Asymmetric epoxidation, Michael addition, and triple cascade reaction using polymer-supported prolinol-based auxiliaries

Article abstract of DOI:10.1016/j.tet.2008.08.013

The applicability of polymer-supported diphenylprolinol derivatives in directing either asymmetric epoxidation or Michael addition of suitable α,β-unsaturated substrates has been assessed. Epoxidation of cinnamaldehyde in the solid state give poorer yield

Full text of DOI:10.1016/j.tet.2008.08.013

Tetrahedron 64 (2008) 10087–10090
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric epoxidation, Michael addition, and triple cascade reaction using
polymer-supported prolinol-based auxiliaries
,
Michael C. Varela a, Seth M. Dixon b, Kit S. Lam b, Neil E. Schore a
*
a Department of Chemistry, University of California, One Shields Avenue, Davis, CA 95616, United States
b Division of Hematology and Oncology, UC Davis Cancer Center, 4501 X Street, Sacramento, CA 95817, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The applicability of polymer-supported diphenylprolinol derivatives in directing either asymmetric ep-
Received 1 July 2008
Accepted 6 August 2008
Available online 9 August 2008
oxidation or Michael addition of suitable a,b-unsaturated substrates has been assessed. Epoxidation of
cinnamaldehyde in the solid state give poorer yields and stereoselectivities than in the solution-phase
systems. In contrast Michael additions of several aldehyde enolates to 2-nitro-1-arylalkenes gave results
that approached or surpassed those in solution, and could be extended successfully to a three-compo-
nent Michael/Michael/aldol cascade process. Comparisons of the results of pendant- versus crosslinked
functionalized resins in these applications were revealing of the benefits and limitations of each, as were
attempts to reuse the polymer-bound auxiliaries.
Keywords:
Crosslinking monomer
Diphenylprolinol
Enantioselective epoxidation
Enantioselective Michael addition
Triple cascade reaction
Polymer beads
Ó 2008 Published by Elsevier Ltd.
1. Introduction
interact with species in the solid phase, a process that can be dif-
fusionally slowcompared with interactions in solution. Thus there is
Asymmetric epoxidations and C–C bond forming reactions are
cornerstones of modern synthetic methodology. Methods utilizing
solution and solid-phase titanium, manganese, and copper com-
plexes have led the way in the synthesis of enantiopure epoxides.1–4
Asymmetric epoxidations on a wide range of compounds have
also been performed using organocatalysts such as TMS-protected
diphenylprolinol, 1.5,6 Carried out with relative ease and under
environmentally friendly conditions, these epoxidations give
products in high yields and enantiopurities. Enantioselective Mi-
chael additions have similarly been carried out with considerable
success using the same proline-based system.7 In considering solid-
state conditions that might permit recycling and reuse of reaction
catalysts, we chose to examine these processes using polystyrene-
based polymer-supported crosslink- and pendant-bound TMS-
protected diarylprolinols 2 and 3, respectively (the shaded circles
represent linkages to a polystyrene backbone).8,9
a possibility of interference by unselective side reactions in solution
whose rates are too slow to compromise pure solution-phase sys-
tems but fast enough to compete against similar processes that in-
volve a solid-state component. Our previous results comparing
oxaborolidines related to 1–3 (‘CBS’-type catalysts) in asymmetric
aldehyde reductions8,9 showed that background reactions do indeed
play an important role in processes involving solid-phase catalysts.
Our goals in this study, therefore, were to ascertain the advantages
and disadvantages of the two polymer systems compared with so-
lution phase in minimizing the effect of deleterious side reactions
and optimizing these processes with regard to yield and selectivity.
i
Ph
Ph
p-Pr-Ph
OTMS
OTMS
OTMS
NH
NH
NH
The most significant potential benefits of a solid-phase system
are ease of product separation and purification, and ability to reuse
the chiral species that facilitate the transformation. In practice,
however, many solid-phase systems simply do not perform as well
in either yield or selectivity as their solution-phase counterparts.
Heterogeneous catalysis depends on the ability of reagents to
1
2
3
2. Results and discussion
2.1. Solution-phase asymmetric epoxidation
Prior to working in the solid state, we examined modifications of
the reported solution-phase experiments6 to identify solvent
* Corresponding author. Tel.: þ1 530 752 6263; fax: þ1 530 754 7610.
E-mail address: neschore@chem.ucdavis.edu (N.E. Schore).
0040-4020/$ – see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tet.2008.08.013

10088
M.C. Varela et al. / Tetrahedron 64 (2008) 10087–10090
systems that would best suit solid-phase experiments (Eq. 1). A
solution of catalyst 1 (0.025 mmol, 10 mol %), derived from the
reaction of diphenylprolinol with trimethylsilyl trifluoromethane-
sulfonate (TMS-OTf), was prepared in 2 mL of a variety of typical
Merrifield resin swelling solvents. Once the catalyst was completely
dissolved, 0.3 mmol of aqueous H2O2 and 0.25 mmol trans-cinna-
maldehyde were added and the mixtures stirred vigorously for 4
days. No significant product formation was observed using CH2Cl2
(DCM), CHCl3, benzene, or toluene. In THF a 64% conversion to the
epoxide was observed, and use of a 1:1 ethanol/DCM mixture gave
83% conversion to the epoxide in 24 h, suggesting that inefficient
mixing was responsible for the lack of conversion in less polar
media. On the basis of these and other results we therefore chose
THF and 1:1 EtOH/DCM as solvent systems for initial solid-state
experiments.
solvent for Merrifield type resins.7 Thus for our preliminary solu-
tion-phase studies we added propionaldehyde and trans- -nitro-
styrene to a solution of 1 (5 mol %) in 2 mL of benzene, a superior
swelling solvent. After agitation at 25 ꢀC for 2 days an 88:12 syn/
b
anti diastereomer mixture of the g-nitroaldehyde Michael adduct
was obtained in 85% yield and 99% ee, nearly the same results as
reported in hexane (Eq. 2).7
O
NO2
10 mol% 1
O
ð2Þ
+
H
benzene, 2d, rt
NO2
H
2.4. Solid-phase asymmetric Michael addition and triple
cascade reaction
O
O
O
Based upon these results we proceeded to examine chiral Mi-
chael additions in benzene using 2 and 3.8,9 At the time we started
this work there were reports of asymmetric Michael additions us-
ing solid-phase auxiliaries, but these resulted in generally poor to
mediocre enantioselectivies.10
10 mol% 1
ð1Þ
H
H
1:1 H2O2/H2O, 24 h
Beads of resins 2 and 3 were swollen in minimum quantities of
benzene followed by addition of the aldehyde and nitrostyrene. The
reactions were allowed to proceed for 4 days followed by filtration,
acidic workup, and drying. Results are summarized in Table 1 (ee
values are corrected for the enantiopurities of the monomeric
precursors to 2 and 3). Both 2 and 3 do well, affording results quite
comparable to those obtained in solution with 1.
Given the slightly superior performance of 2, we proceeded to
examine several combinations of enolates and nitroalkenes using
this polymer-supported catalyst. Initial attempts at room temper-
ature with more sterically demanding aldehydes gave lower yields
and selectivities. However, reducing the reaction temperature to
5 ꢀC and using a hexane/benzene mixture as solvent gave quite
good results. Slightly reduced enantioselectivities were observed in
additions of propionaldehyde to p-substituted nitrostyrenes, but
isolated chemical yields were consistently good and syn/anti se-
lectivity exceeded that observed in solution in all cases (see Eq. 3
and Table 2).
2.2. Solid-phase asymmetric epoxidation
Crosslink-functionalized polymer 2 and pendant-functionalized
polymer 3 were prepared by reaction of beads of the polymeric
aminoalcohol precursors8 with TMS-OTf in DCM at 0 ꢀC in the
presence of triethylamine (TEA). Polymer 2 was then swollen in
a 1:1 DCM/EtOH mixture followed by addition of trans-cinna-
maldehyde and 50% aqueous H2O2. After 7 days of agitation, we
found less than 5% conversion to product. Suspecting that the poor
yield was a result of inefficient imine formation, we repeated the
experiment by adding trimethylorthoformate (TMOF), which is
known to promote imine formation on solid phase by removing
water and shifting the equilibrium to product.11 Surprisingly, no
improvement in conversion was observed.
Returning to THF as the next-most promising medium for solid-
state chemistry, we found that solution-phase reactions using 1 in
1:1 THF/TMOF and TMOF as solvents gave 84% and 99% conversion
to the epoxide, respectively. In the solid state, using TMOF as the
solvent with crosslink-functionalized polymer 2, conversion over
the course of 72 h improved to 22% but still fell considerably short
R2
NO2
of solution-phase results. However, ‘seeding’ the resin with the a,b-
O
unsaturated aldehyde for 24 h prior to addition of the acid showed
promise. Using this technique, after 72 h we observed conversions
of 54% with 2. GC analysis of the epoxide showed 85% enantiomeric
excess (ee) and 60:40 trans/cis diastereomeric ratio (dr). Pendant-
functionalized polymer 3 gave 28% conversion and 84% ee with
a 57:43 dr. Taking into account the enantiopurities of the mono-
mers used in the preparation of these resinsd90% for 2 and 88% for
39dthe intrinsic ee values produced by these systems are 94% for 2
and 95% for 3. These results may be compared with the comparable
solution phase outcome using S-1 in TMOF: 99% conversion, 99% ee,
and an 81:19 dr. It is difficult to draw any mechanistic conclusions
from these data, given the fact that the same reaction in solution
gives wildly differing yields and stereochemical outcomes with
even minor alterations in solvent or catalyst structure.6
ð3Þ
10 mol% 2
O
+
H
1:1 hexane:benzene
7d, 5 °C
NO2
H
R1
R1
R2
In 2006, Enders and co-workers described a TMS-protected
prolinol-catalyzed three-component Michael/Michael/aldol cas-
cade reaction that affords tetrasubstituted cyclo-
hexenecarbaldehydes in modest yield but with excellent
stereocontrol.12 In as much as Enders’ reaction conditions closely
resembled those of the simpler Michael processes described above,
we thought it would be instructive to try to replicate this cascade
process in the solid state. The prototype system is shown in Eq. 4.
The components are propionaldehyde, trans-
cinnamaldehyde; the catalyst is again
diarylprolinol.
b
a
-nitrostyrene, and
TMS-protected
2.3. Solution-phase asymmetric Michael addition
Table 1
In contrast to the imine-based mechanism for epoxidation,
Michael additions catalyzed by secondary amines proceed via en-
amine intermediates, whose formation and reactivity might be
affected differently in the relatively low-polarity interior of a poly-
styrene matrix. The reported solution-phase asymmetric Michael
additions using 1 were carried out in hexane, a poor swelling
Michael additions of propionaldehyde to trans-b-nitrostyrene in benzene
Catalyst
ee
syn/anti
Isolated yield (%)
1
2
3
99
99
99
88:12
98:2
94:6
85
87
83

M.C. Varela et al. / Tetrahedron 64 (2008) 10087–10090
10089
Table 2
analysis showed its decomposition to multiple uncharacterized
aromatic products and free methylated silane material, including
hexamethyldisiloxane. Similarly, resin-bound moieties 2 and 3 re-
leased methylsilanes during use. On this basis, before reuse we
treated the resin as though it had undergone partial deprotection.
We completed the deprotection by washing with acid and then
with base, and then carefully reprotected the alcohol. This pro-
cedure afforded resins that catalyzed additional Michael addition of
Michael additions using resin 2 at 5 ꢀ
C
R1
R2
ee
syn/anti
Isolated yield (%)
Et
Pr
i-Pr
Me
Me
H
H
H
Br
OMe
99
99
99
94
89
95:5
ꢁ99:1
ꢁ99:1
ꢁ99:1
ꢁ99:1
85
80
83
82
85
propionaldehyde to b-nitrostyrene with high stereoselectivity but
NO2
+
O
in yields of only 20% for 2 and 17% for 3. These results and our
previous work9 all point toward the diphenylprolinol system being
insufficiently robust for reuse in these sorts of applications. A
simple pyrrolidine-based polymer-bound catalyst has recently
been successfully reused for asymmetric Michael additions of cy-
clohexanone to nitroolefins.14 That system appears to be more ro-
bust and gives higher yields but slightly lower stereoselectivities
than resin 2.
H
O
H
O
1, 2, or 3
toluene, rt
+
H
NO2
ð4Þ
In the proposed mechanism,12 the sequence begins with the
same Michael addition of propionaldehyde enamine to nitrostyrene
described above (cf. Eq. 2). The -nitroaldehyde product then un-
3. Conclusions
g
dergoes Michael addition to the iminium derivative of cinna-
maldehyde. Intramolecular aldol cyclocondensation of the resulting
enamine completes the sequence. For a variety of examples Enders
reports isolated yields of 25–58% and virtually total enantiose-
lectivity for the major diastereomer, using 20 mol % of 1 as catalyst.
The specific example in Eq. 4 gives 40% yield and ꢁ99% ee.
In accordance with our previous results this study has demon-
strated that the crosslinker resin 2 is generally a superior polymer-
bound catalyst as compared to its pendant counterpart 3, at least
for simple two-component chemistry. While the two resins give
low yields for asymmetric epoxidations, Michael additions proceed
quite efficiently. Stereoselectivities for epoxidation are somewhat
lower for the polymer-bound catalysts than that found in solution,
while in the case of Michael additions the results generally match
or exceed those obtained in solution. In addition, three-component
tandem Michael/Michael/aldol processes can be adapted to the
solid state, giving superior results to solution phase using resin 3.
This difference in efficacy between resins 2 and 3 suggests that the
crosslink-functionalized 2, in which the reactive sites are likely to
be in uniformly well-defined environments, is the better choice for
good yield and stereoselectivity in cases where the reactions being
examined are compatible with its rather non-polar and sterically
constrained reactive environment. Where such compatibility is
reduced, as in multicomponent chemistry, conventional pendant-
functionalized systems such as 3 may emerge as the preferred
choice. Despite their capabilities in solution, diphenylprolinol-
based systems are not reliably applicable for more than a single use.
However, they do afford at least the basic advantages of chemistry
carried out on the solid phase in terms of ease of isolation of
products of quite high purity after no more than simple filtration,
drying, and removal of solvent.
In the solid state, this process requires a polymer-supported
proline derivative to form an enamine with the saturated aldehyde
in the first step and an iminium salt from the unsaturated aldehyde
in the second. These requirements would appear to place signifi-
cant and somewhat differing demands on the characteristics of the
reaction environment in solid-state systems. Indeed, replication of
the process described in Eq. 4 using crosslink-functionalized poly-
mer 2 gives disappointing results: after 7 days only 15% yield of
product is isolated with ee¼89%. In dramatic contrast, however, the
pendant-functionalized system 3 catalyzes this process remarkably
well, giving 45% yield and 99% ee. This rather startling result implies
that the pendant-proline moieties in 3 are unusually well suited for
catalysis via both enamine and iminium pathways. While 2 is still
capable of simple enamine-based chemistry, it fares poorly in the
multicomponent process. We hypothesize that the more con-
strained steric environment in 2, associated with the location of the
functionality at a crosslink, is poorly suited to stabilize iminium
intermediates and less compatible with construction of the bulky
three-component product. For this process to succeed, the initial
polymer-bound Michael product must form, detach from the
polymer, and then add to the
a,b-unsaturated aldiminium salt,
4. Experimental
4.1. General
which is polymer-bound at, presumably, a different functionalized
site. The pendant functionality in 3 is clearly better suited for this
sequence of events.
All reactions were performed in oven-dried glassware under an
atmosphere of dry argon unless otherwise stated. An orbital shaker
was used for agitation of reactions involving polymer beads. 1H and
13C NMR spectra were recorded at 400 MHz in CDCl3. IR spectra of
solids were recorded using an FTIR with an ATR attachment. Optical
purities of chiral auxiliaries and their precursors were determined
using a Waters Alliance LC/MS, a Waters 2695 HPLC, and a Waters
PDA 996, equipped with a Chiralcel OD-RH 0.46 cm by 15 cm (I.D.
2.5. Attempted polymer recycling and regeneration
Direct reuse of the resin recovered from successful epoxidation
of cinnamaldehyde gave only very low (>10%) yields of epoxide,
although ee remained at 90%. Assuming that deprotection of the
alcohol was responsible for the poor results, we attempted to re-
generate the active resin by reprotection; however, the supposedly
regenerated resins gave no product. Further attempts to regenerate
an active polymer, including full deprotection using tetrabutyl-
ammonium fluoride (TBAF) followed by careful reprotection using
TMS-OTf were also fruitless. Clearly the epoxidation conditions
themselves caused destruction of the polymer-bound auxiliary in
a way that could not be reversed.
by length) 5.0 mm column employing the following gradient
elution: 0–5 min, 100% A; 5–25 min, 0–100% B; 25–30 min, 100–0%
B; 30–35 min, 100% A (solvent A: water/0.1% TFA; B: acetonitrile/
0.1% TFA); monitored from 200–400 nm with a 0.2 mL/min flow
rate. A Waters Micromass ZQ Mass Detector was used for the iden-
tification of MS (ESI) for various products, using sample concentra-
Before setting out to examine the reuse of polymers 2 and 3 in
tions of w1
mg/mL. Further chiral analyses were performed on
Michael additions, we investigated the fate of catalyst 1. 1H NMR
a Waters 2996 Photodiode Array Detector, a Waters 2525 Binary

10090
M.C. Varela et al. / Tetrahedron 64 (2008) 10087–10090
Gradient Module, and a Waters 2767 Sample Manager equipped
4.1.6. Representative procedure for polymer-supported Michael
addition
Into a 2-dram vial, 0.10 g of resin (0.050 mmol 2 or 0.045 mmol
3) was swollen in ca. 3 mL benzene followed by the addition of
with a 4.6ꢂ150 mm Waters XterraÒ MS C18 5.0
mm column
employing: 0–3 min,100% A; 3–23 min, 0–100% B; 23–27 min,100–
0% B; 27–32 min, 100% A (solvent A: water/0.1% TFA; B: acetonitrile/
0.1% TFA); and monitored from 200 to –600 nm with a 1.0 mL/min
flow rate. Products were analyzed using a Chromasil CP-Chirasil-Dex
CB 25 m GC chiral column.
trans-b-nitrostyrene (0.20 g, 1.3 mmol) and propionaldehyde
(0.70 mL, 10 mmol). The solution was agitated for 4 days at the
specified temperature. The resin was filtered away and washed
with 15 mL THF followed by 15 mL of methanol. The combined
filtrates were washed with 15 mL 1 N HCl and extracted twice
with 10 mL EtOAc, and the organic layers combined, dried over
anhydrous Na2SO4, and concentrated under reduced pressure.
Yield and enantiomeric excess data are summarized in Tables 1
and 2.
4.1.1. Solution-phase epoxidation of cinnamaldehyde in TMOF
In a 2-dram vial, 10 mg (0.030 mmol) of 1 was dissolved in 2 mL
of trimethylorthoformate. A 50% H2O2/H2O solution (0.020 mL,
0.30 mmol) was added to the solution and stirred vigorously for
10 min. trans-Cinnamaldehyde (0.030 mL, 0.24 mmol) was then
added via syringe and the solution stirred for 1 day at the end of
which a sample was taken for NMR and GC analyses, revealing
a 99þ% conversion to product, which consisted of (within experi-
mental error) optically pure trans and cis epoxide in an 81:19 ratio.
1H and 13C NMR data for the products were identical to the litera-
ture values.13
4.1.7. Polymer-supported triple cascade reaction
Into a 2-dram vial, 0.10 g of resin (0.050 mmol 2 or 0.045 mmol
3) was swollen in 2–3 mL of toluene. trans-b-Nitrostyrene (0.040 g,
0.26 mmol) was added at 0 ꢀC and allowed to stir for 10 min. Pro-
pionaldehyde (0.020 mL, 0.30 mmol) and trans-cinnamaldehyde
(0.033 mL, 0.26 mmol) were added and the solution was allowed to
stir for 1 day during which time the 0 ꢀC bath warmed to room
temperature. The reaction mixture was agitated for 7 days further
and the product worked up and purified in accordance with the
literature.12 Using resin 3, the product was obtained as a colorless
solid, 0.038 g (45% yield), ee¼87% (99%, corrected for the 88% ee of
the resin precursor).
4.1.2. Solution-phase Michael addition of propionaldehyde to trans-
b-nitrostyrene in benzene
In a 2-dram vial, 20 mg (0.060 mmol) of 1 was dissolved in 2 mL
benzene. trans-b-Nitrostyrene (0.20 g, 1.3 mmol) and propio-
naldehyde (0.70 mL, 10 mmol) were added followed by 2 days of
stirring. HCl (1 N, 2 mL) was added followed by extraction with
10 mL EtOAc, dried over anhydrous Na2SO4, and concentration
under reduced pressure. Conversion and stereochemical data for
the product mixture are summarized in Table 1. 1H and 13C NMR
data for the products agreed with the literature values.7
Acknowledgements
We gratefully acknowledge support from the National Science
Foundation (Grant CHE-0614756). MCV gratefully acknowledges
support from an Alfred P. Sloan Foundation Graduate Scholarship.
4.1.3. Crosslink-functionalized beads of polymer-supported
catalyst 2
Into a 100 mL flask, 0.90 g of the aminoalcohol precursor resin
(4.2% crosslinked and 0.45 mmol crosslink-functionalized8,9) was
swollen in 20 mL of dichloromethane (DCM) and cooled to 0 ꢀC.
Triethylamine (0.040 mL, 0.26 mmol) and trimethylsilyl tri-
fluoromethanesulfonate (0.050 mL, 0.25 mmol) were added fol-
lowed by 1 h of agitation. The resin was filtered, and washed with
15 mL of DCM, water, THF, and methanol. Drying under reduced
pressure in a 50 ꢀC oil bath yielded 0.80 g (89%) of polymer 2 as off-
white beads.
References and notes
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4.1.4. Pendant-functionalized beads of polymer-supported
catalyst 3
Into a 100 mL flask, 1.00 g of the precursor resin (3.7% cross-
linked and containing 0.45 mmol pendant-functionalized8,9) was
swollen in 25 mL of dichloromethane followed by cooling to 0 ꢀC.
Triethylamine (0.080 mL, 0.59 mmol) and trimethylsilyl tri-
fluoromethanesulfonate (0.120 mL, 0.59 mmol) were added fol-
lowed by 1 h of agitation. The resin was then filtered, and washed
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4.1.5. Polymer-supported asymmetric epoxidation
Into a 2-dram vial, 0.10 g of resin (0.050 mmol 2 or 0.045 mmol
3) was swollen in 1.5–2 mL of trimethylorthoformate. A 50% H2O2/
H2O solution (0.02 mL, 0.30 mmol) was added to the heteroge-
neous mixture and allowed to stir vigorously for 10 min. trans-
Cinnamaldehyde (0.045 mL, 0.36 mmol) was added to the mixture
via syringe and the solution stirred for 1 day, at the end of which
time a sample was removed for NMR and GC analyses.
´
14. Alza, E.; Cambeiro, X. C.; Jimeno, C.; Pericas, M. A. Org. Lett. 2007, 9, 3717–3720.