Aspartate-catalyzed asymmetric epoxidation reactions

Article abstract of DOI:10.1021/ja073055a

We report enantioselective epoxidation reactions that are catalyzed by aspartic acid-containing peptides. The strategy involves the transient conversion of the aspartate carboxylic acid side chain to the corresponding peracid. Reaction of olefin with the

Full text of DOI:10.1021/ja073055a

Published on Web 06/26/2007
Aspartate-Catalyzed Asymmetric Epoxidation Reactions
Gorka Peris, Charles E. Jakobsche, and Scott J. Miller*
Department of Chemistry, Yale UniVersity, P.O. Box 208107, New HaVen, Connecticut 06520-8107‡
Received May 1, 2007; E-mail: scott.miller@yale.edu
Table 1. Development of Epoxidation Conditions
Asymmetric epoxidation reactions comprise a venerable method
in organic synthesis and just as storied a testing ground for new
concepts in asymmetric catalysis.1 Among many highlights of this
history are potent metal-catalyzed methods,2 powerful ketone cata-
lysts,3,4 sulfide-catalyzed processes,5 and also the Julia´-Colonna
reaction of chalcones catalyzed by oligoamides such as poly(ala)n.6
Our own interest in this area stemmed from the hypothesis that tun-
able, peptide-based catalysts could be developed that could provide
either enantioselectivity or regioselectivity for a range of alkenes or
polyenes. In contrast to the classical nucleophilic epoxidation of
enones, as exemplified in the Julia´-Colonna epoxidation, we sought
to develop a system involving well-defined peptide-based catalysts
that could operate by an alternative, potentially generalizable
electrophilic mechanism.
The key issue to be established initially was the nature of the
catalytic moiety to reside within the peptide. As we wished to use
only readily available amino acids as the catalytic residue, we were
drawn to the carboxylic acid functionality of aspartic acid (Asp) and
glutamic acid (Glu). The plan then emerged to develop a catalytic
cycle based on Asp-derived peracids, as illustrated by the shuttle
between 1 and 2 (Scheme 1). Our plan was to capitalize on concepts
developed for carboxyl activation in peptide synthesis to generate
and regenerate the aspartic peracid 2.7 As such, we found that carbo-
diimide activation of 1, in the presence of 30% aqueous H2O2 or,
less efficiently, urea-hydrogen peroxide (UHP), led to oxygen trans-
fer to olefin 3 (Table 1, entries 2 and 3). The presence of an acyl
transfer cocatalyst such as DMAP accelerates the entire process, so
that catalytic epoxidation occurs to deliver epoxide rac-4, with up
to nearly 15 catalytic turnovers (5 mol % of 1 leading to 74% yield
of epoxide rac-4 within 3.5 h; Table 1, entry 5). To our knowledge,
these results constitute a unique demonstration of catalytic epoxi-
dation employing acid-peracid shuttles that exhibit turnover.8
entry
peroxide source
nucleophile
equiv of 1
yielda
1
2
3
aq H2O2
aq H2O2
UHP
aq H2O2
aq H2O2
0.1
0.1
0.1
0.1
0.05
10%
83%
19%
25%
74%
DMAP
DMAP
NMO
4
5b
DMAP
a Yield was measured by comparison to an internal NMR standard.
b Reaction time was 3.5 h.
5 retards the oxygen transfer process, as 5 only slowly undergoes
perhydrolysis (i.e., 5 to 2 in Scheme 2).10 Fortunately, the addition
of DMAP accelerates the oxygen transfer event (Table 1, entries 1
and 2), presumably by making the formation of 5 a reversible
process and promoting the productive catalytic cycle. Although
DMAP may undergo fast in situ oxidation to the DMAP-N-oxide
6,11 either DMAP or DMAP-N-oxide may function as a nucleophilic
catalyst, promoting the generation of 2. Indeed, NMO may be used
in the place of DMAP, albeit with reduced efficiency (Table 1,
entry 4). In any case, independent control experiments demonstrated
the critical role of each component for efficient reactions. In
particular, no reaction occurs in the absence of 1, and all the
components may coexist with essentially no conversion of 3 to 4
until Asp derivative 1 is introduced.12
Scheme 2
Scheme 1
With a robust catalytic cycle in hand, we turned our attention to
the critical issue of asymmetric induction. For this objective, we
wished to introduce Asp into a peptide sequence that would be
favorable for asymmetric catalyst-substrate interactions. We chose
peptide 7 as an initial scaffold, as this array of residues was known
to adopt â-turn-type structures that support enantioselectivity for
other processes.13 Although we expected that epoxidation would
have its own nuanced requirements for enantioselective catalysis,
â-turns have emerged as a reasonable starting place for catalyst
development. We then looked at the proficiency of catalyst 7 for
the asymmetric epoxidation of 8 to give 9 (eq 1). Carbamate
functionality was incorporated to facilitate potential catalyst-
substrate interactions through hydrogen bonding.
Several additional experiments suggest a number of competing
pathways that may operate alongside the productive catalytic cycle
shown in Scheme 1. For example, control experiments aimed at
establishing the role of each component of the reaction mixture
show that, as expected from literature precedent,9 the known9b Asp-
derived diacyl peroxide 5 is formed under the reaction conditions
(Scheme 2); this event has been shown to occur by reaction of
peracid with O-acyl urea or with carbodiimide.9a The formation of
‡ Portions of this work were conducted in the Chemistry Department at Boston
College, Chestnut Hill, Massachusetts 02467.
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10.1021/ja073055a CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
is formed with 10% ee, possibly due to the lack of a catalyst-
substrate H-bond in the transition state (Table 2, entry 10).
Nonetheless, carbamates (like 10) do lead to efficient reactions.
The basis of enantioselectivity is difficult to describe at this time.
However, our current thinking is that one or several catalyst-
substrate ensembles may operate. One limiting case involves
transition state A.15 Yet, it is difficult to exclude alternatives such
as transition state B or C. Ensembles B/C are consistent with ideas
advanced to explain the “Henbest” directed epoxidation of func-
tionalized alkenes.16,17 The experimental evaluation of modes of
asymmetric induction is currently underway.
The initial epoxidations of 8 were encouraging, with 9 exhibiting
54% ee after isolation, when 10 mol % of catalyst was employed
(eq 1). An initial survey of the nature of the carbamate revealed
that enantioselectivity could be amplified to 76% ee if the benzyl
carbamate were exchanged for the phenyl-substituted substrate 10
(Table 2, entry 1). The efficiency of the catalytic cycle allowed 17
catalytic turnovers at 25 °C, without appreciable loss in ee or yield
(full conversion of alkene 10 with 5 mol % of catalyst, Table 2,
entry 2). Simple optimization of the reaction conditions led to
further increases in ee. For example, by performing the reaction at
-10 °C, the product derived from 10 could be isolated in 97%
yield with 89% ee (Table 2, entry 3). Further improvement in
enantioselectivity (92% ee) was accomplished by running the
reaction in toluene with UHP (Table 2, entry 4).
Homologation of the carbamate function (substrate 11) results
in near total loss of enantiocontrol (Table 2, entry 5). However,
catalyst 7 exhibits excellent selectivities for a family of N-aryl-
substituted substrates. For example, p-substitution with either
electron-donating or electron-withdrawing groups does not lead to
a significant change in the efficiency. p-Fluoro-substituted com-
pound 12, for example, is processed under the reaction conditions
with 89% ee (Table 2, entry 6). p-Methoxy carbamate 13 is also
epoxidized with comparable results (Table 2, entry 7), as is acyclic
substrate 14 which delivers the corresponding epoxide with 89%
ee (Table 2, entry 8). Cyclopentene derivative 15 is also a reasonable
substrate for catalyst 7, with the corresponding epoxide formed with
86% ee (Table 2, entry 9). Although electronic substitution does
not significantly perturb selectivity, despite the possible modulation
of H-bonding capacity of substrates, we do believe that these are
H-bond-directed epoxidations.14 For example, while phenylcyclo-
hexene 3 is a substrate for catalytic epoxidation with 7, epoxide 4
Figure 1. Limiting, hypothetical transition structures indicating potential
catalyst-substrate contacts.
In summary, we have reported nonenzymatic, enantioselective
epoxidation catalysts based on transient generation of peptide-based
peracids in a catalytic mode with turnover. We note with some
curiosity that, to our knowledge, the Asp-catalyzed epoxidations
are not biomimetic with respect to “epoxidase” enzymes in biosyn-
thesis.18 Yet, given the presence of Asp and Glu in nature, ample
biochemical mechanism for carboxyl activation, and reasonable
biological concentrations of hydrogen peroxide, we wonder if
analogous epoxidations might be relevant in natural biosynthesis
in some way.
Acknowledgment. We thank the NIH (NIGMS), Merck & Co.,
and Yale University, each for partial support of this work.
Supporting Information Available: Experimental procedures and
characterization. This material is available free of charge via the Internet
at http://pubs.acs.org.
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