Novel poly(2-oxazoline)s with pendant l-prolinamide moieties as efficient organocatalysts for direct asymmetric aldol reaction

Article abstract of DOI:10.1039/c6cy00448b

Poly(2-oxazoline)-supported bifunctional organocatalysts have been prepared through a bottom-up protocol, which involves synthesis of well-defined poly(2-oxazoline) precursors bearing amino groups in the side-chains followed by amide coupling with N-Boc-l-proline then deprotection. The resultant l-prolinamido-functionalized polymers have proven to be significantly more active than their monomeric counterparts for the aldolisation of cyclic ketones with several substituted benzaldehydes under neat conditions. By using 15 mol% of the polymer as a catalyst, the direct aldol reaction products were isolated in high yields and with good diastereo- and enantioselectivity. Based on circular dichroism spectrum analysis, the enhancement in catalytic activity is probably related to the conformational changes of the pseudo-peptide scaffold of poly(2-oxazoline)s. In addition, these soluble polymeric catalysts can be recovered and reused by precipitation in ether for five catalytic cycles without significantly diminishing their efficiency.

Full text of DOI:10.1039/c6cy00448b

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Novel poly(2-oxazoline)s with pendant L-prolinamide moieties as efficient
organocatalysts for direct asymmetric aldol reaction
Yao Wang, Huifang Shen, Le Zhou, Fangyu Hu, Shoulei Xie, and Liming Jiang*
MOE Key Laboratory of Macromolecular Synthesis and Functionalization,
Department of Polymer Science and Engineering,
Zhejiang University, Hangzhou 310027, China
Keywords: Organocatalysis / Poly(2ꢀoxazoline)s / Polymerꢀsupported catalysts /
Direct asymmetric aldol reaction
Abstract:
Poly(2ꢀoxazoline)ꢀsupported bifunctional organocatalysts have been prepared through
a bottomꢀup protocol, which involves synthesis of wellꢀdefined poly(2ꢀoxazoline)
precursors bearing amino groups in the sideꢀchains followed by amide coupling with
NꢀBocꢀLꢀproline then deprotection. The resultant Lꢀprolinamidoꢀfunctionalized
polymers have proven to be significantly more active than their monomeric
counterpart for the aldolisation of cyclic ketones with several substituted
benzaldehydes under neat conditions. By using 15 mol% of the polymer as catalyst,
the direct aldol reaction products were isolated in high yields and with good diastereoꢀ
and enantioselectivity. Based on the circular dichroism spectrum analysis, the
enhancement in catalytic activity is probably related to the conformational changes of
the pseudoꢀpeptide scaffold of poly(2ꢀoxazoline)s. In addition, these soluble
polymeric catalysts can be recovered and reused by precipitation in ether for five
catalytic cycles without significantly diminishing its efficiency.
1

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Introduction
As interest in asymmetric organocatalysis is on the increase, the immobilization of
organic catalysts, especially their polymeric immobilization has also attracted much
attention.1 Undoubtedly, the use of solid supports usually facilitates the isolation of
the reaction products, the catalyst recovery and recycling.2 For polymerꢀsupported
chiral organocatalysts, however, the polymer matrix seems to integrate itself as a
more natural part of the overall catalytic system, influencing both catalyst activity and
stereoselectivity.3 Unlike what traditionally has been the case, the polymer scaffolds
could even enhance catalyst performance by providing a favorable microenvironment
around the catalytic active sites as is the case for enzymatic catalysis.1,3 For example,
Pericàs and coworkers constructed an artificial aldolase by bonding proline to
polystyrene through a 1,2,3ꢀtriazole linker.3a The artificial aldolase with the optimum
linker shows a high activity and enantioselectivity toward the direct aldol
condensation in water. To mimic the property of type I aldolase enzyme, Cozzi et al.3b
synthesized a soluble polymerꢀbased biomimetic catalyst by anchoring (2S,
4R)ꢀ4ꢀhydroxyproline to the monomethyl ether of PEG5000. Deng’s group pioneered
in creating artificial enzymes using optically active polyacetylene derivatives as
scaffolds.3c They found that the helical chirality of the main chain plays a crucial role
in the asymmetric aldol reaction of cyclohexanone with 4ꢀnitrobenzaldehyde.
Recently, Tenhu and coworkers reported new polymeric chiral ionic liquids prepared
by controlled radical polymerization.3d The polymeric catalyst is able to promote the
consecutive aldolꢀdehydration process behaving as a synthetic mimic of the
2

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aldolaseꢀdehydrogenase enzymatic system.
Among the enormous amount of publications on organocatalysts for
transformations of carbonyl compounds via enamine or iminium activation, the
bifunctional aminocatalysts such as prolinamide derivatives are probably a kind of
interesting candidate for polymeric immobilization owing to their powerful catalytic
capability and stereoselectivity in a wide range of asymmetric bond forming organic
reactions.4 In this regard, Gruttadauria and coꢀworkers conducted thorough
investigations.5 They synthesized a series of polymerꢀsupported prolinamides and
dipeptides through the thiol–ene coupling of styrenic derivatives onto the
mercaptoꢀfunctionalized Merrifield resin and subsequent deprotection. It was proven
that these polymeric catalysts could give better selectivity compared to their small
molecule counterparts, indicating the existence of a cooperative effect between the
polymer matrices and catalytic units. Hansen et al.6 applied an acrylic
copolymerization strategy to immobilize Lꢀproline moiety through an ester linkage.
The resulted heterogeneous acrylic resins exhibited excellent catalytic properties in
water and lead to aldol products in high yields and stereoselectivity. In addition to
styrenic and acrylic resins, other types of polymer, such as dendrimer7 and
hyperbranched polymers,8 were also employed as supports to bind prolinamideꢀbased
catalysts for the asymmetric aldol condensation and its variants.
Compared with the postꢀmodification approach based on the commercial resins,
the bottomꢀup methodology is generally more flexible within the design of polymeric
catalysts to enable the catalyst loading and swelling characteristics to be tuned easily.
3

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This synthetic scheme would allow construction of new polymeric architectures for
organocatalytic systems when combining with refined synthetic techniques, although
such examples have scarcely been reported so far.[3d,6−9] On the other hand, we thought
that it is still very interesting to explore different types of polymer scaffolds to link an
everꢀwidening assortment of organocatalysts besides styrenic and acrylic polymers.
Herein, we describe a bottomꢀup strategy to synthesize novel polymerꢀbound
Lꢀprolinamide catalysts via the cationic ringꢀopening polymerization (CROP) of
2ꢀoxazoline monomers with a protected amine functionality followed by subsequent
postꢀmodifications. Notably, poly(2ꢀoxazoline) (POX) was chosen as a scaffold is due
to its plenty of chemistry that would offer a great deal of flexibility with respect to the
molecular design and polymer synthesis. The CROP of 2ꢀoxazolines usually exhibits
controlled/“living” character, which provides ready access to various wellꢀdefined
POXs, whereby the endꢀgroup functionality can be controlled during initiation and
termination, and sideꢀchain functionalities can be introduced by the copolymerization
with a (protected) functional monomer.10 More importantly, the pseudoꢀpeptide
backbone10a,b of POXs is expected to confer a good compatibility on the polymer
matrices with the anchored active moieties and thereby to produce a synergistic effect
on the outcome of the catalytic transformation. As a proof of concept, we investigated
the catalytic performance of the prolinamidoꢀPOX derivatives in the asymmetric aldol
addition of cyclohexanone to various substituted benzaldehydes and the recyclability.
Furthermore, to gain some additional insight into the specific role of the polymer
backbone on the catalytic property, the chiroptical properties in solution of the
4

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polymer catalysts have been examined by circular dichroism and compared with those
of the corresponding low molecular weight model compound. To the best of our
knowledge, the construction of organocatalytic systems based on poly(2ꢀoxazoline)
scaffolds has remained unexplored, although the potential of this kind of polymers in
biomedical applications has been reported in the literature.10b,c
Results and Discussion
In the present work, we designed a series of poly(2ꢀoxazoline)s bearing Lꢀproline
residues as the pendants through an amide linkage. As shown in Fig. 1, an interesting
feature of these polymers is the presence of a tertiary amide backbone and a
hydrogenꢀdonating prolinamide moiety in the side chains. Introduction of the second
chiral subunit in the lateral group was to test for possible effect of the various
configuration combinations on the stereoselectivity and whether catalyst activity is
affected by the substituents at the stereogenic center.
<Figure 1 here>
Scheme 1 illustrates the employed protocol, which involving synthesis of the
monomers (step i−ii), ringꢀopening polymerization (step iii), and postꢀmodification of
the corresponding polymers (step iv−vi). 2ꢀOxazoline monomers, (S/R)ꢀPheOX,
(RS)ꢀPheOX, and (R/S)ꢀPhgOX, were prepared easily from 2ꢀchloroethylamine and
Bocꢀphenylalanine or Bocꢀphenylglycine via twoꢀstep reactions in a total yield of
65~80% according to a general adapted method.11 The chemical structure of
monomers was confirmed by NMR and mass spectral analyses (see Experimental part
and the ESI).
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<Scheme 1 here>
Taking the synthesis of (S)ꢀPPheOXNHPro as an example, we examined the
cationic ringꢀopening polymerization features of (S)ꢀPheOX and the feasibility of
postꢀmodification for the resulted polymers. On the basis of our previous work,12 the
polymerization was allowed to conduct in CH3CN using Sc(OTf)3 as initiator. The
data summarized in Table 1 showed that the polymerization leads to the
corresponding polymers ((S)ꢀPPheOXNHBoc) with fairly narrow PDIs (Mw/Mn =
1.21−1.39) when it is carried out at 80−90°C. Performing the polymerization at higher
temperature (100°C) or at a higher monomer concentration gave rise to higher yields,
albeit with a slightly broad polydispersity in the latter case (entries 3, 5 and 6, 7; Fig.
S6). Also observed were increasing the molar ratio of monomerꢀtoꢀinitiator in the
range of 60−400 results in an increase in the molar mass of the polymers (entries
1−4).
The polymerization kinetics was studied under the optimized conditions. As can
be seen from Figure 2, the polymerization process reveals a firstꢀorder kinetic
behavior within 3 h and the Mn values increased linearly in proportion to the monomer
conversion in the range of 60−95%. The results indicate that a good control of
polymerization was achieved with this system, which was also supported by the
unimodel molar mass distribution for the resultant polymers. Related SEC analysis
data are provided in ESI (Fig. S15−16).
<Table 1 here>
<Figure 2 here>
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The asꢀsynthesized poly(2ꢀoxazoline)s represent an ideal substrate for preparing
functional materials since the Boc protecting group can be easily hydrolyzed exposing
a pendant amino group that is readily functionalized. To this end, the parent polymers
(POXNHBoc’s) were first deprotected using mildly acidic conditions according to
wellꢀestablished procedures (see Experimental Section). Fig. 3a−b plots as an
1
example the changes in the H NMR spectra of (S)ꢀPPheOXNHBoc before and after
treatment with trifluoroacetic acid (TFA) in CH2Cl2 at ambient temperature. We can
see that the characteristic signal of the Boc protons (~1.45 ppm) disappeared fully in
the spectrum of the deprotected product, and the methine peak labeled “a” has now
shifted from
δ 4.9 to ~4.1 ppm as a result of the removal of Boc groups. The results
suggest that the deprotection process is finished almost quantitatively. Moreover, the
tertiary amide linkages in the backbone remained intact during the acidic treatment,
which could be deduced from the synthesis of the model compound.13
Afterwards, the resultant polymer with free amino groups ((S)ꢀPPheOXNH2) was
converted to its Lꢀprolinamide derivative, (S)ꢀPPheOXNHProBoc, followed by
eliminating Boc groups from the proline ring to afford the goal product
(S)ꢀPPheOXNHPro in ~86% yield. 1H NMR spectroscopic monitoring of the
postꢀmodification revealed that new proton signals assignable to the pyrrolidine unit
can be observed at 4.10 ppm (b) and around 1.5−2 ppm (c, d) in the spectrum of
(S)ꢀPPheOXNHProBoc (Fig. 3a and 3b), whereas the signals of another methylene
protons labeled “e” merged with that of the CH2 backbone (δ: 2.5–3.5 ppm). At the
last step, the hydrolytic detachment of Boc groups was also nearly quantitative.
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Judged from the relative peak integrations, i.e., “a” vs. “b” in Fig. 3c or “a” vs. “c + d”
in Fig. 3d, the degree of incorporation of Lꢀprolinamide moiety was estimated to be
94%. By using the same route, other POXNHPro’s were also prepared for comparison
and evaluation of the possible presence of structural effects. In all cases, Lꢀproline
residue can be efficiently introduced into the POX scaffolds, the amide coupling
efficiency of the repeating monomeric units being more than 92% (see: Table 1 and
Table S1).
<Figure 3 here>
The presence of a plenty of polar functionalities in the side chains enables
POXNHPro to be easily soluble in the polar solvents including methanol, but it leads to
difficulties in the SEC measurements due to their strong interaction with column
fillers. Accordingly, their molecular weights were characterized in the protected form
(POXNHProBoc). As shown in Fig. 4 and Fig. S17, SEC analyses of POXNHProBoc gave
unimodal traces with a longer retention time than POXNHBoc. In fact, POXNHProBoc has
a larger molecular weight when compared to its precursors, as evident from the
MALDIꢀTOF mass spectra (Fig. 5). It can be seen that the spacing between major
peaks for (S)ꢀPPheOXNHBoc and (S)ꢀPPheOXNHProBoc agrees reasonably well with the
mass of their respective repeating units (m/z 290.4, 387.4). Furthermore, the
difference in the m/z values for both samples roughly corresponds to the mass of the
coupled prolinamide moiety (~97 Da), confirming the nearꢀquantitative attachment of
the active group onto each repeat unit (Table 1 and Fig. S9).
<Figure 4 here>
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<Figure 5 here>
To evaluate the catalytic activity of the Lꢀprolinamidoꢀfunctionalized POXs, the
aldolisation of cyclohexanone with 4ꢀnitrobenzaldehyde to give anti/syn
diastereomers of 2ꢀ[hydroxyl(4ꢀnitrophenyl)methyl]cyclohexanone was chosen the
benchmark reaction as often reported in the literature.3d,14 Taking (S)ꢀPPheOXNHPro as
an example, we started the preliminary optimization of reaction conditions focusing
on the solvent effect in the presence of an excess of the aldol donor (Table S2, ESI).
The results showed that in only water the reaction produced antiꢀaldol in a moderate
stereoselectivity (65% ee) at 20 mol% of catalyst loading, and the presence of water
as cosolvent is essential to obtain a higher catalytic efficiency. Considering the good
solubility of the polymers in cyclohexanone, we decided to perform the aldol
reactions under neat conditions, which might be highly desirable because this process
is more economic and environmentꢀfriendly.
Typically, the bulk reactions were performed in cyclohexanone of 0.516 mL (5
mmol) with 0.05 equivalent of 4ꢀnitrobenzaldehyde (0.25 mmol) at 10°C. As
anticipated, a very small amount of water has a significant effect on the catalytic
transformation (Table 2). For example, at a catalyst loading of 20 mol% the addition
of water (9 ꢀL, ~1.7% relative to cyclohexanone in volume) led to a high conversion
of the aldehyde in a shorter time, affording the product with 91% yield and 63% ee
(entries 2 vs. 1). When decreasing the catalyst loading to 15 mol%, the highest ee
value (78%) was obtained with the amount of water fixed, and the further increase or
decrease in water content resulted in a lower enantioselectivity although somewhat
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higher anti/syn ratios occurred in some cases (entries 4−6). The accelerating effect of
water on both the catalytic rate and/or stereoselectivity has been well documented in
many aldolaseꢀtype organocatalytic reactions.4g−h,14−15
<Table 2 here>
At the same time, we noted that trifluoroacetic acid (TFA) as an additive also
exhibited a remarkable acceleration on the aldol reaction (Table 2, entry 7). Further
careful optimization revealed that an adequate combination of water (9 ꢀL) with TFA
(2 ꢀL, 0.8 equiv. relative to the catalytic unit) can greatly promote the catalytic
conversion, leading to the formation of aldol with high transꢀselectivity (80% de) and
good enantioselectivity (91% ee) in 96% yield (Table 2, entries 7−12).17 Examination
of the effect of the reactant ratio on the reaction indicated that 20 equiv of donor
cyclohexanone to 1 equiv of the aldehyde gave the best results (entries 10 and 13−15).
By holding H2O/TFA at 9:2 and modulating the temperature from 10°C to 25°C the
reaction resulted in an increased diastereoselectivity (88% de) at the cost of a small
drop in the ee value to 87% (entry 16). Decreasing or increasing the catalyst loading
would deviate from the optimal outcomes in terms of both the selectivity and/or yield
(entries 17−18). Also, for the polymer catalysts the variation in the molecular weight
(Mn 4 000~10 400) does not seem to have a large influence on the catalytic activity
(Table S3).
With the optimal reaction parameters in hand, the further extension of the scope
of the aldol reaction was investigated by the choice of aromatic aldehydes as aldol
acceptors to react with cyclic ketones using (S)ꢀPPheO XNHPro as the catalyst (Table 3).
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When cyclohexanone was used as a pronucleophile, the reaction of benzaldehydes
bearing electronꢀwithdrawing substituents, such as nitro, cyano, and methoxycarbonyl,
proceeded smoothly to afford the corresponding antiꢀaldol products in excellent yields
with high enantioselectivities (entries 1–5, yield 85–96% and ee 79–91%). The
aldehyde substituted by a nitro group at the ortho position gave a lower ee value (81%)
than its paraꢀ/metaꢀsubstituted counterparts; however, a higher diastereoselectivity
(85:15) was observed in this case (entry 3). For the neutral and electronꢀrich aromatic
aldehydes the poor results were obtained (entries 6−8), giving low yields (< 20%)
despite the longer reaction time. Similar phenomena were also observed by other
groups, which may be related to the electronic and steric effects of aromatic
aldehydes.18
Entries 9–10 in Table 3 show that the reaction of 4ꢀnitrobenzaldehyde with
4ꢀpyranone was remarkably fast, providing the corresponding antiꢀaldol product in
very high yield and good stereoselectivity even in the absence of acid additive.
Interestingly, the aldol reactions using a cyclopentanone donor with the aldehyde led
to the preferential formation of synꢀadducts in excellent yields (entries 11−12).
However, the observed ee of the synꢀaldol leaves much to be desired, reaching only
23−41%. Also, when (S)ꢀPPheOXNHPro was used in the aldol reactions of cyclic
ketones with aliphatic aldehydes, such as propanal and isobutyraldehyde, under the
same conditions, very low conversions (<5%) were recorded after 24 h.
<Table 3 here>
Subsequently, the polymers (R)ꢀPPheOXNHPro and (RS)ꢀPPheOXNHPro were tested
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as reference catalysts for the standard aldol reaction under the previously optimized
conditions. Compared with (S)ꢀPPheOXNHPro, the former afforded a slightly poorer
enantioselectivity (86% ee), whereas the latter led to an ee value identical to and
trans/cis ratio only 4% higher than those obtained with its (S)ꢀcounterpart (Table 4,
entries 1, 3, and Table 2, entry 10). As was the case for the quasiꢀenantiomeric pair
(S)ꢀ/(R)ꢀPPheOXNHPro, two additional polymers (S)ꢀ and (R)ꢀPPhgOXNHPro gave
comparable trends with respect to the catalytic activity and stereoselectivity in the
aldolisation (Table 4, entries 3−4). In all cases, the configuration of the favored
stereoisomer of the aldol adduct was dictated by the chiral center of Lꢀprolinamide
moiety, rather than by that of the spacer, as previously reported by Portnoy et al.20
This indicates that there did not appear to be a clear match/mismatch effect of
configuration between the Lꢀproline ring and chiral linker, and the substituents at the
linker had a minor influence on the catalytic outcomes only. Nonetheless, these
POXꢀbound Lꢀprolinamides could indeed exhibit a significant improvement in
catalytic efficiency as compared to the nonꢀsupported compound (S)ꢀM1 (entry 5),
implicating the existence of a fortunate symbiosis between the polymer scaffolds and
catalytic sites. In terms of the aldol reaction between 4ꢀnitrobenzaldehyde and
cyclohexanone, the POXꢀsupported prolinamides as a homogeneous catalyst
performed not only comparable to Lꢀprolyl dipeptides described earlier,16 but also
better than some silicaꢀ18b and PSꢀsupported5d analogues under similar reaction
conditions.
<Table 4 here>
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It is widely accepted that the aldol reaction of unactivated ketones follow an acid
assisted enamine mechanism.21 For the polymer catalyst under study, however, the
catalyst activation observed upon addition of acid additives may be partly associated
with the conformational mobility of the polymer chains originating from the
reorganization of intraꢀ and intermolecular hydrogen bonding responsive to the
solvent environment. To clarify this point, we undertook circular dichroism (CD)
titrations with TFA under such conditions almost identical to those for the catalytic
reaction. The spectroscopic measurements were performed in the transparent CH2Cl2
containing trace amounts of water in an effort to exclude the influence of solvent
composition on spectroscopy.
By way of example, the results of CD titration of (S)ꢀPPheOXNHPro with TFA are
shown in Figure 6. It can be seen that the polymer itself displays an intense CD signal
at the positions almost completely corresponding to the UVꢀvis absorption peaks.
Upon addition of TFA, the negative Cotton effect around 222 nm gradually
decreases and nearly vanishes when about 0.3 equiv of TFA is added. With the
incremental addition of the acid, a positive CD band emerges and finally reaches a
maximum upon introduction of 0.8~1.0 equiv of TFA. Similar spectral response was
also observed upon titration of (RS)ꢀPPheOXNHPro with TFA (Fig. S22). For the model
compound (S)ꢀM1, however, addition of TFA did not lead to a noticeable change in
CD spectra as in the case of the polymers (Fig. S23). These observations seem to
suggest a close relationship with the outcomes of aldol reaction observed above,
where the optimal results in terms of both the yield and enantioselectivity were
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obtained in the presence of catalytic amounts of water and TFA (~0.8 equiv.; in Table
2, entries 10−11). Therefore, we hypothesize that upon complexation with the acidic
additives the polymer scaffolds, residing in the proximity of the active site,
presumably create an appropriate microenvironment via the conformational transition
for the hydrogen bondꢀbased asymmetric induction.
<Figure 6 here>
Finally, we investigated reꢀuse of the catalyst (S)ꢀPPheOXNHPro in the benchmark
reaction in an aqueous medium (MeOH/H2O) and neat ketone as well. At the end of
each reaction cycle, the polymer could be precipitated out by addition of ethyl ether
into the reaction mixture followed by centrifugation and reused for next catalytic
cycle. As shown in Table 5, the polymer catalyst was used five times with
reproducible anti/syn and ee values. However, the activity of the recycled catalyst was
somewhat lower than that of the previous one and a ~5% weight loss of catalyst for
each recovery was unavoidable.
<Table 5 here>
In conclusion, we developed a class of novel poly(2ꢀoxazoline)ꢀsupported
Lꢀprolinamide catalysts that are able to imitate to some extent the aldolase biomimetic
system. The polymer catalysts proved to be highly efficient for the asymmetric
aldolisation of cyclohexanone with several aromatic aldehydes. When the reaction
was performed neat using 15 mol% of catalyst loading, the antiꢀaldol products could
be obtained in excellent isolated yields with a 95:5 anti/syn ratio and 93% ee in the
presence of H2O/TFA as additive. Moreover, product isolation and catalyst recycling
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can be easily accomplished by precipitation several times without noticeable loss of
stereoselectivity. The present work offers proofꢀofꢀprinciple and indicates that high
asymmetric induction may be profit from the peculiar pseudoꢀpeptide scaffold of
poly(2ꢀoxazoline)s, in which it would provide a suitable chain architecture for
locating the chiral catalytic groups.
Experimental
Materials
BocꢀLꢀproline, BocꢀL/Dꢀphenylalanine, BocꢀL/Dꢀphenylglycine, 2ꢀchloroethylamine
hydrochloride, trifluoroacetic acid (TFA), and Oꢀ(1Hꢀbenzotriazolꢀ1ꢀyl)ꢀN,N,N',N'ꢀ
tetramethyluronium tetrafluoroborate (TBTU) were used as received from Acros.
Dichloromethane, triethylamine, acetonitrile and piperidine were distilled from
calcium hydride and stored under dry nitrogen atmosphere before use. Scandium
triflate [Sc(OTf)3] was prepared as the reported method22 and used after drying in
vacuum at 200°C for 48 h.
Instrumentation
1H and 13C NMR spectra were recorded on a Bruker Avance III 400 spectrometer with
DMSOꢀd6 or CDCl3 as solvent. The chemical shifts were reported in ppm relative to
tetramethylsilane (TMS) as an internal standard. Size exclusion chromatography (SEC)
data were acquired on a Waters−150C apparatus equipped with two PLgel 5 ꢀm
MIXEDꢀC (300 mm × 7.5 mm) columns and a differential refractometer detector
using tetrahydrofuran (THF) or DMF as the eluent (flow rate 1 mL min−1, 40°C). The
numberꢀaverage molecular weight (Mn) and polydispersity index (PDI) of the
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polymers were calculated on the basis of a polystyrene (PS) or PMMA calibration.
MALDIꢀTOF mass spectra were obtained on a Bruker Ultraflextreme mass
spectrometer in the positive reflector mode with an acceleration voltage of 25 kV,
using sodium iodide (10 mg mL−1 in THF) as ionization salt and dithranol (20 mg
mL−1 in THF) as matrix. Electrospray ionizationꢀmass spectrometry (ESIꢀMS)
measurements were performed with a Varian 500 mass spectrometer. CD spectra were
recorded on a Biologic MOSꢀ450 CD spectropolarimeter (France) at ambient
temperature (cell length: 1 cm, scanning speed: 10 nm sec−1). Chiral
highꢀperformance liquid chromatography (HPLC) data were collected on a
Chromeleon® apparatus equipped with a Chiralpak ADꢀH (4.6 mm × 250 mm)
column using a solution of hexane/2ꢀpropanol (90:10, v/v) as an eluent at a flow rate
of 0.8 mL min−1.
Synthesis of 2-oxazoline monomers (Scheme 1), general procedure
Synthesis of (S)ꢀ2ꢀ(1ꢀBocꢀaminoꢀ2ꢀphenyl)ethylꢀ2ꢀoxazoline ((S)ꢀPheOX) is
described as an example. BocꢀLꢀPhenylalanine (5.3 g, 20 mmol), 2ꢀchloroethylamine
hydrochloride (2.55 g, 22 mmol), and Oꢀ(1Hꢀbenzotriazolꢀ1ꢀyl)ꢀN,N,N',N'ꢀ
tetramethyluronium tetrafluoroborate (TBTU, 7.06 g, 22 mmol) were placed in a 100
mL oven dried 2ꢀneck round bottom flask, followed by adding 50 mL of
dichloromethane. To the solution was added dropwise triethylamine of 5.5 mL (40
mmol) at 0°C and then the mixture was allowed to stir for 4 h at ambient temperature
under N2 atmosphere. After removal of solvent under reduced pressure, the resultant
residue was purified via column chromatography using a 1/2 EtOAc/petroleum ether
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eluent to give the intermediate 1 as a white solid (5.88 g, 90%).
To a solution of NaOH (1.2 g) in methanol (20 mL) was added 1 (3.268 g, 10
mmol) and then the mixture was stirred at 40°C in a N2 atmosphere. After stirring the
mixture for 6 h, the solvent was removed under reduced pressure. The resulted residue
was dissolved in 30 mL of dichloromethane (DCM), followed by washing with
deionized water (3 × 40 mL). The aqueous phase was extracted with DCM (2 × 20
mL). The collected organic phase was dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. The obtained crude product was recrystallized from ethyl
acetate to afford (S)ꢀPheOX as a white solid in 81% yield (2.35 g).
Other
2ꢀoxazoline
monomers,
((R)ꢀPheOX),
((S)ꢀPhgOX),
i.e.,
(RS)ꢀPheOX,
and
(R)ꢀ2ꢀ(1ꢀBocꢀaminoꢀ2ꢀphenyl)ethylꢀ2ꢀoxazoline
(S)ꢀ2ꢀ(1ꢀBocꢀamino)benzylꢀ2ꢀoxazoline
(R)ꢀ2ꢀ(1ꢀBocꢀamino)benzylꢀ2ꢀoxazoline ((R)ꢀPhgOX), were prepared in a similar
procedure to that described for (S)ꢀPheOX, except for the use of BocꢀDꢀphenylꢀ
alanine, (±)ꢀBocꢀphenylalanine, or BocꢀL/Dꢀphenylglycine as their respective chiral
materials.
Characterization data of monomers
(S)ꢀPheOX. White solid; total yield 73%; m.p. = 128.5−129.6°C; [α]2D0 = +8° (c
0.01, MeOH); 1H NMR (CDCl3, 400 MHz, TMS): δ = 7.38–7.04 (m, 5H), 5.10 (d, J =
7.4 Hz, 1H), 4.67 (d, J = 6.6 Hz, 1H), 4.38–4.18 (m, 2H), 3.92–3.66 (m, 2H), 3.28–
2.90 (m, 2H), 1.41 (s, 9H); 13C NMR (101 MHz, CDCl3): δ = 167.09, 154.9, 136.31,
129.50, 128.30, 126.79, 79.66, 68.11, 54.09, 49.74, 38.78, 28.31 ppm. MS (ESI+): m/z
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(%) = 290.9 (8.8) [M + H]+, 312.9 (10) [M + Na]+, 602.9 (100) [2M + Na]+.
(R)ꢀPheOX. White solid; total yield 80%; m.p. = 128.1−128.9°C; [α]2D0 = −8° (c
0.01, MeOH); 1H NMR (CDCl3, 400 MHz, TMS): δ = 7.35–7.09 (m, 5H), 5.11 (d, J =
7.6 Hz, 1H), 4.67 (d, J = 6.8 Hz, 1H), 4.37–4.23 (m, 2H), 3.88–3.68 (m, 2H), 3.09 (dd,
J = 48.7, 13.7, 5.7 Hz, 2H), 1.41 (s, 9H); 13C NMR (101 MHz, CDCl3): δ = 167.10,
154.95, 136.31, 129.50, 128.30, 126.78, 79.65, 77.04, 76.72, 68.11, 54.08, 49.73,
38.76, 28.30 ppm. MS (ESI+): m/z (%) = 291.2 (100) [M + H]+, 313.1 (51) [M +
Na]+.
1
(RS)ꢀPheOX. White solid; total yield 82 %; m.p. = 127.81−28.6°C; H NMR
(CDCl3, 400 MHz, TMS): δ = 7.43–7.07 (m, 5H), 5.15 (d, J = 7.9 Hz, 1H), 4.80–4.57
(m, 1H), 4.42–4.18 (m, 2H), 3.97–3.62 (m, 2H), 3.28–2.93 (m, 2H), 1.39 (d, J = 15.6
Hz, 9H); 13C NMR (101 MHz, CDCl3): δ = 167.11 , 154.98 , 136.32, 129.51, 128.31,
126.80, 79.65, 77.40, 77.08, 76.76, 68.13, 54.09, 49.74, 38.76, 28.32 ppm. MS (ESI+):
m/z (%) = 291.2 (56) [M + H]+, 603.2 (100) [2M + Na]+.
(S)ꢀPhgOX. Solid; m.p. = 112.5−113.4°C; [α]2D0 = +6° (c 0.01, MeOH); H NMR
1
(CDCl3, 400 MHz, TMS): δ = 7.44–7.27 (m, 5H), 5.78 (s, 1H), 5.42 (d, J = 7.3 Hz,
1H), 4.28 (dq, J = 17.8, 8.6 Hz, 2H), 3.94–3.81 (m, 2H), 1.48–1.29 (m, 9H); 13C NMR
(101 MHz, CDCl3): δ = 166.99, 154.74, 138.20, 128.74, 128.17, 127.00, 79.93, 76.72,
68.50, 54.00, 52.91, 28.31 ppm. MS (ESI+): m/z (%) = 299.1 (23) [M + Na]+, 575.0
(100) [2M + Na]+.
(R)ꢀPhgOX. Solid; m.p. = 112.3−113.1°C, [α]2D0 = −6° (c 0.01, MeOH); 1H NMR
(CDCl3, 400 MHz, TMS): δ = 7.51–7.27 (m, 5H), 5.71 (d, J = 5.32 Hz, 1H), 5.42 (d, J
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= 7.3 Hz, 1H), 4.46–4.09 (m, 2H), 3.98–3.73 (m, 2H), 1.37 (d, J = 41.0 Hz, 9H); 13C
NMR (101 MHz, CDCl3): δ = 166.99, 154.73, 138.20, 128.73, 128.17, 127.00, 79.92,
77.04 (s), 76.73, 68.50, 54.00, 52.91, 28.31 ppm. MS (ESI+): m/z (%) = 299.1 (30) [M
+ Na]+, 575.0 (100) [2M + Na]+.
Synthesis of the model compound (S)-M1 (Scheme 2)
BocꢀLꢀPhenylalanine (2.65 g, 10 mmol), TBTU (3.852 g, 12 mmol) were dissolved
in CH2Cl2 of 50 mL, followed by adding diethylamine (3.1 g, 30 mmol) with stirring
at ambient temperature in a nitrogen atmosphere. The resultant mixture was allowed
to stir for 12 h and then washed with deionized water (3 × 40 mL), and the layers
were separated. The aqueous layer was extracted several times with CH2Cl2, and the
combined organic layers were dried (anhydrous MgSO4), filtered, and concentrated
under reduced pressure. The resulted residue was chromatographed over silica gel
with 1/3 EtOAc/petroleum ether eluent to produce 3 (4.59 g, 70%) as a powder
matter.
To a solution of 3 (3 g) in 15 mL CH2Cl2 was added TFA (15 mL) and then the
mixture was stirred at room temperature for 4 h. The solvent was removed under
reduced pressure, the residue was dissolved in CH2Cl2 (25 mL) and the resultant
solution was successively washed by a saturated sodium bicarbonate aqueous solution
and water. The organic layer was dried over Na2SO4, filtered, and concentrated under
reduced pressure to give 4 as a paleꢀyellow liquid in 83% yield.
TBTU (6.42 g, 20 mmol), BocꢀLꢀproline (4.3 g, 20 mmol), and 4 (3.6 g, 16.7 mmol)
were dissolved in CH2Cl2 (50 mL), and then to the resultant mixture was added
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triethylamine (4.8 mL, 33 mmol) with stirring at 0°C. After stirring at room
temperature for 12 h, the reaction mixture was washed by saturated aq. NaHCO3 (3 ×
60 mL). The aqueous layer was extracted several times with dichloromethane, and the
combined organic layers were dried (anhydrous Na2SO4), filtered, and concentrated
under reduced pressure to afford 5 as a white solid (72%). To obtain the unprotected
model compound (S)ꢀM1, 5 was treated with TFA/CH2Cl2 (2:3) solution for 6 h at
room temperature. Then CH2Cl2 was added to the reaction mixture, the resulting
solution was washed three times with saturated sodium bicarbonate solution. The
organic extracts were dried (Na2SO4) and the solvent were evaporated under vacuum
to give (2S)ꢀ2ꢀLꢀprolinamidoꢀ3ꢀphenylꢀN,Nꢀdiethylpropanamide as a waxy solid
((S)ꢀM1, yield 70%). [α]2D0 = +34° (c 0.01g/mL, CH3OH); 1H NMR (CDCl3, 400 MHz,
TMS): δ = 8.11 (d, J = 8.8 Hz, 1H), 7.30–7.03 (m, 5H), 4.97 (dd, J = 15.8, 8.0 Hz,
1H), 3.64 (dd, J = 9.2, 5.1 Hz, 1H), 3.47 (dq, J = 14.2, 7.2 Hz, 1H), 3.11–2.74 (m, 7H),
2.06–1.89 (m, 3H), 1.67 (tt, J = 9.0, 4.7 Hz, 1H), 1.04–0.91 (m, 6H); 13C NMR (101
MHz, CDCl3): δ = 173.14, 169.59, 135.48, 128.52, 127.31, 125.84, 76.33, 76.02,
75.70, 59.32, 48.39, 46.14, 40.70, 39.48, 38.81, 29.66, 24.96, 13.21 ppm. MS (ESI+):
m/z (%) = 318 (66) [M + H]+, 635 (100) [2M + H]+, 657 (79) [2M + Na]+.
<Scheme 2 here>
Synthesis of poly(2-oxazoline)-bound L-prolinamide catalysts (POXNHPro
)
The preparation of polymer catalysts includes the polymerization of 2ꢀoxazolines
and postꢀmodification of the corresponding polymers. Taking the synthesis of
(S)ꢀPPheOXNHPro as an example, a typical experimental procedure is as follows. To a
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flameꢀdried Schlenk tube (S)ꢀPheOX (1.00 g, 3.45 mmol), 0.8 mL of a solution of
Sc(OTf)3 in acetonitrile (4.18 × 10−2 M) and additional solvent (0.925 mL) were
successively added under N2 atmosphere. After being heated at 90°C for a definite
period of time with magnetic stirring, the reaction was quenched by the addition of
deionized water. The resulting mixture was left to stir at ambient temperature for 1 h
and the crude product was precipitated out by the addition of Et2O. To completely
remove the catalyst residue and unreacted monomer, the collected powder matter was
redissolved in CH3CN and then precipitated again from Et2O. This process was
repeated three times to give the desired product (S)ꢀPPheOXNHBoc (0.896 g, yield
90%).
The obtained polymer (1.0 g) was treated with a 1:1 TFA/CH2Cl2 solution (10 mL)
for 12 h at room temperature. After evaporation of the solvent and addition of MeOH
(10 mL) and saturated aq. NaHCO3 (~2 mL) the product was dialyzed against water
using 1 kDa cutꢀoff tubes, and it was finally freezeꢀdried to yield the deprotected
polymer (S)ꢀPPheOXNH2 (quantitative). The intermediate (1 g) was dissolved in
DMSO (~2 mL) and to the resulting solution was added BocꢀLꢀproline (0.88 g, 4
mmol), TBTU (1.3 g, 4 mmol), and Et3N (0.97 mL, 6.67 mmol) in turn. The mixture
was allowed to react for 24 h at room temperature and mixed with water of ~15 mL.
Then, the mixture was extracted with CH2Cl2 (3 × 5 mL), dried (MgSO4), filtered, and
concentrated. The residue was subject to the deprotection and dialysis purification in a
similar way to that described for (S)ꢀPPheOXNH2, affording the target product
(S)ꢀPPheOXNHPro (yield 98%).
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General procedure for the direct asymmetric aldol reaction
The selected catalyst (15 mol %, based on the repeating unit in the polymer),
aldehyde (0.25 mmol), cyclohexanone (0.526 mL, 5 mmol) and an appropriate
amount of additives were added in a 10 mL roundꢀbottom flask in turn under an
atmosphere of air. The reaction mixture was stirred at ambient temperature (10~25°C)
in a closed system for an appropriate time until the reaction was complete, as
monitored by TLC. Then, to the mixture was added saturated ammonium chloride
solution (~2 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic
layer was dried anhydrous MgSO4, filtered, and concentrated. The residue was
purified by flash column chromatography on silica (nꢀhexane/EtOAc = 4:1) to obtain
the aldol product as mixtures of anti and syn diastereomers. The diastereomeric ratio
1
was determined by H NMR spectroscopy on the crude samples. The enantiomeric
excess was determined by HPLC on a chiral stationary phase (1:5 EtOAc/petroleum
ether eluent).
The recyclability of the polymer catalyst
After carrying out the reaction, the mixture was poured into ethyl ether (~10 mL)
followed by centrifugation to separate the polymer. After washing with Et2O and
drying, the catalyst can be reused directly without further purification.
Acknowledgments
The authors gratefully thank the National Natural Science Foundation of China (Grant
No. 21274122) for financial support.
Notes and references
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1 For reviews on immobilized organocatalysts, see: (a) M. Benaglia, A. Puglisi and F.
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3 (a) D. Font, S. Sayalero, A. Bastero, C. Jimeno and M. A. Pericàs, Org. Lett., 2008,
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Brindle, Chem. Soc. Rev., 2010, 39, 1600–1632. For recent examples on aldol
reactions with Lꢀprolinamides, see: (c) H. W. Zhao, Y. Y. Yue, H. L. Li, X. Q. Song,
Z. H. Sheng, Z. Yang, W. Meng and Z. Yang, Synlett, 2013, 24, 2160–2164; (d) H. W.
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Synlett, 2013, 24, 1501–1504; (f) M. Orlandi, M. Benaglia, L. Raimondi and G.
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8, 4417−4420.
5 For a few selected papers on prolinamideꢀbased polymeric catalysts, see: (a) F.
Giacalone, M. Gruttadauria, A. Mossuto Marculescu and R. Noto, Tetrahedron Lett.,
2007, 48, 255–259; (b) M. Gruttadauria, F. Giacalone, A. Mossuto Marculescu and R.
Noto, Adv. Synth. Catal., 2008, 350, 1397–1405; (c) M. Gruttadauria, F. Giacalone, A.
M. Marculescu, A. M. P. Salvo and R. Noto, ARKIVOC, 2009, 8, 5–15; (d) M.
Gruttadauria, A. M. P. Salvo, F. Giacalone, P. Agrigento and R. Noto, Eur. J. Org.
Chem., 2009, 5437–5444; (e) J. Yan and L. Wang, Synthesis, 2008, 2065–2072.
6 (a) T. E. Kristensen, K. Vestli, K. A. Fredriksen, F. K. Hansen and T. Hansen, Org.
Lett., 2009, 11, 2968–2971; (b) T. E. Kristensen, K. Vestli, M. G. Jakobsen, F. K.
Hansen and T. Hansen, J. Org. Chem., 2010, 75, 1620–1629.
7 (a) M. Kazuhiko and J. R. Parquette, Israel J. Chem., 2009, 49, 119–127; (b) M.
Kazuhiko, S. A. Hyatt, D. A. Turner, C. M. Hadad and J. R. Parquette, Chem.
Commun., 2009, 22, 3261–3263; (c) S. Wang, P. Liu, W.ꢀJ. Wang, Z. Zhang and B.ꢀG.
Li, Catal. Sci. Technol., 2015, 5, 3798–3805.
8 Y. G. Chi, S. T. Scroggins, E. Boz and J. M. J. Fréchet, J. Am. Chem. Soc., 2008,
130, 17287–17289.
9 C. Röben, M. Stasiak, B. Janza, A. Greiner, J. H. Wendorff and A. Studer, Synthesis,
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2008, 2163–2168.
10 For recent reviews on poly(2ꢀoxazoline)s, see: (a) K. Aoi and M. Okada, Prog.
Polym. Sci., 1996, 21, 151–208; (b) R. Hoogenboom, Angew. Chem. Int. Ed., 2009, 48,
7978–7994; (c) H. Schlaad, C. Diehl, A. Gress, M. Meyer, A. L. Demirel, Y. Nur and
A. Bertin, Macromol. Rapid Commun., 2010, 31, 511–525; (d) R. Luxenhofer, Y. Han,
A. Schulz, J. Tong, Z. He, A. V. Kabanov and R. Jordan, Macromol. Rapid Commun.,
2012, 33, 1613–1631.
11 (a) S. Kobayashi, Prog. Polym. Sci., 1990, 15, 751−823; (b) H. Wenker, J. Am.
Chem. Soc., 1938, 60, 2152−2153.
12 Recently, we demonstrated that the ringꢀopening polymerization of 2ꢀoxazolines
initiated with Sc(OTf)3 can conduct smoothly without the need for microwave
irradiation as often observed in the case of using tosylates or triflates as initiator. See:
F. Hu, S. Xie, L. Jiang and Z. Shen, RSC Adv., 2014, 4, 59917–59926.
13 To confirm this point, the precursor of (S)ꢀM1 (i.e., 3 in Scheme 2) was stirred in
TFA under the same reaction conditions. We found that this process afforded no
detectable byꢀproducts such as phenylalanine besides the formation of the expected
product 4 even at a relatively higher temperature, indicating the tertiary amide linkage
is tolerant towards the deprotection.
14 see, for example: (a) M. Angeloni, O. Piermatti, F. Pizzo and L. Vaccaro, Eur. J.
Org. Chem., 1716–1726; (b) A. I. Nyberg, A. Usano and P. M. Pihko, Synlett, 2004,
1891−1896; (c) K. Sakthivel, W. Notz, T. Bui and C. F. Barbas III, J. Am. Chem. Soc.,
2001, 123, 5260–5267; (d) N. Mase, Y. Nakai, N. Ohara, H. Yoda, K. Takabe, F.
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Tanaka and C. F. Barbas III, J. Am. Chem. Soc., 2006, 128, 734–735; (e) S. Aratake, T.
Itoh, T. Okano, N. Nagae, T. Sumiya, M. Shoji and Y. Hayashi, Chem.–Eur. J., 2007,
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Am. Chem. Soc., 2007, 129, 15100–15101; (g) K. Goren, J. KarablineꢀKuks, Y.
Shiloni, E. BarakꢀKulbak, S. J. Miller and M. Portnoy, Chem.− Eur. J. 2015, 21,1191–
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15 The role of water has been rationalized recently, see: (a) M. Gruttadauria, F.
Giacalone and R. Noto, Adv. Synth. Catal., 2009, 351, 33–57; (b) J. Paradowska, M.
Stodulski and J. Mlynarski, Angew. Chem., Int. Ed., 2009, 48, 4288–4297; (c) M. Raj
and V. K. Singh, Chem. Commun., 2009, 6687–6703.
16 see, for example: (a) M. Lei, L. Shi, G. Li, S. Chen, W. Fang, Z. Ge, T. Cheng, R.
Li, Tetrahedron, 2007, 63, 7892–7898; (b) F. Chen, S. Huang, H. Zhang, F. Liu, Y.
Peng, Tetrahedron, 2008, 64, 9585–9591; (c) J. G. Hernández, E. Juaristi, J. Org.
Chem., 2011, 76, 1464−1467; (d) S. Bayat, B. A. Tejo, A. B. Salleh, E. Abdulmalek,
N. M. Yahya and M. B. A. Rahman, Chirality, 2013, 25, 726–734.
17 Under the neat conditions identical to those used for entry 10 in Table 1, acetic
acid and benzoic acid gave the antiꢀaldol products in high yields (~95%) with slightly
lower enantioselectivity (~84% ee) when they were applied as additive instead TFA.
This seems to suggest that there was no direct correlation between enantioselectivity
and acidity of the carboxylic acid used, which is different from that observed by
Pearson et al. (see: ref. 4g).
18 (a) G. Liu, H. Zhao, Y. Lan, B. Wu, X. Huang, J. Chen, J. Tao and X. Wang,
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Tetrahedron, 2012, 68, 3843−3850; (b) Y. Kong, R. Tan, L. Zhao and D. Yin, Green
Chem., 2013, 15, 2422–2433.
19 I. K. Sagamanova, S. Sayalero, S. MartínezꢀArranz, A. C. Albéniz and M. A.
Pericàs, Catal. Sci. Technol., 2015, 5, 754−764.
20 L. TuchmanꢀShukron, S. J. Miller and M. Portnoy, Chem.−Eur. J. 2012, 18, 2290–
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21 A. S. Saiyed and A. V. Bedekar, Tetrahedron: Asymmetry, 2013, 24, 1035–1041.
22 S. Kobayashi and I. Hachiya, J. Org. Chem., 1994, 59, 3590–3596.
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Captions:
Figure 1 The structural feature of POXꢀbound Lꢀprolinamide catalysts (collectively
referred to as POXNHPro) and a monomeric counterpart (S)ꢀM1 in this study.
Scheme 1 Synthetic route for the preparation of polymerꢀsupported organocatalysts
using enantiopure, racemic Bocꢀphenylalanine or Bocꢀphenylglycine as starting
materials. (i) ClCH2CH2NH2·HCl, TBTU, Et3N, 0°C~r.t. (ii) NaOH, CH3OH, 40°C.
(iii) Sc(OTf)3, CH3CN, 90°C. (iv) TFA, CH2Cl2, r.t. (v) BocꢀLꢀproline, TBTU, Et3N,
DMSO, r.t. (vi) TFA, CH2Cl2, r.t.
Figure 2 (a) Kinetic plots for the cationic ringꢀopening polymerization of (S)ꢀPheOX
using Sc(OTf)3 as initiator in acetonitrile at 90°C. [M]0/[I]0 = 100, [M]0 = 2 M. (b)
Evolution of the molar mass (Mn) and the PDI values with the monomer conversion
(determined by SEC, PS calibration, THF as the eluent).
1
Figure 3 H NMR spectra of (a) (S)ꢀPPheOXNHBoc (CDCl3), (b) (S)ꢀPPheOXNH2
(DMSOꢀd6), (c) (S)ꢀPPheOXNHProBoc (DMSOꢀd6), and (d) (S)ꢀPPheOXNHPro (CDCl3).
Figure 4 Typical SEC traces of (S)ꢀPPheOXNHBoc (blue) and (S)ꢀPPheOXNHProBoc (red)
showing a longer retention time for the latter (the molecular weight values are based
on calibration against PMMA in DMF with 50 mM LiBr; see: Table 1, entry 1).
Figure 5 Typical MALDIꢀTOF mass spectra of (A) (S)ꢀPPheOXNHBoc (Mn,SEC = 5 500,
PDI = 1.21) and (B) (S)ꢀPPheOXNHProBoc (Mn,SEC = 4 100, PDI = 1.20). See: Fig. 4.
Figure 6 CD spectral evolution of (S)ꢀPPheOXNHPro (10−3 M) upon addition of TFA
(0 ~ 1 equiv., relative to the active units in the catalyst) in CH2Cl2 containing ~1%
water at 25°C.
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Page 29 of 37
Catalysis Science & Technology
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DOI: 10.1039/C6CY00448B
Scheme 2 Synthesis of model compound (S)ꢀM1. (i) LꢀBocꢀPheꢀOH (10 mmol),
TBTU (12 mmol), Et2NH (30 mmol), CH2Cl2 ~50 mL, r.t., N2 atmosphere; (ii)
TFA/CH2Cl2 (1:1), r.t., 4 h; (iii) 4 (16.7 mmol), BocꢀLꢀproline (20 mmol), TBTU,
Et3N, (iv) TFA/CH2Cl2 (2:3), r.t., 6 h.
Figure 1
Scheme 1
Figure 2
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