Chiral phosphoric acid catalyzed desymmetrization of meso-1,3diones: Asymmetric synthesis of chiral cyclohexenones

Article abstract of DOI:10.1002/anie.200905271

Chiral effectiveness: The title transformation is applicable to a wide variety of substrates to give chiral cyclohexenones in high yields and with excellent enantioselecti vity (see scheme). To clarity the origin of the enantioselectivity ONIOM calculations were carried out

Full text of DOI:10.1002/anie.200905271

Communications
DOI: 10.1002/anie.200905271
Asymmetric Synthesis
Chiral Phosphoric Acid Catalyzed Desymmetrization of meso-1,3-
Diones: Asymmetric Synthesis of Chiral Cyclohexenones**
Keiji Mori, Takuya Katoh, Tohru Suzuki, Takuya Noji, Masahiro Yamanaka, and
Takahiko Akiyama*
Cyclohexenones are important building blocks in synthetic
organic chemistry. In particular, Hajos–Parrish[1] and Wie-
land–Miescher[2] ketones are useful synthetic intermediates
not only for the preparation of steroids[3] but also for a range
of natural products.[4] The most facile and conventional
method used to obtain these ketones in enantiomerically
pure form is the desymmetrization of meso-1,3-dicarbonyl
compounds, in which (S)-proline is commonly used as a highly
reliable chiral catalyst (Scheme 1).[1,2] This protocol consists
of two consecutive transformations: 1) desymmetrization of
meso-1,3-dione by (S)-proline-catalyzed aldol reaction, and
2) dehydration.
As a result of our initial findings,[5] chiral phosphoric acids
1 derived from (R)-BINOL have been extensively studied as
versatile chiral Brønsted acid catalysts. They exhibited
remarkable asymmetric inducing ability in the nucleophilic
addition to imine, the 1,4-addition to a,b-unsaturated com-
pounds, and the transfer hydrogenation with Hantzsch ester.[6]
Although the asymmetric ring-opening of meso-aziridines by
means of chiral phosphoric acid had already been reported by
Antilla and co-workers,[7a] the chiral phosphoric acid induced
desymmetrization of meso-1,3-diones still remains a challen-
ge.[7b,c] The control of stereoselectivity by weak, noncovalent
bond interaction (hydrogen bond) is not a trivial issue in
comparison with the control by covalent bonds ((S)-proline
catalysis).[8] Herein, we report the asymmetric synthesis of
synthetically useful chiral cyclohexenones through the desym-
metrization of meso-1,3-dicarbonyl compounds induced by a
chiral phosphoric acid.[9] By this method, both desymmetri-
zation of the 1,3-dione compound and dehydration could be
accomplished in a single-step, one-pot operation, to afford
chiral cyclohexenones with excellent enantioselectivity.
An initial study was conducted by treatment of triketone 2
with 10 mol% of 1a in toluene. Gratifyingly, enone 3a was
obtained in the enantioenriched form (46% ee; Table 1,
Table 1: Screening of catalyst (R)-1.[a]
Scheme 1. Synthetic strategy for the preparation of chiral cyclohexe-
nones.
Entry
Ar
Yield [%][b]
ee [%][c]
1
2
3
4
Ph (1a)
SiPh3 (1b)
56 (43)
85 (5)
91 (4)
92 (5)
>99
46
84
70
90
90
90
À60
[*] Dr. K. Mori, T. Katoh, T. Suzuki, T. Noji, Prof. Dr. T. Akiyama
Department of Chemistry, Faculty of Science
Gakushuin University
9-anthryl (1c)
2,4,6-(iPr)3C6H2 (1d)
2,4,6-(iPr)3C6H2 (1d)
2,4,6-(iPr)3C6H2 (1d)
(S)-proline
5[d]
6[d,e]
7[f]
1-5-1, Mejiro, Toshima-ku, Tokyo, 171-8588 (Japan)
Fax: (+81)3-5992-1029
E-mail: takahiko.akiyama@gakushuin.ac.jp
Homepage: http://www-cc.gakushuin.ac.jp/~940020/akiyama_-
site/index_e.html
95
57[g]
[a] Unless otherwise noted, all reactions were conducted with 0.2 mmol
of 2a in toluene (2.0 mL). [b] Determined by 1H NMR spectroscopy.
Amount of recovered starting material in parenthesis. [c] Determined by
HPLC on a chiral stationary phase using a Daicel Chiralcel OD-H
column; flow rate=0.5 mLminÀ1; eluent=n-hexane/iPrOH=5:1. [d] n-
Hexane was used as the reaction solvent. [e] 5 mol% catalyst loading.
[f] Triketone 2 was treated with 10 mol% of (S)-proline in DMF at 258C
for 48 h, and the resulting product was treated with TsOH·H2O
(10 mol%) in benzene at reflux for 20 min. [g] Yield of isolated product.
DMF=N,N-dimethylformamide, Ts=4-toluenesulfonyl.
Prof. Dr. M. Yamanaka
Department of Chemistry, Rikkyo University
3-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501 (Japan)
[**] This work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science and
Technology (Japan).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200905271.
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Chemie
entry 1), even when the reaction was performed at 708C.
Screening of catalysts and reaction conditions (Table 1,
entries 2–5) revealed that the use of 5 mol% of 2,4,6-
triisopropylphenyl-substituted catalyst 1d in n-hexane at
gentle reflux (708C) was the optimal set of the conditions,
and gave 3a in excellent yield and enantioselectivity (95%,
90% ee; Table 1, entry 6).[10] Significantly, the selectivity of
the chiral phosphoric acid was overwhelmingly higher than
that of (S)-proline (57%, 60% ee; Table 1, entry 7).
essential owing to the poor solubility of the substrate.
Excellent yield and enantioselectivity were also observed in
the case of naphthalene derivative 3 f (90%, 84% ee; Table 2,
entry 5). Chiral phosphoric acid was applied to the asymmet-
ric synthesis of Hajos–Parrish and Wieland–Miescher ketones
(3g and 3h), and gave moderate to high yields with good
enantioselectivity (70 and 82% ee; Table 2, entries 6 and 7).[12]
The absolute configurations of these cyclohexenone deriva-
tives were surmised by analogy with 3a.
The generality of this method was examined under the
optimal reaction conditions (Table 2). Ethyl-substituted 3b
was obtained in excellent yield and enantioselectivity (89%,
To clarify the origin of the enantioselectivity, ONIOM
(B3LYP/6-31G*:HF/3-21G) calculations[13] were carried out
based on the transition state (TS) controlled by hydrogen
bonding, as shown in Scheme 1. In the TS, chiral phosphoric
acid could simultaneously activate carbonyl and enol moieties
with Brønsted acidic and Lewis basic sites, respectively.[14] The
attack of the TS from the si face (TSsi) was 1.3 kcalmolÀ1 more
stable than attack from the re face (TSre), which is in
agreement with the experimental results (Figure 1). The
Table 2: Substrate scope of the desymmetrization reaction.[a]
Entry
Product
t [h]
Yield [%]
ee [%][b]
1
3b
48
89
92
2
3c
3d
3e
3 f
72
96
48
24
24
24
82
94
72
90
86
64
94
87
90
84
70
82
3[c]
4[c,d]
5[c]
6[c]
7[c]
3g
3h
Figure 1. 3D structures and schematic representation of models of TSre
and TSsi calculated by ONIOM (B3LYP/À31G*:HF/3-21G).
energy difference would be mainly caused by the steric
repulsion between the aryl moiety of the substrate and the
3,3’-triisopropylphenyl group.
In summary, we have developed the first example of chiral
phosphoric acid catalyzed desymmetrization of meso-1,3-
dicarbonyl compounds. This method could be applied to a
wide variety of substrates to give chiral cyclohexenones in
high yields and with excellent enantioselectivity. Further
investigation of its application to the synthesis of natural
products is currently under way in our laboratory.
[a] Unless otherwise noted, all reactions were conducted with 0.2 mmol
of 2 and 5 mol% 1d in n-hexane (2.0 mL) at 708C. [b] Determined by
HPLC on a chiral stationary phase. [c] 10 mol% of 1d was employed.
[d] In toluene at 908C.
92% ee; Table 2, entry 1). In the case of propargyl substrate
3c, a key synthetic intermediate in the synthesis of the
gibbane framework,[11] the enantioselectivity was also excel-
lent (94% ee; Table 2, entry 2). Benzyl- and phenyl-substi-
tuted substrates (3d and 3e) were obtained in good enantio-
selectivity (87 and 90% ee; Table 2, entries 3 and 4). In these
two reactions, higher catalyst loading (10 mol%) and pro-
longed reaction times (96 and 48 h, respectively) were
required. In particular, in the case of the phenyl-substituted
substrate 3e the use of toluene as the reaction solvent was
Experimental Section
General procedure for Table 1, entry 6: Chiral phosphoric acid 1d
(7.5 mg, 0.010 mmol) was added to a solution of triketone 2a (46 mg,
0.20 mmol) in n-hexane (2.0 mL) at room temperature, and the
reaction mixture was heated at 708C. After heating for 24 h, the
reaction mixture was directly purified by column chromatography on
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silica gel (eluent: CH2Cl2/AcOEt 10:1) to give 3a (40 mg, 0.19 mmol)
in 95% yield.
Akiyama, Chem. Rev. 2007, 107, 5744 – 5758; c) S. J. Connon,
Angew. Chem. 2006, 118, 4013 – 4016; Angew. Chem. Int. Ed.
2006, 45, 3909 – 3912; d) T. Akiyama in Acid Catalysis in Modern
Organic Synthesis (Eds.: H. Yamamoto, K. Ishihara), Wiley-
VCH, Weinheim, 2008, pp. 62 – 107; e) M. Terada, Chem.
Commun. 2008, 4097 – 4112, and references therein.
Received: September 21, 2009
Published online: November 18, 2009
[7] a) E. B. Rowland, G. B. Rowland, E. Rivera-Otero, J. C. Antilla,
J. Am. Chem. Soc. 2007, 129, 12084 – 12085; b) D. K. Sala, A.
Lattanzi, Org. Lett. 2009, 11, 3330 – 3333; c) G. L. Hamilton, T.
Kanai, F. D. Toste, J. Am. Chem. Soc. 2008, 130, 14984 – 14986.
[8] a) S. Bahmanyar, K. N. Houk, J. Am. Chem. Soc. 2001, 123,
12911 – 12912; b) L. Hoang, S. Bahmanyar, K. N. Houk, B. List,
J. Am. Chem. Soc. 2003, 125, 16 – 17; c) C. Allemann, R.
Gordillo, F. R. Clemente, H.-Y. Cheong, K. N. Houk, Acc.
Chem. Res. 2004, 37, 558 – 569.
Keywords: aldol reaction · asymmetric synthesis ·
chiral phosphoric acids · computational chemistry ·
desymmetrization
.
[1] a) U. Eder, G. Sauer, R. Wiechert, Angew. Chem. 1971, 83, 492 –
493; Angew. Chem. Int. Ed. Engl. 1971, 10, 496 – 497; b) Z. G.
Hajos, D. R. Parrish, J. Org. Chem. 1974, 39, 1615 – 1621; c) R. A.
Micheli, Z. G. Hajos, N. Cohen, D. R. Parrish, L. A. Poland, W.
Sciamanna, M. A. Scott, P. A. Wehrli, J. Org. Chem. 1975, 40,
675 – 681; d) Z. G. Hajos, D. R. Parrish, Org. Synth., Collect Vol.
VII, Wiley, New York, 1990, pp. 363 – 369.
[2] a) P. Wieland, K. Miescher, Helv. Chim. Acta 1950, 33, 2215 –
2228; b) J. Gutzwiller, A. Buchschacher, A. Furst, Synthesis
1977, 167 – 168; c) S. Ramachandran, M. S. Newman, Org. Synth.
1961, 41, 38.
[3] For selected references, see: a) P. Wieland, H. Unberwasser, G.
Annre, K. Miescher, Helv. Chim. Acta 1953, 36, 1231 – 1241; b) P.
Wieland, G. Anner, K. Miescher, Helv. Chim. Acta 1953, 36,
1803 – 1809; c) T. A. Spencer, T. D. Weaver, R. M. Villarica, R. J.
Friary, J. Posler, M. A. Schwartz, J. Org. Chem. 1968, 33, 712 –
719; d) S. J. Danishefsky, P. Cain, J. Am. Chem. Soc. 1975, 97,
5282 – 5284.
[4] For selected references, see: a) E. J. Corey, M. Ohno, R. B.
Mitra, P. A. Vatakencherry, J. Am. Chem. Soc. 1964, 86, 478 –
485; b) E. J. Corey, M. Ohno, R. B. Mitra, R. A. Vatakencherry,
J. Am. Chem. Soc. 1964, 86, 478 – 485; c) J. E. McMurry, S. J.
Isser, J. Am. Chem. Soc. 1972, 94, 7132 – 7137; d) R. C. A. Isaacs,
R. M. J. Di Grandi, S. J. Danishefsky, J. Org. Chem. 1993, 58,
3938 – 3941; e) L. A. Paquette, T.-Z. Wang, M. R. Sivik, J. Am.
Chem. Soc. 1994, 116, 11323 – 11334; f) T. J. Reddy, G. Bordeau,
L. Trimble, Org. Lett. 2006, 8, 5585 – 5588; g) S. Yamashita, K.
Iso, M. Hirama, Org. Lett. 2008, 10, 3413 – 3415.
[9] For our previous approach to chiral cyclohexenones, see: T.
Akiyama, T. Katoh, K. Mori, Angew. Chem. 2009, 121, 4290 –
4292; Angew. Chem. Int. Ed. 2009, 48, 4226 – 4228.
[10] The absolute configuration of 3a was unambiguously established
by single-crystal X-ray analysis of the corresponding bromide.
CCDC 743645 contains 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. See the Supporting Information.
[11] S. Takano, C. Kasahara, K. Ogasawara, J. Chem. Soc. Chem.
Commun. 1981, 635 – 637.
[12] The absolute configuration of Hajos–Parrish and Wieland–
Miescher ketones were determined by comparing optical
rotation values with those reported. E. Lacoste, E. Vaique, M.
Berlande, I. Pianet, J. M. Vincent, Y. Landais, Eur. J. Org. Chem.
2007, 167 – 177.
[13] Details of chemical models of ONIOM calculations are shown in
the Supporting Information. All calculations were performed
with the Gaussian 03 package, see: Gaussian03, RevisionE.01.,
M. J. Frisch, et al. Gaussian, Inc., Wallingford CT, 2004.
[14] For theoretical studies on chiral phosphoric acid catalysis, see:
a) M. Yamanaka, J. Itoh, K. Fuchibe, T. Akiyama, J. Am. Chem.
Soc. 2007, 129, 6756 – 6764; b) L. Simꢀn, J. M. Goodman, J. Am.
Chem. Soc. 2008, 130, 8741 – 8747; c) T. Marcelli, P. Hammar, F.
Himo, Chem. Eur. J. 2008, 14, 8562 – 8571; d) L. Simꢀn, J. M.
Goodman, J. Am. Chem. Soc. 2009, 131, 4070 – 4077; e) M.
Yamanaka, T. Hirata, J. Org. Chem. 2009, 74, 3266 – 3271; f) T.
Akiyama, H. Morita, P. Bachu, K. Mori, M. Yamanaka, T.
Hirata, Tetrahedron 2009, 65, 4950 – 4956.
[5] a) T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe, Angew. Chem.
2004, 116, 1592 – 1594; Angew. Chem. Int. Ed. 2004, 43, 1566 –
1568; b) D. Uraguchi, M. Terada, J. Am. Chem. Soc. 2004, 126,
5356 – 5357.
[6] For reviews on Brønsted acid catalysis, see: a) T. Akiyama, J.
Itoh, K. Fuchibe, Adv. Synth. Catal. 2006, 348, 999 – 1010; b) T.
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