A common sugar as model for many-sided natural product modification. From D-fructose via D-tagatose to 2-C-chlorodifluoro-methylated D-arabinopyranos-5- ulose derivatives

Article abstract of DOI:10.1081/CAR-120037572

Starting with 3,4-O-[(R)-2,2,2-trichloroethylidene]-1,2-O-isopropylidene- β-D-tagatopyranose 2 obtained from 1,2-O-isopropylidene-β-D- fructopyranose 1 by a non-classical one-step acetalization with chloral/DCC, the fluoroalkylated glycosyl donors 15 and

Full text of DOI:10.1081/CAR-120037572

This article was downloaded by: [Colorado College]
On: 18 November 2014, At: 15:35
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer
House, 37-41 Mortimer Street, London W1T 3JH, UK
Journal of Carbohydrate Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lcar20
A Common Sugar as Model for Many‐Sided Natural
Product Modification. From D‐Fructose via
D‐Tagatose to 2‐C‐Chlorodifluoro‐methylated
D‐Arabinopyranos‐5‐ulose Derivatives
Ralf Miethchen a , Stefan Tews a , Arun K. Shaw b , Svenja Röttger a & Helmut Reinke a
a Department of Chemistry , University of Rostock , Albert‐Einstein‐Strasse 3a, D‐18059,
Rostock, Germany
b Medicinal Chemistry Division , Central Drug Research Institute , Lucknow, India
Published online: 18 Aug 2006.
To cite this article: Ralf Miethchen , Stefan Tews , Arun K. Shaw , Svenja Röttger & Helmut Reinke (2004)
A Common Sugar as Model for Many‐Sided Natural Product Modification. From D‐Fructose via D‐Tagatose to
2‐C‐Chlorodifluoro‐methylated D‐Arabinopyranos‐5‐ulose Derivatives, Journal of Carbohydrate Chemistry, 23:2-3, 147-161,
DOI: 10.1081/CAR-120037572
To link to this article: http://dx.doi.org/10.1081/CAR-120037572
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of
the Content. Any opinions and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied
upon and should be independently verified with primary sources of information. Taylor and Francis shall
not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other
liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

JOURNAL OF CARBOHYDRATE CHEMISTRY
Vol. 23, Nos. 2 & 3, pp. 147–161, 2004
A Common Sugar as Model for Many-Sided Natural
Product Modification.# From D-Fructose via
D-Tagatose to 2-C-Chlorodifluoro-methylated
D-Arabinopyranos-5-ulose Derivatives
1
2
Ralf Miethchen,1, Stefan Tews, Arun K. Shaw,
*
1
Svenja Rottger, and Helmut Reinke
1
¨
1Department of Chemistry, University of Rostock, Rostock, Germany
2Medicinal Chemistry Division, Central Drug Research Institute, Lucknow, India
ABSTRACT
Starting with 3,4-O-[(R)-2,2,2-trichloroethylidene]-1,2-O-isopropylidene-b-D-tagato-
pyranose 2 obtained from 1,2-O-isopropylidene-b-D-fructopyranose 1 by a non-classi-
cal one-step acetalization with chloral/DCC, the fluoroalkylated glycosyl donors 15
and 17 were synthesised in 3–4 steps. By this sequence, one stereogenic center was
inverted, one new chiral center was introduced, and one stereogenic center, for the
time being eliminated, was later re-introduced. The glycals 11 and 12, key intermedi-
ates of the synthesis sequence, were accessible from triflate precursors (e.g., 10) by
treatment with DBU. Corresponding halogeno-(6, 7), tosyl-(5, 8), or mesyl-(9) precur-
sors were unsuitable. The stereoselective introduction of a chlorodifluoromethyl group
was realised by dithionite-mediated CF2ClBr-addition to the glycal double bond. Sub-
sequently, either the chlorodifluoromethylated glycosyl bromide (13) or the corre-
sponding pyranoses (14 and 16) were isolated. The latter were still acetylated to the
#Organofluorine Compounds and Fluorinating Agents, Part 30. Part 29: Ref.[1]
.
Correspondence: Ralf Miethchen, Department of Chemistry, University of Rostock, Albert-
Einstein-Strasse 3a, D-18059 Rostock, Germany; E-mail: ralf.miethchen@chemie.uni-rostock.de.
*
147
DOI: 10.1081/CAR-120037572
0732-8303 (Print); 1532-2327 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

ORDER
REPRINTS
148
Miethchen et al.
1-O-acetyl derivatives 15 and 17, respectively. An x-ray analysis is given for the 5-O-
tosylate 8.
Key Words: Epimerization; Esterification; Fluoroalkylation; D-Tagatose.
INTRODUCTION
Regioselectivity and stereochemical control over the chemistry used in the building of
molecular frameworks are essential conditions in syntheses of chiral structures. Reason-
able common natural products can be used as precursors to synthesise less available
analogues of chiral natural substances or of modified chiral building blocks. A second
point is that there has been a resurgent interest in recent years in the chemistry of fluori-
nated compounds, due to their potential pharmaceutical, agrochemical, and material appli-
cations.[2] Especially, fluorinated sugars play an important role in the development of
potential biological targets as enzyme inhibitors and carbohydrate drug candidates; fluori-
nated building blocks can also be regarded as very useful tools, e.g., in 19F in vivo NMR
spectroscopy. Under consideration of the two aspects mentioned above, 1,2-O-isopropy-
lidene-b-D-fructopyranose (1) was selected as working model. After conversion of this
compound into a D-tagatose derivative (2), a fluoroalkyl substituted aldoketose was
prepared from that. Simultaneously, one new anomeric center is introduced and a
second stereogenic center, firstly removed by a b-elimination reaction, is stereoselec-
tively re-introduced by addition of a fluorinated “building block.” Thus, a previously
unknown branched sugar is generated, which is used as new fluorinated building block
for nucleoside analogues (Sch. 1).
RESULTS AND DISCUSSION
Based on our recent short communication[3] 1,2-O-isopropylidene-b-D-fructopyranose
(1) was converted into 5-O-cyclohexylcarbamoyl-3,4-O-(2,2,2-trichloroethylidene)-1,2-O-
isopropyli-dene-b-D-tagatopyranose (2) by a non-classical one-pot epimerization reaction
(for a review of this reaction type see Ref.[4]).
The D-tagatose derivative was starting material for the final aldoketose derivative 16.
The reaction proceeds via generation of an enolether function in 5,6-position of 2 followed
by a selective addition of ClF2CBr to the enolic double bond; Schs. 4–6. Because the
cyclohexylcarbamoyl group of 2 proved to be unsuitable for a direct b-elimination reac-
tion initiated by bases, compound 2 was firstly decarbamoylated by refluxing of 2 in 2%
methanolic sodium methoxide yielding hydroxy derivative 3, or by treatment of 2 with
tributyl stannane/AIBN in boiling toluene. The latter procedure caused, simultaneously,
a complete hydrodechlorination of the trichloroethylidene group, so that 3,4-O-ethyli-
dene-1,2-O-isopropylidene-b-D-tagatopyranose (4) was obtained. Compound 4 was tosyl-
ated generating the ester 5; Sch. 2.
Cyclic enol ethers are generally important tools for organic syntheses. Especially, mole-
cules with chiral information and an enolic double bond are also suitable precursors for
stereoselective fluoroalkylations. In search of the most favorable elimination method to
prepare the corresponding enol, different precursors and procedures were studied. Therefore,
the halogen derivatives 6, 7 and the sulfonic acid esters 5, 8, 9, 10 were prepared from

ORDER
REPRINTS
Common Sugar as Model for Natural Product Modification
149
Scheme 1.
compound 3 and 4, respectively, as shown in Schs. 2 and 3. However, dehydrohalogenation
experiments with 6 and 7 were not successful using DBU. The sulfonic acid esters 5, 8, and 9
gave likewise only unsatisfactory yields (20–35%) of the desired 3,4-O-(2,2,2-trichloro-
ethylidene)-5,6-dideoxy-1,2-O-isopropylidene-b-D-erythro-hexen-5-ulopyranose (11) on
heating with DBU in different solvents [THF, DMSO, (CH2Cl)2]. Compared with this,
the triflic acid ester 10 turned out to be an excellent precursor for the elimination. After
heating of 10 and DBU in toluene, glycal 11 could be isolated in yields of 98%; Sch. 4.
Therefore, the second key intermediate 12 was likewise prepared via a triflic acid
ester. The procedure was simplified to the effect that the esterification of 4 with triflyl
chloride and the following 5,6-elimination mediated by DBU were carried out without
chromatographic purification of the triflic acid ester intermediate. In this way an overall
yield of 97% was achieved for enolether 12; Sch. 5.
Scheme 2. i: MeONa, MeOH, reflux, 8 hr; ii: Bu3SnH, AIBN, toluene, reflex; iii. TsCl, pyridine, r.t.

ORDER
REPRINTS
150
Miethchen et al.
Scheme 3. i: I2, PPh3, toluene; ii: Br2, PPh3, toluene; iii: tribromoimidazole, PPh3, toluene; iv:
TsCl, Et3N, (CH2Cl)2, reflux, 6 hr; v: MsCl, Et3N, (CH2Cl)2, reflux, 3–4 hr; vi: tribromoimidazole,
PPh3, toluene; TfCl, pyridine.
The next step of our strategy was the introduction of the fluorine containing marker
group into the enolethers 11 and 12. Radical additions of halogeno-fluoroalkanes to
unsaturated precursors rank among the well suitable methods for the introduction of
fluoroalkyl groups into organic compounds. One of the most convenient methods in this
field is the dithionite-mediated addition of halogeno-fluoroalkanes to unsaturated
precursors;[5–8] first applications of this method in carbohydrate chemistry were already
published.[9–11]
Recently, we could show[1] that dithionite-mediated additions of CF2ClBr to glycals
proceed very selectively. In the products, the CF2Cl-group introduced in 2-position was
practically always trans-arranged to the neighbouring C-3 substituent. Because the
enolethers 11 and 12 are to be conceived as glycals of an aldoketose, the latter method
was used to introduce the CF2Cl-marker group as shown in Sch. 6. The primarily formed
glycosyl bromides hydrolyse easily. Therefore, we isolated this intermediate only in the
case of 2-deoxy-2-chlorodifluoromethyl-5,6-O-isopropylidene-3,4-di-O-(2,2,2-trichloro-
ethylidene)-b-D-arabinohexopyranos-5-ulosyl bromide (13) generated from the glycalic
Scheme 4. i: TfCl, pyridine, r.t.; ii: DBU, toluene, reflux.

ORDER
REPRINTS
Common Sugar as Model for Natural Product Modification
151
Scheme 5. i: TfCl, pyridine; ii: DBU, toluene, reflux.
precursor 11. Otherwise, the corresponding 2-chlorodifluoromethyl-2-deoxy-pyranoses 14
and 16 were isolated. These products were subsequently acetylated to the 1-O-acetyl
derivatives 15 and 17, respectively; Sch. 6. The target products 15 and 17 contain, related
to fructose derivative 1, one new and one inverted stereogenic center, a C-fluoroalkylated
marker group, and a favorable protecting group pattern.
1
The structures of all new compounds are supported by their H, 13C, and 19F NMR
spectra. The relative small 1-H/2-H-coupling constants of glycosyl bromide 13 (1.6 Hz)
indicate an a-configuration. A comparison of the 4-H/5-H-coupling constants of
5-hydroxy-derivative 3 (4.2 Hz), 5-O-tosyl-derivative 8 (5.5 Hz), and 5-O-mesyl-deriva-
tive 9 (4.6 Hz) with those of 5-deoxy-5-iodo-derivative 6 (2.8 Hz) and 5-deoxy-5-
bromo-derivative 7 (2.8 Hz) indicates the inversion of configuration at C-atom 5 during
the halogenation. The structure of 5-O-tosyl-D-tagatose derivative 8 was confirmed by
an x-ray analysis (Fig. 1).
The glycals 11 and 12 show characteristic downfield shifts for 1-H (11: d ¼ 6.43; 12:
d ¼ 6.41) and for the C-atoms 1 and 2 (11: dC-1 ¼ 144.9/dC-2 ¼ 100.1; 12: dC-1 ¼ 145.1/
Scheme 6. i: CF2ClBr, Na2S2O4, NaHCO3, MeCN, H2O; ii: Ag2CO3, MeOH, H2O; iii: Ac2O,
pyridine.

ORDER
REPRINTS
152
Miethchen et al.
Figure 1. X-ray structure of 3,4-O-[(R)-2,2,2-trichloroethylidene]-1,2-O-isopropylidene-5-O-
tosyl-b-D-tagatopyranose (8) with 30% probability of the thermal ellipsoids. The ring oxygen O3
takes disordered positions (here only one position is shown).
dC-2 ¼ 100.6). For the CF2Cl-substituted derivatives 13–17, the triplet of ring C-atom 2 in
the range of d ꢀ 50.6–53.4 (2JC-2,F ꢀ 22–23 Hz) is characteristic. The CF2Cl-group itself
produces 19F-signals in the range of d ꢀ 248.6 to 254.9 with geminal F–F-couplings
1
of 169–174 Hz and JF,C-couplings of 278–298 Hz. The configuration of the new
chiral center (C-2) was assigned on the basis of the 2-H/3-H and 2-H/1-H couplings.
The compounds 13, 14, 16, 17 adopt a slightly distorted 1C4 conformation with
3
3
3
couplings of J2,3 ꢀ 7.9–9.0 Hz, J1,2 ꢀ 1.6–2.2 Hz (b-anomers), and J1,2 ꢀ 8.1–8.5Hz
(a-anomers). The relative large 2-H/3-H coupling constants of the b-anomers of 13, 14, 16,
17 indicate that these protons come close to a trans-diaxial arrangement. NOE-experiments
were carried out to assign the configuration of the chlorodifluoromethylated C-atom in
compounds 13–17. Correlations were found between the acetal-H and the proton located
at the chlorodifluoromethylated C-atom. Such correlations are only to expect when the
latter has S-configuration.
CONCLUSION
The target compounds 15 and 17 are suitable glycosyl donors, whereas the sequence
and individual steps of the demonstrated model reaction are usable for various other
synthesis strategies, which use the chiral pool of natural substances. An example using
a similar synthesis strategy is sketched in the following illustration; Sch. 7. It stands for
conversions of pentopyranoses into fluorinated glycosyl donors with two anomeric posi-
tions, which are alternatively usable for subsequent glycosylations.
Key intermediates for C-fluoroalkylations are cyclic enol ethers inclusive of glycals.
The latter are above all accessible via triflic acid ester precursors. The strategy of com-
bined epimerization–fluoroalkylation, reported in this paper at one selected example, is

ORDER
REPRINTS
Common Sugar as Model for Natural Product Modification
153
Scheme 7. RF: F, CF3, CF2Cl . . .
transferable to various other models in carbohydrate chemistry (for a review about the
application of the non-conventional epimerization step see Ref.[4]). Sch. 7 shows such
an example for pentoses. The target molecule has, after the reaction sequence, two reactive
“anomeric” centers (marked by arrows) which can be alternatively activated for
glycosylations.
EXPERIMENTAL
General Remarks
Melting points were obtained using a Leitz polarizing microscope (Laborlux 12 Pol)
equipped with a hot stage (Mettler FP 90) and are uncorrected. 1H, 13C, and 19F NMR spec-
tra were recorded on Bruker instruments: AC 250 and ARX 300, internal standard TMS
1
1
for 1H and 13Cf Hg NMR spectra, CFCl3 for 19Ff Hg NMR spectra. Optical rotations were
measured on a polar LmP (IBZ Meßtechnik) instrument. Column chromatography was
carried out with Merck Silica Gel 60 (63–200 mm) and TLC on Merck Silica Gel 60 F254
sheets. Table 1 summarises in detail the analytical data of the new compounds 3–17.
X-ray Structure Determination of 8
X-ray diffraction data were collected with a Bruker P4 four circle diffractometer, Mo-Ka
3
˚
radiation (l ¼ 0.71073A), graphite monochromator, crystal size 0.64 ꢁ 0.62 ꢁ 0.52 mm ,
T ¼ 293(2)K, C18H21Cll3O8S, M ¼ 503.76, colourless prism, orthorhombic, space group
(H.-M.) P212121, space group (Hall) P2ac 2ab, a ¼ 10.1650(10), b ¼ 11.1790(10),
3
c ¼ 19.847(2)A, a ¼ b ¼ g ¼ 908, V ¼ 2255.3(4)A , Z ¼ 4, rcalc 1.484Mgm23, m ¼
0.540mm21, F(00 0) ¼ 1040, data collection range: 2.05 ꢂ Q ꢂ 21.998, 210 ꢂ h ꢂ 10,
211 ꢂ k ꢂ 11, 220 ꢂ l ꢂ 20, 3194 reflections collected, 2755 independent reflections
[R(int) ¼ 0.0247], 2576 observed [I . 2s(I)], completeness to Q ¼ 21.998: 99.6%,
˚
˚
R1 ¼ 0.0347(obs.), wR2 ¼ 0.0885(obs.), GOF (F2) ¼ 1.066, max./min. residual electron
density: þ0.142/ 2 0.132 e A23. The weighting scheme was calculated according to w21
¼
˚
s2(Fo2) þ (0.0368P)2 þ 0.4213P with P ¼ (Fo2 þ 2F2c)/3.
The central sugar ring adopts a distorted chair conformation with puckering para-
meters[12] of Q ¼ 0.519(3) A (puckering amplitude), Q ¼ 159.0(3)8, and F ¼ 177.7(11)8.
˚
In analogy to the literature[12] it could be designated as a 2C5 conformation.

ORDER
REPRINTS
154
Miethchen et al.
Table 1. Analytical data of the compounds 3–17.
Product
Precursor
Yield (%)
Mp (solvent 8C)
[a]2D2 CHCl3 (c)
Rf (eluents, v/v)
3
4
5
2
3 (2)
83
73
93
138 (pentane)
Colourless syrup
Colourless syrup
220.5 (0.52)
256.2 (0.49)
[a]2D7 233.9
(0.31)
0.12 (3 : 1)a
0.36 (2 : 1)b
0.14 (5 : 1)a
4
6
3
71
180 subl.
239.6 (1.11)
0.23 (5 : 1)a
(pentane/ether)
195 (pentane/ether)
157 (heptane/ether)
181 (EtOAc)
7
8
3
3
3
3
81
93
90
53
240.0 (1.11)
214.7 (1.03)
234.5 (1.10)
Unstable
0.24 (5 : 1)a
0.34 (3 : 1)a
0.35 (5 : 1)b
0.43 (5 : 1)a
9
10
113–114 (heptane)
compound
266.5 (1.02)
224.0 (1.25)
11
12
10
4
96
97
179–181 (heptane)
101
0.28 (10 : 1)a
0.27 (5 : 1)a
(heptane/EtOAc)
Unstable compound
Colourless syrup
Colourless syrup
180–190 (heptane)
Colourless syrup
13
14
15
16
17
11
11
14
12
16
23
42
55
57
92
0.31 (3 : 1)a
0.22 (3 : 1)a
0.17 (6 : 1)a
0.17 (4 : 1)a
0.34 (4 : 1)a
Anomers
Anomers
Anomers
Anomers
aHeptane–EtOAc.
bToluene–EtOAc.
The structure was solved by direct methods (Bruker SHELXTL). All non-hydrogen
atoms were refined anisotropically, with the hydrogen atoms introduced into theoretical
positions and refined according to the riding model. CCDC 207041 contains the sup-
plementary crystallographic data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: þ44-1223-336033; E-mail: deposit@ccdc.cam.ac.uk).
3,4-O-[(R)-2,2,2-trichloroethylidene]-1,2-O-isopropylidene-b-D-tagatopyranose
(3). Decarbamoylation of 2 by refluxing for 8 hr in 2% methanolic sodium methoxide
solution (TLC-control) yielded 3 in quantitative yield. Purification by column
chromatography.
3
1H NMR (250.1 MHz, CDCl3): 5.55 (s, 1H, acetal-H), 4.61 (m, 1H, J3,4 ¼ 5.2 Hz,
3
2
3
4-H), 4.48 (d, 1H, J3,4 ¼ 5.2 Hz, 3-H), 4.27 (dd, 1H, J6a,6b ¼ 12.8 Hz, J6a,5 ¼ 2.0 Hz,
3
3
6a-H), 4.12 (dd, 1H, J4,5 ¼ 4.2 Hz, J6a,5 ¼ 2.0 Hz, 5-H), 4.09 (s, 2H, 1a-H, 1b-H),
2
3
3.62 (dd, 1H, J6a,6b ¼ 12.8 Hz, J6b,5 ¼ 1.7 Hz, 6b-H), 2.20 (broad s, 1H, OH), 1.53,
1.44 (2s, 6H, 2 ꢁ CH3). 13Cf Hg NMR (62.9 MHz, CDCl3): 113.4 [C(CH3)2], 108.1
1
(CH–CCl3), 102.8 (C-2), 99.3 (CCl3), 76.5 (C-3), 73.2 (C-1), 72.3 (C-4), 65.7 (C-5),
61.1 (C-6), 27.4, 25.1 (2 ꢁ CH3); Anal. calcd for C11H15Cl3O6 (349.59): C, 37.79; H,
4.32; found C, 37.91, H, 4.35.
3,4-O-[(R)-Ethylidene]-1,2-O-isopropylidene-b-D-tagatopyranose (4). Compound 3
(0.9g, 2.58mmol) was dissolved in dry toluene (30 mL). Under argon Bu3SnH (2.7mL)
and AIBN (20 mg) were added and the mixture was refluxed for 4 hr (TLC-control).
When the reaction was finished, an excess of KF-soln. was added and the precipitate was

ORDER
REPRINTS
Common Sugar as Model for Natural Product Modification
155
filtered and intensively washed by toluene. The organic layer was separated, washed with
brine (30 mL) and water (30 mL), and was dried over Na2SO4. Column chromatography
gave pure 4.
3
1H NMR (250.1 MHz, CDCl3): 5.48 (q, 1H, JH,CH3 ¼ 5.0 Hz, acetal-H), 4.15 (dd,
3
2
1H, J6,5 ¼ 2.8 Hz, J6a,6b ¼ 11.6 Hz, 6a-H), 4.04–4.16 (m, 3H, 3-H, 4-H, 5-H), 4.00
2
(t, 2H, J1a,1b ¼ 9.0 Hz, 1a-H, 1b-H), 3.53 (dd, 1H, 6b-H), 2.37 (broad s, 1H, OH),
1
1.49, 1.38 (2s, 6H, 2 ꢁ CH3), 1.31 (d, 3H, acetal-CH3). 13Cf Hg NMR (62.9 MHz,
CDCl3): 112.8 [C(CH3)2], 103.5 (CH–CH3), 103.3 (C-2), 75.5 (C-5), 73.1 (C-1), 71.0
(C-3), 66.2 (C-4), 61.8 (C-6), 27.3, 25.4 (2 ꢁ CH3), 21.2 (acetal-CH3); Anal. calcd for
C11H18O6 (246.26): C, 53.65, H, 7.37, found C, 53.31, H, 7.35.
3,4-O-[(R)-Ethylidene]-1,2-O-isopropylidene-5-O-(p-tosyl)-b-D-tagatopyranose
(5). To a solution of 4 (0.55 g, 2.24 mmol) in dry pyridine (10 mL) p-toluenesulfonyl
chloride (0.53 g, 2.75 mmol) was added and then the mixture was stirred for 26 hr at
room temperature. Subsequently, the mixture was diluted with dried toluene and the
solvent was evaporated at reduced pressure. After the residue was dissolved in ethyl
acetate (20 mL), the further work-up procedure was analogous to that for 8. Column
chromatography [eluent (v/v): heptane/EtOAc ¼ 6/1, RF ¼ 0.23]; giving 0.83 g (93%)
of 5 for analytical data of the colourless syrupy product see Table 1.
1H NMR (250.1 MHz, CDCl3): 7.80–7.34 (4d, 4H, 3JH,H ¼ 8.3 Hz, phenyl-H), 5.41
3
(q, 1H, JCH3,acetal-H ¼ 5.0 Hz, acetal-H), 4.82 (m, 1H, 5-H), 4.14 (m, 2H, 3-H, 4-H),
2
3
2
4.07 (dd, 1H, J6a,6b ¼ 12.8 Hz, J6a,5 ¼ 2.8 Hz, 6a-H), 4.01 (d, 1H, J1a,1b ¼ 9.0 Hz,
1a-H), 3.97 (d, 1H, 1b-H), 3.53 (dd, 1H, 6b-H), 2.44 (s, 3H, tosyl-CH3), 1.46, 1.41
(2s, 6H, 2 ꢁ CH3), 1.24 (d, 3H, JCH3,acetal-H ¼ 5.0 Hz, acetal-CH3). 13Cf Hg NMR
(62.9 MHz, CDCl3): 145.0 (tosyl-C–SO3–), 133.3 (tosyl-C–CH3), 129.9, 127.9
(tosyl-CH), 113.6 [C(CH3)2], 103.6 (acetal-C), 103.0 (C-2), 74.9 (C-5), 73.0 (C-1),
72.7 (C-3), 70.8 (C-4), 58.6 (C-6), 27.3, 25.3 (2 ꢁ CH3), 21.7 (tosyl-CH3), 21.2
(acetal-CH3); Anal. calcd for C18H24O8S (400.44): C, 53.99, H, 6.04, S, 8.01, found
C, 54.53, H, 6.15, S, 8.12.
3
1
3,4-O-[(R)-2,2,2-Trichloroethylidene]-5-deoxy-5-iodo-1,2-O-isopropylidene-b-L-
psico-pyranose (6).[13] Compound 3 (0.7 g, 2.0 mmol) was dissolved in dry toluene
(50 mL) and triphenylphosphine (1.55 g, 5.8 mmol), imidazole (0.4 g, 5.8 mmol), and iod-
ine (0.89 g, 3.5 mmol) were added under strong stirring and argon atmosphere. The mix-
ture was heated for 5 hr (bath temperature 1208C) then quenched with sat. NaHCO3-soln.
(TLC-control). The layers were separated, and the aqueous phase was washed with toluene
(2 ꢁ 30 mL). The combined organic layers were washed with brine (2 ꢁ 50 mL) and
water (50 mL), dried over Na2SO4, and evaporated under reduced pressure. Column chro-
matography gave pure 6. As by-product compound 11 was detected.
3
1H NMR (250.1 MHz, CDCl3): 5.66 (s, 1H, acetal-H), 4.87 (m, 1H, J3,4 ¼ 4.7 Hz,
3
3J4,5 ¼ 2.8 Hz, 4-H), 4.39 (d, 1H, J3,4 ¼ 4.7 Hz, 3-H), 4.14–4.28 (m, 2H, 6a-H, 6b-H),
2
2
4.05 (d, 1H, J1,1 ¼ 9.1 Hz, 1a-H), 4.03 (d, 1H, J1,1 ¼ 9.1 Hz, 1b-H), 3.66 (m, 1H,
1
3J4,5 ¼ 2.8 Hz, 5-H), 1.53 (s, 3H, CH3), 1.45 (s, 3H, CH3). 13Cf Hg NMR (62.9 MHz,
CDCl3): 113.7 [C(CH3)2], 107.5 (CH–CCl3), 102.5 (C-2), 99.2 (CCl3), 76.2 (C-3), 73.6
(C-4), 73.1 (C-1), 61.2 (C-6), 27.3, 25.0 (2 ꢁ CH3), 16.4 (C-5); MS: chemical ionisation
(isobutane): 460.0 (Molpeak 15%), 445.0 (Mþ 2 CH3, 100%); Anal. calcd for
C11H14Cl3IO5 (459.49): C, 28.75, H, 3.07, found C, 29.13, H, 3.07.
5-Bromo-3,4-O-[(R)-2,2,2-trichloroethylidene]-5-deoxy-1,2-O-isopropylidene-b-
L-psico-pyranose (7) (modified Ref.[13]). Compound 3 (0.35 g, 1.0 mmol) was dissolved

ORDER
REPRINTS
156
Miethchen et al.
in dry toluene (30 mL) and triphenylphosphine (0.76 g, 2.9 mmol), imidazole (0.4 g,
5.8 mmol), and bromine (0.1 mL, 3.9 mmol) were added under strong stirring and argon
atmosphere. The mixture was heated for 5 hr (bath temperature 1208C) then quenched
with sat. NaHCO3-soln. (TLC-control). The layers were separated, and the aqueous
phase was washed with toluene (2 ꢁ 20 mL). The combined organic layers were washed
with brine (2 ꢁ 30 mL) and water (30 mL), dried over Na2SO4, and evaporated under
reduced pressure. Column chromatography gave pure 6. As by-product compound 11
was detected.
3
1H NMR (250.1 MHz, CDCl3): 5.67 (s, 1H, acetal-H), 4.91 (m, 1H, J3,4 ¼ 4.7 Hz,
3
3J4,5 ¼ 2.8 Hz, 4-H), 4.38 (d, 1H, J3,4 ¼ 4.7 Hz, 3-H), 4.07–4.24 (m, 2H, 6a-H, 6b-H),
2
2
4.07 (d, 1H, J1,1 ¼ 9.0 Hz, 1a-H), 4.03 (d, 1H, J1,1 ¼ 9.0 Hz, 1b-H), 3.69 (m, 1H,
1
3J4,5 ¼ 2.8 Hz, 5-H), 1.53 (s, 3H, CH3), 1.45 (s, 3H, CH3). 13Cf Hg NMR (62.9 MHz,
CDCl3): 113.8 [C(CH3)2], 108.1 (CH–CCl3), 102.4 (C-2), 99.1 (CCl3), 75.6 (C-3), 74.4
(C-4), 72.9 (C-1), 59.4 (C-6), 39.8 (C-5), 27.4, 25.1 (2 ꢁ CH3); MS: chemical ionisation
(isobutane): 413.0 (Molpeak 21%), 398.0 (Mþ 2 CH3, 100%); Anal. calcd for C11H14-
BrCl3O5 (412.49): C, 32.03, H, 3.42, found C, 32.52, H, 3.64.
3,4-O-[(R)-2,2,2-Trichloroethylidene]-1,2-O-isopropylidene-5-O-(p-tosyl)-b-D-
tagato-pyranose (8). To a solution of 3 (0.75 g, 2.15 mmol) in dry DCE (15 mL) and Et3N
(5.6 mL, 40 mmol) p-toluenesulfonyl chloride (0.76 g, 4.0 mmol) was batchwise added
under cooling and then the mixture was refluxed for 6 hr (argon atmosphere). After the
mixture was allowed to cool down, water (20 mL) was added and the product was
extracted with CHCl3 (50 mL). The chloroform phase was washed with NaHSO4-soln.
(3%, 3 ꢁ 30 mL) and water (30 mL), then dried over Na2SO4, and concentrated under
reduced pressure. The brown residue was purified by column chromatography [eluent
(v/v): heptane/ethyl acetate ¼ 3/1, RF ¼ 0.34]; for analytical data of the crystalline
product 8 see Table 1.
1H NMR (250.1 MHz, CDCl3): 7.64, 7.51, 7.19, 7.11 (4d, 4H, 3JH,H ¼ 8.2 Hz, phenyl-
3
3
H), 5.32 (s, 1H, acetal-H), 4.67 (dd, 1H, J3,4 ¼ 3.7 Hz, J5,4 ¼ 5.5 Hz, 4-H), 4.33 (ddd,
3
3
3
1H, J5,4 ¼ 5.5 Hz, J5,6a ¼ 3.7 Hz, J5,6b ¼ 1.8 Hz, 5-H), 4.25 (d, 1H, 3-H), 3.96 (dd,
2
2
1H, J6a,6b ¼ 13.7 Hz, 6a-H), 3.90 (d, 2H, J1a,1b ¼ 9.5 Hz, 1a-H, 1b-H), 3.42 (dd, 1H,
1
6b-H), 2.28 (s, 3H, tosyl-CH3) 1.31, 1.25 (2s, 6H, 2 ꢁ CH3). 13Cf Hg NMR (62.9 MHz,
CDCl3): 145.5 (tosyl-C–SO3–), 133.2 (tosyl-C–CH3), 129.5, 127.8 (tosyl-CH), 113.5
[C(CH3)2], 107.9 (CH–CCl3), 102.2 (C-2), 98.8 (CCl3), 74.2, 73.0, 72.0 (C-5, C-3,
C-4), 73.7 (C-1), 58.6 (C-6), 27.2, 25.0 (2 ꢁ CH3), 21.7 (tosyl-CH3); Anal. calcd for
C18H21Cl3O8S (503.77): C, 42.92, H, 4.20, found C, 43.15, H, 4.17.
3,4-O-[(R)-2,2,2-Trichloroethylidene]-1,2-O-isopropylidene-5-O-mesyl-b-D-tagato-
pyranose (9). To a solution of 3 (440 mg, 1.78 mmol) in DCE (10 mL) and Et3N (1.3 mL,
9.0 mmol), methanesulfonyl chloride (0.28 mL, 3.56 mmol) was added under cooling and
the mixture was refluxed for 3–4 hr (TLC-control). The work-up procedure was analogous
to that for 8. Column chromatography: [eluent (v/v): heptane/ethyl acetate ¼ 2/1,
RF ¼ 0.19]; for analytical data of the crystalline product 9 see Table 1.
3
1H NMR (250.1 MHz, CDCl3): 5.47 (q, 1H, JH,CH3 ¼ 4.9 Hz, acetal-H), 5.06 (dd,
3
3
3
3
1H, J5,4 ¼ 4.6 Hz, J5,6a ¼ 8.6 Hz, J5,6b ¼ 4.6 Hz, 5-H), 4.31 (dd, 1H, J4,3 ¼ 2.1 Hz,
2
4-H), 4.21 (d, 1H, 3-H), 4.17 (dd, 1H, J6a,6b ¼ 12.5 Hz, 6a-H), 4.02 (d, 2H,
2J1a,1b ¼ 9.2 Hz, 1a-H, 1b-H), 3.73 (dd, 1H, 6b-H), 3.11 (s, 3H, –SO2–CH3), 1.50, 1.38
(2s, 6H, 2 ꢁ CH3), 1.32 (d, 3H, acetal-CH3). 13Cf Hg NMR (62.9 MHz, CDCl3): 113.1
1
[C(CH3)2], 103.4 (CH–CH3), 103.2 (C-2), 74.9, 73.6, 71.3 (C-3, C-4, C-5), 72.9 (C-1),

ORDER
REPRINTS
Common Sugar as Model for Natural Product Modification
157
59.9 (C-6), 38.8 (–SO2–CH3), 27.2, 25.3 (2 ꢁ CH3), 20.8 (acetal-CH3); Anal. calcd for
C12H17Cl3O8S (427.68): C, 33.70, H, 4.01, S, 7.50, found C, 34.00, H, 4.02, S, 7.64.
3,4-O-[(R)-2,2,2-Trichloroethylidene]-5,6-dideoxy-1,2-O-isopropylidene-b-D-erythro-
hexen-5-ulopyranose (11). 3,4-O-[(R)-2,2,2-Trichloroethylidene]-5-O-trifluorometha-
nesulfonyl-1,2-O-isopropylidene-b-tagatopyranose (10). To a suspension of com-
pound 3 (1.7 g, 4.86 mmol) in pyridine (65 mL) trifluoromethanesulfonyl chloride
(2 mL) was added carefully at 08C (argon atmosphere). After the mixture was allowed
to warm up to r.t., it was stirred over night. Then, CHCl3 (100 mL) was added and the mix-
ture was washed with NaHSO4-soln. (5%, 5 ꢁ 100 mL), water (100 mL), dried (Na2SO4)
and concentrated under reduced pressure. Column chromatographic separation gave
compound 10 as a white powder. Traces of 11 were detected. The triflate 10 was used
for the following synthetic step without further purification.
3
1H NMR (250.1 MHz, CDCl3): 5.57 (s, 1H, acetal-H), 5.22 (d, 1H, J4,5 ¼ 1.9 Hz,
3
3
3
5-H), 4.69 (dt, 1H, J4,5 ¼ 1.9 Hz, J3,4 ¼ 5.3 Hz, 4-H), 4.53 (d, 1H, J3,4 ¼ 5.3 Hz,
3
2
3-H), 4.34 (dd, 1H, J5,6a ¼ 1.8 Hz, J6a,6b ¼ 14.2 Hz, 6a-H), 4.13 (s, 2H, 1a-H, 1b-H),
3
2
3.88 (dt, 1H, J5,6b ¼ 1.7 Hz, J6a,6b ¼ 14.2 Hz, 6b-H), 1.53 (s, 3H, CH3), 1.45 (s, 3H,
CH3). 13Cf Hg NMR (62.9 MHz, CDCl3): 121.3 (CF3), 113.9 (C(CH3)2), 108.1 (CH-
1
CCl3), 102.3 (C-2), 98.5 (CCl3), 80.3 (C-5), 74.0 (C-3), 73.1 (C-1), 71.9 (C-4), 58.6 (C-
6), 27.3, 25.0 (2 ꢁ CH3). 19Ff Hg NMR (235.4 MHz, CDCl3): 274.62 (s, CF3).
1
3,4-O-[(R)-2,2,2-Trichloroethylidene]-1,2-dideoxy-5(R),6-O-isopropylidene-b-D-
erythro-hexen-5-ulopyranose (11). Triflate 10 (700 mg, 1.45 mmol) was dissolved in
dry THF (20 mL). Under stirring DBU (0.35 mL) was added and the mixture was refluxed
for 2.5 hr (TLC-control). After cooling the mixture was poured into ice/water (30 mL). It
was extracted with chloroform (3 ꢁ 20 mL). The organic layer was washed with water
(20 mL), dried over Na2SO4, and was evaporated under reduced pressure. Column chroma-
tography gave 11 quantitatively.
1H NMR (250.1 MHz, CDCl3): 6.43 (dd, 1H, J1,2 ¼ 6.1 Hz, J1,3 ¼ 0.8 Hz, 1-H),
3
4
3
3
5.50 (s, 1 H, acetal-H), 5.30 (dd, 1H, J2,3 ¼ 4.3 Hz, J1,2 ¼ 6.1 Hz, 2-H), 4.91 (m, 1H,
4J1,3 ¼ 0.8 Hz, J2,3 ¼ 4.3 Hz, J3,4 ¼ 6.2 Hz, 3-H), 4.52 (d, 1H, J3,4 ¼ 6.2 Hz, 4-H),
3
3
3
3
4.21 (2d, 2H, J6a,6b ¼ 9.2 Hz, 6a-H, 6b-H), 1.53 (s, 3H, CH3), 1.46 (s, 3H, CH3).
13Cf Hg NMR (62.9 MHz, CDCl3): 144.9 (C-1), 113.8 [C(CH3)2], 108.1 (CH–CCl3),
1
102.1 (C-5), 100.1 (C-2), 99.8 (CCl3), 73.5 (C-4), 71.7 (C-3), 69.6 (C-6), 27.1, 25.4
(2 ꢁ CH3); MS: chemical ionisation (isobutane): 332.0 (Molpeak 100%); Anal. calcd
for C11H13Cl3O5 (331.58): C, 39.85, H, 3.95, found C, 40.04, H, 3.98.
3,4-O-[(R)-Ethylidene]-1,2-dideoxy-5(R),6-O-isopropylidene-b-D-erythro-hexen-
5-ulo-pyranose (12). To a suspension of compound 4 (1.38 g, 5.61 mmol) in pyridine
(40 mL) trifluoromethanesulfonyl chloride (2 mL) was added carefully at 08C (argon
atmosphere). The work-up procedure was analogous to that for 10 (without chromato-
graphic purification). The crude product 4 was dissolved in dry THF (20 mL). DBU
(0.35 mL) was added and the mixture was refluxed for 2.5 hr. After cooling the mixture
was poured onto ice (40 g) and extracted with chloroform (2 ꢁ 30 mL). The combined
organic layers were washed with water (20 mL) and dried over Na2SO4. Purification by
column chromatography yielded 12 quantitativly.
3
1H NMR (250.1 MHz, CDCl3): 6.41 (d, 1H, J6,5 ¼ 6.1 Hz, 1-H), 5.44 (q, 1H,
3
3JH,CH3 ¼ 5.0 Hz, acetal-H), 5.01 (dd, 1H, J5,4 ¼ 3.7 Hz, 2-H), 4.62 (dd, 1H,
3J4,3 ¼ 5.8 Hz, 3-H), 4.18 (d, 1H, 4-H), 4.13 (d, 1H, 2J6a,6b ¼ 9.2 Hz, 6a-H), 4.02 (d, 1H,
3
2J6a,6b ¼ 9.2 Hz, 6b-H), 1.54, 1.43 (2s, 6H, 2 ꢁ CH3), 1.36 (d, 3H, JH,CH3 ¼ 5.0 Hz,

ORDER
REPRINTS
158
Miethchen et al.
1
acetal-CH3). 13Cf Hg NMR (62.9 MHz, CDCl3): 145.1 (C-1), 113.4 (CH–CH3), 102.1 (C-
5), 100.6 (C-2), 73.9 (C-6), 72.1 (C-3), 68.9 (C-4), 26.9, 25.8 (2 ꢁ CH3), 20.9 (acetal-
CH3); Anal. calcd for C11H16O5 (228.24): C, 57.89, H, 7.07, found C, 57.56, H, 7.12.
2-C-Chlorodifluoromethyl-3,4-di-O-[(R)-2,2,2-trichloroethylidene-2-deoxy-5(R),6-
O-iso-propylidene]-b-D-arabinohexopyranos-5-ulosyl bromide (13). Compound 11
(0.5g, 1.5 mmol) was dissolved in acetonitrile (20 mL) and water (10 mL). NaHCO3
(1.0g) was suspended and the mixture cooled to 2108C. Then, CF2ClBr (approx. 0.2 mL
or 25 drops) was condensed via a cooling trap (dry ice/acetone) into the mixture and
Na2S2O4 (1.0g) was added. The suspension was allowed to warm up slowly to 208C within
2 hr. A constant dropwise reflux of the freon is preferable. If the reaction is not finished
(TLC-control) a second addition of dithionite should follow. When total turnover was
achieved diethylether (30 mL) was added and the layers separated. The organic layer was
washed with brine (20 mL) and water (20 mL) and was dried over Na2SO4. Compound 13
was separated by column chromatography. Because the product is very sensitive to
hydrolyses (formation of 14), the C, H, N-microanalyses differed significantly.
1H NMR (250.1 MHz, CDCl3): 5.60 (d, 1H, 3J1,2 ¼ 1.6 Hz, 1-H), 5.52 (s, 1H, acetal-
3
3
H), 5.09 (t, 1H, J3,4 ¼ 6.8 Hz, J2,3 ¼ 7.9 Hz, 3-H), 4.86 (d, 1H, 4-H), 4.28 (d, 1H,
2J6a,6b ¼ 9.1 Hz, 6a-H), 4.06 (d, 1H, 6b-H), 3.26–3.41 (m, 1H, 2-H), 1.52, 1.43 (2s, 6H,
1
1
2 ꢁ CH3). 13Cf Hg NMR (62.9 MHz, CDCl3): 132.4 (t, JC,F ¼ 288 Hz, CF2Cl), 113.0
[C(CH3)2], 109.5 (CH–CCl3), 103.0 (CCl3), 99.4 (C-5), 89.6 (C-1), 74.7 (C-4), 72.6
(C-6), 71.8 (C-3), 52.9 (t, JC-2,F ¼ 23 Hz, C-2), 27.1, 25.4 (2 ꢁ CH3). 19Ff Hg NMR
2
1
2
2
(235.4 MHz, CDCl3): 251.7 (d, JFa,Fb ¼ 169 Hz), 254.7 (d, JFa,Fb ¼ 169 Hz); MS:
chemical ionisation (isobutane): 497.0 (Molpeak 100%).
2-C-Chlorodifluoromethyl-3,4-di-O-[(R)-2,2,2-trichloroethylidene-2-deoxy-5(S),6-
O-isopropylidene]-a/b-D-arabinohexopyranos-5-ulose (14). Compound 11 (0.5 g,
1.5 mmol) were used as for 13. Hydrolysis of 13 happens in reaction conditions partially
but when the mixture was stirred over night NaHCO3 conditions only 14 could be
observed. Compound 13 reacts in methanol/water (v/v ¼ 25/1) with silver carbonate
more quickly yielding in 14 within 1 hr. Purification by column chromatography yielded
the syrupy product 14.
1H NMR (250.1 MHz, CDCl3): 5.62 (d, 1H, 3J1,2 ¼ 1.6Hz, 1-H), 5.51 (s, 1H, acetal-H),
3
3
3
5.03 (t, 1H, J3,4 ¼ 6.8Hz, J2,3 ¼ 7.9 Hz, 3-H), 4.92 (d, 1H, J3,4 ¼ 6.8 Hz, 4-H), 4.25
2
2
(d, 1H, J6a,6b ¼ 9.1 Hz, 6a-H), 4.10 (d, 1H, J6a,6b ¼ 9.1Hz, 6b-H), 3.16–3.29 (m, 1H,
2-H), 2.97 (broad s, 1H, OH), 1.51, 1.41 (2s, 6H, 2 ꢁ CH3). 13Cf Hg NMR (62.9MHz,
1
1
CDCl3): 129.7 (t, JC,F ¼ 278 Hz, CF2Cl), 114.1 [C(CH3)2], 108.6 (CH–CCl3), 103.2
2
(CCl3), 99.3 (C-5), 90.8 (C-1), 73.9 (C-4), 72.2 (C-6), 71.9 (C-3), 52.8 (t, JC-2,F ¼ 22 Hz,
C-2), 27.0, 25.1 (2 ꢁ CH3). 19Ff Hg NMR (235.4 MHz, CDCl3): 248.6 (d, JFa,Fb ¼ 169 Hz),
1
252.3 (d, JFa,Fb ¼ 169Hz); MS: chemical ionisation (isobutane): 433.0 (Molpeak 100%).
Anal. calcd for C12H14Cl4F2O6 (434.04): C, 33.21, H, 3.25, found C, 33.47, H, 3.52.
1-O-Acetyl-2-C-chlorodifluoromethyl-3,4-di-O-[(R)-2,2,2-trichloroethylidene-2-
deoxy-5(S),6-O-isopropylidene]-D-arabinohexopyranos-5-ulose (15). Compound 14
(100 mg, 0.23 mmol) was dissolved in pyridine (5 mL) and acetic anhydride (5 mL) and
was stirred at 208C over night. Evaporation to dryness and column chromatography
gave 15 as anomeric mixture (a/b ¼ 1/2).
a-Anomer of 15: 1H NMR (250.1 MHz, CDCl3): 6.53 (dd, 1H, J1,F ¼ 0.6 Hz,
4
3J1,2 ¼ 2.2 Hz, 1-H), 5.53 (s, 1H, acetal-H), 5.06 (t, 1H, J3,4 ¼ 6.9 Hz, 3-H), 4.72 (d, 1H,
3
3J3,4 ¼ 6.9 Hz, 4-H), 4.27 (d, 1H, 2J6a,6b ¼ 9.2 Hz, 6a-H), 4.13 (d, 1H, 2J6a,6b ¼ 9.2 Hz, 6b-

ORDER
REPRINTS
Common Sugar as Model for Natural Product Modification
159
1
H), 3.45–3.57 (m, 1H, 2-H), 2.06 (s, 3H, C(O)CH3), 1.53, 1.43 (2s, 6H, 2 ꢁ CH3). 13Cf Hg
NMR (62.9 MHz, CDCl3): 168.3 (C55O), 127.2 (t, 1JC,F ¼ 278 Hz, CF2Cl), 113.6 [C(CH3)2],
109.6 (CH–CCl3), 103.2 (C-5), 99.2 (CCl3), 87.2 (C-1), 74.7 (C-4), 72.4 (C-6), 71.8 (C-3),
2
1
51.5 (t, JC-2,F ¼ 22.5 Hz, C-2), 26.8, 25.6 (2 ꢁ CH3), 20.9 [C(O)CH3]. 19Ff Hg NMR
(235.4 MHz, CDCl3): 252.3 (d, 2JFa,Fb ¼ 170 Hz, Fa), 254.9 (d, 2JFa,Fb ¼ 170 Hz, Fb).
1
3
b-Anomer of 15: H NMR (250.1 MHz, CDCl3): 6.27 (d, 1H, J1,2 ¼ 8.1 Hz, 1-H),
3
3
5.52 (s, 1H, acetal-H), 4.91 (t, 1H, J3,4 ¼ 7.8 Hz, 3-H), 4.49 (d, 1H, J3,4 ¼ 7.8 Hz,
2
2
4-H), 4.23 (d, 1H, J6a,6b ¼ 8.4 Hz, 6a-H), 4.08 (d, 1H, J6a,6b ¼ 8.4 Hz, 6b-H), 3.45–
3.57 (m, 1H, 2-H), 2.08 [s, 3H, C(O)CH3], 1.55, 1.45 (2s, 6H, 2 ꢁ CH3). 13Cf Hg NMR
1
1
(62.9 MHz, CDCl3): 169.2 (C55O), 129.1 (t, JC,F ¼ 298 Hz, CF2Cl), 114.3 [C(CH3)2],
109.0 (CH–CCl3), 103.3 (C-5), 99.3 (CCl3), 87.3 (C-1), 74.3 (C-4), 72.4 (C-6), 71.8
(C-3), 53.4 (t, JC-2,F ¼ 22.5 Hz, C-2), 26.7, 25.5 (2 ꢁ CH3), 20.9 [C(O)CH3]. 19Ff Hg
NMR (235.4 MHz, CDCl3): 252.3 (d, 2JFa,Fb ¼ 174 Hz, Fa), 254.9 (d, 2JFa,Fb ¼ 174 Hz,
Fb); a/b-15: GC-MS (for anomeric mixture): (30 eV): 2 compounds found with closed
retention times. Both show same mass spectra: 475.0 (Molpeak, isotopic signal for four
chlorine atoms). Anal. calcd for C14H16Cl4F2O7 (476.08): C, 35.32, H, 3.39, found C,
35.42, H, 3.60.
2
1
2-C-Chlorodifluoromethyl-2-deoxy-3,4-di-O-[(R)-ethylidene-5(S),6-O-isopropyl-
idene]-a/b-D-arabino-hexopyranos-5-ulose (16). Compound 12 (1.85 g, 8.1 mmol)
were used as for 13. Hydrolysis of the intermediate glycosyl bromide happens in reaction
conditions when the mixture is stirred over night in basic conditions. Purification by
column chromatography yielded 16.
3
1H NMR (250.1MHz, CDCl3): 5.56 (m, 1H, 1-H), 5.50 (q, 1H, JH,CH3 ¼ 4.9 Hz,
3
3
3
acetal-H), 4.76 (dd, 1H, J3,4 ¼ 7.2 Hz, J2,3 ¼ 9.0 Hz, 3-H), 4.51 (d, 1H, J3,4 ¼ 7.2 Hz,
2
2
4-H), 4.18 (d, 1H, J6a,6b ¼ 9.0 Hz, 6a-H), 4.01 (d, 1H, J6a,6b ¼ 9.0 Hz, 6b-H), 3.04–
3.34 (m, 1H, 2-H), 3.13 (broad s, 1H, OH), 1.48 (s, 3H, CH–CH3), 1.35, 1.34 (2s, 6H,
2 ꢁ CH3). 13Cf Hg NMR (62.9 MHz, CDCl3): 127.8 (t, JC,F ¼ 295 Hz, CF2Cl), 112.8
1
1
[C(CH3)2], 104.0 (CH–CH3), 102.3 (C-5), 89.9 (C-1), 73.1 (C-3), 72.9 (C-4), 69.3 (C-6),
51.9 (t, JC-2,F ¼ 22Hz, C-2), 27.2, 25.4 (2 ꢁ CH3), 20.8 (acetal-CH3). 19Ff Hg NMR
2
1
2
2
(235.4MHz, CDCl3): 250.2 (d, JFa,Fb ¼ 169 Hz), 253.4 (d, JFa,Fb ¼ 169 Hz). Anal.
calcd for C12H14Cl4F2O6 (330.71): C, 43.58, H, 5.18, found C, 43.80, H, 5.51.
1-O-Acetyl-2-C-chlorodifluoromethyl-2-deoxy-3,4-di-O-[(R)-ethylidene-5(S),6-
O-isopropylidene]-a/b-D-arabinohexopyranos-5-ulose (17). Compound 16 (910 mg,
0.23 mmol) was dissolved in pyridine (20 mL) and acetic anhydride (20 mL) and was
stirred at 208C over night. Evaporation to dryness and column chromatography gave 17
as anomeric mixture (a/b ꢀ 0.9/1).
b-Anomer of 17: 1H NMR (250.1 MHz, CDCl3): 6.49 (dd, 1H, J1,F ¼ 0.6 Hz,
4
3J1,2 ¼ 2.1 Hz, 1-H), 5.52 (q, 1H, JH,CH3 ¼ 4.9 Hz, acetal-H), 4.75 (dd, 1H,
3
3J3,4 ¼ 7.2 Hz, J2,3 ¼ 8.9 Hz, 3-H), 4.42 (d, 1H, J3,4 ¼ 7.2 Hz, 4-H), 4.08–4.23
3
3
3
(m, 2H, 6a-H, 6b-H), 3.39–3.50 (m, 1H, 2-H), 2.05 (d, 3H, JH,CH3 ꢀ 4.9 Hz, acetal-
CH3), 1.54, 1.40 (2s, 6H, 2 ꢁ CH3). 13Cf Hg NMR (62.9 MHz, CDCl3): 169.3 (C55O),
1
1
129.4 (t, JC,F ¼ 297 Hz, CF2Cl), 114.1 [C(CH3)2], 104.3 (CH–CH3), 102.5 (C-5), 87.8
2
(C-1), 73.0 (C-4), 72.6 (C-6), 71.3 (C-3), 51.2 (t, JC-2,F ¼ 23 Hz, C-2), 26.9, 25.5
(2 ꢁ CH3), 20.9 [C(O)CH3]. 19Ff Hg NMR (235.4 MHz, CDCl3): 250.8 (d, 2JFa,Fb ¼ 172
1
2
Hz, Fa), 253.8 (d, JFa,Fb ¼ 172 Hz, Fb).
a-Anomer of 17: 1H NMR (250.1MHz, CDCl3): 6.24 (d, 1H, 3J1,2 ¼ 8.5 Hz, 1-H), 5.37
3
3
3
(q, 1H, JHac,CH3 ¼ 4.9 Hz, acetal-H), 4.62 (dd, 1H, J3,4 ¼ 8.0 Hz, J2,3 ¼ 9.2 Hz, 3-H),

ORDER
REPRINTS
160
Miethchen et al.
4.08–4.23 (m, 3H, 4-H, 6a-H, 6b-H), 3.26–3.42 (m, 1H, 2-H), 2.05 (d, 3H, 3JH,CH3 ¼ 4.9
1
Hz, CHCH3), 1.51, 1.37 (2s, 6 H, 2 ꢁ CH3). 13Cf Hg NMR (62.9 MHz, CDCl3): 168.5
1
(C55O), 127.6 (t, JC,F ¼ 294 Hz, CF2Cl), 113.3 [C(CH3)2], 104.1 (CH–CH3), 102.5
2
(C-5), 87.8 (C-1), 72.9 (C-4), 72.5 (C-6), 69.3 (C-3), 50.6 (t, JC-2,F ¼ 23Hz, C-2),
1
26.8, 25.3 (2 ꢁ CH3), 20.8 [C(O)CH3]. 19Ff Hg NMR (235.4MHz, CDCl3): 250.8
2
2
(d, JFa,Fb ¼ 172 Hz, Fa), 253.8 (d, JFa,Fb ¼ 172 Hz, Fb). Anal. calcd for C14H19ClF2O7
(372.75): C, 45.11, H, 5.14, found C, 45.93, H, 5.40.
ACKNOWLEDGMENTS
The authors are grateful to Prof. Dr. Manfred Michalik (Leibniz-Institut fuer
Organische Katalyse Rostock) for recording the NMR spectra and helpful discussions
and to Claudia Vinke for technical assistance.
REFERENCES
1. Tews, S.; Miethchen, R.; Reinke, H. Stereoselective synthesis and reactivity of
2-chlorodifluoromethyl-substituted monosaccharides. Synthesis 2003, 707–716.
2. Baasner, B.; Hagemann, H.; Tatlow, J.C., Eds. Organofluorine compounds. In
Houben-Weyl, Methods of Organic Chemistry; Thieme-Verlag: Stuttgart, 1999/2000;
Vol. E 10a-c, and papers cited therein.
3. Frank, M.; Miethchen, R.; Degenring, D. D-Tagatose derivatives from D-fructose by a
facile epimerisation procedure. Carbohydr. Res. 1999, 318, 167–170.
4. Miethchen, R. Epimerization by non-classical acetalization—a new three component
reaction for carbohydrates and inositols. J. Carbohydr. Chem. 2003, 22, 801–825.
5. Huang, W.-Y. Perfluoroalkylation initiated with sodium dithionite and related reagent
systems. J. Fluorine Chem. 1992, 58, 1–8.
6. Wu, F.-H.; Huang, B.N.; Lu, L.; Huang, W.-Y. Addition reactions of dibromodifluoro-
methane promoted by sulfinatodehalogenation reagents. J. Fluorine Chem. 1996, 80,
91–94.
7. Huang, W.-Y.; Wu, F.-H. The sulfinatodehalogenation reaction. Israel J. Chem. 1999,
39, 167–170, and papers cited therein.
8. Plenkiewicz, H.; Dmowski, W.; Lipinski, M. Sodium dithionite initiated reactions of
Halothane with enol ethers. Facile synthesis of 3-trifluoromethyl substituted vinyl
carbonyl compounds. J. Fluorine Chem. 2001, 111, 227–232, and papers cited therein.
9. Huang, W.-Y.; Xie, Y. Studies on sulfinatodehalogenation. XIII. Synthesis of
2-perfluoroalkyl-2-deoxy-D-glucose, mono- and poly-O-polyfluoroalkylated-D-glucoses.
Chinese J. Chem. 1991, 9, 351–359; Chem. Abstr. 1992, 116, 106596.
10. Zur, C.; Miethchen, R. Organofluorine compounds and fluorinating agents, 19.
Dithionite-catalysed addition of perfluoroalkyl iodides to unsaturated carbohydrates.
Eur. J. Org. Chem. 1998, 531–539.
11. Miethchen, R.; Hein, M.; Reinke, H. Organofluorine compounds and fluorinating
agents, 22 A new method for the selective introduction of difluoromethyl and trifluor-
omethyl groups into sugar moieties. Eur. J. Org. Chem. 1998, 919–923.

ORDER
REPRINTS
Common Sugar as Model for Natural Product Modification
161
12. (a) Cremer, D.; Pople, J.A. A general definition of ring puckering coordinates. J. Am.
Chem. Soc. 1975, 97, 1354–1358; (b) Cremer, D.; Pople, J.A. Molecular orbital
theory of the electronic structure of organic compounds. XXIII. Pseudorotation in
saturated five-membered ring compounds. J. Am. Chem. Soc. 1975, 97, 1358–1367.
13. Garregg, P.J.; Samuelsson, B. Novel reagent system for converting a hydroxy-group
into an iodo-group in carbohydrates with inversion of configuration. J. Chem. Soc.
Perkin 1 1980, 2866–2869.

Request Permission or Order Reprints Instantly!
Interested in copying and sharing this article? In most cases, U.S. Copyright
Law requires that you get permission from the article’s rightsholder before
using copyrighted content.
All information and materials found in this article, including but not limited
to text, trademarks, patents, logos, graphics and images (the "Materials"), are
the copyrighted works and other forms of intellectual property of Marcel
Dekker, Inc., or its licensors. All rights not expressly granted are reserved.
Get permission to lawfully reproduce and distribute the Materials or order
reprints quickly and painlessly. Simply click on the "Request Permission/
Order Reprints" link below and follow the instructions. Visit the
U.S. Copyright Office for information on Fair Use limitations of U.S.
copyright law. Please refer to The Association of American Publishers’
Fair Use in the Classroom.
(AAP) website for guidelines on
The Materials are for your personal use only and cannot be reformatted,
reposted, resold or distributed by electronic means or otherwise without
permission from Marcel Dekker, Inc. Marcel Dekker, Inc. grants you the
limited right to display the Materials only on your personal computer or
personal wireless device, and to copy and download single copies of such
Materials provided that any copyright, trademark or other notice appearing
on such Materials is also retained by, displayed, copied or downloaded as
part of the Materials and is not removed or obscured, and provided you do
not edit, modify, alter or enhance the Materials. Please refer to our
Website
User Agreement for more details.
Request Permission/Order Reprints
Reprints of this article can also be ordered at
http://www.dekker.com/servlet/product/DOI/101081CAR120037572