Enantioselective synthesis of encecaline-derived potent antimalarial agents

Article abstract of DOI:10.1039/c3ob41583j

The high antiplasmodial activity of racemic benzylamines rac-1 and rac-2 stimulated the synthesis of pure enantiomers. Ellman's chiral sulfinamides (S)-6 and (R)-6 were used as chiral auxiliaries. Condensation of prochiral ketone 5 with enantiomerically pure sulfinamides (S)-6 and (R)-6 and subsequent NaBH ₄ reduction provided predominantly unlike configured diastereomers (S,R)-8 and (R,S)-8 (ratio unlike-8: like-8 = 90:10). The same transformation of phenol 4 led to the diastereomeric sulfinamides (S,R)-12 and (S,S)-12 in the ratio 60:40. Acid hydrolysis of the diastereomerically pure sulfinamides followed by monobenzylation yielded the enantiomerically pure benzylamines (R)-1, (S)-1, (R)-2 and (S)-2. The enantiomeric purity of the products was proven by chiral HPLC and the absolute configuration by CD-spectroscopy. Generally, benzylamines with (R)-configuration show higher antiplasmodial activity than their corresponding (S)-configured enantiomers. Phenol (R)-2 represents a very potent lead against P. falciparum, with an IC₅₀ value of only 0.026 μM against the NF54 strain. The very high eudismic ratio of 34 indicates the enantioselective interaction of phenol (R)-2 with a particular target protein of P. falciparum.

Full text of DOI:10.1039/c3ob41583j

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Enantioselective synthesis of encecaline-derived potent antimalarial agents
a)
a)
b)
c)
*a)
Dipak Harel, Dirk Schepmann, Reto Brun, Thomas J. Schmidt, Bernhard Wünsch
a
Institut für Pharmazeutische und Medizinische Chemie der Westfälischen WilhelmsꢀUniversität
Münster, Corrensstraße 48, Dꢀ48149 Münster, Germany
Tel.: +49ꢀ251ꢀ8333311; Fax: +49ꢀ251ꢀ8332144; Eꢀmail: wuensch@uniꢀmuenster.de
b
Swiss Tropical and Public Health Institute (Swiss TPH), Socinstraße 57, CHꢀ4002 Basel,
Switzerland
c
Institut für Pharmazeutische Biologie und Phytochemie der Westfälischen Wilhelmsꢀ
Universität Münster, Corrensstraße 48, Dꢀ48149 Münster, Germany
Abstract
The high antiplasmodial activity of racemic benzylamines racꢀ1 and racꢀ2 stimulated the
synthesis of pure enantiomers. Ellman’s chiral sulfinamides (S)ꢀ6 and (R)ꢀ6 were used as chiral
auxiliaries. Condensation of prochiral ketone 5 with enantiomerically pure sulfinamides (S)ꢀ6
and (R)ꢀ6 and subsequent NaBH reduction provided predominantly unlike configured
4
diastereomers (S,R)ꢀ8 and (R,S)ꢀ8 (ratio unlike-8:like-8 = 90 : 10). The same transformation of
the phenol 4 led to the diastereomeric sulfinamides (S,R)ꢀ12 and (S,S)ꢀ12 in the ratio 60 : 40.
Acid hydrolysis of the diastereomerically pure sulfinamides followed by monobenzylation
yielded the enantiomerically pure benzylamines (R)ꢀ1, (S)ꢀ1, (R)ꢀ2 and (S)ꢀ2. The enantiomeric
purity of the products was proven by chiral HPLC and the absolute configuration by CDꢀ

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spectroscopy. Generally, benzylamines with (R)ꢀconfiguration show higher antiplasmodial
activity than their corresponding (S)ꢀconfigured enantiomers. The phenol (R)ꢀ2 represents a very
potent lead against P. falciparum, with an IC value of only 0.026 ꢁM against the NF54 strain.
5
0
The very high eudismic ratio of 34 indicates the enantioselective interaction of phenol (Rꢀ2 with
a particular target protein of P. falciparum.
Key words: Malaria; antiplasmodial activity; enantioselective bioactivity; Ellman’s chiral
sufinamide; stereoselective synthesis; enantiomerically pure amines; encecalineꢀderived
antimalarial agents
Introduction
Malaria is one of the most significant public health problem in the world. There are about 250
million new cases every year and nearly 1 million people, mostly children less than 5 years old,
die due to the inaccessibility of proper treatment. The disease occurs mainly in tropical and
subtropical climates and represents a serious problem in South Asia and Africa, where it is
1
ꢀ3
responsible for one in every five childhood deaths. Malaria is caused by the parasites
Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and
Plasmodium knowlesi, among which P. falciparum is responsible for the most serious form,
Malaria tropica. The rapid development of multiresistant P. falciparum strains often renders the
4
therapy difficult. Many of the common antimalarial drugs, i.e. quinine, chloroquine, primaquine,
atovaquone, and artemisinine suffer from parasitological resistance developing in many regions

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5
ꢀ7
of the world, especially in South Asia and Africa. Therefore, there is an urgent need for the
development of new antimalarial drugs to ensure the availability of an efficient antimalarial
treatment.
Recently, our antiprotozoal activity studies of chromenes derived from encecalol angelate
resulted in 7ꢀmethoxychromene rac-1 showing high in vitro activity against P. falciparum (IC50
8
=
0.64 ꢁM). Conversion of the methyl ether rac-1 into the phenol rac-2 increased the
antiplasmodial activity dramatically. With an IC ꢀvalue of 0.02 ꢁM the phenol rac-2 was found
5
0
tenfold more potent than the reference compound chloroquine (IC = 0.263 ꢁM) when tested
5
0
8
against the chloroquineꢀresistant K1 strain. Both methyl ether rac-1 and phenol rac-2 were
tested as racemic mixtures. The high antiplasmodial activity of rac-1 and rac-2 encouraged us to
study the pharmacological properties of the pure enantiomers.
Figure 1: Chromene based methyl ether rac-1 and phenol rac-2 with high antimalarial activity.
Herein the synthesis and in vitro activity against P. falciparum of enantiomerically pure methyl
ethers (R)ꢀ1 and (S)ꢀ1 and phenols (R)ꢀ2 and (S)ꢀ2 are reported.

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Chemistry
Synthesis
Scheme 1
Synthesis of prochiral ketones 4 and 5 (encecalin).
Reagents and reaction conditions: (a) 3 steps (formation of chromane, acetylation,
9
9
dehydrogenation). (b) CH I, K CO , DMF, rt.
3
2
3
In order to synthesize the enantiomerically pure methyl ethers 1 and phenols 2 the prochiral
ketones 4 and 5 (= natural product encecalin) were synthesized starting with resorcinol (3).
(Scheme 1) The oꢀhydroxyketone 4 was obtained in a three step synthesis comprising formation
of the chromane ring system by reaction of resorcinol (3) with 2ꢀmethylbutꢀ3ꢀenꢀ2ꢀol, acetylation
and dehydrogenation with DDQ. Methylation of phenol 4 with methyl iodide provided the
9
natural product encecalin 5.

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Scheme 2
Synthesis of the four stereoisomers of sulfinamide 8.
Reagents and reaction conditions: (a) Ti(OEt) , THF, reflux. (b) NaBH , THF, 0 C.
o
4
4
For the synthesis of enantiomerically pure benzylamines with methoxy group the chiral auxiliary
1
0,11
approach using Ellman’s chiral sulfinamides (S)ꢀ6 and (R)ꢀ6
was pursued. (Scheme 2) The
prochiral ketone 5 was condensed with (S)ꢀconfigured sulfinamide (S)ꢀ6 and Ti(OEt) to afford
4
the sulfinylimine (S)ꢀ7. Without purification the sulfinylimine (S)ꢀ7 was reduced with NaBH to
4
provide the diastereomeric sulfinamides (S,R)ꢀ8 and (S,S)ꢀ8 in the ratio 90 : 10. Chromatographic
separation of the diastereomeric mixture led to the major diastereomer (S,R)ꢀ8 in 57 % and the
minor diastereomer (S,S)ꢀ8 in 5 % yields, respectively. Due to the high diastereoselectivity of
90:10 in the reduction step, only small amounts of the minor diastereomer (S,S)ꢀ8 were obtained.

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In order to synthesize the enantiomers (R,S)ꢀ8 and (R,R)ꢀ8 the ketone 5 was condensed with the
enantiomeric (R)ꢀconfigured sulfinamide (R)ꢀ6 and the resulting sulfinylimine (R)ꢀ7 was reduced
with NaBH to yield the diastereomeric sulfinamides (R,S)ꢀ8 and (R,R)ꢀ8 in the ratio 90 : 10.
4
Flash chromatographic separation provided the pure diastereomers (R,S)ꢀ8 and (R,R)ꢀ8 in 55 %
and 2.2 % yields, respectively.
Scheme 3
(
S,R)-8
(a)
NH2
NR
(b)
H CO
O
3
H CO
O
3
(
R)-9
(
R)-1: R = H
(c)
(
R)-10: R = CH3
Synthesis of enantiomerically pure amines with methoxy group.
Reagents and reaction condition: (a) HCl, MeOH, THF, rt. (b) PhCHO, NaBH(OAc) , THF, rt.
3
(
c) HCHO, NaBH(OAc) , THF, rt. The enantiomers (S)ꢀ1, (S)ꢀ9 and (S)ꢀ10, were prepared in the
3
same manner starting with (R,S)ꢀ8.
Hydrolysis of the enantiomerically pure major sulfinamide (S,R)ꢀ8 with HCl in methanol at room
temperature led to the enantiomerically pure primary amine (R)ꢀ9. (Scheme 3) Monobenzylation
of the primary amine (R)ꢀ9 with one equivalent of benzaldehyde and NaBH(OAc) in THF
3
afforded the benzylamine (R)ꢀ1, which was converted into the tertiary amine (R)ꢀ10, upon

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reaction with formaldehyde and NaBH(OAc) . Analogous reactions performed with the
3
enantiomer (R,S)ꢀ8 yielded the enantiomers (S)ꢀ1, (S)ꢀ9 and (S)ꢀ10.
Scheme 4
Synthesis of enantiomerically pure phenols 2.
o
Reagents and reaction condition: (a) Ti(OEt) , THF, reflux. (b) NaBH , THF, 0 C. (c) HCl,
4
4
o
Et O, 0 C. (d) PhCHO, NaBH(OAc) , THF, rt.
2
3
The enantiomers of the phenol 2 were synthesized starting from the prochiral ketone 4. (Scheme
) Condensation of 4 with (S)ꢀconfigured sulfinamide (S)ꢀ6 and Ti(OEt) led to the sulfinylimine
4
4

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(
S)ꢀ11, which was reduced with NaBH to give the diastereomeric sulfinamides (S,R)ꢀ12 and
4
(S,S)ꢀ12 in the ratio 60 : 40. Both diastereomers (S,R)ꢀ12 and (S,S)ꢀ12 were isolated in 28 % and
27 % yields, respectively. An attempt to cleave the sulfinamides (S,R)ꢀ12 and (S,S)ꢀ12 with
methanolic HCl similar to the cleavage of the sulfonamides 8, resulted in rapid decomposition of
o
the starting material. However, performing the sulfinamide cleavage with HCl in Et O at 0 C
2
resulted in the enantiomerically pure primary amines (R)ꢀ13 and (S)ꢀ13. Benzylation of primary
amines (R)ꢀ13 and (S)ꢀ13 with one equivalent of benzaldehyde and NaBH(OAc) in THF
3
provided the monobenzylamines (R)ꢀ2 and (S)ꢀ2 with a phenolic hydroxy moiety, respectively.
Enantiomeric purity
Figure 2: Chiral HPLC chromatograms of pure enantiomers (R)ꢀ2 and (S)ꢀ2 using Chiralpak ADꢀ
H column. Isohexane : methanol = 95 : 5, flow rate: 1 mL/min. injection: 5 ꢂL. A: HPLC
analysis of (R)ꢀ2, t = 4.47 min. B: HPLC analysis of (S)ꢀ2, t = 5.32 min.
R
R
The enantiomeric purity of the synthesized phenols (R)-2 and (S)-2 was determined by chiral
HPLC analysis using a Chiralpak ADꢀH column. (Figure 2) In order to develop a separation

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method, an artificial mixture (1:1) of both enantiomers (R)-2 and (S)-2 was prepared. The
enantiomers were baseline separated by an isocratic elution with isohexane : methanol = 95 : 5.
According to the HPLC analysis the ratio of enantiomers (R)ꢀ2 : (S)ꢀ2 is 98.6 : 1.4 (97.2 %ee) for
(R)ꢀ2 (Figure 2A) and 3.3 : 96.7 (93.4 %ee) for (S)ꢀ2 (Figure 2B).
Absolute configuration of benzylamines
The absolute configuration of the synthesized benzylamines (R)ꢀ1, (S)ꢀ1, (R)ꢀ2 and (S)ꢀ2 was
determined by circular dichroism (CD) spectroscopy. For this purpose the CD spectra of the
enantiomers (R)ꢀ1, (S)ꢀ1, (R)ꢀ2, and (S)ꢀ2 were compared with the CD spectra of the structurally
related enantiomerically pure (R)ꢀ and (S)ꢀconfigured 1ꢀphenylethylamines (R)ꢀ14 and (S)ꢀ14
whose structure around the center of chirality is identical to that of the chromenylethylamines 1
and 2.
The CDꢀspectrum of (R)ꢀconfigured 1ꢀphenylethylamine (R)ꢀ14 displays Cotton effects (CEs)
1
1
attributable to the typical benzene absorption bands L , L and E bands at around 260, 220
b
a
1u
and 200 nm with negative, negative and positive signs, respectively, which are in accordance
1
2
with literature and opposite in the enantiomer (S)ꢀ14 (Figure 3, right top panel). Comparison of
the CEs observed in the CD spectra of the pure enantiomers of 1 and 2 with those of (R)ꢀ and (S)ꢀ
1
1
4 allowed assignment of the absolute configuration on the basis of the CEs of the L and E
b
1u
bands occurring around 300 nm and 230 nm. These bands showed negative and positive signs,
respectively, in case of the (R)ꢀ and the opposite behavior in case of the (S)ꢀenantiomer (Figure
2, left panels, spectra of the phenols (R)ꢀ2 and (S)ꢀ2). Additionally, CD spectra of the
enantiomeric sulfinamides (S,R)ꢀ8 and (R,S)ꢀ8 as well as of the diastereomeric sulfinamides

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(S,R)ꢀ12 and (S,S)ꢀ12 were recorded. Here the first stereodescriptor describes the configuration
of the sulfonamide substructure and the second one relates to the configuration of the
arylethylamine stereocenter. The structure of the corresponding CD spectra is determined by the
center of chirality adjacent to the chromophoric system defined by the second stereodescriptor.
Therefore, the CD spectra of (S,R)ꢀ8 and (S,R)ꢀ12 correspond to the CD spectra of (R)ꢀ
configured 1ꢀphenylethylamine (R)ꢀ14 and (R)ꢀconfigured chromenylethylamines (R)ꢀ1 and (R)ꢀ
2
. Analogously, the CDꢀspectra of (R,S)ꢀ8 and (S,S)ꢀ12 show similar structures as the CD spectra
of (S)ꢀconfigured 1ꢀphenylethylamine (S)ꢀ14 and (S)ꢀconfigured chromenylethylamines (S)ꢀ1 and
S)ꢀ2.
(
Figure 3: CD and UV absorption spectra of enantiomerically pure phenols (R)ꢀ2 and (S)ꢀ2 (left
panels, blue and red, respectively) compared to the reference compounds (R)ꢀ14 and (S)ꢀ14 (right
panels, blue and red, respectively) (solvent: acetonitrile, concentration: 0.25 mg/mL for 2, 0.1
mg/mL for 14; insets in the CD panels: 1 mg/mL for all compounds).

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Antiplasmodial and antitrypanosomal activity of enantiomerically pure chromenes
The antiplasmodial and antitrypanosomal activity of the enantiomerically pure secondary and
tertiary amines (R)ꢀ1, (S)ꢀ1, (R)ꢀ2, (S)ꢀ2, (R)ꢀ10, and (S)ꢀ10 as well as one sulfinamide couple
(S,R)ꢀ8 and (R,S)ꢀ8 was investigated in vitro. Intraerythrocytic stages of P. falciparum (Pfc) and
bloodstream forms of T. brucei rhodesiense (Tbr) were used in the antiplasmodial and
antitrypanosomal assay, respectively. Moreover, the cytotoxicity against L6 rat skeletal
myoblasts was recorded, which allowed calculation of selectivity indices for the tested
1
3
compounds. In Table 1 the antiprotozoal activity data of the enantiomerically pure test
compounds are compared with the activity of the corresponding racemic mixtures as well as
reference compounds.
The antiꢀPfc and antiꢀTbr activity of enantiomerically pure sulfinamides 8 and benzylamines 1, 2
indicate that the amines are more potent than the sulfinamides. Obviously a basic amino group is
required for antiꢀPfc and antiꢀTbr activity. The benzylamines (R)ꢀ1 and (S)ꢀ1 showed high
antiplasmodial activity, the (R)-enantiomer (R)ꢀ1 being three times more active (IC = 0.28 ꢂM)
5
0
than (S)ꢀ1. The activity of (R)ꢀ1 against the K1 strain of Pfc is in the same range as that of the
positive control, chloroquine (IC = 0.26 ꢂM). The Pfc selectivity of (R)ꢀ1 is also significantly
5
0
greater than that of (S)ꢀ1, since the cytotoxicity of both enantiomers differs only slightly.
Concerning their antiꢀTbr activity, (R)ꢀ1 and (S)ꢀ1 show an opposite behavior than observed for
the antiplasmodial activity, the (S)ꢀenantiomer (S)ꢀ1 being more potent than (R)ꢀ1. The
enantiomerically pure tertiary amines (R)ꢀ10 and (S)ꢀ10 are less active compared to nonꢀ
methylated secondary amines (R)ꢀ1 and (S)ꢀ1.

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Table 1: Antiprotozoal activity of chromenes and reference compounds against P. falciparum
and T. brucei rhodesiense, as well as cytotoxicity against rat skeletal myoblasts (L6 cells) with
selectivity indices (SI) for Pfc and Tbr.
IC (ꢂM)
5
0
SI
SI
(
Pfc) (Tbr)
cytotoxicity
L6 cells
21
1
compd.
NR2
R config.
Pfc
Tbr
8
a
a
a
a
rac-1
NHBn CH rac.
0.64
0.28
0.75
0.02
2.38
2.28
1.53
12.4
2.17
17.2
67.0
46.3
16.0
9.88
33
59
22
8.8
7.3
3
(
R)ꢀ1
NHBn CH (R)
16.7
3
(
S)ꢀ1
NHBn CH3 (S)
16.2
10.6
8.8
8
rac-2
R)ꢀ2
S)ꢀ2
NHBn
NHBn
NHBn
H rac.
109
5450
723
202
58
b
b
(
H
H
(R)
(S)
0.026
0.884
18.8
8.7
(
179
10.4
2.1
+
a
a
a
a
a
(
S,R)ꢀ8
R,S)ꢀ8
NHS(=0) BnCH (S,R)
2.46
15.7
1.24
1.28
144
3
+
(
NHS(=0) BnCH (R,S)
99.1
6.3
37
2.1
3
(
R)ꢀ10
N(CH )Bn CH (R)
46.3
2.9
3
3
(
S)ꢀ10
N(CH )Bn CH (S)
45.4
35
4.6
3
3
0.26
chloroquine
ꢀ
b
0
.009
melarsoprol
ꢀ
ꢀ
0.005
ꢀ
podophyllotoxin
0.010
a
b
strain K1 strain NF54
The phenolic congener of the methyl ether (R)ꢀ1, (R)ꢀ2, was found to be the most potent
antimalarial compounds within the series. It was found to be much more potent than its (S)ꢀ
configured enantiomer with an eudismic ratio for the antiplasmodial activity of 34. This very
high enantioselective activity indicates the stereoselective interaction of (R)ꢀ2 with a particular

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target of P. falciparum. However, the mode of action of these novel potential antimalarial drugs
remains to be elucidated.
The free phenolic group of this novel type of compounds appears to be crucial for high
antiplasmodial activity, since the phenol (R)ꢀ2 is about tenfold more active than the methyl ether
(R)ꢀ1. Additionally the phenolic structural element is also responsible for the high selectivity
index, which is increased from 59 for the methyl ether (R)ꢀ1 to 723 for the phenol (R)ꢀ2.
In contrast to the antiplasmodial activity the antitrypanosomal activity of the enantiomerically
pure methyl ethers and phenols is rather low. This result also points to a specific antiplasmodial
rather than an unspecific toxic effect.
Conclusion
Ellman’s chiral sulfinamide allowed the stereoselective synthesis of enantiomerically pure
encecaline derived amines. The finding that antiplasmodial activity of (R)ꢀconfigured phenol (R)ꢀ
2
is more than 30ꢀfold higher than the antiplasmodial activity of (S)ꢀconfigured phenol (S)ꢀ2
indicates specific and stereoselective interactions of (R)ꢀ2 with a clearly defined molecular
target, which are responsible for the observed biological activity. Search for the hitherto
unknown target and evaluation of the in vivo activity of this new and very promising class of
antiplasmodial agents is stimulated in particular, since already the racemic mixture of phenol
racꢀ2 was about 10fold more potent against the chloroquineꢀresistant K1ꢀstrain than chloroquine.

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Experimental Section
General, chemistry
Unless otherwise mentioned, THF was dried with sodium/benzophenone and was freshly
distilled before use. Thin layer chromatography (tlc): Silica gel 60 F254 plates (Merck). Flash
chromatography (fc): Silica gel 60, 40–64 ꢁm (Merck); parentheses include: diameter of the
column, length of column, fraction size, eluent, Rf value. Melting point: Melting point apparatus
SMP 3 (Stuart Scientific), uncorrected. IR: IR spectrophotometer 480Plus FTꢀATRꢀIR (Jasco).
1H NMR (400 MHz), 13C NMR (100 MHz): Mercury plus 400 spectrometer (Varian);  in ppm
related to tetramethylsilane; coupling constants are given with 0.5 Hz resolution. Where
necessary, the assignment of the signals in the 1H NMR and 13C NMR spectra was performed
using 1Hꢀ1H and 1Hꢀ13C COSEY NMR spectra. MS: EI = electron impact, ESI = electro spray
ionization: MicroTof (Bruker Daltronics, Bremen), Calibration with sodium formate clusters
before measurement. HPLC method for determination of the product purity: Merck Hitachi
Equipment; UV detector: Lꢀ7400; autosampler: Lꢀ7200; pump: Lꢀ7100; degasser: Lꢀ7614;
Method: column: LiChrospher® 60 RPꢀselect B (5 ꢁm), 250ꢀ4 mm cartridge; flow rate: 1.00
mL/min; injection volume: 5.0 ꢁL; detection at λ = 210 nm; solvents: A: water with 0.05 % (v/v)
trifluoroacetic acid; B: acetonitrile with 0.05 % (v/v) trifluoroacetic acid: gradient elution: (A
%): 0ꢀ4 min: 90 % , 4ꢀ29 min: gradient from 90 % to 0 %, 29ꢀ31 min: 0 %, 31ꢀ31.5 min: gradient
from 0 % to 90 %, 31.5ꢀ40 min: 90 %. CD spectra were recorded on a Jasco Jꢀ815
spectropolarimeter in CH OH, H O and CH CN at a sample concentration of 0.1mg/mL using a
3
2
3
0.1 cm quartz cuvette. Chiral HPLC: Equipment; Pump: Lꢀ6200; injection: Rheodyne 7125i;
DiodeꢀArrayꢀDetector: Lꢀ7455; data acquisition: HSM software (all except Rheodyne 7125i

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®
Merck Hitachi); Column: Chiralpak ADꢀH (5 ꢂM, 250ꢀ4.6 mm); Injection: volume: 5.0 ꢂL;
Detection: wavelength: 223 nm; Solvent: isohexane : MeOH = 90 : 10; Flow rate: 1.0 mL/min.
General procedure A: Synthesis of enantiomerically pure sulfinamides 8 and 12
9
9
Under N phenol 4 or methyl ether 5 (1 equiv.) was dissolved in dry THF (10 mL). The
2
enantiomerically pure 2ꢀmethylpropaneꢀ2ꢀsulfinamide (S)ꢀ6 or (R)ꢀ6 (1.2 equiv.) and Ti(OEt)4
(1.5 equiv.) were added and the reaction mixture was heated to reflux for 12 h. The reaction
o
mixture was cooled to 0 C. Then NaBH (1.6 equiv.) was added and the reaction mixture was
4
stirred at rt for 3 h. Water was added and the reaction mixture was extracted with ethyl acetate (3
x 150 mL). The organic layer was dried (Na SO ) and concentrated in vacuum. The formed
2
4
diastereomers were separated by fc.
(S)-N-[(R)-1-(7-Methoxy-2,2-dimethyl-2H-chromen-6-yl)ethyl]-2-methylpropane-2-
sulfinamide ((S,R)-8) and (S)-N-[(S)-1-(7-methoxy-2,2-dimethyl-2H-chromen-6-yl)ethyl]-2-
methylpropane-2-sulfinamide ((S,S)-8)
According to general procedure A methyl ether 5 (250 mg, 1.06 mmol) was reacted with (S)ꢀ(ꢀ)ꢀ
2
ꢀmethylpropaneꢀ2ꢀsulfinamide ((S)ꢀ6, 143 mg, 1.30 mmol) and NaBH (61 mg, 1.62 mmol).
4
The diastereomeric mixture was purified by fc (petroleum ether/EtOAc = 70/30, ø = 2.5 cm, h =
5 cm,).
S,R)ꢀ8 (R = 0.27): Colorless oil, yield, 210 mg, (57 %). Purity: 98.2 %, (t = 18.7 min). [α]
1
23
(
=
D
f
R
+
38.2 (c = 0.10, CHCl ). Exact mass (ESI): m/z = calcd. for (C H NO S)H 338.1712, found
3 18 27 3
1
3
38.1716. H NMR (CDCl ): δ (ppm) = 1.14 (s, 9H, 3xCH ), 1.36 (s, 6H, 2xCH ), 1.37 (d, J =
3 3 3
6
.7 Hz, 3H, HNCHCH ), 3.61 (d, J = 4.8 Hz, 1H, tꢀbutySONH), 3.72 (s, 3H, OCH ), 4.66 (qd, J
3
3

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=
6.7, 4.8 Hz, HNCHCH ), 5.39 (d, J = 9.8 Hz, 1H, 3ꢀCH), 6.18 (d, J = 9.8 Hz, 1H, 4ꢀCH), 6.28
3
1
3
(
s, 1H, 8ꢀCH), 6.82 (s, 1H, 5ꢀCH). C NMR (CDCl ): δ (ppm) = 21.7 (1C, HNCHCH ), 22.6
3 3
(
3C, 3xCH ), 28.2, 28.1 (2C, CH ), 48.9 (1C, NHCHCH ), 55.3 (1C, NHSOC(CH ) ), 55.5 (1C,
3
3
3
3 3
OCH ), 76.5 (1C, Cꢀ2), 99.8 (1C, Cꢀ8), 113.7 (1C, Cꢀ4a), 121.8 (1C, Cꢀ4), 124.3, 124.5(2C, Cꢀ3,
3
Cꢀ5), 127.7 (1C, Cꢀ6), 153.3, 157.3 (2C, Cꢀ7, Cꢀ8a).
(
S,S)ꢀ8 (R = 0.25): Colorless oil, yield, 18 mg (5 %), Purity: 96.1 %, (t = 19.2 min). Exact mass
f
R
1
(
ESI): m/z = calcd. for (C H NO S)H 338.1712, found 338.1714. H NMR (CDCl ): δ (ppm) =
18 27 3 3
1
.13 (s, 9H, 3xCH ), 1.37 (s, 6H, 2xCH ), 1.38 (d, J = 6.7 Hz, 3H, HNCHCH ), 3.62 (d, J = 4.8
3 3 3
Hz, 1H, tꢀbutySONH), 3.71 (s, 3H, OCH ), 4.67 (qd, J = 6.7, 4.8 Hz, HNCHCH ), 5.38 (d, J =
3
3
9.8 Hz, 1H, 3ꢀCH), 6.17 (d, J = 9.8 Hz, 1H, 4ꢀCH), 6.29 (s, 1H, 8ꢀCH), 6.80 (s, 1H, 5ꢀCH).
(R)-N-[(S)-1-(7-Methoxy-2,2-dimethyl-2H-chromen-6-yl)ethyl]-2-methylpropane-2-
sulfinamide (R,S)-8 and (R)-N-[(R)-1-(7-methoxy-2,2-dimethyl-2H-chromen-6-yl)ethyl]-2-
methylpropane-2-sulfinamide (R,R)-8
According to general procedure A methyl ether 5 (250 mg, 1.06 mmol) was reacted with (R)ꢀ(+)ꢀ
2
ꢀmethylpropaneꢀ2ꢀsulfinamide ((R)ꢀ6, 143 mg, 1.30 mmol) and NaBH (61 mg, 1.62 mmol).
4
The diastereomeric mixture was purified by fc (petroleum ether/EtOAc = 70/30, ø = 2.5 cm, h =
5 cm,).
R,S)ꢀ8 (R = 0.28): Colorless oil, yield, 200 mg, (55 %). Purity: 96.5 %, (t = 17.6 min). [α]
1
23
(
=
D
f
R
ꢀ
38.5 (c = 0.10, CHCl ). Exact mass (ESI): m/z = calcd. for (C H NO S)H 338.1712, found
3 18 27 3
1
3
6
=
38.1718. H NMR (CDCl ): δ (ppm) = 1.14 (s, 9H, 3xCH ), 1.36 (s, 6H, 2xCH ), 1.37 (d, J =
3 3 3
.7 Hz, 3H, HNCHCH ), 3.59 (d, J = 4.8 Hz, 1H, tꢀbutySONH), 3.72 (s, 3H, OCH ), 4.69 (qd, J
3
3
6.7, 4.8 Hz, HNCHCH ), 5.39 (d, J = 9.8 Hz, 1H, 3ꢀCH), 6.18 (d, J = 9.8 Hz, 1H, 4ꢀCH), 6.28
3

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17
1
3
(
s, 1H, 8ꢀCH), 6.81 (s, 1H, 5ꢀCH). C NMR (CDCl ): δ (ppm) = 21.7 (1C, HNCHCH ), 22.6
3 3
(
3C, 3xCH ), 28.0, 28.1 (2C, CH ), 48.7 (1C, NHCHCH ), 55.3 (1C, NHSOC(CH ) ), 55.5 (1C,
3
3
3
3 3
OCH ), 76.5 (1C, Cꢀ2), 99.8 (1C, Cꢀ8), 113.7 (1C, Cꢀ4a), 121.8 (1C, Cꢀ4), 124.3, 124.5(2C, Cꢀ3,
3
Cꢀ5), 127.7 (1C, Cꢀ6), 153.3, 157.3 (2C, Cꢀ7, Cꢀ8a).
1
(
R,R)ꢀ8 (R = 0.26): Colorless oil, yield, 8 mg (2.2 %). H NMR (CDCl ): δ (ppm) = 1.13 (s, 9H,
f
3
3
xCH ), 1.37 (s, 6H, 2xCH ), 1.37 (d, J = 6.7 Hz, 3H, HNCHCH ), 3.59 (d, J = 4.8 Hz, 1H, tꢀ
3 3 3
butySONH), 3.72 (s, 3H, OCH ), 4.57 (qd, J = 6.7, 4.8 Hz, HNCHCH ), 5.36 (d, J = 9.8 Hz, 1H,
3
3
3ꢀCH), 6.17 (d, J = 9.8 Hz, 1H, 4ꢀCH), 6.26 (s, 1H, 8ꢀCH), 6.78 (s, 1H, 5ꢀCH).
(R)-N-Benzyl-1-(7-methoxy-2,2-dimethyl-2H-chromen-6-yl)ethanamine ((R)-1)
Under N sulfinamide (S,R)ꢀ8 (200 mg, 0.59 mmol) was dissolved in Et O (5 mL), 2.0 M
2
2
MeOH:HCl (5 mL) was added and the reaction mixture was stirred for 3 h. The reaction mixture
was concentrated in vacuum and the residue ((R)ꢀ9) was dissolved in dry THF (5 mL).
Benzaldehyde (63 mg, 0.59 mmol) and NaBH(OAc) (186 mg, 0.89 mmol) were added and the
3
reaction mixture was stirred at rt for 5 h. Water was added and the mixture was extracted with
EtOAc (3 x 100 mL). The organic layer was dried (Na SO ), concentrated in vacuum and the
2
4
residue was purified by fc (dichloromethane/MeOH = 95/5, ø = 2.5 cm, h = 15 cm, R = 0.26).
f
23
Colorless oil, yield, 70 mg, (37 %). Purity: 97 % (t = 19.2 min). [α]
= +40.6 (c = 0.10,
D
R
1
CHCl ). Exact mass (ESI): m/z = calcd. for (C H NO )H 324.1885, found 324.11892. H NMR
3
21 25
2
(
CDCl ): δ (ppm) = 1.27 (d, J = 6.7 Hz, 3H, HNCHCH ), 1.35 (s, 6H, 2xCH ), 1.94 (bs, 1H,
3
3
3
NH), 3.53 (d, J = 13.0 Hz, 1H, PhCH NH), 3.58 (d, J = 13.0 Hz, 1H, PhCH NH), 3.69 (s, 3H,
2
2
OCH ), 3.97 (q, J = 6.7 Hz, HNCHCH ), 5.38 (d, J = 9.8 Hz, 1H, 3ꢀCH), 6.21 (d, J = 9.8 Hz, 1H,
3
3
1
3
4
ꢀCH), 6.29 (s, 1H, 8ꢀCH), 6.89 (s, 1H, 5ꢀCH), 7.29 – 7.10 (m, 5H, Ph). C NMR (CDCl ): δ
3

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18
(
ppm) = 22.3 (1C, HNCHCH ), 28.1 (2C, CH ), 51.6 (1C, HNCHCH , 51.8 (1C, HNCH Ph),
3 3 3 2
5
1
1
5.4 (1C, OCH ), 76.4 (1C, Cꢀ2), 99.8 (1C, Cꢀ8), 113.8 (1C, Cꢀ4a), 122.1 (1C, Cꢀ4), 125.0,
3
25.2 (2C, Cꢀ3, Cꢀ5), 126.7 (1C, Cꢀ6), 127.5 (1C, Ph), 128.2 (2C, oꢀPh), 128.3 (2C, mꢀPh),
40.8 (1C, Ph), 152.7, 157.8 (2C, Cꢀ7, Cꢀ8a).
(S)-N-Benzyl-1-(7-methoxy-2,2-dimethyl-2H-chromen-6-yl)ethanamine ((S)-1)
Under N sulfinamide (R,S)ꢀ8 (200 mg, 0.59 mmol) was dissolved in Et O (5 mL), 2.0 M
2
2
MeOH:HCl (5 mL) was added and the reaction mixture was stirred for 3 h. The reaction mixture
was concentrated in vacuum and the residue ((S)ꢀ9) was dissolved in dry THF (5 mL).
Benzaldehyde (63 mg, 0.59 mmol) and NaBH(OAc) (186 mg, 0.89 mmol) were added and the
3
reaction mixture was stirred at rt for 5 h. Water was added to reaction mixture and extracted with
EtOAc (3x100 mL). The organic layer was dried (Na SO ), and concentrated in vacuum and the
2
4
residue was purified by fc (dichloromethane/MeOH = 95/5, ø = 2.5 cm, h = 15 cm, R = 0.27).
f
23
Colorless oil, yield, 65 mg, (34 %). Purity: 97 % (t = 19.5 min). [α]
= ꢀ40.9 (c = 0.10,
D
R
1
CHCl ). Exact mass (ESI): m/z = calcd. for (C H NO )H 324.1885, found 324.1891. H NMR
3
21 25
2
(
CDCl ): δ (ppm) = 1.27 (d, J = 6.7 Hz, 3H, NHCHCH ), 1.36 (s, 6H, 2xCH ), 1.77 (bs, 1H,
3
3
3
NH), 3.53 (d, J = 13.0 Hz, 1H, PhCH NH), 3.59 (d, J = 13.0 Hz, 1H, PhCH NH), 3.70 (s, 3H,
2
2
OCH ), 3.98 (q, J = 6.7 Hz, HNCHCH ), 5.39 (d, J = 9.8 Hz, 1H, 3ꢀCH), 6.21 (d, J = 9.8 Hz, 1H,
3
3
1
3
4
ꢀCH), 6.29 (s, 1H, 8ꢀCH), 6.90 (s, 1H, 5ꢀCH), 7.18 – 7.26 (m, 5H, Ph). C NMR (CDCl ): δ
3
(
ppm) = 22.3 (1C, HNCHCH ), 28.1 (2C, CH ), 51.6 (1C, HNCHCH ), 51.8 (1C, HNCH Ph),
3 3 3 2
5
1
1
5.3 (1C, OCH ), 76.4 (1C, Cꢀ2), 99.5 (1C, Cꢀ8), 113.7 (1C, Cꢀ4a), 122.0 (1C, Cꢀ4), 125.0,
3
25.1 (2C, Cꢀ3, Cꢀ5), 126.7 (1C, Cꢀ6), 127.5 (1C, Ph), 128.1 (2C, oꢀPh), 128.3 (2C, mꢀPh),
40.9 (1C, Ph) 152.6, 157.9 (2C, Cꢀ7, Cꢀ8a).

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(R)-N-Benzyl-1-(7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-N-methylethanamine ((R)-10)
Benzylamine (R)ꢀ1 (50 mg, 0.15 mmol), was dissolved in THF (5 mL), formaline (5.0 mg, 0.17
mmol) and NaBH(OAc) (48 mg, 0.23 mmol) were added and the reaction mixture was stirred
3
for 2 h at rt. Water was added and reaction mixture was extracted with EtOAc (3x25 mL). The
organic layer was dried (Na SO ), concentrated in vacuum and the residue was purified by fc
2
4
(
dichloromethane/MeOH = 90/10, ø = 2.5 cm, h = 15 cm, R = 0.24). Pale yellow oil, yield 35
f
27
D
mg, (69 %). Purity: 96 %, (t = 18.7 min.). [α] = +42.1 (c = 0.10, CHCl ). Exact mass (ESI):
R
3
1
m/z = calcd. for (C H NO )H 338.2042, found 338.2047. H NMR (CDCl ): δ (ppm) = 1.34 (d,
2
2
27
2
3
J = 6.7 Hz, 3H, NCHCH ), 1.43 (s, 6H, 2xCH ), 2.12 (s, 3H, PhCH NCH ), 3.26 (d, J = 13.0 Hz,
3
3
2
3
1
H, PhCH NCH ), 3.61 (d, J = 13.0 Hz, 1H, PhCH NCH ), 3.77 (s, 3H, OCH ), 4.01 (q, J = 6.8
2 3 2 3 3
Hz, NCHCH ), 5.46 (d, J = 9.8 Hz, 1H, 3ꢀCH), 6.31 (d, J = 9.8 Hz, 1H, 4ꢀCH), 6.36 (s, 1H, 8ꢀ
3
13
CH), 7.11 (s, 1H, 5ꢀCH), 7.22 – 7.37 (m, 5H, Ph). C NMR (CDCl ): δ (ppm) = 19.8 (1C,
3
NCHCH ), 28.3, 28.4 (2C, CH ), 38.7 (1C, PhCH NCH ) 55.4 (1C, NCHCH ), 55.7 (1C,
3
3
2
3
3
PhCH NCH ), 59.5 (1C, OCH ), 76.5 (1C, Cꢀ2), 99.7 (1C, Cꢀ8), 113.9 (1C, Cꢀ4a), 122.5 (1C, Cꢀ
2
3
3
4), 124.8, 125.8 (2C, Cꢀ3, Cꢀ5), 126.3 (1C, Ph), 126.8 (1C, Cꢀ6), 128.3 (2C, oꢀPh), 129.1 (2C,
mꢀPh), 140.6 (1C, Ph) 152.8, 158.1 (2C, Cꢀ7, Cꢀ8a).
(S)-N-Benzyl-1-(7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-N-methylethanamine ((S)-10)
Sulfinamide (S)ꢀ1 (50 mg, 0.15 mmol), was dissolved in THF (5 mL), formaline (5.0 mg, 0.17
mmol) and NaBH(OAc) (48 mg, 0.23 mmol) were added and the reaction mixture was stirred
3
for 2 h at rt. Water was added and reaction mixture was extracted with EtOAc (3x25 mL). The
organic layer was dried (Na SO ), concentrated in vacuum and the residue was purified by fc
2
4

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20
(
dichloromethane/MeOH = 90/10, ø = 2.5 cm, h = 15 cm, R = 0.24). Pale yellow oil, yield 28
f
27
D
mg, (55 %). Purity: 95.2%, (t = 18.7 min.). α] = ꢀ 41.9 (c = 0.10, CHCl ). Exact mass (ESI):
R
3
1
13
m/z = calcd. for (C H NO )H 338.2042, found 338.2043. H NMR and C NMR data are
2
2
27
2
identical with the data of its enantiomer (R)ꢀ10.
(S)-N-[(R)-1-(7-Hydroxy-2,2-dimethyl-2H-chromen-6-yl)ethyl]-2-methylpropane-2-
sulfinamide ((S,R)-12) and (S)-N-[(S)-1-(7-hydroxy-2,2-dimethyl-2H-chromen-6-yl)ethyl]-2-
methylpropane-2-sulfinamide ((S,S)-12)
According to general procedure A phenol 4 (300 mg, 1.38 mmol) was reacted with Sꢀ(ꢀ)ꢀ2ꢀ
methylpropaneꢀ2ꢀsulfinamide ((S)ꢀ6, 140 mg, 1.66 mmol) and Ti(OEt) (472 mg, 2.07 mmol).
4
The diastereomers were separated by fc (petroleum ether/EtOAc = 80/20, ø = 1.5 cm, h = 10
cm).
2
3
(
S,R)ꢀ12 (R = 0.32): Colorless oil, yield 125 mg (28 %). Purity: 95.1 %, (t = 14.2 min.). [α]
f
R
D
=
+24.6 (c = 0.10, CHCl ). Exact mass (ESI): m/z = calcd. for (C H NO S)H 324.1555, found
3 17 25 3
1
3
24.1547. H NMR (CDCl ): δ (ppm) = 1.24 (s, 9H, 3xCH ), 1.38 (s, 3H, CH ), 1.40 (s, 3H,
3 3 3
CH ), 1.55 (d, J = 6.8 Hz, 3H, HNCHCH ), 3.62 (s, OH), 4.55 (q, J = 6.8 Hz, HNCHCH ), 5.44
3
3
3
(d, J = 9.8 Hz, 1H, 3ꢀCH), 6.22 (d, J = 9.8 Hz, 1H, 4ꢀCH), 6.37 (s, 1H, 8ꢀCH), 6.74 (s, 1H, 5ꢀ
1
3
CH), 8.36 (bs, 1H, SONH). C NMR (CDCl ): δ (ppm) = 20.7 (1C, NCHCH ), 22.8 (3C,
3
3
3
1
6
xCH ), 28.2, 28.3 (2C, CH ), 51.7 (1C, HNCHCH ), 55.8 (1C, NHSOC(CH ) ), 76.4 (1C, Cꢀ2),
3 3 3 3 3
05.6 (1C, Cꢀ8), 113.9 (1C, Cꢀ4a), 120.9 (1C, Cꢀ4), 122.1, 124.9 (2C, Cꢀ3, Cꢀ5), 128.0 (1C, Cꢀ
), 155.2, 156.7 (2C, Cꢀ7, Cꢀ8a).
23
(
S,S)ꢀ12 (R = 0.30): Colorless oil, yield 120 mg (27 %). Purity: 94.2 %, (t = 13.6 min.). [α]
=
D
f
R
ꢀ
23.5 (c = 0.10, CHCl ). Exact mass (ESI): m/z = calcd. for (C H NO S)H 324.1555, found
3
17 25
3

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1
3
24.1547. H NMR (CDCl ): δ (ppm) = 1.24 (s, 9H, 3xCH ), 1.40 (s, 3H, CH ), 1.41 (s, 3H,
3 3 3
CH ), 1.56 (d, J = 6.7 Hz, 3H, HNCHCH ), 3.66 (s, OH), 4.58 (q, J = 6.7 Hz, HNCHCH ), 5.46
3
3
3
(d, J = 9.8 Hz, 1H, 3ꢀCH), 6.22 (d, J = 9.8 Hz, 1H, 4ꢀCH), 6.32 (s, 1H, 8ꢀCH), 6.72 (s, 1H, 5ꢀ
1
3
CH), 7.88 (s, 1H, SONH). C NMR (CDCl ): δ (ppm) = 20.7 (1C, NCHCH ), 22.8 (3C, 3xCH ),
3
3
3
2
8.2, 28.3 (2C, CH ), 51.5 (1C, NHCHCH ), 55.8 (1C, NHSOC(CH ) ), 76.4 (1C, Cꢀ2), 105.6
3 3 3 3
(1C, Cꢀ8), 113.9 (1C, Cꢀ4a), 120.9 (1C, Cꢀ4), 122.1, 124.9 (2C, Cꢀ3, Cꢀ5), 128.0 (1C, Cꢀ6),
154.1, 156.2 (2C, Cꢀ7, Cꢀ8a).
(R)-6-[1-(Benzylamino)ethyl]-2,2-dimethyl-2H-chromen-7-ol ((R)-2)
Sulfinamide (S,R)ꢀ12 (150 mg, 0.46 mmol) was dissolved in dry Et O (5 mL), 2M Et O:HCl
2
2
solution (5 mL) was added and the mixture was stirred for 2 h. The mixture was concentrated in
vacuum and the residue ((R)ꢀ13) was dissolved in dry THF (5 mL). Benzaldehyde (54 mg, 0.51
mmol) and NaBH(OAc) (146 mg, 0.69 mmol) were added and reaction mixture was stirred at rt
3
for 3 h. Water was added and the reaction mixture was extracted with EtOAc (3x100 mL). The
organic layer was dried (Na SO ), concentrated in vacuum and the residue was purified by fc
2
4
(
petroleum ether/EtOAc = 70/30, ø = 1.5 cm, h = 15 cm, R = 0.26). Colorless oil, yield 45 mg
f
2
3
(
32 %). Purity: 95.2 %, (t = 18.2 min.). [α] = + 4.5 (c = 0.10, CHCl ). Exact mass (ESI): m/z
R D 3
1
=
calcd. for (C H NO )H 310.4021, found 310.4029. H NMR (CDCl ): δ (ppm) = 1.34 (s, 3H,
20 23 2 3
CH ), 1.35 (s, 3H, CH ), 1.37 (d, J = 6.7 Hz, 3H, HNCHCH ), 3.59 (d, J = 12.9 Hz, 1H,
3
3
3
HNCH Ph), 3.77 (d, J = 12.9 Hz, 1H, HNCH Ph), 3.84 (q, J = 6.7 Hz, NHCHCH ), 5.36 (d, J =
2
2
3
9
–
5
.8 Hz, 1H, 3ꢀCH), 6.15 (d, J = 9.8 Hz, 1H, 4ꢀCH), 6.26 (s, 1H, 8ꢀCH), 6.49 (s, 1H, 5ꢀCH), 7.29
13
7.16 (m, 5H, Ph). C NMR (CDCl ): δ (ppm) = 22.6 (1C, HNCHCH ), 28.4, 28.3 (2C, CH ),
3
3
3
1.5 (1C, HNCHCH ), 57.9 (1C, HNCH Ph), 76.4 (1C, Cꢀ2), 105.1 (1C, Cꢀ8), 113.6 (1C, Cꢀ4a),
3
2

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1
18.5 (1C, Ph), 122.1 (1C, Cꢀ4), 126.1, 127.6 (2C, Cꢀ3, Cꢀ5), 127.8 (1C, Cꢀ6), 128.7 (2C, oꢀPh),
28.9 (2C, mꢀPh), 138.4 (1C, Ph), 153.8, 158.5 (2C, Cꢀ7, Cꢀ8a).
1
(S)-6-[1-(Benzylamino)ethyl]-2,2-dimethyl-2H-chromen-7-ol ((S)-2)
Sulfinamide (S,S)ꢀ12 (150 mg, 0.46 mmol) was dissolved in dry Et O (5 mL), 2M Et O:HCl
2
2
solution (5 mL) was added and the mixture was stirred for 2 h at rt. The mixture was
concentrated in vacuum and residue ((S)ꢀ13) was dissolved in dry THF (5 mL). Benzaldehyde
(
54 mg, 0.51 mmol) and NaBH(OAc) (146 mg, 0.69 mmol) were added and mixture was stirred
3
at rt for 3 h. Water was added and the mixture was extracted with EtOAc (3x100 mL). The
organic layer was dried (Na SO ), concentrated in vacuum and the residue was purified by fc
2
4
(petroleum ether/EtOAc = 70/30, ø = 1.5 cm, h = 15 cm, R = 0.27). Colorless oil, yield 30 mg
f
23
(
21 %). Purity: 96.2 %, (t = 18.5 min.). [α] = ꢀ 5.2 (c = 0.10, CHCl ). Exact mass (ESI): m/z =
R
D
3
1
calcd. for (C H NO )H 310.4021, found 310.4029. H NMR (CDCl ): δ (ppm) = 1.34 (s, 6H,
2
0
23
2
3
CH ), 1.48 (d, J = 6.7 Hz, 3H, HNCHCH ), 3.59 (d, J = 13.0 Hz, 1H, HNCH Ph), 3.78 (d, J =
3
3
2
1
3.0 Hz, 1H, HNCH Ph), 3.83 (q, J = 6.7 Hz, HNCHCH ), 5.36 (d, J = 9.8 Hz, 1H, 3ꢀCH), 6.16
2
3
(d, J = 9.8 Hz, 1H, 4ꢀCH), 6.26 (s, 1H, 8ꢀCH), 6.49 (s, 1H, 5ꢀCH), 7.29 – 7.16 (m, 5H, Ph).
Investigation of the antiprotozoal activity
In vitro assays for activity against Trypanosoma brucei rhodesiense (bloodstream trypomastigote
stage, STIB 900 strain) and Plasmodium falciparum (erythrocytic stage, K1 or NF54
(compounds (R)ꢀ2 and (S)ꢀ2) strain) as well as cytotoxicity determinations against L6 rat skeletal
myoblasts were carried out at the Swiss Tropical and Public Health Institute according to
1
3
established standard protocols described earlier. Compounds used as positive controls were of

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DOI: 10.1039/C3OB41583J
23
commercial origin, with the exception of melarsoprol, which was a gift from WHO. Their purity
generally >95%) was specified by the manufacturers.
(
Acknowledgement
This work was done within the framework of the NRW International Graduate School of
Chemistry, Münster, which is funded by the Government of the state NordrheinꢀWestfalen and
Westfälische WilhelmsꢀUniversity Münster. The financial support is deeply acknowledged. The
biological part of this study is an activity of the Research Network Natural Products against
Neglected Diseases (ResNet NPND, http://www.uniꢀmuenster.de/ResNetNPND)

Organic & Biomolecular Chemistry
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Graphical Abstract