Highly diastereo- and enantioselective construction of both central and axial chiralities by Rh-catalyzed [2 + 2 + 2] cycloaddition

Article abstract of DOI:10.1039/b814014f

The cationic Rh-SEGPHOS complex catalyzed an intermolecular [2 + 2 + 2] cycloaddition of enynes, possessing an ortho-substituted aryl group on their alkyne terminus, with acetylenedicarboxylates. Bicyclic cyclohexa-1,3-dienes with both central and axial c

Full text of DOI:10.1039/b814014f

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Highly diastereo- and enantioselective construction of both central and axial
chiralities by Rh-catalyzed [2 + 2 + 2] cycloaddition†
Takanori Shibata,* Mayumi Otomo, Yu-ki Tahara and Kohei Endo
Received 12th August 2008, Accepted 30th September 2008
First published as an Advance Article on the web 15th October 2008
DOI: 10.1039/b814014f
The cationic Rh–SEGPHOS complex catalyzed an inter-
molecular [2 + 2 + 2] cycloaddition of enynes, possessing an
ortho-substituted aryl group on their alkyne terminus, with
acetylenedicarboxylates. Bicyclic cyclohexa-1,3-dienes with
both central and axial chiralities were obtained in extremely
highly diastereo- and enantioselective manner.
at 40 ◦C (Table 1). When BINAP was used, [2 + 2 + 2] cycloadduct
3aa was obtained in high yield, and the enantiomeric excess of
minor diastereomer exceeded 90% but diastereoselectivity was
low (Entry 1). In the case of tolBINAP, which was the best
ligand for the intermolecular [2 + 2 + 2] cycloaddition of enynes
with alkyne 2a for the construction of a central chirality,9b the
enyne was smoothly consumed but yield and enantioselectivities
decreased (Entry 2). XylylBINAP and H8-BINAP gave poorer
results (Entries 3 and 4). On the contrary, SEGPHOS (5,5¢-
bis(diphenylphosphino)-4,4¢-bi-1,3-benzodioxole) resulted in the
best yield within 1 h and the ee of minor diastereomer exceeded
99% (Entry 5). But the diastereoselectivity remained low despite
using several phosphorus ligands.
We further investigated the reaction conditions to im-
prove diastereoselectivity (Table 2). When tetrakis(3,5-di-
trifluoromethylphenyl)borate (BARF) was used as a counter anion
for the Rh-complex, the catalytic activity drastically increased
(Entries 1 and 2): enyne 1a was completely consumed within
10 min at 40 ◦C and within 1 h even at room temperature,
however, diastereoselectivity was not improved. Solvent screening
using toluene and tetrahydrofuran affected the ee of the major
diastereomer but diastereoselectivity was low (Entries 3 and 4).
We next focused on the choice of alkynes: when more bulky
TBS-protected but-2-yne-1,4-diol 2b was used, the ratio of major
isomer against minor one was dramatically improved but its ee
Catalytic asymmetric synthesis has made remarkable progress in
recent years, and chiralities have been efficiently induced in a highly
enantioselective manner: various approaches to the construction
of central, axial, facial and helical chiralities were reported.1 In
general, a chiral motif is only generated in a reaction using a
chiral catalyst, such as the asymmetric alkylation of carbonyl
compounds. In some examples, multiple chiral motifs were formed
in a multiple bond-forming reaction, however, the induction of
different kinds of chiral motifs in a reaction has been scarcely
reported. On the contrary, there are many compounds possessing
both central and axial chiralities,2 and some of them are used
as efficient chiral ligands and catalysts.3 Chirality transfer from
central to axial chirality4 and vice versa5 are known procedures but
we here disclose the generation of two different kinds of chiralities
in a reaction, namely a highly diastereo- and enantioselective
construction of both central and axial chiralities.
Transition metal-catalyzed [2 + 2 + 2] cycloaddition of two
alkyne and an alkene moieties is an established protocol for the
synthesis of cyclohexa-1,3-diene.6 A Co-catalyzed diastereoselec-
tive reaction using chiral alkynes7 and a Ni-catalyzed enantioselec-
tive reaction8 are pioneering works of asymmetric variants. Evans
et al. and we independently reported a highly enantioselective
[2 + 2 + 2] cycloaddition of enynes and alkynes using chiral
cationic Rh catalysts, where a central chirality was generated at
the ring-fused position.9 We assume that axial chirality can be
further constructed by introduction of a bulky ortho-substituted
aryl group on the alkyne terminus of enynes. The generation of
axial chirality in a biaryl system by [2 + 2 + 2] cycloaddition of
alkynes was already reported by us and other groups,10 but that in
aryl–diene system has not been reported as far as we know.
We chose the reaction of nitrogen-tethered enyne 1a with a
naphthyl group on its alkyne terminus and 1,4-dimethoxybut-2-
yne (2a) as a model reaction, and examined several chiral phos-
phorus ligands for the cationic Rh complex in 1,2-dichloroethane
Table 1 Screening of chiral ligands in the Rh-catalyzed intermolecular
[2 + 2 + 2] cycloaddition of enyne 1a with alkyne 2a
Entrya
Ligandb
Time/h
Yield (%)
drc
ee (%)d
1
2
3
4
5
BINAP
24
6
48
48
1
85
69
44
59
96
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
84, 94
60, 82
38, 82
31, 95
80, >99
tolBINAP
xylylBINAP
H8-BINAP
SEGPHOS
Department of Chemistry and Biochemistry, School of Advanced Science and
Engineering, Waseda University, 3-4-1, Okubo, Shinjuku, Tokyo, 169-8555,
Japan. E-mail: tshibata@waseda.jp; Fax: +81 352868098
† Electronic supplementary information (ESI) available: Experimental
procedure and full characterization of enynes and cycloadducts. CCDC
reference number 696283. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/b814014f
a 1a : 2a = 1 : 2. b S isomers were used. c Diastereomeric ratio was
1
determined by integration of H-NMR spectra. d Enantiomeric excess of
major and minor diastereomers.
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Table 2 Effect of the alkynes on the diastereoselectivity using [Rh–
SEGPHOS]BARF catalyst
Table 3 Examination of several enynes in the Rh-catalyzed intermolecu-
lar [2 + 2 + 2] cycloaddition
Entrya R2
Z
Enyne Temp/◦C Time/h Yield (%) ee (%)
Entrya R1
Temp./◦C Time/h Yield (%) drb
ee (%)c
1
2
2-MePh
NTs 1b
2-biphenyl NTs 1c
2-biphenyl NTs 1c
2-biphenyl NTs 1c
60
60
rt
rt
rt
60
60
0.25
2
24
3
0.3
0.25
0.25
91 (3bc) >99
1
CH2OMe (2a) 40
0.2
1
5
24
1
1
88 (3aa)
71 (3aa)
76 (3aa)
15 (3aa)
97 (3ab)
48 (3ac)
2 : 1 73, 98
2 : 1 79, >99
1 : 1 69, >99
1 : 1 94, >99
10 : 1 75, —
10 : 1 NDf
33 (3cc)b
99c
2
CH2OMe (2a) rt
CH2OMe (2a) rt
CH2OMe (2a) rt
CH2OTBS (2b) rt
CO2t-Bu (2c) rt
CO2t-Bu (2c) 60
3d
4d,f
5d
6
48 (3cc)e >99c
98 (3cc) >99
3d
4e
5
1-naphthyl
1-naphthyl CE2 1e
1-naphthyl CE2 1e
O
1d
85 (3dc)
34 (3ec)
95 (3ec)
98
99
99
g
6
7f
g
7g
8g
0.25
0.25
93 (3ac) >20 : 1 >99, —
CO2Me (2d)
80
97 (3ad) 7 : 1 >99, —
a 1b–e : 2c = 1 : 2. Alkyne was added dropwise. b Diastereomeric ratio is
2 : 1. c Enantiomeric excess of major diastereomer. d Both enyne and alkyne
were added simultaneously and dropwise. e Diastereomeric ratio is 6 : 1.
f 1c or 1e : 2c = 1.2 : 1. The yield was based upon the amount of alkyne 2c.
g E = CO2Me.
a 1a : 2a–d = 1 : 2. b Diastereomeric ratio was determined by integration
of 1H-NMR spectra. c Enantiomeric excess of major and minor diastere-
omers. d Toluene was used as a solvent. e THF was used as a solvent. f Not
determined. g Alkyne was added dropwise.
was moderate, which could be speculated from the results above
(Entry 5). As bulky substituents on the alkyne, we installed tert-
butoxycarbonyl groups (Entry 6): The high diastereoselectivity
was also achieved but the yield was low because enyne 1a was
recovered. In order to consume the enyne and to prevent the
◦
trimerization of the alkyne, the reaction was examined at 60 C
along with the dropwise addition of acetylene dicarboxylate 2c
(Entry 7): enyne 1a was completely consumed within 15 min and
the minor diastereomer was not detected by NMR analysis.11,12
Moreover, the ee of the single diastereomer exceeded 99%. When
dimethyl acetylenedicarboxylate 2d was used, an excellent yield
and enantioselectivity were accomplished but diastereoselectivity
significantly decreased (Entry 8). These results imply that the
bulkyness of alkynes controlled the diastereoselectivity.
Several enynes were submitted to the reaction with alkyne
2c using Rh–SEGPHOS complex as a chiral catalyst (Table 3):
when an o-tolyl group was introduced to the alkyne terminus,
the corresponding cycloadduct 3bc was obtained in high yield
with excellent diastereo- and enantioselectivities (Entry 1). On the
contrary, in the reaction of enyne 1c, product 3cc was afforded
in low yield with low diastereomeric ratio and unidentified by-
products were formed (Entry 2). When the reaction was examined
at room temperature, and both enyne and alkyne were added
simultaneously and dropwise, yield and diastereoselectivity were
improved but the yield was moderate (Entry 3). When a slight
excess of enyne was used, the reaction smoothly proceeded and
cycloadduct 3cc was obtained in high yield as a single diastereomer
with excellent ee (Entry 4). The structure of cycloadduct 3cc was
determined by X-ray analysis, and the central and axial chiralities
were determined to be the S and R form, respectively (Fig. 1).
Oxygen-tethered enyne 1d was reactive and good results were
attained at room temperature (Entry 5). On the contrary, carbon-
tethered enyne 1e was inactive: diastereo- and enantioselectivity
were extremely high, but the yield was low probably because of
the formation of a [2 + 2 + 2] cycloadduct derived from two
alkynes and the alkyne moiety of 1e (Entry 6). Also in this case,
the use of a slight excess amount of the enyne improved the yield:
Fig. 1 Ortep diagram of cycloadduct 3cc.
the excellent yield was achieved with the same stereoselectivity
(Entry 7).
Scheme 1 shows the asymmetric induction of two different
chiralities: a central chirality is generated at the ring-fused position
of the bicyclic metallacyclopentene intermediate by the oxidative
coupling of the metal center with an enyne. We assume that axial
chirality cannot be completely controlled at this stage, but the
following reaction with an alkyne induces the axial chirality.
Scheme 1 Induction of central and axial chiralities.
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In conclusion, we have developed a [Rh–SEGPHOS]BARF
complex-catalyzed [2 + 2 + 2] cycloaddition with excellent
diastereo- and enantioselectivities. The intermolecular reaction
of enynes, possessing an ortho-substituted aryl group on their
alkyne terminus, with di(tert-butyl) acetylenedicarboxylate gave
the bicyclic cyclo-1,3-dienes with both central and axial chiralities.
As far as we know, this is the first example of generation
of two different chiral motifs in the transition metal-catalyzed
cycloaddition.
We thank Takasago International Corp. for the gift of SEG-
PHOS and H8-BINAP. This research was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
S. Fukuzawa and S. Uemura, J. Chem. Soc., Perkin Trans. 1, 1995, 22,
2871; (m) K. H. Doetz, C. Christoffers, J. Christoffers, D. Boettcher,
M. Nieger and S. Kotila, Chem. Ber., 1995, 128, 645.
4 (a) A. V. Vorogushin, W. D. Wulff and H. -J. Hansen, Tetrahedron, 2008,
64, 949; (b) G. Stavrakov, M. Keller and B. Breit, Eur. J. Org. Chem.,
2007, 5726; (c) Y. Nishii, K. Wakasugi, K. Koga and Y. Tanabe, J.
Am. Chem. Soc., 2004, 126, 5358; (d) T. Hattori, M. Date, K. Sakurai,
N. Morohashi, H. Kosugi and S. Miyano, Tetrahedron Lett., 2001, 42,
8035; (e) F. Fabris, O. De, Lucchi and V. Lucchini, J. Org. Chem., 1997,
62, 7156; (f) M. Tichy, J. Gunterova and J. Zavada, Collect. Czech.
Chem. Commun., 1997, 62, 1080; (g) R. W. Baker, T. W. Hambley, P.
Turner and B. J. Wallace, Chem. Commun., 1996, 2571; (h) A. I. Meyers
and D. G. Wettlaufer, J. Am. Chem. Soc., 1984, 106, 1135.
5 (a) Y. Zhang, Y. Wang and W.-M. Dai, J. Org. Chem., 2006, 71,
2445; (b) M. Ogasawara, K. Ueyama, T. Nagano, Y. Mizuhata and
T. Hayashi, Org. Lett., 2003, 5, 217; (c) A. V. Vorogushin, W. D. Wulff
and H.-J. Hansen, J. Am. Chem. Soc., 2002, 124, 6512; (d) M. Tichy,
M. Budesinsky, J. Gunterova, J. Zavada, J. Podiaha and I. Cisarova,
Tetrahedron, 1999, 55, 7893; (e) K. Ohmori, M. Kitamura and K.
Suzuki, Angew. Chem., Int. Ed., 1999, 38, 1226; (f) M. Amadji, D.
Cahard, J.-D. Moriggi, L. Toupet and J.-C. Plaquevent, Tetrahedron:
Asymmetry, 1998, 9, 1657; (g) M. Bertrand, M. L. Roumestant and P.
Sylvestre-Panthet, Tetrahedron Lett., 1981, 22, 3589.
6 (a) C.-A. Chang, J. A. Jr, King and K. P. C. Vollhardt, J. Chem. Soc.,
Chem. Commun., 1981, 53; (b) R. Grigg, R. Scott and P. Stevenson,
J. Chem. Soc., Perkin Trans. 1, 1988, 1365; (c) B. M. Trost and G. J.
Tanoury, J. Am. Chem. Soc., 1987, 109, 4753; (d) H . - Y. R hyo o, B. Y.
Lee, H. K. B. Yu and Y. K. Chung, J. Mol. Catal., 1994, 92, 41; (e) C.
H. Oh, H. R. Sung, S. H. Jung and Y. M. Lim, Tetrahedron Lett., 2001,
42, 5493; (f) Y. Yamamoto, S. Kuwabara, Y. Ando, H. Nagata, H.
Nishiyama and K. Itoh, J. Org. Chem., 2004, 69, 6697; (g) S. Kezuka,
T. Okado, E. Niou and R. Takeuchi, Org. Lett., 2005, 7, 1711.
7 (a) R. Halterman and K. P. C. Vollhardt, Organometallics, 1988, 7, 883;
(b) F. Slowinski, C. Aubert and M. Malacria, Tetrahedron Lett., 1999,
40, 5849.
Notes and references
1 (a) Comprehensive Asymmetric Catalysis II, ed. E. N. Jacobsen, A.
Pfaltz and H. Yamamoto, Springer-Verlag, Berlin, 1999; (b) Catalytic
Asymmetric Synthesis, ed. I. Ojima, Wiley-VCH, New York, 2nd edn,
2000; (c) Comprehensive Asymmetric Catalysis: Supplement 1, ed. E. N.
Jacobsen, A. Pfaltz and H. Yamamoto, Springer-Verlag, Berlin,
2003; (d) Methodologies in Asymmetric Catalysis, ed. S. V. Malhotra,
American Chemical Society, Washington, DC, 2004.
2 (a) D. J. Edwards, D. House, H. M. Sheldrake, S. J. Stone and T. W.
Wallace, Org. Biomol. Chem., 2007, 5, 2658; (b) G. Arnott and R.
Hunter, Tetrahedron, 2006, 62, 992; (c) K. Beattie, C. Elsworth, M.
Gill, N. M. Milanovic, D. P. -Putra and E. Raudies, Phytochemistry,
2004, 65, 1033; (d) O. Baudoin, A. Decor, M. Cesario and F. Gueritte,
Synlett, 2003, 2009; (e) Y. Wang, X. Li and K. Ding, Tetrahedron Lett.,
2002, 43, 159; (f) Y. Yamamoto, R. Hattori, T. Miwa, Y. Nakagai, T.
Kubota, C. Yamamoto, Y. Okamoto and K. Itoh, J. Org. Chem., 2001,
66, 3865.
3 (a) D.-Y. Wang, X.-P. Hu, J.-D. Huang, J. Deng, S.-B. Yu, Z.-C. Duan,
X.-F. Xu and Z. Zheng, Angew. Chem., Int. Ed., 2007, 46, 7810; (b) W.-L.
Duan, Y. Imazaki, R. Shintani and T. Hayashi, Tetrahedron, 2007, 63,
8529; (c) V. A. Soloshonok, H. Ueki, J. L. Moore and T. K. Ellis, J.
Am. Chem. Soc., 2007, 129, 3512; (d) I. Mikhael, C. Goux-Henry and
D. Sinou, Tetrahedron: Asymmetry, 2006, 17, 1853; (e) L. Qiu, F. Y.
Kwong, J. Wu, W. H. Lam, S. Chan, W.-Y. Yu, Y.-M. Li, R. Guo, Z.
Zhou and A. S. C. Chan, J. Am. Chem. Soc., 2006, 128, 5955; (f) T.
Fekner, H. Muller-Bunz and P. J. Guiry, Org. Lett., 2006, 8, 5109;
(g) S. E. Denmark, Y. Fan and M. D. Eastgate, J. Org. Chem., 2005, 70,
5235; (h) A. Patti, S. Pedotti, A. Forni and G. Casalone, Tetrahedron:
Asymmetry, 2005, 16, 3049; (i) A. V. Malkov, M. Bell, M. Orsini, D.
Pernazza, A. Massa, P. Herrmann, P. Meghani and P. Kocovsky, J.
Org. Chem., 2003, 68, 9659; (j) O. Tissot, M. Gouygou, J.-C. Daran
and G. G. A. Balavoine, Chem. Commun., 1996, 19, 2287; (k) A. Kless,
J. Holz, D. Heller, R. Kadyrov, R. Selke, C. Fischer and A. Boerner,
Tetrahedron: Asymmetry, 1996, 7, 33; (l) Y. Nishibayashi, J. D. Singh,
8 S. Ikeda, H. Kondo, T. Arii and K. Odashima, Chem. Commun., 2002,
2422.
9 (a) P. A. Evans, K. W. Lai and J. R. Sawyer, J. Am. Chem. Soc., 2005,
127, 12466; (b) T. Shibata, Y. Arai and Y. Tahara, Org. Lett., 2005, 7,
4955.
10 (a) A. Gutnov, B. Heller, C. Fischer, H.-J. Drexler, A. Spannenberg, B.
Sundermann and C. Sundermann, Angew. Chem., Int. Ed., 2004, 43,
3795; (b) T. Shibata, T. Fujimoto, K. Yokota and K. Takagi, J. Am.
Chem. Soc., 2004, 126, 8382; (c) K. Tanaka, G. Nishida, A. Wada and
K. Noguchi, Angew. Chem., Int. Ed., 2004, 43, 6510.
11 When adduct 3ac was heat at 80 ◦C in DCE for 1 h, a significant
decrease of diastereomeric ratio was observed (from 10 : 1 to 5 : 1).
12 As a reference experiment, the cycloaddition of alkynes 2a and 2c with a
diyne, in place of enynes, was examined under the same reaction condi-
tions: the reaction of alkyne 2c achieved much higher enantioselectivity
than that of 2a (details in supplemental information†). These results
suggest that diastereoselectivity was determined by the induction of
axial chirality at the stage of alkyne insertion.
4298 | Org. Biomol. Chem., 2008, 6, 4296–4298
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The Royal Society of Chemistry 2008
©