Enantioselective synthesis of chiral tripodal cage compounds by [2 + 2 + 2] cycloaddition of branched triynes

Article abstract of DOI:10.1021/ol9014893

Cyclotrimerization of triynes branched by a nitrogen atom of 2-aminophenol yielded planar-chiral tripodal cage compounds. When a cationic Rh-Me-DUPHOS catalyst was used, the cycloadducts were obtained in high yield and excellent ee, and a macrocyclic comp

Full text of DOI:10.1021/ol9014893

ORGANIC
LETTERS
2009
Vol. 11, No. 17
3906-3908
Enantioselective Synthesis of Chiral
Tripodal Cage Compounds by [2 + 2 +
2] Cycloaddition of Branched Triynes
Takanori Shibata,* Toshifumi Uchiyama, and Kohei Endo
Department of Chemistry and Biochemistry, School of AdVanced Science and
Engineering, Waseda UniVersity, Okubo, Shinjuku, Tokyo 169-8555, Japan
tshibata@waseda.jp
Received July 2, 2009
ABSTRACT
Cyclotrimerization of triynes branched by a nitrogen atom of 2-aminophenol yielded planar-chiral tripodal cage compounds. When a cationic
Rh-Me-DUPHOS catalyst was used, the cycloadducts were obtained in high yield and excellent ee, and a macrocyclic compound with a
[15]cyclophane system was also obtained. This method can be further applied to the synthesis of a triarmed pyridinophane by the intramolecular
reaction of a diyne-nitrile.
The transition-metal-catalyzed enantioselective [2 + 2 + 2]
cycloaddition of alkynes and alkenes as C2 sources is the
Scheme 1
.
Intramolecular [2 + 2 + 2] Cycloaddition of a
most atom-economical and reliable method for the construc-
tion of chiral ring systems.1 Intramolecular reactions, in
particular, are fascinating because they provide multicyclic
compounds in one pot. In a previous study, we developed
an Ir-catalyzed reaction of triynes for the generation of axial
chiralities.2 Then, we and Tanaka’s group independently
carried out a Rh-catalyzed reaction of enediynes3 and
dienynes4 for the generation of two central chiralities. In these
studies, the substrates were linear compounds, where three
C2-unsaturated motifs are present in a straight chain. In
contrast, we have recently focused on the reaction of
branched compounds because this reaction provides cage
Branched Triyne
compounds with chiralities: a reaction of branched dienynes,
wherein the alkyne and alkene moieties are connected by
1,1-disubstituted alkene, give various unique and strained
chiral carbon skeletons with multicyclic systems.5
We next came up with an intramolecular cycloaddition of
branched triynes; the [2 + 2 + 2] cycloaddition of triyne A
yields tripodal compounds, namely 1,3,5-trisubstituted ben-
(1) (a) Shibata, T.; Tsuchikama, K. Org. Biomol. Chem. 2008, 1317.
(b) Tanaka, K. Chem. Asian J. 2009, 4, 508.
(2) (a) Shibata, T.; Tsuchikama, K.; Otsuka, M. Tetrahedron: Asymmetry
2006, 17, 614. (b) Shibata, T.; Yoshida, S.; Arai, Y.; Otsuka, M.; Endo, K.
Tetrahedron 2008, 64, 821.
(3) (a) Shibata, T.; Kurokawa, H.; Kanda, K. J. Org. Chem. 2007, 72,
6521. (b) Tanaka, K.; Nishida, G.; Sagae, H.; Hirano, M. Synlett 2007,
1426.
(5) (a) Shibata, T.; Tahara, Y. J. Am. Chem. Soc. 2006, 128, 11766. (b)
Shibata, T.; Tahara, Y.; Tamura, K.; Endo, K. J. Am. Chem. Soc. 2008,
130, 3451.
(4) Sagae, H.; Noguchi, K.; Hirano, M.; Tanaka, K. Chem. Commun.
2008, 3804.
10.1021/ol9014893 CCC: $40.75
Published on Web 08/10/2009
 2009 American Chemical Society

(1,2-bis(2,5-dimethylphospholano)benzene) catalyst in tolu-
ene, which efficiently operated in the intramolecular reaction
of linear triynes.2a The reaction proceeded at 60 °C, and the
desired cycloadduct 2a was obtained with high ee (86%);
however, the yield was low, probably because of the
intermolecular reaction (entry 1 in Table 1).11 To promote
the intramolecular reaction, triyne 1a was added dropwise
over 10 min to a solution of the chiral catalyst at a higher
temperature (120 °C), the yield improved drastically (entry
2). Next, we replaced the neutral Ir complex with the cationic
Rh complex; the reaction proceeded to completion within
2 h in 1,2-dichloroethane (DCE) at 80 °C, and the enanti-
oselectivity reached 98% using Me-DUPHOS (entry 3).12
Ph-BPE (1,2-bis(2,5-diphenylphospholano)ethane) gave a
better yield, but the enantioselectivity decreased (entry 4).
In the present [2 + 2 + 2] cycloaddition, BINAP derivatives
were not preferred chiral ligands as only moderate enanti-
oselectivity was achieved with their use (entries 5-7).13
Finally, we screened the counteranions of the Rh catalyst:
triflate gave the best results with regard to both yield and ee
(entries 3, 8, and 9).14
Table 1. Optimization of the Reaction Conditions
entrya
chiral catalystb
T/°C time/h yield/% ee/%
1
2
3
4
5
6
7
8
9
[IrCl(cod)]2 + 2Me-DUPHOS
[IrCl(cod)]2 + 2Me-DUPHOS
[Rh(cod)2]BF4 + Me-DUPHOS
[Rh(cod)2]BF4 + Ph-BPE
60 16
120 0.3
80
6
62
70
76
77
81
74
61
77
86
88
98
91
40
36
56
94
98
2
9
80
80
80
80
80
[Rh(cod)2]BF4 + BINAP
0.5
0.5
0.5
1
[Rh(cod)2]BF4 + H8-BINAP
[Rh(cod)2]BF4 + SEGPHOS
[Rh(cod)2]BARF + Me-DUPHOS
[Rh(cod)2]OTf + Me-DUPHOS 80
1
a The reaction was examined in toluene (entries 1 and 2) or in DCE (entries
3-9). Triyne 1a was added dropwise over 10 min to a solution of chiral catalyst
except entry 1. b (S)- or (S,S)-isomers were used as chiral ligands. Me-DUPHOS:
1,2-bis(2,5-dimethylphospholano)benzene. Ph-BPE: 1,2-bis(2,5-diphenylphos-
pholano)ethane. SEGPHOS: 5,5′-bis(diphenylphosphino)-4,4′-bi-1,3-benzo-
dioxole. BARF: tetrakis(3,5-bis(trifluoromethyl)phenyl)borate.
When isolated Rh-Me-DUPHOS complex was used, the
yield improved further and exceeded 80% (entry 1 in Table
2). Under the optimal reaction conditions, triynes 1b-d with
zene isomer B and 1,2,4-trisubstituted benzene isomers C
and C′, which are enantiomers (Scheme 1).6 To the best of
our knowledge, there have been only two reported examples
of [2 + 2 + 2] cycloaddition of branched triyne: the reaction
of carbon-branched (Z ) CH)7 and silicon-branched (Z )
SiBut) triynes8 with the Ziegler catalyst yielded type B
cycloadduct as a major product, but in low yield. We report
herein the first example of enantioselective [2 + 2 + 2]
cycloaddition of branched triynes, which yields chiral tripodal
cage compounds.9
Table 2. Reaction of Triynes Possessing Various Substituents
on Their Diyne Termini
As a model substrate we chose nitrogen-branched triyne 1a
because it has the following three advantages: (1) selective
oxidative coupling of dipropargylamine, namely the 1,6-diyne
moiety in the triyne, with a metal catalyst, (2) favorable
orientation of side chain with alkyne moiety by rigid
2-aminophenol tether, and (3) activation of alkyne moiety
by methoxy methyl group.10 First, we used Ir-Me-DUPHOS
entry
R
triyne
time/h
yield/%
ee/%
1
2
3
4
C6H5
1a
1b
1c
1d
2
0.5
1
84 (2a)
95 (2b)
84 (2c)
57 (2d)
98
98
98
99
4-BrC6H4
4-(MeO)C6H4
Me
(6) The synthesis of dipodal compounds, namely o, m, p-cyclophanes
by transition-metal-catalyzed [2 + 2 + 2] cycloaddition, is an established
protocol: Co catalysts: (a) Moretto, A. F.; Zhang, H.-C.; Maryanoff, B. E.
J. Am. Chem. Soc. 2001, 123, 3157. (b) Bon˜aga, L. V. R.; Zhang, H.-C.;
Moretto, A. F.; Ye, H.; Gautheir, D. A.; Li, J.; Leo, G. C.; Maryanoff,
B. E. J. Am. Chem. Soc. 2005, 127, 3473. Rh catalysts: (c) Kinoshita, H.;
Shinokubo, H.; Oshima, K. J. Am. Chem. Soc. 2003, 125, 7784. (d) Tanaka,
K.; Toyoda, K.; Wada, A.; Shirasaka, K.; Hirano, M. Chem.sEur. J. 2005,
11, 1145.
1
other substituents at their diyne termini were examined: the
reaction of bromophenyl-substituted triyne 1b concluded
within 30 min, and both the yield and the enantioselectivity
were excellent. The electron-donating group on the phenyl
group was also acceptable, and the results were the same as
those of triyne 1a (entry 3). In the case of the methyl-
substituted triyne 1d, the corresponding cycloadduct 2d was
(7) Hubert, A.; Hubert, M. Tetrahedron Lett. 1966, 46, 5779.
(8) Damrauer, R.; Hankin, J. A.; Haltiwanger, R. C. Organometallics
1991, 10, 3962.
(9) Tanaka’s group reported an intramolecular reaction of linear triynes.
Rh-H8-BINAP catalyst induced excellent enantioselectivity to give chiral
[7]-[10]metacyclophanes but in low yield (10-33%): Tanaka, K.; Sagae,
H.; Toyoda, K.; Noguchi, K.; Hirano, M. J. Am. Chem. Soc. 2007, 129,
1522.
(11) The formation of highly polar products was ascertained but they
could not be identified.
(10) The methoxymethyl group efficiently activates the alkyne moiety
as a coupling partner of a diyne: (a) Shibata, T.; Fujimoto, T.; Yokota, K.;
Takagi, K. J. Am. Chem. Soc. 2004, 126, 8382. (b) Shibata, T.; Arai, Y.;
Takami, K.; Tsuchikama, K.; Fujimoto, T.; Takebayashi, S.; Takagi, K.
AdV. Synth. Catal. 2006, 348, 2475.
(12) When Ir-Me-DUPHOS catalyst was used in DCE at 80 °C for
2 h, only a trace amount of product 2a was obtained.
(13) Cationic Rh-BINAP derivatives operated as efficient catalysts in
various enatnioselective [2 + 2 + 2] cycloadditions of alkynes; see: Tanaka,
K. Synlett 2007, 1977.
Org. Lett., Vol. 11, No. 17, 2009
3907

obtained in moderate yield and the highest ee of 99% was
achieved (entry 4). In triynes 1a-d, there exists a three-
carbon tether between phenol and the alkyne moiety, and
tripodal cage compounds with the [8]cyclophane skeleton
were obtained.
was determined by X-ray diffraction analysis (Figure 1).15
When triyne 9 was used in the reaction, the best yield of
91% was achieved along with an excellent ee (entry 4). It is
noteworthy that the reaction of triyne 11, which possesses a
C10 tether, also proceeded under the same conditions to
afford the planar-chiral cycloadduct 12 in acceptable yield
with excellent ee; this implies that the [15]cyclophane
structure was definitely constructed, and that the long carbon
ansa chain was not flipped to racemize (entry 5).
Next, we screened various triynes with longer tethers
(Table 3): the reaction of triynes 3 and 5 with C4 and C5
We further examined a hetero-[2 + 2 + 2] cycloaddition
of diyne-nitrile 13 (eq 1).16 Rh-Me-DUPHOS catalyst did
not yield pyridinophane 14; Rh-BINAP, however, was an
efficient catalyst, and planar-chiral cycloadduct 1417 was
obtained in high ee.18,19
Table 3. Reaction of Triynes with Various Tethers of the
Length
entry
n
Ar
triyne
time/h
yield/%
ee/%
In summary, we developed a highly enantioselective
intramolecular reaction of nitrogen-branched triynes. A
cationic Rh-Me-DUPHOS complex efficiently catalyzed the
reaction to yield tripodal cage compounds with tethers having
different lengths. The design and synthesis of such functional
cage molecules with chiral recognition ability are currently
in progress.
1
2
3
4
5
2
3
3
4
8
Ph
Ph
3
5
7
9
11
1
2
1.5
1
2
67 (4)
88 (6)
80 (8)
91 (10)
59 (12)
98
98
97
98
96
4-BrC6H4
Ph
Ph
tethers, respectively, also proceeded smoothly, and the
corresponding tripodal cage compounds 4 and 6 were
obtained in excellent ee (entries 1 and 2). Recrystallization
Acknowledgment. This research was supported by a
Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
We also thank Takasago International Corp. for the gift of
SEGPHOS and H8-BINAP.
Supporting Information Available: Experimental pro-
cedures and spectral data for new products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL9014893
(14) Rh-(R,R)-Me-DUPHOS catalyst surely afforded an opposite enan-
tiomer with the same ee of 98% ee.
(15) The absolute configuration of other cycloadducts was speculated
on the basis of that of cycloadduct 8.
(16) Non-asymmetric intermolecular reactions of diynes with nitrile
compounds for the synthesis of pyridinophanes were reported in
ref 6a,b.
(17) The absolute configuration of pyridinophane 14 was not determined
yet.
(18) The first enantioselective hetero-[2 + 2 + 2] cycloaddition of two
alkynes and a nitrile compound, which induced an axial chirality: Gutnov,
A.; Heller, B.; Fischer, C.; Drexler, H.-J.; Spannenberg, A.; Sundermann,
Figure 1. ORTEP diagram of tripodal cycloadduct 8.
B.; Sundermann, C. Angew. Chem., Int. Ed. 2004, 43, 3795
.
(19) Asymmetric synthesis and use of planar-chiral pyridinophanes: (a)
of cycloadduct 8, derived from bromophenyl-substituted
triyne 7, yielded a single crystal (entry 3), and its structure
Kanomata, N.; Nakata, T. Angew. Chem., Int. Ed. 1997, 36, 1207. (b)
Kanomata, N.; Nakata, T. J. Am. Chem. Soc. 2000, 122, 4563
.
3908
Org. Lett., Vol. 11, No. 17, 2009