Enantioselective direct aldol-tishchenko reaction: Access to chiral stereopentads

Article abstract of DOI:10.1021/ol0517675

(Chemical Equation Presented) The aldol-Tishchenko reaction of aromatic aldehydes in the presence of titanium(IV) tertbutoxide and amino alcohols is described. When used with cinchona alkaloids, stereopentads were isolated for the first time with a high d

Full text of DOI:10.1021/ol0517675

ORGANIC
LETTERS
2005
Vol. 7, No. 20
4499-4501
Enantioselective Direct Aldol-Tishchenko
Reaction: Access to Chiral
Stereopentads
Kerstin Rohr, Robert Herre, and Rainer Mahrwald*
Humboldt-UniVersita¨t zu Berlin, Chemisches Institut, Brook-Taylor Str. 2,
12489 Berlin, Germany
rainer.mahrwald@rz.hu-berlin.de
Received July 26, 2005 (Revised Manuscript Received August 29, 2005)
ABSTRACT
The aldol-Tishchenko reaction of aromatic aldehydes in the presence of titanium(IV) tertbutoxide and amino alcohols is described. When used
with cinchona alkaloids, stereopentads were isolated for the first time with a high degree of diastereo- and enantioselectivity.
Stereochemical control is the most important aspect in the
synthesis of organic molecules that contain one or more
stereogenic elements. The introduction of new stereogenic
centers into a target molecule is most commonly achieved
by addition to one face of a double bond. Most synthetic
processes involve stereoselective additions of nucleophiles
to aldehydes and ketones. Seen from this point of view, the
aldol-Tishchenko reaction is a very valuable method with
respect to chiral economy.1
For classical C-C bond formation there are a number of
known limitations. With reactions of carbanions with car-
bonyl functionalities (aldehydes or ketones), the alkylation
of a carbonyl compound can produce only one new stereo-
genic carbon center. An aldol addition can create two new
stereogenic carbon atoms depending on the choice of enolate
substituent and the aldehyde or ketone. By means of the
Tishchenko reaction, three adjacent stereogenic centers can
be obtained. These so-called stereotriads are produced in a
single reaction step with an exceptional high degree of
diastereoselectivity.
addition of isobutyraldehyde in the presence of chiral BINOL
complexes.2 Morken et al. described for the first time a
successful asymmetric aldol-Tishchenko reaction, catalyzed
by an yttrium-salen complex.3 Addition results were obtained
by cross aldol-Tishchenko reactions of isobutyraldehyde with
aromatic aldehydes. Mlynarski et al. described aldol-Tish-
chenko reactions of diethyl ketone with aromatic aldehydes
in the presence of chiral lanthanide complexes with moderate
enantioselectivities.4 Schneider et al. used chiral zirconium
alkoxides in aldol-Tishchenko reactions5 and obtained prod-
ucts with moderate enantioselectivities. Recently Shibasaki
et al. demonstrated the usefulness of La(OTf)3-BINOL
catalysts in enantioselective aldol-Tishchenko reactions of
propiophenone and aromatic aldehydes.6 The Tishchenko
stereotriads were isolated by the authors in a high degree of
enantioselectivity.
Herein we describe our preliminary results of the enan-
tioselective execution of the aldol-Tishchenko reaction.
Inspired by the ligand exchange mediated aldol addition,7
we were able to determine conditions for an aldol-Tishchenko
Examples of the enantioselective performance of the aldol-
Tishchenko reaction are rare. There are only a limited number
of publications describing the enantioselective execution of
this important C-C bond formation process.
Early attempts of an asymmetric aldol-Tishchenko reaction
were published by Loog and Ma¨eorg, who observed the self-
(2) Loog, O.; Ma¨eorg, U. Tetrahedron: Asymmetry 1999, 10, 2411-
2415.
(3) Mascarenhas, C. M.; Miller, S. P.; White, P. S.; Morken, J. P. Angew.
Chem., Int. Ed. 2001, 40, 601-603.
(4) Mlynarski, J.; Jankowska, J.; Rakiel, B. Tetrahedron: Asymmetry
2005, 16, 1521-1526.
(5) Schneider, C.; Hansch, M. Synlett 2003, 837-841.
(6) Gnanadesikan, V.; Horiuchi, Y.; Oshima, T.; Shibasaki, M. J. Am.
Chem. Soc. 2004, 126, 7782-7783.
(1) Mahrwald, R. Curr. Org. Chem. 2003, 7, 1713-1723.
10.1021/ol0517675 CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/07/2005

reaction in the presence of titanium(IV) alkoxides and amino
alcohols. Initial studies, using diethyl ketone and benzalde-
hyde in the presence of titanium(IV) isopropoxide and 1,2-
amino alcohols, revealed that ligand exchange of titanium(IV)
alkoxides and amino alcohols also promote the aldol-
Tishchenko reaction. The reactions were carried out at room
temperature. The Tishchenko products 4 were isolated with
a high degree of diastereoselectivity. In addition, compounds
were detected that were produced both by an aldol-Tish-
chenko reaction and by a second aldol addition. 1,3,5-Triol
monoesters 3, so-called stereopentads, were obtained with a
high degree of stereoselectivity (Scheme 1). Different
Table 1. Aldol-Tishchenko Reaction in the Presence of
Ti(OtBu)4 and Cinchona Alkaloids
Scheme 1. Aldol-Tishchenko Reaction in the Presence of
Ti(OtBu)4 and Amino Alcohols.
entry
Ar
compd conditionsa yield (%)b ee (%)c
1
2
3
4
5
6
7
8
Ph
Ph
3a
ent3a method B
3b method A
ent3b method B
3c method A
ent3c method B
3d method A
ent3d method B
method A
52
59
61
65
72
61
36
32
>98
97
96
>98
98
>98
97
4-MeOC6H4
4-MeOC6H4
4-MeC6H4
4-MeC6H4
4-NO2C6H4
4-NO2C6H4
>98
9
10
2.4-(MeO)2C6H3 3e
2.4-Me2C6H3 3f
a Method A: 5 equiv of aldehyde, 1 equiv of aldol adduct, 1 equiv of
cinchonine, 1 equiv of Ti(OtBu)4, rt. Method B: 5 equiv of aldehyde, 1
equiv of aldol adduct, 1 equiv of cinchonidine, 1 equiv of Ti(OtBu)4, rt.
b Isolated yields. c The enantiomeric excess was determined by 1H NMR
analysis of the corresponding Mosher esters.8
titanium(IV) alkoxides were tested in these reactions. Highest
yields were obtained by using titanium(IV) tertbutoxide.
Additional byproducts derived from reduction and aldol
condensation were observed by application of titanium(IV)
alkoxides containing an R-hydrogen.
A variety of amino alcohols are useful for this transforma-
tion. Nevertheless, it was observed that only amino alcohols
containing a tertiary nitrogen atom are suitable for a clean
reaction with satisfactory yields. Further optimization studies
revealed that by the use of the corresponding aldol adducts
2a-d as starting compounds, instead of separated aldehydes
and diethyl ketone, resulted in higher yields and a cleaner
reaction. In addition, by employing cinchona alkaloids as
1,2-amino alcohols the stereopentads 3a-d were isolated
with an exceptional high degree of diastereo- and enanti-
oselectivity (Table 1).
A set of substituted aldehydes were tested in these
reactions in order to explore scope and limitation of the
aldehyde substrate. The use of aromatic aldehydes with
electron-withdrawing substituents decreases yields and ho-
mogeneity of this reaction (entries 7 and 8, Table 1). No
triol monoesters 3 were detected by applying disubstituted
aldehydes 1e and 1f in these reactions. Best results were
obtained by using aldehydes with electron-donating substit-
uents (entries 1-6, Table 1). Access to both enantiomers of
the stereopentads 3a-d and ent3a-d can be realized by the
optional use of cinchonine (Method A) or cinchonidine
(Method B) during these reactions (Table 1).8 Similar high
enantioselectivities were detected by using both methods. It
is very noteworthy that almost exclusively only one product
was formed, although 31 other stereoisomers of the 1,3,5-
triol monoester 3 are statistically possible. The 1,3-diol
monoesters 4 were found as minor byproducts during these
transformations without any enantioselectivity.
These surprising results encouraged us to more intensively
analyze the relationship between the stereoselectivities
obtained and the configuration of the starting aldol adducts
2a-d. For that reason we reacted defined mixtures of syn-
and anti-configurated aldol adducts 2a-d with an excess of
aldehydes in the presence of titanium(IV) tertbutoxide and
cinchona alkaloids. The same diastereo- and enantiomeric
ratios were obtained in the isolated stereopentads 3a-d,
independent of the diastereomeric ratio of the starting aldol
adducts 2a-d. These findings verify results we obtained in
previously works.9 They indicate a clean retro-aldol cleavage
(8) The absolute configuration of the stereopentads 3a-d and ent3a-d
were determined by 1H NMR studies using the Mosher ester technique:
Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991,
113, 4092-4096. For a comprehensive review, see: Seco, J. M.; Qinoa,
E.; Riguera, R. Chem. ReV. 2004, 104, 17-118. For more details see
Supporting Information.
(7) Mahrwald, R. Org. Lett 2000, 2, 4011-4012. Mahrwald, R.; Ziemer,
B. Tetrahedron Lett. 2002, 43, 4459-4461.
(9) Mahrwald, R.; Costisella, B. Synthesis 1996, 1087-1090.
4500
Org. Lett., Vol. 7, No. 20, 2005

and demonstrate that the control of stereoselectivity is
realized during the Tishchenko reaction.6,9 This seems to be
true for both diastereo- and enantioselectivity.
Stereopentads 3a-d were found with a “nonclassical”
Tishchenko configuration. An explanation for the exceptional
high stereoselectivities is given by the assumption of a
tricyclic transition state model as shown in Scheme 2. This
two publications appeared so far describing the direct
synthesis of racemic stereopentads.10,11 For the employment
of silylenolethers and ketones in Tishchenko reactions see
ref 12.
These experiments demonstrate that the ligand exchange
of titanium(IV) alkoxides and 1,2-amino alcohols mediate
the aldol-Tishchenko reaction. This simple and useful process
is applicable to the diastereo- and enantioselective formation
of 1,3,5-triol monoesters. Further studies to extend this
method to enolizable aldehydes are ongoing.
Scheme 2. Proposed Transition State.
Acknowledgment. The authors would like to thank the
Deutsche Forschungsgemeinschaft for its financial support.
Supporting Information Available: Experimental pro-
1
cedures and characterization of the products by 13C and H
NMR spectroscopy and mass spectroscopy. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0517675
(10) Bodnar, P. M.; Shaw, J. T.; Woerpel, K. A. J. Org. Chem. 1997,
62, 5674-5675. The authors isolated and characterized the rac-1,2-anti,
1,3-anti, 1,4-anti, 1,5-anti-configured 1,3,5-triol monobenzoates by X-ray
structure analysis.
(11) Markert, M.; Mahrwald R. Synthesis 2004, 1429-1433. The rac-
1,2-syn, 1,3-syn, 1,4-syn, 1,5-anti-configured 1,3,5-triol monoesters were
characterized by X- ray structure analysis.
(12) Delas, C.; Blacque, O.; Mo¨ıse, C. J. Chem. Soc., Perkin Trans. 1
2000, 2265-2270. Delas, C.; Mo¨ıse, C. Synthesis 2000, 251-254.
is the first report of an enantioselective approach to chiral
1,3,5-triol monoesters by an aldol-Tishchenko reaction. Only
Org. Lett., Vol. 7, No. 20, 2005
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