Fused N-Heterocycles with Contiguous Stereogenic Centers Accessed by an Asymmetric Catalytic Cascade Reaction of Tertiary Enamides

Article abstract of DOI:10.1002/chem.201904596

We report in this article a cascade reaction strategy for the synthesis of complex N-heterocyclic compounds with contiguous and tetrasubstituted stereogenic carbons. Under the sequential catalysis of a chiral binol–Ti complex and BF₃, cyclopentanone-derived tertiary enamides undergo an enantioselective enamine addition to ketone carbonyls followed by diastereoselective trapping of the resulting acyliminiums by electron-rich aryl moieties to furnish four- and five-membered ring-fused N-heterocyclic products as the sole diastereomers in high yields with up to 99 % ee.

Full text of DOI:10.1002/chem.201904596

A Journal of
Accepted Article
Title: Fused N-Heterocycles with Continuous Stereogenic Centers
Accessed by an Asymmetric Catalytic Cascade Reaction of
Tertiary Enamides
Authors: Li Zhen, Shuo Tong, Jieping Zhu, and Mei-Xiang Wang
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To be cited as: Chem. Eur. J. 10.1002/chem.201904596
Link to VoR: http://dx.doi.org/10.1002/chem.201904596
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Fused N-Heterocycles with Continuous Stereogenic Centers
Accessed by an Asymmetric Catalytic Cascade Reaction of
Tertiary Enamides
Li Zhen[a], Shuo Tong*[a], Jieping Zhu[b], Mei-Xiang Wang*[a]
Abstract: We report in this article a cascade reaction strategy for the
expeditious catalytic synthesis of complex N-heterocyclic compounds
with continuous and tetrasubstituted stereogenic carbons. Under the
domino synthesis based on novel synthons and unique reaction
sequences remains largely unexplored. [5]
sequential catalysis of
a chiral binol-Ti complex and BF3,
cyclopentanone-derived tertiary enamides underwent initially an
enantioselective enaminic addition to ketonic carbonyls followed by
diastereoselective trapping of the resulting acyliminiums by electro-
riched aryl moieties to furnish four- and five-ring fused N-heterocyclic
products as the sole diastereomers in high yields with up to 99% ee.
Fused
N-heterocyclic
structures
with
multiple
(tetrasubstituted) stereogenic centers occur in various natural
products (Scheme 1a). They are also privileged core skeletons in
the synthesis of complex compounds in drug discovery. Synthesis
of these chiral N-heterocyclic compounds in enantiomeric pure
form is by no means trivial. Lengthy and tedious multistep
reactions are generally required. For example, the early total
synthesis of strychnine, one of the most significant landmarks in
total synthesis, required 28 steps with a very low overall yield.[1]
Domino reactions or cascade reactions involve two or more
chemical bond-forming transformations that take place in time-
resolved fashion under the same reaction conditions.[2] In
comparison with traditional stepwise synthesis of fused polycyclic
structures, domino reactions offer great advantages in terms of
synthetic efficiency and practical simplicity. Remarkably, the
rational design of reaction substrates and reaction pathways
allows the rapid and precise construction of diverse organic
compounds that are not readily obtainable by other methods.[3] In
a recent synthesis of strychnine, for instance, an anion-induced
biscyclization involving a Michael addition/Mannich reaction led to
the formation of a key tetracycle skeleton of strychnine, which
largely shortened the synthetic steps.[4] Although the power of
domino reactions have been demonstrated in literature, the full
capacity of the methodology, especially the catalytic asymmetric
Scheme 1. a) Representative examples of polycyclic natural products with
multiple (tetrasubstituted) stereogenic centers; b) reaction modes for the
functionalization of tertiary enamides and c) the design of a catalytic asymmetric
cascade reaction for the construction of ABCD-ring fused N-heterocyclic
structures.
Tertiary enamides are a unique type of synthons in organic
synthesis. First of all, there are a number of synthetic methods
documented in literature, allowing the preparation of diverse
tertiary enamides readily from commodity chemicals and
reagents.[6] Secondly, being enamine variants, tertiary enamides
show however much higher stability than enamines because of
the electronic effect of an electron-withdrawing group on nitrogen
atom. In general, no special cautions are necessary to handle
these bench stable compounds. In addition, on the contrary to the
old notion that tertiary enamides are chemically inert and not
useful in synthesis, tertiary enamides have been shown to react
smoothly with a large number of electrophilic compounds[7-15] in
the presence of catalysts. Furthermore, one of the salient
advantages is the nucleophilic reactivity of tertiary enamides is
amenable to regulation by the nature of electron-withdrawing
substituents on nitrogen atom or the reaction media because
these factors tune subtly the cross conjugation system of enamide
[a]
[b]
Li Zhen, Shuo Tong, Mei-Xiang Wang
Key Laboratory of Bioorganic Phosphorous and Chemical Biology
(Ministry of Education), Tsinghua University
Beijing 100084 (China)
Email: tongshuo@mail.tsinghua.edu.cn;
wangmx@mail.tsinghua.edu.cn
Jieping Zhu
Laboratory of Synthesis and Natural products
Institute of Chemical Sciences and Engineering
Ecole Poltechnique Fédérale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Table 1. Development of catalytic enantioselective tandem reaction.
segment (C=C-N-EWG). From their enaminic reactions with
electrophiles, tertiary enamides generally produce the
corresponding mono-functionalized products. The reactions are
believed to proceed through the iminium intermediate followed by
iminium-enamine tautomerization (Scheme 1b). We envisioned
that if there is another nucleophile in presence and its reaction
with the iminium intermediate proceeds faster than the step of
isomerization, di-functionalization of tertiary enamides would be
accomplished (Scheme 1b). In other words, the domino or
cascade reaction comprising enaminic reaction of tertiary
enamides followed by the interception of the resulting iminium
ions by other nucleophiles would provide a simple, general and
unique approach to functionalized organic compounds with very
rich structure diversity and complexity. Following the working
hypothesis, we have recently developed successfully a chiral
Lewis acid-catalyzed intermolecular cascade reaction between
tertiary enamides and salicylaldehydes, generating a library of
highly enantiomerically pure 4-chromanol derivatives.[11c] We
have also demonstrated a catalytic asymmetric intramolecular
cascade intermolecular of tertiary enamides to synthesize
pyrrolo[2,1-a]isoquinoline compounds.[12c] To continue our
research to explore the reactions of tertiary enamides and to
construct complex small molecular structures of biological and
medicinal relevance, we undertook the current study.
Our design of a cascade reaction, which is depicted in
Scheme 1c, shows the following features. The use of cyclic
ketone-derived tertiary enamides would lead to the formation of
ABCD ring-fused N-heterocyclic compounds. During the course
of reaction, three continuous stereogenic centers including two
tetrasubstituted carbons are generated. The enantioselectivity
resulted from the initial chiral catalyst-promoted nucleophilic
addition of an enamide to the ketonic carbonyl would dictate the
selectivity and stereochemistry of the consecutive cyclization
reaction between the resulting acyliminium and aromatic moiety,
Entry
Cat.
(0.2 eq)
Additive
(0.2 eq)
Solvent
t
[h]
d.r.
Yield
[%][b]
ee
[%][c]
1
p-TSA
BF3
-
DCM
2
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
92
99
99
trace
47
0
-
2
-
DCM
2
-
3
InCl3
-
DCM
2
-
4
Cat-1
Cat-2
Cat-3
Cat-4
Cat-5
Cat-6
Cat-7
Cat-7
Cat-7
Cat-7
Cat-7
Cat-7
Cat-7
Cat-7
Cat-7
Cat-7[f]
Cat-7[f]
Cat-7[h]
-
DCM
12
72
72
48
12
24
24
24
24
48
24
24
12
24
24
24
24
24
n.d.[d]
31
-
5
-
DCM
6
-
DCM
7
-
DCM
82
45
46
50
42
18
0
29
26
14
57
44
85
-
8
-
DCM
9
-
DCM
10
11
12
13
14
15
16
17
18[e]
19[e]
20[g]
21[g]
-
DCM
-
DCE
-
CHCl3
CCl4
-
furnishing most likely
a
highly enantioselective and
-
THF
47
72
18
33
84
95
92
89
28
39
82
94
94
92
98
85
diastereoselective catalytic cascade reaction. The heterocyclic
compounds obtained are not only densely functionalized
amenable to further chemical transformations but resemble the
structure of natural products such as erythrina and homoerythrina
alkaloids, which have various bioactivities in addition to their well-
known curare-like activity.[16]
-
CH3CN
toluene
xylenes
xylenes
xylenes
xylenes
xylenes
-
-
p-TSA
p-TSA
BF3
BF3
We began our study with the examination of the cascade
reaction of tertiary enamide 1a, which was prepared conveniently
from the condensation between amine and cyclopentanone
following by the acylation of the resulting imine with 2-oxo-2-
phenylacetyl chloride (Supporting Information). As a prelude to
asymmetric catalysis, achiral Lewis acid- and Brønsted acid-
catalyzed reactions were tested. A brief survey of catalysts and
[a] Conditions: 1a (0.2 mmol), catalyst (20 mol%), solvent (6 mL), RT. [b] Yield
of isolated product. [c] Measured by chiral-phase HPLC. [d] Not determined. [e]
p-TSA (20 mol%) was added after 12 h. [f] Used Cat-7 (15 mol%). [g] BF3 Et2O
(20 mol%) was added after 12 h. [h] Used Cat-7 (10 mol%).
.
.
reaction conditions revealed that InCl3, BF3 OEt2 and para-
indicating that the stereochemistry of iminium intermediate
dictated excellently diastereoselectivity of second cyclization
reaction in the cascade. Encouraged by high reaction efficiency
and excellent diastereoselectivity, we then commenced the
investigation of asymmetric catalysis to develop enantioselective
and diastereoselective synthesis of complexed heterocyclic
compounds. A few easy-to-handle privileged chiral catalysts,
which structures are depicted in Table 1, were selected in the
screening and optimization study. We first looked at the catalytic
performance of chiral salen/metal complexes (Cat-1,2,3), which
toluenesulfonic acid (p-TSA) were the most efficient catalysts to
afford the desired tandem reaction within 2 h in DCM. Pleasingly,
the reaction afforded an anticipated nitrogen-containing
tetracyclic ring product 2a in 99% yield (Table 1, entries 2-3). It is
notable that, although the second cyclization or the interception of
iminium by 2,3-dimethoxyphenyl may take place on two sites of
the arene ring, no other reigoisomeic product was formed actually.
This is mainly attributable to the steric effect. As determined by
means of 1H NMR method, the diastereomeric ratio was >19:1,
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had been validated in catalysing the enantioselective addition of
tertiary enamides to ketones. Surprisingly, they either showed
virtually no catalytic activity (Table 1, entries 4 and 6) or induced
low enantioselectivity (Table 1, entry 5). It was also disappointing
that chiral catalysts derived from the complexation of Pybox with
tin and copper (Cat-4,5) gave moderate yields of product with ee
values below 30% (Table 1, entries 7 and 8). Neither a good yield
nor a high ee value was observed from chiral phosphoric acid
(Cat-6) catalysed reaction (Table 1, entry 9). The complex of R-
binol with Ti(OiPr)4 (Cat-7) was then examined as the chiral Lewis
acid catalyst. Gratifying, the first reaction conducted at room
temperature in DCM yielded 2a in 50% yield with ee being 57%
(Table 1, entry 10). The promising result promoted us to scrutinize
other reaction parameters in order to improve the efficiency and
selectivities. As indicated by the results compiled in Table 1
(entries 10-17), reaction media played
a crucial role in
determining the conversion and stereoselectivity. Switching from
DCM to other halogen-containing solvents like DCE, CHCl3, and
CCl4 diminished either reactivity or enantioselectivity (Table 1,
entries 11-13 vs entry 10). Polar solvents such as THF and
CH3CN also had a detrimental effect on the enantioselective
control (entries 14-15). Aromatic solvents toluene and xylenes
turned out to be the better choices (entries 16-17). However,
although the ee value of product 2a was improved dramatically to
94% when xylenes was employed as the solvent, the chemical
yield of 2a was far from satisfaction. Monitoring the reaction
course using TLC revealed the formation of by-products. They
were probably generated from reaction pathways other than
designed second cyclization of putative iminium intermediate
(Scheme 3). To facilitate the second cyclization reaction, an
additional Lewis acid or Brønsted acid was added after 12 hours’
interaction of 1a with R-binol-Ti(OiPr)4 complex. To our delight,
.
the addition of either BF3 OEt2 or p-TSA (10 - 20 mol%) showed
significantly a beneficial effect, leading the formation of highly
enantioenriched 2a in high yields (Table 1, entries 18 - 21). Finally,
the reaction of 1a in xylenes (c = 0.33 M) at room temperature in
.
the presence of catalysts Cat-7 (0.15 eq) and BF3 OEt2 (added
after 12 h) was established as the best conditions. Under these
optimized conditions, pure nitrogen-containing fused tetracyclic
compound 2a was obtained in 92% yield with excellent
enantioselectivity (98% ee) and diastereoselectivity (>19 : 1 d.r.)
(Table 1, entry 20).
Scheme 2. Binol-Ti-catalyzed enantioselective synthesis of
structure of 2a. Yields are those of the isolated products and the ee values were
2 and X-ray
With optimal conditions in hand, we then examined the
scope of the cascade reaction for the synthesis 2. First of all,
tertiary enamides having both an electron-withdrawing and
electron-donating group on the aromatic ring (1b-1e) underwent
as same efficient and stereoselective cascade reaction as 1a to
afford the corresponding fused tetracyclic products 2b-2e in 87 –
94% yields and 90 – 99% ee (Scheme 2). The 2-naphthyl
substituted product 2f was synthesized analogously in a high yield
with excellent enantioselectivity and diastereoselectivity. When
the aryl group was replaced with an alkyl substitute such as a t-
butyl, substrate 1g was transformed similarly into the product 2g,
albeit in a slightly diminished yield and enantioselectivity. The
alkyl group seemed to be less powerful than aryl to govern the
diastereoselectivity of the reaction to form ring C. In addition to
3,4-dimethoxyphenyl (ring D), other electron-rich aromatic
components such as 3,4,5-trimethoxyphenyl,
determined by chiral HPLC analysis.
3,5-dimethoxyphenyl, and piperonyl in the reactant 1 were also
capable of intercepting the acyliminium intermediate formed from
initial R-binol-Ti complex-catalyzed nucleophilic addition of
enamide to ketonic carbonyl, thus enabling the preparation of the
tetracyclic compounds 2j-2k and even pentacyclic compounds
2h-2i. All products were obtained with high enantiomeric and
diastereomeric purity. As we expected, when the S-binol-Ti
complex Cat-8 was applied as a chiral catalyst, the reaction of 1a
gave product 2a’, the enantiomer of 2a, in comparable yield and
stereoselectivity. The structure of all products were supported by
their spectroscopic data (Supporting Information). The absolute
configuration of products (3S, 4S, 5R)-2 was assigned
unambiguously based on the X-ray single crystal and molecular
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structure of 2a (Table 1, entry 1 and Supporting Information).[17]
The similarity of the core structure and the same stereochemistry
of 2a’ to the skeleton of erythrina-type alkaloids are noteworthy.
The excellent stereoselectivities of cascade cyclization
reaction of tertiary enamides under the catalysis of chiral binol-
.
Ti(OiPr)4 and BF3 OEt2 were intriguing. To understand the
stereochemical course, we replaced the electron-rich arene
moieties by simply a phenyl group. The reaction stopped with the
formation of 2l with ee of 98% (Scheme 3a), indicating the
excellent enantioselectivity induced by the chiral catalyst.
Moreover, for the reaction of 1a, when the second catalyst
.
BF3 Et2O was not added, a monocyclization product 3 was also
isolated in 30% yield and 94% ee in addition to 2a (33% yield,
d.r. >19:1, 94% ee) (Scheme 3b). Taking all results into account,
a reaction pathway was proposed. As depicted in Scheme 3c, R-
binol-Ti complex activated the ketonic carbonyl trigging a highly
enantioselective intramolecular enaminic addition to form the
acyliminium, which reacted with water to generate N,O-
hemiacetal. Sequentially, the presence of BF3 accelerated the
formation of acyliminium and its interception by the tethered
electron-rich aryl moiety from the Si-face to afford 2a in a
dominant diastereoselective manner. The Re-face trapping was
hardly happened because of the steric hindrance of both
cyclopentane ring and a bulky aryl substituent.
Scheme 4. Post-transformation of 2a. a) LiAlH4 (5 equiv), THF, reflux, 8 h, 64%;
b) MsCl (3.6 equiv), Et3N (7 equiv), DCM, RT, 12 h, 96%; c) Pd/C (10% w/w),
H2 (1 atm), MeOH, RT, 12 h, 93%; d) LiAlH4 (3.5 equiv), THF, 60 oC, 4 h, 67%.
In summary, we have developed a novel and asymmetric
catalytic cascade reaction of tertiary enamides. The method
enabled the rapid synthesis of complex N-heterocyclic
compounds with continuous and tetrasubstituted stereogenic
centers in high yield and excellent enantioselectivity and
diastereoselectivity. We have also shown the synthetic
application of the method by transforming the resulting products
into four types of different derivatives. The structure of all these
products, which are hardly accessible by other synthetic methods,
resembled the key structure motif found in many bioactive
alkaloids. Currently, synthesis of erythrina-type and iboga-type
alkaloids based on this methodology is being actively pursued in
this laboratory and results will be reported in due course.
Acknowledgements
Financial supports from National Natural Science Foundation of
China (21920102001,21320102002) and Swiss State Secretariat
for Education, Research and Innovation, EPFL (Switzerland) are
gratefully acknowledged. S.T. also thanks the Thousand Young
Talents Program for support.
Scheme 3. Control experiments and a proposed reaction pathway.
Keywords: asymmetric catalysis • cascade reactions • tertiary
enamides • cyclization reactions • alkaloids analogs
The acquired products would constitute a versatile platform
for elaboration of diverse N-heterocyclic compounds potentially
useful in drug discovery. To illustrate the application of the method,
several transformations of 2a were attempted. As shown in
Scheme 4, lactam reduction of 2a with an excess amount of
LiAlH4 in refluxing THF afforded 4 in 64% yield. Dehydration of 2a
afforded the α,β-unsaturated lactam 5 in 96% yield. Further
catalytic hydrogenation of 5 in the presence of Pd/C produced 6
in 93% yield with a diastereomeric ratio of >19:1. We also found
that reaction of 2a under milder reduction conditions delivered 7,
a nonacyclic compound in a decent yield.
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[16] a) Y. Tsuda, T. Sano, in The Alkaloids, Vol. 48 (Ed.: G. A . Cordel),
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[9]
[17] CCDC 1948733 (2a) contains the supplementary crystallographic data
for this paper. This data can be obtained free of charge from The
[10] For reaction with epoxides, see: a) L. Yang, G. Deng, D.-X. Wang, Z.-T.
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Cambridge
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10.1002/chem.201904596
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
Li Zhen, Shuo Tong*, Jieping Zhu, Mei-
Xiang Wang*
Page No. – Page No.
Fused N-Heterocycles with
Continuous Stereogenic Centers
Accessed by an Asymmetric Catalytic
Cascade Reaction of Tertiary
Enamides
Under the sequential catalysis of a chiral binol-Ti complex and BF3,
cyclopentanone-derived tertiary enamides underwent initially an enantioselective
enaminic addition to ketonic carbonyls followed by diastereoselective trapping of
the resulting acyliminiums by electro-riched aryl moieties to furnish four- and five-
ring fused N-heterocyclic products as the sole diastereomers in high yields with up
to 99% ee.
This article is protected by copyright. All rights reserved.