.18 (CH2, CH2Ph), 73.52 (CH2, CH2Ph), 3.77–3.84 (m, 1H, 6-Ha), 3.89–3.94 (m, 1H, 6-Hb), 4.03–4.06 (m,
74.54 (CH2, CH2Ph), 75.78 (CH, 1-C), 79.59 (CH, 4-C), 81.01 1H, 4-H), 4.29–4.31 (m, 1H, 5-H), 4.47–4.85 (m, 8H, 3 × CH2Ph
(Cq, 2-C), 127.88–128.61 (ArC), 137.34 (Cq), 137.93 (Cq), 137.98 + 2H of OMsCl), 5.22–5.27 (m, 1H, 3-H), 7.30–7.32 (m, 15H,
(Cq), 138.16 (Cq); IR (neat, cm−1) 3451, 2919, 2367, 1644, 1218, ArH); 13C NMR (200 MHz, CDCl3): δ 54.23 (CH2, OMsCl), 68.71
768; ESI-HRMS m/z [M + H]+: calcd for C27H28O4 417.2060, (CH2, 6-C), 68.81 (CH, 5-C), 71.28 (CH2, CH2Ph), 73.55 (CH2,
measured 417.2059.
CH2Ph), 75.18 (CH2, CH2Ph), 77.20 (CH, 1-C), 79.30 (Cq, 2-C),
(2R,3R,4R)-1,3,4-Tris(benzyloxy)hex-5-yn-2-ol (8b). The 80.42 (CH, 4-C), 83.61 (CH, 3-C), 128.04–128.61 (ArC), 137.13
experimental procedure for synthesis of 8b is the same as that (ArCq), 137.39 (ArCq), 137.50 (ArCq); IR (neat, cm−1) 3230,
of compound 8a. Analytical data of 8b: colorless oil, the eluent 1638, 1217, 770; ESI-HRMS m/z [M + H2O]+: calcd for
for column chromatography: EtOAc–hexane (1/19, v/v); [α]D28
−50.77 (c 0.11 CHCl3); Rf 0.31 (3/17, EtOAc–hexane); H NMR
=
C28H29ClO6S 546.1474, measured 546.1700.
(2R,3R,4R)-1,3,4-Tris(benzyloxy)hex-5-yn-2-yl chloro(oxo)-
1
(300 MHz, CDCl3): δ 2.55 (d, J = 2.1 Hz, 1H, 1-H), 3.59–3.65 (m, methanesulfinate (9c). The experimental procedure for syn-
2H, 6-H), 3.73–3.76 (m, 1H, 4-H), 4.10–4.14 (m, 1H, 5-H), thesis of 9c is the same as that of compound 9b. Analytical
4.41–4.64 (m, 5H, 2 × CH2Ph + 3-H), 4.81–4.88 (m, 2H, CH2Ph), data of 9c: light orange oil, the eluent for column chromato-
7.26–7.33 (m, 15H, ArH); 13C NMR (75 MHz, CDCl3): δ 68.92 graphy: EtOAc–hexane (1/49, v/v); [α]2D8 = −19.65 (c 0.15
(CH, 3-C), 70.36 (CH, 5-C), 70.87 (CH2, 6-C), 71.22 (CH2, CH3OH) Rf 0.46 (3/17, EtOAc–hexane); 1H NMR (300 MHz,
CH2Ph), 73.58 (CH2, CH2Ph), 74.59 (CH2, CH2Ph), 76.18 (CH, CDCl3): δ 2.58 (d, J = 1.6 Hz, 1H, 1-H), 3.56–3.60 (m, 1H, 6-H),
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 6855–6868 | 6863

View Article Online
Paper
Organic & Biomolecular Chemistry
3.72–3.77 (m, 1H, 6-H), 3.88–3.91 (m, 1H, 4-H), 4.39–4.65 (CH2, 1-C), 71.70 (CH2, 6-C), 73.26 (CH, 5-C), 73.55 (CH2,
(m, 7H, 2 × CH2Ph + CH2 of OMsCl + 3-H), 4.81–4.94 (m, 2H, CH2Ph), 73.57 (CH2, CH2Ph), 78.38 (CH, 4-C), 127.76–128.49
CH2Ph), 5.11–5.15 (m, 1H, 5-H), 7.30–7.32 (m, 15H, ArH); (ArC), 138.31 (ArCq), 138.62 (ArCq); IR (neat, cm−1) 3264, 2924,
13C NMR (200 MHz, CDCl3): δ 54.43 (CH2, OMsCl), 68.59 (CH, 1638, 1217, 762; ESI-HRMS m/z [M + Na]+: calcd for C26H38O5Si
3-C), 69.30 (CH2, 6-C), 71.32 (CH2, CH2Ph), 73.70 (CH2, 481.2381, measured 481.2379.
CH2Ph), 75.13 (CH2, CH2Ph), 76.42 (CH, 1-C), 78.79 (Cq, 2-C),
((1R,2R)-1,3-Bis(benzyloxy)-1-((2R,3S)-3-(chloromethyl)oxiran-
80.31 (CH, 4-C), 82.48 (CH, 5-C), 128.14–128.72 (ArC), 137.21 2-yl)propan-2-yloxy)(tert-butyl)dimethylsilane (11a). The experi-
(ArCq), 137.47 (ArCq); IR (neat, cm−1) 3436, 3020, 2400, 1216, mental procedure for synthesis of 11a is the same as that of
757; ESI-HRMS m/z [M + Na]+: calcd for C28H29ClO6S 551.1266, compound 6a. Analytical data of 11a: colorless oil, the eluent
measured 551.1268.
for column chromatography: EtOAc–hexane (1/99, v/v); [α]D28
=
(2R,3S)-3-(1R,2R)-1,3-Bis(benzyloxy)-2-(tert-butyldimethylsilyl- −1.13 (c 0.07 CH3OH) Rf 0.68 (1/4, EtOAc–hexane); 1H NMR
oxy)propyl(oxiran-2-yl) methanol (10a). A solution of Ti (O-i-Pr)4 (300 MHz, CDCl3): δ 0.01–0.08 (m, 6H, 2 × CH3), 0.86–0.89
(1.83 mL, 6.24 mmol) and D-(−)-diethyltartarate (1.16 mL, (m, 9H, 3 × CH3), 3.12–3.27 (m, 3H, 2-H + 3-H + 4-H), 3.35–3.87
6.79 mmol) in dry DCM (20 mL) was stirred at −25 °C for 0.5 h (m, 4H, 1-H + 6-H), 3.93–4.06 (m, 1H, 5-H), 4.50–4.81 (m, 4H,
in the presence of MS 4 Å. To this mixture, a solution of sub- 2 × CH2Ph), 7.26–7.34 (m, 10H, ArH); 13C NMR (50 MHz,
strate 4a (6.24 g, 14.09 mmol) in dry DCM (20 mL) was added CDCl3): δ −4.82 (CH3, OTBS), −4.47 (CH3, OTBS), 18.15 (Cq,
and the mixture was stirred at the same temperature. After OTBS), 25.94 (3 × CH3, OTBS), 44.51 (CH2, 1-C), 53.85 (CH,
0.5 h of stirring, a 6.0 M solution of t-BuOOH (11.25 mL, 3-C), 58.81 (CH, 2-C), 71.51 (CH2, 6-C), 72.35 (CH2, CH2Ph),
67.5 mmol) was added and the temperature of the reaction 72.85 (CH, 5-C), 73.51 (CH2, CH2Ph), 80.43 (CH, 4-C),
was raised to 0 °C and was left for stirring till the completion 127.74–128.39 (ArC), 138.16–138.25 (ArCq); IR (neat, cm−1
)
of the reaction. After completion, 10% solution of tartaric acid 3269, 1639, 1217, 764 ESI-HRMS m/z [M + Na]+: calcd for
(20 mL) was added to quench the reaction at 0 °C and stirred C26H37ClO4Si, 499.2042, measured 499.2039.
for 0.5 h. The solution was filtered through a Celite pad. The
((1S,2R)-1,3-Bis(benzyloxy)-1-((2R,3S)-3-(chloromethyl)oxiran-
organic layer was extracted with DCM, concentrated, dissolved 2-yl)propan-2-yloxy) (tert-butyl)dimethylsilane (11b). The experi-
in ether (15 mL) and again cooled to 0 °C. To this 4% NaOH in mental procedure for synthesis of 11b is the same as that of
brine solution was added and stirred for 15–20 minutes. The compound 6a. Analytical data of 11b: colorless oil, the eluent
organic layer was extracted with ether, dried over Na2SO4, con- for column chromatography: EtOAc–hexane (1/99, v/v); [α]D28
=
centrated and evaporated under reduced pressure to obtain +7.44 (c 0.37, CH3OH), Rf0.68 (1/4, EtOAc–hexane); 1H NMR
clear oil which on column purification yielded 10a (2.3 g, (300 MHz, CDCl3): 0.06 (s, 6H, 2 × CH3), 0.89 (s, 9H, 3 × CH3),
35.6% from 4a). Analytical data of 10a: pale yellow oil, the 3.15–3.22 (m, 2H, 2-H + 3-H), 3.41–3.63 (m, 5H, 1-H + 4-H +
eluent for column chromatography: EtOAc–hexane (9/91, v/v); 6-H), 4.03 (dd, J = 5.3, 9.1, 1H, 5-H), 4.49–4.64 (m, 4H, 2 ×
[α]2D8 = −6.57 (c 0.25 CH3OH) Rf 0.46 (1/4, EtOAc–hexane); 1H CH2Ph), 7.24–7.31 (m, 10H, ArH); 13C NMR (75 MHz, CDCl3):
NMR (300 MHz, CDCl3): δ 0.00–0.09 (m, 6H, 2 × CH3), δ −4.62 (CH3, OTBS), −4.42 (CH3, OTBS), 18.32 (Cq, OTBS),
0.87–0.89 (m, 9H, 3 × CH3), 3.06–3.26 (m, 2H, 2-H + 3-H), 26.01 (3 × CH3, OTBS), 44.70 (CH2, 1-C), 54.97 (CH, 2-C), 57.73
3.48–4.02 (m, 6H, 1-H + 4-H + 5-H + 6-H), 4.40–4.83 (m, 4H, 2 × (CH, 3-C), 71.65 (CH2, 6-C), 73.30 (CH, 5-C), 73.56 (CH2, 2 ×
CH2Ph), 7.31–7.36 (m, 10H, ArH); 13C NMR (50 MHz, CDCl3): CH2Ph), 78.15 (CH, 4-C), 127.78–128.77 (ArC), 138.32 (ArCq),
δ −4.76 (CH3, OTBS), −4.46 (CH3, OTBS),18.24 (Cq, OTBS), 138.51 (ArCq); IR (neat, cm−1
) 2923, 2853, 1218, 770;
25.98 (3 × CH3, OTBS), 54.76 (CH, 3-C), 56.38 (CH, 2-C), 61.71 ESI-HRMS m/z [M + Na]+: calcd for C26H37ClO4Si 499.2042,
(CH2, 1-C), 71.56 (CH2, 6-C), 72.37 (CH2, CH2Ph), 72.88 (CH, measured 499.2039.
5-C), 73.68 (CH2, CH2Ph), 81.21 (CH, 4-C), 127.93–128.51 (ArC),
(3S,4R,5R)-4,6-Bis(benzyloxy)-5-(tert-butyldimethylsilyloxy)-
138.22 (ArCq), 138.42 (ArCq); IR (neat, cm−1) 3433, 2925, 2856, hex-1-yn-3-ol (12a). The experimental procedure for synthesis
1366, 698 ESI-HRMS m/z [M + Na]+: calcd for C26H38O5Si, of 12a is the same as that of compound 7a. Analytical data of
481.2381, measured 481.2408.
12a: colorless oil, the eluent for column chromatography:
((2R,3S)-3-((1S,2R)-1,3-Bis(benzyloxy)-2-(tert-butyldimethyl- EtOAc–hexane (1/39, v/v); [α]2D8 = −3.34 (c 0.15, CH3OH) Rf 0.36
silyloxy)propyl)oxiran-2-yl) methanol (10b). The experimental (1/9, EtOAc–hexane); 1H NMR (300 MHz, CDCl3): δ 0.05–0.07
procedure for synthesis of 10b is the same as that of com- (m, 6H, 2 × CH3), 0.87–0.88 (m, 9H, 3 × CH3), 2.45–2.46 (m,
pound 10a. Analytical data of 10b: colorless oil, the eluent for 1H, 1-H), 3.53–3.70 (m, 3H, 4-H, 6-H), 4.01–4.06 (m, 1H, 5-H),
column chromatography: EtOAc–hexane (9/91, v/v); [α]D28
=
4.47–4.56 (m, 2H, CH2Ph), 4.61–4.66 (m, 1H, 3-H), 4.70–4.87
+8.12 (c 0.51 CH3OH), Rf 0.46 (1/4, EtOAc–hexane); 1H NMR (m, 2H, CH2Ph), 7.32–7.36 (m, 10H, ArH); 13C NMR (50 MHz,
(300 MHz, CDCl3): δ 0.06 (s, 6H, 2 × CH3), 0.89 (s, 9H, 3 × CDCl3): δ −4.83 (CH3, OTBS), −4.39 (CH3, OTBS), 18.33 (Cq,
CH3), 3.13–3.15 (m, 1H, 3-H), 3.20–3.22 (m, 1H, 2-H), 3.48–3.63 OTBS), 26.01 (3 × CH3, OTBS), 61.21 (CH, 3-C), 71.59 (CH2,
(m, 4H, 6-H + 1-H + 4-H), 3.82 (dd, J = 2.28, 12.6, 1H, 1-H), 4.03 6-C), 71.96 (CH, 5-C), 73.60 (2 × CH2, 1-C + CH2Ph), 74.61
(dd, J = 5.4, 9.15, 1H, 5-H), 4.50 (s, 2H, CH2Ph), 4.59 (s, 2H, (CH2, CH2Ph), 82.33 (CH, 4-C), 83.92 (Cq, 2-C), 127.83–128.56
CH2Ph), 7.24–7.31 (m, 10H, ArH); 13C NMR (75 MHz, CDCl3): (ArC), 138.11 (ArCq), 138.23 (ArCq); IR (neat, cm−1) 3278, 2921,
δ −4.67 (CH3, OTBS), −4.45 (CH3, OTBS), 18.29 (Cq, OTBS), 1217, 764; ESI-HRMS m/z [M + Na]+: calcd for C26H36O4Si,
25.98 (3 × CH3, OTBS), 54.91 (CH, 2-C), 55.98 (CH, 3-C), 61.68 463.2275, measured 463.2274.
6864 | Org. Biomol. Chem., 2014, 12, 6855–6868
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
(3S,4S,5R)-4,6-Bis(benzyloxy)-5-(tert-butyldimethylsilyloxy)- (m, 1H, 5-H), 7.25–7.32 (m, 15H, ArH); 13C NMR (50 MHz,
hex-1-yn-3-ol (12b). The experimental procedure for synthesis CDCl3): δ 54.41 (CH2, OMsCl), 68.91 (CH, 3-C), 69.17 (CH2,
of 12b is the same as that of compound 7a. Analytical data of 6-C), 71.39 (CH2 CH2Ph), 73.62 (CH2 CH2Ph), 75.35 (CH2
12b: colorless oil, the eluent for column chromatography: CH2Ph), 78.89 (CH, 4-C), 79.14 (Cq, 2-C), 83.58 (CH, 5-C),
EtOAc–hexane (1/39, v/v); [α]2D8 = +16.11 (c 0.24, CH3OH) Rf 0.36 128.13–128.68 (ArC), 137.00–137.51 (ArCq); IR (neat, cm−1
)
1
(1/9, EtOAc–hexane); H NMR (300 MHz, CDCl3): δ 0.06 (s, 3H, 3436, 1635, 1219, 772; ESI-HRMS m/z [M + NH4]+: calcd for
CH3), 0.09 (s, 3H, CH3), 0.89 (s, 9H, 3 × CH3), 2.46 (d, J = C28H29ClO6S, 546.1712, measured 546.1699.
2.0 Hz, 1H, 1-H), 3.53–3.58 (m, 1H, 6-H), 3.70–3.77 (m, 2H, 4-H
(2R,3S,4S)-1,3,4-Tris(benzyloxy)hex-5-yn-2-yl chloro(oxo)-
+ 6-H), 4.11–4.16 (m, 1H, 5-H), 4.48–4.76 (m, 5H, 3-H + 2 × methanesulfinate (14b). The experimental procedure for syn-
CH2Ph), 7.22–7.33 (m, 10H, ArH); 13C NMR (75 MHz, CDCl3): thesis of 14b is the same as that of compound 9b. Analytical
δ −4.75 (CH3, OTBS), −4.30 (CH3, OTBS), 18.18 (Cq, OTBS), data of 14b: light orange oil, the eluent for column chromato-
25.98 (3 × CH3, OTBS), 63.75 (CH, 3-C), 71.12 (CH2, 6-C), 72.81 graphy: EtOAc–hexane (1/49, v/v); [α]2D8 = +14.80 (c 0.28 CH3OH)
(CH, 5-C), 73.59 (CH2, CH2Ph), 74.40 (CH2, CH2Ph), 74.40 (CH, Rf 0.46 (3/17, EtOAc–hexane); 1H NMR (300 MHz, CDCl3):
1-C), 82.41 (CH, 4-C), 82.86 (CH, 2-C), 127.88–128.55 (ArC), δ 2.56 (d, J = 1.7 Hz, 1H, 1-H), 3.69–3.81 (m, 2H, 6-H), 4.02 (dd,
137.83 (ArCq), 138.39 (ArCq); IR (neat, cm−1) 2849, 1637, 1217, J = 3.4, 5.9 Hz, 1H, 4-H), 4.24–4.27 (m, 1H, 3-H), 4.41–4.84 (m,
670; ESI-HRMS m/z [M + Na]+: calcd for C26H36O4Si 463.2275, 8H, 3 × CH2Ph + CH2 of OMsCl), 5.19–5.23 (m, 1H, 5-H),
measured 463.2271.
7.24–7.32 (m, 15H, ArH); 13C NMR (50 MHz, CDCl3): δ 54.35
(2R,3S,4S)-1,3,4-Tris(benzyloxy)hex-5-yn-2-ol (13a). The experi- (CH2, OMsCl), 68.68 (CH, 3-C), 68.84 (CH2, 6-C), 71.08 (CH2,
mental procedure for synthesis of 13a is the same as that of CH2Ph), 73.64 (CH2, CH2Ph), 74.79 (CH2, CH2Ph), 76.36 (CH,
compound 8a. Analytical data of 13a: colorless oil, the eluent 1-C), 79.68 (Cq, 2-C), 80.40 (CH, 4-C), 84.19 (CH, 5-C),
for column chromatography: EtOAc–hexane (1/19, v/v); [α]D28
=
128.06–128.68 (ArC), 136.94 (ArCq), 137.45 (ArCq); IR (neat,
+35.96 (c 0.04); Rf 0.31 (3/17, EtOAc–hexane); 1H NMR cm−1) 2853, 1606, 1461, 1217, 763; ESI-HRMS m/z [M + NH4]+:
(300 MHz, CDCl3): δ 2.57 (d, J = 2.0 Hz, 1H, 1-H), 3.40–3.51 (m, calcd for C28H29ClO6S 546.1712, measured 546.1708.
2H, 6-H), 3.75–3.78 (m, 1H, 4-H), 4.19 (d, J = 4.8 Hz, 1H, 3-H),
(4R,5S,6S)-4,5-Bis(benzyloxy)-6-(benzyloxymethyl)-5,6-dihydro-
4.40–4.60 (m, 5H, 5-H + 2 × CH2Ph), 4.85–4.94 (m, 2H, CH2Ph), 4H-pyrrolo[1,2-c][1,2,3]triazole (15a). Any of the procedure
7.28–7.34 (m, 15H, ArH); 13C NMR (50 MHz, CDCl3): δ 70.26 p, q, r or s can be followed for the cycloaddition reaction.
(CH, 3-C), 71.17 (CH + CH2, 5-C + 6-C), 71.49 (CH2, CH2Ph),
Procedure p: To a 20 mL two necked oven dried round
73.45 (CH2, CH2Ph), 75.29 (CH2, CH2Ph), 76.57 (CH, 1-C), bottom flask fitted with a reflux condenser and septum was
80.01 (CH, 4-C), 80.29 (Cq, 2-C), 128.01–128.56 (ArC), added a solution of compound 9a (39 mg, 0.088 mmol) dis-
137.60–138.21 (ArCq); IR (neat, cm−1) 3371, 2923, 1639, 766; solved in dry degassed toluene (3 mL) through a syringe. The
ESI-HRMS m/z [M + NH4]+: calcd for C27H28O4 434.2326, reaction mixture was refluxed for 4.5 h. After complete disap-
measured 434.2316.
pearance of azido alkyne (as indicated by monitoring the reac-
(2R,3R,4S)-1,3,4-Tris(benzyloxy)hex-5-yn-2-ol (13b). The experi- tion by TLC), the reaction mixture was cooled to room
mental procedure for synthesis of 13b is the same as that of temperature. The solvent was removed under vacuum and the
compound 8a. Analytical data of 13b: colorless oil, the eluent product was purified by silica gel chromatography to yield the
for column chromatography: EtOAc–hexane (1/19, v/v); [α]D28
+60.73 (c 0.40, CH3OH); Rf 0.31 (3/17, EtOAc–hexane); H NMR
=
1,5-triazole 15a as a clear oil (30.5 mg, 78% from 9a).
1
Procedure q: To a 20 mL two necked oven dried round
(300 MHz, CDCl3): δ 2.55 (d, J = 1.9 Hz, 1H, 1-H), 3.54–3.66 (m, bottom flask fitted with a reflux condenser and septum was
2H, 6-H), 3.77–3.85 (m, 1H, 4-H), 3.94 (s, 1H, 5-H), 4.42–4.92 added Cp*RuCl(PPh3)2 (3.3 mg, 5 mol%) under a nitrogen
(m, 7H, 3 × CH2Ph + 3-H), 7.23–7.35 (m, 10H, ArH); 13C NMR atmosphere. To this was added a solution of compound 9a
(300 MHz, CDCl3): δ 70.66 (CH, 5-C), 70.88 (CH2, 6-C), 71.25 (42 mg, 0.10 mmol) dissolved in dry degassed toluene (3 mL)
(CH, 3-C), 71.40 (CH2, CH2Ph), 73.49 (CH2, CH2Ph), 74.30 through a syringe. The reaction mixture was refluxed for 2 h.
(CH2, CH2Ph), 76.90 (CH, 1-C), 80.00 (Cq, 2-C), 80.31 (CH, 4-C), After complete disappearance of azido alkyne (as indicated by
127.78–128.54 (ArC), 137.72 (ArCq), 138.05 (ArCq), 138.37 monitoring the reaction by TLC), the reaction mixture was
(ArCq); IR (neat, cm−1) 3020, 2923, 2853, 1217, 770; ESI-HRMS cooled to room temperature. The solvent was removed
m/z [M
+
H]+: calcd for C27H28O4 417.2065, measured under vacuum and the product was purified by silica
417.2064.
gel chromatography to yield 15a as a brown oil (37 mg, 88%
(2R,3R,4S)-1,3,4-Tris(benzyloxy)hex-5-yn-2-yl
methanesulfinate (14a). The experimental procedure for syn-
chloro(oxo)- from 9a).
Procedure r: To a 20 mL two necked oven dried round
thesis of 14a is the same as that of compound 9b. Analytical bottom flask fitted with a reflux condenser was added sodium
data of 14a: reddish brown oil, the eluent for column azide (5 mg, 0.076 mmol), sealed with a septum and flushed
chromatography: EtOAc–hexane (1/49, v/v); [α]2D8 = +29.44 with nitrogen. To this was added a solution of compound 9c
(c 0.31 CH3OH) Rf 0.46 (3/17, EtOAc–hexane) 1H NMR (20.5 mg, 0.038 mmol) dissolved in dry DMF (2 mL) through a
(300 MHz, CDCl3): δ 2.62 (d, J = 1.7 Hz, 1H), 3.59–3.71 (m, 2H, syringe under a nitrogen atmosphere. The reaction mixture
6-H), 3.89 (t, J = 5.2 Hz, 1H, 4-H), 4.32–4.36 (m, 1H, 3-H), was refluxed for 4 to 6 h. After completion, the reaction
4.40–4.88 (m, 8H, 3 × CH2Ph + 2 × CH2 of OMsCl), 5.11–5.16 mixture was cooled to room temperature and diluted with
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 6855–6868 | 6865

View Article Online
Paper
Organic & Biomolecular Chemistry
water. The aqueous layer was extracted with ethyl acetate, (m, 2H, 9-H), 4.45–4.58 (m, 7H, 8-H + 3 × CH2Ph), 4.71 (t, J =
dried with Na2SO4 and concentrated under vacuum. The 3.0 Hz, 1H, 7-H), 4.85 (d, J = 2.3 Hz, 6-H), 7.18–7.28 (m, ArH,
residue was purified by silica gel column chromatography to 15H), 7.42 (s, 1H, 4-H); 13C NMR (50 MHz, CDCl3): δ 64.03
furnish 15a as a clear oil (17 mg, 99% from 9c).
(CH, 8-C), 68.40 (CH2, 9-C), 72.02 (CH2, CH2Ph), 72.49 (CH2,
Procedure s: A sealed microwave vial containing sodium CH2Ph), 73.73 (CH2, CH2Ph), 76.98 (CH, 6-C), 89.96 (CH, 7-C),
azide (6 mg, 0.092 mmol) was flushed with N2 and to it was 127.91–128.96 (ArC + 4-C), 136.93–137.49 (ArCq), 139.15 (Cq,
added chloromesylate 9c (20 mg, 0.037 mmol) dissolved in dry 5-C); IR (neat, cm−1) 3438, 1638, 767; ESI-HRMS m/z [M + H]+:
DMF (2 mL) (kept in another flask under a N2 atmosphere). calcd for C27H27N3O3 442.2125, measured 443.2172.
The reaction mixture was heated to 80 °C for 2 h in a micro-
(4S,5R,6S)-4,5-Bis(benzyloxy)-6-(benzyloxymethyl)-5,6-dihydro-
wave reactor to allow the complete formation of the azido 4H-pyrrolo[1,2-c][1,2,3]triazole (16b). For synthesis of 16b pro-
alkyne intermediate. CAUTION! The reaction should only be cedure r was followed. Analytical data of 16b: colorless oil, the
carried out in a microwave reactor that can withstand an eluent for column chromatography: EtOAc–hexane (3/7, v/v);
explosion of the reaction vial as the reaction generating small [α]2D8 = +12.88 (c 0.07 CH3OH) Rf 0.19 (2/3, EtOAc–hexane);
alkyl azides is potentially explosive. The vial was taken out of 1H NMR (300 MHz, CDCl3): δ 3.89 (dd, J = 8.3, 10.4 Hz,
the reactor and to it was injected a solution of the Cp*RuCl- 1H, 9-Ha), 4.11 (dd, J = 4.4, 10.5 Hz, 1H, 9-Hb), 4.50–4.79 (m,
(PPh3)2 catalyst (5 mol%, 1.5 mg) in dry DMF (0.5 mL) under a 8H, 3 × CH2Ph + 7-H + 8-H), 4.91–4.98 (m, 1H, 6-H), 7.25–7.36
N2 atmosphere. The reaction mixture was again heated up to (m, 15H, ArH), 7.56 (s, 1H, 4-H); 13C NMR (50 MHz, CDCl3):
120 °C for 20 minutes. The resulting reaction mixture was δ 60.63 (CH, 6-C), 69.11 (CH2, 9-C), 69.23 (CH, 8-C), 71.57
diluted with water. The aqueous layer was extracted with ethyl (CH2, CH2Ph), 72.76 (CH2, CH2Ph), 73.49 (CH2, CH2Ph),
acetate, dried with Na2SO4 and concentrated under vacuum. 81.16 (CH, 7-C), 125.18 (CH, 4-C), 127.80–128.78 (ArC),
The residue was purified by silica gel column chromatography 136.87–137.96 (Cq, ArCq + 5-C); IR (neat, cm−1) 3436, 1635,
to furnish 15a as pale brown oil (15 mg, 90% from 9c).
Analytical data of 15a: pale brown liquid, the eluent for measured 464.1917.
column chromatography: EtOAc–hexane (3/7, v/v); [α]D28
(4R,5S,6S)-6-(Hydroxymethyl)-5,6-dihydro-4H-pyrrolo[1,2-c]-
772; ESI-HRMS m/z [M + Na]+: calcd for C27H27N3O3 464.1945,
=
−28.19 (c 0.34 CHCl3); Rf 0.19 (2/3, EtOAc–hexane); 1H NMR [1,2,3]triazole-4,5-diol (17a). Conventional catalytic hydrogen-
(300 MHz, CDCl3): δ 3.92–3.96 (m, 1H, 9-Ha), 4.24–4.28 (m, 1H, ation of 15a was carried out with Pd(OH)2 in MeOH for 10 h at
9-Hb), 4.43–4.78 (m, 8H, 3 × CH2Ph + 7-H + 8-H), 4.86–4.87 room temperature. Then, the catalyst was filtered over Celite
(m, 1H, 6-H), 7.13–7.15 (m, 2H, ArH), 7.26–7.35 (m, 13H, ArH), and the solvent was removed under reduced pressure and
7.58 (s, 1H, 4-H); 13C NMR (75 MHz, CDCl3): δ 62.76 (CH, 8-C), the residue was purified by silica gel column chromatography
66.04 (CH2, 9-C), 68.96 (CH, 6-C), 71.33 (CH2, CH2Ph), 72.75 to give 17a as a colorless oil (17 mg from 44 mg 15a,
(CH2, CH2Ph), 73.64 (CH2, CH2Ph), 81.87 (CH, 7-C), quantitative).
127.82–128.76 (ArC), 129.46 (CH, 4-C), 136.98 (ArCq), 137.16
Analytical data of 17a: colorless oil, the eluent for column
(ArCq), 137.50 (ArCq), 138.80 (Cq, 5-C); IR (neat, cm−1) 3419, chromatography: MeOH–CHCl3 (3/7, v/v); [α]D28 = −23.60 (c 0.02
2925, 2363, 1637, 771; ESI-HRMS m/z [M + H]+: calcd for CH3OH) Rf 0.5 (3/7, MeOH–CHCl3); 1H NMR (400 MHz,
C27H27N3O3 442.2125, measured 442.2120.
CD3OD): δ 7.68 (s, 1H, 4-H), 5.11 (d, J = 5.4 Hz, 1H, 6-H), 4.78
(4R,5R,6S)-4,5-Bis(benzyloxy)-6-(benzyloxymethyl)-5,6-dihydro- (t, J = 5.2 Hz, 1H, 7-H), 4.46–4.49 (m, 1H, 8-H), 4.25 (dd, J =
4H-pyrrolo[1,2-c][1,2,3]triazole (15b). For synthesis of 15b pro- 2.92, 12.20 Hz, 1H, 9-H), 4.03 (dd, J = 3.2, 12.20 Hz, 1H, 9-H).
cedures r and s were followed. Analytical data of 15b: colorless 13C NMR (100 MHz, CD3OD): 144.05 (Cq, 5-C), 129.14 (4-C),
oil, the eluent for column chromatography: EtOAc–hexane 78.25 (7-C), 68.19 (6-C), 65.96 (8-C), 60.49 (9-C); ESI-HRMS m/z
(3/7, v/v); [α]2D8 = −58.95 (c 0.08 CHCl3); Rf 0.19 (2/3, EtOAc– [M + H]+: calcd for C6H9N3O3 172.07222, measured 172.06881.
1
hexane); H NMR (300 MHz, CDCl3): δ 3.88–3.99 (m, 2H, 9-H),
(4R,5R,6S)-6-(Hydroxymethyl)-5,6-dihydro-4H-pyrrolo[1,2-c]-
4.34–4.46 (m, 2H, CH2Ph), 4.68–4.80 (m, 5H, 2 × CH2Ph + 7-H), [1,2,3]triazole-4,5-diol (17b). The experimental procedure for
4.86–4.89 (m, 1H, 8-H), 5.06 (d, J = 4.8 Hz, 1H, 6-H), 7.13–7.35 synthesis of 17b is the same as that of compound 17a. Analyti-
(m, 16H, ArH + 4-H); 13C NMR (50 MHz, CDCl3): δ 60.28 (CH, cal data of 17b: colorless oil, the eluent for column chromato-
8-C), 66.87 (CH2, 9-C), 72.74 (CH2, CH2Ph), 73.53 (CH2, graphy: MeOH–CHCl3 (3/7, v/v); [α]2D8 = −27.70 (c 0.02 CH3OH)
1
CH2Ph), 73.58 (CH2, CH2Ph), 77.48 (CH, 6-C), 87.39 (CH, 7-C), Rf 0.5 (3/7, MeOH–CHCl3); H NMR (400 MHz, CD3OD): δ 7.64
127.59–128.79 (Ar C + CH), 137.16 (Ar Cq), 137.27 (Ar Cq), (s, 1H, 4-H), 5.08 (d, J = 5 Hz, 1H, 6-H), 4.81–4.82 (m, 1H, 7-H),
137.71 (Ar Cq), 139.06 (Cq, 5-C); IR (neat, cm−1) 3067, 1638, 4.75–4.78 (m, 1H, 8-H), 4.01–4.13 (m, 2H, 9-H).13C NMR
1217, 767; ESI-HRMS m/z [M + H]+: calcd for C27H27N3O3 (100 MHz, CD3OD): 143.35 (Cq, 5-C), 128.59 (4-C), 84.04 (7-C),
442.2125, measured 442.2125.
(4S,5S,6S)-4,5-Bis(benzyloxy)-6-(benzyloxymethyl)-5,6-dihydro- calcd for C6H9N3O3 172.07222, measured 172.07208.
4H-pyrrolo[1,2-c][1,2,3]triazole (16a). For synthesis of 16a pro- (4S,5S,6S)-6-(Hydroxymethyl)-5,6-dihydro-4H-pyrrolo[1,2-c]-
73.04 (6-C), 64.45 (8-C), 60.24 (9-C); ESI-HRMS m/z [M + H ]+:
cedures r and s were followed. Analytical data of 16a: pale [1,2,3]triazole-4,5-diol (18a). The experimental procedure for
yellow syrup, the eluent for column chromatography: EtOAc– synthesis of 18a is the same as that of compound 17a. Analyti-
hexane (3/7, v/v); [α]D28 = −0.42 (c 0.26 CH3OH) Rf 0.19 (2/3, cal data of 18a: colorless oil, the eluent for column chromato-
EtOAc–hexane); 1H NMR (300 MHz, CDCl3): δ 3.82–3.93 graphy: MeOH–CHCl3 (3/7, v/v); [α]D28 = −22.79 (c 0.02 CH3OH)
6866 | Org. Biomol. Chem., 2014, 12, 6855–6868
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
1
Rf 0.5 (3/7, MeOH–CHCl3); H NMR (400 MHz, CD3OD): δ 7.65
G. W. J. Fleet, R. A. Dwek, S. Petursson, N. G. Namgoong,
S. K. Ramsden, G. S. Jacob and T. W. Rademacher, Proc.
Natl. Acad. Sci. U. S. A., 1988, 85, 9229–9233; Anti-tuberculo-
sis (e) J. P. Shilvock, J. R. Wheatley, R. J. Nash,
A. A. Watson, R. C. Griffiths, T. D. Butters, M. Muller,
D. J. Watkin, D. A. Winkler and G. W. J. Fleet, J. Chem. Soc.,
Perkin Trans. 1, 1999, 2735–2745; Against lysosomal storage
disorder (f) See ref. 2a; (g) T. D. Butters, R. A. Dwek and
F. M. Platt, Chem. Rev., 2000, 100, 4683–4696; (h) J. Q. Fan,
S. Ishii, N. Asano and Y. Suzuki, Nat. Med., 1999, 5, 112–
115; (i) F. M. Platt, G. R. Neises, G. Reinkensmeier,
M. J. Townsend, V. H. Perry, R. L. Proia, B. Winchester,
R. A. Dwek and T. Butters, Science, 1997, 276, 428–431;
Against cystic fibrosis ( j) C. Norez, S. Noel, M. Wilke,
M. Bijvelds, H. Jorna, P. Melin, H. DeJonge and F. Becq,
FEBS Lett., 2006, 580, 2081–2086.
(s, 1H, 4-H), 4.92 (d, J = 3.2, 1H, 6-H), 4.67 (t, J = 3.84, 7.64 Hz,
1H, 7-H), 4.37 (dd, J = 3.9, 8.0 Hz, 1H, 8-H), 4.22 (dd, J = 3.9,
12.0 Hz, 1H, 9-H), 4.00 (dd, J = 3.9, 12.0 Hz, 1H, 9-H). 13C NMR
(100 MHz, CD3OD): 143.62 (Cq, 5-C), 128.92 (4-C), 85.11 (7-C),
72.73 (6-C), 69.03 (8-C), 60.81 (9-C). ESI-HRMS m/z [M + H]+:
calcd for C6H9N3O3 172.07222, measured 172.0717.
(4S,5R,6S)-6-(Hydroxymethyl)-5,6-dihydro-4H-pyrrolo[1,2-c]-
[1,2,3]triazole-4,5-diol (18b). The experimental procedure for
synthesis of 18b is the same as that of compound 17a. Analyti-
cal data of 18b: colorless oil, the eluent for column chromato-
graphy: MeOH–CHCl3 (3/7, v/v); [α]2D8 = +12.84 (c 0.14 CH3OH)
1
Rf 0.5 (3/7, MeOH–CHCl3); H NMR (300 MHz, CD3OD): δ 8.37
(s, 1H, 4-H), 5.22 (s, 1H, 6-H), 5.04 (s, 2H, 7-H + 8-H), 4.12 (dd,
J = 18.36, 12.63 Hz, 2H, 9-H). 13C NMR (100 MHz, CD3OD):
143.43 (5-C), 129.01 (4-C), 76.29 (7-C), 65.27 (6-C), 64.27 (8-C),
59.60 (9-C). ESI-HRMS m/z [M + H]+: calcd for C6H9N3O3
172.07222, measured 172.07287.
5 R. Storer, “IminosugarTheraupetics: time for a new look?”
can be found under http://www.maggichurchouseevents.co.
uk/bmcs/Downloads/CBDD-Storer Richard.pdf.
6 B. L. Stocker, E. M. Dangerfield, A. L. Win-Mason,
G. W. Haslett and M. S. M. Timmer, Eur. J. Org. Chem.,
2010, 1615–1637.
Acknowledgements
This work was supported by the Department of Science and
Technology [DST, grant no. SR/SI/OC-17/2010]. We are thankful
to Mr A. K. Pandey for technical assistance, and SAIF, CDRI,
for providing spectral data. I. A., V. K. K. and A. K. S. thank
CSIR for awarding the Senior Research Fellowships. CDRI com-
munication no. 8730.
7 M. E. C. Caines, S. M. Hancock, C. A. Tarling, T. M. Wrodnigg,
R. V. Stick, A. E. Stutz, A. Vasella, S. G. Withers and
N. C. Strynadka, Angew. Chem., Int. Ed., 2007, 46, 4474–4476.
8 A. A. Watson, G. W. J. Fleet, N. Asano, R. J. Molyneux and
R. J. Nash, Phytochemistry, 2001, 56, 265–295.
9 J. Streith, H. Rudyk, T. Tschamber, C. Tarnus, C. Strehler,
D. Deredas and A. Frankowski, Eur. J. Org. Chem., 1999,
893–898.
10 (a) J. V. Ameijde, G. Horne, M. R. Wormald, R. A. Dwek,
R. J. Nash, P. W. Jones, E. L. Evinsonb and G. W. J. Fleet,
Tetrahedron: Asymmetry, 2006, 17, 2702–2712; (b) A. Kato,
E. Kano, I. Adachi, R. J. Molyneux, A. A. Watson, R. J. Nash,
G. W. J. Fleet, M. R. Wormald, H. Kizu, K. Ikedag and
N. Asano, Tetrahedron: Asymmetry, 2003, 14, 325–331.
Notes and references
1 (a) T. M. Gloster and D. J. Vocadlo, Nat. Chem. Biol., 2012,
8, 683–694; (b) T. M. Gloster and G. D. Davies, Org. Biomol.
Chem., 2010, 8, 305–320; (c) B. P. Rempel and S. G. Withers,
Glycobiology, 2008, 18, 570–586; (d) V. H. Lillelund,
H. H. Jensen, X. Liang and M. Bols, Chem. Rev., 2002, 102, 11 (a) P. Thirumurugan, D. Matosiuk and K. Jozwiak, Chem.
515–553; (e) D. L. Zechel and S. G. Withers, Acc. Chem. Res.,
2000, 33, 11–18.
2 (a) P. Compain and O. R. Martin, Iminosugars: From Syn-
Rev., 2013, 113, 4905–4979; (b) G. C. Tron, T. Pirali,
R. A. Billington, P. L. Canonico, G. Sorba and
A. A. Genazzani, Med. Res. Rev., 2008, 28, 278–308.
thesis to Therapeutics Applications, John Wiley, Chichester, 12 H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew. Chem.,
2007; (b) G. Horne, F. X. Wilson, J. Tinsley, D. H. Williams Int. Ed., 2001, 40, 2004–2021.
and R. Storer, Drug Discovery Today, 2011, 16, 107–118; 13 H. Heightman and A. T. Vasella, Angew. Chem., Int. Ed.,
(c) G. Horne and F. X. Wilson, Prog. Med. Chem., 2011, 50, 1999, 38, 750–770.
135–176; (d) R. J. Nash, A. Kato, C. Y. Yu and G. W. J. Fleet, 14 For a recent review on bicyclic hybrid sugars see: R. Lahiri,
Future Med. Chem., 2011, 3, 1513–1521.
A. A. Ansari and Y. D. Vankar, Chem. Soc. Rev., 2013, 42,
5102–5118.
3 A. E. Stutz, Iminosugars as Glycosidase Inhibitors: Nojiri-
mycin and Beyond, Wiley-VCH, Weinheim, Germany, 1999.
4 For various activities of iminosugars: Anti-cancer.
(a) P. E. Goss, M. A. Baker, J. P. Carver and J. W. Dennis,
Clin. Cancer Res., 1995, 1, 935–944; Anti-diabetic
(b) L. Somsak, V. Nagy, Z. Hadazy, T. Docsa and P. Gergely,
15 (a) A. Farrington and L. Hough, Carbohydr. Res., 1974, 38,
107–115; (b) I. Kumar, N. A. Mir, C. V. Rode and
B. P. Wakhloo, Tetrahedron: Asymmetry, 2012, 23, 225–229;
(c) Z. Liu, H. Byun and R. Bittman, J. Org. Chem., 2011, 76,
8588–8598.
Curr. Pharm. Des., 2003, 9, 1177–1189; Antiviral 16 L. V. R. Reddy, V. Kumar, R. Sagar and A. K. Shaw, Chem.
(c) T. M. Block, X. L. Xu, F. M. Platt, G. R. Foster, Rev., 2013, 113, 3605–3631.
W. H. Gerlich, B. S. Blumberg and R. A. Dwek, Proc. Natl. 17 For examples on the synthesis of N-fused triazoles via intra-
Acad. Sci. U. S. A., 1994, 91, 2235–2239; (d) A. Karpas,
molecular cycloaddition reaction see: (a) T. M. Krtille,
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 6855–6868 | 6867

View Article Online
Paper
Organic & Biomolecular Chemistry
C. Fuente, L. Pickering, R. T. Aplin, K. E. Tsitsanou, 21 S. Takano, K. Samizu, T. Sugahara and K. Ugasawara,
S. E. Zographos, N. G. Oikonomakos, R. J. Nash, J. Chem. Soc., Chem. Commun., 1989, 1344–1345.
R. C. Griffiths and G. W. J. Fleet, Tetrahedron: Asymmetry, 22 O. Mitsunobu, Synthesis, 1981, 1–28.
1997, 8, 3807–3820; (b) H. Yanai and T. Taguchi, Tetra- 23 X. Creary, A. Anderson, C. Brophy, F. Crowell and Z. Funk,
hedron Lett., 2005, 46, 8639–8643; (c) F. Dolhem, F. A. Tahli,
J. Org. Chem., 2012, 77, 8756–8761.
C. Lièvre and G. Demailly, Eur. J. Org. Chem., 2005, 5019– 24 L. Zhang, X. Chen, P. Xue, H. H. Y. Sun, I. D. Williams,
5023; (d) S. Hotha, R. I. Anegundi and A. A. Natu, Tetra-
hedron Lett., 2005, 46, 4585–4588; (e) E. Balducci,
K. B. Sharpless, V. V. Fokin and G. Jia, J. Am. Chem. Soc.,
2005, 127, 15998–15999 and references therein.
L. Bellucci, E. Petricci, M. Taddei and A. Tafi, J. Org. Chem., 25 M. M. T. Khan, M. M. Bhadbhade, K. Siddiqui and
2009, 74, 1314–1321; (f) V. S. Sudhir, R. B. N. Baig and
S. Chandrasekaran, Eur. J. Org. Chem., 2008, 2423–2429;
M. R. H. Venkatasubramanian, Acta Crystallogr., Sect. C:
Cryst. Struct. Commun., 1994, 50, 502–504.
(g) V. S. Sudhir, N. Y. P. Kumar, R. B. N. Baig and 26 J. R. Johansson, P. Lincoln, B. Norden and N. Kann, J. Org.
S. Chandrasekaran, J. Org. Chem., 2009, 74, 7588–7591; Chem., 2011, 76, 2355–2359.
(h) A. I. Oliva, U. Christmann, D. Font, F. Cuevas, 27 B. J. Ayers, N. Ngo, S. F. Jenkinson, R. F. Martínez,
P. Ballester, H. Buschmann, A. Torrens, S. Yenes and
M. A. Perica’s, Org. Lett., 2008, 10, 1617–1619;
(i) V. Declerck, L. Toupet, J. Martinez and F. Lamaty, J. Org.
Y. Shimada, I. Adachi, A. C. Weymouth-Wilson,
A. Kato and G. W. J. Fleet, J. Org. Chem., 2012, 77, 7777–
7792.
Chem., 2009, 74, 2004–2007; ( j) J. M. Contelles and 28 S. F. Jenkinson, D. Best, A. W. Saville, J. Mui,
M. R. Fernández, Tetrahedron Lett., 2000, 41, 381–384;
(k) X. Zhang, R. P. Hsung and H. Li, Chem. Commun., 2007,
2420–2422.
R. F. Martínez, S. Nakagawa, T. Kunimatsu, D. S. Alonzi,
T. D. Butters, C. Norez, F. Becq, Y. Blériot, F. S. Wilson,
A. C. Weymouth-Wilson, A. Kato and G. W. J. Fleet, J. Org.
Chem., 2013, 78, 7380–7397.
18 (a) F. Gonzalez, S. Lesage and A. S. Perlin, Carbohydr. Res.,
1975, 42, 267–274; (b) R. Sagar, R. Pathak and A. K. Shaw, 29 T. B. Mercer, S. F. Jenkinson, B. Bartholomew, R. J. Nash,
Carbohydr. Res., 2004, 339, 2031–2035.
19 J. Hua;, Z. Y. Jiang and Y. G. Wang, Chin. Chem. Lett., 2004,
15, 1430–1432.
S. Miyauchi, A. Kato and G. W. J. Fleet, Tetrahedron: Asym-
metry, 2009, 2, 2368–2373.
30 L. Gunter and P. Stefan, Carbohydr. Res., 1986, 155, 119–
129.
20 (a) Y. Gao, R. M. Hanson, J. M. Klunder, S. Y. Ko,
H. Masamune and K. B. Sharpless, J. Am. Chem. Soc., 1987, 31 Y. X. Li, M. H. Huang, Y. Yamashita, A. Kato, Y. M. Jia,
109, 5765–5780; (b) R. Sagar, L. V. R. Reddy and A. K. Shaw,
Tetrahedron: Asymmetry, 2006, 17, 1189–1198.
W. B. Wang, G. W. J. Fleet, R. J. Nash and C. Yu, Org.
Biomol. Chem., 2011, 9, 3405–3414.
6868 | Org. Biomol. Chem., 2014, 12, 6855–6868
This journal is © The Royal Society of Chemistry 2014