Asymmetric acid-catalyzed meerwein-ponndorf-verley-aldol reactions of enolizable aldehydes

Article abstract of DOI:10.1021/ol100093u

A highly, stereo- and regioselective Meerwein-Ponndorf-Verley-Aldol etherification process of enolizable aldehydes is described. This new transformation is catalyzed by trifluoroacetic acid. The method also allows cross-aldol reactions with α-branched enolizable aldehydes and thus provides access to defined configured quaternary stereogenic centers.

Full text of DOI:10.1021/ol100093u

ORGANIC
LETTERS
2010
Vol. 12, No. 8
1660-1663
Asymmetric Acid-Catalyzed
Meerwein-Ponndorf-Verley-Aldol
Reactions of Enolizable Aldehydes†
Andrea Seifert, Ulf Scheffler, Morris Markert, and Rainer Mahrwald*
Institute of Chemistry, Humboldt-UniVersity, Brook-Taylor Str. 2, 12489 Berlin, Germany
rainer.mahrwald@rz.hu-berlin.de
Received January 14, 2010
ABSTRACT
A highly, stereo- and regioselective Meerwein-Ponndorf-Verley-Aldol etherification process of enolizable aldehydes is described. This new
transformation is catalyzed by trifluoroacetic acid. The method also allows cross-aldol reactions with r-branched enolizable aldehydes and
thus provides access to defined configured quaternary stereogenic centers.
The aluminum alkoxide-catalyzed redox equilibrium of alcohols
with various carbonyl compounds is called Meerwein-
Ponndorf-Verley reduction (MPV). This transformation gener-
ally uses inexpensive 2-propanol as the hydride source.1
Extensive studies have been carried out to expand the potential
of the classical Meerwein-Ponndorf-Verley reduction.
Several synthetic enlargements of this important redox
process have been reported for the MPV-aldol condensation,2
MPV-Michael addition3 and MPV/Brook rearrangement/
aldol addition.4 Also, the formal MPV-alkynylation,5 MPV-
cyanation,6 MPV-allylation,7 and MPV-transfer aldol reac-
tion8 should be mentioned here. The purpose of the present
communication is to report an enantioselective MPV-aldol
process of enolizable aldehydes giving access even to defined
configured quaternary stereogenic carbon atoms.9
During our ongoing studies of the deployment of LiClO4
in stereoselective C-C bond formation processes10 we have
(5) (a) Ooi, T.; Miura, T.; Ohmatsu, K.; Saito, A.; Maruoka, K. Org.
Biol. Chem. 2004, 2, 3312. (b) Ooi, T.; Miura, T.; Takaya, K.; Ichikawa,
H.; Maruoka, K. Tetrahedron 2001, 57, 867. (c) Ooi, T.; Takaya, K.; Miura,
T.; Maruoka, K. Synlett 2000, 69. (d) Ooi, T.; Miura, T.; Maruoka, K. J. Am.
Chem. Soc. 1998, 120, 10790.
(6) (a) Watanabe, A.; Matsumoto, K.; Shimada, Y.; Katsuki, T.
Tetrahedron Lett. 2004, 45, 6229. (b) Ooi, T.; Takaya, K.; Miura, T.;
Ichikawa, H.; Maruoka, K. Synlett 2000, 1133. (c) Mori, A.; Kinoshita, K.;
Osaka, M.; Inoue, S. Chem. Lett. 1990, 1171. (d) Mori, A.; Osaka, M.;
Inoue, S. Chem. Lett. 1993, 375.
(7) (a) Nokami, J.; Yoshizane, K.; Matsuura, H.; Sumida, S.-i. J. Am.
Chem. Soc. 1998, 120, 6609. (b) Sumida, S.-i.; Ohga, M.; Mitani, J.;
Nokami, J. J. Am. Chem. Soc. 2000, 122, 1310.
† Dedicated to Pelayo Camps in honor of his 65th birthday.
(1) For reviews, see: (a) Zassinovich, G.; Mestroni, G.; Gladiali, S. Chem.
ReV. 1992, 92, 1051. (b) de Graauw, C. F.; Peters, J. A.; van Bekkum, H.;
Huskens, J. Synthesis 1994, 1007. (c) Nishide, K.; Node, M. Chirality 2002,
14, 759. (d) Graves, C. R.; Campbell, E. J.; Nguyen, S. B. T. Tetrahedron:
Asymmetry 2005, 16, 3460. (e) Cha, J. S. Org. Process Res. DeV. 2006, 10,
1032.
(8) (a) Simpura, I.; Nevalainen, V. Tetrahedron Lett. 2001, 42, 3905.
(b) Simpura, I.; Nevalainen, V. Tetrahedron 2003, 59, 7435. (c) Xi, B.;
Nevalainen, V. Tetrahedron Lett. 2006, 47, 2561. (d) Xi, B.; Nevalainen,
V. Tetrahedron Lett. 2006, 47, 7133. (e) Chandrasekhar, S.; Narsihmulu,
C.; Reddy, N. R.; Sultana, S. S. Chem. Commun. 2004, 2450. (f) Schneider,
C.; Hansch, M.; Sreekumar, P. Tetrahedron: Asymmetry 2006, 17, 2738.
(g) Schneider, C.; Weide, T. Chem.sEur. J. 2005, 11, 3010. (h) Schneider,
C.; Klapa, K.; Hansch, M. Synlett 2005, 91. (i) Schneider, C.; Hansch, M.
Synlett 2003, 837. (j) Schneider, C.; Hansch, M. Chem. Comm. 2001, 1218.
(k) Rohr, K.; Herre, R.; Mahrwald, R. Org. Lett. 2005, 7, 4499. (l) Rohr,
K.; Herre, R.; Mahrwald, R. J. Org. Chem. 2009, 74, 3744.
(2) Mahrwald, R.; Schick, H. Synthesis 1990, 592.
(3) (a) Ozeki, M.; Hashimoto, D.; Nishide, K.; Kajimoto, T.; Node, M.
Tetrahedron: Asymmetry 2005, 16, 1663. (b) Ozeki, M.; Nishide, K.;
Teraoka, F.; Node, M. Tetrahedron: Asymmetry 2004, 15, 895. (c) Nishide,
K.; Shigeta, Y.; Obata, K.; Node, M. J. Am. Chem. Soc. 1996, 118, 13103.
(d) Nishide, K.; Ozeki, M.; Kunishige, H.; Shigeta, Y.; Patra, P. K.;
Hagimoto, Y.; Node, M. Angew. Chem., Int. Ed. 2003, 42, 4515.
(4) (a) Geszler, S. N.; Johnson, J. S. Org. Lett. 2009, 11, 827. (b) Xin,
L.; Satterfield, A. D.; Johnson, J. S. J. Am. Chem. Soc. 2006, 128, 9302.
(9) (a) Shibasaki, M.; Kanai, M. Chem. ReV. 2008, 108, 2853. (b) Cozzi,
P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2007, 5969. (c)
Quaternary stereocenters; Christoffers, J., Baro, A., Eds.; Wiley-VCH:
Weinheim, 2005. (d) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int.
Ed. 1998, 37, 389.
10.1021/ol100093u  2010 American Chemical Society
Published on Web 03/21/2010

also demonstrated the successful execution of Prins reac-
tions.11 These transformations were carried out in the
presence of catalytic amounts of tartaric acid and tertiary
alcohols. By extension of these reaction conditions to
secondary alcohols, instead of Prins products corresponding
1,3-diol ethers were obtained, formed by a tandem aldol
MPV/etherification process.12
In both series, the corresponding 1.3-diol ethers 3a and 3b
were isolated as single diastereoisomers (Scheme 2).
Scheme 2
.
Intramolecular Meerwein-Ponndorf-Verley-Aldol
Etherification Process
During initial studies of this new reaction, the best yields
were obtained with no solvents in the presence of dry LiClO4
and 1 mol % of trifluoroacetic acid at room temperature.13
As an example, isobutyraldehyde or isovaleraldehyde reacts
with secondary alcohols under these standard conditions to
give the corresponding 1,3-diol ethers 1a-d (Scheme 1).
By deployment of isovaleraldehyde, extremely high diaste-
reoselectivities were detected. The isopropyl ether 1c and
cyclopentylether 1d were isolated as single diastereoisomers.
Reactions of unbranched enolizable aldehydes resulted in the
expected 1,3-diol ether with very low yields under these
reaction conditions (n-Pr-CHO, n-Bu-CHO < 5%).
These results highlight the crucial role of the choice of
alcohol for a successful performance of this transformation.
The yields of isolated ethers 1a-d and 3a,b are correlated
to the secondary alcohols applied. Highest yields were
obtained with cyclopentanol (Schemes 1 and 2). This trend
matches tendencies of oxidation enthalpies measured for
several alcohols.14 The lowest oxidation enthalpy was
calculated for cyclopentanol (stabilization of the correspond-
ing carbocation by hyperconjugation), while the highest
enthalpies were found for primary alcohols, in particular for
methanol.
Scheme 1. Acid-Catalyzed Meerwein-Ponndorf-Verley-Aldol
Etherification Reactions of Enolizable Aldehydesa
In order to analyze the source and fate of hydride in these
reactions, we carried out experiments with C1-deuterated
cyclohexanol. As depicted in Scheme 3, 1 equiv of C1-
deuterated cyclohexanol was oxidized, and deuterium was
used for the reduction of the assumed intermediate hydroxy-
aldehyde. A second equivalent of C1-deuterated cyclohexanol
was used for the etherification. Subsequent analysis revealed
the full incorporation of deuterium.15,16 Only one diastere-
1
oisomer was detected by H NMR experiments, albeit with
low yields (Scheme 3).
Scheme 3. Meerwein-Ponndorf-Verley-Aldol Reaction of
a
1
Diastereoselectivities were determined by H NMR analysis.
Isobutyraldehyde with C1-Deuterated Cyclohexanol
Further, we have investigated the applicability of this
protocol in intramolecular aldol/MPV/etherification pro-
cesses. To this end we reacted R-methyladipaldehyde 2 with
2-propanol or cyclopentanol under these reaction conditions.
(10) (a) Markert, M.; Mahrwald, R. Synthesis 2004, 1429. (b) Arnold,
A.; Markert, M.; Mahrwald, R. Synthesis 2006, 1099. (c) Seifert, A.;
Mahrwald, R. Tetrahedron Lett. 2009, 50, 6466.
During these studies, we detected neither the intermediate
aldol adducts nor the corresponding 1,3-diols. Ethers of the
secondary hydroxy group of 1,3-diols were not found either.
In the absence of alcohols, no reactions occurred at all. And
(11) Markert, M.; Buchem, I.; Kruger, H.; Mahrwald, R. Tetrahedron
2004, 60, 993.
(12) (a) For a similar process in the presence of Ti(i-OPr)4 but without
any stereoselectivity, see: Aremo, N.; Hase, T. Tetrahedron Lett. 2001, 42,
3637. (b) For a Meewein-Ponndorf-etherification process, see: Corma,
A.; Renz, M. Angew. Chem. Int. Ed 2007, 46, 298.
(13) For rate enhancement of MVP reactions in the presence of protonic
acids, see: (a) Kow, R.; Nygren, R.; Rathke, M. W. J. Org. Chem. 1977,
42, 826. (b) Akamanchi, K. G.; Varalakshmy, N. R. Tetrahedron Lett. 1995,
36, 3571. (c) For optimization of deployment of protonic acids in these
reactions see ref 16.
(14) Kamitanaka, T.; Ono, Y.; Morishima, H.; Hikida, T.; Matsuda, T.;
Harada, T. J. Supercrit. Fluids 2009, 49, 221.
(15) For similar experiments but without any stereoselection, see:
Kamitanaka, T.; Matsuda, T.; Harada, T. Tetrahedron 2007, 63, 1429
(16) See the Supporting Information.
.
Org. Lett., Vol. 12, No. 8, 2010
1661

finally, isolated aldol adducts or 1,3-diols cannot be trans-
formed into the corresponding ethers under these reaction
conditions. These results prove the assumption that all three
theoretical reaction steps must be strongly associated (aldol
addition, MPV-process, etherification).
Scheme 5
. Asymmetric Meerwein-Ponndorf-Verley-Homo-
Aldol Etherification Reactions of Enolizable Aldehydesa
Since these defined configured 1,3-diol ethers are valuable
building blocks in natural product synthesis, we strove to
realize an enantioselective execution of this transformation.
Scheme 4
. Meerwein-Ponndorf-Verley-Aldol Etherification
Reactions with Chiral Secondary Alcohols
a The configuration of the minor diastereoisomer is unknown.
a For determination of diastereo- and enantioselectivities see ref 16.
To this end, we tested several chiral secondary alcohols
in these reactions. When used with optically pure (S)-2-
butanol or (-)-menthol the corresponding ethers 4a and 4b
were isolated with 25% yield. Partial racemization of the
chiral secondary alcohols under the conditions of this MPV-
aldol process was assumed for lowering of stereoselectivities
of the corresponding 1,3-diol ethers (4a: 20% ee, 4b: 78%
de, Scheme 4). Also, when used with chiral protonic acids
no enantioselectivities could be detected. Racemic 1,3-diol
ethers were isolated by deployment of tartaric acid or
camphoric acid in low yields.
In addition, reactions of two different enolizable aldehydes
were investigated. An extremely high differentiation between
the deployed aldehydes was observed. The key to the
regioselectivity of this reaction is the preferred formation of
enolates of R-branched enolizable aldehydes under these
reaction conditions. R-Branched enolizable aldehydes act
exclusively as ene components in every reaction we tried
(7a and 7b, Scheme 6). Even in reactions of two different
R-branched enolizable aldehydes an extremely strong dif-
These problems can be overcome by a strict discrimination
between the hydride source and the alcohol that is used for
the etherification. This competition can be decided by the
considerable difference of oxidation enthalpies of varying
alcohols. To this end, methanol was deployed for the
etherification (highest oxidation enthalpy).17 Menthol, a
chiral, secondary, and competitive sterically demanding
alcohol, served as the chiral hydride source. Under these
reaction conditions, we were not able to detect products
indicating the formation of formaldehyde. Instead of that
menthone, the oxidation product of menthol was isolated in
equimolar amounts.
Scheme 6. Asymmetric Meerwein-Ponndorf-Verley-Cross-
Aldol Etherification Reactions with R-Branched Enolizable
Aldehydesa
After optimization of reaction conditions, we elaborated
the following protocol. The reactions were carried out in the
presence of dry LiClO4 and catalytic amounts of trifluoro-
acetic acid (1 mol %) at room temperature. Best results with
regard to yields were obtained in the absence of any solvents.
By application of oxygen-containing solvents no reactions
were observed. Furthermore, higher yields and shorter
reactions times were obtained by deployment of the trim-
ethylsilyl ether of optically pure menthol. The results of these
investigations are shown in Scheme 5.
a For determination of diastereo- and enantioselectivities see ref 16.
(17) Application of other primary alcohols such as propanol or benzylic
alcohol yielded a more complex reaction mixture.
1662
Org. Lett., Vol. 12, No. 8, 2010

ferentiation is observed. In these cases, a less sterically
demanding aldehyde acts exclusively as the ene component
(7c and 7d, Scheme 6). No other cross-aldol adducts or self-
aldol adducts were observed under these reaction conditions.
In addition, high enantioselectivities were detected.
In order to confirm the configuration, methyl ethers 6a-e
have been converted into the 1,3 diols by treatment with
Me3SiI in the presence of catalytic amounts of NaI. Subse-
quent reactions with dimethoxypropane yield the correspond-
ing dimethyl acetals. For details of these investigations, see
ref 16.
When used with TMS-ether of (+)-menthol and of
isobutyraldehyde in these reactions, similar results with
regard to yields and selectivities were obtained.16 Thus, an
access to R-configured 1,3-diol methyl ethers is given.
The configurative outcome detected during these investi-
gations is best explained by the transition state models shown
in Figure 1. Based on steric interactions in model A, a strong
preference for structure B seems to be likely. The rigid model
B matches the configurative outcome of reactions when used
with the trimethylsilyl ether of (-)-menthol.
Figure 1. Proposed transition-state models for the configurative
outcome of formation of 6a: green, lithium; blue, C1-hydrogen from
(-)-menthol.
anism, and application to natural product synthesis will be
reported in due course.
Acknowledgment. We thank the Deutsche Forschungs-
gemeinschaft, Bayer-Schering, Pharma AG, Bayer Ser-
vices GmbH, BASF AG, and Sasol GmbH for financial
support.
In summary, we have developed an asymmetric Meer-
wein-Ponndorf-Verley-Aldol etherification reaction se-
quence of enolizable aldehydes. Thus, an access to defined
configured quaternary stereogenic centers is given. High
regio-, diastereo-, and enantioselectivity were observed.
Further optimizations, investigations on the reaction mech-
Supporting Information Available: Experimental details,
characterization, and spectra of new products. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL100093U
Org. Lett., Vol. 12, No. 8, 2010
1663