Enantioselective [2 + 2] cycloaddition of unactivated alkenes with α-acyloxyacroleins catalyzed by chiral organoammonium salts

Article abstract of DOI:10.1021/ja073435w

We report the first example of an organocatalytic enantioselective [2 + 2] cycloaddition reaction of unactivated alkenes with α-acyloxyacroleins to give optically active 1-acyloxycyclobutanecarbaldehydes and subsequent ring expansion to give optically active 2-hydroxycyclopentanone derivatives. Organoammonium salt, H-L-Phe-L-Leu-N(CH₂CH₂)₂-reduced triamine?2.6HNTf₂, is a highly effective chiral catalyst for the above enantioselective [2 + 2] cycloaddition. Thus, we have developed a novel and useful formal enantioselective [2 + 3] cycloaddition through two steps. Copyright

Full text of DOI:10.1021/ja073435w

Published on Web 07/04/2007
Enantioselective [2 + 2] Cycloaddition of Unactivated Alkenes with
r-Acyloxyacroleins Catalyzed by Chiral Organoammonium Salts
Kazuaki Ishihara* and Kazuhiko Nakano
Graduate School of Engineering, Nagoya UniVersity, Furo-cho, Chikusa, Nagoya 464-8603, Japan
Received May 15, 2007; E-mail: ishihara@cc.nagoya-u.ac.jp
Scheme 1. Enantioselective Diels-Alder (ref 1) and [2 + 2]
Cycloaddition Reactions with 3
We have recently developed an enantioselective Diels-Alder
reaction of dienes with R-acyloxyacroleins (3) induced by chiral
organoammonium salts such as H-L-Phe-L-Leu-N(CH2CH2)2-
reduced triamine (1)•2.75C6F5SO3H1a and (S)-1,1′-binaphthyl-2,2′-
diamine (2)•1.9HNTf21b,c (Scheme 1).2,3 While examining various
asymmetric reactions using these organosalt catalysts, we found
that 1•2.6HNTf2 catalyzes the enantioselective [2 + 2] cycloaddition
reaction of unactivated alkenes 4 with 3, to give optically active
1-acyloxycyclobutanecarbaldehydes 5. To the best of our knowl-
edge, there are only three previous examples of catalytic enantio-
selective [2 + 2] cycloaddition reactions for the synthesis of
optically active cyclobutanes or cyclobutenes.4-7 The previous
methods were limited to the [2 + 2] cycloaddition of highly
nucleophilic alkenyl or alkynyl sulfides5,6 and sterically demanding
alkenes such as norbornene derivatives.7 We report here the first
example of the organocatalytic enantioselective [2 + 2] cycload-
dition reaction of 4 with 3 to give optically active 5 and subsequent
ring expansion to give optically active 2-hydroxycyclopentanone
derivatives 6 and 7.
First, the [2 + 2] cycloaddition reaction of 2,4-dimethylpent-2-
ene (4a) with R-benzoyloxyacrolein (3a) was examined in the
presence of chiral amines (10 mol %) and Brønsted acids (x mol
%) in nitroethane (Table 1). Although 1•2.75C6F5SO3H and
1•2.75TfOH were inert at 0 °C (entries 1 and 2), more acidic
2•1.9HNTf2 was found to catalyze the cycloaddition even at -78
°C (entry 3). However, the enantioselectivity was moderate (64%
ee for major diastereomeric cycloadduct 5aa). Fortunately, the
enantioselectivity was increased to 80% ee with the use of
1•2.6HNTf2 at 0 °C. Moreover, the enantioselectivity was increased
to 85% ee when the reaction temperature was lowered to -20 °C
(entry 5). The absolute and relative stereochemistry of 5aa, which
was obtained in the experiments shown in Table 1, was determined
to be a (1S,3R)-anti configuration based on the X-ray crystal
analysis of (1′S)-camphanyl ester 8 derived from 5aa (see Sup-
porting Information).
Table 1. Enantioselective [2 + 2] Cycloaddition of 4a with 3aa
conditions
C, h)
yield
(%)
eeb
(%)
entry
amine
•
HX
(
°
syn:anti
1
2
3
4
5
1•2.75C6F5SO3H
1•2.75TfOH
2•1.9HNTf2
1•2.6HNTf2
1•2.6HNTf2
0, 24
0, 24
-78, 36
0, 24
N.R.
N.R.
24
71
64
8:92
10:90
8:92
64
80
85
-20, 48
Next, several acyloxy groups of 3 were screened for the
enantioselective [2 + 2] cycloaddition of 4a in nitroethane at room
temperature in the presence of 10 mol % of 1•2.6HNTf2 (Table 2).
The result indicated that the electronic and steric effects of the
acyloxy group of 3 did not greatly influence the enantioselectivity
or reactivity. Nevertheless, when 2,6-difluorobenzoyloxyacrolein
(3f) was used in place of 3a, the ee value was slightly improved
from 73 to 84% (entries 1 and 5).
To explore the generality and scope of the 1•2.6HNTf2-induced
enantioselective [2 + 2] cycloaddition with 3, structurally diverse
alkenes 4 were examined (Table 3). In most cases, cycloadducts 5
were obtained in slightly better yield when the reaction was
performed in nitropropane, which is less polar than nitroethane.
Cyclic and acyclic trialkylethenes 4a-f were reacted with R-(fluo-
robenzoyloxy)acroleins 3e-g to give 5 in moderate to good yield
with high ee. In contrast, 1,1- and 1,2-dialkylethenes showed no
a 4a (2 equiv) and 3a (1 mmol, 1 equiv) were used in EtNO2 (0.3 mL).
b The ee value of anti-5aa was determined by chiral HPLC.
reactivity. However, the cycloaddition of a 1,1-disubstituted styrene
derivative, such as 4g with 3a, gave 5ag with 80% ee (entry 12).
The absolute and relative stereochemistry of 5ge, which was
obtained in the experiment (entry 10) shown in Table 3, was also
determined to be a (1S,2S,3R)-anti configuration based on an X-ray
crystal analysis (see Supporting Information).
A possible stepwise mechanism that accounts for the observed
absolute and relative stereochemistries of cycloadducts 5aa and 5gd
is shown in Scheme 1 and Figure 1.8 Initially, the enantioselective
Michael addition of alkenes to a (Z)-iminium intermediate,9 which
would be generated from 3 and 1•2.6HNTf2, should occur through
enantiofacial approach between the re face of electron-rich alkenes
9
8930
J. AM. CHEM. SOC. 2007, 129, 8930-8931
10.1021/ja073435w CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective [2 + 2] Cycloaddition of 4a with 3-5a
enantioselective total syntheses of 4a-methylhydrofluorene diter-
penoids such as (-)-taiwaniquinol B.11,12
time
(h)
5,
eeb
(%)
entry
3, R2
yield (%)
syn:anti
1
2
3
4
5
3a, Ph
3b, c-C6H11
3c, p-(MeO)C6H4
3d, p-FC6H4
3e, 2,6-F2C6H3
7
6
7
18
12
5aa, 74
5ba, 72
5ca, 69
5da, 73
5ea, 80
14:86
13:87
13:87
13:87
11:89
73
78
75
71
84
a The reaction of 4a (2 equiv) with 3 (1 mmol, 1 equiv) was carried out
in the presence of 1•2.6HNTf2 (10 mol %) in EtNO2 (0.3 mL) at room
temperature. b The ee value of anti-5 was determined by chiral HPLC.
(1S,3R)-anti-5 was the major enantiomer.
Table 3. Enantioselective [2 + 2] Cycloaddition of 4 with 3-5a
In summary, we have described a novel and useful formal [2 +
3] cycloaddition of 4 with 3 by an organocatalytic enantioselective
[2 + 2] cycloaddition and subsequent ring expansion to give
optically active 6 or 7 with high ee.
Acknowledgment. Financial support for this project was
provided by MEXT.KAKENHI(19020021) and the Toray Science
Foundation.
Supporting Information Available: Experimental procedures and
full characterization of new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
a Unless otherwise noted, 3 (1.0 mmol, 1.0 equiv) and 4 (1.2 equiv) were
used in PrNO2 (1.0 mL) in the presence of 1•2.6HNTf2 (10 mol %). b The
ee value of anti-5 was determined by chiral HPLC. c EtNO2 was used. d 4
(2.0 equiv) was used. e 1•2.6HNTf2 (20 mol %) was used. f 3g (R2 ) C6F5).
g PrNO2 (2.0 mL) was used. h 3f (R2 ) 2,4,6-F3C6H2). i 1,1,2,2,3,3-
Hexafluoropropane-1,3-disulfonimide was used in place of HNTf2. j Water
(2.0 equiv) was added. k The relative stereochemistry of 5ag is unknown.
References
(1) (a) Ishihara, K.; Nakano, K. J. Am. Chem. Soc. 2005, 127, 10504, 13079
(additions and corrections). (b) Sakakura, A.; Suzuki, K.; Nakano, K.;
Ishihara, K. Org. Lett. 2006, 8, 2229. (c) Sakakura, A.; Suzuki, K.;
Ishihara, K. AdV. Synth. Catal. 2006, 348, 2457.
(2) For chiral secondary ammonium salt catalysts for the Diels-Alder reaction,
see: (a) Ahrendt, K.; Borths, C. J.; MacMillan, D. W. J. Am. Chem. Soc.
2000, 122, 4243. (b) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2002, 124, 2458.
(3) For an account article, see: Ishihara, K.; Sakakura, A.; Hatano, M. Synlett
2007, 686.
(4) For a review, see: Lee-Ruff, E.; Mladenova, G. Chem. ReV. 2003, 103,
1449.
(5) For the titanium-catalyzed enantioselective [2 + 2] cycloaddition reaction
of acryloyl oxazolidinone derivatives with alkenyl sulfides and alkynyl
sulfides (10-30 mol % catalyst loading, 30 to >99% yield, 80 to >98%
ee), see: Narasaka, K.; Hayashi, Y.; Shimadzu, H.; Niihata, S. J. Am.
Chem. Soc. 1992, 114, 8869.
(6) For the copper-catalyzed enantioselective [2 + 2] cycloaddition reaction
of 2-methoxycarbonyl-2-cyclopenten-1-one with phenylthioacetylene (20
mol % catalyst loading, 67% yield, 73% ee), see: (a) Ito, H.; Hasegawa,
M.; Takenaka, Y.; Kobayashi, T.; Iguchi, K. J. Am. Chem. Soc. 2004,
126, 4520. (b) Takenaka, Y.; Ito, H.; Hasegawa, M.; Iguchi, K.
Tetrahedron 2006, 62, 3380. (c) Takenaka, Y.; Ito, H.; Iguchi, K.
Tetrahedron 2007, 63, 510.
Figure 1. Possible TS 9 and TS 10 for the present [2 + 2] cycloaddition.
(7) For the rhodium-catalyzed enantioselective [2 + 2] cycloaddition reaction
of alkynyl esters with norbornene derivatives (5 mol % catalyst loading,
54 to >99% yield, 55-99% ee), see: Shibata, T.; Takami, K.; Kawachi,
A. Org. Lett. 2006, 8, 1343.
and the si face of the electron-deficient (Z)-iminium intermediate
in an extended transition-state assembly (TS) 9. The (Z)-iminium
isomer of 9 is expected to be more stabilized by intramolecular
hydrogen-bonding interactions between R2-CdO or o-F substit-
uents in R2 and H-N+(CH2CH2)2. Subsequently, the resulting
tertiary carbocation intermediate would be intramolecularly cyclized
through a folded TS 10. The high anti-selectivity of cycloadducts
might also be achieved by an intramolecular hydrogen-bonding
interaction in 9 and 10.
(8) The possibility of a concerted [π2s + π2s] cycloaddition and the possibility
of a folded transition state for the initial Michael addition step are forbidden
by orbital symmetry considerations. The possibility of a concerted [π2s
+ π2a] pathway is also excluded because of the steric hindrance of
substrates.
(9) It was ascertained by 1H NMR spectral analysis that a new species was
generated from 1•2.6HNTf2 and 4 in CD3CN in ca. 10% conversion.
However, we could not clearly assign it as an iminium salt intermediate.
Therefore, we cannot deny the possibility of chiral Brønsted acid catalysis
through hydrogen bonding.
To demonstrate the synthetic utility of cycloadducts 5, 5ea was
expanded to 2-acyloxycyclopentanone 7ea by treatment with AlCl3
(1.2 equiv) through successive 1,2-shifts of a tertiary alkyl group
and a hydride (eq 1).10 On the other hand, 5ge was expanded to
2-hydroxycyclopentanone 6e in 95% yield with 64% ds by treatment
with Bu4NF•3H2O (2 equiv) through hydrolysis and the subsequent
1,2-shift of a tertiary alkyl group (eq 2). It is expected that 6e may
become a new chiral common intermediate candidate in the
(10) (a) Davies, H. M. L.; Dai, X. J. Am. Chem. Soc. 2004, 126, 2692. (b)
Dai, X.; Davies, H. M. L. AdV. Synth. Catal. 2006, 348, 2449.
(11) For syntheses of (()-4a-methylhydrofluorene diterpenoids, see: (a) Fillion,
E.; Fishlock, D. J. Am. Chem. Soc. 2005, 127, 13144. (b) Banerjee, M.;
Mukhopadhyay, R.; Achari, B.; Banerjee, A. K. J. Org. Chem. 2006, 71,
2787. (c) Liang, G.; Xu, Y.; Seiple, I. B.; Trauner, D. J. Am. Chem. Soc.
2006, 128, 11022.
(12) For the synthesis of (+)-dichroanone, see: McFadden, R. M.; Stoltz, B.
M. J. Am. Chem. Soc. 2006, 128, 7738.
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