Direct catalytic asymmetric aldol reaction: Synthesis of either syn-or anti-α,β-dihydroxy ketones

Full text of DOI:10.1021/ja015580u

2466
J. Am. Chem. Soc. 2001, 123, 2466-2467
Direct Catalytic Asymmetric Aldol Reaction:
Synthesis of Either syn- or anti-r,â-Dihydroxy
Ketones
Naoki Yoshikawa, Naoya Kumagai, Shigeki Matsunaga,
Guido Moll, Takashi Ohshima, Takeyuki Suzuki, and
Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences
The UniVersity of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Figure 1. Structure of (S)-heterobimetallic catalyst 4 and the proposed
structure of (S,S)-Zn-Zn-linked-BINOL complex 5.
ReceiVed January 24, 2001
Table 1. Aldol Reaction Using Heterobimetallic Catalyst 4a
The development of a range of catalytic asymmetric aldol
reactions has proven to be a valuable contribution to asymmetric
synthesis.1 In all of these catalytic asymmetric aldol reactions,
however, preconversion of the ketone moiety to a more reactive
species such as an enol silyl ether and ketene silyl acetal is an
unavoidable necessity. Thus, the development of a direct catalytic
asymmetric aldol reaction is highly desirable in terms of atom
economy.2 In 1997, we achieved success in carrying out the direct
catalytic asymmetric aldol reactions of aldehydes with unmodified
ketones using heterobimetallic asymmetric catalysis.3 List et al.4
and Trost et al.5 also reported direct asymmetric aldol reactions
using L-proline or a chiral semi-crown Zn complex as a catalyst.
In this communication we report the synthesis of either syn- or
anti-R,â-dihydroxy ketones in a highly enantioselective manner
using two types of bimetallic asymmetric catalysis (Scheme 1).
Scheme 1. General Scheme for the Direct Catalytic
Asymmetric Aldol Reaction of 2-Hydroxyacetophenone and
Aldehydes
a All reactions were carried out at -50 °C. b The yield was
1
determined by H NMR of the crude reaction mixture with anisole as
an internal standard. The isolated yields after conversion to acetonides
1
are given in parentheses. c The dr was determined by H NMR of the
crude reaction mixture. d The ee was determined after conversion to
the corresponding acetonide. See Supporting Information. e The reaction
was carried out at -40 °C.
The fact that the 1,2-diol unit occurs in many natural products,
for example, carbohydrates and alkaloids, and that 1,2-diols are
very important as ligands in asymmetric synthesis makes the
demand for the asymmetric synthesis of these compounds even
bigger. Due to the impressive work of Sharpless on the asym-
metric dihydroxylation (AD) of (E)-olefins, the synthesis of syn-
1,2-diols can be accomplished easily.6a However, (Z)-olefins
leading to anti-1,2-diols show low enantioselectivities in the AD.6b
Recently List et al. reported the first catalytic asymmetric synthesis
of anti-1,2-diols using hydroxyacetone in the aldol reaction, giving
rise to products in high enantiomeric excesses and high diaster-
eomeric ratios.7-9 However, except for 3,3-dimethylbutanal, no
example for normal primary aldehydes has been reported.
Therefore, we planned to develop a general direct catalytic
asymmetric aldol reaction of primary aldehydes, leading to anti-
R,â-dihydroxy ketones in a highly enantioselective manner.
On the basis of our previous results we started to investigate
the aldol reaction of 2-hydroxyacetophenone (2, 2 equiv) and
4-phenylbutanal (1a) using heterobimetallic asymmetric catalysts.
After the screening of many catalysts and reaction conditions,
we were pleased to find that the corresponding aldol product (3a)
could be obtained in 87% yield in a ratio of 5 (anti, 95% ee) to
1 (syn, 74% ee) using 10 mol % of 4 (Figure 1) prepared from
LaLi3tris((S)-binaphthoxide) ((S)-LLB)3a,b (10 mol %), KHMDS
(9 mol %) and H2O (20 mol %) (entry 1, Table 1).10,11 Moreover,
(1) For a general review on the 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. See also: (b) Machajewski, T. D.; Wong, C.-H. Angew. Chem., Int. Ed.
2000, 39, 1352-1374. (c) Gro¨ger, H.; Vogl, E. M.; Shibasaki, M. Chem. Eur.
J. 1998, 4, 1137-1141. (d) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9,
357-389.
(2) For a general discussion of atom economy in organic synthesis, see:
(a) Trost, B. M. Science 1991, 254, 1471-1477. (b) Trost, B. M. Angew.
Chem., Int. Ed. Engl. 1995, 34, 259-281.
(3) (a) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1871-1873. (b) Yoshikawa, N.; Yamada, Y.
M. A.; Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168-
4178. (c) Yamada, Y. M. A.; Shibasaki, M. Tetrahedron Lett. 1998, 39, 5561-
5564. For a partially successful attempt, see: (d) Nakagawa, M.; Nakao, H.;
Watanabe, K.-I. Chem. Lett. 1985, 391-394.
(8) For the catalytic asymmetric synthesis of syn-1,2-diols by Mukaiyama
aldol reactions, see: Kobayashi, S.; Kawasuji, T. Synlett 1993, 911-913.
(9) 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, 627-635. (b) Fessner, W.-D.; Sinerius, G.;
Schneider, A.; Dreyer, M.; Schulz, G. E.; Badia, J.; Aguilar, J. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 555-558. (c) List, B.; Shabat, D.; Barbas, C. F., III.;
Lerner, R. A. Chem. Eur. J. 1998, 4, 881-885. (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, 2768-2779.
(4) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000,
122, 2395-2396.
(5) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003-12004.
(6) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483-2547. (b) Wang, L.; Sharpless, K. B. J. Am. Chem. Soc.
1992, 114, 7568-7570.
(10) The use of LLB showed less satisfactory results in terms of reactivity
and diastereoselectivity.
(7) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386-7387.
10.1021/ja015580u CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/20/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 10, 2001 2467
Table 2. Aldol Reaction Using Zn-Zn-linked-BINOL Complex 5a
or Ln-Ln-linked-BINOL (Ln ) La or Yb), but the results were
not satisfactory. On the basis of the results obtained by Trost et
al.5 and in our group14c in bimetallic asymmetric catalysis, Zn
metal was expected to be effective for the direct asymmetric aldol
reaction, and after trying many catalysts, for example, Ln-Zn-
linked-BINOL14c (Ln ) La, Gd, Y or Yb) we found that the (S,S)-
Zn-Zn-linked-BINOL complex 5 prepared from linked-BINOL
and 2 equiv of Et2Zn (see Figure 1) showed promising results.
The structure of 5 is discussed in detail in the Supporting
Information. Surprisingly, the syn-aldol 3f was selectively ob-
tained in a ratio of 5 (syn, 86% ee) to 1 (anti, 67% ee) on treatment
of 2-methylpropanal (1f) with 2-hydroxyacetophenone (2, 2 equiv)
in the presence of 5 (10 mol %) and triphenylphosphine oxide
(20 mol %)15 (entry 1, Table 2).16 Moreover, as shown in Table
2, the reaction of 2 with a variety of aldehydes afforded the
corresponding syn-aldols stereoselectively in good ees. It is
noteworthy that the reaction of the aldehyde 1c with a C-C
double bond was efficiently promoted by 5 to give the syn-aldol
product 3c (entry 5, Table 2), which may be inaccessible by
Sharpless AD due to a chemoselectiviy problem.6a
The observed stereoselectivities (see Scheme 1) can be
understood by assuming the following mechanism. The formation
of a chelate complex between catalyst (S)-4 or (S,S)-5 and the
enolate generated from 2 can result in an efficient shielding of
the Si face of the enolate from the attack of aldehydes. Thus,
anti- and syn-product were obtained with an identical configu-
ration at the R-position (2R) in good to excellent selectivities.
This mechanism differs from that of direct asymmetric aldol
reaction of acetophenone, in which the enantioface of the aldehyde
is differentiated.3a,b On the other hand, the stereochemistry at the
â-position can be effected by the enantioface selection of the
aldehyde.13
In summary, we were able to synthesize either syn- or anti-
1,2-diols using the heterobimetallic catalyst 4 or the newly
developed (S,S)-Zn-Zn-linked-BINOL complex 5. Although the
diastereomeric ratios are not very high, these catalysts can be
seen as a new tool to synthesize optically active 1,2-diols. Further
investigations on the use of tertiary aldehydes and on the precise
mechanism are currently ongoing.
a All reactions were carried out at -40 °C. b Isolated yield after
conversion to the corresponding acetonide. c The dr was determined
1
by H NMR. d The ee was determined after conversion to the corre-
sponding acetonide. For full details see Supporting Information. e The
ee was determined at the stage of the free diol.
as shown in Table 1, the reaction of 2 with a variety of aldehydes
produced the corresponding anti-aldols stereoselectively in good
yields and excellent ees, and even by the use of 5 mol % 4 the
anti-aldol 3a was obtained in a ratio of 4 (anti, 92% ee) to
1 (syn, 70% ee) (entry 2, Table 1).
Due to the instability of some anti-1,2-diols, we decided to
determine the ee of the aldol products after conversion to the
corresponding acetonides.12,13 The relative and absolute config-
uration of the syn-isomers was revealed by conversion to the
acetonides and comparison with authentic samples obtained after
Sharpless AD followed by acetonide formation.13 Determination
of the relative and absolute configuration of the anti-isomers was
performed after epimerization of the acetonides obtained from
the anti-aldol products.13 To the best of our knowledge, this is
the first example of a general, anti-selective, direct catalytic
asymmetric aldol reaction using primary aldehydes and 2-hy-
droxyacetophenone.
Note Added in Proof. For the syn-selective direct catalytic
asymmetric aldol reaction of 2-hydroxyacetophenone, see: Trost,
B. M.; Oi, Shiuchi J. Am. Chem. Soc. 2001, 123, 1230-1231.
Acknowledgment. This study was financially supported by CREST
and RFTF. N.Y. and S.M. thank the Japan Society for the Promotion of
Science (JSPS) for a research fellowship.
Unfortunately, secondary or tertiary aldehydes gave no satisfac-
tory results, and therefore we turned our attention to the
development of a new catalyst system. Using (S,S)-linked-
BINOL14 as a ligand of choice we first investigated various
catalysts, for example, Ln-linked-BINOL14a (Ln ) La, Gd or Yb)
Supporting Information Available: Spectral data of the acetonides,
the detailed experimental procedure, a discussion about the stereoselec-
tivities and the structural determination studies of 5 (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
(11) General procedure: To a solution of KHMDS in toluene (0.027 mmol,
0.5 M) at 0 °C, was added H2O in THF (0.06 mmol, 1 M). After stirring for
15 min a solution of (S)-LLB in THF (0.03 mmol, 300 µL) was added, and
the stirring was continued at 0 °C for 30 min. The resulting solution was
cooled to -50 °C, and a solution of 2 (0.6 mmol in 2 mL THF) and 1a (0.3
mmol) were added successively. The stirring was continued for 24 h at -50
°C and quenched by addition of 1 M HCl. The mixture was extracted with
ether, and the combined organic layers were washed with brine and dried
over Na2SO4. Evaporation of solvent gave a crude mixture of the aldol
products.
JA015580U
(15) For interesting effects of phosphine oxide, see: (a) Daikai, K.;
Kamaura, M.; Inanaga, J. Tetrahedron Lett. 1998, 39, 7321-7322. (b) Nemoto,
T.; Ohshima, T.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. In press.
(c) Yamasaki, S.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123,
1256-1257. The result in the absence of Ph3P(O): 48 h, y. 71%, anti:syn )
1:3, anti ) 78% ee, syn ) 73% ee.
(16) General procedure: To a stirred solution of (S,S)-linked-BINOL (0.03
mmol) in THF (0.3 mL) at -78 °C, was added Et2Zn (60 µL, 0.06 mmol, 1.0
M in hexane). The resulting solution was stirred for 30 min at -20 °C before
a solution of Ph3P(O) (0.06 mmol) in THF (0.1 mL) was added. The resulting
mixture was stirred for 20 min at -20 °C, and a solution of 2 (0.6 mmol in
1.6 mL THF) was added. After the mixture was cooled to -40 °C, 1f (0.3
mmol) was added, and the reaction mixture was stirred for 36 h. The reaction
was worked up using the same procedure as described in ref 11.
(12) No change of ee and dr was observed during this conversion.
(13) See Supporting Information.
(14) For catalytic asymmetric syntheses using linked-BINOL as ligand,
see: (a) Kim, Y. S.; Matsunaga, S.; Das, J.; Sekine, A.; Ohshima, T.; Shibasaki,
M. J. Am. Chem. Soc. 2000, 122, 6506-6507. (b) 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. (c) Matsunaga, S.; Ohshima,
T.; Shibasaki, M. Tetrahedron Lett. 2000, 41, 8473-8478.