Synthesis of novel 2-alkoxy-3-amino-3-arylpropan-1-ols and 5-alkoxy-4-aryl-1,3-oxazinanes with antimalarial activity

Article abstract of DOI:10.1021/jm9002632

A variety of novel syn-2-alkoxy-3-amino-3-arylpropan-1-ols was prepared through LiAlH₄-promoted reductive ring-opening of cis-3-alkoxy-4-aryl-β-lactams in Et₂O. The latter γ-aminoalcohols were easily converted into cis-5-alkoxy-4-aryl-1,3- oxazinanes using formaldehyde in THF. Both series of compounds were evaluated against a chloroquine sensitive strain of Plasmodium falciparum (D10), revealing micromolar potency for almost all representatives. Eleven compounds exhibited antimalarial activity with IC₅₀ values of ≤30 μM, and the majority of these compounds did not show cytotoxicity at the concentrations tested.

Full text of DOI:10.1021/jm9002632

4058
J. Med. Chem. 2009, 52, 4058–4062
Synthesis of Novel 2-Alkoxy-3-amino-3-arylpropan-1-ols and 5-Alkoxy-4-aryl-1,3-oxazinanes
with Antimalarial Activity
Matthias D’hooghe,‡ Stijn Dekeukeleire,†,‡ Karen Mollet,‡ Carmen Lategan,§ Peter J. Smith,§ Kelly Chibale,| and
Norbert De Kimpe*,‡
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent UniVersity, Coupure Links 653, B-9000 Ghent, Belgium, DiVision
of Pharmacology, UniVersity of Cape Town, K45, OMB, Groote Schuur Hospital, ObserVatory, 7925, South Africa, Department of Chemistry
and Institute of Infectious Disease & Molecular Medicine, UniVersity of Cape Town, Rondebosch 7701, South Africa
ReceiVed March 2, 2009
A variety of novel syn-2-alkoxy-3-amino-3-arylpropan-1-ols was prepared through LiAlH4-promoted reductive
ring-opening of cis-3-alkoxy-4-aryl-ꢀ-lactams in Et2O. The latter γ-aminoalcohols were easily converted
into cis-5-alkoxy-4-aryl-1,3-oxazinanes using formaldehyde in THF. Both series of compounds were evaluated
against a chloroquine sensitive strain of Plasmodium falciparum (D10), revealing micromolar potency for
almost all representatives. Eleven compounds exhibited antimalarial activity with IC50 values of e30 µM,
and the majority of these compounds did not show cytotoxicity at the concentrations tested.
Scheme 1. Staudinger Synthesis of cis-4-Aryl-ꢀ-lactams 2 and
Their Reduction toward 3-Aminopropan-1-ols 3
Introduction
With 300-500 million clinical cases and 2 million deaths
each year, malaria remains a major issue in health control,
especially in developing countries.1 Quinoline containing com-
pounds have long been used for the treatment of malaria, and
systematic modification has led to a variety of antimalarial drugs
with diverse substitutions around the quinoline ring.2 One of
the first drugs to be prepared was the potent and inexpensive
chloroquine (CQ), which is a 7-chloroquinoline with an amino
substituent at position 4.3
In the present paper, the synthesis and biological evaluation
of a structurally more complex type of aminopropanols is
described, i.e., new 2-alkoxy and 2-phenoxy substituted 3-amino-
3-arylpropan-1-ols, starting from suitable azetidin-2-ones through
reductive ring-opening. We reasoned that the combination of a
γ-aminoalcohol moiety and an aryl group in these propanes
might result in novel and easily accessible classes of antimalarial
agents. Furthermore, cyclization of 3-amino-3-arylpropan-1-ols
into 4-aryl-1,3-oxazinanes was performed in order to introduce
conformational constraint into the target compounds.
Besides their biological relevance as potential antibiotics,
ꢀ-lactams have acquired a prominent place in organic chemistry
as synthons for further elaboration (“ꢀ-lactam synthon
method”).6 Since then, the constrained azetidin-2-one ring has
been employed successfully in a large variety of different
synthetic methodologies toward all kinds of nitrogen-containing
target compounds.7 In spite of the fact that in theory a broad
variety of different γ-aminoalcohols can be obtained by reduc-
tive ring-opening of ꢀ-lactams, mainly by means of complex
metal hydrides, this methodology has been applied to a rather
limited extend so far.8
The antimalarial activity of chloroquine appears to be linked
to the haem metabolism of the causative agent, Plasmodium
falciparum.4 However, the spread of chloroquine-resistant P.
falciparum strains has dashed hopes of global malaria eradica-
tion and has complicated the clinical management of malaria
in endemic areas. Consequently, many efforts are devoted to
the design and synthesis of novel and structurally diverse
compounds with potential antimalarial activity. Recently, 1-ami-
nopropan-2-ols were presented as novel antimalarial agents, with
activities of the best seven compounds from a library in the
1-10 µM range against both a chloroquine sensitive (3D7) and
chloroquine resistant (FCR3) strain of the parasite.5 From a
chemical point of view, the presented methodology was based
on the ring-opening of 2-(alkoxymethyl)- and 2-(aminometh-
yl)epoxides by amines, resulting in the 1-aminopropan-2-ol
motif due to ring-opening at the unsubstituted epoxide carbon
atom.
Results and Discussion
Synthesis. The synthesis of 3-alkoxy and 3-phenoxy substi-
tuted 4-aryl-ꢀ-lactams 2 was performed by means of the
Staudinger reaction between the appropriate imines and ketenes.
Thus, treatment of N-(arylmethylidene)amines 1, obtained by
condensation of different benzaldehydes in dichloromethane in
the presence of MgSO4 and Et3N utilizing 1 equiv of the
appropriate amine,9 with 1.1 equiv of methoxy-, phenoxy-, or
benzyloxyacetyl chloride in dichloromethane in the presence
of 3 equiv of triethylamine afforded the corresponding novel
4-arylazetidin-2-ones 2 in good yields at room temperature for
15 h (Scheme 1, also see Supporting Information). The relative
* To whom correspondence should be addressed. Phone: +32-92645951.
Fax: +32-92646243. E-mail: norbert.dekimpe@UGent.be.
†
Aspirant of the Fund for Scientific ResearchsFlanders (FWOs
Vlaanderen).
‡
Department of Organic Chemistry, Faculty of Bioscience Engineering,
Ghent University.
§
Medical School, University of Cape Town.
Department of Chemistry and Institute of Infectious Disease &
|
Molecular Medicine, University of Cape Town.
10.1021/jm9002632 CCC: $40.75  2009 American Chemical Society
Published on Web 05/22/2009

Brief Articles
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 13 4059
Scheme 2. Conversion of 3-Aminopropan-1-ols 3 into
4-Aryl-1,3-oxazinanes 4
Scheme 3. Reductive Ring-Opening of 5-Benzyloxy-3-
isobutyl-4-(4-methylphenyl)-1,3-oxazinane 4b to
3-(N-Methylamino)propan-1-ol 5 by Means of NaBH4
stereochemistry of ꢀ-lactams 2 was assigned as cis based on
the coupling constants between the protons at C3 and C4 in 1H
NMR (4.4-4.7 Hz, CDCl3), in accordance with literature data.10
Subsequently, cis-azetidin-2-ones 2 were subjected to a reductive
ring-opening by means of 2 mol equiv of lithium aluminum
hydride in diethyl ether, affording the corresponding 2-alkoxy
or 2-phenoxy substituted syn-3-amino-3-arylpropan-1-ols 3 in
good yields after reflux for 3 h (Scheme 1, also see Supporting
Information).
To obtain molecular diversity within γ-aminoalcohols 3, a
variety of different representatives of this class of compounds
was prepared by altering the amino group (R1 ) iPr, nPr, iBu,
tBu, cHex, Ph, Bn), the aryl moiety (R2 ) H, 4-Me, 3-OMe,
4-OMe, 4-Cl, 2-Br, 2-F) and the alkoxy or phenoxy substituent
(R3 ) Me, Ph, Bn). This small library of novel γ-aminoalcohols
3 was then screened for potential antimalarial activity (see
section Biological Evaluation).
Table 1. In Vitro Antiplasmodial Activity against P. falciparum (CQS)
D10 Strain
compd IC50 (µM) IC90 (µM)
compd
IC50 (µM) IC90 (µM)
3a
3b
3c
3d
3e
3f
3g
3h
3i
45.89
15.3
175.1
6.36
164.73
70.76
ND
12.48
ND
43.09
223.44
ND
251.63
47.78
101.9
ND
4b
4c
4d
4e
4f
4g
4h
4i
30.34
42.57
19.35
121.46
14.08
16.81
84.87
129.02
87.08
ND
NDa
ND
137.52
ND
38.55
118.46
ND
ND
ND
ND
ND
ND
10.46
25.13
85.22
13.73
16.42
25.24
66.31
4j
4k
5
3j
3k
4a
81.97
0.017
CQ (n ) 8)b
0.067
a ND ) not determined. b n ) number of data sets averaged.
With the intention to introduce conformational constraint into
the target compounds, 3-aminopropan-1-ols 3 were subsequently
converted into new cis-5-alkoxy-4-aryl-1,3-oxazinanes 4 by
treatment with 1 equiv of formaldehyde (37% in water) in THF
at room temperature for 6 h (Scheme 2, also see Supporting
Information). There are only a few reports in the literature on
the synthesis of oxazinanes,11 either as biologically relevant
targets12 or as synthons for further elaboration.13,14 Oxazinanes
4 appear to be highly stable, as these compounds can be stored
(neat) for prolonged times without any loss of purity. Further-
more, oxazinanes 4 were shown to be stable under hydrolytic
conditions, as these compounds were recovered completely and
without loss of purity after stirring for 15 h at room temperature
in water or in a water/DMSO (1/1) system.
In accordance with literature data, the methylene group
between oxygen and nitrogen in oxazinanes 4 appeared as two
doublets with characteristic chemical shifts between 4 and 5
ppm (with a ∆δ > 0.5 ppm) and a coupling constant of 9 Hz
(1H NMR, CDCl3).15 Also, in 13C NMR, this methylene carbon
resonated at 79-84 ppm (CDCl3), in accordance with the
literature.15 The cis-relationship of the alkoxy group with respect
to the aryl moiety is a direct consequence of the stereodefined
Staudinger formation of cis-ꢀ-lactams 2, followed by transfer
of the stereochemical information through the following reaction
steps toward 2-alkoxy or 2-phenoxy substituted syn-3-amino-
3-arylpropan-1-ols 3 and cis-1,3-oxazinanes 4.
This small library of novel oxazinanes 4, in which different
substitution patterns have been incorporated, was then screened
for potential antimalarial activity (see section Biological Evalu-
ation).
Further evidence for the presence of a methylene bridge in
1,3-oxazinanes 4 was provided by reductive ring-opening of
5-benzyloxy-3-isobutyl-4-(4-methylphenyl)-1,3-oxazinane 4b as
a selected example by means of 2 equiv of sodium borohydride
in methanol under reflux for 3 h, resulting in the corresponding
3-(N-methylamino)propan-1-ol 5 in 83% yield (Scheme 3).
Biological Evaluation. Subsequently, 3-aminopropan-1-ols
3a-k, 5, and 1,3-oxazinanes 4a-k were screened for in vitro
antiplasmodial activity. These samples were tested in duplicate
on one occasion against a chloroquine sensitive (CQS) strain
of P. falciparum (D10). Continuous in vitro cultures of asexual
erythrocyte stages of P. falciparum were maintained using a
modified method of Trager and Jensen.16
Quantitative assessment of antiplasmodial activity in vitro
was determined via the parasite lactate dehydrogenase assay
using a modified method described by Makler.17
The samples were prepared to a 2 mg/mL stock solution in
10% DMSO and sonicated to enhance solubility. Samples were
tested as a suspension if not completely dissolved. Stock
solutions were stored at -20 °C. Further dilutions were prepared
on the day of the experiment. Chloroquine (CQ) was used as
the reference drug in all experiments. A full dose-response was
performed for all compounds to determine the concentration
inhibiting 50% of parasite growth (IC50 value). Test samples
were tested at a starting concentration of 100 µg/mL, which
was then serially diluted 2-fold in complete medium to give 10
concentrations, with the lowest concentration being 0.2 µg/mL.
The same dilution technique was used for all samples. CQ was
tested at a starting concentration of 100 ng/mL. The highest
concentration of solvent to which the parasites were exposed
had no measurable effect on the parasite viability (data not
shown). The IC50 values were obtained using a nonlinear
dose-response curve fitting analysis via Graph Pad Prism v.4.0
software (see Supporting Information). The results of this
biological study are presented in Table 1.
Interestingly, these results show micromolar potency for
almost all representatives, pointing to the significant biological
potential of γ-aminoalcohols 3 and 1,3-oxazinanes 4. Moreover,
11 compounds exhibited antimalarial activity with IC50 values
of e30 µM against P. falciparum (CQS) D10 strain, and
compounds 3b, 3d, 3f, 3i and 4f showed promising biological
activity with IC50 values e15 µM. 2-Alkoxy-3-amino-3-
arylpropan-1-ols 3 were generally more active than the corre-
sponding oxazinanes 4, with the most active compound being
3d. It is noteworthy that these compounds were synthesized in
racemic form, and it is conceivable that enantiomerically pure
variants could deliver superior activities. Nevertheless, 2-alkoxy-

4060 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 13
Brief Articles
Table 2. IC50 Values of Compounds Tested in Vitro for Antiplasmodial
Activity and Cytotoxicity
performed with a PerkinElmer series II CHNS/O analyzer 2400.
Dichloromethane was distilled over calcium hydride, while diethyl
ether was dried over sodium benzophenone ketyl. Other solvents
were used as received from the supplier. The purity of all new
compounds has been assessed by means of gas chromatographic
analysis (purity >95%).
Synthesis of cis-4-Aryl-ꢀ-lactams (2). General procedure: To
an ice-cooled solution of N-(arylmethylidene)amine 1 (10 mmol)
and triethylamine (30 mmol) in dichloromethane (25 mL) was added
dropwise a solution of alkoxyacetyl chloride (11 mmol) in CH2Cl2
(10 mL). After stirring for 15 h at room temperature, the reaction
mixture was poured into water (30 mL) and extracted with CH2Cl2
(2 × 25 mL). Drying (MgSO4), filtration of the drying agent, and
removal of the solvent afforded cis-3-alkoxy-4-aryl-ꢀ-lactam 2,
which was purified by recrystallization from ethanol or column
chromatography on silica gel.
compd
D10: IC50 (µM)
CHO: IC50 (µM)
SIa
3b
3d
3f
3i
3j
4f
4g
15.3
6.36
143.5
NTc
NT
326.38
144.58
NT
9.4
NDd
ND
23.8
8.8
10.46
13.73
16.42
14.08
16.81
ND
ND
ND
NT
0.108
emetine (n ) 2)b
a Selectivity index (SI) ) IC50 CHO/IC50 D10. b n ) number of data
sets averaged. c NT ) not toxic at 100 µg/mL. d ND ) not determined.
3-amino-3-arylpropan-1-ols 3 can be considered as a potential
new class of antimalarial agents.
cis-3-Benzyloxy-1-isopropyl-4-phenylazetidin-2-one (2a). Re-
crystallization from absolute EtOH; mp ) 101.3 °C. 1H NMR (300
MHz, CDCl3): δ 1.04 and 1.25 (6H, 2 × d, J ) 6.6 Hz), 3.83 (1H,
septet, J ) 6.6 Hz), 4.10 and 4.25 (2H, 2 × d, J ) 11.3 Hz), 4.74
(1H, d, J ) 4.4 Hz), 4.78 (1H, d, J ) 4.4 Hz), 6.91-6.95,
7.18-7.21 and 7.36-7.44 (10H, 3 × m). 13C NMR (75 MHz,
CDCl3): δ 20.2, 21.4, 44.8, 60.9, 72.2, 82.7, 127.8, 128.2, 128.3,
128.5, 128.7, 135.4, 136.5, 166.6. IR (NaCl, cm-1): νCdO ) 1739.
MS (70 eV): m/z (%) 296 (M++1, 100). Anal. calcd for C19H21NO2:
C 77.26, H 7.17, N 4.74; found: C 77.40, H 7.42, N 4.61.
In addition to the above-described antimalarial screenings,
cytotoxicity studies were performed on the samples that showed
an antimalarial activity of less than 17 µM. Thus, γ-aminoal-
cohols 3b, 3d, 3f, 3i, and 3j and 1,3-oxazinanes 4f and 4g were
subjected to further testing using the MTT-assay [3-(4,5-
dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-assay].
The MTT-assay is used as a colorimetric assay for cellular
growth and survival and compares well with other available
assays.18 The tetrazolium salt MTT was used to measure all
growth and chemosensitivity. The test samples were tested in
triplicate on one occasion. The test samples were prepared to a
2 mg/mL stock solution in 10% methanol or 10% DMSO and
were tested as a suspension if not properly dissolved. Test
compounds were stored at -20 °C until use. Emetine was used
as the reference drug in all experiments. The initial concentration
of emetine was 100 µg/mL, which was serially diluted in
complete medium with 10-fold dilutions to give six concentra-
tions, the lowest being 0.001 µg/mL. The same dilution
technique was applied to all the test samples. The highest
concentration of solvent to which the cells were exposed had
no measurable effect on the cell viability (data not shown). The
50% inhibitory concentration (IC50) values were obtained from
full dose-response curves, using a nonlinear dose-response
curve fitting analysis via Graph Pad Prism v.4.0 software (see
Supporting Information).
The results of this biological study are presented in Table 2.
Interestingly, the in vitro cytotoxicity results showed that only
compounds 3b and 3j have SI’s of 9 (Table 2), whereas all
other compounds did not show cytotoxicity at the concentrations
tested.
In summary, the relevance of 3-alkoxyazetidin-2-ones as
synthetic precursors for the biologically important class of
2-alkoxy-3-aminopropan-1-ols has been demonstrated by the
preparation of a variety of novel syn-2-alkoxy-3-amino-3-
arylpropan-1-ols. Cyclization of the latter γ-aminoalcohols by
means of formaldehyde afforded a convenient entry into the
corresponding new cis-5-alkoxy-4-aryl-1,3-oxazinanes. The
biological importance of these classes of compounds was
demonstrated by evaluation of their in vitro antiplasmodial
activity and cytotoxicity, pointing to the promising potential of
syn-2-alkoxy-3-amino-3-arylpropan-1-ols 3 as a novel type of
antimalarial agents.
Synthesis of syn-2-Alkoxy-3-amino-3-arylpropan-1-ols (3).
General procedure: To an ice-cooled solution of cis-3-alkoxy-4-
aryl-ꢀ-lactam 2 (10 mmol) in dry diethyl ether (50 mL) was added
lithium aluminum hydride (20 mmol) in small portions. After reflux
for 3 h, the reaction mixture was cooled to 0 °C and water (10
mL) was added in order to quench the excess of LiAlH4. The
resulting suspension was filtered over celite and washed with diethyl
ether (40 mL), and the filtrate was poured into water (50 mL) and
extracted with Et2O (3 × 30 mL). Drying (MgSO4), filtration of
the drying agent, and removal of the solvent in vacuo afforded syn-
2-alkoxy-3-amino-3-arylpropan-1-ol 3, which was purified by means
of column chromatography on silica gel or recrystallization from
absolute EtOH.
syn-2-Benzyloxy-3-isopropylamino-3-phenylpropan-1-ol (3a). Rf
1
) 0.14 (hexane/EtOAc 4/1). H NMR (300 MHz, CDCl3): δ 1.01
(6H, d, J ) 6.2 Hz), 2.58 (1H, septet, J ) 6.2 Hz), 3.46-3.49
(1H, m), 3.79 and 3.99 (2H, 2 × (d × d), J ) 12.2, 3.3, 2.2 Hz),
4.05 (1H, d, J ) 3.4 Hz), 4.35 and 4.60 (2H, 2 × d, J ) 11.8 Hz),
7.15-7.20 and 7.23-7.38 (10H, 2 × m). 13C NMR (75 MHz,
CDCl3): δ 21.4, 24.3, 45.0, 63.3, 63.7, 71.6, 81.0, 127.4, 127.6,
127.6, 127.9, 128.3, 128.4, 138.1, 140.6. IR (NaCl, cm-1): νNH,OH
) 3329. MS (70 eV): m/z (%) 300 (M+ + 1, 100). Anal. calcd for
C19H25NO2: C 76.22, H 8.42, N 4.68; found: C 76.05, H 8.57, N
4.52.
Synthesis of cis-5-Alkoxy-4-aryl-1,3-oxazinanes (4). General
procedure: To a solution of syn-2-alkoxy-3-amino-3-arylpropan-
1-ol 3 (5 mmol) in THF (20 mL) was added formaldehyde (5 mmol,
37% solution in H2O) at room temperature. The resulting mixture
was stirred for 6 h at room temperature, after which the solvent
was removed in vacuo. The crude cis-5-alkoxy-4-aryl-1,3-oxazinane
4 was purified by column chromatography on silica gel.
cis-5-Benzyloxy-3-isopropyl-4-phenyl-1,3-oxazinane (4a). Rf
1
) 0.19 (hexane/EtOAc 6/1). H NMR (300 MHz, CDCl3): δ 0.84
and 1.15 (6H, 2 × d, J ) 6.6 Hz), 3.05 (1H, septet, J ) 6.6 Hz),
3.36-3.39 (1H, m), 3.62 (1H, d × d, J ) 12.0, 2.0 Hz), 3.88 (1H,
d, J ) 3.3 Hz), 4.10 (1H, d × d, J ) 12.0, 2.7 Hz), 4.12 (1H, d,
J ) 8.8 Hz), 4.22 (2H, s), 4.74 (1H, d, J ) 8.8 Hz), 6.89-6.93,
7.12-7.17, 7.24-7.37, and 7.50-7.54 (10H, 4 × m). 13C NMR
(75 MHz, CDCl3): δ 14.7, 21.3, 47.6, 65.5, 69.1, 71.9, 74.4, 79.1,
127.2, 127.4, 127.9, 127.95, 128.04, 129.3, 137.9, 139.3. IR (NaCl,
cm-1): νmax ) 2965, 2868, 1182, 1076, 1067, 1052, 1028, 738,
697. MS (70 eV): m/z (%) 312 (M+ + 1, 100). Anal. calcd for
C20H25NO2: C 77.14, H 8.09, N 4.50; found: C 76.96, H 8.32, N
4.58.
Experimental Section
1H NMR spectra were recorded at 300 MHz (JEOL ECLIPSE+)
with CDCl3 as solvent and tetramethylsilane as internal standard.
13C NMR spectra were recorded at 75 MHz (JEOL ECLIPSE+)
with CDCl3 as solvent. Mass spectra were obtained with a mass
spectrometer Agilent 1100, 70 eV. IR spectra were measured with
a Spectrum One FT-IR spectrophotometer. Elemental analyses were

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Biomol. Chem. 2008, 6, 1190–1196. (s) Taubinger, A. A.; Fenske,
D.; Podlech, J. Synthesis of ꢀ,ꢀ′-diamino acids from R-amino acid
derived ꢀ-lactams. Synlett 2008, 539–542. (t) Sakaguchi, H.; Tokuya-
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Synthesis of syn-2-Benzyloxy-3-(N-isobutyl-N-methylamino)-
3-(4-methylphenyl)propan-1-ol (5). To an ice-cooled solution of
5-benzyloxy-3-isobutyl-4-(4-methylphenyl)-1,3-oxazinane 4b (5
mmol) in methanol (20 mL) was added sodium borohydride (10
mmol), after which the resulting suspension was heated under reflux
for 3 h. Afterward, the reaction mixture was poured into water (25
mL), extracted with dichloromethane (3 × 20 mL), and dried
(MgSO4). Filtration of the drying agent and removal of the solvent
yielded the crude syn-2-benzyloxy-3-(N-isobutyl-N-methylamino)-
3-(4-methylphenyl)propan-1-ol 5, which was purified by means of
column chromatography on silica gel (hexane/EtOAc 6/1).
Rf ) 0.07 (hexane/EtOAc 6/1). 1H NMR (300 MHz, CDCl3): δ
0.88 and 0.90 (6H, 2 × d, J ) 6.4 Hz), 1.70-1.94 (1H, m), 2.07
and 2.17 (2H, 2 × (d × d), J ) 12.0, 7.2, 6.9 Hz), 2.27 (3H, s);
2.33 (3H, s), 3.59 (1H, d × d, J ) 11.8, 4.7 Hz), 3.74 (1H, d, J )
4.9 Hz), 3.83 (1H, d × d, J ) 11.8, 4.1 Hz), 3.89-3.93 (1H, m),
4.70 (2H, s), 7.11-7.41 (9H, m). 13C NMR (75 MHz, CDCl3): δ
20.76, 20.81, 21.1, 25.9, 38.9, 63.5, 64.3, 71.3, 72.4, 79.0, 127.6,
127.8, 128.4, 128.6, 129.9, 132.4, 137.0, 138.6. IR (NaCl, cm-1):
νOH ) 3403. MS (70 eV): m/z (%) 342 (M+ + 1, 100). Anal. calcd
for C22H31NO2: C 77.38, H 9.15, N 4.10; found: C 77.59, H 9.33,
N 3.96.
Acknowledgment. We are indebted to Ghent University
(GOA) and the Fund for Scientific Research (FWOsFlanders)
for financial support.
Supporting Information Available: Spectroscopic data of
compounds 2b-2k, 3b-3g, and 4b-4k, and full dose-response
curves. This material is available free of charge via the Internet at
http://pubs.acs.org.
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