Ugi four-center three-component reaction for the parallel solid-phase synthesis of N-substituted thiomopholinones

Article abstract of DOI:10.1016/j.tetlet.2011.12.074

Starting with resin-bound bifunctional 2-(2-aminoethylthio)acetic, an efficient synthesis of a variety of N-cycloakyl thiomopholinones is described utilizing the Ugi four-center three-component reaction (U-4C-3CR).

Full text of DOI:10.1016/j.tetlet.2011.12.074

Tetrahedron Letters 53 (2012) 1013–1014
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ugi four-center three-component reaction for the parallel solid-phase
synthesis of N-substituted thiomopholinones
⇑
Zhang Liu, Adel Nefzi
Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port Saint Lucie, FL 34987, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Starting with resin-bound bifunctional 2-(2-aminoethylthio)acetic, an efficient synthesis of a variety of
N-cycloakyl thiomopholinones is described utilizing the Ugi four-center three-component reaction (U-
4C-3CR).
Received 15 September 2011
Revised 16 December 2011
Accepted 19 December 2011
Available online 29 December 2011
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Solid phase synthesis
UGI reaction
MCR
Thiomorpholinones
Heterocycles
Combinatorial chemistry
Solid-phase organic synthesis (SPOS) has emerged as a powerful
approach for the rapid generation of structurally diverse com-
pounds in the drug discovery community.1 Multi-component reac-
tions (MCRs) play an important role in combinatorial chemistry
because of its ability to synthesize small drug-like molecules with
several degrees of structural diversity.2 One of the most important
MCRs is the Ugi four-component reaction (U-4C), in which a car-
boxylic acid, an amine, a carbonyl compound, and an isocyanide re-
act in one step reaction, affording related compounds with variable
structures.3 Ugi four-component reaction is a powerful way to
make library scaffolds containing high number of substitution
diversities. Therefore, it has been utilized very efficiently in conju-
gation with solid-phase organic synthesis to prepare large collec-
tion of molecules in a short reaction sequence.4
The N-substituted thiomopholinone is an attractive drug tem-
plate because of its important biological activities in various drug
targets, such as inhibitors of autophagy,5 and norepinephrine reup-
take.6 The development of new synthetic protocols for N-substi-
tuted thiomopholinone derivatives is topics of continuous
interest.7 Herein, we would like to present our approach to the
solid-phase synthesis of enantiopure N-substituted thiomopholi-
nones, utilizing resin-bound 2-(2-aminoethylthio) acetic acid as
bifunctional reagent in a Ugi four-center three-component reaction
(U-4C-3CR),8 and we illustrate the use of this approach for the par-
allel synthesis of diverse N-substituted thiomopholinones.
Our approach toward the synthesis of N-substituted thiomoph-
olin-2-one derivatives is illustrated in Scheme 1. Polymer sup-
ported
L-Fmoc-Cys(Trt)-OH was prepared following the coupling
of -Fmoc-Cys(Trt)-OH to MBHA resin using conventional peptide
L
coupling reagents HOBt/DIC in anhydrous DMF for 2 h. Following
the removal of the Trt group with TFA/TIS/DCM (5:5:90), the
resin-bound Fmoc-cysteine was allowed to react with 2-bromoace-
tic acid at room temperature overnight. Following the removal of
Fmoc with 20% piperidine in DMF, resin-bound bifunctional 2-(2-
aminoethylthio) acetic 2 was obtained. Recently we reported an
efficient method for the multi-component reaction of bifunctional
reactant in solid phase.8 Using our well-established reaction condi-
tions, bifunctional resin 2 was treated with a solution of a ketone in
ACN/MeOH (4:1) for 1 h, followed by the addition of an isocyanide.
The mixture was allowed to react at 65 °C for 24 h, the resin was
washed and dried. The product was released from the resin by clas-
sic HF cleavage at 0 °C for 1.5 h, and then purified by preparative
HPLC (Scheme 1).9
To illustrate the versatility of this methodology, we used three
different isocyanides and four different symmetrical ketones to
perform the parallel synthesis of twelve enantiopure compounds
(4a–l) (Table 1). The desired N-substituted thiomopholinones were
obtained in good yield and high purity.
In conclusion, we used polymer attached 2-amino-3-carboxy-
methyl thiopropanic acid as an effective bifunctional component
in multi-component reaction. Using this powerful tool, we per-
formed the parallel solid phase synthesis of twelve enantiopure
N-substituted thiomopholinone derivatives.
⇑
Corresponding author. Tel.: +1 (772) 345 4739; fax: +1 (772) 345 3649.
E-mail addresses: adeln@tpims.org, anefzi@tpims.org (A. Nefzi).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.074

1014
Z. Liu, A. Nefzi / Tetrahedron Letters 53 (2012) 1013–1014
O
H
O
b, c, d
N
Fmoc
NH2
S
a
N
H
NH2
N
H
OH
S
O
1
Tr t
2
O
O
R1
X
O
R1
X
O
N
H
O
N
H
O
n
N
n
N
e
f
N
H
H2N
S
S
3
4
Scheme 1. Reagents and conditions: (a) L-Fmoc-Cys(Trt)-OH, DIC, HOBt, DMF, 2 h; (b) TFA/TIS/DCM (5:5:90), 30 min; (c) 2-bromoacetic acid, DIEA, DMF, overnight; (d) 20%
piperidine/DMF, (2 Â 10 min); (e) isocyanides, ketones, acetonitrile/methanol (4:1), 65 °C, 24 h8; (f) HF cleavage, 0 °C, 1.5 h.
Table 1
3. (a) Dömling, A. Chem. Rev. 2006, 106, 17–89; (b) Marcaccini, S.; Torroba, T. Nat.
Protoc. 2007, 2, 632–639; (c) Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39,
3168–3210; (d) Ugi, I.; Werner, B.; Dömling, A. Molecules 2003, 8, 53–56; (e)
Main, M.; Snaith, J. S.; Meloni, M. M.; Jauregui, M.; Sykes, D.; Faulkner, S.;
Kenwright, A. M. Chem. Commun. 2008, 5212–5214.
4. (a) Pulici, M.; Quartieri, F.; Felder, E. R. J. Comb. Chem. 2005, 7, 463–473; (b)
Hoel, A. M. L.; Nielson, J. Tetrahedron Lett. 1999, 40, 3941–3944.
5. Gray, D. L.; Xu, W.; Campbell, B. M.; Dounay, A. B.; Barta, N.; Boroski, S.; Denny,
L.; Evans, L.; Stratman, N.; Probert, A. Bioorg. Med. Chem. Lett. 2009, 19, 6640–
6670.
6. Carr, G.; Williams, D. E.; Diaz-Marrero, A. R.; Patrick, B. O.; Bottriell, H.; Balgi, A.
D.; Donohue, E.; Roberge, M.; Andersen, R. J. J. Nat. Prod. 2010, 73, 422–427.
7. Nefzi, A.; Dooley, C.; Ostresh, J. M.; Houghten, R. A. Bioorg. Med. Chem. Lett.
1998, 8, 2273–2278.
8. Liu, Z.; Nefzi, A. J. Comb. Chem. 2010, 12, 566–570.
9. General procedure for the synthesis of N-substituted thiomopholinone
R1
O
NH
( )n
X
H2N
O
N
O
S
Entry
R1
X
n
Obtained MW
Yielda (%)
Purityb (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
Benzyl
Benzyl
Benzyl
Benzyl
C
C
C
O
C
C
C
O
C
C
C
O
1
2
3
2
1
2
3
2
1
2
3
2
362.5 (MH+)
376.5 MH+)
390.5 (MH+)
378.5 (MH+)
354.5 (MH+)
368.5 (MH+)
382.5 (MH+)
370.5 (MH+)
328.4 (MH+)
342.5 (MH+)
356.5 (MH+)
344.4 (MH+)
78
81
72
73
75
79
75
67
71
76
73
62
82
85
86
85
91
82
86
90
89
81
83
93
derivatives:
A 100 mg sample of p-methylbenzhydrylamine (MBHA) resin
(1.1 mequiv/g, 100–200 mesh) was contained within a sealed polypropylene
mesh packet. Reactions were carried out in polyethylene bottles. Following
neutralization with 5% diisopropylethylamine (DIEA) in dichloromethane
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
nButyl
(DCM),
L-Fmoc-Cys(Trt)-OH (6 equiv) was coupled in the presence of
hydroxybenzotriazole (HOBt, 6 equiv) and diisopropylcarbodiimide (DIC,
6 equiv.) in anhydrous DMF for 2 h. Following removal of the Trt group with
TFA/TIS/DCM (5:5:90) and washing with DCM (3Â), the resin was allowed to
react overnight with 2-bromoacetic acid (10 equiv) and DIEA (5 equiv) in DMF,
and then the Fmoc group was deprotected with 20% piperidine in DMF
(2 Â 10 min). The generated resin 2 was put in a solution of a ketone (2 equiv)
in acetonitrile/methanol (4:1) for 1 h at 65 °C, and then an isocyanide (2 equiv)
was added. After allowing the mixture to react at 65 °C for 24 h, the resin was
washed with MeOH (3Â), DMF (3Â), DCM (3Â) and dried. The crude product
was released from the resin by HF cleavage at 0 °C for 1.5 h and then purified by
preparative HPLC10 and characterized by LC–MS under ESI positive mode. 1H
NMR and 13C NMR. ESI-MS (m/z) of 4b: 376.5 (M+H); 1H NMR (500 MHz, DMSO
d6): d 1.23–1.69 (m, 6H); 1.84–2.21 (m, 4H); 3.10–3.52 (m, 4H); 4.24 (m, 2H);
4.91 (m, 1H); 7.19–7.24 (m, 5H); 7.62 (s, 1H); 8.58 (s, 1H); 8.88 (t, 1H, J = 5.75).
13C NMR (125 MHz, DMSO d6): d 21.89, 22.17, 24.78, 28.20, 29.31, 30.00, 32.73,
42.33, 56.30, 65.63, 126.43, 126.89, 128.04, 139.62, 167.65, 173.33, 174.52.
4j
4k
4l
nButyl
nButyl
nButyl
a
Yields based on the weight of crude product and are relative to the initial
loading of the resin.
b
The products were run on a Vydac column, gradients 5–95% formic acid in ACN
in 7 min. The purity was estimated on analytical traces at k = 214 and 254 nm.
References and notes
1. (a) Ziegert, R. E.; Toräng, J.; Knepper, K.; Bräse, S. J. Comb. Chem. 2005, 7, 147–
169; (b) Kundu, B. Curr. Opin. Drug Discovery Dev. 2003, 6, 815–826; (c) Feliu, L.;
Vera-Luque, P.; Albericio, F.; Alvarez, M. J. Comb. Chem. 2007, 9, 521–565; (d)
Gil, C.; Bräse, S. J. Comb. Chem. 2009, 11, 175–197.
2. Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH: Weinheim,
2005. and references therein.
10. The column used was
a Phenomenex (Luna 5u C18(2) 100 Å AX,
150 Â 21.20 mm 5 micron). A 5–95% gradient of water (0.1% Formic acid)
and ACN (0.1% Formic) was used at 15 ml/min for 30 min, fractions were
monitored using a Shimadzu LC–MS 2010 ESI positive mode.