Enantioselective construction of bridged multicyclic skeletons: Intermolecular [2+2+2] cycloaddition/intramolecular diels-alder reaction cascade

Article abstract of DOI:10.1002/anie.201004150

Bridging a gap: A cationic rhodium(I)/ligand complex catalyzes the title reaction of alkynes and amide-linked 1,5-dienes, leading to bridged multicyclic compounds, with high chemo-, regio-, and enantioselectivity (see scheme; Bn=benzyl).

Full text of DOI:10.1002/anie.201004150

Communications
DOI: 10.1002/anie.201004150
Asymmetric Catalysis
Enantioselective Construction of Bridged Multicyclic Skeletons:
Intermolecular [2+2+2] Cycloaddition/Intramolecular Diels–Alder
Reaction Cascade**
Masayuki Kobayashi, Takeshi Suda, Keiichi Noguchi, and Ken Tanaka*
The intramolecular Diels–Alder (IMDA) reaction is a power-
ful strategy for the construction of complex multicyclic
skeletons.[1] The construction of the bridged multicyclic
skeleton C, from phenol A, has been reported to proceed
through oxidative dearomatization to give allyl cyclohexa-
dienyl ether B, which then undergoes the IMDA reaction to
yield C (Scheme 1).[2,3] This novel strategy was successfully
reaction of 1,6-diynes 1 with the amide-linked 1,5-dienes 2,
which bear two sterically and/or electronically different
alkene units. A subsequent IMDA reaction would furnish
the desired chiral bridged multicyclic compound 3 or its
enantiomer (Scheme 2).[9] The use of an ester-linked 1,5-diene
Scheme 1. Oxidative dearomatization/IMDA reaction cascade.
applied to the synthesis of various complex natural pro-
ducts,[3a,b,d,e] but an asymmetric variant has not yet been
developed because of the difficulty of the enantioselective
dearomatization of phenols.[4]
Scheme 2. Chemo-, regio-, and enantioselective [2+2+2] cycloaddi-
tion/IMDA reaction cascade. Bn=benzyl.
Chiral cyclohexadienes can be accessed with high yields
and ee values through the enantioselective [2+2+2] cyclo-
addition[5,6] of 1,6-diynes with acrylates[7a] and enamides[7b,8]
catalyzed by a cationic rhodium(I)/axially chiral biaryl
bisphosphine complex. Importantly, the ester and amide
moieties of these chiral cyclohexadienes possessed the same
absolute configurations relative to starting material. There-
fore, in the presence of a chiral cationic rhodium(I) catalyst,
chiral cyclohexadienes D or E, containing the required
pendant alkene unit, could be generated from the selective
should furnish a chiral bridged multicyclic compound, which
is similar to compound C. However, we have already reported
that rapid aromatization through the selective [2+2+2]
cycloaddition of the enol double bond and subsequent
elimination of methacrylic acid proceeds in the reaction of a
1,6-diyne and vinyl methacrylate, catalyzed by the cationic
rhodium(I)/rac-binap complex (Scheme 3).[8c,10] Therefore,
the amide-linked 1,5-dienes 2 were selected for this cascade
reaction.
[*] M. Kobayashi, T. Suda, Prof. Dr. K. Tanaka
Department of Applied Chemistry, Graduate School of Engineering
Tokyo University of Agriculture and Technology
Koganei, Tokyo 184-8588 (Japan)
We first examined the reaction of the tosylamide-linked
1,6-diyne 1a and amide-linked 1,5-diene 2a as shown in
Scheme 4. Pleasingly,
a cationic rhodium(I)/(R)-segphos
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
complex effectively catalyzes the desired enantioselective
cycloaddition cascade at room temperature to yield amide
3aa with a high yield and ee value. In addition to 1a,
Instrumentation Analysis Center, Tokyo University of Agriculture
and Technology, Koganei, Tokyo 184-8588 (Japan)
[**] This work was supported partly by the Grants-in-Aid for Scientific
Research (Nos. 20675002 and 20·8746) from MEXT (Japan). We
thank Dr. Hidetomo Imase and Maho Takahashi (TUAT) for their
preliminary experiments, Takasago Int. Co. for the gift of segphos,
and Umicore for generous support in supplying a rhodium complex.
Scheme 3. Rhodium-catalyzed [2+2+2] cycloaddition/aromatization of
a 1,6-diyne with vinyl methacrylate.[8c] binap=2,2’-bis(diphenylphos-
phino)-1,1’-binaphthyl.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004150.
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Angew. Chem. Int. Ed. 2011, 50, 1664 –1667

Next we investigated the enantioselective intermolecular
[2+2+2] cycloaddition/IMDA reaction cascade as shown in
Scheme 5, even though an enantioselective intermolecular
Scheme 5. Enantioselective cycloaddition cascade of alkynes 5a,b, alkynes
6a–d, and 1,5-dienes 2a–d. A solution of 6 in CH2Cl2 was added to a
solution of 2, 5, and the Rh catalyst in CH2Cl2 over 1 min. Cited yields are
of isolated products. [a] A solution of 6d (1.5 equiv) in CH2Cl2 was added
to a solution of 2a, 5a, and the Rh catalyst in CH2Cl2 over 2 h by using a
syringe pump.
Scheme 4. Enantioselective cycloaddition cascade of 1,6-diynes 1a–g with
1,5-dienes 2a–e. A solution of 1 in CH2Cl2 was added to a solution of 2
and the Rh catalyst in CH2Cl2 over 1 min. Cited yields are of isolated
products. [a] At 408C. [b] Catalyst: 10 mol%. Isolated as a mixture of 3ea
and 4ea. cod=1,5-cyclooctadiene, segphos=5,5’-bis(diphenylphosphino)-
4,4’-bi-1,3-benzodioxole, Ts=4-toluenesulfonyl.
three-component co-cyclotrimerization has not been reported
to date.[11–13] After screening substrate combinations and
catalysts, we were pleased to find that a cationic rhodium(I)/
(R)-binap complex effectively catalyzes the desired chemo-,
regio-, and enantioselective cycloaddition cascade of
dimethyl acetylenedicarboxylate (5a), trimethylsilylacetylene
(6a), and 1,5-diene 2a at room temperature to yield the
corresponding tricyclic amide 7aaa as a single regioisomer
with an excellent ee value. The reaction employing diethyl
acetylenedicarboxylate (5b) gave 7baa in a lower yield, but
the ee value was still high. The conjugated terminal alkynes
6b and 6c were also suitable substrates for this process
yielding 7aba and 7aca, respectively. Although the initial yield
of 7ada was very low, by adding the aliphatic terminal alkyne
6d over a period of 2 hours to a solution of 1,5-diene 2a, 5a,
and the Rh catalyst, the yield was significantly improved from
17% to 36%. With respect to the 1,5-dienes, acrylamide 2b
could also be employed to give amide 7aab with a high yield
and high ee value. Phenyl substitution of the acrylamide
malonate- (1b), acetyl acetone- (1c), and dimethoxypropane-
linked (1d) 1,6-diynes also reacted with 2a to yield amides
3ba, 3ca, and 3da, respectively, with high yields and ee values.
The unsymmetrical 1,6-diynes 1e and 1 f, yielded the corre-
sponding pairs of regioisomeric products, 3ea/4ea and 3 fa/
4 fa with moderate regio- and enantioselectivities. With
respect to 1,5-dienes, not only methacrylamide 2a but also
acrylamide 2b, N-styryl 2d, and N-cyclopentenyl 2e deriva-
tives reacted with 1a to yield amides 3ab, 3ad, and 3ae,
respectively, with high yields and ee values. Unfortunately, the
phenyl substitution of the acrylamide moiety (2c) resulted in
the formation of the racemic amide 3ac. The reactions of
unsymmetrical electron-deficient 1,6-diyne 1g and 1,5-dienes
2a, 2c, and 2d proceeded with high regioselectivity to yield
the corresponding amides 3ga, 3gc, and 3gd with good to high
yields and ee values.
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Communications
Table 1: Reactions of 1a,g, acrylamides 11, and enamides 12.[a]
moiety (2c) gave the amide 7aac
with an excellent ee value, but
phenyl substitution of the enamide
moiety (2d) did not deliver the
expected 7aad.
The transformation of bridged
chiral multicyclic amides was briefly
examined. Treatment of the tetra-
cyclic amide 3aa with DDQ fur-
nished the pyrrole derivative
8
(Scheme 6). The ruthenium-cata-
lyzed oxidation of the tetracyclic
amide 3ba and of tricyclic amide
7aba furnished the tricyclic amide 9
(Scheme 6) and bicyclic amide 10
(Scheme 7), respectively.
To clarify which alkene unit of
the amide-linked 1,5-dienes 2 reacts
with 1,6-diynes 1 in the [2+2+2]
cycloaddition step, competition
experiments were conducted as
shown in Table 1. The electron-rich
Entry
1 (R1)
11 (R2)
12 (R3)
13
14 or 15
yield [%][b]
ee [%]
yield [%][b]
ee [%]
1
2
3
4
5
6
1a (Me)
1a (Me)
1a (Me)
1g (CO2Me)
1g (CO2Me)
1g (CO2Me)
11a (Me)
11b (Ph)
11a (Me)
11a (Me)
11b (Ph)
11a (Me)
12a (Me)
12a (Me)
12b (Ph)
12a (Me)
12a (Me)
12b (Ph)
13a: 70
13b: 36
13a: 82
13c: 10
13d: <5
13c: 80
99
98
99
95
–
14a: 22
15: 40
14b: 7
14c: 79
14c: 63
14d: <5
97
–
–
>99
>99
–
99
[a] A solution of 1 in CH2Cl2 was added to a solution of 11, 12, and Rh catalyst in CH2Cl2 over 1 min.
[b] Yield of isolated product.
both these olefinic units, results in the formation of racemic
3ac. 1,6-Diyne 1g preferentially reacted with enamide 12a
over acrylamides 11a,b (Table 1, entries 4 and 5), thus
accounting for the absolute configuration observed for
amides (+)-3ga and (+)-3gc, which are presumably gener-
ated via intermediate E (Scheme 2). The remaining amides in
Scheme 4 have the opposite configuration because they are
thought to have been generated via intermediate
D
(Scheme 2). Indeed, the opposite absolute configurations
were confirmed by the X-ray crystallographic analysis of (À)-
3aa,[14] (+)-3ae,[14] and (+)-3gc.[14]
The same competition experiments were conducted in the
intermolecular [2+2+2] cycloaddition as shown in Table 2. As
enamide 12a is the only substrate that could participate in this
reaction, the same enantioselection as (+)-3ga and (+)-3gc
would be expected for 7 (Scheme 5). Again, the expected
absolute configuration was confirmed by the X-ray crystallo-
graphic analysis of (+)-7ada.[14]
Scheme 6. DDQ oxidation of tetracyclic amide 3aa and ruthenium-
catalyzed oxidation of tetracyclic amide 3ba. DDQ=2,3-dichloro-5,6-
dicyanobenzoquinone.
In conclusion, we have determined that a cationic
rhodium(I)/segphos or binap complex catalyzes the intermo-
Scheme 7. Ruthenium-catalyzed oxidation of tricyclic amide 7aba.
Table 2: Reactions of 5a, 6a, acrylamides 11, and enamides 12.[a]
1,6-diyne 1a preferentially reacted with the electron-deficient
acrylamide 11a over the electron-rich enamide 12a (Table 1,
entry 1). In contrast, the electron-deficient 1,6-diyne 1g
preferentially reacted with electron-rich 12a over electron-
deficient 11a (Table 1, entry 4). Phenyl substitution of the
alkenes improved the chemoselectivity (Table 1, entries 3, 5,
and 6), which accounts for higher ee values of (À)-3ad and
(+)-3gc relative to those of (À)-3aa and (+)-3ga (Scheme 4).
Phenyl-substituted acrylamide 11b and methyl-substituted
enamide 12a showed similar reactivity (Table 1, entry 2),
therefore the reaction involving substrate 2c, which contains
Entry
11 (R2)
12 (R3)
16
17
yield [%][b]
yield [%][b]
ee [%]
1
2
3
11a (Me)
11b (Ph)
11a (Me)
12a (Me)
12a (Me)
12b (Ph)
16a: –
16b: –
16a: –
17a: 24
17a: 28
17b: –
99
99
–
[a] A solution of 6a in CH2Cl2 was added to a solution of 5a, 11, 12, and
Rh catalyst in CH2Cl2 over 1 min. [b] Yield of isolated product.
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[9] A ruthenium(II)-catalyzed, one-pot [2+2+2]/[4+2] cycloaddi-
tion of one terminal 1,6-diyne with two N-phenylmaleimides was
reported. See: Y. Yamamoto, H. Kitahara, R. Ogawa, H.
Kawaguchi, K. Tatsumi, K. Itoh, J. Am. Chem. Soc. 2000, 122,
4310.
[10] The reaction of 1,6-diyne 1a and sterically more demanding
styryl methacrylate was also investigated. However, the [2+2+2]
cycloaddition of the enol double bond, and not the methacrylic
double bond, occurred and this was followed by aromatization to
yield the corresponding substituted benzene. As well as this
product, the carboxylative cyclization product of 1a with
methacrylic acid and the homo-[2+2+2] cycloaddition product
of 1a were generated. For the rhodium-catalyzed carboxylative
cyclization of 1,6-diynes, see: K. Tanaka, S. Saito, H. Hara, Y.
Shibata, Org. Biomol. Chem. 2009, 7, 4817.
lecular [2+2+2] cycloaddition/intramolecular Diels–Alder
reaction[15] cascade of alkynes and amide-linked 1,5-dienes
with high chemo-, regio-, and enantioselectivity. Future
studies will focus on expanding the reaction scope and its
application to natural product synthesis.
Received: July 7, 2010
Revised: November 22, 2010
Published online: January 11, 2011
Keywords: asymmetric catalysis · cascade reactions ·
.
cycloaddition · Diels–Alder reaction · rhodium
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[14] CCDC 782581
[(À)-3aa],
CCDC 782582
[(+)-3ae],
CCDC 782583 [(+)-3gc], and CCDC 782584 [(+)-7ada] contain
the supplementary crystallographic data for this paper. This data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[15] A control experiment was conducted to see if the rhodium
catalyst is required for the Diels–Alder reaction step. As a result
of this control experiment, it was concluded that the rhodium
catalyst is not necessary for the Diels–Alder reaction step. See
the Supporting Information.
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