Synthesis of tin-containing cyclodextrins as potential enzyme models

Article abstract of DOI:10.1002/ejoc.201200756

The synthesis and the characterization of two types of water-soluble β-cyclodextrin-supported organotin derivatives is described. These new tin-containing macromolecules were prepared through a free radical bishydrostannylation of the corresponding β-cyclodextrin propargylic ethers using Me₂SnClH prepared in situ with AIBN as initiator. The tin moieties were attached both on the primary and on the secondary rim of β-cyclodextrin in excellent yield.

Full text of DOI:10.1002/ejoc.201200756

FULL PAPER
DOI: 10.1002/ejoc.201200756
Synthesis of Tin-Containing Cyclodextrins as Potential Enzyme Models
You Zhou,[a] Lavinia Marinescu,[a] Christian Marcus Pedersen,[a] and Mikael Bols*[a]
Keywords: Enzyme models / Cyclodextrins / Radical reactions / Reduction / Tin / Stannanes
The synthesis and the characterization of two types of water-
responding β-cyclodextrin propargylic ethers using
soluble β-cyclodextrin-supported organotin derivatives is de- Me2SnClH prepared in situ with AIBN as initiator. The tin
scribed. These new tin-containing macromolecules were pre-
pared through a free radical bishydrostannylation of the cor-
moieties were attached both on the primary and on the sec-
ondary rim of β-cyclodextrin in excellent yield.
Introduction
Tin hydrides are valuable reagents in synthetic organic
chemistry. Many free radical reactions such as C–C bond
formations and reductions are performed with the assist-
ance of tin hydrides.[1] A number of tin hydrides are known,
with tributyltin hydride being by far the most commonly
used. The main drawback of using tin reagents is the prob-
lem of separating the tin products from the reaction mixture
and the toxicity of tin compounds, which becomes still
more crucial when tin hydrides are used in stoichiometric
quantities.[2] Several techniques have been used to overcome
these problems such as special workup procedures,[2g,2h]
modified stannane species,[3] polymer-supported tin rea-
gents,[4] and the use of catalytic amounts of tin hydrides.[5]
Cyclodextrins are cone-shaped water-soluble macrostruc-
tures, capable of binding lipophilic substrates inside their
hydrophobic cavity. They are commonly used as supra-
molecular hosts and can occasionally perform catalysis on
the complexed guest.[6] In fact, a number of different reac-
tions have been found to be catalyzed by cyclodextrin deriv-
atives in aqueous solution in an enzymatic manner.[7] The
underlying goal behind the present work was to obtain a
potential artificial enzyme that could catalyze radical reac-
Figure 1. The overall purpose with the tin hydride containing artifi-
cial enzymes was to achieve shape-selective radical reduction of
halides.
Whereas cyclodextrin–tin conjugates are, to the best of
tions (Figure 1). We envisaged that this could be achieved our knowledge, unprecedented, the interactions between
by, for the first time, linking a cyclodextrin covalently to a cyclodextrins and tin reagents have been studied before, and
tin hydride. This could provide higher efficiency and shape complicated equilibrium species were observed.[8] Studies of
selectivity of the catalysis while also making the tin enzyme organotin complexes with cyclodextrin in aqueous media[9]
easy to remove from the product.
have revealed that the tin atom is positioned close to the
secondary rim of the cyclodextrin cavity. β-Cyclodextrin
has also been used as ligand to SnIV in aqueous alkaline
solutions.[10] However, to obtain reliable data for the effect
of cyclodextrin binding on tin catalysis, the use of cova-
lently linked tin is vastly preferred. Therefore, we have pre-
pared cyclodextrin tin derivatives 1–7 (Figure 2) in which
the tin moiety is attached to either the primary or second-
ary rim. The combination of tin hydride and cyclodextrin
[a] Department of Chemistry, University of Copenhagen,
Universitetsparken 5, 2100 Copenhagen Ø, Denmark
Fax: +45-35320214
E-mail: bols@chem.ku.dk
Homepage: www.ki.ku.dk
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200756.
Eur. J. Org. Chem. 2012, 6383–6389
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Y. Zhou, L. Marinescu, C. M. Pedersen, M. Bols
FULL PAPER
is intended to mimic an enzyme active site and, indeed, a
few preliminary experiments with 6 suggests that they may
work as intended.
Scheme 1. Synthesis of monosubstituted β-cyclodextrin precursors.
Compounds 9 and 10 were used as cyclodextrin precur-
sors for the β-cyclodextrin-supported tin reagents. Di-
methyl-tin derivatives were considered to be the most suit-
able tin moiety beause self-inclusion into the cyclodextrin
cavity is less likely than with a large aliphatic or aromatic
group. To connect the tin moiety with the cyclodextrin, a
Grubbs diene metathesis between the allyl-cyclodextrin 9
and vinyl-dimethylphenyl-tin compound 11, was attempted
as outlined in Scheme 2.
Figure 2. Sn-containing cyclodextrins prepared in this work.
Results and Discussion
To selectively modify cyclodextrins is a rather demanding
task and the chemistry behind it is often difficult and low
yielding. Compounds 1–7 are each modified in different po-
sitions, which make different protection–deprotection stra-
tegies necessary. All compounds were prepared via partly
protected intermediates with a single free hydroxyl group
that can be functionalized. When a selective mono-modifi-
cation at the primary hydroxyl groups is needed, there are
two possible strategies: a direct mono-substitution pro-
cedure[11] that will provide a mixture of products that is
difficult to separate, or the diisobutylaluminum hydride
(DIBAL-H) deprotection method,[12] which has recently
been successfully optimized by the Sollogoub group. The
latter method was employed to obtain the starting β-per-
benzylated mono-alcohol 8 (Scheme 1), which was used as
the starting material for the benzylated tin derivatives 1
(Figure 2).
Scheme 2. Proposed synthesis of tin-β-cyclodextrin derivative 12.
For the synthesis of the organotin compound 11, a step-
wise synthesis was followed as presented in Scheme 3. Phen-
yldimethyltin chloride 14 was prepared by double substitu-
tion of dimethyltin dichloride 13 with a large excess
(20 equiv.) of phenylmagnesium bromide in tetrahydrofuran
(THF) at –78 °C, followed by a controlled hydrochloric acid
mediated cleavage with 1 equiv. HCl in methanol.[15] Unfor-
tunately, compound 14 proved to be inactive to the next
substitution step (Scheme 3). When reacted with vinylmag-
nesium bromide or allylmagnesium bromide in THF, only
starting material could be isolated, and the formation of tin
derivatives 11 or 15 was not observed.
Compound 9 was made through allylation of β-cyclodex-
trin mono-alcohol 8 as outlined in Scheme 1; the procedure
was based on previously reported allylations.[13] The 6A-
alcohol 8 was treated with allyl bromide in the presence of
sodium hydride at 0 °C in N,N-dimethylformamide (DMF)
to give the desired product in 82% yield.
Alternatively, 8 was converted into the corresponding
propargyl ether 10[14] (Scheme 1). Treatment of the alcohol
with sodium hydride in DMF at 0 °C, and subsequent ad-
dition of freshly distilled propargyl bromide resulted, after
four hours, in full conversion into propargyl ether 10 in
88% yield after flash chromatography.
Scheme 3. Attempted synthesis of tin reagents 10 and 14.
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Tin-Containing Cyclodextrins as Enzyme Models
Because realization of the strategy presented in Scheme 2 tions.[21] Better results were obtained when the reaction was
proved difficult, direct hydrostannylation of 6A-allyl-β- driven towards the formation of ditin-derivative 18. Due to
cyclodextrin derivative 9 with Me2SnClH, prepared in situ, problematic separations from the excess of low molecular
was tried (Scheme 4).
weight tin compounds, compound 18 was used in the next
step without purification. Consequently, addition of phen-
ylmagnesium bromide (50 equiv.) in THF to the reaction
mixture of 18, afforded the final cyclodextrin-supported tin
derivative 1 in 60% yield (from 10) after chromatography
(Scheme 5).
However, final deprotection by hydrogenolysis of the
benzyl groups proved impossible. Attempts to perform
standard Pd/C hydrogenolysis and/or to use Pearlman’s cat-
alyst with H2, either at normal pressure or at 10 mbar, with
or without acid present, resulted in cleavage of the tin moi-
ety and decomposition of the product to the starting β-
cyclodextrin.
Scheme 4. Attempted direct hydrostannylation of 6A-allyl-β-cyclo-
dextrin derivative 9.
The instability of tin compounds under hydrogenolysis
conditions is, unfortunately, not unprecedented,[22] and
therefore another strategy for the synthesis of tin-contain-
ing β-cyclodextrins was needed that avoided the use of
benzyl groups.
Therefore, compounds 5–7 (Figure 1) were made by
monopropargylation of β-cyclodextrin as outlined in
Scheme 6. β-Cyclodextrin was treated with propargyl brom-
ide in aqueous NaOH, which gave a mixture of unreacted,
mono-, di- and poly-propargylated β-cyclodextrins. The
mono-propargylated fractions could be isolated at this step
from the unreacted and overreacted mixture by flash
chromatography using 2-propanol/aqueous ammonia mix-
ture.
Dialkylhalotin hydrides are readily available by in situ
hydride exchange between tri-n-butyltin hydride and dialk-
yltin dihalide[16] (Scheme 4). When allyl-β-cyclodextrin de-
rivative 9 was added to a solution of Me2SnClH in toluene,
in the presence of radical initiator AIBN, only starting ma-
terials were isolated even after reacting for several hours at
60 °C. In spite of this, there are examples in literature of
radical hydrostannylation of alkenes[17,18] and, specifically,
the addition of tin hydride to allyl ethers has been reported
previously.[4b,19] However, because alkynes are known to be
more reactive in radical hydrostannylation than their alkene
counterparts,[20] these were tried. Indeed, when the corre-
sponding 6A-propargyl ether β-cyclodextrin derivative 10
was heated to 60 °C in toluene with Me2SnClH, in the pres-
ence of AIBN, full conversion into cyclodextrin-supported
tin derivatives 17 and 18 was observed (Scheme 5).
Scheme 6. Monopropargylation of β-cyclodextrin.
Peracetylation of the monopropargylated fraction with
Ac2O/Et3N at elevated temperature gave a separable mix-
ture of 3A-, 6A-, and 2A-O-propargyl ethers. These regioiso-
mers were separated by chromatography in 11, 13, and 25%
yield, respectively (eluted in this order).
Scheme 5. Hydrostannylation of 6A-propargyl ether β-cyclodextrin
9.
By controlling the number of Me2SnClH equivalents and
Synthesis of the three possible tin-supported β-cyclodex-
the time, the reaction could be stopped at the monotin ad- trins 2–4 proceeded smoothly as outlined in Scheme 7. A
dition product 17. However, this was difficult to reproduce free-radical stannylation reaction of the propargyl ethers
due to difficulties in controlling the amount of catalytic 19–21 was achieved by using an excess of Me2SnClH
AIBN and the reaction time. Among the side-products were (5 equiv.) in toluene and AIBN as initiator at 60 °C.
distannanes, which are common in these types of reac- Me2SnClH was prepared in situ from 5 equiv. Bu3SnH and
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Y. Zhou, L. Marinescu, C. M. Pedersen, M. Bols
FULL PAPER
8–10 equiv. Me2SnCl2 in toluene, 30 min prior to the reac- mary or the secondary face was devised. The synthetic work
tion. Tin-derivatives 2–4 were isolated after chromatog- showed that benzyl protection groups should be avoided on
raphy in 71, 64, and 73% yield, respectively. Zemplén de- the cyclodextrin because they could not be removed with-
acetylation with NaOMe in methanol then gave the final out cleaving the carbon–metal bond. The Me2SnCl moiety
tin-supported β-cyclodextrin derivatives 5–7 in 96–100% is known to provide Me2SnH derivatives in situ upon re-
yield after ion exchange chromatography (Scheme 7).
duction with NaBH4 and, indeed, in a preliminary experi-
ment this appears to work. Further work is needed to im-
prove the conditions and find more suitable substrates for
the reactions.
Experimental Section
General: Solvents were distilled under anhydrous conditions. All
reagents were used as purchased without further purification.
Evaporation was carried out with a rotary evaporator. Glassware
used for water-free reactions was dried for 2 h at 130 °C before
use. Columns were packed with silica gel 60 (230–400 mesh) as the
stationary phase. TLC plates (Merck, kieselgel 60, F254) were visu-
alized by spraying with cerium sulfate (1%) and molybdic acid
(1.5%) in 10% H2SO4 and heating until colored spots appeared.
1H, 13C NMR and COSY experiments were carried out with a
Bruker 500 MHz spectrometer.
Scheme 7. Synthesis of β-cyclodextrin–tin conjugates 2–7.
Per-O-benzyl-6A-O-allyl-β-cyclodextrin (9): NaH (60%, 150 mg,
3.68 mmol, 5.0 equiv.) was added portionwise to a solution of 8
(2.16 g, 0.736 mmol) in anhydrous DMF (50 mL) at 0 °C under
nitrogen. After stirring at 0 °C for 30 min, allyl bromide (0.072 mL,
0.832 mmol, 1.13 equiv.) was then added dropwise at 0 °C. The re-
action mixture was stirred at 0 °C for 1 h and then kept at room
temperature for another 2 h under nitrogen. Cold water was added
dropwise to quench the reaction and the solution was removed in
vacuo. The residue was dissolved in EtOAc (30 mL), washed with
saturated aqueous NH4Cl, and the aqueous layer was extracted
with EtOAc (3ϫ20 mL). The organic layers were combined,
washed with brine, dried with MgSO4, filtered, and the solvent was
removed in vacuo. Purification on a silica column afforded com-
pound 9 (82%, 1.8 g) as a white foam; Rf = 0.45 (pentane/EtOAc,
A few radical reduction experiments of bromides con-
ducted according to the catalytic cycle depicted in Figure 1
were tried (Table 1). 4-Bromobenzyl bromide (22) or 2-(bro-
momethyl)naphthalene (23) were suspended in water at
70 °C with AIBN, NaBH4, and 6 (0.1 equiv.). No reaction
was observed with 23 and 22 when lower concentrations of
NaBH4 were used (Table 1, entries 1 and 5). Some re-
duction could be observed by GC–MS analysis of the reac-
tion of 22 with 2 equiv. NaBH4 (Table 1, entries 2 and 3).
When no tin-cyclodextrin was present, hydrolysis appeared
to occur. These preliminary experiments show that the con-
cept appears to work, but also revealed that the lack of
solubility of the substrate is a major problem. The use of
cosolvents (Table 1, entries 3 and 4) or more cyclodextrin
catalyst may help address this problem, but neither are ideal
solutions because cosolvents can inhibit complexation, and
the amount of catalyst is limited. The use of water-soluble
substrates as more attractive alternatives will be considered
in future experiments.
1
5:1). [α]D = +32.5 (c = 0.8, CHCl3). H NMR (300 MHz, CDCl3):
δ = 7.31–7.07 (m, 100 H, PhH), 5.82–5.69 (m, 1 H, CH=CH2),
5.27–4.98 (m, 16 H, 7ϫ 1-H, 1ϫ CH=CHH, 1ϫ CH=CHH, 7ϫ
CHHPh), 4.85–4.72 (m, 7 H, 7ϫ CHHPh), 4.60–4.33 (m, 26 H,
CH2Ph), 4.09–3.86 (m, 28 H, 7ϫ 3-H, 7ϫ 4-H, 7ϫ 5-H, 7ϫ 6-H),
3.82 (d, J = 5.1 Hz, 2 H, 1ϫ OCH2CH), 3.66–3.44 (m, 14 H, 7ϫ 6-
H, 7ϫ 2-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 139.32, 139.29,
138.38, 138.31, 138.21 (Cipso), 134.76 (CH=CH2), 128.31, 128.17,
128.00, 127.87, 127.84, 127.55, 127.45, 127.37, 127.33, 127.29,
127.19, 126.94 (CAr), 116.80 (CH=CH2), 98.65, 98.62, 98.48,
98.44, 98.37, 98.34 (C-1), 80.98, 80.90 (C-3), 79.01, 78.81, 78.31 (C-
2, C-4), 75.47, 75.30, 73.29, 72.82, 72.69, 72.10 (OCH2CH,
CH2Ph), 71.51 (C-5), 69.29 (C-6) ppm. MALDI-TOF-MS: m/z
calcd. for C185H194O35Na 2998.329; found 2998.059.
Table 1. Preliminary results from the reduction of bromides with
NaBH4 in water catalysed by 6 at 70 °C. AIBN (0.1 equiv.) was
present in all experiments. n.r.: no reaction, r: reaction observed.
Entry Substrate Solvent
NaBH4
(equiv.)
6
Result
(equiv.)
1
2
3
4
5
22
22
22
22
23
H2O
H2O
1.2
2
2
2
2
0.1
0.1
0.1
0
n.r.
r[a]
r[a]
r[b]
n.r.
H2O/MeOH[c]
H2O/MeOH[c]
H2O
Per-O-benzyl-6A-O-{3,3-bis[dimethyl(phenyl)stannyl]}propanyl-β-
cyclodextrin (1): Tributyltin hydride (0.498 mL, 1.816 mmol,
5.0 equiv.) was added to a solution of dimethyltin dichloride
(0.799 g, 3.632 mmol, 10.0 equiv.) in anhydrous toluene (27 mL) at
room temp. under nitrogen. After stirring for 20 min, this mixture
was added to a solution of 10[14] (1.080 g, 0.363 mmol) in anhy-
drous toluene (32 mL). The reaction flask was evacuated and back-
filled with nitrogen three times before the initiator AIBN was
added in one portion. The reaction mixture was then heated to
70 °C, stirred at this temperature for 2 h, and monitored by
0.1
[a] GC–MS indicated 4-bromotoluene. [b] GC–MS indicated 4-
bromobenzyl alcohol. [c] Ratio 39:1.
Conclusions
A synthetic method to prepare several β-cyclodextrin de-
rivatives containing a Me2SnCl moiety either on the pri- MALDI. When the starting material and monotin addition prod-
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Tin-Containing Cyclodextrins as Enzyme Models
uct 17 had been converted into ditin addition product 18, the sol-
vent was removed in vacuo. The residue was dissolved in anhydrous
THF (10 mL), and freshly made phenylmagnesium bromide
(18.15 mmol, 50 equiv.) solution in THF (35 mL) was added. The
reaction mixture was stirred at room temp. overnight. Water was
added slowly to quench the reaction and the aqueous layer was
extracted with EtOAc (3ϫ30 mL). The organic layers were com-
bined, washed with brine, dried with MgSO4, filtered, and the sol-
vent was removed in vacuo. Purification on a silica column afforded
compound 1 (60% over two steps, 741 mg) as a white foam; Rf =
0.29 (pentane/EtOAc, 4:1). [α]D = +124 (c = 1.0, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 7.21–7.16 (m, 4 H, SnPh), 7.12–6.91 (m,
106 H, Ph), 5.15 (m, 1 H, 1-H), 5.10–5.05 (m, 4 H, 1-H, CHHPh),
5.01 (m, 1 H, 1-H), 4.98–4.92 (m, 3 H, 1-H, CHHPh), 4.90–4.82
(m, 5 H, 1-H, CHHPh), 4.64–4.57 (m, 7 H, 1-H, CHHPh), 4.40–
4.15 (m, 26 H, CHHPh), 3.91–3.76 (m, 27 H, 7ϫ6-H, 7ϫ4-H,
7ϫ3-H, 6ϫ5-H), 3.68 (d, J = 9.2 Hz, 1 H, 1ϫ5-H), 3.48–3.30 (m,
13 H, 6ϫ6-H, 7ϫ2-H), 3.24 (d, J = 11.1 Hz, 1 H, 6-H), 3.22–3.16
(m, 1 H, OCHHCH2), 3.12 (dd, J = 14.3, 8.0 Hz, 1 H, OCHHCH2),
1 H, 4-H), 2.73 (t, J = 2.3 Hz, 1 H, CϵCH), 2.18 (s, 3 H, 1ϫ OAc),
2.13–2.04 (m, 51 H, 17ϫ OAc), 2.03 (s, 3 H, 1ϫ OAc), 2.00 (s, 3 H,
1ϫ OAc) ppm. 13C NMR (126 MHz, CDCl3): δ = 171.22, 170.88,
170.85, 170.82, 170.71, 170.69, 170.66, 170.61, 170.55, 170.53,
170.45, 170.37, 169.79, 169.77, 169.67, 169.64, 169.54, 169.51
(C=O), 98.23, 97.51, 97.19, 96.95, 96.59, 96.32 (C-1), 81.38 (C-4),
80.33 (CϵCH), 78.15 (C-4), 77.27 (C-4), 76.68 (C-3A), 76.57 (C-
4), 76.15 (C-4), 75.41 (CϵCH), 72.45, 71.67, 71.54, 70.98, 70.85,
70.68, 70.64, 70.52, 70.18, 69.83, 69.29 (C-3, C-2, C-5), 62.86,
62.69, 62.54, 62.44 (C-6), 61.32 (OCH2CϵCH), 21.43, 21.18, 21.02,
20.94, 20.87 (COCH3) ppm. MALDI-TOF-MS: m/z calcd. for
C85H112O55Na+ 2035.586; found 2035.194.
Further elution afforded compound 21 (13%, 1.15 g) as a white
foam. Rf = 0.31 (CHCl3/MeOH, 50:1). [α]D = +117.2 (c = 1.0,
1
CHCl3). H NMR (500 MHz, CDCl3): δ = 5.36–5.23 (m, 7 H, 3-
H), 5.15 (d, J = 4.0 Hz, 1 H, 1-H), 5.10–5.04 (m, 6 H, 6ϫ1-H),
4.84–4.75 (m, 7 H, 7ϫ2-H), 4.60–4.54 (m, 5 H, 5ϫ6-H), 4.50 (dd,
J = 12.3, 1.4 Hz, 1 H, 6-H), 4.32 (d, J = 4.2 Hz, 1 H, 6-H), 4.29
(d, J = 4.0 Hz, 1 H, 6-H), 4.27–4.08 (m, 12 H, 4 ϫ 6-H, 1 ϫ
OCHHCϵCH, 6ϫ5-H), 4.01 (dd, J = 11.4, 2.9 Hz, 1 H, 6-H), 3.95
(d, J = 9.6 Hz, 1 H, 5-H), 3.84–3.79 (m, 1 H, 4-H), 3.77–3.65 (m,
7 H, 1ϫ6-H, 6ϫ4-H), 2.49 (t, J = 2.4 Hz, 1 H, CϵCH), 2.13–2.00
(m, 60 H, 20 ϫ OAc) ppm. 13C NMR (126 MHz, CDCl3): δ =
170.90, 170.79, 170.73, 170.67, 170.54, 170.52, 170.45, 170.38,
170.34, 169.58, 169.44, 169.38, 169.36 (C=O), 97.01, 96.91, 96.87,
96.77, 96.62, 96.55, 96.51 (C-1), 79.11 (CϵCH), 77.13, 76.91, 76.72,
76.63, 76.54, 76.43, 75.99 (C-4), 75.41, 75.39 (CϵCH), 71.65, 71.58,
71.12, 70.93, 70.86, 70.80, 70.71, 70.56, 70.42, 70.32, 70.18, 69.89,
69.71, 69.67, 69.59, 69.29 (C-2, C-3, C-5), 67.67 (C-6A), 62.77,
62.54 (C-6), 58.73 (OCH2CϵCH), 20.85, 20.81, 20.79, 20.77
(COCH3) ppm. MALDI-TOF-MS: m/z calcd. for C85H112O55Na+
2035.586; found 2035.780.
2
2.04–1.90 (m, 2 H, CH2CH2CH), 0.82–0.77 (m, JSn,H = 63 Hz, 1
2
H, CH2CHSnSn), 0.05–0.01 (m, JSn,H = 50 Hz, 12 H, 4 ϫ
SnCH3) ppm. 13C NMR (126 MHz, CDCl3): δ = 142.24, 142.23,
139.35, 139.32, 139.31, 139.28, 139.25, 139.21, 138.41, 138.38,
138.36, 138.34, 138.31, 138.29, 138.26, 138.24, 138.20 (Cipso),
136.16, 136.02, 135.89 (1JSn,C = 35 Hz, SnPhAr), 128.30, 128.16,
128.13, 128.01, 127.98, 127.92, 127.87, 127.81, 127.75, 127.69,
127.53, 127.51, 127.49, 127.43, 127.39, 127.32, 127.29, 127.25,
127.18, 127.09, 126.93 (CAr), 98.51, 98.42, 98.23 (C-1), 80.92, 80.89,
80.72, 79.77, 79.49, 79.33, 78.84, 78.68, 78.61, 78.44, 77.95, 77.65
(C-3, C-2, C-4), 75.83, 75.68, 75.42, 75.35, 75.16, 75.03 (CH2Ph,
OCH2CH2), 73.31, 73.28, 73.26, 73.24, 72.84, 72.76, 72.73, 72.63,
72.60, 72.55 (CH2Ph), 71.83 (C-5Ј), 71.57, 71.51, 71.38 (C-5), 69.60,
69.45, 69.29 (C-6), 30.82 (3JSn,C = 22 Hz, CH2CH2CH), 3.14 (1JSn,C
= 290 Hz, CH2CHSnSn), –8.82, –8.95, –8.98, –9.01 (1JSn,C
=
Further elution afforded compound 19 (25 %, 2.2 g) as a write
foam. Rf = 0.24 (CHCl3/MeOH, 50:1). [α]D = +109.2 (c = 1.0,
CHCl3). 1H NMR (500 MHz, CDCl3): δ = 5.38–5.20 (m, 7 H,
7ϫ3-H), 5.13–5.05 (m, 5 H, 5ϫ1-H), 5.03 (d, J = 4.0 Hz, 1 H, 1-
H), 5.01 (d, J = 3.4 Hz, 1 H, 1-H), 4.84–4.75 (m, 6 H, 6ϫ2-H),
4.61–4.49 (m, 7 H, 7ϫ6-H), 4.33–4.25 (m, 6 H, 6ϫ6-H), 4.22 (dd,
J = 10.1, 5.3 Hz, 1 H, 6-H), 4.18–4.10 (m, 8 H, 1ϫ CH2CϵCH,
6ϫ5-H), 4.05 (dd, J = 9.7, 2.4 Hz, 1 H, 5-H), 3.75–3.69 (m, 6 H,
6ϫ4-H), 3.64 (t, J = 9.3 Hz, 1 H, 4A-H), 3.55 (dd, J = 10.0, 3.4 Hz,
1 H, 2A-H), 2.45 (t, J = 2.3 Hz, 1 H, CϵCH), 2.13–2.11 (m, 21 H,
7ϫ OAc), 2.10–2.08 (m, 21 H, 7ϫ OAc), 2.07–2.02 (m, 18 H, 6ϫ
OAc) ppm. 13C NMR (126 MHz, CDCl3): δ = 170.99, 170.92,
170.82, 170.78, 170.75, 170.53, 170.48, 170.46, 170.43, 170.39,
170.31, 169.49, 169.42, 169.37, 169.36, 169.33, 169.12 (C=O), 98.67
(C-1A), 97.20, 97.05, 96.90, 96.63, 96.52 (C-1), 79.55 (CϵCH),
78.51, 77.89, 77.13, 76.88, 76.47, 76.42, 76.26 (C-4, C-2A), 75.30
(CϵCH), 72.48 (C-3A), 71.18, 71.00, 70.83, 70.75, 70.52, 70.37,
70.02, 69.68, 69.56 (C-3, C-2, C-5), 62.89, 62.56, 62.52, 62.50 (C-
6), 58.40 (OCH2CϵCH), 29.73, 21.06, 20.95, 20.84, 20.82
(COCH3) ppm. MALDI-TOF-MS: m/z calcd. for C85H112O55Na+
2035.586; found 2035.504.
330 Hz, SnCH3 ) ppm. MALDI-TOF-MS: m/z calcd. for
C201H216O35Sn2Na+ 3452.306; found 3452.771.
Per-O-acetyl-3A-O-propargyl-β-cyclodextrin (20), Per-O-acetyl-6A-
O-propargyl-β-cyclodextrin (21), and Per-O-acetyl-2A-O-propargyl-
β-cyclodextrin (19): To a stirred solution of β-cyclodextrin hydrate
(10.0 g, 8.8 mmol) and sodium hydroxide (3.88 g, 96.8 mmol) in
water (44 mL), propargyl bromide (490 uL, 4.4 mmol) was slowly
added and the resulting emulsion was stirred at room temp. for
12 h. The mixture was then neutralized with sulfuric acid, evapo-
rated to dryness, and a mixture of mono-propargyl-β-cyclodextrin
regioisomers was separated from β-cyclodextrin and di- and poly-
substituted β-cyclodextrin derivatives by chromatography on silica
gel (1-PrOH/H2O/concd. aq. NH3, 8:3:1). The resulting mixture of
mono-regioisomers was peracetylated: acetic anhydride (20 mL)
and triethylamine (20 mL) were added, and the mixture was stirred
at 90 °C for 3 h. The reagents were then coevaporated with toluene
and the residue was dissolved in EtOAc (400 mL), washed with 1 m
HCl (400 mL) and H2O (3ϫ 400 mL), and the organic phase was
dried with MgSO4 and concentrated under reduced pressure. Puri-
fication on a silica column afforded compound 20 (11%, 975 mg)
as a white foam; Rf = 0.39 (CHCl3/MeOH, 50:1). [α]D = +99.6 (c
= 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 5.52 (dd, J =
Per-O-acetyl-3A-O-[3,3-bis(chlorodimethylstannyl)]propanyl-β-cyclo-
dextrin (3): Tributyltin hydride (0.33 mL, 1.193 mmol, 8 equiv.) was
10.3, 9.1 Hz, 1 H, 3-H), 5.39–5.32 (m, 3 H, 3-H), 5.30–5.26 (m, 2 added to a solution of dimethyltin dichloride (0.524 g, 2.387 mmol,
H, 3-H), 5.12 (d, J = 3.8 Hz, 1 H, 1-H), 5.10 (d, J = 3.7 Hz, 1 H, 16.0 equiv.) in anhydrous toluene (11 mL) at room temp. under ni-
1-H), 5.08–5.04 (m, 4 H, 4ϫ1-H), 5.02 (d, J = 3.8 Hz, 1 H, 1-H), trogen. After stirring for 20 min, this mixture was added to a solu-
4.80–4.68 (m, 7 H, 2-H), 4.63–4.49 (m, 7 H, 7ϫ 6-H), 4.45–4.20
(m, 10 H, 7ϫ6-H, 1ϫ CH2-CϵCH, 1ϫ5-H), 4.15–4.00 (m, 6 H,
tion of compound 20 (300 mg, 0.149 mmol) in anhydrous toluene
(13 mL). Before AIBN was added, the reaction flask was evacuated
5 ϫ 5-H, 1 ϫ 3-H), 3.89–3.85 (m, 1 H, 5-H), 3.78 (dd, J = 9.6, and back-filled with nitrogen three times. Then the reaction mix-
8.6 Hz, 1 H, 4-H), 3.75–3.65 (m, 5 H, 5ϫ4-H), 3.58 (t, J = 9.3 Hz, ture was warmed to 70 °C, stirred at this temperature for 2 h and
Eur. J. Org. Chem. 2012, 6383–6389
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6387

Y. Zhou, L. Marinescu, C. M. Pedersen, M. Bols
FULL PAPER
monitored by MALDI. When the starting material and mono-tin
addition product were converted into di-tin addition product, the
reaction solution was removed in vacuo. The residue was dissolved
in CH2Cl2 (30 mL), washed with H2O (5ϫ20 mL) and the aqueous
phase was extracted with CH2Cl2 (5ϫ30 mL). The combined or-
ganic phase was dried with MgSO4, filtered, concentrated under
reduced pressure, and the residue was purified by flash chromatog-
raphy [CH3CN/MeOH, 20:1 (0.1% HCOOH)] to give 3 (228 mg,
(C-2A, C-4), 71.81, 71.44, 71.27, 70.95, 70.71, 69.95, 69.62, 69.28
(C-3, C-2, C-5), 62.80, 62.64, 62.44, 62.24, 62.12 (C-6), 60.44
(OCH2CH2), 30.34 (CH2CHSnSn), 29.73 (CH2CH2CH), 21.16,
21.00, 20.82 (COCH3), 1.96 (SnCH3) ppm. MALDI-TOF-MS: m/z
calcd. for C89H126Cl2O55Sn2Na+ 2407.438; found 2407.024.
3A-O-[3,3-Bis(chlorodimethylstannyl)]propanyl-β-cyclodextrin
(6):
Compound 3 (180 mg, 0.076 mmol) was dissolved in MeOH
(3 mL). NaOMe (0.1 m in MeOH, 3 mL) was added and the solu-
tion was stirred at room temp. overnight. Water (6 mL) was then
added, and the solution was neutralized with Dowex 120 (H+ form)
and concentrated. The solid was dissolved in water (10 mL) and
treatment with Dowex was repeated once more. The product was
obtained by freeze-drying; yield 118 mg (100%). 1H NMR
(500 MHz, D2O): δ = 5.41 (br., 1 H, 1-H), 5.30–4.98 (m, 6 H, 6ϫ1-
H), 4.01–3.56 (m, 44 H), 2.48–2.12 (m, 2 H, CH2CH2CH), 1.25
64%). Rf = 0.39 [CH3CN/MeOH, 18:1 (0.4% HCOOH)]. [α]D
=
+101.2 (c = 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 5.55
(dd, J = 10.2, 8.8 Hz, 1 H, 3A-H), 5.42–5.23 (m, 6 H, 6ϫ3-H),
5.16–5.00 (m, 7 H, 7ϫ1-H), 4.90–4.65 (m, 7 H, 7ϫ2-H), 4.59–
4.01 (m, 21 H, 7ϫ6-H, 7ϫ6Ј-H, 7ϫ5-H), 3.82–3.57 (m, 9 H, 1ϫ
OCH2CH2, 7ϫ4-H), 2.45–2.25 (m, 2 H, 1ϫ CH2CH2CH), 2.17–
2.00 (m, 60 H, 20ϫ OAc), 1.62–1.59 (m, 1 H, CH2CHSnSn), 0.87–
0.49 (m, 12 H, 4ϫ SnCH3) ppm. 13C NMR (126 MHz, CDCl3): δ
= 170.84, 170.79, 170.67, 170.59, 170.50, 170.45, 170.34, 170.27,
169.59, 169.43, 169.38, 169.16 (C=O), 96.88, 96.80, 96.71, 96.54,
96.49 (C-1), 78.28, 77.98, 77.87, 77.76, 77.68, 77.22, 77.06, 76.63
(C-4), 71.45, 71.31, 70.93, 70.83, 70.69, 70.60, 69.95, 69.92, 69.76,
69.59, 69.41, 69.29 (C-2, C-3, C-5), 68.25 (OCH2CH2), 62.58 (C-
6), 27.86 (3JSn,C = 23 Hz, CH2CH2CH), 23.47 (CH2CHSnSn),
20.98, 20.81 (COCH3), 1.28 (SnCH3) ppm. MALDI-TOF-MS: m/z
calcd. for C89H126Cl2O55Sn2Na+ 2407.438; found 2407.802.
2
(br., 1 H, CH2CHSnSn), 0.77–0.47 (m, JSn,H = 64 Hz, 12 H, 4ϫ
SnCH3) ppm. 13C NMR (126 MHz, D2O): δ = 101.90, 101.87,
101.82, 101.77 (C-1), 81.13, 81.12, 81.08, 81.03 (C-4), 78.14
(OCH2CH2), 73.04, 72.05, 72.01, 71.95, 71.82, 71.76, 71.70, 71.53
(C-2, C-3, C-5), 60.69, 60.47, 60.38, 60.28, 60.21, 60.15, 60.06 (C-
6), 27.46 (CH2CH2CH), 20.92 (CH2CHSnSn), –0.38 (SnCH3) ppm.
MALDI-TOF-MS: m/z calcd. for C49H86Cl2O35Sn2Na+ 1567.226;
found 1568.002.
Per-O-acetyl-6A-O-[3,3-bis(chlorodimethylstannyl)]propanyl-β-cyclo-
dextrin (4): Compound 21 (351 mg, 0.175 mmol) was subjected to
the procedure used for the preparation of 3, to give 4 (304 mg,
6A-O-[3,3-Bis(chlorodimethylstannyl)]propanyl-β-cyclodextrin
(7):
Compound 4 (300 mg, 0.128 mmol) was subjected to the procedure
1
used for the preparation of 7, to give 8 (190 mg, 98%). H NMR
73%). Rf = 0.29 [CH3CN/MeOH, 18:1 (0.4 %HCOOH)]. [α]D
=
(500 MHz, CD3OD): δ = 4.99–4.96 (m, 7 H, 7ϫ1-H), 3.91–3.84
(m, 19 H), 3.82–3.73 (m, 9 H), 3.70–3.61 (m, 2 H, OCH2CH2),
+95.2 (c = 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 5.38–
5.23 (m, 6 H, 6ϫ3-H), 5.17–5.04 (m, 7 H, 1ϫ3-H, 6ϫ1-H), 4.98 3.56–3.47 (m, 14 H), 2.53–2.20 (m, 2 H, CH2CH2CH), 1.68–1.48
2
2
(d, J = 3.9 Hz, 1 H, 1-H), 4.87–4.70 (m, 7 H, 7ϫ2-H), 4.66 (d, J
= 11.1 Hz, 1 H, 6-H), 4.59–4.50 (m, 4 H, 4ϫ6-H), 4.44 (d, J =
10.8 Hz, 1 H, 6-H), 4.33–4.04 (m, 13 H, 7ϫ6-H, 6ϫ5-H), 3.91 (d,
(m, JSn,H = 68 Hz, 1 H, CH2CHSnSn), 0.83–0.61 (m, JSn,H =
64 Hz, 12 H, 4ϫ SnCH3) ppm. 13C NMR (126 MHz, CD3OD): δ
= 104.05, 103.98, 103.91, 103.81 (C-1), 83.61, 83.04, 82.88, 82.77,
J = 9.6 Hz, 1 H, 5-H), 3.81–3.59 (m, 10 H, 1ϫ6-H, 7ϫ4-H, 1ϫ 82.72 (C-4), 75.60 (OCH2CH2), 74.99, 74.82, 74.74, 74.59, 74.35,
OCH2CH2), 2.41–2.32 (m, 1 H, 1ϫ CH2CHHCH), 2.28–2.21 (m, 74.27, 74.17, 74.06, 74.01, 73.68, 73.58, 72.01 (C-2, C-3, C-5),
1 H, 1ϫ CH2CHHCH), 2.14–2.02 (m, 60 H, 20ϫ OAc), 1.72–1.66
(m, 1 H, 1ϫ CH2CHSnSn), 0.89–0.65 (m, 12 H, 4ϫ SnCH3) ppm.
13C NMR (126 MHz, CDCl3): δ = 170.87, 170.83, 170.79, 170.68,
170.61, 170.59, 170.54, 170.50, 170.37, 170.30, 170.28, 169.58,
169.54, 169.48, 169.37, 169.35 (C=O), 97.14, 97.00, 96.93, 96.84,
96.70, 96.55, 96.33 (C-1), 77.65, 76.68, 76.56, 76.52 (C-4), 76.27
(OCH2CH2), 76.10 (C-4), 71.41, 71.35, 71.12, 70.96, 70.54, 70.41,
70.10, 69.84, 69.74, 69.65, 69.51, 69.39, 69.26 (C-5A, C-3, C-2, C-
5), 69.07 (C-6A), 62.65, 62.50, 62.27 (C-6), 29.26 (CH2CH2CH),
22.12 (CH2CHSnSn), 20.95, 20.90, 20.84, 20.80, 20.75, 20.69
(COCH3), 1.93, 1.86 (SnCH3) ppm. MALDI-TOF-MS: m/z calcd.
for C89H126Cl2O55Sn2Na+ 2407.438; found 2406.708.
62.05, 62.01, 61.95, 61.87, 61.80 (C-6), 30.47 (CH2CH2CH), 25.17
(CH2CHSnSn), 2.23 (SnCH3) ppm. MALDI-TOF-MS: m/z calcd.
for C49H86Cl2O35Sn2Na+ 1567.226; found 1566.922.
2A-O-[3,3-Bis(chlorodimethylstannyl)]propanyl-β-cyclodextrin
(5):
Compound 2 (250 mg, 0.105 mmol) was subjected to the procedure
1
used for the preparation of 6, to give 5 (155 mg, 96%). H NMR
(500 MHz, CD3OD): δ = 5.13 (d, J = 3.4 Hz, 1 H, 1-H), 5.01–4.95
(m, 6 H, 6ϫ1-H), 4.04–3.97 (m, 2 H), 3.90–3.83 (m, 21 H), 3.77–
3.72 (m, 7 H), 3.55–3.48 (m, 14 H, 7ϫ4-H, 7ϫ2-H), 2.58–2.40 (m,
2
2
H, CH2CH2CH), 1.79–1.61 (m, JSn,H
=
60 Hz,
1 H,
2
CH2CHSnSn), 0.78–0.67 (m, JSn,H
= 63 Hz, 12 H, 4ϫ
SnCH3) ppm. 13C NMR (126 MHz, CD3OD): δ = 103.98, 103.89,
103.88, 103.80, 103.75 (C-1), 102.32 (C-1A), 83.67, 83.28, 83.04,
82.90 (C-4), 75.03, 74.80, 74.25, 73.72, 73.54, 71.90, 71.77 (C-2, C-
3, C-5), 62.75 (OCH2CH2), 62.17, 61.87 (C-6), 30.47
(CH2CH2CH), 25.29 (CH2CHSnSn), 2.34 (SnCH3) ppm. MALDI-
TOF-MS: m/z calcd. for C49H86Cl2O35Sn2Na+ 1567.226; found
1567.679.
Per-O-acetyl-2A-O-[3,3-bis(chlorodimethylstannyl)]propanyl-β-cyclo-
dextrin (2): Compound 19 (342 mg, 0.170 mmol) was subjected to
the procedure used for the preparation of 3, to give 2 (288 mg,
71%). Rf = 0.47 [CH3CN/MeOH, 18:1 (0.4%HCOOH)]. [α]D
=
1
+110.0 (c = 1.0, CHCl3). H NMR (500 MHz, CDCl3): δ = 5.49–
5.22 (m, 7 H, 7ϫ3-H), 5.17–5.00 (m, 7 H, 7ϫ1-H), 4.85–4.69 (m,
6 H, 6ϫ2-H), 4.66–4.43 (m, 7 H, 7ϫ6-H), 4.42–4.01 (m, 15 H,
7ϫ6-H, 6ϫ5-H, 1ϫ OCH2CH2), 3.94–3.64 (m, 8 H, 1ϫ5-H,
Radical Reduction of Bromides 22 and 23: 4-Bromobenzyl bromide
H, 2A-H), 2.50–2.24 (m,
1 2 H, 22 (42.5 mg, 0.17 mmol, 1.0 equiv.) was added to a solution of 6
7ϫ4-H), 3.63–3.54 (m,
CH2CH2CH), 2.18 (s, 3 H, 1ϫ CH3), 2.15–2.07 (m, 42 H, 14ϫ (26 mg, 0.017 mmol, 0.1 equiv.) in water (5 mL) at room temp. un-
CH3), 2.06–2.00 (m, 15 H, 5ϫ CH3), 1.45–1.36 (m, 1 H,
der nitrogen. After stirring for 5 min, NaBH4 (12.9 mg, 0.34 mmol,
2.0 equiv.) was added. The reaction flask was evacuated and back-
filled with nitrogen three times before the initiator AIBN (2.8 mg,
0.017 mmol, 0.1 equiv.) was added in one portion. The reaction
mixture was heated to 70 °C, stirred at this temperature and moni-
tored by GC–MS.
2
CH2CHSnSn), 0.94–0.56 (m, JSn,H
= 62 Hz, 12 H, 4ϫ
SnCH3) ppm. 13C NMR (126 MHz, CDCl3): δ = 170.89, 170.81,
170.70, 170.66, 170.61, 170.53, 170.47, 170.39, 170.31, 169.91,
169.62, 169.53, 169.48 (C=O), 96.95, 96.90, 96.86, 96.58, 96.55,
96.46 (C-1), 78.34, 78.28, 78.07, 78.04, 78.00, 77.22, 76.62, 76.59
6388
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6383–6389

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Received: June 6, 2012
Published Online: October 5, 2012
Eur. J. Org. Chem. 2012, 6383–6389
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6389