Organocatalytic Enantioselective Synthesis of Tetrahydrofluoren-9-ones via Vinylogous Michael Addition/Henry Reaction Cascade of 1,3-Indandione-Derived Pronucleophiles

Article abstract of DOI:10.1021/acs.orglett.5b03663

An unprecedented organocatalytic enantioselective vinylogous Michael addition/Henry cyclization cascade is presented for the synthesis of highly substituted tetrahydrofluoren-9-ones 3 employing novel 1,3-indandione-derived pronucleophiles 1a-g and nitroalkenes 2. Following a very simple protocol, a wide range of products were obtained in good to excellent yields and with excellent enantioinduction (43-98% yield, up to 98% ee). The reaction proceeded with excellent diastereocontrol despite the simultaneous generation of four stereogenic centers. Surprisingly, when 2-(1-phenylethylidene)-1H-indandione (1h) was used as a pronucleophile, no cyclization was observed, and only Michael addition adducts 4a-x were furnished in very good yields and excellent enantioselectivities. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.orglett.5b03663

Letter
pubs.acs.org/OrgLett
Organocatalytic Enantioselective Synthesis of Tetrahydrofluoren-9-
ones via Vinylogous Michael Addition/Henry Reaction Cascade of
1,3-Indandione-Derived Pronucleophiles
Lennart Mohlmann, Geng-Hua Chang, G. Madhusudhan Reddy, Chia-Jui Lee, and Wenwei Lin*
̈
Department of Chemistry, National Taiwan Normal University, 88, Sec. 4, Tingchow Road, Taipei 11677, Taiwan, R.O.C.
S
* Supporting Information
ABSTRACT: An unprecedented organocatalytic enantiose-
lective vinylogous Michael addition/Henry cyclization cascade
is presented for the synthesis of highly substituted
tetrahydrofluoren-9-ones 3 employing novel 1,3-indandione-
derived pronucleophiles 1a−g and nitroalkenes 2. Following a
very simple protocol, a wide range of products were obtained
in good to excellent yields and with excellent enantioinduction (43−98% yield, up to 98% ee). The reaction proceeded with
excellent diastereocontrol despite the simultaneous generation of four stereogenic centers. Surprisingly, when 2-(1-
phenylethylidene)-1H-indandione (1h) was used as a pronucleophile, no cyclization was observed, and only Michael addition
adducts 4a−x were furnished in very good yields and excellent enantioselectivities.
Scheme 1. Vinylogous Michael Addition/Henry Reaction
Cascade
symmetric vinylogous Michael addition (VMA), which
involves the enantioselective γ-addition of nucleophiles to
A
the suitable Michael acceptors, has emerged as a versatile and
powerful transformation in organic synthesis.1 Although various
metal-2 and organocatalyzed3 strategies have been reported, the
enormous potential of this γ-addition reaction is often restricted
to a single-step transformation. Until now, applications of
asymmetric VMAs in tandem processes are uncommon, yet
highly desired, since they enable a rapid synthesis of elaborated
chemical structures starting from cheaper and easily available
substrates.4
Furthermore, the development of an enantioselective Henry
reaction with ketones is met with limited success5 due to their
inherently low reactivity when compared to aldehydes. The
intramolecular versions of Henry cyclizations are seldom
reported due to the difficulty in the synthesis of required
nitrocarbonyl precursors bearing an electrophilic and a
nucleophilic site in the same substrate.6 However, this could
be overcome by incorporating the Henry reaction in a cascade
process where a more reactive transient intermediate could
serve the purpose, resulting in efficient cyclizations. So far, only
a few such tandem processes involving Henry reaction on
ketones have been reported7 and offer a large scope for
exploration.
A very elegant VMA/Henry reaction cascade using a chiral
magnesium complex has been reported by Wang and co-
workers (Scheme 1, eq 1).8 Following this method, substituted
cyclohexene derivatives were obtained as products in moderate
to good yields, good diastereoselectivities, and excellent
enantioselectivities. However, to date, there are no reports on
the organocatalytic enantioselective VMA/Henry reaction
cascade involving ketones.
envisaged that due to the strong electron-withdrawing effect of
the 1,3-indandione moiety, 1 would feature substantially high γ-
acidity which is essential for its reactivity. Additionally, the
carbonyl functionalities of the indandione moiety could be
exploited for further tandem processes. Owing to the large
planar structure, we presumed that it would be possible to
achieve high levels of enantioinduction by employing a
sterically bulky chiral organocatalyst. Hence, we expected that
the treatment of 1 with a suitable Michael acceptor such as
nitroalkene 2 in the presence of a chiral base catalyst would give
a direct access to precious, highly complex tetrahydrofluoren-9-
one derivatives9 via a vinylogous Michael addition/Henry
cyclization pathway.
In the present work, we introduce a novel and versatile
Received: December 25, 2015
pronucleophile 1 which has never been explored for VMAs. We
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03663
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
We started our investigations using 1a and 2a as model
substrates in the presence of DABCO as catalyst in xylenes.
The reaction proceeded smoothly, and the expected product
rac-3aa was obtained in moderate yield (Table 1, entry 1). A
catalyst 5b could enhance the yield and enantiomeric excess of
the product ent-3aa to 84% and 87%, respectively (Table 1,
entry 4).11 When thiourea catalyst 5c was used, the
enantioselectivity increased, while the yield dropped slightly
(Table 1, entry 5).12 By changing the catalyst to 5d, the yield of
3aa could be further enhanced, retaining the similar
enantioselectivity (Table 1, entry 6). Finally, different
squaramide catalysts 5e−g were tested (Table 1, entries 7−
9).13 To our delight, when the catalyst 5e was used, the yield
and enantiomeric excess of 3aa could be enhanced to 93% and
95%, respectively (Table 1, entry 7).
a
Table 1. Optimization of the Reaction Conditions
A quick solvent screening was then performed that
confirmed xylenes as the best choice (Table 1, entries 10−
12). It is worth mentioning that there was no difference in the
outcome of the reaction when it was conducted in either o-, m-
or p-xylene. Furthermore, both moisture and air were tolerated
well and did not affect the reaction result, making this protocol
very simple and easy to reproduce. Finally, a low temperature
experiment (−10 °C) (Table 1, entry 14) and a reduced
catalyst loading (5 mol %) (Table 1, entry 13) were examined.
In both cases, the reaction failed to accomplish full conversion
within 24 h, and 3aa was obtained in poor yields. Therefore, we
decided to set the conditions in entry 7 as our optimal reaction
conditions and started with the exploration of the substrate
scope.
First, differently substituted nitroalkenes 2a−o were
examined (Table 2, entries 1−15). In each case, the product
3 could be obtained as a single diastereomer. Various
functionalities could be tolerated well under the reaction
conditions. Halogen-substituted nitrostyrenes gave the desired
products in excellent yields and enantioselectivities (Table 2,
entries 2−5). The position of the functionality did not have a
strong influence on the reaction outcome, and comparable
results were obtained (Table 2, entries 2 and 3). Interestingly,
in the case of the o-Br-substituted electrophile 2c, the
appearance of two rotamers (1:1) was evident from NMR-
spectroscopic analysis. The absolute configuration could be
identified as (2S,3R,4R,4αS) by X-ray analysis of 3ac (CCDC
1449770). Other strong electron-withdrawing groups, such as
nitro and cyano, were also compatible with good to excellent
yields and enantioselectivities (Table 2, entries 6 and 7).
Surprisingly, p-trifluoromethyl nitrostyrene (2h) showed
reduced reactivity, and it is necessary to increase the catalyst
loading to 15 mol % in order to achieve full consumption of 2h
(Table 2, entry 8).
b
b
c
entry
1
cat.
solvent
3aa (%)
4aa (%)
ee (%)
d
d
DABCO
xylenes
xylenes
xylenes
xylenes
xylenes
xylenes
xylenes
xylenes
xylenes
toluene
DCM
41
30
e
2
DABCO
5a
11
55
84
77
91
93
87
81
81
70
65
15
35
71
<5
<5
<5
<5
<5
<5
<5
8
3
40
f
4
5b
87
5
5c
90
90
95
6
5d
7
5e
f
8
5f
93
9
5g
96
95
95
93
10
11
12
5e
5e
14
14
52
24
5e
THF
e
g
13
h
5e
xylenes
xylenes
99
14
5e
nd
a
Reaction conditions: 0.055 mmol of 1a, 0.05 mmol of 2a, 0.5 mL of
b
1
solvent, 10 mol % of catalyst at 30 °C. Yields as determined by H
NMR analysis of crude reaction mixture using Ph3CH as internal
standard. ee of 3aa was determined by HPLC analysis on a chiral
stationary phase. rac-3aa and rac-4aa were obtained. 5 mol % of
catalyst was used. Opposite enantiomer (ent-3aa) was in excess. ee of
c
d
e
f
g
h
4aa. Reaction was carried out at −10 °C.
significant amount of rac-4aa was also initially observed, which
later transformed into the cyclized product rac-3aa, affirming
the expected two-step VMA/Henry reaction pathway.10
Despite the fact that four stereogenic centers are formed
simultaneously, tetrahydrofluoren-9-one rac-3aa was obtained
as a single diastereomer, making this protocol highly efficient.
After the successful proof of principal, a selection of chiral
organocatalysts 5a−g (Figure 1) were evaluated for the VMA/
As compared to electron-withdrawing substituents, electron-
donating groups displayed slightly diminished reactivities
(Table 2, entries 9−12). Hence, in some cases it was necessary
to increase the catalyst loading to 15 mol % (Table 2, entries 10
and 11). Heteroaryl-substituted nitroolefins 2m,n were also
compatible with this protocol (Table 2, entries 13 and 14), and
satisfactory results were obtained. In case of the aliphatic
substitution, the reaction had to be prolonged for 36 h (Table
2, entry 15) because of its lower reactivity. The desired product
3ao was obtained with excellent enantioselectivity, albiet in
moderate yield. However, the reaction did not work with other
aliphatic substituents.
We then examined a variety of 1,3-indandione-derived
pronucleophiles 1b−h. Bromo substitution on the aryl group
was tolerated, although its location had an obvious influence on
the reaction outcome. Usage of (p-bromophenyl)propylidene
indandione (1b) resulted in the formation of 3ba and 3bb with
excellent yields and enantioselectivities (Table 2, entries 16 and
Figure 1. Chiral catalysts screened during optimization.
Henry cyclization cascade. Reducing the catalyst loading to 5
mol % resulted in the intermediate rac-4aa as the major
product, which was isolated and characterized (Table 1, entry
2). This further confirmed that the reaction followed a stepwise
VMA/Henry cyclization rather than a concerted pathway.
Quinidine 5a could result in the product 3aa in only moderate
yield and enantioselectivity (Table 1, entry 3). Takemoto’s
B
DOI: 10.1021/acs.orglett.5b03663
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Organic Letters
Letter
Henry reaction would be equally feasible irrespective of
whether R2 = H or R2 = alkyl. Hence, we believe that even
when R2 = H, the cyclization is indeed taking place (Scheme 2).
Table 2. Substrate Scope for the Enantioselective VMA/
Henry Reaction Cascade
a
Scheme 2. Ring Opening of 3 Resulting in the Retro-Henry
Product 4
b
c
entry
R1/R2
Ph/Me
R3
3, yield (%)
ee (%)
1
2
3
4
5
6
7
Ph
3aa (91)
3ab (89)
97
95
95
92
94
93
94
98
95
94
91
94
93
94
95
93
92
95
93
90
94
94
nd
Ph/Me
p-BrPh
o-BrPh
p-ClPh
p-FPh
p-NO2Ph
p-CNPh
p-CF3Ph
p-MePh
p-OMePh
m-OMePh
3,4-OMePh
2-furyl
2-thienyl
Cy
d
Ph/Me
3ac (98)
Ph/Me
3ad (94)
3ae (96)
3af (91)
3ag (83)
3ah (80)
3ai (76)
3aj (85)
3ak (93)
3al (76)
3am (80)
3an (92)
3ao (43)
3ba (91)
3bb (91)
Ph/Me
Ph/Me
Ph/Me
e
8
Ph/Me
9
Ph/Me
e
10
Ph/Me
e
11
Ph/Me
12
13
14
Ph/Me
Ph/Me
Ph/Me
e
,
,
f
f
15
16
17
18
19
20
21
22
23
Ph/Me
p-BrPh/Me
p-BrPh/Me
o-BrPh/Me
p-OMePh/Me
3,4-ClPh/Me
2-thienyl/Me
Ph/n-Pr
Ph/H
Ph
However, as a consequence of the sufficiently high γ-acidity
imparted to the carbon bearing R2 group in 3, there is a
subsequent ring-opening occurring, and the intermediate 4 is
being regenerated, which seems to be thermodynamically more
stable than 3. However, when R2 = alkyl, deprotonation of the
sterically congested acidic γ-site by the bulky catalyst 5 would
be difficult, preventing the ring opening and thereby resulting
in the retention of the cyclized product 3. This also explains the
result in entry 1 of Table 1, where a considerable amount of
intermediate 4aa is retained as a consequence of ring-opening
of initially formed product 3aa.
Hence, we focused on the synthesis of thermodynamically
more stable intermediate 4 with R2 = H. After an additional
tuning of the reaction parameters, the yield of the product 4ha
could be greatly enhanced (Table 3, entry 1), while the
enantioselectivity was retained. Subsequently, the substrate
scope of this transformation was examined by employing
various substrates, and the results are summarized in Table 3.
When 1h or 1i was used as the pronucleophile, good to
excellent yields and enatioselectivities were achieved for all
nitroalkenes in short reaction times (Table 3, entries 1−13).
However, when the symmetric pronucleophile 1j bearing two
methyl groups was tested, the yield of the product 4ja dropped
significantly while the excellent enantioselectivity still remained
(Table 3, entry 14).
To demonstrate the generality of the indandione-derived
pronucleophiles, we then tested the other Michael acceptor,
such as 6a derived from oxindole, in our preliminary study.
When 1a or 1f was treated with 6a under the slightly modified
reaction conditions using the catalyst 5d, the reactions
proceeded well and the products were obtained in excellent
yields and enantioselectivities (Scheme 3). However, the
formation of two diastereomers could be observed in these
cases. The relative configuration of 7fa was established by X-ray
crystallography (CCDC no. 1436597).
In summary, we have established indandione derivatives 1a−j
as novel, highly efficient pronucleophiles for the enantiose-
lective VMAs. We can successfully obtain the subsequent
cyclization products 3 via a Henry reaction which is an
infrequently used transformation involving a ketone. The
p-BrPh
Ph
d
3ca (77)
e
Ph
3da (78)
3ea (83)
3fa (70)
3ga (79)
Ph
Ph
Ph
g
Ph
3ha (12)
a
Reaction conditions: 0.11 mmol of 1, 0.1 mmol of 2, 1.0 mL of
b
c
xylenes, 10 mol % of 5e at 30 °C. Isolated yield. Determined by
HPLC analysis on a chiral stationary phase. The product appears as a
mixture of two atropisomers. 15 mol % of 5e was used. Reaction time
was 36 h. 33% of the corresponding acyclic product 4ha was formed.
d
e
f
g
17). For the o-Br-substituted pronucleophile 1c, the yield of
3ca decreased significantly to 77%, although the enantiose-
lectivity remained excellent (Table 2, entry 18). Even in this
case, characterization of 3ca via NMR analysis revealed the
appearance of two rotamers in a ratio of 2:1. For
pronucleophile 1d bearing an electron-donating methoxy
group, 15 mol % of 5e and a prolonged reaction time had to
be employed to afford 3da in 78% yield and 94% ee (Table 2,
entry 19).
The strongly electron-deficient dichloroaryl-substituted
pronucleophile 1e also performed well in this cascade reaction
(Table 2, entry 20). The thienyl-substituted pronucleophile 1f
resulted in slightly diminished yield of the product 3fa, while
the excellent enantioselectivity was retained (Table 2, entry
21).
Finally, the variation of the R2 substitution was investigated.
When a longer alkyl chain was presented, the corresponding
product 3ga was obtained in good yield with excellent
enantioselectivity (Table 2, entry 22). However, when
methyl-substituted pronucleophile 1h (R2 = H) was used,
only a small amount of 3ha was obtained while the
intermediate 4ha appeared as the major product (Table 2,
entry 23). The strikingly different results with R2 = H and R2 =
alkyl made us wonder about the possible reasons for such
outcome. It would be expected that the remote R2 group would
have no role to play in assisting the cyclization of 4, and the
C
DOI: 10.1021/acs.orglett.5b03663
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Notes
Table 3. Substrate Scope for the Enantioselective VMA
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Ministry of Science and Technology of the
Republic of China (MOST 103-2113-M-003-009-MY3) for
financial support.
b
c
entry
R1/R3
Ph/Ph
time (h)
4, yield (%)
ee (%)
d
1
2
1.5
1.5
1.5
3
4ha (84)
92
90
94
93
90
90
98
93
95
95
95
94
83
93
e
2
3
4
5
6
7
8
Ph/p-BrPh
Ph/p-ClPh
Ph/p-FPh
4hb (78)
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4hl (77)
4hn (68)
4ia (80)
4ja (45%)
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03663.
■
S
Experimental procedures, characterization data, and
spectra for all compounds (PDF)
Crystallographic data for 3ac (CIF)
Crystallographic data for 4hb (CIF)
Crystallographic data for 7fa (CIF)
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: wenweilin@ntnu.edu.tw.
D
DOI: 10.1021/acs.orglett.5b03663
Org. Lett. XXXX, XXX, XXX−XXX