Organocatalytic formal [2+2] cycloaddition initiated by vinylogous Friedel-Crafts alkylation: Enantioselective synthesis of substituted cyclobutane derivatives

Article abstract of DOI:10.1039/c3cc41785a

An organocatalytic vinylogous Friedel-Crafts alkylation-initiated formal [2+2] cycloaddition was successfully developed based on tandem iminium-enamine activation of enals. Transformable pyrrole-functionalized cyclobutanes with three contiguous stereocenters were readily obtained with excellent levels of regio-, diastereo- and enantiocontrol. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc41785a

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Organocatalytic formal [2+2] cycloaddition initiated by
vinylogous Friedel–Crafts alkylation: enantioselective
synthesis of substituted cyclobutane derivatives†
Cite this: Chem. Commun., 2013,
49, 4625
Received 9th March 2013,
Accepted 28th March 2013
Guo-Jian Duan, Jun-Bing Ling, Wei-Ping Wang, Yong-Chun Luo and Peng-Fei Xu*
DOI: 10.1039/c3cc41785a
www.rsc.org/chemcomm
An organocatalytic vinylogous Friedel–Crafts alkylation-initiated salt-promoted [2+2] cycloaddition of unactivated alkenes with
formal [2+2] cycloaddition was successfully developed based on a-acyloxyacroleins.5c More recently, Jørgensen and Vicario
tandem iminium–enamine activation of enals. Transformable groups independently discovered two [2+2] cycloaddition reac-
pyrrole-functionalized cyclobutanes with three contiguous stereo- tions of enals and nitroalkenes on the basis of dienamine
centers were readily obtained with excellent levels of regio-, catalysis.5d,e Herein, we report a method for the organocatalytic
diastereo- and enantiocontrol.
synthesis of chiral cyclobutanes using organocatalytic [2+2]
cycloaddition of enals and 2-vinylpyrroles, generating chiral
Cyclobutanes represent an intriguing strained molecular scaf- cyclobutanes with high stereocontrol.
fold and constitute the backbone of a large number of natural
The vinylogy principle is a commonly encountered strategy
products and biologically interesting molecules (Fig. 1).1,2 to implement new reactivity and diversity in organic synthesis
Driven by the relief of the ring strain, the functionalized and catalysis.6 Over the past decade, with the rapid develop-
cyclobutanes can act as reactive intermediates for further ment of organocatalysis, a wide array of organocatalytic trans-
ring-opening and ring expansion reactions enabling the develop- formations involving vinylogous nucleophiles or electrophiles
ment of new synthetic methods as well as complex molecule were devised to furnish valuable enantiomerically enriched
synthesis.3 Therefore, many reports directed toward the syn- molecules.7 Recently, vinylindole-involved vinylogous Friedel–
thesis of these privileged building blocks have appeared so far. Crafts alkylation has been successfully incorporated into
Among them, the [2+2] cycloaddition reaction stands out as the organocatalytic [4+2] cycloaddition.8 Chiral amine-mediated
most versatile and powerful strategy for the construction of Friedel–Crafts alkylation of aromatic substrates to enals is
such systems.4 Surprisingly, however, the asymmetric catalytic a reliable strategy to generate synthetically versatile b-aryl
[2+2] cycloaddition, especially organocatalytic variants to carbonyls.9 We envisioned that aminocatalyzed vinylogous
construct enantioenriched cyclobutanes are extremely rare Friedel–Crafts alkylation-initiated [2+2] cycloaddition of 2-vinyl-
and less explored.5 In 2007, Ishihara and co-workers reported pyrroles10 and enals would be feasible on the basis of tandem
an elegant example of the enantioselective synthesis of sub- iminium–enamine activation of enals.11 Importantly, this chemistry
stituted cyclobutanes by means of chiral organoammonium will allow for the enantioselective synthesis of challenging but
significant pyrrole-functionalized cyclobutanes.
As a proof of concept study, 2-vinyl-1-allyl-pyrrole (1a) was
reacted with trans-cinnamaldehyde (2a) as a model reaction
under the influence of the commonly used a,a-diphenylprolinol
trimethylsilyl ether (4a).12 The preliminary results demon-
strated a strong solvent effect on reactivity and selectivity.
Under the specified time, no desired product could be found
with toluene or CH2Cl2 as the solvent (Table 1, entries 1 and 2),
while in Et2O and THF, the desired product was readily
obtained with high enantioselectivities albeit in low yields
(Table 1, entries 3 and 4). Improved results were observed by
means of alcoholic solvents (Table 1, entries 5–7) and EtOH
gave a satisfactory yield and excellent enantioselectivity (76%
yield, 93% ee). Apparently, these results showed that the protic
solvent is helpful for the hydrolysis of the intermediate to
Fig. 1 Representative natural products containing a cyclobutane scaffold.
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and
Chemical Engineering, Lanzhou University, Lanzhou 730000, P.R. China.
E-mail: xupf@lzu.edu.cn
† Electronic supplementary information (ESI) available: Experimental procedures
and spectra of all new compounds. CCDC 915787. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c3cc41785a
c
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Table 1 Screening of the reaction parametersa
Table 2 Scope of the asymmetric formal [2+2] cycloaddition of 2-vinyl pyrroles
with a,b-unsaturated aldehydesa
R2
3
t (h)
Yieldb (%)
eec (%)
Entry
Catalyst
Solvent
t (h)
Yieldb (%)
eec (%)
Entry
1
1
2
3
4
5
6
7
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
4e
4f
Toluene
CH2Cl2
Et2O
48
48
48
48
48
48
48
48
48
72
60
72
48
72
—
Trace
43
—
n.d.
90
90
92
93
88
n.d.
n.d.
n.d.
87
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1d
1e
1f
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3a
3q
60
72
60
60
60
60
60
60
60
60
60
72
72
60
60
60
60
72
72
76
53
78
63
68
62
70
65
72
79
71
70
65
53
62
68
72
70
65
93
91
95
92
91
91
89
94
96
95
92
98
97
65
92
90
90
90
85
2-MeC6H4
2-ClC6H4
2-BrC6H4
3-ClC6H4
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-FC6H4
4-CNC6H4
4-CF3C6H4
4-CNC6H4
4-CF3C6H4
Ph
THF
40
70
76
50
MeOH
EtOH
iPrOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
8d
9e
10
11
12
13
14
o10
o10
Trace
60
9
10
11
12
13
14
15
16
17
18d
19e
46
67
30
83
90
80
Ph
Ph
Ph
Ph
a
Unless otherwise noted, the reaction was carried out with 1a
(0.15 mmol), 2a (0.10 mmol) and 4 (0.02 mmol) in the specified solvent
b
c
(0.5 mL) at room temperature. The isolated yield. Determined using
HPLC analysis. PhCO2H (20 mol%) was added. TsOH (20 mol%)
was added.
1a
1f
d
e
Ph
a
Unless otherwise noted, the reaction was carried out with
1
(0.15 mmol), 2 (0.10 mol) and 4a (0.02 mmol) in EtOH (0.5 mL) at
room temperature. The isolated yield. Determined using HPLC
analysis. The reaction was carried out with 1 (9.0 mmol), 2 (6.0 mmol)
and 4a (1.2 mmol). The reaction was carried out with 1 (6.0 mmol),
b
c
release the catalyst and thus increase the catalytic turnover.
Further screening revealed a dramatic negative effect of acidic
additives possibly due to the acid-sensitive nature of the pyrrole
ring (Table 1, entries 8 and 9). Next, the impact of various
chiral secondary amine catalysts on the reaction was tested
in ethanol at room temperature. Among them, MacMillan
imidazolidinone catalyst 4b proved to be ineffective under the
tested conditions (Table 1, entry 10), while diphenylprolinol
4c and 4d gave the desired product in moderate yield and
slightly decreased stereoinduction (Table 1, entries 11 and 12).
Compared with 4a, its analogues 4e and 4f exhibited relatively
inferior results with respect to reactivity and selectivity
(Table 1, entries 13 and 14). In all the tested cases described
above, the diastereocontrol was perfect with only one of the four
possible diastereomers found. We then decided to investigate
the scope of the reaction under the optimal reaction conditions
(Table 1, entry 6).
The results are summarized in Table 2. With regard to the
a,b-unsaturated aldehydes, it was found that a wide range of
cinnamaldehyde derivatives are well tolerated regardless of the
nature and position of the substituent of the aromatic ring
(Table 2, entries 1–11). However, a remarkable substituent
effect on reactivity was observed (Table 2, entries 2 and 4 vs.
9–11). Reaction of the pyrrole component bearing a bromide
atom at the C4-position proceeded smoothly under the
standard conditions, giving rise to the desired products in
comparable yields and enantioselectivities while the 5-methyl
pyrroles exhibited diminished reactivity and ee possibly
owing to steric hindrance (entries 12–14). Simple variation of
the substituent at the nitrogen atom had little impact on
d
e
2 (4.0 mmol) and 4a (0.8 mmol).
Notably, gram-scale synthesis of the product also could be
achieved (Table 2, entries 18 and 19).
To further demonstrate the generality of this formal [2+2]
cycloaddition reaction, 4,7-dihydroindole-derived substrate 1g
was explored under the established conditions.13 Gratifyingly,
the desired cycloadduct 3s was readily achieved with high
enantioselectivity. The dihydroindole tether could be oxidated
under mild conditions to deliver the trisubstituted cyclobutane
with an indole pendant in high yield with no loss of enantio-
selectivity (Scheme 1a). Subsequently, a representative example of
the generation of a biologically interesting fused 12-membered
macrolide was performed to demonstrate the synthetic potential
of this reaction. As illustrated in Scheme 1b, the target molecule
could be obtained efficiently in a simple esterification step
and ring closing metathesis sequence in satisfactory yield and
enantioselectivity.14
Scheme 1 (a) Synthesis of indole-functionalized cyclobutane; (b) transforma-
reactivity and enantioselectivity (Table 2, entries 15–17). tion of cycloadduct 3a to the fused 12-membered macrolide.
c
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experimental observations, a proposed catalytic cycle is illustrated
in Scheme 2. First, chiral iminium ion A was formed from the
catalyst and enal, which was susceptible to attack by the electron-
rich 2-vinylpyrroles from the unshielding Si-face to generate the
chiral triiminium ion B. The intermediate B was immediately
trapped by the tethered enamine from the Si-face of the reactive
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In summary, we have developed an efficient approach for the
construction of functionalized chiral cyclobutanes via organo-
catalyzed formal [2+2] cycloaddition of 2-vinyl pyrroles with
a,b-unsaturated aldehydes in moderate to high yields and with
excellent enantioselectivities. For the first time, based on
tandem iminium–enamine activation of a,b-unsaturated alde-
hydes, vinylogous Friedel–Crafts reaction was efficiently incor-
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chemistry holds great potential in novel reaction design and
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c
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