Synergistic Stereocontrol in the Enantioselective Ruthenium-Catalyzed Sulfoxidation of Spirodithiolane-Indolones

Article abstract of DOI:10.1002/chem.201501780

A chiral ruthenium catalyst was developed for the enantioselective sulfoxidation of the title compounds. The catalyst combines two elements of chirality, a chiral pybox ligand and a chiral bicylic lactam unit, to which the ligand is attached. The latter unit was shown to improve significantly the performance of the catalyst by exposing one of the two enantiotopic sulfur atoms to the active site via hydrogen-bond mediated coordination. Ten differently substituted substrates were converted into the respective sulfoxides in yields of 52-71% and with ≥90% ee. Hand-in-hand: Two spatially remote chiral entities act synergistically together in the Ru-catalyzed sulfoxidation reaction of the title compounds. Hydrogen bonds and π-π interactions are invoked to explain the preferential formation of a single stereoisomer in this reaction. High enantioselectivities (90-99% ee).

Full text of DOI:10.1002/chem.201501780

DOI: 10.1002/chem.201501780
Communication
&
Asymmetric Catalysis |Hot Paper|
Synergistic Stereocontrol in the Enantioselective Ruthenium-
Catalyzed Sulfoxidation of Spirodithiolane-Indolones
Fangrui Zhong, Alexander Pçthig, and Thorsten Bach*[a]
strates[7,8] and we have now studied their enantioselective oxi-
Abstract: A chiral ruthenium catalyst was developed for
dation employing chiral ruthenium catalysts with N,N,N-pyri-
the enantioselective sulfoxidation of the title compounds.
dine-2,6-bisoxazoline (pybox) ligands.[9]
The catalyst combines two elements of chirality, a chiral
Multifunctional ruthenium complexes 4 were readily pre-
pybox ligand and a chiral bicylic lactam unit, to which the
pared from commercially available starting materials (Figure 1).
ligand is attached. The latter unit was shown to improve
Optically pure 4-bromo-substituted pybox ligands 2 were gen-
significantly the performance of the catalyst by exposing
erated from chelidamic acid (1) in high yields using known
one of the two enantiotopic sulfur atoms to the active
methods,[10] and were accordingly attached to chiral lactam
site via hydrogen-bond mediated coordination. Ten differ-
3[5a] via a CÀC triple bond linker employing a Sonogashira
ently substituted substrates were converted into the re-
cross-coupling protocol (72–93% yield). Ligands 3 were further
spective sulfoxides in yields of 52–71% and with ꢀ90%
treated with commercially available [{Ru(p-cymene)Cl2}2] in the
ee.
presence of dipicolinic acid under established conditions[9a] to
furnish the desired ruthenium pybox complexes 4a–4b’ in 60–
81% chemical yield. For comparison, the known complexes
There is a variety of synergistic effects, which have been de-
scribed in the design of chiral catalysts.[1] Generally speaking,
any two or more parameters, the modification of which pro-
vides an improved enantioselectivity in a given catalytic reac-
tion “work favorably together” (sune1gó&) and are by definition
synergistic. In more specific terms, changing the chirality of
the individual construction elements of a catalyst can lead to
an enhancement or decrease of enantioselectivity. This effect is
notable for example in the design of peptide-based organoca-
talysts, with a defined set of amino acids providing the highest
enantioselectivities as compared to other epimeric sets of
amino acids.[2] Similarly, synergistic effects can be observed in
enzymatic catalysis with a specific set of mutants being highly
superior to others.[3]
5a–5d were prepared according to previously described pro-
cedures.[9]
In previous work, we explored the catalytic effect of certain
substrate-specific[4] ruthenium–porphyrin complexes, which
display lactam-based hydrogen-bonding ligands.[5] We have
stressed the enzyme-like character of their supramolecular ar-
rangement,[6] in which the lactam acts as a binding pocket and
the transition metal as a prosthetic group. In the present work
we sought to explore a possible synergy of the chiral ligand
environment at the metal center and the chirality of the
lactam backbone. To this end, we selected spiro[1,3-dithiolane-
2,3’-indol]-2’(1’H)-ones (spirodithiolane-indolones) as sub-
Figure 1. Starting materials and intermediates required for the synthesis of
bifunctional ruthenium complexes 4a–4b’ and structure of the known
ruthenium complexes 5a–5d.
While the enantioselective oxidation of sulfides has been ex-
tensively investigated in the past,[11] there are comparably few
reports on the enantioselective oxidation of 1,3-dithiolanes.[12]
An interesting feature of their oxidation is the fact that two
stereogenic centers are created in one step if the 1,3-dithiolane
is derived from a non-symmetric carbonyl compound. Initial
experiments were performed in the present work with dithio-
lane 6a which in turn was readily obtained by thioacetal for-
mation from isatin.[8a,13] Applying dipivaloyloxyiodobenzene
[PhI(OPiv)2] as the oxidant in benzene as the solvent,[14] we
found the achiral ruthenium compound 5a to be a competent
catalyst for the desired oxidation although the diastereoselec-
[a] Dr. F. Zhong, Dr. A. Pçthig, Prof. Dr. T. Bach
Department Chemie and Catalysis Research Center (CRC)
Technische Universität München
Lichtenbergstr. 4, 85747 Garching
Fax: (+49)89-289-13315
E-mail: thorsten.bach@ch.tum.de
Homepage: http://www.oc1.ch.tum.de/home_en/
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501780.
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tivity was relatively low (Table 1, entry 1). Upon replacing the
achiral pybox ligand with chiral analogues (catalysts 5b–5d)
an enantioselective reaction course was observed (entries 2–4)
with ligand 5b providing the best result (entry 2). Ruthenium
pybox complex 4a, in which the octahydro-1H-4,7-methanoi-
soindol-1-one backbone is the only source of chirality, provid-
ed product 7a in a low ee but with improved diastereoselectiv-
ity as compared to catalysts 5a–5d (entry 5). Remarkably, the
major product stereoisomer was the same as for catalyst 5b.
Consequently, a synergistic effect was expected and indeed
found for catalyst 4b (entry 6), with which an enantioselectivi-
ty of 70% ee was achieved. If the two chiral entities were com-
bined in a mismatched fashion, the enantioselectivity was low
in favor of ent-7a, the enantiomer of 7a (entry 7). Further opti-
mization work was performed regarding the solvent (entry 8),
the oxidant (entry 9), the substrate concentration (entry 10)
and the stoichiometry (entry 11). Details of the optimization ex-
periments can be found in the Supporting Information. Optimi-
zation eventually culminated in a reaction, which proceeded
with good yield (71%) to a major diastereoisomer (d.r. 84:16)
in significant enantioselectivity (90% ee).
Table 2. Products 7 obtained by enantioselective ruthenium-catalyzed
sulfoxidation.[a]
Table 1. Influence of the ligand configuration on the enantioselective Ru-
catalyzed sulfoxidation of spirodithiolane-indolone 6a.
[a] Yields are given as combined yields for the separated diastereoiso-
mers. The d.r. was determined by 1H NMR analysis of the crude product
mixture but remained unchanged upon work-up. [b] In this single in-
stance, a Ru complex with an (1S,2R)-(À)-cis-1-amino-2-indanol-derived
pybox ligand turned out to be a superior catalyst (see Supporting Infor-
mation for further details).
Entry
Ru cat.
Oxidant
Solvent
Yield[a] [%]
d.r.[b]
ee[c] [%]
1
2
3
4
5
6
7
8
5a
5b
5c
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
CHP[d]
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhF
PhF
PhF
PhF
51
57
45
52
51
55
53
73
69
62
71
66:34
68:32
69:31
67:33
80:20
84:16
75:25
87:13
87:13
87:13
84:16
–
53
14
22
21
70
À21[e]
73
82
84
90
5d
4a
4b
4b’
4b
4b
4b
4b
but with diminished enantioselectivity (86% ee) compared to
the spirodithiolanes.
The ee of the minor diastereoisomers, which could be sepa-
rated from the major diastereoisomers by chromatography,
was not determined in all cases. It was determined, however,
for the epimer of 7a to be 45% ee and for the epimer of prod-
uct 7 f, epi-7 f (see below), to be 41% ee.
Diastereomerically pure sulfoxides 7 could be converted to
the respective sulfones 8 by oxidation (Scheme 1). Initial at-
tempts under aqueous conditions[15] led to partial racemization
and in a side reaction to thioketones by elimination.[16] The re-
action could be successfully performed, however, with tetrabu-
tylammonium bromide as a phase-transfer catalyst in a biphasic
solvent mixture.[17]
9
10[f]
11[f,g]
CHP
CHP
[a] Yield of isolated product after chromatographic purification. [b] Dia-
steromeric ratio (d.r.) as determined by 1H NMR analysis of the crude
product mixture. [c] Enantiomeric excess (ee) calculated from the enantio-
meric ratio as determined by HPLC analysis on a chiral stationary phase.
[d] Cumene hydroperoxide. [e] The major enantiomer was not 7a but its
enantiomer ent-7a.[f] c=10 mm.[g] 1.5 equiv of oxidant.
The optimized conditions were subsequently applied to dif-
ferent substrates (Table 2). It turned out that the enantioselec-
tivity remained high for the sulfoxidation of various spirodi-
thiolane-indolones with substituents in positions C4’ to C6’ of
the indolone core (products 7b–7j). For one substrate (6 f) the
diastereoselectivity of the sulfoxidation decreased significantly
while for the 7’-fluoroindolone 6k there was a significant drop
in enantioselectivity (77% ee). Spirodithiane-indolone 6l deliv-
ered the sulfoxide with perfect diastereoselectivity (d.r. >95:5)
The limited stability of products 7 prohibited attempts to
obtain crystals suitable for single crystal X-ray crystallography
by solvent evaporation and diffusion methods. Eventually, the
N-methylated derivatives of product 7a were obtained, which
turned out to be more stable. Compound 7a was purified to
>99% ee by chiral semipreparative HPLC (Daicel Chiralpak,
AD-H, n-hexane/iPrOH 70:30) and was subjected to methyla-
tion conditions (Scheme 2). Surprisingly, two diastereoisomers
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Scheme 3. Further oxidation of the product mixture 7 f/epi-7 f from sulfoxi-
dation of substrate 6 f supports the configuration assignment for epi-7 f.
Although we have not yet done any further mechanistic
work, the product composition and previous work on the
enantioselective olefin epoxidation by related ruthenium
pybox complexes[9d] can serve as basis for a preliminary mecha-
nistic model. Accordingly, a ruthenium oxo complex with a dis-
torted octahedral conformation is assumed to be the active
catalyst.[9d] Product analysis indicates that it is the pro-S elec-
tron pair of the pro-R sulfur atom, which is preferentially at-
tacked by the oxidant (Scheme 4). This preference is suggested
to be the result of two synergestic effects. Attractive p–p inter-
actions[19] between the phenyl group of the ligand and the aro-
matic ring of the substrate guide the pro-R sulfur atom to the
active center. Without any further assistance the enantioselec-
tivity is only moderate, however, and, in addition, the sulfur
atom is not sufficiently fixed so that attack at the two electron
pairs is not selective (low d.r., see Table 1, entry 2). This fixation
is significantly improved by hydrogen bonding to catalyst 4b
resulting in a higher diastereoselectivity and a further increase
in enantioselectivity (Table 1, entries 6, 8–10).
Scheme 1. Conversion of enantiomerically and diastereomerically pure sulf-
oxides 7 into sulfones 8.
9 and epi-9 were produced, both of which were still enantio-
pure. Based on NMR data, it could be unambiguously shown
that the relative configuration of 9 and 7a were identical. The
absolute configuration of 9 was subsequently proven by
anomalous X-ray diffraction techniques thus also establishing
the absolute configuration of product 7a. We assume that the
epimerization is due to the intermediacy of isocyanate 10[18]
during the methylation protocol. The absolute configuration at
the sulfoxide sulfur atom is retained as proven by the enantio-
purity of both products.
Scheme 2. Conversion of enantiomerically and diastereomerically pure indo-
lone 7a into its N-methyl derivatives 9 and epi-9.
While the latter experiments established the absolute config-
uration of the major stereoisomer in the sulfoxidation to be
(1S,3’R) and the configuration of its enantiomer to be (1R,3’S),
the absolute configuration of the minor diastereoisomers re-
mained unclear. In other words, it was not clear whether the
catalyst selectively attacks one of the two enantiotopic sulfur
atoms [leading preferentially to the (1R,3’R)-stereoisomer] or
whether it has a preference for one of the two enantiotopic
electron pairs at sulfur [leading preferentially to the (1S,3’S)-
stereoisomer]. Since further oxidation to the sulfone (cf.
Scheme 1) leads to a deletion of the stereogenic center at
sulfur, we were able to clarify this issue by oxidation of the
product mixture obtained from enantioselective sulfoxidation
of substrate 6 f. In this specific example the formation of the
other diastereomer epi-7 f was particularly high. Upon oxida-
tion, product 8 f with R-configuration at carbon C3’ was ob-
tained in 77% ee (Scheme 3), which is only possible if the
major enantiomer of epi-7 f was also R-configured at this ste-
reogenic center. Had it been S-configured the product ee
should have been significantly lower.
Scheme 4. Topicity of the prostereogenic elements in spirodithiolane-indo-
lones and a model for the enantioselective attack of the putative oxidant.
From the data of Table 1 it is evident that an excess of the
stoichiometric oxidant improves the enantioselectivity at the
expense of diastereoselectivity (Table 1, entries 10, 11). Indeed,
based on the mechanistic model, further oxidation will occur
preferentially at the pro-S electron pair of the pro-R sulfur
atom. The enantiomers of products 7 will thus be more rapidly
transformed to the respective disulfoxides than any other ste-
reoisomer. If the amount of this specific stereoisomer decreas-
es, the ee increases but the d.r. decreases, which is in line with
the data. Still, it should be stressed, that the major mode of
action in the present case is not a kinetic resolution but an
enantioselective sulfoxidation.
Hydrogen bonding strongly facilitates the enantioselective
sulfoxidation as evident when employing a substrate, which is
not capable of two-point hydrogen bonding. The N-methyl de-
rivative of substrate 6a was converted into the corresponding
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sulfoxides 7 and epi-7 under standard conditions (catalyst 4b)
in 70% yield but with significantly diminished stereoselectivity
(d.r. 70:30, 5% ee). The N-methyl derivative of catalyst 4b was
a competent catalyst for the sulfoxidation but delivered for the
conversion 6a!7a similar results as the monofunctional cata-
lyst 5b (65%, d.r. 76:24, 59% ee).
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In summary, we have shown that non-covalent hydrogen-
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metal catalyst can be favorably used to increase the given
asymmetric induction of a chiral ligand at the metal center
and vice versa. If, like in the chosen catalytic system, the two
chiral entities (the chiral ligand and the substrate-binding site)
are linked in a modular fashion substrate-specific catalysts can
be easily assembled and they can be tailored to a given reac-
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and regioselectivity.
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dation for a postdoctoral scholarship (F.Z.) and the Deutsche
Forschungsgemeinschaft (DFG) for financial support in the
framework of grant Ba 1372/17-1 (T.B.). We also thank Olaf Ac-
kermann, Florian Mayr, and Marcus Wegmann for assistance
with HPLC analyses.
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Keywords: asymmetric catalysis · hydrogen bond · oxidation ·
ruthenium · sulfur heterocycles
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Received: May 7, 2015
Published online on June 10, 2015
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