The grignard reaction of cyclodextrin-6-aldehydes revisited: A study of the stereoselectivity upon addition of organometallic reagents to aldehydes and ketones

Article abstract of DOI:10.1002/ejoc.201000295

2^A-G, 3^A-G, 6^B-G -Icosakis-O-benzyl-6 ^A-O-oxo-ss-cyclodextrin was treated with aromatic and aliphatic Grignard reagents to give diastereomeric mixtures of the secondary alcohols with remarkable difference in polarity. Moderate-to-good yields and selectivity were obtained. By oxidizing the secondary alcohols, followed by a second Grignard reaction, good to excellent yields and selectivity of tertiary alcohols could be obtained. The stereochemistry of the reaction outcome was shown to be dependent on the order of addition of the Grignard reagents and could be efficiently controlled.

Full text of DOI:10.1002/ejoc.201000295

FULL PAPER
DOI: 10.1002/ejoc.201000295
The Grignard Reaction of Cyclodextrin-6-aldehydes Revisited: A Study of the
Stereoselectivity Upon Addition of Organometallic Reagents to Aldehydes and
Ketones
Emil Lindbäck,[a] You Zhou,[a] Lavinia Marinescu,[a] Christian M. Pedersen,[a] and
Mikael Bols*[a]
Keywords: Supramolecules / Carbohydrates / Cyclodextrins / Nucleophilic addition
2A–G,3A–G,6B–G-Icosakis-O-benzyl-6A-O-oxo-β-cyclodextrin
was treated with aromatic and aliphatic Grignard reagents to
give diastereomeric mixtures of the secondary alcohols with
remarkable difference in polarity. Moderate-to-good yields
and selectivity were obtained. By oxidizing the secondary
alcohols, followed by a second Grignard reaction, good to
excellent yields and selectivity of tertiary alcohols could be
obtained. The stereochemistry of the reaction outcome was
shown to be dependent on the order of addition of the Grig-
nard reagents and could be efficiently controlled.
Introduction
tively. Because of their ability to bind hydrophobic sub-
strates in their cavity, cyclodextrins are attractive com-
pounds as starting materials for the synthesis of artificial
enzymes,[2–4] and other supramolecular devices. Though
Cyclodextrins are readily available cyclic amylose oligo-
mers consisting of 6, 7 or 8 glucose units.[1] These com-
pounds are referred to as α-, β-, and γ-cyclodextrins respec-
Figure 1. Benzylated β-cyclodextrin-aldehyde and its reaction with organometallic reagents. This leads to two stereoisomers with rather
different polarity.
many interesting enzyme mimics have been made, a limiting
[a] Department of Chemistry, University of Copenhagen,
2100 Copenhagen, Denmark
factor in this research is probably the difficult and often low
yielding methods available for the preparation of modified
cyclodextrins.[5] Consequently new and elegant ways of
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000295.
Eur. J. Org. Chem. 2010, 3883–3896
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E. Lindbäck, Y. Zhou, L. Marinescu, C. M. Pedersen, M. Bols
FULL PAPER
Figure 2. TLC plate showing the different polarity of diastereomeric 6A,D-di-C-allyl-substituted nonadeca-O-benzylated β-cyclodextrins
in the eluent pentane/ethyl acetate 4:1 (left). Depiction showing how steric hindrance from the subsequent glucose residue prevents
substituents at C-6 to enter the tg conformation thereby forcing each diastereomer to adopt the shown conformers (right).
modifying these compounds are required and are indeed 1–17). Aliphatic Grignard reagents gave generally a modest
continuously being developed.[6] One of the very powerful yield of product, except methylmagnesium bromide which
methods with which to modify cyclodextrins is the method gave 82% of adducts 2a and 3a (entry 1).
developed by Sollogoub and Sinaÿ,[6–8] where perbenzylated
cyclodextrins are selectively mono- or di-6-debenzylated
with DIBAL-H in high yield. From the resulting alcohols,
Table 1. Results of reaction of organometallic reagents with benzyl-
ated β-cyclodextrin-aldehyde 1, methyl ketone 4a, phenyl ketone
aldehydes, such as 1 (Figure 1), can readily be obtained
from oxidation by Dess–Martin periodane (DMP)[9] or
Swern conditions.[10] These are potentially important build-
ing blocks for artificial enzymes or molecular machines
since C–C bond formation at the oxidized position can be
achieved.
4b and phenyl ethynyl ketone 4c (* ratio may be reversed. iPr =
isopropyl).
Entry
Substrate Reagent
% Yield
Products (ratio)
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
MeMgBr
allylMgBr
BnMgBr
iPrMgCl
c-pentylMgBr
propargyl MgBr
Ph-ethynylMgBr
Ph-ethynylMgBr
(+ PhMe)
82
31
Ͻ14
Ͻ10
0
82
70
47
2a and 3a (1:1)
2b and 3b (3:4)
–
–
The Grignard reaction of perbenzylated β-cyclodextrin
derivatives containing one 6-aldehyde group, or two 6-al-
dehydo groups in the A and D rings, was therefore investi-
gated quite early with aliphatic Grignard reagents.[10] The
reaction gave the stereoisomeric secondary alcohols ex-
pected for 1,2-addition in diastereomeric ratios of about
1 : 3 ratio for the 6R- and 6S-isomers. Surprisingly the 6R-
isomers were consistently found to be much less polar in
terms of chromatographic retention times than the 6S-iso-
mers. The polarity difference, which disappeared upon
acetylation or oxidation, was interpreted as being caused by
the presence or absence of intramolecular hydrogen bond-
ing. The configurations of the diastereomers were deter-
mined showing that the polar isomer was the S-isomer, and
the apolar isomer is the R-isomer. Modeling studies sug-
gested that 6-C-alkylation restricts the conformation
around the C5–C6 bond such that the 6S-isomer will adopt
a gg conformation, which has the hydroxy group pointing
outwards, while the 6R-isomer will adopt a gt conforma-
tion, which has the OH group pointing towards the inner
face of the cyclodextrin (Figure 2).
–
2c and 3c (1:5)
2d and 3d (5:1)
2d and 3d (2:1)
9
1
1
1
1
1
1
1
Ph-ethynylLi
Ph-ethynylCeCl2
Ph-ethynylZnCl
PhMgBr
60
42
49
60
0
2d and 3d (8:1)
2d and 3d (4:1)
2d and 3d (5:4)
2e and 3e (11:1)
–
2f and 3f (15:1)
2f and 3f (5:1)
10
11
12
13
14
15
PhLi
4-F-C6H4MgBr
4-F-C6H4MgBr
(+ MgBr2)
71
57
16
17
18
19
20
21
22
23
1
1
2-pyridylMgBr
2-pyridylLi
ethynylMgBr
PhMgBr
4-F-C6H4MgBr
allylMgBr
4-F-C6H4MgBr
Ph-ethynylMgBr
73
0
2g and 3g (7:1)
–
8a and 9a (4:1*)
8b and 9b (4:1*)
8c and 9c (4:1*)
8d (Ͼ99:1)
7a
7a
7a
7d
7e
7f
86
81
77
41
68
90
8e (Ͼ99:1)
9e (Ͼ99:1)
Benzylmagnesium bromide and isopropylmagnesium
Recently we wanted to attach other functional groups, chloride (entries 3–4) gave low yield of products that were
particularly pyridine, to the cyclodextrin. This led us to re- difficult to purify or separate from the aldehyde, and cy-
visit this reaction now using other, predominantly aromatic, clopentylmagnesium bromide (entry 5) gave no yield. Enoli-
organometallic reagents. We have also studied reaction of zation and possibly reduction of the aldehyde in the latter
organometallic reagents to the corresponding ketones, cases is the most likely reason why these reactions fare so
which are readily obtained from oxidation of the Grignard badly. Allyl and propargylmagnesium bromide (entries 2
products. We find that the yield and stereoselectivity of and 5) gave 33 and 82% of predominantly the polar S-iso-
these Grignard reactions depend very much on the reagent mers 3b and 3c. Again the difference in yield is remarkable
used.
and is a result of the allyl reagent giving unreacted starting
material and possibly side products; presumably enolisation
is a bigger problem with allylmagnesium bromide.
Results and Discussion
The aromatic Grignard reagents, phenyl, 4-fluorophenyl
β-Cyclodextrin-aldehyde[11] (1) (Figure 1) was treated and 2-pyridylmagnesium bromide gave good yields of pre-
with Grignard and organolithium reagents (Table 1, entry dominantly the apolar R-isomers 2e, 2f and 2g with selec-
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Grignard Reaction of Cyclodextrin-6-aldehydes Revisited
tivities up to 11:1 (entries 12, 14 and 16). However none of conformation around the C-5/C-6 bond and that the 6-H is
the aromatic organolithium reagents gave any product and not in gg position. This is consistent with the interpretation
starting material appeared to be present after reaction. It is that the 6-H is in tg position, the aromatic group in gg
believed that these strongly basic compounds caused enoli- position, thereby on the outside of the cyclodextrin and the
zation of the aldehyde in 1. Phenylethynylmagnesium bro- hydroxyl group in gt position pointing towards the cavity;
mide behaved similar to aromatic Grignards giving a 70% the only alternative staggered conformer would leave the
yield of 2d in a 5:1 ratio over 3d (entry 7). The better yields 4-fluorophenyl group in the space-demanding tg-position
may be due to the lower reactivity of aryl and alkyl reagents which is improbable.
compared with the more reactive alkyl Grignard reagents,
In summary aromatic Grignard reagents yield rather se-
lectively the R-isomer upon addition to aldehyde 1, while
which causes more side reactions.[12]
All the stereoisomeric Grignard products had a polarity aliphatic Grignard reagents give a mixture with predomi-
similar to what had been observed previously, with one C- nance for S-isomer. If empirical stereoselectivity models can
6 stereoisomer being significantly more polar than the be applied here, and assuming that C4 is a sterically larger
other, and stereochemistry was assigned accordingly. How- group than O5 (intuitively reasonable), the Felkin–Anh po-
ever, to check if aromatic substituents might behave dif- lar model[13] (Figure 5) predict that the R-isomer should be
ferently we hydrolyzed the apolar, major isomer from the the preferred product. In this model a polar α-substituent,
reaction of 4-fluorophenylmagnesium bromide, presumably here O5, in the reacting aldehyde or ketone have to be ori-
2f, separated the arylated glucose residue from the unmodi- ented perpendicular to the carbonyl group so that there is
fied glucose residues by chromatography, and subjected it a favorable orbital overlap between its π*-orbital and the
to Fisher glycosylation to give 5a (Figure 3). Simulta- antibonding orbital of the C5–O5 bond. Attack by the nu-
neously the two reference compounds 5a and 5b were pre- cleophile (Nu) near the smallest group (H5) then result in
pared from methyl 2,3,4-O-benzyl-α--glucopyran-1,6-di- the observed stereochemistry.
uloside (4) by reaction with 4-fluorophenylmagnesium bro-
The observation that addition of MgBr2 result in a small
mide followed by hydrogenolysis (Figure 3). The identity of lowering of R-selectivity (entry 15) supports that chelation
5a and 5b was established by conversion of the major iso- is not involved in formation of the major product. Also the
mer 5b to the 4,6-benzylidene derivative 6 with benzalde- experiment with phenethynyllithium, where chelation can-
hyde dimethyl acetal and acid catalysis. In 6 NMR showed not occur and which gives R-product, fits the Felkin–Anh
a small coupling constant (5.4 Hz) between H-5 and H-6 polar model.
which is only consistent with the 6S-stereochemistry. This
Albeit the S-selectivity observed with some aliphatic
confirms that also for aromatic substituents the less polar reagents not is large, the difference in selectivity is never-
isomer has R-stereochemistry. A TOCSY spectrum of the theless puzzling. It suggests a difference in mechanism or
debenzylated 2f showed a very small J5,6 in the modified rate-determining step between aliphatic and aromatic
glucose residue. This shows that the compound has a fixed reagents.
Figure 3. Preparation of two reference monosaccharide derivatives, 5a and 5b, that could be used to determine the stereochemistry at C-
6. The major isomer 5b from addition of (4-fluorophenyl)magnesium bromide to glucose-6-aldehyde 4 was converted into the benzylidene
derivative 6. This compound had a small J5,6, which is consistent with S-stereochemistry only. Hydrolysis of the β-cyclodextrin derivative
2f and conversion to methyl glycoside led to the minor R-isomer 5a.
Eur. J. Org. Chem. 2010, 3883–3896
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E. Lindbäck, Y. Zhou, L. Marinescu, C. M. Pedersen, M. Bols
The single product formed from 7d has not been specifi-
FULL PAPER
Oxidation of the secondary alcohols 2 and 3 to the
ketone 7 is readily achieved with Dess–Martin periodinane cally determined, but it is assumed to be the S-isomer 8d
(DMP) or pyridinium dichromate solution (PDC) (Fig- based on the observed stereoselectivity in the Grignard re-
ure 4). This was done on 4 different alcohols giving ketones actions.
7a,7d,7e, and 7f. Addition of Grignard reagents to these
The stereochemistry of 8e and 9e was determined as out-
ketones proceeded in good yield with both aliphatic and lined in Figure 5. Cyclodextrin derivative 9e was hydro-
aromatic reagents to give the tertiary alcohols. From the genolyzed and subjected to acidic hydrolysis with IR-120
methyl ketone 7a mixtures of isomers, 8 and 9, were ob- ion-exchange resin followed by Fischer glycosylation with
tained, but from the other ketones 7d–f only a single isomer methanol and acid. The product was a mixture of methyl
of either 8 or 9 was formed. The relative ratio of the two glycosides from which the C6-modified methyl glycoside
isomers is readily determined by NMR, but the stereochem- was isolated and compared with reference samples using
ical identity of the isomers is not, and 8 and 9 have essen- TLC and HPLC. The reference samples were made from 4
tially identical chromatographic retention. For 8/9 a–c by reaction with the corresponding Grignard reagents fol-
(Table 1, entries 18–20) the stereochemistry of the isomers lowed by oxidation to the ketones 11 and 12 respectively
was not determined, because the product was mixtures that (Figure 5). These were then reacted with Grignard reagent
could not be separated. On the other hand for 8e and 9e, and deprotected to give 13S and 13R with high diastereo-
which gave pure products, the product was identified by hy- selectivity. Reaction of the isomer mixture with dimeth-
drolytic degradation and comparison with reference com- oxytoluene and acid gave the 4,6-benzylidene derivatives
pounds (see below).
10R and 10S that could be separated by chromatography.
These results show that reaction of 7e with 4-fluorophen- The relative stereochemistry of 14R and 14S could conclu-
ylmagnesium bromide exclusively yields the S-isomer 8e sively be determined from NOE experiments: In 14S there
(Table 1, entry 22), while reaction of 7f with phenethynyl- is strong NOE between the benzylidene proton and the aro-
magnesium bromide exclusively yield the R-isomer 9e matic protons of the 4-fluorophenyl group, that is not the
(Table 1, entry 23). This means that ketones 7e and 7f gives case in 14R, which shows a strong NOE to one of the pro-
stereoselectivity accordance with the Felkin–Anh polar tons on C7. Acidic hydrolysis of 14R and 14S to reference
model and thereby with the same mode of reaction as the compounds 10R and 10S was performed (not shown). The
aldehydes. It also means that the stereochemistry of the ter- hydrolysis product from 9e was found to be identical with
tiary center can be controlled: When starting from aldehyde 10S (Figure 5).
1 and reacting with Grignard reagent, oxidizing to ketone
Overall it can be concluded that the stereoselectivity of
and Grignard reaction the order of Grignard reagents de- the addition is similar for the reaction of ketones and for
termines the stereochemistry, so reversion of the order will the addition of large Grignard reagents to aldehydes: The
generate the antipode.
selectivity follows the one predicted by Felkin–Anh’s polar
Figure 4. Oxidation of secondary alcohols to the β-cyclodextrin ketone 4, 7e and 7f followed by reaction with organometallic reagents
to give tertiary alcohols.
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Grignard Reaction of Cyclodextrin-6-aldehydes Revisited
Figure 5. Preparation of two reference monosaccharide derivatives, 10S and 10R that could be used to determine the stereochemistry at
C-6 of tertiary alcohols 8e and 9e. The mixture of secondary alcohols from the Grignard reaction with 4 was oxidized to the ketones 11
and 12 followed by an additional Grignard reaction. After hydrogenolysis the reference compounds 10S and 10R were obtained. By
converting them into the 4,6-benzylidene derivatives 14S and 14R the stereochemistry could be determined by NMR studies. The insert
(bottom left) show nucleophilic addition to carbonyl group according to Felkin–Anh’s polar model.
as matrix. Spectra were calibrated using a polymer calibration stan-
dard.
2A–G,3A–G,4A–G,6B–G-Icosakis-O-benzyl-6A-deoxy-6A-oxy-6A-phenyl-
model. The selectivity is high and stereoselectivity of the
tertiary alcohols can be controlled by the order in which
the organometallic reactions are carried out.
β-cyclodextrin (7d):
A solution of compound 2e (706 mg,
0.234 mmol) in DCM (16 mL) was added PDC (793 mg,
2.1 mmol). The reaction mixture was left stirring overnight at room
temperature. Then Celite was added and the solvent was removed
under reduced pressure. The crude product was added on the top
of a silica pad, elution (EtOAc/n-pentane: 1/1) afforded compound
7d (98%, 693.1 mg) as a white foam; Rf = 0.59 (EtOAc/n-pentane:
Experimental Section
General: Solvents were distilled under anhydrous conditions. All
reagents were used as purchased without further purification.
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, 60, F254) were visual-
ized 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
Varian Mercury 300 or a Varian Unity 500 instrument. Monoiso-
topic mass spectra (MALDI-TOF MS) were obtained on a Bruker
Daltonics mass spectrometer using ditranol (1,8-dihydroxyanthron)
1
3/5); [α]D = +41.5 (c = 1.0, DCM). H NMR (300 MHz, CDCl3):
δ = 7.97–7.95 (m, 2 H, H arom.), 7.31–6.97 (m, 103 H, H arom.),
5.25–5.16 (m, 5 H), 5.13–5.09 (m, 3 H), 5.05–4.95 (m, 4 H), 4.91
(d, 2J = 11 Hz, 1 H, CHPh), 4.83–4.75 (m, 5 H), 4.68 (d, 2J =
11 Hz, 1 H, CHPh), 4.63 (d, 2J = 11 Hz, 1 H, CHPh), 4.59–4.32
2
(m, 22 H), 4.26 (d, J = 12 Hz, 1 H, CHPh), 4.16–3.78 (m, 28 H),
3.66–3.35 (m, 15 H), 2.78 [d, 2J(H,H) = 11 Hz, 1 H,] ppm. 13C
Eur. J. Org. Chem. 2010, 3883–3896
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E. Lindbäck, Y. Zhou, L. Marinescu, C. M. Pedersen, M. Bols
FULL PAPER
NMR (75 MHz, CDCl3): δ = 194.0 (C=O), 139.7–137.9 (C arom.
quat.), 135.6, 133.8 (C arom. quat.), 129.6–127.2 (Carom. tert.),
(0.95 mL, 8.52 mmol) in THF (2 mL) under nitrogen was cooled
down to 0 °C before slowly adding EtMgBr (8.52 mL, 1 molL–1
99.1, 99.0, 98.8, 98.7, 98.5, 98.2, (C-1), 81.5, 81.1, 80.9, 80.8, 80.5, in THF). Then the reaction mixture was allowed to reach room
79.7, 79.6, 79.3, 79.2, 79.0, 78.7, 78.2, 78.1, 77.6, 76.1, 75.8, 75.7,
75.5, 75.2, 73.8, 73.7, 73.5, 73.3, 73.1, 73.0, 72.9, 72.8 71.9, 71.8,
temperature and stirring for 30 min. The Grignard reagent was
added a solution of aldehyde 1 (1.0 g, 0.341 mmol) in THF
69.9,, 69.6, 68.9, 68.7 (CH, CH2) ppm. MALDI-TOF-MS: m/z (7.5 mL) at room temperature. The reaction mixture was left stir-
calcd. for C188H192O35Na 3034.321 found 3034.398.
ring at room temperature for 2 h before quenching by slowly adding
saturated aqueous NH4Cl (15 mL) at 0 °C. Then the layers were
separated and the water phase was extracted with DCM
(3ϫ15 mL). The combined organic phases were dried (MgSO4)
and concentrated in vacuo. The crude was dissolved in DCM
(25 mL) and was added Dess–Martin periodinane (444 mg,
1.02 mmol). The reaction mixture was left stirring overnight under
nitrogen at room temperature. The reaction was quenched by add-
ing Et2O (50 mL) and saturated aqueous NaHCO3 (50 mL) and
Na2S2O3 (2 g), followed by stirring for 1 h. Then the layers were
separated and the organic phase was washed with saturated aque-
ous NaHCO3 (50 mL) and H2O (50 mL). The organic layer was
dried (MgSO4) and concentrated under reduced pressure. Purifica-
tion on a silica column (EtOAc/n-pentane: 1/10Ǟ1/5) afforded the
desired product (70%, 721.6 mg) as a white foam; Rf = 0.37
2A–G,3A–G,4A–G,6B–G-Icosakis-O-benzyl-6A-deoxy-6A-(4-fluorophen-
yl)-6A-oxy-β-cyclodextrin (7f): See experimental part for compound
7d; yield (98%, 1.62 g); Rf = 0.35 (EtOAc/n-pentane: 2/3); [α]D
=
+34.4 (c = 0.5, DCM). 1H NMR (500 MHz, CDCl3): δ = 7.94 (dd,
3
4JH,F = 6, JH,H = 9 Hz, 2 H, H arom.), 7.26–6.98 (m, 102 H, H
3
arom.), 5.25–5.20 (m, 3 H, 1-H), 5.16 (d, J1,2 = 3 Hz, 1 H, 1-H),
5.14 (d, 3J1,2 = 3 Hz, 1 H, 1-H), 5.09–5.07 (m, 7 H, 2 1-H, 5CHPh),
5.02 (d, 2J = 10 Hz, 1 H, CHPh), 4.94 (d, 2J = 11 Hz, 1 H, CHPh),
4.88 (d, 2J = 11 Hz, 1 H, CHPh), 4.81–4.75 (m, 4 H), 4.72 (d, J =
2
11 Hz, 1 H, CHPh), 4.68–4.62 (m, 2 H, 2CHPh), 4.57–4.53 (m, 3
H), 4.51–4.41 (m, 12 H), 4.39–4.33 (m, 6 H), 4.31–4.26 (m, 3 H),
4.18 (br. s, 2 H), 4.11–3.76 (m, 25 H), 3.58–3.44 (m, 11 H), 3.41–
2
3.37 (m, 2 H), 2.90 (d, JH,H = 10 Hz, 1 H) ppm. 13C NMR
1
(75 MHz, CDCl3): δ = 193.0 (C=O), 166.1 (d, JC,F = 254 Hz, C
1
(EtOAc/n-pentane: 4/5); [α]D = +46.2 (c = 0.5, CHCl3). H NMR
arom. quat.), 139.7- 138.0 (C arom. quat.), 132.4–132.1 (C arom.
quat., C arom. tert.), 128.6–127.2 (C arom. tert.), 116.2 (d, 2JC,F
=
(300 MHz, CDCl3): δ = 7.52–6.96 (m, 105 H, H arom.), 5.46 (br.
2
s, 2 H, 1-H), 5.30 (d, J = 11 Hz, 1 H, CHPh), 5.21–5.08 (m, 8 H,
21 Hz, C arom. tert.), 99.2, 98.9, 98.7, 98.3, 98.2 (C-1), 81.4, 81.0,
80.8, 80.5, 80.0, 79.8, 79.5, 79.3, 79.1, 78.8, 78.1, 77.6, 75.9, 75.8,
75.4, 75.3, 73.8, 73.7, 73.5, 73.3, 73.1, 73.0, 72.9, 72.8, 72.1, 71.8,
71.7, 69.8, 69.6 69.5, 69.4, 68.9, 68.6 (CH, CH2) ppm. 19F NMR
(300 MHz, CDCl3): δ = –103.67 ppm. MALDI-TOF-MS: m/z
calcd. for C188H191FO35Na 3052.311, found 3052.307.
5 1-H, 3CHPh) 4.92–4.66 (m, 10 H), 4.50–3.94 (m, 51 H), 3.79–3.59
(m, 5 H), 3.54–3.40 (m, 10 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 183.5 (C=O), 139.9–138.4 (C arom. quat.), 133.6, 131.3 (C arom.
tert.), 129.2–127.3 (C arom. tert.), 119.8 (C arom. quat.), 99.3, 99.1,
98.9, 98.4, 98.1, 97.8 (C-1), 94.8, 86.8 (Csp), 81.9, 81.6, 81.5, 81.4,
81.2, 80.9, 80.4, 80.0, 79.8, 79.6, 79.4, 79.2, 79.1, 78.6, 77.1, 76.3,
76.1, 75.3, 75.2, 73.7, 73.6, 73.5, 73.1, 72.9, 71.8, 71.6, 71.4, 70.0,
69.7, 69.5, 69.3 (CH, CH2) ppm. MALDI-TOF-MS: m/z calcd. for
C190H192O35Na 3058.3 found 3058.1.
2A–G,3A–G,4A–G,6B–G-Icosakis-O-benzyl-6A-deoxy-6A-methyl-6A-
oxy-β-cyclodextrin (7a): A solution of aldehyde 1 (1.0 g,
0.341 mmol) in THF (5.5 mL) under nitrogen was slowly added
MeMgBr (1.14 mL, 3 molL–1 in Et2O) at room temperature. The
reaction mixture was left stirring for 1 h before quenching by slowly
addition of saturated aqueous NH4Cl (15 mL) at 0 °C. Then the
phases were separated and the aqueous phase was extracted with
DCM (3 ϫ 15 mL). The combined organic layers were dried
(MgSO4) and concentrated under reduced pressure. Then the crude
was dissolved in DCM (25 mL) and was added Dess–Martin
periodinane (444 mg, 1.02 mmol). The reaction mixture was left
stirring overnight under a nitrogen atmosphere. Quenched by add-
ing Et2O (50 mL) and saturated aqueous NaHCO3 (50 mL) con-
sisting of Na2S2O3 (2 g), followed by stirring for 1 h. Then the lay-
ers were separated and the organic phase was washed with satu-
rated aqueous NaHCO3 (50 mL) and H2O (50 mL). The organic
layer was dried (MgSO4) and concentrated in vacuo. Purification
on a silica column (EtOAc/n-pentane: 1/5) afforded ketone 6 (58%,
Preparation of (4-Fluorophenyl)magnesium Bromide (in THF): A
suspension of Mg turnings (485 mg, 20.0 mmol) in THF under ni-
trogen at room temperature was slowly added 1-bromo-4-fluoro-
benzene (1.57 mL, 14.3 mmol). The reaction mixture was left stir-
ring for 90 min before use.
2A–G,3A–G,6B–G-Icosakis-O-benzyl-6AR-(4-fluorophenyl)-β-cyclodex-
trin (2f) and 2A–G,3A–G,6B–G-Icosakis-O-benzyl-6AS-(4-fluoro-
phenyl)-β-cyclodextrin (3f)
Method A-1: A freshly prepared solution of (4-fluorophenyl)mag-
nesium bromide (3.17 mL in THF) was slowly added to a solution
of aldehyde 1 (559 mg, 0.190 mmol) in THF (7.4 mL) under nitro-
gen at ambient temperature. The reaction mixture was stirred for
2.5 h before quenching by slowly adding saturated aqueous NH4Cl
(10 mL) at 0 °C. The phases were separated and the water phase
was extracted with DCM (4ϫ10 mL). The combined organic
phases were dried (MgSO4) and concentrated under reduced pres-
585 mg) as a white foam; Rf = 0.35 (EtOAc/n-pentane: 3/5); [α]D
=
+27.6 (c = 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.27–
7.01 (m, 100 H, H arom.), 5.32 (d, 3J1,2 = 4 Hz, 1 H, 1-H), 5.25 (d,
3J1,2 = 4 Hz, 1 H, 1-H), 5.23–5.17 (m, 4 H, 2 1-H, 2CHPh), 5.13–
4.98 (m, 7 H, 3 1-H, 4CHPh), 4.87–4.76 (m, 6 H), 4.71 (d, 2J =
11 Hz, 1 H, CHPh), 4.66–4.60 (m, 2 H), 4.56–4.28 (m, 24 H), 4.26–
4.17 (m, 2 H), 4.12–3.82 (m, 25 H), 3.71–3.68 (m, 1 H), 3.62–3.35
(m, 13 H), 1.98 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3):
δ = 203.9 (C=O), 139.8–138.1 (C arom. quat.), 128.6–127.2 (C
arom. tert.), 99.0, 98.8, 98.6, 98.4, 98.2 (C-1) 81.6, 81.3, 81.1, 80.9,
80.5, 80.2, 79.6, 79.5, 79.3, 79.1, 78.9, 78.8, 77.6, 76.5, 76.1, 75.9,
75.8, 75.5, 75.4, 73.8, 73.7, 73.6, 73.5, 73.1, 73.0, 71.8, 71.6, 69.6,
69.2, 69.0 (CH, CH2), 26.4 (CH3) ppm. MALDI-TOF-MS: m/z
calcd. for C183H190O35Na 2971.302 found 2971.681.
sure. Purification on
a
silica column (EtOAc/n-pentane:
1/10Ǟ1/5) afforded the monol 2f (67%, 386.6 mg) as a white foam;
Rf = 0.40 (EtOAc/n-pentane: 3/5); [α]D = +35.0 (c = 1.0, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 7.36–7.17 (m, 102 H, H arom.),
7.05–6.99 (m, 2 H, H arom.), 5.57 (d, 3J1,2 = 3 Hz, 1 H, 1-H), 5.38–
5.32 (m 3 H, 2 1-H, CHPh), 5.27 (d, 2J = 11 Hz, 1 H, CHPh),
3
5.20–5.00 (m, 8 H), 4.93–4.86 (m, 4 H), 4.81 (d, JH,H = 5 Hz, 1
H), 4.76–4.41 (m, 30 H), 4.26–3.91 (m, 26 H), 3.78–3.36 (m, 15 H)
1
ppm. 13C NMR (75 MHz, CDCl3): δ = 162.5 (d, JC,F = 244 Hz,
C arom. quat.), 139.8–137.1 (C arom. quat.), 130.4 (d, 3JC,F = 8 Hz,
C arom. tert.), 128.7–127.2 (C arom. tert.), 114.9 (d, 2JC,F = 21 Hz,
2A–G,3A–G,4A–G,6B–G-Icosakis-O-benzyl-6A-deoxy-6A-oxy-6A-(phen- C arom. tert.), 99.5, 99.4, 99.3, 99.0, 98.7, 97.7 (C-1), 81.5, 81.4,
ylethynyl)-β-cyclodextrin (7e):
A
solution of phenylacetylene
81.3, 80.9, 80.4, 80.2, 79.8, 79.4, 79.3, 79.2, 76.4, 76.2, 75.9, 75.7,
3888
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3883–3896

Grignard Reaction of Cyclodextrin-6-aldehydes Revisited
75.2, 75.0, 74.7, 73.9, 73.8, 73.7, 73.6, 73.4, 73.2, 73.0, 72.9, 72.5,
72.4, 72.0, 71.9, 71.6, 70.1, 69.8, 69.6, 69.1 (CH, CH2) ppm. 19F
NMR (300 MHz, CDCl3): δ = –115.05 ppm. MALDI-TOF-MS:
m/z calcd. for C188H193FO35Na 3054.327 found 3054.110. Further
elution afforded monol 3f (4%, 23.5 mg) as a white foam; Rf = 0.34
4.87 (m, 5 H, 1 1-H, 4CHPh), 4.83–4.67 (m, 6 H), 4.62–4.48 (m,
20 H), 4.45–4.39 (m, 2 H), 4.34–3.94 (m, 26 H), 3.86–3.71 (m, 8
H), 3.67–3.37 (m, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
ppm. 141.6–138.5 (C arom. quat.), 128.7–127.2 (C arom. tert.) 99.7,
99.6, 99.3, 98.7, 98.4, 97.6 (C-1), 81.5, 81.3, 81.0, 80.8, 80.6, 80.5,
80.0, 79.8, 79.5, 79.4, 79.1, 77.8, 76.5, 76.2, 76.0, 75.9, 75.1 74.9,
1
(EtOAc/n-pentane: 3/5); [α]D = +33.4 (c = 1.0, CHCl3). H NMR
(300 MHz, CDCl3): δ = 7.47–7.05 (m, 102 H, H arom.), 6.99–6.93 74.6, 74.5, 73.8, 73.5, 73.3, 73.1, 72.9, 72.6, 72.5, 72.1, 72.0, 71.8,
3
(m, 2 H, H arom.), 5.76 (br. s, 1 H, 1-H), 5.60 (d, J1,2 = 4 Hz, 1
71.7, 69.9, 69.6, 69.0 (CH, CH2). MALDI-TOF-MS: m/z calcd. for
2
H, 1-H), 5.36–5.18 (m, 5 H, 1 1-H, 4CHPh), 5.14 (d, J = 11 Hz, C188H194O35Na 3036.337 found 3036.204.
1 H, CHPh), 4.99 (d, 3J1,2 = 3 Hz, 1 H, 1-H), 4.95 (d, 3J1,2 = 3 Hz,
Further elution afforded monol 3e (5%, 50.6 mg) as a white; Rf =
1 H, 1-H), 4.91–4.72 (m, 11 H), 4.63–4.60 (m, 2 H), 4.58–4.44 (m,
15 H), 4.42–4.37 (m, 2 H), 4.35–4.28 (m, 4 H), 4.23–4.04 (m, 12
H), 4.02–3.85 (m, 11 H), 3.79–3.64 (m, 9 H), 3.59–3.41 (m. 8 H)
3.21–3.02 (m, 3 H), 2.80–2.76 (m, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 161.7 (d, JC,F = 277 Hz, C arom. quat.), 139.9–138.6
(C arom. quat.), 138.4 (d, JC,F = 4 Hz, C arom. quat.), 138.1,
0.30 (EtOAc/n-pentane: 3/5); [α]D = +35.1 (c = 1.0, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 7.36–6.84 (m, 105 H, H arom.), 5.68
(br. s, 1 H, 1-H), 5.50 (d, 3J1,2 = 3 Hz, 1 H, 1-H), 5.28–5.23 (m, 2 H,
2CHPh), 5.19–5.09 (m, 3 H, 1 1-H, 2CHPh), 5.04 (d, 2J = 11 Hz, 1
1
3
H, CHPh), 4.86 (d, J1,2 = 3 Hz, 1 H, 1-H), 4.82–4.57 (m, 14 H),
4
4.57–4.51 (m, 2 H), 4.48–4.50 (m,11 H), 4.37–4.25 (m, 8 H), 4.22–
3.94 (m, 18 H), 3.92–3.75 (m, 7 H), 3.68–3.54 (m, 10 H), 3.49–3.22
2
137.9 (C arom. quat.), 128.7–127.0 (C arom. tert.), 114.9 (d, JC,F
= 20 Hz, C arom. tert.), 100.4, 100.2, 100.0, 98.8, 98.5, 98.4, 97.7
(C-1), 82.1, 81.6, 81.5, 81.4, 81.2, 81.0, 80.9, 80.7, 80.2, 80.1, 80.0,
79.5, 79.1, 79.0, 78.8, 77.6, 76.8, 76.5, 76.2, 76.1, 75.4, 74.9, 74.7,
74.4, 73.8, 73.7, 73.6, 73.4, 73.3, 73.0, 72.8, 72.7, 72.6, 72.3, 72.1,
72.0, 71.8, 71.5, 70.0, 69.2, 67.9 (CH, CH2) ppm. 19F NMR
(300 MHz, CDCl3): δ = –115.26 ppm. MALDI-TOF-MS: m/z
calcd. for C188H193FO35Na 3054.327 found 3054.012.
2
(m, 6 H), 3.06–3.00 (m, 2 H), 2.86 (d, JH,H = 17 Hz, 1 H), 2.58
2
(d, JH,H = 17 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
143.0–138.0 (C arom. quat.), 128.6–126.0 (C arom. tert.) 100.6,
100.0, 99.7, 98.7, 98.4, 97.7 (C-1) 82.1, 82.0, 81.5, 81.4, 81.1, 80.8,
80.7, 80.2, 80.1, 80.0, 79.6, 79.5, 79.0, 78.8, 79.0, 78.8, 77.6, 76.6,
76.5, 76.2, 76.1, 75.4, 74.9, 74.5, 73.8, 73.6, 73.5, 73.4, 73.3, 73.1,
73.0, 72.8, 72.6, 72.2, 72.1, 71.9, 71.7, 71.5, 69.9, 69.7, 69.3, 67.8
(CH, CH2) ppm. MALDI-TOF-MS: m/z calcd. for C188H194O35Na
3036.337 found 3036.152.
Method A-2: A suspension of MgBr2 [prepared by slowly adding
1,2-dibromoethane (0.49 mL, 5.53 mmol) to a suspension of Mg
turnings (134.4 mg, 5.53 mmol) in Et2O (3.2 mL) under nitrogen at
room temperature and stirring for 45 min] under nitrogen at room
temperature was slowly added aldehyde 1 (650 mg, 0.221 mmol)
dissolved in Et2O (5.3 mL). Then the mixture was left stirring for
45 min before cooling it down to 0 °C and slowly adding (4-fluo-
rophenyl)magnesium bromide (3.69 mL) [prepared by slowly add-
ing 1-bromo-4-fluorobenzene (1.5 mL, 14.1 mmol) to a suspension
of Mg turnings (480 mg, 19.7 mmol) in Et2O (7.9 mL) under nitro-
gen at room temperature, and stirring for 1.5 h]. The obtained reac-
tion mixture was left stirring for 10 min before adjusting to room
temperature and stirring for 80 min more followed by quenching
with saturated aqueous NH4Cl (10 mL) at 0 °C. Then the phases
were separated and the water layer was extracted with DCM
(3ϫ15 mL). The combined organic phases were dried (MgSO4)
and concentrated in vacuo. Purification on a silica column (EtOAc/
n-pentane: 1/10Ǟ1/5) afforded diastereoisomers 3 (48%, 323 mg)
and 7 (9%, 61.7 mg).
6AR-Propargyl-2A–G,3A–G,6B–G-icosakis-O-benzyl-β-cyclodextrin
(2c) and 6AS-Propargyl-2A–G,3A–G,6B–G-icosakis-O-benzyl-β-cyclo-
dextrin (3c): A solution of aldehyde 1 (540 mg, 0.184 mmol) in
Et2O (12 mL) at ambient temperature under nitrogen was slowly
added propargylmagnesium bromide solution in Et2O (12 mL)
[prepared by adding a solution of propargyl bromide (0.82 mL,
7.360 mmol) in Et2O (7 mL) to a suspension of Mg turnings
(203.4 mg, 8.464 mmol) and ZnBr2 (82 mg, 0.368 mmol) in Et2O
(5 mL) under nitrogen at room temperature and stirring for 2.5 h
before use]. The reaction mixture was left stirring for 3 h before
cooling it down to 0 °C and slowly adding saturated aqueous
NH4Cl (30 mL). The two phases were separated and the water
phase was extracted with Et2O (3ϫ30 mL). The combined organic
layers were dried (MgSO4) and concentrated in vacuo. Purification
on a silica column (EtOAc/n-pentane: 1/8Ǟ1/5) afforded monol 2c
(14%, 76 mg) as a white foam; Rf = 0.44 (EtOAc/petroleum ether:
1
1/3); [α]D = +37.7 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3):
2A–G,3A–G,6B–G-Icosakis-O-benzyl-6AR-phenyl-β-cyclodextrin (2e)
3
δ = 7.28–6.99 (m 100 H, H arom.), 5.43 (d, J1,2 = 3 Hz, 1 H, 1-
and
2A–G,3A–G,6B–G-Icosakis-O-benzyl-6AS-phenyl-β-cyclodextrin
3
H), 5.38 (d, J1,2 = 3 Hz, 1 H, 1-H), 5.20–5.12 (m, 2 H, 1 1-H,
(3e): A solution of aldehyde 1 (1.0 g, 0.341 mmol) in Et2O (3 mL)
under nitrogen was cooled down to –78 °C and was slowly added
PhMgBr (7.57 mL) [prepared by adding a solution of PhBr
(1.42 mL, 13.5 mmoL) in Et2O (10.7 mL) to a suspension of Mg
turnings (1.31 g, 54 mmol) in Et2O (4.3 mL) at room temperature
under nitrogen. Then the reaction mixture was stirred for 4 h before
use]. The reaction mixture was left stirring for 5 min at –78 °C be-
fore increasing the temperature to ambient temperature and stirring
for 24 h. The reaction was quenched by adding saturated aqueous
NH4Cl (15 mL) at 0 °C. Then the phases were separated and the
water phase was extracted with DCM (4ϫ15 mL). The combined
organic layers were dried (MgSO4) and concentrated in vacuo. Pu-
rification chromatography (EtOAc/n-pentane: 1/10Ǟ1/5) afforded
compound 2e (55%, 561.8 mg) as a white foam; Rf = 0.35 (EtOAc/
n-pentane: 3/5); [α]D = +36.8 (c = 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.52–7.20 (m, 105 H, H arom.), 5.65 (d,
3
1CHPh), 5.11–5.02 (m, 3 H, 1 1-H, 2CHPh), 4.98 (d, J1,2 = 3 Hz,
1 H, 1-H), 4.96–4.88 (m, 3 H, 1 1-H, 2CHPh), 4.85 (d, 3J1,2 = 3 Hz,
1 H, 1-H), 4.82–4.64 (m, 7 H), 4.55–4.27 (m, 26 H), 4.23 (dd, 1 H),
3
4.18–3.73 (m, 27 H), 3.73–3.35 (m, 14 H), 3.31 (dd, J = 9, 3 Hz,
1 H, 2-H), 3.13 (s, 1 H, OH), 2.62 (m, 1 H, CH2Cϵ), 2.31 (m, 1
H, CH2Cϵ), 2.00 (s, 1 H, CϵCH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 139.7–138.1 (C arom. quat.), 128.4–126.8 (C arom.
tert.), 99.5, 99.2, 99.1, 99.0, 98.8, 97.7, 97.5 (C-1), 82.2, 81.1, 81.0,
80.9, 80.6, 80.5, 80.0, 79.9, 79.5, 79.0, 78.8, 78.6, 77.3, 76.2, 75.9,
75.5, 75.4, 74.9, 74.8, 73.4, 73.2, 72.9, 72.8, 72.6, 72.4, 72.2, 71.7,
71.6, 71.2, 70.5, 70.2, 70.0, 69.6, 69.4, 69.2, 69.0, 68.7, 68.1, 22.4
(CH2Cϵ) ppm. MALDI-TOF-MS: m/z calcd. for C185H192O35Na
2996.324 found 2996.252.
Further elution afforded monol 3c (68%, 370 mg); Rf = 0.30
(EtOAc/petroleum ether: 1/3); [α]D = +30.7 (c = 1.0, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 7.37–6.96 (m, 100 H, H arom.), 5.67
3J1,2 = 3 Hz, 1 H, 1-H), 5.55 (d, J1,2 = 3 Hz, 1 H, 1-H), 5.41–5.35
(m, 3 H, 1 1-H, 2CHPh), 5.27–5.06 (m, 8 H, 3 1-H, 5CHPh), 4.99–
3
3
3
(d, J1,2 = 4 Hz, 1 H, 1-H), 5.42 (d, J1,2 = 3 Hz, 1 H, 1-H), 5.25–
Eur. J. Org. Chem. 2010, 3883–3896
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3889

E. Lindbäck, Y. Zhou, L. Marinescu, C. M. Pedersen, M. Bols
5.18 (m, 2 H, 1 1-H, 1CHPh), 5.10 (m, 1 H, CHPh), 5.07 (m, 1 H, (CH2CH =) ppm. MALDI-TOF-MS: m/z calcd. for
FULL PAPER
3
CHPh), 5.00 (d, J1,2 = 3 Hz, 1 H, 1-H), 4.91–4.58 (m, 10 H, 2 1-
H, 8CHPh), 4.56–4.14 (m, 26 H), 4.12–3.67 (m, 30 H), 3.65–3.33
(m,15 H), 3.15 (br. s, 1 H, OH), 2.35–2.24 (m, 2 H, CH2Cϵ), 2.18
(s, 1 H, CϵCH) ppm. 13C NMR (75 MHz, CDCl3): δ = 139.8–
137.4 (C arom. quat.), 128.4–126.8 (C arom. tert.), 99.7, 99.2, 99.1,
98.5, 98.0, 97.3 (C-1), 82.0, 81.7, 81.3, 81.2, 81.0, 80.9, 80.7, 80.3,
80.2, 80.0, 79.9, 79.6, 79.5, 79.2, 79.1, 78.7, 78.1, 77.3, 76.8, 76.3,
76.0, 76.0, 75.5, 75.3, 75.1, 74.7, 74.4, 74.3, 73.4, 73.3, 73.2, 73.1,
72.9, 72.7, 72.3, 72.0, 71.7, 71.6, 71.4, 71.2, 71.1, 71.0, 69.8, 69.4,
69.3, 68.5, 67.1, 23.9 (CH2Cϵ) ppm. MALDI-TOF-MS: m/z calcd.
for C185H192O35Na 2996.324 found 2996.121.
C185H194O35Na 2998.330 found 2998.268.
6AR-Phenylethynyl-2A–G,3A–G,6B–G-icosakis-O-benzyl-β-cyclodextrin
(2d) and 6AS-Phenylethynyl-2A–G,3A–G,6B–G-icosakis-O-benzyl-β-
cyclodextrin (3d)
Method B-1: A solution of phenylacetylene (0.484 mL, 4.32 mmol)
in THF (1 mL) at 0 °C under nitrogen was slowly added EtMgBr
(4.32 mL, 1 molL–1 in THF). Then the reaction mixture was al-
lowed to reach room temperature and stirring for additional
30 min. Then the solution of Grignard reagent was slowly added a
solution of aldehyde 1 (507 mg, 0.173 mmol) in THF (3.8 mL). The
reaction mixture was left stirring for 2 h at ambient temperature
before quenching the reaction by slowly adding saturated aqueous
NH4Cl (15 mL). After separation of the phases the water layer was
extracted with DCM (3ϫ15 mL). The combined organic phases
were dried (MgSO4) and concentrated under reduced pressure. Pu-
rification of the crude product by chromatography (EtOAc/n-pen-
tane: 1/10Ǟ1/5) afforded compound 2d (57%, 300.8 mg) as a white
foam; Rf = 0.45 (EtOAc/n-pentane: 4/5); [α]D = +39.9 (c = 1.0,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.42–6.95 (m, 105 H,
6AR-Allyl-2A–G,3A–G,6B–G-icosakis-O-benzyl-β-cyclodextrin (2b) and
6AS-Allyl-2A–G,3A–G,6B–G-icosakis-O-benzyl-β-cyclodextrin (3b): To
a solution of aldehyde 1 (1.0 g, 0.341 mmol) in Et2O (40 mL) at
ambient temperature under nitrogen was slowly added allylmagne-
sium bromide (5.16 mL) [prepared by adding a solution of allyl
bromide (0.685 mL, 7.92 mmol) in Et2O (8.5 mL) to a suspension
of Mg turnings (385.1 mg, 15.84 mmol) in Et2O (2.8 mL) under
nitrogen at room temperature and stirring for 90 min before use].
The reaction mixture was left stirring for 3 h before cooling it down
to 0 °C and slowly adding saturated aqueous NH4Cl (30 mL). The
two phases were separated and the water phase was extracted with
DCM (3ϫ30 mL). The combined organic layers were dried and
concentrated under reduced pressure. In order to separate the enol-
ization product from the two diastereoisomers the crude was dis-
solved in EtOH/THF (2/3, 8 mL) and was added NaBH4 (53.9 mg,
1.36 mmol) at room temperature. The reaction mixture was left stir-
ring overnight before slowly adding aqueous HCl (0.5 molL–1,
10 mL) and DCM (15 mL). Then the phases were separated and
the organic layer was washed with aqueous NaHCO3 (15 mL) and
H2O (15 mL). Then the organic phase was dried with MgSO4 and
concentrated under reduced pressure. Purification on a silica col-
umn afforded compound 2b (14%, 137 mg) as a white foam; Rf =
0.61 (EtOAc/n-pentane: 4/5); [α]D = +36.5 (c = 1.0, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 7.24–7.02 (m 100 H, H arom.), 5.78–
3
3
H arom.), 5.44 (d, J1,2 = 3 Hz, 1 H, 1-H), 5.30 (d, J1,2 = 3 Hz, 1
2
H, 1-H), 5.21.5.08 (m, 9 H, 5 1-H, 4CHPh), 5.00 (d, J = 11 Hz, 1
H, CHPh), 4.88–4.70 (m, 7 H), 4.63–4.28 (m, 26 H), 4.20–3.87 (m,
28 H), 3.68–3.46 (m, 15 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 139.7–138.1 (C arom. quat.), 132.2 (C arom. tert.), 128.9–127.3
(C arom. tert.), 122.9 (quat, C arom.), 98.8, 98.5, 98.4, 98.3 (C-1),
87.23, 87.18 (Csp), 81.5, 81.3, 81.1, 81.0, 80.1, 80.0, 79.6, 79.4, 79.2,
78.9, 78.7, 78.5, 76.1, 76.0, 75.7, 75.6, 75.5, 74.1, 73.9, 73.6, 73.3,
73.1, 73.0, 72.9, 72.2, 72.1, 72.0, 71.8, 71.7, 69.7, 69.6, 63.5 (CH,
CH2) ppm. MALDI-TOF-MS: m/z calcd. for C190H194O35Na
3060.337 found 3060.281.
Further elution afforde compound 3d (13%, 66.2 mg); Rf = 0.38
(EtOAc/n-pentane: 4/5); [α]D = +36.2 (c = 1.0, CHCl3). H NMR
1
(300 MHz, CDCl3): δ = 7.30–7.00 (m, 105 H, H arom.), 5.30 (br.
s, 2 H, 2 1-H), 5.23 (d, 3J1,2 = 3 Hz, 1 H, 1-H), 5.15–4.95 (m, 8 H),
4.91–4.84 (m, 2 H), 4.78–4.60 (m, 8 H), 4.57–4.21 (m, 26 H), 4.14–
3.76 (m, 27 H), 3.68–3.38 (m, 15 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 139.6–138.1 (C arom. quat.), 131.74 (C arom. tert.),
128.6–127.1 (C arom. tert.), 123.0 (C arom. tert.), 99.4, 99.3, 99.0,
98.8, 98.5 (C-1), 89.2, 85.7 (Csp), 81.5, 81.2, 81.1, 80.9, 80.4, 79.9,
79.6, 79.4, 79.3, 79.2, 79.1, 78.9, 78.6, 76.1, 75.9, 75.8, 75.4, 75.2,
74.9, 73.6, 73.5, 73.4, 73.2, 72.9, 72.7, 72.5, 72.1, 72.0, 71.8, 71.6,
69.6, 69.5, 69.3, 68.7 (CH, CH2) ppm. MALDI-TOF-MS: m/z
calcd. for C190H194O35Na 3060.337 found 3060.243.
3
6.63 (m, 1 H, CH=CH2), 5.32 (d, J1,2 = 3 Hz, 1 H, 1-H), 5.29 (d,
3J1,2 = 4 Hz, 1 H, 1-H), 5.21 (d, J1,2 = 3 Hz, 1 H, 1-H), 5.16–4.92
3
(m, 11 H), 4.79–4.61 (m, 8 H), 4.54–4.25 (m, 26 H), 4.12–3.89 (m,
28 H), 3.61–3.31 (m, 15 H), 2.26–2.02 (m, 2 H, CH2CH =) ppm.
13C NMR (75 MHz, CDCl3): δ = 139.7–138.2 (C arom. quat.),
135.9 (CH=CH2), 128.6–127.1 (C arom. tert.), 117.2 (CH=CH2),
99.31, 99.2, 98.8, 98.5, 98.4, 97.6 (C-1), 81.5, 81.4, 81.2, 80.9, 80.4,
80.3, 79.9, 79.7, 79.4, 79.2, 78.9, 78.4, 78.3, 77.5, 76.2, 76.0, 75.8,
75.7, 75.6, 75.4, 74.8, 74.3, 73.7, 73.6, 73.5, 73.3, 73.1, 73.0, 72.9,
72.8, 72.0, 71.9, 71.8, 71.6, 69.7, 69.5, 69.1 (CH, CH2), 35.1
(CH2CH =) ppm. MALDI-TOF-MS: m/z calcd. for
C185H194O35Na 2998.330 found 2998.169.
Method B-2: A solution of phenylacetylene (0.11 mL, 0.94 mmol)
in PhMe (0.2 mL) under nitrogen at 0 °C was slowly added EtMgBr
(0.94 mL, 1 molL–1 in THF). Then the temperature was adjusted
to room temperature and stirring for 30 min. Aldehyde 1 (110 mg,
37.5 µmol) dissolved in PhMe (0.9 mL) was slowly added to the
Grignard reagent, followed by stirring for 1.5 h at room tempera-
ture. Then quenching and workup as described for method B-1
afforded diastereoisomers 2d (33%, 37.5 mg) and 3d (15%,
16.5 mg).
Further elution afforded monol 3b (17%, 177 mg); Rf = 0.54
(EtOAc/n-pentane: 4/5); [α]D = +32.5 (c = 1.0, CHCl3). H NMR
(300 MHz, CDCl3): δ = 7.24–6.93 (m, 100 H, H arom.), 5.78–5.64
(m, 1 H, CH=CH2), 5.57 (d, J1,2 = 4 Hz, 1 H, 1-H), 5.48 (d, J1,2
= 4 Hz, 1 H, 1-H), 5.26–5.20 (m, 2 H), 5.16, 4.96 (m, 8 H), 4.91–
4.59 (m, 12 H), 4.56–4.50 (m, 4 H), 4.46–4.30 (m, 20 H), 4.09–3.71
1
3
3
(m, 30 H), 3.59–3.36 (m,12 H), 2.79 (br. s, 1 H, OH), 2.33–2.23 (m. Method B-3: A solution of phenylacetylene (61 µL, 0.511 mmol) in
1 H, CH2CH =), 2.12–2.04 (m, 1 H, CH2CH =) ppm. 13C NMR THF (0.55 mL) under nitrogen at –78 °C was slowly added nBuLi
(75 MHz, CDCl3): δ = 139.7–138.1 (C arom. quat.), 135.9, (0.32 mL, 1.6 molL–1 in n-hexane). Then stirring for 30 min before
(CH=CH2), 128.7 (C arom. tert.), 117.9 (CH=CH2), 100.1, 99.3,
slowly adding 1 (100 mg, 34.1 µmol) dissolved in THF (1 mL). The
99.0, 98.6, 98.3, 98.2, 97.9 (C-1), 82.0, 81.8, 81.2, 81.1, 80.9, 80.7, reaction mixture was left stirring for 1.5 h before increasing to
80.1, 79.8, 79.6, 79.4, 79.2, 79.1, 79.0, 78.9, 76.5, 76.2, 76.1, 76.0,
75.7, 75.4, 75.3, 75.0, 74.9, 73.6, 73.5, 73.2, 73.1, 73.0, 72.9, 72.8,
72.2, 72.1, 71.8, 71.6, 69.9, 69.6, 69.4, 68.7, 68.0 (CH, CH2), 39.1
room temperature and stirring for 30 min more. Then quenching
and workup as described for method B-1 afforded the diastereoiso-
mers 2d (53%, 55.3 mg) and 3d (7 mg, 7%).
3890
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3883–3896

Grignard Reaction of Cyclodextrin-6-aldehydes Revisited
Method B-4: A suspension of CeCl3 (210 mg 0.853 mmol) in THF
(2.6 mL) was left stirring for 2 h. Then the suspension was cooled
down to –78 °C and was slowly added a solution of Ph-ethynylLi
[prepared by mixing phenylacetylene (90 µL, 0.80 mmol) in THF
(0.8 mL) with nBuLi (0.49 mL, 1.6 molL–1 in n-hexane) at –78 °C,
for 30 minn]. The mixture was left stirring for 30 min before adding
5 (100 mg, 34.1 µmol) dissolved in THF (1 mL). Then the mixture
was stirred at –78 °C for 1.5 h and room temperature for 30 min.
Then quenching and workup as described for method B-1 afforded
diastereoisomers 2b (33%, 34.6 mg) and 3b (9%, 9.1 mg).
stirring for 14 h at this temperature. Then the solution of Grignard
reagent was cooled down to –78 °C and was slowly added a solu-
tion of aldehyde 1 (1.62 g, 0.550 mmol) in THF (5.5 mL). The reac-
tion mixture was stirred at –78 °C for 1 h before increasing to room
temperature and stirring for 2 h before quenching by slowly adding
H2O (25 mL) at 0 °C. Then the layers were separated and the water
phase was extracted with DCM (3ϫ40 mL). The combined organic
phases were dried (MgSO4) and concentrated in vacuo. Purification
of the crude product on a silica column (EtOAc/n-pentane: 1/9Ǟ1/
4) afforded compound 2g (64%, 1.06 g) as a white foam; Rf = 0.26
1
(EtOAc/n-pentane: 1/3); [α]D = +40.2 (c = 1.0, CHCl3). H NMR
Method B-5: A suspension of ZnCl2 (116.2 mg, 0.85 mmol) in Et2O
(1.7 mL) was cooled down to 0 °C and was added Ph-ethynylLi
[prepared by mixing phenylacetylene (97 µL, 0.87 mmol) in Et2O
(3.3 mL) and nBuLi (0.54 mL, 1.6 molL–1 in n-hexane) at –78 °C,
for 30 min] followed by stirring for 45 min. Then a solution of 1
(100 mg, 34.1 µmol) in Et2O (3.3 mL) was added and the tempera-
ture was adjusted to room temperature and the reaction stirred for
2 h. Quenching and workup as described for method B-1 afforded
diastereoisomers 2d (27%, 28.2 mg) and 3d (22%, 23.2 mg).
(300 MHz, CDCl3): δ = 8.81 (d, 3JH,H = 5 Hz, 1 H, H arom.), 7.61–
7.55 (m, 1 H, H arom.), 7.49–7.46 (m, 1 H, H arom.), 7.34–7.13
(m, 101 H, H arom.), 5.84 (d, 3J1,2 = 3 Hz, 1 H, 1-H), 5.47 (d, 3J1,2
3
3
= 3 Hz, 1 H, 1-H), 5.36 (d, J1,2 = 3 Hz, 1 H, 1-H), 5.30 (d, J1,2
3
= 3 Hz, 1 H, 1-H), 5.26–5.03 (m, 9 H), 4.95 (d, J1,2 = 3 Hz, 1 H,
1-H), 4.88–4.71 (m, 8 H), 4.62–4.27 (m, 28 H), 4.21–4.01 (m, 25
2
H), 3.81 (d, JH,H = 12 Hz, 1 H), 3.71–3.46 (m, 11 H), 3.23 (dd,
3
3J2,1 = 3, J2,3 = 9 Hz, 1 H, 2-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 159.6 (C arom. quat.), 148.1 (C arom. tert.), 139.7–
138.3 (C arom. quat.), 136.3 (C arom. tert.), 128.6–127.2 (C arom.
tert.), 122.5, 122.4 (C arom. tert.), 99.1, 99.0, 98.9, 98.7, 98.3, 97.6
(C-1), 81.5, 81.3, 80.8, 80.4, 80.0, 79.7, 79.4, 79.3, 78.9, 78.8, 78.7,
78.3, 78.0, 77.6, 76.3, 75.8, 75.7, 75.3, 73.6, 73.5, 73.4, 73.1, 73.0,
72.4, 72.0, 71.8, 71.7, 69.8, 69.6, 69.5, 69.1 (CH, CH2) ppm.
MALDI-TOF-MS: m/z calcd. for C187H193NO35Na 3014.342
found 3014.910.
6AR-Methyl-2A–G,3A–G,6B–G-icosakis-O-benzyl-β-cyclodextrin (2a)
and 6AS-Methyl-2A–G,3A–G,6B–G-icosakis-O-benzyl-β-cyclodextrin
(3a): A solution of aldehyde 1 (443 mg, 0.151 mmol) in THF
(2.4 mL) under nitrogen at room temperature was slowly added
MeMgBr (0.503 mL, 3 molL–1 in Et2O). The reaction mixture was
left stirring for 2 h at room temperature before slowly adding satu-
rated aqueous NH4Cl (15 mL) at 0 °C. Then the phases were sepa-
rated and the water layer was extracted with DCM (3ϫ15 mL).
The combined organic layers were dried (MgSO4) and concentrated
in vacuo. Purification on a silica column (EtOAc/n-pentane: 1/4)
afforded compound 2a (40%, 180.2 mg) as a white foam; Rf = 0.30
Further elution afforded an 85% pure mixture of 3g (9%, 150 mg);
Rf = 0.18 (EtOAc/n-pentane: 1/3). MALDI-TOF-MS: m/z calcd.
for C187H193NO35Na 3014.3 found 3014.7.
1
(EtOAc/n-pentane: 3/5); [α]D = +36.1 (c = 1.0, CHCl3). H NMR
6A(R)-(4-Fluorophenyl)-β-cyclodextrin: Compound 2f (392.2 mg,
0.129 mmol) and TFA (cat) were dissolved in 2-methoxyethanol
(85 mL) under nitrogen. Palladium on carbon (10%, 200 mg) was
added, and a hydrogen atmosphere (1 atm) was introduced. Then
the reaction mixture was left stirring for 20 h at room temperature
before filtration through a pad of Celite. Concentration of the fil-
trate afforded the desired product (74%, 117 mg) as a white solid;
Rf = 0.69 (iPrOH/MeOH/H2O: 5/4/3); [α]D = +151.8 (c = 0.5,
(300 MHz, CDCl3): δ = 7.34–7.13 (m, 100 H, H arom.), 5.39 5.37
3
(m, 2 H, 2 1-H), 5.35 (d, J1,2 = 4 Hz, 1 H, 1-H), 5.27–5.07 (m, 9
3
H), 5.02 (d, J1,2 = 4 Hz, 1 H, 1-H), 4.88–4.73 (m, 9 H) 4.64–4.37
(m, 25 H), 4.19–3.98 (m, 27 H), 3.73–3.51 (m, 13 H), 3.42 (dd, 3J2,1
3
= 4, 3J2,3 = 9 Hz, 1 H, 2-H), 1.05 (d, J7,6 = 6 Hz, 3 H, CH3) ppm.
13C NMR (75 MHz, CDCl3): δ = 139.7–138.3 (C arom. quat.),
128.6–127.2 (C arom. tert.), 99.3, 98.9, 98.7, 98.6, 98.0 (C-1), 81.5,
81.4, 81.1, 80.4, 80.3, 80.0, 79.7, 79.5, 79.4, 79.2, 78.8, 78.2, 78.0,
76.2, 76.0, 75.6, 74.9, 74.4, 73.8, 73.6, 73.4, 73.1, 72.9, 72.7, 71.2,
72.0, 71.9, 71.8, 71.7, 71.2, 69.5, 69.3, 66.8 (CH, CH2); 17.1 (CH3)
ppm. MALDI TOF-MS: m/z calcd. for C183H192O35K 2988.3
found 2988.2.
1
4
MeOH). H NMR [300 MHz, (CD3O)2SO2]: δ = 7.52 (dd, JH,F
=
6, 3JH,H = 8 Hz, 2 H, H arom.), 7.08–7.02 (m, 2 H, H arom.), 6.08
(d, 3JH,H = 5 Hz, 1 H), 5.81- 5.63 (m, 10 H), 5.48 (d, 3JH,H = 7 Hz,
3
1 H), 5.13 (d, J1,2 = 4 Hz, 1 H, 1-H), 4.92–4.77 (m, 7 H),
4.59–4.40 (m, 5 H), 4.03–3.93 (m, 2 H), 3.63–3.21 (m, 40 H), 3.01–
2.94 (m, 1 H), 2.71–2.65 (m, 1 H) ppm. 13C NMR [75 MHz,
Further elution afforded compound 3a (41%, 183.7 mg); Rf = 0.23
1
1
(CD3O)2SO2]: δ = 162.0 (d, JC,F = 220 Hz, C arom. quat.), 137.3
(EtOAc/n-pentane: 3/5); [α]D = +34.7 (c = 1.0, CHCl3). H NMR
(d, 4JC,F Ͼ = 0 Hz, C arom. quat.), 131.3 (d, 3JC,F = 8 Hz, C arom.
(300 MHz, CDCl3): δ = 7.25 ppm. 7.01 (m, 100 H, H arom.), 5.54–
5.49 (m, 2 H, 2 H-1), 5.29–5.08 (m, 5 H), 4.97–4.88 (m, 4 H), 4.79–
4.67 (m, 7 H), 4.64–4.30 (m, 26 H), 4.16–3.78 (m, 28 H), 3.70–3.39
2
tert.), 114.6 (d, JC,F = 21 Hz, C arom. tert.), 102.7, 102.5, 102.4,
101.9 (C-1), 82.4, 82.3, 82.2, 81.9, 81.7, 74.6, 74.5, 73.8, 73.6, 73.5,
73.4, 73.3, 73.1, 73.0, 72.8, 72.7, 72.4, 70.3, 60.6, 60.4 (CH) ppm.
Ms (ES) m/z calcd. C48H73FO35Na 1251.4 found 1251.7.
3
(m, 15 H), 2.72–2.65 (m, 2 H), 1.06 (d, 3 H, J7,6 6 Hz, CH3), 13C
NMR (75 MHz, CDCl3): δ = 139.7–139.1 (C arom. quat.), 128.6–
127.1 (C arom. tert.), 99.9, 98.9, 98.7, 98.5, 98.2, 97.8, 97.5 (C-1),
82.1, 81.6, 81.4, 81.0, 80.8, 79.8, 79.6, 79.5, 78.9, 78.8, 77.5, 76.0,
75.8, 75.2, 75.0, 73.7, 73.6, 73.5, 73.1, 73.0, 72.8, 72.0, 71.7, 71.6,
69.7, 69.6, 69.4, 69.2, 68.6, 63.9 (CH, CH2); 20.7 (CH3) ppm.
MALDI TOF-MS: m/z calcd. for C183H192O35K 2988.288 found
2988.423.
2A–G,3A–G,6B–G-Icosakis-O-benzyl-6AR-(4-fluorophenyl)-(phenyleth-
ynyl)-β-cyclodextrin (9e): A solution of phenylacetylene (0.66 mL,
5.85 mmol) in THF (1.3 mL) under nitrogen at 0 °C was slowly
added EtMgBr (5.73 mL, 1 molL–1 in THF). Then the temperature
was adjusted to room temperature and the stirring was continued
for 30 min. Then the solution of Grignard reagent was cooled down
6AR-(2-Pyridyl)-2A–G,3A–G,6B–G-icosakis-O-benzyl-β-cyclodextrin to –10 °C and a solution of ketone (709 mg, 0.243 mmol) in THF
(2 g) and 6AS-(2-Pyridyl)-2A–G,3A–G,6B–G-icosakis-O-benzyl-β-cyclo-
dextrin (3g): A solution of 2-pyridylMgBr was prepared by slowly
adding iPrMgCl (4.40 mL, 2 molL–1 in THF) to a solution of 2-
bromopyridine (0.848 mL, 8.806 mmol) in THF (7.3 mL) under ni-
(7 mL) was slowly added. The reaction mixture was left stirring at
this temperature for 2 h before increasing to room temperature and
stirring for 1 h more. The reaction was quenched at 0 °C by slowly
adding saturated aqueous NH4Cl (15 mL). Then the phases
trogen at room temperature. The obtained reaction mixture was left were separated and the water phase was extracted with DCM
Eur. J. Org. Chem. 2010, 3883–3896
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3891

E. Lindbäck, Y. Zhou, L. Marinescu, C. M. Pedersen, M. Bols
(3ϫ 15 mL). The combined organic phases were dried (MgSO4) 65.1 mg) as a white foam; Rf = 0.48 (EtOAc/n-pentane: 1/2).
FULL PAPER
and concentrated under reduced pressure. Purification of the crude
product on a silica column (EtOAc/n-pentane: 1/9Ǟ1/3) afforded
compound 9e (90%, 659.4 mg) as a light yellow foam; Rf = 0.39
MALDI-TOF-MS: m/z calcd. for C189H195F535Na 3066.3 found
3066.4.
Further elution afforded compound 8c (61%, 252.3 mg); Rf = 0.46
1
(EtOAc/n-pentane: 2/3); [α]D = +36.4 (c = 1.0, CHCl3). H NMR
1
(EtOAc/n-pentane: 1/2); [α]D = +30.7 (c = 1.0, CHCl3). H NMR
4
3
(300 MHz, CDCl3): δ = 7.74 (dd, JH,F = 5, JH,H = 8 Hz, 2 H, H
arom.), 7.49–7.46 (m, 2 H, H arom.), 7.37–6.87 (m, 105 H, H
arom.), 5.98 (br. s, 1 H, OH), 5.81 (d, 3J1,2 = 4 Hz, 1 H, 1-H), 5.43–
(300 MHz, CDCl3): δ = 7.35–6.98 (m, 102 H, H arom.), 6.87–6.81
3
(m, 2 H, H arom.), 5.73 (d, J1,2 = 4 Hz, 1 H, 1-H), 5.32–5.37 (m,
3
2 H, 2CHPh), 5.12 (d, J1,2 = 3 Hz, 1 H, 1-H), 4.99–4.90 (m, 2 H,
3
2
5.28 (m, 4 H, 4CHPh), 5.07 (d, J1,2 = 3 Hz, 1 H, 1-H), 5.01 (d, J
= 12 Hz, 1 H, CHPh), 4.95–4.54 (m, 16 H), 4.50–3.91 (m, 40 H),
3.87–3.79 (m, 5 H), 3.76–3.73 (m, 2 H), 3.68–3.54 (m, 8 H), 3.46–
3.28 (m, 5 H), 3.10 (d, 2JH,H = 10 Hz, 1 H), 2.82 (d, 2JH,H = 11 Hz,
1 H), 2.60–2.49 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
2CHPh), 4.84–4.70 (m, 10 H), 4.61–4.52 (m, 7 H), 4.48–4.28 (m,
19 H), 4.23–4.80 (m, 28 H), 3.71–3.25 (m, 17 H), 1.39 (s, 3 H, Me)
1
ppm. 13C NMR (75 MHz, CDCl3): δ = 161.7 (d, JC,F = 243 Hz,
C arom. quat.), 140.1–138.5 (C arom. quat.), 138.4 (d, 4JC,F = 3 Hz,
2
C arom. quat.), 128.8–126.9 (C arom. tert.), 114.6 (d, JC,F
=
4
162.3 (d, 1JC,F = 245 Hz, C arom. quat.), 140.6 (d, JC,F = 2 Hz, C
20 Hz, C arom. tert.), 100,6, 100.4, 99.9, 99.1, 98.7, 97.6 (C-1),
82.1, 82.0, 81.4, 81.1, 81.0, 80.8, 80.4, 79.5, 79.2, 79.0, 77.6, 77.2,
76.5, 76.3, 76.1, 75.7, 75.2, 74.1, 73.7, 73.6, 73.3, 73.1, 72.4, 72.2,
72.1, 71.4, 71.2, 69.8, 69.4, 69.3, 69.1, 69.0, 67.9 (CH, CH2); 32.3
(CH3) ppm. 19F NMR (300 MHz, CDCl3): δ = –116.07 ppm.
MALDI-TOF-MS: m/z calcd. for C189H195FO35Na 3068.343 found
3068.387.
arom. quat.), 140.2–138.1 (C arom. quat.), 132.6 (C arom. tert.),
3
129.5 (d, JC,F = 7 Hz, C arom. tert.), 129.2–126.8 (C arom. tert.),
2
123.7 (C arom. quat.), 114.9 (d, JC,F = 20 Hz, C arom. tert.),
101.2, 100.7, 100.1, 98.5, 97.5 (C-1), 88.9 (Csp), 82.4, 82.0, 81.6,
81.4, 81.2, 80.8, 80.4, 79.9, 79.6, 79.0, 78.5, 76.6, 76.4, 76.2, 76.8,
75.2, 74.2, 73.8, 73.6, 73.5, 73.4, 73.3, 73.1, 73.0, 72.5, 72.4, 72.2,
72.0, 71.4, 71.1, 69.8, 69.7, 69.3, 67.5 (CH, CH2) ppm. 19F NMR
(300 MHz, CDCl3): δ = –114.04 ppm. MALDI-TOF-MS: m/z
calcd. for C196H197FO35Na 3154.4 found 3154.3.
6A-Allylphenyl-2A–G,3A–G,6B–G-icosakis-O-benzyl-β-cyclodextrin
(8d): A solution of ketone 7d (210 mg, 69.7 µmol) in Et2O (3.1 mL)
at room temperature under nitrogen was slowly added allylmagne-
sium bromide (1.59 mL) [prepared by adding a solution of allyl
bromide (286 µL, 3.3 mmol) in Et2O (3.5 mL) to a suspension of
Mg turnings (160.4 mg, 6.6 mmol) in Et2O (1.2 mL) under nitrogen
at room temperature, then stirring for 90 min before use]. The reac-
tion mixture was left stirring for 3 h at room temperature before
adjusting the temperature to 0 °C and slowly adding saturated
aqueous NH4Cl (10 mL). Then the phases were separated and the
water phase was extracted with DCM (3ϫ10 mL). The combined
organic phases were dried (MgSO4) and concentrated in vacuo. Pu-
rification on a silica gel (EtOAc/n-pentane: 1/10Ǟ1/5) afforded
compound 8d (41%, 86.2 mg) as a pure diastereoisomer; Rf = 0.28
2A–G,3A–G,6B–G-Icosakis-O-benzyl-6AS-(4-fluorophenyl)-(phenyleth-
ynyl)-β-cyclodextrin (8e): To a solution of the ketone (438 mg,
0.144 mmol) in THF (5.6 mL) at –10 °C under nitrogen atmosphere
was slowly added (4-fluorophenyl)magnesium bromide (2.4 mL in
THF). Then the reaction mixture was left stirring for 1.5 h before
adjusting to 0 °C and slowly adding saturated aqueous NH4Cl
(10 mL). The layers were separated and the water phase was ex-
tracted with DCM (3ϫ10 mL). The combined organic layers were
dried (MgSO4) and concentrated in vacuo. Purification by
chromatography (EtOAc/n-pentane: 1/9Ǟ1/4) afforded compound
8e (68%, 308.1 mg) as alight yellow foam; Rf = 0.39 (EtOAc/n-
pentane: 2/3); [α]D = +36.1 (c = 1.0, CHCl3). 1H NMR (300 MHz,
1
4
3
(EtOAc/n-pentane: 3/5); [α]D = +28.4 (c = 1.0, CHCl3). H NMR
CDCl3): δ = 7.83 (dd, JH,F = 5, JH,H = 8 Hz, 2 H, H arom.),
(300 MHz, CDCl3): δ = 7.35–6.89 (m, 105 H, H arom.) 5.76 (d,
3J1,2 = 4 Hz, 1 H, 1-H), 5.63–5.54 (m, 1 H, CH=CH2), 5.34–5.28
(m, 2 H, 2CHPh), 5.15–4.95 (m, 7 H), 4.87–4.72 (m, 8 H), 4.68–
4.58 (m, 5 H), 4.53–4.25 (m, 25 H), 4.14–3.94 (m, 23 H), 3.76–3.32
(m, 17 H), 2.93–2.86 (m, 1 H, CH2CH =), 2.76–2.69 (m, 1 H,
CH2CH =) ppm. 13C NMR (75 MHz, CDCl3): δ = 144.4 (C arom.
quat.), 139.9–138.3 (C arom. quat.), 134.7 (CH=CH2), 128.6–126.9
(C arom. tert.), 117.5 (CH=CH2), 100.2, 99.8, 98.7, 98.3, 98.1 (C-
1), 82.1, 81.8, 81.2, 81.0, 80.8, 80.5, 80.3, 79.5, 79.3, 78.9, 76.4,
76.1, 75.8, 74.7, 74.3, 73.5, 73.4, 73.0, 72.5, 72.2, 71.9, 71.7, 71.6,
71.2, 69.9, 69.6, 69.4, 69.3, 68.9 (CH, CH2) ppm. MALDI-TOF-
MS: m/z calcd. for C191H198FO35Na 3075.4 found 3075.4.
7.78–7.73 (m, 1 H, H arom.), 7.58–7.55 (m, 2 H, H arom.), 7.45–
3
6.96 (m, 104 H, H arom.), 6.07 (br. s, 1 H, 1-H), 5.89 (d, J1,2
=
3
4 Hz, 1 H, 1-H), 5.52–5.37 (m, 4 H), 5.16 (d, J1,2 = 3 Hz, 1 H, 1-
H), 5.10 (d, 2J = 12 Hz, 1 H, CHPh), 4.59–4.37 (m, 76 H), 3.32 (d,
2
2JH,H = 10 Hz, 1 H), 2.91 (d, JH,H = 11 Hz, 1 H), 2.69–1.42 (m, 2
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 162.3 (d, 1JC,F = 245 Hz,
C arom. quat.), 140.7 (d, 4JC,F = 2 Hz, C arom. quat.), 140.2–138.1
3
(C arom. quat.), 132.4 (C arom. tert.), 129.5 (d, JC,F = 7 Hz, C
arom. tert.), 129.2–126.8 (C arom. tert.), 122.8 (C arom. quat.),
2
114.9 (d, JC,F = 20 Hz, C arom. tert.), 101.2, 100.8, 100.1, 98.6,
97.6, 97.3, (C-1); 88.9 (Csp), 82.4, 82.1, 81.6, 81.5, 81.3, 80.8, 80.5,
80.0, 79.6, 79.0, 78.5, 76.6, 76.4, 76.3, 75.9, 75.3, 74.5, 74.2, 73.8,
73.7, 73.5, 73.3, 73.2, 73.1, 73.0, 72.5, 72.4, 72.2, 72.1, 71.5, 71.4,
71.2, 69.8, 69.7, 69.3, 69.0, 67.5 (CH, CH2) ppm. 19F NMR
(300 MHz, CDCl3): δ = –114.03 ppm. MALDI-TOF-MS: m/z
calcd. for C196H197FO35Na 3154.358 found 3154.390.
2A–G,3A–G,6B–G-Icosakis-O-benzyl-6A-(ethynylmethyl)-β-cyclodextrin
(8a and 9a): To a solution of the ketone 7a (100 mg, 33.9 µmol) in
THF (0.2 mL) under nitrogen at –78 °C was slowly added ethynyl-
magnesium bromide (1.69 mL, 0.5 molL–1 in THF). The reaction
mixture was left stirring at this temperature for 3 h before increas-
2A–G,3A–G,6B–G-Icosakis-O-benzyl-6A-(4-fluorophenyl)methyl-β-
cyclodextrin (8c and 9c): To a solution of the ketone (399 mg, ing to room temperature and stirring for additional 1 h. The reac-
0.135 mmol) in THF (5.3 mL) under nitrogen atmosphere at room
temperature was slowly added (4-fluorophenyl)magnesium bromide
(2.3 mL in THF). The reaction mixture was left stirring for 3 h
adjusting the temperature to 0 °C followed by slowly addition of
saturated NH4Cl (10 mL). Then the phases were separated and the
aqueous phase was extracted with DCM (3ϫ10 mL). The com-
bined organic layers were dried (MgSO4) and concentrated in
vacuo. Purification of the crude product on a silica column
tion was quenched by adjusting the temperature to 0 °C and slowly
adding saturated aqueous NH4Cl (5 mL). Then the phases were
separated and the water phase was extracted with DCM
(3ϫ5 mL). The combined organic phases were dried (MgSO4) and
concentrated in vacuo. Purification on a silica gel (EtOAc/n-pen-
tane: 1/3) afforded compounds 8a an 9a (86%, 86.7 mg) as a mix-
ture of diastereoisomers (4/1); Rf = 0.38 (EtOAc/n-pentane: 3/5).
1H NMR (300 MHz, CDCl3): δ = 7.29–6.93 (m, H arom.), 5.62 (d,
(EtOAc/n-pentane: 1/10 Ǟ 1/7) afforded compound 9c (15 %, 3J1,2 = 3 Hz, 1-H), 5.53 (d, 3J1,2 = 3 Hz, 1-H), 5.32 (d, 3J1,2 = 3 Hz,
3892
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3883–3896

Grignard Reaction of Cyclodextrin-6-aldehydes Revisited
2
3
2
1-H), 5.26 (d, J = 11 Hz, CHPh), 5.22–5.04 (m), 5.02 (d, J1,2
=
127.5 (C arom. tert.), 114.6 (d, JC,F = 21 Hz, C arom. tert.), 98.1
3
3 Hz, 1-H), 4.98 (d, J1,2 = 3 Hz, 1-H), 4.90–4.71 (m), 4.66–4.55 (C-1), 82.4 (C-3), 79.9 (C-2), 77.7, 75.9, 75.2, 73.53, 73.46, 70.3
(m), 4.52–4.29 (m), 4.25–3.94 (m), 3.91–3.71 (m), 3.67–3.35 (m), (CH, CH2 ), 54.8 (OCH3 ) ppm. Ms (ES) m/z calcd. for
2.42 (s, OH), 2.08 (s, OH), 1.47 (s, CH3), 1.31 (s, CH3) ppm. 13C
C34H35FO6Na 581.2 found 581.2. Further elution afforded the S-
NMR (75 MHz, CDCl3): δ = 139.9–138.0 (C arom. quat.), 128.6– isomer (26%, 94 mg) as a light yellow syrup; Rf = 0.30 (EtOAc/n-
127.0 (C arom. tert.), 99.8, 99.3, 98.9, 98.7, 98.4, 98.3, 98.1, 97.7,
97.6, 97.3 (C-1), 87.5, 85.4 (Csp), 82.1, 81.6, 81.4, 81.2, 81.1, 80.6,
80.3, 80.0, 79.3, 79.2, 79.1, 76.4, 76.3, 76.1, 75.7, 75.5, 73.7, 73.4,
73.2, 73.0, 72.7, 72.5, 72.2, 72.1, 71.9, 71.6, 71.5, 71.3, 70.2, 70.0,
69.9, 69.6, 69.3, 69.0 (CH, CH2, Csp), 29.2, 26.0 (CH3) ppm.
MALDI-TOF-MS: m/z calcd. for C185H192O35Na 2996.314 found
2996.364.
pentane: 1/3); [α]D = +37.9 (c = 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 7.37–7.23 (m, 17 H, H arom.), 7.00–6.93 (m, 2 H, H
arom.), 5.02 (d, 2J = 11 Hz, 1 H, CHPh), 5.01 (d, 2J = 11 Hz, 1 H,
CHPh), 4.79–4.76 (m, 3 H, 6-H, 2CHPh), 4.61 (d, 2J = 12 Hz, 1
2
3
H, CHPh), 4.60 (d, J = 12 Hz, 1 H, CHPh), 4.48 (d, J1,2 = 4 Hz,
1 H, 1-H), 4.07–4.01 (m, 3 H, 3-H), 3.82–3.74 (m, 2 H, 5-H, OH),
3.49–3.43 (m, 2 H, 2-H, 4-H), 3.08 (s, 3 H, OCH3) ppm. 13C NMR
1
(75 MHz, CDCl3): δ = 162.4 (d, JC,F = 244 Hz, C arom. quat.),
2A–G,3A–G,6B–G-Icosakis-O-benzyl-6A-(methylethynyl)-β-cyclodextrin
(8b and 9b): To a solution of the ketone 7a (258 mg, 87.4 µmol) in
THF (1.5 mL) under nitrogen atmosphere at room temperature was
slowly added PhMgBr (3.3 mL) [prepared by adding a solution of
PhBr (0.7 mL, 6.60 mmol) in THF (7 mL) to a suspension of Mg
turnings (481 mg, 19.8 mmol) in THF (2.3 mL) under nitrogen at
room temperature, then stirring for 3 h before use]. The reaction
mixture was left stirring at the same temperature for 2 h before
quenching by slowly adding saturated aqueous NH4Cl (5 mL).
Then the phases were separated and the aqueous phase was ex-
tracted with DCM (3ϫ5 mL). The combined organic phases were
dried (MgSO4) and concentrated in vacuo. Purification on silica
gel (EtOAc/n-pentane: 1/10Ǟ1/3) afforded compounds 8b and 9b
(81%, 213.1 mg) as a mixture of diastereoisomers (4/1); Rf = 0.34
(EtOAc/n-pentane: 3/5). 1H NMR (300 MHz, CDCl3): δ = 7.44–
6.97 (m, H arom.), 5.75 (d, 3J1,2 = 4 Hz, 1-H), 5.48 (d, 3J1,2 = 3 Hz,
138.5, 138.0, 137.6 (C arom. quat.), 136.6 (d, 4JC,F = 3 Hz, C arom.
quat.), 129.2 (d, 3JC,F = 8 Hz, C arom. tert.), 128.7–127.8 (C arom.
tert.), 114.6 (d, 2JC,F = 21 Hz, C arom. tert.), 97.7 (C-1), 82.4, 81.1,
80.4, 75.7, 75.1, 74.9, 73.4, 71.6 (CH, CH2), 55.1 (OCH3) ppm. Ms
(ES) m/z calcd. for C34H35FO6Na 581.2 found 581.3.
(2R,3S,4S,5R,6S)-2-[(S)-4(-Fluorophenyl)(hydroxy)methyl]-6-meth-
oxy-tetrahydro-2H-pyran-3,4,5-triol (5b): To a solution of the benz-
ylated sugar (160 mg, 0.286 mmol) in MeOH (10 mL) under nitro-
gen was added Pd/C (10%, 96 mg) before degassing the mixture
and introducing a hydrogen atmosphere (1 atm). The reaction mix-
ture was left stirring at room temperature for 7 h before filtering
the mixture through a pad of Celite. Concentration of the filtrate
and purification on a pad of silica (EtOAc/MeOH: 20/1) afforded
compound 5b (99%, 82 mg) as a white solid; Rf = 0.18 (EtOAc/
1
4
MeOH: 20/1). H NMR (300 MHz, CD3OD): δ = 7.45 (dd, JH,F
3
3
1-H), 5.33–5.16 (m), 5.12 (d, J1,2 = 3 Hz, 1-H), 5.03–4.90 (m),
= 6, JH,H = 8 Hz, 2 H, H arom.), 7.07–7.01 (m, 2 H, H arom.),
5.07 (br. s, 1 H, 6-H), 4.59 (d, J1,2 = 4 Hz, 1 H, 1-H), 3.68–3.58
3
4.83–4.69 (m), 4.63–4.30 (m), 4.26–4.14 (m), 4.12–3.92 (m), 3.81–
3.67 (m), 3.61–3.50 (m), 3.46–3.20 (m), 1.58 (s, CH3), 1.43 (s, CH3)
ppm. 13C NMR (75 MHz, CDCl3): δ = 147.6, 146.4 (C arom.
quat.), 139.9–130.1 (C arom. quat.), 128.5–126.7 (C arom. tert.),
100.7, 100.1, 99.5, 99.1, 98.9, 98.8, 98.6, 98.4, 97.3, 97.2 (C-1), 82.5,
81.7, 81.3, 81.2, 80.9, 80.7, 80.6, 80.4, 80.2, 79.8, 79.5, 79.2, 79.0,
78.8, 78.6, 77.9, 77.3, 76.2, 76.1, 75.9, 75.8, 75.5, 75.3, 74.7, 74.6,
74.5, 73.8, 73.5, 73.4, 73.3, 73.0, 72.9, 72.8, 72.5, 72.2, 72.1, 71.9,
71.7, 71.4, 71.3, 71.1, 71.0, 69.6, 69.5, 69.1, 69.0, 68.8, 68.5, 67.5
(CH, CH2), 31.2, 30.4 (CH3) ppm. MALDI-TOF-MS: m/z calcd.
for C189H196O35Na 3048.3 found 3048.31.
(m, 2 H, 3-H, 4-H), 3.53–3.50 (m, 1 H, 5-H), 3.46–3.42 (m, 1 H,
1
2-H) ppm. 13C NMR (75 MHz, CD3OD): δ = 163.3 (d, JC,F
=
4
242 Hz, C arom. quat.), 140.2 (d, JC,F = 3 Hz, C arom. quat.),
3
2
129.2 (d, JC,F = 8 Hz, C arom. tert.), 115.3 (d, JC,F = 22 Hz, C
arom. tert.), 101.2 (C-1), 76.0, 75.5,73.4, 71.5, 70.9 (CH), 54.9
(OCH3) ppm. MS (ES) m/z calcd. for C13H17FO6Na 311.1 found
311.1.
(2R,3S,4S,5R,6S)-2-[(R)-(4-Fluorophenyl)(hydroxy)methyl]-6-meth-
oxy-tetrahydro-2H-pyran-3,4,5-triol (5a): The benzylated sugar
(74 mg, 0.132 mmol) was debenzylated in the same way as for 5b
to afford 5a (100%, 38 mg); Rf = 0.18 (EtOAc/MeOH: 20/1). 1H
NMR (300 MHz, CD3OD): δ = 7.47–7.43 (m, 2 H, H arom.), 7.06–
(S)-(4-Fluorophenyl)[(2R,3S,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-meth-
oxy-tetrahydro-2H-pyran-2-yl]methanol and (R)-(4-Fluorophen-
yl)[(2R,3S,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-methoxy-tetrahydro-
2H-pyran-2-yl]methanol: To a solution of aldehyde 4 (296 mg,
0.64 mmo) in THF (5.1 mL) under nitrogen at room temperature
was slowly added (4-fluorophenyl)magnesium bromide (3.4 mL in
THF). The reaction mixture was left stirring at this temperature
for 1 h before adjusting the temperature to 0 °C and slowly adding
saturated aqueous NH4Cl (10 mL). The two phases were separated
and the water phase was extracted with DCM (4ϫ10 mL). The
combined organic layers were dried (MgSO4) and concentrated in
vacuo. Purification on a silica column (EtOAc/n-pentane: 1/20Ǟ1/
12) afforded the R-isomer (41%, 146 mg) as a yellow syrup; Rf =
0.45 (EtOAc/n-pentane: 1/3); [α]D = +20.5 (c = 1.0, CHCl3). 1H
3
7.02 (m, 2 H, H arom.), 4.87 (d, J6,5 = 5 Hz, 1 H, 6-H), 4.57 4.59
3
3
3
(d, J1,2 = 4 Hz, 1 H, 1-H), 3.73 (dd, J5,6 = 5, J5.4 = 10 Hz, 1 H;
5-H), 3.64–3.58 (m, 1 H, 3-H), 3.23–3.19 (m, 4 H, 2-H, OCH3),
3.13–3.06 (m, 1 H, 4-H) ppm. 13C NMR (75 MHz, CD3OD): δ =
163.3 (d, 1JC,F = 242 Hz, C arom. quat.), 138.3 (d, JC,F = 3 Hz, C
4
3
2
arom. quat.), 130.8 (d, JC,F = 8 Hz, C arom. tert.), 115.3 (d, JC,F
= 22 Hz, C arom. tert.), 101.2 (C-1), 75.2, 75.1, 74.4, 74.3, 73.3
(CH), 55.7 (OCH3) ppm. MS (ES) m/z calcd. for C13H17FO6Na
311.1 found 311.1.
(2R,4S,4aR,6S,7R,8R,8aS)-4-(4-Fluorophenyl)-6-methoxy-2-phenyl-
hexahydropyrano[3,2-d][1,3]dioxine-7,8-diol (6): To a solution of 5b
NMR (300 MHz, CDCl3): δ = 7.38–7.25 (m, 17 H, H arom.), 7.00– (68 mg, 0.236 mmol) and p-toluenesulfonic acid monohydrate
6.93 (m, 2 H, H arom.), 5.01–4.94 (m, 3 H, 6-H, 2CHPh), 4.84 (d, (4.49 mg, 23.6 µmol) in DMF (3 mL) under nitrogen was added
2J = 11 Hz, 1 H, CHPh), 4.76 (d, 2J = 12 Hz, 1 H, CHPh), 4.73
PhCH(OMe)2 (0.248 mL, 1.65 mmol). The reaction mixture was
(d, 2J = 11 Hz, 1 H, CHPh), 4.62 (d, 2J = 12 Hz, 1 H, CHPh), 4.47 heated to 100 °C and left stirring for 18 h. Then an additional
3
(d, J1,2 = 4 Hz, 1 H, 1-H), 4.02–3,96 (m, 1 H, 3-H), 3.75–3.65 (m, amount of PhCH(OMe)2 (0.48 mL, 3.304 mmol) was added and
3
3
2 H, 4-H, 5-H), 3.52 (dd, J2,1 = 4, J2,3 = 10 Hz, 1 H, 2-H), 2.84
the reaction was allowed continue at the same temperature for 24 h.
The reaction mixture was then added PhCH(OMe)2 (0.248 mL,
1.625 mmol) and the reaction mixture was stirred for 5 h more at
100 °C before cooling it down to room temperature and neutralized
(s, 3 H, OCH3), 2.33 (br. s, OH) ppm. 13C NMR (75 MHz, CDCl3):
δ = 162.0 (d, JC,F = 243 Hz, C arom. quat.), 138.7, 138.3, 138.1
(C arom. quat.), 137.7 (d, JC,F = 3 Hz, C arom. quat.), 128.6–
1
4
Eur. J. Org. Chem. 2010, 3883–3896
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3893

E. Lindbäck, Y. Zhou, L. Marinescu, C. M. Pedersen, M. Bols
FULL PAPER
by adding Et3N. The solvent was removed under reduced pressure.
Purification of the crude product on a silica column (EtOAc/n-
(150 mL) and saturated aqueous NaHCO3 (250 mL) containing
Na2S2O3 (12 g) followed by stirring for 1 h. The phases were sepa-
pentane: 1/3Ǟ1/1) afforded the benzylidene 6 (27%, 23.8 mg) as a rated and the organic layer was washed with NaHCO3
white solid; Rf = 0.68 (EtOAc); [α]D = +37.5 (c = 0.27, CHCl3). 1H (2 ϫ 150 mL) and H2O (150 mL). The organic layer was dried
NMR (300 MHz, CD3OD): δ = 7.83–7.79 (m, 2 H, H arom.), 7.49– (MgSO4) and concentrated under reduced pressure. Purification of
7.46 (m, 2 H, H arom.), 7.36–7.33 (m, 3 H, H arom.), 7.17–7.11
the residue by chromatography (Et2O/n-pentane: 1/5) afforded
3
(m, 2 H, H arom.), 5.60 (s, 1 H, CHPhO2), 5.40 (d, J6,5 = 5 Hz, 1 ketone 12 (57%, 2.05 g) as a light yellow syrup; Rf = 0.59 (EtOAc/
3
H,, 6-H), 4.89 (d, J1,2 = 4 Hz, 1 H, 1-H), 4.41–4.36 (m, 1 H, 5- n-pentane: 2/3); [α]D = +3.6 (c = 1.0, CHCl3). 1H NMR (300 MHz,
H), 3.93–3.82 (m, 2 H, 4-H, 3-H), 3.62–3.58 (m, 1 H, 2-H), 3.51 (s,
CDCl3): δ = 7.51–7.41 (m, 4 H, H arom.), 7.39–7.29 (m, 11 H, H
3 H, OCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 163.8 (d, 1JC,F arom.), 7.27–7.19 (m, 5 H, H arom.), 4.99 (d, 2J = 11 Hz, 1 H,
4
2
2
= 246 Hz, C arom. quat.), 138.7 (C arom. quat.), 133.8 (d, JC,F
=
CHPh), 4.85 (d, J = 11 Hz, 1 H, CHPh), 4.84 (d, J = 11 Hz, 1
3 Hz, C arom. quat.), 131.8 (d, JC,F = 8 Hz, C arom. tert.), 130.8, H, CHPh), 4.82 (d, 2J = 12 Hz, 1 H, CHPh), 4.72–4.65 (m, 3 H,
3
130.0, 127.9 (C arom. tert.), 117.1 (d, 2JC,F = 22 Hz, C arom. tert.), 1-H, 2CHPh), 4.35 (d, J5,4 = 10 Hz, 1 H, 5-H), 4.11–4.05 (m, 1
3
3
3
101.3, 97.1 (CHPhO2, C-1), 76.8, 75.2, 74.1, 74.0, 69.2 (CH), 57.4
(OCH3) ppm. MS (ES) m/z calcd. for C20H21FO6Na 399.1 found
399.1.
H, 3-H), 3.83 (dd, J4,3 = 9, J4,5 = 10 Hz, 1 H, 4-H), 3.62 (dd,
3J2,1 = 4, J2,3 = 10 Hz, 1 H, 2-H), 3.54 (s, 3 H, OCH3) ppm. 13C
3
NMR (75 MHz, CDCl3): δ = 183.2 (C=O), 138.6, 138.0, 137.8 (C
arom. quat.), 133.4, 131.1 (C arom. tert.), 128.7–127.8 (C arom.
tert.), 119.6 (C arom. quat.), 98.8 (C-1), 94.2, 87.3 (Csp), 81.7, 79.5,
79.1 (CH), 76.1 (CH2), 75.6 (CH), 75.3, 73.7 (CH2), 55.7 (OCH3)
ppm. HRMS (ES) m/z calcd. for C36H34O6Na 585.2253 found
585.2286.
(4-Fluorophenyl)[(2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-methoxy-tet-
rahydo-2H-pyran-2-yl]methanone (11): Dess–Martin periodinane
(720 mg, 1.70 mmol) was added to a solution of the alcohol
(621.2 mg, 1.11 mmol) in DCM (30 mL) under nitrogen. The reac-
tion mixture was left stirring overnight at room temperature. The
reaction was quenched by adding Et2O (50 mL) and saturated
aqueous NaHCO3 (30 mL) consisting of Na2S2O3 (3 g) and stirring
for 1 h at room temperature. Then Et2O (50 mL) was added and
the phases were separated. The organic layer was washed with
(R)-1-(4-Fluorophenyl)-3-phenyl-[(2S,3S,4S,5R,6S)-3,4,5-tris(benz-
yloxy)-6-methoxy-tetrahydro-2H-pyran-2-yl]prop-2-yn-ol (13R): A
solution of ketone 12 (866 mg, 1.54 mmol) in THF (9 mL) under
nitrogen at –10 °C was slowly added (4-fluorophenyl)magnesium
NaHCO3 (40 mL) and H2O (40 mL). Then the organic phase was bromide (6.2 mL in THF). The reaction mixture was left stirring at
dried (MgSO4) and concentrated in vacuo. Purification by this temperature for 30 min before increasing to room temperature
chromatography (EtOAc/n-pentane: 1/9) afforded ketone 11 (89%,
followed by stirring for 30 min more. The reaction was quenched
552 mg) as a light yellow syrup; Rf = 0.58 (EtOAc/n-pentane: 1/4); by adjusting adding saturated aqueous NH4Cl (20 mL) at 0 °C.
1
[α]D = +40.7 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3): δ = Then the phases were separated and the water phase was extracted
8.04 (dd, 4JH,F = 5, 3JH,H = 9 Hz, 2 H, H arom.), 7.38–7.26 (m, 10
H, H arom.), 7.16–7.05 (m, 5 H, H arom.), 6.93–6.90 (m, 2 H, H
arom.), 5.07–4.99 (m, 2 H, 5-H, CHPh), 4.88–4.81 (m, 2 H,
with DCM (3ϫ20 mL). The combined organic layers were dried
(MgSO4) and concentrated in vacuo. The concentrate was purified
on a silica column (Et2O/n-pentane: 1/3) affording compound 13R
(85%, 862.3 mg) as a light yellow syrup; Rf = 0.55 (EtOAc/n-pent-
ane: 2/3); [α]D = +50.2 (c = 1.0, CHCl3). 1H NMR (300 MHz,
2
2CHPh), 4.73 (d, J = 10 Hz, 1 H, CHPh), 4.68–4.64 (m, 2 H, 1-
H, CHPh), 4.43 (d, 2J = 11 Hz, 1 H, CHPh), 4.15–4.09 (m, 1 H,
3
3
3-H), 3.93–3.86 (m, 1 H, 4-H), 3.63 (dd, J2,1 = 4, J2,3 = 10 Hz, 1
CDCl3): δ = 7.66 (dd, 4JH,F = 5, 3JH,H = 9 Hz, 2 H, H arom.), 7.4–
H, 2-H), 3.46 (s, 3 H, OCH3) ppm. 13C NMR (75 MHz, CDCl3): 7.21 (m, 18 H, H arom.), 7.00–6.91 (m, 4 H, H arom.), 4.96 (d, J
2
1
δ = 194.7 (C=O), 166.3 (d, JC,F = 255 Hz, C arom. quat.), 138.9,
= 11 Hz, 1 H, CHPh), 4.90 (d, 2J = 11 Hz, 1 H, CHPh), 4.77 (d,
2J = 12 Hz, 1 H, CHPh), 4.70–4.66 (m, 2 H, 1-H, CHPh), 4.62 (d,
138.3, 137.9 (C arom. quat.), 132.9 (d, 4JC,F = 3 Hz, C arom. quat.),
3
2
132.1 (d, JC,F = 9 Hz, C arom. tert.), 128.8–128.0 (C arom. tert.),
2J = 12 Hz, 1 H, CHPh), 4.49 (s, 1 H, OH), 4.43 (d, J = 11 Hz, 1
2
116.0 (d, JC,F = 22 Hz, C arom. tert.), 99.7 (C-1), 82.0, 79.83,
H, CHPh), 4.18 (d, 3J4,5 = 10 Hz, 1 H, 5-H), 4.10–4.04 (m, 1 H, 3-
79.75, 76.2, 72.5, 74.0, 70.0 (CH, CH2), 56.7 (OCH3) ppm. 19F
H), 3.56–4.47 (m, 2 H, 2-H, 4-H) 3.47 (s, 3 H, OCH3) ppm. 13C
1
NMR (300 MHz, CDCl3): δ = –104.20 ppm. MS (ES) m/z calcd. NMR (75 MHz, CDCl3): δ = 162.5 (d, JC,F = 245 Hz, C arom.
for C34H33FO6Na 579.2 found 579.2.
4
quat.), 138.2, 138.0, 137.6 (C arom. quat.), 136.9 (d, JC,F = 3 Hz,
C arom. quat.), 131.7 (C arom. tert.), 128.6–127.9 (C arom. tert.),
3-Phenyl-1-[(2S,3S,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-methoxy-
tetrahydro-2H-pyran]prop-2-yn-1-one (12): A solution of phenyl-
acetylene (1.60 mL, 14.0 mmol) in THF (3.5 mL) under nitrogen
was cooled down to 0 °C. Then EtMgBr (12.76 mL, 1 molL–1 in
THF) was slowly added and the temperature was adjusted to room
temperature and stirring for 30 min. The solution of Grignard rea-
gent was cooled down to –10 °C and was slowly added a solution
of aldehyde 4 (2.95 g, 6.38 mmol) in THF (30 mL). The stirring
was continued at the same temperature for 1 h before increasing to
room temperature and stirring for additional 5 min followed by
quenching by slowly adding saturated aqueous NH4Cl (30 mL) at
0 °C. The phases were separated and the water phase was extracted
with EtOAc (2ϫ30 mL). The combined organic layers were dried
(MgSO4) and concentrated in vacuo. The concentrate was purified
by chromatography (Et2O/n-pentane: 1/5) affording a mixture if
diastereoisomers. Then the mixture was dissolved in DCM
(120 mL) under nitrogen atmosphere and Dess–Martin periodinane
(2.7 g, 6.38 mmol) was added, followed by stirring overnight at
room temperature. The reaction was quenched by adding Et2O
3
127.6 (d, JC,F = 8 Hz, C arom. tert.), 127.1 (C arom. tert.), 122.3
2
(C arom. quat.), 114.7 (d, JC,F = 21 Hz, C arom. tert.), 97.9 (C-
1), 89.7, 86. 4 (Csp), 82.4, 80.1 79.3 (CH), 75.8 (CH2), 74.4 (CH),
74.3 (C-6), 74.2, 73.3 (CH2), 55.4 (OCH3) ppm. 19F NMR
(300 MHz, CDCl3): δ = –115.05 ppm. HRMS (ES) m/z calcd. for
C42H39FO6Na 681.2628 found 681.2646.
(S)-1-(4-Fluorophenyl)-3-phenyl-[(2S,3S,4S,5R,6S)-3,4,5-tris(benz-
yloxy)-6-methoxy-tetrahydro-2H-pyran-2-yl]prop-2-yn-ol (13S): A
solution of phenylacetylene (0.27 mL, 2.37 mmol) in THF (0.6 mL)
under nitrogen was cooled to 0 °C. To the solution was slowly
added EtMgBr (2.30 mL, 1 molL–1 in THF) and the temperature
was adjusted to room temperature. The reaction mixture was
stirred at this temperature for 30 min before cooling it down to
–10 °C and slowly adding a solution of ketone 11 (426 mg,
0.765 mmol) in THF (8 mL). Then the reaction mixture was left
stirring for 1 h before increasing to 0 °C and slowly adding satu-
rated aqueous NH4Cl (10 mL). The phases were separated and the
aqueous layer was extracted with DCM (3ϫ10 mL). The combined
3894
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3883–3896

Grignard Reaction of Cyclodextrin-6-aldehydes Revisited
organic phases were dried (MgSO4) and concentrated in vacuo. Pu-
rification of the concentrate by chromatography (EtOAc/n-pentane:
1/25) afforded compound 13S (85%, 430.5 mg) as a light yellow
syrup; Rf = 0.36 (EtOAc/n-pentane: 1/3); [α]D = +57.3 (c = 1.0,
(OCH3), 42.2, 29.2 (CH2) ppm. 19F NMR (300 MHz, CD3OD): δ
= –119.03 ppm. HRMS (ES) m/z calcd. for C21H25FO6Na 415.1533
found 415.1554.
(2S,4S,4aS,6S,7R,8R,8aS)-4-(4-Fluorophenyl)-6-methoxy-4-phen-
ethyl-2-phenyl-hexahydropyrano[3,2-d][1,3]dioxine-7,8-diol (14S): To
a solution of the triol (15 mg, 38.2 µmol) and PhCH(OMe)2 (40 µL,
268 µmol) in DMF (0.3 mL) under nitrogen was added p-tolu-
enesulfonic acid monohydrate (2.23 mg, 11.5 µmol). The obtained
reaction mixture was left stirring overnight at room temperature
before neutralizing it by adding Et3N. The solvent was removed
and the crude product was purified by column chromatography.
(EtOAc/n-pentane: 1/2 Ǟ 3/1) afforded compound 15S (50 %,
9.1 mg) with minor impurities; Rf = 0.57 (EtOAc). 1H NMR
1
4
3
CHCl3). H NMR (300 MHz, CDCl3): δ = (dd, JH,F = 6, JH,H
=
9 Hz, 2 H, H arom.), 7.55–7.52 (m, 2 H, H arom.), 7.39–7.24 (m,
18 H, H arom.), 7.03–6.97 (m, 2 H, H arom.), 5.39 (s, 1 H, OH),
5.18 (d, 2J = 10 Hz, 1 H, CHPh), 5.06 (d, 2J = 11 Hz, 1 H, CHPh),
4.93 (d, 2J = 10 Hz, 1 H, CHPh), 4.85 (d, 2J = 11 Hz, 1 H, CHPh),
4.74 (d, 2J = 12 Hz, 1 H, CHPh), 4.60 (d, 2J = 12 Hz, 1 H, CHPh),
4.40 (d, 3J1,2 = 4 Hz, 1 H, 1-H), 4.24–4.18 (m, 1 H, 4-H), 4.12–4.06
3
3
(m, 1 H, 3-H), 3.71 (d, J5,4 = 9 Hz, 1 H, 5-H), 3.60 (dd, J2,1 = 4,
3J2,3 = 9 Hz, 1 H, 2-H), 2.70 (s, 3 H, OCH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 162.5 (d, JC,F = 245 Hz, C arom. quat.),
138.3, 137.93 (C arom. quat.), 137.3 (d, JC,F = 3 Hz, C arom.
1
4
3
(300 MHz, CDCl3): δ = 7.77 (dd, JH,F = 5, JH,H = 9 Hz, 2 H, H
arom.), 7.55–7.72 (m, 2 H, H arom.), 7.43–7.34 (m, 3 H, H arom.),
7.23–7.21 (m, 2 H, H arom.), 7.17–7.05 (m, 5 H, H arom.), 5.75 (s,
4
quat.), 136.9 (C arom. quat.), 131.9 (C arom. tert.) 128.8–127.9 (C
arom. tert.), 122.9 (C arom. quat.), 114.4 (d, 2JC,F = 21 Hz, C arom.
tert.), 97.9 (C-1), 89.2, 87.9 (Csp), 82.5, 82.1, 80.5 (CH), 76.31, 75.9
(CH2), 75.2 (C-6), 73.8 (CH), 73.6 (CH2), 54.8 (OCH3) ppm.
HRMS (ES) m/z calcd. for C42H39FO6Na 681.2628 found
681.2571. Further elution afforded compound other isomer (1%,
5 mg).
3
3
1 H, CHPhCO2), 5.01 (d, J1,2 = 4 Hz, 1 H, 1-H), 4.24 (d, J5,4
=
10 Hz, 1 H, 5-H), 3.98–3.92 (m, 1 H, 3-H), 3.74 (dd, 3J4,3 = 9, 3J4,5
= 10 Hz, 1 H, 4-H), 3.68–3.64 (m, 1 H, 2-H), 2.58 (s, 3 H, OCH3),
2.77–2.56 (m, 2 H), 2.27–2.21 (m, 2 H) ppm. 13C NMR (75 MHz,
1
CDCl3): δ = 162.1 (d, JC,F = 246 Hz, C arom. quat.), 141.9, 137.5
4
(C arom. tert.), 135.7 (d, JC,F = 3 Hz, C arom. quat.), 129.6 (d,
3JC,F = 8 Hz, C arom. tert.), 129.2–125.9 (C arom. tert.), 115.4 (d,
2JC,F = 21 Hz, C arom. tert.), 99.7 (C-1), 96.3 (CHPhCO2), 80.4
(C-6), 75.8, 72.4, 72.2, 71.7 (CH), 56.2 (OCH3), 44.7, 29.5 (CH2)
ppm. 19F NMR (300 MHz, CDCl3): δ = –115.05 ppm. HRMS (ES)
m/z calcd. for C28H29FO6Na 503.1846 found 503.1866.
(2S,3S,4S,5R,6S)-2-[(R)-1-(4-Fluorophenyl)-1-hydroxy-3-phenyl-
propyl]-6-methoxy-tetrahydro-2H-pyran-3,4,5-triol: To a solution of
13R (425 mg, 0.647 mmol) and TFA (cat) in EtOH/EtOAc (2/1,
60 mL) under nitrogen at room temperature was added Pd/C (10%,
260 mg). The mixture was degassed and a hydrogen atmosphere
(1 atm) was introduced. Then the reaction mixture was left stirring
for 48 h before filtering it through Celite. Concentration of the fil-
trate afforded the product (90%, 228 mg) as a white solid; Rf = 0.49
(EtOAc/MeOH: 12/1); [α]D = +9.3 (c = 0.25, MeOH). 1H NMR
(2S,4R,4aS,6S,7R,8R,8aS)-4-(4-Fluorophenyl)-6-methoxy-4-phen-
ethyl-2-phenyl-hexahydropyrano[3,2-d][1,3]dioxine-7,8-diol
(14R):
The benzylidene 14R was prepared in the same way as benzylidene
(14S). (50%, 6.0 mg); Rf = 0.66 (EtOAc); [α]D = +4.3 (c = 0.4,
(300 MHz, CD3OD): δ = 7.65–7.60 (m, 2 H, H arom.), 7.27–7.22
4
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.71 (dd, JH,F = 6,
3
(m, 2 H, H arom.), 7.15–7.05 (m, 5 H, H arom.), 4.57 (d, J1,2
=
=
3JH,H = 9 Hz, 2 H, H arom.), 7.64–7.61 (m, 2 H, H arom.), 7.49–
7.42 (m, 3 H, H arom.), 7.29–7.24 (m, 2 H, H arom.), 7.20–7.15
(m, 1 H, H arom.), 7.12–7.05 (m, 4 H, H arom.), 6.01 (s, 1 H,
3
4 Hz, 1 H, 1-H), 3.69–3.57 (m, 2 H, 3-H, 4-H), 3.50 (d, J5,4
3
3
9 Hz, 1 H, 5-H), 3.38 (dd, J2,1 = 4, J2,3 = 9 Hz, 1 H, 2-H), 2.82
(s, 3 H, OCH3), 2.77–2.68 (m, 1 H), 2.54–2.45 (m, 1 H), 2.35–2.16
3
CHPhO2), 4.78 (d, J1,2 = 4 Hz, 1 H, 1-H), 3.93–3.80 (m, 2 H, 3-
(m, 2 H) ppm. 13C NMR (75 MHz, CD3OD): δ = 163.0 (d, JC,F
1
H, 4-H), 3.63–3.58 (m, 2 H, 2-H, 5-H), 3.01 (s, 3 H, OCH3), 2.83–
4
= 242 Hz, C arom. quat.), 144.1 (C arom. quat.), 141.0 (d, JC,F
=
2.73 (m, 1 H, 7-H), 2.62–2.38 (m, 2 H, 7-H, 8-H), 2.28–2.19 (m, 1
3 Hz, C arom. quat.), 129.9 (d, 3JC,F = 8 Hz, C arom. tert.), 129.3,
129.2, 126.6 (C arom. tert.), 114.0 (d, 2JC,F = 21 Hz, C arom. tert.),
100.8 (C-1), 78.6 (C-6), 75,5, 73.2, 73.1 (CH), 55.0 (OCH3), 38.6,
30.6 (CH2) ppm. 19F NMR (300 MHz, CD3OD): δ = –118.89 ppm.
HRMS (ES) m/z calcd. for C21H25FO6Na 415.1533 found
415.1541.
1
H, 8-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 162.2 (d, JC,F
=
=
4
246 Hz, C arom. quat.), 140.1 (C arom. quat.), 139.1 (d, JC,F
3 Hz, C arom. quat.), 137.7 (C arom. quat.), 129.5, 128.7, 128.6,
3
128.4 (C arom. tert.), 127.6 (d, JC,F = 8 Hz, C arom. tert.), 126.6,
2
126.1 (C arom. tert.), 114.9 (d, JC,F = 21 Hz, C arom. tert.), 99.6
(C-1), 95.5 (CHPhO2), 79.2 (C-6), 75.7, 72.84, 72.77, 70.8 (CH),
55.4 (OCH3), 30.2 (C-7), 28.7 (C-8) ppm. 19F NMR (300 MHz,
(2S,3S,4S,5R,6S)-2-[(S)-1-(4-Fluorophenyl)-1-hydroxy-3-phenyl-
propyl]-6-methoxy-tetrahydro-2H-pyran-3,4,5-triol: To a solution of
13S (496 mg, 0.753 mmol) and TFA (cat) in MeOH/EtOAc (2/1,
60 mL) under nitrogen at room temperature was added Pd/C (10%,
300 mg). The mixture was degassed and a hydrogen atmosphere
(1 atm) was introduced. The reaction mixture was left stirring for
48 h before filtering it through a pad of Celite. Concentration of
the filtrate afforded the desired product (95%, 281 mg) as a white
solid; Rf = 0.56 (EtOAc/MeOH: 12/1); [α]D = +80.7 (c = 0.3,
CDCl3):
δ = –116.07 ppm. HRMS (ES) m/z calcd. for
C28H29FO6Na 503.1846 found 503.1868.
Degradation of 2f: A solution of the debenzylated 9e (117 mg,
95 µmol) in H2O (35 mL) was added Amberlite IR-120 (H+) and
the mixture was refluxed for 48 h. The resin was removed by fil-
tration and the filtrate was neutralized by adding Amberlite (OH–).
The resin was removed and the filtrate was concentrated. The fil-
trate was dissolved in MeOH (35 mL) and was added Amberlite
IR-120 (H+) followed by reflux for 24 h. Then the resin was re-
moved and the filtrate was concentrated. Purification by
chromatography (EtOAc/DCM: 4/1) afforded a mixture (6.5 mg)
consisting of 10 as the major component.
1
MeOH) H NMR (300 MHz, CD3OD): δ = 7.67–7.63 (m, 2 H, H
arom.), 7.24–7.19 (m, 2 H, H arom.), 7.14–7.06 (m, 5 H, H arom.),
3
3
4.72 (d, J1,2 = 4 Hz, 1 H, 1-H), 3.80 (d, J5,4 = 10 Hz, 1 H, 5-H),
3
3.69–3.63 (m, 1 H, 3-H), 3.43 (s, 3 H, OCH3), 3.20 (d, J2,1 = 4,
3J2,3 = 10 Hz, 1 H, 2-H), 3.03–2.97 (m, 1 H, 4-H), 2.79–2.71 (m, 1
H), 2.48–2.39 (m, 1 H), 2.30–2.13 (m, 2 H) ppm. 13C NMR
Degradation of 8e: The S-isomer (8e) (300 mg,9.6 µmol) was deben-
zylated in the same way as 2f. The crude product was dissolved in
1
(75 MHz, CD3OD): δ = 162.2 (d, JC,F = 242 Hz, C arom. quat.),
142.9 (C arom. quat.), 139.3 (d, 4JC,F = 3 Hz, C arom. quat.), 128.5 methanolic HCl (0.3 molL–1 in MeOH, 34 mL) [prepared by mix-
3
2
(d, JC,F = 8 Hz, C arom. tert.), 114.2 (d, JC,F = 21 Hz, C arom. ing MeOH (34 mL) and AcCl (0.74 mL, 10.5 mmol) for 10 min]
tert.), 100.3 (C-1) 78.4 (C-6), 74.2, 73.9, 72.7, 72.0 (CH), 55.2 and refluxed for 10 h. Then the reaction mixture was allowed to
Eur. J. Org. Chem. 2010, 3883–3896
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3895

E. Lindbäck, Y. Zhou, L. Marinescu, C. M. Pedersen, M. Bols
FULL PAPER
[4] J. Bjerre, C. Rousseau, L. Marinescu, M. Bols, Appl. Microbiol.
Biotechnol. 2008, 81, 1–11.
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1998, 98, 1977–1996.
reach room temperature and concentrated under reduced pressure.
Purification on a silica column (EtOAc/DCM: 4/1) afforded a mix-
ture (14.7 mg) consisting of mainly 10R.
[6] M. Sollogoub, Eur. J. Org. Chem. 2009, 1295–1303.
[7] A. Pearce, P. Sinaÿ, Angew. Chem. Int. Ed. 2000, 39, 3610–
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[8] T. Lecourt, A. Herault, A. J. Pearce, M. Sollogoub, P. Sinaÿ,
Chem. Eur. J. 2004, 10, 2960–2971.
Degradation of 9e: Compound 9e (610 mg, 0.194 mmol) was de-
benzylated in the same way as 2f followed by degradation and
methyl glycosylation following the same procedure as for 9e.
Affording a mixture (7 mg) consisting of mostly 10S.
[9] C. Rousseau, N. Nielsen, M. Bols, Tetrahedron Lett. 2004, 45,
8709–8711.
Supporting Information (see footnote on the first page of this arti-
[10] T. Hardlei, M. Bols, J. Chem. Soc. Perkin Trans. 1 2002, 2880–
1
cle): Copies of H and 13C NMR spectra of all new compounds.
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Published Online: May 27, 2010
3896
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3883–3896