Versatile enantioselective [3+2] cyclization between imines and allenoates catalyzed by dipeptide-based phosphines

Article abstract of DOI:10.1002/anie.201106672

A fast one: The title reaction proceeds in the presence of 5 mol % of the catalyst 1, and is complete within an hour. The 2-alkyl- and 2-aryl-substituted 3-pyrroline products are obtained in good yield and with high enantioselectivity. The application of the method to the concise formal synthesis of (+)-trachelanthamidine is also demonstrated. Boc=tert- butoxycarbonyl, M.S.=molecular sieves, TBDPS=tert-butyldiphenylsilyl. Copyright

Full text of DOI:10.1002/anie.201106672

Angewandte
Chemie
DOI: 10.1002/anie.201106672
Organocatalysis
Versatile Enantioselective [3+2] Cyclization between Imines and
Allenoates Catalyzed by Dipeptide-Based Phosphines**
Xiaoyu Han, Fangrui Zhong, Youqing Wang, and Yixin Lu*
Optically pure five-membered N-heterocycles are valuable
intermediates in chemical synthesis, and they are also
prevalent structural motifs in bioactive molecules and natural
products.[1] Over the past decade, many synthetic methods
have been devised for the construction of such ring systems.[2]
In this context, [3+2] cyclization of imines with allenes or
alkynes is one of the most straightforward and efficient
methods for the creation of pyrrolines[3] and pyrrolidines,[4]
which are classes of compounds that are of synthetic and
biological importance. In 1997, Xu and Lu disclosed the [3+2]
cycloadditions between imines and alkynes or allenes for the
synthesis of pyrroline rings.[5] However, asymmetric variants
of these phosphine-catalyzed [3+2] cyclizations only
appeared almost a decade later. The groups of Marinetti
and Gladysz independently reported chiral-phosphine-trig-
gered asymmetric [3+2] annulations of allenes with N-tosyl
imines, thus affording functionalized 3-pyrrolines with mod-
erate enantioselectivity.[6] The breakthrough came when Fang
and Jacobsen introduced phosphinothiourea catalysis of the
imine–allene cyclization; by utilizing diphenylphosphinoyl
(DPP) imines,[7] substituted 2-aryl-2,5-dihydropyrroles were
formed in good yields and with excellent enantioselectiv-
ities.[8] Despite all the above advances, the utilization of
aliphatic imines in phosphine-catalyzed [3+2] cycloaddition
reaction remains elusive.[9] Aliphatic imines are challenging
substrates because of their isomerizable nature[10] and relative
instability. Nonetheless, their synthetic value is remarkable.
Apparently, accessing five-membered N-heterocycles through
cycloaddition reactions of aliphatic imines holds significant
synthetic utility. As illustrated in Scheme 1, pyrrolidines with
2-alkyl substituents are very common substructures in bioac-
tive molecules and natural products.[11]
Scheme 1. Pyrrolidine-containing bioactive molecules. Bn=benzyl.
using l-threonine-derived phosphine sulfonamides[13] and
phosphine thioureas,[14] respectively. We also demonstrated
that dipeptide-derived phosphines were powerful catalysts for
promoting enantioselective [3+2] cycloadditions of allenes to
acrylates or acrylamides.[15] Very recently, we discovered that
l-threonine-derived phosphine thioureas were capable of
promoting MBH carbonates as C3 synthons in the [3+2]
cyclization.[16] Given the relative instability of aliphatic
imines, we reasoned that highly reactive phosphines are
probably necessary for their effective activations in the
cycloaddition reaction, since potential decomposition of
imines may be avoided. It is noteworthy that our amino-
acid-based phosphines possess remarkably high nucleophilic-
ity. We hypothesized that employment of highly nucleophilic
bifunctional phosphines may result in a practical asymmetric
[3+2] annulation protocol in which alkyl imines can be
conveniently utilized (Scheme 2).
We recently embarked on an exciting adventure of
developing amino-acid-based bifunctional phosphines and
their applications in asymmetric organic transformations.[12]
We showed that highly enantioselective aza-Morita–Baylis–
Hillman (MBH) and MBH reactions could be realized by
The [3+2] cycloaddition between the DPP imine 1a and
tert-butyl allenoate 2 was selected as a model reaction for the
initial explorations (Table 1). For the catalysts, we chose to
focus on dipeptide-based bifunctional phosphines, which were
shown to be highly efficient in our previous studies.[15a] To our
[*] X. Han, F. Zhong, Prof. Dr. Y. Lu
Department of Chemistry & Medicinal Chemistry Program
Life Sciences Institute, National University of Singapore
3 Science Drive 3, Singapore 117543 (Singapore)
E-mail: chmlyx@nus.edu.sg
Prof. Dr. Y. Wang
Provincial Key Laboratory of Natural Medicine and
Immuno-Engineering, Henan University
Jinming Campus, Kaifeng, Henan, 475004 (China)
[**] We thank the National University of Singapore (R-143-000-469-112)
for generous financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201106672.
Scheme 2. Phosphine-triggered [3+2] cyclization of imines with alle-
noates.
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Table 1: Screening of reaction conditions.[a]
system accelerated the reaction, however, the enantioselec-
tivity was descreased (entry 14).[18] When the reaction was
carried out at 08C for 30 minutes in the presence of 5 mol%
of 7d and molecular sieves, the imine–allene cycloaddition
product was obtained in 92% yield with 96% ee (entry 15).
Having established the optimal reaction conditions for the
preparation of 3-pyrroline, the substrate scope for 7d-
catalyzed [3+2] cyclization was then investigated (Table 2).
A wide range of alkyl imines could be employed, and the
enantioselectivity of the reaction was independent to the alkyl
Table 2: Enantioselective [3+2] cycloaddition of allenoates with aliphatic
DPP imines catalyzed by 7d.[a]
Entry
R
Product
Yield [%][b]
ee [%][c]
Entry
Cat.
Solvent
t [min]
Yield [%][b]
ee [%][c]
1
2
3
3b
3c
3d
75
78
80
95
96
97
1
2
3
4
5
6
7
8
4
5
6
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
Et2O
DME
Et2O
Et2O
3
3
3
3
3
3
3
3
3
3
3
10
20
12
30
88
91
86
91
90
88
90
85
91
87
92
91
89
81
92
À11
À88
À82
92
85
89
92
86
93
91
4
5
6
7
3e
3 f
84
85
82
81
97
97
96
95
7a
7b
7c
7d
7a
7a
7a
7d
7d
7d
7d
7d
3g
3h
8
9
3i
3j
90
81
95
99
9
10
11
12[d]
13[d,e]
14[e,f]
15[d,g]
94
95
96
92
10
11
3k
3l
83
81
99
96
Et2O
Et2O
Et2O
96
[a] Reactions conditions: 1 (0.1 mmol), 2 (0.15 mmol), and 7d
[a] Reaction conditions: 1a (0.05 mmol), 2 (0.075 mmol), and the
catalyst (0.005 mmol) in toluene (0.5 mL) at room temperature. [b] Yield
of isolated product. [c] The ee value was determined by HPLC analysis
using a chiral stationary phase. [d] 5 ꢀ molecular sieves were added.
[e] The reaction was performed at 08C. [f] H2O (20 mol%) was added.
[g] The catalyst loading was 5 mol%. Boc=tert-butoxycarbonyl,
DME=dimethyl ether, TBDPS=tert-butyldiphenylsilyl, TBS=tert-butyl-
dimethylsilyl, TDS=thexyldimethylsilyl, THF=tetrahydrofuran, TIP-
S=triisopropylsilyl.
(0.005 mmol) in Et2O (1 mL) containing 5 ꢀ molecular sieves at 08C for
30 min. [b] Yield of isolated product. [c] The ee value was determined by
HPLC analysis using a chiral stationary phase. M.S.=molecular sieves.
substituents of the imines. The reaction was applicable to a-
methyl-substituted imine, which tends to form isomeric
enamide readily (entry 1). a-Unbranched alkyl imines were
found to be excellent substrates; not only were simple linear
alkyl groups of different length applicable, but also the alkyl
imine bearing a phenyl group at the end was suitable
(entries 2–7). The reaction also tolerated branched alkyl
imines, and the cycloaddition proceeded remarkably well with
imines bearing sec-butyl, isopropyl, or cyclohexyl groups
(entries 8–10). Furthermore, the imine with a vinylic sub-
stituent also proved to be a suitable substrate. Notably, only
5 mol% catalyst was sufficient to promote the allenoate–
imine cyclizations, thus affording the 3-pyrrolines in good to
excellent yields, and with nearly perfect enantioselectivities.
Moreover, the reactions were very fast, and all the cycliza-
tions could be completed in less than 30 minutes. The absolute
configuration of [3+2] products were determined by compar-
ing the optical rotation of a 3j derivative with the value
reported in the literature.[19]
delight, all the phosphines examined displayed remarkable
catalytic effects, thus affording the desired 3-pyrrolines in just
a few minutes. While the l-Thr-l-Val-derived phosphine 4
induced very low enantioselectivity, the catalyst 5 consisting
of l-Thr and d-Val subunits turned out to be very effective in
asymmetric induction (entries 1–2), thus suggesting that the
chirality matching is very important in our catalytic system.
The structures of the catalysts were optimized by introducing
tert-Leu as the second amino acid residue and varying the
carbamate group on the N-terminal of the dipeptide, and it
was discovered that the O-TBDPS-d-Thr-l-tert-Leu-based 7d
was the best catalyst (entries 4–7). To additionally improve
the enantioselectivity of the reaction, solvent screening[17] was
performed and diethyl ether was found to be the best solvent
(entries 8–10). Notably, the addition of water to the reaction
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Table 3: Enantioselective [3+2] cycloaddition of allenoates with aromatic
imines catalyzed by 7d.[a]
2-Alkyl-substituted chiral 3-pyrrolines are structures of
high synthetic value, and can potentially be elaborated into
many biologically useful molecules.[11] As an illustration, a
formal synthesis of pyrrolizidine alkaloid (+)-trachelantha-
midine using our cyclization protocol as a key step was
performed (Scheme 3). The [3+2] cycloaddition between
imine 8 and allenoate 2 occurred smoothly in the presence of
7d to afford the functionalized pyrroline 9 in 82% yield and
96% ee. Treatment of 9 with boron trifluoride resulted in
Entry
Ar
Product
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Ph
3m
3n
3o
3p
3q
3r
82
83
85
94
78
86
83
78
95
95
96
98
93
96
94
95
4-BrC6H4
3-BrC6H4
4-OMeC6H4
3-CNC6H4
2-naphthyl
2-furyl
3s
3t
2-thienyl
[a] Reaction conditions: 1 (0.1 mmol), 2 (0.15 mmol), and 7d
(0.005 mmol) in Et2O (1 mL) containing 5 ꢀ molecular sieves at 08C for
1 h. [b] Yield of isolated product. [c] The ee value was determined by
HPLC analysis using a chiral stationary phase.
Scheme 3. A formal synthesis of (+)-trachelanthamidine. Ts=4-tolue-
nesulfonyl.
simultaneous removal of the DPP group and cleavage of the
silyloxy group, thus giving the intermediate 10 in good yield.
Installation of a tosyl group on the free NH yielded N-tosyl
sulfonylamide 11, which can be converted into (+)-trache-
lanthamidine using the procedures described in the litera-
ture.[20]
The broad applicability of dipeptide-based phosphine-
catalyzed [3+2] annulations to various alkyl imines suggested
that such enantioselective process should be applicable to aryl
imines. We therefore investigated the imine–allenoate cycli-
zation using aryl imines (Table 3). Under the optimized
reaction conditions and in the presence of phosphine 7d, the
[3+2] cycloadditions of aryl imines with allenes were com-
pleted within one hour, and the desired products were
obtained in high yields and excellent enantioselectivities.
The reaction was applicable to aryl imines having different
electronic characteristics and substitution patterns on the
aromatic rings. 2-Naphthyl and heteroaryl imines were also
found to be suitable.
Scheme 4. Proposed transition state (top) and the [3+2] annulations
between 1a and 2 in toluene when promoted by different catalysts
(bottom).
We propose that amide and carbamate portions of the
catalyst interact with imines through hydrogen-bonding
interactions, which contribute significantly to the key tran-
sition state leading to the formation of the major stereoisomer
(Scheme 4). The preferential adoption of an s-cis conforma-
tion by DPP imines[8] facilitates the intramolecular delivery of
the phosphonium enolate to the imine. The catalytic effects of
the N-methylated catalyst 12 were examined, and cyclization
product 3a was obtained in 82% yield after 4 hours, but with
only 59% ee. In comparison, similar catalysts having a free
carbamate (5 and 7d in Table 1) afforded products in
excellent yield and with around a 90% ee in just a few
minutes. These results clearly support the importance of the
hydrogen-bond donor groups in our catalytic systems. Thio-
ureas are known to provide excellent activation and stereo-
chemical control for reactions involving imines, as demon-
strated by Fang and Jacobsen.[8] However, the dipeptide- or
threonine-based phosphine thiourea 13 or 14 was found to be
completely ineffective in our reactions.[21]
In conclusion, we have developed a highly enantioselec-
tive [3+2] cyclization between imines and allenoates by
employing dipeptide-based chiral phosphines as catalysts.
Notably, this is the first time that alkyl imines have been
applied successfully in the asymmetric [3+2] cycloaddition.
Moreover, such an enantioselective cyclization is versatile
and worked equally well for aryl imines. The synthetic value
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Received: September 20, 2011
Published online: December 7, 2011
Keywords: allenes · cycloadditions · heterocycles ·
.
nucleophilic catalysis · phosphines
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[17] For complete solvent screening results, see the Supporting
Information.
[18] The rate enhancement is consistent with Jacobsenꢀs observation
(Ref. [8]). The decreased enantioselectivity suggested the impor-
tance of hydrogen bonding interaction in the ee determining
step, which was slightly disrupted by water molecules.
[19] See the Supporting Information for details.
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[21] Since catalysts 13 and 14 are conformationally flexible, we
believe the thiourea group of the catalyst preferentially stabilizes
the phosphonium enolate, rather than the DPP imines, through
hydrogen-bonding interactions.
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[9] In the nonchiral version of [3+2] annulations reported by Xu
and Lu, only a trace amount of product was detected when
aliphatic N-tosylimine was used; See Ref. [5]. Fang and Jacobsen
observed decomposition of aliphatic imines under their reaction
conditions; See Ref. [8].
770
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