Exploiting Substrate Diversity for Preparing Synthetically Valuable Sulfoxides via Asymmetric Hydrogenative Kinetic Resolution

Article abstract of DOI:10.1002/ejoc.202000592

A detailed study is disclosed on the Rh-mediated hydrogenative kinetic resolution of α,β-unsaturated sulfoxides with alkyl and aryl substituents at the α-, E- and Z-positions of the double bond. This stereoselective catalytic methodology has enabled the p

Full text of DOI:10.1002/ejoc.202000592

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Exploiting Substrate Diversity for Preparing Synthetically
Valuable Sulfoxides via Asymmetric Hydrogenative Kinetic
Resolutions
Authors: Héctor Fernández-Pérez, Joan Ramon Lao, Arnald
Grabulosa, and Anton Vidal-Ferran
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000592
Link to VoR: https://doi.org/10.1002/ejoc.202000592
01/2020

10.1002/ejoc.202000592
European Journal of Organic Chemistry
FULL PAPER
Exploiting Substrate Diversity for Preparing Synthetically
Valuable Sulfoxides via Asymmetric Hydrogenative Kinetic
Resolutions
Héctor Fernández-Pérez,[c] Joan R. Lao,[c] Arnald Grabulosa,[a] and Anton Vidal-Ferran*[a],[b],[c]
[a]
Dr. Arnald Grabulosa, Prof. Anton Vidal-Ferran
Section of Inorganic Chemistry – Department of Inorganic and Organic Chemistry
University of Barcelona (UB)
Carrer Martí i Franquès 1-11 – 08028 Barcelona, Spain
E-mail: anton.vidal@icrea.cat
[b]
Prof. Anton Vidal-Ferran
ICREA
P. Lluís Companys 23, 08010 Barcelona, Spain
https://www.icrea.cat/Web/ScientificStaff/anton-vidal-i-ferran-288
Dr. Héctor Fernández-Pérez, Dr. Joan R. Lao, Prof. Anton Vidal-Ferran
Institute of Chemical Research of Catalonia (ICIQ)
[c]
Av. Països Catalans 16, 43007 Tarragona, Spain
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract:
A detailed study is disclosed on the Rh-mediated
hydrogenative kinetic resolution of -unsaturated sulfoxides with
alkyl and aryl substituents at the -, E- and Z-positions of the double
bond. This stereoselective catalytic methodology has allowed for the
preparation of highly enantioenriched (or even enantiopure) alkyl
and aryl substituted (un)saturated sulfoxides via a simple and
efficient synthetic operation. Moreover, the application of the
hydrogenative KR to the preparation of valuable optically active
sulfoxide-containing building blocks or biologically active
intermediates is described.
Introduction
The catalytic stereoselective synthesis of enantiopure sulfoxides
has attracted the interest of the synthetic community due to the
broad applicability of enantiopure sulfoxides in asymmetric
synthesis (as chiral auxiliaries or ligands).[1] Apart from their
usefulness in asymmetric synthesis, and also due to the crucial
role of sulfur in living systems,[2] sulfoxide groups can be found
in a myriad of bioactive compounds that naturally participate in
the metabolism (e.g., mustard oils[2] or L-methionine S-oxides[3];
see Figure 1) or in a broad array of enantiopure synthetic drugs
(e.g., the hydroxyamic acids[ 4 ] and sulfinyl propanamines[ 5 ]
indicated in Figure 1).
Regarding the preparation of optically active S-stereogenic
sulfoxides via catalytic methods, the most common strategy
involves the direct oxidation of thioethers using metal complexes
or biocatalysts (see Scheme 1a).[ 6 ] More recently, efficient
strategies for the preparation of optically active sulfoxides based
on kinetic resolutions using an oxidant have also been reported
(see Scheme 1b).[6a,7] (Dynamic) kinetic resolutions relying on a
hydrolytic step,[8] a Mislow-Evans rearrangement coupled with
the hydrogenation of an allyl group,[9] or a CH olefination of
diaryl compounds[10] efficiently lead to optically active sulfoxides
Figure 1. Selected examples of naturally occurring or synthetically produced
biologically active sulfoxides.[2-5]
(see Scheme 1c). Finally, elegant methodologies based on CS
bond forming reactions onto in situ-generated sulfenate anions
have also been reported (see Scheme 1d).[11]
We recently reported efficient catalytic tools for the preparation
of highly enantioenriched unsubstituted vinyl and ethyl
sulfoxides through a hydrogenative kinetic resolution (KR)
catalyzed by
a Rh complex derived from a phosphine-
phosphite[12] ligand.[13] The success of this KR methodology is
based on the complexation of the starting substrates on the
rhodium catalyst (coordination of the CC double bond with
chelating assistance of the oxygen of the sulfoxide group) and
differentiation of the reaction rates of the two enantiomers of the
substrate towards hydrogenation of the alkenyl group.[13]
Given our ongoing interest in developing highly stereoselective
catalytic tools,[14], and encouraged by the precise stereocontrol
exhibited in the hydrogenative kinetic resolution of unsubstituted
1
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10.1002/ejoc.202000592
European Journal of Organic Chemistry
FULL PAPER
Scheme 1. Reported catalytic methods towards optically active S- stereogenic sulfoxides and present work on Rh-catalyzed hydrogenative KR of ,-unsaturated
sulfoxides.
vinyl sulfoxides,[13] we studied herein the effects of precisely
positioning alkyl or aryl substituents at the -, E- and Z-positions
of the double bond in the (stereo)chemical outcome of the
reactions (Scheme 1). The selective synthesis of some of the
synthetic protocols[18] remained elusive in our hands. However,
we efficiently performed the hydrogenation of allenyl sulfoxide
rac-2 at the mmol scale[19] and we were able to include sulfoxide
rac-1c as a substrate in our studies (Scheme 2). Lastly, -
racemic starting -unsaturated sulfoxides constituted
a
substituted
-unsaturated
sulfoxides
rac-1e,f
were
challenging task. In this manuscript, we also detail interesting
synthetic protocols for their preparation that can be useful for the
synthetic community. Lastly, to demonstrate the synthetic utility
of hydrogenative kinetic resolutions, we report herein the
application of this method for the catalytic enantioselective
synthesis of intermediates of selected biologically active relevant
enantiopure sulfoxides.
conveniently prepared by reaction of the required organo-
magnesium reagent with methyl benzenesulfinate after adapting
a
previously reported synthetic procedure for analogous
chemistry.[20]
With the array of structurally diverse -unsaturated sulfoxides
in hand (rac-1af), we then turned our attention to the
assessment of the catalytic activity of our highest performing Rh-
catalysts (i.e. those incorporating ligand L;[13] see Scheme 1) in
hydrogenative kinetic resolutions (HKR) of the selected
sulfoxides rac-1af.
Results and Discussion
The presence of substituents at the vinyl moiety of these
substrates translated into lower hydrogenation rates than those
observed for sulfoxides containing the unsubstituted vinyl
group.[13] After some experimentation, efficient kinetic resolution
conditions (5 mol% of [Rh(nbd)(L)]BF4 as precatalyst and PhCH3
and CH2Cl2 (4:1 v/v) as solvents) were identified and the H2
As previously mentioned, the initial set of substrates in our
studies to explore the effects of structural complexity on the
stereochemical outcome of the reaction encompassed racemic
alkyl and aryl substituted -unsaturated sulfoxides at the -, E-
and Z-positions (sulfoxides rac-1af in Scheme 2). trans-
Substituted -unsaturated sulfoxides rac-1a,b were prepared
straightforwardly following a Horner-Wittig protocol.[15] While cis-
phenyl derivative rac-1d was easily prepared following
a
reported procedure,[16] we developed an efficient synthesis for
the methyl substituted analogue (rac-1c) by the chemoselective
hydrogenation of allenyl sulfoxide rac-2 (see Scheme 2). After
some experimentation, we identified selective hydrogenation
conditions towards rac-1c (2.5 mol% of [Rh(nbd)(L)]BF4, 5 bar of
H2 and 10 ºC). Experiments led to full conversion and under the
developed reaction conditions, we observed that the addition of
hydrogen occurred exclusively at the allene CC-position with
complete (Z)-selectivity.[ 17 ] It is worth mentioning that the
preparation of sufficient amounts of rac-1c following other
Scheme 2. Initial set of substrates (rac-1af) and preparation of rac-1c by
selective hydrogenation of racemic allenyl-substituted sulfoxide rac-2.
2
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10.1002/ejoc.202000592
European Journal of Organic Chemistry
FULL PAPER
pressure and reaction temperature and time were specifically
optimized for both recovered and hydrogenated products
(Scheme 3).
selectivity factors than those observed for the methyl substituted
analogues rac-1a and rac-1c (compare data in Scheme 3).
Moreover, moderate values of enantioselectivity were obtained
for the aryl-substituted recovered and hydrogenated sulfoxides
1d and 3d (up to 62% ee, see Scheme 3).
In general terms, efficient and selective catalytic conditions were
identified for all substrates, with the exception of compound rac-
1b (efficient kinetic resolution conditions remained elusive for
this substrate, as low enantioselectivities were observed under
all reaction conditions assayed, Scheme 3). Having mentioned
this exception, it should be noted that the presence of methyl or
phenyl substituents at the vinyl moiety (substrates rac-1a and
rac-1cf) was well tolerated and that enantioselectivities ranging
from 62 to 99% ee and from 56 to 93% ee for recovered and
hydrogenated products were observed, respectively (Scheme
3).[21] As evidenced by the results, high selectivity factors (s = 58
and s = 25, Scheme 3) were observed in the kinetic resolution of
(E)-Me-substituted substrate rac-1a. These selectivity factors
translated into high enantioselectivities for the recovered and
hydrogenated products (99% and 91% ee for 1a and 3a,
respectively; see Scheme 3). A lower selectivity factor was
observed for the analogous -unsaturated sulfoxide with the
methyl group in the (Z)-position (rac-1c; s = 8, Scheme 3).
Despite the low selectivity factor in the kinetic resolution of rac-
1c, optically pure starting material 1c could be obtained at 92%
of conversion (99% ee for 1c, Scheme 3). Although the
enantioselectivity of the hydrogenated product from rac-1c could
not be further improved, this result was no drawback for
obtaining this product in high enantioselectivity with our method,
as it can also be obtained by hydrogenatively resolving substrate
rac-1a (Scheme 3) instead of rac-1c. Regarding the kinetic
resolutions of (Z)- and (E)-2-phenylethenyl substituted sulfoxides
rac-1b and rac-1d, those transformations proceeded with lower
The hydrogenative kinetic resolution of -unsaturated
sulfoxides bearing substituents at the -position (rac-1e,f)
proceeded with higher selectivity and under milder reaction
conditions than those of the substrates with substituents at the
-position (rac-1ad; compare data in Scheme 3). Substrates
rac-1e,f provided the best results of the whole series (Scheme
3), with high to excellent ee values for the recovered starting
material (99% ee both for 1e and 1f; Scheme 3) and for the
hydrogenated products (89 and 93% ee for 3e and 3f,
respectively; Scheme 3). Slightly beneficial effects on the
enantioselectivity were observed for the phenyl substituted
substrate (rac-1f) with selectivity values as high as s = 154 and s
= 62 for 1f and 3f, respectively. Most remarkably, the hydroge-
nation of rac-1f took place with perfect diastereoselectivity,
leading to the exclusive formation of the anti-diastereoisomer
anti-3f (dr of anti-3f:syn-3f ≥ 99:1; see Scheme 3).[26]
Having expanded the use of hydrogenative KR on a set of
substituted -unsaturated sulfoxides, the practicality of this
methodology was further demonstrated by preparing a number
of advanced synthetic intermediates of biologically active
molecules containing sulfoxide groups: (R)-sulforaphene,[22] (S)-
sulforaphane[23] and a histone deacetylase (HDAC) inhibitor[24]
(see Scheme 4 and Scheme 5). To this end, the strategically
devised starting materials rac-4 and rac-6 were easily prepared
using the above-mentioned procedures.[15]
a [Substrate] = 0.2 M. b Determined by 1H NMR. c Determined by HPLC on chiral stationary phases. d The absolute configurations of products 1e,f and 3e,f were
determined by comparison with reported optical rotations for 3e,f.[19] The absolute configuration of products 1ad and 3ad were tentatively assigned by analogy
e
f
with the results for 3e,f. The selectivity factor (s) was calculated with the equation: s = ln[1C(1+ee3)]/ln[1C(1ee3)] where C = ee1/(ee1ee3).[7a] Reaction
g
h
products could not be separated by standard column chromatography. Solvent mixture = Cyclohexane:CH2Cl2 (4:1 v/v). 5% of isomerized product 1a was
detected in the reaction crude, as determined by NMR.[19] i Isolated yields.[25] j dr ratio of anti-3f:syn-3f ≥ 99:1, as determined by 1H NMR.[26]
Scheme 3. Kinetic resolution of sulfoxides 1afa
3
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10.1002/ejoc.202000592
European Journal of Organic Chemistry
FULL PAPER
intermediate (R)-7 could be transformed into the bioactive
molecule following a well-established experimental procedure.[30]
The results summarized in Table
1 indicate that kinetic
resolutions of alkyl substituted -unsaturated sulfoxides (i.e.
R1 = Me or benzyl) take place with lower selectivity factors than
the kinetic resolutions of their aryl substituted counterparts 6 and
10 (i.e. R1 = Ar). Though computational studies for rationalizing
these results have not been performed, the higher difference in
relative size between R1 and R4 in substrates 6 and 10 than in
sulfoxides 4 and 8 could account for the higher selectivity factors
that have been observed in the hydrogenative kinetic resolution
of aryl substituted ,-unsaturated sulfoxides.
Scheme 4. Preparation of advanced synthetic intermediates of (R)-sulforaphene
and (S)-sulforaphane.
Resolution of sulfoxide rac-4 furnished unreacted starting
material (R)-4 with notable enantioselectivities (84% ee; see
Scheme 4), whilst the hydrogenated product (S)-5 could only be
obtained with moderate enantioselectivity (50% ee; Scheme 4).
The resulting products are valuable precursors of anticancer
agents.[27] In this particular reaction, minor amounts of the over
reduced sulfide derived from product 5 were detected in the
reaction crude (6%). However, this by-product could be easily
separated by standard SiO2 column chromatography. (R)-
sulforaphene and (S)-sulforaphane can be easily prepared from
the advanced synthetic intermediates (R)-4 and (S)-5 following
well-established synthetic protocols.[28]
Gratifyingly, the kinetic resolution of rac-6 (Scheme 5) took place
in a highly chemo- and stereo-selective way and excellent
values of enantioselectivity were obtained for both recovered
and reduced products (99% and 94% ee for (S)-6 and (R)-7,
respectively; Scheme 5). Notably, the optimized reaction for the
target intermediate (R)-7 (Conditions B; Scheme 5) proceeded
with a high selectivity factor (s = 65; Scheme 5) and the desired
sulfoxide (R)-7 could be efficiently isolated in high optical purity
(41% isolated yield and 94% ee; Scheme 5). It should be noted
herein that the formal synthesis of the HDAC inhibitor precursor
indicated in Scheme 5 employing a hydrogenative kinetic
resolution competes in terms of stereoselectivity with those
previously reported in the literature using oxidative catalytic
methods.[29]The resulting hydrogenated product (R)-7 is a
Table 1. Kinetic resolutions of vinyl sulfoxides: Dependence of the selectivity
factor on the substrate structure
Pro
du
ct
s-
factor
%ee
(conf.)
Entry
R1
R2
H
R3
H
R4
1a
2a
3a
4a
5b
6b
7b
8b
4
5
7
7
84 (R)
50 (S)
99 (S)
94 (R)
99 (R)
80 (S)
99 (S)
97 (R)
Me
(CH2)2OBz
6
81
65
11
13
56
148
p-Cl-
C6H4
H
H
(CH2)3CO2Me
7
8
Bn
H
H
H
H
9
10
11
o-F-
C6H4
H
H
a Results from this manuscript. b Results published in reference [13]
Finally, taking into consideration the experimental results above-
mentioned, the stereochemical outcome of our hydrogenative
kinetic resolution for structurally diverse substituted ,-
unsaturated vinyl sulfoxides can be summarized in Scheme 6. In
the presence of the rhodium catalyst derived from ligand L, the
(S)-configured enantiomers at the sulfur atom in the starting
vinyl sulfoxide are less prone to hydrogenation of the alkenyl
fragment and remain unreacted with high enantioselectivities in
favor of the (S)-configured substrates (changes in the S
configuration at the sulfur atom in 1f and 4 are due to an
inversion in the CIP priority rules as indicated in Scheme 6). On
the other hand, the CC double bond of the enantiomers of the
starting material with a R configuration at the sulfur atom are
hydrogenated faster and lead to the corresponding
enantioenriched compounds (changes in the R configuration at
the sulfur atom in 3f and 5 are due to an inversion in the CIP
priority rules as indicated in Scheme 6).
Scheme 5. Preparation of the histone deacetylase (HDAC) inhibitor
intermediate (R)-7.
Conclusion
valuable precursor to chiral drugs that are currently in clinical
development for cancer therapy.[24] The advanced synthetic
In summary, we have exploited the potentially high structural
diversity of the substrates to be hydrogenatively resolved (i.e.
4
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European Journal of Organic Chemistry
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the concentration of the substrate in the reaction medium was adjusted to
0.20 M. Once the reaction mixture had been prepared, the glass vessel
was placed into one of the positions of a steel autoclave reactor (HEL
Cat-24 parallel pressure multireactor). The autoclave was taken out of
the glove box. Then, the autoclave was purged three times with nitrogen
gas and pressurized at 5 bar of nitrogen gas. The autoclave was cooled
at the desired temperature and remained at this temperature for 45
minutes in order to stabilize the temperature. After that, the autoclave
was slowly depressurized and purged five times with H2 gas without
stirring (at a pressure not higher than the selected one), and finally, the
autoclave was pressurized under the required pressure of H2 gas. The
reaction mixture was stirred at this temperature during the adequate
period of time. The autoclave was then slowly depressurized. The
reaction mixture was filtered through a short pad of SiO2, eluting with
EtOAc (1.5 mL). The resulting solution was concentrated in vacuo, and
the conversion was determined by 1H NMR spectroscopy. Finally,
purification by silica gel column chromatography afforded both the
desired starting substrate and the hydrogenated product. Enantiomeric
ratios for both isolated products were determined by HPLC analysis on
chiral stationary phases.
-unsaturated sulfoxides with alkyl and aryl substituents at the
-, E- and Z-positions of the double bond) to give access to an
array of new and valuable highly enantioenriched (or even
enantiopure) sulfoxide-containing synthetic intermediates.
We have discovered a new catalytic tool that mediates the
chemo- and stereo-selective hydrogenation of an allenyl
sulfoxide with the exclusive formation of the corresponding (Z)-
configured sulfinyl alkene, opening further avenues for the
(stereo)selective preparation of valuable (Z)-configured alkenyl
sulfoxides. Moreover, we have further expanded the applicability
of the enantioselective Rh-mediated hydrogenative kinetic
resolution by preparing enantioenriched advanced synthetic
intermediates of biologically active sulfoxide-containing
molecules. Catalytic hydrogenative kinetic resolutions have
generally proceeded with high selectivity factors and enabled the
preparation of the final sulfoxides in a highly enantioenriched (or
even enantiopure) form. Ongoing investigations include the
extension of the application of this chemistry to other substrates,
to other transition metals and study of alternative ligand designs.
Characterization of the reaction products and determination of the
absolute configurations.
(S)-(E)-(prop-1-en-1-ylsulfinyl)benzene (S)-1a: (optimized result for
product 1a; Scheme 3 in the article): This product was prepared following
the general procedure starting from substrate rac-1a (27.8 mg, 0.2 mmol),
and [Rh(nbd)(L)]BF4 (9.2 mg, 8.3 µmol). The reaction mixture after
hydrogenation was filtered through a short pad of SiO2, eluting with
EtOAc. This product could not be purified by standard chromatographic
techniques from its hydrogenated analogue and was obtained as a
mixture (molar ratio 1a:3a  39:61). Enantiomeric excess: 99% ee in
favor of the (S)-configured enantiomer (assumed configuration). The
spectroscopic data were in agreement with those reported.[18b]
(R)-(propylsulfinyl)benzene (R)-3a (optimized result for product 3a;
Scheme 3 in the article): This product was prepared following the general
procedure starting from substrate rac-1a (27.9 mg, 0.2 mmol), and
[Rh(nbd)(L)]BF4 (9.2 mg, 8.3 µmol). The reaction mixture after
hydrogenation was filtered through a short pad of SiO2, eluting with
EtOAc. This product could not be purified by standard chromatographic
techniques from its vinyl analogue and was obtained as a mixture (molar
ratio 1a:3a  75:25). Enantiomeric ratio: 91% ee in favor of the (R)-
configured enantiomer (assumed configuration). The spectroscopic data
were in agreement with those reported.[18b]
Scheme 6. Stereochemical outcome of the hydrogenative kinetic resolution of
substituted ,-unsaturated vinyl sulfoxides
Experimental Section
(S)-(E)-(2-(phenylsulfinyl)vinyl)benzene (S)-1b (optimized result for
product 1b; Scheme 3 in the article): This product was prepared following
the general procedure starting from substrate rac-1b (26.2 mg, 0.1 mmol),
and [Rh(nbd)(L)]BF4 (6.4 mg, 5.7 µmol). The reaction mixture after
hydrogenation was filtered through a short pad of SiO2, eluting with
EtOAc. This product could not be purified by standard chromatographic
techniques from its hydrogenated analogue and was obtained as a
mixture (molar ratio 1b:3b  47:53). Enantiomeric ratio was a racemic
mixture. The spectroscopic data were in agreement with those
General considerations. Air- and moisture-sensitive manipulations or
reactions were performed under inert atmosphere using anhydrous
solvents, either in a glove box or with standard Schlenk techniques.
Glassware was dried under vacuum and heated with a hot air gun before
use. All solvents were dried in a Solvent Purification System (SPS). Silica
gel 60 (230−400 mesh) was used for column chromatography. NMR
spectra were recorded on
a 400-MHz or 500-MHz UltraShield
spectrometer in CDCl3, unless otherwise cited. 1H NMR and 13C{1H}
NMR chemical shifts are quoted in ppm relative to the residual solvent
peaks. 31P{1H} NMR chemical shifts are quoted in ppm relative to 85%
phosphoric acid in water. High-resolution mass spectra (HRMS) were
recorded using the ESI ionization method in positive mode, unless
otherwise stated. Enantiomeric excesses were determined by HPLC
analyses, using chiral stationary phases.
reported.[18b]
.
(S)-(Z)-(prop-1-en-1-ylsulfinyl)benzene (S)-1c (optimized result for
product 1c; Scheme 3 in the article): This product was prepared following
the general procedure starting from substrate rac-1c (23.7 mg, 0.2 mmol),
and [Rh(nbd)(L)]BF4 (7.8 mg, 7.1 µmol). The reaction mixture after
hydrogenation was filtered through a short pad of SiO2, eluting with
EtOAc. This product could not be purified by standard chromatographic
techniques from its hydrogenated analogue and was obtained as a
mixture (molar ratio 1c:3c  8:92). Enantiomeric ratio: 99% ee in favor of
the (S)-configured enantiomer (assumed configuration). The
spectroscopic data were in agreement with those reported. [18b, 32]
The preparation and characterisation of ligand L and its corresponding
Rh-precatalyst [Rh(nbd)(L)]BF4 have been previously described in the
literature.[13,31]
General procedure for the KR by Rh-mediated asymmetric
hydrogenations. A solution of the required amount of [Rh(nbd)(L)]BF4
(5.0 mol%) and the corresponding vinyl sulfoxide substrate (0.1 mmol) in
anhydrous and degassed CH2Cl2 (0.50 mL), unless otherwise indicated,
was prepared in a glass vessel under a nitrogen atmosphere. In all cases,
(S)-(Z)-(prop-1-en-1-ylsulfinyl)benzene (S)-1d (optimized result for
product 1d; Scheme 3 in the article): This product was prepared following
5
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10.1002/ejoc.202000592
European Journal of Organic Chemistry
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the general procedure starting from substrate rac-1d (28.1 mg, 0.1 mmol),
and [Rh(nbd)(L)]BF4 (6.8 mg, 6.2 µmol). The reaction mixture after
hydrogenation was filtered through a short pad of SiO2, eluting with
EtOAc. This product could not be purified by standard chromatographic
techniques from its hydrogenated analogue and was obtained as a
mixture (molar ratio 1d:3d  25:75). Enantiomeric ratio: 62% ee in favor
of the (S)-configured enantiomer (assumed configuration). The
spectroscopic data were in agreement with those reported.[16]
[]26 43.0 (c 0.28, CH2Cl2) for 84% ee (R). This product was
D
prepared following the general procedure starting from substrate rac-4
(29.6 mg, 0.1 mmol), and [Rh(nbd)(L)]BF4 (6.9 mg, 6.2 µmol). The
reaction mixture after hydrogenation was filtered through a short pad of
SiO2, eluting with EtOAc. This product was purified by standard
chromatographic techniques from its hydrogenated analogue and was
obtained as a colorless liquid (5.5 mg, 37% isolated yield[25]). New
compound. Enantiomeric ratio: 84% ee in favor of the (R)-configured
enantiomer (assumed configuration). M.p. = 92.3-93.6 ˚C; 1H NMR (500
MHz, CDCl3)  8.06-8.04 (m, 2H, CHAr), 7.61-7.57 (m, 1H, CHAr), 7.48-
7.45 (m, 2H, CHAr), 6.61-6.55 (m, 1H, CH), 6.45 (dt, J = 15.1 Hz, J = 1.2
Hz, 1H, CH), 4.48 (t, J = 6.3 Hz, 2H, CH2), 2.76 (m, 2H, CH2), 2.60 (s, 3H,
CH3);13C{1H} NMR (126 MHz, CDCl3)  166.3 (CO), 136.5 (CH), 135.0
(CH), 133.1 (CHAr), 129.8 (C), 129.5 (CHAr), 128.4 (CHAr), 62.7 (CH2),
40.6 (CH3), 31.3 (CH2). HRMS (ESI) m/z calcd for C12H14NaO3S [MNa]
261.0556, found 261.0552.
(R)-(propylsulfinyl)benzene (R)-3d (optimized result for product 3d;
Scheme 3 in the article): This product was prepared following the general
procedure starting from substrate rac-1d (24.8 mg, 0.1 mmol), and
[Rh(nbd)(L)]BF4 (6.0 mg, 5.4 µmol). The reaction mixture after
hydrogenation was filtered through a short pad of SiO2, eluting with
EtOAc. This product could not be purified by standard chromatographic
techniques from its vinyl analogue and was obtained as a mixture (molar
ratio 1d:3d  76:24). Enantiomeric ratio: 56% ee in favor of the (R)-
configured enantiomer (assumed configuration). The spectroscopic data
were in agreement with those reported.[33]
(S)-4-(methylsulfinyl)butyl benzoate (S)-5 (optimized result for product
5; Scheme 4 in the article): This product was prepared following the
general procedure starting from substrate rac-4 (29.6 mg, 0.10 mmol),
and [Rh(nbd)(L)]BF4 (6.9 mg, 6.21 µmol). The reaction mixture after
hydrogenation was filtered through a short pad of SiO2, eluting with
EtOAc. This product was purified by standard chromatographic
techniques from its vinyl analogue and was obtained as a colorless liquid
(3.0 mg, 20% isolated yield[25]). Enantiomeric ratio: 50% ee in favor of the
(S)-configured enantiomer. New compound. Enantiomeric ratio: 50% ee
(S)-(prop-1-en-2-ylsulfinyl)benzene (S)-1e (optimized result for product
1e; Scheme 3 in the article): This product was prepared following the
general procedure starting from substrate rac-1e (21.0 mg, 0.1 mmol),
and [Rh(nbd)(L)]BF4 (6.9 mg, 6.2 µmol). The reaction mixture after
hydrogenation was filtered through a short pad of SiO2, eluting with
EtOAc. This product was purified by standard chromatographic
techniques from its hydrogenated analogue and was obtained as a
colorless liquid (2.0 mg, 20% isolated yield[25]). Enantiomeric ratio: 99%
in favor of the (S)-configured enantiomer (assumed configuration). []26
D
10 (c 0.15, CH2Cl2). 1H NMR (400 MHz, CDCl3)  8.06-8.04 (m, 2H),
7.60-7.44 (m, 3H), 4.40 (bs, 2H), 2.84-2.73 (m, 2H), 2.61 (s, 3H), 2.01-
1.96 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3)  166.5 (C=O), 133.0 (CH),
130.0 (C), 129.5 (CH), 128.4 (CH), 64.0 (CH2), 54.1 (CH2), 38.6 (CH3),
27.9 (CH2), 19.5 (CH2); HRMS (ESI) m/z calcd for C12H16NaO3S [MNa]
263.0712, found 263.0721.
ee in favor of the (S)-configured enantiomer. []27 40 (c 1.17, CHCl3)
D
[Lit:[11c] []20 72.2 (c 0.6, CHCl3) for 89% ee. (S)]. The spectroscopic
D
data were in agreement with those reported.[34]
(R)-(isopropylsulfinyl)benzene (R)-3e (optimized result for product 3e;
Scheme 3 in the article): This product was prepared following the general
procedure starting from substrate rac-1e (22.9 mg, 0.1 mmol), and
[Rh(nbd)(L)]BF4 (7.6 mg, 6.8 µmol). The reaction mixture after
hydrogenation was filtered through a short pad of SiO2, eluting with
EtOAc. This product was purified by standard chromatographic
techniques from its vinyl analogue as a colorless liquid (3.7 mg, 32%
isolated yield[25]). Enantiomeric ratio: 89% ee in favor of the (R)-
configured enantiomer. []27 126 (c 0.31, CHCl3) [Lit:[ 35 ] []20
(S)-methyl-(E)-6-((4-chlorophenyl)sulfinyl)hex-5-enoate
(S)-6
(optimized result for product 6; Scheme 5 in the article): New compound.
99% ee (S). []25 78.8 (c 0.64, CHCl3) for 99% ee (S). This product
D
was prepared following the general procedure starting from substrate
rac-6 (31.3 mg, 0.1 mmol), and [Rh(nbd)(L)]BF4 (6.0 mg, 5.4 µmol). The
reaction mixture after hydrogenation was filtered through a short pad of
SiO2, eluting with EtOAc. This product was purified by standard
chromatographic techniques from its hydrogenated analogue and was
obtained as a colorless liquid (11.0 mg, 71% isolated yield[25]). New
compound. Enantiomeric ratio: 99% ee in favor of the (S)-configured
enantiomer (assumed configuration). 1H NMR (500 MHz, CDCl3)  7.57-
7.49 (m, 4H), 6.64-6.58 (m, 1H), 6.25 (dt, J = 15.2 Hz, J = 1.4 Hz, 1H),
3.68 (s, 3H), 2.36-2.28 (m, 4H), 1.85-1.79 (m, 2H); 13C{1H} NMR (126
MHz, CDCl3)  173.3 (C), 142.6 (C), 139.9 (CH), 137.1 (C), 135.6 (CH),
129.6 (CH), 125.8 (CH), 51.6 (CH3), 33.0 (CH2), 31.2 (CH2), 23.2 (CH2);
HRMS (ESI) m/z calcd for C13H15ClNaO3S [MNa] 309.0323, found
309.0319.
D
D
146.9 (c 0.42, CHCl3) for 72% ee (S)]. The spectroscopic data were in
agreement with those reported. [35]
(R)-(1-(phenylsulfinyl)vinyl)benzene (R)-1f (optimized result for
product 1f; Scheme 3 in the article): This product was prepared following
the general procedure starting from substrate rac-1f (26.9 mg, 0.1 mmol),
and [Rh(nbd)(L)]BF4 (6.4 mg, 5.8 µmol). The reaction mixture after
hydrogenation was filtered through a short pad of SiO2, eluting with
EtOAc. This product was purified by standard chromatographic
techniques from its hydrogenated analogue and was obtained as a
colorless liquid (10.2 mg, 76% isolated yield[25]). Enantiomeric ratio: 99%
ee in favor of the (R)-configured enantiomer (assumed configuration).
(R)-methyl-6-((4-chlorophenyl)sulfinyl)hexanoate (R)-7 (optimized
result for product 7; Scheme 5 in the article): This product was prepared
following the general procedure starting from substrate rac-6 (30.6 mg,
0.10 mmol), and [Rh(nbd)(L)]BF4 (5.8 mg, 5.28 µmol). The reaction
mixture after hydrogenation was filtered through a short pad of SiO2,
eluting with EtOAc. This product was purified by standard
chromatographic techniques from its vinyl analogue and was obtained as
a colorless liquid (6.2 mg, 41% isolated yield[25]). Enantiomeric ratio: 94%
ee in favor of the (R)-configured enantiomer. Absolute configuration of
the hydrogenated sulfoxide (R)-7 was assigned by comparison of
chromatographic elution orders with reported data (see vide infra in
section 5).39 []25D 64 (c 0.60, CHCl3). The spectroscopic data were in
agreement with those reported.
[]24 53.1 (c 0.28, acetone) for 99% ee (R). The spectroscopic data
D
were in agreement with those reported.[36]
(((RS,RC)-1-phenylethyl)sulfinyl)benzene (RS,RC)-3f (optimized result
for product 3f; Scheme 3 in the article): This product was prepared
following the general procedure starting from substrate rac-1f (15.6 mg,
0.1 mmol), and [Rh(nbd)(L)]BF4 (3.7 mg, 3.4 µmol). The reaction mixture
after hydrogenation was filtered through a short pad of SiO2, eluting with
EtOAc. This product was purified by standard chromatographic
techniques from its vinyl analogue and was obtained as a colorless liquid
(3.8 mg, 49% isolated yield[25]). Enantiomeric ratio: 93% ee in favor of the
(RS,RC)-configured enantiomer. []24 122.3 (c 0.42, acetone) [Lit:[37]
D
[]25 204.2 (c 1.5, acetone) for 99% ee. (RS,RC)]. The spectroscopic
D
data were in agreement with those reported for anti-3f.[38]
(R)-(E)-4-(methylsulfinyl)but-3-en-1-yl benzoate (R)-4 (optimized result
for product 4; Scheme 4 in the article): New compound. 84% ee (R).
6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000592
European Journal of Organic Chemistry
FULL PAPER
Acknowledgements
We thank MINECO (CTQ2017-89814-P) and the ICIQ
Foundation for financial support. Joan R. Lao thanks the ICIQ
Foundation for a predoctoral fellowship.
Keywords: kinetic resolution • hydrogenation • asymmetric
catalysis • rhodium • alkenes
7
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000592
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
Key topic: Hydrogenative Kinetic Resolutions
The ability of a rhodium catalyst derived from phosphine-phosphite ligands to hydrogenatively resolve a set of
structurally diverse ,-unsaturated vinyl sulfoxides is reported. The practicality of the methodology was applied
to the preparation of precursors of biologically active compounds.
8
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000592
European Journal of Organic Chemistry
FULL PAPER
[17] To the best of our knowledge, there is only one report on the Rh
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9
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