Stereoselective amine-catalyzed carbohydrate chain elongation

Article abstract of DOI:10.1039/c2cc31541f

Aldol additions of unprotected carbohydrates to 1.3-dicarbonyl compounds have been described. This transformation is based on a dual activation by tertiary amines and 2-hydroxypyridine.

Full text of DOI:10.1039/c2cc31541f

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Stereoselective amine-catalyzed carbohydrate chain elongationwz
Benjamin Voigt, Ulf Scheffler and Rainer Mahrwald*
Received 29th February 2012, Accepted 26th March 2012
DOI: 10.1039/c2cc31541f
Aldol additions of unprotected carbohydrates to 1.3-dicarbonyl
compounds have been described. This transformation is based on
a dual activation by tertiary amines and 2-hydroxypyridine.
of amines at room temperature in neat. As a result we were
able to isolate hemiketal 3a with 29% yield as a single
diastereoisomer in a rapid and clear reaction (eqn (1)).
Chain elongated carbohydrates—higher carbon sugars—are
important compounds with biologically fundamental properties.
Nature realizes these important transformations, apparently
effortless, through a deployment of distinctly working aldolases
and ketolases with extremely high degrees of stereoselectivity
(Scheme 1).1 However this high specificity is limited to a small
number of substrates. Also, not all possible stereoisomers can be
accessed by enzymatic transformations.
ð1Þ
The C–C bond formation process occurs via an aldol
addition step. Aldol condensation products were not detected
under these reaction conditions. Successful aldol additions of
aldehydes to 1.3-dicarbonyl compounds are rare and difficult to
realize. Mostly, a competitive condensation process cannot be
prevented. For a successful execution of this reaction in the absence
of amines see ref. 7. Next, the C–C bond formation process
proceeds with an extremely high degree of syn-diastereoselectivity.
One single stereoisomer was detected by NMR-techniques. In
addition high chemoselectivity is observed. An aldol addition
at the methyl group was not detected. Comparable reactions
have not been described in the literature so far.8
Today a multitude of methods exists to accomplish these
transformations. These synthetic maneuvers are associated
with extensive handling of protecting groups and additional
activation of the anomeric carbon atom.2 Recent results of
organocatalyzed aldol reactions in this field however promise
to overcome these problems.3
Recently we have tested several organocatalyzed transformations
for their utility in the synthesis of carbohydrates. We demonstrated
the value of amines as catalysts in direct aldol additions of
dihydroxyacetone4 and in decarboxylative aldol additions.5
Based on these results we proceeded to test also unprotected
carbohydrates as carbonyl compounds in direct aldol additions.
Thus we have reacted these substrates with 1.3-dicarbonyl
compounds. In preliminary experiments we have tested deoxyribose
1a6 in reactions with acetoacetic ester 2a as the enol component.
The reactions were performed in the presence of catalytic amounts
Several attempts were made to react unprotected and unactivated
carbohydrates with 1.3-dicarbonyl compounds. These studies
describe condensation processes that are connected with the
loss of stereogenic centers (Knoevenagel-reaction9). Furan-
derivatives or C-glycosides10 were obtained depending on reaction
conditions. Recently this methodology was extended to synthesize
fused pyridine/pyrrole derivatives of carbohydrates.11
Inspired by the results we obtained, several carbohydrates
of the pentose set were tested as carbonyl compounds in an
initial series. To this end D-ribose 1b, D-arabinose 1c, D-xylose
1d and D-lyxose 1e were reacted with acetoacetic ester 2a at rt
in the presence of catalytic amounts of diisopropylethylamine.
In preliminary experiments the expected products 3a–e were
isolated with different and low yields. A pronounced correlation
of yields in this reaction to deployed carbohydrates was observed.
Highest yields were obtained with deoxyribose 1a and ribose 1b
and other carbohydrates resulted in decreasing yields. Finally, the
lowest yields were obtained by the deployment of arabinose 1c
and lyxose 1e. Yields and reaction rates correlate with the
tendency of the corresponding carbohydrates to exist in acyclic
structure.12 Comparable results were obtained by glycosidation of
unprotected and unactivated carbohydrates.13 To overcome the
problems of long reaction times and low yields we have tested
2-pyridone as an additive in these reactions. 2-Pyridone is known
Scheme 1 Examples of aldolase- and transketolase-catalyzed reactions.
Institute of Chemistry, Humboldt-University, Brook-Taylor Str. 2,
12489 Berlin, Germany. E-mail: rainer.mahrwald@rz.hu-berlin.de;
Fax: +49 (0)30 2093 5553
w Electronic supplementary information (ESI) available: General
information, detailed experimental procedures, characterization data
for all products. See DOI: 10.1039/c2cc31541f
z This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
c
5304 Chem. Commun., 2012, 48, 5304–5306
This journal is The Royal Society of Chemistry 2012

Scheme 2 Aldol additions of ribose 1b, arabinose 1c, xylose 1d or lyxose
1e to acetoacetic ester 2a. Reaction conditions: 1.0 mmol carbohydrate,
1.5 mmol acetoacetic ester 2a, 20 mol% iPr2NEt, 25 mol% 2-pyridone,
0.5 ml DMSO, rt, 60–96 h. aInternal syn/anti ratio.
to potentially catalyze the mutarotation of carbohydrates
by forming hydrogen bonds.14 As expected, yields increase under
comparable conditions when catalytic amounts of 2-hydroxy-
pyridine are used. The results of these investigations are
depicted in Scheme 2.
Extremely high syn-diastereoselectivities were observed during
the C–C bond formation process. Anti-configured products were
not detected under these reaction conditions. These results are
consistent with those obtained in aldol additions with dihydroxy-
acetone.4 In addition, an asymmetric induction is observed. The
internal syn- and anti-configured products were detected in a ratio
of about 3/1. Scheme 3 illustrates an example for the reaction of
ribose 1b with acetoacetic ester 2a as a substitutional explanation
for all other carbohydrates. The syn-configured aldol product
3b is obtained in its pyranoid structure. In contrast, the internal
anti-configured aldol product develops a furanoid structure to
avoid unfavored 1.3-diaxial interactions (anti-3b, Scheme 3).
The anomeric hydroxyl group was installed at the axial position
in every reaction (see ESIw).
Scheme 3 Stereochemical course of aldol reaction of ribose with
methyl acetoacetate 2a.
In the next series we have tested several different hexoses in
reactions with acetoacetic ester 2a. Comparable results with
those of the pentose-series were obtained (Scheme 4). Again,
extremely high syn-diastereoselectivity is observed during the
C–C bond formation.
The structure of carbohydrates determines both yields and
internal diastereoselectivity (Schemes 2 and 4). 2.3-anti-Configured
carbohydrates give mainly internal syn-configured products in
good yields (3b, 3e and 5a). In contrast, when 2.3-syn-configured
carbohydrates are used internal anti-configured products are
mainly obtained with lower yields (3c, 3d, 5b and 5c). In this
context deoxyribose represents an exception, because of the
absence of a hydroxy group at the 2-position (3a, Scheme 2).
Subsequent formation of pyranoid or furanoid structures
depends on steric interactions and is also determined by the
configuration of the deployed carbohydrates.
Scheme 4 Aldol additions of mannose 4a, glucose 4b or galactose 4c
to acetoacetic ester 2a. Reaction conditions: 1 mmol carbohydrate,
1.5 mmol acetoacetic ester 2a, 20 mol% iPr2NEt, 25 mol% 2-pyridone,
a
0.5 ml DMSO, rt, 60–96 h. Internal syn/anti ratio.
In the final series we have tested several different 1.3-
dicarbonyl compounds in this amine-catalyzed reaction with
ribose 1b. Results of this investigation are depicted in
Scheme 5.
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This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 5304–5306 5305

Notes and references
1 For recent reviews in this field see: (a) A. K. Samland, M. Rale,
G. A. Sprenger and W.-D. Fessner, ChemBioChem, 2011, 12,
1454–1474; (b) P. Clapes and W.-D. Fessner, Stereoselective Synthesis,
Science of Synthesis, Thieme, 2011, vol. 2, pp. 677–734; (c) W.-D.
Fessner, in Asymmetric Organic Synthesis with Enzymes, ed. W.-D.
Fessner and T. Anthonsen, Wiley, 2008, pp. 275–318.
2 For recent reviews in this field see: (a) R. N. Monrad and
R. Madsen, Tetrahedron, 2011, 67, 8825–8850; (b) P. Vogel and
I. Robina, in Comprehensive Glycoscience, ed. J. P. Kamerling,
Elsevier, 2007, vol. 1, pp. 261–310.
3 For an overview in this field see: (a) R. Mahrwald, Aldol Reactions,
Springer, 2009; (b) M. Markert and R. Mahrwald, Chem.–Eur. J.,
2008, 14, 40–48.
4 M. Markert, M. Mulzer, B. Schetter and R. Mahrwald, J. Am.
Chem. Soc., 2007, 129, 7258–7259.
5 K. Rohr and R. Mahrwald, Org. Lett., 2011, 13, 1878–1880.
6 Ribose consists in solution at rt of a mixture of furanoid and
pyranoid structures of appr. 2/8.
7 K. Rohr and R. Mahrwald, Adv. Synth. Catal., 2008, 350,
2877–2880.
8 With the sole exception of reaction of 2-acetamido-glyceraldehyde
with tert-butyloxalacetate: M. Miljkovic and P. Hagel, Carbohydr.
Res., 1985, 141, 213–220.
Scheme 5 Aldol reactions of ribose to different acetoacetic esters
2b–f. Reaction conditions: 1 mmol carbohydrate, 1.5 mmol ethyl
acetoacetate 2a, 20 mol% iPr2NEt, 25 mol% 2-pyridone, 0.5 ml
a
DMSO, rt, 60–96 h. Internal syn/anti ratio.
9 M.-C. Scherrmann, Top. Curr. Chem., 2010, 295, 1–18.
10 (a) P. M. Foley, A. Phimphachanh, E. S. Beach, J. B. Zimmerman and
P. T. Anastas, Green Chem., 2011, 13, 321–332; (b) A. Cavezza,
C. Boulle, A. Gueguiniat, P. Pichaud, S. Trouille, L. Ricard and
M. Dalko-Csiba, Bioorg. Med. Chem. Lett., 2009, 19, 845–849;
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Carbohydr. Res., 2007, 342, 2716–2728; (d) J. Zeitouni, S. Norsikian and
A. Lubineau, Tetrahedron Lett., 2004, 45, 7761–7763; (e) Y. Hersant,
R. Abou-Jneid, Y. Canac, A. Lubineau, M. Philippe, D. Semeria,
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741–745; (f) I. Riemann, M. A. Papadopoulos, M. Knorst and
W.-D. Fessner, Aust. J. Chem., 2002, 55, 147–154; (g) F. Rodrigues,
Y. Canac and A. Lubineau, Chem. Commun., 2000, 2049–2050.
11 (a) B. V. S. Reddy, C. D. Vani, Z. Begum, J. S. Yadav and
T. P. Rao, Synthesis, 2011, 168–172; (b) L. Nagarapu,
V. N. Cheemalapati, S. Karnakanti and R. Bantu, Synthesis,
2010, 3374–3378.
These findings indicate that the internal diastereoselectivity
is influenced by substituents of the acetoacetic esters deployed.
Moreover these results demonstrate that this new transformation
can further be extended to 1.3-dicarbonyl compounds.
In summary, we have developed an organocatalyzed aldol
addition of unprotected carbohydrates to 1.3-dicarbonyl com-
pounds without using the classical tedious protecting and depro-
tecting procedure. These investigations show great advantages in
terms of time and atom economy. The successful execution of this
process is based on a dual activation by tertiary amines and
2-hydroxypyridine. Also, this operationally simple transformation
mimics aldolase-catalyzed transformations, which were identified in
many biochemical processes. Further optimization and enlargement
of this methodology to more general C–C bond formation pro-
cesses of unprotected carbohydrates are underway.
12 B. Capon, Chem. Rev., 1969, 69, 407–498.
13 M. Pfaffe and R. Mahrwald, Org. Lett., 2012, 14, 792–795.
14 (a) W. T. Smith and T. L. Hearn, Bioorg. Chem., 1972, 2, 39–43;
(b) P. R. Rony, J. Am. Chem. Soc., 1968, 90, 2824; (c) C. G. Swain
and J. F. Brown, J. Am. Chem. Soc., 1952, 74, 2534–2537;
(d) C. G. Swain and J. F. Brown, J. Am. Chem. Soc., 1952, 74,
2538–2543.
The authors thank Deutsche Forschungsgemeinschaft,
Bayer-Schering Pharma AG, Bayer Services GmbH, BASF
AG, and Sasol GmbH for financial support.
c
5306 Chem. Commun., 2012, 48, 5304–5306
This journal is The Royal Society of Chemistry 2012