Rhodium-catalyzed asymmetric 1,4-additions, in water at room temperature, with in-flask catalyst recycling

Article abstract of DOI:10.1002/adsc.201200160

Using the newly introduced designer surfactant polyethylene glycol ubiquinol sebacate (PQS), as the platform for micellar catalysis, non-racemic BINAP has been covalently attached and rhodium(I) inserted to form PQS-BINAP-Rh. This species, the first examp

Full text of DOI:10.1002/adsc.201200160

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DOI: 10.1002/adsc.201200160
Rhodium-Catalyzed Asymmetric 1,4-Additions, in Water at Room
Temperature, with In-Flask Catalyst Recycling
Bruce H. Lipshutz,a,* Nicholas A. Isley,a Ralph Moser,a Subir Ghorai,a
Helena Leuser,a and Benjamin R. Tafta
a
Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106, USA
Fax : (+1)-805-893-8265; e-mail: lipshutz@chem.ucsb.edu
Received: February 25, 2012; Revised: July 3, 2012; Published online: July 29, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200160.
Abstract: Using the newly introduced designer sur-
factant polyethylene glycol ubiquinol sebacate
(PQS), as the platform for micellar catalysis, non-
racemic BINAP has been covalently attached and
rhodium(I) inserted to form PQS-BINAP-Rh. This
species, the first example of a non-racemically-ligat-
ed transition metal catalyst-tethered amphiphile,
can be utilized for Rh-catalyzed asymmetric conju-
gate addition reactions of arylboronic acids to acy-
clic and cyclic enones. These are performed in
water at room temperature, while the catalyst can
be recycled without its removal from water in the
reaction vessel.
Since this platform is derived from a hydroquinone,
one hydroxy moiety remains available for further de-
rivatization. Previously, we have described opportuni-
ties to covalently attach both Grubbs–Hoveyda-1[5]
and -2[6] ruthenium carbene catalysts, thereby leading
to olefin metathesis reactions within these aqueous
nanomicelles. Likewise, we recently disclosed a strat-
egy for effecting organocatalysis in water at room
temperature using the related PQS-containing pro-
line,[7] which serves as both the reaction medium and
catalyst. In each type of chemistry, the amphiphile
was designed to remain in the water; extraction with
minimal organic solvent (e.g., EtOAc) leads to subse-
quent product isolation without loss of catalyst from
the reaction vessel; i.e., the catalyst remains in the
aqueous phase within the flask ready for recycling.
An important, alternative application of PQS tech-
nology yet to be documented focuses on asymmetric
catalysis. In this regard, we are now pleased to report
the first example of a recyclable, amphiphile-bound,
non-racemic transition metal catalyst that functions in
water at room temperature. Given the rich history of
BINAP in asymmetric catalysis,[8] this ligand was se-
Keywords: 1,4-additions; catalyst recycling; chemis-
try in water; green chemistry; homogeneous cataly-
sis; in-flask recycling; micellar catalysis; polyethy-
lene glycol ubiquinol sebacate (PQS); rhodium-cat-
alyzed 1,4-additions
The chemical enterprise is rapidly gaining an aware- lected as a “proof of principle” example for covalent
ness of, and an appreciation for, the 12 Principles of attachment to the PQS skeleton 2 in the form of cata-
Green Chemistry[1] as guidelines in the design of new lyst 1. Complexation of non-racemic BINAP to rho-
chemical processes. One component highlights cataly- dium(I) is well known from the work of Miyaura,[9]
sis, and implied in this context is the highly desirable Hayashi,[10] and Carreira[11] to mediate 1,4-addition re-
feature of catalyst recycling.[2a] Another important actions of arylboronic acids to enones with high levels
component of green chemistry is the use of “safer sol- of enantiocontrol.[12,13] Catalyst 1 was prepared via
vents”, ideally being “innocuous when used.” Thirdly, (R)-BINAP derivative 4 by esterification of PQS with
“safer chemicals” of minimal toxicity should be uti- known BINAP acid 3 (Scheme 1).[14] Subsequent addi-
lized, while maintaining functionality. Based on these tion of [RhACTHNUGRTNEUNG(nbd)2]BF4 to 4 leads to complex 1, which
key teachings, a new amphiphile, polyethylene glycol readily dissolves and self-assembles in water forming
ubiquinol sebacate (PQS, 2; Scheme 1), was construct- 43 nm nanomicelles as shown by dynamic light scat-
ed[3] derived from the reduced form of readily avail- tering.[15] As illustrated in Figure 1, water-soluble,
able coenzyme Q10; i.e., ubiquinol.[4] This species un- highly colored catalyst 1 is untouched upon attempted
dergoes spontaneous self-aggregation in water, with extraction into solvents such as Et2O.
the resulting nanomicelles enabling homogeneous cat-
Conditions most amenable to micellar catalysis
alysis within their lipophilic hydrocarbon cores.[2b] using the model system 2-cyclohexenone and
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Scheme 1. Synthesis of PQS-BINAP-Rh (1).
PhB(OH)2 focused on the selection of the base, which
can be a major factor in such Rh-catalyzed conjugate
additions.[16] On the one hand, use of KOH would be
expected to accelerate both the transmetalation event
from an ate salt of the boronic acid, as well as arrive
at a more reactive RhOH-containing species.[17] Un-
fortunately, given the diester nature of the PQS plat-
form, presumed saponification of PQS led to little-to-
none of the desired 1,4-adduct (Table 1, entry 1).
While Hꢁnigꢂs base was far more effective (entry 2),
Et3N (3.0 equiv.) provided the best balance of basicity
and lipophilicity, leading to the product of 1,4-addi-
tion in 95% yield and >99% ee (entry 3), results that
compare quite favorably with those using alternative
ligand and catalyst arrays.[18,19] Only three mole per-
cent of the catalyst PQS-BINAP-Rh (1) is needed,
and that only 1.2 equivalents of boronic acid suffice
may reflect the high concentrations of reactants nor-
mally present within the limited amounts of surfactant
in the aqueous medium.[20b] Less base (entry 4) led to
essentially no reaction. While dilution of the reaction
by an equal volume had little impact (entry 5), drop-
Figure 1. Aqueous solution of PQS-BINAP-Rh complex 1 in
water in the presence of Et2O.
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Rhodium-Catalyzed Asymmetric 1,4-Additions, in Water at Room Temperature
Table 1. Screening for the optimal base.[a]
Figure 2. Comparisons with literature results.
case of ortho-methylboronic acid reacted smoothly as
well, affording the conjugate adduct in close to 98%
ee. Furthermore, asymmetric additions of phenylbor-
onic acid to five- and seven-membered cyclic enones
were both quite successful, affording good yields with
excellent levels of asymmetric induction.
Comparison cases with literature examples using
the identical catalyst, albeit in organic media, docu-
ment the potential improvements that may be realiz-
ed, perhaps in a general sense, based on the hydro-
phobic effect.[20] Thus, examples in both the 2-cyclo-
hexenone and 2-cycloheptenone series afford yields
and ees of conjugate adducts that are comparable to,
or better than, those previously described (Figure 2).
The inherent water solubility of PQS-BINAP-Rh is
conducive to in-flask catalyst recycling. Hence, upon
[a]
General procedure: 0.20 mmol cyclohexenone, 0.24 mmol
PhB(OH)2, 0.006 mmol PQS-BINAP-Rh, 0.60 mmol
base, and 0.4 mL H2O (0.5M).
Yield of isolated product.
Determined by HPLC on a chiral stationary phase.
0.5 equiv. of base.
[b]
[c]
[d]
[e]
[f]
Reaction run in 0.8 mL H2O (0.25M).
1 mol% of PQS-BINAP-Rh.
ping the catalyst loading from three to one percent
slowed the 1,4-addition considerably (entry 6).
Representative examples of both cyclic and acyclic completion of the 1,4-addition, the product was ex-
enones are illustrated in Scheme 2. Arylboronic acids tracted from the reaction mixture with a single, suita-
bearing either electron-donating or electron-with- ble organic solvent (e.g., EtOAc). Re-introduction of
drawing groups participated in good to high yields fresh substrate, base, and boronic acid only (i.e., no
with excellent enantioselectivities. The more hindered additional catalyst, solvent, or co-solvent) resulted in
product, likewise, of excellent enantioselectivity, as
well as in good isolated yield (Scheme 3). Different
substrates could be used, added to the same reaction
mixture sequentially, and in each case the anticipated
product was obtained. While the integrity of the PQS-
BINAP-Rh system appears to remain intact judging
from the consistently high ees obtained, the extent of
conversion, and hence, isolated yield from cycle 4 was
only 50%. This suggests that the PQS-BINAP-Rh cat-
alyst may have a fundamentally limited lifetime under
such conditions, or perhaps eventual oxidation of the
phosphines is responsible for this drop in activity.
Since the starting enone could be easily recovered
from the reaction mixture, it was initially thought that
potential build-up of boronic acid(s) might be hinder-
ing reactivity. However, a control experiment con-
ducted in the presence of three equivalents of boronic
acid (rather than the usual 1.2 equivalents) had no in-
fluence on reaction rate.
Tests for loss of metal from catalyst 1 were conduct-
ed to assess the level of anticipated bleed under our
micellar catalysis conditions, an important factor for
future applications to the potential syntheses of phar-
Scheme 2. Representative examples using PQS-BINAP-Rh
as the catalyst for 1,4-addition reactions.
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Scheme 3. In-flask recycling of aqueous PQS-BINAP-Rh (1).
macologically active targets. Analysis of the toluene/ 0.6 mmol) were added to the vial and stirred for
Et2O extract containing the desired 1,4-addition 15 min. When the solution became homogeneous,
adduct by induced coupled plasma mass spectrometry enone (0.2 mmol) was added via syringe and the mix-
(ICP-MS) revealed that each extract contained rhodi- ture was stirred at room temperature for 12 h. The
um in a range of 1–40 ppb, with an average of 17 ppb homogeneous reaction mixture was then diluted with
(see Supporting Information). Thus, over four recycles EtOAc (0.5 mL), filtered through a bed of silica gel,
essentially none of the metal was lost in work-up, su- and the bed further washed (3ꢃ2 mL) with EtOAc to
gesting that the decrease in catalyst activity is due to collect all of the coupled material. The volatiles were
factors other than removal of 1 from the reaction removed under vacuum to afford the crude product
mixture (e.g., ligand oxidation).
which was subsequently purified by flash chromatog-
In summary, a new catalyst system, PQS-BINAP- raphy on silica gel using EtOAc/hexanes.
Rh, has been constructed that enables homogeneous
catalysis in the form of asymmetric conjugate addi-
tions of arylboronic acids to enones to be conducted
in water at ambient temperatures. Yields are high
Acknowledgements
given the mild reaction conditions, and the extent of Financial support provided by the NIH (GM 86485) is
warmly acknowledged with thanks. Additionally, we ac-
knowledge Sean Duncan of Scripps Institute of Oceanogra-
phy for his ICP analytical work. Lastly, Wendy Leong is
thanked for her assistance in synthesizing the PQS-BINAP-
Rh used to complete the presented work.
enantiocontrol is found to be comparable to that pre-
viously seen for related methodologies. No organic
solvents are needed as reaction media, and neither
heating nor cooling is required, a phenomenon that
takes advantage of the high concentrations associated
with the micellar effect.[20b] Most noteworthy is the
opportunity to recycle the water-soluble, covalently
bound catalyst without its removal from the reaction
flask. Finally, this study should highlight the many al-
ternatives available for attaching and thereby recy-
cling other ligand arrays to the PQS platform, espe-
cially those that are lengthy to prepare, and that ulti-
mately involve an investment in precious metals.
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