Various cyclization scaffolds by a truly Ugi 4-CR

Article abstract of DOI:10.1039/c3ob40523k

Efficient access to a large chemical space based on new scaffolds with defined 3D conformations and highly variable in the side chains is needed to find novel functional materials. Four heterocyclic scaffolds based on a four component Ugi reaction of α-amino acids, oxo components, isocyanides and primary or secondary amines suitably functionalized are described. A handful of examples are described for each scaffold.

Full text of DOI:10.1039/c3ob40523k

Organic &
Biomolecular Chemistry
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Various cyclization scaffolds by a truly Ugi 4-CR†
Mantosh K. Sinha,a Kareem Khoury,a Eberhardt Herdtweckb and
Cite this: Org. Biomol. Chem., 2013, 11,
Alexander Dömling*a,c
4792
Efficient access to a large chemical space based on new scaffolds with defined 3D conformations and
highly variable in the side chains is needed to find novel functional materials. Four heterocyclic scaffolds
based on a four component Ugi reaction of α-amino acids, oxo components, isocyanides and primary or
secondary amines suitably functionalized are described. A handful of examples are described for each
scaffold.
Received 14th March 2013,
Accepted 17th May 2013
DOI: 10.1039/c3ob40523k
www.rsc.org/obc
Ivar Ugi, half a century ago, pioneered the use of multicompo- isocyanide 4, thus comprising a novel truly 4-CR (Scheme 1).9
nent reaction technology (MCR) for the discovery of novel Herein, we would like to report on the design of Ugi post-
agents with preferred properties.1 MCR is now widely recog- condensation reactions leading to four highly variable hetero-
nized for its impact on drug discovery projects and is strongly cyclic scaffolds.
endorsed by academia in addition to industry.2 Recent reviews
Due to the well-known functional group compatibility of
on chemistry and biology of MCRs give comprehensive proof the Ugi starting materials, we envisioned the construction of
for the increasing number of marketed products based on heterocyclic scaffolds involving the unique and reactive sec-
MCRs including Boceprevir,3 Retosiban,4 or Mandipropamid,5 ondary amine formed during our Ugi reaction variation.
just to name a few. Based on the sheer number of theoretically Several intramolecular lactamizations based on different Ugi
accessible MCR products, recent trends in drug discovery are scaffolds have been reported in the past.10 However, our syn-
geared toward leveraging MCR chemistry for use in various thesis differs from them by (1) yielding a different scaffold and
virtual screening tools.6 For example, the recently introduced (2) using much milder conditions of cyclization. By introdu-
ANCHOR.QUERY freeware offers >25 million virtual MCR com- cing methyl 2-formylbenzoate as an oxo component and some
pounds for structure- and web-based drug design purposes.6c optimization of the reaction conditions, we could in fact see
While there are hundreds of different MCRs described in the formation of the expected isoindolinone scaffold (Table 1).
chemical literature, only a few are highly variable in all starting
One equivalent amount of amino acids, isocyanide, primary
materials, such as the Ugi, Passerini, and van Leusen reac- or secondary amine and methyl 2-formylbenzoate were added
tions.1,7 The size of the chemical space of different MCR together in a microwave vial in one-tenth molar concentration
scaffolds has major implications for the usefulness of a particu- for one hour at 80 °C. The crude reaction mixture was checked
lar MCR serving as a suitable virtual search space. Amongst the via supercritical fluid chromatography-mass spectrometry
different strategies for the design of molecular complexity using (SFC-MS) and both masses for the Ugi product and the
MCR chemistry,8 post-Ugi secondary cyclization has been a very newly cyclized product 7 could be seen from the mixture of 6.
fruitful strategy in the past to accomplish novel scaffolds.
Work-up was done to remove any unreacted amino acid and
We have recently introduced a stereoselective Ugi-type reac- the reaction was heated again in ethanol. SFC-MS then
tion using four highly variable starting materials: primary or revealed that only cyclized product 7 remained. Either one dia-
secondary amine 1, α-amino acid 2, oxo component 3, and stereomer precipitated out (7a and 7b) or a crude mixture was
aUniversity of Pittsburgh, Biomedical Science Tower 3, 3501 Fifth Avenue, Pittsburgh,
PA 15261, USA
bTechnische Universität München, Department Chemie, Lehrstuhl für Anorganische
Chemie, Lichtenbergstrasse 4, D-85747 Garching bei Munchen, Germany
cUniversity of Groningen, Department of Drug Design, A. Deusinglaan 1, 9713 AV
Groningen, The Netherlands. E-mail: a.s.s.domling@rug.nl
†Electronic supplementary information (ESI) available: Experimental procedures
including the synthesis and characterizations of small molecules, crystal data, as
well as the analysis of virtual libraries are provided. CCDC 922313–922315. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ob40523k
Scheme 1 The previously reported Ugi 4-CR of α-amino acid, oxo-component,
isocyanide and primary or secondary amine.
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Table 1 Cyclization of the Ugi 4-CR to yield the isoindolone scaffold
Comp
Yielda [%]
35
7a
7b
50
7c
42
40
7d
a Overall yield in one step.
purified via SFC (7c and 7d). When primary amines were used
(7a and 7b), crude SFC traces revealed diastereomeric ratios of
7 : 3 and only the major diastereomer precipitated (see ESI-21,
ESI-25†). When secondary amines were used (7c and 7d), SFC
traces using chiral cell OD revealed four stereoisomers in
equal ratio, thus suggesting the racemization of the amino
acid stereocenter by secondary amines as previously discov-
ered9 (see ESI-28, SI-29†).
As reported previously, the Ugi reaction generally works
well with aromatic and aliphatic aldehydes and ketones.
Another available building block of suitable bifunctional
orthogonal starting materials is the β-ketoester. In fact, when
employing 2-oxocyclohexane carboxylic acid ethyl ester under
heating conditions at 85 °C, SFC-MS revealed the formation of
the Ugi product as well as trace amounts of the corresponding
pyrrolidinedione scaffold 9 (Table 2). Upon addition of 3
equivalents of cesium carbonate, complete cyclization of the
Fig. 1 Structure of pyrrolidinedione product 9a in solid state.
Ugi product to the pyrrolidinedione 9 was observed. Benzyl based MCRs.11 Stereochemical analysis SFC-MS revealed that
3-oxobutanoate also produced similar pyrrolidinedione 9d.
compound 9c gave a single diastereomer. However, 9b (9 : 1)
and 9d (9.5 : 0.5) formed a mixture of two distereomers (see
Several analogous reactions were performed and all yielded
the products in satisfactory yields (Table 2). The finding of this ESI-38, ESI-41†). The major distereomers were isolated using
reaction is remarkable since few other orthogonal methods
exist to access the pyrrolidinedione scaffold by isocyanide
preparative TLC plates. Pyrrolidinedione 9a is exclusively
formed as the cis relative stereoisomer. The X-ray structure of
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Table 2 Cyclization of the Ugi 4-CR to yield the pyrrolidinedione scaffold
Comp
Yielda [%]
40
9a
9b
9c
49
45
9d
34
a Overall yield in two steps in one pot (crude Ugi product was directly used for the cyclization).
Table 3 Pictet–Spengler cyclization of the Ugi 4-CR to yield the tricyclic 3,9-di-
azabicyclo[3.3.1]nonane scaffold
Comp
Yielda [%]
44
11a
11b
40
Fig. 2 Structure of Ugi/Pictet–Spengler product 11d in solid state.
11c
11d
48
30
polycyclic scaffolds.12 For example, the use of suitable starting
materials allows for the convergent synthesis of the important
schistosomiasis medication Praziquantel.13 The two required
functional groups of the Pictet–Spengler reaction, an electron
rich aromatic group such as tryptophan and an oxo group, can
be conveniently introduced via the α-amino acid component
and the primary amine component respectively (Table 3). By
performing the Pictet–Spengler reaction under formic acid at
room temperature conditions, we indeed could isolate the
strained tricyclic 3,9-diazabicyclo[3.3.1]nonane system 11 from
a Overall yield in two steps in one pot (crude Ugi product was directly
used for the Pictet–Spengler reaction).
9a shows the solid state conformation and also proves the
overall structure of the scaffold (Fig. 1).
The Pictet–Spengler reaction recently became popular for
performing Ugi post-condensation reactions to yield complex
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Table 4 Cyclization of the Ugi 4-CR to yield bicyclic tetrahydroimidazo-
[1,2-a]pyrazine-2,6(3H,5H)-dione scaffold
Comp
Yielda [%]
63
13a
13b
13c
13d
87
40
54
a Overall yield in two steps in one pot (crude Ugi product was directly
used for the cyclization).
Fig. 4 Principal moment of inertia (PMI) calculated for 1000 randomly gene-
rated compounds for each of the four scaffolds 7 (green triangles), 9 (light blue
triangles), 11 (purple triangles) and 13 (navy blue triangles) compared to 1000
randomly chosen compounds from the Zinc Library15 (yellow squares). PMI of
specific compounds from this paper can be seen in all four graphs as red
squares.
Fig. 3 Bicyclic Ugi/condensation product 13c in solid state.
mixture 10. Several analogous reactions show the general char-
acter of this transformation (Table 3).
Indolo annulated tricyclic 3,9-diazabicyclo[3.3.1]nonane rich aromatic α-amino acids such as phenylalanine (Table 4).
systems or substructures thereof occur in several alkaloids, Using similar conditions as seen in Table 3 the bicyclic tetra-
such as 11d. The herein described convergent synthesis could hydroimidazo[1,2-a]pyrazine-2,6(3H,5H)-dione scaffold 13 was
therefore be of use in the synthesis of the corresponding back- obtained from mixture 12 (Table 4). In all cases, the formation
bones. A crystal structure analysis of 11d has been performed of only the trans diastereomer was observed. A crystal structure
supporting the proposed scaffold structure (Fig. 2).
analysis of 13c has been performed showing the formation of
As a final example of how our new Ugi variation, together the trans stereoisomer and supporting the proposed overall
with carefully chosen orthogonal functional groups in the scaffold structure (Fig. 3).
other starting materials which can be used for the synthesis of
Lastly, we were interested in the question of how some phy-
novel and complex scaffolds, involves the use of other electron siochemical properties of our scaffolds cluster and compare
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with other commonly used virtual screening libraries. Thus we
calculated the descriptors c log P, rotatable bonds, molecular
weight, and other drug-like properties from a randomly gene-
rated library of 1000 compounds based on all four scaffolds
(ESI Fig. 1–8†). The majority of these compounds pass at least
3 out of 4 of Lipinski’s rules of five; most of them, however,
only fail the molecular weight rule. Interestingly the two later
scaffolds (11 and 13) possess a low number of rotatable bonds
and are highly stiff, increasing their chance of oral bio-avail-
ability. We were especially interested in the recently introduced
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Acknowledgements
This work was supported partially by grants from
NIH
(1R21GM087617-01A1,
1P41GM094055-01,
and
1R01GM09708201). KK acknowledges the ACS Medicinal
Chemistry predoctoral fellowship (2011–2012).
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