In situ generation of sulfoxides with predetermined chirality via a structural template with a chiral-at-metal ruthenium complex

Article abstract of DOI:10.1039/c4cc01907e

The reaction of Δ/Λ-[Ru(bpy)₂(py)₂] ²⁺ with a prochiral sulfide ligand, and then in situ oxidation, provide the corresponding Δ-[Ru(bpy)₂{(R)-OSO-iPr}]⁺ and Λ-[Ru(bpy)₂{(S)-OSO-iPr}]⁺ (OSO-iPr = 2-isopropylsulfonylbenzonate) enantiomers in a yield of 83% with 98% ee. The chiral sulfoxides were obtained by treatment of the sulfoxide complexes with TFA in a yield of 90% with 88-91% ee. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc01907e

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In situ generation of sulfoxides with
predetermined chirality via a structural template
with a chiral-at-metal ruthenium complex†
Cite this: Chem. Commun., 2014,
50, 5644
Received 14th March 2014,
Accepted 3rd April 2014
Zheng-Zheng Li, Su-Yang Yao, Jin-Ji Wu and Bao-Hui Ye*
DOI: 10.1039/c4cc01907e
www.rsc.org/chemcomm
The reaction of D/K-[Ru(bpy)2(py)2]2+ with a prochiral sulfide one instance of the enantioselective oxidation of sulfides to
ligand, and then in situ oxidation, provide the corresponding sulfoxides mediated by the chiral-at-metal complex has been
D-[Ru(bpy)2{(R)-OSO-iPr}]+ and K-[Ru(bpy)2{(S)-OSO-iPr}]+ (OSO- reported so far with chemoselectivity (sulfoxide/sulfone = 9 : 1)
iPr = 2-isopropylsulfonylbenzonate) enantiomers in a yield of 83% and the enantiomeric excess in the range of 7–18%.10 Although
with 98% ee. The chiral sulfoxides were obtained by treatment of its stereoselectivity was modest, the chirality mediated by the
the sulfoxide complexes with TFA in a yield of 90% with 88–91% ee. ‘‘chiral-at-metal’’ opened a new approach for asymmetric syn-
thesis of sulfoxides. This encouraged us to observe the in situ
Chiral sulfoxides are widely used as intermediates, auxiliaries, and oxidation of prochiral sulfides to chiral sulfoxides via a structural
ligands in asymmetric synthesis, and commercial pharmaceuticals.1 template with a chiral-at-metal ruthenium complex.
Three principal approaches can be utilized to prepare chiral sulf-
Early studies have shown that the diastereoselectivity has been
oxides, including separation of a racemic mixture, transformation of found in the reaction of [Ru(bpy)2Cl2] (bpy = 2,20-bipyridine) and
a reagent from the chiral pool, or the use of chiral catalysts for chiral sulfoxides.9b,c,11 We perceived that octahedral stereocenters
enantioselective synthesis. Since the first enantioselective catalyst permit the straightforward generation of D and L enantiomers,
for the oxidation of sulfides to sulfoxides was reported in 1984 by which may serve as rigid scaffolds for in situ generation of the
the groups of Kagan2 and Modena,3 some excellent asymmetric enantiomeric sulfoxides. To examine this hypothesis, a prochirally
sulfoxidation reactions have been developed.4–6 However, they still chelated sulfide was chosen to coordinate to D/L-[Ru(bpy)2(py)2]2+,
have certain disadvantages, such as low turnover numbers and ee generating D/L-[Ru(bpy)2(OS-R)]+ (OS-R = 2-alkylthiobenzonate)
values, the need to precisely control the reaction conditions and the enantiomers. We found that the bulky alkyl group of the sulfide
water content, and overoxidation to sulfones, which stimulate the always keeps away from the a-pyridyl proton to avoid steric conges-
search for other catalytic systems.1
tion (see Scheme 1).12 If this site was blocked by the alkyl group, the
Traditionally, the metal-dependent asymmetric catalysts are oxygen atom was only positioned on the other site and hydrogen
based on a combination of a metal ion and a chiral ligand bonded to the a-pyridyl proton when the sulfide was oxidated to the
responsible for the asymmetric environment. Therefore, the stereo- sulfoxide OSO-R (OSO-R = 2-alkylsulfonylbenzonate), leading to the
selective processes often rely on the chirality transfer from a chiral predetermined chirality of the sulfoxide. Moreover, the overoxida-
ligand to a catalytically active center.7 Contrarily, the chiral-at-metal tion to sulfones can also be avoided by the coordination of the
complexes with achiral ligands (for example D and L enantiomers sulfur atom to ruthenium. The oxidation-adducts can be converted
in octahedral complexes) as a source of the asymmetric environ- to the corresponding sulfoxides in good yields without a loss of their
ment for catalysis have been still very rarely exploited.8 This depends enantiopurity. Herein, we report our preliminary results on genera-
mostly on the available approaches for the preparation of the chiral- tion of enantiomeric sulfoxides with predictable stereospecificity via
at-metal complex in an enantiopure form and its configurational a chiral-at-metal complex.
stability in a catalytic reaction.9 To the best of our knowledge, only
The chiral precursors D/L-[Ru(bpy)2(py)2]2+ were prepared
according to the literature.13 The synthesis procedures for sulfoxides
are briefly summaried in Scheme 2. When D/L-[Ru(bpy)2(py)2]2+
reacted with 2-(isopropylthio)benzoic acid (OS-iPr) in ethylene glycol
at 120 1C for 4 h under argon protection, the corresponding
products D/L-[Ru(bpy)2(OS-iPr)]+ (D-1 and L-1) were afforded in a
yield of ca. 81% after a chromatographic separation (see ESI†). The
absolute metal-centered configuration of the D-1 enantiomer was
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry
and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, China.
E-mail: cesybh@mail.sysu.edu.cn
† Electronic supplementary information (ESI) available: Experimental details and
additional spectroscopic data. CCDC 990972, 990805 and 990806. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/
c4cc01907e
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Fig. 1 Crystal structure of D-1 (ellipsoids set at 50% probability; the anion
and solvent molecules are omitted for clarity).
determining enantiomeric excesses. The spectra (Fig. S2, ESI†) show
very high enantiopurity in both cases and the enantiopurity was
found to be 498% ee from the ratio of the integrals of the a-H
peaks of the two enantiomers.
Scheme 1 Generation of enantiomeric sulfoxides from prochiral sulfides.
The sulfoxide complexes, D-[Ru(bpy)2{(R)-OSO-iPr}]+ (OSO-iPr =
2-(isopropylsulfonyl)benzonate, D-2) and L-[Ru(bpy)2{(S)-OSO-iPr}]+
(L-2), were prepared by reaction of the ruthenium thioether com-
plexes D-1 and L-1 with m-CPBA in methanol, respectively. The
excess m-CPBA and the reduced product, 3-chlorobenzonate, were
removed by ultrasonic extraction of the solid ruthenium product
with ether. The yield was almost quantitative (96%) and no over-
oxidation to sulfones was found. The absolute metal-centered and
sulfoxide configurations in D-2 and L-2 were determined by X-ray
crystallography16 and are shown in Fig. 2. They crystallize in a pair
of chiral space groups P41212 and P43212. Structural analyses show
that the D and L configurations at the ruthenium center are
consistent with their parent configurations, indicating that the
absolute configuration at the metal center is unchanged during
the oxidation reaction. Interestingly, the isopropyl group is far away
from the a-pyridyl proton and the oxygen atom of the sulfoxide
group indeed sits on the site near the a-pyridyl proton with a
hydrogen bond between them (OꢁꢁꢁH = 2.6 Å), leading to enantio-
selective oxidation. According to the Cahn–Ingold–Prelog priority
rules, the absolute stereochemistry at the sulfur atom is assigned an
R configuration in the D complex, and an S configuration in the L
complex. That is, the D complex gave an R configuration sulfoxide
and the L complex gave an S configuration sulfoxide, resulting in
predetermined chirality of the sulfoxides. The CD spectra of D-2 and
L-2 are almost mirror images with a negative Cotton effect at
Scheme 2 An outline of the asymmetric synthesis of sulfoxides.
determined by X-ray crystallography14 and is shown in Fig. 1. It
crystallizes in a chiral space group C2. The structure verifies a D
configuration at the ruthenium center and the Flack parameter
(ꢀ0.015(6)) is close to zero, demonstrating that the assignment of
chirality at the metal center is correct and the absolute configuration
at the metal center is preserved during the reaction. Moreover, the
sulfur atom indeed coordinates to the Ru atom and the isopropyl
group keeps away from the a-pyridyl proton to avoid steric conges-
tion. The optical properties of D-1 and L-1 were investigated via
circular dichroism (CD). The CD spectra of the enantiomers are
almost mirror images with a negative Cotton effect at 282 nm and a
positive Cotton effect at 297 nm for D-1, and a positive Cotton effect
at 281 nm and a negative Cotton effect at 297 nm for L-1 (see
Fig. S1, ESI†), suggesting that the configuration at the metal center
is the dominant factor in the appearance of the spectra. The NMR
spectra of D-1 and L-1 are almost the same, however, the two
enantiomers become distinguishable in the presence of (S)-1,10-
binaphtol (S-binol) as a chiral NMR shift reagent.15 The resonance
peak at 9.47 ppm in the rac-1 was split into two peaks and shifted to
9.30 and 9.22 ppm (see Fig. S2, ESI†). Which can be assigned to the
a-H of the py ring in bpy of L-1 and D-1 enantiomers, and used for
Fig. 2 Crystal structure of D-2 (left) and L-2 (right) (ellipsoids set at 50%
probability; the anion and solvent molecules are omitted for clarity).
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This work was financially supported by NSF of China
(21071154 and 21272 284), the DPF of MOE of China
(2012017111004) and CERS-1-85.
Notes and references
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´
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Thus, the processes of removal of the chiral sulfoxide ligands 14 Crystal data for [D-1](PF6)ꢁ0.25CH2Cl2ꢁ0.25H2O: C30H27RuN4O2SPF6ꢁ
0.25CH2Cl2ꢁ0.25H2O, M = 779.35, monoclinic, space group C2, a =
occurred with retention of chiral configuration at the metal
center.
It should be pointed out that the absolute stereochemistry at
the sulfur atom changes from R to S upon removal of coordina-
tion. Although the direct oxidation of metal-bound thiolato
37.5718(9) Å, b = 10.8548(2) Å, c = 16.9834(4) Å, b = 113.393(4)1, V =
6357.1(2) Å3, T = 160(2) K, Z = 8, 54 163 reflections measured, 10 100
independent reflections (Rint = 0.0644). The final R1 values were
0.0379 (I 4 2s(I)). The final wR(F2) values were 0.0995 (I 4 2s(I)).
The final R1 values were 0.0385 (all data). The final wR(F2) values
were 0.1005 (all data). Flack parameter = ꢀ0.015(6).
ligands has been reported,17 the oxidation in situ generation 15 O. Hamelin, M. Rimboud, J. Pecaut and M. Fontecave, Inorg. Chem.,
2007, 46, 5354.
of enantiomeric sulfoxides is unprecedented. The results
described herein may provide a novel approach for asymmetric
synthesis of sulfoxides.
16 Crystal data for [D-2](PF6)ꢁ0.5H2O: C30H28RuN4O3.5SPF6, M = 778.66,
tetragonal, space group P41212, a = 9.4645(5) Å, b = 9.4645(5) Å, c =
68.310(4) Å, V = 6119.0(5) Å3, T = 163(2) K, Z = 8, 16 030 reflections
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measured, 4881 independent reflections (Rint = 0.0720). The final R1
values were 0.0884 (I 4 2s(I)). The final wR(F2) values were 0.1878
(I 4 2s(I)). The final R1 values were 0.0910 (all data). The final
wR(F2) values were 0.1890 (all data). Flack parameter = 0.07(3).
(Rint = 0.0545). The final R1 values were 0.1040 (I 4 2s(I)). The final
wR(F2) values were 0.2233 (I 4 2s(I)). The final R1 values were 0.1079
(all data). The final wR(F2) values were 0.2255 (all data). Flack
parameter = 0.08(4).
Crystal data for [L-2](PF6)ꢁ0.5H2O: C30H28RuN4O3.5SPF6,
M
=
17 (a) C. A. Grapperhaus and M. Y. Darensbourg, Acc. Chem. Res., 1998,
31, 451; (b) H. Petzold, J. Xu and P. J. Sadler, Angew. Chem., Int. Ed., 2008,
47, 3008; (c) D. Zhang, Y. Bin, L. Tallorin, F. Tse, B. Hernandez, E. V.
Mathias, T. Stewart, R. Bau and M. Selke, Inorg. Chem., 2013, 52, 1676.
778.66, tetragonal, space group P43212, a = 9.4537(4) Å, b =
9.4537(4) Å, c = 68.322(12) Å, V = 6106.1(11) Å3, T = 153(2) K,
Z = 8, 8861 reflections measured, 3907 independent reflections
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Chem. Commun., 2014, 50, 5644--5647 | 5647