Asymmetric [3+2] annulation of allenes with maleimides catalyzed by dipeptide-derived phosphines: Facile creation of functionalized bicyclic cyclopentenes containing two tertiary stereogenic centers

Article abstract of DOI:10.1039/c2cc16904e

d-Threonine-l-tert-leucine-derived bifunctional phosphine, Cat. 11, catalyzed highly enantioselective [3+2] annulation of maleimides with allenes has been disclosed, allowing the synthesis of optically active functionalized bicyclic cyclopentenes containing two tertiary stereogenic centers in good to high yields along with good to high enantioselectivities.

Full text of DOI:10.1039/c2cc16904e

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COMMUNICATION
Asymmetric [3+2] annulation of allenes with maleimides catalyzed by
dipeptide-derived phosphines: facile creation of functionalized bicyclic
cyclopentenes containing two tertiary stereogenic centersw
Qianyi Zhao,a Xiaoyu Han,b Yin Wei,c Min Shi*ac and Yixin Lu*ab
Received 8th November 2011, Accepted 23rd November 2011
DOI: 10.1039/c2cc16904e
D-Threonine-L-tert-leucine-derived bifunctional phosphine, Cat. 11,
catalyzed highly enantioselective [3+2] annulation of maleimides
with allenes has been disclosed, allowing the synthesis of optically
active functionalized bicyclic cyclopentenes containing two tertiary
stereogenic centers in good to high yields along with good to high
enantioselectivities.
Recently, a PPh3-catalyzed [3+2] annulation reaction of
cyanoallenes with maleimides to give the functionalized bicyclic
cyclopentene derivatives has been reported by Kinderman.14
Lu and his coworkers also reported a PPh3-catalyzed [3+2]
reaction of 2-(bromomethyl)acrylates with maleimides to give
the similar compounds.15,16 Herein, we wish to describe a
highly enantioselective maleimide–allene [3+2] cycloaddition
catalyzed by dipeptide derived bifunctional phosphines, affording
the corresponding functionalized bicyclic cyclopentenes containing
two tertiary stereogenic centers in good to high yields along with
good to high enantioselectivities.
It has been well known that phosphine-mediated [3+2]
cycloaddition between electron-deficient alkenes and allenes
or alkynes is a powerful approach for the construction of
functionalized cyclopentenes,1 which are important structural
motifs presented in a huge number of pharmaceutically interesting
substances and biologically active natural products.2 The
pioneering work of phosphine-catalyzed [3+2] cycloaddition
was developed by Lu in 1995,3 while the first asymmetric [3+2]
annulation of allenoates with acrylates catalyzed by a bicyclic
chiral phosphine was achieved by Zhang in 1997.4 Later on,
significant progress on the asymmetric phosphine-mediated [3+2]
cycloaddition between electron-deficient alkenes and allenes or
alkynes had been made by Fu,5 Miller,6 Jacobsen7 and other
researchers.8–10 Very recently, Lu’s group developed a new family
of dipeptide-based11 chiral phosphines which could smoothly
promote the [3+2] cycloaddition of allenoates and a-substituted
acrylates, furnishing the corresponding functionalized cyclo-
pentenes with quaternary stereogenic centers in high yields with
excellent enantioselectivities.12 Moreover, they disclosed the first
direct application of acrylamides in the phosphine-catalyzed
asymmetric [3+2] cycloaddition with allenes using such dipeptide-
based chiral phosphines, but only giving the desired products in
moderate enantioselectivities (36–66% ee’s).13
We initiated our investigations by seeking the optimal
reaction conditions for the [3+2] cycloaddition of maleimide
1a with ethyl allenoate 2a. After screening of the catalyst and
the investigation of solvent effects, reaction time and temperature
on the reaction outcomes, we identified that the optimal reaction
conditions are to carry out the reaction in toluene at room
temperature for 9 h using triphenylphosphine (PPh3) (5 mol%)
as the catalyst (see Table S1 in the ESIw for details). Under the
optimal reaction conditions, we next set out to examine the scope
and limitations of this reaction using various maleimides 1 and
electron-deficient allenes 2 and we found that all of these N-alkyl,
N-aryl, and N-benzyl substituted maleimides 1 could react with 2
smoothly to give the corresponding [3+2] cycloaddition products
3 in excellent yields (90–99%) under the standard conditions
(Scheme 1) (see Table S2 in the ESIw for details).
In view of our results on the [3+2] cycloaddition of
maleimides 1 with allenes 2 catalyzed by PPh3 effectively, the
next logical step was to investigate the asymmetric version of
this reaction by using phosphine containing chiral organo-
catalysts under the above standard conditions. Screening of
chiral phosphine catalysts revealed that D-threonine-L-tert-
leucine-derived bifunctional phosphine, Cat. 11, developed
by Lu’s group12 was the most effective catalyst in this reaction,
a Key Laboratory for Advanced Materials and Institute of Fine
Chemicals, East China University of Science and Technology,
130 MeiLong Road, Shanghai 200237, P. R. China
b Department of Chemistry & Medicinal Chemistry Program,
Life Sciences Institute, National University of Singapore,
3 Science Drive 3, Republic of Singapore 117543.
E-mail: chmlyx@nus.edu.sg
c State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Road, Shanghai 200032, P. R. China.
E-mail: mshi@mail.sioc.ac.cn
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization data of new compounds. CCDC
783732, 844461 and 805801. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c2cc16904e
Scheme 1 PPh3-catalyzed [3+2] cycloaddition of maleimides 1 with
allenes 2.
c
970 Chem. Commun., 2012, 48, 970–972
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Table 1 Substrate scope of the asymmetric [3+2] cycloaddition of
maleimides 1 with electron deficient allenes 2 catalyzed by Cat. 11a
Scheme 2 Optimization of the asymmetric [3+2] cycloaddition reac-
Entry R1
R2
Yieldb (%) eec (%)
tion conditions.
1
2
3
4
5
6
7
8
1a, Bn
2a, OEt
2a, OEt
2a, OEt
2a, OEt
3aa, 92
3ba, 84
3ca, 80
3da, 79
3ea, 78
3fa, 81
3ga, 86
3ha, 82
3ia, 89
92
85
91
92
92
91
90
90
95
91
77
87
70
80
—
68
64
61
38
1b, 1-naphthalenemethyl
1c, 4-MeOC6H4CH2
1d, 3-MeOC6H4CH2
giving 3aa in 97% yield and 86% ee within 24 h (see Fig. S1 in
the ESIw for details). Further screening of the solvent effects
and reaction temperature on the reaction outcome revealed
that using 10 mol% of Cat. 11 as the catalyst and carrying out
the reaction in toluene/CHCl3 = 1 : 1 (v/v) at 0 1C for 72 h
were the optimal reaction conditions, giving 3aa in 92%
yield and 92% ee within 72 h (Scheme 2) (see Table S3 in
the ESIw for details). The mixed solvent can improve the
enantioselectivities of the reaction products, but decelerate
the reaction rates according to the investigation of the reaction
conditions shown in Table S3 in the ESI.w It is necessary to
prolong the reaction time to achieve both good yields and high
enantioselectivities.
1e, 3, 4-(MeO)2C6H3CH2 2a, OEt
1f, 4-BrC6H4CH2
1g, 4-FC6H4CH2
1h, 2-thienylmethyl
1i, cyclohexylmethyl
1i, cyclohexylmethyl
1i, cyclohexylmethyl
1i, cyclohexylmethyl
1i, cyclohexylmethyl
1j,Me
1k, H
1l, Ph
1m, 4-MeOC6H4
1n, 3, 5-(MeO)2C6H3
1o, 2,4,6-Br3C6H2
2a, OEt
2a, OEt
2a, OEt
2a, OEt
9
10
11
12
13
14
15
16
17
18
19
2b, OiPr 3ib, 80
2c, OtBu 3ic, 82
2d, OBn 3id, 98
2e, Me
3ie, 94
3ja, 85
3ka, trace
3la, 76
3ma, 87
3na, 83
3oa, 79
2a, OEt
2a, OEt
2a, OEt
2a, OEt
2a, OEt
2a, OEt
With these optimal reaction conditions in hand, we sub-
sequently turned our attention to examine the substrate scope
of this interesting asymmetric [3+2] cycloaddition with respect
to a variety of maleimides and electron deficient allenes. The
results are summarized in Table 1. As can be seen from
Table 1, N-benzyl maleimide 1a and a variety of N-benzyl
maleimide derivatives 1b–1g having electron-rich or electron-
poor aromatic groups on their R1 groups or N-2-thienylmethyl
maleimide 1h bearing a heteroaromatic group on its R1 group
could react with electron deficient allene 2a smoothly to give
the corresponding [3+2] cycloaddition products 3aa–3ha in
good to high yields along with 85–92% enantiomeric excesses
(Table 1, entries 1–8). When R1 is cyclohexylmethyl, the
highest enantiomeric excess (up to 95%) was obtained along
with 89% yield for the cycloaddition of maleimide 1i with
allenoate 2a (Table 1, entry 9). Employing allenoates 2b–2d
with more sterically bulky substitutents or allenic ketone 2e led
to relatively lower yields and enantiomeric excesses (Table 1,
entries 10–13). Maleimide 1j bearing an N-Me group gave the
corresponding cycloaddition product 3ja in 85% yield with
80% ee, however, maleimide 1k bearing an N-H group led to
almost no product (Table 1, entries 14 and 15). In the case of
maleimides 1l–1o in which R1 are aromatic groups, the reactions
also proceeded smoothly to give the corresponding cycloaddition
products 3la–3oa in 76–87% yields with 38–68% enantiomeric
excesses (Table 1, entries 16–19). The relatively lower enantio-
meric excesses of 3ic–3oa (Table 1, entries 11–19) were presum-
ably due to the electronic and steric effects of N-aryl or N-alkyl
maleimides 1i–1o and allenes 2c–2e. The absolute configuration
of products 3 was unambiguously assigned as S,S-configuration
on the basis of the X-ray crystallographic analysis of product 3fa
which has a bromine atom on the benzene ring (Fig. S3, ESIw).
To illustrate the synthetic utility of these obtained optically
active [3+2] cycloaddition products 3, further transformation
of 3id was performed in the presence of Pd/C and H2 under
mild conditions (Scheme 3). Upon hydrogenation of 3id with
Pd/C in THF for 7 h, the corresponding product 4 was
a
The reaction was carried out on a 0.15 mmol scale with 10 mol%
catalyst under Ar in toluene/CHCl3 = 1 : 1 (v/v) (1.0 mL) at 0 1C for
b
c
72 h, and the ratio of 1/2 was 1.0/2.0. Isolated yield. Determined by
chiral HPLC analysis, and the absolute configuration was determined
by X-ray diffraction of 3fa.
produced in over 99% yield and excellent diastereoselectivity
(dr > 99 : 1), which could be further transformed to amide 5
in 76% yield with the ee value retained by the reaction with
m-bromoaniline (2.0 equiv.) in the presence of N-ethyl-N0-
(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI)
(3.0 equiv.) and 1-hydroxy N-hydroxybenzotriazole (HOBt)
(4.0 equiv.) in N,N-dimethylformamide (DMF). As for product 4,
the newly generated stereogenic center at the C3 position was
assigned as 3R on the basis of the X-ray crystallographic
analysis of racemic product rac-5 (see Fig. S4 in the ESIw for
details) and the S,S-configuration of 3id could be determined
by the X-ray crystallographic analysis of [3+2] annulation
product 3fa. Furthermore, imide 4 could also be transformed
to the corresponding amino alcohol 6 in 99% yield with 87% ee
by the standard reduction of carbonyl groups with lithium
aluminium hydride (LiAlH4),17 which contains a core unit
Scheme 3 Further transformation of the obtained [3+2] annulation
product 3id.
c
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Chem. Commun., 2012, 48, 970–972 971

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In summary, we have developed a highly enantioselective
[3+2] annulation of maleimides with allenes, affording the
corresponding functionalized bicyclic cyclopentenes containing
two tertiary stereogenic centers in good to high yields along with
good to high enantioselectivities catalyzed by D-threonine-L-tert-
leucine-derived bifunctional phosphine Cat. 11 (5 mol%) in
toluene/CHCl3 = 1 : 1 (v/v) at 0 1C. A plausible transition-state
model has also been proposed on the basis of previous literature.
We thank the Shanghai Municipal Committee of Science and
Technology (08dj1400100-2), National Basic Research Program
of China (973)-2010CB833302, the Fundamental Research
Funds for the Central Universities and the National Natural
Science Foundation of China for financial support (21072206,
20872162, 20672127, 20732008, 20821002 and 20702013).
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