A Gold(I)-Catalyzed Hydroamination/Cycloisomerization Cascade: Concise Synthesis of (±)-seco-Antofine and (±)-Septicine

Article abstract of DOI:10.1021/acs.orglett.0c03062

A concise and flexible procedure for the synthesis of highly functionalized N-heterocyclic 1,6-annulated 2-pyridones and 2,3-annulated 4-pyrimidinones has been elaborated through a gold-catalyzed tandem hydroamination/cycloisomerization cascade. This novel and highly efficient method allows the rapid construction of these diverse N-heterocyclic scaffolds starting from readily available building blocks, and shows a wide scope and good functional group tolerance. The total synthesis of (±)-seco-antofine and (±)-septicine were realized employing this strategy.

Full text of DOI:10.1021/acs.orglett.0c03062

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Letter
A Gold(I)-Catalyzed Hydroamination/Cycloisomerization Cascade:
Concise Synthesis of ( )-seco-Antofine and ( )-Septicine
Guilong Tian, Liangliang Song, Zhenghua Li, Koen Robeyns, Luc Van Meervelt,
and Erik V. Van der Eycken*
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ABSTRACT: A concise and flexible procedure for the synthesis of highly functionalized N-heterocyclic 1,6-annulated 2-pyridones
and 2,3-annulated 4-pyrimidinones has been elaborated through a gold-catalyzed tandem hydroamination/cycloisomerization
cascade. This novel and highly efficient method allows the rapid construction of these diverse N-heterocyclic scaffolds starting from
readily available building blocks, and shows a wide scope and good functional group tolerance. The total synthesis of ( )-seco-
antofine and ( )-septicine were realized employing this strategy.
atural products as the inspiration and the starting point of
Recently, homogeneous gold catalysis has been successfully
applied for the construction of C−C(hetero) bonds.11
Furthermore, the arsenal of tandem cyclization protocols to
synthesize structurally complex molecules and natural products
has been expanded tremendously through the employment of
gold catalysis.12 In this regard, our research group has explored
new effective strategies based on the combination of multi-
component reactions and tandem gold catalysis, for the
diversity-oriented construction of various N-heterocyclic
scaffolds, starting from readily available building blocks.13
Based on our knowledge and experience in this field, we
combined a gold-catalyzed tandem cyclization for the synthesis
of 1,6-annulated 2-pyridones and 2,3-annulated 4-pyrimidi-
nones, as outlined in Scheme 1b. An intramolecular tandem
hydroamination/cycloisomerization process is envisaged, start-
ing from diverse precursors which can be easily prepared by Ugi
four-multicomponent reaction (Ugi-4CR) or the condensation
of alkynoic amine and propiolic acid.14
N
novel drugs have attracted medicinal chemists’ attention.1
However, many initial drug development studies with natural
products failed, because of their poor solubility and unpredict-
able toxicity.2 Molecules with the same key scaffold potentially
have similar biological or physicochemical activity.3 As a
consequence, the development of practical methods for the
synthesis of scaffolds present in pharmacologically potent
compounds led to the successful finding of novel drug
candidates.4
The 1,6-annulated 2-pyridone and 2,3-annulated 4-pyrimidi-
none skeletons are common in bioactive natural products5 and
many pharmacologically potent compounds.6 They show a
diversity of bioactive properties such as antitumor, antimicro-
bial, anti-inflammatory, cardiotonic, antiviral, and antimalarial
activity.7 These scaffolds are also important intermediates in
many organic transformations.8 A series of methods have been
developed for the synthesis of 1,6-annulated 2-pyridones and
2,3-annulated 4-pyrimidinones9 such as intramolecular nucleo-
philic substitution, radical cyclization, intramolecular alkenyla-
tion, and intramolecular Heck reaction. Most of these methods
involve the modification of 2-pyridone or 4-pyrimidinone
derivatives limiting the synthetic potential of these scaffolds.
Moreover, most of the reported procedures need multiple steps,
and only in a few cases the direct synthesis of the 1,6-annulated
2-pyridone and the 2,3-annulated 4-pyrimidinone scaffolds is
described from scratch.10 Therefore, new concise and flexible
methods for the synthesis of these scaffolds, from simple starting
materials, are highly desirable.
We started our investigation using N-(2-ethynylbenzyl)-
propiolamide 1aa as a model substrate, which is readily
furnished through Ugi-4CR of 2-ethynylbenzaldehyde, ammo-
Received: September 13, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03062
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Scheme 1. Representative Natural Products and
Retrosynthetic Analysis for the Core Scaffolds
Table 2. Scope of Tandem Cyclization Process for the
a
Synthesis of 1,6-Annulated 2-Pyridones
nia, tert-butyl isocyanide, and phenylpropiolic acid. Initially, the
screening of various gold catalysts such as AuCl, AuCl3, and in
situ generated Ph3PAuOTf, IPrAuOTf, and JohnPhosAuOTf
(Table 1, entries 1−5) showed that IPrAuOTf gave the desired
a
Table 1. Optimization of Reaction Condition
yield of 2aa
b
entry
catalyst
solvent
T (°C) t (h)
(%)
1
2
3
4
5
AuCl
AuCl3
Ph3PAuCl/AgOTf
IPrAuCl/AgOTf
JohnPhosAuCl/
AgOTf
DCE
DCE
DCE
DCE
DCE
60
60
60
60
60
12
12
12
12
12
26
<10
39
75
56
6
7
8
9
IPrAuCl/AgOTf
IPrAuCl/AgOTf
IPrAuCl/AgOTf
IPrAuCl/AgOTf
IPrAuCl/AgOTf
Toluene
MeCN
Dioxane
THF
60
60
60
60
60
12
12
12
12
12
42
55
31
21
50
a
Unless otherwise stated, all reactions were run with 0.1 mmol of 1ab-
bt, 5 mol % of IPrAuCl/AgOTf, and 2.0 mL of DCE at 60 °C in a
sealed flask for 12 h; all yields are isolated yields. TMB = 1,1,3,3-
tetramethylbutyl; Nap = naphthalenyl.
10
DCM
a
Unless otherwise stated, all reactions were run with 0.05 mmol of
Ugi adduct 1aa, 5 mol % of catalyst, and 1.0 mL of solvent in a sealed
flask. Isolated yields. DCE = 1,2-dichloroethane; OTf = trifluoro-
b
methanesulfonate; IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-
ylidene; JohnPhos = (1,1′-biphenyl-2-yl)ditert-butylphosphine.
Then, the effect of the R2-substituent on the 2-ynamide was
examined. Switching a small hydrogen (2ag and 2am) into a
larger alkyl or aryl substituent (2ah−al and 2an−at) resulted in
an increase of the yield. The application of electron-rich
(hetero)arene groups such as phenyl or thiophene (2al and
2ar−at) conjugated with the 2-ynamide resulted in reasonable
good yields.
1,6-annulated 2-pyridone 2aa in the highest yield of 75% (Table
1, entry 4). No amelioration was observed when changing the
solvent to toluene, MeCN, dioxane, THF, or DCM (Table 1,
entries 6−10).
Next, various N-alkynic 2-ynamides 1 assembled by Ugi-4CR
were subjected to the optimal conditions for the evaluation of
the scope and limitations (Table 2). First, the effect of the R1-
substituent resulting from the isonitrile was evaluated. While
employing bulky groups like adamantyl and 1,1,3,3-tetrame-
thylbutyl (TMB), the tandem process performed smoothly and
gave the 1,6-annulated 2-pyridone 2ab and 2ac in good yields.
However, slightly lower yields were observed in the case of less
bulky groups like cyclohexyl, naphthyl, and benzyl (2ad−af).
Examination of the effect of the R3-substituent on the benzene
ring of the phenylacetylene fragment revealed no significant
influence in the case of halides (2au−az and 2bd−bi) while the
employment of electron-rich groups yielded the compounds
2ba−bc and 2bj−bl in decreased yields. The structure of
compound 2ax was confirmed by X-ray diffraction. The
substrate 1bm derived from 4-pentynal successfully underwent
the tandem cyclization resulting in the formation of the 1,6-
annulated 2-pyridone 2bm in 61% yield. In addition, the
B
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substrate 1bn lacking the amide chain provided the 1,6-
annulated 2-pyridone 2bn in 85% yield. Then this gold-
catalyzed hydroamination/cycloisomerization process was also
applied to the Ugi adducts 1bo−bt derived from 2-(2-
ethynylphenyl)acetaldehydes with the aim of constructing a
library of pyrido[2,1-a]isoquinolin-4-ones (n = 1, Table 2). To
our satisfaction, this process worked well with various aliphatic
and aromatic substituents on the 2-ynamide moiety, affording
the targeted 1,6-annulated 2-pyridones 2bo−bt in good yields of
71−89%.
2ac in 92% yield (Scheme 2). This indicates that the first step of
this tandem process is a hydroamination of the alkyne or cyanide
a
Scheme 2. Mechanism Study
For the synthesis of diverse 2,3-annulated 4-pyrimidinones,
we next planned to use the Ugi adducts 1ca−cm assembled from
2-formylbenzonitrile and 2-(2-oxoethyl)benzonitrile. As sum-
marized in Table 3, treatment of various substrates under the
Table 3. Scope of Tandem Cyclization Process for the
Synthesis of 2,3-Annulated 4-Pyrimidinones
a
b
a
The reaction was run on a 0.05 mmol scale. Isolated yield. TMB =
1,1,3,3-tetramethylbutyl.
and the compound 3ac is an intermediate of the tandem process.
When AgOTf was utilized as a catalyst, the reaction delivered
2ac in only a moderated yield (Condition B). No conversion
was observed when IPrAuCl was utilized as catalyst (Condition
C). Neither HOTf (5 mol %) nor NaOTf (5 mol %) can catalyze
the reaction (Condition D, E). These results indicate that the
cationic gold catalyst is the real catalyst for the cyclo-
isomerization.
Based on these observations and previous reports,15,16
a
plausible mechanism for this gold(I)-catalyzed tandem hydro-
amination/cycloisomerization process is depicted in Scheme 3.
Scheme 3. Plausible Mechanism of Gold(I)-Catalyzed
Hydroamination/Cycloisomerization Process
a
Unless otherwise stated, all reactions were run with 1ca−cm, (0.1
mmol), 5 mol % of IPrAuCl/AgOTf, and 2.0 mL of DCE at 60 °C in
a sealed flask for 12 h; all yields are isolated yields. TMB = 1,1,3,3-
tetramethylbutyl.
optimal conditions smoothly produced the desired fused 2,3-
annulated 4-pyrimidinones 2ca−cm in moderate to good yields.
In particular, substrates bearing an alkyl or an aryl substituent on
the 2-ynamide are compatible, yielding the products 2cc−ch in
62−82%. A high tolerance for halides (F and Br) on the
benzonitrile moiety was observed (2ci−ck). The substrates 1cl
and 1cm derived from the 2-(2-oxoethyl)benzonitrile, success-
fully gave 2cl and 2 cm in 61% and 72% yield, respectively. The
structure of compound 2cb was confirmed by X-ray
crystallography.
We propose compound 3ac is an intermediate for the tandem
cyclization. To shed light on the reaction process, treatment of
compound 3ac with IPrAuCl/AgOTf (5 mol %) in DCE (1,2-
dichloroethane) at 60 °C for 12 h delivered the desired product
First, the intramolecular hydroamination of the gold π- activated
terminal alkyne (X = CH) or nitrile group (X = N) occurs in an
exo-dig fashion producing the isoindoline (n = 0) or
isoquinolinone (n = 1) intermediate B, which upon proto-
deauration gives N-alkenyl or N-(iminomethyl) alkynylamide
intermediate C.11 Subsequently, the second annulation of the
newly formed double bond with the cationic gold π-activated
alkyne of the 2-ynamide occurs, delivering iminium intermediate
D,12 which after isomerization and protodeauration affords 1,6-
annulated 2-pyridones or 2,3-annulated 4-pyrimidinones.
C
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The alkaloids ( )-seco-antofine and ( )-septicine have
interesting physiological effects on the respiratory system as
well as antibiotic, antileukemic, and anticancer activity (Scheme
4).17 To demonstrate the utility of our method, we prepared
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Scheme 4. Total Synthesis of ( )-seco-Antofine and
( )-Septicine
Erik V. Van der Eycken − Laboratory for Organic & Microwave-
Assisted Chemistry (LOMAC) Department of Chemistry, KU
Leuven, B-3001 Leuven, Belgium; Peoples’ Friendship University
of Russia (RUDN University), Moscow 117198, Russia;
orcid.org/0000-0001-5172-7208;
Email: erik.vandereycken@kuleuven.be
Authors
Guilong Tian − Laboratory for Organic & Microwave-Assisted
Chemistry (LOMAC) Department of Chemistry, KU Leuven, B-
3001 Leuven, Belgium
Liangliang Song − Laboratory for Organic & Microwave-Assisted
Chemistry (LOMAC) Department of Chemistry, KU Leuven, B-
3001 Leuven, Belgium
Zhenghua Li − Laboratory for Organic & Microwave-Assisted
Chemistry (LOMAC) Department of Chemistry, KU Leuven, B-
3001 Leuven, Belgium
Koen Robeyns − IMCN, Molecules Solids and Reactivity division
́
(MOST), Universite Catholique de Louvain, B-1348 Louvain-la-
Neuve, Belgium
Luc Van Meervelt − Biomolecular Architecture, Department of
Chemistry, KU Leuven, B-3001 Leuven, Belgium; orcid.org/
0000-0003-2186-5209
these alkaloids using the tandem cyclization as a key step. 1,6-
Annulated 2-pyridone 1da was synthesized in 56% yield
employing the optimized conditions. Selective iodination of
the 2-pyridone ring and subsequent Suzuki cross-coupling
generated intermediates 5da and 5db in good yields. Reduction
under Moore’s conditions delivered ( )-seco-antofine and
( )-septicine, respectively.18 These two alkaloids could be
converted into ( )-antofine and ( )-tylophorine as described
in the literature.19
In conclusion, we have designed a novel and highly efficient
tandem process for the synthesis of diverse 1,6-annulated 2-
pyridones and 2,3-annulated 4-pyrimidinones. First, the Ugi-
4CR, which generates diversity into the molecule from readily
available starting materials, is performed. Next, an efficient
gold(I)-catalyzed tandem hydroamination/cycloisomerization
process leads to the formation of highly functionalized N-
heterocyclic scaffolds. The wide substrate scope, the high
functional group tolerance, and the operational simplicity of this
protocol render this method an attractive way to generate these
interesting scaffolds. Further, we utilized this tandem cyclization
process as the key step for the synthesis of ( )-seco-antofine and
( )-septicine in a concise way.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03062
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are thankful to the F.W.O. [Fund for Scientific
Research−Flanders (Belgium)], the Research Fund of the
University of Leuven (KU Leuven), and the support of RUDN
University Program 5-100 for financial support. L.V.M. thanks
the Hercules Foundation for supporting the purchase of the
diffractometer through Project AKUL/09/0035.
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ASSOCIATED CONTENT
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https://pubs.acs.org/doi/10.1021/acs.orglett.0c03062.
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Experimental procedures, characterization data, and
copies of NMR spectra for all compounds (PDF)
Accession Codes
CCDC 1850841 and 2007686 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
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