Chemical clockwise tridifferentiation of α- and β-cyclodextrins: Bascule-bridge or deoxy-sugars strategies

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DOI: 10.1002/chem.200700971

Chemical Clockwise Tridifferentiation of a- and b-Cyclodextrins:

Bascule-Bridge or Deoxy-Sugars Strategies

Olivia Bistri,^[a]Pierre Sinaþ,^[a]Jess JimØnez Barbero,^[b]and Matthieu Sollogoub*^[a]

Abstract: The selective and efficient

functionalisation of large concave mol-

ecules is a chemical challenge opening

the door to various applications, such

as artificial enzymes. We propose here

a method, based on deprotection of

benzylated cyclodextrins, to selectively

access a variety of complex structures

with two or three new different func-

tionalities on the primary platform.

Our strategy is based on a mechanistic

hypothesis involving the approach of

an aluminium reagent between the pri-

mary oxygen atom and the endocyclic

one of the same sugar unit. Due to its

cyclic directionality, a change in steric

hindrance on a given position of the cy-

clodextrin has a different effect on the

clockwise or the counterclockwise di-

rections. This concept is illustrated and

exploited in two complementary ways:

deoxygenation of the primary position

of two diametrically opposed sugars in-

duces a debenzylation reaction on the

neighbouring clockwise sugars of a-

and b-cyclodextrins. Reversible cap-

ping, or bascule-bridging, of the same

pair of sugars has the same effect on

the debenzylation of a-cyclodextrin,

but induces an important change of the

geometry of b-cyclodextrin, hence al-

lowing the selective access to yet an-

other functionalisation pattern. A com-

bined use of deoxygenation and bas-

cule-bridging allows the access to an a-

cyclodextrin with its three pairs of pri-

mary functions differentiated and

ready for further modifications. Bas-

cule-bridge or deoxy-sugars are two

complementary means to operate steric

decompression and induce selective re-

actions to efficiently access a number

of new patterns of functionalities on

concave molecules.

Keywords: aluminum

molecules cyclodextrins

oligosaccharides · regioselectivity

·

concave

·

Introduction

mainly aromatics or sugars in the case of CDs. This uniform-

ity is inherent to the difficulty to topologically differentiate

distinct positions of the cavity, a classical problem in the de-

velopment of artificial enzymes. The design of the now clas-

sical CD–diimidazole ribonuclease enzyme mimic^[3]was

indeed intimately related to the possibility of functionalizing

two adjacent positions on the primary rim of CDs.^[4]Two

major problems are encountered when one wants to func-

tionalise a cyclic structure formed of n identical subunits:

the control on one hand of the number of similar functional-

ities introduced, and, on the other hand, of the regioselectiv-

ity of the functionalisation of this structure. Due to clear

symmetry reasons, incorporating a new functionality on a

single site is rather straightforward through control of the

reagentꢀs quantity,^[5]but when two or more sites need to be

transformed, then the number of possibilities implies more

sophisticated techniques. So far, two strategies have been

developed to selectively polyfunctionalise the primary rim

of CDs. The first one is based on the use of sterically hin-

dered reagents and proved for geometrical reasons to be

mainly efficient on a-CDs.^[6]The second one, more efficient

on b-CDs, consists in capping the CD with bifunctional re-

Concave molecules are at the root of host–guest chemistry,^[1]

which bears great promises as well as stimulating challenges

for chemists. The analogy of their cavities with those natu-

rally occurring in proteins, the role of which is not only to

host but also to transform, qualify concave molecules as po-

tential artificial enzymes.^[2]Common concave molecules,

such as cyclodextrins (CDs), calixarenes and resorcinarenes,

are cyclic oligomers made of identical repeating units,

[a] Dr. O. Bistri, Prof. P. Sinaþ, Dr. M. Sollogoub

Universite Pierre et Marie Curie (Paris 6)

Institut de Chimie Moleculaire (FR 2769)

Laboratoire de Chimie Organique (UMR CNRS 7611)

4 place Jussieu, C. 181, 75005 Paris (France)

Fax : (+33)144-275-504

E-mail: matthieu.sollogoub@upmc.fr

[b] Prof. J. JimØnez Barbero

Departamento de Estructura y Función de Proteínas

Centro de Investigaciones Biológicas

CSIC. Ramiro de Maeztu 9, 28040 Madrid (Spain)

Supporting information for this article is available on the WWW

under http://www.chemeurj.org/ or from the author.

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agents.^[7,8]When one wants to go one step further and intro-

duce a second functional group different from the first one

in order to get a tridifferentiated cycle (Scheme 1) the same

rim of CDs only two patterns of tridifferentiation are so far

selectively accessible: a tridifferentiated b-CD based on the

regioselective opening of a 6^A,6^B-cap^[10]and an asymmetric

6^A,6^B-capping of g-CD.^[11]We wish to present herein a full

account of our work on the sequential functionalisation of

the upper rim of a- and b-cyclodextrins efficiently affording

previously inaccessible tridifferentiation patterns.

The starting point of this story is the discovery of an origi-

nal blueprint strategy to regioselectively deprotect sugars^[12]

that allowed the spectacular differentiation of cyclodex-

trins.^[13]A fully benzyl-protected CD is selectively bis-depro-

tected by using diisobutylaluminium hydride (DIBAL-H) to

afford 6^A,6^D-diols 3 and 4 in 82and 83% yield from a- and

b-CDs 1 and 2, respectively (Scheme 2).^[13]A remarkable

Scheme 1. Schematic representation of differentiated and tridifferentiated

cyclic oligomers.

problems are encountered, with even more possible re-

gioisomers formed. For the sake of clarity, we wish to define

these terms. A cyclic structure based on the assembly of n

monomeric units bearing two different functionalities will

be called a differentiated structure. If it contains three dif-

ferent functionalities, this structure will be tridifferentiated,

and so on.

As a consequence, only very few examples of tridifferenti-

ated macrocycles are reported.^[9]In the case of the primary

Abstract in French: La fonctionnalisation sØlective et efficace

de grosses molØcules concaves constitue un dØfi ouvrant la

voie à de nombreuses applications, notamment dans le do-

maine des enzymes artificielles. Nous proposons dans ce tra-

vail une mØthode, basØe sur la dØprotection de cyclodexyrines

benzylØes, donnant un accs sØlectif à une variØtØ de structu-

res complexes possØdant deux ou trois fonctionnalitØs nouvel-

les et diffØrentes sur la plateforme primaire. Notre stratØgie

repose sur une hypothse mØcanistique impliquant lꢀapproche

dꢀun rØactif aluminique entre lꢀatome dꢀoxygne primaire et

celui inclus dans le cycle dꢀune mÞme unitØ glucosidique. Par

suite de la directionalitØ cyclique dꢀune cyclodextrine, une

modification de lꢀencombrement stØrique sur une position

primaire donnØe a un effet diffØrent sur lꢀunitØ voisine selon

sa position dans le cycle: horaire ou trigonomØtrique. Ce con-

cept a ØtØ illustrØ et exploitØ de deux faÅons complØmentaires:

une dØsoxygØnation des positions primaires de deux sucres

diamØtralement opposØs induit une rØaction de dØbenzylation

de lꢀa- et de la b-cyclodextrine sur les deux sucres voisins

dans le sens horaire. Un pontage rØversible, ou pont à bascu-

le, de la mÞme paire de sucres oriente la dØbenzylation de la

mÞme faÅon dans le cas de lꢀa-cyclodextrine, mais produit un

changement important dans la conformation de la b-cyclo-

dextrine, permettant ainsi un accs sØlectif à un autre type de

substitution. Un emploi combinØ de la dØsoxygØnation et du

pont à bascule sur lꢀa-cyclodextrine permet lꢀaccs à une cy-

clodextrine ayant trois paires de groupements protecteurs or-

thogonaux. Le pont à bascule ou les sucres dØsoxygØnØs con-

stituent ainsi deux moyens complØmentaires de dØcompres-

sion stØrique induisant des rØactions sØlectives donnant un

accs efficace à de nombreux profils de substitution de molØ-

cules concaves.

Scheme 2. Debenzylation of a- and b-CDs

1 and 2. i) DIBAL-H

(15 equiv, 1.5m, or 30 equiv, 1m), toluene, 508C, 2h. ^[15]

feature of this reaction is that it is a rare example of selec-

tive CD bis-functionalisation being as efficient on a- and b-

CDs.^[8]As an illustration of our previous assumption on the

link between easy functionalisation and access to novel arti-

ficial enzymes, M. Bols et al. nicely used this methodology

to build up a series of efficient artificial enzymes.^[14]

We would now like to give the full account of the duplica-

tion of this process that allows the tridifferentiation of the

upper rim of a- and b-CDs.

Results and Discussion

a-Cyclodextrin: Our strategy is based on our ability to syn-

thesise an a-CD (5) functionalised on positions 6^A,6^Dby an

appropriate OR group resistant to DIBAL-H (Scheme 3).

The question we wish to address here is whether it is possi-

ble to duplicate the DIBAL-H deprotection in a regioselec-

tive manner on this functionalised 6^A,6^D-cyclodextrin 5, that

is, to operate a clockwise (6) or counterclockwise (7) double

debenzylation reaction, considering the CD as seen from the

primary rim. Only two diametrically opposed hydroxyl

groups are expected to be deprotected, by analogy with the

first deprotection process. CDs 3 and 5 bearing two different

functionalities will be defined as differentiated CDs; CDs 6

and 7 possessing three different functionalities will be de-

fined as tridifferentiated CDs. Finally, another DIBAL-H re-

sistant functionalisation followed by a final debenzylation

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Scheme 3. Principles of the duplication of the DIBAL-H process.

would lead to a tetradifferentiated CD such as 8 with four

different functionalities, three on the primary rim, one on

the secondary rim (Scheme 3). To the best of our knowl-

edge, these compounds would be the first examples of tri-

and tetradifferentiated a-cyclodextrins.

lectivity was observed resulting in the formation of the

single diol 11.

Considering our mechanistic hypothesis involving the ap-

proach of two molecules of aluminium reagent on the che-

late O5/O6,^[13]we deduced from this result that the ap-

proach of aluminium derivatives on a glucopyranoside unit

was highly sensitive to the steric hindrance exerted by the

protecting group located on the primary position of the

neighbouring counter-clockwise sugar, for example on sugar

D of capped-CD 10. Indeed, as shown on Figure 1, the ap-

proach of an aluminium derivative on the O5^A/O6^Apair is

kinetically hindered by the presence of a benzyl moiety on

the 6-position of the counterclockwise sugar B. Due to the

cyclic directionality of the CD, the 6-benzyloxy group of the

clockwise sugar F seems too far away to interact with the

aluminium derivative (Figure 1).

Bascule-bridged CD—tridifferentiation: During the course of

the elucidation of the reaction mechanism,^[13]we had to

decide whether the second debenzylation on the CD was in-

duced by an aluminium derivative connected to the first de-

benzylation site, or by an independent process. To address

this question, we synthesised the capped-CD 10 by means of

a ring-closing metathesis (RCM) of the diallyl derivative 9

and reduction, hence reasonably preventing interaction be-

tween the two diametrically opposed potential debenzyla-

tion sites (Scheme 4). Subjected to the action of DIBAL-H

the capped a-CD 10 reacted in a very informative way: not

only two independent debenzylation reactions occurred,

thus answering our question, but a most remarkable regiose-

According to this hypothesis, we supposed that the meth-

ylenic bridge induced a steric modification, resulting in the

regioselective clockwise debenzylation of the capped-CD 10

into diol 11. Furthermore, we

thought that this result might

be independent from the nature

of the bridge. Indeed, we

showed by molecular modeling

that the tetramethylene-capping

of the CD induces the orienta-

tion of the O6^Aand O6^Dto-

wards the inside of the cavity.^[13]

Very interestingly, this confor-

mational change precludes the

formation of chelates on these

glucose moieties, making the

Scheme 4. Duplication of the DIBAL-H process on the capped CD 10. i) [Cl₂

A

reflux, 1.5 h, then Pb(OAc)₄, RT, 3 h, 92%; ii) PtO₂, H₂, EtOAc, 90%; iii) DIBAL-H, toluene, 508C, 2h, 86%.

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ing double bond critically allowed the reopening of the

bridge and the restoration of the allyl protecting groups

through another metathesis reaction in the presence of

Grubbs catalyst under an atmosphere of ethylene

(Scheme 6). This reversible process clearly reminds of the

machinery of

a bascule-bridge allowing regioselectivity

through its closing. To illustrate the importance of the cap-

ping step, we also submitted the diallylic CD 9 to the action

of DIBAL-H and not surprisingly obtained a mixture of the

three possible regioisomers. This way to temporarily turn off

the reactivity of an allyl group through a conformational

bias is quite noticeable.

Figure 1. Approach of the aluminium atom on the perbenzylated CD.

cap DIBAL-H resistant, and also relieves steric hindrance

on sugar units C and F (Scheme 5).

The re-opening of the bridge nicely illustrated the utility

of the reversibility of the metathesis reaction in an original

way, but its direct removal would alleviate the synthesis. To

this purpose, we designed a new double de-allylation process

involving the successive formation of two p-allyl complexes.

When placed in the presence of Pd⁰, a Lewis acid (ZnCl₂)

and a hydride donor (Bu₃SnH) CD 17 afforded diol 18 in

75% yield. The Lewis acid on the allyl ether helps the for-

mation of the p-allyl 19, which is reduced on its less hin-

dered side, restoring an allylic ether 20 cleaved in the same

way to afford diol 18 (Scheme 7).^[17]

Scheme 5. Capping of the CD induces regioselectivity.

We hence supposed that the difference in reactivity be-

tween the bridge and a pair of benzyl groups is independent

from the nature and electronic properties of these two

ethers. We therefore capped the diallylic CD 9 by means of

a RCM using Grubbs catalyst, but did not reduce the

formed double bond, and submitted this unsaturated

capped-CD 12 to the action of DIBAL-H.^[16]As hoped, the

nature of the bridge did not change the outcome of the reac-

tion, which afforded the diol 13 in 79% yield. The structure

of this regioisomer was confirmed by selective hydrogena-

tion of the alkene and comparison of the spectroscopic data

of the resulting compound with that of CD 11. The remain-

This double de-allylation allowed us to use another cap-

ping: the methallyl bridge introduced by Bols in another

context.^[18]It has been introduced in one step using 3-

chloro-2-(chloromethyl)-1-propene and sodium hydride, af-

fording CD 21 in 92% yield. This bridge also promotes the

regioselective debenzylation reaction in the presence of

DIBAL-H in 90% yield. Silylation of the obtained diol 22

followed by Pd⁰-catalysed double de-allylation then gives

the diol 17 in 88% yield. This synthetic scheme provides an

efficient access to the doubly tridifferentiated CD 18, thus

obtained in six steps and in 58% overall yield from native

a-CD (Scheme 8).^[19]

Scheme 6. Action of DIBAL-H on bis-allylated CD 9. Reagents and conditions: i) [Cl₂

92%; ii) DIBAL-H, toluene, 50 8C, 1 h, 84% ; iii) TBSOTf, pyr, CH₂Cl₂, RT, 2h, 95%; iv) [Cl ₂

[Pb(OAc)₄], RT, 3 h, 70%; v) DIBAL-H, toluene, 508C, 2h, 79% ( 3:15:16, 51:18:9).

A

(OAc)₄, RT, 3 h,

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outcome of the reaction was the expected clockwise di-de-

benzylation of compound 23 affording the diol 24 in 75%

yield (Scheme 9).^[20]

We hereby confirmed that a steric decompression on the

6^A,6^D-positions could explain and induce the clockwise

6^C,6^F-duplication of the DIBAL-H deprotection. As illustrat-

ed on Scheme 10, the aluminium reagent approaches the

O5^C/O6^Cpair more easily than the O5^B/O6^Bone due to the

difference of steric hindrance between a hydrogen and a

benzyloxy group. However, the drawback of this concept is

the impossibility to further functionalise the deoxy sugars A

and D.

We therefore synthesised 6^A,6^D-dideoxy CD 26 bearing

vinyl groups, because they can be reversibly converted into

alcohols. This deoxy CD 26 is obtained from diol 3 by an ox-

idation–Wittig olefination sequence. When submitted to the

action of DIBAL-H, it readily afforded the expected clock-

wise diol 27 in 90% yield. This diol can be converted into

the tridifferentiated CD 18, previously synthesised using the

capping strategy, by means of a silylation and reductive ozo-

nolysis in 61% yield over three steps (Scheme 11). This con-

version also confirms the regioselectivity of the debenzyla-

tion reaction. This reaction pathway gives a new access to

the tridifferentiated CD 18 by using the concept of deoxy

sugars. It also illustrates the versatility of the vinyl protec-

tion of hydroxyl groups, the importance of which will vividly

appear in the next section, as well as in that on b-cyclodex-

trins.

Scheme 7. Direct synthesis of diol 18 through double de-O-allylation. Re-

agents and conditions: i) [Pd

12h, 75%.

A

Hence, we have demonstrated that the reversible bridging

of CD diol 3 allows the duplication of the DIBAL-H-pro-

moted debenzylation reaction in a fully regioselective coun-

terclockwise manner and the synthesis of a useful tridiffer-

entiated CD synthon in high yield. The proposed explana-

tion for the regioselectivity lies in the steric decongestion in-

duced by the bridge of the O5/O6 pair of the glucose units

located clockwise to it. This is a rather sophisticated way to

achieve steric decompression and we decided to simplify

this process while sustaining

A combination of both techniques—tetradifferentiation: A

last pair of benzyl groups on the primary rim remains to be

removed preferentially to the ones on the secondary rim.

this hypothesis.

Deoxysugars—tridifferentia-

tion: An obvious way to de-

crease the steric hindrance in-

duced by a benzyloxy group is

to remove it. We therefore syn-

thesised 6^A,6^D-dideoxy CD 23,

through mesylation and reduc-

tion of the diol 3, and submit-

ted it to the action of DIBAL-

H. Much to our delight, the

Scheme 9. Dehydroxylation and regioselective clockwise de-O-benzylation. Reagents and conditions: i) a)

MsCl, Et₃N, DCM, 08C!RT, 1 h; b) LiAlH₄, THF, RT, 2h, 78% over two steps; ii) DIBAL-H, toluene, 50 8C,

1 h, 75%.

Scheme 8. Synthesis and regioselective de-O-benzylation of capped-CD 21. Reagents and conditions: i) 3-chloro-2-(chloromethyl)-1-propene, NaH, RT,

2h, 92%; ii) DIBAL-H, toluene, 50 8C, 1 h, 90%; iii) TBSOTf, pyr, CH₂Cl₂, RT, 2h, 95%; iv) [Pd (PPh₃)₄], ZnCl₂, Et₃SiH, THF, reflux, 6 h, 88%.

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being next removed using Pd⁰

to afford diol 30. This com-

pound was classically acetylat-

ed. Finally, the double bonds

were transformed back into hy-

droxyl groups by ozonolysis/re-

duction sequence, affording the

diol 31. We thus obtained a

new CD 31 from CD 29 for

which all three pairs of func-

tionalities on primary positions

of the sugars were changed into

another one, showing the ortho-

gonality of the original protec-

tions

on

compound

29

(Scheme 13).

In summary, the principle of

steric decompression induced

by dehydroxylation and bridg-

Scheme 10. Approach of the aluminium atom on the deoxy-CD 23

ing allows the functionalisation

We would then get the first CD bearing four different func-

tional groups: three pairs on the primary rim and a different

one on the secondary rim.

of all three pairs of hydroxyl

groups on the primary rim of a-CD in a fully selective

manner, completing the stripping of this rim. We next

turned our attention to the b-CD.

An orderly sequential use of the two previously described

strategies fulfilled the purpose in view. The tridifferentiated

CD diol 27, collected through the use of deoxysugar ap-

proach was bridged to capped-CD 28. This compound was

submitted to the action of DIBAL-H for the third time. It

solely afforded the CD 29 in a rewarding 93% yield. This

molecule is the first example of a tetradifferentiated CD

bearing three pairs of orthogonal functionalities on the pri-

mary rim and benzyl groups on the secondary positions

(Scheme 12). The use of this

b-Cyclodextrin: As we previously mentioned, a remarkable

feature of the debenzylation reaction lies in its equal effi-

ciency on both a- and b-CDs. We therefore had to show

that the regioselective duplication of this process could also

be performed on b-CD. The challenge here is even more

stimulating, because of lack of symmetry: the duplication of

strategy was made necessary by

the reactivity of esters, silyl

groups or methyl and allyl

ethers, with the aluminium re-

agent.

To demonstrate that the suc-

cessive liberation of the three

pairs of hydroxyl groups on the

primary rim of CD 29 is possi-

ble, the two free primary alco- Scheme 12. Tetradifferentiation of the a-CD - i) NaH, 26, DMF, RT, 2h 30, 89%; ii) DIBAL-H, toluene, 50 8C,

30 min, 93%.

hols were first silylated, the cap

Scheme 11. Synthesis of the tridifferentiated a-CD 18. i) a) (COCl)₂, DMSO, CH₂Cl₂, ꢀ788C, then Et₃N, RT; b) Ph₃PCH₃Br, nBuLi, THF, ꢀ408C ! RT,

4 h, 70% (over two steps); ii) DIBAL-H, toluene, 508C, 1 h 20, 90%; iii) TBSOTf, pyr, CH₂Cl₂, RT, 2h; iv) 1) O ₃, CH₂Cl₂, ꢀ788C, then Me₂S, RT; 2)

NaBH₄, CH₂Cl₂/MeOH, RT, 61% over three steps.

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lar modeling, described in a fol-

lowing section, will confirm that

assumption.

Deoxysugars—tridifferentia-

tion: The unexpected and sur-

prising result obtained with the

bascule-bridge process led us to

investigate the deoxy-sugar

concept on b-CD. Indeed, in

this case no distortion of the

CD should be observed, and a

simple clockwise debenzylation

outcome is expected. Hence,

diol 4 was easily converted into

the divinyl compound 43 by

means of a Swern oxidation

and a Wittig olefination in 65%

yield. The dideoxy CD 43 was

then treated with DIBAL-H

and also afforded a mixture of

two diols, which appeared to be

compounds 44 and 45, as dem-

onstrated after silylation and

reductive ozonolysis, delivering

CDs 41 and 42, in an approxi-

mately inverse ratio to the one

obtained previously with bridg-

ed CD 38. Much to our delight

and according to our expecta-

tion, the outcome of the deben-

zylation reaction was indeed

the 6^C,6^G-clockwise process, to-

gether with a small amount of

Scheme 13. Synthesis of the tetradifferentiated a-CD 31. i) TBSOTf, pyr, CH₂Cl₂, RT, 1 h, quant.; ii) [Pd⁰-

A

ꢀ788C, b) Me₂S, RT; v) NaBH₄, CH₂Cl₂/MeOH, RT, 55% over three steps.

Scheme 14. Duplication of the DIBAL-H process on b-CD—four possible regioisomers.

the

(Scheme 16).

The complementary features

other

6^C,6^F-diol

the debenzylation process can lead to four different diamet-

rically opposed diols (Scheme 14).

of the two concepts, bascule-bridge and deoxy-sugars, is

therefore strongly highlighted here. We now have a regiose-

lective access to two different tridifferentiated b-CDs 41 and

42 with totally unprecedented patterns of functionality.

Bascule-bridged CD—tridifferentiation: We first investigated

the bascule-bridge strategy, with capped-CD 38, synthesised

as previously described, through bis-allylation and RCM.

Subjected to the action of DIBAL-H, capped-CD 38 afford-

ed an inseparable mixture of two diols that we finally identi-

fied, as it will be explained later on, as CD 39 and 40 in a

4:1 ratio. After silylation and removal of the bridge tridiffer-

entiated CDs 41 and 42 could be separately isolated. Very

surprisingly, the major product of the duplicate debenzyla-

tion on the capped-CD 38 is not the expected 6^C,6^G-clock-

wise diol 40, but the unexpected 6^C,6^F-diol 39, as a result of

a debenzylation clockwise to the bridge on 6^Cand one on

unit F clockwise to a sugar bearing a benzyl group on its pri-

mary position (Scheme 15). We hypothesised that, due to

the capping, the conformation of CD 38 is such that the

O5^F/O6^Fpair—the central pair of the triad EFG—must be

less hindered than the one borne by glucose unit G. Molecu-

Structural assignment: A rather difficult part in this work

has been the structural assignment of the obtained regioiso-

meric b-CDs 41 and 42. For proper NMR analysis we first

needed to simplify the NMR spectra of our molecules 41

and 42: it was necessary to get rid of the benzylic protons

that overlap some of the proton sugar signals. We hence

chose to convert the benzyl groups into acetyl moieties. We

also needed reliable tags to be able to clearly identify the

different groups on the 6-position of the sugar units. We se-

lected a methyl ether, a deoxygenation of the 6-position and

acetyl groups. Indeed, the deoxygenated 6-positions will be

very easily detected through their chemical shifts, H6 next

to an acetyl group will be deshielded and the remaining H6

will be next to the methyl ethers. Diol 41 was therefore me-

thylated, affording diol 46 after standard desilylation. The

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Scheme 15. Tridifferentiation of the b-CD via the capped b-CD 38. i) DIBAL-H, toluene, 508C, 2h, 74% ; ii) TBSOTf, pyr, CH ₂Cl₂, RT, 2h, quant.; iii)

[Pd

A

Scheme 16. Tridifferentiation of the b-CD via the di-vinyl b-CD 43. i) (COCl)₂, DMSO, CH₂Cl₂, ꢀ788C, then Et₃N, RT; ii) Ph₃PCH₃Br, nBuLi, THF,

ꢀ408C!RT, 4 h, 65% (over two steps); iii) DIBAL-H, toluene, 508C, 1 h, 56%; iv) TBSOTf, pyr, CH₂Cl₂, RT, 1 h ; v) O₃, CH₂Cl₂, ꢀ788C, then Me₂S,

RT; vi) NaBH₄, CH₂Cl₂/MeOH, RT, 60% (over three steps).

obtained diol was dehydroxylated by mesylation and reduc-

tion to give CD 47, which was fully debenzylated and acety-

lated to give CD 48 (Scheme 17).

This compound 48 was analysed by NMR spectroscopy by

using a Bruker 600 MHz spectrometer by using COSY,

TOCSY, and NOESY experiments as well as the program

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Cyclodextrins

FULL PAPER

Scheme 17. Synthesis of compound 48. i) NaH, MeI, DMF, 08C!RT, 1 h 30, 88%; ii) nBu₄NF, THF, RT, 3 h, 74%; iii) a) MsCl, Et₃N, CH₂Cl₂, 08C!RT,

2h; b) LiAlH ₄, THF, RT, 1 h 30, 53% over two steps; iv) a) H₂, Pd/C, THF/H₂O, RT, 15 h; b) Ac₂O, Pyr., DMAP, RT, 24 h, 65% over two steps.

TOPSPIN for spectrum analysis. First of all, we had to

assign H6 protons of the different glucose units. We clearly

identified three sets of H6 protons: the more deshielded

ones (over 4 ppm) were assigned to the acetylated O6 of

units B,E,G, the most shielded ones were attributed to the

deoxy sugars C,F (Figure 2a). Furthermore, a NOE correla-

ing tetraiodinated-CD 49, which was further degraded by

Zn-mediated reductive cleavage.^[22]The resulting mixture

was reduced for stability reasons, and analysed as such by

mass spectrometry. Two peaks indicated the presence of two

sets of fragments of 760 and 328 molecular mass, which con-

firmed our NMR analysis (Scheme 18).

The same set of transformations on the other regioisomer

42 afforded the acetylated compound 52 (Scheme 19). The

same NMR analytical techniques, illustrated on Figure 3,

clearly allowed the structure elucidation of this compound.

Figure 3a shows the coupling between protons H5 and the

deoxy positions on units C,G. In this case, we also observed

a NOE correlation between H6 protons and OMe groups of

cycles A and D (Figure 3b). Cross correlations between H1

and H4 protons of successive glucose units finally allows the

reconstitution of the order of substitutions (Figure 3c).

CD 42 was also transformed into tetraiodinated CD 53,

which was subjected to reductive fragmentation, affording a

mixture analysed as such by mass spectroscometry

(Scheme 20). The three expected molecular peaks were de-

tected, allowing the confirmation of the structural assign-

ment of CD 42.

Extensive NMR and MS measurements indicated that the

major product of the debenzylation of the capped b-CD 38

was the unexpected diol 39. As we said, we could only pre-

sume at this point that O5^F,O6^F-chelate was less hindered

than the one on sugar G.

Figure 2. Structural assignment of compound 48: a) COSY spectrum, b)

NOE spectrum, c) NOE spectrum.

Regioselectivityrational : To sustain this hypothesis, we per-

formed molecular modelling. Molecular mechanics calcula-

tions were performed with the MM3* program^[23]as inte-

grated in the MACROMODEL 7.0 package.^[24]First, X-ray

structure of permethylated b-CD was used to build the de-

sired compounds 38 by constructing the ethylene bridge be-

tween the primary hydroxyl groups of a-Glc units A and D

of the macrocycle and adding the benzyl groups, by using

the BUILDER option of MACROMODEL. After the

bridge was set, energy optimisations were carried out by

using standard conjugate gradient minimisations until con-

tion between the methyl ethers and the H6 clearly pointed

out the A,D methyl ethers (Figure 2b). The COSY and

TOCSY experiments then allowed the assignment of all sig-

nals on each cycle; the ones bearing the deoxy function are

unambiguously identified as illustrated by Figure 2a. Finally,

the sequence of the cycles was reconstituted through H1/H4

NOE cross correlations between different cycles, as shown

on Figure 2c.

Considering the complexity of the NMR spectra, we pro-

posed to use another spectroscopic method to confirm our

first deduction. The “hex-5-enose degradation” method

proved to be useful in related cases.^[21]We therefore substi-

tuted the four hydroxyl groups of desilylated CD 41, afford-

vergence was reached.

A bulk dielectric constant of

10 Debyes was employed. The resulting simplified structure

is shown in the upper part of Figure 4, for sake of clarity we

erased the secondary benzyloxy groups and schematised the

Chem. Eur. J. 2007, 13, 9757 – 9774

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9765

M. Sollogoub et al.

Scheme 18. Hex-5-enose degradation applied to compound 41. i) nBu₄NF, THF, RT, 3 h; ii) I₂, PPh₃, imidazole, toluene, 708C, 15 h, 51% over two steps;

iii) Zn, nPrOH/H₂O, reflux; iv) NaBH₄, MeOH, RT.

Scheme 19. Synthesis of compound 52. i) NaH, MeI, DMF, 08C! RT, 1 h 30, 77%; ii) nBu₄NF, THF, RT, 3 h, 100%; iii) a) MsCl, Et₃N, CH₂Cl₂, 08C!

RT, 1 h 30; b) LiAlH₄, THF, RT, 1 h 30, 40% over two steps; iv) a) H₂, Pd/C, THF/H₂O, RT, 15 h; b) Ac₂O, Pyr., DMAP, RT, 24 h, 49% over two steps.

3D structures in the lower part of Figure 4. First of all, it

seems clear that the bridging of the b-CD by a tetramethy-

lenic bridge induces a major conformational disruption on

the regular structure of the CD. Two major consequences of

the capping are the orientation of cycles A and D towards

the inside of the cavity and the exclusion of glucose F from

the median plan of the CD. This last fact seems to account

for the easier access of aluminium derivatives to the

O5^F,O6^F-chelation site. Molecular modelling experiments

hence confirm our initial hypothesis concerning the particu-

lar steric availability of cycle F induced by the CD-capping.

benzylated a- and b-cyclodextrins by pairs of benzyl groups

(Scheme 21). To that purpose we developed two techniques

to duplicate a first DIBAL-H double deprotection, a first

one so-called bascule-bridging based on the consequences of

a conformational change induced by a reversible capping of

the CD, and a second one based on the steric decompression

induced by dehydroxylation of primary positions. These two

tricks allow regioselective clockwise debenzylation of a-

CDs, and give access to two different patterns of tridifferen-

tiated b-CD. We have also combined those two techniques

to obtain, through a third DIBAL-H reaction, the first tetra-

differentiated a-CD possessing three functionalities on the

primary rim different from that on the secondary rim. This

work also strongly supports our proposed mechanism based

on the approach of a pair of aluminium derivatives on the

less hindered O5/O6 pair of the same glucose subunit.^[13]

Hence we can say that DIBAL-H is able to read the cyclic

Conclusion

We have presented herein a full account of our work on the

sequential regioselective stripping of the upper rim of per-

9766

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Chem. Eur. J. 2007, 13, 9757 – 9774

Cyclodextrins

FULL PAPER

The next step is the use of

this novel access to unprece-

dented complexity in the pat-

tern of functions on the CDs. A

few of the possible tracks are

currently being explored, for

example, asymmetric catalysis

and functional materials.

Experimental Section

General: Solvents were freshly dis-

tilled from Na/benzophenone (THF,

toluene), or P₂O₅(CH₂Cl₂). Reactions

were carried under Ar. Optical rota-

tions were measured on

a Perkin–

Elmer 241 digital polarimeter with a

path length of 1 dm. Fast atom bom-

bardment mass spectra (FAB-MS)

were obtained with a JMS-700 spec-

trometer. Elemental analyses were

performed by the Service de Micro-

analyse de lꢀICSN (Gif sur Yvette,

Figure 3. Structural assignment of compound 52: a) COSY spectrum, b) NOE spectrum, c) NOE spectrum.

France) and Centre RØgional de Me-

sures Physiques de lꢀOuest (Rennes,

1

directionality and, as a consequence, can promote, in a

rather unique manner, a regioselective chemistry at the

upper rim of cyclodextrins.

France). H NMR spectra were recorded with a Bruker DRX 400 for sol-

utions of the samples in CDCl₃at ambient temperature. Assignments

were aided by COSY experiments. ¹³C NMR spectra were recorded at

100.6 MHz with a Bruker DRX 400 spectrometer for solutions of samples

Scheme 20. Hex-5-enose degradation applied to compound 42. i) nBu₄NF, THF, RT, 3 h; ii) I₂, PPh₃, imidazole, toluene, 708C, 15 h, 49% over two steps;

iii) Zn, nPrOH/H₂O, reflux; iv) NaBH₄, MeOH, RT.

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9767

M. Sollogoub et al.

9.8 Hz, 2H; 2ꢂCHPh), 4.82 (d, ²J=9.0 Hz, 1H; 1ꢂCHPh), 4.93 (d, ²J=

11.0 Hz, 1H; 1ꢂCHPh), 5.18 (d, ²J=1.0 Hz,

J_cis=10.4 Hz, 1H;

OCH₂CH=CH₂), 5.22 (d, ²J=10.8 Hz, 1H; 1ꢂCHPh), 5.25 (d, ²J=

2

1.5 Hz, J_trans=17.3 Hz, 1H; OCH₂CH=CH₂), 5.49 (d, J=10.3 Hz, 1H; 1ꢂ

CHPh), 5.79 (d, ³J_1,2=3.9 Hz, 1H; 1-H), 5.85 (ddt, J_cis=10.8 Hz, J_trans

=

16.3 Hz, ³J=5.8 Hz, 1H; OCH₂CH=CH₂), 7.10–7.32ppm (m, 35H; CH

arom.); ¹³C NMR (100 MHz, CDCl₃): d=61.4, 69.5, 69.9 (3ꢂC-6), 71.2,

71.7, 72.0 (3ꢂC-5), 72.4 (OCH₂CH=CH₂, 2 ꢂCHPh), 72.9 (CH₂Ph), 73.4

2

(2ꢂCH₂Ph), 73.7 (C-4), 73.9, 76.1, 76.4 (3ꢂCH₂Ph), 77.6 (C-2), 79.0 (C-

2), 79.8 (C-2), 80.6 (C-3), 80.9 (C-3), 81.2 (C-4), 81.7 (C-3), 81.9 (C-4),

97.6 (C-1), 97.7 (C-1), 98.4 (C-1), 117.6 (OCH₂CH=CH₂), 126.3–128.3

(35ꢂCH arom.), 134.3 (OCH₂CH=CH₂), 137.8, 137.9, 138.3, 138.6, 139.2

(5ꢂC arom.quat.), 139.25 ppm (2ꢂC arom.quat.); MS (FAB): m/z:

2337.4 [M+Na]⁺; elemental analysis calcd (%) for C₁₄₀H₁₅₂O₃₀: C 72.64,

H 6.62; found: C 72.29, H 6.91.

1

Diol 16: [a]²_D⁰=+35 (c=1.0 in CHCl₃); H NMR (400 MHz, CDCl₃): d=

3.46 (dd, ³J_2,1=3.3 Hz, ³J_2,3=9.6 Hz, 1H; 2-H), 3.50 (dd, ³J_2,1=3.2Hz,

³J_2,3=9.9 Hz, 1H; 2-H), 3.60 (dd, ³J_1,2=3.9 Hz, ³J_2,3=9.8 Hz, 1H; 2-Ha),

Figure 4. Molecular modelling of the capped b-CD 38.

2

3.68 (brd, J=11.4 Hz, 1H; 6-H), 3.75–4.03 (m, 13H; 3ꢂ4-H, 3ꢂ5-H, 5ꢂ

6-H, 2ꢂ OCH₂CH=CH₂), 4.06 (dd, ³J=6.9 Hz, ³J=8.4 Hz, 1H; 3-H),

4.14 (dd, ³J=8.0 Hz, ³J=9.3 Hz, 1H; 3-H), 4.24 (dd, ³J=7.0 Hz, ³J=

9.6 Hz, 1H; 3-H), 4.34 (d, ²J=12.6 Hz, 1H; 1ꢂCHPh), 4.40 (d, ²J=

12.6 Hz, 1H; 1ꢂCHPh), 4.48 (d, ²J=11.9 Hz, 1H; 1ꢂCHPh), 4.49 (d,

2

²J=12.1 Hz, 1H; 1ꢂCHPh), 4.56 (d, J=12.6 Hz, 1H; 1ꢂCHPh), 4.62 (d,

²J=11.9 Hz, 1H; 1ꢂCHPh), 4.74 (d, ³J_1,2=3.4 Hz, 1H; 1-H), 4.76 (d,

2

³J_1,2=3.4 Hz, 1H; 1-H), 4.78 (d, J=11.7 Hz, 1H; 1ꢂCHPh), 4.80 (d, J=

11.0 Hz, 1H; 1ꢂCHPh), 4.81 (d, ²J=11.4 Hz, 1H; 1ꢂCHPh), 4.93 (d,

²J=11.9 Hz, 1H; 1ꢂCHPh), 4.94 (d, J=10.3 Hz, 1H; 1ꢂCHPh), 5.20 (d,

2

²J=1.5 Hz, J_cis=10.5 Hz, 1H; OCH₂CH=CH₂), 5.23 (d, ²J=11.0 Hz, 1H;

1ꢂCHPh), 5.27 (d, ²J=1.6 Hz, J_trans=17.0 Hz, 1H; OCH₂CH=CH₂), 5.51

(d, ²J=10.4 Hz, 1H; 1ꢂCHPh), 5.79 (d, ³J_1,2=4.0 Hz, 1H; 1-H), 5.89

3

(ddt, J_cis=10.5 Hz, J_trans=16.3 Hz, J=5.8 Hz, 1H; OCH₂CH=CH₂), 7.09–

7.33 ppm (m, 35H; CH arom.); ¹³C NMR (100 MHz, CDCl₃): d=61.3,

69.4, 69.7 (3ꢂC-6), 71.2, 71.6, 72.0 (3ꢂC-5), 72.2, 72.4 (CH₂Ph,

OCH₂CH=CH₂), 73.1, 73.3, 73.4 (3ꢂCH₂Ph), 73.6 (C-4), 73.8 (CH₂Ph),

76.1, 76.5 (2ꢂCH₂Ph), 77.6, 79.0, 79.8 (C-2), 80.6 (C-3), 80.9 (C-3), 81.3

(C-4), 81.6 (C-4), 81.65 (C-3), 97.7, 97.8, 98.4 (C-1), 117.6 (OCH₂CH=

CH₂), 126.2–128.4 (35ꢂCH arom.), 134.4 (OCH₂CH=CH₂), 137.8, 137.9,

138.2, 138.6, 139.2, 139.25, 139.3 ppm (7ꢂC arom.quat.); MS (FAB): m/z:

2337.1 [M+Na]⁺; elemental analysis calcd (%) for C₁₄₀H₁₅₂O₃₀: C 72.64,

H 6.62; found: C 72.29, H 6.91.

Scheme 21. New accessible functionalisation patterns through DIBAL-H

reactions.

in CDCl₃adopting 77.00 ppm for the central line of CDCl₃. Assignments

were aided by J-mod technique and HMQC. C₂-Symmetric CDs such as

13, 14, 15, 16, 18, 22, 23, 24, 26, 27, 28, 29, 30 and 31 are described as tri-

saccharides to avoid confusion between overlapping signal and those cor-

responding to equivalent carbons or protons due to the compound sym-

metry. Reactions were monitored by thin-layer chromatography (TLC)

on a precoated plate of silica gel 60 F₂₅₄(layer thickness 0.2mm; Merck,

Darmstadt, Germany) and detection by charring with sulfuric acid. Flash

column chromatography was performed on silica gel 60 (230–400 mesh,

E. Merck). Diisobutylaluminium was purchased from Aldrich as a 1.5m

solution in toluene.

Diol 13: DIBAL-H (1.5m in toluene, 36 mL, 54 mmol) was slowly added

to a solution of 12 (4.4 g, 1.8 mmol) in toluene (18 mL) under argon at

room temperature. The reaction mixture was heated at 508C for 2h, then

cooled to room temperature and poured on ice. The aqueous layer was

extracted with EtOAc (3ꢂ60 mL). The combined organic layers were

dried (MgSO₄), filtered and concentrated. Silica gel flash chromatogra-

phy of the residue (cyclohexane/EtOAc, 2:1) gave 13 (3.43 g, 84%) as a

white foam. ¹H NMR (400 MHz, CDCl₃): d=3.32(dd, ³J=7.9 Hz, ³J=

9.5 Hz, 1H; 2-H), 3.37–3.62 (m, 9H; 5ꢂ2-H, 4ꢂ6-H), 3.70–3.77 (m, 1H;

Deprotection of CD 9: DIBAL-H (1.5m in toluene, 1.8 mL, 2.7 mmol)

was slowly added to a solution of 9 (230 g, 92 mmol) in toluene (1 mL)

under argon at room temperature. The reaction mixture was heated at

508C for 2h, then cooled to room temperature and poured on ice. The

aqueous layer was extracted with EtOAc (3ꢂ15 mL). The combined or-

ganic layers were dried (MgSO₄), filtered and concentrated. Silica gel

chromatography of the residue (cyclohexane/EtOAc, 3:1 then 2:1) gave

15 (38 mg, 19%), 16 (19 mg, 9%), and diol 3 (113 mg, 51%), as white

foams.

ꢀ

OCH₂CH=CH CH₂O), 3.82–4.27 (m, 29H; 6ꢂ3-H, 6ꢂ4-H, 6ꢂ5-H, 8ꢂ6-

H, 3ꢂOCH₂CH=CH CH₂O), 4.36 (d, ²J=12.5 Hz, 1H; 1ꢂCHPh), 4.43–

ꢀ

4.60 (m, 14H; 14ꢂCHPh), 4.62(d, ²J=12.1 Hz, 1H; 1ꢂCHPh), 4.66 (d,

²J=12.3 Hz, 1H; 1ꢂCHPh), 4.77 (d, J=10.4 Hz, 1H; 1ꢂCHPh), 4.78 (d,

2

³J_1,2=3.8 Hz, 1H; 1-H), 4.82(d, ³J_1,2=3.1 Hz, 1H; 1-H), 4.83 (d, J_1,2

=

3

3.3 Hz, 1H; 1-H), 4.86–4.91 (m, 2H; 2ꢂCHPh), 4.92 (d, ²J=10.1 Hz, 1H;

2

1ꢂCHPh), 4.95 (d, J=10.3 Hz, 1H; 1ꢂCHPh), 4.98 (d, J=11.8 Hz, 1H;

1ꢂCHPh), 4.99 (d, ³J_1,2=3.4 Hz, 1H; 1-H), 5.03 (d, ²J=11.8 Hz, 1H; 1ꢂ

CHPh), 5.09 (d, ²J=10.9 Hz, 1H; 1ꢂCHPh), 5.27 (d, ²J=10.4 Hz, 1H;

1ꢂCHPh), 5.28 (d, ²J=11.0 Hz, 1H; 1ꢂCHPh), 5.33 (d, ³J_1,2=3.9 Hz,

1

Diol 15: [a]²_D⁰=+39 (c=1.0 in CHCl₃); H NMR (400 MHz, CDCl₃): d=

3.44 (dd, ³J_2,1=3.2Hz, ³J_2,3=9.9 Hz, 1H; 2-H), 3.51 (dd, ³J_2,1=3.4 Hz,

³J_2,3=9.7 Hz, 1H; 2-H), 3.61 (dd, ³J_1,2=3.9 Hz, ³J_2,3=9.7 Hz, 1H; 2-H),

3.72(dd, ³J_4,3=³J_4,5=8.9 Hz, 1H; 4-H), 3.78–4.03 (m, 13H; 2ꢂ4-H, 3ꢂ5-

2

3

1H; 1-H), 5.44 (d, J=10.1 Hz, 1H; 1ꢂCHPh), 5.48 (d, J_1,2=3.7 Hz, 1H;

3

ꢀ

1-H), 5.69 (t, J=4.3 Hz, 2H; OCH₂CH=CH CH₂O), 5.95 (t, J=3.0 Hz,

H, 6ꢂ6-H, 2ꢂ OCH₂CH=CH₂), 4.05 (dd, ³J_3,2=³J_3,4=9.1 Hz, 1H; 3-H),

ꢀ

2H; OCH₂CH=CH CH₂O), 7.00–7.30 ppm (m, 70H; CH arom.);

3

4.15 (dd, ³J_3,2=³J_3,4=8.8 Hz, 1H; 3-H), 4.25 (dd, ³J_3,2=9.6 Hz, J_3,4

=

¹³C NMR (100 MHz, CDCl₃): d=66.1, 69.3, 69.4 (6ꢂC-6), 70.8, 71.0 (2ꢂ

7.5 Hz, 1H; 3-H), 4.38 (d, ²J=12.8 Hz, 1H; 1ꢂCHPh), 4.41 (d, ²J=

12.8 Hz, 1H; 1ꢂCHPh), 4.48 (d, ²J=12.2 Hz, 1H; 1ꢂCHPh), 4.50 (d,

ꢀ

OCH₂CH=CH CH₂O), 70.7, 70.85, 71.2, 71.7, 71.9, 73.5 (6ꢂC-5), 72.1,

72.4, 72.8, 72.9, 73.05, 73.1, 73.2, 73.3, 74.4, 74.7, 75.6, 75.8, 76.3, 76.4

(14ꢂCH₂Ph), 77.9, 78.1, 78.2, 79.1, 79.15, 79.2 (6ꢂC-2), 79.7, 80.0, 80.4,

80.5, 80.6, 83.0 (6ꢂC-4), 80.7, 80.9, 81.1, 81.6, 81.7, 81.8 (6ꢂC-3), 96.7,

97.1, 98.8, 99.2, 99.3, 99.35 (6ꢂC-1), 126.6–128.3 (70ꢂCH arom.), 129.5,

2

²J=11.9 Hz, 1H; 1ꢂCHPh), 4.54 (d, J=12.6 Hz, 1H; 1ꢂCHPh), 4.58 (d,

2

²J=12.6 Hz, 1H; 1ꢂCHPh), 4.65 (d, J=12.2 Hz, 1H; 1ꢂCHPh), 4.72 (d,

³J_1,2=3.3 Hz, 1H; 1-H), 4.76 (d, ³J_1,2=3.4 Hz, 1H; 1-H), 4.79 (d, ²J=

9768

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Chem. Eur. J. 2007, 13, 9757 – 9774

Cyclodextrins

FULL PAPER

ꢀ

131.5 (2ꢂOCH₂CH=CH CH₂O), 137.9, 137.95, 138.0, 138.05, 138.1,

138.2, 138.3, 138.6, 139.15, 139.2, 139.25, 139.3, 139.4, 139.45 ppm (14ꢂC

arom.quat.); MS (FAB): m/z: 2309.1 [M+Na]⁺; elemental analysis calcd

(%) for C₁₃₈H₁₄₈O₃₀: C 72.49, H 6.52; found: C 71.97, H 6.58.

72.8, 73.3, 73.4 (3ꢂCH₂Ph), 74.0 (CH₂Ph), 74.05 (C-4c), 76.1, 76.2(2ꢂ

CH₂Ph), 77.9 (C-2), 79.0 (C-2), 79.7 (C-2), 80.6 (C-3), 80.65 (C-4), 80.8

(C-3), 81.7 (C-3, C-4), 97.3 (C-1), 97.7 (C-1), 98.3 (C-1), 126.5–128.3 (35ꢂ

CH arom.), 137.8, 138.0, 138.3, 138.5, 139.2, 139.25, 139.3 ppm (7ꢂC ar-

om.quat.); MS (FAB): m/z: 2485.2 [M+Na]⁺; elemental analysis calcd

(%) for C₁₄₆H₁₇₂O₃₀Si₂: C 71.19, H 7.04; found: C 70.81, H 7.04.

Tridifferentiated a-CD 14: A solution of 13 (145 mg, 63 mmol), pyridine

(41 mL, 0.5 mmol) and tert-butyldimethylsilyltrifluoromethanesulfonate

(116 mL, 0.5 mmol) in dichloromethane (2.5 mL) was stirred at room tem-

perature for 2h, diluted with dichloromethane (10 mL), washed with sat.

aq. NH₄Cl (2ꢂ5 mL), dried (MgSO₄), filtered and concentrated. Silica

gel flash chromatography (cyclohexane/EtOAc, 6:1) on silica gel gave a

disilylated compound 17 (150 mg, 95%) directly used in the next step.

Grubbs catalyst (9.8 mg, 12 mmol) was added to stirred solution of this

compound (150 mg, 60 mmol) in degassed dichloromethane (3.6 mL),

under ethylene at room temperature. The reaction mixture was stirred at

room temperature under ethylene atmosphere for 18 h, then Grubbs cat-

alyst (9.8 mg, 12 mmol) was added and the reaction mixture was stirred

Capped a-CD 21: Sodium hydride (60% w/w in oil, 400 mg, 10 mmol)

was added at room temperature under argon to a solution of diol 3 (3 g,

1.24 mmol) in dry DMF (188 mL). The reaction mixture was stirred for

30 min, then 3-chloro-2-chloromethyl-1-propene (158 mL, 1.40 mmol) was

added. After 2h of stirring, MeOH (10 mL) was slowly added and the

solvents were removed in vacuo. The residue was dissolved in EtOAc

(70 mL) and washed with

a saturated aqueous solution of NH₄Cl

(50 mL). The aqueous layer was extracted with EtOAc (3ꢂ30 mL) and

the organic layers were combined, washed with brine, dried over MgSO₄,

filtered and concentrated. Silica gel flash chromatography of the residue

(cyclohexane/EtOAc, 6:1) gave 21 (2,82 g, 92%) as a white foam. [a]_D²⁰

=

for additional 30 h at room temperature, then treated with Pb(OAc)₄

A

18

+30 (c=1.0 in CHCl₃), lit. [a]²_D⁰=+31.4 (c=1.1 in CHCl₃); MS (FAB):

(16 mg, 36 mmol), stirred under argon for 3 h, concentrated and purified

by silica gel flash chromatography (cyclohexane/EtOAc, 10:1) to give 14

(112mg, 70%) as a white foam. [ a]²_D⁰=+35 (c=1.1 in CHCl₃); ¹H NMR

(400 MHz, CDCl₃): d=0.01 (s, 6H; CH₃Si), 0.04 (s, 6H; CH₃Si), 0.90 (s,

18H; (CH₃)₃Si), 3.35–3.50 (m, 6H; 6ꢂ2-H), 3.55–4.05 (m, 28H; 4ꢂ

OCH₂CH=CH₂, 6ꢂ4-H, 6ꢂ5-H, 12ꢂ6-H), 4.10–4.25 (m, 6H; 6ꢂ3-H),

4.30 (brd, 4H; 4ꢂCHPh), 4.42–4.70 (m, 12H; 12ꢂCHPh), 4.80–4.95 (m,

6H; 6ꢂCHPh), 5.00 (d, ³J_1,2=3.2Hz, 2H; 2ꢂ1-H), 5.08–5.30 (m, 16H;

6ꢂCHPh, 4ꢂ1-H, 4ꢂOCH₂CH=CH₂), 5.74–5.84 (ddt, ³J_cis=10.5 Hz,

³J_trans=16.0 Hz, 2H; 2ꢂOCH ₂CH=CH₂), 7.18–7.31 ppm (m, 70H; CH

arom.); ¹³C NMR (100 MHz, CDCl₃): d=ꢀ5.1 (2ꢂCH₃Si), ꢀ4.9 (2ꢂ

CH₃Si), 18.3 (2ꢂ(H₃C)₃CSi), 25.9 (3ꢂ(H₃C)₃CSi), 26.0 (3ꢂ(H₃C)₃CSi),

62.4 (2ꢂC-6), 68.85 (2ꢂC-6), 69.0 (2ꢂC-6), 71.3, 71.4, 72.5 (6ꢂC-6), 72.2,

72.4, 72.8, 72.9, 73.3 (2ꢂCH₂Ph, 2ꢂOCH₂CH=CH₂), 75.1, 75.4, 75.7 (6ꢂ

CH₂Ph), 78.1 (2ꢂC-4), 78.75 (4ꢂC-4), 78.8, 79.0, 79.1 (6ꢂC-2), 80.7, 81.1,

81.2(6ꢂC-3), 98.0, 98.3, 98.4 (6ꢂC-1), 116.9 (2ꢂOCH ₂CH=CH₂), 126.8–

138.6 (70ꢂCH arom.), 132.2 (2ꢂ OCH₂CH=CH₂), 138.1, 138.2, 138.25,

138.3 (8ꢂC arom.quat), 139.25, 139.3, 139.4 ppm (6ꢂC arom.quat.); MS

(FAB): m/z: 2565.2 [M+Na]⁺; elemental analysis calcd (%) for

C₁₅₂H₁₈₀O₃₀Si₂: C 71.78, H 7.13; found: C 71.81, H 7.15.

m/z: 2490.0 [M+Na]⁺.

Diol 22: DIBAL-H (1.5m in toluene, 12mL, 18 mmol) was slowly added

to a solution of 21 (1.5 g, 0.6 mmol) in toluene (6 mL) under argon at

room temperature. The reaction mixture was heated at 508C for 2h, then

cooled to room temperature and poured onto ice. The aqueous layer was

extracted with EtOAc (3ꢂ60 mL). The combined organic layers were

dried (MgSO₄), filtered, and concentrated. Silica gel flash chromatogra-

phy of the residue (cyclohexane/EtOAc, 2:1) gave 22 (1.25 g, 90%) as a

white foam. The regioselectivity of this reaction was deduced when the

known product 18 was obtained from this compound. [a]²_D⁰=+32( c=1.0

in CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=1.95 (brs, 1H; OH), 3.39

3

(dd, J_2,1=3.3 Hz, J_2,3=9.6 Hz, 1H; H-2), 3.42–3.62 (m, 4H; 2ꢂH-2, H-4,

H-5), 3.71–4.05 (m, 9H; 2ꢂH-4, 2ꢂH-5, 3ꢂH-6, 2ꢂOC H₂C=), 4.08–4.16

(m, 4H; 2ꢂH-3, 2ꢂH-6), 4.25–4.42 (m, 6H; 3ꢂCHPh, H-3, H-5, H-6),

4.43–4.55 (m, 4H; 4ꢂCHPh), 4.72(d, ³J_1,2=3.3 Hz, 1H; H-1), 4.80 (d,

³J_1,2=3.3 Hz, 1H; H-1), 4.81 (d, ²J=11.8 Hz, 1H; CHPh), 4.85 (d, ²J=

10.0 Hz, 1H; CHPh), 4.87 (d, ²J=11.5 Hz, 1H; CHPh), 4.90 (d, ²J=

11.7 Hz, 1H; CHPh), 5.01 (d, ²J=10.4 Hz, 1H; CHPh), 5.13 (s, 1H;

CH₂=C), 5.28 (d, ²J=10.6 Hz, 1H; CHPh), 5.55 (d, ³J_1,2=4.1 Hz, 1H; H-

1), 5.59 (d, ²J=10.5 Hz, 1H; CHPh), 7.09–7.34 ppm (m, 35H; H arom.);

¹³C NMR (100 MHz, CDCl₃): d=62.2 (2ꢂC-6), 69.05 (C-6), 69.1 (C-5),

71.7 (OCH₂C=), 71.9 (C-5), 71.95 (CH₂Ph), 72.6 (C-5), 72.9, 73.2, 73.4,

73.7, 76.1, 76.5 (6ꢂ CH₂Ph), 77.6 (C-4), 78.7, 79.2, 79.9 (3ꢂC-2), 80.5,

80.8, 81.1 (3ꢂC-3), 81.6–82.1 (2ꢂC-4), 97.7, 99.5, 99.6 (3ꢂC-1), 114.5

(CH₂C=), 123.3–125.9 (CH arom.), 137.8, 137.9, 138.3, 138.6, 139.2,

139.25, 139.6 (7ꢂCquat. arom.), 142.8 ppm (C=CH₂); MS (FAB): m/z:

2309.1 [M+Na]⁺; elemental analysis calcd (%) for C₁₃₈H₁₄₈O₃₀: C 72.49,

H 6.52; found: C 72.13, H 6.68.

Tridifferentiated a-CD 18: [Pd⁰

(PPh₃)₄] was prepared according to the

G

Rosevear methodology: PPh₃(13.1 g, 0.05 mol) was dissolved in warm

ethanol (200 mL). Na₂PdCl₄(2.94 g, 0.01 mol) dissolved in ethanol

(50 mL) and water (5 mL) was added. The reaction mixture was cooled

to room temperature and NaBH₄(1 g, 0.04 mol) in water (25 mL) and

ethanol (25 mL) was added. The yellow solid was filtered off, washed

with ethanol, dried under vacuum and stored at 48C under argon. [Pd⁰-

(PPh₃)₄] (53 mg, 46 mmol) was added to a solution of compound 17

(1.15 g, 460 mmol) in THF (12mL). A 1 m solution of anhydrous ZnCl₂in

THF (6.9 mL, 6.9 mmol) was added dropwise to the reaction mixture at

room temperature 10 min later, Bu₃SnH (1.85 mL, 6.9 mmol) was added

slowly. The reaction mixture was refluxed for 20 h under argon and con-

centrated. The crude was dissolved in toluene and purified by silica gel

flash chromatography (cyclohexane/EtOAc, 4:1) to give 18 (849 mg,

Tridifferentiated a-CD 18 from diol 22:

A solution of 22 (1.94 g,

850 mmol), pyridine (411 mL, 5 mmol) and tert-butyldimethylsilyltrifluoro-

methanesulfonate (1.17 mL, 5 mmol) in dichloromethane (30 mL) was

stirred at room temperature for 2h. The reaction mixture is then diluted

with dichloromethane (10 mL), washed with a saturated aqueous solution

of NH₄Cl (2ꢂ5 mL), dried (MgSO₄), filtered and concentrated. Silica gel

flash chromatography of the residue (cyclohexane/EtOAc, 6:1) afforded

the bis-silylated cyclodextrine (2.10 g, 98%) directly used in the next

75%) as

a

white foam. [a]_D²⁰=+43 (c=1.0 in CHCl₃); ¹H NMR

(400 MHz, CDCl₃): d=0.11 (s, 3H; CH₃Si), 0.12(s, 3H; CH ₃Si), 0.96 (s,

9H; (CH₃)₃Si), 3.42(dd, 1H; ³J_2,1=3.5 Hz, J_2,3=9.6 Hz, 1H; 2-Hc), 3.51–

3

3.57 (m, 2H; 2ꢂ2-H), 3.62–3.75 ppm (m, 2H; 2ꢂ6-H), 3.78–3.87 (m, 4H;

step. [Pd⁰

(PPh₃)₄] (7 mg, 6 mmol) was added to a solution of bis-silylated

A

2ꢂ4-H, 5-H, 6-H), 3.90 (brd, ²J=11.0 Hz, 1H; 6-H), 3.93–4.05 (m, 4H;

4-H, 2ꢂ5-H, 6-H), 4.09 (t, ³J_3,2=³J_3,4=9.7 Hz, 1H; 3-H), 4.11 (t, J_3,2

=

3

compound (150 mg, 60 mmol) in degassed THF (2.5 mL). A 1m solution

of ZnCl₂in degassed THF (900 mL, 900 mmol) was added and the reac-

tion mixture was stirred at room temperature under argon for 10 min.

After addition of Et₃SiH (144 mL, 900 mmol), the reaction mixture was re-

fluxed under argon for 6 h, diluted with EtOAc (10 mL), poured on

water (10 mL). Layers were separated and the aqueous layer was extract-

ed with EtOAc (3ꢂ10 mL). Organic layers were combined, dried over

MgSO₄, filtered and concentrated. Silica gel flash chromatography of the

residue (cyclohexane/EtOAc, 6:1 then 4:1) afforded the diol 18 (129 mg,

88%) as white foam. [a]_D²⁰=+43 (c=1.0 in CHCl₃); ¹H NMR (400 MHz,

CDCl₃): d=0.11 (s, 3H; CH₃Si), 0.12(s, 3H; CH ₃Si), 0.96 (s, 9H;

(CH₃)₃Si), 3.42(dd, ³J_2,1=3.5 Hz, ³J_2,3=9.6 Hz , 1H; H-2), 3.51–3.57 (m,

2H; 2ꢂH-2), 3.62–3.75 (m, 2H; 2ꢂH-6), 3.78–3.87 (m, 4H; 2ꢂH-4, H-5,

³J_3,4=9.5 Hz, 1H; 3-H), 4.21 (dd, ²J=11.5 Hz, ³J_6,5=4.1 Hz, 1H; 6-H),

4.27 (dd, ³J_3,2=7.8 Hz, ³J_3,4=9.7 Hz, 1H; 3-H), 4.32(d, ²J=12.6 Hz, 1H;

2

1ꢂCHPh), 4.38 (d, J=12.6 Hz, 1H; 1ꢂCHPh), 4.47 (d, J=12.0 Hz, 1H;

1ꢂCHPh), 4.52(d, ²J=11.9 Hz, 1H; 1ꢂCHPh), 4.62(d, ²J=12.7 Hz, 1H;

1ꢂCHPh), 4.65 (d, ²J=12.2 Hz, 2H; 2ꢂCHPh), 4.73 (d, ³J_1,2=3.4 Hz,

1H; 1-H), 4.80 (d, ²J=10.6 Hz, 2H; 2ꢂCHPh), 4.84 (d, ²J=11.2Hz, 1H;

1ꢂCHPh), 4.87 (d, J=10.9 Hz, 1H; 1ꢂCHPh), 4.92(d, ²J=10.3 Hz, 1H;

2

1ꢂCHPh), 4.98 (d, ³J_1,2=3.3 Hz, 1H; 1-H), 5.20 (d, ²J=10.8 Hz, 1H; 1ꢂ

CHPh), 5.49 (d, ²J=10.3 Hz, 1H; 1ꢂCHPh), 5.68 (d, ³J_1,2=3.8 Hz, 1H;

1-H), 7.10–7.33 ppm (m, 35H; CH arom.); ¹³C NMR (100 MHz, CDCl₃):

d=ꢀ5.2(1ꢂCH Si), ꢀ5.0 (1ꢂCH₃Si), 18.5 ((H₃C)₃CSi), 26.0 ((H₃C)₃CSi),

3

61.9, 63.1, 69.6 (3ꢂC-6), 71.2 (C-5), 72.0 (C-5), 72.2 (CH₂Ph), 72.7 (C-5),

Chem. Eur. J. 2007, 13, 9757 – 9774

ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

9769

M. Sollogoub et al.

H-6), 3.90 (brd, ²J=11.0 Hz, 1H; H-6), 3.93–4.05 (m, 4H; H-4, 2ꢂH-5,

³J_1,2=3.6 Hz, 1H; 1-H), 5.37 (d, ²J=10.4 Hz, 1H; 1ꢂCHPh), 5.43 (d,

³J_1,2=3.7 Hz, 1H; 1-H), 7.19–7.36 ppm (m, 35H; CH arom.); ¹³C NMR

(100 MHz, CDCl₃): d=18.7 (CH₃), 61.6 (C-6), 67.4 (C-5), 69.6 (C-6),

71.6, 72.1 (2ꢂC-5), 72.6, 72.9, 73.3, 73.5, 74.8, 75.4, 76.3 (7ꢂCH₂Ph), 78.1,

79.3, 79.6 (3ꢂC-2), 80.6 (C-3), 80.7 (C-3), 81.3 (C-3), 81.4 (2ꢂC-4), 85.3

(C-4), 97.7, 97.75, 98.2(3ꢂC-1), 126.9 ꢀ128.4 (CH arom.), 137.5–138.5 (C

arom. quat.), 139.1–139.3 ppm (C arom. quat.); MS (FAB): m/z: 2225.1

[M+Na]⁺; elemental analysis calcd (%) for C₁₃₄H₁₄₄O₂₈: C 73.07, H 6.59;

found: C 72.68, H 6.55.

H-6), 4.09 (t, ³J_3,2=³J_3,4=9.7 Hz, 1H; H-3), 4.11 (t, ³J_3,2=³J_3,4=9.5 Hz,

3

1H; H-3), 4.21 (dd, ²J=11.5 Hz, ³J_6,5=4.1 Hz, 1H; H-6), 4.27 (dd, J_3,2

=

3

7.8 Hz, J_3,4=9.7 Hz, 1H; H-3), 4.32(d, ²J=12.6 Hz, 1H; CHPh), 4.38 (d,

²J=12.6 Hz, 1H; CHPh), 4.47 (d, ²J=12.0 Hz, 1H; CHPh), 4.52 (d, ²J=

11.9 Hz, 1H; CHPh), 4.62(d, ²J=12.7 Hz, 1H; CHPh), 4.65 (d, ²J=

12.2Hz, 2H; 2ꢂCHPh), 4.73 (d, ³J_1,2=3.4 Hz, 1H; H-1), 4.80 (d, ²J=

10.6 Hz, 2H; 2ꢂCHPh), 4.84 (d, ²J=11.2Hz, 1H; CHPh), 4.87 (d, ²J=

3

10.9 Hz, 1H; CHPh), 4.92(d, ²J=10.3 Hz, 1H; CHPh), 4.98 (d, J_1,2

=

3.3 Hz, 1H; H-1), 5.20 (d, ²J=10.8 Hz, 1H; CHPh), 5.49 (d, ²J=10.3 Hz,

1H; CHPh), 5.68 (d, ³J_1,2=3.8 Hz, 1H; H-1), 7.10–7.33 ppm (m, 35H;

CH arom.); ¹³C NMR (100 MHz, CDCl₃): d=ꢀ5.2(CH ₃Si), ꢀ5.0

(CH₃Si), 18.5 ((H₃C)₃CSi), 26.0 ((H₃C)₃CSi), 61.9, 63.1, 69.6 (3ꢂC-6), 71.2

(C-5), 72.0 (C-5), 72.2 (CH₂Ph), 72.7 (C-5), 72.8, 73.3, 73.4 (3ꢂCH₂Ph),

74.0 (CH₂Ph), 74.05 (C-4), 76.1, 76.2(2ꢂCH ₂Ph), 77.9 (C-2), 79.0 (C-2),

79.7 (C-2), 80.6 (C-3), 80.65 (C-4), 80.8 (C-3), 81.7 (C-3, C-4), 97.3 (C-1),

97.7 (C-1), 98.3 (C-1), 126.5–128.3 (35ꢂCH arom.), 137.8, 138.0, 138.3,

138.5, 139.2, 139.25, 139.3 ppm (7ꢂC quat. arom.); MS (FAB): m/z:

2485.2; elemental analysis calcd (%) for C₁₄₆H₁₇₂O₃₀Si₂: C 71.19, H, 7.04;

found: C 70.81, H 7.04.

Deoxy a-CD 26: A solution of DMSO (7.1 mL, 58 mmol) in CH₂Cl₂

(32mL) was added dropwise to a solution of oxalyl chloride (2.5 mL,

29 mmol) in CH₂Cl₂(32mL) cooled to ꢀ788C under argon. The reaction

mixture was stirred at ꢀ788C for 30 min, then a solution of diol 3 (7 g,

2.9 mmol) in CH₂Cl₂(83 mL) was added. After 2h at ꢀ788C, Et₃N

(8.2mL, 58 mmol) was added, the reaction mixture was warmed to room

temperature and treated with water (100 mL). The aqueous layer was ex-

tracted with CH₂Cl₂(3ꢂ75 mL). The organic layers were combined,

dried over MgSO₄, filtered and concentrated to give a bis-aldehyde.

Ph₃PCH₃Br (24 g, 68 mmol) was suspended in THF (40 mL), cooled to

ꢀ408C and treated dropwise with nBuLi (2.5m in hexane, 23 mL,

58 mmol). The reaction mixture was stirred at ꢀ408C for 15 min, then at

08C for 5 min, and a solution of the bis-aldehyde diluted in THF (40 mL)

was added. The reaction mixture was stirred at room temperature for 4 h

under Argon, diluted with Et₂O (100 mL), and poured on a saturated so-

lution of NH₄Cl (100 mL). The layers were separated and the aqueous

layer was extracted with Et₂O (3ꢂ70 mL). The organic layers were com-

bined, dried over MgSO₄, filtered and concentrated. After purification by

silica gel chromatography (cyclohexane 100%, then cyclohexane/EtOAc

10:1, then 8:1), the olefinic CD 26 (4.85 g, 70% over two steps) was ob-

Bis-deoxy a-CD 23: Et₃N (41 mL, 0.5 mmol) and MsCl (116 mL,

0.5 mmol) were added to a solution of diol 3 (235 mg, 97 mmol) in

CH₂Cl₂(2.5 mL) at 08C. The reaction mixture was stirred at room tem-

perature for 1 h under argon, diluted with CH₂Cl₂(10 mL), washed with

water (2ꢂ5 mL), dried over MgSO₄, filtered and concentrated. Silica gel

flash chromatography of the residue (cyclohexane/EtOAc, 6:1) afforded

the bis-mesylated cyclodextrin, which was dissolved in THF (1.8 mL) and

treated with LiAlH₄(870 mmol). EtOAc (5 mL) was added at 08C and

the mixture was filtered through a Celite pad, concentrated and purified

by silica gel flash chromatography (cyclohexane/EtOAc, 4:1) to afford

tained as

a

white foam. [a]_D²⁰=+39 (c=1.1 in CHCl₃); ¹H NMR

the compound 23 (150 mg, 78% over two steps) as a white foam. [a]_D²⁰

=

(400 MHz, CDCl₃): d=3.45 (dd, ³J_2,1=3.3 Hz, ³J_2,3=9.7 Hz, 1H; 2-H),

+49 (c=1.0 in CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=1.25 (d, ³J=

3.48 (dd, J_2,1=3.2Hz, ³J_2,3=9.9 Hz, 1H; 2-H), 3.58–3.67 (m, 4H; 1ꢂ2-H,

3

6.3 Hz, 3H; CH₃), 3.42(dd, ³J_2,1=3.4 Hz, ³J_2,3=9.7 Hz , 1H; 2-H), 3.47

1ꢂ4-H, 2ꢂ6-H), 3.89–3.96 (m, 2H; 1ꢂ4-H, 1ꢂ5-H), 4.06–4.22 (m, 6H;

3

(dd, ³J_2,1=3.7 Hz, ³J_2,3=9.5 Hz, 1H; 2-H), 3.60 (dd, ³J_2,1=3.5 Hz, J_2,3

=

2ꢂ3-H, 1ꢂ4-H, 1ꢂ5-H, 2ꢂ6-H), 4.27 (dd, ³J=7.3 Hz, J=9.6 Hz, 1H; 3-

9.9 Hz, 1H; 2-H), 3.61 (brd, ²J=9.9 Hz, 1H; 6-H), 3.67 (brd, ²J=

10.2Hz, 1H; 6-H), 3.90 5 m, 2H; 4-H, 5-H), 3.95–4.18 (m, 8H; 2ꢂ3-H,

2ꢂ4-H, 2ꢂ5-H, 2ꢂ6-H), 4.24 (dd, ³J_3,2=9.9 Hz, ³J_3,4=8.0 Hz, 1H; 3-H),

H), 4.34 (d, ²J=12.7 Hz, 1H; 1ꢂCHPh), 4.42–4.57 (m, 9H; 1ꢂ5-H, 8ꢂ

CHPh), 4.77–4.97 (m, 7H; 2ꢂ1-H, 4ꢂCHPh), 5.01 (d, ²J=10.5 Hz, 1H;

1ꢂCHPh), 5.04 (brd, ³J_cis=10.5 Hz, 1H; CH=CH₂), 5.28 (d, ²J=10.6 Hz,

1H; 1ꢂCHPh), 5.31 (brd, ³J_trans=17.2Hz, 1H; CH =CH₂), 5.55 (d, ²J=

10.4 Hz, 1H; 1ꢂCHPh), 5.61 (d, ³J_1,2=3.9 Hz, 1H; 1-H), 5.98 (ddd, ³J=

6.7 Hz, ³J_cis=10.4 Hz, ³J_trans=17.1 Hz, 1H; CH=CH₂), 6.46–7.36 ppm (m,

40H; CH arom.); ¹³C NMR (100 MHz, CDCl₃): d=69.0, 69.2(2ꢂC-6),

70.8, 70.9 (2ꢂC-5), 71.6 (C-5), 72.0, 72.8, 73.1, 73.2, 73.3, 73.9, 76.0, 76.4

(8ꢂCH₂Ph), 78.1, 79.0, 79.8 (3ꢂC-2), 80.6 (C-3, C-4), 80.9 (C-4), 80.95,

81.2(2ꢂC-3), 81.6 (C-4), 98.0, 98.5, 98.8 (3ꢂC-1), 118.9 (CH =CH₂),

126.1–128.2 (CH arom.), 136.6 (CH=CH₂), 137.9, 138.0, 138.3, 138.35,

138.6, 139.3 (6ꢂC arom. quat.), 139.4 ppm (2ꢂC arom. quat.); MS

(FAB): m/z: 2429.1 [M+Na]⁺, elemental analysis calcd (%) for

C₁₅₀H₁₅₆O₂₈: C 74.85, H 6.53; found: C 74.93, H 6.65.

2

4.36 (d, J=12.6 Hz, 1H; 1ꢂCHPh), 4.39 (d, J=11.9 Hz, 1H; 1ꢂCHPh),

4.43 (d, ²J=12.6 Hz, 1H; 1ꢂCHPh), 4.46–4.60 (m, 6H; 6ꢂCHPh), 4.75

(d, ³J_1,2=3.5 Hz, 1H; 1-H), 4.77 (d, ²J=12.1 Hz, 1H; 1ꢂCHPh), 4.82 (d,

3

2

²J=10.8 Hz, 1H; 1ꢂCHPh), 4.86 (d, J_1,2=3.4 Hz, 1H; 1-H), 4.87 (d, J=

11.3 Hz, 1H; 1ꢂCHPh), 4.91 (d, ²J=11.0 Hz, 1H; 1ꢂCHPh), 4.94 (d,

2

²J=10.4 Hz, 1H; 1ꢂCHPh), 5.23 (d, J=10.8 Hz, 1H; 1ꢂCHPh), 5.46 (d,

²J=10.5 Hz, 1H; 1ꢂCHPh), 5.64 (d, ³J_1,2=3.8 Hz, 1H; 1-H), 7.20–

7.40 ppm (m, 40H; CH arom.); ¹³C NMR (100 MHz, CDCl₃): d=19.4

(CH₃), 66.4 (C-5), 69.3, 69.4 (2ꢂC-6), 71.5, 71.8 (2ꢂC-5), 73.2, 73.0,

73.25, 73.3, 73.35, 74.3, 76.0, 76.3 (8ꢂCH₂Ph), 78.1, 79.1, 80.0 (3ꢂC-2),

80.5 (C-4), 80.7 (C-3), 80.9 (C-4), 81.1 (C-3), 81.3 (C-3), 81.4 (C-4), 97.7,

98.0, 98.1 (3ꢂC-1), 126.5–128.3 (40ꢂCH arom.), 131.4 (CH₂=CHC=O),

138.05, 138.1, 138.3, 138.4, 138.6, 139.25, 139.3, 139.4 ppm (8ꢂC arom.

quat.); MS (FAB): m/z: 2436.1 [M+Na]⁺; elemental analysis calcd (%)

for C₁₄₉H₁₅₈O₂₉: C 74.60, H 6.60; found: C 74.79, H 6.55.

Diol 27: DIBAL-H (1.5m in toluene, 40 mL, 60 mmol) was slowly added

to a solution of 26 (4.80 g, 2.0 mmol) in toluene (20 mL) under argon at

room temperature. The reaction mixture was heated at 508C for 1.3 h,

then cooled to room temperature and poured on ice. The aqueous layer

was extracted with EtOAc (100 mL) then treated with HCl (1m, 35 mL)

and extracted again with EtOAc (2ꢂ70 mL). The combined organic

layers were dried (MgSO₄), filtered and concentrated. Silica gel flash

chromatography of the residue (cyclohexane/EtOAc, 2:1) gave 27 (4 g,

Diol 24: A solution of 23 (150 mg, 63 mmol) in toluene (640 mL) was

treated with DIBAL-H (1.5m in toluene, 1.3 mL, 1.9 mmol) under argon

at room temperature. The reaction mixture was stirred at 508C for

20 min, cooled at room temperature, poured on ice and diluted with

EtOAc (15 mL). The layers were separated. The aqueous layer was treat-

ed with a 1m solution of HCl (8 mL) and extracted by EtOAc (2ꢂ

15 mL). Organic layers were combined, dried over MgSO₄, filtered and

concentrated. Silica gel flash chromatography of the residue (cyclohex-

ane/EtOAc, 3:1 then 2:1) afforded the diol 24 (116 mg, 84%) as a white

foam. [a]²_D⁰=+44 (c=1.1 in CHCl); ¹H NMR (400 MHz, CDCl₃): d=

90%) as

a

white foam. [a]_D²⁰=+34 (c=0.8 in CHCl₃); ¹H NMR

3

(400 MHz, CDCl₃): d=2.27 (brs, 1H; OH), 3.44 (dd, ³J_2,1=3.3 Hz, J_2,3

=

9.7 Hz, 1H; 2-H), 3.51–3.58 (m, 3H; 2ꢂ2-H, 1ꢂ4-H), 3.72 (brs, ²J=

9.9 Hz, 1ꢂ6-H), 3.80–4.07 (m, 7H; 2ꢂ4-H, 2ꢂ5-H, 3ꢂ6-H), 4.12 (t, ³J=

10.0 Hz, 1ꢂ3-H), 4.14 (dd, ³J=8.3 Hz, ³J=9.9 Hz, 1ꢂ3-H), 4.21 (dd, ³J=

8.4 Hz, ³J=9.6 Hz, 1ꢂ3-H), 4.35–4.49 (m, 5H; 1ꢂ5-H, 4ꢂCHPh), 4.53

1.36 (d, ³J=6.2Hz, 3H; CH ₃), 2.82 (brs, 1H; OH), 3.39 (t, ³J_4,3=³J_4,5

=

(d, J=12.4 Hz, 1H; 1ꢂCHPh), 4.60 (d, J=11.9 Hz, 1H; 1ꢂCHPh), 4.67

2

8.9 Hz, 1H; 1ꢂ4-H), 3.45 (dd, ³J_2,1=3.3 Hz, ³J_2,3=9.8 Hz, 1H; 2-H), 3.56

(d, J=12.4 Hz, 1H; 1ꢂCHPh), 4.68 (d, J=12.2 Hz, 1H; 1ꢂCHPh), 4.76

2

3

(dd, ³J_2,1=3.7 Hz, ³J_2,3=9.6 Hz, 1H; 2-H), 3.59 (dd, ³J_2,1=3.6 Hz, J_2,3

=

(d, ³J_1,2=3.3 Hz, 1H; 1-H), 4.87 (d, ²J=10.7 Hz, 1H; 1ꢂCHPh), 4.89 (d,

2

9.5 Hz, 1H; 2-H), 3.72–4.24 (m, 12, 3ꢂ3-H, 2ꢂ4-H, 3ꢂ5-H, 4ꢂ6-H),

²J=11.3 Hz, 1H; 1ꢂCHPh), 4.93 (d, J=10.9 Hz, 1H; 1ꢂCHPh), 5.01 (d,

4.42–4.67 (m, 7H; 7ꢂCHPh), 4.78 (d, ²J=12.1, 1H; 1ꢂCHPh), 4.87 (d,

²J=11.5 Hz, 1H; 1ꢂCHPh), 5.14 (brd, ³J_cis=11.5 Hz, 1H; CH=CH₂),

2

3

2

²J=11.0 Hz, 1H; 1ꢂCHPh), 4.88 (d, J=10.5 Hz, 1H; 1ꢂCHPh), 4.94 (d,

5.18 (d, J_1,2=3.5 Hz, 1H; 1-H), 5.25 (d, J=10.9 Hz, 1H; 1ꢂCHPh), 5.29

²J=11.2Hz, 1H; 1ꢂCHPh), 5.09 (d, ²J=10.9 Hz, 2H; 2ꢂCHPh), 5.14 (d,

(d, ³J_1,2=3.8 Hz, 1H; 1-H), 5.30 (d, ²J=10.9 Hz, 1H; 1ꢂCHPh), 5.34

9770

www.chemeurj.org

ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2007, 13, 9757 – 9774

Cyclodextrins

FULL PAPER

3

(brd, ³J_trans=18.7 Hz, 1H; CH=CH₂), 6.08 (ddd, ³J=6.2Hz, J_cis

=

layers were dried (MgSO₄), filtered, and concentrated. Silica gel flash

chromatography of the residue (cyclohexane/EtOAc, 2:1) gave 29

(290 mg, 93%) as a white foam. [a]²_D⁰=+31 (c=0.6 in CHCl₃); ¹H NMR

(400 MHz, CDCl₃): d=1.89 (dd, J=4.5 Hz, J=7.9 Hz, 1H; OH), 3.34 (t,

³J_4,3=³J_4,5=9.0 Hz, 1H; 4-H), 3.42–3.62 (m, 5H; 3ꢂ2-H, 1ꢂ4-H, 1ꢂ6-H),

3.78 (dd, ³J_5,6=1.8 Hz, ²J=10.1 Hz, 1H; 6-H), 3.85–3.97 (m, 4H; 1ꢂ4-H,

10.5 Hz, ³J_trans=16.9 Hz, 1H; CH=CH₂), 7.16–7.35 ppm (m, 35H; CH

arom.); ¹³C NMR (100 MHz, CDCl₃): d=61.8, 69.2(2ꢂC-6), 71.0, 71.4,

71.8 (3ꢂC-5), 72.3, 73.05, 73.1, 73.4, 74.8, 75.3, 76.1 (7ꢂCH₂Ph), 78.5 (C-

2), 78.7 (C-4), 78.8, 79.4 (2ꢂC-2), 80.4, 80.8, 81.1 (3ꢂC-3), 81.5 (C-4),

82.9 (C-4), 98.1, 98.3, 98.4 (3ꢂC-1), 118.6 (CH=CH₂), 126.7–128.3 (CH

arom.), 136.2( CH=CH₂), 137.8, 138.15, 138.2, 138.4, 139.2, 139.25,

139.3 ppm (7ꢂC arom. quat.); MS (FAB): m/z: 2249.0 [M+Na]⁺; ele-

mental analysis calcd (%) for C₁₃₆H₁₄₄O₂₈: C 73.36, H 6.52; found: C

73.21, H 6.73.

1ꢂ5-H, 1ꢂ6-H, 1ꢂ OCH₂C

OCH₂C(CH₂O)=CH₂), 4.08–4.17 (m, 3H; 2ꢂ3-H, 1ꢂ6-H), 4.28–4.40 (m,

5H; 1ꢂ3-H, 2ꢂ5-H, 2ꢂCHPh), 4.46 (d, ²J=12.5 Hz, 1H; 1ꢂCHPh),

G

AHCTREUNG

2

4.49 (d, J=13.5 Hz, 1H; 1ꢂCHPh), 4.55 (d, J=12.9 Hz, 1H; 1ꢂCHPh),

4.69 (d, ³J_1,2=3.3 Hz, 1H; 1-H), 4.77–4.90 (m, 5H; 1ꢂ1-H, 4ꢂCHPh),

Tridifferenciated a-CD 18 from bis-olefinic diol 27: A solution of 27

(2.14 g, 960 mmol), pyridine (470 mL, 6 mmol) and tert-butyldimethylsilyl-

trifluoromethanesulfonate (1.3 mL, 6 mmol) in dichloromethane (25 mL)

was stirred at room temperature for 2h, diluted with dichloromethane

(20 mL), washed with aqeous saturated NH₄Cl (2ꢂ40 mL), dried over

MgSO₄, filtered and concentrated. Silica gel flash chromatography (cyclo-

hexane/EtOAc, 6:1) afforded the silylated compound which was dis-

solved in CH₂Cl₂(100 mL). The solution was cooled to ꢀ788C and ozone

was bubbled through it for 1 min, until the solution turned slightly blue.

Me₂S (15 mL, excess) was added. The reaction mixture was stirred at

room temperature for 10 min and then evaporated; the residue was dis-

solved in CH₂Cl₂/MeOH (1:1, 100 mL) and treated at 08C by NaBH₄

(360 mg, 9.6 mmol). After 2h stirring at room temperature, H ₂O (60 mL)

was added. The aqueous layer was extracted with CH₂Cl₂(3ꢂ60 mL) and

the organic layers were combined, dried over MgSO₄, filtered and con-

centrated. Silica gel flash chromatography (cyclohexane/EtOAc, 3:1) af-

forded the tridifferenciated a-CD 18 (1.44 g, 61% over three steps) as a

white foam.

5.01 (d, ²J=10.6 Hz, 1H; 1ꢂCHPh), 5.11 (s, 1H; 1ꢂOCH₂C

(CH₂O)=

A

CH₂), 5.12(brd, ³J_cis=11.4 Hz, 1H; CH=CH₂), 5.28 (d, ²J=10.6 Hz, 1H;

1ꢂCHPh), 5.38 (dd, ³J_trans=17.3 Hz, ²J=1.5 Hz, 1H; CH=CH₂), 5.54 (d,

³J_1,2=4.3 Hz, 1H; 1-H), 5.56 (d, ²J=10.9 Hz, 1H; 1ꢂCHPh), 6.60 (ddd,

³J=4.3 Hz, ³J_cis=10.9 Hz, ³J_trans=17.1 Hz, 1H; CH=CH₂), 7.06–7.31 ppm

(m, 30H; CH arom.); ¹³C NMR (100 MHz, CDCl₃): d=62.0 (C-6), 69.3,

70.8 (2ꢂC-5), 71.5 (C-6), 72.1 (O CH₂C(CH₂O)=CH₂), 72.3 (C-5), 72.35,

E

72.8, 73.4, 73.8, 75.9, 76.4 (6ꢂCH₂Ph), 77.8 (C-2), 78.6 (C-2), 79.2 (C-4),

80.3 (C-2), 80.4 (C-3), 80.8 (C-3), 81.2 (C-3), 81.8 (C-4), 87.6 (C-4), 97.6,

99.4, 99.6 (3ꢂC-1), 115.1 (OCH₂C

A

126.0–128.4 (CH arom.), 135.5 (CH=CH₂), 137.7, 138.2, 138.5, 139.2,

139.3, 139.5 (6ꢂC arom. quat.), 142.3 ppm (OCH₂C(CH₂O)=CH₂); MS

U

(FAB): m/z: 2120.9 [M+Na]⁺; HRMS (ESI) calcd for C₁₂₆H₁₃₆O₂₈Na:

2119.91159, found: 2119.9169 (2 ppm).

Diol 30: A solution of 29 (260 mg, 124 mmol), pyridine (60 mL, 744 mmol)

and tert-butyldimethylsilyltrifluoromethanesulfonate (171 mL, 744 mmol)

in dichloromethane (5 mL) was stirred at room temperature for 2h, di-

luted with dichloromethane (10 mL), washed with aq. sat. NH₄Cl (2ꢂ

15 mL), dried over MgSO₄, filtered and concentrated. Silica gel flash

chromatography (cyclohexane/EtOAc, 6:1) gave the disilylated com-

Capped-CD 28: NaH (60% w/w, 27 mg, 670 mmol) was added to a solu-

tion of diol 27 (373 mg, 167 mmol) in DMF (26 mL). After 30 min stirring

at room temperature, 1-chloro-2-chloromethylpropene (21 mL, 184 mmol)

was added dropwise. The reaction mixture was stirred at room tempera-

ture for 2.5 h under argon, treated with MeOH (10 mL) then concentrat-

ed. The residue was diluted with CH₂Cl₂(25 mL) and washed with a satu-

rated solution of NH₄Cl (20 mL). The aqueous layer was extracted with

CH₂Cl₂(3ꢂ25 mL) and the organic layers were combined, dried over

MgSO₄, filtered and concentrated. After purification by silica gel chro-

matography (cyclohexane/EtOAc, 6:1), the compound 28 (340 mg, 89%)

was isolated as a white foam. [a]²_D⁰=+35 (c=0.7 in CHCl₃); ¹H NMR

(400 MHz, CDCl₃): d=3.29 (t, ³J_4,3=³J_4,5=9.0 Hz, 1H; 4-H), 3.40 (dd,

pound (290 mg, 100%). [Pd(PPh₃)₄] (6 mg, 5.5 mmol) was added to a solu-

U

tion of disilylated compound (128 mg, 55 mmol) in degassed THF

(2.3 mL). The reaction mixture was stirred at room temperature under

argon for 10 min, then a degassed 1m solution of ZnCl₂in THF (825 mL,

825 mmol) was added, followed by a slow addition of Et₃SiH (133 mL,

825 mmol). The reaction mixture was refluxed under argon for 2h, then

diluted with EtOAc (5 mL). Water (5 mL) was added, and layers were

separated. The aqueous layer was extracted with EtOAc (3ꢂ5 mL). The

organic layers were combined, dried over MgSO₄, filtered and evaporat-

ed. The crude was dissolved in toluene and purified by silica gel flash

chromatography (cyclohexane/EtOAc, 6:1, then 3:1) to give diol 30

(100 mg, 80%) as a white foam. [a]²_D⁰=+33 (c=0.4 in CHCl₃); ¹H NMR

(400 MHz, CDCl₃): d=0.05 (s, 3H; CH₃Si), 0.06 (s, 3H; CH₃Si), 0.91 (s,

9H; (CH₃)₃Si), 2.12 (dd, J=5.1 Hz, J=7.7 Hz, 1H; OH), 3.45–3.53 (m,

³J_2,1=3.2Hz, ³J_2,3=9.9 Hz, 1H; 2-H), 3.45 (dd, J_2,1=3.3 Hz, J_2,3=9.6 Hz,

1H; 2-H), 3.57 (dd, ³J_4,3=³J_4,5=8.4 Hz, ²J=9.9 Hz, 2H; 1ꢂ4-H, 1ꢂ6-H),

3.67 (dd, ³J_2,1=4.0 Hz, ³J_2,3=9.8 Hz, 1H; 2-H), 3.69–3.77 (brd, 3H; 2ꢂ6-

3

H, 1ꢂOCH₂C(CH₂O)=CH₂), 3.92–3.98 (m, 2H; 1ꢂ5-H, 1ꢂOCH₂C-

A

3

3H; 3ꢂ2-H), 3.57 (t, J_4,3=³J_4,5=9.1 Hz, 1H; 4-H), 3.77–3.81 (m, 3H; 1ꢂ

(CH₂O)=CH₂), 4.02–4.21 (m, 4H; 2ꢂ3-H, 1ꢂ4-H, 1ꢂ6-H), 4.28–4.52 (m,

9H; 1ꢂ3-H, 2ꢂ5-H, 6ꢂCHPh), 4.59 (d, ²J=11.8 Hz, 1H; 1ꢂCHPh),

4.66 (d, ³J_1,2=3.3 Hz, 1H; 1-H), 4.72–4.90 (m, 5H; 1ꢂ1-H, 4ꢂCH₂Ph),

5-H, 2ꢂ6-H), 3.84 (t, ³J_4,3=³J_4,5=9.0 Hz, 1H; 4-H), 3.86 (t, ³J_4,3=³J_4,5

=

9.0 Hz, 1H; 4-H), 3.90–4.03 (m, 2H; 1ꢂ5-H, 1ꢂ6-H), 4.04–4.20 (m, 4H;

3ꢂ3-H, 1ꢂ6-H), 4.38–4.46 (m, 3H; 1ꢂ5-H, 2ꢂCHPh), 4.50 (d, ²J=

12.7 Hz, 1H; 1ꢂCHPh), 4.57 (d, ²J=12.3 Hz, 1H; 1ꢂCHPh), 4.67 (d,

²J=12.3 Hz, 1H; 1ꢂCHPh), 4.68 (d, ²J=12.2 Hz, 1H; 1ꢂCHPh), 4.82–

5.00 (m, 5H; 1ꢂ1-H, 4ꢂCHPh), 5.10 (d, ³J_1,2=3.4 Hz, 1H; 1-H), 5.20

(brd, ³J_cis=11.3 Hz, 1H; CH=CH₂), 5.28 (d, ²J=10.8 Hz, 1H; 1ꢂCHPh),

5.02(s, 1H; 1ꢂOCH ₂C

(CH₂O)=CH₂), 5.03 (d, ²J=10.5 Hz, 1H; 1ꢂ

G

CHPh), 5.09 (dd, ³J_cis=11.3 Hz, ²J=1.4 Hz, 1H; CH=CH₂), 5.26 (dd,

³J_trans=17.5 Hz, ²J=1.7 Hz, 1H; CH=CH₂), 5.28 (d, ²J=10.5 Hz, 1H; 1ꢂ

CHPh), 5.60 (d, ²J=10.5 Hz, 1H; 1ꢂCHPh), 5.64 (d, ³J_1,2=4.2Hz, 1H;

1-H), 6.61 (ddd, ³J=4.2Hz, ³J_cis=10.9 Hz, ³J_trans=17.1 Hz, 1H; CH=

CH₂), 7.03–7.34 ppm (m, 35H; CH arom.); ¹³C NMR (100 MHz, CDCl₃):

d=68.9 (C-6), 69.2(C-5), 70.6 (C-5), 71.5 (C-6), 71.6 (C-5), 71.9

2

3

5.30 (d, J=10.6 Hz, 1H; 1ꢂCHPh), 5.33 (d, J_1,2=3.8 Hz, 1H; 1-H), 5.41

(brd, ³J_trans=17.2Hz, 1H; CH =CH₂), 6.07 (ddd, ³J=6.2Hz, J_cis

=

3

10.4 Hz, ³J_trans=16.9 Hz, 1H; CH=CH₂), 7.13–7.30 ppm (m, 30H; CH

arom.); ¹³C NMR (100 MHz, CDCl₃): d=ꢀ5.4 (CH₃Si), ꢀ5.1 (CH₃Si),

17.5 ((H₃C)₃CSi), 25.9 ((H₃C)₃CSi), 61.9, 62.7 (2ꢂC-6), 70.9, 71.3 (2ꢂC-

5), 72.1 (CH₂Ph), 72.9 (C-5), 73.0, 73.1, 74.6, 75.4, 76.2 (5ꢂCH₂Ph), 78.6

(C-2), 78.9 (C-2, C-4), 79.5 (C-2), 80.4 (C-3), 80.9 (C-3), 81.0 (C-4), 81.1

(C-3), 82.4 (C-4), 98.0, 98.1, 98.3 (3ꢂC-1), 118.6 (CH=CH₂), 126.6–128.2

(CH arom.), 136.2( CH=CH₂), 137.7, 138.2, 138.5, 139.2, 139.3, 139.5 ppm

(6ꢂC arom. quat.); MS (FAB): m/z: 2298.3 [M+Na]⁺; elemental analysis

calcd (%) for C₁₃₄H₁₆₀O₂₈Si₂: C 70.75, H 7.09; found: C 70.95, H 7.21.

(OCH₂C

77.8 (C-2), 78.8 (C-2), 78.9 (C-4), 80.4 (C-2), 80.5 (C-3), 81.2 (2ꢂC-3),

81.8 (C-4), 87.9 (C-4), 97.8, 99.1, 99.6 (3ꢂC-1), 114.7 (OCH₂C(CH₂O)=

(CH₂O)=CH₂), 72.3, 72.7, 73.3, 73.4, 73.6, 76.1, 76.5 (7ꢂCH₂Ph),

AHCTREUNG

CH₂), 115.4 (CH=CH₂), 125.9–128.4 (CH arom.), 135.9 (CH=CH₂), 137.8,

138.1, 138.4, 138.8, 139.3, 139.4, 139.5 (7ꢂC arom. quat.), 142.4 ppm

(OCH₂C

(CH₂O)=CH₂); MS (FAB): m/z: 2300.8 [M+Na]⁺; elemental

A

analysis calcd (%) for C₁₄₀H₁₄₈O₂₈: C 73.79, H 6.55; found: C 73.79, H

6.59.

Diol 29: DIBAL-H (1.5m in toluene, 3 mL, 4.5 mmol) was slowly added

to a solution of 28 (340 mg, 150 mmol) in toluene (1.5 mL) under argon at

room temperature. The reaction mixture was heated at 508C for 30 min,

then cooled to room temperature and poured on ice. The aqueous layer

was extracted with EtOAc (15 mL) then treated with HCl (1, 10 mL)

and extracted again with EtOAc (2ꢂ20 mL). The combined organic

Tetradifferenciated a-CD 31: Compound 30 (70 mg, 31 mmol) was dis-

solved in pyridine (2mL) and was treated with acetic anhydride (1 mL)

and DMAP (1 mg). The reaction mixture was stirred at room tempera-

ture for 1 h, then concentrated. After purification by silica gel flash chro-

matography (cyclohexane/EtOAc, 4:1), the acetylated compound (75 mg,

Chem. Eur. J. 2007, 13, 9757 – 9774

ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

9771

M. Sollogoub et al.

quant.) was isolated as a white foam and dissolved in CH₂Cl₂(3 mL).

The solution was cooled to ꢀ788C and ozone was bubbled through it for

1 min, until the solution turned slightly blue. Me₂S (0.1 mL, excess) was

added. The reaction mixture was stirred at room temperature for 10 min

and then evaporated; the residue was dissolved in CH₂Cl₂/MeOH (1:1,

2mL) and treated at 0 8C by NaBH₄(8 mg, 186 mmol). After 2h stirring

at room temperature, the reaction mixture was concentrated and purified

by silica gel flash chromatography (cyclohexane/EtOAc, 3:1). Compound

31 (40 mg, 55% over three steps) was obtained as a white foam. [a]²_D⁰=+

33 (c=0.8 in CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=0.06 (s, 3H;

CH₃Si), 0.09 (s, 3H; CH₃Si), 0.91 (s, 9H; (CH₃)₃Si), 2.09 (s, 3H; CH₃C=

O), 3.158 (brs, 1H; OH), 3.43 (dd, ³J_2,1=3.3 Hz, ³J_2,3=9.9 Hz, 1H; 2-H),

3.53 (dd, ³J_2,1=3.4 Hz, ³J_2,3=9.7 Hz, 1H; 2-H), 3.58 (dd, ³J_2,1=3.9 Hz,

Diols 39 and 40: DIBAL-H (1.5m in toluene, 24 mL, 36 mmol) was

added To a solution of bridged b-cyclodextrin 38 (3 g, 1.0 mmol) in tolu-

ene (12mL) at room temperature under argon. The reaction mixture was

stirred at 508C for 2h, cooled to room temperature and poured on ice.

The aqueous layer was extracted with EtOAc (100 mL) then treated with

HCl (1m, 35 mL) and extracted again with EtOAc (2ꢂ70 mL). The com-

bined organic layers were dried (MgSO₄), filtered and concentrated.

Silica gel flash chromatography of the residue (cyclohexane/EtOAc, 2:1)

afforded an unseparable mixture of two regioisomers 39 and 40 (2.1 g,

74%) as a white foam. ¹H NMR (400 MHz, CDCl₃): d=2.33 (brs, 1H;

OH), 2.55 (brs, 1H; OH), 3.41–3.54 (m, 4H; 4ꢂ2-H), 3.55–4.25 (m, 42H;

3ꢂ2-H, 7ꢂ3-H, 7ꢂ4-H, 7ꢂ5-H, 16ꢂ6-H, 4ꢂOCH₂CH=CHCH₂O), 4.38–

4.68 (m, 20H; 20ꢂCHPh), 4.70–4.90 (m, 10H; 1ꢂ1-H, 9ꢂCHPh), 4.92

(d, ³J_1,2=3.3 Hz, 1H; 1-H), 5.05 (d, ²J=10.9 Hz, 1H; CHPh), 5.06 (d,

³J_2,3=9.7 Hz, 1H; 2-H), 3.72–3.92 (m, 7H; 3ꢂ4-H, 1ꢂ5-H, 3ꢂ6-H), 4.08–

3

³J_1,2=3.7 Hz, 1H; 1-H), 5.10 (d, ²J=10.9 Hz, 1H; CHPh), 5.17 (d, J_1,2

=

3

4.19 (m, 5H; 2ꢂ3-H, 1ꢂ5-H, 1ꢂ6-H), 4.23 (dd, ³J_3,2=9.5 Hz, J_3,4

=

3.8 Hz, 1H; 1-H), 5.18 (d, ³J_1,2=3.8 Hz, 1H; 1-H), 5.22 (d, ²J=10.8 Hz,

1H; CHPh), 5.30 (d, ²J=10.3 Hz, 1H; CHPh), 5.32(d, ²J=10.7 Hz, 1H;

CHPh), 5.47 (d, ³J_1,2=3.8 Hz, 1H; 1-H), 5.57 (d, ³J_1,2=3.9 Hz, 1H; 1-H),

5.75 (s, 2H; OCH₂CH=CHCH₂O), 7.00–7.31 ppm (m, 85H; CH arom.);

¹³C NMR (100 MHz, CDCl₃): d=61.3, 61.4 (2ꢂC-6), 68.85, 68.9, 69.0 (3ꢂ

C-6), 70.4 (2ꢂC-6), 71.05 (1ꢂC-5), 71.1 (OCH₂CH=CHCH₂O), 71.2,

71.4, 71.45 (3ꢂC-5), 71.7 (OCH₂CH=CHCH₂O), 71.9 (C-5), 71.95 (2ꢂC-

5), 72.2, 72.3, 72.6, 72.8 (4ꢂCH₂Ph), 73.0 (2ꢂCH₂Ph), 73.2(2ꢂCH ₂Ph),

73.3 (2ꢂCH₂Ph), 74.0, 74.3, 75.15, 75.2, 75.4, 75.5, 76.2 (7ꢂCH₂Ph), 77.7,

77.9 (2ꢂC-2), 78.3 (2ꢂC-4), 78.5 (2ꢂC-2), 79.2 (C-4), 79.3 (C-2), 79.4 (C-

4), 79.85 (2ꢂC-2), 79.9 (2ꢂC-4), 80.1 (C-4), 80.55, 80.6, 80.65, 80.85, 80.9,

81.2,81.4 (7ꢂC-3), 97.3, 97.6, 97.8, 98.3, 99.1, 99.3, 99.4 (7ꢂC-1), 127.0–

138.2 (85ꢂCH arom.), 128.5, 129.3 (OCH₂CH=CHCH₂O), 137.8, 137.9,

138.0 (3ꢂC arom.quat.), 138.05 (2ꢂC arom.quat.), 138.15, 138.25, 138.3,

138.35, 138.5, 138.9, 138.95, 139.1, 139.2, 139.25, 139.3, 139.4 ppm (12ꢂ C

8.0 Hz, 1H; 3-H), 4.41–4.55 (m, 6H; 4ꢂCHPh, 2ꢂ6-H), 4.61 (d, ²J=

3

12.5 Hz, 1H; CHPh), 4.75 (d, ²J=12.1 Hz, 1H; CHPh), 4.78 (d, J_1,2

=

3.4 Hz, 1H; 1-H), 4.81 (d, ²J=10.7 Hz, 1H; CHPh), 4.85 (d, ²J=11.8 Hz,

1H; CHPh), 4.92(d, ²J=10.7 Hz, 1H; CHPh), 4.93 (d, ²J=11.9 Hz, 1H;

CHPh), 4.96 (d, ³J_1,2=3.5 Hz, 1H; 1-H), 5.24 (d, ²J=10.6 Hz, 1H;

CHPh), 5.37 (d, ²J=10.7 Hz, 1H; CHPh), 5.58 (d, ³J_1,2=3.9 Hz, 1H; 1-

H), 7.12–7.30 ppm (m, 30H; CH arom.); ¹³C NMR (100 MHz, CDCl₃):

d=ꢀ5.4 (CH₃Si), ꢀ5.3 (CH₃Si), 18.4 (CH₃C=O), 20.8 ((H₃C)₃CSi), 26.0

((H₃C)₃CSi), 62.7

, 63.3, 64.4 (3ꢂC-6), 69.8 (C-5), 71.6 (C-5), 72.

(CH₂Ph), 73.15 (CH₂Ph), 73.2(C-5), 73.3, 74.2, 75.7, 76.3 (4ꢂCH ₂Ph),

76.8 (C-4), 77.9 (C-2), 78.9 (C-2), 79.8 (C-2), 80.6 (C-3), 80.9 (2ꢂC-4),

81.2 (C-3), 97.4, 98.2, 98.9 (3ꢂC-1), 126.4–128.3 (CH arom.), 137.9, 138.1,

138.6, 139.15, 139.2, 139.3 (6ꢂC arom. quat.), 170.6 ppm (CH₃C=O);

MS (FAB): m/z: 2389.1 [M+Na]⁺; HRMS (ESI) calcd for

arom.quat.); MS

(FAB): m/z: 2741.5 [M+Na]⁺; elemental analysis calcd

G

C

₁₃₆H₁₆₄O₃₂Si₂Na: 2388.06420, found: 2388.0640 (0 ppm).

(%) for C₁₆₅H₁₇₆O₃₅: C 72.88, H 6.51; found: C 72.46, H 6.51.

Capped b-CD 38: nBu₄NI (16 mg, 44 mmol), NaH 60% w/w (67 mg,

1.69 mmol) and allyl bromide (146 mL, 1.69 mmol) were added to a solu-

tion of diol 4 (1.2g, 442 mmol) in THF (25 mL). The reaction mixture

was stirred for 6 h at room temperature. MeOH was added and the reac-

tion mixture was concentrated, diluted with CH₂Cl₂(80 mL) and washed

with a saturated aqueous solution of NH₄Cl (2ꢂ40 mL) and with brine

(40 mL). The organic layer was dried over MgSO₄, filtered and concen-

trated. The residue was purified by silica gel flash chromatography (cy-

clohexane/EtOAc, 6:1). Compound 37 (1.15 g, 89%) was obtained as a

white foam. [a]²_D⁰=+34 (c=1.0 in CHCl₃); ¹H NMR (400 MHz, CDCl₃):

d=3.56–3.73 (m, 14H; 7ꢂ2-H, 7ꢂ6-H), 3.92–4.18 (m, 32H; 7ꢂ3-H, 7ꢂ4-

H, 7ꢂ5-H, 7ꢂ6-H, 4ꢂOCH₂CH=CH₂), 4.50–4.65 (m, 24H; 24ꢂCHPh),

4.86–4.91 (m, 7H; 7ꢂCHPh), 5.11–5.32(m, 17H; 6ꢂ1-H, 4ꢂOCH ₂CH=

CH₂, 7ꢂCHPh), 5.35 (d, ³J_1,2=3.4 Hz, 1H; 1-H), 5.80–5.90 (m, 2H; 2ꢂ

OCH₂CH=CH₂), 7.20–7.36 ppm (m, 95H; H-arom.); ¹³C NMR (100 MHz,

CDCl₃): d=69.0–69.1 (7ꢂC-6), 71.1 (2ꢂC-5), 71.3 (2ꢂC-5), 71.4 (2ꢂC-

5), 71.5 (C-5), 72.0, 72.1 (2ꢂOCH₂CH=CH₂), 72.5 (OCH₂Ph), 72.55 (2ꢂ

OCH₂Ph), 72.6, 72.65, 72.7, 72.8 (4ꢂOCH₂Ph), 73.1 (OCH₂Ph), 73.15 (2ꢂ

OCH₂Ph), 73.2, 73.3 (2ꢂOCH₂Ph), 75.1, 75.2, 75.3, 75.4 (4ꢂOCH₂Ph),

75.45 (2ꢂOCH₂Ph), 75.5 (OCH₂Ph), 77.7, 78.2, 78.5 (3ꢂCH), 78.6–78.7

(8ꢂCH), 78.9 (CH), 79.0 (2ꢂCH), 80.8–80.9 (7ꢂC-3), 98.3, 98.35 (2ꢂC-

1), 98.4 (2ꢂC-1), 98.5 (3ꢂC-1), 116.75, 116.8 (2ꢂOCH ₂CH=CH₂), 126.8–

128.2 (CH-arom.), 134.6 (2ꢂOCH₂CH=CH₂), 138.05 (3ꢂC-arom. quat.),

138.1, 138.15, 138.2, 138.25 (4ꢂC-arom. quat.), 138.3 (3ꢂC-arom. quat.),

138.35, 138.40 (2ꢂC-arom. quat.), 139.1 (2ꢂC-arom. quat.), 139.2ppm

(5ꢂC-arom. quat.); MS (FAB): m/z: 2948.5 [M+Na]; elemental analysis

calcd (%) for C₁₈₁H₁₉₂O₃₅: C 74.26, H 6.61; found: C 70.16, H 6.40.

Tridifferenciated b-CDs 41 and 42: A solution containing the mixture of

39 and 40 (2g, 754 mmol), pyridine (370 mL, 4.5 mmol) and tert-butyldi-

methylsilyltrifluoromethanesulfonate (1 mL, 4.5 mmol) in CH₂Cl₂

(25 mL) was stirred at room temperature 2 h under argon, diluted with

CH₂Cl₂(10 mL), washed with a saturated solution of NH₄Cl (2ꢂ30 mL),

dried over MgSO₄, filtered and concentrated. Silica gel flash chromatog-

raphy of the residue (cyclohexane/EtOAc, 6:1) afforded an unseparable

mixture of the two silyl-protected regioisomers (2.2 g, 100%). [Pd-

A

regioisomers (2g, 679 mmol) dissolved in THF (18 mL). A degassed 0.5m

solution of ZnCl₂in THF (20 mL, 10.2 mmol) was added dropwise under

argon. The reaction mixture was stirred at room temperature for 10 min.

Bu₃SnH (2.74 mL, 10.2 mmol) was slowly added. The reaction mixture

was refluxed for 20 h under argon, concentrated, dissolved in toluene,

and purified by silica gel flash chromatography (cyclohexane/EtOAc, 4:1)

to afford 41 (1.2g, 60%) and 42 (290 mg, 15%) as white foams.^[25]

Tridifferenciated b-CD 41:^[25][a]_D²⁰=+40 (c=1.0 in CHCl₃); ¹H NMR

(400 MHz, CDCl₃): d=0.06 (s, 3H; CH₃Si), 0.08 (s, 3H; CH₃Si), 0.12(s,

3H; CH₃Si), 0.15 (s, 3H; CH₃Si), 0.91 (s, 9H; (CH₃)₃Si), 0.98 (s, 9H;

(CH₃)₃Si), 3.40 (dd, ³J_2,1=3.0 Hz, ³J_2,3=9.6 Hz, 2H; 2ꢂ2-H), 3.45 (dd,

3

³J_2,1=3.4 Hz, J_2,3=9.2Hz, 1H; 2-H), 3.50 (dd, ³J_2,1=3.6 Hz, J_2,3=8.9 Hz,

1H; 2-H), 3.59 (dd, ³J_2,1=3.7 Hz, ³J_2,3=8.6 Hz, 3H; 3ꢂ2-H), 3.65–4.12

(m, 35H; 7ꢂ3-H, 7ꢂ4-H, 7ꢂ5-H, 14ꢂ6-H), 4.45–4.79 (m, 28H; 28ꢂ

CHPh), 4.81 (d, ²J=11.2Hz, 1H; 1ꢂCHPh), 4.86 (d, ²J=10.4 Hz, 1H;

1ꢂCHPh), 4.87 (d, ³J_1,2=3.4 Hz, 1H; 1-H), 4.97 (d, ³J_1,2=3.4 Hz, 1H; 1-

3

H), 5.06 (d, J_1,2=3.4 Hz, 1H; 1-H), 5.11 (d, ²J=11.2Hz, 1H; 1ꢂCHPh),

5.12–5.25 (m, 4H; 2ꢂ1-H, 2ꢂCHPh), 5.28 (d, ²J=10.1 Hz, 1H; 1ꢂ

CHPh), 5.49 (d, ³J_1,2=3.5 Hz, 1H; 1-H), 5.56 (d, ³J_1,2=3.9 Hz, 1H; 1-H),

7.18–7.30 ppm (m, 85H; CH arom.); ¹³C NMR (100 MHz, CDCl₃): d=

ꢀ5.2(2ꢂCH ₃Si), ꢀ5.0 (2ꢂCH₃Si), 18.3, 18.4 (2ꢂ(H₃C)₃CSi), 25.9, 26.0

(6ꢂ(H₃C)₃CSi), 61.7, 61.75, 62.35, 62.5 (4ꢂC-6), 68.8, 68.9, 69.5 (3ꢂC-6),

71.4, 71.5, 71.6, 71.7, 71.9, 72.7, 72.9 (7ꢂC-5), 72.2, 72.35, 72.4, 72.6,

72.65, 72.8, 72.9 (7ꢂCH₂Ph), 73.3, 73.4, 73.5 (3ꢂ CH₂Ph), 74.4, 74.5, 74.9

(3ꢂCH₂Ph), 75.6, 75.8, 76.0, 76.1 (4ꢂCH₂Ph), 77.3, 77.4 (2ꢂC-2), 78.8,

78.9, 78.95, 79.1 (3ꢂC-2, C-4), 79.4, 79.45, 79.6, 79.9 (6ꢂC-4), 81.25, 81.2,

81.1, 80.9, 80.8, 80.6, 80.4 (7ꢂC-3), 97.0, 97.6, 97.7, 98.2, 98.3, 98.35, 99.1

(7ꢂC-1), 127.3–128.25 (85ꢂCH arom.), 137.95, 137.9, 138.0, 138.15,

A first-generation Grubbs catalyst (11 mg, 13 mmol) was added to a solu-

tion of 37 (800 mg, 273 mmol) in CH₂Cl₂(35 mL). The reaction mixture

was refluxed for 5 h. The solution was allowed to cool down to room

temperature, Pb(OAc)₄(9 mg, 1.5 equiv/Ru) was added and the reaction

A

mixture was stirred at room temperature for 3 h and then concentrated.

The residue was purified by silica gel flash chromatography (cyclohex-

ane/EtOAc, 5:1) to afford bridged b-CD 38 (1.15 g, 89%) as a white

foam. ¹H NMR (400 MHz, CDCl₃): disappearance of the ethylenic

proton (CH=CH₂); MS (FAB): m/z: 2922.2 [M+Na]⁺; elemental analysis

calcd (%) for C₁₇₉H₁₈₈O₃₅: C 74.15, H 6.54; found: C 73.84, H 6.76.

9772

www.chemeurj.org

ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2007, 13, 9757 – 9774

Cyclodextrins

FULL PAPER

138.1, 138.2, 138.3, 138.4, 138.45, 138.5 (10ꢂC arom.quat.), 138.9, 138.95,

139.0, 139.1, 139.3, 139.4, 139.45 ppm (7ꢂC arom.quat.); MS (FAB): m/z:

2917.6 [M+Na]⁺; elemental analysis calcd (%) for C₁₇₃H₂₀₀O₃₅Si₂: C

71.76, H 6.96; found: C 71.51, H 6.88.

Tridifferenciated b-CD 42:^[25][a]_D²⁰=+49 (c=0.8 in CHCl₃); ¹H NMR

(400 MHz, CDCl₃): d=0.05 (s, 3H; CH₃Si), 0.06 (s, 3H; CH₃Si), 0.07 (s,

(7ꢂC-2), 79.9–81.5 (7ꢂC-3, 3ꢂC-4), 81.7, 81.9 (2ꢂC-4), 97.4, 97.5, 97.6,

97.9 (4ꢂC-1), 99.1 (2ꢂC-1), 99.8 (C-1), 119.0, 119.4 (2ꢂCH =CH₂),

126.4–128.3 (CH arom.), 136.9, 137.0 (2ꢂ CH=CH₂), 137.8, 137.9 (2ꢂC

arom. quat.), 137.95 (2ꢂC arom. quat.), 138.0, 138.1 (2ꢂC arom. quat.),

138.2 (2ꢂC arom. quat.), 138.3 (C arom. quat.), 138.5 (2ꢂC arom. quat.),

138.6 (C arom. quat.), 139.0, 139.1, 139.2, 139.4, 139.5 (5ꢂC arom. quat.),

139.6 ppm (2ꢂC arom. quat.); MS (FAB): m/z: 2862.1 [M+Na]⁺; ele-

mental analysis calcd (%) for C₁₇₇H₁₈₄O₃₃: C 74.87, H 6.53; found: C

74.93, H 6.59.

3H; CH₃Si), 0.085 (s, 3H; CH₃Si), 0.90 (s, 9H; (CH₃)₃Si), 0.93 (s, 9H;

3

(CH₃)₃Si), 2.32 (brs, 1H; OH), 2.40 (brs, 1H; OH), 3.36 (dd, J_2,1

=

3.5 Hz, ³J_2,3=9.6 Hz, 1H; 2-H), 3.41 (dd, ³J_2,1=3.5 Hz, ³J_2,3=9.5 Hz, 1H;

2-H), 3.43–3.60 (m, 5H; 5ꢂ2-H), 3.62–3.72 (m, 4H; 4ꢂ6-H), 3.78–4.15

(m, 30H; 7ꢂ3-H, 7ꢂ4-H, 7ꢂ5-H, 9ꢂ6-H), 4.17 (dd, ³J_6,5=4 Hz, ²J=

11.9 Hz, 1H; 6-H), 4.37–4.57 (m, 16H; 16ꢂCHPh), 4.62–4.77 (m, 14H;

Diols 44 and 45: DIBAL-H (1.5m in toluene, 1.56 mL, 2.34 mmol) was

slowly added to a solution of 43 (189 mg, 67 mmol) in toluene (780 mL)

under argon at room temperature. The reaction mixture was heated at

508C for 1 h, then cooled to room temperature and poured on ice. The

aqueous layer was extracted with EtOAc (10 mL) then treated with HCl

(1m, 5 mL) and extracted again with EtOAc (2ꢂ10 mL). The combined

organic layers were dried (MgSO₄), filtered, and concentrated. Silica gel

flash chromatography of the residue (cyclohexane/EtOAc, 2:1) afforded

an unseparable mixture of the two regioisomeric diols 44 and 45 (99 mg,

56%). ¹H NMR (400 MHz, CDCl₃): d=2.11 (brs, 1H; OH), 2.51 (brs,

1H; OH), 3.30–4.14 (m, 36H; 7ꢂ2-H, 7ꢂ3-H, 7ꢂ4-H, 5ꢂ5-H, 10ꢂ6-H),

3

14ꢂCHPh), 4.86 (d, J_1,2=3.3 Hz, 1H; 1-H), 5.00 (d, J_1,2=3.4 Hz, 1H; 1-

H), 5.03(d, ³J_1,2=3.5 Hz, 1H; 1-H), 5.06 (d, ²J=11.2Hz, 1H; 1ꢂCHPh),

2

5.13 (d, J=11.5 Hz, 1H; 1ꢂCHPh), 5.14 (d, J=10.9 Hz, 1H; 1ꢂCHPh),

5.15 (d, ³J_1,2=3.5 Hz, 1H; 1-H), 5.17 (d, ³J_1,2=3.5 Hz, 1H; 1-H), 5.18 (d,

²J=10.7 Hz, 1H; 1ꢂCHPh), 5.22 (d, J=10.8 Hz, 1H; 1ꢂCHPh), 5.40 (d,

2

³J_1,2=3.6 Hz, 1H; 1-H), 5.44 (d, ³J_1,2=3.6 Hz, 1H; 1-H), 7.00–7.40 ppm

(m, 85H; CH arom.); ¹³C NMR (100 MHz, CDCl₃): d=ꢀ5.2(2ꢂCH ₃Si),

ꢀ5.15 (2ꢂCH₃Si), 18.3, 18.4 (2ꢂ(H₃C)₃CSi), 26.0 (6ꢂ(H₃C)₃CSi), 61.7

(4ꢂC-6), 69.2, 68.8, 68.9 (3ꢂC-6), 71.4–71.65 (7ꢂC-5), 72.4 (CH₂Ph),

72.6 (3ꢂ CH₂Ph), 72.7–72.9 (3ꢂCH₂Ph), 73.3 (CH₂Ph), 73.4 (2ꢂCH₂Ph),

74.6 (3ꢂ CH₂Ph), 75.8 (2ꢂ CH₂Ph), 76.0 (2ꢂ CH₂Ph), 77.7, 77.8 (2ꢂC-

2), 78.8 (2ꢂC-2), 78.9 (2ꢂC-2), 79.5 (C-2), 79.7 (C-4), 79.8 (2ꢂC-4), 80.3

(2ꢂC-4), 80.4 (2ꢂC-4), 80.7 (C-3), 80.8 (2ꢂC-3), 80.9 (2ꢂC-3), 81.2, 81.3

(2ꢂC-3), 97.3, 97.4, 97.8, 98.2, 98.3, 98.5, 99.0 (7ꢂC-1), 137.0–129.0 (85ꢂ

CH arom.), 137.7, 137.9 (2ꢂC arom.quat.), 138.1 (2ꢂC arom.quat.),

138.2(2ꢂC arom.quat.), 138.3, 138.4, 138.5, 138.6, 138.7 (5ꢂC arom.-

quat.), 139.0, 139.05, 139.1, 139.3, 139.4, 139.5 ppm (6ꢂC arom.quat.);

[a]²_D⁰=+49 (c=0.8 in CHCl₃); MS (FAB): m/z: 2917.6 [M+Na]⁺; ele-

mental analysis calcd (%) for C₁₇₃H₂₀₀O₃₅Si₂: C 71.76, H 6.96; found: C

71.51, H 6.88.

4.29–4.62 (m, 22H; 2ꢂ5-H, 20ꢂCHPh), 4.64–5.55 ppm (m, 25H; 7ꢂ1-H,

3

14ꢂCHPh, 4ꢂCH=CH₂), 5.98 (ddd, ³J=7.0 Hz, ³J_cis=10.3 Hz, J_trans

=

3

17.2Hz, 1H; C H=CH₂), 6.08 (ddd, ³J=6.4 Hz, ³J_cis=10.4 Hz, J_trans

=

16.9 Hz, 1H; CH=CH₂), 7.17–7.32ppm (m, 85H; CH arom.); ¹³C NMR

(100 MHz, CDCl₃): d=61.0, 61.8, 63.0 (CH₂), 68.9–69.3 (CH₂), 71.2–71.9

(CH), 72.1–73.3 (CH₂), 74.5–76.1 (CH₂), 76.4 (CH), 77.8, 78.1 (CH),

78.3–81.2(CH), 97.5, 97.9, 98.05, 98.3, 98.5, 98.7, 98.75 (7ꢂC-1), 118.2,

118.8 (2ꢂCH=CH₂), 126.6–128.3 (CH arom.), 135.9, 136.7 (2ꢂCH=CH₂),

137.7–138.5 (C arom. quat.), 138.9–139.4 ppm (C arom. quat.); MS

(FAB): m/z: 2681.2 [M+Na]⁺; HRMS (ESI) calcd for C₁₆₃H₁₇₂O₃₃Na:

2680.16786; found: 2680.1704 (1 ppm).

Tridifferenciated b-CD 41 and 42: A solution of 44 and 45 (260 mg,

124 mmol), pyridine (14 mL, 176 mmol) and tert-butyldimethylsilyltrifluor-

omethanesulfonate (40 mL, 176 mmol) in dichloromethane (1.2mL) was

stirred at room temperature for 1 h, diluted with dichloromethane

(10 mL), washed with aq. sat. NH₄Cl (2ꢂ10 mL), dried over MgSO₄, fil-

tered and concentrated. Silica gel flash chromatography (cyclohexane/

EtOAc, 5:1) afforded the silylated compounds, which were dissolved in

CH₂Cl₂(10 mL). The solution was cooled to ꢀ788C and ozone was bub-

bled through it for 1 min, until the solution turned slightly blue. Me₂S

(0.5 mL, excess) was added. The reaction mixture was stirred at room

temperature for 10 min and then evaporated; the resulting residue was

dissolved in CH₂Cl₂/MeOH (1:1, 2mL) and treated at 0 8C with NaBH₄

(10 mg, excess). After 2h stirring at room temperature, the reaction mix-

ture was concentrated and purified by silica gel flash chromatography

(cyclohexane/EtOAc, 6:1, then 4:1). Compound 42 (30 mg) and com-

pound 41 (8 mg) were obtained as white foams (79:21, 60% global yield

over 3 steps).^[25]

Bis-olefinic b-CD 43: A solution of DMSO (202 mL, 2.8 mmol) in CH₂Cl₂

(1.6 mL) was added dropwise to a solution of oxalyl chloride (123 mL,

1.4 mmol) in CH₂Cl₂(1.6 mL) cooled to ꢀ788C under argon. The reac-

tion mixture was stirred at ꢀ788C for 30 min, then a solution of diol 4

(405 mg, 142 mmol) in CH₂Cl₂(4.1 mL) was added to it. After 2h at

ꢀ788C, Et₃N (400 mL, 2.8 mmol) was added, the reaction mixture was

warmed to room temperature and treated with water (20 mL). The aque-

ous layer was extracted with CH₂Cl₂(3ꢂ20 mL). The organic layers were

combined, dried over MgSO₄, filtered and concentrated to give a bis-al-

dehyde. Ph₃PCH₃Br (1.15 g, 3.2mmol) was suspended in THF (2mL),

cooled to ꢀ408C and treated dropwise with nBuLi (2.5m in hexane,

1.1 mL, 2.8 mmol). The reaction mixture was stirred at ꢀ408C for 15 min,

then at 08C for 5 min, and a solution of the bis-aldehyde diluted in THF

(2mL) was added. The reaction mixture was stirred at room temperature

for 4 h under argon, diluted with Et₂O (10 mL), and poured on a saturat-

ed solution of NH₄Cl (10 mL). The layers were separated and the aque-

ous layer was extracted with Et₂O (3ꢂ10 mL). The organic layers were

combined, dried over MgSO₄, filtered and concentrated. After purifica-

tion by silica gel chromatography (cyclohexane, 100%, then cyclohexane/

EtOAc, 10:1, then 8:1), the bis-olefinic CD 43 (257 mg, 65% over two

steps) was obtained as a white foam. [a]²_D⁰=+49 (c=0.8 in CHCl₃);

¹H NMR (400 MHz, CDCl₃): d=3.40–3.55 (m, 6H; 5ꢂ2-H, 1ꢂ6-H),

3.58–3.70 (m, 7H; 2ꢂ2-H, 2ꢂ4-H, 3ꢂ6-H), 3.72–4.18 (m, 22H; 7ꢂ3-H,

5ꢂ4-H, 5ꢂ5-H, 5ꢂ6-H), 4.23 (brd, ²J=9.8 Hz, 1H; 6-H), 4.30–4.63 (m,

Acknowledgements

The authors would like to warmly thank Cyclolab (Hungary) for a gener-

ous supply of a- and b-CDs as well as Dr. A. Jutand for the synthesis

24H; 2ꢂ5-H, 22ꢂCHPh), 4.65–4.84 (m, 6H; 6ꢂCHPh), 4.88–4.94 (m,

3

9H; 4ꢂ1-H, 5ꢂCHPh), 5.00 (d, ³J_1,2=3.4 Hz, 1H; 1-H), 5.04 (dd, J_cis

=

[Pd(PPh₃)₄] and her expertise. Our gratitude also goes to Prof. Dr. G.

A

10.6 Hz, ²J=1.7 Hz, 1H; CH=CH₂), 5.07 (dd, ³J_cis=10.4 Hz, ²J=1.3 Hz,

1H; CH=CH₂), 5.25 (d, ²J=10.6 Hz, 1H; CHPh), 5.30 (d, ²J=10.9 Hz,

1H; CHPh), 5.34 (d, ²J=10.4 Hz, 1H; CHPh), 5.36 (d, ³J_trans=17.1 Hz,

Bodenhausen, Dr. P. Pelupessy and Dr. F. Ferrage for allowing us to use

the 600 MHz NMR spectrometer, and for their help and tutoring in the

analysis.

2

2H; 2ꢂCH=CH₂), 5.46 (d, J=11.0 Hz, 1H; CHPh), 5.50 (d, J=10.5 Hz,

3

1H; CHPh), 5.68 (d, J_1,2=4.3 Hz, 1H; 1-H), 5.69 (d, J_1,2=4.5 Hz, 1H; 1-

H), 5.75 (ddd, ³J=7.6 Hz, ³J_cis=10.2Hz, ³J_trans=17.4 Hz, 1H; CH=CH₂),

5.86 (ddd, ³J=7.6 Hz, ³J_cis=10.1 Hz, ³J_trans=17.4 Hz, 1H; CH=CH₂),

7.14–7.38 ppm (m, 95H; CH arom.); ¹³C NMR (100 MHz, CDCl₃): d=

68.6, 68.8, 69.9, 69.2, 69.6 (5ꢂC-6), 70.6, 70.8, 71.4, 71.5, 71.7 (6ꢂC-5),

72.0 (CH₂Ph), 72.3 (C-5), 72.5–73.3 (CH₂Ph), 74.1–74.2(CH ₂Ph), 75.7–

76.5 (CH₂Ph), 77.4, 77.5 (2ꢂC-4), 78.05, 78.1, 78.6, 78.9, 78.95, 79.4, 79.7

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Revised: September 20, 2007

Published online: November 16, 2007

9774

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Chem. Eur. J. 2007, 13, 9757 – 9774

Article Doi

Chemical clockwise tridifferentiation of α- and β-cyclodextrins: Bascule-bridge or deoxy-sugars strategies

DOI: 10.1002/chem.200700971

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