Ketenimine mediated synthesis of lactam iminosugars: development of one-pot process via tandem hydrative amidation of amino-alkynes and intramolecular transamidation

Article abstract of DOI:10.1016/j.tet.2016.07.036

Cu-catalysed ketenimine mediated multicomponent reaction led to an efficient installation of N-allyl N-sulfonyl amide functionality onto a sugar derived terminal alkyne via intramolecular 3,3 sigmatropic rearrangement of an initially formed N-sulfonyl imi

Full text of DOI:10.1016/j.tet.2016.07.036

Tetrahedron xxx (2016) 1e9
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Ketenimine mediated synthesis of lactam iminosugars:
development of one-pot process via tandem hydrative amidation of
amino-alkynes and intramolecular transamidation
*
Inderpreet Arora, Arun K. Shaw
Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Cu-catalysed ketenimine mediated multicomponent reaction led to an efficient installation of N-allyl N-
sulfonyl amide functionality onto a sugar derived terminal alkyne via intramolecular 3,3 sigmatropic
rearrangement of an initially formed N-sulfonyl imidate. This strategy is further extended to the appli-
cation of hydrative amide synthesis on chiral alkynyl amines followed by in situ intramolecular trans-
Received 7 June 2016
Received in revised form 7 July 2016
Accepted 10 July 2016
Available online xxx
amidation which led to the development of a novel one-pot reaction for the construction of a
iminosugar.
d-lactam
Keywords:
Ó 2016 Elsevier Ltd. All rights reserved.
Amidation
Iminosugar
Ketenimine
Lactams
N-heterocycles
1. Introduction
pathway.4 This analogy corresponds to the mimicry of the transi-
tion state of enzyme catalysed reaction by iminosugars either in
terms of charge or shape or both.5 Charge mimics are anticipated to
replicate the positive charge distribution of the oxocarbenium ion-
like transition state whereas compounds that mimic the planar
geometry of the transition state are classified as Shape mimics. An
important feature of the shape mimics is the presence of a trigonal
centre at the anomeric position and/or the endocyclic oxygen of the
corresponding substrate. Examples of non-iminosugar shape
mimics include glyconohydroximolactam 8 and gluconolactam 9
(Fig. 2) which show low micromolar inhibition of glycosidases and
iminosugar shape mimics 10 (Zanamivir or Relenza) and 11
Iminosugars are monosaccharide mimics with a nitrogen atom
in place of ring oxygen atom.1 Fig. 1 represents some biologically
active polyhydroxylated piperidine iminosugars. Currently counted
amongst the most promising classes of glycosidase inhibitors,2
iminosugars are therapeutically relevant3 largely because of their
ability to act as transition state analogs of glycosidase catalysed
Fig. 1. Representative examples of polyhydroxylated piperidine iminosugars.
* Corresponding author. Fax: þ91 522 2623405; e-mail address: akshaw55@ya-
hoo.com (A.K. Shaw).
Fig. 2. Examples of shape mimics of transition state of glycosyl hydrolases.
http://dx.doi.org/10.1016/j.tet.2016.07.036
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.
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I. Arora, A.K. Shaw / Tetrahedron xxx (2016) 1e9
(Oseltamivir or Tamiflu) which are approved drugs and act against
viral neuraminidases.
derived alkynes and alkynyl amines as one of the components of
a three-component MCR. This would involve generation of sugar
ketenimines followed by their conversion to sugar amides by
trapping them with appropriate nucleophiles. These sugar amides
could then be intramolecularly cyclised for the construction of
lactam iminosugars. To the best of our knowledge, the use of
ketenimine intermediates in sugar chemistry has so far not been
explored. Furthermore, from the synthetic point of view, these
polyhydroxylated lactams can also be exploited for the construc-
tion of iminosugar aglycone mimics through reductive alkylation to
create quaternary centered and C-alkylated iminosugars which
may further be elaborated to bicyclic and spiro templates for the
synthesis of novel second-generation iminosugars.
According to literature reports,6 it is evident from the kinetic
isotopic effect studies that during glycoside hydrolysis the transi-
tion state has various degrees of sp2 hybridisation at the anomeric
carbon. Lactone and lactam sugars have sp2 carbon at the anomeric
centre and thus inhibit glycosidases despite being uncharged which
suggests that these molecules mimic the shape of the transition
state very closely. Additionally the carbonyl group interacts with
the catalytic acid residues thereby enhancing the binding affinity.
Consequently, various lactam iminosugars have been synthesised
and evaluated for glycosidase inhibition.7 Some selected lactam
iminosugars and their activity against glycosidases are represented
in Fig. 3. For example, Isofagomine lactam 14 was found to be
a xylanase inhibitor.8a The X-ray crystallographic studies revealed
that this lactam bound to the enzyme as the amide tautomer.8b
2. Results and discussion
The retrosynthetic strategy for the construction of fagomine
based lactam iminosugar 18 is represented in Scheme 1. Enantio-
pure acetylenes of general structure 21 are easily accessible from
pentoses of type 22 employing Bestmann-Ohira reagent. The pro-
tected acetylene 21 could be used as the alkyne component of N-
sulfonyl ketenimine mediated MCR to yield amide 20. Amide 20 on
deprotection of silyl ether and desulfonylation followed by sub-
sequent cyclisation would furnish N-allylated iminosugar lactam 19
which after required deprotections would yield the desired fag-
omine lactam iminosugar 18.
Fig. 3. Examples of iminosugar lactams as glycosidase inhibitors.
Lactam iminosugars are also known to act as anti-cancer agents.
Inhibitors of both tumor metastasis and tumor angiogenesis are
rapidly emerging as important drug candidates for cancer therapy.
Iminosugars are found to interact with enzymes involved in met-
abolic pathway of glycans responsible for tumor cell invasion and
Scheme 1. Retro-analysis for the synthesis of Fagomine lactam iminosugars.
migration. Sodium
from Nojirimycin is known as a potent competitive
D
-glucuro-
d
-lactam (ND2001) 17 (Fig. 3) derived
-glucor-
M, bovine liver) and in vivo9
b-D
The proposed lactam derivative 36 of L-4-epi-fagomine 35
onidase inhibitor in vitro (IC50 0.18
m
and also inhibits invasion and metastasis of tumor cells.10 Thus,
lactam iminosugars hold promise for new drug candidates for
cancer chemotherapy. A recent report describes N-arylated lactam
iminosugars as potent immunosuppressive agents.11
(Scheme 2) should be accessible from
above described strategy. To begin with,
D
-Ribose according to the
-(ꢀ)-ribose was con-
D
verted to its O-benzyl protected hemiacetal 23 according to liter-
ature procedures.15 The hemiacetal 23 on treating with freshly
prepared Bestmann-Ohira reagent16 and K2CO3 as a base in MeOH
at room temperature for 8e12 h furnished enantiopure terminal
alkyne 24.17 The free hydroxyl group of 24 was protected as silyl
ether using TBDMSCl and imidazole in DCM to give fully protected
alkyne 25 for examining the intramolecular imidate-amide rear-
rangement on carbohydrate derived substrate.18 The key reaction
comprised of the synthesis of N-sulfonylimidate 26 from acetylene
25 via copper-catalysed MCR. For this 25 was treated with p-tol-
uenesulfonyl azide and allyl alcohol using catalytic amount of
copper (I) iodide and Et3N as a base in anhydrous chloroform and
N2 atmosphere at room temperature to yield imidate 26 in 78%
yield (Scheme 2).13a
The allylic imidate 26 was then subjected to a Pd-catalysed
rearrangement to form tertiary amide 27 (Scheme 2) by treating
it with 7e15 mol % of Pd (II) catalyst in DCE whereby it undergoes
3,3 sigmatropic rearrangement to yield N-allyl N-tosyl amide
27.19,20 This efficiency of this transformation was explored with two
palladium catalysts viz. bis(acetonitrile)palladium (II) chloride,
Ketenimines, the imine analogues of ketenes, are an important
class of reactive species and useful synthetic intermediates. Except
for a few isolable ketenimines, these species are exceptionally labile
and mostly prepared in situ as reactive intermediates followed by
their use in one-pot reactions. They have been reported to undergo
nucleophilic additions, radical additions, cycloaddition reactions,
electrocyclic ring closure reactions and sigmatropic rearrange-
ments.12 Various methodologies involving these intermediates
have been utilised to construct complex organic compounds and
biologically attractive heterocycles. One of the interesting applica-
tions of ketenimines demonstrated by Chang and co-workers is the
synthesis of amides via a copper-catalysed MCR involving the in-
termediacy of N-sulfonyl imidates.13
Our recent efforts in the construction of conformationally re-
stricted iminosugars as glycosidase inhibitors gained success.14
Inspired by the activity of lactam iminosugars and reactivity of
ketenimine intermediates to form amides, we intended to install
the amide functionality onto sugar motifs employing carbohydrate
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I. Arora, A.K. Shaw / Tetrahedron xxx (2016) 1e9
3
Scheme 2. Attempted synthesis of L-4-epi-fagomine.
PdCl2(CH3CN)2 and bis(benzonitrile)palladium (II) dichloride,
PdCl2(C6H5CN)2. The former palladium catalyst gave better yield in
this case with lower catalyst loadings (7 mol % for PdCl2(CH3CN)2
and 15 mol % for PdCl2(C6H5CN)2). An excess of catalyst loading or
stirring for a prolonged time led to reduced yield due to formation
of by-products. The rearranged product 27 could not be distin-
guished from its precursor 26 solely on the basis of TLC, 1H NMR
spectrum and HRMS. For imidate 26, the 13C NMR signal for oxygen
completely characterised by its 1H and 13C NMR spectra which
showed the disappearance of signals for allylic functionality and
thus indicated that deallylation had taken place presumably due to
the nucleophilicity of chloride ions from chloromethanesulfonyl
chloride.
The structure was initially assigned as a cyclised product 30 on
the basis of further support from DEPT and 2D spectra. However,
the observed HRMS of product 30 was not in agreement with the
calculated value (For compound 30, the observed peak corre-
sponding to [MþH]þ ion was 433.1981 and was one unit more than
the expected [MþH]þ ion peak calculated 431.2097 for C27H29NO4)
which indicated that O-cyclisation has taken place instead of N-
cyclisation. This could be attributed to the ambident nature of the
amide functionality. The actual product formed was indicated to be
32 ([MþH]þ calculated 433.2010 for C27H28O5) which could have
been formed by the initial formation of cyclic imidate 31 which is
prone to hydrolysis under aqueous work up conditions.
bonded methylene carbon of O-allyl group appeared at
13C NMR spectrum. For amide 27 this signal disappeared and in-
stead a new signal appeared at 48.72 which corresponds to the
d 69.31 in
d
nitrogen bonded methylene carbon of N-allyl group. Structure of
amide 27 was thus assigned on the basis of 13C and 2D NMR
(Supplementary data).
The desulfonylation of N-sulfonyl functionality of amide 27 was
then affected with sodium naphthalenide in THF at ꢀ78 ꢁC under
inert conditions whereby complete disappearance of starting ma-
terial was observed in 15e20 min. The crude desulfonylated
product 28 can be used without further purification for the silyl
ether deprotection to furnish N-allylated tertiary amide 29. When
the free hydroxyl group of 29 was activated by its esterification
either with methanesulfonyl or chloromethanesulphonyl chloride,
formation of a single product was indicated (TLC). This product was
To confirm this, the so formed product 32 was subjected to LAH
reduction followed by debenzylation to afford 34. The 1H NMR of 34
did not match exactly with the supposed natural product, L-4-epi-
fagomine, 35. Thus 32 was identified to be a pyranone which on
LAH reduction gave protected pyran 33 which on subsequent
debenzylation led to the formation of a pyran 34 whose structure
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I. Arora, A.K. Shaw / Tetrahedron xxx (2016) 1e9
has not been previously reported in literature. The ambident nature
of amide during its cyclisation onto alkene21 and alkynes22 and
methods for regioselective N- or O-cyclisation is well documented
in literature and is a current field of explorations.
In continuation of our present efforts for application of MCRs for
the synthesis of lactam type iminosugars, we tried the direct
hydrative amide synthesis on alkynes. In this process water (in-
stead of allyl alcohol) was employed as a nucleophile to trap the
intermediate ketenimine to form amide directly from terminal
alkynes.13b The application of this process to terminal alkyne with
free hydroxyl group 17 led to the formation of desired amide in very
low yield. When silyl ether protected terminal alkyne 25 was used,
the desired amide was formed but on further deprotection of silyl
ether functionality, the product obtained degraded on column
purification. Similarly, when O-sulfonylated (mesylated/chlor-
omesylated) alkyne substrates were subjected to similar reaction
conditions, it formed a mixture of two inseparable products in low
yield.
Since, the application of hydrative amide synthesis on variously
modified alkyne substrates did not yield any promising result as
described above, we turned our attention to the hydration of amino
substituted alkynes to form amino-amides. Since amino-amides are
prone to intramolecular transamidation reaction25 under base
catalysed conditions, we envisioned a one-pot procedure where the
application of hydrative amide synthesis on alkynyl amine 38
would lead to the generation of amino-amide 40 with a concomi-
tant base-mediated intramolecular aminolysis (transamidation) at
room temperature yielding the protected lactam ring 30 in a one-
pot fashion (Scheme 3).
Discouraged by the above results, we switched over to another
cyclisation strategy which would involve oxidation of the second-
ary hydroxyl functionality of 29 to a ketone and simultaneous in
situ generation of a cyclic N-acyliminium ion 37.23 For this purpose,
oxidation under Albright Goldman conditions24 was considered to
be a method of choice for our sterically crowded substrate. Thus 29
was treated with a large excess of acetic anhydride in DMSO and the
reaction mixture was either warmed to 40 ꢁC for 2 h or allowed to
stir at room temperature for 8e10 h. This led to the formation of
cyclic N-allylated N-acyliminium ion 37 whose mass was confirmed
by its HRMS data ([M]þ calculated for C30H32NOþ4 470.2326 ob-
served 470.2331). This N-acyl iminium ion was then reduced with
NaCNBH3 under acidic conditions using formic acid. This reaction
proceeded with a concomitant deallylation to afford protected
lactam iminosugar 30 as the major diastereomer. Lactam 30 was
then debenzylated with H2 in the presence of a catalytic Pd(OH)2/C
in MeOH to yield the desired L-4-epi-fagomine lactam 36 (90% from
30) (dr 89:11). For compound 30 NOESY correlations between H4
and H6 (Fig. 4) established the stereochemistry at C-6 and thus the
stereochemical outcome of NaCNBH3 reduction of N-acyliminium
ion to form 30 as the major isomer can be explained as shown in
Fig. 5.
Fig. 4. (a) Selected NOESY interactions for L-4-epi-fagomine lactam 36. (b) NOESY
expansion of 36 showing correlation between H4 and H6.
Scheme 3. Synthesis of L-4-epi-fagomine.
We envisaged two different routes for the one-pot process. First
route involved the conversion of alkyne functionality of amino-
alkyne 38 to amide 40 with in situ base catalysed transamidation
to form lactam 30 (Scheme 4). An alternative pathway would in-
volve conversion of alkyne functionality of azido-alkyne 39 to
azido-amide 41 followed by Staudinger ligation26 that would again
lead to in situ base mediated transamidation and hence formation
of lactam 30.
Fig. 5. Hydride ion attack on N-acyliminium ion 37 is favoured from the
iminium ion double bond to form 30 as a predominant product.
b-face of the
The N-acyliminium ion on reduction with hydride ion gives
a mixture of 30 and 300 (with concomitant deallylation) of which
30 is the predominant product formed which implicates the
steric features of the transition state of the hydride addition to
the intermediate 37. The allylic 1,2 strain owing to C5-OBn and
R (]CH2OBn) in the transition state 37 (Fig. 5) favours the ap-
To accomplish this we synthesised the suitable alkynyl amine
substrate 38 starting from -ribose derived alkyne 24 (Scheme 5).
D
For this, the terminal alkyne 24 was subjected to Mitsunobou27
amination reaction conditions whereby it was treated with
2 equiv each of phthalimide, TPP and DIAD (diisopropyl azodi-
carboxylate) in dry THF under inert conditions to obtain the desired
inverted phthalimido substituted alkyne 42 as a single stereoiso-
mer. Complex 42 was column purified (65% from 24) and sub-
proach of the hydride ion from the
b-face of the iminium ion
double bond. Its approach from -face of the iminium ion double
a
28
bond will find steric crowding due to the axial C4-OBn and car-
bonyl functionality thus resulting in the formation of 30 as the
major product. The enzyme inhibition studies of lactam iminosu-
gar 36 and its reduction to natural product 35 are currently
underway.
sequently hydrolysed by treating with MeNH2 (40% aq soln) for
48 h to yield the required alkynyl amine 38. Alternatively, the free
hydroxyl functionality of 24 was esterified to 43 with chlor-
omethanesulfonyl chloride. Compound 43 was then subjected to
azidation by refluxing with NaN3 in DMF at 80 ꢁC for 4 h to obtain
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I. Arora, A.K. Shaw / Tetrahedron xxx (2016) 1e9
5
Scheme 4. Strategy for the synthesis of lactam 30 via one-pot reaction from alkynyl amine 38 (Path a) through intermediate amino-amide 40 or a sequential process from azido-
alkyne 39 through intermediate azido-amide 41 (Path b).
Scheme 5. Synthesis of N-sulfonyl lactam 44.
the azido-alkyne 39. Refluxing 39 with TPP, H2O and THF under
Staudinger ligation conditions afforded 38 in 75% yield.
sulfonylated cyclised product 44 whose structure was later con-
firmed by NMR analysis. However, when 39 was subjected to
hydrative amidation via similar method as described for alkynyl
amine 38, it led to the formation of azido-amide 41 with low yields
and thus the method (Path b, Scheme 4) was not suitable for further
transformations.
The formation of 44 can be explained by the initial formation of
the N-sulfonyl amide 40 under reaction conditions from the alkynyl
amine 38, which then undergoes a base catalysed intramolecular
transamidation reaction to form cyclic amidine 45 (Scheme 6). At
This alkynyl amine 38 was then treated with p-toluenesulfonyl
azide, water and CuI in CHCl3 at room temperature under N2 en-
vironment followed by slow addition of Et3N and was allowed to
stir till complete disappearance of starting material as monitored
by TLC.13b To our surprise, we obtained a product whose mass
neither corresponded to the N-sulfonyl amide product 40 (Scheme
4) nor to the expected cyclised product 30 that would have been
formed via one pot sequence. It rather corresponded to the N-
Scheme 6. Explanation for the formation of 44 from 38 involving 1, 3 N, N0 sulfonyl migration followed by hydrolysis of intermediate cyclic amidine 46.
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I. Arora, A.K. Shaw / Tetrahedron xxx (2016) 1e9
this stage 1, 3 N, N0 intramolecular tosyl migration takes place to
form a rearranged cyclic amidine 46 whose hydrolysis then takes
place which involves the formation of a tetrahedral intermediate
47. This cyclic hemi-orthoamide 47 cleaves to amino-amide 48 first
(kinetic product) which then cyclises to N-sulfonyl lactam 44
(thermodynamic product).29
clear oil which on column purification yielded 25 (662 mg, 98%
from 24). Analytical data of 25: Colorless oil, eluent for column
28
chromatography: EtOAc/Hexane (1/49, 1/49 v/v); [
a
]
D
¼þ37.13 (c
0.00400 CHCl3); Rf 0.8 (1/4, EtOAc/Hexane); 1H NMR (400 MHz,
CDCl3):
d
0.03 (s, 6H), 0.82 (s, 9H), 2.52 (d, J¼2.2 Hz, 1H), 3.52e3.61
(m, 2H), 3.8H (dd, J¼6.9, 4.0 Hz, 1H), 3.99e4.03 (m, 1H), 4.44 (s, 2H),
4.50e4.54 (m, 2H), 4.67 (d, J¼11.4 Hz, 1H), 4.90 (q, J¼11.3 Hz, 2H),
3. Conclusions
7.25e7.38 (m, 15H); 13C NMR (100 MHz, CDCl3):
d
ꢀ4.9, ꢀ4.1, 18.2,
26.0, 71.0, 71.10, 72.3, 73.4, 74.6, 75.8, 80.5, 81.2, 127.6e128.5, 137.8,
138.5, 138.8; IR (neat, cmꢀ1) 3397, 1631, 1403, 1217, 770; ESI-HRMS
m/z [MþH]þ: calcd for C33H42O4Si 531.2925, measured 531.2923.
In summary, the application of
a copper-catalysed MCR
employing carbohydrate derived terminal alkynes as one of the
components led to the efficient installation of N-sulfonyl amide
functionality on sugar substrates. The transformation of this sugar
amide into sp2 iminosugar, L-4-epi-fagomine lactam 36 was ach-
ieved, which shall be evaluated for glycosidase inhibition to ex-
plore the effect of sp2 carbon at anomeric position. Lactam
iminosugars of this type are synthetically useful intermediates as
they are amenable to the construction of bicyclic, multibranched
and spiro iminosugars in addition to N-alkylated and C-alkylated
analogues. This feature opens up the possibility to synthesize and
explore a range of structurally modified iminosugars for biological
evaluation from a single template. The intramolecular reactions of
the N-acyliminium ions have been widely used in the stereo-
controlled syntheses of a variety of nitrogen heterocycles. Our
current efforts involve exploitation of intermediate endocyclic N-
allyl N-acyliminium ion 30 for the construction of bicyclic hybrid
iminosugars.
4.3. (3S,4S,5R,Z)-Allyl3, 4, 6-tris (benzyloxy)-5-(tert-butyldi-
methylsilyloxy)-N-tosylhexanimidate (26)
To a stirred mixture of protected alkyne 25 (472 mg, 0.89 mmol),
p-toluenesulfonyl azide (0.16 mL, 1.07 mmol), allyl alcohol
(0.072 mL, 1.07 mmol) and CuI (16.9 mg, 0.089 mmol) in CHCl3
(5.0 mL) was slowly added Et3N (0.12 mL, 0.89 mol) at room tem-
perature under N2 atmosphere. After stirring the reaction mixture
for 12 h at room temperature, it was diluted with CH2Cl2 and then
with aqueous NH4Cl solution. The mixture was stirred for an addi-
tional 10 min at room temperature and two layers were separated.
The aqueous layer was extracted with CH2Cl2 and the combined
organic layers were dried over Na2SO4 and evaporated under re-
duced pressure to obtain clear oil which on column purification
yielded 26 (526 mg, 78% from 25). Analytical data of 26: Colorless
The application of hydrative amide synthesis on chiral alkynyl
amine followed by in situ transamidation led to the development of
oil, eluent for column chromatography: EtOAc/Hexane (3/47, v/v);
28
a novel one-pot reaction for the construction of N-sulfonyl
d-lac-
[a]
¼ꢀ6.33 (c 0.00366 CHCl3); Rf (0.46, 1/9 EtOAc/Hexane); 1H
D
tams from alkynes. The application of this one-pot process to
construct lactams of various ring sizes in general, its substrate
scope and synthesis of iminosugar lactams in particular is currently
underway.
NMR (400 MHz, CDCl3): d 0.14 (s, 6H), 0.98 (s, 9H), 2.46 (s, 3H), 3.23
(dd, J¼15.4, 4.6 Hz, 1H), 3.60e3.73 (m, 3H), 3.86 (t, J¼4.7 Hz, 1H),
4.05e4.15 (m, 1H), 4.39e4.64 (m, 7H), 4.73e4.85 (m, 2H), 5.22e5.29
(m, 2H), 5.77e5.87 (m, 1H), 7.26e7.42 (m, 17H), 7.85 (d, J¼8.2, 2H);
13C NMR (100 MHz, CDCl3):
d
ꢀ4.7 (CH3), ꢀ4.3 (CH3), 18.3 (Cq), 21.7
4. Experimental section
4.1. General methods
(CH3), 26.1 (CH3), 35.7 (CH2), 69.2 (CH2), 72.1 (CH2), 72.3 (CH2), 72.4
(CH), 73.5 (CH2), 73.7 (CH2), 76.8 (CH), 81.3 (CH), 119.7 (CH2), 126.9
(CH), 127.5e128.4 (ArC), 129.4 (CH), 131.2 (CH), 138.4 (ArCq), 138.5
(ArCq), 138.8 (ArCq), 139.4 (ArCq), 143.1 (ArCq), 173.8 (Cq). IR (neat,
cmꢀ1) 3411, 1642, 1403, 1216, 699, 669; ESI-HRMS m/z [MþH]þ:
calcd for C43H55NO7SSi 758.3541, measured 758.3525.
Organic solvents used in the present study were dried by stan-
dard methods. All the products were characterized by 1H, 13C, two-
dimensional heteronuclear single quantum coherence (HSQC), IR
and ESI-MS. NMR spectra of the synthesized compounds were
recorded in CDCl3 at 25ꢁ at 400 MHz (1H) and 100 MHz (13C), re-
4.4. (3S,4S,5R)-N-Allyl-3, 4, 6-tris (benzyloxy)-5-(tert-butyldi-
methylsilyloxy)-N-tosylhexanamide (27)
spectively. Chemical shifts are given on the
d scale and are refer-
enced to the TMS at 0.00 ppm for proton and 0.00 ppm for carbon.
Reference CDCl3 for 13C NMR appeared at 77.20 ppm. Optical ro-
tations were determined using a 1 dm cell at 28 ꢁC in chloroform as
solvent; concentrations mentioned are in g/100 mL. Analytical TLC
was performed on 2.5ꢂ5 cm plates coated with a 0.25 mm thick-
ness of silica gel (60F-254), and the spots were visualized with
CeSO4 (1% in 2 N H2SO4) followed by charring over hot plate. Silica
gel (100e200 and 230e400 mesh) was used for column chroma-
tography. Low-temperature reactions were performed by using
immersion cooler with ethanol as the cooling agent.
A
mixture of imidate 26 (200 mg, 0.26 mmol) and
PdCl2(CH3CN)2 (6 mg, 0.02 mmol) in 1,2-dichloroethane (4 mL) was
stirred for 2 h at room temperature. The organic solvent was
evaporated under reduced pressure and the crude residue was
purified by flash column chromatograph to give the desired prod-
uct 27 (196 mg, 98% from 26). Analytical data of 27: Colorless oil,
eluent for column chromatography: EtOAc/Hexane (1/25, v/v);
28
[a
]
¼ꢀ21.25 (c 0.00360 CHCl3); Rf (0.46, 1/9 EtOAc/Hexane); 1H
D
NMR (400 MHz, CDCl3): d 0.06 (s, 3H), 0.07 (s, 3H), 0.91 (s, 9H), 2.37
(s, 3H), 2.28 (dd, J¼16.8, 2.6 Hz, 1H), 3.09 (dd, J¼16.8, 9.3 Hz, 1H),
3.53e3.62 (m, 2H), 3.73e3.76 (m, 1H), 3.95 (dd, J¼9.6, 4.9 Hz, 1H),
4.30e4.34 (m, 1H), 4.93e4.64 (m, 8H), 5.20e5.30 (m, 2H),
5.83e5.92 (m, 1H), 7.13e7.16 (m, 4H), 7.26e7.37 (m, 13H), 7.80 (d,
4.2. tert-Butyldimethyl((2R,3S,4S)-1,3,4-tris(benzyloxy)hex-5-
yn-2-yloxy)silane (25)
To a stirred solution of 24 (530 mg, 1.27 mmol) in DCM (10 mL),
was added imidazole (370 mg, 5.43 mmol) and tert-butyl dime-
thylsilylchloride (530 mg, 150.72 mmol) at 0 ꢁC and the reaction
mixture was allowed to stir for 2 h. On completion, the reaction
was quenched with aqueous NH4Cl solution. The reaction mixture
was extracted with DCM. The extracted organic layer was dried
over Na2SO4 and evaporated under reduced pressure to obtain
J¼8.2 Hz, 2H); 13C NMR (100 MHz, CDCl3):
ꢀ4.7 (CH3), ꢀ4.3 (CH3),
d
18.3 (Cq), 21.7 (CH3), 26.1 (CH3), 38.4 (CH2), 48.7 (CH2), 72.2 (CH2),
72.4 (CH), 72.7 (CH2), 73.5 (CH2), 73.8 (CH2), 77.0 (CH), 80.7 (CH),
118.1 (CH2), 127.5e128.5 (ArC), 129.6 (CH), 133.1 (CH), 137.0 (ArCq),
138.4 (ArCq), 138.7 (ArCq), 138.8 (ArCq), 144.5 (ArCq), 171.8 (Cq); IR
(neat, cmꢀ1) 4305, 3019, 2929, 1643, 1216, 669; ESI-HRMS m/z
[MþH]þ: calcd for C43H55NO7SSi 758.3541, measured 758.3513.
Please cite this article in press as: Arora, I.; Shaw, A. K., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.07.036

I. Arora, A.K. Shaw / Tetrahedron xxx (2016) 1e9
7
4.5. (3S,4R,5R)-N-Allyl-3, 4, 6-tris (benzyloxy)-5-
hydroxyhexanamide (29)
completion, H2O and a 15% aqueous NaOH solution were succes-
sively added to the mixture. The resulting mixture was filtered over
a Celite pad and the filtrate was concentrated to afford a viscous
liquid which on purification by column chromatography yielded 33
as a clear oil (25 mg, 45.4% from 32). Analytical data of 33: Col-
To a solution of naphthalene (422 mg, 3.2 mmol) in dry THF
(12 mL), sodium (94 mg, 4.1 mmol) was added at room tempera-
ture. The reaction mixture was stirred at room temperature for 1 h.
A deep green color appeared. Then the stirring was stopped and the
solution was allowed to stand for 30 min. N-sulfonyl amide 27
(248 mg, 0.32 mmol) was dissolved in THF (10 mL) and cooled to
ꢀ78 ꢁC. Then the Na-naphthalenide solution that was prepared
initially was cannulated into it with stirring. After 15 min, the re-
action was quenched with H2O (5 mL) and extracted with EtOAc.
EtOAc layer was washed sequentially with H2O, brine and dried
over anhydrous Na2SO4. The reaction mixture was concentrated in
vacuo to obtain 28 (Rf (0.2, 1/9 EtOAc/Hexane)) which can be col-
umn purified (eluent for column chromatography: EtOAc/Hexane
(1/9, v/v)) or can be used as such for silyl ether deprotection.
Compound 28 (140 mg, 0.2 mmol) was dissolved in dry THF (7 mL),
cooled to 0 ꢁC and TBAF (0.67 mL, 1.0 M solution in THF) was slowly
added. The mixture was allowed to stir at room temperature for 2 h.
After completion of the reaction, the reaction mixture was
quenched with water; THF was evaporated, extracted with CHCl3,
dried over Na2SO4 and concentrated under reduced pressure. The
residue on purification by silica gel column chromatography
afforded 29 as a clear liquid (101 mg, 62.7% from 27). Analytical
orless oil, eluent for column chromatography: EtOAc/Hexane (1/19,
28
v/v); [
a]
¼ꢀ13.31 (c 0.29 CHCl3); Rf (0.4, 3/7 EtOAc/Hexane); 1H
D
NMR (400 MHz, CDCl3):
d 1.86e1.99 (m, 2H), 3.56e3.59 (m, 2H),
3.73e3.80 (m, 3H), 3.90e3.94 (m, 1H), 3.98e3.99 (m, 1H),
4.51e4.62 (m, 4H), 4.78 (dd, J¼11.3, 36.0 Hz, 2H), 7.28e7.39 (m,
15 H); 13C NMR (100 MHz, CDCl3):
d 33.4 (CH2), 60.2 (CH2), 70.2
(CH), 71.2 (CH2), 72.8 (CH2), 73.6 (CH2), 74.2 (CH2), 78.5 (CH), 79.4
(CH), 128.0e128.7 (ArC), 138.0 (ArCq), 138.1 (ArCq), 138.1 (ArCq); IR
(neat, cmꢀ1) 3390, 1443, 1217, 772, 669; ESI-HRMS m/z [MþH]þ:
calcd for C27H30O4 419.2217, measured 419.2175.
4.8. (2S,3S,4S)-2-(Hydroxymethyl) tetrahydro-2H-pyran-3,4-
diol (34)
Conventional catalytic hydrogenation of 33 was carried out with
Pd(OH)2 in MeOH for 10 h at room temperature. Then, the catalyst
was filtered over Celite and the solvent removed under reduced
pressure and residue was purified by silica gel column chroma-
tography to give 34 as a colorless oil (8 mg, 91% from 33). Analytical
data of 29: Colorless oil, eluent for column chromatography:
data of 34: Colorless oil, eluent for column chromatography:
28
28
EtOAc/Hexane (3/7, v/v); [
a
]
D
¼þ27.54 (c 0.00210 CHCl3); Rf (0.2, 3/
MeOH/CHCl3 (3/17, v/v); [
a
]
¼ꢀ14.80 (c 0.35 CHCl3); Rf (0.5, 3/7
D
7 EtOAc/Hexane); 1H NMR (400 MHz, CDCl3):
d
2.48e2.59 (m, 2H),
MeOH/CHCl3); 1H NMR (400 MHz, CD3OD):
d 1.67e1.74 (m, 1H),
3.49 (dd J¼9.6, 5.8 Hz, 1H), 3.57 (dd, J¼9.7, 3.0 Hz, 1H), 3.67 (dd,
J¼7.8, 2.5 Hz, 1H), 3.71e3.78 (m, 3H), 4.22e4.25 (m, 1H), 4.40e4.51
(m, 4H), 4.58e4.71 (m, 2H), 4.97e5.07 (m, 2H), 5.62e5.72 (m, 1H),
5.93 (br s, 1H), 7.16e7.27 (m, 15H); 13C NMR (100 MHz, CDCl3):
1.96e2.04 (m, 1H), 3.5 (dd, J¼7.4, 2.7 Hz, 1H), 3.65e3.73 (m, 2H),
3.75e3.86 (m, 3H), 3.93e3.97 (m, 1H); 13C NMR (100 MHz, CD3OD):
d
34.7 (CH2), 58.6 (CH2), 63.1 (CH2), 68.2 (CH), 70.5 (CH), 73.5 (CH);
IR (neat, cmꢀ1) 3405, 3391, 786, 668; ESI-HRMS m/z [MþH]þ: calcd
d
29.9, 37.9, 42.1, 70.4, 71.4, 72.6, 73.6, 73.9, 77.7, 79.8, 116.6,
for C6H12O4 149.0808, measured 149.0793.
127.9e128.6, 134.2, 138.1, 138.2, 138.4, 171.5; IR (neat, cmꢀ1) 3401,
3019, 2921, 1644, 1216, 699, 669; ESI-HRMS m/z [MþH]þ: calcd for
C
30H35NO5 490.2588, measured 490.2587.
4.9. (4S,5R,6S)-4,5-bis (Benzyloxy)-6-(benzyloxymethyl) pi-
peridine-2-one (30)
4.6. (4S,5S,6S-4,5-bis (Benzyloxy)-6-(benzyloxymethyl) tetra-
hydro-2H-pyran-2-one (32)
A solution of 29 (141 mg, 0.29 mmol) and acetic anhydride
(0.60 mL, 6.38 mmol) in DMSO (1.2 mL) was warmed to 40 ꢁC and
allowed to stir at same temperature for 4 h. The mixture was then
cooled to 0 ꢁC and H2O (2 mL) was added. The mixture was stirred
for another 15 min and then extracted with Et2O. The combined
organic layers were washed with brine, dried over Na2SO4, filtered
and concentrated. The product was used for the next step without
further purification. The resulting liquid was dissolved in CH3CN
(5.5 mL) and formic acid (1.2 mL) was added NaCNBH3 (60 mg,
0.95 mmol) was then added and the mixture heated under reflux
for 3 h. The mixture was then cooled at 0 ꢁC and a 0.1 M aqueous
HCl solution (8 mL) was added. The resulting mixture was poured
into a 1:1 mixture of ethyl acetate/saturated aqueous NaHCO3
(15 mL). The aqueous layer was extracted with ethyl acetate. The
combined organic layers were dried over Na2SO4, filtered and
concentrated. The residue on purification by silica gel column
chromatography afforded 30 as a clear liquid (79 mg, 63.7% over
A solution of compound 29 (100 mg, 0.2 mmol) and chlor-
omethanesulphonyl chloride (0.01 mL, 0.12 mmol) in pyridine
(1.5 mL) was stirred at room temperature for 20 min. On comple-
tion of the reaction, the mixture was diluted with ethyl acetate and
washed with water and brine and dried over Na2SO4 and concen-
trated under reduced pressure. The residue on purification by col-
umn chromatography yielded 32 as a clear oil (48 mg, 54.5% from
29). Analytical data of 32: Colorless oil, eluent for column chro-
28
matography: EtOAc/Hexane (3/17, v/v); [
a
]
D
¼þ4.50 (c 0.00200
CHCl3); Rf (0.5, 3/7 EtOAc/Hexane); 1H NMR (400 MHz, CDCl3):
d
2.78e2.93 (m, 2H), 3.59 (dd, J¼9.2, 5.5 Hz, 1H), 3.66e3.70 (m, 1H),
3.77e3.82 (m, 1H), 4.10 (s, 1H), 4.24e4.27 (m, 1H), 4.37e4.58 (m,
5H), 4.87 (d, J¼11.4 Hz, 1H), 7.18e7.31 (m, 15H); 13C NMR (100 MHz,
CDCl3):
d 33.2, 68.1, 70.5, 70.9, 73.9, 74.5, 74.6, 78.4, 127.7e128.8,
137.5, 137.7, 138.2, 169.2; IR (neat, cmꢀ1) 3400, 3256, 1755, 1631,
1443, 1217, 772; ESI-HRMS m/z [MþH]þ: calcd for C27H28O5
433.2010, measured 433.1981.
two steps from 29). Analytical data of 30: Colorless oil, eluent for
28
column chromatography: EtOAc/Hexane (1/9, v/v); [
a
]
D
¼þ20.14 (c
0.00230 CHCl3); Rf (0.4, 3/7 EtOAc/Hexane); 1H NMR (400 MHz,
CDCl3):
4.7. (2S,3S,4S)-3,4-bis (Benzyloxy)-2-(benzyloxymethyl) tetra-
hydro-2H-pyran (33)
d
2.55 (dd, J¼3.7, 17.7 Hz, 1H), 2.91 (dd, J¼17.7, 5.0 Hz, 1H),
3.69e3.77 (m, 2H), 3.95 (dd, J¼7.8, 2.2 Hz, 1H), 4.00e4.03 (m, 1H),
4.46e4.63 (m, 6H), 4.70e4.74 (m, 1H), 7.24e7.33 (m, 15H); 13C NMR
A solution of 32 (57 mg, 0.13 mmol) in dry THF (3 mL) was
stirred under nitrogen atmosphere 0 ꢁC and LiAlH4 (20 mg,
0.53 mmol) was added dropwise. The reaction mixture was then
brought to room temperature and refluxed for 2 h, until TLC anal-
ysis showed the disappearance of the starting material. After
(100 MHz, CDCl3): d 34.8 (CH2), 68.8 (CH2), 70.0 (CH), 71.7 (CH2),
72.3 (CH2), 72.8 (CH), 73.8 (CH2), 78.0 (CH), 127.9e128.7 (ArC), 137.6
(ArCq), 137.9 (ArCq), 168.9 (ArCq); IR (neat, cmꢀ1) 3407, 3019, 1630,
1155, 669; ESI-HRMS m/z [MþH]þ: calcd for C27H29NO4 431.2169,
measured 431.2097.
Please cite this article in press as: Arora, I.; Shaw, A. K., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.07.036

8
I. Arora, A.K. Shaw / Tetrahedron xxx (2016) 1e9
4.10. (4S,5R,6S)-4,5-Dihydroxy-6-(hydroxymethyl)piperidin-2-
4.13. (4S,5R,6S)-4,5-bis(Benzyloxy)-6-(benzyloxymethyl)-1-
one (36)
tosylpiperidin-2-one (44)
Conventional catalytic hydrogenation of 30 was carried out with
Pd(OH)2 in MeOH for 10 h at room temperature. Then, the catalyst
was filtered over Celite and the solvent removed under reduced
pressure. The residue was purified by silica gel column chroma-
tography to give 36 as a colorless oil (25 mg, 83.3% from 30). An-
alytical data of 36: Colorless oil, eluent for column
chromatography: MeOH/CHCl3 (1/49, v/v); Rf (0.2, 1/4 MeOH/
To a stirred mixture of p-toluenesulfonyl azide (0.17 mL,
1.44 mmol), amino-alkyne 38 (500 mg, 1.2 mmol), H2O (0.02 mL,
1.2 mmol) and CuI (10 mg, mmol) in CHCl3 (1.7 mL) was slowly
added Et3N (0.2 mL, 1.4 mmol) at room temperature under N2 at-
mosphere. After stirring the reaction mixture for 3 h at room
temperature under N2, it was diluted by adding CH2Cl2 (1 mL) and
saturated NH4Cl solution (1.5 mL). The mixture was stirred for ad-
ditional 30 min and two layers were separated. The aqueous layer
was extracted with CH2Cl2. The combined organic layers were dried
over MgSO4, filtered, and concentrated under reduced pressure.
The crude residue was purified by flash column chromatograph on
silica gel to obtain pure 44 as a clear viscous oil (422 mg, 60% from
CHCl3); 1H NMR (400 MHz, CD3OD):
d
2.33 (dd, J¼2.1, 18.0 Hz, 1H),
2.90 (dd, J¼18.0, 6.8 Hz, 1H), 3.57e3.66 (m, 2H), 3.72e3.75 (m, 1H),
4.4 (dd, J¼4.2, 1.6 Hz, 1H), 4.56 (td, J¼1.9, 6.8 Hz, 1H); 13C NMR
(100 MHz, CD3OD):
d 39.1 (CH2), 63.7 (CH2), 68.3 (CH), 72.5 (CH),
90.1 (CH), 178.7 (Cq); IR (neat, cmꢀ1) 3431, 3258, 1711, 1631, 1443,
1217, 772, 669; ESI-HRMS m/z [MþNa]þ: calcd for C6H11NO4
185.0659, measured 185.0422.
38). Analytical data of 44: Colorless oil, eluent for column chro-
28
matography: EtOAc/Hexane (3/7, v/v); [
a
]
D
¼þ23.4985 (c 0.00222
CHCl3); Rf (0.6, 2/3 EtOAc/Hexane); 1H NMR (400 MHz, CDCl3):
d
2.30 (s, 3H), 2.71e2.87 (m, 2H), 3.39 (dd, J¼8.4, 3.7 Hz, 1H),
4.11. 2-((2S,3R,4S)-1,3,4-tris (Benzyloxy) hex-5-yn-2-yl) iso-
indoline-1,3-dione (42)
3.46e3.55 (m, 2H), 3.66e3.70 (m, 1H), 3.87- (m, 1H), 4.37e4.51 (m,
5H), 4.79 (d, J¼11.64, 1H), 7.11e7.28 (m, 17H), 7.69 (d, J¼8.2 Hz, 2H);
13C NMR (100 MHz, CDCl3):
d 21.6 (CH3), 33.1 (CH2), 56.2 (CH), 69.8
A solution of phthalimide (70.6 mg, 0.48 mmol), triphenyl-
phosphine (125 mg, 0.48 mmol), and alkyne 24 (100 mg,
0.24 mmol) in dry THF (2 mL) was cooled to 0 ꢁC under argon at-
mosphere. An ice cooled solution of DIAD (0.09 mL, 0.48 mmol) in
dry THF (0.5 mL) was added dropwise to the solution and then the
reaction mixture was stirred at the same temperature for 2 h and
then at room temperature until complete disappearance of start-
ing material. The reaction mixture was evaporated under reduced
pressure to give a residue, which on column chromatographic
purification provided compound 42 (85 mg, 65% from 24). Ana-
lytical data of 42: Colorless oil, eluent for column chromatogra-
phy: EtOAc/Hexane (1/19, v/v); Rf (0.31, 3/17 EtOAc/Hexane); 1H
(CH2), 71.0 (CH2), 71.2 (CH), 73.8 (CH2), 74.0 (CH2), 74.5 (CH),
126.6e129.4 (ArC), 137.4 (ArCq), 137.6 (ArCq), 137.9 (ArCq) 139.8
(ArCq), 142.7 (ArCq), 164.0 (ArCq); IR (neat, cmꢀ1) 3402, 3021, 1601,
1276, 669, 566; ESI-HRMS m/z [M]þ: calcd for C34H35NO6S
585.2258, measured 585.2384.
4.14. (2R,3S,4S)-1,3,4-tris (Benzyloxy) hex-5-yn-2-yl chlor-
omethanesulfonate (43)
A solution of compound 24 (178 mg, 0.42 mmol) and chlor-
omethanesulphonyl chloride (0.04 mL, 0.44 mmol) in pyridine
(3 mL) was stirred at room temperature for 10 min. After comple-
tion of the reaction, the mixture was diluted with ethyl acetate and
washed with water and brine and dried over Na2SO4 and concen-
trated under reduced pressure. The residue on purification by col-
umn chromatography yielded 43 as a clear oil (200 mg, 88.5% from
NMR (400 MHz, CDCl3):
d 2.60e2.61 (m, 1H), 3.89e3.94 (m, 1H),
4.07e4.12 (m, 1H), 4.34e4.72 (m, 6H), 4.83e4.99 (m, 3H),
7.03e7.12 (m, 4H), 7.22e7.43 (m, 11H), 7.67e7.90 (m, 4H); 13C NMR
(100 MHz, CDCl3):
d 52.4 (CH), 67.0 (CH2), 70.8 (CH), 71.2 (CH2),
72.7 (CH2), 74.3 (CH2), 76.6 (CH), 78.2 (CH), 79.5 (Cq), 123.2 (CH),
127.4e128.5 (ArC), 132.0 (Cq), 133.7 (CH), 137.5 (ArCq), 137.9 (ArCq),
138.0 (ArCq), 168.5 (Cq); IR (neat, cmꢀ1) 3425, 3305, 3019, 1633,
699, 669; ESI-HRMS m/z [MþH]þ: calcd for C35H31NO5 546.2275,
measured 546.2274.
24). Analytical data of 43: Colorless oil, eluent for column chro-
28
matography: EtOAc/Hexane (1/49, v/v); [
a]
¼þ73.7674 (c 0.00622
D
CHCl3) Rf 0.46 (3/17, EtOAc/Hexane); 1H NMR (400 MHz, CDCl3):
d
2.57 (d, J¼2.1, 1H), 3.70e3.80 (m, 2H), 4.02 (dd, J¼3.6 Hz, 1H), 4.25
(dd, J¼2.1 Hz, 1H), 4.45e4.54 (m, 4H), 4.63e4.71 (m, 2H), 4.76e4.84
(m, 2H), 5.19e5.23 (m, 1H), 7.23e7.33 (m, 15H); 13C NMR (100 MHz,
CDCl3):
d 54.3 (CH2), 68.6 (CH), 68.8 (CH2), 71.0 (CH2), 73.6 (CH2),
4.12. (2S,3R,4S)-1,3,4-tris(Benzyloxy)hex-5-yn-2-amine (38)
74.8 (CH2), 76.4 (CH), 79.7 (Cq), 80.4, 84.2 (CH), 128.0e128.7 (ArC),
136.9 (ArCq), 137.4 (ArCq), 137.4 (ArCq). IR (neat, cmꢀ1) 2853, 1606,
1461, 1217, 763; ESI-HRMS m/z [MþH]þ: calcd for C28H30ClO6S
530.1524, measured 530.1529.
A solution of compound 42 (85 mg, 0.16 mmol) in EtOH/H2O
(1:1, 10 mL) was treated with a 40% aqueous solution of methyl
amine (20 equiv) and stirred at room temperature for 48 h. The
reaction mixture was then concentrated under reduced pressure,
dissolved in water, and extracted with ethyl acetate. The combined
organic extracts were washed twice with brine, dried over Na2SO4,
and evaporated under reduced pressure. The residue was sub-
jected to column for purification to obtain pure 38 as a clear oil
(55 mg, 85% from 42). Analytical data of 38: Colorless oil, eluent
4.15. (2R,3R,4S)-1,3,4-tris (Benzyloxy) hex-5-yn-2-yl azide (39)
To a 20 mL two necked oven dried round bottom flask fitted
with
a reflux condenser was added sodium azide (10 mg,
0.156 mmol), sealed with septum and flushed with nitrogen. To this
was added a solution of compound 43 (42 mg, 0.072 mmol) dis-
solved in dry DMF (3 mL) through a syringe under nitrogen at-
mosphere. The reaction mixture was heated to 80 ꢁC for 2 h. After
completion, the reaction mixture was cooled to room temperature
and diluted with water. The aqueous layer was extracted with ethyl
acetate, dried with Na2SO4 and concentrated under vacuum. The
residue was purified by silica gel column chromatography to fur-
nish 39 as a clear oil (30 mg, 80% from 43). Analytical data of 39:
Colorless oil, eluent for column chromatography: EtOAc/Hexane (1/
49, v/v); Rf 0.50 (3/17, EtOAc/Hexane); 1H NMR (400 MHz, CDCl3):
for column chromatography: EtOAc/Hexane (3/2, v/v);
28
[
a
]
¼þ75.1781 (c 0.01731 CHCl3); Rf (0.2, 3/7 EtOAc/Hexane); 1H
D
NMR (400 MHz, CDCl3):
d
2.44 (d, J¼2.08, 1H), 3.20e3.24 (m, 1H),
3.30e3.37 (m, 2H), 3.68 (dd, J¼6.2, 3.1 Hz, 1H), 4.28e4.45 (m, 5H),
4.75e4.83 (m, 2H), 7.41e7.29 (m, 15H); 13C NMR (100 MHz, CDCl3):
d
51.5 (CH), 69.2 (CH), 70.9 (CH2), 72.5 (CH2), 73.3 (CH2), 74.6 (CH2),
80.5 (CH), 81.6 (Cq), 127.8e128.6 (ArC), 137.6 (ArCq), 138.3 (ArCq),
138.5 (ArCq); IR (neat, cmꢀ1) 3399, 3018, 2928, 1935, 698, 668; ESI-
HRMS m/z [MþH]þ: calcd for C27H29NO3 416.2220, measured
416.2220.
d
2.46 (d, J¼2 Hz, 1H), 3.44e3.55 (m, 2H), 3.71e3.79 (m, 2H), 4.25
Please cite this article in press as: Arora, I.; Shaw, A. K., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.07.036

I. Arora, A.K. Shaw / Tetrahedron xxx (2016) 1e9
9
Fassbender, K.; Gulbins, E.; Liu, Y.; Rieschel, M.; Herten, M.; Bertsch, T.; En-
gelhardt, B. J. Neuroimmunol. 2002, 132, 1; (q) Hino, M.; Nakayama, O.; Tsurumi,
Y.; Adachi, K.; Shibata, T.; Terano, H.; Kohsaka, M.; Aoki, H.; Imanaka, J. J. An-
tibiot. 1985, 38, 926; (r) Zhang, L.; Sun, F.; Wang, Q.-L.; Zhou, J.; Zhang, L.-H.;
Zhang, X.-L.; Ye, X.-S. ChemMedChem 2009, 4, 756; (s) Wang, G.-N.; Xiong, Y.;
Ye, J.; Zhang, L. H.; Ye, X. S. ACS Med. Chem. Lett. 2011, 2, 682.
4. Stutz, A. E. Iminosugars as Glycosidase Inhibitors: Nojirimycin and beyond; Wiley-
VCH: Weinheim, Germany, 1999.
(dd, J¼7.3, 2.1 Hz, 1H), 4.34e4.51 (m, 4H), 4.75e4.85 (m, 2H),
7.15e7.27 (m, 15H); 13C NMR (100 MHz, CDCl3):
61.1, 68.7, 69.5,
71.1, 73.6, 75.1, 75.8, 79.7, 81.2, 127.9e128.6, 137.2, 137.8, 137.9; IR
(neat, cmꢀ1) 3400, 2954, 2090, 1219, 766; ESI-HRMS m/z [MþH]þ:
calcd for C27H27N3O3 442.2125, measured 442.2176.
d
5. Gloster, T. M.; Vocadlo, D. J. Nat. Chem. Biol. 2012, 8, 683.
6. Lillelund, V. H.; Jensen, H. H.; Liang, X.; Bols, M. Chem. Rev. 2002, 102, 515.
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Acknowledgements
This work was supported by Department of Science and Tech-
nology [DST, grant No. SB/S1/OC-28/2014]. We are thankful to Mr. A.
K. Pandey for technical assistance, and SAIF, CDRI, for providing
spectral data. I. A. thanks CSIR for awarding Senior Research Fel-
lowship. CDRI manuscript no. 9273.
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