A peptide-embedded trifluoromethyl ketone catalyst for enantioselective epoxidation

Article abstract of DOI:10.1021/ol3000712

The development of peptide-based oxidation catalysts that use a transiently generated dioxirane as the chemically active species is reported. The active catalyst is a chiral trifluoromethyl ketone (Tfk) with a pendant carboxylic acid that can be readily incorporated into a peptide. These peptides were capable of epoxidizing alkenes in high yield (up to 89%) and enantiomeric ratios (er) ranging from 69.0:31.0 to 91.0:9.0, depending on the alkene substitution pattern.

Full text of DOI:10.1021/ol3000712

ORGANIC
LETTERS
2012
Vol. 14, No. 4
1138–1141
A Peptide-Embedded Trifluoromethyl
Ketone Catalyst for Enantioselective
Epoxidation
David K. Romney and Scott J. Miller*
Department of Chemistry, Yale University, P.O. Box 208107, New Haven,
Connecticut 06520, United States
scott.miller@yale.edu
Received January 12, 2012
ABSTRACT
The development of peptide-based oxidation catalysts that use a transiently generated dioxirane as the chemically active species is reported. The
active catalyst is a chiral trifluoromethyl ketone (Tfk) with a pendant carboxylic acid that can be readily incorporated into a peptide. These peptides
were capable of epoxidizing alkenes in high yield (up to 89%) and enantiomeric ratios (er) ranging from 69.0:31.0 to 91.0:9.0, depending on the
alkene substitution pattern.
The impact of chiral and achiral dioxiranes on the field
of organic synthesis has been extensive.1 Of the myriad
transformations executed by these highly reactive oxi-
dants, catalytic asymmetric epoxidation is perhaps the best
known (Figure 1a).2 In particular, the work of Shi, which
employs chiral fructose-based ketone catalysts, has been
remarkable for its generality and outstanding levels of
enantioselectivity.3 The application of dioxiranes in CÀH
bond oxidations is also significant.4 In a particularly dra-
matic illustration of this reaction, Wender reported the use
of an isolated dioxirane for the regioselective and stereo-
specific oxidation of a Bryostatin analogue (Figure 1b).5
With the goal of developing diverse catalyst libraries for
the oxidation of complex substrates, we wondered if it might
be possible to develop a peptide-embedded ketone that would
be competent for catalytic dioxirane-based oxidations.
€
(1) Adam, W.; Zhao, C.-G.; Saha-Moller, C. R.; Jakka, K. Oxidation
of Organic Compounds by Dioxiranes; Wiley: Hoboken, NJ, 2009.
(2) Wong, O.; Shi, Y. Chem. Rev. 2008, 108, 3958–3987.
(3) Wang, Z. X.; Tu, Y.; Frohn, M.; Zhang, J. R.; Shi, Y. J. Am.
Chem. Soc. 1997, 119, 11224–11235.
(4) Curci, R.; D’Accolti, L.; Fusco, C. Acc. Chem. Res. 2006, 39, 1–9.
(5) Wender, P. A.; Hilinski, M. K.; Mayweg, A. V. W. Org. Lett.
2005, 7, 79–82.
Figure 1. Venerable reactions of dioxiranes. (a) Asymmetric
epoxidation with the catalyst of Shi. (b) Regioselective CÀH
oxidation of a Bryostatin analogue reported by Wender.
r
10.1021/ol3000712
Published on Web 02/08/2012
2012 American Chemical Society

Peptide-based catalysts6 and ligands7 offer inherent
modularity and can be tuned for optimization of
various properties, such as stereo- and regioselectivity.
Peptide-based oxidation catalysts in particular have a
venerable history and have also been the subject of more
trifluoromethyl ketone 3 (Scheme 1) for a number of
reasons. First, our desire to develop catalysts that would
proceed through highly reactive dioxiranes dictated the use
of a trifluoromethyl group over simple aliphatic sub-
stitution.10 Second, we chose to replace the NHBoc group
of 1 with the methyl group of 3 to simplify synthesis in this
first generation study. The latter decision was inspired by
earlier studies of aspartyl peptide-based catalysts, in which
we observed that the NHBoc group could be replaced
with a methyl substituent without loss of selectivity.11 Our
synthesisof3 ispresentedbelow and has beenused tomake
over 5 g of monomer.
ꢀ
recent studies. The JuliaÀColonna epoxidation of chal-
cones employs oligomeric peptides to control the reactivity
of hydrogen peroxide in a putatively nucleophilic epoxida-
tion reaction (Figure 2a).8 On the other hand, peptide-
embedded aspartic acids may be engaged as catalysts
for asymmetric electrophilic epoxidation via the intermedi-
ate peracid (Figure 2b).9 Our goal in this study was to
explore whether or not peptide-embedded ketones such as
1 could be converted to the dioxirane (2) in situ and used
as electrophilic oxidants without undergoing intramolecu-
lar oxidation (Figure 2c). If so, the stage would be set
for a broad study of peptide-based ketones for catalytic
oxidation.
Scheme 1. Synthesis of Tfk Precursor
The monomer synthesis began with the chiral auxiliary
of Seebach (4),12 which was acylated with propionyl chlo-
ride and subsequently alkylated with allyl bromide to
give 5 as a single diastereomer after recrystallization. The
auxiliary was cleaved with BnOLi to give the enantiopure
benzyl ester 6. Ozonolysis of the terminal alkene af-
forded aldehyde 7, which underwent nucleophilic tri-
fluoromethylation to generate the trifluoromethyl car-
binol. This was immediately protected as the acetate
ester (8). Finally, the benzyl group was removed through
hydrogenolysis to give the free acid 9, which served as a
Tfk precursor that could be efficiently incorporated into
a peptide and subsequently converted to the ketone to
give 3 (Scheme 2).
Figure 2. Peptide-based catalysts for asymmetric epoxidation.
ꢀ
cess. (b) Catalytic asymmetric epoxidation with aspartyl pep-
tides. (c) Proposed peptide-embedded ketone catalysts for
oxidation.
(a) Nucleophilic epoxidation through the JuliaÀColonna pro-
We thus began with consideration of the appropriate
catalytic monomer to be incorporated into a peptide
catalyst. Our design criteria converged on the chiral
(6) (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138–
5175. (b) Berkessel, A. Curr. Opin. Chem. Biol. 2003, 7, 409–419. (c)
Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58, 2481–2495.
(7) (a) Agarkov, A.; Greenfield, S.; Xie, D.; Pawlick, R.; Starkey, G.;
Gilbertson, S. R. Biopolymers 2006, 84, 48–73. (b) Shimizu, K. D.;
Snapper, M. L.; Hoveyda, A. H. Chem.;Eur. J. 1998, 4, 1885–1889.
Scheme 2. Incorporation of 9 into a Peptide
ꢀ
(8) (a) Julia, S.; Masana, J.; Vega, J. C. Angew. Chem., Int. Ed. 1980,
19, 929–931. (b) Kelly, D. R.; Roberts, S. M. Biopolymers 2006, 84, 74–
89. (c) Berkessel, A.; Koch, B.; Toniolo, C.; Rainaldi, M.; Broxterman,
Q. B.; Kaptein, B. Biopolymers 2006, 84, 90–96.
(9) Peris, G.; Jakobsche, C.; Miller, S. J. Am. Chem. Soc. 2007, 129,
8710–8711.
Org. Lett., Vol. 14, No. 4, 2012
1139

We proceeded to synthesize a variety of peptide-
embedded ketones (Figure 3) in order to test their ability to
convert 1-phenylcyclohex-1-ene (10, Table 1) to the corre-
sponding epoxide (11). Our exploration began with pep-
tide 12 (entry 1) because of its structural similarity to a
previous epoxidation catalyst9 and because peptides of
analogous composition are known to adopt β-type turns
that can potentially control enantioselectivity.13 The reac-
tion conditions were based on those developed by Shi14
and modified to give full conversion of the substrates.
Notably, in the absence of ketone, negligible epoxidation
occurs (as assessed by 1H NMR).
Table 1. Screen of Peptide Catalysts for Epoxidation of 10
Figure 3. Structures of representative catalysts.
provided by catalysts 18 and 19 (entries 7 and 8) suggests
that the substrate interacts mainly with the Tfk residue of
the peptide.
entry
catalyst
era
In light of these discoveries, we have considered a transi-
tion state model in which the substrate approaches from
the side of the dioxirane that is opposite the peptide
backbone (Figure 4a). We arranged the molecule by mini-
mizing allylic strain15 between the Tfk stereocenter and the
amide and then drawing the side chain in an “all anti”
configuration to minimize steric repulsion. The substrate
was oriented by matching the smallest alkene substituent
(H) with the largest dioxirane substituent (CF3) and by
assuming a spiro transition state, which has been shown
both experimentally3 and theoretically16 to be favored,
ostensibly due to secondary orbital overlap between the
lone pairs on oxygen with the π* orbital of the alkene.
Additionally, we were able to obtain a crystal structure of
18 in its hydrated form that correlates well with the
structure of the dioxirane in our transition state model
(Figure 4b).
1
2
3
4
5
6
7
8
Tfk-Pro-D-Val-(R)-Mba (12)
Tfk-Pro-D-Val-(S)-Mba (13)
Tfk-Pro-Val-(R)-Mba (14)
Tfk-Pro-tert-Butylamine (15)
Tfk-Pro-OCH3 (16)
87.0:13.0
85.0:15.0
89.5:10.5
88.5:11.5
88.0:12.0
86.5:13.5
84.5:15.5
84.0:16.0
Tfk-D-Pro-OCH3 (17)
Tfk-Pyrrolidine (18)
Tfk-Dimethylamine (19)
a Enantioselectivity was determined by HPLC using a chiral sta-
tionary phase (Chiralcel OJ-H). Mba = R-methylbenzylamine.
We were gratified to see that under the exploratory reac-
tionconditions, epoxide11was formed in an er of 87.0:13.0
(Table 1, entry 1). This ratio decreased when the terminal
residue was changed to the S-configuration (catalyst 13,
entry 2), but interestingly, when the D-Val residue was
changed to L-Val, the er increased to 89.5:10.5 (catalyst 14,
entry 3). This result made us question whether or not a
β-turn was important to the enantioselectivity of this
reaction. To probe this hypothesis, we synthesized catalyst
15, in which the capacity for a β-turn was absent. Surpris-
ingly, this catalyst provided almost the same selectivity as
catalyst 14 (entry 4 vs 3). The er was minimally perturbed
when the catalyst was simplified further (catalysts 16 and
17, entries 5 and 6).
Finally, we synthesized catalysts 18 and 19, in which the
only chiral element was the stereocenter found in Tfk.
Although they afforded slightly lower enantioselectivities
than the previous catalysts, the asymmetric induction
Figure 4. (a) Spiro transition state that gives the observed
stereochemistry. (b) X-ray crystal structure of 18•H2O.
(10) Blank, J. T.; Miller, S. J. Biopolymers 2006, 84, 38–47.
(11) Jakobsche, C.; Peris, G.; Miller, S. Angew. Chem., Int. Ed. 2008,
47, 6707–6711.
(12) Hintermann, T.; Seebach, D. Helv. Chim. Acta 1998, 81, 2093–
2126.
Having explored the simplest catalysts, we returned to
our initial hit catalyst (14). We found that the selectivity
increased slightly when we lowered the concentration of
(13) (a) Haque, T. S.; Gellman, S. H. J. Am. Chem. Soc. 1996, 118,
6975–6985. (b) Miller, S. J. Acc. Chem. Res. 2004, 37, 601–610.
(14) (a) Shu, L.; Shi, Y. Tetrahedron Lett. 1999, 40, 8721–8724. (b)
Burke, C. P.; Shu, L.; Shi, Y. J. Org. Chem. 2007, 72, 6320–6323.
(15) Hoffman, R. W. Chem. Rev. 1989, 89, 1841–1860.
(16) Bach, R. D.; Andres, J. L.; Owensby, A. L.; Schlegel, H. B.;
McDouall, J. J. W. J. Am. Chem. Soc. 1992, 114, 7207–7217.
1140
Org. Lett., Vol. 14, No. 4, 2012

K2CO3 and changed to a solvent mixture of tert-amyl
alcohol and water (Scheme 3 and Table 2). These condi-
tions proved operationally straightforward and applicable
to a broad set of substrates.17
Table 2. Substrate Scope for Epoxidation with 14a
Scheme 3. Optimized Conditions for Epoxidation
With our optimized conditions, we tested a variety of
substrates. We found that our initial substrate, 1-phenyl-
cyclohex-1-ene (10), gave the corresponding epoxide in
88% yield and with an er of 90.5:9.5 (Table 2, entry 1).
Similarly, the analogous cyclopentene (20) was also epox-
idized in high yield, with only a slight drop in enantios-
electivity (entry 2). Acyclic variant 21 showed a greater
drop in selectivity, but the high reactivity was maintained
(entry 3). Remarkably, the highly reactive 1-(4-methoxy-
phenyl)cyclohex-1-ene (22) could also be epoxidized with
high enantioselectivity (entry 4), suggesting that the back-
ground rate for these conditions is minimal. Finally,
naphthyl analogue 23, despite its low solubility, could still
be epoxidized in 75% yield and even higher enantioselec-
tivity than 10 (entry 5).
With disubstituted alkenes, the selectivity was only
modest, but the yields remained high. Substrate 24 was
epoxidized in 89% yield with 71.0:29.0 er (entry 6), and
substrate 25 afforded the corresponding epoxide in 75%
yield with 69.5:30.5 er (entry 7).
In conclusion, we have developed a trifluoromethyl
ketone that can be efficiently incorporated into a peptide
and used as a catalyst for the asymmetric epoxidation of
alkenes. We were able to tune the selectivity of the catalyst
by varying the sequence of the peptide scaffold, and this
a The reaction conditions are shown in Scheme 3. b Products were
isolated by flash chromatography. c Enantioselectivity was determined
by HPLC with a chiral stationary phase. d Absolute stereochemistry was
assigned by measuring the optical rotations and comparing them to the
literature. e Yield is for mixture of trans and cis isomers (3.8:1.0). This
phenomenon corresponds to the fact that the starting material was
employed as a mixture of cis/trans isomers. f For this substrate, 12 equiv
of H2O2 and CH3CN were used.
approach may enable us to address classes of substrates for
which current methods give poor selectivity. The next phase
of this research will involve the evaluation of peptide-
embedded ketones (e.g., 1) as a family of catalysts for
selective reactions proceeding throughtransient dioxiranes.
Acknowledgment. We are grateful for research support
from the National Institute of General Medical Sciences of
the National Institutes of Health (GM096403). We also
thank N. D. Schley for performing the X-ray crystallography.
(17) We note that the results are highly analogous when Oxone is
used as the oxidant, under the standard conditions of Shi and co-workers
(ref 3).
(18) Berti, G.; Macchia, B.; Macchia, F.; Monti, L. J. Org. Chem.
1968, 33, 4045–4049.
(19) Bulman Page, P. C.; Buckley, B. R.; Blacker, A. J. Org. Lett.
Supporting Information Available. Procedures and char-
acterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
2004, 6, 1543–1546.
(20) Absolute stereochemistry was inferred by analogy to the other
substrates.
(21) Witkop, B.; Foltz, C. M. J. Am. Chem. Soc. 1957, 79, 197–201.
(22) Fujisawa, T.; Takemura, I.; Ukaji, Y. Tetrahedron Lett. 1990,
31, 5479–5482.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 4, 2012
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