A new procedure for highly regio- and stereoselective iodoacetoxylation of protected glycals and α-1,2-cyclopropanated sugars

Article abstract of DOI:10.1080/07328300701351524

Protected glycals and -1,2-cyclopropanated sugars were converted in high yields and selectivities in less than 2h at low temperatures to 2-deoxy-2-iodoglycosyl acetates or novel 2-deoxy-2-iodomethylglycosyl acetates using the simple, inexpensive reagent m

Full text of DOI:10.1080/07328300701351524

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A New Procedure for Highly Regio‐ and
Stereoselective Iodoacetoxylation of
Protected Glycals and α‐1,2‐Cyclopropanated
Sugars
David W. Gammon a , Henok H. Kinfe a , Dirk E. De Vos b , Pierre A. Jacobs b
& Bert F. Sels b
a Department of Chemistry , University of Cape Town , Rondebosch, South
Africa
b CSIR Biosciences , Ardeer Road , Johannesburg, South Africa
c Center for Surface Chemistry and Catalysis , Katholieke Universiteit
Leuven , Belgium
Published online: 01 Jun 2007.
To cite this article: David W. Gammon , Henok H. Kinfe , Dirk E. De Vos , Pierre A. Jacobs & Bert F.
Sels (2007) A New Procedure for Highly Regio‐ and Stereoselective Iodoacetoxylation of Protected
Glycals and α‐1,2‐Cyclopropanated Sugars, Journal of Carbohydrate Chemistry, 26:3, 141-157, DOI:
10.1080/07328300701351524
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Journal of Carbohydrate Chemistry, 26:141–157, 2007
Copyright # Taylor & Francis Group, LLC
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1080/07328300701351524
A New Procedure for Highly
Regio- and Stereoselective
Iodoacetoxylation of
Protected Glycals and a-1,2-
Cyclopropanated Sugars
David W. Gammon
Department of Chemistry, University of Cape Town, Rondebosch, South Africa
Henok H. Kinfe
CSIR Biosciences, Ardeer Road, Johannesburg, South Africa
Dirk E. De Vos, Pierre A. Jacobs, and Bert F. Sels
Center for Surface Chemistry and Catalysis, Katholieke Universiteit Leuven, Belgium
Protected glycals and a-1,2-cyclopropanated sugars were converted in high yields and
selectivities in less than 2 h at low temperatures to 2-deoxy-2-iodoglycosyl acetates or
novel 2-deoxy-2-iodomethylglycosyl acetates using the simple, inexpensive reagent
mixture of ammonium iodide, hydrogen peroxide, and acetic anhydride/acetic acid in
acetonitrile. The protected glycals gave rise to 2-deoxy-2-bromoglycosyl acetates when
ammonium bromide was used instead of the iodide, although longer reaction times
were required and selectivities were inferior. Other simple olefins such as styrene and
indene were also converted to their corresponding 1,2-trans-iodoacetates.
Keywords Glycals, 2-Iodoglycosides, Iodoacetates, 1,2-Cyclopropanated sugars
INTRODUCTION
Unsaturated sugars such as the glycals and 1,2-cyclopropanated derivatives
are versatile building blocks for the synthesis of oligosaccharides, glycosides,
Received January 8, 2007; accepted March 4, 2007.
Address correspondence to David W. Gammon, Department of Chemistry, University of
Cape Town, Rondebosch 7701, South Africa. E-mail: david.gammon@uct.ac.za
141

D. W. Gammon et al.
142
Scheme 1: Transformations and synthetic utility of glycals and 1,2-cyclopropanated sugars.
and modified sugars.[1–3] As summarized in Scheme 1, the a- or b-1,2-cyclopro-
panated sugars IV can be prepared stereoselectively from the glycals I, and all
can be readily converted to the corresponding haloglycosyl acetates or halohy-
drins (II and V). These are in turn useful intermediates for producing a
variety of sugar derivatives: the 1-acetates are glycosyl donors in their own
right, or could be easily converted to other donors for preparation of glyco-
sides III or VI, with the 2-iodo substituent (in II) known to provide stereo-
directing anchimeric assistance in glycosylation reactions. In addition, the
iodo- or bromo-substituents are amenable to reductive cleavage to give 2-
deoxyglycosides or 2-C-methyl glycosides, and while it is known that
2-haloglycosides have limited utility in nucleophilic substitution reactions,
the primary halides in the 2-halomethyl substituents of V could be precursors
for further elaboration or extension of the C-2 side chain. Finally, the
halogenated sugars also provide the basis for radical-mediated introduction
of alkenyl substituents.
It was our efforts in this latter context[4] together with our interest in devel-
oping environmentally benign synthetic protocols[5] that led to an investigation
of an alternative method for the preparation of 2-deoxy-2-iodoglycopyranosyl
acetates from protected glycals, reported briefly in a preliminary publication.[6]
We have now further explored the scope and limitations of this procedure,
demonstrating its effectiveness on a wider range of glycal substrates and 1,2-
cyclopropanated sugars, its compatibility with acid-sensitive benzylidene
protecting groups, and the effective functionalization of a few simple noncarbo-
hydrate olefinic substrates. Herein we report the results along with full exper-
imental conditions and spectroscopic data of the compounds prepared.
The existing synthetic approaches to the 2-deoxy-2-iodoglycopyranosyl
acetates can be divided into three categories, summarized for the gluco-
and manno- cases in Scheme 2. The first, involving displacement of

Regioselective and Stereoselective Iodoacetoxylation
143
Scheme 2: Existing synthetic approaches to 2-deoxy-2-iodoglycopyranosyl acetates.
2-triflates from otherwise protected glycosyl acetates VII and VIII,[7]
provides access in good yields to the desired products IX and X, but
relies on selective preparation and careful handling of the moderately
stable 2-triflates. The second category proceeds via formation of iodohydrins
XII from glucals XI followed by acetylation to give mixtures of iodoacetates
IX and X.[1,8] In most cases this is limited by the low diastereoselectivity of
the iodohydrin formation, although in one instance[9] the exclusive for-
mation of 3,4,6-tri-O-acetyl-2-deoxy-2-iodo-a-D-mannose has been reported.
The third category provides direct access to the iodoacetates IX and X
from glucals XI using, in most cases, a source of electrophilic iodine
together with acetic acid as solvent or cosolvent.[2,3] A useful addition to
this latter category, and of relevance to our consideration of synthetic proto-
cols with low environmental impact, is Kirschning’s use of polymer-sup-
ported reagents for haloacetoxylation, which work efficiently when applied
to glycals.[10] Yields in all these methods are generally good to excellent,
and product selectivities range from a modest ꢀ2:1 to the synthetically
useful ꢀ11:1 in favor of the a-manno-configuration, achieved with the
CAN/NaI/AcOH procedure.[2] The regio- and stereoselectivities have been
extensively discussed, with the observed a-manno-selectivities rationalized
in terms of the favored irreversible formation of the bridged iodonium inter-
mediate on the b-face, due to its steric demands and its tendency not to equi-
librate to oxocarbenium and other intermediates as is the case for the
corresponding bromonium or chloronium species. Concerted a-face nucleo-
philic attack at the anomeric carbon and cleavage of the C-1 to iodine
bond leads to the formation of a-manno-derivatives. In contrast, selectivity
in favor of the gluco-isomer results when tert-butyldiphenylsilyl protecting
groups are used, and has been explained[11] in terms of the preference in
this glycal for the 5H4 conformation, which minimizes significant steric
interactions of the bulky silyl groups but also restricts access of the electro-
phile to the b-face of the glucal.

D. W. Gammon et al.
144
RESULTS AND DISCUSSION
Our approach to the direct halo-acetoxylation of glycals centered on the gener-
ation of iodonium ion equivalents through the oxidation of readily available
iodide salts. The synthetic possibilities of iodination of organic substrates
with halide salts in the presence of hydrogen peroxide and a catalyst have
been highlighted,[1,12,13] and we have shown previously that under these con-
ditions glycals are readily converted to iodohydrins or methyl-2-deoxy-2-halo-
glycosides, the latter with methanol as solvent. While this heterogeneously
catalyzed procedure is attractive, expansion of the synthetic utility by attempt-
ing direct glycosylations by combining glycals with more complex glycosyl
acceptors in the reaction mixture in non-nucleophilic solvents was not success-
ful. The halohydrins can, of course, be activated further in an additional step to
produce glycosyl donors, but it was recognized that a simple, efficient method
for direct and highly stereoselective conversion to 2-iodo-glycosyl acetates
would provide synthetically useful intermediates for the preparation of C-2
modified glycosides.
To this end a series of protected glucals were prepared from tri-O-acetyl-D-
glucal (1) as outlined in Scheme 3. These were chosen in order to evaluate not
only the tolerance of the protecting groups to the reaction conditions, but also
the steric and stereoelectronic impact of electron-withdrawing (acetyl),
electron-donating (benzyl, silyl), sterically demanding (bulky silyl), and
Scheme 3: (i) 50% aq NaOH, t-BuOH, n-Bu4NHSO4, 508C, then BnCl, 4.5 h, 50%; (ii) cat. NaOMe
in MeOH, rt, 0.5 h, 91%; (iii) TBDMSCl (1.1 equiv.), imidazole, DMF, rt, 1 h, 66%; (iv) Ac2O,
DMAP, Et3N, rt, 1 h, 90%; (v) NaH, n-Bu4NI, BnBr in THF, rt, 15 h, 70%; (vi) TBDMSCl (3.1 equiv.),
imidazole, DMF, rt, 15 h, 85%; (vii) PhCH(OMe)2, TsOH, DMF, rt, 15 h, 41%.

Regioselective and Stereoselective Iodoacetoxylation
145
conformationally restrictive (4,6-O-benzylidene) groups on the reaction
outcomes. Benzylated glucal 2 was prepared directly in a one-pot procedure
from 1.[14a] Deacetylation of 1 gave glucal 3, which, upon treatment with one
equivalent of TBDPSCl, gave the 6-O-silyl derivative 4, which was converted
to either its acetylated (5),[14b,c] benzylated (6),[14b,c] or silylated (7)[14b] form
by standard methods. Glucal 3 was also converted to its 4,6-O-benzylidene
derivative 8 and acetylated to give 9.[14d,e]
In a first attempt at direct oxidative iodination/acetylation (Scheme 3), we
treated tri-O-acetyl-D-glucal (1) and tri-O-benzyl-D-glucal (2) with NH4I and
50% aqueous H2O2 in acetic acid, using conditions reported to achieve easy
iodination of phenol[15,16] and also analogous to those reported by Barluenga
et al.[1] The desired 2-iodoacetates were indeed formed but were accompanied
by significant amounts of the corresponding iodohydrins. However, addition
of acetic anhydride to the reaction mixture ensured clean and selective conver-
sion to the iodoacetates 10a,b or 11a,b, while the further modification of intro-
ducing acetonitrile as solvent with concomitant reduction of the amounts of
Ac2O and AcOH allowed for lowering of the reaction temperature without
the solution freezing. The latter modification followed observations that low
temperatures favored high stereoselectivities. Further optimizations estab-
lished that little more than one equivalent each of the iodide and the oxidant
H2O2 was sufficient to realize full conversion of substrates in most instances,
thus demonstrating excellent atom economies in this reaction.
A full summary of the transformations of the glycals is presented in
Scheme 4 and Table 1. These results show the effective conversion of a range
of protected glucals (1, 2, 5, 6, 7, and 9) and a benzylated galactal (19)[14a] to
the corresponding 2-deoxy-2-iodoglycosylacetates. In all cases complete conver-
sion of the starting glycal was achieved, and products were identified by 1H and
13C NMR spectroscopy after chromatographic separation.
In reactions of protected glucals, only the 1,2-trans addition products were
detected, and in accordance with previous findings[2] the a-manno products
predominated except in the case of the per-O-silylated derivatives 14
(Table 1, entry 5).[2] Interestingly, the highest selectivity toward the
a-manno product was observed when the bulky silyl group was present only
on O-6 (substrates 5 and 6), while protection as a conformationally constrained
4,6-O-benylidene acetal (9) led to loss of selectivity, although the manno-
product still predominated and 1,2-trans addition took place exclusively. The
product distribution in the reaction of benzylated galactal 19 was similar to
previously reported results, with a 3:1 ratio of the talo- to galacto-isomers.
The a-talose 20a was the major product, representing concerted b-face
addition of the iodonium species and a-attack by the nucleophile, while the
mixture of galacto-isomers formed as minor products attested to a different
mechanism involving approach of the electrophile from the a-face and an oxo-
carbenium ion intermediate.

D. W. Gammon et al.
146
Scheme 4: (i) NH4I, H2O2, Ac2O, AcOH/CH3CN (1:1), 08C ! rt, ,2 h; (ii) NH4I, H2O2, Ac2O,
AcOH/CH3CN (1:1), 608C, 15 h; (iii) 50% aq NaOH, t-BuOH, n-Bu4NHSO4 in benzene, 508C;
then BnCl in benzene over 4.5 h, 54%.
The reaction conditions were notably tolerant of a range of protecting
groups, including the acid-sensitive benzylidene acetal (reaction (b) in
Scheme 4). The selectivities and yields in this mild procedure compared
very favorably with reported methods, with those obtained with benzyl or
silyl protecting groups being the best yet reported. Interestingly, formation
of silylated 2-iodo derivatives 14a,b using NIS in AcOH required heating at
100ºC for 10 min,[11] whereas in the protocol described here the reaction pro-
ceeded at room temperature within 2 h. In general, we observed that selectiv-
ities were dependent on temperature, with lower temperatures favoring
a-manno selectivity, although cooling below 0ºC led to unacceptably slow
reactions.
The possibility of using this methodology for bromoacetoxylation reactions
was demonstrated by replacement of NH4I with NH4Br in reactions of acetyl-
ated and benzylated glucals 1 and 6 (Scheme 4 and entries 6 and 7 in Table 1),
with the bromoacetoxylation being less stereoselective as expected from earlier
findings. NaI was also evaluated as an iodide source instead of NH4I in the

Regioselective and Stereoselective Iodoacetoxylation
147
Table 1: Yields and selectivities in the iodoacetoxylation of
protected glucals (see Scheme 3).
Entry
Substrate
Products
10a, 10b
Yield (%)
Ratioa
1
2
3
4
5
6
7
8
9
10
11
12
13
1
2
5
6
7
6
1
9
19
22
24
27
29
85
83:17
91:9
93:7
11a, 11b
12a, 12b
13a, 13b
14a, 14b
15a, 15b
16a, 16b
17a, 17b
20a, 20b, 20c
23a, 23b
25a, 25b
28
100
100
95
94
70
82
88
96
100
96
93:7
17:83
25:75
60:40
66:34
75:5:20
60:40
66:34
—
90
67
30
—
aDetermined from 1H NMR of the reaction products before separation.
conversion of acetylated glucal 1 to 10a,b. In this instance, an improved stereo-
selectivity of 7:1 in favor of 10a was observed but the yield (64% overall) was
inferior and the 1H NMR spectrum of the reaction products provided
evidence for inseparable, hitherto unidentified products.
The final set of substrates examined for reactivity under these iodoacetox-
ylation conditions were the protected a-1,2-cyclopropanated sugars 22 and 24
and their b-counterpart 26. Benzylated derivative 22 was prepared from ben-
zylated glucal 2 using the dichlorocarbene methodology described by
Nagarajan.[17] The preparation of acetylated derivative 24 from acetylated
D-glucal has been reported, but yields are low and limited spectroscopic data
provided for the product.[18] We found that a more efficient preparation of
this compound was achieved by subjecting benzyl-protected dichlorocyclopro-
panated derivative 21 to Ca/NH3 reduction followed by immediate acety-
lation.[19] The structure of 24 was then fully verified by 1H and 13C NMR
experiments. The b-cyclopropanated sugar 26 was prepared by Simmons-
Smith cyclopropanation of benzylated glucal 2.[20]
The NIS- and NBS-mediated openings of these and related cyclopropanes in
the presence of simple alcohols have been reported,[17,21] but the direct prep-
aration of the corresponding glycosyl acetates has not. The a-cyclopropanated
derivatives were accordingly treated under the standard conditions described
above (Sch. 5) to produce, respectively, the novel 2-C-iodomethyl glycosyl
acetates 23a,b and 25a,b in excellent yields. The structures of these products
were established with the help of NMR spectroscopy. The anomeric protons of
23a,b resonated as doublets in the appropriate downfield region at dH 6.36
and 5.59 with the coupling constants of 3.6 Hz and 8.4 Hz, respectively,
suggesting the former is the a-anomer and the latter the b-anomer. Further

D. W. Gammon et al.
148
Scheme 5: (i) 50% aq NaOH, CHCl3, Bn(Et)3NCl, 358C, 4 h, 73%; (ii) LAH in THF, 8 days, 75%;
(iii) a. Ca, liq. NH3, 10 min; (iv) Ac2O, pyridine, rt, 15 h, 60% (over two steps); (v) NH4I, H2O2,
Ac2O, AcOH/CH3CN (1:1), 08C ! rt, ,1 h, 100% (23a : 23b ¼ 3 : 2); (vi) NH4I, H2O2, Ac2O,
AcOH/CH3CN (1:1), 608C, 15 h, 95% (25a : 25b ¼ 7:3); (vii) Zn, CuCl2, CH2I2, AcCl in ether, 408C,
2 h, 95%.
1
crucial H NMR evidence for opening of the cyclopropyl ring concerned the
signals for H-7a and H-7b. They appeared as doublets of doublets in the region
between dH 2.60 and 3.80, which was considerably further downfield than the
multiplet for the C-7 protons at dH 0.70 in the spectrum of the parent cyclopro-
panated compound 22. The NMR spectrum of 25a,b showed a similar pattern of
signals. In addition, a DEPT spectrum of iodoacetates 23a,b and 25a,b con-
firmed that the iodinated C-7 was a methylene and not a methine carbon, indi-
cating that ring opening had taken place as opposed to ring expansion.
These results therefore represent a simple entry to variously protected
glycosyl donors, which incorporate a synthetically useful iodomethyl substituent
at the 2-position. The b-cyclopropanated derivative 26 did not, however, react
under these conditions, a result that is consistent with previous observations
of its sluggish reactivity toward electrophilic opening due to steric hindrance.[17]
The broader generality of the iodoacetoxylation reaction was briefly
explored by successfully converting styrene (27) and indene (29) to their
corresponding iodoacetates 28 and 30 (Sch. 6). However, attempts to form
1,2-iodoacetates from the less reactive olefins such as those in cholesterol
and cholest-5-ene were not successful, with no evidence for reaction under
the standard iodoacetoxylation conditions used for the glycals.
Concerning the proposed mechanism and stereoselectivity of the reactions,
we consider firstly the generation of the active reagents. While it is presumed
that hypoiodous acid HOI is present, the observation of a brown/yellow color in
the reaction solutions upon addition of H2O2 to the other reactants suggests the
presence of molecular I2, formed either by reaction of I2 with H2O2 under acidic
conditions[22–25] or by reaction of I2 with peracetic acid, generated upon

Regioselective and Stereoselective Iodoacetoxylation
149
Scheme 6: (i) NH4I, H2O2, Ac2O/AcOH, CH3CN (solvent), 08C ! rt, ,1 h.
addition of H2O2 to acetic anhydride in the presence of acetic acid.[26] The
reaction then presumably proceeds by addition of Iþ to the olefin, or by rapid
formation of a p-complex between the olefin and I2 followed by a rate-
determining abstraction of I2 by the peracetic acid.[26] The high degree of
stereoselectivity in solvolysis of the resulting iodonium species and the fact
that in the absence of acetic anhydride the iodoacetates predominate over iodo-
hydrins suggest that acetic acid attacks the iodonium species directly, probably
in a concerted process. The presence of an excess of acetic anhydride ensures
that the concentration of water in the reaction mixture is minimized,
allowing for successful addition of the acetate or acetic acid to the cyclic
iodonium species.
The stereoselectivities observed are generally in agreement with reported
studies on addition of electrophilic halogen species to the glycals. The stereo-
chemistry of addition of electrophiles to glycals has been extensively investi-
gated. The face selectivity is dependent inter alia on the nature and steric
demand of the electrophile, the substitution patterns in the glycal as well as
the electron-withdrawing or electron-donating character of substituents,
stereoelectronic effects, and solvent and other reaction parameters. Our
iodoacetylation results are in agreement with the widely observed phenomenon
of b-face selectivity of iodonium species to glucal derivatives and concerted
additions of electrophile and nucleophile. Figure 1 illustrates the confor-
mational possibilities for the glycals: with the exception of the silylated deriva-
tive 7 (R ¼ TBDPS), the 4H5 half-chair conformation I is expected to
predominate for the glucals, and while b-face addition of iodonium species is
unexpected on steric grounds alone, it would be stereoelectronically favored
in that a chair-like transition state would ensue. This, together with the
fact that a-attack of the nucleophile is favored due to the stereoelectronic
a-anomeric effect, accounts for the dominance of a-manno products. In the
Figure 1: Conformational preferences of glycals.

D. W. Gammon et al.
150
case of 7 (R ¼ TBDPS), the 5H4 half-chair conformation is thought to predomi-
nate to alleviate steric interactions of the substituents, with consequent
lowering of selectivity of the addition. In galactal derivatives the energy differ-
ences between conformation III and IV may not be as large, but the pseudo-
axial substituent at C-4 in III will provide steric hindrance to the b-face
addition. This is reflected in the resulting 3:1 ratio of talo- to galacto-isomers
resulting from benzylated galactal 19 compared to the 91:9 ratio of manno-
to gluco-isomers resulting from benzylated glucal 2. Reactions involving
bromine electrophiles are known to proceed via a different mechanism, with
oxocarbenium ion intermediates favored over cyclic bromonium ion intermedi-
ates. In our case the observation of exclusive 1,2-trans addition products seems
to suggest a concerted addition of electrophile and nucleophile, rather than the
existence of a long-lived oxocarbenium intermediate. This would almost cer-
tainly have given rise to a-gluco products due to the anomeric effect, but
these were not observed. It seems therefore that the highly polar reaction con-
ditions favor the concerted pathway.
In summary, we have shown that the simple, cost-effective, and environ-
mentally benign combination of NH4I (or NH4Br), 50% aq. H2O2, and Ac2O/
AcOH in CH3CN at low temperatures achieves efficient and highly stereoselec-
tive haloacetoxylation of protected glycals and a-1,2-cyclopropanated sugars.
EXPERIMENTAL
Solvents were dried according to standard methods and freshly distilled.
Commercial reagents were used without further purification. Reactions were
monitored by thin layer chromatography (TLC) on aluminum-backed Merck
silica gel 60 F254 plates using an ascending technique. The plates were visual-
ized by spraying with ceric ammonium sulphate in 8 M sulphuric acid or a 1:1
solution of 5% p-anisaldehyde in ethanol and 10% sulphuric acid in ethanol
baking at 1508C. Gravity column chromatography was done on Merck silica
gel 60 (70–230 mesh). Melting points were determined using a Reichert-
Jung Thermovar hot-stage microscope and are uncorrected. Optical rotations
were determined on a Perkin-Elmer 141 polarimeter in chloroform solutions
unless otherwise stated. The concentration c refers to g/100 mL. Infrared
spectra were recorded using a Perkin-Elmer Spectrum One FT-IR spec-
trometer. Proton nuclear magnetic resonance (1H NMR) spectra were
recorded, unless otherwise specified, as deuteriochloroform solutions using tet-
ramethylsilane as an internal standard on a Varian Mercury 300 MHz or a
Varian Unity 400 MHz spectrometer. Carbon-13 nuclear magnetic resonance
(13C NMR) spectra were recorded on the same instruments at 75 or 100 MHz
using tetramethylsilane as an internal standard. Chemical shifts are
reported in ppm. Elemental (C, H, N) analyses were carried out using a

Regioselective and Stereoselective Iodoacetoxylation
151
Thermo Flash 1112 Series analyzer. Low-resolution FAB mass spectra were
recorded on a VG70 SEQ micromass spectrometer.
General Iodoacetoxylation Procedure
To a solution of a glycal (0.37 mmol) or 1,2-cyclopropanated sugar in AcOH/
CH3CN (1:1, 2 mL) was added NH4I (0.44 mmol) and Ac2O (0.5 mL) and the
resulting reaction mixture was allowed to cool to 08C. Fifty percent aq H2O2
(0.44 mmol) was added and the solution was stirred at 08C (or at 608C if necess-
ary) until TLC showed the reaction to be complete. A solution of sodium thio-
sulphate (0.1 M) was then added until the brownish color disappeared, and
the solution was cooled in an ice-water bath before adding 10% aq NaOH
until the solution became slightly basic. The resultant mixture was extracted
with ethyl acetate, and the combined organic phases were washed successively
with water, 10% sodium thiosulfate, and brine; dried over MgSO4; and concen-
trated. The diastereoisomers were separated by column chromatography on
silica gel using a mixture of ethyl acetate and petroleum ether as eluent.
The following compounds were prepared using the foregoing iodoacetoxyla-
tion procedure:
From tri-O-acetyl-D-glucal (1): 1,3,4,6-tetra-O-acetyl-2-deoxy-2-iodo-a-D-man-
nopyranose (10a)[7,22] (71%) and 1,3,4,6-tetra-O-acetyl-2-deoxy-2-iodo-b-D-glu-
copyranose (10b)[7,22] (14%).
From tri-O-benzyl-D-glucal (2): 1-O-acetyl-3,4,6-tri-O-benzyl-2-deoxy-2-iodo-
a-D-mannopyranose (11a)[1] (91%) and 1-O-acetyl-3,4,6-tri-O-benzyl-2-deoxy-
2-iodo-b-D-glucopyranose (11b),[1] colorless crystals, m.p. 90–958C (lit.1
reported as oil) (1%).
From 6-O-tert-butyldiphenylsilyl-3,4-di-O-acetyl-D-glucal (5): 1,3,4-tri-O-acetyl-
2-deoxy-2-iodo-6-O-tert-butyldiphenylsilyl-a-D-mannopyranose (12a) (93%),
colorless crystals, m.p. 153–1558C; [a]D ¼ þ31.9 (c 1.0, CHCl3); dH (CDCl3,
300 MHz): 7.77–7.34 (m, 10H, 2 ꢀ Ph), 6.45 (d, 1H, J ¼ 1.5 Hz, H-1), 5.63
(t, 1H, J ¼ 9.6 Hz, H-4), 4.60 (dd, 1H, J ¼ 4.2 and 9.6 Hz, H-3), 4.52 (dd, 1H,
J ¼ 1.5 and 4.2 Hz, H-2), 3.98–3.92 (m, 1H, H-5), 3.72 (d, 2H, J ¼ 2.7 Hz, H-6a
and H-6b), 2.12, 2.09, 1.93 (3s, 9H, 3 ꢀ CH3CO2), 1.08 (s, 9H, Me3C-Si); dC
(CDCl3, 100 MHz): 170.0, 169.0, 168.2 (3 ꢀ CH3CO2), 135.8, 135.7, 133.2, 133.1,
129.7, 129.6, 127.6 (2 ꢀ Ph), 95.0 (C-1), 74.0 (C-5), 69.2 (C-3), 67.1 (C-4), 62.0
(C-6), 27.3 (C-2), 26.7 (Me3C-Si), 20.9, 20.8, 20.5 (3 ꢀ CH3CO2), 19.2 (Me3C-Si).
IR (CHCl3): 1751 cm21. Anal. calcd for C28H35IO8Si: C, 51.38; H, 5.39. Found:
C, 51.42; H, 5.31. LRFAB MS calcd for C28H35IO8Si [M-OOAc]þ 595.6, found
594.8; and 1,3,4-tri-O-acetyl-2-deoxy-2-iodo-6-O-tert-butyldiphenylsilyl-b-D-glu-
copyranose (12b), (7%), white crystals, m.p. 149–1568C; [a]D ¼ þ44.0 (c 1.0,

D. W. Gammon et al.
152
CHCl3); dH (CDCl3, 300 MHz): 7.67–7.33 (m, 10H, 2 ꢀ Ph), 5.87 (d, 1 H,
J ¼ 9.3 Hz, H-1), 5.30 (dd, 1H, J ¼ 9.3 and 11.2 Hz, H-4), 5.12 (t, 1H, J ¼ 9.3 Hz,
H-3), 3.98 (dd, 1H, J ¼ 9.3 and 11.0 Hz, H-2), 3.80–3.65 (m, 3H, H-5, H-6a and
H-6b), 2.18, 2.09, 1.89 (3s, 9H, CH3CO2), 1.04 (s, 9H, Me3C-Si); dC (CDCl3,
100 MHz): 169.6, 169.3, 168.4 (3 ꢀ CH3CO2), 135.7, 135.6, 133.1, 129.7, 129.7,
127.7, 127.6, 127.5 (2 ꢀ Ph), 94.0 (C-1), 75.7, 75.4, 68.8, 62.2 (C-3, C-4, C-5 and
C-6), 29.7 (C-2), 26.7 (Me3C-Si), 20.7, 20.6, 20.5 (3 ꢀ CH3CO2), 19.2 (Me3C-Si);
IR (CHCl3): 1759 cm21. Anal. calcd for C28H35IO8Si: C, 51.38; H, 5.39.
Found: C, 51.50; H, 5.55. LRFAB MS calcd for C28H35IO8Si [M–7H]þ 647.6,
found 647.2.
From 6-O-tert-butyldiphenylsilyl-3,4-di-O-benzyl-D-glucal (6): 1-O-Acetyl-3,
4-di-O-benzyl-2-deoxy-2-iodo-6-O-tert-butyldiphenylsilyl-a-D-mannopyranose
(13a), (88%), colorless oil, [a]D ¼ þ55.2 (c 1.0, CHCl3); dH (CDCl3, 400 MHz):
7.77–7.18 (m, 20H, 4 ꢀ Ph), 6.45 (d, 1H, J ¼ 1.6 Hz, H-1), 4.97 (d, 1H,
J ¼ 10.4 Hz, CH2Ph), 4.74 (d, 1H, J ¼ 11.6 Hz, CH2Ph), 4.65 (d, 1H,
J ¼ 10.4 Hz, CH2Ph), 4.57 (d, 1H, J ¼ 11.6 Hz, CH2Ph), 4.48 (dd, 1H, J ¼ 1.6
and 4.4 Hz, H-2), 4.26 (t, 1H, J ¼ 9.4 Hz, H-4), 3.40 (dd, 1H, J ¼ 3.2 and
11.6 Hz, H-6a), 3.88–3.82 (m, 2H, H-5 and H-6b), 3.25 (m, 1H, H-3), 2.01
(s, 3H, CH3CO2), 1.11 (s, 9H, Me3C-Si); dC (CDCl3, 100 MHz): 168.5
(CH3CO2), 135.9, 135.7, 129.6, 129.6, 128.5, 128.4, 128.1, 128.0, 127.9,
127.7, 127.6, 127.5 (4 ꢀ Ph), 95.8 (C-1), 75.6, 75.5, 75.4, 75.1, 71.2 (C-3, C-4,
C-5, and 2 ꢀ CH2Ph), 62.2 (C-6), 31.2 (C-2), 26.9 (Me3C-Si), 20.8 (CH3CO2),
19.3 (Me3C-Si). IR (CHCl3): 1750 cm21. Anal. calcd for C38H43IO6Si: C,
60.80; H, 5.77. Found: C, 61.14; H, 5.94. LRFAB MS calcd for C38H43IO6Si
[M–2H]þ 748.7, found 747.9; and 1-O-acetyl-3,4-di-O-benzyl-2-deoxy-2-iodo-
6-O-tert-butyldiphenylsilyl-b-D-glucopyranose (13b), (7%), colorless oil,
[a]D ¼ þ25.3 (c 1.0, CHCl3); dH (CDCl3, 400 MHz): 7.70–7.21 (m, 20H,
4 ꢀ Ph), 5.84 (d, 1H, J ¼ 9.6 Hz, H-1), 4.98 (d, 1H, J ¼ 10.4 Hz, CH2Ph),
4.91 (d, 1H, J ¼ 4.2 Hz, CH2Ph), 4.89 (d, 1H, J ¼ 4.2 Hz, CH2Ph), 4.77
(d, 1H, J ¼ 10.4 Hz, CH2Ph), 4.00 (dd, 1H, J ¼ 9.6 and 10.4 Hz, H-2), 3.95
(m, 2H, H-6a and H-6b), 3.87 (t, 1H, J ¼ 9.0 Hz, H-4), 3.78 (dd, 1H, J ¼ 9.0
and 10.4 Hz, H-3), 3.53–3.49 (m, 1H, H-5), 2.19 (s, 3H, CH3CO2), 1.05
(s, 9H, Me3C-Si); dC (CDCl3, 100 MHz): 168.8 (CH3CO2), 135.9, 135.5, 129.6,
126.5, 128.5, 128.4, 128.2, 128.0, 127.9, 127.7, 127.6, 127.5 (4 ꢀ Ph), 94.4
(C-1), 85.4 (C-3), 78.9 (C-4), 76.6 (C-5), 75.8, 75.1 (2 ꢀ CH2Ph), 62.0 (C-6),
30.5 (C-2), 26.8 (Me3C-Si), 20.7 (CH3CO2), 19.3 (Me3C-Si). IR
(CHCl3): 1760 cm21. Anal. calcd for C38H43IO6Si: C, 60.80; H, 5.77. Found:
C, 61.18; H, 5.75. LRFAB MS calcd for C38H43IO6Si [M–H]þ 750.7,
found 749.0.
From 3,4,6-tri-O-tert-butyldiphenylsilyl-D-glucal (7): 1-O-Acetyl-2-deoxy-2-iodo-
3,4,6-tri-O-tert-butyldiphenylsilyl-a,b-D-glucopyranose (14a, 14b)[11] (94%,

Regioselective and Stereoselective Iodoacetoxylation
153
a:b ¼ 17:83); pure crystalline 14b was obtainedafter separationof the mixture on
a column of silica gel; m.p. 1538C (not reported in literature).
From 3-O-acetyl-4,6-O-benzylidene-D-glucal (9): 1,3-di-O-acetyl-4,6-O-benzyli-
dene-2-deoxy-2-iodo-a-D-manno and -b-D-glucopyranoses (17a and 17b) (86%,
a-manno:b-gluco ¼ 56:44); dH (CDCl3, 300 MHz): 7.49–7.34 (m, 5H, Ph), 6.40
(d, 0.56H, J ¼ 1.0 Hz, H-1 of 17a), 5.98 (d, 0.44H, J ¼ 9.3 Hz, H-1 of 17b), 5.61
(s, 0.56H, H-7 of 17a), 5.53–5.47 (m, 0.88H, H-3 and H-7 of 17b), 4.69 (dd,
0.56H, J ¼ 1.3 and 4.4 Hz, H-2 of 17a), 4.51 (dd, 0.56H, J ¼ 4.6 and 9.7 Hz, H-3
of 17a), 4.38–3.56 (m, 4.44H), 2.17, 2.16, 2.14 (3s, 6H, CH3CO2); dC (CDCl3,
75 MHz): 169.9, 169.1, 168.3 (CH3CO2), 136.8, 136.6, 130.8, 129.2, 129.2, 128.8,
128.3, 128.2, 126.2, 126.1 (Ph), 102.1 (C-7 of 17a), 101.6 (C-7 of 17b), 95.7 (C-1
of 17a), 94.4 (C-1 of 17b), 79.4, 76.6, 73.7, 68.4, 68.2, 67.6, 67.5, 66.8, 30.4, 29.2,
21.1, 20.9, 20.8, 20.6. Anal. calcd for C17H19IO7: C, 44.17; H, 4.14. Found: C,
44.77; H, 3.98. LRFAB MS calcd for C17H19IO7 [M–2H]þ 460.2, found 460.0.
From tri-O-benzyl-D-galactal (19): 1-O-acetyl-3,4,6-tri-O-benzyl-2-deoxy-2-iodo-
a-D-talopyranose (20a) and 1-O-acetyl-3,4,6-tri-O-benzyl-2-deoxy-2-iodo-a,b-D-
galactopyranoses (20b, 20c),[3,27] (96%, a-talo:b-galacto:a-galacto ¼ 15:1:4,
colorless oil).
From 3,4,6-tri-O-benzyl-1,5-anhydro-2-deoxy-1,2-C-methylene-D-glycero-D-gulo-
hexitol (22): 1-O-acetyl-3,4,6-tri-O-benzyl-2-deoxy-2-C-iodomethyl-a- and -b-D-
glucopyranoses (23a, 23b) (inseparable, colorless oil, 100%, a:b ¼ 2:3); dH
(CDCl3, 400 MHz): 7.35–7.16 (m, 15H, 3 ꢀ Ph), 6.36 (d, 0.44H, J ¼ 3.6 Hz,
H-1 of 23a), 5.59 (d, 0.56H, J ¼ 8.4 Hz, H-1 of 23b), 4.99 (d, 0.56H,
J ¼ 10.8 Hz), 4.95 (d, 0.44H, J ¼ 11.2 Hz), 4.84–4.58 (m, 4H), 4.50 (dd, 1H,
J ¼ 4.4 and 12.0 Hz), 3.89–3.65 (m, 4.4H), 3.60 (ddd, 0.56H, J ¼ 2.0, 3.2 and
9.6 Hz), 3.54 (dd, 0.56H, J ¼ 3.0 and 10.2 Hz), 3.46 (dd, 0.44H, J ¼ 3.6 and
10.0 Hz), 3.28 (dd, 0.56H, J ¼ 3.0 and 10.2 Hz), 2.85 (dd, 0.44H, J ¼ 10.2
and 11.0 Hz), 2.24 (tt, 0.44H, J ¼ 3.4 and 10.8 Hz, H-2 of 23a), 2.14 (s, 1.68H,
CH3CO2 of 23b), 2.10 (s, 1.32H, CH3CO2 of 23a), 1.56–1.50 (m, 0.56H, H-2 of
23b); dC (CDCl3, 100 MHz): 168.8 (CH3CO2), 168.7 (CH3CO2), 138.1, 137.8,
128.4, 128.3, 128.2, 127.9, 127.8, 127.7, 127.6 (Ph), 94.9 (C-1 of 23b), 93.6 (C-1
of 23a), 81.3, 80.7, 78.8, 78.4, 75.5, 75.4, 74.8, 74.6, 73.6, 73.5, 73.3, 68.1, 46.6
(C-2 of 23a), 45.0 (C-2 of 23b), 20.8 (CH3CO2 of 23b), 20.7 (CH3CO2 of 23a),
4.1 (C-7 of 23a), 0.6 (C-7 of 23b). IR (CHCl3): 1759 cm21. Anal. calcd for
C30H33IO6: C, 58.45; H, 5.40. Found: C, 57.99; H, 5.28. LRFAB MS calcd for
C30H33IO6 [M–3H]þ 613.5, found 612.9.
From styrene (27): 1-acetoxy-2-iodo-1-phenylethane (28)[28] (67%).
From indene (29): trans-1-acetoxy-2-iodo-indane (30)[10] (90%).

D. W. Gammon et al.
154
3,4,6-Tri-O-acetyl-1,5-anhydro-2-deoxy-1,2-C-methylene-D-glycero-D-gulo-hexitol
(24): a solution of 21 (300 mg, 0.60 mmol) in dry THF (1 mL) was added dropwise to
a stirred solution of calcium metal (60 mg, 1.50 mmol) in predried liquid ammonia
(ꢀ10 mL) at 2788C and the reaction mixture was stirred under reflux for 10 min.
The blue color was discharged by careful addition of ammonium chloride and the
ammonia was allowed to evaporate at rt. The solid residue was then dispersed in
pyridine (10 mL) and treated with acetic anhydride (5 mL) and a catalytic
amount of DMAP. After stirring overnight at rt, the reaction was quenched by
addition of water and the aqueous phase was extracted several times with ethyl
acetate. The combined organic phases were then washed with 1N aq HCl
solution, followed by water, and then dried over MgSO4. After filtration, the
solvent was evaporated in vacuo and the residue purified by column chromato-
graphy on silica gel (ethyl acetate/petroleum ether, 1:9) to give the title
compound 24 (103 mg, 60%) as a low viscous oil; [a]D ¼ þ26.6 (c 1.0, CHCl3); dH
(CDCl3, 300 MHz): 4.95 (dd, 1H, J ¼ 3.0 and 6.3 Hz, H-3), 4.83 (dd, 1H, J ¼ 4.5
and 6.3 Hz, H-4), 4.51 (dd, 1H, J ¼ 7.5 and 12.0 Hz, H-6a), 4.14 (dd, 1H, J ¼ 4.1
and 12.0 Hz, H-6b), 3.88–3.83 (m, 1H, H-5), 3.62 (dt, 1H, J ¼ 3.0 and 6.0 Hz,
H-1), 2.09, 2.08, 2.04 (3s, 9H, 3 ꢀ CH3CO2), 1.02–0.93 (m, 1H, H-2), 0.86 (tdd,
2H, J ¼ 4.6, 10.1, and 12.3 Hz, H-7a and H-7b); dC (CDCl3, 75 MHz): 170.6, 169.8,
169.7 (3 ꢀ CH3CO2), 73.7 (C-5), 70.2 (C-3), 69.6 (C-4), 62.4 (C-6), 48.8 (C-1), 21.0,
20.8, 20.7 (3 ꢀ CH3CO2), 13.7 (C-2), 11.1 (C-7). Anal. calcd for C13H18O7: C,
54.54; H, 6.34. Found: C, 54.68; H, 6.21.
From 3,4,6-Tri-O-acetyl-1,5-anhydro-2-deoxy-1,2-C-methylene-D-glycero-D-gulo-
hexitol (24): 1,3,4,6-tetra-O-acetyl-2-deoxy-2-C-iodomethyl-a and -b-D-glucopyra-
noses (25a and 25b) (colorless oil, 96%, a:b ¼ 3:7); dH (CDCl3, 400 MHz): 6.39
(d, 0.3H, J ¼ 3.6 Hz, H-1 of 25a), 5.65 (d, 0.7H, J ¼ 8.8 Hz, H-1 of 25b), 5.28–
5.16 (m, 1H, H-3), 5.12–4.99 (m, 1H, H-4), 4.35–4.24 (m, 1H, H-6a), 4.11–3.96
(m, 1.3H, H-6b and H-5 of 25a), 3.87–3.78 (m, 0.7H, H-5 of 25b), 3.22 (dd, 0.7H,
J ¼ 3.3 and 10.9 Hz, H-7a of 25b), 3.16–3.07 (m, 1H, H-7b of 25b and H-7a of
25a), 2.87 (t, 0.3H, J ¼ 10.6 Hz, H-7b of 25a), 2.40 (tt, 0.3H, J ¼ 3.6 and 10.8 Hz,
H-2 of 25a), 2.16, 2.15, 2.07, 2.06, 2.02, 2.01 (6s, 12H, CH3CO2), 1.85–1.75
(m, 0.7H, H-2 of 25b); dC (CDCl3, 100 MHz): 170.5, 170.4, 169.8, 169.6, 169.5,
168.4, 168.3, 94.7 (C-1 of 25b), 92.8 (C-1 of 25a), 72.8, 72.4, 72.0, 69.8, 69.0, 68.3
(C-3, C-4 and C-5), 61.7 (C-6), 45.4 (C-2 of 25a), 43.4 (C-2 of 25b), 20.8, 20.7,
20.6, 20.5 (CH3CO2), 0.43 (C-7 of 25b), –2.0 (C-7 of 25a). Anal. calcd for
C15H21IO9: C, 38.15; H, 4.48. Found: C, 38.55; H, 4.86.
1-O-Acetyl-3,4-di-O-benzyl-2-bromo-2-deoxy-6-O-tert-butyldiphenylsilyl-a,b-
D-mannopyranose (15a, 15b): To a solution of glucal 6 (488 mg, 0.86 mmol)
in AcOH/CH3CN (1:1, 24 mL) was added NH4Br (102 mg, 1.04 mmol),
Ac2O (0.9 mL), and 50% aq H2O2 (60 mL, 1.04 mmol). After stirring at rt
for 4 h, the reaction mixture was diluted with 0.1 M sodium thiosulfate

Regioselective and Stereoselective Iodoacetoxylation
155
solution, then cooled to 08C and 10% aq NaOH added until the solution
became slightly basic. The resultant mixture was extracted with ethyl
acetate and the combined organic phases were washed successively
with water and brine, dried over MgSO4, and concentrated to dryness.
The product mixture was separated by column chromatography on silica
gel (ethyl acetate/petroleum ether, 1:9) to give 15a and 15b as colorless
oils:
15a (106 mg, 17.5%), [a]D ¼ þ21.8 (c 1.0, CHCl3); dH (CDCl3, 400 MHz): 7.79–
7.23 (m, 20H, 4 ꢀ Ph), 6.40 (d, 1H, J ¼ 1.6 Hz, H-1), 5.00 (d, 1H, J ¼ 10.8 Hz,
CH2Ph), 4.79 (d, 1H, J ¼ 12.0 Hz, CH2Ph), 4.68 (t, 2H, J ¼ 11.4 Hz, CH2Ph),
4.38 (dd, 1H, J ¼ 1.8 and 3.8 Hz), 4.35 (t, 1H, J ¼ 9.4 Hz), 4.05 (dd, 1H,
J ¼ 3.2 and 11.6 Hz), 3.96 (dd, 1H, J ¼ 3.8 and 9.0 Hz), 3.90 (dd, 1H, J ¼ 1.6
and 11.2 Hz, H-2), 3.85–3.75 (m, 1H, H-5), 2.04 (s, 3H, CH3CO2), 1.13 (s, 9H,
Me3C-Si); dC (CDCl3, 100 MHz): 168.3 (CH3CO2), 138.2, 137.4, 135.8, 135.5,
133.6, 132.9, 129.5, 128.4, 128.3, 128.0, 127.9, 127.8, 127.6, 127.5 (4 ꢀ Ph),
94.2 (C-1), 76.7, 75.4, 75.3, 73.7, 71.3, 62.1 (C-3, C-4, C-5, C-6 and
2 ꢀ CH2Ph), 49.8 (C-2), 26.7 (Me3C-Si), 20.7 (CH3CO2), 19.2 (Me3C-Si). Anal.
calcd for C38H43BrO6Si: C, 64.85; H, 6.16. Found: C, 64.88; H, 6.34. LRFAB
MS calcd for C38H43BrO6Si [M]þ 703.7, found 703.1.
15b (318 mg, 52.5%), [a]D ¼ þ28.4 (c 1.0, CHCl3); dH (CDCl3, 400 MHz): 7.71–
7.22 (m, 20H, 4 ꢀ Ph), 5.78 (d, 1H, J ¼ 8.8 Hz, H-1), 5.01 (d, 2H, J ¼ 10.4 Hz,
CH2Ph), 4.93–4.88 (m, 2H, CH2Ph), 3.96–3.86 (m, 4H), 3.80 (dd, 1H, J ¼ 8.8
and 10.0 Hz, H-2), 3.53 (dt, 1H, J ¼ 2.4 and 9.6 Hz, H-5), 2.21 (s, 3H,
CH3CO2), 1.07 (s, 9H, Me3C-Si); dC (CDCl3, 75 MHz): 168.9 (CH3CO2), 137.8,
135.9, 135.6, 133.5, 132.9, 129.7, 129.6, 128.5, 127.7, 127.5 (4 ꢀ Ph), 93.6 (C-
1), 85.1, 78.5, 76.5, 76.3, 75.2 (C-3, C-4, C-5 and 2 ꢀ CH2Ph), 62.1 (C-6), 51.4
(C-2), 26.8 (Me3C-Si), 20.8 (CH3CO2), 19.3 (Me3C-Si). Anal. calcd for
C38H43BrO6Si: C, 64.85; H, 6.16. Found: C, 64.95; H, 6.03. LRFAB MS calcd
for C38H43BrO6Si [M]þ 703.7, found 703.0.
1,3,4,6-Tetra-O-acetyl-2-bromo-2-deoxy-a,b-D-mannopyranose (16a, 16b): Using
the procedure described above for the synthesis of 15a and 15b, bromoacetoxyla-
tionofacetylated glucal 1 at 608C afforded, as colorless oils, the separable bromoa-
cetates 16a (51%) and 16b (31%).[7,22]
ACKNOWLEDGEMENTS
We thank the NRF (South Africa) and the Ministry of the Flemish Community
(Flanders, Belgium) for financial support for this research under the RSA-
Flemish Community bilateral agreement.

D. W. Gammon et al.
156
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