Shorter synthesis of trifunctionalized cryptophane - A derivatives

Article abstract of DOI:10.1021/ol200088f

Efficient syntheses of trisubstituted cryptophane-A derivatives that are versatile host molecules for many applications are reported. Trihydroxy cryptophane was synthesized in six or seven steps with yields as high as 9.5%. By a different route, trihydrox

Full text of DOI:10.1021/ol200088f

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1414–1417
Shorter Synthesis of Trifunctionalized
Cryptophane-A Derivatives
Olena Taratula, P. Aru Hill, Yubin Bai, Najat S. Khan, and Ivan J. Dmochowski*
Department of Chemistry, University of Pennsylvania, 231 South 34th Street,
Philadelphia, Pennsylvania 19104, United States
ivandmo@sas.upenn.edu
Received January 12, 2011
ABSTRACT
Efficient syntheses of trisubstituted cryptophane-A derivatives that are versatile host molecules for many applications are reported. Trihydroxy
cryptophane was synthesized in six or seven steps with yields as high as 9.5%. By a different route, trihydroxy cryptophane modified with three
propargyl, allyl, or benzyl protecting groups was synthesized with yields of 4.1-5.8% in just six steps. Hyperpolarized 129Xe NMR chemical shifts
of 57-65 ppm were measured for these trisubstituted cryptophanes.
Cryptophane organic host molecules, constructed from
two cyclotriguaiacylene (CTG) units connected by three
alkane linkers, possess a hydrophobic cavity that can en-
capsulate a wide variety of guests. One important application
involves xenon binding to cryptophane, which can be deliv-
ered to specific cellular targets for detection and resolu-
tion by 129Xe magnetic resonance spectroscopy or imaging.1
Currently, water-soluble cryptophane-A derivatives show
the highest known xenon affinity with KA ≈ 30 000 M-1 in
buffer at rt.2 129Xe can be hyperpolarized to generate ∼105
NMR signal enhancements and provides a greater than 200
ppm 129Xe NMR chemical shift window, with resonance
frequencies that depend sensitively on the molecular
environment.3 Thus, cryptophane hosts functionalized with
different recognition moieties allow the simultaneous detec-
tion of multiple targets (i.e., multiplexing), as is desirable for
biomolecular imaging.4 The importance of in vivo studies has
motivated the development of synthetic routes capable of
producing large quantities of functionalized cryptophane.5
A previously described multistep template strategy al-
lowed the synthesis of diverse mono-6 and trifunctiona-
lized cryptophane-A derivatives2,7 as well as enantiopure
(-)-cryptophane-A.8 However, even improved synthetic
routes typically involve nine or more steps with low
yields.5b The preparation of separate connecting linkers
and CTG units is time-consuming, and the hydroxyl
functionalities must be protected to avoid side products
(5) Traore, T.; Delacour, L.; Garcia-Argote, S.; Berthault, P.; Cin-
trat, J. C.; Rousseau, B. Org. Lett. 2010, 12, 960. (b) Brotin, T.; Dutasta,
J. P. Chem. Rev. 2009, 109, 88.
(6) (a) Spence, M. M.; Rubin, S. M.; Dimitrov, I. E.; Ruiz, E. J.;
Wemmer, D. E.; Pines, A.; Yao, S. Q.; Tian, F.; Schultz, P. G. Proc. Natl.
Acad. Sci. U.S.A. 2001, 98, 10654. (b) Wei, Q.; Seward, G. K.; Hill, P. A.;
Patton, B.; Dimitrov, I. E.; Kuzma, N. N.; Dmochowski, I. J. J. Am.
Chem. Soc. 2006, 128, 13274.
(1) Rudkevich, D. M. E. J. Org. Chem. 2007, 3255.
(2) Hill, P. A.; Wei, Q.; Eckenhoff, R. G.; Dmochowski, I. J. J. Am.
Chem. Soc. 2007, 129, 9262.
(7) Chambers, J. M.; Hill, P. A.; Aaron, J. A.; Han, Z. H.; Chris-
tianson, D. W.; Kuzma, N. N.; Dmochowski, I. J. J. Am. Chem. Soc.
2009, 131, 563.
(3) (a) Raftery, D. Annu. Rep. NMR Spectrosc. 2006, 57, 205. (b)
Taratula, O.; Dmochowski, I. J. Curr. Opin. Chem. Biol. 2010, 14, 97.
(4) Berthault, P.; Huber, G.; Desvaux, H. Prog. Nucl. Magn. Reson.
Spectrosc. 2009, 55, 35.
(8) (a) Brotin, T.; Dutasta, J. P. Eur. J. Org. Chem. 2003, 973. (b)
Brotin, T.; Barbe, R.; Darzac, M.; Dutasta, J. P. Chem.;Eur. J. 2003, 9,
5784.
(9) Gabard, J.; Canceill, J.; Collet, A. Tetrahedron 1987, 43, 4531.
r
10.1021/ol200088f
Published on Web 02/18/2011
2011 American Chemical Society

Scheme 1. Synthesis of Trisubstituted Derivatives of Cryptophane-Aa
a Tripropargyl (6a), triallyl (6b), and tribenzyl (6c) cryptophane-A derivatives were synthesized in six steps in good yields.
during the cryptophane synthesis. Moreover, the two
cyclization reactions to produce first CTG and finally
cryptophane typically involve strong acid such as perchlo-
ric acid in methanol or formic acid.9 These conditions are
incompatible with the synthesis of new CTG derivatives
bearing acid-sensitive moieties, and very often dilute con-
ditions are required to avoid polymerization, as in the case
with propargyl groups.2 Recently, Brotin and co-workers
reported cyclization reaction conditions using a milder
reagent as a Lewis acid, Sc(OTf)3.10 Notably, in some
cases even better yields were obtained, and the purification
steps were made easier.
Based on these observations, we developed a shorter,
six-step synthesis of trisubstituted cryptophanes (6,
Scheme 1) from commercial starting materials vanillyl
alcohol, 1,2-dibromoethane, and 3,4-dihydroxybenzalde-
hyde. Importantly, the trimerization of compound 1 with
catalytic Sc(OTf)3 yields tri-(2-bromoethyl)-cyclotriguaia-
cylene 2, which eliminates the need for vanillyl alcohol
protection and deprotection steps to obtain a functiona-
lized CTG intermediate by a widely used method. Linkers
3 carrying propargyl, allyl, or benzyl groups were prepared
by the reaction of 3,4-dihydroxybenzaldehyde with the
desired bromo-derivatives. The alkyl-brominated CTG 2
was reacted with hydroxy linkers 3 (3.3 equiv) deproto-
nated with Cs2CO3 to produce 4. It was easier to solubilize
and purify the trialkylated intermediates by maintaining
the aldehyde functionality of the linkers. For similar
reasons, tetrahydropyranyl (THP) protecting groups were
used previously to mask the benzyl alcohol functionalities
in the synthesis of monosubstituted cryptophanes.10,11
Finally, borohydride reduction of the CTG-trialdehyde 4
gave the CTG-trialcohol 5 without the need for column
chromatography purification, followed by cyclization with
Sc(OTf)3 to give trifunctionalized cryptophane 6 in six
total steps.
Both cyclization steps performed under mild conditions
with catalytic amounts of Sc(OTf)3 gave product in yields
similar to or higher than those reported previously in reac-
tions run in strong acid.12 The overall yield of tripropargyl
cryptophane-A derivative 6a via this synthetic route was
5.8%, which improves the lab’s previously published nine-
step procedure.2 We have shown previously that 6a can
undergo a copper(I)-catalyzed [3 þ 2] cycloaddition with
organic azides in nearly quantitative yields.13 This approach
allows the introduction of one, two, or three different moieties
(11) (a) Darzac, M.; Brotin, T.; Rousset-Arzel, L.; Bouchu, D.;
Dutasta, J. P. New J. Chem. 2004, 28, 502.
(12) (a) Brotin, T.; Devic, T.; Lesage, A.; Emsley, L.; Collet, A.
Chem.;Eur. J. 2001, 7, 1561. (b) Brotin, T.; Dutasta, J. P. Chem. Rev.
2009, 109, 88.
(13) (a) Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org.
Chem. 2005, 51. (b) Bock, V. D.; Perciaccante, R.; Jansen, T. P.;
Hiemstra, H.; van Maarseveen, J. H. Org. Lett. 2006, 8, 919. (c) Gil,
M. V.; Arevalo, M. J.; Lopez, O. Synthesis-Stuttgart 2007, 1589.
(14) (a) Hill, P. A.; Wei, Q.; Troxler, T.; Dmochowski, I. J. J. Am.
Chem. Soc. 2009, 131, 3069. (b) Seward, G. K.; Wei, Q.; Dmochowski,
I. J. Bioconjugate Chem. 2008, 19, 2129.
(10) Brotin, T.; Roy, V.; Dutasta, J. P. J. Org. Chem. 2005, 70, 6187.
Org. Lett., Vol. 13, No. 6, 2011
1415

Sc(OTf)3 in dry dichloromethane or perchloric acid in
methanol in diluted conditions to form 8 in ∼65% yield.
It is particularly useful that aldehyde groups in 4b can be
reduced to alcohols simultaneously with allyl group re-
moval using 10equiv NaBH4 ina 48h reactiontogive7. By
this last approach, cryptophane 8 was obtained in just six
steps with an overall yield of 9.5% (Scheme 3).
Scheme 2. Synthesis of Trihydroxy Cryptophane (8) via Two
Different Seven-Step Routes
Scheme 3. Six-Step Synthesis of Trihydroxy Cryptophane (8)
on the cryptophane periphery in order to tune the biological
and spectroscopic properties of the xenon biosensor.5a,14
Propargyl, allyl, and benzyl moieties in synthesized
trifunctionalized cryptophanes 6a-6c can be removed to
give trihydroxy cryptophane 8 (Scheme 2, Route 1), which
is useful for preparing functionalized cryptophane deri-
vatives.14,16 One approach involved removal of propargyl
and allyl groups of 6a,b in the presence of a Pd(II) catalyst
to afford 8 in ∼70% yield (Scheme 2, Route 1). Debenzyla-
tion of 6c using ammonium formate and 10% Pd/C gave
trihydroxy cryptophane 8 in similar yields. The overall
synthetic yield of 8 via Route 1 (Scheme 2) in seven total
steps was 4.0%.
However, by Route 2 (Scheme 2) trihydroxy crypto-
phane was prepared with a higher overall yield of 6.0%
where propargyl, allyl, and benzyl groups were eliminated
to give 7 before cyclization into 8. Thus, depropargylation
and deallylation of 5a and 5b were performed using Pd-
(PPh3)Cl2 in ∼70% yield to give precursor 7. Compound 7
can be also obtained via removal of benzyl groups of 5c in
the presence of ammonium formate and 10% Pd/C at
reflux in 75% yield. Notably, 7 could be cyclized using
Xenon binding to the synthesized trifunctionalized cryp-
tophane-A derivatives can be readily studied by hyperpo-
larized 129Xe NMR spectroscopy. As 129Xe NMR chemical
shifts are very sensitive to host molecule structures, each of
these compounds shows distinct chemical shifts for the
cryptophane-Xe complex (Table 1; experimental details
can be found in the Supporting Information).
Table 1. Hyperpolarized 129Xe NMR Chemical Shifts for
Cryptophane-A and Trisubstituted Cryptophane-A
Derivativesa
129Xe NMR chemical
shift of cryptophane-Xe
cryptophane
peak (ppm)
cryptophane-A (R = CH3)
tripropargyl cryptophane (6a)
triallyl cryptophane (6b)
tribenzyl cryptophane (6c)
trihydroxy cryptophane (8)
63.96 ( 0.03
65.33 ( 0.03
64.98 ( 0.05
63.1 ( 0.5b
57.16 ( 0.03
a Cryptophanes were dissolved in C2D2Cl4, and spectra were re-
corded at 284.5 ( 0.1 K. All spectra are calibrated by the Xe@C2D2Cl4
peak chemical shift (227.85 ppm at 284.5 K).17 b This value has tem-
perature fluctuation (1 K, which leads to greater uncertainty (details
included in the Supporting Information).
(15) Taratula, O.; Hill., P. A.; Khan, N. S.; Carroll, P. J.; Dmo-
chowski, I. J. Nat. Commun. 2010, 1, 148 (doi: 10.1038/ncomms1151).
(16) Sears, D. N.; Jameson, C. J. J. Chem. Phys. 2003, 119, 12231.
(17) Huber, G.; Beguin, L.; Desvaux, H.; Brotin, T.; Fogarty, H. A.;
Dutasta, J. P.; Berthault, P. J. Phys. Chem. A 2008, 112, 11363.
1416
Org. Lett., Vol. 13, No. 6, 2011

As shown in Table 1, the hyperpolarized 129Xe NMR
chemical shifts of cryptophane-A-Xe, 6a-Xe, 6b-Xe, and
6c-Xe complexes appear between 63 and 65 ppm, indicating
similar stereoelectronic environments of the encapsulated Xe
nuclei. This is consistent with similar cryptophane conforma-
tions and Xe binding environments observed for crypto-
phane-A-Xe, 6a-Xe, and 6b-Xe by X-ray cry-
stallography.15 By comparison, the 129Xe NMR resonance
for the 8-Xe complex is shifted significantly upfield. Lacking
all three methyl groups on one CTG unit, 8 has somewhat
larger portals than cryptophane-A for greater Xe accessibil-
ity. It is likely that 8 can sample more open conformations in
which Xe has fewer close-range deshielding interactions,
particularly with the cage benzene rings.16 Efforts are under-
way to crystallize the 8-Xe complex, in order to quantify
more directly these important van der Waals interactions.
The range of 129Xe NMR chemical shifts observed in these
experiments should allow the detection of multiple analytes in
solution, e.g., in biosensing applications.
In conclusion, shorter- and higher-yielding syntheses of
trisubstituted cryptophane-A derivatives were developed,
which eliminate the protection and deprotection steps
typically required to produce these versatile host mole-
cules. 129Xe NMR chemical shifts of 57-65 ppm were
reported for trifunctionalized cryptophane-xenon com-
plexes in C2D2Cl4.
Acknowledgment. I.J.D. appreciates support from
the DOD (W81XWH-04-1-0657), NIH (CA110104), a
Camille and Henry Dreyfus Teacher-Scholar Award, and
UPenn Chemistry Department. We thank George Furst
(Chemistry Department, University of Pennsylvania) for
NMR support.
Supporting Information Available. Experimental pro-
cedures and characterization data for all synthesized
compounds and 129Xe NMR data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 6, 2011
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