Asymmetric construction of functionalized bicyclic imides via [3 + 2] annulation of MBH carbonates catalyzed by dipeptide-based phosphines

Article abstract of DOI:10.1021/ol301647g

A highly enantioselective [3 + 2] annulation of MBH carbonates and maleimides catalyzed by chiral phosphines has been developed. In the presence of 5 mol % of l-Thr-l-Val-derived phosphine 6, functionalized bicyclic imides were prepared in excellent yields, and with high diastereoselectivities and nearly perfect enantioselectivities.

Full text of DOI:10.1021/ol301647g

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Asymmetric Construction of
Functionalized Bicyclic Imides via [3 þ 2]
Annulation of MBH Carbonates Catalyzed
by Dipeptide-Based Phosphines
Fangrui Zhong, Guo-Ying Chen, Xiaoyu Han, Weijun Yao, and Yixin Lu*
Department of Chemistry & Medicinal Chemistry Program, Life Sciences Institute,
National University of Singapore, 3 Science Drive 3, Republic of Singapore, 117543
chmlyx@nus.edu.sg
Received June 15, 2012
ABSTRACT
A highly enantioselective [3 þ 2] annulation of MBH carbonates and maleimides catalyzed by chiral phosphines has been developed. In the
presence of 5 mol % of L-Thr-L-Val-derived phosphine 6, functionalized bicyclic imides were prepared in excellent yields, and with high
diastereoselectivities and nearly perfect enantioselectivities.
Synthesisof enantiomericallypure imidederivatives is of
significant importance because of the wide occurrence of
optically active imide moieties in natural products and
biologically active molecules.1 For instance, imides are the
key building blocks for thalidomide,2a ethosuximide,2b
phensuximide,2c and andrimid.2d Not surprisingly, con-
siderable effort has been devoted to the construction of
these structure motifs in the past decades.3 However,
apart from the DielsꢀAlder reaction of maleimides,4
enantioselective preparation of bicyclic imides employing
maleimides has rarely been explored,5 despite the fact that
such a structural scaffold is ubiquitous in many natural
products and pharmaceutical agents (Figure 1).6
Nucleophilic phosphine catalysis represents one of the
most straightforward methods for efficient assembly of
cyclic compounds.7 In particular, phosphine-triggered [3 þ 2]
annulations are extremely useful for the creation of cyclopen-
tene ring structures.8 Our group has been actively investigating
in this research area in recent years.9 We have developed a
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2012, 48, 970.
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20120209, 2012.
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Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535. (b) Methot, J. L.;
Roush, W. R. Adv. Synth. Catal. 2004, 346, 1035. (c) Ye, L.-W.; Zhou, J.;
Tang, Y. Chem. Soc. Rev. 2008, 37, 1140. (d) Kwong, C. K.-W.; Fu,
M. Y.; Lam, C. S.-L.; Toy, P. H. Synthesis 2008, 2307. (e) Cowen, B. J.;
Miller, S. J. Chem. Soc. Rev. 2009, 38, 3102. (f) Marinetti, A.; Voituriez,
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r
10.1021/ol301647g
XXXX American Chemical Society

series of amino acid based10 bifunctional phosphine catalysts
and demonstrated that they are remarkably effective in a wide
range of enantioselective organic transformations.11 By utiliz-
ing L-threonine-derived bifunctional phosphines, we11h re-
cently successfully applied MoritaꢀBaylisꢀHillman (MBH)
carbonates as a C3 synthon in the asymmetric [3 þ 2]
cycloaddition reaction.12 Given the ready availability and
strutural variation of the MBH carbonates, they are undoubt-
edly valuable reaction partners in the cylizations. We envi-
sioned that a phosphine catalyzed [3 þ 2] annulation of MBH
carbonates with maleimides can lead to a facile access to
bicyclic imides bearing three contiguous tertiary stereogenic
centers (Scheme 1). Herein, we document a highly enantio-
selective [3 þ 2] annulation mediated by dipeptide-based
phosphines, furnishing bicyclic imides in excellent yields and
nearly perfect enantioselectivities.
We began our investigation by examining the catalytic
effects of various amino acid derived chiral phosphines in
the [3 þ 2] annulation reaction between MBH carbonate
1a and N-phenyl maleimide 2a, and the results are sum-
marized in Table 1. Different L-Valine derived phosphines
4aꢀd were effective, and the reaction proceeded smoothly
at room temperature (entries 1ꢀ4). The influence of differ-
ent Brønsted acid moieties was found to be signi-
ficant. Employment of amide-bearing 4b led to the forma-
tion of products with high enantioselectivity, but with no
diastereoselectivity (entry 2). Catalyst 4c with a carbamate
group resulted in the formation of a single diastereomer
(entry 3). Turning to our privileged threonine core13 offered
remarkable improvement. In the presence of L-Thr-derived
5, the annulation took place to yield a single diastereomer
with excellent enantioselectivity. The chemical yield of the
reaction, however, was modest (entry 5). To make further
improvement, we next examined dipeptide-based phos-
phines, which were recently developed by us for several
enantioselective annulation processes.11cꢀg To our delight,
L-Thr-L-Val-derived phosphine 6 and L-Thr-L-tert-Leu-
derived phosphine 8worked remarkably well for the reaction,
affording the desired product in excellent yield, in a diaster-
eomerically pure form and with a very high enantiomeric
excess (entries 6 and 8). Contrary to our previous report,11c
L-Thr-D-Val-derived phosphine 7ledtotheproductswitha1:1
diastereomeric ratio (entry 7), which again proved the vital
importance of chirality matching in our stereoselective cataly-
tic processes. Variation of the ester moiety in MBH carbonate
1 offered a slight improvement in ee (entry 9). Different
solvents were examined, and none were found to be superior
to toluene (entries 10ꢀ12).Notably,wewereabletoreducethe
catalyst loading to 5 mol %, and both the chemical yield and
stereoselectivities of the reaction were maintained (entry 13).
With the optimized reaction conditions in hand, the
generality of phosphine 6 catalyzed [3 þ 2] annulations
Figure 1. Selected bioactive bicyclic imides.
Scheme 1. Construction of Bicyclic Imides via Phosphine Cat-
alyzed [3 þ 2] Annulation
(10) For reviews on asymmetric catalysis mediated by amino acids
and synthetic peptides, see: (a) Xu, L.-W.; Luo, J.; Lu, Y. Chem.
Commun. 2009, 1807. (b) Xu, L.-W.; Lu, Y. Org. Biomol. Chem. 2008,
6, 2047. (c) Davie, E. A. C.; Mennen, S. M.; Xu, Y.; Miller, S. J. Chem.
Rev. 2007, 107, 5759. (d) Revell, J. D.; Wennemers, H. Curr. Opin. Chem.
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Lu, Y. Org. Biomol. Chem. 2011, 9, 6734. (b) Zhong, F.; Wang, Y.; Han, X.;
Huang, K.-W.; Lu, Y. Org. Lett. 2011, 13, 1310. (c) Han, X.; Wang, Y.;
Zhong, F.; Lu, Y. J. Am. Chem. Soc. 2011, 133, 1726. (d) Han, X.; Zhong, F.;
Wang, Y.; Lu, Y. Angew. Chem., Int. Ed. 2012, 51, 767. (e) Han, X.; Wang,
S.-X.; Zhong, F.; Lu, Y. Synthesis 2011, 1859. (f) Zhao, Q.; Han, X.; Wei, Y.;
Shi, M.; Lu., Y. Chem. Commun. 2012, 48, 970. (g) Zhong, F.; Han, X.;
Wang, Y.;Lu, Y.Chem. Sci. 2012, 3, 1231. (h) Zhong, F.; Han, X.; Wang, Y.;
Lu, Y. Angew. Chem., Int. Ed. 2011, 50, 7837. (i) Zhong, F.; Luo, J.; Chen,
G.-Y.; Dou, X.; Lu, Y. J. Am. Chem. Soc. 2012, 134, 10222.
(12) For other examples of applying MBH adducts in cycloaddition
reactions, see: (a) Tan, B.; Candeias, N. R.; Barbas, C. F., III. J. Am. Chem.
Soc. 2011, 133, 4672. (b) Deng, H.-P.; Wei, Y.; Shi, M. Adv. Synth. Catal.
2012,354, 783. (c) Peng, J.; Huang, X.; Jiang, L.; Cui, H.-L.; Chen, Y.-C. Org.
Lett. 2011, 13, 4584. For a recent review on applications of MBH adducts,
see: (d) Liu, T.-Y.; Xie, M.; Chen, Y.-C. Chem. Soc. Rev. 2012, 41, 4101.
(13) For selected L-Thr-based catalytic systems reported by us, see: (a)
Cheng, L.;Han, X.;Huang, H.;Wong, M. W.;Lu, Y. Chem. Commun. 2007,
4143. (b) Cheng, L.; Wu, X.; Lu, Y. Org. Biomol. Chem. 2007,5, 1018. (c) Wu,
X.; Jiang, Z.; Shen, H.-M.; Lu, Y. Adv. Synth. Catal. 2007, 349, 812. (d) Zhu,
Q.; Lu, Y. Chem. Commun. 2010, 46, 2235. (e) Dou, X.; Han, X.; Lu, Y.
Chem.;Eur. J. 2012, 18, 85; also see refs 11aꢀ11i.
(8) For selected examples, see: (a) Zhu, G.; Chen, Z.; Jiang, Q.; Xiao,
D.; Cao, P.; Zhang, X. J. Am. Chem. Soc. 1997, 119, 3836. (b) Wilson,
J. E.; Fu, G. C. Angew. Chem., Int. Ed. 2006, 45, 1426. (c) Cowen, B. J.;
Miller, S. J. J. Am. Chem. Soc. 2007, 129, 10988. (d) Fang, Y. Q.;
Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 5660. (e) Voituriez, A.;
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Panossian, A.; Fleury-Bregeot, N.; Retailleau, P.; Marinetti, A. J. Am.
Chem. Soc. 2008, 130, 14030. (f) Sampath, M.; Loh, T.-P. Chem. Sci.
2010, 1, 739. (g) Voituriez, A.; Pinto, N.; Neel, M.; Retailleau, P.;
Marinetti, A. Chem.;Eur. J. 2010, 16, 12541. (h) Xiao, H.; Chai, Z.;
Zheng, C.-W.; Yang, Y.-Q.; Liu, W.; Zhang, J.-K.; Zhao, G. Angew.
Chem., Int. Ed. 2010, 49, 4467. (i) Pinto, N.; Retailleau, P.; Voituriez, A.;
Marinetti, A. Chem. Commun. 2011, 1015–1017. (j) Fujiwara, Y.; Fu,
G. C. J. Am. Chem. Soc. 2011, 133, 12293. For excellent mechanistic
studies, see: (k) Lin, M.; Kang, G.-Y.; Guo, Y.-A.; Yu, Z.-X. J. Am.
Chem. Soc. 2012, 134, 398. (l) Xia, Y.; Liang, Y.; Chen, Y.; Wang, M.;
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B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Screening of Chiral Phosphines for the [3 þ 2] Annu-
lation of MBH Carbonates 1 with Maleimide 2aa
Table 2. Scope of the Reactiona
yield
(%)c
ee
(%)d
entry
R
2
3
drb
1e
2
Ph
Ph
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
3f
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
18:1
91
93
95
93
95
93
96
93
98
93
95
98
92
95
93
88
90
92
94
93
92
99
99
3
4-MeC6H4
4-NO2C6H4
4-FC6H4
4-CNC6H4
3-BrC6H4
3-ClC6H4
2-BrC6H4
2,4-ClC6H3
2-thiophenyl
2-naphthyl
(E)-PhCHdCH
CO2Et
>99
98
4
5
>99
98
6
7
3g
3h
3i
99
8
>99
>99
99
9
10
11
12
13f
14
15g
16g
17h
18
19
20
21
3j
t
yield
(%)c
ee
(%)d
3k
3l
>99
>99
99
entrya
1
cat.
(h)
drb
>25:1
3:1
1
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
4a
4b
4c
4d
5
24
3
1:1.3
1:1
<50
76
ꢀ
3m
3n
3o
3p
3q
3r
3s
3t
2
87
51
41
92
98
97
99
99
99
ꢀ
12:1
>99
>99
95
3
3
>25:1
2:1
71
Me
9:1
4
3
62
H
>25:1
>25:1
>25:1
>25:1
13:1
5
3
>25:1
>25:1
1:1.2
>25:1
>25:1
>25:1
ꢀ
73
Ph
>99
>99
>99
>99
>99
6
6
3
92
4-ClC6H4
Ph
7
7
3
93
8
8
3
94
Ph
9
6
3
94
Ph
3u
15:1
10e
11f
12g
13h
6
12
24
24
24
65
a Reactions were performed with 1 (0.06 mmol), 2 (0.05 mmol), and 6
(0.0025 mmol) in toluene (0.5 mL). b Determined by 1H NMR analysis of
the crude products. c Isolated yield. d Determined by HPLC analysis
on a chiral stationary phase. e CO2Me was used in 1. f When catalyst 5
(0.005 mmol) was used, 3m was isolated in 93% yield and with 12:1 dr
and 91% ee. g The catalyst loading was 10 mol %. h C(O)Me was used in 1.
6
<30
<10
93
6
ꢀ
ꢀ
6
>25:1
99
a Reactions were performed with 1 (0.06 mmol), 2a (0.05 mmol), and
1
catalyst (0.005 mmol) in toluene (0.5 mL). b Determined by H NMR
analysis of the crude products. c Isolated yield. d Determined by HPLC
analysis on a chiral stationary phase. e Reaction was performed in
CHCl3 (0.5 mL). f Reaction was performed in CH2Cl2 (0.5 mL). g Reac-
tion was performed in THF (0.5 mL). h The catalyst loading was 5 mol %.
Scheme 2. Proposed Mechanism
was subsequently studied (Table 2). In all the examples
evaluated, excellent yields and extremely high enantio-
mericexcesseswereattainable. The reaction was applicable
to MBH carbonates bearing different aromatic groups,
regardless of their substitution pattern and electronic
nature (entries 1ꢀ10). 2-Naphthyl and 2-thiophenyl-con-
taining MBH substrates could also be used (entries
11ꢀ12). Moreover, MBH carbonates with a vinylic group,
an ester, or a methyl group, as well as a hydrogen atom
(MBH carbonate derived from formaldehyde), were all
suitable for the reaction, albeit diastereoselectivities
dropped in a few cases (entries 13ꢀ16). Furthermore,
maleimides containing different N-substituents, including
both aryl and alkyl groups, were all found to work
wonderfully for the annulation reaction (entries 17ꢀ21).
The absolute configurations of the bicyclic imides were
determined based on X-ray crystal structural analysis of
3r (see the Supporting Information for details).
A plausible reaction mechanism is depicted in Scheme 2.
The nucleophilic attack of phosphine 6 to MBH carbonate
1b gives rise to intermediate A, with cocurrent release of
CO2. The in situ generated tert-butoxide deprotonates A
to afford ylide B, which then undergoes γ-addition to
Org. Lett., Vol. XX, No. XX, XXXX
C

maleimide 2a to furnish intermediate C. Intramolecular
cyclization of C, followed by β-elimination, yields final
product 3b and regenerates catalyst 6. To account for the
observed stereochemical outcome, we propose a transition
state model as shown in Scheme 2. Hydrogen bonding
interactions between the maleimide and phosphonium
intermediate not only lock the position of the maleimide,
contributing to the stereoselectivity of the reaction, but
also make γ-attack from the phosphonium enolate more
favorable due to the activation of an oxygen atom in imide.
In view of the biological significance of chiral bicyclic imides,
and to demonstrate the practicality of our method, we per-
formed the annulation reaction at the gram scale. As shown in
Scheme 3, when maleimide 2b was treated with MBH carbon-
ate 1d under the optimal reaction conditions, the reaction
proceeded smoothly to afford the desired imide 3r at the gram
scale without loss of reactivity or enantioselectivity (Scheme 3).
In summary, we have developed a highly stereoselective
[3 þ 2] annulation of MBH carbonates with maleimides.
By utilizing dipeptide-based bifunctional phosphines, dia-
stereomerically pure and highly enantiomerically enriched
bicyclic imides (g98% ee in most cases) could be readily
preparedinexcellent yields under mild reaction conditions.
Biological evaluations of our synthetic chiralbicyclic imides
are underway in our laboratory.
Scheme 3. Gram Scale [3 þ 2] Annulation between MBH
Carbonate 1d and Maleimide 2b
Acknowledgment. Financial support from the National
University of Singapore (R-143-000-469-112), the
SingaporeꢀPekingꢀOxford Research Enterprise (COY-
15-EWI-RCFSA/N197-1), and GSKꢀEDB (R-143-000-
491-592) is gratefully acknowledged.
Supporting Information Available. Representative ex-
perimental procedures, determination of absolute con-
figurations, X-ray structure of 3r, HPLC chromato-
gram, and NMR spectra of the products. This material
is available free of charge via the Internet at http://
pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX