1,4-Diazepinone and pyrrolodiazepinone syntheses via homoallylic ketones from cascade addition of vinyl Grignard reagent to α-aminoacyl-β- amino esters

Article abstract of DOI:10.1021/ol061036k

1,4-Diazepinones 5 and pyrrolodiazepinones 8 and 9 were synthesized from common homoallylic ketone precursors 4 prepared by copper-catalyzed cascade addition of a vinyl Grignard reagent to α-aminoacyl β-amino esters 3. Nitrogen deprotection and intramolec

Full text of DOI:10.1021/ol061036k

ORGANIC
LETTERS
2006
Vol. 8, No. 16
3425-3428
1,4-Diazepinone and Pyrrolodiazepinone
Syntheses via Homoallylic Ketones from
Cascade Addition of Vinyl Grignard
Reagent to
Hassan S. Iden and William D. Lubell*
r-Aminoacyl-â-amino Esters
De´partement de chimie, UniVersite´ de Montre´al, C.P. 6128, Succursale Centre Ville,
Montre´al, Que´bec, Canada H3C 3J7
lubell@chimie.umontreal.ca
Received April 28, 2006
ABSTRACT
1,4-Diazepinones 5 and pyrrolodiazepinones 8 and 9 were synthesized from common homoallylic ketone precursors 4 prepared by copper-
catalyzed cascade addition of a vinyl Grignard reagent to -aminoacyl -amino esters 3. Nitrogen deprotection and intramolecular reductive
amination yielded 1,4-diazepinones 5. Olefin oxidation, Boc removal, and intramolecular Paal Knorr condensation gave pyrrolodiazepinones
8 and 9. X-ray structures of diazepinones 5c and 5d depicted dihedral angles about the -amino acid moiety similar to those of the central
residue in an ideal reverse -turn.
r
â
−
r
γ
Among the small molecules employed in drug discovery,
molecular scaffolds that mimic peptide secondary structures
are particularly useful for lead identification and the develop-
ment of therapeutic agents. In this respect, 1,4-benzodiaze-
pines display a wide range of pharmacological activities
likely due to their potential to mimic peptide turn confor-
mations.1-3
1,4-Diazepinones have exhibited activity as high-affinity
antagonists of the lymphocyte function-associated antigen-
1/immunoglobulin superfamily ICAM-1 interaction.4 They
have shown anticonvulsant activity.5 The diazepinone system
is also present in the liposidomycin nucleoside antibiotics
that inhibit bacterial peptidoglycan synthesis (Figure 1).6
The pyrrolobenzodiazepine structure is contained in the
natural anthramycin family of antitumor antibiotics.7 Syn-
thetic pyrrolobenzodiazepines have acted as non-nucleoside
reverse transcriptase inhibitors8 and CNS agents;9 they have
also exhibited antiproliferative10 and antidepressant11 activity
(Figure 1).
The synthesis of diazepinone ring systems has attracted
considerable interest. Annulation of the diazepinone ring has
been accomplished from linear precursors by reductive
amination12,13 and lactam formation.14 Ring expansion of
N-protected-4-piperidones by azido-Schmidt reactions with
(6) Isono, K. J. Antibiot. 1988, 41, 1711-1739.
(7) Leimgruber, W.; Batcho, A. D.; Czajkowski, R. C. J. Am. Chem.
Soc. 1968, 90, 5641-5643.
(1) Abrous, L.; Hynes, J., Jr.; Friedrich, S. R.; Smith, A. B., III.;
Hirschmann, R. Org. Lett. 2001, 3, 1089-1092 and refs 1-6 therein.
(2) Han, Y.; Mierke, D. F.; Chorev, M. Biopolymers 2002, 64, 1-15.
(3) Ramanathan, S. K.; Keeler, J.; Lee, H.-L.; Reddy, D. S.; Lushington,
G.; Aube´, J. Org. Lett. 2005, 7, 1059-1062.
(4) Wattanasin, S.; Kallen, J.; Myers, S.; Guo, Q.; Sabio, M.; Ehrhardt,
C.; Albert, R.; Hommel, U.; Weckbecker, G.; Welzenbach, K.; Weitz-
Schmidt, G. Biorg. Med. Chem. Lett. 2005, 15, 1217-1220.
(5) Kesheva Murthy, K. S.; Knaus, E. E. Drug DeV. Res. 1999, 46, 155-
162.
(8) De Lucca, G. V.; Otto, M. J. Biorg. Med. Chem. Lett. 1992, 2, 1639-
1644.
(9) Hara, T.; Kayama, Y.; Mori, T.; Itoth, K.; Fujimori, H.; Sunami, T.;
Hashimoto, Y.; Ishimoto, S. J. Med. Chem. 1978, 21, 263-268.
(10) Lisowski, V.; Fabis, F.; Pierre, A.; Caignard, D.-H.; Renard, P.;
Rault, S. J. Enzyme Inhib. Med. Chem. 2002, 17, 403-407.
(11) Massa, S.; Artico, M.; Mai, A.; Corelli, F.; Botta, M.; Tafi, A.;
Pantaleomi, G. C.; Giorgi, R.; Coppolino, M. F.; Cagnotto, A.; Skorupska,
M. J. Med. Chem. 1992, 35, 4533-4541.
10.1021/ol061036k CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/12/2006

Scheme 1. Synthesis of Diazepinones 5
acids as chiral educts, we conceived efficient synthetic
approaches for making diazepinone and pyrrolodiazepinone
heterocycles that use a common homoallylic ketone 4. Four
diazepinones 5 and eight pyrrolodiazepinones 8 and 9
(Schemes and Tables 1 and 2) were synthesized starting from
combinations of Ala, Phe, â-Ala, and â-homophenylalanine
to provide R-aminoacyl-â-amino esters 3. Homoallylic
ketones 4 were then made by Cu-catalyzed cascade addition
of a vinyl Grignard reagent to esters 3.19
R-Aminoacyl-â-amino esters 3 were synthesized by cou-
pling â-amino ester 1 to the respective N-Boc-R-amino acid
2 using TBTU and HOBt in dichloromethane (Scheme 1).20
Dipeptides 3 were isolated by chromatography on silica gel
in 85-92% yields. Homoallylic ketones 4 were synthesized
by treating R-aminoacyl-â-amino esters 3 with an excess of
freshly prepared vinylmagnesium bromide (600 mol %) in
the presence of copper cyanide (30-40 mol %) in THF at
-78 °C to room temperature.19 After quenching the Grignard
reaction at 0 °C, workup, and solvent removal under vacuum,
homoallylic ketones 4a-c were isolated by chromatography
on silica gel in 60-75% yields (Table 1). Isolation of ketone
Figure 1. Representative 1,4-diazepin-2-one and pyrrolodiazepi-
none systems and related biologically active structures.
2-hydroxyalkyl azides has given N-substituted diazepinones.3
1,4-Diazepin-5-ones have been recently made by acid-
catalyzed hydrolysis of azeto[1,2-a]imidazoles.15 In addition,
a combinatorial library of 1,4-diazepinone derivatives was
synthesized by a solid-phase approach.16
Syntheses of the pyrrolobenzodiazepine structures were
reviewed in a recent note on pyrroloaryldiazepine construc-
tion by modification of the four-component Ugi condensa-
tion.17 To the best of our knowledge, only one synthesis of
the parent pyrrolodiazepinone has been described featuring
a Paal-Knorr condensation/lactam cyclization sequence to
form sequentially the pyrrole and diazepinone rings.18
Table 1. Yields of Isolated Products in the Synthesis of 5
entry
R1
R2
3 (%)
4 (%)
5 (%)
Their remarkable biological activity has inspired the
development of new synthesis methodology for making
diazepinone and fused aryl- and heteroaryldiazepinone
structures. Present methods employ often expensive starting
materials, give low to moderate yields, and provide com-
pounds of limited diversity. Employing inexpensive amino
a
b
c
CH3
CH2Ph
CH3
H
H
CH2Ph
CH2Ph
85
90
90
92
75
60
65
45
45
40
50
50
d
CH2Ph
4d was best accomplished by chromatography over silica
gel impregnated with silver nitrate in 45% yield.21
Diazepinones 5 were synthesized from homoallylic ketones
4 by a route featuring nitrogen deprotection with TFA/DCM
(1:1), treatment of the trifluoroacetate salt with triethylamine
at 0 °C, and reduction of the imine intermediate with sodium
(12) Knapp, S.; Nandan, S.; Resnick, L. Tetrahedron Lett. 1992, 33,
5485-5486.
(13) Nakajima, N.; Isobe, T.; Irisa, S.; Ubukata, M. Heterocycles 2003,
59, 107-113.
(14) Gravier-Pelletier, C.; Charvet, I.; Le Merrer, Y.; Depezay, J.-C. J.
Carbohydr. Chem. 1997, 16, 129-141.
(15) Alajar´ın, M.; Vidal, A.; Tovar, F. Tetrahedron 2005, 61, 1531-
1537.
(16) Wattanasin, S.; Albert, R.; Ehrhardt, C.; Roche, D.; Sabio, M.;
Hommel, U.; Welzenbach, K.; Weitz-Schmidt, G. Biorg. Med. Chem. Lett.
2003, 13, 499-502.
(17) Ilyn, A. P.; Triflenkov, A. S.; Kuzovkova, J. A.; Kutepov, S. A.;
Niktin, A. V.; Ivachtchenko, A. V. J. Org. Chem. 2005, 70, 1478-1481.
(18) Stetter, H.; Lappe, P. Liebigs Ann. Chem. 1980, 703-714.
(19) Hansford, K. A.; Dettwiler, J. E.; Lubell, W. D. Org. Lett. 2003, 5,
4887-4890.
(20) Cardilo, G.; Gentilucci, L.; Tolomelli, A.; Calienni, M.; Qasem, A.
R.; Spampinato, S. Org. Biomol. Chem. 2003, 1, 1498-1502.
(21) Bednas, M. E.; Russell, D. S. Can. J. Chem. 1958, 36, 1272-1276.
3426
Org. Lett., Vol. 8, No. 16, 2006

Scheme 2. Synthesis of Pyrrolodiazepinones 8 and 9
Figure 2. X-ray diffraction structures of compounds 5c (upper)
and 5d (lower).
aldehydes 6 and 1,4-diketones 7 were obtained from oxida-
tion of olefin 4 using either ozonolysis or periodate/osmium
tetraoxide and by Tsuji-Wacker oxidation, respectively
(Scheme 2).
triacetoxyborohydride in dilute dichloroethane.22 The progress
of the imine reduction was followed by LCMS analysis,
which showed only one diastereoisomer in the crude product
as confirmed by 1H NMR spectroscopy. After workup,
diazepinone 5a was isolated after this sequence from 4a in
45% yield by preparative HPLC, and 5b-d were purified
by precipitation as hydrochloride salts and isolated in 40-
50% overall yields from ketones 4b-d (Scheme 1, Table
1).
4-Keto aldehydes 6 were isolated in 80-85% yields by
chromatographic purification after ozonolysis of homoallylic
ketones 4 in CH2Cl2/MeOH (1:1) at -78 °C and treatment
with excess dimethyl sulfide in the presence of NaHCO3.25
Alternatively, oxidative cleavage of the double bond of
homoallylic ketones 4 was performed with sodium periodate
26
The hydrochloride salts of diazepinones 5c and 5d were
recrystallized from methanol in ethyl acetate to furnish
crystals for X-ray analysis. The newly formed stereocenter
at the 5-position of diazepinones 5 was found to have a cis
relationship with respect to the 3-position substituent as
expected on the basis of the literature precedent in which
reduction of the cyclic iminium intermediate occurred with
hydride attack on the face opposite of the ring substitu-
ents.16,23 A survey of the Cambridge structural database
indicated that the X-ray structures of 5c and 5d represent
the first 1,4-diazepin-2-one examples. On comparison of the
dihedral angle geometry of the R-amino acid portion of
diazepinones 5c (ψ ) 70, φ ) -80) and 5d (ψ ) 67, φ )
-83) with ideal values of turn conformations, we noted the
close resemblance to the dihedral angle geometry of the
central residue in a reverse γ-turn conformation (ψ ) 60-
in the presence of catalytic amounts of OsO4 to afford
aldehydes 6 in 65-85% yield after chromatography. Com-
paring the two methods for making aldehyde 6, we found
the ozonolysis to be more advantageous because the crude
product was obtained in suitable purity for the subsequent
Paal-Knorr reaction.
1,4-Diketones 7 were produced by Tsuji-Wacker oxida-
tion27 employing PdCl2 (0.2 equiv) and CuCl (2 equiv), in
DMF/H2O (9:1) at room temperature under an atmosphere
of oxygen. After workup and chromatography on silica gel,
1,4-diketones 7 were isolated in 80-85% yields (Scheme 2,
Table 2). Yields were improved for olefins 4c and 4d by
using more PdCl2 (40 mol %) and 2 equiv of CuCl in THF/
H2O (4:1) at room temperature under an oxygen atmosphere
and agitation in a sonicator.
Pyrrolodiazepinones 8 and 9 were, respectively, prepared
from 4-keto aldehydes 6 and 1,4-diketones 7 by a generally
effective albeit moderate yielding route featuring nitrogen
deprotection and Paal-Knorr condensation.28 Acid-induced
Boc group removal was accomplished using either HCl gas
or TFA in CH2Cl2, with better success on keto aldehyde 6
24
70, φ ) -70-85; Figure 2).
Pyrrolodiazepinones 8 and 9 were made next from the
common homoallylic ketone intermediate 4. First, 4-keto
(22) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C.
A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849-3862.
(23) The footnote of ref 16 notes: Compounds without the R2 substit-
uents show a 1:1 mixture of two diastereomers. Moreover, a discerning
referee pointed out that “seven-membered rings containing an amide bond
usually adopt chairlike conformations; in this analysis, the observed product
can be seen to arise from axial attack. This is borne out by the crystal
structures of the products”.
(25) Schreiber, S.; Claus, R. E.; Regan, J. Tetrahedron Lett. 1982, 23,
3867-3870.
(26) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6,
3217-3219.
(24) (a) Rose, G. D.; Gierasch, L. M.; Smith, J. D. AdV. Protein Chem.
1985, 37, 1. (b) Kessler, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 512-
523.
(27) Tsuji, J. Synthesis 1984, 369-384.
(28) (a) Knorr, L. Chem. Ber. 1885, 18, 299. (b) Paal, C. Chem. Ber.
1885, 18, 367.
Org. Lett., Vol. 8, No. 16, 2006
3427

Table 2. Yields of Isolated Products in the Synthesis of 8 and
9
entry
R1
R2
6 (%)
7 (%)
8 (%)
9 (%)
a
b
c
CH3
CH2Ph
CH3
H
H
CH2Ph
CH2Ph
85
85
80
85
85
80
80
80
30
40
55
60
65
45
50
50
Figure 3. Dimer 10.
d
CH2Ph
methylpyrrolodiazepinones 8a-d and 9a-d all were made
in four to six steps and 16-31% overall yields from
inexpensive amino acid building blocks 1 and 2. Considering
the tolerance of the Cu-catalyzed cascade additions of vinyl
Grignard reagent to a variety of N-(acyl)-amino esters
possessing different side chains,19 a wealth of peptide-based
diazepinone and pyrrolodiazepinone structures may now be
obtained by this practical approach.
using TFA instead of the HCl conditions. Paal-Knorr
cyclization occurred on treatment with triethylamine and a
catalytic amount of toluenesulfonic acid in dilute DCM at 0
°C. After quenching with saturated NaHCO3 solution,
pyrrolodiazepinones 9 were isolated by chromatography on
silica gel in 45-65% overall yield from 7. An improved
Paal-Knorr condensation was then developed using basic
Amberlyst A-21 ion-exchange resin for generating the free
amine after Boc deprotection with TFA in DCM.29
Acknowledgment. The authors would like to acknowl-
edge Franc¸ine Be´langer-Garie´py from the Regional Labora-
tory of X-ray Analysis, Dalbir Sekhon from the Regional
Laboratory of Mass Spectrometry, and Dr. Ramesh Kaul,
Simon Suprenant, and Dr. Susan Seaman, at the Universite´
de Montre´al, for their helpful assistance as well as the Natural
Sciences and Engineering Research Council of Canada
(NSERC) and Fonds Que´be´cois de la Recherche sur la
Nature et les Technologies (FQRNT), for financial support.
The use of higher concentrations of keto aldehydes 6 and
diketones 7 in the Paal-Knorr annulation to form pyrrolo-
diazepinones 8 and 9 provided mixtures of monomers and
dimers as observed by LCMS analyses. Dimer 10 was
isolated by preparative HPLC and identified by its doubling
1
in mass and relatively simple H and 13C NMR spectra due
to C2 symmetry (Figure 3) .
A practical, diversity-oriented methodology for the syn-
thesis of diazepinone structures has been developed that
features treatment of R-aminoacyl-â-amino esters 3 with
excess vinyl Grignard reagent to yield a common homoallylic
ketone intermediate. Diazepinones 5a-d, pyrrolo-, and
Supporting Information Available: Experimental de-
tails, spectroscopic characterization for all compounds, and
X-ray crystallographic data of 5c and 5d. This material is
available free of charge via the Internet at http://pubs.acs.org.
(29) Natarajan, S.; Yurek-George, A.; Ganesan, A. Mol. DiVersity 2005,
9, 291-293.
OL061036K
3428
Org. Lett., Vol. 8, No. 16, 2006