Modified routes to the "designer" surfactant PQS

Article abstract of DOI:10.1021/jo202564b

Described herein are newly developed, straightforward entries to polyethyleneglycol ubiquinol succinate (PQS, n = 2), a designer surfactant that serves as precursor to micelle-forming, covalently bound catalysts for a variety of transformations in water w

Full text of DOI:10.1021/jo202564b

Article
pubs.acs.org/joc
Modified Routes to the “Designer” Surfactant PQS
Ralph Moser, Subir Ghorai, and Bruce H. Lipshutz*
Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States
S
* Supporting Information
ABSTRACT: Described herein are newly developed, straightforward entries
to polyethyleneglycol ubiquinol succinate (PQS, n = 2), a designer surfactant
that serves as precursor to micelle-forming, covalently bound catalysts for a
variety of transformations in water with in-flask catalyst recycling.
available hydroquinone, ubiquinol (i.e., the reduced form of
CoQ10), that supplies the lipophilicity in its 50-carbon side-
chain, within which organic substrates are to be dissolved.
Importantly, it also bears a second phenolic handle enabling
covalent attachment of a catalyst that will reside inside the
nanoreactor of its micellar array; (2) polyethyleneglycol
monomethyl ether (MPEG-2000), which ensures water
solubility; and (3) a linker unit, either sebacic acid, n = 8, or
succinic acid, n = 2, that connects the lipophilic interior (i.e.,
ubiquinol) to the hydrophilic exterior (i.e., MPEG).
The concept of in-flask catalyst recycling was successfully
demonstrated on olefin ring-closing and cross-metathesis
reactions in water employing Grubbs−Hoveyda’s first- and
second-generation catalysts, which were independently cova-
lently attached to PQS (4: PQS-GH-1 and 5: PQS-GH-2,
Figure 2).4 A study of up to 10 recycles without significant loss
of catalyst activity highlighted the potential of the PQS
platform. Likewise, a related system based on PQS that does
not focus on transition metal catalysts, e.g., PQS-proline (7) for
use in organocatalysis, has recently appeared.5
Although a first generation synthesis (i.e., for 1) gave
satisfactory results, limited selectivity in each coupling step
using sebacoyl chloride resulted in purification issues.4
Moreover, scale-up experiments suggested that removal of
impurities would be impractical through chromatographic
means. Therefore, a synthetically more attractive route to the
PQS platform was sought. Herein, we describe two novel and
improved entries to the designer surfactant PQS-1 (1). We also
disclose a synthesis of PQS-3 (3), a third generation surfactant,
employing a succinic acid linker that enhances significantly the
availability of the PQS platform.
INTRODUCTION
■
Catalysis is now considered among the major milestones of last
century’s developments in organic chemistry. Catalyst recycling,
in particular the case of homogeneous catalysis, despite its
many advantages (e.g., reduced waste and/or more efficient
energy usage) still remains challenging. This is especially true
when costly ligands and/or precious metals are involved.
Aqueous biphasic systems have become an important industrial
technique and offer one solution: the catalyst can be recovered
from the aqueous phase, although the overall transformation
occurs in the organic solvent.1,2 We have previously shown that
a variety of transition-metal-catalyzed transformations can be
carried out within micellar media, generated by simply mixing a
selected surfactant in water.3 Organic solvents, therefore, are no
longer needed, as the self-assembled micelles provide the
lipophilic interior that serves, in essence, as the solvent for
catalysis, i.e., as nanoreactors in water. Moreover, since only 1−
2 wt % of surfactant in water easily exceeds the required critical
micelle concentration (CMC), a catalytic amount of the
amphiphile is sufficient. While other surfactants typically
contain only lipophilic and hydrophilic subsections, poly-
ethyleneglycol ubiquinol sebacate (PQS) was originally
designed to accommodate a third component: an internally
connected catalyst (Figure 1).4 Hence, the three major
subsections of PQS consist of the following: (1) the readily
RESULTS AND DISCUSSION
■
Initial attempts toward 1 focused on commercially available
sebacic acid (8), which, after anhydride (9) formation,6 was
treated with MPEG-2000 to obtain PEGylated sebacic acid 10
(Scheme 1; Route A). Subsequent coupling with ubiquinol,
Received: December 17, 2011
Published: March 13, 2012
Figure 1. Designed components of PQS.
© 2012 American Chemical Society
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both mono- and (undesired) diacylation due to the open chain
nature of sebacoyl chloride. Replacement of the C10 unit by a
C4 fragment originating from succinic anhydride would
eliminate opportunities for undesired by-products due to
reactions at both termini. Thus, starting with (inexpensive)
MPEG-2000 (14) and succinic anhydride, mono-PEGylated
succinic acid 15 was formed in excellent yield (Scheme 2).
a
Scheme 2.
Figure 2. PQS as a platform for covalent attachment of a catalyst.
a
Reagents and conditions: (a) succinic anhydride, NEt3, toluene, 60
°C, 99%. (b) N-hydroxysuccinimide, EDCI, CH2Cl2, rt, 99%. (c)
a
Scheme 1.
ubiquinol, NaH, THF, 0 °C to rt, 65%.
EDCI-mediated coupling of acid 15 and N-hydroxysuccinimide
led to activated ester 16. Neither of these two steps required
product purification. Lastly, ester 16 was coupled with
ubiquinol9 in THF to provide PQS-3 (3) after straightforward
purification on silica gel.8 This streamlined, cleaner procedure
could be successfully repeated on various scales10 in up to 64%
overall yield.
After lyophilization, PQS-3 (3) appears as a white, fluffy
solid, which readily dissolves in water to provide micelles
having an average diameter size of 21 nm, as determined by
DLS measurements (Figure 3; r = radius). By contrast, PQS-1
a
Reagents and conditions: (a) Ac2O, reflux, 76%. (b) HO-PEG-OMe,
DMAP, pyridine, 100 °C, 99%. (c) SOCl2, reflux, then redissolution in
THF, ubiquinol, NaH, THF, rt, 80%. (d) EDCI, DMAP, ubiquinol,
NEt3, CH2Cl2, rt, 31%. (e) BnOH, NEt3, Et2O, −78 °C to rt, then 1 N
HCl, 57%. (f) SOCl2, reflux, then HO-PEG-OMe, NEt3, CH2Cl2, rt,
92%. (g) Pd/C, H2, MeOH, rt, 98%.
either through its acid chloride or via EDCI/DMAP, led to
PQS-1 (1) in high isolated yield and of good purity. To obtain
1 of higher quality, a modified approach from sebacoyl chloride
(11) was investigated (Route B). Formation of monobenzy-
lated sebacic acid 12 (57% yield after chromatography) and
then coupling and deprotection steps via 13 gave mono-
PEGylated sebacic acid 10 in high purity following simple
precipitation from Et2O. Although the overall yield for PQS-1
(1) was generally lower using route B, the quality of the
material was consistently higher than that obtained via route
A.7,8
Figure 3. Particle size of PQS-3 (3) measured by DLS (r = radius).
(1) in water consists of particles of ca. 9 nm. The spherical
nature of these self-aggregated nanoparticles, which can appear,
in part, to be agglomerated and therefore oblong in shape, was
confirmed by cryo-TEM measurements (Figure 4).
To ensure that the minor difference between PQS-1 and
PQS-3 (i.e., the 10- vs 4-carbon linker) does not translate into
differences in the observed catalysis, 3 was attached to acid 1711
to yield carbene precursor 18 (Scheme 3). Subsequent
insertion of Ru yielded 6 in good overall yield. PQS-3-GH1
(6) appears as a brown solid that is freely soluble in water and
The linker unit between ubiquinol and MPEG in PQS-1 (1)
is derived from 10-carbon sebacic acid (8), which underwent
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Figure 5. Particle size of PQS-3-GH1 (6) measured by DLS (r =
radius).
Figure 4. Cryo-TEM measurements of PQS-3 (3).
a
Scheme 3.
Figure 6. Cryo-TEM measurements of PQS-3-GH1 (6).
Scheme 4.
a
Pd-catalyzed transformations in water, providing similar options
for straightforward catalyst recycling (Figure 7).
Reagents and conditions: (a) EDCI, DMAP, NEt3, CH2Cl2, rt, 85%.
(b) Grubbs first generation, CuCl, CH2Cl2, rt, 98%.
forms nanoreactors with an average diameter of 30 nm by DLS
(Figure 5; r = radius).
Cryo-TEM measurements of PQS-3-GH1 (6) confirmed the
size of these particles and showed their spherical appearance
(Figure 6).
Diene 19 was subjected to RCM to yield the cyclized product
20 using 6 as the micelle forming catalyst (Scheme 4.).
Compared to results obtained previously with 4,4a the newly
developed third generation platform (i.e., 6) functions virtually
identically.
CONCLUSIONS
■
Two alternative synthetic entries to PQS-1 (1) are presented. A
further improved, third-generation designer surfactant in the
PQS series, PQS-3 (3), has been developed, the synthesis of
which is straightforward, higher yielding than existing routes,
and potentially scalable. Both surfactants function equally well,
as manifested by the representative case of a covalently
derivatized ruthenium catalyst, which enables olefin metathesis
reactions to be carried out under homogeneous conditions in
water at room temperature with in-flask catalyst recycling.
New systems, such as PQS-(R)-BINAP (21) are currently
under investigatation for applications to asymmetric Rh- and
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ubiquinol (4.89 g, 5.65 mmol), and sodium hydride (170 mg, 4.24
mmol, 60% w/w in mineral oil). Outside the glovebox, under an
atmosphere of argon, dry THF (10 mL, distilled from Na/
benzophenone) was added, and the suspension was stirred at room
temperature for 1 h and cooled to 0 °C. The solution of MeOPEG
sebacic chloride in THF (flask A) was added via canulla dropwise to
flask B at 0 °C. Flask A was rinsed with additional dry THF (5−10
mL) and transferred to flask B. Under continuous stirring, the orange
suspension was slowly warmed to room temperature overnight. The
reaction was quenched by the dropwise addition of water and
subsequent addition of 1 N aq HCl until pH < 7. The mixture was
extracted using CH2Cl2 (1 × 100 mL, 2 × 50 mL); the combined
organic layers were washed with brine, dried over anhydrous Na2SO4,
and concentrated to yield a pale orange oil that can be purified by two
different procedures.
Figure 7. PQS-(R)-BINAP (21) for Rh and/or Pd catalysis.
Purification A, Short Path Column. An empty 240 g single step
column (Thomson Instrument Company) was slurry packed with
∼240 g of silica gel in Et2O. The pale orange oil was evenly loaded
onto the column using a minimal amount of CH2Cl2, and the column
was carefully closed using a head space frit. Using a Biotage SP4
system, the column was flashed with Et2O (500 mL, flow rate 45 mL/
min) and CH2Cl2 (500 mL, flow rate 40 mL/min) and eluted with
10−15% MeOH/CH2Cl2 over 2 L (flow rate 30 mL/min). Fractions
containing PEG-ylated material were combined, evaporated, and dried
on a high vacuum overnight to yield PQS-1 (1) as an amber solid
(3.45 g, 1.12 mmol, 86% pure by NMR). Obtained spectral data
matched the previously reported compound.4a
Purification B, Precipitation in Ether. The pale orange oil was
dissolved in a minimal amount of CH2Cl2, a strong stir bar was added,
and under continuous stirring, an excess of Et2O (∼1 L) was added
and if necessary cooled to −20 °C using an NaCl/ice bath. Stirring was
continued for 1 h to yield a white suspension of PEG-ylated material in
Et2O. Because of the fine particle size, all attempts for filtration failed,
and centrifugation was used instead. Unfortunately, the centrifuge used
for this purpose could not be cooled during the centrifugation process,
which led to a significant loss of material. Furthermore, the centrifuge
could only be operated with 6 × 10 mL and was therefore not suited
for scale-up purposes. An analytical sample (∼50 mg) confirmed the
purity of PQS.
EXPERIMENTAL SECTION
■
Materials and Methods. Unless otherwise noted, all reactions
were performed in oven-dried glassware under an atmosphere of
argon. Poly(ethylene glycol) methyl ether (14, MPEG-2000) was
obtained from Aldrich (catalog # 202509). H and 13C spectra were
1
recorded at 22 °C on a 400 or 500 MHz NMR spectrometer.
1
Chemical shifts in H NMR spectra are reported in parts per million
(ppm) on the δ scale from an internal standard of residual chloroform
(7.26 ppm). Data are reported as follows: chemical shift, multiplicity (s
= singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling
constant in hertz (Hz), and integration. Chemical shifts of 13C NMR
spectra are reported in ppm from the central peak of CDCl3 (77.23
ppm) on the δ scale.
Route A:7 Synthesis of Mono-PEGylated Sebacic Acid 10. A
250 mL round-bottom flask containing a strong magnetic stir bar was
charged with poly(ethylene glycol) methyl ether (14, 10.00 g, 5.00
mmol, typical Mn 2000), sebacic acid derivative6 (1.38 g, 7.50 mmol),
4-dimethylaminopyridine (90 mg, 0.75 mmol), and pyridine (25 mL).
After a reflux condenser was attached, the system was purged with
argon and heated to 100 °C in an oil bath for 4 h, whereby all solids
dissolved. After the clear solution was cooled to room temperature, the
reaction mixture was acidified with 1.5 N aq HCl until pH < 7 and
extracted with CH2Cl2 (3×). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, concentrated, and
placed overnight under a high vacuum to give 10 as a white waxy solid
(10.84 g, 4.96 mmol, 99% isolated yield). Alternatively, the product
can be purified by the following procedure: after concentration and
high vacuum (∼1 h), the crude product mixture was dissolved in a
minimal amount of CH2Cl2, a strong stir bar was added, and under
continuous stirring, an excess of Et2O (∼1 L) was added to precipitate
out the product (if necessary, cooling to −20 °C using an NaCl/ice
bath helps the precipitation process). Stirring was continued for 1 h at
−20 °C, and the formed white precipitate was filtered to yield 10 as a
white crystalline solid. Special care needs to be taken during the
filtration step: water has to be excluded, and a glass frit should be used.
A regular empty glass column (4.5 × 30 cm) with frit was used for this
purpose. The cooled suspension was poured into the column, and a
positive pressure of dried argon was applied immediately. The residue
was washed twice with cold Et2O and dried under a stream of argon.
To finally dry the product, the stopcock of the column was closed and
a high vacuum was applied. The product 10 was isolated as a white
crystalline solid.
Route B: Synthesis of Monobenzylated Sebacic Acid 12. A
100 mL round-bottom flask was charged with sebacoyl chloride (10,
8.42 g, 35.2 mmol) and closed with a rubber septum. Et2O (25 mL)
was added, and the solution was cooled to −78 °C. Benzyl alcohol
(2.51 g, 23.2 mmol) and NEt3 (4.9 mL, 35.2 mmol) were added
slowly, the cooling bath was removed, and the reaction was warmed to
rt. After addition of 1 N HCl, the aqueous phase was extracted with
Et2O (3 × 25 mL), and the combined organic layers were washed with
brine, dried, and concentrated in vacuo. The residue was purified by
flash column chromatography on silica gel, eluting with hexanes to 1:1
EtOAc/hexanes gradient to afford monobenzylated sebacic acid 12
(3.90 g, 57%) as a white solid: mp 52−53 °C (recrystallized from
hexanes); IR (thin-film) 2934, 2914, 2849, 1737, 1699, 1463, 1412,
1
1299, 1225, 1194, 1172, 940, 906, 745 cm−1; H NMR (500 MHz,
CDCl3) δ 7.39−7.31 (m, 5H), 5.12 (s, 2H), 2.36 (t, J = 7.0 Hz, 2H),
2.35 (t, J = 7.0 Hz, 2H), 1.67−1.60 (m, 4H), 1.34−1.27 (m, 8H); 13C
NMR (125 MHz, CDCl3) δ 180.0, 173.9, 136.3, 128.7, 128.39, 128.38,
66.3, 34.5, 34.2, 29.22, 29.21, 29.15, 25.1, 24.8; MS (EI) m/z (%) 292
(M, 1), 274 (6), 264 (13), 185 (19), 107 (41), 98 (29), 91 (100);
HRMS (EI) calcd for C17H24O4 [M]+ = 292.1675, found 292.1671.
Synthesis of Benzyl-Protected PEG Sebacic Acid 13.
Monobenzylated sebacic acid 12 (2.00 g, 6.85 mmol) was dissolved
and refluxed in SOCl2 (4 mL). After 3 h, excess SOCl2 was removed
through distillation under reduced pressure. The residue was taken up
in dry CH2Cl2 (6 mL). A solution of poly(ethylene glycol) methyl
ether (14, 6.17 g, 3.08 mmol) and NEt3 (1.0 mL, 6.85 mmol) in dry
CH2Cl2 (6 mL) was added dropwise and stirred overnight at rt. After
addition of 1 N HCl, the aqueous phase was extracted with CH2Cl2 (3
× 20 mL), and the combined organic layers were dried and
concentrated in vacuo. The residue was taken up in a minimal
amount of CH2Cl2, and an excess of ice cold Et2O was added to form a
Synthesis of PQS-1 (1). An oven-dried 50 mL round-bottom flask
(A) containing a magnetic stir bar was charged with MeOPEG sebacic
acid 10 (3.08 g, 1.41 mmol), a reflux condenser was attached, and the
system was purged with argon. Thionyl chloride (5 mL) was added
through the reflux condenser and heated to reflux for 2 h while the
evolving gas was bubbled through water and aq NaOH. The reaction
mixture was cooled to room temperature under argon, and excess
thionyl chloride was taken off using an aspirator. Further drying on a
high vacuum overnight gave a pale orange solid that was dissolved in
dry THF (10 mL, distilled from Na/benzophenone) and used in the
next step without further purification. In a glovebox, an oven-dried 250
mL round-bottom flask (B) was loaded with a strong magnetic stir bar,
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white precipitate. After further cooling for 1 h, the precipitate was
filtered to yield 13 (6.45 g, 92%) as a white solid: IR (thin-film) 3484,
2885, 2740, 2695, 1734, 1469, 1414, 1360, 1344, 1280, 1235, 1147,
1118, 1062, 947, 844 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.36−7.28
(m, 5H), 5.09 (s, 2H), 4.21−4.19 (m, 2H), 3.77−3.46 (m, PEG), 3.36
(s, 3H), 2.33 (t, J = 7.5 Hz, 2H), 2.30 (t, J = 7.5 Hz, 2H), 1.64−1.56
(m, 4H), 1.27 (br s, 8H); 13C NMR (125 MHz, CDCl3) δ 173.9,
173.7, 136.3, 128.7, 128.3, 72.1, 70.75, 70.70, 70.65, 69.3, 66.2, 63.5,
59.2, 34.4, 34.3, 29.2, 25.03, 24.97; MS (ESI) m/2z ∼ 1167 (M +
2Na)+2.
1761, 1738, 1663, 1467, 1360, 1343, 1280, 1242, 1147, 1114, 1062,
964, 843 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.78 (s, 0.3H), 5.74 (s,
0.7H), 5.12−5.06 (m, 9H), 4.98−4.93 (m, 1H), 4.27−4.24 (m, 2H),
3.89 (s, 3H), 3.78 (s, 3H), 3.70−3.44 (m, PEG), 3.37 (s, 3H), 3.31 (d,
J = 6.4 Hz, 1.4H), 3.16 (d, J = 6.4 Hz, 0.6H), 2.94−2.89 (m, 2H),
2.80−2.75 (m, 2H), 2.11−1.96 (m, 39H), 1.74 (s, 2.1H), 1.72 (s,
0.9H), 1.66 (s, 3H), 1.58−1.56 (m, 27H); 13C NMR (100 MHz,
CDCl3) δ 172.04, 171.96, 170.9, 170.7, 145.4, 145.0, 142.1, 141.9,
137.8, 137.6, 135.3, 135.1, 135.0, 134.9, 134.8, 131.1, 128.4, 124.9,
124.4, 124.2, 124.1, 124.0, 121.9, 121.6, 117.9, 71.9−69.0 (m, PEG),
63.9, 60.9, 60.8, 60.6, 60.5, 59.0, 39.7, 29.0, 28.8, 28.7, 26.7, 26.6, 26.0,
25.7, 25.3, 17.7, 16.3, 16.2, 16.0, 12.0, 11.3; MS (ESI) m/4z ∼ 763 (M
+ 4Na)+4.
Synthesis of Mono-PEGylated Sebacic Acid 10. A round-
bottom flask was charged with 13 (6.41 g, 2.82 mmol) and Pd/C (0.60
g, 0.28 mmol, 5% Pd/C, Fluka) and closed with a rubber septum.
MeOH (30 mL) was added, and an atmosphere of H2 was provided
(balloon). After stirring overnight, the reaction was filtered through
Celite, washed with MeOH, and concentrated in vacuo. The residue
was taken up in a minimal amount of CH2Cl2, and an excess of ice cold
Et2O was added to form a white precipitate. After further cooling for 1
h, the precipitate was filtered to afford 10 (6.05 g, 98%) as a white
solid: IR (thin-film) 3527, 2887, 1735, 1639, 1467, 1346, 1281, 1243,
Synthesis of Carbene Precursor 18. 3 (0.50 g, 0.17 mmol) was
dissolved in CH2Cl2 (2.2 mL) and cooled to 0 °C. 1-(p-Isopropoxy-m-
vinylphenyl)propionic acid (17)11 (0.05 g, 0.22 mmol), 1-(3-
dimethylaminopropyl)-3-ethyl carbodiimide (EDCI) (0.04 g, 0.26
mmol), and DMAP (0.008 g, 0.07 mmol) were then directly added in
succession to the mixture as solids. Et3N (0.04 mL, 0.30 mmol) was
added through a syringe. The resulting mixture was stirred at 22 °C for
20 h. Water was added to the reaction mixture and extracted with
CH2Cl2. The combined organic layers were washed with saturated
NaHCO3, water, and brine, dried, and concentrated in vacuo, affording
a colorless liquid, which was purified by flash column chromatography
on silica gel, eluting with Et2O, followed by CH2Cl2 to 1:12 MeOH/
CH2Cl2 gradient, affording the compound 18 (0.45 g, 85%, mixture of
two regioisomers) as a white foam: IR (thin-film) 2885, 1765, 1737,
1
1148, 948, 843 cm−1; H NMR (500 MHz, CDCl3) δ 4.24−4.21 (m,
2H), 3.79−3.48 (m, PEG), 3.38 (s, 3H), 2.33 (t, J = 7.5 Hz, 2H), 2.30
(t, J = 7.5 Hz, 2H), 1.64−1.58 (m, 4H), 1.31 (br s, 8H); 13C NMR
(125 MHz, CDCl3) δ 175.8, 173.5, 71.7−69.0 (m, PEG), 63.1, 58.8,
33.9, 33.7, 28.87, 28.84, 28.79, 24.6; MS (ESI) m/2z ∼ 1122 (M +
2Na)+2.
Route C: Synthesis of Mono-PEGylated Succinic Acid 15. To
a solution of poly(ethylene glycol) monomethyl ether-2000 (14, 15.00
g, 7.50 mmol) and succinic anhydride (1.50 g, 15.00 mmol) in toluene
(7.5 mL), Et3N (0.53 mL, 3.75 mmol) was added at rt with stirring,
and the stirring was continued at 60 °C for 8 h. Water was added to
the reaction mixture and extracted with CH2Cl2. The combined
organic layers were washed with 1 N HCl (3 × 50 mL) and brine (2 ×
30 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to
afford the poly(ethylene glycol) monomethyl ether-2000 succinate 15
(15.6 g, 99%) as a white solid: IR (thin-film) 3512, 2874, 1734, 1647,
1
1467, 1360, 1344, 1280, 1242, 1147, 1113, 1061, 963, 843 cm−1; H
NMR (400 MHz, CDCl3) δ 7.39−7.37 (m, 1H), 7.12−7.08 (m, 1H),
7.03 (dd, J = 18.0, 11.2 Hz, 1H), 6.84−6.81 (m, 1H), 5.74 (dt, J =
18.0, 1.6 Hz, 1H), 5.23 (d, J = 11.2 Hz, 1H), 5.13−5.06 (m, 9H),
4.97−4.94 (m, 1H), 4.50 (sep, J = 6.4 Hz, 1H), 4.28−4.25 (m, 2H),
3.80 (s, 3H), 3.74 (s, 3H), 3.72−3.45 (m, PEG), 3.38 (s, 3H), 3.19−
3.14 (m, 2H), 3.06−3.00 (m, 2H), 2.97−2.87 (m, 4H), 2.82−2.76 (m,
2H), 2.10−1.94 (m, 39H), 1.72−1.58 (m, 33H), 1.34 (d, J = 6.4 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ 171.0, 170.9, 169.9, 169.7,
169.4, 169.3, 152.9, 142.7, 142.5, 139.9, 139.8, 139.6, 139.5, 134.6,
134.0, 133.8, 131.4, 131.1, 130.1, 127.8, 127.4, 127.0, 125.6, 125.57,
124.0, 123.9, 123.6, 123.5, 123.2, 120.7, 113.8, 113.7, 113.1, 71.2,
70.9−69.3 (m, PEG), 68.2, 63.1, 59.8, 59.6, 58.1, 39.0, 38.9, 34.9, 29.4,
28.2, 28.1, 26.1, 25.9, 25.5, 25.0, 21.5, 17.0, 15.6, 15.4, 11.4, 11.3; MS
(ESI) m/4z ∼ 839 (M + 4Na)+4.
1
1468, 1349, 1284, 1250, 1109, 949, 844 cm−1; H NMR (400 MHz,
CDCl3) δ 4.28−4.25 (m, 2H), 3.83−3.46 (m, PEG), 3.38 (s, 3H),
2.69−2.61 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 173.1, 171.7,
71.4−68.5 (m, PEG), 63.2, 58.5, 28.6, 28.2; MS (ESI) m/4z ∼ 551 (M
+ 4Na)+4.
Synthesis of Activated PEGylated Succinic Acid 16. Poly-
(ethylene glycol) monomethyl ether-2000 succinate 15 (2.10 g, 1.00
mmol) was dissolved in CH2Cl2 (10 mL) and cooled to 0 °C. N-
Hydroxysuccinimide (0.14 g, 1.20 mmol) and 1-(3-dimethylamino-
propyl)-3-ethyl carbodiimide (EDCI, 0.25 g, 1.30 mmol) were then
directly added in succession to the mixture as solids. The resulting
mixture was stirred at rt for 12 h. Water was added to the reaction
mixture and extracted with CH2Cl2. The combined organic layers were
washed with water and brine, dried, and concentrated in vacuo to
afford 16 (2.17 g, 99%) as a white waxy solid: IR (thin-film) 2883,
1814, 1784, 1739, 1645, 1468, 1360, 1280, 1234, 1205, 1147, 1116,
Synthesis of PQS-3-GH1 Catalyst (6). 18 (0.44 g, 0.137 mmol)
was weighed into a 25 mL round-bottom flask and dissolved in 6.5 mL
of CH2Cl2. (PCy3)2Cl2RuCHPh (0.14 g, 0.17 mmol) and CuCl
(0.018 g, 0.18 mmol) were added directly to this solution as solids.
The mixture was stirred for a period of 4 h at 22 °C, during which time
the original purple solution turned dark brown. The following workup
procedures were conducted in air with reagent-grade solvents. The
mixture was concentrated at reduced pressure and passed through a
short column of silica gel eluting with CH2Cl2 followed by Et2O.
Finally, the column was flushed with 8% MeOH/CH2Cl2, at which
point the product eluted (brown band). Solvent removal afforded the
catalyst 6 (0.49 g, 98%, mixture of two regioisomers) as dark brown
foam: IR (thin-film) 2883, 1764, 1737, 1644, 1468, 1449, 1359, 1344,
1
1062, 947, 843 cm−1; H NMR (400 MHz, CDCl3) δ 4.29−4.27 (m,
2H), 3.83−3.46 (m, PEG), 3.38 (s, 3H), 2.97 (t, J = 7.2 Hz, 2H), 2.84
(br s, 4H), 2.79 (t, J = 7.2 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ
170.9, 168.9, 167.6, 71.8−68.8 (m, PEG), 64.1, 59.0, 28.6, 26.2, 25.5;
MS (ESI) m/4z ∼ 576 (M + 4Na)+4.
1
1280, 1234, 1146, 1113, 1061, 946, 843 cm−1; H NMR (400 MHz,
CDCl3) δ 17.40 (d, JPH = 4.4 Hz, 1H), 7.60−7.58 (m, 1H), 7.56−7.52
(m, 1H), 7.02−7.00 (m, 1H), 5.25 (sep, J = 6.4 Hz, 1H), 5.13−5.10
(m, 9H), 5.00−4.95 (m, 1H), 4.29−4.25 (m, 2H), 3.80 (s, 3H), 3.75
(s, 3H), 3.70−3.47 (m, PEG), 3.38 (s, 3H), 3.22−3.16 (m, 2H), 2.97−
2.87 (m, 4H), 2.82−2.76 (m, 2H), 2.36−2.28 (m, 2H), 2.10−1.98 (m,
39H), 1.81−1.58 (m, 66H), 1.42−1.24 (m, 6H); 13C NMR (200
MHz, CDCl3) δ 279.1, 171.95, 171.86, 170.8, 170.7, 170.3, 170.2,
151.5, 144.0, 143.4, 143.3, 143.2, 140.6, 140.4, 140.3, 135.8, 135.1,
134.8, 134.43, 134.39, 131.1, 129.45, 129.37, 128.4, 128.3, 125.0,
124.9, 124.4, 124.2, 124.0, 123.9, 122.5, 121.1, 116.0, 113.3, 75.5, 71.9,
70.5−69.0 (m, PEG), 63.90, 63.87, 60.6, 59.0, 39.7, 39.6, 35.9, 35.8,
35.7, 35.6, 31.7, 30.1, 29.7, 29.0, 28.8, 28.7, 27.74, 27.7, 26.9, 26.7,
26.67, 26.64, 26.3, 26.24, 26.16, 26.1, 25.7, 22.1, 22.0, 17.7, 16.34, 16.3,
16.0, 12.1; MS (ESI) m/4z ∼ 927 (M + 4Na)+4.
Synthesis of PQS-3 (3). NaH (0.026 g, 0.65 mmol, 60%
suspension in mineral oil) was added to a stirred solution of ubiquinol
(0.52 g, 0.60 mmol) in THF (5.0 mL) at 0 °C. After addition, the
reaction mixture was stirred at 22 °C for 1 h. A solution of 16 (1.10 g,
0.50 mmol) in THF (5.0 mL) was added to the mixture at 0 °C, and
the stirring was continued for 30 min. The mixture was then stirred for
another 8 h at rt. It was then cooled to 0 °C, and saturated aqueous
NH4Cl was added and then extracted with CH2Cl2. The combined
organic layers were washed with water and brine, dried, and
concentrated in vacuo, affording a yellowish liquid, which was purified
by flash column chromatography on silica gel eluting with a CH2Cl2 to
1:19 MeOH/CH2Cl2 gradient to afford 3 (0.95 g, 65%, mixture of two
regioisomers) as a white waxy solid: IR (thin-film) 3518, 2885, 2740,
3147
dx.doi.org/10.1021/jo202564b | J. Org. Chem. 2012, 77, 3143−3148

The Journal of Organic Chemistry
Article
N-Benzoyl-3-pyrroline (20). Diene 19 (20 mg, 0.10 mmol) and
catalyst 6 (7.5 mg, 0.002 mmol) were both added into a Teflon-coated
stir-bar-containing Biotage 2−5 mL microwave reactor vial at room
temperature and sealed with a septum. H2O (1.0 mL) was added via
syringe, and the resulting solution was allowed to stir at rt for 4 h. The
homogeneous reaction mixture was then diluted with EtOAc (2 mL)
and filtered through a bed of silica gel layered over Celite, and the bed
was further washed (2 × 4 mL) with EtOAc to collect all of the
cyclized material. The volatiles were removed in vacuo to afford the
crude product, which was subsequently purified by flash chromatog-
raphy using silica gel (40% EtOAc/hexanes) to afford the title
compound 20 as a colorless liquid (17 mg, 96%). The 1H NMR
spectral data obtained was in accord with data previously reported for
this compound.4a
Soluble Ubiquinone Compositions, Prodrugs, and Methods Relating
Thereto. PCT 1996; CAN 125:123707.
(10) Reactions were performed between 0.25 and 2.2 mmol scales,
with consistently good overall yields above 60% in all cases.
(11) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168−8179.
ASSOCIATED CONTENT
■
S
* Supporting Information
A detailed comparison of route A vs B and spectral data,
including copies of 1H and 13C NMR spectra of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: lipshutz@chem.ucsb.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support provided by the NIH (GM 86485) is warmly
acknowledged.
■
REFERENCES
■
(1) For biphasic catalysis, see: Cornils, B., Herrmann, W. A., Eds.;
Aqueous Phase Organometallic Catalysis  Concepts and Applications;
Wiley-VCH: Weinheim, Germany, 1998.
(2) For industrial importance of biphasic catalysis, see: (a) Cornils,
B.; Herrmann, W. A.; Eckl, R. W. Industrial Aspects of Aqueous
Catalysis. J. Mol. Catal. A: Chem. 1997, 116, 27−33. (b) Cornils, B.
Bulk and Fine Chemicals via Aqueous Biphasic Catalysis. J. Mol. Catal.
́
A: Chem. 1999, 143, 1−10. (c) Horvath, I. T., Joo, F., Eds.; Aqueous
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Catalysis: Status and Directions. Org. Process Res. Dev. 1998, 2,
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(3) (a) Lipshutz, B. H.; Ghorai, S. Aldrichimica Acta 2008, 41, 59−72.
(b) Lipshutz, B. H.; Abela, A. R.; Boskovic, Z. V.; Nishikata, T.;
Duplais, C.; Krasovskiy, A. Top. Catal. 2010, 53, 985−990.
(c) Lipshutz, B. H.; Ghorai, S.; Abela, A. R.; Moser, R.; Nishikata,
T.; Duplais, C.; Krasovskiy, A.; Gaston, R. D.; Gadwood, R. J. Org.
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Angew. Chem., Int. Ed. 2005, 44, 7174−7199 and references therein.
(4) (a) Lipshutz, B. H.; Ghorai, S. Org. Lett. 2009, 11, 705−708.
(b) Lipshutz, B. H.; Ghorai, S. Tetrahedron 2010, 66, 1057−1063.
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(6) For a similar procedure, see: Rath, P.; Gomez-Orellana, M. I.;
Vuocolo, E. A. Aryl Ketone Compounds and Compositions for
Delivering Active Agents. U.S. Patent WO/2005/117854, Dec 15,
2005.
(7) For a detailed comparison of the quality of PQS-1 obtained
through route A or B, see the Supporting Information.
(8) PQS is usually obtained as a mixture of regioisomers: PQS-1 (1,
Route A) 2:1; PQS-1 (1, Route B) 2:1; PQS-3 (3, Route C) 3:1.
(9) Obtained through Zn/HOAc reduction of coenzyme Q10; for
procedure, see: Morgan, A. C.; Graves, S. S.; Woodhouse, C. S.;
Sikorska, M.; Walker, R.; Wilbur, D. S.; Borowy-Borowski, H. Water
3148
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