Permanganate oxidation revisited: Synthesis of 3-deoxy-2-uloses via indium-mediated chain elongation of carbohydrates

Article abstract of DOI:10.1002/ejoc.201000623

Application of the Barbier-type indium-mediated allylation method to suitable substrates offers access to carbohydrates bearing a terminal olefin moiety. The C-C bond, forming reaction generates a defined stereochemistry of the new chiral center and tolerates a wide variety of starting aldehydes thus allowing modifications in the carbohydrate backbone. Further transformations of the alkene moiety via an environmentally benign and subtle controlled protocol using potassium permanganate gives rise to the structural motif of 3-deoxy-2-uloses in good yields. The final part of the reaction sequence focuses on the deprotection of the acetyl groups essential for the success of the oxidation step. The acidic and labile 3-deoxy position of the target molecule is prone to elimination applying standard deacetylation conditions and therefore demands derivatisation of the molecule. The introduction of a thioketal moiety using microwave conditions shows promising results and subsequent standard transformations are applicable leading to the desired products.

Full text of DOI:10.1002/ejoc.201000623

FULL PAPER
DOI: 10.1002/ejoc.201000623
Permanganate Oxidation Revisited: Synthesis of 3-Deoxy-2-uloses via Indium-
Mediated Chain Elongation of Carbohydrates
[a]
[a]
[a]
Christoph Schmölzer, Michael Fischer, and Walther Schmid*
Keywords: Carbohydrates / Allylation / Oxidation / Indium / Thioketals
Application of the Barbier-type indium-mediated allylation
method to suitable substrates offers access to carbohydrates
bearing a terminal olefin moiety. The C–C bond forming re-
action generates a defined stereochemistry of the new chiral
center and tolerates a wide variety of starting aldehydes thus
allowing modifications in the carbohydrate backbone. Fur-
ther transformations of the alkene moiety via an environmen-
tally benign and subtle controlled protocol using potassium
permanganate gives rise to the structural motif of 3-deoxy-2-
uloses in good yields. The final part of the reaction sequence
focuses on the deprotection of the acetyl groups essential for
the success of the oxidation step. The acidic and labile 3-
deoxy position of the target molecule is prone to elimination
applying standard deacetylation conditions and therefore de-
mands derivatisation of the molecule. The introduction of a
thioketal moiety using microwave conditions shows promis-
ing results and subsequent standard transformations are ap-
plicable leading to the desired products.
Introduction
strate or solvent tolerance and stability.[13] However, numer-
ous excellent preparative methods have been published.
Carbohydrates are essential for many biological pro-
[14]
[
1]
cesses, yet the family of the ketoses is less widespread than
The consecutive utilization of epimerases, isomerases and
[
2]
aldoses. Despite their relatively minor occurrence their
biological function is unquestioned. They play key roles in
[15]
dehydrogenases shows promising results.
Our synthetic approach focused on the preparation of
different members of the 3-deoxy-2-ulose family. These C1-
reduced analogues of 3-deoxy-2-ulosonic acids (sialic acids,
etc.) have been scarcely examined although their biological
[3]
many biochemical pathways, such as glycolysis or cell–cell
[
4]
interactions.
Deoxyketoses represent an essential subcategory among
the ketose family. They frequently occur in very low concen-
trations in nature and their isolation is usually difficult and
[16]
importance has been reported.
Here we present a chemical method leading to this struc-
tural motif, which offers nearly unlimited variety in the
carbohydrate backbone. We applied an indium-mediated al-
lylation to different aldoses for chain elongation. The key
step in our synthesis is the oxidation of the terminal double
bond to introduce the hydroxy ketone moiety. Thus, we
thoroughly reinvestigated the well known and environmen-
[
5]
demanding. But there is an increasing interest to investi-
gate their properties and precise mode of action and higher
carbohydrate analogues demand attention regarding to new
[
6]
therapeutic targets.
Modern organic chemistry developed many strategies to
produce rare carbohydrates. Total synthesis provides these
compounds independently from natural sources and is
able to produce non-natural analogues. Aldol reactions
[
7]
tally benign oxidation of olefins with potassium permanga-
[8]
[9]
[17,18]
nate in acidic media.
This reaction type led directly
as well as Grignard type reagents[ make use of the car-
bonyl functionality to construct and modify the carbo-
hydrate backbone. The deoxygenation of sugars has been
extensively used to synthesize deoxy analogues.[ These
approaches need sophisticated protecting group strategies
and mostly rely on the selective removal of halogens or sul-
fur-containing groups.
10]
to the desired 3-deoxy-2-uloses in good to excellent yields
Scheme 1).
(
11]
Alternatively, research focuses on the application of en-
zymes such as aldolases, and their use in organic synthe-
sis.[ General application is often rendered by limited sub-
12]
[
a] Department of Organic Chemistry, University of Vienna,
Währingerstrasse 38, 1090 Vienna, Austria
Fax: +43-1-4277-9521
Scheme 1. Reagents and conditions: (i) allyl bromide, In, ultra-
sound; then Ac O, DMAP, pyridine; (ii) KMnO , buffer/acetone;
(iii) EtSH, SnCl ·2H O, DCM, microwave; (iv) NaOMe, MeOH;
E-mail: walther.schmid@univie.ac.at
2
4
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000623.
2
2
2
(v) N-bromophthalimide, THF/H O.
View this journal online at
wileyonlinelibrary.com
4886
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4886–4892

Synthesis of 3-Deoxy-2-uloses
Results and Discussion
Table 2. Optimization of pH value.
Entry Alkene
pH value[a]
Hydroxy ketone Dihydroxylation
Our approach leading to 3-deoxy-2-uloses is outlined in
Scheme 1. We started with the chain elongation of five dif-
ferent commonly available carbohydrates (Table 1) leading
to bioactive target molecules. The indium mediated al-
lylation of aldehydes generated a system containing a ter-
minal double bond and additionally introduced the 3-deoxy
functionality. The stereochemistry of the new chiral center
formed during the Barbier-type reaction was influenced by
(
% yield)
(% yield)
1
2
3
4
5
6
7
8
9
2b
2b
2b
2b
2b
2c
2c
2c
2c
7,5
5
4
3b (31)
3b (21)
3b (51)
3b (59)
3b (16)
3c (31)
3c (50)
3c (58)
3c (42)
7b (7)
7b (28)
7b (14)
7b (1)
3
acetic acid[
b]
7b (13)
7c (26)
7c (12)
7c (9)
5
4
3
[
19]
the functional group attached to the α-C-atom (Table 1).
2,5
7c (10)
Free hydroxyl groups achieved a threo configuration via
chelation control. This syn relation is found between C4
and C5 in N-acetyl--neuraminic acid (Neu5Ac), 3-deoxy-
[
a] Solvent: 1  acetic acid buffer/acetone, 1:4. [b] c = 0.03 .[22]

-glycero--galacto-nonulosonic acid (KDN), 3-deoxy-- is preferred and leads to dihydroxylated products 7a–e,[25]
gluco-octulosonic acid (4-epi-KDO) and -arabino-3-deoxy- whereas acidic reaction conditions generate hydroxy ketone
heptulosonic acid (DAH). Starting from O-isopropylidene- moieties via oxidative cleavage of the intermediate manga-
protected alcohols the reaction offered access to erythro- nate ester.[26] Consequently, we examined the pH-depen-
configured products found in 3-deoxy--manno-octulosonic dency of the product ratio of 3a–e and 7a–e in different
acid (KDO) and 3-deoxy--erythro-2-hexulose (3-deoxy-- 1  acetate buffer/acetone systems (Table 2). The optimum
fructose). Only in case of -arabinose-derived products results were obtained using the conditions shown in entries
separation of the diastereomers by conventional column 4 and 8 at pH = 3.
chromatography could be achieved. In all other cases the
major diastereomeric products were purified at a later stage
of the synthesis.
Table 1. Diastereoselectivities observed during chain elongation re-
action.
Entry Starting material
threo/erythro Product Combined
yield
1
N-acetyl--
mannosamine (1a)
-mannose (1b)
-arabinose (1c)
-erythrose (1d)
O-isopropylidene--
glyceraldehyde (1e)
4:1
5:1
7:1
8:1
2a
2b
74%
95%
99%
78%
2
3
4
5
2c[
20]
Scheme 2. Possibilities of permanganate oxidation.
2d
Since the amount of water present in the reaction media
proved to be crucial regarding to the yield of the oxi-
1:3
2e
76%
[
27]
dation
we decided to increase the amount of aqueous
The oxidation with potassium permanganate was investi-
buffer to optimize the conditions towards the desired hy-
droxy ketone formation (Table 3). The best results were ob-
tained using acetate buffer and acetone in a ratio 1:1. Fur-
ther increase of the aqueous component resulted in decreas-
ing yields mainly because of solubility problems of our sub-
strates (Table 3, entry 4). The optimization of the solvent
system was accompanied by a decrease of the reaction time
and formation of decomposition products.
gated using a variety of substrates.[ Since it is an unselec-
tive oxidant, free hydroxyl groups led to numerous byprod-
ucts and to partly decomposition of the molecules. In order
to prevent overoxidatition and cleavage, protecting groups
had to be introduced and peracetylation ensured the preser-
vation of the carbohydrate backbone.
21]
In our first efforts towards the oxidation of the terminal
double bond we applied conditions reported by Bonini et
al.[ using a solvent system containing 0.03  acetic acid
and acetone in a ratio of 1:4. However, the yields obtained
22]
Table 3. Optimization of solvent composition.
with our substrates were rather low (Table 2, entry 5) and Entry
additionally to the desired hydroxy ketone a remarkable
Alkene
Solvent
buffer /acetone)
Product
(% yield)
[a]
(
1
2
3
4
5
6
7
8
2d
2d
2d
2d
2a
2b
2c
2e
1:4[22]
2:3
1:1
5:1
1:1
1:1
1:1
1:1
3d (27)
3d (45)
3d (53)
3d (34)
3a (52)
3b (64)
3c (65)
3e (60)
amount of byproduct was isolated mostly resulting from
dihydroxylation of the double bond.
During the reaction the pH value increased dramatically
[
23]
due to the release of hydroxy ions. As reported earlier
the reaction mechanism proceeds via a cyclic manga-
nate(VI) ester as the key intermediate in the oxidation
(
Scheme 2), which is formed initially via a [3+2] cycload-
[
24]
dition.
At high pH-values hydrolysis of this cyclic ester [a] Acetic acid buffer (1 ).
Eur. J. Org. Chem. 2010, 4886–4892
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4887

C. Schmölzer, M. Fischer, W. Schmid
FULL PAPER
The removal of the acetyl groups could not be achieved oxyketoses 6a–e were accessible starting with N-acetyl--
[
30]
by Zemplén deacetylation or comparable basic protocols. mannosamine (leading to 6a ), -mannose (leading to
Instead of a deprotection an α,β-unsaturated compound 6b), -arabinose (leading to 6c), -erythrose (leading to
[
16]
was formed exclusively. Attempts towards deprotection via 6d ) and O-isopropylidene--glyceraldehyde (leading to
[
33]
acidic transesterification approaches failed and change of 6e ) as starting material in the initial chain-elongation re-
the protection group to benzyl ethers were unsuccessful due action.
to the attack of the permanganate to the benzyl moieties.
Since the acidity of the deoxy position α to the carbonyl
group prohibited standard deprotection methods we de-
Conclusions
We herein report on a straightforward synthetic route
towards the 3-deoxy-2-ulose family, which opens access to
a great variety of bioactive carbohydrates in excellent yields.
Starting from chain-elongated carbohydrate derivatives
with terminal double bonds we were able to introduce the
hydroxy ketone moiety by potassium permanganate oxi-
dation in acidic media. In addition, we present a new
method for the preparation of thioketals for unreactive and
labile compounds using microwave conditions within very
short reaction times.
cided to establish a thioketal moiety to enable deacetylation
Scheme 1). However, the formation of acetals of labile
(
compounds is often crucial. Strong acidic reaction condi-
tions often limit the application and additionally long reac-
tion times up to days are required leading frequently to
moderate to poor yields. Attempts to enhance the reaction
rate by heating did not improve the product formation,
since elimination products were obtained as major compo-
nents. Recently, deoxy sugars have been synthesized using
microwave conditions[28] without decomposition or side re-
actions. Adopting this approach to our substrates and pro-
viding energy using microwave irradiation resulted in a less Experimental Section
complicated product distribution. The use of tin chloride as
Lewis acid additionally improved the yields (50–60%) and
shortened the reaction time to minutes.
General Methods: 1H and 13C NMR spectra were recorded at
4
00 MHz on a Bruker Avance DPX 400 using CDCl or CD OD
3
3
for calibration. MS experiments were done in the ESI mode on a
Finnigan MAT 900 spectrometer. Flash chromatography was per-
The cleavage of thioketals is usually achieved using N-
halosuccinimide in aqueous acetone.[ Application of this formed using Merck silica gel 60 (0.004–0.063 mm). TLC monitor-
29]
method to our substrates provided good yields but separa- ing was done on Merck plates (silica gel 60 F254), compounds were
tion from the hydrophilic succinimide using standard col- visualized by treatment with a solution of (NH
4
)
6
Mo
(1 L), followed by heating.
Solvents were distilled, if necessary, before use. O-Isopropylidene-
7 2
O24·4H O
(
4 2 2 4
48 g) and Ce(SO ) (2 g) in 10% H SO
umn chromatography was not successful and caused de-
composition of the unprotected carbohydrates. Addition-
ally, the acidic reaction medium induced the formation of
an isopropylidene ketal as byproduct. By using the more
lipophilic N-bromophthalimide as deprotecting reagent and
[
32]

-glyceraldehyde was prepared following literature procedure.
Optical rotations were measured on a Perkin–Elmer Polarimeter
41. Microwave reactions were performed using a Biotage Initiator.
3
Chemicals were purchased in reagent grade.
a mixture of THF/H O as solvent we obtained the products
2
General Procedure for the Allylation of Aldoses. Synthesis of 2a–e
after neutralisation and extraction of the aqueous phase
with dichloromethane and lyophilisation in excellent yields
and purity.
Following our route developed we were able to synthesize
a variety of bioactive 3-deoxy-2-uloses (Figure 1). The de-
(
Method A): The monosaccharide was dissolved in the correspond-
ing solvent and indium powder and allyl bromide were added. The
reaction was sonicated until complete consumption of the starting
material (3–18 h) as judged by TLC (acetone/ 2-propanol/water:
5:4:1). After evaporation of the solvent pyridine, acetic anhydride
and DMAP were added. After completion of the reaction (TLC:
EtOAc/PE: 1:1) excess of reagents was removed under reduced
pressure and the precipitate was diluted with ethyl acetate and ex-
tracted 3 times with 0.1  HCl. The organic phase was washed with
brine and dried with MgSO . Evaporation of the solvent produced
4
the crude compounds 2a–e, which were purified by column
chromatography on silica gel.
General Procedure for the Oxidation with Potassium Permanganate.
Synthesis of 3a–e (Method B): The alkene 2a–e was dissolved in a
mixture of acetone and 1  acetate buffer (pH = 3) in a 1:1 ratio.
Potassium permanganate was solubilised in the same solvent and
added dropwise to the reaction medium. When the purple colour
disappeared the precipitate was removed by filtration through celite
and washed with dichloromethane. The organic phase was dried
with MgSO
a–e, which were used in the next reaction step without purifica-
tion.
4
and evaporation of the solvent led to the compounds
3
General Procedure for the Thioketal Formation. Synthesis of 4a–e
Method C): Compound 3a–e (0.02–0.06 mmol) was dissolved in
dichloromethane (1 mL) in a microwave tube and EtSH (2 mL) and
(
Figure 1. 3-Deoxy-2-uloses synthesized.
4888
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4886–4892

Synthesis of 3-Deoxy-2-uloses
1
equiv. SnCl
generator for 7 min at 75 °C the reaction mixture was washed with
water and the organic phase dried with MgSO . The solvent was
2
·2H
2
O was added. After irradiation in a microwave
achieved {manno [2c(erythro)]/gluco [2c(threo)]: 1:7}; yield 400 mg
[99%; R [2c(erythro)] = 0.35, PE/EtOAc = 2:1; R [2d(threo)] = 0.28,
PE/EtOAc = 2:1]. [2c(erythro)] α = +24.2 (c = 16.6 mg/mL
): δ [2c(erythro)] = 5.71 (m, 1 H, H7) 5.44
(dd, J = 8.84, J = 2.25 Hz, 1 H, H3) 5.30 (dd, J = 8.08, J = 2.25 Hz,
1 H, H5) 5.07 (m, 1 H, H2) 5.05 (m, 2 H, H8a, H8b) 5.00 (m, 1
H, H4) 4.21 (dd, J = 12.63, J = 2.77 Hz, 1 H, H1a) 4.06 (dd, J =
f
f
2
0
4
D
1
removed and the crude product was purified via column
chromatography on silica gel and separation of the diastereomers
was achieved (PE/EtOAc: 3:1).
DCM). H NMR (CDCl
3
General Procedure for the Deacetylation. Synthesis of 5a–e (Method
D): The peracetylated thioketal 4a–e was dissolved in dry MeOH
1
2.63, J = 5.56 Hz, 1 H, H1b) 2.36 (m, 1 H, H6a) 2.24 (m, 1 H,
1
3
3 3
H6b) 2.09–2.01 (5s, 15 H, 5 CH , OAc) ppm. C NMR (CDCl ):
(c = 0.015 mmol/mL) and 0.1 equiv. of NaOMe were added. After
δ [2c (erythro)] = 170.6–169.7 (5 C=O, OAc) 132.7 (C7) 118.4 (C8)
completion of the reaction dry ice was added to quench the reac-
tion. The solvent was removed under reduced pressure and the
product was purified using column chromatography on silica gel
7
2
0.1 (C5) 69.1 (C4) 68.1 (C2) 67.6 (C3) 61.9 (C1) 35.6 (C6) 20.4–
+
3
0.2 (5 CH , OAc) ppm. MS (ESI): m/z = 425.1 [M + Na] .
2
0
1
[2c (threo)] α
D 3
= +26.4 (c = 128 mg/mL DCM). H NMR (CDCl ):
(
DCM/MeOH: 5:1).
General Procedure for the Deprotection of the Thioketal. Synthesis
of 6a–e (Method E): Compound 5a–e was dissolved in H O (c =
.018 mmol/mL) at 10 °C and a solution of 6 equiv. of N-bromo-
δ [2c (threo)] = 5.57 (m, 1 H, H7) 5.25 (dd, J = 4.22, J = 6.30 Hz,
1
4
H, H3) 5.14 (dd, J = 4.22, J = 6.90 Hz, 1 H, H4) 4.98–4.86 (m,
H, H2, H5, H8a, H8b) 4.08 (dd, J = 3.31, J = 12.30 Hz, 1 H,
2
0
H1a) 3.96 (dd, J = 5.63, J = 12.30 Hz, 1 H, H1b) 2.26 (m, 1 H,
H6a) 2.16 (m, 1 H, H6b) 1.96–1.87 (5s, 15 H, 5 CH , OAc) ppm.
): δ = 170.1–169.5 (5 C=O, OAc) 131.9 (C7)
18.6 (C8) 70.4 (C5) 70.1 (C4) 68.7 (C2) 68.5 (C3) 61.2 (C1) 34.9
C6) 20.5–20.2 (5 CH , OAc) ppm. MS (ESI): m/z = 425.1 [M +
phthalimide in THF (c = 0.1 mmol/mL) was added dropwise until
the yellow colour remained. After 15 min the reaction was diluted
with water and extracted 4 times with DCM. The aqueous phase
was adjusted to pH = 7 with ion exchange resin (OH form) and
after filtration the solvent was removed by lyophilisisation.
3
13
C NMR (CDCl
3
1
–
(
3
+
Na] .
1
,2,3,4,6-Penta-O-acetyl-5-acetylamino-5,7,8,9-tetradeoxy-
cero- -galacto-8-nonenitol (2a): N-Acetyl--mannosamine hydrate
100 mg, 0.42 mmol) was treated according to method A with in-
dium (191 mg, 4 equiv., 1.66 mmol) and allyl bromide (216 µL,
equiv., 2.52 mmol) in EtOH/0.1  HCl: 6:1 (3.5 mL). Purification
D-gly-
1
,2,3,4-Tetra-O-acetyl-5,6,7-trideoxy-
D-arabino-6-heptenitol (2d):
D
2,3-Di-O-formyl--erythrose was prepared starting from -glucose
(
[
31]
according to the literature procedure.
The erythrose derivative
(
103 mg, 0.58 mmol) was deformylated with Dowex W50 ion ex-
6
+
change resin (50 mg, H form) in water (1.5 mL) for 3 h at 60 °C.
The solution was filtered and the carbohydrate was treated accord-
ing to method A using EtOH (6 mL), indium (75 mg, 1.1 equiv.,
was achieved using column chromatography and PE/EtOAc: 1:1 as
eluent; yield 147 mg (74%) of inseparable diastereomers [glycero-
galacto (2a)/glycero-talo: 4:1]. H NMR (400 MHz, CDCl
=
=
1
3
): δ (2a)
0
.65 mmol) and allyl bromide (150 µL, 3 equiv., 1.7 mmol). After
5.69 (m, 1 H, H8) 5.61 (d, J = 10.52 Hz, 1 H, NH) 5.30 (dd, J
8.25, J = 2.16 Hz, 1 H, H3) 5.19 (dd, J = 2.16, J = 10.52 Hz, 1
conversion and purification (PE/EtOAc = 3:1) 149 mg of 2d (78%)
were obtained as a mixture of inseparable diastereomers [arab-
ino(2d)/ribo: 8:1]. H NMR (CDCl
5
H, H4) 5.04 (m, 1 H, H9a) 5.00 (m, 1 H, H9b) 4.97 (m, 1 H, H2)
1
3
): δ (2d) = 5.66 (m, 1 H, H6)
4
1
2
.79 (m, 1 H, H6) 4.42 (m, 1 H, H5) 4.20 (dd, J = 3.09, J =
.26 (dd, J = 2.86, J = 8.43 Hz, 1 H H4) 5.16 (m, 1 H, H2) 5.12–
.02 (m, 3 H, H3, H7a, H7b) 4.19 (dd, J = 2.77, J = 12.42 Hz, 1
2.48 Hz, 1 H, H1a) 3.93 (m, 1 H, H1b) 2.18 (m, 2 H, H7a, H7b)
5
3
.07–1.96 (6s, 18 H, 6 CH
3
, OAc/NHAc) ppm. 1 C NMR
H, H1a) 4.09 (dd, J = 5.09, J = 12.42 Hz, 1 H, H1b) 2.42–2.19 (m,
(
400 MHz. CDCl
C=O, OAc) 132.9 (C8) 119.0 (C9) 71.0 (C6) 69.2 (C2) 68.6 (C4)
8.4 (C3) 62.5 (C1) 49.2 (C5) 36.3 (C7) 23.5 –21.0 (6 CH
3
): δ (2a) = 174.9 (C=O, NHAc) 170.5–189.8 (5
, OAc) ppm. 1 C NMR
3
2
(
7
H, H5a H5b) 2.10–2.00 (4s, 12 H, 4 CH
CDCl ): δ (2d) = 170.5–169.7 (4 C=O, OAc) 132.3 (C6) 118.6 (C7)
0.1 (C2) 69.7 (C4) 68.4 (C3) 61.9 (C1) 35.4 (C5) 20,7–20.5 (4 CH
3
3
6
3
,
3
,
+
OAcNHAc) ppm. MS (ESI): m/z = 496.2 [M + Na] .
+
OAc) ppm. MS (ESI): m/z = 353.2 [M + Na] .
1,2,3,4,5,6-Hexa-O-acetyl-7,8,9-trideoxy- -glycero- -galacto-8-non-
D
D
1
,2,3-Tri-O-acetyl-4,5,6-trideoxy-D-erythro-5-hexenitol (2e): O-Iso-
enitol (2b): -Mannose (303 mg, 1.68 mmol) was dissolved (20 mL,
EtOH/0.1  HCl: 10:1) and indium powder (386 mg, 2 equiv.,
[
32]
propylidene--glyceraldehyde
(48 mg, 0.369 mmol) was dis-
solved in EtOH (5 mL) and indium powder (59 mg, 1.4 equiv.,
.52 mmol) and allyl bromide (93 µL, 3 equiv., 1.08 mmol) were
3
.36 mmol) and allyl bromide (580 µL, 4 equiv., 6.8 mmol) were
added and treated according to method A (PE/EtOAc: 1:2); yield
59 mg (95%) of inseparable diastereomers [glycero-galacto (2b)/
0
added. The reaction was completed within 3 h of sonication and
after removal of the solvent dioxane (1 mL), water (5 mL) and
Dowex W50 ion exchange resin (40 mg, H -form) were added. Af-
ter 1 h the solvent was removed and the crude product was peracet-
ylated by dissolving in pyridine (5 mL) and acetic anhydride (5 mL)
and adding DMAP (5 mg). After complete conversion 2e was puri-
fied via column chromatography using PE/EtOAc: 4:1 as the eluent;
7
1
glycero-talo: 5:1]. H NMR (CDCl
3
): δ (2b) = 5.57 (m, 1 H, H8)
.34 (dd, J = 1.90, J = 9.88 Hz, 1 H, H5) 5.20 (dd, J = 1.90, J =
.65 Hz, 1 H, H3) 5.05 (dd, J = 1.9, J = 9.88 Hz, 1 H, H4) 4.95
+
5
8
(m, 1 H, H9a) 4.91 (m, 1 H, H9b) 4.87 (m, 1 H, H2) 4.83 (m, 1 H,
H6) 4.08 (dd, J = 2.80, J = 12.42 Hz, 1 H, H1a) 3.89 (dd, J = 5.28,
J = 12.42 Hz, 1 H, H1b) 2.07 (m, 2 H, H7a, H7b) 1.99–1.90 (6s,
, OAc) ppm. 1 C NMR (CDCl
3
yield 72 mg (76 %) as a mixture of inseparable diastereomers
1
(
6
8 H, 6 CH
6 C=O, OAc) 132.4 (C8) 118.1 (C9) 69.3 (C6) 68.8 (C2) 67.9 (C4)
7.2 (C3) 66.7 (C5) 61.6 (C1) 35.4 (C7) 20.6–20.3 (6 CH , OAc)
3
3
): δ (2b) = 170.2–169.3
1
[erythro (2e)/threo: 3:1]. H NMR (CDCl
3
): δ (2e) = 5.72 (m, 1 H,
H5) 5.18–5.07 (m, 4 H, H2, H3, H6a, H6b) 4.31 (m, 1 H, H1a)
4.16 (m, 1 H, H1b) 2.44–2.29 (m, 2 H, H4a, H4b) 2.07–2.04 (3s, 9
3
+
ppm. MS (ESI): m/z = 497.2 [M + Na] .
,2,3,4,5-Penta-O-acetyl-6,7,8-trideoxy-
2c (erythro)] and 1,2,3,4,5-Penta-O-acetyl-6,7,8-trideoxy-
1
3
H, 3 CH
C=O, OAc) 132.4 (C5) 118.6 (C6) 71.5 (C2) 70.5 (C3) 61.9 (C1)
4.9 (C4) 20.9–20.7 (3 CH , OAc) ppm. MS (ESI): m/z = 281.2 [M
3 3
, OAc) ppm. C NMR (CDCl ): δ (2e) = 170.7–170.0 (3
1
[
D
-manno-7-octenitol
-gluco-7-
D
3
+
3
octenitol [2c (threo)]: -Arabinose (1 mmol, 150 mg) was treated ac-
cording to method A in EtOH/H2O: 4:1 (10 mL) with indium
+
Na] .
(
5
172 mg, 1.5 equiv., 1.5 mmol) and allyl bromide (345 µL, 5 equiv.,
mmol). The crude product was purified with column chromatog-
raphy (PE/EtOAc: 5:1) and the separation of the diastereomers was
4,6,7,8,9-Penta-O-acetyl-5-acetylamino-3,5-dideoxy-D-glycero-D-ga-
lacto-2-nonulose (3a): Alkene 2a (18 mg, 0.036 mmol) was treated
according to method B in 5 mL of solvent and was oxidized with
Eur. J. Org. Chem. 2010, 4886–4892
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4889

C. Schmölzer, M. Fischer, W. Schmid
FULL PAPER
KMnO
4
(8 mg, 1.4 equiv., 0.05 mmol) in 5 mL of solvent; yield
4,5,6-Tri-O-acetyl-3-deoxy-
(78.5 mg, 0.24 mmol) was dissolved in 10 mL solvent and treated
): δ (3a) = 5.61 (d, J = 10.61 Hz, 1 according to method B with KMnO (62 mg, 1.5 equiv.,
H, NH) 5.38 (dd, J = 2.27, J = 8.40 Hz, 1 H, H7) 5.29 (dd, J = 0.39 mmol) in 5 mL solvent; yield 52 mg (60%) of inseparable dia-
D-erythro-2-hexulose (3e): Substrate 2e
10 mg (52%) of inseparable diastereomers [glycero-galacto(3a)/gly-
1
cero-talo: 4:1] H NMR (CDCl
3
4
1
2
4
.27, J = 10.28 Hz, 1 H, H6) 5.19 (m, 1 H, H4) 5.04 (m, 1 H, H8) stereomers [erythro (3e)/threo: 3:1]. H NMR (CDCl
.40 (m, 1 H, H5) 4.25 (dd, J = 3.06, J = 12.54 Hz, 1 H, H9a) 4.16 (m, 1 H, H4) 5.27 (m, 1 H, H5) 4.28 (m, 1 H, H6a) 4.23 (m, 2 H,
3
): δ (3e) = 5.54
(
1
=
d, J = 15.05 Hz, 2 H, H1a, H1b) 3.99 (dd, J = 5.63, J = 12.54 Hz, H1a, H1b) 4.07 (dd, J = 6.84, J = 11.85 Hz, 1 H, H6b) 2.72–2.69
1
3
H, H9b) 2.67 (dd, J = 8.19, J = 16.64 Hz, 1 H, H3a) 2.55 (dd, J
5.38, J = 16.64 Hz, 1 H, H3b) 2.11–2.01 (6s, 18 H, 6 CH , OAc/
3
): δ (3a) = 206.7 (C2) 171.3–170.1 (C5) 68.9 (C1) 67.8 (C4) 62.4 (C6) 39.6 (C3) 21.1–21.0 (3 CH ,
(m, 2 H, H3a, H3b) 2.11–2.05 (3s, 9 H, 3 CH
3
, OAc) ppm.
C
3
NMR (CDCl ): δ (3e) = 206.0 (C2) 170.9–170.2 (3 C=O, OAc) 71.2
3
13
NHAc) ppm. C NMR (CDCl
3
+
(
(
6 C=O, OAc/NHAc) 69.2 (C8) 68.7 (C1) 68.3 (C6) 68.2 (C7) 68.1 OAc) ppm. MS (ESI): m/z = 313.1 [M + Na] .
C4) 62.4 (C9) 49.6 (C5) 39.7 (C3) 23.6–21.0 (6 CH , OAc/NHAc)
3
4
,6,7,8,9-Penta-O-acetyl-5-acetylamino-3,5-dideoxy-
cero- -galacto-2-nonulose Diethyl Dithioketal (4a): Treatment of 3a
(13 mg, 0.026 mmol) according to method C yielded in 8 mg (51%;
D-gly-
+
ppm. MS (ESI): m/z = 528.1 [M + Na] .
,5,6,7,8,9-Hexa-O-acetyl-3-deoxy- -glycero-
3b): Compound 2b (190 mg, 0.4 mmol) was dissolved in 10 mL of
the solvent mixture and treated according to method B with
KMnO (108 mg, 1.7 equiv., 0.68 mmol) in 10 mL solvent; yield J = 8.97, J = 1.14 Hz, 1 H, H7) 5.19 (m, 1 H, H6) 5.18 (m, 1 H,
29 mg (64%) of inseparable diastereomers [glycero-galacto (3b)/
D
4
(
D
D-galacto-2-nonulose
2
0
R
f
D
= 0.32 PE/EtOAc: 2:1) of 4a. α = +18.2 (4.5 mg/mL DCM).
1
H NMR (CDCl ): δ = 5.68 (d, J = 10.61 Hz, 1 H, NH) 5.32 (dd,
3
4
1
H4) 5.04 (m, 1 H, H8) 4.52 (m, 1 H, H5) 4.27 (dd, J = 12.45, J =
3.06 Hz, 1 H, H9a) 3.97 (dd, J = 12.45, J = 5.89 Hz, 1 H, H9b)
1
glycero-talo: 5:1]. H NMR (CDCl
10.11 Hz, 1 H, H6) 5.36 (dd, J = 2.00, J = 8.98 Hz, 1 H, H7)
.27 (m, 1 H, H4) 5.08 (dd, J = 1.68, J = 10.11 Hz, 1 H, H5) 5.00
m, 1 H, H8) 4.19 (dd, J = 2.70, J = 12.59 Hz, 1 H, H9a) 4.14 (d,
J = 5.53 Hz, 2 H, H1a, H1b) 4.02 (dd, J = 12.59, J = 5.21 Hz, 1
H, H9b) 2.57 (m, 2 H, H3a, H3b) 2.11–2.02 (6s, 18 H, 6 CH , OAc) 68.0 (C7) 64.8 (C1) 64.2 [C2, C(SEt)
ppm. 13C NMR (CDCl
): δ (3b) = 205.1 (C2) 170.6–169.7 (6 C=O, 23.3 (CH
OAc) 68.8 (C5) 68.1 (C1) 67.9 (C8) 67.3 (C7) 66.7 (C6) 66.5 (C4)
1.8 (C9) 38.9 (C3) 20.8–20.5 (6 CH , OAc) ppm. MS (ESI): m/z
3
): δ (3b) = 5.48 (dd, J = 2.00, J
=
5
(
3.66 (m, 2 H, H1a, H1b) 2.68–2.59 (m, 4 H, 2 CH
(6s, 6 CH , OAc/NHAc) 2.10 (m, 1 H, H3a) 1.86 (m, 1 H, H3b)
1.26–1.20 (m, 6 H, 2 CH
170.8–169.9 (6 C=O, OAc/NHAc) 69.0 (C6) 68.9 (C8) 68.5 (C4)
] 62.1 (C9) 50.9 (C5) 37.0 (C3)
, SEt) 21.2–20.7 (5 CH , OAc)
, SEt) ppm. MS (ESI): m/z = 634.2 [M + Na] .
2
, SEt) 2,17–2.02
3
1
3
3 3
, SEt) ppm. C NMR (CDCl ): δ =
3
2
3
3
, NHAc) 22.3–22.2 (2 CH
2
3
+
13.9–13.8 (2 CH
3
6
3
4
,5,6,7,8,9-Hexa-O-acetyl-3-deoxy-
D
-glycero- -galacto-2-nonulose
Diethyl Dithioketal (4b): Compound 3b (15 mg, 0.03 mmol) was
treated according to method C; yield 9.2 mg (50%; R = 0.31 PE/
= +9.2 (12.5 mg/mL DCM). H NMR (CDCl ): δ
D
+
=
529.3 [M + Na] .
,5,6,7,8-Penta-O-acetyl-3-deoxy-
The substrate 2c (erythro) (35 mg, 0.087 mmol) was solubilised in
mL solvent and KMnO (16 mg, 1.1 equiv., 0.1 mmol) in 5 mL
solvent was used for the oxidation following method B; yield
4
D
-manno-2-octulose [3c (erythro)]:
f
2
0
1
EtOAc: 2:1) α
D
3
5
4
= 5.32 (dd, J = 9.60, J = 2.02 Hz, 1 H, H5) 5.28 (m, 1 H, H4) 5.25
(dd, J = 8.59, J = 2.53 Hz, 1 H, H7) 5.10 (dd, J = 9.60, J = 2.53 Hz,
3
): δ = 5.41 (m, 1 H, H7) 5.37 (m, 1 H, H6) 4.93 (m, 1 H, H8) 4.15 (dd, J = 12.45, J = 2.91 Hz, 1 H,
1
2
1
4.4 mg (65%). H NMR (CDCl
H, H5) 5.36 (m, 1 H, H4) 5.09 (m, 1 H, H6) 4.24 (m, 2 H, H8a, H9a) 3.95 (dd, J = 12.45, J = 5.30 Hz, 1 H, H9b) 3.61 (m, 1 H,
H1a) 3.50 (m, 1 H, H1b) 2.57–2.50 (m, 4 H, 2 CH , SEt) 2.05–1.97
): (6s, 6 CH , OAc) 1.96 (m, 2 H, H3a, H3b) 1.19–1.13 (m, 6 H, 2
δ = 205.7 (C2) 170.6–169.7 (5 C=O, OAc) 70.3 (C4) 68.5 (C8) 68.3 CH ): δ = 170.9–170.3 (6 C=O, OAc)
, SEt) ppm. 13C NMR (CDCl
C6) 67.6 (C7) 66.6 (C5) 61.7 (C1) 39.5 (C3) 20.79–20.59 (5 CH 70.8 (C6) 68.8 (C8) 68.1 (C7) 67.6 (C4) 67.5 (C5) 65.0 (C1) 64.6
[C2, C(SEt) ] 62.3 (C9) 36.9 (C3) 22.8–22.6 (2 CH , SEt) 21.7–21.1
6 CH , OAc) 14.5–14.3 (2 CH , SEt) ppm. MS (ESI): m/z = 635.2
M + Na] .
H8b) 4.23 (m, 1 H, H1a) 4.11 (m, 1 H, H1b) 2.73 (m, 2 H, H3a,
H3b) 2.10–2.02 (5s, 15 H, 5 CH
, OAc) ppm. 13C NMR (CDCl
2
3
3
3
3
3
(
3
,
+
OAc) ppm. MS (ESI): m/z = 457.2 [M + Na] .
,5,6,7,8-Penta-O-acetyl-3-deoxy- -gluco-2-octulose [3c (threo)]:
Compound 2c (threo) (120 mg, 0.298 mmol) was dissolved in
2
2
(
[
3
3
4
D
+
1
1
8
5
0 mL solvent and KMnO
4
(52 mg, 1.1 equiv., 0.33 mmol) in
4,5,6,7,8-Penta-O-acetyl-3-deoxy-D-manno-2-octulose Diethyl Di-
thioketal [4c (erythro)]: Treatment of 3c (erythro) (14.4 mg,
0 mL solvent was used for the oxidation following method B; yield
1
4 mg (65%). H NMR (CDCl
3
): δ = 5.42 (m, 3 H, H4, H5, H6)
0.033 mmol) according to method C resulted in 10 mg (56%) of
2
0
1
.03 (m, 1 H, H7) 4.22 (dd, J = 3.26, J = 12.61 Hz, 1 H, H8a) 4.16
4c (erythro). α
D 3
= +21.6 (12.3 mg/mL DCM). H NMR (CDCl ):
(
1
d, J = 2.67 Hz, 2 H, H1a, H1b) 4.10 (dd, J = 5.64, J = 12.61 Hz, δ = 5.45 (m, 1 H, H4) 5.41 (dd, J = 7.96, J = 3.45 Hz, 1 H, H6)
H, H8b) 2.71 (m, 2 H, H3a, H3b) 2.03–1.98 (5s, 15 H, 5 CH 5.19 (dd, J = 5.05, J = 3.45 Hz, 1 H, H5) 5.13 (m, 1 H, H7) 4.25
): δ = 202.8 (C2) 170.5–169.8 (5 C=O, (dd, J = 12.38, J = 2.79 Hz, 1 H, H8a) 4.11 (dd, J = 12.38, J =
3
,
13
OAc) ppm. C NMR (CDCl
OAc) 70.1 (C5) 68.8 (C6) 68.6 (C7) 68.4 (C1) 67.6 (C4) 61.3 (C8)
9.1 (C3) 20.6–20.3 (5 CH , OAc) ppm. MS (ESI): m/z = 457.1 [M
3
5.48 Hz, 1 H, H8b) 3.59 (dd, J = 8.40, J = 12.17 Hz, 1 H, H1a)
3.47 (dd, J = 5.07, J = 12.17 Hz, 1 H, H1b) 2.66–2.58 (m, 4 H, 2
3
3
+
+
Na] .
,5,6,7-Tetra-O-acetyl-3-deoxy-
d (66.8 mg, 0.2 mmol) was dissolved in 5 mL of solvent and oxi-
(48 mg, 1.5 equiv., 0.3 mmol) in 5 mL solvent
according to method B; yield 38.5 mg (53%) of inseparable dia-
CH
2 3
, SEt) 2.21 (m, 1 H, H3a) 2.10–2.01 (5s, 15 H, 5 CH , OAc)
1
3
2.05 (m, 1 H, H3b) 1.25–1.20 (m, 6 H, 2 CH
3
, SEt) ppm. C NMR
): δ = 170.6–169.9 (5 C=O, OAc) 71.1 (C5) 68.6 (C7) 68.3
4
2
D-arabino-2-heptulose (3d): Alkene
(CDCl
3
(
2
2
C4) 67.6 (C6) 64.7 (C1) 64.2 [C2, C(SEt) ] 61.7 (C8) 35.9 (C3)
dised with KMnO
4
2.5–22.3 (2 CH
2 3 2
, SEt) 21.3–20.7 (5 CH , OAc) 14.1–13.9 (2 CH ,
+
SEt) ppm. MS (ESI): m/z = 563.3 [M + Na] .
1
stereomers [arabino (3d)/ribo: 8:1]. H NMR (CDCl
m, 1 H, H4) 5.26 (dd, J = 2.31, J = 8.94 Hz, 1 H, H5) 5.11 (m, 1
H, H6) 4,24–4.15 (m, 4 H, H1a, H1b, H7a, H7b) 2.63 (m, 2 H,
3
): δ (3d) = 5.58
(
4,5,6,7,8-Penta-O-acetyl-3-deoxy- -gluco-2-octulose Diethyl Di-
D
thioketal [4c (threo)]: Treatment of 3c (threo) (16.4 mg, 0.038 mmol)
according to method C resulted in 11.5 mg (56%) of 4c (threo).
α = +32.1 (14 mg/mL DCM). H NMR (CDCl ): δ = 5.41 (m, 1
D 3
H, H4) 5.38 (m, 1 H, H6) 5.23 (dd, J = 4.12, J = 6.44 Hz, 1 H,
H5) 5.10 (m, 1 H, H7) 4.26 (dd, J = 3.04, J = 12.45 Hz, 1 H, H8a)
, OAc) ppm. 1 C NMR
): δ (3d) = 205.6 (C2) 170.6–169.8 (4 C=O, OAc) 70.1 (C5)
8.8 (C6) 68.2 (C7) 66.4 (C4) 61.8 (C1) 39.3 (C3) 20.8–20.6 (4 CH
3
H3a, H3b) 2.21–2.02 (4s, 12 H, 4 CH
3
2
0
1
(CDCl
3
6
3
,
+
OAc) ppm. MS (ESI): m/z = 385.2 [M + Na] .
4890
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4886–4892

Synthesis of 3-Deoxy-2-uloses
4
=
2
.09 (dd, J = 5.64, J = 12.45 Hz, 1 H, H8b) 3.65 (dd, J = 5.05, J
12.01 Hz, 1 H, H1a) 3.53 (d, J = 8.05, 12.01 Hz, 1 H, H1b) 2.71–
3-Deoxy-
Substrate 4c (erythro) (21 mg, 0.039 mmol) was treated following
, SEt) 2.11–2.09 (m, 2 H, H3a, H3b) 2.12–2.04 method D yielding 12.5 mg (97%) of 5c (erythro) after purification.
D-manno-2-octulose Diethyl Dithioketal [5c (erythro)]:
.57 (m, 4 H, 2 CH
2
1
3
20
1
(
5s, 15 H, 5 CH
3
, OAc) 1.28–1.19 (m, 6 H, 2 CH
3
, SEt) ppm.
C
D 3
α = –15.7 (6.3 mg/mL MeOH). H NMR (CD OD): δ = 4.15 (m,
NMR (CDCl
3
): δ = 170.6–169.8 (5 C=O, OAc) 71.1 (C5) 68.9 (C7) 1 H, H4) 3.79 (m, 2 H, H7, H8a) 3.78 (m, 1 H, H1a) 3.69 (m, 1
] 61.7 (C8) 36.0 (C3) H, H1b) 3.67 (m, 1 H, H6) 3.63 (m, 1 H, H8b) 3.57 (dd, J = 7.96,
, OAc) 14.0–13.7 (2 CH J = 1.14 Hz, 1 H, H5) 2.76–2.62 (m, 4 H, 2 CH , SEt) 2.39 (dd, J
= 15.00, J = 9.53 Hz, 1 H, H3a) 1.83 (dd, J = 15.00, J = 1.05 Hz,
6
2
8.5 (C6) 67.8 (C4) 64.6 (C1) 64.0 [C2, C(SEt)
2.4–22.3 (2 CH , SEt) 21.2–20.5 (5 CH
2
2
3
3
,
2
+
SEt) ppm. MS (ESI): m/z = 563.3 [M + Na] .
1
3
1
H, H3b) 1.24–1.20 (m, 6 H, 2 CH
3
, SEt) ppm. C NMR
4
,5,6,7-Tetra-O-acetyl-3-deoxy- -arabino-2-heptulose Diethyl Di-
D
(CD
3
OD): δ = 73.6 (C5) 73.1 (C6) 71.1 (C7) 69.9 (C4) 68.4 (C1)
thioketal (4d): Dissolving 3d (15 mg, 0.041 mmol) and treatment
according to method C yielded 10 mg of 4d (52%; R = 0.27 PE/
= +23.5 (5.9 mg/mL DCM). H NMR (CDCl ):
δ = 5.57 (m, 1 H, H4) 5.25 (dd, J = 8.08, J = 3.16 Hz, 1 H, H5)
.05 (m, 1 H, H6) 4.26 (dd, J = 12.50, J = 2.75 Hz, 1 H, H7a) 4.13
dd, J = 12.50, J = 5.09 Hz, 1 H, H7b) 3.64 (dd, J = 11.49, J =
6
1
2 2
6.1 [C2, C(SEt) ] 65.1 (C8) 42.8 (C3) 23.8–22.7 (2 CH , SEt) 14.5–
f
–
3
4.2 (2 CH , SEt) ppm. MS (ESI): m/z = 329.2 [M – H] .
EtOAc: 2:1). α2
0
1
D
3
3
-Deoxy- -gluco-2-octulose Diethyl Dithioketal [5c (threo)]: Sub-
D
strate 4c (threo) (15.9 mg, 0.03 mmol) was treated following method
D yielding 9.5 mg (96%) of 5c (threo) after purification. α
+
H4) 3.78 (m, 1 H, H1a) 3.77 (m, 1 H, H8a) 3.68 (m, 1 H, H1b)
3.69–3.60 (m, 3 H, H5, H6, H7) 3.63 (m, 1 H, H8b) 2.71–2.59 (m,
5
(
2
0
D
=
1
3
10.3 (5 mg/mL MeOH). H NMR (CD OD): δ = 4.25 (m, 1 H,
7
2
2
.45 Hz, 1 H, H1a) 3.54 (dd, J = 11.49, J = 4.92 Hz, 1 H, H1b)
.66–2.57 (m, 4 H, 2 CH
2
, SEt) 2.13–2.04 (4s, 12 H, 4 CH
3
, OAc)
1
3
.05 (m, 2 H, H3a, H3b) 1.26–1.21 (m, 6 H, 2 CH
3
, SEt) ppm.
C
4
H, 2 CH
CH
, SEt) ppm. 13C NMR (CD
1.4 (C4) 68.3 (C1) 65.9 [C2, C(SEt)
22.9 (2 CH , SEt) 14.5–14.3 (2 CH , SEt) ppm. MS (ESI): m/z =
2
, SEt) 2.05 (m, 2 H, H3a, H3b) 1.24–1.99 (m, 6 H, 2
OD): δ = 73.8 (C6, C7) 73.2 (C5)
] 64.8 (C8) 42.5 (C3) 23.7–
NMR (CDCl
3
): δ = 170.7–169.9 (4 C=O, OAc) 72.0 (C5) 68.6 (C6)
7.1 (C4) 64.5 (C1) 64.2 [C2, C(SEt) ] 61.8 (C7) 36.7 (C3) 22.4–
2.3 (2 CH , SEt) 21.2–20.7 (4 CH , OAc) 14.0–13.8 (2 CH , SEt)
3
3
6
2
2
7
2
2
3
3
+
2
3
ppm. MS (ESI): m/z = 491.2 [M + Na] .
–
3
29.2 [M – H] .
4
,5,6-Tri-O-acetyl-3-deoxy- -erythro-2-hexulose Diethyl Dithioketal
D
3
-Deoxy- -arabino-2-heptulose Diethyl Dithioketal (5d): Com-
D
(
4e): Compound 3e (17 mg, 0.058 mmol) was treated according to
method C yielding 13.5 mg (59%; R = 0.20 PE/EtOAc: 2:1) of
inseparable diastereomers [erythro (4e)/threo: 3:1]. H NMR
CDCl ): δ (4e) = 5.52 (m, 1 H, H4) 5.16 (m, 1 H, H5) 4.27 (dd, J
12.12, J = 3.79 Hz, 1 H, H6a) 4.13 (dd, J = 12.12, J = 7.58 Hz,
H, H6b) 3.55 (m, 2 H, H1a, H1b) 2.66–2.58 (m, 4 H, 2 CH
pound 4d (9 mg, 0.019 mmol) was treated according to method D;
f
20
1
yield 5.2 mg (91%). α
CD OD): δ = 4.38 (m, 1 H, H4) 3.79 (m, 1 H, H7a) 3.78 (m, 1 H,
H1a) 3.68 (m, 1 H H1b) 3.65 (m, 1 H, H6) 3.62 (m, 1 H, H7b) 3.35
dd, J = 8.08, J = 2.02, Hz, 1 H, H5) 2.71–2.60 (m, 4 H, 2 CH
SEt) 2.17 (dd, J = 15.30, J = 9.47 Hz, 1 H, H3a) 1.95 (dd, J =
5.30, J = 0.66 Hz, 1 H, H3b) 1.30–1.20 (m, 6 H, 2 CH , SEt) ppm.
OD): δ = 75.9 (C5) 73.2 (C6) 68.8 (C4) 68.2 (C1)
] 65.1 (C7) 42.9 (C3) 23.7–23.0 (2 CH , SEt) 14.5–
, SEt) ppm. MS (ESI): m/z = 323.2 [M + Na] .
D
= +8.5 (2 mg/mL MeOH). H NMR
1
(
3
(
=
1
3
(
2
,
2
,
SEt) 2.16 (m, 1 H, H3a) 2.05 (m, 1 H, H3b) 2.07–2.05 (3s, 9 H, 3
1
3
, SEt) ppm. 1 C NMR
3
CH
(
6
3
, OAc) 1.27–1.18 (m, 6 H, 2 CH
CDCl ): δ (4e) = 170.6–169.9 (3 C=O, OAc) 72.8 (C5) 69.1 (C4)
4.7 (C1) 64.4 [C2, C(SEt) ] 61.8 (C6) 35.8 (C3) 22.5–22.3 (2 CH
, OAc) 14.0–13.9 (2 CH , SEt) ppm. MS
3
13
C NMR (CD
6.1 [C2, C(SEt)
4.4 (2 CH
3
3
6
1
2
2
2
2
,
+
3
SEt) 21.1–20.7 (3 CH
3
3
+
3-Deoxy-
D
-erythro-2-hexulose Diethyl Dithioketal (5e): Synthesis of
e following method D starting from compound 4e (17 mg,
0.043 mmol) yielded 11 mg (95%) after purification as inseparable
(ESI): m/z = 419.2 [M + Na] .
5
5
-Acetylamino-3,5-dideoxy-D-glycero-D-galacto-2-nonulose Diethyl
1
Dithioketal (5a): Treatment of 4a (13 mg, 0.021 mmol) according
diastereomers [erythro (5e)/threo: 3:1]. H NMR (CD
= 4.15 (m, 1 H, H4) 3.75 (m, 3 H, H1a, H1b, H6a) 3.69 (m, 1 H,
H6b) 3.56 (m, 1 H, H5) 2.70–2.56 (m, 4 H, 2 CH , SEt) 2.10 (dd,
H8) 3.84 (m, 1 H, H5) 3.81 (m, 1 H, H1a) 3.79 (m, 1 H, H9a) 3.71 J = 15.00, J = 9.30 Hz, 1 H, H3a) 1.93 (dd, J = 15.00, J = 0.5 Hz,
3
OD): δ (5e)
2
0
to method D yielded 7.6 mg (90%) of 5a. α
D
= –21.9 (3.2 mg/mL
1
MeOH). H NMR (CD
3
OD): δ = 4.66 (m, 1 H, H4) 3.89 (m, 1 H,
2
1
3
(
0
(
1
m, 1 H, H7) 3.65 (m, 1 H, H1b) 3.61 (m, 1 H, H9b) 3.39 (dd, J =
.25, J = 8.84 Hz, 1 H, H6) 2.70–2.59 (m, 4 H, 2 CH , SEt) 2.04
m, 1 H, H3a) 2.02 (s, 3 H, CH
, NHAc) 1.84 (m, 1 H, H3b) 1.24– C(SEt)
, SEt) ppm. 13C NMR (CD
OD): δ = 174.4 CH , SEt) ppm. MS (ESI): m/z = 293.1 [M + Na] .
1 H, H3b) 1.26–1.22 (m, 6 H, 2 CH
(CD OD): δ (5e) = 74.3 (C5) 70.0 (C4) 66.3 (C6) 64.8 [C2,
] 66.3 (C1) 40.5 (C3) 22.8–22.1 (2 CH , SEt) 14.1–14.0 (2
3
, SEt) ppm. C NMR
2
3
3
2
2
+
.20 (m, 6 H, 2 CH
3
3
3
(
6
C=O, NHAc) 72.6 (C7) 71.4 (C6) 69.8 (C8) 67.9 (C1) 67.1 (C4)
5.9 [C2, C(SEt) ] 65.2 (C9) 57.2 (C5) 43.1 (C3) 23.7–23.1 (2 CH
SEt) 22.5 (CH , NHAc) 14.5–14.1 (2 CH , SEt) ppm. MS (ESI):
m/z = 424.2 [M + Na] .
5
-Acetylamino-3,5-dideoxy- -glycero- -galacto-2-nonulose (6a):
D
D
2
2
,
Compound 5a (8.4 mg, 0.021 mmol) was treated according to
3
3
20
method E yielding 5.3 mg of 6a (86%). α
D
= +23.4 (2.15 mg/mL
OD, pyranose): δ = 4.04 (m, 1 H, H4) 3.93
dd, J = 9.98, J = 0.63 Hz, 1 H, H6) 3.81 (dd, J = 2.78, J =
+
1
MeOH). H NMR (CD
(
3
3
-Deoxy-
D-glycero-D-galacto-2-nonulose Diethyl Dithioketal (5b):
1
1.21 Hz, 1 H, H9a) 3.72 (m, 1 H, H5) 3.70 (m, 1 H, H7) 3.63 (dd,
Compound 5b was prepared according to method D starting from
substrate 4b (20 mg, 0.033 mmol); yield 11 mg (93%). α
2
0
J = 5.81, J = 11.21 Hz, 1 H, H9b) 3.49 (m, 1 H, H8) 3.47 (d, J =
11.36 Hz, 1 H, H1a) 3.36 (d, J = 11.36 Hz, 1 H, H1b) 2.02 (m, 1 H,
D
= +7.2
OD): δ = 4.43 (m, 1 H, H4) 3.88
m, 1 H, H6) 3.81 (m, 1 H, H9a) 3.80 (m, 1 H, H1a) 3.79 (m, 1 H,
1
(4 mg/mL MeOH). H NMR (CD
3
H3a) 2.02 (s, 3 H, CH
3
, NHAc) 1.76 (dd, J = 11.87, J = 12.38 Hz, 1
H, H3b) ppm. C NMR (CD OD, pyranose): δ = 175.2 (C=O,
NHAc) 98.6 (C2) 71.6 (C7) 71.3 (C6) 70.4 (C8) 69.5 (C1) 68.3 (C4)
4.9 (C9) 54.6 (C5) 39.5 (C3) 22.7 (CH , NHAc) ppm. MS (ESI):
(
1
3
3
H7) 3.70 (m, 1 H, H8) 3.69 (m, 1 H, H1b) 3.63 (m, 1 H, H9b) 3.51
dd, J = 9.09, J = 1.52 Hz, 1 H, H5) 2.75–2.57 (m, 4 H, 2 CH
SEt) 2.19 (dd, J = 14.53,16, J = 9.60 Hz, 1 H, H3a) 1.99 (dd, J =
(
2
,
6
3
m/z = 318.2 [M + Na]+. HRMS calcd. for C11
318.1165; found 318.1162.
21 8
H O NNa:
1
4.53, J = 0.63 Hz, 1 H, H3b) 1.24–1.20 (m, 6 H, 2 CH
3
, SEt) ppm.
OD): δ = 74.7 (C5) 73.3 (C8) 71.4 (C7) 70.9 (C6)
9.0 (C4) 68.2 (C1) 66.1 [C2, C(SEt)
3.0 (2 CH , SEt) 14.5–14.3 (2 CH , SEt) ppm. MS (ESI): m/z =
83.1 [M + Na] .
1
3
C NMR (CD
3
6
2
3
2
] 65.2 (C9) 42.9 (C3) 23.7– 3-Deoxy-
D-glycero-D-galacto-2-nonulose (6b): Compound 5b (5 mg,
2
3
0.014 mmol) was treated according to method E yielding 3.4 mg of
6b (96%). α
+
20
1
D
= –26.6 (1.5 mg/mL MeOH). H NMR (CD
3
OD,
Eur. J. Org. Chem. 2010, 4886–4892
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4891

C. Schmölzer, M. Fischer, W. Schmid
FULL PAPER
pyranose): δ = 3.94 (m, 1 H, H4) 3.85 (m, 1 H, H9a) 3.81 (m, 1 H,
H7) 3.66 (m, 1 H, H8) 3.64 (m, 1 H, H9b) 3.54 (m, 1 H, H6) 3.44
[6] D. Rao, D. Best, A. Yoshihara, P. Gullapalli, K. Morimoto,
M. R. Wormald, F. X. Wilson, K. Izumori, G. W. J. Fleet, Tet-
rahedron Lett. 2009, 50, 3559–3563, and refererences therein.
(m, 1 H, H1a) 3.37 (m, 1 H, H5) 3.36 (m, 1 H, H1b) 1.92 (dd, J =
[
7] a) R. R. Schmidt, M. Maier, Tetrahedron Lett. 1985, 26, 2065–
5
.27, J = 12.98 Hz, 1 H, H3a) 1.75 (dd, J = 1.28, J = 12.98 Hz, 1
2
5
068; b) W. R. Roush, R. J. Brown, J. Org. Chem. 1983, 48,
093–5101; c) G. Devianne, J. M. Escudier, M. Baltas, L. Gor-
13
H, H3b) ppm. C NMR (CD
3
OD, pyranose): δ = 98.6 (C2) 72.5
C8) 72.2 (C4, C6) 70.9 (C5) 70.1 (C7) 69.4 (C1) 65.2 (C9) 38.6
C3) ppm. MS (ESI): m/z = 277.1 [M + Na]+. HRMS calcd. for
Na: 277.0899; found 277.0896.
-Deoxy- -manno-2-octulose [6c (erythro)]: Compound 5c (erythro)
64 mg, 0.194 mmol) was treated according to method E yielding
(
(
richon, J. Org. Chem. 1995, 60, 7343–7347; d) D. Enders, M.
Voith, A. Lenzen, Angew. Chem. Int. Ed. 2005, 44, 1304–1325.
8] L. S. Li, Y. L. Wu, Tetrahedron 2002, 58, 9049–9054.
9] M. Markert, R. Mahrwald, Chem. Eur. J. 2008, 14, 40–80.
10] M. Reiner, F. Stolz, R. R. Schmidt, Eur. J. Org. Chem. 2002,
57–60.
9 18 8
C H O
[
[
[
3
(
D
20
1
4
1 mg of 6c (erythro) (94%). α
OD, pyranose): δ = 3.98 (m, 1 H, H4) 3.96 (m, 1 H,
H5) 3.82 (m, 1 H, H7) 3.79 (m, 1 H, H6) 3.75 (dd, J = 3.17, J =
D
= +28.0 (2.5 mg/mL MeOH). H
[11] M. de Lederkremer, C. Marino, Adv. Carbohydr. Chem. and
NMR (CD
3
Biochem. 2008, 144–147.
[
12] a) D. Crestia, C. Demuynck, J. Bolte, Tetrahedron 2004, 60,
1
3
1
1.65 Hz, 1 H, H8a) 3.63 (dd, J = 5.09, J = 11.65 Hz, 1 H, H8b)
.44 (d, J = 11.30 Hz, 1 H, H1a) 3.40 (d, J = 11.30 Hz, 1 H, H1b)
.87 (m, 1 H, H3a) 1.70 (dd, J = 1.47, J = 4.52 Hz, 1 H, H3b)
2417–2425; b) P. Gullapalli, T. Shiji, D. Rao, A. Yoshihara, K.
Morimoto, G. Takata, G. W. J. Fleet, K. Izumori, Tetrahedron:
Asymmetry 2007, 18, 1995–2000; G. M. Whitesides, C.-H.
Wong, Angew. Chem. 1985, 97, 617–638.
13
ppm. C NMR (CD
C7) 69.7 (C1) 68.4 (C5) 67.9 (C4) 64.8 (C8) 34.0 (C3) ppm. HRMS
calcd. for C Na: 247.0794; found 247.0792.
-Deoxy- -gluco-2-octulose [6c (threo)]: Compound 5c (threo)
11 mg, 0.033 mmol) was treated according to method E yielding
3
OD, pyranose): δ = 98.6 (C2) 72.2 (C6) 71.2
(
[13] I. Ibrahem, A. Cordova, Tetrahedron Lett. 2005, 46, 3363–
H
16
O
7
3367.
8
[
14] a) W. Schmid, J. Heidlas, J. P. Mathias, G. M. Whitesides, Lie-
bigs Ann. Chem. 1992, 95–97; b) R. Duncan, D. G. Drueckh-
ammer, J. Org. Chem. 1996, 61, 438–439; c) A. Yoshihara, S.
Haraguchi, P. Gallapulli, D. Rao, K. Morimoto, G. Takata, N.
Jones, S. F. Jenkinson, M. R. Wormald, R. D. Dwek, G. F. J.
Fleet, K. Izumori, Tetrahedron: Asymmetry 2008, 19, 739–745.
3
(
7
D
mg of 6c (threo) (95%). α2
OD, pyranose): δ = 4.11 (dd, J = 1.34, J = 8.37 Hz, 1
H, H6) 3.99 (m, 1 H, H4) 3.85 (m, 1 H, H7) 3.80 (m, 1 H, H5)
.77 (dd, J = 3.41, J = 11.43 Hz, 1 H, H8a) 3.64 (dd, J = 5.72, J
11.43 Hz, 1 H, H8b) 3.37 (m, 2 H, H1a, H1b) 2.11 (dd, J = 3.68, [16] R. H. Prenner, W. Schmid, Monatsh. Chem. 1996, 1045–1050.
0
1
D
= +56.0 (3.7 mg/mL MeOH). H
NMR (CD
3
3
=
[15] K. Izumori, J. Biotechnol. 2006, 717–722.
[
[
[
17] N. Singh, D. G. Lee, Org. Process Res. Development 2001, 599–
J = 14.29 Hz, 1 H, H3a) 1.69 (dd, J = 2.97, J = 14.29 Hz, 1 H,
H3b) ppm. 1 C NMR (CD
9.7 (C4) 69.4 (C1) 68.2 (C6) 67.8 (C5) 64.7 (C8) 31.5 (C3) ppm.
HRMS calcd. for C Na: 247.0794; found 247.0799.
-arabino-2-heptulose (6d): Compound 5d (22 mg,
.073 mmol) was treated according to method E yielding 13.6 mg
3
603.
3
OD, pyranose): δ = 98.4 (C2) 71.6 (C7)
18] J. Cheng, Z. Fang, S. Li, B. Zheng, Y. Jiang, Carbohydr. Res.
6
2009, 344, 2093–2095.
8
16 7
H O
19] a) L. A. Paquette, T. M. Mitzel, Tetrahedron Lett. 1995, 36,
6863–6868; b) L. A. Paquette, T. M. Mitzel, H. B. Isaac, C. F.
Crasto, W. W. Schomer, J. Org. Chem. 1997, 62, 4293–4301.
3
-Deoxy-D
0
[
16,34]
20
(96%) of 6d (spectroscopic data agree with the literature
) α
D
[20] For a procedure leading to the erythro compound as major
product, see: J. Gao, R. Härter, D. M. Gordon, G. M. Whites-
ides, J. Org. Chem. 1994, 59, 3714–3715.
1
=
+25.7 (1.4 mg/mL MeOH). H NMR (CD OD, pyranose): δ =
3
3.91 (m, 1 H, H4) 3.77 (m, 2 H, H7a, H7b) 3.70 (m, 1 H, H6) 3.44
[
[
21] A. J. Fatiadi, Synthesis 1987, 85–127.
22] C. Bonini, L. Chiummiento, M. Funicello, P. Lupatelli, M. Pul-
lez, Eur. J. Org. Chem. 2006, 80–83.
(
(
d, J = 11.12 Hz, 1 H, H1a) 3.38 (d, J = 11.12 Hz, 1 H, H1b) 3.27
m, 1 H, H5) 1.95 (dd, J = 5.05, J = 11.76 Hz, 1 H, H3a) 1.66 (dd,
13
J = 11.76, J = 12.88 Hz, 1 H, H3b) ppm. C NMR (CD
3
OD,
[
[
23] S. Wolfe, C. F. Ingold, J. Am. Chem. Soc. 1983, 105, 7755–7757.
24] a) A. J. DelMonte, J. Haller, K. N. Houk, K. B. Sharpless,
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Chem. 1999, 64, 800–802; c) T. Strasser, M. Busold, J. Org.
Chem. 2001, 66, 672–676.
pyranose): δ = 98.2 (C2) 74.6 (C6) 73.0 (C5) 70.6 (C4) 69.4 (C1)
+
6
2.7 (C7) 39.1 (C3) ppm. MS (ESI): m/z = 217.1 [M + Na] .
-Deoxy- -erythro-2-hexulose (6e): Compound 5e (20 mg,
.074 mmol) was treated according to method E yielding 9 mg
3
0
D
(
74%) of inseparable diastereomers. Spectroscopical data agree
[
33]
[25] a) N. S. Srinivasan, D. G. Lee, Synthesis 1979, 520–521; b) J.
Szammer, M. Jaky, O. V. Gerasimov, Int. J. Chem. Kinet. 1992,
with published data
chain form). MS (ESI): m/z = 187.1 [M + Na] .
(mixture of pyranose, furanose and open-
+
2
4, 14–154; c) J. E. Taylor, T. E. Janini, O. C. Elmer, Org. Proc.
Supporting Information (see also the footnote on the first page of
Res. Dev. 1998, 147–150.
1
13
this article): H- and C-NMR spectra of compound 6a–d.
[26] S. Wolfe, C. F. Ingold, R. U. Lemieux, J. Am. Chem. Soc. 1981,
103, 938–939.
[
[
[
[
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[
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[
[
[
[33] W. A. Szarek, R. J. Rafka, T.-F. Yang, O. R. Martin, Can. J.
Chem. 1995, 73, 1639–1644.
[34] NMR shifts for compound 6d in ref.[ represent the furanose
16]
11, 319–335; b) K. J. Knecht, M. S. Feather, J. W. Baynes, Arch.
2
form, which can be found after equilibration in D O.
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Received: May 4, 2010
Published Online: July 16, 2010
4892
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4886–4892