Isoleucine-catalyzed direct asymmetric aldol addition of enolizable aldehydes

Article abstract of DOI:10.1021/ol300754n

Isoleucine-catalyzed direct enantioselective aldol additions between enolizable aldehydes are reported. Intermediate acetal structures dictate the configurative outcome and were supported by a hydrogen bond. This direct isoleucine-catalyzed aldol addition represents a welcome complement to both proline- and histidine-catalyzed aldol additions of enolizable aldehydes.

Full text of DOI:10.1021/ol300754n

ORGANIC
LETTERS
2012
Vol. 14, No. 8
2180–2183
Isoleucine-Catalyzed Direct Asymmetric
Aldol Addition of Enolizable Aldehydes
Kerstin Rohr and Rainer Mahrwald*
Institute of Chemistry, Humboldt-University, Brook-Taylor Sr. 2, 12489 Berlin, Germany
rainer.mahrwald@rz.hu-berlin.de
Received March 23, 2012
ABSTRACT
Isoleucine-catalyzed direct enantioselective aldol additions between enolizable aldehydes are reported. Intermediate acetal structures dictate the
configurative outcome and were supported by a hydrogen bond. This direct isoleucine-catalyzed aldol addition represents a welcome
complement to both proline- and histidine-catalyzed aldol additions of enolizable aldehydes.
A vast number of publications over the past decade have
demonstrated the successful application of amino acids as
organocatalysts in aldol reactions of ketones with enoliz-
able aldehydes. Particularly, proline-catalyzed direct aldol
additions of enolizable aldehydes and ketones have been
investigated extensively.1 Targeted investigations on cata-
lytic activities of other amino acids are rare.2 In contrast,
the search for general, efficient methods of direct aldol
reactions between two different, enolizable aldehydes re-
mains an illusive challenge and intensively investigated
topic. Although amino acids have been utilized as organo-
catalysts, systematic studies on the catalytic deployment of
amino acids in direct aldol additions of enolizable
aldehydes do not exist.3 For cross-aldol additions be-
tween enolizable aldehydes with other organocatalysts,
see ref 4.
Recently, we demonstrated the suitability of histidine as
a catalyst in direct, asymmetric aldol additions between
enolizable aldehydes.5 During these ongoing studies we
systematically tested all proteinogenic amino acids in the
aldol addition of isobutyraldehyde 1 to ethyl glyoxylate 2.
The results of these investigations are summarized in Table 1.
Our results only include reactions, where aldol adduct 7b
was detected in a clear reaction in more than 50% yield.6
Table 1. L-Amino Acid-Catalyzed Aldol Additions
(1) For overviews in this field, see: (a) Guillena, G.; Najera, C.;
Ramon, D. J. Enantioselective Organocatalyzed Reactions; Mahrwald, R.,
Ed.; Springer: 2011; Vol. II, p 245. (b) Panday, S. K. Tetrahedron:
Asymmetry 2011, 22, 1817. (c) Pihko, P. M.; Majander, I. E. Top. Curr.
Chem. 2010, 291, 29. (d) Trost, B. M.; Brindle, C. S. Chem. Soc. Rev.
2010, 39, 1600. (e) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B.
Chem. Rev. 2007, 107, 5471. (f) Guillena, G.; Najera, C.; Ramon, D. J.
Tetrahedron: Asymmetry 2007, 18, 2249. (g) Tanaka, F.; Barbas, C. F.,
III. In Enantioselective Organocatalysis; Dalko, P., Ed.; WILEY-VCH:
€
Weinheim, 2007; pp 19ꢀ55. (h) Berkessel, A.; Groger, H. Asymmetric
Organocatalyis; WILEY-VCH: Weinheim, 2005. (i) Notz, W.; Tanaka, F.;
Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580. (j) List, B. Tetrahedron
2002, 58, 5573.
entry
amino acid
yield, %
ee, %
1
2
3
4
5
6
7
8
leucine
76
81
65
78
90
75
71
79
64
77
60
74
16
76
17
72
(2) (a) Jiang, Z.; Yang, H.; Han, X.; Luo, J.; Wong, M. W.; Lu, Y.
Org. Biomol. Chem. 2010, 8, 1368. (b) Deng, D.; Liu, P.; Ji, B.; Fu, W.; Li,
L. Catal. Lett. 2010, 137, 163. (c) Hayashi, Y.; Itoh, T.; Nagae, N.;
Ohkubo, M.; Ishikawa, H. Synlett 2008, 1565. (d) Deng, D.-S.; Cai, J.
Helv. Chim. Acta 2007, 90, 114. (e) Nagamine, T.; Inomata, K.; Endo,
Y.; Paquette, L. A. J. Org. Chem. 2007, 72, 123. (f) Amedjkouh, M.
Tetrahedron: Asymmetry 2007, 18, 390. (g) Cordova, A.; Zou, W.;
Dziedzic, P.; Ibrahem, I.; Reyes, E.; Xu, Y. Chem.;Eur. J. 2006, 12,
5383. (h) Cordova, A.; Zou, W.; Ibrahem, I.; Reyes, E.; Engqvist, M.;
Liao, W.-W. Chem. Commun. 2005, 3586.
isoleucine
alanine
valine
lysine
asparagine
arginine
phenylalanine
r
10.1021/ol300754n
Published on Web 04/10/2012
2012 American Chemical Society

In general, the best results with regard to both yields and
stereoselectivities were obtained with neutral, aliphatic amino
acids (entries 1, 2, 3, 4, and 8, Table 1). Also, there is a marked
stereochemical dependence on the amino acids deployed
(compare entries 1 and 2, Table 1). The highest enantioselec-
tivities were obtained using β-branched amino acids (with the
exception of phenylalanine and asparagine, entries 6 and 8,
Table 1). Consequently, we selected isoleucine to test this
amino acid in cross-aldol additions of isobutyraldehyde with
enolizable and nonenolizable aldehydes.
The results of this investigation are depicted in Table 2.
Differences to proline catalysis and similarities and differ-
ences to histidine catalysis were noticed. First of all, aldol
adducts 7aꢀf are not accessible by proline catalysis for
chemoselectivity reasons.7 Like histidine catalysis, a high
chemoselectivity was observed. Isoleucine strictly differ-
entiates between electron-rich and electron-deficient alde-
hydes. Isobutyraldehyde 1, an electron-rich aldehyde,
reacts exclusively as an enamine component whereas
electron-deficient aldehydes 3, 4, 5, and 6 act as carbonyl
components in isoleucine-catalyzed aldol additions.
In contrast to L-proline and L-histidine catalysis, oppo-
site configured aldol adducts 7bꢀf were detected with
L-isoleucine. The aldol adducts 7bꢀd were also isolated
with good enantioselectivities. Complete enantioselectivity
was observed when using with oxygen-containing alde-
hydes 5 and 6. An exception was the self-aldol addition of
isobutyraldehyde 1. No enantioselectivity was observed;
aldol adduct 7a was isolated in racemic form. Moreover,
substantial amounts of the corresponding aminoacetal 8a
were detected (65%, Table 2). This compound was isolated
in enantiopure form.8
Aminoacetals were also encountered as side products
when benzyloxyacetaldehyde 6 was employed (entry 6,
Table 2). In addition to aldol adduct 7f (ee >98%)
enantiopure isobutyracetal 8f was isolated with 21% yield.
These results prompted us to look more closely at the
stereochemical events of this reaction. To this end, iso-
butyraldehyde 1 was reacted with isovaleraldehyde 9 in the
presence of L-isoleucine. A mixture of aldol adduct 7g and
corresponding acetals 8g and 8h was detected. The aldol
adduct 7g was obtained in racemic form (19% yield). The
aminoacetals 8g and 8h differ in the aldehyde component,
as can be seen in Scheme 1.
After straightforward separation of the acetals and acidic
treatment, the aldol adduct 7g was isolated in enantiopure
form (46% yield). Isoleucine strictly differentiates between
isobutyraldehyde 1 (R-branched aldehyde) as an enamine
component and isovaleraldehyde 9 as a carbonyl compo-
nent. Self-aldol adducts or reversed aldol adducts (in this
case isovaleraldehyde 9 acts as the enol component) were
not observed under these reaction conditions. In addition,
formation of the corresponding aminoacetals 8aꢀf of iso-
lated aldol adducts 7aꢀf was not accomplished under the
described reaction conditions. These results indicate two
reaction modes, which may operate with different rates
under these conditions. One mode proceeds without stereo-
control. The other one, the stereocontrolled mode, runs
through acetalization, which yields indeed enantiopure
aldol adducts. These considerations are supported by the
experiments depicted in Scheme 1.
Scheme 1. Isoleucine-Catalyzed Aldol Addition of Isobutyral-
dehyde and Isovaleraldehydea
Table 2. Isoleucine-Catalyzed Cross Aldol Addition between
Enolizable Aldehydes
7aꢀf
yield, %
(ee, %)
8aꢀf
entry
compound
7a: R = iPr
yield, %
1
2
3
4
5
6
23a (0)
65b
ꢀ
7b: R = EtO2C
81 (77)
62 (85)
76 (63)
83 (>98)
45 (>98)
a Reaction conditions: 50 mol % L-isoleucine, DMSO, rt, 10 h.
7c: R = ClCH2
ꢀ
7d: R = 4-NO2-C6H4
7e: R = (MeO)2CH
7f: R = BnOCH2
ꢀ
ꢀ
21b
(5) Markert, M.; Scheffler, U.; Mahrwald, R. J. Am. Chem. Soc. 2009,
131, 16642.
a Yield related to isobutyraldehyde. b Yield related to isoleucine.
(6) Same results were obtained when used with 25 mol% isoleucine. In
these reactiones longer reaction times are required (up to 6ꢀ8 days at rt).
(7) With the exceptions of cross-aldol additions of isobutyraldehyde
1 as the ene component and 4-nitrobenzaldehyde 4 as the carbonyl
component: (a) Mase, N.; Tanaka, F.; Barbas, C. F., III. Angew. Chem.,
Int. Ed. 2004, 43, 2420. (b) Wang, W.; Li, H.; Wang, J. Tetrahedron Lett.
2005, 46, 5077. (c) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe,
K.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 734.
(8) Thus, for the first time by cleavage of acetal 8a an access to
optically pure aldehyde 7a is given. See Supporting Information.
(3) For an overview of organocatalyzed cross-aldol additions of
enolizable aldehydes, see: Scheffler, U.; Mahrwald, R. Synlett 2011, 1660.
(4) (a) Chiral sulfonamides: Kano, T.; Sugimoto, H.; Maruoka, K.
J. Am. Chem. Soc. 2011, 133, 18130. (b) Diarylprolinols: Hayashi, Y.;
Itoh, T.; Aratake, S.; Ishikawa, H. Angew. Chem., Int. Ed. 2008, 47, 2082.
(c) Diarylprolinos: Hayashi, Y.; Yasui, Y.; Kawamura, T.; Kojima, M.;
Ishikawa, H. Angew. Chem., Int. Ed. 2011, 50, 2804.
Org. Lett., Vol. 14, No. 8, 2012
2181

In order to gain a deeper insight into the stereochemical
course of this reaction, oxygen-containing chiral aldehydes
10-14 were reacted with isobutyraldehyde 1. Aldol adducts
7hꢀn were isolated with high degrees of diastereoselectiv-
ity, in some cases even in diastereopure form. The corre-
sponding aminoacetals were not detected in these
transformations. Racemization of starting aldehydes
10ꢀ14 was not detected. Matched/mismatched cases were
not observed by isoleucine catalysis.
with oxygen-containing aldehydes. Thus, isoleucine deter-
mines the chirality of the new stereogenic center, without
being influenced by the chirality of oxygen-containing
aldehydes 10ꢀ14.
In reactions of protected R- or S-configured lactal-
dehyde 12 and 13, similar values of diastereoselectiv-
ities and yields were detected (compare aldol adduct 7k
and 7l, Scheme 2). Also, when D- or L-isoleucine were
used, syn- and anti-configured aldol adducts 7m and 7n
were isolated with the same high degrees of diastereo-
selectivity (Scheme 2). These results contrast with those
obtained through histidine catalysis. TBS-protected
lactaldehyde 14 does not react at all in histidine
catalysis.
Figure 1. Proposed stereochemical models.
To emphasize these considerations, comparable re-
sults for the histidine and isoleucine catalysis are de-
picted in Scheme 3. Anti-configured aldol adducts 7h
and 7k were obtained via isoleucine catalysis, whereas
the corresponding syn-configured products were acces-
sible by histidine catalysis. In contrast to that, identical
syn-aldol adducts 7i were obtained in both the histi-
dine- and isoleucine-catalyzed aldol additions of
isobutyraldehyde.
Scheme 2. Isoleucine-Catalyzed Cross-Aldol Addition with
Chiral Oxygen-Containing Aldehydes
Scheme 3. Comparison between Histidine and Isoleucine Cat-
alysisa
a R0 = R00 = CMe2. bD-isoleucine was used.
Based on these results the following considerations can
be made. The configuration of amino acid deployed clearly
dictates installation of the absolute configuration of the
newly created stereogenic center during the aldol step. The
reaction proceeds via an enamine mechanism and the direc-
tion of the incoming aldehyde is determined by hydrogen
bonds. The enamine is formed by the primary amine of the
amino acid permitting the deployment of R-branched alde-
hydes. Structure A is favored over B (steric interactions of
the incoming aldehyde with sec-butyl group of isoleucine;
Figure 1). In addition, formation of preferred conforma-
tions by further hydrogen bonds as known from histidine
catalysis9 is not observed in isoleucine catalysis when used
a R0 = R00 = CMe2.
With the advent of isoleucine a further amino acid is
now on hand to catalyze the direct asymmetric aldol addi-
tion of two potentially enolizable aldehydes of different
electronic character. These new transformations are
characterized by operationally simple and very mild
conditions as well as high stereoselectivities and yields.
The direct isoleucine-catalyzed aldol addition repre-
sents a welcome alternative to both proline and histi-
dine catalysis of direct aldol additions of enolizable
(9) (a) Scheffler, U.; Mahrwald, R. J. Org. Chem. 2012, 77, 2310. (b)
Lam, Y.-h.; Houk, K. N.; Scheffler, U., Mahrwald, R. J. Am. Chem. Soc.
2012, 134, 6286.
2182
Org. Lett., Vol. 14, No. 8, 2012

aldehydes. Further investigations and extensions of
these findings are underway.
Supporting Information Available. Experimental proce-
dures, details on method development, and product char-
acterization including spectroscopic data can be found in
the Supporting Information. This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. The authors thank Deutsche Fors-
chungsgemeinschaft, Bayer Pharma AG, Chemtura Orga-
nometallics GmbH Bergkamen, Bayer Services GmbH,
BASF AG, and Sasol GmbH for financial support.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 8, 2012
2183