SS symmetry

Article
Synthesis of (R)-Modafinil via Organocatalyzed and
Article
Synthesis
Non-HemeofIron-Catalyzed
(R)-Modafinil via Organocatalyzed
Sulfoxidation and
Using H 2 O2
Non-Heme Iron-Catalyzed Sulfoxidation
as an Environmentally Benign Oxidant Using H2 O2
as an Environmentally Benign Oxidant
Felix E. Held, Kerstin A. Stingl and Svetlana B. Tsogoeva *
Felix E. Held,ofKerstin
Department A. and
Chemistry Stingl and Svetlana
Pharmacy, OrganicB. Tsogoeva
Chemistry * I and Interdisciplinary Center for
Chair
Molecular Materials
Department (ICMM),
of Chemistry and University of Erlangen-Nuremberg,
Pharmacy, Organic Chemistry Chair Henkestraße 42, 91054 Center
I and Interdisciplinary Erlangen,
for Germany;
Molecular
felix.held@fau.de (F.E.H.); kerstin.stingl@gmx.de (K.A.S.)
Materials (ICMM), University of Erlangen-Nuremberg, Henkestraße 42, 91054 Erlangen, Germany;
* Correspondence:
felix.held@fau.de svetlana.tsogoeva@fau.de;
(F.E.H.); kerstin.stingl@gmx.de Tel.: +49-9131-85-22541
(K.A.S.)
Correspondence:
*Academic svetlana.tsogoeva@fau.de;
Editor: Stephane Béllemin-LaponnazTel.: +49-9131-85-22541
Received: 11
Academic May Stephane
Editor: 2017; Accepted: 7 June 2017; Published: 16 June 2017
Béllemin-Laponnaz
Received: 11 May 2017; Accepted: 7 June 2017; Published: 16 June 2017
Abstract: The first organocatalyzed sulfoxidation reaction towards enantioenriched (R)-modafinil
(Armodafinil
Abstract: ), a drug
The® first against narcolepsy,
organocatalyzed is reported
sulfoxidation here.towards
reaction A seriesenantioenriched
of chiral organocatalysts, e.g.,
(R)-modafinil
(Armodafinil ®
different chiral),BINOL-phosphates, or a fructose-derived
a drug against narcolepsy, N-substituted
is reported here. A series oxazolidinone ketone (Shi
of chiral organocatalysts,
catalyst)
e.g., werechiral
different applied for the sulfoxidation
BINOL-phosphates, reaction with environmentally
or a fructose-derived friendly H2Oketone
N-substituted oxazolidinone 2 as a

convenient
(Shi oxygen
catalyst) transferring
were applied agent.
for the Furthermore,
sulfoxidation the potential
reaction of a biomimetic
with environmentally catalytic
friendly system
H2 O 2 as a
consisting of
convenient FeCl3 transferring
oxygen and a dipeptide-based chiral ligand
agent. Furthermore, was demonstrated,
the potential whichcatalytic
of a biomimetic constitutes the
system
most successful asymmetric non-heme iron-catalyzed synthesis of (R)-modafinil so
consisting of FeCl3 and a dipeptide-based chiral ligand was demonstrated, which constitutes the far.
most successful asymmetric non-heme iron-catalyzed synthesis of (R)-modafinil so far.
Keywords: sulfoxidation; (R)-modafinil; organocatalysis; non-heme iron catalyst; hydrogen
peroxide sulfoxidation; (R)-modafinil; organocatalysis; non-heme iron catalyst; hydrogen peroxide
Keywords:

1. Introduction
bioactive compounds
Sulfoxides demonstrate versatile properties and are ubiquitous in bioactive compounds and
drugs [1]. Being of medicinal interest, chiral sulfoxides serve as building blocks for the generation of
biologically active compounds [2]. With the discovery of their presence in naturally chiral sulfoxide
metabolites [3], such as cysteine sulfoxide derivatives, the demand for new synthetic routes was
growing, especially
steadily growing, especially since
since the
the pioneering
pioneering work
work of
of Kagan
Kagan andand Modena
Modena [4–6].
[4–6].
important representatives
Optically active sulfoxides are important representatives ofof therapeutically
therapeutically used
used drugs.
drugs. There
are several examples that playing an important role in medicinal and pharmaceutical chemistry [2],
including Esomeprazole [7,8], which acts as as proton-pump
proton-pump inhibitor;
inhibitor; the
the selective
selective NKNK22 antagonist
antagonist
anti-cancer agent
ZD7944 [9]; and the anti-cancer Sulindac®® (Figure 1) [10].
agent Sulindac

Figure 1.
Figure 1. Examples
Examples of
of chiral
chiral biologically
biologically active
active sulfoxides.
sulfoxides.

Symmetry 2017, 9, 88; doi:10.3390/sym9060088 www.mdpi.com/journal/symmetry

Symmetry 2017, 9, 88; doi:10.3390/sym9060088 www.mdpi.com/journal/symmetry

Symmetry 2017, 9, 88 2 of 9
Symmetry 2017, 9, 88 2 of 9

Provigil®® [11], Figure 2), another important sulfoxide, is administered

Modafinil (also known as Provigil
as a drug against narcolepsy [12] with significant advantages compared to dexamphetamine [13] and
because of
several other stimulants [14] because of aa lower
lower abuse
abuse potential
potential [15,16].
[15,16].

Figure2.2.The
Figure Thehippocampal
hippocampalactivator
activator in
in its
its racemic (Armodafinil®®) )forms.
racemic (modafinil) and optically pure (Armodafinil forms.

It is
It is furthermore
furthermore used used for for the
the treatment
treatment of of depression
depression [17], [17], attention-deficit
attention-deficit hyperactivity
hyperactivity
disorder [18],
disorder [18], Parkinson’s
Parkinson’s diseasedisease [19],
[19], and
and epilepsy
epilepsy [20]. [20]. Moreover,
Moreover, it it is
is aa memory-improving
memory-improving and and
mood-brightening psychostimulant
mood-brightening psychostimulant [21]. [21].
After the
After the first
first synthesis
synthesis was was developed
developed in in 1979
1979 by by Lafon
Lafon [22], [22], several
several methods
methods have have been
been
envisioned for its racemic generation using hydrogen peroxide
envisioned for its racemic generation using hydrogen peroxide as an abundant, environmentally as an abundant, environmentally
benign oxidant
benign oxidant [23–29].
[23–29].
The fact
The fact that
that there
there isis aa continued
continued demand demand for for novel
novel synthetic
synthetic methods
methods to to attain
attain modafinil
modafinil is is
further demonstrated by a recently published one-pot parallel
further demonstrated by a recently published one-pot parallel synthetic approach [29] as well as synthetic approach [29] as well as
another strategy,
another strategy, established
established by Cibulka
by Cibulka and co-workers,and co-workers, employing electron-deficient
employing electron-deficient heteroarenium
heteroarenium salts for the activation
salts for the activation of hydrogen peroxide [30]. of hydrogen peroxide [30].
The quantitative
The quantitative potency
potency of of the
the two
two enantiomers
enantiomers of of modafinil,
modafinil, however,
however, is is indeed
indeed influenced
influenced by by
the stereogenic sulfoxide group. (R)-modafinil has a longer half-life
the stereogenic sulfoxide group. (R)-modafinil has a longer half-life in the human body compared in the human body compared to to
(S)-modafinil [31],
(S)-modafinil [31], which
which is is metabolized
metabolized three three times
times faster
faster [32].
[32].
An ester, amide, or carboxylic acid moiety
An ester, amide, or carboxylic acid moiety close to the sulfide close to the sulfide function,
function, however,
however, can can adversely
adversely
affect enantioselectivity
affect enantioselectivity [33]. [33].GivenGiven thatthatno nodirecting
directing group is available
group adjacent
is available to thetosulfur
adjacent atom,
the sulfur
compared, for instance, to omeprazole [7], most known
atom, compared, for instance, to omeprazole [7], most known procedures aim to circumvent an procedures aim to circumvent an
enantioselective oxidation. As an alternative, racemic resolution of diastereomers
enantioselective oxidation. As an alternative, racemic resolution of diastereomers [34,35], preferential [34,35], preferential
crystallization or
crystallization or chiral
chiral chromatography
chromatography can can bebe applied
applied [36].
[36]. Thus,
Thus, the the variety
variety of of enantioselective
enantioselective
synthetic approaches is limited to a small selection, namely, a microbial
synthetic approaches is limited to a small selection, namely, a microbial sulfoxidation [37], an advanced sulfoxidation [37], an
advanced Kagan method patented by Cephalon [33], and an oxygen-transfer
Kagan method patented by Cephalon [33], and an oxygen-transfer by a chiral oxaziridine in ionic by a chiral oxaziridine
in ionic[38].
liquid liquid [38].
These methods,however,
These methods, however, suffer
suffer from from the need
the need for hazardous
for hazardous oxidizing oxidizing agents, expensive
agents, expensive solvents,
solvents,
and metaland metal catalysts.
catalysts. Apart from Apart from a vanadium-based
a vanadium-based catalyticcatalytic
system, system,
developed developed in our which
in our group, group,
which was able to provide (R)-modafinil in excellent yield and moderate
was able to provide (R)-modafinil in excellent yield and moderate enantiomeric excess within a very enantiomeric excess within
a veryreaction
short short reaction time [39],
time [39], all other
all other attempts
attempts making
making useuseof of convenientmetal
convenient metalcomplexes
complexes generally
generally
resulted in
resulted in aa drastically
drastically decreased
decreased performance
performance of of the
the catalyst
catalyst [38].
[38].
For the pharmaceutical industry it is a permanent
For the pharmaceutical industry it is a permanent issue to free issue to free biologically
biologically active
active compounds
compounds
from metal traces. Thus, the development of a metal-free sulfoxidation
from metal traces. Thus, the development of a metal-free sulfoxidation process is in high demand. process is in high demand.
A class
A class ofofpowerful
powerful organocatalysts
organocatalysts is represented
is represented by Brønsted
by Brønsted acid catalysts such as such
acid catalysts BINOL-as
derived phosphoric acids, which have already been
BINOL-derived phosphoric acids, which have already been applied in numerous highly applied in numerous highly enantioselective
transformations [40–49]
enantioselective since the pioneering
transformations [40–49] since studies the bypioneering
the groupsstudies of Akiyama by the et al. [50] and
groups of
Uraguchi and Terada [51].
Akiyama et al. [50] and Uraguchi and Terada [51].
Wang, Tao
Wang, Tao andand co-workers
co-workers [52] [52] were
were the the first
first toto develop
develop aa sulfoxidation
sulfoxidation reaction
reaction catalyzed
catalyzed by by
BINOL-phosphates, and
BINOL-phosphates, and List
Listet etal.
al.[53,54]
[53,54]impressively
impressivelydemonstrated
demonstratedthe thepotential
potential ofofa new
a new family of
family
chiral phosphoric acids with results analogous to the best obtained
of chiral phosphoric acids with results analogous to the best obtained with metal catalysts. Having with metal catalysts. Having
already shown
already shown aa very very good
good performance
performance in in aa patented,
patented, efficient,
efficient, andand direct
direct route
route towards
towards Sulindac
Sulindac®®
(Figure 1)
(Figure 1) [53,54],
[53,54], BINOL-derived
BINOL-derived phosphoricphosphoric acids acids have surprisingly never
have surprisingly never been applied for
been applied for the
the
enantioselective synthesis of
enantioselective synthesis of modafinil. modafinil.
Following our
Following our previous
previous successes
successes in in applying
applying Lewis Lewis base/Brønsted
base/Brønsted acid catalysts for
acid catalysts for various
various
organic transformations [55–57], we decided to test
organic transformations [55–57], we decided to test BINOL-phosphates (chiral bifunctional BINOL-phosphates (chiral bifunctional
organocatalysts, Scheme 1) and additional catalytic systems. To the best of our knowledge, we
Symmetry 2017, 9, 88 3 of 9
Symmetry 2017, 9, 88 3 of 9

present herein Scheme

organocatalysts, the first1)organocatalyzed synthesis
and additional catalytic of enantiomerically
systems. To the best of ourenriched modafinil
knowledge, via
we present
sulfoxidation.
herein the first organocatalyzed synthesis of enantiomerically enriched modafinil via sulfoxidation.

Scheme 1.1. Proposed

Scheme Proposed Lewis base/Brønsted acid
Lewis base/Brønsted catalysis—BINOL-phosphates as
acid catalysis—BINOL-phosphates bifunctional
as bifunctional
organocatalysts in the oxidation of sulfide with hydrogen peroxide as an oxidant.
organocatalysts in the oxidation of sulfide with hydrogen peroxide as an oxidant.

2. Materials
2. and Methods
Materials and Methods
Solvents were
Solvents were purified
purified by
by standard
standard procedures
procedures and
and distilled
distilled prior
prior to
to use.
use. Reagents
Reagents obtained
obtained
from commercial
from commercial sources
sources were
were used
used without
without further
further purification.
purification. Thin
Thin layer
layer chromatography
chromatography (TLC)
(TLC)
chromatography was performed on pre-coated aluminum silica
chromatography was performed on pre-coated aluminum silica gel ALUGRAM gel ALUGRAM SIL G/UV254 plates
SIL G/UV254
(Macherey,
plates Nagel &Nagel
(Macherey, Co., Düren,
& Co.,Germany). Flash chromatography
Düren, Germany). was performedwas
Flash chromatography using silica gel
performed
ACROS
using 60 gel
silica Å , ACROS
(particle60 size 0.035–0.070
Å, (particle mm, Thermofischer
size 0.035–0.070 ACROS Organics,
mm, Thermofischer Janssen-
ACROS Organics,
Pharmaceuticalaan 3a, 2440 Geel, Belgium). Proton nuclear magnetic resonance spectroscopy
Janssen-Pharmaceuticalaan 3a, 2440 Geel, Belgium). Proton nuclear magnetic resonance spectroscopy (1H-
(NMR) spectra
1 H-NMR) were
spectra recorded
were recordedin CDCl 3 with Bruker Avance 300 or 400 (Bruker, Billerica, MA, USA).
in CDCl 3 with Bruker Avance 300 or 400 (Bruker, Billerica, MA, USA).
Enantioselectivities were determined by
Enantioselectivities were determined by chiral chiral high
high pressure liquid chromatography
pressure liquid chromatography (HPLC)(HPLC) analysis
analysis
in comparison with authentic racemic
in comparison with authentic racemic material.material.

2.1. (Methylsulfinyl)Benzene (1a):

corresponding BINOL-phosphate
The corresponding BINOL-phosphatecatalystcatalyst(0.048
(0.048mmol)
mmol)was wasdissolved
dissolvedininCH
CH22ClCl22 (0.5 mL) at
−10
− ◦ C.After
10°C. Afterthe
theaddition
additionofofthe
thesulfide
sulfide(0.24
(0.24 mmol,
mmol, 29.8
29.8 mg)
mg) aqueous
aqueous 30% H22O O22(1.2
(1.2equiv,
equiv, 0.29
0.29 mmol,
mmol,
29.4 µL)
µ L) was added in one portion. The reaction reaction mixture was stirred at room temperature for 24
mixture was stirred at room temperature for 24 h.
h.
product was
The product was obtained
obtained viavia direct
direct purification
purification by
bycolumn
columnchromatography
chromatography(SiO (SiO22,, EtOAc/PE
EtOAc/PE 4:1).4:1).
The enantiomeric
The enantiomeric excess
excess of
of the
the product
product was
was determined
determined by by chiral
chiral HPLC
HPLC analysis.
analysis. 1H-NMR
H-NMR (300 (300 MHz,
MHz,
CDCl ): δ = 2.70 (s, 3H), 7.47–7.54 (m, 3H), 7.60–7.64 (m,
CDCl3 ): δ = 2.70 (s, 3H), 7.47–7.54 (m, 3H), 7.60–7.64 (m, 2H).
3 2H).

2.2. 1-(Methylsulfinyl)-4-Nitrobenzene
1-(Methylsulfinyl)-4-Nitrobenzene (1b):
(1b):
The corresponding
corresponding BINOL-phosphate
BINOL-phosphatecatalyst catalyst(0.048
(0.048mmol)
mmol)was
wasdissolved
dissolvedin inCH
CH22Cl
Cl22 (0.5 mL) at
− ◦ C. The sulfide (0.24 mmol, 40.6
10°C.
−10 The sulfide (0.24 mmol, 40.6 mg) was added, followed by the the addition
addition of of aqueous
aqueous30% 30%H H22O
O22
(1.2 equiv,
equiv, 0.29
0.29 mmol,
mmol, 29.4 µ L) in
29.4 µL) in one
one portion.
portion. The reaction mixture was stirred at room temperature
for 24
24 h.h. The
The product
product was
was directly
directlypurified
purifiedbybycolumn
columnchromatography
chromatography(SiO (SiO2 ,2,EtOAc/PE
EtOAc/PE 4:1).
4:1). The
enantiomeric excess of the product product was was determined
determined by by chiral
chiral HPLC analysis. 11H-NMR
HPLC analysis. H-NMR (300 MHz,
CDCl33 ): δδ == 2.77
2.77 (s,
(s, 3H),
3H), 7.82 (d, JJ ==8.9
7.82 (d, 8.9Hz,
Hz,2H),
2H),8.38 (d,JJ==8.9
8.38(d, 8.9Hz,
Hz,2H).
2H).

2.3.
2.3. 2-(Benzhydrylsulfinyl)Acetamide
2-(Benzhydrylsulfinyl)Acetamide (2):
(2):
BINOL-phosphate
BINOL-phosphate V V (0.048
(0.048mmol,
mmol,36 36mg)
mg)was wasdissolved
dissolvedininCH CH2 Cl
2Cl22(0.5
(0.5mL) 10 ◦°C,
mL)atat−−10 C, followed
followed
by the addition of aqueous 30% H O (1.2 equiv, 0.29 mmol, 29.4 µL) in one
by the addition of aqueous 30% H22O22 (1.2 equiv, 0.29 mmol, 29.4 µ L) in one portion. Then, the portion. Then, the sulfide
sulfide
(0.24 at −at ◦
(0.24 mmol,
mmol,61.8
61.8mg)
mg)was
wasadded
added toto
thethe
reaction
reactionmixture,
mixture,which waswas
which stirred
stirred 10 −10
C. The product
°C. The was
product
directly purified by column chromatography
was directly purified by column chromatography (SiO 2 , EtOAc). The isolated enantiomerically
(SiO2, EtOAc). The isolated enantiomerically enriched
(R)-modafinil was identified
enriched (R)-modafinil through comparison
was identified of 1 H-NMR
through comparison of spectra
1H-NMR with literature
spectra data [38]. data
with literature The
enantiomeric excess of the product was determined by chiral HPLC analysis
[38]. The enantiomeric excess of the product was determined by chiral HPLC analysis (Daicel (Daicel Chiralpak AS,
n-hexane/i-PrOH (60:40), flow 0.9 mL/min, 25 ◦ C, 31 bar). 1 H-NMR (300 MHz, DMSO-d ): δ = 3.21 (d,
Chiralpak AS, n-hexane/i-PrOH (60:40), flow 0.9 mL/min, 25 °C, 31 bar). H-NMR (300 MHz, 1 6 DMSO-
Jd=6):13.5 Hz, 1H),
δ = 3.21 (d, J 3.36
= 13.5 J = 1H),
(d,Hz, 13.5 Hz,
3.361H),
(d, J 5.34 (s,Hz,
= 13.5 1H),1H),
7.32–7.43
5.34 (s,(m, 7H),
1H), 7.50–7.52
7.32–7.43 (m,
(m, 4H),
7H), 7.68 (s, 1H).
7.50–7.52 (m,
4H), 7.68 (s, 1H).
3. Results and Discussion
Our initial work started with the screening of different BINOL-phosphates for the synthesis of
thioanisole via sulfoxidation as a model reaction. The required organocatalysts I–VII for the reaction
were prepared by conventional means [58].
Initially,
Symmetry 2017, 9, the
88 reaction was performed in dichloromethane using 20 mol % of the organocatalyst 4 of 9
at −10 °C within 24 h. In case of BINOL-phosphate II, only moderate yield was observed (44% yield,
entry 1, Table 1) and the enantiomeric excess was rather low (10% ee). A further reduction of the
3. Results
amount ofand Discussion
catalyst from 20 mol % to 10 mol % resulted in a decreased yield, but the enantiomeric
ratioOurremained constant
initial work started (26% yield,
with the 10% ee, entry
screening 2, TableBINOL-phosphates
of different 1). Surprisingly, BINOL-phosphate
for the sulfoxidation III
provided
of the corresponding
thioanisole sulfoxide
as a model reaction. The in high yield
required (98%) with an
organocatalysts enantiomeric
I–VII excesswere
for the reaction of 20% (entry
prepared
3, Table 1) and we
by conventional means [58]. continued to investigate catalyst I. To our delight, the enantiomeric excess
increased to the
Initially, 36%reaction
ee, but was
the yield was lowered
performed to 68% (entry
in dichloromethane using4, 20
Table
mol1).
% ofIn the
theorganocatalyst
case of BINOL- at
− ◦
phosphate
10 C within with24a h.more sterically
In case hindered moiety,II,a only
of BINOL-phosphate complete loss of
moderate activity
yield was was the consequence
observed (44% yield,
(entry1,5,Table
entry Table1) 1).and
With thecatalyst V, on the
enantiomeric otherwas
excess hand, the low
rather product
(10%could
ee). Abefurther
isolatedreduction
with 73%ofyieldthe
and an enantiomeric
amount of catalyst from excess of 30%
20 mol % to(entry
10 mol6,%Table 1). Furthermore,
resulted in a decreased carrying outthe
yield, but oneenantiomeric
reaction withoutratio
an external
remained catalyst,(26%
constant we could
yield, preclude
10% ee, entrya background
2, Table 1).reaction (entryBINOL-phosphate
Surprisingly, 7, Table 1). III provided
the corresponding sulfoxide in high yield (98%) with an enantiomeric excess of 20% (entry 4-position
We investigated the oxidation of a thioanisole derivative bearing a nitro moiety in 3, Table 1)
(entries
and 8–11, Table
we continued to 1). We applied
investigate BINOL-phosphate
catalyst I. To our delight,VI, theand found thatexcess
enantiomeric the product
increased could
to 36%be
isolated with a low yield of 11% and a moderate enantiomeric excess of
ee, but the yield was lowered to 68% (entry 4, Table 1). In the case of BINOL-phosphate with a more 33% (entry 8, Table 1).
Carrying hindered
sterically out the reaction
moiety, awith a lower
complete lossamount of was
of activity hydrogen peroxide (0.27
the consequence (entryequivalent)
5, Table 1).under
With
otherwise
catalyst V, identical
on the otherconditions,
hand, thethe isolated
product product
could had a significantly
be isolated with 73% yield higher
and anenantiomeric
enantiomeric excess
excessof
59% (entry 9, Table 1). With catalyst VII, bearing an electron withdrawing substituent
of 30% (entry 6, Table 1). Furthermore, carrying out one reaction without an external catalyst, we could on the phenyl
moiety inapara
preclude position,reaction
background the desired product
(entry was1).generated only in traces (entry 10, Table 1).
7, Table

Table 1.
Table 1. BINOL-phosphate
BINOL-phosphate catalyzed
catalyzed oxidation
oxidation of
of thioanisole
thioanisole derivatives.
derivatives.

Entry Product BINOL-Phosphate Yield, a % ee, % (S)

Entry Product BINOL-Phosphate Yield, a % ee, % (S)
1 1 1a 1a II II 4444 1010b b
2 2 1a 1a d d
II II 2626 1010b b
3 3 1a 1a III III 9898 2020b b
4 4 1a 1a I I 6868 3636b b
5 5 1a 1a IVIV Traces
Traces n.d.
n.d.
6 1a V 73 30 b b
6 1a V 73 30
7 1a – Traces n.d.
7 1a – Traces n.d.
8 1b VI 11 33 c
8 9 1b 1b VIVI e 1411 5933c
c

9 10 1b 1b VIVIIe 14
Traces 1859c c

10 1b VII Traces 18 c
aYield b determined by HPLC (OD, n-hexanes/iPrOH (93:7), flow 1.0 mL/min); c determined
a Yieldofofisolated product;
isolated product; b determined by HPLC (OD, n-hexanes/iPrOH (93:7), flow 1.0 mL/min); c
by HPLC (IA, n-hexanes/iPrOH (90:10), flow 1.0 mL/min); d 10 mol % catalyst loading; e c (educt) = 0.8 mol/l; H O
2 2
determined by HPLC (IA, n-hexanes/iPrOH (90:10), flow 1.0 mL/min); d 10 mol % catalyst loading;
= 0.27 equiv. For details of the reaction procedures and product characterizations, see Supplementary Information.
e c (educt) = 0.8 mol/l; H2O2 = 0.27 equiv. For details of the reaction procedures and product
characterizations, see Supplementary Information.
We investigated the oxidation of a thioanisole derivative bearing a nitro moiety in 4-position
(entries 8–11, Table 1). We applied BINOL-phosphate VI, and found that the product could be isolated
with a low yield of 11% and a moderate enantiomeric excess of 33% (entry 8, Table 1). Carrying out
the reaction with a lower amount of hydrogen peroxide (0.27 equivalent) under otherwise identical
conditions, the isolated product had a significantly higher enantiomeric excess of 59% (entry 9, Table 1).
Symmetry 2017, 9, 88 5 of 9

Subsequently, we studied the sulfoxidation of the prochiral sulfide in the presence of 20 mol %
of BINOL-phosphate V, which had previously performed best. The reaction proceeded at −10 °C, in
Symmetry 2017, 9, 88 5 of 9
CH2Cl2 as a solvent (Table 2). Initially, we applied the optimized reaction conditions, and the product
could be isolated after 24 h in quantitative yield with an enantiomeric excess of 10% (entry 1, Table 2)
In order
With to examine
catalyst the temperature
VII, bearing effect on the reaction,
an electron withdrawing substituentweon carried out the
the phenyl sulfoxidation
moiety at 0 °C.
in para position,
Thedesired
the productproduct
was obtained quantitatively
was generated only inbut with(entry
traces a slightly lower1).ee value of 7% (entry 2, Table 2). A
10, Table
shorter
Subsequently, we studied the sulfoxidation of the prochiral and
reaction time of 12 h resulted in a lower yield of 61%, no in
sulfide enantioselectivity
the presence of 20could
mol be%
detected
of (entry 3, Table
BINOL-phosphate 2). A higher
V, which initial concentration
had previously performed best.of theThe
sulfide hadproceeded
reaction a positive at −10 ◦ C, on
influence in
the 2stereoselectivity
CH of the 2).
Cl2 as a solvent (Table oxidation.
Initially,Thus, following
we applied the previous
the optimized trend conditions,
reaction concerning and
the oxidation
the product of
thioanisole (entry 9, Table 1), we observed this supporting effect on the reaction
could be isolated after 24 h in quantitative yield with an enantiomeric excess of 10% (entry 1, Table 2) outcome for
modafinil
In order to as well. Due
examine to an accelerated
the temperature effect on reaction, the desired
the reaction, we carriedcompound could be isolated
out the sulfoxidation in
at 0 ◦ C.
quantitative yield already after 12 h and the ee value slightly increased to 13%
The product was obtained quantitatively but with a slightly lower ee value of 7% (entry 2, Table 2). (entry 4, Table 2).
The Shi’s
A shorter N-substituted
reaction time of 12 h oxazolidinone
resulted in a ketone VIII of
lower yield belongs
61%, and to the attractive class of could
no enantioselectivity fructose-
be
derived asymmetric
detected (entry 3, Table organocatalysts, generally
2). A higher initial employedoffor
concentration thethe epoxidation
sulfide of unfunctionalized
had a positive influence on
terminal
the alkenes [59,60].
stereoselectivity of the Having
oxidation.successfully applied
Thus, following theitprevious
to the one-pot, two-step the
trend concerning synthesis of of
oxidation β-
adrenergic (entry
thioanisole blockers via epoxidation
9, Table 1), we observedas a this
keysupporting
enantioselective step
effect on the[60], we decided
reaction outcometofor evaluate its
modafinil
activity
as for the
well. Due sulfoxidation
to an accelerated reaction
reaction,as thewell. Modafinil
desired compound was generated with a in
could be isolated yield of 38% and
quantitative an
yield
enantioselectivity
already of 26%
after 12 h and the ee
ee (entry 5, Tableincreased
value slightly 2). to 13% (entry 4, Table 2).

Table 2.
Table 2. Organocatalytic
Organocatalytic synthesis
synthesis of
of modafinil.
modafinil.

Entry Catalyst Time, h Yield, a % ee, bb % (R)

Entry Catalyst Time, h Yield, a % ee, % (R)
1 1 V Vc 2424 >99
>99 10
10
2 V 24 >99 7
2 Vc 24 >99 7
3 V 12 61 rac
3 d V 12 61 rac
4 V 12 >99 13
4d 5 VVIII 1224 >99
38 13
26
5 6 VIII
IX e 2496 38
66 26
16
6 IX e 96 66 16
aaYield b b (AS, n-hexanes/iPrOH
Yieldofofisolated
isolatedproduct;
product;determined by chiral
determined HPLCHPLC
by chiral (60:40), flow
(AS, n-hexanes/iPrOH 0.9 mL/min,
(60:40), flow 0.9
25 ◦ C, 31 bar); c T = 0 ◦ C; d c (sulfide) = 0.8 mol/l; e without H O , 1.5 equiv of IX, T = −30 o C > room
2 2
mL/min, 25 °C, 31 bar); T = 0 °C; c (sulfide) = 0.8 mol/l; without H2O2, 1.5 equiv of IX, T = −30 oC >
c d e
temperature (RT), tetrahydrofuran (THF). For details of the reaction procedures and product characterizations, see
room temperature
Supplementary (RT), tetrahydrofuran (THF). For details of the reaction procedures and product
Information.
characterizations, see Supplementary Information.
The Shi’s
In order N-substituted
to minimize oxazolidinone
the number ketone
of reactants, VIII
we next belongs
intended to the attractive
to combine class
the oxidizing of
agent
fructose-derived
and the chiral source.asymmetric
Therefore,organocatalysts,
we applied the generally
synthesizedemployed for the epoxidation
chiral hydroperoxide TADOOH IX, of
unfunctionalized terminal alkenes [59,60]. Having successfully applied it to the one-pot, two-step
which is generally known for its high efficiency for sulfoxidation reactions [61]. A striking feature of
synthesis
this method of β-adrenergic blockers
is that no further via epoxidation
external as a key With
catalyst is needed. enantioselective
an amount step [60],
of 1.5 we decided
equivalent to
of the
evaluate
oxidant initstetrahydrofuran
activity for the sulfoxidation reactionwas
(THF), the product as well. Modafinil
generated was
in 66% generated
yield with anwith a yield of 38%
enantioselectivity
and an enantioselectivity
of 16% (entry 6, Table 2). of 26% ee (entry 5, Table 2).
In order to minimize the number of reactants, we next intended to combine the oxidizing agent
and the chiral source. Therefore, we applied the synthesized chiral hydroperoxide TADOOH IX, which
Symmetry 2017, 9, 88 6 of 9

is generally known for its high efficiency for sulfoxidation reactions [61]. A striking feature of this
method is that no further external catalyst is needed. With an amount of 1.5 equivalent of the oxidant
in tetrahydrofuran
Symmetry 2017, 9, 88 (THF), the product was generated in 66% yield with an enantioselectivity of 616%
of 9
(entry 6, Table 2).
Following our previous interest in the application of the non-heme iron-catalyzed sulfoxidation
reaction, which exhibited high activity in the oxidation of the thioanisol but, up to now, showed
unsatisfactory results for the modafinil precursor [39], we decided
decided to investigate
investigate a dipeptide-based
dipeptide-based
chiral ligand as an alternative chiral source
source (Scheme
(Scheme 2).
2).

Scheme 2. Application of a dipeptide-based ligand X to the

the biomimetic
biomimetic iron-catalyzed synthesis of
(R)-modafinil.
(R)-modafinil.

Under these conditions, modafinil could be isolated in good yield of 75% and with an ee value
Under these conditions, modafinil could be isolated in good yield of 75% and with an ee
of 24%. This represents the most successful asymmetric non-heme iron-catalyzed synthesis of (R)-
value of 24%. This represents the most successful asymmetric non-heme iron-catalyzed synthesis of
modafinil so far.
(R)-modafinil so far.

4. Conclusions
4. Conclusions
We report
We report here
here the
the first
firstorganocatalytic
organocatalytic synthesis
synthesis of
of enantiomerically
enantiomerically enriched
enriched (R)-modafinil
(R)-modafinil
(Armodafinil ),),accomplished
(Armodafinil
®® accomplishedwith withthe
thechiral
chiralbifunctional
bifunctionalBINOL-phosphate
BINOL-phosphate V, V,
a fructose-derived
a fructose-derived N-
substituted oxazolidinone ketone VIII, or the chiral peroxide TADOOH IX, respectively.
N-substituted oxazolidinone ketone VIII, or the chiral peroxide TADOOH IX, respectively. The desired The desired
compound could
compound couldbe beobtained
obtainedvia sulfoxidation
via sulfoxidation using H2O
using H22with excellent
O2 with yieldyield
excellent up to up
>99%to and
>99%ee values
and ee
up to 23%.
values up toThis protocol
23%. includesincludes
This protocol all the advantages of metal-free
all the advantages asymmetric
of metal-free organocatalysis.
asymmetric organocatalysis.
We additionally
We additionally showed
showed the the successful
successful application
application of
of aa dipeptide-based ligand in
dipeptide-based ligand in the
the biomimetic
biomimetic
non-heme iron-catalyzed sulfoxidation towards enantiomerically enriched (R)-modafinil, whichwhich
non-heme iron-catalyzed sulfoxidation towards enantiomerically entioenriched (R)-modafinil, could
could be isolated in good yield of 75% with an enantioselectivity of 24% ee. The sulfoxidation
be isolated in good yield of 75% with an enantioselectivity of 24% ee. The sulfoxidation reported reported
here makes
here makes useuse of
of mild
mild reaction
reaction conditions
conditions using
using aqueous
aqueous hydrogen
hydrogen peroxide
peroxide as as an
an environmentally
environmentally
friendly oxidant.
friendly oxidant.

Supplementary Materials:
Materials:The following
The are available
following onlineonline
are available at www.mdpi.com/link: Experimental Procedures,
at www.mdpi.com/2073-8994/9/6/88/s1:
Experimental
Analytical andProcedures, Analytical
Spectroscopic Data of and Spectroscopic Data of Products.
Products.

Acknowledgments: We
Acknowledgments: We gratefully
gratefully acknowledge
acknowledge thethe financial
financial support
support from
from Deutsche
Deutsche Forschungsgemeinschaft
Forschungsgemeinschaft
(DFG) by grant TS 87/16-3. We also thank the Interdisciplinary Center for Molecular Materials (ICMM), the
(DFG) by grant TS 87/16-3. We also thank the Interdisciplinary Center for Molecular Materials (ICMM), the
Graduate School Molecular Science (GSMS) for research support, as well as the Wilhelm Sander-Stiftung (Grant
Graduate
No. Schoolfor
2014.019.1) Molecular
funding. Science (GSMS) for research support, as well as the Wilhelm Sander-Stiftung (Grant
No. 2014.019.1) for funding.
Author Contributions: Felix E. Held conducted the sulfoxidation reactions. Kerstin A. Stingl contributed to the
catalyst
Author screening of the Felix
Contributions: modelE.reaction. Svetlana the
Held conducted B. Tsogoeva conceived
sulfoxidation and directed
reactions. theStingl
Kerstin A. research, supervised
contributed to the
synthetic experiments.
catalyst screening of theThe manuscript
model reaction.was writtenB.through
Svetlana Tsogoeva contribution
conceived of
andalldirected
authors.the research, supervised
the synthetic
Conflicts experiments.
of Interest: The manuscript
The authors declare nowas written
conflict through contribution of all authors.
of interest.
Conflicts of Interest: The authors declare no conflict of interest.
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