Asymmetric Construction of Highly Functionalized Spirobarbiturate-Cyclopentenes through Chiral Phosphine-Catalyzed [3+2] Annulation of Morita–Baylis–Hillman Carbonates with Barbiturate-Derived Alkenes

Article abstract of DOI:10.1002/adsc.201600450

A multifunctional chiral phosphine-catalyzed enantioselective [3+2] annulation of Morita–Baylis–Hillman carbonates with barbiturate-derived alkenes has been achieved under mild conditions, providing a variety of chiral spirobarbiturate-cyclopentenes in moderate to excellent yields with moderate to excellent diastereo- and enantioselectivities. (Figure presented.).

Full text of DOI:10.1002/adsc.201600450

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DOI: 10.1002/adsc.201600450
Asymmetric Construction of Highly Functionalized Spirobarbitu-
rate-Cyclopentenes through Chiral Phosphine-Catalyzed [3+2]
Annulation of Morita–Baylis–Hillman Carbonates with Barbitu-
rate-Derived Alkenes
Yang Liu,a Wenjun Yang,a Yang Wu,a Biming Mao,a Xing Gao,a Honglei Liu,a
Zhanhu Sun,a Yumei Xiao,a and Hongchao Guoa,*
a
Department of Applied Chemistry, China Agricultural University, 2 West Yuanmingyuan Road, Beijing 100193, Peopleꢀs
Republic of China
Fax : (+86)-10-6273-0784; e-mail: hchguo@cau.edu.cn
Received: April 27, 2016; Revised: June 9, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600450.
Abstract: A multifunctional chiral phosphine-cata-
lyzed enantioselective [3+2] annulation of Morita–
Baylis–Hillman carbonates with barbiturate-derived
alkenes has been achieved under mild conditions,
providing a variety of chiral spirobarbiturate-cyclo-
pentenes in moderate to excellent yields with mod-
erate to excellent diastereo- and enantioselectivi-
ties.
lective tool to synthesize chiral spirobarbiturate-cyclo-
pentenes through phosphine-catalyzed asymmetric
[3+2] annulation of barbiturate-derived alkenes with
Morita–Baylis–Hillman (MBH) carbonates.
Phosphine-catalyzed annulation reactions are very
powerful methods in the syntheses of carbocyclic and
heterocyclic compounds and serve as the key step in
the total synthesis of some natural products.[6] Particu-
larly, these annulations have also successfully been
applied in the synthesis of complex spirocyclic com-
pounds.[7] Among various annulation reactions, the
phosphine-catalyzed [3+2] annulation reaction of
MBH carbonates with olefins has emerged as an im-
portant tool to synthesize cyclopentenes since Lu first
reported a phosphine-catalyzed [3+2] annulation of
Keywords: alkenes; allenoates; annulation; phos-
phines; spirobarbiturates
Barbituric acid derivatives are important pharmaco- MBH carbonates as a three-carbon synthon with elec-
logical compounds, displaying various activities such tron-deficient alkenes.[6j,8] Employing this reaction,
as sedative, anesthetic, anxiolytic, anticonvulsant, ana- a few spirocyclic molecules fused with a cyclopentene
leptic, anticancer, anti-AIDS and immunomodulating moiety have been constructed. Lu, Shi and Barbas in-
activities.[1] As a type of barbiturate, spirobarbiturates dependently developed chiral phosphine-catalyzed
also showed a range of pharmacological and physio- asymmetric [3+2] annulation reactions of methy-
logical activities and have attracted much attention.[2,3]
Considering functionalized five-membered carbocy-
cles are a common structural motif in medicinally im-
portant compounds and natural products,[4] spirobar-
biturate-cyclopentenes with the combination of barbi-
turate and cyclopentene moieties are very appealing
in the search for medicinally active compounds. Re-
cently, a synthetic approach to spirobarbiturate-cyclo-
pentenes has been achieved through a ring-closing
metathesis (RCM) reaction (Scheme 1).[5] However,
this method is not feasible for multi-substituted spiro-
barbiturate-cyclopentenes. Especially, to the best of
our knowledge, an asymmetric construction of spiro-
barbiturate-cyclopentenes has not been reported. In
ACHTUNGTRENlNUNG eneindolinones with MBH carbonates to prepare
this context, we considered developing an enantiose- Scheme 1. Synthesis of spirobarbiturate-cyclopentenes.
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chiral spirocyclopentene oxindoles.[9] Barbas achieved enantioselectivity (entry 1). In contrast, chiral phos-
the asymmetric [3+2] annulation of methylenebenzo- phine P2 displayed excellent enantioselectivity but
furanone with MBH carbonates to give spirocyclopen- moderate catalytic activity under otherwise identical
tene benzofuranones.[10] Shi described the asymmetric conditions (entry 2). Spirocyclic chiral phosphine
[3+2] annulation of MBH carbonates with 2-aryli- P3[15] promoted the reaction to give the product 3aa
ACHTUNGTRENNUNGdeneindane-1,3-diones to provide spirocyclopente- in 83% yield albeit with 65% ee (entry 3). Satisfacto-
neindenediones.[11] Chen and Liu used MBH carbo- rily, two multifunctional phosphines P4 and P5[16]
nates of isatin for the asymmetric [3+2] annulation demonstrated good catalytic capability (entries 4 and
with alkenes to furnish cyclopentene-fused spirocyclic 5). Although P5 delivered better enantioselectivity
heterocycles.[12] As part of our continuing efforts on than P4 did, P4 is a preferred catalyst for this reaction
phosphine-catalyzed annulations,[13] herein, we pres- in terms of both yield and enantioselectivity (entry 4
ent the multifunctional chiral phosphine-catalyzed vs. 5). With P4 as the catalyst, we next performed sol-
asymmetric [3+2] annulations of MBH carbonates vent screening to improve the enantioselectivity.
with barbiturate-derived alkenes to synthesize These experiments revealed that trifluorotoluene was
enantioenriched
(Scheme 1).
spirobarbiturate-cyclopentenes an optimal solvent (entries 6 and 7). In trifluoroto-
luene, the ee value was increased to 93% (entry 7).
In our initial attempts, we screened different kinds Using 4ꢂ MS as an additive, the yield was slightly in-
of chiral phosphines in the asymmetric reaction be- creased to 80% (entry 8). Since the base has been
tween barbiturate-derived alkene (1a) and MBH car- demonstrated to be favorable to phosphine-catalyzed
bonate (2a) in toluene at 808C. As shown in Table 1, annulations in the previous report,[17] a catalytic
Kwon phosphines P1 and P2[14] displayed opposing re- amount of K2CO3 was also examined as an additive.
sults. With the use of chiral phosphine P1 as the cata- To our delight, the yield was indeed marginally en-
lyst, the desired spirobarbiturate-cyclopentene 3aa hanced to 85% (entry 9). The base might help in for-
was obtained in excellent yield but with moderate mation of a phosphonium enolate zwitterion from
Table 1. Catalyst screen and optimization studies.[a]
Entry
Px
Solvent
Temperature [8C]
Time [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
P1
P2
P3
P4
P5
P4
P4
P4
P4
toluene
toluene
toluene
toluene
toluene
DCE
PhCF3
PhCF3
PhCF3
80
80
80
80
80
80
80
80
80
18
18
16
16
16
18
16
16
16
98
45
83
87
67
76
76
80
85
37
91
65
85
91
90
93
93
96
7
8[d]
9[e]
[a]
Unless otherwise stated, reactions of 1a (0.1 mmol) and 2a (0.12 mmol) were performed in the presence of phosphine
(0.02 mmol) in 2 mL of solvent.
Isolated yield. The dr is >20:1, determined by H NMR analysis.
Determined by chiral HPLC analysis.
50 mg of 4ꢂ MS were used as the additive.
50 mg of 4ꢂ MS and 20 mol% of K2CO3 were used.
[b]
[c]
[d]
[e]
1
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Table 2. Scope of MBH carbonates 2.[a]
Entry
R
Time [h]
3
Yield [%][b]
ee [%][c]
1[d]
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
2-MeC6H4 (2b)
3-MeC6H4 (2c)
4-MeC6H4 (2d)
2-MeOC6H4 (2e)
4-MeOC6H4 (2f)
2-FC6H4 (2g)
3-FC6H4 (2h)
4-FC6H4 (2i)
2-ClC6H4 (2j)
3-ClC6H4 (2k)
4-ClC6H4 (2l)
2-BrC6H4 (2m)
3-BrC6H4 (2n)
2-naphthyl (2o)
2-thienyl (2p)
i-Pr (2q)
18
18
16
16
17
18
16
18
16
18
16
20
18
16
18
24
24
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3am
3an
3ao
3ap
3aq
3ar
88
99
80
98
98
90
80
81
97
64
86
96
85
87
91
93
91
91
93
90
91
91
87
93
93
85
87
93
90
–
90
NR[e]
NR
cyclohexyl (2r)
–
[a]
Reactions of 1a (0.1 mmol) and 2 (0.12 mmol) were performed in the presence of P4 (0.02 mmol), K2CO3 (0.02 mmol)
and 50 mg of 4ꢂ MS at 808C in 2 mL of PhCF3.
Isolated yield. Unless otherwise stated, the dr is >20:1, determined by H NMR analysis.
Determined by chiral HPLC analysis.
dr=10:3.
No reaction.
[b]
[c]
[d]
[e]
1
MBH carbonate, thus slightly increasing the yield. On work (entries 16 and 17). The absolute configuration
the basis of the above-mentioned results, the opti- of the spirocyclic products was assigned by an X-ray
mized conditions are as follows: reaction of 1a and 2a crystallographic analysis of the product 3al
in trifluorotoluene at 808C using 20 mol% of P4 in (entry 11).[18]
the presence of 4ꢂ MS and K2CO3.
Application of the standard conditions to various
is summarized in
Under the optimal conditions, the scope of the barbiturate-derived alkenes
1
MBH carbonates 2 in this [3+2] annulation was inves- Table 3. Variations of the substituents on the benzene
tigated (Table 2). Generally, whether using electron- moiety were tolerated. A variety of barbiturate-de-
rich or electron-deficient aryl-substituted MBH car- rived alkenes, regardless of the substitution pattern
bonates, the spirocyclic products were obtained in and electronic nature, worked well to produce the
good to excellent yields (64–99%) with good to excel- corresponding cycloadducts in high yields (60–99%)
lent diastereo- and enantioselectivities (85–93% ee) with excellent enantioselectivities (91–99% ee) (en-
(entries 1–15). The high diastereoselectivities might tries 1–13). All products, except 3ca and 3ka (entries 3
be attributed to steric hindrance from the phosphine and 11), were generated with >20:1 diastereomeric
and the special structure of barbiturate ring. The posi- ratios. A 2-naphthyl-substituted alkene (1m) led to
tion of the substituent on the benzene ring seemed to excellent yield, diastereoselectivity and enantioselec-
have no remarkable influence on the activities and tivity (86% yield, >20:1 dr, 93% ee) (entry 14). The
stereoselectivities (entries 1–15). Notably, 2-naphthyl- 2-furanylalkene 1n was also compatible with the cur-
and 2-thienyl-substituted substrates also reacted effi- rent system, affording the product 3na in 99% ee,
ciently with barbiturate-derived alkene, affording the albeit in only 45% yield (entry 15). For phosphine-
corresponding spirocyclic products with high yields catalyzed annulation reactions, alkenes bearing ali-
and excellent ee values (entries 14 and 15). Unfortu- phatic substituents are generally challenging sub-
nately, two alkyl-substituted MBH carbonates did not strates. In this [3+2] annulation, a cyclohexyl-substi-
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Table 3. Scope of barbiturate-derived alkenes 1.[a]
Entry
R
Time [h]
3
Yield [%][b]
ee [%][c]
1
Ph (1a)
16
16
18
16
18
18
18
18
15
15
20
20
16
16
24
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
3ja
3ka
3la
3ma
3na
3oa
85
98
97
98
98
92
87
90
60
99
70
89
86
45
30
96
91
99
93
97
91
99
91
97
98
99
98
93
99
81
2
2-MeC6H4 (1b)
3-MeC6H4 (1c)
4-MeC6H4 (1d)
2-MeOC6H4 (1e)
4-MeOC6H4 (1f)
2-FC6H4 (1g)
4-FC6H4 (1h)
2-ClC6H4 (1i)
4-ClC6H4 (1j)
2-BrC6H4 (1k)
4-BrC6H4 (1l)
2-naphthyl (1m)
2-thienyl (1n)
cyclohexyl (1o)
3[d]
4
5
6
7
8
9
10
11[e]
12
14
15
16
[a]
Unless otherwise stated, reactions of 1 (0.1 mmol) and 2a (0.12 mmol) were carried out in the presence of P4
(0.02 mmol), K2CO3 (0.02 mmol) and 50 mg of 4ꢂ MS at 808C in 2 mL of PhCF3.
Isolated yield. Unless otherwise stated, the dr is >20:1, determined by H NMR analysis.
Determined by chiral HPLC analysis.
dr=4:1.
dr=4:5.
[b]
[c]
[d]
[e]
1
tuted alkene displayed moderate activity, leading to in THF at 08C for 4 h, giving the reduction product 4
the spirocyclic product 3oa in 30%yield, but gratify- in 70% yield. In the presence of Pd(Ph3P)4 and butyl-
ingly, an 81% ee was obtained (entry 16).
di(1-adamantyl)phosphine, the coupling of 3an with 4-
The products could further be transformed into chlorophenylboronic acid proceeded smoothly in 1,1-
other useful compounds (Scheme 2). The spirobarbi- dimethoxyethane (DME) at 808C to afford the corre-
turate-cyclopentene 3an was treated with DIBAL-H sponding product 5 in 95% yield.
A reasonable mechanism is proposed in Scheme 3.
The allylic phosphonium ylide A formed from nucleo-
philic addition of phosphine to MBH carbonate 2 un-
Scheme 2. Synthetic transformations of the product.
Scheme 3. A proposed mechanism.
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ment, Wiley, Hoboken, 2010; i) J. Wang, C. Medina,
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dergoes a nucleophilic attack from the bottom of the
carbon-carbon double bond of the barbiturate-derived
alkene to give the phosphonium ylide B, which subse-
quently carries out intramolecular conjugate addition
to furnish the [3+2] annulation and afford the phos-
phonium ylide C. Consequent formation of a carbon-
carbon double bond and simultaneous ejection of
phosphine leads to the annulation product 3.
In summary, we have developed an efficient
method for the asymmetric construction of biological-
ly significant chiral spirobarbiturate-cyclopentenes
through chiral phosphine-catalyzed asymmetric [3+2]
annulation of MBH carbonates with barbiturate-de-
rived alkenes in moderate to excellent yields with
moderate to excellent diastereo- and enantioselectivi-
ties. The method will be a useful tool in the synthesis
of biologically active compounds for the discovery of
novel therapeutic agents.
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Experimental Section
General Procedure
Under a nitrogen atmosphere, to a stirred mixture of alkene
1
(0.1 mmol), MBH carbonate 2 (0.12 mmol), K2CO3
(0.02 mmol) and 4ꢂ MS (50 mg) in 2 mL of trifluorotoluene
was added chiral phosphine P4 (11 mg, 0.02 mmol) and the
resulting mixture was stirred at 808C. Upon completion of
the reaction as monitored by TLC, the mixture was concen-
trated under vacuum. The residue was purified through flash
column chromatography (ethyl acetate/petroleum ether) to
afford the corresponding annulation product.
Acknowledgements
This work is supported by the NSFC (21372256 and
21572264), the National S&T Pillar Program of China
(2015BAK45B01), Research Fund for the Doctoral Program
of Higher Education of China (20120008110038) and Chi-
nese Universities Scientific Fund (2016QC090).
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