En route to novel furanoside mimics through stereoselective zinc-mediated propargylation of N -benzyl glycofuranosylamines using ultrasound activation

Article abstract of DOI:10.1055/s-0034-1379551

Preliminary results on a novel zinc-mediated, ultrasound-promoted chain extension of glycofuranosylamines with a propargyl group are reported. The procedure was applied to d-arabino and d-xylo substrates to give, via Cram-chelate transition states, 1-C-1-(3-trimethylsilyl-2-propynyl)-1-benzylamino pentionols in moderate to good yields and acceptable stereoselectivities (syn/anti ≥4:1). To apply the reaction to the synthesis of galactofuranoside mimics, the d-xylo intermediate was cyclized to afford a 1-C-1-(2-propynyl)-1,4-dideoxy-1,4-imino-l-arabinitol derivative in excellent yield. This building block was used in three examples of CuAAC click reactions with azide compounds to provide the corresponding galactofuranoside mimics.

Full text of DOI:10.1055/s-0034-1379551

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
©
Georg Thieme Verlag Stuttgart · New York
2015, 26, 187–192
187
letter
Synlett
C. Nicolas et al.
Letter
En Route to Novel Furanoside Mimics through Stereoselective
Zinc-Mediated Propargylation of N-Benzyl Glycofuranosylamines
Using Ultrasound Activation
SiMe3
Cyril Nicolas
H
Br
N
N
Francis Engo-Ilanga
Chloé Cocaud
Olivier R. Martin*
HO
Me3Si
OH
N
O
3 reactions
NHBn
N
THF, 45 °C, 48 h
BnO
BnO
NHBn
OBn
HO
OH
4
2 kHz, 0.47 W/cm2
sonochemistry
Zn dust
+
BnO
OBn
BnO
CuAAC
Institut de Chimie Organique et Analytique, UMR 7311,
Université d’Orléans and CNRS, BP 6759, 45067 Orléans
HO
1
6
R/1S = 8:2
2% (1.5 g)
Galf mimic
cedex 2, France
+
3
3
2
(
3
8
4
)
1
7
2
8
1
olivier.martin@univ-orleans.fr
Received: 24.09.2014
Accepted after revision: 25.10.2014
Published online: 02.12.2014
ing multidrug resistance and the improved knowledge of
bacterial cell glycoconjugates, furanoses and furanosides
are becoming increasingly important structural elements.
Indeed, carbohydrates in the thermodynamically less favor-
able furanose form are absent in mammalian glycoconju-
gates, but are widespread in the glycans produced by many
algae, lichen and marine sponges and, more importantly, in
DOI: 10.1055/s-0034-1379551; Art ID: st-2014-d0798-l
Abstract Preliminary results on a novel zinc-mediated, ultrasound-
promoted chain extension of glycofuranosylamines with a propargyl
group are reported. The procedure was applied to D-arabino and D-xylo
substrates to give, via Cram-chelate transition states, 1-C-1-(3-trimeth-
ylsilyl-2-propynyl)-1-benzylamino pentionols in moderate to good
yields and acceptable stereoselectivities (syn/anti ꢀ4:1). To apply the re-
action to the synthesis of galactofuranoside mimics, the D-xylo interme-
5
several fungi, protozoa and bacterial pathogens. In bacte-
ria, these furanosides are often found in cell-surface glycans
and are essential for viability, virulence and/or integrity of
the organisms. Thus it becomes evident that enzymes pro-
moting the biosynthesis/biodegradation of bacterial fura-
nosides are of general interest as targets to produce novel
selective antimicrobial chemotherapeutics.
diate was cyclized to afford
a 1-C-1-(2-propynyl)-1,4-dideoxy-1,4-
imino-L-arabinitol derivative in excellent yield. This building block was
used in three examples of CuAAC click reactions with azide compounds
to provide the corresponding galactofuranoside mimics.
Key words propargylation, N-benzyl glycofuranosylamines, stereose-
lective synthesis, iminosugars, Huisgen cycloaddition, furanoside mim-
ics
For instance, the major structural component of the
Mycobacterium tuberculosis cell wall, known as the mAGP
complex, contains a galactan chain of approximately 35
6
D-galactofuranose (D-Galf) units, and its biosynthesis is es-
7
Carbohydrates are involved in numerous key biological
processes such as signal transduction, recognition by the
immune system, glycolysis and gluconeogenesis. Carbohy-
sential for viability of the mycobacterium. Typically, UDP-
Galf biosynthesis occurs from uridine diphosphogalactopy-
ranose (UDP-Galp) by the action of UDP-Galp Mutase
1
8
drate-processing enzymes such as glycosidases and glycosyl
transferases are increasingly important targets in medicinal
chemistry, and their inhibitors can be used in therapies di-
rected at cancer, viral infections, lysosomal storage diseas-
es, diabetes, etc.2 In this context, the six-membered ring
form of sugars has so far attracted most attention in the de-
sign of carbohydrate mimics. Nonetheless, as a result of the
increasing demand for original therapeutic agents, emerg-
(UGM), which promotes the ring contraction. In the sec-
ond step, UDP-Galf is converted into a glycoside by the ac-
tion of two galactofuranosyltransferases (e.g., GalfT1 and
GalfT2) usually with inversion of configuration to form a
–4
8,9
ꢀ-glycoside (Scheme 1). Recent elegant bioorganic exper-
iments have underlined the fact that the two biochemical
reactions occur by way of oxocarbenium-like transition
9
,10
states.
O
HO
O
UDP-galactopyranose
OH
UDP-Galf
transferase
HO
HO
mutase
HO
OH
O
HO
O
HO
OH
O-UDP
OH
O
HO
OH
O
O-UDP
UDP-Galf (5–8%)
UDP-Galp (92–95%)
O
OH
cell-wall galactans
HO
Scheme 1 UDP-galactofuranose and galactan biosynthesis
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 187–192

1
88
Synlett
C. Nicolas et al.
Letter
Since iminosugars constitute mimics of such positively
charged transition state,2 our group has focused on the
synthesis of a diversity of 1,4-imino-D-galactitol carrying
C-linked aglycones, designed to mimic UDP-Galf, the sub-
strate of both UGM and GalfTs.12 Of note, the new com-
pounds showed modest inhibitions of UGM but significant
activities towards GalfT2 were observed.13
However, the synthesis of 1,4-iminogalactitol deriva-
tives required the rather tedious preparation of 2,3,5,6-tet-
ra-O-benzyl-D-glucofuranose,12a,b,d,14 and we decided to
continue to work in this area in the pentofuranose series,
the L-arabinofuranose structure being equivalent in ring
configuration to the D-Galf structure. In addition, we sought
a strategy that would allow the rapid tethering of a diversi-
ty of functional groups to the iminopentitol scaffold, in or-
der to access a variety of UDP-Galf mimics, as outlined in
Scheme 2 (see below).
Retrosynthetic analysis from L-arabino iminopentitols
requires a D-xylofuranosylamine as the starting material,
the addition of a metalated species, followed by a cycliza-
tion with inversion at C-4, to generate the desired L-arabino
configuration (Scheme 2).
,11
For initial investigations, and to determine the feasibili-
ty of our methodology, we first selected N-benzyl-2,3,5-tri-
O-benzyl-ꢁ/ꢀ-L-arabinofuranosyl amine 1 as a standard
substrate, this compound being more easily accessible than
its D-xylo isomer, as it can be obtained from commercial
2,3,5-tri-O-benzyl-L-arabinofuranose 2 and an excess of
benzylamine (2 equiv) in anhydrous CH Cl . The alkylation
2
2
process was then investigated (Table 1).
Overall, promoting the reaction by indium gave no
1
7
propargylation at all. Degradation was observed on heat-
ing from 20 °C to 60 °C and some N-propargylation of 1
gave compound 3 which was isolated in 7% yield (entry 1).
1
8
This could be achieved using a propargyl appendage on
the iminopentitol moiety that could be used to connect var-
ious groups by azide-click chemistry or other cycloaddition
processes. Thus, the synthesis of 1-C-(2-propynyl)imino-
pentitols became our first objective. To our knowledge, a
single example of a 1-C-iminosugar featuring a terminal 2-
Addition of propargyl Grignard reagent, prepared using
magnesium turnings under mercury-free catalysis (ZnBr2
catalysis) was not successful either, with a mixture of de-
benzylated 1 and 4 being obtained (entry 2). Copper(I) re-
agents were also considered using Kobayashi conditions,
1
8
but no reaction was detected (entry 3).
1
5
propynyl group has been reported in the literature. How-
ever, in this work by Compain et al., the propargyl group
was generated from an allyl group. In our previous work,
we have shown that the addition of propargyl-TMS in the
presence of TMSOTf to N-CbZ glycosylamines predictably
led to allenyl-substituted derivatives that were cyclized to
Next, reactions with propargyl zinc were examined.
Zinc reagents are known to be less basic than their Grignard
1
9
and copper counterparts and we considered that this
might prevent debenzylation and/or elimination by-prod-
ucts. These reagents are also more reactive than indium-
based reagents, but less so than copper and magnesium de-
12d
19
1
-C-allenyl iminogalactitol derivatives.
We therefore
rivatives. They have been shown to react with N-benzyl
looked for a different methodology that would allow the di-
rect introduction of the propargyl group by an addition to a
glycosylamine, this sequence offering a very concise ap-
glycosylamines to give the corresponding adducts in rea-
2
0
sonable yields. However, in our case, no addition was ob-
served when using zinc dust preactivated with iodine
1
6
21
proach to 1-C-substituted iminosugar derivatives. We re-
port herein our preliminary results on a novel methodology
to produce 1-C-propargyl iminopentitols in moderate
yields and its application to prepare galactofuranoside
mimics. The method involves the stereoselective addition of
a propargylic zinc reagent onto N-benzyl glycofuranosyl-
amines.
(entry 4), LiCl (entry 5) or dilute HCl (entry 6). It should
be noted that glycosylamines are somewhat sensitive to
traces of acid. In the case of I preactivation, 2 was observed
2
among other degradation products. We assumed this to be
due to the formation of Lewis acidic ZnI . Using Et Zn with
2
2
Wilkinson catalyst or CuI to promote zinc insertion, yet
again no propargylation was observed (entries 9 and 10).21
Ultrasound is an efficient and relatively innocuous
2
2
means of activation in synthetic chemistry. Recent re-
2
3
nucleoside mimics
ports, by Suslick in particular, have highlighted the impor-
tance of ultrasound to promote generation of
organometallic reagents and for the activation of zinc pow-
der.
H
Bn
N
N
tether
nucleoside
mimics
HO
BnO
N3
HO
OH
BnO
OBn
Sonication had a very beneficial effect on our system;
when the reaction mixture was partly submerged in a stan-
O
NHBn
2
dard ultrasound laboratory cleaner (0.47 W/cm , 42 KHz) at
BnO
4
0 °C, compound 4 was formed and then isolated in 48%
BnO
OBn
yield with a 9:1 diastereoselectivity (entry 7). Interestingly
similar yields (48% vs. 39%) and diastereoselectivities were
observed when the reactions were carried out under Barbi-
er conditions or by preforming the zinc reagent during two
Scheme 2 Retrosynthetic strategy
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 187–192

1
89
Synlett
C. Nicolas et al.
Letter
Table 1 Optimization of the Propargylation Reaction
SiMe3
Bn
O
N
1
BnO
Br
Me3Si
(3.3 equiv)
BnO
OBn
3
O
O
OH
NHBn
BnNH2 (2 equiv)
1
1
BnO
BnO
+
metal
additive, THF
CH2Cl2, MS., 2 d
69%
BnO
BnO
OBn
BnO
OBn
OBn
2
1
1
HO
BnO
NHBn
SiMe3
4
Entry
Metal (equiv)a
Additive (equiv)
Time (h)
Temp (°C)
Ratio
Yield (%)c
Observation
syn/antib
1
2
3
In (3.3)d
–
48
20
20
20–60
0–20
0–20
–
–
–
–
–
–
1 <15% recovered
3
(7%) + degradation
Mg (6.6)
CuCN (6.9)
ZnBr
ZnBr
2
2
(0.2)
mixture of partially debenzylated 1
and 4
(0.2)
(6.6)
no reaction
MgCl
2
4
5
6
7
Zn (15)d
Zn (10)d
I
2
(0.45)
48
48
48
48
0–40
–
–
1 (60%) + degradation + 2
no reaction
LiCl (10)
–
0–50
–
–
Zn (HCl)d,e (10)
0–50
–
–
no reaction
Zn (15)
I
2
(0.45)
0–45, )))
9:1f
48
4 + degradation
(
procedure A)
8
9
Zn (15)d
I
2
(0.45)
48
0–45, )))
9:1e
39
4 + degradation
procedure B)
(
Et
2
2
Zn (3.3)
Zn (3.3)
RhCl(PPh
3
)
3
(0.05)
72
48
0–50
0–50
–
–
–
–
no reaction
no reaction
1
0
Et
CuI (0.05)
a
b
c
d
e
f
Reactions were carried out on 0.1–0.2 mmol scales of 1.
1
Diastereoselectivity was determined by H NMR analysis.
Isolated yield.
Barbier conditions.
Dilute aq HCl (0.1 M) was used for activation.
We propose (syn)-4 to be the major diastereomer by analogy with compound 6.
hours at 0 °C [see procedure A (entry 7) and procedure B25
24
provide (1R)-9 and (1S)-9 in a 4:1 ratio which were separat-
(
entry 8), respectively]. We assumed the major diastereo-
ed by silica chromatography (ethyl acetate–petroleum ether
1
13
mer to be the (1R)-4 epimer (the syn diastereomer) based
on Cram-chelate control (see Supporting Information and
Scheme 3).26 To validate the method, we reacted N-benzyl-
7:3). Using H NMR, C NMR, correlation spectroscopy
(COSY) and nuclear Overhauser effect spectroscopy (NO-
ESY), compound (1R)-9 (arising from syn-6) was estab-
lished to be the major diastereomer (see Supporting
Information). The Galf derivatives were then synthesized by
CuAAC click chemistry from the parent imino-L-arabinitol 8
and a set of azide derivatives (Scheme 3: 3-azidopropan-1-
ol, path a; benzyl azide, path b; and 1-azido-4-methoxy-
benzene, path c). This small set of molecules was carefully
chosen to ensure a relatively high degree of diversity for fu-
ture potential Galf mimics. The corresponding clicked de-
rivatives 10a–10c were obtained in low to good
unoptimized yields (25%, 67% and 58% for 10a–c, respec-
tively). To finalize the synthetic strategy, compound (R)-10a
was then submitted to hydrogenation for 24 hours at 20 °C
2
,3,5-tri-O-benzyl-D-xylofuranosylamine (5) under the
conditions of procedure A. To our satisfaction, compound 6
was obtained in 62% yield (1.5 g scale) with 4:1 diastereose-
lectivity.27 Compound 6 was cyclized under the typical con-
ditions (mesylation using mesyl chloride in pyridine at 100
°
C) to give 1-C-(3-trimethylsilyl-2-propynyl)imino-L-ara-
binitol 7 in 75% yield. The trimethylsilyl protecting group
was then removed (K CO in MeOH, 20 °C) to afford imino-
2
3
L-arabinitol 8 in 92% yield. No erosion of the diastereoselec-
tivity was noticed. To determine the diastereoselectivity of
the propargylation process, compound 8 was partly hy-
drogenolyzed (H , 2-propanol, Et N, 10% Pd–C, 20 °C) to
2
3
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 187–192

1
90
Synlett
C. Nicolas et al.
Letter
using standard conditions [H2, 20% Pd(OH) /C in AcOH].
Galf mimic based on an imino-ꢁ-L-arabinitol core, a tri-
2
Further Pd(OH) /C was added and the reaction mixture was
azolyl linker and a functionalized chain (vide infra, Equa-
2
2
8
stirred for another 48 hours to afford (R)-11a as a model
tion 1).
Br
BnO
HO
OBn
Me3Si
(3.3 equiv)
O
NHBn
1
1
BnO
BnO
6
NHBn
SiMe3
1
. Zn (15 equiv), I2 (0.45), 0 °C, 2 h
BnO
OBn
. ))) (42 kHz, 0.47 W/cm2)
6
2
5
2% (1.5 g)
THF, 45 °C, 48 h
(1 equiv)
1R/1S = 8:2
procedure A
syn–anti 8:2
MsCl (2.5 equiv)
Pyr, MS (4 Å)
00 °C, 2 h
Me3Si
1
Bn
ZnBr
H
N
Bn
[
M]
N
H
1
BnO
HO
OBn
Cram-chelate T.S.
SiMe3
BnO
OBn
7
5%
H
7
BnO
OBn
1R/1S = 8:2
K2CO3 (1.2 equiv)
MeOH
0 °C, 6 h
HO
N3
3
2
path a
50 min, 20 °C
Bn
N
1
N
RN3 (1.1 equiv)
CuSO4 (0.6 equiv)
Bn
BnO
N
N
N
Ph
N3
1
DMF–H O
2
BnO
BnO
OBn
R
path b
path c
BnO
8
OBn
1R/1S = 8:2
2 h, 20 °C
ONa
HO
O
92%
R/1S = 8:2
1
1
1
0a; R = (CH2)3OH, 25%, path a
0b; R = Bn, 67%, path b
0c; R = 4-MeOC6H4, 58%, path c
OH
1
O
OH
4
-MeOC6H4 N3
H2–Pd/C
Et3N
(0.4 equiv)
50 min, 20 °C
20 °C, 5 d
H
N
4
1
BnO
BnO
H
H
BnO
OBn
N
H
(1R)-9 (33.5%)
OBn
H
BnO
+
main NOE contacts of
compound (1R)-9
H
N
H
H
H
OBn
4
1
BnO
OBn
(1S)-9 (7.4%)
Scheme 3 Synthetic strategy to prepare original Galf analogues using a novel zinc-mediated propargylation and postfunctionalization
In summary, we report herein preliminary results on a
new, convenient method to generate quickly furanoside
mimics based on 1-C-substituted iminopentitol scaffold.
The methodology involves a novel, stereoselective zinc-me-
diated propargylation of N-benzyl glycofuranosylamines
and uses ultrasounds as a critical mode of activation, fol-
lowed by a mesylation, cyclization, cycloaddition and
deprotection sequence. To illustrate this strategy, a 1-C-
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 187–192

1
91
Synlett
C. Nicolas et al.
Letter
1
-(2-propynyl)-1,4-dideoxy-1,4-imino-L-arabinitol scaffold
12, 1455. (c) Evitt, A.; Tedaldi, L.; Wagner, G. K. Chem. Commun.
2
012, 48, 11856. (d) Tedaldi, L.; Wagner, G. K. Med. Chem.
was thus prepared (1.5 g scale) and three galactofuranoside
mimics were generated by CuAAC click chemistry.
Commun. 2014, 5, 1106; and references cited therein.
5) Taha, H. A.; Richards, M. R.; Lowary, T. L. Chem. Rev. 2013, 113,
1851; and references 1–10 cited therein.
(
H
N
N
Bn
(6) Brennan, P. J. Tuberculosis 2003, 83, 91.
7) Pan, F.; Jackson, M.; Ma, Y. F.; McNeil, M. J. Bacteriol. 2001, 183,
991.
1
N
HO
. H2, Pd(OH)2/C
N
N
(
1
BnO
N
N
3
1
HO
OH
N
AcOH, 20 °C, 68 h
(8) Richards, M. R.; Lowary, T. L. ChemBioChem 2009, 10, 1920; and
BnO
OBn
references therein.
2
. Amberlite® IRA-400
(OH– form)
HO
(1R)-11a (81%)
(9) (a) Rose, N. L.; Completo, G. C.; Lin, S.; McNeil, M. R.; Palcic, M.
M.; Lowary, T. L. J. Am. Chem. Soc. 2006, 128, 6721. (b) Breton,
C.; Snajdrova, L.; Jeanneau, C.; Koca, J.; Imberty, A. Glycobiology
2006, 16, 29R. (c) Berg, S.; Kaur, D.; Jackson, M.; Brennan, P. J.
Glycobiology 2007, 17, 35R. (d) Alderwick, L.; Dover, L.;
Veerapen, N.; Gurcha, S.; Kremer, L.; Roper, D.; Pathak, A.;
Reynolds, R.; Besra, G. Protein Expression Purif. 2008, 58, 332.
HO
(1R)-10a
Equation 1 Hydrogenolysis of (1R)-10a to prepare Galf mimic (1R)-11a
Acknowledgment
(e) Szczepina, M. G.; Zheng, R. B.; Completo, G. C.; Lowary, T. L.;
The authors are grateful for financial support from the Centre Nation-
al de la Recherche Scientifique (CNRS) and Labex SynOrg (ANR-11-
LABX-0029).
Pinto, B. M. ChemBioChem 2009, 10, 2052. (f) May, J. F.;
Levengood, M. R.; Splain, R. A.; Brown, C. D.; Kiessling, L. L. Bio-
chemistry 2012, 51, 1148. (g) Levengood, M. R.; Splain, R. A.;
Kiessling, L. L. J. Am. Chem. Soc. 2011, 133, 12758. (h) Wheatley,
R. W.; Zheng, R. B.; Richards, M. R.; Lowary, T. L.; Ng, K. K. S. J.
Biol. Chem. 2012, 287, 28132. (i) Poulin, M. B.; Zhou, R.; Lowary,
T. L. Org. Biomol. Chem. 2012, 10, 4074.
Supporting Information
Supporting information for this article is available online at
(
(
10) Lowary, T. L.; Li, J. Med. Chem. Commun. 2014, 5, 1130; and ref-
erences cited therein.
http://dx.doi.org/10.1055/s-0034-1379551
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
o
nrtIo
i
g
f
rm oaitn
11) (a) Cren, S.; Gurcha, S. S.; Blake, A. J.; Besra, G. S.; Thomas, N. R.
Org. Biomol. Chem. 2004, 2, 2418. (b) Schramm, V. L. ACS Chem.
Biol. 2013, 8, 71.
12) (a) Liautard, V.; Christina, A. E.; Desvergnes, V.; Martin, O. R. J.
Org. Chem. 2006, 71, 7337. (b) Liautard, V.; Desvergnes, V.;
Martin, O. R. Org. Lett. 2006, 8, 1299. (c) Desvergnes, S.;
Desvergnes, V.; Martin, O. R.; Itoh, K.; Liu, H. W.; Py, S. Bioorg.
Med. Chem. 2007, 15, 6443. (d) Liautard, V.; Desvergnes, V.; Itoh,
K.; Liu, H. W.; Martin, O. R. J. Org. Chem. 2008, 73, 3103.
Primary Data
(
for this article are available online at http://www.thieme-connect.com/
products/ejournals/journal/10.1055/s-00000083 and can be cited
using the following DOI: 10.4125/pd0061th. Pmri aryD atPmri aryD at104.1
2
5
p/
d
0
0
6
1
htPm.ri ary
D
atZ
a
heln
1
0
1
C
h
e
msytri
(
e) Liautard, V.; Desvergnes, V.; Martin, O. R. Tetrahedron: Asym-
metry 2008, 19, 1999. (f) Liautard, V.; Desvergnes, V.; Martin, O.
References and Notes
R. Carbohydr. Res. 2008, 343, 2111.
13) Unpublished results.
(
(
(
(
(
1) Carbohydrates in Chemistry and Biology; Ernst, B.; Hart, G. W.;
14) Ferrières, V.; Bertho, J. N.; Plusquellec, D. Carbohydr. Res. 1998,
Sinay, S., Eds.; Wiley: New York, 2000.
3
11, 25.
2) Iminosugars: From Synthesis to Therapeutic Applications;
Compain, P.; Martin, O. R., Eds.; Wiley-VCH: Weinheim, 2007.
3) (a) Kajimoto, T.; Node, M. Curr. Top. Med. Chem. 2009, 9, 13.
(
15) Serra-Vinardell, J.; Díaz, L.; Casas, J.; Grinberg, D.; Vilageliu, L.;
Michelakakis, H.; Mavridou, I.; Aerts, J. M. F. G.; Decroocq, C.;
Compain, P.; Delgado, A. ChemMedChem 2014, 9, 1744.
16) Biela, A.; Oulaïdi, F.; Gallienne, E.; Górecki, M.; Frelek, J.; Martin,
O. R. Tetrahedron 2013, 69, 3348.
(b) Cullen, V.; Sardi, P.; Ng, J.; Xu, Y. H.; Sun, Y.; Tomlinson, J. J.;
(
Kolodziej, P.; Kahn, I.; Saftig, P.; Woulfe, J.; Rochet, J. C.;
Glicksman, M. A.; Cheng, S. H.; Grabowski, G. A.; Shihabuddin, L.
S.; Schlossmacher, M. G. Ann. Neurol. 2011, 69, 940. (c) Lopez,
O.; Merino-Montiel, P.; Martos, S.; Gonzalez-Benjumea, A. In
SPR Carbohydrate Chemistry; Pilar Rauter, A.; Lindhorst, T., Eds.;
RSC Publishing: Cambridge, 2012, 215–262. (d) Kim, J. H.;
Resende, R.; Wennekes, T.; Chen, H. M.; Bance, N.; Buchini, S.;
Watts, A. G.; Pilling, P.; Streltsov, V. A.; Petric, M.; Liggins, R.;
Barrett, S.; McKimm-Breschkin, J. L.; Niikura, M.; Withers, S. G.
Science 2013, 340, 71. (e) Lahiri, R.; Ansari, A. A.; Vankar, Y. D.
Chem. Soc. Rev. 2013, 42, 5102.
(
(
(
17) Behr, J.-B.; Hottin, A.; Ndoye, A. Org. Lett. 2012, 14, 1536.
18) Acharya, H. P.; Miyoshi, K.; Kobayashi, Y. Org. Lett. 2007, 9, 3535.
19) Knochel, P. Handbook of Functionalized Organometallics; Wiley-
VCH: Weinheim, 2005.
(
20) (a) Rao, J. P.; Rao, B. V.; Swarnalatha, J. L. Tetrahedron Lett. 2010,
5
1, 3083. (b) Rajender, A.; Rao, J. P.; Rao, V. B. Tetrahedron:
Asymmetry 2011, 22, 1306.
(
21) (a) Organozinc Reagents; Knochel, P.; Jones, P., Eds.; Oxford Uni-
versity Press: New York, 1999. (b) Kanai, K.; Wakabayashi, H.;
Honda, T. Org. Lett. 2000, 2, 2549. (c) Honda, T.; Wakabayashi,
H.; Kanai, K. Chem. Pharm. Bull. 2002, 50, 307.
(
4) (a) Descroix, K.; Pesnot, T.; Yoshimura, Y.; Gehrke, S. S.;
Wakarchuk, W.; Palcic, M. M.; Wagner, G. K. J. Med. Chem. 2012,
(
(
22) Synthetic Organic Sonochemistry; Luche, J. L., Ed.; Plenum Press:
New York, 1998.
23) Suslick, K. S.; Doktycz, S. J. Am. Chem. Soc. 1989, 111, 2342.
5
5, 2015. (b) Merino, P.; Tejero, T.; Delso, I.; Hurtado-Guerrero,
R.; Gomez-Sanjuan, A.; Sadaba, D. Mini-Rev. Med. Chem. 2012,
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 187–192

1
92
Synlett
C. Nicolas et al.
Letter
(
24) Procedure A: In a 10-mL round-bottom flask under an argon
3.62–3.70 (m, 1 H), 3.48–3.62 (m, 2.2 H), 3.33 (dd, J = 9.4, 3.6 Hz,
0.8 H), 3.08 (dd, J = 12.0, 4.0 Hz, 0.2 H), 2.71–2.84 (m, 1 H), 2.63–
2.70 (m, 0.2 H), 2.48 (dd, J = 16.7, 9.5 Hz, 0.8 H), 0.06–0.19 (m, 9
atmosphere were added zinc dust (96.2 mg, 1.47 mmol) and
iodine (11.2 mg, 0.04 mmol). The flask was placed under
vacuum and the vessel was heated with a heat gun during 5
min. The vessel was filled with argon and allowed to reach r.t.
The cycle was repeated once and anhyd THF (2 mL) was then
added followed by 3-bromo-1-trimethylsilyl-1-propyne at 0 °C
1
3
H). C NMR (101 MHz, CDCl /TMS): ꢄ = 139.1, 138.7, 138.6,
3
138.5, 138.4, 138.2, 138.1, 137.9, 127.5–128.8, 104.2, 103.7,
88.0, 87.5, 79.0, 78.9, 77.9, 75.3, 73.9, 73.7, 73.6, 73.2, 73.7, 73.2,
73.0, 71.1, 70.8, 68.0, 66.4, 57.3, 53.9, 50.6, 50.6, 22.5, 20.9, 0.1–
0.5. IR (film): 3030, 2862, 2171, 1496, 1453, 1360, 1249, 1207,
(
53 ꢂL, 0.32 mmol; mixture A). The reaction mixture was
–
1
allowed to warm to r.t. and stirred for a further 2 h. In parallel, a
solution of the N-benzyl-2,3,5-tri-O-benzyl-ꢁ/ꢀ-furanosyl-
amine (0.10 mmol) in anhyd THF (2 mL) under argon was pre-
pared in a 10-mL round-bottom flask (mixture B). Solution A
was added to solution B via cannula, avoiding transferring too
much zinc powder into solution B. The reaction mixture was
stirred under ultrasonication for 48 h (45 °C, 42 kHz, 0.47
1071, 1027, 907, 841, 726, 696, 645 cm . HRMS (ESI): m/z [M +
+
H] calcd for C39H48NO Si: 622.334712; found: 622.334699.
4
(1R)- and (1S)-1-C-(3-Trimethylsilyl-2-propynyl)-N-benzyl-
2,3,5-tri-O-benzyl-1,4-dideoxy-1,4-imino-L-arabinitol
(7):
light yellow oil; 8:2 mixture of diastereomers (1R)-7 and (1S)-7;
2
0
1
[ꢁ]
ꢃ14.5° (CHCl , c = 0.4). H NMR (400 MHz, CDCl /TMS): ꢄ
D
3
3
= 7.14–7.39 (m, 20 H), 4.22–4.60 (m, 6 H), 4.06–4.12 (m, 0.4 H),
3.97 (d, J = 10.9 Hz, 0.8 H), 3.95 (br s, 0.8 H), 3.91–3.94 (m, 0.2
H), 3.88 (br s, 0.8 H), 3.76 (d, J = 13.9 Hz, 0.8 H), 3.71 (d, J = 14.6
Hz, 0.2 H), 3.53–3.58 (m, 0.4 H), 3.27–3.38 (m, 1.8 H), 3.20–3.26
(m, 0.2 H), 3.07–3.16 (m, 1.6 H), 2.56 (dd, J = 16.6, 9.3 Hz, 0.8 H),
2.44–2.59 (m, 0.2 H), 2.34 (br s, 0.2 H), 2.40 (dd, J = 16.6, 5.1 Hz,
2
®
W/cm ). The resulting mixture was then filtered through Celite
and the residue was washed with EtOAc. The organic phase was
washed with H O, aq NH Cl, sat. aq NaHCO and dried over
2
4
3
MgSO . The organic phase was filtered and concentrated under
4
vacuum. The residue was purified by column chromatography
1
3
(silica gel, petroleum ether–EtOAc, 8:2) to give the correspond-
0.8 H), 0.05–0.19 (m, 9 H). C NMR (101 MHz, CDCl /TMS): ꢄ =
3
ing propargylated pentitols as a mixture of two diastereomers.
25) Procedure B: In a 10-mL round-bottom flask under an argon
atmosphere were added zinc dust (96.2 mg, 1.47 mmol) and
iodine (11.2 mg, 0.04 mmol). The flask was placed under
vacuum and the vessel was heated with a heat gun during 5
min. The vessel was filled with argon and allowed to reach r.t.
The cycle was repeated once and anhyd THF (4 mL) was then
added followed by 3-bromo-1-trimethylsilyl-1-propyne (53 ꢂL,
139.6, 139.5, 138.7, 138.5, 125.4–129.2, 106.0, 105.2, 86.8, 86.3,
86.0, 85.4, 83.5, 82.7, 73.3, 73.0, 72.7, 71.7, 71.6, 71.0, 72.0, 70.6,
69.7, 66.5, 65.2, 63.8, 59.0, 51.4, 20.8, 19.5, 0.3. IR (film): 3029,
2858, 2172, 1495, 1453, 1363, 1248, 1205, 1097, 1071, 1027,
(
–
1
+
908, 839, 731, 695, 645 cm . HRMS (ESI): m/z [M + H] calcd for
C39H46NO Si: 604.324147; found: 604.324106.
3
(1R)-1-C-[1-(3-Hydroxypropyl)triazol-4-ylmethyl]-2,3,5-tri-
O-benzyl-1,4-dideoxy-1,4-imino-L-arabinitol
[(1R)-10a]:
2
0
1
0.32 mmol) and the N-benzyl-2,3,5-tri-O-benzyl-ꢁ/ꢀ-furano-
amber oil; [ꢁ]
–4.24° (CHCl , c = 1.1). H NMR (400 MHz,
D
3
sylamine (0.10 mmol) under argon atmosphere. The reaction
mixture was stirred under ultrasonication for 48 h (45 °C, 42
CDCl /TMS): ꢄ = 7.15–7.35 (m, 21 H), 6.83 (s, 1 H), 4.55 (d, J =
3
12.2 Hz, 1 H), 4.46 (d, J = 12.3 Hz, 1 H), 4.45 (d, J = 12.0 Hz, 1 H),
4.38 (d, J = 12.0 Hz, 1 H), 4.30 (dt, J = 6.7, 2.2 Hz, 2 H), 4.25 (d, J =
12.1 Hz, 1 H), 4.21 (d, J = 11.9 Hz, 1 H), 4.01 (d, J = 12.0 Hz, 1 H),
3.93 (br s, 1 H), 3.71–3.78 (m, 2 H), 3.52 (t, J = 5.8 Hz, 2 H), 3.43
(dt, J = 9.2, 4.5 Hz, 1 H), 3.35 (dd, J = 12.0, 8.0 Hz, 1 H), 3.03–3.17
(m, 3 H), 2.92 (dd, J = 14.4, 4.4 Hz, 1 H), 1.97 (p, J = 6.5 Hz, 2 H).
2
kHz, 0.47 W/cm ). The resulting mixture was then filtered
through Celite® and washed with EtOAc. The organic phase was
washed with H O, aq NH Cl, sat. aq NaHCO and dried over
2
4
3
MgSO . The organic phase was filtered and concentrated under
4
vacuum. The residue was purified by column chromatography
1
3
(
silica gel, petroleum ether–EtOAc, 8:2) to give the correspond-
C NMR (101 MHz, CDCl /TMS): ꢄ = 145.7, 139.4, 138.7, 138.5,
3
ing propargylated pentitols as a mixture of two diastereomers.
138.3, 127.7–129.4, 122.1, 82.4, 82.1, 73.0, 71.4, 70.8, 71.9, 69.1,
66.6, 59.0, 58.8, 46.7, 32.6, 25.1. IR (neat): 3342, 2919, 2861,
(
(
(
26) (a) Cram, D. J.; Elhafez, F. A. A. J. Am Chem. Soc. 1952, 74, 5828.
–
1
+
(
b) Cram, D. J.; Kopecky, K. R. J. Am Chem. Soc. 1959, 81, 2748.
c) Leitereg, T. J.; Cram, D. J. J. Am Chem. Soc. 1968, 90, 4019.
1453, 1097, 1068 cm . HRMS (ESI): m/z [M + H] calcd for
(
C39H45N O : 633.343529; found: 633.343532.
4
4
27) Diastereomers of compound 6 could not be separated on regular
silica gel column chromatography and were thus further pro-
cessed as a mixture of isomers.
(1R)-1-C-[1-(3-Hydroxypropyl)triazol-4-ylmethyl]-1,4-
2
0
dideoxy-1,4-imino-L-arabinitol [(1R)-11a]: yellow oil; [ꢁ]
D
1
–4.24° (CHCl , c = 1.1). H NMR (400 MHz, CD OD/TMS): ꢄ =
3
3
28) Spectroscopic Data for Selected Compounds:
7.79 (s, 1 H), 4.47 (t, J = 7.0 Hz, 2 H), 3.86 (dd, J = 3.7, 1.6 Hz, 1 H),
3.78 (dd, J = 4.0, 1.6 Hz, 1 H), 3.68 (dd, J = 10.8, 4.4 Hz, 1 H), 3.65
(dd, J = 11.2, 4.8 Hz, 1 H), 3.57 (t, J = 6.4 Hz, 2 H), 3.44 (dt, J = 7.3,
(
1R)- and (1S)-1-C-(3-Trimethylsilyl-2-propynyl)-2,3,5-tri-O-
benzyl-1-benzylamino-1-deoxy-D-xylitol [(1R)-6 and (1S)-6]:
colorless oil; (1R)-6 and (1S)-6 were obtained as a 8:2 mixture
4.0 Hz, 1 H), 3.02 (dd, J = 14.7, 7.1 Hz, 1 H), 2.96 (br q, J = 4.8 Hz,
20
1
13
of diastereomers; [ꢁ]
ꢃ17.3° (CHCl , c = 0.5). H NMR (400
1 H), 2.88 (dd, J = 14.6, 7.5 Hz, 1 H), 2.09 (p, J = 6.5 Hz, 2 H).
C
D
3
MHz, CDCl /TMS): ꢄ = 7.19–7.36 (m, 20 H), 4.34–4.71 (m, 6 H),
NMR (101 MHz, CD OD/TMS): ꢄ = 146.6, 124.2, 81.2, 79.1, 68.4,
3
3
4
.12 (d, J = 6.5 Hz, 0.8 H), 4.08–4.11 (dd, J = 8.2, 5.8 Hz, 0.8 H),
.00–4.06 (m, 0.2 H), 3.88 (d, J = 12.5 Hz, 0.2 H), 3.85 (d, J = 12.1
63.5, 62.5, 59.3, 48.2, 34.0, 26.1. IR (neat): 3265, 2922, 1652,
–
1
+
4
1557, 1429, 1216, 1060 cm . HRMS (ESI): m/z [M + H] calcd for
Hz, 0.8 H), 3.80–3.82 (m, 0.2 H), 3.78 (br d, J = 6.6 Hz, 0.8 H),
C11H20N O : 273.155732; found: 273.155429.
4
4
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 187–192