preferred position has made some significant progress, there are still some central
chemical challenges in cyclodextrin chemistry. Some examples are described in the
following sections.
14.2.1 Functionalization of Cyclodextrins on the Primary Rim
14.2.1.1 Cyclodextrin Capping Strategy
In cyclodextrin chemistry, capping strategies are very useful and historical techniques for functionalization of cyclodextrins. They can be traced back to 1976, when
the first rigid cap (a diphenylmethane cap) was reported by Tabushi et al. [7]. They
then developed a series of rigid aromatic disulfonyl chloride capping systems, which
enriched regioselective functionalization in cyclodextrin chemistry [8] (Fig. 1).
The method for introducing two different groups on the primary rim of β-CD was
first reported by Tabushi [9]. They used oxidized N-benzyl-N-methylaniline-p,
p
0 -disulfonate as a cap on the primary rim of β-CD moieties to produce four
inseparable isomers, 1–4, which were treated with NaN 3 and then thiophenol—
two different kinds of nucleophilic reagents—to afford “combination selectivity” in
the preparation of unsymmetrically substituted cyclodextrins (CDXYs) 9–12
(Scheme 1).
Breslow also employed a similar strategy to introduce a selective cap at positions
A and B of β-CD via phenylsulfonyl chloride substituted then treated with KI to
obtain CD 13. The iodine-substituted CD 13 was treated with dithiol reagent 14 to
afford asymmetric A,B and B,A capping of β-CD isomers 15 and 16. This was
another early-stage example of regioselective functionalization of CDs to produce A,
B and B,A isomers, which were not controllable [10] (Scheme 2).
14.2.1.2 Site-Oriented Selectively Functionalized Cyclodextrins
As mentioned above, several significant sulfonylation techniques have been demonstrated that are applicable to preparation of di-sulfonylations on the primary rim of
CDs, the use of sulfonylation techniques is required to design and synthesize special
regioselective sulfonyl reagents, which are not a general solution for regioselective
functionalization of CDs. Scientists never stop trying to devise more general, more
efficient, higher-yielding, and more selective methods for functionalization of CDs.
To selectively deprotect the per-protected CDs was another way of achieving
regioselective functionalization of CDs. When Sinaÿ and coworkers [11, 12, 13a]
studied benzyl deprotection of sugars with aluminum reagents, they found that a
structure of two oxygen atoms was necessary for these reactions (Table 1).
They proposed a mechanism for diisobutylaluminum hydride (DIBAL-H)–mediated deprotection: the first aluminum reagent was chelated by the two oxygen atoms
to form 18, and the second aluminum reagent would attach the less-hindered oxygen
atom by coordination to form 19. During this process, the aluminum plays a Lewis
acid role in activating the C–O bond and also delivers its hydride to form a PhMe at
the same time, giving 20. After being quenched by H 2 O, complex 20 will give
alcohol 21. On the basis of this mechanism, they found that some aluminum reagents
such as DIBAL-H could be used to remove the benzyl group from the perbenzylated
14 Functionalized Cyclodextrins and Their Applications in Biodelivery
387
chemical challenges in cyclodextrin chemistry. Some examples are described in the
following sections.
14.2.1 Functionalization of Cyclodextrins on the Primary Rim
14.2.1.1 Cyclodextrin Capping Strategy
In cyclodextrin chemistry, capping strategies are very useful and historical techniques for functionalization of cyclodextrins. They can be traced back to 1976, when
the first rigid cap (a diphenylmethane cap) was reported by Tabushi et al. [7]. They
then developed a series of rigid aromatic disulfonyl chloride capping systems, which
enriched regioselective functionalization in cyclodextrin chemistry [8] (Fig. 1).
The method for introducing two different groups on the primary rim of β-CD was
first reported by Tabushi [9]. They used oxidized N-benzyl-N-methylaniline-p,
p
0 -disulfonate as a cap on the primary rim of β-CD moieties to produce four
inseparable isomers, 1–4, which were treated with NaN 3 and then thiophenol—
two different kinds of nucleophilic reagents—to afford “combination selectivity” in
the preparation of unsymmetrically substituted cyclodextrins (CDXYs) 9–12
(Scheme 1).
Breslow also employed a similar strategy to introduce a selective cap at positions
A and B of β-CD via phenylsulfonyl chloride substituted then treated with KI to
obtain CD 13. The iodine-substituted CD 13 was treated with dithiol reagent 14 to
afford asymmetric A,B and B,A capping of β-CD isomers 15 and 16. This was
another early-stage example of regioselective functionalization of CDs to produce A,
B and B,A isomers, which were not controllable [10] (Scheme 2).
14.2.1.2 Site-Oriented Selectively Functionalized Cyclodextrins
As mentioned above, several significant sulfonylation techniques have been demonstrated that are applicable to preparation of di-sulfonylations on the primary rim of
CDs, the use of sulfonylation techniques is required to design and synthesize special
regioselective sulfonyl reagents, which are not a general solution for regioselective
functionalization of CDs. Scientists never stop trying to devise more general, more
efficient, higher-yielding, and more selective methods for functionalization of CDs.
To selectively deprotect the per-protected CDs was another way of achieving
regioselective functionalization of CDs. When Sinaÿ and coworkers [11, 12, 13a]
studied benzyl deprotection of sugars with aluminum reagents, they found that a
structure of two oxygen atoms was necessary for these reactions (Table 1).
They proposed a mechanism for diisobutylaluminum hydride (DIBAL-H)–mediated deprotection: the first aluminum reagent was chelated by the two oxygen atoms
to form 18, and the second aluminum reagent would attach the less-hindered oxygen
atom by coordination to form 19. During this process, the aluminum plays a Lewis
acid role in activating the C–O bond and also delivers its hydride to form a PhMe at
the same time, giving 20. After being quenched by H 2 O, complex 20 will give
alcohol 21. On the basis of this mechanism, they found that some aluminum reagents
such as DIBAL-H could be used to remove the benzyl group from the perbenzylated
14 Functionalized Cyclodextrins and Their Applications in Biodelivery
387