Polymethylhydrosiloxane (PMHS): A convenient option for synthetic applications of the iodine/silane combined reagent - Straightforward entries to 2-hydroxyglycals and useful building-blocks of glucuronic acid and glucosamine

Article abstract of DOI:10.1002/ejoc.201201084

Polymethylhydrosiloxane (PMHS) proved to be a practically convenient alternative to triethylsilane in a large set of synthetic elaborations entailing the quick generation of glycosyl iodides with a iodine/silane combined reagent. In addition, the scope of this combined reagent was expanded to the especially fast generation of 2-acetoxyglycals, and the rapid synthesis of useful building-blocks of D-glucuronic acids and D-glucosamine. All the synthetic targets were obtained in especially short times either via one-pot procedures or through experimental sequences devoid of laborious chromatographical purifications of intermediates. Polymethylhydrosiloxane (PMHS) is a practically convenient alternative to triethylsilane in a large set of synthetic elaborations entailing the quick generation of glycosyl iodides with a iodine/silane combined reagent. Copyright

Full text of DOI:10.1002/ejoc.201201084

FULL PAPER
DOI: 10.1002/ejoc.201201084
Polymethylhydrosiloxane (PMHS): A Convenient Option for Synthetic
Applications of the Iodine/Silane Combined Reagent – Straightforward Entries
to 2-Hydroxyglycals and Useful Building-Blocks of Glucuronic Acid and
Glucosamine
Maddalena Giordano[a] and Alfonso Iadonisi*[a]
Dedicated to the memory of Professor Ernesto Fattorusso
Keywords: Synthetic methods / Carbohydrates / Silanes / Iodine
Polymethylhydrosiloxane (PMHS) proved to be a practically
convenient alternative to triethylsilane in a large set of syn-
thetic elaborations entailing the quick generation of glycosyl
iodides with a iodine/silane combined reagent. In addition,
the scope of this combined reagent was expanded to the es-
pecially fast generation of 2-acetoxyglycals, and the rapid
synthesis of useful building-blocks of
D-glucuronic acids and
D-glucosamine. All the synthetic targets were obtained in es-
pecially short times either via one-pot procedures or through
experimental sequences devoid of laborious chromatograph-
ical purifications of intermediates.
Very recently, the combination of iodine and polymethyl-
hydrosiloxane (PMHS) was found to promote the reductive
Ferrier rearrangement, a reaction that was promoted
equally effectively with iodine/triethylsilane.[11] The fact that
polymeric PMHS has a lower cost per silane unit than tri-
ethylsilane (about 7–10 times less expensive) spurred us to
evaluate this reagent in the wide repertoire of transforma-
tions previously mentioned. It should also be noted that
PHMS has some additional advantages: (a) it is regarded
as an easy to handle and environmentally friendly reducing
agent; (b) it is more stable to air and moisture than other
silanes; (c) it can be stored for long periods of time without
loss of activity.[12]
Introduction
In recent years, the iodine/triethylsilane reagent combina-
tion has proved to be a very effective tool for a wide range
of synthetic applications, and it can be used under simple
experimental conditions.[1] In this context, we have demon-
strated the successful application of this reagent combina-
tion to a large set of transformations in carbohydrate chem-
istry. Many of these transformations go via glycosyl iodide
intermediates, which can be quickly generated (generally in
a few minutes) by exposing 1-O-acetylated sugars to a mod-
erate excess of the two reagents (1.4 equiv.) in refluxing
CH2Cl2. It is reasonable to assume that HI generated in situ
is the actual promoter of the process. The crude glycosyl
iodides thus obtained can, in turn, be converted into a wide
variety of useful intermediates, such as 1,2-orthoesters,[2,3]
1,2-ethylidenes,[2] glycals,[2] thio- and selenoglycosides,[4,5]
estradiol glycosides,[6] 2-O-deprotected allyl glycosides,[7]
(selenophenyl)thioglycosides,[8,9] and glycosyl disulfides.[10]
Advantages associated with all of these applications include
the avoidance of chromatographic purification of the
glycosyl iodide intermediates, and the especially high reac-
tivity of these intermediates in the subsequent reactions.
In addition to establishing even more cost-effective pro-
cedures, another goal of the work reported in this paper was
to extend the scope of the iodine/silane-based procedures to
substrates and functional group manipulations that had not
previously been examined.
Results and Discussion
At the outset of this investigation, we examined the abil-
ity of the iodine/PMHS combined system to promote the
anomeric iodination of per-O-acetylated sugars. In this re-
action, the replacement of Et3SiH (1.4 equiv.) with PMHS
(1.4 equiv. silane units) resulted in very similar iodination
rates when keeping the same stoichiometric ratios of the
reagents. The reactions were complete in 5–10 min in re-
fluxing CH2Cl2 according to TLC analysis, starting from
[a] Dipartimento di Scienze Chimiche, Università degli Studi di
Napoli “Federico II”,
Via Cintia 4, 80126, Naples, Italy
Fax: +39-81-674393
E-mail: iadonisi@unina.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201084.
Eur. J. Org. Chem. 2013, 125–131
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
125

M. Giordano, A. Iadonisi
FULL PAPER
Scheme 1. Synthetic applications of the I2/PMHS system.
the diverse set of per-O-acetylated sugars shown in
Revisiting these synthetic sequences with the simple re-
Scheme 1. Having obtained these promising preliminary re- placement of triethylsilane by PMHS was rewarding, and
sults, a critical issue for the success of these modified condi- very good results were obtained in the synthesis of a wide
tions was to ascertain the reactivity of the resulting crude range of model products, such as 1,2-orthoester 1, 1,2-ethyl-
iodides in the wide range of protocols previously established idene 2, 1,2-glycal 3, alkylthioglycoside 4, symmetrical
with the iodine/Et3SiH system.
glycosyl disulfide 5, and phenyl thioglycoside 6 (Scheme 1).
Indeed, we had shown that iodides generated from the
These results show the versatility of this approach, as a
iodine/Et3SiH combination did not need to be chromato- varied set of saccharide building-blocks may be formed, but
graphically isolated, but could be obtained by a simple ex- the results also highlight the fact that it is feasible to use
tractive work-up, contaminated only by triethylsilane-de- structurally diverse per-O-acetylated starting materials, in-
rived by-products that proved to be inert in all the transfor- cluding gluco-, galacto-, or manno-configured hexoses, 6-de-
mations mentioned above. In the case of the synthesis of oxyhexoses, and disaccharides.
1,2-orthoesters and 1,2-ethylidenes, the two steps could be
Having proved the reliable reproducibility of a large set
even performed in a one-pot mode by simple addition of of established protocols at a lower cost, our research was
the requisite reagents to the iodination vessel (a preliminary next directed towards expanding the repertoire of applica-
change of solvent was required for 1,2-ethylidene synthe- itons of the iodine/silane reagent. The extension of the an-
sis).[2]
omeric iodination protocol to per-O-acetylated methyl
126
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 125–131

Applications of Iodine/Polymethylhydrosiloxane
Scheme 2. Anomeric iodination of glucuronic acid and subsequent synthetic transformations.
uronate 7 (Scheme 2) initially proved difficult, as expected
Another original application of the glycosyl iodide inter-
from the lower anomeric reactivity of uronic acid deriva- mediates that was pursued was the synthesis of allyl glycos-
tives. Indeed, exposure of 7 to I2 and Et3SiH (1.4 equiv. ides of glucosamine. The allyl group is a useful protecting
each) in refluxing dichloromethane resulted in only partial group for the anomeric position of sugars, due both to its
anomeric iodination. A simple and effective solution was chemical versatility and its stability to a wide range of con-
achieved by switching the solvent to the higher boiling 1,2- ditions. Anomeric allylation of N-protected amino sugars
dichloroethane (DCE) under reflux conditions. With this is commonly carried out under Fischer conditions, which
modification, the precursor was smoothly converted into requires prolonged reaction times and the use of toxic and
the corresponding iodide in about 30 min, and also under- high-boiling allyl alcohol as the solvent under refluxing
went the same transformation when PHMS was used conditions. Alternative approaches have been described in
(Scheme 2). Notably, the efficacy of the protocol was not which N-phthalimido precursor 11 (Scheme 3) was con-
influenced by the anomeric composition of 7, with the less verted into the corresponding β-allyl glycosides under the
reactive α-anomer also reacting under the reported condi- influence of SnCl4 or FeCl3.[16] Searching for alternative
tions.[13,14]
procedures that would avoid the use of moisture-sensitive
The utility of iodide intermediate 8 was demonstrated by promoters and tedious work-up procedures, we took advan-
its high-yielding conversion into orthoester 9 and thioglyco- tage of the rapid conversion of 11 into iodide 12 under the
side 10 (Scheme 2). The orthoester was easily obtained in a influence of the I2/PMHS system, which once again pro-
one-pot approach by addition to the iodination mixture of ceeded with a rate similar to the I2/Et3SiH reagent.[4]
MeOH, lutidine, and TBAB (tetrabutylammonium brom-
It has been described previously that iodide 12 may be
ide)[2] at room temp., and immediately re-submitting the transformed into 13 (Scheme 3) upon prolonged exposure
whole mixture to refluxing conditions. The thioglycosid- to an excess of toxic allyl alcohol (used as the solvent).[17]
ation steps were performed after a rapid extractive work-up We pursued an alternative strategy that would require much
of the crude iodide, similarly to the corresponding pro- lower amounts of allyl alcohol by aiming for the possible
cedures on other sugars.[4] As expected, the synthesis of activation of the iodide leaving group. In fact, the anomeric
thioethyl glycoside 10 took a longer time than had been allylation of 12 was achieved by adapting a recently re-
seen for sugars not oxidized at C-6 (ca 6 h vs. ca 1–2 h). ported procedure in which we showed that 2,3,4,6-tetra-O-
However, it should be noted that an alternative published acetylated glycosyl iodides can be O-allylated at the anom-
procedure for the synthesis of the same target required an eric position, with concomitant 2-O-deprotection, by acti-
even longer reaction time, and suffered from the limitation vation with substoichometric amounts (0.3 equiv.) of
that it worked only with the β-anomer of 7.[15]
BiBr3.[7] Under those conditions, a moderate excess of allyl
Scheme 3. Anomeric allylation of N-protected glucosamine derivatives.
Eur. J. Org. Chem. 2013, 125–131
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
127

M. Giordano, A. Iadonisi
FULL PAPER
Scheme 4. One-pot synthesis of 2-acetoxyglycals from the corresponding per-O-acetylated precursors.
alcohol (4 equiv.) was sufficient to obtain high yields of 1- related elimination schemes applied to thioglycosides[22]
O-allylated products. In addition, in the same study, we ob- using appropriate thiophilic reagents.[23] As both glycosyl
served that 2-O-deacylation was largely suppressed when 2- bromides and thioglycosides are commonly prepared from
O-benzoylated substrates were used.
the corresponding per-O-acetylated precursors, we searched
On this basis, the robust N-phthalimido group was ex- for a very streamlined approach to 2-acetoxyglycals based
pected to survive the same conditions, while providing a on an unprecedented one-pot sequence of anomeric iodin-
significant participation effect leading to a β-selective allyl- ation and base-promoted elimination. This sequence proved
ation. Exposure of intermediate 12 to allyl alcohol and a to be viable, and examples shown in Scheme 4 show that a
sub-stoichiometric quantity of BiBr3 resulted in the smooth simple addition of excess 1,8-diazabicyclo[5.4.0]undec-7-ene
generation of 13, exclusively as the β-anomer (Scheme 3). (DBU)[21b,21c] to the iodination mixtures at 0 °C results in
Interestingly, this reaction proceeded quickly enough at a very fast elimination. The procedure gave moderate to
room temp., whereas the BiBr3 activation of 2-O-acet- high yields of the 2-hydroxyglycal derivatives starting from
ylated glycosyl iodides conditions required reflux condi- a range of O-acetylated sugars, with a lower yield being
tions.[7]
recorded for glucuronate ester 9, presumably due to other
Due to the frequent use of N-Troc-protected glucosamine competing elimination pathways. The elimination procedure
building-blocks in oligosaccharide synthesis, the same se- proved to be less effective when applied to highly O-benzyl-
quence was applied to precursor 14 (in this case, only the ated model precursor 21, and only modest amounts of the
β-anomer was reactive in the iodination reaction),[6] and the desired glycal (i.e., 22)[24] could be detected in the resulting
final allylated product (i.e., 16) was obtained in almost the crude mixture. Interestingly, in this case, the main reaction
same yield as 13 (Scheme 3). In this latter sequence, the was the DBU-promoted reattachment of the acetate moiety
reaction time of the preliminary iodination step was short- to C-1, a process favoured by the enhanced anomeric elec-
ened by using DCE in place of dichloromethane.
trophilicity of highly O-benzylated sugars.[25]
Another result of this investigation was the development
of a very streamlined synthetic entry to per-O-acetylated 2-
hydoxyglycals. These derivatives are versatile building-
blocks that are amenable to a wide range of transforma-
tions,[18,19] and numerous applications of these compounds
Conclusions
In this paper, we have shown that polymethylhydrosilox-
in the synthesis of complex targets have also been de- ane (PMHS) can be a practically convenient alternative to
scribed.[20] These derivatives are commonly prepared either triethylsilane in a large set of synthetic transformations go-
by base-induced elimination of glycosyl bromides,[21] or by ing via glycosyl iodides, which can be quickly generated
128
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 125–131

Applications of Iodine/Polymethylhydrosiloxane
Synthesis of Glycal 3:[27] The crude glycosyl iodide residue from the
extractive work-up was dissolved in THF (2.5 mL), and Cp2Cl2Ti
(610 mg, 2.5 mmol) and manganese (50 mesh, 275 mg, 5 mmol)
were added at room temperature under argon. After completion of
the reaction (TLC), the mixture was concentrated and the residue
was purified by chromatography on silica gel (eluent: hexane/ethyl
acetate, 1:1).
Synthesis of Ethyl Thioglycosides 4 and 10:[28] Thiourea (114 mg,
1.5 mmol) was added to the crude glycosyl iodide residue from the
exctractive work-up, and the mixture was suspended in acetonitrile
(2 mL) and then heated to 60 °C. When TLC analysis indicated the
consumption of the iodide and the generation of a polar product
(see Schemes for the times), the vessel was cooled to room temp.,
and then ethyl iodide (160 μL, 2 mmol) and Et3N (0.55 mL,
4 mmol) were sequentially added. When the reaction was complete
(TLC), the mixture was concentrated under vacuum. The resulting
residue was dissolved in CH2Cl2, and the organic phase was washed
with water. The aqueous phase was then re-extracted with dichloro-
methane and the combined organic extracts were dried and concen-
trated in vacuo. The residue was purified by flash silica gel
chromatography (eluent: hexane/ethyl acetate mixtures).
using an iodine/silane reagent combination. PMHS has nu-
merous practical advantages, such as a low cost per silane
unit, ease of handling and storage, and a higher stability to
air and moisture than other silanes.
In addition, in this study, we have also expanded the
scope of the iodine/silane reagent combination to allow the
straightforward and high-yielding generation of per-O-acet-
ylated 2-hydroxyglycals, as well as useful building blocks
based on d-glucuronic acid and d-glucosamine. All the syn-
thetic targets were obtained in particularly short reaction
times, either in one-pot procedures or following reaction
sequences devoid of laborious chromatographic purification
of intermediates.
Experimental Section
General Remarks: Commercially available PMHS (average Mn
=
1700–3200) was used as supplied in all the experiments described.
The spectroscopic data of known compounds 2,[2] 3,[2] 4,[4] 5,[10]
and 13[16] were consistent those reported in the literature.
Synthesis of Symmetrical Disulfide 5: Thiourea (114 mg, 1.5 mmol)
was added to the crude glycosyl iodide residue from the exctractive
work-up, and the mixture was suspended in acetonitrile (2 mL) and
then heated to 60 °C. When the reaction was complete (TLC), The
vessel was cooled to room temp., and then phenyl diselenide
(0.03 mmol, 9.4 mg) and Et3N (0.55 mL, 4 mmol) were sequentially
added. After 10 min, the reaction vessel was placed in an oil bath
at 50 °C, and kept for 1 h at this temperature. The mixture was
then concentrated in vacuo, the residue was dissolved in CH2Cl2,
and the organic phase was washed with water. The aqueous phase
was then re-extracted with CH2Cl2, and the combined organic ex-
tracts were dried and concentrated. The residue was purified by
flash silica gel chromatography (eluent: hexane/ethyl acetate, 6:4).
Synthesis of Phenyl Thioglycoside 6:[29] Ethanol (12 mL) was added
to a mixture of phenyl disulfide (152 mg, 0.7 mmol) and NaBH4
(53 mg, 1.4 mmol). The mixture was stirred until the evolution of
hydrogen ceased, and then was briefly heated at 50 °C to ensure
completion of the reduction. The mixture was then added to the
crude glycosyl iodide obtained from the extractive work-up as de-
scribed above. Upon completion of the reaction (TLC), acetic acid
was added until neutrality was reached, and then the mixture was
diluted with CH2Cl2, and washed with water. The aqueous phase
was re-extracted with CH2Cl2, and the combined organic extracts
were dried anc concentrated under vacuum. The residue was puri-
fied by silica gel flash chromatography (eluent: hexane/ethyl acet-
ate, 7:3).
General Procedure for the Synthesis of the Glycosyl Iodide Interme-
diates: I2 (356 mg, 1.4 mmol) and PMHS (85 μL, 1.4 mmol silane
units) were added to a solution of a per-O-acetylated sugar
(1 mmol) in anhydrous CH2Cl2 or 1,2-dichloroethane (see the
schemes for the selected solvent; 4–6 mL) (Caution: exothermic re-
action). The mixture was heated to reflux until complete consump-
tion of the starting material was observed (monitored by TLC, see
the schemes for the times). For the synthesis of 1,2-orthoesters and
2-acetoxyglycals, the appropriate reagents were directly added to
the iodination mixture (see specific procedures below), whereas for
the synthesis of 1,2-ethylidenes, dichloromethane was replaced by
acetonitrile before addition of the reagents (see below). For the
remaining targets (thioglycosides, disulfides, glycals, and glucos-
amine allyl glycosides), the mixture was submitted to the following
extractive work-up: it was diluted with CH2Cl2, and the organic
phase was washed with aqueous sodium carbonate containing so-
dium thiosulfate (the latter reagent was added portionwise until
complete consumption of the residual iodine in the organic phase
was observed). The aqueous phase was then re-extracted with
dichloromethane, and the combined organic extracts were dried
and concentrated in vacuo. The residue was used directly in subse-
quent elaborations.
Synthesis of 1,2-Orthoesters 1 and 9: Lutidine (465 μL, 4 mmol),
methanol (245 μL, 6 mmol), and tetrabutylammonium bromide
(129 mg, 0.4 mmol) were added sequentially to the iodination mix-
ture. The resulting mixture was left to stir at room temp. (synthesis
of 1, Scheme 1) or under reflux (synthesis of 9, Scheme 2). When
the reaction was complete (TLC), the mixture was concentrated
and purified by chromatography on silica gel (eluent: hexane/ethyl
acetate mixtures).
Synthesis of 1,2-Ethylidene 2:[26] The glycosyl iodide intermediate
was synthesised as described above, then the dichloromethane was
removed with a stream of nitrogen. The residue was dissolved in
acetonitrile (5 mL), and then sodium borohydride (190 mg,
5 mmol) was added, keeping the vessel in an ice bath (Note: exo-
thermic reaction). On completion of the reaction (TLC), the mix-
ture was diluted with dichloromethane, and washed with water. The
aqueous phase was then re-extracted with dichloromethane, and
the combined organic extracts were dried and concentrated in
vacuo. The residue was purified by silica gel chromatography (elu-
ent: hexane/ethyl acetate, 6:4).
Synthesis of Allyl Glycosides 13 and 16: Freshly activated 4 Å mo-
lecular sieves were added to the crude iodide (obtained from
0.3 mmol of 1-O-acetylated precursor), and the mixture was sus-
pended in anhydrous dichloromethane (4 mL) under argon. After
stirring for 15 min, allyl alcohol (80 μL, 1.2 mmol) and BiBr3
(39 mg, 0.090 mmol) were added, and the mixture was stirred at
room temp. until TLC analysis indicated complete consumption of
the UV-detectable glycosyl iodide (see Scheme 3 for the times).
Some drops of pyridine were added, and the mixture was filtered
through a short pad of silica gel (eluent: ethyl acetate). The filtrate
was concentrated, and the residue was purified by silica gel flash
chromatography (eluent: hexane/ethyl acetate mixtures).
Synthesis of 2-Acetoxyglycals 17–20: The iodination vessel was
placed in an ice-bath, and then DBU was added dropwise (0.6 mL,
4 mmol). Upon completion of the reaction (TLC) the mixture was
Eur. J. Org. Chem. 2013, 125–131
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
129

M. Giordano, A. Iadonisi
FULL PAPER
diluted with CH2Cl2 and washed with water. The aqueous phase
was re-extracted with CH2Cl2, and combined organic extracts were
dried and concentrated under vacuum. The residue was purified by
silica gel flash chromatography (eluent: hexane/ethyl acetate mix-
tures).
12.5 Hz, 1 H, 6a-H), 4.13 (br. d, J = 12.5 Hz, 1 H, 6b-H), 4.09
(br. dd, J = 6.0 and 12.5 Hz, 1 H, -OCHaHbCH=CH2), 3.74–3.64
(overlapping signals, 2-H and 5-H), 2.08, 2.02 (ϫ2) (3 s, 9 H, 3
-COCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.7 (ϫ2)
(-COCH3), 154.1 (-COCCl3), 133.3 (CH=CH2), 118.0 (CH=CH2),
99.6 (C-1), 95.4, 74.4, 71.7 (ϫ2), 70.2, 68.7, 62.0, 56.1 (C-2),
20.6 ppm. MALDI-TOF MS: m/z
C18H24Cl3NO10 (520.75): calcd. C 41.52, H 4.65; found C 41.25, H
4.75.
3,4,6-Tri-O-acetyl-1,2-O-(1-methoxyethylidene)-α-D-glucopyranose
= 542.80 [M +
Na]+.
(1): Diastereoisomeric ratio 11:1. 1H NMR (500 MHz, CDCl3) sig-
nals of the major diastereoisomer: δ = 5.67 (d, J = 5.0 Hz, 1 H, 1-
H), 5.17 (t, J = 3.0 Hz, 1 H, 3-H), 4.85 (dd, J = 3.0 and 9.5 Hz, 1
H, 4-H), 4.28 (m, 1 H, 2-H), 4.20–4.10 (m, 2 H, 6-H2), 3.91 (m, 1
H, 5-H), 3.24 (s, 3 H, -OCH3), 2.07, 2.05 (ϫ2) (3 s, 9 H, 3
-COCH3), 1.67 (s, 3 H, orthoester -CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 170.6, 169.6, 169.1 (-COCH3), 121.5, 96.8
(C-1), 73.0, 70.0, 68.2, 66.9, 63.0, 20.7, 20.0 ppm. MALDI-TOF
MS: m/z = 385.30 [M + Na]+. C15H22O10 (362.33): calcd. C 49.72,
H 6.12; found C 49.85, H 6.05.
2,3,4,6-Tetra-O-acetyl-2-hydroxy-D-glucal (17): [α]D = –32.5 (c =
1.6, in CHCl3). 1H NMR (400 MHz, CDCl3): δ = 6.57 (s, 1-H),
5.49 (d, J = 4.4 Hz, 1 H, 3-H), 5.16 (dd, J = 4.4 and 5.6 Hz, 1 H,
4-H), 4.36 (dd, J = 6.4 and 11.6 Hz, 1 H, 6a-H), 4.35–4.25 (m, 1
H, 5-H), 4.16 (dd, J = 3.2 and 11.6 Hz, 1 H, 6b-H), 2.04 (ϫ2), 2.03,
1.99 (3 s, 12 H, 4 -COCH3) ppm. 13C NMR (100 MHz, CDCl3): δ
= 170.2, 169.8, 169.3, 169.2 (-COCH3), 139.1 (C-1), 127.2 (C-2),
74.0, 67.3, 66.2, 60.8, 20.5 (ϫ3), 20.2 ppm. MALDI-TOF MS: m/z
= 353.20 [M + Na]+. C14H18O9 (330.29): calcd. C 50.91, H 5.49;
found C 50.75, H 5.55.
Phenyl 2,3,4-Tri-O-acetyl-1-thio-β-L-fucopyranoside (6): [α]D =
1
–10.1 (c = 1.3, in CHCl3). H NMR (500 MHz, CDCl3): δ = 7.60–
7.20 (aromatic H), 5.25 (bd, J = 3.0 Hz, 1 H, 4-H), 5.22 (t, J =
10.0 Hz, 1 H, 2-H), 5.05 (dd, J = 3.0 and 10.0 Hz, 1 H, 3-H), 4.70
(d, J = 10.0 Hz, 1 H, 1-H), 3.83 (br. q, J = 6.5 Hz, 1 H, 5-H), 2.14,
2.08, 1.97 (3 s, 9 H, 3 -COCH3), 1.23 (d, J = 6.5 Hz, 3 H, 6-H3)
ppm. 13C NMR (100 MHz, CDCl3): δ = 170.5, 170.0, 169.4
(-COCH3), 132.3, 128.8, 127.9 (aromatic CH), 86.5 (C-1), 73.1,
72.4, 70.2, 69.0, 67.3, 20.7, 20.5 (ϫ2), 16.3 ppm. MALDI-TOF
MS: m/z = 405.15 [M + Na]+. C18H22O7S (382.43): calcd. C 56.53,
H 5.80; found C 56.40, H 5.90.
2,3,4,6-Tetra-O-acetyl-2-hydroxy-D-galactal (18): [α]D = –3.8 (c =
1.6, in CHCl3). 1H NMR (500 MHz, CDCl3): δ = 6.59 (s, 1-H),
5.80 (d, J = 4.5 Hz, 1 H, 3-H), 5.45 (dd, J = 2.0 and 5.0 Hz, 1 H,
4-H), 4.38–4.34 (m, 1 H, 5-H), 4.25 (dd, J = 3.2 and 12.0 Hz, 1 H,
6a-H), 4.16 (dd, J = 3.6 and 12.0 Hz, 1 H, 6b-H), 2.09, 2.07, 2.05,
2.00 (4 s, 12 H, 4 -COCH3) ppm. 13C NMR (100 MHz, CDCl3): δ
= 170.3, 169.8, 169.7, 169.2 (-COCH3), 138.7 (C-1), 127.1 (C-2),
73.1, 63.8 (ϫ2), 61.2, 20.5, 20.4 (ϫ2), 20.2 ppm. MALDI-TOF
MS: m/z = 353.20 [M + Na]+. C14H18O9 (330.29): calcd. C 50.91,
H 5.49; found C 50.75, H 5.55.
Methyl 3,4-Di-O-acetyl-1,2-O-(1-methoxyethylidene)-α-D-glucopyr-
anuronate (9): Diastereoisomeric ratio 10:1. 1H NMR (400 MHz,
CDCl3): δ = 5.85 (d, J = 4.8 Hz, 1 H, 1-H), 5.23 (t, J = 2.4 Hz, 1
H, 3-H), 5.15 (ddd, J = 1.2, 2.4, and 7.6 Hz, 1 H, 4-H), 4.32–4.25
(2 H, 2-H and 5-H), 3.74 (s, 3 H, -CO2CH3), 3.26 (s, 3 H, orthoes-
ter -OCH3), 2.07, 2.06 (2 s, 6 H, 2 -COCH3), 1.70 (s, 3 H, orthoester
CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.3, 168.7 (ϫ2)
(-COCH3 and -CO2CH3), 122.5 (orthoester C), 95.8 (C-1), 73.0,
70.3, 68.9, 68.3, 52.5, 50.5, 21.0, 20.6 ppm. MALDI-TOF MS: m/z
= 371.35 [M + Na]+ . C14H20O10 (348.31): calcd. C 48.28, H 5.79;
found C 48.40, H 5.70.
2,3,4-Tri-O-acetyl-2-hydroxy-L-fucal (19): [α]D = –6.2 (c = 1.1, in
1
CHCl3). H NMR (500 MHz, CDCl3): δ = 6.60 (d, J = 1.2 Hz, 1-
H), 5.87 (d, J = 5.2 Hz, 1 H, 4-H), 5.32 (d, J = 1.2 and 5.2 Hz, 1
H, 3-H), 4.29 (q, J = 6.4 Hz, 1 H, 5-H), 2.15, 2.10, 2.01 (3 s, 9 H,
3 -COCH3), 1.29 (d, J = 6.4 Hz, 3 H, 6-H3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 170.4, 169.9, 169.3 (-COCH3), 139.3 (C-
1), 126.8 (C-2), 72.1, 66.3, 64.5, 20.5, 20.3, 16.0 ppm. MALDI-
TOF MS: m/z = 295.20 [M + Na]+. C12H16O7 (272.25): calcd. C
52.94, H 5.92; found C 52.85, H 5.95.
Methyl (Ethyl 2,3,4-Tri-O-acetyl-1-thio-β-D-glucopyranoside)uron-
2,3,4-Tri-O-acetyl-2-hydroxy-D-glucuronal Methyl Ester (20): [α]D =
ate (10): Anomeric ratio β/α, 5:1, 1H NMR (500 MHz, CDCl3)
signals of the β-anomer: δ = 5.24 (t, J = 10.0 Hz, 1 H, 3-H), 5.18
(t, J = 10.0 Hz, 1 H, 4-H), 5.03 (t, J = 10.0 Hz, 1 H, 2-H), 4.51 (d,
J = 10.0 Hz, 1 H, 1-H), 4.02 (d, J = 10.0 Hz, 1 H, 5-H), 3.72 (s, 3
H, -CO2CH3), 2.80–2.60 (m, 2 H, -SCH2CH3), 2.03, 1.99 (ϫ2) (2
s, 9 H, 3 -COCH3), 1.24 (t, J = 7.5 Hz, 3 H, -SCH2CH3) ppm.
Significant signals of the α-anomer: δ = 5.71 (d, J = 5.0 Hz, 1 H,
1-H), 5.34 (t, J = 9.5 Hz, 1 H, 3-H), 5.15 (t, J = 9.5 Hz, 1 H, 4-H),
4.98 (dd, J = 5.00 and 10.0 Hz, 1 H, 2-H), 4.73 (d, J = 9.5 Hz, 1
H, 5-H), 2.04, 2.02, 2.00 (3 s, 9 H, 3 -COCH3), 1.24 (t, J = 7.5 Hz,
3 H, -SCH2CH3) ppm. 13C NMR (100 MHz, CDCl3) signals of the
β-anomer: δ = 169.9, 169.2 (ϫ2), 166.9 (-COCH3 and -CO2CH3),
83.5 (C-1), 76.2, 73.0, 69.5, 69.3, 52.7, 24.0, 20.6, 20.5, 14.6 ppm.
MALDI-TOF MS: m/z = 401.20 [M + Na]+. C15H22O9S (378.39):
calcd. C 47.61, H 5.86; found C 47.50, H 5.95.
1
–26.4 (c = 1.2, in CHCl3). H NMR (400 MHz, CDCl3): δ = 6.81
(d, J = 1.2 Hz, 1-H), 5.45 (m, 1 H), 5.37 (m, 1 H), 4.82 (m, 5-H),
3.79 (s, 3 H, -OCH3), 2.14, 2.09, 1.99 (3 s, 9 H, 3 -COCH3) ppm.
13C NMR (100 MHz, CDCl3): δ = 169.4, 169.3, 169.2, 166.6
(-COCH3 and -CO2CH3), 139.5 (C-1), 127.5 (C-2), 72.3, 69.0, 63.5,
52.4, 20.6 (ϫ2), 20.5 ppm. MALDI-TOF MS: m/z = 339.20 [M +
Na]+. C13H16O9 (316.26): calcd. C 49.37, H 5.10; found C 49.45,
H 5.00.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra of all synthesized
products (1–6, 9, 10, 13, 16–20).
Acknowledgments
Allyl 3,4,6-Tri-O-acetyl-2-deoxy-2-(2,2,2-trichloroethoxycarbonyl-
The NMR and MS facilities of CIMCF (“Centro Interdipartimen-
tale di Metodologie Chimico-Fisiche dell’Università di Napoli”)
are acknowledged.
amino)-β-D-glucopyranoside (16): [α]D = +4.3 (c = 1.4, in CHCl3).
1H NMR (500 MHz, CDCl3): δ = 5.80–5.65 (m, 1 H, -OCH2-
CH=CH2), 5.35–5.25 (overlapping signals, 2 H, 3-H and -CH2-
CH=CHcisHtrans), 5.18 (bd, J = 10.0 Hz, 1 H, CH2CH=CHcis
-
Htrans), 5.06 (t, J = 9.5 Hz, 1 H, 4-H), 4.67 (d, J = 9.0 Hz, 1 H, 1-
H), 4.77–4.65 (AB, J = 11.5 Hz, 1 H, -OCH2CCl3), 4.35 (br. dd, J
= 3.2 and 12.5 Hz, 1 H, -OCHaHbCH=CH2), 4.27 (dd, J = 4.5 and
[1] For a very recent review focussed on the synthetic applications
of this combined reagent, see: M. Adinolfi, A. Iadonisi, A. Pas-
tore, S. Valerio, Pure Appl. Chem. 2012, 84, 1.
130
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 125–131

Applications of Iodine/Polymethylhydrosiloxane
[2] M. Adinolfi, A. Iadonisi, A. Ravidà, M. Schiattarella, Tetrahe-
dron Lett. 2003, 44, 7863.
[3] For applications by other groups, see: Y.-F. Tsai, C.-H. Shih,
Y.-T. Su, C.-H. Yao, J.-F. Lian, C.-C. Liao, C.-W. Hsia, H.-A.
Shui, R. Rani, Org. Biomol. Chem. 2012, 10, 931.
[4] S. Valerio, A. Iadonisi, M. Adinolfi, A. Ravidà, J. Org. Chem.
2007, 72, 6097.
Vankar, Org. Biomol. Chem. 2008, 6, 3948; b) D. Ellis, S. E.
Norman, H. M. I. Osborn, Tetrahedron 2008, 64, 2832; c) P. A.
Colinas, R. D. Bravo, Carbohydr. Res. 2007, 342, 2297; d) R.
Saeeng, M. Isobe, Org. Lett. 2005, 7, 1585; e) M. Hayashi, S.
Nakayama, H. Kawabata, Chem. Commun. 2000, 1329.
For their use as key intermediates in the synthesis of difficult
glycosidic linkages, see: F. W. Lichtenthaler, Chem. Rev. 2011,
111, 5569.
For some examples, see: a) N. V. Ganesh, N. Jayaraman, J. Org.
Chem. 2007, 72, 5500; b) F. W. Lichtenthaler, K. Nakamura, J.
Klotz, Angew. Chem. 2003, 115, 6019; Angew. Chem. Int. Ed.
2003, 42, 5838; c) F. W. Lichtenthaler, E. Cuny, O. Sakanaka,
Angew. Chem. 2005, 117, 5024; Angew. Chem. Int. Ed. 2005,
44, 4944; d) Y. Ichikawa, K. Hirata, M. Ohbayashi, M. Isobe,
Chem. Eur. J. 2004, 10, 3241; e) U. E. Udodong, B. Fraser-
Reid, J. Org. Chem. 1989, 54, 2103; f) S. Hanessian, A. M.
Faucher, S. Lerger, Tetrahedron 1990, 46, 231.
a) M. G. Blair, Methods Carbohydr. Chem. 1963, 2, 411; b)
D. R. Rao, L. M. Lerner, Carbohydr. Res. 1971, 19, 133; c) O.
Varela, G. M. Fina, R. M. Lederkremer, Carbohydr. Res. 1987,
167, 187; d) S. Jain, S. N. Suryawanshi, S. Misra, D. S.
Bhakuni, Indian J. Chem. Sect. B 1988, 27, 866; e) K. M. Khan,
S. Perveen, R. A. S. Al-Qawasmeh, M. Shekhani, S. T.
Ali Shah, W. Voelter, Lett. Org. Chem. 2009, 6, 191.
[19]
[20]
[5] For applications by other groups, see: a) D. Comegna, F.
De Riccardis, Org. Lett. 2009, 11, 3898; b) D. Comegna, E.
Bedini, M. Parrilli, Tetrahedron 2008, 64, 3381.
[6] M. Adinolfi, A. Iadonisi, A. Pezzella, A. Ravidà, Synlett 2005,
1848.
[7] A. Pastore, M. Adinolfi, A. Iadonisi, Eur. J. Org. Chem. 2008,
6206.
[8] A. Pezzella, A. Iadonisi, S. Valerio, L. Panzella, A. Napolitano,
M. Adinolfi, M. d’Ischia, J. Am. Chem. Soc. 2009, 131, 15270.
[9] M. Adinolfi, M. d’Ischia, A. Iadonisi, L. Leone, A. Pezzella,
S. Valerio, Eur. J. Org. Chem. 2012, 4333.
[10] M. Adinolfi, D. Capasso, S. Di Gaetano, A. Iadonisi, L. Leone,
A. Pastore, Org. Biomol. Chem. 2011, 9, 6278.
[11] J. S. Yadav, S. B. V. Reddy, K. Premalatha, T. Swamy, Tetrahe-
dron Lett. 2005, 46, 2687.
[12] For some examples of recent applications of PMHS as a reduc-
ing reagent in organic Synthesis see: a) X.-F. Bai, F. Ye, L.-S.
Zheng, G.-Q. Lai, C.-G. Xia, L.-W. Xu, Chem. Commun. 2012,
48, 8592; b) R. J. Rahaim Jr, R. E. Maleczka Jr, Org. Lett.
2011, 13, 584; c) S. Huang, K. R. Voigtritter, H. B. Unger, B. H.
Lipshutz, Synlett 2010, 2041; d) C. Dal Zotto, D. Virieux, J.-
M. Campagne, Synlett 2009, 276.
[13] The anomeric iodination was successful with a chromato-
graphic fraction of 7 consisting nearly exclusively of the α-an-
omer.
[14] A glucuronyl iodide methyl ester has been synthesised starting
from a β-configured tetra-O-pivaloylated precursor: a) J. Bic-
kley, J. A. Cottrell, J. R. Ferguson, R. A. Field, J. R. Harding,
D. L. Hughes, K. P. R. Kartha, J. L. Law, F. Scheinmann, A. V.
Stachulski, Chem. Commun. 2003, 1266; b) J. A. Perrie, J. R.
Harding, C. King, D. Sinnott, A. V. Stachulski, Org. Lett.
2003, 5, 4545.
[21]
[22]
[23]
B. Qian, Q.-D. You, Tetrahedron Lett. 2012, 53, 3750.
For alternative routes to 2-hydroxyglycals, see: a) J. Liu, C. Y.
Huang, C. H. Wong, Tetrahedron Lett. 2002, 43, 3447; b) D. J.
Chambers, G. R. Evans, A. J. Fairbanks, Tetrahedron 2004, 60,
8411.
C. M. Storkey, A. L. Win, J. O. Hoberg, Carbohydr. Res. 2004,
339, 897.
[24]
[25] An analogous process was recently used to convert highly reac-
tive glycosyl iodide intermediates from O-benzylated sugars
into their isolable 1-O-acetylated counterparts: A. Pastore, S.
Valerio, M. Adinolfi, A. Iadonisi, Chem. Eur. J. 2011, 17, 5881.
[26] V. I. Betaneli, M. V. Ovchinnicov, L. L. Backinowsky, N. K.
Kochetkov, Carbohydr. Res. 1982, 107, 285.
[27] T. Hansen, S. L. Krintel, K. Daasbjerg, N. Skrydstrup, Tetrahe-
dron Lett. 1999, 40, 6087.
[28] F. M. Ibatullin, S. I. Selivanov, A. G. Shavva, Synthesis 2001,
419.
[15] M. Lahmann, M. A. Bergstrom, D. Turek, S. Oscarsson, J.
Carbohydr. Chem. 2004, 23, 123.
[16] a) M. T. Campos-Val Des, J. R. Marino Albernas, V. Verez-
Bencomo, J. Carbohydr. Chem. 1987, 6, 519; b) M. Kiso, L.
Anderson, Carbohydr. Res. 1985, 136, 309.
[17] N. Miquel, S. Vignando, G. Russo, L. Lay, Synlett 2004, 341.
[18] For examples of O-, C-, N- and S-glycosidations by Ferrier
rearrangements, see: a) P. Gupta, N. Kumari, A. Agarwal, Y. D.
[29] R. V. Stick, D. M. G. Tilbrook, S. J. Williams, Aust. J. Chem.
1997, 50, 233.
Received: August 9, 2012
Published Online: November 9, 2012
Eur. J. Org. Chem. 2013, 125–131
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
131