Diastereoselective Synthesis of Axially Chiral Xylose-Derived 1,3-Disubstituted Alkoxyallenes: Scope, Structure, and Mechanism

Article abstract of DOI:10.1021/acs.joc.0c01240

The deprotonation of differently substituted propargyl xylosides with s-BuLi/TMEDA followed by protonation with t-butanol at -115 °C provided a range of new axially chiral 1,3-disubstituted alkoxyallenes in a diastereoselective way. Numerous reaction parameters such as solvent, temperature, or protonating agent were examined as well as protecting groups on the xyloside moiety and the influence of the substituents on the alkyne part. The configuration of the main diastereoisomer of 3-methyl-1-xyloside-allene was determined for the first time by single-crystal X-ray diffraction analysis and nOe NMR experiments. Furthermore, DFT calculations on the propargyl/allenyl lithium intermediates formed in the course of the deprotonation reaction provided new structural insights of these complexes. The subsequent protonation process with alcohols was investigated by theoretical surface exploration, revealing the importance of the approach of the alcohol toward the lithium compounds on the reaction outcome.

Full text of DOI:10.1021/acs.joc.0c01240

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Article
Diastereoselective synthesis of axially chiral xylose-derived 1,3-
disubstituted alkoxyallenes: scope, structure and mechanism
Moustapha Fortunato, Yves Gimbert, Elodie Rousset, Pedro Lameiras, Agathe
Martinez, Sylvain Gatard, Richard Plantier-Royon, and Florian Jaroschik
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01240 • Publication Date (Web): 23 Jul 2020
Downloaded from pubs.acs.org on July 23, 2020
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Page 1 of 18
The Journal of Organic Chemistry
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Diastereoselective synthesis of axially chiral xylose-derived
1,3-disubstituted alkoxyallenes: scope, structure and
mechanism
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Moustapha Fortunato,§ Yves Gimbert,*¶ Elodie Rousset, § Pedro Lameiras, § Agathe Martinez, § Sylvain
Gatard,* § Richard Plantier-Royon,* § and Florian Jaroschik*‡
§ Institut de Chimie Moléculaire de Reims, UMR CNRS 7312, Université de Reims Champagne-Ardenne, 51687 Reims,
France
¶ Département de Chimie Moléculaire, UMR CNRS 5250, Université Grenoble Alpes, 38058 Grenoble, France
‡ ICGM, Université de Montpellier, ENSCM, 34090 Montpellier, France
ABSTRACT: The deprotonation of differently substituted propargyl xylosides with s-BuLi/TMEDA followed by protonation
with t-butanol at –115 °C provided a range of new axially chiral 1,3-disubstituted alkoxyallenes in a diastereoselective way.
Numerous reaction parameters such as solvent, temperature or protonating agent were examined as well as protecting
groups on the xyloside moiety and the influence of the substituents on the alkyne part. The configuration of the main
diastereoisomer of 3-methyl-1-xyloside-allene was determined for the first time by single crystal X-ray diffraction analysis
and nOe NMR experiments. Furthermore, DFT calculations on the propargyl/allenyl lithium intermediates formed in the
course of the deprotonation reaction provided new structural insights of these complexes. The subsequent protonation
process with alcohols was investigated by theoretical surface exploration, revealing the importance of the approach of the
alcohol towards the lithium compounds on the reaction outcome.
Introduction
Scheme 1. Synthetic access to diastereomerically
enriched 1,3-disubstituted alkoxyallenes.
In recent years, the number of applications of allenes
as building blocks in organic synthesis has considerably
increased due to their unique properties.1 Indeed, their
reactivity and their intrinsic chirality make them the
precursors of choice to access more complex molecules
such as heterocycles or natural products.2 Therefore,
there is an increasing need for efficient synthetic
methodologies to access axially chiral allenes in an
enantio- or diastereoselective manner.3 Among the
recently developed procedures, only very few studies
were dedicated to the synthesis of diastereomerically
enriched alkoxyallenes,4 a widely employed class of
allenes.2e,5 The applied strategy used chiral auxiliaries,
however, the scope remained restricted to 1,3-
disubstituted allenes bearing alkyl substituents, hence
limiting more molecular complexity. For instance, the
groups of Tius4a and Reissig4b,c, respectively, reported
the highly diastereoselective synthesis of some 1,3-
disubstituted alkoxyallenes using fructose- or camphor-
derived chiral auxiliaries in the well-known metal-
mediated isomerization1a,b of propargyl ethers (Scheme
1).
a) Tius, 2002
O
O
H
1) n-BuLi (2 eq.)
- 78 °C, 2 h
O
O
•
2) t-BuOH
H
R
R
via
O
Li
R = CH3, 55% yield, 90% d.e.
R = t-Bu, > 65% yield, 50% d.e.
SE2’
O
H
R
t-BuO-H
b) Reissig, 2018
O
O
O
O
O
O
1) n-BuLi, THF
O
O
O
+
H
•
H
•
O
O
O
2) HMPA or t-BuOK
3) H2O
O
O
O
O
O
O
C9H19
H
C9H19
H
(aR)
(aS)
C9H19
90% conv.
75% conv.
(aR)/(aS) 80/20
(aR)/(aS) 10/90
c) this work
O
OTBS
•
O
HO
HO
O
H
O
H
R
OH
OTBS
OTBS
1
R = alkyl, silyl, aryl
up to 100% conv., up to 85% d.e.
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To rationalize the observed selectivities, several on the use of its intrinsic chirality for stereoselective
processes.9 One of the advantages of using this sugar
moiety as a chiral auxiliary in this isomerization
reaction lies in the presence of oxygen atoms with
different spatial arrangements which have the capacity
to coordinate lithium to promote the formation of the
1
2
3
4
5
6
7
8
aspects must be considered. These reactions usually
operate via a two-step mechanism (Scheme 2). First, a
basic treatment in the presence of an organolithium
reagent yields the Li-propargyl (P)/Li-allenyl (A)
intermediates in equilibrium. Then, the protonation of
this metallotropic equilibrium leads to a mixture of
regio- and diastereoisomers. The protonation step can
proceed either by a SE2 or a SE2’ type mechanism. The
regio- and stereoselectivity of these reactions depend
on a certain number of parameters including the
solvent, the temperature and the metal, as well as the
transition states of the reaction and the rate constants.
Li-propargyl/allenyl intermediates stabilized in
a
defined configuration. In order to provide further
synthetic insights and gain a better understanding on
the underlying reaction mechanisms, we explored the
influence of protecting groups on the sugar moiety and
the alkyne substituents on the structural parameters of
the Li-propargyl (P)/allenyl (A) intermediates in
equilibrium and studied the protonation pathways
during the isomerization step by DFT studies. It should
be noted that Reich and co-workers have extensively
studied the structures and the equilibrium between Li-
propargyl (P)/allenyl (A) species for a range of alkyl
and silyl substituted compounds.[10] However, this is the
first report on a detailed study with alkoxy derivatives.
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Scheme 2. Metallotropic equilibrium between
generally proposed Li-propargyl and Li-allenyl
intermediates and protonation pathways.
H
H
Li
RO
H
RLi
RO
RO
Li
R1
R1
R1
H
(P)
(A)
H+
SE2 H+
SE2 H+
Results and Discussion
SE2’
+
H
H
RO
RO
R1
R1
H
Synthesis of various substituted propargyl
xylosides 3a-f from 1. Propargyl β-D-xylopyranoside 1
can be obtained either by a classical three-step chemical
sequence from D-xylose or through an enzymatic
transglycosylation process directly from beechwood
xylans and propargyl alcohol.6c,11 The fully TBS
protected propargyl xyloside 2 was readily prepared in
H
In the case of Reissig’s work,4b,c the addition of HMPA
or t-BuOK to the Li-propargyl/Li-allenyl intermediates
in equilibrium led to the formation of considerably
more basic separated ion pairs and proton migration to
form allenyl carbanions with fixed configurations. The
subsequent protonation occurred via a SE2 mechanism
to yield the diastereoisomers (aR) or (aS) with high
conversion and good diastereomeric ratio (d.r.),
depending on the additive (Scheme 1b). On the other
hand, Tius suggested an assistance of the chiral
auxiliary to selectively deprotonate the pro-S
propargylic proton leading to the chelation of the cyclic
oxygen of camphor to the lithium atom to stabilize the
Li-propargyl (P) intermediate (without considering the
usual Li-propargyl/Li-allenyl equilibrium). This would
give access to the corresponding allene via a SE2’
mechanism (Scheme 1a).4a These examples leave open a
certain number of questions concerning the different
stages of this mechanism, in particular on the existence
of an equilibrium between the lithiated species and its
influence on the regio- and the diastereoselectivity
observed, but also on the role of the proton source in
the process. As part of our work dedicated to the
development of new chemical or enzymatic
up to 91
% yield from 1 by reaction with t-
butyldimethylsilyl chloride (TBS-Cl) in presence of
imidazole and a catalytic amount of DMAP (Scheme 3)
after heating at 80 °C for 6 days.5b Lower temperatures
or shorter reaction times led to the formation of
product mixtures containing di- and triprotected
xylosides. Introduction of substituents on the alkyne
was carried out via deprotonation and nucleophilic
substitution for alkyl or silyl groups leading to 3a,b or
Pd-catalyzed Sonogashira12 coupling for aryl groups
providing 3c-e in good to excellent yields. The t-butyl
substituted compound 3f could not be obtained by
these pathways, but via a 4-step procedure from D-
xylose (see S1 in SI).
transformation
pathways
for
pentoses
from
lignocellulosic biomass,6 we herein report on the
diastereoselective synthesis of 1,3-disubstituted
alkoxyallenes (R = alkyl, aryl, silyl) from propargyl
xyloside 1.7 Despite the high natural abundance of D-
xylose in plants,8 only few examples have been reported
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The molecular structure of 2 was determined in a
solid-state X-ray diffraction study from single crystals
obtained by slow evaporation of concentrated
petroleum ether solution at room temperature (Scheme
3). Unexpectedly, the structure revealed a conformation
with an equatorial positioning of the silyl ether groups.
Further crystallographic details are provided in the
supporting information. The structure of 2 is a rare
1
2
3
4
5
6
a
Scheme 3. Synthesis of various propargyl
xylosides 2 and 3a-e.
3 steps
HO
O
1 step
D-xylose
HO
xylans
7
8
O
H
OH
example of
a
terminal propargyl appended
1
9
carbohydrate and the structural parameters compare
i)
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well with the literature.14
O
OTBS
O
In order to gain further insights on the
conformational equilibrium in compound 3a with the
OTBS groups in either axial or equatorial positions, DFT
calculations were performed at the B3P86/6-31+G(d,p)
level. No significant energetic difference between the
optimised structures of the two conformations could be
observed at room temperature (ΔG (ax/eq) = 0.12
kcal/mol) (see Table S3), hence a rapid equilibrium
could be envisaged, leading to the crystallisation of the
equatorial form, possibly due to packing effects.
H
OTBS
OTBS
2
: 91%
ii) or iii)
2
X-ray structure of
3a
3b
3c
3d
3e
: R = Me, 94%
: R = TMS, quant.
: R = Ph, quant.
: R = p-C6H4OMe, 93%
: R = p-C6H4CF3, 98%
O
OTBS
O
R
OTBS
OTBS
i) Imidazole (5 eq.), TBSCl (4 eq.), DMAP cat., DMF, 80 °C; ii) n-BuLi (2 eq.),
TMSCl or MeI (2 eq.), THF, -78 °C -> r.t., 14 h; iii) ArI (1.1 eq.), Pd(PPh3)4
(0.005 eq.), CuI (0.01 eq.), Et3N/THF, 55 °C, 24h.
3
Table 1. J1,2 values (in Hz) observed in the 1H
NMR spectra (in toluene-d8 and THF-d8) of 2 and 3a,
recorded at different temperatures.
Structural characterization of 2 and 3a. A pseudo-
axial conformation of the silylated groups for
compounds 2 and 3a-f was revealed by 1H NMR.11a,13
Small coupling constants between 3.0 and 4.0 Hz were
usually obtained for the ring protons of these
compounds, showing a 1,2-trans-diaxial relationship
between the silyl groups. For comparison, the
1 with the OH groups in
equatorial position, showed values of 7.5 to 9.0 Hz for
the analogous coupling constants (see Table S2).
O
H2
SiO
O
H1
H2
O
SiO
SiO
R
O
H1
R
SiO
SiO
SiO
2
: R = H
3a
High temperature
: R = Me
Low temperature
SiO = OTBS
unprotected xyloside
T (°C) 3J1,2 (Hz)[a]
3J1,2 (Hz)[b]
3J1,2 (Hz)[a]
2
2
3a
To better analyse the preferred conformation of the
silyl groups of the pyranosic cycle, H NMR spectra of 2
and 3a in toluene-d8 and in THF-d8 were recorded at
different temperatures between -40 °C and +70 °C and
the values for J1,2 for each temperature are reported in
Table 1. Decreasing the temperature from r.t. to -40 °C,
the J1.2 coupling constants gradually increased to
values above 6.0 Hz indicating an equatorial positioning
of the silylated groups. On the other hand, increasing
the temperature up to 70 °C led to a decrease of the 3J1.2
values towards 3.0 Hz, showing the preference of the
OTBS groups for a pseudo-axial conformation. These
results clearly evidence the influence of the
temperature on the conformational equilibrium of the
TBS protected propargyl xylosides 2 and 3a-f. It should
be noted that variation in chemical shifts and
differences in multiplicity were also observed at
different temperatures, phenomena linked to the
different conformations (see SI for the different 1H NMR
spectra recorded in toluene-d8 and THF-d8 at different
temperatures).
1
70
40
3.2
3.9
4.0
5.0
5.4
5.8
6.1
-
3.3
3.8
3.8
5.6
6.1
6.4
6.8
3.6
4.1
5.2
5.6
6.0
6.4
3
25
3
-10
-20
-30
-40
[a]: determined in toluene-d8; [b]: determined in THF-d8
Diastereoselective synthesis of a xylose-derived
1,3-disubstituted alkoxyallene. We then set out our
studies on the synthesis of allene 4a from the TBS
protected 3-methyl substituted propargyl xyloside 3a.
After deprotonation with 3 eq. n-BuLi in THF at -78 °C,
the reaction was quenched at -78 °C with 1N HCl to
afford a 70:30 mixture of 3a and 4a, however, with no
diastereoselectivity for 4a (Scheme 4).4b,c Interestingly,
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the ratio 3a to 4a changed to 30:70 when the reaction
was quenched at -30 °C, providing first evidence for an
equilibrium between the Li-propargyl/allenyl
1
2
3
4
5
6
7
8
1
intermediates. The ratios were determined by H NMR
spectroscopy in CDCl3 showing the appearance of the
allenic protons (H3’) at 5.70 ppm and 5.80 ppm
corresponding to the two diastereoisomers of allene 4a.
As in the case of propargyl derivatives 3a-f, small
coupling constants between 4.0 and 5.0 Hz were
observed for allene 4a indicating a privileged pseudo-
Table 2. Optimisation studies for conversion of
propargyl xyloside 3a to allene 4a using t-BuOH as
the proton source.
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axial conformation at room temperature (see SI for J1,2
values observed in the 1H NMR spectra recorded at
different temperatures).
O
OTBS
O
OTBS
O
OTBS
•
•
1) Base, solvent
additive, -78 °C
H
O
Me
O
O
Me
H
Me
+
2) t-BuOH
Tprotonation, 1 h
OTBS
OTBS
OTBS
OTBS
OTBS
OTBS
Scheme 4. Conversion of propargyl xyloside 3a to
allene 4a with HCl as the proton source.
3a
4a-(aS)
4a-(aR)
O
OTBS
O
OTBS
O
OTBS
•
•
1) n-BuLi (3 eq.)
THF, -78 °C
Entry
Base
(eq.)
Solvent
T[a]
(°C)
Additive
-
Conv.[b]
(%)
d.r.[b]
60:40
70:30
93:7
50:50
67:33
93:7
70:30
-
H
O
Me
O
O
Me
H
Me
+
2) HCl,
-78 °C, 1 h
OTBS
OTBS
OTBS
OTBS
OTBS
OTBS
1
2
3
4
5
6
7
8
n-BuLi
(3)
THF
Et2O
- 78
90
90
90
75
55
90
50
0
3a
4a
-(aS)
4a
-(aR)
n-BuLi
(3)
- 78
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
Inspired by the work of the group of Tius,4a we then
switched to t-BuOH as the proton source (Table 2).
Addition of t-BuOH to the lithiated compound at -78 °C
afforded 90% conversion to 4a. However, only a modest
60:40 diastereoselectivity was observed (entry 1).
Switching the solvent to diethyl ether and addition of
equimolar amounts of TMEDA, with respect to n-BuLi,
provided a better 70:30 diastereoselectivity (entry 2).
As previously mentioned, a decrease in temperature can
increase the chirality transmission from the starting
material,15 and the configurational stability of the
organometallic species.16 Therefore, we performed the
addition of t-BuOH at -115 °C to yield 4a still with a
good conversion but, at the same time, with even better
stereoselectivity 93:7 (entry 3). The major
diastereoisomer was isolated as a pure compound in
75% yield. Other solvents (hexanes or toluene)
provided less satisfying results (entries 4 and 5).
Finally, the amount of alkyllithium reagent could be
reduced to 1.2 equivalent when s-BuLi was employed
instead of n-BuLi (entry 6). Attempted transmetallation
with ZnBr2 did not improve the outcome (entry 7).16
With the use of another chelating amine ligand, such as
the chiral (+)-spartein ligand (entry 8), no conversion
into the allene was observed. It should be noted that in
the absence of TMEDA no reaction took place in diethyl
ether.
n-BuLi
(3)
Et2O
- 115
- 115
- 115
- 115
- 115
- 115
n-BuLi
(3)
Toluene
Hexanes
Et2O
n-BuLi
(3)
s-BuLi
(1.2)
s-BuLi
(1.2)
Et2O
TMEDA,
ZnBr2
s-BuLi
Et2O
(+)-
(1.2)
sparteine
[a]: Protonation temperature; [b]: determined by 1H NMR.
Determining the configuration of the major
diastereoisomer of 4a. In previous studies, the
structure of the major diastereoisomer of allene was
deduced from the stereochemistry of the products of
consecutive transformations, e.g. Nazarov cyclisation4a
or allene oxidation.4b In this study, we provide direct,
analytical evidence for the elucidation of the
configuration of the major isomer of 4a. The presence of
a bulky OTBS group in vicinity to the allenyl moiety
encouraged us to carry out nOe NMR experiments to
gain structural insights on the allene configuration. The
nOe experiments carried out on a diastereomeric
mixture of allenes 4a-(aS) and 4a-(aR) showed that the
t-Bu group of the OTBS group on the carbon in position
2 of the pyranosic cycle correlated both with the allenic
proton H3' and the Me group linked to the allene
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function (for NMR spectra see SI). Interestingly, the equatorial position, as per compound 2. Further
1
2
3
4
5
6
7
8
correlation spots did not have the same intensity for
each of the two diasteroisomers, indicating a closer
distance between H3’ and the t-Bu group for the major
diastereoisomer. In parallel, we carried out molecular
modeling (B3P86/6-31+G(d,p) level) on the two
diastereoisomers of allene 4a, in order to determine the
distances between the different groups. The distance
calculated for 4a-(aS) between the t-Bu group was
smaller with the proton H3’ (5.23 Å, higher intensity for
correlation task in NMR) than with the methyl group
(Me) (5.69 Å) (Figure 1; see SI for 4a-(aR)). From these
results, we assigned the configuration (aS) for the major
isomer.
crystallographic details are provided in the supporting
information. The bond lengths and bond angles are in
good agreement with the only other structurally
characterized example of a sugar-based alkoxyallene,
carrying
a
fructose fragment in that case.17
Interestingly, DFT calculations on 4a with the OTBS
groups in axial or equatorial position, show a slight
preference for their axial positioning at room
temperature (ΔG(ax/eq) for 4a-(aS) = -3.5 kcal/mol;
ΔG(ax/eq) for 4a-(aR) = -2.3 kcal/mol) (see Table S3),
in agreement with the NMR data. However, an
equilibrium still exists leading to the crystallization of
the product with the silylated groups in equatorial
position.
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Evidence and study of the metallotropic
equilibrium. To evidence a deprotonation step driving
to
a
metallotropic equilibrium between Li-
propargyl/allenyl intermediates during the process of
the formation of the allenes 4a-(aS) and 4a-(aR), the
same reaction was carried out using t-BuOD instead of
t-BuOH (Scheme 5). Deuterated allene 4a-(aS)-D was
obtained with high conversion (90%) and d.r. (90:10).
Moreover, propargyl xyloside 3a-D was also formed,
indicating that the 90% conversion, observed under the
best conditions, was not due to incomplete
deprotonation of the starting material.
Scheme 5. Conversion of propargyl xyloside 3a to
allene 4a-D and propargyl 3a-D with t-BuOD as the
proton source.
D
O
OTBS
O
OTBS
O
OTBS
•
1) s-BuLi (1.1 eq.)
Et2O, -78 °C, TMEDA
O
Me
O
O
Me
Me
D
+
2) t-BuOD
-115 °C, 1.5 h
OTBS
OTBS
OTBS
OTBS
OTBS
OTBS
3a
4a
-(aS)
3a
-D
We were then interested in studying the influence of
this metallotropic equilibrium on the regioselectivity
previously obtained for the allenes 4a. We tested
several proton sources by varying the size and the
nature of the alcohol (Table 3). Whereas primary
alcohols, such as methanol or n-butanol still provided
good d.r. values, significantly lower conversion was
observed (entries 2 and 3). Surprisingly, isopropanol
repeatedly furnished very low conversion (10%) (entry
4). Quenching with phenol provided moderate
conversion and d.r. (entry 5), whereas the more acidic
1,1,1,3,3,3-hexafluoroisopropanol (HFIP) resulted in
observations similar to HCl, i.e. low conversion with no
diastereoselectivity (entry 6).
Figure 1. Above: Optimized structure of the major
diastereoisomer 4a-(aS) with OTBS groups in axial
position obtained by DFT calculations (B3P86/6-
31+G(d,p) level) showing the distances (in Å) between
H3’ and methyl group on allene with OTBS group.
Below: Crystal structure of 4a-(aS) with OTBS groups in
equatorial position. Ellipsoids are represented at 30 %
probability; hydrogen atoms are omitted for clarity,
except for the allene hydrogens.
Inspired by the work from Yoshida and co-workers,18
we also considered using chiral alcohols to have a
double asymmetric induction in addition of the sugar
moiety, expecting some "match" or "mismatch" effects
in terms of stereoselectivity. With the chiral alcohol (R)-
The absolute configuration of the major
diastereoisomer 4a-(aS) was then confirmed by X-Ray
diffraction studies. Single crystals were grown from a
concentrated pentane solution at 0 °C. The structure
showed again the presence of all OTBS groups in the
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pantolactone very good conversion and moderate over silica gel than the corresponding OTBS products,
1
2
3
4
5
6
7
8
diastereoselectivity were observed (entry 7). With the
(S)-isomer poor conversion of 40% and no
diastereoselectivity were observed (entry 8). Finally,
with (R)- and (S)-mandelate, despite very good
conversions, poor diastereoselectivities were obtained
(entries 9 and 10).
leading to low isolated yields.
Scheme 6. Conversion of propargyl xyloside 5a
into allene 6a.
O
H
MeO
MeO
O
•
Me
OMe
1) s-BuLi/TMEDA
Et2O, -78 °C
O
6a
-(aS)
MeO
MeO
O
Me
The variation in regioselectivity obtained with the
various proton sources indicates that the equilibrium
between Li-propargyl /allenyl intermediates is rapid
and the predominant formation of the allenes 4a mainly
depends on the protonation step.16,19
+
OMe
2) t-BuOH, -115 °C
O
Me
H
MeO
MeO
9
O
•
5a
OMe
6a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
-(aR)
6a
: 91% conv., (aS):(aR) = 65:35
Table 3. Study of the metallotropic equilibrium
with various proton sources.
Extension of the scope to the synthesis of allenes
4b-f with various substituents. With the optimised
conditions in hand (Table 2, entry 6), we next extended
this approach to other alkyl-substituted as well as silyl
and aryl-substituted propargyl xylosides 3b-f (Table 4).
O
OTBS
O
OTBS
O
OTBS
•
1) s-BuLi (1.1 eq.)
Et2O, -78 °C, TMEDA
O
O
O
Me
Me
Me
+
H
2) Proton source
-115 °C, 1.5 h
OTBS
OTBS
OTBS
OTBS
OTBS
OTBS
3a
3a
4a
-(aS)
Trialkylsilyl substitution on the sp-hybridized carbon
atom of the propargyl alkyne group has previously been
shown to significantly influence the reaction outcome
for allene synthesis.10 We therefore examined the
substrate 3b having a TMS substituent. Low conversion
to the allene 4b with moderate d.r. was observed (entry
2). Due to the small difference in polarity between 3b
and 4b these products could not be separated by
column chromatography. With the phenyl substituted
starting compound 3c moderate conversion and d.r.
values were obtained, even though these are the highest
value to date in the literature (entry 3). Substitution of
the aromatic nucleus by an electron-donating group
(entry 4) brings a slight reduction in the conversion
while the substitution by an electron-withdrawing
group (entry 5) leads to total conversion to the allene
with a diastereoisomeric ratio of 55:45. In agreement
Entry
Proton source
3a:4a.[a]
d.r.[a]
4a-(aS):4a-(aR)
1
2
t-BuOH
n-BuOH
10:90
60:40
60:40
90:10
40:60
90:10
10:90
60:40
10:90
10:90
90:10
80:20
3
MeOH
80:20
4
i-PrOH
50:50
5
Phenol
70:30
6
HFIP
50:50
7
(R)-pantolactone
(S)-pantolactone
(R)-mandelate
(S)-mandelate
70:30
8
50:50
with
a
previous literature report,21 these aryl-
substituted allenes showed significantly lower stability
over time and over silica gel (or alumina), compared to
their alkyl analogues, and therefore could not be
isolated in a pure form. With the propargyl xyloside
having a bulky t-Bu group 3f (entry 6) full conversion to
allene 4f was observed, however with a slightly lower
d.r. compared to the methyl group. It was found that
this compound was stable for purification over silica gel
and a mixture of the two diastereomers could be
obtained with a quantitative yield.
9
65:35
10
65:35
[a]: 1H NMR shifts in ppm determined in CDCl3.
Influence of protecting groups on the sugar
moiety on the diastereoselectivity. We next studied
the impact of the alcohol protecting groups on the
diastereoselectivity, using the OMe protected propargyl
xyloside 5a. Under the optimised conditions
determined for 4a (Table 2, entry 6), compound 5a gave
only a 65:35 diastereomeric mixture of allenes 6a with
high conversion (Scheme 6). This result clearly
indicated that steric factors due to the bulky TBS groups
are important in this transformation. Because the
1
signals of the allenic protons H3’ in the H NMR spectra
of the diastereoisomers of 4a and 6a deviated by less
than 0.1 ppm in all cases, the configuration of the major
stereoisomer was assumed to be (aS). It should be
noted that the OMe protected allene 6a is less stable
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1
Table 4. Scope of the synthesis of allenes 4a-f from
propargyl xylosides 3a-f.
Table 5. Chemical shifts observed by H NMR for
1
protons H1’ et H3’ of new allenes 4a-f and 6a,b.
2
3
4
5
6
7
O
OTBS
O
OTBS
O
OTBS
•
•
1) s-BuLi/TMEDA
Et2O, -78 °C
H1’
H
O
R
O
O
R
H
R
+
O
OTBS
•
O
H3'
R
2) t-BuOH, -115 °C
MeO
MeO
OTBS
OTBS
OTBS
OTBS
OTBS
OTBS
O
H3’
O
•
OMe
R
3a-f
4a-f
4a-f
-(aR)
-(aS)
H1'
OTBS
OTBS
4a
4b
4c
: R = Me; : R = SiMe3; : R = C6H5;
4d 4e
4f
: R = p-C6H4OMe; : R = p-C6H4CF3; : R = t-Bu.
4a-f
6a,b
8
9
Entry
R
Conv. (%)[a]
(isolated yields)
d.r.[a]
4-(aS):4-
(aR)[b]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[a]
[a]
Entry Compound
R
 H1’
 H3’
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
Me
6.47 (aS)
6.50 (aR)
5.70 (aS)
5.80 (aR)
1
2
3
4
5
6
Me (3a)
90 (75 %)
42 (-)
(4a) 93:7
(4b) 70:30
(4c) 70:30
(4d) 70:30
(4e) 55:45
(4f) 80:20
TMS (3b)
C6H5 (3c)
SiMe3
Ph
6.48 (aS)
6.53 (aR)
5.83 (aS)
5.86 (aR)
65 (-)
6.94 (aS + aR)
6.90 (aS + aR)
7.00 (aS + aR)
6.66 (aS)
6.76 (aR)
p-C6H4OMe (3d)
p-C6H4CF3 (3e)
t-Bu (3f)
50 (-)
100 (-)
p-C6H4OMe
p-C6H4CF3
t-Bu
6.62 (aS)
6.72 (aR)
100 (quant.)
[a]: d.r. were determined by 1H NMR in CDCl3 from crude reaction
mixtures; [b]: we assumed that the stereochemistry preferentially formed for
all the allenes 4b-f was (aS), taking into account previous result obtained
with 4a and previous works.4
6.67 (aS)
6.78 (aR)
6.53 (aR)
6.57 (aS)
5.72 (aR)
5.80 (aS)
Table 5 provides the values of the chemical shifts for
the signals of the allenic protons H1' and H3' in solution
in CDCl3 for the new allenes 4a-f and 6a,b. Literature
data on alkoxyallenes with aryl groups are scarce due to
their poor stability.21,22 In the case of 4c-4e, we have
assigned the signals from the spectra of the crude
reaction mixtures. These data are in agreement with
those of the slightly more stable compound 6b with a p-
F-C6H4 group on the allene and OMe protecting groups,
obtained under different conditions and fully
characterized in solution by NMR. From these values, a
strong influence on the chemical shifts of H1’ and H3’ can
be observed between alkyl/SiMe3 groups (entries
1,2,6,7) and aryl groups (entries 3,4,5,8). Only a weak
electronic effect of the aryl groups on the chemical shift
became evident.
6a
6b
Me
6.55 (aS + aR)
7.01 (aR + aS)
5.75 (aS)
5.83 (aR)
p-C6H4F
6.66 (aS)
6.75 (aR)
[a]: 1H NMR shifts in ppm determined in CDCl3
.
Scheme 7. Deprotonation of 3a leading to four
intermediates lithium species: 3a-Li-(S), 3a-Li-(R),
4a-Li-(aS) and 4a-Li-(aR).
DFT studies on the diastereoselective formation
of allene 4a-(aS). The mechanism leading to the major
diastereoisomer 4a-(aS) was next studied by DFT
calculations. As the reaction was performed at – 110°C,
the OTBS groups were placed in equatorial position for
the calculations, as this was found to be the major
conformation at low temperature (-70 °C), according to
1
our variable-temperature H NMR studies (Table 1). In
agreement with previous works,1a,b we propose a two-
step mechanism for the allene formation. The first step
would consist in the deprotonation of the propargyl
xyloside 3a with the base, leading to four possible
intermediates in equilibrium 3a-Li-(S), 3a-Li-(R), 4a-Li-
(aS) and 4a-Li-(aR) as revealed by DFT calculations
(Scheme 7).23
In contrast to the general description of lithium-
allenyl species with the lithium bound to the terminal
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carbon atom, DFT calculations show that in 4a-Li- H---C3’, step by step of 0.1 Å, the MeOH molecule is
(aS)/(aR) the lithium is η 3-coordinated to the allenyl
moiety as indicated by the Li-C distances in the range of
2.04 to 2.56 Å (Figure 2).10 Furthermore, an interaction
between Li and the oxygen atom of the pyranosic cycle
was observed for lithium propargyl complex 3a-Li-(R),
with a Li-O distance of 1.98 Å (Figure 2). For 3a-Li-(S)
such an interaction was not observed.
positioned so as to allow interaction between the
oxygen, which will transfer a proton, and the lithium
ion. After the proton transfer, this generates a TMEDA-
1
2
3
4
5
6
7
8
Li-OMe species and the allene 4a-(aS) in
a SE2
mechanism without energy barrier (Scheme 8 and
Figure 3a). The formation of the Li-OMe bond (distance
O-Li 1.83 Å just before the proton transfer) seems to
increase the effectiveness of this protonation step. This
point became further evident when in another surface
exploration, the MeOH was approached from the side
opposite of the Li-TMEDA chelate (Figure 3b). In this
case, a very high energy cost was observed as the
methanolate is too far away from the Li-ion and
therefore this approach seems an unfavorable
protonation pathway.
3a
-Li-(R)
4a
-Li-(aR)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1.98
2.19
2.68
2.11
2.08
1.22
1.33
1.29
Si
O Li
N
3a
-Li-(S)
4a
-Li-(aS)
2.09
2.56
Scheme 8. Possible SE2 pathway for the
2.06
protonation of 4a-Li-(aS).
2.04
1.29
N
N
1.22
H
O
O
Li
SE2
TBSO
TBSO
TBSO
TBSO
H-OMe
1.33
O
C3’
CH3
O
•
Me
OTBS
OTBS H
4a
-Li-(aS)
4a
-(aS)
Figure 2. Calculated structures of 3a-Li-(S), 3a-Li-(R),
4a-Li-(aS) and 4a-Li-(aR) at B3P86/6-31+G(d,p) level,
distances in Å.
Among the four isomers, the allenyllithium 4a-Li-(aS)
is thermodynamically favoured and should lead to the
major diastereoisomer 4a-(aS) upon protonation.
Variation of temperature or taking into account the
solvent did not significantly influence the calculated
equilibrium. As described experimentally, the
protecting groups and the alkyne substituents can lead
to considerable variation in the reaction outcome.
Therefore, we also calculated the four lithiated
structures for the trimethylsilyl substrate 3b and the
OMe protected sugar substrate 5a (see SI).
Considerable changes in the ΔG values for the different
propargyl and allenyllithium species of the equilibrium
could be observed, which might be responsible for the
lower conversion and d.r. values observed with these
substrates.
Figure 3. DFT Calculations: (a) favored and (b)
unfavored protonation pathways of 4a-Li-(S).
We then studied the second step of this mechanism,
the protonation step of the lithium species, using MeOH
as the protonation agent.24 We sought to obtain a stable
structure, where a MeOH molecule would present an
interaction with one of the different lithium species
shown in Scheme 7. We studied these processes by
scanning the potential energy surface corresponding to
the approach of MeOH on the C1’ atom or the C3’ atom of
the lithium species. First, we explored the protonation
of 4a-Li-(aS), which is the thermodynamically favoured
complex and should lead to the observed major allene
4a-(aS). In a first scan by shortening the distance MeO-
For the formation of allenes, a protonation of the Li-
propargyl-intermediate has also been proposed by
Tius.4a From the propargylic structure 3a-Li-(S), two
protonation pathways were studied (Scheme 9): a) a
protonation leading to the recovery of starting product
3a (SE2), and b), a protonation leading to allene 4a
(SE2’).1a,b These two pathways position the MeOH
initially in the Li-TMEDA chelate environment.
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1
2
3
Scheme 9. Two possible pathways for the
protonation of 3a-Li-(S): SE2 and SE2’.
(a) by shortening the distance MeO-H—-C1’
4
2.96
5
6
7
8
C1’
N
N
2.21
Li
O
TBSO
O
H
TBSO
C3’
iii
favored
H-OMe
CH3
C1’
OTBS
C3’
9
3a
-Li-(S)
SE2’
SE2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
favored
3a
-Li-(S) + MeOH
3a
+ TMEDA-Li-OMe
O
H
O
TBSO
TBSO
TBSO
TBSO
O
Me
O
•
Me
OTBS
OTBS
H
(b) by shortening the distance MeO-H—-C3’
H
3a
4a
-(aS)
In
a first surface exploration corresponding to
pathway a), the distance MeO-H---C1’ was shortened
and the MeOH molecule was positioned so as to allow
interaction between the oxygen, which will transfer a
proton, and the lithium ion to generate after transfer, a
TMEDA-Li-OMe species and the propargyl xyloside 3a
(Figure 4a). This process is globally barrier-less and the
driving force for this reaction seems again the
formation of the Li-OMe bond (distance O-Li 1.85 Å just
before the proton transfer). In a second surface
exploration (pathway b), we brought the H of MeOH
closer to C3’ to see if the allenic structure could be
formed in this way (Figure 4b). And indeed, it is
possible to access 4a-(aS), the major diastereoisomer
experimentally observed in agreement with the X-ray
studies, in an almost barrier-free process judging by the
observation of the evolution of energy during the
shortening of the MeO-H---C3’ distance. Once again,
allowing interaction between the O that will transfer the
proton and the Li (distance O-Li of 1.83 Å) stabilizes the
system. The situation became again very different,
when in a third scan in analogy to the process shown in
Figure 3b, the MeOH was brought closer to the opposite
side of the Li-TMEDA chelate. As the methanolate
formed during the proton transfer cannot be stabilized
by the Li ion, too far away on the opposite side, the
energy cost of this transfer, was found much higher (the
evolution of energy is in adequacy, see Scheme S6 in SI),
and therefore the formation of 4a-(aR) is highly
disadvantaged.
4a
-(aS) + TMEDA-Li-OMe
Figure 4. DFT Calculations: favored protonation
pathways of 3a-Li-(S).
Conclusion
In conclusion, we have reported an in-depth study on
the diastereoselective synthesis of new 1,3-
disubstituted alkoxyallenes using a xyloside as chiral
auxiliary. This procedure could be applied to a variety
of substituted propargyl xylosides, including alkyl, silyl
and aryl groups. Depending on the steric bulk and the
electronic influence good to excellent yields and
moderate to high d.r. values were observed. NMR
spectroscopy, DFT calculations and X-ray structure
analysis provided insights on the structure of the major
diastereoisomer 4a-(aS) as well as the underlying
mechanism of its formation. At this stage of the study, it
is not possible to definitively discriminate between the
two mechanisms SE2 and SE2’ for the protonation step.
The large size of the system and the protonation almost
without energy barrier did not allow to obtain
transition states of the reaction and thus data
concerning the kinetics of the reaction. In addition,
other parameters, such as the aggregation of the alcohol
in ether at -115 °C of the intermediate lithium
complexes, are not known. Nevertheless, this study
brings a certain number of new general elements for
these isomerization processes with alkoxy derivatives.
The existence of the metallotropic equilibrium has been
demonstrated by deuteration reactions, variable
temperature reactions and by DFT studies. The different
regioselectivities obtained depending on the proton
source show that the interconversion between Li-
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propargyl/allenyl
intermediates
during the
beamline at the Australian Synchrotron facility.27 The
1
2
3
4
5
6
7
8
metallotropic equilibrium is rapid and has no real
influence on the regio- and the diastereo-selective
outcome of the reaction. The predominant formation of
the allenes 4a mainly depends on the protonation step.
The DFT studies have also evidenced structural aspects
on the lithium species in particular about the chelation
of the lithium atom i) in the Li-propargyl (P), to the
cyclic oxygen of the sugar, ii) in the Li-allenyl (A), over
the whole allenyl fragment. In addition, these
theoretical studies have also shown that during the
protonation step, the approach of the proton source
must be done on the same side as the chelate Li-TMEDA
and the driving force for this reaction seems the
formation of a LiOMe-TMEDA complex. Since we now
dispose of a new family of allenes, their use as
precursors in the diastereoselective synthesis of more
complex molecules such as new heterocycles will be
investigated.2e,5b
melting points were measured in capillary tubes with
an SMP3 melting point device from Stuart Equipment.
Optical rotations were measured on a Perkin Elmer 341
polarimeter. Infrared spectra were obtained from neat
compounds, on a Nicolet ‘Magna 550’ spectrometer
using an ATR (Attenuated Total Reflection) module.
Elemental analyses were performed on a Thermo
Electron
Flash
EA.
All
reagents
were
9
purchased from commercial sources and were used as
received, unless noted otherwise.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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41
42
43
44
45
46
47
48
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58
59
60
Synthesis
of
2-(prop-2-yn-1-yl)-2,3,4-tri-O-t-
butyldimethylsilyl-β-D-xylopyranoside 2. To a solution of
the unprotected xyloside 1 (0.61 g, 8.56 mmol) in DMF
(10 mL) were added imidazole (2.9 g, 42.8 mmol),
TBSCl (5.18 g, 34.24 mmol) and DMAP (45 mg, 0.17
mmol ca) and the mixture was heated at 80 °C with an
oil bath for 6 days. Then, the resulting mixture was
diluted with water, extracted with CH2Cl2, washed with
10% NaHCO3 and brine. The combined organic extracts
were dried over MgSO4, filtered and concentrated under
reduced pressure. The crude residue was purified by
flash column chromatography over silica gel (10%
EtOAc in hexanes) to afford the TBS-protected xyloside
2 as a colorless solid in 91% yield (4.15 g). 1H NMR (500
MHz, CDCl3) δ 4.75 (d, J = 3.3 Hz, 1H, H1), 4.25 (dd, J =
15.7, 2.4 Hz, 1H, H1’), 4.21 (dd, J = 15.7, 2.4 Hz, 1H, H1’),
4.02 (dd, J = 11.6, 2.9 Hz, 1H, H5), 3.61 (t, J = 3.9 Hz, 1H,
H4), 3.56 (m, 1H, H3), 3.52 (t, J = 3.3 Hz, 1H, H2), 3.40
(dd, J = 11.6, 3.9 Hz, 1H, H5), 2.37 (t, J = 2.4 Hz, 1H, H3’),
0.90-0.74 (27H, CH3(Sit-Bu)), 0.12-0.06 (18H, CH3(SiMe)).
13C{1H} NMR (126 MHz, CDCl3) δ 99.7 (C1), 79.5 (C2’),
74.3 (C3’), 74.1 (C3), 73.3 (C2), 70.5 (C4), 63.2 (C5), 54.4
(C1’), 26.3, 26.2, 26.1 (CH3(Sit-Bu)), 18.4, 18.0 (Cq(Sit-Bu)), -
3.8, -3.9, -4.0, -4.1, -4.6 (CH3(SiMe)). HRMS (EI) m/z:
[M+Na]+ Calcd for C26H54O5NaSi3 553.3177; Found
Experimental part
General Information
All manipulations were performed under strict
exclusion of air or moisture on a vacuum line using
Schlenk techniques or in dry boxes under purified argon
atmosphere. All solvents (THF, diethyl ether) were
dispensed by a solvent dispenser (PureSolvTM by
Innovative
commercially available and used as received. 1,2,3,4-
tetra-O-acetyl-β-D-xylopyranose 3-(4-
7,11b
Technology).
But-2-yn-1-ol
was
fluorophenyl)prop-2-yn-1-ol25 and 4,4-dimethylpent-2-
yn-1-ol26 were synthesized as previously described in
the literature. NMR measurements were obtained using
a Bruker Avance I spectrometer equipped with a QNP
probe (250 MHz for the 1H), a Bruker Avance III
spectrometer equipped with a BBFO+ probe (500 MHz
for 1H, 126 MHz for 13C and 471 MHz for 19F) or a
Bruker Avance III spectrometer equipped with a CPTCI
553.3190. [α]20 = -12.5 (c 1.1, CHCl3). m.p. 37 °C. IR
D
(neat, cm-1) 2928, 2855, 1471, 1463, 1389, 1256, 1251,
1091, 1011, 831, 673.
General procedure for the alkylation/silylation
reactions with 2
Cryosonde (600 MHz for H and 151 MHz for 13C). The
1
To a solution of 2 in dry THF, was slowly added n-BuLi
(1.1 eq.) at –78 °C. After 1h, the corresponding CH3I or
TMSCl (2 eq.) was added dropwise. The mixture was
stirred for 1 h whilst being allowed to warm to room
temperature. A saturated aqueous NaHCO3 solution was
added, and the two phases were separated. The
aqueous phase was then extracted with Et2O. The
combined organic phases were dried over MgSO4,
filtered and the solvents were evaporated. The crude
reaction mixture was purified by a flash column
chromatography over silica gel (eluent: PE/EtOAc 9:1)
to afford the substituted alkyne.
spectra were recorded at 298 K in CDCl3, dried over
molecular sieves unless mentioned otherwise. Chemical
shifts are expressed in parts per million (ppm) and
pattern abbreviations are s for singlet, d for doublet, dd
for doublet of doublet, t for triplet, q for quartet, quint
for quintuplet, sext for sextuplet and m for multiplet.
High resolution ESI-MS spectra were recorded on a
hybrid tandem quadrupole/time-of-flight (Q-TOF)
instrument, equipped with a pneumatically assisted
electrospray (Z-spray) ion source (Micromass,
Manchester, UK) operated in positive mode. High
resolution EI-MS spectra were obtained on a GCT-TOF
mass spectrometer (Micromass, Manchester, UK) with
EI source. Crystallographic data was collected on a
Bruker D8 Venture diffractometer and on the MX2
Synthesis
of
2-(but-2-yn-1-yl)-2,3,4-tri-O-t-
butyldimethylsilyl-β-D-xylopyranoside 3a. According to
ACS Paragon Plus Environment

Page 11 of 18
The Journal of Organic Chemistry
the general procedure, 2 (1.47 g, 2.79 mmol), n- the general procedure, 2 (210 mg, 0.39 mmol), Pd
1
2
3
4
5
6
7
8
butyllithium (1.34 mL, 3.32 mmol) and iodomethane
(0.6 mL, 5.58 mmol) were reacted in THF (15 mL) to
afford product 3a as a colorless oil in 94% yield (1.46 g,
(PPh3)4 (5 mg), CuI (6 mg) and iodobenzene (0.05 mL,
0.44 mmol) were reacted in a mixture of THF (0.5 mL)
and Et3N (2 mL) to afford product 3c as a colorless oil in
1
1
2.68 mmol). H NMR (500 MHz, CDCl3) δ 4.75 (d, J = 3.4
quantitative yield (223 mg, 0.37 mmol). H NMR (500
Hz, 1H, H1), 4.26 (d, J = 15.3 Hz, 1H, H1’), 4.20 (d, J = 15.3
Hz, 1H, H1’), 4.00 (dd, J = 11.6, 3.0 Hz, 1H, H5), 3.60 (m,
1H, H3), 3.55 (m, 1H, H4), 3.49 (t, J = 3.4 Hz, 1H, H2), 3.37
(dd, J = 11.6, 4.0 Hz, 1H, H5), 1.82 (t, J = 2.3 Hz, 3H, CH3),
0.95-0.84 (27H, CH3(Sit-Bu)), 0.12-0.05 (18H, CH3(SiMe)).
13C{1H} NMR (151 MHz, CDCl3) δ 99.3 (C1), 82.4 (C2’),
74.9 (C3’), 74.2 (C3), 73.5 (C2), 70.6 (C4), 63.3 (C5), 55.0
(C1’), 26.3, 26.2, 26.1 (CH3(Sit-Bu)), 18.5, 18.4, 18.0 (Cq(Sit-
Bu)), 3.7 (CH3), -3.8, -3.9, -4.0, -4.1, -4.6 (CH3(SiMe)). HRMS
(EI) m/z: [M+Na]+ Calcd for C27H56O5NaSi3 567.3333;
MHz, CDCl3) δ 7.41 (m, 2H, HAr), 7.30 (m, 2H, HAr), 4.83
(d, J = 3.4 Hz, 1H, H1), 4.48 (d, J = 15.3 Hz, 1H, H1’), 4.43
(d, J = 15.3 Hz, 1H, H1’), 4.05 (dd, J = 11.5, 3.0 Hz, 1H, H5),
3.62 (m, 1H, H3), 3.57 (m, 1H, H4), 3.54 (t, J = 3.4 Hz, 1H,
H2), 3.41 (dd, J = 11.5, 4.0 Hz, 1H, H5), 0.90 (27H, CH3(Sit-
Bu)), 0.13-0.03 (18H, CH3(SiMe)). 13C{1H} NMR (126 MHz,
CDCl3) δ 131.8 (CAr), 128.4 (CAr), 128.3 (CAr), 99.6 (C1),
86.2 (C2’), 85.0 (C3’), 74.1 (C3), 73.4 (C2), 70.6 (C4), 63.3
(C5), 55.1 (C1’), 26.3, 26.2, 26.1 (CH3(Sit-Bu)), 18.5, 18.0
(Cq(Sit-Bu)), -3.7, -3.9, -4.0, -4.6 (CH3(SiMe)). HRMS (EI) m/z:
[M+Na]+ Calcd for C32H58O5NaSi3 629.3490; Found
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Found 567.3340. [α]20 = -27 (c 0.55, CHCl3). IR (neat,
D
cm-1) 2928, 2894, 1472, 1463, 1389, 1256, 1255, 1096,
1011, 939, 836, 776.
629.3488. [α]20 = -30 (c 0.59, CHCl3). IR (neat, cm-1)
D
2928, 2856, 1748, 1471, 1361, 1251, 1043, 1078, 831.
Synthesis of the 2-(3-(trimethylsilyl)prop-2-yn-1-yl)-
Synthesis of 2-(3-(4-methoxyphenyl)prop-2-yn-1-yl)-
2,3,4-tri-O-t-butyldimethylsilyl- β -D-xylopyranoside 3d.
According to the general procedure, 2 (370 mg, 0.69
mmol), Pd(PPh3)4 (5 mg), CuI (6 mg) and 1-iodo-4-
methoxybenzene (180 mg, 0.76 mmol) were reacted in
a mixture of THF (1 mL) and Et3N (3.5 mL) to afford
product 3d as a colorless oil in 93% yield (409 mg, 0.64
2,3,4-tri-O-t-butyldimethylsilyl-β-D-xylopyranoside
3b.
According to the general procedure, 2 (175 mg, 0.33
mmol), n-butyllithium (0.19 mL, 0.36 mmol) and TMSCl
(0.05 mL, 0.36 mmol), were reacted in THF (1 mL) to
afford product 3b as a colorless oil in quantitative yield
1
(199 mg, 0.33 mmol). H NMR (500 MHz, CDCl3) δ 4.74
1
(d, J = 3.0 Hz, 1H, H1), 4.24 (d, J = 15.3 Hz, 1H, H1’), 4.19
(d, J = 15.3 Hz, 1H, H1’), 3.99 (dd, J = 11.4, 2.8 Hz, 1H, H5),
3.60 (t, J = 3.9 Hz, 1H, H3), 3.56-3.52 (m, 1H, H4), 3.50 (t,
J = 3.3 Hz, 1H, H2), 3.37 (dd, J = 11.4, 3.3 Hz, 1H, H5),
0.92-0.86 (27H, CH3(Sit-Bu)), 0.15 (s, 9H, CH3(TMS)), 0.11-
0.05 (18H, CH3(SiMe)). 13C{1H} NMR (126 MHz, CDCl3) δ
101.4 (C2’), 99.3 (C1), 91.1 (C3’), 73.7 (C3), 73.1 (C2), 70.4
(C4), 62.8 (C5), 54.9 (C1’), 26.3, 26.2, 26.0 (CH3(Sit-Bu)),
18.5, 18.4, 18.0 (Cq(Sit-Bu)), 0.0 (CH3(TMS)), -3.8, -3.9, -4.0, -
4.1, -4.6 (CH3(SiMe)). HRMS (EI) m/z: [M+Na]+ Calcd for
mmol). H NMR (500 MHz, CDCl3) δ 7.35 (d, J = 8.4 Hz,
2H, HAr), 6.82 (d, J = 8.4 Hz, 2H, HAr), 4.82 (d, J = 3.2 Hz,
1H, H1), 4.46 (d, J = 15.3 Hz, 1H, H1’), 4.41 (d, J = 15.3 Hz,
1H, H1’), 4.04 (dd, J = 11.6, 2.7 Hz, 1H, H5). 3.81 (s, 3H,
OCH3), 3.61 (m, 1H, H3), 3.57 (m, 1H, H4), 3.53 (t, J = 3.5
Hz, 1H, H2), 3.40 (dd, J = 11.6, 3.9 Hz, 1H, H5), 0.90 (27H,
CH3(Sit-Bu)), 0.13-0.03 (18H, CH3(SiMe)). 13C{1H} NMR (126
MHz, CDCl3) δ 159.7 (CAr), 133.3 (CAr), 114.0 (CAr), 99.5
(C1), 86.1 (C2’), 83.5 (C3’), 74.1 (C3), 73.4 (C2), 70.6 (C4),
63.3 (C5), 55.4 (C1’), 55.2 (OCH3), 26.3, 26.2, 26.1 (CH3(Sit-
Bu)), 18.5, 18.4 (Cq(Sit-Bu)), -3.8, -3.9, -4.0, -4.6 (CH3(SiMe)).
HRMS (EI) m/z: [M+Na]+ Calcd for C33H60O6NaSi3
C29H62O5NaSi4 625.3572; Found 625.3580. [α]20 = -31
D
(c 0.64, CHCl3). IR (neat, cm-1) 2953, 2928,2895, 1732,
1472, 1462, 1388, 1360, 1250, 1094, 1011, 938, 832,
773.
659.3595; Found 659.3599. [α]20 = -19 (c 0.263,
D
CHCl3). IR (neat, cm-1) 2929, 2895, 2857, 1509, 1404,
1388, 1322, 1250, 1079, 774.
General procedure for the Sonagashira coupling
reactions with 3
Synthesis of 2-(3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-
yl)-2,3,4-tri-O-t-butyldimethylsilyl-β-D-xylopyranoside 3e.
According to the general procedure, 2 (370 mg,0.69
mmol), Pd(PPh3)4 (5 mg), CuI (6 mg) and 1-iodo-4-
trifluoromethylbenzene (0.12 mL, 0.76 mmol) were
reacted in a mixture of THF (1 mL) and Et3N (3.5 mL) to
afford product 3e as a colorless oil in 98% yield (459
mg, 0.68 mmol). 1H NMR (500 MHz, CDCl3) δ 7.56 (d, J =
8.1 Hz, 2H, HAr), 7.50 (d, J = 8.1 Hz, 2H, HAr), 4.82 (d, J =
3.1 Hz, 1H, H1), 4.49 (d, J = 15.3 Hz, 1H, H1’), 4.44 (d, J =
15.3 Hz, 1H, H1’), 4.05 (dd, J = 11.5, 2.8 Hz, 1H, H5), 3.62
(m, 1H, H3), 3.57 (m, 1H, H4), 3.54 (t, J = 3.3 Hz, 1H, H2),
3.42 (dd, J = 11.5, 3.6 Hz, 1H, H5), 0.90 (27H, CH3(Sit-Bu)),
0.15-0.00 (18H, CH3(SiMe)). 13C{1H} NMR (126 MHz,
CDCl3) δ 132.0 (CAr), 125.3 (CAr), 125.3 (CAr), 99.7 (C1),
87.7 (C2’), 84.8 (C3’), 73.9 (C3), 73.3 (C2), 70.4 (C4), 63.2
(C5), 54.9 (C1’), 26.3, 26.2, 26.0 (CH3(Sit-Bu)), 18.5, 18.4,
A dry Schlenk tube under argon atmosphere was
charged with Pd(PPh3)4 (0.005 eq.) and CuI (0.01 eq.), 2
(1 eq.) and iodobenzene (1 eq.) were added followed by
a mixture of THF/Et3N (1:1). After 24 h heating at 55 °C
with an oil bath, the reaction mixture was hydrolyzed
with an aqueous solution of NH4Cl and extracted with
diethyl ether. The organic phase was washed with a
saturated NaCl solution, dried over MgSO4 and
concentrated under reduced pressure. The crude
reaction mixture was purified by a flash column
chromatography over silica gel (eluent: PE/EtOAc 9:1)
to afford the substituted alkyne.
Synthesis of 2-(3-phenylprop-2-yn-1-yl)-2,3,4-tri-O-t-
butyldimethylsilyl- β -D-xylopyranoside 3c. According to
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 18
18.0 (Cq(Sit-Bu)), 1.2 (C8’), -3.8, -3.9, -4.0, -4.1, -4.6
0.02 mmol ca) were reacted in DMF (1 mL) to afford
(CH3(SiMe)). 19F{1H} NMR (471 MHz, CDCl3) δ -62.9. HRMS
product 3f as a colorless oil in 97 % yield (501 mg, 0.85
1
2
3
4
5
6
7
8
1
(EI) m/z: [M+Na]+ Calcd for C33H57F3O5NaSi3 697.3364;
mmol). H NMR (500 MHz, CDCl3) δ 4.70 (d, J = 3.4 Hz,
Found 697.3365. [α]20 = -29 (c 0.476, CHCl3). IR (neat,
1H, H1), 4.23 (d, J = 15.0 Hz, 1H, H1’), 4.16 (d, J = 15.0 Hz,
1H, H1’), 3.99 (dd, J = 11.5, 3.0 Hz, 1H, H5), 3.59 (m, 1H,
H3), 3.54 (m, 1H, H4), 3.49 (t, J = 3.4 Hz, 1H, H2), 3.36
(dd, J = 11.5, 4.0 Hz, 1H, H5), 1.20 (s, 9H, H5’), 0.96-0.85
(27H, CH3(Sit-Bu)), 0.14-0.04 (18H, CH3(SiMe)). 13C{1H} NMR
(126 MHz, CDCl3) δ 99.2 (C1), 95.0 (C2’), 74.2 (C3), 74.1
(C3’), 73.4 (C2), 70.6 (C4), 63.1 (C5), 54.8 (C1’), 31.1 (C5’),
26.4, 26.3, 26.1 (CH3(Sit-Bu)), 22.7 (C4’), 18.5, 18.0 (Cq(Sit-
Bu)), -3.7, -3.9, -4.0, -4.5 (CH3(SiMe)). HRMS (EI) m/z:
[M+Na]+ Calcd for C30H62O5NaSi3 609.3796; Found
D
cm-1) 2929, 2895, 2857, 1471, 1322, 1079, 1065, 774,
657, 439.
Synthesis of 2-(4,4-dimethylpent-2-yn-1-yl)-2,3,4-tri-O-
tert-butyldimethylsilyl-β-D-xylopyranoside 3f in 3 steps
(see SI for synthesis scheme).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To a solution of 1,2,3,4-tetra-O-acetyl-β-D-xylopyranose
7 (4.0 g, 12.58 mmol) and 4,4-dimethylpent-2-yn-1-ol
(2 mL, 15.09 mmol) in dry CH2Cl2 (30 mL) at 0 °C, was
added dropwise BF3·Et2O (2.4 mL, 18.87 mmol). The
reaction mixture was stirred for 3h at 0 °C. The reaction
mixture was warmed to r.t. then extracted with CH2Cl2
(3 times), washed with 10 % NaHCO3 (3 times) and
brine (3 times). The organic layer was dried over
MgSO4, filtered and concentrated under reduced
pressure. The crude residue was purified by flash
column chromatography over silica gel (10% EtOAc in
PE) to afford the acetylated xyloside. 8c as a white solid
609.3803. [α]20 = -30 (c 1.06, CHCl3). IR (neat, cm-1)
D
2953, 2856, 1472, 1251, 1085, 1011, 969, 832.
General procedure for the synthesis of disubstituted
allenes 4a-f
To a solution of the propargyl xyloside 3a-f (1 eq.) and
TMEDA (1.1 eq.) in Et2O at -78 °C was added s-BuLi (1.1
eq.). The resulting mixture was stirred at -78 °C for 1h,
and then the temperature was decreased to reach -115
°C. After 30 min at -115 °C, a solution of t-BuOH (20
eq.) in Et2O was added dropwise. The reaction mixture
was stirred over 1h, warmed to r.t. and diluted with
diethyl ether and water. The two phases were separated
and the aqueous phase was extracted again with ether.
The combined organic extracts were washed with 10%
NaHCO3 and brine, dried over MgSO4, filtered and
concentrated under reduced pressure to afford the
1
in 68 % yield (3.13 g, 8.45 mmol). H NMR (600 MHz,
CDCl3) δ 5.19 (t, J = 8.4 Hz, 1H, H3), 4.96-4.89 (2H, H2 +
H4), 4.74 (d, J = 6.7 Hz, 1H, H1), 4.30 (s, 2H, H1’), 4.12
(dd, J = 11.9, 5.0 Hz, 1H, H5), 3.39 (dd, J = 11.9, 8.5 Hz,
1H, H5), 2.07 (s, 3H, CH3(OAc)), 2,05 (s, 3H, CH3(OAc)), 2.04
(s, 3H, CH3(OAc)), 1.22 (s, 9H, H5’). 13C{1H} NMR (151
MHz, CDCl3) δ 170.3 (C=O), 170.0 (C=O), 169.7 (C=O),
97.9 (C1), 96.4 (C2’), 73.0 (C3’), 71.4 (C3), 70.6 (C2), 69.1
(C4), 62.1 (C5), 56.4 (C1’), 31.0 (C5’), 27.6 (C4’), 21.0, 20.9
(CH3(OAc)). HRMS (EI) m/z: [M+Na]+ Calcd for
crude product as
a
mixture of allenes (two
diasteroisomers (aS):(aR))/propargyl.
C18H26O8Na 393.1525; Found 393.1526. [α]20 = -17 (c
D
0.6, CHCl3). m.p. 117 °C. IR (neat, cm-1) 3320, 2971,
1771, 1444, 1357, 1161, 1104, 1038, 637, 615.
Synthesis
of
2-(buta-1,2-dien-1-yl)-2,3,4-tri-O-t-
butyldimethylsilyl-β-D-xylopyranoside 4a. According to
the general procedure, 3a (177 mg, 0.325 mmol),
TMEDA (0.1 mL, 0.65 mmol), s-BuLi (0.46 mL, 0.65
mmol) and t-BuOH (1 mL) were reacted in Et2O (4 mL +
2 mL) to obtain the crude product (177 mg) as a
To a solution of 8c (3.13 g, 8.45 mmol) in methanol (30
mL) was added Na (10 mg). The mixture was stirred at
r.t. for 2 h. The resulting mixture was filtered through a
short pad of DOWEX-50H+ resin, concentrated under
reduced pressure and the residue was then purified by
flash column chromatography over silica gel (5 % MeOH
in CH2Cl2) to afford the unprotected xylosides 9c as a
mixture
of
allenes
4a-(aS)/(aR)
(93:7)
/propargyl (91:9). The crude product was purified by
flash column chromatography over silica gel (1% Et2O,
1% Et3N in PE) and the major diastereoisomer of the
allenes 4a-(aS) was isolated as a white solid (158.6 mg,
75%). Diastereoisomer 4a-(aS): 1H NMR (500 MHz,
CDCl3) δ 6.47 (qd, J = 5.5, 2.3 Hz, 1H, H1’), 5.70 (qd, J =
6.9, 5.5 Hz, 1H, H3’), 4.77 (d, J = 4.3 Hz, 1H, H1), 4.04 (dd,
J = 11.6, 3.4 Hz, 1H, H5), 3.60-3.58 (3H, H2 + H3 + H4),
3.39 (dd, J = 11.6, 5.0 Hz, 1H, H5), 1.75 (dd, J = 6.9, 2.3
Hz, 3H, CH3(allene)), 0.91-0.88 (27H, CH3(Sit-Bu)), 0.09-0.07
(18H, CH3(SiMe)). 13C{1H} NMR (126 MHz, CDCl3) δ 194.9
(C2’), 117.4 (C1’), 100.9 (C3’), 100.1 (C1), 74.9 (C4), 73.5
(C2), 70.8 (C3), 64.4 (C5), 26.0, 26.1, 26.2, 26.3 (CH3(Sit-
Bu)), 18.5, 18.4 (Cq(Sit-Bu)), 16.8 (CH3(allene)), -3.6, -3.8, -3.9,
-4.1, -4.6 (CH3(SiMe)). HRMS (EI) for C27H56O5NaSi3: calc.
1
white solid in quantitative yield (2.06 g, 8.45 mmol). H
NMR (500 MHz, CD3OD) δ 4.40 (d, J = 7.6 Hz, 1H, H1),
4.28 (m, 2H, H1’), 3.88 (dd, J = 11.5, 5.3 Hz, 1H, H5), 3.49
(m, 1H, H4), 3.31 (m, 1H, H3), 3.22-3.16 (2H, H2 + H5),
1.23 (s, 9H, (CH3)3). 13C{1H} NMR (126 MHz, CD3OD) δ
102.7 (C1), 96.4 (C2’), 77.7 (C3), 74.9 (C3’), 74.6 (C2), 71.2
(C4), 66.9 (C5), 57.1 (C1’), 31.3 (C5’), 28.4 (C4’). HRMS (EI)
for C12H20O5Na: calc. (m/z) 267.1208; found (m/z)
267.1215. [α]20 = -21 (c 0.7, CH3OH); m.p. 102 °C. IR
D
(neat, cm-1) 3306, 2971, 2925, 2864, 1444, 1359, 1248,
1138, 1071, 1053, 615.
(m/z) 567.3333; found (m/z) 567.3329. [α]20 = -5.5 (c
According to the synthesis of 2, unprotected D-xyloside
9c (230 mg, 0.87 mmol), imidazole (300 mg, 4.35
mmol), TBSCl (530 mg, 3.48 mmol) and DMAP (5 mg,
D
0.61, CHCl3). m.p. 54 °C. IR (neat, cm-1) 2891, 2931,
2836, 1981, 1471, 1250, 830. Anal. Calcd for
ACS Paragon Plus Environment

Page 13 of 18
The Journal of Organic Chemistry
C27H56O5Si3: C, 59.50; H, 10.36. Found: C, 59.30; H, from spectrum of
a
a crude reaction mixture.
1
1
2
3
4
5
6
7
8
10.66.
Diastereoisomer 4d-(aS): H NMR (500 MHz, CDCl3) δ
7.35 (d, J = 8.4 Hz, 2H, HAr), 6.90 (d, J = 5.7 Hz, 1H, H1’),
6.84 (d, J = 8.4 Hz, 2H, HAr), 6.62 (d, J = 5.6 Hz, 1H, H3’),
4.82 (d, J = 2.9 Hz, 1H, H1), 4.03 (m, 1H, H5), 3.81 (s, 3H,
OCH3), 3.57-3.46 (3H, H3 + H2 + H4), 3.33 (m, 1H, H5),
0.94-0.85 (27H, CH3(Sit-Bu)), 0.13-0.07 (18H, CH3(SiMe)).
Synthesis of the 2-(3-trimethylsilylpropa-1,2-dien-1-yl)-
2,3,4-tri-O-t-butyldimethylsilyl-β-D-xylopyranoside
4b.
According to the general procedure, 3b (159 mg, 0.26
mmol), TMEDA (0.08 mL, 0.52 mmol), s-BuLi (0.1 mL,
0.52 mmol) and t-BuOH (0.3 mL) were reacted in Et2O
(1 mL + 0.6 mL) to obtain the crude product 4b (159
mg) as a mixture of allenes (d.r.: 70:30) /propargyl
(42:58). Due to the small difference in polarity between
3b and 4b, these products could not be separated by
column chromatography. However, attempts to assign
signals are given below from a spectrum of a crude
reaction mixture. Diastereoisomer 4b-(aS): 1H NMR
(500 MHz, CDCl3) δ 6.48 (d, J = 6.4 Hz, 1H, H1’), 5.83 (d, J
= 6.4 Hz, 1H, H3’), 4.65 (d, J = 4.2 Hz, 1H, H1), 3.99 (dd, J =
11.4, 2.8 Hz, 1H, H5), 3.60-3.47 (3H, H3 + H2 + H4), 3.37
(dd, J = 11.4, 3.3 Hz, 1H, H5), 0.92-0.86 (27H, CH3(Sit-Bu)),
0.15 (s, 9H, CH3TMS), 0.11-0.05 (18H, CH3(SiMe)).
1
Diastereoisomer 4d-(aR): H NMR (500 MHz, CDCl3) δ
7,35 (d, J = 8.4 Hz, 2H, HAr), 6.90 (d, J = 5.7 Hz, 1H, H1’),
6.84 (d, J = 8.4 Hz, 2H, HAr), 6.72 (d, J = 5.6 Hz, 1H, H3’),
4.85 (d, J = 2.9 Hz, 1H, H1), 4.03 (m, 1H, H5), 3.81 (s, 3H,
OCH3), 3.57-3.46 (3H, H3 + H2 + H4), 0.94-0.85 (27H,
CH3(Sit-Bu)), 0.13-0.07 (18H, CH3(SiMe)).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Synthesis of the 2-(3-(4-(trifluoromethyl)phenyl)propa-
1,2-dien-1-yl)-2,3,4-tri-O-t-butyldimethylsilyl-β-D-
xylopyranoside 4e. According to the general procedure,
3e (52 mg, 0.08 mmol), TMEDA (0.05 mL, 0.09 mmol),
s-BuLi (0.07 mL, 0.09 mmol) and t-BuOH (0.3 mL) were
reacted in Et2O (1 mL + 0.6 mL) to obtain the crude
product 4e as a mixture of allenes (aS)/(aR) (55:45).
The allenes were not isolated in a pure form, due to
their low stability over time and on silica gel (or
alumina). However, attempts to assign some signals are
given below from a spectrum of a crude reaction
mixture. Diastereoisomer 4e-(aS): 1H NMR (500 MHz,
CDCl3) δ 7.55 (d, J = 8.0 Hz, 2H, HAr), 7.46 (m, 2H, HAr),
7.00 (d, J = 5.6 Hz, 2H, H1’), 6.67 (d, J = 5.6 Hz, 1H, H3’),
4.86 (d, J = 3.2 Hz, 1H, H1). 19F{1H} NMR (471 MHz,
1
Diastereoisomer 4b-(aR): H NMR (500 MHz, CDCl3) δ
6.53 (d, J = 6.4 Hz, 1H, H1’), 5.86 (d, J = 6.4 Hz, 1H H3’),
4.67 (d, J = 3.1 Hz, 1H, H1), 3.99 (dd, J = 11.4, 2.8 Hz, 1H,
H5), 3.60-3.47 (3H, H3 + H2 + H4), 3.37 (dd, J = 11.4, 3.3
Hz, 1H, H5), 0.92-0.86 (27H, CH3(Sit-Bu)), 0.15 (s, 9H,
CH3TMS), 0.11-0.05 (18H, CH3(SiMe)).
Synthesis of 2-(3-phenylpropa-1,2-dien-1-yl)-2,3,4-tri-O-t-
butyldimethylsilyl-β-D-xylopyranoside 4c. According to
the general procedure, 3c (76 mg, 0.12 mmol), TMEDA
(0.02 mL, 0.13 mmol), s-BuLi (0.1 mL, 0.13 mmol) and t-
BuOH (0.4 mL) were reacted in Et2O (1 mL + 0.8 mL) to
obtain the crude product 4c (75 mg) as a mixture of
1
CDCl3) δ -62.4. Diastereoisomer 4e-(aR): H NMR (500
MHz, CDCl3) δ 7.55 (d, J = 8.0 Hz, 2H, H5’), 7.46 (m, 2H,
H6’), 7.00 (d, J = 5.6 Hz, 2H, H1’), 6.78 (d, J = 5.7 Hz, 1H,
H3’), 4.88 (d, J = 3.2 Hz, 1H, H1). 19F{1H} NMR (471 MHz,
CDCl3) δ -62.5.
allenes (aS)/(aR) (70:30)/propargyl (65:35).
The
allenes were not isolated from the propargyl 3c, due to
their low stability over time and over silica gel (or
alumina). However, attempts to assign signals are given
below from a spectrum of a crude reaction mixture.
Synthesis of 2-(4,4-dimethylpenta-1,2-dien-1-yl)-2,3,4-tri-
O-t-butyldimethylsilyl-β-D-xylopyranoside 4f. According
to the general procedure, 3f (90 mg, 0.17 mmol),
TMEDA (0.1 mL, 0.25 mmol), s-BuLi (0.25 mL, 0.25
mmol) and t-BuOH (0.25 mL) were reacted in Et2O (1
mL + 0.5 mL) to obtain the crude (90 mg) as a mixture
of allene (aS):(aR) (80:20). The crude product was
purified by flash column chromatography on silica gel
(1% Et2O, 1% Et3N in PE) and a small amount of the
major diastereoisomer of the allenes 4f-(aS) was
isolated in a pure form as a white solid (13 mg, 14%)
and mixture of allenes (75 mg). Diastereoisomer 4f-
(aS): 1H NMR (500 MHz, CDCl3) δ 6.57 (d, J = 5.6 Hz, 1H,
H1’), 5.80 (d, J = 5.6 Hz, 1H, H3’), 4.75 (d, J = 3.4 Hz, 1H,
H1), 4.04 (dd, J = 11.8, 2.9 Hz, 1H, H5), 3.62-3.56 (3H, H3
+ H2 + H4), 3.39 (dd, J = 11.8, 3.7 Hz, 1H, H5), 1.04 (s, 9H,
CH3(t-Bu)), 0.93-0.87 (27H, CH3(Sit-Bu)), 0.10-0.04 (18H,
CH3(SiMe)). 13C{1H} NMR (126 MHz, CDCl3) δ 190.2 (C2’),
119.1 (C1’), 117.3 (C3’), 99.9 (C1), 74.2 (C4), 73.2 (C2),
70.5 (C3), 63.6 (C5), 33.2 (Cq(t-Bu,allene)), 29.7 (CH3(t-
Bu,allene)), 26.3, 26.1 (CH3(Sit-Bu)), 18.5, 18.4 (Cq(Sit-Bu)), -3.7,
-3.9, -4.0, -4.2, -4.5 (CH3(SiMe)). HRMS (EI) m/z: [M+Na]+
Calcd for C30H62O5NaSi3 609.3803; Found 697.3815.
[α]20D -19.4 (c 0.175, CHCl3).
1
Diastereoisomer 4c-(aS): H NMR (500 MHz, CDCl3) δ
7.42-7.29 (5H, HAr), 6.94 (d, J = 5.7 Hz, 1H, H1’), 6.66 (d, J
= 5.6 Hz, 1H, H3’), 4.82 (d, J = 3.2 Hz, 1H, H1), 4.05 (m,
1H, H5), 3.62-3.50 (3H, H3 + H2 + H4), 3.34 (dd, J = 11.5,
3.6 Hz, 1H, H5), 0.90-0.84 (27H, CH3(Sit-Bu)), 0.12-0.08
1
(18H, CH3(SiMe)). Diastereoisomer 4c-(aR): H NMR (500
MHz, CDCl3) δ 7.42-7.29 (5H, HAr), 6.94 (d, J = 5.7 Hz, 1H,
H1’), 6.76 (d, J = 5.6 Hz, 1H, H3’), 4.86 (d, J = 3.2 Hz, 1H,
H1).
Synthesis of 2-(3-(p-methoxy)propa-1,2-dien-1-yl)-2,3,4-
tri-O-t-butyldimethylsilyl-β-D-xylopyranoside
4d.
According to the general procedure, 3d (62 mg, 0.1
mmol), TMEDA (0.05 mL, 0.12 mmol), s-BuLi (0.1 mL,
0.13 mmol) and t-BuOH (0.3 mL) were reacted in Et2O
(1 mL + 0.6 mL) to obtain the crude product 4d (62 mg)
as
a
mixture
of
allenes
(aS)/(aR)
(70:30)/propargyl (50:50). The allenes were not
isolated from the propargyl 3d, due to their low
stability over time and on silica gel (or alumina).
However, attempts to assign signals are given below
ACS Paragon Plus Environment

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Page 14 of 18
General procedure for synthesis of methoxy-
protected propargyl xylosides 5a and 5b in 3 steps
(see SI for synthetic scheme).
Synthesis of (3-(4-fluorophenyl)prop-2-ynyl)-2,3,4-tri-O-
acetyl-β-D-xylopyranoside 8b. According to the general
procedure, 1,2,3,4-tetra-O-acetyl-β-D-xylopyranose
1
2
3
4
5
6
7
8
7
(668 mg, 2.16 mmol), 3-(4-fluorophenyl)prop-2-yn-1-ol
(357 mg, 2.38 mmol) and BF3·Et2O (0.41 mL, 3.24
mmol) were reacted in CH2Cl2 (20 mL) to afford 8b as a
white solid in 62 % yield (548 mg, 1.35 mmol). 1H NMR
(500 MHz, CDCl3) δ 7.42 (dd, J = 8.7, 1.6 Hz, 2H, H5’),
7.02 (t, J = 8.7 Hz, 2H, H6’), 5.20 (t, J = 8.4 Hz, 1H, H1),
5.00-4.91 (2H, H2 + H4), 4.81 (d, J = 6.6 Hz, 1H, H3), 4.54
(d, J = 1.6 Hz, 2H, H1’), 4.16 (dd, J = 11.9, 5.0 Hz, 1H, H5),
3.43 (dd, J = 11.9, 8.4 Hz, 1H, H5), 2.06 (s, 6H, CH3(OAc)),
2.05 (s, 3H, CH3(OAc)). 13C{1H} NMR (126 MHz, CDCl3) δ
170.1 (C=O), 169.9 (C=O), 169.5 (C=O), 162.8 (d, J =
250.0 Hz, C7’), 133.8 (d, J = 8.4 Hz, C5’), 118.4 (d, J = 3.4
Hz, C4’), 115.8 (d, J = 22.2 Hz, C6’), 98.5 (C1), 86.0 (C2’),
83.4 (C3’), 71.3 (C3), 70.6 (C2), 68.9 (C4), 62.1 (C5), 56.5
(C1’), 20.9, 20.8 (CH3(OAc)). 19F{1H} NMR (471 MHz,
CDCl3) δ -110.2. HRMS (EI) m/z: [M+Na]+ Calcd for
To a solution of 1,2,3,4-tetra-O-acetyl-β-D-xylopyranose
7 and the corresponding propargyl alcohol (1.2 eq.) in
dry CH2Cl2 at 0 °C, was added dropwise BF3·Et2O (1.5
eq.). The reaction mixture was stirred for 3h at 0 °C. The
reaction mixture was warmed to r.t. then extracted with
CH2Cl2 (3 times), washed with 10 % NaHCO3 (3 times)
and brine (3 times). The organic layer was dried over
MgSO4, filtered and concentrated under reduced
pressure. The crude residue was purified by flash
column chromatography over silica gel (10% EtOAc in
PE) to afford the corresponding acetylated xylosides
8a,b.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To a solution of the acetylated xyloside derivatives 8a,b
in methanol was added Na (0.3 eq.). The mixture was
stirred at r.t. for 2 h. The resulting mixture was filtered
C20H21O8NaF 431.1118; Found 431.1122. [α]20 = -28 (c
D
through
a
short pad of DOWEX-50H+ resin,
0.80, CHCl3). m.p. 85 °C. IR (neat, cm-1) 3478, 2960,
2239, 1754, 1602, 1508, 1433, 1224, 1077, 840, 757.
concentrated under reduced pressure and the residue
was then purified by flash column chromatography over
silica gel (5
% MeOH in CH2Cl2) to afford the
Synthesis of 2-(but-2-yn-1-yl)-β-D-xylopyranoside 9a.
According to the general procedure, acetylated xylose
derivative 8a (2.87 g, 8.75 mmol) and Na (5 mg) were
reacted in methanol (20 mL) to afford product 9a as a
unprotected xylosides 9a,b.
For the methylation, a literature procedure known for
galactosides was modified for xylosides.28 To a solution
of unprotected D-xylosides 9a,b (1 eq.) in dry
acetonitrile (1 mL / 0.06 mmol), was added MeI (20
eq.), followed by Ag2O (1.2 mmol/OH) and a catalytic
amount of Me2S. The mixture was stirred in the dark at
room temperature. After 21 h, the reaction mixture was
diluted with water. The aqueous phase was extracted
with EtOAc and the combined organic extracts were
washed with brine and dried over MgSO4. The crude
residue was purified by flash column chromatography
over silica gel (10% EtOAc in PE) to afford the
corresponding methylated xyloside 5a,b.
1
white solid in quantitative yield (1.76 g, 8.75 mmol). H
NMR (500 MHz, CD3OD) δ 4.41 (d, J = 7.5 Hz, 1H, H1),
4.31 (dq, J = 15.2, 2.3 Hz, H1’), 3.87 (dd, J = 11.5, 5.3 Hz,
1H, H5), 3.51–3.47 (m, 1H, H4), 3.33–3.31 (m, 1H, H3),
3.23–3.14 (2H, H2 + H5), 1.84 (t, J = 2.3 Hz, 3H, H4’).
13C{1H} NMR (126 MHz, CD3OD) δ 102.6 (C1), 83.6 (C2’),
77.7 (C3), 75.2 (C3’), 74.7 (C2), 71.2 (C4), 66.9 (C5) , 57.1
(C1’) , 3.1 (C4’). HRMS (EI) m/z: [M+Na]+ Calcd for
C9H14O5Na 225.0739; Found 225.0742. [α]20 = -54 (c
D
0.60, CH3OH); m.p. 152 °C ; IR (neat, cm-1) 3385, 2959,
2925, 2869, 1435, 1359, 1243, 1164, 1109, 1046, 975.
Synthesis of 2-((3-(4-fluorophenyl) prop-2-yn-1-yl)-β-D-
xylopyranoside 9b. According to the general procedure,
acetylated xylose derivative 8b (260 mg, 0.63 mmol)
and Na (2 mg) were reacted in methanol (20 mL) to
afford product 9b as a white solid in quantitative yield
(176 mg, 0.63 mmol). 1H NMR (600 MHz, CD3OD) δ
7.46–7.43 (m, 2H, H5’), 7.07 (t, J = 8.8 Hz, 2H, H6’), 4.58
(d, J = 15.8 Hz, 1H, H1’), 4.53 (d, J = 15.7 Hz, 1H, H1’), 4.46
(d, J = 7.4 Hz, 1H, H1), 3.89 (dd, J = 11.5, 5.3 Hz, 1H, H5),
3.50 (ddd, J = 10.1, 8.7, 5.3 Hz, 1H, H4), 3.34 (m, 1H, H3),
3.24-3.20 (2H, H2 + H5). 13C{1H} NMR (151 MHz, CD3OD)
δ 164.9 (d, J = 248.5 Hz, C7’), 134.9 (d, J = 8.7 Hz, C5’),
120.2 (C4’), 116.6 (d, J = 22.5 Hz, C6’), 103.0 (C1), 86.2
(C2’), 85.2 (C3’), 77.6 (C3), 74.7 (C2), 71.1 (C4), 66.9 (C5),
57.2 (C1’). 19F{1H} NMR (235 MHz, CD3OD) δ -112.9.
HRMS (EI) m/z: [M+Na]+ Calcd for C14H15O5NaF
305.0801; Found 305.0803. [α]20D = -29 (c 0.65, CH3OH).
m.p. 181 °C. IR (neat, cm-1) 3386, 2926, 2868, 2780,
1597, 1510, 1361, 1234, 1159, 1046, 977, 837.
Synthesis of the (but-2-ynyl)-2,3,4-tri-O-acetyl-β-D-
xylopyranoside 8a. According to the general procedure,
1,2,3,4-tetra-O-acetyl-β-D-xylopyranose 7 (6.0 g, 18.86
mmol), but-2-yn-1-ol (1.7 mL, 22.63 mmol) and
BF3·Et2O (3.53 mL, 28.29 mmol) were reacted in CH2Cl2
(50 mL) to afford product 8a as a white solid in 92 %
1
yield (5.69 g, 17.35 mmol). H NMR (500 MHz, CDCl3) δ
5.19 (t, J = 8.5 Hz, 1H, H3), 4.97–4.88 (2H, H2 + H4), 4.73
(d, J = 6.8 Hz, 1H, H1), 4.28 (q, J = 2.4 Hz, 2H, H1’), 4.14
(dd, J = 11.9, 5.1 Hz, 1H, H5), 3.39 (dd, J = 11.9, 8.6 Hz,
1H, H5), 2.07 (s, 3H, CH3(OAc)), 2.05 (s, 3H, CH3(OAc)), 2.04
(s, 3H, CH3(OAc)), 1.86 (t, J = 2.4 Hz, 3H, H4’). 13C{1H} NMR
(126 MHz, CDCl3) δ 170.3 (C=O), 170.0 (C=O), 169.6
(C=O), 98.2 (C1), 83.6 (C2’), 73.8 (C3’), 71.5 (C3), 70.7
(C2), 69.0 (C4), 62.2 (C5), 56.4 (C1’), 20.9, 20.8 (CH3(OAc)),
3.8 (C4’). HRMS (EI) m/z: [M+Na]+ Calcd for C15H20O8Na
351.1050; Found 351.1056. [α]20 = -29 (c 0.752,
D
CHCl3); m.p. 108 °C ; IR (neat, cm-1) 2927, 2822 ,1744,
1460, 1368, 1219, 1157, 1046, 904, 879.
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Synthesis of 2-(but-2-yn-1-yl)-2,3,4-tri-O-methyl-β-D- NMR (126 MHz, CDCl3) δ 194.1 (C2’), 117.9 (C1’), 101.9
1
2
3
4
5
6
7
8
xylopyranoside 5a. According to the general procedure,
unprotected D-xylosides 9a (753.7 mg, 3.73 mmol),
Ag2O (3.12 g, 1.2 mmol/OH), Me2S (0.1 mL, ca) and
methyl iodide (12 mL, 186 mmol), were reacted in
acetonitrile (60 mL), to afford product 5a as a white
(C3’), 101.3 (C1), 85.0 (C3), 82.7 (C2), 79.3 (C4), 63.3 (C5),
60.7, 60.5, 58.7 (OCH3), 16.6 (C4’). Diastereoisomer 6a-
1
(aR): H NMR (500 MHz, CDCl3) δ 6.55 (tq, J = 5.2, 2.2
Hz, 1H, H1’), 5.83 (qd, J = 6.9, 5.4 Hz, 1H, H3’), 4.51 (d, J =
6.9 Hz, 1H, H1), 3.99 (m, 1H, H5), 3.59 (s, 3H, OCH3), 3.56
(s, 3H, OCH3), 3.45 (s, 3H, OCH3), 3.25 (m, 1H, H3), 3.17-
3.08 (2H, H2 + H4 + H5), 1.77 (t, J = 2.2 Hz, 3H, H4’).
13C{1H} NMR (126 MHz, CDCl3) δ 194.6 (C2’), 118.1 (C1’),
101.9 (C3’), 101.7 (C1), 85.0 (C3), 82.7 (C2), 79.3 (C4),
63.3 (C5), 60.7, 60.5, 58.7 (OCH3), 16.9 (C4’). IR (neat,
cm-1) 2972, 2931, 2836, 1970, 1736, 1460, 1383, 1324,
1165, 1096, 1020.
1
solid in 95 % yield (856 mg, 3.51 mmol). H NMR (600
MHz, CDCl3) δ 4.38 (d, J = 7.2 Hz, 1H, H1), 4.24 (dq, J =
15.2, 2.4 Hz, 2H, H1’), 3.90 (dd, J = 11.6, 5.1 Hz, 1H, H5),
3.53 (s, 3H, OCH3), 3.50 (s, 3H, OCH3), 3.40 (s, 3H, OCH3),
3.17-3.18 (m, 1H, H4), 3.11-3.05 (2H, H2 + H5), 2.95 (dd, J
= 8.8, 7.2 Hz, 1H, H3), 1.79 (t, J = 2.3 Hz, 3H, H4’). 13C{1H}
NMR (151 MHz, CDCl3) δ 101.4 (C1), 84.9 (C3), 83.0 (C2),
82.9 (C2’), 79.3 (C4), 74.2 (C3’), 63.1 (C5), 60.6 (OCH3),
60.3 (OCH3), 58.6 (OCH3), 56.3 (C1’), 3.7 (C4’). HRMS (EI)
m/z: [M+Na]+ Calcd for C12H20O5Na 267.1208; Found
267.1213. [α]20D = -49 (c 1.2, CHCl3). m.p. 65 °C.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Synthesis of 2-(3-(4-fluorophenyl)propa-1,2-dien-1-yl)-
2,3,4-tri-O-methyl-β-D-xylopyranoside 6b. To a solution
of 5b (98.7 mg, 0.31 mmol) in THF (1mL) at -78 °C was
added n-BuLi (0.18 mL, 0.37 mmol). The resulting
mixture was stirred at -78 °C for 15 min then warmed
to -40 °C and stirred for 25 min. Then, a HCl (1M in H2O)
solution was added dropwise. The reaction mixture was
allowed to warm to room temperature and diluted with
diethyl ether and water. The two phases were separated
and the aqueous phase was extracted again with
diethylether. The combined organic extracts were
washed with 10 % NaHCO3 and brine, dried over
MgSO4, filtered and concentrated under reduced
pressure to afford the crude product (95.4 mg) as a
Synthesis of 2-(3-(4-fluorophenyl)prop-2-yn-1-yl)-2,3,4-
tri-O-methyl-β-D-xylopyranoside 5b. According to the
general procedure, unprotected D-xyloside 9b (280 mg,
1 mmol), Ag2O (1.4 g, 1.2 mmol/OH), Me2S (0.1 mL, ca)
and methyl iodide (3.2 mL, 50 mmol), were reacted in
acetonitrile (20 mL), to afford product 5b as a white
1
solid in 97 % yield (313 mg, 0.96 mmol). H NMR (500
MHz, CDCl3) δ 7.40 (m, 2H, H5’), 6.99 (m, 2H, H6’), 4.55
(m, 2H, H1’), 4.52 (d, J = 7.7 Hz, 1H, H1), 3.99 (dd, J =
11.6, 5.0 Hz, 1H, H5), 3.59 (s, 3H, OCH3), 3.58 (s, 3H,
OCH3), 3.46 (s, 3H, OCH3), 3.27 (m, 1H, H4), 3.21-3.14
(2H, H2 + H5), 3.05 (dd, J = 8.7, 7.1 Hz, 1H, H3). 13C{1H}
NMR (126 MHz, CDCl3) 162.7 (d, J = 249.7 Hz, C7’), 133.8
(d, J = 8.4 Hz, C5’), 118.7 (d, J = 3.7 Hz, C4’), 115.7 (d, J =
22.1 Hz, C6’), 101.7 (C1), 85.6 (C2’), 84.8 (C3), 84.0 (C3’),
83.0 (C2), 79.4 (C4), 63.2 (C5), 60.7 (OCH3), 60.4 (OCH3),
58.7 (OCH3), 56.5 (C1’). 19F{1H} NMR (235 MHz, CDCl3) δ
-110.5. HRMS (EI) m/z: [M+Na]+ Calcd for C17H21O5NaF
347.1271; Found 347.1264. [α]20D = -47 (c 0.62, CHCl3).
m.p. 85 °C. IR (neat, cm-1) 3100, 3065, 2930, 2859,
2745, 2222, 1600, 1506, 1462, 1368, 1221, 1096, 890,
637.
mixture
of
allenes
6b
(aS)/(aR)
(60:40)/propargyl (93:7). The allenes 6b were not
isolated as pure compounds, due to their low stability
over silica gel or alumina, but were fully characterized
in solution by multinuclear NMR spectroscopy.
1
Diastereoisomer 6b-(aS): H NMR (500 MHz, CDCl3) δ
7.34 (m, 2H, H5’), 7.01 (3H, H1’ + H6’), 6.66 (d, J = 5.4 Hz,
1H, H3’), 4.54 (d, J = 7.1 Hz, 1H, H1), 3.85 (dd, J = 11.8, 5.1
Hz, 1H, H5), 3.59 (s, 3H, OCH3), 3.58 (s, 3H, OCH3), 3.44
(s, 3H, OCH3), 3.27 (m, 1H, H4), 3.17-3.13 (2H, H2 + H3),
2.99 (dd, J = 11.8, 9.6 Hz, 1H, H5). 13C{1H} NMR (126
MHz, CDCl3) δ 195.5 (d, J = 2.7 Hz, C2’), 163.7 (d, J =
249.7 Hz, C7’), 133.9 (C1’), 130.6 (d, J = 3.3 Hz, C4’), 129.3
(d, J = 8.1 Hz, C5’), 121.8 (C1), 115.7 (d, J = 22.0 Hz, C6’),
107.4 (C3’) 85.1 (C3), 82.7 (C2), 79.3 (C4), 63.3 (C5), 60.8,
58.8, 58.7 (OCH3). 19F{1H} NMR (471 MHz, CDCl3) δ -
113.7. Diastereoisomer 6b-(aR): 1H NMR (500 MHz,
CDCl3) δ 7.34 (m, 2H, H5’), 7.01 (3H, H1’ + H6’), 7.42 (dd, J
= 8.8, 5.4 Hz, 1H, H3’), 6.75 (d, J = 5.4 Hz, 1H, H1’), 4.58
(d, J = 6.5 Hz, 1H, H1), 4.00 (dd, J = 11.8, 5.3 Hz, 1H, H5),
3.59 (s, 3H, OCH3), 3.58 (s, 3H, OCH3), 3.41 (s, 3H, OCH3),
3.27 (m, 1H, H4), 3.17-3.13 (3H, H2 + H3+ H5). 13C{1H}
NMR (126 MHz, CDCl3) δ 194.8 (d, J = 2.7 Hz, C2’), 161.8
(d, J = 249.7 Hz, C7’), 133.8 (C1’), 130.4 (d, J = 3.3 Hz, C4’),
29.2 (d, J = 8.1 Hz, C5’ + C9’), 121.7 (C1), 115.8 (d, J = 21.9
Hz, C6’ + C8’), 107.4 (C3’), 84.8 (C3), 82.7 (C2), 79.2 (C4),
63.3 (C5), 60.7, 58.8, 58.7 (OCH3). 19F{1H} NMR (471
MHz, CDCl3) δ -113.5.
Synthesis of disubstituted allenes 6a,b
Synthesis of 2-(buta-1,2-dien-1-yl)-2,3,4-tri-O-methyl-β-
D-xylopyranoside 6a. According to the general
procedure, 5a (99.8 mg, 0.41 mmol), TMEDA (0.05 mL,
0.45 mmol), s-BuLi (0.35 mL, 0.45 mmol) and t-BuOH
(0.6 mL) were reacted in Et2O (1 mL + 0.8 mL) to obtain
the crude product 6a (99.8 mg) as a mixture of allenes
6a-(aS)/(aR) (65:35)/propargyl (91:9). The crude
product was purified by flash column chromatography
on silica gel (10% EtOAc in PE) to afford the substituted
allene as a colorless oil for analyses in 15% yield, due to
its low stability over silica gel. Diastereoisomer 6a-(aS):
1H NMR (500 MHz, CDCl3) δ 6.55 (tq, J = 5.2, 2.2 Hz, 1H,
H1’), 5.75 (qd, J = 6.9, 5.4 Hz, 1H, H3’), 4.48 (d, J = 6.9 Hz,
1H, H1), 3.96 (m, 1H, H5), 3.59 (s, 3H, OCH3), 3.55 (s, 3H,
OCH3), 3.45 (s, 3H, OCH3), 3.25 (m, 1H, H3), 3.17-3.08
(2H, H2 + H4 + H5), 1.75 (t, J = 2.2 Hz, 3H, H4’). 13C{1H}
ASSOCIATED CONTENT
Supporting Information.
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Hu, Y. Z.; Wang, Z.-F.; Tao, H.-Y.; Wang, C.-J. Synergistic
Cu/Pd-Catalyzed Asymmetric Allenylic Alkylation of Azomethine
Ylides for the Construction of α-Allene-Substituted
Crystal data (CIF)
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details on conformational studies of xylosides; details on
determination of absolute configuration of 4a(aS) by NOESY
NMR experiments; spectra for all synthetic compounds;
details for X-ray diffraction analysis; mechanistic study details
for DFT calculation including Cartesian coordinates (PDF)
“This material is available free of charge via the Internet at
http://pubs.acs.org.”
Nonproteinogenic α-Amino Acids. Chem. Eur. J. 2019, 25, 8681-
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Functionalized Tetrahydropyridines. Chem. Asian J. 2019, 14,
3409-3413; i) Artigas, A.; Vila, J.; Lledó, A.; Solà, M.; Pla-Quintana,
A.; Roglans, A. A Rh-Catalyzed Cycloisomerization/Diels–Alder
Cascade Reaction of 1,5-Bisallenes for the Synthesis of Polycyclic
Heterocycles. Org. Lett. 2019, 21, 6608-6613.
(3) Reviews: a) Ogasawara, M. Catalytic enantioselective
synthesis of axially chiral allenes. Tetrahedron: Asymmetry 2009,
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2017, 7, 4570-4579; Recent original publications: c)
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of chiral allene moiety from Morita–Baylis–Hillman adduct of
isatin derivatives via Claisen rearrangement. Tetrahedron Lett.
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Zhang, P.; Huang, Q.; Cheng, Y.; Li, R.; Li, P.; Li, W. Remote
Stereocontrolled Construction of Vicinal Axially Chiral
AUTHOR INFORMATION
Corresponding Author
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* Email: yves.gimbert@univ-grenoble-alpes.fr
* Email: sylvain.gatard@univ-reims.fr
* Email: richard.plantier-royon@univ-reims.fr
* Email: florian.jaroschik@enscm.fr
Author Contributions
The manuscript was written through contributions of all
authors.
Notes
The authors declare no conflict of interest.
ACKNOWLEDGMENT
Financial support from the CNRS and the University of Reims
Champagne-Ardenne are gratefully acknowledged. We thank
Carine Machado and Dominique Harakat for mass
spectrometric analyses and we are grateful for the support of
the technological platform PlAneT (ICMR, URCA) for the X-Ray
Diffraction and NMR analyses. Part of this research was also
undertaken on the MX2 beamline at the Australian
Synchrotron, part of ANSTO, and made use of the Australian
Cancer Research Foundation (ACRF) detector. The authors
thank Maja Dunstan for her help collecting XRD data as well as
Robert Gable and Louis Ricard for fruitful discussion. The
authors acknowledge support from the ICMG Chemistry
Nanobio Platform-PCECIC, Grenoble, for calculation facilities.
Tetrasubstituted
Allenes
and
Heteroatom-Functionalized
Quaternary Carbon Stereocenters. Org. Lett. 2019, 21, 503-507; f)
Cheng, X.; Wang, Z.; Quintanilla, C. D.; Zhang, L. Chiral Bifunctional
Phosphine Ligand Enabling Gold-Catalyzed Asymmetric
Isomerization of Alkyne to Allene and Asymmetric Synthesis of
2,5-Dihydrofuran. J. Am. Chem. Soc. 2019, 141, 3787-3791; g)
Yamano, M. M.; Knapp, R. R.; Ngamnithiporn, A.; Ramirez, M.;
Houk, K. N.; Stoltz, B. M.; Garg, N. K. Cycloadditions of Oxacyclic
Allenes and a Catalytic Asymmetric Entryway to Enantioenriched
Cyclic Allenes. Angew. Chem. Int. Ed. 2019, 58, 5653 –5657
(4) a) Harrington, P. E.; Murai, T.; Chu, C.; Tius, M. A.
Asymmetric Cyclopentannelation:ꢀ Camphor-Derived Auxiliary. J.
Am. Chem. Soc. 2002, 124, 10091-10100; b) Hausherr, A.; Reissig,
H.-U. Preparation of 3-Alkyl-Substituted 1-Alkoxyallenes
–
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(23) The lithium species under consideration may form
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in
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macromolecular crystallography communities at the Australian
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O
O
1) s-BuLi
Et2O/TMEDA
-78 °C
•
OTBS
O
OTBS
O
H
R
R
2) t-BuOH
-110 °C
OTBS
OTBS
OTBS
OTBS
R = alkyl, silyl, aryl
42-100% conv.
up to 85% d.e.
DFT calculations
Insert Table of Contents artwork here
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