A Synergistic Combinatorial and Chiroptical Study of Peptide Catalysts for Asymmetric Baeyer-Villiger Oxidation

Article abstract of DOI:10.1002/adsc.201500230

We report an approach to the asymmetric Baeyer-Villiger oxidation utilizing bioinformatics-inspired combinatorial screening for catalyst discovery. Scaled-up validation of our on-bead efforts with a circular dichroism-based assay of alcohols derived from

Full text of DOI:10.1002/adsc.201500230

FULL PAPERS
DOI: 10.1002/adsc.201500230
A Synergistic Combinatorial and Chiroptical Study of Peptide
Catalysts for Asymmetric Baeyer–Villiger Oxidation
a
b
a
a,
Michael W. Giuliano, Chung-Yon Lin, David K. Romney, Scott J. Miller, *
b,
and Eric V. Anslyn *
Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06520-8107, USA
a
Fax: (+1)-203-436-4900; phone: (+1)-203-432-9885; e-mail: scott.miller@yale.edu
Department of Chemistry, The University of Texas at Austin, Austin, Texas 78712, USA
b
Fax: (+1)-512-471-8696; phone: (+1)-512-471-0068; e-mail: anslyn@austin.utexas.edu
Received: March 5, 2015; Revised: April 14, 2015; Published online: July 14, 2015
th
Dedicated to Prof. Stephen L. Buchwald on the occasion of his 60 birthday.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500230.
Abstract: We report an approach to the asymmetric in its speed of analysis. Further solution-phase
Baeyer–Villiger oxidation utilizing bioinformatics-in- screening of a focused library suggested a mode of
spired combinatorial screening for catalyst discovery. asymmetric induction that draws distinct parallels
Scaled-up validation of our on-bead efforts with a cir- with the mechanism of Baeyer–Villiger monooxyge-
cular dichroism-based assay of alcohols derived from nases.
the products of solution-phase reactions established
the absolute configuration of lactone products; this
assay proved equivalent to HPLC in its ability to Keywords: Baeyer–Villiger oxidation; catalysis; cir-
evaluate catalyst performance, but was far superior cular dichroism; peptides
Introduction
a DIC-activated aspartic acid side-chain with hydro-
gen peroxide (Figure 1a). While initially developed
[5]
Over the course of the storied evolution of asymmet- for asymmetric epoxidation reactions, we have also
ric catalysis, certain families of catalysts have proven applied this catalytic cycle to the B–V oxidation of
[1]
[6]
to be applicable to many different organic reactions.
a variety of cyclic ketones. Very recently, our group
While a universal understanding of why such ꢀprivi- reported the application of this combinatorial ap-
legedꢁ catalyst scaffolds are able to translate from one proach to the discovery of a peptide-based B–V oxi-
[6b]
reaction to another remains elusive, it is noteworthy dation catalyst. This catalyst was proficient at over-
that many catalysts operate in a similar fashion: re- coming the substratesꢁ inherent regioselectivity biases
striction of the orientations of reacting molecules in by means of directing group interactions (Fig-
[7]
solution in the key bond-forming steps. However, ure 1b). Catalyst-substrate interactions predicated
there are many asymmetric transformations in which on hydrogen-bonding seem to be at the heart of the
the initial bond-forming steps of a reaction are not observed high selectivity in our earlier studies, but
stereodetermining, and thus these scaffolds and/or ra- substrates that lack functionality for the same type of
tional design-based approaches have not been particu- phenomena present a special challenge. Herein we
larly successful. One such reaction is the venerable report the synergistic use of combinatorial screening,
[
2]
Baeyer–Villiger (B–V) oxidation, which remains rational library design, HPLC analysis, and a recently
[3]
a formidable challenge to asymmetric catalysis.
reported chiroptical assay that involves a multi-com-
Our laboratory has employed a combinatorial ap- ponent assembly, all of which lays the foundation for
proach to develop aspartic acid-containing peptide- the use of peptide-based B–V catalysts with substrates
based oxidation catalysts to address chemical transfor- that lack directing groups (Figure 1c). The chiroptical
[8]
mations that are often recalcitrant to hypothesis- assay played a crucial role in evaluating catalyst per-
[
4]
driven catalyst design. The catalysts operate via in formance, and provided stereochemical information
situ generation of a peracid from the reaction of about the oxidation products that will inform our
Adv. Synth. Catal. 2015, 357, 2301 – 2309
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Michael W. Giuliano et al.
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Figure 2. (a) Tetrahedral sulfate anion bound by helical pro-
tein loop. PDB: 1YCC. (b) Library composition informed
by bioinformatics analysis of protein binding loop sequen-
ces. (c) Screening results using 50 beads from combinatorial
peptide library. Reactions were 0.1M in ketone substrate on
a scale of 0.69 mmol ketone. Each bead contained 69 nmol
peptide catalyst, corresponding to a loading of 10 mol%.
H O was added from a stock solution at a concentration of
2
2
3.0M.
Figure 1. (a) Catalytic cycle for peracid-mediated B–V oxi-
purposes of a peptide-catalyzed asymmetric B–V oxi-
dations based on DIC/H O activation of aspartic acid. Inset
2
2
–
Newman projection of the Criegee intermediate. (b) Inver- dation, owing to the structural similarities between
sion of inherent substrate regioselectivity preferences via tetrahedral anions and Criegee intermediates (cf. IV
use of a combinatorially discovered peptide catalyst and an
amide directing group (ovals). (c) Work-up and assembly
used herein to measure ee values via CD spectroscopy.
in Figure 1a). We prepared a combinatorial library
[6b]
based on a bioinformatic analysis of a so-called
[10b,c]
CaNN’ motif,
in which the first two variable resi-
dues were biased toward helix-promoting amino acids
future efforts in catalyst development for the B–V ox- and the last position incorporated Val to accommo-
idation. Its successful implementation has established date b-strand torsion angles. Alanine was chosen as
an important benchmark toward our future goal of re- the C-terminal residue of the library to account for
alizing ultra-high throughput screening, with, poten- the helical preferences of a number of the anion-bind-
[9]
[10c]
tially, hundreds of ee values determined per hour.
ing protein loops.
The N-terminal residues consist-
ed of the catalytically active Asp followed by an l-
Pro residue, preempting the possibility of aspartimide
[11]
Results and Discussion
rearrangement under the reaction conditions. This
library comprised 450 unique sequences immobilized
Our attention was drawn to a body of literature con- onto Rink linker-functionalized polystyrene macro-
[
10]
cerning protein-anion interactions.
a number of different protein loop sequences have
been observed to interact with phosphate, sulfate, and oxidation of the sterically challenging ketone sub-
Specifically, beads (Figure 2b).
Our on-bead screening commenced with the B–V
[
10b,c]
other anions (e.g., Figure 2a).
We wondered if strate, cis-2,6-diphenylcyclohexanone (Figure 2c); the
this sequence space could be reappropriated for the previously reported peptide B–V catalyst was unable
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A Synergistic Combinatorial and Chiroptical Study of Peptide Catalysts
Table 1. Solution-phase validation and focused library screening of peptide catalysts for the B–V oxidation.
[a]
[c,d]
[c,d]
[c,e]
Entry
Sequence (i+2, i+3, i+4)
Conversion [%]
ee [HPLC, %]
ee [CD, %]
[
g]
1
2
3
4
5
6
7
8
9
Leu-Phe-Tyr(O-t-Bu)
Leu-Phe-Thr(OBn)
Lys(Z)-Lys(Z)-Ala
Leu-Lys(Z)-Thr(OBn)
Leu-Leu-Thr(OBn)
Leu-Cha-Ala
Boc-Asp(OH)-OBn
Ser(OBn)-Gly-Val
Ser(OBn)-Lys(Z)-Ser(OBn)
Ser(OBn)-Cha-Tyr(O-t-Bu)
Ser(OBn)-Leu-Ser(OBn)
Ser(OBn)-Leu-Leu
75
63
70
59
74
77
> 99
55
76
82
77
75
46
42
24
39
33
40
À2
À35
À41
À37
À47
À51
–
43
22
36
29
36
[
g]
–
À32
À42
À42
À44
1
1
1
0
1
2
[
g]
–
[b]
[c,d]
[c,d]
[c,e]
Entry
Sequence (i+2, i+3)
Conversion [%]
ee [HPLC, %]
ee [CD, %]
1
1
1
1
1
1
1
2
2
2
3
4
5
6
7
8
9
0
1
2
Pro-Ser(O-t-Bu)
Hyp(O-t-Bu)-Ser(O-t-Bu)
Pip-Ser(O-t-Bu)
Ala-Ser(O-t-Bu)
Pro-Ser(OH)
82
90
90
59
85
41
47
20
88
91
À8
9
5
À9
8
3
4
1
À10
À6
À3
1
À5
À6
À4
1
Hyp(O-t-Bu)-Ser(OH)
[f]
Pip-Ser(OH)
Ala-Ser(OH)
Pro-Thr(OBn)
Hyp(O-t-Bu)-Thr(OBn)
À10
À8
1
0
[
[
[
a]
Parent sequence of library hits: Boc-Asp-Pro-Xaa-Xaa-Xaa-Ala-Gly-OMe.
Parent sequence of focused library: Boc-Asp-Xaa-Xaa-Leu-Leu-Ala-Gly-OMe.
b]
c]
Average of two runs. Note: sign of ee corresponds to favoring the first (+) or second (À) lactone enantiomer to elute on
an HPLC assay, not optical rotation.
[
[
d]
e]
Determined from HPLC traces of worked up reactions.
Determined from CD intensity at 270 nm of complex that incorporated lactone-derived secondary alcohol. All runs car-
ried out on a scale of 0.3 mmol ketone.
Single run due to limited catalyst material.
Catalyst used to develop CD calibration curve.
[
[
f]
g]
to provide a positive result under on-bead condi- the l configuration. MS/MS sequencing indicated that
[
6]
tions. After screening only fifty beads, we observed the two groups of sequences had distinct preferences
a number of catalysts that seemed to converge into at the (i+2) position. One group universally had an
two groups. Each favored opposite enantiomers of the O-benzyl serine (i+2) residue while the other group
lactone product up to approximately 30% ee, despite favored an (i+2) leucine residue (Table 1, entries 1–
the library being composed solely of amino acids with 12).
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To determine the absolute configuration and the ee plan was to utilize this assay in the screening of pep-
of these two distinct stereochemical preferences, we tide catalysts in solution to develop models of cata-
[8]
turned to a recently described CD assay (Figure 3a).
lyst–Criegee intermediate interactions. Furthermore,
Incorporation of chiral secondary alcohols into a tren- we were intrigued to compare the accuracy of this
like ligand creates a dynamically assembled zinc(II) very rapid CD assay with our HPLC assay.
complex that exhibits characteristic Cotton effects at
We resynthesized 11 peptide hits from our combi-
[
8]
270 nm. The intensity of this signal varies linearly natorial screen, except with a glycine methyl ester res-
with the ee of the incorporated alcohol, while its sign idue replacing the aminohexanoic acid linker used in
correlates to the M or P twist of the pyridyl ligands solid phase screening. These peptides were contrasted
about the zinc(II) center. In turn, this twist is indica- to N-Boc aspartic acid benzyl ester as a negative con-
tive of the absolute configuration, S or R, respectively, trol catalyst. Catalyst performance in solution was
of the enantiomer of alcohol that is in excess. Our markedly improved compared to the on-bead sequen-
ces, with ee for the best catalysts increasing to 46%
for the Leu series (Table 1, entry 1) and 51% for the
Ser(OBn) series (Table 1 entry 12); such improve-
ments are a common phenomenon in bead-based op-
[4]
timization of catalyst architecture.
Because we were in the advantageous situation of
having catalysts that favored opposite enantiomers,
we used a catalyst of each stereochemical preference
and N-Boc aspartic acid benzyl ester to establish
a three-point calibration curve. The curve relates CD
signal intensity at 270 nm to the ee of the alcohols de-
rived from our product lactones via methanolysis
[12]
(
Figure 3b; Table 1, entries 1, 7, and 12). The y-in-
tercept of the calibration curve corresponded to ap-
proximately a 4% error in ee (Figure 3b, from the ex-
pected value of 0 for racemic), which is clearly usea-
ble for a rapid screening method. In addition, we ob-
served equivalent performance of the CD-assay when
compared to HPLC for the remaining 9 combinatorial
hits (Figure 3c, black trend line). Alcohols derived
from the lactones produced by peptide catalysts with
(
i+2) Ser(OBn) residues favored negative CD sig-
nals, while those with (i+2) Leu residues favored
positive CD signals (Figure 3a). We thus assign the
stereochemistry of the lactones produced by
Ser(OBn) catalysts as (2S,6R) and that produced by
[8]
Leu catalysts as (2R,6S). The excellent correlation
we observe between the CD and HPLC data is key to
another feature of the CD assay – the additional ste-
reocenter in the lactone-derived alcohols does not in-
terfere because the assembly is only responsive to al-
cohol functional groups. Furthermore, all of the alco-
hol samples were analyzed without the need for re-
moval of ketone starting material, which remains
a spectator; oxidation and methanolysis-related by-
products/reagents were removed via a simple silica
plug.
Previous study of peptide-catalyzed epoxidations of
the terpene natural product farnesol led to the discov-
ery of a remotely directed catalyst that implicated an
Figure 3. (a) Derivation of lactone absolute configuration
from CD spectra of complexed lactone-derived 28 alcohols
with catalysts 1 and 12 (cf. Table 1; open and filled circles,
respectively). (b) Calibration curve of ee vs. CD intensity
using catalysts 1, 7, and 12 (Table 1). (c) Comparison of ee
by HPLC and ee by CD for duplicate screened combinatori-
(
i+2) ether side-chain in its mode of stereochemical
[4c]
induction. We were intrigued by a possible parallel
observation in the Ser(OBn) series of catalysts. Addi-
al hits and focused library. Error bars in b and c indicate tionally, we were curious if any changes to the (i+1)
standard deviation from the average of duplicate runs.
l-Pro residue might alter the stereochemical outcome.
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A Synergistic Combinatorial and Chiroptical Study of Peptide Catalysts
While speculative, some thoughts about this series in-
clude the possibility of an H-bond between the O-
atom of the (i+2) Ser(OBn) residue and the OH of
the catalyst-bound Criegee intermediate, potentially
directing migration of the pro-R CÀC bond (Fig-
ure 4a). Hence, there is a potential parallel with the
mode of action of B–V monooxygenases, which direct
flavin-bound Criegee intermediate rearrangement via
interaction with an active site arginine side-chain
[13]
(
Figure 4b). Structural characterization of these cat-
alysts is a focus of our ongoing efforts to explore this
intriguing possibility.
Figure 4. (a) Putative H-bonding between Criegee inter-
mediate and Ser(OBn) side-chain. (b) Drawing of an Arg Conclusions
side-chain interacting with FAD-bound Criegee intermedi-
ate, the key stereodetermining interaction in B–V monooxy- We have reported two families of peptide catalysts
[
13]
genases.
that induce enantioselective B–V oxidation by virtue
of what we believe to be direct peptide–Criegee inter-
mediate interactions. Both series of catalysts readily
We screened ten additional peptide catalysts targeted oxidize a highly encumbered ketone, which is itself
to address these questions (Table 1, entries 13–22), a minimal model of the encumbered ketones found in
maintaining the (i+3) and (i+4) Leu residues of the terpene and polyketide natural products. The design
best performing sequence of the Ser(OBn) series. We principles used in our combinatorial library, namely
found that, once again, the CD and HPLC assays of targeting sequence space involved in the recognition
product ee were equivalent in performance, with of moieties similar to the key intermediate of our re-
a strong linear correlation between the ee values ob- action, led to the discovery of two distinct catalyst
tained with each method (Figure 3c, dashed trend families by screening only fifty beads. Our previous
line).
B–V and epoxidation reaction efforts based on de
We were intrigued by catalysts 13, 17, and 21 novo sequence discovery each required the screening
Table 1), which, relative to peptide 12, varied the (i of hundreds of beads to yield hits.
[4,6b]
(
+
2) residue to Ser(OtBu), Ser(OH), and Thr(OBn),
The CD assay we employed proved crucial in our
respectively. In all three cases, we observed lower analysis of the stereochemical course of reactions as it
product ee, which directly implicates this side-chain in yielded the absolute configuration of the lactone
the enantiodetermining CÀC bond migration. In light products. We find that its ability to evaluate catalyst
of these results, and based on the aforementioned performance is equivalent to HPLC, even for samples
precedent involving ether-containing peptide oxida- with low ee. The assay provided enormous time-sav-
[
4c]
tion catalysts, we entertained the possibility of the ings in the analysis of alcohol samples, reducing the
(
i+2) side-chain acting as a hydrogen bond acceptor. time from ~30 min to just a few seconds per sample.
Based on this hypothesis, it would seem that increased The added configurational information, available
steric bulk about the side-chain oxygen, as for 13 and even for samples with low levels of enantioenrich-
2
1, decreases the ability of this atom to act as an H- ment, combined with the operational simplicity and
bond acceptor. This putative H-bond between the per-sample speed of the assay itself make a case for
Criegee intermediate and the (i+2) side-chain would wide implementation of this method in the synthetic
also be weakened if the Lewis basicity of the oxygen chemistry community.
were reduced. This may be the case for peptide 17 al-
though we cannot discount potentially deleterious in-
terference of a free hydroxy group with the catalytic Experimental Section
cycle.
Peptides with non-Pro (i+1) residues and altered Materials and Instrumentation
(
i+2) residues were not drastically changed relative
Methylene chloride, diethyl ether, and N,N-dimethylforma-
mide (DMF) solvents were purified using a Seca Solvent Pu-
rification System by Glass Contour. Ethyl acetate, pentane,
and methanol were used as obtained in glass bottles from
Pharmaco-Aapger, Brand-Nu, and JT Baker, respectively.
to peptides 13, 17, and 21. The nature of these effects,
although small, may suggest that a determinant of
asymmetric induction in the directing group-free pep-
tide-catalyzed B–V oxidation is interaction between
the aspartic peracid-bound Criegee intermediate and Biotech-grade N-methylpyrrolidone (NMP), N-methylmor-
the side-chain of the (i+2) Ser(OBn) catalyst series. pholine, N,N-diisopropylethylamine, and 2,2,2-trifluoroacetic
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Michael W. Giuliano et al.
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acid were used as received from Acros Organics. 2-Chloro-
trityl resin for combinatorial hit and focused library synthe-
sis was obtained from Peptides International while amino-
ethyl polystyrene resin macrobeads (Polystyrene A RAM)
used in library synthesis were obtained from Rapp Polyme-
re. Amino acids were obtained from Peptides International,
Novabiochem (EMD), Advanced ChemTech (Creosalus),
and Chem-Impex. HCTU [O-(1H-6-chlorobenzotriazol-1-
yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate] and
spectrometer. The Q-Tof Ultima mass spectrometer was pur-
chased in part with a grant from the National Science Foun-
dation, Division of Biological Intrastrcture (DBI-0100085).
Preparation of cis-2,6-Diphenylcyclohexanone
[15]
(
Adapted from ref.
)
A mixture of the cis and trans isomers of 2,6-diphenylcyclo-
hexanone (5.0 g, 20 mmol, 1.0 equiv.) was slurried in 150 mL
EDCI
[1-ethyl-3-(3-dimethylaminopropyl)carbodiimide]
2:1 (v/v) CH OH:H O at 23.58C (room temperature). Pyrro-
3 2
were obtained from Chem-Impex and 6-chloro-HOBt (1-hy-
droxybenzotriazole) was obtained from Advanced Chem-
Tech Creosalus). Dipicolylamine and zinc(II) triflate were
obtained from TCI. All other reagents were used as re-
ceived from Sigma–Aldrich.
lidine (30 drops; quantity was adapted from the cited proce-
dure which stated that 3 drops were added on a scale of
2.0 mmol ketone) was added from 12-gauge needle. The re-
action vessel was equipped with a water reflux condenser,
heated, and held at reflux (oil bath temperature of ~95–
1058C) for thirty minutes. The reaction vessel was removed
from heat and allowed to slowly cool to room temperature
without stirring. Over this time a large quantity of colorless/
pale yellow crystals (needles) formed. The flask was sealed
with a septum and cooled for 12 h in a 48C refrigerator to
maximize product crystallization. Crystals were isolated
onto a filter paper in a porcelain Büchner funnel and
1
H NMR spectra were obtained on 400 MHz, 500 MHz, or
1
6
00 MHz Agilent spectrometers. H chemical shifts are re-
ported in ppm (d) with respect to tetramethylsilane (TMS)
at 0.00 ppm. Spectra were referenced to the solvent residual
peak for CDCl at 7.26 ppm. Data are reported as: chemical
3
shift (d) [multiplicity, coupling constants (Hz), integration].
Multiplicities are abbreviated according to the following
convention: singlet (s); doublet (d); triplet (t); quartet (q);
pentet (p); doublet of doublets (dd); doublet of triplets (dt);
doublet of doublet of doublets (ddd), broad singlet (bs),
washed with ~10 mL ice-cold 2:1 (v/v) CH OH:H O. Prod-
3
2
uct was transferred to a tared vial and dried under high
vacuum; isolated yield: 2.3072 g (46%). R (3:1 v/v penta-
f
1
13
ne:Et O)=0.55; H NMR (600 MHz, CDCl ): d=7.32 (t, J=
multiplet (m). C NMR spectra were obtained on 400 MHz
100 MHz), 500 MHz (125 MHz), or 600 MHz (150 MHz)
2
3
7.5 Hz, 4H), 7.25 (t, J=7.5 Hz, 2H), 7.18 (d, 7.2 Hz, 4H),
(
13
3.82 (dd, J=5.4 Hz, 13.2 Hz, 2H), 2.41 (m, 2H), 2.16 (m,
Agilent spectrometers. C chemical shifts are reported in
1
3
3
1
H), 2.09 (m, 1H); C NMR (150 MHz, CDCl ): d=208.3,
ppm (d) with respect to TMS at 0.00 ppm. Spectra are refer-
3
38.6, 128.9, 128.3, 127.0, 58.1, 36.5, 26.2; HR-MS (calculat-
enced to the solvent residual peak for CDCl at 77.16 ppm.
3
+
+
ed/found for C H O ; [M+H ]): 251.1436/251.1443.
Normal-phase HPLC data were collected on an Agilent
18 19
1100 series chromatograph equipped with a photodiode
array detector and a Chiralpak IC column or a Chiralcel
OD-H column. Data at 210 nm were used for integrations to
yield ee and conversions. IR data were obtained using Crystallization
À1
a Nicolet 6700 FT-IR and a partial list of peaks in n (cm )
are reported according to convention.
cis-2,6-Diphenylcyclohexanone (4 mg) was weighed into
a 4 mL (1 dram) glass vial equipped with a Teflon-lined cap.
E
Peptide sequencing was obtained with MS (MS/MS) data
obtained on a Waters XEVO instrument equipped with ESI,
a QToF mass spectrometer, and a photodiode array detector
using a Waters Acquity UPLCꢃ BEH C8 column (1.7 mm,
H O (1 mL) was added to the vial and the mixture was
2
heated to boiling with a heat gun. CH OH was added drop-
3
wise via Pasteur pipet until the sample became a homoge-
nous solution. The vial was set on the bench-top and
capped, vented only slightly to air. Colorless needle-like
crystals were observed within 18 h of slow evaporation.
Crystals were submitted to the Yale CBIC for structure de-
termination by Brandon Q. Mercado. See section VII of the
Supporting Information for full structural data. An image of
the crystal structure (ORTEP) is shown in Figure S1 in the
Supporting Information.
Additionally, CCDC 1052232 contains the supplementary
crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
2
.1”100 mm). Sequences were determined from b and y ion
[
14]
series. High-resolution mass spectrometry (HR-MS) used
electrospray ionization (ESI) and was conducted by the
Mass Spectrometry Laboratory at the University of Illinois
at Urbana-Champaign.
Hit peptides and the focused library sequences were puri-
fied using reverse phase chromatography on a Biotage Iso-
lera 1 system using KP-C18-HS cartridges. Analytical thin
layer chromatography (TLC) was obtained using EMD Mil-
lipore silica gel 60 plates coated with F254 ultraviolet indica-
tor. Spots were visualized for ketone/lactone/alcohol mix-
tures using the UV-indicator and ceric ammonium molyb-
date (CAM) stain. Peptides were visualized using phospho-
molybdic acid stain.
High resolution mass spectrometry (HR-MS) data was ob-
tained via the mail-in service at the Mass Spectrometry Lab-
oratory at the University of Illinois at Urbana-Champaign
for solid samples of all tested catalysts and characterized
compounds. Data were obtained for small molecules on
a Waters Synapt G2-Si ESI mass spectrometer and data for
peptides were obtained on a Waters Q-Tof Ultima ESI mass
Procedure for Peptide-Catalyzed Baeyer–Villiger
Oxidation with an On-Bead Catalyst (Combinatorial
Library Screening, cf. Figure 2c)
Because of the small scale of the reactions (0.069 mmol pep-
tide on bead, 0.69 mmol ketone substrate), reagents were
prepared into two solutions. Solution 1: 12.5 mg cis-2,6-di-
phenylcyclohexanone,
0.6 mg
4-dimethylaminopyridine
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A Synergistic Combinatorial and Chiroptical Study of Peptide Catalysts
(
DMAP), and 32 mL of N,N-diisopropylcarbodiimide (DIC)
Lactone opening: The worked up reaction mixtures were
concentrated to afford a solid white residue by rotovap. This
residue was pushed through a plug of 10–15 mL (dry
volume) silica in a 2.5 cm diameter column that was packed
were dissolved in 436 mL CH Cl . Solution 2: 3.06 mL of
3
H O to afford a 3.0M solution of aqueous hydrogen perox-
2
2
0 wt% H O (aq.) was diluted to a volume of 10 mL with
2 2
2
ide. Individual beads from the combinatorial library were
sorted with tweezers into 250 mL glass inserts in 2 mL glass
HPLC vials equipped with septa. 6.9 mL of solution 1 was
added to the reaction vessel, adding ketone substrate
with 3:1 (v/v) pentane:Et O. Ketone/lactone mixtures were
fully eluted with a total volume of 150–175 mL 3:1 (v/v)
2
pentane:Et O. The plug was necessary to remove peptide,
2
DMAP, and DIC-related reaction by-products that could co-
ordinate and potentially interfere with the CD assay. We
note that ketones and esters do not interfere with the assay,
which is designed specifically for alcohol functional groups.
The eluent was concentrated, transferred to a 24-mL glass
vial, and fully concentrated to a white residue. The residue
(0.69 mmol, 1.0 equiv.), DIC (2.76 mmol, 4.0 equiv.), and
DMAP co-catalyst (0.069 mmol, 0.1 equiv.). 1.9 mL of solu-
tion 2 (H O , 5.52 mmol, 8.0 equiv.) were then carefully
2
2
added directly into the reagent solution in the reaction
vessel. The small reaction volumes did not necessitate either
stirring or any other agitation. The reactions were carried
out standing at 23.58C (room temperature) for 36 h prior to
quenching.
was rinsed into the bottom of the vial with 2–3 mL CH Cl2
2
and this mixture was allowed to evaporate to dryness in the
fume hood. This step was necessary as in the course of our
study we discovered that the racemate of the lactone prod-
uct was substantially less soluble than the enriched material.
If all solid was not dissolved in the ring-opening step, the in-
formation obtained by either HPLC or the CD assay led to
falsely high ee values. The dried residue was then ring
opened (we note that other common lactone-opening meth-
ods led to full or partial epimerization of the C-2 stereocen-
ter, confounding the analysis of our data). According to
Quench and assay: Reactions were quenched by addition
of 20 mL saturated aqueous Na SO . 200 mL HPLC-grade
2
3
hexanes were added to each vial and the layers were mixed.
The organics were removed, leaving the beads behind, and
passed through a solid mixture of Na SO and oxalic acid
2
4
(roughly 1:1 by solid volume) in a cotton-plugged Pasteur
pipet. The filter was washed with 300 mL additional hexanes.
Samples were analyzed via normal-phase HPLC with
a chiral stationary phase. 5 mL of reaction extract were in-
jected and analyzed on a Chiralpak IC column at a flow rate
[
12]
a modification of the procedure of Seebach, a solution in
CH OH of 0.1M DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)
3
À1
of 1 mLmin , eluting with 20% (v/v) EtOH in hexanes at
and 1.0M LiBr was prepared in a volumetric flask. An ali-
quot of this solution was added to the lactone sample to
afford a reaction mixture that was 0.2M in lactone
(1.0 equiv.), 0.1M in DBU (0.5 equiv.), and 1.0M in LiBr
(5.0 equiv.). The mixture was sonicated for 1 min and then
stirred for 30 min at room temperature with occasional soni-
cation to break up agglomerated solids. At 30 min, 1–2 mL
CH Cl were added to the mixture and the reaction was
ambient temperature over a period of 17 min. A representa-
tive HPLC trace is shown in Figure S2 of the Supporting In-
formation. Library design and full on-bead screening data
are summarized in section II of the Supporting Information.
Procedure for Peptide-Catalyzed Baeyer–Villiger
Oxidation in Solution (Screening of Hit Peptides and
Focused Library) and Ring Opening to Secondary
Alcohol (cf. Table 1, Figure 3)
2
2
stirred 15 min further over which time all solids dissolved.
The reaction was quenched with 1 mL of 1N HCl (aq.).
1 mL brine was added and the mixture was extracted three
times with 3 mL (each extract) CH Cl . Extracts were
2
2
Peptide catalyst (0.03 mmol, 0.1 equiv.), cis-2,6-diphenylcy-
clohexanone (75 mg, 0.3 mmol, 1.0 equiv.) and DMAP
passed through a Pasteur pipet filter containing silica and
Na SO into a 24-mL glass vial. Solvent was removed via ro-
2
4
(3.7 mg, 0.03 mmol, 0.1 equiv.) were weighed into a 4-mL
tovap and the remaining residue for the calibration curve
samples was analyzed by HLPC. All samples were dried
under high vacuum and then evaluated in the CD assay for
ee (see below and section IV of the Supporting Informa-
tion).
vial equipped with a Teflon-coated magnetic stirbar. The
mixture was dissolved in 0.6 mL CH Cl2 and H O was
2
2
2
added [50 wt% (aq.); 64.8 mL, 1.14 mmol, 3.8 equiv.]. The
vials were sealed with Teflon tape and septum caps and the
contents stirred at 23.58C (room temperature). DIC
HPLC sample preparation: <1 mg of each ring-opened
product mixture was dissolved in ~250 mL of 15% (v/v)
EtOH in hexanes. Samples were analyzed on a Chiralcel
OD-H column, eluting with 3% (v/v) EtOH in hexanes at
(
135 mL, 0.9 mmol, 3.0 equiv.) was added via syringe pump
À1
at a rate of 0.13 equiv. per hour (5.9 mLh ) over a period of
23 h. The reactions were stirred one hour past this time for
a total reaction time of 24 h, over which time white precipi-
tate formed.
Quench and work-up: Reactions were quenched with
À1
a flow rate of 1 mLmin at ambient temperature over
a period of 32 min. HPLC analysis of lactones and their cor-
responding alcohols is summarized with representative
traces in Figure S3 of the Supporting Information. Section
IV of the Supporting Information contains tabulated HPLC
integrations and CD270 values for all runs used to generate
Table 1 and Figure 3.
2
00 mL saturated aqueous Na SO . The mixtures were trans-
2 3
ferred to a separatory funnel quantitatively by rinsing sever-
al times with a total volume of 10 mL ethyl acetate
(
3
EtOAc). The mixture was diluted to a total volume of
0 mL with EtOAc and washed twice each (15 mL each
wash) with saturated aqueous Na SO and saturated aque-
2
3
ous NaHCO . The organic layer was dried over Na SO , fil-
3
2
4
tered, and sampled for HPLC analysis (~100 mL from the
worked up solution). Samples were analyzed via HPLC
using the same method as used for analyzing the reactions
from the combinatorial screen (vide supra).
Adv. Synth. Catal. 2015, 357, 2301 – 2309
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2307

Michael W. Giuliano et al.
FULL PAPERS
Baeyer–Villiger Oxidation of cis-2,6-Diphenylcyclo-
hexanone with mCPBA (3-Chloroperoxybenzoic
Acid) and Ring Opening to Alcohol (Racemic
Standard Preparation and Characterization)
gradient as follows: 1 CV (column volume) 1:9 (v/v); 1 CV
:4; 1 CV 3:7; 1 CV 2:3, 1 CV 1:1. The product was isolated
as a clear, colorless oil; isolated yield: 144 mg (72%; conver-
1
sion complete by TLC). R (3:1 v/v pentane:Et O)=0.12:
f
2
1
H NMR: (400 MHz, CD CN): d=7.30 (m, 10H), 4.54 (dt,
3
cis-2,6-Diphenylcaprolactone:
none (500 mg, 2.0 mmol, 1.0 equiv.) was dissolved in 4 mL
cis-2,6-Diphenylcyclohexa-
J=7.8 Hz, 4.8 Hz, 1H), 3.58 (s, 3H), 3.57 (t, J=7.5 Hz, 1H),
3.13 (d, J=4.2 Hz, 1H), 2.01 (m, 1H), 1.75 (m, 1H), 1.68
(m, 1H), 1.62 (m, 1H), 1.33 (m, 1H), 1.17 (m, 1H);
CH Cl at 23.58C (room temperature) in a 100-mL round-
2
2
1
3
bottom flask equipped with a Teflon-coated magnetic stir-
C NMR: (100 MHz, CD CN): d=175.52, 146.83, 140.56,
3
bar. mCPBA (1.425 g, 6.0 mmol, 3.0 equiv.) was added and
129.56, 129.08, 128.83, 128.11, 127.87, 126.76, 74.00, 52.38,
52.02, 39.82, 34.11, 24.54; HR-MS (calculated/found for
C H O ; [M ]): 298.1569/298.1567; IR: n=3394 (broad),
19 22 3
the reaction mixture was stirred under an N atmosphere for
2
+
+
36 h at 23.58C (room temperature).
Quench and work-up: The reaction mixture was quenched
2917, 1732, 1602, 1494, 1454, 1206, 1165, 1068, 1028, 734,
698 cm .
À1
by careful addition of 5 mL saturated aqueous Na SO and
2
3
stirred for 15 min at 23.58C (room temperature) open to air.
The mixture was diluted with 50 mL EtOAc and transferred
quantitatively to a separatory funnel. The reaction mixture
was then washed twice with 30 mL (each wash) saturated
Circular Dichroism Assay
CD spectra were obtained on a Jasco J-815 CD Spectrome-
ter with Starna Type 1 GL14-S 10 mm quartz cells at 258C.
The assembly stock solution was prepared by mixing 2-pyri-
aqueous NaHCO and once with 30 mL brine. The organic
3
layer was then dried over Na SO , filtered, and concentrated
2
4
dinecarboxaldehyde
(1 equiv.),
2,2’-dipicolylamine
to afford the crude product mixture as a white solid. The
solid was purified by flash column chromatography on silica
using a 3.5 cm diameter glass column and ~200 mL silica
(
1.2 equiv.), Zn(OTf) (1 equiv.), and 4-(2-chloroethyl)mor-
2
pholine hydrochloride (1 equiv.) in acetonitrile at 50 mM
with respect to 2-pyridinecarboxaldehyde. The stock solu-
tion was then added to a sample containing 3–5 equiv.
methyl 6-hydroxy-2,6-diphenylhexanoate of unknown enan-
tioenrichment with molecular sieves (3Š) and left at room
temperature (208C) for 12–16 h. The alcohol assembly (see
Figure S8 in the Supporting Information) was then diluted
to 0.175 mM, with respect to 2-pyridinecarboxaldehyde,
before taking CD measurements. Note: This arrangement of
testing allowed for the blind testing of samples by CD,
which, as discussed in the main text, provided equivalent
data to HPLC with added information regarding the abso-
lute configuration of the incorporated alcohol stereocenter.
Calibration curve derivation and all CD270 data are summar-
ized in section IV of the Supporting Information.
(
dry volume) packed with 9:1 (v/v) pentane:Et O. The crude
2
product was loaded with minimal 9:1 (v/v) pentane:Et O
2
with small amounts of CH Cl to aid in solubility and eluted
2
2
with 4 column volumes (~150 mL solvent) of 9:1 (v/v) pen-
tane:Et O, followed by 3:1 (v/v) pentane:Et O until all lac-
2
2
tone product was observed to elute by TLC. TLC plates
were developed with 3:1 (v/v) pentane:Et O and visualized
2
with CAM stain. The product was isolated as a white solid;
yield: 177 mg (33%). Rf (3:1 v/v pentane:Et O)=0.42;
2
1
H NMR: (400 MHz, CDCl ): d=7.46 (d, J=7.2 Hz, 2H),
3
7
6
1
.39 (t, J=7.2 Hz, 2H), 7.37 (t, J=6.8 Hz, 2H), 7.30 (t, J=
.4 Hz, 4H), 5.54 (d, J=9.2 Hz, 1H), 4.02 (d, J=8.8 Hz,
H), 2.16 (m, 5H), 2.01 (m, 1H); C NMR: (100 MHz,
13
CDCl ): d=174.69, 140.84, 140.39, 128.75, 128.57, 128.57,
3
1
28.36, 127.41, 126.17, 81.88, 49.60, 37.19, 31.75, 28.63; HR-
+ +
Peptide Synthesis
MS (calculated/found for C H O ; [M+H ]): 267.1385/
18
19
2
2
67.1384.
Methyl 6-hydroxy-2,6-diphenylhexanoate (lactone open-
ing): Lactone (177 mg, 0.67 mmol, 1.0 equiv.) was slurried in
All peptides for on-bead and solution phase reactions were
synthesized using standard Fmoc solid phase synthesis tech-
niques on Rink amide or 2-chlorotrityl-functionalized poly-
styrene resins, respectively. Sequences were purified using
a combination of normal-phase flash chromatography on
silica and reverse phase chromatography on a Biotage Iso-
lera 1 system. Explicit details for these procedures, MS/MS
CH OH at 23.58C. LiBr (286.7 mg, 3.3 mmol, 5.0 equiv.) was
3
added and some of the solids dissolved upon sonication of
the mixture. DBU was added (49 mL, 0.33 mmol, 0.5 equiv.)
and the reaction mixture was stirred for ~30 min at 23.58C
with TLC monitoring (1:1 v/v Et O:pentane). The reaction
2
sequencing protocols, full characterization for peptides
1
mixture became entirely soluble over this time. We note
that this procedure is simpler than that described above. We
suspect that this was due to the lack of other reaction-relat-
ed materials and the fact that the opening of the products of
catalytic runs could yield false positives in the absence of
the described rigor with respect to ensuring lactone solubili-
ty.
Work-up: The reaction was quenched with 5 mL 1N HCl
and the mixture was diluted with 25 mL brine. The mixture
was extracted three times with 50 mL CH Cl (each extract).
1
and 12, and H NMR and HRMS data for all other solu-
tion phase peptides are summarized in sections II, III, and
VI of the Supporting Information. Characterization data for
peptides 1 and 12 are shown below:
1
Peptide 1: isolated yield: 202 mg (71%). Note: H NMR
data show highly broadened resonances, suggesting peptide
aggregation, which precludes full assignment of multiplets in
1
many cases. H NMR (600 MHz, CDCl ): d=7.43 (broad,
3
1H), 7.32 (d, J=7.2 Hz, 1H), 7.23 (m, 2H). 7.19 (m, 2H),
7.12 (d, J=7.8 Hz, 2H), 7.03 (broad, 2H), 6.92 (d, J=
8.4 Hz, 2H), 4.95 (d, J=8.4 Hz, 1H), 4.74 (m, 1H), 4.48 (m
2H), 4.33 (m, 1H), 4.21 (m, 1H), 4.16 (q, J=7.2 Hz, 1H),
3.90 (broad, 4H), 3.69 (s, 3H) – the next three signals
belong to three different ABX patterns, but the resonances
are not resolved sufficiently for proper analysis – 3.19 (m,
2
2
The organics were combined, dried over Na SO , filtered
2
4
and concentrated to afford a pale yellow oil as crude prod-
uct. The product was purified via flash column chromatogra-
phy in a 2.5 cm diameter glass column with ~100 mL silica
(dry volume). The column was eluted with an Et O:pentane
2
2
308
asc.wiley-vch.de
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 2301 – 2309

FULL PAPERS
A Synergistic Combinatorial and Chiroptical Study of Peptide Catalysts
1
1
1
H), 3.04, (m, 2H), 2.94 (m, 1H), 2.64 (m, 1H), 2.58 (m,
H), 2.35 (broad, 2H), 2.04 (broad, 4H), 1.60 (broad, 2H),
.46 (s, 9H), 1.42 (d, J=7.2 Hz, 3H), 1.31 (s, 9H), 0.91 (d,
Gusso, C. Baccin, F. Pinaa, G. Strukul, Organometallics
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J=6 Hz, 3H), 0.88 (m, 3H), 0.84 (d, J=6 Hz, 3H);
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C NMR (150 MHz, CDCl ): d=175.03, 173.81, 173.83,
3
1
1
5
3
2
71.56, 170.57, 154.89, 154.36, 136.75, 132.11, 129.82, 128.77,
28.65, 126.97, 124.44, 80.88, 78.56, 66.01, 62.06, 56.69, 55.85,
3.29, 52.43, 49.72, 49.42, 48.35, 48.19, 41.42, 38.53, 37.35,
6.04, 35.86, 34.27, 30.75, 29.97, 28.98, 28.47, 25.20, 25.07,
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13
lated/observed for C H N O ): 952.5032/952.5035.
48
70
7
1
Peptide 12: isolated yield: 176 mg (67%). Note: H NMR
data shows highly broadened resonances, suggesting peptide
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1
7
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2
[
321–326; b) P. A. Lichtor, S. J. Miller, Nat. Chem. 2012,
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H), 4.19 (m, 1H), 4.07 (m, half an ABX pattern; other half
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.87 (m, 1H), 3.78 (m, 1H), 3.69 (s, 3H), 2.72 (m, 2H), 2.34
m, 1H), 2.00 (m, 4H), 1.70 (m, 7H), 1.43 (s, 9H), 1.43 (d,
unresolved, 3H), 0.97 (d, J=6 Hz, 3H), 0.94 (d, J=6.6 Hz,
4504–4511.
3
(
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3
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(150 MHz, CDCl ): d=174.13, 173.52, 173.30, 173.09, 171.92,
3
1
8
4
2
71.39, 170.36, 154.90, 137.07, 128.72, 128.42, 128.29, 127.73,
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[
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This work was supported by the National Institutes of Health
NIH GM-096403 to S. J. M. and NIH GM-077437 to
E. V. A). We thank Dr. Brandon Q. Mercado of the Yale
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Adv. Synth. Catal. 2015, 357, 2301 – 2309
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2309