Asymmetric Construction of 3-Azabicyclo[3.1.0]hexane Skeleton with Five Contiguous Stereogenic Centers by Cu-Catalyzed 1,3-Dipolar Cycloaddition of Trisubstituted Cyclopropenes

Article abstract of DOI:10.1021/acs.orglett.8b01686

A highly diastereo- and enantioselective desymmetrization of prochiral cyclopropenes via a Cu(CH₃CN)₄BF₄/Ph-Phosferrox complex catalyzed 1,3-dipolar cycloaddition of azomethine ylides was described. A variety of complex 3-azabicyclo[3.1.0]hexane derivatives bearing five contiguous stereogenic centers and two all-carbon quaternary stereogenic centers were directly synthesized as a single isomer in excellent yields (up to 99%) and enantioselectivities (97 → 99% ee). Notably, various functional groups (CO₂R, CN, CONMe₂, and Ph) of cyclopropenes were found to be well-tolerated in this transformation. The cycloadduct was conveniently converted to a biologically important GABA derivative via LiAlH₄ reduction and subsequent hydrolysis.

Full text of DOI:10.1021/acs.orglett.8b01686

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Asymmetric Construction of 3‑Azabicyclo[3.1.0]hexane Skeleton
with Five Contiguous Stereogenic Centers by Cu-Catalyzed 1,3-
Dipolar Cycloaddition of Trisubstituted Cyclopropenes
Hua Deng,† Wu-Lin Yang,*,† Fei Tian,† Wenjun Tang,†,‡ and Wei-Ping Deng*,†,‡
†School of Pharmacy and Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, 130
Meilong Road, Shanghai 200237, China
‡State Key Laboratory of Bio-Organic and Natural Products Chemistry Center for Excellence in Molecular Synthesis, Shanghai
Institute of Organic Chemistry, University of Chinese Academy of Sciences, 345 Ling Ling Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A highly diastereo- and enantioselective
desymmetrization of prochiral cyclopropenes via a Cu-
(CH3CN)4BF4/Ph-Phosferrox complex catalyzed 1,3-dipolar
cycloaddition of azomethine ylides was described. A variety of
complex 3-azabicyclo[3.1.0]hexane derivatives bearing five
contiguous stereogenic centers and two all-carbon quaternary
stereogenic centers were directly synthesized as a single
isomer in excellent yields (up to 99%) and enantioselectivities (97 → 99% ee). Notably, various functional groups (CO2R, CN,
CONMe2, and Ph) of cyclopropenes were found to be well-tolerated in this transformation. The cycloadduct was conveniently
converted to a biologically important GABA derivative via LiAlH4 reduction and subsequent hydrolysis.
hiral 3-azabicyclo[3.1.0]hexane motifs, especially those
bearing bridgehead quaternary carbons, have found
utility in a variety of natural products and pharmaceuticals
with a broad spectrum of biological activities (Figure 1). For
analgesic bicifadine5a and drug candidates amitifadine5b and
centanafadine.5c Furthermore, this rigid framework can act as
analogues of piperidines, often showing enhanced binding
affinities with their targets in medicinal chemistry.6 However,
compared to the well-developed synthetic method of racemic
3-azabicyclo[3.1.0]hexane derivatives,7,8 the enantioselective
synthesis of this scaffold bearing multiple stereogenic centers is
very limited. Recently, the group of Cramer9 employed a Pd-
catalyzed cyclopropane C−H functionalization/addition se-
quence in one-pot processes to access a substituted 3-
azabicyclo[3.1.0]hexane with three stereogenic centers
(Scheme 1a). Despite this elegant progress, the development
of a more efficient and practical method for the convenient
synthesis of such a densely substituted bicyclic scaffold
particularly containing multiple contiguous stereogenic centers
remains a distinct challenge.
C
The catalytic asymmetric 1,3-dipolar cycloaddition of
azomethine ylides with substituted alkenes has become a
powerful method for preparing functionalized pyrrolidines with
multiple stereogenic centers.10,11 However, a fully substituted
alkene serving as the dipolarophile for the construction of
functionalized-pyrrolidines bearing two all-carbon quaternary
stereogenic centers at the bridgehead positions still remains
challenging. By strain release, the [3 + 2] cycloaddition of
azomethine ylides with a trisubstituted cyclopropenes would
offer an effective method to form 3-azabicyclo[3.1.0]hexane
with two bridgehead all-carbon quaternary centers.8 Its
Figure 1. Selected examples of bioactive molecules with 3-
azabicyclo[3.1.0]hexane scaffold bearing bridgehead quaternary
carbons.
instance, the duocarmycin family of natural products,
exemplified by (+)-duocarmycin A, represent one class of the
most promising antitumor agents.1 The selective dopamine D3
receptor (DRD3) antagonist GSK598809 has been proposed
as a medication to treat cocaine use disorder.2 As a member of
the clavine-type ergot alkaloids, (−)-cycloclavine has exhibited
potential pesticidal and antiparasitic activities.3 Procymidone is
a commercially available fungicide to control plant diseases.4
Moreover, the 3-azabicyclo[3.1.0]hexane core is also present in
Received: May 29, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01686
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Cs2CO3 as the base in CH2Cl2 at room temperature (Table 1,
entry 1). However, the expected cycloaddition did not occur
under the reaction conditions (Table 1, entry 1). Fortunately,
bisphosphine ligand (Sa)-L2 led to a dramatic improvement in
yield, affording the desired cycloadduct 3aa with moderate
enantioselectivity (−40% ee) (Table 1, entry 2). Encouraged
by this result, the (S,Sp)-Phosferrox ligands L3−L6 were then
examined (Table 1, entries 3−6). Interestingly, all the tested
ligands promoted this process smoothly within 0.5 h and L6
exhibited the optimal reaction outcome (95% yield, 97% ee)
(Table 1, entry 6). A survey of the solvent effect revealed that
THF was the best solvent of choice (Table 1, entries 7−10).
Subsequently, no improved results were obtained by varying
the bases for this transformation (see Supporting Information
(SI) for details). In addition, Cu(MeCN)4BF4 was the best
metal source compared to others tested such as AgOAc and
Cu(OAc)2 (Table 1, entries 11 and 12). Furthermore,
reducing the temperature to 0 °C resulted in a slight
improvement in enantioselectivity (99% ee) (Table 1, entry
13). When a lower catalyst loading (5 mol %) was employed at
0 °C, there was no significant influence on the reaction
outcome, and the desired adduct 3aa was obtained in 97%
yield with an excellent ee value (99% ee, Table 1, entry 14).
We then examined the scope of the substrate under the
optimal conditions (5 mol % Cu(MeCN)4BF4, 5.5 mol % L6,
20 mol % Cs2CO3 in THF at 0 °C) as summarized in Table 2.
Scheme 1. Enantioselective Synthesis of 3-
Azabicyclo[3.1.0]hexane Derivatives
enantioselective version would provide access to chiral
pyrrolidines with five contiguous stereogenic centers. In
connection with our continuing efforts in structural diversity-
oriented synthesis of chiral pyrrolidines through asymmetric
cycloaddition of azomethine ylides,12 we herein describe the
first example of a highly efficient and stereoselective synthesis
of chiral bicyclic 3-azabicyclo[3.1.0]hexanes via a copper(I)-
catalyzed asymmetric [3 + 2] cycloaddition of azomethine
ylides with trisubstituted cyclopropenes (Scheme 1b).
Initially, imino ester 1a and prochiral cyclopropene 2a were
chosen as model substrates for the enantioselective desymmet-
rization reaction. We carried out our investigation using
Cu(MeCN)4BF4 (10 mol %)/Feringa ligand (S,S,Sa)-L1 (11
mol %) as the catalyst system, in the presence of 20 mol % of
a
Table 2. Substrate Scope of Azomethine Ylides 1
a
Table 1. Optimization of the Reaction Conditions
b
c
entry
1, R1/R2
3
yield (%)
ee (%)
1
2
3
4
5
6
7
8
1a, p-ClC6H4/Me
1b, p-ClC6H4/Et
1c, p-ClC6H4/t-Bu
1d, o-ClC6H4/Me
1e, m-ClC6H4/Me
1f, p-BrC6H4/Me
1g, p-CO2MeC6H4/Me
1h, o-MeC6H4/Me
1i, m-MeC6H4/Me
1j, p-MeC6H4/Me
1k, p-MeOC6H4/Me
1l, Ph/Me
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
3ja
3ka
3la
3ma
3na
3oa
3pa
97
99
97
95
95
99
97
96
97
99
97
98
99
98
99
95
99
>99
99
98
99
99
>99
98
99
99
>99
99
>99
98
97
97
9
b
c
entry
ligand
metal
solvent
yield (%)
ee (%)
10
11
12
13
14
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L6
L6
L6
L6
L6
L6
L6
L6
CuBF4
CuBF4
CuBF4
CuBF4
CuBF4
CuBF4
CuBF4
CuBF4
CuBF4
CuBF4
AgOAc
Cu(OAc)2
CuBF4
CuBF4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
trace
97
97
91
96
95
98
80
94
93
89
93
98
97
−
−40
96
96
92
97
98
98
97
97
86
97
99
99
1m, 2-naphthyl/Me
1n, 2-thienyl/Me
1o, Cy/Me
d
15
16
d
1p, t-Bu/Me
a
All reactions were performed with 1 (0.18 mmol), 2a (0.15 mmol)
in 1.5 mL of THF, under a N2 atmosphere at 0 °C, CuBF4
=
Et2O
b
c
Cu(MeCN)4BF4. Isolated yield. The ee was determined by chiral
9
toluene
MeCN
THF
THF
THF
d
HPLC analysis. 10 mol % catalyst and 10 mol % t-BuOK was used as
10
11
12
13
14
base.
d
Initially, substrate generality was explored by changing the
ester groups of imino ester, providing the target cycloadducts
in high yields (97−99%), with extremely high enantioselectiv-
ities (99 → 99% ee) (Table 2, entries 1−3). Then, a wide
range of imino esters (1d−1m) containing electron-deficient
(Table 2, entries 4−7), electron-rich (Table 2, entries 8−11),
de
,
THF
a
All reactions were performed with 1a (0.12 mmol), 2a (0.10 mmol)
in 1.0 mL of solvent, under an N2 atmosphere at rt, CuBF4
=
b
c
Cu(MeCN)4BF4. Isolated yield. The ee was determined by chiral
HPLC analysis. Temp = 0 °C. 5 mol % cat., 0.15 mmol scale.
d
e
B
DOI: 10.1021/acs.orglett.8b01686
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
and electron-neutral (Table 2, entries 12−13) substituents on
any position of the phenyl ring were employed, and the
transformation worked efficiently, affording the corresponding
cycloadducts in good yields (95−99%), with excellent
enantioselectivities (98 → 99% ee). Noteworthily, the
outstanding outcome was still obtained for heteroaromatic 2-
thienyl derived imino ester 1n (Table 2, entry 14).
Furthermore, when challenging aliphatic-substituted imino
esters 1o, 1p were tested, the annulation process could
proceed smoothly by employing 10 mol % t-BuOK as the base
instead of Cs2CO3; the desired adducts were obtained in good
yields (99% and 95% respectively) with excellent enantiose-
lectivities (both 97% ee) (Table 2, entries 15−16). The
absolute configuration of bicyclic cycloadduct 3fa was
determined as (1S,2S,4S,5R,6S) by X-ray analysis of the single
crystal (see the SI).
with a lower catalyst loading (1 mol %), and 3aa was obtained
in 95% yield with 99% ee (Scheme 2a). Then, treatment of 3aa
Scheme 2. Gram-Scale Synthesis and Synthetic
Transformations
Next, the scope of enantioselective desymmetrization was
further evaluated by a range of prochiral cyclopropenes 2b−2i.
Various functional groups on cyclopropenes were examined in
this methodology; isopropyl ester and tert-butyl ester
substituted cyclopropenes (2b, 2c) performed well under the
reaction conditions (Table 3, entries 1−2). Notably, the
a
Table 3. Substrate Scope of Cyclopropenes 2
b
c
entry
2, R3/R4
3
yield (%)
ee (%)
1
2
3
2b, Ph/CO2iPr
2c, Ph/CO2tBu
2d, Ph/CN
2e, Ph/CONMe2
2f, Ph/Ph
2g, p-BrC6H4/CO2Et
2h, p-MeC6H4/CO2Et
2i, Me/CO2Et
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
99
95
99
95
85
95
98
80
>99
98
98
99
98
99
99
98
with LiAlH4 (4 equiv) led to the reduction of both ester groups
without any loss of stereochemical integrity (Scheme 2b).
Additionally, selective reduction of the ester group was realized
by reducing the amount of LiAlH4 (2 equiv) and lowering the
temperature (−78 °C), which was then converted into
optically pure γ-amino butyric acid (GABA) derivative 613
by simple hydrolysis (Scheme 2c).
d
4
5
6
7
de
,
8
a
All reactions were performed with 1a (0.18 mmol), 2 (0.15 mmol)
In summary, we have developed a highly efficient
desymmetrization process for the asymmetric construction of
3-azabicyclo[3.1.0]hexane derivatives possessing five contigu-
ous stereogenic centers and two bridgehead quaternary
stereogenic centers, via a catalytic enantioselective 1,3-dipolar
cycloaddition of azomethine ylides with prochiral trisubstituted
cyclopropenes. With the Cu(I)/Ph-Phosferrox complex as the
catalyst, a wide range of densely functionalized 3-azabicyclo-
[3.1.0]hexane derivatives were synthesized in high yields (up
to 99%) with excellent levels of stereoselectivity (97 → 99%
ee) under mild reaction conditions. Various functional groups
(CO2R, CN, CONMe2) of cyclopropenes, especially an
unactivated triphenylcyclopropene, were found to be well-
tolerated. This synthetic method offers a straightforward
approach to a structurally important chiral 3-azabicyclo[3.1.0]-
hexane skeleton for biological research and drug discovery.
Further transformation of the bicyclic cycloadducts and
asymmetric syntheses of bioactive molecules is underway.
in 1.5 mL of THF, under a N2 atmosphere at 0 °C, CuBF4
Cu(MeCN)4BF4. Isolated yield. The ee was determined by chiral
HPLC analysis. 10 mol % catalyst and 2 equiv of Cs2CO3 was used
as base. Temp = 25 °C.
=
b
c
d
e
success of this process could be extended to other substituted
cyclopropenes, e.g. cyclopropenyl nitrile (2d) and cyclo-
propenyl amide (2e), especially unactivated triphenylcyclopro-
pene (2f) furnishing the desymmetrized cycloadducts in good
yields (85−99%) with excellent ee values (98−99%) (Table 3,
entries 3−5). Meanwhile, both electron-donating and -with-
drawing substituents on the phenyl ring are well tolerated in
the optimal conditions, and products were respectively
obtained in 95% and 98% yields both with 99% ee (Table 3,
entries 6−7). Noteworthily, aliphatic-substituted cyclopropene
2i was also tested. Because of the lower reactivity, the reaction
was completed by raising the temperature to 25 °C and
increasing the amount of Cs2CO3 from 20 mol % to 1 equiv
giving the target product 3ai with a slight decrease in yield
(80%) but with admirable enantioselectivity (98% ee).
ASSOCIATED CONTENT
■
S
* Supporting Information
As a further demonstration of the utility of this process, the
asymmetric cycloaddition between imino ester 1a and
prochiral cyclopropene 2a was carried out on a gram scale
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01686.
C
DOI: 10.1021/acs.orglett.8b01686
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Experimental details, characterization of new com-
Letter
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pounds, crystallographic data, NMR and HPLC spectra
(PDF)
Accession Codes
CCDC 1844508 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: weiping_deng@ecust.edu.cn.
*E-mail: yangwl@ecust.edu.cn.
ORCID
Wenjun Tang: 0000-0002-8209-4156
Wei-Ping Deng: 0000-0002-4232-1318
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (No. 21772038), Shanghai Sailing
Program (No. 18YF140560), and the Fundamental Research
Funds for the Central Universities.
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DOI: 10.1021/acs.orglett.8b01686
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