Direct Catalytic Enantio- And Diastereoselective Aldol Reaction Using a Zn-Zn-Linked-BINOL Complex: A Practical Synthesis of syn-1,2-Diols

Article abstract of DOI:10.1021/ol015878p

matrix presented The direct catalytic enantio- and diastereoselective aldol reaction with 2-hydroxy-2′-methoxyacetophenone proceeded smoothly using as little as 1 mol % of a dinuclear zinc catalyst, Zn-Zn-linked-BINOL complex 2, to afford α,β-dihydroxy ke

Full text of DOI:10.1021/ol015878p

ORGANIC
LETTERS
2001
Vol. 3, No. 10
1539-1542
Direct Catalytic Enantio- and
Diastereoselective Aldol Reaction Using
a Zn−Zn-Linked-BINOL Complex: A
Practical Synthesis of syn-1,2-Diols
Naoya Kumagai, Shigeki Matsunaga, Naoki Yoshikawa, Takashi Ohshima, and
Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo,
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
mshibasa@mol.f.u-tokyo.ac.jp
Received March 22, 2001
ABSTRACT
The direct catalytic enantio- and diastereoselective aldol reaction with 2-hydroxy-2′-methoxyacetophenone proceeded smoothly using as little
as 1 mol % of a dinuclear zinc catalyst, Zn−Zn-linked-BINOL complex 2, to afford r,â-dihydroxy ketones in a highly syn-selective manner (up
to syn/anti 97/3) and in excellent yields (up to 95%) and ees (up to 99%). Efficient transformations of the r,â-dihydroxy ketone into an
r,â-dihydroxy ester and an r,â-dihydroxy amide via regioselective rearrangements are also described.
The aldol reaction is generally regarded as one of the most
powerful and efficient carbon-carbon bond-forming reac-
tions. Many efforts have been devoted to the development
of catalytic asymmetric aldol reactions,1 but almost all of
these reactions require a preconversion of the ketone or ester
moiety into a more reactive species such as an enol silyl
ether or a ketene silyl acetal by using no less than stoichio-
metric amounts of reagents. Since our success in carrying
out direct catalytic asymmetric aldol reactions with unmodi-
fied ketones,2 this potentially advantageous strategy has
attracted much interest in terms of atom economy.3 List et
al.4 and Trost et al.5 reported direct asymmetric aldol
reactions using L-proline or a chiral semi-crown Zn complex
as catalysts. Moreover, recently several groups reported
enantio- and diastereoselective direct aldol reactions using
biological-type catalysts6 or small molecular catalysts,7,8
which considerably widened the scope of this field. We also
reported an enantio- and diastereoselective direct aldol
reaction with 2-hydroxyacetophenone (1a), which provided
(2) (a) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M.
Angew. Chem., Int. Ed. Engl. 1997, 36, 1871. (b) Yoshikawa, N.; Yamada,
Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121,
4168. (c) Yamada, Y. M. A.; Shibasaki, M. Tetrahedron Lett. 1998, 39,
5561. (d) Yoshikawa, N.; Shibasaki, M. Tetrahedron 2001, 57, 2569. For
a partially successful attempt, see: (e) Nakagawa, M.; Nakao, H.; Watanabe,
K.-I. Chem. Lett. 1985, 391.
(3) (a) Trost, B. M. Science 1991, 254, 1471. (b) Trost, B. M. Angew.
Chem., Int. Ed. Engl. 1995, 34, 259.
(4) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000,
122, 2395.
(1) For a general review on the catalytic enantioselective aldol reaction,
see: (a) Carreira, E. M. In ComprehensiVe Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Heidelberg, 1999; Vol.
3, Chapter 29.1. (b) Machajewski, T. D.; Wong, C.-H. Angew. Chem., Int.
Ed. 2000, 39, 1352. (c) Gro¨ger, H.; Vogl, E. M.; Shibasaki, M. Chem. Eur.
J. 1998, 4, 1137. (d) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357.
See also: (e) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325.
(5) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003.
10.1021/ol015878p CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/21/2001

either the anti- or the syn-R,â-dihydroxy ketones when using
two different catalysts, a LaLi3tris(binaphthoxide)‚KOH
(LLB‚KOH) complex (anti selective) or Zn-Zn-linked-
BINOL complex 2 (Scheme 1, syn selective).9 In the case
Table 1. Direct Aldol Reaction of 3a with
Methoxy-Substituted 2-Hydroxyacetophenone 1 Catalyzed by
(S,S)-Zn-Zn-Linked-BINOL 2a
Scheme 1. syn-Selective Direct Catalytic Asymmetric Aldol
Reaction Using (S,S)-Zn-Zn-Linked-BINOL Complex 2
catalyst
(mol
drc
eed
temp time yieldb (syn/ (syn/
entry
X
%)
(°C)
(h)
(%)
anti) anti)
1
2
3
4
5e
6
7
8
H
1a
10
10
10
10
10
3
-40
-20
-30
-30
-30
-30
-30
-30
48
24
12
3
3
4
81
73
85
93
93
94
94
94
67/33 78/76
60/40 86/86
70/30 77/77
89/11 86/88
86/14 86/77
90/10 90/89
89/11 92/89
87/13 93/91
4′-MeO 1b
3′-MeO 1c
2′-MeO 1d
2′-MeO 1d
2′-MeO 1d
2′-MeO 1d
2′-MeO 1d
1
1
20
16
of the aldol reaction catalyzed by 2, however, there remained
much room to be improved in respect to catalyst amount
(10 mol %), diastereomeric ratio (syn/anti ) 2/1 to 7/1),
enantiomeric excess (77-86% for syn isomer), reaction rate,
and yield. Herein, we now report the great improvement of
the syn-selective direct catalytic asymmetric aldol reaction
in all aspects mentioned above by modifying the donor
substrate. In addition, efficient further transformations of the
aldol adduct into an ester and an amide via regioselective
rearrangements, enhancing the utility of the present reaction,
are also reported.
On the basis of our previous results,10 we supposed that
substituents on the aromatic ring of acetophenones should
affect both diastereoselectivity and enantioselectivity. We
chose methoxy-substituted acetophenones, considering the
following background: from a synthetic point of view, the
use of aryl ketones is potentially advantageous over the use
of dialkyl ketones such as acetone and hydroxyacetone,11
because the aromatic ring functions as a placeholder for
further conversions via regioselective rearrangements. By
using electron-rich methoxy-substituted acetophenones, con-
versions such as a Baeyer-Villiger oxidation would become
facile. We first investigated the direct aldol reaction of
3-phenylpropanal (3a) using methoxy-substituted 2-hydroxy-
acetophenones 1b-1d (Table 1). The aldol adducts were
a Reactions were run on a 0.30 mmol scale (entry1-5), a 0.67 mmol
scale (entry 6), a 1.0 mmol scale (entry 7), and an 8.0 mmol scale (1.05 g
of 3a, entry 8) at 0.2 M in aldehyde. b Isolated yield after conversion to
acetonides. c Determined by 1H NMR of crude mixture. d Determined by
chiral HPLC analysis of diols. e In the presence of Ph3P(O) (20 mol %).
isolated after their conversion into the corresponding ac-
etonides.12 In the case of 2-hydroxy-4′-methoxyacetophenone
(1b), the reaction was run at -20 °C due to the poor
solubility of 1b. Although a slightly higher ee was obtained,
dr and yield were lower than those in the case of 1a (entry
2). In the case of 2-hydroxy-3′-methoxyacetophenone (1c),
the reaction was run at -30 °C. Yield, dr, and ee were
comparable with those of 1a and the reaction rate increased
(entry 3). Gratifyingly, the reaction rate, yield, dr, and ee
all were improved when using 2-hydroxy-2′-methoxy-
acetophenone (1d) (entry 4). In contrast to the case of 1a,13
Ph3P(O) as an additive had no positive effects (entry 5). It
is noteworthy that the aldol reaction of 1d still proceeded
smoothly even when the catalyst amount was reduced. The
reaction was completed within 4 h with 3 mol % of catalyst
2 (entry 6). Moreover, satisfactory yield (94%), dr (syn/anti
) 89/11), and ee (syn ) 92%, anti ) 89%) were achieved
after 20 h with as little as 1 mol % of 2 (entry 7), and the
reaction proceeded smoothly without any problem on a gram
scale (entry 8). To the best of our knowledge, in terms of
catalyst loading, this is the most effective small molecular
catalyst for direct asymmetric aldol reactions. In combination
with the successful gram scale experiment, the simple
protocol proves the present reaction to be practically useful.
The catalyst was prepared by just mixing commercially
available Et2Zn in hexanes and easily available linked-
BINOL14 in THF without any other additives, followed by
the addition of ketone 1d and the aldehyde.15
(6) For the synthesis of syn- or anti-1,2-diols by aldolases or catalytic
antibodies, see: (a) Bednarski, M. D.; Simon, E. S.; Bischofberger, N.;
Fessner, W.-D.; Kim, M.-J.; Lees, W.; Saito, T.; Waldmann, H.; Whitesides,
G. M. J. Am. Chem. Soc. 1989, 111, 627. (b) Fessner, W.-D.; Sinerius, G.;
Schneider, A.; Dreyer, M.; Schulz, G. E.; Badia, J.; Aguilar, J. Angew.
Chem., Int. Ed. Engl. 1991, 30, 555. (c) List, B.; Shabat, D.; Barbas, C. F.,
III.; Lerner, R. A. Chem. Eur. J. 1998, 4, 881. (d) Hoffmann, T.; Zhong,
G.; List, B.; Shabat, D.; Anderson, J.; Gramatikova, S.; Lerner, R. A.;
Barbas, C. F., III. J. Am. Chem. Soc. 1998, 120, 2768.
(7) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386.
(8) Trost, B. M.; Ito, H.; Silcoff, E. R. J. Am. Chem. Soc. 2001, 123,
3367.
(9) Yoshikawa, N.; Kumagai, N.; Matsunaga, S.; Moll, G.; Ohshima,
T.; Suzuki, T.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 2466.
(10) For the direct catalytic asymmetric aldol reaction of acetophenones
promoted by the LLB‚KOH complex, the use of 3′-nitroacetophenone was
effective in some cases. See ref 2b.
(12) No change of ee and dr was observed. For detailed procedures, see
Supporting Information. Isolation of diols was also possible.
(13) When 1a was used as the donor, Ph3P(O) had positive effects. The
result in the presence of Ph3P(O) (20 mol %): -40 °C, 48 h, yield 89%,
syn/anti ) 72/28, syn ) 81% ee, anti ) 81% ee. See ref 9.
(11) The use of hydroxyacetone gave unasatisfactory results with Zn-
Zn-linked-BINOL 2. Further studies are currently under investigation.
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Org. Lett., Vol. 3, No. 10, 2001

Zn-Zn-linked-BINOL 2 was also applicable to various
primary (R-unsubstituted) and secondary (R-monosubstituted)
aldehydes (Table 2). In all cases, 1 mol % of catalyst 2 was
It should be mentioned that primary (R-unsubstituted)
aldehydes gave the corresponding aldol adducts in good to
excellent yields and ees without forming any self-condensa-
tion products. The results indicate the high chemoselectivity
of the present catalysis. In the case of trans-4-decenal (3e,
entry 5), the synthesis of the corresponding diol 4e via
Sharpless asymmetric dihydroxylation (AD)17 may be dif-
ficult due to the chemoselectivity issue. Aldehydes with
oxygen functionalities such as 3f (entry 6) and 3g (entry 7),
which lead to useful intermediates for the synthesis of
polyoxygenated compounds, were also converted into diols
in excellent ee (syn: 95% in entry 6 and 96% in entry 7).
Remarkably, secondary (R-monosubstituted) aldehydes (entry
8-10) showed good yield (83-95%) and excellent dr
(syn/anti ) 96/4 to 97/3) and ee (98-99%).
Table 2. Direct Aldol Reaction of Various Aldehydes with
2-Hydroxy-2′-methoxyacetophenone (1d)a
The relative and absolute configurations of the syn-aldol
adducts 4 ((2R,3S) from (S,S)-catalyst 2, Scheme 1) were
determined by comparison with authentic samples prepared
by Sharpless AD. The absolute configurations of the anti-
aldol adducts 4 ((2R,3R) from (S,S)-catalyst 2, Scheme 1)
were analyzed after epimerization of the acetonides.18 The
observed stereoselectivity obtained with ketone 1d is well
explained by assuming the following reaction mechanism.
The formation of a chelate complex between the (S,S)-
catalyst 2 and the enolate generated from 1d would result in
an efficient shielding of the Si-face of the enolate (Figure
1), so that both syn- and anti-aldol adducts were obtained
a All reactions were run on a 1.0 mmol scale at 0.2 M in aldehyde.
1
b Isolated yield after conversion to acetonides. c Determined by H NMR
of crude mixture. d Determined by chiral HPLC analysis of diols.
sufficient to complete the reaction within 24 h.16 Both normal
(entry 1-3 and 5-7) and branched (entry 4) primary
aldehydes afforded good results (yield, 81-94%, dr, syn/
anti ) 72/28 to 88/12; ee, syn ) 87-96%, anti ) 87-93%).
Figure 1. Working model for transition state.
(14) For catalytic asymmetric syntheses using linked-BINOL as ligand,
see: ref 9 and the following: (a) Matsunaga, S.; Das, J.; Roels, J.; Vogl,
E. M.; Yamamoto, N.; Iida, T.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem.
Soc. 2000, 122, 2252-2260. (b) Kim, Y. S.; Matsunaga, S.; Das, J.; Sekine,
A.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 6506-6507.
(c) Matsunaga, S.; Ohshima, T.; Shibasaki, M. Tetrahedron Lett. 2000, 41,
8473-8478 and references therein.
(15) General procedure: To a stirred solution of (S,S)-linked-BINOL
(0.01 mmol) in THF (0.3 mL) at -78 °C was added Et2Zn (20 µL, 0.02
mmol, 1.0 M in hexanes). The resulting mixture was stirred for 30 min at
-20 °C, and a solution of 1d (2.0 mmol) in THF (4.7 mL) was added.
After the mixture was cooled to -30 °C, 3a (1.0 mmol) was added and the
reaction mixture was stirred for 20 h, followed by addition of 1 M HCl.
The mixture was extracted with ethyl acetate, and the combined organic
layers were washed with brine and dried over Na2SO4. Evaporation of
solvent gave a crude mixture of the aldol products.
with an identical configuration at the R-position (2R) after
the attack toward the aldehyde. Moreover, the electron-
donating substituent (methoxy group) on the aromatic ring
should increase the preference of one chelate complex
(shielding Si-face) to the other (shielding Re-face) through
(16) In all cases, the reaction was quenched after an appropriate time
(<24 h). A prolonged reaction time resulted in a lower ee of syn-4, probably
due to the epimerization of anti-4 under the reaction conditions.
(17) Review: Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B.
Chem. ReV. 1994, 94, 2483.
(18) See Supporting Information for detailed synthetic procedures.
Org. Lett., Vol. 3, No. 10, 2001
1541

participation of the 2′-methoxy group in chelate formation
(Figure 1). Thus, the Si-face shielding would become more
effective, resulting in the higher ee of both syn- and anti-
products. On the other hand, enhanced syn-selectivity is
explained by the steric hindrance of the aromatic ring in the
enolate against aldehydes. Considering the positions of the
two Zn atoms in the proposed structure of 2, it seems
reasonable to assume that the enolate would coordinate to
one Zn metal and the aldehyde would coordinate to the other
in a manner as shown in A or B (Figure 1).19 The transition
state A, which leads to syn-diols, is sterically more favorable
than B. By using ketone 1d instead of nonsubstituted 1a,
the steric bias should increase, thus resulting in the higher
syn-selection.
As mentioned in the introduction, the usefulness of the
aldol adducts becomes much higher by assuming that the
2-methoxyphenyl moiety is a placeholder for further conver-
sions. As shown in Scheme 2, the Baeyer-Villiger oxidation
proceeded smoothly by treating the ketones 5a and 6a with
mCPBA, probably with the aid of neighboring oxygen atoms.
Interestingly, benzoate 7a was obtained in 89% yield when
acetonide 5a was used. On the other hand, phenyl ester 8a
was obtained in 93% yield when carbonate analogue 6a20
was subjected to the same conditions. In both cases, no
regioisomer was observed. Furthermore, 6a afforded amide
9a exclusively in 97% yield in one step via Beckmann
rearrangement with O-mesitylenesulfonylhydroxylamine
(MSH).21 The amide 9a was readily transformed into 10a
by reduction with DIBAL. 10a can be converted into an
amino-diol after oxidative removal of the 2-methoxyphenyl
group.22
In conclusion, we have achieved a highly enantio- and
diastereoselective direct catalytic aldol reaction, which
afforded R,â-dihydroxy ketones from a variety of aldehydes
using as little as 1 mol % of the Zn-Zn-linked-BINOL
complex 2. The reaction was also performed on a gram scale
and reached completion within 24 h. The simple reaction
protocol, in combination with options for further efficient
transformations of the resulting aldol adducts into syntheti-
cally interesting compounds, makes this process more useful.
Detailed investigation on the reaction mechanism as well as
the development of a direct catalytic asymmetric aldol
reaction with an unmodified ester is currently underway in
our group.
Acknowledgment. We thank CREST and RFTF for
financial support. S. M. and N. Y. thank JSPS Research
Fellowships for Young Scientists.
Supporting Information Available: Experimental pro-
cedures and characterization data for products 4-10. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Scheme 2. Transformations of Aldol Adducts via
Regioselective Rearrangementa
OL015878P
(19) Similar mechanisms are proposed for the hydrolysis of phosphates
catalyzed by achiral dinuclear Zn complexes. (a) Abe, K.; Izumi, J.; Ohba,
M.; Yokoyama, T.; Okawa, H. Bull. Chem. Soc. Jpn. 2001, 74, 85 and
references therein. For selected examples of recent dinuclear Zn catalysts,
see refs 5 and 8 and references therein. See also: (b) Hikichi, S.; Tanaka,
M.; Moro-oka, Y.; Kitajima, N. J. Chem. Soc., Chem. Commun. 1992, 814.
(c) Chapman, W. H., Jr.; Breslow, R. J. Am. Chem. Soc. 1995, 117, 5462.
(d) Yashiro, M.; Ishikubo, A.; Komiyama, M. J. Chem. Soc., Chem.
Commun. 1995, 1793. (e) Koike, T.; Inoue, M.; Kimura, E.; Shiro, M. J.
Am. Chem. Soc. 1996, 118, 3091. (f) Molenveld, P.; Kapsabeils, S.;
Engbersen, J. F. J.; Reinhoudt, D. N. J. Am. Chem. Soc. 1997, 119, 2948.
(g) Bazzicalupi, C.; Bencini, A.; Bianchi, A.; Fusi, V.; Giorgi. C.; Paoletti,
P.; Valtancoli, B.; Zanchi, D. Inorg. Chem. 1997, 36, 2784. (h) Kaminskaia,
N. V.; Spingler, B.; Lippard, S. J. J. Am. Chem. Soc. 2000, 122, 6411. (i)
Rossi, P.; Felluga, F.; Tecilla, P.; Formaggio, F.; Crisma, M.; Toniolo, C.;
Scrimin, P. J. Am. Chem. Soc. 1999, 121, 6948. (j) Kim, H.-S.; Kim, J.-J.;
Lee, B.-G.; Jung, O.-S.; Jang, H.-G.; Kang, S.-O. Angew. Chem., Int. Ed.
2000, 39, 4096 and references therein.
(20) The carbonate 6a was prepared by treating syn-4a with triphosgene
(93% yield). See Supporting Information.
(21) Tamura, Y.; Fujiwara, H.; Sumoto, K.; Ikeda, M.; Kita, Y. Synthesis
1973, 215.
(22) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122,
8180 and references therein.
a (i) mCPBA, NaH2PO4, ClCH2CH2Cl, 50 °C, 2 h; (ii) O-
mesitylenesulfonylhydroxylamime, CH2Cl2, rt, 4 h; (iii) DIBAL,
-78 °C to rt, 2 h.
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Org. Lett., Vol. 3, No. 10, 2001