Hydrogenative Kinetic Resolution of Vinyl Sulfoxides

Article abstract of DOI:10.1021/acs.orglett.5b02139

Enantiopure sulfoxides are valuable precursors of organosulfur compounds with broad application in organic and pharmaceutical chemistry. An unprecedented strategy for obtaining highly enantioenriched sulfoxides based on a hydrogenative kinetic resolution using Rh-complexes of phosphine-phosphite ligands as catalysts is reported. After optimization, highly efficient conditions for the kinetic resolution of racemic sulfoxides have been identified. This methodology has been applied to a set of racemic aralkyl or aryl vinyl sulfoxides and allowed the isolation of both recovered and reduced products in excellent yields and enantioselectivities (up to 99% and 97% ee, respectively; 16 examples).

Full text of DOI:10.1021/acs.orglett.5b02139

Letter
pubs.acs.org/OrgLett
Hydrogenative Kinetic Resolution of Vinyl Sulfoxides
Joan R. Lao,† Hector Fernandez-Perez,† and Anton Vidal-Ferran*,†,‡
́
́
́
†Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans, 16, 43007 Tarragona, Spain
‡Catalan Institution for Research and Advanced Studies (ICREA), P. Lluís Companys, 23, 08010 Barcelona, Spain
S
* Supporting Information
ABSTRACT: Enantiopure sulfoxides are valuable precursors
of organosulfur compounds with broad application in organic
and pharmaceutical chemistry. An unprecedented strategy for
obtaining highly enantioenriched sulfoxides based on a
hydrogenative kinetic resolution using Rh-complexes of
phosphine-phosphite ligands as catalysts is reported. After
optimization, highly efficient conditions for the kinetic
resolution of racemic sulfoxides have been identified. This
methodology has been applied to a set of racemic aralkyl or
aryl vinyl sulfoxides and allowed the isolation of both recovered and reduced products in excellent yields and enantioselectivities
(up to 99% and 97% ee, respectively; 16 examples).
sulfoxides.7 There are a few studies reporting reductive KRs of
ptically pure sulfoxides are a valuable family of chiral
Ocompounds which have proven to be highly efficient vinyl sulfoxides with optically active reagents;8 however, to the
chiral ligands1 as well as useful intermediates in the synthesis of
best of our knowledge, there are no previous reports on the KR
of vinyl sulfoxides via asymmetric hydrogenation.9
relevant biologically active compounds.1a,2 Among the
approaches that asymmetric catalysis offers, kinetic resolution
(KR) of racemic sulfoxides3 should be considered an appealing
method for the preparation of two optically pure sulfoxides in
only one synthetic step, provided that some requisites are
fulfilled. First and foremost, it is necessary that efficient
enantioselective catalysts working at low catalyst loadings are
available and, second, that starting materials and products can
be isolated in good yields and enantiomerically enriched forms.4
While the reported nonenzymatic KRs on racemic sulfoxides
are mainly based on oxidative transformations (Scheme 1a),3,5
nonoxidative KRs, including reductive transformations
(Scheme 1b), have received much less attention. Moreover,
nonoxidative KRs have normally offered unsatisfactory stereo-
selectivities, with the exception of enzymatic6 transformations
and hydrogenative dynamic kinetic resolutions (DKR) of allyl
Our group recently reported the highly enantioselective
hydrogenation of a structurally diverse set of substrates
mediated by phosphine−phosphite (P−OP)10 ligands. The
high catalytic activities achieved with our ligands prompted us
to address the challenge of hydrogenatively resolving racemic
vinyl sulfoxides (Scheme 1c), whose resolved products have
found broad applicability in catalytic asymmetric synthesis.1,2
Herein we describe our results, which include the catalyst
optimization studies and the application of the lead catalyst to
the highly efficient hydrogenative KR of an array of racemic
aralkyl or aryl vinyl sulfoxides. At the onset of our study, we
chose phenyl vinyl sulfoxide rac-1a as a model substrate. The
reaction conditions and the results of this initial screening are
summarized in Table 1.
As indicated in Table 1, both activity and selectivity were
highly dependent on the P−OP ligand used. Rhodium
complexes derived from ligands L1 and L2 afforded the
hydrogenated product 2a with 37−73% ee, though conversions
were very low and ee values for the recovered starting material
1a poor (see entries 1 and 2 in Table 1). In contrast, rhodium
complexes of the new ligands L3 and L4 displayed an opposite
trend with high conversions and excellent enantioselectivities
for 1a (up to 99% ee) (see entries 3 and 4 in Table 1).
Therefore, these results clearly identified L1 and L3 as the
optimal ligands for this chemistry with the stereogenic
phosphite group being the principal stereochemical director
(opposite absolute configurations for sulfoxides 1a and 2a are
obtained depending on the configuration of the phosphite
Scheme 1. Kinetic Resolution Strategies for Racemic
Sulfoxides
Received: July 25, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02139
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Moreover, this catalyst provided at 54% conversion the
recovered vinyl sulfoxide 1a with perfect enantioselectivity
(up to 99% ee in favor of the (S)-enantiomer) and the
corresponding hydrogenated product 2a (see entry 6 in Table
2).
Table 1. Ligand Screening for the KR of rac-1a
With the optimal catalyst in hand, we then attempted to
broaden the substrate scope to a set of structurally diverse vinyl
sulfoxides (rac-1a−h). In order to maximize the yield for both
the recovered and hydrogenated products (1a−h and 2a−h,
respectively), specific reaction conditions for 1a−h and for 2a−
h were investigated.13 The results and optimized reaction
conditions are listed in Table 3.
b
c
d
c
d
entry ligand conv, % ee of 1a, %; (config.) ee of 2a, %; (config.)
Table 3. Substrate Scope of the Hydrogenative KR of
Racemic Vinyl Sulfoxides rac-1a−h
a
1
2
3
4
L1
L2
L3
L4
25
16
79
81
22 (S)
7 (R)
73 (R)
37 (S)
28 (R)
20 (S)
99 (S)
85 (R)
a
b
c
1
[Substrate] = 0.2 M. Determined by H NMR. Determined by
d
HPLC on chiral stationary phases. The absolute configuration was
assigned by comparison with reported data.
product, isol.
conv,
b
yield, %;14
c
d
e
entry
R
t, min
%
ee, %; (config.)
s
group: compare entries 1 with 2 for L1 and L2, or entries 3
with 4 for L3 and L4 in Table 1, respectively).
Next, we proceeded to optimize the reaction conditions with
P−OP ligands L1 and L3 in a range of different solvent
mixtures.11 The assayed reaction conditions and results are
shown in Table 2. According to these results, a mixture of
f
1
Ph (rac-1a)
60
30
80
10
15
8
54
44
55
35
55
42
61
39
54
44
64
39
66
40
67
33
1a, 74, 99 (S)
2a, 62, 86 (R)
1b, 74, 98 (S)
2b, 58, 95 (R)
1c, 80, 99 (S)
2c, 80, 97 (R)
1d, 54, 98 (S)
2d, 76, 92 (R)
1e, 70, 98 (S)
2e, 56, 90 (R)
1f, 64, 99 (S)
2f, 76, 88 (R)
1g, 64, 99 (S)
2g, 72, 82 (R)
30
35
25
55
56
148
25
44
33
40
26
29
13
18
11
13
2
3
p-Me-Ph (rac-1b)
o-F-Ph (rac-1c)
m-F-Ph (rac-1d)
p-F-Ph (rac-1e)
p-MeO-Ph (rac-1f)
p-NO2-Ph (rac-1g)
Bn (rac-1h)
4
5
6
a
7
30
10
30
15
120
30
25
10
240
25
Table 2. Solvent Optimization Using Ligands L1 or L3
8
9
10
11
12
13
14
ee of
ee of
c
c
conv,
b
1a, %;
2a, %;
b
d
d
entry
L
solvent
Cy
t, h
%
1a:2a:3a
(S)
(R)
g
h
15
g
1h, 62, 99 (R)
h
1
2
L1
L1
L1
L1
L1
L3
L3
L3
L3
L3
2
2
2
2
2
1
1
1
1
56
10
44
56
25
54
79
60
58
68
44:34:12
90:6:4
99
9
80
73
83
76
73
72
28
64
64
45
16
2h, 56, 80 (S)
MeOH
MeTHF
toluene
CH2Cl2
Cy
a
b
c
See footnote a in Table 1. See footnote b in Table 1. See footnote c
e
d
3
56:42:2
44:52:4
75:25:0
46:54:0
21:79:0
40:60:0
42:58:0
32:68:0
65
92
22
99
99
99
99
in Table 1. The absolute configurations of 1a,b and 2a,b,f−h was
established by comparison with reported optical rotations. The
absolute configurations of 1c−h and 2c−e were tentatively assigned
by analogy with the stereochemical outcome of the reactions leading to
4
5
6
1a,b and 2a,b,f−h.12 The selectivity factor (s)4 was determined by the
e
7
MeOH
MeTHF
toluene
CH2Cl2
e
equations = krel(fast/slow) = ln[1 − C(1 + ee2)]/ln[1 − C(1 − ee2)].
8
f
g
This result has been already shown in Table 2. Solvent ratio used was
9
h
Cy/CH2Cl2 (2.6:1). The opposite R or S prefixes in 1h and 2h arise
10
1
99
c
from different priorities in the CIP rules.
a
b
See footnote a in Table 1. See footnote b in Table 1. See footnote c
d
e
in Table 1. See footnote d in Table 1. MeTHF ≡ 2-methyl-
tetrahydrofuran.
As illustrated in Table 3, different substitution patterns on
the aryl groups of vinyl sulfoxides rac-1c−e (o-F, m-F, and p-F
substitution, respectively) were well tolerated to furnish
sulfoxides 2c−e in 56−80% isolated yield14 with 90−97% ee,
and the recovered vinyl sulfoxides 1c−e in 54−80% isolated
yield14 with very high enantioselectivities (98−99% ee; see
entries 5−10 in Table 3). The results obtained for the ortho-
substituted substrate rac-1c were the best among all the
substrates assessed (see entries 5 and 6 in Table 3). Plots of ee
values of resolved products against conversion displayed that
the highest enantioselectivities for such compounds were
achieved in the range 40−60% conversion (see Figure 1,
which corresponds to the KR of substrate rac-1c), demonstrat-
cyclohexane and CH2Cl2 was identified as the optimal solvent
for rac-1a, as it provided the highest ee values for sulfoxides 1a
and 2a (see entries 1 and 6 in Table 2). Unfortunately, the
rhodium complex derived from ligand L1 led to the formation
of significant amounts of ethyl phenyl sulfide 3a as the
byproduct arising from the overreduction of the starting
material (see entry 1 in Table 2).12 This phenomenon was also
observed for L1 in all the mixtures of solvents tested (see
entries 1 to 4 in Table 2). However, we were pleased to find
that this side reaction was completely eliminated by using the
rhodium complex derived from the P−OP ligand L3.
B
DOI: 10.1021/acs.orglett.5b02139
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
coordinated CC and phosphorus groups in related rhodium
complexes.15 Furthermore, intense cross-peaks between the
olefinic H−Cβ proton trans to H−Cα and aromatic protons of
the diphenylphosphino group in NOESY correlation experi-
ments were observed for bound (S)-1g, thus confirming the
previous structural assignment.12 This coordination mode of
the CC double bond places the R group of the sulfoxide in
close proximity to the phosphite group, which accounts for this
group being the principal stereochemical director in the KR. By
comparing the results of these coordination studies and the
configuration of the resolved products, a tentative reaction
pathway for the stereochemical outcome of the KR is proposed
in Figure 2.
Figure 1. Ee values (%) of 1c and 2c vs conversion (%).
ing the high efficiency of this KR to provide unreacted starting
material and hydrogenated product in high yields and ee’s.
Electronic effects were also studied by the examination of
para-substituted substrates rac-1b,e,f,g (p-Me, p-F, p-MeO, p-
NO2, respectively). Regardless of the electronic nature of the
substituent on the aromatic ring, the substrates were hydro-
genated leading to both unreacted and reduced sulfoxides with
high enantioselectivities (from 82 to 99% ee) in 56−76%
isolated yields14 (see entries 3, 4, and 9−14 in Table 3).
However, an electron-withdrawing group at the para-position
increased the reaction rate (compare entries 9, 10 and 13, 14
with entries 3, 4 and 11, 12 in Table 3). The lead catalytic
system was also capable of efficiently resolving benzyl vinyl
sulfoxide (rac-1h): hydrogenation of rac-1h for 4 h provided
(R)-1h in 62% isolated yield14 with perfect enantioselectivity
(99% ee, see entry 15 in Table 3), while optimal reaction
conditions for the hydrogenated product (S)-2h led to its
isolation in 56% isolated yield14 and 80% ee (see entry 16 in
Table 3). In order to demonstrate the practicality of this KR
method, experiments at the mmol scale were performed for
racemic substrates rac-1a,g to afford products 1a,g and 2a,g
with the same efficiency as catalytic experiments.12
Figure 2. Tentative reaction pathways for the hydrogenative KR of
racemic vinyl sulfoxides in the Rh-L3 complexes with the CC and P
(red) groups coordinated in a cis fashion (aR or S configurations of the
product have been established assuming the highest CIP’s priority for
the R group).
In summary, we have developed a highly efficient hydro-
genative KR of vinyl sulfoxides mediated by rhodium
complexes of P−OP ligand L3, which are responsible for the
differentiation of the reaction rates of the two enantiomers of
the starting material toward hydrogenation. This KR method is
an unprecedented approach for preparing optically active vinyl
sulfoxides and their hydrogenated products in notable yields
and high enantioselectivities (up to 99% ee). The easy
availability of racemic vinyl sulfoxides, together with the
excellent catalytic profile of the catalyst derived from L3,
makes the herein described synthetic methodology a valuable
synthetic entry for chiral sulfoxides. Further studies on the
application of this synthetic methodology, together with
mechanistic investigations, are underway in our laboratory
and will be reported in due course.
To shed light on the favored stereodifferentiating routes, we
studied the coordination of (R)-1g and (S)-1g to the [Rh(P−
OP)]+ complex of the lead ligand (L3). We pursued the in situ
preparation of [Rh(1g)(L3)]BF4 by hydrogenation of [Rh-
(nbd)(L3)]BF4 in 1,2-dimethoxyethane followed by the
addition of 1.1 equiv of (R)-1g or (S)-1g. Based on related
literature precedents,7,9 we hypothesized that the KR proceeds
via hydrogenation of the CC bond with chelating assistance
of the oxygen atom of the sulfoxide group. Examination of the
NMR data in solution indicated that both (R)-1g and (S)-1g
coordinate to the [Rh(P−OP)]+ motif. The coordination of
(S)-1g led to the formation of a stable complex at rt, as
1
evidenced by the sharpness of the vinylic signals in the H
NMR spectrum.12 The formation of the substrate−catalyst
adduct [Rh((R)-1g)(L3)]+ was evidenced by the appearance of
broad vinylic signals in the 1H NMR spectrum, which
sharpened up upon recording the spectra at a lower
temperature (253 K). With regard to the geometry of the
complexes between (R)-1g or (S)-1g and the [Rh(P−OP)]+
motif, cross-peaks only between the olefinic protons and the
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02139.
1
phosphino group in heteronuclear H−31P correlation experi-
ments were observed.12 These observations strongly suggest
that the CC bonds of (R)-1g and (S)-1g are coordinated to
the phosphino group in a cis fashion, as these data are
practically coincident with that reported in the literature for cis-
Experimental procedures, spectral data, and determina-
tion of the enantiomeric excess (PDF)
C
DOI: 10.1021/acs.orglett.5b02139
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Per
15375.
́
ez, H.; Benet-Buchholz, J.; Vidal-Ferran, A. Chem. - Eur. J. 2014, 20,
AUTHOR INFORMATION
■
Corresponding Author
(11) A certain amount of CH2Cl2 was kept in order to ensure the
complete solubility of both the rhodium precursor and ligand.
(12) See the Supporting Information for further details.
(13) The reaction conditions were optimized by modifying the
reaction times (controlling in this way the value of conversion) in an
optimal compromise amongst enantiopurity and amounts of unreacted
starting material and product.
(14) Yields are calculated with respect to the 50 mol % amount of
starting material that was subjected to KR.
(15) (a) Bircher, H.; Bender, B. R.; von Philipsborn, W. v. Magn.
Reson. Chem. 1993, 31, 293. (b) Gridnev, I. D.; Higashi, N.; Asakura,
*E-mail: avidal@iciq.cat.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank MINECO (CTQ2014-60256-P and Severo
Ochoa Excellence Accreditation SEV-2013-0319) and the ICIQ
Foundation for financial support. J.-R. L. thanks the ICIQ
Foundation for a predoctoral fellowship. Dr. P. Etayo (ICIQ) is
acknowledged for discussions at the beginning of the project.
K.; Imamoto, T. J. Am. Chem. Soc. 2000, 122, 7183. (c) Suar
Mendez-Rojas, M. A.; Pizzano, A. Organometallics 2002, 21, 4611.
́
ez, A.;
́
REFERENCES
■
(1) For selected recent reviews, see: (a) Fernan
Chem. Rev. 2003, 103, 3651. (b) Fernan
́
dez, I.; Khiar, N.
dez, I.; Khiar, N. In
́
Organosulfur Chemistry in Asymmetric Synthesis; Toru, T., Bolm, C.,
Eds.; WILEY-VCH Verlag GmbH & Co. KGaA: Weinheim, 2008; p
265. (c) Trost, B. M.; Rao, M. Angew. Chem., Int. Ed. 2015, 54, 5026.
(d) Sipos, G.; Drinkel, E. E.; Dorta, R. Chem. Soc. Rev. 2015, 44, 3834.
(2) For a recent review, see: Legros, J.; Dehli, J. R.; Bolm, C. Adv.
Synth. Catal. 2005, 347, 19.
(3) For example, see: Kagan, H. B. In Organosulfur Chemistry in
Asymmetric Synthesis; Toru, T., Bolm, C., Eds.; WILEY-VCH Verlag
GmbH & Co. KGaA: Weinheim, 2008; p 1.
(4) Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. Adv. Synth. Catal. 2001,
343, 5.
(5) The following article has been selected as an oxidative method
considering oxidative as all transformations in which the formal
oxidation state of the S-atom increases: Wang, J.; Frings, M.; Bolm, C.
Chem. - Eur. J. 2014, 20, 966.
(6) For selected examples on enzymatically catalyzed KRs, see for
example: (a) Boyd, D. R.; Sharma, N. D.; King, A. W. T.; Shepherd, S.
D.; Allen, C. C. R.; Holt, R. A.; Luckarift, H. R.; Dalton, H. Org.
Biomol. Chem. 2004, 2, 554. (b) Boyd, D. R.; Sharma, N. D.; Byrne, B.
E.; Haughey, S. A.; Kennedy, M. A.; Allen, C. C. R. Org. Biomol. Chem.
2004, 2, 2530.
(7) Though DKRs are not the same as the aimed transformations in
this manuscript (KRs), the following reference on the DKR of allyl
sulfoxides has been included due to the high enantioselectivities
achieved (up to 90% ee): Dornan, P. K.; Kou, K. G. M.; Houk, K. N.;
Dong, V. M. J. Am. Chem. Soc. 2014, 136, 291.
(8) (a) Mikolajczyk, M.; Para, M. J. Chem. Soc. D 1969, 1192.
(b) Mikolajczyk, M.; Drabowicz, J. Phosphorus Sulfur Relat. Elem. 1976,
1, 301. (c) Drabowicz, J.; Pacholczyk, M. Phosphorus Sulfur Relat. Elem.
1981, 10, 233. (d) Annunziata, R.; Borgogno, G.; Montanari, F.; Quici,
S.; Cucinella, S. J. Chem. Soc., Perkin Trans. 1 1981, 113.
(9) To the best of our knowledge, the only reported transformation,
which is close to the chemistry herein described (see: Ando, D.; Bevan,
C.; Brown, J. M.; Price, D. W. J. Chem. Soc., Chem. Commun. 1992, 592
involves asymmetric hydrogenation of vinyl sulfoxides and kinetic
resolution of one vinyl sulfone.
(10) For selected references on the application of P−OP ligands in
iridium-mediated hydrogenations, see: (a) Nunez-Rico, J. L.;
́
̃
Fernan
́ ́
dez-Perez, H.; Benet-Buchholz, J.; Vidal-Ferran, A. Organo-
metallics 2010, 29, 6627. (b) Nunez-Rico, J. L.; Vidal-Ferran, A. Org.
Lett. 2013, 15, 2066. (c) Nunez-Rico, J. L.; Fernandez-Perez, H.; Vidal-
́ ́
Ferran, A. Green Chem. 2014, 16, 1153. For those on rhodium-
́
̃
́
̃
mediated hydrogenation, see: (d) Donald, S. M. A.; Vidal-Ferran, A.;
Maseras, F. Can. J. Chem. 2009, 87, 1273. (e) Fernan
Donald, S. M. A.; Munslow, I. J.; Benet-Buchholz, J.; Maseras, F.;
Vidal-Ferran, A. Chem. - Eur. J. 2010, 16, 6495. (f) Etayo, P.; Nunez-
́ ́
dez-Perez, H.;
́
̃
Rico, J. L.; Fernan
17, 13978. (g) Nunez-Rico, J. L.; Etayo, P.; Fernan
́
dez-Per
́
ez, H.; Vidal-Ferran, A. Chem. - Eur. J. 2011,
dez-Perez, H.;
Vidal-Ferran, A. Adv. Synth. Catal. 2012, 354, 3025. (h) Fernandez-
́
́
́
̃
́
D
DOI: 10.1021/acs.orglett.5b02139
Org. Lett. XXXX, XXX, XXX−XXX