A novel Δ-thiolactone scaffold by a versatile intramolcular multicomponent reaction

Article abstract of DOI:10.3987/COM-08-S(F)101

The three component reaction of α-aminoacids, mercaptoacetaldehyde and an isocyanide smoothly and stereoselectively yields the novel scaffold 1,2-disubstituted N-alkyl(aryl)-6-oxo thiomorpholine-3-carboxamide. In this communication we present our prelimin

Full text of DOI:10.3987/COM-08-S(F)101

HETEROCYCLES, Vol. 77, No. 2, 2009
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HETEROCYCLES, Vol. 77, No. 2, 2009, pp. 731 - 738. © The Japan Institute of Heterocyclic Chemistry
Received, 8th April, 2008, Accepted, 10th November, 2008, Published online, 11th November, 2008
DOI: 10.3987/COM-08-S(F)101
A
NOVEL Δ-THIOLACTONE SCAFFOLD BY
A
VERSATILE
INTRAMOLCULAR MULTICOMPONENT REACTION
Stuti Srivastava,#1 Barbara Beck,#1 Eberhardt Herdtweck,2 Kareem
Khoury,1 and Alexander Dömling*1
1asd30@pitt.edu, University of Pittsburgh, Departments of Pharmaceutical
Sciences and Chemistry, Pittsburgh, PA 12580, USA
2Technische Universität München, Garching, Germany
Abstract
mercaptoacetaldehyde and an isocyanide smoothly and stereoselectively
yields the novel scaffold 1,2-disubstituted N-alkyl(aryl)-6-oxo
–
The three component reaction of α-aminoacids,
thiomorpholine-3-carboxamide. In this communication we present our
preliminary results on six compounds derived from this unprecedented
reaction.
INTRODUCTION
6-Oxothiomorpholine derivatives comprise a class of synthetic and biologically active
compounds. Recently reported activities include antibiotic, anticancer and plant protection
activities.1-3 In addition thiolactones are part of the natural product class of thiolactomycins,
including U-68204, TUE-3010 and thiotetromycin with antibiotic activity (Scheme 1).4,5 Analysis
of the recent high resolution X-ray structure analysis of thiolactomycin in its biological target
β-ketoacyl acyl carrier protein synthase II (FAS-II) prompted us to design novel inhibitors of this
important and essential antibacterial target (Figure 1).6
H2N
O
S
S
S
S
O
O
O
O
O
HO
HO
HO
HO
NH2
thiolactomycin
thiotetromycin
TUE-3010
U-68204
Scheme 1. Biologically active compounds with a thiolactone moiety.
This paper is dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th
birthday.

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HETEROCYCLES, Vol. 77, No. 2, 2009
Figure 1. The analysis of the binding site of thiolactomycin serves as a template to design novel bioactive
MCR scaffolds, the herein reported thiomorpholine. The binding site of thiolactomycin (PDB ID: 1FJ4)
reveals the important hydrogen bond contact between the thiolactone carbonyl and two adjacent histidine
protons as well as the hydrogen bond network around the enol moiety including several water molecules
and a valine backbone carbonyl. Crucial for the activity of thiolactomycins and derivatives is the soft and
hydrophobic sulfur as well as the hydrophobic side chain undergoing strong van der Waals interactions
with several surrounding hydrophobic aminoacids phenylalanine, methionine, alanine and proline. The
picture was generated using PyMol.
Multicomponent reactions (MCRs) are a very economic way to produce biological active lead
structures, since quite elaborated structures are accessible in only one key step, eventually
followed by a subsequent chemical transformation.7 In addition several hundred scaffolds have
been described in the past thus potentially offering considerable chemical diversity.8 Several
bioactive MCR products are currently undergoing clinical evaluation or are already marketed.9-11
As part of our ongoing studies directed to the discovery of novel antibacterial agents against
neglected diseases including Tuberculosis, we herein communicate our preliminary results of a
recently discovered multicomponent reaction leading to the novel scaffold of 1,2-disubstituted
N-alkyl(aryl)-6-oxo thiomorpholine-3-carboxamides.12-14

HETEROCYCLES, Vol. 77, No. 2, 2009
733
RESULTS AND DISCUSSION
The classical Ugi MCR of an isocyanide, an oxo component, an amine and an acid component
yields structurally diverse scaffolds depending on the nature of the acid component, which
governs the rearrangement step of the key intermediate α-adduct. The α-adduct is formed as an
intermediate, comprising the highly unusual addition of the nucleophilic acid anion and the
electrophilic immonium ion onto the isocyano carbon.15 Another source of scaffold diversity in
isocyanide-based MCR arises from intermolecular or intermolecular reactions with nucleophiles
and the α-adduct. A very fruitful and stereoselective way to perform Ugi MCRs is using
unprotected α-aminoacids, yielding several interesting scaffolds, including iminodicarboxylicacid
methylester monoamide, γ-lactones, lactames, ketomorpholine and diketopiperazine.16-23 All
these reactions depend on the intermediate formation of a cyclic α-adduct and a subsequent
reaction with an intra- or intermolecular nucleophile. The intermediately formed hetero carbonic
acid anhydride represents a strong acylating intermediate and can react in an intermolecular (e.g.
with methanol as the solvent) or intramolecular fashion (with nucleophilic side chains in one of
the starting materials) and thus determines the structural fate of the formed scaffold (Scheme 2).
The ratio inter- vs. intramolecular acylation can be governed by the choice of solvent. E.g. if
trifluoroethanol as a non nucleophilic solvent is used the intramolecular reaction pathway is
dominant.
R
NC
CHO
+
+
COOH
R
R
H2N
O
R
R
R
O
O
O
H
H
IE
IA
N
O
N
R
H2N
R
R
N
N
N
O
H
H
O
O
R
IA
O
R
H
R
N
N
R
HN
O
R
O
Scheme 2. Intra- (IA) and intermolecular (IE) nucleophilic acylation reactions in order to generate
scaffold diversity through isocyanide based MCRs of α-aminoacids.

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HETEROCYCLES, Vol. 77, No. 2, 2009
Recently, we discovered the reaction of homocysteine with oxo components and isocyanides in
trifluorethanol forming end-on γ-thiolactones.24 Here we describe a related MCR transformation,
in which the intramolecular nucleophile comes with the oxo component, e.g.
mercaptoacetaldehyde 2. To test this reaction hypothesis, we reacted 1 equivalent of each,
mercaproacetaldehyde 2, proline 1 and benzylisocyanide 3 in a 0.1 M solution of trifluoroethanol
at rt (Scheme 3). After warming to 20 oC the initial amino acid suspension became clear and by
TLC and HPLC-MS control new products were formed. Isolation of the new material by
preparative silicagel chromatography and analysis by NMR revealed the formation of a new
compound 4 which was in accordance with the designed thiomorpholine scaffold, e.g. the
formation of a downfield signal for the thioester carbonyl carbon at ~200 ppm in the 13C NMR is
very indicative.25 Luckily, a diffraction quality crystal could be grown and the corresponding X-ray
structure analysis confirmed the predicted structure (Figure 2).26
O
O
S
S
NC
TFE
rt
+
COOH
+
CHO
HS
N
O
N
O
N
+
H
N
H
N
H
Molecular Weight =115.13
Exact Mass =115
Molecular Formula =C5H9NO2
1
21%
96:4
2
3
4
5
Molecular Weight =290.39
Exact Mass =290
Molecular Formula =C15H18N2O2S
Scheme 3 The reaction of proline 1, mercaptoacetaldehyde 2, and benzylisocyanide 3 in TFE
yields highly specifically the syn-isomer 4.
Figure 2. Left: Stereopicture of the X-ray structure of thiomorpholine 4. The picture was
generated using PyMol (www.pymol.com). Right: ORTEP plot of compound 4 with atom
numbering.

HETEROCYCLES, Vol. 77, No. 2, 2009
735
Next, we performed some variations in the α-aminoacid, including methionine 9, glycine 7,
alanine 6, valine 10 and isocyanide component, including aromatic 6, 7, sterically hindered
aliphatic 9, complex ones 10. All performed reactions yielded the expected thiomorpholines. The
compounds were generally formed as a mixture of diastereomers. Cyclic amino acids, however,
afforded mostly one diastereomer. The diastereomers can be easily separated by silicagel
chromatography. We noted that the conversion of the reaction in no case better than 50%.
Although the reaction products are formed in medium to pure isolated yields only (much higher
based on conversion), the complexity of the products formed, we feel, deserves reporting (Table
1). The two thiolactone scaffolds we reported are complementary in their sterical access of the
thioester moiety. Whereas, the earlier described γ-thiolactones is very accessible, the herein
described δ-thiolactone is sterically hindered due to the nature of the amino acid motif and the
isocyanide. Therefore one can expect differential reaction of the two scaffolds towards biological
nucleophiles, which can be leveraged for the design of their biological activity.
Table 1. Structures and isolated yields of thiomorpholines prepared.
no
structure
Yield*
[%]
no
structure
yield
[%]
(de)
S
O
S
O
6
24
9
34
H
H
N
N
(78:22)
(96:4)
N
N
H
H
O
O
S
S
O
S
O
7
8
16
10
22
O
NO2
H
H
N
N
(73:27)
N
N
H
N
H
N
O
O
MeO
MeO
S
O
68
O
H
N
(76:24)
N
O
*Yields are calculated on 50% conversion
In summary, we have described a novel 3-component isocyanide-based multicomponent
reaction of isocyanides, mercaptoacetaldehyde and α-amino acids yielding substituted
N-alkyl(aryl)-6-oxo thiomorpholine-3-carboxamide. Noteworthy, the described scaffold is

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HETEROCYCLES, Vol. 77, No. 2, 2009
unprecedented in chemical literature and is of interest with potential inherent biological activities.
Current investigations in our laboratory are targeted towards the synthesis of libraries of
δ-thiolactone and their biological investigation.
ACKNOWLEDGEMENT
We thank Sukhpreet Kaur and Kelly Hey for their help in the preparation of some compounds.
We thank The Drug Discovery Institute and University of Pittsburgh for funding.
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25. Representative procedure for 1-oxo-hexahydro-pyrrolo[2,1-c][1,4]thiazine-4-carboxylic acid
benzylamide (4): Amino acid (1 mmol) was dissolved in trifluoroethanol (TFE) (10 mL) at rt.
Isocyanide (1 mmol) and 2,5-dihydroxy-1,4-dithiane (0.5 mmol) were added simultaneously
to it. The reaction mixture was stirred over night at rt. The solvent was evaporated and the
residue was dissolved in EtOAc (10mL) and extracted with 2 x 5mL of water, and 1x 5mL of
brine. The organic layer was dried over magnesium sulfate and concentrated. The crude
product was purified by column chromatography on silica gel with petroleum ether/EtOAc
elution gradient from 2/1 to 1/2. 4 Yield: 60 mg (41%), 57 mg of not converted amino acid
could be recovered (~50% conversion) [diasteriomeric ratio by 1H NMR of the crude mixture
96:4] Molecular Formula = C15H18N2O2S (290.4 g/mol); Calc. Mass = 290.109; HRMS found:
m/z: 291.1271 [M+H]+, 313.1153 [ M+Na]+; 1H-NMR for the major diastereomer (CDCl3, 600
MHz): δ 1.80-1.87 (2H, m), 1.94-2.00 (1H, m), 2.15-2.22 (1H, m), 2.59 (1H, q, J= 8.5 Hz),
3.16-3.19 (1H, m), 3.46 (1H, brd, J= 14.28 Hz), 3.56 (1H, t, J= 7.92 Hz), 3.65 (1H, dd, J=
4.52 Hz & 14.28 Hz), 3.72 (1H, d, J= 6.48 Hz), 4.50 (2H, d, J= 6.06 Hz), 7.23-7.28 (3H, m),
7.32-7.34 (2H, m), 7.54 (1H, brs); 13C-NMR (CDCl3, 150 MHz): δ 22.01, 24.19, 31.64, 43.47,

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HETEROCYCLES, Vol. 77, No. 2, 2009
53.14, 61.90, 65.45, 127.53, 128.70, 138.15, 171.47, 201.35.
26. Crystal structure analysis of compound 4: C15H18N2O2S, Mr = 290.38, colorless needle (0.18
× 0.18 × 0.71 mm3), triclinic, P (No.: 2), a = 10.2106(8), b = 11.757(2), c = 13.056(2) Å, α =
102.868(13)°, β = 101.942(11)°, γ = 102.836(12)°, V = 1434.6(4) Å3, Z = 4, dcalc = 1.344
gcm-3, F000 = 616, μ = 0.229 mm-1, T = 153. K, Θ range of 3.03° < Θ < 25.33°. A total of
17362 reflections were integrated. After merging (Rint = 0.031), 5233 [3150: Io>2σ(Io)]
independent reflections remained and all were used to refine 361 parameters. Full-matrix
least-squares refinements converged with R1 = 0.0384 [Io>2σ(Io)], wR2 = 0.0984 [all data],
GOF = 0.921, and shift/error < 0.001. For more details see Supporting Information.
Crystallographic data (excluding structure factors) for the structure reported in this paper
have been deposited with the Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC-683992. Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: (+44)1223-336-033;
e-mail: deposit@ccdc.cam.ac.uk).