Efficient assembly of iminodicarboxamides by a truly four-component reaction

Article abstract of DOI:10.1002/anie.201205366

Mix and match: Similar to a galaxy consisting of millions of stars, a multicomponent reaction (MCR) system can result in millions of compounds. The MCR of α-amino acids, oxo components, isocyanides, and amines leads to numerous and diverse compounds, thus having enormous potential for drug discovery or catalyst screening. Copyright

Full text of DOI:10.1002/anie.201205366

Angewandte
Chemie
DOI: 10.1002/anie.201205366
Molecular Diversity
Efficient Assembly of Iminodicarboxamides by a “Truly” Four-
Component Reaction**
Kareem Khoury, Mantosh K. Sinha, Tadamichi Nagashima, Eberhardt Herdtweck, and
Alexander Dçmling*
Dedicated to Ivar Ugi
Multicomponent reaction (MCR) technology is now widely
recognized for its impact on drug discovery projects and is
strongly endorsed by industry as well as academia.[1] Thus, an
increasing number of products based on MCRs are marketed
Scheme 1. The U-5C-4CR.
or under development. Recent examples include bocepre-
vir,[2] retosiban,[3] and mandipropamide,[4] just to name a few.
While the number of described MCRs is enormous, only
a small portion has a wide breath within all classes of educts
and allows the quasi-infinite variation of all starting materi-
als.[5] The size of the chemical space of the different MCR
scaffolds, however, has major implications on the usefulness
of the particular MCR. For example, the classical Ugi four-
component reactions (U-4CR) allows the simultaneous
variation of four very common starting materials (amine,
oxo component, carboxylic acid, and isocyanide, which is
derived from a primary amine).[6] Thus the number of possible
products is very large.[7] In contrast, the three-component
reaction of sulfur, carbon monoxide, and an epoxide yielding
oxathiolan-2-ones, though synthetically very useful, can yield
only a rather limited number of products.[8] Different
strategies for the design of molecular complexity using
MCR chemistry have been devised.[9] We report herein
a novel stereoselective Ugi-type reaction of the four highly
variable starting materials: a-amino acid, oxo component,
isocyanide, and primary or secondary amine, thus comprising
a novel 4-CR.
oxo components, isocyanides, and an alcohol as a solvent and
reactant. The reaction proved to be versatile and several
reports document their usefulness.[11] Remarkably, this reac-
tion also lead to the first potent orally available and selective
nonpeptide oxytocin antagonist, which is currently under-
going clinical trials for preterm birth.[3,12]
This reaction, however only comprises a MCR where
three components show a great variability: the a-amino acid
1, the oxo-component 2, and the isocyanide 3. The variability
of the alcohol component 4, which is also the solvent, is rather
restricted to low-molecular-weight liquids such as MeOH and
EtOH. The restriction is a result of the poor solubility of the
amino acids in other alcohols as well as the reduced
nucleophilic reactivity of the alcohols.
The key reaction intermediate is the six-membered
a adduct of the a-amino acid, the oxo component, and the
isocyanide. This adduct then undergoes nucleophilic attack by
the solvent (4) methanol to give the linear product 5
(Scheme 2). We envisioned that an N nucleophile, such as
About 15 years ago Ugi et al. described for the first time
the discovery of a novel variant of his reaction (Scheme 1).[10]
The reaction was termed a 5-center-4-component reaction
(U-5C-4CR) because of the use of bireactive a-amino acids,
[*] K. Khoury, Dr. M. K. Sinha, Dr. T. Nagashima, Prof. A. Dçmling
Departments of Pharmaceutical Sciences and Chemistry
University of Pittsburgh, Biomedical Science Tower 3
3501 Fifth Avenue, Pittsburgh, PA 15261 (USA)
Scheme 2. Proposed key intermediate and the two competing reaction
pathways.
E. Herdtweck
Technische Universitꢀt Mꢁnchen, Department Chemie
Lehrstuhl fꢁr Anorganische Chemie
Lichtenbergstrasse 4, 85747 Garching bei Munchen (Germany)
the primary or secondary amine 6, could potentially also work
as a nucleophile and successfully compete with the alcohol
solvent to attack the six-membered a adduct, thus leading to
the iminodicarboxamide derivative 7. The outcome of the
projected reaction however was a priori unclear since the
amino acid amine and the external primary or secondary
amine could compete for the oxo component and result in
different types of Ugi or Passerini products (e.g., by U-5C-
4CR, U-4CR, U-3CR, or P-3CR) or mixtures thereof. We
hypothesized however, that an intramolecular reaction
involving the Schiff base of the bifunctional a-amino acid as
Prof. A. Dçmling
University of Groningen, Department of Drug Design
A. Deusinglaan 1, 9713 AV Groningen (The Netherlands)
E-mail: a.s.s.domling@rug.nl
Homepage: http://adoemling.wix.com/laboratories
[**] This work was supported by the NIH grants 1R21GM087617-01,
1P41GM094055-01, and 1R01GM097082-01.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201205366.
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opposed to an intermolecular reaction of the Schiff base or
enamine formed by the additional primary or secondary
amine should be more favorable and would preferentially
form the cyclic a adduct, thus leading to the new scaffold
versus the acyclic a adduct leading to the classic intermolec-
ular Ugi product. Additionally a reaction proceeding by the
projected reaction pathway would be of high value since this
would represent one of the very few four-component reac-
tions which are truly variable in all components.
To test our MCR hypothesis we first reacted leucine
(1{7}), 2-fluorobenzaldehyde (2{16}), benzyl isocyanide (3{1}),
and morpholine (6{14}) and surprisingly found the expected
compound 7{7,16,1,14} as the major product (see Figure 1 for
structures). Extensive optimization of the reaction was
performed including a look at the solvent, temperature,
microwave versus thermal conditions, reaction time, and
catalyst and their influence on different combinations of
starting materials. In previous Ugi-type reactions where
intramolecular cyclization of the a-adduct occurs, trifluoro-
ethanol (TFE) or similar solvents were advantageously used
because of their reduced nucleophilicity.[13] Unexpectedly
when TFE was attempted in this reaction it was found to
produce a significant amount of the trifluoroethylester 5’ as
side product. An optimal solvent mixture was found to be
MeOH/H2O (4:1), which is a compromise in solubility for the
different classes of starting materials. As a result of the poor
solubility of most amino acids we attempted to speed up the
reaction by using microwave conditions (from 60–1208C for
anywhere from 30 min to 2 h). Under these reaction con-
ditions the amino acid completely solubilized in the reaction
mixture, however no increase in yield was found. Also as
a result of the formation of unwanted side products, and
therefore an increased difficulty in separation, the benefit
from the time gained by using microwave conditions was
outweighed by the amount of extra time spent optimizing
separation conditions. Instead the reactions were run at room
temperature for three days.
Next we investigated the scope of the reaction by using
representative starting materials of each class and synthesiz-
ing a library of iminobisamides (Figure 1). Not surprisingly it
was found that the identity of the starting materials and their
specific combinations played a role in the overall yield and
selectivity of the reaction. We successfully used virtually all
the natural a-amino acids and some nonnatural ones (1),
including the hindered 1{3} or oxidation labile 1{9} and 1{16}.
It was found that while use of Tyr (1{13}) gave the desired
product 7{13,7,9,17}, the use of the tert-butyl-protected Tyr
1{14} gave the product 7{14,7,9,17} in much better yields (25%
versus 47%). Similar results were seen for Ser (1{5}) and the
tert-butyl-protected Ser 1{10} giving the products 7{5,5,4,3}
(23%) and 7{10,5,4,3} (40%), respectively. Therefore a-
amino acids with reactive side chains (e.g. Ser, Glu, Asp, Lys)
were used in their side-chain-protected form. As oxo compo-
nents (2) we often used symmetrical ketones for the sake of
formation of only one stereoisomer, however both aldehydes
and ketones worked equally well in this reaction. Cyclic
ketones, cyclobutanone (2{3}), cyclopentanone (2{4}), and
cyclohexanone (2{5}) worked well in the reaction, while
cycloheptanone (2{6}) and ketones having a larger ring size
Figure 1. The classes of stating materials as used for the U-4CR
reported herein. Boc=tert-butoxycarbonyl, Trt=trityl.
reacted with suboptimal yields (e.g., 7{14,6,5,9}: 23%).
Different isocyanides (3) were used, including aromatic,
heteroaromatic, aliphatic, and bulky isocyanides and they
generally worked well. Primary and secondary amines (6)
were used as the fourth component, and generally worked
well, including functionalized, heterocyclic, aromatic, and
heteroaromatic amines. As part of the National Institutes of
Health roadmap initiative, a project aimed at addressing
roadblocks to research and transforming the way biomedical
research is conducted by providing a large and diverse
publicly available compound library for the discovery of
2
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molecular probes, we have now synthesized more than 400
compounds based on this reaction.[14] Yields of representative
compounds are summarized in Table 1.
Table 1: Products of the U-4CR.
Compound
Yield [%][a]
Compound
Yield [%][a]
7{2,11,9,6}
7{9,5,9,10}
7{14,7,9,17}
7{15,6,1,16}
7{1,10,4,17}
7{6,3,1,3}
7{11,2,4,19}
7{15,9,5,10}
7{15,2,8,6}
7{14,5,7,16}
7{10,7,3,7}
7{11,2,2,6}
7{18,5,1,8}
7{6,4,6,5}
54
50
47
43
42
54
40
51
52
47
41
45
41
33
54
44
51
53
47
7{12,13,5,16}
7{7,15,9,19}
7{10,5,4,3}
7{19,4,2,20}
7{12,4,3,13}
7{15,4,3,13}
7{12,5,9,12}
7{17,5,9,18}
7{12,5,9,11}
7{7,5,3,13}
7{7,5,3,3}
7{14,14,5,2}
7{2,16,2,14}
7{2,16,2,15}
7{15,2,10,15}
7{3,12,5,9}
7{1,12,10,4}
7{8,8,5,3}
40
34
40
41
38
37
63
62
30
48
46
31
32
28
38
30
41
40
34
Figure 2. a) Example of Cs- and C2-symmetrical products conveniently
formed by the new U-4CR. b) ORTEP diagram for the compound
7{15,4,3,13} in the solid state.[22] Thermal ellipsoids are shown at 50%
probability.
potentially serve as chiral tridental ligands for catalytic
organic transformations.
7{4,5,9,2}
7{7,8,4,9}
7{6,9,2,1}
7{4,8,1,4}
In another attempt to explore the potential of this four-
component reaction we used bifunctional starting materials to
cyclize the initially formed Ugi products. Thus we performed
cyclizations based on the Pictet–Spengler reaction, and
deprotective cyclization. Representative examples (8–10)
are shown in Scheme 3. Remarkably these cyclizations can
be performed without purification of the initial Ugi product.
Iminodicarboxamides are a particular useful class of
scaffold and have been reported to have diverse biological
activities, including factor Xa,[15] HIV-1 protease,[16] renin,[17]
thrombin,[18] and most recently p53/mdm2 inhibition.[19] Our
one-pot synthesis towards this scaffold constitutes a major
7{15,5,4,9}
7{16,5,4,15}
[a] Yields of isolated product after preparative SFC purification (see the
Supporting Information).
All reactions were performed on a 0.5 mmol scale and the
products were separated into their component diastereoiso-
mers by efficient and fast supercritical fluid carbon dioxide
(SFC) technology. The yields in most cases are between 40
and 60% after chromatographic separation and are satisfac-
tory taking into account the complexity of the reaction.
Next we asked the question of the stereochemical
integrity of the formed products. Thus all reactions performed
were investigated by SFC using a chiral stationary phase (see
the Supporting Information). We investigated the influence of
the amine component on the integrity of the amino acid
stereocenter. We found that primary amines lead to retention
of the stereochemical integrity of the amino acid stereocenter,
whereas secondary amines lead to partial racemization. This
racemization can be rationalized by the higher pKB value (by
1–2 units) of secondary amines. For example, use of the
aldehyde 2{17} with l-Ala (1{2}), benzyl isocyanide (3{1}),
and morpholine (6{14}) leads to the formation of four
stereoisomers, which were separated. When 2-morpholinoe-
thylamine 6{15} was used only two stereoisomers were found.
Racemic d,l-Ala in these reactions was used as a control (see
Figures 1–4 in the Supporting Information). As a further
proof of the structures we solved several compounds in
molecular detail using single-crystal X-ray analysis and the
structure of
The structure of 7{15,4,3,13} is shown in Figure 2. An
example of a noteworthy combination is phenylacetaldehyde
(2{13}), Phe (1{12}), isobutyl isocyanide (3{5}), and isobutyl
amine (6{16}), the reaction of which leads to C2- and Cs-
symmetric products in a ratio of 6:1 (Figure 1). These
otherwise difficult to access C2-symmetric compounds could
Scheme 3. Example products resulting from the cyclization of the
reported U-4CR (7). The newly formed bonds of the cyclization are
indicated in red. MW=microwave.
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Received: July 7, 2012
Published online: && &&, &&&&
Keywords: cyclization · drug discovery · molecular diversity ·
.
multicomponent reactions · synthetic methods
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Angew. Chem. Int. Ed. 2012, 51, 1 – 5
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Angewandte
Chemie
Communications
Molecular Diversity
Mix and match: Similar to a galaxy con-
sisting of millions of stars, a multicom-
ponent reaction (MCR) system can result
in millions of compounds. The MCR of a-
amino acids, oxo components, isocya-
nides, and amines leads to numerous
and diverse compounds, thus having
enormous potential for drug discovery or
catalyst screening.
K. Khoury, M. K. Sinha, T. Nagashima,
E. Herdtweck,
A. Dçmling*
&&&& — &&&&
Efficient Assembly of
Iminodicarboxamides by a “Truly” Four-
Component Reaction
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!