One-pot multi-component asymmetric cascade reactions catalyzed by soluble star polymers with highly branched non-interpenetrating catalytic cores

Article abstract of DOI:10.1021/ja8013456

Non-interpenetrating star polymer catalysts designed to mimic the site isolation characteristics of enzymes enable the one-pot combination of multiple otherwise incompatible catalysts for asymmetric cascade reactions that involve iminium, enamine, and H-b

Full text of DOI:10.1021/ja8013456

Published on Web 04/24/2008
One-Pot Multi-Component Asymmetric Cascade Reactions Catalyzed by
Soluble Star Polymers with Highly Branched Non-Interpenetrating Catalytic
Cores
Yonggui Chi, Steven T. Scroggins, and Jean M. J. Fre´chet*
DiVision of Materials Sciences, Lawrence Berkeley National Laboratory, and College of Chemistry, UniVersity of
California, Berkeley, California 94720-1460
Received February 22, 2008; E-mail: frechet@berkeley.edu
Scheme 1. Study of Each Individual Reaction Step Using Small
Living cells often concurrently make many complex molecules via
multistep cascade reactions. For these multiple simultaneous enzymatic
reactions to work well, one key concept nature adopts is “compartmen-
talization” or “site isolation”, through which incompatible substrates and
enzymes are spatially separated to avoid undesired interactions.1 Chemists
have applied the principle of site isolation to catalysis by using solid
supports2 or sol-gels3 to encapsulate opposite reagents.4 In recent years,
soluble dendritic and other hyperbranched polymers have emerged as
attractive systems for the encapsulation and isolation of various functional
groups within the interior of the polymers.5 We have recently explored
the use of soluble hyperbranched polymers to combine the normally
incompatible acid and base catalysts in one pot for a simple two-step
sequential reaction.6 In this paper, we report the design of non-
interpenetrating star polymer catalysts to combine iminium,7 enamine,8
and hydrogen-bond9 catalysts in one pot for asymmetric reactions that
generate cascade products with more than one chiral center. We also
demonstrate that the proper combination of catalyst chirality allows
straightforward access to all possible stereoisomers of the cascade products
individually. To the best of our knowledge, our work represents the most
sophisticated study on soluble polymers for site isolation asymmetric
catalysis.
Previous research has established MacMillan imidazolidinone pairing
with strong acid as optimal iminium ion catalyst10 and proline-derived
chiral pyrrolidine as excellent enamine catalyst.11 In some cases, a single
imidazolidinone or proline-derived pyrrolidine has also been used to
mediate one-pot reactions involving both iminium and enamine catalysis.
This approach has certain advantages, as it uses a single catalyst to mediate
multiple catalytic cycles. However, the same amine catalyst is often only
optimal for one catalytic cycle (poor for other cycles). Additionally, the
use of a single asymmetric catalyst for one-pot multiple catalytic cycles
can only give access to a limited set of diastereomer(s) of the cascade
products. We aimed to develop a general system to combine optimal
enamine and iminium catalysts in one pot for sophisticated multistep
reactions. Our work began with careful investigation on an imidazolidi-
none-mediated nucleophilic addition of N-methyl indole to 2-hexenal to
give 1 [iminium catalysis; reaction (a), Scheme 1] previously developed
by MacMillan and co-workers12 and a chiral pyrrolidine-catalyzed Michael
addition of 1 to methyl vinyl ketone (MVK) [enamine catalysis; reaction
(b), Scheme 1]8,13 using small molecule catalysts. Our results (see
Supporting Information) showed that none of the three catalysts and
cocatalysts (3, pTSA, and 4) nor any of their combinations can mediate
both reaction steps. In particular, the presence of strong acid pTSA (alone
or paired with imidazolidinone 3) diminished the ability of 4 to effect
enamine catalysis. Consequently, a simple combination of these catalysts
in one pot cannot mediate a cascade reaction involving both reactions (a)
and (b).
Molecule Catalysts
molecule imidazolidinone 3 can diffuse to the core of the acid star polymer
5 to form a desired salt 6, which is an optimal iminium catalyst.
Electrostatic attraction should retain 3 within the core of 5 during catalysis.
Additionally, a hydrogen-bond donor catalyst (8, a much weaker acid than
pTSA)14 added to the one-pot reaction is expected to activate the relatively
nonreactive Michael acceptor (MVK) in the enamine catalysis cycle.
To test our hypotheses, we synthesized star polymers with core-confined
catalytic entities using the arm-first approach previously developed in the
Hawker and Fre´chet groups.15 Acid star polymer 5 was prepared according
to a known procedure.6 Elemental analysis of the sulfur content of 5
revealed 0.60 to 0.67 mmols of sulfonic acid per gram of polymer.
Similarly, amine star polymer 7 (SEC with THF: Mn ) 70 014, Mw )
92 151, PDI ) 1.32; MALLS: Mw ) 216 900) core-confined with chiral
pyrrolidine was synthesized from polystyrene macroinitiator 9 (SEC with
THF: Mn ) 6577, Mw ) 7301, PDI ) 1.11), divinylbenzene cross-linker,
and functional monomer 10 (Scheme 2).16 1H NMR analysis of 7 indicated
approximately 0.30 mmol amine catalyst per gram of polymer.16
We therefore proposed to encapsulate analogues of pTSA or 4 in the
core of a star polymer to give 5 and 7, respectively (Figure 1). Star
polymers 5 and 7 cannot penetrate each other’s core and therefore are
expected to maintain their catalytic integrity. On the other hand, small
molecule reagents and catalysts can freely diffuse to the core of the star
polymers, allowing efficient catalysis to take place. For instance, small
Figure 1. Illustration of our design: non-interpenetrating star polymers
for one-pot cascade catalysis.
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6322 J. AM. CHEM. SOC. 2008, 130, 6322–6323
10.1021/ja8013456 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Synthesis of Star Polymer
when H-bonding catalyst 8 was used to activate MVK (100 mol % relative
to 2-hexenal; Table 1, entry 2). This result showed that the widely studied
hydrogen bonding catalysis could be combined in one pot with iminium
and enamine catalysis to perform sophisticated tasks. Excellent yield (89%)
and stereoselectivity (100:7 dr, >99% ee for the major diastereomer) of
the cascade product can be achieved in 2 days when the non-interpenetrat-
ing star polymer catalysts are employed for the one-pot reaction. When
acid star polymer 5 was replaced with pTSA, and/or amine star polymer
7 with 4, no cascade product was observed (Table 1, entries 3-5).
Additionally, replacing either of the star polymers (5 and 7) with their
linear polymer analogues (11 and 12) resulted in little cascade product
formation (Table 1, entries 6 and 7). These linear polymers were made to
represent the chemical composition but not the architecture of the star
polymers. The lack of cascade product formation likely arises from
penetration of small molecule or linear polymer catalysts to the core of
the star polymers. Finally, we demonstrated that individual access to all
four possible stereoisomers of the cascade reactions can easily be achieved
through a simple combination of catalyst chirality. For instance, when
catalyst 3 is replaced with its enantiomer [(R,R)-3], a diastereomer of
cascade product 2 can be obtained with excellent stereoselectivity (Table
1, entry 8).
Table 1. One-Pot Multi-Catalyst Cascade Reactions
catalyst combinationb
yield%d (2)
drd
eee
entrya
1
2
3
4
5
6
7
8
3, 5, 7
3, 5, 7, 8
3, pTSA, 7, 8
3, 5, 4, 8
3, pTSA, 4, 8
3, 11, 7, 8
3, 5, 12, 8
star polymers
star polymers
controlsc
33
89
0
0
0
4
0
80
100:7
100:8
n.d.f
>99%
controlsc
In summary, we have demonstrated that proper site isolation with star
polymers enables the combination of otherwise incompatible catalysts for
sophisticated asymmetric cascade reactions. Our strategy may be extended
to combine stereo-incompatible catalysts (i.e., catalysts that give opposite
stereoselectivities) for one-pot cascade reactions.
controlsc
controlsc
controlsc
(R,R)-3, 5, 7, 8 star polymers
8:100 (S,S)-2 >99%
(relative to
a See Supporting Information. b About 20 mol
%
Acknowledgment. Financial support from DOE-BES (Contract No.
DE-AC02-05CH11231) and NSF (DMR 0317514) is acknowledged (S.S.)
with thanks.
2-hexenal) of each catalyst (8 is 100 mol %). c Star polymer catalyst
was replaced by its small molecule or linear polymer analogue. d Sum of
diastereomers; measured by 1H NMR of the crude reaction mixture.
e Determined by chiral phase HPLC after proper derivatization. f Not
determined.
Supporting Information Available: Addtional experimental details.
This material is available free of charge via the Internet at http://pubs.acs.org.
The catalytic activities of star polymers 5 and 7 were first evaluated
separately. Polymer 5 showed a catalytic activity comparable to that of
pTSA paired to imidazolidinone 3 for the iminium catalytic reaction (a)
in Scheme 1. While the catalytic efficiency of unoptimized star 7 is
somewhat lower than that of its corresponding small molecule analogues
for enamine catalytic reaction (b) in Scheme 1, good catalytic turnover
can still be obtained by extending the reaction time.17
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We then employed the star polymer catalysts for the one-pot multiple-
component cascade reaction shown in Table 1. In early experiments, the
three catalyst components (3, 5, 7; ∼ 20 mol % each, relative to 2-hexenal)
and the three substrates (N-methyl indole, 2-hexenal, MVK) were mixed
in one pot, and approximately 30% cascade product was observed after 5
days. Control experiments using small molecule catalysts (3, pTSA, and
4) under the same conditions did not give any cascade product. Reaction
condition optimization suggested that addition of 7 to the reaction mixture
after the iminium catalytic cycle neared its completion gave better results
(Table 1, entry 1).18 The overall reaction efficiency was further enhanced
(16) See Supporting Information for details.
(17) The reaction rate with star polymer catalysts may be affected by mass
transport, which can be influenced by solvent properties and reaction
temperature.
(18) This is likely because 7 undergoes Michael addition to 2-hexenal (presum-
ably reversibly), leading to partial consumption of 7.
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J. AM. CHEM. SOC. VOL. 130, NO. 20, 2008 6323