Highly anti-selective catalytic asymmetric aldol reactions [9]

Full text of DOI:10.1021/ja9943389

J. Am. Chem. Soc. 2000, 122, 5403-5404
Table 1. Effect of Catalysts and Alcohols
5403
Highly anti-Selective Catalytic Asymmetric Aldol
Reactions
Haruro Ishitani, Yasuhiro Yamashita, Haruka Shimizu, and
Shuj Kobayashi*
Graduate School of Pharmaceutical Sciences
The UniVersity of Tokyo, CREST
Japan Science and Technology Corporation (JST)
Hongo, Bunkyo-ku, Tokyo 113-0033 Japan
ReceiVed December 13, 1999
The Lewis acid-mediated aldol reactions of silyl enol ethers
with aldehydes (Mukaiyama aldol reaction) provide one of the
most convenient carbon-carbon bond-forming processes in
organic synthesis.1 Since the first catalytic asymmetric version
of this reaction using chiral tin(II) Lewis acids appeared in 1990,2
several efficient Lewis acid catalysts based on boron, titanium,
copper, etc., have been reported.3 While these highly selective
reactions have been regarded as one of the most efficient reactions
for the preparation of chiral â-hydroxy ketone and ester deriva-
tives, temperatures of -20 to -78 °C and strict anhydrous
conditions are required in most cases.3-5 In addition, while several
excellent syn-selective aldol reactions have been developed, few
general highly anti-selective aldol reactions have been reported.6
In this paper, we address these problems and report highly anti-
selective catalytic asymmetric aldol reactions using a novel chiral
zirconium catalyst.
activate aldehydes to create excellent asymmetric enivironments.
After testing several zirconium catalysts in a model reaction of
benzaldehyde with the silyl enol ether of (S)-ethyl ethanethioate,
it was found that the chiral zirconium catalyst (1a) prepared from
Zr(OtBu)4 and (R)-3,3′-dibromo-1,1′-bi-2-naphthol ((R)-3,3′-
BrBINOL)7c,11 gave promising results. When the reaction was
performed using 10 mol % of 1a in toluene at 0 °C, the desired
aldol adduct was obtained in 46% yield with 4% ee. Although
the yield and the selectivity were less than satisfactory, an
interesting finding was the formation of a monotrimethylsilylated
BINOL derivative detected by thin-layer chromatography (TLC).
At this stage, it was thought that the catalyst regeneration step
(vide infra) was slow and that the monotrimethylsilylated BINOL
derivative was detected when the reaction was quenched with
water. To accelerate this step, we then decided to add a proton
source to convert the monotrimethylsilylated BINOL derivative
to a BINOL derivative. After testing several proton sources, it
was found that the yield and the enantioselectivity were improved
to 54 and 61%, respectively, by using propanol as the source.12,13
We further tested chiral ligands (BINOL derivatives), and the
desired aldol adduct was obtained in 81% yield with 92% ee when
(R)-3,3′-diiodo-1,1′-bi-2-naphthol ((R)-3,3′-IBINOL)11 was used
as the chiral ligand. The amounts and the kinds of alcohols also
influenced the yield and the selectivity (Table 1), and it is noted
that lower yield and selectivity were obtained when 2-methyl-2-
propanol (tBuOH) was used.
Our catalyst shown here is based on a chiral zirconium
complex. We have recently shown that catalytic asymmetric
Mannich-type,7 aza Diels-Alder,8 and Strecker reactions9 pro-
ceeded smoothly in the presence of chiral zirconium catalysts.10
While the zirconium catalysts effectively activated aldimines in
these reactions, it was expected that the catalyst would also
(1) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1012.
(2) (a) Kobayashi, S.; Fujishita, Y.; Mukaiyama, T. Chem. Lett. 1990, 1455.
(b) Kobayashi, S.; Uchiro, H.; Fujishita, Y.; Shiina, I.; Mukaiyama, T. J. Am.
Chem. Soc. 1991, 113, 4247.
(3) ReView: (a) Carreira, E. M. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Heidelberg, 1999;
Vol. 3, p 998. (b) Mahrwald, R. Chem. ReV. 1999, 99, 1095. (c) Gro¨ger, H.;
Vogl, E. M.; Shibasaki, M. Chem. Eur. J. 1998, 4, 1137. (d) Nelson, S. G.
Tetrahedron: Asymmetry 1998, 9, 357. (e) Bach, T. Angew. Chem., Int. Ed.
Engl. 1994, 33, 417.
(4) (a) Kobayashi, S.; Nagayama, S.; Busujima, T. Chem. Lett. 1999, 71.
(b) Kobayashi, S.; Nagayama, S.; Busujima, T. Tetrahedron 1999, 55, 8739
and references therein.
(5) Some catalytic asymmetric aldol reactions were performed at higher
temperatures (-20 to 23 °C): (a) Mikami, K.; Matsukawa, S. J. Am. Chem.
Soc. 1993, 115, 7039. (b) Carreira, E. M.; Singer, R. A.; Lee, W. J. Am.
Chem. Soc. 1994, 116, 8837. (c) Keck, G. E.; Krishnamurthy, D. J. Am. Chem.
Soc. 1995, 117, 2363. Catalytic asymmetric aldol reactions in wet dimethyl-
formamide were reported: (d) Sodeoka, M.; Ohrai, K.; Shibasaki, M. J. Org.
Chem. 1995, 60, 2648.
We then tested other examples of aldehydes and silyl enolates,
and the results are summarized in Table 2.14 Aromatic aldehydes
as well as R,â-unsaturated and aliphatic aldehydes reacted with
silyl enolates to afford the corresponding aldol adducts in high
yields with high ees using 1b as a catalyst. Only 2 mol % of 1b
(6) Masamune et al. reported anti-selective catalytic asymmetric aldol
reactions; however, the enantioselectivities of the anti-adducts were 60-82%
ees. (a) Parmee, E. R.; Hong, Y.; Tempkin, O.; Masamune, S. Tetrahedron
Lett. 1992, 33, 1729. For other anti-selective catalytic asymmetric aldol
reactions: (b) Mikami, K.; Matsukawa, S. J. Am. Chem. Soc. 1994, 116, 4077.
(c) Yanagisawa, A.; Matsumoto, Y.; Nakashima, H.; Asakawa, K.; Yamamoto,
H. J. Am. Chem. Soc. 1997, 119, 9319. (d) Denmark, S. E.; Stavenger, R. A.;
Wong, K.-T.; Su, X. J. Am. Chem. Soc. 1999, 121, 4982. (e) Evans, D. A.;
MacMillan, W. C.; Campos, K. R. J. Am. Chem. Soc. 1997, 119, 10859.
Although high selectivities are obtained in some of these reactions, substrates
are limited in all cases.
(7) (a) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 1997, 119,
7153. (b) Kobayashi, S.; Ueno, M.; Ishitani, H. J. Am. Chem. Soc. 1998, 120,
431. (c) Kobayashi, S.; Hasegawa, Y.; Ishitani, H. Chem. Lett. 1998, 1131.
(8) (a) Kobayashi, S.; Komiyama, S.; Ishitani, H. Angew. Chem., Int. Ed.
1998, 37, 979. (b) Kobayashi, S.; Kusakabe, K.; Komiyama, S.; Ishitani, H.
J. Org. Chem. 1999, 64, 4220. (c) Kobayashi, S.; Kusakabe, K.; Ishitani, H.
Org. Lett. 2000, 2, 1225.
(10) For other examples of zirconium-based asymmetric catalysts: (a)
Nugent, W. A. J. Am. Chem. Soc. 1992, 114, 2768. (b) Bedeschi, P.; Casolari,
S.; Costa, A. L.; Tagliavini, E.; Umani-Ronchi, A. Tetrahedron Lett. 1995,
36, 7897. (c) Yu, C.-M.; Yoon, S.-K.; Choi, H.-S.; Baek, K. Chem. Commun.
1997, 763. (d) Hoveyda, A. H.; Morken, J. P. Angew. Chem., Int. Ed. Engl.
1996, 35, 1262.
(11) Cox, P. J.; Wong, W.; Snieckus, V. Tetrahedron Lett. 1992, 33, 2253.
(12) The aldol adduct was obtained as a free alcohol form mainly, while
products were obtained as silylated forms in previous reports on catalytic
asymmetric aldol reactions of silyl enolates.
(13) Katsuki et al. reported a fluorinated alcohol accelerated catalytic
asymmetric Michael reactions: (a) Kitajima, H.; Katsuki, T. Synlett 1997,
568. See also: (b) Evans, D. A.; Johnson, D. S. Org. Lett. 1999, 1, 595. It
should be noted in our case that an alcohol not only accelerates the catalyst
regeneration step but also blocks an undesired achiral side reaction. See ref
4.
(14) While the diastereoselectivities were determined by 1H NMR analyses,
the enantiomeric excesses were determined using chiral HPLC analyses. The
absolute configuration assignments were made by comparison with the
authentic samples.2b
(9) (a) Ishitani, H.; Komiyama, S.; Kobayashi, S. Angew. Chem., Int. Ed.
1998, 37, 3186. (b) Ishitani, H.; Komiyama, S.; Hasegawa, Y.; Kobayashi, S.
J. Am. Chem. Soc. 2000, 122, 762.
10.1021/ja9943389 CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/20/2000

5404 J. Am. Chem. Soc., Vol. 122, No. 22, 2000
Table 2. Catalytic Asymmetric Aldol Recations Using 1ba
Communications to the Editor
Scheme 2. Assumed Catalytic Cycle
were obtained when the aldol reaction of benzaldehyde with 2
was carried out using the catalyst prepared from Zr(OPr)4 and
(R)-3,3′-IBINOL (72% yield, 84% ee, cf. Table 1, run 6). Catalyst
3 activates an aldehyde, and a silyl enolate attacks the aldehyde
to form key intermediate 4. When no alcohol is present, it is
thought that the catalyst regeneration step (from 4 to 3) would
be slow, and when the reaction is quenched with water, 4 forms
the monotrimethylsilylated BINOL derivative. On the other hand,
4 immediately reacts with an alcohol to regenerate the catalyst 3
along with formation of the aldol adduct and an alcohol
trimethylsilyl ether. The formation of the trimethylsilyl ether was
confirmed by GC-MS analysis.
a 1b (10 mol%) was used unless otherwise noted. b 5 mol%. c 2
mol%. d BuOH (50 mol%) was used. Toluene-benzotrifluoride (3:2)
was used as a solvent. e Room temperature. f EtOH (80 mol%). g PrOH
(80 mol%). h 2 equiv of 2c was used.
Scheme 1. Effect of Geometrical Isomers
A typical experimental procedure is described for the reaction
of benzaldehyde with 2a. To a suspension of (R)-3,3′-diiodo-
1,1′-bi-2-naphthol (0.048 mmol) in toluene (1.0 mL) was added
Zr(OtBu)4 (0.04 mmol) in toluene (0.50 mL) at room temperature.
The mixture was stirred for 0.5 h at the same temperature, and
n-propanol (0.20 mmol) in toluene (1.0 mL) was added. The
mixture was stirred for 0.5 h, and was then cooled to 0 °C.
Toluene solutions (1.5 mL) of benzaldehyde (0.4 mmol) and 2a
(0.48 mmol) were successively added. The mixture was stirred
for 18 h, and saturated NaHCO3 was added to quench the reaction.
The aqueous layer was extracted with dichloromethane, and the
crude adduct was treated with THF-1 N HCl (20:1) at 0 °C for
1 h to hydrolyze a small amount of the silylated adduct. After
usual workup, the crude product was chromatographed on silica
gel to give the desired adduct. The optical purity was determined
by HPLC analysis using a chiral column.20
In summary, we have developed anti-selective asymmetric aldol
reactions that proceeded at 0 °C to room temperature under mild
conditions with high yields and high diastereo- and enantiose-
lectivities using a novel chiral zirconium catalyst in the presence
of an alcohol additive. Use of the protic additive is key to facilitate
catalyst turnover and is a unique feature of this reaction compared
to other traditional catalytic asymmetric aldol reactions.
catalyzed the reaction efficiently. It is noteworthy that high yields
and selectivities were obtained even at 0 °C to room temperature
in the presence of free alcohols, while most previous catalytic
asymmetric aldol reactions required temperatures of -20 to -78
°C under strict anhydrous conditions.5 Moreover, anti-aldol
adducts were obtained in the reactions of silyl enolates of
propionate derivatives with several aldehydes in high selectivi-
ties.15,16 It was also confirmed that the selectivities were inde-
pendent of the geometry of the silyl enolates. Namely, anti-
selectivities were obtained using both (E)- and (Z)-silyl enolates
(Scheme 1).17 Although the precise transition state is not clear at
this stage, we assume the acyclic transition state and the rather
bulky zirconium catalyst may prefer the anti-selectivities.18
The assumed catalytic cycle of the present asymmetric aldol
reaction is shown in Scheme 2. We postulate the true catalyst as
(naphthalenediolato)-dialkoxyzirconium 3 which was suggested
Acknowledgment. This work was partially supported by a Grant-
in-Aid for Scientific Research from the Ministry of Education, Science,
Sports, and Culture, Japan.
1
by H and 13C NMR analysis.19 In addition, comparable results
(15) syn-Selective catalytic asymmetric aldol reactions were reported.
Furuta, K.; Maruyama, T. Yamamoto, H. Synlett 1991, 439.
Supporting Information Available: Experimental details. (PDF).
This material is available free of charge via the Internet at http://pubs.acs.org.
(16) Bulky aliphatic aldehydes such as pivalaldehyde and isobutyraldehyde
reacted with 2c sluggishly. While R-benzyloxyaldehyde reacted with 2c to
afford the corresponding aldol adduct in a good yield (∼75%), lower
selectivities were obtained (syn/anti ) ∼1/4, anti ) ∼50% ee). Investigations
to improve these lower yields and selectivities are in progress.
(17) Evans et al. reported chiral tin(II)-catalyzed aldol-type reactions of
pyruvate esters with silyl enolates.6e In these reactions, both (E)- and (Z)-
silyl enolates gave anti-adducts.
JA9943389
(19) 1H NMR (CD2Cl2) δ 6.75 (d, 2H, J ) 8.2 Hz), 6.89 (d, 2H, J ) 8.2
Hz), 7.02-7.10 (m, 4H), 7.21-7.25 (m, 4H), 7.72 (d, 2H, J ) 8.2 Hz), 7.80-
7.82 (m, 2H), 8.49 (s, 2H), 8.56 (s, 2H); 13C NMR (CD2Cl2) δ 92.8, 95.0,
116.8, 119.0, 122.5, 123.1, 125.5, 125.6, 125.7, 126.0, 126.3, 126.8, 130.3,
130.4, 134.1, 134.2, 138.1, 139.4, 154.4, 156.1.
(18) (a) Mukaiyama, T.; Kobayashi, S.; Murakami, M. Chem. Lett. 1985,
447. (b) Gennari, C.; Beretta, M. G.; Bernardi, A.; Moro, G.; Scolastico, C.;
Todeschini, R.; Tetrahedron 1986, 42, 893.
(20) Details are shown in Supporting Information.