Bifunctional-Phosphine-Catalyzed Sequential Annulations of Allenoates and Ketimines: Construction of Functionalized Poly-heterocycle Rings

Article abstract of DOI:10.1002/anie.201605189

A highly stereoselective sequential annulation reaction between γ-substituted allenoates and ketimines was reported. By using bifunctional N-acyl aminophosphine catalysts, poly-heterocycle rings were obtained with high stereocontrol in good to excellent yields. The desired products have four contiguous stereogenic centers (one quaternary and three tertiary carbon centers), and only one isomer was obtained in all reactions.

Full text of DOI:10.1002/anie.201605189

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201605189
German Edition: DOI: 10.1002/ange.201605189
Organocatalysis
Bifunctional-Phosphine-Catalyzed Sequential Annulations of
Allenoates and Ketimines: Construction of Functionalized Poly-
heterocycle Rings
Erqing Li, Hongxing Jin, Penghao Jia, Xuelin Dong, and You Huang*
Abstract: A highly stereoselective sequential annulation reac-
tion between g-substituted allenoates and ketimines was
reported. By using bifunctional N-acyl aminophosphine cata-
lysts, poly-heterocycle rings were obtained with high stereo-
control in good to excellent yields. The desired products have
four contiguous stereogenic centers (one quaternary and three
tertiary carbon centers), and only one isomer was obtained in
all reactions.
S
equential annulations are one of the most powerful
methods for preparing structurally divergent polycyclic sys-
tems. Over the last decades, many chemists have devoted
efforts to develop a highly efficient strategy to construct these
polycyclic skeletons, which are widely found in natural
products with significant biological properties.[1] In this field,
the success is predominant at transition-metal-catalyzed
intramolecular annulation reactions.[2] Nevertheless, such
transition-metal-catalyzed reactions always rely on the use
of non-commercially available or expensive ligands and has
limited substrate scope, which severely restrict application in
organic and pharmaceutical synthesis. Thus, developing
a novel way to build the polycyclic systems in one step from
readily available starting materials remains necessary.
Nucleophilic phosphine-catalyzed annulation reactions
have been developed in laboratories worldwide.[3] Among
them, Luꢀs [3+2] annulations demonstrated that phosphines
are good catalysts for the construction of five-member
carbocyclic and heterocyclic skeletons [Scheme 1, Eq. (1)].[4]
Later, Kwon and co-workers developed the [4+2] annulations
to build six-membered cyclic compounds [Scheme 1,
Eq. (2)].[5] In 2010, Tongꢀs group developed a [4+1] annula-
tion reaction, which demonstrated that allenoates could work
as 1,4-biselectrophiles and four-atom units [Scheme 1,
Eq. (3)].[6] In 2013, Huangꢀs group was first to develop
phosphine-catalyzed [4+2] annulations with g-benzyl alle-
noates [Scheme 1, Eq. (4)].[7] In 2003, Krische and co-workers
developed the first intramolecular [3+2] annulations and
applied it in total synthesis of (Æ)-Hirsutene.[8] Shortly
Scheme 1. Phosphine-catalyzed domino annulation reaction of alle-
noates.
afterwards, phosphine-catalyzed intramolecular annulation
reactions were developed by Tang, Kwon, and other groups.[9]
Recently, our group developed a series of phosphine-cata-
lyzed sequential annulation reactions to build the bicyclic
compounds by intermolecular way.[10] No examples of asym-
metric annulation reaction have been developed to build
polycyclic compounds by intermolecular sequential annula-
tions to date. This is because of the existence of some
challenges: 1) Complex products are often formed in these
reactions; 2) sequential chiral centers increase the difficulty in
steric-control; and 3) multiple diastereoisomers are often
obtained in these reactions. As part of our interest in
asymmetric phosphine catalysis,[11] we aimed to design
sequential annulation strategy for construction polycyclic
compounds with high diastereoselectivity and enantioselec-
tivity by selecting an appropriate chiral catalyst.
[*] E. Li, H. Jin, P. Jia, X. Dong, Prof. Y. Huang
State Key Laboratory and Institute of Elemento-Organic Chemistry
Nankai University, Tianjin 300071 (China)
E-mail: hyou@nankai.edu.cn
Prof. Y. Huang
Poly-heterocyclic compounds containing dihydropyrrole
skeleton represent an important structural motif featured in
bioactive molecules and natural products.[12] For example, the
alkaloid nakadomarin A,[1e–g,12c] the melodinus alkaloids
isolated from either Apocynaceae or Kopsia species, Melo-
Collaborative Innovation Center of Chemical Science and
Engineering (Tianjin)
Tianjin 300071 (China)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201605189.
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scine.[1h] Thus a lot of methods were developed to synthesize
these compounds, including organic-catalyst-catalyzed annu-
lation reactions.[13] To the best of our knowledge, synthesizing
a chiral poly-heterocyclic skeleton through sequential annu-
lation method by a chiral phosphine catalyst has been rarely
reported.[14] Given the importance of these molecules, we
designed chiral-phosphine-catalyzed sequential [2+3]/[3+2]
annulation reaction between g-benzyl allenoates and keti-
mines derived from saccharin. We envisaged that by the
introduction of phenyl to allenoates could stabilize g-
methyene anion of allenoates, the normal Lu [3+2] reaction
could be prevented. On the other hand, allenoates has
multiple reactive sites. However, from previous experience,
only two sites of allenoates could take part in the formation of
chemical bonds in one reaction. We envisaged that more sites
of allenates could take part in the formation of bonds by using
suitable electrophilic reagent. In our previous work, g-methyl
substitution of allenoates could take part in the formation of
chemical bonds with salicyl N-thiophosphinyl imines as the
C2 synthon.[15] We wondered whether another nucleophilic
addition could take place by using ketimines derived from
saccharin after the first [2+3] cyclizations instead of normally
regenerating catalyst to obtain products (Scheme 2). Herein,
Table 1: Screening of catalysts and optimization of the reaction con-
ditions.[a]
Entry
Cat. [%]
Solvent
T [h]
Yield [%][b]
ee [%][c]
1
2
PPh3
CHCl3
CHCl3
CHCl3
toluene
CH2Cl2
THF
CH3CN
(CH2Cl)2
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
1
9
144
144
5
82
74
74
80
76
99
74
45
57
47
78
91
trace
80
26
66
83
–
–
85
86
66
46
51
54.5
60
59
72
50
89
–
4a (20)
4a (20)
4a (20)
4a (20)
4a (20)
4a (20)
4a (20)
4b (20)
4c (20)
4d (20)
4e (20)
4 f (20)
4g (20)
4h (20)
4i (20)
4j (20)
4a (20)
4a (10)
3[d]
4
5
6
7
8
3
5
72
9
96
22
4
96
4
36
3
9
10
11
12
13
14
15
16
17
18[e]
19
92.5
45
À54
48
–
4
9d
9d
–
–
[a] All reactions were carried out using 0.05 mmol in a solvent (0.5 mL)
at RT unless otherwise noted. The ratio of 1a:2a was 1:2. [b] Yields of
isolated products; no other isomers were detected by 1H NMR.
[c] Determined by HPLC analysis on a chiral stationary phase. [d] Reac-
tion at 08C. [e] PhCOOH (20%) was added.
in 74% yield and 85% ee (Table 1, entry 2). Encouraged by
this result, we screened various solvents and found that
chloroform was the best solvent (Table 1, entries 3–8). Low-
ering the reaction temperature to 08C, no better result was
received (Table 1, entry 3). To optimize the reaction con-
ditions, a series of chiral catalysts derived from a-amino acids
were used, and the application of catalyst 4g gave both high ee
values (92.5%) and yield (80%; Table 1, entries 14 vs. 9–13,
15–17). Catalyst 4 f with the most acidic NH-functional group
gave no desired product (Table 1, entry 13). Further studies
suggested that adding the additive (PhCO2H,) or decreasing
the amount of catalysts inhibited the reaction (Table 1,
entries 18, 19). It should be addressed that the sequential
annulation reaction was completely regioselective and highly
diastereoselective (only one isomer was detected in all
reactions).
Scheme 2. Strategies for sequential annulations.
we document a novel phosphine-catalyzed sequential [2+3]/
[3+2] annulation reaction between g-benzyl substituted
allenoates and ketimines derived from saccharin, leading to
highly enantioselective construction of cyclopenta-
[b]dihydropyrrole architectures. In this reaction, we success-
fully solved the problem of diastereoselectivity and stereose-
lectivity in this reaction, obtaining a series of poly-hetero-
cyclic skeletons including four contiguous stereogenic centers
with high diastereoselectivity and stereoselectivity.
Based on our previous work, we initiated the study by
investigating the reaction between the 1-azadiene 1a and g-
benzyl allenoates 2a by using triphenylphosphine as the
catalysts. To our delight, the reaction proceeded smoothly in
chloroform at room temperature (Table 1, entry 1). The chiral
phosphine 4a derived from l-phenylalanine[16] as catalyst was
used in the reaction, and the desired product 3a was obtained
Having established the optimal conditions, we were first
to explore the generality of this reaction with a variety of g-
substituted allenoates, and the results are shown in Table 2.
The reaction was tolerant of a broad range of allenoates
2
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Table 2: Enantioselective [2+3]/ [3+2] cycloadditions of g-substituted
allenoates 2 and ketimine 1a.[a]
Table 3: Enantioselective [2+3]/ [3+2] cycloadditions of g-substituted
allenoates 2 and ketimine 1.[a]
Entry
Ar
R1
T [h]
Yield [%][b]
ee [%][c]
Entry
R2
R3
T [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
C6H5
C6H5
Et
Bn
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
4
18
4
4
2
4
2
4
80
59
98
85
89
70
98
95
73
98
93
97
92.5
91
90
93
97
88
82
81
87
90
90
88
1
2
3
4
5
6
7
8
4-CN
2-Me
5-piperonyl
4-F
4-Cl
2.4-Cl2
3,4-Me2
3-Me
2-Br
2-F
H
H
H
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
85
91
57
67
98
78
90
49
66
51
98
60
91
86
48
90
85
53
99
94
88
90
89
87
96
91
90
84
92
86
98
90
92
90
83
91
4-MeC6H4
4-OMeC6H4
4-ClC6H4
3-FC6H4
3-OMeC6H4
5-piperonyl
2-MeC6H4
2-FC6H4
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-CN
9
24
24
4
10
11
12
9
1-naphthyl
2-naphthyl
10
11
12
13
14
15
16
17
18
2
2-Me
5-piperonyl
1-naphthyl
2-naphthyl
2-thienyl
2-furyl
4-CN
[a] All reactions were carried out using 0.05 mmol in a solvent (0.5 mL)
at RT unless otherwise noted. The ratio of 1a:2a was 1:2. [b] Yields of
isolated products; no other isomers were detected by 1H NMR.
[c] Determined by HPLC analysis on a chiral stationary phase.
1-naphthyl
derived from 3-aryl propionyl chloride, and those with either
electron-withdrawing or electron-donating groups on an
aromatic ring moiety resulted in high yields and ee values
(Table 2). Allenoates with electron-withdrawing groups (such
as 4-Cl, 3-F, 2-F) on the phenyl ring exhibited higher
enantioselectivity (Table 2, entries 5, 6, 10), with 5-(4-chlor-
ophenyl)penta-2, 3-dienoates giving highest enantioselectiv-
ity (table 2, entry 5). In contrast, strong electron-donating (5-
(benzo[d][1,3]dioxol-5-yl)penta-2, 3-dienoate) lowered the
enantioselectivity to 81% ee (Table 2, entry 8). The steric
properties of the g-benzyl allenoates 2 have a slight effect on
the reaction, and reaction of benzyl 5-phenylpenta-2,3-
dienoate gave similar enantioselectivity, albeit with lower
yield (Table 2, entry 2). However, the positions of substituent
at the aromatic ring have certain influence, and substituents at
the meta-position resulted in low ee values (Table 2, entries 6–
8). Furthermore, 1-naphthyl and 2-naphthyl allenoates also
showed very high enantioselectivity (Table 2, entries 11, 12).
Next, we examined the scopes of the sequential annula-
tion reaction with a series of 1-azadiene, and the results are
[a] All reactions were carried out using 0.05 mmol in a solvent (0.5 mL)
at RT unless otherwise noted. The ratio of 1a:2a was 1:2. [b] Yields of
isolated products; no other isomers were detected by 1H NMR.
[c] Determined by HPLC analysis on a chiral stationary phase.
In summary, we have developed a novel chiral phosphine-
catalyzed sequential annulation reaction between g-benzyl
allenoates and ketimines derived from saccharin. Highly
stereoselectivity and yields could be obtained in most cases
(up to 99% ee and up to 98% yield). It should be noted that
we are first to report an asymmetrical intermolecular method
to obtain poly-heterocyclic products by using chiral phos-
phine catalyst and the desired products gave four-contiguous
stereogenic centers (one quaternary and three tertiary
carbon), and only one isomer was obtained in all reactions.
We are currently investigating the asymmetric synthesis of
other heteroatom-containing ring systems by extending the
strategy developed herein.
shown in Table 3. The reactions were applicable to a wide Experimental Section
Compound 1 (0.05 mmol) and 2 (0.1 mmol) in 0.5 mL CHCl3 were
range of ketimines bearing different aromatic groups, regard-
less of the steric and electronic properties of the substituents
on the aromatic ring (Table 3, entries 1–13). Furthermore,
a lower yield was obtained when the meta-substituent group
was employed (Table 3, entry 8). 1-Naphthyl, 2-naphthyl, 2-
furyl, and 2-thiophenyl-containing substrates were also exam-
ined, and the reaction could proceed smoothly to receive the
desired products with high stereoselectivity (Table 3,
entries 14–17). It should be noted that only one isomer was
produced in all these reactions. The structure and stereo-
chemistry of 3 were determined using a combination of NMR
spectroscopy, HPLC, HRMS, and single-crystal X-ray analy-
sis (3a).[17]
added to a dry flask filled with nitrogen. Chiral bifunctional catalyst
4g (0.01 mmol) was added. This solution was stirred at room
temperature until the complete consumption of the starting material
as monitored by TLC. After the removal of the solvent, the residue
was subjected to chromatography on a silica gel column (60–120
mesh) using 10:1 petroleum ether–ethyl acetate solvent mixture as
eluent to afford 3.
Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China (21472097, 21172115), the
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Education of China (20120031110002).
Keywords: allenoates · bifunctional phosphines ·
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Received: May 27, 2016
Published online: && &&, &&&&
4
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E. Li, H. Jin, P. Jia, X. Dong,
Y. Huang*
&&&& — &&&&
Bifunctional-Phosphine-Catalyzed
Sequential Annulations of Allenoates and
Ketimines: Construction of
Functionalized Poly-heterocycle Rings
A highly stereoselective sequential annu-
lation reaction between g-substituted
allenoates and ketimines is presented.
Using bifunctional N-acyl aminophos-
phine catalysts, poly-heterocycle rings
were obtained in good to excellent yields.
The desired products have four contigu-
ous stereogenic centers (one quaternary
and three tertiary carbon centers), and
only one isomer was obtained in all
reactions.
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
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