Enantioselective heterogeneous synergistic catalysis for asymmetric cascade transformations

Article abstract of DOI:10.1002/adsc.201400291

A modular design for a novel heterogeneous synergistic catalytic system, which simultaneously activates the electrophile and nucleophile by the combined activation modes of a separate metal and non-metal catalyst, for asymmetric cascade transformations on a solid surface is disclosed. This modular catalysis strategy generates carbocycles (up to 97.5:2.5 er) as well as spirocyclic oxindoles (97.5:2.5 to >99:0.5 er), containing all-carbon quaternary centers, in a highly enantioselective fashion via a one-pot dynamic relay process.

Full text of DOI:10.1002/adsc.201400291

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DOI: 10.1002/adsc.201400291
Enantioselective Heterogeneous Synergistic Catalysis for
Asymmetric Cascade Transformations
Luca Deiana,b,c Lorenza Ghisu,b,c Samson Afewerki,a Oscar Verho,b,c
Eric V. Johnston,b,c Niklas Hedin,c,d Zoltan Bacsik,d and Armando Cꢀrdovaa,b,c,
*
a
Department of Natural Sciences, Engineering and Mathematics, Mid Sweden University, SE-851 70 Sundsvall, Sweden
Fax : +(46) 8-154-908; e-mail: armando.cordova@miun.se or acordova@organ.su.se
Department of Organic Chemistry, The Arrhenius Laboratory, Stockholm University, 106 91 Stockholm, Sweden
The Berzelii Center EXSELENT, Stockholm University, SE-106 91 Stockholm, Sweden
Department of Materials and Environmental Chemistry, Stockholm University, Stockholm SE-106 91, Sweden
b
c
d
Received: March 24, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400291.
À
Abstract: A modular design for a novel heterogene-
ous synergistic catalytic system, which simultane-
ously activates the electrophile and nucleophile by
the combined activation modes of a separate metal
and non-metal catalyst, for asymmetric cascade
transformations on a solid surface is disclosed. This
modular catalysis strategy generates carbocycles
(up to 97.5:2.5 er) as well as spirocyclic oxindoles
(97.5:2.5 to >99:0.5 er), containing all-carbon qua-
ternary centers, in a highly enantioselective fashion
via a one-pot dynamic relay process.
zymes can catalyze enantioselective C C bond-form-
ing reactions using synergistic catalysis within their
active sites.[2b,c,3] Here, metal ions (e.g., Zn2+, class II
aldolases) perform Lewis acid activation of the react-
ing electrophile and nucleophile in cooperation with
the amino acid residues.[3] In comparison, non-metal
dependent class I aldolase enzymes perform enamine
activation of the carbonyl nucleophile in cooperation
with the specific amino acid residues of the active
site.[3] Following the pioneering work of Whitesides
on creating artificial metalloenzymes,[4] hybrid cata-
lysts for sequential catalysis between metals and en-
zymes were recently disclosed.[5] Here the enzymes
work in cooperation with the metal catalysts by cata-
lyzing separate reactions that operate in sequence
and/or parallel. For example, an improvement in per-
formance was observed in the dynamic kinetic resolu-
tion of a primary amine using a hybrid catalyst made
by immobilization of palladium nanoparticles and
Keywords: all-carbon quaternary stereocenters; car-
bocycles; co-catalysis; dynamic transformations;
heterogeneous synergistic catalysis
Homogeneous synergistic catalysis is a synthetic strat- a lipase on silica of the mesocellular type.[5d] In anoth-
egy wherein both the nucleophile and the electrophile er early approach, Breslow and co-workers designed
are simultaneously activated by two separate catalysts metalloenzyme mimics where the cooperative action
in solution to afford a single chemical transforma- of a metal-complex and an organic base on a solid cy-
tion.[1] This formidable catalysis strategy leads to ben- clodextrin surface accelerated phosphate hydrolysis.[6]
efits such as introduction of novel, previously unat- The development of synergistic catalytic systems im-
tainable chemical transformations, improvement of ef- mobilized on nanostructured solid surfaces has recent-
ficiency, stereoselectivity and creation of catalytic ly attracted considerable attention.[7] Of particular
enantioselectivity in existing transformations. Direct- utility are heterogeneous synergistic catalytic systems
ed by billion years of evolution, enzymes catalyze or- that combine the use of both a Brønsted base site and
ganic transformations with remarkable stereoselectivi- an acid site on a solid surface to achieve acid-base co-
ties using synergistic catalysis within their active sites operative catalysis.[8] These catalysts include achiral
by cooperation of amino acid residues and/or metal amines that are anchored to the supports in the pres-
co-factors.[2] Thus, specific chemical functionalities are ence of a Brønsted acid. Recently, an example of
organized and incorporated within the surface of the a synergistic system was reported where an achiral or-
protein’s active sites and thereby synergistically ac- ganic base and a transition metal complex were co-
complish state of the art catalysis of life-essential anchored[9] and successfully employed for the acceler-
chemical transformations. For example, metalloen- ation of the addition of malonate to allyl methyl car-
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bonate (Tsuji–Trost reaction).[9a] However, the devel- synergistic action of a Lewis acid metal center on the
opment of synergistic catalysis on a solid surface for solid surface would allow for stereoselective carbocy-
asymmetric synthesis is a challenge and has not been
ACHTUNGTRENcNUGN lization. Subsequent protonation, isomerization and
disclosed. Based on the above important advances, we hydrolysis of the catalytic iminium intermediate gives
envisioned the design of a modular system for the cre- a chiral cyclopentene derivative. Thus, the synergistic
ation of tailor-made synergistically cooperating cata- activation of the enaminyne intermediate is essential
À
lytic active sites on a heterogeneous surface for asym- for accomplishing the intermolecular C C bond-form-
metric transformations by anchoring a chiral amine ing step. However, the use of a heterogeneous sup-
by “click chemistry”[10] for iminium/enamine activa- port could potentially be cumbersome due to the ri-
tion and a transition metal for Lewis acid activation, gidity of the system, which would prevent carbocycli-
respectively (Figure 1), thus, mimicking the combined zation and potential self-quenching of either the
activation modes of type I and type II aldolases,[3] re- amine or Lewis acid catalysts. Furthermore, a careful
spectively.
selection of the chiral amine is necessary for ensuring
Here, the enantioselective construction of all- the desired product formation and obtaining high ster-
carbon quaternary stereocenters, which is a difficult eoselectivity.[14a] Herein, we disclose the design of
task in organic synthesis,[11] and the development of
a
heterogeneous synergistic catalysis system on
domino and cascade reactions,[12] which deliver multi- a silica surface for highly enantioselective synthesis of
À
À
ple C C and C heteroatom bonds in high chemo- cyclopentenes and spirocyclic oxindoles with an all-
and stereoselectivity, would be highly attractive appli- carbon quaternary stereocenter by a cascade Michael/
cations for the asymmetric synergistic catalysis ap- carbocyclization relay sequence.
proach. This would merge the advantages of heteroge-
We initially began with the synthesis of a silica sup-
neous and cascade catalysis and allow for the more ported chiral amine and diaminopalladium complex
economic synthesis of complex molecules by improv- (6:SiO2/diamine/Pd/chiral amine) according to
ing the step-economy and minimizing waste genera- Scheme 2. Thus, a 50:50 ratio of (3-azidopropyl)trime-
tion and solvent use, which is in line with the princi- thoxysilane
1
and N-(3-(trimethoxysilyl)propyl)-
ples of green chemistry.[13] One-potential reaction to ethane-1,2-diamine 2 was immobilized on the SiO2
investigate for the above concept would be the Pd surface (chromatographic silica media, LC60A, 60–
and chiral amine co-catalyzed cascade Michael/carbo- 200 mm) to give a silica-supported diamine and azide
cyclization reaction between propargylic nucleophiles (SiO2/diamine/azide) 3 (see the Supporting Informa-
and enals.[14,15]
tion for details). The azide functionality was selected
In this reaction, the chiral amine residue of the since it can take part in “click chemistry”[4] reactions
active site of the heterogeneous catalyst would first allowing for the linking of a large variety of highly
catalyze a reversible Michael reaction via iminium ac- modular and general molecules. Next, the difunction-
tivation to render an activated enamine intermediate alized silica 3 was impregnated with Li2PdCl4 in water
containing a triple bound (enamineyne species) on (pH 9) to furnish SiO2/diamine/azide/Pd (4). The syn-
the solid surface of the heterogeneous catalyst thesis of bifunctional catalyst (SiO2/diamine/azide/Pd/
(Scheme 1). Next, hydrolysis renders a Michael inter- chiral amine) 6 was completed by a Cu(I)-mediated
mediate that is in equilibrium with the enamineyne 1,3-dipolar reaction[10b,16] between the alkyne-contain-
species. However, simultaneous intramolecular nucle- ing chiral amine 5[17] and 4 (see the Supporting Infor-
ophilic attack on the activated alkyne moiety by the mation for details). Transmission electron microscopic
Figure 1. A modular approach for generating a heterogeneous synergistic catalyst surface for the asymmetric synthesis of
chiral molecules.
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Enantioselective Heterogeneous Synergistic Catalysis
(TEM) analysis of 6 revealed that no Pd nanoparticles amine/Pd (6a). However, with this procedure, the Pd
had been formed during the catalytic cycloaddition is not only coordinated to the diamine but also to the
transformation. We also prepared SiO2/diamine/chiral chiral amine moiety, and thereby inhibits it catalytic
amine (7) by the catalytic azide-alkyne Hꢂisgen cyclo- activity. The amounts of immobilized amine and Pd
addition[4b,16] between 5 and 3. Impregnation of 7 with species on 6 were determined by elemental analysis
Li2PdCl4 in water (pH 9) gave SiO2/diamine/chiral using inductively coupled plasma-optical emission
Scheme 1. Pd-chiral amine-co-catalyzed dynamic Michael/carbocyclization transformation; Nu=nucleophile.
Scheme 2. Synthesis of SiO2/diamine/Pd/chiral amine (6) catalyst.
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spectroscopy (ICP-OES) technique (Pd=6.3 wt%, tion).[21] In the 13C{1H}CPMAS NMR spectrum of the
Cl=3.7 wt%, C=17 wt% and N=3.9 wt%, H= synergistic catalyst 6 (Figures S2 and S3, Supporting
2.4 wt%). Infrared spectra of the modified silica sup- Information), the chemical shift at 128 ppm was as-
ports 3 and 6 are shown in Figure 2a and b, respec- signed to the secondary carbon nuclei of the phenyl
tively. The most significant change between the IR ring. The presence of the TMS moiety is confirmed
spectra in Figure 2 is the decreased intensity of the by the chemical shift at 2.0 ppm. In addition, the peak
band at 2101 cmÀ1, which was assigned to the azide ca 145 ppm was in good accordance with literature
+
À
[18,19]
À
( N=N =N ) group
indicating that 4 and the values of a quaternary carbon belonging to the 1,2,3
chiral amine 5 give SiO2/diamine/Pd/chiral amine (6). triazole.[22,23] Collectively the results from the IR and
The remaining azido band intensity is calculated to be 13C{1H}CPMAS NMR analyses provided clear evi-
~5% of the original intensity according to measure- dence for the successful incorporation of the chiral
ments on several selected silica particles. Thus, the amine in 6.
conversion of the catalytic heterogeneous “click
With the heterogeneous dual catalyst 6 in hand, we
chemistry” reaction was ~ >95%. The decreased in- began probing its ability to catalyze the co-catalytic
tensity of the azide functional group suggests that the cascade reaction between cinnamic aldehyde 9a
triazole is formed. The clear identification of the tri- (0.1 mmol) and methyl 2-cyanopent-4-ynoate 10a
ACHTUNGTRENNUNGazole moiety was not possible from the spectrum in (0.12 mmol) in different solvents (0.25 mL) to give
Figure 2b, since that compound does not have a very the corresponding cyclopentane 11a containing a qua-
characteristic strong band in the region investigat- ternary and tertiary stereocenter (Table 1).
ed.[20] The other important change in 6 as compared
The screening revealed that 6 synergistically cata-
to 3 is the appearance of bands for the phenyl groups lyzed the formation of 11a with high stereoselectivity
belonging to the chiral amine moiety. The in several solvents. The highest yield was obtained
13C{1H}CPMAS NMR spectrum of the silica 3 con- when CH2Cl2 was used as the solvent (73% yield,
firmed the linkage of propylethylenediamine and 87:13 dr and 95:5 er, entry 2) while the reactions in
propyl azide moieties (Figure S2, Supporting Informa- CHCl3 (11a: 62% yield, 88:12 dr and 97:3 er, entry 7)
Figure 2. Infrared spectra of (a) support 3 (SiO2/diamine/azide) and (b) modified silica support 6 (SiO2/diamine/Pd/chiral
amine). (The spectra are not baseline corrected, but shifted by the absorbance axis for clarity.)
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Table 1. Screening of the reaction conditions.[a]
[a]
Catalyst (51 mg), 9a (0.1 mmol), 10a (0.12 mmol), solvent (0.25 mL), room temperature. See
the Supporting Information for details.
[b]
[c]
Isolated yield of pure 11a.
1
Determined by H NMR analysis of the crude reaction mixture. See the Supporting Informa-
tion for details.
[d]
[e]
[f]
The er of 11a was determined by chiral-phase HPLC analysis.
Performed with 6 (18 mg, 6 wt% Pd, 3 wt% N).
59% conversion to 12a.
0.5 mL solvent.
Performed at 408C.
12a was formed with 67:33 dr and 78:22 er.
5 (10 mol%), PdCl2 (5 mol%).
5 (10 mol%), Pd(II)-AmP-MCF (5 mol% Pd); AmP-MCF=aminopropyl mesocellular foam,
n.d.=not determined.
[g]
[h]
[i]
[j]
[k]
and toluene (59% yield, 85:15 dr and 97.2:2.5 er, tries 11 and 12) when homogeneous chiral amine 5
entry 8) gave the highest er. We also performed the was used as the co-catalyst in combination with PdCl2
reaction with catalyst 7 and only the Michael inter- or Pd(II)-AMP-MCF[8c] (AMP-MCF=aminoprolyl
mediate 12a was formed in 59% conversion with mesocellular foam) (94.5:5.5 and 93.5:6.5 er, respec-
67:33 dr. Thus, the synergistic surface catalysis with tively). Thus, a clear beneficial synergistic effect of
the transition metal catalytic center is essential for the two active sites of 6 can be seen with respect to
the carbocyclization to occur (entry 3). Moreover, the enantioselectivity of the cascade transformation.
when 6a was employed as the catalyst products 11a However, the rigidity of the heterogeneous surface
and 12a were not formed (entry 4). Decreasing the catalysis decreases the reaction rates of the dynamic
concentration or increasing the temperature did not cascade transformation. Moreover, after hot filtration
increase the yield or er of 11a (entries 8 and 9). The of 6 at approximately 45% conversion no further re-
er of Michael adduct 12a after 3 h was 78:22 action between 9a and 10a proceeded in the filtrate.
(entry 10), which is significantly lower than the er With these results in hand, we decided to test the re-
(97:3) of the final product carbocycle 11a (entry 7). action for a set of enals 9 and propargyl nucleophiles
Thus, enantiomer 12a reacted faster than its mirror 10a and 10b, respectively, using 6 as the catalyst in
image ent-12a and the other two minor stereoisomers CHCl3 at room temperature (Scheme 3). Propargylic
during the dynamic relay process, which is in accord- oxindole 10b was selected as a substrate since the suc-
ance with the homogeneous co-catalytic transforma- cessful Michael/carbocyclization reaction with enal 9
tion.[8a] Notably, 12a was formed with lower er (en- would give access to the corresponding spirocyclic ox-
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Scheme 3.
indole structural motif 11,[15c] which is present in sev- 99.5:0.5 er), respectively. For example, the 6-cocata-
eral natural products and pharmaceuticals.[24]
lyzed Michael/carbocyclization relay sequence be-
The synergistic surface 6-catalyzed cascade transfor- tween n-hexenal 9g and 11b gave the corresponding
mations between 9 and 10a were highly enantioselec- n-propyl-substituted spirocyclic oxindole 11k in 67%
tive and gave the corresponding cyclopentenes 11a– yield with 95:5 dr and 99:1 er. We also investigated
11f[25] in good to high yields with ers ranging from the recyclability of catalyst 6. Thus, the 6-catalyzed re-
95:5 to 97.5:2.5 (Scheme 3). It is noteworthy that the action between 9c and 10b was performed again in
heterogeneous synergistic catalyst system 6 mediated the presence of benzoic acid (20 mol%) in CHCl3.
the assembly of spirolactams 11g–11k in high yields After 48 h, spirooxindole 11i was isolated in 85%
and with excellent enantioselectivity (97.5:2.5– yield with 75:25 dr and 99.5:0.5 er. Next, the recycled
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catalyst 6 (51 mg) was added. After stirring for 5 min at room
temperature, the enal (0.1 mmol, 1 equiv.) and benzoic acid
(2.5 mg, 20 mol%) were added sequentially. The reaction
mixture was vigorously stirred for the time shown in the
Schemes. Next the crude reaction mixture was directly loaded
on to and purified by silica-gel column chromatography (pen-
tane/EtOAc) to afford the corresponding products 11.
catalyst 6 was used for a subsequent identical reac-
tion. However, the reaction was slow and 11i was iso-
lated in 25% yield with 78:22 dr and 99.5:0.5 er after
96 h. A similar observation was made for the 6-cata-
lyzed reaction between 9a and 10a. We confirmed
that no leaching of Pd occurred as determined by ele-
mental analysis and that the metal was still active for
carbocyclization. Moreover, no chiral amine was re-
leased from the support as determined by HR-MS
AHCTUNGTERG(NNUN 1R,2R)-4-Methyl-2’-oxo-2-propylspiro[cyclopent[3]ene-
1
1,3’-indoline]-3-carbaldehyde (11k): oil. H NMR (400 MHz,
CDCl3): d=10.07 (s, 1H), 8.29 (bs, 1H), 7.24–7.21 (m, 1H),
7.16 (d, J=7.2 Hz, 1H), 7.01 (m,1H), 6.91 (d, J=7.6 Hz,
1H),3.55 (d, J=11.3 Hz, 1H), 3.09 (d, J=18.4 Hz, 1H), 2.67
(d, J=18.4 Hz, 1H), 2.21 (s, 3H), 2.07–2.00 (m, 1H), 1.29–
1.22 (m, 1H), 1.01–0.94 (m, 1H), 0.69–0.59 (m, 4H);
13C NMR (100 MHz, CDCl3): d=188.1, 183.1, 159.4, 140.4,
138.9, 132.4, 128.4, 124.2, 122.5, 110.1, 55.6, 52.9, 50.8, 31.3,
20.6, 14.6, 14.0; HR-MS (ESI): m/z=292.1303, calcd. for
[M+Na] (C17H19NO2): 292.1308; [a]2D5: +6.6 (c 1,
CHCl3).The enantiomeric excess was determined by HPLC
analysis in comparison with authentic racemic material
1
analysis, H NMR analysis and IR analysis of the su-
pernatant. Instead, IR analysis of the recycled 6 con-
firmed that the substrate and product had been cova-
lently attached to the support and inhibited the chiral
amine moiety (see the Supporting Information).
Hence, catalytic off-cycle intermediates in the forma-
tion of 11 and oligomerization of 10 deactivate and in-
hibit the chiral amine group of 6. In fact, we have seen
these types of side reactions in homogeneous chiral
amine-catalyzed reactions.[14] Thus, the two catalysts
act in concert, however, inhibition of the chiral amine
residue of 6 starts to play a significant role with time.
In summary, we have disclosed a novel and modu-
lar heterogeneous synergistic catalyst system for
asymmetric cascade transformations to generate com-
plex molecular architectures in a highly enantioselec-
tive fashion. This designed cooperative surface strat-
egy consisting of a transition metal and a chiral amine
catalyzes the formation of carbocycles and spirocyclic
oxindoles having an all-carbon quaternary stereocen-
ter with up to 99.5:0.5 er. These products were not
formed without the surface containing both the im-
mobilized Pd complex and the “click chemistry” an-
(ODH-column,
n-hexane/i-PrOH=80/20,
l=254 nm,
1.0 mLminÀ1): tr (major enantiomer)=7.8 min, tr (minor
enantiomer)=6.5 min.
Acknowledgements
We gratefully acknowledge financial support from the Euro-
pean Union, Mid Sweden University and Swedish National
Research Council. The Berzelii Center EXSELENT is finan-
cially supported by VR and the Swedish Governmental
Agency for Innovation Systems (VINNOVA).
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groups on a designed solid surface[25] as in enzymes,
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˝
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