γ-Turn Mimicry with Benzodiazepinones and Pyrrolobenzodiazepinones Synthesized from a Common Amino Ketone Intermediate

Article abstract of DOI:10.1021/acs.orglett.5b01679

To investigate diazepinone analogues as γ-turn mimics, seven 1,4-benzodiazepin-2-ones 6 and fourteen pyrrolo[1,2-d][1,4]benzodiazepin-6-ones 4 and 5 were synthesized from 1-(2-aminophenyl)pent-4-en-1-one (7). Acylation of aniline 7 with N-Boc-amino acids,

Full text of DOI:10.1021/acs.orglett.5b01679

Letter
pubs.acs.org/OrgLett
γ‑Turn Mimicry with Benzodiazepinones and
Pyrrolobenzodiazepinones Synthesized from a Common Amino
Ketone Intermediate
Aurelie A. Dorr and William D. Lubell*
́
̈
́ ́ ́ ́ ́
Departement de Chimie, Universite de Montreal, C.P.6128, Succursale Centre-Ville, Montreal, Quebec H3C 3J7, Canada
S
* Supporting Information
ABSTRACT: To investigate diazepinone analogues as γ-turn mimics, seven 1,4-benzodiazepin-2-ones 6 and fourteen
pyrrolo[1,2-d][1,4]benzodiazepin-6-ones 4 and 5 were synthesized from 1-(2-aminophenyl)pent-4-en-1-one (7). Acylation of
aniline 7 with N-Boc-amino acids, olefin oxidation, Boc removal, and intramolecular Paal−Knorr condensation gave 4 and 5.
Alternatively, Boc removal prior to oxidation gave benzodiazepinones 6, which were converted to 4 by ozonolysis and cyclization.
Comparison of dihedral angle values for the amino acid component from X-ray analyses of 4g, 5f, and 6f and related
diazepinones has catalogued the manner by which ring substituents affect the component’s ability to mimic the central residues of
γ-turns.
urn mimicry may lie at the heart of the wide range of
biological, pharmacological, and clinical activities of 1,4-
diazepin-2-ones and their aryl-fused ring analogues. Considered
“privileged structures” because they exhibit high affinity to
multiple receptors,1−3 diazepinones have the capacity to mimic
natural γ- and β-turn peptide secondary structures (Figure 1).4,5
1,4-Benzodiazepines are CNS drugs that show sedative,
anxiolytic, anticonvulsant, antihypnotic, muscle relaxing, and
anterograde amnesia activities.1,2,7 They modulate hormone
receptors,1,8,9 block ion channels,1a−c,8 and inhibit enzyme-
s.1a,b,5b,8,10 They exhibit antimalarial,5b,10b antiviral,1a,8,10c and
antileukemic10a activity as well as the potential to treat lupus by
inhibiting protein−DNA interactions.1a
T
Pyrrolo[2,1-c][1,4]benzodiazepinones exhibit anticancer and
antitumor activity due to their ability to sequence-selectively
bind and alkylate double-stranded DNA.11,12 Their synthetic
dimers are potent DNA cross-linking agents that have entered
phase II clinical trials.13 Pyrrolobenzodiazepinones have also
shown anti-ischemic and herbicidal activity.14 Pyrrolo[1,2-
d][1,4]benzodiazepinones (e.g., 4f) act as non-nucleoside
HIV-1 reverse transcriptase inhibitors,15b albeit few publications
have reported on this tricyclic system.15
Interested in their potential as turn mimics,4c,6,16 we have
pursued diazepinone analogues (e.g., 1 and 2) using
solution-4c,6,18a and solid-phase16,17,18b methods featuring
diastereoselective Pictet−Spengler reactions6,16,17 and copper-
catalyzed cascade addition of vinyl Grignard reagents to α-
aminoacyl-β-amino esters to afford γ,δ-unsaturated ketone
precursors.4c,18 Employing the latter reaction on methyl
anthranilate, we synthesized effectively 1-(2-aminophenyl)-
pent-4-en-1-one (7), which has previously served to make
Figure 1. Representative diazepinones and γ- and β-turns.
X-ray structural analyses of diazepin-2-ones (e.g., 1 and 2) have
shown that their amino acid components adopt dihedral angle
values similar to those of the central residue in a γ-turn (Figure
1).4c,6,16 Moreover, spectroscopic and computational analyses
have revealed that benzodiazepin-2-one scaffolds (e.g., 3) can
mimic β-turn backbone and side-chain geometry.5e,f Knowledge
of ring substituent influences on turn geometry is thus valuable
for rational application of such scaffolds in drug discovery.
Received: June 10, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01679
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Letter
aminophenylpyrroles,19 pyrrolo[1,2-c]quinazolin-5(6H)-ones,19
and 2,3,4-trisubstituted quinolines (e.g., 8−10, Figure 2).20 To
gain more insight into tools for γ-turn mimicry,21 benzodiaze-
pinone and pyrrolobenzodiazepinone analogues 4−6 have now
been made from amino ketone 7 and examined by X-ray
diffraction.
protocols provided material exhibiting, respectively, >94% and
>93% enantiomeric excess by SFC analysis, albeit in 47% and
36% yields (92% and 71% yields based on recovered starting
material, Scheme 1). With amino acids that are less susceptible
to epimerization, such conditions may similarly yield high
enantiomeric purity.
Benzodiazepinones 6 were synthesized in 65−97% yields
from ketones 12 by Boc group removal with HCl gas in DCM,
free-basing with triethylamine in the presence of 4 Å molecular
sieves in DCM, and chromatography on silica gel (Scheme 1).
Pyrrolo[1,2-d][1,4]benzodiazepinones 4 and 5 were made from
olefin 12 as the common starting material. 4-Ketoaldehydes 13
and 1,4-diones 14 were obtained, respectively, by olefin
27
oxidation using OsO4/NaIO4 and Tsuji−Wacker condi-
tions.28 4-Ketoaldehydes 13 were isolated in 61−74% yields
by chromatographic purification after oxidative cleavage of
olefins 12 using sodium periodate and catalytic osmium
tetraoxide in dioxane/H2O at room temperature for 45 h.
Chromatography of the products after treatment of olefins 12
with PdCl2 and CuCl in DMF/H2O at room temperature
under oxygen atmosphere for 38 h afforded 1,4-diones 14 in
58−90% yields.
Figure 2. Amino ketone 7 as common precursor for heterocycle
synthesis.
Among benzodiazepine syntheses,22 the preparation of 1,4-
benzodiazepin-2-ones has been less widely explore-
d.1a,5a,b,8,9a,c,10a,23,24 We perceived ring annulation by an
N(4)−C(5) bond connection as an attractive route to 1,4-
benzodiazepin-2-ones (e.g., 6) because the requisite precursor
may be synthesized by amino acylation of 2-aminophenones
with amino acid derivatives. We have now validated this
synthetic strategy by surmounting issues, low yield and
racemization, in the amino acylation of electron-poor aniline
7. Pyrrolo[1,2-d][1,4]benzodiazepinones 4 and 5 were also
made by using 2-aminophenone 7 as a common precursor.
Electron-deficient aniline 7 was coupled to N-Boc-L-α-amino
acids 11a−g using DCC and DMAP in DCM at room
temperature for 40 h to give amides 12 after chromatography
on silica gel in 67−97% yields (Scheme 1). Fears of
racemization from employing DMAP during peptide coupling
were, however, realized by examining acylation products 12 by
chiral SFC. For example, aspartate analogue 12f exhibited a
56:44 enantiomeric ratio of (S)-12f:(R)-12f.25,26 To overcome
racemization, HOBt was added, and the DCC and DMAP
procedure was run at 0 °C. In addition, the mixed anhydride
method employing isobutyl chloroformate and N-methylmor-
pholine in THF at −15 °C was used to synthesize amide 12f.
The modified DCC coupling and mixed anhydride activation
Various conditions were examined to synthesize pyrrolo-
benzodiazepinones from the dicarbonyl compounds by intra-
molecular Paal−Knorr condensations (Scheme 1).29 For
example, the Boc group of 1,4-diones 14 was removed with
1:2 TFA/DCM, and the resulting trifluoroacetates were free-
based using Amberlyst A-21 ion-exchange resin.30 Catalytic p-
toluenesulfonic acid in dilute DCM at 45 °C provided
pyrrolo[1,2-d][1,4]benzodiazepinones 5 in 46−63% yields
after chromatography on silica gel. Under the same protocols,
however, 4-ketoaldehydes 13 gave lower yields (10−39%) of
pyrrolobenzodiazepinones 4. Prior to chromatographic purifi-
cation, the TLC profiles of crude 4 exhibited significant
amounts of impurities. Attempts were unsuccessful to improve
the yield of 4 by treating 13 with HCl gas in DCM to remove
the Boc group prior to free-basing with triethylamine and Paal−
Knorr cyclization. Limited success was also obtained by
employing microwave irradiation of 4-ketoaldehyde 13
supported on silica gel at 100 °C to both remove the Boc
group and effect in situ Paal−Knorr cyclization. On the other
hand, pyrroles 4 were isolated in 52−83% yields from
microwave irradiation of an aqueous mixture of 1,4-
Scheme 1. Synthesis of Benzodiazepinones 6a−g and Pyrrolobenzodiazepinones 4a−g and 5a−g from Amino Ketone 7
B
DOI: 10.1021/acs.orglett.5b01679
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Letter
ketoaldehydes 13 at 150 °C for 5−10 min and chromatog-
raphy.31
Table 1. Diazepinone Crystal Analyses with ϕ and ψ
Dihedral Angles Compared with Ideal γ-Turns
Pyrrolobenzodiazepinones 4 were also prepared from
benzodiazepinones 6 in 44−77% yields by ozonolysis in
CH2Cl2/MeOH (1:1) at −78 °C, reduction of the ozonide
with excess dimethyl sulfide, and chromatography on silica gel
(Scheme 1). Attempts failed, however, to prepare pyrroloben-
zodiazepinone 4f by oxidation of olefin 13f using sodium
periodate/osmium tetraoxide. Employing enantiomerically
enriched amide 12f (>93% ee) in routes to pyrrolo[1,2-
d][1,4]benzodiazepinones 4f and 5f featuring ozonolysis of
benzodiazepinone 6f and Tsuji−Wacker oxidations prior to
Paal−Knorr cyclization of 1,4-dione 14f gave products with
high enantiomeric purity as assessed by SFC analysis (Scheme
1).
type of turn
ϕ
ψ
γ-turn31
75
−65
65
inverse γ-turn31
−75
−80
−83
−93
−79
59
diazepinone 1a4c
70
diazepinone 1b4c
67
pyrrolodiazepinone 2a6
pyrrolodiazepinone 2b16
pyrrolobenzodiazepinone (S)-4g
pyrrolobenzodiazepinone (R)-4g
pyrrolobenzodiazepinone (S)-5f
pyrrolobenzodiazepinone (R)-5f
benzodiazepinone (S)-6f
benzodiazepinone (R)-6f
72
74
−55
52
−60
61
−57
57
−61
−72
75
69
−68
2a and 2b.6,16 Although all of the analogues presented torsion
angle values indicative of the central residue of an ideal γ-turn
(75° 16 and −65° 10) and an ideal inverse γ-turn (−75°
18 and 65° 13), benzodiazepinone 6f exhibited the best fit.
Relatively smaller and larger dihedral angle values were
observed, respectively, for pyrrolobenzodiazepinones 4g and
5f and diazepinones 1 and pyrrolodiazepinones 2 (Table 1).
The NMR spectra of benzodiazepinones 6 and pyrroloben-
zodiazepinones 4 and 5 exhibited diastereomeric as well as
broad signals due to atropisomerism contingent on ring
substituent and environment. Typically, benzodiazepinones
6b−g and pyrrolobenzodiazepinones 5b−g and 4c exhibited
resolved spectra, with doubling of certain signals, such as the
amide NH protons in chloroform. On the other hand,
pyrrolobenzodiazepinones 4b−g exhibited broad proton and
missing carbon signals in chloroform, due likely to equilibrating
atropisomers. Improved resolution of the NMR spectra of the
benzodiazepinones was obtained in acetone, which may
hydrogen bond with the amide proton. Temperature could
also be varied to obtain better spectral resolution. For example,
the 1H and 13C NMR spectra of 4b were resolved by heating to
313 K to accelerate interconversion of the atropisomers. On the
other hand, 1:1 to 3:2 diastereomeric mixtures of 4d, 4e, and 4g
were well resolved at low temperatures (e.g., 193 K), which
1
slowed interconversion of the atropisomers. Finally, the H
NMR spectrum of 4f at 193 K indicated a single set of resolved
signals in acetone.
Figure 3. X-ray crystal structures of (RS)-4g, -5f, and -6f.
Insight has been gained into the capacity of diazepinone
structures to mimic γ-turn conformations. Furthermore, by
employing methyl anthranilate as common starting material,
practical methods were conceived to synthesize benzodiazepi-
none and pyrrolobenzodiazepinone scaffolds. X-ray analyses
demonstrated subtle effects of ring fusion and unsaturation in
the 1,4-diazepinones on the capacity of their amino acid
component to mimic the central residue of peptide γ-turns.
This method offers interesting potential for applications in
peptide mimicry and medicinal chemistry because of the
importance of γ-turns in peptide biology33 and the activity of
related small molecules. Testing is underway to assess the
biological activity of these novel diazepine analogues.
For X-ray analyses, crystals of benzodiazepinone (RS)-6f and
pyrrolobenzodiazepinone (RS)-5f were grown by diffusion of
hexanes into an ethyl acetate/hexane mixture. Crystals of
pyrrolobenzodiazepinone (RS)-4g were grown by diffusion of
hexanes into acetone. In both crystal structures, the
enantiomers paired up in the unit cell. The amino acid side
chain adopted, respectively, pseudoequatorial and pseudoaxial
orientations for 6f and for 4g and 5f in the solid state. The ϕ
and ψ dihedral angles of the amino acid component of (S)-4g,
(S)-5f, and (R)-6f and those of their enantiomers (R)-4g, (R)-
5, and (S)-6f correlated, respectively, with the central residues
of classical (75° 16 and −65° 10) and inverse (−75° 15
and 65°
13) γ-turns (Table 1).32 The subtle changes of
dihedral angle geometry may affect differences in receptor
affinity and activity of related diazepinone ligands.
Comparing their respective crystal structures, substituent
effects were observed on the dihedral angles of the amino acid
component in benzodiazepinone 6f, pyrrolobenzodiazepinones
4g and 5f, diazepinones 1a and 1b,4c and pyrrolodiazepinone
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, spectroscopic characterization (1H and
13C NMR) for all compounds, SFC traces, and X-ray
crystallographic data for 4g, 5f, and 6f. The Supporting
C
DOI: 10.1021/acs.orglett.5b01679
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Kromis, T.; Cullis, H.; De Knaep, F.; Pauwels, r.; Andries, K.; De
Clercq, E.; Janssen, M. A.C.; Janssen, P. A J. Bioorg. Med. Chem. 1999,
7, 2427−2436.
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/acs.orglett.5b01679.
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AUTHOR INFORMATION
Corresponding Author
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*E-mail: lubell@chimie.umontreal.ca.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the Natural Sciences and Engineering Research
Council of Canada (NSERC) for funding and members of the
■
Universite
Marie-Christine Tang for mass spectrometry and SFC analyses,
Dr. Francine Belanger-Gariepy for X-ray analyses, and Dr.
́
de Montreal facilities: Dr. Alexandra Furtos and
́
̈
̈
́
Sylvie Bilodeau for NMR experiments.
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