Organocatalytic Enantioselective Synthesis of Tetrasubstituted α-Amino Allenoates by Dearomative γ-Addition of 2,3-Disubstituted Indoles to β,γ-Alkynyl-α-imino Esters

Article abstract of DOI:10.1002/anie.201911420

The first asymmetric synthesis of tetrasubstituted α-amino allenoates by a chiral phosphoric acid catalyzed dearomative γ-addition reaction of 2,3-disubstituted indoles to β,γ-alkynyl-α-imino esters is reported. This method provides access to a series of

Full text of DOI:10.1002/anie.201911420

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Accepted Article
Title: Organocatalytic Enantioselective Synthesis of Tetrasubstituted
α-Amino Allenoates by Dearomative γ-Addition of β,γ-alkynyl-α-
imino esters and 2,3-disubstituted indoles
Authors: Junxian Yang, Zheng Wang, Zeyuan He, Guofeng Li, Liang
Hong, Wangsheng Sun, and Rui Wang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201911420
Angew. Chem. 10.1002/ange.201911420
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10.1002/anie.201911420
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Organocatalytic Enantioselective Synthesis of Tetrasubstituted α-
Amino Allenoates by Dearomative γ-Addition of β,γ-alkynyl-α-
imino esters and 2,3-disubstituted indoles
Junxian Yang,[a] Zheng Wang,[b] Zeyuan He,[a] Guofeng Li,[c] Liang Hong,[c] Wangsheng Sun*[a] and Rui
Wang*[a]
Abstract: The first asymmetric synthesis of tetrasubstituted α-amino
allenoates by chiral phosphoric acid catalyzed dearomative γ-
addition reaction of 2,3-disubstituted indoles to β,γ-alkynyl-α-imino
esters is reported. This methodology allows access to a series of
highly functionalized tetrasubstituted allenes featuring adjacent
quaternary stereocenter in high yields, with excellent regio-,
diastereo-, and enantioselectivities under mild conditions without
generation of any waste. The representative large-scale reactions
and diverse transformations of products to various scaffolds with
potential biological activities render it more attractive. Moreover, the
mechanism of the reaction was disclosed by control reaction and
DFT calculations.
(Figure 1).[1] Accordingly, the synthesis of enantioenriched
allenic compounds has inspired ample interest,[2] thus resulting
in a variety of strategies towards their construction, such as
chirality transfer from enantioenriched propargylic derivatives,[3]
resolution of racemic allenes,[4] asymmetric synthesis of chiral
allenes based on metal catalysis[5] and organocatalysis.[6]
Despite these graceful efforts, most of the cases enabled
constructing the allenes with relatively limited types of
substituents and atomic economy. Therefore, it is urgently
needed to develop a novel and direct strategy to achieve
asymmetric construction of multifunctional tetrasubstituted chiral
allenes.
Axially chiral allenes and derivatives are ubiquitous not only in
natural products, pharmaceutical compounds and functional
materials, but also as key intermediates in organic synthesis
Figure 1. Biologically active compounds featuring allenic group.
[a]
Dr. J. Yang, Z. He, Prof. Dr. W. Sun, Prof. Dr. R. Wang
Key Laboratory of Preclinical Study for New Drugs of Gansu
Province, Institute of Drug Design & Synthesis, Institute of
Pharmacology, School of Basic Medical Sciences
Lanzhou University
Scheme 1. Reaction development ofβ,γ-alkynyl-α-imino esters.
On the other hand, nonproteinogenic amino acids are vital
synthetic building blocks of biologically active natural products
and novel non-natural peptides with improved potency and
increased the ability of resistance towards protease degradation
under physiological conditions.[7] β,γ-Alkynyl-α-imino esters have
been recognized as potential useful precursors for the synthesis
alkynyl or alkenyl α-amino acids derivatives for more than a
decade.[8] Surprisingly, however, very limited success has been
achieved using this building block, probably due to its multiple
reactive sites. For instance, Shimizu et al. reported an umpolung
N-addition to β,γ-alkynyl α-imino esters followed by nucleophilic
α- or γ-acylation for the synthesis of α-quatenary alkynyl amino
199 West Donggang Rd, Lanzhou 730000, Gansu, P. R. China.
E-mail: sunws@lzu.edu.cn; wangrui@lzu.edu.cn
Dr. Z. Wang
Guangdong Key Lab of Nano-Micro Material Research, School of
Chemical Biology and Biotechnology, Peking University Shenzhen
Graduate School, Shenzhen 518055, China.
Dr. G. Li, Prof. Dr. L. Hong
School of Pharmaceutical Sciences
Sun Yat-sen University
Guangzhou 510006, P. R. China
[b]
[c]
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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10.1002/anie.201911420
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esters and allenoates (Scheme 1, path a).[8a] Meanwhile,
Ishihara et al. developed a regio- and diastereoselective C-alkyl
addition to chiral β,γ-alkynyl α-imino esters using a Grignard
reagent (RMgX)-derived zinc(II)ate to construct optically active
α-quaternary alkynyl amino acid derivatives (Scheme 1, path
b).[8b] More recently, the same group has accomplished an
enantioselective aza-Friedel-Crafts reaction of 2-methoxyfuran
with β,γ-alkynyl-α-imino esters through the use of a chiral
Brønsted acid catalyst, albeit with only one successful case.[8c]
Nevertheless, a direct γ-addition of a nucleophile to β,γ-alkynyl-
α-imino esters to form α-quatenary amino allenoates has never
been disclosed (Scheme 1, path c).
improved to 96% when the amount of substrate 1a was
increased to 1.2 equiv along with a slightly lower ee value.
Further investigation revealed that lowering the reaction
temperature was beneficial for improving the enantioselectivity
(Table 1, entry 17-18). Ultimately, we recognized that the axially
chiral α-amino allenoates 4a could be obtained in 96% isolated
yield with > 20:1 dr and 98% ee when the reaction was run at
0 °C with catalyst 3l (10 mol%) and solvent DCE (0.05 M) (Table
1, entry 18). It was noteworthy that, in addition to replacing the
catalyst with 3e, the products with the opposite configuration
could also be acquired with excellent efficiencies (92% yield,
18:1 dr, - 97% ee) under the optimum conditions.
Table 1. Optimization of the Reaction Conditions.a
In this context, as part of our recent interests in unnatural
amino acid synthesis[9] and indole chemistry[10], we first chose
indole as nucleophilic reagent to react with β,γ-alkynyl-α-imino
ester. As a result, only the α-addition reaction occurs, which is
consistent with the above precedents. Considering the steric
hindrance may has an effect on the regioselectivity of the
reaction, we replaced the nucleophilic reagent with 2,3-
disubstituted indoles[11] in order to explore a new synthetic route
to valuable tetrasubstituted α-amino allenoates. However,
several challenges have to be considered: 1) the choice of an
appropriate catalytic system to effective control of the
regioselectivity, diastereoselectivity and enantioselectivity, 2) the
formation of a vicinal all-carbon quaternary stereocenter, 3) the
construction of a highly functionalized tetrasubstituted allene and
4) overcoming energy barriers caused by dearomatization.
Considering the significant advantages of chiral phosphoric acid
in the realm of asymmetric catalysis,[12,13,10a,10b] we hypothesized
that a double-activation mode by hydrogen bonding could be
applied to promote asymmetric γ-addition of 2,3-disubstituted
indoles to β,γ-alkynyl-α-imino esters. If successful, this
formidably challenging process would provide an attractive
approach for efficient synthesis for fully substituted chiral α-
amino allenoates.
Entry
Cat
Solvent
T(℃)
t(h) Conv(%)b
dr b
ee(%)c
1
2
3a
3b
3c
3d
3e
3f
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
CHCl3
Tol.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
90
90
1:1
6:1
-43/44
-93
-97
-82
-96
-90
-3/44
84
We began our investigations by using the β,γ-alkynyl-α-imino
esters 2a in combination with 2,3-dimethylindole 1a as a
nucleophile in the presence of a catalyst 3 with 3 Å MS as an
additive[14] (Table 1). As expected, the reaction proceeded
smoothly at room temperature in the presence of catalyst 3a,
providing allene 4a in satisfactory conversion within 6 h, albeit
with poor selectivity (Table 1, entry 1). Some other catalysts with
different scaffold were then evaluated. It was found that the
chiral backbone and the steric environment of the catalysts have
very strong influence on the diastereoselectivity and
enantioselectivity (Table 1, entries 2−12). Pleasingly, we found
that the use of 3l resulted in quantitative conversion of 1a and
excellent diastereoselectivity, although the enantioselectivity of
4a is not the highest (Table 1, entry 12). Notably, the 4a with the
3
95
6:1
4
85
10:1
15:1
5:1
5
> 99
92
6
7
3g
3h
3i
70
1:1
8
80
5:1
9
89
4:1
-99
92
10
11
12
13
14
15
16
3j
> 99
70
2:1
3k
3l
3:2
-17/3
95
opposite configuration could be synthesized in
> 99%
> 99
97
> 20:1
20:1
15:1
2:1
conversion with 96% ee and 15:1 dr when 3e was used as a
catalyst (Table 1, entry 5). Encouraged by these promising
results, we then evaluated various solvents and a significant
solvent effect was observed (Table 1, 12 - 16). The reaction has
the worst outcome (7% ee, 2:1 dr) when THF was used as the
solvent, while DCE was the most ideal for the reaction, affording
4a in 88% yield , > 20:1 dr and 99% ee. The yield could be
3l
84
3l
93
82
3l
THF
80
77
3l
DCE
> 99(88) d
> 20:1
99
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10.1002/anie.201911420
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17e
18e
19e
3l
3l
DCE
DCE
DCE
r.t.
0
6
> 99(96) d
> 99(96) d
> 99(92) d
> 20:1
> 20:1
18:1
96
98
To further study the scope of this catalytic system, we then
evaluated the reaction of 2,3-dimethylindole with various β,γ-
alkynyl-α-imino esters (Scheme 3). The catalytic system proved
to be suitable for the γ-addition of β,γ-alkynyl-α-imino esters with
10
10
3e
0
-97
either electron-donating (4o
- 4s) or electron-withdrawing
aUnless otherwise stated, the reaction was carried out with 1a (0.07 mmol), 2a
(0.07 mmol), 3 (0.007 mmol) and 3 Å molecular sieves (70 mg) in 1.4 ml of the
solvent. bDetermined by 1H NMR analysis of the crude reaction mixture. cEe of
the major product was determined by HPLC using a chiralcel stationary phase.
substituents (4t - 4v) present in the phenyl ring at R3 group,
giving rise to the allenoates with ee values generally higher than
95%. Furthermore, not only bulky naphthyl groups (4w, 4x) but
also heterocycle (4y), alkenyl (4z, 4aa), alkyl (4ab) could be
incorporated into the reactions. It is particularly noteworthy that
this protocol can also be applied to side chain modification of
Cbz-Tyr-OBn to construct new diaminodiacid derivative with
different types of protective groups (4ac, 91% yield, 16:1 dr,
95% ee). Similarly, late-stage installation to an estrone-derived
complex molecule (4ad, 92% yield, 18:1 dr, 91% ee) could be
achieved. By this means, we might introduce complex active
molecules into amino acid molecules. In addition, the reactions
were also applicable to β, γ-alkynyl-α-imino esters with N-Cbz,
COOMe or COOBn substitution, producing the corresponding
products 4ae - 4ag in outstanding results.
d
Isolated yield of the major product was given in the parentheses. eThe
reaction was carried out with 1a (0.084 mmol), 2a (0.07 mmol).
With the established optimal conditions, we next investigated
the substrate scope of the dearomative γ-addition reaction of
2,3-disubstituted indoles with β,γ-alkynyl-α-imino esters. In
general, the protocol was applicable to a wide range of 2,3-
disubstituted indoles 1, affording the desired products in
moderate to excellent yields (69 − 99%), dr (9:1 - >20:1) and
excellent ees (91 − 99%)(Scheme 2). Representative 2,3-
dimethyl indoles with different electronic substituents at C5
position were all tolerated to give the corresponding products 4a
– 4f in 96 - 98% yields, >20:1 dr with 99% ee. 2,3-Disubstituted
indoles with various substitutions at C2 and C3 positions were
also examined, and exhibited high efficiency in the reaction (4g
–
4n). Notably, the cyclic tetrahydrocarbazole and
hexahydrocyclohepta[b]indole participated smoothly in the
desired reaction, affording the polycyclic product 4m – 4n with
moderate to excellent yield, diastereoselectivity with excellent
enantioselectivity. The absolute stereochemistry of the products
4 were assigned by analogy to 4i, which was determined
unambiguously by X-ray crystallographic analysis[15]
.
Scheme 3. Scope of β,γ-alkynyl-α-imino esters.a aUnless otherwise stated, the
reaction was carried out with 1a (0.084 mmol), 2a (0.07 mmol), 3l (0.007
mmol) and 3 Å molecular sieves (70 mg) in 1.4 ml of DCE for 10 h. The yield
refers to the isolated yield of the major product. Dr was determined by 1H NMR
analysis of the crude reaction mixture. Ee was determined by HPLC using a
chiralcel stationary phase. bThe reaction was carried out for 14 h. cThe reaction
was carried out for 6 h.
Scheme 2. Scope of the disubstituted indoles.a aUnless otherwise stated, the
reaction was carried out with 1a (0.084 mmol), 2a (0.07 mmol), 3l (0.007
mmol) and 3 Å molecular sieves (70 mg) in 1.4 ml of DCE for 10 h. The yield
refers to the isolated yield of the major product. Dr was determined by 1H NMR
analysis of the crude reaction mixture. Ee was determined by HPLC using a
chiralcel stationary phase. bThe reaction was carried out for 6 h. cThe reaction
was carried out for 14 h.
To demonstrate the potential scalability and utility of this
protocol, we conducted a gram-scale reaction with 1a and 2a
under the standard reaction conditions (Scheme 4a). Gratifyingly,
the reaction proceeded smoothly and product 4a was isolated
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10.1002/anie.201911420
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without significant erosion of yield, diastereoselectivity, and
role in the reaction, possibly by generation of spatial steric
hindrance.
enantioselectivity. Furthermore,
a series of representative
transformations of the products 4a and 4i were also carried out.
In the presence of catalyst diphenyl phosphates and Hantzsch
esters 8, 4i and 4a could be straightforward transformed into
tetrahydrocyclopenta[b]indoline 5 and 4H-1,4-methanoquinoline
6 with perfect diastereoselectivities (d.r. > 20:1) and moderate
yields (76% and 58%)(Scheme 4b and 4c). These two products
might serve as candidates or building blocks of biologically
active molecules.[16] Notably, the N-Boc protecting group in 6
could be removed to give product 7 bearing a free amino group
in 94% yield (Scheme 4c). Furthermore, subjecting 4a to a Pd/C
In an effort to better understand the reaction profile, density
functional theory (DFT) calculations at the the M06-2X/6-
311+G(d,p)-PCM
(dichloroethane)//B3LYP/6-31G(d)-PCM
(dichloroethane) level of theory were carried out[17].It revealed
that a kinetically favored transition state of TSBC-R (Figure 2. For
more details, see the SI) could be formed during the reaction.
The phosphoric acid moiety of the catalyst plays a bifunctional
role for activation of both partners via H-bond interaction and the
steric chiral backbone of the catalyst controls the
stereoselectivity via steric effect and π-πinteraction.
catalyzed
reduction
reaction
afforded
hexahydrocyclopenta[b]indoline 9 in 39% yield and >20:1 dr
under H2 atm (Scheme 4d). In addition, 10 was formed by
treating 4a with AcCl in DCM without any loss of enantiopurity
(Scheme 4e).
Figure 2. The geometrical structures of TSBC-R (left) and proposed transition
state (right).
Scheme 4. Gram-scale Preparation of 4a and Representative Transformations
of Products 4.
Scheme 5. Control experiments.
To get an insight of this reaction, control experiments were
performed (Scheme 5). Under the above optimized reaction
conditions, in contrast to the above high efficiency of the
reaction, moderate yield and enantioselectivity of γ-addition
product 12 was obtained when 3-methyl indole was used
(Scheme 5a), while only α-addition product 14 was formed when
2-methyl indole was used (Scheme 5b). It indicated that the
steric hindrance of the C3 substituents of indoles is vital for the
selectivity of α or γ-addition to β, γ-alkynyl-α-imino esters 2a,
meanwhile, the C2 substituent of indoles is beneficial for its
enantioselectivity. In addition, when an alkynyl trifluoromethyl
ketimine was subjected to the reaction, only the α-addition
product 16 was still prepared (Scheme 5c), thus implying that
the COOR group of the β,γ-alkynyl-α-imino esters plays a crucial
In summary, we have developed a chiral phosphoric acid
catalyzed asymmetric dearomative γ-addition reaction of 2,3-
disubstituted indoles with β,γ-alkynyl-α-imino esters, which
represented the first example of synthesis chiral tetrasubstituted
α-amino allenoates featuring adjacent quaternary stereocenters
with outstanding efficiencies, ample reaction scope and high
atom economy. The resultant amino allenoates could be easily
converted into other important building blocks as exemplified by
the synthesis of the cyclopenta[b]indolines and 4H-1,4-
methanoquinoline. Furthermore, the reaction mechanism was
investigated by control reactions and DFT calculations.
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10.1002/anie.201911420
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Acknowledgements ((optional))
[7]
[8]
We are grateful for financial support from NSFC (21432003,
21502079, 21572278, 21907111), the Fundamental Research
Funds for the Central Universities (lzujbky-2018-95, lzujbky-
2019-kb11) and China Postdoctoral Science Foundation Grant
(No. 2018M631240).
Keywords: allenes • α-amino acid • disubstituted indoles • γ-
addition • organocatalysis
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10.1002/anie.201911420
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Junxian Yang, Zheng Wang, Zeyuan He,
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Organocatalytic Enantioselective
Synthesis of Tetrasubstituted α-
Amino Allenoates by Dearomative γ-
Addition of β,γ-alkynyl-α-imino esters
and 2,3-disubstituted indoles
The first asymmetric synthesis of tetrasubstituted α-amino allenoates by chiral
phosphoric acid catalyzed dearomative γ-addition reaction of 2,3-disubstituted
indoles to β,γ-alkynyl-α-imino esters is reported. This methodology allows access to
a series of highly functionalized tetrasubstituted allenes featuring adjacent
quaternary stereocenter in high yields, with excellent regio-, diastereo-, and
enantioselectivities.
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