Facile Synthesis of Pyridines from Propargyl Amines: Concise Total Synthesis of Suaveoline Alkaloids

Article abstract of DOI:10.1002/anie.201811812

A general and efficient protocol was developed for the synthesis of polysubstituted pyridines from propargyl amines and unsaturated carbonyl compounds through a tandem condensation/alkyne isomerization/6π 3-azatriene electrocyclization sequence. This process was found to be applicable to a wide range of readily available substrates (30 examples, up to 95 % yield) and could be readily performed on a preparative (20 g) scale. By taking advantage of this method for late-stage pyridine incorporation, we successfully completed the collective total synthesis of suveoline, norsuveoline, and macrophylline.

Full text of DOI:10.1002/anie.201811812

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Facile Synthesis of Pyridines from Propargyl Amines： Concise
Total Synthesis of Suaveoline Alkaloids
Authors: Zhiwen Zhao, Hongbo Wei, Ke Xiao, Bing Cheng, Hongbin
Zhai, and Yun Li
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201811812
Angew. Chem. 10.1002/ange.201811812
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10.1002/anie.201811812
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Facile Synthesis of Pyridines from Propargyl Amines: Concise
Total Synthesis of Suaveoline Alkaloids
Zhiwen Zhao+, Hongbo Wei+, Ke Xiao, Bin Cheng, Hongbin Zhai and Yun Li*
Dedication ((optional))
Abstract: A general and efficient protocol was developed for the
synthesis of polysubstituted pyridines from propargyl amines and
unsaturated carbonyl compounds through a tandem condensation/
alkyne isomerization/ 6-3-azatriene electrocyclization sequence.
This process displays a wide scope of readily available substrates
(30 examples, up to 95% yield) and could be easily performed at
preparative scale (20 gram scale).Taken advantage of the late-stage
pyridine incorporation protocol, the synthetic utility of this chemistry
has been successfully applied to the collective total synthesis of
suveoline, norsuveoline and macrophylline.
including Cook, [16] Bailey,[17] Ohba[18] and co-workers. In most
case, pyridine motif incorporation requires multiple synthetic
manipulations in their synthesis. Thus, more efficient strategy
especially with new synthetic methodology involved divergent
total synthesis is highly desirable. Based on our experience in
the synthesis of polysubstituted pyridines from propargyl
azides,[19] we sought to new synthetic possibility for quick access
to suaveoline type alkaloids that enabled by new synthetic
methodology. Herein, we report
polysubstituted pyridines from propargyl amines and
unsaturated carbonyl compounds through tandem
condensation/ alkyne isomerization/ 6-3-azatriene
a
facile synthesis of
a
Pyridine is one of the privileged structural motifs present in a
electrocyclization sequence. The concise total synthesis of
suaveoline, norsuaveoline and macrophylline were also
achieved by using the present protocol.
[1]
large number of biologically important natural products
synthetic pharmaceuticals.
and
[2]
Some of the world’s top selling
drugs, such as Atazanavir [3] and Gleevec [4] undoubtedly render
their medicinal importance of pyridine derivatives. In fact,
pyridines also play pivotal role in coordination chemistry,
catalysis and materials science. [5] Consequently, highly efficient
methods for construction of pyridines will remain in high demand.
Beside the conventional Hantzsch, [6] Chichibabin, [7] Bohlmann–
[8]
[9]
[10]
Rahtz,
Bonnemann
and Diels-Alder
methods for the
synthesis of pyridine derivatives, different approaches have
[11]
been developed in recent years.
Given its important role
recognized by multiple disciplines, the alternate methods to
access highly functionalized pyridine derivatives under mild
reaction conditions especially from steadily available materials
are always highly desirable.
Suaveoline (1)[12] and its structurally related other four
[13]
alkaloids (scheme 1) including norsuaveoline (2),
sellowiine
[15]
[15b]
(3),[14] macrophylline (4)
and macrocaffrine (5)
were
isolated from various botanical genus of Rauwolfia.
The
suaveoline series of indole alkaloids highlight such a case that
their structures possess an interesting bicylic pyridine skeleton.
Their synthetic access has been investigated by pioneers
Scheme 1. Structures of Suaveoline-type alkaloids and the designed synthetic
strategy.
[a]
Z. Zhao, H. Wei, K. Xiao, B. Cheng and Prof. Y. Li,
State Key Laboratory of Applied Organic Chemistry, College of
Chemistry and Chemical Engineering, Lanzhou University
Lanzhou 730000 (China)
From a retrosynthetic perspective, for the suaveoline-type
alkaloids, we envisioned an atom-economical approach (scheme
1) to access the substituted pyridine systems. The designed
tandem process is expected to proceed through a condensation
of aldehyde 8 with propargyl amine 9, and the resulting imine
would then isomerize to allenic imine 6.[20] A thermal 6-3-
azatriene electrocyclization and a sequential aromatization
would produce the suaveoline (1) as one of the represent
Rauwolfia pyridine alkaloids.
Given that the success of above mentioned synthetic
strategy of suaveoline-type alkaloids was highly depended on
the proposed synthesis of pyridines from steadily available
propargyl amines and unsaturated carbonyl compounds. As
indicated in our previous work,[19] this proof of concept has been
preliminarily evaluated by a single example. However, a more
E-mail: liyun@lzu.edu.cn
Homepage: http://liyunblog.com
Prof. H. Zhai
Laboratory of Chemical Genomics, School of Chemical Biology and
Biotechnology, Shenzhen Graduate School of Peking University
Shenzhen 518055 (China)
[b]
[+]
These authors contributed equally to this work
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comprehensive profile for this reaction would insure its
application in more complex structural context. Thus, propargyl
amine 10a and cinnamaldehyde 11a were selected as the
substrates to screen the reaction conditions for the desired
transformation. As summarized in Table 1, treatment of 10a and
moderate yield under much elavated reaction temperature (150
oC). Next, we continued to investigate the substrate generality
with a range of substituted propargyl amines (10b-10f).
Table 2. Reaction scope.[a][b]
o
11a with DBU (1.2 equiv) in toluene at 50 C only gave trace
amount of desired pyridine 12aa (Table 1, entry 1). Gratifyingly,
it was found that the yield of pyridine could be improved to 51%
o
by increasing reaction temperature to 70 C (Table 1, entry 2).
Further elevation of temperature did not give much improved
result (entry 3). A survey of solvents including EtOH, THF, DMF
and PhCl demonstrated that PhCl is the best choice (entry 7).
Considering that one molecule of water is the only byproduct in
this reaction, water scavengers might benefit to the reaction
conversion. In this regard, molecular sieve (entry 9) and MgSO4
(entry 10) was then added as the additives and the yield of the
pyridine could be further improved to 82% (entry 10) when
MgSO4 was employed as dehydrating agent. A significant
inhibition of this reaction was observed when Lewis acid such as
ZnCl2 was added (entry 11). Other base such as K2CO3, NaOH,
Et3N gave inferior results compared to DBU.
Table 1. Sceening of reaction conditions.[a]
Entry
solvent
additive
T (oC)
Yield [b] (%)
1
toluene
toluene
toluene
EtOH
THF
none
none
none
none
none
none
none
none
4Å MS
Mg2SO4
ZnCl2
50
Trace
51
2
70
3
100
100
100
100
100
120
100
100
100
55
4
50
5
52
6
DMF
Trace
70
7
PhCl
8
PhCl
68
9c
10c
11d
PhCl
75
PhCl
82
PhCl
trace
[a] Reaction conditions: The reaction mixture of 11a (0.8 mmol), 10a (1.2
equiv), and DBU (1.2 equiv) in 4 mL of solvent were stirred under indicating
temperature in sealed tube. [b] Isolated yield based on 11a. [c] 100% weight of
additive based on 11a was added. [d] 0.1 equiv of ZnCl was added.
With optimized conditions in hand, we next sought to
determine the scope of this reaction. As illustrated in table 2,
with propargyl amine 10a, an array ofcinnamyl aldehyde
derivatives (11a -11g) bearing various substituents were firstly
evaluated in the cyclization reaciton. Both electronic rich and
deficient aldehydes performed well and delivered the expected
pyridine product (12aa – 12ag) in 51- 91% yields. Moreover, the
cyclic aliphatic aldehydes (11h, 11i) and even sterically
encumbered substrate (11j) also proceeded smoothly to give
pyridine products 12ah-12aj in good yield. Furthermore, the
unsaturated ketone 11k was also proved to be the suitable
substrate. The desired pyridine (12ak) could be obtained in
[a] Conditions: 1.2 equiv of 10, 1.0 equiv of 11, 1.2 equiv of DBU, 100% weight
of MgSO4 based on 11, 0.2 M in PhCl. [b] Isolated yield. [c] Reaction was
performed under 150 oC.
Generaly, the substitution patterns and electroic characteristics
of propargyl amine showed only a negligible influence on the
cyclization. Both aromatic, aliphatic aldehydes and ketones are
suitable substrates and delivered the desired products (12ba-
12fl) in good yields. Interestingly, when 4-aminobut-2-yn-1-yl
benzoate (10g) was employed as the substrate, 3-vinylpyridines
were isolated as the the main product instead of expected
ethoxybenzoate pyridines with moderate to good yields (Table 2,
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12ga-12gi). It is believed that the vinyl groups might come from
the in situ elimination of initially generated benzoate in the
presence of DBU.
synthesized from aldehyde 14 by quick switching the propargyl
amine counterpart to 18. The desired pyridine 19 was steadily
obtained in 64% yield and was further converted to
marcrophylline (4) through Pd(OH)2 catalyzed N-benzyl
deprotection and subsequential reductive amination. The full
structure proof of marcrophylline was obtained by X-ray
crystallographic analysis.[22] It should be noted, the 1H NMR
spectrum of our synthetic samples do not perfectly matched with
the reported data by the isolation team for marcrophylline.[15a]
While such kind of cases have been noted in many alkaloid
syntheses. [23]
Table 2. Reaction scope with 4-aminobut-2-yn-1-yl benzoate as substrate.[a][b]
[a] Conditions: 1.2 equiv of 10g, 1.0 equiv of 11, 1.2 equiv of DBU, 100%
weight of MgSO4 based on 11, 0.2 M in PhCl. [b] Isolated yield.
Thoes results undoubtedly great expand the structural diversity
of resulted pyridine compounds and offer an extra synthetic
manipulation site as well. To further test the practicality of our
protocol, a 20-gram-scale (152 mmol) preparation of 12aa was
then executed (Schme 2). The reaction proceeded smoothly to
give desired product in 52% yield (13.4 g), indicating the good
scalability of present method.
Scheme 2. Preparative scale synthesis of 12aa.
After establishment of the synthetic methodology, we then
turned our attention to the total synthesis of pyridine-containing
alkaloids suaveoline, norsuaveoline, and macrophylline
(Scheme 3). To this end, the requisite tricyclic aldehyde 14 was
prepared from methyl tryptophanate 13 according to the
literature procedure.[16c] Under the slightly modified standard
condition,[21] aldehyde 14 reacted smoothly with amine 15 and
delivered the desired tricyclic pyridine 16 in 81% yield. In
contrast, limited by the synthetic methodolgy in 1980s, Cook and
coauthor took nine steps to incorporate the pyridine motiff from
aldehyde 14.[16a] Cleavage of benzyl protection of 16 by Pd-
catalyzed hydrogenation gave norsuaveoline (2). Its structure
was unambiguously confirmed by X-ray crystallographic
analysis.[22] Total synthesis of suaveoline (1) was then achieved
from pyridine 16 through methylation of indole N1 nitrogen and
following benzyl deprotection in 63% combined yield. Its
structure was also confirmed by X-ray crystallographic
analysis.[22] Reductive amination of suaveoline with NaCNBH3 in
formalin led to a pseudonatural product Nb-methyl sueveoline
(17) in 82% yield. The spectral data were identical to the
literature that previously reported by Cook.[16c] To demonstrate
the flexibility of our late-stage pyridine incorporation protocol,
another natural product named marcrophylline was also
Scheme 3. Total synthesis of suaveoline, norsuaveoline, and macrophylline.
In summary, we have described a convergent and atom-
economical method for the synthesis multisubstituted pyridines
from steadily available propargyl amines and -unsaturated
carbonyl compounds. Incorporation of different substituents at
various positions of pyridine moiety could be easily accessed by
the present method. The practicality of this process is
showcased by the collective total synthesis of three pyridine-
containing natural products suaveoline, norsuaveoline, and
macrophylline. With a scalable route established to this family of
alkaloids, current efforts are underway to further explore the
biological activities of the suaveoline-type alkaloids and their
synthetic derivatives.
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Acknowledgements
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (21572089), the
program for Changjiang Scholars and the Innovative Research
Team in University (PCSIRT: IRT_15R28), the FRFCU (lzujbky-
2018-61) and the Gansu Provincial Sci. & Tech. Department
(2016B01017).
Keywords: pyridine alkaloid • 6-electrocyclization •
heterocycles • total synthesis
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Z. Zhao, H. Wei, K. Xiao, B. Cheng, H.
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Facile Synthesis of Pyridines from
Propargyl Amines: Concise Total
Synthesis of Suaveoline Alkaloids
A
facile synthesis of polysubstituted pyridines from propargyl amine and
unsaturated aldehydes through a tandem condensation/ alkyne isomerization/ 6-3-
azatriene electrocyclization sequence in good yields with a wide scope of substrate.
This discovery enabled the collective total synthesis of suveoline, norsuveoline and
macrophylline.
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