Thiourea-based non-nucleoside inhibitors of HIV reverse transcriptase as bifunctional organocatalysts in the asymmetric Strecker synthesis

Article abstract of DOI:10.1016/j.bmc.2005.05.014

The potential of novel and known pyridyl thiourea derivatives (non-nucleoside inhibitors (NNI) of HIV reverse transcriptase) as bifunctional organic catalysts in the asymmetric Strecker synthesis was investigated. It was shown that incorporation of the im

Full text of DOI:10.1016/j.bmc.2005.05.014

Bioorganic & Medicinal Chemistry 13 (2005) 5680–5685
Thiourea-based non-nucleoside inhibitors of HIV
reverse transcriptase as bifunctional organocatalysts in
the asymmetric Strecker synthesis
Svetlana B. Tsogoeva,a,* Martin J. Hateley,b Denis A. Yalalov,a Kathrin Meindl,c
Christoph Weckbeckerb and Klaus Huthmacherb
aInstitut fu¨r Organische und Biomolekulare Chemie der Georg-August-Universita¨t Go¨ttingen, Tammannstrasse 2,
37077 Go¨ttingen, Germany
bDegussa AG, Feed Additives, Rodenbacher Chaussee 4, 63457 Hanau-Wolfgang, Germany
cInstitut fu¨r Anorganische Chemie der Georg-August-Universita¨t Go¨ttingen, Tammannstrasse 4, 37077 Go¨ttingen, Germany
Received 15 March 2005; revised 6 May 2005; accepted 10 May 2005
Available online 16 June 2005
Abstract—The potential of novel and known pyridyl thiourea derivatives (non-nucleoside inhibitors (NNI) of HIV reverse transcrip-
tase) as bifunctional organic catalysts in the asymmetric Strecker synthesis was investigated. It was shown that incorporation of the
imidazolyl moiety in place of a pyridyl group results in a new thiourea derivative that displays a much higher catalytic activity.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
pyridine residue.17–21 For instance, chiral a-methyl ben-
zyl pyridyl thiourea compounds 1 and 2 (Fig. 1) were re-
ported by Uckun and co-workers to be non-nucleoside
inhibitors (NNI) of the reverse transcriptase enzyme of
the human immunodeficiency virus (HIV).22–25
Chiral catalysts that contain both an acidic and a basic/
nucleophilic structural unit are of growing importance
in the development of asymmetric catalysis.1,2
Recently, several enantioselective bifunctional organic
catalysts have been identified.3 Among them are chiral
organic catalysts for the Strecker synthesis, including a
guanidine-bearing diketopiperazine,4 a C2-symmetric
guanidine catalyst5 and the chiral peptide-like catalysts
described by Jacobsen, which possess both acidic (urea
and/or thiourea moiety) as well as basic functionality
(Schiff base).6–9 Furthermore, the use of chiral bifunc-
tional thiourea-based organocatalysts in the enantio-
selective Michael addition,10 the Aza-Henry,11 Baylis–
Hillman,12,13 Acyl-Pictet-Spengler14 and Nitro-Man-
nich15 reactions as well as for the dynamic kinetic reso-
lution of azalactones16 has recently been reported.
These structures incorporate both the acidic and the
basic/nucleophilic bifunctionality of interest with
respect to potential enantioselective bifunctional
organocatalysts.
This prompted us to apply these pyridine based thiourea
compounds, as well as the novel thiourea derivatives 3–5
(Fig. 1), synthesised in our laboratory, as catalysts for
C–C bond formation reactions.
In particular, we were interested in the Strecker synthe-
sis,26,27 which provides synthetically useful building
blocks and has many important applications both in
natural product synthesis as well as in the industrial
preparation of pharmaceuticals and agrochemicals.
Many known compounds displaying important biologi-
cal activity contain both a thiourea moiety as well as a
2. Results and discussion
Keywords: NNI; Inhibitor; Thiourea derivative; Strecker synthesis;
Bifunctional organocatalyst.
*
The syntheses of the thiourea compounds were accom-
plished by known methods28,29 as summarised in
Corresponding author. Tel.: +49 0 551 393285; fax: +49 0 551
399660; e-mail: stsogoe@gwdg.de
0968-0896/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2005.05.014

S. B. Tsogoeva et al. / Bioorg. Med. Chem. 13 (2005) 5680–5685
5681
Figure 1.
Scheme 1. Three different amines: (R)-(+)-1-phenylethyl-
amine (6), (1R,2S)-(ꢀ)-2-amino-1-methoxy-1-phenyl-
propane (7) and (S)-phenylalanine methyl ester (8)
were employed for the synthesis of chiral isothiocya-
nates 9–11. Subsequent treatment of these chiral isothio-
cyanates with 2-amino-6-methylpyridine (12) and
2-amino-5-chloropyridine (13) gave the target pyridyl
thioureas 1–4.
Scheme 2.
The addition of hydrogen cyanide to aldimines 15 and
16 (Scheme 2) was employed to determine the catalytic
activity of the pyridyl thiourea derivatives 1–4 (Fig. 1)
and thus their potential as bifunctional organocatalysts.
Aldimines 15 and 16 were selected as the substrates of
choice to enable an effective comparison with earlier
investigations in the literature.5,9 All reactions were per-
formed as solutions in toluene with 10 mol % of the
appropriate catalyst and were stirred for 2.5 h at
ꢀ40 ꢁC and subsequently for a further 16 h at ꢀ20 ꢁC.
fore, we continued our investigation with an examina-
tion of the catalytic efficacy of some available organic
bases (entries 5–8, Table 1). We have found that use
of imidazole as a base generally gave a better conversion
(32%, entry 8) than pyridine (5%, entry 5), pyrrolidine
(11%, entry 6) or Et3N (6%, entry 7).
Thus, in the chiral thiourea 5 (Scheme 1), the methylpyr-
idyl group of 1 was replaced by an imidazolyl
substituent.
Low conversions (up to 25%) and enantioselectivities
(up to 14%) were observed in all cases (entries 1–4, Table
1).
Intriguingly, whereas imidazole and/or biotin alone, as
well as their mixture gave the Strecker product from
the substrate 15 in only 32%, 10% and 37% yields,
respectively (entries 8–10), high conversion was ob-
served with substrates 15 and 16 under the same
In searching for ways to improve the catalyst activity,
we were drawn to the strategy of base variation. There-
Scheme 1.

5682
S. B. Tsogoeva et al. / Bioorg. Med. Chem. 13 (2005) 5680–5685
Table 1. Strecker reactions catalyzed by thiourea derivatives 1–5
Entry
Catalyst (10 mol %)
Substrate
2.5 h at ꢀ40 ꢁC;
16 h at ꢀ20 ꢁC
Conversion (%)a
ee (%)a
1
2
1
15
15
15
15
15
15
15
15
15
15
15
16
17
25
9
14
12
6
2
3
3
4
4
Pyridine
9
4
5
5
—
—
—
—
4
6
Pyrrolidine
Et3N
11
6
7
8
Imidazole
Biotin
Biotinb + Imidazoleb
32
10
37
85
100
9
10
11
12
4
5
5
6
7
a Determined by HPLC after 16 h of reaction at ꢀ20 ꢁC. Reported conversions and ee values are the average of 2 runs.
b 10 mol % of co-catalyst.
conditions in the presence of imidazolyl thiourea cata-
lyst 5 (85% and 100%, respectively, entries 11 and 12,
Table 1), which represented up to 76% improvement in
the conversion of imine 15 over the corresponding pyr-
idyl thiourea based catalysts 1–4 (entries 1–4). These re-
sults indicate that for a high conversion the catalyst
should possess both an imidazole group and a urea/thio-
urea moiety within one molecule. More probably, the
basic group and the thiourea reaction centre act in a syn-
ergistic manner within the catalyst.
As already reported by Vachal and Jacobsen9 and
Schreiner and Wittkopp,31 ureas and thioureas are able
to provide two hydrogen bonds to bind the H-bond
acceptors (carbonyl or imine groups). It appears likely
that a bridged structure, in which the imine forms
hydrogen-bonds to both thiourea hydrogen atoms
simultaneously, is important for catalyst activity and
selectivity.9 The X-ray structure30 of methylpyridyl thio-
urea 3 shows, however, that an intramolecular hydrogen
bond is formed between the thiourea N10–H group and
the basic nitrogen atom (N7) of the pyridyl group as well
as an intermolecular hydrogen bond from N8–H to the
sulfur of a crystallographic independent second mole-
cule leading to a dimer. There are two of these nearly
identical dimers in the asymmetric unit (Fig. 2).
The enantioselectivities obtained with imidazolyl thio-
urea 5, however, proved to be in the same range as those
observed with pyridyl thioureas 1–4.
The X-ray crystal structure of the new thiourea deriva-
tive 3 (chiral methylpyridyl thiourea) sheds light on
the cause of the low chiral induction observed in the
Strecker reaction using bifunctional catalysts 1–5.
As a result, the imine substrate cannot be placed in a
bridging mode between the two thiourea hydrogen
atoms, which might serve to explain the low enantiose-
Figure 2. X-ray crystal structure of two molecules of compound 3; thermal ellipsoids are shown at 50% probability level.

S. B. Tsogoeva et al. / Bioorg. Med. Chem. 13 (2005) 5680–5685
5683
lectivities obtained with catalyst 3, as well as with all the
other thiourea derivatives presented here (since struc-
tural similarities are evident). These observations are
consistent with the postulation that H-bonding interac-
tions are central to reaction selectivity.9
chromatography on SiO2 (hexane/EA, 3:0.5) gave 1 as a
20
D
white solid. Yield 47%; ½aꢁ ꢀ134.8 (c 0.25, CHCl3); 1H
NMR (CDCl3) d 12.4 (br s, 1H, NH), 8.1 (s, 1H, NH),
7.47–7.52 (m, 1H), 7.26–7.43 (m, 5H), 6.78 (d, J = 6.9,
1H), 6.46 (d, J = 8.1 Hz, 1H), 5.56–5.61 (m, 1H), 2.39
(s, 3H), 1.67 (d, J = 7.2, 3H); 13C NMR (CDCl3) d
178.50, 154.87, 152.96, 142.93, 138.89, 128.59, 127.23,
126.26, 117.08, 108.92, 55.08, 23.74, 22.47. EI-MS m/z
(rel intensity) 271.2 (M+, 100), 151.1 (33), 120.1 (53),
109.1 (42), 92.1 (25); the exact molecular mass m/
z = 271.1143 2 ppm (M+) was confirmed by HRMS
(EI, 70 eV).
Based on these results and the observation that imida-
zole as a base is essential for catalyst activity, we have
targeted imidazolyl thiourea derivative 5 as a candidate
that might be further modified to improve catalyst
enantioselectivity.
3. Conclusion
4.3. Compound 2
The examination of the catalytic potential of the pyridyl
thiourea derivatives 1–4, as well as an X-ray analysis of
the new compound 3 proved that the formation of H-
bonding interactions between imine substrates and the
thiourea moiety of the catalysts is crucial for good yields
and enantioselectivities.
This compound was prepared from (R)-1-phenylethylis-
othiocyanate (9) and 2-amino-5-chloropyridine (13) in a
manner analogous to that used for 1 with the difference
that the reaction was carried out in DMF and that the
reaction mixture was stirred at 65 ꢁC for 5 days. Product
20
2 was obtained as a colourless solid. Yield 46%; ½aꢁ
D
1
ꢀ189.0 (c 0.5, CHCl3); H NMR (DMSO-d6) d 11.74
(d, 1H, NH), 10.7 (s, 1H, NH), 8.32 (d, J = 2.7, 1H),
7.87–7.91 (dd, 1H), 7.36–7.38 (m, 5H), 7.22 (m, 1H),
5.53–5.62 (m, 1H), 1.55 (d, J = 6.6, 3H). ESI-MS (posi-
tive ion): m/z 314.1 [M+Na]+. ESI-MS (negative ion): m/
z 290.1 [MꢀH]ꢀ; EI-MS m/z (rel intensity) 291 (M+, 90),
149.1 (25), 129.0 (39), 120.1 (100), 105.1 (44); the exact
molecular mass m/z = 291.0597 2 ppm (M+) was con-
firmed by HRMS (EI, 70 eV).
Furthermore, we established that the substitution of an
imidazolyl moiety for a pyridyl group (derivative 5) re-
sulted in a much more active catalyst.
The results presented herein indicate that the combina-
tion of an imidazolyl group with suitable chiral aliphatic
or aromatic substituents leads to substantial improve-
ments in the catalytic activity of the thiourea catalyst.
Further design, synthesis and application of new im-
proved bifunctional organocatalysts are presently
underway in our laboratories.
4.4. Compound 3
This compound was prepared from isothiocyanate 10
and 2-amino-6-methylpyridine (12) in a manner analo-
gous to that used for 1 with the difference that the reac-
tion was carried out in toluene and that the reaction
4. Experimental
4.1. General
mixture was stirred at 60 ꢁC for 4 days. Product 3 was
20
D
obtained as a white solid. Yield 54%; ½aꢁ ꢀ11.5 (c
0.4, CHCl3); 1H NMR (DMSO-d6) d 12.18 (d, 1H,
NH), 10.45 (s, 1H, NH), 7.62 (t, 1H), 7.28–7.43 (m,
5H), 6.95 (dd, 2H), 4.57–4.61 (m, 2H), 3.31 (s, 3H,
CH3O), 2.43 (s, 3H), 1.02 (d, J = 6.3, 3H); 13C NMR
(DMSO-d6) d 178.42, 154.31, 153.25, 139.02, 138.60,
128.26, 127.44, 126.40, 116.72, 109.28, 84.12, 57.32,
55.44, 23.37, 12.99. EI-MS m/z (rel intensity) 315.2
(M+, 4), 283.2 (12), 194.1 (54), 151.1 (100), 92.1 (42);
the exact molecular mass m/z = 315.1405 2 ppm (M+)
was confirmed by HRMS (EI, 70 eV). Anal. Calcd for
C17H21N3OS: C, 64.73; H, 6.71; N, 13.32. Found: C,
64.84; H, 6.46, N, 13.78.
All solvents were purified by standard procedures and
distilled prior to use. Reagents obtained from commer-
cial sources were used without further purification.
TLC was performed on precoated aluminium silica gel
SIL G/UV254 plates (Marcherey, Nagel&Co.) or silica
gel 60-F254 precoated glass plates (Merck). All reactions
were conducted under an argon or nitrogen atmosphere.
1H NMR spectra were recorded on a Varian Unity 300
spectrometer. EI mass spectra were measured with a
Finnigan MAT 95: Alpha AXP DEC station 3000-
300LX; ESI mass spectra were recorded with a LCQ
Finnigan spectrometer. A Perkin-Elmer 241 polarimeter
was used for optical rotation measurements.
4.5. Compound 4
4.2. Compound 1
This compound was prepared from isothiocyanate 11 and
2-amino-6-methylpyridine (12) in a manner analogous
20
D
(R)-1-Phenylethylisothiocyanate (9) (350 mg, 2.14 mmol)
was added to a stirred solution of 2-amino-6-methylpyri-
dine (12) (231 mg, 2.14 mmol) in ethanol (10.7 ml). The
reaction mixture was heated to reflux for 5 h. The solvent
was removed under reduced pressure and the residue was
allowed to cool. The precipitate formed was filtered off
and washed with ethanol. Further purification by flash
to 3 and was obtained as a white solid. Yield 90%; ½aꢁ
1
ꢀ2.8 (c 1, CHCl3); H NMR (CDCl3) d 12.55 (d, 1H,
NH), 8.88 (s, 1H, NH), 7.50 (t, 1H), 7.11–7.21 (m, 5H),
6.74 (d, J = 7.5, 1H), 6.47 (d, J = 9.0, 1H), 5.45–5.55
(m, 1H), 3.71 (s, 3H), 3.30–3.35 (m, 2H), 2.21 (s, 3H);
13C NMR (CDCl3) d 178.98, 171.45, 155.47, 152.47,
138.82, 136.01, 129.38, 128.30, 126.00, 117.36, 108.54,

5684
S. B. Tsogoeva et al. / Bioorg. Med. Chem. 13 (2005) 5680–5685
59.47, 52.18, 37.81, 23.44. ESI-MS (positive ion): m/z
352.1 [M + Na]+. EI-MS m/z (rel intensity) 329.2 (M+,
38), 167.1 (100), 151.1 (95), 134.1 (56), 108.1 (81), 92.1
(71); the exact molecular mass m/z = 329.1198 2 ppm
(M+) was confirmed by HRMS (EI, 70 eV).
for 9 with the difference that the reaction was carried
out in dry DMF. Product 11 was obtained as a liquid.
20
D
Yield 80%; ½aꢁ ꢀ60.0 (c 1, toluene); 1H NMR
(DMSO-d6) d 7.22–7.34 (m, 5H), 5.09–5.13 (m, 1H),
3.74 (s, 3H), 3.13–3.23 (m, 2H); 13C NMR (DMSO-
d6), d 167.92, 135.32, 129.22, 128.37, 127.15, 60.04,
52.94, 38.17. EI-MS m/z (rel intensity) 221.1 (M+, 9.5),
162.1 (100), 128.1 (20), 91.1 (72).
4.6. Compound 5
This compound was prepared from (R)-1-phenylethylis-
othiocyanate (9) and 2-aminoimidazole (14) in a manner
analogous to that used for 1 with the difference that the
reaction was carried out in a 9:2 mixture of DMF and
toluene and that the reaction mixture was stirred at
4.10. General procedure for the addition of hydrogen
cyanide to substituted imines 15 and 16
A solution of hydrogen cyanide (1.5 mmol) in dry tolu-
ene (1.5 ml) was added in one batch to a suspension of
catalyst (10 mol %) and an aldimine (15 or 16, 1 mmol)
in dry toluene (3.5 ml) under an argon atmosphere at
ꢀ40 ꢁC. The mixture was then stirred at ꢀ40 ꢁC for
2.5 h and subsequently at ꢀ20 ꢁC for a further 16 h.
The crude reaction mixture was analysed by HPLC
using a Daicel Chiralpak AS 250 column at 22 ꢁC
(n-hexane/2-propanol = 90:10, flow rate 1 ml/min,
k = 210 nm; amino nitrile 17: tR (major) = 8.9 min, tR
(minor) = 14.4 min; amino nitrile 18: tR1 (major) =
9.8 min, tR2 (minor) = 8.7 min).
60 ꢁC for 20 h. The desired product was obtained as a
20
colourless solid. Yield 30%; ½aꢁ ꢀ238.0 (c 0.2, CHCl3);
D
1H NMR (DMSO-d6) d 11.26 (br s, NH), 10.6 (br s, 2H,
2· NH), 7.22–7.40 (m, 5H), 6.78 (br s, 2H of imidazole),
5.50–5.60 (m, 1H), 1.52 (d, J = 6.9 Hz, 3H); 13C NMR
(DMSO-d6, 150.8 MHz) d 176.27, 143.22, 142.85,
128.41, 126.87, 125.93, 53.31, 22.25. ESI-MS (positive
ion): m/z 247.1 [M+H]+, 269.1 [M+Na]+: ESI-MS
(negative ion): m/z 245.2 [MꢀH]ꢀ; EI-MS m/z (rel inten-
sity) 246.2 (M+, 100), 126.0 (38), 120.1 (30), 105.1 (83),
84.0 (52), 83.0 (72), 77.0 (32); the exact molecular mass
m/z = 246.0939
HRMS (EI, 70 eV).
2 ppm (M+) was confirmed by
1
Compound 17: H NMR (CDCl3) d 7.2–7.6 (m, 15H),
5.25 (s, 1H), 4.60 (s, 1H), 2.15 (d, 1H).
4.7. Compound 9
1
Compound 18: H NMR (DMSO-d6) d 7.56–7.23 (m,
10H), 5.0 (d, 1H, NH), 3.89–3.75 (m, 2H), 3.62–3.57
(m, 1H).
To a solution of (R)-1-phenylethylamine (6) (0.42 ml,
3.3 mmol) in dry ether (4.2 ml) at ꢀ10 ꢁC were added
CS2 (1.26 ml) and DCC (680 mg, 3.3 mmol). The reac-
tion mixture was allowed to warm slowly to room tem-
perature over a period of 3 h and was then stirred for a
further 12 h at room temperature. The thiourea which
precipitated was removed by filtration and the solvent
was subsequently removed under vacuum. The residue
was taken up in ether and more of the thiourea was able
to be removed by filtration. Evaporation of the solvent
References and notes
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and rapid filtration on silica gel (with hexane) gave
20
D
product 9 as a liquid. Yield 94%; ½aꢁ ꢀ4.3 (c 1.0, ace-
1
tone); H NMR (CDCl3) d 7.30–7.43 (m, 5H), 4.93 (q,
1H), 1.69 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3,
150.8 MHz) d 140.11, 128.84, 128.14, 125.35, 56.98,
24.90. EI-MS m/z (rel intensity) 163.1 (M+, 16), 105.1
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This compound was prepared from (1R,2S)-(ꢀ)-2-ami-
no-1-methoxy-1-phenylpropane (7) in a manner analo-
gous to 9 and was isolated as a yellowish solid. Yield
20
1
94%; ½aꢁ ꢀ100.0 (c 1, acetone); H NMR (DMSO-d6)
D
d 7.32–7.42 (m, 5H), 4.35 (d, J = 4.8, 1H), 4.25–4.27 (m,
1H), 3.22 (s, 3H, CH3O), 1.17 (d, J = 6.3, 3H); 13C
NMR (DMSO-d6) d 136.76, 128.15, 127.33, 84.11,
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This compound was prepared from (S)-phenylalanine
methyl ester (8) in a manner analogous to that used
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(3)ꢁ,
V = 3503.0(9)
A ,
T = 100(2)
K,
Z = 8,
¨
Dx = 1.196 Mg mꢀ3, l = 1.675 mmꢀ1. A total of 47,774
reflections were collected, final R1 (I > 2r(I)) = 0.0319,
wR2 (all data) = 0.0833 for 839 parameters and 9899
reflections, GOF = 1.025, h = 2.89–59.56ꢁ. Absolute struc-
ture parameter = ꢀ0.005(8), maximum and minimum
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residual electron density 0.332 and ꢀ0.209 eAꢀ3. Data
˚
were collected on a Bruker three-circle diffractometer
˚
(CuKa radiation, k = 1.54178 A) equipped with a SMART
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6000 area detector. The structure was solved by using
direct methods and refined by full-matrix least squares on
F2 for all data. All non-hydrogen atoms were refined
anisotropically. H atoms at nitrogens were located in the
difference Fourier map and refined isotropically with
distance restraints. All other H atoms were placed at
calculated positions and refined using a riding model. (G.
M. Sheldrick, SHELXS97 and SHELXL97, University of
Go¨ttingen, Germany, 1997). Data were collected on a non-
merohedrally twinned crystal. The fractional contribution
of the second twin domain was refined to 0.0609(6).
CCDC-266193 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained
free of charge at www.ccdc.cam.ac.uk/data_request/cif (or
from the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; e-mail:
deposit@ccdc.cam.ac.uk).
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