Direct enantioselective aldol-tishchenko reaction catalyzed by chiral lithium diphenylbinaphtholate

Article abstract of DOI:10.1021/ol103156h

Chiral lithium diphenylbinaphtholate is an effective catalyst for the enantioselective aldol-Tishchenko reaction, affording 1,3-diol derivatives with three contiguous chiral centers and high stereoselectivities. Successive aldol-aldol-Tishchenko reactions

Full text of DOI:10.1021/ol103156h

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1579–1581
Direct Enantioselective
Aldol-Tishchenko Reaction Catalyzed by
Chiral Lithium Diphenylbinaphtholate
Tomonori Ichibakase and Makoto Nakajima*
Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi,
Kumamoto 862-0973, Japan
nakajima@gpo.kummaoto-u.ac.jp
Received December 28, 2010
ABSTRACT
Chiral lithium diphenylbinaphtholate is an effective catalyst for the enantioselective aldol-Tishchenko reaction, affording 1,3-diol derivatives with
three contiguous chiral centers and high stereoselectivities. Successive aldol-aldol-Tishchenko reactions gave a triol derivative with five
consecutive chiral centers. The present reaction was applicable to highly enantioselective Evans-Tishchenko reduction.
The direct enantioselective aldol reaction is a powerful tool
in organic synthesis because it constructs C-C bonds from
Scheme 1. Aldol-Tishchenko Reaction
two carbonyl compounds without the need to prepare silyl
enol ethers.1,2 Recently, a direct aldol reaction followed by
acetalization and a hydride shift, which is called the direct
aldol-Tishchenko reaction (Scheme 1),3,4 has attracted
much attention because it creates three contiguous asym-
metric centers, affording monoacyl-protected 1,3-diols.5
An early attempt at the enantioselective aldol-
€
Tishchenko reaction was reported by Maeorg, who observed
the first enantioselectivities in the self-condensation
of 2-methylpropanal using the monolithium salt of
binaphthol.6 However, Morken, who obtained optically
active monoacyl-protected 1,3-diol from two aldehydes
using chiral yttrium complex as a catalyst, reported the
successful examples of an enantioselective aldol-
Tishchenko reaction in 2001.7 Later, Shibasaki,8
(1) (a) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M.
Angew. Chem., Int. Ed. Engl. 1997, 36, 1871–1973. (b) Trost, B. M.; Ito,
H. J. Am. Chem. Soc. 2000, 122, 12003–12004. (c) List, B.; Lerner, R. A.;
Barbas, C. F. J. Am. Chem. Soc. 2000, 122, 2395–2396.
(2) Reviews on the enantioselective direct aldol reaction: (a) Alcaide,
B.; Almendros, P. Eur. J. Org. Chem. 2002, 1595–1601. (b) Saito, S.;
Yamamoto, H. Acc. Chem. Res. 2004, 37, 570–579. (c) Guillena, G.;
Najera, C.; Ramon, D. J. Tetrahedron: Asymmetry 2007, 18, 2249–2293.
(e) Trost, B. M.; Brindle, C. S. Chem. Soc. Rev. 2010, 39, 1600–1632.
(3) Herein an “aldol-Tishchenko reaction” refers to an aldol reaction
followed by acetalization and a hydride shift, while an “Evans-Tishchenko
reduction” indicates the formation of β-acyloxy alcohol from β-hydroxy
ketone with aldehyde.
(4) Reviews on the enantioselective direct aldol-Tishchenko reac-
tion: (a) Mahrwald, R. Curr. Org. Chem. 2003, 7, 1713–1723. (b)
Mlynarski, J. Eur. J. Org. Chem. 2006, 4779–4786.
ꢀ
ꢀ
(6) An aldol-Tishchenko adduct was obtained in 21% yield with
€
33% ee: Loog, O.; Maeorg, U. Tetrahedron: Asymmetry 1999, 10, 2411–
2415.
(7) Mascarenhas, C. M.; Miller, S. P.; White, P. S.; Morken, J. P.
Angew. Chem., Int. Ed. 2001, 40, 601–603.
(8) (a) Gnanadesikan, V.; Horiuchi, Y.; Ohshima, T.; Shibasaki, M.
J. Am. Chem. Soc. 2004, 126, 7782–7783. (b) Horiuchi, Y.; Gnanadesikan,
V.; Ohshima, T.; Masu, H.; Katagiri, K.; Sei, Y.; Yamaguchi, K.; Shibasaki,
M. Chem.;Eur. J. 2005, 11, 5195–5204.
(5) Reviews on the stereoselective synthesis of 1,3-diols: Bode, S. E.;
€
Wolberg, M.; Muller, M. Synthesis 2006, 557–588.
r
10.1021/ol103156h
2011 American Chemical Society
Published on Web 02/28/2011

Mlynarski,9 and Mahrwald10 independently reported
enantioselective aldol-Tishchenko reactions of ketones
with aldehydes using lanthanum, ytterbium or titanium
complexes, enabling three or more contiguous chiral
centers with high selectivities to be created. Herein we
report a highly enantioselective aldol-Tishchenko reac-
tion with wide range of substrates using a simple lithium
base, chiral lithium diphenylbinaphtholate.11
The aldol-Tishchenko reaction of 2a and 3a at 0 °C
and subsequent debenzoylation gave the 1,3-diol as a
single product 6aa (1,2-anti-1,3-anti) with high enantios-
electivity (Table 1, entry 1). Transition-state model A
Table 1. Aldol-Tishchenko Reaction Catalyzed by 1b
We initially investigated the aldol-Tishchenko reac-
tion of 3-pentanone (2a) and benzaldehyde (3a) (2 equiv)
in the presence of lithium binaphtholate12 (1a) (10 mol %)
prepared from binaphthol and butyllithium (Scheme 2).
entry ketone
R3 (aldehyde)
product yield,a % ee,b %
Scheme 2. Aldol-Tishchenko Reaction Catalyzed by Lithium
Binaphtholate
1
2
3
4
5
6
7
8
9c
2a
2a
2a
2a
2a
2b
2c
2d
2e
Ph (3a)
6aa
6ab
6ac
6ad
6ae
6ba
6ca
7da
7ea
81
81
87
80
61
71
80
91
88
93
95
95
88
94
93
87
90
85
4-MeC6H4 (3b)
4-MeOC6H4 (3c)
4-BrC6H4 (3d)
PhCHdCH (3e)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
a Isolated yield. b Determined by HPLC. c -23 °C.
The reaction proceeded to give the product as a mixture of
1-O-ester 4aa and 3-O-ester 5aa, but the chemical yields
and selectivities were unsatisfactory (13% yield, 24% ee
for 4aa and 20% yield, 24% ee for 5aa). After screening
binaphthol derivatives, we found that the dilithium salt of
3,30-diphenylbinaphthol (1b) gave monobenzoyl diols as
a mixture of 4aa (44%) and 5aa (23%) with enantioselec-
tivities of 85% ee.13 Isolated 4aa easily isomerized into a
mixture of 4aa and 5aa without losing enantioselectivi-
ties, suggesting that 5aa was produced by the acyl migra-
tion of the original aldol-Tishchenko product 4aa.14
proposed by early pioneers can explain the formation of
the 1,2-anti-1,3-anti isomer.7-10,15 Although slight de-
creased selectivity was observed in the reaction of bro-
mobenzaldehyde (3d) (entry 4), tolualdehyde (3b), and
anisaldehyde (3c) gave similar selectivities of 95% ee were
obtained in the reaction with 2a (entries 2 and 3). The
reaction of cinnamaldehyde 3e gave a slightly lower
chemical yield but with high selectivity (entry 5).
High enantioselectivities were also obtained using
other ketones as substrates. 4-Heptanone 2b gave a
similar result with 2a (entry 6). Cyclic ketones, cyclohex-
anone (2d), and cyclohexenone (2e) (entries 8 and 9) gave
diols of 1,2-syn-1,3-anti isomers 7da, 7ea in high enantios-
electivities as a single product, probably via tricyclic
transition state B proposed by Fang (Figure 1).15f It is
noteworthy that this is the highest level of enantioselec-
tivity for the aldol-Tishchenko reaction using simple
aliphatic ketones.
(9) (a) Mlynarski, J.; Mitura, M. Tetrahedron Lett. 2004, 45, 7549–
7552. (b) Mlynarski, J.; Jankowska, J.; Rakiel, B. Chem. Commun. 2005,
4854–4856. (c) Mlynarski, J.; Jankowska, J.; Rakiel, B. Tetrahedron:
Asymmetry 2005, 16, 1521–1526. (d) Mlynarski, J.; Rakiel., B.; Stodulski,
M.; Suszczynska, A.; Frelek, J. Chem.;Eur. J. 2006, 12, 8158–8167.
(10) (a) Rohr, K.; Herre, R.; Mahrwald, R. Org. Lett. 2005, 7, 4499–
4501. (b) Rohr, K.; Herre, R.; Mahrwald, R. J. Org. Chem. 2009, 74,
3744–3749.
(11) (a) Nakajima, M.; Orito, Y.; Ishizuka, T.; Hashimoto, S. Org.
Lett. 2004, 6, 3763–3765. (b) Orito, Y.; Hashimoto, S.; Ishizuka, T.;
Nakajima, M. Tetrahedron 2006, 62, 390–400. (c) Ichibakase, T.; Orito,
Y.; Nakajima, M. Tetrahedron Lett. 2008, 49, 4427–4429. (d) Tanaka,
K.; Ueda, T.; Ichibakase, T.; Nakajima, M. Tetrahedron Lett. 2010, 51,
2168–2169.
In the case of cyclopentanone (2f), which is a highly
reactive aldol donor, the byproduct derived from the
(12) Recent examples of using lithium binaphtholate as a catalyst:(a)
Schiffers, R.; Kagan, H. B. Synlett 1997, 1175–1178. (b) Holmes, I. P.;
Kagan, H. B. Tetrahedron Lett. 2000, 41, 7453–7456. (c) Hatano, M.;
Ikeno, T.; Miyamoto, T.; Ishihara, K. J. Am. Chem. Soc. 2005, 127,
10776–10777. (d) Hatano, M.; Ikeno, T.; Matsumura, T.; Torii, S.;
Ishihara, K. Adv. Synth. Catal. 2008, 350, 1776–1780. (e) Hatano, M.;
Horibe, T.; Ishihara, K. J. Am. Chem. Soc. 2010, 132, 56–57.
(13) Selectivities using catalysts derived from other 3,30-disubsituted
binaphthols: dimethyl; 28% ee, dichloro 58% ee.
(15) Mechanistic studies of the aldol-Tishchenko reaction: (a)
Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112, 6447–
6449. (b) Burkhardt, E. R.; Bergman, R. G.; Heathcock, C. H. Organo-
metallics 1990, 9, 30–44. (c) Mahrwald, R.; Costisella, B. Synthesis 1996,
1087–1089. (d) Bodnar, P. M.; Shaw, J. T.; Woerpel, K. A. J. Org. Chem.
1997, 62, 5674–5675. (e) Abu-Hasanayn, F.; Streitwieser, A. J. Org.
Chem. 1998, 63, 2954–2960. (f) Lu, L.; Chang, H.-Y.; Fang, J.-M. J. Org.
Chem. 1999, 64, 843–853. (g) Mascarenhas, C. M.; Duffey, M. O.; Liu,
S.-Y.; Morken, J. P. Org. Lett. 1999, 1, 1427–1429. (h) Markert, M.;
Mahrwald, R. Synthesis 2004, 1429–1433.
(14) Acyl migration of the products is often observed in the aldol-
Tishchenko reaction; see ref 15.
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Org. Lett., Vol. 13, No. 7, 2011

Scheme 4. Plausible Reaction Pathway
Figure 1. Plausible transition-state models.
double aldol reaction was significant even using a stoi-
chiometric amount of benzaldehyde (3a) (Scheme 3).
Hence, we employed 3.5 equiv of benzaldehyde (3a) as
an aldol acceptor to afford inseparable two diastereo-
mers, which were converted to acetonides for the separa-
tion of the isomers and the following deprotection
afforded triol 9 with five consecutive chiral centers10 with
extremely high enantioselectivity. The relative configura-
tion of 9 was determined by X-ray crystallographic
analysis.
expanded to the Evans-Tishchenko reduction. In the
presence of catalyst 1b, β-hydroxy ketone 11 reacted with
benzaldehyde (3a) to afford acyloxy alcohol 12 in high
chemical and optical yields (Scheme 5).
Scheme 5. Enantioselective Evans-Tishchenko Reduction
Scheme 3. Construction of Five Contiguous Chiral Centers
In conclusion, we have demonstrated that chiral
lithium diphenylbinaphtholate is an effective catalyst
for the highly enantioselective aldol-Tishchenko reac-
tion. The catalyst is easily prepared from common re-
agents and does not contain rare metals. In the case of
cyclopentanone, a single manipulation controlled five
successive chiral centers. The present reaction was applic-
able to a highly enantioselective Evans-Tishchenko re-
duction. Studies on the mechanism as well as the design of
chiral catalysts to further enhance enantioselectivity are
currently in progress.
According to the early pioneers’ reports,7-10,15 the
enantioselectivity in the aldol-Tishchenko reaction is
controlled by the stability of the cyclic transition state
of the hydride shift step because the aldolization process
is reversible. To confirm this mechanism, we added
benzaldehyde (3a) to the mixture of aldol adducts pre-
pared from cyclohexanone (2d) and benzaldehyde (3a)
(10 syn/anti = 1/2, racemic) in the presence of catalyst 1b
(Scheme 4). As expected, 1,3-diol 7da with the same
stereochemistry as entry 8 was produced as a single
diastereomer in high yield (1,2-syn-1,3-anti 86% ee vs
90% ee in entry 8). These results suggest the cyclic
transition state of hydride shift step B, which is more
stable than the other transition state B0, controls the
stereochemistry.
Supporting Information Available. Experimental pro-
cedures and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The reaction of β-hydroxy ketone and aldehyde (the so-
called Evans-Tishchenko reduction), which produces β-
acyloxy alcohol, is often used as a chemical tool in natural
product syntheses due to its high diastereoselectivities.16
However, the enantioselective version of this reaction
is still being developed.17 Our reaction could easily be
(16) (a) Aird, J. I.; Hulme, A. N.; White, J. W. Org. Lett. 2007, 9, 631–
634. (b) Smith, A. B.; Lee, D. J. Am. Chem. Soc. 2007, 129, 10957–10962.
(c) Youngsaye, W.; Lowe, J. T.; Pohlki, F.; Ralifo, P.; Panek, J. S.
Angew. Chem., Int. Ed. 2007, 46, 9211–9214.
(17) (a) Schneider, C.; Hansch, M. Synlett 2003, 837–840. (b) Schneider,
C.; Hansch, M.; Sreekumar, P. Tetrahedron: Asymmetry 2006, 17, 2738–
2742.
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