Hydrogen bond induced enantioselectivity in Mn(salen)-catalysed sulfoxidaton reactions

Article abstract of DOI:10.1039/c0cc04636a

A chiral Mn(salen) complex exhibiting two lactam binding sites at two rigid 1,5,7-trimethyl-3-azabicyclo[3.3.1]nonan-2-one skeletons is capable of enantioselective sulfoxidation due to spatially remote substrate hydrogen bonding.

Full text of DOI:10.1039/c0cc04636a

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COMMUNICATION
Hydrogen bond induced enantioselectivity in Mn(salen)-catalysed
sulfoxidaton reactionsw
Felix Voss, Eberhardt Herdtweck and Thorsten Bach*
Received 27th October 2010, Accepted 6th December 2010
DOI: 10.1039/c0cc04636a
A chiral Mn(salen) complex exhibiting two lactam binding sites
at two rigid 1,5,7-trimethyl-3-azabicyclo[3.3.1]nonan-2-one
skeletons is capable of enantioselective sulfoxidation due to
spatially remote substrate hydrogen bonding.
The enantioselective oxidation of sulfides (sulfoxidation) has
over the last two decades been established as the most
straightforward access to enantiomerically enriched sulfoxides.1
Pioneering work on the Ti-catalysed sulfoxidation2 was
followed by further studies, in which the catalytically active
metal centre has been broadly varied.3 In most cases enantio-
selectivity relies on a size differentiation between the two
different substituents at a given sulfide. Although hydrogen
bonding has been invoked to explain high enantioselectivities
in certain sulfoxidation reactions4 hydrogen bonds have so far
not been used as a design principle for exposing a prochiral
sulfide to a spatially remote catalytically active metal centre. In
the study, which we herein present in preliminary form, the
well established oxidation properties of manganese salen
complexes5,6 were combined with a chiral hydrogen bonding
scaffold.7 Enantioselective sulfoxidation reactions were
Scheme 1 Synthesis of catalyst 5 starting from enantiomerically pure,
chiral alkyne 1.
delivered after recrystallisation a light-brown solid, the
analytical data of which (see ESIw) are in agreement with the
structure 5 depicted in Scheme 1.
achieved (up to 71% ee), the success of which relied exclusively
on the hydrogen bonding properties of the scaffold.8–10
It was shown recently that a chemical modification of 1,5,7-
trimethyl-3-azabicyclo[3.3.1]nonan-2-ones, which were used
previously as chiral auxiliaries,11 as chiral templates12 and as
chiral sensitisers,13 is possible at the 7-position via an alkyne
unit. Alkyne 1,7b which can be readily synthesised from
Kemp’s triacid was in the present study connected to the
salicylic aldehyde 214 by a Sonogashira cross-coupling reaction
(Scheme 1).15 Salen formation was achieved from aldehyde 3
It was anticipated that binding of a sulfide-containing
lactam to one of the d-lactam units in catalyst 5 would place
the substrate in a chiral environment, in which an enantio-
selective oxidation was possible. Initial experiments were
performed with commercially available 2H-benzo[e][1,4]thiazin-
3-one (6), which was oxidised under typical conditions
(c = 0.06 M) with iodosobenzene (1.3 equiv.) in benzene at
ambient temperature (Scheme 2).3a In the presence of 1 mol%
of catalyst 5 the reaction proceeded smoothly delivering the
desired enantiomerically enriched (47% ee) sulfoxide 7 in 63%
yield, together with 8% re-isolated starting material and 5% of
the respective sulfone (product of overoxidation). N-Methylated
2H-benzo[e][1,4]thiazin-3-one (8) reacted under identical
conditions to yield sulfoxide 9, which was formed as a
racemate (Scheme 2). The latter result strongly supports the
hypothesis that the enantioselectivity in the former reaction
was due to hydrogen bonding.
following
a 4 was
procedure by Hong et al.16 Salen
subsequently converted into the manganese complex 5 following
established procedures.17 Oxidation of Mn(II) to Mn(III) was
achieved by purging oxygen through the crude reaction
mixture in toluene. Subsequent treatment with sodium chloride
Department Chemie and Catalysis Research Center (CRC),
Technische Universitat Munchen, 85747 Garching, Germany.
¨
¨
E-mail: thorsten.bach@ch.tum.de; Fax: +49 89 28913315;
Tel: +49 89 28913330
w Electronic supplementary information (ESI) available: Preparation
and analytical data for all new compounds, selected HPLC traces.
CCDC 798187 (10). For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c0cc04636a
The absolute configuration of the major enantiomer of
compound 7 was elucidated by single crystal X-ray crystallo-
graphy.18 Derivatisation of the enantiomerically enriched
c
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while the enantioselectivity was not concentration dependent
in benzene. Through employing an extended reaction time of
72 h and a substrate concentration of 0.02 M in iodobenzene it
was possible to obtain product 7 in 67% ee and with a yield of
76% (based on conversion). The influence of other parameters
was less pronounced. At lower temperature (0 1C) the
enantioselectivity was slightly higher (70% ee) than at room
temperature. The enantioselectivity also increased if more
catalyst was employed. With 5 mol% of catalyst an ee of
71% was recorded. The use of other oxidants or the use of
varying amounts of iodosobenzene had no effect. As a result of
the optimisation studies further experiments with different
substrates were performed at ambient temperature in
iodobenzene as the solvent (Table 1).
Scheme 2 Catalytic oxidation of sulfides 6 and 8.
Table 1 Enantioselective sulfoxidation of various sulfides catalysed
by Mn(salen) catalyst 5
Entry
Substratea
Productb
Yieldc (%)
eed (%)
1e
76
67
Fig. 1 Single crystal structure analysis of the N-menthyloxycarbonyl
derivative 10 of chiral sulfoxide 7.
2
90
91
13
20
product 7 (90% ee) with (À)-(1R,2S,5R)-menthyl chloroformate
delivered a major diastereoisomer 10 (Fig. 2), which was
isolated by column chromatography. From the crystal structure
depicted in Fig. 1 and from the known absolute configuration
of the menthyl substituent it can be concluded that the
stereogenic sulfur atom in the sulfoxide is (S)-configured.
The outcome of the reaction can be understood by assuming
a coordination of the substrate to one of the d-lactam units in
the active catalyst and by formation of complex 11, the
relevant features of which are depicted in Fig. 2. Oxygen
transfer to the sulfide occurs intramolecularly to provide the
observed (S)-enantiomer. Kinetic resolution of the sulfoxide
by a preferred further oxidation of one enantiomer to the
respective sulfone is not relevant as proven by the reaction of
racemic sulfoxide 7 under prolonged reaction conditions.19
The recovered sulfoxide was not enantiomerically enriched.
Optimisation experiments were conducted with sulfide 6
varying the oxidation conditions. Regarding the solvent,
CH2Cl2 (65%, 43% ee) and iodobenzene (56%, 46% ee)
delivered under otherwise unchanged conditions similar
results as benzene. Lowering the concentration resulted in a
significant ee increase if iodobenzene was used as the solvent
3e
4
5
85
66
72
64
59
64
6
a
Catalyst 5 (1 mol%) and iodosobenzene (1.30 eq.) were consecutively
added to a solution of the substrate in iodobenzene (c = 0.02 M). The
reaction mixture was stirred at room temperature for 72 hours and
b
purified directly by column chromatography over silica gel. The
absolute configuration of the major enantiomer of compound 7 was
determined as (S). Based on the mechanistic model (Fig. 2) the
absolute configuration of the other major sulfoxide enantiomers can
c
be deduced. Yield of the isolated product based on the recovered
d
starting material. The enantiomeric excess (ee) was determined
Fig.
2 Structure and configuration of N-menthyloxycarbonyl
e
by chiral HPLC analysis (see ESIw). Minor overoxidation to the
corresponding sulfone was observed.
derivative 10; possible mechanism for the oxygen transfer in the
complex 11 of sulfide 6 with the catalytically active Mn(salen) species.
c
2138 Chem. Commun., 2011, 47, 2137–2139
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Compared to the quinolone lactam binding motif of
2H-benzo[e][1,4]thiazin-3-one (6) (entry 1) the analogous
isoquinolone binding motif in 2H-benzo[e][1,4]thiazin-4(3H)-
one (12) (entry 2) was less suited for hydrogen bonding and
enantioselective sulfoxidation. The resulting sulfoxide 13 was
only produced in 13% ee. Presumably, a disfavoured steric
interaction of the benzo unit in 12 with the tert-butyl groups
at the salen prevents efficient binding. Consequently, the
homologous sulfide 1420 suffers from a similar steric clash
resulting in a low enantioselectivity for product 15. In stark
contrast, the other substrates 16,21 18,20 and 20 reacted with
good enantiocontrol. Given the fact that the groups adjacent
to the sulfur atom in sulfides 16 and 18 are both methylene
groups the enantioselectivities recorded for sulfoxides 17
(entry 4) and 19 (entry 5) are remarkable. As expected from
our initial consideration, the selectivity in this hydrogen-bond
mediated sulfoxidation relies exclusively on an efficient
binding but not on the size difference of the groups around
the sulfur atom. Substrate 20 was chosen to probe the
reactivity and selectivity in a sulfide, which is not part of a
ring. Also in this case (entry 6) formation of the respective
sulfoxide 21 proceeded with good enantioselectivity.
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In summary, the enantioselective oxidation of sulfides 6, 12,
14, 16, 18 and 20 containing a lactam binding motif was
achieved by the chiral Mn(salen) catalyst 5, which exhibits a
chiral hydrogen bonding pocket. The hydrogen bonding event
occurs more than ten carbon–carbon bonds away from the
active metal centre. The directing effect of the hydrogen bonds
at the spatially remote chiral template is solely responsible for
the face differentiation.
This project was supported in part by the Deutsche
Forschungsgemeinschaft (Ba 1372-10) and by the Fonds der
Chemischen Industrie.
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P212121 (no. 19), a = 9.2813(2), b = 13.9405(3), c = 14.3069(3) A,
V = 1851.11(7) A3, Z = 4, l(CuKa) = 1.54180 A, m =
1.747 mmÀ1, rcalcd = 1.304 g cmÀ3, T = 123(1) K, F(000) =
776, 0.25
Â
0.30
Â
0.64 mm, ymax: 66.531, R1 = 0.0190
(3130 observed data), wR2 = 0.0476 (all 3167 data), GOF =
1.069, 327 parameters, Drmax/min = 0.17/À0.16 eAÀ3; CCDC
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c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 2137–2139 2139