Kinetic resolution in chiral phosphoric acid catalyzed aldol reactions: Enantioselective robinson-type annulation reactions

Article abstract of DOI:10.1002/ejoc.201200338

A remarkable kinetic resolution was achieved in a chiral phosphoric acid catalyzed intramolecular aldol reaction. Its combination with an enantioselective Michael reaction resulted in the formation of cyclohexenone derivatives with excellent enantioselectivities. DFT calculations on the intramolecular aldol reaction revealed the importance of the 3,3'-substituents of the phosphoric acid for the high enantioselectivity in the kinetic resolution process. A remarkable kinetic resolution was achieved in a chiral phosphoric acid catalyzed intramolecular aldol reaction. Its combination with an enantioselective Michael reaction gave rise to cyclohexenones with excellent enantioselectivities. DFT calculations on the intramolecular aldol reaction revealed the importance of the 3,3'-substituents of the phosphoric acid for the enantioselectivity. Copyright

Full text of DOI:10.1002/ejoc.201200338

Job/Unit: O20338
/KAP1
Date: 09-07-12 15:49:08
Pages: 8
FULL PAPER
DOI: 10.1002/ejoc.201200338
Kinetic Resolution in Chiral Phosphoric Acid Catalyzed Aldol Reactions:
Enantioselective Robinson-Type Annulation Reactions
Masahiro Yamanaka,*[a] Masaya Hoshino,[a] Takuya Katoh,[b] Keiji Mori,[b] and
Takahiko Akiyama*[b]
Keywords: Kinetic resolution / Organocatalysis / Michael addition / Density functional calculations / Brønsted acids
A remarkable kinetic resolution was achieved in a chiral
phosphoric acid catalyzed intramolecular aldol reaction. Its
combination with an enantioselective Michael reaction re-
sulted in the formation of cyclohexenone derivatives with ex-
cellent enantioselectivities. DFT calculations on the intramo-
lecular aldol reaction revealed the importance of the 3,3Ј-
substituents of the phosphoric acid for the high enantio-
selectivity in the kinetic resolution process.
methyl vinyl ketone in the presence of 2 in m-xylene at
40 °C to give, after 24 h, adduct 4a in 99% yield and with
78%ee (Figure 1, Scheme 1).
Introduction
Kinetic resolution is a classical yet still useful method for
the preparation of chiral compounds.[1] Biocatalysis has
been extensively investigated in kinetic resolution studies.[2]
Non-enzymatic kinetic resolution has also attracted a lot of
attention, and a range of useful synthetic methods have
been developed,[3] including acylation, silylation, and oxi-
dation of alcohols, as well as oxidation of alkenes. In strik-
ing contrast, kinetic resolution occurring during carbon–
carbon bond-forming reactions has been less extensively
studied.[4]
Enantiopure cyclohexenone derivatives are important
building blocks for the preparation of a range of biolo-
gically useful compounds, including steroids, terpenoids,
and so on.[5] A number of methods for the preparation of
chiral cyclohexenones have been reported. The desymme-
trization of triketones catalyzed by (S)-proline has provided
cyclohexenone derivatives:[6] intramolecular aldol reaction
and subsequent dehydration gave the cyclohexenone deriva-
tives with high to excellent enantioselectivities.
Figure 1. Chiral phosphoric acids.
Chiral phosphoric acid 1 emerged as a new chiral
organocatalyst in 2004,[7] and it has been used to ac-
complish a range of transformations enantioselectively.[8,9]
As part of our ongoing study of chiral phosphoric acid cat-
alyzed reactions,[10] we studied the Michael reaction, and
found that β-keto ester 3a underwent Michael addition with
Scheme 1. Enantioselective Michael reaction.
Interestingly, treatment of 3a and methyl vinyl ketone
with 1f (10 mol-%) under forcing conditions (100 °C, 24 h)
promoted an intramolecular aldol reaction and subsequent
dehydration to give cyclohexenone derivative 5a in 46%
yield and with 86%ee, along with Michael addition product
4a in 47% yield and 56%ee (Scheme 2). To our delight, the
optical purity of 5a proved to be higher than that of the 4a
formed in the Michael reaction (Scheme 1). This result
clearly shows that a kinetic resolution is operating in the
[a] Department of Chemistry, Rikkyo University
3-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8588, Japan
Fax: +81-3-3985-2395
E-mail: myamanak@rikkyo.ac.jp
[b] 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
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200338.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O20338
/KAP1
Date: 09-07-12 15:49:08
Pages: 8
M. Yamanaka, M. Hoshino, T. Katoh, K. Mori, T. Akiyama
FULL PAPER
second intramolecular aldol reaction. Because kinetic reso-
lution by chiral phosphoric acids has not been reported ex-
tensively, we further studied the effect of the structure of
the phosphoric acid on the intramolecular aldol reaction of
4a. In this paper, we report details of the phosphoric acid
catalyzed intramolecular reaction, and also the results of
theoretical studies to elucidate the mechanism of the kinetic
resolution.[11]
Scheme 2. Enantioselective synthesis of cyclohexenones.
Figure 2. Model structures: (a) reaction mechanism and
(b) enantioselectivity.
Results and Discussion
Chemical Models and Computational Methods
We investigated the kinetic resolution in the phosphoric
All calculations were performed with the Gaussian 03 acid catalyzed aldol reaction of racemic 4a, and the results
package.[12] Geometries were fully optimized and charac- are shown in Table 1. Treatment of racemic 4a with 1a
terized by frequency calculation using the ONIOM(B3LYP/ (10 mol-%) in toluene at 100 °C for 24 h furnished 5a in 6%
6-31G*:HF/3-21G) method.[13] Free energies were also yield and with 33%ee. This was accompanied by recovered
computed for the gas phase. Single-point energy calcula- 4a in 84% yield and with 2%ee (Table 1, entry 1). The use
tions were evaluated at the M05–2X/6-311+G* level for the of phosphoric acids bearing bulky groups, such as 9-anthryl
ONIOM-optimized structures. To reduce computational (as in 1b), mesityl (1c), or triphenylsilyl (1d), at the 3,3Ј-
costs, the reaction mechanism was explored using smaller positions improved the enantioselectivity (Table 1, en-
model structures. A phosphoric acid based on a biphenol tries 2–4). It is noteworthy that the use of a phosphoric acid
unit (i.e., Cat) and the R configured Michael adduct with bearing 2,4,6-triisopropyl groups (i.e., 1e) further increased
an H atom instead of the CO2Me group (i.e., RT) were used the enantioselectivity to 92%ee, albeit with a yield of 23%
(Figure 2a). When investigating the effects of the 3,3Ј-sub- (Table 1, entry 5). The S-value (selectivity) reached as high
stituents on the enantioselectivity, the transition state (TS) as 33.[14] When the aldol reaction was carried out under
properties (structures and energies) were compared using reflux conditions in toluene, the yield was increased to 40%,
realistic model structures of the phosphoric acids 1 – based albeit with a slight decrease in the enantioselectivity to 81%
on a 3,3Ј-disubstituted BINOL unit – and the R or S con- (Table 1, entry 6). Phosphoric acids bearing 2,4-bis(tri-
figured Michael adduct 4a (Figure 2b).
fluoromethyl)phenyl groups (i.e., 1f and 2), which showed
Table 1. Effect of the phosphoric acid on the kinetic resolution.
Entry
X
Catalyst
Product 5a
Yield [%]
Recovered 4a
S
ee [%]
Yield [%]
ee [%]
1
Ph
9-anthryl
1a
1b
1c
1d
1e
1e
1f
2
6
31
8
15
23
40
29
13
33
54
59
71
92
81
42
48
84
60
81
84
68
39
66
87
2
28
5
2.0
4.4
4.1
2
3[a]
4
2,4,6-Me3C6H2
SiPh3
2,4,6-(iPr)3C6H2
2,4,6-(iPr)3C6H2
2,4-(CF3)2C6H3
2,4-(CF3)2C6H3
9
6.4
5
32
48
16
8
32.9
15.3
2.8
6[b]
7
8[a]
1.7
[a] m-Xylene was used as a solvent. [b] Toluene was used at reflux.
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20338
/KAP1
Date: 09-07-12 15:49:08
Pages: 8
Kinetic Resolution in Chiral Phosphoric Acid Catalyzed Aldol Reactions
high catalytic activity in the Michael reaction (Scheme 1), TS2r1. In addition, TS2r1 is more stable than TS1r1 by
were less effective in the kinetic resolution.
8.7 kcal/mol (10.0 kcal/mol in free energy). Therefore, the
To elucidate the mechanism of the kinetic resolution in dicoordination pathway via TS2r1 is the most energetically
the intramolecular aldol reaction, a DFT study was carried favored pathway in the phosphoric acid catalyzed intramo-
out. The effects of the 3,3Ј-substituents on the enantio- lecular aldol reaction of the R configured Michael adduct.
selectivity were also investigated in detail. Two possible Dicoordinated TS2r1, in which the ketone and enol moie-
pathways (path 1: monocoordination pathway; path 2: dico- ties are simultaneously activated, is also kinetically reactive,
ordination pathway) were compared to clarify whether the having a relatively low activation barrier of ca. 10 kcal/mol.
phosphoric acid moiety uses its dual functionality in the The thermodynamic stability and the kinetic reactivity
mechanism (Scheme 3). In TS1 along path 1, the ketone would be achieved through the dual function of the phos-
moiety is activated by the acidic proton, with the enol moi- phoric acid.
ety being coordinated to the same oxygen atom on the
phosphoric acid. On the other hand, TS2 along path 2 takes
advantage of the dual functionality of the phosphoric acid
moiety, which activates both the ketone and the enol moie-
ties with its Brønsted acidic (proton) and Lewis basic (phos-
phoryl oxygen) sites, respectively. There are two possibilities
for facial diastereoselectivity (Re or Si facial attack on the
ketone moiety) in both TS1 and TS2. Therefore, four TSs
(TS1r1,2: path 1, TS2r1,2: path 2) were geometrically opti-
mized.
Figure 3. Energy profiles of the monocoordination pathway
(path 1) and the dicoordination pathway (path 2). The potential
energy of the sum of Cat and RT is set to zero. The free energies
are shown in parentheses.
Figure 4 shows the 3D structures of the four TSs. The
Michael adduct (i.e., RT) parts of TS1r1 and TS1r2 have
almost the same overall structures as those of TS2r1 and
TS2r2, respectively, apart from the hydrogen-bonding moie-
ties (Figure 4a and b). In TS1r1 and TS1r2, the P–O1 bonds
(1.539 Å and 1.552 Å) are longer than the P–O2 bonds
(1.485 Å and 1.476 Å). The two P–O bonds are regarded as
being the P–O1 single bond in the Brønsted acidic site and
the P=O2 double bond in the Lewis basic site. The enol
H atoms coordinate weakly to O1 (O1–Henol: 1.757 Å and
1.893 Å) before protonation of the ketone moieties
(H–Oketone and O1–H: 1.046 Å and 1.484 Å, 1.105 Å and
1.347 Å). On the other hand, in both TS2r1 and TS2r2,
almost the two P–O bonds are almost the same length
(1.50–1.52 Å). In these two transition-state structures, the
negative charge is delocalized over the O1–P–O2 fragment.
Therefore, the coordination of the enol H atoms to O2 be-
comes relatively strong (O2–Henol: 1.579 Å, 1.590 Å) before
Scheme 3. Two possible reaction pathways.
protonation of the ketone moieties (H–Oketone and O1–H:
The relative energies of the hydrogen-bonding complexes 1.063 Å and 1.423 Å, 1.084 Å and 1.391 Å) in TS2r1 and
(CPs) and TSs were compared for path 1 and path 2 (Fig- TS2r2. Similar zwitterionic properties in TSs have been
ure 3). Focusing on the facial diastereoselectivity, TS1r2 found in other computational studies of phosphoric acid
and TS2r2 are overwhelmingly less stable than TS1r1 and catalyzed reactions.[15] Enhancement of the hydrogen-bond-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O20338
/KAP1
Date: 09-07-12 15:49:08
Pages: 8
M. Yamanaka, M. Hoshino, T. Katoh, K. Mori, T. Akiyama
FULL PAPER
ing strength by the cooperative functions of the Brønsted Table 2. Energy differences between TS2r1 and TS2s2.
acidic and Lewis basic sites of the phosphoric acid stabilizes
dicoordinated TS2. Regarding the facial diastereoselectivity
on the ketone moiety, the greater stability of transition
states TS1r2 and TS2r2 over TS1r1 and TS2r1 was mainly
due to the structural stability of the RT part. The instability
of TS1r2 and TS2r2 is attributed to distortion of the five-
membered ring moiety and sp3 hybridization on the carb-
onyl carbon.
Entry
X
ΔE [kcal/mol] Exp. ee [%] (R)
[a,b]
1
2
3
4
5
Ph (a)
9-anthryl (b)
2,4,6-Me3C6H2 (c)
SiPh3 (d)
2,4,6-(iPr)3C6H2 (e)
0.4 (0.6)
1.5 (0.1)
1.8 (–0.3)
2.2 (1.6)
3.1 (1.9)
33
54
59
71
92
[a] ΔE = E(TS2s2) – E(TS2r1). [b] Single-point energy calculations
at the M05–2X/6-311+G* level are shown in parentheses.
X = 2,4,6-(iPr)3C6H2 and X = Ph. In TS2s2, The benzene
ring and the ethylene linker moieties of the Michael adduct
were located in the upper left-hand quadrant and the lower
right-hand quadrant, respectively, leading to steric clashes
with the 3,3Ј-substituents (Figure 5b and S1b). In contrast,
in TS2r1, these moieties of the Michael adduct were located
in the empty lower left-hand quadrant and the upper right-
hand quadrant, and consequently were directed away from
the 3,3Ј-substituents (Figure 5a and S1a). Therefore, the ste-
rically demanding 2,4,6-(iPr)3C6H2 group enhanced these
steric repulsions (shown as pink curved lines in Figure 5),
which are responsible for the asymmetric induction. The
larger substituents destabilized TS2s2e increased the rela-
Figure 4. 3D structures of (a) TS1r1, TS1r2 and (b) TS2r1, TS2r2.
Relative energy differences [kcal/mol] are shown in parentheses.
It was found experimentally that the highest enantio-
selectivity was obtained using 2,4,6-(iPr)3C6H2 substituted
phosphoric acid 1e. The sterically demanding 3,3Ј-substitu-
ents are essential for the high enantioselectivity. Focusing
on the effect of the 3,3Ј-substituents of the phosphoric acid
on the enantioselectivity, two diastereomeric TSs were com-
pared, based on favored dicoordinated transition structure
TS2r1. The relationship between the enantioselectivity of
the reaction and the energy differences between dia-
stereomeric TSs was investigated. Thus, Re facial attacking
transition state TS2r1 for the R configured Michael adduct
was compared with Si facial attacking transition state
TS2s2 for the S configured Michael adduct. The energy dif-
ferences between TS2r1 and TS2s2 for X = Ph (a), 9-an-
thryl (b), 2,4,6-Me3C6H2 (c), SiPh3 (d), and 2,4,6-(iPr)3-
C6H2 (e) were explored (Table 2). In agreement with the
experimental results, the relative energy difference increased
with increasing steric bulk of the 3,3Ј-substituents [as seen
for X = SiPh3 and 2,4,6-(iPr)3C6H2]. Single-point energy
calculations using M05–2X/6-311+G* of the ONIOM-opti-
mized structures showed a similar tendency, albeit with a
weaker energetic differentiation.
To clarify the origin of the highest enantioselectivity for
X = 2,4,6-(iPr)3C6H2, structural analysis was carried out in
detail. Figure 5 and S1 (in the Supporting Information)
Figure 5. 3D structures of the two diastereomeric TSs of (a) TS2r1e
and (b) TS2s2e {[X = 2,4,6-(iPr)3C6H2]Ph}. Relative energy differ-
show the 3D structures of the two diastereomeric TSs for ences [kcal/mol] are shown in parentheses.
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20338
/KAP1
Date: 09-07-12 15:49:08
Pages: 8
Kinetic Resolution in Chiral Phosphoric Acid Catalyzed Aldol Reactions
tive energy difference. On the other hand, no steric effect of
Keto ester 3 was treated with methyl vinyl ketone under
the 3,3Ј-substituents was noted in the case of X = Ph. In reaction conditions identical to those in Table 1, and subse-
TS2s2e, the phosphoric acid fragment is expected to be de- quent purification of the reaction mixture gave 1,4-adducts
formed by these steric repulsions as it is structurally more 4. Adducts 4 were treated with 1e (10 mol-%) under toluene
flexible than the Michael adduct fragment. Single-point en- reflux conditions to furnish Robinson annulation products
ergy calculations on the phosphoric acid (dotted circle) and 5 in high yields and with excellent enantioselectivities
the Michael adduct fragments were performed to compare (Table 3).
their stabilities (Scheme 4). Although the phosphoric acid
fragment was 4.0 kcal/mol less stable in TS2s2e than in
Table 3. Results of the Robinson-type reactions.
TS2r1e, the relative energy difference of the Michael adduct
fragments was kept to within 1.0 kcal/mol. The phosphoric
acid fragment in TS2s2e was distorted mainly in the angles
formed by the 3,3Ј-substituents (a1 and a2 in Scheme 4).
Both of these angles in TS2s2e (a1: 122.2°, a2: 121.5°) were
wider than those in TS2r1e (a1: 120.2°, a2: 119.6°) because
of the repulsive interaction between the 3,3Ј-substituents
Entry
X
Y
Z
Yield [%]
ee [%]
and the benzene ring and ethylene linker moieties.
1
2
3
4
5
6
7
8
H
H
H
Cl
Br
H
H
H
H
H
H
H
H
Cl
Br
Me
CH2
CH2
CH2
CH2
O
O
O
64
61
67
64
66
72
71
54
96
99
99
98
99
97
96
99
O
Conclusions
We have studied a kinetic resolution in the intramolecu-
lar aldol reaction promoted by a chiral phosphoric acid. A
remarkable kinetic resolution was observed using 1e as a
chiral Brønsted acid catalyst. Theoretical studies have eluci-
Scheme 4. Single-energy calculations of the phosphoric acid (dot-
ted circle) and the Michael adduct fragments.
Because we have observed a remarkable kinetic resolu- dated the dicoordination mechanism for the kinetic resolu-
tion in the intramolecular aldol-dehydration process to give tion in the intramolecular aldol reaction. As regards the
cyclohexenones with high enantioselectivities, we combined effects of the 3,3Ј-substituents, the relative energy differ-
the reaction with an enantioselective Michael reaction ences between the diastereomeric TSs were remarkably well
(Scheme 5). We took advantage of phosphoric acid catalysis correlated with the experimental ee values. The origin of the
in both the Michael reaction and aldol reaction to give cy- excellent enantioselectivity using a phosphoric acid bearing
clohexenones with high yields and excellent enantio- 2,4,6-(iPr)3C6H2 substituents was rationalized by an in-
selectivities.
crease in steric repulsion between the 3,3Ј-substituents and
Scheme 5. Strategy for the Robinson-type reaction.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O20338
/KAP1
Date: 09-07-12 15:49:08
Pages: 8
M. Yamanaka, M. Hoshino, T. Katoh, K. Mori, T. Akiyama
FULL PAPER
6853; Angew. Chem. Int. Ed. 2011, 50, 6706–6720 and refer-
the benzene ring and ethylene linker moieties of the Michael
adduct. The combination of the Michael addition and the
intramolecular aldol reaction gave the corresponding cyclo-
hexenone derivatives with excellent enantioselectivities. It is
expected that the concept of kinetic resolution by chiral
phosphoric acid catalyzed aldol reaction will be extended
to other carbon–carbon bond-forming reactions.
ences cited therein.
[9]
For selected recent examples, see: a) M. Rueping, A. P. Anton-
chick, E. Sugiono, K. Grenader, Angew. Chem. 2009, 121, 925–
927; Angew. Chem. Int. Ed. 2009, 48, 908–910; b) W. Schrader,
P. P. Handayani, J. Zhou, B. List, Angew. Chem. 2009, 121,
1491–1494; Angew. Chem. Int. Ed. 2009, 48, 1463–1466; c) M.
Terada, H. Tanaka, K. Sorimachi, J. Am. Chem. Soc. 2009,
131, 3430–3431; d) M. Lu, D. Zhu, Y. Lu, X. Zeng, B. Tan, Z.
Xu, G. Zhong, J. Am. Chem. Soc. 2009, 131, 4562–4563; e) Q.-
W. Zhang, C.-A. Fan, H.-J. Zhang, Y.-Q. Tu, Y.-M. Zhao, P.
Gu, Z.-M. Chen, Angew. Chem. 2009, 121, 8724–8726; Angew.
Chem. Int. Ed. 2009, 48, 8572–8574; f) Q. Cai, C. Zheng, S.-L.
You, Angew. Chem. 2010, 122, 8848–8851; Angew. Chem. Int.
Ed. 2010, 49, 8666–8669; g) O. Lifchits, C. M. Reisinger, B.
List, J. Am. Chem. Soc. 2010, 132, 10227–10229; h) M. Hatano,
K. Moriyama, T. Maki, K. Ishihara, Angew. Chem. 2010, 122,
3911–3914; Angew. Chem. Int. Ed. 2010, 49, 3823–3826; i) T.
Liang, Z. Zhang, J. C. Antilla, Angew. Chem. 2010, 122, 9928–
9930; Angew. Chem. Int. Ed. 2010, 49, 9734–9736; j) Q. Gu, Z.-
Q. Rong, C. Zheng, S.-L. You, J. Am. Chem. Soc. 2010, 132,
Experimental Section
Typical Experimental Procedure for the Synthesis of 5a: A solution
of racemic β-keto ester 4a (52.1 mg, 0.020 mmol) and phosphoric
acid 1e (15.1 mg, 0.02 mm) in toluene (1.0 mL) was heated to reflux
for 24 h. The reaction mixture was directly purified by SiO2 column
chromatography (CH2Cl2/AcOEt = 10:1) to remove 1e. The mix-
ture was further purified by preparative TLC to give the corre-
sponding Robinson-type product 5a (19.4 mg, 40%), together with
the Michael adduct 4a (20.4 mg, 39%). The optical purity of the
products was determined by chiral HPLC analysis [Daicel Chi-
ralpak AD-H, hexane/iPrOH = 7:3, flow rate = 1.0 mL/min, UV
= 300 nm, tR = 6.3 min (major), tR = 8.2 min (minor)].
ˇ
4056–4057; k) I. Coric´, S. Vellalath, B. List, J. Am. Chem. Soc.
2010, 132, 8536–8537; l) S. Xu, Z. Wang, Y. Li, X. Zhang, H.
Wang, K. Ding, Chem. Eur. J. 2010, 16, 3021–3035; m) P. Jain,
J. C. Antilla, J. Am. Chem. Soc. 2010, 132, 11884–11886; n) M.
Rueping, U. Uria, M.-Y. Lin, I. Atodiresei, J. Am. Chem. Soc.
2011, 133, 3732–3735; o) J. Jiang, H.-D. Xu, J.-B. Xi, B.-Y.
Ren, F.-P. Lv, X. Guo, L.-Q. Jiang, Z.-Y. Zhang, W.-H. Hu, J.
Am. Chem. Soc. 2011, 133, 8428–8431; p) G. Dagousset, J. Zhu,
G. Masson, J. Am. Chem. Soc. 2011, 133, 14804–14813.
Supporting Information (see footnote on the first page of this arti-
cle): 3D structures of the two diastereomeric TSs of TS2r1a and
TS2s2a (X = Ph) and details of computation (Cartesian coordi-
nates).
[10]
Selected examples from our group: a) T. Akiyama, H. Morita,
J. Itoh, K. Fuchibe, Org. Lett. 2005, 7, 2583–2585; b) J. Itoh,
T. Akiyama, K. Fuchibe, Angew. Chem. 2006, 118, 4914–4916;
Angew. Chem. Int. Ed. 2006, 45, 4796–4798; c) T. Akiyama, H.
Morita, K. Fuchibe, J. Am. Chem. Soc. 2006, 128, 13070–
13071; d) M. Yamanaka, J. Itoh, K. Fuchibe, T. Akiyama, J.
Am. Chem. Soc. 2007, 129, 6756–6764; e) T. Akiyama, Y.
Honma, J. Itoh, K. Fuchibe, Adv. Synth. Catal. 2008, 350, 399–
402; f) J. Itoh, K. Fuchibe, T. Akiyama, Angew. Chem. 2008,
120, 4080–4082; Angew. Chem. Int. Ed. 2008, 47, 4016–4018;
g) T. Akiyama, T. Suzuki, K. Mori, Org. Lett. 2009, 11, 2445–
2447; h) W. Kashikura, J. Itoh, K. Mori, T. Akiyama, Chem.
Asian J. 2010, 5, 470–472; i) P. Bachu, T. Akiyama, Chem.
Commun. 2010, 46, 4112–4114; j) W. Kashikura, K. Mori, T.
Akiyama, Org. Lett. 2011, 13, 1860–1863; k) K. Mori, K.
Ehara, K. Kurihara, T. Akiyama, J. Am. Chem. Soc. 2011, 133,
6166–6169; l) A. Henseler, M. Kato, K. Mori, T. Akiyama,
Angew. Chem. 2011, 123, 8330–9333; Angew. Chem. Int. Ed.
2011, 50, 8180–8183.
For a communication on kinetic resolution, see: a) T. Akiyama,
T. Katoh, K. Mori, Angew. Chem. 2009, 121, 4290–4292; T.
Akiyama, T. Katoh, K. Mori, Angew. Chem. 2009, 121, 4290;
Angew. Chem. Int. Ed. 2009, 48, 4226–4228; see also: b) K.
Mori, T. Katoh, T. Suzuki, T. Noji, T. Akiyama, Angew. Chem.
2009, 121, 9832–9834; Angew. Chem. Int. Ed. 2009, 48, 9652–
9654.
Details of chemical models of ONIOM calculations are shown
in the Supporting Information. All calculations were per-
formed with the Gaussian 03 package, see: M. J. Frisch, G. W.
Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Chee-
seman, J. A. Montgomery Jr., T. Vreven, K. N. Kudin, J. C. Bu-
rant, J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone, B. Men-
nucci, M. Cossi, G. Scalmani, N. Rega, G. A. Petersson, H.
Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J.
Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H.
Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratchian, J. B.
Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E.
Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli,
J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Sal-
vador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D.
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific Research
on Innovative Areas “Advanced Transformation by Organocata-
lysts” from the Ministry of Education, Culture, Sports, Science and
Technology, Japan and a Grant-in-Aid for Scientific Research from
the Japan Society for the Promotion of Science.
[1] H. B. Kagan, J. C. Fiaud, Top. Stereochem. 1985, 18, 249–330.
[2] H. Stecher, K. Faber, Synthesis 1997, 1–16.
[3] E. Vedejs, M. Jure, Angew. Chem. 2005, 117, 4040–4069; An-
gew. Chem. Int. Ed. 2005, 44, 3974–4001.
[4] S.-y. Tosaki, K. Hara, V. Gnanadesikan, H. Morimoto, S. Har-
ada, M. Sugita, N. Yamagiwa, S. Matsunaga, M. Shibasaki, J.
Am. Chem. Soc. 2006, 128, 11776–11777.
[5] M. Miyashita, M. Sasaki, I. Hattori, M. Sakai, K. Tanino, Sci-
ence 2004, 305, 495–499.
[6] a) Z. G. Hajos, D. R. Parrish, J. Org. Chem. 1974, 39, 1615–
1621; b) U. Eder, G. Sauer, R. Wiechert, Angew. Chem. 1971,
83, 492–493; Angew. Chem. Int. Ed. Engl. 1971, 10, 496–497;
c) T. Bui, C. F. Barbas III, Tetrahedron Lett. 2000, 41, 6951–
6954.
[7] For pioneering work on chiral phosphoric acid catalysis, 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) D. Uraguchi, M. Terada, J. Am. Chem. Soc. 2004, 126,
5356–5357.
[8] For selected reviews on chiral phosphoric acid catalysis, see: a)
T. Akiyama, J. Itoh, K. Fuchibe, Adv. Synth. Catal. 2006, 348,
999–1010; b) T. 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, vol. 1, pp. 62–107;
e) M. Terada, Chem. Commun. 2008, 4097–4112; f) M. Terada,
Synthesis 2010, 1929–1982; g) M. Rueping, B. J. Nachtsheim,
W. Ieawsuwan, I. Atodiresei, Angew. Chem. 2011, 123, 6838–
[11]
[12]
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20338
/KAP1
Date: 09-07-12 15:49:08
Pages: 8
Kinetic Resolution in Chiral Phosphoric Acid Catalyzed Aldol Reactions
Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D. Rabuck,
K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Ba-
boul, S. Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A. Lia-
shenko, P. Piskorz, I. Komaromi, R. L. Martin, D. J. Fox, T.
Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, M.
Challacombe, P. M. W. Gill, B. Johnson, W. Chen, M. W.
Wong, C. Gonzalez, J. A. Pople, Gaussian 03, Revision E.01,
Gaussian, Inc., Wallingford, CT, 2004.
b) L. Simón, J. M. Goodman, J. Am. Chem. Soc. 2008, 130,
8741–8747; c) T. Akiyama, H. Morita, P. Bachu, K. Mori, M.
Yamanaka, T. Hirata, Tetrahedron 2009, 65, 4950–4956; d) M.
Yamanaka, T. Hirata, J. Org. Chem. 2009, 74, 3266–3271; e)
X.-H. Chen, Q. Wei, S.-W. Luo, H. Xiao, L.-Z. Gong, J. Am.
Chem. Soc. 2009, 131, 13819–13825; f) F.-Q. Shi, B.-A. Song,
Org. Biomol. Chem. 2009, 7, 1292–1298; g) L. Simn, J. M.
Goodman, J. Org. Chem. 2010, 75, 589–597; h) C. Zheng, Y.-
F. Sheng, Y.-X. Li, S.-L. You, Tetrahedron 2010, 66, 2875–2880;
i) S. Xu, Z. Wang, Y. Li, X. Zhang, H. Wang, K. Ding, Chem.
Eur. J. 2010, 16, 3021–3035; j) T. Hirata, M. Yamanaka, Chem.
Asian J. 2011, 6, 510–516; k) L. He, X.-H. Chen, D.-N. Wang,
S.-W. Luo, W.-Q. Zhang, J. Yu, L. Ren, L.-Z. Gong, J. Am.
Chem. Soc. 2011, 133, 13504–13518; l) L. Simón, J. M. Good-
man, J. Org. Chem. 2011, 76, 1775–1788.
[13] a) S. Dapprich, I. Komaromi, K. S. Byun, K. Morokuma, M. J.
Frisch, J. Mol. Struc. Theochem 1999, 461–462, 1–21; b) M.
Svensson, S. Humbel, K. Morokuma, J. Chem. Phys. 1996, 105,
3654–3661; c) T. Vreven, K. Morokuma, J. Comput. Chem.
2000, 21, 1419–1432.
[14] a) C. S. Chen, Y. Fujimoto, G. Girdaukas, C. J. Sih, J. Am.
Chem. Soc. 1982, 104, 7294–7299; b) H. B. Kagan, J. C. Fiaud,
Top. Stereochem. 1988, 18, 249–330.
Received: March 18, 2012
[15] For theoretical studies, see: a) M. Yamanaka, J. Itoh, K. Fu-
chibe, T. Akiyama, J. Am. Chem. Soc. 2007, 129, 6756–6764;
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20338
/KAP1
Date: 09-07-12 15:49:08
Pages: 8
M. Yamanaka, M. Hoshino, T. Katoh, K. Mori, T. Akiyama
FULL PAPER
Kinetic Resolution
M. Yamanaka,* M. Hoshino, T. Katoh,
K. Mori, T. Akiyama* ...................... 1–8
Kinetic Resolution in Chiral Phosphoric
Acid Catalyzed Aldol Reactions: Enan-
tioselective Robinson-Type Annulation Re-
actions
A
remarkable kinetic resolution was
enones with excellent enantioselectivities.
DFT calculations on the intramolecular
aldol reaction revealed the importance of
the 3,3Ј-substituents of the phosphoric acid
for the enantioselectivity.
achieved in a chiral phosphoric acid cata-
lyzed intramolecular aldol reaction. Its
combination with an enantioselective
Michael reaction gave rise to cyclohex-
Keywords: Kinetic resolution / Organo-
catalysis / Michael addition / Density func-
tional calculations / Brønsted acids
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0