Organocatalyzed Knoevenagel-addition - Simple access to carbon chain-elongated branched carbohydrates

Article abstract of DOI:10.1016/j.tet.2013.03.063

Chain elongations of unprotected carbohydrates via a Knoevenagel-addition are described. The reactions were carried out in the presence of catalytic amounts of tertiary amines. The C-C bond formation processes yielded high syn-stereoselectivities. Additionally, through an asymmetric induction controlled by the configuration of the deployed carbohydrates pyranoid or furanoid products were formed. Yields were strongly increased by the use of 5-protected carbohydrates in these transformations.

Full text of DOI:10.1016/j.tet.2013.03.063

Tetrahedron 69 (2013) 4302e4310
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Organocatalyzed Knoevenagel-additiondsimple access to carbon
chain-elongated branched carbohydrates
*
Benjamin Voigt, Anastassia Matviitsuk, Rainer Mahrwald
Institute of Chemistry, Humboldt-University, Brook-Taylor Str. 2, 12 489 Berlin, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Chain elongations of unprotected carbohydrates via a Knoevenagel-addition are described. The reactions
were carried out in the presence of catalytic amounts of tertiary amines. The CeC bond formation
processes yielded high syn-stereoselectivities. Additionally, through an asymmetric induction controlled
by the configuration of the deployed carbohydrates pyranoid or furanoid products were formed. Yields
were strongly increased by the use of 5-protected carbohydrates in these transformations.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 26 November 2012
Received in revised form 12 March 2013
Accepted 18 March 2013
Available online 26 March 2013
Keywords:
Knoevenagel-addition
Organocatalysis
Branched carbohydrates
Chain elongation
Stereoselectivity
1. Introduction
subsequent dehydration and further reactions.13 In contrast, nature
accomplishes chain elongation of carbohydrates quite easilydby
Chain elongateddso-called higher carbohydratesdare naturally
occurring compounds with important biological properties. Starting
from readily available hexoses or pentoses, various methods exist to
accomplish carbon chain elongation at the anomeric centre. Best-
known are the Kiliani extension,1 FishereSowden homologation,2
BayliseHillman reaction,3 aldol additions,4 allylation reactions5
and reactions with various kinds of carbanions derived from
dithioacetals,6 vinylmetal reagents7 or from thiazole.8 For a com-
prehensive overview see Ref. 9.
Also, 1,3-dicarbonyl compounds were deployed in Knoevenagel
reactions to elongate corresponding carbohydrates at the anomeric
centre. Depending on reaction conditions different products were
obtained. Furan derivatives were detected under acidic condi-
tions.10 These condensation processes are connected with the loss
of the stereogenic centres of the starting carbohydrates. In contrast,
under basic conditions, the direct formation of unprotected C-gly-
cosidic ketones (deoxyketoses) is observed.11 Thus, the so-called
Lubineau-reaction provides an access to C-glycosides. The forma-
tion of higher carbohydrates has not been reported under these
aqueous reaction conditions. For an overview of this development
see Ref. 12. To sum up, carbon-chain elongations of carbohydrates
by Knoevenagel-addition have not been realized so far, due to
the deployment of several distinctive working transaldolases.14
2. Results and discussion
Recently, we have reported a Knoevenagel-addition process
of unprotected carbohydrates with 1,3-dicarbonyl compounds.15
These reactions give operationally simple access to carbon chain
elongated carbohydrates. The formation of competitive Knoevenagel-
condensation products was not observed as expected in the presence
of amines. Initial experiments with deoxyribose 1a and acetoacetic
ester 2 have been conducted in the presence of catalytic amounts of
diisopropylethylamine. Knoevenagel-adduct 3a was isolated in
moderate yields (29%) with an extremely high degree of stereo-
selectivity. The CeC bond formation process proceeds with an ex-
tremely high degree of syn-diastereoselectivity. Only one single
stereoisomer was detected by NMR experiments. In particular, the
anti-configured product was not detected. This observation is con-
sistent with results we obtained in amine-catalyzed direct aldol ad-
ditions.16 Further extension of these observations to other pentoses
1bee yields the Knoevenagel-addition adducts 3bee albeit with
lower yields. Moreover, long reaction times are required for these
conversions. When used with deoxyribose 1a and ribose 1b highest
yields were obtained, whereas lowest yields were found by the de-
ployment of xylose 1d. The observed yields clearly correlate with the
existence of acyclic structures of pentoses deployed.17 Similar trends
* Corresponding author. Tel.: þ49 30 2093 8397; fax: þ49 30 2093 5553; e-mail
address: rainer.mahrwald@rz.hu-berlin.de (R. Mahrwald).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.063

B. Voigt et al. / Tetrahedron 69 (2013) 4302e4310
4303
were observed indirectglycosidation ofunprotected carbohydrates.18
To overcome these problems (low yields, long reaction times)
we have tested 2-hydroxypyridine as an additional catalyst.
2-Hydroxypyxridine has a large effect on the anomerization equili-
bration of carbohydrates by formation of hydrogen bonds.19 Thus,
by increasing the equilibrium constant a higher amount of active
acyclic form should be available per defined time-unit. Indeed,
an increase of yields was noticed by addition of catalytic amounts of
2-hydroxypyridine. The results of these optimization works are
depicted in Scheme 1.
of pentoses deployed. Reactions of deoxyribose 1a (Scheme 1) or
5-protected deoxyribose 4a (Scheme 3) impressively demonstrate
this statement (missing hydroxy group in 2-position). In the
deoxyribose-series only one single stereoisomer is detected with
identical configuration: unprotected 3a as well as 5-protected
Knoevenagel-adduct 5a.
Relative 2,3-anti-configured ribose 1b and lyxose 1e20 yield syn-
configured product 3b and 3e as the main products. In contrast,
when used with 2,3-syn-configured arabinose 1c and xylose 1d
anti-configured products 3c and 3d were obtained as the main
O
CO2Et
HO
H
2
HO
O
OH
OH
O
HO
HO
CO2Et
HO
deoxyribose
1a
OH
3a: 45 %, >95/5a
HO
H
OH
HO
OH
H
O
HO
O
OH
O
HO
HO
CO2Et
CO2Et
OH
OH
HO
HO
OH
anti-3b: 14 %
syn-3b: 28 %
ribose
1b
HO
H
OH
OH
OH
HO
O
HO
O
OH
H
O
HO
HO
HO
CO2Et
CO2Et
OH
HO
HO
OH
syn-3c: 5 %
arabinose
1c
anti-3c: 20 %
HO
OH
OH
HO
H
O
H
OH
OH
O
HO
O
HO
HO
CO2Et
OH
HO
HO
CO2Et
HO
OH
syn-3d: 3 %
anti-3d: 7 %
xylose 1d
HO
HO
H
H
OH
OH
O
OH
OH
HO
O
O
HO
CO2Et
HO
OH
HO
CO2Et
HO
HO
OH
anti-3e: 8 %
syn-3e: 30 %
lyxose 1e
Scheme 1. Amine-catalyzed reactions of D-pentoses 1aee with acetoacetic ester 2. Reaction conditions: 1.0 mmol of carbohydrate 1aee, 1.5 mmol acetoacetic ester 2, 20 mol % i-
Pr2NEt, 25 mol % 2-pyridone, 0.5 ml DMSO, rt, 60e96 h. Ratio of diastereoisomers was determined by analysis of 1H NMR spectra. Compounds 3c and 3d were separated and
characterized as inseparable mixtures of diastereoisomers.
In reactions of deoxyribose 1a only one single stereoisomer was
detected. When used with pentoses 1bee the pyranoid forms 3bee
were obtained as major products. Again extremely high syn-ster-
eoselectivities were obtained during the CeC bond formation
process. In addition, an asymmetric induction (internal diaster-
eoselectivity) of the starting carbohydrates was observed. Two di-
astereoisomers were detected.
products. The relative configuration of the deployed carbohydrates
1bee does not only determine the internal diastereoselectivity but
also simultaneously dictates the formation of pyranoid or furanoid
structures of the products 3aee.
To use consistent stereodescriptors in further discussions, the
results of reaction of lyxose 1e with acetoacetic ester 2 are repre-
sentatively depicted in Scheme 2. The proposed intermediately
formed acyclic structures are shown to underline these consider-
ations (in brackets, not detected or isolated).
The internal diastereoselectivity is dictated by the existence and
additionally by the relative configuration of the 2,3-hydroxy groups

4304
B. Voigt et al. / Tetrahedron 69 (2013) 4302e4310
Fig. 2. Observed nO-interactions of syn-3e.
These results unambiguously demonstrate the assignment for the
2,3-syn-configured pyranoid structure 3e in the 1C4-conformation.
Based on this analysis the other possible three diastereoisomers
(1C4-conformation), four diastereoisomers of the 4C1-series and
four furanoid structures can be ruled out (for these structures see
Supplementary data).
A similar analysis was accomplished for the minor product
obtained by reactions of lyxose 1e with acetoacetic ester 2. The two
possible cyclic hemiketal structures of minor 3e are depicted in Fig. 3.
Scheme 2. Configurative outcome of reaction of lyxose 1e and acetoacetic ester 2.
Structural assignments of ring size, configuration as well as
conformation of Knoevenagel-products have been done by a com-
bination of NOE-experiments and analysis of coupling constants of
1H NMR experiments. This analysis is exemplified discussed for
stereoisomers 3e (reaction of lyxose 1e with acetoacetic ester 2,
Scheme 2). The possible furanoid and pyranoid hemiketal struc-
tures of the major product 3e are depicted independently of the
configuration of the new-formed stereogenic centers (indicated in
red colour in Fig. 1). The indicated coupling constants were un-
ambiguously determined by 1H NMR experiments.
Fig. 3. Possible hemiketal structures of anti-3e.
The coupling constant of 8.7 Hz indicates a dihedral angle of 30ꢀ
or 130ꢀ between the H-atoms at C-2 and C-3, 6.0 Hz an angle of 45ꢀ
or 120ꢀ between the H-atoms at C-3 and C-4 and 7.9 Hz a dihedral
angle of 40ꢀ or 130ꢀ between the H-atoms at C-4 and C-5 (Fig. 4).
Fig. 1. Possible hemiketal structures of syn-3e.
Fig. 4. Observed nO-interactions of anti-3e.
NOE-interactions between the H-atom at C-2 and the methyl
group strongly support the claim that only this anomeric form is
obtained. The analysis of coupling constants in connection with the
observed NOE-interactions, which determines the relative position
of 1,3-situated H-atoms excludes a pyranoid structure for the minor
product 3e. Thus, these experiments prove the furanoid structure
with a relative anti, 2,3-syn-configuration. For other possible con-
formers and stereoisomers see Supplementary data.
The coupling constant of 11.1 Hz indicates a dihedral angle of
0ꢀ or 160e180ꢀ between the H-atoms at C-2 and C-3 (For no-
menclature used see Ref. 21.). These findings suggest a 2,3-
diaxial configuration in a ring structure. Furthermore, 9.5 Hz
was detected between the H-atoms at C-3 and C-4 (20ꢀ or 140ꢀ)
and 9.8 Hz between the H-atoms at C-4 and C-5 (dihedral angle
of 20ꢀ or 140ꢀ).
Subsequent NOE-experiments indicate a diaxial position of the
H-atoms at C-2 and C-4 at the same side of the ring plane. Additional
nO-interactions were observed between the protons on C-3 and C-5.
Also, nO-interaction between the H-atoms of the methyl group and
the proton at C-2 indicates the equatorial position of the methyl
group. Only one anomer was detected by NMR experiment (Fig. 2).
Analogue analyses were carried out for Knoevenagel-products
of the other deployed carbohydrates. The assigned structures for
these diastereoisomers are shown in Supplementary data.
At this point of the investigation we suspected that yields could
be raised further by increasing the effective amount of reactive
acyclic species within the mutarotation equilibrium. This can be

B. Voigt et al. / Tetrahedron 69 (2013) 4302e4310
4305
Table 1
easily accomplished by protection of the 5-hydroxy group of
Yields and selectivities of amine-catalyzed Knoevenagel reaction
starting pentoses 1aee. Thus, thermodynamically favoured pyr-
anoid structures of the starting carbohydrates are no longer avail-
able to participate in the mutarotation equilibrium.22
Entry
Compound
Yielda [%]
syn
antib
To test this principle, readily available 5-tritylethers 4aee23 of
pentoses were deployed as substrates in the Knoevenagel-addition.
As expected, Knoevenagel-addition products 5aee were obtained
with higher yields. The results of these investigations are depicted
in Scheme 3. A strong enhancement of yields was noticed in all
described reactions. Even yields of the Knoevenagel-addition
product of notoriously difficult carbohydrate xylose 1d were
quintupled (3d: 10%/5d: 52%).
Furthermore, a general inversion of internal diastereoselectivity
was noticed by deployment of 5-tritylated pentoses 4bee in this
transformation. The observed results of Schemes 1 and 3 are
summarized in Table 1.
1
2
3
4
5
6
7
8
9
10
3a
3b
3c
3d
3e
5a
5b
5c
5d
5e
45
28
5
14
20
7
3
30
75
25
20
31
14
8
50
16
21
34
a
Isolated yields.
syn/anti ratios were evaluated from the 1H NMR spectra by integration of sig-
b
nificant signals of crude reaction mixtures.
O
CO2Et
HO
H
2
TrO
O
OH
OH
O
TrO
TrO
CO2Et
HO
OH
5a: 75 %, >95 / 5
4a
HO
H
OH
HO
TrO
O
OH
OH
OH
H
O
O
TrO
HO
CO2Et
CO2Et
OH
HO
HO
OH
anti-5b: 50 %
4b
syn-5b: 25 %
HO
H
OH
OH
HO
H
O
TrO
O
OH
OH
O
TrO
TrO
TrO
HO
OH
CO2Et
CO2Et
OH
HO
HO
4c
anti-5c: 16 %
syn-5c: 20 %
HO
H
OH
OH
HO
H
O
OH
O
TrO
O
OH
TrO
CO2Et
OH
HO
HO
CO2Et
HO
OH
anti-5d: 21 %
syn-5d: 31 %
4d
HO
H
HO
H
OH
O
OH
OH
TrO
O
OH
O
TrO
CO2Et
TrO
OH
HO
OH
CO2Et
HO
HO
4e
syn-5e: 14 %
anti-5e: 34 %
Scheme 3. Amine-catalyzed reactions of 5-protected pentoses 4aee with acetoacetic ester 2. Reaction conditions: 1.0 mmol of carbohydrate 1aee, 1.5 mmol acetoacetic ester 2,
20 mol % i-Pr2NEt, 25 mol % 2-hydroxypyridine, 0.5 ml DMSO, rt, 60e96 h. Ratio of diastereoisomers was determined by analysis of 1H NMR spectra. Compounds 5c and 5d were
separated and characterized as inseparable mixtures of diastereoisomers.

4306
B. Voigt et al. / Tetrahedron 69 (2013) 4302e4310
An explanation for these different configurative outcomes is
stereochemical repulsion models A and E are assumed to be the
favoured ones (follow red arrows in model B and F).
given representatively for reactions of lyxose 1e and tritylated
lyxose 4e with acetoacetic ester 2 in Scheme 4 and for arabinose
1c and tritylated arabinose 4c in Scheme 5. The extremely high
syn-diastereoselectivity that is observed in all reactions during
the CeC bond formation process is based upon two configura-
tive requirements. Firstly, a Z-enolate of acetoacetic ester 2 is the
only reactive species. This configuration is stabilized by a hy-
drogen bond. Furthermore, the installation of syn-configuration
during the CeC bond formation is a consequence of a like-ap-
proach (Re-side attack of acetoacetic ester to the Re-side of
carbohydrate aldehyde or Si-side attack of acetoacetic ester 2 to
the Si-side of carbohydrate aldehyde). The correlated proposed
stereochemical models are shown in Scheme 4 (A and B for
lyxose) and in Scheme 5 (E and F for arabinose). The transition
state models (A/B and E/F), which result in the different internal
stereochemical outcomes, differ in the ring size of hydrogen
bond stabilized cycles of pentoses (A and E/six-membered
rings; B and F/five-membered ring). As a result of that two
transition state models are proposed. For reasons of
As mentioned above, an overall reversal of the internal dia-
stereoselectivity was observed by the deployment of 5-tritylated
pentoses 4bee. These findings indicate a general steric shielding,
which works independently of possible hydrogen bonds. Now the
formation of the five-membered ring is favoured due to the bulky
trityl-group, which assembles in a maximum distance to the CeC
bond formation site.
When used with 5-tritylated arabinose 4c the bulky trityl sub-
stituent directs the acetoacetic ester 2 to an Si-side access. As
a consequence, syn-configured product 5c was detected as the main
product (model H in Scheme 5). Similar considerations hold true for
the preference of model D in the lyxose-series (Scheme 4).
3. Conclusions
In summary, we have developed
a highly stereoselective
Knoevenagel-addition process catalyzed by tertiary amines.
Through the deployment of unprotected carbohydrates this
HO
OH OH
O
HO
H
OH
OH OH
O
H
HO
O
O
OH
HO
HO
HO
OH OH CO2Et
OH
HO
HO
CO2Et
OH OH CO2Et
CO2Et
OH
anti-3e: 8 %
syn-3e: 30 %
H
O
EtO
H
HO
O
OH
HO
O
HO
O
H
O
O
HO
HO
O
EtO
H
O
B
A
O
O
OEt
HO
H
O
2
OH
O
H
HO
O
1e
HO
HO
O
OH
TrO
H
O
OH
O
H
O
TrO
HO
HO
O
4e
OH
O
O
OEt
2
H
O
H
OH
HO
O
O
O
EtO
TrO
O
TrO
H
O
O
O
EtO
H
HO
HO
O
C
D
HO
HO
H
H
OH
TrO
O
O
OH OH
O
TrO
TrO
OH OH
OH
CO2Et
TrO
OH
HO
HO
CO2Et
OH OH CO2Et
OH OH CO2Et
OH
syn-5e: 14 %
anti-5e: 34 %
Scheme 4. Stereochemical results of chain elongation of lyxose 1e and 5-tritylated lyxose 4e with acetoacetic ester 2.

B. Voigt et al. / Tetrahedron 69 (2013) 4302e4310
4307
OH
HO
OH OH
O
H
OH OH
O
H
OH
HO
O
OH
O
HO
HO
HO
HO
OH OH CO2Et
HO
CO2Et
OH OH CO2Et
CO2Et
HO
OH
syn-3c: 5 %
anti-3c: 20 %
H
O
OH
OH
EtO
O
O
O
H
HO
H
OH
HO
HO
O
O
H
EtO
O
O
F
E
O
O
OEt
2
H
O
OH
O
OH
H
OH
O
O
HO
1c
HO
OH
H
O
OH
OH
O
OH
H
O
O
TrO
4c
OH
TrO
O
O
OEt
H
O
EtO
OH
2
O
OH
H
O
O
OH
H
TrO
O
O
H
EtO
O
TrO
O
HO
H
G
HO
H
HO
H
OH
OH OH
O
OH OH
O
O
OTr
O
OH
CO2Et
OTr
OTr
OTr
OH
HO
HO
CO2Et
OH OH CO2Et
OH OH CO2Et
OH
anti-5c: 16 %
syn-5c: 20%
Scheme 5. Stereochemical results of chain elongation of arabinose 1c and 5-tritylated arabinose 4c with acetoacetic ester 2.
transformation gives access to chain elongated and branched car-
bohydrates. High syn-selective CeC bond formation of the carbo-
hydrates and acetoacetic esters was observed. Also, the internal
diastereoselectivity can be predicted by the configuration of the
carbohydrates deployed. Explanations for the configurative out-
come of these reactions are given above. Further research to extend
this transformation is in progress.
chromatography using silica, which was made into a slurry with
a mixture of DCM/MeOH (9:1) containing 1% of tert-butylamine
before packing of the chromatography column.
4.2. General procedure for the reaction of pentoses 1aee with
ethyl acetoacetate 2
Pentoses 1aee (1.0 mmol), ethyl acetoacetate 2 (195 mg,
1.5 mmol), 2-pyridone (19 mg, 0.2 mmol) and N,N-diisopropy-
lethylamine (26 mg, 0.2 mmol) were dissolved in 0.5 ml di-
methyl sulfoxide and the reaction mixture was stirred for 72 h at
room temperature. The mixture was purified by silica flash
chromatography, using solvent mixtures of dichloromethane/
methanol (9:1 to 8:2). The products 3c,d were isolated as in-
separable mixtures of diastereoisomers. Diastereoisomers of
products 3b and 3e were isolated by repeated chromatography.
4. Experimental
4.1. General
1H NMR, 13C NMR and correlation experiments were carried out
at 500 MHz and 125 MHz or 300 MHz and 75 MHz (as described in
characterization of products). Chemical shifts are given in parts per
million (ppm). Purification of products was accomplished by flash

4308
B. Voigt et al. / Tetrahedron 69 (2013) 4302e4310
4.2.1. (2S,3R,4S,6S)-Ethyl 6-((R)-1,2-dihydroxyethyl)-2,4-dihydroxy-
4.2.8. (2R,3S,4S,5R,6S)-Ethyl 6-((R)-1,2-dihydroxyethyl)-2,4,5-
trihydroxy-2-methyltetrahydro-2H-pyran-3-carboxylate (syn-3e).
25
2-methyltetrahydro-2H-pyran-3-carboxylate (3a). Yield 45%; [
a
]
D
25
35.2 (c 1.0, MeOH); 1H NMR (500 MHz, DMSO-d6)
d¼4.10 (dq,
Yield 30%; [
d
a]
ꢁ51.2 (c 1.0, H2O); 1H NMR (300 MHz, D2O)
D
J¼10.9, 7.1 Hz, 1H), 4.08e4.05 (m, 1H), 4.02 (dq, J¼10.9, 7.1 Hz, 1H),
3.70 (ddd, J¼11.8, 5.8, 1.9 Hz, 1H), 3.46e3.41 (m, 1H), 3.33 (ddd,
J¼11.27, 5.8, 5.1 Hz, 1H), 3.27 (dd, J¼11.27, 5.8 Hz, 1H), 2.09 (d,
J¼10.6 Hz,1H),1.89 (ddd, J¼12.4, 4.8, 2.0 Hz,1H),1.30 (s, 3H),1.16 (d,
J¼7.1 Hz, 3H), 1.20e1.12 (m, 1H); 13C NMR (125 MHz, DMSO-d6)
¼4.29e4.17 (m, 2H), 4.10 (dd, J¼11.1, 9.1 Hz, 1H), 4.01 (ddd, J¼7.2,
5.7, 1.3 Hz, 1H), 3.73 (dd, J¼10.0, 1.3 Hz, 1H), 3.66 (dd, J¼11.6, 7.2 Hz,
1H), 3.60 (dd, J¼11.6, 5.8 Hz, 1H), 3.53 (dd, J¼10.1, 9.2 Hz, 1H), 2.66
(d, J¼11.1 Hz, 1H), 1.46 (s, 3H), 1.27 (t, J¼7.1 Hz, 4H); 13C NMR
(75 MHz, D2O)
d
¼172.57, 96.86, 71.70, 71.35, 70.38, 69.14, 63.60,
d¼170.10, 95.66, 73.59, 68.17, 64.77, 63.15, 59.68, 59.51, 35.21, 28.49,
62.96, 58.37, 27.43, 14.00; HRMS-ESI: calcd for: C11H19O8: 279.1085,
found: 279.1082.
14.23; HRMS-ESI: calcd for: C11H19O7: 263.1136, found: 263.1134.
4.2.2. (2S,3R,4R,5S,6R)-Ethyl 6-((R)-1,2-dihydroxyethyl)-2,4,5-
4.2.9. (2S,3R,4R,5R)-Ethyl-2,4-dihydroxy-2-methyl-5-((1S,2R)-1,2,3-
trihydroxy-2-methyltetrahydro-2H-pyran-3-carboxylate (syn-3b).
trihydroxypropyl)-tetrahydrofuran-3-carboxylate
(anti-3e). Yield
25
25
Yield 28%; [
a
]
ꢁ30.2 (c 0.5, H2O); 1H NMR (500 MHz, D2O)
8%; [a
]
ꢁ4.3 (c 1.0, H2O); 1H NMR (300 MHz, D2O)
¼4.89 (dd,
d
D
D
d
¼4.29e4.19 (m, 2H), 4.08(dd, J¼11.1, 9.0 Hz,1H), 3.98(ddd, J¼7.4, 3.5,
J¼8.8, 6.0 Hz, 1H), 4.29e4.18 (m, 2H), 3.91 (dd, J¼7.9, 6.0 Hz, 1H),
3.83 (ddd, J¼10.2, 5.2, 2.6 Hz, 1H), 3.73 (dd, J¼7.9, 2.5 Hz, 1H),
3.70e3.64 (m, 2H), 3.15 (d, J¼8.8 Hz, 1H), 1.64 (s, 3H), 1.28
3.1 Hz, 1H), 3.87e3.83 (m, 1H), 3.77 (dd, J¼11.9, 3.5 Hz, 1H), 3.70 (dd,
J¼11.9, 7.4 Hz,1H), 3.49 (dd, J¼10.2, 9.0 Hz,1H), 2.86 (d, J¼11.1 Hz,1H),
1.49 (s, 3H),1.28 (t, J¼7.3 Hz, 3H); 13C NMR (125 MHz, D2O)
d¼171.83,
(t, J¼7.1 Hz, 3H); 13C NMR (75 MHz, D2O)
¼171.43, 104.73, 82.65,
d
96.14, 72.56, 72.07, 71.99, 70.64, 62.30, 62.27, 57.56, 26.73, 13.29;
HRMS-ESI: calcd for: C11H19O8: 279.1085, found: 279.1082.
74.92, 72.74, 71.41, 63.45, 63.00, 61.94, 26.31, 13.98.
4.3. General procedure for the tritylation of pentoses
4.2.3. (2R,3S,4S,5S)-Ethyl-2,4-dihydroxy-2-methyl-5-((1S,2S)-1,2,3-
trihydroxypropyl)-tetrahydrofuran-3-carboxylate
(anti-3b). Yield
The reactions were carried out after the procedure described by
Kam and Oppenheimer.21
25
14%; [
a]
ꢁ2.5 (c 0.5, H2O); 1H NMR (500 MHz, D2O)
¼4.92 (dd,
d
D
J¼9.2, 6.9 Hz, 1H), 4.29e4.19 (m, 2H), 4.03 (dd, J¼6.7, 5.2 Hz, 1H),
3.85e3.80 (m, 1H), 3.70e3.65 (m, 1H), 3.69 (m, 1H), 3.68e3.66 (m,
1H), 3.16 (d, J¼9.2 Hz, 1H), 1.66 (s, 3H), 1.28 (t, J¼7.3 Hz, 3H); 13C
4.3.1. (4S,5R)-5-((Trityloxy)methyl)tetrahydrofuran-2,4-diol
(4a).21 1H NMR (500 MHz, CD3Cl)
d
¼7.40e7.08 (m, 15H), 5.47 (dd,
NMR (125 MHz, D2O)
62.40, 61.95, 61.02, 25.62, 13.29.
d
¼170.72, 103.75, 82.52, 72.54, 72.12, 70.83,
J¼5.25, 2.63 Hz, 1H), 4.26 (ddd, J¼7.99, 5.25, 4.43 Hz, 1H), 4.18e4.15
(m,1H), 3.04 (dd, J¼9.87, 4.43 Hz,1H), 2.99 (dd, J¼9.87, 5.25 Hz,1H),
2.09e1.91 (m, 2H); 13C NMR (125 MHz, CD3Cl)
d¼143.33, 128.71,
4.2.4. (2S,3R,4R,5R,6R)-Ethyl 6-((R)-1,2-dihydroxyethyl)-2,4,5-
trihydroxy-2-methyltetrahydro-2H-pyran-3-carboxylate (anti-3c).
127.88,127.71, 99.41, 86.60, 73.53, 64.31, 41.03; HRMS-ESI: calcd for:
C24H23O4: 375.1602, found: 375.1602.
Yield 20%; 1H NMR (500 MHz, D2O)
d
¼4.29e4.21 (m, 2H),
4.26e4.23 (m, 2H), 4.07e4.06 (m, 1H), 3.83e3.79 (m, 1H),
3.62e3.59 (m, 1H), 2.84 (d, J¼11.4 Hz, 1H), 1.50 (s, 3H), 1.29
4.3.2. (3R,4S,5R)-5-((Trityloxy)methyl)tetrahydrofuran-2,3,4-triol
(4b).21 1H NMR (500 MHz, CD3Cl)
d
¼7.38e7.05 (m, 15H), 5.27 (d,
(t, J¼7.2 Hz, 3H); 13C NMR (125 MHz, D2O)
d
¼173.43, 97.00, 70.70,
J¼4.40 Hz, 1H), 4.11 (ddd, J¼10.51, 3.25 Hz, 1H), 4.08 (dd, J¼9.69,
4.40 Hz, 1H), 3.92 (dd, J¼3.25, 9.69 Hz, 1H), 3.17e2.98 (dd, J¼10.51,
69.65, 68.45, 66.72, 63.61, 62.84, 53.52, 27.73, 13.99. HRMS-ESI:
calcd for: C11H19O8: 279.1085 found: 279.1085.
4.26 Hz, 2H); 13C NMR (125 MHz, CD3Cl)
d¼143.67, 128.69, 127.91,
127.12, 96.75, 86.83, 83.11, 75.85, 71.76, 64.13; HRMS-ESI: calcd for:
C24H24O5: 391.1551, found: 391.1550.
4.2.5. (2R,3R,4S,5R)-Ethyl-2,4-dihydroxy-2-methyl-5-((1R,2R)-1,2,3-
trihydroxypropyl)tetrahydrofuran-3-carboxylate (syn-3c). Yield 5%;
1H NMR (500 MHz, D2O)
d
¼4.83 (dd, J¼9.6, 7.8 Hz, 1H), 4.29e4.21
4.3.3. (3S,4S,5R)-5-((Trityloxy)methyl)tetrahydrofuran-2,3,4-triol
(m, 2H), 4.08 (dd, J¼7.8, 2.4 Hz, 1H), 3.89e3.85 (m, 1H), 3.83e3.79
(m, 1H), 3.71e3.66 (m, 1H), 3.67e3.64 (m, 1H), 3.19 (d, J¼9.6 Hz,
1H), 1.67 (s, 3H), 1.29 (t, J¼7.2 Hz, 3H); 13C NMR (125 MHz, D2O)
(4c).21 1H NMR (500 MHz, CD3Cl)
d
¼7.52e7.21 (m, 15H), 5.27
(d, J¼4.36 Hz, 1H), 4.39 (ddd, J¼8.87, 6.51, 4.34 Hz, 1H), 4.26
(ddd, 9.08, 5.99, 3.24 Hz, 1H), 4.13 (dd, J¼8.87, 5.87 Hz, 1H), 3.98
(dd, J¼5.87, 4.36 Hz, 1H), 3.54 (dd, J¼10.75, 3.24 Hz, 1H), 3.24
d
¼171.38, 104.00, 82.34, 72.15, 71.92, 70.19, 63.50, 62.93, 61.25,
26.55, 13.99.
(dd, J¼10.75, 5.99 Hz, 1H); 13C NMR (125 MHz, CD3Cl)
¼143.05,
d
128.80, 127.94, 127.43, 95.90, 85.13, 80.15, 78.03, 63.85; HRMS-ESI:
calcd for: C24H24O5: 391.1551, found: 391.1550.
4.2.6. (2R,3S,4S,5S,6S)-Ethyl 6-((R)-1,2-dihydroxyethyl)-2,4,5-
trihydroxy-2-methyltetra-hydro-2H-pyran-3-carboxylate (anti-3d).
Yield 7%; 1H NMR (500 MHz, D2O)
d
¼4.30e4.24 (m, 2H), 4.23
4.3.4. (3R,4R,5R)-5-((Trityloxy)methyl)tetrahydrofuran-2,3,4-triol
(dd, J¼11.4, 3.3 Hz, 1H), 3.94 (dd, J¼7.6, 1.0 Hz, 1H), 3.93 (dd, J¼3.3,
1.0 Hz,1H), 3.90 (ddd, J¼7.6, 5.6, 3.5 Hz,1H), 3.77 (dd, J¼12.3, 3.5 Hz,
1H), 3.66 (dd, J¼12.3, 5.6 Hz,1H), 2.86 (d, J¼11.4 Hz,1H),1.53 (s, 3H),
(4d).21 1H NMR (500 MHz, CD3Cl)
d
¼7.55e7.24 (m, 15H), 5.54 (d,
J¼3.94 Hz, 1H), 4.41e4.37 (m, 1H), 4.28 (dd, J¼7.37, 4.67 Hz, 1H),
4.14 (dd, J¼7.37, 3.94 Hz, 1H), 3.52e3.46 (m, 1H), 3.32e3.27 (m, 1H);
1.29 (t, J¼7.2 Hz, 3H); 13C NMR (125 MHz, D2O)
d
¼173.44, 96.88,
13C NMR (125 MHz, CD3Cl)
d
¼143.45, 128.55, 128.07, 127.69, 96.14,
72.01, 71.92, 68.24, 68.04, 62.87, 62.39, 53.54, 27.68, 13.99; HRMS-
ESI: calcd for: C11H19O8: 279.1085, found: 279.1085.
80.87, 80.05, 77.23, 62.64; HRMS-ESI: calcd for: C24H24O5: 391.1551,
found: 391.1552.
4.2.7. (2S,3R,4R,5S)-Ethyl-2,4-dihydroxy-2-methyl-5-((1S,2R)-1,2,3-
trihydroxypropyl)-tetrahydrofuran-3-carboxylate (syn-3d). Yield 3%;
4.3.5. (3S,4R,5R)-5-((Trityloxy)methyl)tetrahydrofuran-2,3,4-triol
(4e).21 1H NMR (500 MHz, CD3Cl)
d
¼7.57e7.16 (m, 15H), 5.24 (d,
1H NMR (500 MHz, D2O)
d
¼4.78 (dd, J¼9.6, 7.3 Hz, 1H), 4.30e4.24
J¼3.76 Hz, 1H), 4.39 (ddd, J¼8.87, 6.51, 4.34 Hz, 1H), 4.18 (dd, 8.87,
4.59 Hz, 1H), 3.98 (dd, J¼4.59, 3.76 Hz, 1H), 3.38 (dd, J¼11.75,
4.34 Hz, 1H), 3.33 (dd, J¼11.75, 6.51 Hz, 1H); 13C NMR (125 MHz,
(m, 2H), 3.98 (dd, J¼7.3, 5.1 Hz, 1H), 3.85e3.80 (m, 1H), 3.73 (dd,
J¼5.1, 4.0 Hz, 1H), 3.70 (dd, J¼11.6, 4.6 Hz, 1H), 3.64 (dd, J¼11.6,
6.9 Hz, 1H), 3.17 (d, J¼9.5 Hz, 1H), 1.66 (s, 3H), 1.29, (t, J¼7.2 Hz, 3H);
CD3Cl)
d
¼143.86, 128.57, 127.38, 126.65, 123.84, 101.50, 79.08, 77.59,
13C NMR (125 MHz, D2O)
d
¼171.37, 104.25, 83.30, 72.91, 72.81,
71.45, 63.09; HRMS-ESI: calcd for: C24H24O5ꢁ: 391.1551, found:
391.1551.
72.27, 71.80, 63.19, 62.97, 26.48, 13.99.

B. Voigt et al. / Tetrahedron 69 (2013) 4302e4310
4309
4.4. General procedure for the reaction of 5-protected pen-
toses 4aee with ethyl acetoacetate 2
4.4.6. (2R,3S,4S,5S,6S)-Ethyl-2,4,5-trihydroxy-6-((S)-1-hydroxy-2-
(trityloxy)ethyl)-2-methyltetrahydro-2H-pyran-3-carboxylate (anti-
5d). Yield 21%; 1H NMR (500 MHz, CD3OD)
d¼7.52e7.21 (m, 15H),
Tritylated pentoses 4aee (1.0 mmol), ethyl acetoacetate 2
(195 mg, 1.5 mmol), 2-pyridone (19 mg, 0.2 mmol) and N,N-diiso-
propylethylamine (26 mg, 0.2 mmol) were dissolved in 0.5 ml di-
methyl sulfoxide and the reaction mixture was stirred for 72 h at
room temperature. The mixture was purified by silica flash chro-
matography, using solvent mixtures of dichloromethane/methanol
(9:1 to 8:2). The products 5c,d were isolated as inseparable mix-
tures of diastereoisomers. Diastereoisomers of products 5b and 5e
were isolated by repeated chromatography.
4.25e4.17 (m, 2H), 4.16 (dd, J¼11.20, 3.18 Hz, 1H), 3.93 (dd, J¼8.39,
1.18 Hz, 1H), 3.91 (dd J¼3.18, 1.18 Hz, 1H), 3.87 (ddd, J¼8.39, 5.40,
3.22 Hz, 1H), 3.49e3.47 (m, 1H), 3.20e3.17 (m, 1H), 2.84 (d,
J¼11.20 Hz, 1H), 1.53 (s, 3H), 1.28 (t, J¼7.07 Hz, 3H); 13C NMR
(125 MHz, CD3OD)
87.88, 72.63, 72.26, 69.91, 69.39, 65.71, 62.95, 54.64, 28.45, 14.53;
HRMS-ESI: calcd for: C30H34O8K: 561.1887, found: 561.1885.
d
¼173.18, 145.59, 130.04, 126.84, 128.14, 97.41,
4.4.7. (2S,3R,4R,5S)-Ethyl-5-((1R,2R)-1,2-dihydroxy-3-(trityloxy)pro-
pyl)-2,4-dihydroxy-2-methyltetrahydrofuran-3-carboxylate
(syn-
¼7.52e7.21 (m, 15H),
4.4.1. (2S,3R,4S,6S)-Ethyl-2,4-dihydroxy-6-((S)-1-hydroxy-2-(trity-
loxy)ethyl)-2-methyltetrahydro-2H-pyran-3-carboxylate(5a). Yield
5d). Yield 31%; 1H NMR (500 MHz, CD3OD)
d
4.93 (dd, J¼9.21, 6.62 Hz, 1H), 4.25 (dd, J¼6.62, 1.67 Hz, 1H),
4.25e4.17 (m, 2H), 3.94 (dd, J¼6.62, 5.01 Hz, 1H), 3.87 (dd, J¼5.01,
4.05 Hz, 1H), 3.86e3.83 (m, 1H), 3.47e3.44 (m, 1H), 3.21e3.19 (m,
1H), 2.91 (d, J¼9.21 Hz, 1H), 1.57 (s, 3H), 1.27 (t, J¼7.07 Hz, 3H); 13C
25
75%; [
d
a
]
D
þ15.1 (c 1.0, MeOH); 1H NMR (500 MHz, CD3OD)
¼7.54e7.17 (m, 15H), 4.32 (ddd, J¼11.07, 8.17, 4.61 Hz, 1H),
4.25e3.97 (m, 2H), 3.82 (dq, J¼11.09, 5.93 Hz,1H), 3.26 (dd, J¼12.02,
3.88 Hz, 1H), 3.20 (dd, J¼12.02, 6.01 Hz, 1H), 3.14e3.09 (m, 1H),
2.32e2.28 (m, 1H), 2.33 (d, J¼11.07 Hz, 1H), 1.93e1.83 (m, 1H), 1.42
NMR (125 MHz, D2O)
d
¼170.62, 145.59, 130.17, 128.92, 128.17,
104.69, 88.04, 85.09, 74.08, 73.22, 72.58, 66.23, 63.14, 61.79, 27.17,
14.53.
(s, 3H),1.27 (t, J¼7.51 Hz, 3H); 13C NMR (125 MHz, CD3OD)
¼171.15,
d
144.25, 128.50, 127.43, 126.68, 95.97, 86.54, 72.65, 71.90, 68.80,
64.61, 60.35, 54.15, 33.95, 27.33, 13.17; HRMS-ESI: calcd for:
C30H32O6Na: 511.2093, found: 511.2091.
4.4.8. (2R,3S,4S,5R,6R)-Ethyl-2,4,5-trihydroxy-6-((S)-1-hydroxy-2-
(trityloxy)ethyl)-2-methyltetrahydro-2H-pyran-3-carboxylate (syn-
25
5e). Yield 14%; [
CD3OD)
a
]
ꢁ16.8 (c 1.0, MeOH); 1H NMR (500 MHz,
D
4.4.2. (2S,3R,4R,5S,6R)-Ethyl-2,4,5-trihydroxy-6-((S)-1-hydroxy-2-
(trityloxy)ethyl)-2-methyltetrahydro-2H-pyran-3-carboxylate (syn-
d
¼7.57e7.25 (m, 15H), 4.26e4.20 (m, 2H), 4.16 (dd, J¼11.28,
9.67 Hz, 1H), 3.98 (ddd, J¼8.34, 6.26, 2.94 Hz, 1H), 3.88 (dd, J¼10.02,
1.41 Hz, 1H), 3.28 (dd, J¼9.30, 7.28 Hz, 1H), 3.21 (dd, J¼9.30, 6.19 Hz,
1H), 3.34 (dd, J¼10.98,10.21 Hz,1H), 2.52 (d, J¼11.28 Hz,1H),1.40 (s,
25
5b). Yield 25%; [
CD3OD)
a
]
þ24.7 (c 1.0, MeOH); 1H NMR (500 MHz,
D
d
¼7.51e7.18 (m, 15H), 4.21e4.12 (m, 2H), 4.08 (dd, J¼10.98,
8.96 Hz, 1H), 3.98 (ddd, J¼7.86, 6.52, 3.82 Hz, 1H), 3.81e3.78 (m,
1H), 3.39e3.23 (m, 2H), 3.34 (dd, J¼10.21, 8.96 Hz, 1H), 2.41 (d,
J¼10.98 Hz, 1H), 1.34 (s, 3H), 1.18 (t, J¼7.18 Hz, 3H); 13C NMR
3H), 1.30 (t, J¼7.31 Hz, 3H); 13C NMR (125 MHz, CD3OD)
¼172.19,
d
145.76, 130.25, 129.05, 128.49, 97.03, 87.74, 73.53, 73.18, 72.38,
71.70, 66.54, 61.74, 59.58, 28.21, 14.72; HRMS-ESI: calcd for:
C30H38O8N: 540.2594, found: 540.2592.
(125 MHz, CD3OD)
d
¼170.65, 145.38, 129.91, 128.67, 128.00, 96.89,
87.88, 73.86, 73.50, 73.01, 72.66, 66.24, 61.77, 59.24, 28.18, 14.42;
HRMS-ESI: calcd for: C30H38O8N: 540.2594, found: 540.2592.
4.4.9. (2S,3R,4R,5R)-Ethyl-5-((1S,2R)-1,2-dihydroxy-3-(trityloxy)pro-
pyl)-2,4-dihydroxy-2-methyltetrahydrofuran-3-carboxylate
(anti-
25
4.4.3. (2S,3S,4S,5S)-Ethyl-5-((1R,2R)-1,2-dihydroxy-3-(trityloxy)pro-
5e). Yield 34%; [
a
]
þ4.8 (c 1.0, MeOH); 1H NMR (500 MHz,
D
pyl)-2,4-dihydroxy-2-methyltetrahydrofuran-3-carboxylate
(anti-
CD3OD)
d
¼7.53e7.20 (m, 15H), 5.01 (dd, J¼8.68, 5.79 Hz, 1H), 4.23
25
5b). Yield 50%; [
a
]
ꢁ9.7 (c 1.0, MeOH); 1H NMR (500 MHz,
(dd, J¼10.86, 3.62 Hz, 1H), 4.16 (dd, J¼10.86, 6.83 Hz, 1H), 3.91 (dd,
J¼6.69, 5.79 Hz, 1H), 3.82 (ddd, J¼10.44, 4.91, 2.77 Hz, 1H), 3.29 (dd,
J¼6.69, 2.33 Hz, 1H), 3.31e3.26 (m, 2H), 2.98 (d, J¼8.68 Hz, 1H), 1.64
(s, 3H), 1.27 (t, J¼7.36 Hz, 3H); 13C NMR (125 MHz, CD3OD)
D
CD3OD)
d
¼7.51e7.18 (m, 15H), 4.99 (dd, J¼9.00, 6.63 Hz, 1H),
4.21e4.12 (m, 4H), 4.01 (dd, J¼6.63, 4.04 Hz,1H), 3.84 (ddd, J¼10.67,
6.52, 4.04 Hz,1H), 3.81e3.79 (m,1H), 2.93 (d, J¼9.00 Hz,1H),1.59 (s,
3H), 1.18 (t, J¼7.18 Hz, 3H); 13C NMR (125 MHz, D2O)
d
¼172.00,
d
¼171.08, 145.46, 130.01, 128.84, 128.10, 104.91, 87.95, 85.11, 74.99,
145.38, 129.91, 128.67, 128.00, 104.56, 87.88, 85.31, 73.99, 73.29,
72.28, 66.64, 63.30, 61.90, 26.89, 14.42.
73.85, 71.27, 66.49, 63.57, 61.88, 26.89, 14.35.
Acknowledgements
4.4.4. (2S,3R,4R,5R,6R)-Ethyl-2,4,5-trihydroxy-6-((S)-1-hydroxy-2-
(trityloxy)ethyl)-2-methyltetrahydro-2H-pyran-3-carboxylate (anti-
The authors thank Deutsche Forschungsgemeinschaft, Bayer-
Schering Pharma AG, Bayer Services GmbH, BASF AG, and Sasol
GmbH for financial support.
5c). Yield 16%; 1H NMR (500 MHz, CD3OD)
d
¼7.59e7.23 (m, 15H),
4.23e4.15 (m, 2H), 4.11 (dd, J¼11.36, 3.14 Hz, 1H), 3.94 (dd, J¼9.24,
3.14 Hz, 1H), 3.83e3.80 (m, 1H), 3.81e3.79 (m, 1H), 3.33 (dd, J¼3.46,
12.73 Hz, 1H), 3.21 (dd, J¼7.65, 12.73 Hz, 1H), 2.82 (d, J¼11.36 Hz,
1H), 1.40 (s, 3H), 1.29 (t, J¼6.67 Hz, 3H); 13C NMR (125 MHz, CD3OD)
Supplementary data
d
¼172.84, 145.78, 130.60, 130.07, 128.61, 97.22, 87.81, 74.56, 72.78,
Proofs of relative configuration by NO-experiments are de-
scribed. 1H and 13C NMR spectra are given for compounds 3aee and
5aee. Supplementary data associated with this article can be found
in the online version, at http://dx.doi.org/10.1016/j.tet.2013.03.063.
71.79, 70.76, 67.02, 61.69, 54.64, 28.49, 14.62; HRMS-ESI: calcd for:
C30H34O8Na: 545.2147, found: 545.2146.
4.4.5. (2R,3S,4S,5R)-Ethyl-5-((1R,2R)-1,2-dihydroxy-3-(trityloxy)pro-
pyl)-2,4-dihydroxy-2-methyltetrahydrofuran-3-carboxylate
(syn-
¼7.59e7.23 (m, 15H),
5c). Yield 20%; 1H NMR (500 MHz, CD3OD)
d
References and notes
4.93 (dd, J¼9.01, 6.76 Hz, 1H), 4.25 (dd, J¼6.76, 1.67 Hz, 1H),
4.23e4.15 (m, 2H), 3.86e3.83 (m, 1H), 3.82e3.79 (m, 1H),
3.30e3.20 (m, 2H), 2.98 (d, J¼9.01 Hz, 1H), 1.63 (s, 3H), 1.29 (t,
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d
128.92, 128.17, 104.51, 87.84, 84.51, 73.66, 72.71, 71.38, 67.31, 63.35,
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4310
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structures.
9. Monrad, R. N.; Madsen, R. Tetrahedron 2011, 67, 8825.
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Norsikian, S.; Lubineau, A. Tetrahedron Lett. 2004, 45, 7761; (e) Hersant, Y.;
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21. Nomenclature used in this discussions:
12. Scherrmann, M.-C. Top. Curr. Chem. 2010, 295, 1.
13. (a) With the sole exception of reaction of 2-acetamido-glyceraldehyde with
tert-butyloxalacetate: Miljkovic, M.; Hagel, P. Carbohydr. Res. 1985, 141, 213; (b)
For an uncatalyzed Knoevenagel addition process see Rohr, K.; Mahrwald, R.
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14. For recent reviews in this field see: (a) Samland, A. K.; Rale, M.; Sprenger, G. A.;
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Science of Synthesis. Stereoselective Synthesis; Thieme: Stuttgart, 2011; Vol. 2,
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W. D., Anthonsen, T., Eds.; Wiley: Weinheim, 2008; p 275.
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16. High syn-diastereoselectivities were obtained in amine-catalyzed direct aldol
additions with dihydroxyacetone. See Markert, M.; Mulzer, M.; Schetter, B.;
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22. For a similar observation in the synthesis of imines of carbohydrates see
Angyal, S. J. Angew. Chem., Int. Ed. 1969, 8, 157.
23. Kam, B. K.; Oppenheimer, N. J. Carbohydr. Res. 1979, 69, 308.