Highly Regio-, Diastereo-, and Enantioselective Synthesis of Tetrahydroazepines and Benzo[b]oxepines through Palladium-Catalyzed [4+3] Cycloaddition Reactions

Article abstract of DOI:10.1002/anie.201911537

A novel Pd⁰-catalyzed asymmetric [4+3] annulation reaction of two readily accessible starting materials has been developed for building seven-membered heterocyclic architectures. The potential [3+2] side pathway could be suppressed though fine tuning of the conditions. A broad scope of cycloaddition donors and acceptors participated in the transformation with excellent chemo-, regio-, diastereo-, and enantioselectivtities, leading to valuable tetrahydroazepines and benzo[b]oxepines.

Full text of DOI:10.1002/anie.201911537

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Accepted Article
Title: Highly Regio-, Diastereo-, and Enantioselective Synthesis of
Tetrahydroazepines and Benzo[b]oxepines via Palladium-
Catalyzed [4+3] Cycloaddition Reactions
Authors: Barry M. Trost and Zhijun Zuo
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201911537
Angew. Chem. 10.1002/ange.201911537
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
Highly Regio-, Diastereo-, and Enantioselective Synthesis of
Tetrahydroazepines and Benzo[b]oxepines via Palladium-
Catalyzed [4+3] Cycloaddition Reactions
Barry M. Trost*, Zhijun Zuo
Abstract: A novel Pd(0)-catalyzed asymmetric [4+3] annulation
reaction of two readily accessible starting materials has been
developed for building seven-membered heterocyclic architectures.
The potential [3+2] side pathway could be suppressed though fine
tuning of the conditions. A broad scope of cycloaddition donors and
acceptors participated in the transformation with excellent chemo-,
regio-, diastereo- and enantioselectivtities, leading to valuable
tetrahydroazepines and benzo[b]oxepines.
transformations feature [3+2] cycloadditions between TMM in-
[
9]
termediates and two atom synthons such as olefin, carbonyl
[10]
[11]
compounds
and imines
to form various five-membered
cyclic skeletons. From the viewpoint of synthetic utility, it would
also be desirable to construct larger ring systems via catalytic
asymmetric TMM cycloaddition. In 2007, the Hayashi group
described the development of
a palladium-catalyzed [3+3]
cycloaddition of trimethylenemethane with nitrones to synthesize
six-membered heterocycles with high diastereoselectivity and
[
12]
enantioseletivity.
palladium-catalyzed
trimethylenemethane derivatives with tropones to provide
Later, our group reported an asymmetric
Introduction
[6+3] cycloaddition of substituted
The development of efficient and atom-economic protocols to
access medium-sized ring systems is of significance owing to
their ubiquitous occurrence in natural products and
[
13]
bicyclo[4.3.1]decadienes in high enantiomeric purity.
Surprisingly, an enantioselective [4+3] TMM cycloaddition
reaction has never been achieved.
[
1]
pharmacologically active substances. Among them, seven-
membered ring systems containing heteroatoms are key
structural motifs in many natural products and bioactive
[
2]
compounds. Unfavorable entropy effects and transannular
interactions make it more challenging to access these ring
systems. Despite extensive efforts in the development of various
strategies for accessing medium-sized rings, including ring
isomerization, ring expansion and rearrangement, the discovery
of more efficient and versatile routes is still highly desired.
The cycloaddition reaction has been recognized as one of the
most straightforward and powerful approaches for constructing
[
3]
diversely functionalized ring systems.
In particular, tri-
[
4]
methylenemethane (TMM) derivatives have served as an
efficient source of three-carbon building blocks for generating
[
5]
both carbocycles and heterocycles.
Consequently, the
development of reliable methods to access enantio-enriched
cyclic compounds through TMM cycloaddition is of great interest.
Previously, the asymmetric TMM reaction largely relied on
[
6]
induction from chiral auxiliaries on the acceptors. Compared
with traditional auxiliary-based processes, catalysis-controlled
asymmetric reactions have broader substrate scope and
functional group tolerance. However, only a single example of
catalytic
enantioselectivity (up to 78% ee) was disclosed before 2006.
The subsequent discovery of new class of pyrrolidine-
asymmetric
TMM
reaction
with
modest
[
7]
a
substituted phosphoramidite ligands led to a rapid revival in the
development of highly enantioselective catalytic cycloadditions
[
8]
over the past decade (Scheme 1a). Most of these fascinating
[*]
Prof. Dr. B. M. Trost, Dr. Z. Zuo
Scheme 1. Background of asymmetric TMM reactions and its challenge in
Department of Chemistry, Stanford University
Stanford, CA 94305-5080 (USA)
[
4+3] cycloaddition.
E-mail: bmtrost@stanford.edu
Homepage: https://web.stanford.edu/group/bmtrost/
In conjunction with our interest in Pd-catalyzed cycloaddition
Supporting information for this article is given via a link at the end of
the document.
reaction, we previously investigated the racemic [4+3]
[
14]
cycloaddition of TMM donors with vinylcyclopentene. However,
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RESEARCH ARTICLE
we consistently observed mixtures of [4+3] and [3+2] annulation
Pd
2
(dba)
3
•CHCl
3
(entry 9-10). Performing the reaction at lower
[
14c]
products with low selectivity (Scheme 1b).
We speculated
temperature led to the same enantiomer excess, albeit with
decreased yield (entry 11). Both the yield and enantioselectivity
were slightly diminished at elevated reaction temperatures (entry
12). It should be noted that no [3+2] cycloaddition product was
observed during the optimization. Moreover, only single
diastereoisomer could be detected in the reaction, presumably
owing to the conformation of the medium-sized ring.
that similar nucleophilicities of the terminal positions of π-allyl
anion in intermediate I may contribute to the poor results, and
wondered if fine-tuning of the zwitterionic intermediate I could
overcome this limitation.
Azadienes and ortho-quinomethides were envisioned to be ef-
fective four-atom partners for cycloaddition reactions due to the
[
15]
driving force of aromatization.
In 2016, Zhao’s group
Table 1. Optimization of Reaction Conditions.
developed a facile approach to access the diverse substituted N-
tosyl azadienes from commercially available cyclic ketones in
[
16]
two steps with good yields (eq 1). Later on, they demonstrated
some elegant examples of the Pd-catalyzed cycloadditions
between N-tosyl azadienes and vinylethylene carbonates or
[
17]
vinyl oxetanes for the construction of medium-sized systems.
However, the construction of seven-membered rings by means
of related annulations has not been disclosed yet. We herein
present the first asymmetric [4+3] cycloaddition reaction to
synthesize enantioenriched seven-membered heterocyclic
scaffolds, which are observed as the structural cores of many
[
a]
[b]
[c]
Entry
[Pd]
ligand solvent
yield ee
dr
1
2
3
4
5
6
7
8
9
Pd
Pd
2
2
(dba)
(dba)
3
3
•CHCl
•CHCl
3
3
3
3
3
3
3
3
L1
L2
L3
L1
L1
L1
L1
L1
L1
L1
L1
L1
THF
THF
67% 90% >19:1
70% 62% >19:1
[
18]
bioactive compounds (Scheme 1c).
We proposed that the
reaction proceeded through the zwitterionic Pd-TMM
intermediate I', generated in situ by ionization of the donor
followed by base-assisted deprotonation and nucleophilic
addition to the acceptors. Nucleophilic attack onto the Pd-π-allyl
intermediate from either of the two termini of the allyl anion
would lead to divergent cyclic products. We believed that the
significant difference in nucleophilicity and steric hindrance
between these positions would play a crucial role in determining
the regioselectivity of this process. The terminal nucleophilic
attack to the π-allyl intermediate should override the internal
nucleophilic attack, resulting in a single [4+3] cycloadduct. On
the other hand, we hope to get the enantioselective and
diastereoselective [4+3] product by induction of chiral palladium
specie.
Pd (dba) •CHCl
THF
<10%
/
/
2
2
2
2
2
2
3
3
3
3
3
3
Pd
Pd
Pd
Pd
Pd
(dba)
(dba)
(dba)
(dba)
(dba)
•CHCl
•CHCl
•CHCl
•CHCl
•CHCl
Dioxane
MeCN
DCM
77% 94% >19:1
86% 79% >19:1
79% 83% >19:1
74% 96% >19:1
87% 98% >19:1
78% 94% >19:1
84% 96% >19:1
80% 97% >19:1
85% 87% >19:1
DME
Toluene
Toluene
Toluene
Toluene
Toluene
Pd(OAc)
2
3
1
0
[(η -cinnamyl)PdCp]
[
d]
1
1
Pd
Pd
2
2
(dba)
(dba)
3
3
•CHCl
•CHCl
3
3
[
e]
12
[
a] reactions on 0.1 mmol scale at 0.25 M at room temperature for 12 h. [b] ee
1
determined using chiral HPLC. [c] dr determined by crude H NMR. [d]
reaction was run at 0 °C. [e] reaction was run at 60 °C.
With the optimal reaction conditions in hand, the scope with
respect to the azadienes was first examined (Table 2).
Substrates with different sulfonamide substituents were able to
perform the [4+3] cycloaddition reaction smoothly with excellent
diastereo- and enantioselectivity. A range of N-tosyl azadienes
bearing both electron-withdrawing and electron-donating groups
on any vacant position of the aryl ring participated in the
unprecedented transformation efficiently, indicating that the vast
change in electronic properties does not impact the formation of
intermediate I' and its subsequent reactivity. It is worth noting
that synthetically variable functional groups such as chloro- (1h),
bromo- (1i), nitro- (1k) and cyano- (1l) were well tolerated, thus
offering valuable synthetic handles for further derivatization of
benzofuro[3,2-b]azepines. Moreover, substrates containing
heterocyclic moieties (3o, p) could also undergo the
cycloaddition efficiently with good results. The reactions of
azadienes with substituents on the benzofuran rings
successfully afforded the desired products (3q, r) in 83% and
Results and Discussion
At the outset, we commenced our efforts by examining the
coupling of the azadiene 1a with amino-TMM precursor 2a
(
Table 1). The chiral phosphoramidite ligand (Feringa ligand) L1
gave a reasonable yield (67%) of the desired product 3a with
high level of diastereo- and enantioselectivity (entry 1). To
improve the reactivity, we turned to other chiral ligands which
were effective in TMM reactions. The results showed that
diamidophophite ligand L2 afforded similar reactivity with a
distinct erosion of enantioselectivity (entry 2), whereas chiral
bis(2-naphthyl) ligand L3, surprisingly shut down the reactivity
completely (entry 3). After screening various solvents, toluene
6
5% yield with excellent diasetero- and enantioselectivities. In
addition, aliphatic-substituents even the sterically bulky tert-butyl
1s) was compatible without compromising the yield, diastereo-
was found to be ideal in terms of reactivity and selectivity (entry
(
3
4
-8). Other palladium sources such as Pd(OAc)
2
and [(η -
and enantioselectivites. Gratifyingly, the tetrahydroazepines
which could be constructed by [4+3] annulation reactions were
cinnamyl)PdCp] did not give better results compared with
2
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RESEARCH ARTICLE
not limited to the benzofuran skeletons. The N-tosyl azadiene 1t-
v, which did not have strong aromatize force, also reacted
smoothly and give the corresponding Indene-based and
aliphatic-based carbocylic tetrahydroazepines (3t-v) in good
enantioselectivity and moderate diseteroselectivity. The relative
and absolute configuration of 3b was unambiguously assigned
by X-ray analysis and the configuration of all other products was
was not only amenable to o-QMs bearing substituted phenyl
rings (1a'-d') but also was applicable to a series of styryl-
substituted o-QMs (1e'-g'). It seems that the position and the
electronic properties of the substituents on the styryl moieties
have little effect on either the diastereo- or enantioselectivities.
Moreover, heterocyclic substituted o-QM 1h' was also
compatible, affording the product 3h' with good results. The
prenyl-substituted o-QM 1i' could also participate in this
transformation to give the anticipated product 3i' with 86% ee
and 3.6:1 dr. It is notable that the formal dienone 1e’-i’ only gave
the [4+3] cycloaddition products without the [6+3] cycloaddition
being observed, presumably determined by the bias created by
the geometry of the second C-C double bond as well as the
charge distribution.
[
19]
assigned by analogy.
Table 2. Scope with respect to azadienes.
Table 3. Scope with respect to o-quinomethides.
To
benzo[b]oxepines, an array of TMM donors were investigated
Table 4). Different electronic nature of the substituents on the
aromatic moieties of benzophenone imines participated in the
4+3] cycloaddition reactions with excellent yield, dr and ee
obtain
more
valuable
tetrahydroazepines
and
(
We next turned our attention to study the asymmetric [4+3]
cycloaddition of various ortho-quinomethides (o-QMs) with
amino-TMM precursor 2a (Table 3). After further optimization
[
values in standard reaction condition. However, when we turned
to other substituted TMM donors, the reaction condition only
produced inferior to moderate enantioselectivities. After
screening some ligands and solvents, the bis-diamidophosphite
L2 and 1,4-dioxane improved the enantioselectivities
significantly, presumably due to the unique steric control of the
Pd-TMM intermediate. Delightfully, the TMM donor 2g, bearing
(
details see SI), we found that more reactive palladium
3
precatalyst [(η -cinnamyl)PdCp] and acetonitrile showed better
performance in this cycloaddition reaction. Remarkably, a wide
range of benzo[b]oxepines could be generated in good yields
(
65-96%), excellent enantioselectivities (86-94% ee) and
acceptable diastereoselectivities (3.6:1-13:1 dr). This approach
3
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RESEARCH ARTICLE
an electron-withdrawing group (nitro-) on the phenyl ring,
reacted smoothly with excellent diastereoselectivity and modest
enantioselectivity. Additionally, the nitrile- and phenylsulfonyl-
substituted TMM donors (2h-i) performed well in the title
transformation and gave the desired products with good
enantioselectivities (98% and 83%), which could be easily
Delightfully, the levels of diastereomeric and enantiomeric
2 3 3
enrichment at 0.5 mol % of Pd (dba) •CHCl (Scheme 2, top)
remained unchanged. Moreover, various modifications of the
parent cycloadduct 3a were conducted (Scheme 2, bottom). The
benophenone imine moiety could be easily removed by treating
3
4
a with 1 N aqueous hydrochloric acid to give the primary amine
. To our surprise, the poly-cyclic benzofuro[3,2-b]azepine 5 was
[
7,20]
converted to synthetically useful structures.
The highly
isolated in 92% yield via highly diastereoselective
dihydroxylation of the 1,1-disubstituted double bond in 3a
followed by nucleophilic addition of one of the hydroxyl groups to
the imine moiety. Cleavage of the exocyclic C-C double bond to
ketone 6 was achieved by exposure of the cycloadduct to ozone.
functionalized benzo[b]oxepines 3i'' containing a quaternary
carbon center, which is still a big challenge in the TMM
[
11c]
reaction,
was isolated as a single diastereoisomer with an
impressive result (72% yield and 95% ee).
Table 4. Scope with respect to TMM donor.
Conclusion
In summary, we have developed a reliable and straightforward
entry to optically-active seven-membered heterocycles through
an unprecedented Pd-catalyzed [4+3] cycloaddition. This
methodology features unique regioselectivity that contrasts with
the conventional TMM cycloaddition reaction. The readily
accessibility of the two reaction partners impacts great
practicality to this synthetic method. Furthermore, exposure of
the available multifunctional cycloadducts allows rapid access to
a diverse array of structural types, as would be present in
complex molecular targets.
Experimental Section
●
Chiral ligand L1 (10.8 mg, 10.0 mmol %) and Pd
2
(dba)
3
CHCl
3
(5.1 mg,
2
.5 mol %) was added to an argon purged vial. Then, freshly distilled
toluene (0.20 mL) was added and stirred for 5 minutes under argon. N-
substituted azadienes 1a (75.0 mg, 0.20 mmol) and TMM-donors 2a
(
73.7 mg, 0.21 mmol) were added to another oven dried vial and
dissolved using toluene (0.20 mL). The above catalyst solution was then
transferred to the reactant vial using syringe. The reaction mixture was
stirred for 10 hours at room temperature under argon and then
concentrated and purified by chromatography to give the desired product
3
a (105.8 mg, 87% yield).
Acknowledgements
We gratefully thank the Hadi Gholami and Christopher A.
Kalnmal from Stanford University for the helpful discussion. We
also thank the Tamaki Foundation for their generous partial
funding support for our program. The crystal structure analysis
of this work was performed at the Stanford Nano Shared
Facilities (SNSF)/Stanford Nanofabrication Facility (SNF),
supported by the National Science Foundation under award
ECCS-1542152.
Keywords: annulation • asymmetric catalysis • palladium •
heterocycle
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Scheme 2. Large scale reaction and chemoselective transformation.
To showcase the synthetic potential of our protocol for scale
up applications, the enantioselective [4+3] annulation was
conducted with reduced loadings of the catalyst and the ligand.
4
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Angewandte Chemie International Edition
10.1002/anie.201911537
RESEARCH ARTICLE
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Angewandte Chemie International Edition
10.1002/anie.201911537
RESEARCH ARTICLE
RESEARCH ARTICLE
Prof. Dr. B. M. Trost*, Dr. Z. Zuo
Page No. – Page No.
Highly Regio-,
Diastereo-,
Synthesis
and
of
Enantioselective
Tetrahydroazepines
Benzo[b]oxepines
and
via
Palladium-
A novel Pd(0)-catalyzed asymmetric [4+3] annulation reaction of two readily
accessible starting materials has been developed for building seven-membered
heterocyclic architectures. The potential [3+2] side pathway could be suppressed
though fine tuning of the conditions. A broad scope of cycloaddition donors and
acceptors participated in the transformation with excellent chemo-, regio-,
diastereo- and enantioselectivtities, leading to valuable tetrahydroazepines and
benzo[b]oxepines
Catalyzed
Reactions
[4+3]
Cycloaddition
This article is protected by copyright. All rights reserved.