Ambient temperature synthesis of high enantiopurity N-protected peptidyl ketones by peptidyl thiol ester-boronic acid cross-coupling

Article abstract of DOI:10.1021/ja0658719

α-Amino acid thiol esters derived from N-protected mono-, di-, and tripeptides couple with aryl, π-electron-rich heteroaryl, or alkenyl boronic acids in the presence of stoichiometric Cu(I) thiophene-2-carboxylate and catalytic Pd₂(dba)₃/triethylphosphite to generate the corresponding N-protected peptidyl ketones in good-to-excellent yields and in high enantiopurity. Triethylphosphite plays a key role as a supporting ligand by mitigating an undesired palladium-catalyzed decarbonylation-β-elimination of the α-amino thiol esters. The peptidyl ketone synthesis proceeds at room temperature under nonbasic conditions and demonstrates a high tolerance to functionality.

Full text of DOI:10.1021/ja0658719

Published on Web 01/17/2007
Ambient Temperature Synthesis of High Enantiopurity
N-Protected Peptidyl Ketones by Peptidyl Thiol Ester-Boronic
Acid Cross-Coupling
Hao Yang, Hao Li, Ru¨diger Wittenberg,† Masahiro Egi,‡ Wenwei Huang,§ and
Lanny S. Liebeskind*
Contribution from the Department of Chemistry, Emory UniVersity, 1515 Dickey DriVe NE,
Atlanta, Georgia 30322
Received August 12, 2006; E-mail: chemLL1@emory.edu
Abstract: R-Amino acid thiol esters derived from N-protected mono-, di-, and tripeptides couple with aryl,
π-electron-rich heteroaryl, or alkenyl boronic acids in the presence of stoichiometric Cu(I) thiophene-2-
carboxylate and catalytic Pd2(dba)3/triethylphosphite to generate the corresponding N-protected peptidyl
ketones in good-to-excellent yields and in high enantiopurity. Triethylphosphite plays a key role as a
supporting ligand by mitigating an undesired palladium-catalyzed decarbonylation-â-elimination of the
R-amino thiol esters. The peptidyl ketone synthesis proceeds at room temperature under nonbasic conditions
and demonstrates a high tolerance to functionality.
Introduction
While this chemistry is of value in the synthesis of simple
R-amino ketones from R-amino acid derivatives, the use of
Enantiomerically pure N-protected R-amino ketones are
valuable compounds that can be used as chiral, nonracemic
building blocks to construct a great diversity of molecules.1-5
Those R-amino ketones derived from peptides display a wide
range of biological activities.6-13
The transformation of R-amino acids and small peptides to
the corresponding C-terminal ketones without epimerization is
an ongoing challenge to synthetic chemists. Most methodologies
are based on the reaction of basic and nucleophilic organome-
tallic reagents with derivatives of N-protected R-amino acids
such as acid halides, mixed anhydrides, or Weinreb amides.1,4,14-23
strongly nucleophilic and basic organomagnesium and lithium
reagents precludes the involvement of this chemistry in the
synthesis of more complex molecules containing base-sensitive
stereogenic centers and nucleophile incompatible functional
groups. Hanzawa and co-workers introduced a novel solution
to the problem: the preparation of R-amino ketones using
acylzirconocene chloride complexes as acyl anion equivalents
for the addition to substituted N-benzylideneaniline derivatives,
but the reactivity is not high and enantioselectivity was not
addressed.24
To further generalize the synthesis of R-amino ketones under
mild reaction conditions, a small number of transition-metal-
catalyzed cross-coupling protocols have been developed. By far
the mildest method for the synthesis of R-amino ketones from
R-amino acids and small peptides is the palladium-catalyzed
coupling of thiol esters with organozinc reagents developed by
Fukuyama and co-workers.25,26 Using this cross-coupling pro-
† Current address: Altana Coatings and Sealants, DS-Chemie GmbH,
Straubinger Str. 12, 28219 Bremen, Germany.
‡ Current address: School of Pharmaceutical Sciences, University of
Shizuoka, 52-1 Yada, Shizuoka-shi 422-8526, Japan.
§ Current address: NIH Chemical Genomics Center, National Institutes
of Health, 9800 Medical Center Dr. MSC 3370, Bethesda, MD 20892-
3370.
(1) Ooi, T.; Takeuchi, M.; Kato, D.; Uematsu, Y.; Tayama, E.; Sakai, D.;
Maruoka, K. J. Am. Chem. Soc. 2005, 127, 5073-5083.
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T. J. Braz. Chem. Soc. 1998, 9, 381-387.
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43, 8223-8226.
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T. P.; Taylor, R. J. K. Tetrahedron Lett. 1996, 37, 7457-7460.
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9
1132
J. AM. CHEM. SOC. 2007, 129, 1132-1140
10.1021/ja0658719 CCC: $37.00 © 2007 American Chemical Society

High Enantiopurity N-Protected Peptidyl Ketones
A R T I C L E S
Scheme 1. Peptidyl Ketones from Peptidyl Thiol Esters and Boronic Acids
Table 1. N-Protected Phenylalanine Thiol Ester-Boronic Acid
Cross-Couplings
cedure, the authors prepared a few examples of R-amino ketones
from alkylzinc reagents. In a related study, Rovis and Zhang
employed a Ni catalyst for the coupling of R-amino acid
fluorides with organozinc reagents to give ketones.27 While
organozinc reagents provide superior functional group compat-
ibility relative to organolithium and organomagnesium reagents,
they are, nevertheless, still basic and nucleophilic.
entry
thiolester
R1
R2
R3
ketone
yield (%)
A new, nonbasic method for synthesizing ketones from thiol
esters and either boronic acids or organostannanes was recently
developed.28,29 In the presence of a Pd catalyst and copper(I)
thiophene-2-carboxylate (CuTC) or related Cu(I) oxygenates,
thiol esters react with boronic acids to give ketones in good-
to-excellent yields. In contrast to organolithium, -magnesium,
and -zinc reagents, boronic acids are nonbasic and non-
nucleophilic, and they are easily prepared and handled.30 A great
variety of aryl, heteroaryl, and alkenyl boronic acids are now
commercially available. Since no base is required and the thiol
ester-boronic acid cross-coupling reaction conditions are mild,
boronic acids could be superior partners in cross-couplings with
peptidyl thiol esters to make functionally rich and epimerization-
sensitive peptidyl ketones. In fact, there are related reactions
of boronic acids with a variety of acid equivalents such as
anhydrides,31-34 esters,35,36 acid fluorides,27 and acid chlorides;37-39
howeVer, none of the published transformations use acyl
reactants or take place under reaction conditions that would
be suitable for application to pH-sensitiVe peptides. Described
herein is a study of the scope and limitations of peptidyl ketone
synthesis from mono-, di-, and tripeptidyl thiol esters and
boronic acids (Scheme 1).
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
Boc
Boc
Boc
Cbz
CF3CO
tosyl
trityl
phthaloyl
Boc
H
Et
Ph
2a
2a
2a
2b
2c
2d
2e
2f
10a
19b
15b
18b
20b
15b
0b
H
H
H
H
H
H
CH2CONHPh
Ph
Ph
Ph
Ph
Ph
Ph
54a
28a
Boc
2g
a Isolated yield. b Not isolated or fully characterized. Determined by 1H
NMR using pentamethylbenzene as an internal standard.
amino acid thiol esters were surveyed. While a trityl-protected,
basic nitrogen completely prevented coupling (Table 1, entry
7), N-Cbz, N-CF3CO, and N-tosyl gave low yields (Table 1,
entries 4-6). Somewhat improved, but still low to modest yields
of ketone could be obtained when the R-amino group was
doubly protected as the phthalimide or as the N,N-bis-Boc imide
(Table 1, entries 8 and 9). Even though N,N-bis-Boc-Phe-SPh
(1i) produced an unacceptable yield of cross-coupling product
2g, the experiment allowed the easy isolation and identification
of E-â-(N,N-bis-Boc) styrene 3 as a significant side product
(Scheme 2). As described below, this observation proved useful
in guiding the development of a more effective cross-coupling
protocol.
The enimide side product 3 is clearly the result of a facile
metal-catalyzed decarbonylation-â-hydride elimination se-
quence (Scheme 3). Oxidative addition of the thiol ester to Ln-
Pd(0) will generate an acylpalladium(II) intermediate (RCOPdL2-
SR). If transmetalation from the boronic acid to RCOPdL2SR
is slow, and if the decarbonylation of the acylpalladium thiolate
occurs at a reasonable rate,40,41 then the enimide 3 can be
generated by the sequence of reactions depicted in the lower
half of Scheme 3.
Results and Discussion
The feasibility of coupling R-amino acid thiol esters with
boronic acids was first probed using N-Boc-protected phenyl-
alanine thiol esters and PhB(OH)2 as depicted in Table 1, entries
1-3.
In contrast to the high yields of ketones typically produced
from non-amino acid-derived thiol esters and boronic acids,29
N-Boc-Phe-SR reacted with PhB(OH)2 in the presence of 10
mol % Pd(PPh3)4 and stoichiometric CuTC to give the corre-
sponding N-Boc R-amino ketone 2 in very low yield, regardless
of the choice of thiol ester SR moiety. Other mono-N-protected
Crisp and Bubner observed a similar enimide as the only
product in the Pd(PPh3)4-catalyzed cross-coupling of N-tosyl-
protected proline acid chloride with vinyl(tri-n-butyl)stannane
(Scheme 4).42 In the Crisp system, the undesired decarbonylation
pathway was inhibited by using Pd(dppf)Cl2 as the catalyst.
Decarbonylation can be suppressed by carrying out reactions
in the presence of high concentrations of CO, but control
experiments of the cross-coupling of an N-protected R-amino
acid thiol ester and a boronic acid conducted under 1 atm of
(27) Zhang, Y.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 15964-15965.
(28) Wittenberg, R.; Srogl, J.; Egi, M.; Liebeskind, L. S. Org. Lett. 2003, 5,
3033-3035.
(29) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122, 11260-11261.
(30) Hall, D. G. Structure, Properties, and Preparation of Boronic Acid
Derivatives: Overview of Their Reactions and Applications. In Boronic
Acids; Hall, D. G., Ed.; Wiley-VCH Verlag GmbH & Co KGaA:
Weinheim, Germany, 2005.
(31) Xin, B.; Zhang, Y.; Cheng, K. J. Org. Chem. 2006, 71, 5725-5731.
(32) Kakino, R.; Yasumi, S.; Shimizu, I.; Yamamoto, A. Bull. Chem. Soc. Jpn.
2002, 75, 137-148.
(33) Goossen, L. J.; Ghosh, K. Angew. Chem., Int. Ed. 2001, 40, 3458-3460.
(34) Goossen, L. J.; Ghosh, K. Chem. Commun. 2001, 2084-2085.
(35) Tatamidani, H.; Kakiuchi, F.; Chatani, N. Org. Lett. 2004, 6, 3597-3599.
(36) Tatamidani, H.; Yokota, K.; Kakiuchi, F.; Chatani, N. J. Org. Chem. 2004,
69, 5615-5621.
(37) Urawa, Y.; Ogura, K. Tetrahedron Lett. 2003, 44, 271-273.
(38) Haddach, M.; McCarthy, J. R. Tetrahedron Lett. 1999, 40, 3109-3112.
(39) Bumagin, N. A.; Korolev, D. N. Tetrahedron Lett. 1999, 40, 3057-3060.
(40) Osakada, K.; Yamamoto, T.; Yamamoto, A. Tetrahedron Lett. 1987, 28,
6321-6324.
(41) Kato, T.; Kuniyasu, H.; Kajiura, T.; Minami, Y.; Ohtaka, A.; Kinomoto,
M.; Terao, J.; Kurosawa, H.; Kambe, N. Chem. Commun. 2006, 868-870.
(42) Crisp, G. T.; Bubner, T. P. Synth. Commun. 1990, 20, 1665-1670.
9
J. AM. CHEM. SOC. VOL. 129, NO. 5, 2007 1133

A R T I C L E S
Yang et al.
Scheme 2. Identification of a Decarbonylation Side Product
Scheme 3. Decarbonylation Pathway
Scheme 4. Precedent for the Decarbonylation Pathway
CO did not lead to improvements.43 If the acyl (M-CO-R) /
metal alkyl (M-R) equilibrium is not easily perturbed, at least
under simple experimental conditions, the reaction outcome
might instead be adjusted by influencing the rate of the
decarbonylation. Decarbonylation is problematic in the cross-
couplings of R-amino acid-derived thiol esters with boronic acids
because the rate of boron-to-palladium transmetalation is slow
relatiVe to that of decarbonylation. Therefore, to achieve a
successful cross-coupling one must either increase the rate of
boron-to-palladium transmetalation or decrease the rate of
decarbonylation. Since both the transmetalation and decarbonyl-
ation mechanisms require an open coordination site at pal-
ladium,44 both rates should be influenced by the ligands present
in the reaction system (solvent as ligand, added supporting
ligands, intramolecular ligation at Pd by the N-protecting group).
If we assume that the decarbonylation and transmetalation
pathways can respond differently to variations in the electronic
and steric effects of added ligands, it might prove possible to
develop a successful cross-coupling by using ligand electronic
and steric effects to retard the decarbonylation without hindering
the rate of the transmetalation.
With the reaction of N,N-bis-Boc-Phe-SPh and PhB(OH)2/
CuTC depicted in Scheme 2 as a starting point, the response of
the system to variations in the palladium precatalyst (Pd(PPh3)4,
Pd2(dba)3, Pd(dppf)Cl2) with and without various added sup-
porting ligand (PPh3, PMePh2, PMe2Ph, PEt3, and P(OPh)3) was
explored. Two trends emerged from the study: (1) formation
of the undesired enimide side product was suppressed as ligand
loadings were increased and (2) stronger donor ligands gave
higher ratios of ketone-to-enimide, but this was counterbalanced
by the recovery of significant portions of unreacted thiol ester
in most cases when strong donor ligands were used. Increasing
reaction times did not improve conversions, and an increase of
the reaction temperature led to an increase in the decarbonylation
side reaction.45 A bidentate ligand such as diphenylphosphino-
ferrocene (dppf) completely prevented formation of the ketone
and gave a high yield of the undesired enimide, an observation
in contrast to the results of Crisp and Bubner (Scheme 4).42
Finally, of the various precatalyst/ligand systems tried, Pd-
(PPh3)4/PMe2Ph (1:4 ratio, or 1:8 palladium/total phosphine)
gave the best ratio of ketone-to-enimide-to-starting material (61:
5:20).
Is the Pd(PPh3)4/PMe2Ph (1:4 ratio) catalyst system mentioned
above generally useful for N-protected R-amino acid thiol ester-
boronic acid cross-coupling? The results shown in Table 2
suggest that the answer is a qualified “yes”.
Doubly N-protected R-amino acid thiol esters, such as the
N,N-bis-Boc and N-phthaloyl derivatives, gave good yields of
ketone products, regardless of the thiol ester SR group used.
Unfortunately, the same Pd/PPh3/PMe2Ph mixed ligand system
did not provide satisfactory cross-coupling yields of the
synthetically more important N-Cbz-protected systems (Table
2, entries 9 and 10): N-Cbz-Phe-SPh reacted with phenylboronic
acid, producing the desired ketone Cbz-Phe-COPh in only 49%
yield along with 25% of (E)-PhCHdCH-NHCbz, 11, the
enimide product generated by a decarbonylation-â-elimination
(45) Extending the reaction time from 16 to 36 h or raising the reaction
temperature from 50 to 60 °C did not increase the yield of the ketone.
However, an effective reaction was resumed when additional CuTC and
phenylboronic acid were added to the reaction mixture after 14 h, an
indication that the Pd catalyst was still robust. For example, a mixture of
thiol ester N,N-bis-Boc-phenylalanine p-chlorophenylthiol ester (56.4 mg,
0.11 mmol, 1.0 equiv), CuTC (32.7 mg, 0.17 mmol, 1.5 equiv), phenyl-
boronic acid (21.4 mg, 0.18 mmol, 1.5 equiv), Pd2(dba)3 (5.6 mg, 0.061
mmol, 0.05 equiv), PPh3 (11.9 mg, 0.045 mmol, 0.4 equiv), and PMe2Ph
(6.5 µL, 0.045 mmol, 0.4 equiv) in 3 mL of dry THF was stirred at 50 °C
for 14 h. Then, additional CuTC (21.9 mg, 0.11 mmol, 1.0 equiv),
phenylboronic acid (14.1 mg, 0.11 mmol, 1.0 equiv), and 1.0 mL of dry
THF were added. The reaction was stirred for another 8 h at 50 °C. After
the aqueous workup, the yield of the ketone (81%) was determined by
proton NMR using pentamethylbenzene as an internal standard.
(43) Reactions carried out at high pressures of CO might well be successful,
but were not pursued in favor of perturbing the reaction outcome through
other variables as described in the text.
(44) Four-coordinate, square-planar palladium(II) complexes are coordinatively
unsaturated (16-electron), but often react by further ligand loss to a three-
coordinate, 14-electron intermediate.
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1134 J. AM. CHEM. SOC. VOL. 129, NO. 5, 2007

High Enantiopurity N-Protected Peptidyl Ketones
A R T I C L E S
Table 2. Cross-Couplings Examples
entry
thiol-ester
R1
R2
Ar
boronic acid, R
ketone
yield (%)
1
2
1h
1h
phthaloyl
phthaloyl
Ph
Ph
4-methoxyphenyl
4-carbomethoxy-
phenyl
4
5
98
74
3
4
1j
1j
Boc
Boc
Boc
Boc
p-NO2Ph
p-NO2Ph
phenyl
3,4-methylenedioxy-
2g
6
73
77
phenyl
5
6
7
8
9
10
1j
1j
1j
1j
1d
1k
Boc
Boc
Boc
Boc
Cbz
Cbz
Boc
Boc
Boc
Boc
H
p-NO2Ph
p-NO2Ph
p-NO2Ph
p-NO2Ph
Ph
4-methoxyphenyl
3-nitrophenyl
2-formyl-4-methoxy
E-1-hexenyl
phenyl
7
8
9
10
2b
2b
91
58
62
99
49a
20b
H
p-NO2Ph
phenyl
a 25% of (E)-PhCHdCH-NHCbz 11 was isolated. b 34% of (E)-PhCHdCH-NHCbz 11 was isolated.
pathway. Changing to a more reactive p-nitrophenylthiol ester
moiety did not improve the outcome of the reaction (Table 2,
entry 10).
% Pd2(dba)3 as a precatalyst in combination with different
phosphorus ligands. Among tris-2-furylphosphine, SbPh3,
P(OMe)3, P(OEt)3, P(OBu)3, and P(OPh)3 as supporting ligands
(20 mol % each), P(OEt)3 delivered the best proved perfor-
mance. In fact, 2.5 mol % Pd2(dba)3 and between 10 and 20
mol % triethylphosphite (1:2-1:4 Pd/P ratio) proved to be an
excellent catalyst system for the cross-coupling of N-Cbz-
protected R-amino acid thiol esters (ee ) 99%) and boronic
acids (between room temperature and 30 °C) to give the
corresponding N-Cbz R-amino ketones with complete retention
of stereochemistry (Table 3). Of significance, higher reaction
temperatures caused increased proportions of the undesired
decarbonylation side product, suggesting, in retrospect, that the
ability of triethylphosphite to support ambient temperature cross-
couplings is probably an important factor in the development
of a general cross-coupling protocol for the N-Cbz-protected
systems.
A Room-Temperature Synthesis of High Enantiopurity
N-Cbz R-Amino Ketones. The data presented in Table 2
demonstrate the capricious nature of the Pd(PPh3)4/PMe2Ph
catalyst system: it provides good-to-excellent yields of product
with doubly N-protected substrates, such as N,N-bis-Boc-Phe-
SAr and N-Phth-Phe-SAr, but not for the synthetically more
useful N-Cbz (or N-Boc)-protected R-amino thiol esters as
substrates. For the widest possible applications in the synthesis
of high enantiopurity R-amino ketones, it is essential to develop
a robust catalyst system that will work with R-amino acid thiol
esters bearing simple N-Cbz (or N-Boc) protecting groups and
then confirm that the cross-coupling proceeds without racem-
ization.
It was noted that high ligand loadings are effective in sup-
pressing the undesired â-elimination pathway. At the same time,
product yields are compromised, most likely because boron-
to-palladium transmetalation will be retarded by (1) an increase
in the steric bulk around palladium when large ligands are used
and (2) a decrease in the electrophilicity at palladium when
strong donor ligands are used. Does the effectiveness of the
doubly N-protected N,N-bis-Boc and N-phthaloyl R-amino acid
thiol esters (compared to mono-N-protected R-N-Cbz or R-N-
Boc thiol esters) in cross-coupling with minimal decarbonylation
direct us to a more general solution? Perhaps this difference
can be attributed to the ability of the N,N-bis-Boc and N-
phthaloyl protecting groups to function effectively as the internal
equivalent of high loadings of small, but weakly donating,
external ligands. This might help maintain four-coordination at
palladium and block decarbonylation but not sterically or
electronically retard transmetalation. If so, the use of a small,
weakly donating, external supporting ligand might be ideal for
the palladium-catalyzed cross-coupling of N-Cbz (or N-Boc)-
protected R-amino thiol esters. A poorly basic and small
phosphine or phosphite would fill coordination sites at Pd but
not attenuate electrophilicity and thus not suppress transmeta-
lation (perhaps directly to a four-coordinate, 16-electron
RCOPdL2SR intermediate), even at higher ligand loadings.
To test this analysis, cross-coupling experiments (with N-Cbz-
Phe-SPh, PhB(OH)2, and CuTC) were carried out using 2.5 mol
A variety of aryl (electron-rich, electron-deficient) and
heteroaryl (thienyl and furyl) boronic acids and (E)-â-styryl-
boronic acid were efficiently coupled with thiophenyl esters of
N-Cbz-protected R-amino acids (Table 3). No racemization was
detected during the cross-coupling process (the ketonic product
was formed with the same ee as the thiol esters precursor),
reinforcing, once again, the very mild and nonbasic nature of
the Cu(I) carboxylate-mediated couplings of thioorganics and
boronic acids.46 Moreover, even unprotected tyrosine and
tryptophan thiol esters were excellent cross-coupling substrates
highlighting the compatibility of unprotected phenolic and
indolic residues in this chemistry (Table 3, entries 7-11, 13,
14). Unfortunately, π-deficient heteroaromatic boronic acids
were not effective substrates, giving only low yields of ketone
products in this cross-coupling.
Synthesis of Dipeptidyl and Tripeptidyl Ketones. The
successful synthesis of high enantiopurity N-Cbz-protected
R-amino ketones using 2.5 mol % Pd2(dba)3/20 mol % trieth-
ylphosphite and 1.2 equiv of CuTC encouraged an investigation
of the synthesis of more complicated structures such as
dipeptidyl and tripeptidyl ketones. In the first attempt to
synthesize dipeptidyl ketones, N-Cbz-(L)-Trp-(L)-Phe-SPh was
treated with 1.2 equiv of p-methoxyphenylboronic acid in the
(46) Lory, P.; Gilbertson, S. R. Chemtracts 2005, 18, 569-583.
9
J. AM. CHEM. SOC. VOL. 129, NO. 5, 2007 1135

A R T I C L E S
Yang et al.
Table 3. Synthesis of N-Cbz R-Amino Ketones in High Enantiomeric Purity
a ee was determined by HPLC chiral OD, AD, or AS column using racemic mixtures. b Reaction carried out at 30 °C using 10 mol % P(OEt)3 as supporting
ligand. All others at were carried out at room temperature in the presence of 20% P(OEt)3. c Boronic acid was used (1.5 equiv); all other reactions were
conducted with 1.2 equiv of boronic acid.
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1136 J. AM. CHEM. SOC. VOL. 129, NO. 5, 2007

High Enantiopurity N-Protected Peptidyl Ketones
A R T I C L E S
Table 4. Probing Dipeptide Thiol Ester-Boronic Acid
Cross-Coupling: Influence of Boronic Acid Stoichiometry on the
Cross-Coupling Yield
erature conditions of the Pd-catalyzed, Cu(I) carboxylate-medi-
ated cross-couplings of peptidyl thiol esters and boronic acids.
It is known from earlier studies in these laboratories that
boronic acids and not boronate esters are uniquely reactive with
thiol esters under the mild and nonbasic Pd-catalyzed, Cu(I)
carboxylate-mediated conditions. It is therefore assumed that
boroxines are likewise unreactive in Pd-catalyzed, Cu(I) car-
boxylate-mediated cross-couplings with thioorganics. The re-
quirement of nonbasic and ambient temperature reaction con-
ditions for the peptidyl thiol ester cross-couplings therefore
precludes any possible rapid in situ conversion of the boroxine
to the boronic acid, thus complicating the production of high
yields of peptidyl ketones when only a simple stoichiometric
quantity of the boronic acid is used.
entry
boronic acid
equivalents
yield (%)
1
2
3
4
5
p-methoxyphenyl
p-methoxyphenyl
p-tolyl
p-tolyl
p-tolyl
1.2
2.0
1.2
2.0
3.0
53
72
26
42
62
presence of 2.5 mol % Pd2(dba)3/20 mol % triethylphosphite/
1.2 equiv of CuTC in THF at room temperature (Table 4, entry
1).
Indirect proof of the presence of boroxines in the boronic
acid samples and the low cross-coupling reactivity of boroxines
under the current reaction conditions was obtained. A com-
mercial sample of 4-methoxyphenylboronic acid showed two
The peptidyl ketone formed very rapidly within the first 3 h
of the reaction (according to HPLC monitoring), but the rate of
formation of the product then dropped rapidly, even though
significant quantities of the thiol ester and the boronic acid were
still apparent in HPLC traces. It is relevant that the addition of
either CuTC or the boronic acid alone did not induce consump-
tion of the unreacted dipeptide thiol ester. However, charging
the reaction mixture with an additional 0.5 equiv of both Cu(I)
thiophenecarboxylate and the boronic acid reactivated the cross-
coupling to generate more ketone and led to almost complete
consumption of the dipeptide thiol ester as determined by HPLC.
These combined observations were a clear indication that the
palladium catalyst was still active and that the well-known
metal-binding affinity of polypeptides and proteins47 was not
the cause of the low conversion to ketone in this reaction system.
However, the experiments gave no insight into why additional
boronic acid was a necessary prerequisite to restart the cross-
coupling reaction, in particular when HPLC traces indicated that
boronic acid was still present in the reaction mixture.
Ultimately, the low conversions to ketone and the ambiguous
stoichiometry of the boronic acid were traced to the unprevent-
able presence of boroxines (boronic acid cyclic trimers) in the
boronic acid starting materials.30 The synthesis of boronic acids
uncontaminated by the corresponding boroxine is highly prob-
lematic in most cases.48,49 Furthermore, the facile boroxine /
boronic acid equilibrium at acidic or basic pH complicates
monitoring of the peptidyl thiol ester-boronic acid cross-
couplings: HPLC analysis is not able to differentiate between
a boronic acid and its boroxine trimer, because the boroxine is
easily transformed to the boronic acid by the HPLC eluent
system (CH3CN/H2O/TFA).
1
pairs of H NMR signals in CDCl3, at 8.18 and 7.03 ppm and
at 7.70 and 6.95 ppm. Addition of D2O to the NMR tube led to
an increase in the intensity of the 7.70/6.95 peaks and a decrease
in intensity of those at 8.18/7.03. Therefore, the signals at 8.18
and 7.03 ppm are attributed to the boroxine and the others to
the boronic acid. Indeed, 1H NMR analysis of the crude reaction
mixture that resulted from the transformation depicted in Table
4, entry 1, showed almost complete disappearance of the boronic
acid resonances, while those of the boroxine appeared un-
changed. Clearly, the reactivity of boronic acid is much higher
than that of the boroxine under the nonbasic and room-
temperature reaction conditions of this cross-coupling.
Unfortunately, the simple expedient of intentionally adding
water to the nonbasic cross-coupling reaction mixture did not
improve the yield of peptidyl ketone. The collected observations
suggest that the use of extra equivalents of freshly prepared
boronic acid will be critical to any attempt to improve the yields
of the peptidyl ketones. In fact, the simple expedient of
increasing the amount of boronic acid compensated for any
unreactive boroxine present in the starting material and led to
much improved yields of the peptidyl ketones (Table 4, compare
entries 1, 2, and 3-5).
With a mechanism-based rationale for the significance of
boronic acid stoichiometry as an important reaction variable in
nonbasic, room-temperature cross-couplings, nine dipeptidyl and
tripeptidyl ketones were easily prepared in good-to-excellent
yields (Table 5) using 1.5-3.0 equiv of boronic acid, 2.5 mol
% Pd2(dba)3, 20 mol % P(OEt)3, and 1.5 equiv of CuTC in
THF at room temperature.
The diastereomeric purity of the peptidyl ketone product was
identical to that of the starting thiol ester: no epimerization
was detectable during the coupling reaction. In general, THF
was the best of those solvents explored, although a 1:1 THF/
hexanes mixed solvent system gave an improved yield of
product in one case shown in Table 5 (40% in THF; 68% in
1:1 THF/hexanes). This mimics the same solvent effect observed
in an earlier project,28 where a 1:1 THF/hexanes mixture led to
improved yields of ketone in some cases.52
Under standard Suzuki-Miyaura cross-coupling conditions,
the boroxine / boronic acid equilibrium is not problematic
because the boroxine can be shifted to the boronic acid under
the reaction conditions by the presence of a requisite base (such
as K2CO3) and the higher reaction temperatures typically
used.50,51 A similar rapid in situ boroxine / boronic acid
interconversion is not feasible under the nonbasic, room-temp-
(47) Sigel, H.; Martin, R. B. Chem. ReV. 1982, 82, 385-426.
(48) Snyder, H. R.; Konecky, M. S.; Lennarz, W. J. J. Am. Chem. Soc. 1958,
80, 3611-3615.
Conclusion
(49) Snyder, H. R.; Kuck, J. A.; Johnson, J. R. J. Am. Chem. Soc. 1938, 60,
105-111.
A general and efficient synthesis of high enantiopurity N-Cbz
R-amino mono-, di-, and tripeptidyl ketones was developed from
(50) Bedford, R. B. Chem. Commun. 2003, 1787-1796.
(51) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
9
J. AM. CHEM. SOC. VOL. 129, NO. 5, 2007 1137

A R T I C L E S
Yang et al.
Table 5. Structures, Isolated Yields, and Diastereomeric Purity of Peptidyl Ketones
a The de of each ketone is identical to the de of the thiol ester reactant; no epimerization occurred during the cross-coupling reaction. b The reaction was
carried out in 1:1 THF/hexanes.
the corresponding thiol esters and aryl, heteroaryl, or alkenyl
boronic acids using the catalyst system Pd2(dba)3/P(OEt)3/CuTC.
Using this mild and versatile cross-coupling reaction, we
detected no epimerization throughout the cross-coupling process
and the configuration of stereogenic centers was completely
preserved. Isolated yields ranged from moderate to excellent.
Importantly, unprotected sensitive polar functional groups and
variations in electronic nature of boronic acids were well
tolerated by the reaction system. It is anticipated that the mild
and nonbasic features of this new ketone synthesis and its
significant functional group compatibility will prove useful for
the C-terminal or side-chain modification of proteins. Studies
are underway to probe that feasibility and to assay the
comparative scope, limitations, and utility of organotin reagents
in palladium-catalyzed, Cu(I)carboxylate-mediated cross-cou-
plings of peptidyl thiol esters.
Experimental Section
Starting Materials. All boronic acids were obtained from Frontier
Scientific, Inc. All protected amino acids, N,N′-dicyclohexylcarbodi-
imide (DCC), 1,1′-carbonyldiimidazole (CDI), N-ethyl-N′-(3-dimethyl-
aminopropyl)carbodiimide hydrochloride (EDC), thiophenol, 4-nitrothio-
phenol, [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II),
tetrakis(triphenylphosphine)palladium(0), methyldiphenylphosphine, tri-
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1138 J. AM. CHEM. SOC. VOL. 129, NO. 5, 2007

High Enantiopurity N-Protected Peptidyl Ketones
A R T I C L E S
methyl-, tributyl-, and triphenylphosphite, dimethylphenylphosphine,
triphenylphosphine, triphenylantimony, triethylphosphine, and tris-2-
furylphosphine were purchased from Sigma-Aldrich. N-Trifluoro-
acetylphenylalanine, tris(dibenzylideneacetone)dipalladium(0), 1-hy-
droxybenzotriazole (HOBt), and triethylphosphite were purchased from
Acros. N-Tosylphenylalanine was purchased from TCI. Triethylphos-
phite was purified by distillation at 1 atm (157 °C).53 CuTC was
prepared by using a previous procedure.29 N,N-Bis-Boc-L-Phe and N,N-
phthaloyl-L-Phe-SPh were prepared according to literature proce-
dures.54,55 N-Protected dipeptide and tripeptide acids were prepared
using the standard DCC/HOBt method followed by hydrolysis with
lithium hydroxide.56
was stirred at 30 °C overnight. The reaction progress was monitored
by HPLC analysis. For workup, the reaction mixture was diluted with
25 mL of ether, washed with saturated aqueous NaHCO3 and brine
(15 mL each), and followed by drying over MgSO4. The drying agent
was filtered off through a short plug of silica gel (to aid removal of
metal containing products), and the filtrate was concentrated under
vacuum. The crude product was purified by preparative TLC (silica
gel, 20 × 20 cm, 2 mm, 33% ethyl acetate in hexanes) to afford (+)-
(2S)-1-(3-acetylphenyl)-2-benzyloxycarbonylamino-3-(1H-indol-3-yl)-
propan-1-one as a yellow oil. Yield: 60 mg (68%). TLC (Rf ) 0.45,
silica gel, 50% ethyl acetate in hexanes). HPLC chiral AS-RH standard
method: L-isomer tR ) 7.3 min, D-isomer tR ) 6.8 min, ee > 99%. 1H
NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 8.09 (d, J ) 7.9 Hz, 1H),
8.03 (m, 2H), 7.48 (m, 2H), 7.40-7.28 (m, 5H), 7.25 (d, J ) 7.9 Hz,
1H), 7.14 (m, 1H), 7.05 (app t, J ) 7.5 Hz, 1H), 6.73 (d, J ) 2.2 Hz,
1H), 5.85 (d, J ) 7.6 Hz, 1H), 5.71 (m, 1H), 5.17 and 5.13 (AB q, J
) 12.1 Hz, 2H), 3.33 (m, 2H), 2.41 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 198.4, 197.2, 155.8, 137.2, 136.3, 135.9, 135.4, 132.6, 129.0,
128.5, 128.2, 128.1, 127.3, 122.9, 122.2, 119.7, 118.6, 111.1, 109.7,
67.0, 56.0, 29.4, 26.4. IR (neat, cm-1) 3350 (br m), 3061 (w), 2926
(w), 1683 (vs), 1598 (m), 1428 (m), 1278 (s), 1212 (s), 1061 (m), 745
(m), 698 (m). HRMS (FAB) Calcd for C27H25N2O4 ([M + H]+):
N-Protected R-amino thiol esters of high enantiopurity were prepared
using the method of Steglich and Neises (DCC/DMAP/EtSH).57 For
the synthesis of di- and tripeptidyl thiol esters, an excess of the thiol
(1.5-20.0 equiv) was employed to secure high diastereomer purity (de
91-99%).
HPLC analyses were carried out using an Agilent 1100 system with
a quaternary pump. Separations were achieved on a Zorbax Eclipse
XDB C8 4.6 × 150 mm column or DAICEL chiral AD, AS, OD
reversed-phase column (standard elution method: λ ) 254 nm; flow:
1.0 mL/min; T ) 30 °C; gradient: 50% H2O in CH3CN during 10 min
to 75% CH3CN during 12.5 min to 100% CH3CN hold for 4.5 min).
Representative Examples. Full details for all compounds can be
found in the Supporting Information.
441.1809. Found: 441.1815. [R]20 +113.4 (c 1.46, CHCl3).
D
(-)-N-Cbz-L-tryptophan-L-phenylalanine Thiophenyl Ester. To
a solution of the N-Cbz-L-Trp-L-Phe (945 mg, 2.0 mmol) in EtOAc
(20 mL) were added HOBt (408 mg, 3.0 mmol) and thiophenol (340
mg, 3.0 mmol), followed by the dropwise addition of 1,3-dicyclohexyl-
carbodiimide (415 mg, 2.0 mmol, in 10 mL of EtOAc) at 0 °C for 30
min. The reaction progress was monitored by HPLC analysis. After be-
ing stirred overnight at room temperature, the reaction was treated with
1 mL of acetic acid (50% in ethyl acetate) for 30 min. The mixture was
filtered through Celite, and the organic phase was washed with 1 M
HCl, NaHCO3 solution, and brine, dried over MgSO4, filtered, and evap-
orated. The crude was purified by recrystallization from MeOH (induced
by addition of water) to afford N-Cbz-L-Trp-L-Phe-SPh as a white solid.
Yield: 1.066 g (95%). TLC (Rf ) 0.54, silica gel, 50% ethyl acetate
in hexanes). Mp ) 159-160 °C. HPLC chiral OD-RH standard
method: L,L-isomer tR ) 13.8 min, de ) 91% (determined by 1H NMR).
1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.71 (d, 1H), 7.44-7.13
(m, 16H), 6.99 (s, 1H), 6.86 (d, J ) 6.0 Hz, 2H), 6.24 (d, J ) 6.4 Hz,
1H), 5.36 (s, 1H), 5.10 (s, 2H), 4.96 (dd, J ) 14.8, 8.4 Hz, 1H), 4.55
(s, 1H), 3.34 (s, 1H), 3.16 (dd, J ) 14.8, 7.2 Hz, 1H), 2.95 (d, J ) 6.8
Hz, 2H). 13C NMR (150 MHz, CDCl3) δ 197.8, 171.4, 156.2, 136.4,
135.3, 134.8, 129.8, 129.5, 128.8, 128.7, 128.4, 128.3, 127.4, 127.0,
123.6, 122.7, 120.2, 119.1, 111.5, 110.4, 67.3, 59.8, 55.4, 38.3, 28.2.
IR (neat, cm-1) 3405 (w), 3304 (w), 3061 (m), 3034 (m), 2926 (m),
1698 (s), 1664 (s), 1513 (s), 1455 (m), 1343 (m), 1231 (s), 1054 (m),
1027 (m), 741 (s). HRMS (FAB) Calcd for C34H31N3O4SLi ([M + Li]+):
(-)-L-Cbz-tryptophan Thiophenyl Ester. N-Cbz-L-tryptophan (3.384
g, 10.0 mmol) and thiophenol (1.322 g, 12.0 mmol) were dissolved in
dry ethyl acetate (20 mL) at 0 °C, and then N,N′-dicyclohexylcarbo-
diimide (2.478 g, 12.0 mmol) was added. The reaction was stirred at
0 °C for the first 30 min and then at room temperature overnight.
Progress was monitored by HPLC analysis. At the end of the reaction,
a few drops of 50% acetic acid in ethyl acetate were added. The reaction
mixture was filtered through a short plug of Celite and concentrated in
vacuo. The crude product was triturated with hexanes to remove excess
thiophenol, dissolved in MeOH, and crystallized by addition of water.
Filtration and drying at high vacuum afforded (-)-L-Cbz-tryptophan
thiophenyl ester as a white solid. Yield: 4.127 g (96%). TLC (Rf )
0.22, silica gel, 25% ethyl acetate in hexanes). Mp ) 47-51 °C. HPLC
chiral OD-RH standard method: L-isomer tR ) 14.2 min, D-isomer tR
) 15.2 min, ee > 99%. 1H NMR (400 MHz, CDCl3) δ 8.10 (br s, 1H),
7.56 (d, J ) 8.1 Hz, 1H), 7.42-7.25 (m, 11H), 7.23 (t, J ) 7.2 Hz,
1H), 7.12 (t, J ) 7.5 Hz, 1H), 7.04 (d, J ) 2.2 Hz, 1H), 5.33 (d, J )
9.1 Hz, 1H), 5.14 (s, 2H), 4.92-4.85 (m, 1H), 3.43 (dd, J ) 15.0, 5.9
Hz, 1H), 3.32 (dd, J ) 14.7, 5.6 Hz, 1H). 13C NMR (100 MHz, CDCl3)
δ 199.6, 155.8, 136.1, 136.1, 134.6, 129.5, 129.2, 128.5, 128.2, 128.0,
127.4, 127.1, 123.2, 122.3, 119.8, 118.8, 111.3, 109.2, 67.2, 61.0, 28.2.
IR (neat, cm-1) 3405 (m), 3061 (w), 1698 (vs), 1502 (s), 1455 (m),
1239 (s), 1061 (m), 741 (s). HRMS (FAB) Calcd for C25H22N2O3SLi
584.2195. Found: 584.2179. [R]20 -28.8 (c 0.57, CHCl3).
([M + Li]+): 437.1511. Found: 437.1515. [R]20 -68.4 (c 1.02,
D
D
CHCl3).
(+)-2-(S)-Benzyloxycarbonylamino-N-[1-(S)-benzyl-2-(4-methox-
yphenyl)-2-oxoethyl]-3-(1H-indol-3-yl)-propionamide. A mixture of
N-Cbz-L-Trp-L-Phe-SPh (57 mg, 0.10 mmol), p-methoxylphenylboronic
acid (30 mg, 0.20 mmol), CuTC (29 mg, 0.15 mmol), and Pd2(dba)3
(2 mg, 2.5 µmol) was placed under an argon atmosphere. THF (3 mL,
degassed and dried over 4 Å molecular sieves) and triethylphosphite
(20 mol %, 3.4 µL, 20 µmol) were added, and the mixture was stirred
at room temperature until the N-Cbz-peptidyl-thiophenyl ester was
consumed (3 h). Reaction progress was monitored by HPLC analyses.
The reaction mixture was diluted with ether (25 mL), washed with
NaHCO3 solution and brine (15 mL each), and then dried over MgSO4.
The drying agent was filtered off through a short plug of silica gel (to
aid removal of metal containing products) and concentrated under
vacuum using a rotary evaporator. The crude material was subjected
to purification by preparative TLC (silica gel, 20 × 20 cm, 2 mm,
50% ethyl acetate in hexanes) to afford (+)-2-(S)-benzyloxycarbonyl-
amino-N-[1-(S)-benzyl-2-(4-methoxyphenyl)-2-oxoethyl]-3-(1H-indol-
(+)-(2S)-1-(3-Acetylphenyl)-2-benzyloxycarbonylamino-3-(1H-in-
dol-3-yl)-propan-1-one. N-Cbz-L-Trp-SPh (86 mg, 0.20 mmol),
3-acetylphenylboronic acid (39 mg, 0.24 mmol), CuTC (46 mg, 0.24
mmol), and Pd2(dba)3 (4 mg, 5 µmol) were placed under an argon
atmosphere. THF (3 mL, degassed and dried over 4 Å molecular sieves)
and P(OEt)3 (3.4 µL, 20 µmol, 10 mol %) were added, and the mixture
(52) THF/hexanes solvent mixtures were used to maintain a low concentration
of the active Cu(I) carboxylate in solution throughout the course of the
cross-coupling reaction. Cu(I) carboxylate that is not complexed to the thiol
ester or to the putative palladium(II) thiolate catalytic intermediate leads
to competitive destruction of the boronic acid by a Cu-mediated protode-
borylation.
(53) Taira, K.; Gorenstein, D. G. Tetrahedron Lett. 1984, 40, 3215-3222.
(54) Gunnarsson, K.; Ragnarsson, U. Acta Chem. Scand., Ser. A 1990, 44, 944-
951.
(55) Weygand, F.; Kaelicke, J. Chem. Ber. 1962, 95, 1031-1038.
(56) Koenig, W.; Geiger, R. Chem. Ber. 1970, 103, 788-798.
(57) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17, 522-524.
9
J. AM. CHEM. SOC. VOL. 129, NO. 5, 2007 1139

A R T I C L E S
Yang et al.
3-yl)-propionamide as a colorless oil. Yield: 41 mg (72%). TLC (Rf
) 0.32, silica gel, 50% ethyl acetate in hexanes). HPLC chiral OD-
RH: L,L-isomer tR ) 13.3 min, L,D-isomer tR ) 12.7 min, de ) 91%.
1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.83 (d, J ) 8.4 Hz, 2H),
7.63 (d, J ) 7.2 Hz, 1H), 7.36-6.91 (m, 14H), 6.74 (d, J ) 7.2 Hz,
2H), 6.61 (d, J ) 7.6 Hz, 1H), 5.58 (m, 2H), 5.13 (m, 2H), 4.54 (d, J
) 6.0 Hz, 1H), 3.89 (s, 3H), 3.33 (m, 1H), 3.12 (m, 2H), 2.88 (dd, J
) 14.0, 5.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 195.6, 170.9,
164.3, 156.1, 136.4, 135.7, 131.2, 129.6, 128.7, 128.4, 128.3, 128.3,
127.6, 127.0, 123.4, 122.4, 119.9, 118.9, 114.2, 111.4, 110.5, 67.2,
55.7, 55.7, 54.6, 39.1, 28.8. IR (neat, cm-1) 3327 (w), 3061 (m), 3034
(m), 2957 (m), 2934 (m), 1710 (s), 1652 (s), 1513 (s), 1455 (m), 1343
(m), 1258 (s), 1170 (m), 1027 (m), 737 (s). HRMS (FAB) Calcd for
C35H33N3O5Li ([M + Li]+): 582.2580. Found: 582.2552. [R]20D +13.2
(c 0.68, CHCl3).
Acknowledgment. The National Institute of General Medical
Sciences, DHHS, supported this investigation through Grant No.
GM066153.
Supporting Information Available: Complete refs 7 and 10;
experimental procedures, synthesis, and characterization of all
1
new compounds; H and 13C NMR spectra of all new com-
pounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
JA0658719
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1140 J. AM. CHEM. SOC. VOL. 129, NO. 5, 2007