Remarkable oxidation stability of glycals: Excellent substrates for cerium(IV)-mediated radical reactions

Article abstract of DOI:10.1021/ja8052706

The remarkable stability of glycals under oxidative conditions becomes apparent by their redox data in solution, computed HOMO energies, and behavior on the addition of electrophilic radicals generated in the presence of cerium(IV) ammonium nitrate. Oxida

Full text of DOI:10.1021/ja8052706

Published on Web 10/31/2008
Remarkable Oxidation Stability of Glycals: Excellent
Substrates for Cerium(IV)-Mediated Radical Reactions
Torsten Linker,*,† Dirk Schanzenbach,† Elangovan Elamparuthi,†
Thomas Sommermann,† Werner Fudickar,† Viktor Gyo´llai,‡ La´szlo´ Somsa´k,‡
Wolfgang Demuth,§ and Michael Schmittel§
Department of Chemistry, UniVersity of Potsdam, Karl-Liebknecht-Strasse 24-25,
D-14476 Potsdam, Germany, Department of Organic Chemistry, UniVersity of Debrecen,
P.O. Box 20, H-4010 Debrecen, Hungary, and Department of Chemistry, UniVersity of Siegen,
Adolf Reichwein Strasse 2, D-57068 Siegen, Germany
Received July 8, 2008; E-mail: linker@chem.uni-potsdam.de
Abstract: The remarkable stability of glycals under oxidative conditions becomes apparent by their redox
data in solution, computed HOMO energies, and behavior on the addition of electrophilic radicals generated
in the presence of cerium(IV) ammonium nitrate. Oxidation potentials up to 2.03 V vs ferrocene were
obtained, which are exceptionally high for cyclic enol ethers but correlate nicely with the reaction times of
the radical reactions. Protecting groups have a strong influence on the oxidation stability and HOMO energies
of glycals as Eox is shifted from O-silyl over O-benzyl to O-acetyl by more than 500 mV. Interestingly, this
effect must be transmitted through σ-bonds, even up to the para-position of a benzoate group, as verified
by a wide variation of remote substituents in the carbohydrate. Favorable interactions of the σ*-orbital of
the adjacent C-O bond with the HOMO of the double bond are proposed as a mechanistic rationale,
which might be important for the redox behavior of other allylic systems. Finally, donors and acceptors in
the 1-position exert the strongest influence on the oxidation stability, shifting the potentials by almost 1 V
and resulting in different follow-up reactions of the cerium(IV)-mediated additions of malonates. It is the
remarkable oxidation stability of glycals that makes them valuable building blocks in carbohydrate chemistry.
total synthesis of natural products4 and as enzyme inhibitors.5
Importantly, epoxidation of glycals, discovered in the seminal
Introduction
Glycals (1,5- or 1,4-anhydrohex(pent)-1-enitols) 1 are 1,2-
unsaturated carbohydrate derivatives that were described and
denominated by Emil Fischer almost 100 years ago.1 Their
synthesis is easily accomplished by reductive elimination of
O-protected glycosyl halides on a large scale,2 and several of
the most prominent and widely used glycals (e.g., tri-O-acetyl-
D-glucal, 1a) are nowadays commercially available.
work of Danishefsky, resulted in many examples from the
synthesis of biologically interesting oligosaccharides and glyco-
conjugates.6 While dimethyldioxirane (DMDO) is a conven-
ient reagent for this transformation, other oxidants such as
methyltrioxorhenium (MTO) have received growing attention
recently.7 These reactions work remarkably well with glycals
1, whereas simple cyclic enol ethers such as 2,3-dihydropyran
are easily cleaved under acidic conditions or in the presence of
(4) (a) Hanessian, S. Total Synthesis of Natural Products: The “Chiron”
Approach; Pergamon: Oxford, 1983. (b) Fraser-Reid, B. O. In
Strategies and Tactics in Organic Synthesis; Lindberg, T., Ed.;
Academic Press: New York, 1989; Vol. 2, pp 123-149. (c) Very recent
example: Denmark, S. E.; Regens, C. S.; Kobayashi, T. J. Am. Chem.
Soc. 2007, 129, 2774–2776.
Glycals have been applied as enantiomerically pure starting
materials for various stereoselective transformations3 and the
(5) (a) Chenault, H. K.; Mandes, R. F. Bioorg. Med. Chem. 1994, 2, 627–
629. (b) Lai, E. C.; Morris, S. A.; Street, I. P.; Withers, S. G. Bioorg.
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1996, 35, 1380–1419. (b) Seeberger, P. H.; Danishefsky, S. J. Acc.
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Chem. Soc. ReV. 2000, 100, 4349–4393. (d) Danishefsky, S. J.; Allen,
J. R. Angew. Chem., Int. Ed. 2000, 39, 836–863. (e) Nicolaou, K. C.;
Mitchell, H. J. Angew. Chem., Int. Ed. 2001, 40, 1576–1624. (f)
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2716.
† University of Potsdam.
‡ University of Debrecen.
§ University of Siegen.
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Fischer, E. Chem. Ber. 1914, 47, 196–210.
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R. J. AdV. Carbohydr. Chem. 1969, 24, 199–266. (c) Somsa´k, L. Chem.
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579–601. (b) Priebe, W.; Grynkiewicz, G. In Glycoscience: Chemistry
& Chemical Biology; Fraser-Reid, B. O., Tatsuta, K., Thiem, J., Eds.;
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Chapleur, Y. Chem. ReV. 2004, 104, 263–292.
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9
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2008 American Chemical Society
J. AM. CHEM. SOC. 2008, 130, 16003–16010 16003

A R T I C L E S
Linker et al.
Chart 1. Glycals 1a-w with Various Configurations and Protecting Groups
manganese(III).8 Interestingly, the oxidation of glycals with
hypervalent iodine reagents affects only the allylic position and
leaves the double bond intact.9
a reactivity remarkably different from that of simple cyclic enol
ethers, which has been disregarded previously.
Herein, we describe a comprehensive study on the oxidation
stability of variously substituted glycals 1 by a combination of
cyclic voltammetry (CV), calculation of HOMO energies, and
product distribution studies from radical additions. The present
results establish a strong influence of protecting groups and of
substitution patterns both in the allylic 3-position and in position
1 of the double bond on the oxidation potentials. Furthermore,
our studies provide a rationale for the unusual reactivity of
glycals compared to simple enol ethers, demonstrating their
value as stable starting materials for radical and other oxidative
transformations.
During the course of our investigations on transition-metal-
mediated radical reactions,10 we became interested in the
addition of malonates to various glycals 1 in the presence of
cerium(IV) ammonium nitrate (CAN).11 This reaction is similar
to Lemieux’s azidonitration,12 but provides easy access to C-2-
branched carbohydrates, a valuable complement to the cyclo-
propanation of glycals.13 More recently, we applied this
methodology to other CH acidic radical precursors (e.g.,
nitromethane or nitro esters)14 and to unsaturated carbohydrates
with benzyl protecting groups.15 In all cases, the double bond
of glycals 1 was not directly affected by CAN, although this
ox
Results
reagent has an oxidation power (E1/2 ) 1.52-1.60 V vs
NHE)16 sufficient to oxidize unsubstituted 2,3-dihydropyran (Epa
) 1.60 V vs NHE).17 Furthermore, the addition of radicals to
2,3-dihydropyran was not successful.8d Thus, glycals 1 exhibit
Synthesis of Glycals 1. To investigate the oxidation stability
of a broad variety of glycals, we synthesized more than 20
different 1,2-unsaturated carbohydrate derivatives. The simple
O-acetyl-protected glycals 1a-d were easily available from the
parent glycosyl bromides for pentoses, hexoses, and disaccha-
rides on a large scale via known procedures.2,18 For further
functionalized systems, we focused on derivatives of D-glucal
and D-galactal, which furnished high yields and selectivities in
radical additions in our previous studies.11 Thus, the protecting
groups were easily exchanged by literature procedures,19 and
glycals 1e-j were obtained in one- or two-step reactions from
the corresponding tri-O-acetyl-D-glycals 1a and 1b (Chart 1,
Supporting Information). To investigate the influence of various
substituents adjacent to the double bond, we altered the
structures in the 1- and 3-positions of the glycals requiring some
more laborious transformations. The 3-O-acetyl group of glucal
1a was selectively removed by enzymatic saponification to give
1k,20 and subsequent reaction with acid chlorides afforded esters
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1997, 119, 9377–9384. (c) Gyo´llai, V.; Schanzenbach, D.; Somsa´k,
L.; Linker, T. Chem. Commun. 2002, 1294–1295.
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T. Chem. Commun. 2004, 2624–2625. (b) Elamparuthi, E.; Linker, T.
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16004 J. AM. CHEM. SOC. VOL. 130, NO. 47, 2008

Remarkable Oxidation Stability of Glycals
A R T I C L E S
Table 1. Oxidation Potentials (Eox) of Various Glycals 1 Determined by CV and Addition of Dimethyl Malonate (2)a
g
Eox (V)
entry
D-glycal
PG
R1
R2
tb (h)
eq-3 yieldc (%)
ax-3 yieldc (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
glucal
galactal
xylal
maltal
galactal
galactal
galactal
galactal
galactal
glucal
glucal
glucal
glucal
glucal
glucal
glucal
glucal
galactal
glucal
Ac
Ac
Ac
Ac
H
Bn
Me
SiMe3
Si(i-Pr)3
Si(i-Pr)3
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
OAc
OAc
OAc
OAc
OH
OBn
OMe
OSiMe3
OSi(i-Pr)3
OSi(i-Pr)3
OH
O2CPh
O2CPhpOMe
O2CPhpNO2
O2CC(CH3)3
H
OAc
OAc
OAc
OAc
OAc
OAc
OAc
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
6
6
6
6
0.5
2
1
80
87
81
83
d
83
76
d
15
1.87h
1.89
1.76
1.87
1.35
1.62
1.48
1.37
i
6
0.5
e
e
i
2
12
6
12
6
2
1
1
1
1
8
12
12
45
78
74
73
75
47
71
73
89
82
70
38f
53f
3
16
20
17
16
40
1.67
2.03
1.86
2.00
1.94
1.62
1.57
1.55
1.41
1.35
1.96
>2.2j
>2.2j
1.21k
Me
Me
Ph
Ph
CONH2
CO2Me
CN
1t
galactal
galactal
galactal
galactal
Ac
Ac
Ac
Ac
1u
1v
1w
2,3-dihydropyran
a Reaction of glycal 1 (1.0 mmol) with malonate 2 (10 mmol) in the presence of anhydrous CAN (3-6 mmol) and NaHCO3 (4.0 mmol) in MeOH
(10 mL) at 0 °C. b Reaction time until TLC showed complete conversion of glycal 1. c Yield of isolated product after column chromatography.
d Decomposition of glycal 1. e Glycals 1i and 1j were not soluble in methanol. f Formation of ortho esters 4 and other minor side products. g Oxidation
potentials Eox (V) obtained from cyclic voltammograms from the anodic peak potential. Determined at 100 mV/s in acetonitrile (10-3 M) in the
presence of Bu4NPF6 (0.1 M) vs ferrocene. h Literature value 1.80 V.27 i Glycals 1i and 1j were not soluble in acetonitrile. j No oxidation peak was
observed, due to dominating oxidation of the bare electrolyte solution at Eox > 2.2 V. k Literature value 1.20 V.17
1l-o in high yields (Supporting Information). Finally, 3-deoxy-
glucal 1p was obtained by Ferrier rearrangement and reduction
with lithium aluminum hydride.21
carbohydrates should provide sufficient information for the
subsequent studies.
Cyclic Voltammetry of Glycals 1. Although anodic and PET
oxidations of enol ethers are of significant synthetic interest,
their oxidation potentials are not well established.17,24 Besides
oxidative DNA damage via nucleotide radical cations, whose
kinetics has been thoroughly studied,25 the oxidation potential
of only one glycal, i.e., tri-O-acetyl-D-glucal (1a), has been
described until now.26 Therefore, we investigated the redox
behavior of various glycals 1 by CV (Table 1).27 All measure-
ments were conducted in dry acetonitrile with tetra-n-butyl-
ammonium hexafluorophosphate (Bu4NPF6) as the supporting
electrolyte applying a scan rate of 100 mV/s (Supporting
Information). Most glycals were readily soluble, except the silyl-
To alter the electronic nature of the double bond, which
should have an influence on the oxidation stability, we
introduced donor and acceptor groups into the 1-position. Due
to the acidity of the vinylic position, deprotonation of silyl-
protected glycals is possible with strong bases.2c,22 After
alkylation or arylation and exchange of the protecting groups,
the 1-C-methyl- and 1-C-phenylglycals 1q-t were isolated in
moderate to good overall yields in analytically pure form (Chart
1, Supporting Information). Acceptor-substituted galactals 1u23a
and 1w23b were prepared by methods published earlier. Ester
1v23c was obtained from C-(3,4,6-tri-O-acetyl-2-deoxy-D-lyxo-
hex-1-enopyranosyl)carbaldehyde by oxidation with MnO2 and
subsequent in situ esterification (Chart 1, Supporting Informa-
tion). In summary, we have synthesized more than 20 different
glycals 1, some of which were hitherto unknown. Due to the
broad variation of the substitution pattern, these unsaturated
(24) (a) Koch, D.; Scha¨fer, H.; Steckhan, E. Chem. Ber. 1974, 107, 3640–
3657. (b) Lopez, L.; Troisi, L. Tetrahedron Lett. 1989, 30, 489–492.
(c) Moeller, K. D.; Marzabadi, M. R.; New, D. G.; Chiang, M. Y.;
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M.; Ro¨ck, M. Chem. Ber. 1992, 125, 1611–1620. (e) Schmittel, M.;
Burghart, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 2550–2589. (f)
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grahi, M.; Huang, X.; Crich, D. J. Am. Chem. Soc. 2001, 123, 6445–
6446, and references therein.
(21) Fraser-Reid, B. O.; Tam, Y.-K.; Radatus, B. Can. J. Chem. 1975, 53,
2005–2016.
(22) (a) Friesen, R. W.; Sturino, C. F.; Daljeet, A. K.; Kolaczewska, A. J.
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Rainier, J. D. Org. Lett. 2003, 5, 913–916. (c) Lehmann, U.; Awasthi,
S; Minehan, T. Org. Lett. 2003, 5, 2405–2408.
(23) (a) Somsa´k, L. Carbohydr. Res. 1989, 195, C1–C2. (b) Somsa´k, L.;
Bajza, I.; Batta, G. Liebigs Ann. Chem. 1990, 1265–1268. (c)
Mahmoud, S. H.; Somsa´k, L.; Farkas, I. Carbohydr. Res. 1994, 254,
91–104. (d) Banaszek, A. Tetrahedron 1995, 51, 4231–4238. (e) Kiss,
L.; Somsa´k, L. Carbohydr. Res. 1996, 291, 43–52.
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Colovic, M.; Vukicevic, M.; Segan, D.; Manojlovic, D.; Sojic, N.;
Somsa´k, L.; Vukicevic, R. D. AdV. Synth. Catal. 2008, 350, 29–34.
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A R T I C L E S
Linker et al.
Table 2. Comparison of Oxidation Potentials, Calculated HOMO
protected derivatives 1i and 1j. The cyclic voltammograms of
glycals 1 displayed irreversible oxidation peaks in the broad
range from 1.35 to 2.03 V vs ferrocene, which are remarkably
higher than that of 2,3-dihydropyran (1.21 V, entry 24).
Furthermore, the oxidation potential (Eox) of the acceptor-
Energies, and Reactivities in CAN-Mediated Radical Reactions of
Variously Configured and Protected Glycals 1
substituted carbohydrates 1v and 1w must be very high (Eox
>
2.2 V, entries 22 and 23), since only the anodic current of the
bare electrolyte solution was observed. As is typical for chemical
follow-up reactions after the electron transfer step, i.e., for EC
or ECE mechanisms, the anodic peak of all glycals shifted to
higher potentials with increasing scan rate, with the peak current
dropping in the second sweep.28 In summary, for the first time
we obtained a whole data set of oxidation potentials of a broad
variety of glycals 1. The high values of 1.35-2.03 V vs
ferrocene demonstrate their remarkable oxidation stability and
the strong influence of the substitution pattern on their reactivity.
Radical Additions to Glycals 1. Radical reactions in the
presence of tri-n-butyltin hydride have become an important
methodology for the selective formation of carbon-carbon
bonds.29 Electrophilic radicals, typically characterized by ad-
jacent acceptor groups, are conveniently generated by transition-
metal-mediated oxidation of CH acidic precursors.30 In previ-
ously reported addition reactions of such radicals to glycals
1a-c, the enol ether structure was not directly affected by CAN
and the C-2-branched analogues 3 were isolated in high yields.11
To examine the scope and limitations of the addition of dimethyl
malonate (2) and to find an explanation for the remarkable
oxidation stability of glycals 1, we compared more than 20
substrates (Table 1, Supporting Information). Reaction times,
which are indicative of the reactivity of the glycals 1 toward
the electrophilic malonyl radicals, were measured by monitoring
full conversion by thin layer chromatography (TLC). The rate
of addition was expected to reflect the electronic nature of the
double bond and should correlate with the determined redox
potentials (see the Discussion).
a
entry
D-glycal
PG
Eox (V) tb (h) HOMO energyc (eV)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1f
1g
1h
1i
glucal
galactal
xylal
Ac
Ac
Ac
Ac
Bn
1.87
1.89
1.76
1.87
1.62
1.48
1.37
d
6
-9.66
-9.72
-9.63
-9.62
-9.36
-9.16
-8.55
-8.59
-8.87
-9.22
6
6
6
2
maltal
galactal
galactal
galactal
galactal
galactal
Me
1
SiMe3
Si(i-Pr)3
H
0.5e
d
1e
1.35
0.5e
10
2,3-dihydropyran
1.21
0.5e
a Oxidation potentials Eox (V) vs ferrocene obtained from cyclic
voltammograms. b Reaction time until TLC showed complete conversion
of glycal 1. c HOMO energies computed by the semiempirical PM3
method implemented in MOPAC from Sybyl 8.0. All structures were
minimized by the Tripos force field using the Gasteiger-Hu¨ckel
method. d Glycal 1i was not soluble in acetonitrile or methanol.
e Decomposition of glycal 1.
and trimethylsilyl-protected (1h) glycals afforded only oxidative
decomposition after short reaction times. An acid-catalyzed
cleavage of the silyl groups is unlikely, due to the presence of
sodium bicarbonate as the base. The triisopropylsilyl-protected
glycals 1i and 1j were not soluble in methanol, and no reaction
times were obtained (entries 9 and 10).
To further elucidate the influence of functional groups on
the oxidation stability of glycals, we altered the substitution
pattern at the 3-position (entries 11-16). Indeed, even a remote
effect of para-substituents of the benzoate groups on the reaction
time was established (entries 12-14), and again, the unprotected
3-position afforded some oxidative byproduct (entry 11).
Finally, variation of the 1-position of glycals 1q-w resulted
in the strongest change in both reactivity and product distribution
(entries 17-23). We performed the CAN-mediated addition of
dimethyl malonate (2) to donor-substituted unsaturated carbo-
hydrates for the first time, and the products 3q-t were isolated
in good yields in analytically pure form after only 1 h (entries
17-20, Supporting Information). On the other hand, acceptor
groups reduced the rate of additions remarkably, and the
unexpected ortho esters 4v and 4w were obtained in moderate
yields as diastereomeric mixtures.
Additions to the per-O-acetylated glycals 1a-d proceeded
smoothly within 6 h, affording products 3 in high overall yields
(Table 1, entries 1-4). The exclusive formation of one
regioisomer and the higher selectivity observed with galactals
have already been explained in our previous studies.11 No
influence of the configuration on the reaction time was observed.
On the other hand, the protecting groups altered the reactivity
of the glycals 1e-h remarkably (entries 5-8). The benzyl- and
methyl-substituted substrates 1f and 1g gave already faster
conversions and still high yields of the addition products 3f and
3g (entries 6 and 7), whereas the completely unprotected (1e)
(28) Nicholson, R. S.; Shain, I. Anal. Chem. 1964, 36, 706–723.
(29) (a) Giese, B. Radicals in Organic Synthesis: Formation of Carbon-
Carbon Bonds; Pergamon Press: Oxford, U.K., 1986. (b) Houben-
Weyl, Methods of Organic Chemistry, 4th ed.; Regitz, M., Giese, B.,
Eds.; Thieme: Stuttgart, Germany, 1989; Vol. E19a. (c) Fossey, J.;
Lefort, D.; Sorba, J. Free Radicals in Organic Chemistry; Wiley:
Chichester, U.K., 1995. (d) Curran, D. P.; Porter, N. A.; Giese, B.
Stereochemistry of Radical Reactions; VCH: Weinheim, Germany,
1996. (e) Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.;
Wiley-VCH: Weinheim, Germany, 2001. (f) Zard, S. Z. Radical
Reactions in Organic Synthesis; Oxford University Press: New York,
2003. (g) Gansa¨uer, A. Radicals in Synthesis; Topics in Current
Chemistry, Vol. 263; Springer: Berlin, 2006.
(30) (a) Iqbal, J.; Bhatia, B.; Nayyar, N. K. Chem. ReV. 1994, 94, 519–
564. (b) Dalko, P. I. Tetrahedron 1995, 51, 7579–7653. (c) Snider,
B. B. Chem. ReV. 1996, 96, 339–363. (d) Melikyan, G. G. Org. React.
1996, 49, 427–675. (e) Linker, T. AdV. Synth. Catal. 1997, 339, 488–
492. (f) Nair, V.; Mathew, J.; Prabhakaran, J. Chem. Soc. ReV. 1997,
127–132. (g) Nair, V.; Balagopal, L.; Rajan, R.; Mathew, J. Acc. Chem.
Res. 2004, 37, 21–30. (h) Nair, V.; Deepthi, A. Chem. ReV. 2007,
107, 1862–1891.
Discussion
Influence of the Configuration and the Protecting Groups
on the Oxidation Stability of Glycals 1. With a large data set of
oxidation potentials (Eox) for variously substituted glycals 1 at
hand, their electronic properties on one side and reactivities
toward malonates on the other side can now be compared (Table
2). It is well-known that the addition of radicals to alkenes
proceeds by orbital control, suggesting a strong interaction of
the SOMO of the electrophilic malonyl radical with the HOMO
9
16006 J. AM. CHEM. SOC. VOL. 130, NO. 47, 2008

Remarkable Oxidation Stability of Glycals
A R T I C L E S
Chart 2. Electron Density of the HOMO of Tri-O-benzyl-D-galactal
(1f)
acetyl-D-galactal (1b) and tri-O-benzyl-D-galactal (1f) in a
competition experiment. Dimethyl malonate (2) was added to
a 1:1 mixture of both substrates in the presence of CAN, and
the reaction was monitored by NMR spectroscopy at different
times (Supporting Information). After 60 min, 82% of the
electron-rich O-benzyl-protected galactal 1f was consumed,
whereas 70% of 1b remained unreacted. This difference in
reactivity can be rationalized by the higher propensity of an
ester group to withdraw electrons compared to a benzyl ether.
However, since the functional groups are not directly linked to
the double bond, this remarkable influence must be transmitted
through space or σ-bonds. Such strong transmission was hitherto
unknown for radical additions to glycals and will be discussed
in the next section. Interestingly, this phenomenon can be
consideredasanewmanifestationoftheknownarming-disarming
effect of protecting groups observed and utilized in glycosyla-
tions.32 Although not directly comparable to radical additions,
for such cationic reactions at the anomeric center the influence
of various functional groups over many bonds was semiquan-
tified by Ley33 and Wong.34
of the double bond component.29 This interaction is very
sensitive to the substitution pattern and correlates directly with
the rate of radical addition. Thus, if the HOMO energy is
increased, the reaction with malonates is much faster, which is
indicated qualitatively by the reaction times (Table 2). For the
addition of malonyl radicals to para-substituted styrenes,
detailed kinetics were measured and even Hammett correlations
were obtained, irrespective of the generation of the radicals by
CAN or tri-n-butyltin hydride.31 Likewise in our systems, the
addition of the radicals to the double bond seems to be involved
in the rate-determining step, apparently preceded by the forma-
tion of a cerium(III)-malonyl radical complex in a preequilib-
rium. Indeed, if no glycal 1 was added to the reaction mixture,
no conversion and decoloration of CAN was observed. To
further investigate the importance of orbital interactions, HOMO
energies were calculated by the semiempirical PM3 method.
Indeed, the HOMO of tri-O-benzyl-D-galactal (1f) (Chart 2) has
its highest electron density at the double bond, and thus, an
oxidation of protecting groups is unlikely. Overall three
parameters (oxidation potentials, reaction times, HOMO ener-
gies) are available to discuss the remarkable oxidation stability
of glycals.
Although the reaction times may reflect the kinetics only
qualitatively, they nicely correlate with the oxidation potentials.
For example, the O-acetyl-protected derivatives 1a-d with the
highest Eox (up to 1.89 V vs ferrocene; see entries 1-4) reacted
with the malonyl radicals only slowly. No influence of the
configuration of the glycals 1 on the oxidation potential was
observed; only di-O-acetyl-D-xylal (1c) has a slightly lower
oxidation potential, due to one missing O-acetyl group. Thus,
the functional groups seem to be responsible for the remarkable
oxidation stability of glycals. In contrast, the completely
unsubstituted 2,3-dihydropyran is oxidized already at 1.21 V,
furnishing only decomposition products with CAN after 30 min
(entry 10).
To exclude a direct oxidation of the benzyl ethers,35 we
investigated the corresponding tri-O-methyl-D-galactal (1g)
equipped with oxidation-stable protecting groups. Its oxidation
potential (Eox ) 1.48 V vs ferrocene, entry 6) is even lower
than that of the benzyl-protected galactal 1f (entry 5), in good
accordance with the calculated HOMO energies. The addition
of dimethyl malonate (2) in the presence of CAN proceeded
with both substrates smoothly, without affecting the protecting
groups (Table 1). Thus, the redox potentials indeed reflect the
MO energies of the double bonds and not those of the protecting
groups.
The limit for synthetic applications of cerium(IV)-mediated
additions of radicals to glycals 1 was reached with silyl-
substituted systems 1h and 1i or the unprotected D-galactal 1e,
since the unsaturated carbohydrates were not soluble or decom-
posed within minutes (entries 7-9). For glycal 1h, deprotection
under the reaction conditions cannot be excluded, but the low
oxidation potential of 1.37 V vs ferrocene is in the same range
as that of 2,3-dihydropyran (1.21 V, entry 10), supporting an
oxidation of the double bond. In summary, we established (i)
the remarkable oxidation stability of glycals and (ii) a strong
influence of protecting groups, thus providing a rationale for
this unusual behavior. However, the way the protecting groups
influence the oxidation potential of the enol ether structure
through space or σ-bonds is not yet explained properly and will
be discussed in the next section.
(32) (a) Collins, P. M.; Ferrier, R. J. MonosaccharidessTheir Chemistry
and Their Roles in Natural Products; John Wiley & Sons: Chichester,
U.K., 1995. (b) Fu¨gedi, P. Oligosaccharide synthesis. In The Organic
Chemistry of Sugars; Levy, D. E., Fu¨gedi, P., Eds.; CRC Taylor &
Francis: Boca Raton, FL, 2006; pp 181-221. (c) Jensen, H. H.; Bols,
M. Acc. Chem. Res. 2006, 39, 259–265.
(33) (a) Ley, S. V.; Priepke, H. W. M. Angew. Chem., Int. Ed. Engl. 1994,
33, 2292–2294. (b) Cheung, M. K.; Douglas, N. L.; Hinzen, B.; Ley,
S. V.; Pannecoucke, X. Synlett 1997, 257–260. (c) Green, L. G.;
Hinzen, B.; Langer, P.; Ley, S. V.; Warriner, S. L. Synlett 1998, 440–
442. (d) Review: Green, L. G.; Ley, S. V. Carbohydr. Chem. Biol.
2000, 1, 427–448.
To further understand the influence of protecting groups, a
look at galactals 1e-i (Table 2, entries 5-9) is highly
instructive. A simple change from an O-acetyl (1b) to an
O-benzyl (1f) group shifts the oxidation potential cathodically
by a notable 270 mV. The same clear trend is reflected in the
reaction times and especially the calculated HOMO energies
(entries 2 and 5). For additional insight, we compared tri-O-
(34) (a) Zhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T;
Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 734–753. (b) Ye, X.-S.;
Wong, C.-H. J. Org. Chem. 2000, 65, 2410–2431. (c) Mong, T. K. K.;
Huang, C.-Y.; Wong, C.-H. J. Org. Chem. 2003, 68, 2135–2142.
(35) (a) Lines, R.; Utley, J. H. P. J. Chem. Soc., Perkin Trans. 2 1977,
803–809. (b) Boyd, J. W.; Schmalzl, P. W.; Miller, L. L. J. Am. Chem.
Soc. 1980, 102, 3856–3862. (c) Baciocchi, E.; Piermattei, A.; Rol,
C.; Ruzziconi, R.; Sebastiani, G. V. Tetrahedron 1989, 45, 7049–
7062.
(31) Baciocchi, E.; Giese, B.; Farshchi, H.; Ruzziconi, R. J. Org. Chem.
1990, 55, 5688–5691.
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A R T I C L E S
Linker et al.
Table 3. Comparison of Oxidation Potentials, Calculated HOMO Energies, and Reactivities in CAN-Mediated Radical Reactions of Variously
3-Substituted Glycals 1
a
Eox (V)
entry
glucal
R
tb (h)
HOMO energyc (eV)
eq-3 yieldd (%)
ax-3 yieldd (%)
1
2
3
4
5
6
7
1a
1l
1m
1n
1o
1k
1p
OAc
O2CPh
O2CPh-p-OMe
O2CPh-p-NO2
O2CC(CH3)3
OH
1.87
2.03
1.86
2.00
1.94
1.67
1.62
6
12
6
12
6
-9.66
-9.80
-9.54
-9.99
-9.70
-9.52
-9.47
80
78
74
73
75
45
47
15
16
20
17
16
3
2
2
H
40
a Oxidation potentials Eox (V) vs ferrocene obtained from cyclic voltammograms. b Reaction time until TLC showed complete conversion of glycal 1.
c HOMO energies computed by the semiempirical PM3 method implemented in MOPAC from Sybyl 8.0. All structures were minimized by the Tripos
force field using the Gasteiger-Hu¨ckel method. d Yield of isolated product after column chromatography.
Chart 3. Orbital Interactions in Glycals 1l-n
Influence of the Substituents at the 3-Position on the
Oxidation Stability of Glycals 1. To find a mechanistic rationale
for the remarkable influence of protecting groups on the
oxidation stability of glycals, we varied the substitution pattern
at the 3-position that is located adjacent to the double bond. To
exclude poor overlap with the electrode by steric interactions,
possibly leading to slow heterogeneous electron-transfer, we
selected 3-O-pivaloylglucal 1o as a test substrate (entry 5). Even
for this bulky substituent, the oxidation potential was in the
expected range, suggesting that exclusively electronic effects
are operative. The successful comparison of oxidation potentials,
calculated HOMO energies, and reactivities was thus applied
again (Table 3).
The change of the O-acetyl into an O-benzoyl group resulted
in an anodic shift of the oxidation potential by 160 mV and a
longer reaction time (entry 2). Such findings can be explained
by the slightly stronger acceptor propensity of the benzoyl group
and are in accordance with a decrease in the HOMO energy by
140 mV. Even the remote para-substituent of the O-benzoyl
group exerted an influence on the redox potential and reaction
time, promoting a faster addition of malonyl radicals to the donor
(OMe) than to the acceptor (NO2) substituted system (entries 3
and 4). Why the benzoyl and p-nitrobenzoyl showed almost the
same oxidation potential could not be explained until now, as
the nitro compound 1n displayed the lowest calculated HOMO
energy (-9.99 eV) in the whole series of 3-substituted glycals,
about 190 mV more negative than that of 1l (Ph). For the (p-
methoxybenzoyl)glucal 1m, on the other hand, the oxidation
potential and the computed HOMO energies are in due
agreement (entry 3).
These influences of substituents are very interesting, since
such remote effects over many bonds, including σ-bonds, were
hitherto unknown in radical reactions. However, the results can
again be compared with the stereoelectronic effects in glyco-
sylation reactions, transmitted through space or σ-bonds as
well.32-34 In contrast to the ester-substituted systems, the
unprotected and 3-deoxy substrates exhibited considerably lower
oxidation potentials and faster reaction times (Table 3, entries
6 and 7), which can be explained by the lack of an acceptor
group.
Our explanation for the remarkable influence of the substit-
uents in the 3-position on the oxidation potentials and reactivities
through σ-bonds is based on orbital interactions (Chart 3). Thus,
electron acceptors such as esters are expected to lower the
energy of the σ*-orbital of the C-O bond, resulting in a stronger
interaction with the adjacent HOMO of the double bond. As a
result, the HOMO energy drops (as demonstrated by computa-
tions) and a higher oxidation potential is measured by cyclic
voltammetry. Even the para-substituents R on the aromatic ring
slightly influence the oxidation potentials (entries 2-4), which
is also reflected in the calculations of the HOMO energies. For
a perfect overlap, the σ*- and π-orbitals should adopt an almost
parallel alignment, which is readily possible in the quite flexible
ring system of glycals. The important influence of orbital
interactions on the conformation of carbohydrates is nicely
reflected in the structure of glycosyl radicals.36 In summary,
we could provide a mechanistic rationale for the unusual
oxidation stability of glycals by variation of the functional
groups in the 3-position. The effect is transmitted through
σ-bonds even up to the para-substituents of the benzoate rings,
which might be important for the discussion of the redox
behavior of other allylic systems.
Influence of the Substituents in the 1-Position on the
Oxidation Stability of Glycals 1. With substituents in the
3-position already exhibiting a sizable influence on the HOMO
energies of glycals, this effect is expected to be much stronger
in the 1-position. Now the functional group is directly connected
with the double bond and interacts by conjugation and not
through σ-bonds. Indeed, glycals 1q-w showed the broadest
alteration of oxidation potentials, calculated HOMO energies,
and reactivities (Table 4). Compared to tri-O-acetyl-D-glucal
(1a), already the presence of a methyl group reduced the anodic
peak potential in 1q by 300 mV (entry 2), demonstrating the
strong donor propensity of this substituent. Even lower oxidation
potentials were obtained for the better electron-donating phenyl
groups (entries 4 and 5), confirmed by the HOMO energies
shifting from -9.66 to -9.52 and -9.23 eV. The carbohydrate
C-2 analogues 3q-t were isolated in high yields (entries 2-5),
(36) Review: Praly, J.-P. AdV. Carbohydr. Chem. Biochem. 2000, 56, 65–
151.
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Remarkable Oxidation Stability of Glycals
A R T I C L E S
Table 4. Comparison of Oxidation Potentials, Calculated HOMO Energies, and Reactivities in CAN-Mediated Radical Reactions of Various
1-Substituted Glycals 1
a
Eox (V)
entry
glycal
group in 4-position
R
tb (h)
HOMO energyc (eV)
eq-3 yieldd (%)
ax-3 yieldd (%)
1
2
3
4
5
6
7
8
1a
1q
1r
1s
eq
eq
ax
eq
ax
ax
ax
ax
H
1.87
1.57
1.55
1.41
1.35
6
1
1
1
1
8
12
12
-9.66
-9.52
-9.43
-9.23
-9.17
-9.80
-10.03
-10.41
80
71
73
89
82
70
38f
53f
15
Me
Me
Ph
Ph
CONH2
CO2Me
CN
1t
1u
1v
1w
1.96
>2.2e
>2.2e
a Oxidation potentials Eox (V) vs ferrocene obtained from cyclic voltammograms. b Reaction time until TLC showed complete conversion of glycal 1.
c HOMO energies computed by the semiempirical PM3 method implemented in MOPAC from Sybyl 8.0. All structures were minimized by the Tripos
force field using the Gasteiger-Hu¨ckel method. d Yield of isolated product after column chromatography. e No oxidation peak was observed, due to
dominating oxidation of the bare electrolyte solution at Eox > 2.2 V. f Formation of ortho esters 4 and other minor side products.
and for the first time we prepared methyl glycosides with
quaternary anomeric centers by this radical methodology.
On the other hand, 1-acceptor-substituted glycals 1u-w
reacted only sluggishly with dimethyl malonate (3a), most likely
due to the remarkably lowered HOMO energies and conse-
quential unfavorable orbital interactions. This is in accordance
with other transition-metal-mediated radical reactions, which
do not proceed efficiently with electron-poor alkenes.30 The
cyclic voltammograms support this mechanistic rationale, since
the SOMO of the electrophilic malonyl radical with the HOMO
of the double bond.
The configuration of the glycals had no influence on their
oxidation stability. On the other hand, a strong dependence of
the oxidation potentials over 500 mV on the protecting groups
was found. Thus, O-silylated and unprotected glycals were
readily oxidized to undesired side products, proving themselves
as unsuitable substrates for radical additions under oxidative
conditions. On the contrary, per-O-acetylated glycals exhibited
the highest oxidation stability (Eox up to ∼2 V), but benzyl ethers
were tolerated as well. These results are important for the general
applicability of oxidation reactions in carbohydrate chemistry,
with a high tolerance of various functional groups.
Interestingly, the protecting groups influence the oxidation
stability of the enol ether structure through σ-bonds. This effect
was verified by variation of the substitution pattern in the 3-position,
with a remarkable spread of oxidation potentials over 400 mV.
As a mechanistic model, we propose a favorable interaction of the
σ*-orbital of the adjacent C-O bond with the HOMO of the double
bond. Thus, electron acceptors in the allylic position lower the
HOMO energy, which was nicely supported by calculations. This
effect is transmitted even into the para-substituents of the benzoate
rings, which may be important for the discussion of the redox
behavior of other allylic esters.
Finally, donors and acceptors in the 1-position had the strongest
influence on the oxidation stability, obviously due to the direct
conjugation to the double bond. The potentials varied over a range
of almost 1 V, and the radical additions in the presence of CAN
proceeded via different follow-up reactions. With strong acceptor
groups, the intermediate radicals at the captodatively substituted
anomeric center were not further oxidized, and ortho esters were
isolated as carbohydrate C-2 analogues.
Besides these new mechanistic aspects, the results are
important for synthetic applications of transition-metal-mediated
radical reactions in carbohydrate chemistry and the scope and
limitations of the addition of CH acidic compounds to glycals.
Due to oxidative decomposition by CAN, substrates with too
low oxidation potentials are not suitable, whereas radical
addition to glycals with a too high oxidation potential proceeds
inefficiently. Thus, a window of 1.5-2.0 V for the oxidation
potential seems to be ideal, provided by per-O-acetylated and
-benzylated glycals. By following these guidelines, we expect
only the anodic current of the bare electrolyte solution (Eox
≈
2.1 V) was observed for glycals 1v and 1w (entries 7 and 8).
Therefore, the oxidation potentials of such acceptor-substituted
unsaturated carbohydrates must be >2.2 V, a value never before
observed for enol ethers. The difficult electrochemical oxidation
of glycals 1v and 1w was confirmed by computations, as they
showed the HOMO energies to be below -10 eV. Thus, the
orbital interaction of the electrophilic malonyl radicals with the
double bond is drastically diminished, resulting in slower
additions and lower yields. Additionally, the glycals 1v and 1w
afforded ortho esters 4 and no methyl glycosides 3 as addition
products in moderate yields (Table 3, entries 7 and 8). The
formation of such bicyclic compounds is interesting from the
mechanistic point of view and was explained previously.11c
Conclusions
We established a remarkable oxidation stability of glycals
and provide an explanation for their unusual reactivity and their
application as valuable starting materials for other synthetic
transformations. More than 20 variously substituted unsaturated
carbohydrates were synthesized and investigated under oxidative
reaction conditions. The method of choice was a combination
of CV, calculation of HOMO energies, and examination of the
product distribution from cerium(IV)-mediated additions of
radicals. Depending on the substitution pattern, the oxidation
potentials of glycals were in the range of 1.35-2.03 V vs
ferrocene. Compared with 2,3-dihydropyran (Eox ) 1.21 V),
such high values are unusual for enol ethers and demonstrate a
remarkable oxidation stability of 1,2-unsaturated carbohydrates,
which was hitherto disregarded. Moreover, the different reaction
times for the addition of dimethyl malonate in the presence of
CAN correlate nicely with the oxidation potentials and the
HOMO energies. This was rationalized by the interaction of
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A R T I C L E S
Linker et al.
many applications for the synthesis of C-2-branched carbohy-
drates or other oxidative transformations of glycals to arise in
the near future.
Supporting Information Available: Experimental part in-
cluding spectroscopic data and complete characterization of
all new compounds and voltammograms of glycals 1. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Acknowledgment. This work was generously supported by the
Deutsche Forschungsgemeinschaft (Grant Li 556/7-3), the Unversity
of Debrecen, and the University of Siegen. We thank Dr. Holla
(Norvartis) for a generous gift of the crude glycal 1k.
JA8052706
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