One-pot synthesis of hybrid macrocyclic pentamers with variable functionalizations around the periphery

Article abstract of DOI:10.1021/ol200538d

Chemical equations presented. Rather than four- or six-residue macrocylces, one-pot macrocyclization allows for the highly selective formation of five-residue macrocycles rigidified by intramolecular hydrogen bonds. Variable functionalizations around the

Full text of DOI:10.1021/ol200538d

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2270–2273
One-Pot Synthesis of Hybrid Macrocyclic
Pentamers with Variable Functionalizations
around the Periphery
Bo Qin,† Chang Sun,† Ying Liu,† Jie Shen,† Ruijuan Ye,† Jia Zhu,‡ Xin-Fang Duan,‡ and
Huaqiang Zeng*,†
Department of Chemistry and NUS MedChem Program of the Office of Life Sciences,
3 Science Drive 3, National University of Singapore, Singapore 117543, and
College of Chemistry, Beijing Normal University, Beijing 100875, China
chmzh@nus.edu.sg
Received February 28, 2011
ABSTRACT
Rather than four- or six-residue macrocylces, one-pot macrocyclization allows for the highly selective formation of five-residue macrocycles rigidified by
intramolecular hydrogen bonds. Variable functionalizations around the pentameric periphery were achieved by reacting monomers with higher oligomers
bearing different exterior side chains. The formation of these hybrid pentamers suggests a chain-growth mechanism for the one-pot macrocyclizationwhere
the successive addition of monomers onto higher oligomers is faster than those between two monomers or two higher oligomers.
The “macrocyclic effect” is physically conferred by the
preorganized macrocyclic backbones, the formation of
which, however, being entropically disfavored. This largely
accounts for the low yield formation of the desired macro-
cycles along with an observation of many byproducts,
including linear/cyclic oligomers of various lengths.1a To
diminish this entropic cost and also to promote the effective
macrocyclization, various strategies1 have been developed
that include one-step cyclization, templated cyclization,
intramolecular ring closure, intermolecular coupling, and
dynamic covalent bond formation.
Within the context of establishing alternative protocols
for improved macrocyclization efficiency, conformation-
assisted2 and H-bonding-directed3 macrocyclizations
were conceived that utilize the conformationally biased
† National University of Singapore.
‡ Beijing Normal University.
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r
10.1021/ol200538d
Published on Web 04/06/2011
2011 American Chemical Society

backbone to purposely predispose the two reactive termini
into a predictable geometry and thus to induce a “template
effect” to facilitate the intramolecular macrocyclization
reaction. Despite these advancements, most of the cycliza-
tion reactions are still carried out under conditions of high
dilution, and critical challenges remain in the efficient
construction of macrocycles with precise control over the
ring sizes and variable functionalizations around the
periphery.
Table 1. Chemical Yields7a for One-Pot Preparationa of
Circular Pentamer 1 from the Corresponding Oligomers 1aꢀ1e
After extensive research, recently we successfully dis-
covered phosphoryl trichloride, POCl3, as a powerful
macrocyclization reagent for selectively promoting the
one-pot synthesis of aromatic pentamers such as 1 from
its monomeric units 1a (Table 1) whereby five identical
unsymmetrical bifunctional monomers are assembled via
intramolecular H-bonds to arrive at a unique pentagon
shape,3n an intrinsic property shared by this class of
crescent-shaped molecules,4 and rarely found in others.5
As illustrated in the present work, our very recent
continued exploration reveals further that POCl3 also selec-
tively produces five-residue macrocycles 2d, 2f, and 2d
(Figure 1 and Table 2) comprised of mixed building blocks
that bear exterior side chains of different types, enabling
variable functionalization around the pentameric periphery.
To the best of our knowledge, we are not aware of other
macrocyclic systems1ꢀ3,5,6 that allow specific hybrid macro-
cycles containing variable repeating units to be prepared via
one-pot comacrocyclization as the major product that is
determined predominantly by a chain-growth mechanism
rather than more or less by a statistical distribution
reacting
partners
molar
ratio
entry
yield (%)b
1
2
3
4
5
6
7
8
9
1a
N.A.c
1:3
46 (6)d
49
1b:1a
1c:1a
1d:1a
1b:1c
1e
1:2
38
1:1
40
1:1
39
N.A.
N.A.
N.A.
N.A.
76
e
1b
ꢀ
1c
29d
e
1d
ꢀ
a Reaction conditions: reactants 1aꢀ1e (total = 0.2 mmol), POCl3
(0.4 mmol), TEA (0.6 mmol), CH3CN (2.0 mL), room temperature, 12 h.
b Isolated yield by flash column chromatography. c N.A. = not applic-
able. d Yield of the hexamer. e No tetramer was formed.
pattern.6d,e Moreover, mechanistic investigations on one-
pot macrocyclization1ꢀ3,5aꢀ5c,6d,6e have been very rare with
only one recent report by Gong.3j
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Zhang, D. W.; Su, H. B.; Zeng, H. Q. J. Am. Chem. Soc. 2010, 132, 5869.
(5) For reviews on H-bonded shape-persistent macrocycles, see: (a)
Gong, B. Acc. Chem. Res. 2008, 41, 1376. (b) Li, Z. T.; Hou, J. L.; Li, C.;
Yi, H. P. Chem.;Asian J. 2006, 1, 766. (c) Hecht, S. M.; Huc, I.
Foldamers: Structure, Properties and Applications; Wiley-VCH:
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S. H. Acc. Chem. Res. 1998, 31, 173. (e) Stigers, K. D.; Soth, M. J.;
Nowick, J. S. Curr. Opin. Chem. Biol. 1999, 3, 714. (f) Gong, B. Chem.;
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ItwasdemonstratedbyGong and hisco-workersthat, in
the presence of a symmetrical bifunctional monomeric
diacid chloride, longer oligomers such as a trimeric dia-
mine and a trimeric diacid chloride still preferentially react
with each other to undergo one-pot 3 þ 3 bimolecular
cyclization reactions, producing a H-bonded macrocyclic
hexamer.3j This finding suggests that one-pot macrocycli-
zation from the respective monomers to produce hexamers
does not occur via a chain-growth mechanism.3j We were
intrigued to find out whether this privileged cross-reactiv-
ity seen in higher oligomers is equally applicable to our
unsymmetrical bifunctional building blocks or not. In
other words, what is the mechanism that underlies the
preferred formation of aromatic pentamers?
Among our initial attempts to identify the likely reaction
mechanism, the macrocyclization yields of circular penta-
mer 1 were examined using various pairs of reacting
partners (Table 1). Although it cannot be completely ruled
out, the insignificant differenceinyields among entries 1ꢀ5
does not favor the formation of 1 by a mechanism invol-
ving an n þ m (both n and m g 2) bimolecular reaction
between longer oligomers such as dimer 1b and trimer 1c
(entry 5). The high yield production of 1 by acyclic
pentamer 1e (76%; entry 6) suggests the existence of low-
yielding steps among entries 1ꢀ5. It is obvious that the
bimolecular reaction of 2 þ 3 type between dimer 1b and
trimer 1c (entry 5) constitutes one of those low-yielding
(6) (a) Berni, E.; Dolain, C.; Kauffmann, B.; Lger, J.-M.; Zhan, C.;
Huc, I. J. Org. Chem. 2008, 73, 2687. (b) Zhu, Y. Y.; Li, C.; Li, G. Y.;
Jiang, X. K.; Li, Z. T. J. Org. Chem. 2008, 73, 1745. For one-pot
synthesis of 3D-shaped pentameric macrocycle whose yields are more or
less determined by a statistical distribution pattern, see: (c) Zhang, Z.;
Xia, B.; Han, C.; Yu, Y.; Huang, F. Org. Lett. 2010, 12, 3285. (d) Zhang,
Z.; Luo, Y.; Xia, B.; Han, C.; Yu, Y.; Chena, X.; Huang, F. Chem.
Commun. 2011, 2417. For an outstanding work on producing unsym-
metrical macrocycles by programmed dynamic covalent assembly, see:
(e) Hartley, C. S.; Moore, J. S. J. Am. Chem. Soc. 2007, 129, 11682.
Org. Lett., Vol. 13, No. 9, 2011
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Table 2. Variable Functionalization of Pentamers 2d, 2f, and 2g
by One-Pot Co-macrocyclizationa of Oligomers 1bꢀ1d with 2a
reacting
partners
molar
ratio
product
(yield, %)b
entry
1
2
3
1b:2a
1c:2a
1d:2a
1:3
1:2
1:1
2d (38)
2f (42)
2g (39)
Figure 1. Structures of pentamers 1, 2, and 2bꢀ2g containing
monomeric units of 1a and 2a in varying ratios. Using ethyl
acetate/hexane/dichloromethane (5:18:5, v/v) as the eluent, all
of the eight pentamers 1, 2, and 2bꢀ2g can be well separated in
TLC plate. Lanes 3ꢀ5 = macrocylization reaction products
generated by reacting 1a and 2a in molar ratios of 4:1, 1:1, and
1:4, respectively. From lanes 3ꢀ5, it can be seen that 1a and 2a
indiscriminately cross-reacted with each other. Please note that
the dark spots at the origin line actually derive from very tiny
amounts of unknown compounds from the reaction.
a Reaction conditions: reactants 2a and 1bꢀ1d (total = 0.2 mmol),
POCl3 (0.4 mmol), TEA (0.6 mmol), CH3CN (2.0 mL), room tempera-
ture, 12 h. b Isolated yield by flash column chromatography.
process that is highly likely, whether or not and to what
extent a bimolecular reaction between in situ generated dimer
1b and trimer 1c does take place in entries 1ꢀ3, however,
remain unclear.
To further clarify the reaction mechanism, a few com-
petition experiments were designed and carried out.
Although the macrocylization yields of 1 (46%, entry 1
of Table 1) and 2 (42%) from their respective monomers 1a
and 2a are comparable,3n to ensure a fair comparison, the
cross-reactivity between monomers 1a and 2a within the
sameexperimental settingata constant total concentration
of 100 mM involving both reactants1a and 2a was assessed
first. Combinatorially, up to eight pentamers (Figure 1)
containing monomers 1a and 2a in varying ratios in the
backbone can be produced. After 1a and 2a were reacted in
molar ratios of 4:1, 1:1, and 1:4 under the optimized one-
pot cyclization conditions, the produced reaction mixtures
containing circular aromatic pentamers of different types
were analyzed using Thin Layer Chromatography (TLC)
and the results are presented in Figure 1.
Mixing 1a and 2a in a 4:1 ratio produced two major
spots, corresponding to pentamers 17b and 2g, containing
five and four 1a units (Lane 3, Figure 1), respectively.
Similarly, mixing 1a and 2a in 1:4 ratio produced two more
major spots, corresponding to pentamers 2 and 2b, con-
taining five and four 2a units (Lane 5, Figure 1), respec-
tively. The isolated chemical yields for 2g from Lane 3 and
2b from Lane 5 were 20% and 21%, respectively, illustrat-
ing an excellent compatibility between 1a and 2a in the
participating one-pot cyclization reaction. On the other
hand, from the reaction involving 1a and 2a in equivalent
amounts, the six pentamers 2bꢀ2g statistically should be
produced in equal amounts that are five times as much as
either 2 or 1 that also should be produced in equal amounts.
This statistical distribution pattern matchs quite well with
steps with an estimated chemical yield of ∼50% that leads to
acyclic pentamer 1e, which subsequently undergoes an in-
tramolecular ring cyclization with a 76% yield to afford 1
in an overall yield of 39%. The 2 þ 2 or 3 þ 3 bimole-
cular reaction types involving dimer 1b (entry 7) or trimer 1c
(entry 8), respectively, are not favored, either, as evidenced
from no or low yield production of their respective cyclized
tetramer or hexamer. In fact, the crescent-shaped acyclic
tetramer cannot even undergo an intramolecular ring cycli-
zation to produce the circularly folded tetramer (entry 9).
The production of a hexamer from 1c (entry 8) was also
completely suppressed in the presence of competing mono-
mer 1a (entry 3), suggesting that the reaction between
monomer 1a and trimer 1c or between dimer 1b (generated
in situ from 1a) and trimer 1c is faster than that between
trimer 1c itself. A low yield production of hexamer from entry
1 further suggests that the reaction rate involving an acyclic
pentamer and a momomer to produce the hexamer is slower
than that dictating the intramolecular cyclization of an
acyclic pentamer into a circular one. Possibly, this may be
due to the remote steric effect between the two end residues
that disencourage the formation of oligomers longer than a
pentamer.3j Therefore, in addition to a chain-extension
(7) (a) Our examination of possible identities of the remaining
50ꢀ60% reaction mixture produced from entry 1 of Table 1 by TLC,
1
MS, and H NMR only allows us to confidently conclude that it does
contain small amounts of intermediate amino acids (e.g., dimer amino
acid, trimer amino acid, and tetra amino acid) and does not contain any
unreacted starting monomer amino acid such as 1a. Other than these, the
identity of any other remaining is unknown to us. (b) Please note that
pentamer 1 stains much less intensely when compared to pentamers 2
and 2bꢀ2g.
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Org. Lett., Vol. 13, No. 9, 2011

the experimental distribution pattern seen by TLC (Lane 4
in Figure 1), further providing a convincing illustration of
the excellent cross-reactivity between 1a and 2a, and among
oligomers containing 1a and 2a in varying ratios.
to the inference that except for the 4 þ 1 type reaction that
could be a low yielding step, all the other chain growth
steps of n þ 1 type reactions likely give high yields of the
corresponding oligomers. Reasonably assuming all n þ 1
(n = 1ꢀ3) type reactions give a quantitative yield, then
based on the respective 40% (entry 4, Table 1), 39% (entry
3, Table 2), and 76% (entry 6, Table 1) yields, the chemical
yield of the 4 þ 1 reactiontoproduceacyclic pentamerscan
be estimated to be ∼50%. The predominant formation of
hybrid pentamers 2d, 2f, and 2g made up of different
building blocks is a direct demonstration of variable
functionalization around the periphery achievable by re-
acting monomers with higher oligomers that differ by
exterior side chains.
In conclusion, we established here that the POCl3-
mediated one-pot macrocyclization proceeds predomi-
nantly by a chain-growth mechanism whereby the addition
of a monomer into the growing backbones is faster than
other competing bimolecular reactions between two mono-
mers or between two higher oligomers. This one-pot
macrocyclization protocol now allows an efficient prepara-
tion of aromatic pentamers carrying side chains of varying
types in both its interior as previously reported by us3n and
exterior as demonstrated in the present work. These
H-bonded pentagon-shaped molecules with a modifiable
interior and exterior may promise some good applications
in chemistry, materials sciences, and biology.3n,4a,4b
On the basis of the above demonstrated excellent cross-
reactivity between 1a and 2a as well as the in situ genearted
oligomeric intermediates, competition experiments invol-
ving monomer 2a and oligomers 1bꢀ1d in various ratios
were performed (Table 2). The reaction involving a 1:3
molar ratio of 1b:2a produced pentamer 2d with an
undetectable occurrence of pentamer 2 (entry 1), suggest-
ing that the formation of pentamer 2d proceeds largely by a
chain-growth mechanism, rather than by 2 þ 2 or 2 þ 3
bimolecular condensation reactions between higher oligo-
mers, e.g. between dimer 1b and the in situ generated
octyloxy-containing dimer or trimer. If the latter is the
predominant mechanism to produce pentamer 2d, the in
situ generated octyloxy-containing dimer and trimer
should be present in substantial amounts that should
further couple to each other to form 2 directly by a 2 þ 3
reaction, orindirectly by a 2 þ 2 reaction, followed by a 4 þ
1 reaction with a chemical yield comparable to that for 2d.
This, however, iscontradictorywiththe negligible presence
of pentamer 2 from the reaction. In addition, the 1 þ 1
bimolecular reaction involving monomer 2a should be
comparably slower than n þ 1 (n g 2) reaction involving
oligomers 1bꢀ1d and monomer 2a. Otherwise, the in situ
generated octyloxy-containing dimer by the 1 þ 1 reaction
involvingmomomer2amay leadtoanappreciableamount
of pentamer 2 by 2 þ 3 or 2 þ 2 reactions.
Acknowledgment. Financial support of this work by the
NUS AcRF Tier 1 grants (R-143-000-375-112 and R-143-
000-398-112 to H.Z.) and A*STAR BMRC research con-
sortia (R-143-000-388-305 to H.Z.) are gratefully
acknowledged.
The above conclusions are also consistent with and can
be inferred from entries 2 and 3 from Table 2 whereby
pentamers2f and 2g were produced as major products with
pentamer 2 remaining insignificant. Similar to 2d, the
formation of pentamers 2f and 2g as well as 1 (Table 1)
should also proceed by a continuous chain-growth me-
chanism. Examination of similar chemical yields among
entries 1ꢀ4 from Table 1 and entries 1ꢀ3 from Table 2 led
Supporting Information Available. Synthetic proce-
dures and a full set of characterization data including
1H, 13C NMR and MS. This material is available free of
charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 9, 2011
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