Quick Access to Pyridines through 6π-3-Azatriene Electrocyclization: Concise Total Synthesis of Suaveoline Alkaloids

Article abstract of DOI:10.1055/s-0037-1611811

Pyridine is a prevalent structural heterocyclic motifs in natural products, pharmaceuticals, and advanced materials. Several different methodologies have been developed for the synthesis of these kinds of molecules. However, a sustainable and efficient procedure for the synthesis of pyridines is still highly desirable. In this Synpacts article, we highlight our recent approach to the construction of highly substituted pyridines though a tandem condensation/alkyne isomerization/6π-3-azatriene electrocyclization sequence. The present protocol was used to synthesize a series of polysubstituted pyridines (30 examples) in moderate to good yields. The process also permitted the development of a concise strategy for collective total syntheses of suaveoline, norsuaveoline, and macrophylline.

Full text of DOI:10.1055/s-0037-1611811

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–F
synpacts
A
en
H. Wei, Y. Li
Synpacts
Synlett
Quick Access to Pyridines through 6-3-Azatriene Electrocycliza-
tion: Concise Total Synthesis of Suaveoline Alkaloids
Hongbo Weia
R2
Yun Li*b
0
0
0
0-0
0
0
3-2
2
3
6-9
8
8
0
R2
R4
R1
N
DBU, MgSO4
R3
R5
a Shaanxi Key Laboratory of Natural Products and Chemical Biol-
ogy College of Chemistry and Pharmacy, Northwest A&F Uni-
versity 22 Xinong Road, Yangling 712100, P. R. of China
b State Key Laboratory of Applied Organic Chemistry, College of
Chemistry and Chemical Engineering, Lanzhou University,
Lanzhou 730000, P. R. of China
NH2
R3
R5
+
PhCl, 100 °C
R1
O
R4
30 examples
liyun@lzu.edu.cn
N
NH
NH
This paper is dedicated to the Lanzhou University on the occa-
sion of its 110th anniversary.
N
N
N
H
H
HN
H
OH
HN
N
H
H
H
Suaveoline (1)
Norsuaveoline (2)
macrophylline (3)
Received: 18.03.2019
Accepted after revision: 03.04.2019
Published online: 15.04.2019
DOI: 10.1055/s-0037-1611811; Art ID: st-2019-p0154-sp
Abstract Pyridine is a prevalent structural heterocyclic motifs in natu-
ral products, pharmaceuticals, and advanced materials. Several differ-
ent methodologies have been developed for the synthesis of these
kinds of molecules. However, a sustainable and efficient procedure for
the synthesis of pyridines is still highly desirable. In this Synpacts article,
we highlight our recent approach to the construction of highly substi-
tuted pyridines though a tandem condensation/alkyne isomeriza-
tion/6-3-azatriene electrocyclization sequence. The present protocol
was used to synthesize a series of polysubstituted pyridines (30 exam-
ples) in moderate to good yields. The process also permitted the devel-
opment of a concise strategy for collective total syntheses of suaveo-
line, norsuaveoline, and macrophylline.
Key words pyridines, alkaloids, 6-electrocyclization, total synthesis,
tandem reaction
Yun Li completed his undergraduate studies at Sichuan University in
2004. He then pursued his Ph.D. studies under the supervision of Pro-
fessor Yikang Wu at Shanghai Institute of Organic Chemistry. After
completing his doctorate in 2009, he spent three years (2009–2012) as
a postdoctoral researcher at the Novartis Institutes for BioMedical Re-
search in Shanghai, where he was involved in an early-stage drug-dis-
covery project, as well as asymmetric catalysis. In July 2012, he
accepted a position as an associate professor at Lanzhou University. His
research interests include total synthesis of natural products and or-
ganometallic catalysis.
Nitrogen-containing heterocycles are abundant in na-
ture and they exhibit a diverse and important range of uses.
The pyridine system, as a key heterocycle, forms the core
skeleton of a number of synthetic pharmaceuticals, natural
products, and materials.1 In the pharmaceutical industry,
pyridine forms the nucleus of over 7000 existing drugs,2 in-
cluding pioglitazone (Actos),3 eszopiclone (Lunesta),4 and
esomeprazole (Nexium) [Figure 1(a)].5 Furthermore, pyri-
dines are also extensively involved in coordination chemis-
try6 in the form of pyBOX derivatives,7 bipyridines, and
tris[2-phenylpyridinato]iridium(III) {fac-[Ir(ppy)3]} [Figure
1(b)],8,9 which are privileged ligands or organometallic cat-
alysts that have been widely applied in asymmetric cataly-
sis and photoredox reaction in recent decades. As the sim-
plest azine-type heterocycle found in nature, pyridine is
widely present in natural products from many biological
sources with a diverse range of bioactivities,10 including the
important biosynthesis cofactor pyridoxine (vitamin B6),
the natural pigment chromophore rubralone, and the in-
dole alkaloid angustine [Figure 1(c)].11,12 Owing to their
large spectrum of fascinating applications, pyridines have
distinguished themselves as heterocycles of profound
chemical and biological significance. Consequently, the syn-
thesis of substituted and specifically functionalized pyri-
dines is a continuing challenge in organic chemistry and
has drawn considerable attention.1,2,13
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

B
H. Wei, Y. Li
Synpacts
Synlett
an ynone leads directly to the heteroaromatic product,
thereby eliminating the need for a final aromatizing oxida-
tive step. Compared with the above-mentioned protocols,
the condensation of 1,5-diones with ammonia followed by
oxidation is the most straightforward approach to the syn-
thesis of pyridines (Figure 2; Approach e);18 however a mul-
tistep preparation of the 1,5-dione precursor is always re-
quired, which limits the overall synthetic efficiency of this
approach. Cycloaddition reactions are among the most im-
portant classes of approaches to pyridines as they permit
the simultaneous formation of several bonds in one reac-
tion step. The most attractive disconnection of pyridines in-
volves a hetero-Diels–Alder reaction of a 1-azadiene with
an alkene or alkyne, followed by subsequent oxidation (Fig-
ure 2; Approach f);19 however, this approach is rarely used
because the transformation is disfavored electronically and
thermodynamically. Therefore, cobalt-catalyzed [2+2+2]
cycloaddition reactions of nitriles and alkynes provide a
rapid alternative route to polysubstituted pyridines (Figure
2; Approach g),20 but there are difficulties in separating the
many similar products and byproducts that are formed as a
result of the poor regioselectivity of the cycloaddition. In
addition to those divergent strategies, the 6-electrocy-
clization approach represents one of the most important
means for the bespoke synthesis of substituted pyridines,
and the reaction is compatible with a range of common
functional groups (Figure 2; Approach h).21 This process
might provide the most atom-economical and straightfor-
ward route to polysubstituted pyridine building blocks.
However, most of these transformations are based on pure-
ly intramolecular cascade reactions, requiring prior multi-
step syntheses of the requisite precursors, which might
preclude their extensive application.22
Therefore, the development of a new method for access-
ing polysubstituted pyridine derivatives in an atom- and
step-economical fashion, especially from readily available
materials, is still highly desirable. In 2015, Balci and co-
workers reported an intermolecular cycloaddition reaction
between the an alkyne and an azadiene generated in situ to
give chromenopyridine and chromenopyridinone deriva-
tives.23 The success of this reaction was attributed to a pro-
posed isomerization of a propargylic imine to an allenic in-
termediate, which facilitates a subsequent intramolecular
[4+2] cycloaddition. Inspired by this seminal result, we sur-
mised that an imine 5, easily accessible through condensa-
tion of a propargylic amine with an unsaturated carbonyl
compound 4, might undergo the above-mentioned isomeri-
zation to deliver an allenic imine 6 (Scheme 1). Theoretical-
ly, a 6-3-azatriene electrocyclization of this active inter-
mediate should be trigged, followed by spontaneous aroma-
tization to deliver the polysubstituted pyridine 8. Here, we
report a successful implementation of this idea and we
present a mild, convenient, and broadly applicable strategy
for the synthesis of substituted pyridines.24
(a) Substituted pyridines used in pharmaceutical applications
O
O
N
O
S
N
O
H
O
N
H
S
N
NH
O
N
N
NH
N
O
OMe
MeO
Nexium
Cl
Actos
Lunesta
(b) Substituted pyridines in coordination chemistry
N
N
O
O
N
Ir
N
N
N
N
N
R
R
bipyridines
(metal ligands)
pyBOX derivatives
(metal ligands)
fac-Ir(ppy)3
photosensitizer
(c) Substituted pyridines in natural products
OH
O
N
O
OH
HO
HO
N
H
N
OH
N
N
nPr
rubralone chromophore
O
pyridoxine
angustine
Figure 1 Selected examples of pyridine-containing drugs, ligands, and
natural products
Among the various methods for the synthesis of pyri-
dines, the Hantzsch synthesis is one of the most popular
and gives symmetrically substituted pyridines (Figure 2;
Approach a).14 This method involves a multicomponent
condensation of an aldehyde, a 1,3-dicarbonyl derivative,
and ammonia, with subsequent oxidation of the resulting
1,4-dihydropyridine; however, the lack of environmentally
friendly conditions for the final oxidation remains an issue
in need of an urgent solution. Analogously, the Chichibabin
approach (Figure 2; Approach b) is also a pseudo-four-com-
ponent synthesis of a pyridine from three equivalents of an
enolizable aldehyde and one equivalent of ammonia or an
ammonia derivative.15 This offers a rapid and convergent
approach to the synthesis of alkyl-substituted pyridines. A
major limitation of this reaction is its low overall yield and
high proportion of byproducts, which necessitates a multi-
tude of purification processes. Related to this methodology,
is the Kröhnke pyridine synthesis, another important meth-
od for the preparation of highly functionalized pyridines
through the condensation of -pyridinium ketone salts and
,-unsaturated carbonyl compounds (Figure 2; Approach
c).16 Unlike the Hantzsch synthesis, the Kröhnke method
does not require oxidation to generate the desired product,
because the -pyridinium ketone is already in the correct
oxidation state. However, the atom economy is not ideal,
given that the pyridine motif in the pyridinium ketone pre-
cursor is eventually eliminated. The Bohlmann–Rahtz pyri-
dine synthesis is based on the thermal condensation of an
ynone with an enamine (Figure 2; Approach d).17 The use of
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

C
H. Wei, Y. Li
Synpacts
Synlett
(9a) and propargylamine (10a) as model substrates (Table
1). After a systematic optimization of the reaction tempera-
ture, additives, and solvents, the optimal conditions were
determined to be those shown in Entry 10, which gave the
desired product 11a in 82% yield.
O
O
2 x
R1
R2
NH3
+
O
R
R4
3 x
H
R3
R3
R2
R5
R1
CHO
+
N
a
NH3
Table 1 Screening of the Reaction Conditions.
b
h
N
R3
R
N
NH3
•
N
R2
R1
R4
R5
NH2
g
Ph
O
CHO
c
conditions
+
+
Ph
O
N
N
R
9a
Ph
O
10a
11a
f
d
R3
Entry
Solvent
Additive
Temp
(°C)
Yieldb (%)
R2
e
+
R1
N
+
N
N
H2N
1
toluene
toluene
toluene
EtOH
THF
–
50
trace
51
R4
O
2
–
70
O
+
NH3
3
–
100
100
100
100
100
120
100
100
100
55
4
–
50
a) Hantzsch pyridine synthesis
c) Kröhnke pyridine synthesis
e) 1,5-Dicarbonyls condensation
b) Chichibabin pyridine synthesis
d) Bohlmann pyridine synthesis
f) aza-Diels–Alder approach
5
–
52
6
DMF
–
trace
70
g) Bonnemann pyridine synthesis
h) 6π-electrocyclization approach
7
PhCl
–
Figure 2 Well-established approaches to pyridine synthesis
8
PhCl
–
68
9c
10c
11d
PhCl
4 Å MS
MgSO4
ZnCl2
75
R4
PhCl
82
R4
R4
PhCl
trace
H2N
O
N
N
R5
R5
a Reaction conditions: 9a (0.8 mmol), 10a (1.2 equiv), DBU (1.2 equiv), sol-
vent (4 mL), stirring, sealed tube.
base
R1
isomerization
R5
R3
R1
R3
R3
R1
b Isolated yield based on 9a.
R2
R2
5
R2
c 100% by weight of the additive (based on 9a) was present.
d 0.1 equivalents of ZnCl2 were added.
4
H2O
6
R5
R3
R4
R5
R3
R4
Subsequent investigation of the substrate scope re-
vealed that a variety of propargylic amines and unsaturated
aldehydes or ketones afforded the required products in
good yields. As shown in Scheme 2, with cinnamaldehyde
(9a), an array of propargylic amines with various substitu-
tion patterns and electronic characteristics gave generally
moderate to good yields of the required pyridines 11a–f.
The electronic nature of the propargylic amine had little in-
fluence on the reaction. Cinnamyl aldehydes derivatives
bearing either electron-donating or electron-withdrawing
groups were also tolerated, and gave the desired pyridine
products 11g–l in yields of 51–91%. Moreover, the reaction
with cyclic aliphatic aldehydes and even sterically encum-
bered substrate also proceeded smoothly to provide the de-
sired products 11m–o in high yields. Similarly, good yields
of 11p–v were obtained from a range of substituted propar-
gylic amines or even structurally complex aliphatic alde-
hydes.
N
aromatization
6π-3-azatriene
N
electrocyclization
R1
R1
R2
R2
7
8
Scheme 1 A designed pathway for pyridine synthesis based on a 6-3-
azatriene electrocyclization
In 2015, we first reported a one-pot synthesis of pyri-
dines from aldehydes, phosphorus ylides, and propargylic
azides.25 This reaction involves a sequential Wittig reaction,
Staudinger reaction, aza-Wittig reaction, and 6-3-aza-
triene electrocyclization. Here, we describe one seminal ex-
ample of the synthesis of pyridines through the condensa-
tion of an ,-unsaturated carbonyl compound with a prop-
argylic
amine
followed
by
a
6-3-azatriene
electrocyclization process. Encouraged by our initial results,
we optimized the reaction conditions with cinnamaldehyde
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

D
H. Wei, Y. Li
Synpacts
Synlett
R4
R2
N
R4
NH2
R2
DBU, MgSO4
PhCl, 100 °C
R3
R1
BzO
R5
N
R3
R1
DBU, MgSO4
R3
R1
+
NH2
O
R3
R1
R2
+
R5
9
10g
PhCl, 100 °C
O
11
R2
11
9
10
N
N
N
Et
BnO
Me
Bn
N
N
N
N
R
N
11z, R = H: 52%
11aa, R = Me: 43%
11ab, 45%
11ac, 61%
11ad, 81%
82%
Me
11a,
11b, 78%
11c, 88%
11d, 60%
Scheme 3 Scope with 4-aminobut-2-yn-1-yl benzoate (10g) as sub-
strate
Me
Me
Me
Bn
N
N
N
N
We then tested the practicality of our protocol. A 20-
gram-scale (152 mmol) preparation of 11a gave the desired
product in 52% yield (13.4 g), indicating that our method
has good scalability.
11e, 83%
11f, 62%
11g, 74%
11h, 85%
Me
Me
Me
Me
N
N
N
N
Pyridine-containing indole alkaloids, such as suaveoline
(1),26 norsuaveoline (2),27 sellowiine (12),28 macrophylline
(3), and macrocaffrine (13)29 (Figure 3), have been isolated
from a number of Rauwolfia species. Given their intriguing
chemical structures and broad range of biological proper-
ties, these natural products have elicited intense synthetic
efforts over the years, including the groups of Cook,30 Bailey,31
and Ohba.32 In most case, the introduction of the pyridine
motif in these syntheses required multiple synthetic ma-
nipulations.
R
Cl
Cl
11k, R = Me: 57%
11l, R = Ph: 91%
11i 76%
11j, 51%
11m, 86%
BnO
Et
Me
N
N
N
N
Me
11n, 74%
11o, 82%
11p, 72%
11q 95%
Me
Bn
Et
Me
N
N
N
N
BnO
NH
NH
N
R1
N
N
H
N
H
H
N
R2
HN
HN
H
11r, 76%
11s, 88%
11t, 50%
11u, 75%
H
H
Suaveoline (1): R1= Me
Norsuaveoline (2): R1= H
Macrophylline (3)
2 = CH2CH2OH
Sellowiine (12)
Me
R
Bn
Me
N
Me
N
Bn
Macrocaffrine (13)
R2 = CH2OH
N
N
Ph
Et
Ph
11x, 63%c
Me
Ph
11y, 61%c
Me
Figure 3 Structures of representative suaveoline alkaloids
11w, 59% c
11v, 69%
In connection with our developed methodology for the
synthesis of polysubstituted pyridines from propargylic
amines and unsaturated carbonyl compounds, we envi-
sioned an approach involving late-stage pyridine installa-
tion for a collective total synthesis of suaveoline alkaloids.
As shown in Scheme 4, this approach would require an al-
lenic imine intermediate 16 to undergo an expected 6-3-
azatriene electrocyclization. This compound could be de-
rived from aldehyde 14 and propargylic amine 10b through
condensation and a subsequent alkyne isomerization se-
quence. In comparison with Cook’s synthesis, our approach
offers a one-step incorporation of a pyridine moiety from
14, whereas Cook’s approach needed a nine-step approach
to achieve the same end.
Scheme 2 Scope of the pyridine synthesis
Unsaturated ketones were also accommodated in this
process, but at a much higher reaction temperature (150
°C); however, the products 11w–y were obtained in slightly
lower yields. Interestingly, when 4-aminobut-2-yn-1-yl
benzoate (10g) was employed as the substrate, the 3-vin-
ylpyridines 11z–ad were obtained as the main products in
moderate to good yields (Scheme 3), possibly as a result of
sequential elimination of the initially generated benzoates
in the presence of DBU.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

E
H. Wei, Y. Li
Synpacts
Synlett
H
N
O
3 steps
7 steps
N
CHO
H
H
H
Ph
H
N
O
15
Cook's approach
N
Me
N
N
H
H
H
Ph
HN
H
14
N
R1
suaveoline (1)
N
H
.
HN
H
16
Our approach
Scheme 4 Strategic comparison of suaveoline syntheses
As shown in Scheme 5, we began our exploration by
probing the slightly modified standard conditions to access
the tricyclic pyridine 18. Aldehyde 14 reacted with amine
17 to give the desired products smoothly in 81% yield. Sub-
sequent, the benzyl protecting group of 18 was removed by
hydrogenation to provide norsuaveoline (2) in high yield.
The structure of 2 was confirmed by X-ray crystallographic
analysis. The synthesis of suaveoline from pyridine 18 was
then completed in 63% combined yield through methylation
of the indole N1 nitrogen and subsequent benzyl deprotec-
tion. The structure of suaveoline proved amenable to un-
ambiguous characterization by single-crystal X-ray analy-
sis. Finally, reductive amination of suaveoline with
NaBH3CN in formalin led to a pseudonatural product Nb-
methylsuaveoline (19). The spectroscopic data collected for
19 were in full agreement with those reported by Cook. The
synthetic flexibility of our pyridine synthesis was also
demonstrated by a total synthesis of macrophylline (3),
simply by changing the propargylic amine from 17 to 20.
Under the standard conditions, aldehyde 14 reacted
smoothly with propargylic amine 20 to provide the desired
pyridine 21 in 64% yield. The desired natural product mac-
rophylline (3) was readily obtained by N-deprotection and
subsequent reductive amination. Its full structure was un-
ambiguously confirmed by single-crystal X-ray diffraction
analysis.
In conclusion, we have developed a convergent and
atom-economical method for the synthesis of multisubsti-
tuted pyridines. This flexible protocol is applicable to the
efficient construction of a series of pyridine scaffolds
through an appropriate choice of the propargylic amine and
unsaturated carbonyl compound. The practicality of this
process was showcased by a collective total synthesis of
three natural products: suaveoline, norsuaveoline, and
macrophylline. Because pyridine and its derivatives having
great relevance in many areas of chemistry, we expect that
our method, with its ability to permit rapid establishment
Scheme 5 Total syntheses of suaveoline, norsuaveoline, and macro-
phylline
of the pyridine core and to provide controllable diverse sub-
stitutions of that core, will find a broad range of applica-
tions in the future.
Funding Information
We gratefully acknowledge the financial support from the National
Natural Science Foundation of China (21572089, 201702166), and the
Program for Changjiang Scholars and the Innovative Research Team in
Universities (PCSIRT: IRT_15R28), the FRFCU (lzujbky-2018-61), and
the Gansu Provincial Sci. & Tech. Department (2016B01017).Progra
m
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Synlett
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