Gold-Catalyzed Unexpected Ring Transformation of Pyrimidodiazepine Derivatives

Article abstract of DOI:10.1021/acs.orglett.6b03520

Pyrimidodiazepine derivatives underwent an unexpected gold-catalyzed retro-Mannich-type carbon-carbon bond cleavage and intramolecular nucleophilic cyclization. The pyrimidodiazepines bearing an alkyne moiety showed novel orthogonal reactivity in the presence of a gold catalyst, as opposed to the alkynophilicity that is commonly observed with gold catalysts. The ring transformation reaction of pyrimidodiazepines probably proceeds through an acyclic iminium intermediate. The potential of this synthetic method for the skeletal diversification of pyrimidine-containing macrocycles was also demonstrated.

Full text of DOI:10.1021/acs.orglett.6b03520

Letter
pubs.acs.org/OrgLett
Gold-Catalyzed Unexpected Ring Transformation of
Pyrimidodiazepine Derivatives
†
†
,†,‡
Jaeyoung Koo, Jonghoon Kim, and Seung Bum Park*
†Department of Biophysics and Chemical Biology, Seoul National University, Seoul 08826, Korea
‡Department of Chemistry, Seoul National University, Seoul 08826, Korea
*
S Supporting Information
ABSTRACT: Pyrimidodiazepine derivatives underwent an
unexpected gold-catalyzed retro-Mannich-type carbon−carbon
bond cleavage and intramolecular nucleophilic cyclization. The
pyrimidodiazepines bearing an alkyne moiety showed novel
orthogonal reactivity in the presence of a gold catalyst, as
opposed to the alkynophilicity that is commonly observed with
gold catalysts. The ring transformation reaction of pyrimido-
diazepines probably proceeds through an acyclic iminium
intermediate. The potential of this synthetic method for the
skeletal diversification of pyrimidine-containing macrocycles
was also demonstrated.
he chemical and biological properties of privileged
Scheme 1. Unexpected Discovery of a Novel Gold-Catalyzed
Reaction
T
heterocycles are of continued interest because of the
existence of these moieties in many bioactive natural products
1
and FDA-approved pharmaceutical drugs. Among them,
pyrimidine has been extensively utilized in pharmaceutics as a
key structural motif owing to its ability to mimic the structures
2
and properties of nucleosides. Pyrimidine and its derivatives
3
exhibit diverse biological activities, including antibacterial,
antifungal, antiviral, and anticancer properties.
4
5
6
Recently, we reported the synthesis of pyrimidine-containing
polyheterocycles via the recombination of a pyrimidine ring with
various heterocycles to expand molecular diversity using the
privileged substructure-based diversity-oriented synthesis
7
,8
(
pDOS) strategy. We also showed that privileged structures
As part of our continuing interest in the diversification of
pyrimidine-embedded molecular frameworks, herein we report a
novel synthetic method using a gold catalyst; this involves a
retro-Mannich-type C−C bond cleavage in pyrimidodiazepines
followed by intramolecular cyclization. The unique reactivity of
the gold catalyst is mainly discussed. Under the AuCl-catalyzed
microwave reaction conditions, the pyrimidodiazepine moiety
can be transformed into imidazolidines, oxazinanes, and
oxazolidines depending on the location and type of intra-
molecular nucleophiles through an iminium intermediate
(Scheme 1B). This gold-catalyzed ring transformation can be
used for the skeletal diversification of one pyrimidine-containing
macrocycle to another in a single step at a late stage of synthesis.
Moreover, this gold-catalyzed C−C bond cleavage occurs in
preference to alkynophilic activation. To the best of our
serve as “chemical navigators” to efficiently access the bioactive
8
−10
chemical space.
Indeed, skeletal diversity has evolved as a key
element in the design strategy for the construction of druglike
11
small molecule libraries, and there is a high demand for
developing efficient methods to increase skeletal diversity. Thus,
we have been pursuing new intramolecular transformations of
pyrimidine-embedded polyheterocycles using transition-metal
catalysts. In fact, transition-metal catalysis provides an efficient
way to induce remarkable changes within molecular frameworks
1
2
in a single step. In particular, gold-catalyzed reactions have
attracted much interest in organic synthesis because of the
unique ability of gold catalysts to activate unsaturated carbon−
13
carbon bonds so that they can react with various nucleophiles.
Gold catalysts have been widely used as selective alkynophiles for
inter- and intramolecular nucleophilic reactions under mild
conditions with excellent functional group tolerance to afford
Received: November 24, 2016
14
various heterocyclic products (Scheme 1A).
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03520
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
knowledge, no gold-catalyzed methodology with orthogonal
reactivity of substrates in the presence of an terminal acetylene
moiety has been reported.
Table 1. Optimization of Reaction Conditions
We recently focused on the diversification of pyrimidodiaze-
7
,8
pine using the pDOS strategy
to construct various
polyheterocyclic scaffolds for molecular diversity to systemati-
8
cally explore the protein−protein and protein−DNA/RNA
9
interactions. During this exploration, we designed and
synthesized substrate 1a bearing a terminal acetylene group
which can be activated by a gold catalyst; subsequent cyclization
via the intramolecular nucleophilic attack of primary alcohol
group would afford a fused morpholine moiety. However, we
failed to obtain the fused morpholine moiety under typical gold-
catalyzed reaction conditions using microwave irradiation
(
Scheme 2A). Instead, the terminal acetylene moiety was
Scheme 2. Initial Discovery of a Novel Gold-Catalyzed
Reaction
a
Reaction conditions: SM, catalyst (10 mol %), solvent (0.1 M).
DCE: 1,2-dichloroethane. DMF: dimethylformamide. THF: tetrahy-
b
c
1
drofuran. ACN: acetonitrile. Yields determined by the H NMR
analysis of crude products using an internal standard (1,3,5-tri-MeO-
C H ). Microwave conditions.
d
6
3
result, we confirmed that anilinic nitrogen has a higher priority
19
over the alcoholic nucleophile when both are available.
With the optimized conditions in hand, we performed a series
of reactions to investigate the substrate scope of this gold-
catalyzed ring transformation. As shown in Table 2, alkylamines
1
and cyclic amines at the R position were well tolerated,
found to be intact by 1H and 13C NMR spectroscopy.
Surprisingly, this unexpected product 2a was a ring-contracted
heterocycle containing an imidazolidine moiety, formed by gold-
catalyzed C−C bond cleavage and subsequent intramolecular
nucleophilic cyclization of the anilinic nitrogen. To confirm this
transformation, we designed and tested 1b containing a terminal
acetylene group as substrate 1a and no primary alcohol
nucleophile. As shown in Scheme 2B, the imidazolidine-
containing product 2b was obtained with the terminal acetylene
moiety intact, as determined by H NMR spectroscopy. The
exact structure of 2b was confirmed by X-ray crystallography (see
the Supporting Information).
Intrigued by this unexpected result, we attempted to optimize
the gold-catalyzed transformation under various conditions
providing imidazolidine products in good-to-excellent yields.
2
Diverse substituents on the secondary amine at the R position
were also tolerated, including alkynyl (1a, 1b, and 1d), allyl (1e),
and benzyl (1c, 1g, 1i, and 1k−o) as well as unmodified
secondary amines (1f, 1h, and 1j). The ester moiety (1h) at the
C-7 position and the silyl ether moiety (1c−g and 1i−k) at the
C-7 and C-8 positions of the pyrimidodiazepine provided the
corresponding products in good yields. However, tosyl or
2
carbonyl substituents at the R position failed to provide the
1
desired products, probably because of the electron-withdrawing
2
nature of the substituents at the R position for this reaction (data
not shown). Next, the ability of alcohol nucleophile to form
different types of heterocycles (Table 2, 1l−o) was investigated.
The primary alcohol substituents at the C-7 or C-8 position in
the gold-catalyzed transformation of pyrimidodiazepine afforded
either 1,3-oxazinanes (3l and 3m) or oxazolidines (4n and 4o),
respectively. To decrease the nucleophilicity of aniline, electron-
donating alkyl substituents as well as electron-withdrawing
(Table 1). The feasibility of this process was investigated using
substrate 1c without the terminal acetylene moiety and various
coinage metal catalysts and conditions. First, 1c was thermally
activated in the presence of various gold and silver catalysts
3
(
entries 1−5). Among the tested coinage metal catalysts, AuCl
carbonyl substituents were introduced at the R position.
showed the efficient transformation of 1c to 2c, but this thermal
Notably, different reactive nucleophiles in pyrimidodiazepine 1
result in the diverse ring transformations, generating different
heterocycles from the same skeleton.
reaction was quite slow (23 h, entry 1). Although the reaction
rate of AuCl was faster than that of other catalysts, the reaction
3
was not clean (entry 2). In the case of microwave-assisted
Using the synthetic method for the pyrimidodiazepine core
skeleton (see Scheme S6), various R4 substituents were
introduced at the C-5 position at the stage of the formation of
iminium intermediate, generated by N-alkylation of SI-4, using
Grignard reagents. The diastereomeric outcome of the alkyl
substituents in 1p−s varied due to the chiral environment
generated by the TIPS-containing substituent at the C-7 position
15
activation, the reaction time was effectively reduced, but the
yield was also significantly decreased (entry 6). To solve this
problem, different solvents were screened; the desired product
2
c was obtained in an excellent yield within a short reaction time
when acetonitrile was used (entry 10). Model substrate 1c
contains two potential nucleophiles, anilinic nitrogen and TIPS-
protected alcohol. To investigate the priority of two competing
nucleophiles, the following experiment were performed by
changing the reaction sequence (see Scheme S9). Based on this
8
of the iminium intermediate. As shown in Table 3, the
diastereomeric ratio of the starting materials (1p−s) was
2
influenced by the size of R substituent at the N-6 position
B
DOI: 10.1021/acs.orglett.6b03520
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Organic Letters
Letter
Table 2. Substrate Scope of Gold-Catalyzed Ring
Transformation Reaction
understand the mechanistic origin of this diastereoselectivity, the
reactivity of gold-catalyzed ring transformation was further
investigated using a 1:1 mixture of pyrimidodiazepine substrate
a
1p containing benzyl and methyl moieties at the C-5 and N-6
position, respectively. When this gold-catalyzed reaction of 1p
was quenched prior to its full conversion, the desired
imidazolidine 5p was obtained as a single diastereomer, and
the remaining starting material 1p was obtained as a 1:1 mixture
1
as confirmed by crude H NMR spectroscopy (Scheme 3A). This
Scheme 3. Experimental Investigation To Elucidate the
Reaction Mechanism of Gold-Catalyzed Ring Transformation
observation indicates that the gold-catalyzed reaction occurred
through the formation of an identical intermediate from both the
diastereomeric starting materials with the same reaction rate
followed by the intramolecular nucleophilic addition of anilinic
nitrogen to afford the desired product 5p as a single
diastereomer.
a
Reaction conditions: SM, AuCl (10 mol %), ACN (0.1 M),
b
microwave, 100 W, 80 °C, 30 min. Yield of the isolated product.
c
Based on recovered starting materials.
On the basis of these experimental results, a probable
mechanism of this gold-catalyzed ring transformation involving
2
4
Table 3. Steric Effects of R and R Substituents on
Diastereomeric Ratio
16
an iminium intermediate is proposed (Scheme 4). Strongly
Scheme 4. Plausible Mechanism of Gold-Catalyzed Ring
Transformation of Pyrimidodiazepine
R4
R2
SM dr ratio
b
pdt dr ratio
b
yield (%)
c
entry
1
2
3
4
Bn
Bn
Me
Me
Me (1p)
Bn (1q)
Bn (1r)
Me (1s)
4:1
3.6:1
2.7:1
3.6:1
≫99:1
≫99:1
2:1
5p, 72
5q, 81
5r, 70
5s, 92
1.21:1
a
Reaction conditions: SM, AuCl (10 mol %), ACN (0.1 M),
b
microwave, 100 W, 80 °C. Diastereomeric ratio was determined by
1
c
H NMR analysis. Yield of the isolated product.
nucleophilic trimethylsilyl cyanide (TMSCN) was added to trap
the acyclic iminium intermediate of the gold-catalyzed reaction
of 1c; the CN-trapped product 6c was observed along with the
owing to the facial selectivity of Grignard reagents. After the
preparation of a full matrix of either methyl or benzyl substituents
at the C-5 and N-6 positions, the gold-catalyzed ring trans-
formation reaction was performed. Surprisingly, a single product
19
desired imidazolidine product 2c (Scheme 3B). Therefore, it
can be concluded that this AuCl-catalyzed ring transformation of
pyrimidodiazepine is mediated via the in situ generation of an
acyclic iminium intermediate through gold-catalyzed ring
(
5p and 5q) was observed from a 4:1 mixture of 1p and 3.6:1
17
mixture of 1q, respectively, in good yield and excellent
diastereoselectivity under the optimized reaction conditions.
However, the corresponding diastereoselectivity decreased when
opening and subsequent intramolecular nucleophilic cycliza-
tion. The stereochemical enrichment of this unusual gold-
catalyzed reaction can be attributed to the retro-Mannich-type
4
18
the size of the R substituent at the C-5 position was smaller
cleavage of C−C bond, followed by the face-selective trapping
(
methyl instead of benzyl) in the case of 1r and 1s. To
of iminium intermediates (Scheme 4).
C
DOI: 10.1021/acs.orglett.6b03520
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Organic Letters
Letter
To demonstrate the potential of this synthetic method, the
gold-catalyzed reaction was used to transform medium-sized
rings into larger macrocycles at the last stage of synthesis for
skeletal diversification (Scheme 5). The starting materials (1t
ACKNOWLEDGMENTS
■
This work was supported by the Creative Research Initiative
Grant (2014R1A3A2030423) and the Bio & Medical Technol-
ogy Development Program (2012M3A9C4048780) through the
National Research Foundation of Korea (NRF) funded by the
Korean Government (Ministry of Science, ICT & Future
Planning). We thank Prof. Seunghoon Shin at Hanyang
University for discussion of this gold-catalyzed reaction
mechanism. J.K. and J.K. are grateful for their fellowship awarded
by the BK21 Plus Program.
Scheme 5. Synthetic Utility of This Method
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Corresponding Author
*E-mail: sbpark@snu.ac.kr.
(19) See the Supporting Information.
ORCID
Seung Bum Park: 0000-0003-1753-1433
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.6b03520
Org. Lett. XXXX, XXX, XXX−XXX