Stereoselective direct amine-catalyzed decarboxylative aldol addition

Article abstract of DOI:10.1021/ol200412r

A stereoselective decarboxylative aldol addition of β- and α-keto acids in the presence of catalytic amounts of amines is described. By the optional deployment of chiral enolizable aldehydes an access to enantiopure configurative defined ketopentoses, ketohexoses, or ketoheptoses is given.

Full text of DOI:10.1021/ol200412r

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1878–1880
Stereoselective Direct Amine-Catalyzed
Decarboxylative Aldol Addition
Kerstin Rohr and Rainer Mahrwald*
Department of Chemistry, Humboldt-University, Brook-Taylor Str. 2, 12 489 Berlin,
Germany
rainer.mahrwald@rz.hu-berlin.de
Received February 15, 2011
ABSTRACT
A stereoselective decarboxylative aldol addition of β- and R-keto acids in the presence of catalytic amounts of amines is described. By the optional
deployment of chiral enolizable aldehydes an access to enantiopure configurative defined ketopentoses, ketohexoses, or ketoheptoses is given.
Only a few reports in the metal-catalyzed series so far
have tried to demonstrate the synthetic usefulness of
deployment of direct decarboxylative aldol additions
in asymmetric C-C bond formation processes.1 This
mild and operationally simple transformation plays a
very important role in aldol processes of polyketide2 or
carbohydrate3 biochemical pathways. Also, organoca-
talytic solutions of this transformation have been
tackled. β-Keto carboxylic acids, typically malonic
monoesters, were reacted with aldehydes in the pre-
sence of stoichiometric or catalytic amounts of tertiary
amines at room temperature.4 Only a very limited
number of manuscripts have been published that re-
port the deployment of R-keto carboxylic acids in
direct decarboxylative aldol additions.5 Accounts on
the synthesis of enantiopure aldol adducts by direct
and amine-catalyzed decarboxylative aldol addition
have not been reported so far.
During our ongoing studies in the field of amine-
catalyzed direct aldol additions6 we have been able to
develop a direct amine-catalyzed decarboxylative al-
dol addition of β- as well as R-keto carboxylic acids
with enolizable aldehydes. Thus, by deployment of
chiral enolizable aldehydes, an access to defined con-
figured optically pure aldol products is given. Herein,
we want to discuss the results of these investigations.
Preliminary experiments indicate that tertiary amines
(1) (a) Mukaiyama, T.; Sato, T.; Suzuki, S.; Inoue, T.; Naka mura, H.
Chem. Lett. 1976, 95. (b) Nokami, J.; Mandai, T.; Watanabe, H.;
Ohyama, H.; Tsuji, J. J. Am. Chem. Soc. 1989, 111, 4126. (c) Nokami,
J.; Konishi, H.; Matsuura, H. Chem. Lett. 1991, 2023. (d) Baskaran, S.;
Nagy, E.; Braun, M. Lieb. Ann. 1997, 311. (e) Luo, S.; Westbrook, J. A.;
Schaus, S. E. J. Am. Chem. Soc. 2004, 126, 11440. (f) Orlandi, S.;
Benaglia, M.; Cozzi, F. Tetrahedron Lett. 2004, 45, 1747. (g) Fortner,
K. C.; Shair, M. D. J. Am. Chem. Soc. 2007, 129, 1032. (h) Magdziak, D.;
Lalic, G.; Lee, H. M.; Fortner, K. C.; Aloise, A. D.; Shair, M. D. J. Am.
Chem. Soc. 2005, 127, 7284. (i) Lalic, G.; Aloise, A. D.; Shair, M. D. J.
Am. Chem. Soc. 2003, 125, 2852.
(2) (a) Staunton, J.; Wilkinson, B. Chem. Rev. 1997, 97, 2611. (b)
Staunton, J.; Weissman, K. J. Nat. Prod. Rep. 2001, 18, 380. (c) Piel, J.
Nat. Prod. Rep. 2010, 27, 996.
(3) For recent reviews, see: (a) Hailes, H. C.; Dalby, P. A.; Lye, G. J.;
Baganz, F.; Micheletti, M.; Szita, N.; Ward, J. M. Curr. Org. Chem.
2010, 14, 1883. (b) Wohlgemuth, R. J. Mol. Catal. B: Enzym. 2009, 61,
23.
(4) (a) Binder, D.; Noe, C. R.; Baumann, K.; Wildburger, J. M. F.
Arch. Pharm. 1985, 318, 243. (b) Grayson, D. H.; Tuite, M. R. J. Chem.
Soc., Perkin Trans. 1 1986, 2137. (c) Tanaka, M.; Ooota, O.; Hiramatsu,
H.; Fujiwara, K. Bull. Chem. Soc. Jpn. 1988, 61, 2473. (d) Thalji, N. K.;
Crowe, W. E.; Waldrop, G. L. J. Org. Chem. 2009, 74, 144. (e) Blaquiere,
N.; Shore, D. G.; Rousseaux, S.; Fagnou, K. J. Org. Chem. 2009, 74,
6190. (f) Khodakovskiy, P. V.; Volochnyuk, D. M.; Tolmachev, A. A.
Synthesis 2009, 1099. (g) For an unselective lipase-catalyzed decarbox-
ylative aldol process, see: Feng, X.-W.; Li, C.; Wang, N.; Li, K.; Zhang,
W.-W.; Wang, Z.; Yu, X.-Q. Green Chem. 2009, 11, 1933. (h) Baudoux,
J.; Lefebvre, P.; Legay, R.; Lasne, M.-C.; Rouden, J. Green Chem. 2010,
12, 252. (i) Ramachary, D. B.; Ramakumar, K.; Bharanishashank, A.;
Narayana, V. V. J. Comb. Chem. 2010, 12, 855.
(5) (a) Smith, M. E. B.; Smithies, K.; Senussi, T.; Dalby, P. A.; Hailes,
H. C. Eur. J. Org. Chem. 2006, 1121. Three examples were described in
the presence of morpholinopropane-sulfonic acid. The aldol adducts
were isolated with yields betweeen 35 and 25%, with the exception of
hydroxyacetaldehyde (63%).(b) Cazares, A.; Galmann, J. L.; Crago,
L. G.; Smith, M. E. B.; Strafford, J.; Rios- Solis, L.; Lye, G. J.; Dalby,
P. A.; Hailes, H. C. Org. Biomol. Chem. 2010, 8, 1301. Eight examples in
the racemic series were described in this report. The aldol adducts were
isolated with yields between 35% and 2%.
(6) Markert, M.; Mulzer, M.; Schetter, B.; Mahrwald, R. J. Am.
Chem. Soc. 2007, 129, 7258.
r
10.1021/ol200412r
Published on Web 03/07/2011
2011 American Chemical Society

catalyze a direct decarboxylative aldol addition of β-
keto carboxylic acids with enolizable aldehydes, pro-
ducing the corresponding aldol adducts in high yield.
To this end, we reacted isobutyraldehyde with benzoyl-
acetic acid in the presence of catalytic amounts of
triethylamine (eq 1).
product 3c could be expected by assumption of an
unfavored axial attack on the R-configured aldehyde
2c (transition state model B, Figure 1).
The reactions were complete after 2-3 h at room tem-
perature. Longer reaction times caused side reactions and
thus diminished yields (among others aldol condensation).
Yields do not depend on the amines employed. The same
yields and reaction times were observed with secondary,
primary, or tertiary amines.7 In a very clean reaction, the
corresponding aldol adduct was isolated in 71% yield.
Products derived from a competitive self-aldol addition of
isobutyraldehyde were not detected.
In further investigations we were able to extend this
transformation. By deployment of several chiral enolizable
aldehydes 2a-h, aldol adducts 3a-h were isolated in good
to excellent yields.
Figure 1. Proposed transition states.
In a next series of experiments several different β-
ketoacids were tested in these reactions (Scheme 2).
Again high anti-selectivities were detected under these
reaction conditions. The formation of chiral 1.5-di-
ketone 5d can be explained by an aldol condensation/
Michael addition. With malonic ester a different be-
havior is observed. By reacting the monophenyl mal-
onate 4c with protected lactaldehyde 1c the formation
of lactone 5c was observed. In order to determine the
configuration, lactone 5c was reduced with LiAlH4 to
afford the syn-configured diol 5e (Scheme 2).
Racemization or epimerization was not detected during
these processes. The aldol adducts were obtained in enan-
tiopure form (Scheme 1).
Scheme 1. Direct Decarboxylative Amine-Catalyzed Aldol Ad-
dition of Benzoylacetic Acid
Scheme 2. Decarboxylative Amine-Catalyzed Aldol Additions
of Different β-Keto Acetic Acids
The configurational outcome of this reaction was
not influenced by the deployment of different tertiary
amines. As a rule, high anti-selectivities were observed
under these reaction conditions. In some cases practi-
cally only one diastereoisomer could be detected. The
high anti-selectivity observed for aldol adduct 3c can
be explained by transition state model A. An equator-
ial attack on the benzyl-protected R-configured lac-
taldehyde 2c would give rise to the anti-configured
product 3c (91% de). The syn-configured aldol
Further investigations revealed that even R-keto
acids engage in the decarboxylative C-C bond form-
ing process under these reaction conditions. This
transformation is very sensitive to the amines and
aldehydes deployed. When pyruvate, phenylpyruvate,
or bromopyruvate was treated with protected lactal-
dehyde 1c, no reaction was observed. However, a clear
decarboxylative addition of hydroxypyruvate 6 with
protected lactaldehyde 1c was observed in the presence
of catalytic amounts of triethylamine.
(7) See Supporting Information
Org. Lett., Vol. 13, No. 7, 2011
1879

spectral data of pentulose 8 matched in full those
described in the literature.9
Scheme 3. Amine-Catalyzed Decarboxylative Addition of
Aldehydes to R-Keto Acids
In conclusion, we have described an amine-catalyzed
decarboxylative addition of chiral aldehydes to β-keto as well
as R-keto acids. This operationally simple protocol gives a
very easy access to polyhydroxylated defined configured
carbohydrate derivatives. Especially chiral aldol adducts of
the β-keto acetic acid series are of particular interest, since
asymmetric synthesis of these so-called “acetate”-aldol ad-
ducts cannot be as easily accomplished by other aldol
methodologies10 as it is demonstrated by this procedure.
Further investigations of the mechanism and an asymmetric
and catalytic version of this transformation are underway.
On the other hand, no reactions took place when hydro-
xypyruvate 6 was reacted with protected aldehyde 1a, 1g, or
1h in the presence of triethylamine. Optimization indicated
that N-methylmorpholine (NMM) as the optimal catalyst
for these substrates. When catalytic amounts of N-methyl-
morpholine were used, the corresponding aldol adducts
7a-7d were isolated in good yields and with a slight anti-
diastereoselectivity (Scheme 3).8
In order to demonstrate the utility of this transfor-
mation in the total synthesis of carbohydrate deriva-
tives, anti-configured aldol adduct 7a was converted
into D-erythro-2-pentulose 8 (eq 2). This was easily
accomplished by deprotection of the acetal of hydro-
xyketone 7a followed by spontaneous cyclization. The
Acknowledgment. The authors thank the Pharma AG,
Bayer Services GmbH, BASF AG, and Sasol GmbH for
financial support. B. Braun (Department of Chemistry,
Humboldt-University) is gratefully acknowledged for the
X-ray structure analysis.
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.
(8) Reaction times strongly depend on the amount of amines de-
ployed: by application of 10 mol% NMM a complete reaction was
observed after 24-36 h, whereas when used with equimolar amounts of
NMM the end of the reaction was detected after 2-3 h.
(9) Vuorinen, T.; Serianni, A. S. Carbohydr. Res. 1990, 209, 13. 100
mg of D-erythro-2-pentulose 8 = $435.
(10) Carreira, E. M.; Fettes, A.; Marti, C. Org. React. 2006, 67, 1.
1880
Org. Lett., Vol. 13, No. 7, 2011