Enantioselective construction of oxa- and aza-angular triquinanes through tandem [4 + 1]/[3 + 2] cycloaddition of sulfur ylides and nitroolefins

Article abstract of DOI:10.1021/ol303363r

A formal [4 + 1]/[3 + 2] cycloaddition sequence of sulfur ylides and alkene-tethered nitroolefins has been developed. The use of (R)-binol-derived chiral sulfide leads to an asymmetric process that allows the construction of oxa- and aza-angular triquinanes in good to excellent diastereo- and enantioselectivities.

Full text of DOI:10.1021/ol303363r

ORGANIC
LETTERS
2013
Vol. 15, No. 3
542–545
Enantioselective Construction of Oxa- and
Aza-Angular Triquinanes through Tandem
[4 þ 1]/[3 þ 2] Cycloaddition of Sulfur
Ylides and Nitroolefins
Jing An, Liang-Qiu Lu, Qing-Qing Yang, Tao Wang, and Wen-Jing Xiao*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of
Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan, Hubei 430079, China
wxiao@mail.ccnu.edu.cn
Received December 10, 2012
ABSTRACT
A formal [4 þ 1]/[3 þ 2] cycloaddition sequence of sulfur ylides and alkene-tethered nitroolefins has been developed. The use of (R)-binol-derived
chiral sulfide leads to an asymmetric process that allows the construction of oxa- and aza-angular triquinanes in good to excellent diastereo- and
enantioselectivities.
The angular triquinanes and their heteroatom-substituted
analogues form the core architecture of numerous natural
products which display a broad and interesting range of
biological activities.1ꢀ3 Consequently, these complex poly-
cyclic frameworks have become interesting targets for the
synthetic organic chemistry community. Recently, several
strategies have been developed for the synthesis of
heterotriquinanes, including cascade radical methods,4
tandem enyne/ring closing metathesis approaches,5 and
others.6 Despite these successes, the search for new effi-
cient, especially stereospecific approaches to such a motif
bearing three fused rings and multiple consecutive stereo-
genic centers, including a chiral quaternary center, remains
a substantial challenge.
Over the past decade, sulfur ylides7 were used as diverse
reagents to construct complex cyclic molecules beyond
three-memberedrings. For instance, we recently developed
a [4 þ 1]/[3 þ 2] cycloaddition of sulfur ylides with
nitroolefins,8 wherein a transiently generated cyclic
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r
10.1021/ol303363r
Published on Web 01/17/2013
2013 American Chemical Society

nitronate was involved. This cascade reaction provided
rapid access tofused heterocyclic compounds inhighyields
and stereoselectivities. On the basis of the success of the
initial study, we became interested in the possibility of
expanding the synthetic utility of this strategy to prepare a
variety of heterotriquinanes. Herein, we report the tandem
intermolecular [4 þ 1] and intramolecular [3 þ 2] cycloaddi-
tion process of sulfur ylides and R-tethered nitroolefins9
affording the previously unknown tetrahydrofuro[3,4-c]-
isoxazolo[2,3-b]isoxazol-3(1H)-ones in good yields. This se-
quence involves the formation of four new σ bonds and five
consecutive stereogenic centers in excellent stereoselectivities
(Scheme 1).
110 °C for 6 h, to give the desired triquinane 4a in 90%
isolated yield with >95:5 dr.
In order to carry out the enantioselective version, the
strategy of chiral substrate control was applied to this
transformation. Thus, a series of chiral sulfur ylides were
prepared with atropisomeric sulfide 5 as the starting
material.10 The reaction of chiral ylide 1a0 with acrylate-
tethered nitrostyrene 2a was initially examined in CH2Cl2
at 0 °C, and itwas found thatenantioenrichednitronate3a0
was formed in good yield (Table 1, entry 1, 77% yield and
26% ee). A survey of reaction media showed that this
asymmetric [4 þ 1] process was remarkably influenced by
the polarity of solvents (Table 1, entries 1ꢀ9). Weakly
polar solvents, such as toluene and benzene, improved the
enantioselectivity to 76% ee at 0 °C and rt, respectively
(Table 1, entries 8 and 9). Then we examined a toluene and
benzene mixture at lower temperature in an effort to
elevate the stereoselectivity of this process (Table 1, entries
10ꢀ13). We found that the reaction in toluene and benzene
with a ratio of 1:1 at ꢀ40 °C provided 3a in 84% ee
(Table 1, entry 12). The reaction conditions were further
Scheme 1. Reaction Design
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of phenylacyl sulfur ylide 1a with (E)-2-nitro-3-phenylallyl
cinnamate 2a in CHCl3. When the reaction was performed
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product was the formal [4 þ 1] adduct 3a (eq 1). Compared
withthe previous[4 þ 1]/[3 þ 2] cycloaddition tosynthesize
fused oxa- and aza-cycles, this reaction is more challenging
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including a quaternary center in the [3 þ 2] cycloaddition.
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lated nitronate 3a was facilitated by heating in toluene at
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Org. Lett., Vol. 15, No. 3, 2013
543

Table 1. Optimization of Reaction Conditions for Asymmetric
[4 þ 1] Annulationa
Table 2. Scope of Substrates in Asymmetric [4 þ 1] Annulationa
entry
R1
R2
yieldb (%)
drc
eed (%)
entry
solvent
temp (°C) concn (M) yieldb (%) eec (%)
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3a0, 93
3b, 87
3c, 91
3d, 94
3e, 93
3f, 91
3g, 78
3h, 90
3i,e 95
3j, 89
3k, 95
3l, 91
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
92
90
94
86
86
88
90
86
90
96
90
94
1
CH2Cl2
CHCl3
0
0
0
0
0
0
0
0
rt
0
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
77
97
49
58
48
62
35
75
74
74
26
25
42
49
19
27
3
2
4-MePh
4-MeOPh
4-FPh
2
3
3
Et2O
4
4
THF
5
4-ClPh
4-BrPh
2-FPh
5
DMF
6
6
CH3CN
CH3OH
toluene
benzene
toluene/
benzene
toluene/
benzene
toluene/
benzene
toluene/
benzene
toluene/
benzene
toluene/
benzene
toluene/
benzene
7
7
8
3-BrPh
8
76
76
80
9
thiophenyl Ph
9
10d
10
11
12
Ph
Ph
Ph
4-MeOPh
4-ClPh
3,4-
11
12
13
14
15
16
ꢀ25
ꢀ40
ꢀ78
ꢀ40
ꢀ40
ꢀ40
0.05
0.05
0.05
0.1
86
93
92
83
89
95
80
84
84
77
89
92
(MeO)2Ph
2-naphthyl
13
Ph
3m, 87
>95:5
90
a Unless noted, reactions were performed with 1 (0.30 mmol), 2
(0.20 mmol) in toluene/benzene (1:1, 40 mL) at ꢀ40 °C. b Isolated yield.
c Determined by 1H NMR methods. d Determined by HPLC analysis.
e The absolute configuration of product 3i was established by X-ray
analysis.
0.01
0.005
Table 3. Scope of Substrates in [3 þ 2] Cycloadditiona
a Unless noted, reactions were performed with 1a0 (0.30 mmol), 2a
(0.20 mmol) in the noted solvent at the indicated temperature. b Isolated
yield. c Determined by chiral HPLC analysis. d The ratio of toluene and
benzene is 1:1.
entry
R1
R2
yieldb (%)
drc
eed (%)
optimized by adjusting the concentration (Table 1, entries
14ꢀ16). Finally, the superior levels of asymmetric induc-
tion and efficiency exhibited in a toluene and benzene
mixture at ꢀ40 °C (Table 1, entry 16, 95% yield and
92% ee) prompted us to use these conditions for further
exploration.
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4a,e 83
4b, 76
4c, 91
4d, 82
4e, 72
4f, 81
4g, 68
4h, 81
4i, 90
4j, 84
4k, 70
4l, 80
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
92
90
94
86
86
88
90
86
90
96
92
94
2
4-MePh
4-MeOPh
4-FPh
3
4
5
4-ClPh
4-BrPh
2-FPh
6
With the optimal conditions established, the substrate
scope of this annulation was then investigated and repre-
sentative results are listed in Table 2. Significant structural
variation in sulfurylides could be carried out. Note that the
reaction is quite general with respect to the electronic
contribution of the substituent in the aryl ring of sulfur
ylides (Table 2, entries 1ꢀ6, 87ꢀ94% isolated yield,
86ꢀ94% ee, and >95:5 dr). As highlighted in entries
6ꢀ8 of Table 2, variation in the position of the substituent
on the aryl group of the ylides is also tolerated without
remarkable effects on the chemical yield and stereoselec-
tivities of the transformation. To our delight, the scope of
sulfur ylides could be significantly extended to the hetero-
arylacyl sulfur ylide, and the corresponding enantio-
enriched nitronate was obtained in excellent yield and
stereoselectivities (Table 2, entry 9, 95% yield, >95:5 dr,
and 90% ee).
7
8
3-BrPh
9
thiophenyl Ph
10
11
12
Ph
Ph
Ph
4-MeOPh
4-ClPh
3,4-
(MeO)2Ph
2-naphthyl
13
Ph
4m, 82
>95:5
92
a Unless noted, reactions were performed with 3 in toluene (0.01 M)
at 110 °C. b Isolated yield. c Determined by 1H NMR methods. d Deter-
mined by HPLC analysis. e The absolute configuration of product 4a
was established by X-ray analysis.
As revealed in entries 1 and 10 to 13 of Table 2, this
asymmetric [4 þ 1] annulation was also general with
respect tothe nitroolefin component. Significant structural
variation on the benzene ring was well tolerated. The
544
Org. Lett., Vol. 15, No. 3, 2013

electronic nature of the benzene ring did not greatly affect
the yield, and usually excellent stereoselectivities were
achieved (89ꢀ95% yields, >95:5 dr, 90ꢀ96% ee). Further-
more, the disubstituted nitrostyrene derivative could readily
participate in this reaction and afforded the corresponding
nitronate in good stereoselectivities (Table 2, entry 12). It
was also found that the naphthalene-derived nitroolefin was
a suitable reaction partner, generating product 3m in 87%
yield and 90% ee (Table 2, entry 13).11
Scheme 2. Proposed Model
The two stereogenic centers which were created in the
[4 þ 1] process might undergo racemization easily. As
highlighted in Table 3, to our delight, the substrate-
induced asymmetric [3 þ 2] cycloaddition provided the
desired triquinanes smoothly and efficiently in good yields
and excellent diastereoselectivities in refluxing toluene
(Table 3, entries 1ꢀ13).
Furthermore, we were pleased to find that the hetero-
triquinanes could also be comparably obtained directly
without isolating the nitronate intermediate. For example,
when the (E)-2-nitro-3-phenylallyl cinnamate 2a was con-
sumed, the reaction mixture was concentrated and then
warmed to 110 °C in toluene to give the desired triquinane
4a in 73% yield, with 92% ee and greater than 95:5 dr (eq 2).
unambiguously confirmed to be (3aS, 4S, 8R, 9R, 9aS) by
X-ray crystallographic analysis of the optically pure ni-
tronate 3i and racemic 4a, and the stereochemistry of other
products could be tentatively assigned by assuming an
analogous enantioinduction (Scheme 2).12
In summary, we have described a tandem formal [4 þ 1]/
[3 þ 2] cycloaddition of sulfur ylides and alkene-tethered
nitroolefins. This strategy gave optically active oxa- and
aza-triquinanes in a concise way, with excellent stereose-
lectivities by using the low cost and readily availabile chiral
sulfur ylides. Further investigations on the synthetic trans-
formation and bioactivity screening are currently under-
way in our laboratory.
In light of previous work,8c,d one can rationalize the
origin of stereodiscrimination in this tandem reaction. The
sulfur ylides attack the Re face of nitroolefins in order to
minimize the steric interaction of the side chain in alkene-
tethered nitroolefins with the binaphthalene motif in the
chiral ylide component. Then the folding of the dipolar-
ophile tether occurred in an exo fashion through the
transition state I, because of the unfavorable steric inter-
action between the phenyl group and the dipolarophile
tether. The absolute configuration of triquinane 4a was
Acknowledgment. We are grateful to the National Basic
Research Program of China (2011CB808603), the National
Natural Science Foundation of China (Nos. 21232003 and
21202053), and Excellent Doctorial Dissertation Cultivation
Grant from CCNU for support of this research.
Supporting Information Available. Experimental pro-
cedures and compound characterization data including
X-ray crystal data (CIF) for 3i and 4a. This material is
available free of charge via the Internet at http://pubs.acs.org.
(11) The reaction with the alkylacyl-substituted sulfur ylide was very
slow even at room temperature, and the reaction with aliphatic nitro-
olefin derivative was complex.
(12) CCDC 904983 (3i) and 905855 (4a) contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 3, 2013
545