"Sulfolefin": Highly modular mixed S/Olefin ligands for enantioselective Rh-catalyzed 1,4-addition

Article abstract of DOI:10.1039/c2ob07132k

Reported is a single high yielding step approximation to mixed olefin/sulfinamide ligands enclosing a chiral sulfur atom as the sole chiral center. The synthetic design is validated by a rapid optimization of the substituent at the sulfinyl sulfur, and by

Full text of DOI:10.1039/c2ob07132k

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COMMUNICATION
“Sulfolefin”: Highly modular mixed S/Olefin ligands for enantioselective
Rh-catalyzed 1,4-addition†‡
Noureddine Khiar,*a Álvaro Salvador,a Ahmed Chelouan,b Ana Alcudiab and Inmaculada Fernández*b
Received 3rd November 2011, Accepted 21st December 2011
DOI: 10.1039/c2ob07132k
excellent catalyst precursors for the Rh-catalyzed 1,4-addition.
However, in the case of the ligands with a tert-butyl sulfinyl
group, the synthetic routes developed so far depend extremely
on the utilization of tert-butane sulfinamide as a chiral source.
Thus, besides limiting the modularity of the approximation, the
synthesis of the ligands is not direct and includes a non-comple-
tely diastereoselective reduction/addition step. In a project
directed toward the synthesis of chiral sulfinyl derivatives and
their applications in stoichiometric asymmetric synthesis,15a,b as
well as in organic15c,d and organometallic asymmetric cataly-
sis,9a in the present work we report our preliminary results on
the synthesis of modular sulfinamide/olefin mixed ligands and
their application in highly enantioselective 1,4-addition of
boronic acids to cyclic and acyclic α,β-unsaturated ketones. The
designed “sulfolefin” ligands, Fig. 1, are derived from allyl-
amines, contain a chiral sulfur atom as the sole chiral center, and
can be easily obtained in a single step from a diastereomerically
pure sulfinylating agent.
A large number of structurally different olefin-tethered amines
are commercially available, so the modularity of the approxi-
mation depends greatly upon the capacity of the method used for
the synthesis of the sulfinylating agents to create molecular and
stereochemical diversity. The DAG-methodology,16 developed in
our laboratories is a general synthetic approximation for the syn-
thesis of diastereomerically pure alkane and arene sulfinate
esters. Additionally, using a single chiral auxiliary, both epimers
at sulfur of the DAG-sulfinate esters are accessible in an enantio-
divergent manner by a simple change of the tertiary amine used
to catalyze the reaction.17 Based on these premises, the synthesis
of the sought “sulfolefin” ligands has been done by condensation
of a lithium amide, obtained by treatment of the starting amine
with butyllithium in THF at −78 °C, and a diastereomerically
pure DAG-sulfinate esters, Scheme 1. In this preliminary work,
DAG-sulfinate esters with p-tolyl, methyl, isopropyl, and tert-
butyl substituents were used in order to assess the importance of
the steric and electronic character of the substituent at the
sulfinyl sulfur on the stereochemical outcome of the reaction.
Reported is a single high yielding step approximation to
mixed olefin/sulfinamide ligands enclosing a chiral sulfur
atom as the sole chiral center. The synthetic design is vali-
dated by a rapid optimization of the substituent at the
sulfinyl sulfur, and by the synthesis of an efficient, highly
enantioselective catalyst for the Rh-catalyzed 1,4-addition of
boronic acids to both, cyclic and acyclic olefins.
While chiral sulfinyl derivatives are known since the mid-
sixties,1 the last decade has witnessed a renewed interest toward
their applications in asymmetric synthesis.2 At the basis of this
renaissance is the significant progress made in the synthesis of
efficient chiral sulfinylating agents,3 and the exceptional behav-
iour of sulfinamides as chiral intermediates for the production of
enantiopure amines.4 Chiral sulfinyl derivatives (sulfoxides,5 and
sulfinamides6), can indeed be considered as privileged chiral
auxiliaries, as they have been used with success in a plethora of
asymmetric chiral C–C and C–X bond formation. Surprisingly,
despite their interesting metal-coordinating abilities,7 the great
efforts devoted to their applications in asymmetric catalysis have
met with little success.8 In all the catalytic processes where they
were assayed, the reactivity and enantioselectivities obtained
were far to compete with gold standard catalysts used in the lit-
erature.9 An exception of this statute was reported in 2008 by
Dorta’s group, who found that C2-symmetric atropoisomeric
sulfoxides were among the best ligands for the Rh-catalyzed 1,4-
addition of aryl boronic acids to cyclohexenones.10 Beside bis-
sulfoxides,11 and in the course of this work, a second break-
through was reported simultaneously by Knochel’s,12 Xu’s,13
and Du’s14 groups, who found that mixed sulfinyl-olefins are
aInstituto de Investigaciones Químicas, C.S.I.C-Universidad de Sevilla,
c/. Américo Vespucio 49. Isla de la Cartuja, 41092 Sevilla, Spain.
E-mail: khiar@iiq.csic.es; Fax: +34954460565; Tel: +34954489559
bDepartamento de Química Orgánica y Farmacéutica, Facultad de
Farmacia, Universidad de Sevilla, c/Profesor García González 2, 41012
Sevilla, Spain. E-mail: inmaff@us.es; Fax: +34954556737;
Tel: +34954555993
†Electronic supplementary information (ESI) available: Experimental
1
procedures for the synthesis of ligands 1–5, and of the 1,4 addition, H,
and 13C spectra of the ligands and of the adducts 8, 12–15, structural
studies of the Rh-complexes derived from ligands 1 and 5, and HPLC
chromatograms of racemic and enantiopure ligands and adducts are
given. See DOI: 10.1039/c2ob07132k
‡Dedicated to the memories of Prof. Rafael Suau and Prof. Mohamed
Soufiaoui
Fig. 1 Sulfolefin ligands.
2366 | Org. Biomol. Chem., 2012, 10, 2366–2368
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Table 2 Substrate scope of the enantioselective Rh-catalyzed 1,4-
addition using sulfolefin 5a
Entry Starting enone Product
Solvent
Toluene
Yield (%)b ee (%)c
Scheme 1 Synthesis of sulfolefin ligands.
1
2
98
90
99
Methanol 93
Table 1 Enantioselective Rh-catalyzed 1,4-addition using sulfolefins
1–5a
3
4
Toluene
Methanol 93
91
99
99
5
6
Toluene
Methanol 92
83
84
96
Entry Liganda T/°C Solvent
Yield (%)b eec (Config.)
1
2
3
4
5
6
7
8
9
1
2
3
4
4
4
5
5
5
40
40
40
40
r.t.
60
40
r.t.
r.t.
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
1,4-Dioxane
Methanol
89
87
89
92
80
89
98
93
95
34 (S)
12 (30)d (S)
38 (S)
7
8
Toluene
Methanol 96
94
99
99
84 (R)
80 (R)
50 (R)
90 (R)
99 (R)
99 (R)
a All reactions were conducted using 5 mol% of the ligand together with
2.5 mol% of [Rh(C2H4)Cl]2. b Isolated product. c Determined by chiral
stationary phase HPLC using Chiralcel OD-H column.
a All reactions were conducted using 5 mol% of the ligand together with
2.5 mol% of [Rh(C2H4)Cl]2. b Isolated product. c Determined by chiral
stationary phase HPLC using Chiralcel OD-H column. d Reaction
conducted in methanol at room temperature.
Chaykovsky reaction of chiral sulfinylimines and in the organo-
catalytic allylation of acyl hydrazones.16a A temperature effect
study on the stereochemical outcome of the reaction done with
ligand 4 shows that the ee drops from 84% ee at 40 °C (Table 1,
entry 4) to 50% at 60 °C (Table 1, entry 6). Finally, the excellent
result obtained with ligand 5, derived from cinnamylamine,
highlights the importance of the substituent at the terminal pos-
ition of the olefin in this kind of ligand (Table 1, entry 7). Fixing
the best temperature at 40 °C, we conducted a solvent effect
study using the best ligand 5 (Table 1, entries 8 and 9). Interest-
ingly, using 1,4-dioxane or methanol as solvents, the desired
product 8 was obtained as a single enantiomer, with 93 and 95%
yield respectively.
Owing to the excellent results obtained with sulfolefin 5, we
decided to determine the substrate scope of the reaction using
various cyclic enones in methanol and also in toluene as it is
described as the best solvent for this transformation in the litera-
ture, and the results obtained are summarized in Table 2.
In the case of cyclopentenone 9, adduct 12 was obtained as a
single enantiomer both in toluene and methanol with 91 and
93% yield, respectively (Table 2, entries 3–4). On the contrary,
in the case of cycloheptenone 10, the product 13 was obtained
with only 84% ee in toluene (Table 2, entry 5), while in metha-
nol the reaction was highly selective allowing the formation of
13R in 96% ee and 93% yield (Table 2, entry 6). The reaction is
not limited to unsaturated cyclic alkenones, as the reaction of
phenyl boronic acid with the unsaturated lactone 11 leads to the
Ligands 1–5, Scheme 1, were obtained in excellent yields and
were then assayed in the model reaction pioneered by Hayashi
and Miyaura, namely the Rh-catalyzed 1,4-addition of aryl
boronic acids to electron-deficient olefins.18 Using 5 mol% of
the ligand, the reaction of 2-cyclohexanone 6 and phenyl
boronic acid 7 in toluene at 40 °C is clean and affords compound
8 with full conversion in less than two hours in all cases. The
results obtained in this study are collected in Table 1.
We were delighted to find that all the assayed ligands were
active catalyst precursors for the reaction as the final adduct 8
was always obtained in good chemical yield. Comparison of the
results obtained with the ligands derived from allylamine 1–4
(Table 1, entries 1–4) illustrates clearly the dependence of the
enantioselectivity of the process on the nature of the substituent
at the sulfinyl sulfur. Ligand 1 with a simple methylsulfinyl
group affords the desired product with 89% yield and with an
interesting 34% ee (Table 1, entry 1). On the other hand,
although the result obtained with ligand 3 was expected, the be-
havior of ligand 2 was disappointing (Table 1, entry 2),
especially if compared with the good result obtained with ligand
4 (Table 1, entry 4). In contrast to this, we have recently shown
that the isopropylsulfinyl group confers higher chemical reactiv-
ity and better enantiomeric discrimination than the p-tolylsulfinyl
group and equal to the tert-butyl group in the Corey–
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“sulfolefin” ligands in an enantiodivergent manner. The appli-
cation of the present approximation for the synthesis of other
enantiopure sulfolefins, as well as their applications in other
metal promoted enantioselective processes, are being actively
investigated in our laboratories, and will be reported in due
course.
Scheme 2
Acknowledgements
γ-valerolactone derivative 14R as a single enantiomer, both in
toluene and in methanol, with excellent yields in both solvents
(Table 2, entries 7 and 8). The Rh-catalyzed 1,4-adition of aryl
boronic acids to acyclic unsaturated ketones is a more challen-
ging task, and most of the catalysts described in the literature
afford the addition product with only moderate enantioselectiv-
ity. Based on the excellent catalytic behavior of ligand 5, with
cyclic substrates, we decided to prove its capacity in acyclic sub-
strates. We were pleased to find that addition of phenyl boronic
acid to 3-pentenone 15, afforded the desired 4-phenylpentan-2-
one 16 in 78% yield and an interesting 94% ee (Scheme 2),
which represents one of the highest enantioselective processes
described to date.
This work was supported by the Ministerio de Ciencia e Innova-
ción (grant No. CTQ2010-21755-CO2-00), and the Junta de
Andalucía (P07-FQM-2774). A. Chelouan thanks the “Minis-
terio de Asuntos Exteriores y de Cooperacion” for a predoctoral
MAEC-AECID grant.
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described process, and to unravel the motives of the high enan-
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solution. Together with the alkene moiety, the sulfolefin ligands
possess three other heteroatoms, which can coordinate to the
rhodium, namely the nitrogen, sulfur, and oxygen. Considering
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troscopy.3a,8 Therefore, ligand 1 with three methinic protons con-
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ligand 1 with 0.5 equiv of [Rh(C2H4)Cl]2 in deuterated methyl-
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In conclusion, we have developed an efficient approximation
to mixed olefin/sulfinamide ligands enclosing a chiral sulfur
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