A copper-catalyzed, pH-neutral construction of high-enantiopurity peptidyl ketones from peptidic S-acylthiosalicylamides in air at room temperature

Article abstract of DOI:10.1002/anie.200804524

A copper-catalyzed transformation of peptidic thiol esters and boronic acids gives peptidyl ketones and takes place in DMF or DMF/H2O at room temperature in air (see scheme). This aerobic reaction only occurs at a thiol ester group capable of coordinating

Full text of DOI:10.1002/anie.200804524

Angewandte
Chemie
DOI: 10.1002/anie.200804524
Synthetic Methods
A Copper-Catalyzed, pH-Neutral Construction of High-Enantiopurity
Peptidyl Ketones from Peptidic S-Acylthiosalicylamides in Air at
Room Temperature**
Lanny S. Liebeskind,* Hao Yang, and Hao Li
In the past decade great strides have been made in discov-
ering novel methods for the metal-catalyzed construction of
“second-generation” desulfitative coupling of thiol esters and
boronic acids that takes place through a mechanistically novel
copper-catalyzed, aerobic desulfitative process.[73,74]
À
À
C C and C X bonds from organic halides/sulfonates/phos-
[12–24]
phonates,[1–11] and through C H functionalization.
The
In probing the benefits of copper-catalyzed, aerobic,
desulfitative coupling for the construction of peptidyl
ketones, we conducted a control experiment using trypto-
phan-derived thiol esters which validated the importance of
the nature of the S-pendant group of the thiol ester on the
reactivity of the substrate (Scheme 1). At 508C in DMF with
copper(I) 3-methylsalicylate (CuMeSal; 5 mol%), the reac-
tion occurred only with the tryptophan-derived thiophenyl
ester bearing an ortho CONHtBu group and not with the
simple thiophenyl ester.
À
majority of these metal-catalyzed coupling reactions are now
carried out using mild organic transfer agents such as boronic
acids, organostannanes, and organosilanes. The synthetic
power and broad impact of these modern methods used for
the efficient and selective generation of a variety of bond
types in a vast array of target molecules are unquestioned.
Yet, significant challenges remain to be addressed by
synthetic scientists. One “holy grail” is the highly chemo-
À
À
selective, non-enzymatic formation of a C C or C X bond at
a specific site on a functionally complex biomolecule under
biologically relevant conditions (minimal or no protecting
groups, ambient temperatures, compatibility with protic
solvents, and pH-neutral, aerobic, or anaerobic reaction
conditions).[25–42]
New discoveries that can address this challenge will be of
significant value, both for the discovery and development of
new therapeutics, and as diagnostic tools in chemical biology.
Herein, we describe one contribution toward that goal: a
copper-catalyzed transformation of peptidic thiol esters and
boronic acids into peptidyl ketones,[43–60] which are important
compounds in the development of molecular therapeu-
tics.[44,61–72] This new reaction takes place at room temperature
in DMF or in DMF/H2O (2:1 v/v) in air and requires only a
catalytic amount of a CuI/carboxylate to mediate the reaction.
This aerobic transformation is highly chemoselective and
occurs only at a thiol ester capable of coordinating to Cu
through its S appendage. The process is hampered neither by
racemization of the reactants or products, nor by the presence
of disulfide bonds or of unprotected phenol, alcohol, or indole
groups. This chemistry is based upon a recently disclosed
Scheme 1. Control experiments to demonstrate the effect of the
pendant group on the sulfur center. Cbz=benzyloxycarbonyl, CuMe-
Sal=copper(I) 3-methylsalicylate, DMF=N,N-dimethylformamide.
This result clearly confirmed the requirement of a
coordinating moiety on the pendant group of the thiol ester
for this copper-catalyzed, aerobic reaction. As described by
our research group, [73] the reaction is rendered catalytic in CuI
under aerobic conditions through “scavenging” of the thiolate
residue with a second “sacrificial” equivalent of the boronic
acid. A copper-centered transmetalation/reductive elimina-
tion sequence generates a thioether, thus removing thiolate
from the reaction system and thereby regenerating CuI, which
is available for subsequent reaction with O2 and therefore
continues the catalytic cycle.
[*] Prof. Dr. L. S. Liebeskind, H. Li
Department of Chemistry, Emory University
1515 Dickey Drive, Atlanta, GA 30322 (USA)
Fax: (+1)404-727-6604
E-mail: chemLL1@emory.edu
A brief study on the influence of the amide group in the
ortho position on the reaction rate and yield of the peptidyl
ketone formation was undertaken. The reaction was carried
out at room temperature, and it benefited from an increase in
the CuMeSal loading to 20 mol%. Four tryptophan-derived
thiol esters bearing different thiosalicylamide pendant groups
(NHMe, NHiPr, NHtBu, N-morpholino) were treated with
2,4-difluorophenylboronic acid (2.5 equiv) in the presence of
CuMeSal (20 mol%) in DMF at room temperature in air
H. Yang
Abbott Laboratories, GPRD, Process R&D, R450-NCR13-323A
1401 Sheridan Road, North Chicago, IL 60064 (USA)
[**] The National Institutes of General Medical Sciences, Department of
Health and Human Services supported this investigation through
grant no. GM066153. Dr. Gary Allred of Synthonix provided many of
the boronic acids used in our studies.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804524.
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(Figure 1). Missing from the series of thiosalicylamide pend-
less hindered amides better ligands for Cu, thus increasing the
concentration of the copper-templated species, and accord-
ingly providing faster rates of reaction.
ant groups is the parent, NH2, because the handling and
transformation of this compound proved unexpectedly prob-
lematic.
The reasons for the different efficiencies of the four
reactions are not fully understood at this time. The reactions
of both the NHiPr and NHtBu amide substrates showed
excellent mass balances by HPLC analysis—all materials
were quantitatively accounted for in the products and the
unchanged starting material. In contrast, no residual starting
materials were apparent in the reaction of the NHMe amide
substrate, although the yield of product reached a maximum
of 71%. The reaction of the N-morpholino amide substrate
showed some residual starting material by HPLC analysis,
even though the reaction stopped to give a low conversion
into peptidyl ketone. Therefore, the best performing substrate
was the somewhat hindered NHiPr amide which reacted at a
slower initial rate than the NHMe amide, but produced an
excellent yield of the peptidyl ketone product within
90 minutes.
Several examples of this room-temperature, copper-cata-
lyzed, aerobic cross-coupling reaction used for the construc-
tion of peptidyl ketones are shown in Table 1. Awide range of
aryl (electron-rich or electron-deficient), heteroaryl (furyl,
thienyl, benzothienyl, pyridinyl), and alkenyl boronic acids
coupled efficiently with an amino acid and a dipeptide-
derived thiol ester. Furthermore, sterically bulky boronic
acids like 2-tolyl boronic acid and 2-N-Boc-pyrolyl boronic
acids gave peptidyl ketones in satisfactory yields. n-Butyl
boronic acid, the only aliphatic boronic acid examined, did
not produce a peptidyl ketone upon reaction with N-Cbz-l-
Trp-S-C6H4(o-CONHiPr). In addition to the range of boronic
acids already mentioned, this reaction also tolerated thiol
esters bearing metal-binding and oxidation-sensitive func-
tional groups, such as thioether (methionine), disulfide
(cystine), unprotected indole (tryptophan), and unprotected
phenol (tyrosine). It can be seen from these examples that this
reaction appears to be broadly useful for sensitive, highly
functionalized systems. Also, the products of this aerobic
desulfitative cross-coupling reaction inherit the stereochem-
istry of the thiol ester substrates with high fidelity. Through-
out the coupling reaction and the purification process for all
of the peptidyl ketones synthesized, neither racemization of
the monopeptidyl ketones nor epimerization of the dipeptidyl
ketone was detected.
This mild, copper-catalyzed aerobic reaction is surpris-
ingly tolerant of the presence of water. For example, when
DMF/H2O (2:1 v/v) was used as the solvent, N-Boc-l-Phe-S-
C6H4(o-CONHiPr) efficiently coupled with thiophene-2-bor-
onic acid and produced the peptidyl ketone in 70% yield
(accompanied by a 73% yield of the mechanistically required
thiol ether, 2-thienyl-S-C6H4(o-CONHiPr). The compatibility
of this reaction (namely, that of thiol ester N-Cbz-l-Trp-S-
C6H4(o-CONHiPr) and 2,4-difluorophenylboronic acid) with
other functional groups was probed by the addition of a
stoichiometric amount of selected additives.[75] The coupling
reaction was unperturbed by the addition of a primary amine
(benzylamine), a secondary amine (diisopropylamine), or a
tertiary amine (triethylamine). The addition of benzoic acid
or of glucose did not hinder the formation of the peptidyl
Figure 1. Influence of the thiosalicylamide substituent. In the plot
1
2
1
2
1
2
1
À
a: R =H, R =Me; b: R =H, R =iPr; c: R =H, R =tBu; d: R
R2 =N-morpholino. For each thiol ester in Figure 1, two identical
reactions were carried out, both containing decafluorobiphenyl as an
internal standard. One reaction was used for HPLC analysis and the
other to determine the yields of the isolated peptidyl ketone. Reaction
time was 6 hours. No oxidative homocoupling of the boronic acid to
the biphenyl was observed during the first 3 hours of the reaction. In
addition to the peptidyl ketone product, these reactions also generate
(2,4-C6H3F2)S-C6H4(o-CONHiPr), which is a mechanistically required
side product.
Four thiosalicylamide derivatives were tested, and the
initial reaction rates were inversely proportional to the steric
encumbrance about the amide. The tertiary N-morpholino
thiol ester gave the slowest initial reaction rate followed by
the NHtBu, NHiPr, and then NHMe analogues (Figure 1).
The initial rates are consistent with a reaction that proceeds
through a CuII/III intermediate that templates the S-acylth-
iosalicylamide and the boronic acid, such that the reactants
are proximal and the thiol ester has enhanced electrophilicity
(Scheme 2).[73] Diminished nonbonded steric effects make the
Scheme 2. The putative CuII/III-templated intermediate.
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Chemie
Table 1: Synthesis of peptidyl ketones by aerobic Cu catalysis.[a–d]
[76–89]
À
of the C S bond of the protein thiol esters
at both the
C terminus and the side chain. It is hoped that additional
modification of the S-pendant will help in the design of easily
extractable thiosalicylamide residues to facilitate simple
retrieval of the peptidic ketones, and the discovery of
alternative copper-catalyzed second-generation desulfitative
couplings that do not require two equivalents of the boronic
acid.
Experimental Section
DMF (0.1m based on the thiol ester) was added to a mixture of N-
Cbz-l-Trp-S-C6H4(o-CONHiPr) (0.05 mmol, 26 mg, 1.0 equiv), 2,4-
difluorophenylboronic acid (0.125 mmol, 20 mg, 2.5 equiv), copper(I)
3-methylsalicylate (0.01 mmol, 2 mg, 20 mol%). The reaction mixture
was stirred in air at room temperature for 180 min and then
concentrated under vacuum to remove most of the DMF (0.5 mL).
The crude concentrate was then diluted with 10 volumes (5 mL) of
diethyl ether. The diluted solution was washed with water and the
aqueous layer was back-extracted (twice) with the same volume of
diethyl ether. The combined organic layers were dried over MgSO4,
filtered, and concentrated. The crude material was further purified by
flash chromatography on silica gel (CHCl3/EtOAc/hexanes 20:1:5) to
afford the peptidyl ketone as a yellow oil (21 mg, 97%) and the
corresponding thioether (16 mg, 99%). Peptidyl ketone data: TLC
(Rf = 0.20, silica gel, (CHCl3/EtOAc/hexanes 20:1:5)); HPLC on a
chiral stationary phase using a Daicel Chirapak OD-RH column, l =
254 nm, flow rate: 1.0 mLminÀ1, T= 308C, Gradient: 50% H2O in
CH3CN for 10 min, 75% CH3CN, for 12.5 min, and 100% CH3CN for
4.5 min, l isomer tR = 13.8 min, d isomer tR = 12.2 min, > 99% ee;
1H NMR (400 MHz, CDCl3): d = 7.99 (s, 1H), 7.81 (dd, J = 14.8,
8.4 Hz, 1H), 7.35–7.27 (m, 7H), 7.14 (t, J = 7.6 Hz, 1H), 7.00 (t, J =
7.6 Hz, 1H), 6.93–6.80 (m, 3H), 5.67 (d, J = 7.6 Hz, 1H), 5.51 (dd, J =
13.2, 5.6 Hz, 1H), 5.11–5.04 (m, 2H), 3.44 (dd, J = 15.2, 5.6 Hz, 1H),
3.16 ppm (dd, J = 14.8, 5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): d =
195.5, 156.0, 136.6, 136.1, 133.5, 128.7, 128.3, 127.7, 123.0, 122.3, 119.8,
118.7, 112.8, 112.6, 111.3, 109.8, 105.3, 105.1, 104.8, 67.1, 60.0, 59.9,
27.8 ppm; IR (neat): n˜ = 3405 (m), 1687 (s), 1610 (s), 1502 (m), 1235
(m), 972 (m), 741 cmÀ1 (m); HRMS (FAB) calcd for C25H21N2O3F2
[a] Yields of isolated products. [b] Reaction conditions: peptidyl thiol ester
(1.0 equiv), boronic acid (2.5 equiv), and copper(I) 3-methylsalicylate
(20 mol%) in DMF in air at room temperature for 0.5–24 hours. [c] ee values
were determined by chiral HPLC on a reverse phase OD, AD, AS, or OJ
column. In some cases the racemates were not resolved by HPLC methods
and the ee values were not determined. [d] In addition to the peptidyl ketone
product, each reaction also generated a mechanistically required thioether
side product (R3S-C6H4(o-CONHiPr)) that formed from a “sacrificial”
second equivalent of boronic acid and thiosalicylamide reagents. The
thioether side product is removed upon chromatographic purification of the
peptidyl ketone. See the Supporting Information for full experimental
details. Boc=tert-butoxycarbonyl, Bn=benzyl.
([M + H]+): 435.1514; found: 435.1513; [a]D + 33.6 (c = 1.4 gcmÀ3
,
20
CHCl3).
Received: September 14, 2008
Published online: January 14, 2009
Keywords: copper · cross-coupling · peptidomimetics ·
.
protein modifications · synthetic methods
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