A Concise Organocatalytic Synthesis of 3-Deoxy-2-ulosonic Acids through Cinchona-Alkaloid-Promoted Aldol Reactions of Pyruvate

Article abstract of DOI:10.1002/ejoc.201600784

Direct cross-aldol reactions of a pyruvate ester with chiral aldehydes, mediated by purely organic catalysts, is described as a crucial step in the synthesis of ulosonic acids. Cinchona alkaloids containing a tertiary amine group efficiently promote direc

Full text of DOI:10.1002/ejoc.201600784

DOI: 10.1002/ejoc.201600784
Full Paper
Organocatalytic Aldol Reactions
A Concise Organocatalytic Synthesis of 3-Deoxy-2-ulosonic
Acids through Cinchona-Alkaloid-Promoted Aldol Reactions of
Pyruvate
Marta A. Molenda,[a] Sebastian Baś,[a] and Jacek Mlynarski*[a,b]
Abstract: Direct cross-aldol reactions of a pyruvate ester with ured aldols, as desired. As a result, concise syntheses of diverse
chiral aldehydes, mediated by purely organic catalysts, is de- six-, seven-, eight-, and nine-carbon ulosonic acid esters are de-
scribed as a crucial step in the synthesis of ulosonic acids. Cin- scribed, by using a biomimetic three-carbon chain elongation
chona alkaloids containing a tertiary amine group efficiently of various sugar aldehydes. Consequently, short and practical
promote direct aldol reactions of a sterically hindered pyruvate syntheses of several ulosonic acids, including three important
ester with various sugar aldehydes. The pyruvic acid ester can naturally occurring sugars – 3-deoxy-
D-erythro-hex-2-ulosonic
be directly used as chemical equivalent of PEP (phosphoenol- acid (KDG), 3-deoxy- -manno-oct-2-ulosonic acid (KDO), and
D
pyruvate) in imitation of the synthetic principle used in nature. the rare 3-deoxyglucosone (3DG), in good overall yields are pre-
The appropriate combination of a chiral aldehyde with a chiral sented.
catalyst allows the flexible preparation of anti- or syn-config-
Introduction
the highly reactive chloral hydrate.[10] To solve this synthetic
problem, stoichiometrically preformed masked pyruvate equiv-
alents such as 2-acetylthiazole[11] or pyruvic acid dimethyl
acetal[12] have been used for the C3-elongation of chiral sugar
aldehydes en route to the ulosonic acids. Therefore, the search
for efficient catalysts[13] for asymmetric cross-aldol reactions of
pyruvate esters with enolisable optically pure aldehydes has re-
mained a challenging and important area of research, particu-
larly for the flexible and efficient formation of 3-deoxy-2-ulos-
onic and sialic acids.
The aldol reaction is one of the most significant procedures for
the stereoselective formation of carbon–carbon bonds.[1] This
reaction is also important in a metabolic context, where it is a
vital step in the enzyme-catalysed synthesis of carbohydrates.[2]
Of the known variants, the aldol reactions of 1,2-dicarbonyl
compounds[3] such as pyruvic acid and phosphoenolpyruvate
(PEP) are particularly important. These C3-donors are involved
in the enzyme-promoted biosynthesis of 3-deoxy-2-ulosonic ac-
ids and sialic acids,[4] which are essential sugar units for many
biological processes and pathways.[5] In an attempt to mimic
the activity of enzymes in catalytic asymmetric synthesis,[6]
chemists recently developed methods for using small organic
catalysts for the synthesis of natural products, even including
synthetically demanding monosaccharides.[7] However, despite
the huge synthetic importance of these 1,2-dicarbonyl com-
pounds, practical applications of pyruvates in asymmetric syn-
thesis have been mainly limited to the homo-aldol reactions of
ethyl pyruvate.[8]
We recently described the efficient aldol reactions of pyruvic
esters with chiral aldehydes[14] promoted by Trost's chiral zinc
complexes, thus conceptually mimicking type II aldolases.[15]
This valuable method was, however, restricted to the synthesis
of products with the configuration resulting from the configura-
tion of the starting aldehyde. A catalytically preformed zinc
enolate attacked the chiral aldehyde according to the Felkin–
Anh principle (Scheme 1) to give the anti-configured aldols.
These products could be used for the synthesis of many
valuable natural acids, including syn-configured 3-deoxy-
D
-
-
In this well-developed field, the direct activation of pyruvate
towards reaction with aliphatic aldehydes has long been seen
as an elusive goal,[9] and organocatalytic cross-aldol reactions
of pyruvate esters have been limited to just one example with
arabino-hept-2-ulosonic acid (DAH) and 3-deoxy- -glycero-
D
D
galacto-non-2-ulosonic acid (KDN; Scheme 1). In the other
words, an efficient method for the stereoselective synthesis of
the ulosonic acid backbone from pyruvate esters and optically
pure aldehydes still has to be developed. Particularly, if a chiral
catalyst that could control the configuration of the newly gen-
erated stereogenic centre was available, such an aldol reaction
would be complementary in terms of product configuration.
In our preliminary work,[16] we showed that this elusive
biomimetic direct aldol reaction between pyruvate esters and
chiral aldehydes can be efficiently promoted by various classes
[a] Faculty of Chemistry, Jagiellonian University,
Ingardena 3, 30-060 Krakow, Poland
E-mail: jacek.mlynarski@gmail.com
www.jacekmlynarski.pl
[b] Institute of Organic Chemistry, Polish Academy of Sciences,
Kasprzaka 44/52, Warsaw, Poland
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600784.
Eur. J. Org. Chem. 0000, 0–0
1
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Scheme 1. Retrosynthesis of DAH and KDN. Both sugars need a syn configuration between C-5 and the newly formed stereogenic centre.
of catalyst, including metal-based catalysts and also purely
organic molecules. The latter approach, in which activation of
the sterically hindered 2,6-di-tert-butyl-4-methoxyphenyl pyr-
uvate[17] is efficiently combined with the catalytic control of
tertiary amine-based organocatalysts, seems particularly inter-
esting. In this paper, we present the results of our broader in-
vestigation into the application of this method to the synthesis
of ulosonic acids from several sugar aldehydes. From a practical
point of view, the application of unmodified, naturally occurring
Cinchona alkaloids, instead of their derivatives, would be more
desirable, and for this reason we focus on these structures in
this study. We show that the proposed method can be used
practically for the synthesis of natural products. We also de-
scribe the stereochemical principles that apply in the construc-
tion of 1,3-dioxygenated carbon fragments from a pyruvic ester
(PEP equivalent). We report that the tertiary amine group of
Cinchona alkaloids[18] can flexibly control the stereoselective
aldol reactions of the pyruvate ester to give both the anti- and
the syn-configured precursors of various ulosonic acids.
Scheme 2. Cinchona alkaloids used as catalysts.
First, the cross-aldol reaction of (R)-glyceraldehyde acetonide
5 and pyruvic acid ester 6 was studied using four Cinchona
alkaloids (1a, 1b, 2a, 2b). The results are summarised in Table 1.
As the results show, when natural quinine (2a) was used in
Results and Discussion
Aldol Reaction of Pyruvate with Chiral Aldehydes
Quinine (QN), quinidine (QD), cinchonidine (CD), and cinch- CHCl3 at room temp., aldol 7 was obtained in very good yield
onine (CN) are the four major constituents of Cinchona bark (65 %) and with excellent stereoselectivity anti/syn (91:9;
extract, and thus we used these structures as the main catalysts Table 1, entry 3). To our delight, this product was found to have
in our initial studies. Some other cinchona alkaloid derivatives, the 4,5-anti configuration of natural 3-deoxy-
such as 3a, 3b, and Soos' thiourea 4[19] (Scheme 2), were also ulosonic acid (2-keto-3-deoxy-
-gluconic acid, KDG). This initial
screened as catalysts for the aldol reactions between chiral result demonstrates a practical application of the developed
D-erythro-hex-2-
D
aldehyde 5 and pyruvic acid ester 6.
method for the synthesis of natural products. Based on this
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
2
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
achievement, we decided to use natural alkaloids for the total whereas quinidine promoted the formation of syn aldol 9, in
synthesis of ulosonic acids. Further investigation of the catalytic lower yield (Table 2, entry 2). When isopropyl derivative 3a,
properties of Cinchona alkaloids revealed that the pseudoenan- with the quinine configuration, was used, aldol product 9 was
tiomeric compound quinidine (2b) was unselective, and re- formed in a higher yield and with the same anti selectivity
sulted in the formation of both diastereomers in equimolar when the catalyst loading was increased to 25 mol-% (Table 2,
amounts (Table 1, entry 4). In this case, increasing the steric entry 3). It is worth noting that the lower yields of the reactions
interaction caused by the size of the R substituent in the cata- promoted by quinidines 2b and 3b resulted from undesired
lyst structure (catalysts 2a vs. 3a) resulted in a slight decrease epimerisation at C-2 of aldehyde 8. This tendency was not ob-
in the anti selectivity (Table 1, entry 5). Moreover, the catalysts served for the catalysts with the quinine configuration (2a, 3a).
3a and 3b turned out to be more capricious when the aldol Interestingly, the epimerisation issue was not observed with the
reaction was performed on a lower scale. The use of quinine glyceraldehyde derivative described above. The other catalysts
(2a) was more predictable, and resulted in more reproducible (1a and 1b) gave lower selectivities, and for this reason were
aldol formation, irrespective of the substrate concentration. In not used in the synthesis of ulosonic acids from 8. Both isomers
the light of its promising application in the aldol reactions of of the aldol product could be used: syn-9 has the valuable con-
keto esters,[9] we also tested the activity of thiourea-type cata- figuration of natural 3-deoxy-
D-arabino-hept-2-ulosonic acid
lyst 4, but it gave a lower yield and a lower diastereoselectivity (DAH), while the anti isomer is a precursor of 3-deoxy-
(Table 1, entry 7). At this stage, we did not screen intensively hept-2-ulosonic acid (DRH).
for syn-selective catalysts, as the corresponding aldol was not a
D-ribo-
Table 2. Aldol reactions of D
-erythrose 8 with pyruvic acid ester 6.[a]
precursor of any natural product, in contrast to its anti isomer.
Table 1. Aldol reactions of (R)-glyceraldehyde acetonide 5 with pyruvic acid
ester 6.[a]
Catalyst
Yield [%]
anti/syn[b]
1
2
3
4
2a QN
2b QD
3a
51[c]
31[c]
72[c]
33[e]
71:29
25:75
75:25
15:85
Catalyst
Yield [%]
anti/syn[b]
3b
1
2
3
4
5
6
7
1a CD
1b CN
2a QN
2b QD
3a
31
31
65
46
35
48
38
83:17
67:33
91:9
50:50
75:25
38:62
71:29
[a] Reaction conditions: aldehyde (0.1 mmol), 6 (0.2 mmol), carried out in
chloroform. [b] Determined by 1H NMR spectroscopy. [c] Catalyst (15 mol-%),
aldehyde concentration 0.2
alyst (25 mol-%), aldehyde concentration 0.2
[e] Catalyst (25 mol-%), aldehyde concentration 0.4
temperature for 4 d.
M
. Reaction was carried out at 4 °C for 5 d. [d] Cat-
M
. Carried out at –25 °C for 7 d.
M. Carried out at room
3b
4
[a] Reaction conditions: aldehyde (0.1 mmol), 6 (0.1 mmol), catalyst (20 mol-
An excellent result in terms of yield and selectivity was
achieved for glucose aldehyde 10, which has the same configu-
ration at C-2 as 5 and 8. In the reaction promoted by cinchon-
idine (1a), the expected aldol product (i.e., 11) was obtained in
D-erythrose very good yield (76 %) and with a high anti selectivity (92:8).
%), aldehyde concentration 0.2 M. Reaction was carried out in chloroform at
room temp. for 4 d. [b] Determined by 1H NMR spectroscopy.
A similar investigation was made for protected
8, which has the same configuration at C-2 as glyceraldehyde In this case, pseudoenantiomeric compound 1b operated less
5. In this case, an interesting reversal of the stereoselectivity efficiently and unselectively (Table 3, entries 1 and 2). Further
was observed for the pseudoenantiomeric pair of quinine and experimentation identified quinine 2a as the best catalyst for
quinidine (2a and 2b; Table 2, entries 1 and 2). Quinine pro- this aldol reaction. Aldol 11 was isolated after the reaction in
moted the preferential formation of the anti aldol product, good yield and with an excellent anti/syn selectivity (93:7;
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
3
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Table 3, entry 3). Again, quinidine 2b was an unselective cata-
lyst for this (R)-2-configured substrate. However, the use of cata-
lyst 3b (with the same configuration as 2b) resulted in the pref-
erential formation of syn aldol 11, which was isolated in reason-
able yield (Table 3, entry 6). Nevertheless, the formation of anti
aldol 11 in high yield and with excellent selectivity (Table 3,
Table 4. Aldol reactions of
D
-arabinose 12 with pyruvic acid ester 6.[a]
entry 3) opens a synthetic route to 3-deoxy-D-glycero-D-
gulo-non-2-ulosonic acid, the C-5 epimer of naturally occurring
KDN.
Table 3. Aldol reactions of D
-glucose 10 with pyruvic acid ester 6.[a]
Catalyst
Yield [%]
anti/syn[b]
1
2
2a QN
2b QD
75
63
25:75
80:20
[a] Reaction conditions: aldehyde (0.1 mmol), 6 (0.2 mmol), catalyst (25 mol-
%), aldehyde concentration 0.2 . Reaction was carried out in chloroform at
room temperature for 5 d. [b] Determined by 1H NMR spectroscopy.
M
Table 5. Aldol reactions of D
-mannose 14 with pyruvic acid ester 6.[a]
Catalyst
Yield [%]
anti/syn[b]
1
2
3
4
5
6
1a CD
1b CN
2a QN
2b QD
3a
76
55
70
63
traces
52
92:8
50:50
93:7
50:50
–
3b
28:72
[a] Reaction conditions: aldehyde (0.1 mmol), 6 (0.1 mmol), catalyst (25 mol-
%), aldehyde concentration 0.2 M. Carried out in chloroform at room tempera-
ture for 4 d. [b] Determined by 1H NMR spectroscopy.
To our delight, this method could be also successfully ap-
plied to aldehydes with the opposite configuration at C-2:
D-
arabinose 12 and -mannose 14 are the key substrates for the
D
synthesis of KDO and KDN. Reactions of 12 promoted by either
quinine or quinidine resulted in the formation of precursors
of 4-epi-KDO and KDO (3-deoxy-D-manno-oct-2-ulosonic acid),
respectively, in high yields (75 and 63 %) and with good select-
ivities (Table 4).
The same stereochemical outcome was observed for the re-
action of
D
-mannose 14 (Table 5). Reaction with quinine (2a)
-glycero- -galacto-non-2-
Catalyst
Yield [%]
anti/syn[b]
gave a precursor of natural 3-deoxy-
D
D
1
2
3
4
5
6
2a QN
2b QD
2a QN
2b QD
1a CD
1b CN
37
29
25:75
90:10
35:65
65:35
80:20
65:35
ulosonic acid (KDN) in lower yield and with syn selectivity (37 %
yield, anti/syn, 25:75). Pseudoenantiomeric catalyst 2b resulted
in the formation of aldol 15 with a higher anti selectivity, but
in a lower yield (Table 5, entries 1 and 2). When the substrate
concentration increased, the yield increased, but unfortunately
this was at the expense of stereoselectivity (Table 5, entries 3
and 4). The use of cinchonidine (1a) or cinchonine (1b) fa-
voured the formation of the anti diastereoisomer (Table 5, en-
56[c]
52[c]
59
66
[a] Reaction conditions: aldehyde (0.1 mmol), 6 (0.2 mmol), catalyst (25 mol-
%), aldehyde concentration 0.4 . Reaction was carried out in chloroform at
room temperature for 4 d. [b] Determined by 1H NMR spectroscopy. [c] Alde-
hyde concentration 2.0
M
M.
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
4
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
tries 5 and 6). The alternatively protected 4-O-benzyl-2,3:5,6-di- ulosonic acid esters starting from the previously isolated aldols.
O-isopropylidene-
strate. To summarise the results given in Table 5, the synthesis hydrogenolysis of benzyl residues gave a mixture of anomers
of 3-deoxy- -glycero-
-galacto-non-2-ulosonic acid (KDN) was of the pyranose and furanose forms.[21]
D-mannose proved to be a less reactive sub- In all cases, cleavage of the 1,3-dioxolane ring (DOWEX) and/or
D
D
possible by using catalyst 2a, while the formation of its C-4
epimer required the use of catalyst 2b.
Previously published results hint that the selectivity of these
reactions depends mainly on the configuration of the catalysts,
although the conformation of the starting aldehyde seems also
to be important for the efficient formation of the expected aldol
products. Thus, not all aldehydes, even when they have the
same configuration at C-2, are equally good substrates for
matching chiral catalysts. On the basis of the stereochemical
outcome of the reactions promoted by chiral tertiary amines,
unified plausible transition-state models are proposed accord-
ing to Scheme 3. We presume that the basic catalyst not only
deprotonates the pyruvate ester, but also forms an asymmetric
environment for the reaction through a network of hydrogen
bonds. This was also postulated recently by Houk on the basis
of calculations for cinchonidine.[20] Generally, alkaloids 2a and
3a lead to (S)-configured aldols, whereas the use of pseudo-
enantiomeric compounds 2b and 3b results in the predominant
formation of the diastereomeric (R)-aldols (Scheme 3). The R
substituent at the C-6′ position of the quinoline core may im-
prove diastereoselectivity, but this strongly depends on the
conformation of the aldehyde. Increasing the size of the R
group from methoxyl to isopropyl may result in an increase in
the yield and diastereoselectivity (
D
-erythrose 8), but it can also
affect the reaction as seen for -glucose (10).
D
Scheme 4. Synthesis of various ulosonic acid esters.
Thus, anti aldol 9 obtained by the C4 + C3 protocol from D-
erythrose was easily transformed into 3-deoxy-
ulosonic acid (DRH) in a significant 46 % overall yield. Naturally
occurring DAH (3-deoxy- -arabino-hept-2-ulosonic acid) was
D-ribo-hept-2-
D
prepared from syn-9 in an overall yield of 24 % (Scheme 4).
The C5 + C3 strategy delivered two octulosonic acid precur-
sors (13). Esters of KDO and 4-epi-KDO were obtained in yields
of 49 and 55 %, respectively. In this case, the epimeric acid is
also a valuable compound due to its pharmaceutical use.[22]
Compound anti-11 was obtained in a highly selective syn-
thesis from
20, which was isolated in a remarkable 64 % overall yield. Start-
ing from -mannose 14, and using the same C6 + C3 strategy
to form a nine-carbon chain, KDN 22 and its C-4 epimer 21
were synthesised in 26 and 28 % yields, respectively (Scheme 4).
The most valuable achievement is undoubtedly the short
D-glucose; this was then transformed into 5-epi-KDN
D
Scheme 3. Proposed transition states.
Synthesis of Ulosonic Acids
stereoselective synthesis of protected 3-deoxy-D-erythro-hex-2-
All the aldol products obtained are valuable intermediates for ulosonic acid KDG (anti-7; Table 1). This efficient C3 + C3 strat-
the synthesis of numerous ulosonic acids (3-deoxy-2-keto egy imitates the biosynthesis of KDG in the Entner–Doudoroff
acids). We envisioned that these polyoxygenated aldols could pathway – the prokaryotic analogue of glycolysis. To demon-
serve as substrates for the synthesis of cyclic ulosonic acids strate the practical utility of the developed method, we decided
through easy deprotection and hemiketalisation. The reason for to scale up the synthesis of the sugar. Scheme 5 shows the
attempting the flexible synthetic pathway presented here is synthesis of ca. 1 g of aldol 7 with the same high anti selectivity,
that ulosonic acids occur with a variety of natural configura- controlled by the quinine catalyst. The resulting aldol 7 was
tions and chain lengths. Scheme 4 shows the synthesis of the easily deprotected by treatment with an acidic ion-exchange
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
5
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
resin (DOWEX 50 WX 4) in methanol to give cyclic ulosonic acid alcohol (LiAlH4), just as for the KDG synthesis. Next, there were
ester 23. However, hydrolysis of the sterically hindered aromatic only two further steps, as shown in Scheme 5. In nature, en-
ester turned out to be a more puzzling issue. Attempts using zymes limit the amount of 3-deoxyglucosone by its reduction
known methods – hydrolysis with potassium tert-butoxide[23] to the less reactive 3-deoxyfructose.[27] For our synthesis, we
and oxidation with ceric ammonium nitrate to the acid[24]
–
used the reverse order – oxidation of the protected 3-deoxy-
failed in this case due to the sensitive sugar core. After many fructose (the product after the reduction by LiAlH4) to 3DG 25
trials, we decided to combine the reduction of the ester moiety using Dess–Martin periodinane. This efficient protocol (24 %
to the alcohol (using LiAlH4) with a subsequent oxidation to overall yield from glyceraldehyde 5) demonstrates the first non-
the corresponding acid. The initial reduction step required the enzymatic biomimetic synthesis of this valuable sugar.
hydroxyl groups to be protected as benzyl ethers. After oxid-
ation, the carboxyl group was treated with acidic ion-exchange
resin (DOWEX 50 WX 4) in methanol. To finish the synthesis
Conclusions
of KDG methyl ester 24, the benzyl groups were removed by
hydrogenolysis over palladium on charcoal, which took place
with simultaneous glycosidation in acidic methanol. By using
this protocol, the synthesis of the final ester was easily accom-
plished without purification after all the reaction steps. The de-
sired ester (i.e., 24) was isolated in a satisfactory yield of 23 %
over five steps (14 % overall yield over seven steps from pro-
tected glyceraldehyde 5; Scheme 5).
In conclusion, we have shown that Cinchona alkaloids can initi-
ate the formation of a stable enol from a hindered pyruvate
ester. This can then be trapped by aliphatic chiral aldehydes.
We have successfully developed an efficient stereoselective di-
rect aldol reaction between a pyruvate ester and sugar alde-
hydes that represents a biomimetic synthesis of ulosonic acids.
Our method opens up synthetic routes to both anti- and syn-
configured aldol products, which was impossible by using pre-
vious methods based on stoichiometric amounts of lithium
enolates or chiral zinc complexes. Using this method, we have
developed practical protocols for the stereoselective organocat-
alytic synthesis of several six- to nine-carbon 3-deoxy-2-ulos-
onic acid esters. Moreover, we have presented total syntheses
of two naturally occurring oxidised sugars – 3-deoxy-D-erythro-
hex-2-ulosonic acid (KDG) and 3-deoxyglucosone (3DG) – both
of which show biological activity.
Experimental Section
General Information: All starting materials and reagents were ob-
tained from commercial sources, and were used as received unless
otherwise noted. All solvents were freshly distilled before use. Opti-
cal rotations were measured at room temperature with a digital
polarimeter. High-resolution mass spectra were acquired using elec-
trospray (ESI) ionisation with a time-of-flight (TOF) detector. 1H NMR
spectra were recorded with spectrometers operating at 600 MHz in
CDCl3, [D6]acetone, CD3OD, or D2O. Data are reported as follows:
chemical shifts in parts per million (ppm) from tetramethylsilane
(used as an internal standard), integration, multiplicity (s = singlet,
d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m =
multiplet, br. = broad), coupling constants (in Hz), and assignment.
13C NMR spectra were measured at 150 MHz with complete proton
decoupling. Chemical shifts are reported in ppm, and spectra were
calibrated using the residual solvent as an internal standard. Reac-
tions were monitored using TLC on silica [aluminium-backed plates
(0.2 mm)]. Plates were visualised with UV light (254 nm), and by
treatment with: aqueous cerium(IV) sulfate solution with molybdic
and sulfuric acids followed by heating. All organic solutions were
dried with anhydrous sodium sulfate. Reaction products were puri-
fied by flash chromatography using silica gel 60 (240–400 mesh).
Scheme 5. Total synthesis of KDG and 3DG. BAIB = (diacetoxyiodo)benzene;
TEMPO = (2,2,6,6-tetramethylpiperidin-1-yl)oxyl.
Ester 23 was also used in the total synthesis of another natu-
ral product – 3-deoxyglucosone (3-deoxy-D-erythro-hexos-2-
Sugar aldehydes were synthesised by using previously published
protocols: (R)-2,3-O-isopropylidene-glyceraldehyde (5),[28] 4-O-
ulose, 3DG). 3DG is synthesised by the Maillard reaction, and is
metabolised to 3-deoxyfructose and KDG.[25] This highly react-
ive sugar is related to vascular complications of diabetes, neuro-
degenerative disorders like Alzheimer's disease, and even ag-
ing.[26] The synthesis of 3DG 25 was carried out from 23, start-
benzyl-2,3-O-isopropylidene-
D
-erythrose (8),[29] 4-O-benzyl-2,3:5,6-
di-O-isopropylidene-
D
-glucose (10),[30] 2,3:4,5-di-O-isopropylidene-
D
-arabinose (12)[31] and 2-O-benzyl-3,4:5,6-di-O-isopropylidene-
D-
mannose (14).[11] The synthesis of 2,6-di-tert-butyl-4-methoxy-
phenyl pyruvate (6) was carried out based on a method reported
ing with protection with benzyl ethers, and reduction to the by Morin.[17]
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
6
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Representative Procedure for the Direct Aldol Reaction of Pyr-
uvic Ester 6 with Protected Sugar Aldehydes: A mixture of alde-
hyde (0.1 mmol), aryl pyruvate 6 (30.6 mg, 0.1 mmol; or 61.2 mg,
0.2 mmol), and catalyst (20–25 mol-%) in chloroform (0.5 mL) was
(dd, J = 3.8, 2.2 Hz, 1 H), 3.81 (s, 3 H), 3.30 (dd, J = 17.1, 3.5 Hz, 1
H), 3.19 (dd, J = 17.1, 8.5 Hz, 1 H), 1.37 (s, 3 H), 1.33 (s, 3 H), 1.32 (s,
3 H), 1.31 (s, 12 H), 1.31 (s, 9 H) ppm. 13C{1H} NMR (151 MHz, [D6]ace-
tone): δ = 192.7, 162.7, 157.9, 144.1, 142.0, 139.9, 129.1, 128.5, 128.3,
stirred for 4 d at room temperature. The solvent was then evapo- 112.6, 110.2, 108.7, 81.9, 79.7, 78.9, 78.6, 75.7, 70.1, 66.2, 55.6, 45.1,
rated, and the crude mixture was purified on silica gel using hex-
ane/ethyl acetate (4:1 or 9:1) as eluent to give the desired aldols.
36.2, 31.8, 27.7, 27.1, 26.9, 25.6 ppm. HRMS (ESI-TOF): calcd. for
C37H52O10Na 679.3458; found 679.3461. IR (neat): ν = 3496, 2984,
˜
2932, 1744, 1585 cm–1. [α]D25 = –3.4 (c = 1.0, CHCl3).
3-Deoxy-5,6-O-isopropylidene-D-erythro-hex-2-ulosonic 2,6-Di-
tert-butyl-4-methoxyphenyl Ester (anti-7): Table 1. Based on the
general procedure, aldehyde 5 (425 mg, 3.27 mmol) reacted with
pyruvate 6 (1000 mg, 3.27 mmol) to give aldol anti-7 (844 mg, 59 %)
as a pale yellow oil. 1H NMR (600 MHz, CDCl3): δ = 6.88 (s, 2 H),
4.18 (m, 1 H), 4.11 (dd, J = 8.3, 6.3 Hz, 1 H), 4.04 (dd, J = 11.9, 6.5 Hz,
1 H), 3.97 (dd, J = 8.3, 5.3 Hz, 1 H), 3.80 (s, 3 H), 3.30 (dd, J = 18.3,
2.9 Hz, 1 H), 3.12 (dd, J = 18.3, 8.9 Hz, 1 H), 2.69 (s,1 H), 1.42 (s, 3
H), 1.35 (s, 3 H), 1.31 (s, 9 H), 1.30 (s, 9 H) ppm. 13C{1H} NMR
(150 MHz, CDCl3): δ = 193.3, 161.7, 156.9, 143.2, 140.9, 111.9, 109.7,
77.5, 68.5, 66.5, 55.3, 43.1, 35.7, 31.5, 31.4, 26.7, 25.1 ppm. HRMS
(ESI-TOF): calcd. for C24H36O7Na 459.2359; found 459.2345. IR (neat):
7-O-Benzyl-3-deoxy-5,6:8,9-di-O-isopropylidene-D-glycero-D-
ido-non-2-ulosonic 2,6-Di-tert-butyl-4-methoxyphenyl Ester
(syn-11): Table 3. Based on the general procedure, aldehyde 10
(35 mg, 0.1 mmol) reacted with pyruvate 6 (30.6 mg, 0.1 mmol) to
give aldol syn-11 (24 mg, 37 %) as a pale yellow oil. 1H NMR
(600 MHz, [D6]acetone): δ = 7.44–7.25 (m, 5 H), 6.91 (s, 2 H), 4.89
(d, J = 11.4 Hz, 1 H), 4.77 (d, J = 11.3 Hz, 1 H), 4.37–4.31 (m, 1 H),
4.29 (td, J = 6.9, 4.1 Hz, 1 H), 4.24 (dd, J = 8.1, 2.9 Hz, 1 H), 4.15 (dd,
J = 8.1, 2.8 Hz, 1 H), 4.03 (m, 2 H), 3.83 (dd, J = 4.1, 2.9 Hz, 1 H),
3.82 (s, 3 H), 3.35 (dd, J = 17.5, 8.8 Hz, 1 H), 3.12 (dd, J = 17.5, 4.0 Hz,
1 H), 1.38 (s, 3 H), 1.35 (s, 3 H), 1.33 (s, 3 H), 1.31 (s, 12 H), 1.31 (s, 9
H) ppm. 13C{1H} NMR (151 MHz, [D6]acetone): δ = 192.7, 162.7,
157.9, 144.1, 144.1, 139.7, 129.1, 128.8, 128.4, 112.6, 109.9, 108.9,
79.5, 78.7, 78.5, 78.0, 75.6, 66.4, 65.9, 55.6, 44.4, 36.2, 31.8, 27.4, 27.2,
26.9, 25.6 ppm. HRMS (ESI-TOF): calcd. for C37H52O10Na 679.3458;
ν = 3441, 2961, 2931, 2873, 1739, 1590 cm–1. [α]D25 = –3.6 (c = 1.0,
˜
CHCl3).
7-O-Benzyl-3-deoxy-5,6-O-isopropylidene-D-ribo-hept-2-ulosonic
2,6-Di-tert-butyl-4-methoxyphenyl Ester (anti-9): Table 2. Based
on the general procedure, aldehyde 8 (25 mg, 0.1 mmol) reacted
with pyruvate 6 (61.2 mg, 0.2 mmol) to give aldol anti-9 (30 mg,
found 679.3448. IR (neat): ν = 3466, 2956, 2923, 2868, 2853, 1734,
˜
1589 cm–1. [α]2D5 = –0.7 (c = 1.1, CHCl3).
1
54 %) as a pale yellow oil. H NMR (600 MHz, CDCl3): δ = 7.41–7.28
3-Deoxy-5,6:7,8-di-O-isopropylidene-D-manno-oct-2-ulosonic
(m, 5 H), 6.88 (s, 2 H), 4.62 (d, J = 11.7 Hz, 1 H), 4.59 (d, J = 11.8 Hz,
1 H), 4.49–4.42 (m, 1 H), 4.41 (ddd, J = 9.5, 5.5, 4.1 Hz, 1 H), 4.11–
4.05 (m, 1 H), 3.81 (s, 3 H), 3.73 (t, J = 9.5 Hz, 1 H), 3.54 (dd, J = 9.7,
4.0 Hz, 1 H), 3.28 (dd, J = 17.2, 3.5 Hz, 1 H), 3.22 (dd, J = 17.3, 8.6 Hz,
1 H), 1.36 (s, 3 H), 1.32 (s, 3 H), 1.31 (s, 18 H) ppm. 13C{1H} NMR
(151 MHz, CDCl3): δ = 192.0, 161.9, 156.9, 143.5, 141.2, 136.8, 128.7,
128.4, 128.3, 112.0, 109.0, 79.9, 75.5, 74.2, 68.5, 65.7, 55.4, 43.9, 35.8,
35.7, 31.7, 31.6, 28.0, 25.5 ppm. HRMS (ESI-TOF): calcd. for
2,6-Di-tert-butyl-4-methoxyphenyl Ester (anti-13): Table 4. Based
on the general procedure, aldehyde 12 (23 mg, 0.1 mmol) reacted
with pyruvate 6 (61.2 mg, 0.2 mmol) to give aldol anti-13 (27 mg,
1
50 %) as a pale yellow oil. H NMR (600 MHz, CDCl3): δ = 6.88 (s, 2
H), 4.34 (tdd, J = 8.2, 3.7, 1.7 Hz, 1 H), 4.20 (dd, J = 8.7, 6.1 Hz, 1 H),
4.07 (ddd, J = 9.3, 7.8, 4.3 Hz, 1 H), 4.02 (dd, J = 8.7, 5.2 Hz, 1 H),
3.83 (t, J = 7.4 Hz, 1 H), 3.80 (s, 3 H), 3.77 (dd, J = 8.6, 7.4 Hz, 1 H),
3.61 (s, 1 H), 3.36 (dd, J = 17.5, 3.7 Hz, 1 H), 3.17 (dd, J = 17.5, 8.2 Hz,
1 H), 1.45 (s, 3 H), 1.37 (s, 3 H), 1.36 (s, 6 H), 1.31 (s, 9 H), 1.31 (s, 9
H) ppm. 13C{1H} NMR (151 MHz, CDCl3): δ = 192.0, 161.9, 156.9,
143.4, 141.2, 112.0, 110.4, 109.8, 82.9, 81.1, 76.5, 68.5, 68.1, 55.4,
43.6, 35.8, 35.8, 31.6, 31.6, 27.0, 26.9, 26.6, 25.2 ppm. HRMS (ESI-
C32H44O8Na 579.2934; found 579.2894. IR (neat): ν = 3454, 3059,
˜
3029, 2960, 2935, 2911, 2868, 1758, 1739, 1588 cm–1. [α]D25 = –2.2
(c = 0.5, CHCl3).
7-O-Benzyl-3-deoxy-5,6-O-isopropylidene-D-arabino-hept-2-
ulosonic Acid 2,6-Di-tert-butyl-4-methoxyphenyl Ester (syn-9):
Table 2. Based on the general procedure, aldehyde 8 (25 mg,
0.1 mmol) reacted with pyruvate 6 (61.2 mg, 0.2 mmol) to give aldol
TOF): calcd. for C29H44O9Na 559.2883; found 559.2842. IR (neat): ν =
˜
3447, 2963, 2931, 2873, 1739, 1590 cm–1. [α]D25 = +10.2 (c = 1.0,
CHCl3).
1
syn-9 (15 mg, 28 %) as a pale yellow oil. H NMR (600 MHz, CDCl3):
3-Deoxy-5,6:7,8-di-O-isopropylidene-D-gluco-oct-2-ulosonic
δ = 7.38–7.27 (m, 5 H), 6.88 (s, 2 H), 4.58 (d, J = 2.3 Hz, 2 H), 4.56–
4.52 (m, 1 H), 4.47–4.41 (m, 1 H), 3.80 (s, 3 H), 3.57 (dd, J = 9.6,
4.3 Hz, 1 H), 3.52 (dd, J = 9.6, 6.0 Hz, 1 H), 3.22 (dd, J = 18.0, 8.0 Hz,
1 H), 3.14 (dd, J = 18.0, 4.3 Hz, 1 H), 2.69 (d, J = 4.6 Hz, 1 H), 1.33
(s, 3 H), 1.31 (s, 3 H), 1.30 (s, 9 H), 1.30 (s, 9 H) ppm. 13C{1H} NMR
(151 MHz, CDCl3): δ = 192.6, 161.8, 156.9, 143.4, 141.0, 137.8, 128.7,
128.6, 127.9, 112.0, 109.6, 73.9, 73.6, 73.1, 66.5, 65.5, 55.4, 43.2, 35.8,
35.8, 31.6, 31.6, 27.9, 25.5 ppm. HRMS (ESI-TOF): calcd. for
2,6-Di-tert-butyl-4-methoxyphenyl Ester (syn-13): Table 4. Based
on the general procedure, aldehyde 12 (23 mg, 0.1 mmol) reacted
with pyruvate 6 (61.2 mg, 0.2 mmol) to give aldol syn-13 (30 mg,
1
56 %) as a pale yellow oil. H NMR (600 MHz, CDCl3): δ = 6.88 (s, 2
H), 4.42 (tt, J = 9.0, 3.1 Hz, 1 H), 4.16 (dd, J = 8.6, 6.1 Hz, 1 H), 4.09–
4.04 (m, 1 H), 3.99 (dd, J = 8.7, 4.8 Hz, 1 H), 3.98–3.93 (m, 2 H), 3.80
(s, 3 H), 3.33 (dd, J = 17.2, 9.2 Hz, 1 H), 3.16 (dd, J = 17.2, 3.4 Hz, 1
H), 2.74 (d, J = 8.3 Hz, 1 H), 1.43 (s, 3 H), 1.42 (s, 3 H), 1.38 (s, 3 H),
1.34 (s, 3 H), 1.31 (s, 18 H) ppm. 13C{1H} NMR (151 MHz, CDCl3): δ =
192.2, 161.9, 156.9, 143.4, 143.4, 141.2, 112.0, 110.1, 109.9, 82.6, 77.3,
68.1, 66.6, 55.4, 44.0, 35.8, 35.8, 31.6, 31.6, 27.3, 27.0, 26.8, 25.4 ppm.
HRMS (ESI-TOF): calcd. for C29H44O9Na 559.2883; found 559.2854. IR
C32H44O Na 579.2934; found 579.2915. IR (neat): ν = 3448, 3087,
˜
8
3063, 3029, 2960, 2935, 2914, 2868, 1758, 1743, 1588 cm–1. [α]D25
+1.1 (c = 0.9, CHCl3).
=
7-O-Benzyl-3-deoxy-5,6:8,9-di-O-isopropylidene-D-glycero-D-
gulo-non-2-ulosonic 2,6-Di-tert-butyl-4-methoxyphenyl Ester
(anti-11): Table 3. Based on the general procedure, aldehyde 10
(35 mg, 0.1 mmol) reacted with pyruvate 6 (30.6 mg, 0.1 mmol) to
(neat): ν = 3481, 2962, 2929, 2873, 1738 (and 1590) cm–1. [α]D25
–2.8 (c = 1.0, CHCl3).
=
˜
give aldol anti-11 (43 mg, 65 %) as a pale yellow oil. 1H NMR 5-O-Benzyl-3-deoxy-6,7:8,9-di-O-isopropylidene-
D
-glycero-
talo-non-2-ulosonic 2,6-Di-tert-butyl-4-methoxyphenyl Ester
(anti-15) and 5-O-Benzyl-3-deoxy-6,7:8,9-di-O-isopropylidene-
-glycero- -galacto-non-2-ulosonic 2,6-Di-tert-Butyl-4-
D-
(600 MHz, [D6]acetone): δ = 7.44–7.25 (m, 5 H), 6.91 (s, 2 H), 4.90
(d, J = 11.3 Hz, 1 H), 4.76 (d, J = 11.3 Hz, 1 H), 4.32 (dd, J = 6.7,
3.8 Hz, 2 H), 4.19 (dd, J = 7.3, 2.2 Hz, 1 H), 4.11 (t, J = 7.6 Hz, 1 H),
4.05 (dd, J = 8.3, 7.1 Hz, 1 H), 4.00 (dd, J = 8.3, 6.6 Hz, 1 H), 3.92
D
D
methoxyphenyl Ester (syn-15): Table 4. The aldols were formed
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
7
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
as a complex inseparable mixture that was used in the next step:
deprotection and cyclisation to the pyranose forms.
HRMS (ESI-TOF): calcd. for C23H36O9Na 479.2257; found 479.2229. IR
(neat): ν = 3354, 2964, 2926, 2870, 1745 (and 1591) cm–1
.
˜
3-Deoxy-D-gluco-oct-2-ulosonic Acid 2,6-Di-tert-butyl-4-
3-Deoxy-D-ribo-hept-2-ulosonic Acid 2,6-Di-tert-butyl-4-
methoxyphenyl Ester (19; 4-epi-KDO Ester): Scheme 4. Com-
pound syn-13 (30 mg, 0.056 mmol) was dissolved in MeOH (1 mL)
with DOWEX 50 WX 4 (60 mg), and the mixture was stirred vigor-
ously at room temperature for 24 h. The reaction mixture was then
filtered through a filter funnel, the solvent was evaporated, and the
residue was purified by column chromatography using ethyl acet-
ate/methanol (15:1) as eluent to give 19 (25 mg, 98 %) as a pale
yellow oil. 1H NMR (600 MHz, CD3OD): δ = 6.86 (s, 2 H), 4.24 (dd,
J = 1.5, 8.6 Hz, 1 H), 4.08 (dd, J = 3.1, 3.3, 6.7 Hz, 1 H), 3.91 (ddd,
J = 3.1, 5.5, 8.6 Hz, 1 H), 3.87 (m, 1 H), 3.83 (dd, J = 3.1, 11.6 Hz, 1
H), 3.78 (s, 3 H), 3.70 (dd, J = 5.5, 11.6 Hz, 1 H), 2.69 (dd, J = 3.4,
14.2 Hz, 1 H), 1.93 (ddd, J = 0.8, 3.1, 14.2 Hz, 1 H), 1.33 (s, 18 H)
ppm. 13C{1H} NMR (151 MHz, CD3OD): δ = 171.3, 158.1, 145.1, 144.9,
143.4, 112.6, 112.6, 97.1, 71.1, 69.2, 68.9, 68.9, 67.1, 64.6, 55.8, 36.6,
36.6, 31.9, 31.7 ppm. HRMS (ESI-TOF): calcd. for C23H36O9Na
methoxyphenyl Ester (16; DRH Ester): Scheme 4. Compound anti-
9 (30 mg, 0.054 mmol) was dissolved in MeOH (1 mL) with DOWEX
50 WX 4 (60 mg) and palladium on carbon (30 mg) under a
hydrogen atmosphere, and the mixture was stirred vigorously at
room temperature for 24 h. The reaction mixture was then filtered
through a short pad of silica gel, then the solvent was evaporated,
and the residue was purified by column chromatography using
ethyl acetate/methanol (15:1) as eluent to give 16 (20 mg, 86 %) as
a pale yellow oil. 1H NMR (600 MHz, CD3OD): δ = 6.88–6.86 (m, 6
H), 4.29 (dd, J = 9.5, 5.2 Hz, 1.2 H), 4.21 (q, J = 3.2 Hz, 0.7 H), 4.16
(dd, J = 7.5, 3.2 Hz, 1.3 H), 4.00 (dd, J = 9.2, 5.6 Hz, 1.3 H), 3.92–3.88
(m, 3 H), 3.82 (dd, J = 6.2, 3.6 Hz, 1 H), 3.79–3.78 (m, 10 H), 3.74
(dd, J = 12.7, 3.7 Hz, 2.7 H), 3.62 (dd, J = 10.7, 5.7 Hz, 1.3 H), 3.60–
3.57 (m, 1.6 H), 3.56–3.52 (m, 1 H), 2.87 (dd, J = 13.7, 7.1 Hz, 1 H),
2.72 (dd, J = 12.8, 8.6 Hz, 1 H), 2.47 (dd, J = 12.8, 7.1 Hz, 1 H), 2.37
(dd, J = 14.3, 3.0 Hz, 1 H), 2.33 (dd, J = 14.3, 3.6 Hz, 1 H), 2.18 (dd,
J = 13.7, 2.7 Hz, 1 H), 1.35–1.32 (m, 59 H) ppm. 13C{1H} NMR
(151 MHz, CD3OD): δ = 171.0, 170.7, 169.5, 157.6, 157.5, 144.7, 144.6,
144.5, 144.5, 143.2, 143.1, 112.3, 112.2, 110.2, 104.3, 102.8, 96.4, 76.5,
73.6, 73.3, 73.1, 72.8, 71.3, 70.9, 69.1, 68.5, 64.3, 64.2, 63.5, 55.5, 55.0,
49.8, 45.3, 44.7, 37.4, 36.3, 36.3, 31.8, 31.8, 31.6 ppm. HRMS (ESI-
479.2257; found 479.2237. IR (neat): ν = 3354, 2964, 2926, 2870,
˜
1745 (and 1591) cm–1. [α]D25 = +5.5 (c = 1.0, CH3OH).
3-Deoxy-D-glycero-D-gulo-non-2-ulosonic Acid 2,6-Di-tert-butyl-
4-methoxyphenyl Ester (20; 5-epi-KDN): Scheme 4. Compound
anti-11 (43 mg, 0.065 mmol) was dissolved in MeOH (1 mL) with
DOWEX 50 WX 4 (80 mg) and palladium on carbon (40 mg) under
a hydrogen atmosphere, and the mixture was stirred vigorously at
room temperature for 24 h. The reaction mixture was filtered
through a short pad of silica gel, the solvent was evaporated, and
the residue was purified by column chromatography using ethyl
acetate/methanol (9:1) as eluent to give 20 (31 mg, 98 %) as a pale
TOF): calcd. for C22H34O8Na 449.2151; found 449.2129. IR (neat): ν =
˜
3372, 3002, 2959, 2908, 2871, 2832, 1758, 1589 cm–1
.
3-Deoxy-D-arabino-hept-2-ulosonic Acid 2,6-Di-tert-butyl-4-
methoxyphenyl Ester (17; DAH Ester): Scheme 4. Compound syn-
9 (15 mg, 0.027 mmol) was dissolved in MeOH (1 mL) with DOWEX
50 WX 4 (30 mg) and palladium on carbon (15 mg) under a
hydrogen atmosphere, and the mixture was stirred vigorously at
room temperature for 24 h. The reaction mixture was then filtered
through a short pad of silica gel, the solvent was evaporated, and
the residue was purified by column chromatography using ethyl
acetate/methanol (15:1) as eluent to give 17 (10 mg, 86 %) as a
pale yellow oil. 1H NMR (600 MHz, CD3OD): δ = 6.88 (s, 2 H), 3.99
(ddd, J = 11.5, 9.0, 5.0 Hz, 1 H), 3.93–3.87 (m, 2 H), 3.79 (s, 3 H), 3.75
(m, 1 H), 3.33–3.31 (m, 1 H), 2.37 (dd, J = 12.9, 5.0 Hz, 1 H), 2.16
(dd, J = 12.9, 11.6 Hz, 1 H), 1.35 (s, 9 H), 1.35 (s, 9 H) ppm. 13C{1H}
NMR (151 MHz, CD3OD): δ = 170.4, 156.7, 143.6, 143.5, 141.8, 111.2,
95.3, 74.4, 72.1, 69.0, 61.9, 54.4, 39.2, 35.2, 35.2, 30.5, 30.4 ppm.
HRMS (ESI-TOF): calcd. for C22H34O8Na 449.2151; found 449.2162. IR
1
yellow oil. H NMR (600 MHz, CD3OD): δ = 6.92–6.89 (m, 5 H), 4.59
(dd, J = 6.7, 5.3 Hz, 2 H), 4.42 (d, J = 3.6 Hz, 2 H), 4.41–4.39 (m, 3
H), 4.31 (d, J = 4.4 Hz, 1 H), 4.15 (dd, J = 3.6, 2.3 Hz, 3 H), 4.05–4.01
(m, 2 H), 3.81–3.80 (m, 5 H), 3.74–3.70 (m, 2 H), 3.66 (dd, J = 11.2,
5.5 Hz, 2 H), 3.60 (dd, J = 11.4, 6.1 Hz, 2 H), 3.02 (dd, J = 13.6, 7.7 Hz,
0.2 H), 2.75 (dd, J = 12.6, 9.0 Hz, 0.3 H), 2.64 (t, J = 12.2 Hz, 1 H),
2.51 (dd, J = 12.6, 7.1 Hz, 0.3 H), 2.22 (dd, J = 13.6, 4.5 Hz, 0.2 H),
2.04 (dd, J = 12.3, 4.2 Hz, 1 H), 1.39–1.36 (m, 27 H) ppm. 13C{1H}
NMR (151 MHz, CD3OD): δ = 177.3, 174.8, 159.5, 158.5, 145.0, 144.8,
142.6, 142.2, 112.6, 110.9, 110.5, 97.1, 82.2, 81.3, 75.0, 74.9, 74.8,
74.5, 74.5, 73.4, 72.9, 72.1, 72.1, 71.6, 71.5, 64.7, 64.3, 52.7, 52.6, 52.6,
36.6, 36.6, 33.9, 31.7 ppm. HRMS (ESI-TOF): calcd. for C24H38O10Na
509.2363; found 509.2330. IR (neat): ν = 3333, 2940, 2887, 2835,
˜
1733, 1594 cm–1
.
(neat): ν = 3426, 3323, 3253, 3002, 2956, 2916, 2868, 2850, 1740,
˜
1593, 1416 cm–1. [α]2D5 = +12.1 (c = 0.8, MeOH).
5-O-Benzyl-3-deoxy-D-glycero-D-talo-non-2-ulosonic Acid 2,6-
Di-tert-butyl-4-methoxyphenyl Ester (21; 5-OBn-4-epi-KDN Es-
ter): Scheme 4. Based on the general procedure, aldehyde 14
(35 mg, 0.1 mmol) reacted with pyruvate 6 (61.2 mg, 0.2 mmol),
and the products were purified by column chromatography using
hexane/ethyl acetate (4:1) as eluent to give an inseparable mixture
contaminated with aldehyde.
3-Deoxy-D-manno-oct-2-ulosonic Acid 2,6-Di-tert-butyl-4-
methoxyphenyl Ester (18; KDO Ester): Scheme 4. Compound anti-
13 (27 mg, 0.05 mmol) was dissolved in MeOH (1 mL) with DOWEX
50 WX 4 (60 mg), and the mixture was stirred vigorously at room
temperature for 24 h. The reaction mixture was then filtered
through a filter funnel, the solvent was evaporated, and the residue
was purified by column chromatography using ethyl acetate/meth- This mixture was dissolved in MeOH (1 mL) with DOWEX 50 WX 4
anol (15:1) as eluent to give 18 (22.5 mg, 98 %) as a pale yellow oil.
1H NMR (600 MHz, CD3OD): δ = 6.90 (s, 0.15 H), 6.89 (s, 2 H), 4.12
(ddd, J = 11.9, 4.7, 3.0 Hz, 1 H), 4.06 (dd, J = 13.4, 4.7 Hz, 1 H), 3.97
(dd, J = 8.8, 1.1 Hz, 1 H), 3.95–3.92 (m, 1 H), 3.83 (dd, J = 11.6,
2.8 Hz, 1 H), 3.81 (s, 0.45 H), 3.81 (s, 3 H), 3.74 (dd, J = 11.7, 4.6 Hz,
(60 mg), and the mixture was stirred vigorously at room tempera-
ture for 24 h. The reaction mixture was then filtered through a filter
funnel, the solvent was evaporated, and the residue was purified
by column chromatography using ethyl acetate/methanol (15:1) as
eluent to give 21 (16 mg, 28 %) as a pale yellow oil. 1H NMR
1 H), 2.75 (dd, J = 12.5, 9.4 Hz, 0.15 H), 2.56 (t, J = 12.2 Hz, 1 H), (600 MHz, CD3OD): δ = 7.48–7.45 (m, 2 H), 7.39–7.34 (m, 2 H), 7.33–
2.48 (dd, J = 12.5, 7.0 Hz, 0.15 H), 1.97 (ddd, J = 12.5, 4.7, 0.7 Hz, 1
H), 1.37 (s, 1.4 H), 1.37 (s, 1.4 H), 1.37 (s, 9 H), 1.36 (s, 9 H) ppm.
13C{1H} NMR (151 MHz, CD3OD): δ = 171.7, 170.3, 158.1, 145.1, 144.9,
143.4, 112.6, 112.6, 102.7, 97.4, 86.7, 73.5, 73.0, 71.3, 70.8, 67.8, 67.6,
65.7, 65.0, 64.5, 55.8, 49.8, 36.6, 36.6, 34.9, 31.9, 31.9, 31.8, 31.7 ppm.
7.29 (m, 1 H), 6.91 (s, 2 H), 4.79 (d, J = 11.3 Hz, 1 H), 4.65 (d, J =
11.3 Hz, 1 H), 4.58 (dd, J = 10.1, 1.1 Hz, 1 H), 4.53 (dd, J = 6.2, 3.1 Hz,
1 H), 3.96 (dd, J = 9.2, 1.2 Hz, 1 H), 3.91–3.85 (m, 2 H), 3.83 (dd, J =
9.1, 1.7 Hz, 1 H), 3.82 (s, 3 H), 3.75–3.70 (m, 1 H), 2.37 (dd, J = 14.3,
2.9 Hz, 1 H), 2.33 (dd, J = 14.3, 3.7 Hz, 1 H), 1.38 (s, 9 H), 1.37 (s, 9
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
8
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
H) ppm. 13C{1H} NMR (151 MHz, CD3OD): δ = 171.2, 158.1, 145.0, Step 2: This mixture was subsequently dissolved in dry THF (10 mL),
144.8, 143.3, 139.7, 129.3, 129.1, 128.7, 112.6, 112.6, 97.2, 75.0, 72.3,
and the solution was cooled in an ice bath. A solution of lithium
71.7, 70.5, 68.3, 66.0, 65.2, 55.8, 55.8, 36.7, 36.5, 31.9, 31.7 ppm. aluminium hydride (1
M
in THF; 7.6 mL, 7.60 mmol, 4 equiv.) was
HRMS (ESI-TOF): calcd. for C31H44O10Na 599.2832; found 599.2806. then added by syringe. The reaction mixture was allowed to reach
IR (neat): ν = 3375, 2953, 2929, 2868, 1749, 1589 cm–1. [α]D25 = +2.1 room temperature, and was stirred overnight. After TLC (using hex-
˜
(c = 0.6, MeOH).
ane/ethyl acetate, 4:1 as eluent) showed that the reaction was com-
plete, the excess LiAlH4 was quenched with EtOAc and a saturated
solution of potassium sodium tartrate. The mixture was extracted
with ethyl acetate (3 × 50 mL), and the combined organic extracts
were dried with Na2SO4. The solvent was evaporated, and the resi-
due was purified by column chromatography using hexane/ethyl
acetate (4:1) to give a mixture of 2,4,5-tri-O-benzyl-3-deoxy-D-fruc-
tose contaminated with dibenzylated derivatives (747 mg). HRMS
(ESI-TOF): calcd. for C27H30O5Na 457.1991; found 457.1996.
5-O-Benzyl-3-deoxy-D-glycero-D-galacto-non-2-ulosonic Acid
2,6-Di-tert-butyl-4-methoxyphenyl Ester (22; 5-OBn-KDN Ester):
Scheme 4). Based on the general procedure, aldehyde 14 (35 mg,
0.1 mmol) reacted with pyruvate 6 (61.2 mg, 0.2 mmol), and the
products were purified by column chromatography using hexane/
ethyl acetate (4:1) as eluent to give an inseparable mixture contami-
nated with aldehyde.
This mixture was dissolved in MeOH (1 mL) with DOWEX 50 WX 4
(60 mg), and the mixture was stirred vigorously at room tempera-
ture for 24 h. The reaction mixture was then filtered through a filter
funnel, the solvent was evaporated, and the residue was purified
by column chromatography using ethyl acetate/methanol (15:1) as
eluent to give 22 (15 mg, 26 %) as a pale yellow oil. 1H NMR
(600 MHz, CD3OD): δ = 7.46–7.44 (m, 2 H), 7.38–7.34 (m, 2 H), 7.32–
7.28 (m, 1 H), 6.91 (s, 2 H), 5.04 (d, J = 10.9 Hz, 1 H), 4.78 (d, J =
10.9 Hz, 1 H), 4.23 (ddd, J = 11.5, 9.0, 5.3 Hz, 1 H), 4.21 (dd, J = 9.9,
1.3 Hz, 1 H), 3.92 (dd, J = 9.4, 1.3 Hz, 1 H), 3.88 (dd, J = 11.3, 3.1 Hz,
1 H), 3.82 (s, 3 H), 3.80 (m, 1 H), 3.71 (dd, J = 11.3, 5.8 Hz, 1 H),
3.70–3.66 (m, 1 H), 2.34 (dd, J = 12.8, 5.1 Hz, 1 H), 2.23 (dd, J = 12.8,
11.7 Hz, 1 H), 1.38 (s, 18 H) ppm. 13C{1H} NMR (151 MHz, CD3OD):
δ = 171.8, 164.9, 162.8, 158.1, 145.0, 129.2, 129.0, 128.5, 112.6, 97.2,
80.4, 78.0, 76.0, 72.7, 72.2, 71.0, 70.3, 65.1, 55.8, 36.7, 36.6, 31.9,
31.8 ppm. HRMS (ESI-TOF): calcd. for C31H44O10Na 599.2832; found
Step 3: The mixture of fructoses (747 mg) was dissolved in a di-
chloromethane/water mixture (3:1; 15 mL), and then (diacetoxyi-
odo)benzene (2.19 g, 6.80 mmol, about 4 equiv.) and TEMPO
(80 mg, 0.51 mmol, about 0.3 equiv.) were added. The reaction mix-
ture was stirred vigorously for 4 h at room temperature. The mixture
was then washed with saturated Na2S2O3, and extracted with di-
chloromethane (3 × 50 mL). The combined organic extracts were
dried with Na2SO4, and the solvents were evaporated. The crude
product was purified on a short pad of silica gel, eluting with ethyl
acetate, to give the acid (431 mg) still contaminated by dibenzyl-
ated by-products. HRMS (ESI-TOF): calcd. for C27H28O6Na 471.1784;
found 471.1779.
Step 4: The mixture of acids (431 mg) was dissolved in anhydrous
methanol (10 mL) under an argon atmosphere, and acidic ion-ex-
change resin (DOWEX 50 WX 4; 1000 mg) was added. The reaction
mixture was stirred overnight at room temperature, then it was
filtered through a filter funnel, and the solvents were evaporated.
The residue was purified by column chromatography using hexane/
ethyl acetate (4:1) as eluent to give a mixture of 2,4,5-tri-O-benzyl-
599.2834. IR (neat): ν = 3445, 2961, 2911, 2874, 2832, 2067, 1733,
˜
1589 cm–1. [α]2D5 = –1.3 (c = 1.2, MeOH).
3-Deoxy-D-erythro-hept-2-ulosonic Acid 2,6-Di-tert-butyl-4-
methoxyphenyl Ester (23; KDG Ester): Scheme 5. Compound anti-
7 (844 mg, 1.93 mmol) was dissolved in MeOH (10 mL) with DOWEX
50 WX 4 (1000 mg), and the mixture was stirred vigorously at room
temperature for 24 h. The reaction mixture was filtered through a
filter funnel, the solvent was evaporated, and the residue was puri-
fied by column chromatography using hexane/ethyl acetate (1:1) as
eluent to give 23 (754 mg, 98 %) as a pale yellow oil. 1H NMR
(600 MHz, CD3OD): δ = 6.91 (s, 2 H), 6.91 (s, 4 H), 3.83 (s, 3 H), 3.82
(s, 6 H), 4.58–4.48 (m, 1.3 H), 4.38–4.24 (m, 3 H), 4.20–4.11 (m, 2 H),
4.01 (ddd, J = 6.9, 5.0, 3.4 Hz, 1 H), 2.98 (dd, J = 13.7, 7.2 Hz, 0.75
H), 2.76 (dd, J = 12.7, 8.8 Hz, 1 H), 2.51 (t, J = 12.5 Hz, 0.8 H), 2.50
(dd, J = 12.7, 6.9 Hz, 1 H), 2.38 (dd, J = 14.3, 3.1 Hz, 0.4 H), 2.31 (dd,
J = 14.2, 4.1 Hz, 0.4 H), 2.21 (dd, J = 13.6, 3.9 Hz, 0.75 H), 2.06 (dd,
J = 12.5, 4.8 Hz, 0.8 H), 1.39 (s, 7 H), 1.38 (s, 9 H), 1.38 (s, 22 H), 1.37
(s, 8 H), 1.36 (s, 6 H) ppm. 13C{1H} NMR (151 MHz, CD3OD): δ =
180.5, 171.9, 158.1, 145.0, 143.3, 112.6, 106.4, 102.9, 98.5, 97.2, 88.7,
88.3, 75.2, 73.3, 73.1, 72.8, 71.4, 68.8, 66.5, 66.0, 63.7, 63.6, 63.5,
55.8, 55.1, 36.6, 35.3, 31.9, 31.8, 31.7 ppm. HRMS (ESI-TOF): calcd.
3-deoxy-
2-O-methoxy-3-deoxy-
and 4,5-di-O-benzyl-3-deoxy-
D
-erythro-hex-2-ulosonic acid methyl ester, 4,5-di-O-benzyl-
-erythro-hex-2-ulosonic acid methyl ester,
-erythro-hex-2-ulosonic acid methyl
D
D
ester (302 mg). The masses of all three compounds were observed
by HRMS: HRMS (ESI-TOF): calcd. for C28H30O6Na 485.1940; found
485.1923; HRMS (ESI-TOF): calcd. for C22H26O6Na 409.1627; found
409.1619; and HRMS (ESI-TOF): calcd. for C21H24O6Na 395.1471;
found 395.1457.
Step 5: The mixture of methyl esters (302 mg) was dissolved in
anhydrous methanol (10 mL) with acidic ion-exchange resin
(DOWEX 50 WX 4; 1000 mg) and palladium on carbon (100 mg)
under a hydrogen atmosphere, and the reaction mixture was stirred
overnight at room temperature. After TLC indicated that the reac-
tion was complete, the mixture was filtered through a filter funnel,
and the solvent was evaporated. The residue was purified by col-
umn chromatography using petroleum ether (60–90)/acetone (1:1)
as eluent to give clean KDG methyl ester methyl glycoside (24;
90 mg, 0.44 mmol) in α and ꢀ furanose forms, yield of steps 1–5:
23 %; overall yield: 14 %. 1H NMR (600 MHz, D2O): δ = 4.33–4.28 (m,
1 H), 4.24 (ddd, J = 7.6, 3.5, 2.3 Hz, 1 H), 4.09 (dt, J = 5.3, 3.7 Hz, 1
H), 4.05 (dt, J = 6.3, 4.5 Hz, 1 H), 3.76 (s, 3 H), 3.74 (s, 3 H), 3.69–
3.64 (m, 2 H), 3.60 (dd, J = 12.4, 5.4 Hz, 1 H), 3.56 (dd, J = 12.3,
6.4 Hz, 1 H), 3.19 (s, 3 H), 3.19 (s, 3 H), 2.43 (dd, J = 14.2, 6.9 Hz, 1
for C21H32O7Na 419.2046; found 419.2021. IR (neat): ν = 3403, 2957,
˜
2924, 2873, 1754 (and 1590) cm–1
.
Methyl (Methyl 3-Deoxy-D-erythro-hex-2-ulofuranosid)onate
(24; KDG)
Step 1: Scheme 5. Aromatic ester of KDG 23 (754 mg, 1.90 mmol)
was dissolved in dry toluene (20 mL). After a few minutes, Ag2O
(2.20 g, 9.50 mmol, 5.0 equiv.) and BnBr (3.16 mL, 26.6 mmol, H), 2.40 (dd, J = 14.8, 7.8 Hz, 1 H), 2.23 (dd, J = 14.0, 6.2 Hz, 1 H),
14 equiv.) were added. The mixture was stirred for 4 d at room
temperature in the dark, and then the mixture was purified on silica
gel using hexane/ethyl acetate (9:1) as eluent to give an inseperable
mixture of tri- and dibenzylated esters in pyranose and furanose
forms.
2.09 (dd, J = 14.6, 2.2 Hz, 1 H) ppm. 13C{1H} NMR (151 MHz, D2O):
δ = 170.1, 169.6, 105.5, 105.2, 87.1, 86.9, 69.9, 69.3, 60.9, 60.3, 52.6,
52.6, 50.5, 50.1, 43.1, 42.5 ppm. HRMS (ESI-TOF): calcd. for
C8H14O6Na 229.0688; found 229.0685. IR (neat): ν = 3416, 3002,
˜
2953, 2832, 1739, 1439 cm–1
.
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
9
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[6] D. Enders, A. A. Narine, J. Org. Chem. 2008, 73, 7858–7870.
[7] J. Mlynarski, B. Gut, Chem. Soc. Rev. 2012, 41, 587–596.
[8] a) K. Juhl, N. Gathergood, K. A. Jørgensen, Chem. Commun. 2000, 2211–
2212; b) N. Gathergood, K. Juhl, T. B. Poulsen, K. Thordrup, K. A. Jørgen-
sen, Org. Biomol. Chem. 2004, 2, 1077–1085; c) P. Dambruoso, A. Massi,
A. Dondoni, Org. Lett. 2005, 7, 4657–4660.
[9] a) For recent example of an organocatalytic aldol reaction of α-keto am-
ides, see: H. Echave, R. López, C. Palomo, Angew. Chem. Int. Ed. 2016, 55,
3364–3368; Angew. Chem. 2016, 128, 3425–3429; b) For a recent exam-
ple of an organocatalytic aldol reaction of unsaturated α-keto esters, see:
S. Konda, Q.-S. Guo, M. Abe, H. Huang, H. Arman, J. C.-G. Zhao, J. Org.
Chem. 2015, 80, 806–815.
[10] H. Torii, M. Nakadai, K. Ishihara, S. Saito, H. Yamamoto, Angew. Chem. Int.
Ed. 2004, 43, 1983–1986; Angew. Chem. 2004, 116, 2017–2020.
[11] a) A. Dondoni, P. Merino, Org. Chem. 1991, 56, 5294–5301; b) A. Dondoni,
A. Marra, P. Merino, J. Am. Chem. Soc. 1994, 116, 3324–3336.
[12] D. Enders, T. Gasperi, Chem. Commun. 2007, 88–90.
3-Deoxy-D-erythro-hexos-2-ulose (25; 3-deoxyglucosone, 3DG)
Steps 1–2: Scheme 5. The first two steps were carried out according
to the procedure described for compound 24.
Step 3: The mixture of fructoses (745 mg) was dissolved in dry
dichloromethane (8 mL) under an Ar atmosphere, then Dess–Martin
periodinane (540 mg, 1.27 mmol, about 1.5 equiv.) was added. The
reaction mixture was stirred overnight at room temperature. After
TLC (hexane/ethyl acetate, 4:1) indicated that the reaction was com-
plete, the dichloromethane was evaporated. The residue was dis-
solved in diethyl ether (10 mL), and the insoluble solid material
was removed by filtration. The filtrate was washed with saturated
aqueous sodium hydrogen carbonate (25 mL). The organic layer
was dried with Na2SO4, and the solvents were evaporated. The
product was purified by column chromatography using hexane/
ethyl acetate (4:1) as eluent to give the mixture of aldehydes as a
pale yellow oil. HRMS (ESI-TOF): calcd. for C27H28O5Na 455.1834;
found 455.1842.
[13] O. El-Sepelgy, D. Schwarzer, P. Oskwarek, J. Mlynarski, Eur. J. Org. Chem.
2012, 2724–2727.
[14] M. A. Molenda, S. Baś, O. El-Sepelgy, M. Stefaniak, J. Mlynarski, Adv. Synth.
Catal. 2015, 357, 2098–2104.
Step 4: The mixture of aldehydes was dissolved in a mixture of THF
and water (4:1; 8 mL), then palladium on carbon (100 mg) was
added. The suspension was stirred 24 h at room temperature under
a hydrogen atmosphere, then it was filtered through a short pad of
silica gel, and the solvents were evaporated. The residue was puri-
fied by column chromatography using ethyl acetate/methanol
(10:1) as eluent to give 25 (126 mg, 0.78 mmol) as a beige solid,
yield of steps 1–4: 46 %; overall yield: 24 %. 1H and 13C NMR spectra
are consistent with the literature.[32] 1H NMR (600 MHz, D2O): δ =
8.46 (s, 1 H), 8.29 (s, 0.1 H), 8.23 (s, 0.1 H), 5.32 (m, 0.2 H), 5.08 (m,
0.5 H), 4.59 (m, 0.2 H), 4.55 (m, 0.3 H), 4.43 (dd, J = 11.4, 2.7 Hz, 0.4
H), 4.27 (dd, J = 14.3, 7.2 Hz, 1 H), 4.05 (m, 1.3 H), 4.00 (m, 1 H),
3.87 (m, 1 H), 3.76 (dd, J = 11.0, 2.6 Hz, 1.4 H), 3.63 (m, 2 H), 3.06
(dd, J = 18.5, 7.0 Hz, 0.3 H), 2.63 (dd, J = 15.4, 3.8 Hz, 0.3 H), 2.57
(dd, J = 15.3, 3.8 Hz, 1 H), 2.35 (dd, J = 15.3, 9.3 Hz, 1 H), 2.00 (m,
0.2 H) ppm. 13C{1H} NMR (151 MHz, D2O): δ = 181.5, 172.2, 75.9,
71.0, 64.0, 41.7 ppm. HRMS (ESI-TOF): calcd. for C6H10O5Na 185.0426;
found 185.0435; and calcd. for C7H14O6Na (methyl hemiacetal)
[15] a) B. M. Trost, H. Ito, J. Am. Chem. Soc. 2000, 122, 12003–12004. For other
papers relevant to the use of a Zn-ProPhenol catalyst, see: b) B. M. Trost,
E. R. Silcoff, H. Ito, Org. Lett. 2001, 3, 2497–2500; c) B. M. Trost, A. Fettes,
B. T. Shireman, J. Am. Chem. Soc. 2004, 126, 2660–2661; d) B. M. Trost, S.
Schin, J. A. Sclafani, J. Am. Chem. Soc. 2005, 127, 8602–8603; e) B. M.
Trost, H. Ito, E. R. Silcoff, J. Am. Chem. Soc. 2001, 123, 3367–3368; f) B. M.
Trost, D. J. Michaelis, M. I. Truica, Org. Lett. 2013, 15, 4516–4519; g) B. M.
Trost, D. Amans, W. M. Seganish, C. K. Chung, J. Am. Chem. Soc. 2009,
131, 17087–17089; h) B. M. Trost, F. Miege, J. Am. Chem. Soc. 2014, 136,
3016–3019.
[16] O. El-Sepelgy, J. Mlynarski, Adv. Synth. Catal. 2013, 355, 281–286.
[17] a) D. Enders, H. Dyker, G. Raabe, Angew. Chem. Int. Ed. Engl. 1992, 31,
618–620; Angew. Chem. 1992, 104, 649–651; b) D. Enders, H. Dyker, G.
Raabe, Angew. Chem. Int. Ed. Engl. 1993, 32, 421–423; Angew. Chem.
1993, 105, 420–423; See also c) O. J.-C. Nicaise, D. M. Mans, A. D. Morrow,
E. Villa Hefti, E. M. Palkovacs, R. K. Singh, M. A. Zukowska, M. D. Morin,
Tetrahedron 2003, 59, 6433–6443.
[18] a) M. Shi, W. Zhang, Tetrahedron 2005, 61, 11887–11894; b) M. Market,
M. Mulzer, B. Schetter, R. Mahrwald, J. Am. Chem. Soc. 2007, 129, 7258–
7259; c) J. Paradowska, M. Rogozińska, J. Mlynarski, Tetrahedron Lett.
2009, 50, 1639–1641.
217.0688; found 217.0689. IR (neat): ν = 3271, 2959, 2924, 2850,
˜
1729, 1574, 1414 cm–1
.
[19] B. Vakulya, S. Varga, A. Csámpai, T. Soós, Org. Lett. 2005, 7, 1967–1969.
[20] M. N. Grayson, K. N. Houk, J. Am. Chem. Soc. 2016, 138, 1170–1173.
[21] The stereochemistry of all the products was established by 1H NMR spec-
troscopic analysis of the cyclic products derived from the aldols after
appropriate deprotection of the hydroxy groups. For detailed informa-
tion, see the Supporting Information.
[22] T. K. M. Shing, Tetrahedron: Asymmetry 1994, 5, 2405–2414.
[23] D. Enders, H. Sun, F. R. Leusink, Tetrahedron 1999, 55, 6129–6138.
[24] C. H. Heathcock, M. C. Pirrung, S. H. Montgomery, J. Lampe, Tetrahedron
1981, 37, 4087–4095.
Acknowledgments
Financial support from the Polish National Science Centre (MAE-
STRO grant number 2013/10/A/ST5/00233) is gratefully ac-
knowledged.
Keywords: Organocatalysis · Asymmetric synthesis ·
[25] T. Niwa, J. Chromatogr. B 1999, 731, 23–36.
Biomimetic synthesis · Aldol reactions · Carbohydrates
[26] M. A. Grillo, S. Colombatto, Amino Acids 2008, 35, 29–36.
[27] K. J. Knecht, M. S. Feather, J. W. Baynes, Arch. Biochem. Biophys. 1992,
294, 130–137.
[28] C. R. Schmid, J. D. Bryant, M. Dowlatzedah, J. L. Phillips, D. E. Prather,
R. D. Schantz, N. L. Sear, C. S. Vianco, J. Org. Chem. 1991, 56, 4056–4058.
[29] X. Shen, Y.-L. Wu, Y. Wu, Helv. Chim. Acta 2000, 83, 943–953.
[30] P. Herczegh, I. Kovács, L. Szilágyi, F. Sztaricskai, Tetrahedron 1995, 51,
2969–2978.
[1] a) R. Mahrwald, Modern Aldol Reactions, Wiley-VCH, Weinheim, Germany,
2004; b) B. M. Trost, C. S. Brindle, Chem. Soc. Rev. 2010, 39, 1600–1632.
[2] a) S. M. Dean, W. A. Greenberg, C.-H. Wong, Adv. Synth. Catal. 2007, 349,
1308–1320; b) M. Brovetto, D. Gamenara, P. S. Méndez, G. A. Seoane,
Chem. Rev. 2011, 111, 4346–4403.
[3] W. Raimondi, D. Bonne, J. Rodriguez, Chem. Commun. 2012, 48, 6763–
6775.
[31] S. J. Eitelman, D. Horton, Carbohydr. Res. 2006, 341, 2658–2668.
[32] Y. V. Pfeifer, P. T. Haase, L. W. Kroh, J. Agric. Food Chem. 2013, 61, 3090–
3096.
[4] a) M. F. Utter, D. B. Keech, J. Biol. Chem. 1963, 238, 2603–2608; b) D. Voet,
J. G. Voet, Biochemistry, 3rd ed., John Wiley & Sons, New York, 2004.
[5] a) F. M. Unger, Adv. Carbohydr. Chem. Biochem. 1980, 38, 323–329; b) R.
Schauer, Adv. Carbohydr. Chem. Biochem. 1982, 40, 132–234; c) B. Lind-
berg, Adv. Carbohydr. Chem. Biochem. 1990, 48, 279–318; d) A. Banaszek,
J. Mlynarski, Stud. Nat. Prod. Chem. 2005, 30, 419–482.
Received: June 27, 2016
Published Online: ■
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
10
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Organocatalytic Aldol Reactions
M. A. Molenda, S. Baś,
J. Mlynarski* ..................................... 1–11
A Concise Organocatalytic Synthesis
of
through
3-Deoxy-2-ulosonic
Acids
Cinchona-Alkaloid-Pro-
moted Aldol Reactions of Pyruvate
We have developed diastereoselective ary amine group. Short and practical
cross-aldol reactions of a pyruvate es- syntheses of several ulosonic acids in
ter with chiral aldehydes, mediated by good overall yields were achieved us-
Cinchona alkaloids containing a terti- ing this protocol.
DOI: 10.1002/ejoc.201600784
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
11
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim