Separation tagging with cyclodextrin-binding groups: Mitsunobu reactions with bis-(2-(1-adamantyl)ethyl) azodicarboxylate (BadEAD) and bis-(1-adamantylmethyl) azodicarboxylate (BadMAD)

Article abstract of DOI:10.1016/j.tetlet.2004.07.009

A new method for separation tagging with cyclodextrin-binding groups is introduced and is exemplified in the context of the Mitsunobu reaction with adamantyl tags. HPLC experiments showed that molecules containing adamantyl groups were especially well retained on Sumichiral OA7500 β-methylated cyclodextrin bonded silica columns relative to many other types of molecules. Two new Mitsunobu reagents, bis-(1-adamantylmethyl) azodicarboxylate (BadMAD) and bis-(2-(1-adamantyl)ethyl) azodicarboxylate (BadEAD), were prepared, used in typical Mitsunobu reactions and separated with both β-methylated cyclodextrin bonded silica and standard silica.

Full text of DOI:10.1016/j.tetlet.2004.07.009

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6653–6656
Separation tagging with cyclodextrin-binding groups:
Mitsunobu reactions with bis-(2-(1-adamantyl)ethyl)
azodicarboxylate (BadEAD) and bis-(1-adamantylmethyl)
azodicarboxylate (BadMAD)
Sivaraman Dandapani, Jeffery J. Newsome and Dennis P. Curran*
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
Received 29 June 2004; accepted 2 July 2004
Available online 22 July 2004
Abstract—A new method for separation tagging with cyclodextrin-binding groups is introduced and is exemplified in the context of
the Mitsunobu reaction with adamantyl tags. HPLC experiments showed that molecules containing adamantyl groups were espe-
cially well retained on Sumichiral OA7500 b-methylated cyclodextrin bonded silica columns relative to many other types of mole-
cules. Two new Mitsunobu reagents, bis-(1-adamantylmethyl) azodicarboxylate (BadMAD) and bis-(2-(1-adamantyl)ethyl)
azodicarboxylate (BadEAD), were prepared, used in typical Mitsunobu reactions and separated with both b-methylated cyclodex-
trin bonded silica and standard silica.
Ó 2004 Elsevier Ltd. All rights reserved.
Modern strategy level separations are often designed
based on concepts of separation tagging.1 A selected
reaction component (substrate, reactant, reagent, cata-
lyst, etc.) bearing a separation tag is reacted with one
or more other reaction components lacking the tag. Fol-
lowing the reaction, a tag-complementary Ôworkup-levelÕ
separation technique is applied to bifurcate the reaction
mixture into fractions containing tagged and untagged
reaction components (Fig. 1). Separation tags in com-
mon use or actively being developed include soluble
and insoluble polymers, fluorous tags, ionic tags, lipo-
philic tags, polymerizable tags, and precipitons, among
others.1
Many demands are placed on separation tags. Among
other things, they should be easy to introduce, exhibit
broad control during tag-complementary separations,
be chemically stable to diverse reaction conditions, be
recyclable, and be as small, as inexpensive and as readily
available as possible. They should not be toxic, interfere
with or limit reactions, or complicate spectroscopic
characterization or chromatographic analysis, and ide-
ally they should not require extra reactions after the tar-
get reaction to effect separation. Just as there is no
ÔuniversalÕ protecting group, there is no tag that can
meet all of the requirements all of the time, so a diverse
assortment of tags is needed.
untagged
fraction
C
tag-based
react
A + B–Tag
separation
tagged
D–Tag
fraction
A,B = substrates, reactants, reagents, catalysts, etc.
C,D = products derived from A,B
Tag = separation tag
This work: the tag is a cyclodextrin binding group;
the tag-based separation media is silica gel with a
cyclodextrin bonded phase
The broad fields of molecular recognition and supra-
molecular chemistry provide a gold mine of potential
separation tags (guests) and tag-complementary separa-
tion techniques (hosts). Unfortunately, hydrogen bond
interactions often contribute significantly to host/guest
binding. The functional groups responsible for hydro-
gen bonding––carbonyl groups, OH groups, NH
groups, and the like––are generally not attractive as
Figure 1. A schematic illustration of separation tagging.
Keywords: Separation tagging; Mitsunobu reaction; Cyclodextrin.
*
Corresponding author. Tel.: +1-412-624-8240; fax: +1-412-624-
9861; e-mail: curran@pitt.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.009

6654
S. Dandapani et al. / Tetrahedron Letters 45 (2004) 6653–6656
Table 1. Retention times of adamantyl and control carbonyl hydraz-
ides R1OCONHNHCOOR2 on a Sumichiral OA7500 column eluting
with 100% acetonitrile
tag components because their reactivity limits potential
chemical transformations.
Entry
R1
R2
tR (min)a
An important exception to this generalization is cyclo-
dextrin chemistry, where binding of relatively unfunc-
tionalized guests is primarily driven by hydrophobic
interactions and shape complementarity.2 Among the
molecular sub-units that bind to cyclodextrin (halo-,
nitro-, and alkyl-substituted phenols and derivatives,
substituted benzoic acids, naphthalenes, biaryls, to
name a few), we selected the adamantyl group for study
as a cyclodextrin-binding tag because of its strong inter-
actions with cyclodextrins,3 its inertness, its ready
availability and its low cost. To demonstrate the use of
adamantyl tagging with cyclodextrin separation, we
selected the Mitsunobu reaction,4 which has become a
focal point of strategy separation methods because of
the difficulties of separating target products from rea-
gents and derived byproducts.5 We report herein two
new adamantyl-tagged Mitsunobu reagents and we use
the reagents in Mitsunobu reactions followed by cyclo-
dextrin and standard silica separations. Concurrently,
Blodgett and Li introduce the 4-tert-butylphenyl group
as a tag for cyclodextrin-based separation.6
1
Oct
tBu
tBu
Oct
PhCH2
iBu
4.8
5.4
2
3
5.0
5.7
4
c-C6H11
tBu
c-C6H11
Menthyl
1-AdCH2
1-AdCH2CH2
5
5.9
6b
7c
1-AdCH2
1-AdCH2CH2
23.5
26.5
a The solvent front is at about 3.7min.
b Hydrazide 2a.
c Hydrazide 2b.
not retained either.9 In contrast, 2a is retained for
23.5min and 2b is retained for 26.5min.
These results show that bis-adamantyl-tagged com-
pounds are strongly retained by Sumichiral OA7500 col-
umns, even under powerfully eluting conditions. To
further show that they are selectively retained, we in-
jected members of a series of representative organic
compounds, many of which were made by Mitsunobu
reactions. The structures and retention times for these
compounds are shown in Figure 2. All compounds elute
at or near the solvent front except bis-(2(1-adaman-
tyl)ethyl)carbonate, which was strongly retained as
expected (40.5min).
The two new Mitsunobu reagents, bis-(1-adamantyl-
methyl) azodicarboxylate (BadMAD) 1a and bis-(2-(1-
adamantyl)ethyl) azodicarboxylate (BadEAD) 1b, were
prepared in the manner shown in Eq. 1.7 Reaction of
the appropriate alcohol with phosgene followed by addi-
tion of hydrazine hydrochloride and pyridine provided
the dicarbonyl hydrazides 2a,b. These in turn were oxi-
dized with bromine to provide the Mitsunobu reagents
1a,b as yellow solids.
While the reverse phase nature of the methylated b-
cyclodextrin media could contribute to the retention of
2a,b, the lack of retention of other nonpolar compounds
suggests that this is not the only factor. Accordingly, we
hypothesize that the complexation of the adamantyl
groups to the cyclodextrin on the stationary phase is
important. Regardless of the mechanism, the results sug-
gest that the cyclodextrin-based separation of adamant-
yl-tagged hydrazides 2a,b from typical Mitsunobu
reaction products will have considerable generality.
To complement the separation studies, we conducted
Mitsunobu reactions with reagents 1a and 1b to show
that they couple alcohols and acidic pronucleophiles in
the expected fashion. Eq. 2 shows the coupling of 3,5-di-
nitrobenzoic acid with methanol. After standard
reaction of the alcohol and pronucleophile with tri-
phenylphosphine and 1b, a part of the reaction mixture
was purified by repeated injection onto the Sumichiral
OA7500 analytical column. Triphenylphosphine oxide
(tR =11min) emerged after 3,5-dinitrobenzoic acid
methyl ester (tR =4.0min), so we were able to obtain
the pure ester product by collecting the solvent front
peak. In ÔoverloadÕ injections designed to mimic flash
chromatographic or solid phase extraction separations,
the ester and the triphenylphosphine oxide peaks
merged together, but this merged peak was still very eas-
ily separated from the hydrazide peak of 2b. This proof-
of-principle experiment demonstrates the viability of the
proposed cyclodextrin separation. A separate reaction
mixture was purified by standard flash chromatography,
and the Mitsunobu product was isolated in 97% yield.
ð1Þ
Following Mitsunobu reactions with these reagents, tar-
get products must be separated from the dicarbonyl hy-
drazides 2a,b, so we initially explored the HPLC
retention behavior of these compounds in comparison
with assorted controls. Preliminary experiments showed
that the adamantyl hydrazides were much better
retained on a Sumichiral OA75008 column than on a
Cyclobond I-2000 (Astec) column, so we focused our
efforts on the former.
Retention times on a Sumichiral OA7500 column of a
series of dicarboxy hydrazides (R1OCONHNHCOOR2)
including 2a and 2b are summarized in Table 1. The col-
umn was eluted under isocratic conditions with 100%
acetonitrile. Hydrazides bearing lipophilic alkyl groups
like t-butyl, menthyl, benzyl, octyl, and cyclohexyl all
emerge at or near the solvent front (3.7min) under these
powerfully eluting conditions. Fluorous hydrazides are

S. Dandapani et al. / Tetrahedron Letters 45 (2004) 6653–6656
6655
O
O
O2N
O2N
H2N
OEt
O
O2N
O
O2N
Me
O
F
COOMe
O
NO2
3.8
NO2
O
4.0
4.0
4.3
3.9
Me
Me
O2N
O2N
O2N
Me Me
O
Me
O
O
tBu
O
Me
H
H
O
O
O
Me
O
4.2
4.1
4.3
3.8
O
O
F
tBu
Me
O
Me
O
O
tBu
Me
O
O
N Me
NO2
Me
N
OMe
N
SO2
COOMe
3.9
O
4.4
3.8
3.8
4.4
F
(rac)-pinene, 5.3
(–)-(ipc)2BOMe, 6.3
OH
O
O
Me
O
C10F21
O
NC
4.1
4.3
3.9
4.4
1-AdCH2CH2OCOOCH2CH2-1-Ad, 40.5
bis-(2-(1-adamantyl)ethyl)carbonate
Figure 2. Retention times (min) of assorted esters, ether, and other compound on a Sumichiral OA7500 column eluting with 100% acetonitrile.
New Mitsunobu reagents BadMAD 1a and BadEAD 1b
show excellent promise as practical alternatives to exist-
ing classes of reagents. While methylated b-cyclodextrin
is well known, it is not widely available in bonded for-
mats suitable for large scale separation, and we hope
ð2Þ
that this work will spur further commercialization
efforts. In the meantime, small scale separation with
commercial Sumichiral OA7500 columns is a technique
The scope of the BadEAD reagent 1b was briefly probed
by reacting a series of four nucleophiles (3,5-dinitroben-
zoic acid, phthalimide, 4-(4-nitrophenyl)butyric acid,
and 4-cyanophenol) with four alcohols (methanol, 3,3-
dimethyl-1-butanol, isopropanol, and 4-fluorobenzyl
alcohol). The degree of difficulty of the pairings ranges
from very easy (reactions with methanol) to quite diffi-
cult (less acidic nucleophiles and hindered alcohols).
The coupled products shown in Figure 2 were isolated
by standard flash chromatography. Eight pairings gave
good to excellent yields of coupled products, while four
did not. Among these failures are three of the four alco-
hol couplings with phthalimide; only methanol coupled
with this nucleophile. Two successful couplings were
also conducted with BadMAD reagent 1a. No effort
was made to vary the Mitsunobu procedure, so these re-
sults should not be viewed as optimized. Even so, they
suggest that reagents 1a,b should exhibit a good scope
in the Mitsunobu reaction.
that is immediately accessible. And the new Mitsunobu
reagents have different separation properties from the
standard DEAD and DIAD reagents,10 so they will find
use in combination with traditional separation tech-
niques such as chromatography over standard silica
gel (Fig. 3).
Clearly, the use of adamantyl tags will extend beyond
the Mitsunobu reaction, and the selective retention of
molecules with adamantyl groups on methylated b-
cyclodextrin silica gel makes this an especially
attractive tag/separation media pair. The adamantyl
group is stable, and has a relatively low molecular
weight compared to many existing separation tags.1 A
range of simple adamantane-containing molecules
are available at modest price, and this constitutes a
starting point for fashioning tags, reagents, protecting
groups, catalysts, scavengers, etc., by using standard
reactions.

6656
S. Dandapani et al. / Tetrahedron Letters 45 (2004) 6653–6656
and 2a,b along with experimental procedures for reagent
synthesis and Mitsunobu reactions (5 pages).
O
O
O2N
OR
HO–R
N–R
O
NO2
References and notes
HOMea
HOCH2CH2 Bub
HO-i-Pra
HOCH2C6H4-p-Fb
97%
76%
88%
97%
93% (100%)c
t
1. (a) Curran, D. P. Chemtracts––Org. Chem. 1996, 9, 75–87;
(b) Curran, D. P. Angew. Chem., Int. Ed. Eng. 1998, 37,
1175–1196; (c) Yoshida, J.-I.; Itami, K. Chem. Rev. 2002,
102, 3693–3716; (d) Tzschucke, C. C.; Markert, C.;
Bannwarth, W.; Roller, S.; Hebel, A.; Haag, R. Angew.
Chem., Int. Ed. 2002, 41, 3964–4000.
nf
nf
nf
(CH2)3CO2R
OR
2. (a) Szejtli, J. Cyclodextrin Technology; Kluwer: Boston,
1988; (b) Harada, A. In Large Ring Molecules; Semlyen,
J. A., Ed.; Wiley: NY, 1996; pp 407–432; (c) Atwood,
J. L.; Lehn, J. M. In Comprehensive Supramolecular
Chemistry, 1st ed.; Pergamon: New York, 1996; Vol. 3;
(d) Connors, K. A. Chem. Rev. 1997, 97, 1325–1357; (e)
DÕSouza, V. T.; Lipkowitz, K. B. Chem. Rev. 1998, 98,
1741–1742, and the subsequent papers in this special issue
on cyclodextrins, pp 1743–2076.
3. (a) MacNicol, D. D. Tetrahedron Lett. 1975, 38,
3325–3326; (b) Redondo, J.; Jaime, C.; Virgili, A.;
Sanchez-Fernando, F. J. Mol. Struct. 1991, 248,
317–327; (c) Vashi, P. R.; Cukowski, I.; Havel, J. S. S.
Afr. J. Chem. 2001, 54, 84–102.
O2N
NC
HOMea
93% (100%)c
100%
nf
HOCH2CH2 Bub
59%
76%
97%
t
HO-i-Pra
89%
95%
HOCH2C6H4-p-Fb
nf = not formed in significant amounts
a) alcohol in excess (1.5 equiv)
b) nucleophile in excess (1.5 equiv)
c) yield with DadMAD reagent 1a
Figure 3. Isolated yields of Mitsunobu products in couplings pro-
moted by BadEAD 1b and triphenylphosphine.
More generally, this work and that of Blodgett and Li6
set the stage for a broad strategy of separation tagging
with cyclodextrin-binding tags. Such tags will be appli-
cable in all the usual substrate-, reagent-, and catalyst-
tagging applications as well as in phase switching
techniques such as scavenging and product capture.1b
Attachments of cyclodextrin tags to resin-bound prod-
ucts will provide a useful adjunct to solid phase synthe-
sis.11 The large amount of literature on the host–guest
chemistry of cyclodextrins provides the foundation for
selecting cyclodextrin-binding tags and appropriate cy-
clodextrin-based separation media. The ready availabil-
ity of cyclodextrins, and the small size and lack of
reactive functionality of many cyclodextrin-binding
groups conspire with other factors to make this new sep-
aration tagging strategy useful and appealing.
4. (a) Hughes, D. L. Org. React. 1992, 42, 335–656; (b)
Hughes, D. L. Org. Prep. Proced. Int. 1996, 28, 127–164.
5. (a) Dembinski, R. Eur. J. Org. Chem. 2004, 2763–2772;
(b) Dandapani, S.; Curran, D. P. Chem. Eur. J. 10, 3130–
3137.
6. Blodgett, J.; Li, T. See: preceding paper in this issue.
Tetrahedron Lett. 2004, 45, doi:10.1016/j.tetlet.2004.07.
010.
7. The synthesis and characterization of 1a,b and 2a,b are
described in the Supporting information.
8. Sumichiral QA7500 is methylated b-cyclodextrin bonded
to silica with an alkylene spacer. It is available from
Sumika at http://www002.upp.so-net.ne.jp/sas/oa_column.
html.
9. Curran, D. P.; Dandapani, S.; Werner, S.; Matsugi, M.
Synlett 2004, 1545–1548.
10. RfÕs on silica TLC plates eluting with CH2Cl2/EtOAc, 3/1
show that BadEAD and BadMAD hydrazides are signif-
icantly less polar than the DIAD-derived hydrazide so the
use of these reagents with standard flash chromatographic
separation can be recommended whenever target products
exhibit RfÕs similar to the DIAD-derived hydrazide:
Ph3PO, 0.29; i-PrOCONHNHCO2i-Pr, 0.46; AdCH2OC-
ONHNHCO2CH2Ad, 0.63; AdCH2CH2OCONHNHC-
O2CH2CH2Ad, 0.64.
Acknowledgements
We thank the National Institutes of Health for funding
this work.
11. For comparable uses of fluorous tagging in solid phase
synthesis, see: (a) Palmacci, E. R.; Hewitt, M. C.;
Seeberger, P. H. Angew. Chem., Int. Ed. 2001, 40,
4433–4437; (b) Filippov, D. V.; van Zoelen, D. J.; Oldfield,
S. P.; van der Marel, G. A.; Overkleeft, H. S.; Drijfhout,
J. W.; van Boom, J. H. Tetrahedron Lett. 2002, 43,
7809–7812.
Supplementary material
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2004.07.009. Contains characterization data for 1a,b