Glycosidations of 2-deoxy glycosyl dithiophosphates using a tagged iodine(iii)-promoter for simple purification

Article abstract of DOI:10.1039/b718642h

The preparation of the 4-i-butylsulfonate derivative of the Zefirov reagent (5) and its use in a novel purification strategy for iodine(iii)-promoted glycosidations of 2-deoxy diethyldithiophosphate glycosides is described. The Royal Society of Chemistry.

Full text of DOI:10.1039/b718642h

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Glycosidations of 2-deoxy glycosyl dithiophosphates using a tagged
iodine(III)-promoter for simple purification
Eike Kunst,a Florian Gallier,a,b Gilles Dujardinb and Andreas Kirschning*a
Received 3rd December 2007, Accepted 3rd January 2008
First published as an Advance Article on the web 24th January 2008
DOI: 10.1039/b718642h
The preparation of the 4-i-butylsulfonate derivative of the Zefirov reagent (5) and its use in a novel
purification strategy for iodine(III)-promoted glycosidations of 2-deoxy diethyldithiophosphate
glycosides is described.
During the past decades, hypervalent iodine compounds have at-
tracted increased interest as mild and selective oxidizing reagents.1
Recently, iodine(III) chemistry has been extended to catalytic
processes.2 Iodobenzene is a common by-product and has to
be removed chromatographically. As this can be a cumbersome
task, concepts for facile purification have been developed that
are commonly based on solid phase bound and perfluoro tagged
iodine(III) reagents.3,4
All these concepts are based on the covalent attachment of
the iodo moiety to the solid phase or a tag. Regeneration of
the iodine(III) species requires reoxidation of the immobilized
or tagged aryl iodide, which is not always a straightforward
procedure. Alternatively, scavenger reagents can be used for easy
removal of excess reagent as well as by-products.3,5 Here, we report
on a general scavenging concept that can be applied in iodine(III)-
promoted glycosylations of complex glycosyl donors with aglycons
(Scheme 1).
Thus, the sulfonate anion is liberated by a SN2-step, thereby
being removed from solution by an anion exchange resin. Excess
of the tagged iodine reagent is also removed by this method. As a
polymer-bound nucleophile, we chose the azide anion, because the
alkyl azide that is formed as by-product from the SN2-displacement
is a volatile compound.
The preparation of a set of tagged iodine(III) reagents started
from commercially available p-iodo-benzenesulfonyl chloride 1
(pipsyl chloride), which was converted into the correspond-
ing i-butyl sulfonate 2 (Scheme 2). Oxidation of 27 yielded
bis(acetoxy)iodoarene 3, which was transformed into iodosylben-
zene 4 and the Zefirov reagent 58 both containing the dormant
sulfonate anion. Like iodosylbenzene, derivative 4 is insoluble
in organic solvents, very likely because of its oligomeric nature.
In triflic anhydride, depolymerization proceeds within several
minutes to afford a highly labile yellow solid (decomposition to p-
iodophenylsulfonic acid occurs within a few hours in a glove-box),
which is expected to be the tagged l-oxo complex 5.
Scheme 1 The concept of a dormant ion exchange group for a new
scavenging protocol in glycosidations.
The concept relies on a sulfonate ester tag, which acts as a
dormant ion exchange group. Recently, we successfully applied this
concept in several ionic and radical mediated iodine(III) reactions.6
Scheme 2 Preparation of iodanes 3–5.6
In continuation of our research dedicated to the development
of solid-phase assisted protocols for glycosidations using elec-
trophilic polymer bound reagents9 as well as scavengers,10,11 we
studied the concept of a dormant ion exchange group for the
electrophilic activation of glycosyl donors and promotion of
glycosidations.
aInstitut fu¨r Organische Chemie and Zentrum fu¨r Biomolekulare Wirkstoffe
(BMWZ), Leibniz Universita¨t Hannover, Schneiderberg 1b, 30167
Hannover, Germany. E-mail: andreas.kirschning@oci.uni-hannover.de;
Fax: +49 (0)511-7623011
bUCO2M, UMR CNRS 6011, Universite´ du Maine, F-72085 Le Mans
Cedex 9, France
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In this context, we already utilized this concept for phenylthio-
glycosides. However, we had experienced that only simple glycosyl
acceptors like benzyl alcohol or 1:2,3:4-di-O-isopropylidene-
galactose furnished the glycosidation products in good yields.6
Therefore, we searched for other thio-based glycosyl donors that
can be activated by iodine(III) reagents. We found that the rarely
employed glycosyl diethyldithiophosphates (Schemes 1, 3 and 4
and Table 1) are very well suited as glycosyl donors. This glycosyl
donor group was first introduced by Thiem et al.12 and was
recently applied for the synthesis of the trisaccharide unit of the
chaperone down-regulator versipelostatin.13 Complete activation
occurs within minutes even at low temperature (−78 ◦C), and
glycoconjugates 10–12 were formed in satisfactory yields. Here,
we chose glycosyl acceptors of enhanced complexity such as
the decanolides decarestrictines B and D.14 In order to reduce
work-up to a minimum, it is not only removal of the iodoarenes
that has to be guaranteed, but also the scavenging of other by-
Scheme 4 Iodine(III)-promoted preparation of decarestrictine-based
glycoconjugates using diethyldithiophosphonates 13 and 16 as glycosyl
donors.
products such as traces of TfOH, thiols, disulfides and oxygenated
disulfides, which are formed during the glycosidation process.
Except for glycoside 12, the crude product was pure enough
for complete NMR analysis of the anomeric mixture. Related
Scheme 3 Iodine(III)-promoted glycosidations of diethyldithiophosphate
9 and scavenging protocol. a See Table 1, footnote a.
Table 1
Glycosyl acceptor
Glycosidation product
a–b-ratio
Yield (%)
3 : 1
3 : 1
92% for Tf2O
73% for TMSOTf
10 : 1
50%b
1 : 0.9
72% Conversion
41% Isolated yield
28% 8
a Isolated yield. b Scavenging of aryl iodide was not performed on 11.
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glycosidations in solution resulted in crude products that still
contained thiophosphate-derived by-products after classical work-
up.13
are reported using the following abbreviations: s = singlet (due
to quaternary carbon), d = doublet (methine), q = quartet
(methyl), t = triplet (methylene). Mass spectra were recorded
on a type LCT-spectrometer (Micromass) and on a type VG
autospec (Micromass). Ion mass (m/z) signals are reported as
values in atomic mass units followed, in parentheses, by the peak
intensities relative to the base peak (100%). Optical rotations [a]
were collected on a Polarimeter 341 (Perkin Elmer) at a wavelength
of 589 nm and are given in 10−1 deg cm2 g−1. All solvents used were
of reagent grade and were further dried. Reactions were monitored
by thin layer chromatography (tlc) on silica gel 60 F254 (E. Merck,
Darmstadt) and spots were detected either by UV-absorption
or by charring with H2SO4–4-methoxybenzaldehyde in ethanol.
Preparative column chromatography was performed on silica gel
60 (E. Merck, Darmstadt). For the synthesis of dithiophosphates,
refer to ref. 12, 13 and 16.
Thus, addition of Amberlyst A-21 removes traces of acidic
by-products.10 Finally, all sulfonate tagged iodine species are
scavenged by the azido exchange resin under microwave irradiating
conditions to yield the purified glycosidation products 10–12.
Particularly important to note is the presence of the olefinic
double bond in decarestrictine derivative 8 (leading to glycoside
12), which is not affected by this electrophilic promoter system,
despite the fact that hypervalent iodine reagents are known to
react with olefins. In this example, we also detected glyconjugate
by-products that originate from O-desilylations (<5%). Further-
more, formation of glycoside 12 is remarkable because 4,7-di-
O-TBS protected decarestrictine D9b is a challenging glycosyl
acceptor. The 3-OH group shows reduced reactivity for which the
intramolecular hydrogen bond with the lactone carbonyl group
has to be made responsible.15 The high yielding formation of
glycoside 10 using 4-acetoxybut-2-en-1-ol 6 as acceptor strongly
supports this chemoselectivity toward olefinic double bonds. This
example also demonstrates that activation of iodosyl arene 4 is
favourably achieved with Tf2O instead of TMSOTf.
In contrast, the partially protected decarestrictine D derivative
149b with a free hydroxyl group at C-7 shows enhanced reactivity as
is demonstrated in the glycosidation with diethyldithiophosphate
glycoside 13 (Scheme 4). Finally, we investigated the glycosidation
of a disaccharide glycosyl donor 16, composed of protected
D-digitoxose and D-oleandrose with bis-O-acylated decarestric-
tine 14. After two hours at −78 ◦C, full transformation was
encountered and solid-phase assisted work-up yielded complex
glycoconjugate 17 in good yield.
Hazard warning
Aliphatic azides are regarded to be potentially explosive. For i-
butyl azide, which is formed as a by-product and removed under
reduced pressure here, no data are available in the literature. We
never encountered any hazards during these studies. However, this
observation does not exclude the possibility of explosions.
Preparation of tagged iodine(III) reagent 5
(2ꢀ-Methyl)-propyl-4-iodo-phenylsulfonate (2). To a solution of
pipsyl chloride 1 (5.52 g, 18.2 mmol) in 20 mL absolute pyridine
at rt was added i-butanol (1.68 mL, 1 eq.). After 90 min, the
reaction was hydrolyzed by addition of 20 mL of a saturated
NaHCO3 solution. The aqueous phase was extracted with CH2Cl2
(3 times), and the combined organic layers were dried (Na2SO4).
After concentration under reduced pressure, the crude product
was co-distilled with toluene to remove traces of pyridine. The title
product 2 was obtained as a colorless, amorphous solid (5.40 g,
In conclusion, we developed a powerful glycosidation method
for diethyldithiophosphates that utilizes a tagged version of
Zefirov’s reagent. In combination with the scavenging protocol,
the method allows us to prepare glycoconjugates based on 2-
deoxysugars. In principle, we believe that the i-butylsulfonyl
tag and this scavenging concept are of general applicability for
purification protocols of reagents as well as catalysts.
Support from the Fonds der Chemischen Industrie is gratefully
acknowledged. F. G. thanks the DAAD for a sandwich scholarship
(A/04/20592).
1
15.9 mmol; 87% yield). H NMR (400 MHz, CDCl3) d 0.90 (d,
6H, J = 6.7), 1.95 (m, 1H), 3.82 (d, J = 6.5, 2H), 7.61 (d, J =
8.2, 2H), 7.92 (d, J = 8.2, 2H) ppm; 13C NMR (100 MHz, CDCl3)
d 18.9 (q), 28.5 (d), 77.2 (t), 101.7 (s), 129.5 (d), 136.4 (d), 138.9
(s) ppm; HRMS (ESI): calculated for C10H13IO3S (M+): 339.9630,
observed 339.9633.
(2ꢀ-Methyl)-propyl-4-[bis(acetoxy)iodo]-phenylsulfonate (3).
A
Experimental
mixture of 60 mL Ac2O and 14 mL 30% H2O2 was kept for
4 h at 40 ◦C (keeping the exact temperature is essential) in the
dark. It was then poured onto finely ground (2ꢀ-methyl)-propyl-4-
iodo-phenylsulfonate 2 (6.06 g, 17.8 mmol) and cooled to room
temperature. After 2 days, this reaction mixture was poured onto
150 mL of ice-water, and the crystals were allowed to grow for 5–10
minutes, before being recovered by filtration on a Bu¨chner funnel.
The crystalline material was then washed with another 150 mL of
ice-water, dried under a high vacuum and the title compound 3
was collected as colorless crystals (5.89 g, 12.8 mmol; 72% yield).
Mp 117–123 ◦C (dec.); 1H NMR (400 MHz, CDCl3) d 0.94 (d, J =
6.6, 6H), 2.04 (sept, J = 6.5, 1H), 3.92 (d, J = 6.5, 2H), 7.97 (d,
J = 8.7, 2H), 8.26 (d, J = 8.0, 2H) ppm; 13C NMR (100 MHz,
CDCl3) d 18.5 (q), 20.3 (q), 28.1 (d), 77.2 (t), 125.8 (s), 129.7 (d),
136.5 (d), 139.5 (s), 176.7 (s) ppm; HRMS (ESI): calculated for
C14H19IO7S (M+) 457.9896, observed 457.9903.
General remarks
1H NMR, 13C NMR and 1H, 13C-COSY as well as NOESY spectra
were measured on an Avance 200/DPX (Bruker) with 200 MHz
(50 MHz), Avance 400/DPX (Bruker) 400 MHz (100 MHz) and
Avance 500/DRX (Bruker) respectively, using tetramethylsilane
as the internal standard. If not otherwise noted, CDCl3 was the
solvent for all NMR experiments. Multiplicities are described
using the following abbreviations: s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet, br = broad. Chemical shift
values of 13C NMR spectra are reported as values in ppm relative
to residual CHCl3 (77 ppm) or CD3OD (49 ppm) as internal
standards. The multiplicities refer to the resonances in the off-
resonance spectra and were elucidated using the distortionless
enhancement by polarisation transfer (DEPT) spectral editing
technique, with secondary pulses at 90 ◦ and 135◦. Multiplicities
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(2ꢀ -Methyl)-propyl-4-iodosyl-phenylsulfonate
(4). Finely
separation of anomers, a sample was chromatographically purified
over silica gel.
ground (2ꢀ-methyl)-propyl-4-[bis(acetoxy)iodo]-phenylsulfonate 3
(846 mg, 1.85 mmol) was placed in a 100 mL beaker and 30 mL
of NaOH (3 N) was added over 5 minutes with vigorous stirring.
The mixture was triturated with a spatula for 15 minutes in order
to become homogeneous. After standing for 45 minutes, water
was added (20 mL) with vigorous stirring, and the solid was
collected on a Bu¨chner funnel. It was returned to the beaker,
triturated with water (40 mL) and collected again. Washing with
water (3 times, 40 mL) and drying under a high vacuum yielded
a yellowish solid 4 (523.4 mg; 1.47 mmol; 80% yield), which is
insoluble in common solvents. Mp 151–153 ◦C (dec.); IR (film)
708, 729, 745, 768, 811, 843, 944, 976, 1091, 1176, 1182, 1357,
1469, 1568, 2962 cm−1.
1-O-[4ꢀ-O-Acetyl-(Z)-but-2ꢀ-enyl]-3,4,6-tri-O-acetyl-a/b-D-
galactoside (10).
Tf2O method. General procedure with thioglycoside 9 (43 mg,
0.1 mmol), glycosyl acceptor 6 (25 mg, 2 eq.) in CH2Cl2–CH3NO2
˚
(4 + 1 mL) with MS 4 A (100 mg) and oxidizing reagent (prepared
from 4 (49 mg, 1.5 eq.) and Tf2O (8.5 lL, 14 mg, 0.75 eq.) in
◦
0.5 mL CH2Cl2), for 3 hours at 0 C, followed by basic work-up
(200 mg, A-21), and iodophenylsulfonate scavenging (200 mg azide
resin, 2 mL CH3CN, microwave irradiation) gave 22.4 mg a-10
(59% yield), 5.8 mg b-10 (15% yield) and 7.0 mg of an a–b-mixture
(1 : 5; 18% yield) as a colorless oil after column chromatography
(petroleum ether–AcOEt = 5 : 1). The overall yield is therefore
92% (a–b-ratio = 3 : 1).
l-Oxo-bis-[triflyloxy(4-isobutyl)benzenesulfonato]-iodane (5).
In an oven dried round-bottom flask, under an argon atmosphere,
freshly distilled CH2Cl2 (3 mL) was added to 4 (1 g, 2.80 mmol).
After cooling to 0 ◦C, triflic anhydride (235 lL, 0.5 eq.) was
added to the suspension, which immediately turned into a
yellow solution. A yellow solid precipitated after 15–30 minutes,
which was recovered by filtration under an argon atmosphere
(using the Schlenk filtration technique) and dried under a high
vacuum for 2 h. The title compound 5 was isolated (553 mg)
and stored at 0 ◦C under an inert atmosphere (preferentially in a
glove-box). This solid is very temperature sensitive and storage
at room temperature (under an argon atmosphere) commonly
affords 4-iodophenylsulfonic acid overnight. Although the title
compound 5 was prepared freshly before each reaction, it can be
stored as a suspension (in dichloromethane under argon at 0 ◦C)
TMSOTf method. General procedure with thioglycoside 9
(43 mg, 0.095 mmol), glycosyl acceptor 6 (25 mg, 2 eq.) in CH2Cl2–
˚
CH3NO2 (4 + 1 mL) with MS 4 A (100 mg) and oxidizing reagent
(prepared from 4 (49 mg, 1.5 eq.) and TMSOTf (25 lL, 1.5 eq.)
◦
in 0.5 mL CH2Cl2), for 3 hours at 0 C followed by basic work-
up (100 mg, A-21), and iodophenylsulfonate scavenging (200 mg
azide resin, 2 mL CH3CN, microwave irradiation) gave 30.3 mg 10
(73% yield) as an a–b-mixture (3 :1). HRMScalcdfor C18H26O10Na
[M + Na] 425.1424, observed 425.1425, calcd for C18H25O10 [M −
H] 401.1448, observed 401.1455.
a-10. 1H NMR (400 MHz, CDCl3) d 1.86 (m, 1H, 2ax-H), 1.97
(s, 3H, OAc), 2.05 (s, 3H, OAc), 2.05 (s, 3H, OAc), 2.08 (m, 1H,
2eq-H), 2.13 (s, 3H, OAc), 4.06–4.22 (m, 5H, 5-H + 2 × 6-H + 2 ×
1ꢀ-H), 4.64 (d, J = 5.1, 2H, 4ꢀ-H), 5.04 (bd, J = 3.1, 1H, 1-H),
5.28 (ddd, J = 12.6, 4.8, 3.1, 1H, 3-H), 5.32 (m, 1H, 4-H), 5.74 (m,
2H, 2ꢀ-H + 3ꢀ-H) ppm. 13C NMR (100 MHz, CDCl3) d 20.7, 20.7,
20.8, 20.9, 30.0, 60.0, 62.5, 62.7, 66.1, 66.6, 66.8, 96.7, 127.3, 129.6,
170.0, 170.3, 170.5, 170.7 ppm. [a]2D0 = +75.3 (c 2.23, CH2Cl2).
1
for several days, without a significant loss of activity. H NMR
(400 MHz, CD3CN, CHD2CN = 1.94 ppm) d 0.74 (d, J = 6.6,
6H), 1.78–1.86 (m, 1H), 3.73 (d, J = 6.6, 2H), 7.90 (m, 2H), 8.21
(m, 2H) ppm; 13C NMR (100 MHz, CD3CN, CD3CN = 1.32
ppm) d 18.4 (q), 28.2 (d), 117.1 (t), 129.3 (d), 130.6 (d), 135.2 (s),
138.8 (s) ppm.
b-10. 1H NMR (400 MHz, CDCl3) d 1.95–2.10 (m, 2H, 2ax-
H + 2eq-H), 2.00 (s, 3H, OAc), 2.05 (s, 3H, OAc), 2.07 (s, 3H, OAc),
2.14 (s, 3H, OAc), 3.82 (ddd, J = 6.8, 6.5, 1.0, 1H, 5-H), 4.16 (bdd,
J = 6.6, 1.4, 2H, 1ꢀ-H), 4.32 (dd, J = 12.4, 6.1, 1H, 6-H), 4.42 (dd,
J = 12.4, 5.8, 1H, 6-H), 4.58–4.65 (m, 2H, 4ꢀ-H), 4.68 (dd, J =
12.9, 6.0, 1H, 1-H), 5.00 (ddd, J = 11.2, 6.4, 3.1, 1H, 3-H), 5.26
General procedure for the glycosidation of diethyldithiophosphates
To a solution of thioglycoside and glycosyl acceptor (azeotropi-
cally dried with toluene followed by 1 hour under a high vacuum)
in a mixture of dry acetonitrile and nitromethane (4 : 1; 50 mL
(dd, J = 3.1, 1.0, 1H, 4-H), 5.74 (m, 2H, 2ꢀ-H + 3ꢀ-H) ppm. [a]2D0
=
−1
˚
mmol ) was added freshly activated molecular sieves (4 A, 1 g
+0.9 ◦ (c 0.58, CH2Cl2).
mmol−1). This suspension was cooled to −80 ◦C.
The activating agent was freshly prepared by adding Tf2O
(0.5 eq.) or TMSOTf (1 eq.) to a suspension of compound 4
in absolute dichloromethane (5 mL mmol−1) at 0 ◦C. Within
a few minutes, a yellow precipitate was formed (formation of
compound 5) which, after dissolution in a minimum amount of
dry acetonitrile, was transferred (1.3 eq.) to the reaction mixture
described above. After completion of the reaction (monitored by
tlc), dry Amberlyst A-21 (1 g mmol−1) was added to terminate
the reaction. Filtration through a pad of silica or celite afforded a
crude oil, which was then submitted to the scavenging protocol.
The crude compound was dissolved in acetonitrile (20 mL
mmol−1) and azide resin was added (∼2 g mmol−1). The scavenging
proceeds within 1 hour at 100 ◦C under microwave irradiating
conditions (150 W) or within two days at 60 ◦C under thermal
conditions. The compounds obtained were usually free of by-
products. In order to collect analytically pure material, or for
5-O-[3ꢀ,4ꢀ,6ꢀ-Tri-O-acetyl-a/b-D-galactosyl]-decarestrictine
B
(11). General procedure with thioglycoside 9 (25 mg, 0.05 mmol),
decarestrictine B (12 mg, 1 eq.) in CH2Cl2–CH3NO2 (2 + 0.5 mL)
˚
with MS 4 A (50 mg) and oxidizing reagent (prepared from 4
(30 mg, 1.5 eq.) and TMSOTf (15 lL, 1.5 eq.) in 0.5 mL CH2Cl2),
for 5 hours at −80 ◦C, followed by basic work-up (100 mg, A-21),
after column chromatography (petroleum ether–AcOEt = 2 : 1),
gave 13.3 mg 11 (50% yield) of a colourless oil as an a–b-mixture
(10 : 1). HRMS calcd for C22H31O12 (M + H) 487.1816, observed
487.1802, calc for C22H29O12 (M − H) 485.1659 observed 485.1661.
a-11. 1H NMR (400 MHz, CDCl3) d 1.32 (d, J = 6.3, 3H,
10-H), 1.55 (ddd, J = 14.7, 11.4, 10.3, 1H, 8ax-H), 1.86 (m, 1H,
2ꢀax-H), 1.98 (s, 3H, OAc), 2.02 (s, 3H, OAc), 2.13 (s, 3H, OAc),
2.15 (m, 1H, 2ꢀeq-H), 2.34 (ddd, J = 14.7, 4.3, 0.9, 1H, 8eq-H), 2.57
(dd, J = 14.3, 3.2, 1H, 4-H), 2.98 (ddd, J = 14.3, 4.4, 0.9, 1H,
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◦
4-H), 3.01 (dd, J = 9.3, 4.0, 1H, 6-H), 3.10 (ddd, J = 10.3, 4.3,
4.0, 1H, 7-H), 3.41 (d, J = 15.9, 1H, 2-H), 3.51 (d, J = 15.9, 1H,
2-H), 3.73 (ddd, J = 9.3, 4.4, 3.2, 1H, 5-H), 4.03 (dd, J = 11.2,
6.5, 1H, 6ꢀ-H), 4.07 (dd, J = 11.2, 6.5, 1H, 6ꢀ-H), 4.45 (ddd, J =
6.5, 6.5, 1.0, 1H, 5-H), 5.07 (ddq, J = 11.4, 6.3, 0.9, 1H, 9-H), 5.32
(ddd, J = 8.6, 4.8, 3.1, 1H, 3ꢀ-H), 5.34 (d, J = 3.5, 1H, 4ꢀ-H), 5.40
(bd, J = 3.0, 1H, 1ꢀ-H) ppm. 13C NMR (100 MHz, CDCl3) d 20.7,
20.7, 20.8, 20.9, 30.3, 36.5, 47.4, 51.8, 54.2, 58.6, 62.4, 66.1, 66.5,
66.8, 69.1, 72.2, 95.0, 165.4, 170.0, 170.3, 170.4, 200.4 ppm.
The 1H NMR data for the anomeric proton of b-11: d 4.92 (dd,
J = 9.5, 2.5, 1ꢀ-H).
15 hours at −78 C, followed by basic work-up (120 mg, A-21),
and iodophenylsulfonate scavenging (200 mg azide resin, 2 mL
CH3CN, microwave irradiation) gave 33.3 mg of 15 (76% yield;
a–b-mixture = 4.7 : 1, determined by NMR on crude product).
Purification by column chromatography led to substantial loss of
material. However, pure samples of both anomers were obtained
ꢀ
by semi-preparative HPLC purification: 7.3 mg of a -15; 19%
yield and 2.4 mg of bꢀ-15; 6% yield. HRMS calcd for C34H38O12Na
[M + Na] 661.2261, observed 661.2270.
aꢀ-15. 1H NMR (400 MHz, CDCl3) d 1.27 (d, J = 6.2, 3H),
1.28 (d, J = 6.4, 3H), 1.89–1.99 (m, 3H), 2.15 (s, 3H), 2.17 (s, 3H),
2.37 (ddd, J = 12.8, 5.1, 1.1, 1H), 2.56 (dd, J = 14.2, 2.3, 1H),
2.73 (dd, J = 14.2, 6.9, 1H), 4.03 (dq, J = 9.7, 6.2, 1H), 4.17 (ddd,
J = 9.4, 8.4, 6.1, 1H), 4.95 (bd, J = 2.8, 1H), 5.03 (ddd, J = 6.9,
4.9, 2.3, 1H), 5.20 (dd, J = 9.7, 9.4, 1H), 5.21 (m, 1H), 5.37 (ddd,
J = 4.9, 3.3, 1.4, 1H), 5.61 (ddd, J = 11.6, 9.5, 5.1, 1H), 5.65 (ddd,
J = 16.0, 9.5, 1.4, 1H), 5.87 (dd, J = 16.0, 3.3, 1H), 7.33–7.41 (m,
4H), 7.46–7.54 (m, 2H), 7.90–8.00 (m, 4H) ppm.
3ꢀ,4ꢀ,6ꢀ -Tri-O-acetyl-a/b-D-galactosyl-(1ꢀ→3)-4,7-di-O-(tert-
butyldimethylsilyl)-decarestrictine D (12). General procedure
with thioglycoside
9 (23 mg, 0.05 mmol), 4,7-di-O-TBS-
decarestrictine D (8) (23 mg, 1 eq.) in CH2Cl2–CH3NO2
˚
(2 + 0.5 mL) with MS 4 A (50 mg) and oxidizing reagent (prepared
from 4 (30 mg, 1.6 eq.) and Tf2O (5.5 lL, 0.8 eq.) in 0.5 mL CH2Cl2)
◦
for 13 hours at −78 C, followed by basic work-up (200 mg, A-
21), and iodophenylsulfonate scavenging (200 mg azide resin, 2 mL
CH3CN, microwave irradiation) gave 16.0 mg of 12 (a–b-mixture:
1 : 0.6; 41% yield) as a colourless oil after column chromatography
(petroleum ether–AcOEt = 20 : 1). Unreacted decarestrictine D
8 was also recovered (28%) after purification. HRMS calcd for
C34H59O12Si2 [M − H] 715.3545, observed 715.3539, calcd for
C34H60O12NaSi2 [M + Na] 739.3521, observed 739.3518.
bꢀ-15. 1H NMR (400 MHz, CDCl3) d 1.24 (d, J = 6.4, 3H),
1.26 (d, J = 6.2, 3H), 1.89 (ddd, J = 12.3, 11.8, 9.9, 1H), 1.81–1.97
(m, 2H), 2.13 (s, 3H), 2.15 (s, 3H), 2.50 (ddd, J = 12.3, 5.1, 2.0,
1H), 2.59 (dd, J = 14.2, 2.8, 1H), 2.68 (dd, J = 14.2, 7.3, 1H), 3.62
(dq, J = 9.5, 6.2, 1H), 4.17 (ddd, J = 10.1, 9.6, 3.7, 1H), 4.69 (dd,
J = 9.9, 2.0, 1H), 5.05 (ddd, J = 7.3, 5.2, 2.8, 1H), 5.15 (ddq, J =
10.7, 6.4, 2.2, 1H), 5.17 (dd, J = 9.5, 9.5, 1H), 5.28 (ddd, J = 11.8,
9.5, 5.1, 1H), 5.35 (ddd, J = 5.2, 3.5, 1.3, 1H), 5.77 (dd, J = 16.0,
3.5, 1H), 5.90 (ddd, J = 16.0, 9.5, 1.3, 1H), 7.33–7.40 (m, 4H),
7.47–7.54 (m, 2H), 7.90–7.95 (m, 4H) ppm.
a-12. 1H NMR (400 MHz, CDCl3) d 0.00–0.12 (m, 12H,
t
t
SiMe2 Bu), 0.85–0.97 (m, 18H, SiMe2 Bu), 1.21 (d, J = 5.5, 3H,
10-H), 1.65–1.87 (m, 2H, 8-H), 2.02 (s, 3H, OAc), 2.06 (s, 3H,
OAc), 2.11–2.17 (m, 2H, 2ꢀ-H), 2.17 (s, 3H, OAc), 2.49 (dd, J =
14.0, 6.0, 1H, 2ax-H), 2.58 (dd, J = 14.0, 1.3, 1H, 2eq-H), 3.94 (ddd,
J = 6.0, 4.1, 1.3, 1H, 3-H), 4.00–4.21 (m, 4H, 6ꢀ-H + 5ꢀ-H + 7-H),
4.32 (ddd, J = 4.1, 2.2, 1.9, 1H, 4-H), 4.92–4.99 (m, 1H, 9-H),
5.31–5.37 (m, 2H, 4ꢀ-H + 3ꢀ-H), 5.40 (bd, J = 2.8, 1H, 1ꢀ-H), 5.58
(dd, J = 15.7, 2.2, 1H, 5-H), 5.88 (ddd, J = 15.7, 9.5, 1.9, 1H, 6-H)
ppm. 13C NMR (100 MHz, CDCl3) d −5.2, −5.0, −4.7, −4.2, 18.1,
18.2, 20.8, 20.8, 20.9, 21.4, 25.8, 25.8, 29.4, 29.6, 44.1, 62.7, 66.2,
66.6, 67.1, 68.0, 71.4, 73.3, 75.7, 93.7, 126.2, 136.5, 170.3, 170.4,
170.4, 170.5 ppm.
(3ꢀꢀ,4ꢀꢀ-Di-O-benzoyl-aꢀꢀ-D-digitoxyl)-(1ꢀꢀ→4ꢀ)-(aꢀ/bꢀ-D-oleandro-
syl)-(1ꢀ→7)-3,4-di-O-acetyl decarestrictine
D (17). General
procedure with disaccharide 16 (40 mg, 0.06 mmol), 3,4-di-
OAc-decarestrictine D (14) (18 mg, 1 eq.) in CH2Cl2–CH3NO2
˚
(2 + 0.5 mL) with MS 4 A (50 mg) and oxidizing reagent
(prepared from 4 (30 mg, 1.4 eq.) and Tf2O (7.1 lL, 0.7 eq.)
in 0.5 mL CH2Cl2), for 15 hours at −78 ◦C, followed by basic
work-up (120 mg, A-21), and iodophenylsulfonate scavenging
(200 mg azide resin, 2 mL CH3CN, microwave irradiation) gave,
ꢀ
after purification, 15.7 mg of a -17 (33% yield), 12.9 mg of
b-12. 1H NMR (400 MHz, CDCl3) d 0.00–0.12 (m, 12H,
bꢀ-17 (28% yield) and 4.1 mg of a fraction of a–b-anomers (1 :
1; 9% yield). The overall yield of the reaction is 70% and the
a–b-selectivity is 1.15 : 1. HRMS calcd C41H50O15Na [M + Na]
805.3047, observed 805.3053, calcd C41H49O15 [M − H] 781.3071,
observed 781.3076.
t
t
SiMe2 Bu), 0.85–0.97 (m, 18H, SiMe2 Bu), 1.22 (d, J = 6.14, 3H,
10-H), 1.65–1.87 (m, 2H, 8-H), 1.93–2.07 (m, 2H, 2ꢀ-H), 2.03 (s,
3H, OAc), 2.06 (s, 3H, OAc), 2.16 (s, 3H, OAc), 2.35 (dd, J = 14.3,
9.8, 1H, 2ax-H), 2.83 (dd, J = 14.3, 3.6, 1H, 2eq-H), 3.81 (dt, J =
6.7, 1.0, 1H, 5ꢀ-H), 3.87 (ddd, J = 9.8, 6.5, 3.6, 1H, 3-H), 4.00–
4.21 (m, 4H, 4-H + 7-H + 6ꢀ-H), 4.80 (dd, J = 9.3, 3.4, 1H, 1ꢀ-H),
4.93–4.99 (m, 1H, 3ꢀ-H), 5.21 (ddq, J = 6.3, 6.3, 1.7, 1H, 9-H),
5.24 (bd, J = 3.0, 1H, 4ꢀ-H), 5.61 (dd, J = 16.0, 4.1, 1H, 5-H),
5.85 (ddd, J = 16.0, 9.2, 1.0, 1H, 6-H) ppm. 13C NMR (100 MHz,
CDCl3) d −4.9, −4.8, −4.6, −4.4, 18.1, 18.1, 20.7, 20.8, 20.8, 21.6,
25.7, 25.8, 31.8, 38.2, 43.5, 61.8, 65.3, 67.9, 68.5, 70.9, 72.1, 73.5,
82.6, 101.1, 126.1, 138.6, 170.0, 170.4, 170.4, 170.5 ppm.
aꢀ-17. 1H NMR (400 MHz, CDCl3) d 1.24 (d, J = 6.5, 3H),
1.26 (d, J = 6.5, 3H), 1.32 (d, J = 6.2, 3H), 1.50 (ddd, J = 12.9,
11.4, 3.5, 1H), 1.71 (ddd, J = 14.2, 11.1, 11.0, 1H), 1.89 (ddd, J =
14.2, 3.3, 1.5, 1H), 2.07 (s, 3H), 2.10–2.25 (m, 2H), 2.37 (s, 3H),
2.37 (ddd, J = 15.0, 3.7, 1.3, 1H), 2.60 (dd, J = 14.1, 3.3, 1H),
2.66 (dd, J = 14.1, 7.5, 1H), 3.24 (dd, J = 9.1, 8.9, 1H), 3.27 (s,
3H), 3.44 (ddd, J = 11.4, 8.9, 5.0, 1H), 3.63 (dq, J = 9.1, 6.2,
1H), 4.04 (ddd, J = 11.0, 9.2, 3.3, 1H), 4.59 (dq, J = 9.5, 6.5,
1H), 4.93 (bd, J = 3.5, 1H), 5.02 (dd, J = 9.5, 3.3, 1H), 5.12 (m,
2H), 5.35 (bdd, J = 4.5, 1.3, 1H), 5.38 (ddd, J = 6.0 3.6, 1.0, 1H),
5.65 (ddd, J = 3.7, 3.5, 3.3, 1H), 5.73 (dd, J = 16.0, 3.6, 1H), 5.87
(ddd, J = 16.0, 9.2, 1.0, 1H), 7.37 (m, 2H), 7.45 (m, 2H), 7.53 (m,
1H), 7.62 (m, 1H), 7.93 (m, 2H), 8.06 (m, 2H) ppm. 13C NMR
(100 MHz, CDCl3) d 17.5, 18.0, 20.9, 21.0, 21.5, 33.8, 34.1, 34.7,
(3ꢀ,4ꢀ-Di-O-benzoyl-2-deoxy-a-L-arabino-hexopyranosyl)-(1ꢀ→7)-
3,4-di-O-acetyl-decarestrictine D (15). General procedure with
thioglycoside 13 (32 mg, 0.06 mmol), 3,4-di-OAc-decarestrictine
D (18.4 mg, 1 eq.) in CH2Cl2–CH3NO2 (2 + 0.5 mL) with MS
˚
4 A (50 mg) and oxidizing reagent (prepared from 4 (33 mg,
1.5 eq.) and Tf2O (7.7 lL, 13 mg, 0.75 eq.) in 0.5 mL CH2Cl2), for
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39.8, 56.6, 62.9, 67.0, 67.3, 68.2, 70.6, 72.1, 73.0, 77.2, 78.9, 82.0,
95.6, 97.5, 122.9, 128.1–133.2 (12 C), 136.5, 165.6, 165.8, 169.0,
169.3, 169.9 ppm.
4195; S. V. Ley and I. R. Baxendale, Nat. Rev. Drug Discovery, 2002, 1,
573–586.
4 Recent examples of hypervalent iodine reagents in solid phase assisted
synthesis: S. V. Ley, A. W. Thomas and H. Finch, J. Chem. Soc., Perkin
Trans. 1, 1999, 669–671; Md. D. Hossain and T. Kitamura, Synthesis,
2006, 1253–1256.
5 M. S. Yusubov, M. P. Gilmkhanova, V. V. Zhdankin and A. Kirschning,
Synlett, 2007, 563–566; A. Kirschning, M. S. Yusubov, R. Ya.
Yusubova, K.-W. Chi and J. Y. Park, Beilstein J. Org. Chem., 2007,
19.
6 E. Kunst, F. Gallier, G. Dujardin, M. S. Yusubov and A. Kirschning,
Org. Lett., 2007, 9, 5199–5202.
7 J. G. Sharefkin and H. Saltzman, Org. Synth, 1973, Coll. Vol. 5, p. 660
or 1963, vol. 43, p. 62.
8 N. S. Zefirov, V. V. Zdhankin, V. V. Dan’kov and A. S. Koz’min,
Russ. J. Org. Chem., 1984, 20, 401–403.
9 A. Kirschning, A. Scho¨nberger and M. Jesberger, Org. Lett., 2001, 3,
3623–3626; J. Jaunzems, D. Kashin, A. Scho¨nberger and A. Kirschning,
Eur. J. Org. Chem., 2004, 3435–3446.
10 J. Jaunzems, E. Hofer, M. Jesberger, G. Sourkouni-Argirusi and A.
Kirschning, Angew. Chem., Int. Ed., 2003, 42, 1166–1170; J. Jaunzems,
G. Sourkouni-Argirusi, M. Jesberger and A. Kirschning, Tetrahedron
Lett., 2003, 44, 637–639.
bꢀ-17. 1H NMR (400 MHz, CDCl3) d 1.22 (d, J = 6.3, 3H),
1.26 (d, J = 6.3, 3H), 1.28–1.42 (m, 1H), 1.44 (d, J = 6.0, 3H),
1.81 (ddd, J = 14.1, 11.2, 11.2, 1H), 1.97 (ddd, J = 14.1, 3.2, 1.6,
1H), 2.15 (s, 3H), 2.17 (s, 3H), 2.10–2.23 (m, 2H), 2.38 (ddd, J =
15.0, 3.6, 1.1, 1H), 2.56 (dd, J = 14.2, 2.4, 1H), 2.70 (dd, J = 14.2,
7.1, 1H), 3.10–3.19 (m, 2H), 3.27 (s, 3H), 3.25 (dd, J = 8.8, 8.8,
1H), 4.27–4.35 (m, 2H), 4.60 (dq, J = 9.7, 6.3, 1H), 5.01 (dd, J =
9.7, 3.2, 1H), 5.05 (ddd, J = 7.1, 5.0, 2.4, 1H), 5.15–5.22 (m, 1H),
5.33–5.40 (m, 2H), 5.62 (ddd, J = 3.6, 3.4, 3.2, 1H), 5.63 (ddd,
J = 16.1, 9.5, 1.2, 1H), 5.80 (dd, J = 16.1, 3.4, 1H), 7.30–8.10 (m,
10H) ppm.13C NMR (100 MHz, CDCl3) d 17.5, 18.5, 20.9, 21.0,
21.4, 33.5, 33.7, 35.7, 41.0, 56.3, 62.6, 67.4, 68.2, 70.8, 70.9, 72.0,
73.0, 76.4, 80.8, 81.4, 95.5, 97.1, 126.1, 127.5–133.5 (12 C), 134.2,
165.5, 165.9, 169.1, 169.5, 169.8 ppm.
11 For other examples of polymer-assisted glycosidations in solution see:
R. N. MacCoss, P. E. Brennan and S. V. Ley, Org. Biomol. Chem., 2003,
1, 2029; H. Paulsen and O. Lockhoff, Chem. Ber., 1981, 114, 3102–
3114.
Notes and references
1 Reviews on hypervalent iodine reagents: V. V. Zdhankin and P. J. Stang,
Chem. Rev., 2002, 102, 2523–2584; M. Ochiai, Top. Curr. Chem., 2003,
224, 5–68; A. Varvoglis, The Chemistry of Polycoordinated Iodine, VCH,
Weinheim, 1992.
2 R. D. Richardson and T. Wirth, Angew. Chem., Int. Ed., 2006, 45,
4402–4404.
12 J. Thiem and H. Karl, Synthesis, 1978, 696–698; L. Laupichler, H. Sajus
and J. Thiem, Synthesis, 1992, 1133–1136.
13 E. Kunst and A. Kirschning, Synthesis, 2006, 2397–2403.
14 G. Dra¨ger, A. Kirschning, R. Thiericke and M. Zerlin, Nat. Prod. Rep.,
1996, 13, 365–375.
15 G. Dra¨ger, A. Garming, C. Maul, M. Noltemeyer, R. Thiericke, M.
Zerlin and A. Kirschning, Chem. Eur. J., 1998, 4, 1324–1333.
16 F. Gallier, Ph. D. thesis, Universite´ du Maine, Le Mans, France,
2007.
3 A. Kirschning, H. Monenschein and R. Wittenberg, Angew. Chem.,
Int. Ed., 2001, 40, 650–679; S. V. Ley, I. R. Baxendale, R. N. Bream,
P. S. Jackson, A. G. Leach, D. A. Longbottom, M. Nesi, J. S. Scott,
R. I. Storer and S. J. Taylor, J. Chem. Soc., Perkin Trans. 1, 2000, 3815–
898 | Org. Biomol. Chem., 2008, 6, 893–898
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