Functional analysis of an aspartate-based epoxidation catalyst with amide-to-alkene peptidomimetic catalyst analogues

Article abstract of DOI:10.1002/anie.200802223

Subtle exchange: Replacement of an amide function with alkene or fluoroalkene groups provides a new class of epoxidation catalysts (see scheme). The structure-dependent catalytic behavior of these isosteric peptides provides mechanistic insights in their mode of action. (Chemical Equation Presented).

Full text of DOI:10.1002/anie.200802223

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DOI: 10.1002/anie.200802223
Asymmetric Epoxidation
Functional Analysis of an Aspartate-Based Epoxidation Catalyst with
Amide-to-Alkene Peptidomimetic Catalyst Analogues**
Charles E. Jakobsche, Gorka Peris, and Scott J. Miller*
The biosynthesis of natural products that contain epoxides
represents a powerful stimulus for the study of epoxidase
enzymes.[1] Likewise, these processes have inspired a gener-
ation of science focused on small-molecule catalysts that
mediate selective epoxidations through a variety of mecha-
nisms.[2] With respect to the naturally occurring epoxidases,
the mechanistic basis of O-atom transfer is often associated
with the chemistry of either flavinoid cofactors, P450 enzymes
containing a heme group, or chloroperoxidases that lead to
stepwise ring formation.[3] In thinking about the known
biosynthetic apparatus for epoxide formation, we became
curious about an alternative mode for O-atom transfer—one
based on functional groups available in proteins, but perhaps
not well-documented in the biosynthesis of epoxides. In
particular, we speculated and recently showed that aspartic
acid containing peptides (e.g., 1; Scheme 1a) might shuttle
between the side-chain carboxylic acid and the corresponding
peracid (e.g., 2) creating a catalytic cycle competent for
asymmetric epoxidation with turnover of the aspartate-
derived catalyst. Such an approach is orthogonal to the
Julia–Colonna epoxidation, a complementary peptide-based
epoxidation based on a nucleophilic mechanism.[4] Indeed, as
Scheme 1. a) Previously reported catalytic cycle for epoxidation.
shown in Scheme 1b, this new electrophilic epoxidation
b) Asymmetric catalytic epoxidation with peptide 5. Conditions: 5
catalytic cycle mediates the asymmetric epoxidation of
(10 mol%), DIC (2.0 equiv), DMAP (10 mol%), H2O2 (30% aq,
substrates like 3 to give products like 4 with up to 92% ee.[5]
2.5 equiv) or urea–H2O2 (2.5 equiv), CH2Cl2 or toluene (1.0m), À10 or
Mechanistic questions abound in this catalytic system. To
date, we have identified a number of relevant aspects. For
example, we observed off-catalytic cycle intermediates,
including catalytically inactive diacyl peroxides (6).[6] We
also showed that these off-cycle intermediates could be
reinserted into the productive pathway through the action of
nucleophiles such as DMAP or DMAP-N-oxide (7). On the
other hand, the basis of stereochemical information transfer
was not immediately clear. Indeed, the high precision
delineation of the stereochemical mode of action of chiral
catalysts is a critical aspect in the discipline of asymmetric
catalysis, whether the catalysts are enzymes or small mole-
cules. With this back-drop, we began a detailed study of the
mode of action for catalyst 5.
48C, 1–3 d. DIC = diisopropylcarbodiimide, DMAP = 4-dimethylami-
nopyridine.
The conversion of 3 to 4 was originally undertaken with
the hypothesis that substrate–catalyst hydrogen bonding
might contribute to transition state organization.[7] Indeed, a
substrate lacking obvious H-bonding capability (phenylcyclo-
hexene) was found to undergo epoxidation with catalyst 5
with low enantioselectivity (ca. 10% ee). Thus, we envisioned
several potential loci for contacts between
3 and 5
(Scheme 2a). Shown in blue is the site that represents
possible Henbest-type interactions (e.g., ensembles A and
B).[8] Shown in red are other H-bonding sites that might
contribute to the preferential formation of 4. Of these, hand-
held models suggested that C is consistent with the formation
of the major enantiomer. Nevertheless, we sought to inter-
rogate each potential binding site to identify the site(s) of
interaction.
To evaluate the importance of the NHBoc functionality,
we synthesized catalyst analogue 8, in which the NHBoc
group is replaced with a methyl group.[9] As shown by X-ray
crystallography (Scheme 3), analogue 8 adopts the expected
Type-II b-turn in the solid state.[10,11] Notably, when catalyst 8
is evaluated in the asymmetric epoxidation of 3 under a
[*] C. E. Jakobsche, G. Peris, Prof. S. J. Miller
Department of Chemistry, Yale University
225 Prospect Street, New Haven, CT 06520-4900 (USA)
Fax: (+1)203-496-4900
E-mail: scott.miller@yale.edu
[**] We thank the NIH (National Institute of General Medical Sciences)
and Merck Research Laboratories, each for partial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200802223.
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Scheme 4. a) Synthesis and b) catalytic efficiency of 9. Conditions:
238C, toluene, 30% H2O2, DCC, DMAP, 0.4m, 12 h.
From the functional perspective, catalyst 9 affords a result
that suggests that the Pro-d-Val amide could well be involved
in a catalyst–substrate H-bond in the transition state. As
shown in Scheme 4b, the conversion of 3 to 4 occurs with a
much-reduced 16% ee under catalysis by peptide 9. Notably,
our observations suggest that self-epoxidation of catalyst 9 is
significantly slower than epoxidation of substrate 3 under
these conditions.[17]
Scheme 2. a) Possible catalyst–substrate H-bonding loci shown in
color. b) Representative transition-state ensembles.
Perhaps of great significance, however, is the observation
that peptidomimetic catalyst 9 exhibits conformational prop-
erties that are surprisingly different from catalyst 5. Whereas
catalyst 5 appears as a single conformation in solution by
1H NMR (400 MHz) (Figure 1a), consistent with the b-turn
Scheme 3. Catalytic performance and X-ray analysis of peptide 8.
Conditions: a) 48C, toluene, urea/H2O2 complex, DIC, DMAP, 1.0m,
33 h; b) 238C, toluene, 30% H2O2, DCC, DMAP, 0.4m, 12 h. DCC =
dicyclohexylcarbodiimide.
Figure 1. Partial 1H NMR spectra of catalysts 5, 9, and 11.
common set of conditions (238C, toluene, 12 h),[12] product 4
is produced with 88% ee, which is analogous to that observed
with original catalyst 5. The fact that peptides 5 and 8 are both
selective catalysts suggests that they likely exhibit similar
three-dimensional structures. In this vein, the data suggests
that the NHBoc group is not involved in an important H-
bonding interaction with substrate.
For the functional evaluation of the Pro-d-Val amide, we
turned to the application of alkene isosteric replacements of
the amide bond.[13] We have previously used this strategy in
the mechanistic dissection of peptide-based asymmetric
acylation catalysts.[14] We therefore sought to synthesize and
study catalyst 9 (Scheme 4a). Peptide 9 was prepared in five
steps from known compound 10.[15,16]
observed in the X-ray structure of 8, catalyst 9 appears as a
heterogeneous 3.5:1 mixture of two distinct catalyst confor-
mations (Figure 1b). Notably, the signals coalesce when the
NMR sample is heated to 1008C ([D6]DMSO solvent).
Nevertheless, the lack of good homology between the room
temperature conformational profiles of catalysts 5 and 9
warranted additional experiments to ascertain the functional
role of the Pro-d-Val amide in catalyst 5.
Whereas dipeptide alkene isosteres have been found to be
good steric mimics of amide bonds in peptides and proteins,[18]
it is also well-recognized that they provide a poor mimic of
other properties intrinsic to amides. In order to recapture
amide-like character in an olefinic mimic, dipeptide fluoro-
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olefin isosteres have been introduced.[19] In this context, it is
also increasingly appreciated that the structural features that
cause peptides to adopt secondary structures (including b-
turns) are complex. In addition to hydrogen bonding,[20] allylic
strain about the Pro-d-Val amide,[21] dipole neutralization of
the Pro-d-Val carbonyl,[22] and n-to-p* donation[23] from the
Xaa-Pro carbonyl lone pair to the Pro-Yaa carbonyl may each
contribute to the b-turnꢀs stability.
Indeed, fluoroalkene 11 proves to be conformationally
more robust than alkene-isostere catalyst 9. Whereas the
1H NMR spectra for catalyst 9 reveal a 3.5:1 conformational
mixture (238C), fluoroalkene catalyst 11 exhibits an approx-
imately 10:1 mixture of conformations at the same temper-
ature (Figure 1c). Once again, coalescence of the spectrum is
observed when the sample is examined by 1H NMR at 1008C
([D6]DMSO).
Stimulated by these ideas, we
undertook a synthesis of catalyst
analogue 11. Our hypothesis was
that the fluoroalkene moiety would
be a better mimic of the local proper-
ties contributing to faithful b-turn
Further 1H NMR data (1H-1H NOESY) support the
conformational analogies between peptide 5 and the major
conformers of both 9 and 11 (Scheme 6). These data suggest
that the original peptide and the major conformations of the
isosteres adopt b-turn structures similar to that exhibited in
the crystal structure of peptide 8 (see Scheme 3).
nucleation, and that this catalyst
would therefore be a better probe
of catalyst 5.
Scheme 5 shows the synthesis of fluoroalkene isostere
11.[24] The catalyst was prepared in twenty-one steps and 2%
overall yield from phenylalanine (sixteen steps from com-
pound 12).[9,25] The configuration of enoate 16 was set by a
two-step olefination procedure. The stereogenic center in
sulfinamide 20 was introduced using an auxiliary-controlled
reductive amination.[26] Oxidation of alcohol 22 and coupling
to amine 23 gave catalyst 11.[27]
Scheme 6. Select NOE contacts from the major conformational iso-
mers of peptide 5 and its isosteres 9 and 11.
The actual asymmetric epoxidation reactions catalyzed by
11 offer intriguing results, delivering the product with 52%
ee—intermediate between the selectivity afforded by catalysts
5 (81% ee) and 9 (16% ee) under a common set of conditions
(Scheme 7).
Scheme 5. Synthesis of fluoroalkene isostere 11: a–e) See Supporting
Information; f) DiPEA, MOMCl, CH2Cl2, 08C, 2.5 h; g) LiOH, H2O2,
THF, H2O, 08 to 238C, 3 h; h) oxalyl chloride, DMF, diethyl ether,
238C, 15 min, 80% yield (3 steps); i) 14, NaH, THF, 238C, 1 h, then
13, À408C, 1 h, (5:1 d.r., use mixture); j) NaBH4, EtOH, À408C, 2.5 h,
69% (2 steps, >20:1 d.r.); k) MeNHOMeHCl, iPrMgCl, THF, 08C,
1.5 h, 79%; l) 17, diethyl ether, tBuLi, À788 to 238C, 30 min, then
Weinreb amide of 16, À788C, 1 h, 59%; m) 19, Ti(OEt)4, THF, reflux,
3 h; n) DiBAl-H, À788C, 3 h; o) TBAF, THF, 238C, 40 min, 95%
(3 steps); p) DEAD, PPh3, THF, 238C, 2 h, 80%; q) HCl/dioxane,
MeOH, 238C, 1.5 h; r) Boc-Asp(OBn)-OH, EDC, HOBt, TEA, CH2Cl2,
238C, 14 h, 70% (2 steps); s) PDC, DMF, 238C, 6 h, 90%; t) 23, EDC,
HOBt, CH2Cl2, 238C, 14 h, 47%; u) LiOH, dioxane, water, 238C, 16 h,
89%. DiPEA = diisopropylethylamine, MOM = methoxymethyl,
DiBAl-H = diisobutylaluminum hydride, TBAF = tetrabutylammo-
nium fluoride, DEAD = diethyl azodicarboxylate, EDC = N’-(3-
dimethylaminopropyl)-N-ethylcarbodiimide, PDC = pyridinium dichro-
mate.
Scheme 7. Catalytic epoxidation data with catalysts 5, 9, and 11.
Conditions: a) 238C, toluene, 30% H2O2, DCC, DMAP, 0.4m, 12 h.
The intermediate selectivity observed with fluoroalkene
isosteric catalyst 11 allows for a number of interpretations.
One is that indeed, transition state C (Scheme 2b, above) may
be the dominant pathway leading to the preferential forma-
tion of the major enantiomer in the conversion of 3 to 4. The
near eradication of enantioselectivity with catalyst 9 (16% ee)
may signal the loss of operation of the dominant pathway,
revealing a base level of enantioselectivity through simple
shape-selectivity associated with the catalyst. The appearance
of partially recovered enantioselectivity with catalyst 11
(52% ee; cf. 81% ee with 5), might then be explained by a
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weaker, but still significant H-bonding interaction in the
transition state involving catalyst 11. The energetics of
=
C O···HN hydrogen bonds versus CF···HN have been dis-
cussed in the literature, with some debate. Evidence
against,[28] and in favor of such interactions has been
described.[29] In the present case, the structure–selectivity
relationship revealed by catalysts 5, 9, and 11 may suggest that
a continuum exists with these catalysts (Scheme 8) that is
consistent with a moderate, but attractive CF···HN interaction
in the dominant transition state.
Scheme 9. Consequences of C-terminal amide replacements for ee.
Conditions: a) 238C, toluene, 30% H2O2, DCC, DMAP, 0.4m, 12 h.
function. The detailed interrogation of structure–function
relationships is a critical step for increasing our understanding
of asymmetric catalysis. Mechanistic studies of peptide-based
systems may also help to elevate our appreciation of analogies
between synthetic catalysts and enzymes, an activity at the
heart of biomimetic science.[30]
Received: May 12, 2008
Published online: July 22, 2008
Keywords: asymmetric catalysis · epoxidation · fluorine ·
.
olefin isostere · peptides · peptidomimetic
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;
CCDC 687520 contains the supplementary crystallographic
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