Enantioselective synthesis of axially chiral phthalides through cationic [Rh1(H8-binap)]-catalyzed cross alkyne cyclotrimerization

Article abstract of DOI:10.1002/anie.200461533

(Chemical equation presented). Easy access to axially chiral phthalides that bear one or two oxymethylene functionalities is provided by an enantioselective cross alkyne cyclotrimerization in the presence of the cationic complex [Rh¹{(S)-H₈-binap}]⁺. The axial chirality is introduced during the formation of the benzene ring with high enantioselectivity.

Full text of DOI:10.1002/anie.200461533

Communications
cyclotrimerization of terminal alkynes and an electron-
deficient alkyne (diethyl acetylene dicarboxylate) catalyzed
by the cationic [RhI(H8-binap)][9] complex.[10] We anticipated
that cross cyclotrimerization of terminal alkynes and electron-
deficient 1,6-diynes (bearing a ortho-substituted phenyl group
and a hydrogen atom at each terminal position) would install
the axial chirality during the formation of the benzene rings
(Scheme 1).[11–14] Very recently, Gutnov, Heller, and co-work-
Scheme 1. Cationic [RhI(H8-binap)]-catalyzed cross alkyne cyclotrimer-
ization to give axially chiral phthalides.
Biaryl Compounds
Enantioselective Synthesis of Axially Chiral
ers reported the synthesis of axially chiral 2-aryl pyridines
through the CoI-catalyzed asymmetric [2 + 2 + 2] cycloaddi-
tion of alkynes and nitriles,[15] and Shibata et al. reported the
synthesis of axially chiral teraryl compounds through a
neutral [IrI(Me-duphos)] complex catalyzed asymmetric [2 +
2 + 2] cycloaddition of symmetrical a,w-diynes and symmet-
rical monoynes.[16] Herein we describe a highly enantioselec-
tive synthesis of axially chiral phthalides by the cationic
[RhI(H8-binap)] complex catalyzed cross alkyne cyclotrime-
rization of unsymmetrical a,w-diynes and unsymmetrical or
symmetrical monoynes.[17]
The reaction of 2-methylphenyl-substituted 1,6-diyne 1a
with various terminal monoynes was investigated in the
presence of the cationic complex [RhI{(S)-H8-binap}]. We
were pleased to find that the use of propargyl acetate (2a;
5 equiv) furnished axially chiral phthalide (+)-3aa in high
yield with high enantioselectivity (Table 1, entry 1). Not only
Phthalides through Cationic [RhI(H8-binap)]-
Catalyzed Cross Alkyne Cyclotrimerization**
Ken Tanaka,* Goushi Nishida, Azusa Wada, and
Keiichi Noguchi
Axially chiral biaryl compounds are widely found as key
structures of effective chiral ligands and biologically active
compounds. Therefore, several catalytic enantioselective
syntheses of these compounds have been developed to date.
These methods are based on three types of asymmetric cross-
coupling approaches: 1) cross-coupling of aryl compounds
(such as the Kumada coupling,[1] Suzuki coupling,[2] and
oxidative coupling[3]), 2) cross-coupling of biaryl ditriflates,[4]
and 3) cross-coupling of dinaphthothiophene.[5] In these
reactions, the axial chirality is constructed during the
formation of the biaryl link, the selective substitution of one
of two triflates, and the selective cleavage of one of two
carbon–sulfur bonds, respectively.[6,7]
Table 1: Enantioselective cross alkyne cyclotrimerization of 1,6-diynes 1
and terminal monoynes 2.
Cyclotrimerization of alkynes is an attractive method for
the synthesis of substituted benzenes, and various transition-
metal complexes catalyze this reaction.[8] We recently
reported the chemo- and regioselective intermolecular cross
[*] Prof.Dr.K.Tanaka, G.Nishida, A.Wada
Department of Applied Chemistry, Graduate School of Engineering
Tokyo University of Agriculture and Technology
Koganei, Tokyo, 184-8588 (Japan)
Fax: (+81)42-388-7037
E-mail: tanaka-k@cc.tuat.ac.jp
Prof.Dr.K.Noguchi
Instrumentation Analysis Center
Tokyo University of Agriculture and Technology
Koganei, Tokyo 184-8588 (Japan)
Entry
1
2
Phthalide
Yield [%][a]
3/4
ee (3) [%]
1
2
3
4
5
1a
1b
1c
1d
1a
2a
2a
2a
2a
2b
(+)-3aa/4aa
(À)-3ba/4ba
(À)-3ca/4ca
(À)-3da/4da
(+)-3db/4db
79
91
86
91
90
90:10
88:12
66:34
87:13
70:30
87
82
81
73
78
[**] This work was supported by Mitsubishi Chemical Corporation Fund
and Asahi Glass Fund.We thank Takasago International Corpora-
tion for the gift of H8-binap.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
[a] Yields of isolated products.
6510
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200461533
Angew. Chem. Int. Ed. 2004, 43, 6510 –6512

Angewandte
Chemie
2-methylphenyl-, but also 1-naphthyl- (1b, Table 1, entry 2),
2-trifluoromethylphenyl- (1c, Table 1, entry 3), and 2-chloro-
phenyl-substituted 1,6-diynes (1d, Table 1, entry 4) were
suitable substrates in this process. Importantly, the generation
of sterically demanding regioisomers 3 was predominant. In
the case of 1d, the use of propargyl alcohol (2b) improved the
enantioselectivity (Table 1, entry 5).
Interestingly, the use of symmetrical internal monoyne,
1,4-diacetoxy-2-butyne (2c; 5 equiv), enhanced the enantio-
selectivity to yield axially chiral phthalides 3ac–dc in good
yield with excellent enantioselectivity (Table 2, entries 1–4).
Table 2: Enantioselective cross alkyne cyclotrimerization of 1,6-diynes 1
and internal monoynes 2.
Scheme 2. Cross alkyne cyclotrimerization of 1d and symmetrical inter-
nal diyne 2e.
In conclusion, we have discovered an enantioselective
cross alkyne cyclotrimerization of unsymmetrical 1,6-diynes
and both terminal and internal alkynes. This method provides
easy access to axially chiral phthalides that bear one or two
oxymethylene functionalities. Work toward developing a wide
variety of asymmetric reactions in the presence of cationic
complexes of RhI and modified binap is underway in our
laboratory.
Entry
1
2
Phthalide
Yield [%][a]
ee [%]
1
2
3
1a
1b
1c
1d
1a
2c
2c
2c
2c
2d
(+)-3ac
(+)-3bc
(+)-3cc
(+)-3dc
(+)-3dd
67
57
73
45
63
>99
94
>99
86
4
5[b]
>99
Experimental Section
[a] Yields of isolated products.[b] Solvent: THF.
Full procedures and characterization data are given in the Supporting
Information.3ac: Under an Ar atmosphere, (S)-H8-binap (7.9 mg,
0.0125 mmol) and [Rh(cod)2]BF4 (5.1 mg, 0.0125 mmol) were dis-
solved in CH2Cl2 (1.0 mL), and the mixture was stirred for 5 min. H2
was introduced to the resulting solution in a Schlenk tube. The
resulting mixture was stirred for 30 min at room temperature and then
concentrated to dryness. The residue was taken up in CH2Cl2
(1.0 mL), and to this solution was added a solution of 1a (49.8 mg,
0.250 mmol) and 2c (212.7 mg, 1.25 mmol) in CH2Cl2 (1.0 mL) at
room temperature; the vial was rinsed with CH2Cl2 (0.5 mL). The
mixture was stirred at room temperature for 3 h. The resulting
mixture was concentrated and purified by preparative TLC to furnish
(+)-3ac (61.7 mg, 0.167 mmol, 67%, > 99% ee) as a yellow solid.
M.p. 95.0–97.58C; [a]2D5 = + 17.38 (c = 0.274, CHCl3); IR (neat): n˜ =
1740, 1220, 1020 cmÀ1; 1H NMR (CDCl3, 400 MHz): d = 7.60 (s, 1H),
7.22–7.36 (m, 3H), 7.01 (dd, J = 7.6 and 1.2Hz, 1H), 5.33 (s, 2H), 5.29
(d, J = 3.2Hz, 2H), 4.99 (d, J = 12.8Hz, 1H), 4.88 (d, J = 12.8Hz, 1H),
2.17 (s, 3H), 1.98 (s, 3H), 1.97 ppm (s, 3H); 13C NMR (CDCl3,
100 MHz): d = 170.3, 170.0, 168.6, 147.5, 143.2, 142.6, 135.8, 133.7,
133.2, 129.7, 128.6, 128.5, 125.5, 123.4, 121.5, 68.2, 63.4, 59.8, 20.9, 20.6,
20.0 ppm; HRMS (EI): calcd for C21H20O6 [M]+: 368.1260; found:
In the case of 1d, the use of 2-butyne-1,4-diol (2d) improved
the yield and enantioselectivity (Table 2, entry 5). The
absolute configuration of the diol (+)-3dd was determined
to be R by an anomalous dispersion method, and that of the
diacetate (+)-3dc was also determined to be R (Figure 1).[18]
368.1226; CHIRALPAK AS, hexane/iPrOH 80:20, 0.8 mLminÀ1
,
retention times: 28.6 min (minor isomer) and 30.3 min (major
isomer).
Received: August 4, 2004
Keywords: asymmetric catalysis · atropisomerism · biaryls ·
cyclotrimerization · rhodium
.
Figure 1. ORTEP Diagram of (R)-(+)-3dd drawn at the 50% probability
level.Hydrogen atoms have been omitted for clarity.
[1] a) T. Hayashi, K. Hayashizaki, Y. Ito, Tetrahedron Lett. 1989, 30,
215; b) T. Hayashi, K. Hayashizaki, T. Kiyoi, Y. Ito, J. Am. Chem.
Soc. 1988, 110, 8153.
[2] a) J. Yin, S. L. Buchwald, J. Am. Chem. Soc. 2000, 122, 12051;
b) A. N. Cammidge, K. V. L. CrØpy, Chem. Commun. 2000, 1723.
The present enantioselective cross alkyne cyclotrimeriza-
tion was applied to the symmetrical internal diyne 2e, and the
chiral phthalides 5 and 6 were obtained in excellent yield with
high enantioselectivity (Scheme 2).
Angew. Chem. Int. Ed. 2004, 43, 6510 –6512
www.angewandte.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6511

Communications
[3] a) X. Li, J. B. Hewgley, C. A. Mulrooney, J. Yang, M. C.
Kozlowski, J. Org. Chem. 2003, 68, 5500; b) Z. Luo, Q. Liu, L.
Gong, X. Cui, A. Mi, Y. Jiang, Chem. Commun. 2002, 914; c) C. -
Y, Chu, D.-R. Hwang, S.-K. Wang, B.-J. Uang, Chem. Commun.
2001, 980; d) S. Saito, T. Kano, H. Muto, H. Nakadai, H.
Yamamoto, J. Am. Chem. Soc. 1999, 121, 8943; e) M. Nakajima,
K. Kanayama, I. Miyoshi, S.-I. Hashimoto, Tetrahedron Lett.
1995, 36, 9519.
[4] a) T. Kamikawa, T. Hayashi, Tetrahedron 1999, 55, 3455; b) T.
Hayashi, S. Niizuma, T. Kamikawa, N. Suzuki, Y. Uozumi, J. Am.
Chem. Soc. 1995, 117, 9101.
[5] a) Y.-H. Cho, A. Kina, T. Shimada, T. Hayashi, J. Org. Chem.
2004, 69, 3811; b) T. Shimada, Y.-H. Cho, T. Hayashi, J. Am.
Chem. Soc. 2002, 124, 13396.
[6] For the synthesis of axially chiral biaryl compounds through
chirality exchange from sp3 central chirality to axial chirality,
see: Y. Nishi, K. Wakasugi, K. Koga, Y. Tanabe, J. Am. Chem.
Soc. 2004, 126, 5358.
[7] For the synthesis of axially chiral biaryl compounds by utilizing a
planar chiral arene–chromium complex, see: a) T. Watanabe, Y.
Tanaka, R. Shoda, R. Sakamoto, K. Kamikawa, M. Uemura, J.
Org. Chem. 2004, 69, 4152; b) K. Kamikawa, T. Sakamoto, Y.
Tanaka, M. Uemura, J. Org. Chem. 2003, 68, 9356, and
references therein.
[8] For reviews, see: a) S. Saito, Y. Yamamoto, Chem. Rev. 2000, 100,
2901; b) M. Lautens, W. Klute, W. Tam, Chem. Rev. 1996, 96, 49.
[9] X. Zhang, K. Mashimo, K. Koyano, N. Sayo, H. Kumobayashi, S.
Akutagawa, H. Takaya, Tetrahedron Lett. 1991, 32, 7283.
[10] K. Tanaka, K. Shirasaka, Org. Lett. 2003, 5, 4697.
[11] For the [RhCl(PPh3)3]-catalyzed non-asymmetric synthesis of
phthalides with acetylene gas, see: B. Witulski, A. Zimmermann,
Synlett 2002, 1855.
[12] For the nickel-catalyzed non-asymmetric synthesis of phthalides,
see: Y. Sato, K. Ohashi, M. Mori, Tetrahedron Lett. 1999, 40,
5231.
[13] For the nickel-catalyzed asymmetric construction of sp3 central
chirality, see: Y. Sato, T. Nishimata, M. Mori, Heterocycles 1997,
44, 443.
[14] For the nickel-catalyzed asymmetric synthesis of
a chiral
helicene, see: I. G. Stara, I. Stary, A. Kollarovic, F. Teply, S.
Vyskocil, D. Saman, Tetrahedron Lett. 1999, 40, 1993.
[15] A. Gutnov, B. Heller, C. Fischer, H.- J. Drexler, A. Spannenberg,
B. Sundermann, C. Sundermann, Angew. Chem. 2004, 116, 3883;
Angew. Chem. Int. Ed. 2004, 43, 3795.
[16] T. Shibata, T. Fujimoto, K. Yokota, K. Takagi, J. Am. Chem. Soc.
2004, 126, 8382.
[17] Shibata et al. reported one example of an asymmetric [2 + 2 + 2]
cycloaddition of an unsymmetrical a,w-diyne and a symmetrical
monoyne (neutral [IrI(Et-duphos)] catalyst, 81% ee).[16]
[18] CCDC-246690 (3dd) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from
the Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB21EZ, UK; fax: (+ 44)1223-336-033; or deposit@
ccdc.cam.ac.uk).
6512
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2004, 43, 6510 –6512