Asymmetric histidine-catalyzed cross-aldol reactions of enolizable aldehydes: Access to defined configured quaternary stereogenic centers

Article abstract of DOI:10.1021/ja907054y

(Chemical Equation Presented) A histidine-catalyzed asymmetric direct cross-aldol reaction of enolizable aldehydes is described. In contrast to proline, histidine is able to clearly differentiate the reactivity of various aldehydes. In addition, this appr

Full text of DOI:10.1021/ja907054y

Published on Web 10/30/2009
Asymmetric Histidine-Catalyzed Cross-Aldol Reactions of Enolizable
Aldehydes: Access to Defined Configured Quaternary Stereogenic Centers
Morris Markert, Ulf Scheffler, and Rainer Mahrwald*
Institut fu¨r Chemie, Humboldt-UniVersita¨t zu Berlin, Brook-Taylor Str. 2, 12489 Berlin, Germany
Received August 26, 2009; E-mail: rainer.mahrwald@rz.hu-berlin.de
Scheme 1. Asymmetric L-Histidine-Catalyzed Aldol Addition of
Organocatalysis has emerged within the past decade as the third
pillar of asymmetric catalysis in addition to metal and enzyme
catalysis.1 Several long-standing problems of asymmetric aldol
addition have been solved via organocatalysis. One important
example is the direct catalytic asymmetric cross-aldol addition
between enolizable aldehydes, which has been realized through the
use of proline,2 derivatives of proline,3 and chiral imidazolidinones.4
However, despite tremendous efforts, several serious problems of
this reaction still remain. First, these aldol additions are mostly
anti-diastereoselective. Moreover, R-branched aldehydes react only
as carbonyl components in proline-catalyzed cross-aldol additions.
As a result of that, the construction of quaternary stereogenic carbon
centers cannot be accomplished. This selectivity is explained by
the steric demands of R-branched aldehydes, which cause thermo-
dynamic instability of the intermediate enamine.5 On the other hand,
R-unbranched aldehydes can react as both the ene component and
the carbonyl component. This lack of chemoselectivity renders
careful and cumbersome syringe pump techniques necessary to
avoid self-aldol addition.6
Isobutyraldehyde to Enolizable Aldehydesb d
,
D-Histidine was used as the catalyst. b Isolated yields are given, unless
a
During initial studies of amine-catalyzed direct aldol additions
of aldehydes to ketones,7 we observed that histidine also promotes
cross-aldol additions between enolizable aldehydes.8
otherwise noted. c The ratio of diastereomers was determined by 1H NMR
spectroscopy. d The enantiomeric excess was calculated from the er based
on the 1H NMR integration of the corresponding Mosher esters. For
determination of the absolute configurations, see the Supporting Information.
We started our investigations by considering aldol additions of
several aldehydes to isobutyraldehyde (1a). The histidine-catalyzed
aldol addition provides a direct and enantioselective access to
variously substituted and functionalized ꢀ-hydroxyaldehydes 3a-g
(Scheme 1). A varying mixture of aldol adducts 3a-c,e and their
corresponding hemiacetals 2a-c,e was observed (with exception
of aldehydes 3d, 3f, and 3g). In order to obtain defined reaction
products, the aqueous reaction mixtures were treated with an acidic
ion exchanger to yield ꢀ-hydroxyaldehydes 3a-c,e. The formation
of acetals is consistent with observations in chiral imidazolidinone-
catalyzed aldol additions4 and tertiary amine-catalyzed aldol
additions.7
A stringent chemoselectivity, which is dictated by the electronic
nature of the aldehydes, was noticed in all of these reactions.
Histidine differentiates strictly as well as efficiently between
electron-rich and electron-deficient aldehydes. Electron-rich alde-
hydes react exclusively as the ene component, whereas electron-
deficient aldehydes act as the carbonyl component in histidine-
catalyzed aldol additions.9 Thus, when used with R-branched
electron-rich aldehydes, this reaction gives access to aldol adducts
with an R-quaternary carbon atom. Hence, syringe pump techniques
are no longer necessary. Moreover, when electron-deficient alde-
hydes are used, a decrease in the formation of the corresponding
acetals is observed. When used with R-oxygen-containing alde-
hydes, higher stereoselectivities were observed.
ꢀ-hydroxyaldehydes 6a-d were accessed directly. In general,
intermediate acetals could not be detected (exception in the case
of 6e).
The ꢀ-hydroxyaldehydes 6a-d were isolated with yields up to
90%. High chemoselectivies were observed again. Dimethoxyac-
etaldehyde 4 acted exclusively as the carbonyl component in every
case we explored. Syn diastereoselectivities were observed under
these reaction conditions (6b, 6c, and 6e; Scheme 2).10
This comfortable situation of histidine in direct aldol additions
enabled us to realize several total syntheses of branched-chain
natural products (Scheme 3). For example, aldol addition of
ethylglyoxylate 1g to isobutyraldehyde 1a and subsequent reduction
yielded R-configured pantolactone (7), a vitamin-B5 precursor.
Pantolactone was obtained with 65% ee (see also 3d in Scheme
1). The enantiomerically pure product could then be obtained by a
single recrystallization. Even aldol adducts containing defined-
configuration R-tertiary alcohols were accessible with this method.
Stereoselective homodimerization of protected (R)-glyceraldehyde
1g in the presence of catalytic amounts of L-histidine gave direct
access to 2-hydroxymethyl-D-lyxose (8). Histidine-catalyzed dimer-
ization of benzyl-protected lactaldehyde 1f yielded protected
branched-chain5-deoxy-2-methyl-L-lyxose(9)asasinglestereoisomer.
Most existing techniques for the synthesis of 7 suffer from being
long and complex.11 The same is true for the synthesis of 9. For a
multistep-synthesis of 9 based on the SAMP-/RAMP-hydrazones
method, see ref 12. At this point, there exists no direct aldol addition
In order to avoid the formation of intermediate acetals, we
analyzed aldol additions of dimethoxyacetaldehyde (4) as the
carbonyl compound with different R-branched aldehydes as the ene
component. During these histidine-catalyzed aldol reactions, the
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16642 J. AM. CHEM. SOC. 2009, 131, 16642–16643
10.1021/ja907054y CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Asymmetric L-Histidine-Catalyzed Aldol Addition of
Dimethoxyacetaldehyde to Enolizable Aldehydes
configuration quaternary stereogenic centers becomes possible.
Aldol adducts of such a substitution pattern have not been accessible
by organocatalyzed aldol reactions to date. This operationally simple
method opens access to polyfunctionalized chiral building blocks
and thus provides an approach to branched-chain carbohydrates.
Acknowledgment. The authors thank the Deutsche Forschungs-
gemeinschaft (Priority Program Organocatalysis), Bayer-Schering
Pharma AG, Bayer Services GmbH, BASF AG, and Sasol GmbH
for financial support. P. Neubauer and B. Ziemer are gratefully
acknowledged for the X-ray structure analyses.
Supporting Information Available: NMR data for all of the
synthesized compounds, full characterization of novel compounds, and
X-ray crystallographic data (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
References
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Scheme 3. Utility of Histidine-Catalyzed Aldol Addition in the Total
Synthesis of Pantolactone, Hydroxymethyl-D-lyxose, and
5-Deoxy-L-lyxose
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for accessing these configurative-complex natural products discussed
in Scheme 3.
(9) This different behavior based on the electronic nature of aldehydes was
also observed in proline catalysis (see ref 6a).
In summary, we have developed a chemo-, diastereo-, and
enantioselective cross-aldol addition between enolizable aldehydes.
This transformation is accomplished with catalytic amounts of
readily available histidine. The reactions were carried out in water
at room temperature. In contrast to proline as the catalyst, histidine
is able to differentiate and control the reactivity of various
aldehydes. With the use of this protocol, the construction of defined-
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