Expedient one-pot synthesis of novel chiral 2-substituted 5-phenyl-1,4-benzodiazepine scaffolds from amino acid-derived amino nitriles

Article abstract of DOI:10.1021/jo034286c

An efficient and stereocontrolled synthesis of phenylalanine- and tryptophan-derived 5-phenyl-1,4-benzodiazepines is described. This new methodology involves, as a key step, the synthesis of 5-phenyl-2,3-dihydro-1H-1,4-benzodiazepines by a one-pot cyano reduction and reductive cyclization of the appropriate amino nitrile, which were obtained via a modified Strecker reaction of N-protected α-amino aldehydes with 2-aminobenzophenone and trimethylsilyl cyanide. The subsequent reduction of these 2,3-dihydro-1H-1,4-benzodiazepines, followed by regioselective alkylation or acylation at position 4, led to 2,4-disubstituted-5-phenyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine.

Full text of DOI:10.1021/jo034286c

SCHEME 1. Retr osyn th esis of
5-P h en yl-1,4-ben zod ia zep in e Der iva tives
Exp ed ien t On e-P ot Syn th esis of Novel
Ch ir a l 2-Su bstitu ted
5-P h en yl-1,4-ben zod ia zep in e Sca ffold s fr om
Am in o Acid -Der ived Am in o Nitr iles
Susana Herrero, M. Teresa Garc´ıa-Lo´pez, and
Rosario Herranz*
Instituto de Qu´ımica Me´dica (CSIC), J uan de la Cierva 3,
E-28006 Madrid, Spain
rosario@iqm.csic.es
tuted 5-phenyl-1,4-benzodiazepine derivatives 1 and 2,
from amino acid-derived amino nitriles 3, as shown in
the retrosynthetic Scheme 1. This strategy would involve
the synthesis of the 2,3-dihydro-1H-1,4-benzodiazepines
2, by cyano reduction and reductive cyclization of amino
nitriles 3, which could be prepared by adapting our
methodology for the synthesis of Ψ[CH(CN)NH]pseudopep-
tides from R-amino aldehydes.7-10 The reduction of 2,
followed by functionalization at position 4, would give
access to the 2,3,4,5-tetrahydro-1H-1,4-benzodiazepine
derivatives 1. We have studied and reported herein the
applicability of retrosynthetic Scheme 1 to the prepara-
tion of phenylalanine- and tryptophan-derived 1,4-ben-
zodiazepines.
Initially, the synthesis of the starting amino nitriles
7a and 7b, by a modified Strecker reaction of 2-ami-
nobenzophenone (5) with the N-protected R-amino alde-
hydes N-Boc-L-Phe-H (4a ) or N-Boc-L-Trp-H (4b) and
trimethylsilyl cyanide (TMSCN) (Scheme 2), was at-
tempted by applying the reaction conditions developed
for the synthesis of Ψ[CH(CN)NH]pseudopeptides,7 which
involved reaction of an R-amino aldehyde with an amino
acid in the presence of ZnCl2 at -20 °C for 1 h, followed
by in situ reaction with TMSCN for 24 h at 0 °C.
However, under these conditions, amino nitriles 7a ,b
Received March 5, 2003
Abstr a ct: An efficient and stereocontrolled synthesis of
phenylalanine- and tryptophan-derived 5-phenyl-1,4-benzo-
diazepines is described. This new methodology involves, as
a key step, the synthesis of 5-phenyl-2,3-dihydro-1H-1,4-
benzodiazepines by a one-pot cyano reduction and reductive
cyclization of the appropriate amino nitrile, which were
obtained via a modified Strecker reaction of N-protected
R-amino aldehydes with 2-aminobenzophenone and tri-
methylsilyl cyanide. The subsequent reduction of these 2,3-
dihydro-1H-1,4-benzodiazepines, followed by regioselective
alkylation or acylation at position 4, led to 2,4-disubstituted-
5-phenyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine.
Because of the wide range of biological activities
displayed by benzodiazepine-derived compounds, benzo-
diazepine scaffolds are considered among the most im-
portant privileged structures for drug discovery.1 Par-
ticularly, 5-aryl-1,4-benzodiazepine templates are recurrent
structures in anxiolytics, hypnotics and anticonvulsants,2
anti-HIV agents,3 and antiarrhythmics.4 Furthermore,
diverse 1,4-benzodiazepine derivatives have also been
used as constrained dipeptide mimics or nonpeptide
scaffolds in the search of peptidomimetics either as
enzyme inhibitors5 or as ligands of diverse G-protein
coupled receptors6 such as cholecystokinin, fibrinogen,
integrin, vasopressin, oxytocin, bradykinin, or k-opioid
receptors.
(6) (a) De Tullio, P.; Delarge, J .; Pirotte, B. Exp. Opin. Invest. Drugs
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W. H.; Newlander, K. A.; Nichols, A.; Parker, M. F.; Southhall, L. S.;
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Huffman, W. F. J . Med. Chem. 1999, 42, 545. (c) Miller, W. H.; Alberts,
D. P.; Bhatnagar, P. K.; Bondinell, W. E.; Callahan, J . F.; Calvo, R.
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C.; Manley, P. J .; Newlander, K. A.; Ross, S. T.; Samanen, J . M.;
Uzinskas, I. N.; Venslavsky, J . W.; Yuan, C. C.; Haltiwanger, R. C.;
Gowen, M.; Hwang, S. M.; J ames, I. E.; Lark, M. W.; Rieman, D. J .;
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W.; J ohanson, K. O.; Huffman, W. F. J . Med. Chem. 2000, 43, 22. (d)
Albright, J . D.; Reich, M. F.; Delos Santos, E. G.; Dusza, J . P.; Sum,
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H.; Bailey, T. J . Med. Chem. 1998, 41, 2442. (e) Wyatt, P. G.; Allen,
M. J .; Chilcott, J .; Hickin, G.; Miller, N. D.; Woollard, P. M. Bioorg.
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In the context of our current interest in methodologies
for generating peptidomimetics, particularly directed
toward the search of new cholecystokinin receptor ligands,
we envisioned a versatile access to novel chiral 2-substi-
(1) (a) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.;
Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.;
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10.1021/jo034286c CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/02/2003
4582
J . Org. Chem. 2003, 68, 4582-4585

SCHEME 2. Syn th esis of Am in o Acid -Der ived
Am in o Nitr iles 7a a n d 7ba
SCHEME 3. Syn th esis a n d Con figu r a tion
Assign m en t of
5-P h en yl-2,3-d ih yd r o-1H-1,4-ben zod ia zep in esa
a
Reagents: (a) ZnCl2, MeOH; (b) TMSCN, MeOH.
TABLE 1. In flu en ce of Tem p er a tu r e a n d Tim e of
Rea ction of 4a w ith 5, P r eviou s to th e Ad d ition of
TMSCN, on th e Yield of Am in o Nitr ile 7a
solvent
T (°C)
t (h)
% 7a
MeOHa
MeOHa
MeOHb
MeOHb
benzeneb
-20
0
20
65
80
1
1
12
12
12
30
37
59
83
20
a
Conditions for the formation of imine 6a , followed by reaction
b
with TMSCN at 0 °C for 24 h. Conditions for the formation of
imine 6a , followed by reaction with TMSCN at room temperature
for 24 h.
a
Reagents: (a) Raney Ni, NH2-NH2‚H2O, MeOH; (b) 2.5 N HCl
in EtOAc; (c) (Cl3CO)2CO, TEA, CH2Cl2.
were obtained as minor compounds (30%) along with
cyanohydrins 8a ,b (50%). This result indicated that, due
to the lower nucleophilic character of the aniline amino
group of 5, in comparison with the amino group of amino
acids, a low formation of the imines 6a ,b had occurred
when the TMSCN was added, and, therefore, the reaction
equilibrium was shifted toward the faster formation of
cyanohydrins 8. The formation of imines 6 was detected
by TLC and RP-HPLC, but they could be neither isolated
nor quantified, as they reverted to 2-amino-benzophenone
and the corresponding amino aldehyde 4a or 4b. To
improve the yield of amino nitriles 7, it was necessary
to increase the temperature and reaction time for the
imine formation up to 65 °C and 24 h (Table 1), as well
as the temperature of the subsequent in situ reaction
with TMSCN up to room temperature. Under these
conditions, amino nitriles 7a and 7b were obtained in
83 and 86% yields, respectively, as (1:2) (R,S)-epimeric
mixtures at the new stereogenic center, which could not
be resolved. It is interesting to note that attempts to
obtain the imine 6a by azeotropic distillation in benzene
of a mixture of 4a and 5, followed by in situ reaction with
TMSCN at room temperature in the presence of ZnCl2,
gave the amino nitrile 7a only in 20% yield within a
complex mixture of degradation compounds. In all cases
the reaction was selective at the aldehyde carbonyl group,
and no reaction was detected at the benzophenone ketone
group.
in refluxing MeOH,11 which directly led to the 5-phenyl-
2,3-dihydro-1H-1,4-benzodiazepines (2R)- and (2S)-10a ,b,
without detection of the formation of the corresponding
triamine intermediates 9a and 9b. As shown in Scheme
3, the 2,3,4,5-tetrahydro derivatives 11a ,b were also
obtained as minor products of reduction. The phenyla-
lanine derivatives (2R)- and (2S)-10a and (2R,5S)- and
(2S,5R)-11a were chromatographically resolved in a 28:
14:2:1 ratio. In the case of the reduction of the tryp-
tophan-derived amino nitriles 7b, the pair of 2,3-dihydro-
1H-1,4-benzodiazepines (2R)- and (2S)-10b was isolated
and resolved in a 2:1 ratio, while the traces of 2,3,4,5-
tetrahydro derivatives (2R*,5S*)-11b could not be iso-
lated. To assign the C2 absolute configuration, the 2,3-
dihydro derivatives (2R)- and (2S)-10a,b were transformed
into their 1-oxo-2,3,3a,4-tetrahydroimidazo[3,4-a][1,4]-
benzodiazepine derivatives (3S,3aR)- and (3S,3aS)-12a ,b,
by N-Boc protection removal, followed by reaction with
bis(trichloromethyl)carbonate. The NOE effects observed
in the DPGSE-NOE spectra of compounds 12a ,b, shown
in Scheme 3, allowed the configuration assignment at C3a
and, therefore, at C2 in 10a ,b.
Although no racemization had been observed in
our previous syntheses of amino acid-derived amino
nitriles,7-10 taking into account the known configura-
tional unstability of R-amino aldehydes and the stronger
reaction conditions required for the synthesis of amino
The reduction of both epimeric pairs of amino nitriles
7a and 7b was satisfactorily carried out by Raney nickel-
catalyzed hydrogen transfer from hydrazine monohydrate
(11) Bauer, A.; Weber, K. H. Z. Naturforsch. 1974, 29b, 670.
J . Org. Chem, Vol. 68, No. 11, 2003 4583

SCHEME 4. Mosh er Acid Am id e a n d Red u ction of
SCHEME 5. Alk yla tion a n d Acyla tion of
2,3,4,5-Tetr a h yd r o-1H-1,4-ben zod ia zep in es
2,3-Dih yd r o-1H-1,4-ben zod ia zep in esa
hydride attacked preferably from the face opposite to that
in which the 2-substituent is situated, giving in each case
the corresponding 2,5-cis isomer as the major reduction
product. All the epimeric pairs 11 were chromatographi-
cally resolved, except for (2S,5RS)-11b resulting from the
tryptophan derivative (2S)-10b. The assignment of ab-
solute configuration at position 5 in the phenylalanine
derivatives 11a was based on the NOE effects between
2-H and 5-H observed in the DPGSE-NOE spectra of
(2R,5S)- and (2S,5R)-11a , shown in Scheme 4, indicative
of a relative 2,5-cis-diaxial relative disposition for those
protons. However, in tryptophan derivatives 11b, the
analysis of their NOE effects was hampered because the
signal corresponding to 2-H appeared overlapped with
the signals corresponding to the 3-H and the indolyl-
methylenic protons. Therefore, the configuration of these
compounds was tentatively assigned by comparison of
a
Reagents: (a) 2.5 N HCl, EtOAc; (b) (R)-MTPA-Cl, TEA,
CH2Cl2; (c) NaBH3CN, AcOH, CH3CN.
nitriles 7a ,b, the possibility of racemization could not be
now discharged. To clarify this point, the major epimer
of the phenylalanine-derived 1,4-benzodiazepine (2R)-10a
was N-Boc deprotected and treated with an excess of the
Mosher acid chloride [(R)-R-methoxy-R-(trifluoromethyl)-
phenylacetic acid chloride [(R)-MTPA-Cl]]. As shown in
Scheme 4, this treatment yielded the corresponding
amide derivative (2R)-13a , whose RP-HPLC and 1H NMR
analyses did not show the presence of signal duplicity.
This result indicated the absence of racemization.
As traces of the 2,3,4,5-tetrahydro-1H-1,4-benzodiaz-
epine derivatives 11 had been obtained in the reduction
of amino nitriles 7 by Raney nickel-catalyzed hydrogen
transfer from hydrazine monohydrate, these conditions
were initially attempted to prepare the phenylalanine-
derived compounds 11a from their 2,3-dihydro analogues
(2R)- and (2S)-10a . However, after the reaction mixture
in MeOH was refluxed for 24 h, (2R)- and (2S)-10a were
recovered unchanged. Similar results were obtained by
10% Pd(C)-catalyzed hydrogenation (at 3 atm of H2
pressure and 50 °C) or by reaction with NaBH4 or LiAlH4,
conditions usually described for the reduction of 2,3-
dihydro-1,4-benzodiazepines.12 Finally, this reduction was
satisfactorily carried out by treatment with NaBH4CN
in CH3CN in the presence of acetic acid. Interestingly,
the use of the this reduction agent in MeOH and in the
presence of ZnCl2 gave negative results. As it is shown
in Scheme 4, the reduction of both epimers (2R)- and (2S)-
led to a 2:1 mixture of two diastereoisomeric 2,3,4,5-
tetrahydro-1H-1,4-benzodiazepines 11, epimers at posi-
tion 5. Independently on the configuration at position 2
in the starting 2,3-dihydro-1,4-benzodiazepines 10, the
1
their H and 13C NMR chemical shifts with those of their
phenylalanine analogues 11a , in particular observing
that in the 2,5-cis isomers, the 2-H proton appeared at a
lower field than in the 2,5-trans isomer, while the 5-H
appeared at a higher field.
In the major diastereoisomer of the phenylalanine-
derived 2,3,4,5-tetrahydro-1H-1,4-benzodiazepines, we
explored the functionalization at position 4 by N-alky-
lation and N-acylation reactions. Thus, as shown in
Scheme 5, the treatment of (2R,5S)-11a with NaH,
followed by reaction with methyl bromoacetate, led to the
selective alkylation at position 4, with no detection of any
alkylation at position 1. It is worth mentioning that the
resulting 1,4-benzodiazepine derivative (2R,5S)-14a rep-
resents a N- and C-orthogonally protected and confor-
mationally restricted tripeptide analogue, which could be
used for introducing conformational restrictions into
larger peptides. On the other hand, due to the importance
of arylureido groups as privileged structures in chole-
cystokinin (CCK) receptor ligands,6a we also explored the
introduction of these groups by acylation at position 4.
The treatment of (2R,5S)-11a with phenyl isocyanate in
the presence of NaH led, also selectively, to the product
of acylation at position 4 (2R,5S)-15a .
All the 1,4-benzodiazepine derivatives described herein
(10-15) were evaluated as CCK1 and CCK2 receptor
ligands by measuring the inhibition of the specific [3H]-
propionyl-CCK-8 binding to rat pancreas and cerebral
(12) Walser, A.; Fryer, R. I. In Bicyclic Diazepines; Fryer, R. I., Ed.;
J ohn Wiley & Sons: New York, 1991; pp 545 and 849.
4584 J . Org. Chem., Vol. 68, No. 11, 2003

cortex homogenates.13 Unfortunately, none of these com-
pounds showed significant binding affinity for any of
these receptor subtypes at concentrations below 10-5 M.
In conclusion, herein we report an efficient and ver-
satile methodology for the synthesis of new highly
functionalized chiral 1,4-benzodiazepine derivatives from
amino acid-derived amino nitriles, which opens access
to a variety of scaffolds of potential use in the search for
peptidomimetics.
Ack n ow led gm en t. This work has been supported
by CICYT (SAF2000-0147)
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for compounds 7-15. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Dauge´, V.; Bohme, G. A.; Crawley, J . M.; Duriex, C.; Stutzman,
J . M.; Feger, J .; Blanchard, J . C.; Roques, B. P. Synapse 1990, 6, 73.
J O034286C
J . Org. Chem, Vol. 68, No. 11, 2003 4585