Synthesis of chiral tetrasubstituted alkenes by an asymmetric cascade reaction catalyzed cooperatively by cationic rhodium(I) and silver(I) complexes

Article abstract of DOI:10.1002/anie.200904024

Fantastic four: Tetrasubstituted alkenes have been prepared with high enantioselectivity by the title transformation. This reaction was successfully applied to the enantio- and diastereoselective synthesis of tetrasubstituted helical alkenes possessing bo

Full text of DOI:10.1002/anie.200904024

Angewandte
Chemie
DOI: 10.1002/anie.200904024
Asymmetric Catalysis
Synthesis of Chiral Tetrasubstituted Alkenes by an Asymmetric
Cascade Reaction Catalyzed Cooperatively by Cationic Rhodium(I)
and Silver(I) Complexes**
Daiki Hojo, Keiichi Noguchi, and Ken Tanaka*
Cascade reactions that can furnish complex organic molecules
in one step have attracted much attention in organic syn-
thesis.[1] Obviously, asymmetric cascade reactions that can
control the chirality of the product are more attractive.[2]
Herein, we describe a novel asymmetric cascade reaction
that is catalyzed cooperatively by cationic rhodium(I) and
Scheme 1. Rhodium-catalyzed enantioselective [4+2] annulation of 2-
silver(I) complexes. The reaction can produce tetrasubsti-
alkynylbenzaldehydes 1 with carbonyl compounds 2.
tuted alkenes which possess helical and/or central chirality.[3]
Feringa and co-workers have demonstrated that tetrasubsti-
tuted helical alkenes, which possess both central and helical
chirality, can be applied to light-driven molecular motors.[4]
Therefore helical alkenes are attracting growing interest.
Furthermore, the present asymmetric cascade reaction might
include unprecedented sequential activation of p- and s-
bonds by cationic transition-metal complexes.
terminus, and N-methylisatin (2a) was conducted in the
presence of a cationic rhodium(I)/(R,R)-SL-W001-1 ((R,R)-
5) catalyst, the unexpected benzopyranone 4aa, possessing a
tetrasubstituted alkene moiety, was obtained along with the
expected benzopyranone 3aa (Scheme 2). Screening of chiral
Our research group has recently reported that a cationic
rhodium(I)/chiral bisphosphine complex catalyzes a highly
enantioselective [4+2] annulation of 2-alkynylbenzaldehydes
1 with carbonyl compounds 2, and the reaction leads to
benzopyranones 3 in high yields and with high ee values
(Scheme 1).[5] The mechanism of the [4+2] annulation is
proposed as follows:[5,6] A rhodium hydride species is
ꢀ
generated through activation of the C H bond of the
formyl group of 1, which adds intramoleculary to the pendant
alkyne to give five-membered acylrhodacycle A. An inter-
molecular [4+2] cycloaddition between A and the carbonyl
group of 2, and subsequent reductive elimination furnishes
optically active benzopyranone 3.
On the other hand, when the reaction of 2-alkynylben-
zaldehyde 1a, possessing a cyclohexenyl group at the alkyne
[*] D. Hojo, Prof. Dr. K. Tanaka
Department of Applied Chemistry, Graduate School of Engineering
Tokyo University of Agriculture and Technology
Koganei, Tokyo 184-8588 (Japan)
Scheme 2. Rhodium-catalyzed enantioselective synthesis of tetrasubsti-
tuted alkene 4aa from 1a and 2a. cod=cycloocta-l,5-diene.
Fax: (+81)42-388-7037
E-mail: tanaka-k@cc.tuat.ac.jp
Homepage: http://www.tuat.ac.jp/~tanaka-k/
Prof. Dr. K. Noguchi
Instrumentation Analysis Center, Tokyo University of Agriculture
and Technology
ligands revealed that the use of (R,R)-SL-W005-1 ((R,R)-6)
furnished 4aa in almost quantitative yield with a high ee value
(Scheme 2). However the reactions of 2-alkynylbenzalde-
hydes 1, possessing an alkyl, isopropenyl, or aryl group at the
alkyne terminus, and 2a in the presence of the cationic
rhodium(I) catalyst with (R,R)-5 or (R,R)-6 furnished benzo-
pyranones 3 in high yields, and only trace amounts (< 2%
yield) of benzopyranones 4 were generated.
Koganei, Tokyo 184-8588 (Japan)
[**] This work was supported by Grants-in-Aid for Scientific Research
from MEXT (Japan) (grant nos. 20675002, 19028015, and 21·7999).
We thank Solvias AG for the gift of walphos ligands (R,R)-5 and
(R,R)-6, Takasago Int. Co. for the gift of (R)-segphos, and Umicore
for generous support in supplying a rhodium complex.
A possible mechanism for the formation of tetrasubsti-
tuted alkene 4aa is shown in Scheme 3. There are many
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200904024.
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the cationic rhodium(I)/(R,R)-6 complex (5 mol%) and an
additional strongly p-electrophilic transition-metal complex
(10 mol%, Table 1, entries 1–4). Although AgBF4 showed the
highest selectivity for the formation of tetrasubstituted alkene
4ba (Table 1, entry 4), the yield was extremely low. As the
brownish CH2Cl2 solution of the cationic rhodium(I)/(R,R)-6
complex became green by adding AgBF4, we anticipated that
AgBF4 might interact with rhodium to form the greenish
Table 2: Enantioselective synthesis of chiral tetrasubstituted alkenes 4
from alkynylarylaldehydes 1b–k and carbonyl compounds 2a–e.[a]
Scheme 3. Possible mechanism for the formation of 4aa.
Entry 1 (R1)
2 (R2)
4, Yield [%][a], (ee [%][g]),
[d.r.]
precedents for the formation of a metalbenzopyrilium
[7]
intermediate through the reaction of the 2-alkynylbenzal-
dehyde and a p-electrophilic transition-metal complex, which
reacts intermolecularly with alkenes[8] or alkynes[9] to form
various six-membered compounds.[10] Therefore the p-elec-
trophilic cationic rhodium(I) complex would react with an
alkyne moiety of 1a to form rhodiumbenzopyrilium inter-
mediate B. Although there is no precedent for a cycloaddition
1
2
3
4
5
6
7
8
1b (nBu)
1c (Cy)
1d (Cl(CH2)3)
1e (2-isopropenyl) 2a
1 f (Ph)
1g (2-ClC6H4)
1b
1b
2a (Me)
2a
2a
(ꢀ)-4ba, 82, (98)
(ꢀ)-4ca, 67[c], (98)
(ꢀ)-4da, 86, (98)
(ꢀ)-4ea, 75, (>99)
(ꢀ)-4 fa, 96, (96)
(ꢀ)-4ga, 74, (99)
(ꢀ)-4bb, 82, (98)
(ꢀ)-4bc, 96, (96)
2a
2a
2b (Ph)
2c (H)
=
between the metalbenzopyrilium intermediate and a C O
bond, cyclic dicarbonyl compound 2a might react with
intermediate B to form ketoaldehyde 7aa through intermedi-
ate C.[11] Enantioselective intramolecular ketone hydroacyla-
tion of 7aa proceeds through rhodacycle D to give tetrasub-
stituted alkene 4aa.[12]
As the p-electrophilicity of the cationic rhodium(I)
complex might not be strong enough to promote the
formation of intermediate B, the reaction of 2-(1-hexynyl)-
benzaldehyde (1b) and 2a was investigated in the presence of
9
10
1b
1d
2d
2d
(ꢀ)-4bd, 52, (94)
(S)-(ꢀ)-4dd, 53, (95)
Table 1: Screening of additives for the reaction of 1b and 2a.
11
12
13
14
1h (nBu)
1i (Cl(CH2)3)
1j (2-isopropenyl) 2a
1k (Ph)
2a
2a
(+)-4ha, 72, (94), [>99:1]
(+)-4ia, 68[d], (95), [>99:1]
(+)-4ja, 79, (>99), [>99:1]
(ꢀ)-4ka, 95, (>99), [>99:1]
2a
Entry Additives
Conv. Yield of
Yield of
(ꢀ)-4ba
[%][a]
ee of
[%]
(ꢀ)-3ba
(ꢀ)-4ba
[%][a]
[%][b]
1
[Pd(MeCN)4](BF4)2
100
10
2
98
(10 mol%)
2
3
4
5
PtCl2 (10 mol%)
Cu(OTf)2 (10 mol%)
AgBF4 (10 mol%)
AgBF4 (10 mol%),
PPh3 (10 mol%)
AgBF4 (10 mol%),
PPh3 (5 mol%)
AgBF4 (5 mol%),
PPh3 (5 mol%)
100
30
30
89
5
3
3
<1
6
87
–
98
98
15[e] 1h
16[e] 1k
2e
2e
(ꢀ)-4he, 58, (30), [>99:1]
(ꢀ)-4he, 19, (99), [>99:1][f]
(+)-4ke, 79, (20), [>99:1]
100
4
53
[a] Reactions were conducted using [Rh(cod)2]BF4 (5 mol%), (R,R)-6
(5 mol%), PPh3 (5 mol%), AgBF4 (10 mol%), 1b–k (1.0 equiv), and 2a–e
(1.1 equiv) in CH2Cl2 at RT for 18–72 h. [b] Yield of isolated product.
[c] Conversion of 1c was about 85% after 66 h. [d] Conversion of 1i was
about 80% after 72 h. [e] (R)-Segphos was used as a ligand. [f] After a
single recrystallization from n-hexane/EtOAc (3:1). [g] The ee values were
determined by chiral HPLC methods. Cy=cyclohexyl, (R)-Segphos=(R)-
(4,4’-bi-1,3-benzodioxole)-5,5’-diylbis(diphenylphosphine).
6
7
100
100
3
82
82
98
98
17
[a] Yield of isolated product. [b] Determined by chiral HPLC methods.
Tf =trifluoromethanesulfonyl.
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mixture, which lowers the catalytic activity towards both p-
and s-bond activation. Indeed, addition of 10 mol% of PPh3,
which would occupy free coordination sites of rhodium,
significantly increased the yield of 4ba (Table 1, entry 5).[13]
Decreasing the amount of PPh3 to 5 mol% further increased
the yield of 4ba (Table 1, entry 6), while decreasing the
amount of AgBF4 to 5 mol% increased the yield of 3ba,
which was not easily separable from 4ba by silica gel
chromatography (Table 1, entry 7). It was reported that a
cationic silver(I) complex reacts with a 2-alkynylbenzalde-
hyde to form the corresponding benzopyrilium intermedi-
ate.[14] Therefore, AgBF4 might catalyze the formation of
ketoaldehyde 7ba (R = nBu in Scheme 3). Contrary to our
expectation, the reaction of 1b, 2a, and AgBF4 (10 mol%) at
room temperature did not furnish 7ba and an unidentified
mixture of products, derived from 1b, was generated. This
result suggests that rhodium(I) and silver(I) complexes
cooperatively catalyze the present cascade reaction, although
the precise role of AgBF4 is not clear at present.
Photophysical properties of helical alkenes 4 were briefly
examined (Table 3). As expected, overcrowded helical
alkenes 4he and 4ke (Table 3, entries 5 and 6) exhibit larger
optical rotation values and bathochromic shifts in UV
absorption values in comparison with the less crowded helical
alkenes 4ha–4ka (Table 3, entries 1–4).
Table 3: Photophysical data of helical alkenes 4.[a]
25[b]
Entry
4
½aꢂD
UV absorption
lmax [nm][c]
1
2
3
4
5
6
(+)-4ha
(+)-4ia
(+)-4ja
(ꢀ)-4ka
(ꢀ)-4he
(+)-4ke
+340
368
369
368
369
479
483
+301
+238
ꢀ28
ꢀ1219
+2064
[a] Measured in CHCl3. [b] Values are calculated as 100% ee. [c] Only the
longest absorption maximum wavelengths are given.
Thus, we explored the scope of this process by using
5 mol% of the cationic rhodium(I)/(R,R)-6/PPh3 complex
and 10 mol% of AgBF4 at room temperature as shown in
Table 2. Alkyl- (Table 2, entries 1–3), alkenyl- (Table 2,
entry 4), and aryl-substituted 2-alkynylbenzaldehydes
(Table 2, entries 5 and 6) could participate in this reaction.
Not only N-methylisatin (Table 2, entries 1–6) but also N-
phenylisatin (Table 2, entry 7), NH-isatin (Table 2, entry 8),
and acenaphthenequinone (Table 2, entries 9 and 10) could
be employed for this reaction.[15–17] Also, this reaction was
successfully applied to the enantio- and diastereoselective
synthesis of tetrasubstituted helical alkenes possessing both
central and helical chirality. 1-Alkynyl-2-naphthaldehyde 1h
reacted with 2a to give helical alkene 4ha as a single
diastereomer in good yield with a high ee value (Table 2,
entry 11). Chroloalkyl- (Table 2, entry 12), isopropenyl-
(Table 2, entry 13), and phenyl-substituted 2-alkynyl-1-naph-
thaldehydes (Table 2, entry 14) could also participate in this
reaction. Sterically more demanding helical alkenes 4he and
4ke could be synthesized using (R)-segphos as a ligand
(Table 2, entries 15 and 16). Although low enantioselectivity
was observed, the ee value could be readily improved after a
single recrystallization (Table 2, entry 15). The relative con-
figuration of 4ha and 4he were determined by X-ray
crystallographic analysis (Figure 1).[17]
Future studies will focus on elucidation of the precise
mechanism of this cooperative catalysis and the behavior of
helical alkenes under UV irradiation.[18]
Received: July 21, 2009
Published online: September 22, 2009
Keywords: alkenes · asymmetric catalysis · cascade reactions ·
.
helical chirality · rhodium
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Tetrahedron 2006, 62, 2143.
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ꢀ
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2009, 121, 1475; Angew. Chem. Int. Ed. 2009, 48, 1447.
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[6] For rhodium-catalyzed [4+2] annulations of 2-alkynylbenzalde-
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Hagiwara, K. Noguchi, Angew. Chem. 2005, 117, 7426; Angew.
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Figure 1. ORTEP diagrams of tetrasubstituted helical alkenes (ꢁ)-4ha
(left) and (ꢁ)-4he (right) drawn at the 30% probability level.
[7] For reviews, see: a) N. Asao, Synlett 2006, 1645; b) H. Kusama,
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Angew. Chem. Int. Ed. 2009, 48, 8129 –8132
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Communications
[8] For examples, see: a) N. Asao, K. Sato, Org. Lett. 2006, 8, 5361;
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[12] For a rhodium-catalyzed enantioselective intramolecular hydro-
acylation of ketones with aldehydes, see: Z. Shen, H. A. Khan,
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[13] The color of the catalyst mixture became brown upon the
addition of PPh3.
[14] A. B. Beeler, S. Su, C. A. Singleton, J. A. Porco, Jr., J. Am.
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[15] Acyclic 1,2-dicarbonyl compounds, such as a-ketoesters and 1,2-
diketones, failed to react with 1b.
[16] The absolute configuration of (ꢀ)-(E)-4dd was determined to be
S by X-ray crystallographic analysis of the corresponding
Z isomer.
[17] CCDC 738708 (4aa), 738707 ((S)-(ꢀ)-(Z)-4dd), 738706 (4ha),
and 738705 (4he) 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.
[18] Our preliminary study revealed that a red (CH2Cl)2 solution of
(E)-4he was maintained at room temperature for a week under
irradiation with visible light to give a blue (CH2Cl)2 solution of
(Z)-4he.
b) D. Hildebrandt, W. Hꢀggenberg, M. Kanthak, T. Plꢁger, I. M.
Mꢀller, G. Dyker, Chem. Commun. 2006, 2260; c) N. Asao, K.
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=
[11] Alternatively, a carbonyl alkyne metathesis between the C O
bond of 2a and the alkyne moiety of 1a might proceed to yield
7aa. However, the reactions of diphenylacetylene and 2a in the
presence of the cationic rhodium(I) and silver(I) complexes at
room temperature did not furnish the corresponding metathesis
product and the starting materials were recovered. Therefore the
mechanism of the carbonyl alkyne metathesis might be
excluded. For AgI-catalyzed carbonyl alkyne metathesis, see:
a) J. U. Rhee, M. J. Krische, Org. Lett. 2005, 7, 2493; for RhI-
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