Direct asymmetric aldol-Tishchenko reaction of aliphatic ketones catalyzed by syn-aminoalcohol-Yb(III) complexes

Article abstract of DOI:10.1039/b509505k

The asymmetric direct aldol condensation of aldehydes with ethyl- and propylketones is catalyzed by syn-α-aminoalcohol-Yb(OTf)₃ complexes, yielding the anti-1,3-diol monoesters with high diastereocontrol and good enantioselectivity. Three adjac

Full text of DOI:10.1039/b509505k

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COMMUNICATION
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Direct asymmetric aldol-Tishchenko reaction of aliphatic ketones
catalyzed by syn-aminoalcohol–Yb(III) complexes{
Jacek Mlynarski,* Joanna Jankowska and Bartosz Rakiel
Received (in Cambridge, UK) 7th July 2005, Accepted 2nd August 2005
First published as an Advance Article on the web 30th August 2005
DOI: 10.1039/b509505k
The asymmetric direct aldol condensation of aldehydes with
ethyl- and propylketones is catalyzed by syn-a-aminoalcohol–
Yb(OTf)3 complexes, yielding the anti-1,3-diol monoesters with
high diastereocontrol and good enantioselectivity. Three
adjacent stereogenic centers are created in a simultaneous aldol
condensation and Evans–Tishchenko reduction in an acyclic
system.
The control of stereochemistry during aldol addition is a crucial
problem as this reaction is a fundamental method for the
construction of carbon–carbon bonds.1 In this regard, the metal-
catalyzed asymmetric direct aldol reaction of aldehydes with
unmodified ketones still remains a challenge for synthetic
chemists.2 Remarkable success in this area is a result of Trost’s3
and Shibasaki’s4 outstanding work on homo- and heterobimetallic
catalysts.5–7 To date however, the scope of possible substrates and
the selection of applicable catalytic systems still remains limited.2b,c
In general, the elaborated methodology offers a versatile access to
aldol-type products from methyl ketones,3a,5a,b while the develop-
ment of catalytic systems applicable to their methylene analogues8
is more challenging and restricted mainly to a-hydroxymethyl
ketones.3b,5c The bulkiness of methylene ketones was anticipated to
make it more difficult for the catalyst to abstract an a-hydrogen,8c
and additionally, a strong tendency towards retro-aldol reactions
was observed for such substrates.
In this regard, Shibasaki9 and ourselves10 have attempted the
direct catalytic asymmetric aldol-Tishchenko reaction as a useful
method for overcoming the problem of unreactivity of higher
ketones. In the one-step process, aldehydes were reacted with
methylene ketones to give 1,3-diol monoesters,11 which were
formed as a result of bond reorganization in a cyclic Evans-type12
intermediate 1 (Scheme 1).
Scheme 1 Postulated mechanism of the aldol-Tishchenko reaction.11
the state-of-the-art in this area provides condensation products in
good ee only for activated aromatic donors (typically, p-trifluoro-
methyl propiophenone, for which the Tishchenko product was
mixed with simple aldol in a 1 : 1 ratio).9 Our laboratory has
recently described the use of diol10 and aminoester14 ligands for the
condensation of aliphatic ketones. Our catalytic systems were
highly diastereoselective, but unsatisfactory levels of enantio-
selectivity forced us to carry on with research.
Here, we report the first efficient application of a chiral
aminoalcohol-based catalyst to the enantioselective aldol-
Tishchenko reactions between aldehydes and aliphatic ketones.
This process provides high product yields and good ee values,
leading to anti-1,3-diols without tedious stoichiometric preactiva-
tion of the ketones.
Since our initial studies had revealed that, in particular, Yb
complexes combined with diol/amine and aminoalcohols can
catalyze the aldol-Tishchenko reaction, we tested combinations of
ytterbium triflate with a representative family of ligands 4–13 (L)
(Fig. 1). All of the materials tested were commercial, except
for compound 5.15 Our experiments showed that ligands having
free amino functions, unreactive in the desired process, must be
excluded. Thus, unprotected amines—precursors of 5, 6 and
10—were efficiently methylated using formaldehyde and formic
acid.16
In contrast to the previously presented examples of
a
stereoselective Tishchenko reaction of two different aldehydes,13
three adjacent stereogenic centers are created by use of a ketone as
the substrate in the process, making this methodology very
effective in terms of chiral economy.
Despite the clear potential of the aldol-Tishchenko reaction of
unmodified ketones with aldehydes leading to protected 1,3-diols 2
and 3, its enantioselective variant presents an unexplored
problem that has only been preliminarily unravelled. In general,
Preliminary studies using benzaldehyde with 3-pentanone in the
presence of 20 mol% of the catalyst, which was prepared from
Yb(OTf)3 and (S)-3-dimethylamino-2-propane 4 in the 1 : 2 ratio,
revealed that the anticipated sequential reaction is achievable with
excellent diastereoselectivity (. 95 : 5) and low enantiocontrol
(Table 1, entry 1).{ Unfortunately, the observed catalytic efficiency
was unsatisfactory (34% yield). Similarly, our experiments with
other aliphatic alcohols, i.e. (2)-DAIB (5) and 1-amino-2-indanol
derivative 6, were disappointing.
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka
44/52, 01-224, Warsaw, Poland. E-mail: mlynar@icho.edu.pl;
Fax: +48 22 632 66 81
{ Electronic Supplementary Information (ESI) available: Representative
experimental procedures and full characterisation of all compounds as well
as their stereochemical assignment. See http://dx.doi.org/10.1039/b509505k
4854 | Chem. Commun., 2005, 4854–4856
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2-pyrrolidynyl substituted (1R,2S)-propanol 13 giving the best
result with 42% ee (Table 1, entry 10).
With the best catalyst in hand, we turned our attention to other
reaction aspects. Changing the reaction medium to a more
coordinating one resulted in further increasing the enantioselec-
tivity (Table 2). 1,2-dimethoxyethane (DME) proved to be the best
solvent, giving the product in 66% yield with 60% ee (Table 2,
entry 6). Decreasing the reaction temperature to 0 uC only slightly
increased the ee, albeit at the expense of the overall yield.
In an effort to study the influence of the metal–ligand ratio on
the enantioselectivity of the reaction, we tested many combinations
of Yb(OTf)3 with ligand 13 (Table 2). These experiments revealed
the best reaction enantioselectivity for (4 : 1) complex architecture.
Such ligands-reach complex(es) were previously recorded in the
literature.17
Next, we attempted to reduce the catalyst loading. Decreasing
the amount of Yb complex to 10 mol% resulted in a diminished
overall yield (33%), while the ee stayed at almost the same level
(Table 2, entry 13). We were glad to find, however, that 15 mol%
of the catalyst promoted the reaction with a comparable yield and
ee. We kept this loading in further experiments.
Fig. 1 Selected chiral ligands used in the initial studies.
In contrast, the condensation promoted by a catalyst containing
the Cinchona ligand with benzyl-type OH 7 was much more
effective (83% yield) but unselective (Table 1, entry 4). This
observation confirms our previous conclusion that a benzyl-type
hydrogen atom is necessary in the catalyst structure.14
The structural assignment of the obtained esters 14 was
corroborated by high-resolution NMR experiments, and is in full
agreement with previously published data.18 The assigned 1,2-anti-
1,3-anti stereochemistry of 14 was supported in both cases by the
NMR analysis of separately-derived diols as well as a sterically
rigid O-isopropylidene derivative.{19
Experiments to probe the scope of the aldehyde substrate are
summarized in Table 3. Reactions were performed at room
temperature, demonstrating the practical utility of the elaborated
catalytic system.
Next, a series of benzyl-type aminoalcohols were tested to find
an optimal ligand. Reactive a-aminoalcohol 8 was unselective,
presumably because of having the N-center removed from the
oxygen atom by three carbon atoms. Shorter analogues 10 and 11
showed some level of enantioselectivity, retaining a good level of
reactivity. Comparison of syn-11 and anti-12 N-methylephedrines
proved that the syn-orientation of substituents is necessary for
both reactivity and selectivity (Table 1, entry 8 vs. 9).
Structural variations in the amino function had significant
effects on the enantioselectivity of the reaction. In particular, more
bulky amino-protection enhanced the enantioselectivity, with the
Resulting mixtures of 1-O- and 3-O-esters could be easily
saponified to deliver appropriate anti-1,3-diols9,18a with huge
synthetic potential. For this detailed study however, we decided to
separate and characterize all ester-type products.
Substituted aromatic aldehydes are acceptable substrates, and
conspicuously the reaction selectivity depends on the electron
acceptor character of the substituents. For instance, p-chloroben-
zaldehyde was more reactive but a worse substrate (76% yield,
Table 1 Ligand studies: Reaction of 3-pentanone with benzaldehyde
promoted by various chiral ligands 4–13
Table 2 Solvent and catalyst studies: Reaction of 3-pentanone with
benzaldehyde promoted by ligand 13
Overall yield
14a + 14b (%)a
ee
Entry
Solvent
Yb(OTf )3 : 13
(%)b
Entry
L
Overall yield 14a + 14b (%)a
ee (%)b
20 mol% of the catalyst:
1
2
3
4
5
6
7
8
9
10
a
4
5
6
7
8
34c
20
16
83
90
23
70
69
n.d.
88
9
23d
7
rac.
rac.
rac.
8
10
—
42
1
2
3
4
5
6
7
8
THF
THF
1 : 1
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 3
1 : 4
1 : 4
1 : 5
1 : 10
0
—
42
—
52
35
60
55
62
76
61
50
88
trace
35
16
66
76
86
82
86
83
CH2Cl2
Dioxane
MeCN
DME
THF
9
10
11
12
13
THF
9
10
11
DME
THF
THF
b
Isolated yield. The ee values of esters and diols were determined
c
by HPLC (Chiralpak AD-H column). Major anti-aldol anti-
Tishchenko isomer (1,2-anti-1,3-anti) 14 formation was accompanied
by some traces (less then 3%) of 1,2-syn-1,3-anti co-products. The
use of ‘¡’ signs is only
enantiomers.
10 mol% of the catalyst:
12
13
a
THF
DME
1 : 4
1 : 4
60
33
55
67
d
b
a
convention to designate opposite
Isolated yield. The ee values of esters and diols were determined
by HPLC (Chiralpak AD-H column).
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ketones (diethyl and dipropyl ketones) to give aldol-Tishchenko
Table 3 Substrate studies: Condensation of ethyl and propyl ketones
with various aldehydes promoted by Yb(OTf)3 and (1R,2S)-13 (1 : 4,
15 mol%)
products with a dramatic increase in molecular complexity, created
in a single operation. 1,3-Diol monoesters were formed in good to
excellent yields with high anti-diastereocontrol and up to 85% ee.
The ligand studies presented herein should provide a useful
starting point for the development of more effective catalytic
asymmetric aldol-Tishchenko reactions. Experiments on the scope
and limitation of this reaction, as well as on further elucidation of
the reaction mechanism, are in progress in our laboratory.
Entry Aldehyde
1
Ketone
Yield (%)a
ee (%)b
3-O-ester 14a: 42
1-O-ester 14b: 39
75
2
3
4
3-O-ester 15a: 9
1-O-ester 15b: 49
86
80
55
65
Financial support by the Polish State Committee for Scientific
Research (KBN Grant 3 T09A 126 27) is gratefully acknowledged.
3-O-ester 16a: 25
1-O-ester 16b: 51
Notes and references
1 Modern Aldol Recations, ed. R. Mahrwald, Wiley-VCH, Weinheim,
2004.
3-O-ester 17a: 37
1-O-ester 17b: 39
2 (a) M. Shibasaki, in Modern Aldol Reactions, ed. R. Mahrwald, Wiley-
VCH, Weinheim, 2004, Vol. 11, ch. 6, pp. 197–227; (b) B. Alcaide and
P. Almendros, Eur. J. Org. Chem., 2002, 1595–1601; (c) C. Palomo,
M. Oiarbide and J. M. Garcia, Chem. Soc. Rev., 2004, 33, 65–75.
3 (a) B. M. Trost and H. Ito, J. Am. Chem. Soc., 2000, 122, 12003–12004;
(b) B. M. Trost, H. Ito and E. R. Silcoff, J. Am. Chem. Soc., 2001, 123,
3367–3368; (c) B. M. Trost, E. R. Silcoff and H. Ito, Org. Lett., 2001, 3,
2497–2500.
5
6
7
3-O-ester 18a: 23
1-O-ester 18b: 54
3-O-ester 19a: n.d. 75
1-O-ester 19b: 85
4 M. Shibasaki and N. Yoshikawa, Chem. Rev., 2002, 102, 2187–2209 and
references therein.
1-O-ester 20a: 40
3-O-ester 20b: 29
70
5 (a) Y. M. A. Yamada, N. Yoshikawa, H. Sasai and M. Shibasaki,
Angew. Chem., Int. Ed. Engl., 1997, 36, 1871–1873; (b) N. Yoshikawa,
Y. M. A. Yamada, J. Das, H. Sasai and M. Shibasaki, J. Am. Chem.
Soc., 1999, 121, 4168–4178; (c) N. Yoshikawa, N. Kumagai,
S. Matsunaga, G. Moll, T. Ohshima, T. Suzuki and M. Shibasaki,
J. Am. Chem. Soc., 2001, 123, 2466–2467.
a
b
Isolated yield. The ee values of esters and diols were determined
by HPLC (Chiralpak AD-H and AS-H columns).
6 M. A. Yamada and M. Shibasaki, Tetrahedron Lett., 1998, 39,
5561–5564.
7 T. Suzuki, N. Yamagiwa, Y. Matsuo, S. Sakamoto, K. Yamaguchi,
M. Shibasaki and R. Noyori, Tetrahedron Lett., 2001, 42, 4669–4671.
8 For the first example of a direct aldol reaction of ethyl ketones see: (a)
R. Mahrwald, Org. Lett., 2000, 2, 4011–4012; (b) R. Mahrwald and
B. Ziemer, Tetrahedron Lett., 2002, 43, 4459–4461; (c) N. Yoshikawa
and M. Shibasaki, Tetrahedron, 2001, 57, 2569–2579.
9 V. Gnanadesikan, Y. Horiuchi, T. Ohshima and M. Shibasaki, J. Am.
Chem. Soc., 2004, 126, 7782–7783.
10 J. Mlynarski and M. Mitura, Tetrahedron Lett., 2004, 45, 7549–7552.
11 For a review on aldol-Tishchenko reactions see: R. Mahrwald, Curr.
Org. Chem., 2003, 7, 1713–1723.
12 D. A. Evans and A. H. Hoveyda, J. Am. Chem. Soc., 1990, 112,
6447–6449.
13 For an enantioselective Tishchenko reaction of two different aldehydes
(one stereocenter, ee up to 74%) see: (a) C. M. Mascarenhas, S. P. Miller,
P. S. White and J. P. Morken, Angew. Chem., Int. Ed., 2001, 40,
601–603; (b) For an enantioselective aldol-Tishchenko-type reaction of
ketone aldols (two stereocenters, ee up to 57 %) see: C. Schneider and
M. Hansch, Synlett, 2003, 6, 837–840.
Scheme 2 Condensation of propiophenone with benzaldehyde.
55% ee) than p-anisaldehyde, which gave the condensation product
in 86% ee. p-Methylbenzaldehyde condensed smoothly, leading to
the desired product in 76% overall yield and 80% ee.
14 J. Mlynarski, J. Jankowska and B. Rakiel, Tetrahedron: Asymmetry,
2005, 16, 1521–1526.
Dipropyl ketone was reactive under the tested catalytic system
(77% yield, 65% ee), but its isopropyl counterpart was unreactive,
probably because of steric interaction of the substrate with the
active metal species in cyclic system 1.
15 R. A. Chittenden and G. H. Cooper, J. Chem. Soc. C, 1970, 49–54.
16 L. Bernardi, B. F. Bonini, M. Comes-Franchini, M. Fochi, G. Mazzanti,
A. Ricci and G. Varchi, Eur. J. Org. Chem., 2002, 2776–2784.
17 For two different aldehydes, a condensation catalyst composed of
Y5O(OiPr)13 and salen in 1 : 6.5 ratio was used in ref. 13(a). For
aromatic ketones and aldehydes, a condensation catalyst composed of
La(OTf)3, BINOL and BuLi in 1 : 3 : 5.6 ratio was applied in ref. 9.
18 (a) R. Mahrwald and B. Costisella, Synthesis, 1996, 1087–1089; (b)
P. M. Bodnar, J. T. Shaw and K. A. Woerpel, J. Org. Chem., 1997, 62,
5674–5675; (c) L. Lu, H.-Y. Chang and J.-M. Fang, J. Org. Chem.,
1999, 64, 843–853.
To assign the sense of the asymmetric induction we deprotected
ester 19 and compared its optical rotation, as well as comparing
the HPLC analysis of the obtained diol 21, with published data
(Scheme 2).9 The same experiments in the case of the p-chloro-
substituted diol (condensation of propiophenone and p-chloro-
benzaldehyde, Table 3, entry 7) confirmed the same (1S,2S,3S)
orientation of asymmetric carbon atoms.{
19 For a discussion on the determination of the stereochemistry of diols by
acetonide derivatives see: S. D. Rychnovsky, B. Rogers and G. Yang,
J. Org. Chem., 1993, 58, 3511–3515.
In conclusion, we established a new catalyst for the enantiose-
lective aldol-Tishchenko reaction between aldehydes and aliphatic
4856 | Chem. Commun., 2005, 4854–4856
This journal is ß The Royal Society of Chemistry 2005