Enhanced single-isomer separation and pseudoenantiomer resolution of new primary rim heterobifunctionalized α-cyclodextrin derivatives

Article abstract of DOI:10.3762/bjoc.14.261

The synthesis of batch-to-batch reproducible cyclodextrin (CD) derivatives often requires functionalization at specific positions of the CD skeleton. However, the regioselective preparation of this type of CD derivatives remains a challenge in synthetic c

Full text of DOI:10.3762/bjoc.14.261

Enhanced single-isomer separation and pseudoenantiomer
resolution of new primary rim heterobifunctionalized
α-cyclodextrin derivatives
Iveta Tichá1, Gábor Benkovics1,2, Milo Malanga2 and Jindřich Jindřich*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 2829–2837.
1Department of Organic Chemistry, Faculty of Science, Charles
University, Hlavova 8, 128 43 Prague 2, Czech Republic and
2CycloLab, Cyclodextrin R&D Ltd., Illatos út 7, H-1097 Budapest,
Hungary
doi:10.3762/bjoc.14.261
Received: 23 August 2018
Accepted: 22 October 2018
Published: 13 November 2018
Email:
Jindřich Jindřich* - jindrich@natur.cuni.cz
Associate Editor: H. Ritter
* Corresponding author
© 2018 Tichá et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
diazido-alpha-cyclodextrin; heterobifunctionalized alpha-cyclodextrin;
homobifunctionalized alpha-cyclodextrin; regioisomers;
regioselectivity
Abstract
The synthesis of batch-to-batch reproducible cyclodextrin (CD) derivatives often requires functionalization at specific positions of
the CD skeleton. However, the regioselective preparation of this type of CD derivatives remains a challenge in synthetic chemistry.
Thus, the present study aimed to prepare all positional regioisomers on the primary rim of homobifunctionalized diazido-α-CDs by
selective substitution on the primary rim. Specifically, three positional regioisomers 6A,6B-, 6A,6C-, and 6A,6D-diazido-α-CDs were
prepared via different intermediates (using sulfonylation with capping agents, bromination and tosylation). Furthermore, heterobi-
functionalized 6A-azido-6X-mesitylenesulfonyl-α-CDs were also synthesized, and all regioisomers were successfully separated by
HPLC. Moreover, the heterobifunctionalized α-CD regioisomers were isolated in gram-scale quantities, isomers AB and AC in the
form of a pseudoenantiomeric mixture. The pseudoenantiomers AC/CA and AB/BA were resolved on an analytical scale by
HPLC–MS at 10 °C. Thus, the presented synthetic and analytical methods for homo- and heterodisubstituted α-CDs are efficient
and reproducible for the preparation of various pure regioisomeric CD derivatives. Accordingly, our findings indicate, (i) the versa-
tility of selectively modified azido and mesitylene CD skeletons in preparing new types of α-CD derivatives and (ii) the potential of
using resolved α-CD pseudoenantiomers in other research fields such as organocatalysis.
Introduction
Cyclodextrins, cyclic cone-shaped oligosaccharides [1], have industry, among other fields [2]. Recent studies have improved
long attracted interest for their properties in host–guest com- the properties of CD scaffolds primarily by selective persubsti-
plexes both in research and in pharmaceutical and food tution and monosubstitution [2,3], thereby broadening their ap-
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Beilstein J. Org. Chem. 2018, 14, 2829–2837.
plication. However, the synthesis of selectively disubstituted butylphenyl)methyl ethers on the primary rim of α-CD which
CD derivatives with the same or different functional groups at resulted in predominant AD species [20]. Trityl groups for
selected positions remains a challenging task because of the regioselective bi- and trifunctionalization of α-CD were also in-
similar reactivity of the hydroxy groups.
vestigated [21]. Thus, the use of either a direct single-step or
indirect method generally led to selectively homobifunctional-
Nevertheless, selectively disubstituted CD derivatives are used ized CDs.
to prepare artificial enzymes [4,5], metallocatalysts and organo-
catalysts [6-8] or amino acid mimics [9]. Among the methods In contrast, heterobifunctionalized CDs have been prepared via
used to prepare these derivatives on α-, β- or γ-CDs, disubstitu- multistep synthesis (depending on the steric hindrance of the
tions of the α-CD primary rim occurring at two different moiety on the CD scaffold and on the bulkiness of reagents
glucose units (Figure 1) stands out for well-explored direct and [22]) or by modification of homobifunctionalized CDs [23,24].
indirect approaches.
These and previous studies [25,26] confirmed that CD deriva-
tives with bulky substituents such as tosyl groups can be sepa-
rated by reversed-phase column chromatography and HPLC
separation methods can be easily scaled up to obtain grams of
pure regioisomers. However, to the best of our knowledge, no
such comparative regiochemical study of homobifunctionalized
α-CDs prepared from the most commonly used CD intermedi-
ates has been conducted thus far although the regioisomer
pattern of these intermediates is crucial for the investigation of
new single isomer CDs with reproducible and definite struc-
tures. Furthermore, the direct synthesis of new pure heterobi-
functionalized α-CD derivatives remains a challenging task due
to problematic regioisomer separations. Subsequently, the phe-
nomenon of pseudoenantiomers on the heterobifunctionalized
α-CD primary rim (AB/BA, AC/CA, AD/DA) has not yet been
studied in detail by HPLC–MS methods. Nevertheless, the
Figure 1: Schematic representation of native α-CD (1) and top view of
its primary rim with alphabetic clockwise numbering of the glucose
units.
The indirect preparation of selectively disubstituted CDs, in- studies on the perbenzylated α-CD skeletons by Sollogoub et al.
cluding protecting and deprotecting steps, was introduced by [27] did not confirm an existence of an AD/DA pseudoenan-
Sinaÿ et al. [10] and continued in the studies by Sollogoub et al. tiomeric pair.
[11,12]. The addition of diisobutylaluminum hydride (DIBAL-
H) to perbenzylated CDs exclusively formed a single AD regio- The present study reports a fast and reproducible approach for
isomer on the primary rim of α-CD.
the synthesis of six types of 6A,6X-disubstituted α-CD interme-
diates. Initially, these intermediates were transformed into
Conversely, the direct, straightforward modification is mostly stable, non-hydrolyzing 6A,6X-diazido-6A,6X-dideoxy-α-CDs
performed using capping agents. For example, Tabushi et al. (6A,6X-diazido-α-CDs). The regioisomeric pattern of each
[13-15] studied regioselectively capped-β-CDs with disulfonyl 6A,6X-diazido-α-CD was thoroughly assessed, compared and
chlorides. Subsequently, Fujita et al. [16] introduced the disul- used to develop methods for the separation of new regioselec-
fonyl groups on the primary rim of α-CDs, albeit using non- tively pure α-CD derivatives with two non-identical functional
capping reagents, mesitylenesulfonyl chloride and observed groups, such as azido and mesitylenesulfonyl. This comparison
almost no preferential selectivity for AB, AC or AD regio- between regioisomeric patterns of disubstituted α-CD deriva-
isomers. Breslow et al. [17] used the 1,3-dimethoxy-4,6- tives is the key to the development of new heterodisubstituted
benzenedisulfonyl chloride as a capping agent to prepare the α-CDs with exact structures.
AB regioisomer. Subsequently, Fujita et al. [18] selectively
capped the primary rim of α-CD using a special, sterically Thus in this study, we prepared all possible regioisomers of pri-
hindered sulfonylation agent, dibenzofuran-2,8-disulfonyl chlo- mary rim-disubstituted α-CD derivatives using the most
ride, but observed only a negligible selectivity towards the common CD intermediates by commonly used derivatization
AC regioisomer. Notwithstanding, these researchers were more (bromination, tosylation and capping). The three positional
successful in achieving selectivity for the AB regioisomer by isomers (AB, AC, AD) were separated by ad hoc-developed
introducing auxiliary groups (phthalimide) [19]. Armspach et HPLC methods, and the regioisomeric pattern was elucidated.
al. investigated the regioselective synthesis of tris(4-tert- Furthermore, new heterobifunctionalized α-CD derivatives with
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easily transformable functional groups were also prepared and then separated by HPLC to afford the single AB, AC and AD
unambiguously confirmed, to study in detail possible α-CD pri- regioisomers.
mary rim pseudoenantiomers. These pseudoenantiomers were
undoubtedly confirmed via HPLC–MS methods. Moreover, After the reaction with m-benzenedisulfonyl chloride (reaction
these regioselectively pure derivatives will be further trans- 1, Scheme 1), a ratio AB/AC/AD = 70:20:10 was found, thus
formed to create key intermediates for a wide range of new showing that the AB regioisomer is the predominant species, in
single-isomer CD derivatives, thereby opening a new area of agreement with previous findings [17]. This AB regioisomer
research in CD chemistry.
was used as one standard in subsequent HPLC analyses. The
regioisomeric ratios are given as the percentages of areas
of the HPLC peaks (100 correspond to the sum of areas
of AB, AC and AD peaks). Conversely, using of biphenyl-4,4´-
disulfonyl chloride (reaction 2, Scheme 1), the ratio
AB/AC/AD = 44:40:16 indicated almost no selectivity. This is
in contrast to Tabushi [14] who observed 84% selectivity for the
AD regioisomer on β-CD. This different regioisomeric ratio
could be caused by the formation of intermolecular bridges
among α-CDs during the capping which resulted in the higher
ratio for AC and AD regioisomers. Nevertheless, the fast hydro-
lysis of these intermediates did not allow to study this phenome-
Results and Discussion
Synthesis of homobifunctionalized α-CD
derivatives
The first part of this study focused on the synthesis of all prima-
ry rim regioisomers of 6A,6X-diazido-α-CDs through different
types of reactions (two different capping agents; direct and indi-
rect brominations; tosylations in pyridine), their analytical sepa-
ration and regioisomer elucidation using ad hoc-developed
HPLC methods.
The synthetic approach started with the preparation of 6A,6X- non in more detail.
capped α-CD derivatives. From special capping agents
previously used on α-CD [17,18,26], we selected the most The second synthetic approach for homobifunctionalized α-CDs
common, relatively inexpensive and commercially available was based on the preparation of 6A,6X-dibromo-α-CD interme-
m-benzenedisulfonyl chloride and biphenyl-4,4´-disulfonyl diates, both directly (5) and indirectly (5d). On one hand, a
chloride. The prepared 6A,6X-disulfonyl-capped CDs 2 and 3 direct bromination of α-CD was performed under Vilsmeier/
were immediately converted to the more stable 6A,6X-diazido- Haack conditions (reaction 3, Scheme 2) with N-bromosuccin-
α-CDs 4 to prevent hydrolysis. However, the yields were low imide (NBS) and Ph3P in N,N-dimethylformamide (DMF).
because the hydrolysis of sulfonyl groups could not be com- Previous studies have shown that this reaction is highly regiose-
pletely suppressed. The prepared 6A,6X-diazido-α-CDs were lective for the primary rim of CD [28]. After a fast work-up, the
Scheme 1: Synthesis of 6A,6X-diazido-α-CD derivatives 4 via 6A,6X-capped α-CDs 2 and 3 and their regioisomeric ratios.
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Beilstein J. Org. Chem. 2018, 14, 2829–2837.
Scheme 2: Synthesis of 6A,6X- and 6A,6D-diazido-α-CDs via 6A,6X-dibromo-α-CD 5, 6A,6D-dibromo-α-CD 5d intermediates and their regioisomeric
ratios.
reaction mixture, consisting of unreacted α-CD, mono-, di- and (TsCl) in pyridine (reaction 5, Scheme 3). A previous study has
trisubstituted products, was converted into the corresponding shown [31] that tosyl groups exclusively attach to the primary
6A,6X-diazido-α-CDs 4 [29]. The ratio of the regioisomers was rim of α-CD. Subsequently, the reaction mixture was converted
assessed as AB/AC/AD = 39:33:29. The distribution of the into 6A,6X-diazido-α-CD 4 and the HPLC method revealed a
positional isomers is almost statistical, and practically no regio- regioisomeric ratio AB/AC/AD = 38:34:28. Therefore, the
selectivity was observed.
α-CD ditosylation is still a primary rim-selective process with
negligible selectivity towards the AB regioisomer.
On the other hand, the dibromo-α-CD derivative was also
prepared using a four-step indirect method involving DIBAL-H The regioisomeric ratios from reactions 1–5 provided crucial
deprotection (reaction 4, Scheme 2) [10,30]. This method data for the unambiguous determination of the regioisomeric
generated the AD regioisomer exclusively without AB or pattern of primary rim-homodisubstituted α-CDs, and the com-
AC regioisomers as byproducts (based on the published mecha- parative analysis revealed the regioisomeric ratios of the most
nism [10]). Nevertheless, it is a method demanding much more commonly used disubstituted CD intermediates.
time and reagents compared to the direct dibromination. This
HPLC Analysis of homobifunctionalized
finding was the second key data for the unambiguous elucida-
tion of the regioisomer pattern, and the AD regioisomer was α-CDs
used as the second standard (the AB reference comes from reac- The regioisomeric ratios of the series of 6A,6X-diazido-α-CDs
tion 1). The 6A,6D-dibromo-α-CD intermediate 5d was con- were determined using ad hoc-developed HPLC methods with
verted again to 6A,6D-diazido-α-CD 4d. The regioisomer ratio an evaporative light scattering (ELS) detector and acetonitrile
AB/AC/AD = 0:0:100 observed thus undoubtedly confirmed the (ACN)/water gradient elution. The retention times of each
selectivity for the AD regioisomer.
6A,6X-diazido-α-CD 4 from reactions 1 to 5 were compared
(Figure 2). Nevertheless, the crucial information for the deter-
The last synthetic approach for the homobifunctionalized α-CDs mination of the regioisomeric pattern was gathered in reactions
included the preparation of 6A,6X-ditosyl-α-CD 6 under clas- 1 and 4. Reaction 1 yielded mostly AB regioisomer 4b, where-
sical tosylation conditions with an excess of tosyl chloride as reaction 4 exclusively generated pure AD regioisomer 4d.
Scheme 3: Synthesis of 6A,6X-diazido-α-CDs via 6A,6X-ditosyl-α-CD intermediates 6 and their regioisomeric ratios.
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These compounds, previously prepared by disulfonyl capping sterically hindered than a tosyl group. The idea of attaching the
[17] (reaction 1) and DIBAL-H deprotection [10] (reaction 4) mesitylenesulfonyl moiety instead of the tosyl group to the
were used as standards. The regioisomeric pattern was thus con- β-CD skeleton was first reported in the study by Tang et al. [32]
cluded: the AD regioisomer eluted first, the AC regioisomer who observed regioselectivity for the AC isomer. In turn, the
second and the AB regioisomer last.
azido functional group was selected for its stability and versa-
tility of subsequent modification: this group can be reduced to
an amino group able to react with a large variety of electro-
philes and is commonly used in click reactions [33].
At first, 6A-azido-α-CD 7 was prepared via bromination of
α-CD (as previously described for direct bromination) [28].
Then, 6A-azido-6X-mesitylenesulfonyl-α-CD 8 was prepared
(reaction 6, Scheme 4) by adapting the reported procedure for
β-CD based on mesitylenesulfonyl chloride in pyridine [32].
After work-up of the reaction, a small part of the crude mixture
was transformed into the corresponding 6A,6X-diazido-α-CD 4
(reaction 7, Scheme 4), and HPLC retention times were com-
pared with data from reactions 1–5 to elucidate the regioisomer-
ic pattern.
Figure 2: HPLC chromatograms of 6A,6X-diazido-α-CDs 4 of the reac-
tions 1–5, with ACN/water gradient elution and ELS detection.
The analytical HPLC analysis of 6A,6X-diazido-α-CD 4
(prepared in reaction 7) revealed the regioisomeric ratio
AB/AC/AD = 37:44:19 (Figure 3). This regioisomeric ratio of
AB and AC was similar, however, the AD derivative was
slightly suppressed. The measurements were performed with the
Synthesis and large-scale separation of
heterobifunctionalized α-CDs
After elucidating the homofunctionalized regioisomeric pattern, crude reaction mixture comprising the starting material 7, all
we prepared the target 6A,6X-heterobifunctionalized α-CDs. regioisomers of 6A,6X-diazido-α-CD 4 and oversubstituted
Mesitylenesulfonyl was chosen as the appropriate functional 6A,6X,6Y-triazido-α-CD derivatives. The HPLC signals of all
group for insertion in the α-CD skeleton because it is suffi- components of the reaction mixture were nicely separated and
ciently stable for reverse column chromatography and more thus allowed the isolation of each regioisomer in a single step
Scheme 4: Synthesis of 6A-azido-6X-mesitylenesulfonyl-α-CD 8 and conversion into 6A,6X-diazido-α-CD 4.
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Beilstein J. Org. Chem. 2018, 14, 2829–2837.
with no need to separate the starting material first and then responding AB, AC, AD heterodisubstituted products is incom-
separate the corresponding 6A,6X-diazido-α-CD regioisomers. plete due to the formation of additional substituted derivatives
(6A-azido-6X,6Y-dimesitylenesulfonyl-α-CD) that could not be
avoided. Consequently, the starting material 6A-azido-α-CD
remains the main component of the reaction mixture and thus
can be recovered. To our surprise, we observed a peak splitting
(Figure 4a) for the AC regioisomer which could be caused by
the presence of pseudoenantiomers (AC/CA) as will be dis-
cussed further in the section on pseudoenantiomers identifica-
tion.
Pure AB, AC and AD regioisomers were isolated by reversed-
phase column chromatography eluting with an ACN/H2O
gradient. The AB 8b and AC 8c regioisomers were separated
and obtained in the same yield 4% and 4%, whereas the AD
regioisomer 8d was obtained in 3% yield (calculated from the
starting 6A-azido-α-CD) thus corresponding with the HPLC
Figure 3: HPLC chromatograms of reaction 7 with separated 6A-azido-
α-CD 7 as starting material and regioisomers of 6A,6X-diazido-α-CD 4.
regioisomeric ratios. Subsequently, each regioisomer was char-
acterized by NMR, HRMS, IR and optical rotation measure-
ments.
Once, the regioisomer pattern has been identified (Figure 3), we
NMR characterization of
developed separation methods for the 6A-azido-6X-mesitylene-
sulfonyl-α-CD regioisomers 8b, 8c, and 8d. First, the analytical heterobifunctionalized-α-CD derivatives
method was developed (Figure 4a) using UV–vis detection with Each regioisomer separated after reaction 6 was dissolved in
an ACN/water gradient elution and the regioisomeric ratio of deuterated water (D2O) to simplify NMR peak assignment (as-
AB/AC/AD = 32:44:24. The analytical-scale method also con- signment in DMSO-d6 included OH groups). Overall, the
firmed that the mesitylenesulfonyl moiety was not hydrolyzed 1H NMR spectra of all three regioisomers match the disubsti-
during the separation and that this functional group can be used tuted α-CD derivatives pattern. The separated AC regioisomer
to separate heterodisubstituted regioisomers in gram-scale quan- 8c was chosen as a representative example (measurements were
tities by reversed-phase column chromatography (Figure 4b). done with the mixture of pseudoenantiomers). Specifically,
The starting material 6A-azido-α-CD 7, each 6A-azido-6X- three basic sets of signals were observed (Figure 5). The first
mesitylenesulfonyl-α-CD regioisomers 8b, 8c, 8d and the over- (Mes-1) corresponded to the mesitylene aromatic peak
substituted 6A-azido-6X,6Y-dimesitylenesulfonyl-α-CD prod- (7.15 ppm), the second to the α-CD region (5.24–3.41 ppm) and
ucts were separated in a single, quick and reproducible separa- the third (Mes-2) to methyl groups on the mesitylene skeleton
tion step. Figures 4a,b also shows that the conversion to the cor- (2.60–2.30 ppm). In the CD region, three areas are well distin-
Figure 4: HPLC chromatograms of 6A-azido-6X-mesitylenesulfonyl-α-CD 8 (reaction 6): a) analytical and b) preparative scale at 25 °C.
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Beilstein J. Org. Chem. 2018, 14, 2829–2837.
Figure 5: 1H NMR spectrum of the AC regioisomer 8c as a mixture of pseudoenantiomers prepared through reaction 6 (D2O, 600 MHz).
guished – peaks about 5.07 ppm (CD H-1) belong to mesitylenesulfonyl moieties. Both substituents on the α-CD pri-
H-1 protons of four unsubstituted glucose units, whereas mary rim were also confirmed by HSQC in the anomeric region
H-1 protons of glucoses with the azido moiety and the mesityle- distinguished in three different parts. However, the crucial split-
nesulfonyl group are shifted upfield (4.98–4.95 ppm). The ting of six C-1 anomeric doublets for the characterization of
separated signal of the CD region refers to H-6 protons each glucose unit was not achieved.
(CD H-6 Mes) attached to the mesitylenesulfonyl group
(≈ 4.40 ppm).
Overall, the two different substituents (mesitylenesulfonyl and
azido) are attached to the primary rim of α-CD. The incomplete
In Figure 6, the 13C NMR spectrum also shows the substituted anomeric doublets splitting prevented us from identifying the
C-6 carbons at 51 ppm for the azido and 68 ppm for the different regioisomeric peaks fully by NMR measurements.
Figure 6: 13C NMR spectrum of the AC regioisomer 8c as a mixture of pseudoenantiomers prepared through reaction 6 (D2O, 125 MHz).
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Beilstein J. Org. Chem. 2018, 14, 2829–2837.
Pseudoenantiomers identification of
heterodisubstituted α-CDs by HPLC–MS
CDs were separated via ad hoc-developed HPLC analytical
methods, and the regioisomeric patterns of these disubstituted
Furthermore, we observed (Figure 4a) a peak splitting in the α-CD derivatives was unambiguously identified. Furthermore,
case of the AC heterodisubstituted CD regioisomer 8c at room this study clarified the regioisomeric pattern of the most com-
temperature (25 °C) during HPLC which was explained by the monly used and key intermediates of α-CD primary rim homo-
formation of possible pseudoenantiomers AC/CA (or AC/AE). disubstitution. The regioisomeric pattern was applied to the
A further HPLC–MS analysis unambiguously confirmed our effective, large-scale separation of heterobifunctionalized
hypothesis because the splitting was also observed in the case of 6A-azido-6X-mesitylenesulfonyl-α-CD regioisomers (as mix-
AB regioisomer 8b at 10 °C in the HPLC trace (Figure 7). Con- tures of pseudoenantiomers). These new heterobifunctionalized
versely, no peak splitting was observed in the case of the AD AB, AC, AD regioisomers of the α-CD decorated with azido
regioisomer 8d as this symmetrically heterodisubstituted regio- and mesitylenesulfonyl functional groups can be used as key
isomer could not contain a pair of pseudoenantiomers intermediates for a wide range of new α-CD derivatives.
(AD/DA). The separation of the pseudoenantiomers was done Finally, their pseudoenantiomers (AB/BA and AC/CA) were
on an analytical scale only. The regioisomers from preparative confirmed and resolved for the first time. Ultimately, these
column chromatography were isolated as mixtures of pseu- results enable the preparation of new types of pure, single
doenantiomers (in cases AB and AC). More details about the isomer, pseudoenantiomer-resolved disubstituted α-CD deriva-
analytical-scale pseudoenantiomer separations are given in Sup- tives, which may be used in a wide range of applications, partic-
porting Information File 1. Our results were also compared with ularly in organocatalysis.
the studies by Sollogoub et al. [27] who did not observe pseu-
doenantiomers for AD heterodisubstituted α-CD derivatives.
Supporting Information
Nevertheless, our findings open a way to study pseudoenan-
tiomers on the primary rim of heterobifunctionalized α-CD
Supporting Information File 1
skeletons, which have remained mostly overlooked thus far.
Instruments, materials, detailed experimental procedures,
data for each regiochemical analysis, pseudoenantiomer
resolution. NMR and HRMS data of prepared compounds.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-261-S1.pdf]
Acknowledgements
The support of the Grant Agency of Charles University
(277015) and the Charles University Grant SVV (260429) are
gratefully acknowledged. The authors also thank to Dr. Carlos
V. Melo for proofreading the manuscript.
ORCID® iDs
Iveta Tichá - https://orcid.org/0000-0002-7628-0665
Milo Malanga - https://orcid.org/0000-0001-7952-0268
Jindřich Jindřich - https://orcid.org/0000-0003-3770-0214
Figure 7: HPLC–MS chromatogram with the separated pseudoenan-
tiomers of 6A-azido-6B-mesitylenesulfonyl-α-CD 8b and 6A-azido-6C-
mesitylenesulfonyl-α-CD 8c at 10 °C.
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