A General Method for Synthesis of Unclosed Cryptands via H-Bond Templated Macrocyclization and Subsequent Mild Postfunctionalization

Article abstract of DOI:10.1021/acs.orglett.5b02324

A practical four-step synthesis of a model 26-membered N-Boc-protected macrocycle, starting from commercially available and inexpensive materials, is reported. The crucial macrocyclization step does not require high-dilution conditions and is completed in

Full text of DOI:10.1021/acs.orglett.5b02324

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A General Method for Synthesis of Unclosed Cryptands via H‑Bond
Templated Macrocyclization and Subsequent Mild
Postfunctionalization
Kajetan Dabrowa,† Patryk Niedbala,† Maciej Majdecki,‡ Piotr Duszewski,† and Janusz Jurczak*,†
†Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
‡Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
S
* Supporting Information
ABSTRACT: A practical four-step synthesis of a model 26-membered N-Boc-protected macrocycle, starting from commercially
available and inexpensive materials, is reported. The crucial macrocyclization step does not require high-dilution conditions and is
completed in a short time (8 h). The high yield of macrocyclization (61%) is achieved owing to templation by intramolecular H-
bonds and a chloride anion, which both help to adopt a favorable folded conformation of the open-chain intermediate. Finally,
mild, selective, and efficient incorporation of intraannular amide function leading to five diversely functionalized unclosed
cryptands (UCs) is described.
rom its very beginnings, supramolecular chemistry has
been based on macrocyclic compounds.1 The geometrical
appropriate cation14 or anion.15 These strategies greatly
enhance macrocyclization; however, further functionalization
of the resulting macrocycles is not always straightforward. In
fact, few methods solving the latter problem have been
reported.16 Nevertheless, such an approach is highly desirable
since it would allow for construction of a broad array of
macrocycle structures with tailored chemical and physical
properties from just one macrocyclic precursor.
In our previous work on anion receptors, we developed a
simple one-step procedure for the preparation of macrocyclic
tetralactams from appropriate α,ω-diamines and methyl esters
of α,ω-dicarboxylic acids in methanol, in the presence of
sodium methoxide.17 Very recently, we have extended this
research to more complex macrocyclesunclosed cryptands
(UCs),18 having a suitably functionalized and flexible
substituent (lariat arm) connected directly to the interior of
the macroring. Although optimized conditions to favor their
macrocyclization were developed, the previous methodology
did not allow for a posteriori functionalization of the lariat arm.
Therefore, when one would like to synthesize an appropriately
F
constraints produced by the cyclic scaffold ensure a high level
of preorganization leading to a well-defined spatial arrangement
of substituents, in particular those capable of binding neutral
and ionic guests. Crown ethers,2 cyclodextrins,3 calixarenes,4,5
calixpyrroles,6 cucurbiturils,7 and pillararenes8 are commonly
utilized as host molecules. Very recently, drug-like macrocycles
have started to be exploited in medicinal chemistry mainly due
to their increased bioactivity and improved biostability.9
Preparation of macrocyclic compounds, however, is often
challenging as it requires multistep syntheses.10 Moreover, the
yield of the crucial step, i.e. formation of the desired macroring,
is generally low for both steric and entropic reasons. This is a
particularly serious issue when the corresponding intermediates
are expensive due to low-yielding and difficult preparation
procedures. For this reason, a number of attempts have been
made to favor ring-closure over linear oligomerization; of these
methods incorporation of an appropriate rigid scaffold11 and
templation by cationic12 or anionic species13 are used. The
latter is of particular interest because it provides access to
geometrically disfavored macrocycles.13b Moreover, in dynamic
covalent systems, tuning of the macroring size has been
reported to be strongly influenced by application of an
Received: August 11, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02324
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
functionalized UC, the intraannular substituent (lariat arm) has
to be introduced at the very beginning of the multistep
synthesis. This methodology proved to be highly inconvenient
when a very large lariat substituent is introduced and
completely failed for a base-labile function due to the presence
of a very strong base (MeONa) in the macrocyclization step.
In this letter, we report a novel synthetic methodology that
overcomes these limitations and allows efficient preparation of
diversely substituted UCs employing simple and high-yielding
chemical transformations (Schemes 1−3). Based on our
Scheme 2. Route to Macrocyclic N-Boc-Protected
Macrocycle 6
Scheme 1. Synthetic Methodologies toward Unclosed
Cryptands (lariat arm shown in black color; PG = protection
a
group)
Scheme 3. One-Pot Deprotection and Post-
Functionalization of Lariat Arm of the N-Boc-Protected
Macrocycle 6
a
Not effective for base-labile and large lariat substituents.
preliminary studies, we decided to use UCs with a 26-
membered ring as a synthetic target, owing to their potential
binding compatibility with tetrahedral anions as well as their
ability to stabilize transient water clusters in the solid state.18,19
As an amine protecting group, we chose tert-butyloxycarbonyl
(Boc) as the best one. The macrocyclization substrates 2 and 5
were prepared in three high-yielding steps in multigram
quantities, without employing column chromatography, from
either commercially available and inexpensive 2,6-pyridinedi-
carboxylic derivative 1a (R = Cl) or 1b (R = OMe) and 2-
nitroresorcinol (Scheme 2).
Briefly, the dihydrochloride salt 2 was obtained by amidation
of 1 in neat 1,4-diaminobutane and subsequent acidification of
the resulting diamine using hydrochloride in methanol.
Alternatively, 2 can be synthesized by the reaction of 2,6-
pyridine dicarbonyl dichloride with a N-Boc-1,4-butanediamine
followed by acid hydrolysis. The nitro-group reduction and
subsequent protection using Boc2O in a water−acetone mixture
yielded 4 which, after double O-alkylation, delivered the second
partner for macrocyclization, i.e. α,ω-diester 5. In the next step,
these two intermediates were subjected to macrocyclization,
which does not require high-dilution conditions (c = 27 mM)
and was completed in just 8 h, leading to macrocyclic product 6
in good yield (61%).
employed, namely 1-ethyl-3-(3-(dimethylamino)propyl)-
carbodiimide (EDC), than in terms of the steric demands of
the intermediate macrocyclic amine, since 1-pyreneacetic and
benzoic acids gave comparable yields of macrocyclic products.
The previous route,18 by comparison, produced 7c, with 23%
overall yield after three tedious column chromatography stages,
whereas under the present approach compound 7c was
synthesized with 35% overall yield after two simple column
chromatography stages. The compounds 4−7 were charac-
terized by NMR, ESI-MS, and elemental analysis. Furthermore,
the structures of products 7c and 7d were additionally
confirmed by single crystal X-ray diffraction (Figure 1). Despite
differences in macrocycle and crystal composition, both
macrocycles adopt a similar conformation with a molecule of
DMSO entrapped in the macrocyclic cavity.
Interestingly, in-depth analysis of the crystal structure of
macrocycle 7c-DMSO solvate reveals an absence of any
intramolecular H-bond (Figure S13). In the second solvate,
however, the crystal is stabilized by multiple intramolecular H-
bonds originating from amide groups and water molecules.
Despite these differences, crystal packing efficiencies CPk are
high for both solvates (0.79 and 0.83 for 7c and 7d,
respectively). All of these findings confirm the unusual, yet to
some extent predictable, packing properties of this class of
macrocycles in the solid state, as have been previously
highlighted.18,19 It is worth stressing that the high yield and
Finally, one-pot postfunctionalization of the lariat arm was
achieved by amine function deprotection and subsequent
amidation under mild conditions (Scheme 3). Near-quantita-
tive yield of incorporation of the lariat arm was observed within
15 min for acyl chlorides, regardless of the type of chloride
employed.20 Application of carboxylic acids, however, led to
lower yields and a longer reaction time. This can be rationalized
more readily in terms of the low activity of the coupling reagent
B
DOI: 10.1021/acs.orglett.5b02324
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Scheme 4. Proposed Mechanism of Intramolecular H-Bond
(left) and Chloride Anion (right) Stabilization of TS‡
a
Leading to 6
a
H-bonds are marked with green dotted lines.
Figure 1. X-ray structures of 7c·DMSO (top) and 7d·H2O·DMSO
(bottom); nonacidic protons and disorder of DMSO molecule in 7c
were omitted for clarity, and asterisks within atom labels denote
symmetry-equivalent atoms.
complex of the linear intermediate are shown in Figure 2.
Analysis of the structures suggests that the intraannular alkyl-
rate of macrocyclization leading to 6, with a 26-membered
macroring incorporating two flexible 1,4-butanediamine
spacers, indicates that the folded conformation required for
the ring closure is considerably stabilized by intramolecular H-
bonds and/or templation by the guest, presumably anionic,
present in the examined system (MeO− and Cl− anions). As a
result, the reactive amine and ester groups are brought into
close proximity, highly accelerating the rate of the second
lactamization leading to the final macrocyclic product over the
oligomerization byproducts (Scheme 4).
To experimentally determine how template (internal H-
bonds vs chloride anion) influences macrocyclization yield, we
conducted test reactions using free α,ω-diamine 2, instead of its
hydrochloride salt, without and with addition of 2 equiv of very
well grounded NaCl or LiCl salts. The yield in the former case
was considerably smaller (47%) in comparison with the
chloride salt added (63% for NaCl and 67% for LiCl). These
results clearly demonstrate that the chloride anion plays an
essential role in the stabilization of the folded conformation
whereas the inorganic cation has only a small impact. Based on
our previous studies19 indicating that chloride complexes with
this type of macrocyclic scaffold are rather weak (e.g., K < 10
M−1 for 7c in DMSO + 0.5% water), we envisioned that the
chloride anion could act as a kinetic template which stabilizes
the transition state (TS‡) leading to product 6. A similar
observation was recently reported by Luis and co-workers13c in
studies of macrocyclization of C2-symmetric pseudopeptides,
where using spherical halogens greatly enhanced macro-
cyclization rates and yields. To gain deeper insight into the
nature of these interactions we decided to carry out ab initio
calculations (see Supporting Information for details). The
representative results of the conformational analysis for the
lowest energy structures of the pure ligand and its chloride
Figure 2. Energy-minimized structures (DFT/M062X/6-31G*) of the
folded conformations templated by intramolecular H-bonds (top) and
chloride anion (bottom); second lactamization (indicated by blue
arrows) gives macrocycle; methyl group was used instead of Boc in
order to reduce computational cost.
carbamoyl group participated strongly in the stabilization of
both open-chain intermediates. In the first structure (Figure 2,
top), the carbamoyl group is tightly bound by its oxygen atoms
in the cleft created by two near-perpendicular aromatic rings
connected by an aliphatic linker. The remaining carbamoyl NH
proton bonded to the carbonyl oxygen atom of the ester group,
placing it in close proximity to the free amine group. In the
C
DOI: 10.1021/acs.orglett.5b02324
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(7) Kim, K.; Selvapalam, N.; Ko, Y. H.; Park, K. M.; Kim, D.; Kim, J.
Chem. Soc. Rev. 2007, 36 (2), 267−279.
second structure (Figure 2, bottom), binding of the chloride
anion by all available NH amide protons stabilizes the folded
conformation.
The reactive groups are then brought into close proximity by
H-bond formation between the amine and oxygen atom of the
ester group. Interestingly, computational calculations for
complexes of the linear intermediate with either water and
methanol suggest that they are more conducive to the
formation of oligomers than the desired macrocycle (Figure
S15 and Tables S3−S4).
In summary, 26-membered N-Boc-protected macrocycle 6
was prepared in a four-step synthesis (37% overall yield)
starting from commercially available and cheap precursors
utilizing only single column chromatography. Its subsequent
deprotection and site-selective postfunctionalization paves the
way for the preparation of diversely functionalized UCs in high
yields and under mild conditions. Moreover, installation of
base-sensitive groups in the lariat arm, previously infeasible due
to the presence of a strong base in the macrocyclization step, is
now unlocked. Studies toward rationally functionalized UCs
tailored to bind salts and chiral anions are currently underway.
(8) Xue, M.; Yang, Y.; Chi, X.; Zhang, Z.; Huang, F. Acc. Chem. Res.
2012, 45 (8), 1294−1308.
(9) (a) Lindoy, L. F.; Park, K.-M.; Lee, S. S. Chem. Soc. Rev. 2013, 42
(4), 1713−1727. (b) Levin, J. I. Macrocycles in Drug Discovery; Royal
Society of Chemistry: 2014; Vol. 40.
(10) (a) For a recent review on macrocycles synthesis, see: Martí-
Centelles, V.; Pandey, M. D.; Burguete, M. I.; Luis, S. V. Chem. Rev.
2015, 115 (16), 8736−8834. (b) Diederich, F.; Stang, P. J.; Tykwinski,
R. R. Modern supramolecular chemistry: strategies for macrocycle
synthesis; John Wiley & Sons: 2008.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02324.
(16) For selected examples, see: (a) Van Loon, J. D.; Arduini, A.;
Coppi, L.; Verboom, W.; Pochini, A.; Ungaro, R.; Harkema, S.;
Reinhoudt, D. N. J. Org. Chem. 1990, 55 (21), 5639−5646.
(b) Fairfull-Smith, K.; Redon, P. M. J.; Haycock, J. W.; Williams, N.
H. Tetrahedron Lett. 2007, 48 (8), 1317−1319. (c) Van Rossom, W.;
Maes, W.; Kishore, L.; Ovaere, M.; Van Meervelt, L.; Dehaen, W. Org.
Lett. 2008, 10 (4), 585−588. (d) Strutt, N. L.; Zhang, H.; Schneebeli,
S. T.; Stoddart, J. F. Acc. Chem. Res. 2014, 47 (8), 2631−2642.
(e) Lavendomme, R.; Leroy, A.; Luhmer, M.; Jabin, I. J. Org. Chem.
2014, 79 (14), 6563−6570. (f) Kubota, N.; Segawa, Y.; Itami, K. J. Am.
Chem. Soc. 2015, 137 (3), 1356−1361.
(17) (a) Gryko, D. T.; Gryko, D.; Jurczak, J. Synlett 1999, 1999 (08),
1310−1312. (b) Szumna, A.; Jurczak, J. Eur. J. Org. Chem. 2001, 2001
(21), 4031−4039. (c) Chmielewski, M. J.; Szumna, A.; Jurczak, J.
Tetrahedron Lett. 2004, 45 (47), 8699−8703.
(18) Dąbrowa, K.; Pawlak, M.; Duszewski, P.; Jurczak, J. Org. Lett.
2012, 14 (24), 6298−6301.
(19) Dąbrowa, K.; Ceborska, M.; Jurczak, J. Cryst. Growth Des. 2014,
14 (10), 4906−4910.
Detailed experimental procedures for the compounds
synthesis and NMR (1H, 13C) spectra, calculation
procedure, and Cartesian coordinates of calculated
structures (PDF)
X-ray crystallographic information for 7c·DMSO and
7d·H2O·DMSO (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: janusz.jurczak@icho.edu.pl.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would like to acknowledge Poland’s National Science
Centre (Project 2011/02/A/ST5/00439) for financial support.
The X-ray structures of 7c and 7d were determined in the
Institute of Physical Chemistry by Dr. Magdalena Ceborska and
in the Advanced Crystal Engineering Laboratory (aceLAB) at
the Chemistry Department of the University of Warsaw by Dr.
Łukasz Dobrzycki, respectively.
(20) Note that during purification by column chromatography, host
7b and 7c left the column as pure 1:1 complexes with a TEA
hydrochloride. Free macrocycles were then quantitatively liberated by
the addition of water, subsequent short sonification (∼2 min), and
filtration (see Figures S5−S6). The reverse approach, i.e. extraction of
the host and subsequent column chromatography, resulted in
significantly lower yields of macrocycles (∼60%).
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́
D
DOI: 10.1021/acs.orglett.5b02324
Org. Lett. XXXX, XXX, XXX−XXX