Proline organocatalysis as a new tool for the asymmetric synthesis of ulosonic acid precursors

Article abstract of DOI:10.1039/b611265j

PEP and aldolase mimicry is the key for a direct organocatalytic entry to precursors of ulosonic acids, biomolecules of enormous importance in biology, chemistry and medicine; in the key aldol reaction the dimethylacetal of pyruvic aldehyde is used as pho

Full text of DOI:10.1039/b611265j

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Proline organocatalysis as a new tool for the asymmetric synthesis of
ulosonic acid precursors{
Dieter Enders* and Tecla Gasperi
Received (in Cambridge, UK) 4th August 2006, Accepted 21st September 2006
First published as an Advance Article on the web 12th October 2006
DOI: 10.1039/b611265j
Over recent years a number of useful chemical and enzymatic
methodologies have been reported and implemented to develop
efficient syntheses of sialic and ulosonic acids8,9 as well as of
certain analogues.10,11 However, in enzyme-catalyzed reactions the
loss of stereocontrol regarding the substrate scope is often a
problem12 and the total synthesis approaches have suffered from
long reaction sequences13 due to protecting group manipulations.
Consequently the need for short and practical synthetic routes
remained a challenging endeavour of great interest, as proved by
the most recent achievements.14
PEP and aldolase mimicry is the key for a direct organocata-
lytic entry to precursors of ulosonic acids, biomolecules of
enormous importance in biology, chemistry and medicine; in
the key aldol reaction the dimethylacetal of pyruvic aldehyde is
used as phosphoenolpyruvate (PEP) equivalent and the amino
acid proline functions as an organocatalyst, imitating the
enzyme.
The forthcoming advent of a post-antibiotic era has driven much
research towards developing new tools to fight the emergence of
devastating diseases and has prompted much effort to identify the
biological functions of carbohydrates in physiological processes.1
Naturally occurring 2-keto-3-deoxy-nonulosonic acids such as
Neu5Ac (1) and KDN (2), generally known as sialic acids, have
been significantly implicated in the pathogenesis of microorgan-
isms and various disease states.2,3 Likewise, pivotal biological roles
are constantly ascribed to widely diffuse higher 3-deoxy-2-ulosonic
acids.4 For example, 3-deoxy-D-manno-2-octulosonic acid (KDO,
3), present in the outer membrane lipopolysaccharide (LPS) of
Gram-negative bacteria, is essential for their replication.2,5 The
7-phosphate of the 3-deoxy-D-arabino-2-heptulosonic acid (DAH,
4) is a key intermediate in the biosynthesis of aromatic amino acids
via the shikimate pathway.6 The phosphorylated form of 2-keto-3-
deoxy-D-glucosonic acid (D-KDG, 5) is part of the Entner–
Doudoroff pathway7 (Fig. 1).
Previous efforts from our laboratories led to structurally
modified deoxygenated ulosonic acids via metalated SAMP-/
RAMP-hydrazones as efficient chiral equivalents of phosphoenol
pyruvate (PEP).15 This strategy resembled the natural biosynthetic
pathway, whereby PEP undergoes C–C linkage to aldehydes by
means of class I aldolase catalysed reactions. Recently we have
been utilizing an organocatalytic approach towards the asym-
metric synthesis of various carbohydrates and amino sugars as well
as phytosphingosines and polyoxamic acid starting from 2,2-
dimethyl-1,3-dioxan-5-one as dihydroxyacetone equivalent.16
Pursuing these biomimetic routes, we herein report the first results
of our investigations towards the asymmetric organocatalytic
synthesis of sialic and ulosonic acids that led us to obtain a direct
precursor of D-KDG (5) as well as advanced intermediates of
KDO (3) and analogues. In our biomimetic approach we chose the
pyruvic aldehyde dimethyl acetal 7 as masked pyruvic acid in aldol
reactions with various aldehydes 6 (Scheme 1).
Since a number of amine-catalytic systems gave different
results17 with respect to the employed substrates, we initially
tested the enantiopure pyrrolidine derivatives 9–13 (30 mol%) in
the reaction of 7 with 2-methyl propanal (5a, R = iPr) as a model
Fig. 1 Sialic and ulosonic acids.
Institut fu¨r Organische Chemie, RWTH Aachen, Landoltweg 1, Aachen,
52074, Germany. E-mail: enders@rwth-aachen.de;
Fax: (+49) 241 809 2127; Tel: (+49) 241 809 4676
{ Electronic supplementary information (ESI) available: Experimental
data for 14c and 14c9. See DOI: 10.1039/b611265j
Scheme 1 Organocatalysed aldol reactions of the pyruvic aldehyde
dimethyl acetal 7 with aldehydes 6.
88 | Chem. Commun., 2007, 88–90
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carbonyl component by performing the reaction in DMSO. In
contrast with the results reported by Barbas et al.,17a the amine 12
did not yield the aldol product 8 in spite of the presence of
CF3CO2H as additive. Likewise, the catalysts 10–11 predomi-
nantly afforded the corresponding aldol condensation product,
which was always present in the tested reactions. Independent
experiments performed by treating the aldol 8a with each catalyst
did not yield any of the corresponding dehydration compound,
which is probably due to a Mannich-reaction-elimination sequence
as also observed by List et al.18 The best results were observed in
the reactions with (S)-proline (9) and the tetrazole 1317e affording
the aldol 8a in reasonable yield (51–53%) and good enantioselec-
tivity (73–75% ee; Table 1).{
As both catalysts produced comparable results, the optimisation
of the reaction was performed with the much less expensive and
proteinogenic amino acid proline. While screening diverse solvents
of varying polarity failed to improve either the yield or the
enantiomeric excess, cooling the reaction mixture to 4 uC and using
an excess of 7 revealed that the aldol 8a was obtained with a
considerably higher enantioselectivity (93% ee). However, the
Mannich-elimination side reaction could not be avoided, as well as
the formation of the acetal self-aldolization product, which should
lead to a decreasing efficiency of the catalyst towards the desired
pathway.
Fig. 2 X-Ray crystal structure of (R,S)-8d. Relative stereochemistry of
the molecule is C1–(S), C11–(R). Certain hydrogen atoms have been
omitted for clarity.
in very good diastereomeric excess (Table 1) with an increase in the
reaction rate when aldehydes bearing a heteroatom in the b
position were employed. As noted in our previous report, (S)-
proline proved to be the most suitable catalyst when (S)-configured
aldehydes (6d,e) were used, whilst with (R)-configured 2,3-O-
(isopropylidene)-D-glyceraldehyde (6c) (R)-proline afforded the
best results in terms of yield.
The given stereochemical assignments are based on the X-ray
crystal structure analysis of the aldol product (R,S)-8d (Fig. 2),§
which proved an (R)-configuration at the newly formed stereo-
genic centre, and are confirmed by a polarimetric comparison with
independently synthesized aldol products 8c.19
Afterwards the developed conditions were evaluated using the
a-branched aldehydes 6b–e as carbonyl components. In spite of the
modest yields, in all cases the expected aldol product was obtained
The observed R configuration is in agreement with the transition
state model for the proline-catalyzed aldol reaction.20 The epimeric
aldol products (R,R)-8c and (S,R)-8c were easily deprotected with
an acidic ionic-exchange resin (Amberlyst1 15) to give the
hemiketals 14 (Scheme 2).
Table 1 (S)-Proline-catalyzed asymmetric aldol reaction of 7 with
aldehydes 6 to afford 8
Time/
days
Yield
(%)a
de
(%)b
ee
(%)
8
R
Temp/uC
Upon acidic treatment (R,R)-8c afforded only the pyranose
form 14c as a single anomer, which could be straightforwardly
converted into the 4-epi-KDG. In contrast, the aldol (S,R)-8c
provided only the furanose ring 14c9 in both possible anomeric
forms (a : b, 1 : 1), whose stereogenic centres C(4) and C(5) have
the correct configurations to make it a direct precursor of 2-keto-3-
deoxy-D-glucosonic acid (D-KDG, 5).
a
a
a
b
c
iPr
iPr
iPr
cHex
rt
rt
4
4
4
6
6
8
10
5
51
53
48
37
38
—
—
—
—
91
73b
75b,c
93b
85b
¢99d
ce
4
4
4
5
7
9
45
31
35
90
90
92
¢99d
¢99f
¢99g
In conclusion, we have developed a direct entry to precursors of
ulosonic and sialic acids by means of an organocatalytic approach
closely resembling the natural pathway. Despite the modest yields,
d
e
a
Yields of
8
isolated by flash chromatography on silica gel.
Determined by HPLC on chiral stationary phases (Chiralpak AD,
b
c
Chiralpack IA 5 m, Daicel IA, Daicel OJ, Whelk 01). Tetrazole
d
(R)-13 was used as catalyst. Based on the ee value of 6c. (R)-
e
f
g
Proline was used as catalyst. Based on the ee value of 6d. Based
on the ee value of 6e.
Scheme 2 Deprotection of (R,R)-8c and (S,R)-8c to give 14c and 14c9.
Chem. Commun., 2007, 88–90 | 89
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the proline catalyzed aldol reaction might easily be scaled up to
yield gram amounts of key intermediates for the synthesis of
biologically challenging molecules. The high stereoselectivity of our
protocol as well as the broad range of proline organocatalysis
makes it suitable to a wide scope of substrates. Moreover, the
availability of both enantiomeric forms of proline combined with
the typically mild conditions and the exceedingly simple protocol
avoid the use of protecting group manipulations and open a
straightforward access for the synthesis of acid sugars.
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This work was supported by the Fonds der Chemischen
Industrie. We wish to thank Dr J. W. Bats, University of
Frankfurt for the X-ray structure determination of (R,S)-8d. We
thank BASF AG, Degussa AG, Bayer AG and Wacker-Chemie
for the donation of chemicals.
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{ Unless otherwise stated, all chemicals are commercially available and
were used without further purification. All new compounds were fully
characterized (IR, NMR, MS, elemental analysis, optical rotation). (S,R)-
8c: To a suspension of (R)-proline (172.5 mg, 1.5 mmol, 30 mol%) in
DMSO (2.0 mL) the pyruvic aldehyde dimethyl acetal 7 (2.95 g, 25 mmol)
was added. The suspension was stirred at 4 uC for 2 h after which freshly
distilled aldehyde 6c (650 mg, 5 mmol) was slowly added. The mixture
became completely clear within ca. 30 min. After 5 days at 4 uC (R)-proline
precipitated, the reaction was quenched with sat. ammonium chloride
solution (5 mL) and extracted with ethyl acetate (3 6 15 mL). The
combined organic layers were washed with brine, dried (MgSO4),
concentrated and purified by flash chromatography (silica gel, pentane :
ethyl acetate, 6 : 4). The product (S,R)-8c (533.2 mg, 43%) was obtained as
a colourless solid. Mp = 45 uC (Et2O:pentane); [a]2D4 219.5 (c 1.13 in
CHCl3); Found C, 53.0; H, 8.1. Calc. for: C11H20O6: C, 53.2, H, 8.11; IR
(CHCl3 ): nmax/cm21 3471, 2986, 2938, 2361, 2335, 1733, 1376, 1254, 1214,
1068, 852; 1H NMR dH (400 MHz, CDCl3, Me4Si) 1.30 (s, 3H, CCH3),
1.36 (s, 3H, CCH3), 2.69 (dd, 1H, COCHH, J 17.8 Hz, J 9.0 Hz), 2.92 (dd,
1H, COCHH, J 17.8 Hz, J 2.7 Hz), 3.03 (bs, 1H, OH), 3.44 (s, 6H, OCH3),
3.93–4.05 (m, 2H, OCH2), 4.04–4.12 (m, 2H, CH2CHOH, OCHCH2O),
4.45 (s, 1H, CH(OCH3)2; 13C NMR dC (125 MHz; CDCl3) 25.1 (CCH3),
26.6 (CCH3), 41.1 (CCH2), 54.7 (OCH3) 54.7(OCH3), 66.5 (CH2O), 68.3
(CCH2CHO), 77.6 (OCH2CHO), 103.7 (CHOCH3), 109.3 (C(CH3)2),
205.4 (CO); m/z (CI, methane): 249 (M+ + 1, 1), 231 (M+ 2 17, 100), 217
(M+ 2 31, 37), 185 (M+ 2 63, 78) 159 (M+ 2 89, 86).
§ Crystal data for (R,S)-8d: C16H29NO7, M = 347.40 g mol21, monoclinic,
˚
˚
˚
space group P21, a = 10.7551(14) A, b = 6.1499(5) A, c = 13.849(3) A, a =
3
˚
90u, b = 96.077(10)u, c = 90u, V = 910.8(2) A , Z = 2, calculated density r =
1.267 mg m23, m = 0.099 mm21, F(000) = 376, crystal size = 0.55 6 0.50 6
˚
0.14 mm, T = 159(2) K, l = 0.71073 A. Total reflections collected 16581
ˇ
44, 4079; (d) D. Enders, J. Palecek and C. Grondal, Chem. Commun.,
(1.90 , h , 33.52u), 3651 unique [R(int) = 0.0301]. Final R indices [I .
2s(I)]: R1 = 0.0314, wR2 = 0.0788; R indices (all data): R1 = 0.0366, wR2 =
0.0829. The structure was refined on F2 value using program SHELXL-97.
CCDC 617147. For crystallographic data in CIF or other electronic format
see DOI: 10.1039/b611265j
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90 | Chem. Commun., 2007, 88–90
This journal is ß The Royal Society of Chemistry 2007