Enantioselective robinson-type annulation reaction catalyzed by chiral phosphoric acids

Full text of DOI:10.1002/anie.200901127

Communications
DOI: 10.1002/anie.200901127
Organocatalysis
Enantioselective Robinson-Type Annulation Reaction Catalyzed by
Chiral Phosphoric Acids**
Takahiko Akiyama,* Takuya Katoh, and Keiji Mori
The Robinson annulation reaction is one of the most useful
methods for the construction of the cyclohexenone structure
and is widely employed in the synthesis of complex natural
products.[1] It consists of three consecutive processes:
1) Michael addition of a carbonyl compound to an a,b-
unsaturated ketone, 2) an intramolecular aldol reaction, and
3) dehydration. Both acid and base catalysts have been
extensively utilized in the Robinson annulation reaction. To
synthesize the cyclohexenone substructures in an optically
pure form with the Robinson annulation reaction, a chiral
ketone is used as the starting material and an enantioenriched
Scheme 1. Strategy for the asymmetric Robinson-type annulation reac-
tion.
Robinson annulation product is furnished by the diastereo-
selective Michael addition reaction.[2] Alternatively, the
enantioselective Michael addition reaction is a key reaction
for the enantioselective Robinson annulation reaction.[3] In
the 1970s Hermann and Wynberg conducted seminal work on
the enantioselective conjugate addition of b-keto esters to
methyl vinyl ketone in the presence of cinchona alkaloid as
catalyst.[4,5] Sasai and Shibasaki disclosed the highly enantio-
selective conjugate addition reaction of b-keto esters with
methyl vinyl ketone.[6] Chiral scandium(III) catalysts,[7] palla-
dium catalysts,[8] and ruthenium catalysts[9] have been also
employed. Maruoka and co-workers have reported phase-
transfer catalysis.[10] Recently, Deng and co-workers have
developed an efficient cinchona alkaloid catalyst.[11]
At the outset, the Michael addition reaction of b-keto
ester 3a (X = Y= H, Z = CH2) with methyl vinyl ketone in
the presence of a chiral phosphoric acid was examined.
Screening for the phosphoric acid revealed that phosphoric
acid 1 was the most effective as a catalyst for the Michael
In our ongoing studies of synthetic methods which are
catalyzed by phosphoric acid,[12–14] we found a novel strategy
for the enantioselective Robinson-type annulation reaction
which includes: 1) a chiral Brønsted acid catalyzed enantio-
selective Michael addition reaction of a-alkyl-b-keto esters
with methyl vinyl ketone, and 2) a chiral Brønsted acid
catalyzed kinetic resolution in the intramolecular aldol
reaction followed by dehydration. The enantiomer that was
obtained selectively by the Michael addition reaction reacted
preferentially to give the corresponding Robinson-type
annulation product with excellent enantioselectivities
(Scheme 1). Herein, we wish to describe the details of our
strategy.
addition reaction in terms of both chemical yield and
enantioselectivity. The corresponding Michael adduct 4a
was obtained in 99% yield with 78% ee (Table 1, entry 1).
The enantioselectivity was determined by HPLC analysis.[15]
The substrate scope of the Michael addition reaction is shown
in Table 1. Substituted indanone derivative 3 (Z = CH2)
proved to be a suitable substrate (Table 1, entries 1–4). b-
Keto esters 3 (Z = O) obtained from salicylic acid also gave
the corresponding adducts with high enantioselectivities
(Table 1, entries 5–8). Notably, a catalyst loading of as low
as 2 mol% was enough for the Michael addition reactions
(Table 1, entries 5 and 8). Methyl 2-oxocyclopentanecarbox-
ylate also afforded the corresponding adduct with high
enantioselectivity (Table 1, entry 9).
[*] Prof. Dr. T. Akiyama, T. Katoh, Dr. K. Mori
Department of Chemistry, Gakushuin University
1-5-1, Mejiro, Toshima-ku, Tokyo 171-8588 (Japan)
Fax: (+81)3-5992-1029
E-mail: takahiko.akiyama@gakushuin.ac.jp
Next, we investigated the kinetic resolution in the
phosphoric acid catalyzed aldol reaction of 4a. Treatment of
racemic 4a with 10 mol% of 1 in m-xylene at 1008C for
13 hours furnished 5a in 13% yield with 48% ee. This product
was accompanied by recovered 4a in 56% yield with 25% ee.
[**] This work was supported by a Grant-in-Aid for Scientific Research
(B) (No: 19350026) from the Japan Society for the Promotion of
Science.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200901127.
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Angew. Chem. Int. Ed. 2009, 48, 4226 –4228

Angewandte
Chemie
Table 1: Enantioselective Michael addition reaction.
Table 2: Enantioselective Robinson-type annulation reaction.[a]
Yield [%][a] ee [%][b]
Entry
X
Y
Z
Yield [%][a] ee [%][b]
Entry
X
Y
Z
1[c]
2[c,d]
3[c]
4[c]
5[e]
6[c]
7[c]
8[e]
H
H
Br
Cl
H
H
H
H
H
H
H
H
CH2
CH2
CH2
CH2
O
O
O
O
99
99
89
99
99
99
79
87
88
78
80
78
81
83
78
75
70
78
1
H
H
H
Br
Cl
H
H
H
H
H
H
H
H
H
Cl
Br
Me
CH2
CH2
CH2
CH2
CH2
O
O
O
O
64
61
74
67[e]
64
66
72
71
54
53
96
99
97
99
98
99
97
96
99
83
2[c]
3[d]
4
H
5
6
7
8
9
10
Cl
Br
Me
9[c,f] methyl 2-oxocyclopentane-
carboxylate
H
methyl 2-oxocyclopentane-
carboxylate
[a] Yield of isolated product. [b] Enantiomeric excess was determined by
HPLC methods on a chiral stationary phase. [c] Reactions were carried
out with 3 (0.2 mmol), and methyl vinyl ketone (0.6 mmol; 3 equiv) in
the presence of 1 (10 mol%) in m-xylene (1.0 mL). [d] Benzyl ester was
employed instead of methyl ester. [e] Reactions were carried out with 1
(2 mol%) and methyl vinyl ketone (2 equiv) at 208C. [f] The reaction was
carried out at 508C for 48 h.
[a] Yield of isolated product. [b]Enantiomeric excess was determined by
HPLC methods on a chiral stationary phase. [c] The second reaction was
carried out at 1008C. [d] Benzyl ester was employed instead of methyl
ester. [e] Yield based on 1H NMR spectroscopy.
The present aldol reaction is considered
to proceed via the following cyclic transition
state model in which the phosphoric acid
worked as a multifunctional catalyst: The
phosphoric acid hydrogen atom activated the
ketone group by acting as a Brønsted acid and
Although phosphoric acid 1 was not effective, a detailed
survey of other chiral phosphoric acids revealed that prom-
inent kinetic resolution was observed by using 2 at high
temperature (Scheme 2). Treatment of racemic 4a with
Figure 1. Pro-
thus promoted the formation of an enol from
posed transi-
the ketone unit (Figure 1). Furthermore, the
tion state.
phosphoryl oxygen atom formed a hydrogen
bond with the enol hydrogen atom, acting as a
Lewis base.
In summary, we have developed a chiral phosphoric acid
catalyzed enantioselective Robinson-type annulation reac-
tion based on the enantioselective Michael addition reaction
and the subsequent aldol reaction. Further investigations to
clarify the reaction mechanism and its application to other
enantioselective reactions are underway.
Scheme 2. Kinetic resolution in the Aldol reaction.
10 mol% of 2 in toluene at 1008C for 24 hours resulted in
the formation of 5a in 23% yield with 92% ee. Further
increasing the reaction temperature (heating at reflux in
toluene) improved the chemical yield, albeit with a the slight
decrease of the enantioselectivity. Overall notable kinetic
resolution was achieved by means of a chiral Brønsted acid,
even at high temperature.
Experimental Section
Typical procedure for the Robinson-type annulation reaction: Methyl
vinyl ketone (49 mL, 0.60 mmol) was added to a solution of keto ester
3a (38 mg, 0.20 mmol) and chiral phosphoric acid
1 (16 mg,
The pronounced kinetic resolution observed in the aldol
reaction inspired us to study the enantioselective Robinson-
type annulation reaction in combination with the enantiose-
lective Michael addition reaction. Compound 3 was treated
with methyl vinyl ketone under identical reaction conditions
with those used in Table 1, and subsequent purification of the
reaction mixture gave 1,4-adducts 4. Compounds 4 were
treated with 10 mol% of 2 in toluene at reflux and furnished
Robinson-type annulation products 5 with high yields and
with excellent enantioselectivities (Table 2). In the case of
methyl 2-oxocyclopentanecarboxylate, kinetic resolution was
not observed in the aldolization process (compare Table 1,
entry 9 with Table 2, entry 10).
0.02 mmol) in m-xylene (1 mL) at 408C. After the reaction was
stirring at that temperature for 24 h, the mixture was directly purified
by column chromatography on silica gel (hexanes/EtOAc = 3:1)to
give the corresponding Michael adduct 4a. The adduct was dissolved
in toluene (1 mL) and chiral phosphoric acid 2 (15 mg, 0.020 mmol)
was added. The reaction mixture was heated to reflux for 48 h. Upon
cooling, 2 was removed by column chromatography on silica gel
(CH2Cl2/AcOEt = 10:1). The crude mixture was further purified by
preparative TLC to give 5a (32 mg, 0.12 mmol) in 64% yield (Table 2,
entry 1).
Received: February 27, 2009
Revised: March 25, 2009
Published online: April 29, 2009
Angew. Chem. Int. Ed. 2009, 48, 4226 –4228
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Communications
Angew. Chem. Int. Ed. 2006, 45, 4796 – 4798; f) T. Akiyama, H.
Morita, K. Fuchibe, J. Am. Chem. Soc. 2006, 128, 13070 – 13071;
g) M. Yamanaka, J. Itoh, K. Fuchibe, T. Akiyama, J. Am. Chem.
Soc. 2007, 129, 6756 – 6764; h) T. Akiyama, Y. Honma, J. Itoh, K.
Fuchibe, Adv. Synth. Catal. 2008, 350, 399 – 402; i) J. Itoh, K.
Fuchibe, T. Akiyama, Angew. Chem. 2008, 120, 4080 – 4082;
Angew. Chem. Int. Ed. 2008, 47, 4016 – 4018.
Keywords: asymmetric synthesis · chiral phosphoric acids ·
kinetic resolution · Michael addition · Robinson-type annulation
.
[1] R. E. Gawley, Synthesis 1976, 777 – 794.
[2] For an example, see: J. D. White, P. Hrnciar, F. Stappenbeck, J.
Org. Chem. 1999, 64, 7871 – 7884.
[14] For selected examples of phosphoric acid catalyzed reactions,
see: a) D. Uraguchi, M. Terada, J. Am. Chem. Soc. 2004, 126,
5356 – 5357; b) D. Uraguchi, K. Sorimachi, M. Terada, J. Am.
Chem. Soc. 2004, 126, 11804 – 11805; c) G. B. Rowland, H.
Zhang, E. B. Rowland, S. Chennamadhavuni, Y. Wang, J. C.
Antilla, J. Am. Chem. Soc. 2005, 127, 15696 – 15697; d) R. I.
Storer, D. E. Carrera, Y. Ni, D. W. C. MacMillan, J. Am. Chem.
Soc. 2006, 128, 84 – 86; e) J. Seayad, A. M. Seayad, B. List, J. Am.
Chem. Soc. 2006, 128, 1086 – 1087; f) M. Rueping, E. Sugiono, C.
Azap, Angew. Chem. 2006, 118, 2679 – 2681; Angew. Chem. Int.
Ed. 2006, 45, 2617 – 2619; g) X.-H. Chen, X.-Y. Xu, H. Liu, L.-F.
Cun, L.-Z. Gong, J. Am. Chem. Soc. 2006, 128, 14802 – 14803;
h) M. Rueping, C. Azap, Angew. Chem. 2006, 118, 7996 – 7999;
Angew. Chem. Int. Ed. 2006, 45, 7832 – 7835; i) M. Terada, K.
Sorimachi, J. Am. Chem. Soc. 2007, 129, 292 – 293; j) Q. Kang,
Z.-A. Zhao, S.-L. You, J. Am. Chem. Soc. 2007, 129, 1484 – 1485;
k) G. Li, Y. Liang, J. C. Antilla, J. Am. Chem. Soc. 2007, 129,
5830 – 5831; l) J. Zhou, B. List, J. Am. Chem. Soc. 2007, 129,
7498 – 7499; m) M. Terada, K. Machioka, K. Sorimachi, J. Am.
Chem. Soc. 2007, 129, 10336 – 10337; n) M. Rueping, A. P.
Antonchick, C. Brinkmann, Angew. Chem. 2007, 119, 7027 –
7030; Angew. Chem. Int. Ed. 2007, 46, 6903 – 6906; o) M.
Rueping, B. J. Nachtsheim, S. A. Moreth, M. Bolte, Angew.
Chem. 2008, 120, 603 – 606; Angew. Chem. Int. Ed. 2008, 47, 593 –
596; p) X.-H. Chen, W.-Q. Zhang, L.-Z. Gong, J. Am. Chem. Soc.
2008, 130, 5652 – 5653; q) K. Sorimachi, M. Terada, J. Am. Chem.
Soc. 2008, 130, 14452 – 14453; r) Q.-S. Guo, D.-M. Du, J. Xu,
Angew. Chem. 2008, 120, 771 – 774; Angew. Chem. Int. Ed. 2008,
47, 759 – 762; s) P. Jiao, D. Nakashima, H. Yamamoto, Angew.
Chem. 2008, 120, 2445 – 2447; Angew. Chem. Int. Ed. 2008, 47,
2411 – 2413; t) M. Sickert, C. Schneider, Angew. Chem. 2008,
120, 3687 – 3690; Angew. Chem. Int. Ed. 2008, 47, 3631 – 3634;
u) M. Terada, K. Soga, N. Momiyama, Angew. Chem. 2008, 120,
4190 – 4193; Angew. Chem. Int. Ed. 2008, 47, 4122 – 4125; v) D.
Enders, A. A. Narine, F. Toulgoat, T. Bisschops, Angew. Chem.
2008, 120, 5744 – 5748; Angew. Chem. Int. Ed. 2008, 47, 5661 –
5665; w) X. Cheng, R. Goddard, G. Buth, B. List, Angew. Chem.
2008, 120, 5157 – 5159; Angew. Chem. Int. Ed. 2008, 47, 5079 –
5081; x) M. Rueping, A. P. Antonchick, Angew. Chem. 2008, 120,
10244 – 10247; Angew. Chem. Int. Ed. 2008, 47, 10090 – 10093;
y) G. Li, F. R. Fronczek, J. C. Antilla, J. Am. Chem. Soc. 2008,
130, 12216 – 12217; z) M. Rueping, A. P. Antonchick, E. Sugiono,
K. Grenader, Angew. Chem. 2009, 121, 925 – 927; Angew. Chem.
Int. Ed. 2009, 48, 908 – 910.
[3] For proline-catalyzed reactions, see: 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) T. Bui, C. F. Barbas III,
Tetrahedron Lett. 2000, 41, 6951 – 6954; d) P. H.-Y. Cheong, K. N.
Houk, J. S. Warrier, S. Hanessian, Adv. Synth. Catal. 2004, 346,
1111 – 1115; e) K. Inomata, M. Barraguꢀ, L. A. Paquette, J. Org.
Chem. 2005, 70, 533 – 539; f) F. R. Clemente, K. N. Houk, J. Am.
Chem. Soc. 2005, 127, 11294 – 11302; g) E. Lacoste, E. Vaique,
M. Berlande, I. Pianet, J.-M. Vincent, Y. Landais, Eur. J. Org.
Chem. 2007, 167 – 177.
[4] For antibody-catalyzed reaction, see: G. Zhong, T. Hoffmann,
R. A. Lerner, S. Danishefsky, C. F. Barbas III, J. Am. Chem. Soc.
1997, 119, 8131 – 8132.
[5] K. Hermann, H. Wynberg, J. Org. Chem. 1979, 44, 2238 – 2244.
[6] H. Sasai, T. Arai, M. Shibasaki, J. Am. Chem. Soc. 1994, 116,
1571 – 1572.
[7] a) M. Nakajima, Y. Yamaguchi, S. Hashimoto, Chem. Commun.
2001, 1596 – 1597; b) M. Nakajima, S. Yamamoto, Y. Yamaguchi,
S. Nakamura, S. Hashimoto, Tetrahedron 2003, 59, 7307 – 7313;
c) C. Ogawa, K. Kizu, H. Shimizu, M. Takeuchi, S. Kobayashi,
Chem. Asian J. 2006, 1, 121 – 124.
[8] a) Y. Hamashima, D. Hotta, M. Sodeoka, J. Am. Chem. Soc.
2002, 124, 11240 – 11241; b) Y. Hamashima, D. Hotta, N.
Umebayashi, Y. Tsuchiya, T. Suzuki, M. Sodeoka, Adv. Synth.
Catal. 2005, 347, 1576 – 1586.
[9] F. Santoro, M. Althaus, C. Bonaccorsi, S. Gischig, A. Mezzetti,
Organometallics 2008, 27, 3866 – 3878.
[10] T. Ooi, T. Miki, M. Taniguchi, M. Shiraishi, M. Takeuchi, K.
Maruoka, Angew. Chem. 2003, 115, 3926 – 3928; Angew. Chem.
Int. Ed. 2003, 42, 3796 – 3798.
[11] F. Wu, H. Li, R. Hong, L. Deng, Angew. Chem. 2006, 118, 961 –
964; Angew. Chem. Int. Ed. 2006, 45, 947 – 950.
[12] For reviews on phosphoric acid catalysis and related acid
catalysis, see: a) S. J. Connon, Angew. Chem. 2006, 118, 4013 –
4016; Angew. Chem. Int. Ed. 2006, 45, 3909 – 3912; b) T.
Akiyama, Chem. Rev. 2007, 107, 5744 – 5758; c) T. Akiyama in
Acid Catalysis in Modern Organic Synthesis, Vol. 1 (Eds.: H.
Yamamoto, K. Ishihara), Wiley-VCH, Weinheim, 2008, pp. 62 –
107; d) M. Terada, Chem. Commun. 2008, 4097 – 4112.
[13] For reports from our research group, see: a) T. Akiyama, J. Itoh,
K. Yokota, K. Fuchibe, Angew. Chem. 2004, 116, 1592 – 1594;
Angew. Chem. Int. Ed. 2004, 43, 1566 – 1568; b) T. Akiyama, H.
Morita, J. Itoh, K. Fuchibe, Org. Lett. 2005, 7, 2583 – 2585; c) T.
Akiyama, Y. Saitoh, H. Morita, K. Fuchibe, Adv. Synth. Catal.
2005, 347, 1523 – 1526; d) T. Akiyama, Y. Tamura, J. Itoh, H.
Morita, K. Fuchibe, Synlett 2006, 141 – 143; e) J. Itoh, T.
Akiyama, K. Fuchibe, Angew. Chem. 2006, 118, 4914 – 4916;
[15] The absolute configuration of 4a was determined by HPLC
methods on a chiral stationary phase and by comparison of the
retention time described in Ref. [7b]. The configurations of the
other compounds were surmised by analogy.
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