Highly diastereoselective synthesis of 1-carbamoyl-4-aminoindoloazepinone derivatives via the Ugi reaction

Article abstract of DOI:10.1021/ol402940x

A one-pot procedure for the highly diastereoselective synthesis of 1-carbamoyl-4-amino-1,2,4,5-tetrahydroindolo[2,3-c]azepin-3-one derivatives is described. Using 2-formyl-L-tryptophan as a bifunctional building block, a catalyst-free Ugi-three-component

Full text of DOI:10.1021/ol402940x

ORGANIC
LETTERS
2
013
Vol. 15, No. 22
866–5869
Highly Diastereoselective Synthesis of
‑Carbamoyl-4-aminoindoloazepinone
Derivatives via the Ugi Reaction
5
1
,†
†
‡
†
Mouhamad Jida,* Cecilia Betti, Zofia Urbanczyk-Lipkowska, Dirk Tourw ꢀe , and
Steven Ballet*
,†
Department of Organic Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, B-1050
Brussels, Belgium, and Institute of Organic Chemistry, Polish Academy of Sciences,
Kasprzaka Str. 44/52, 01-224 Warsaw, Poland
mouhamad.jida@vub.ac.be; sballet@vub.ac.be
Received October 11, 2013
ABSTRACT
A one-pot procedure for the highly diastereoselective synthesis of 1-carbamoyl-4-amino-1,2,4,5-tetrahydroindolo[2,3-c]azepin-3-one derivatives
is described. Using 2-formyl-L-tryptophan as a bifunctional building block, a catalyst-free Ugi-three-component reaction (Ugi-3CR) was developed
to present trisubstituted indoloazepinones in good yields and excellent diastereomeric excess.
4
Multicomponent reactions (MCRs) are one-pot pro-
cesses during which three or more substrates react in a
single chemical step to produce a product that incorpo-
synthetic potential. The Ugi-4CR involves a condensa-
tion of a carbonyl component, an isonitrile, an amine, and
a carboxylic acid to present R-acylaminoamides. Conco-
mitantly, a new stereogenic center is created. Hence, it
provides a powerful tool to access diversity as well as
complexity in a one-step procedure. Several strategies
have been applied to control the chirality of the newly
1
rates all of the educts. Since MCRs represent one of the
most powerful approaches for combinatorial chemistry
and diversity-oriented synthesis, they play an important
role in the development of drug discovery methodology
2
and biological probes. The Ugi four-component reaction
3
Ugi-4CR) is one of the most widely applied MCRs, and
formed stereocenter by using chiral substrates or chiral
4a,5
(
great efforts have been dedicated to the exploration of its
auxiliaries.
phenylethylamines, ferrocenylamines, glycosylamines,
For example, chiral amines such as (S)-R-
6 7 8
9
xylopyranose-derived peracylated thiosugar, and esters
†
10
Vrije Universiteit Brussel.
Polish Academy of Sciences.
of R-amino acids are capable to induce excellent stereo-
selectivity in Ugi-4CRs. In contrast, chiral oxo components
‡
(
1) (a) Zhu, J.; Bienayme, H. Multicomponent Reactions; Wiley-VCH:
Weinheim, 2005. (b) Ramon, D. J.; Yus, M. Angew. Chem. 2005, 117, 1628.
c) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602. (d)
Ganem, B. Acc. Chem. Res. 2009, 42, 463.
2) (a) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51. (b) Nair,
(
(5) Asymmetric Isocyanide-based MCRs:Banfi, L.; Basso, A. ;
Guanti, G. In Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.;
Wiley-VCH: Weinheim, 2005; pp 1À32.
(
V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Bindu, A. R.; Sreekanth, A. R.;
Mathen, J. S.; Balagopal, L. Acc. Chem. Res. 2003, 36, 899. (c)
Akakritopoulou-Zanze, I. Curr. Opin. Chem. Biol. 2008, 12, 324. (d)
Wessjohann, L. A.; Rivera, D. G.; Vercillo, O. E. Chem. Rev. 2009, 109,
(
6) Ugi, I.; Kaufhold, G. Liebigs Ann. Chem. 1967, 709, 11.
(7) Marquarding, D.; Hoffman, P.; Heitzer, H.; Ugi, I. J. Am. Chem.
Soc. 1970, 92, 1969.
7
96. (e) El Kaim, L.; Grimaud, L. Tetrahedron 2009, 65, 2153.
3) (a) Marcaccini, S.; Torroba, T. Nat. Protoc. 2007, 2, 632. (b) Ugi,
I. Angew. Chem. 1962, 74, 9. (c) Ugi, I. Angew. Chem., Int. Ed. 1962, 1, 8.
4) (a) Domling, A. Chem. Rev. 2006, 106, 17. (b) Domling, A.; Ugi, I.
(8) Kunz, H.; Sager, W. Angew. Chem., Int. Ed. 1987, 26, 557.
(9) Ross, F. G.; Herdtweck, E.; Ugi, I. Tetrahedron 2002, 58, 6127.
(10) Faggi, C.; Mercaccini, S.; Pepino, R.; Pozo, C. M. Synthesis
2002, 2756.
(
(
Angew. Chem. 2000, 112, 3300. (c) Domling, A.; Ugi, I. Angew. Chem.,
Int. Ed. 2000, 39, 3168. (d) Ugi, I.; Werner, B.; Domling, A. Molecules
(11) (a) Zhdanko, A. G.; Nenajdenko, V. G. Eur. J. Org. Chem. 2009,
74, 884. (b) Banfi, L.; Basso, A.; Riva,R. In Isocyanide Chemistry;
Nenajdenko, V., Eds.; Wiley-VCH: Weinheim, 2012; pp 1À33. (c) Carney,
D. W.; Truong, J. V.; Sello, J. K. J. Org. Chem. 2011, 76, 10279.
2003, 8, 53. (e) Ugi, I.; Meyr, R.; Fetzer, U.; Steinbruckner, C. Angew.
Chem. 1959, 44, 1602.
1
0.1021/ol402940x r 2013 American Chemical Society
Published on Web 10/25/2013

and chiral isocyanides do not have a great influence on the
1
1
stereoselectivity of the reaction. Furthermore, a negligible
stereoselectivity was observed when chiral carboxylic acids
1
2
were used. Additionally, using 1,8-naphthalaldehydic
acid, 2-formylphenoxyacetic acid, and 2-formylphenoxy-2-
benzoic acid as bifunctional reagents in Ugi condensations,
a series of rare six-, seven-, and eight-membered heterocyclic
13
rings was obtained. In all cases, the compounds were
isolated in low yield and racemic form and with poor
diastereoselectivity. The steric biases imposed by a cyclic
transition state can, however, facilitate the achievement of
good diastereoselectivity in intramolecular Ugi reactions.
As such, a diastereomeric ratio of 9:1 was observed by a
Figure 1. Conformationally constrained amino acid scaffolds
Aba 1a, Aia 1b/2, and Ata 1c.
14
reaction using an N-protected 2-formyltryptophan reagent 3
1
,4 long-range asymmetric induction for the formation of
22
that was previously developed by us (see the Supporting
Information for more details). The preparation of racemic
14c
2,5-substituted tetrahydrobenzoxazepines.
Seven-membered N-heterocycles, including pyrrolo-
5- or 7-carboxamidoindolobenzazepinones was reported by
application of an intramolecular Ugi-3CR.
and indoloazepinones, are very interesting in medicinal
chemistry, where they represent an important class of
23
In this paper, we report the development of a new
stereoselective Ugi-3CR that allows the synthesis of
novel, optically pure 1-carbamoyl-Aia heterocycles by
condensation of 2-formyl-L-Trp 3 with different amines
and isocyanides. In order to find the best reaction condi-
tions for the synthesis of the prototype Aia derivatives,
Boc-2-formyl-L-tryptophan 3, 4-methoxy-benzylamine
1
5
“
privileged scaffolds”. Previously, we have suggested
that the 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one
a (Aba), 4-aminoindoloazepinone 1b (Aia), and 4-ami-
1
1
6
notriazolodiazepinone 1c (Ata) (Figure 1) might also
serve as privileged templates since these scaffolds were
used to obtain a variety of peptide and peptidomimetic
ligands for several G protein-coupled receptors. Examples
5
d, and tert-butyl isocyanide 4c were chosen as model
1
7
18
include opioid GPCRs, neurokinin 1, and somatostatin
substrates to optimize the reaction conditions (Table 1).
Because we recently investigated microwave-assisted,
19
receptors. 1-Substituted analogues such as 2 (Figure 1),
having three points of diversification, are therefore interest-
ing in medicinal chemistry.
2
4
solvent- and catalyst-free conversions, the development
of such conditions was of particular interest.
Only the 1-phenyl-substituted analogues of 1a have
In a first step, we optimized the microwave irradiation
parameters. Initially, under solvent-free microwave
2
been reported. As a continuation of our studies on
0
2
1
isocyanide-based multicomponent reactions, we proposed
that the 1-carboxamido-substituted Aia scaffold 2 (R =
2
4b
conditions,
the reaction did not proceed when the
3
mixture was heated at 100 °C for 3 min (entry 1, Table 1).
In addition, performing the reaction in MeOH (0.1 M)
under microwave conditions and increasing the tempera-
ture to 80 °C for 2 h did not lead to the desired Ugi
product (entries 2 and 3, Table 1). To our delight, the
desired product was, however, observed upon further
increase of the temperature (entries 4À9, Table 1). Suc-
cessive temperature increase from 80 to 175 °C and
applying a reaction time of 1 h 30 to 2 h afforded total
conversion to 6f (75% yield, 44/56 dr, entry 8, Table 1).
CO-NHR ) could be synthesized via the intramolecular Ugi
3
(
12) (a) Yamada, T.; Motoyama, N.; Taniguchi, T.; Kazuta, Y.;
Miyazawa, T.; Matsumoto, K.; Sugiura, M. Chem. Lett. 1987, 723. (b)
Golebioski, A.; Klopfenstein, S. R.; Shao, X.; Chen, J. J.; Colson, A. O.;
Grieb, A. L.; Russel, A. F. Org. Lett. 2000, 2, 2615.
(
13) (a) Ley, S. V.; Taylor, S. J. Bioorg. Med. Chem. Lett. 2002, 12,
813. (b) Harriman, G. C. B. Tetrahedron Lett. 1997, 38, 5591.
14) (a) Basso, A.; Banfi, L.; Riva, R. Eur. J. Org. Chem. 2010, 1831.
b) van Berkel, S. S.; B o€ gels, B. G. M.; Wijdeven, M. A.; Westermann,
1
(
(
B.; Rutjes, F. P. J. T. Eur. J. Org. Chem. 2012, 3543. (c) Banfi, L.; Bagno,
A.; Basso, A.; De Stanis, C.; Riva, R.; Rastrelli, F. Eur. J. Org. Chem.
2013, 5064.
1
Two diastereomers were observed by HPLC and H
(
15) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.;
Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.;
Anderson, P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen,
T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfield, J. J. Med.
Chem. 1988, 3, 2235.
NMR, and these could be separated by silica gel column
chromatography (see the Supporting Information). No
reaction occurred at room temperature in methanol with
reaction times of up to 48 h (entry 10, Table 1). Because of
a lack in stereoselectivity, we turned our attention to
exploring lower temperatures and prolonged reaction
(
16) Buysse, K.; Farad, J.; Nikolaou, A.; Vanderheyden, P.; Vau-
quelin, G.; Sejer Pedersen, D.; Tourw ꢀe , D.; Ballet, S. Org. Lett. 2011, 13,
468.
17) Novoa, A.; Van Drope, S.; Wynendaele, E.; Spetea, M.; Bracke,
6
(
N.; Stalmans, S.; Betti, C.; Chung, N. N.; Lemieux, C.; Zuegg, J.;
Cooper, M. A.; Tourw ꢀe , D.; De Spiegeleer, B.; Schiller, P. W.; Ballet,
S. J. Med. Chem. 2012, 55, 9549.
(18) Ballet, S.; Feytens, D.; Buysse.; Chang, N. C.; Lemieux, C.;
Tumati, S.; Keresztes, A.; Van Duppen, J.; Lai, J.; Varga, E.; Porreca,
(22) Pulka, K.; Feytens, D.; Van den Eynde, I.; De Wachter, R.;
Kosson, P.; Misicka, A.; Lipkowski, A.; Chung, N. N.; Schiller, P. W.;
Tourw ꢀe , D. Tetrahedron 2007, 63, 1459.
(23) Beaumont, S.; Retailleau, P.; Dauban, P.; Dodd, R. H. Eur. J.
Org. Chem. 2008, 5162.
(24) For selected examples, see: (a) Jida, M.; Deprez-Poulain, R.;
Malaquin, S.; Roussel, P.; Agboussou-Niedercorn, F.; Deprez, B.;
Laconde, G. Green Chem. 2010, 12, 961. (b) Jida, M.; Malaquin, S.;
Deprez-Poulain, R.; Laconde, G.; Deprez, B. Tetrahedron Lett. 2010, 51,
5109. (c) Jida, M.; Soueidan, O. M.; Deprez, B.; Laconde, G.;
Deprez-Poulain, R. Green Chem. 2012, 14, 909.
F.; Schiller, P. W.; Vanden Broeck, J.; Tourw ꢀe , D. J. Med. Chem. 2011,
5
4, 2467.
19) Feytens, D.; De Vlaeminck, M.; Cescato, R.; Tourw ꢀe , D.; Reubi,
J. C. J. Med. Chem. 2009, 52, 95.
20) Ballet, S.; Urbanczyk-Lipkowska, Z.; Tourw ꢀe , D. Synlett 2005,
8, 2791.
21) Malaquin, S.; Jida, M.; Gesquiere, J.-C.; Deprez-Poulain, R.;
(
(
1
(
Deprez, B.; Laconde, G. Tetrahedron Lett. 2010, 51, 2983.
Org. Lett., Vol. 15, No. 22, 2013
5867

a
a
Table 1. Optimization of Ugi-3CR Reaction Conditions
Table 2. Substrate Scope
b
b
entry
temp (°C)
time (h)
conv (%)
dr
c
1
100
50
3 min
8
0
d
2
0
d
3
80
2
traces
40
d
4
100
120
150
150
175
175
25
2
80:20
78:22
42:58
44:56
44:56
50:50
d
5
2
78
d,e
6
2
100
90
d
7
1.5
1.5
1
d,f
8
100
84
d
9
g
1
0
48
48
48
12
16
18
40
42
48
48
0
h
11
40
traces
46
h
1
1
1
1
1
1
1
1
2
3
4
5
6
7
60
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
h
70
48
h
70
53
h
70
61
h
70
93
h
70
95
h,i
8
70
100
100
d
9
70
a
Reaction conditions: 3, 4, and 5 (0.3 mmol), MeOH (3 mL).
Determined by HPLC of the crude reaction mixture. The reaction
b
c
d
was performed under solvent-free microwave irradiation. The reaction
e
was performed in MeOH (0.1 M) under microwave irradiation. Iso-
lated in 75% yield, and diastereomers 6f and 6f’ were separated by silica
gel column chromatography. The substrate partially decomposed, and
f
g
secondary products appeared. The reaction was carried out at room
h
temperature in methanol for 48 h. The reaction was performed in a
i
sealed vial in an oil bath. Isolated in 92% yield as a single trans
diastereomer.
times. For this purpose, the optimization of the Ugi
reaction was performed in sealed vials which were placed
in an oil bath (entries 11À18, Table 1). Gratifyingly, when
using conventional heating, only one diastereomer was
obtained in all cases. In order to determine the origin of
the stereoselectivity, we compared the optimal reaction
conditions obtained for conventional heating (entry 18,
7
0 °C for 48 h) to the equivalent conditions under micro-
wave irradiation (entry 19, Table 1). As expected, the
microwave conditions also give way to one diastereomer,
concluding that the stereoselectivity is dependent on
temperature.
Next, the optimal conditions (entry 18, Table 1) were
chosen to explore the substituent scope of this protocol.
At this temperature and reaction time, full conversion
and high diastereomeric excesses were obtained. Detailed
results for a wide array of enantiopure Aia scaffolds are
summarized in Table 2.
With enantiopure N-Boc-2-formyl-Trp-OH 3 as a chir-
al formylcarboxylic acid in hand, we initiated a study to
explore the scope of this new stereoselective Ugi-3CR. In
a
Reaction conditions: 3, 4, and 5 (0.3 mmol), MeOH (3 mL), 48 h,
b
7
0 °C. Isolated yields after silica gel column chromatography.
Diastereomeric excess determined by H and C NMR spectra or HPLC.
equiv of Et N was added. The reaction was stopped after 1 week.
3
c
1
13
d
e
1
all cases, excellent diastereoselectivity and high yields
were observed for various amines and isocyanides. The
reaction of three different isocyanides with benzylamine
was examined (entries 1À3, Table 2), and the desired
5
868
Org. Lett., Vol. 15, No. 22, 2013

products 6aÀc were isolated with high yields and excel-
lent de (%). To check that no racemization takes place
during the cyclization step, a reaction with (S)-1-methyl-
benzylamine and (R)-1-methylbenzylamine was realized.
Only single diastereomeric Aia’s (6d,e) were observed by
Scheme 1. Suggested Rationale for Induction of
Diastereoselectivity
1
H NMR and HPLC (entries 4 and 5, Table 2). The
electron-donating or electron-withdrawing properties of
the substituent of the amine component were well toler-
ated and have no influence on the yield and diastereo-
meric excess of the reaction, and the compounds (6f,g)
were isolated in an enantiopure form (entries 6 and 7,
Table 2). Also, a heteroaromatic amine could be used to
give compound 6h (entry 8, Table 2). A moderate yield of
Ugi product 6i was observed upon use of tert-butylamine
(
entry 9, Table 2). This result could be attributed to its
weak reactivity (and hence long reaction times) and lower
thermal stability leading to possible byproducts.
In contrast, a cyclic, an aliphatic R-branched and
R-unbranched amine gave the expected compounds (6j,k)
in excellent yields and diastereomeric excess (entries 10À13,
Table 2). Finally, amino esters such as glycine and pheny-
lalanine methyl ester could also be used and reacted
smoothly with Boc-2-formyl-L-Trp 3 to give the desired
dipeptidomimetics 6n and 6o in high yield and diastereo-
meric ratio (entries 8À10). It is noteworthy that the reported
procedure is an attractive methodology for the single step
synthesis of conformationally constrained Aia-Xxx dipep-
tides (with Xxx: a variable R-amino acid residue) in its
enantiopure form. The configuration of the Ugi-Aia products
was confirmed by NOESY studies of 6f and X-ray crystal-
lographic analysis of 6c (see the Supporting Information).
Mechanistically, the reaction proceeds via the forma-
tion of an imine, formed in situ from formyltryptophan 3
and an amine (Scheme 1). A pseudocyclic intermediate 7
is proposed by intramolecular protonation of the imine
by the carboxylic acid, in which the bulky N-Boc sub-
stituent adopts a pseudoequatorial conformation and
which fixes the orientation of the imine. The isocyanide
can add immediately to the iminium ion or the iminium
ion is first attacked by the carboxylate, especially in polar
media, followed by a substitution by the isocyanide with
trans-diastereoisomer 12. Alternatively, addition of the
carboxylate from the bottom side (si-face) of the iminium
ion occurs through another boatlike transition state 13, in
which the pseudoaxial NH-R substituent has unfavor-
β
able transannular interactions with one of protons at C
of the Trp structure. The formation of intermediate 14,
ultimately leading to the cis-isomer 17, is therefore pro-
posed to be disfavored compared to 9.
In conclusion, we have described an efficient and useful
stereoselective Ugi-3CR reaction for the synthesis of
optically pure amino indoloazepinone (Aia) derivatives
starting from N-Boc-2-formyl-L-tryptophan 3 as a chiral
formylcarboxylic acid. The desired seven-membered pro-
ducts are formed in excellent yields and diastereomeric
excess under catalyst-free conditions and simple experi-
mental procedures. Dipeptide building blocks of type 6n
and 6o can be applied to different bioactive peptide chains by
incorporation of enantiopure and trisubstituted Aia scaffolds
into peptide sequences but also used to prepare new combi-
natorial libraries with a wide structural diversity. The com-
plexity of and substitution patterns in these compounds will
allow their use in various biological applications.
2
2
5
inversion of configuration.
Since the second mechanism involves an intramolecu-
lar addition in the present case, this may be the preferred
pathway. Addition of the carboxylate can occur from the
top side (reface) through a boatlike transition state 8 in
Acknowledgment. This work was supported by the
Research Foundation - Flanders (FWO) and the Ministere
ꢁ
de Developpement Economique, de l’Innovation et de
ꢀ
l’Exportation (MDEIE) du Quebec.
2
which the NH-R substituent is placed in a pseudoequa-
ꢀ
torial position, thus avoiding unfavorable allylic strain
with the indole NÀH. Substitution by the isocyanide with
inversion of configuration then leads to intermediate 10,
which rearranges to 11, followed by acyl transfer to the
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(
25) (a) Banfi, L.; Basso, A.; Chiappe, C.; De Moliner, F.; Riva, R.;
Sonaglia, L. Org. Biomol. Chem. 2012, 10, 3819. (b) Basso, A.; Banfi, L.;
Riva, R.; Guanti, G. Tetrahedron Lett. 2004, 45, 587.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 22, 2013
5869