An approach for disaccharide chiron synthesis using a Ferrier-type rearrangement

Article abstract of DOI:10.1016/j.tetlet.2014.05.025

We report a new approach for the synthesis of new chiral synthons in which two unsaturated sugars are linked via a glycosidic bond. The di-unsaturated disaccharide can be further functionalized using effective, highly selective methods and used in convergent syntheses of relatively complex glycoconjugates. Our approach utilizes in situ generation of active glycosyl donors via Ferrier-type rearrangement under phase-transfer conditions and subsequent reaction with a nucleophile.

Full text of DOI:10.1016/j.tetlet.2014.05.025

Tetrahedron Letters 55 (2014) 3709–3712
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An approach for disaccharide chiron synthesis using a Ferrier-type
rearrangement
⇑
´
Katarzyna Komor , Wiesław Szeja, Tadeusz Bieg, Nikodem Kuznik, Gabriela Pastuch-Gawołek,
Roman Komor
Faculty of Chemistry, Chair of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Silesian University of Technology, Krzywoustego 4, 44-100 Gliwice, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a new approach for the synthesis of new chiral synthons in which two unsaturated sugars are
linked via a glycosidic bond. The di-unsaturated disaccharide can be further functionalized using effec-
tive, highly selective methods and used in convergent syntheses of relatively complex glycoconjugates.
Our approach utilizes in situ generation of active glycosyl donors via Ferrier-type rearrangement under
phase-transfer conditions and subsequent reaction with a nucleophile.
Received 20 January 2014
Revised 23 April 2014
Accepted 7 May 2014
Available online 20 May 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Chiral synthons
Glycosylation
Glycals
Ferrier-type rearrangement
Phase-transfer conditions
The synthesis of stereochemically complex naturally occurring
bioactive compounds using highly functionalized monosaccharide
derivatives as chiral synthons, has become an important synthetic
strategy.1 The chiral building blocks are available in various forms
and can be obtained from sugar derivatives by suitable chemical
transformations. The most versatile monosaccharide chiral starting
materials are derivatives of 1,2- and 2,3-unsaturated monosaccha-
rides. Due to their utility in a variety of processes, glycals have
received considerable attention in the carbohydrate field. Exam-
ples include glycosylation,2 Danishefsky epoxidation/glycosylation
methodology,3 Ferrier-type rearrangement,4 C-glycosylation,5 and
metal-catalyzed transformation.6 Carbohydrates appended to nat-
ural products are increasingly recognized as being crucial to their
activity. Therefore, the utilization of glycals as building blocks for
the total synthesis of various natural products is of significant
interest in bioorganic and medicinal chemistry. Glycals are versa-
tile synthetic intermediates for the preparation of 2-deoxyglyco-
sides and 2,3-unsaturated glycosides.7 2-Deoxyglycosides are
found in a variety of carbohydrate-containing natural products,
including many compounds exhibiting anticancer, antibiotic, and
cardiotonic effects. For instance, digitoxin and other cardiac glyco-
mithamycin) include both D-arabino and D
-lyxo diastereomers.8
Hence, new conceptual approaches to glycosylation are still wel-
come in order to investigate the intrinsic diversity of
carbohydrates.
In connection with our own studies in these areas9 we became
interested in developing a method that would lead to simple as
well as relatively complex glycoside derivatives of biologically
active compounds. We reasoned that the formation of diastereo-
merically pure chirons in which unsaturated sugars are joined
via glycosidic linkages would lead to building blocks that can be
used in the convergent synthesis of relatively complex glycoconju-
gates. This concept is shown in Scheme 1 where the transformation
of a 1,2-unsaturated sugar leads to a glycoside, and functionaliza-
tion of a 2,3-unsaturated sugar opens the possibility to synthesize
different unusual sugars and complex glyconjugates.
sides contain D-ribo-2,6-dideoxyhexoses, and the family of aureolic
acid anticancer natural products (olivomycin, chromomycin,
⇑
Corresponding author. Tel.: +48 32 327 1654.
E-mail address: katarzyna.komor@polsl.pl (K. Komor).
Scheme 1. General concept for the synthesis and utilization of disaccharide
chirons.
http://dx.doi.org/10.1016/j.tetlet.2014.05.025
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

3710
K. Komor et al. / Tetrahedron Letters 55 (2014) 3709–3712
The synthesis of new disaccharide building blocks containing
1,2- and 2,3-unsaturated hexoses was optimized for 4-O-benzyl-
-rhamnal (1) as a substrate. This concept was put into practice
with readily available models, namely 4-O-benzyl- -fucal (2), 4,6-
O-benzylidene- -glucal (3), 4,6-O-di(tert-butyl)silanediyl- -glucal
(4), and 4,6-O-di(tert-butyl)silanediyl- -galactal (5) (Scheme 1,
L
L
D
D
D
Table 1).10 These glycals have an unprotected hydroxyl group at
position C-3, which is obligatory for further steps. Our approach
involves a domino reaction which has the following successive
steps: (a) generation of an active nucleophile (alkoxide ion) by
deprotonation of the 3-OH group; (b) transformation into a good
leaving group by sulfonation; (c) formation of an allyloxycarbeni-
um ion intermediate stabilized by the Ferrier-type rearrangement;
(d) nucleophilic substitution.
The first step was the alkoxide ion formation (at the C-3 posi-
tion) in the presence of a strong base to improve the reactivity of
the substrate. Various bases were examined, including saturated
NaOH aqueous solution or NaH in dry DMF. In the reaction with
NaH as the base the resulting mixture was very complex. Also,
several sulfonating agents were tested (for step b) such as
methylsulfonyl chloride, para-nitrobenzene-sulfonyl chloride, and
para-toluenesulfonyl chloride. The best results were obtained in
phase-transfer (PT)11 conditions when a saturated aqueous NaOH
solution was used with para-toluenesulfonyl chloride. Using these
conditions the reaction proceeded practically in the anhydrous
organic phase. All the newly prepared disaccharides were obtained
in good yields (Table 1) via the optimized procedure12 and were
characterized by complex NMR experiments and mass spectrome-
Figure 1. X-ray structure of D1a with 50% probability ellipsoids.
by NOESY experiments and X-ray crystallographic analysis
(Fig. 1).14
Although the mechanism of the glycosylation remains to be
defined precisely, it seems reasonable to assume (Scheme 2) that
3-O-tosyl glycal is formed under PT conditions, followed by hetero-
lytic cleavage to give a resonance-stabilized carboxonium ion. For
stereoelectronic reasons15 attack at the anomeric center is anti-
periplanar to an oxygen orbital so that an
formed preferentially. This is in accordance with the Ferrier reac-
tion of glycals proceeding in most cases with high
-selectivity.16
a-L-glycosidic bond is
try.13 The diastereomerically pure isomers of disaccharides D1
D1b, and D2 were separated by crystallization. The structure
a,
a
a
This method is restricted by the reactivity of the allylic 3-OH
group (transformation into a good leaving group by sulfonation)
and configuration of compound D1
a was additionally confirmed
Table 1
Disaccharide synthesis in reactions of glycals in toluene, NaOH aq (saturated), Bu4NI, with TsCl
Entry
Substrate
Time
Product
Yield
65%
α:β
1
1 day
D1
D2
D3
4:1a
1
2
3
2
3
1 day
49%
49%
9:1a,b
2:1b
3 days
4
5
3 days
D4
50%
2.5:1b
4
5
14 days
-
-
-
a
Isomers separated after column chromatography and crystallization.
Isomer ratio based on 1H NMR spectroscopy.
b

K. Komor et al. / Tetrahedron Letters 55 (2014) 3709–3712
3711
Scheme 2. Proposed scheme for the formation of doubly unsaturated disaccharides under phase-transfer conditions.
3. Seeberger, P. H.; Danishefsky, S. J. Acc. Chem. Res. 1998, 31, 685–695.
which is related to the steric effect of the substituents on the sugar
4. Ferrier, R. J. Top. Curr. Chem. 2001, 215, 153–175.
ring. This step determines the rate of the entire process, because
the substitution of the intermediate allylic cation formed in the
next step is very fast, thus formation of the tosylate intermediate
was not observed. Rapid glycosylation under the Ferrier-type reac-
tion conditions is observed.17 In the case of 6-deoxy glycals 1 and 2
in which C4 substituent is relatively small, the reaction time is one
day. In the case of glucal derivatives 3 and 4 in which C4 and C6 are
protected with large cyclic benzylidene and di-tert-butylsilylene
groups, the reaction time is longer (3 days). For the galactal deriv-
ative 5 we observed no reaction. Probably this is due to large steric
hindrance resulting from the cis configuration between the 3-OH
group and the 4,6-O-benzylidene substituent.
In summary, we have developed a mild and efficient method for
the synthesis of selectively protected doubly unsaturated disaccha-
rides under PT conditions. This method is of low cost, simple, and
gives satisfactory yields on both milligram and gram scale. Further
studies on the synthesis of complex glycoconjugates by functional-
ization of these disaccharides are in progress.
5. Levy, D. E.; Tang, C. The Chemistry of C-Glycosides; Pergamon Press: Oxford,
1995.
6. (a) Spencer, R. R.; Schwartz, J. Tetrahedron 2000, 56, 2103–2112; (b) Daves, G.
D., Jr. Acc. Chem. Res. 1990, 23, 201–206; (c) Steinhuebel, D. P.; Fleming, J. J.;
DuBois, J. Org. Lett. 2002, 4, 293–295.
7. Priebe, W.; Fokt, I.; Grynkiewicz, G. Glycal Derivatives In Glycoscience: Chemistry
and Chemical Biology, 2nd ed.; Fraser-Reid, B.; Tatsuta, K.; Thiem, J. Eds.;
Springer-Verlag: Berlin, 2008; pp 699–735.
8. (a) Borovika, A.; Nagorny, P. J. Carbohydr. Chem. 2012, 31, 255–283; (b) Wohlert,
S. E.; Kunzel, E.; Machinek, R.; Mendez, C.; Salas, J.; Rohr, J. J. Nat. Prod. 1990, 62,
119; (c) Korynevska, A.; Heffter, P.; Matseyukh, B.; Elbling, L.; Micksche, M.;
Stoika, R.; Berger, W. Biochem. Pharm. 2007, 73, 1713–1726; (d) McDonald, F.
E.; Reedy, K. S.; Diaz, Y. J. Am. Chem. Soc. 2000, 122, 4304–4309; (e) Hou, D.;
Lowary, T. L. Carbohydr. Res. 2009, 344, 1911–1940; (f) Boutureira, O.;
Rodriguez, M. A.; Benito, D.; Matheu, M. I.; Diaz, Y.; Castillon, S. Eur. J. Org.
Chem. 2007, 3564–3572.
9. (a) Krol, E.; Wandzik, I.; Szeja, W.; Grynkiewicz, G.; Szewczyk, B. Antiviral Res.
2010, 86, 154–162; (b) Pastuch, G.; Komor, R.; Grec, M.; Szeja, W. Acta Pol.
Pharm. Drug Res. 2010, 67, 642–651; (c) Pastuch, G.; Wandzik, I.; Szeja, W. Pol. J.
Chem. 2007, 81, 161–170; (d) Wandzik, I.; Bieg, T. Carbohydr. Res. 2006, 341,
2702–2707.
10. (a) Priebe, W.; Fokt, I.; Przewloka, T.; Krawczyk, M.; Skibicki, P.; Grynkiewicz,
G.; Perez-Soler, R.; PCT Int. Appl. 2000, WO 2000056267 A2 (Chem. Abstr. 2000,
133, 238250w); (b) Sharma, M.; Brown, R. K. Can. J. Chem. 1966, 44, 2825–
2835; (c) Gabrielli, G.; Melani, F.; Bernasconi, S.; Lunghi, C.; Richichi, B.; Rollin,
P.; Venturi, C.; Nativi, C. J. Carbohydr. Chem. 2009, 28, 124–141.
Acknowledgments
11. (a) Fiedoryn´ ski, M.; Jezierska-Zie˛ba, M.; Ka˛kol, B. Acta Pol. Pharm. Drug Res.
2008, 65, 647–654; (b) Seela, F.; Westerman, B.; Bingig, U. J. Chem. Soc. Perkin.
Trans. 1 1988, 697–702.
Research studies were part-financed by the European Regional
Development Fund (POIG. 01.01.02-14-102/09). Katarzyna Komor
and Roman Komor received scholarships under the project
‘DoktoRIS-Scholarship Program for Innovative Silesia’.
12. Typical experimental procedure. To a solution of the sugar 1 (1 g, 4.5 mmol) in
toluene (40 mL) satd. aq NaOH (4 mL) was added. The mixture was stirred for
20 min then a catalytic amount of Bu4N+Iꢀ (84 mg, 0.23 mmol) and pTsCl
(438 mg, 2.3 mmol) was added. The reaction was stirred at room temperature
until TLC (hexane–ethyl acetate, 3:1, v:v) showed complete consumption of the
starting material. The solution was then diluted with toluene (50 mL) and
quenched with H2O (100 mL). The aqueous layer was extracted with toluene
(60 mL). The combined organic phases were washed with brine (2 ꢁ 100 mL),
dried over anhydrous MgSO4, and concentrated to give a crude residue, that
was purified by column chromatography on silica gel with hexane–EtOAc
Supplementary data
Supplementary data (spectroscopic data for all compounds)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2014.05.025. These data include
MOL files and InChiKeys of the most important compounds
described in this article.
(20:1) elution system to give 623 mg of D1 as a colorless syrup (
65%. Diasteroisomers D1 and D1b were separated after crystallization in
diethyl ether-hexane system.
13. Spectroscopic data for representative compounds:
3-O-[4-O-benzyl-2,3,6-trideoxy- -erythro-hex-2-enopyranosyl]-1,5-anhydro-4-
O-benzyl-2,6-dideoxy- -arabino-hex-1-enitol (D1a): 53%, white solid, mp 90-
a:b 4:1), yield
a
a-L
References and notes
L
21
92 °C, [a]
ꢀ18.0 (c 1.0, CHCl3); 1H NMR (600 MHz, CDCl3) d 7.23–7.36 (m,
D
10H, Harom), 6.29 (dd, J = 6.1, 1.5 Hz, 1H, H-1), 6.05 (ddd, J = 10.3, 1.5, 1.2 Hz,
1H, H-30), 5.66 (ddd, J = 10.3, 2.7, 1.9 Hz, 1H, H-20), 5.15 (dddd, J = 2.7, 1.3, 1.2,
0.6 Hz, 1H, H-10), 4.79 (dd, J = 6.1, 2.4 Hz, 1H, H-2), 4.80, 4,71 (qAB, J = 11.4 Hz,
2H, 4-O-Bn), 4.66, 4.54 (qAB, J = 11.7 Hz, 2H, 40-O-Bn), 4.36 (ddd, J = 7.0, 2.4,
1.5 Hz, 1H, H-3), 3.98 (dq, J = 9.0, 6.3 Hz, 1H, H-50), 3.93 (dq, J = 9.5, 6.4 Hz, 1H,
H-5), 3.71 (dddd, J = 9.0, 1.9, 1.5, 1.3 Hz, 1H, H-40), 3.44 (dd, J = 9.5, 7.0 Hz, 1H,
H-4), 1.36 (d, J = 6.4 Hz, 3H, 6-CH3), 1.30 (d, J = 6.3 Hz, 3H, 60-CH3); 13C NMR
(151 MHz, CDCl3) d 144.2 (C-1), 138.3 (4-O-Bn, C-100), 138.1 (40-O-Bn, C-1000),
130.8 (C-30), 128.4, 128.4, 127.8, 127.7 (10C, Carom), 126.8 (C-20), 102.8 (C-2),
95.8 (C-10), 80.6 (C-4), 77.5 (C-3), 76.3 (C-40), 74.6 (40-O-Bn, PhCH2ꢀ), 74.2 (C-
5), 70.8 (4-O-Bn, PhCH2ꢀ), 65.7 (C-50), 18.2 (C-60), 17.6 (C6); HRMS (ESI) calcd
for C26H30O5Na ([M+Na]+): m/z 445.1991, found: m/z 445.1985.
1. (a) Lichtenthaler, F. W. Pure Appl. Chem. 1978, 50, 1343–1362; (b) Fraser-Reid,
B.; Anderson, R. C. Carbohydrate derivatives in the asymmetric synthesis of
natural products. In Fortschr. Chem. Org. Naturst.; Springer: Wien, 1980; p 1; (c)
Vasella, A. Chiral Building Blocks from Sugars In Modern Synthetic Methods,
Scheffold, R., Ed.; Salle & Sauerländer: Frankfurt, 1980; p 173; (d) Hanessian, S.
Total Synthesis of Natural Products: The Chiron Approach; Pergamon: New York,
1983; (e) Inch, T. D. Tetrahedron 1984, 40, 3161–3213; (f) Casiraghi, G.; Zanardi,
F.; Rassu, G.; Spanu, P. Chem. Rev. 1995, 95, 1677–1716; (g) Hudlicky, T. Chem.
Rev. 1996, 96, 3–30; (h) Wu, Y.-L.; Wu, W.-L.; Li, Y.-L.; Sun, X.-L.; Peng, Z.-H.
Pure Appl. Chem. 1996, 68, 27–734.
2. (a)Handbook of Chemical Glycosylation; Demchenko, A. V., Ed.; Wiley-VCH:
Weinheim, 2008; (b) Zhu, X.; Schmidt, R. R. Angew. Chem., Int. Ed. 2009, 48,
1900–1934; (c) Toshima, K. Carbohydr. Res. 2006, 341, 1225–1240; (d) Davis, B.
G. J. Chem. Soc. Perkin Trans. 1 2000, 2137–2160; (e) Pellissier, H. Tetrahedron
2005, 61, 2947–2993.
3-O-[4-O-benzyl-2,3,6-trideoxy-b-L-erythro-hex-2-enopyranosyl]-1,5-anhydro-4-
O-benzyl-2,6-dideoxy-L-arabino-hex-1-enitol (D1b): 12%, light yellow syrup,
21
[a]
D
ꢀ65.4 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.43–7.20 (m, 10H,

3712
K. Komor et al. / Tetrahedron Letters 55 (2014) 3709–3712
14. Crystallographic data for D1
Harom), 6.35 (d, J = 6.1 Hz, 1H, H-1), 6.05 (dt, J = 10.4, 1.7 Hz, 1H, H-30), 5.74 (dd,
a
are available in the Supplementary data and
J = 10.3, 1.3 Hz, 1H, H-20), 5.33 (br.d, J = 1.5 Hz, 1H, H-10), 4.86 (dd, J = 6.2,
2.9 Hz, 1H, H-2), 4.92, 4.65 (qAB, J = 11.4 Hz, 2H, CH2Ph), 4.65, 4.55 (qAB,
J = 11.6 Hz, 2H, CH2Ph), 4.50 (dd, J = 5.7, 2.8 Hz, 1H, H-3), 4.00 (dq, J = 13.5,
6.6 Hz, 1H, H-5), 3.78 – 3.64 (m, 2H, H-40, H-50), 3.48 (dd, J = 8.0, 5.8 Hz, 1H, H-
4), 1.35 (d, J = 6.5 Hz, 3H, (CH3) H-6), 1.32 (d, J = 5.9 Hz, 3H, (CH3) H-60); 13C
NMR (101 MHz, CDCl3) d 144.7 (C-1), 138.4 (4-O-Bn, C-100), 138.0 (4-O-Bn, C-
1000), 130.2 (C-30), 129.4 (C-20), 128.4, 128.3, 128.1, 127.9, 127.8, 127.6, (10C,
Carom), 100.1 (C2), 95.2 (C-10), 79.1 (C-4), 75.8 (C-40), 73.8 (C-5), 73.6 (PhCH2ꢀ),
72.6 (C-50), 72.4 (C-3), 71.4 (PhCH2ꢀ), 18.7 (C-60), 17.3 (C-6); HRMS (ESI) calcd
for C26H30O5Na ([M+Na]+): m/z 445.1991, found: m/z 445.1990. Spectral data of
all the disaccharides are available in the Supplementary data.
were deposited with the Cambridge Crystallographic Data Centre as
supplementary publications number: CCDC 971885.
15. Deslongchamps P., In Stereoelectronic Effects in Organic Chemistry, Baldwin J. E.
Ed.; Organic Chemistry Series, Pergamon Press; Oxford, England, 1983; Vol. I.
16. (a) Gorityala, B. K.; Cai, S.; Lorpitthaya, R.; Ma, J.; Pasunooti, K. K.; Liu, X.-W.
Tetrahedron Lett. 2009, 50, 676–679; (b) Nagaraj, P.; Ramesh, N. G. Tetrahedron
Lett. 2009, 50, 3970–3973; (c) Mukherjee, D.; Yousuf, S. K.; Taneja, S. C.
Tetrahedron Lett. 2008, 49, 4944–4948.
17. Banik, B. K.; Manhas, M. S.; Base, A. K. J. Org. Chem. 1994, 59, 4714–4716.