Photo-induced coupling of tertiary amines with Ugi-derived dehydroalanines as a practical device in the synthesis to 2,4-diaminobutyric acid derivatives

Article abstract of DOI:10.1016/j.tetlet.2019.151152

An Ir-mediated photocatalytic coupling of tertiary amines with Ugi-dehydroalanines was developed as an entry to medicinally important 2,4-diaminobutyric acid derivatives. In the process the 2,4-diaminobutyric acid framework is assembled directly embedded

Full text of DOI:10.1016/j.tetlet.2019.151152

Tetrahedron Letters 60 (2019) 151152
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Photo-induced coupling of tertiary amines with Ugi-derived
dehydroalanines as a practical device in the synthesis to
2,4-diaminobutyric acid derivatives
⇑
Katy Medrano-Uribe, Luis D. Miranda
Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior S.N., Ciudad Universitaria, Coyoacán 04510, Ciudad de México, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 July 2019
Revised 6 September 2019
Accepted 12 September 2019
Available online 13 September 2019
An Ir-mediated photocatalytic coupling of tertiary amines with Ugi-dehydroalanines was developed as an
entry to medicinally important 2,4-diaminobutyric acid derivatives. In the process the 2,4-diaminobu-
tyric acid framework is assembled directly embedded into a peptoide structure, via the construction of
the C (sp )–C (sp ) bond, through a CAH functionalization. The photocatalyzed oxidation of the tertiary
3 4
amine produce a free radical intermediate which reacts with the double bond present in the dehydroala-
nines. The complete protocol comprises an Ugi 4-CR followed by an elimination reaction and the photo-
3
3
Keywords:
Ugi reaction
Dehydroalanines
Amine coupling
Photo-induced reaction
induced coupling. Using this strategy, 15 new diversely substituted unnatural
derivatives were prepared in low to good yields.
a,c-diamino acids peptide
Ó 2019 Elsevier Ltd. All rights reserved.
L
-2,4-Diaminobutyric acid 1 (
L
-DABA) [1] is a neurotoxic natu-
formal cycloaddition between simple ethyl acrylate and dia-
zomethane has also been described to generate the DABA ethyl
ester, after a reductive ring opening process of the pyrazoline inter-
mediate [13].
rally occurring non-proteinogenic diamino acid found in significant
quantity in certain Lathyrus and related seeds (Fig. 1) [2]. It is also
an important component of particular bacterial cell walls [3].
Although this amino acid is not frequently incorporated into pro-
tein chains, it is an important molecular motif found in a number
of natural peptide antibiotics, including members of the non-ribo-
somal cyclic polypeptide polymyxin family [4]. Polymyxins B (2
On the other hand, due to its balance between stability and
reactivity, the double bond in dehydroalanine (Dha) scaffolds 6 is
a unique synthetic platform for further modifications. In this con-
text, in the last years post-translationally modified proteins have
been accessed by the direct functionalization of dehydrolanine
double bonds [14,15]. The olefin present in the Dha has served as
a pivotal template for various synthetic transformations such as
polar and radical additions, metal-catalyzed cross-couplings, and
cycloadditions [16]. The direct radical addition to Dha‘s holds spe-
cial significance because this process allows formation of a new
CAC bond, and reaction conditions utilized for this purpose range
and 3) and E (colistin) which include up to six L-DABA units, are
used as the last therapeutic alternative for the treatment of mul-
tidrug-resistant Pseudomonas aeruginosa, Acinetobacter baumannii,
and Klebsiella pneumoniae [5]. Among other important peptide
antibiotics incorporating
comirin [7]. -DABA is commercially available and is generally used
in classic stepwise peptide coupling sequences when necessary.
Furthermore, synthesis of the 2,4-diaminobutyric acid derivatives
involves reaction of an amine source, either by a substitution pro-
cess with methyl 4-bromo-2-phthalimidobutyrate, or via the ring-
opening process of N-acylated-2-amino-4-butyrolactones [8].
Michael addition of the enolate of glycine derivatives to nitroalke-
nes gives access to 2-substituted-4-diaminobutyric acids (after
reduction) through the construction of the C
syntheses involves the Hofmann degradation [10] or the Curtius
11] and Schmidt reactions of glutamic acid [12]. Interestingly, a
L-DABA units are polypeptin [6] and
L
3
from the use of classic Bu SnH as propagator [17] to metal-cat-
alyzed processes [18]. Along this line, Jui and coworkers recently
developed a photocatalytic method for the direct addition of ter-
tiary amines (4) to Dha derivatives (6) via the SET-induced gener-
ation of an
a-amino radical intermediate 5 through a CAH
functionalization (Scheme 1) [19]. It is important to note that this
highly valuable process assembles the DABA framework directly
embedded into a peptide structure, via the construction of the
2 3
-C bond [9]. Other
3
3
[
C
3
(sp )–C
4
(sp ) bond (Scheme 1).
As part of our ongoing program to the diversification of
Ugi-derived Dha’s 6 [20], we observed that a tertiary amine could
undergo also photocatalytic-induced reductive addition to the
⇑
Corresponding author.
E-mail address: lmiranda@unam.mx (L.D. Miranda).
https://doi.org/10.1016/j.tetlet.2019.151152
040-4039/Ó 2019 Elsevier Ltd. All rights reserved.
0

2
K. Medrano-Uribe, L.D. Miranda / Tetrahedron Letters 60 (2019) 151152
We started our investigation with the synthesis of different Ugi
adducts under the reported optimized conditions using equimolar
amounts of the four components in methanol (1 M) at room tem-
perature, for 24 h (Table 1). As reported earlier the use of the ben-
zoyloxyacetaldehyde 9 was necessary as the aldehyde component
since this substitution allows the subsequent elimination process.
Complementary commercial benzoic, indoleacetic, acetic and
furoic acids were used as the acid components 7. Furthermore,
amines such as 2-Br-benzylamine, n-hexylamine, benzylamine,
tert-butylamine, 3,4-dimethoxybenzylamine, and 4-methoxyben-
zylamine were chosen to expand diversification of the protocol.
Two isocyanides (tert-butylisocyanide and cyclohexylisocyanide)
completed the four-component set of the study. As described in
Table 1, the Ugi reaction proceeded in low to moderate yields
Fig. 1. l-2,4-Diaminobutyric acid (L-DABA) and polymyxins B.
(
20–65%). Then, with the Ugi adducts in hand, the elimination pro-
cess of the benzoyloxy group was carried out. After a short opti-
mization process, we found that the reaction showed better
performance using a combination of Et N and DBU as the basic
3
medium [21]. Thus, under these conditions the corresponding
dehydroalanines 6a-l, were obtained in moderate to good yields
(
20–95%). In general, the adducts derived from cyclohexyl iso-
cyanide showed improved efficiency as compared to their tert-
butyl analogs, perhaps owing to steric issues (Table 1).
Then, we began the investigation of the optimal reaction condi-
tions for the proposed photocatalytic coupling process to obtain
Scheme 1. Photocatalytic addition of tertiary amines to Dha derivatives.
3
3
the 1,4-DABA peptoide scaffolds via the C
3
(sp )–C
4
(sp ) bond for-
0
mation. To this end, dehydroalanine 6e and N ,N-diisopropylethy-
lamine (DIPEA, Hünig base) were utilized as model substrates. In
the first attempt, reaction of 1.5 equivalents of DIPEA and [Ir
double bond of these readily available substrates (Table 2). Fur-
thermore, considering that earlier we had demonstrated that dehy-
droalanines 6 could be prepared by using an Ugi four-component
reaction (Ugi 4-CR) followed by an elimination process (Table 1)
2 6
(dtbbpy)(ppy) ] PF (1% mol) with 6e gave the expected coupling
product 12a in 36% yield (Table 2, entry 1). In control experiments,
we verified that, the reaction did not work in either the absence of
light irradiation or in the absence of the photocatalyst (Table 2,
entries 2 and 3). We found that acetonitrile provided a greater
yield of the expected product 12a compared with other solvents
such as dimethylacetamide, dichloroethane and toluene (entries
[
21], the protocol might represent a practical three-step entry to
diversely substituted peptide-DABA libraries. Diversification vec-
tors would result simply by the judicious choice of the starting four
component-input set in the Ugi-4CR. Herein, we address this task
and describe our earlier results of the development of a photocat-
alytic-induced addition of tertiary amines to Ugi-derived
dehydroalanines.
4–6). Photocatalysts such as Ir(ppy)
3
3
and Ru(BPY) were evaluated,
however the [Ir(dtbbpy)(ppy) ]PF
2
6
complex was found to be the
more efficient for the process (entries 7 and 8) [10]. Then, the
Table 2
Table 1
Optimization of the photocatalytic coupling process.
Ugi 4-CR and the elimination process.
Exp[a]
Photocatalyst
Base[b]
Solvent[c]
Yield (%)
Exp[a]
R
R
R
Yield (%)
1
2
3
1
2
3
4
5
6
7
8
[Ir(dtbbpy)(ppy)
[Ir(dtbbpy)(ppy)
ꢀ
2
] PF
] PF
6
ꢀ
MeCN
MeCN
MeCN
DMA
36
NR
NR
10
20
25
NR
NR
47
44
12
43
51
1
2
3
4
5
6
7
8
9
Ph-
Ind-CH
Ind-CH
CH
CH
Furan
Furan
Furan
CH
CH
CH
CH
2-Br-Bn-
2-Br-Bn-
(CH
4-OMe-Bn-
2-Br-Bn-
(CH
(CH
2-Br-Bn-
Bn
Bn
t-Bu
3,4-OMe-Bn-
t-Bu
11a (30)
11b (30)
11c (53)
11d (58)
11e (30)
11f (58)
11g (51)
11h (25)
11i (37)
11j (39)
11k (65)
11l (26)
6a (42)
6b (76)
6c (54)
6d (94)
6e (95)
6f (27)
6g (46)
6h (46)
6i (70)
6j (43)
6k (59)
6l (22)
2
6
ꢀ
2
-
-
CyHex
CyHex
t-Bu
t-Bu
CyHex
t-Bu
t-Bu
CyHex
t-Bu
CyHex
t-Bu
ꢀ
2
2
)
5
CH
3
-
[Ir(dtbbpy)(ppy)
[Ir(dtbbpy)(ppy)
[Ir(dtbbpy)(ppy)
2
2
2
] PF
] PF
] PF
6
6
6
ꢀ
3
ꢀ
DCM
3
ꢀ
Toluene
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
2
)
)
5
CH
CH
3
-
-
Ir(ppy)
Ru(BPY)
3
ꢀ
2
5
3
3
ꢀ
9
[Ir(dtbbpy)(ppy)
[Ir(dtbbpy)(ppy)
[Ir(dtbbpy)(ppy)
[Ir(dtbbpy)(ppy)
[Ir(dtbbpy)(ppy)
2
2
2
2
2
] PF
] PF
] PF
] PF
] PF
6
6
6
6
6
ꢀ
3
3
3
3
10
11
12
13
DMAP
DBU
10
11
12
Na
Na
2
HPO
CO
4
2
3

K. Medrano-Uribe, L.D. Miranda / Tetrahedron Letters 60 (2019) 151152
3
substrate molar ratio was investigated, observing a higher yield
when three equivalents of amine and 2 mol% of the iridium photo-
catalyst were utilized (entry 9). Different organic and inorganic
troscopy data and further confirmed by single crystal X-ray analy-
sis [22] (Table 3). The minor diastereoisomer (minor-12a) was
isolated in 13% yield along with 7% of the corresponding dehalo-
genated product 14 (see Supporting Information).
2 4 2 3
bases such as DMAP, DBU, Na HPO , Na CO were evaluated as
additives, with Na CO being the most effective with 51% yield of
the desired product 12a (entries 10–13).
2
3
With the optimized conditions in hand, we set out to synthesize
a series of different 2,4-diaminobutyric acid peptide derivatives
using the Hünig base. However, as expected this reagent always
afforded an inseparable and complicated to identified,
diastereoisomeric mixture of the product. For this reason, at this
point, we chose to focus on isolating only the major product in fur-
ther three more examples (12b-d, Table 3). Fortunately,
diastereoisomeric mixture is not possible when the N’N-dimethy-
laniline is used, and superior yields were observed in the coupling
process using this amine. In general good yields (32–89%) were
observed in most experiments when the Ugi-derived dehydroala-
nines were submitted to the photocatalytic coupling conditions.
It is important to note that bromo-aromatic derivatives (12a, d
and 13a, b, d, g), which might be reactive in related coupling con-
ditions (e.g., Pd-mediated cross-coupling or anionic protocols),
proved to be compatible with the photocatalytic conditions. The
reaction worked well with dehydroalanines bearing aromatic (with
MeO- groups) and heteroaromatic systems such as furan (12d and
At this point, we set up the conditions of entry 13 as the optimal
ones and used them in further experiments. It is worth mentioning
that at the outset of the study, we faced some problems for the iso-
lation and characterization of compound 12a, because it was unde-
tectable under UV light. This problem was resolved using
ninhydrin stain. The complete identification of the structure of
the diastereomer major-12a was initially carried out by its spec-
Table 3
Products of the Ir-mediated photo-induced.
1
3e-g) and indole (12b and 13b) as well as aliphatic chains (12b
and 13e-f). However, we did not observe a clear trend regarding
how the substituent on the dehydroalanines affected the reaction
(Table 3). At this stage, Table 3 demonstrates, at least preliminarily,
that the photoredox coupling process provides a straightforward
method to incorporate tertiary amines to Ugi-dehydroalanines as
an entry to medicinally important 2,4-DABA derivatives. Indeed,
the three-step protocol delivered 15 new and interesting deriva-
tives of unnatural
substituents.
a,c-diamino acid peptoids with diverse
In summary, an Ir-mediated photocatalytic coupling of tertiary
amines with Ugi-dehydroalanines was developed as an entry to
medicinally important 2,4-diaminobutyric acid derivatives. This
highly valuable process assembles the DABA framework directly
embedded into a peptoide structure, via the construction of the
3
3
3 4
C (sp )–C (sp ) bond, through a CAH functionalization. The com-
plete protocol comprises a Ugi 4-CR followed by an elimination
reaction and the photo-induced coupling. Using this strategy, 15
interesting new unnatural
a,c-diamino acid peptide derivatives
with diverse substitution patterns were prepared. The structure
of the 2,4-DABA derivatives might be adjusted by a judicious
choice of the starting four component-input set in the Ugi-4CR.
This study streamlines the photocatalytic-induced formation of
an
a-amino carbon radical and its further functionalization. Fur-
ther optimization of the protocol and extension to more complex
substrates is currently under study in our laboratory.
Acknowledgments
Financial support from CONACYT (284976) is gratefully
acknowledged. We also thank R. Patiño, A. Peña, E. Huerta, I. Cha-
vez, R. Gabiño, Ma. C. García-González, L. Velasco and J. Pérez for
technical support with a special acknowledgement to S. Hernán-
dez-Ortega for the X-ray analysis.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.151152.
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