Catalytic enantioselective [2 + 4] and [2 + 2] cycloaddition reactions with propiolamides

Article abstract of DOI:10.1021/ja8015318

We report here the catalytic and highly enantioselective [2 + 4] and [2 + 2] cycloaddition reactions of electron-rich dienes or silyl enol ethers with electron-deficient propiolamide derivatives induced by copper(II)?3-(2-naphthyl)-L-alanine amide complex

Full text of DOI:10.1021/ja8015318

Published on Web 05/22/2008
Catalytic Enantioselective [2 + 4] and [2 + 2] Cycloaddition Reactions with
Propiolamides
Kazuaki Ishihara* and Makoto Fushimi
Graduate School of Engineering, Nagoya UniVersity, Furo-cho, Chikusa, Nagoya 464-8603, Japan
Received March 5, 2008; E-mail: ishihara@cc.nagoya-u.ac.jp
Chart 1. Chiral Lewis Acid Catalysts 1 and Dienophiles 2 and 3
Although several examples of the catalytic enantioselective
Diels-Alder (DA) reaction of dienes with acetylenic dienophiles
have been reported,1 the enantioselectivity and chemical yield of
the adducts have never been high, and the range of suitable
substrates is quite narrow. In general, acetylene derivatives are less
reactive than the corresponding ethylene derivatives as electron-
deficient dienophiles. Acetylene derivatives with a linear sp-sp
bond make the asymmetric induction with chiral Lewis acid difficult
because the alkynyl moiety is far from the acidic metal center.
Therefore, a more conformationally rigid and larger chiral sub-
stituent is needed around the metal center. We report here the
catalytic and highly enantioselective DA and [2 + 2] cycloaddition
reactions with propiolamide derivatives (2) induced by the Cu(II)•3-
(2-naphthyl)-L-alanine amide (1a) complex (Chart 1). To the best
of our knowledge, there have been only three examples of catalytic
enantioselective [2 + 2] cycloaddition reactions with alkynes.2
We previously reported that Cu(II)•L-DOPA amide (1b) complex
was highly effective for the enantioselective DA reaction of dienes
with 1-(3,5-dimethyl-1H-pyrazol-1-yl)prop-2-en-1-ones (3).3,4 An
asymmetric environment to induce the enantioselective reaction was
constructed around the metal center of Cu(II)•1b through intramo-
lecular cation-π attractive interaction between the Cu(II) center
and the 3,4-dimethoxyphenyl group of 1b.3b On the basis of the
previous results, the DA reaction of cyclopentadiene (CP) with 2a
was examined in the presence of 10 mol % of Cu(II)•1b in MeCN.
Fortunately, bicycloadduct 4a was obtained in 94% yield with 77%
ee (entry 1, Table 1). The absolute configuration of the major
enantiomer of 4a was determined to be (1R,4S) (see Supporting
Information). Next, to expand the asymmetric environment of the
catalyst, 1a was used instead of 1b. Although the catalytic activity
of Cu(II)•1a was lower than that of Cu(II)•1b, the enantioselectivity
was increased to 83% ee (entry 2) and further to 87% ee in CH2Cl2
(entry 3).5 The addition of molecular sieves 4 Å was effective for
activating Cu(II)•1a and preventing the hydrolysis of 2a (entry 4).5,6
To explore the scope and limitations of the present enantiose-
lective DA reaction, several cyclic dienes and ꢀ-substituted
propiolamides 2 were examined under the optimized conditions
shown for entry 4 of Table 1. Representative results are shown in
Table 2. The reaction of CP with 2a at -78 °C gave 4a with 93%
ee in 50% yield (entry 1). When the reaction was carried out at
-40 °C, 4a was obtained with 88% ee in 91% yield (entry 2).
Although more electron-rich but-2-ynamide (2b) was a less reactive
dienophile, the enantioselectivity was still high under the reaction
conditions at -20 °C (entry 3). Fortunately, more electron-deficient
3-iodopropiolamide (2c) reacted with CP at -40 °C to give 3-iodo
adduct 4c with 89% ee in 82% yield (entry 4). 4c can be transformed
to 3-nonsubstituted derivative and 3-alkyl derivative by known
methods.1a Therefore, 2c is an outstanding dienophile as a synthetic
equivalent of 2a and 2b. The DA reaction of 1,3-cyclohexadiene
gave bicycloadduct 5a with up to 96% ee, although the chemical
yield of 5a was still moderate (entries 5-7). The absolute
Table 1. Enantioselective DA Reaction of CP with 2aa
entry
1
solvent
additive
time (h)
yield (%)
ee (%)
1
2
3
4
1b
1a
1a
1a
MeCN
MeCN
CH2Cl2
CH2Cl2
7
21
7
94
91
85
91
77 (1R,4S)
83 (1R,4S)
87 (1R,4S)
88 (1R,4S)
MS 4 Åb
7
a The DA reaction of CP (4 equiv) with 2a (0.3 mmol) was
conducted in the presence of 1•Cu(NTf2)2 (10 mol %) in solvent (1.2
mL). b MS 4 Å (100 mg) was added.
configuration of 5a was (1R,4S), as seen for 4a. The DA reaction
of cyclohexadiene with 2c gave 5c in up to 89% yield and up to
98% ee (entries 8-10). Several 2- and 1-substituted 1,3-cyclo-
hexadienes could also be used as DA dienes, and 5- and 1-substi-
tuted bicyclo[2.2.2]octadienyl-2-carboxamides (6-8) were obtained
with 87-96% ee without the production of any 6- and 4-substituted
regioisomers, respectively (entries 11-15).7
Recently, impressive progress has been made in the development
of chiral diene ligands for the asymmetric catalysis of Rh and Ir.8,9
The DA reaction of cyclic dienes with acetylenic dienophiles may
provide a concise method for the preparation of chiral bicyclic 2,5-
diene ligand candidates.
Unexpectedly, [2 + 2] cycloadduct 9 was obtained with 80% ee
in 65% yield in the reaction of 2-methoxy-5,5-dimethylcyclohexa-
diene with 2a catalyzed by 1a•Cu(NTf2)2 (10 mol %) (Table 3,
entry 1). No corresponding DA adducts were obtained. 5,5-Dimethyl
substituents of the diene might sterically suppress the DA reaction.
1-Trialkylsilyloxy-1-cyclopentenes and its 2-methyl analogue also
reacted with 2a to give cyclobutenecarboxamides 10-12 in higher
yields with 81-83% ee (entries 2-4). Interestingly, Michael adduct
13 was enantioselectively obtained along with 12 when the [2 +
2] cycloaddition was conducted by using 1 equiv of the silyl enol
ether in the presence of 1b•Cu(NTf2)2 (10 mol %) (entry 5).7
The bicyclic [2 + 2] adducts shown in Table 3 are very useful
chiral intermediates for further synthetic elaboration. For instance,
the adduct 12 was transformed efficiently into the known (S)-
bicyclo[4.3.0]nonenone (15)10 as shown in Scheme 1.11 Thus, the
absolute configuration of 12 was established.
9
7532 J. AM. CHEM. SOC. 2008, 130, 7532–7533
10.1021/ja8015318 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective DA Reaction of Cyclic Dienes with 2a
Figure 1. Proposed exo,trans-chelated TS 16 and the frontier molecular
orbital explanation of exo-TS 17 and endo-TS 18.
of exo-TS 17 in terms of secondary antibonding interaction12
between the lobes on the C-2 position of cyclopentadiene (HOMO)
and the carbonyl oxygen of 2a (LUMO) in endo-TS 18.
For the [2 + 2] cycloaddition, a stepwise mechanism through
Michael aldol reactions might be reasonable, judging from the
experimental results shown in entry 5 in Table 3.13 According to
the observed absolute configuration of cycloadduct 12, the Michael
reaction should occur through the enantiofacial approach of 2a to
the re face of the silyl enol ether.
In summary, we have developed the catalytic enantioselective
[2 + 4] and [2 + 2] cycloadditions of electron-rich dienes or silyl
enol ethers with electron-deficient propiolamide derivatives.
a The reaction was conducted under the same conditions as entry 4 in
Table 1. b CP (2 equiv) was used. c Cu(NTf2)2 (20 mol %) and 1a (22
mol %) were used. d Cyclohexadiene (0.6 mL) was used. e CH2Cl2 (0.6
mL) was used. f Only 5-substituted isomer was obtained. g CH2Cl2 (1.6
mL) was used. h Only 1-substituted isomer was obtained.
Acknowledgment. Financial support for this project was
provided by MEXT.KAKENHI (19020021), JSPS.KAKENHI
(20245022), the Toray Science Foundation and the Global COE
Program of MEXT. This paper is dedicated to Professor Elias J.
Corey on the occasion of his 80th birthday.
Table 3. Enantioselective [2 + 2] Cycloaddition of Enes with 2aa
Supporting Information Available: Experimental procedures, full
characterization of new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
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a The reaction was conducted under the same conditions as entry 4 in
Table 1. b The ene (2 equiv) was used. c Only (5+n)-R3O substituted
regioisomeric adduct was obtained. The reaction of the ene (1.0 equiv)
with 2a (1.74 mmol) was conducted in the presence of 1b instead of 1a.
d The yield and ee of the Michael adduct 13 are shown in brackets. For
the chemical structure of 13, see Supporting Information.
Scheme 1. Conversion of (1S,5R)-12 to (S)-(+)-15
(5) Cu(II)•1a could not be prepared in CH2Cl2 because of the poor solubility
of 1a. Cu(II)•1a was prepared in MeCN, and then the solvent was
exchanged to CH2Cl2 before adding CP and 2a. A trace amount of MeCN
remained in the reaction mixture.
(6) A trace amount of MeCN in the reaction mixture might also be removed
by molecular sieves 4 Å.
(7) Acyclic dienes and acyclic silyl enol ethers were not suitable as reactants. .
(8) For a mini review, see: Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 3364.
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On the basis of our previous experimental results with the DA
reaction of dienes with 3 catalyzed by 1b•Cu(II),3 we propose the
following reaction mechanism: 2a would be predominantly trans-
chelated with 1a•Cu(II) due to steric hindrance between the
N-cyclopentyl group of 1a and the pyrazolyl moiety of 2a, and
then the carbonyl re face of 2a would be preferentially shielded
by the 2-naphthyl face of 1a, which would be conformationally
folded through cation-π interaction with Cu(II). CP would
predominantly approach the si face side of 2a to give (1R,4S)-4a
through exo-transition-state (TS) assembly 16 (Figure 1). The
frontier molecular orbital theory also explains the predominance
(11) Canales, E.; Corey, E. J. J. Am. Chem. Soc. 2007, 129, 12686.
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(13) Ishihara, K.; Nakano, K. J. Am. Chem. Soc. 2007, 129, 8930.
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