Phosphite-Thiother Ligands Derived from Carbohydrates allow the Enantioswitchable Hydrogenation of Cyclic β-Enamides by using either Rh or Ir Catalysts

Article abstract of DOI:10.1002/chem.201604483

Phosphite-thioether ligands with a simple modular architecture, derived from inexpensive l-(+)-tartaric acid and d-mannitol, have been for the first time successfully applied (ee values up to 99 %) in the synthesis of 2-aminotetralines and 3-aminochromane

Full text of DOI:10.1002/chem.201604483

A Journal of
Accepted Article
Title: Novel phosphite-thiother ligands derived from carbohydrates
allow the enantioswitchable hydrogenation of cyclic β-enamides
using either Rh- or Ir-catalysts
Authors: Montserrat Dieguez, Jèssica Margalef, and Oscar Pàmies
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Chemistry - A European Journal
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Novel phosphite-thiother ligands derived from carbohydrates
allow the enantioswitchable hydrogenation of cyclic β-enamides
using either Rh- or Ir-catalysts
[
a]
[a],
[a],
Jèssica Margalef, Oscar Pàmies * and Montserrat Diéguez *
Abstract: Phosphite-thioether ligands with
a simple modular
architecture, derived from inexpensive L-(+)-tartaric acid and D-
mannitol, have been for the first time successfully applied (ee's up to
99%) in the synthesis of 2-aminotetralines and 3-aminochromanes
via metal-catalyzed asymmetric hydrogenation of cyclic β-enamides.
The ligands have the advantages of the robustness of the
thioether/phosphite moieties and the extra control provided by the
flexibility of the chiral pocket through the presence of a biaryl
phosphite group and a modular carbohydrate derived backbone.
Moreover, they are solid and stable to air and they are therefore
easy to handle, manipulate and store. Usefully, both enantiomers of
the hydrogenated products were obtained by simply switching from
Rh to Ir. Low hydrogen pressure and environmentally friendly
propylene carbonate can be used, with no loss of selectivity.
Figure 1. Examples of chiral 2-aminotetralines and 3-aminochromanes with
pharmaceutical applications.
diphosphine ligand synthesized in nine steps (Figure 2).[4k] Very
recently, Verdaguer et al. have shown for the first time that Ir-
P,N catalysts, which have been mainly applied to hydrogenate
minimally functionalized olefins,[ are also able to hydrogenate
these elusive substrates.[6] In particular, they were able to
hydrogenate cyclic β-enamides derived from 2-tetralones with an
Introduction
5]
Asymmetric hydrogenation of prochiral olefins is a widely used
process for preparing optically active compounds. It is highly
efficient, has a perfect atom economy, requires low catalyst
loadings and is operationally simple.[1] Over the last decades the
Ir-catalyst modified with MaxPHOXs,
a
P-stereogenic
aminophosphine-oxazoline
ligand
(Figure 2), with
substrate scope has been substantially expanded and
enantioselectivities up to 99% ee.[ Just afterwards, our group
showed that Ir-catalysts modified with PHOX-based phosphite-
oxazoline ligands can also be successfully used to reduce cyclic
β-enamides derived from both, 2-tetralones and 3-chromanones
6]
[
2]
commercial processes have been developed. However, there
are substrate classes such as the cyclic β-enamides whose
hydrogenation is still a challenge. Whilst the hydrogenation of
related α-enamides can be carried out with acceptable success,
the asymmetric hydrogenation of β-enamides remains one of the
most puzzling transformations, albeit the corresponding
hydrogenated products, i.e. 2-aminotetralines and 3-
aminochromanes, are key units for many drugs and biologically
active natural products (Figure 1).[3]
Most of the catalysts, predominantly based on Rh- and Ru-,
provide unsatisfactory enantioselectivities in the asymmetric
hydrogenation of cyclic β-enamides.[4] Among the most
successful examples (Figure 2),[4a,c,e,f,j,k] Ratovelomanana et al.
(
ee's up to 99%).[7] Despite these advances, the use of
alternative Ir-P,X catalysts in that process remains unexplored,
and the performance of Ir-P,X catalysts must be further studied
by screening new accessible Ir-heterodonor catalysts. Therefore,
the need for easy to synthesize, easy to handle (air-stable, solid
and robust) and highly efficient P,X ligands for the metal-
catalyzed asymmetric hydrogenation of cyclic β-enamides,
derived from both 2-tetralones and 3-chromanones, continues.
reported
the
synthesis
3-aminochromanes
with
enantioselectivities up to 96% ee using Ru-diphosphine
catalysts.[4f] More recently, Tang et al reported similar high
enantioselectivities in the hydrogenation of enamides derived
from 2-tetralones (ee's up to 96%) and enamides derived from 3-
chromanones (ee's in the range 94-98%), using a Rh-catalyst
modified with WingPhos, a specially designed P-stereogenic
Figure 2. Selection of most successful ligands applied in the asymmetric
hydrogenation of the cyclic β-enamides.
[
a]
Dr. J. Margalef, Dr. O. Pàmies, Prof. M. Diéguez
Departament de Química Física i Inorgànica
Universitat Rovira i Virgili
A simple way to prepare chiral ligands is to transform or
derivatize natural chiral compounds (chiral pool) such as
carbohydrates. These are extremely useful not only because
they are available at low price, but also because they can be
C/ Marcel·li Domingo, 1. 43007 Tarragona. Spain
E-mail: oscar.pamies@urv.cat; montserrat.dieguez@urv.cat
Supporting information for this article is given via a link at the end of
the document
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Chemistry - A European Journal
10.1002/chem.201604483
FULL PAPER
easily modulated, with
a
well-established chemistry.[8] An
inconvenience of using natural products as precursors is that
only one enantiomer (in the case of carbohydrates, the D-series)
is readily accessible from the chiral pool. This makes their use
more difficult when both enantiomers are demanded for
biological and medical applications, although pseudo-
[
9]
[10]
enantiomeric ligands and different transition metals
have
been used to overcome this limitation. For example, it was
shown that for asymmetric hydrosilylation and asymmetric
hydroboration,[10a,b,e,h] both enantiomers can be accessible by
switching from Rh- to Ir-catalysts.
Our group has wide expertise in the design of easy to handle
phosphite-containing ligand families prepared from readily
available starting materials.[ In this context, we have shown
the benefits of using heterodonor biaryl phosphite-oxazoline
ligand families for the Ir-catalyzed hydrogenation of minimally
functionalized olefins, which in the last decades have become
the state of art for the reduction of these challenging
substrates.[12] We have also recently found that the previously
mentioned PHOX-based phosphite-oxazoline ligands can be
considered privileged ligands not only for their ability to control
the stereochemistry in the Ir-catalyzed hydrogenation,[7] with a
exceptionally broad substrate scope, but also because they work
well in a variety of processes, such as Pd-catalyzed Heck[13a]
and allylic substitution[13b] reactions and Ir-catalyzed
Figure 3. Phosphite-thioether ligands L1-L5a-c derived from carbohydrates.
11]
Results and Discussion
Synthesis of ligands L1-L5a-c
The synthesis of phosphite-thioether ligands L1-L5a-c is
straightforward (Scheme 1). They were efficiently synthesized
from the corresponding easily accessible hydroxyl-thioether
compounds 4 and 9-12. Compounds 4 and 9-12 are easily
prepared in a multrigram scale by highly effective methods from
compounds 1[16] and 2[17], which are obtained in a few steps from
[
13c]
hydroboration . The reason for this exceptional performance is
the flexible biaryl phosphite group that allows the chiral pocket of
the catalyst to accommodate itself according to the steric
demands of the substrate.[11, 13b] Moreover, phosphite ligands are
less sensitive to air and other oxidizing agents and also easier to
prepare than the most commonly used phosphines, which have
dominated the field of asymmetric hydrogenation. More recently,
our research progressed toward mixed ligands, with groups
more robust than oxazolines. The thioether group adds the
inexpensive natural L-(+)-tartaric acid and D-(+)-mannitol.
Compounds 4 and 9-12 were chosen as intermediates for the
preparation of ligands because they easily allow incorporating
the desired diversity in the ligand structure. For the preparation
of hydroxyl-thioether compound 4,[18] compound 1 was treated
with 1 equiv of p-toluenesulfonyl chloride to produce the desired
monotosylated compound 3 (Scheme 1, step (i)). Subsequent
reaction with in situ formed sodium thiophenolate provided
hydroxyl-thioether 4 (Scheme 1, step (ii)).
advantages of higher stability and easier synthesis than
oxazolines.[
14]
In addition, the intrinsic stereogenic sulphur
chirality upon coordination can benefit the reaction stereocontrol
since the chiral center is adjacent to the metal centre. This
allows the thioether-containing ligands to have
a simple
structure. In this respect, we have recently identified the
successful use of two simple families of heterodonor phosphite-
thioether ligands for hydrogenation of minimally functionalized
olefins[15] with results comparable to the best ones reported to
date.
Inspired by the pioneering work of Verdaguer, the success of
P-S ligands in hydrogenation and the similarities of the
elementary steps involved in hydrosilylation/hydroboration and
hydrogenation, we reasoned that both enantiomers of the 2-
aminotetralines and 3-aminochromanes might be accessed for
the first time using either Rh- or Ir-catalysts modified with the
same ligand. To prove this, we developed a new carbohydrate-
derived phosphite-thioether ligand library (L1-L5a-c) with a very
simple architecture (Figure 3). The new ligands are easily
prepared in a large scale from L-tartaric acid (L1) and D-
mannitol (L2-L5) and their advantageous properties derive from
the sugar core, the biaryl phosphite group and the thioether
moiety.
Scheme 1. Synthesis of phosphite-thioether ligands L1-L5a-c. (i) TsCl, Py,
2
CH
2
Cl
2
; (ii) NaSR , THF; (iii) ClP(OR)
2
; (OR)
, THF; (vi) DIAD, pNBA, PPh
(vii) TBDMSCl, imidazole, DMF.
2
= a-c, Py or NEt
3
, toluene; (iv)
AcOH (dil); (v) LiAlH
4
3
, THF then MeOH, NaOH;
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For the preparation of hydroxyl-thioethers 9-12, that differ
from 4 in the substituent on the carbon adjacent to the alcohol
group, compound 2 was transformed to the desired thioether
compounds 5 and 6 by treatment of 2 with 1 equiv of p-
toluenesulfonyl chloride followed by reaction with the
corresponding NaSR2 (Scheme 1, steps (i-ii)). Subsequent
standard acid catalyzed acetal deprotection provided
compounds 7 and 8 (Scheme 1, step (iv)). From this point, the
syntheses followed different pathways depending of the ligand to
be prepared. Hydroxyl-thioethers 9 and 10 were easily obtained
by treating compounds 7 and 8 with 1 equiv of p-toluenesulfonyl
enantioselectivity (entry 1 vs 2 and 3). The ligand backbone is
therefore not able to control the tropoisomerism of the biphenyl
phosphite group (a). There is also a cooperative effect between
the configuration of the biaryl phosphite moiety and the ligand
backbone (entries 2-3), which results in a matched combination
for ligand L1b that contains an R-biaryl phosphite. This
cooperative effect is more significant for Rh-L1b, allowing us to
increase enantioselectivity up to 84% ee (entry 2), than for the
Ir-catalyst (entry 2, ee's only up to 59%). Advantageously, both
enantiomers of the hydrogenated products could be obtained
with the same ligand by simply exchanging Rh for Ir.
4
chloride followed by reaction with LiAlH (Scheme 1, steps (i and
Table
1. Asymmetric metal-catalyzed hydrogenation of N-(3,4-
v)). For the preparation of hydroxyl-thioether 11, which differs
from 9 in the configuration of the carbon adjacent to the alcohol
group, the methyl group was inverted using Mitsunobu
methodology (Scheme 1, step (vi)). Finally, treatment of 8 with 1
equiv of tert-butyldimethylsilyl chloride gave access to the
desired hydroxyl-thioether 12 (Scheme 1, step (vii)).
dihydronaphthalen-2-yl)acetamide S1 using ligand L1-L4a-c[
a]
[
2 4
Rh(cod) ]BF /L
2 F
[Ir(cod) ]BAr /L
The last step in the ligand synthesis is common for all the
ligands (Scheme 1, step (iii)). Treating the corresponding
hydroxyl-thioethers (9-12) with 1.1 equiv of the desired in situ
Entry
Ligand
L1a
L1b
L1c
L2a
L2b
L2c
L3c
L4c
L5b
L5c
% Conv[b]
100
% ee[c]
16 (R)
84 (R)
73 (S)
13 (S)
83 (R)
86 (S)
87 (S)
90 (S)
81 (R)
59 (S)
% Conv[b]
100
100
100
100
100
100
100
100
95
% ee[c]
11 (S)
59 (S)
34 (R)
35 (R)
50 (S)
90 (R)
89 (R)
97 (R)
80 (S)
6 (R)
formed phosphorochloridite (ClP(OR)
presence of base provided easy access to the desired ligands
Scheme 1, step (iii)). All the ligands were purified on neutral
2 2
; (OR) = a-c) in the
1
2
3
4
5
6
7
8
9
100
(
alumina under argon atmosphere and were isolated in
moderate-to-good yields as white solids. Advantageously, they
were stable in air and very stable to hydrolysis, so further
100
100
manipulation/storage was carried out in air. HRMS-ESI spectra
1
agreed with the assigned structures. The H, 31P and 13C NMR
100
spectra were as expected for these ligands. One singlet for each
compound was observed in the 31P NMR spectrum. Rapid ring
inversions (tropoisomerization) in the biphenyl-phosphorus
moiety (a) occurred in the NMR time scale because the
expected diastereoisomers were not detected by low-
temperature 31P NMR.[19]
100
100
100
100
10
100
92
Asymmetric hydrogenation of N-(3,4-dihydronaphthalen-2-
yl)acetamide
[
a]
Reactions conditions: [M(cod)
2
]X (1 mol%), ligand (1 mol%), S1 (0.5 mmol),
CH Cl (2 mL), H (30 bar for Rh-catalysts and 100 bar for Ir-catalysts), 12 h
2
2
2
Initially, we evaluated carbohydrate-derived phosphite-thioether
ligands L1-L5a-c in the asymmetric Rh- and Ir-catalyzed
(for Rh-catalyst) or 24 h (for Ir-catalyst) at rt. [b] Conversion determined by
NMR. [ Enantiomeric excesses determined by chiral HPLC.
1
H
c]
hydrogenation
of
model
N-(3,4-dihydronaphthalen-2-
Ligands L2 differ from L1 in that they contain a methyl group
next to the phosphite moiety that generates a new chiral center.
The introduction of the methyl group does not affect significantly
the ee for Rh-catalyst, that keep being high (entry 6), but has a
remarkable positive effect in Ir-catalysts and makes the ee's
increase to 90% (L2c, entry 6) from 59% (L1b, entry 2). The
results also indicates a new cooperative effect in L2 between the
configuration of the biaryl phosphite moiety and the ligand
backbone (entries 5-6 vs 2-3), that is larger in Ir-catalysts than in
Rh-catalysts and that results in a matched combination for
ligand L2c with a S-biaryl phosphite (entry 6).
yl)acetamide S1 (Table 1). For initial reaction conditions, we
tested L1-L5a-c using the same optimal reaction conditions
found in our previous studies with related Ir-P,S catalytic
systems for the hydrogenation of minimally functionalized
olefins[ and related Rh-P,S catalysts for the hydrogenation of
dehidroaminoacid derivatives[20]. The reactions were therefore
performed at room temperature in dichloromethane using 1
15]
2
mol % of the corresponding catalyst under 30 bar of H for Rh-
catalysts and 100 bar for Ir-catalysts. In both cases, the
catalysts were prepared in situ by adding the corresponding
ligands to the appropriate catalyst precursor (either
Ligands L4 differ from L1 in that they contain
a
[
Rh(cod)
2 4 2 F
]BF or [Ir(cod) ]BAr ).
CH
2
OTBDMS group next to the phosphite moiety. The
Concerning the ligand architecture, the results with ligands
L1a-c, derived from L-(+)-tartaric acid, indicated that the
presence of a chiral biaryl phosphite moiety increases the
introduction of this new group also had a positive effect on
enantioselectivity compared to L1 (entry 8 vs 2) but also the high
ee's (up to 97%) surpassed those obtained with L2 that contain
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Chemistry - A European Journal
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a methyl group (entry 8 vs 6). Like for L1 and L2, both
enantiomers can be obtained by using either Rh or Ir.
hydrogenated product by simply choosing the metal centre in
enantioselectivities (up to 97% ee) comparable to the best ones
reported.
Ligands L5 differ from L2 in the configuration of the carbon
adjacent to the phosphite moiety that is S instead of R. This
change affected the enantioselectivity negatively (entries 6 vs 9).
Finally the effect of the thioether group was studied with ligands
L2c and L3c. The nature of the thioether group had little effect
on enantioselectivity (entries 6 and 7).
Substrate scope
In the optimal conditions found, we next studied the substrate
scope using [Rh(cod)(L4c)]BF and [Ir(cod)(L4c)]BAr catalyst
4 F
In summary, the highest enantioselectivities (ee’s up to 90%
with Rh and ee’s up to 97% with Ir) were achieved using
phosphite-thioehter ligand L4c, which contains the optimal
combination of ligand parameters.
precursors. For this purpose a range of cyclic β-enamides, which
contemplate all possible monosubstitution patterns as well as
different substituents at position 6 of the 3,4-dihydronaphthalene
core, were investigated (Table 3). We were pleased to discover
that not only the replacement of the metal gave access to both
We next studied the effect of several experimental
parameters on the catalytic performance with the best ligand
L4c (Table 2). We started our investigations testing different
temperatures (entries 1, 3-5 for Rh-L4c and entries 7-9 for Ir-
L4c). Lowering the reaction temperature to 5 ºC increased the
enantioselectivity to 94% (from 90% at rt) for Rh-L4c, combined
with good activity (entry 4). Lower temperatures did not improve
enantioselectivities further. We next evaluated the effect of
lowering the pressure (entries 1 and 2 for Rh-L4c and 7 and 10
for Ir-L4c). The catalytic performance was maintained
regardless of the lower hydrogen pressure and, advantageously,
high enantioselectivities were still obtained for both catalysts at
enantiomers
of
the
hydrogenated
products
with
enantioselectivity comparable to the best one reported, but also
that the [M(cod)(L4c)]X (M=Rh or Ir) were very tolerant to the
electronic properties and to variations in the substitution pattern
of the 3,4-dihydronaphthalene core. Several substituted cyclic
enamides
derived
from
β-tetralones
were
therefore
hydrogenated in high yields and high enantioselectivities (ee’s
up to 99%; entries 1-10).
Table 3. Asymmetric Rh- and Ir-catalyzed hydrogenation of cyclic β-enamides
S2-S10 using ligand L4c[
a]
1
0 bar of H
2
(entries 2 and 10). Finally, the use of preformed
and [Ir(cod)(L4c)]BAr
% Conv (% Yield)[b]
% ee[c]
Entry
Substrate
catalyst precursors [Rh(cod)(L4c)]BF
4
F
1
2
100 (83)
100 (86)
95 (S)
99 (R)
provided the same results (entries 4 vs 6 and 11 vs 7). There is
no need therefore to synthesize and isolate the precatalysts
prior to use.
3
4
100 (91)
100 (92)
92 (S)
97 (R)
Table
2. Asymmetric metal-catalyzed hydrogenation of N-(3,4-
[
a]
dihydronaphthalen-2-yl)acetamide S1 using ligand L4c. Optimization studies
5
6
100 (86)
99 (85)
91 (S)
95 (R)
[b]
P
H2
T[c]
25
25
40
5
% Conv (h)[d]
100 (12)
89 (12)
%ee[e]
90 (S)
88 (S)
84 (S)
94 (S)
93 (S)
94 (S)
97 (R)
89 (R)
96 (R)
97 (R)
97 (R)
Entry
Catalyst precursor
7
8
100 (87)
100 (86)
90 (S)
97 (R)
1
2
3
4
5
6
7
8
9
[Rh(cod)
[Rh(cod)
[Rh(cod)
[Rh(cod)
[Rh(cod)
2
2
2
2
2
]BF
]BF
]BF
]BF
]BF
4
4
4
4
4
30
10
30
30
30
30
9
100 (91)
100 (90)
91 (S)
97 (R)
100 (8)
10
100 (36)
48 (36)
1
1
1
2
100 (80)
100 (83)
94 (S)
98 (R)
-5
5
[Rh(cod)(L4c)]BF
4
100 (36)
100 (24)
100 (18)
23 (24)
1
1
3
4
100 (85)
99 (82)
93 (S)
97 (R)
[Ir(cod)
[Ir(cod)
[Ir(cod)
[Ir(cod)
2
2
2
2
]BAr
]BAr
]BAr
]BAr
F
F
F
F
100
100
100
10
25
40
5
1
1
5
6
100 (91)
98 (90)
92 (R)
97 (S)
1
1
7
8
100 (86)
99 (84)
92 (R)
98 (S)
1
0
1
25
25
89 (24)
[
a]
Reactions conditions: [Rh(cod)(L4c)]BF
mol%), substrate (0.5 mmol), CH Cl (2 mL), H
catalyst) or at rt (for Ir-catalyst). Conversion determined by H NMR. Isolated
yields shown in parentheses
HPLC.
4
(1 mol%) or [Ir(cod)(L4c)]BAr
F
(1
1
[Ir(cod)(L4c)]BAr
F
100
100 (24)
2
b]
2
2
(10 bar), 36 h at 5 °C (for Rh-
[
1
[
a]
Reactions conditions: [M(cod)
2
]X (1 mol%), ligand (1 mol%), S1 (0.5 mmol),
[c]
Enantiomeric excesses determined by chiral
[
b]
[c]
[d]
2 2
CH Cl (2 mL). Hydrogen pressure in bars. Reaction temperature in °C.
1
[e]
Conversion determined by H NMR. Enantiomeric excesses determined by
chiral HPLC.
Advantageously, the nature of the amido group had no effect
on conversion and enantioselectivities. Therefore, cyclic β-
enamides S7 and S8 were also hydrogenated to the desired
As a summary, under these new mild reaction conditions we
were therefore able to obtain both enantiomers of the
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Chemistry - A European Journal
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amines in similar high enantioselectivities than S1 (entries 11-
A novel class of phosphite-thioether ligands with a simple
modular architecture has been successfully applied for the first
time in the Rh- and Ir-catalyzed hydrogenation of cyclic β-
enamides. The ligands can be easily prepared on large scale
from inexpensive L-(+)-tartaric acid and D-mannitol, and they
14; ee’s up to 98%). We could also efficiently reduce enamides
derived from 3-chromanones S9 and S10 in high yields and
enantioselectivities (entries 15-18; ee’s up to 98%). Among all
these results, it should be pointed out the successful
hydrogenation
of
N-(5-methoxy-3,4-dihydronapththalen-2-
have
the
advantages
of
the
robustness
of
the
yl)acetamide S6 and N-(2H-chromen-3-yl)acetamide S9 (ee’s up
to 97%) that give access to key chiral intermediates for the
thioether/phosphite moieties and the extra control provided by
the flexibility of the chiral pocket through the presence of a biaryl
phosphite group and a modular carbohydrate derived backbone.
Moreover, they are solid and stable to air and they are therefore
easy to handle, manipulate and store. These ligands allowed to
obtain 2-aminotetralines and 3-aminochromanes in high yields
and enantioselectivities comparable to the best ones reported
(ee's up to 99%). Three novel features of these ligands are that
both enantiomers are accessible in high enantioselectivities by
simple switching from Rh to Ir, excellent yields and
enantioselectivities are obtained also at low pressure and that
the environmentally friendly propylene carbonate can be used as
solvent, with no loss of selectivity. These results open up the
use of phosphite-thioether ligands to the challenging
enantioselective M-catalyzed hydrogenation of cylic β-enamides.
synthesis of rotigotine and alnespirone. The former is
a
dopamine agonist used for the treatment of Parkinson’s
disease,[ while alnespirone is a selective 5-HT1A receptor with
3a]
antidepressant and anxiolytic properties[3d]
.
Encouraged by these excellent results we decided to go one
step further and study the metal-catalyzed hydrogenation of
various cyclic β-enamides S1-S3 using 1,2-propylene carbonate
(
"
PC) as solvent (Scheme 2). PC has emerged as a sustainable
green" alternative to standard organic solvents because of its
high boiling point, low toxicity and environmentally friendly
synthesis.[21] We were pleased to see that the
enantioselectivities with PC remained as high as those observed
with dichloromethane.
Experimental Section
General considerations
Scheme 2. Asymmetric hydrogenation of cyclic β-enamides S1-S3 using 1,2-
propylene carbonate. Reaction conditions: catalyst precursor (1 mol%),
substrate (0.5 mmol), PC (2 mL), H (30 bar for Rh-catalyst and 100 bar for Ir-
2
catalyst), 5 °C (for Rh-catalyst) or rt (for Ir-catalyst) for 36 h.
All syntheses were performed by using standard Schlenk techniques
under an argon atmosphere. Solvents were purified by standard
procedures. Phosphorochloridites are easily prepared in one step from
the corresponding biaryls.[22] Compounds 1[16] and 2[17] were easily
prepared on a multigram scale from L-(+)-tartaric acid and D-(+)-mannitol,
respectively. Hydroxyl-thioether 4 was prepared following previously
described methodology by Chida and coworkers.[18] Cylic β-enamides
S1-S10[23] were prepared following literature procedures. All other
To demonstrate the potential usefulness of these Rh- and Ir-
catalyst processors modified with simple carbohydrate-derived
phosphite-thioether ligand L4c we performed the hydrogenation
of N-(6-bromo-3,4-dihydronaphthalen-2-yl)acetamide S2 at 7.5
mmol scale and at a low catalyst loading. Both isomers of the
reagents were used as commercially available. 1H, 13C{ H}, P{ H} NMR
1
31
1
spectra experiments were recorded using a 400 MHz spectrometer.
Chemical shifts are relative to that of SiMe
4
(1H and 13C) as internal
desired
yl)acetamide
N-(6-bromo-1,2,3,4-tetrahydronaphthalen-2-
were achieved in high yields and
1
standard or H PO
3 4
(3 P) as external standard. 1H and 13C assignments
were done based on H- H gCOSY and H-13C gHSQC experiments.
1
1
1
enantioselectivities (Scheme 3).
Typical procedure for the preparation of phosphite-thioether ligands
L1-L5a-c
The corresponding phosphorochloridite (1.1 mmol) produced in situ was
dissolved in toluene (5 mL), and pyridine (0.3 mL, 3.9 mmol) was added.
The corresponding thioether-hydroxyl compound (1 mmol) was
azeotropically dried with toluene (3 x 2 mL) and then dissolved in toluene
(5 mL) to which pyridine (0.3 mL, 3.9 mmol) was added. The alcohol
solution was transferred slowly to a solution of phosphorochloridite. The
reaction mixture was stirred at 80 °C for 90 min, after which the pyridine
salts were removed by filtration. In the case of ligands L4b-c,
triethylamine was added instead of pyridine (0.5 ml, 3.9 mmol) and the
reaction mixture was stirred overnight at 80 °C. In the case of ligands
L5b-c, triethylamine (0.5 ml, 2.8 mmol) and DMAP (0.11 mmol, 13.4 mg)
were added and the reaction mixture was stirred overnight at room
temperature. Evaporation of the solvent gave a white foam, which was
purified by flash chromatography (see Supporting Information for copies
of the NMR spectra).
Scheme 3. Practical synthesis of N-(6-bromo-1,2,3,4-tetrahydronaphthalen-2-
yl)acetamide.
Conclusions
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201604483
FULL PAPER
L1a.
Yield:
413
mg
(65%);
SiO
2
-flash
chromatography
) δ: 135.7 (s).
, tBu), 1.29 (s,
, tBu), 1.59 (s, 9H, CH , tBu),
-S), 3.03 (dd, 1H, 2
L2b.
(toluene/hexane/NEt
(s). 1H NMR (400 MHz, C
CH , SiMe ), 1.22 (s, 3H, CH
=6.4 Hz), 2.33 (dd, 1H, CH
-S, 2
1H, CH
-S, 2 H-H =14.0 Hz, 2
=7.6 Hz), 4.08 (m, 1H, CHCH
Yield:
429
mg
(59%);
SiO
2
-flash
chromatography
31
31
(
toluene/hexane/NEt
H NMR (C
3
= 5:5:0.1). P NMR (400 MHz, C
6
D
6
3
= 8:2:0.1). P NMR (161.9 MHz, C D ): δ=147.4
6
6
1
, tBu), 1.28 (s, 9H, CH
D
6 6
), : 1.27 (s, 9H, CH
3
3
6
D
6
): δ=0.52 (s, 9H, CH
), 1.32 (s, 3H, CH
H-H =13.6 Hz, 2
3
, SiMe
3
), 0.56 (s, 9H,
3
3
2
1
1
H, CH
3
), 1.32 (s, 3H, CH
3
), 1.57 (s, 9H, CH
3
3
3
3
3
3
), 1.49 (d, 3H, CH
3
, JH-H
.88 (dd, 1H, JH-H= 13.6 Hz, 3
2
J
H-H= 6.4 Hz, CH
J
J
J
H-H =4.3 Hz), 2.40 (dd,
2
H-H
=
2
3.6 Hz, 3
H, CHCH
J
=
5.6 Hz, CH
-S), 3.93-3.96 (m, 1H, CHCH
J
J
H-H =3.6 Hz), 3.83 (pt, 1H, CHCHO, 3JH-H
H-H
2
2
O), 4.02 (m,
2
-O), 6.87-7.60 (m, 9H, CH=). 13C
S), 4.49 (m, 1H, CH-O), 6.84-7.16 (m, 9H,
2
S), 4.08-4.11 (m, 2H, CH
2
2
t
, tBu),
-S),
CH=), 7.28 (d, 1H, CH=, 3JH-H =8.8 Hz), 7.33 (d, 1H, CH=, 3JH-H =8.4 Hz),
NMR (C
6
D
6
), : 26.9 (CH
3
), 27.1 (CH
3
), 30.8 (CH
3
, Bu), 30.9 (CH
3
t
t
t
t
7.69 (dd, 2H, CH=, 3JH-H =10.8 Hz, 3
3
6
1.2 (CH
4.6 (CH
), 124.1 (CH=), 125.3 (C), 125.7 (CH=), 126.7 (CH=), 128.1 (CH=),
28.7 (CH=), 128.9 (CH=), 129.0 (CH=), 133.2 (C), 136.4 (C), 140.1 (C),
40.2 (C), 146.5 (C), 146.6 (C). MS HR-ESI [found
15.3556, C41 PS (M-Na) requires 715.35.57].
3
, Bu), 34.3 (C, Bu), 35.3 (C, Bu), 35.3 (C, Bu), 36.5 (CH
2
J
H-H =8.4 Hz), 8.11 (s, 1H, CH=),
8.16 (s, 1H, CH=). C NMR (100.6 MHz, C ): δ=-0.9 (d, CH , SiMe
C-P =4.6 Hz), 0.7 (CH , SiMe ), 18.3 (CH ), 26.0 (CH ), 26.2 (CH ), 37.4
(CH S), 81.2 (d, CHCHO,
-S), 72.1 (d, CH-O, 2JC-P = 4.6 Hz), 77.4 (CHCH
3JC-P =2.7 Hz), 111.2 (CMe
), 124.0-136.4 (aromatic carbons). MS HR-
ESI [found 749.2313, C40 PSSi
(M-Na)+ requires 749.2318]. Anal.
calc (%) for C40 PSSi : C 66.08, H 6.52, S 4.41; found: C 65.89, H
.49, N 4.39.
13
2
-O), 76.5 (CHCH
2
S), 79.7 (d, CHCH
2
O, JC-P= 3.8 Hz), 109.4
6
D
6
3
3
,
(CMe
2
J
3
3
3
3
3
1
1
7
2
2
2
+
H
57
O
5
H O
47 5
2
47
H O
5
2
6
L1b.
Yield:
toluene/hexane/NEt
s). 1H NMR (400 MHz, C
, SiMe ), 1.27 (s, 3H, CH
2JH-H =13.2 Hz, 3
H-H =6.0 Hz), 2.95 (dd, 1H, CH
5.2 Hz), 3.39-3.44 (m, 1H, CH -O), 3.72-3.76 (m, 1H, CHCH
335.2
= 5:5:0.1). P NMR (161.9 MHz, C
): δ=0.51 (s, 9H, CH , SiMe ), 0.55 (s, 9H,
), 1.30 (s, 3H, CH ), 2.77 (dd, 1H, CH -S,
-S, 2 H-H =13.6 Hz, 2
O), 3.94-
-O), 6.85-7.16 (m, 9H,
mg
(47%);
SiO
2
-flash
chromatography
31
(
(
3
6 6
D ): δ=134.1
6
D
6
3
3
L2c.
(toluene/hexane/NEt
(s). 1H NMR (400 MHz, C
Yield:
480
mg
(66%);
SiO
2
-flash
chromatography
): δ=140.9
), 0.54 (s, 9H,
31
CH
3
3
3
3
2
3
= 8:2:0.1). P NMR (161.9 MHz, C D
6 6
J
2
J
J
H-H
6
D
6
): δ=0.50 (s, 9H, CH
3
, SiMe
3
3
=
3
2
2
3
CH , SiMe
3
), 0.78 (d, 3H, CH
3
, JH-H =6.8 Hz), 1.32 (s, 3H, CH
3
), 1.35 (s,
-S, 3JH-H =5.6 Hz), 3.93 (dd, 1H, CHCHO, JH-H
3
.99 (m, 1H, CHCH
2
S), 4.29-4.35 (m, 1H, CH
2
3H, CH
3
), 3.00 (d, 2H, CH
2
CH=), 7.23 (d, 1H, CH=, JH-H =8.4 Hz), 7.34 (d, 1H, CH=, 3JH-H =8.4 Hz),
3
=5.6 Hz, 3JH-H =1.1 Hz), 4.20 (m, 1H, CHCH
2
S), 4.66 (m, 1H, CH-O),
.70 (d, 2H, CH=, 3
J
H-H =8.0 Hz), 8.11 (s, 1H, CH=), 8.13 (s, 1H, CH=).
C NMR (100.6 MHz, C ): δ=-0.5 (CH , SiMe ), -0.3 (d, CH , SiMe
C-P =4.6 Hz), 26.8 (CH ), 26.9 (CH ), 36.5 (CH -S), 63.9 (CH -O), 75.9
S), 79.6 (CHCH O), 109.2 (CMe
carbons). MS HR-ESI [found 735.2154, C39
35.2156].
6.83-7.22 (m, 10H, CH=), 7.34 (d, 1H, CH=, JH-H =8.8 Hz), 7.69 (dd, 2H,
CH=, JH-H =6.4 Hz, 4JH-H =3.6 Hz), 8.10 (s, 1H, CH=), 8.13 (s, 1H, CH=).
3
7
13
3
D
6 6
3
3
3
3
,
J
3
3
2
2
13C NMR (100.6 MHz, C
(CH , SiMe ), 17.8 (CH ), 26.9 (CH
CH-O, 2JC-P = 6.9 Hz), 77.1 (CHCH
109.3 (CMe ), 122.5-137.3 (aromatic carbons). MS HR-ESI [found
49.2314, , C40 PSSi
(M-Na)+ requires 749.2318]. Anal. calc (%)
: C 66.08, H 6.52, S 4.41; found: C 65.91, H 6.50, N
6 6
D
): δ=0.1 (d, CH
), 27.1 (CH
S), 82.9 (d, CHCHO, 3
3
, SiMe
3
, JC-P =4.0 Hz), 0.1
-S), 72.4 (d,
C-P =4.6 Hz),
(
CHCH
2
2
2
), 122.3-152.6 (aromatic
3
3
3
3
3
), 37.5 (CH
2
+
H
45
5
O PSSi
2
(M-Na) requires
2
J
7
2
7
47
H O
5
2
47 5 2
for C40H O PSSi
L1c.
Yield:
toluene/hexane/NEt
s). 1H NMR (400 MHz, C
, SiMe ), 1.22 (s, 3H, CH
2JH-H =13.6 Hz, 3
H-H =6.0 Hz), 2.92 (dd, 1H, CH
4.8 Hz), 3.57-3.62 (m, 1H, CH -O), 3.77-3.81 (m, 2H, CHCH
CHCH O), 4.10-4.14 (m, 1H, CH -O), 6.84-7.16 (m, 9H, CH=), 7.23 (d,
H, CH=, 3JH-H =8.4 Hz), 7.35 (d, 1H, CH=, 3
H-H =8.4 Hz), 7.69 (t, 2H,
CH=, 3JH-H =6.8 Hz), 8.10 (s, 1H, CH=), 8.14 (s, 1H, CH=). 13C NMR
100.6 MHz, C ): δ=-0.4 (CH , SiMe ), -0.2 (d, CH , SiMe , JC-P =5.4
Hz), 26.7 (CH ), 26.9 (CH ), 36.5 (CH -S), 64.4 (d, CH
-O, 2JC-P = 5.1 Hz),
S), 79.5 (d, CHCH C-P =3.1 Hz), 109.3 (CMe ), 122.2-
O, 3
PSSi
289.7
= 5:5:0.1). P NMR (161.9 MHz, C
): δ=0.51 (s, 9H, CH , SiMe ), 0.57 (s, 9H,
), 1.27 (s, 3H, CH ), 2.73 (dd, 1H, CH -S,
-S, 2 H-H =13.6 Hz, 2
mg
(41%);
2
SiO -flash
chromatography
D ): δ=132.1
6 6
31
4.39.
(
(
3
6
D
6
3
3
CH
3
3
3
3
2
L3c.
Yield:
396.0
mg
(51%);
SiO
2
-flash
chromatography
): δ=141.0
), 0.53 (s, 9H,
31
J
2
J
J
H-H
(toluene/hexane/NEt
3 6 6
= 8:2:0.1). P NMR (161.9 MHz, C D
=
2
2
S,
(s). 1H NMR (400 MHz, C
6
D
6
): δ=0.48 (s, 9H, CH
3
, JH-H =6.0 Hz), 1.34 (s, 3H, CH
3
, SiMe
3
3
2
2
3
CH , SiMe
3
), 0.80 (d, 3H, CH
3
), 1.37 (s,
-S, 3JH-H =5.6 Hz), 3.97 (dd, 1H, CHCHO, JH-H
3
1
J
3
3H, CH ), 3.11 (d, 2H, CH
2
=7.2 Hz, 3JH-H =5.6 Hz), 4.26-4.31 (m, 1H, CHCH
2
S), 4.66-4.71 (m, 1H,
(
6
D
6
3
3
3
3
CH-O), 6.81-6.87 (m, 2H, CH=), 6.99-7.23 (m, 5H, CH=), 7.31-7.53 (m,
5H, CH=), 7.67-7.70 (m, 3H, CH=), 8.10 (s, 1H, CH=), 8.12 (s, 1H, CH=).
3
3
2
2
75.5 (CHCH
2
2
J
2
13C NMR (100.6 MHz, C
(CH , SiMe ), 18.8 (CH ), 28.1 (CH
CH-O, 2JC-P = 6.5 Hz), 78.3 (CHCH
D
6 6
): δ=0.8 (d, CH
), 28.3 (CH
S), 84.1 (d, CHCHO, 3
), 123.6-153.2 (aromatic carbons). MS HR-ESI [found
99.2473, C44 PSSi
(M-Na)+ requires 799.2475]. Anal. calc (%) for
PSSi : C 68.01, H 6.36, S 4.13; found: C 67.88, H 6.33, N 4.09.
3
, SiMe
3
, JC-P =4.7 Hz), 0.9
-S), 73.6 (d,
C-P =3.8 Hz),
152.9 (aromatic carbons). MS HR-ESI [found 735.2155, C39
45
H O
5
2
3
3
3
3
3
), 38.6 (CH
2
+
(
M-Na) requires 735.2156].
2
J
1
7
C
10.5 (CMe
2
H
O
49 5
2
L2a.
Yield:
415.1
mg
(58%);
SiO
2
-flash
chromatography
31
44
H
49
O
5
2
(
toluene/hexane/NEt
3
= 8:2:0.1). P NMR (161.9 MHz, C
6 6
D ): δ=145.3
1
t
(
s). H NMR (400 MHz, C
D
6 6
): δ=1.26 (s, 9H, CH
3
, Bu), 1.27 (s, 9H, CH
3
,
t
Bu), 1.28 (s, 3H, CH
3
), 1.30 (s, 3H, CH
3
), 1.33 (s, 3H, CH
-S, 2
H-H =14.4 Hz, 3
H-H =4.4 Hz), 3.94
pt, 1H, CHCHO, 3JH-H =7.3 Hz), 4.35-4.39 (m, 1H, CHCH
S), 4.57-4.62
m, 1H, CH-O), 6.86-7.15 (m, 3H, CH=), 7.28-7.33 (m, 4H, CH=), 7.57 (d,
H, CH=, 4 H-H =2.4 Hz), 7.60 (d, 1H, CH=, 4JH-H =2.8 Hz). 13C NMR
100.6 MHz, C
CH ), 31.1 (d, CH
3
), 1.55 (s, 9H,
L4c. chromatography
(toluene/hexane/NEt ): δ=143.6
(s). 1H NMR (400 MHz, C
D ): δ=-0.38 (s, 3H, CH , OTBDMS), -0.33 (s,
6 6 3
Yield:
535
mg
(58%);
SiO
2
-flash
t
t
31
CH
3
, Bu), 1.58 (s, 9H, CH
3
, Bu), 2.83 (dd, 1H, CH
2
J
H-H =14.2 Hz,
3 6 6
= 8:2:0.1). P NMR (161.9 MHz, C D
3JH-H =5.6 Hz), 3.08 (dd, 1H, CH
-S, 2
J
J
2
(
(
1
(
(
2
3H, CH
3
, OTBDMS), 0.45 (s, 9H, CH
3
, SiMe
3
), 0.55 (s, 9H, CH
3
, SiMe
3
),
),
t
0.75 (s, 9H, CH
3.10 (dd, 1H, CH
CH
-S, 2 H-H =13.6 Hz, 3
Hz, JH-H =3.6 Hz), 3.51 (dd, 1H, CH
Hz), 4.48 (dd, 1H, CHCHO, 3JH-H =7.2 Hz, 3
3
, Bu, OTBDMS), 1.43 (s, 3H, CH
3
), 1.52 (s, 3H, CH
3
J
2
-OTBDMS, 2JH-H =10.4 Hz, 3JH-H =5.2 Hz), 3.24 (dd, 1H,
H-H =6.4 Hz), 3.38 (dd, 1H, CH H-H =13.6
-S, 2
-OTBDMS, 2JH-H =10.8 Hz, JH-H =8.0
H-H =4.0 Hz), 4.69-4.74 (m,
, 3
J
C-P =3.0 Hz), 26.9 (CH
), 27.1
, tBu),
-S),
J
J
J
3
6
D
6
): δ=19.2 (d, CH
3
3
2
2
t
t
3
3
3
, Bu, JC-P =3.1 Hz), 31.2 (CH
3
, Bu), 31.3 (CH
3
2
t
t
t
t
3
7
3
4.3 (C, Bu), 34.4 (C, Bu), 35.3 (C, Bu), 35.4 (C, Bu), 36.5 (CH
3.0 (d, CH-O, 2 S), 82.6 (d, CHCHO, 3
C-P =6.1 Hz), 78.4 (CHCH
.8 Hz), 109.4 (CMe ), 124.0-146.7 (aromatic carbons). MS HR-ESI
PS (M-Na)+ requires 729.3719]. Anal. calc
PS: C 71.36, H 8.41, S 4.53; found: C 70.98, H 8.36, N
2
J
J
2
J
C-P
=
2
1H, CHCH S), 4.83-4.90 (m, 1H, CH-O), 6.83-6.88 (m, 2H, CH=), 7.02-
7.23 (m, 3H, CH=), 7.32 (d, 1H, CH=, 3JH-H =8.4 Hz), 7.45 (s, 2H, CH=),
7.50-7.53 (m, 2H, CH=), 7.69 (t, 2H, CH=,
2
3
[
found 729.3712, C42
%) for C42
.50.
H
59
O
5
J
H-H =7.2 Hz), 7.82 (s, 1H,
13
(
4
H
59
O
5
CH=), 8.08 (s, 1H, CH=), 8.10 (s, 1H, CH=). C NMR (100.6 MHz, C
δ=-5.5 (CH3, OTBDMS), -5.2 (CH3, OTBDMS), 0.55 (d, CH , SiMe
4.6 Hz), 0.7 (CH , SiMe Bu, OTBDMS), 26.3 (CH
), 18.5 (C t
OTBDMS), 28.1 (CH ), 38.4 (CH -S), 63.2 (CH -OTBDMS), 75.3 (d, CH-
6 6
D ):
3
3
, JC-P
=
3
3
,
3
, tBu,
3
2
2
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201604483
FULL PAPER
O, 2JC-P =7.3 Hz), 76.9 (CHCH
CMe ), 125.5-152.7 (aromatic carbons). MS HR-ESI [found
49.2968, C52 PSSi
(M-Na)+ requires 949.2970]. Anal. calc (%) for
PSSi : C 66.19, H 7.00, S 3.53; found: C 66.12, H 6.96, N 3.50.
S), 80.4 (d, CHCHO, 3JC-P =3.4 Hz), 110.4
1-Deoxy-2,3:4,5-di-O-Isopropylidene-1-(2-naftylthio)-D-arabinitol (6).
2
1
(
9
C
2
Yield: 5.3 g (87%). H NMR (400 MHz, CDCl
3
): δ=1.39 (s, 6H, CH
-S, 2JH-H =13.6 Hz, 3JH-H =7.6 Hz), 3.60 (dd,
H-H =3.2 Hz), 3.83 (pt, 1H, CHCHO, 3
3
), 1.45
H
O
59 6
3
(s, 6H, CH
1H, CH
-S, 2
8.4 Hz), 4.00 (dd, 1H, CH
H, CH-O), 4.14-4.17 (m, 1H, CH
3
), 3.19 (dd, 1H, CH
H-H =14.4 Hz, 3
-O, JH-H =8.4 Hz, 3JH-H =3.2 Hz), 4.07-4.11 (m,
-O), 4.23-4.27 (m, 1H, CHCH S), 7.41-
2
50
H
63
O
6
3
2
J
J
J
H-H
2
=
1
2
L5b.
(
(
Yield:
toluene/hexane/NEt
s). 1H NMR (400 MHz, C
, SiMe ), 0.78 (d, 3H, CH
H, CH ), 2.96 (dd, 1H, CH
237.1
mg
(32%);
2
SiO -flash
chromatography
): δ=143.6
), 0.54 (s, 9H,
), 1.34 (s,
H -H =13.6 Hz, 3
JH-H =6.4 Hz ), 3.10 (dd,
2
2
7.49 (m, 3H, CH=), 7.24-7.80 (m, 3H, CH=), 7.84 (s, 1H, CH=). 13C NMR
31
3
= 8:2:0.1). P NMR (161.9 MHz, C D
6 6
(100.6 MHz, CDCl
36.7 (CH -S), 68.0 (CH
(CHCHO), 110.0 (CMe
3
): δ= 25.6 (CH
3
), 27.1 (CH
3
), 27.4 (CH
3
), 27.5 (CH
S), 80.5
), 125.8 (CH=), 126.4 (CH=), 126.8
3
),
D
6 6
): δ=0.53 (s, 9H, CH
, JH-H =6.4 Hz), 1.31 (s, 3H, CH
3
, SiMe
3
3
2
2
-O), 77.4 (CH-O), 79.3 (CHCH
2
CH
3
3
3
3
-S, 2
2
), 110.2 (CMe
2
3
1
=
6
8
0
3
2
J
-S, 2JH -H =13.6 Hz, 3 H-H =4.0 Hz), 3.97 (dd, 1H, CHCHO, 3JH -H
(CH=), 127.2 (CH=), 127.3 (CH=), 128.0 (CH=), 128.6 (CH=), 131.9 (C=),
134.1 (C=), 134.3 (C=).
H, CH J
2
4.8 Hz, 3
J
2
H-H =7.2 Hz), 4.13 (m, 1H, CHCH S), 4.55 (m, 1H, CH-O),
.83-7.15 (m, 7H, CH=), 7.23-7.34 (m, 4H, CH=), 7.68-7.71 (m, 2H, CH=),
.10 (s, 1H, C=H), 8.14 (s, 1H, C=H). 13C NMR (100.6 MHz, C
): δ=-
.1 (d, CH , SiMe , JC-P =4.5 Hz), 0.1 (CH , SiMe ), 17.6 (CH ), 27.0
), 27.2 (CH ), 37.3 (CH -S), 71.6 (CH-O), 75.8 (CHCH S), 82.2 (d,
CHCHO, 3JC-P =4.6 Hz), 109.5 (CMe
), 122.5-152.3 (aromatic carbons).
MS HR-ESI [found 749.2316, C40 PSSi
(M-Na)+ requires
49.2318]. Anal. calc (%) for C40 PSSi : C 66.08, H 6.52, S 4.41;
found: C 65.87, H 6.48, N 4.38.
D
6 6
Compounds
temperature in 70% aq. acetic acid (3.5 mL). Then, the reaction mixture
was neutralized with aq. NaHCO , and extracted with ethyl acetate (2 x
100 mL). The combined organic extracts were washed with brine (20 mL),
dried over anhydrous MgSO , concentrated under reduced pressure and
purified by SiO -column chromatography (EtOAc/PE = 1/1) to afford the
5 and 6 (1.0 mmol) were stirred overnight at room
3
3
3
3
3
(CH
3
3
2
2
3
2
H O
47 5
2
4
7
H O
47 5
2
2
desired deprotected compounds as colorless oils.
L5c.
(
(
Yield:
toluene/hexane/NEt
s). 1H NMR (400 MHz, C
, SiMe ), 1.15 (s, 3H, CH
2JH -H =14.0 Hz, 3JH-H =6.0 Hz ), 2.69 (dd, 1H, CH
289.0
= 8:2:0.1). P NMR (161.9 MHz, C
): δ=0.51 (s, 9H, CH , SiMe ), 0.53 (s, 9H,
), 1.25 (m, 6H, CH ), 2.53 (dd, 1H, CH -S,
-S, 2JH -H =13.6 Hz, 3JH-H
S), 4.50-4.55 (m, 1H, CH-O),
mg
(39%);
SiO
2
-flash
chromatography
1-Deoxy-2,3-O-isopropylidene-1-phenylthio-D-arabinitol (7). Yield:
31
1
3
6 6
D ): δ=151.4
2.1 g (67%). H NMR (400 MHz, CDCl
3
): δ=1.38 (s, 3H, CH
3
), 1.43 (s, 3H,
-S, 2
D
6 6
3
3
CH
=13.6 Hz, 3JH-H =6.0 Hz), 3.33 (dd, 1H, CH
Hz), 3.68 (dd, 1H, CH
-O, 2 H-H =10.8 Hz, 3
1H, CH-O), 3.80 (dd, 1H, CH
-O, 2 H-H =10.4 Hz, 3JH-H =3.2 Hz), 3.87 (pt,
1H, CHCH-O, 3
H-H =6.8 Hz), 4.18-4.22 (m, 1H, CHCH S), 7.17-7.21 (m,
1H, CH=), 7.26-7.31 (m, 2H, CH=), 7.39-7.41 (m, 2H, CH=). 13C NMR
(100.6 MHz, CDCl ): δ= 27.4 (CH ), 27.5 (CH ), 37.5 (CH -S), 64.2 (CH
O), 72.9 (CH-O), 78.5 (CHCH S), 80.7 (CHCHOH), 110.0 (CMe ), 126.6
(CH=), 129.3 (CH=), 129.6 (CH=), 136.1 (C=).
3
), 2.08 (b, 1H, OH), 2.65 (b, 1H, OH), 3.20 (dd, 1H, CH
-S, 2 H-H =13.6 Hz, 3
H-H =5.2 Hz), 3.72-3.76 (m,
2
J
H-H
CH
3
3
3
3
2
2
J
JH-H =4.8
2
2
J
J
=
6
7
2.6 Hz), 3.95-4.00 (m, 2H, CHCHO, CHCH
2
2
J
.85-6.86 (m, 3H, CH=), 6.92-6.96 (m, 2H, CH=), 6.98-7.00 (m, 1H, CH=),
J
2
.09-7.15 (m, 5H, CH=), 7.24 (d, 1H, C=H, 3JH-H =8.4 Hz), 7.31 (d, 1H,
C=H, JH-H =8.4 Hz), 7.69 (d, 1H, C=H, 3JH-H =8.4 Hz), 8.10 (d, 1H, C=H,
3
3
3
3
2
2
-
3JH-H =8.4 Hz). 13C NMR (100.6 MHz, C
4.6 Hz), 0.2 (CH , SiMe ), 17.6 (CH
-S), 70.1 (d, CH-O, 2JC-P =10.0 Hz), 75.1 (CHCH
D
6 6
): δ=-0.1 (d, CH
), 26.8 (CH ), 27.1 (CH
S), 81.0 (CHCHO),
), 122.5-152.1 (aromatic carbons). MS HR-ESI [found
PSSi
(M-Na)+ requires 749.2318]. Anal. calc (%) for
: C 66.08, H 6.52, S 4.41; found: C 65.92, H 6.50, N 4.40.
3
, SiMe
3
, JC-P
2
2
=
3
3
3
3
3
), 36.3
(CH
2
2
109.1 (CMe
2
1
-Deoxy-2,3-O-Isopropylidene-1-(2-naftylthio)-D-arabinitol (8). Yield:
749.2317, C40
H
47
O
5
2
1
3
.0 g (63%). H NMR (400 MHz, CDCl
3
): δ=1.35 (s, 3H, CH
3
), 1.41 (s, 3H,
H-H =7.2 Hz), 3.46 (dd, 1H,
-O, 2
H-H =11.6
-O, 2
H-H =7.6 Hz), 4.24-4.29
S), 7.36-7.44 (m, 3H, CH=), 7.69-7.74 (m, 3H, CH=), 7.81
s, 1H, CH=). 13C NMR (100.6 MHz, CDCl
): δ= 27.1 (CH ), 27.2 (CH ),
7.0 (CH -S), 63.9 (CH -O), 72.8 (CH-O), 78.3 (CHCH S), 80.2
(CHCHOH), 109.8 (CMe ), 125.7 (CH=), 126.6 (CH=), 126.7 (CH=),
27.1 (CH=), 127.7 (CH=), 128.5 (CH=), 131.7 (C=), 133.4 (C=), 133.7
C=).
40
C H
47 5
O PSSi
2
-S, 2
H-H =13.6 Hz, 3
CH
CH
3
), 3.22 (dd, 1H, CH
-S, 2 H-H =14.0 Hz, 3
2
J
J
2
J
J
H-H =4.4 Hz), 3.65 (dd, 1H, CH
2
J
Preparation of compounds 7 and 8
Hz, 3JH-H =6.0 Hz), 3.67-3.73 (m, 1H, CH-O), 3.79 (dd, 1H, CH
2
J
H-H
=
(
(
10.8 Hz, 3JH-H =2.8 Hz), 3.86 (pt, 1H, CHCHO, 3
m, 1H, CHCH
J
2
A suspension of NaH (3.1 mg, 77.4 mmol), washed three times in hexane,
in THF (25 mL) was cooled to -15 °C, and the corresponding thiol (37.5
mmol) in THF (8 mL), at -15 °C was added. After 10 min a solution of 1-
deoxy-2,3-O-isopropylidene-1-tosyl-D-arabinitol[24] (16.3 mmol) in THF
3
3
3
3
2
2
2
2
1
(
(25 ml) was added at -15 °C. The reaction was stirred for 72 h at room
temperature. The reaction was quenched with water and extracted with
dichloromethane for three times. The extract was dried over anhydrous
MgSO
4
and concentrated. The residue was purified by SiO
2
-column
Synthesis of hydroxyl-thioether compounds 9 and 10
chromatography (PE/EtOAc
=
1/6) to produce the corresponding
thioether-derived compound as colorless oil (see Supporting Information
for copies of the NMR spectra).
To a cooled solution (-15 °C) of compound 2 and 3 (1 mmol) in pyridine
(0.27 mL. 3.4 mmol), a solution of p-toluenesulfonyl chloride (190.0 mg, 1
mmol) in DCM (2 mL) was slowly added. After stirring overnight, water
was added and the reaction mixture was extracted with DCM (3 x 50 mL).
The organic extract was washed with a solution of HCl 0.1 M (x1). The
1
-Deoxy-2,3:4,5-di-O-isopropylidene-1-phenylthio-D-arabinitol
(5).
), 1.37
1
Yield: 3.6 g (84%). H NMR (400 MHz, CDCl
3
): δ=1.35 (s, 3H, CH
3
(
s, 3H, CH
J
3
), 1.40 (s, 3H, CH
3
), 1.42 (s, 3H, CH
3
), 3.09 (dd, 1H, CH
2
-S,
organic layer was dried over MgSO
4
, evaporated to dryness and purified
2
H-H =13.6 Hz, 3
-S, 2
H-H =13.6 Hz, 3
J
H-H =6.8 Hz), 3.46 (dd, 1H, CH
2
J
J
H-H
by SiO -flash chromatography (EtOAc/PE = 1/2) to produce the product
2
3
2
=
3.2 Hz), 3.78 (pt, 1H, CHCHO, JH-H =7.3 Hz), 3.95 (dd, 1H, CH
=8.4 Hz, 3JH-H =4.8 Hz), 4.04-4.08 (m, 1H, CH-O), 4.13 (dd, 1H, CH
2
-O, JH-
as a white solid (see Supporting Information for copies of the NMR
spectra).
H
2
-O,
S), 7.15-7.19 (m,
H, CH=), 7.25-7.29 (m, 2H, CH=), 7.39-7.41 (m, 2H, CH=). 13C NMR
100.6 MHz, CDCl ): δ= 25.5 (CH ), 26.9 (CH ), 27.3 (CH ), 27.4 (CH ),
-O), 77.3 (CH-O), 79.3 (CHCH S), 80.3
), 126.0 (CH=), 129.0 (CH=), 129.1
2JH-H =8.0 Hz, 3
1
(
3
JH-H =6.0 Hz), 4.16-4.19 (m, 1H, CHCH
2
1
-Deoxy-2,3-O-Isopropylidene-1-phenylthio-5-O-tosyl-D-arabinitol.
3
3
3
3
3
1
Yield: 3.0 g (93%). H NMR (400 MHz, CDCl
3
): δ=1.21 (s, 3H, CH
3
), 1.27
H-H =4.4 Hz),
-S,
6.8 (CH
2
-S), 68.0 (CH
2
2
, OTs), 2.58 (d, 1H, OH, 3
(s, 3H, CH
3
), 2.35 (s, 3H, CH
3
J
(CHCHO), 109.9 (CMe
CH=), 136.8 (C=).
2
), 110.1 (CMe
2
-S, 2JH-H =14.0 Hz, 3
3
J
.02 (dd, 1H, CH
2
J
H-H =6.8 Hz), 3.24 (dd, 1H, CH
2
(
2
H-H =13.6 Hz, 3JH-H =4.4 Hz), 3.62 (dd, 1H, CHCHO, JH-H =8.0 Hz, 3JH-H
3
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201604483
FULL PAPER
=
6.4 Hz), 3.71-3.78 (m, 1H, CH-O), 3.94 (dd, 1H, CH
2
-OTs, 2
S), 4.18 (dd, 1H, CH
J
H-H =10.4
-OTs,
and the residue was purifief by SiO
= 1/6) to yield the product as a colorless oil.
2
-column chromatography (EtOAc/PE
Hz, 3JH-H =6.8 Hz), 4.06-4.09 (m, 1H, CHCH
2
2
2JH-H =10.4 Hz, 3JH-H =2.4 Hz), 7.06-7.10 (m, 1H, CH=), 7.15-7.19 (m, 2H,
CH=), 7.24-7.28 (m, 4H, CH=), 7.69-7.71 (m, 2H, CH=). 13C NMR (100.6
1
,5-Dideoxy-2,3-O-isopropylidene-5-methyl-O-4-(p-nitrobenzoate)-1-
MHz, CDCl
1.8 (CH-O), 72.1 (CH
CMe ), 126.4 (CH=), 128.2 (CH=), 129.2 (CH=), 129.4 (CH=), 130.2
CH=), 132.6 (C=), 136.1 (C=), 145.4 (C=).
3 3
): δ= 21.9 (CH , OTs), 27.2 (CH
3
), 27.4 (CH
3
), 37.4 (CH
2
-S),
phenylthio-D-xylitol. Yield: 1.4 g (90%). 1H NMR (400 MHz, CDCl
3
):
),
7
(
(
2
-OTs), 78.8 (CHCHO), 79.2 (CHCH
2
S), 110.3
, 3
δ=1.39 (d, 3H, CH
.13 (dd, 1H, CH
3
J
H-H =6.0 Hz), 1.43 (s, 3H, CH
3
), 1.44 (s, 3H, CH
3
2
-S, JH-H =13.6 Hz, 3
2
3
2
J
H-H =5.6 Hz), 3.24 (dd, 1H, CH
2
-S,
2
H-H =14.0 Hz, 3JH-H =5.6 Hz), 4.02-4.09 (m, 2H, CHCH
J
2
S,
CHCHOpNBA), 5.32-5.35 (m, 1H, CH-OpNBA), 7.07-7.09 (m, 1H, CH=),
7.15-7.20 (m, 2H, CH=), 7.29-7.32 (m, 2H, CH=), 8.10-8.12 (m, 2H, CH=),
1
-Deoxy-2,3-O-Isopropylidene-1-(2-naftylthio)-5-O-tosyl-D-arabinitol.
1
8.20-8.23 (m, 2H, CH=). 13C NMR (100.6 MHz, CDCl
27.2 (CH ), 27.5 (CH ), 36.9 (CH
82.1 (CHCHOpNBA), 109.9 (CMe
Yield: 3.6 g (83%). H NMR (400 MHz, CDCl
3
): δ=1.31 (s, 3H, CH
, OTs), 3.20 (dd, 1H, CH
-S, 2JH-H =14.4 Hz,
H-H =4.4 Hz), 3.76
3
), 1.38
3
): δ=16.7 (CH
-S), 70.9 (CH-OpNBA), 75.2 (CHCH S),
), 123.5 (CH=), 126.4 (CH=), 129.0
3
),
(
s, 3H, CH
J
3
), 2.42 (s, 3H, CH
3
2
3
3
2
2
3
-S, 2
H-H =14.0 Hz, 3
H-H =7.2 Hz), 3.47 (dd, 1H, CH
2
J
J
2
dd, 1H, CHCHO, JH-H =8.4 Hz, 3JH-H =6.8 Hz), 3.83-3.88 (m, 1H, CH-O),
3
(CH=), 129.5 (CH=), 130.7 (CH=), 135.2 (C=), 135.3 (C=), 150.5 (C=),
163.9 (C=O, pNBA).
(
4
.06 (dd, 1H, CH
CHCH S), 4.29 (dd, 1H, CH
H, CH=, 3JH-H =8.8 Hz), 7.42-7.46 (m, 3H, CH=), 7.72-7.81 (m, 6H, CH=).
): δ= 21.7 (CH , OTs), 27.0 (CH ), 27.2
-S), 71.6 (CH-O), 72.0 (CH -O), 78.6 (CHCHOH), 78.9
), 125.7 (CH=), 126.5 (CH=), 126.6 (CH=), 127.1
2
-OTs, 2
J
H-H =10.8 Hz, 3JH-H =6.8 Hz), 4.22-4.26 (m, 1H,
-OTs, 2JH-H =10.4 Hz, 3JH-H =2.4 Hz), 7.31 (d,
2
2
2
1,5-Dideoxy-2,3-O-isopropylidene-5-methyl-O-4-(p-nitrobenzoate)-1-
1
3C NMR (100.6 MHz, CDCl
3
3
3
phenylthio-D-xylitol (1.4 g, 3.6 mmol) was dissolved in MeOH (48.5 mL)
and treated with NaOH ( 1.1 g, 26.9 mL) at room temperature. After
being stirred overnight, the reaction mixture was concentrated and
extracted with diethyl ether. The organic phase was washed with brine,
(
(
(
CH
CHCH
3
), 36.9 (CH
2
2
S), 110.2 (CMe
2 2
CH=), 127.7 (CH=), 128.0 (CH=), 128.5 (CH=), 130.0 (CH=), 131.7 (C=),
32.3 (C=), 133.4 (C=), 133.8 (C=), 145,2 (C=).
1
dried over anhydrous MgSO
purified by SiO -column chromatography (EtOAc/PE = 1/1) to yield the
product as a colorless oil.
4
, filtered, and evaporated. The residue was
2
To
a
cooled solution (0 °C) of the corresponding thioether-tosyl
(56.9 mg, 1.5 mmol) was
compound (1.0 mmol) in THF (2.5 mL), LiAlH
4
added portion-wise. The solution was stirred at reflux for 2 h. Then, drops
of water were carefully added and a white precipitate appeared which
was filtered and clean three times with ethyl acetate. The organic phase
1
(
CH
,5-Dideoxy-2,3-O-isopropylidene-5-methyl-1-phenylthio-D-xylitol
11). Yield: 850 mg (87%). 1H NMR (400 MHz, CDCl
3
): δ=1.17 (d, 3H,
), 2.29 (s, 1H, OH,
-S), 3.72-3.79 (m, 2H, CHCHO,
S, 3
JH-H =6.0 Hz), 7.16-7.20 (m, 1H, CH=),
, 3JH-H =6.0 Hz), 1.40 (s, 3H, CH
3
3
), 1.43 (s, 3H, CH
3
was dried over MgSO
was purified by SiO -column chromatography (EtOAc/PE = 1/3) yielding
the corresponding compounds as colorless oils.
4
and evaporated to dryness. The crude product
3JH-H =10.4 Hz), 3.10-3.23 (m, 2H, CH
CH-O), 4.11 (q, 1H, CHCH
2
2
2
.27 (t, 2H, CH=, , 3 H-H =7.2 Hz), 7.36-7.38 (m, 2H, CH=). 13C NMR
7
J
(100.6 MHz, CDCl
3
): δ= 20.0 (CH ), 37.3 (CH
3
), 27.4 (CH
3
), 27.5 (CH
3
2
-S),
1
,5-Dideoxy-2,3-O-isopropylidene-5-methyl-1-phenylthio-D-
67.2 (CH-O), 76.0 (CHCH
129.1 (CH=), 129.5 (CH=), 135.7 (C=).
2
S), 84.1 (CHCHO), 109.7 (CMe ), 126.4 (CH=),
2
1
arabinitol (9). Yield: 1.2 g (67%). H NMR (400 MHz, CDCl
3
): δ=1.18 (d,
), 2.03 (b, 1H,
H-H =6.8 Hz), 3.26 (dd, 1H,
H-H =4.8 Hz), 3.74 (dd, 1H, CHCHO, 3JH-H =7.2
Hz, JH-H =5.2 Hz), 3.87-3.90 (m, 1H, CH-O), 4.13-4.18 (m, 1H, CHCH S),
.14-7.18 (m, 1H, CH=), 7.23-7.28 (m, 2H, CH=), 7.36-7.39 (m, 2H, CH=).
): δ=19.5 (CH ), 27.5 (CH ), 27.6 (CH ),
-S), 68.2 (CH-O), 77.0 (CHCH S), 84.0 (CHCHO), 109.7
), 126.6 (CH=), 129.3 (CH=), 129.7 (CH=), 136.3 (C=).
3
H, CH
OH), 3.15 (dd, 1H, CH
CH J
-S, 2 H-H =13.6 Hz, 3
3
, 3JH-H =6.8 Hz), 1.38 (s, 3H, CH
-S, 2 H-H =13.6 Hz, 3
J
3 3
), 1.41 (s, 3H, CH
2
J
Synthesis of thioether-hydroxyl compound 12
2
J
3
2
Diol 7 (1 mmol) was solved in DMF (2 mL) in the presence of imidazole
2.5 mmol) and was cooled to -15 ᵒC. solution of tert-
7
(
A
1
3C NMR (100.6 MHz, CDCl
8.2 (CH
CMe
3
3
3
3
butyldimethylsilylchloride (1.2 mmol) in DMF (1 mL) was added and the
reaction was stirred for 1.5 h. When chlorotrimethylsilane was used, the
solution was cooled to -75 ᵒC and the reaction mixture was stirred only
3
2
2
(
2
3
0 min. Then, water was added and the reaction mixture was extracted
with Et O (x3). The organic layer was dried over MgSO , evaporated to
dryness and purified by SiO -column chromatography (EtOAc/PE = 1/4)
1
,5-Dideoxy-2,3-O-isopropylidene-5-methyl-1-(2-naftylthio)-D-
2
4
1
arabinitol (10). Yield: 1.1 g (54%). H NMR (400 MHz, CDCl
3
): δ=1.22 (d,
), 1.91 (b, 1H,
H-H =6.4 Hz), 3.39 (dd, 1H,
H-H =4.4 Hz), 3.79 (dd, 1H, CHCHO, 3JH-H =7.6
Hz, JH-H =5.6 Hz), 3.90-3.93 (m, 1H, CH-O), 4.21-4.24 (m, 1H, CHCH S),
.40-7.48 (m, 3H, CH=), 7.72-7.82 (m, 4H, CH=). 13C NMR (100.6 MHz,
CDCl ): δ=19.3 (CH ), 27.2 (CH ), 27.3 (CH ), 37.7 (CH -S), 68.0 (CH-O),
7.4 (CHCH S), 83.8 (CHCHO), 109.4 (CMe ), 125.8 (CH=), 126.6 (CH=),
2
3
H, CH
OH), 3.26 (dd, 1H, CH
CH J
-S, 2 H-H =13.6 Hz, 3
3
, 3JH-H =6.8 Hz), 1.39 (s, 3H, CH
-S, 2 H-H =13.6 Hz, 3
J
3 3
), 1.44 (s, 3H, CH
to produce the product as a colorless oil (see Supporting Information for
copies of the NMR spectra).
2
J
2
J
3
2
5-O-(tert-Butyldimethylsilyl)-1-deoxy-2,3-O-isopropylidene-1-
7
1
phenylthio-D-arabinitol (12). Yield 263.3 mg (61%). H NMR (400 MHz,
3
3
3
3
2
3 3
, OTBDMS), 0.91 (s, 9H, CH
, tBu, OTBDMS),
CDCl
.38 (s, 3H, CH
-S, 2JH-H =13.6 Hz, 3JH-H =7.2 Hz), 3.46 (dd, 1H, CH
dd, 1H, CH
H-H =6.8 Hz), 3.62-3.68 (m, 2H, CH-O, CH
.81 (m, 2H, CHCHO, CH -OTBDMS), 4.26 (m, 1H, CHCH
3
): δ=0.09 (s, 6H, CH
), 2.62 (d, 1H, OH, 3JH-H =5.2 Hz), 3.12
), 1.42 (s, 3H, CH
3
7
1
1
2
2
1
(
3
26.9 (CH=), 127.1 (CH=), 127.3 (CH=), 127.7 (CH=), 128.5 (CH=),
31.8 (C=), 133.5 (C=), 133.7 (C=).
-S, 2JH-H
2
2
=
3
10.4 Hz, 3
J
2
-OTBDMS), 3.76-
2
2
S), 7.14-7.18
Synthesis of hydroxyl-thioether compound 11 with inversion of
configuration[25]
m, 1H, CH=), 7.25-7.29 (m, 2H, CH=), 7.39-7.42 (m, 2H, CH=). 13C NMR
(
(
(
100.6 MHz, CDCl
C, t
3
): δ=-5.2 (CH3, OTBDMS), -5.1 (CH3, OTBDMS), 18.5
t
,
Bu, OTBDMS), 26.1 (CH
-S), 64.5 (CH
CHCHO), 109.8 (CMe ), 126.0 (CH=), 129.1 (CH=), 136.8 (C=).
3
, Bu, OTBDMS), 27.4 (CH
3
), 27.5 (CH
3
),
DIAD (3.1 mL, 16 mmol) was added dropwise to a solution of thioether-
hydroxyl 4 (1.1 g, 4 mmol), p-nitrobenzoic acid (2.7 g, 16 mmol), and
37.4 (CH
2
2 2
-OTBDMS), 73.3 (CH-O), 79.1 (CHCH
S,
2
PPh
3
(4.2 g, 16 mmol) in THF (33 mL) at 0 °C. After being stirred
overnight at room temperature, the reaction mixture was concentrated
4
Synthesis of [Rh(cod)(L4c)]BF catalyst precursor
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Chemistry - A European Journal
10.1002/chem.201604483
FULL PAPER
Ligand L4c (55.6, 0.05 mmol) was dissolved in CH
2
Cl
2
(1 mL) and
which was purged four times with hydrogen. It was then pressurized at
the desired pressure. After the desired reaction time, the autoclave was
depressurized and the solvent evaporated off. The residue was dissolved
[
2 4
Rh(cod) ]BF (20.3 mg, 0.05 mmol) was added. The reaction was stirred
for 10 min at room temperature. The product was precipitated by adding
cold hexane (5 mL). The product was then filtered and washed with cold
hexane (3 x 5 mL). The solid was then dried to afford the catalyst
precursor as a yellow solid (see Supporting Information for copies of the
2
in Et O (1.5 ml) and filtered through a short celite plug. Conversions were
determined by 1H NMR. The enantiomeric excesses of hydrogenated
products were determined using the conditions previously described (see
Supporting Information for details).
NMR spectra). Yield: 53 mg (89%).31P NMR (161.9 MHz, CDCl
3
):
δ=119.9 (d, 1JP-Rh= 261.5 Hz). H NMR (400 MHz, CDCl
1
): δ=0.59 (s, 9H,
), 0.84 (b, 6H, CH ), 1.04 (s, 9H,
), 1.26 (s, 3H, CH ), 1.79 (m, 2H,
, cod), 2.12 (m, 1H, CH , cod), 2.27 (m, 1H,
, cod), 2.49 (m, 1H, CH , cod), 2.69 (m,
-S), 4.16 (b, 1H, CH=,
3
CH
CH
CH
CH
3
3
2
2
, SiMe
3
), 0.72 (s, 9H, CH
3
, SiMe
3
3
t
, Bu, OTBDMS), 1.20 (s, 3H, CH
3
3
Acknowledgements
, cod), 1.95 (m, 1H, CH
-OTBDMS), 2.37 (m, 2H, CH
, cod), 3.16 (m, 2H, CH
cod), 4.27 (m, 3H, CH
2
2
2
2
1H, CH
2
2
-OTBDMS and CH
2
Financial support from the Spanish Government (CTQ2013-
40568P), the Catalan Government (2014SGR670), and the
ICREA Foundation (ICREA Academia awards to M. Diéguez and
O. Pàmies) is gratefully acknowledged.
2
-S, CH= cod, CH), 4.64 (m, 2H, CH), 5.50 (m, 2H,
CH= cod), 6.918-8.21 (m, 17H, CH= aromatic). 13C NMR (100.6 MHz,
t
CDCl
3
): δ=-0.1 (CH
3
-Si), 0.4 (CH
3
-Si), 14.3 (CH
, Bu-Si), 29.7 (b, CH
), 34.5 (b, CH cod), 34.9 (b, CH
3
), 18.4 (C, Bu-Si), 22.9
cod), 30.4 (b, CH
cod), 42.5 (CH -S), 62.2 (CH -
t
3
(CH ), 26.8 (CH
3
2
2
cod), 31.9
(CH
3
2
2
2
2
Keywords: asymmetric hydrogenation • cyclic β-enamides •
rhodium • iridium • phosphite-thioether ligands
OTBDMS), 75.6 (CH), 75.7 (CH), 81.1 (CH), 82.7 (CH=, cod), 94.0 (CH=,
cod), 112.1 (CMe ), 112.3 (CH=, cod), 114.6 (CH=, cod), 114.6-151.4
aromatic carbons). MS HR-ESI [found 1117.3383, C58 PRhSSi
M)+ requires 1117.3379]. Anal. calc (%) for C58
PRhSSi : C
2
(
(
H
75
O
6
3
H75BF
4
O
6
3
1]
(a) Asymmetric Catalysis in Industrial Scale: Challenges, Approaches
and Solutions; (Eds. H. U. Blaser, H.-J. Federsel); Wiley: Weinheim,
Germany, 2003. (b) G. Shang, W. Li and X. Zhang in Catalytic
Asymmetric Synthesis; 3rd Ed; (Ed. I. Ojima), John Wiley & Sons, Inc.:
Hoboken, 2000, pp 343-436. (c) J. M. Brown in Comprehensive
Asymmetric Catalysis; (Eds: E. N. Jacobsen, A. Pfaltz, H. Yamamoto);
Springer-Verlag: Berlin, 1999; Vol. I, pp 121-182. (d) Asymmetric
Catalysis in Organic Synthesis; (Ed: R. Noyori); Wiley: New York, 1994.
(e) Applied Homogeneous Catalysis with Organometallic Compounds,
2nd Ed; (Eds: B. Cornils, W. A. Herrmann); Wiley-VCH, Weinheim,
2002.
57.80, H 6.27, S 2.66; found: C 57.89, H 6.31, N 2.64
F
Synthesis of [Ir(cod)(L4c)]BAr catalyst precursor
Ligand L4c (41.1 mg, 0.037 mmol) was dissolved in CH
Ir(µ-Cl)(cod)] (12.5 mg, 0.0185 mmol) was added. The reaction was
refluxed at 50 °C for 1 hour. After 5 min at room temperature, NaBAr
38.6 mg, 0.041 mmol) and water (2.5 mL) were added and the reaction
2 2
Cl (2.5 mL) and
[
2
F
(
mixture was stirred vigorously for 30 min at room temperature. The
phases were separated and the aqueous phase was extracted twice with
CH
2
Cl
2
. The combined organic phases were dried with MgSO
4
, filtered
[2]
Asymmetric hydrogenation is the key step for the synthesis of many
commercial products, such as the Parkinson’s drug L-DOPA, antibiotics
levofloxacin and sitagliptin, pesticide (S)-metolachlor, etc. For key
references, see: (a) W. S. Knowles, Angew. Chem. 2002, 114, 2096;
Angew. Chem. Int. Ed. 2002, 41, 1998 (L-DOPA). (b) R. Noyori, Angew.
Chem. 2002, 114, 2108; Angew. Chem. Int. Ed. 2002, 41, 2008
(levofloxacin). (c) C. S. Shultz, S. W. Krska, Acc. Chem. Res. 2007, 40,
1320 (sitagliptin). (d) H.-U. Blaser, Adv. Synth. Catal. 2002, 344, 17
(metolachlor).
through a plug of celite and the solvent was evaporated to give the
product as a red-orange solid (see Supporting Information for copies of
the NMR spectra). Yield: 71 mg (93%).31P NMR (161.9 MHz, CDCl
3
):
1
δ=101.0 (s). H NMR (400 MHz, CDCl
3
): δ=-0.09 (s, 3H, CH
3
, OTBDMS),
), 0.71 (s, 9H, CH
), 1.36 (s, 3H,
-OTBDMS, 2
, cod), 2.29-2.32 (m, 1H, CH , cod),
H-H =11.6 Hz), 3.55-3.60 (m, 1H, CH -S),
.69 (b, 1H, CH=, cod), 4.03 (dd, 1H, CH
-S, 2 H-H =11.2 Hz, 3JH-H =3.2
-
0.02 (s, 3H, CH
SiMe
CH
3
, OTBDMS), 0.63 (s, 9H, CH
3
, SiMe
3
3
,
t
3
), 0.86 (s, 9H, CH
3
, Bu, OTBDMS), 1.27 (s, 3H, CH
3
3
), 1.72-2.07 (m, 6H, CH
12.0 Hz), 2.17-2.21 (m, 1H, CH
.18 (d, 1H, CH
-OTBDMS, 2
2
, cod), 2.05 (d, 1H, CH
2
J
H-H
=
3
3
2
2
2
J
2
[3]
(a) D. Q. Pharm, A. Nogid, Clin. Ther. 2008, 30, 813 (Rotigotine). (b) J.
I. Osende, D. Shimbo, V. Fuster, M. Dubar, J. J. Badimon, J. Thromb.
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Señas, F. Soulière, P. Schmitt, N. Urbain, N. Rentero, L. Bert, L.
2
J
3
Hz), 4.30 (m, 2H, CH-O, CH=, cod), 4.44 (pt, 1H, CHCHO, JH-H =8.4 Hz),
4
6
.57 (b, 1H, CHCH
2
S), 4.93 (b, 1H, CH=, cod), 5.30 (b, 1H, CH=, cod),
): δ=-5.9
, SiMe ),
.98-8.18 (m, 29H, CH= aromatic). 13C NMR (100.6 MHz, CDCl
3
(
CH
3
, SiMe
.9 (CH
6.2 (CH
1.9 (CH
9.5 (CH=, cod), 76.2 (d, CHCHO, 3JC-P =5.3 Hz), 76.6 (CHCH
3
, OTBDMS), -5.3 (CH
3
, SiMe
3
, OTBDMS), 0.0 (CH
3
3
t
t
0
2
3
6
3
, SiMe
), 26.8 (CH
, cod), 33.4 (CH
3
), 18.4 (C, Bu, OTBDMS), 25.8 (CH
3
, Bu, OTBDMS),
Denoroy, B. Renaud, M. Lesourd, C. Muñoz, G. Chouvet, Eur
Pharmacol. 2003, 459, 17 (Alnespirone).
J
3
3
), 27.8 (CH
2
, cod), 29.6 (d, CH
2
, cod, JC-P =13.0 Hz),
-OTBDMS),
S), 79.2
C-P =14.5 Hz), 102.6 (d, CH=, cod, JC-P
2
2
, cod), 45.6 (CH
2
-S), 61.2 (CH
2
[4]
(a) J. L. Renaud, P. Dupau, A.-E. Hay, M. Guingouain, P. H. Dixneouf,
C. Bruneau, Adv. Synth. Catal. 2003, 345, 230. (b) R. Hoen, M. van
den Berg, H. Bernsmann, A. J. Minnaard, J. G. de Vries, B. L. Feringa,
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2
(
CH=, cod), 82.5 (d, CH-O, 2
J
=
1
2
17.6 Hz), 105.5 (d, CH=, cod, JC-P =15.3 Hz), 112.4 (CMe ), 117.4-
51.6 (aromatic carbons), 162.2 (q, C-B, BAr
PSSi
(M)+ requires 1207.3959]. Anal.
: C 52.20, H 4.23, S 1.55; found: C 52.29,
, 1
JC-B =63.4 Hz). MS HR-
F
ESI [found 1207.3964, C58
calc (%) for C90
H75IrO
6
3
4 6 3
H87BF IrO PSSi
H 4.25, N 1.52.
General procedure for the asymmetric hydrogenation of cyclic β-
enamides S1-S10
The enamide (0.25 mmol), catalyst precursor [M(cod)
or M= Ir, X= BAr ; 1 mol%) and the corresponding ligand (1 mol%) were
dissolved in CH Cl (1 mL) and placed in a high-pressure autoclave,
2 4
]X (M= Rh, X= BF
F
2632. (j) I. Arribas, M. Rubio, P. Kleman, A. Pizzano, J. Org. Chem.
2
2
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Chemistry - A European Journal
10.1002/chem.201604483
FULL PAPER
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other functional groups it is due to the formation of mixtures of thioether
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0, 1402. (b) X. Cui, K. Burgess, Chem. Rev. 2005, 105, 32726. (c) O.
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(
Y. Zhu, K. Burgess, Acc. Chem. Res. 2012, 45, 1623. (f) J. J. Verendel,
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Weinheim 2013.
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[
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Chemistry - A European Journal
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FULL PAPER
Entry for the Table of Contents
FULL PAPER
Jèssica Margalef, Oscar Pàmies* and
Montserrat Diéguez*
Page No. – Page No.
Novel
phosphite-thiother
ligands
Phosphite-thioether ligands with a simple modular architecture derived from
carbohydrates have been successfully applied (ee’s up to 99%) in the synthesis of
derived from carbohydrates allow the
enantioswitchable hydrogenation of
cyclic β-enamides using either Rh- or
Ir-catalysts
2-aminotetralines and 3-aminochromanes via metal catalysed asymmetric
hydrogenation of cyclic β-enamides. Both enantiomers were obtained by using
either Rh- or Ir-catalyst precursors.
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