Organic Letters
Letter
with a remote lactam hydrogen-bonding site,17 thus enabling
the precise orientation of an appropriate substrate. The crucial
advantage is that an enantioselective approach can now be
realized irrespective of the steric environment at the reactive
site. Along these lines, compound 5 and related porphyrin
complexes have proven to be efficient catalysts for a variety of
site- and enantioselective oxidative transformations.18−20 Due
to the emerging interest in exploiting noncovalent interactions
as control elements in stereoselective catalysis,21 we antici-
pated that the enantioselective sulfoxidation would be an
appealing supplement to previously reported sulfoxidation
protocols.
Scheme 1. Scope of the Enantioselective Sulfoxidation of
Sulfides 7 to 8 Catalyzed by the Mn Porphyrin Complex 5
a
On the basis of our previous reports,16 we started our
investigation by employing the chiral manganese porphyrin
complex 5 in combination with the stoichiometric oxidant
iodosobenzene (PhIO, 1.5 equiv). Dichloromethane was the
incipient solvent, and after 4 h at 0 °C the optically enriched
sulfoxide 8a was obtained in a reasonable yield (64%) with an
encouraging selectivity (79% ee). A series of optimization
for details) whereupon chloroform was identified as the
superior solvent. Moreover, adding the oxidant in a portion-
wise fashion to ensure a high selectivity (>90% ee) and
enhanced catalyst activity (up to 400 turnovers) proved to be
beneficial. The origin of enantioselectivity in the overoxidation
step was further investigated by submitting the racemic
sulfoxide rac-8a to the sulfoxidation protocol. No kinetic
resolution in favor of sulfoxide 8a was observed en route to the
corresponding sulfone, clearly suggesting that the high
enantioselectivity in the sulfoxidation stems from a single-
oxygen transfer to the prochiral sulfide. Instead, a marginally
enriched sulfoxide ent-8a was reisolated (27% conversion,
−11% ee) when using 0.65 equiv of PhIO, suggesting that the
excessive use of the oxidant should be avoided.
With the optimized conditions in hand, sulfoxide 8a was
produced in a high yield (75%) and remarkable enantiose-
lectivity (92% ee) that in turn further increased on a larger
scale (70% yield, 96% ee) (Scheme 1). The electronic effect of
the thiophenyl linker was explored as the para-substituent was
varied, and the reaction was found to be robust toward a series
of both electron-donating and electron-withdrawing functional
groups (8b−8f, 64−67% yield, 86−92% ee). It was further
examined whether substituents at the quinolone core were
tolerated by introducing methyl groups at both the C-6 (8g)
and C-7 positions (8h) (88% and 92% ee). The steric
influence of the aryl group was studied by altering the
substitution pattern, and the obtained products 8i−8l
displayed consistent results in terms of their yield (65−81%)
and selectivity (89−96% ee). Remarkably, a thiophenyl linker
carrying an ortho-substituent had a profitable effect on not only
the enantioselectivity but also the chemoselectivity. Under
standard conditions, sulfoxide 8l was obtained in a relatively
low yield (53%) with an almost perfect enantioselectivity (97%
ee), but no further oxidation to the sulfone was observed. With
this in mind, the reaction was run to completion by adding a
third portion of the oxidant PhIO (3 × 0.65 equiv) whereupon
product 8l was obtained in a high yield (81%) with an
outstanding selectivity (96% ee). Encouraged by the improved
selectivity induced by an ortho-methyl substituent, a set of
related sulfides was prepared,22 which gave access to the
corresponding sulfoxides 8m and 8n in a continuously high
enantiomeric excess (92% and 95% ee). Finally, using the di-
ortho-methyl-substituted sulfide 7o led to a slow reaction (42%
a
The reactions were performed on a 0.10 mmol scale and initiated by
the addition of the oxidant PhIO (0.65 equiv) to a precooled (0 °C)
solution of catalyst 5 and substrate 7 in CHCl3 (10 mM). A second
portion of PhIO (0.65 equiv) was added after 1 h. The enantiomeric
excess (ee) was determined by HPLC analysis on a chiral stationary
phase. Unless otherwise stated, unsubstituted quinolones were used,
carrying hydrogen atoms at both the C-6 substituent (orange) and the
b
C-7 subsitutent (blue). The reaction was performed on a 1.00 mmol
PhIO (0.65 equiv) was added after 2 h. 63% conversion. 54%
conversion.
c
d
e
yield at 63% conversion); however, the corresponding
sulfoxide 8o was obtained with a flawless selectivity (99%
ee). Along a similar line, the tetrafluoro-substituted sulfoxide
8p was obtained with a very high selectivity (97% ee).23
The importance of hydrogen bonding during this trans-
formation was corroborated by subjecting the N-methylated
substrate 9 and the coumarin congener 10 to the
enantioselective sulfoxidation protocol (Scheme 2). Both
compounds lack the ability to participate in hydrogen bonding,
and the corresponding sulfoxides 11 and 12 were produced
with negligible selectivity (below 2% ee). In line with our
Scheme 2. Sulfoxidation by Mn Complex 5 Using Substrates
9 and 10 with a Blocked Hydrogen Bonding Site
1830
Org. Lett. 2021, 23, 1829−1834
Burg, Finn
