Phase separation as a strategy toward controlling dilution effects in macrocyclic glaser-hay couplings

Article abstract of DOI:10.1021/ja208902t

Macrocycles are abundant in numerous chemical applications, however the traditional strategy for the preparation of these compounds remains cumbersome and environmentally damaging; involving tedious reaction set-ups and extremely dilute reaction media. The development of a macrocyclization strategy conducted at high concentrations is described which exploits phase separation of the catalyst and substrate, as a strategy to control dilution effects. Sequestering a copper catalyst in a highly polar and/or hydrophilic phase can be achieved using a hydrophilic ligand, T-PEG₁₉₀₀, a PEGylated TMEDA derivative. Similarly, phase separation is possible when suitable copper complexes are soluble in PEG₄₀₀, a green and efficient solvent which can be utilized in biphasic mixtures for promoting macrocyclization at high concentrations. The latter phase separation technique can be exploited for the synthesis of a wide range of industrially relevant macrocycles with varying ring sizes and functional groups.

Full text of DOI:10.1021/ja208902t

ARTICLE
pubs.acs.org/JACS
Phase Separation As a Strategy Toward Controlling Dilution Effects
in Macrocyclic Glaser-Hay Couplings
Anne-Catherine Bꢀedard and Shawn K. Collins*
Dꢀepartement de Chimie, Centre for Green Chemistry and Catalysis, Universitꢀe de Montrꢀeal, CP 6128 Station Downtown, Montrꢀeal,
Quꢀebec H3C 3J7 Canada
S Supporting Information
b
ABSTRACT: Macrocycles are abundant in numerous chemical
applications, however the traditional strategy for the preparation
of these compounds remains cumbersome and environmentally
damaging; involving tedious reaction set-ups and extremely
dilute reaction media. The development of a macrocyclization
strategy conducted at high concentrations is described which
exploits phase separation of the catalyst and substrate, as a
strategy to control dilution effects. Sequestering a copper catalyst in a highly polar and/or hydrophilic phase can be achieved using a
hydrophilic ligand, T-PEG1900, a PEGylated TMEDA derivative. Similarly, phase separation is possible when suitable copper
complexes are soluble in PEG400, a green and efficient solvent which can be utilized in biphasic mixtures for promoting
macrocyclization at high concentrations. The latter phase separation technique can be exploited for the synthesis of a wide range of
industrially relevant macrocycles with varying ring sizes and functional groups.
’ INTRODUCTION
Macrocycles are one of the most common cyclic motifs found
in Nature.1 Their unique chemical structures and properties have
important applications in numerous scientific fields. Perhaps the
greatest impact of macrocycles has been felt in the pharmaceu-
tical and cosmetic industries.2 In terms of drug discovery,
synthetic macrocycles with structures inspired from natural
products have been used successfully against many biological
targets, often as rigidified peptide ligand mimics.3 The cosmetic
industry has been exploiting naturally occurring macrocyclic
musks for use as perfumes,4À6 however these compounds are
not obtained from their respective plant sources and are prepared
by synthesis on a multiton scale annually. Strangely, as the
application of macrocycles continues to grow, the general
strategy for the preparation of these compounds remains a
challenge.
The efficiency of a macrocyclization is often controlled by the
nature of the three-dimensional conformation of the macrocy-
clization precursor. Although some exceptions are known where
a precursor adopts a conformation that allows for selective and
efficient macrocyclization,7,8 in most instances the preparation of
Figure 1. (a) Traditional macrocyclization in homogeneous hydropho-
bic media. (b) Macrocyclization employing phase separation.
large rings is plagued by slow rates of intramolecular cyclization
(Figure 1a). Consequently, the rates of the intermolecular
reactions between precursors become competitive and oligomer-
In contrast, the second and most popular strategy to improve
ization or extensive polymerization becomes problematic. Ac-
macrocyclization reactions involves slowing the rate of inter-
cordingly, synthetic chemists have devised two techniques to
molecular reactions. Most often, macrocyclization reactions are
run at very low concentration and it is common that the
improve macrocyclization processes. The first involves confor-
mational control, whereby through some chemical method, the
macrocyclization precursor is made to adopt a conformation
highly conducive to ring closure, thereby increasing the rate of
intramolecular cyclization.
Received: September 21, 2011
Published: October 26, 2011
r
2011 American Chemical Society
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precursor will be added to the reaction mixture via slow addition
over an extended period of time. The extremely dilute reaction
media requires that large volumes of solvent are used. In an era
where most chemical processes are scrutinized for their environ-
mental impact, the traditional macrocycle synthesis is perhaps
one of the greatest offenders of the principles of green
chemistry.9 Indeed, in both academic and industrial laboratories,
macrocycle synthesis involving common methods such as stan-
dard peptide coupling techniques, the Yamaguchi lactonization10
and ring closing olefin metathesis11,12 are all normally conducted
under high dilution conditions. In addition to the obvious
environmental concerns, both the issues of cost and scale-up to
industrially relevant quantities of material combine to make
macrocyclization reactions prohibitive in many industrial appli-
cations. In some rare instances, a significant effort can result in a
substantial increase in yields and concentrations for a macro-
cyclization process,13À15 but the scarcity of examples under-
scores the need for new synthetic strategies. Considering both
the importance of synthetic macrocycles and the widespread
appeal of green chemical processes, the development of a general
and green macrocyclization protocol that could be conducted
via catalysis at high concentration, eliminating the need for
high dilution, is an important synthetic goal that has yet to be
achieved.16 Herein, we describe a phase separation strategy
that can be applied to catalytic macrocyclic Glaser-Hay coupl-
ings and demonstrate its application in the synthesis of macro-
cyclic musks.
In traditional methods, the macrocyclization precursor is
normally placed in a dilute homogeneous solution with a reagent
or catalyst which mediates the cyclization at low concentrations
(Figure 1a). In order to achieve macrocyclization at high con-
centrations, we chose to investigate techniques whereby the
macrocyclization event between the catalyst and precursor would
take place in an environment where the relative concentration of
the precursor is low. It was believed that replacing traditional
homogeneous reaction media with biphasic media could achieve
this goal. While chemistry at the solid/liquid interface has
become common in organic synthesis, organic synthesis at a
liquid/liquid interface is surprisingly rare17 and often instead
exploited in separation techniques.18
In order to force a macrocyclization event to occur at the
interface of the two phases, the catalyst or reagent that catalyzes
or mediates the macrocyclization would be sequestered in a
single phase while the substrate would preferentially solubilize in
a different phase (Figure 1b).19 In doing so, the effective
concentration of the substrate at the interface would be small
and mirror the low concentration typically employed in tradi-
tional macrocyclization reactions. Through phase separation of
the catalyst and precursors, the need for high dilution becomes
unnecessary and intramolecular cyclization should become the
favored reaction pathway. One method to achieve such a process
would be to use two solvents that are sparingly miscible in
conjunction with a catalyst whose ligands allow for it to be
soluble and active in only one of the phases. Given that most
organic substrates are soluble in hydrophobic media, the catalysts
developed for such a process must maintain their activity in
highly polar and/or hydrophilic media.20
Scheme 1. Synthesis of 3 Based upon Traditional Conditions
macrocyclization in industrially relevant processes. We were
attracted by the chemical challenges associated with the synthesis
of macrocyclic musks, particularly the macrolactone exaltolide 1,
which is currently the most industrially produced macrocyclic
musk (Scheme 1).21 In examining a retrosynthesis of 1, we
choose to develop a route to 3 based upon a Glaser-Hay oxidative
coupling of terminal alkynes. The Glaser-Hay coupling22À24 of 2
provides an appropriate starting point for the investigations for a
number of reasons, including: (1) the copper catalysts for these
reactions are inexpensive, nontoxic and can easily be modified
with ligands that permit solubility in hydrophilic media, (2) the
reaction results in the formation of a carbonÀcarbon bond,
classically referred to as one of the most difficult bonds to prepare
in organic synthesis, and (3) the diyne precursor 2 exists as a
linear aliphatic chain devoid of any conformational bias, hence
efficient macrocyclization would only be achieved through con-
trol of the reaction concentration.
The investigations began by conducting a traditional Glaser-
Hay coupling on diyne 2 using standard conditions from the
chemical literature.25 The cyclization of alkyl alkynes is notor-
iously slower than aryl alkynes and superstoichiometric amounts
of copper reagent are normally necessary to achieve acceptable
rates of cyclization. As such, 2 was added by syringe pump to a
solution of CuCl, tetramethylethylene diamine (TMEDA) in
refluxing PhMe under an oxygen atmosphere over 24 h and the
solution was allowed to stir for an additional 24 h (Scheme 1).
Following purification by chromatography, a complete conver-
sion of 2 was observed but only an 11% yield of the desired
macrocycle 3 was obtained. In addition, when the macrocycliza-
tion of 2 is carried out using the same reaction conditions but
at 150X the concentration shown in Figure 2, only extensive
polymerization of 2 is observed. With the result of the tradi-
tional macrocylization at various concentrations in hand, we
sought to explore the phase separation strategy to improve the
synthesis of 3.
’ RESULTS AND DISCUSSION
Developing Hydrophilic Ligands for Transition Metal
Complexes for Use in “Green” Macrocyclizations. In order
to develop a catalyst for macrocyclization via a Glaser-Hay
coupling that could impart a preference for the catalyst complex
to solubilize in hydrophilic media, it was necessary to modify the
traditional TMEDA ligand to increase its water solubility. Our
approach involved replacing one of the methyl groups of the
ligand with a polyethylene glycol (PEG) polymer (Scheme 2).
The PEG alcohol monomethyl ether 4 can be easily transformed
into its corresponding mesylate and used to alkylate trimethyl-
diamine 6, affording the ligand 7 (T-PEG1900). After both the
mesylation of alcohol 4 and the alkylation of amine 6, the
products are easily recovered via precipitation from the reaction
In order to evaluate whether such a process is feasible, we
turned our attention toward developing a macrocyclization
reaction that would not only demonstrate the proof-of-principle
for phase separation as technique for achieving macrocyclization
at high concentration, but also highlight its applicability toward
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Table 1. Model studies on the macrocyclization of 3 using a
copper/T-PEG1900 system and phase separation as a strategy
to control reactivity
entry
Ni catalyst
none
solvent (ratio)
yield (%)
1
2
PhMe/H2O (1:1)
PhMe/H2O (1:1)
PhMe/MeOH (1:1)
Et2O/MeOH (1:1)
Et2O/MeOH (1:1)
Et2O/MeOH (1:1)
0
0
NiCl2
NiCl2
NiCl2
3
15
4
34À42a
35
5b
6c
Ni(NO3)2 6H2O
3
Figure 2. Simplified experimental setup for the “green” macrocycliza-
tion using phase separation.
Ni(NO3)2 6H2O
65
3
a In some cases, complete consumption of the starting material was
observed while in other instances 10À20% could be recovered and up to
38% of a linear dimer could be isolated. b A 5 day reaction time. c 25 mol
Scheme 2. Synthesis of PEGylated TMEDA Derivative,
T-PEG1900
% of CuCl and Ni(NO3)2 6H2O were used. 50 mol % of 7 was used.
3
optimal solvent combination which resulted in a 34À42%
isolated yield of the 1,3-diyne product 3. Under these conditions,
the NiCl2 cocatalyst was finely suspended in the reaction mixture
and it was believed that the heterogeneity was responsible for the
varying yields. A variety of Ni salts were investigated as alter-
natives to NiCl2 and Ni(NO3)2 6H2O was found to be highly
3
soluble and provided similar yields of 3 (35%). Finally, when the
catalyst loading was increased to 25 mol %, the isolated yield of
macrocycle 3 was also increased to 65%
The above results demonstrate that phase separation can be an
effective technique to promote efficient macrocyclization at high
concentrations. A novel Cu- and Ni-based catalyst system was
developed using a PEGylated diamine ligand T-PEG1900 which
allowed the diyne macrocycle 3 to be prepared at significantly
higher concentration (0.0002 M (600 mL) f 0.03 M (5 mL))
and yields (11% f65%) than that utilized in traditional methods.
Polyethylene Glycol (PEG) As a Solvent for “Green”
Macrocyclization. The success of the T-PEG1900 ligand in the
previous macrocyclization reactions encouraged us to investigate
the use of PEG itself as a solvent in the phase separation strategy.
Polyethylene glycol (PEG) has already been extensively studied
as a reaction media for transition metal catalyzed reactions,
particularly cross coupling transformations.27,28 PEG (low mo-
lecular weight) is well suited as a “green” solvent as it is a water-
soluble hydrophilic polymer that is relatively nontoxic, nonvola-
tile, inexpensive and thermally stable.29À31
The aforementioned properties of PEG are normally highly
sought after when searching for alternatives to traditional organic
solvents and consequently, PEG400 was chosen as an ideal
solvent for the development of a “green” macrocyclization
protocol. In order to investigate the macrocyclization of 2 at
high concentrations using PEG400 as a hydrophilic solvent, we
initially performed a control experiment to demonstrate that
complexes of Cu salts with TMEDA or pyridine were soluble and
homogeneous in PEG400 solution under rapid stirring. Control
experiments also demonstrated that in either homogeneous
MeOH or PEG400 solution, only polymerization of 2 is observed
mixture with Et2O. T-PEG1900 7 can also be further purified by
filtration on a short column of neutral alumina.
As only extensive polymerization of 2 is observed under
classical catalysis (CuCl, TMEDA) at 150X greater concentra-
tions than the traditional synthesis depicted in Scheme 1, we next
moved to investigate the macrocyclization of 2 in solvent
mixtures. Initially, it was sought to study complexes of copper
with the T-PEG1900 ligand in a mixture of nonmiscible solvents
such as H2O/PhMe (1:1), again at 150X the traditional con-
centration (Table 1). Under the aqueous solvent conditions,
however, the T-PEG1900 Cu complexes were not active in the
Glaser-Hay coupling, however gratifyingly the starting material 2
was quantitatively recovered. As such, we chose to further
improve the reactivity of the Glaser-Hay coupling through the
inclusion of a Ni-based cocatalyst. Lei and co-workers26 have
previously shown that a Ni cocatalyst can improve the reaction
rates of Glaser-Hay couplings. Despite the addition of NiCl2 to
the reaction mixture, no macrocyclization was observed. Sub-
stitution of H2O with MeOH in the solvent mixture produced a
reaction that was initially biphasic but slowly became homo-
geneous at elevated temperatures. Gratifyingly, an isolated yield
of 15% for 3 was obtained, although the remaining starting
material was oligomerized. Even though we had achieved iden-
tical yields to the traditional macrocycle synthesis (Figure 2), we
sought to further improve the reaction through optimization of
both the nature of the solvent and the ratio of hydrophilic to
hydrophobic media. It was found that Et2O/MeOH (1:1) was an
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Table 2. Model Studies on the Macrocyclization of 2 Using a
Copper/Nickel Catalyst System and Phase Separation As a
Strategy to Control Reactivity
Table 3. Model Studies on the Macrocyclization of 3 Using a
Copper/T-PEG1900 System and Phase Separation As a
Strategy to Control Reactivity
entry
Cu/Ni (mol %); ligand
CuCl (100); TMEDA
time (d) yield (%)
scale
entry (mmol 2) (%)
yield
solvent volume,a
biphasic (mL)
solvent volume,b
1a
2a
3
1
3
1
2
4
1
1
4
4
5
1
1
2
1
1
2
22
24
57
48
26
80
78
79
68
22
67
68
76
83
68
73
monophasic (mL)
CuCl/NiCl2 (100); TMEDA
CuCl/NiCl2 (100); TMEDA
CuCl/NiCl2 (100); bipy
1
2
3
0.12
0.36
1.00
73
65
60
5
600
1800
5400
15
45
4
a Total volume of solvent required for the reaction using PEG400
/
5
CuCl/NiCl2 (100); phen
MeOH solvent mixture. b Total solvent required if an analogous reaction
were performed using the traditional conditions reported in Scheme 1.
6
CuCl/NiCl2 (100); pyridine
CuCl2 /NiCl2 (100); pyridine
CuCl2/NiCl2 (50); pyridine
CuCl2/NiCl2 (25); pyridine
CuCl2/Ni(acac)2 (50); pyridine
CuCl2/NiBr2 (100); pyridine
7
8
2 was performed on three times the previous scale (0.36 mmol),
we were pleased to observe very little change in the overall
isolated yield of the reaction (Table 3, entry 2). When the
reaction was scaled up to 1 mmol scale, an isolated yield of 60%
was obtained for the desired macrocycle 3. Importantly, the
macrocyclization on 1 mmol scale needed only 45 mL of a
mixture of PEG400/MeOH while the analogous macrocyclization
would have required 5400 mL of PhMe or CH2Cl2 to perform
(Table 3).
While further optimization of the catalyst and/or ligand
structure may afford higher yields, the increase in concentration,
reduction of solvent and high yields demonstrate a significant
step toward achieving a general and green macrocyclization
protocol. In addition, it should be noted that the phase separation
strategy allows for a simpler experimental setup when conducting
the macrocyclization (Figure 2), whereby the use of cumbersome
syringe pumps and expensive glassware is avoided and replaced
by a simple screw-cap vial.
To demonstrate some generality of the optimized catalytic
system and reaction conditions, we explored the substrate scope
of the macrocyclization. We first explored the scope of the ring
size for the synthesis of macrolactones using the phase separation
strategy (Table 4, entries 1À6). Each macrocyclization was
performed using both stoichiometric and catalytic amounts of
Cu and Ni complexes. In general, yields are good to excellent
using catalytic amounts of Cu and Ni and only small increases
were observed when using stoichiometric quantities. First, a
smaller rigidified 14-membered macrolactone 8 was isolated in
62% yield (Table 4, entry 1). Second, the macrocyclization of
larger macrolactones was investigated and it was found that
lactones having ring sizes of 18, 21, and 23 atoms at high
concentrations were all possible using the phase separation
strategy. The 18-membered macrolactone 9 was isolated in
74% yield using 25 mol % of catalysts (stoichiometric Cu/Ni =
87%). The synthesis of 21- and 23-membered macrolactones was
equally efficient. The diyne macrocycles 10 and 11 were isolated
in 81% and 78% yield, respectively, under catalytic conditions.
Finally, a 28-membered macrolactone 12 was prepared in 91%
isolated yield using stoichiometric reagents and in 98% when
9
10
11
12
13
14
15
16
CuCl2/NiF2 4H2O (100); pyridine
3
CuCl2/Ni (100); pyridine
CuCl2/Ni(NO3)2 6H2O (100); pyridine
3
CuCl2/Ni(NO3)2 6H2O (50); pyridine
3
CuCl2/Ni(NO3)2 6H2O (25); pyridine
3
a Solvent ratio PEG400/MeOH (1:1).
under classical catalysis (CuCl, TMEDA) at 150X the concen-
tration used in the traditional conditions (Scheme 1).
As with the macrocyclization reactions employing the
T-PEG1900 ligand, we sought to improve the macrocyclization
reaction using PEG400 as a solvent through the use of Ni-based
cocatalysts. Upon repeating the macrocyclization reaction of 2 in
the presence of a stoichiometric amount of NiCl2 a similar yield
of 24% yield was observed (Table 2).32 The reaction yields and
rates could be increased (24 f 57%, 3 f 1 day) by adjusting the
ratio of PEG400/MeOH from 1:1 to 2:1. We investigated other
ligands for the Cu catalyzed process and pyridine was shown to
be superior (66% yield of 3) to TMEDA, phenanthroline or 2,6-
bipyridine (Table 2, entries 3À6). Gratifyingly, the catalyst
loading could be decreased to 25 mol % for both CuCl2 and
NiCl2 without significant decreases in yield, although the reac-
tion time was longer (Table 2, entries 6À9). The macrocycliza-
tion of 2 under these reaction conditions was slightly
irreproducible, perhaps due to the fact that the NiCl2 cocatalyst
was not completely soluble in the reaction media. Analogous to
previous studies, a series of more soluble Ni cocatalysts was
surveyed (Table 2, entries 10À14) and Ni(NO3)2 6H2O was
3
again found to be highly soluble in PEG400, and afforded good
yields of the product 3 (73%) at 25 mol % catalyst loading
(Table 2, entries 16).
Upon optimization of the catalytic system and the reaction
conditions, we performed some preliminary investigations on the
feasibility of scale-up using the phase separation strategy for
macrocyclization (Table 3). When the macrocyclization of diyne
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Table 4. Macrocyclization via Glaser-Hay Coupling of
Various Diynes Using a Copper/Nickel Co-Catalyst System
and Phase Separation
ethers all afforded high yields of the corresponding macrocycliza-
tion products. Under catalytic conditions, the ester-containing
macrocycle 14 was isolated in 70% yield under the catalytic
conditions. In addition, the malonate derived macrocycle 15 was
isolated in 63% yield under catalytic conditions. Macrocycliza-
tion of aryl substituted alkynes was similarly efficient, as the 16-
membered diether 16 was isolated in nearly quantitative yields
(98%) under the optimized catalytic conditions.33
Importantly, in all of the above examples, control reactions
whereby the substrates were placed in homogeneous MeOH
solution at the identical high concentrations only resulted in
complete consumption of the diyne precursors and the forma-
tion of polymer products demonstrating that phase separation
using transitional metal complexes solubilized in PEG400 can be
exploited to promote efficient macrocyclization of a wide range
of diyne macrocycles (8À16) in good to excellent yields
(65À98%) at high concentrations.
’ CONCLUSIONS
Macrocyclic Glaser-Hay coupling at high concentrations can
be achieved using phase separation as a strategy to control
dilution effects. Two different strategies for performing macro-
cyclizations in biphasic media have been developed using the
diyne macrocycle 3 as a target to demonstrate that the developed
macrocyclizations could be performed on industrially relevant
compounds. First, we demonstrated that when necessary, phase
separation between catalyst and substrates can be achieved by
developing hydrophilic ligands for transition metal complexes
that allow for the catalysts to be sequestered in a highly polar
and/or hydrophilic phase. To demonstrate this strategy, a
PEGylated TMEDA derivative T-PEG1900 was prepared and
promoted the cyclization of 2 at a significantly higher concentra-
tion [0.0002 M (600 mL) f 0.03 M (5 mL)] and better yields
(11% f 65%) than that utilized in traditional methods. Second,
solubilization of Cu/pyridine complexes in PEG400 demon-
strates its applicability as a green and efficient solvent for use
in biphasic mixtures for macrocyclization at high concentrations.
Copper/nickel cocatalyst systems can be used to promote the
macrocyclization of a wide range of macrocycles with varying ring
sizes and functional groups. The concept that phase separation
can be used to control dilution effects in macrocyclization
reactions should allow for the practical synthesis of this class of
compounds to provide highly valuable chemical products using
practices that are significantly more environmentally benign. In
addition, the phase separation strategies discussed herein are
currently being applied to develop other macrocyclization pro-
tocols for macrocyclic olefin metathesis and macrolactonization,
using environmentally benign solvents and concentrations.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
spectroscopic data for all new compounds and complete ref 3.
This material is available free of charge via the Internet at http://
pubs.acs.org.
using the catalytic Cu/Ni combination. A variety of functional
groups were also tolerant of the reactions conditions (Table 4,
entries 7À10). An 18-membered diyne macrocycle embedded
within a suitably protected glucose core 13 was isolated in 65%
yield under catalytic conditions. Similarly, esters and phenolic
’ AUTHOR INFORMATION
Corresponding Author
shawn.collins@umontreal.ca
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Journal of the American Chemical Society
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(28) Bai, L.; Wang, J.-X. Curr. Org. Chem. 2005, 9, 535–553.
’ ACKNOWLEDGMENT
(29) Nagarapu, L.; Mallepalli, R.; Arava, G.; Yeramanchi, L. Eur.
J. Chem. 2010, 1, 228–231.
(30) Candeias, N. R.; Branco, L. C.; Gois, P. M. P.; Afonso, C. A. M.;
The authors acknowledge the Natural Sciences and Engineer-
ing Research Council of Canada (NSERC), Universitꢀe de
Montreal and the Centre for Green Chemistry and Catalysis
for generous funding. A.-C.B. thanks NSERC for an Alexander-
Graham Bell Graduate Scholarship and an FQRNT Graduate
Scholarship.
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phase separation effect (see ref 19). To date, we have performed
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