Rapid, two-pot procedure for the synthesis of dihydropyridinones; total synthesis of aza-goniothalamin

Article abstract of DOI:10.3762/bjoc.16.15

A fast, protecting-group-free synthesis of dihydropyridinones has been developed. Starting from commercially available aldehydes, a novel one-pot amidoallylation gave access to diene compounds in good yields. Ring-closing metathesis conditions were then employed to produce the target dihydropyridinones efficiently and in high yields.

Full text of DOI:10.3762/bjoc.16.15

Rapid, two-pot procedure for the synthesis of
dihydropyridinones; total synthesis of aza-goniothalamin
Thomas J. Cogswell1, Craig S. Donald2 and Rodolfo Marquez*1,3,§
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2020, 16, 135–139.
1School of Chemistry, University of Glasgow, Glasgow, G12 8QQ,
U.K, 2Lucideon Limited., Queens Road, Penkhull, Stoke-on-Trent,
Staffordshire, ST4 7LQ, U.K and 3School of Physical and Chemical
Sciences, University of Canterbury, Christchurch, 8140, New Zealand
doi:10.3762/bjoc.16.15
Received: 06 October 2019
Accepted: 16 January 2020
Published: 28 January 2020
Email:
Rodolfo Marquez* - rudi.marquez@canterbury.ac.nz
Associate Editor: B. Stoltz
* Corresponding author
§ Tel: +64 3 3690162
© 2020 Cogswell et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
amidoallylation; aza-goniothalamin; dihydropyridinones;
protecting-group-free; ring-closing metathesis; two-pot procedure
Abstract
A fast, protecting-group-free synthesis of dihydropyridinones has been developed. Starting from commercially available aldehydes,
a novel one-pot amidoallylation gave access to diene compounds in good yields. Ring-closing metathesis conditions were then em-
ployed to produce the target dihydropyridinones efficiently and in high yields.
Introduction
Six-membered nitrogen heterocycles are prevalent in many kidney, ovarian and prostate cancer cell lines (IC50 = 25 µM,
naturally occurring and biologically active compounds. As a U251 cell line) [14-16]. In an attempt to increase the bioavail-
result, their synthesis has received extensive research and wide ability of (R)-(+)-goniothalamin 2, aza-goniothalamin 1 was de-
spread publication in the literature [1-6]. Dihydropyridinones signed and synthesised; however, aza-goniothalamin 1 was
are an important subclass of heterocycles, which often feature found to have significantly lower biological activity compared
both as useful intermediates, and as interesting species in their to the parent compound (IC50 = 942 µM, U251 cell line)
own right [7-13].
[15,16]. However, Pilli and co-workers were able to demon-
strate that acylation of aza-goniothalamin 1 yielded analogues
The relevance of dihydropyridones as lead compounds is exem- such as compound 3 with significantly improved biological
plified by the detailed investigations into the synthesis and bio- profiles (IC50 = 11 µM, U251 cell line, Figure 1). Thus, a path
logical evaluation of aza-goniothalamin 1 and its analogues for the generation of a new class of potential anticancer agents
(Figure 1). (R)-(+)-Goniothalamin 2, a natural product isolated based on the aza-goniothalamin framework was determined
in 1967, was shown to be cytotoxic against human leukaemia, [17,18].
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Beilstein J. Org. Chem. 2020, 16, 135–139.
In order to test this hypothesis, acrylamide was used in an anal-
ogous manner to the carbamates employed by Veenstra
(Scheme 1) [19]. In our initial attempts, the solvent was
changed from dichloromethane to acetonitrile due to solubility
issues with the acrylamide and the postulated imine intermedi-
ate. The reaction proved sluggish, taking four days to reach
completion; however, the dialkene 5 was isolated in a very
encouraging 66% yield (Scheme 2).
Figure 1: Aza-goniothalamin 1, (R)-(+)-goniothalamin 2 and acylated
aza-goniothalamin analogue 3 [14-18].
In an attempt to increase the yield of the overall process, the
reaction conditions were optimized to reach complete forma-
Results and Discussion
Our approach to the synthesis of the dihydropyridinone frame- tion of imine 6, before treatment with allyltrimethylsilane to
work was inspired by the work carried out by Veenstra and generate the desired product. This stepwise addition was suc-
co-workers, who developed a one-pot, three-component reac- cessful in affording an improved 88% yield of diene 5 as well
tion to produce protected homoallylic amines 4 (Scheme 1) as significantly reducing the overall reaction time (Scheme 3).
[19].
Treatment of diene 5 under ring-closing metathesis conditions,
It was reasoned that adaptation of the Veenstra protocol would using Grubbs I catalyst, then proceeded to generate the target
allow us to introduce a second alkene unit during the same dihydropyridinone 7 in excellent yield (Scheme 4) [20-23,26].
process, thus generating a ring-closing metathesis precursor in a
single step. This general strategy towards nitrogen heterocycles The scope of this concise two-pot methodology was then inves-
has been utilized in several reports [20-23], including asym- tigated by using a variety of different aldehydes as starting ma-
metric variants [24,25], but in these cases the ring-closing me- terials (Figure 2). The electron-donating aromatic substrates and
tathesis precursor was always generated in multiple steps.
the aliphatic units gave consistently high results over the 2-pot
Scheme 1: One pot synthesis of benzyl carbamate 4 reported by Veenstra and co-workers [19].
Scheme 2: Formation of diene 5 in 66% through a one pot, three component coupling.
Scheme 3: Optimized conditions for the synthesis of diene 5.
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Beilstein J. Org. Chem. 2020, 16, 135–139.
which we believe was due to poor solubility of the imine inter-
mediate. In contrast, the ring-closing metathesis reaction
worked nicely to give 9b in 99% yield.
Having demonstrated the versatility of our approach, the syn-
thesis of racemic aza-goniothalamin was attempted. Our synthe-
sis began with cinnamaldehyde (Scheme 5), which was
condensed with acrylamide under the same conditions de-
scribed above. Rewardingly, Hosomi–Sakurai allylation of the
conjugated imine intermediate proceeded to afford the desired
Scheme 4: Ring-closing metathesis reaction of diene 5 to yield
dihydropyridone 7 [20-23].
process, producing dihydropyridinones 9a and 9c–e in high diene 10 in working yield (35%). The formation of diene 10 is
yields. The electron-withdrawing substituted aromatic starting significant as the corresponding α,β-enones and α,β-enals
materials on the other hand, gave a low yield in the first step, undergo exclusive conjugate addition under Hosomi–Sakurai
Figure 2: Extension of the two-pot methodology to include a variety of different aldehyde starting materials.
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Beilstein J. Org. Chem. 2020, 16, 135–139.
Scheme 5: Total synthesis of aza-goniothalamin 1.
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conditions [27,28]. Ring-closing metathesis of diene 10 then
proceeded in good yield (68%) to complete a fast and efficient,
protecting-group-free, two-pot procedure for the racemic syn-
thesis of aza-goniothalamin 1.
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Chem. Commun. 2017, 53, 5985–5988. doi:10.1039/c7cc02753b
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doi:10.1039/c7ob01948c
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51, 12040–12043. doi:10.1039/c5cc04593b
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Conclusion
In summary, a two-pot, protecting-group-free procedure for the
synthesis of dihydropyridinones has been developed. The
process requires a one-pot amidoallylation followed by a ring-
closing metathesis step. This approach was used to complete the
racemic synthesis of aza-goniothalamin 1, and is currently
being expanded to generate new biologically relevant deriva-
tives.
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Supporting Information
Supporting Information File 1
Experimental, characterization data and copies of spectra.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-16-15-S1.pdf]
16.Innajak, S.; Mahabusrakum, W.; Watanapokasin, R. Oncol. Rep. 2016,
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Funding
17.Barcelos, R. C.; Pastre, J. C.; Vendramini-Costa, D. B.; Caixeta, V.;
Longato, G. B.; Monteiro, P. A.; de Carvalho, J. E.; Pilli, R. A.
ChemMedChem 2014, 9, 2725–2743. doi:10.1002/cmdc.201402292
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Ferreira-Halder, C. V.; Pilli, R. A. Eur. J. Med. Chem. 2014, 87,
745–758. doi:10.1016/j.ejmech.2014.09.085
We would like to thank the EPSRC and AstraZeneca for post-
graduate support (T.C.) and for a Leadership Fellowship
(R.M.). The authors also thank Dr. Ian Sword and the EPSRC
(grant EP/H005692/1) for funding.
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ORCID® iDs
Rodolfo Marquez - https://orcid.org/0000-0001-9777-2012
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