Methyl 1-imidazolecarbodithioate as a thiocarbonyl transfer reagent: a facile one-pot, three-component synthesis of novel 2-substituted-5-aryl-1-oxo-3-thioxo-1,2,3,5,11,11a-hexahydro-6H-imidazo- [1,5-b]-β-carbolines

Article abstract of DOI:10.1016/j.tetlet.2008.11.008

An efficient one-pot, three-component synthesis of novel 2-substituted-5-aryl-1-oxo-3-thioxo-1,2,3,5,11,11a-hexahydro-6H-imidazo- [1,5-b]-β-carbolines employing 1-aryl-1,2,3,4-tetrahydro-β-carboline-3-carboxylates, primary amines (or amino acid esters) an

Full text of DOI:10.1016/j.tetlet.2008.11.008

Tetrahedron Letters 50 (2009) 366–369
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Methyl 1-imidazolecarbodithioate as a thiocarbonyl transfer reagent:
a facile one-pot, three-component synthesis of novel 2-substituted-5-aryl-
1-oxo-3-thioxo-1,2,3,5,11,11a-hexahydro-6H-imidazo-[1,5-b]-b-carbolines
*
Balendu Singh, G. S. M. Sundaram, Nimesh C. Misra, Hiriyakkanavar Ila
Department of Chemistry, Indian Institute of Technology, Kanpur-208 016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient one-pot, three-component synthesis of novel 2-substituted-5-aryl-1-oxo-3-thioxo-1,2,3,5,11,
11a-hexahydro-6H-imidazo-[1,5-b]-b-carbolines employing 1-aryl-1,2,3,4-tetrahydro-b-carboline-3-
carboxylates, primary amines (or amino acid esters) and methyl 1-imidazolecarbodithioate as the
thiocarbonyl transfer reagent is reported.
Received 20 August 2008
Revised 30 October 2008
Accepted 5 November 2008
Available online 7 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Small molecule inhibition of a new class of proteins, that is,
mitotic kinesin Eg5 (also known as kinesin spindle protein KSP)
represents a novel antimitotic approach for the treatment of can-
cer.1 Inhibition of Eg5 kinesin prevents normal bipolar spindle for-
mation leading to cell-cycle arrest and ultimately to apoptosis.2
Unlike existing antimitotic cancer drugs such as vinca alkaloids,
Taxol and epothilone, which target the tubulin proteins which
are essential for many other cellular processes besides formation
of mitotic spindles,3 inhibition of mitotic kinesin Eg5 leads only
to mitotic arrest without interfering with other microtubule-
dependant processes.
3,5- and 1,3,5-substituted thiohydantoins employing easily acces-
sible amino acid esters, primary amines, and methyl 1-imidazole-
carbodithioate 5 as a thiocarbonyl transfer reagent.8,9
Based on this strategy, we have now developed an efficient syn-
thesis of 2-substituted-5-aryl-1-oxo-3-thioxo-1,2,3,5,11,11a-hexa-
hydro-6H-imidazo-[1,5-b]-b-carboline derivatives 6 and 9 by the
reaction of methyl 1-aryl-1,2,3,4-tetrahydro-b-carboline-3-carbox-
ylates, primary amines (or amino acid esters), and methyl 1-imi-
dazolecarbodithioate 5 in a one-pot, three-component procedure.
The results of these studies are reported in this Letter.
Our initial attempts to obtain the tetracyclic b-carboline deriv-
ative 6a from the reaction of cis-1-phenyl-1,2,3,4-tetrahydro-b-
carboline-3-carboxylic acid 3a10 with 5, and aniline under different
reaction conditions were not successful affording either unreacted
starting materials or 1,3-diphenylthiourea in varying yields. We
therefore employed the corresponding methyl ester hydrochloride
4a11 in this cyclization reaction. Thus in a typical experiment,
A number of Eg5 inhibitors including Monastrol 1,2a (the first
small molecule inhibitor of Eg5), have been reported.2c,4 Subse-
quently, Kapoor and co-workers identified a tetracyclic b-carboline
fused heterocyclic scaffold, HR22C16 2 and its 2-aminoalkyl analog
as very potent Eg5 inhibitors (IC50 = 800 10 nM) inducing mitotic
arrest and cell death in Taxol-resistant cancer cells (Fig. 1).5 They
have also developed an efficient diastereoselective traceless solid
phase synthesis of HR22C16 analogs leading to a library of
16,000 small molecules.5a Based on the structure of HR22C16 as
a known Eg5 inhibitor, Giannis and co-workers recently reported
the synthesis and biological evaluation of a small library of hydan-
toin/thiohydantion fused tetrahydro-b-carboline derivatives.6
The reported method for the synthesis of these hydantion/thi-
ohydantion fused tetrahydro-b-carboline derivatives involves
cyclocondensation of 1-substituted-1,2,3,4-tetrahydro-b-carbo-
line-3-carboxylic acid (obtained by Pictet–Spengler cyclization)
with pre-formed isocyanates or isothiocyanates.5–7 Our own inter-
est in the synthesis of these tetracyclic scaffolds derives from our
recently reported efficient one-pot, three-component synthesis of
Table 1
Synthesis of 2-substituted-5-aryl-1-oxo-3-thioxo-1,2,3,5,11,11a-hexahydro-6H-imi-
dazo-[1,5-b]-b-carbolines 6a–k
Entry
4
R
R1
R2
R3
6
Yield (%)
1
2
3
4
5
6
7
8
9
4a
4b
4b
4b
4b
4b
4c
4c
4d
4d
4d
Ph
C-C6H11
H
H
H
6a
6b
6c
6d
6e
6f
6g
6h
6i
85
81
78
83
76
79
75
79
87
75
85
OMe
OMe
OMe
OMe
OMe
H
H
H
H
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
OMe
OMe
OMe
OMe
OMe
H
3,4-(MeO)2C6H3(CH2)2
3-Indolyl(CH2)2
PhCH2
3-MeOC6H4
Bu
2-Furylch2
Bu
C-C6H11
H
OH
OH
OH
10
11
H
H
6j
6k
* Corresponding author. Tel.: +91 0512 2597436, fax: +91 0512 2590260.
E-mail address: hila@iitk.ac.in (H. Ila).
3-(CF3)C6H4
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.008

B. Singh et al. / Tetrahedron Letters 50 (2009) 366–369
367
O
R
H
N
H
N
Me
O
S
OMe
H3N
Cl
S
R
N
Bu
Et3N (1.2 eqv.)
MeOH / Δ / 2 h
O
OMe
EtO
NH
7
MeS
N
H
+
N
H
O
S
O
8
N
SMe
N
5
O
OH
OH
2, HR22C16
H
1, Monastrol
OMe
Et3N (2.3 eqv.)
Figure 1.
NH
H
MeOH / Δ / 3-4 h
2 Cl
N
H
when equimolar quantities of 4a, 5 and aniline were heated in
methanol at reflux in the presence of triethylamine (2.3 equiv),
work-up of the reaction mixture yielded a solid (85%) which was
characterized as trans-2,5-diphenyl-1-oxo-5,6,11,11a-tetrahydro-
1H-imidazo[10,50:1,6]pyrido[3,4-b]indole-3(2H)-thione (trans-2,5-
diphenyl-1-oxo-3-thioxo-1,2,3,5,11,11a-hexahydro-6H-imidazo-
[1,5-b]-b-carboline) 6a by comparison of its physical and spectral
(1H and 13C NMR) data with the previously reported compound.7a
The other substituted 1-(3,4,5-trimethoxy)phenyl, 1-(4-methoxy)-
phenyl, and 1-(3-hydroxy)phenyl 1,2,3,4-tetrahydro-b-carboline-
3-carboxylates hydrochlorides11 4b–d were similarly reacted with
5 and various aliphatic and aromatic amines yielding only trans-2-
substituted-5-aryl-1-oxo-5,6,11,11a-tetrahydro-1H-imidazo[10,50:
1,6]pyrido[3,4-b] indole-3(2H)-thiones (trans-2-substituted-5-
aryl-1-oxo-3-thioxo-1,2,3,5,11,11a-hexahydro-6H-imidazo-[1,5-b]-
b-carbolines) 6b–k in overall excellent yields and in highly diaste-
reoselective fashion (Table 1).12,13 Formation of only trans diaste-
reomers in this reaction is in line with the earlier observations in
the reaction of l-substituted-1,2,3,4-tetrahydro-b-carboline-3-car-
boxylic acids and alkyl/aryl isothiocyanates6,7a (see Scheme 1).
We next extended our studies toward the synthesis of tetracy-
clic heterocycle peptidomimetics of type 9 by the reaction of amino
acid esters as the amine component (Scheme 2). However, at-
tempted reaction of b-carboline ester hydrochloride 4b with 5
R1
R3
R2
O
H
4b-d
R
N
CO2Me
N
N
H
H
S
R1
R3
R2
SMe
9
Ph
R
OMe
OMe
OMe
H3N
Cl
OMe
H3N
Cl
H3N
Cl
H3N
Cl
=
O
O
7b
O
O
7c
7a
OMe
OMe
NH
H3N
Cl
H3N
Cl
O
O
H3N
Cl
OMe
7d
7f
7e
O
and L-leucine methyl ester hydrochloride 7a in refluxing methanol
in the presence of triethylamine under the earlier described condi-
Scheme 2.
O
H
O
H
OH
OMe
SOCl2
MeOH / RT
NH
H
NH2Cl
H
N
H
N
H
R1
R3
R1
R3
R2
R2
4
1
2
3
3, 4a, R = R = R = H
+
1
2
3
b, R = R = R = OMe
S
1
1
3
2
c, R
=
R
=
H; R = OMe
N
N
2
3
+
d, R = R = H; R = OH
RNH2
SMe
5
O
H
10
11
1
9
8
2
Et3N
11a
N
3
R
(2.3 eqv.)
N
4
N
6
5
MeOH / Δ
2-3 h
7
H
H
S
R1
R3
R2
6
Scheme 1.

368
B. Singh et al. / Tetrahedron Letters 50 (2009) 366–369
trans 9b–c in 82% and 78% yields, respectively. Similarly, the reac-
tion of other amino acid esters such as -phenylalanine (7b),
methionine (7c), -tryptophan (7d), -valine (7e), and -alanine
L
L-
L
L
L
(7f) with either 4b or 4c and imidazole dithioate under identical
conditions also proceeded smoothly yielding only trans tetra-
hydro-b-carboline peptidomimetics 9d-h in high yields.12,13
All newly synthesized compounds 6a–k and 9a–h were found
to be optically active as evidenced by their optical rotation. A study
of the enantiomeric purity15 of a few compounds (6a, 6d, 6g, 6i–j,
and 9a–b) however revealed that the reaction yields enantiomeri-
cally pure products in some cases (>91% ee) whereas racemization
was observed in others (9a–b).
In summary, we have developed an efficient one-pot, three-
component synthesis of novel 2-substituted-5-aryl-1-oxo-3-
thioxo-1,2,3,5,11,11a-hexahydro-6H-imidazo-[1,5-b]-b-carbolines
from easily accessible 1-aryl-1,2,3,4-tetrahydro-b-carboline esters,
amines, and 5 as the thiocarbonyl transfer reagent. The present
method does not require less readily available alkyl/aryl isothiocy-
anates which were previously employed in the synthesis of this
class of compounds. The methodology has also been extended to
the facile one-pot, three-component synthesis of a novel class of
hexahydroimidazo-b-carboline peptidomimetic scaffolds such as
Figure 2. Ortep view of structure of 9a.
9
16 by employing amino acid esters as amine partners in this reac-
tions for 6 yielded only an intractable mixture of several products.
On the other hand, prior generation of dithiocarbamate 8 by reac-
tion of L-leucine ester 7a with 5 followed by sequential addition of
1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydro-b-carboline ester
4b, and triethylamine in refluxing methanol in one-pot yielded a
single diastereomeric product (78%), which was characterized
tion. In view of the broad spectrum of biological activity displayed
by both thiohydantoin and b-carboline derivatives, our initial stud-
ies on the facile synthesis of this tetracyclic scaffold combining
both thiohydantoin and b-carboline skeletons are highly encourag-
ing. Further work to attempt this reaction on solid phase and to
study the biological profile of these newly synthesized compounds
are in progress (see Fig. 3).
as methyl (aS,5S,11aR)-a-isobutyl-1-oxo-3-thioxo-5-(3,4,5-trime-
thoxyphenyl)-1,2,3,5,11,11a-hexahydro-2(6H)-imidazo-[1,5-b]-b-
carbolineacetate (trans 9a) on the basis of its 1H, 13C, and mass
spectral data. Further confirmation of the trans-5,11a stereochem-
istry in 9a was obtained from its X-ray diffraction data14 (Fig. 2).
The other 1-(4-methoxyphenyl)- and 1-(3-hydroxyphenyl)-
1,2,3,4-tetrahydro-b-carboline-3-carboxylate hydrochlorides 4c–d
were also reacted with leucine methyl ester and 5 yielding only
Acknowledgments
GSM thanks IITK and BS and NCM thank the CSIR, New Delhi
for research fellowships. Financial support under DST, New Delhi
project is also acknowledged.
SMe
O
Ph
O
H
H
N
O
H
N
N
CO2Me
N
N
CO2Me
CO2Me
N
N
H
N
H
H
N
H
H
H
S
S
S
R1
R3
MeO
OMe
R2
OMe
OMe
9a, R1 = R2 = R3 = OMe, 78%
b, R1 = R3 = H; R2 = OMe, 82%
c, R1 = R2 = H; R3 = OH, 78%
9d, 73%
9e, 75%
O
H
N
O
Me
CO2Me
NH
CO2Me
O
H
H
N
N
N
N
CO2Me
N
H
N
H
N
N
H
S
H
H
H
S
S
MeO
OMe
MeO
OMe
MeO
OMe
OMe
OMe
OMe
9f, 77%
9g, 84%
9h, 84%
Figure 3.

B. Singh et al. / Tetrahedron Letters 50 (2009) 366–369
369
2.62 (t, J = 13.2 Hz, 2H), 3.18 (t, J = 7.6 Hz, 2H), 3.39 (dd, J = 15.5, 5.7 Hz, 1H),
3.74 (s, 6H), 3.85 (s, 3H), 4.14 (dd, J = 12.7, 6.5 Hz, 2H), 4.29 (dd, J = 10.9, 5.8 Hz,
1H), 6.73 (s, 2H,) 6.91 (t, J = 7.31 Hz, 1H), 6.99 (s, 1H), 7.08 (s, 1H,), 7.17 (t,
J = 7.3 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.33 (ddd, J = 5.9, 5.9, 3.92 Hz, 2H), 7.51
(d, J = 7.8 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 8.01 (br s, 1H), 8.24 (d, J = 9.0 Hz, 1H);
13C NMR (100 MHz, CDCl3): d 23.4, 23.5, 42.3, 55.3, 55.6, 56.2, 60.7, 105.9,
107.6, 111.0, 111.2, 112.3, 118.4, 118.8, 119.4, 120.0, 121.9, 122.2, 122.8, 125.8,
127.6, 130.4, 133.7, 136.0, 136.7, 153.3, 172.9, 180.3 MS-FAB (m/z, %): 566 (M+,
33); Anal. Calcd for C32H30N4O4S (566.20): C, 67.82; H, 5.34; N, 9.89. Found: C,
67.94; H, 5.38; N, 9.81.
References and notes
1. (a) Sharp, D. J.; Rogers, G. C.; Scholey, J. M. Nature 2000, 407, 41; (b) Wood, K.
W.; Cornwell, W. D.; Jackson, J. R. Curr. Opin. Pharmacol. 2001, 1, 370.
2. (a) Mayer, T. U.; Kapoor, T. M.; Haggarty, S. J.; King, R. W.; Schreiber, S. L.;
Mitchison, T. J. Science 1999, 286, 971; (b) Kapoor, T. M.; Mayer, T. U.; Coughlin,
M. L.; Mitchison, T. J. Cell Biol. 2000, 150, 975; (c) Sakowicz, R.; Finer, J. T.;
Beraud, C.; Crompton, A.; Lewis, E.; Fritsch, A.; Lee, Y.; Mak, J.; Moody, R.;
Turincio, R.; Chabala, J. C.; Gonzales, P.; Roth, S.; Weitman, S.; Wood, K. W.
Cancer Res. 2004, 64, 3276.
3. (a) Peterson, J. R.; Mitchison, T. J. Chem. Biol. 2002, 9, 1275; (b) Hadfield, J. A.;
Ducki, S.; Hirst, N.; Mcgown, A. T. Prog. Cell Cycle Res. 2003, 5, 309.
4. (a) Wood, K. W.; Bergnes, G. Ann. Rep. Med. Chem. 2004, 39, 173; (b) Nakazawa,
J.; Yajima, J.; Usoi, T.; Ueki, M.; Takatsuki, A.; Imoto, M.; Toyoshima, Y.; Osada,
H. Chem. Biol. 2003, 10, 131; (c) Cox, C. D.; Breslin, M. J.; Mariano, B. J.; Coleman,
P. J.; Buser, C. A.; Walsh, E. S.; Hamilton, K.; Huber, H. E.; Kohi, N. E.; Torrent, M.;
Yan, Y.; Kuo, L. C.; Hartman, G. D. Bioorg. Med. Chem. Lett. 2005, 15, 2041; (d)
DeBonis, S.; Skoufias, D. A.; Lebeau, L.; Lopez, R.; Robin, G.; Margolis, R. L.;
Wade, R. H.; Kozieski, F. Mol. Cancer Ther. 2004, 3, 1079.
5. (a) Hotha, S.; Yarrow, J. C.; Yang, J. G.; Garrett, S.; Renduchintala, K. V.; Mayer, T.
U.; Kapoor, T. M. Angew. Chem., Int. Ed. 2003, 42, 2379; (b) Marcus, A. I.; Peters,
U.; Thomas, S. L.; Garrett, S.; Zelnak, A.; Kapoor, T. M.; Giannakakou, P. J. Biol.
Chem. 2005, 280, 11569.
6. Sunder-Plassmann, N.; Sarli, V.; Gartner, M.; Utz, M.; Seiler, J.; Huemmer, S.;
Mayer, T. U.; Surrey, T.; Giannis, A. Bioorg. Med. Chem. 2005, 13, 6094.
7. (a) Lopez-Rodriguez, M. L.; Jose Morcillo, M.; Garrido, M.; Benhamu, B.; Perez,
V.; de la Campa, J. G. J. Org. Chem. 1994, 59, 1583; (b) Brafia, F. M.; Garrido, M.;
Lopez-Rodriguez, M. L.; Miguel, P.; Morcillo, M. J.; Riano, A. J. Heterocycl. Chem.
1990, 27, 703.
Compound 6g: Yield 75% (0.37 g); yellow solid; mp 143–144 °C (CHCl3/
hexane); Rf 0.5 (1:1 hexane/EtOAc); ½a D25
ꢁ
ꢂ10 (c 0.5, DMSO); IR (KBr): 3450,
2998, 1727, 1607, 1510, 1460, 1302, 1203, 1064, 782, 750 cmꢂ1
;
1H NMR
(400 MHz, CDCl3): d 0.85 (t, J = 7.32 Hz, 3H), 1.27(q, J = 7.50 Hz, 2H), 1.57 (q,
J = 3.66 Hz, 2H), 2.88 (dd, J = 11.0, 1.58 Hz, 1H), 3.45 (dd, J = 15.36, 5.84 Hz, 1H),
3.69 (s, 3H), 3.75 (t, J = 7.36 Hz, 2H), 4.33 (dd, J = 11.0, 5.5 Hz, 1H), 6.77 (dd,
J = 8.8, 1.96 Hz, 2H), 6.95 (s, 1H), 7.06 (dt, J = 7.56, 0.96 Hz, 1H), 7.12 (dt,
J = 7.96, 1.48 Hz, 1H), 7.24 (d, J = 8.56 Hz, 1H), 7.34 (d, J = 8.8 Hz, 2H), 7.45 (d,
J = 7.8 Hz, 1H), 9.05 (br s, 1H), 13C NMR (100 MHz, CDCl3): d 13.56, 19.87, 23.17,
29.59, 41.17, 54.27, 55.18, 55.26, 106.65, 111.32, 113.97, 118.22, 119.66,
122.38, 125.72, 129.95, 130.72, 136.42, 159.78, 173.21, 186.14; MS-FAB (m/z,
%): 420 (M+1, 100); Anal. Calcd for C24H25N3O2S (419.17): C, 68.71; H, 6.01; N,
10.02. Found: C, 68.79; H, 5.96; N, 10.06.
Compound 6j: Yield 81% (0.54 g); yellow solid; mp 207–208 °C (CHCl3/
hexane); Rf 0.33 (1:1 hexane/EtOAc); ½a D25
ꢁ
ꢂ21.2 (c 0.5, DMSO); IR (KBr): 3350,
2930, 1722, 1595, 1454, 1262, 992, 740 cmꢂ1
;
1H NMR (400 MHz, CDCl3): d
1.20–1.40 (m, 3H), 1.6 (br s, 5H), 2.20 (t, J = 11.48 Hz, 2H), 2.89 (dd, J = 14.64,
12.48 Hz, 1H), 3.46 (dd, J = 15.2, 5.8 Hz, 1H), 4.33 (dd, J = 10.76, 5.88 Hz, 1H),
4.55–4.61 (m, 1H), 5.61 (br s, 1H), 6.80 (s, 1H), 6.94 (d, J = 7.8 Hz, 2H), 7.00 (d,
J = 7.8 Hz, 1H), 7.14–7.22 (m, 2H), 7.28 (d, J = 8.04 Hz, 1H), 7.51 (d, J = 7.6 Hz,
1H); 13C NMR (100 MHz, CDCl3): d 23.75, 25.03, 25.85, 28.57, 55.49, 55.56,
107.25, 111.25, 115.55, 116.14, 118.39, 120.17, 122.88, 125.89, 130.26, 130.67,
136.64, 139.75, 156.17, 173.47, 181.13, MS-FAB (m/z, %): 432 (M+1, 100). Anal.
Calcd for C25H25N3O2S (431.17): C, 69.58; H, 5.84; N, 9.74. Found: C, 69.67; H,
5.77; N, 9.82.
8. Sundaram, G. S. M.; Venkatesh, C.; Ila, H.; Junjappa, H. Synlett 2007, 251.
9. Mohanta, P. K.; Dhar, S.; Samal, S. K.; Ila, H.; Junjappa, H. Tetrahedron 2000, 56,
629.
10. The 1-aryl-b-carboline-3-carboxylic acids 3a–d were synthesized by Pictet–
Spengler cyclization of
L-tryptophan with various aryl aldehydes according to
the reported procedure.6
Compound 9a: Yield 78% (0.46 g); yellow solid; mp 220–221 °C (CHCl3/
11. All the methyl ester hydrochlorides 4a–d were prepared by treatment of the
corresponding acids 3a–d with thionyl chloride in methanol at rt. The ester
hydrochlorides 4a–d thus obtained were used as such in further reactions.
12. The structures and stereochemistry of the newly prepared products 6b–k and
9a–h were confirmed from their spectral and analytical data and by
comparison of the chemical shifts and coupling constants with those of
reported values for the known compounds (6a and 6i).6,7a
13. General procedure for the synthesis of hexahydroimidazo-b-carbolines 6a–k: A
mixture of appropriate amine (2.0 mmol), 1-(methyldithiocarbonyl)imidazole
(0.32 g, 2.0 mmol), appropriate b-carboline-3-carboxylic acid methyl ester
hydrochlorides 4a-d (2.0 mmol) and Et3N (0.64 mL, 4.6 mmol) in 10 mL
absolute MeOH was heated at reflux for 3–4 h (monitored using TLC). The
reaction was then cooled to room temperature and the solvent was removed in
vacuum. The residue was dissolved in CHCl3 (25 mL) and washed with water
(2 ꢀ 20 mL) followed by brine (20 mL). The organic layer was dried over
anhydrous Na2SO4 and the solvent evaporated under reduced pressure to
afford the crude products 6a–k, which were purified by column
chromatography over silica gel using hexane/EtOAc (1:4) as eluent.
hexane); Rf 0.3 (1:1 hexane/EtOAc); ½a D25
ꢁ
ꢂ32 (c 0.5, DMSO); IR (KBr): 3411,
3345, 1747, 1594, 1461, 1321, 1237, 1123 cmꢂ1
;
1H NMR (400 MHz, CDCl3): d
0.90 (d, J = 6.6 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H), 1.53 (br m, 1H), 2.00 (ddd,
J = 16.1, 8.33, 4.88 Hz, 1H), 2.27 (ddd, J = 16.1, 8.8, 4.7 Hz, 1H), 2.98 (dd, J = 15.2,
11.0 Hz, 1H), 3.51 (dd, J = 15.2, 5.40 Hz, 1H), 3.68 (s, 6H), 3.70 (s, 3H), 3.83 (s,
3H), 4.4 (dd, J = 11.0, 5.5 Hz, 1H), 5.45 (dd, J = 8.8, 4.5 Hz, 1H), 6.63 (s, 2H), 6.99
(s, 1H), 7.15 (t, J = 7.08 Hz, 1H); 7.22 (t, J = 8.0 Hz,1H), 7.35 (d, J = 8.04 Hz, 1H);
7.52 (d, J = 7.8 Hz, 1H), 8.73 (s, 1H); 13C NMR (100 MHz, CDCl3): d 21.7, 23.0,
24.1, 25.1, 37.2, 52.7, 54.5, 55.4, 55.7, 56.0, 60.6, 105.5, 107.1, 111.3, 118.3,
120.0, 122.8, 125.8, 130.2, 134.1, 136.7, 137.6, 153.0, 170.0, 173.0, 180.6; MS-
FAB (m/z, %): 551 (M+, 100); Anal. Calcd for C29H33N3O6S (551.21): C, 63.14; H,
6.03; N, 7.62. Found: C, 63.54; H, 5.97; N, 7.69.
Compound 9d: Yield 81% (0.53 g); white solid; mp 171–172 °C (CHCl3/hexane);
Rf 0.6 (1:1 hexane/EtOAc); ½a D25
ꢁ
ꢂ28 (c 0.5, DMSO); IR (KBr): 3378, 3292, 1751,
1609, 1509, 1462, 1374, 1240 cmꢂ1
;
1H NMR (400 MHz, CDCl3): d 2.60 (dd,
J = 15.4, 11.0 Hz, 1H), 3.32 (dd, J = 15.4, 5.5 Hz, 1H), 3.48 (dd, J = 13.5, 5.8 Hz,
1H), 3.56–3.70 (m, 1H,), 3.74 (s, 3H), 3.75 (s, 3H), 4.21 (dd, J = 11.5, 5.5 Hz, 1H),
5.57 (br s, 1H), 6.80–6.90 (m, 3H), 7.0–7.36 (m, 10H), 7.49 (d, J = 8.0 Hz, 1H),
7.79 (s, 1H); 13C NMR (100 MHz, CDCl3): d 23.5, 34.2, 52.8, 54.6, 55.3, 55.4, 55.6,
107.4, 111.2, 114.1, 118.3, 120.2, 123.0, 126.0, 126.7, 128.3, 129.2, 129.7, 130.1,
130.6, 136.3, 136.5, 160.0, 169.0, 172.5, 179.2; MS-FAB (m/z, %): 525 (M+, 90);
Anal. Calcd for C30H27N3O4S (525.17): C, 68.55; H, 5.18; N, 7.99. Found: C,
68.76; H, 5.27; N, 7.87.
General procedure for synthesis of hexahydroimidazo-b-carboline peptidomimetics
9a–h: A mixture of appropriate L-amino acid methyl ester hydrochloride salt
(2.0 mmol) neutralized with Et3N (0.28 mL, 2.2 mmol) and 1-
(methyldithiocarbonyl)imidazole (0.32 g, 2.0 mmol) in 10 mL of absolute
MeOH was heated at reflux for 1 h with constant stirring. After the complete
consumption of 1-(methyldithiocarbonyl)imidazole (as shown using TLC), a
mixture of appropriate b-carboline-3-carboxylic acid methyl ester
hydrochloride 4b–d (2.0 mmol) and Et3N (0.64 mL, 4.6 mmol) in absolute
MeOH (5 mL) was added and the reaction mixture was further heated at reflux
for 3–4 h (monitored using TLC). The reaction was then cooled to room
temperature and the solvent was removed under vacuum. The residue was
dissolved in CHCl3 (25 mL) and washed with water (2 ꢀ 20 mL) followed by
brine (20 mL). The organic layer was dried over anhydrous Na2SO4 and the
solvent evaporated under reduced pressure to afford the crude products 9a–h,
which were purified by column chromatography over silica gel using hexane/
EtOAc (1:4) as eluent.
14. X-ray crystallographic data of structure 9a have been deposited at the
Cambridge Crystallographic Data Centre and has been allocated the
deposition number CCDC 695508.
15. The optical purity was determined by chiral HPLC [Chiralcel OD-H column, 25%
IPA/n-hexane]; ee (%): 6a, 91; 6d, 91; 6g, >93 (IA column); 6i, >99.9; 6j, > 99.9;
9a, 25, 9b, 26.
16. For a few hydantoin/thiohydantoins containing N-terminal amino acids and
peptidomimetics, see: (a) Evindar, G.; Batey, R. A. Org. Lett. 2003, 5, 1201; (b)
Xiao, X.-Y.; Ngu, K.; Chao, C.; Patel, D. V. J. Org. Chem. 1997, 62, 6968; (c) Nefzi,
A.; Dooley, C.; Ostresh, J. M.; Houghten, R. A. Bioorg. Med. Chem. Lett. 1998, 8,
2273; (d) Nefzi, A.; Ostresh, J. M.; Giulianotti, M.; Houghten, R. A. Tetrahedron
Lett. 1998, 39, 8199; (e) Chong, P. Y.; Petillo, R. A. Tetrahedron Lett. 1999, 40,
2493; (f) Zhang, D.; Xing, X.; Cuny, G. D. J. Org. Chem. 2006, 71, 1750.
Data for selected compounds:
Compound 6d: Yield 83% (0.42 g); yellow solid; mp 216–217 °C (CHCl3/
hexane); Rf 0.8 (1:1 hexane/EtOAc); ½a D25
ꢁ
ꢂ18.8 (c 0.5, DMSO); IR (KBr): 3420,
3334, 2928, 1738, 1466, 1149, 1007, 824 cmꢂ1
;
1H NMR (400 MHz, CDCl3): d