Direct stereoselective construction of cyclopropane α-amino acid with contiguous quaternary centers via [4 + 2] annulation reaction

Article abstract of DOI:10.1039/c7ra06465a

A direct diastereoselective synthetic approach to useful cyclopropane α-amino acid was established via base-promoted [4 + 2] annulations between o-aminobenzaldehydes and alkyl 2-aroyl-1-chlorocyclopropanecarboxylates. The annulation reaction proceeded quickly under mildly basic conditions, affording α-aminocyclopropanecarboxylic acid derivatives in moderate to excellent yields with high diastereoselectivities (up to 19 : 1).

Full text of DOI:10.1039/c7ra06465a

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Direct stereoselective construction of
cyclopropane a-amino acid with contiguous
Cite this: RSC Adv., 2017, 7, 38077
quaternary centers via [4 + 2] annulation reaction†
b
a
a
a
a
*
Jun-Hao Hu, Yun-Chao Xu, Dan-Dan Liu, Bing Sun, Ying Yi
a
*
and Fang-Lin Zhang
A direct diastereoselective synthetic approach to useful cyclopropane a-amino acid was established via
base-promoted [4 2] annulations between o-aminobenzaldehydes and alkyl 2-aroyl-1-
Received 9th June 2017
Accepted 13th July 2017
+
chlorocyclopropanecarboxylates. The annulation reaction proceeded quickly under mildly basic
conditions, affording a-aminocyclopropanecarboxylic acid derivatives in moderate to excellent yields
with high diastereoselectivities (up to 19 : 1).
DOI: 10.1039/c7ra06465a
rsc.li/rsc-advances
Since a-aminocyclopropanecarboxylic acid (ACC) was rst iso- a combination of 1-aminocyclopropane-1-carboxylic acid and
¨ ¨
lated from cowberries by Vahatalo and Virtanen in 1955, ACC 1,2,3,4-tetrahydroquinoline-2-carboxylic acid moieties have
motifs and their derivatives have attracted considerable atten- strong affinities with the glycine binding site of the NMDA
tion.1 ACC not only exists in many natural products, bioactive receptor,5 and also play an important role in neuronal cell death
compounds and pharmaceuticals,2 but also serves as valuable during ischaemic or hypoxic conditions such as stroke or
tool for the mechanistic study and characterization of enzymes.3 epilepsy.6–8 Unfortunately, however, a multiple-step synthesis is
Some representative bioactive examples bearing this skeleton essential to construct two contiguous quaternary centers.9
are given in Fig. 1. Great interest has been shown in the efficient Therefore, the development of more efficient and general
construction of ACC frameworks, especially those with tertiary– methods for the synthesis of ACC derivatives containing
quaternary carbon centers.4 In addition, recent medicinal contiguous quaternary centers is highly desirable.
research revealed that compound I and its derivatives as
The previously reported synthetic methods of ACC frame-
work, such as insertion reaction of transition-metal-mediated a-
nitroacetate carbene with disubstituted alkenes (Scheme 1A),10
[3 + 2] cycloaddition (Scheme 1B)11 and multi-step synthesis
(Scheme 1C),9 are outlined in Scheme 1. The main disadvan-
tages for these routes include low functional group tolerance
and the expensive precursors prepared through multiple steps.
Thus, it still remains a challenge to develop a more practical
method for this core structure.
Over the last decade, the eld of transition-metal-catalyzed
aromatic C–H bond functionalization has gained signicant
development, and these strategies to form carbon–carbon and
carbon–heteroatom bond have become increasingly common-
place.12 Recently, Yu et al. reported the use of glycine as a tran-
sient directing group for functionalization of C(sp3)–H bond of
aldehyde.13 Then, Yu and our group have collectively demon-
strated an ortho-C(sp2)–H functionalization of benzaldehyde
Fig. 1 Typical bioactive molecules containing ACC motifs.
aSchool of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of
Technology, Wuhan 430070, People's Republic of China. E-mail: fanglinzhang@ using transient directing groups.14 As part of our ongoing work,
whut.edu.cn; yying630@163.com
bDepartment of Chemistry and Material Science, Key Laboratory of Functional
we found that the products 3 derived from ortho-amidation of
aldehydes were donor–acceptor species substantially which can
Organometallic Materials of Hunan Provincial College, Hengyang Normal
be further transformed into useful core architectures. In addi-
University, Hengyang, Hunan 421008, People's Republic of China
tion, Gong et al. developed a convenient way to prepare a new
† Electronic supplementary information (ESI) available. CCDC 1525861. For ESI
type of electron-decient cyclopropene intermediate II (marked
in Scheme 1) in situ by carrying out a simple 1,2-elimination of
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c7ra06465a
‡ J. H. and Y. X. contributed equally to this work.
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Table 1 Ir(III)-Catalyzed ortho-amidation of aldehydesa,b
Scheme
centers containing ACC.
1 Diastereoselective synthesis of contiguous quaternary
a
0.2 mmol 1 and 0.3 mmol 2 in 2.0 mL DCE. b Isolated yields given.
conrmed by single crystal X-ray diffraction analysis.17 To opti-
mize the reaction conditions, various solvents were taken into
account. As shown in Table 2, in aprotic polar solvents such as
N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO),
this reaction proceeded smoothly to produce 5aa with high dr
value (Table 2, entries 2 and 3), and a satisfactory yield (84%) was
alkyl 2-aroyl-1-chlorocyclopropanecarboxylates under basic
conditions.15 This reagent has been successfully applied to
construct strained ring-fused bioactive molecules through its
base-promoted annulation reactions.16 The above progress
encouraged us to assess the possibility of constructing the
important ACC subunit I directly through the designed [4 + 2]
annulation reaction between donor–acceptor reagents 3 and
alkyl 2-aroyl-1-chlorocyclopropanecarboxylates. To our delight,
the expected products were obtained in moderate to high yields
under mildly basic conditions. The details about the Ir-
catalyzed amidation of benzaldehydes with sulfonyl azides
and subsequent [4 + 2] annulation reaction with alkyl 2-aroyl-1-
chlorocyclopropanecarboxylates are described herein.
Table 2 Optimization of the annulation reaction between 3a and 4aa
Firstly, the preparation of donor–acceptor reagents 3 fol-
lowed our previous work.14 Under the same conditions, the yield
of 3a was obtained only in 50%. Therefore, we preliminarily
screened the inuence of various amines, and found that amine
L1 gave the desired product 3a in 75% yield (Table S1†).
Under the optimal reaction conditions, we obtained various
ortho-aminobenzaldehyde products 3, which are summarized in
Table 1, in good (57%) to excellent (97%) yields.
Yieldb
(%)
Entry
Solvent
Base
T (h)
drc
1
2
3
4
5
THF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
12
2
2
12
12
15
84
86
70
<5
9 : 1
13 : 1
14 : 1
14 : 1
—
DMSO
DMF
CH3CN
1,4-
Dioxane
DMF
DMF
DMF
DMF
DMF
With ortho-aminobenzaldehyde products 3 in hand, we
envisioned the construction of ACC subunit though annulation
reaction of 3 with ethyl 2-aroyl-1-chlorocyclopropanecarboxylates
4, the reaction of 3a with 4a was rst carried out in the presence
of Cs2CO3 as model. In THF, the reaction readily proceeded at
room temperature, and 4a was almost completely consumed
aer 12 h. The product, isolated through silica gel column
chromatography in 15% yield with 9 : 1 dr value, was identied
to be the fused ACC ester 5aa by spectroscopic means (Table 2,
6
7
8
9
NaOH
K3PO4
K2CO3
TEA
1
23
56
<5
—
—
10 : 1
9 : 1
—
—
—
12
12
12
12
10
DBU
a
Reactions carried out using 0.10 mmol of 3a, 0.11 mmol of 4a and
0.20 mmol of Cs2CO3 in 1.0 mL of solvent at room temperature.
Isolated yields given. Diastereomeric ratio (cis : trans) of the crude
product determined by 1H NMR.
1
b
c
entry 1). The diastereomeric ratio of 5aa was determined by H
NMR spectroscopy. The stereochemistry for this process was
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observed in DMF. In acetonitrile, the reaction proceeded slowly, value of the annulation product 5fa, whereas the substrate 3g
and the yield of 5aa was relatively lower than the observed in with 2-chloro group furnished a high yield of the product 5ga
DMF (Table 2, entry 4). In weakly polar solvent 1,4-dioxane, with an excellent dr value (19 : 1) and the substrate 5i with 2,4-
almost none of the desired product was detected (Table 2, dichloro group gave the lowest yield of 5ia. Besides, substrate 3l
entry 5).
In view of the yields observed above, we chose DMF as the the product 5la in a high yield with a good dr value.
most promising solvent to optimize the various bases. As shown Next, we further investigated the structure effect of 2-aroyl-1-
with phenyl group was well tolerated in this reaction, producing
in Table 2, the yield of 5aa was remarkably dependent on the chlorocyclopropanecarboxylates 4 on the reaction. As shown in
properties of the bases used. Strong inorganic base like NaOH Table 3, the electronic nature of the Ar group couldn't obviously
could greatly promote this reaction, giving 5aa only in 23% yield inuence the product yields and the diastereomeric ratios,
(Table 2, entry 6). In contrast, a satisfactory result was achieved affording the products 5ab–5ae in high yields with good dr
when K3PO4 was employed (Table 2, entry 7). On the other hand, values, respectively. When the R1 group was replaced with
the common inorganic base K2CO3, the organic base Et3N and a small methyl group, the corresponding product 5af could be
strong organic base DBU (Table 2, entries 8, 9 and 10) were obtained in the highest yield and good dr value.
hardly able to promote this process.
As known to all, stereoselective construction of ACC subunits
With the optimized conditions of annulation reaction in is a challenging but demanding target. Encouraged by above
hand, we subsequently examined the substrate scope of this results, we chose substrates 4 containing chiral auxiliary to
reaction. First, the range of substrates 3 was investigated and the expand this protocol to the synthesis of chiral ACC subunits. To
observed results are summarized in Table 3. Under the optimal our delight, the substrates 4g–4i underwent a smooth trans-
reaction conditions, substrates 3a–3e with electron-donating formation to afford products 5ag–5ai in high yields and good dr
groups at the benzene ring afforded the products 5aa–5ea in values, respectively (Table 4).
good yields and good dr values, respectively. Among the
Based on the above observations, we proposed a possible
substrates 3f–3k with electron-withdrawing groups, the substrate reaction mechanism as shown in Scheme 2. The reaction could
3f with 2-uoro group afforded the highest yield and high dr
Table 4 Scope of the annulation reaction between 3a and 4a,b,c
Table 3 Scope of the annulation reaction between 3 and 4a,b,c
a
Reactions carried out using 0.10 mmol of 3, 0.11 mmol of 4 and
0.20 mmol of Cs2CO3c in 1.0 mL of DMF at room temperature.
b
Isolated yields given. Diastereomeric ratio (cis : trans) of the crude
product determined by 1H NMR.
a
Reactions carried out using 0.10 mmol of 3, 0.11 mmol of 4 and
0.20 mmol of Cs2CO3c in 1.0 mL of DMF at room temperature.
b
Isolated yields given. Diastereomeric ratio (cis : trans) of the crude
product determined by 1H NMR.
Scheme 2 A possible mechanistic process for the [4 + 2] annulation.
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proceed through a highly regioselective aza-Michael addition to
the strained C]C bond of the highly reactive cyclopropene
intermediate II, generated in situ in the presence of base. We
realize that the diastereoselectivity of the reaction may be
dominated by the coordination state of the intermediate 6.
Owing to the apparent steric hindrance, the coordination state 6
was converted into fused polycyclic intermediate 7 with high dr
value. Then 7 was subsequently protonated into the nal
product 5.
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