Formation of c -glycosides by ferrier reaction

Article abstract of DOI:10.1080/07328303.2013.860160

Peracetylated glycals were treated with terminal alkyne derivatives under Lewis acid catalysis to result in the formation of the pure - or β- anomerically substituted hex-2-enopyranosides carrying 2(E)-halogenated olefins.

Full text of DOI:10.1080/07328303.2013.860160

This article was downloaded by: [York University Libraries]
On: 20 June 2014, At: 06:33
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
Formation of C-Glycosides by Ferrier
Reaction
Eusebius Wieczorek a & Joachim Thiem a
a University of Hamburg, Faculty of Science, Department of
Chemistry, Martin-Luther-King-Platz 6 , D-20146 , Hamburg ,
Germany
Published online: 03 Dec 2013.
To cite this article: Eusebius Wieczorek & Joachim Thiem (2013) Formation of C-Glycosides by Ferrier
Reaction, Journal of Carbohydrate Chemistry, 32:8-9, 502-512, DOI: 10.1080/07328303.2013.860160
To link to this article: http://dx.doi.org/10.1080/07328303.2013.860160
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, 32:502–512, 2013
ꢀ
C
Copyright Taylor & Francis Group, LLC
ISSN: 0732-8303 print / 1532-2327 online
DOI: 10.1080/07328303.2013.860160
Formation of C-Glycosides
by Ferrier Reaction
Eusebius Wieczorek and Joachim Thiem
University of Hamburg, Faculty of Science, Department of Chemistry,
Martin-Luther-King-Platz 6, D-20146, Hamburg, Germany
Peracetylated glycals were treated with terminal alkyne derivatives under Lewis acid
catalysis to result in the formation of the pure α- or β- anomerically substituted hex-2-
enopyranosides carrying 2(E)-halogenated olefins.
Keywords Glycals; C-Glycosylation; Alkyne nucleophiles; Allylic rearrangement
INTRODUCTION
Formation of carbohydrate surrogates and mimetics is attractive due to struc-
tural as well as conformational similarities to natural components occurring
in many complex biopathways.[1,2] In particular, C-glycosylation proved to be
an attractive approach, and reports on such syntheses are abundant[3,4] and
were compiled several times.[5–12] Ferrier et al.[13] first reacted glycal struc-
tures with nucleophiles to arrive at 2,3-unsaturated compounds; it was the
seminal work of Robin J. Ferrier to elaborate this reaction about 50 years
ago.[14] A number of reviews by him[15–18] and others[19,20] gave evidence of
the advantageous use of this reaction to construct a large number of com-
plex carbohydrate-derived components. As a show of appreciation of the then-
[21–23]
called Ferrier reaction
and to the author, who recently passed away,
this short contribution reports on some findings in the use of C-nucleophiles
for formation of C-glycosides. This subject was recently reviewed[24] and com-
piled some 40 papers about Ferrier C-glycosylation reactions within the last
20 years.
Dedicated to the memory of Prof. Karsten Krohn
Received September 4, 2013; accepted October 24, 2013.
Address correspondence to Joachim Thiem, University of Hamburg, Faculty of
Science, Department of Chemistry, 20146, Hamburg, Germany. E-mail: thiem@chemie.
uni-hamburg.de
502

Formation of C-glycosides by Ferrier Reaction
503
Table 1: Assignment of alkene isomers
Compound
(Z) δ calculated
(E) δ calculated
δ observed
2
3
6
7
8
6.39
6.91
6.91
6.39
5.31
6.08
6.29
6.30
6.08
5.46
6.05
6.30
6.28
5.96
5.48
RESULTS AND DISCUSSION
Previously it could be shown that application of propargyl silanes to Fer-
rier conditions resulted in formation of alkynylated hex-2-enopyranosyl struc-
tures.[25–32] Thus, surprisingly, by reaction of tri-O-acetyl-D-glucal (1) with
phenyl acetylene in the presence of SnX4 at −45◦C, the formation of 2-
halide substituted (E) styryl hex 2-enopyranosides 2 and 3 was observed.
Their α-anomerity was evident from the 1H NMR data. The shift assign-
ments of alkene protons were calculated according to the rules of Pascual
et al.:
δ(H) = 5.28 + Sgem + Scis + Strans [ppm]
with Sgem, Scis, and Strans as empirical substituent increments.[33–35] The data
in Table 1 clearly show formation of (E) isomers exclusively.
Catalytic hydrogenation of the chloro derivative 3 on 10% Pd/C in the pres-
ence of triethylamine gave exclusively the α component 4, thus substantiating
the anomer assignment (Scheme 1).
Scheme 1: Ferrier C-Glycosylation of D-Glucal.
In a corresponding reaction, di-O-acetyl-D-xylal (5) was treated at −45◦C
∗
with phenyl acetylene in the presence of SnBr4, SnCl4, and BF3 Et2O. In
keeping with the above results the corresponding 2-halo-substituted and (E)-
configured styryl ß-hex-2-enopyranosides 6, 7, and 8 could be obtained in av-
erage to acceptable yields. Hydrogenation of the bromide 6 gave clearly the
4
pure de-halogenated ß-anomer 11 in C1(D) conformation, thus approving the
structural assignment.

E. Wieczorek and J. Thiem
504
By reaction of hept-1-yne 5, the corresponding ß-C-glycoside 9 could be ob-
tained in fair yield. In connection with studies toward liquid crystalline proper-
ties, the reaction of 5 was also performed with a typically 4-substituted phenyl
acetylene p-alkoxybenzoate to give under corresponding conditions in the pres-
ence of SnCl4 the ß-C-glycoside 10 in 67% yield.
It was interesting to react 5 also with the trimethylsilyl-substituted phenyl
acetylene compound under similar conditions with SnCl4 at −45◦C. In this
case 93% of the ß-C-alkynylated structure 13 resulted, as evident from the
characteristic triple-bond carbon signals at 89.63 and 88.15 in the 13C NMR
spectra. This outcome is in accord with the previously observed formation as
mentioned above[24–32] but deviates clearly from the presented finding. The
mesogenic compound 13 showed a smectic A phase at 89.5◦C and decom-
posed at 100◦C. As expected, both compounds 10 (in the presence of triethy-
lamine) and 13 could be hydrogenated with 10% Pd/C to give the saturated
ß-C-glycoside 12 in good yields. The liquid crystalline derivative 12 melted at
85.2◦C and transferred into a cholesteric phase at 121.5◦C (Scheme 2).
Scheme 2: Ferrier C-Glycosylation of D-Xylal.
CONCLUSION
In this contribution the Ferrier C-glycosylation could be shown to operate
with alkynyl components and the reported Lewis acids, giving anomerically
pure (E)-configured 2-halo hex-2-enopyranosides exclusively. Thus, this ap-
proach differs substantially from the previously reported reaction with alkynyl
silanes, which was also proven by formation of liquid crystalline components
following both approaches.

Formation of C-glycosides by Ferrier Reaction
505
EXPERIMENTAL
Solvents were dried according to standard methods. TLC was performed on
precoated aluminium plates (silica gel 60 F254, Merck 5554), charring with
10% H2SO4 in ethanol for visualization. For column chromatography silica gel
60, 230–400 mesh, 40–63 μm (Merck) was used. 1H NMR and 13C NMR spectra
1
were recorded on a Bruker AMX-400 (400 MHz for H, 100.67 MHz for 13C)
at 300 K. Chemical shifts were calibrated to solvent residual peaks.[19] The
signals were assigned by H, H-COSY, HSQC, and HMBC experiments. Optical
rotations were measured using a Perkin-Elmer Polarimeter 243 (589 nm) at
20◦C.
General Procedure for Ferrier C-Glycosylation (GP 1)
The peracetylated glycal (1 eq.) and the alkyne component (1.2 eq.) are
cooled to –45◦C in anhydrous dichloromethane. The respective stannic tetra-
halide catalyst (0.5 eq.) is added, and after complete transformation (about
10 min), the reaction is quenched by addition of saturated aqueous sodium hy-
drogen carbonate. The organic phase is dried (MgSO4) and concentrated and
the residue purified by column chromatography.
General Procedure for Catalytic Hydrogenation (GP 2)
The compound dissolved in methanol or methanol/ethyl acetate (1:1) is
treated with palladium on charcoal (10%) and hydrogenated under normal
pressure for 10 h. The catalyst is filtered over Celite, the solvent removed in
vacuum, and the residue purified by column chromatography.
(E)-1-(4, 6-Di-O-acetyl-2, 3-dideoxy-α-D-erythro-hex-2-
enopyranosyl)-2-bromo-2-phenyl-ethene(2)
Tri-O-acetyl-D-glucal (1, 100 mg, 0.37 mmol), phenyl acetylene (60 μL,
0.54 mmol), and a 1 M solution of SnBr4 in dichloromethane (50 μL) are treated
according to GP 1. Purification was by flash chromatography in petroleum
20
ether/ethyl acetate 6:1 to give 2 as slightly yellow syrup (65 mg, 45%). [α]D
=
34.5 (c = 0.3, CHCl3). 1H NMR (400 MHz,CDCl3) δ: 7.28–7.44 (m, 5H, phenyl),
6.30 (d, 1H, J1,1 = 9.2 Hz, H-1ꢁ-ethene), 5.77 (ddd, 1H, J1,3 = 2.0, J2,3 = 10.2,
ꢁ
J3,4 = 3.5 Hz, H-3), 5.72 (dd, 1H, J1,2 = 1.5, J2,3 = 10.2 Hz, H-2), 5.09 (dd,
ꢁ
1H, J3,4 = 3.5, J4,5 = 7.1 Hz, H-4), 4.57 (ddd, 1H, J1,1 = 9.2, J1,2 = 1.5, J1,3
= 2.0 Hz, H-1), 4.14 (dd, 1H, J5,6a = 6.1, J6a,6b = 12.2 Hz, H-6a), 4.07 (dd, 1H,
J5,6b = 3.1, J6a,6b = 12.2 Hz, H-6b), 3.93 (ddd, 1H, J4,5 = 7.1, J5,6a = 6.1, J5,6b
= 3.1 Hz, H-5), 2.04 and 2.02 (each s, each 3H, OAc). 13C NMR (100.67 MHz,
CDCl3) δ: 170.2, 169.9 (each C O), 132.2, 130.2, 129.5, 128.9, 128.4(2), 128.0,
127.9, 126.1, 124.3 (C-phenyl, C-2, C-3, C-1ꢁand C-2ꢁ-ethene), 69.8 (C-1), 69.6

E. Wieczorek and J. Thiem
506
(C-5), 64.1 (C-4), 62.5 (C-6), 20.6, 20.4 (COCH3). Calc for C18H19O5Br (395.3):
C 54.70, H 4.85, Br 20.25; found: C 55.25, H 4.80, Br 18.95.
(E)-1-(4, 6-Di-O-acetyl-2, 3-dideoxy-α-D-erythro-hex-2-enopyra-
nosyl)-2-chloro-2-phenyl-ethene(3)
Tri-O-acetyl-D-glucal (1, 200 mg, 0.73 mmol), phenyl acetylene (120 μL,
1.08 mmol), and a 1 M solution of SnCl4 in dichloromethane (100 μL) are
treated according to GP 1. Purification was by flash chromatography in
petroleum ether/ethyl acetate 6:1 to give 3 as yellow syrup (103 mg, 40%).
[α]D = 32.0 (c = 0.2, CHCl3). 1H NMR (400 MHz,CDCl3) δ: 7.29–7.43 (m, 5H,
20
phenyl), 6.05 (d, 1H, J1,1 = 10.2 Hz, H-1ꢁ-ethene), 5.74 (m, 2H, H-2, H-3), 5.10
ꢁ
ꢁ
(dd, 1H, J3,4 = 3.2, J4,5 = 7.1 Hz, H-4), 4.57 (dd, 1H, J1,1 = 10.2, J1,2 = 1.0 Hz,
H-1), 4.15 (dd, 1H, J5,6a = 5.6, J6a,6b = 12.2 Hz, H-6a), 4.08 (dd, 1H, J5,6b = 3.1,
J6a,6b = 12.2 Hz, H-6b), 3.94 (ddd, 1H, J4,5 = 7.1, J5,6a = 5.6, J5,6b = 3.1 Hz,
H-5), 2.04 and 2.01 (each s, each 3H, OAc). 13C NMR (100.67 MHz, CDCl3) δ:
170.3, 169.9 (each C O), 136.8, 135.7, 130.6, 129.0, 128.2, 128.0, 127.8, 126.1,
125.3, 124.3 (C-phenyl, C-2, C-3, C-1ꢁand C-2ꢁ-ethene), 69.6 (C-1), 69.1 (C-5),
64.1 (C-4), 62.5 (C-6), 20.6, 20.4 (COCH3). Calc for C18H19O5Cl (350.8): C 61.63,
H 5.46, Cl 10.11; found: C 59.90, H 6.07, Cl 9.12.
1-(4, 6-Di-O-acetyl-2, 3-dideoxy-α-D-erythro-hexopyranosyl)-
2-phenyl-ethane(4)
Compound 3 (60 mg, 0.17 mmol) is hydrogenated according to GP 2 in
the presence of triethyl amine (0.1 mL) and the resulting material is puri-
fied by flash chromatography with petroleum ether/ethyl acetate 3:1 to give
20
1
23 mg (42%) of 4 as yellow syrup. [α]D = 4.0 (c = 0.75, CHCl3). H NMR
(400 MHz,CDCl3) δ: 7.13–7.32 (m, 5H, phenyl), 4.74 (m, 1H, H-4), 4.23 (dd, 1H,
J5,6a = 5.6, J6a,6b = 12.2 Hz, H-6a), 4.16 (dd, 1H, J5,6b = 2.5, J6a,6b = 12.2 Hz,
H-6b), 3.51 (m, 1H, H-1), 2.58–2.81 (m, 2H, H-2aꢁ-, H-2bꢁ-ethane), 1.52–2.02
(m, 6H, H-2ax, H-2eq, H-3ax, H-3eq, H-1aꢁ-, H1bꢁ-ethane) 2.08 and 2.10 (each
s, each 3H, OAc).
(E)-1-(4-O-Acetyl-2, 3-dideoxy-β-D-glycero-pent-2-enopyranosyl)
-2-bromo-2-phenyl-ethene(6)
Di-O-acetyl-D-xylal (5, 200 mg, 1.0 mmol), phenyl acetylene
(135 μL, 1.22 mmol), and a 1 M solution of SnBr4 in dichloromethane
(200 μL) are treated according to GP 1. Purification was by flash
chromatography in petroleum ether/ethyl acetate 3:1 to give 6 as yel-
low syrup (171 mg, 53%). 1H NMR (400 MHz,CDCl3) δ: 7.28–7.45
ꢁ
(m, 5H, phenyl), 6.28 (d, 1H, J1,1
=
9.7 Hz, H-1ꢁ-ethene), 5.92

Formation of C-glycosides by Ferrier Reaction
507
(ddd, 1H, J1,3 = 2.0, J2,3 = 10.7, J3,4 = 3.5 Hz, H-3), 5.88 (dd, 1H, J1,2
ꢁ
= 2.5, J2,3 = 10.7 Hz, H-2), 5.16 (m, 1H, H-4), 4.57 (ddd, 1H, J1,1 = 9.7, J1,2
= 1.5, J1,3 = 2.0 Hz, H-1), 4.11 (dd, 1H, J4,5e = 4.1, J5a,5e = 12.2 Hz, H-5e),
3.65 (dd, 1H, J4,5a 4.6, J5a,5e = 12.2 Hz, H-5a), 2.05 (s, 3H, OAc). 13C NMR
(100.67 MHz, CDCl3) δ: 170.2 (C = O), 132.2, 130.4(2), 129.2(2), 128.8, 128.2,
127.0, 124.3(2) (C-phenyl, C-2, C-3, C-1ꢁand C-2ꢁ-ethene), 70.9 (C-1), 64.4
(C-5), 64.1 (C-4), 21.0 (COCH3).
(E)-1-(4-O-Acetyl-2, 3-dideoxy-β-D-glycero-pent-2-enopyranosyl)
-2- chloro-2-phenyl-ethene(7)
Di-O-acetyl-D-xylal (5, 200 mg, 1.0 mmol), phenyl acetylene (135 μL,
1.22 mmol), and a 1 M solution of SnCl4 in dichloromethane (200 μL) are
treated according to GP 1. Purification was by flash chromatography in
petroleum ether/ethyl acetate 3:1 to give 7 as yellow syrup (140 mg, 50%).
20
1
[α]D = 147.0 (c = 0.6, CHCl3). H NMR (400 MHz,CDCl3) δ: 7.28–7.42 (m,
5H, phenyl), 5.96 (d, 1H, J1,1 = 10.2 Hz, H-1ꢁ-ethene), 5.86 (ddd, 1H, J1,3
=
ꢁ
2.0, J2,3 = 10.2, J3,4 = 3.6 Hz, H-3), 5.79 (ddd, 1H, J1,2 = 2.5, J2,3 = 10.7, J2,4
ꢁ
= 1.0 Hz, H-2), 5.00 (m, 1H, H-4), 4.56 (ddd, 1H, J1,1 = 10.2, J1,2 = 2.5, J1,3
= 2.0 Hz, H-1), 4.05 (dd, 1H, J4,5e = 4.1, J5a,5e = 12.2 Hz, H-5e), 3.59 (dd, 1H,
J4,5a = 4.6, J5a,5e = 12.2 Hz, H-5a), 1.98 (s, 3H, OAc). 13C NMR (100.67 MHz,
CDCl3) δ: 170.1 (C O), 136.8, 135.8, 132.1, 128.9, 128.7, 128.3, 127.9, 126.1,
125.8, 123.7 (C-phenyl, C-2, C-3, C-1ꢁand C-2ꢁ-ethene), 69.9 (C-1), 64.1 (C-
5), 63.8 (C-4), 20.6 (COCH3). Calc for C15H15O3Cl (278.7): C 64.64, H 5.42,
Cl 12.72; found: C 63.72, H 5.40, Cl 11.60.
(E)-1-(4-O-Acetyl-2, 3-dideoxy-β-D-glycero-pent-2-enopyranosyl)
-2-fluoro-2-phenyl-ethene(8)
Di-O-acetyl-D-xylal (5, 55 m∗g, 0.27 mmol) and phenyl acetylene (35 μL,
0.32 mmol) are treated with BF3 Et2O (10 μL) in anhydrous dichloromethane
according to GP 1. Purification was by flash chromatography in petroleum
20
ether/ethyl acetate 8:1 to give 8 as yellow syrup (20 mg, 28%). [α]D = 123.6
1
(c = 0.1, CHCl3). H NMR (400 MHz, CDCl3) δ: 7.22–7.42 (m, 5H, phenyl),
5.89 (dd, 1H, J1,2 = 2.0, J2,3 = 10.2 Hz, H-2), 5.85 (ddd, 1H, J1,3 = 1.5, J2,3
= 10.2, J3,4 = 3.1 Hz, H-3), 5.48 (d, 1H, J1,1 = 9.7 Hz, H-1ꢁ-ethene), 5.11
ꢁ
ꢁ
(m, 1H, H-4), 4.69 (ddd, 1H, J1,1 = 9.7, J1,2 = 2.0, J1,3 = 1.5 Hz, H-1), 4.06
(dd, 1H, J4,5e = 4.1, J5a,5e = 11.7 Hz, H-5e), 3.60 (dd, 1H, J4,5a = 4.6, J5a,5e
= 11.7 Hz, H-5a), 1.99 (s, 3H, OAc). 13C NMR (100.67 MHz, CDCl3) δ: 170.6
(C O), 133.5, 133.2, 130.81, 129.3, 128.6, 128.3, 128.0, 126.2, 124.9, 123.9 (C-
phenyl, C-2, C-3, C-1ꢁand C-2ꢁ-ethene), 69.3 (C-1), 64.5 (C-5), 63.3 (C-4), 21.0
(COCH3).

E. Wieczorek and J. Thiem
508
(E)-1-(4-O-Acetyl-2, 3-dideoxy-β-D-glycero-pent-2-enopy-
ranosyl)-2- chloro-hept-1-ene (9)
Di-O-acetyl-D-xylal (5, 200 mg, 1.0 mmol), 1-heptyne (160 μL, 1.22 mmol),
and a 1 M solution of SnCl4 in dichloromethane (100 μL) are treated according
to GP 1. Purification was by flash chromatography in petroleum ether/ethyl
20
acetate 3:1 to give 9 as yellow syrup (103 mg, 38%). [α]D = 176.0 (c = 0.5,
CHCl3). 1H NMR (400 MHz,CDCl3) δ: 5.87 (ddd, 1H, J1,3 = 1.5, J2,3 = 10.2, J3,4
ꢁ
= 4.1 Hz, H-3), 5.79 (dd, 1H, J1,2 = 2.0, J2,3 = 10.2 Hz, H-2), 5.61 (d, 1H, J1,1
=
9.2 Hz, H-1ꢁ-heptene), 5.09 (m, 1H, H-4), 4.74 (ddd, 1H, J1,1 = 9.2, J1,2 = 2.0,
J1,3 = 1.5 Hz, H-1), 4.00 (dd, 1H, J4,5e = 4.1, J5a,5e = 12.2 Hz, H-5e), 3.59 (dd,
1H, J4,5a = 5.1, J5a,5e = 12.2 Hz, H-5a), 2.26 (m, 2H, H-3aꢁ,bꢁ-heptene) 2.10 (s,
3H, OAc), 1.51 (m, 2H, 4aꢁ,bꢁ-heptene), 1.24 (m, 4H, H-5aꢁ,bꢁ, H-6aꢁ,bꢁ-heptene).
13C NMR (100.67 MHz, CDCl3) δ: 170.2 (C O), 132.8, 132.8, 124.8, 124.0 (C-2,
C-3, C-1ꢁand C-2ꢁ-heptene), 69.6 (C-1), 64.5 (C-5), 64.3 (C-4), 34.2, 30.9, 27.1,
22.4 (C-3ꢁ, C-4ꢁ, C-5ꢁ, C-6ꢁ-heptene), 21.1 (COCH3). Calc for C14H21O3Cl (272.8):
C 61.65, H 7.76, Cl 13.00; found: C 62.09, H 7.84, Cl 13.03.
ꢁ
(E)-1ꢀ-(4-O-Acetyl-2, 3-dideoxy-β-D-glycero-pent-2-enopyranosyl
-2ꢀ- chloro-2ꢀ- (phenyl-4ꢀꢀꢀ-hexyloxy-dideuterobenzoyl)-
ethene (10)
Di-O-acetyl-D-xylal (5, 25 mg, 0.12 mmol) and 4-ethynyl-phenyl-4ꢁ-
hexyloxy-dideutero benzoate (45 mg, 0.14 mmol) dissolved in dichloromethane
(10 mL) are treated with a 1 M solution of SnCl4 in dichloromethane (30 μL)
according to GP 1. Purification was by flash chromatography in petroleum
20
ether/ethyl acetate 3:1 to give 10 as yellow syrup (40 mg, 67%). [α]D = −4.5
(c = 0.5, CHCl3). 1H NMR (400 MHz,CDCl3) δ: 8.05 (m, 2H, H-2ꢁꢁꢁ-, H-6ꢁꢁꢁ-aryl),
7.48 (m, 2H, H-2ꢁꢁ-, H-6ꢁꢁ-aryl), 7.15 (m, 2H, H-3ꢁꢁ-, H-5ꢁꢁ-aryl), 5.97 (d, 1H, J1,1
ꢁ
= 10.2 Hz, H-1ꢁ-ethene), 5.87 (ddd, 1H, J1,3 = 2.0, J2,3 = 10.2, J3,4 = 4.0 Hz,
H-3), 5.80 (ddd, 1H, J1,2 = 2.6, J2,3 = 10.2, J2,4 = 1.0 Hz, H-2), 5.12 (m, 1H,
ꢁ
H-4), 4.60 (ddd, 1H, J1,1 = 10.2, J1,2 = 2.6, J1,3 = 2.0 Hz, H-1), 4.06 (dd, 1H,
J4,5e = 4.1, J5a,5e = 11.7 Hz, H-5e), 3.98 (t, 2H, OCH2), 3.60 (dd, 1H, J4,5a
=
5.1, J5a,5e = 11.7 Hz, H-5a), 1.98 (s, 3H, OAc), 1.26–1.80 (m, 8H, 4 CH2), 0.85 (t,
3H, CH3). 13C NMR (100.67 MHz, CDCl3) δ: 170.1 (C O), 121.4–136.8 (C-aryl,
C-2, C-3, C-1ꢁand C-2ꢁ-ethene), 69.8 (C-1), 68.0 (OCH2), 64.5 (C-5), 64.2 (C-4),
31.1, 28.6, 25.2, 22.1 (4 CH2), 20.6 (COCH3), 13.6 (CH3). Calc for C28H30O6Cl
(499.0): C 67.40, H 6.26, Cl 7.10; found: C 67.99, H 6.23, Cl 6.03.
1-(4-O-Acetyl-2, 3-dideoxy-β-D-glycero-pentopyranosyl)-
2-phenyl-ethane (11)
Compound 6 (100 mg, 0.31 mmol) is hydrogenated according to GP
2 in the presence of triethyl amine (0.1 mL) and the resulting material

Formation of C-glycosides by Ferrier Reaction
509
is purified by flash chromatography with petroleum ether/ethyl acetate 10:1
20
1
to give 42 mg (55%) of 11 as yellow syrup. [α]D = 79.5 (c = 0.6, CHCl3). H
NMR (400 MHz,CDCl3) δ: 7.32–7.48 (m, 5H, phenyl), 4.95 (m, 1H, H-4), 4.22
(dd, 1H, J4,5e = 5.1, J5a,5e = 10.7 Hz, H-5e), 3.41 (m, 1H, H.1), 3.37 (dd,1H,
J4,5a = 10.2, J5a,5e = 10.7 Hz, H-5a), 2.94 (m, 1H, H-2aꢁ-ethane), 2.84 (m, 1H,
H-2bꢁ-ethane), 2.33 (m, 1H, H-2eq), 1.60–2.06 (m, 5H, H-2ax, H-3ax, H-3eq,
H-1aꢁ-, H1bꢁ-ethane) 2.21 (s, 3H, OAc). 13C NMR (100.67 MHz, CDCl3) δ: 170.1
(C O), 141.9, 128.3(2), 128.2(2), 125.7 (C-phenyl), 76.3 (C-1), 69.1, 63.0 (C-
5), 68.3 (C-4), 37.1 (C-1ꢁ-ethane), 31.7 (C-2ꢁ-ethane), 30.1, 29.0 (C-2, C-3), 21.
(COCH3. Calc for C15H20O3 (248.3): C 72.55, H 8.12; found: C 71.98, H 7.94.
1ꢀ-(4-O-Acetyl-2, 3-dideoxy-β-D-glycero-pentopyranosyl)-2ꢀ-
(phenyl-4ꢀꢀꢀ-hexyloxy-dideuterobenzoyl)-ethane (12)
(A) Compound 10 (100 mg, 0.2 mmol) is hydrogenated according to GP 2 in the
presence of triethyl amine (0.1 mL) and the resulting material is purified by
flash chromatography with petroleum ether/ethyl acetate 6:1 to give 52 mg
(55%) of 12.
(B) Compound 13 (250 mg, 0.54 mmol) is hydrogenated according to GP 2 and
purified by flash chromatography as above to give 159 mg (63%) of 12 as a
20
1
colorless solid. [α]D = −12.0 (c = 0.2, CHCl3). K 85.2 – Ch 121.5 – I. H
NMR (400 MHz,CDCl3) δ: 8.09 (m, 2H, H-2ꢁꢁꢁ-, H-6ꢁꢁꢁ-aryl), 7.20 (m, 2H, H-
2ꢁꢁ-, H-6ꢁꢁ-aryl), 7.08 (m,2H, H-3ꢁꢁ-, H-5ꢁꢁ-aryl), 4.77 (m, 1H, H-4), 4.01–4.07
(m, 3H, H-5e, H-1aꢁ-, H-1bꢁ-hexane), 3.23 (m, 1H, H-1), 3.20 (dd, 1H, J4,5a
= 10.2, J5a,5e = 10.7 Hz, H-5a), 2.78 (m, 1H, H-2aꢁ-ethane), 2.68 (m, 1H,
H-2aꢁ-ethane), 2.15 (m,1H H-2eq), 2.02 (s, 3H, OAc), 1.30–1.89 (m, 13H, H-
2ax, H-3ax, H-3eq, H-1aꢁ-H-1bꢁ-ethane, H-2abꢁꢁ-, H-3abꢁꢁ-, H-4abꢁꢁ-, H-5abꢁꢁ-
hexane), 0.92 (t, 3H, CH3). 13C NMR (100.67 MHz, CDCl3) δ: 170.2 (C O),
121.1–131.7 (C-aryl), 75.8 (C-1), 68.8 (C-4), 67.9, 68.0 (C-5, OCH2-hexane),
36.7, 31.1 (C-1ꢁ-, C-2ꢁ-ethane) 30.8, 29.8, 28.7, 28.6, 25.2, 22.1 (C-2, C-3, 5
CH2-hexane), 20.7 (COCH3), 13.6 (CH3).
1ꢀ-(4-O-Acetyl-2, 3-dideoxy-β-D-glycero-pent-2-enopyranosyl-
2ꢀ- (phenyl-4ꢀꢀꢀ-hexyloxy-dideuterobenzoyl)-ethyne (13)
Di-O-acetyl-xylal (5, 120 mg, 0.6 mmol) and 4-trimethylsylyl-ethynyl-
phenyl -4ꢁ-hexyloxy-dideutero benzoate (250 mg, 0.63 mmol) dissolved in
dichloromethane (10 mL) are treated with a 1 M solution of stannic tetra-
chloride in dichloromethane (30 μL) according to GP 1. Purification was by
flash chromatography in petroleum ether/ethyl acetate 3:1 to give 13 as col-
20
orless crystals (260 mg, 93%). [α]D = −2.7 (c = 0.5, CHCl3); K 104.2 - SA
1
89.1 - I. H NMR (400 MHz,CDCl3) δ: 8.05 (m, 2H, H-2ꢁꢁꢁ-, H-6ꢁꢁꢁ-aryl), 7.44
(m, 2H, H-2ꢁꢁ-, H-6ꢁꢁ-aryl), 7.12 (m, 2H, H-3ꢁꢁ-, H-5ꢁꢁ-aryl), 6.07 (dd, 1H, J1,2
=

E. Wieczorek and J. Thiem
510
3.6, J2,3 = 10.2 Hz, H-2), 5.94 (ddd, 1H, J1,3 = 2.0, J2,3 = 10.2, J3,4 = 5.6 Hz,
H-3), 4.60 (dd, 1H, J1,2 = 3.6, J1,3 = 2.0 Hz, H-1), 5.01 (m, 1H, H-4), 4.20
(dd, 1H, J4,5a = 3.1, J5a,5e = 12.2 Hz, H-5a), 3.98 (t, 2H, OCH2), 3.87 (dd, 1H,
J4,5e = 1.0, J5a,5e = 12.2 Hz, H-5e), 2.02 (s, 3H, OAc), 1.76 (mc, 2H,OCH2CH2),
1.25–1.53 (m, 6H, 3 CH2), 0.85 (t, 3H, CH3). 13C NMR (100.67 MHz, CDCl3)
δ: 170.1 (C = O), 121.5–132.6 (C-aryl, C-2, C-3), 89.6, 88.2 (C-1ꢁ- C-2ꢁ-ethyne),
67.9 (OCH2), 63.9 (C-5), 63.5, 63.0 (C-1, C-4), 31.1, 28.6, 25.2, 22.1 (4 CH2),
20.7 (COCH3), 13.6 (CH3). Calc for C28H30O6 (462.5): C 72.71, H 6.54; found:
C 72.87, H 6.50.
REFERENCES
1. Sears, P.; Wong, C.-H. Carbohydrate mimetics: a new strategy for tackling the
problem of carbohydrate-mediated biological recognition. Angew. Chem. Int. Ed. 1999,
38, 2301–2324.
2. Koester, D.C.; Holkenbrink, A.; Werz, D.B. Recent advances in the synthesis of
carbohydrate mimetics. Synthesis 2010, 3217–3242.
3. Koester, D.C.; Leibeling, M.; Neufeld, R.; Werz, D.B. A Pd-catalyzed approach to
(1→6)-linked C-glycosides. Org. Lett. 2010, 12, 3934–3937.
4. Koester, D.C.; Kriemen, E.; Werz, D.B. Flexible synthesis of 2-deoxy-C-glycosides
and (1→2)-, (1→3) - , and (1→4) - linked C- glycosides. Angew. Chem. Int. Ed. 2013, 52,
2985–2989.
5. Nicotra, F.; Panza, L. Synthesis of C-glycosides and C-disaccharides. Trends Org.
Chem. 1995, 5, 223–230.
6. Levy, D.E.; Tang, C. The Chemistry of C-Glycosides. Pergamon: Elsevier Science
Ltd: Oxford, 1995 .
7. Nicotra, F. Synthesis of C-glycosides of biological interest. Top. Curr. Chem. 1997,
187, 55–83.
8. Gyorgydeak, Z.; Pelyvas, I.F. C-glycosylation. In Glycoscience: Chemistry and
Chemical Biology. Fraser-Reid, B.O.; Tatsuta, K.; Thiem, J., Eds.; Springer: Berlin;
2001, 1, 691–747.
9. Levy, D.E. Strategies towards C-glycosides. In Organic Chemistry of Sugars. Levy,
D.E.; Fuegedi, P., Eds.; 2006, 269–348.
10. Kishore, N.; Mishra, B.B.; Tripathi, V.; Tiwari, V.K. Naturally occurring bioactive
C-glycosides. Trends Carbohydr. Res. 2011, 3, 1–12.
11. Santos, R.G.; Jesus, A.R.; Caio, J.M.; Rauter, A.P. Fries-type reactions for the C-
glycosylation of phenols. Curr. Org. Chem. 2011, 15, 128–148.
12. Rauter, A.P.; Lopes, R.G.; Martins, A. C-Glycosylflavonoids: identification,
bioactivity, and synthesis. Nat. Prod. Commun. 2007, 2, 1175–1196.
13. Ferrier, R.J.; Overend, W.G.; Ryan, A.E. The reaction between 3,4,6-tri-O-acetyl-
D-glucal and p-nitrophenol. J. Chem. Soc. 1962, 3667–3670.
14. Ferrier, R.J. Unsaturated carbohydrates. II. Three reactions leading to unsatu-
rated glycopyranosides. J. Chem. Soc. 1964, 5443–5449.

Formation of C-glycosides by Ferrier Reaction
511
15. Ferrier, R.J. Unsaturated sugars. Advan. Carbohydr. Chem. Biochem. 1969, 24,
199–266.
16. Ferrier, R.J. Substitution with allylic rearrangement reactions of glycal deriva-
tives. Top. Curr. Chem. 2001, 215, 153–175.
17. Ferrier, R.J.; Hoberg, J.O. Synthesis and reactions of unsaturated sugars. Adv.
Carbohydr. Chem. Biochem. 2003, 58, 55–119.
18. Ferrier, R.J.; Zubkov, O.A. Transformation of glycals into 2,3-unsaturated glycosyl
derivatives. Org. Reactions 2003, 62, 569–736.
19. Priebe, W.; Grynkiewicz, G. Formation and reaction of glycal derivatives. In Gly-
coscience: Chemistry and Chemical Biology. Fraser-Reid, B.O.; Tatsuta, K.; Thiem, J.,
Eds. Springer: Berlin, 2001, 1, 749–783.
20. Go´mez, A.M.; Cristo´bal-Lo´pez, J. Recent strategies for the preparation of C-1 gly-
cals. Carbohydr. Chem. 2009, 35, 290–310.
21. Ciment, D.M.; Ferrier, R.J. Unsaturated carbohydrates. IV. Allylic re-
arrangement reactions of 3,4,6-tri-O-acetyl-D-galactal. J. Chem. Soc. 1966,
441–445.
22. Ferrier, R.J.; Prasad, N. Unsaturated carbohydrates. IX. Synthesis of 2,3-dideoxy-
α-D-erythro-hex-2-enopyranosides from tri-O-acetyl-D-glucal. J. Chem. Soc. C 1969,
570–575.
23. Ferrier, R.J.; Prasad, N. Unsaturated carbohydrates. XI. Isomerization and dimer-
ization of tri-O-acetyl-D-glucal. J. Chem. Soc. C 1969, 581–586.
24. Ansari, A.A.; Lahiri, R.; Vankar, Y.D. The carbon-Ferrier rearrangement: an ap-
proach towards the synthesis of C-glycosides. ARKIVOC 2013, 316–362.
25. Nicolaou, K.C.; Hwang, C.K.; Duggan, M.E. Stereospecific synthesis of 1, 1- di-
alkylglycosides. J. Chem. Soc., Chem. Commun. 1986, 925–926.
26. Ichikawa, Y.; Isobe, M.; Konobe, M.; Goto, T. Synthesis of C- glyco-
syl compounds from 3, 4, 6- tri- O- acetyl- 1, 5- anhydro- D- arabino-
hex- 1- enitol and allyltrimethylsilane and bis(trimethylsilyl) acetylene.
Carbohydr. Res. 1987, 171, 193–199.
27. Tsukiyama, T.; Isobe, M. C- Glycosidation with silylacetylenes to D- glucals. Tetra-
hedron Lett. 1992, 33, 7911–7914.
28. Hosokawa, S.; Kirschbaum, B.; Isobe, M. 1, 4- Anti induction in C- glycosylation of
pentose glycals. Tetrahedron Lett. 1998, 39, 1917–1920.
29. Yadav, J.S.; Reddy, B.V.S.; Raju, A.K.; Rao, C.V. Indium tribromide- cat-
alyzed highly stereoselective synthesis of alkynylsugars. Tetrahedron Lett. 2002, 43,
5437–5440.
30. Saeeng, R.; Sirion, U.; Sahakitpichan, P.; Isobe, M. Iodine catalyzes C- glycosida-
tion of D- glucal with silylacetylene. Tetrahedron Lett. 2003, 44, 6211–6215.
31. Isobe, M.; Phoosaha, W.; Saeeng, R.; Kira, K.; Yenjai, C. Different C- glycosidation
products of glucal with alkynyl or propargyl silanes under acidic conditions. Org. Lett.
2003, 5, 4883–4885.
32. Procopio, A.; Dalpozzo, R.; De Nino, A.; Nardi, M.; Russo, B.; Tagarelli, A. Er(OTf) 3
as new efficient catalyst for the stereoselective synthesis of C- pseudoglycals. Synthesis
2006, 332–338.
33. Pascual, C.; Meier, J.; Simon, W. Rule for the estimation of the chemical proton
shift in double bonds. Helv. Chim. Acta 1965, 49, 164–168.

E. Wieczorek and J. Thiem
512
34. Matter, U.E.; Pascual, C.; Pretsch, E.; Pross, A.; Simon, W.; Sternhell, S. Estima-
tion of the chemical shifts of olefinic protons using additive increments. II. Compilation
of additive increments for 43 functional groups. Tetrahedron 1969, 25, 691–697.
35. Matter, U.E.; Pascual, C.; Pretsch, E.; Pross, A.; Simon, W.; Sternhell, S. Estima-
tion of the chemical shifts of olefinic protons using additive increments. III. Examples of
utility in N.M.R. studies and the identification of some structural features responsible
for deviations from additivity. Tetrahedron 1969, 25, 2023–2034.