Asymmetric Reductive and Alkynylative Heck Bicyclization of Enynes to Access Conformationally Restricted Aza[3.1.0]bicycles

Article abstract of DOI:10.1002/anie.202000859

Conformationally restricted azabicycles are becoming increasingly important in medicinal research. Asymmetric Heck bicyclization of enynes proceeds to give medicinally useful aza[3.1.0] and aza[4.1.0] bicycles with excellent enantioselectivity. The key organopalladium species after bicyclization can be trapped by silanes and terminal alkynes.

Full text of DOI:10.1002/anie.202000859

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Accepted Article
Title: Asymmetric Reductive and Alkynylative Heck Bicyclization of
Enynes to Access Conformationally Restricted Aza[3.1.0]bicycles
Authors: Jianrong Steve Zhou, Xiaolei Huang, Minh Hieu Minh,
Maoping Pu, Luoqiang Zhang, Yonggui Robin Chi, and Yun-
Dong Wu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202000859
Angew. Chem. 10.1002/ange.202000859
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10.1002/anie.202000859
Angewandte Chemie International Edition
COMMUNICATION
Asymmetric Reductive and Alkynylative Heck Bicyclization of
Enynes to Access Conformationally Restricted Aza[3.1.0]bicycles
Xiaolei Huang,‡ Minh Hieu Nguyen,‡ Maoping Pu,‖ Luoqiang Zhang,† Yonggui Robin Chi,‡ Yun-Dong
Wu§ and Jianrong Steve Zhou†*
Abstract: Conformationally restricted azabicycles are becoming
increasingly important in medicinal research. Asymmetric Heck
bicyclization of enynes proceeds to give medicinally useful
aza[3.1.0] and aza[4.1.0] bicycles in excellent enantioselectivity.
The key organopalladium species after bicyclization can be
trapped by silanes and terminal alkynes.
most straightforward way to access these azabicycles, but such a
stereoselective variant still remains unavailable.[12] Another
obvious choice is cyclization of 1,5-enynes catalyzed by
carbophilic Au, Pt and Pd,[13] but again its asymmetric version has
not been reported yet.[14] Recently, Trost et al. reported an
enantioselective isomerization of 1,6-enynes using a cationic
cyclopentadienyl ruthenium catalyst (Scheme 1a), which
proceeded via hydride migration from the carbinol to alkyne to
form alkenyl Ru species.[15] In the second example (Scheme 1b),
asymmetric annulation of strained cyclopropenes and N-
Saturated heterocycles such as pyrrolidines, piperidines and
piperazine are among the most frequently used motifs in
medicines.[1] In particularly, saturated azacycles containing
exquisite sp3-stereocenters, instead of flat heteroarenes, confers
unique 3D shapes and also improves druglike properties such as
good solubility and affinities to biological targets.[2] In recent years,
azabicyclo[3.1.0]hexanes emerge as a very useful scaffold in
drug discovery.[3] These 3D-shaped azabicycles have rigid
conformations with substituents pointing at specific directions,
which help to optimize selective binding to desired biological
targets, while minimizing unwanted promiscuous interactions.
Some examples of drugs containing azabicyclo[3.1.0]hexanes
are shown in Fig 1, including a family of triple reuptake inhibitors
(e.g., bicifadine, centanafadine and amitifadine),[4] antibiotics
trovafloxacin and indolizomycin,[5] a selective mu opioid receptor
antagonist for the treatment of alcohol abuse,[6] boceprevir, a
protease inhibitor to combat hepatitis C virus,[7] and others.[8]
Examples of bioactive azabicyclo[4.1.0]heptanes include GSK
1360707, a triple uptake inhibitor for the treatment of depression
(see Fig 1)[9] and orexin receptor antagonists.[10]
allylamines
was
assisted
by
a
moisture-sensitive
cyclopentadienyl lanthanum catalyst.[16] In a recent report by
Cramer et al. (Scheme 1c), Pd-catalyzed desymmetrization of
pendent
cyclopropanes
produced
trifluoromethylated
aza[3.1.0]bicyclohexenes in excellent stereocontrol.[17] Lastly,
asymmetric aminocatalysis resulted in intramolecular -
cyclopropanation of in situ generated iodoaldehydes.[18]
Moreover, enantioselective synthesis of azabicyclo[4.1.0]-
heptanes also remains a challenge, for example, catalytic
cyclopropanation did not provide good enantioselectivity under
many conditions.[19]
Me
Cl
Cl
Cl
Cl
OMe
N
H
N
H
N
H
HN
Bicifadine
chronic lower back pain
Amitifadine
depression
GSK 1360707
depression
Centanafadin
ADHD
MeO2S
NH
O
F
HN
NH2
Et
H
H
To date, efficient enantioselective methods for the preparation
H
H
O
O
N
of azabicyclo[3.1.0]hexanes still remain
a
challenge,
N
N
CN
NH2
unfortunately.[11] Arguably, asymmetric cyclopropanation is the
n-Pr
d-opioid receptor modulator
depression and anxiety
OH
OH
CP-8666,085
alcoholism
Saxaglipin
NH2
Type-2 diabetes
[†*]
Dr. L. Zhang, Prof. Dr. J. S. Zhou
H
H
State Key Laboratory of Chemical Oncogenomics, Key Laboratory
of Chemical Genomics, School of Chemical Biology and
Biotechnology, Peking University Shenzhen Graduate School,
Room F312, 2199 Lishui Road, Nanshan District,
Shenzhen 518055, China. E-mail: jrzhou@pku.edu.cn
Prof. Dr. Y.-D. Wu
Lab of Computational Chemistry and Drug Design, State Key
Laboratory of Chemical Oncogenomics, Peking University
Shenzhen Graduate School, Shenzhen Bay Laboratory,
Shenzhen 518055, China
Me
Me
N
H
N
F
F
Me
HO
N
O
N
Me
N
O
H
H
O
N
O
N
N
Me
O
t-Bu
F
O
t-Bu
O
[§]
CO2H
Trovafloxacin
serious bacterial infection
Boceprevir
hepatitis infection
Indolizomycin
antibiotic
Figure 1. Examples of drugs containing [3.1.0] and [4.1.0]
azabicycles
[‖]
[‡]
Dr. M. Pu
Shenzhen Bay Laboratory, Shenzhen 518055, China
Dr. X. Huang, Mr. M. H. Nguyen, Prof. Dr. Y. R. Chi
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University, 21 Nanyang Link,
637371, Singapore
MHN and MP are co-first authors of this paper.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.202000859
Angewandte Chemie International Edition
COMMUNICATION
disclosed asymmetric Heck cyclization and subsequent
alkynylation that produced -CF3-subsituted oxindoles.[29] It
should be pointed out that all of the aforementioned processes
only allowed construction of
a single (benzo)fused ring.
Asymmetric Heck-type bicyclization to generate the rings as
shown in Fig 2d has remained elusive.
In Pd-catalyzed bicyclization of a model enyne 1a, we first
examined a collection of chiral bisphosphines, including BINAP,
Difluorophos, Segphos and Duphos, and monodendate
phosphoramidites, but to no avail. Only Chiraphos and
Phanephos afforded desired product 2a in appreciable yields and
in 89% and 50% ees, respectively (Scheme 1). To our gratification,
Norphos on a norbonene skeleton[30] furnished 2a in 78% yield of
97% ee. The main side product under most conditions was
derived from premature reduction of the allenyl Pd species (see
Fig 2d). Ph2SiH2 proved to be the optimal hydride donor, whereas
PhSiH3, Et2SiH2 and NaHCO2 were less effective and offered
moderate yields of product 2a. Without any silane, 2a was
produced in 27% yield, suggesting that isopropanol can serve as
a minor source of hydride. The reaction itself did not need a base,
but addition of NaOAc or Hünig base slightly improved the yield
of 2a. Among organic solvents we examined, we found that the
ee was the highest in isopropanol. The model reaction on 1 mmol
scale using 1 mol% Pd catalyst also proceeded well to afford 2a
in 79% yield after 48 h. At 0.2 mol% Pd, the yield of 2a was 67%
along with 16% recovered 1a.
OAc
Pd(dba)2 5 mol%
chiral ligand 5 mol%
Ph
Ph
Ph2SiH2
DIPEA 2 equiv
i-PrOH, 50 oC, 12 h
N
N
Ts
Ts
Figure 2. Examples of catalytic asymmetric synthesis of [3.1.0]
azabicycles (Ts = p-toluenesulfonyl. Ac = acetyl. dba =
dibenzylideneacetone. Cp = cyclopentadienyl)
PPh2
PPh2
PPh2
PPh2
Me
Ph2P
Me
PPh2
L3
PPh2
PPh2
In the 1990s, Grigg and Oppolzer et al. separately reported
L1
2% yield
L2
L4
-50% ee, 53% yield
89% ee, 44% yield
97% ee, 78% yield
reductive Heck cyclization of 1,6-enynes to prepare
aza[3.1.0]bicycles,[20]
using
simple
Pd
catalysts
of
O
O
F
triphenylphosphine and trifurylphosphine. But an enantioselective
version has remained elusive. A fine balance of steric factors
around the chiral pocket must be struck to bias the formation of
one enantiomer during alkene insertion, but also remain relatively
open for sequential allene cyclization to occur (see Fig 2d).
Another issue is premature reduction of the allenyl Pd species by
hydride donors. Furthermore, -hydrogen elimination of the
allenyl Pd species may also compete as a side reaction.[21]
F
PPh2
PPh2
O
O
O
PPh2
PPh2
PPh2
NHPPh2
NHPPh2
PPh2
O
F
F
O
O
L6
L7
L5
L8
0% yield
0% yield
-55% ee, 14% yield
89% ee, 44% yield
Ph
N
Ph
O
Me
Me
Me
Me
Me
O
P
O
O
O
N
O
P
N
P
P
N
O
O
O
Me
Ph
Ph
In line with our interest in generating strained rings via
asymmetric palladium catalysis,[22] we attempted Heck
L9
L10
0% yield
L11
L12
0% yield
56% ee, 20% yield
- 29% ee, 32% yield
Me
i-Pr
bicyclization
to
produce
medicinally
important
i-Pr
Me
P
i-Pr
P
P
azabicyclo[3.1.0]hexanes by intercepting the late-stage
organopalladium species with hydride donors or carbon
nucleophiles such as alkynes (Scheme 2d). In recent years, Pd-
Me
Me
Me
P
i-Pr
i-Pr
P
P
P
P
i-Pr
Me
i-Pr
Me
L13
Me
i-Pr
L14
0% yield
L16
0% yield
[23]
L15
0% yield
and Ni[24]-catalyzed enantioselective reductive Heck reaction
0% yield
has received renewed interest which quickly provide useful chiral
building blocks.[25] Furthermore, Pd-[26] and Ni-catalyzed[27]
asymmetric alkene cyclization were also intercepted with coupling
reagents.[28] For example, in 2017 Jia et al. reported that
intramolecular Heck arylation of indoles was successfully trapped
by alkynylation in good ee values.[26a] Very recently, Ge et al. also
Scheme 1. The effects of chiral ligands on a model cyclization of
model 1,6-enyne (calibrated GC yields and ee values as
determined by chiral HPLC). dba = dibenzylidene-acetone.
DIPEA = diisopropylethylamine.
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10.1002/anie.202000859
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COMMUNICATION
additive test in the model reaction of 1a,[31] azacycles such as
quinoline, isoquinoline, 2-phenylpyridine and unprotected indole
had almost no influence. Moreover, single-crystal X-ray diffraction
of product 2g helped to ascertain the absolute configuration of
products. [32] When an enyne carrying a simple N-allyl group was
used, 2o was generated in 83% ee. This suggested that
intramolecular insertion of the allene is faster than -hydrogen
elimination (see Fig 2).
OAc
Pd(dba)2 5 mol%
(S,S)-Norphos 5 mol%
Ph
Ph2SiH2
Ph
(a)
NaOAc 2 equiv
i-PrOH, 50 oC, 12 h
N
N
Ts
2a 78% yield, 97% ee
Ts
1a
CF3
Other examples
2b Y = Me 76% yield, 96% ee
2c Y = OMe 85% yield, 93% ee
Y
2d Y = CN 75% yield, 96% ee
2e Y = F 70% yield, 97% ee
2f Y = Cl 73% yield, 88% ee
2g Y = CF3 81% yield, 97% ee
N
Ts
N
2h
Ts
Propargylic acetates carrying 1,1-disubstituents reacted
smoothly (2pr). A racemic sample bearing a benzyl group,
however, led to two olefinic isomers 2s in an E/Z ratio of 3:2. The
two isomers overlapped on chiral HPLC traces. After catalytic
hydrogenation of the two isomers over Pd/C, the ee was
determined to 77%. Without any C1-substituent on the propargyl
fragments, the cyclization still proceeded (2t). The cyclization
using an enyne carrying a cinnamyl group furnished a cis-fused
cyclopropane 2v albeit in 40% ee. Thus, C2-substituents on the
alkenes are important for enantiofacial insertion. Furthermore, the
linker of enynes can be changed to arylamines, benzylamine and
a malonate (2w-2ac). However, carbamates and benzamides as
linkers inhibited the insertion process. Asymmetric cyclization of
tosylamide-linked 1,7-enyne also proceeded smoothly to give
azabicyclo[4.1.0]heptanes in over 95% ee (3a-b).
83% yield, 96% ee
R
Ar
N
N
Ts
Ts
2i Ar = m-xylyl 69% yield, 96% ee
2j Ar = 1-naph 77% yield, 98% ee
2k Ar = o-tolyl 65% yield, 99% ee
2l R = c-hexyl 94% yield, 83% ee
2m R = benzyl 71% yield, 89% ee
2n R = methyl 95% yield, 88% ee
Et
Et
(
)
n
Ph
H
Ph
N
N
N
Ts
Ts
Ts
2o 79% yield, 83% ee
2p 68% yield, 94% ee
2q n = 1 72% yield, 95% ee
2r n = 2 69% yield, 95% ee
Bn
Ph
H
R
Ph
N
N
N
Ts
Ts
We also attempted to intercept the alkenyl Pd species after
bicyclization (see Fig 2) with carbon nucleophiles such as
diphenylzinc, PhB(OH)2 and PhSi(OMe)3, but they failed to deliver
the desired alkynylation under many conditions. Later, cognizant
of highly congested alkenyl Pd species after bicyclization, we
attempted to trap with small nucleophiles, terminal alkynes.
Indeed, both aromatic and aliphatic alkynes of different electronic
properties coupled efficiently to give alkynylation adducts
(Scheme 3).[33] Premature propargylic alkynylation was detected
as a minor side reaction.
Ts
2t R = Me 88% yield, 99% ee
2u R = H 85% yield, 40% ee
2s 75% yield, 77% ee
2v 68 % yield, 48% ee
(E/Z 3:2)
S
Ph
3-FC6H4
N
N
N
PMP
PMP
PMP
2w 78% yield, 90% ee
2y 90% yield, 70% ee
2x 90% yield, 93% ee
Ph
Ph
Ph
AcN
N
EtO2C
EtO2C
N
N
PMP
OAc
PMP
Bn
Pd(dba)2 5 mol%
Ph
2ab 68% yield, 74% ee
2z 80% yield, 90% ee
2aa 62% yield, 90% ee
(S,S)-Norphos 5 mol%
Ph
Ph
N
K2CO3 3 equiv
i-PrOH, 50 oC, 12 h
Ts
Ph
N
4a 75% yield, 88% ee
Ts
Ph
1a
other examples
MeO2C CO2Me
Y
2ac 72% yield, 80% ee
Ph
Ph
OAc
Pd(dba)2 5 mol%
(S,S)-Norphos 5 mol%
N
R
t-Bu
Ph
N
Ts
N
Ts
Ts
Ph2SiH2
Y
R
(b)
4b Y = OMe 78% yield, 90% ee
4c Y = CF3 75% yield, 88% ee
NaOAc 2 equiv
i-PrOH, 50 oC, 12 h
4d Y = OMe 72% yield, 85% ee
4e Y = CF3 85% yield, 91% ee
TsN
4f 73% yield, 90% ee
(
)
2
N
3a R = H 82% yield, 95% ee
3b R = Me 60% yield, 98% ee
Ts
1b
Me
Scheme 2. Asymmetric reductive Heck bicyclization of 1,6- and
1,7-enynes to access [3.1.0]azacycles (a) and [4.1.0]azacycles (b)
in isolated yields. PMP = p-methoxyphenyl.
Ph
Ph
Et3Si
N
Ph
N
N
Ts
Ts
Ts
4g 68% yield, 93% ee
4h 70% yield, 93% ee
4i 70% yield, 50% ee
The Pd catalyst of Norphos was then successfully applied to
various 1,6-enynes in reductive Heck cyclization (Scheme 2).
Both electron-donating (2b-c) and electron-withdrawing groups
(2dh) can be present on the aryl substituents of the alkene, as
well as methyl, cyclohexyl and benzyl groups (2n-l). Aryl nitrile,
fluoride and chloride, amides and esters were tolerated well. In an
Scheme 3. Asymmetric Heck bicyclization and alkynyl coupling of
1,6-enynes in isolated yields.
We next conducted DFT calculation of the initial Heck
insertion step of 1a at SMD(2-propanol), M06L/Def2-
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Goldberg, J. G. Kettle, T. Kogej, M. W. D. Perry, N. P. Tomkinson,
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distances were 3.14 Å in both transition states. Secondly, the two
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Fig 3. A favored transition state (left) and a disfavored transition state
(right) for insertion of the allenyl-Pd on alkene fragment. Atoms are colored
in purple (N), red (O), yellow (S) and orange (P) and blue (Pd),
respectively. The 3,3-dimethylallenyl fragment on Pd is highlighted in neon
green.
In conclusion, we have developed an intramolecular reductive
Heck cyclization of 1,6-enynes to generate medicinally important
aza[3.1.0]bicycles in excellent ee values. Furthermore, the key
alkenyl Pd species can be trapped by terminal alkynes to give
alkynylation adducts.
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We acknowledge financial support from Peking University
Shenzhen Graduate School, Shenzhen Bay Laboratory
(21230011-Scripps), National Natural Science Foundation of
China (NSFC 21933004), Nanyang Technological University,
GSK-EDB Trust Fund (2017 GSK-EDB Green and Sustainable
Manufacturing Award) and A*STAR Science and Engineering
Research Council (AME IRG A1783c0010). MP contributed DFT
calculations. We thank Dr Li Yongxin at NTU for X-ray diffraction.
Conflict of interest
The authors declare no conflict of interest
Keywords: palladium catalysis • reductive Heck reaction •
alkynylation • privileged scaffold • azabicycles
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COMMUNICATION
Palladium catalysis
R
R
OAc
Xiaolei Huang, Minh Hieu Nguyen,
Maoping Pu, Luoqiang Zhang, Yonggui
Robin Chi, Yun-Dong Wu and Jianrong
Steve Zhou
PPh2
Pd catalyst
R1
R1
R3SiH
R
PPh2
or alkynes
N
N
R
R
ligand: Norphos
R = H or alkynyl
Page – Page
R = Ts, Boc, Bz
>90% ee in most examples
Asymmetric Reductive and Alkynylative
Heck Bicyclization of Enynes to Access
Conformationally Restricted
Heck bicyclization of enynes is intercepted by silanes and alkynes to give medicinally
important azacycles with rigid conformations in good enantiomeric ratios.
Aza[3.1.0]bicycles
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