Ugi 4-CR synthesis of γ- And δ-lactams providing new access to diverse enzyme interactions, a PDB analysis

Article abstract of DOI:10.1039/c4md00162a

A three step synthesis of N-unsubstituted tetrazolo γ- and δ-lactams involving a key Ugi-4CR is presented. The compounds, otherwise difficult to access, are conveniently synthesized in overall good yields by our route. PDB analysis of the N-unsubstituted γ- and δ-lactam fragment reveals a strongly tri-directional hydrogen bond donor acceptor interaction with the amino acids of the binding sites.

Full text of DOI:10.1039/c4md00162a

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Ugi 4-CR synthesis of g- and d-lactams providing
new access to diverse enzyme interactions, a PDB
analysis†
Cite this: Med. Chem. Commun., 2014,
5, 949
Andre Boltjes,a George P. Liao,a Ting Zhao,a Eberhardt Herdtweckb
´
ac
*
and Alexander Domling‡
¨
Received 8th April 2014
Accepted 13th May 2014
A three step synthesis of N-unsubstituted tetrazolo g- and d-lactams involving a key Ugi-4CR is presented.
The compounds, otherwise difficult to access, are conveniently synthesized in overall good yields by our
route. PDB analysis of the N-unsubstituted g- and d-lactam fragment reveals a strongly tri-directional
hydrogen bond donor acceptor interaction with the amino acids of the binding sites.
DOI: 10.1039/c4md00162a
www.rsc.org/medchemcomm
The g- and d-lactam moiety is an oen found fragment in N-unsubstituted g- and d-lactams has been described up to
bioactive compounds; examples of compounds with a lactam date. Clearly many synthetic approaches towards N-unsub-
fragment include the anti-Parkinson drug oxotremorin1 or the stituted g- and d-lactams are described, however these contain
anti-rhinoviral and -enteroviral rupintrivir.2 Generally, the lac- limitations regarding variability and length of the synthetic
tam nitrogen can be either unsubstituted or substituted which routes.14
inuences its hydrogen bonding prole in the receptor binding
Ammonia is one of the few amine components which does
site. For example in the crystal structure of rupintrivir with the not regularly give convincing results in the Ugi MCRs.14–18
human rhinovirus 3C protease, the g-lactam-N forms a short Therefore we recently introduced tritylamine as an ammonia
hydrogen bond to the Thr142 backbone carbonyl, whereas the surrogate in the Ugi tetrazole MCR.19 This reaction forms the
d-lactam-O forms two short contacts to side chain His161-NH core of our design of a synthetic pathway towards N-unsub-
and the Thr142-OH, respectively (Fig. 1).3 In our ongoing efforts stituted g- and d-lactams (Scheme 1). The rst step comprises
in structure- and computational-based design of bioactive the Ugi tetrazole MCR using tritylamine, followed by cleavage of
compounds we were interested in a short and versatile synthesis the trityl group. The formed primary amine should easily
of N-unsubstituted g- and d-lactams with potential multiple undergo cyclisation to form the target g- and d-lactam
hydrogen bond interactions.4 Combining the lactam function- compounds.
ality with a 1,5 disubstituted tetrazolo peptidomimetic could
enhance the affinity of this tetrazole analog, a well-known cis-
amide bond mimic, which provides new synthetic probes for a
series of biological targets.5–9 Multicomponent reactions
(MCR) were found to be an excellent tool to rapidly access a
large and versatile drug-like chemical space to address the
corresponding biological space.10 A convenient and versatile
synthesis of N-substituted g- and d-lactams using convergent
Ugi-type MCR's was recently introduced by Marcos et al. and
rened by others.11–13 However no MCR-based synthesis of
aDepartment of Pharmacy University of Groningen A. Deusinglaan 1, 9713 AV
Groningen, The Netherlands. E-mail: A.S.S.Domling@rug.nl
b
¨
¨
Department Chemie Technische Universitat Munchen Lichtenbergstrasse 4, D-85747
¨
Garching bei Munchen, Germany
cDepartment of Chemistry University of Pittsburgh 3501 Fih Avenue, Pittsburgh, PA
15261, USA
† Electronic supplementary information (ESI) available: Experimental details in
chemistry, NMR, SFC-MS of all described compounds and crystallographic data
of 4 compounds; CCDC 961190 (6b), CCDC 961191 (6e), CCDC 961188 (6f) and
CCDC 961189 (6j). See DOI: 10.1039/c4md00162a
Fig. 1 Trifurcated hydrogen bonding interactions (red dotted lines) of
an N-unsubstituted g-lactam (cyan sticks) with some protease amino
acids in the example of rupintrivir (PDB ID 1CQQ).
‡ Present address: University of Groningen, The Netherlands.
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Table 1 Cyclization of the Ugi 4-CR to yield the isoindolone scaffold
Entry
R(4)
n
Ugia (%)
Entry
Cyclisationb (%)
5a
5b
2
2
73
50
6a
6b
55
89
Scheme 1 Devised synthetic pathway to tetrazolo N-unsubstituted g-
and d-lactams.
5c
5d
5e
2
2
2
75
56
40
6c
6d
6e
32
72
95
Scheme 2 The two aldehydes utilized in the Ugi tetrazole synthesis.
5f
3
3
78
62
6f
76
42
The Ugi tetrazole synthesis was initially performed under Ugi
azide conditions with tritylamine (1), azidotrimethylsilane (2),
phenylethylisonitrile and various aldehyde esters to check scope
and limitations.20 The aliphatic aldehydes 3a and b were
prepared according to previous described methods starting
from the acid chloride (Scheme 2).21
Due to the steric hindrance of the trityl moiety, the Schiff-
base condensation step of the Ugi reaction only proceeds
smoothly under microwave irradiation.19 Moreover it was found
that only aliphatic aldehydes such as 3a and 3b gave good yields
varying between 40 and 80%. The used number of aldehydes
was bigger with even n ¼ 4 and a cyclopropyl moiety in the
chain. The Ugi tetrazole reaction was also for these aldehydes
successful, however, the subsequent cyclisation gave problems,
not yielding the desired lactams. Aromatic aldehydes were
5g
6g
5h
5i
3
3
43
68
6h
6i
40
99
5j
3
41
6j
79
a
TFA, CH2Cl2, RT. 1 min. b NaH, THF, RT, 4 h.
investigated and only in some reactions a moderate yield was and reasonable to very good yields for the g- and d-lactams
observed.19 Aryl ester aldehydes did not yield any product at all. (Table 1).
Product diversity by using four other isonitriles (4) (Table 1)
We could grow four crystals of g- (6b, 6e) and d-lactams (6f,
showed yields comparable with phenylethylisocyanide. Depro- 6j) suitable for single crystal structure determination (Fig. 2).
tection conditions in order to cleave the trityl from the amine Interestingly the lactam amide group in all cases show inter-
requires at least 2 equivalents of TFA. Full conversion into the molecular hydrogen bonding involving the amide NH and the
amine is achieved within seconds monitored by TLC. Simple carbonyl CO. Five-membered g-lactam 2 shows an intermolec-
purication was performed by pouring the reaction mixture ular hydrogen bonding with a neighbouring g-lactam amide
˚
directly onto a 5 cm silica gel lter wetted with heptane : EtOAc with a distance between the heavy atoms of 2.8 A. Six-membered
(1 : 1) removing the impurities by washing with 50 mL d-lactam 6, however, exhibits a trifurcated hydrogen bonding
heptane : EtOAc. Then the product was eluted from the lter network involving a neighbouring d-lactam and a co-crystallized
using 50 mL CH2Cl2 : MeOH (1 : 1) to obtain the pure amine. water molecule. Thus the oxygen atom shows two hydrogen
Subsequent cyclisation gave difficulties. Generally Et3N or bonds along the lone pair electrons.
potassium carbonate is sufficient to cyclize comparable mole-
The g- and d-lactam moiety is present in many bioactive
cules, however it was found that the resulting TFA salt needed to molecules and therefore we also decided to analyse the moieties
be liberated using a strong base prior to cyclisation. The main in the protein data bank (PDB).22 Structure search (April 24th
disadvantage of using a strong base is that this results in 2013) on g-lactams yielded a total of 817 structures containing
saponication of the initial ester and thus preventing cyclisa- this moiety; d-lactams resulted in 37 structure hits. Aer
tion at all. Sodium hydride was found to be a suitable base removing structures with $ 95% structure similarity, the results
giving in most cases only a minor conversion to amino acids were reduced to 281 structures and 27 structures respectively. Of
950 | Med. Chem. Commun., 2014, 5, 949–952
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those structures, only the N-unsubstituted lactam rings were
included in the analysis. In addition, all lactam structures that
were part of the protein and photosynthesis related structures
were also excluded due to redundancy of the ligands. Although
37 and 11 structures, respectively for the g- and d-lactams, are
not sufficient for a statistical analysis, it well provides the basis
for a trend. Key ndings include: (1) for the majority of struc-
tures, the lactam amide group undergoes a trifurcated hydrogen
bond network involving the carbonyl oxygen twice and the
amide NH once. (2) The g-lactams interact with the histidine
side chains most frequently through the carbonyl oxygen.
Analysis of the structures show that the histidines are, all but
one, part of viral proteases. In addition, the amide–nitrogen
polar interactions are also similar for these structures. (3) The
d-lactams possess more hydrogen bonding interaction possi-
bilities as many amino acid residues are found in close prox-
imity to the lactam moiety. In Fig. 3, ten random structures
(3D23, 3EWJ, 3QZR, 3RHK, 3TNT, 3UR9, 3DPM, 1H0V, 3JUC
and 3Q3Y) are aligned showing the amino acid residues/mole-
cules with which the g-lactam moiety shows polar interactions.
Conclusions
We have designed a fast and reliable synthetic route to 5- and
6-membered unsubstituted tetrazololactams using a key azido-
Ugi reaction, followed by a deprotection and cyclisation step.
Analysis of the scaffold in the protein data bank indicates that
the lactam-NH can undergo multiple and strong H-bonds.
Moreover the scaffold is underused in medicinal chemistry and
thus provides multiple chances for drug design.
Fig. 2 Intermolecular hydrogen bond network of exemplary g- and d-
lactams in the solid state. Molecule 6a shows a pair wise hydrogen
bonding with a neighbour molecule, while 6f shows a bifurcated
hydrogen bonding pattern including a neighbour molecule and a
water molecule.
Acknowledgements
This research has been supported by the NIH (grant
R01GM097082-01) and European Lead Factory (IMI under grant
agreement nꢀ 115489).
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